39	22006374	HER2 positivity was strongly associated with NAC involvement (7% in HER2 negative vs. 18% in HER2 positive tumors, P = 0.0137).	('positivity', 'Var', (5, 15))	('HER2', 'Gene', '2064', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('NAC', 'Chemical', '-', (45, 48))	('HER2', 'Gene', (68, 72))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('HER2', 'Gene', '2064', (68, 72))	('negative', 'NegReg', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('HER2', 'Gene', (0, 4))	('NAC involvement', 'Disease', (45, 60))	('associated', 'Reg', (29, 39))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (93, 97))
62	22006374	The association of HER2 positivity with NAC involvement may be related to the presence of mammary Paget disease, which accounts for one of three of our NAC involvement cases.	('HER2', 'Gene', (19, 23))	('positivity', 'Var', (24, 34))	('HER2', 'Gene', '2064', (19, 23))	('NAC', 'Chemical', '-', (152, 155))	('mammary Paget disease', 'Disease', (90, 111))	('NAC', 'Disease', (40, 43))	('association', 'Reg', (4, 15))	('NAC', 'Chemical', '-', (40, 43))
113	32796631	Three Delta-like ligands (DLL1, DLL3 and DLL4) and two Jagged ligands (JAG1 and JAG2) participate in the initiation of the Notch signaling pathway in mammals and are crucial controllers of the pathway activation.	('JAG2', 'Gene', (80, 84))	('JAG1', 'Gene', (71, 75))	('DLL3', 'Gene', (32, 36))	('JAG2', 'Gene', '3714', (80, 84))	('Notch', 'Gene', (123, 128))	('DLL3', 'Gene', '10683', (32, 36))	('Notch', 'Gene', '31293', (123, 128))	('JAG1', 'Gene', '182', (71, 75))	('participate', 'Reg', (86, 97))	('DLL1', 'Var', (26, 30))	('DLL4', 'Var', (41, 45))
114	32796631	Both hypoactivation and hyperactivation of the Notch pathway can lead to a tumorigenic condition, depending on the type of tissue, the genetic alteration and the type of receptor-ligand interactions.	('hyperactivation', 'Var', (24, 39))	('Notch', 'Gene', '31293', (47, 52))	('hypoactivation', 'Var', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Notch', 'Gene', (47, 52))	('lead to', 'Reg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
115	32796631	Mutations of Notch1, for instance, have been identified in squamous cell carcinoma of the head and neck, esophagus and skin and have been linked with a hypoactivation of the pathway.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (73, 103))	('squamous cell carcinoma', 'Disease', (59, 82))	('identified', 'Reg', (45, 55))	('skin', 'Disease', (119, 123))	('linked', 'Reg', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Mutations', 'Var', (0, 9))	('esophagus', 'Disease', (105, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('Notch1', 'Gene', (13, 19))
116	32796631	On the other hand, Notch1 hyperactivation has been linked to the etiology of T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL), breast cancer, adenoid cystic carcinoma and mantle cell lymphoma.	('cell lymphoma', 'Phenotype', 'HP:0012191', (212, 225))	('CLL', 'Phenotype', 'HP:0005550', (155, 158))	('linked', 'Reg', (51, 57))	('hyperactivation', 'Var', (26, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (217, 225))	('Notch1', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (176, 200))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (77, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (84, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (205, 225))	('mantle cell lymphoma', 'Disease', (205, 225))	('adenoid cystic carcinoma', 'Disease', (176, 200))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (90, 112))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (125, 153))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('T-ALL', 'Phenotype', 'HP:0006727', (114, 119))	('T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia', 'Disease', 'MESH:D054218', (77, 153))
117	32796631	Chromosomal aberrations involving the Notch pathway are often involved in the initiation of a cancerogenic progression.	('Chromosomal aberrations', 'Var', (0, 23))	('Notch', 'Gene', (38, 43))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('involved', 'Reg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Notch', 'Gene', '31293', (38, 43))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
118	32796631	The very first link of the role of Notch in cancer was derived from the identification of an activating mutation in T-ALL patients, and it was linked to a chromosomal translocation of the Notch1 gene.	('T-ALL', 'Phenotype', 'HP:0006727', (116, 121))	('Notch', 'Gene', (188, 193))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Notch', 'Gene', (35, 40))	('patients', 'Species', '9606', (122, 130))	('activating', 'PosReg', (93, 103))	('mutation', 'Var', (104, 112))	('Notch', 'Gene', '31293', (188, 193))	('linked to', 'Reg', (143, 152))	('Notch', 'Gene', '31293', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
120	32796631	Further studies on leukemia and solid tumors revealed that chromosomal translocation was not the only way the Notch signaling pathway can drive cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Notch', 'Gene', '31293', (110, 115))	('solid tumors', 'Disease', 'MESH:D009369', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('chromosomal translocation', 'Var', (59, 84))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))	('Notch', 'Gene', (110, 115))	('solid tumors', 'Disease', (32, 44))	('leukemia', 'Disease', 'MESH:D007938', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('leukemia', 'Disease', (19, 27))
121	32796631	Hyperactivation of its signal can be achieved by either activating mutations, increased expression or stabilization of the active cleaved portion of NOTCH, as well as ligand-independent activation of the pathway.	('NOTCH', 'Gene', '31293', (149, 154))	('activating mutations', 'Var', (56, 76))	('stabilization', 'MPA', (102, 115))	('NOTCH', 'Gene', (149, 154))	('active cleaved', 'MPA', (123, 137))	('increased', 'PosReg', (78, 87))	('expression', 'MPA', (88, 98))
122	32796631	For instance, T-ALL is generated by the ligand-independent activation of the pathway upon point mutations or chromosomal rearrangement that leads to proteolysis of the receptor, resulting in high levels of the active form of NOTCH1 intracellular domain (N1ICD).	('leads to', 'Reg', (140, 148))	('proteolysis', 'MPA', (149, 160))	('active', 'MPA', (210, 216))	('NOTCH1', 'Gene', (225, 231))	('NOTCH1', 'Gene', '4851', (225, 231))	('T-ALL', 'Phenotype', 'HP:0006727', (14, 19))	('point mutations', 'Var', (90, 105))	('T-ALL', 'Disease', (14, 19))
123	32796631	Adenoid cystic carcinoma and breast cancer also contain point mutations or deletions in the Notch1 gene, resulting in the constitutive production of the cleaved, active intracellular form.	('deletions', 'Var', (75, 84))	('Adenoid cystic carcinoma and breast cancer', 'Disease', 'MESH:D001943', (0, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('Notch1', 'Gene', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('point mutations', 'Var', (56, 71))
124	32796631	In non-small lung cancer, mutations on the regulatory portion of the receptor (PEST, NRR or the TAD region) result in aberrant activation of Notch in cancer cells.	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (3, 24))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (150, 156))	('Notch', 'Gene', (141, 146))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('activation', 'PosReg', (127, 137))	('small lung', 'Phenotype', 'HP:0002089', (7, 17))	('Notch', 'Gene', '31293', (141, 146))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
134	32796631	Deletion of Lnfg induces accumulation of the intracellular domain of NOTCH, which in turn stimulates tumor growth.	('NOTCH', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('accumulation', 'PosReg', (25, 37))	('tumor', 'Disease', (101, 106))	('Lnfg', 'Gene', (12, 16))	('stimulates', 'PosReg', (90, 100))	('NOTCH', 'Gene', '31293', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('Deletion', 'Var', (0, 8))
136	32796631	In murine models of pancreatic cancer, the deletion of Lnfg causes an increased expression of Notch1, Notch3 and Hes1, resulting in an accumulation of aldehyde dehydrogenase 1 (ALDH1)-positive undifferentiated progenitor cells.	('aldehyde dehydrogenase 1', 'Gene', (151, 175))	('aldehyde dehydrogenase 1', 'Gene', '11668', (151, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('Hes1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Notch3', 'Gene', (102, 108))	('deletion', 'Var', (43, 51))	('increased', 'PosReg', (70, 79))	('Notch1', 'Gene', (94, 100))	('murine', 'Species', '10090', (3, 9))	('accumulation', 'PosReg', (135, 147))	('expression', 'MPA', (80, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('pancreatic cancer', 'Disease', (20, 37))	('Lnfg', 'Gene', (55, 59))
157	32796631	Ablation of CSL in the mesenchyme activates matrix-remodeling enzymes and dysregulates p53, causing an uncontrolled proliferation of keratinocytes.	('uncontrolled', 'MPA', (103, 115))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('Ablation', 'Var', (0, 8))	('CSL', 'Gene', (12, 15))	('matrix-remodeling enzymes', 'Enzyme', (44, 69))	('dysregulates', 'Var', (74, 86))	('CSL', 'Gene', '3516', (12, 15))	('activates', 'PosReg', (34, 43))	('causing', 'Reg', (92, 99))
171	32796631	Cancerogenic conditions have been associated with the accumulation of mutations, which involve more than one cellular element in driving tumor progression.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (137, 142))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
191	32796631	NOTCH1 and NOTCH2 receptors are expressed in satellite stem cells and their ablation results in an exit from quiescence and a rapid exhaustion of the stem cell pool.	('NOTCH2', 'Gene', (11, 17))	('exit from quiescence', 'MPA', (99, 119))	('NOTCH2', 'Gene', '4853', (11, 17))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('ablation', 'Var', (76, 84))
196	32796631	Ablation of Rbpj or Notch1 induces the acquisition of a neuronal fate, while overexpressing Hes1, Hes5 or the active form of Notch favors proliferation of undifferentiated progenitors.	('favors', 'PosReg', (131, 137))	('Notch', 'Gene', (20, 25))	('Rbpj', 'Gene', (12, 16))	('Hes5', 'Gene', (98, 102))	('Ablation', 'Var', (0, 8))	('neuronal fate', 'CPA', (56, 69))	('Notch', 'Gene', (125, 130))	('induces', 'Reg', (27, 34))	('Notch', 'Gene', '31293', (20, 25))	('Rbpj', 'Gene', '3516', (12, 16))	('Hes5', 'Gene', '388585', (98, 102))	('acquisition', 'CPA', (39, 50))	('Notch', 'Gene', '31293', (125, 130))
206	32796631	In line with the role of Notch in preserving undifferentiation, Hes1 was shown to positively increase the stem cell marker cluster of differentiation 133 (CD133), as well as leading to the overexpression of stemness-related genes such as CD133, ATP-binding cassette super family G member 2 (ABCG2), ALDH1 and Nanog.	('CD133', 'Gene', (155, 160))	('stemness-related', 'CPA', (207, 223))	('Nanog', 'Gene', (309, 314))	('increase', 'PosReg', (93, 101))	('CD133', 'Gene', (238, 243))	('Notch', 'Gene', (25, 30))	('ABCG2', 'Gene', '9429', (291, 296))	('ABCG2', 'Gene', (291, 296))	('overexpression', 'PosReg', (189, 203))	('Nanog', 'Gene', '79923', (309, 314))	('leading to', 'Reg', (174, 184))	('Notch', 'Gene', '31293', (25, 30))	('Hes1', 'Var', (64, 68))	('ALDH1', 'Gene', (299, 304))
231	32796631	Notch1 mutations were mostly detectable at the DN4 (CD25-CD44-) preleukemic stage.	('CD44', 'Gene', '960', (57, 61))	('CD25', 'Gene', '3559', (52, 56))	('mutations', 'Var', (7, 16))	('Notch1', 'Gene', (0, 6))	('CD44', 'Gene', (57, 61))	('detectable', 'Reg', (29, 39))	('CD25', 'Gene', (52, 56))	('DN4', 'Gene', '28488', (47, 50))	('DN4', 'Gene', (47, 50))
232	32796631	These observations suggest that pre-TCR and TCR signaling play an important role in the acquisition of Notch1 activating mutations, which in turn play a role in clonal dominance during leukemia development.	('TCR', 'Gene', '6962', (44, 47))	('mutations', 'Var', (121, 130))	('Notch1', 'Gene', (103, 109))	('leukemia', 'Disease', (185, 193))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('leukemia', 'Disease', 'MESH:D007938', (185, 193))	('TCR', 'Gene', (36, 39))	('TCR', 'Gene', (44, 47))	('activating', 'PosReg', (110, 120))	('TCR', 'Gene', '6962', (36, 39))	('play', 'Reg', (146, 150))
246	32796631	Cancerogenesis might be initiated by the accumulation of mutations to conserve the undifferentiated character of epithelial stem cells or revert committed progenitors to a more immature state.	('revert', 'NegReg', (138, 144))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (57, 66))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('undifferentiated', 'MPA', (83, 99))
251	32796631	It was suggested that alterations in Notch signaling are involved in tumor formation (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Notch', 'Gene', '31293', (37, 42))	('tumor', 'Disease', (69, 74))	('alterations', 'Var', (22, 33))	('Notch', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('involved', 'Reg', (57, 65))
256	32796631	In a genome-wide association study, a single nucleotide polymorphism (rs11249433) in the 1p11.2 region was identified as a genetic risk factor for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('single nucleotide polymorphism', 'Var', (38, 68))	('rs11249433', 'Var', (70, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('risk factor', 'Reg', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('rs11249433', 'Mutation', 'rs11249433', (70, 80))
257	32796631	Notch pathway functions in stem cell differentiation of estrogen receptor positive (ER+) luminal cells, therefore increased Notch2 expression in carriers of rs11249433 may promote development of ER+ luminal tumors.	('Notch2', 'Gene', '4853', (124, 130))	('Notch', 'Gene', '31293', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Notch', 'Gene', (124, 129))	('rs11249433', 'Mutation', 'rs11249433', (157, 167))	('luminal tumors', 'Disease', (199, 213))	('estrogen receptor', 'Gene', '2099', (56, 73))	('luminal', 'Chemical', 'MESH:D010634', (89, 96))	('ER', 'Gene', '2069', (84, 86))	('Notch', 'Gene', (0, 5))	('increased', 'PosReg', (114, 123))	('ER', 'Gene', '2069', (195, 197))	('promote', 'PosReg', (172, 179))	('Notch2', 'Gene', (124, 130))	('rs11249433', 'Var', (157, 167))	('Notch', 'Gene', '31293', (124, 129))	('luminal', 'Chemical', 'MESH:D010634', (199, 206))	('estrogen receptor', 'Gene', (56, 73))	('expression', 'MPA', (131, 141))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('luminal tumors', 'Disease', 'MESH:D009369', (199, 213))
258	32796631	Notch3 was reported to repress Notch1-mediated activation via Hes1 and Hes5.	('Hes5', 'Gene', (71, 75))	('Hes5', 'Gene', '388585', (71, 75))	('Notch3', 'Var', (0, 6))	('repress', 'NegReg', (23, 30))	('Notch1-mediated activation', 'MPA', (31, 57))
264	32796631	In a mammary stem cell population, characterized by CD24+CD29high, N1ICD impairs mammary stem cell self-renewal and leads to their transformation via a cyclin D1-dependent pathway.	('cyclin D1', 'Gene', (152, 161))	('CD29', 'Gene', '3688', (57, 61))	('transformation', 'CPA', (131, 145))	('mammary stem cell self-renewal', 'CPA', (81, 111))	('CD29', 'Gene', (57, 61))	('impairs', 'NegReg', (73, 80))	('N1ICD', 'Var', (67, 72))	('CD24', 'Gene', '100133941', (52, 56))	('cyclin D1', 'Gene', '595', (152, 161))	('CD24', 'Gene', (52, 56))	('leads to', 'Reg', (116, 124))
273	32796631	Cancer initiation is linked to genetic and chromosomal instability, where several mutations accumulated to drive progression from benign malignancies (polyps) to invasive cancer.	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('chromosomal instability', 'Phenotype', 'HP:0040012', (43, 66))	('invasive cancer', 'Disease', 'MESH:D009362', (162, 177))	('polyps', 'Disease', (151, 157))	('malignancies', 'Disease', (137, 149))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('polyps', 'Disease', 'MESH:D011127', (151, 157))	('invasive cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
274	32796631	One of the major targets of cancerogenic mutations is the adenomatous polyposis coli (Apc) gene, which regulates stem cell self-renewal in a variety of systems.	('mutations', 'Var', (41, 50))	('adenomatous polyposis coli', 'Gene', '324', (58, 84))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Apc', 'Phenotype', 'HP:0005227', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('adenomatous polyposis coli', 'Gene', (58, 84))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (58, 84))
276	32796631	Genetic knockout of the tumor suppressor Apc induces intestinal tumor formation in a mouse model of adenoma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (24, 29))	('intestinal tumor', 'Disease', (53, 69))	('induces', 'Reg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('adenoma', 'Disease', 'MESH:D000236', (100, 107))	('intestinal tumor', 'Disease', 'MESH:D007414', (53, 69))	('Apc', 'Phenotype', 'HP:0005227', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('adenoma', 'Disease', (100, 107))	('knockout', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
283	32796631	Mouse genetic models also showed that NICD-induced polyps, aberrant stem cell and progenitor cell proliferation and support the growth of a gastric tumor.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('gastric tumor', 'Disease', (140, 153))	('growth', 'CPA', (128, 134))	('polyps', 'Disease', (51, 57))	('support', 'PosReg', (116, 123))	('Mouse', 'Species', '10090', (0, 5))	('gastric tumor', 'Disease', 'MESH:D013274', (140, 153))	('NICD-induced', 'Var', (38, 50))	('gastric tumor', 'Phenotype', 'HP:0006753', (140, 153))	('polyps', 'Disease', 'MESH:D011127', (51, 57))
286	32796631	Though conflicting results exist, an increase of JAG1, JAG2, DLL1, DLL3, DLL4 and NOTCH1-4 expressions are reported to be present in 75% of the colorectal cancer tissues and specifically, tumor cell-autonomous signaling can occur by a copy number gain of the NOTCH1 receptor, which can be found in 22% of colorectal cancers (Figure 1).	('tumor', 'Disease', (188, 193))	('colorectal cancers', 'Disease', 'MESH:D015179', (305, 323))	('JAG2', 'Gene', '3714', (55, 59))	('NOTCH1', 'Gene', '4851', (82, 88))	('DLL3', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('gain', 'PosReg', (247, 251))	('NOTCH1', 'Gene', (259, 265))	('JAG1', 'Gene', '182', (49, 53))	('colorectal cancer', 'Disease', (144, 161))	('increase', 'PosReg', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('colorectal cancer', 'Phenotype', 'HP:0003003', (305, 322))	('DLL3', 'Gene', '10683', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('NOTCH1', 'Gene', '4851', (259, 265))	('DLL1', 'Gene', (61, 65))	('colorectal cancers', 'Disease', (305, 323))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('DLL4', 'Gene', (73, 77))	('JAG2', 'Gene', (55, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('copy number', 'Var', (235, 246))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('JAG1', 'Gene', (49, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (305, 322))	('NOTCH1', 'Gene', (82, 88))
290	32796631	These mutations contribute to an increased CSCs self-renewal and metastasis formation, while a combination of Notch1 activation and p53 deletion caused metastatic disease in colon cancer.	('metastatic disease', 'Disease', (152, 170))	('caused', 'Reg', (145, 151))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('Notch1', 'Gene', (110, 116))	('CSCs self-renewal', 'CPA', (43, 60))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('deletion', 'Var', (136, 144))	('increased', 'PosReg', (33, 42))	('colon cancer', 'Disease', (174, 186))	('metastasis formation', 'CPA', (65, 85))	('activation', 'PosReg', (117, 127))
302	32796631	reported that Notch2 affects cell growth and apoptosis as well as a knockdown in vitro lead to decreased migration and invasion.	('decreased', 'NegReg', (95, 104))	('Notch2', 'Gene', '4853', (14, 20))	('cell growth', 'CPA', (29, 40))	('affects', 'Reg', (21, 28))	('knockdown', 'Var', (68, 77))	('Notch2', 'Gene', (14, 20))	('apoptosis', 'CPA', (45, 54))
303	32796631	In HNSCC cells, inhibition of NOTCH3 decreases cell proliferation as well as the sphere forming ability, which is related to cancer stem cells.	('sphere forming ability', 'CPA', (81, 103))	('NOTCH3', 'Gene', (30, 36))	('NOTCH3', 'Gene', '4854', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('decreases', 'NegReg', (37, 46))	('inhibition', 'Var', (16, 26))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cell proliferation', 'CPA', (47, 65))
312	32796631	In oral squamous cell carcinoma (OSCC), Notch1 has an orchestrating role in the maintenance of undifferentiation, and blockage of the NOTCH1-Hes1 axis inhibits the CSC phenotype.	('inhibits', 'NegReg', (151, 159))	('blockage', 'Var', (118, 126))	('orchestrating', 'MPA', (54, 67))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('NOTCH1', 'Gene', '4851', (134, 140))	('NOTCH1', 'Gene', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('CSC', 'MPA', (164, 167))	('undifferentiation', 'MPA', (95, 112))
314	32796631	Additionally, in TNFalpha-induced oral cancer, a knock-down of Hes1 leads to a decrease in self-renewal capacity of treated OSCC.	('TNFalpha', 'Gene', (17, 25))	('self-renewal capacity of treated OSCC', 'CPA', (91, 128))	('oral cancer', 'Disease', (34, 45))	('TNFalpha', 'Gene', '7124', (17, 25))	('decrease', 'NegReg', (79, 87))	('knock-down', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('oral cancer', 'Disease', 'MESH:D009369', (34, 45))	('Hes1', 'Gene', (63, 67))
322	32796631	The invasive pancreatic ductal carcinoma is thought to originate from an accumulation of immature cells, which in turn acquires mutations leading to the most advanced stages of the tumor.	('tumor', 'Disease', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('mutations', 'Var', (128, 137))	('invasive pancreatic ductal carcinoma', 'Disease', (4, 40))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('leading to', 'Reg', (138, 148))	('invasive pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (4, 40))
324	32796631	Interestingly, this subpopulation expresses high levels of Notch1 and Notch2 compared to other pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('Notch2', 'Gene', (70, 76))	('pancreatic cancer', 'Disease', (95, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('Notch1', 'Var', (59, 65))	('Notch2', 'Gene', '4853', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
325	32796631	This finding correlates with the fact that pancreatic CSCs have low levels of miRNA-34 and miR-200, which were found to directly inhibit Notch expression.	('pancreatic CSCs', 'Disease', 'MESH:D010195', (43, 58))	('Notch', 'Gene', (137, 142))	('pancreatic CSCs', 'Disease', (43, 58))	('inhibit', 'NegReg', (129, 136))	('Notch', 'Gene', '31293', (137, 142))	('miRNA-34', 'Var', (78, 86))	('miR-200', 'Var', (91, 98))
328	32796631	Blockage of NOTCH suppresses the TGFalpha-induced change of fate, suggesting that the Notch pathway is active since early tumorigenic stages.	('Blockage', 'Var', (0, 8))	('TGFalpha', 'Gene', (33, 41))	('NOTCH', 'Gene', (12, 17))	('NOTCH', 'Gene', '31293', (12, 17))	('fate', 'MPA', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Notch', 'Gene', (86, 91))	('TGFalpha', 'Gene', '7039', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('suppresses', 'NegReg', (18, 28))	('tumor', 'Disease', (122, 127))	('Notch', 'Gene', '31293', (86, 91))
340	32796631	Aberrant activation of Shh is known to be implicated in brain cancers.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Shh', 'Gene', (23, 26))	('brain cancers', 'Disease', 'MESH:D001932', (56, 69))	('brain cancers', 'Disease', (56, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('Shh', 'Gene', '6469', (23, 26))	('implicated', 'Reg', (42, 52))
344	32796631	Blockage of Notch in medulloblastoma dramatically decreases the amount of CD133+-stem cells, consistently with the finding that upon Notch inhibition, Nestin+ undifferentiated cells are more likely to enter apoptosis than other cancer cells in the same tissue.	('Blockage', 'Var', (0, 8))	('Nestin', 'Gene', (151, 157))	('cancer', 'Disease', (228, 234))	('apoptosis', 'CPA', (207, 216))	('Notch', 'Gene', '31293', (12, 17))	('enter', 'PosReg', (201, 206))	('medulloblastoma', 'Disease', 'MESH:D008527', (21, 36))	('Notch', 'Gene', '31293', (133, 138))	('medulloblastoma', 'Phenotype', 'HP:0002885', (21, 36))	('decreases', 'NegReg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Nestin', 'Gene', '10763', (151, 157))	('amount', 'MPA', (64, 70))	('Notch', 'Gene', (12, 17))	('medulloblastoma', 'Disease', (21, 36))	('Notch', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
347	32796631	Notch1 loss-of-function mutations correlate with low-grade gliomas and have the best prognosis, in line with other studies where high expression of CSL, Notch1 or Notch2 sustains the tumor growth.	('Notch2', 'Gene', '4853', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('Notch1', 'Gene', (0, 6))	('loss-of-function', 'NegReg', (7, 23))	('CSL', 'Gene', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Disease', (183, 188))	('CSL', 'Gene', '3516', (148, 151))	('Notch2', 'Gene', (163, 169))	('gliomas', 'Disease', (59, 66))	('mutations', 'Var', (24, 33))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
352	32796631	Importantly, regulation of Notch can result in augmented sensitivity to radiotherapy, as shown by GSI-treated samples exhibiting an increase in cell death following exposure to radiation.	('GSI', 'Chemical', '-', (98, 101))	('regulation', 'Var', (13, 23))	('Notch', 'Gene', (27, 32))	('Notch', 'Gene', '31293', (27, 32))	('sensitivity', 'MPA', (57, 68))	('death', 'Disease', 'MESH:D003643', (149, 154))	('augmented', 'PosReg', (47, 56))	('death', 'Disease', (149, 154))
353	32796631	Consistently, external expression of the active intracellular portion of NOTCH1 and NOTCH2 has a protective effect on glioma CSCs, while knock-out of these receptors increase radioresistance.	('increase', 'PosReg', (166, 174))	('NOTCH2', 'Gene', '4853', (84, 90))	('glioma CSCs', 'Disease', 'MESH:D005910', (118, 129))	('protective effect', 'CPA', (97, 114))	('knock-out', 'Var', (137, 146))	('radioresistance', 'CPA', (175, 190))	('NOTCH2', 'Gene', (84, 90))	('glioma CSCs', 'Disease', (118, 129))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
358	32796631	As a consequence of a chromosomal translocation in 19p, overexpression of Notch3 has been found in 40% of NSCLC patients.	('Notch3', 'Gene', (74, 80))	('chromosomal translocation in', 'Var', (22, 50))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('overexpression', 'PosReg', (56, 70))	('NSCLC', 'Disease', (106, 111))
359	32796631	Similarly, increased activity of Notch1 upon either gain-of-function mutations or downregulation of inhibitors (such as Numb) are linked to NSCLC development (Figure 1).	('mutations', 'Var', (69, 78))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('increased', 'PosReg', (11, 20))	('Numb', 'Gene', (120, 124))	('downregulation', 'NegReg', (82, 96))	('Numb', 'Gene', '8650', (120, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('Notch1', 'Gene', (33, 39))	('gain-of-function', 'PosReg', (52, 68))	('activity', 'MPA', (21, 29))	('NSCLC', 'Disease', (140, 145))
363	32796631	The cancer subpopulation of the ALDH+ cells is also characterized by a high Notch expression, and inhibition of the pathway results in a decreased number of ALDH+ cells.	('Notch', 'Gene', '31293', (76, 81))	('inhibition', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Notch', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('decreased', 'NegReg', (137, 146))	('cancer', 'Disease', (4, 10))
368	32796631	Using a microarray high-throughput assay it was shown that mRNA of the receptor Notch2 is overexpressed in melanoma cells compared to healthy melanocytes (Figure 1).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('Notch2', 'Gene', '4853', (80, 86))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('overexpressed', 'PosReg', (90, 103))	('Notch2', 'Gene', (80, 86))	('mRNA', 'Var', (59, 63))
382	32796631	In a mouse model where mice were treated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), deletion of Notch1 driven by the Keratin14 promoter lead to papilloma development.	('DMBA', 'Chemical', 'MESH:D015127', (93, 97))	('papilloma', 'Disease', (160, 169))	('Keratin14', 'Gene', (133, 142))	('papilloma', 'Phenotype', 'HP:0012740', (160, 169))	('papilloma', 'Disease', 'MESH:D010212', (160, 169))	('7,12-dimethylbenz[a]anthracene', 'Chemical', 'MESH:D015127', (61, 91))	('Notch1', 'Gene', (112, 118))	('mouse', 'Species', '10090', (5, 10))	('deletion', 'Var', (100, 108))	('lead to', 'Reg', (152, 159))	('Keratin14', 'Gene', '16664', (133, 142))	('mice', 'Species', '10090', (23, 27))
386	32796631	A chimeric mouse model carrying Notch1 deletion via Msx2-Cre produces a mosaic pattern resulting in patches of Notch1 deficient and Notch1 expressing keratinocytes within the same microenvironment.	('Msx2', 'Gene', (52, 56))	('mouse', 'Species', '10090', (11, 16))	('Notch1', 'Gene', (32, 38))	('Notch1', 'Gene', (111, 117))	('deletion', 'Var', (39, 47))	('Msx2', 'Gene', '17702', (52, 56))	('deficient', 'NegReg', (118, 127))
388	32796631	Interestingly, it could be demonstrated that tumors containing Notch1-expressing cells were as frequent as tumors predominantly containing Notch1-deficient cells in the same microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Notch1-expressing', 'Var', (63, 80))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
390	32796631	In a murine model of NMSC, the development of spontaneous BCC was observed over time upon Notch1 ablation.	('NMSC', 'Disease', (21, 25))	('Notch1', 'Gene', (90, 96))	('murine', 'Species', '10090', (5, 11))	('BCC', 'Phenotype', 'HP:0002671', (58, 61))	('ablation', 'Var', (97, 105))
393	32796631	A crosstalk between the Notch and the Wnt signaling might exist in skin cancer, as ablation of Notch1 leads to increased beta-catenin, ultimately resulting in hyperplasia and BCC.	('skin cancer', 'Disease', (67, 78))	('hyperplasia', 'Disease', (159, 170))	('skin cancer', 'Disease', 'MESH:D012878', (67, 78))	('Notch', 'Gene', (95, 100))	('increased', 'PosReg', (111, 120))	('Notch', 'Gene', (24, 29))	('Notch', 'Gene', '31293', (95, 100))	('beta-catenin', 'Gene', (121, 133))	('BCC', 'CPA', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('resulting in', 'Reg', (146, 158))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('beta-catenin', 'Gene', '1499', (121, 133))	('BCC', 'Phenotype', 'HP:0002671', (175, 178))	('Notch', 'Gene', '31293', (24, 29))	('skin cancer', 'Phenotype', 'HP:0008069', (67, 78))	('ablation', 'Var', (83, 91))
394	32796631	Inhibition or deletion of Notch1 expression can lead to the development of squamous cell carcinomas of the skin.	('squamous cell carcinomas of the skin', 'Phenotype', 'HP:0006739', (75, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (75, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (75, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('Inhibition', 'Var', (0, 10))	('Notch1', 'Gene', (26, 32))	('lead to', 'Reg', (48, 55))	('deletion', 'Var', (14, 22))	('squamous cell carcinomas', 'Disease', (75, 99))
398	32796631	As p53 plays a major role in UV/DNA damage response, it is possible that sun-exposed downregulation of Notch1 is a consequence of UV induced mutations of p53, as evidence suggests that Notch1 is a downstream target of p53.	('p53', 'Gene', '7157', (3, 6))	('mutations', 'Var', (141, 150))	('downregulation', 'NegReg', (85, 99))	('Notch1', 'Gene', (103, 109))	('p53', 'Gene', (154, 157))	('p53', 'Gene', (218, 221))	('p53', 'Gene', '7157', (154, 157))	('p53', 'Gene', '7157', (218, 221))	('p53', 'Gene', (3, 6))
417	32796631	However, self-renewal of breast CSCs is regulated by Notch signaling and knockdown of Notch4 showed a stronger effect than a Notch1 knockdown, underlining the importance of precise targeting.	('Notch', 'Gene', '31293', (53, 58))	('Notch', 'Gene', '31293', (125, 130))	('Notch', 'Gene', (86, 91))	('Notch', 'Gene', (125, 130))	('Notch', 'Gene', '31293', (86, 91))	('Notch', 'Gene', (53, 58))	('Notch4', 'Gene', (86, 92))	('Notch4', 'Gene', '4855', (86, 92))	('self-renewal', 'CPA', (9, 21))	('knockdown', 'Var', (73, 82))
419	32796631	For instance, PF03084014 targeting advanced solid tumors has completed Phase-I with 72 patients in 2019.	('PF03084014', 'Var', (14, 24))	('solid tumors', 'Disease', 'MESH:D009369', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PF03084014', 'Chemical', 'MESH:C550722', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (87, 95))	('solid tumors', 'Disease', (44, 56))
426	32796631	In the case of PF03084014, side effects included diarrhea, nausea, alopecia, leukopenia, anemia, vomiting, decreased appetite and fatigue.	('nausea', 'Disease', (59, 65))	('anemia', 'Disease', (89, 95))	('decreased appetite', 'Disease', 'MESH:D001068', (107, 125))	('alopecia', 'Disease', (67, 75))	('decreased appetite', 'Disease', (107, 125))	('decreased appetite', 'Phenotype', 'HP:0004396', (107, 125))	('diarrhea', 'Phenotype', 'HP:0002014', (49, 57))	('nausea', 'Disease', 'MESH:D009325', (59, 65))	('fatigue', 'Disease', (130, 137))	('fatigue', 'Phenotype', 'HP:0012378', (130, 137))	('diarrhea', 'Disease', (49, 57))	('anemia', 'Disease', 'MESH:D000740', (89, 95))	('leukopenia', 'Disease', 'MESH:D007970', (77, 87))	('alopecia', 'Phenotype', 'HP:0001596', (67, 75))	('vomiting', 'Disease', 'MESH:D014839', (97, 105))	('PF03084014', 'Chemical', 'MESH:C550722', (15, 25))	('leukopenia', 'Phenotype', 'HP:0001882', (77, 87))	('nausea', 'Phenotype', 'HP:0002018', (59, 65))	('diarrhea', 'Disease', 'MESH:D003967', (49, 57))	('PF03084014', 'Var', (15, 25))	('leukopenia', 'Disease', (77, 87))	('fatigue', 'Disease', 'MESH:D005221', (130, 137))	('vomiting', 'Phenotype', 'HP:0002013', (97, 105))	('anemia', 'Phenotype', 'HP:0001903', (89, 95))	('vomiting', 'Disease', (97, 105))
432	32796631	In-vivo studies demonstrated that treatment with MEDI0639 led to non-functional vessel formation, therefore a Phase-1 trial had been conducted until 2017, in order to determine the effects in patients of solid tumors (; NCT01577745).	('non-functional', 'MPA', (65, 79))	('MEDI0639', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('solid tumors', 'Disease', 'MESH:D009369', (204, 216))	('patients', 'Species', '9606', (192, 200))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('MEDI0639', 'Chemical', '-', (49, 57))	('solid tumors', 'Disease', (204, 216))
433	32796631	The antibody OMP21M18, a humanized IgG2 antibody, blocking the interaction of DLL4 with NOTCH1 and NOTCH4 and had been tested as a cancer stem cell agent in a Phase-I trial in patients with previously treated solid tumors (Figure 3).	('cancer', 'Disease', (131, 137))	('NOTCH1', 'Gene', (88, 94))	('patients', 'Species', '9606', (176, 184))	('NOTCH1', 'Gene', '4851', (88, 94))	('solid tumors', 'Disease', (209, 221))	('DLL4', 'Protein', (78, 82))	('interaction', 'Interaction', (63, 74))	('human', 'Species', '9606', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('blocking', 'NegReg', (50, 58))	('NOTCH4', 'Gene', (99, 105))	('NOTCH4', 'Gene', '4855', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (209, 221))	('OMP21M18', 'Var', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
437	32796631	Additionally, the redundancy of the Notch pathway might induce compensatory effects and bypass antibody-induce blockage.	('compensatory', 'MPA', (63, 75))	('Notch', 'Gene', '31293', (36, 41))	('redundancy', 'Var', (18, 28))	('induce', 'Reg', (56, 62))	('Notch', 'Gene', (36, 41))
439	32796631	Additionally, a prolonged administration of OMP21M18 was associated with increased risk of congestive heart failure and hypertension in patients.	('congestive heart failure', 'Disease', 'MESH:D006333', (91, 115))	('hypertension', 'Disease', 'MESH:D006973', (120, 132))	('congestive heart failure', 'Disease', (91, 115))	('hypertension', 'Disease', (120, 132))	('hypertension', 'Phenotype', 'HP:0000822', (120, 132))	('patients', 'Species', '9606', (136, 144))	('OMP21M18', 'Var', (44, 52))	('congestive heart failure', 'Phenotype', 'HP:0001635', (91, 115))
446	32796631	However, the choice of the target appears to be highly sensitive in regard to the outcome, as a genetic removal of CSL showed accelerated growth of xenografted tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CSL', 'Gene', (115, 118))	('genetic removal', 'Var', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('accelerated', 'PosReg', (126, 137))	('CSL', 'Gene', '3516', (115, 118))	('tumors', 'Disease', (160, 166))	('growth', 'MPA', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
449	32796631	The use of a Notch1 decoy (N110-24) blocked JAG1/JAG2-mediated Notch1 signaling (Figure 3).	('JAG2', 'Gene', '3714', (49, 53))	('blocked', 'NegReg', (36, 43))	('JAG1', 'Gene', '182', (44, 48))	('N110-24', 'Var', (27, 34))	('JAG2', 'Gene', (49, 53))	('JAG1', 'Gene', (44, 48))
451	32796631	Additionally, decoy N11-13 was able to interfere with DLL1-DLL4-mediated NOTCH1 signaling and led to hyper-sprouting.	('decoy N11-13', 'Var', (14, 26))	('interfere', 'NegReg', (39, 48))	('led to', 'Reg', (94, 100))	('hyper-sprouting', 'CPA', (101, 116))	('decoy N11-13', 'Chemical', '-', (14, 26))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
464	25961594	Consistent with this, the expression levels of Module-1/-3 and Module-2 miRs are higher and lower, respectively, in normal mammary tissues relative to ductal-carcinoma-in-situ, invasive-ductal-carcinoma and metastases.	('miR', 'Gene', '220972', (72, 75))	('Module-2', 'Gene', (63, 71))	('miR', 'Gene', (72, 75))	('ductal-carcinoma-in-situ', 'Disease', (151, 175))	('metastases', 'Disease', (207, 217))	('higher', 'PosReg', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('Module-1/-3', 'Var', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('ductal-carcinoma-in-situ', 'Disease', 'MESH:D002285', (151, 175))	('metastases', 'Disease', 'MESH:D009362', (207, 217))	('expression levels', 'MPA', (26, 43))	('invasive-ductal-carcinoma', 'Disease', (177, 202))	('invasive-ductal-carcinoma', 'Disease', 'MESH:D018270', (177, 202))	('lower', 'NegReg', (92, 97))
585	25961594	However, combined transfection of the three miRs significantly stimulates this process (Fig.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('combined', 'Interaction', (9, 17))	('transfection', 'Var', (18, 30))	('stimulates', 'PosReg', (63, 73))
589	25961594	The panel consists of two luminal cell types characterized by ER-positivity (MCF-7) and ERBB2 amplification (MDA-MB-453), as well as two Basal/TN cell types (MDA-MB231 and MDA-MB157).	('amplification', 'Var', (94, 107))	('ERBB2', 'Gene', (88, 93))	('MDA-MB157', 'CellLine', 'CVCL:0618', (172, 181))	('ERBB2', 'Gene', '2064', (88, 93))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (109, 119))	('MDA-MB231', 'CellLine', 'CVCL:0062', (158, 167))	('MCF-7', 'CellLine', 'CVCL:0031', (77, 82))
620	25961594	However, combined transfection of the three miRs in MCF-7 and MDA-MB231 cells causes a significant inhibition of caspase-3/7 activity.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('activity', 'MPA', (125, 133))	('inhibition', 'NegReg', (99, 109))	('combined', 'Interaction', (9, 17))	('MCF-7', 'CellLine', 'CVCL:0031', (52, 57))	('transfection', 'Var', (18, 30))	('caspase-3', 'Gene', (113, 122))	('MDA-MB231', 'CellLine', 'CVCL:0062', (62, 71))	('caspase-3', 'Gene', '836', (113, 122))
623	25961594	Similar to what is observed in SKBR3, only combined transfection of the three Module-2 miRs results in increased migration of the Basal/TN and highly motile MDA-MB157 cells (Fig.	('increased', 'PosReg', (103, 112))	('MDA-MB157', 'CellLine', 'CVCL:0618', (157, 166))	('highly motile', 'CPA', (143, 156))	('transfection', 'Var', (52, 64))	('migration', 'CPA', (113, 122))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('SKBR3', 'CellLine', 'CVCL:0033', (31, 36))
698	25961594	In addition, pathway enrichment analysis indicates that the genes regulated by Module-4 miRs control two specific aspects of cancer cell biology, which are predominantly related to motility and invasiveness.	('miR', 'Gene', (88, 91))	('motility', 'CPA', (181, 189))	('control', 'Reg', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('invasiveness', 'CPA', (194, 206))	('Module-4', 'Var', (79, 87))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('miR', 'Gene', '220972', (88, 91))
713	25961594	In general, the expression results are consistent with the idea that the three miRs are endowed with pro-oncogenic properties in Her2+ (SKBR3; MDA-MB453), Basal/TN (MDA-MB157; MDA-MB231) and Luminal/ER+ (MCF-7) breast cancer cells.	('MDA-MB231', 'Var', (176, 185))	('Her2', 'Gene', (129, 133))	('MDA-MB453', 'CellLine', 'CVCL:0418', (143, 152))	('Her2', 'Gene', '2064', (129, 133))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('SKBR3', 'CellLine', 'CVCL:0033', (136, 141))	('MCF-7', 'CellLine', 'CVCL:0031', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('MDA-MB157', 'CellLine', 'CVCL:0618', (165, 174))	('MDA-MB231', 'CellLine', 'CVCL:0062', (176, 185))	('breast cancer', 'Disease', (211, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))
715	25961594	The general oncogenic properties of Module-2 miRs are confirmed by the effects of miR-125a-5p, miR-193a-5p and miR-210-3p over-expression on the growth of MDA-MB157, MDA-MB231 and MDA-MB453 which are largely in line with what is observed in SKBR3 cells.	('MDA-MB157', 'Var', (155, 164))	('miR-210', 'Gene', (111, 118))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('miR', 'Gene', (45, 48))	('miR-125a', 'Gene', '406910', (82, 90))	('miR', 'Gene', '220972', (82, 85))	('MDA-MB231', 'Var', (166, 175))	('miR-125a', 'Gene', (82, 90))	('SKBR3', 'CellLine', 'CVCL:0033', (241, 246))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (82, 85))	('over-expression', 'PosReg', (122, 137))	('MDA-MB453', 'CellLine', 'CVCL:0418', (180, 189))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (95, 98))	('MDA-MB157', 'CellLine', 'CVCL:0618', (155, 164))	('miR-210', 'Gene', '406992', (111, 118))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (111, 114))
751	25961594	Human miR microarrays (Release 16.0, 8 x 60K, G4870A) were from Agilent (Santa Clara, CA, USA).	('Human', 'Species', '9606', (0, 5))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('G4870A', 'Var', (46, 52))	('G4870A', 'Mutation', 'g.4870G>A', (46, 52))
757	25961594	We used two datasets: GSE38867 from the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/gds) and the Breast Invasive Carcinoma miRNAseq and Gene expression (RNA-seq) dataset from the Cancer Genome Atlas (TCGA, http://cancergenome.nih.gov).	('Breast Invasive Carcinoma', 'Disease', 'MESH:D018270', (111, 136))	('miR', 'Gene', '220972', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('miR', 'Gene', (137, 140))	('Breast Invasive Carcinoma', 'Disease', (111, 136))	('GSE38867', 'Var', (22, 30))	('Carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Cancer', 'Phenotype', 'HP:0002664', (193, 199))
897	19266279	These include altering strategies for follow-up of histologically-normal, but molecularly abnormal breast biopsies, determining which patients might benefit from radiotherapy following lumpectomy, or determining which patients might benefit from mastectomy due to multifocal disease risk.	('patients', 'Species', '9606', (218, 226))	('altering', 'Reg', (14, 22))	('abnormal breast', 'Phenotype', 'HP:0000769', (90, 105))	('abnormal', 'Var', (90, 98))	('patients', 'Species', '9606', (134, 142))	('multifocal disease', 'Disease', (264, 282))	('multifocal disease', 'Disease', 'None', (264, 282))
915	24155762	The Institutional Review Board approved (XC12EIMI0142O, XC12EIMI0142H) this study and required neither patient approval nor patient informed consent for the review of their images and records.	('XC12EIMI0142O', 'Var', (41, 54))	('patient', 'Species', '9606', (103, 110))	('patient', 'Species', '9606', (124, 131))	('XC12EIMI0142H', 'Var', (56, 69))
929	24155762	It detected 5 of 5 breast cancers (100%) in the BI-RADS P1 pattern, 8 of 9 cancers (88.9%) in the BI-RADS P2 pattern (Figure 1), 17 of 18 cancers (94.4%) in the BI-RADS P3 pattern, and 6 of 9 cancers (66.7%) in the BI-RADS P4 pattern.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancers', 'Disease', 'MESH:D001943', (19, 33))	('breast cancers', 'Disease', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('breast cancers', 'Phenotype', 'HP:0003002', (19, 33))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('BI-RADS P1', 'Var', (48, 58))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancers', 'Disease', (138, 145))
932	24155762	The difference between the CAD sensitivity in P1-P3 and P4 cancers seemed large, but this difference was not statistically significant (p=0.245 in the asymptomatic group and p=0.098 in the symptomatic group).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Disease', (59, 66))	('P1-P3', 'Var', (46, 51))
942	24155762	The radiologists missed 3 breast cancers from 3 patients graded BI-RADS P4 in the asymptomatic group and 3 breast cancers from 3 patients with P3 or P4 pattern in the symptomatic group (Figure 3).	('breast cancers', 'Disease', (26, 40))	('BI-RADS P4', 'Var', (64, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('patients', 'Species', '9606', (129, 137))	('breast cancers', 'Phenotype', 'HP:0003002', (107, 121))	('breast cancers', 'Phenotype', 'HP:0003002', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancers', 'Disease', 'MESH:D001943', (107, 121))	('breast cancers', 'Disease', (107, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('patients', 'Species', '9606', (48, 56))	('breast cancers', 'Disease', 'MESH:D001943', (26, 40))
990	33654083	As expected, DCIS patients who developed ALL or NHL (Supplementary Tables 22-26) had shorter OS than matched subjects who did not develop any SHMs (median OS for ALL, 10.3 years vs. 31.3 years; P < 0.001; Fig.	('shorter', 'NegReg', (85, 92))	('HL', 'Phenotype', 'HP:0012189', (49, 51))	('ALL', 'Phenotype', 'HP:0006721', (41, 44))	('HM', 'Phenotype', 'HP:0004377', (143, 145))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))	('patients', 'Species', '9606', (18, 26))	('NHL', 'Var', (48, 51))	('HL', 'CellLine', 'CVCL:2492', (49, 51))	('ALL', 'Phenotype', 'HP:0006721', (162, 165))	('NHL', 'Phenotype', 'HP:0012539', (48, 51))
1002	33654083	Biologically, although radiation for DCIS includes only partial rib irradiation (in contrast to regional node irradiation in cases of invasive breast cancer which includes part of the sternum), RT associated exposures to high acute doses of ionizing radiation causes somatic mutations and chromosomal alterations that may also lead to leukemia and other myeloid malignancies.	('lead to', 'Reg', (327, 334))	('causes', 'Reg', (260, 266))	('leukemia', 'Disease', (335, 343))	('somatic mutations', 'CPA', (267, 284))	('exposures', 'Var', (208, 217))	('leukemia', 'Disease', 'MESH:D007938', (335, 343))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('leukemia', 'Phenotype', 'HP:0001909', (335, 343))	('myeloid malignancies', 'Disease', (354, 374))	('invasive breast cancer', 'Disease', 'MESH:D001943', (134, 156))	('chromosomal alterations', 'CPA', (289, 312))	('myeloid malignancies', 'Disease', 'MESH:D009369', (354, 374))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('invasive breast cancer', 'Disease', (134, 156))
1009	33654083	Expectedly, patients with DCIS who developed ALL or NHL had an inferior OS compared with those who did not develop ALL or NHL, which is supported by the fact that occurrence of second cancers in first unrelated primary cancer survivors increases mortality.	('cancer', 'Disease', (184, 190))	('HL', 'Phenotype', 'HP:0012189', (123, 125))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mortality', 'Disease', 'MESH:D003643', (246, 255))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('patients', 'Species', '9606', (12, 20))	('NHL', 'Phenotype', 'HP:0012539', (52, 55))	('HL', 'CellLine', 'CVCL:2492', (53, 55))	('cancers', 'Disease', (184, 191))	('NHL', 'Phenotype', 'HP:0012539', (122, 125))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('ALL', 'Phenotype', 'HP:0006721', (45, 48))	('HL', 'CellLine', 'CVCL:2492', (123, 125))	('cancer', 'Disease', (219, 225))	('HL', 'Phenotype', 'HP:0012189', (53, 55))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('DCIS', 'Var', (26, 30))	('mortality', 'Disease', (246, 255))	('increases', 'PosReg', (236, 245))	('ALL', 'Phenotype', 'HP:0006721', (115, 118))
1106	31532871	Women felt that multiple terms and discrepancy in language between clinicians amplified confusion and misunderstanding of their condition.	('Women', 'Species', '9606', (0, 5))	('confusion', 'Phenotype', 'HP:0001289', (88, 97))	('misunderstanding', 'CPA', (102, 118))	('confusion', 'Disease', (88, 97))	('amplified', 'PosReg', (78, 87))	('discrepancy', 'Var', (35, 46))
1219	31811009	(Section: recommendations, module 1) Strongly phrased recommendation for adjuvant chemotherapy for patients with an MSI (microsatellite instability) colon carcinoma, combined with a statement about very low-quality evidence.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('patients', 'Species', '9606', (99, 107))	('colon carcinoma', 'Disease', 'MESH:D015179', (149, 164))	('MSI', 'Var', (116, 119))	('colon carcinoma', 'Disease', (149, 164))
1253	31811009	Others were reluctant to include information about preference variation because it could threaten the relationship between specialties (if this information would lead to patients choosing against the generally accepted treatment modality).	('patients', 'Species', '9606', (170, 178))	('relationship', 'Interaction', (102, 114))	('variation', 'Var', (62, 71))	('lead', 'Reg', (162, 166))
1291	29127715	Preoperative MRI in women with DCIS and early stage invasive breast cancer is associated with more frequent mastectomy, CPM, and reconstruction surgical treatment.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MRI', 'Var', (13, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('invasive breast cancer', 'Disease', (52, 74))	('CPM', 'Disease', (120, 123))	('women', 'Species', '9606', (20, 25))	('mastectomy', 'Disease', (108, 118))	('invasive breast cancer', 'Disease', 'MESH:D001943', (52, 74))
1329	29127715	The proportion of women receiving BCS with RT was lower among those with an MRI compared to those without an MRI (42.8% and 48.7%, respectively).	('women', 'Species', '9606', (18, 23))	('lower', 'NegReg', (50, 55))	('MRI', 'Var', (76, 79))
1331	29127715	Mastectomy with CPM was nearly double for all stages among women with MRI compared vs. without MRI (stage 0: 14.1% vs. 7.4%; stage I: 9.8% vs. 5.9%; stage II: 18.4% vs.9.3%; and stage III: 22.9% v 14.6%; respectively) (Table 2).	('MRI', 'Var', (70, 73))	('Mastectomy', 'Disease', (0, 10))	('women', 'Species', '9606', (59, 64))
1332	29127715	Mastectomies without CPM for women who received MRI compared to women without MRI were also more frequent for stage 0 - II.	('women', 'Species', '9606', (29, 34))	('stage 0 - II', 'Disease', (110, 122))	('MRI', 'Var', (48, 51))	('women', 'Species', '9606', (64, 69))	('Mastectomies', 'Disease', (0, 12))
1337	29127715	In adjusted logistic regression models, women with MRI were more likely to have a mastectomy (OR = 1.32; 95% CI 1.16-1.50) compared to women without MRI.	('mastectomy', 'Disease', (82, 92))	('women', 'Species', '9606', (40, 45))	('MRI', 'Var', (51, 54))	('women', 'Species', '9606', (135, 140))
1364	29127715	Our study found that preoperative MRI in women with DCIS and early stage invasive breast cancer is associated with more frequent mastectomy, CPM, and reconstruction.	('mastectomy', 'Disease', (129, 139))	('invasive breast cancer', 'Disease', 'MESH:D001943', (73, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MRI', 'Var', (34, 37))	('reconstruction', 'Disease', (150, 164))	('invasive breast cancer', 'Disease', (73, 95))	('CPM', 'Disease', (141, 144))	('women', 'Species', '9606', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
1373	28752247	Cancer cells are intrinsically genomically unstable which predisposes them to increased mutation rates resulting in evolution of tumor subpopulations with notably distinct phenotypes.	('mutation', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('increased', 'PosReg', (78, 87))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (129, 134))
1376	28752247	Interestingly, despite the fact that tumor evolution is proposed to follow the laws of Darwinian evolution whereby tumor subclones accumulate new genetic alterations that confer growth, survival and metastatic advantages, it must be recognized that these "evolutionary changes" do not dramatically alter the major lesion morphologies or phenotypes within the tumor.	('lesion morphologies', 'Disease', (314, 333))	('growth', 'CPA', (178, 184))	('metastatic advantages', 'CPA', (199, 220))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', (359, 364))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('alterations', 'Var', (154, 165))	('lesion morphologies', 'Disease', 'MESH:D051437', (314, 333))	('survival', 'CPA', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
1381	28752247	This model predicts that cancers arise from a single cell, which over time can develop various combinations of mutations resulting in genetic drift and selection of the fittest.	('mutations', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('resulting in', 'Reg', (121, 133))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('genetic drift', 'CPA', (134, 147))
1385	28752247	CSCs share fundamental properties of stem cells, but harbor tumor-initiating mutations which can be transferred to the progeny, and are recently referred as tumor initiating cells (TICs).	('tumor', 'Disease', (157, 162))	('TIC', 'Disease', 'None', (181, 184))	('TIC', 'Phenotype', 'HP:0100033', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('TICs', 'Phenotype', 'HP:0100033', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (77, 86))	('TIC', 'Disease', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (60, 65))
1386	28752247	As discussed below, our studies suggest that distinct genetic alterations define CSC/TIC subsets which confer them with the ability to generate either unipotent (single phenotype) or multipotent (multiple phenotypes) derivatives (Fig.	('TIC', 'Disease', 'None', (85, 88))	('TIC', 'Disease', (85, 88))	('unipotent', 'MPA', (151, 160))	('alterations', 'Var', (62, 73))	('TIC', 'Phenotype', 'HP:0100033', (85, 88))
1392	28752247	Stable transfection of MCF10A cells with mutant Ha-ras preserved the multipotent stem cell property of MCF10A cells as MCF10AT xenografts produce ductular structures with the myoepithelium properly oriented between a basement membrane and the luminal epithelium.	('MCF10A', 'CellLine', 'CVCL:0598', (103, 109))	('multipotent stem cell property', 'CPA', (69, 99))	('mutant', 'Var', (41, 47))	('ductular structures', 'CPA', (146, 165))	('MCF10A', 'CellLine', 'CVCL:0598', (23, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (119, 125))
1397	28752247	According to the clonal evolution model, a tumor cell gains malignant potential by acquiring new genetic alterations and resultant clonal expansion.	('malignant potential', 'CPA', (60, 79))	('clonal', 'CPA', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gains', 'PosReg', (54, 59))	('tumor', 'Disease', (43, 48))	('genetic', 'Var', (97, 104))
1401	28752247	Breast CSCs were first identified as a CD44+/CD24-/low population that has enhanced ability to initiate tumor growth when xenografted into immunocompromised mice.	('ability', 'MPA', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('enhanced', 'PosReg', (75, 83))	('initiate', 'MPA', (95, 103))	('mice', 'Species', '10090', (157, 161))	('Breast CSCs', 'Disease', (0, 11))	('tumor', 'Disease', (104, 109))	('CD44+/CD24-/low', 'Var', (39, 54))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
1402	28752247	CD44/CD24 expression analysis of MCF10AT xenografts showed CD24-/low and strong CD44 immunoreactivity in regions of DCIS and invasive carcinoma, and whereas CD44-expressing DCIS lesions were eliminated by tamoxifen therapy, tamoxifen had little impact on CD44+/ER+ invasive cancer cells.	('tamoxifen', 'Chemical', 'MESH:D013629', (205, 214))	('CD24-/low', 'Var', (59, 68))	('MCF10AT', 'Gene', (33, 40))	('invasive carcinoma', 'Disease', (125, 143))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('CD44 immunoreactivity', 'MPA', (80, 101))	('cancer', 'Disease', (274, 280))	('tamoxifen', 'Chemical', 'MESH:D013629', (224, 233))	('MCF10A', 'CellLine', 'CVCL:0598', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('invasive carcinoma', 'Disease', 'MESH:D009361', (125, 143))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('DCIS', 'Phenotype', 'HP:0030075', (173, 177))	('DCIS', 'Disease', (116, 120))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
1403	28752247	These data suggest that retention of CD44+ cells in the residual tumor is not responsible for the failure to achieve complete therapy response.	('CD44+', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
1417	28752247	In most cases, basal DCIS were associated with high nuclear grade, central necrosis (resembling comedo DCIS.com lesions) and high proliferative indices.	('comedo', 'Phenotype', 'HP:0025249', (96, 102))	('basal DCIS', 'Disease', (15, 25))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('necrosis', 'Disease', 'MESH:D009336', (75, 83))	('high', 'Var', (47, 51))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('necrosis', 'Disease', (75, 83))
1429	28752247	Interestingly, the growth inhibitory effects of normal fibroblasts are not relieved by addition of endothelial cells to the microenvironment, whereas endothelial cells augment the growth stimulatory effects of tumor derived fibroblasts.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('augment', 'PosReg', (168, 175))	('tumor', 'Disease', (210, 215))	('growth stimulatory effects', 'MPA', (180, 206))	('endothelial', 'Var', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
1430	28752247	These data not only reveal the dominant epigenetic regulatory roles of the stromal microenvironment in activation or maintenance of quiescence of progenitor cells but also demonstrate that stroma-mediated epigenetic forces not only override the genetic constraints of breast epithelial cells but also take advantage of tumor cell plasticity.	('tumor', 'Disease', (319, 324))	('epigenetic', 'Var', (205, 215))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('override', 'PosReg', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))
1448	28752247	These data highlight the impact of tumor variants on the survival and growth potentials of tumor subpopulations in a tumor ecosystem.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('variants', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
1452	28752247	Although the Rad6B-overexpressing subpopulations produced smaller tumors compared to the control polyclonal parental cells, the tumors produced by Rad6B-overexpressing subpopulations were composed exclusively of cancer cells with a homogeneous EMT phenotype consistent with activated Wnt/beta-catenin signaling, and displayed high propensity for lymph node and lung metastasis whereas loss of Rad6B impaired their tumor growth potential.	('Rad6B', 'Gene', '7320', (393, 398))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Disease', (128, 134))	('Rad6B', 'Gene', '7320', (147, 152))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (414, 419))	('Rad6B', 'Gene', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Rad6B', 'Gene', (393, 398))	('tumor', 'Disease', 'MESH:D009369', (414, 419))	('loss', 'Var', (385, 389))	('impaired', 'NegReg', (399, 407))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (212, 218))	('tumor', 'Disease', (128, 133))	('Rad6B', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('tumors', 'Disease', (66, 72))	('beta-catenin', 'Gene', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Rad6B', 'Gene', '7320', (13, 18))	('beta-catenin', 'Gene', '1499', (288, 300))
1468	28752247	In this era of personalized medicine, much effort is focused on taking advantage of single cell-based deep sequence analysis and robust bioinformatics approaches to identify genetic alterations that define intratumoral heterogeneity or have predictive biomarker power.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('genetic alterations', 'Var', (174, 193))	('alterations', 'Var', (182, 193))
1497	26076123	The underlying premise formulates that malignancy perturbations will skew the derived distribution in a given direction relative to a completely benign distribution.	('skew', 'Reg', (69, 73))	('perturbations', 'Var', (50, 63))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('malignancy', 'Disease', (39, 49))
1589	30941233	In the DCIS panel, miRNA-654-5p was significantly upregulated in the patients with poor prognosis.	('upregulated', 'PosReg', (50, 61))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('miRNA-654-5p', 'Chemical', '-', (19, 31))	('patients', 'Species', '9606', (69, 77))	('miRNA-654-5p', 'Var', (19, 31))
1590	30941233	In vitro, miRNA-654-5p promoted MDA-MB-231 cell mobility in healing tests and metastasis in the Transwell study.	('promoted', 'PosReg', (23, 31))	('miRNA-654-5p', 'Var', (10, 22))	('metastasis in the Transwell study', 'CPA', (78, 111))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (32, 42))	('MDA-MB-231', 'Gene', (32, 42))	('miRNA-654-5p', 'Chemical', '-', (10, 22))
1592	30941233	miRNA-654-5p is significantly upregulated DCIS patients having poor prognosis and may be essential for local and distant recurrence in DCIS.	('miRNA-654-5p', 'Var', (0, 12))	('upregulated', 'PosReg', (30, 41))	('patients', 'Species', '9606', (47, 55))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('miRNA-654-5p', 'Chemical', '-', (0, 12))
1603	30941233	Moreover, we analyzed the functional role of miRNA-654-5p in promoting cell invasion in DCIS.	('miRNA-654-5p', 'Var', (45, 57))	('miRNA-654-5p', 'Chemical', '-', (45, 57))	('DCIS', 'Disease', (88, 92))	('promoting', 'PosReg', (61, 70))	('cell invasion', 'CPA', (71, 84))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
1616	30941233	Chemically synthesized of miRNA-654-5p analog mimics (GenePharma, Shanghai, China) were used to overexpress miRNA-654-5p.	('overexpress', 'PosReg', (96, 107))	('miRNA-654-5p', 'Var', (108, 120))	('miRNA-654-5p', 'Chemical', '-', (26, 38))	('miRNA-654-5p', 'Chemical', '-', (108, 120))
1624	30941233	MDA-MB-231 cells were transfected with miRNA-654-5p mimics or negative controls after 24 hours and plated onto fibronectin-coated chamber slides and stained on day 3.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (0, 10))	('fibronectin', 'Gene', (111, 122))	('miRNA-654-5p mimics', 'Var', (39, 58))	('miRNA-654-5p', 'Chemical', '-', (39, 51))	('fibronectin', 'Gene', '2335', (111, 122))
1636	30941233	The 5 were miRNA-654-5p (p = 0.048), miRNA-141-5P (p = 0.037), miRNA-767-5p (p = 0.027), miRNA-4507 (p = 0.042), and miRNA-7g-3p (p = 0.048).	('miRNA-654-5p', 'Chemical', '-', (11, 23))	('miRNA-141-5P', 'Var', (37, 49))	('miRNA-767-5p', 'Var', (63, 75))
1644	30941233	miRNA-654-5p significantly increased cell migration in the treatment group compared with the control.	('cell migration', 'CPA', (37, 51))	('miRNA-654-5p', 'Chemical', '-', (0, 12))	('increased', 'PosReg', (27, 36))	('miRNA-654-5p', 'Var', (0, 12))
1645	30941233	Wound healing assays showed that treatment with miRNA-654-5p for 24 hours markedly increased the migration ability of MDA-MB-231 cells.	('miRNA-654-5p', 'Chemical', '-', (48, 60))	('increased', 'PosReg', (83, 92))	('miRNA-654-5p', 'Var', (48, 60))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (118, 128))	('migration ability', 'CPA', (97, 114))
1648	30941233	After 48 hours, more cells had migrated to the lower wells in the treatment group than in the negative group, which indicated that miRNA-654-5p obviously increased the migration ability of the MDA-MB-231 cells.	('miRNA-654-5p', 'Chemical', '-', (131, 143))	('migration ability', 'CPA', (168, 185))	('miRNA-654-5p', 'Var', (131, 143))	('increased', 'PosReg', (154, 163))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (193, 203))
1649	30941233	Breast cancer cells transfected with miRNA-654-5p mimics displayed a significantly higher rate of metastasis than control cells (p < 0.05) (Figure 5H).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('miRNA-654-5p mimics', 'Var', (37, 56))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('metastasis', 'CPA', (98, 108))	('miRNA-654-5p', 'Chemical', '-', (37, 49))	('Breast cancer', 'Disease', (0, 13))	('higher', 'PosReg', (83, 89))
1650	30941233	To test the molecular effect of miRNA-654-5p on downstream genes in the breast cancer cells, we tested the expression of invasion- and metastasis-related genes in cells transfected with miRNA-654-5p.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miRNA-654-5p', 'Chemical', '-', (32, 44))	('miRNA-654-5p', 'Chemical', '-', (186, 198))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('tested', 'Reg', (96, 102))	('breast cancer', 'Disease', (72, 85))	('miRNA-654-5p', 'Var', (186, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
1651	30941233	The expression of metastasis-associated genes was generally higher in the miRNA-654-5p overexpression group than in the negative control group (Figure 6A).	('metastasis-associated genes', 'Gene', (18, 45))	('higher', 'PosReg', (60, 66))	('expression', 'MPA', (4, 14))	('miRNA-654-5p', 'Chemical', '-', (74, 86))	('overexpression', 'PosReg', (87, 101))	('miRNA-654-5p', 'Var', (74, 86))
1653	30941233	These data were consistent with previous observations that miRNA-654-5p could promote metastasis and proliferation as well as inhibit apoptosis.	('promote', 'PosReg', (78, 85))	('miRNA-654-5p', 'Var', (59, 71))	('apoptosis', 'CPA', (134, 143))	('proliferation', 'CPA', (101, 114))	('inhibit', 'NegReg', (126, 133))	('miRNA-654-5p', 'Chemical', '-', (59, 71))	('metastasis', 'CPA', (86, 96))
1665	30941233	studied miRNAs in eight normal, four atypical ductal hyperplasia, six DCIS and seven IDC samples; miRNA-21, miRNA-200b/c, miRNA-141, and miRNA-183 were consistently overexpressed in ADH, DCIS, and IDC compared to normal patients, while miRNA-557 also had uniquely low expression in DCIS.	('ductal hyperplasia', 'Disease', 'MESH:D002285', (46, 64))	('patients', 'Species', '9606', (220, 228))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('ADH', 'Disease', (182, 185))	('IDC', 'Gene', '4000', (197, 200))	('IDC', 'Gene', (197, 200))	('IDC', 'Gene', '4000', (85, 88))	('IDC', 'Gene', (85, 88))	('DCIS', 'Phenotype', 'HP:0030075', (282, 286))	('miRNA-183', 'Gene', '406959', (137, 146))	('miRNA-183', 'Gene', (137, 146))	('miRNA-141', 'Var', (122, 131))	('ductal hyperplasia', 'Disease', (46, 64))	('overexpressed', 'PosReg', (165, 178))	('miRNA-200b/c', 'Var', (108, 120))	('DCIS', 'Disease', (187, 191))	('miRNA-21', 'Gene', '406991', (98, 106))	('miRNA-21', 'Gene', (98, 106))
1666	30941233	showed, compared with the normal tissues, miRNA-10b, miRNA-125b, miRNA-132, miRNA-145, miRNA-154-3p, miRNA-382-5p, and miRNA-409-3p were significantly deregulated in DCIS.	('miRNA-125b', 'Var', (53, 63))	('miRNA-409-3p', 'Var', (119, 131))	('miRNA-10b', 'Gene', (42, 51))	('miRNA-382-5p', 'Var', (101, 113))	('miRNA-132', 'Gene', (65, 74))	('DCIS', 'Disease', (166, 170))	('miRNA-10b', 'Gene', '406903', (42, 51))	('miRNA-132', 'Gene', '406921', (65, 74))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('miRNA-145', 'Gene', '406937', (76, 85))	('miRNA-145', 'Gene', (76, 85))	('deregulated', 'NegReg', (151, 162))	('miRNA-154-3p', 'Var', (87, 99))
1669	30941233	miRNA-767-5p was previously reported to be expressed at a 15-fold higher rate in a prostate cancer cell line than in the normal prostate epithelial cell.	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('higher rate', 'PosReg', (66, 77))	('miRNA-767-5p', 'Var', (0, 12))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
1670	30941233	The cells would have a greater migratory ability in SK-HEP-1 cells with highly expressed miRNA-767-5p.	('miRNA-767-5p', 'Var', (89, 101))	('migratory ability', 'CPA', (31, 48))	('SK-HEP-1', 'CellLine', 'CVCL:0525', (52, 60))	('greater', 'PosReg', (23, 30))
1674	30941233	The expression of miRNA-654-5p is consistently upregulated in poor prognosis DCIS cases.	('upregulated', 'PosReg', (47, 58))	('poor', 'Disease', (62, 66))	('expression', 'MPA', (4, 14))	('miRNA-654-5p', 'Var', (18, 30))	('DCIS', 'Disease', (77, 81))	('miRNA-654-5p', 'Chemical', '-', (18, 30))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
1675	30941233	It has been reported that miRNA-654-5p can be an inhibitor in prostate cancer that features decreased androgen-induced proliferation.	('miRNA-654-5p', 'Var', (26, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('androgen-induced proliferation', 'CPA', (102, 132))	('decreased androgen', 'Phenotype', 'HP:0030349', (92, 110))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miRNA-654-5p', 'Chemical', '-', (26, 38))	('decreased', 'NegReg', (92, 101))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
1676	30941233	Downregulation miRNA-654-5p was also reportedly related with the classical Hodgkin lymphoma.	('Hodgkin lymphoma', 'Disease', (75, 91))	('Downregulation', 'NegReg', (0, 14))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (75, 91))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (75, 91))	('miRNA-654-5p', 'Chemical', '-', (15, 27))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('miRNA-654-5p', 'Var', (15, 27))	('related', 'Reg', (48, 55))
1677	30941233	Upregulated miRNA-654-5p in late-stage oral squamous cell carcinoma has also been reportedly correlated with poor prognosis.	('oral squamous cell carcinoma', 'Disease', (39, 67))	('miRNA-654-5p', 'Chemical', '-', (12, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('miRNA-654-5p', 'Var', (12, 24))	('Upregulated', 'PosReg', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 67))
1678	30941233	In that study, miRNA-654-5p activated Ras/mitogen-activated protein kinase signaling by targeting Grb-2-related adaptor protein and in the further promotion of the EMT process.	('targeting', 'Reg', (88, 97))	('promotion', 'PosReg', (147, 156))	('Grb-2-related adaptor protein', 'Protein', (98, 127))	('EMT process', 'CPA', (164, 175))	('miRNA-654-5p', 'Chemical', '-', (15, 27))	('Ras/mitogen-activated protein kinase signaling', 'Pathway', (38, 84))	('activated', 'PosReg', (28, 37))	('miRNA-654-5p', 'Var', (15, 27))
1683	30941233	The present and previous findings support the suggestion that miRNA-654-5p is a key biomarker for DCIS and progression of other tumors.	('miRNA-654-5p', 'Chemical', '-', (62, 74))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('miRNA-654-5p', 'Var', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('DCIS', 'Disease', (98, 102))
1688	30941233	The collective results obtained to date indicate that the aberrant expression of miRNA-654-5p may differ in the different stages of breast cancer and may have various effects on breast cancer progression.	('miRNA-654-5p', 'Var', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', (132, 145))	('aberrant', 'Var', (58, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('have', 'Reg', (154, 158))	('breast cancer', 'Disease', (178, 191))	('miRNA-654-5p', 'Chemical', '-', (81, 93))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('effects', 'Reg', (167, 174))	('differ', 'Reg', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
1689	30941233	We had intended to explore the function of miRNA-654-5p in DCIS progression.	('miRNA-654-5p', 'Chemical', '-', (43, 55))	('DCIS', 'Disease', (59, 63))	('miRNA-654-5p', 'Var', (43, 55))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))
1690	30941233	The expression level of miRNA-654-5p was quite low in the MDA-MB-231 invasive carcinoma cell line, which is the reason we chose this cell line for the in vitro test.	('expression level', 'MPA', (4, 20))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (58, 68))	('low', 'NegReg', (47, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('miRNA-654-5p', 'Var', (24, 36))	('invasive carcinoma', 'Disease', (69, 87))	('miRNA-654-5p', 'Chemical', '-', (24, 36))	('invasive carcinoma', 'Disease', 'MESH:D009361', (69, 87))
1691	30941233	The cells in the experimental group had stronger migration ability than the control group, which proved that miRNA-654-5p could increase the capacity to metastasize.	('increase', 'PosReg', (128, 136))	('miRNA-654-5p', 'Chemical', '-', (109, 121))	('migration ability', 'CPA', (49, 66))	('miRNA-654-5p', 'Var', (109, 121))	('stronger', 'PosReg', (40, 48))
1695	30941233	Therefore, we quantified the EMT protein and identified that proteins were upregulated in miRNA-654-5p overexpressed cell lines.	('proteins', 'Protein', (61, 69))	('miRNA-654-5p', 'Chemical', '-', (90, 102))	('upregulated', 'PosReg', (75, 86))	('miRNA-654-5p overexpressed', 'Var', (90, 116))
1696	30941233	miRNA-654-5p may promote metastasis by targeting EMT-related proteins.	('targeting', 'Reg', (39, 48))	('miRNA-654-5p', 'Var', (0, 12))	('promote', 'PosReg', (17, 24))	('miRNA-654-5p', 'Chemical', '-', (0, 12))	('EMT-related', 'Protein', (49, 60))	('metastasis', 'CPA', (25, 35))
1698	30941233	In a few words, the expression of miRNA-654-5p is significantly upregulated in DCIS patients having poor prognosis with the probable mechanism of EMT.	('expression', 'MPA', (20, 30))	('patients', 'Species', '9606', (84, 92))	('miRNA-654-5p', 'Var', (34, 46))	('upregulated', 'PosReg', (64, 75))	('DCIS', 'Disease', (79, 83))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('miRNA-654-5p', 'Chemical', '-', (34, 46))
1761	27401536	First, for breast patients with BI-RADS  0 or 3 by US and/or MMG, high risk, and/or MMG dense breasts, BSGI was a useful adjunctive imaging method to reduce the false-negative rate (missed diagnosis rate).	('BI-RADS', 'Var', (32, 39))	('MMG', 'Var', (84, 87))	('patients', 'Species', '9606', (18, 26))	('false-negative', 'MPA', (161, 175))
1811	26202556	Facility types were defined as community cancer program (100 to 500 newly diagnosed cases/year), comprehensive community cancer program (>=500 newly diagnosed cases/year) and academic / research program (>=500 newly diagnosed cases/year and participate in physician education and research).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('>=500', 'Var', (137, 142))	('100 to', 'Var', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (121, 127))
1830	26202556	Characteristics associated with a higher likelihood of receiving AET were well or moderately differentiated DCIS, ER+ status, black race, treatment at a community cancer program, or treatment in the Northeast, Atlantic, Great Lakes or Midwest.	('black race', 'Var', (126, 136))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('ER', 'Gene', '2099', (114, 116))	('AET', 'Chemical', '-', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
1872	26202556	Absolute decreases in risk remain modest, and the low breast cancer-related mortality associated with DCIS (<5% at 15 years) is not changed with the addition of adjuvant AET.	('DCIS', 'Var', (102, 106))	('low breast cancer', 'Disease', (50, 67))	('low breast cancer', 'Disease', 'MESH:D001943', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('AET', 'Chemical', '-', (170, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
1897	25017040	For example, 3D conditions activated cancer-related signaling pathways such as H-RasV12-induced IL6-STAT3 and initiated ECM dependent responses that were not seen in 2D conditions.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('STAT3', 'Gene', (100, 105))	('IL6', 'Gene', '3569', (96, 99))	('cancer', 'Disease', (37, 43))	('IL6', 'Gene', (96, 99))	('H-RasV12-induced', 'Var', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('STAT3', 'Gene', '6774', (100, 105))	('ECM dependent responses', 'MPA', (120, 143))	('activated', 'PosReg', (27, 36))
1937	25017040	Since studies show that substrate rigidity changes affect malignancy, using a uniform matrix may result in missing this important feature of cancer progression.	('rigidity', 'Disease', (34, 42))	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('rigidity', 'Phenotype', 'HP:0002063', (34, 42))	('malignancy', 'Disease', (58, 68))	('affect', 'Reg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rigidity', 'Disease', 'MESH:D009127', (34, 42))	('changes', 'Var', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
2022	31596602	Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk associated with an interquartile range (IQR) increase in pollutants.	('increase', 'PosReg', (166, 174))	('Cox', 'Gene', (0, 3))	('Cox', 'Gene', '1351', (0, 3))	('interquartile', 'Var', (140, 153))	('pollutants', 'MPA', (178, 188))
2122	31596602	Inhaled toxicants can reach the breast tissue and traffic-related air pollution has been associated with aberrant DNA methylation in breast cancer-related genes measured in tumor tissue.	('associated', 'Reg', (89, 99))	('breast cancer', 'Disease', (133, 146))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('DNA methylation', 'MPA', (114, 129))	('aberrant', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
2123	31596602	Air pollution has also been related to higher breast density, a marker of breast cancer risk.	('breast cancer', 'Disease', (74, 87))	('higher', 'PosReg', (39, 45))	('Air pollution', 'Var', (0, 13))	('breast density', 'Disease', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
2138	31596602	In a subset of our study population with DNA methylation data, among women in Clusters 4 and 7,  was also associated with DNA methylation-based biologic age acceleration, a marker of future breast cancer risk.	('associated', 'Reg', (106, 116))	('methylation', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('women', 'Species', '9606', (69, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
2235	30625220	The sensor of the detector used here limits the efficiency, as well as the gratings on silicon substrate cause substantial unwanted beam absorption.	('efficiency', 'MPA', (48, 58))	('cause', 'Reg', (105, 110))	('limits', 'NegReg', (37, 43))	('silicon', 'Chemical', 'MESH:D012825', (87, 94))	('unwanted beam absorption', 'MPA', (123, 147))	('gratings', 'Var', (75, 83))
2369	28357084	In a cohort of 13,434 women followed up for a median of 15.7 years, Visscher et al found that the presence of SA stratified risk in subsets of women defined by age, involution status and family history, and that SA is a common proliferative lesion of the breast that conveys an approximate doubling of breast cancer risk.	('SA', 'Chemical', '-', (110, 112))	('women', 'Species', '9606', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('breast cancer', 'Disease', 'MESH:D001943', (302, 315))	('breast cancer', 'Disease', (302, 315))	('breast cancer', 'Phenotype', 'HP:0003002', (302, 315))	('presence', 'Var', (98, 106))	('SA', 'Chemical', '-', (212, 214))	('women', 'Species', '9606', (143, 148))
2385	28357084	Of the 151 lesions with SA as the major component, masses with calcification were found in 21 (13.9%) cases on US; the most frequent calcification pattern was clustered punctate and the remaining were diffusely punctate and clustered amorphous calcifications.	('SA', 'Chemical', '-', (24, 26))	('clustered', 'Var', (159, 168))	('calcification', 'Disease', (244, 257))	('calcification', 'Disease', (63, 76))	('calcification', 'Disease', 'MESH:D002114', (133, 146))	('calcification', 'Disease', 'MESH:D002114', (244, 257))	('calcification', 'Disease', 'MESH:D002114', (63, 76))	('calcification', 'Disease', (133, 146))
2392	28357084	As reported in studies on fine-needle aspiration cytology of SA, the most frequent characteristics, although not specific, were low-to-moderate cellularity, bland epithelial cells that focally formed cohesive groups/tubules or occasionally discohesive clusters or individual cells, and fragments of dense fibrous stroma.	('fibrous stroma', 'Disease', 'MESH:D010411', (305, 319))	('fibrous stroma', 'Disease', (305, 319))	('cohesive groups/tubules', 'CPA', (200, 223))	('bland epithelial cells', 'CPA', (157, 179))	('SA', 'Chemical', '-', (61, 63))	('low-to-moderate', 'Var', (128, 143))	('aspiration', 'Phenotype', 'HP:0002835', (38, 48))	('discohesive clusters', 'CPA', (240, 260))
2454	23379630	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1472-6874/13/3/prepub This work was supported by the National Cancer Institute (R01 CA140560) and by the National Cancer Institute-funded Breast Cancer Surveillance Consortium (U01CA86082, U01CA70013, U01CA69976, HHSN261201100031C).	('U01CA70013', 'Var', (283, 293))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('U01', 'CellLine', 'CVCL:2220', (295, 298))	('Cancer', 'Disease', 'MESH:D009369', (239, 245))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Cancer', 'Disease', (156, 162))	('Breast Cancer', 'Disease', 'MESH:D001943', (232, 245))	('R01', 'Var', (174, 177))	('Cancer', 'Disease', (208, 214))	('Breast Cancer', 'Disease', (232, 245))	('U01', 'CellLine', 'CVCL:2220', (283, 286))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('U01CA86082', 'Var', (271, 281))	('Cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Breast Cancer', 'Phenotype', 'HP:0003002', (232, 245))	('Cancer', 'Disease', 'MESH:D009369', (208, 214))	('Cancer', 'Disease', (239, 245))	('U01', 'CellLine', 'CVCL:2220', (271, 274))	('U01CA69976', 'Var', (295, 305))
2480	22531630	It can be used to assess whole lymph nodes, and yields semi-quantitative results for the detection of clinically relevant nodal metastases >0.2 mm in size by the detection and amplification of cytokeratin 19 (CK19) mRNA.	('CK19', 'Gene', '3880', (209, 213))	('nodal metastases', 'Disease', 'MESH:D009362', (122, 138))	('cytokeratin 19', 'Gene', '3880', (193, 207))	('cytokeratin 19', 'Gene', (193, 207))	('CK19', 'Gene', (209, 213))	('nodal metastases', 'Disease', (122, 138))	('amplification', 'Var', (176, 189))
2559	22531630	For patients with pT1miN1miM0 tumours, the current guidelines recommend considering endocrine therapy for hormone receptor-positive tumours and chemotherapy for hormone receptor-negative tumours.	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('hormone receptor', 'Gene', (161, 177))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('hormone receptor', 'Gene', (106, 122))	('tumours', 'Disease', (132, 139))	('hormone receptor', 'Gene', '3164', (161, 177))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', (187, 194))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('patients', 'Species', '9606', (4, 12))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('pT1miN1miM0', 'Var', (18, 29))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('hormone receptor', 'Gene', '3164', (106, 122))
2616	16421596	Our own data from breast cancer cell lines, indicates that COX-2 expression inhibits apoptosis, and Celecoxib (a COX-2 inhibitor) reduces xenograft growth by increasing cell death (with no effects on cell proliferation) in a nude mouse model (Barnes et al, 2004).	('Celecoxib', 'Chemical', 'MESH:D000068579', (100, 109))	('mouse', 'Species', '10090', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('xenograft growth', 'CPA', (138, 154))	('apoptosis', 'CPA', (85, 94))	('inhibits', 'NegReg', (76, 84))	('breast cancer', 'Disease', (18, 31))	('increasing', 'PosReg', (158, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('COX-2', 'Gene', (59, 64))	('reduces', 'NegReg', (130, 137))	('expression', 'Var', (65, 75))	('cell death', 'CPA', (169, 179))	('Celecoxib', 'Var', (100, 109))
2642	33738563	[18F]FDG FAR is a feasible and safe technique for intraoperative tumour margin assessment.	('intraoperative tumour', 'Disease', 'MESH:D007431', (50, 71))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('FDG', 'Chemical', 'MESH:D019788', (5, 8))	('[18F]', 'Var', (0, 5))	('intraoperative tumour', 'Disease', (50, 71))
2706	33738563	Subgroup analysis revealed improved sensitivity, PPV and NPV for women receiving a higher [18F]FDG activity.	('improved', 'PosReg', (27, 35))	('PPV', 'Chemical', '-', (49, 52))	('PPV', 'MPA', (49, 52))	('FDG', 'Chemical', 'MESH:D019788', (95, 98))	('[18F]FDG activity', 'Var', (90, 107))	('women', 'Species', '9606', (65, 70))	('sensitivity', 'MPA', (36, 47))	('NPV', 'MPA', (57, 60))
2728	33738563	An improved sensitivity was seen in patients who received a higher [18F]FDG activity.	('patients', 'Species', '9606', (36, 44))	('improved', 'PosReg', (3, 11))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('[18F', 'Var', (67, 71))	('sensitivity', 'MPA', (12, 23))
2776	23818008	In these cases, heterogeneously mixed fat and breast tissue may have led to heterogeneous FDG accumulation in the PEM images.	('heterogeneously', 'Var', (16, 31))	('heterogeneous FDG accumulation', 'MPA', (76, 106))	('FDG', 'Chemical', '-', (90, 93))	('led to', 'Reg', (69, 75))
2806	21253797	Clinical studies have also shown that PARP inhibitors are effective for the treatment of breast cancers arising in BRCA-1 or -2 mutation carriers, suggesting that targeting PARP may also be useful for the prevention of breast cancers arising in these high-risk individuals.	('BRCA-1', 'Gene', (115, 121))	('BRCA-1', 'Gene', '672', (115, 121))	('breast cancers', 'Disease', 'MESH:D001943', (219, 233))	('breast cancers', 'Disease', (219, 233))	('PARP', 'Gene', (38, 42))	('PARP', 'Gene', '142', (173, 177))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('PARP', 'Gene', (173, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (219, 233))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('mutation', 'Var', (128, 136))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('PARP', 'Gene', '142', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
2852	21253797	Cells carrying heterozygous loss-of-function mutations of BRCA may lose the wild-type allele on the path of oncogenesis, making these cells deficient in their ability of homologous recombination.	('mutations', 'Var', (45, 54))	('BRCA', 'Gene', '672', (58, 62))	('lose', 'NegReg', (67, 71))	('deficient', 'NegReg', (140, 149))	('loss-of-function', 'NegReg', (28, 44))	('BRCA', 'Gene', (58, 62))
2853	21253797	In the absence of PARP1, spontaneous single-strand breaks collapse DNA replication forks and trigger homologous recombination for repair, making any DNA damage lethal to the BRCA mutant cell.	('PARP1', 'Gene', '142', (18, 23))	('BRCA', 'Gene', (174, 178))	('BRCA', 'Gene', '672', (174, 178))	('mutant', 'Var', (179, 185))	('single-strand breaks', 'Var', (37, 57))	('collapse', 'NegReg', (58, 66))	('trigger', 'Reg', (93, 100))	('homologous', 'MPA', (101, 111))	('DNA', 'MPA', (67, 70))	('PARP1', 'Gene', (18, 23))
2855	21253797	The requirement of a BRCA mutation to be present for a PARP inhibitor to be effective constitutes a "synthetic lethal" strategy selectively affecting BRCA1 or 2 mutant tumor cells (a compound targeting a particular pathway is selectively "lethal" to cells harboring a mutation in a complementary pathway).	('mutant', 'Var', (161, 167))	('BRCA1', 'Gene', (150, 155))	('BRCA', 'Gene', (21, 25))	('PARP', 'Gene', '142', (55, 59))	('BRCA', 'Gene', (150, 154))	('tumor', 'Disease', (168, 173))	('affecting', 'Reg', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('PARP', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('BRCA1', 'Gene', '672', (150, 155))	('BRCA', 'Gene', '672', (21, 25))	('BRCA', 'Gene', '672', (150, 154))	('rat', 'Species', '10116', (121, 124))
2863	21253797	To further investigate their clinical applicability as chemopreventive agents, further investigations should be proposed in BRCA mutation carriers to assess the ability of PARP inhibitors of reducing the incidence of breast cancer.	('PARP', 'Gene', '142', (172, 176))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('mutation', 'Var', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('BRCA', 'Gene', '672', (124, 128))	('breast cancer', 'Disease', (217, 230))	('PARP', 'Gene', (172, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('BRCA', 'Gene', (124, 128))	('reducing', 'NegReg', (191, 199))
2867	21253797	There is strong preclinical evidence to suggest that lipophilic statins, atorvastatin, lovastatin, simvastatin, and fluvastatin significantly inhibit the proliferation of breast cancer cell lines, and greater suppression was observed in ER-negative cell lines.	('lipophilic', 'Var', (53, 63))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('inhibit', 'NegReg', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('simvastatin', 'Chemical', 'MESH:D019821', (99, 110))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('lovastatin', 'Chemical', 'MESH:D008148', (87, 97))	('rat', 'Species', '10116', (161, 164))	('fluvastatin', 'Chemical', 'MESH:D000077340', (116, 127))	('proliferation', 'CPA', (154, 167))	('atorvastatin', 'Chemical', 'MESH:D000069059', (73, 85))
2869	21253797	Kumar and coworkers have found a marked reduction of breast cancers associated with the administration of lipophilic statins.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('lipophilic', 'Var', (106, 116))	('reduction of breast cancers', 'Disease', 'MESH:D001943', (40, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (53, 67))	('rat', 'Species', '10116', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('reduction of breast cancers', 'Disease', (40, 67))
2874	21253797	Several phase II prevention trials are ongoing at the NCI using lipophilic statins (JHOC-J0485, V0407, BRSNSTU0010), to assess their cancer-preventive effects using biomarkers.	('JHOC-J0485', 'Var', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('V0407', 'Var', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
2912	21253797	Specifically, the synthetic rexinoids bexarotene and LG100268 have been shown to prevent estrogen receptor-negative breast cancer in various mouse models including transgenic lines of MMTV-ErbB2 overexpressing, p53-null, and C3(1)-SV40 T-antigen (Tag) expressing mice and rats.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('LG100268', 'Var', (53, 61))	('breast cancer', 'Disease', (116, 129))	('prevent', 'NegReg', (81, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('MMTV', 'Species', '11757', (184, 188))	('p53', 'Gene', (211, 214))	('ErbB2', 'Gene', (189, 194))	('transgenic', 'Species', '10090', (164, 174))	('mouse', 'Species', '10090', (141, 146))	('rats', 'Species', '10116', (272, 276))	('p53', 'Gene', '7157', (211, 214))	('LG100268', 'Chemical', 'MESH:C095104', (53, 61))	('bexarotene', 'Chemical', 'MESH:D000077610', (38, 48))	('rexinoids', 'Chemical', '-', (28, 37))	('ErbB2', 'Gene', '2064', (189, 194))	('mice', 'Species', '10090', (263, 267))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
2927	21253797	The chemopreventive potential of PPARgamma was demonstrated in experimental rodent mammary tumorigenesis models, as the PPARgamma ligand GW7845 significantly reduced tumor incidence, multiplicity, and weight.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('PPARgamma', 'Gene', (33, 42))	('reduced', 'NegReg', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PPARgamma', 'Gene', '5468', (33, 42))	('PPARgamma', 'Gene', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (166, 171))	('rat', 'Species', '10116', (54, 57))	('weight', 'CPA', (201, 207))	('PPARgamma', 'Gene', '5468', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('GW7845', 'Var', (137, 143))
2929	21253797	Natural occurring ligands such as conjugated linoleic acids may be regarded as a component of the diet that exert antineoplastic activity and its effect have also been found to inhibit progression of mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('antineoplastic activity', 'MPA', (114, 137))	('inhibit', 'NegReg', (177, 184))	('conjugated linoleic acids', 'Var', (34, 59))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('linoleic acids', 'Chemical', 'MESH:D008041', (45, 59))	('tumor', 'Disease', (208, 213))
2932	21253797	The biochemical effect of NSAIDs is the inhibition of cyclooxigenase (COX) enzymes, which play a crucial role in growth-promoting prostaglandin synthesis via the eicosanoid pathway (Fig.	('prostaglandin', 'Chemical', 'MESH:D011453', (130, 143))	('eicosanoid', 'Chemical', 'MESH:D015777', (162, 172))	('NSAIDs', 'Var', (26, 32))	('inhibition', 'NegReg', (40, 50))
2940	21253797	There is a concern that inhibition of COX-2 in nonneoplastic cell might be harmful and cause unwanted toxicity.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('toxicity', 'Disease', (102, 110))	('COX-2', 'Enzyme', (38, 43))	('cause', 'Reg', (87, 92))	('inhibition', 'Var', (24, 34))
2948	21253797	Breast cancers often arise from aberrant expression or activation of the erbB family of growth factor receptors, consisting of four distinct members, epidermal growth factor receptor (EGFR, erbB1or Her-1), erbB2 (Her2 or neu), erbB3 (Her-3), and erbB4 (Her4).	('erbB', 'Gene', (206, 210))	('erbB1', 'Gene', (190, 195))	('neu', 'Gene', (221, 224))	('Her4', 'Gene', '2066', (253, 257))	('epidermal growth factor receptor', 'Gene', '1956', (150, 182))	('erbB3', 'Gene', (227, 232))	('erbB', 'Gene', '1956', (227, 231))	('erbB', 'Gene', (190, 194))	('erbB', 'Gene', (246, 250))	('aberrant', 'Var', (32, 40))	('Her-3', 'Gene', (234, 239))	('arise from', 'Reg', (21, 31))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('erbB', 'Gene', '1956', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('Breast cancers', 'Disease', (0, 14))	('erbB1', 'Gene', '1956', (190, 195))	('erbB4', 'Gene', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('erbB', 'Gene', (227, 231))	('neu', 'Gene', '2064', (221, 224))	('erbB', 'Gene', '1956', (206, 210))	('erbB2', 'Gene', '2064', (206, 211))	('erbB2', 'Gene', (206, 211))	('Her-1', 'Gene', '1956', (198, 203))	('erbB4', 'Gene', '2066', (246, 251))	('erbB', 'Gene', '1956', (190, 194))	('activation', 'PosReg', (55, 65))	('erbB', 'Gene', '1956', (246, 250))	('erbB', 'Gene', (73, 77))	('Her-3', 'Gene', '2065', (234, 239))	('erbB3', 'Gene', '2065', (227, 232))	('Her-1', 'Gene', (198, 203))	('Her4', 'Gene', (253, 257))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('epidermal growth factor receptor', 'Gene', (150, 182))
2954	21253797	In preclinical models we have demonstrated that gefitinib prevents the development of ER-negative mammary tumors and others have shown that it is superior to herceptin in suppressing growth of DCIS epithelial cells.	('development', 'CPA', (71, 82))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('suppressing', 'NegReg', (171, 182))	('gefitinib', 'Chemical', 'MESH:D000077156', (48, 57))	('rat', 'Species', '10116', (37, 40))	('growth', 'CPA', (183, 189))	('herceptin', 'Chemical', 'MESH:D000068878', (158, 167))	('prevents', 'NegReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('gefitinib', 'Var', (48, 57))
2958	21253797	A number of new EGFR-selective (PD153035, AG1478, AG1517, PD158780, PD165557, PKI 166) and multitarget (lapatinib, HKI-272, BIBW-2992, BMS-599626, targeting EGFR and Her-2; CI-1033 targeting EGFR, Her-2 and erbB4) inhibitors have been developed and are now in clinical testing for the treatment of various solid tumors.	('erbB4', 'Gene', (207, 212))	('BIBW-2992', 'CellLine', 'CVCL:9L82', (124, 133))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('Her-2', 'Gene', (166, 171))	('lapatinib', 'Chemical', 'MESH:D000077341', (104, 113))	('solid tumors', 'Disease', 'MESH:D009369', (306, 318))	('PD158780', 'Var', (58, 66))	('PD165557', 'Var', (68, 76))	('Her-2', 'Gene', '2064', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('Her-2', 'Gene', (197, 202))	('erbB4', 'Gene', '2066', (207, 212))	('solid tumors', 'Disease', (306, 318))	('PD153035', 'Var', (32, 40))	('Her-2', 'Gene', '2064', (166, 171))
2968	21253797	In addition to the important role of the IGF system in normal mammary development, it has been proposed that overproduction of GH or IGF-I can also cause the development of atypical hyperplasias or even carcinoma.	('carcinoma', 'Disease', (203, 212))	('IGF-I', 'Gene', (133, 138))	('overproduction', 'Var', (109, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('atypical hyperplasias', 'Disease', 'MESH:D004714', (173, 194))	('cause', 'Reg', (148, 153))	('atypical hyperplasias', 'Disease', (173, 194))	('carcinoma', 'Disease', 'MESH:D002277', (203, 212))	('IGF-I', 'Gene', '3479', (133, 138))
2971	21253797	As a proof of principle, the new IGF-IR tyrosine kinase inhibitor, BMS-536924 caused a blockade of cell proliferation in monolayer and 3D cell cultures, and reversed the ability of constitutively active IGF-IR to transform MCF10A cells.	('rat', 'Species', '10116', (111, 114))	('cell proliferation', 'CPA', (99, 117))	('BMS-536924', 'Var', (67, 77))	('MCF10A', 'CellLine', 'CVCL:0598', (223, 229))	('IGF-IR', 'Gene', '3480', (33, 39))	('blockade', 'NegReg', (87, 95))	('IGF-IR', 'Gene', (203, 209))	('MCF10A', 'Gene', (223, 229))	('IGF-IR', 'Gene', '3480', (203, 209))	('IGF-IR', 'Gene', (33, 39))
3065	31400007	Candidates for NAC were those who had >=T2 cancers, triple-negative or HER2+ cancers, multiple radiographically suspicious or biopsy-positive axillary lymph nodes, or those who had cancers requiring mastectomy but who wanted breast-conserving operations.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('HER2', 'Gene', (71, 75))	('cancers', 'Disease', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('HER2', 'Gene', '2064', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('triple-negative', 'Var', (52, 67))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('NAC', 'Chemical', '-', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))
3079	31400007	HER2 overexpression was defined as fluorescent in situ hybridization ratio greater than 2.2 or copy number greater than 6.0, or 3+ IHC staining.	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('copy number greater than', 'Var', (95, 119))	('overexpression', 'PosReg', (5, 19))
3100	31400007	For the 12 patients with an FN MRI after NAC (rCR on MRI and positive pathology), the T and N categories of cancer found on the final pathology report and number of patients were: TisN0-2, T1aN0-5, T1cN0-1, T2N0-1, T3N0-2, and T0N1-1.	('TisN0-2', 'Var', (180, 187))	('T2N0-1', 'Var', (207, 213))	('T1aN0-5', 'Var', (189, 196))	('NAC', 'Chemical', '-', (41, 44))	('T1cN0-1', 'Var', (198, 205))	('rCR', 'Gene', (46, 49))	('T3N0-2', 'Var', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Disease', (108, 114))	('rCR', 'Gene', '117059', (46, 49))
3367	27334105	The fraction of assessments where all three readers disagreed was small: 5.1% overall, 2.0% for cases in the benign without atypia reference category, 12.0% for cases of atypia, 3.1% for DCIS, and 0.1% for invasive carcinoma.	('atypia', 'Var', (170, 176))	('invasive carcinoma', 'Disease', (206, 224))	('DCIS', 'Disease', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('invasive carcinoma', 'Disease', 'MESH:D009361', (206, 224))
3410	27861902	Genomic alterations implicated in breast cancer (43 somatic mutations, 45 amplifications, 62 deletions, and six multiple alterations, e.g.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('deletions', 'Var', (93, 102))
3418	27861902	For example, we investigated the association of TP53 mutation in tumours with marked nuclear pleomorphism as compared with tumours with small/moderate nuclear pleomorphism, or genes differentially expressed in tumours with DCIS as compared with tumours without DCIS.	('marked nuclear pleomorphism', 'Var', (78, 105))	('mutation', 'Var', (53, 61))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('DCIS', 'Phenotype', 'HP:0030075', (261, 265))	('tumours', 'Disease', 'MESH:D009369', (210, 217))	('tumours', 'Disease', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('TP53', 'Gene', '7157', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Disease', (245, 252))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('TP53', 'Gene', (48, 52))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('investigated', 'Reg', (16, 28))	('tumours', 'Disease', (123, 130))	('association', 'Interaction', (33, 44))	('tumours', 'Disease', (210, 217))
3430	27861902	Therefore, the presence of inflammation and necrosis, marked nuclear pleomorphism and medium/high mitotic counts are distinctly associated with the highly proliferative basal-like subtype (Table 4).	('marked nuclear pleomorphism', 'Var', (54, 81))	('necrosis', 'Disease', 'MESH:D009336', (44, 52))	('necrosis', 'Disease', (44, 52))	('associated', 'Reg', (128, 138))	('inflammation', 'Disease', 'MESH:D007249', (27, 39))	('inflammation', 'Disease', (27, 39))	('medium/high mitotic counts', 'CPA', (86, 112))	('highly proliferative basal-like subtype', 'CPA', (148, 187))
3433	27861902	These four morphological features also had 13 common downregulated genes involved in membrane signalling (CBLN4, ELFN1, LTBP3, LRP10, TENC1, and TPCN1), including GTPase activity (RAPGEF3 and TBC1D13), transcription (CAMTA2, CRY2, and LOC653501), the cytoskeleton (KIF13B), and lysosome positioning (C10orf32).	('KIF13B', 'Gene', '23303', (265, 271))	('CRY2', 'Gene', '1408', (225, 229))	('LTBP3', 'Gene', '4054', (120, 125))	('CRY2', 'Gene', (225, 229))	('RAPGEF3', 'Gene', '10411', (180, 187))	('CAMTA2', 'Gene', (217, 223))	('TPCN1', 'Gene', '53373', (145, 150))	('CBLN4', 'Gene', '140689', (106, 111))	('C10orf32', 'Gene', (300, 308))	('GTPase', 'MPA', (163, 169))	('CAMTA2', 'Gene', '23125', (217, 223))	('CBLN4', 'Gene', (106, 111))	('KIF13B', 'Gene', (265, 271))	('TBC1D13', 'Gene', '54662', (192, 199))	('TPCN1', 'Gene', (145, 150))	('LRP10', 'Gene', (127, 132))	('C10orf32', 'Gene', '119032', (300, 308))	('ELFN1', 'Gene', '392617', (113, 118))	('LTBP3', 'Gene', (120, 125))	('downregulated', 'NegReg', (53, 66))	('RAPGEF3', 'Gene', (180, 187))	('ELFN1', 'Gene', (113, 118))	('TENC1', 'Gene', '23371', (134, 139))	('TBC1D13', 'Gene', (192, 199))	('TENC1', 'Gene', (134, 139))	('LRP10', 'Gene', '26020', (127, 132))	('LOC653501', 'Var', (235, 244))
3436	27861902	Other studies reported the association of TP53, 8q24.21 (MYC), 19q12 (CCNE1), 20p13.2 (ZNF217) and 9p21.3 (MTAP) with histologic grade.	('9p21.3', 'Var', (99, 105))	('TP53', 'Gene', '7157', (42, 46))	('MTAP', 'Gene', (107, 111))	('association', 'Interaction', (27, 38))	('TP53', 'Gene', (42, 46))	('8q24.21', 'Var', (48, 55))	('MYC', 'Gene', '4609', (57, 60))	('ZNF217', 'Gene', (87, 93))	('20p13.2', 'Var', (78, 85))	('ZNF217', 'Gene', '7764', (87, 93))	('MTAP', 'Gene', '4507', (107, 111))	('CCNE1', 'Gene', '898', (70, 75))	('CCNE1', 'Gene', (70, 75))	('histologic grade', 'Disease', (118, 134))	('19q12', 'Var', (63, 68))	('MYC', 'Gene', (57, 60))
3437	27861902	However, when focussing on the individual components of histological grade, poorly differentiated epithelial tubules shared only a few molecular traits with medium/high mitotic counts and marked nuclear pleomorphism: TP53 mutation, high PAM50 proliferative score, basal-like subtype classified according to methylation, and microRNA data.	('TP53', 'Gene', '7157', (217, 221))	('mutation', 'Var', (222, 230))	('TP53', 'Gene', (217, 221))	('high PAM50 proliferative score', 'CPA', (232, 262))	('basal-like subtype', 'CPA', (264, 282))
3438	27861902	CDH1 mutation, PAM50 luminal A subtype, and inflammation gene sets), although there was no correlation between the two morphological features (supplementary material, Table S3B).	('CDH1', 'Gene', '999', (0, 4))	('inflammation', 'Disease', 'MESH:D007249', (44, 56))	('inflammation', 'Disease', (44, 56))	('mutation', 'Var', (5, 13))	('CDH1', 'Gene', (0, 4))
3441	27861902	LCISs are precursor lesions for ILCs, defined by the hallmark CDH1 loss-of-function mutation, and are almost exclusive to luminal A tumours.	('luminal A tumours', 'Disease', 'MESH:D009369', (122, 139))	('ILCs', 'Disease', (32, 36))	('CDH1', 'Gene', (62, 66))	('LCIS', 'Phenotype', 'HP:0030076', (0, 4))	('CDH1', 'Gene', '999', (62, 66))	('luminal A tumours', 'Disease', (122, 139))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('loss-of-function', 'NegReg', (67, 83))	('mutation', 'Var', (84, 92))
3443	27861902	The expression of HMGCS2, a breast apocrine carcinoma marker involved in the anabolic ketogenesis pathway, was increased by 8.6-fold in tumours with LCIS (supplementary material, Table S4B).	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('HMGCS2', 'Gene', '3158', (18, 24))	('increased', 'PosReg', (111, 120))	('HMGCS2', 'Gene', (18, 24))	('expression', 'MPA', (4, 14))	('tumours', 'Disease', (136, 143))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('breast apocrine carcinoma', 'Disease', (28, 53))	('LCIS', 'Phenotype', 'HP:0030076', (149, 153))	('breast apocrine carcinoma', 'Disease', 'MESH:D057091', (28, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('LCIS', 'Var', (149, 153))
3447	27861902	Mitochondrial dysfunction can lead to inflammation, tumorigenesis, dysregulation of cell-cell adhesion, discohesive morphology, and invasion.	('dysregulation', 'Var', (67, 80))	('lead to', 'Reg', (30, 37))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('discohesive morphology', 'CPA', (104, 126))	('cell-cell adhesion', 'CPA', (84, 102))	('tumorigenesis', 'CPA', (52, 65))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('inflammation', 'Disease', (38, 50))	('invasion', 'CPA', (132, 140))
3474	27861902	PAM50 proliferation scores were more highly correlated with medium/high mitotic count [Spearman's rho = 0.878 (ER-positive) and Spearman's rho = 0.919 (ER-negative)] and marked nuclear pleomorphism (rho = 0.852 and rho = 0.904) than with poorly differentiated epithelial tubules (rho = 0.351 and rho = 0.616) in ER-positive and ER-negative invasive breast cancers (p < 0.001).	('breast cancers', 'Phenotype', 'HP:0003002', (349, 363))	('invasive breast cancers', 'Disease', 'MESH:D001943', (340, 363))	('breast cancer', 'Phenotype', 'HP:0003002', (349, 362))	('medium/high mitotic count', 'CPA', (60, 85))	('cancers', 'Phenotype', 'HP:0002664', (356, 363))	('PAM50', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('invasive breast cancers', 'Disease', (340, 363))
3478	27861902	Inflammation, necrosis, medium/high mitotic count and marked nuclear pleomorphism frequently co-exist in breast tumours, are associated with basal-like subtypes, and have similar molecular bases.	('marked nuclear pleomorphism', 'Var', (54, 81))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('breast tumours', 'Disease', (105, 119))	('necrosis', 'Disease', (14, 22))	('associated', 'Reg', (125, 135))	('medium/high', 'Var', (24, 35))	('Inflammation', 'Disease', (0, 12))	('necrosis', 'Disease', 'MESH:D009336', (14, 22))	('breast tumours', 'Disease', 'MESH:D001943', (105, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))
3498	26041550	Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS.	('c-src', 'Gene', (123, 128))	('LCIS', 'Disease', (158, 162))	('LCIS', 'Phenotype', 'HP:0030076', (158, 162))	('c-src', 'Gene', '6714', (123, 128))	('PIK3CA', 'Gene', '5290', (112, 118))	('E-cadherin', 'Gene', '999', (18, 28))	('altered', 'Reg', (147, 154))	('PIK3CA', 'Gene', (112, 118))	('E-cadherin', 'Gene', (18, 28))	('Disruption', 'Var', (0, 10))
3518	26041550	These two studies posited that it was unlikely that invasive cancer in one breast progressed from a pre-invasive lesion in the opposite breast, and LCIS was, therefore, merely a risk factor for the development of breast cancer in both breasts.	('invasive cancer', 'Disease', 'MESH:D009362', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('LCIS', 'Phenotype', 'HP:0030076', (148, 152))	('breast cancer', 'Disease', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('LCIS', 'Var', (148, 152))	('invasive cancer', 'Disease', (52, 67))	('one breast', 'Phenotype', 'HP:0012813', (71, 81))
3521	26041550	These studies, combined with genomic clonality studies comparing LCIS and IBC, support a non-obligate precursor role of LCIS, in addition to being a risk factor for IBC.	('LCIS', 'Phenotype', 'HP:0030076', (120, 124))	('IBC', 'Chemical', '-', (74, 77))	('LCIS', 'Phenotype', 'HP:0030076', (65, 69))	('LCIS', 'Var', (120, 124))	('IBC', 'Chemical', '-', (165, 168))	('IBC', 'Disease', (165, 168))
3525	26041550	Andrade and colleagues also reached this conclusion comparing single nucleotide polymorphism (SNP) DNA microarrays of matched LCIS and synchronous lesions.	('synchronous lesions', 'Disease', (135, 154))	('single nucleotide polymorphism', 'Var', (62, 92))	('LCIS', 'Phenotype', 'HP:0030076', (126, 130))	('synchronous lesions', 'Disease', 'MESH:D009378', (135, 154))
3547	26041550	The apocrine variant of PLCIS is shown to have more genetic instability, and it is the most likely to have amplified HER2.	('HER2', 'Gene', (117, 121))	('apocrine', 'Gene', (4, 12))	('HER2', 'Gene', '2064', (117, 121))	('LCIS', 'Phenotype', 'HP:0030076', (25, 29))	('amplified', 'PosReg', (107, 116))	('genetic instability', 'MPA', (52, 71))	('variant', 'Var', (13, 20))	('PLCIS', 'Gene', (24, 29))
3553	26041550	LIN2 lesions have acini that are distended but not fused, corresponding to CLCIS lesions.	('lesions', 'Var', (5, 12))	('CLCIS', 'Disease', (75, 80))	('LCIS', 'Phenotype', 'HP:0030076', (76, 80))	('LIN2', 'Gene', (0, 4))	('CLCIS', 'Chemical', '-', (75, 80))	('LIN2', 'Gene', '8573', (0, 4))
3571	26041550	Intriguingly, a recent study showed an inverse relationship between ER/PR status and Ki67 proliferation rate in ductal cancer but not in lobular cancer, such that ER-negative status did not correlate with high Ki67 in invasive lobular cancers whereas it did with invasive ductal cancers.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PR', 'Gene', '5241', (71, 73))	('invasive ductal cancers', 'Disease', (263, 286))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('invasive lobular cancers', 'Disease', 'MESH:D013274', (218, 242))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('high Ki67', 'Var', (205, 214))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('lobular cancer', 'Disease', 'MESH:D013274', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lobular cancer', 'Phenotype', 'HP:0030076', (227, 241))	('ER', 'Gene', '2099', (163, 165))	('lobular cancer', 'Disease', (137, 151))	('Ki67', 'Gene', (85, 89))	('invasive lobular cancers', 'Disease', (218, 242))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('invasive ductal cancers', 'Disease', 'MESH:D018270', (263, 286))	('ER', 'Gene', '2099', (68, 70))	('Ki67', 'Chemical', '-', (85, 89))	('cancer', 'Disease', (235, 241))	('Ki67', 'Chemical', '-', (210, 214))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('Ki67', 'Var', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lobular cancer', 'Phenotype', 'HP:0030076', (137, 151))	('lobular cancer', 'Disease', 'MESH:D013274', (227, 241))
3580	26041550	Amplification of c-erbB-2 (HER2) is a marker of poor prognosis in patients with IBC.	('IBC', 'Disease', (80, 83))	('Amplification', 'Var', (0, 13))	('c-erbB-2', 'Gene', (17, 25))	('c-erbB-2', 'Gene', '2064', (17, 25))	('patients', 'Species', '9606', (66, 74))	('HER2', 'Gene', (27, 31))	('IBC', 'Chemical', '-', (80, 83))	('HER2', 'Gene', '2064', (27, 31))
3589	26041550	In LCIS, p53 overexpression (reflecting protein stabilization as result of mutation) has been shown to be relatively low, ranging from 0 to 19 % using immunohistochemistry.	('LCIS', 'Phenotype', 'HP:0030076', (3, 7))	('mutation', 'Var', (75, 83))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('overexpression', 'PosReg', (13, 27))
3600	26041550	Loss of chromosome 16q, combined with mutations often resulting in premature stop codons and thus truncated proteins, transcriptional repression, and possibly gene promoter methylation, can lead to biallelic inactivation of CDH1.	('CDH1', 'Gene', (224, 228))	('premature stop codons', 'MPA', (67, 88))	('proteins', 'Protein', (108, 116))	('lead to', 'Reg', (190, 197))	('CDH1', 'Gene', '999', (224, 228))	('Loss', 'NegReg', (0, 4))	('mutations', 'Var', (38, 47))	('biallelic', 'MPA', (198, 207))
3602	26041550	Loss or amplification of 11q (containing the cyclin D1 gene) and loss of 8p are seen with a higher incidence in PLCIS compared with CLCIS.	('11q', 'Gene', (25, 28))	('loss', 'Var', (65, 69))	('amplification', 'Var', (8, 21))	('CLCIS', 'Chemical', '-', (132, 137))	('Loss', 'NegReg', (0, 4))	('PLCIS', 'Disease', (112, 117))	('cyclin D1', 'Gene', '595', (45, 54))	('LCIS', 'Phenotype', 'HP:0030076', (113, 117))	('LCIS', 'Phenotype', 'HP:0030076', (133, 137))	('cyclin D1', 'Gene', (45, 54))
3603	26041550	Furthermore, some FLCIS harbor amplification of 17q (spanning the gene encoding HER2), a finding seen less commonly in CLCIS.	('LCIS', 'Phenotype', 'HP:0030076', (120, 124))	('17q', 'Protein', (48, 51))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('LCIS', 'Phenotype', 'HP:0030076', (19, 23))	('FLCIS', 'Disease', (18, 23))	('CLCIS', 'Chemical', '-', (119, 124))	('amplification', 'Var', (31, 44))
3604	26041550	Results of aCGH experiments have shown that while most chromosomal changes in LCIS are not consistent, those that are most consistent (namely, 16q loss and 1q amplification) are found early in the progression to invasive disease.	('LCIS', 'Gene', (78, 82))	('invasive disease', 'Disease', (212, 228))	('invasive disease', 'Disease', 'MESH:D009362', (212, 228))	('16q loss', 'Var', (143, 151))	('LCIS', 'Phenotype', 'HP:0030076', (78, 82))
3606	26041550	There is evidence that germline polymorphisms in the CDH1 gene (E-cadherin) predispose women to LCIS, and LCIS was also found in some patients with CDH1-related hereditary diffuse gastric cancer syndrome.	('LCIS', 'Phenotype', 'HP:0030076', (106, 110))	('germline', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('LCIS', 'Disease', (96, 100))	('hereditary diffuse gastric cancer syndrome', 'Disease', (161, 203))	('predispose', 'Reg', (76, 86))	('LCIS', 'Phenotype', 'HP:0030076', (96, 100))	('CDH1', 'Gene', (148, 152))	('patients', 'Species', '9606', (134, 142))	('E-cadherin', 'Gene', (64, 74))	('found', 'Reg', (120, 125))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (161, 203))	('CDH1', 'Gene', '999', (148, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('E-cadherin', 'Gene', '999', (64, 74))	('women', 'Species', '9606', (87, 92))	('CDH1', 'Gene', (53, 57))	('CDH1', 'Gene', '999', (53, 57))
3612	26041550	A SNP in LGR6 (rs6678914) showed specific associations with LCIS, and not with ILC.	('LGR6', 'Gene', '59352', (9, 13))	('rs6678914', 'Mutation', 'rs6678914', (15, 24))	('associations', 'Interaction', (42, 54))	('LGR6', 'Gene', (9, 13))	('rs6678914', 'Var', (15, 24))	('LCIS', 'Disease', (60, 64))	('LCIS', 'Phenotype', 'HP:0030076', (60, 64))
3613	26041550	Similarly, other variants had stronger effect sizes in LCIS compared with ILC - for example, SNPs at TOX3, ZNF365 and MLLT10 loci.	('TOX3', 'Gene', '27324', (101, 105))	('variants', 'Var', (17, 25))	('LCIS', 'Disease', (55, 59))	('MLLT10', 'Gene', '8028', (118, 124))	('ZNF365', 'Gene', '22891', (107, 113))	('LCIS', 'Phenotype', 'HP:0030076', (55, 59))	('ZNF365', 'Gene', (107, 113))	('MLLT10', 'Gene', (118, 124))	('TOX3', 'Gene', (101, 105))
3614	26041550	There were also SNPs that were more strongly associated with ILC compared with LCIS, including variants in the FGFR2 and MAP3K1 genes.	('LCIS', 'Phenotype', 'HP:0030076', (79, 83))	('FGFR2', 'Gene', (111, 116))	('FGFR2', 'Gene', '2263', (111, 116))	('associated', 'Reg', (45, 55))	('MAP3K1', 'Gene', (121, 127))	('ILC', 'Disease', (61, 64))	('variants', 'Var', (95, 103))	('MAP3K1', 'Gene', '4214', (121, 127))
3619	26041550	A combination of mechanisms has been shown to contribute to the loss of E-cadherin, including somatic mutations, chromosomal loss, epigenetic silencing, and transcriptional repression (Table 2).	('loss', 'NegReg', (64, 68))	('epigenetic silencing', 'Var', (131, 151))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('chromosomal loss', 'Var', (113, 129))	('transcriptional repression', 'CPA', (157, 183))
3623	26041550	There is some evidence that in normal epithelial tissues, TWIST is epigenetically silenced through hypermethylation of its promoter region and its overexpression in LCIS is at least in part a result of hypomethylation.	('LCIS', 'Phenotype', 'HP:0030076', (165, 169))	('hypomethylation', 'Var', (202, 217))	('overexpression', 'PosReg', (147, 161))	('hypermethylation', 'Var', (99, 115))	('TWIST', 'Gene', '7291', (58, 63))	('TWIST', 'Gene', (58, 63))
3632	26041550	Perhaps most frequently, PIK3CA activating point mutations, long implicated in tumorigenesis, are found in both in situ and invasive lobular.	('point mutations', 'Var', (43, 58))	('tumor', 'Disease', (79, 84))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('activating', 'PosReg', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
3633	26041550	In fact, in one study, 44 % (7 of 16 cases) of lobular neoplasias harbored activating PIK3CA mutations.	('mutations', 'Var', (93, 102))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (47, 64))	('lobular neoplasias', 'Disease', (47, 65))	('neoplasias', 'Phenotype', 'HP:0002664', (55, 65))	('PIK3CA', 'Gene', (86, 92))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('PIK3CA', 'Gene', '5290', (86, 92))	('lobular neoplasias', 'Disease', 'MESH:D009369', (47, 65))	('activating', 'PosReg', (75, 85))
3634	26041550	Such mutations are also found in ductal cancers, and are not unique to breast carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('breast carcinoma', 'Disease', 'MESH:D001943', (71, 87))	('ductal cancers', 'Disease', (33, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutations', 'Var', (5, 14))	('breast carcinoma', 'Phenotype', 'HP:0003002', (71, 87))	('found', 'Reg', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast carcinoma', 'Disease', (71, 87))	('ductal cancers', 'Disease', 'MESH:D009369', (33, 47))
3635	26041550	As a comparison, these point mutations were found in 10 out of 21 (48 %) cases of DCIS and 13 out of 37 (35 %) invasive carcinomas.	('point mutations', 'Var', (23, 38))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('found', 'Reg', (44, 49))	('invasive carcinomas', 'Disease', (111, 130))	('invasive carcinomas', 'Disease', 'MESH:D009361', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('DCIS', 'Disease', (82, 86))
3654	26041550	aCGH array comparative genome hybridization ALH atypical lobular hyperplasia CLCIS classical lobular carcinoma in situ  COX-2 cyclooxygenase-2 DCIS ductal carcinoma in situ  EMT epithelial to mesenchymal transition ER estrogen receptor FLCIS florid lobular carcinoma in situ  IBC invasive breast cancer IDC invasive ductal cancer ILC invasive lobular carcinoma LCIS lobular carcinoma in situ  LIN lobular intraepithelial neoplasia LN lobular neoplasia PLCIS pleomorphic lobular carcinoma in situ  PR progesterone receptor SNP single nucleotide polymorphism TDLU terminal duct lobular unit	('lobular carcinoma', 'Disease', 'MESH:D018275', (366, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('LIN', 'Disease', (393, 396))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (93, 118))	('lobular carcinoma', 'Disease', (366, 383))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (101, 118))	('LCIS', 'Phenotype', 'HP:0030076', (237, 241))	('LN', 'Phenotype', 'HP:0030076', (431, 433))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (405, 430))	('single nucleotide polymorphism', 'Var', (526, 556))	('ER', 'Gene', '2099', (215, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('lobular hyperplasia', 'Disease', (57, 76))	('COX-2', 'Gene', '5743', (120, 125))	('pleomorphic lobular carcinoma', 'Disease', 'MESH:D018275', (458, 487))	('cyclooxygenase-2', 'Gene', '5743', (126, 142))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (343, 360))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (148, 172))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (249, 266))	('lobular intraepithelial neoplasia', 'Disease', 'MESH:D019048', (397, 430))	('lobular neoplasia', 'Disease', 'MESH:D009369', (434, 451))	('invasive ductal cancer', 'Disease', 'MESH:D018270', (307, 329))	('invasive ductal cancer', 'Disease', (307, 329))	('lobular intraepithelial neoplasia', 'Disease', (397, 430))	('lobular carcinoma', 'Disease', 'MESH:D018275', (93, 110))	('LIN', 'Disease', 'None', (393, 396))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (155, 172))	('PR', 'Gene', '5241', (497, 499))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (470, 487))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (249, 274))	('LCIS', 'Phenotype', 'HP:0030076', (361, 365))	('lobular carcinoma', 'Disease', (93, 110))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (57, 76))	('estrogen receptor', 'Gene', (218, 235))	('cyclooxygenase-2', 'Gene', (126, 142))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (470, 495))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (478, 495))	('lobular neoplasia', 'Disease', (434, 451))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (257, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('ALH', 'Chemical', '-', (44, 47))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (366, 383))	('IBC', 'Chemical', '-', (276, 279))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (334, 360))	('neoplasia', 'Phenotype', 'HP:0002664', (421, 430))	('lobular carcinoma', 'Disease', 'MESH:D018275', (249, 266))	('progesterone receptor', 'Gene', (500, 521))	('CLCIS', 'Chemical', '-', (77, 82))	('progesterone receptor', 'Gene', '5241', (500, 521))	('lobular carcinoma', 'Disease', 'MESH:D018275', (343, 360))	('breast cancer', 'Phenotype', 'HP:0003002', (289, 302))	('invasive breast cancer', 'Disease', (280, 302))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (148, 172))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (366, 391))	('lobular carcinoma', 'Disease', (249, 266))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (374, 391))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (434, 451))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('pleomorphic lobular carcinoma', 'Disease', (458, 487))	('invasive lobular carcinoma', 'Disease', (334, 360))	('invasive breast cancer', 'Disease', 'MESH:D001943', (280, 302))	('lobular carcinoma', 'Disease', 'MESH:D018275', (470, 487))	('LCIS', 'Phenotype', 'HP:0030076', (453, 457))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('neoplasia', 'Phenotype', 'HP:0002664', (442, 451))	('COX-2', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (93, 110))	('TDLU', 'Chemical', '-', (557, 561))	('LCIS', 'Phenotype', 'HP:0030076', (78, 82))	('ductal carcinoma in situ', 'Disease', (148, 172))	('estrogen receptor', 'Gene', '2099', (218, 235))
3687	22665978	The advantages of the MCF10 series of cell lines include their derivation from a single biopsy and subsequent mutations forming cell lines of ranging metastatic ability.	('MCF10', 'Gene', (22, 27))	('mutations', 'Var', (110, 119))	('MCF10', 'CellLine', 'CVCL:5555', (22, 27))
3692	22665978	AT cells were derived from a 100-day-old MCF10AneoT lesion that formed a squamous carcinoma but failed to produce carcinomas when injected back into mice.	('MCF10A', 'CellLine', 'CVCL:0598', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('MCF10AneoT', 'Var', (41, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('carcinomas', 'Disease', (114, 124))	('squamous carcinoma', 'Disease', 'MESH:D002294', (73, 91))	('carcinomas', 'Disease', 'MESH:D002277', (114, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('squamous carcinoma', 'Disease', (73, 91))	('mice', 'Species', '10090', (149, 153))	('AT', 'Disease', 'None', (0, 2))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (73, 91))
3865	28795370	The simulated active surveillance scenario was based on a diagnosis with low to intermediate nuclear grade DCIS at age 60 years, regular follow-up screening for detection of invasive disease (every 6-months, 80% sensitivity), and usual care treatment (as reported in SEER) upon detection of a cancer.	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('ER', 'Gene', '2099', (269, 271))	('invasive disease', 'Disease', 'MESH:D009362', (174, 190))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('low', 'Var', (73, 76))	('invasive disease', 'Disease', (174, 190))
3872	28795370	High nuclear grade, ER negative, and PR negative status were associated with upstaging to invasive disease (all p<0.01).	('upstaging', 'Disease', (77, 86))	('invasive disease', 'Disease', (90, 106))	('High nuclear', 'Var', (0, 12))	('PR', 'Gene', '5241', (37, 39))	('invasive disease', 'Disease', 'MESH:D009362', (90, 106))	('ER', 'Gene', '2099', (20, 22))
3961	27501902	In these cases, it should be noted that ADC values were significantly lower (p<0.001, adjusted p value = 0.005) for cancers with LVI compared to those in which LVI was absent (LVI status available for 93 cases) (Figure 2c).	('LVI', 'Chemical', '-', (176, 179))	('ADC', 'MPA', (40, 43))	('LVI', 'Chemical', '-', (160, 163))	('lower', 'NegReg', (70, 75))	('LVI', 'Chemical', '-', (129, 132))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('LVI', 'Var', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
4083	26458964	Women who are pregnant, have a known BRCA 1/2 mutation or who had a previous diagnosis of breast cancer or DCIS (irrespective if ipsi- or contralateral) are not eligible.	('Women', 'Species', '9606', (0, 5))	('DCIS', 'Disease', (107, 111))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('BRCA 1', 'Gene', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('BRCA 1', 'Gene', '672', (37, 43))	('mutation', 'Var', (46, 54))
4288	25668012	Although the number of women randomised into the three method groups were virtually identical (Figure 1), among the 12 519 participants who finished the initial screening, the ultrasound group had a significantly higher follow-up rate (n=4214, 94.8%) than those in the mammography group (n=4170, 93.8%) or women in the combined group (n=4135, 93.0%) (P<0.01).	('women', 'Species', '9606', (306, 311))	('women', 'Species', '9606', (23, 28))	('follow-up rate', 'CPA', (220, 234))	('participants', 'Species', '9606', (123, 135))	('higher', 'PosReg', (213, 219))	('ultrasound', 'Var', (176, 186))
4347	18785004	Accordingly, the progression of breast cancer can be characterized by the accumulation of genetic mutations in critical genes accompanied by histological progression from normal epithelium to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS) to the development of an invasive breast carcinoma.	('genetic mutations', 'Var', (90, 107))	('breast cancer', 'Disease', (32, 45))	('DCIS', 'Phenotype', 'HP:0030075', (256, 260))	('breast carcinoma', 'Phenotype', 'HP:0003002', (296, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (201, 219))	('ductal carcinoma', 'Disease', 'MESH:D044584', (230, 246))	('ductal carcinoma', 'Disease', (230, 246))	('breast carcinoma', 'Disease', (296, 312))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ductal hyperplasia', 'Disease', (201, 219))	('breast carcinoma', 'Disease', 'MESH:D001943', (296, 312))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (230, 254))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
4349	18785004	However, telomeres can be critically shortened, and thereby become dysfunctional, by several mechanisms, including incomplete replication of the lagging strand during DNA synthesis, loss or alterations of the telomere-binding proteins involved in telomere maintenance, and DNA damage induced by oxidative stress.	('loss', 'NegReg', (182, 186))	('oxidative stress', 'Phenotype', 'HP:0025464', (295, 311))	('alterations', 'Var', (190, 201))	('dysfunctional', 'Disease', 'MESH:D006331', (67, 80))	('telomere-binding proteins', 'Protein', (209, 234))	('dysfunctional', 'Disease', (67, 80))	('shortened', 'NegReg', (37, 46))
4351	18785004	Abnormalities in telomere length are early and frequent events in the malignant transformation of numerous types of carcinomas.	('carcinomas', 'Disease', (116, 126))	('Abnormalities', 'Var', (0, 13))	('telomere', 'Protein', (17, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))
4352	18785004	In breast, telomere shortening has been observed in invasive carcinomas, in situ lesions, and histologically normal tissue proximal to breast tumors.	('situ lesions', 'Disease', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('breast tumors', 'Disease', (135, 148))	('breast tumors', 'Disease', 'MESH:D001943', (135, 148))	('situ lesions', 'Disease', 'MESH:D002278', (76, 88))	('telomere shortening', 'Var', (11, 30))	('invasive carcinomas', 'Disease', (52, 71))	('invasive carcinomas', 'Disease', 'MESH:D009361', (52, 71))	('observed', 'Reg', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('telomere shortening', 'Phenotype', 'HP:0031413', (11, 30))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('breast tumors', 'Phenotype', 'HP:0100013', (135, 148))	('breast tumor', 'Phenotype', 'HP:0100013', (135, 147))
4360	18785004	To evaluate the link between telomere dysfunction and the generation of allelic imbalance in the progression of breast cancer, we assessed alterations in TC and the extent of AI in a continuum of breast tissues ranging from histologically normal tissue derived from reduction mammoplasty, to ADH, DCIS and invasive carcinomas ranging from Stage I to IIIA.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('imbalance', 'Phenotype', 'HP:0002172', (80, 89))	('breast cancer', 'Disease', (112, 125))	('TC', 'Chemical', '-', (154, 156))	('invasive carcinomas', 'Disease', (306, 325))	('invasive carcinomas', 'Disease', 'MESH:D009361', (306, 325))	('alterations', 'Var', (139, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('carcinomas', 'Phenotype', 'HP:0030731', (315, 325))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('DCIS', 'Phenotype', 'HP:0030075', (297, 301))
4379	18785004	Each multiplex PCR reaction amplifies 16 short tandem repeat (STR) microsatellite loci from independent locations in the genome (Amelogenin, CSF1PO, D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, FGA, TH01, TPOX and vWA).	('D16S539', 'Var', (201, 208))	('D2S1338', 'Var', (149, 156))	('D7S820', 'Var', (175, 181))	('D5S818', 'Var', (167, 173))	('D13S317', 'Var', (192, 199))	('CSF1PO', 'Var', (141, 147))	('FGA', 'Gene', (235, 238))	('D21S11', 'Var', (227, 233))	('D18S51', 'Var', (210, 216))	('D19S433', 'Var', (218, 225))	('TPOX', 'Disease', (246, 250))	('D8S1179', 'Var', (183, 190))	('D3S1358', 'Var', (158, 165))	('FGA', 'Gene', '2243', (235, 238))
4422	18785004	In contrast, the assay used in this study is based on AI at 16 random microsatellite regions that have no known involvement in the development of breast cancer, and thus reflect genomic instability independent of their linkage to genes involved with breast tumorigenesis.	('breast tumor', 'Disease', 'MESH:D001943', (250, 262))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('breast tumor', 'Disease', (250, 262))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('microsatellite regions', 'Var', (70, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('breast tumor', 'Phenotype', 'HP:0100013', (250, 262))
4425	18785004	TC alterations and increased AI) as invasive carcinomas; thus supporting the notion that invasive carcinomas evolve from or in parallel with DCIS.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('TC', 'Chemical', '-', (0, 2))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('invasive carcinomas', 'Disease', (36, 55))	('invasive carcinomas', 'Disease', 'MESH:D009361', (36, 55))	('alterations', 'Var', (3, 14))	('invasive carcinomas', 'Disease', (89, 108))	('invasive carcinomas', 'Disease', 'MESH:D009361', (89, 108))
4441	26119102	However, participants in ECOG 5194 were highly selected for having DCIS with an expected low risk of LR.	('ECOG', 'Var', (25, 29))	('DCIS', 'Disease', (67, 71))	('participants', 'Species', '9606', (9, 21))
4474	26119102	In E5194 the 10-year LR rate among cases with low- or intermediate-grade DCIS and tumor size <= 2.5 cm was 14.6 and 19.0 % for those with small (<=1 cm) high-grade DCIS.	('DCIS', 'Disease', (73, 77))	('E5194', 'Var', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
4480	26119102	The 10-year risk of LR was 33.6 % for those with multifocality compared to 15.5 % for those without multifocal disease (adjusted HR 1.97; 95 % CI 1.27, 3.02; P = 0.003).	('multifocal disease', 'Disease', 'None', (100, 118))	('multifocality', 'Var', (49, 62))	('multifocal disease', 'Disease', (100, 118))
4608	16280035	The signaling pathways activated by PyV-mT include those of Ras, Shc, and phosphotidylinositol 3-kinase, which are frequently activated in human breast cancer (reviewed in) and are also activated by ErbB2 (Her2/neu), a receptor tyrosine kinase that is overexpressed in 30% of breast cancer and is associated with poor outcome.	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('breast cancer', 'Disease', (276, 289))	('activated', 'PosReg', (186, 195))	('Her2/neu', 'Gene', (206, 214))	('Shc', 'Gene', '6464', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('PyV-mT', 'Var', (36, 42))	('ErbB2', 'Gene', (199, 204))	('signaling pathways', 'Pathway', (4, 22))	('Her2/neu', 'Gene', '2064', (206, 214))	('Shc', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('human', 'Species', '9606', (139, 144))	('Ras', 'Gene', (60, 63))	('activated', 'PosReg', (126, 135))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('phosphotidylinositol 3-kinase', 'MPA', (74, 103))
4832	29273956	Four studies examined social outcomes of DCIS diagnosis and found that women reported a high degree of social support and women with DCIS reported less withdrawal from close family/friends (5% vs. 11%, p = 0.08) and strain on interpersonal relationships (0% vs. 6%, p = 0.02) compared with women with early invasive breast cancer.	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('invasive breast cancer', 'Disease', 'MESH:D001943', (307, 329))	('DCIS', 'Var', (133, 137))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('withdrawal', 'CPA', (152, 162))	('women', 'Species', '9606', (71, 76))	('women', 'Species', '9606', (122, 127))	('women', 'Species', '9606', (290, 295))	('less', 'NegReg', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('invasive breast cancer', 'Disease', (307, 329))	('person', 'Species', '9606', (231, 237))	('social support', 'CPA', (103, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (316, 329))
4848	29273956	In another study, 26 women who were interviewed said that they would feel concern regardless of the term used to describe DCIS but preferred the term abnormal cells over other terms such as carcinoma, and expressed interest in active surveillance over immediate treatment provided monitoring was very frequent.	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('carcinoma', 'Disease', 'MESH:D002277', (190, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('abnormal cells', 'Var', (150, 164))	('carcinoma', 'Disease', (190, 199))	('women', 'Species', '9606', (21, 26))
4986	28394473	CYC1 immunoreactivity was detected in 40% of DCIS cases, and the immunohistochemical CYC1 status was significantly associated with tumor size, nuclear grade, comedo necrosis, van Nuys classification, and Ki-67 labeling index.	('necrosis', 'Disease', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('Ki-67', 'Gene', '17345', (204, 209))	('van Nuys classification', 'CPA', (175, 198))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('necrosis', 'Disease', 'MESH:D009336', (165, 173))	('Ki-67', 'Gene', (204, 209))	('associated', 'Reg', (115, 125))	('tumor', 'Disease', (131, 136))	('nuclear grade', 'CPA', (143, 156))	('comedo', 'Phenotype', 'HP:0025249', (158, 164))	('CYC1', 'Var', (85, 89))
5019	28394473	The primer sequences of CYC1 and RPL13A were: CYC1 (NM_001916), 5'-GAGGTGGAGGTTCAAGACGG-3' (forward) and 5'-TAGCTCGCACGATGTAGCTG-3' (reverse)19; and RPL13A (NM_012423), 5'-CCTGGAGGAGAAGAGGAAAGAGA-3' (forward) and 5'-TTGAGGACCTCTGTGTATTTGTCAA-3' (reverse).	('RPL13A', 'Gene', '23521', (33, 39))	('NM_012423', 'Var', (157, 166))	('RPL13A', 'Gene', (149, 155))	('RPL13A', 'Gene', (33, 39))	('RPL13A', 'Gene', '23521', (149, 155))
5031	28394473	The CYC1 status was significantly associated with tumor size (P = 0.048), nuclear grade (P = 0.032), comedo necrosis (P = 0.0065), van Nuys classification (P = 0.0021), and Ki-67 LI (P = 0.011).	('associated', 'Reg', (34, 44))	('Ki-67', 'Gene', '17345', (173, 178))	('necrosis', 'Disease', (108, 116))	('nuclear grade', 'CPA', (74, 87))	('CYC1 status', 'Var', (4, 15))	('comedo', 'Phenotype', 'HP:0025249', (101, 107))	('van Nuys classification', 'CPA', (131, 154))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Ki-67', 'Gene', (173, 178))	('necrosis', 'Disease', 'MESH:D009336', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
5048	28394473	The CYC1 status was significantly associated with nuclear atypia, comedo necrosis, and van Nuys classification in the DCIS cases.	('associated', 'Reg', (34, 44))	('nuclear atypia', 'Disease', (50, 64))	('necrosis', 'Disease', (73, 81))	('CYC1 status', 'Var', (4, 15))	('comedo', 'Phenotype', 'HP:0025249', (66, 72))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('necrosis', 'Disease', 'MESH:D009336', (73, 81))	('van Nuys classification', 'Disease', (87, 110))
5055	28394473	Previously, Li et al.10 reported that CYC1 silencing by shRNA transfection inhibited proliferation activity of osteosarcoma cells in vitro and suppressed tumor growth in a mouse xenograft model in vivo.	('CYC1', 'Gene', (38, 42))	('mouse', 'Species', '10090', (172, 177))	('shRNA', 'Gene', (56, 61))	('silencing', 'NegReg', (43, 52))	('suppressed', 'NegReg', (143, 153))	('inhibited', 'NegReg', (75, 84))	('proliferation activity', 'CPA', (85, 107))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('transfection', 'Var', (62, 74))	('tumor', 'Disease', (154, 159))
5056	28394473	Han et al.11 also showed that silencing CYC1 suppressed proliferation of invasive breast carcinoma cells (MDA-MB-231), consistent with our present results.	('carcinoma cells', 'Disease', 'MESH:C538614', (89, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma cells', 'Disease', (89, 104))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (106, 116))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (73, 98))	('proliferation', 'CPA', (56, 69))	('suppressed', 'NegReg', (45, 55))	('breast carcinoma', 'Phenotype', 'HP:0003002', (82, 98))	('invasive breast carcinoma', 'Disease', (73, 98))	('CYC1', 'Gene', (40, 44))	('silencing', 'Var', (30, 39))
5064	28394473	In summary, we examined gene expression profiles of comedo DCIS using microarray analysis and showed that CYC1 is associated with comedo necrosis.	('necrosis', 'Disease', 'MESH:D009336', (137, 145))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('comedo', 'Phenotype', 'HP:0025249', (130, 136))	('associated', 'Reg', (114, 124))	('CYC1', 'Var', (106, 110))	('necrosis', 'Disease', (137, 145))	('comedo', 'Phenotype', 'HP:0025249', (52, 58))
5066	28394473	In vitro studies indicated that CYC1 was associated with mitochondrial membrane potential, increased proliferation activity, and increased pro-apoptotic caspase 3 activity under hypoxia.	('CYC1', 'Var', (32, 36))	('hypoxia', 'Disease', (178, 185))	('increased', 'PosReg', (129, 138))	('caspase 3', 'Gene', (153, 162))	('pro-apoptotic', 'CPA', (139, 152))	('activity', 'MPA', (163, 171))	('caspase 3', 'Gene', '836', (153, 162))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('increased', 'PosReg', (91, 100))	('mitochondrial membrane potential', 'MPA', (57, 89))	('proliferation activity', 'CPA', (101, 123))
5067	28394473	These results suggest that CYC1 plays an important role in cell proliferation and comedo necrosis by increasing OXPHOS activity in human DCIS.	('necrosis', 'Disease', (89, 97))	('increasing', 'PosReg', (101, 111))	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('human', 'Species', '9606', (131, 136))	('OXPHOS activity', 'MPA', (112, 127))	('comedo', 'Phenotype', 'HP:0025249', (82, 88))	('CYC1', 'Var', (27, 31))
5171	18636423	Prophylactic mastectomy (PM) is one of the few evidence-based, risk-reducing options open to female carriers of BRCA1/2 mutations  whose breast cancer risks are between 56% and 85%.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('BRCA1/2', 'Gene', (112, 119))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BRCA1/2', 'Gene', '672;675', (112, 119))
5173	18636423	In the U.S. and Canada, acceptance of PM has been between 0% and 36%  among BRCA1/2 mutation carriers.	('carriers', 'Reg', (93, 101))	('BRCA1/2', 'Gene', (76, 83))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('mutation', 'Var', (84, 92))
5180	18636423	Stress may be heightened for some newly-diagnosed women offered the option to undergo BRCA1/2 testing at the time of diagnosis, with the intention of providing information on their mutation status within a few weeks so that it can be used in treatment decision making, including decisions about whether to undergo prophylactic mastectomy of their unaffected breast .	('BRCA1/2', 'Gene', (86, 93))	('testing', 'Var', (94, 101))	('Stress', 'Disease', (0, 6))	('BRCA1/2', 'Gene', '672;675', (86, 93))	('used', 'Reg', (234, 238))	('women', 'Species', '9606', (50, 55))	('Stress', 'Disease', 'MESH:D004194', (0, 6))
5204	18636423	The questionnaire solicited information about demographic characteristics, personal (if any) and family cancer history, PM surgical history (if appropriate), and whether or not there was a known BRCA1/2 mutation in their family.	('BRCA1/2', 'Gene', (195, 202))	('BRCA1/2', 'Gene', '672;675', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutation', 'Var', (203, 211))	('person', 'Species', '9606', (75, 81))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
5220	18636423	healthy women (n=21) with significant family history of breast cancer, and/or a known or suspected BRCA mutation who were considering bilateral PM.	('BRCA', 'Gene', (99, 103))	('women', 'Species', '9606', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('mutation', 'Var', (104, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('BRCA', 'Gene', '672', (99, 103))
5244	18636423	As expected, a much higher percentage of participants in the COPM group were aware of the presence of a BRCA1/2 mutation in their families than was the case for the other 2 groups.	('BRCA1/2', 'Gene', (104, 111))	('mutation', 'Var', (112, 120))	('COPM', 'Chemical', '-', (61, 65))	('BRCA1/2', 'Gene', '672;675', (104, 111))	('participants', 'Species', '9606', (41, 53))
5247	18636423	In the UPM group, 9% (n=4) of the women said there was a known BRCA1/2 mutation in their family.	('mutation', 'Var', (71, 79))	('BRCA1/2', 'Gene', '672;675', (63, 70))	('aid', 'Gene', (41, 44))	('aid', 'Gene', '57379', (41, 44))	('women', 'Species', '9606', (34, 39))	('UPM', 'Chemical', '-', (7, 10))	('BRCA1/2', 'Gene', (63, 70))
5250	18636423	In the COPM group, 46% of the women (n=17) said that a specific BRCA1/2 mutation had been found in one or more of their relatives.	('aid', 'Gene', (44, 47))	('women', 'Species', '9606', (30, 35))	('COPM', 'Chemical', '-', (7, 11))	('aid', 'Gene', '57379', (44, 47))	('BRCA1/2', 'Gene', (64, 71))	('mutation', 'Var', (72, 80))	('BRCA1/2', 'Gene', '672;675', (64, 71))
5332	18636423	has commented that genetic counseling and testing will result in there being, "many persons who will not suffer from a psychiatric disorder per se, but who face a complex problem that leads to a variety of thoughts, feelings and behaviors that need to be understood in the context of the person's history.	('result in', 'Reg', (55, 64))	('persons', 'Species', '9606', (84, 91))	('person', 'Species', '9606', (84, 90))	('psychiatric disorder', 'Disease', (119, 139))	('leads to', 'Reg', (184, 192))	('genetic counseling', 'Var', (19, 37))	('person', 'Species', '9606', (288, 294))	('psychiatric disorder', 'Phenotype', 'HP:0000708', (119, 139))	('testing', 'Var', (42, 49))	('psychiatric disorder', 'Disease', 'MESH:D001523', (119, 139))
5356	18636423	As PM is more widely offered to an increasing number of BRCA1/2 mutation carriers, there may be an even greater need for psychological consultation for women who may not have other opportunities to discuss the option of PM with friends, colleagues, or relatives who are medical professionals.	('women', 'Species', '9606', (152, 157))	('BRCA1/2', 'Gene', (56, 63))	('BRCA1/2', 'Gene', '672;675', (56, 63))	('mutation', 'Var', (64, 72))
5360	18636423	This suggests a need for additional specialized training of psycho-oncologists, who could provide targeted psychological services to the growing number of BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', '672;675', (155, 162))	('mutation', 'Var', (163, 171))	('BRCA1/2', 'Gene', (155, 162))
5389	18636423	Cancer genetic testing offers the potential to reduce mortality and morbidity among women at increased hereditary risk for cancer by offering targeted risk reduction measures, such as PM.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('women', 'Species', '9606', (84, 89))	('reduce', 'NegReg', (47, 53))	('genetic testing', 'Var', (7, 22))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (123, 129))
5397	27919043	Genetic factors, such as germline mutations in one of two breast cancer susceptibility genes, BRCA1 and BRCA2, increase the likelihood of developing DCIS.	('increase', 'PosReg', (111, 119))	('BRCA2', 'Gene', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('BRCA1', 'Gene', '672', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA2', 'Gene', '675', (104, 109))	('breast cancer', 'Disease', (58, 71))	('DCIS', 'Disease', (149, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRCA1', 'Gene', (94, 99))	('germline mutations', 'Var', (25, 43))
5398	27919043	Demographic data predict that 5% of women with DCIS carry a germline mutation in both genes.	('germline mutation', 'Var', (60, 77))	('DCIS', 'Disease', (47, 51))	('women', 'Species', '9606', (36, 41))
5422	27919043	Studies have shown that 50-60% of ERBB2/HER2 amplification/overexpression in DCIS is associated with poorly differentiated lesions and the high-grade comedo subtype.	('HER2', 'Gene', (40, 44))	('grade comedo', 'Phenotype', 'HP:0025250', (144, 156))	('HER2', 'Gene', '2064', (40, 44))	('poorly differentiated lesions', 'CPA', (101, 130))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('amplification/overexpression', 'Var', (45, 73))	('comedo', 'Phenotype', 'HP:0025249', (150, 156))	('amplification/overexpression', 'PosReg', (45, 73))	('DCIS', 'Disease', (77, 81))	('high-grade comedo', 'Disease', (139, 156))	('associated', 'Reg', (85, 95))
5449	27919043	Abnormal methylation, such as DNA hyper-methylation of tumour suppressor genes, is a powerful molecular mechanism by which cancer can be triggered and might be associated to pure DCIS progression.	('tumour', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pure DCIS', 'Disease', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('Abnormal', 'Var', (0, 8))	('cancer', 'Disease', (123, 129))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('methylation', 'MPA', (9, 20))	('associated', 'Reg', (160, 170))
5455	27919043	Epigenetic silencing via promoter hyper-methylation seems to be a crucial mechanism of the transcriptional repression in breast cancer.	('promoter hyper-methylation', 'Var', (25, 51))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Epigenetic silencing', 'Var', (0, 20))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
5467	27919043	Mutations in the TP53 and PIK3CA genes have also been identified in DCIS.	('PIK3CA', 'Gene', '5290', (26, 32))	('TP53', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (54, 64))	('DCIS', 'Disease', (68, 72))	('TP53', 'Gene', '7157', (17, 21))	('PIK3CA', 'Gene', (26, 32))
5468	27919043	Mutations in TP53 have been shown to occur more frequently in HG-DCIS compared with the LG subtype.	('TP53', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('occur', 'Reg', (37, 42))	('HG-DCIS', 'Disease', (62, 69))	('TP53', 'Gene', '7157', (13, 17))
5469	27919043	These mutations are also more frequent in HER2-positive tumours than in ER/PR-positive tumours and TN DCIS.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('tumours', 'Disease', (87, 94))	('HER2-positive tumours', 'Disease', 'MESH:D009369', (42, 63))	('HER2-positive tumours', 'Disease', (42, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('frequent', 'Reg', (30, 38))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('mutations', 'Var', (6, 15))
5470	27919043	However, TP53 mutation has not been associated with the risk of DCIS progression.	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('DCIS', 'Disease', (64, 68))	('mutation', 'Var', (14, 22))
5471	27919043	Mutations in the PIK3CA gene have been detected in both in situ and invasive matched breast samples; however, the lower frequency or absence of PIK3CA mutation detected in the invasive component of some matched DCIS and IBC samples suggested that PIK3CA mutation is most likely an early event in breast tumorigenesis and is unlikely to play a role in DCIS progression.	('breast tumorigenesis', 'Disease', (296, 316))	('PIK3CA', 'Gene', (247, 253))	('PIK3CA', 'Gene', (144, 150))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (144, 150))	('IBC', 'Chemical', '-', (220, 223))	('PIK3CA', 'Gene', '5290', (17, 23))	('PIK3CA', 'Gene', '5290', (247, 253))	('mutation', 'Var', (254, 262))
5479	27919043	Thus, E-cadherin down-regulation towards the progression of DCIS to invasive disease might be result of combination of both promoter hypermethylation and action of miRNA.	('promoter hypermethylation', 'Var', (124, 149))	('invasive disease', 'Disease', 'MESH:D009362', (68, 84))	('E-cadherin', 'Gene', (6, 16))	('DCIS', 'Disease', (60, 64))	('down-regulation', 'NegReg', (17, 32))	('E-cadherin', 'Gene', '999', (6, 16))	('invasive disease', 'Disease', (68, 84))
5488	27919043	CAFs can promote the tumorigenic conversion of epithelial cells, whereas fibroblasts derived from normal tissue suppress this transition, reinforcing the existence of molecular modification of fibroblasts induced by epithelial tumour cells.	('promote', 'PosReg', (9, 16))	('CAFs', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('epithelial tumour', 'Disease', 'MESH:D000077216', (216, 233))	('CAFs', 'Chemical', '-', (0, 4))	('epithelial tumour', 'Disease', (216, 233))	('tumorigenic conversion of epithelial cells', 'CPA', (21, 63))	('epithelial tumour', 'Phenotype', 'HP:0031492', (216, 233))
5672	16465174	Similarly, when sensitivity is set to 100%, the specificity displayed by the change in %WMRS at TP2 is 50% (3/6; 95% CI=12-88%), which suggests that this fraction of SD cases can be accurately predicted, that is, at 100% negative predictive value (NPV) by this variable.	('TP2', 'Gene', (96, 99))	('change', 'Var', (77, 83))	('MRS', 'Disease', (89, 92))	('negative predictive', 'NegReg', (221, 240))	('TP2', 'Gene', '7142', (96, 99))	('MRS', 'Disease', 'MESH:D008556', (89, 92))
5673	16465174	The results of Table 2 also suggest that the dominant factor in driving the observed changes in %WMRS at 135 ms (P=0.025) is the change in water T2 (P=0.006) as opposed to changes in the relative water and lipid concentrations, which would be reflected by changes in %WMRS at 30 ms (P=0.788) for which the effects of T2 would be much less.	('water', 'Chemical', 'MESH:D014867', (139, 144))	('MRS', 'Disease', 'MESH:D008556', (269, 272))	('lipid', 'Chemical', 'MESH:D008055', (206, 211))	('MRS', 'Disease', (98, 101))	('changes', 'Var', (85, 92))	('water', 'Chemical', 'MESH:D014867', (196, 201))	('MRS', 'Disease', 'MESH:D008556', (98, 101))	('MRS', 'Disease', (269, 272))	('water T2', 'MPA', (139, 147))
5674	16465174	Two separate analyses were conducted: one with MRI variables only (water T2 at TP0, PC20(tumour volume), D20(water T2) and PC20(%WMRS at 135 ms)) and one with both MRI and pathology data (PRS score and grade).	('water', 'Chemical', 'MESH:D014867', (67, 72))	('PC20', 'CellLine', 'CVCL:0152', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('water', 'Chemical', 'MESH:D014867', (109, 114))	('PC20', 'CellLine', 'CVCL:0152', (123, 127))	('PC20', 'Var', (123, 127))	('tumour', 'Disease', (89, 95))	('PC20', 'Var', (84, 88))	('MRS', 'Disease', (130, 133))	('water T2', 'Var', (67, 75))	('MRS', 'Disease', 'MESH:D008556', (130, 133))
5761	26080617	In contrast with MCF-7 cells, MDA-MB-468 cells showed that A1-7 treatment inhibited growth, survival and invasion, but TMX did not.	('invasion', 'CPA', (105, 113))	('inhibited', 'NegReg', (74, 83))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (30, 40))	('MCF-7', 'CellLine', 'CVCL:0031', (17, 22))	('A1-7', 'Var', (59, 63))	('growth', 'CPA', (84, 90))	('TMX', 'Chemical', 'MESH:D013629', (119, 122))
5765	26080617	Upon MAS1 knockdown, MAS1 expression disappeared in 4T1 cells (Fig.3b).	('expression', 'MPA', (26, 36))	('disappeared', 'NegReg', (37, 48))	('4T1', 'CellLine', 'CVCL:0125', (52, 55))	('MAS1', 'Gene', (5, 9))	('knockdown', 'Var', (10, 19))	('MAS1', 'Gene', (21, 25))
5773	26080617	In the in vitro study, CDDP or A1-7 treatment resulted in mild growth inhibition, whereas CDDP plus A1-7 co-treatment showed synergic inhibitory effects in 4T1 cells exposed to control siRNA (Fig.4c).	('CDDP', 'Var', (23, 27))	('CDDP', 'Chemical', '-', (90, 94))	('A1-7', 'Var', (31, 35))	('mild growth inhibition', 'Phenotype', 'HP:0001530', (58, 80))	('CDDP', 'Chemical', '-', (23, 27))	('growth inhibition', 'CPA', (63, 80))	('4T1', 'CellLine', 'CVCL:0125', (156, 159))
5777	26080617	In contrast, the tumors in mice treated with MAS1 siRNA were larger than those in mice treated with control siRNA, and CDDP showed less pronounced inhibitory effects in these mice.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mice', 'Species', '10090', (27, 31))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('larger', 'PosReg', (61, 67))	('CDDP', 'Chemical', '-', (119, 123))	('MAS1 siRNA', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
5785	26080617	The in vitro findings supported these results, with MAS1 knockdown resulting in increased 4T1 cell growth, survival and invasion.	('MAS1', 'Gene', (52, 56))	('increased', 'PosReg', (80, 89))	('knockdown', 'Var', (57, 66))	('4T1 cell growth', 'CPA', (90, 105))	('invasion', 'CPA', (120, 128))	('survival', 'CPA', (107, 115))	('4T1', 'CellLine', 'CVCL:0125', (90, 93))
5809	26080617	MAS1 is known to activate Src homology 2-containing inositol phosphatase 2 (SHIP2), which inhibits activation of EGFR ERK1/2.	('MAS1', 'Var', (0, 4))	('Src homology 2-containing inositol phosphatase 2', 'Gene', (26, 74))	('activation', 'MPA', (99, 109))	('SHIP2', 'Gene', (76, 81))	('inhibits', 'NegReg', (90, 98))	('SHIP2', 'Gene', '16332', (76, 81))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', '13649', (113, 117))	('Src homology 2-containing inositol phosphatase 2', 'Gene', '16332', (26, 74))
5814	26080617	Silencing of basal phenotype-associated FoxM1 decreases MAS1 expression.	('MAS1', 'Gene', (56, 60))	('FoxM1', 'Gene', (40, 45))	('decreases', 'NegReg', (46, 55))	('FoxM1', 'Gene', '14235', (40, 45))	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (61, 71))
5815	26080617	Silencing of DNA methyltransferase 3a or tripartite motif protein 28 also causes MAS1 overexpression by epigenetic dysregulation Association of MAS1 expression with basal phenotype might explain the cause of MAS1 expression in TNBC, many of which bring basal phenotype.	('MAS1', 'Gene', (144, 148))	('epigenetic', 'Var', (104, 114))	('tripartite motif protein 28', 'Gene', '21849', (41, 68))	('DNA methyltransferase 3a', 'Gene', (13, 37))	('DNA methyltransferase 3a', 'Gene', '13435', (13, 37))	('tripartite motif protein 28', 'Gene', (41, 68))	('Silencing', 'Var', (0, 9))	('overexpression', 'PosReg', (86, 100))	('MAS1', 'Gene', (81, 85))
5891	22392042	Breast cancers in TP53 carriers have recently been reported to more often be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series.	('hormone receptor', 'Gene', (77, 93))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('TP53', 'Gene', '7157', (18, 22))	('HER-2', 'Gene', '2064', (98, 103))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('HER-2', 'Gene', (98, 103))	('TP53', 'Gene', (18, 22))	('positive', 'Reg', (104, 112))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('carriers', 'Var', (23, 31))	('Breast cancers', 'Disease', (0, 14))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('hormone receptor', 'Gene', '3164', (77, 93))
5893	22392042	Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutations carriers were assembled from investigators in the LFS consortium.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('paraffin', 'Chemical', 'MESH:D010232', (21, 29))	('breast cancers', 'Disease', (57, 71))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('tumor', 'Disease', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
5905	22392042	Germline mutations in the TP53 tumor suppressor gene (tumor protein p53, chromosome 17p13; OMIM 191170) are identified in 70% to 90% of families meeting classic criteria for LFS.	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p53', 'Gene', (68, 71))	('TP53', 'Gene', '7157', (26, 30))	('p53', 'Gene', '7157', (68, 71))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
5906	22392042	Breast cancer is the most common tumor among women with germline TP53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('common', 'Reg', (26, 32))	('germline', 'Var', (56, 64))	('tumor', 'Disease', (33, 38))	('Breast cancer', 'Disease', (0, 13))	('women', 'Species', '9606', (45, 50))
5908	22392042	The frequency of TP53 mutations in population-based series of young onset breast cancers (age <30 years at diagnosis) ranges from <1% to approximately 7%.	('breast cancers', 'Disease', 'MESH:D001943', (74, 88))	('breast cancers', 'Disease', (74, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
5915	22392042	Consortium investigators pooled their paraffinembedded breast cancer specimens from women with TP53 mutations to better characterize the features of malignant breast tumors in the context of LFS.	('mutations', 'Var', (100, 109))	('women', 'Species', '9606', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('malignant breast tumors', 'Disease', 'MESH:D001943', (149, 172))	('paraffin', 'Chemical', 'MESH:D010232', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('malignant breast tumors', 'Disease', (149, 172))	('breast cancer', 'Disease', (55, 68))	('breast tumors', 'Phenotype', 'HP:0100013', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
5916	22392042	Forty-three paraffin-embedded tumor blocks or unstained slides from invasive and in situ breast cancers from women with a known TP53 mutation were identified by investigators from the City of Hope, Dana Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Stanford University, University of Michigan, University of Texas Southwestern and Hospital Vall d'Hebron, in Barcelona, Spain.	('TP53', 'Gene', '7157', (128, 132))	('Cancer', 'Disease', (253, 259))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('paraffin', 'Chemical', 'MESH:D010232', (12, 20))	('Cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('Cancer', 'Disease', 'MESH:D009369', (253, 259))	('situ breast cancers', 'Disease', 'MESH:D000071960', (84, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Disease', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Memorial Sloan Kettering Cancer', 'Disease', (228, 259))	('situ breast cancers', 'Disease', (84, 103))	('TP53', 'Gene', (128, 132))	('women', 'Species', '9606', (109, 114))	('Cancer', 'Disease', 'MESH:D009369', (210, 216))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))	('mutation', 'Var', (133, 141))	('Cancer', 'Phenotype', 'HP:0002664', (253, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('tumor', 'Disease', (30, 35))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (228, 259))
5940	22392042	Forty-three specimens from 39 women with confirmed germline TP53 mutations included 32 invasive ductal carcinomas and 11 DCIS.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('DCIS', 'Disease', (121, 125))	('women', 'Species', '9606', (30, 35))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (87, 113))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('TP53', 'Gene', '7157', (60, 64))	('invasive ductal carcinomas', 'Disease', (87, 113))	('TP53', 'Gene', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('mutations', 'Var', (65, 74))
5943	22392042	All women in the cohort were carriers of confirmed deleterious TP53 mutations.	('mutations', 'Var', (68, 77))	('women', 'Species', '9606', (4, 9))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))
5951	22392042	Of note, we found one DCIS specimen with a heterogeneous pattern characterized by adjacent areas of HER2 positivity and negativity (Figure 1).	('positivity', 'Var', (105, 115))	('HER2', 'Gene', (100, 104))	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('HER2', 'Gene', '2064', (100, 104))
5952	22392042	In our series of 43 tumors in 39 women with TP53 mutations we found that 63% of the invasive breast cancers and 73% of DCIS were positive for HER2, and more than three quarters of the tumors were positive for ER.	('women', 'Species', '9606', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('invasive breast cancers', 'Disease', 'MESH:D001943', (84, 107))	('TP53', 'Gene', (44, 48))	('positive', 'Reg', (129, 137))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (49, 58))	('HER2', 'Gene', '2064', (142, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('invasive breast cancers', 'Disease', (84, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('TP53', 'Gene', '7157', (44, 48))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('HER2', 'Gene', (142, 146))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', (184, 190))
5955	22392042	Our study represents the largest cohort of breast cancer in LFS reported to date and adds to the recently published data on the clinical pathological features of breast cancers in TP53 mutation carriers.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('breast cancers', 'Phenotype', 'HP:0003002', (162, 176))	('carriers', 'Reg', (194, 202))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('mutation', 'Var', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancers', 'Disease', 'MESH:D001943', (162, 176))	('breast cancers', 'Disease', (162, 176))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
5958	22392042	The histopathologic profile of breast tumors in women with germline TP53 mutations has been recently characterized in two other cohorts.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('breast tumors', 'Disease', (31, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('breast tumors', 'Phenotype', 'HP:0100013', (31, 44))	('women', 'Species', '9606', (48, 53))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('breast tumors', 'Disease', 'MESH:D001943', (31, 44))	('mutations', 'Var', (73, 82))
5960	22392042	A group from MD Anderson Cancer Center and the University of Chicago confirmed these findings in their analysis of specimens from their cohort of 30 TP53 mutation positive patients, with 70% positive for estrogen receptor and 67% showing HER-2 over-expression and/or amplification in comparison to 68% of ER positive and 25% of HER-2 positive in the control group of TP53 mutation negative patients.	('amplification', 'MPA', (267, 280))	('MD Anderson Cancer', 'Disease', (13, 31))	('patients', 'Species', '9606', (390, 398))	('HER-2', 'Gene', (238, 243))	('HER-2', 'Gene', '2064', (238, 243))	('HER-2', 'Gene', '2064', (328, 333))	('estrogen', 'Protein', (204, 212))	('over-expression', 'PosReg', (244, 259))	('TP53', 'Gene', '7157', (149, 153))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('HER-2', 'Gene', (328, 333))	('TP53', 'Gene', (149, 153))	('positive', 'Reg', (191, 199))	('patients', 'Species', '9606', (172, 180))	('TP53', 'Gene', '7157', (367, 371))	('TP53', 'Gene', (367, 371))	('mutation positive', 'Var', (154, 171))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (13, 31))
5964	22392042	In our paper, the data demonstrate that breast cancers arising in individuals with germline TP53 mutations have a predominant immunohistochemical profile that correlates with molecular phenotype.	('mutations', 'Var', (97, 106))	('breast cancers', 'Disease', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
5966	22392042	Breast cancers arising in BRCA1 mutation carriers are predominantly basal-like by microarray; 80% of breast cancers in women with germline BRCA2 mutations are ER+ and HER2 negative.	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('mutations', 'Var', (145, 154))	('HER2', 'Gene', '2064', (167, 171))	('BRCA2', 'Gene', '675', (139, 144))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('breast cancers', 'Disease', (101, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('women', 'Species', '9606', (119, 124))	('BRCA1', 'Gene', '672', (26, 31))	('Breast cancers', 'Disease', (0, 14))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('mutation', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('BRCA1', 'Gene', (26, 31))	('HER2', 'Gene', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('BRCA2', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))
5967	22392042	In women with CDH1 mutations (Hereditary Diffuse Gastric Cancer Syndrome), the breast tumors have invasive lobular histology.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Hereditary Diffuse Gastric Cancer', 'Disease', (30, 63))	('CDH1', 'Gene', (14, 18))	('Hereditary Diffuse Gastric Cancer', 'Disease', 'MESH:D013274', (30, 63))	('CDH1', 'Gene', '999', (14, 18))	('breast tumors', 'Phenotype', 'HP:0100013', (79, 92))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('breast tumors', 'Disease', (79, 92))	('women', 'Species', '9606', (3, 8))	('breast tumors', 'Disease', 'MESH:D001943', (79, 92))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (49, 63))	('invasive lobular histology', 'CPA', (98, 124))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
5968	22392042	TP53 abnormalities have been detected in sporadic HER2+ breast carcinomas.	('TP53', 'Gene', '7157', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('TP53', 'Gene', (0, 4))	('HER2', 'Gene', (50, 54))	('HER2', 'Gene', '2064', (50, 54))	('abnormalities', 'Var', (5, 18))	('detected', 'Reg', (29, 37))	('breast carcinomas', 'Disease', 'MESH:D001943', (56, 73))	('breast carcinomas', 'Disease', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('breast carcinomas', 'Phenotype', 'HP:0003002', (56, 73))
5969	22392042	It is notable that BRCA1-associated basal-like tumors are frequently TP53 mutant.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('TP53', 'Gene', '7157', (69, 73))	('basal-like tumors', 'Phenotype', 'HP:0002671', (36, 53))	('TP53', 'Gene', (69, 73))	('BRCA1', 'Gene', '672', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutant', 'Var', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('BRCA1', 'Gene', (19, 24))
5971	22392042	The data raise questions about biologic mechanisms underlying the diversity of tumor types, among which differences in cell-of-origin, order of mutation acquisition and epigenetic influences are candidates.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('epigenetic', 'Var', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))
5973	22392042	Over-expression of HER-2 has been associated with an aggressive phenotype which includes poorly differentiated and high-grade tumors, high rates of cell proliferation, lymph-node involvement, and resistance to certain types of hormonal and chemotherapies.	('associated', 'Reg', (34, 44))	('tumors', 'Disease', (126, 132))	('HER-2', 'Gene', '2064', (19, 24))	('lymph-node involvement', 'CPA', (168, 190))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('HER-2', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('resistance', 'CPA', (196, 206))	('cell proliferation', 'CPA', (148, 166))	('poorly differentiated', 'CPA', (89, 110))	('Over-expression', 'Var', (0, 15))
5976	22392042	In addition, it would be interesting to know the prevalence of TP53 mutations among young women with HER2+ breast cancer which may lead to consideration for TP53 testing in young patients with this breast cancer subtype.	('TP53', 'Gene', (157, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('HER2', 'Gene', (101, 105))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('HER2', 'Gene', '2064', (101, 105))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('TP53', 'Gene', '7157', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('mutations', 'Var', (68, 77))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('women', 'Species', '9606', (90, 95))	('breast cancer', 'Disease', (198, 211))
5977	22392042	In conclusion, our results confirm the finding that breast cancers developing in individuals with germline TP53 mutations often feature a hormone receptor positive, HER2 positive subtype.	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('TP53', 'Gene', '7157', (107, 111))	('hormone receptor', 'Gene', (138, 154))	('TP53', 'Gene', (107, 111))	('hormone receptor', 'Gene', '3164', (138, 154))	('mutations', 'Var', (112, 121))	('breast cancers', 'Disease', (52, 66))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', '2064', (165, 169))
5983	32841804	Tumor persistence at RBS was higher for mastectomy vs. re-excision (87.3% vs. 37.8%; p = 0.05), inconclusive vs. positive diagnostic biopsy (48.2% vs. 69.4%; p = 0.003), ductal carcinoma in situ vs. invasive carcinoma (69.0% vs. 51.3%; p = 0.046) and lower after neoadjuvant therapy (14.3% vs. 57.8%; p = 0.044).	('higher', 'PosReg', (29, 35))	('mastectomy', 'Disease', (40, 50))	('ductal carcinoma in situ', 'Disease', (170, 194))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (170, 194))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor', 'MPA', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('lower', 'NegReg', (251, 256))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (170, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('inconclusive', 'Var', (96, 108))	('invasive carcinoma', 'Disease', 'MESH:D009361', (199, 217))	('RBS', 'Chemical', '-', (21, 24))	('invasive carcinoma', 'Disease', (199, 217))
5985	32841804	RBS rate can be reduced by shaving of cavity margins.	('shaving', 'Var', (27, 34))	('RBS rate', 'MPA', (0, 8))	('RBS', 'Chemical', '-', (0, 3))
6028	32841804	Conversely, both neoadjuvant therapy and shaving of cavity margins were associated with a significant reduction of the RBS rate.	('RBS', 'Disease', (119, 122))	('shaving', 'Var', (41, 48))	('reduction', 'NegReg', (102, 111))	('RBS', 'Chemical', '-', (119, 122))
6088	30659696	Sung et al show that the types of tumors detected by MRI and mammography are different, based on a very large cohort of 18,064 screening MRI examinations and 26,866 mammographic examinations; the sensitivity of mammography reduces for more aggressive/invasive types of cancers, whereas the sensitivity of MRI increases,31 which is corroborated by several other studies.37, 38 Consequently, the gain of mammography is mostly in the detection of DCIS, even though the sensitivity of MRI for any grade of DCIS is higher than that of mammography.31, 37 Phi et al conducted a meta-analysis of the earlier studies to determine the impact of mammography in BRCA mutation carriers.39 In BRCA1 mutation carriers the incremental cancer detection was 3.9%, whereas in BRCA2 mutation carriers the incremental detection was 12.6%.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('BRCA2', 'Gene', (757, 762))	('BRCA', 'Gene', '672', (679, 683))	('BRCA', 'Gene', (650, 654))	('BRCA1', 'Gene', '672', (679, 684))	('mutation', 'Var', (685, 693))	('BRCA1', 'Gene', (679, 684))	('BRCA', 'Gene', '672', (757, 761))	('BRCA2', 'Gene', '675', (757, 762))	('BRCA', 'Gene', (679, 683))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('incremental cancer', 'Disease', 'MESH:D009369', (707, 725))	('cancers', 'Disease', (269, 276))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('BRCA', 'Gene', (757, 761))	('DCIS', 'Phenotype', 'HP:0030075', (502, 506))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (719, 725))	('BRCA', 'Gene', '672', (650, 654))	('incremental cancer', 'Disease', (707, 725))	('DCIS', 'Phenotype', 'HP:0030075', (444, 448))	('cancers', 'Disease', 'MESH:D009369', (269, 276))
6091	30659696	In agreement with this, Obdeijn et al reported on more recent data only a 2% incremental cancer detection rate (CDR) in BRCA1 mutation carriers, two cases of DCIS in women over 50.40 In a subsequent modeling study they noted that mammography under 40 had no, or even a negative effect, in this population.41 Narayan et al report a 0% increase in cancer detection by adding mammography in women below 40 with various risk factors.42 In a similar, but much larger, mixed cohort, Vreemann et al reported 13/125 cancers to be solely detected by mammography, including eight cases of DCIS.43 However, they reported no supplemental detection in BRCA mutation carriers below the age of 50, and overall 77% of additional detections in women over 50, leading to a number of mammography screens needed to detect an additional cancer in women younger than 50 of 1427.	('BRCA', 'Gene', (120, 124))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (508, 514))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('women', 'Species', '9606', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (508, 514))	('BRCA', 'Gene', '672', (639, 643))	('women', 'Species', '9606', (826, 831))	('women', 'Species', '9606', (388, 393))	('cancer', 'Disease', (816, 822))	('incremental cancer', 'Disease', (77, 95))	('BRCA1', 'Gene', '672', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (508, 515))	('cancer', 'Phenotype', 'HP:0002664', (816, 822))	('mutation', 'Var', (644, 652))	('cancers', 'Disease', (508, 515))	('BRCA1', 'Gene', (120, 125))	('cancer', 'Disease', (346, 352))	('BRCA', 'Gene', (639, 643))	('women', 'Species', '9606', (727, 732))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (508, 514))	('BRCA', 'Gene', '672', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('DCIS', 'Phenotype', 'HP:0030075', (579, 583))	('cancer', 'Disease', 'MESH:D009369', (816, 822))	('incremental cancer', 'Disease', 'MESH:D009369', (77, 95))	('cancers', 'Disease', 'MESH:D009369', (508, 515))
6105	30659696	Genetic testing has become more extensive in recent years; women suspected of hereditary cancer are subjected to panel tests that include other susceptibility genes such as PALB2, STK11, CDH1, ATM, and CHECK2 that account for relative risks from 2.5-3 for lower-risk alterations such as CHECK2 and ATM to 4-6 for the others.59, 60 Local guidelines are rapidly changing to also include these mutations as an indication for MRI screening.	('ATM', 'Gene', (193, 196))	('PALB2', 'Gene', '79728', (173, 178))	('PALB2', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ATM', 'Gene', '472', (298, 301))	('ATM', 'Gene', (298, 301))	('CDH1', 'Gene', (187, 191))	('ATM', 'Gene', '472', (193, 196))	('CDH1', 'Gene', '999', (187, 191))	('hereditary cancer', 'Disease', 'MESH:D009386', (78, 95))	('STK11', 'Gene', (180, 185))	('women', 'Species', '9606', (59, 64))	('mutations', 'Var', (391, 400))	('hereditary cancer', 'Disease', (78, 95))	('STK11', 'Gene', '6794', (180, 185))
6127	30659696	According to Lee et al, 69% of MRI-detected cancers is smaller than 1 cm.35 For such small tumor sizes, Welch et al reported overall survival estimates that exceed the population average.93 Consequently, MRI has the potential to further downstage the average cancer by earlier detection and improve breast cancer-specific survival.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (299, 312))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('tumor', 'Disease', (91, 96))	('downstage', 'NegReg', (237, 246))	('breast cancer', 'Disease', 'MESH:D001943', (299, 312))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('breast cancer', 'Disease', (299, 312))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MRI', 'Var', (204, 207))	('cancer', 'Disease', (259, 265))	('improve', 'PosReg', (291, 298))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Disease', (306, 312))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancer', 'Disease', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
6137	30659696	Pages et al retrospectively reviewed the priors of 60 MRI screen detected breast cancers, reporting that 28 of these lesions would be regarded as BI-RADS 3-5 lesions in the prior, six lesions had been missed, 15 lesions were misdiagnosed, and seven lesions were mismanaged due to incorrect tissue sampling at second-look ultrasound.98 In a similar study, Yamaguchi et al reported that 7 out of 15 cancers were retrospectively visible.99 In a recent study of 131 cancers with priors, including 16 interval cancers, Vreemann et al reported that overall 34% of cancers were actionable on the prior scan.100 The presence of a BRCA mutation largely reduced the risk on false-negative examinations, which reflects the lower threshold for work-up in these women.	('cancers', 'Phenotype', 'HP:0002664', (462, 469))	('cancers', 'Disease', (558, 565))	('women', 'Species', '9606', (749, 754))	('cancers', 'Disease', (462, 469))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (558, 564))	('interval cancers', 'Disease', (496, 512))	('cancers', 'Disease', 'MESH:D009369', (505, 512))	('cancer', 'Phenotype', 'HP:0002664', (462, 468))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('interval cancers', 'Disease', 'MESH:D009369', (496, 512))	('cancers', 'Disease', (397, 404))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('reduced', 'NegReg', (644, 651))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('breast cancers', 'Disease', 'MESH:D001943', (74, 88))	('BRCA', 'Gene', '672', (622, 626))	('breast cancers', 'Disease', (74, 88))	('cancers', 'Disease', 'MESH:D009369', (558, 565))	('cancers', 'Disease', 'MESH:D009369', (462, 469))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancers', 'Phenotype', 'HP:0002664', (505, 512))	('cancers', 'Disease', (505, 512))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('presence', 'Var', (608, 616))	('mutation', 'Var', (627, 635))	('cancer', 'Phenotype', 'HP:0002664', (505, 511))	('BRCA', 'Gene', (622, 626))	('cancers', 'Phenotype', 'HP:0002664', (558, 565))
6146	30659696	A point of concern is that MRI has a higher sensitivity for all types of breast cancer, including low-grade DCIS, and may therefore also increase overdiagnosis.	('sensitivity', 'MPA', (44, 55))	('low-grade DCIS', 'Disease', (98, 112))	('higher', 'PosReg', (37, 43))	('increase overdiagnosis', 'Disease', (137, 159))	('MRI', 'Var', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('increase overdiagnosis', 'Disease', 'MESH:D019586', (137, 159))
6148	18651949	This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer.	('breast cancer', 'Disease', (232, 245))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutation', 'Var', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('BRCA1/2', 'Gene', (152, 159))	('cancer', 'Disease', (67, 73))	('BRCA1/2', 'Gene', (97, 104))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1/2', 'Gene', '672;675', (152, 159))	('BRCA1/2', 'Gene', '672;675', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
6159	18651949	These criteria have been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutation', 'Var', (105, 113))	('cancer', 'Disease', (67, 73))	('BRCA1/2', 'Gene', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1/2', 'Gene', '672;675', (97, 104))
6160	18651949	As BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer, estimates based on these high-risk families may thus have limited value for the prediction of the age of onset of breast cancer in the general population.	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', (212, 225))	('BRCA1/2', 'Gene', '672;675', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('BRCA1/2', 'Gene', (3, 10))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
6221	18651949	The presence of one of these characteristics more than doubled the breast cancer risk at age 30 (Table 2).	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
6236	18651949	However, due to the low prevalence of early breast cancer in the population, the positive predictive value of the presence of at least 2 of the 4 characteristics (a model score of 2 or more) was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('breast cancer', 'Disease', (294, 307))	('presence', 'Var', (114, 122))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (203, 216))	('breast cancer', 'Disease', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Disease', (247, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))
6248	18651949	A second explanation might be, that these types of cancer are more frequent in the study populations of mentioned studies, than could be expected in the general population, as these studies focused on the prediction of breast cancer risk using estimates on the prevalence and penetrance of BRCA1 and BRCA2 mutations.	('BRCA2', 'Gene', (300, 305))	('BRCA1', 'Gene', (290, 295))	('mutations', 'Var', (306, 315))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('BRCA2', 'Gene', '675', (300, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Disease', (219, 232))	('focused', 'Reg', (190, 197))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('BRCA1', 'Gene', '672', (290, 295))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
6249	18651949	As ovarian cancer, early onset prostate cancer and male breast cancer are associated with such mutations, the study populations of these studies may have included high risk groups more frequently than low risk groups.	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('male breast cancer', 'Disease', 'MESH:D018567', (51, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('male breast cancer', 'Disease', (51, 69))	('ovarian cancer', 'Disease', (3, 17))	('mutations', 'Var', (95, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('prostate cancer', 'Disease', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('associated', 'Reg', (74, 84))
6251	18651949	However, recent studies showed only a weak association of BRCA1/2 mutation status with bilateral breast cancer.	('BRCA1/2', 'Gene', '672;675', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('bilateral breast cancer', 'Disease', (87, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (87, 110))	('mutation', 'Var', (66, 74))	('BRCA1/2', 'Gene', (58, 65))
6294	16832410	Migration and invasion have been shown to be enhanced by PRL-3 and PRL-1 expression in Chinese hamster ovary cells and overexpression of these proteins induced metastatic tumour formation in mice (Zeng et al, 2003).	('induced', 'Reg', (152, 159))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('expression', 'Var', (73, 83))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('PRL-3', 'Gene', (57, 62))	('tumour', 'Disease', (171, 177))	('overexpression', 'PosReg', (119, 133))	('enhanced', 'PosReg', (45, 53))	('Chinese hamster', 'Species', '10029', (87, 102))	('Migration', 'CPA', (0, 9))	('mice', 'Species', '10090', (191, 195))	('invasion', 'CPA', (14, 22))	('PRL-3', 'Gene', '11156', (57, 62))	('PRL-1', 'Gene', (67, 72))
6355	16832410	PRL-3 mRNA expression was significantly higher in neoplastic compared with non-neoplastic breast cancer tissue specimens (mean 1.015+-0.156 vs 0.898+-0.089; P=0.010).	('non-neoplastic breast cancer', 'Disease', (75, 103))	('higher', 'PosReg', (40, 46))	('neoplastic', 'Var', (50, 60))	('non-neoplastic breast cancer', 'Disease', 'MESH:D001943', (75, 103))	('PRL-3', 'Gene', (0, 5))	('mRNA expression', 'MPA', (6, 21))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('neoplastic breast cancer', 'Phenotype', 'HP:0100013', (79, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('PRL-3', 'Gene', '11156', (0, 5))
6391	16832410	The PRL-3 mRNA expression was significantly elevated in neoplastic compared to normal breast tissue.	('PRL-3', 'Gene', '11156', (4, 9))	('elevated', 'PosReg', (44, 52))	('PRL-3', 'Gene', (4, 9))	('neoplastic', 'Var', (56, 66))	('mRNA expression', 'MPA', (10, 25))
6417	16832410	In vitro, knockdown of PRL-3 in ovarian cancer cell lines with small interfering RNA resulted in impaired cancer cell growth (Polato et al, 2005).	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('impaired cancer', 'Disease', (97, 112))	('PRL-3', 'Gene', (23, 28))	('RNA', 'Gene', (81, 84))	('ovarian cancer', 'Disease', (32, 46))	('small interfering', 'Var', (63, 80))	('PRL-3', 'Gene', '11156', (23, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('impaired cancer', 'Disease', 'MESH:D009422', (97, 112))	('knockdown', 'Var', (10, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
6452	33389371	E-index in strain elastography yielded better results than E-ratio in the malignant/benign discrimination of breast diseases.	('breast diseases', 'Disease', (109, 124))	('strain', 'MPA', (11, 17))	('malignant/benign discrimination', 'CPA', (74, 105))	('breast diseases', 'Disease', 'MESH:D001943', (109, 124))	('E-index', 'Var', (0, 7))
6498	30531838	Loss of SIM2s through the introduction of shSIM2 or the mutation of SIM2s at one of the predicted ATM phosphorylation sites (S115) reduces homologous recombination efficiency through disruption of RAD51 recruitment, resulting in genomic instability and induction of EMT.	('SIM2s', 'Gene', (68, 73))	('disruption', 'NegReg', (183, 193))	('reduces', 'NegReg', (131, 138))	('EMT', 'CPA', (266, 269))	('shSIM2', 'Gene', (42, 48))	('genomic instability', 'CPA', (229, 248))	('RAD51', 'Gene', (197, 202))	('SIM2s', 'Chemical', '-', (8, 13))	('mutation', 'Var', (56, 64))	('induction', 'Reg', (253, 262))	('RAD51', 'Gene', '5888', (197, 202))	('SIM2s', 'Chemical', '-', (68, 73))
6499	30531838	The EMT induced by the mutation of S115 is characterized by a decrease in E-cadherin and an induction of the basal marker, K14, resulting in increased invasion and metastasis.	('induction', 'PosReg', (92, 101))	('K14', 'Gene', '3861', (123, 126))	('EMT', 'CPA', (4, 7))	('mutation', 'Var', (23, 31))	('increased', 'PosReg', (141, 150))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('S115', 'Gene', (35, 39))	('invasion', 'CPA', (151, 159))	('decrease', 'NegReg', (62, 70))	('K14', 'Gene', (123, 126))
6510	30531838	Aneuploidy and gene silencing resulting from these mutations can significantly deplete tumor-suppressing factors and lead to the increased expression of pro-proliferative factors, which further enhance breast cancer progression.	('mutations', 'Var', (51, 60))	('deplete', 'NegReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('gene', 'MPA', (15, 19))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('tumor', 'Disease', (87, 92))	('increased', 'PosReg', (129, 138))	('breast cancer', 'Disease', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('expression', 'MPA', (139, 149))	('enhance', 'PosReg', (194, 201))	('Aneuploidy', 'Disease', (0, 10))
6511	30531838	Interestingly, it is mutations within the homologous recombination (HR) DDR pathway that have been implicated in familial breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HR', 'Gene', (68, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('implicated', 'Reg', (99, 109))	('familial breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('familial breast cancer', 'Disease', (113, 135))	('mutations', 'Var', (21, 30))
6512	30531838	Studies show a strong correlation between hereditary mutations in BRCA1/BRCA2 and increased incidence of high-grade DCIS and progression from DCIS to IDC.	('BRCA2', 'Gene', (72, 77))	('BRCA1', 'Gene', '672', (66, 71))	('IDC', 'Gene', '4000', (150, 153))	('IDC', 'Gene', (150, 153))	('BRCA2', 'Gene', '675', (72, 77))	('DCIS', 'Disease', (142, 146))	('high-grade DCIS', 'Disease', (105, 120))	('mutations', 'Var', (53, 62))	('BRCA1', 'Gene', (66, 71))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
6514	30531838	Although previously only associated with familial breast cancer (5-10% of total breast cancer cases), a growing body of evidence shows that BRCA misregulation and mutations are more abundant in sporadic cancers than previously thought, possibly being present in as many as 82% of ovarian cancers.	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('sporadic cancers', 'Disease', 'MESH:D009369', (194, 210))	('BRCA', 'Gene', '672', (140, 144))	('ovarian cancers', 'Phenotype', 'HP:0100615', (280, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('sporadic cancers', 'Disease', (194, 210))	('BRCA', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('misregulation', 'Var', (145, 158))	('familial breast cancer', 'Disease', 'MESH:D001943', (41, 63))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('mutations', 'Var', (163, 172))	('familial breast cancer', 'Disease', (41, 63))	('ovarian cancers', 'Disease', (280, 295))	('ovarian cancers', 'Disease', 'MESH:D010051', (280, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))
6515	30531838	Loss of these crucial DDR factors has been associated with a distinct tumor profile, including loss of ER, progesterone receptor (PR), and HER2, providing a strong association between loss of BRCA and highly invasive triple negative breast cancers (TNBC).	('breast cancers', 'Phenotype', 'HP:0003002', (233, 247))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('HER2', 'Gene', (139, 143))	('progesterone receptor', 'Gene', (107, 128))	('breast cancers', 'Disease', (233, 247))	('breast cancers', 'Disease', 'MESH:D001943', (233, 247))	('tumor', 'Disease', (70, 75))	('progesterone receptor', 'Gene', '5241', (107, 128))	('HER2', 'Gene', '2064', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('Loss', 'NegReg', (0, 4))	('loss', 'Var', (184, 188))	('PR', 'Gene', '5241', (130, 132))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('BRCA', 'Gene', '672', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('BRCA', 'Gene', (192, 196))
6517	30531838	Previously, our lab has shown that the bHLH-PAS transcription factor family member single-minded 2s (SIM2s; short isoform expressed from SIM2) plays a role in mammary gland development, is down-regulated in primary breast, and that loss of SIM2s expression is associated with an epithelial mesenchymal transition (EMT) both in normal breast and breast cancer cell lines.	('epithelial mesenchymal transition', 'CPA', (279, 312))	('SIM2s', 'Chemical', '-', (240, 245))	('mammary gland development', 'CPA', (159, 184))	('down-regulated', 'NegReg', (189, 203))	('SIM2s', 'Gene', (240, 245))	('SIM2s', 'Chemical', '-', (101, 106))	('single-minded 2', 'Gene', '6493', (83, 98))	('breast cancer', 'Disease', 'MESH:D001943', (345, 358))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('breast cancer', 'Disease', (345, 358))	('loss', 'Var', (232, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (345, 358))	('associated with', 'Reg', (260, 275))	('single-minded 2', 'Gene', (83, 98))
6518	30531838	We have used the DCIS.com progression model to demonstrate that re-expression of SIM2s inhibits growth and metastasis and promotes a more luminal-like phenotype; whereas down-regulation of SIM2s leads to an increase in invasive potential.	('SIM2s', 'Chemical', '-', (189, 194))	('SIM2s', 'Gene', (81, 86))	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('re-expression', 'Var', (64, 77))	('increase', 'PosReg', (207, 215))	('promotes', 'PosReg', (122, 130))	('down-regulation', 'NegReg', (170, 185))	('invasive potential', 'CPA', (219, 237))	('inhibits', 'NegReg', (87, 95))	('SIM2s', 'Chemical', '-', (81, 86))	('more luminal-like phenotype', 'MPA', (133, 160))
6533	30531838	To investigate this protective effect of SIM2s, we examined how loss of SIM2s affected genomic stability.	('genomic stability', 'CPA', (87, 104))	('SIM2s', 'Chemical', '-', (41, 46))	('affected', 'Reg', (78, 86))	('SIM2s', 'Chemical', '-', (72, 77))	('SIM2s', 'Gene', (72, 77))	('loss', 'Var', (64, 68))
6551	30531838	To investigate the possibility that SIM2s is stabilized by a post-translational modification in response to IR, we analyzed SIM2s for phosphorylation sites of known DDR kinases and identified 12 total ATM consensus sites, three of which are highly conserved across Mus Musculus, Homo Sapiens, and Xenopus laevis (S35, S115, S363) (Fig.	('S115', 'Var', (318, 322))	('S35', 'Var', (313, 316))	('Xenopus laevis', 'Species', '8355', (297, 311))	('SIM2s', 'Chemical', '-', (124, 129))	('Mus Musculus', 'Species', '10090', (265, 277))	('Homo Sapiens', 'Species', '9606', (279, 291))	('S363', 'Var', (324, 328))	('SIM2s', 'Chemical', '-', (36, 41))
6555	30531838	To determine if ATM is necessary for IR-induced SIM2s stabilization, we pretreated SUM159-SIM2s-FLAG cells with KU55933, a selective ATM inhibitor, for 2 hours prior to treatment with 2GYs of IR.	('SIM2s', 'Chemical', '-', (48, 53))	('SIM2s', 'Chemical', '-', (90, 95))	('SUM159-SIM2s-FLAG', 'Var', (83, 100))	('KU55933', 'Var', (112, 119))	('KU55933', 'Chemical', 'MESH:C495818', (112, 119))
6556	30531838	Western blot analysis showed a significant reduction in SIM2s stabilization in KU55933 treated cells in response to IR (Fig.	('KU55933', 'Chemical', 'MESH:C495818', (79, 86))	('SIM2s', 'Chemical', '-', (56, 61))	('reduction', 'NegReg', (43, 52))	('SIM2s', 'Gene', (56, 61))	('stabilization', 'MPA', (62, 75))	('response to IR', 'MPA', (104, 118))	('KU55933 treated', 'Var', (79, 94))
6558	30531838	We next generated a DCIS.com-SIM2s-FLAG cell line with serine to alanine mutations at all the predicted ATM consensus sites (S35, S115, S203, S216, S309, S343, S352, S361, S363, S392, S393, S426; SIM2sDelta12).	('SIM2sDelta12', 'Gene', '20465', (196, 208))	('S35', 'Var', (125, 128))	('alanine', 'Chemical', 'MESH:D000409', (65, 72))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('S361', 'Var', (166, 170))	('S343', 'Var', (154, 158))	('S216', 'Var', (142, 146))	('S393', 'Var', (184, 188))	('S392', 'Var', (178, 182))	('S352', 'Var', (160, 164))	('S309', 'Var', (148, 152))	('SIM2s', 'Chemical', '-', (29, 34))	('s-FLAG', 'Species', '4465', (33, 39))	('SIM2s', 'Chemical', '-', (196, 201))	('S363', 'Var', (172, 176))	('S115', 'Var', (130, 134))	('serine', 'Chemical', 'MESH:D012694', (55, 61))	('S203', 'Var', (136, 140))	('SIM2sDelta12', 'Gene', (196, 208))
6560	30531838	Interestingly, there was no increase in SIM2s levels with these 12 sites mutated (Fig.	('SIM2s levels', 'MPA', (40, 52))	('mutated', 'Var', (73, 80))	('SIM2s', 'Chemical', '-', (40, 45))
6561	30531838	To narrow down which serine residue is necessary for SIM2s stabilization we generated DCIS.com-SIM2s-FLAG cells lines containing point mutations at the three highly conserved ATM-consensus sites: serine 35 (S35A), 115 (S115A), or 363 (S363A).	('point mutations', 'Var', (129, 144))	('serine', 'Chemical', 'MESH:D012694', (196, 202))	('serine', 'Chemical', 'MESH:D012694', (21, 27))	('serine 35 (S35A', 'Var', (196, 211))	('S35A', 'Mutation', 'p.S35A', (207, 211))	('SIM2s', 'Chemical', '-', (53, 58))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('S363A', 'Mutation', 'p.S363A', (235, 240))	('SIM2s', 'Chemical', '-', (95, 100))	('S115A', 'Mutation', 'p.S115A', (219, 224))
6562	30531838	Utilizing these cells lines, we sought to determine if one of these mutations inhibited SIM2s stabilization.	('inhibited', 'NegReg', (78, 87))	('SIM2s', 'Chemical', '-', (88, 93))	('mutations', 'Var', (68, 77))	('stabilization', 'MPA', (94, 107))	('SIM2s', 'Gene', (88, 93))
6565	30531838	The interaction of SIM2s and ATM, suggests that SIM2s may be acting downstream of ATM; however, western blot analysis revealed that loss of SIM2s does not affect p53 activation (data not shown).	('SIM2s', 'Chemical', '-', (48, 53))	('SIM2s', 'Gene', (140, 145))	('p53', 'Gene', (162, 165))	('loss', 'Var', (132, 136))	('p53', 'Gene', '7157', (162, 165))	('SIM2s', 'Chemical', '-', (19, 24))	('SIM2s', 'Chemical', '-', (140, 145))
6566	30531838	The loss of stabilization observed with S115A led us to predict that cells containing this mutation would behave similarly to cells containing shSIM2 and have impaired DDR.	('DDR', 'MPA', (168, 171))	('S115A', 'Var', (40, 45))	('stabilization', 'MPA', (12, 25))	('S115A', 'Mutation', 'p.S115A', (40, 45))
6567	30531838	Comparing DCIS.com-SIM2s-FLAG to S115A revealed that cells containing S115A had significantly more gammaH2AX foci 6 hours after 2GYs IR than cells over-expressing SIM2s-FLAG (Fig.	('s-FLAG', 'Species', '4465', (23, 29))	('S115A', 'Mutation', 'p.S115A', (70, 75))	('gammaH2AX', 'Protein', (99, 108))	('S115A', 'Var', (70, 75))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('S115A', 'Mutation', 'p.S115A', (33, 38))	('gammaH2AX', 'Chemical', '-', (99, 108))	('SIM2s', 'Chemical', '-', (163, 168))	('SIM2s', 'Chemical', '-', (19, 24))	('more', 'PosReg', (94, 98))	('s-FLAG', 'Species', '4465', (167, 173))
6569	30531838	Interestingly, loss of SIM2s did not have a negative effect on ATM, TP53, 53BP1, BRCA1, BRCA2, or RAD51 levels 6 hours after treatment with 2GYs IR (Supplemental Figure 1).	('53BP1', 'Gene', (74, 79))	('53BP1', 'Gene', '7158', (74, 79))	('RAD51', 'Gene', '5888', (98, 103))	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', (88, 93))	('ATM', 'MPA', (63, 66))	('TP53', 'Gene', '7157', (68, 72))	('SIM2s', 'Chemical', '-', (23, 28))	('loss', 'Var', (15, 19))	('BRCA2', 'Gene', '675', (88, 93))	('RAD51', 'Gene', (98, 103))	('TP53', 'Gene', (68, 72))	('BRCA1', 'Gene', '672', (81, 86))	('SIM2s', 'Gene', (23, 28))
6580	30531838	In line with this hypothesis, we observed that loss of SIM2s leads to a significant decrease in RAD51 recruitment in DCIS.com (p<0.012) and MCF7 (p<0.003) cells after treatment with IR, whereas there was no change in BRCA1 recruitment (Fig.	('decrease', 'NegReg', (84, 92))	('RAD51', 'Gene', (96, 101))	('BRCA1', 'Gene', (217, 222))	('RAD51', 'Gene', '5888', (96, 101))	('SIM2s', 'Chemical', '-', (55, 60))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('SIM2s', 'Gene', (55, 60))	('loss', 'Var', (47, 51))	('recruitment', 'MPA', (102, 113))	('MCF7', 'CellLine', 'CVCL:0031', (140, 144))	('BRCA1', 'Gene', '672', (217, 222))
6582	30531838	Recent studies have shown that loss of factors crucial for HR, including BRCA1, BRCA2, and RAD51, sensitizes cells to PARP inhibitors in pre-clinical and clinical trials.	('BRCA2', 'Gene', (80, 85))	('loss', 'Var', (31, 35))	('sensitizes', 'Reg', (98, 108))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA2', 'Gene', '675', (80, 85))	('RAD51', 'Gene', (91, 96))	('PARP', 'MPA', (118, 122))	('BRCA1', 'Gene', (73, 78))	('RAD51', 'Gene', '5888', (91, 96))
6583	30531838	PARPs are necessary in early DDR to poly-ADP-ribosylate target histones, leading to the destabilization of chromatin structure and exposure of damaged DNA for invasion of DDR machinery.	('poly-ADP-ribosylate', 'Var', (36, 55))	('PARPs', 'Gene', '142;11545;10038', (0, 5))	('destabilization', 'MPA', (88, 103))	('chromatin structure', 'MPA', (107, 126))	('PARPs', 'Gene', (0, 5))	('poly-ADP', 'Chemical', '-', (36, 44))
6584	30531838	As such, we hypothesized that loss of SIM2s would sensitize cells to treatment with PARP inhibitors.	('sensitize', 'Reg', (50, 59))	('loss', 'Var', (30, 34))	('SIM2s', 'Gene', (38, 43))	('SIM2s', 'Chemical', '-', (38, 43))
6586	30531838	Loss of SIM2s significantly reduced cell survival in a dose-dependent manner, further supporting a role for SIM2s in HR (Fig.	('reduced', 'NegReg', (28, 35))	('SIM2s', 'Gene', (8, 13))	('SIM2s', 'Chemical', '-', (108, 113))	('SIM2s', 'Chemical', '-', (8, 13))	('cell survival', 'CPA', (36, 49))	('Loss', 'Var', (0, 4))
6588	30531838	As we have identified a role for SIM2s in the recruitment of RAD51, we sought to determine if the S115A mutation impairs the EMT inhibitory function of SIM2s.	('impairs', 'NegReg', (113, 120))	('EMT', 'CPA', (125, 128))	('SIM2s', 'Chemical', '-', (152, 157))	('S115A', 'Var', (98, 103))	('SIM2s', 'Chemical', '-', (33, 38))	('RAD51', 'Gene', (61, 66))	('S115A', 'Mutation', 'p.S115A', (98, 103))	('RAD51', 'Gene', '5888', (61, 66))
6589	30531838	Using Boyden chamber assays, we found that the S115A mutant resulted in a significant increase in the ability of DCIS.com cells to not only migrate (p<0.0009), but also to invade (p<0.0485), through an extra-cellular matrix (Fig.	('increase', 'PosReg', (86, 94))	('S115A', 'Var', (47, 52))	('invade', 'CPA', (172, 178))	('S115A', 'Mutation', 'p.S115A', (47, 52))	('migrate', 'CPA', (140, 147))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
6590	30531838	We have shown that the invasive phenotype observed with loss of SIM2s can be attributed to an increase in matrix metalloprotease (MMP) activity.	('SIM2s', 'Gene', (64, 69))	('increase', 'PosReg', (94, 102))	('loss', 'Var', (56, 60))	('activity', 'MPA', (135, 143))	('SIM2s', 'Chemical', '-', (64, 69))
6591	30531838	Here, we found that S115A cells have an increase in MMP1 (p<0.006) and MMP9 (p<0.05) expression (Fig.	('expression', 'MPA', (85, 95))	('S115A', 'Var', (20, 25))	('increase', 'PosReg', (40, 48))	('MMP1', 'Gene', '4312', (52, 56))	('MMP9', 'Gene', '4318', (71, 75))	('MMP9', 'Gene', (71, 75))	('MMP1', 'Gene', (52, 56))	('S115A', 'Mutation', 'p.S115A', (20, 25))
6593	30531838	To determine if these characteristics translated into an increased invasive potential in vivo, control, DCIS.com-SIM2s-FLAG, or S115A were injected into the flanks of nude mice and monitored for tumor growth.	('tumor', 'Disease', (195, 200))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('S115A', 'Mutation', 'p.S115A', (128, 133))	('nude mice', 'Species', '10090', (167, 176))	('S115A', 'Var', (128, 133))	('increased', 'PosReg', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('SIM2s', 'Chemical', '-', (113, 118))	('invasive potential', 'CPA', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
6594	30531838	Histological analysis of tumors revealed the SIM2s-FLAG tumors formed distinct lobular structures, whereas the S115A tumors exhibited a more invasive phenotype with increased areas of necrosis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (56, 62))	('necrosis', 'Disease', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SIM2s-FLAG tumors', 'Disease', (45, 62))	('S115A', 'Mutation', 'p.S115A', (111, 116))	('S115A', 'Var', (111, 116))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('SIM2s-FLAG tumors', 'Disease', 'MESH:D009369', (45, 62))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('increased', 'PosReg', (165, 174))	('necrosis', 'Disease', 'MESH:D009336', (184, 192))
6596	30531838	Further, we found that S115A tumors contained decreased E-cadherin compared to SIM2s-FLAG, suggesting induction of EMT (Fig.	('SIM2s', 'Chemical', '-', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('EMT', 'CPA', (115, 118))	('S115A', 'Mutation', 'p.S115A', (23, 28))	('s-FLAG', 'Species', '4465', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('S115A', 'Var', (23, 28))	('decreased', 'NegReg', (46, 55))	('tumors', 'Disease', (29, 35))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
6597	30531838	RT-qPCR analysis of RNA isolated from tumors showed a significant increase of CDH1 in SIM2s-FLAG (p<0.02) but not in S115A (Fig.	('SIM2s-FLAG', 'Var', (86, 96))	('S115A', 'Mutation', 'p.S115A', (117, 122))	('increase', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('SIM2s', 'Chemical', '-', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('CDH1', 'Gene', (78, 82))	('CDH1', 'Gene', '12550', (78, 82))
6599	30531838	Analysis of tumor growth, showed decreased tumor growth in both SIM2s-FLAG (p<0.0001) and S115A (p<0.002) tumors, as compared to controls (Fig.	('tumors', 'Disease', (106, 112))	('S115A', 'Mutation', 'p.S115A', (90, 95))	('S115A', 'Var', (90, 95))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (43, 48))	('SIM2s-FLAG', 'Var', (64, 74))	('tumor', 'Disease', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('SIM2s', 'Chemical', '-', (64, 69))	('s-FLAG', 'Species', '4465', (68, 74))	('decreased tumor', 'Disease', 'MESH:D009369', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('decreased tumor', 'Disease', (33, 48))
6601	30531838	As previous studies have shown that loss of SIM2s leads to an increase in lung metastasis in xenografts, we hypothesized that S115A tumors would have increased lung metastasis.	('SIM2s', 'Gene', (44, 49))	('lung metastasis', 'Disease', 'MESH:D009362', (74, 89))	('lung metastasis', 'Disease', 'MESH:D009362', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('S115A', 'Var', (126, 131))	('lung metastasis', 'Disease', (74, 89))	('loss', 'Var', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('increased lung metastasis', 'Disease', 'MESH:D009362', (150, 175))	('S115A', 'Mutation', 'p.S115A', (126, 131))	('tumors', 'Disease', (132, 138))	('SIM2s', 'Chemical', '-', (44, 49))	('increased lung metastasis', 'Disease', (150, 175))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('increase', 'PosReg', (62, 70))
6603	30531838	We found an increase in human specific beta-2-globulin positive lungs in mice that were injected with S115A cells compared to either the SIM2s-FLAG or control groups (Fig.	('SIM2s', 'Chemical', '-', (137, 142))	('S115A cells', 'Var', (102, 113))	('human', 'Species', '9606', (24, 29))	('mice', 'Species', '10090', (73, 77))	('increase', 'PosReg', (12, 20))	('human specific', 'MPA', (24, 38))	('S115A', 'Mutation', 'p.S115A', (102, 107))
6609	30531838	Possessing a mutated BRCA allele increases an individual's lifetime breast cancer risk by more than 10-fold, raising the risk from 0.08 to 0.82.	('BRCA', 'Gene', (21, 25))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('increases', 'PosReg', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutated', 'Var', (13, 20))	('BRCA', 'Gene', '672', (21, 25))
6610	30531838	A growing body of evidence shows that BRCA1 or BRCA2 mutations are highly prevalent in not only familial breast cancer, but also in sporadic tumors.	('sporadic tumors', 'Disease', (132, 147))	('familial breast cancer', 'Disease', (96, 118))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('BRCA2', 'Gene', (47, 52))	('BRCA1', 'Gene', (38, 43))	('mutations', 'Var', (53, 62))	('prevalent', 'Reg', (74, 83))	('BRCA2', 'Gene', '675', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('sporadic tumors', 'Disease', 'MESH:D009369', (132, 147))	('BRCA1', 'Gene', '672', (38, 43))	('familial breast cancer', 'Disease', 'MESH:D001943', (96, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
6612	30531838	In this study, we show that loss of SIM2s leads to increased genomic instability and correlates with progression from DCIS to IDC (Fig.	('SIM2s', 'Gene', (36, 41))	('loss', 'Var', (28, 32))	('increased', 'PosReg', (51, 60))	('IDC', 'Gene', '4000', (126, 129))	('IDC', 'Gene', (126, 129))	('genomic instability', 'CPA', (61, 80))	('DCIS', 'Disease', (118, 122))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('SIM2s', 'Chemical', '-', (36, 41))
6615	30531838	These findings parallel previous studies demonstrating that the loss of BRCA1 results in increased gammaH2AX foci and sensitivity to mutagenic agents (Fig.	('BRCA1', 'Gene', '672', (72, 77))	('gammaH2AX', 'Protein', (99, 108))	('sensitivity to mutagenic agents', 'MPA', (118, 149))	('BRCA1', 'Gene', (72, 77))	('gammaH2AX', 'Chemical', '-', (99, 108))	('loss', 'Var', (64, 68))	('increased', 'PosReg', (89, 98))
6616	30531838	Previous studies have also suggested that BRCA mutant carriers exhibit higher-grade DCIS cases than would be expected in sporadic tumors.	('BRCA', 'Gene', '672', (42, 46))	('higher-grade', 'Disease', (71, 83))	('BRCA', 'Gene', (42, 46))	('sporadic tumors', 'Disease', 'MESH:D009369', (121, 136))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('mutant', 'Var', (47, 53))	('sporadic tumors', 'Disease', (121, 136))
6618	30531838	Importantly, loss of SIM2s sensitizes cells to synthetic lethality treatments (Fig.	('synthetic lethality treatments', 'MPA', (47, 77))	('SIM2s', 'Chemical', '-', (21, 26))	('SIM2s', 'Gene', (21, 26))	('loss', 'Var', (13, 17))	('sensitizes', 'Reg', (27, 37))
6622	30531838	The discovery of a new factor involved in ATM signaling pathways could have clinical implications as improper ATM signaling has been suggested to result in a 2-5x increase in breast cancer risk, which can be seen in individuals with Ataxia-telangiectasia.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('telangiectasia', 'Phenotype', 'HP:0001009', (240, 254))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('increase', 'PosReg', (163, 171))	('ATM signaling', 'Gene', (110, 123))	('breast cancer', 'Disease', (175, 188))	('Ataxia-telangiectasia', 'Disease', 'MESH:D001260', (233, 254))	('improper', 'Var', (101, 109))	('Ataxia', 'Phenotype', 'HP:0001251', (233, 239))	('Ataxia-telangiectasia', 'Disease', (233, 254))
6627	30531838	Interestingly, loss of SIM2s correlates with a more metastatic phenotype (Fig.	('SIM2s', 'Chemical', '-', (23, 28))	('loss', 'Var', (15, 19))	('SIM2s', 'Gene', (23, 28))
6628	30531838	The S115A point mutation is sufficient to imbue mesenchymal characteristics on what would normally be a highly differentiated xenograft (Fig.	('imbue', 'Reg', (42, 47))	('S115A', 'Var', (4, 9))	('S115A', 'Mutation', 'p.S115A', (4, 9))	('mesenchymal characteristics', 'CPA', (48, 75))
6630	30531838	S115A tumors also exhibit large necrotic centers, a condition associated with group 2 and 3 (intermediate and high-grade) lesions on the Van Duys classification scale (Fig.	('S115A', 'Var', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('necrotic', 'Disease', (32, 40))	('necrotic', 'Disease', 'MESH:D009336', (32, 40))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('S115A', 'Mutation', 'p.S115A', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
6631	30531838	Further, the S115A mutation impairs DDR, showing a significant decrease in gammaH2AX resolution after treatment with IR (Fig.	('gammaH2AX', 'Protein', (75, 84))	('gammaH2AX', 'Chemical', '-', (75, 84))	('decrease', 'NegReg', (63, 71))	('DDR', 'MPA', (36, 39))	('impairs', 'NegReg', (28, 35))	('S115A', 'Mutation', 'p.S115A', (13, 18))	('S115A', 'Var', (13, 18))
6632	30531838	With the dual role of this SNP both in impairing DDR and transitioning cells to a more mesenchymal phenotype, SIM2s could bridge the gap between DDR and EMT.	('DDR', 'MPA', (49, 52))	('SIM2s', 'Chemical', '-', (110, 115))	('SIM2s', 'Var', (110, 115))	('impairing', 'NegReg', (39, 48))	('DDR', 'Disease', (145, 148))
6633	30531838	Here we provide evidence that SIM2s impedes DCIS progression.	('impedes', 'NegReg', (36, 43))	('DCIS progression', 'CPA', (44, 60))	('SIM2s', 'Chemical', '-', (30, 35))	('SIM2s', 'Var', (30, 35))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
6669	28604763	We show that PRH depletion results in increased MCF-7 cell proliferation in part at least due to increased vascular endothelial growth factor signalling.	('increased', 'PosReg', (97, 106))	('MCF-7', 'CellLine', 'CVCL:0031', (48, 53))	('MCF-7', 'Gene', (48, 53))	('increased vascular endothelial growth factor', 'Phenotype', 'HP:0031052', (97, 141))	('depletion', 'Var', (17, 26))	('vascular endothelial growth factor', 'Gene', (107, 141))	('vascular endothelial growth factor', 'Gene', '7422', (107, 141))	('PRH', 'Protein', (13, 16))	('increased', 'PosReg', (38, 47))	('increased MCF', 'Phenotype', 'HP:0005518', (38, 51))
6670	28604763	Moreover, we demonstrate that PRH depletion increases the formation of breast cancer cells with cancer stem cell-like properties.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('depletion', 'Var', (34, 43))	('PRH', 'Protein', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('formation of', 'CPA', (58, 70))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('cancer', 'Disease', (96, 102))	('increases', 'PosReg', (44, 53))
6682	28604763	PRH misregulation is associated with a variety of cancers and leukaemias (reviewed in Gaston et al.and Soufi and Jayaraman).	('misregulation', 'Var', (4, 17))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('PRH', 'Gene', (0, 3))	('associated', 'Reg', (21, 31))	('cancers and leukaemias', 'Disease', 'MESH:D007938', (50, 72))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
6684	28604763	PRH directly regulates the transcription of several genes encoding growth factors, such as VEGFA, growth factor receptors, including FLT1 (VegfR1) and KDR (VegfR2) and inhibits VEGF autocrine signalling.	('VEGF', 'Gene', '7422', (177, 181))	('VEGF', 'Gene', '7422', (91, 95))	('inhibits', 'NegReg', (168, 176))	('PRH', 'Var', (0, 3))	('VEGF', 'Gene', (177, 181))	('transcription', 'MPA', (27, 40))	('regulates', 'Reg', (13, 22))	('FLT1', 'Gene', (133, 137))	('VEGF', 'Gene', (91, 95))	('KDR', 'Gene', (151, 154))
6697	28604763	We have observed previously that transient PRH knockdown (KD) in MCF-7 cells increases cell number.	('MCF-7', 'CellLine', 'CVCL:0031', (65, 70))	('knockdown', 'Var', (47, 56))	('increases', 'PosReg', (77, 86))	('cell number', 'CPA', (87, 98))	('PRH', 'Protein', (43, 46))
6701	28604763	PRH KD in these independent cell lines resulted in increased cell number in MTT cell viability assays (Figure 2b) and increased cell proliferation as measured using a BrdU incorporation assay (Figure 2c).	('cell number', 'CPA', (61, 72))	('BrdU', 'Chemical', 'MESH:D001973', (167, 171))	('increased', 'PosReg', (51, 60))	('increased', 'PosReg', (118, 127))	('cell proliferation', 'CPA', (128, 146))	('PRH KD', 'Var', (0, 6))	('MTT', 'Chemical', 'MESH:C070243', (76, 79))
6709	28604763	Since VEGFA, VEGFC, NRP1 and VEGFR2 are altered in the microarray data and upregulation of KDR (VegfR2) and VEGFA has been observed by us before in transient PRH KD experiments, we set out to determine whether inducible PRH KD also results in cells that have an altered autocrine response to VEGF signalling.	('inducible PRH KD', 'Var', (210, 226))	('VEGF', 'Gene', (108, 112))	('VEGF', 'Gene', (292, 296))	('VEGF', 'Gene', '7422', (13, 17))	('altered', 'Reg', (262, 269))	('VEGF', 'Gene', '7422', (6, 10))	('VEGF', 'Gene', (29, 33))	('VEGF', 'Gene', '7422', (108, 112))	('VEGF', 'Gene', '7422', (292, 296))	('upregulation', 'PosReg', (75, 87))	('NRP1', 'Gene', (20, 24))	('VEGF', 'Gene', (13, 17))	('VEGF', 'Gene', '7422', (29, 33))	('VEGF', 'Gene', (6, 10))
6716	28604763	GO analysis (GATHER) showed that 41 cell cycle (GO:0007049) and 8 angiogenesis genes (GO:00001525) are downregulated upon PRH overexpression including VEGFC (x 0.32) and NRP1 (x 0.47).	('VEGF', 'Gene', '7422', (151, 155))	('PRH', 'Gene', (122, 125))	('overexpression', 'PosReg', (126, 140))	('angiogenesis genes', 'Gene', (66, 84))	('GO:0007049', 'Var', (48, 58))	('downregulated', 'NegReg', (103, 116))	('VEGF', 'Gene', (151, 155))	('NRP1', 'Gene', (170, 174))	('GO:00001525', 'Var', (86, 97))	('expression', 'Species', '29278', (130, 140))	('cell', 'CPA', (36, 40))
6718	28604763	VEGFC expression has recently been shown to be correlated with mammary tumour proliferation and VEGFC falls within the subset of 414 genes that are inversely regulated, that is upregulated in PRH KD but downregulated by PRH overexpression.	('upregulated', 'PosReg', (177, 188))	('PRH', 'Var', (192, 195))	('tumour proliferation', 'Disease', 'MESH:C565054', (71, 91))	('expression', 'Species', '29278', (6, 16))	('falls', 'Phenotype', 'HP:0002527', (102, 107))	('VEGF', 'Gene', '7422', (0, 4))	('downregulated', 'NegReg', (203, 216))	('tumour proliferation', 'Disease', (71, 91))	('VEGF', 'Gene', '7422', (96, 100))	('correlated', 'Reg', (47, 57))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('expression', 'Species', '29278', (228, 238))	('VEGF', 'Gene', (0, 4))	('VEGF', 'Gene', (96, 100))
6719	28604763	Changes in VEGFC may therefore contribute to the growth phenotype observed upon perturbation of PRH levels.	('VEGF', 'Gene', (11, 15))	('VEGF', 'Gene', '7422', (11, 15))	('growth phenotype', 'MPA', (49, 65))	('Changes', 'Var', (0, 7))	('contribute', 'Reg', (31, 41))
6721	28604763	Flow cytometry analysis showed that there is a dramatic increase in the CD44hi/CD24lo population in PRH KD cell lines compared with controls (Figures 4a and b) corresponding to the changes in gene expression in the microarray (Figure 3a).	('CD44hi/CD24lo', 'Var', (72, 85))	('changes', 'Reg', (181, 188))	('increase', 'PosReg', (56, 64))	('expression', 'Species', '29278', (197, 207))
6723	28604763	Significantly more mammospheres (>50mum size particles) were produced by MCF-7 PRH KD cells compared with controls when seeded at 20 000 cells/well but this was not observed at a lower cell density, possibly due to altered autocrine cell signalling at high cell densities (Figure 4c).	('more', 'PosReg', (14, 18))	('MCF-7', 'CellLine', 'CVCL:0031', (73, 78))	('MCF-7 PRH KD cells', 'Var', (73, 91))
6736	28604763	However 4T1L cells overexpressing PRH produced significantly smaller tumours than control cells (Figures 5b and 5c).	('tumours', 'Disease', (69, 76))	('smaller', 'NegReg', (61, 68))	('PRH', 'Var', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
6738	28604763	Since PRH expression is altered in breast cancer cells and PRH depletion in MCF-7 cells results in increased cell proliferation and increased formation CSC-like cells, we examined public databases for evidence linking PRH expression to breast tumour formation and breast tumour progression.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast tumour', 'Disease', 'MESH:D001943', (264, 277))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('altered', 'Reg', (24, 31))	('formation CSC-like', 'MPA', (142, 160))	('breast tumour', 'Disease', (264, 277))	('PRH', 'Gene', (6, 9))	('breast tumour', 'Phenotype', 'HP:0100013', (264, 277))	('increased', 'PosReg', (132, 141))	('increased', 'PosReg', (99, 108))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('PRH', 'Gene', (59, 62))	('depletion', 'Var', (63, 72))	('MCF-7', 'CellLine', 'CVCL:0031', (76, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('cell proliferation', 'CPA', (109, 127))	('breast tumour', 'Disease', 'MESH:D001943', (236, 249))	('expression', 'Species', '29278', (10, 20))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('expression', 'Species', '29278', (222, 232))	('breast tumour', 'Disease', (236, 249))	('breast tumour', 'Phenotype', 'HP:0100013', (236, 249))
6745	28604763	In liver cancer cells, PRH overexpression downregulates tumour growth in mouse xenograft models and PRH antagonizes c-Myc activity.	('antagonizes', 'NegReg', (104, 115))	('PRH', 'Var', (100, 103))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('expression', 'Species', '29278', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('liver cancer', 'Disease', (3, 15))	('tumour growth', 'Disease', (56, 69))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('mouse', 'Species', '10090', (73, 78))	('tumour growth', 'Disease', 'MESH:D006130', (56, 69))	('downregulates', 'NegReg', (42, 55))	('overexpression', 'PosReg', (27, 41))	('c-Myc activity', 'MPA', (116, 130))
6777	28604763	The tissues were stained with the Vector ImmPress Excel anti-mouse Ig or anti-rabbit Ig peroxidase kits (MP-7602 or MP-7601, respectively, Vector Labs, Burlingame, CA, USA) and visualized with the ImmPact NovaRed peroxidase substrate (Vector Labs) according to the manufacturer's instructions.	('rabbit', 'Species', '9986', (78, 84))	('MP-7602', 'Var', (105, 112))	('MP-7601', 'Var', (116, 123))	('mouse', 'Species', '10090', (61, 66))
6791	28604763	Endogenous peroxidase activity was blocked with 3% v/v H2O2 (Sigma) and then DNA denatured using 2 m HCl (Sigma).	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('H2O2', 'Var', (55, 59))	('HCl', 'Chemical', '-', (101, 104))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('activity', 'MPA', (22, 30))	('blocked', 'NegReg', (35, 42))
6795	28604763	Cells resuspended in 100 mul phosphate-buffered saline were stained for 15 min with CD24-FITC and CD44-TRITC or CD133-APC (BD Biosciences, G44-26) and then analysed using a FACS Analyser Cyan ADP (Beckman Coulter, Brea, CA, USA).	('CD24-FITC', 'Chemical', '-', (84, 93))	('phosphate-buffered saline', 'Chemical', '-', (29, 54))	('CD133-APC', 'Var', (112, 121))	('CD24-FITC', 'Var', (84, 93))	('TRITC', 'Chemical', 'MESH:C009434', (103, 108))	('CD44-TRITC', 'Var', (98, 108))	('ADP', 'Chemical', 'MESH:D000244', (192, 195))
6837	17683529	The likelihood of contralateral breast cancer was 1.53-fold higher (95% CI 1.05 - 2.24, p = 0.03) in radiotherapy arms.	('contralateral breast cancer', 'Disease', 'MESH:D001943', (18, 45))	('radiotherapy', 'Var', (101, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('contralateral breast cancer', 'Disease', (18, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
6876	17683529	There were new breast events in 7% of patients in the radiotherapy group and 16% of those in the no-radiotherapy group (P.001).	('breast', 'Disease', (15, 21))	('radiotherapy', 'Var', (54, 66))	('patients', 'Species', '9606', (38, 46))
6892	17683529	Our meta-analysis of four trials that evaluated adjuvant radiotherapy in 3665 patients with CDIS submitted to BCT showed that adjuvant RT leads to a significant reduction (60%) in the risk of a local (invasive and DCIS) in-breast recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (214, 218))	('reduction', 'NegReg', (161, 170))	('adjuvant', 'Var', (126, 134))	('patients', 'Species', '9606', (78, 86))
6901	17683529	A prospectively collected but nonrandomized study suggested that local recurrence rates for lesions with USC/VNPI scores 3 to 4 were acceptably low with excision alone (local recurrence-free survival rates exceeded 99 percent at eight years of follow-up), while those with intermediate scores (5 to 7) required the addition of RT to achieve optimal local control.	('USC/VNPI', 'Gene', (105, 113))	('local recurrence', 'CPA', (65, 81))	('to 7', 'Species', '1214577', (296, 300))	('low', 'NegReg', (144, 147))	('scores 3 to 4', 'Var', (114, 127))
6912	17683529	Moreover, our data evidenced that contralateral tumor rates are slightly increased by radiotherapy (Figure 3).	('increased', 'PosReg', (73, 82))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('radiotherapy', 'Var', (86, 98))
6933	26902100	With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial alphavss3 for differentiating benign from cancerous lesions.	('benign', 'Disease', (172, 178))	('VEGFR-2', 'Gene', '3791', (86, 93))	('cancerous lesions', 'Disease', 'MESH:D009062', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('VEGFR-2', 'Gene', (86, 93))	('endothelial', 'Var', (74, 85))	('cancerous lesions', 'Disease', (184, 201))
6993	26902100	At an optimal cut-off of 0.065% endothelial alphavss3 integrin area fraction, benign and malignant breast lesions were predicted to be diagnosed with a sensitivity of 67.5% and a specificity of 62.5% (Supplementary Table S5).	('malignant breast lesions', 'Disease', (89, 113))	('benign', 'Disease', (78, 84))	('0.065%', 'Var', (25, 31))	('malignant breast lesions', 'Disease', 'MESH:D001943', (89, 113))
7000	26902100	However, besides a pilot phase study on breast cancer patients using radiolabeled alphaVss3-targeted RGD peptides and PET demonstrating a significant probe uptake in the primary lesion and in the metastases, clinical studies comparing the diagnostic power of functional vs. molecular imaging for differentiating (mammographically) suspect tumors or for monitoring recurrent lesions upon breast cancer surgery have not yet been reported.	('breast cancer', 'Phenotype', 'HP:0003002', (387, 400))	('patients', 'Species', '9606', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('breast cancer', 'Disease', 'MESH:D001943', (387, 400))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (387, 400))	('breast cancer', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('probe', 'MPA', (150, 155))	('tumors', 'Disease', (339, 345))	('uptake', 'PosReg', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('peptides', 'Var', (105, 113))	('alphaVss3-targeted', 'Gene', (82, 100))	('metastases', 'Disease', 'MESH:D009362', (196, 206))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('peptides', 'Chemical', 'MESH:D010455', (105, 113))	('metastases', 'Disease', (196, 206))
7030	25252808	The p21-dependent downregulation of H2AX was seen both in cell culture and the MMTV-neu mouse model of Her2-positive breast cancer.	('neu', 'Gene', '2064', (84, 87))	('p21-dependent', 'Var', (4, 17))	('H2AX', 'Protein', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('neu', 'Gene', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('mouse', 'Species', '10090', (88, 93))	('downregulation', 'NegReg', (18, 32))	('MMTV', 'Species', '11757', (79, 83))
7032	25252808	This impairment resulted in both increased DNA instability in the form of somatic copy number alterations, and in increased sensitivity to the chemotherapeutic drug doxorubicin.	('alterations', 'Var', (94, 105))	('increased', 'PosReg', (114, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (165, 176))	('increased', 'PosReg', (33, 42))	('DNA instability', 'MPA', (43, 58))	('sensitivity to the', 'MPA', (124, 142))
7034	25252808	Most cancer cells are characterized by genomic instability manifested by aneuploidy with numerous karyotypic changes including whole chromosome gain and losses, translocations, deletions, amplifications, etc.	('deletions', 'Var', (177, 186))	('gain', 'PosReg', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('amplifications', 'Var', (188, 202))	('losses', 'NegReg', (153, 159))	('neu', 'Gene', '2064', (74, 77))	('cancer', 'Disease', (5, 11))	('neu', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('whole chromosome', 'CPA', (127, 143))	('translocations', 'Var', (161, 175))
7036	25252808	aneuploidy, often results from abnormalities in mitosis, as well as abnormalities in the double strand break repair or telomere maintenance that can lead to repeated chromosome breakage-fusion-bridge cycles.	('abnormalities in mitosis', 'Disease', 'MESH:D000014', (31, 55))	('neu', 'Gene', '2064', (1, 4))	('neu', 'Gene', (1, 4))	('abnormalities in mitosis', 'Disease', (31, 55))	('double', 'CPA', (89, 95))	('results from', 'Reg', (18, 30))	('chromosome breakage', 'Phenotype', 'HP:0040012', (166, 185))	('lead to', 'Reg', (149, 156))	('telomere maintenance', 'CPA', (119, 139))	('abnormalities', 'Var', (68, 81))	('chromosome breakage-fusion-bridge', 'CPA', (166, 199))
7043	25252808	Indeed, amplifications and deletions in ductal carcinoma in situ (DCIS) were similar to those in neighboring tumors.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (40, 64))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('ductal carcinoma in situ', 'Disease', (40, 64))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (40, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (47, 64))	('deletions', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
7047	25252808	For example, expression of H-RasV12 or inactivation of PTEN or Rb1 induces chromosomal instability in various cell lines.	('chromosomal instability', 'Phenotype', 'HP:0040012', (75, 98))	('PTEN', 'Gene', '5728', (55, 59))	('Rb1', 'Gene', '5925', (63, 66))	('inactivation', 'Var', (39, 51))	('chromosomal instability', 'MPA', (75, 98))	('induces', 'Reg', (67, 74))	('Rb1', 'Gene', (63, 66))	('H-RasV12', 'Protein', (27, 35))	('PTEN', 'Gene', (55, 59))
7049	25252808	OIS represents an early barrier to neoplastic transformation, and therefore in order to become cancerous, cells acquire mutations or epigenetic changes that allow them to "turn off" the senescence program.	('cancerous', 'Disease', 'MESH:D009369', (95, 104))	('senescence program', 'CPA', (186, 204))	('epigenetic changes', 'Var', (133, 151))	('cancerous', 'Disease', (95, 104))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
7066	25252808	Importantly, knockout of p21 reversed the downregulation of H2AX in NeuT-expressing mice (Fig.	('p21', 'Gene', (25, 28))	('Neu', 'Gene', (68, 71))	('knockout', 'Var', (13, 21))	('H2AX', 'Protein', (60, 64))	('downregulation', 'NegReg', (42, 56))	('Neu', 'Gene', '2064', (68, 71))	('mice', 'Species', '10090', (84, 88))
7080	25252808	The main mechanism by which p21 may inhibit the transcription of a specific gene involves inhibition of Rb phosphorylation by CDK4, 6.	('inhibition', 'NegReg', (90, 100))	('inhibit', 'NegReg', (36, 43))	('transcription', 'MPA', (48, 61))	('Rb', 'Chemical', 'MESH:D012413', (104, 106))	('CDK4, 6', 'Gene', '1019;1021', (126, 133))	('p21', 'Var', (28, 31))
7083	25252808	We further tested if knockdown of Rb1 reverses the effects of Her2 on H2AX downregulation.	('downregulation', 'NegReg', (75, 89))	('H2AX', 'Protein', (70, 74))	('Rb1', 'Gene', '5925', (34, 37))	('Her2', 'Protein', (62, 66))	('tested', 'Reg', (11, 17))	('Rb1', 'Gene', (34, 37))	('knockdown', 'Var', (21, 30))
7095	25252808	Upon exposure to genotoxic agents that cause double stranded DNA breaks, such as gamma-irradiation, H2AX undergoes phosphorylation at Ser139.	('H2AX', 'Gene', (100, 104))	('double', 'Var', (45, 51))	('Ser139', 'Chemical', '-', (134, 140))	('rad', 'Gene', '6236', (89, 92))	('rad', 'Gene', (89, 92))	('phosphorylation', 'MPA', (115, 130))	('undergoes', 'Reg', (105, 114))
7097	25252808	To test this possibility, NeuT-transformed MCF10A cells were subjected to 5Gy gamma-irradiation while the formation of foci by gammaH2AX and the quantities of two other important DNA repair factors, RPA and p53BP1 were monitored by immunoflourescence.	('rad', 'Gene', (86, 89))	('p53BP1', 'Gene', (207, 213))	('p53BP1', 'Gene', '7158', (207, 213))	('Neu', 'Gene', (26, 29))	('Neu', 'Gene', '2064', (26, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (43, 49))	('gammaH2AX', 'Chemical', '-', (127, 136))	('gammaH2AX', 'Var', (127, 136))	('rad', 'Gene', '6236', (86, 89))
7099	25252808	For all three repair factors, gammaH2AX, RPA and p53BP1, we observed significantly reduced foci formation at the initial 2-hour time point (Fig.	('reduced', 'NegReg', (83, 90))	('gammaH2AX', 'Chemical', '-', (30, 39))	('RPA', 'Var', (41, 44))	('gammaH2AX', 'Var', (30, 39))	('foci formation', 'CPA', (91, 105))	('p53BP1', 'Gene', (49, 55))	('p53BP1', 'Gene', '7158', (49, 55))
7100	25252808	Interestingly, with gammaH2AX and RPA factors, we also observed slower foci resolution, which suggests suppressed DNA repair (Fig.	('slower', 'NegReg', (64, 70))	('foci resolution', 'CPA', (71, 86))	('suppressed', 'NegReg', (103, 113))	('gammaH2AX', 'Chemical', '-', (20, 29))	('DNA repair', 'CPA', (114, 124))	('gammaH2AX', 'Var', (20, 29))
7108	25252808	the sum of each SCNA's copy-number change multiplied by its length, as an aggregate measure of DNA instability (SI).	('DNA instability', 'Disease', (95, 110))	('copy-number', 'Var', (23, 34))	('SI', 'Disease', 'None', (112, 114))
7119	25252808	mutations in BRCA1 or BRCA2), which result in further cancer-driving mutations.	('mutations', 'Var', (69, 78))	('BRCA1', 'Gene', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('BRCA2', 'Gene', (22, 27))	('cancer', 'Disease', (54, 60))	('mutations', 'Var', (0, 9))	('BRCA2', 'Gene', '675', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA1', 'Gene', '672', (13, 18))
7153	25252808	This version of NeuT carries the activating V664E mutation (NeuT).	('Neu', 'Gene', '2064', (16, 19))	('Neu', 'Gene', (60, 63))	('Neu', 'Gene', '2064', (60, 63))	('V664E', 'Var', (44, 49))	('activating', 'PosReg', (33, 43))	('V664E', 'Mutation', 'p.V664E', (44, 49))	('Neu', 'Gene', (16, 19))
7165	25252808	H2AX and p21 staining was performed on these slides via standard ABC method (Vector Laboratory, Burlingame, CA, USA) using the following antibodies: p21Waf-1 Ab-9 (NeoMarkers, RB-032-P1; 1:25); and H2AX (Proteintech Group # 10856-1-AP; 1:100).	('ABC', 'Gene', '10058', (65, 68))	('p21Waf-1', 'Var', (149, 157))	('RB', 'Disease', 'MESH:D012175', (176, 178))	('ABC', 'Gene', (65, 68))
7170	25252808	FVB/N-Tg(MMTVneu)202Mul/J [Neu+/+;p21+/+] (F) was crossed with B6129SF2/J B6;129S2-Cdkn1a<tm1Tyj>/J p21-/- (M); P1 females(Neu+/-; p21+/-) were back-crossed with B6129SF2/J B6;129S2-Cdkn1a<tm1Tyj>/J p21-/- (M) and P2 females from the corresponding litter were genotyped (see below) to identify [Neu+/-; p21-/-] animals.	('Neu', 'Gene', (295, 298))	('Neu', 'Gene', '2064', (295, 298))	('Neu', 'Gene', (123, 126))	('B6129SF2/J B6;129S2-Cdkn1a<tm1Tyj>/J', 'Var', (162, 198))	('Neu', 'Gene', (27, 30))	('Neu', 'Gene', '2064', (123, 126))	('Neu', 'Gene', '2064', (27, 30))
7195	33430113	Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs.	('CCL21', 'Gene', '6366', (166, 171))	('accumulation', 'PosReg', (96, 108))	('Remodeling', 'Var', (0, 10))	('dysregulation', 'MPA', (43, 56))	('CCL21', 'Gene', (166, 171))	('CCL21', 'Gene', '6366', (112, 117))	('CCL21', 'Gene', '6366', (60, 65))	('heparan sulfate', 'Chemical', 'MESH:D006497', (180, 195))	('CCL21', 'Gene', (112, 117))	('CCL21', 'Gene', (60, 65))	('loss', 'NegReg', (158, 162))
7207	33430113	Vascular changes in the TDLNs that affect HEV or FRC functions would thus be predicted to also impair the possibility to develop tumor immunity.	('changes', 'Var', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Vascular changes', 'Phenotype', 'HP:0002597', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('HEV', 'MPA', (42, 45))	('tumor', 'Disease', (129, 134))	('FRC functions', 'MPA', (49, 62))	('impair', 'NegReg', (95, 101))
7221	33430113	Figure 1C summarizes the fraction of vessels (non-dilated, intermediately dilated and highly dilated) across all HEVs in each patient group, with an average of 10% total dilated HEVs in OD and 34% in DCIS to be compared with 48% in IDCmet- and 49% in IDCmet+.	('IDC', 'Gene', (232, 235))	('dilated', 'MPA', (170, 177))	('IDC', 'Gene', '4000', (251, 254))	('patient', 'Species', '9606', (126, 133))	('IDC', 'Gene', (251, 254))	('DCIS', 'Phenotype', 'HP:0030075', (200, 204))	('DCIS', 'Var', (200, 204))	('IDC', 'Gene', '4000', (232, 235))
7227	33430113	Taken together these data suggest that remodeling of paracortical HEVs are common pathological changes in patients with luminal invasive BC, likely to affect the whole axilla, and are independent of the presence of nodal metastasis.	('affect', 'Reg', (151, 157))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('remodeling', 'Var', (39, 49))	('patients', 'Species', '9606', (106, 114))	('luminal invasive BC', 'Disease', (120, 139))	('luminal', 'Chemical', 'MESH:D010634', (120, 127))
7231	33430113	However, paired analysis of non-dilated versus highly dilated HEVs in patients with IDCmet- and IDCmet+, demonstrated that highly dilated HEVs, consistently, displayed higher frequency of CCL21 loss than non-dilated HEVs, in the same patients (Figure S3).	('patients', 'Species', '9606', (70, 78))	('IDC', 'Gene', (84, 87))	('IDC', 'Gene', '4000', (96, 99))	('loss', 'NegReg', (194, 198))	('IDC', 'Gene', (96, 99))	('IDC', 'Gene', '4000', (84, 87))	('patients', 'Species', '9606', (234, 242))	('CCL21', 'Gene', '6366', (188, 193))	('highly dilated', 'Var', (123, 137))	('CCL21', 'Gene', (188, 193))
7250	33430113	The analysis was limited to highly dilated HEVs and the CCL21+/alphaSMA- cells were scored as being 100%, >50%, <50% or 0% CD3+ (Figure 5D).	('CCL21', 'Gene', '6366', (56, 61))	('CCL21', 'Gene', (56, 61))	('alphaSMA', 'Gene', '58', (63, 71))	('<50', 'Var', (112, 115))	('alphaSMA', 'Gene', (63, 71))
7256	33430113	After adhesion to HEVs, lymphocyte recruitment into the LN and extravascular migration into the paracortex has been shown to be dependent on the presence of immobilized CCL21.	('lymphocyte recruitment into the LN', 'CPA', (24, 58))	('CCL21', 'Gene', '6366', (169, 174))	('CCL21', 'Gene', (169, 174))	('adhesion', 'Var', (6, 14))	('extravascular migration into the paracortex', 'CPA', (63, 106))
7286	33430113	This support that in human invasive BC, remodeling of the HEVs is associated with concomitant dysregulation of perivascular FRCs.	('dysregulation', 'MPA', (94, 107))	('BC', 'Phenotype', 'HP:0003002', (36, 38))	('invasive BC', 'Disease', (27, 38))	('human', 'Species', '9606', (21, 26))	('associated', 'Reg', (66, 76))	('remodeling', 'Var', (40, 50))
7292	33430113	Thus, changes in the balance of immobilized CCL21 to free CCL21 in solution is expected to inhibit effective migration of lymphocytes from the HEVs into the LN parenchyma and to lead to increased accumulation of CCL21 on the surface of arrested CCR7+ cells.	('CCL21', 'Gene', (58, 63))	('increased accumulation', 'PosReg', (186, 208))	('inhibit', 'NegReg', (91, 98))	('changes', 'Var', (6, 13))	('arrest', 'Disease', 'MESH:D006323', (236, 242))	('CCL21', 'Gene', '6366', (44, 49))	('CCL21', 'Gene', '6366', (212, 217))	('CCR7', 'Gene', '1236', (245, 249))	('CCL21', 'Gene', (44, 49))	('arrest', 'Disease', (236, 242))	('CCR7', 'Gene', (245, 249))	('CCL21', 'Gene', (212, 217))	('CCL21', 'Gene', '6366', (58, 63))
7296	33430113	Changes in expression of sulfated protein glycans (PG) in the primary tumor is frequently reported and can have multiple effects on e.g., tumor invasion, survival, proliferation and tumor immune evasion.	('glycans', 'Chemical', 'MESH:D011134', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (182, 187))	('proliferation', 'CPA', (164, 177))	('tumor', 'Disease', (138, 143))	('expression', 'MPA', (11, 21))	('survival', 'CPA', (154, 162))	('tumor', 'Disease', (70, 75))	('effects', 'Reg', (121, 128))	('PG', 'Protein', (51, 53))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
7297	33430113	Pre-metastatic effects caused by changes in HS has however, to our knowledge, not earlier been described.	('changes', 'Var', (33, 40))	('Pre-metastatic effects', 'CPA', (0, 22))	('HS', 'Chemical', 'MESH:D006497', (44, 46))
7300	33430113	The underlying mechanism for downregulation of HS and dysregulation of FRC functions in TDLNs in IDC could be multifactorial and will be an interesting question for continued research.	('downregulation', 'NegReg', (29, 43))	('HS', 'Chemical', 'MESH:D006497', (47, 49))	('FRC functions', 'Gene', (71, 84))	('IDC', 'Gene', '4000', (97, 100))	('IDC', 'Gene', (97, 100))	('dysregulation', 'Var', (54, 67))
7304	33430113	Lymphotoxin beta receptor (LTBR) signaling is required for maintaining HEV functions in mice and endothelial-specific deletion of LTBR results in reduced LN formation with effects on HEVs in the LNs that do form.	('LTBR', 'Gene', (27, 31))	('Lymphotoxin beta receptor', 'Gene', '17000', (0, 25))	('reduced', 'NegReg', (146, 153))	('Lymphotoxin beta receptor', 'Gene', (0, 25))	('LTBR', 'Gene', '17000', (130, 134))	('LN formation', 'MPA', (154, 166))	('LTBR', 'Gene', '17000', (27, 31))	('deletion', 'Var', (118, 126))	('mice', 'Species', '10090', (88, 92))	('LTBR', 'Gene', (130, 134))
7311	33430113	Disruption of paracortical immobilized CCL21-gradients is also likely to reduce the possibilities for effective interactions between T-lymphocytes and DCs.	('interactions', 'Interaction', (112, 124))	('CCL21', 'Gene', '6366', (39, 44))	('CCL21', 'Gene', (39, 44))	('reduce', 'NegReg', (73, 79))	('Disruption', 'Var', (0, 10))
7348	33430113	Highly dilated HEVs from IDCmet- and IDCmet+ (n = 14 +- 6 HEVs per patient) were selected and scored as having only (100%), more than 50% (>50%), less than 50% (<50%), or no (0%) CD3+/CCL21+/alphaSMA- cells.	('IDC', 'Gene', '4000', (37, 40))	('less than', 'Var', (146, 155))	('CCL21', 'Gene', '6366', (184, 189))	('alphaSMA', 'Gene', (191, 199))	('IDC', 'Gene', (37, 40))	('IDC', 'Gene', '4000', (25, 28))	('CCL21', 'Gene', (184, 189))	('IDC', 'Gene', (25, 28))	('alphaSMA', 'Gene', '58', (191, 199))	('patient', 'Species', '9606', (67, 74))
7366	28628656	Ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) lesions were more frequently upgraded after CCNB (8/23 and 3/5, respectively) than after VAB (2/26 and 0/4, respectively P = 0.028).	('VAB', 'Chemical', '-', (159, 162))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (0, 16))	('CCNB', 'Var', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (36, 63))	('upgraded', 'PosReg', (99, 107))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 24))	('Ductal carcinoma', 'Disease', (0, 16))	('atypical ductal hyperplasia', 'Disease', (36, 63))	('CCNB', 'Chemical', '-', (114, 118))
7368	28628656	The underestimation rate of ultrasound-detected non-mass lesion was significantly lower with VAB than with CCNB.	('VAB', 'Chemical', '-', (93, 96))	('CCNB', 'Chemical', '-', (107, 111))	('VAB', 'Var', (93, 96))	('lower', 'NegReg', (82, 87))
7439	28628656	Notably, we observed a significantly lower rate of underestimation with VAB than with CCNB; specifically, our DCIS underestimation rate with 13-G VAB (7.7%) was lower than the rates in previous reports with 11-G VAB (17%-41%).	('lower', 'NegReg', (161, 166))	('VAB', 'Chemical', '-', (146, 149))	('VAB', 'Chemical', '-', (72, 75))	('13-G', 'Var', (141, 145))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('DCIS', 'MPA', (110, 114))	('CCNB', 'Chemical', '-', (86, 90))	('VAB', 'Chemical', '-', (212, 215))	('underestimation', 'NegReg', (115, 130))	('13-G VAB', 'Chemical', '-', (141, 149))
7469	24859938	Furthermore, XRT may impede wound healing and increase complication rates, as well as complicate decision making should a patient experience a local recurrence.	('complication rates', 'CPA', (55, 73))	('wound healing', 'CPA', (28, 41))	('increase', 'PosReg', (46, 54))	('patient', 'Species', '9606', (122, 129))	('XRT', 'Var', (13, 16))	('impede wound healing', 'Phenotype', 'HP:0001058', (21, 41))	('complicate', 'Reg', (86, 96))	('complicate decision', 'Phenotype', 'HP:0001289', (86, 105))	('impede', 'NegReg', (21, 27))
7534	25995984	Responders (n = 77) received 2 further cycles of AC and were randomised to 4 cycles of T (100 mg/m2) (Group A) or T (75 mg/m2) and X (2000 mg/m2/day), day one to 14 of each 3 weekly cycle (Group B).	('AC', 'Chemical', 'MESH:D000186', (49, 51))	('T (100 mg/m2', 'Var', (87, 99))	('T (75 mg/m2', 'Var', (114, 125))
7538	25995984	Triple -ve and HER2 +ve tumours, and persistent ALN disease were risk factors for metastases.	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('ALN disease', 'Disease', 'MESH:D004194', (48, 59))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('Triple', 'Var', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('ALN disease', 'Disease', (48, 59))
7540	25995984	NAC-X did not increase breast and ALN pCR but improved 4-year DFS, without detriment to QoL.	('ALN', 'Chemical', '-', (34, 37))	('CR', 'Chemical', 'MESH:D002857', (39, 41))	('DFS', 'MPA', (62, 65))	('improved', 'PosReg', (46, 54))	('NAC-X', 'Chemical', '-', (0, 5))	('NAC-X', 'Var', (0, 5))
7607	25995984	Triple negative and HER2 +ve tumours had the highest pCR, whilst luminal A the lowest.	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('Triple negative', 'Var', (0, 15))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('HER2', 'Gene', (20, 24))	('CR', 'Chemical', 'MESH:D002857', (54, 56))	('pCR', 'MPA', (53, 56))	('HER2', 'Gene', '2064', (20, 24))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
7621	25995984	Severe hand-foot syndrome was more common, with the use of X: Groups A + C versus B + D (chi 2 = 6.035, p = 0.014).	('B + D', 'Var', (82, 87))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (7, 25))	('hand-foot syndrome', 'Disease', (7, 25))
7646	25995984	Two studies have reported an increased pCR in the breast with NAC-X combinations (Lee et al.	('pCR', 'CPA', (39, 42))	('NAC-X combinations', 'Var', (62, 80))	('increased', 'PosReg', (29, 38))	('CR', 'Chemical', 'MESH:D002857', (40, 42))	('NAC-X', 'Chemical', '-', (62, 67))
7658	25995984	However, patients with triple -ve cancers or 3 involved ALNs had an improved 5-year DFS and OS with capecitabine (Joensuu et al.).	('DFS', 'MPA', (84, 87))	('patients', 'Species', '9606', (9, 17))	('triple -ve', 'Var', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('capecitabine', 'Chemical', 'MESH:D000069287', (100, 112))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('OS', 'Chemical', '-', (92, 94))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('improved', 'PosReg', (68, 76))	('ALNs', 'Chemical', '-', (56, 60))
7748	32199230	It is interesting to note that the presence of DCIS at the pathologically close margin (as opposed to invasive cancer) correlated to an increased likelihood of re-excision (p = 0.018).	('presence', 'Var', (35, 43))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('invasive cancer', 'Disease', (102, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('re-excision', 'CPA', (160, 171))	('invasive cancer', 'Disease', 'MESH:D009362', (102, 117))	('DCIS', 'Disease', (47, 51))
7774	31776839	Basically, they recruit screen detected patients presenting with microcalcification alone and diagnosed with either low grade (LORD) or low grade and low end of intermediate grade non-high grade (LORIS, COMET) DCIS on the basis of (large gauge) needle biopsies providing generous sampling.	('patients', 'Species', '9606', (40, 48))	('DCIS', 'Phenotype', 'HP:0030075', (210, 214))	('non-high grade', 'Var', (180, 194))	('microcalcification', 'Disease', (65, 83))
7796	19900937	Postmenopausal HT is associated with an increased risk of ADH with or without cancer.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ADH', 'Disease', (58, 61))	('Postmenopausal', 'Var', (0, 14))
7833	19900937	We found 833 cases of cancer with ADH in the same breast (vs. 8,161 of cancer without ADH).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('ADH', 'Var', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
7840	19900937	Cancer with ADH was more likely to be low grade (grade 1 or 2) when compared to cancer with no ADH (OR for DCIS= 2.38, 95% CI = 1.73, 3.28; OR for invasive cancers = 1.70, 95% CI=1.33, 2.19, Table 4).	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('invasive cancers', 'Disease', 'MESH:D009362', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('low grade', 'CPA', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('invasive cancers', 'Disease', (147, 163))	('Cancer', 'Disease', (0, 6))	('ADH', 'Var', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
7841	19900937	Ninety percent of invasive cancers with ADH were estrogen receptor positive compared to 83% of cancers without ADH (OR=1.77; 95% CI=1.26, 2.57).	('positive', 'Reg', (67, 75))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('estrogen receptor', 'Protein', (49, 66))	('cancers', 'Disease', (95, 102))	('invasive cancers', 'Disease', 'MESH:D009362', (18, 34))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('ADH', 'Var', (40, 43))	('invasive cancers', 'Disease', (18, 34))	('cancers', 'Disease', (27, 34))
7971	19039266	The underestimation rate for a carcinoma was 7.4% in the current study with two of the DCIS lesions identified as an IDC and one of the DCIS lesions identified as a DCIS with microinvasion.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('lesions', 'Var', (92, 99))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('DCIS', 'Disease', (87, 91))	('carcinoma', 'Disease', (31, 40))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('carcinoma', 'Disease', 'MESH:D002277', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
8078	33649333	Heat-mediated epitope retrieval was carried out onboard as follows: CD4 and CD8 using Leica Bond ER2 (high pH, AR9640) for 20 min at 97  C and FOXP3 using Leica Bond ER1 (low pH, AR9961) for 30 min at 97  C. Slides for CK5 (Dako, mouse D5/16 B4, M7237) were stained on the Dako Link48 automated immunostaining platform, and primary antibody detected using the Dako Envision FLEX kit (Agilent, K8023) according to manufacturer's instructions.	('ER', 'Gene', '2069', (97, 99))	('mouse', 'Species', '10090', (230, 235))	('ER', 'Gene', '2069', (166, 168))	('ER1', 'Gene', (166, 169))	('M7237', 'Var', (246, 251))	('CD8', 'Gene', (76, 79))	('CD8', 'Gene', '925', (76, 79))	('ER1', 'Gene', '57708', (166, 169))
8091	33649333	Quantitative measures include DICE, positive predictive value (PPV), negative predictive value (NPV), true positive rate (TPR), true negative rate (TNR), false-positive rate (FPR) and false-negative rate (FNR) for each test dataset across all slides.	('PR', 'Gene', '140738', (176, 178))	('DICE', 'MPA', (30, 34))	('negative predictive value', 'MPA', (69, 94))	('false-positive rate', 'MPA', (154, 173))	('true', 'MPA', (128, 132))	('false-negative rate', 'Var', (184, 203))	('positive predictive value', 'MPA', (36, 61))	('PR', 'Gene', '140738', (123, 125))	('true positive rate', 'MPA', (102, 120))
8116	29495625	On the one hand, Cx43 has long been considered a tumor suppressor with studies demonstrating it was under-expressed at the mRNA and the protein level in cancer cell lines or aberrant localization and phosphorylation in tumors.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('aberrant', 'Var', (174, 182))	('cancer', 'Disease', (153, 159))	('tumors', 'Disease', (219, 225))	('tumor', 'Disease', (219, 224))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('Cx43', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('phosphorylation', 'MPA', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('rat', 'Species', '10116', (86, 89))
8120	29495625	Mice expressing a mutant form of Cx43 (G60S) also showed increased breast tumor metastasis to the lung.	('breast tumor', 'Phenotype', 'HP:0100013', (67, 79))	('Cx43', 'Gene', (33, 37))	('mutant', 'Var', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast tumor', 'Disease', 'MESH:D001943', (67, 79))	('G60S', 'Mutation', 'p.G60S', (39, 43))	('increased', 'PosReg', (57, 66))	('Mice', 'Species', '10090', (0, 4))	('breast tumor', 'Disease', (67, 79))
8127	29495625	Genome-wide gene expression profiling has produced classification schemes including the intrinsic subtypes consisting of luminal A (LumA), luminal B (LumB), basal-like and HER2-enriched (Her2e) tumors.	('luminal', 'Var', (139, 146))	('tumors', 'Disease', (194, 200))	('Her2', 'Gene', '2064', (187, 191))	('LumA', 'Gene', (132, 136))	('LumA', 'Gene', '79188', (132, 136))	('luminal A', 'Gene', '79188', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('luminal A', 'Gene', (121, 130))	('basal-like', 'CPA', (157, 167))	('HER2-enriched', 'Protein', (172, 185))	('Her2', 'Gene', (187, 191))
8144	29495625	We then speculated that GJA1 variability could be linked to the molecular heterogeneity of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variability', 'Var', (29, 40))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('GJA1', 'Gene', (24, 28))	('linked', 'Reg', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
8149	29495625	For the TCGA dataset, a few tumors had amplification or deletion of GJA1, compared to genes known to be amplified in breast cancer (Figure 3a).	('deletion', 'Var', (56, 64))	('GJA1', 'Gene', (68, 72))	('tumors', 'Disease', (28, 34))	('amplification', 'Var', (39, 52))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
8150	29495625	Moreover, tumors with GJA1 amplification did not show an increase in expression while only deep deletions reduced expression (-2 in called copy number, as shown in Figure 3c).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('expression', 'MPA', (69, 79))	('deletions', 'Var', (96, 105))	('expression', 'MPA', (114, 124))	('amplification', 'Var', (27, 40))	('reduced', 'NegReg', (106, 113))	('GJA1', 'Gene', (22, 26))
8151	29495625	Most luminal tumors with the highest expression of GJA1 were found to have either a normal copy number or single deletion (Figure 3b-d).	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('luminal tumors', 'Disease', (5, 19))	('GJA1', 'Gene', (51, 55))	('luminal tumors', 'Disease', 'MESH:D009369', (5, 19))	('single deletion', 'Var', (106, 121))	('expression', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
8152	29495625	Moreover, in tumors with a GJA1 gain or amplification, a slight but significant decrease in expression, rather than an increase, could be observed compared to normal tissues (Figure 3c).	('gain', 'Disease', (32, 36))	('gain', 'Disease', 'MESH:D015430', (32, 36))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('GJA1', 'Gene', (27, 31))	('expression', 'MPA', (92, 102))	('amplification', 'Var', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('decrease', 'NegReg', (80, 88))	('rat', 'Species', '10116', (104, 107))
8156	29495625	Moreover, somatic point mutation data showed that, in the TCGA cohort, only three breast cancer patients out of 977 harbored at least one GJA1 mutation, accounting for 0.31% of the tumors (Figure 3e).	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('mutation', 'Var', (143, 151))	('GJA1', 'Gene', (138, 142))	('patients', 'Species', '9606', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
8157	29495625	Only one tumor with an extremely high number of total mutations (TCGA-AN-A046) was found to have both a GJA1 mutation and a slightly higher expression of the gene (2.76) compared to normal range (-1.01 to 2.20) (Figure 3c,e).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('expression', 'MPA', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (54, 63))	('GJA1', 'Gene', (104, 108))	('higher', 'PosReg', (133, 139))	('tumor', 'Disease', (9, 14))	('mutation', 'Var', (109, 117))
8158	29495625	Together, these results argue that loss or amplification of the GJA1 gene likely does not dictate mRNA and protein dysregulation in breast cancer.	('GJA1', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('amplification', 'Var', (43, 56))	('loss', 'Disease', 'MESH:D015431', (35, 39))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('loss', 'Disease', (35, 39))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('dictate', 'Reg', (90, 97))
8168	29495625	However, when HER2 status was given by HER2 amplicon probes or HER2 mRNA expression (Vanvliet, NKI and Curtis datasets), HER2+ tumors had a significantly lower level of GJA1.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HER2', 'Protein', (63, 67))	('lower', 'NegReg', (154, 159))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mRNA', 'MPA', (68, 72))	('GJA1', 'MPA', (169, 173))	('NKI and Curtis', 'Disease', 'MESH:C537936', (95, 109))	('HER2+', 'Var', (121, 126))
8186	29495625	Observations that Cx43 expression was associated with a worse prognostic in ER-negative and Her2e tumors have been previously reported using the web-based platform KMPlotter while ER-positive tumors had a better prognosis.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('Her2', 'Gene', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Her2', 'Gene', '2064', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Cx43 expression', 'Var', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
8187	29495625	Investigating further the results of BreastMark and KMPlotter Web platforms, survival analysis showed that pooled and luminal tumors with high levels of GJA1 mRNA were associated with a better prognostic (hazard ratio < 1), although results were not always statistically significant (Figure 7 and Figure A7a,b).	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('high levels', 'Var', (138, 149))	('luminal tumors', 'Disease', 'MESH:D009369', (118, 132))	('GJA1', 'Protein', (153, 157))	('better', 'PosReg', (186, 192))	('rat', 'Species', '10116', (212, 215))	('luminal tumors', 'Disease', (118, 132))
8188	29495625	Conversely, basal-like and Her2e tumors followed an opposite trend (hazard ratio > 1), with high expression of GJA1 strongly associated with a worse prognosis in the Her2e subtype (Figure 7 and Figure A7a,b).	('Her2', 'Gene', (166, 170))	('high', 'Var', (92, 96))	('rat', 'Species', '10116', (75, 78))	('Her2', 'Gene', '2064', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GJA1', 'Gene', (111, 115))	('associated with', 'Reg', (125, 140))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('Her2', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('Her2', 'Gene', '2064', (27, 31))	('tumors', 'Disease', (33, 39))
8191	29495625	The log rank test was highly significant for all the analyses (Figure 7, Figure A9 and Figure A12) and for a vast range of cutoffs (Figure A10c), suggesting that GJA1 has the greatest discriminating power when cohorts are unstratified.	('GJA1', 'Var', (162, 166))	('A12', 'Gene', '28887', (94, 97))	('A10', 'Gene', '28870', (139, 142))	('A10', 'Gene', (139, 142))	('rat', 'Species', '10116', (226, 229))	('A12', 'Gene', (94, 97))
8193	29495625	When analyzing individual subtypes, a high expression was also significantly associated with a better prognosis in all analyses for LumA and for most analyses for LumB tumors (Figure 7, Figure A9 and Figure A12).	('B tumors', 'Disease', 'MESH:D006509', (166, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('A12', 'Gene', (207, 210))	('LumA', 'Gene', (132, 136))	('high', 'Var', (38, 42))	('LumA', 'Gene', '79188', (132, 136))	('A12', 'Gene', '28887', (207, 210))	('B tumors', 'Disease', (166, 174))	('expression', 'MPA', (43, 53))	('better', 'PosReg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
8226	29495625	Somatic DNA-level chromosomal aberrations are a defining characteristic of cancer and are common in breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('common', 'Reg', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('breast carcinoma', 'Disease', (100, 116))	('chromosomal aberrations', 'Var', (18, 41))	('breast carcinoma', 'Disease', 'MESH:D001943', (100, 116))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (18, 41))	('rat', 'Species', '10116', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast carcinoma', 'Phenotype', 'HP:0003002', (100, 116))
8227	29495625	Genomic loss and amplification cause decreases and increases in the transcription of genes in the region and often with concomitant effects of protein expression.	('amplification', 'Var', (17, 30))	('transcription', 'MPA', (68, 81))	('increases', 'PosReg', (51, 60))	('loss', 'Disease', 'MESH:D015431', (8, 12))	('loss', 'Disease', (8, 12))
8229	29495625	Our results are also in accordance with previous studies that have shown that the region of human chromosome 6 where GJA1 is located (6q22.31) has a relatively low level of amplification and deletions.	('deletions', 'Var', (191, 200))	('GJA1', 'Gene', (117, 121))	('human', 'Species', '9606', (92, 97))	('amplification', 'MPA', (173, 186))
8258	29495625	However, similar to our results, more recent studies using expression array-based survival curves found that a high GJA1 expression was associated with a better prognosis in ER-positive breast cancer tumors, while an opposite trend was observed in ER-negative tumors and Her2e tumors.	('expression', 'MPA', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('ER-positive', 'Var', (174, 185))	('breast cancer tumors', 'Disease', 'MESH:D001943', (186, 206))	('high', 'Var', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('tumors', 'Disease', (277, 283))	('better', 'PosReg', (154, 160))	('breast cancer tumors', 'Disease', (186, 206))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('tumors', 'Disease', (260, 266))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('GJA1', 'Gene', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Her2', 'Gene', '2064', (271, 275))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Her2', 'Gene', (271, 275))	('tumors', 'Disease', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
8264	29495625	Additional researches are required to better understand the context that allows Cx43 to suppress or promote carcinogenesis in different intrinsic subtypes.	('promote', 'PosReg', (100, 107))	('Cx43', 'Var', (80, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
8303	20361251	However, recurrences do occur and women diagnosed with DCIS are more than four times as likely to develop invasive breast cancer compared to the general population.	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('DCIS', 'Var', (55, 59))	('women', 'Species', '9606', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('develop', 'PosReg', (98, 105))	('invasive breast cancer', 'Disease', (106, 128))
8354	20361251	However, the elevated odds of antidepressant use after diagnosis was most pronounced among users of tamoxifen (OR = 2.28; 95% CI 1.59, 3.26), whereas only a moderate increase in antidepressant use was observed among non-users of tamoxifen (OR = 1.22; 95% CI 0.90, 1.64; Pinteraction = 0.01).	('antidepressant', 'Disease', (30, 44))	('tamoxifen', 'Chemical', 'MESH:D013629', (229, 238))	('tamoxifen', 'Chemical', 'MESH:D013629', (100, 109))	('tamoxifen', 'Var', (100, 109))
8433	28181348	After correcting for multiple hypothesis testing, the feature IMC1 still had a statistically significant P-value of 0.0008 after controlling for the tumor size in terms of the algorithmically computed major axis length of the tumor.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))	('IMC1', 'Var', (62, 66))
8472	17540032	ALH confers a 3-fold elevated risk for the development of IBC, while LCIS has a relative risk equal to 7.	('ALH', 'Var', (0, 3))	('IBC', 'Disease', (58, 61))	('to 7', 'Species', '1214577', (100, 104))
8476	17540032	Confirmatory evidence that precursors and preinvasive lesions are clonal processes arises from studies showing similar genetic changes in low-grade DCIS and ADH (Table 1), and identical genetic abnormalities with synchronous ipsilateral invasive breast cancer.	('genetic abnormalities', 'Disease', (186, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('low-grade', 'Var', (138, 147))	('synchronous ipsilateral invasive breast cancer', 'Disease', (213, 259))	('ADH', 'Gene', (157, 160))	('changes', 'Var', (127, 134))	('genetic abnormalities', 'Disease', 'MESH:D030342', (186, 207))	('synchronous ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (213, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
8477	17540032	These studies were supported by mouse mammary tumor models and by epidemiological studies which showed that the risk for breast cancer increased with the rate of proliferation and atypia in breast biopsies.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mouse', 'Species', '10090', (32, 37))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('atypia', 'Var', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
8487	17540032	More specifically, regarding non-atypical epithelial hyperplasia, ER positivity together with ki-67 expression, seem to make an important distinction between lesions: the existence of ki-67(+)/ER(+) cells seems to correlate with progression to more severe lesions.	('epithelial hyperplasia', 'Disease', (42, 64))	('ki-67(+)/ER(+', 'Var', (184, 197))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (42, 64))
8488	17540032	Alternatively, it has been suggested that an increased percentage of ER(+) cells in the adjacent normal lobules seems to be associated with elevated risk for invasive breast cancer rather than ER-positivity within the lesion per se .	('invasive breast cancer', 'Disease', (158, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('ER(+) cells', 'Var', (69, 80))	('invasive breast cancer', 'Disease', 'MESH:D001943', (158, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
8505	17540032	Of notice, in the normal tissue of BRCA mutation carriers, PRB isoform is strikingly absent.	('BRCA', 'Gene', (35, 39))	('mutation', 'Var', (40, 48))	('BRCA', 'Gene', '672', (35, 39))	('absent', 'NegReg', (85, 91))
8507	17540032	Alterations of c-erbB2 (HER-2/neu) are suggested to be an important event in malignant transformation.	('HER-2/neu', 'Gene', (24, 33))	('Alterations', 'Var', (0, 11))	('HER-2/neu', 'Gene', '2064', (24, 33))	('malignant transformation', 'CPA', (77, 101))	('c-erbB2', 'Gene', '2064', (15, 22))	('c-erbB2', 'Gene', (15, 22))
8509	17540032	However, amplification of Her-2/Neu has been documented with the use of FISH in ADH, supporting the notion that the degree of HER-2/neu amplification increases with progression to carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (180, 189))	('Neu', 'Gene', (32, 35))	('Neu', 'Gene', '2064', (32, 35))	('HER-2/neu', 'Gene', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('HER-2/neu', 'Gene', '2064', (126, 135))	('carcinoma', 'Disease', (180, 189))	('Her-2', 'Gene', '2064', (26, 31))	('amplification', 'Var', (136, 149))	('Her-2', 'Gene', (26, 31))	('increases', 'PosReg', (150, 159))
8514	17540032	Interestingly, given the association of higher grade with c-erb-B2 amplification, the latter has been regarded as an independent prognostic factor.	('amplification', 'Var', (67, 80))	('c-erb-B2', 'Gene', '2064', (58, 66))	('c-erb-B2', 'Gene', (58, 66))
8518	17540032	Regarding the role of p53 as a risk factor in benign breast lesions, there is controversy of data: the immunohistochemical detection of p53 in benign breast lesions has been associated with elevated cancer risk, although there are studies with conflicting results.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('associated', 'Reg', (174, 184))	('immunohistochemical', 'Var', (103, 122))	('breast lesions', 'Disease', 'MESH:D001941', (53, 67))	('p53', 'Gene', '7157', (136, 139))	('p53', 'Gene', (22, 25))	('breast lesions', 'Disease', 'MESH:D001941', (150, 164))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('p53', 'Gene', '7157', (22, 25))	('breast lesions', 'Disease', (53, 67))	('cancer', 'Disease', (199, 205))	('breast lesions', 'Disease', (150, 164))	('p53', 'Gene', (136, 139))
8521	17540032	In ADH, the presence and role of p53 mutations is still an open field: p53 mutations were initially not documented; then, studies pointing to p53 mutations appeared, and, more recently, the presence of mutated p53 in ADH has been demonstrated with the use of laser capture microdissection microscope, single-stranded conformational polymorphism (SSCP) and sequencing.	('mutated', 'Var', (202, 209))	('p53', 'Gene', '7157', (210, 213))	('mutations', 'Var', (146, 155))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('p53', 'Gene', (210, 213))
8523	17540032	p53 mutations/accumulation are present in a significant percentage of DCIS, especially in the comedo type.	('p53', 'Gene', (0, 3))	('mutations/accumulation', 'Var', (4, 26))	('p53', 'Gene', '7157', (0, 3))	('comedo', 'Phenotype', 'HP:0025249', (94, 100))	('comedo', 'Disease', (94, 100))	('DCIS', 'Disease', (70, 74))
8530	17540032	As mentioned above, also in the context of non-atypical hyperplasia, high Ki-67 and ER-alpha expression seem to predict progression to cancer.	('hyperplasia', 'Disease', 'MESH:D006965', (56, 67))	('cancer', 'Disease', (135, 141))	('ER-alpha', 'Gene', (84, 92))	('hyperplasia', 'Disease', (56, 67))	('Ki-67', 'Protein', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ER-alpha', 'Gene', '2099', (84, 92))	('expression', 'MPA', (93, 103))	('high', 'Var', (69, 73))	('predict', 'Reg', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
8540	17540032	Bcl-2 positivity tends to coincide with p53 negativity in normal breast tissue, non-atypical ductal hyperplasia, ADH, LN and in the majority of the DCIS.	('positivity', 'Var', (6, 16))	('p53', 'Gene', (40, 43))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (84, 111))	('p53', 'Gene', '7157', (40, 43))	('atypical ductal hyperplasia', 'Disease', (84, 111))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('negativity', 'MPA', (44, 54))
8543	17540032	Of notice, VEGF gene polymorphisms have been associated with modified breast cancer risk in various populations.	('VEGF', 'Gene', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('VEGF', 'Gene', '7422', (11, 15))	('associated', 'Reg', (45, 55))	('breast cancer', 'Disease', (70, 83))	('polymorphisms', 'Var', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
8551	17540032	In clinical practice, immunohistochemistry for E-cadherin is a helpful marker for differential diagnosis, since most cases of low-grade DCIS exhibit E-cadherin positivity, whereas LN is almost always E-cadherin negative [, reviewed in , ].	('E-cadherin', 'Gene', (200, 210))	('E-cadherin', 'Gene', '999', (200, 210))	('E-cadherin', 'Gene', (47, 57))	('E-cadherin', 'Gene', '999', (47, 57))	('low-grade', 'Var', (126, 135))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
8554	17540032	In the context of DCIS, hypermethylation of E-cadherin 5' CpG islands has been demonstrated, and, at the protein level, E-cadherin has been linked to better differentiation.	('hypermethylation', 'Var', (24, 40))	('better differentiation', 'CPA', (150, 172))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('E-cadherin', 'Gene', (120, 130))	('E-cadherin', 'Gene', '999', (120, 130))	('linked to', 'Reg', (140, 149))
8555	17540032	Moreover, mutational analysis of E-cadherin provided evidence to support that DCIS is the precursor of invasive ductal carcinoma in cases where LCIS coexists.	('invasive ductal carcinoma', 'Disease', (103, 128))	('E-cadherin', 'Gene', '999', (33, 43))	('E-cadherin', 'Gene', (33, 43))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (112, 128))	('DCIS', 'Gene', (78, 82))	('mutational analysis', 'Var', (10, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (103, 128))
8558	17540032	Surprisingly enough, an interesting study recently showed that loss of TGF-beta-RII expression in epithelial cells of hyperplasia without atypia is associated with increased risk of IDC.	('hyperplasia', 'Disease', (118, 129))	('loss', 'Var', (63, 67))	('TGF-beta', 'Gene', '7040', (71, 79))	('hyperplasia', 'Disease', 'MESH:D006965', (118, 129))	('IDC', 'Disease', (182, 185))	('TGF-beta', 'Gene', (71, 79))
8561	17540032	According to some authors, aberrant methylation of p16 is not demonstrated in benign conditions, epithelial hyperplasia and intraductal papillomas, but is restricted in cancerous epithelium.	('epithelial hyperplasia', 'Disease', (97, 119))	('p16', 'Gene', '1029', (51, 54))	('papillomas', 'Phenotype', 'HP:0012740', (136, 146))	('intraductal papillomas', 'Disease', 'MESH:D018300', (124, 146))	('cancerous', 'Disease', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('aberrant methylation', 'Var', (27, 47))	('p16', 'Gene', (51, 54))	('cancerous', 'Disease', 'MESH:D009369', (169, 178))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (97, 119))	('intraductal papillomas', 'Disease', (124, 146))	('methylation', 'Var', (36, 47))
8572	17540032	Umbricht et al identified 14-3-3 sigma as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing.	('breast carcinomas', 'Disease', 'MESH:D001943', (77, 94))	('breast carcinomas', 'Disease', (77, 94))	('methylation-mediated silencing', 'Var', (109, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('breast carcinomas', 'Phenotype', 'HP:0003002', (77, 94))	('lost', 'NegReg', (69, 73))	('expression', 'MPA', (55, 65))	('14-3-3 sigma', 'Gene', '2810', (26, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('breast carcinoma', 'Phenotype', 'HP:0003002', (77, 93))	('14-3-3 sigma', 'Gene', (26, 38))
8638	31011670	Thirty-six patients (59%) were considered cautionary because of the presence of at least 1 high-risk feature, including high-grade disease in 28 (45.9%), size > 2.5 cm but <= 3 cm in 2 (3.3%), HR negative in 8 (1.3%), and age < 50 years in 4 (6.7%).	('patients', 'Species', '9606', (11, 19))	('high-grade disease', 'Disease', (120, 138))	('> 2.5 cm', 'Var', (159, 167))	('HR', 'Gene', '3164', (193, 195))
8843	29876051	Breast specific gamma imaging (BSGI) and genetic testing for BRCA gene mutations were ordered.	('BRCA', 'Gene', '672', (61, 65))	('mutations', 'Var', (71, 80))	('BRCA', 'Gene', (61, 65))
8844	29876051	BRCA testing was negative for both BRCA1 and BRCA2 mutations.	('BRCA', 'Gene', '672', (45, 49))	('BRCA2', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Gene', (45, 49))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA1', 'Gene', '672', (35, 40))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('BRCA1', 'Gene', (35, 40))	('BRCA', 'Gene', '672', (0, 4))
8866	29876051	Men with BRCA2 mutations may have higher risk of developing breast cancer than men with BRCA1 mutations.	('men', 'Species', '9606', (79, 82))	('BRCA1', 'Gene', (88, 93))	('breast cancer', 'Disease', (60, 73))	('BRCA2', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('BRCA2', 'Gene', '675', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1', 'Gene', '672', (88, 93))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('Men', 'Species', '9606', (0, 3))
8881	28881599	The mannose receptor CD206, and the macrophage scavenger receptor CD204 are prototypic markers of anti-inflammatory macrophages and their expression negatively correlates with prognosis in numerous types of cancer.	('correlates with', 'Reg', (160, 175))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('CD206', 'Var', (21, 26))	('cancer', 'Disease', (207, 213))	('negatively', 'NegReg', (149, 159))	('expression', 'MPA', (138, 148))	('CD204', 'Gene', '4481', (66, 71))	('CD204', 'Gene', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
8896	28881599	As described previously, transplantation of p53-/- mammary epithelial cells into the cleared mammary fad pads of syngeneic wildtype mice led to the formation of several premalignant lines that histologically and genetically recapitulated the various subtypes of human breast cancer.	('p53-/-', 'Var', (44, 50))	('human', 'Species', '9606', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('breast cancer', 'Disease', (268, 281))	('mice', 'Species', '10090', (132, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('fad', 'Chemical', 'MESH:D005182', (101, 104))
8917	28881599	The percentage of CD45+F480+CD11b+ macrophages increased as PN1a lesions progressed to palpable tumors, suggesting that they may have tumor-promoting capabilities (Figure 3A).	('PN1', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('CD45+F480+CD11b+', 'Var', (18, 34))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (134, 139))	('PN1', 'Gene', '107569', (60, 63))
8944	28881599	Flow cytometry showed a ~2 fold depletion of macrophages in clodronate liposome-treated animals in both the bone marrow (Supplementary Figure 2A) and in PN1a lesions (Figure 6A) as compared to saline-treated animals, which is consistent with previous reports.	('clodronate', 'Chemical', 'MESH:D004002', (60, 70))	('PN1', 'Gene', '107569', (153, 156))	('depletion', 'NegReg', (32, 41))	('liposome-treated', 'Var', (71, 87))	('saline', 'Chemical', 'MESH:D012965', (193, 199))	('PN1', 'Gene', (153, 156))
8961	28881599	In the polyoma middle T antigen mouse model of mammary tumorigenesis (MMTV-PyMT), genetic ablation of Csf1 - a cytokine required for monocyte to macrophage differentiation - resulted in the attenuation of tumor metastasis and a reduction in multiple foci on the distal duct; however, the growth rate and incidence of primary tumors remained unchanged, suggesting that macrophages do not mediate tumor formation.	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('attenuation', 'NegReg', (190, 201))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduction', 'NegReg', (228, 237))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('MMTV', 'Species', '11757', (70, 74))	('Csf1', 'Gene', (102, 106))	('mouse', 'Species', '10090', (32, 37))	('multiple foci on the distal duct', 'MPA', (241, 273))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('primary tumors', 'Disease', (317, 331))	('polyoma middle T', 'Disease', 'MESH:D020244', (7, 23))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('polyoma middle T', 'Disease', (7, 23))	('ablation', 'Var', (90, 98))	('primary tumors', 'Disease', 'MESH:D009369', (317, 331))	('tumor metastasis', 'Disease', 'MESH:D009362', (205, 221))	('tumor', 'Disease', (325, 330))	('tumor', 'Disease', (395, 400))	('genetic ablation', 'Var', (82, 98))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (395, 400))	('tumor metastasis', 'Disease', (205, 221))
8966	28881599	This model is highly relevant to human premalignancy as mutations in p53 occur in some cases of ADH as well as 20-40% cases of DCIS.	('ADH', 'Disease', (96, 99))	('mutations', 'Var', (56, 65))	('p53', 'Gene', (69, 72))	('human', 'Species', '9606', (33, 38))	('occur', 'Reg', (73, 78))	('ADH', 'Disease', 'MESH:D007177', (96, 99))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))
8980	28881599	In contrast, MHCIIHI macrophages have been shown to be associated with normoxic regions, exhibit a pro-inflammatory, anti-tumor phenotype, and have iNOS-dependent T-cell suppressor activity.	('MHCIIHI', 'Var', (13, 20))	('iNOS', 'Gene', '18126', (148, 152))	('iNOS', 'Gene', (148, 152))	('pro-inflammatory', 'CPA', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('T-cell suppressor activity', 'CPA', (163, 189))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
8981	28881599	The expression of CD206+ and MHCIIHI populations in PN1a lesions suggest that these macrophages may exert both pro-tumor and anti-tumor functions.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD206+', 'Var', (18, 24))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PN1', 'Gene', (52, 55))	('PN1', 'Gene', '107569', (52, 55))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
9000	28881599	For maintaining and expanding tissue, contralateral mammary glands containing PN1a or PN1b lesions after 8 weeks of outgrowth were minced into 1 mm fractions with a scalpel and re-transplanted into the cleared fat pads (#4 contralateral glands) of 3 week old female Balb/c mice (weight 10-13 g) as previously described.	('lesions', 'Var', (91, 98))	('PN1', 'Gene', (78, 81))	('PN1', 'Gene', '107569', (78, 81))	('PN1', 'Gene', '107569', (86, 89))	('PN1', 'Gene', (86, 89))	('mice', 'Species', '10090', (273, 277))
9004	28881599	Immunostaining was performed as previously described with the following modifications: immunohistochemistry with F4/80 was performed in absence of antigen retrieval, endogenous peroxidases were blocked by incubating sections in a solution containing 3% hydrogen peroxide and methanol, and M.O.M.	('F4/80', 'Gene', '13733', (113, 118))	('M.O.M', 'Var', (289, 294))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (253, 270))	('methanol', 'Chemical', 'MESH:D000432', (275, 283))	('F4/80', 'Gene', (113, 118))
9049	30190792	RNA based individualized drug selection in breast cancer patients without patient-matched normal tissue While standard RNA expression tests stratify patients into risk groups, RNA-Seq can guide personalized drug selection based on expressed mutations, fusion genes, and differential expression (DE) between tumor and normal tissue.	('breast cancer', 'Disease', (43, 56))	('patient', 'Species', '9606', (74, 81))	('fusion genes', 'Var', (252, 264))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('patient', 'Species', '9606', (57, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Disease', (307, 312))	('patient', 'Species', '9606', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('differential', 'Reg', (270, 282))	('mutations', 'Var', (241, 250))
9061	30190792	Genetic counselling and blood tests for hereditary breast cancer risk variants in BRCA1, BRCA2, TP53 and other genes are also routinely offered.	('BRCA1', 'Gene', (82, 87))	('BRCA2', 'Gene', '675', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', (96, 100))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (40, 64))	('variants', 'Var', (70, 78))	('BRCA2', 'Gene', (89, 94))	('BRCA1', 'Gene', '672', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('hereditary breast cancer', 'Disease', (40, 64))	('TP53', 'Gene', '7157', (96, 100))
9063	30190792	Patients with hereditary risk variants in BRCA1, BRCA2 or other core breast cancer risk genes may be offered bilateral subcutaneous mastectomy and ovarectomy.	('BRCA1', 'Gene', '672', (42, 47))	('variants', 'Var', (30, 38))	('BRCA1', 'Gene', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('BRCA2', 'Gene', '675', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('BRCA2', 'Gene', (49, 54))
9087	30190792	To identify gene expression that may be confounded by adipocyte content, two experiments were performed: (a) comparison of formalin fixed paraffin embedded normal healthy breast tissue samples with available fresh frozen normal healthy pure subcutaneous fat tissue samples, and (b) halving a fresh breast reduction tissue sample and comparing a macroscopically prepared fresh frozen half with the other half that was prepared by microdissection after formalin fixation and paraffin embedding.	('formalin', 'Chemical', 'MESH:D005557', (451, 459))	('paraffin', 'Chemical', 'MESH:D010232', (138, 146))	('formalin', 'Chemical', 'MESH:D005557', (123, 131))	('halving', 'Var', (282, 289))	('breast reduction', 'Disease', (298, 314))	('breast reduction', 'Disease', 'MESH:D001943', (298, 314))	('paraffin', 'Chemical', 'MESH:D010232', (473, 481))
9107	30190792	However, the gene amplifications detected in patient tumors P24T and P26T (highlighted in light red in Supplementary Table 11) were not seen in our RNA-Seq expression data (Supplementary Table 10).	('P26T', 'Var', (69, 73))	('P24T', 'Mutation', 'p.P24T', (60, 64))	('P26T', 'Mutation', 'p.P26T', (69, 73))	('P24T', 'Var', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('patient', 'Species', '9606', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
9108	30190792	Of note, the DNA-based gene amplifications and the gene deletion detected in patient tumors P25T, P27T and P29T were clearly reflected in our RNA-Seq data.	('P29T', 'Var', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('P27T', 'Var', (98, 102))	('P29T', 'Mutation', 'p.P29T', (107, 111))	('P25T', 'Var', (92, 96))	('P25T', 'Mutation', 'p.P25T', (92, 96))	('P27T', 'Mutation', 'p.P27T', (98, 102))	('patient', 'Species', '9606', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
9179	26819702	Furthermore, there is evidence for progressive allelic damage from stages of ADH to DCIS and finally IDC.	('allelic', 'Var', (47, 54))	('IDC', 'Gene', '4000', (101, 104))	('IDC', 'Gene', (101, 104))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))
9184	26819702	Despite our current capabilities, it is important to recognize that ADH is not an obligate precursor to in situ or invasive cancer, as noted by Kuerer, as only 14-50 % of women with ADH or DCIS will develop invasive cancer in their lifetime if left untreated.	('invasive cancer', 'Disease', (207, 222))	('develop', 'PosReg', (199, 206))	('invasive cancer', 'Disease', 'MESH:D009362', (115, 130))	('invasive cancer', 'Disease', 'MESH:D009362', (207, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('women', 'Species', '9606', (171, 176))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive cancer', 'Disease', (115, 130))	('ADH', 'Var', (182, 185))
9223	26819702	Thus, dysregulation of miRNAs expression can lead to dysregulation of cell cycle and growth, which may cause uncontrolled tumor growth.	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('dysregulation', 'MPA', (53, 66))	('cell cycle', 'CPA', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('dysregulation', 'Var', (6, 19))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (53, 80))	('lead to', 'Reg', (45, 52))	('cause', 'Reg', (103, 108))	('uncontrolled', 'MPA', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('growth', 'CPA', (85, 91))	('tumor', 'Disease', (122, 127))
9253	31921678	Moreover, the combination of FAP-a and GOLPH3 tends to further improve the specificity and sensitivity of DCIS recurrence by 9.72-10.31 and 2.72-3.63%, respectively.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS recurrence', 'Disease', (106, 121))	('GOLPH3', 'Gene', '64083', (39, 45))	('combination', 'Var', (14, 25))	('FAP-a', 'Gene', '2191', (29, 34))	('improve', 'PosReg', (63, 70))	('FAP-a', 'Gene', (29, 34))	('GOLPH3', 'Gene', (39, 45))
9276	31921678	showed that high expression of GOLPH3 was associated with low overall survival rate of breast cancer patients, and overexpression of GOLPH3 increased the proliferation and tumorigenicity of human breast cancer cells.	('GOLPH3', 'Gene', (31, 37))	('tumor', 'Disease', (172, 177))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (87, 100))	('GOLPH3', 'Gene', '64083', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('increased', 'PosReg', (140, 149))	('GOLPH3', 'Gene', (133, 139))	('overexpression', 'PosReg', (115, 129))	('patients', 'Species', '9606', (101, 109))	('GOLPH3', 'Gene', '64083', (133, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('human', 'Species', '9606', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('proliferation', 'CPA', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('high', 'Var', (12, 16))	('low', 'NegReg', (58, 61))	('overall survival rate', 'CPA', (62, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
9310	31921678	The left panel suggested that for the patients with higher expression of FAP-a, the overall recurrent rate will be higher.	('FAP-a', 'Gene', '2191', (73, 78))	('FAP-a', 'Gene', (73, 78))	('recurrent rate', 'CPA', (92, 106))	('patients', 'Species', '9606', (38, 46))	('higher', 'PosReg', (115, 121))	('expression', 'Var', (59, 69))
9313	31921678	It was worth noting that the presence of stromal FAP-a was positively correlated with DCIS recurrence.	('DCIS recurrence', 'Disease', (86, 101))	('FAP-a', 'Gene', (49, 54))	('FAP-a', 'Gene', '2191', (49, 54))	('presence', 'Var', (29, 37))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('correlated', 'Reg', (70, 80))
9323	31921678	Note that the presence of GOLPH3 is specifically associated with DCIS recurrence.	('presence', 'Var', (14, 22))	('DCIS recurrence', 'Disease', (65, 80))	('GOLPH3', 'Gene', '64083', (26, 32))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('associated with', 'Reg', (49, 64))	('GOLPH3', 'Gene', (26, 32))
9330	31921678	Note that the co-expression of FAP-a and GOLPH3 are specifically associated with DCIS recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('GOLPH3', 'Gene', (41, 47))	('FAP-a', 'Gene', '2191', (31, 36))	('FAP-a', 'Gene', (31, 36))	('co-expression', 'Var', (14, 27))	('associated', 'Reg', (65, 75))	('DCIS recurrence', 'Disease', (81, 96))	('GOLPH3', 'Gene', '64083', (41, 47))
9337	31921678	The ability to develop a predictive model would present to be an enormous clinical advance to identify a molecular marker that would have predictive potential of DCIS's prognosis, either DCIS develops invasive cancer or stays DCIS.	('invasive cancer', 'Disease', 'MESH:D009362', (201, 216))	('DCIS', 'Phenotype', 'HP:0030075', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('invasive cancer', 'Disease', (201, 216))	('DCIS', 'Var', (187, 191))	('develops', 'PosReg', (192, 200))
9348	31921678	Interestingly, our study elucidated that the presence of GOLPH3 in carcinoma cells is also specifically associated with DCIS recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('DCIS recurrence', 'Disease', (120, 135))	('GOLPH3', 'Gene', '64083', (57, 63))	('associated with', 'Reg', (104, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('GOLPH3', 'Gene', (57, 63))	('carcinoma cells', 'Disease', 'MESH:D002292', (67, 82))	('carcinoma cells', 'Disease', (67, 82))	('presence', 'Var', (45, 53))
9352	31921678	It has been reported that high GOLPH3 expression is associated with poor overall survival in patients with breast cancer and that GOLPH3 overexpression increases the proliferation and tumorigenicity of human breast cancer cells.	('GOLPH3', 'Gene', (31, 37))	('high', 'Var', (26, 30))	('poor', 'NegReg', (68, 72))	('proliferation', 'CPA', (166, 179))	('human', 'Species', '9606', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GOLPH3', 'Gene', '64083', (31, 37))	('patients', 'Species', '9606', (93, 101))	('overexpression increases', 'PosReg', (137, 161))	('overall', 'MPA', (73, 80))	('tumor', 'Disease', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('GOLPH3', 'Gene', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('GOLPH3', 'Gene', '64083', (130, 136))	('expression', 'MPA', (38, 48))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('breast cancer', 'Disease', (208, 221))
9353	31921678	In prostate cancer, patients with high levels of GOLPH3 will have shorter survival time.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('GOLPH3', 'Gene', (49, 55))	('shorter', 'NegReg', (66, 73))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('GOLPH3', 'Gene', '64083', (49, 55))	('high levels', 'Var', (34, 45))	('survival time', 'CPA', (74, 87))
9357	31921678	found that high expression of GOLPH3 usually indicates poor survival of breast cancer and weak resistance to chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GOLPH3', 'Gene', (30, 36))	('GOLPH3', 'Gene', '64083', (30, 36))	('resistance to chemotherapy', 'CPA', (95, 121))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('high', 'Var', (11, 15))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('expression', 'MPA', (16, 26))
9359	31921678	It had been found that the prognosis of ovarian cancer patients with high expression of GOLPH3L was lower than that of patients with low or no expression of GOLPH3L.	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('GOLPH3L', 'Gene', '55204', (88, 95))	('patients', 'Species', '9606', (119, 127))	('GOLPH3L', 'Gene', '55204', (157, 164))	('lower', 'NegReg', (100, 105))	('ovarian cancer', 'Disease', (40, 54))	('high expression', 'Var', (69, 84))	('GOLPH3L', 'Gene', (88, 95))	('patients', 'Species', '9606', (55, 63))	('GOLPH3L', 'Gene', (157, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))
9366	31921678	We have shown here that the presence of FAP-a in stromal fibroblasts and GOLPH3 in carcinoma cells are reliable biomarker of DCIS recurrence and progression into invasive breast cancer.	('GOLPH3', 'Gene', '64083', (73, 79))	('presence', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('DCIS', 'Disease', (125, 129))	('invasive breast cancer', 'Disease', (162, 184))	('carcinoma cells', 'Disease', 'MESH:D002292', (83, 98))	('carcinoma cells', 'Disease', (83, 98))	('GOLPH3', 'Gene', (73, 79))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('FAP-a', 'Gene', (40, 45))	('invasive breast cancer', 'Disease', 'MESH:D001943', (162, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('FAP-a', 'Gene', '2191', (40, 45))
9390	31160797	The presentation of neo-antigens derived from mutated proteins leads to tumor suppression, indicating that mutation burden functions as a predictor of neo-antigens and sensitivity to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('mutated', 'Var', (46, 53))	('proteins', 'Protein', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
9402	31160797	Fluorescent multiplex (anti-PDL-1, CD3, CD8) immunohistochemistry staining and RNAscope  indicated that human breast cancer tissues with high LINK-A expression exhibited low CD8+CD3+ lymphocyte infiltration (Figs.	('CD3', 'Gene', (178, 181))	('low', 'NegReg', (170, 173))	('CD8', 'Gene', '925', (40, 43))	('PDL-1', 'Gene', '29126', (28, 33))	('CD3', 'Gene', (35, 38))	('CD8', 'Gene', '925', (174, 177))	('expression', 'Species', '29278', (149, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('CD3', 'Gene', '12501', (178, 181))	('human', 'Species', '9606', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('CD3', 'Gene', '12501', (35, 38))	('breast cancer', 'Disease', (110, 123))	('CD8', 'Gene', (40, 43))	('CD8', 'Gene', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PDL-1', 'Gene', (28, 33))	('LINK-A', 'Gene', (142, 148))	('high', 'Var', (137, 141))
9407	31160797	The decreased APC infiltration in LINK-A-high TNBC suggested potentially impaired antigen-presentation machinery, prompting an investigation into the status of the PLC components within the tumors.	('LINK-A-high', 'Var', (34, 45))	('impaired', 'NegReg', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('decreased APC infiltration', 'Disease', (4, 30))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TNBC', 'Gene', (46, 50))	('decreased APC infiltration', 'Disease', 'MESH:D011125', (4, 30))	('tumors', 'Disease', (190, 196))	('antigen-presentation machinery', 'MPA', (82, 112))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
9408	31160797	Using modification-specific antibodies, we demonstrated that the K48-linked polyubiquitination (poly-Ub) of TPSN (Lys537), TAP1 (Lys245), TAP2 (Lys213), and CALR (Lys48) were upregulated in non-responders, although the level of total polyubiquitinated proteins remained unaltered (Fig.	('Lys245', 'Var', (129, 135))	('Lys48', 'Var', (163, 168))	('K48-linked polyubiquitination', 'Disease', 'MESH:D040181', (65, 94))	('Lys213', 'Chemical', 'MESH:C026591', (144, 150))	('upregulated', 'PosReg', (175, 186))	('Lys213', 'Var', (144, 150))	('TPSN', 'Gene', (108, 112))	('K48-linked polyubiquitination', 'Disease', (65, 94))	('poly-Ub', 'Chemical', 'MESH:C110770', (96, 103))	('Lys537', 'Var', (114, 120))	('TAP1', 'Gene', (123, 127))
9410	31160797	These observations suggested the importance of LINK-A in modulating immune balance in favor of immunosuppression and that the expression of LINK-A potentially modulates the protein levels of the PLC.	('expression', 'Species', '29278', (126, 136))	('immune balance', 'MPA', (68, 82))	('protein levels of the PLC', 'MPA', (173, 198))	('expression', 'Var', (126, 136))	('modulates', 'Reg', (159, 168))	('LINK-A', 'Gene', (140, 146))	('modulating', 'Reg', (57, 67))
9420	31160797	88.7% of tumor-bearing MMTV-Tg(LINK-A) animals developed lung metastasis, compared to no lung metastasis in the control MMTV-cre and Tg(LINK-A) animals (Figs.	('lung metastasis', 'CPA', (57, 72))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('MMTV', 'Species', '11757', (23, 27))	('tumor', 'Disease', (9, 14))	('MMTV', 'Species', '11757', (120, 124))	('MMTV-Tg', 'Var', (23, 30))	('developed', 'PosReg', (47, 56))
9425	31160797	Furthermore, MMTV-Tg(LINK-A) tumors harbored non-silencing somatic mutations on Trp53 and Pik3ca genes that are frequently mutated in human TNBCs (Supplementary Fig.	('Trp', 'Chemical', 'MESH:C509690', (80, 83))	('MMTV-Tg(LINK-A) tumors', 'Disease', 'MESH:D009369', (13, 35))	('human', 'Species', '9606', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutations', 'Var', (67, 76))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('non-silencing', 'NegReg', (45, 58))	('Pik3ca', 'Gene', (90, 96))
9435	31160797	Without Cre recombinase, PtdIns(3,4,5)P3 associated with a cohort of lipid-interacting proteins, which is consistent with previous findings (Table 1-green).	('PtdIns(3,4,5)P3', 'Chemical', 'MESH:C060974', (25, 40))	('PtdIns', 'Var', (25, 31))	('associated', 'Reg', (41, 51))	('cohort of lipid-interacting proteins', 'MPA', (59, 95))
9441	31160797	To validate that the Galphai-GPCRs interaction is dependent on PtdIns (3,4,5)P3-bound LINK-A, we observed that full-length LINK-A facilitated the interactions between GST-tagged bacterially-expressed human GPCRs and Galphai (Fig.	('GPCR', 'Gene', (29, 33))	('GPCR', 'Gene', '441931', (29, 33))	('facilitated', 'PosReg', (130, 141))	('Galpha', 'Gene', '8802', (21, 27))	('Galpha', 'Gene', '8802', (216, 222))	('Galpha', 'Gene', (21, 27))	('Galpha', 'Gene', (216, 222))	('GPCR', 'Gene', (206, 210))	('human', 'Species', '9606', (200, 205))	('interactions', 'Interaction', (146, 158))	('GPCR', 'Gene', '441931', (206, 210))	('LINK-A', 'Var', (123, 129))
9450	31160797	Next, we determined the Kd value of PtdIns (3,4,5)P3-GPCRs interactions in the presence of LINK-A or a cardiolipin-binding lncRNA, RP11-383G10.5, as a control (Fig.	('cardiolipin', 'Chemical', 'MESH:D002308', (103, 114))	('RP11', 'Gene', (131, 135))	('GPCR', 'Gene', '441931', (53, 57))	('GPCR', 'Gene', (53, 57))	('interactions', 'Interaction', (59, 71))	('RP11', 'Gene', '26121', (131, 135))	('LINK-A', 'Var', (91, 97))
9455	31160797	3l-q), followed by expression of wild-type or mutants with deletions in the C-terminal lipid raft binding domain (referred to as DeltaCT) which had similar expression levels to endogenous GPCRs.	('deletions in', 'Var', (59, 71))	('GPCR', 'Gene', (188, 192))	('GPCR', 'Gene', '441931', (188, 192))	('DeltaCT', 'Mutation', 'c.delCT', (129, 136))	('expression', 'Species', '29278', (156, 166))	('expression', 'Species', '29278', (19, 29))
9456	31160797	Wild-type GPCRs, but not DeltaCT mutants, rescued the PtdIns(3,4,5)P3-Galphai and GPCRs-Galphai interactions upon CNR2, GABR1, ADA2A, ACM4, or OPRM deletion (Figs.	('deletion', 'Var', (148, 156))	('interactions', 'Interaction', (96, 108))	('OPRM', 'Gene', '4988', (143, 147))	('CNR2', 'Gene', (114, 118))	('PtdIns(3,4,5)P3-Galphai', 'Chemical', 'MESH:C060974', (54, 77))	('GPCR', 'Gene', '441931', (82, 86))	('GPCR', 'Gene', (82, 86))	('Galpha', 'Gene', '8802', (70, 76))	('Galpha', 'Gene', (70, 76))	('GPCR', 'Gene', (10, 14))	('CNR2', 'Gene', '1269', (114, 118))	('DeltaCT', 'Mutation', 'c.delCT', (25, 32))	('Galpha', 'Gene', '8802', (88, 94))	('GPCR', 'Gene', '441931', (10, 14))	('Galpha', 'Gene', (88, 94))	('ADA2A', 'Gene', (127, 132))	('ADA2A', 'Gene', '6871', (127, 132))	('OPRM', 'Gene', (143, 147))
9457	31160797	As a consequence, cellular cAMP levels were increased upon depletion of the GPCRs and were restored upon expression of wild-type GPCRs but not the DeltaCT mutants (Figs.	('GPCR', 'Gene', (76, 80))	('GPCR', 'Gene', (129, 133))	('mutants', 'Var', (155, 162))	('GPCR', 'Gene', '441931', (129, 133))	('cAMP', 'Chemical', 'MESH:D000242', (27, 31))	('DeltaCT', 'Mutation', 'c.delCT', (147, 154))	('restored', 'PosReg', (91, 99))	('expression', 'Species', '29278', (105, 115))	('increased', 'PosReg', (44, 53))	('cellular cAMP levels', 'MPA', (18, 38))	('GPCR', 'Gene', '441931', (76, 80))
9458	31160797	Expression of wild-type GPCRs or mutants showed minimal effect on cellular PtdIns (3,4,5)P3 levels or the expression of LINK-A (Supplementary Figs.	('expression', 'Species', '29278', (106, 116))	('Expression', 'Species', '29278', (0, 10))	('mutants', 'Var', (33, 40))	('LINK-A', 'Protein', (120, 126))	('GPCR', 'Gene', (24, 28))	('GPCR', 'Gene', '441931', (24, 28))
9470	31160797	These findings suggested that inhibiting GPCR signaling may improve the sensitivity of TNBCs to anti-CDK4/6 and anti-EGFR targeted treatments.	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('sensitivity', 'MPA', (72, 83))	('GPCR', 'Gene', (41, 45))	('GPCR', 'Gene', '441931', (41, 45))	('TNBCs', 'Disease', (87, 92))	('inhibiting', 'Var', (30, 40))	('improve', 'PosReg', (60, 67))
9472	31160797	Although PKA depletion leads to carcinogenesis, the underlying molecular mechanism of how PKA prevents tumor initiation is unknown.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('carcinogenesis', 'Disease', (32, 46))	('depletion', 'Var', (13, 22))	('tumor initiation', 'Disease', (103, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (32, 46))	('leads to', 'Reg', (23, 31))	('tumor initiation', 'Disease', 'MESH:D009369', (103, 119))
9476	31160797	5a), validating the conclusion that expression of LINK-A inactivates the cAMP/PKA pathway.	('inactivates', 'NegReg', (57, 68))	('expression', 'Var', (36, 46))	('LINK-A', 'Gene', (50, 56))	('cAMP/PKA pathway', 'Pathway', (73, 89))	('expression', 'Species', '29278', (36, 46))	('cAMP', 'Chemical', 'MESH:D000242', (73, 77))
9478	31160797	Furthermore, TRIM71 was phosphorylated at Ser3 in normal tissues and MMTV-PyVT tumors but not in MMTV-Tg(LINK-A) tumors (Table 2-black, and Figs.	('MMTV-PyVT tumors', 'Disease', 'MESH:D009369', (69, 85))	('MMTV-Tg(LINK-A) tumors', 'Disease', 'MESH:D009369', (97, 119))	('Ser3', 'Chemical', 'MESH:C530429', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('MMTV-PyVT tumors', 'Disease', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TRIM71', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
9479	31160797	We then tested the hypothesis that the phosphorylation of TRIM71 at Ser3 is catalyzed by PKA, finding that CRISPR-mediated ablation of the genes encoding PKA catalytic subunits using sgRNAs reduced the phosphorylation of TRIM71.	('Ser3', 'Chemical', 'MESH:C530429', (68, 72))	('TRIM71', 'MPA', (221, 227))	('PKA', 'Gene', (154, 157))	('ablation', 'Var', (123, 131))	('phosphorylation', 'MPA', (202, 217))	('reduced', 'NegReg', (190, 197))
9480	31160797	The expression of the wild type PKA catalytic subunit, but not the kinase-dead mutant, K72H, restored the phosphorylation of TRIM71 (Supplementary Figs.	('expression', 'Species', '29278', (4, 14))	('TRIM71', 'Gene', (125, 131))	('K72H', 'Var', (87, 91))	('phosphorylation', 'MPA', (106, 121))	('restored', 'PosReg', (93, 101))	('K72H', 'SUBSTITUTION', 'None', (87, 91))
9481	31160797	In TNBC Pembrolizumab treatment responders/non-responders, the status of the p-PKA C-alpha (Thr197) and p-TRIM71 (Ser3) negatively correlated with LINK-A expression (Figs.	('expression', 'Species', '29278', (154, 164))	('Thr197', 'Chemical', 'MESH:C055175', (92, 98))	('TNBC', 'Gene', (3, 7))	('LINK-A expression', 'MPA', (147, 164))	('C-alpha', 'Species', '342041', (83, 90))	('p-TRIM71', 'Var', (104, 112))	('Ser3', 'Chemical', 'MESH:C530429', (114, 118))	('negatively', 'NegReg', (120, 130))
9482	31160797	These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3.	('expression', 'Species', '29278', (41, 51))	('Ser3', 'Chemical', 'MESH:C530429', (148, 152))	('PKA', 'Protein', (73, 76))	('phosphorylation/activity', 'MPA', (77, 101))	('expression', 'Var', (41, 51))	('inhibits', 'NegReg', (64, 72))
9485	31160797	Rb and p53 exhibited GG modifications at Lys803 and Lys126, respectively, which suggested ubiquitination (Ub) modification of these proteins (Table 2-red and Fig.	('Lys803', 'Chemical', 'MESH:C010258', (41, 47))	('Lys126', 'Chemical', 'MESH:C026591', (52, 58))	('Lys803', 'Var', (41, 47))	('Lys126', 'Var', (52, 58))	('p53', 'Gene', '7157', (7, 10))	('ubiquitination', 'MPA', (90, 104))	('p53', 'Gene', (7, 10))
9486	31160797	Ubiquitin contains 7 lysine residues: K6, K11, K27, K29, K33, K48, and K63, through which a specific polyubiquitin chain can be formed upon a target protein.	('formed', 'Reg', (128, 134))	('K33', 'Var', (57, 60))	('K48', 'Var', (62, 65))	('polyubiquitin chain', 'MPA', (101, 120))	('K27', 'Gene', '342574', (47, 50))	('K27', 'Gene', (47, 50))	('K29', 'Var', (52, 55))	('lysine', 'Chemical', 'MESH:C114808', (21, 27))	('K11', 'Var', (42, 45))	('K63', 'Var', (71, 74))
9488	31160797	This data indicated that Ub-Rb and -p53 are modified with K48-linked polyUb and are potentially subjected to proteasomal degradation.	('Ub-Rb and', 'Protein', (25, 34))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('polyUb', 'Chemical', 'MESH:C110770', (69, 75))	('modified', 'Reg', (44, 52))	('K48-linked', 'Var', (58, 68))
9490	31160797	Taken together, our data suggested that expression of LINK-A downregulates intrinsic tumor suppressor barriers via the GPCR-PKA-TRIM71 signaling axis during tumorigenesis.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (85, 90))	('downregulates', 'NegReg', (61, 74))	('expression', 'Var', (40, 50))	('GPCR', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('GPCR', 'Gene', '441931', (119, 123))	('intrinsic tumor', 'Disease', (75, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('LINK-A', 'Gene', (54, 60))	('intrinsic tumor', 'Disease', 'MESH:C563242', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('expression', 'Species', '29278', (40, 50))
9491	31160797	To address the hypothesis that LINK-A-mediated hypophosphorylation of TRIM71 in MMTV-Tg(LINK-A) tumors may catalyze poly-Ub chain formation in a panel of substrates, we identified TRIM71-bindng proteins with post-translational modifications using MMTV-Tg(LINK-A) tumors pre-treated with scramble (Scr) or LINK-A LNAs (Table 3 and Supplementary Table 4), which have been shown to efficiently knockdown LINK-A in vivo.	('MMTV-Tg(LINK-A) tumors', 'Disease', 'MESH:D009369', (247, 269))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('poly-Ub', 'Chemical', 'MESH:C110770', (116, 123))	('MMTV-Tg(LINK-A) tumors', 'Disease', 'MESH:D009369', (80, 102))	('knockdown', 'Var', (391, 400))	('TRIM71-bindng', 'Var', (180, 193))
9495	31160797	In addition to Rb and p53, TRIM71 associated with all six components of the PLC, namely TPSN, TAP1, TAP2, CALR, ERAP1, and PDIA3 in MMTV-Tg(LINK-A) tumors (Table 3-red).	('TRIM71', 'Var', (27, 33))	('associated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p53', 'Gene', (22, 25))	('MMTV-Tg(LINK-A) tumors', 'Disease', 'MESH:D009369', (132, 154))	('p53', 'Gene', '7157', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
9496	31160797	TPSN, TAP1, TAP2, and CALR were all subjected to GG modification at the Lys213 (TPSN), Lys537 (TAP1), Lys245 (TAP2), and Lys48 (CALR) residues (Table 3-red), and all ubiquitin which associated with TRIM71 or TRIM71-binding proteins was K48-linked (Supplementary Fig.	('Lys245', 'Var', (102, 108))	('K48-linked', 'Var', (236, 246))	('ubiquitin', 'Protein', (166, 175))	('Lys213', 'Chemical', 'MESH:C026591', (72, 78))	('Lys537', 'Var', (87, 93))	('Lys48', 'Var', (121, 126))	('Lys213', 'Var', (72, 78))
9497	31160797	Upon LINK-A LNAs treatment, the GG modifications at Lys213 (TPSN), Lys537 (TAP1), Lys245 (TAP2), and Lys48 (CALR) were all abolished (Table 3-red and Supplementary Fig.	('Lys245', 'Var', (82, 88))	('abolished', 'NegReg', (123, 132))	('Lys213', 'Chemical', 'MESH:C026591', (52, 58))	('Lys213', 'Var', (52, 58))	('Lys48', 'Var', (101, 106))	('Lys537', 'Var', (67, 73))
9498	31160797	These observations indicated that the TRIM71-associated PLC components were modified with K48-linked poly-Ub chains, which were diminished upon LINK-A knockdown.	('modified', 'Reg', (76, 84))	('poly-Ub chains', 'Protein', (101, 115))	('K48-linked', 'Var', (90, 100))	('poly-Ub', 'Chemical', 'MESH:C110770', (101, 108))
9499	31160797	We developed modification-specific antibodies targeting ubiquitinated- (referred to as ub-) TPSN (Lys213), ub-TAP1 (Lys537), ub-TAP2 (Lys245), and ub-CALR (Lys48) (Supplementary Fig.	('Lys537', 'Var', (116, 122))	('Lys48', 'Var', (156, 161))	('Lys213', 'Chemical', 'MESH:C026591', (98, 104))	('ubiquitinated-', 'MPA', (56, 70))	('Lys213', 'Var', (98, 104))	('TPSN', 'Gene', (92, 96))	('Lys245', 'Var', (134, 140))
9503	31160797	To demonstrate that expression of LINK-A downregulates PLC components during tumor initiation, we took advantage of the mammary ductal transformation process of the normal-like, hyperplasia, DCIS, and IDC morphologies of MMTV-Tg(LINK-A) mice.	('tumor initiation', 'Disease', (77, 93))	('hyperplasia', 'Disease', 'MESH:D006965', (178, 189))	('PLC components', 'MPA', (55, 69))	('MMTV', 'Species', '11757', (221, 225))	('downregulates', 'NegReg', (41, 54))	('expression', 'Var', (20, 30))	('mice', 'Species', '10090', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LINK-A', 'Gene', (34, 40))	('hyperplasia', 'Disease', (178, 189))	('tumor initiation', 'Disease', 'MESH:D009369', (77, 93))	('expression', 'Species', '29278', (20, 30))
9505	31160797	6b, first column), although the ducts of MMTV-Tg(LINK-A) mouse mammary glands at 8 weeks of age were morphologically similar to normal ducts, the protein status of TPSN and CALR were significantly downregulated in the epithelial cells of these normal-like ducts (Figs.	('MMTV-Tg', 'Var', (41, 48))	('downregulated', 'NegReg', (197, 210))	('protein status', 'MPA', (146, 160))	('TPSN', 'Gene', (164, 168))	('MMTV', 'Species', '11757', (41, 45))	('mouse', 'Species', '10090', (57, 62))
9507	31160797	We addressed the hypothesis that the expression of LINK-A facilities the interactions between TRIM71 and PLC components, which could be reduced upon LINK-A knockdown using Duolink  proximity ligation assay (PLA) signals (Supplementary Fig.	('knockdown', 'Var', (156, 165))	('interactions', 'Interaction', (73, 85))	('TRIM71', 'Gene', (94, 100))	('expression', 'Species', '29278', (37, 47))	('PLA', 'Chemical', 'MESH:C507889', (207, 210))
9508	31160797	Robust PLA signals were detected in MDA-MB-231 cells harboring scramble LNAs, suggesting protein proximity between TRIM71:TAP1, TRIM71: CALR, TRIM71:TAP2, and TRIM71:TPSN, respectively, which were significantly reduced (Supplementary Fig.	('TRIM71', 'Var', (159, 165))	('TRIM71', 'Var', (115, 121))	('TRIM71', 'Var', (128, 134))	('TRIM71', 'Var', (142, 148))	('PLA', 'Chemical', 'MESH:C507889', (7, 10))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (36, 46))
9509	31160797	The majority of PLA signals did not overlap with ER markers, suggesting that a portion of PLC components could be subjected to TRIM71-mediated poly-ubiquitination and protein degradation on the exterior of the ER, which is consistent with previous literature suggesting that a portion of the MHC I complex overlaps with the ER marker.	('protein degradation', 'MPA', (167, 186))	('poly-ubiquitination', 'MPA', (143, 162))	('subjected', 'Reg', (114, 123))	('PLA', 'Chemical', 'MESH:C507889', (16, 19))	('TRIM71-mediated', 'Var', (127, 142))
9510	31160797	Tumor-bearing MMTV-Tg(LINK-A) mice treated with LINK-A LNAs showed restored phosphorylation of PKA (Thr197) and p-TRIM71 (Ser3) and elevated protein levels of TPSN, TAP1, TAP2, and CALR without affecting the total protein levels of PKA and TRIM71 (Fig.	('mice', 'Species', '10090', (30, 34))	('Ser3', 'Chemical', 'MESH:C530429', (122, 126))	('elevated', 'PosReg', (132, 140))	('protein levels', 'MPA', (141, 155))	('MMTV', 'Species', '11757', (14, 18))	('p-TRIM71', 'Var', (112, 120))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TAP1', 'MPA', (165, 169))	('phosphorylation', 'MPA', (76, 91))	('TAP2', 'MPA', (171, 175))	('PKA', 'Protein', (95, 98))	('CALR', 'MPA', (181, 185))	('Thr197', 'Chemical', 'MESH:C055175', (100, 106))	('TPSN', 'MPA', (159, 163))	('restored', 'PosReg', (67, 75))
9514	31160797	To determine the functional role of LINK-A and the TRIM71-dependent molecular mechanism in antigen presentation, we determined the cellular surface MHC I complex of the B16F10 cells with Tet-on induced-expression of LINK-A, finding that expression of LINK-A suppressed the cellular surface expression of H-2Kb with or without IFN-gamma stimulation (Fig.	('LINK-A', 'Var', (251, 257))	('expression', 'Species', '29278', (237, 247))	('expression', 'Species', '29278', (202, 212))	('suppressed', 'NegReg', (258, 268))	('H-2Kb', 'Gene', (304, 309))	('B16F10', 'CellLine', 'CVCL:0159', (169, 175))	('expression', 'Var', (237, 247))	('expression', 'Species', '29278', (290, 300))	('H-2Kb', 'Gene', '14972', (304, 309))	('cellular surface expression', 'MPA', (273, 300))
9515	31160797	Similarly, expression of exogenous TRIM71 led to reduced cell surface expression of H-2Kb (Supplementary Figs.	('TRIM71', 'Var', (35, 41))	('expression', 'Species', '29278', (11, 21))	('cell surface expression', 'MPA', (57, 80))	('reduced', 'NegReg', (49, 56))	('expression', 'Species', '29278', (70, 80))	('H-2Kb', 'Gene', (84, 89))	('H-2Kb', 'Gene', '14972', (84, 89))
9516	31160797	Furthermore, Trim71 knockdown blocked the LINK-A-dependent cellular surface suppression of H-2Kb in B16F10 cells (Supplementary Fig.	('cellular surface', 'MPA', (59, 75))	('B16F10', 'CellLine', 'CVCL:0159', (100, 106))	('suppression', 'NegReg', (76, 87))	('blocked', 'NegReg', (30, 37))	('Trim71', 'Gene', (13, 19))	('H-2Kb', 'Gene', (91, 96))	('knockdown', 'Var', (20, 29))	('H-2Kb', 'Gene', '14972', (91, 96))
9520	31160797	Using B16-OVA cells, we observed that knockdown of Trim71 increases cellular surface expression of the chicken OVA peptide (Fig.	('increases', 'PosReg', (58, 67))	('cellular surface expression', 'MPA', (68, 95))	('chicken', 'Species', '9031', (103, 110))	('Trim71', 'Gene', (51, 57))	('expression', 'Species', '29278', (85, 95))	('knockdown', 'Var', (38, 47))
9526	31160797	The LINK-A LNAs- or Rauwolscine-treated mice also exhibited reduced tumor incidence (Figs.	('tumor', 'Disease', (68, 73))	('LINK-A', 'Var', (4, 10))	('Rauwolscine', 'Chemical', 'MESH:D015016', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('reduced', 'NegReg', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (40, 44))
9528	31160797	In our regression model, the tumor-bearing MMTV-Tg(LINK-A) mice treated with LINK-A LNAs exhibited inhibited tumor growth and reduced lung metastasis compared to those treated with scramble LNAs (Figs.	('reduced', 'NegReg', (126, 133))	('LNAs', 'Var', (84, 88))	('mice', 'Species', '10090', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('inhibited', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LINK-A LNAs', 'Var', (77, 88))	('lung metastasis', 'CPA', (134, 149))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MMTV', 'Species', '11757', (43, 47))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
9537	31160797	Therefore, LINK-A may serve as a valuable biomarker for predicting the outcome of TNBC patients requiring immunotherapy, and targeting LINK-A further sensitizes breast tumors to immune checkpoint inhibitors.	('TNBC', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('LINK-A', 'Gene', (135, 141))	('breast tumors', 'Phenotype', 'HP:0100013', (161, 174))	('breast tumor', 'Phenotype', 'HP:0100013', (161, 173))	('breast tumors', 'Disease', (161, 174))	('sensitizes', 'Reg', (150, 160))	('breast tumors', 'Disease', 'MESH:D061325', (161, 174))	('patients', 'Species', '9606', (87, 95))	('targeting', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
9540	31160797	We demonstrated that during breast cancer initiation, the transformed mammary gland epithelial cells downregulate antigen presentation machinery upon expression of LINK-A, illustrating one of the initial and important mechanisms through which cancer cells escape from immune checkpoints.	('breast cancer initiation', 'Disease', (28, 52))	('antigen presentation machinery', 'MPA', (114, 144))	('breast cancer initiation', 'Disease', 'MESH:D001943', (28, 52))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('expression', 'Var', (150, 160))	('expression', 'Species', '29278', (150, 160))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (35, 41))	('LINK-A', 'Gene', (164, 170))	('downregulate', 'NegReg', (101, 113))
9541	31160797	The peptide-loading complex plays vital roles in antigen presentation and transportation of MHC I. Post-translational modifications of PLC components in cancer cells may serve as an advantageous mechanism for downregulating antigenicity without losing achieved genomic mutations and mutation-derived growth advantages.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('antigenicity', 'MPA', (224, 236))	('downregulating', 'NegReg', (209, 223))	('Post-translational modifications', 'Var', (99, 131))
9546	31160797	TRIM71 has been shown to modulate p53 degradation.	('p53', 'Gene', (34, 37))	('TRIM71', 'Var', (0, 6))	('p53', 'Gene', '7157', (34, 37))	('modulate', 'Reg', (25, 33))
9547	31160797	It is likely that LINK-A/TRIM71-dependent p53 ubiquitination is independent of MDM2, which is consistent with the notion that the major ubiquitination residues of p53 mediated by MDM2 are located within the tetramerization domain of p53 (Lys320, Lys321, Lys351, Lys357, Lys370, Lys372, Lys373), whereas LINK-A-dependent, TRIM71-mediated p53 poly-ubiquitination occurs at Lys126, which is within the DNA-binding domain of p53.	('Lys370', 'Var', (270, 276))	('Lys321', 'Chemical', 'MESH:C026591', (246, 252))	('p53', 'Gene', (337, 340))	('p53', 'Gene', '7157', (42, 45))	('Lys126', 'Var', (371, 377))	('p53', 'Gene', '7157', (421, 424))	('MDM2', 'Gene', (179, 183))	('Lys351', 'Var', (254, 260))	('Lys321', 'Var', (246, 252))	('p53', 'Gene', (42, 45))	('MDM2', 'Gene', '4193', (179, 183))	('p53', 'Gene', (421, 424))	('p53', 'Gene', '7157', (163, 166))	('Lys372', 'Var', (278, 284))	('MDM2', 'Gene', (79, 83))	('Lys357', 'Var', (262, 268))	('p53', 'Gene', '7157', (233, 236))	('Lys126', 'Chemical', 'MESH:C026591', (371, 377))	('Lys373', 'Var', (286, 292))	('p53', 'Gene', '7157', (337, 340))	('p53', 'Gene', (163, 166))	('Lys320', 'Var', (238, 244))	('MDM2', 'Gene', '4193', (79, 83))	('p53', 'Gene', (233, 236))
9549	31160797	Tissue-specific expression of LINK-A in mouse mammary glands led to mammary gland carcinogenesis, implicating it as an oncogene.	('expression', 'Var', (16, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('carcinogenesis', 'Disease', (82, 96))	('expression', 'Species', '29278', (16, 26))	('led to', 'Reg', (61, 67))	('LINK-A', 'Gene', (30, 36))	('mouse', 'Species', '10090', (40, 45))
9553	31160797	With genetic evidence, our results suggested that LINK-A inactivates tumor suppressor pathways and downregulates antigen presentation through inactivation of PKA pathways, which is consistent with the previous notion that PKA knockout leads to carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('antigen presentation', 'MPA', (113, 133))	('PKA pathways', 'Pathway', (158, 170))	('inactivates', 'NegReg', (57, 68))	('downregulates', 'NegReg', (99, 112))	('tumor', 'Disease', (69, 74))	('leads to', 'Reg', (235, 243))	('knockout', 'Var', (226, 234))	('inactivation', 'NegReg', (142, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (244, 258))	('LINK-A', 'Var', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('carcinogenesis', 'Disease', (244, 258))
9568	31160797	For the regression treatment, MMTV-Tg(LINK-A) mice bearing mammary tumors up to 150 mm were randomly assigned to treatment groups and injected with the following drugs: scramble LNAs or LINK-A LNAs (5 mg/kg, SubQ, every other day).	('LINK-A', 'Var', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mice', 'Species', '10090', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('MMTV', 'Species', '11757', (30, 34))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
9587	31160797	For pharmacologic inhibition, cells or tumor spheroids were treated with Abemaciclib (500 nM, Selleckchem), Erlotinib (10muM, Selleckchem), and Rauwolscine hydrochloride (10muM, TOCRIS) for the indicated times and at the indicated concentrations.	('Rauwolscine hydrochloride', 'Chemical', 'MESH:D015016', (144, 169))	('muM', 'Gene', '56925', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('muM', 'Gene', '56925', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('muM', 'Gene', (121, 124))	('tumor', 'Disease', (39, 44))	('muM', 'Gene', (173, 176))	('Erlotinib', 'Chemical', 'MESH:C400278', (108, 117))	('500', 'Var', (86, 89))
9623	31160797	We obtained TCGA triple-negative breast cancer (TNBC) mutations from http://gdac.broadinstitute.org/ as previously described.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('mutations', 'Var', (54, 63))	('TCGA', 'Gene', (12, 16))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
9639	29845782	The TCGA repository of cancer-related molecular information was compiled following data generated at several omics levels including whole exome sequencing- based mutational spectra and DNA copy number changes,  transcriptomic expression patterns (expression data) and  reverse-phase protein array (RRPA)-related alterations.	('mutational', 'Var', (162, 172))	('changes', 'Var', (201, 208))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('copy number changes', 'Var', (189, 208))
9640	29845782	BC-related heterogeneity has been attributed, at least in  part, to potentially reversible epigenetic alterations in the  methylome and miRNA expression.	('methylome', 'MPA', (122, 131))	('epigenetic alterations', 'Var', (91, 113))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))
9667	29845782	Next-generation sequencing  of another cluster of tumours have showed that KCNB2,  UTRN (6q24) and MDN1 (6q15) were mutated often in  this subtype.	('UTRN', 'Gene', '7402', (83, 87))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('MDN1', 'Gene', '23195', (99, 103))	('tumours', 'Disease', (50, 57))	('KCNB2', 'Gene', (75, 80))	('KCNB2', 'Gene', '9312', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutated', 'Var', (116, 123))	('UTRN', 'Gene', (83, 87))	('MDN1', 'Gene', (99, 103))
9668	29845782	The luminal A category tumours have been associatedwith specific mutations in GATA3, PIK3CA and  MAP3K1.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('MAP3K1', 'Gene', '4214', (97, 103))	('associatedwith', 'Reg', (41, 55))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('PIK3CA', 'Gene', '5290', (85, 91))	('GATA3', 'Gene', (78, 83))	('tumours', 'Disease', (23, 30))	('GATA3', 'Gene', '2625', (78, 83))	('MAP3K1', 'Gene', (97, 103))	('mutations', 'Var', (65, 74))	('PIK3CA', 'Gene', (85, 91))
9682	29845782	It is known that tumour  heterogeneity (intra and inter tumoural) can be due to  genetic and epigenetic factors, with these factors affecting  differentiation and cell death.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('epigenetic', 'Var', (93, 103))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('intra and inter tumoural', 'Disease', 'MESH:D009369', (40, 64))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('affecting', 'Reg', (132, 141))	('tumour', 'Disease', (56, 62))
9688	29845782	DNA hypo/hyper-methylation, histone acetylases and  deacetylases, methyltransferases and demethylases are  epigenetic changes considered to be important in BC.	('deacetylases', 'Enzyme', (52, 64))	('demethylase', 'Gene', (89, 100))	('methyltransferases', 'Enzyme', (66, 84))	('demethylase', 'Gene', '8932', (89, 100))	('hypo/hyper-methylation', 'Var', (4, 26))	('histone', 'Protein', (28, 35))
9691	29845782	The following section highlight  the importance of key epigenetic events associated with neoplastic transformation of the human breast as well as BC stem cells.	('human', 'Species', '9606', (122, 127))	('epigenetic', 'Var', (55, 65))	('neoplastic transformation of the human breast', 'Phenotype', 'HP:0100013', (89, 134))	('neoplastic transformation', 'CPA', (89, 114))
9695	29845782	Deregulation of certain tumour suppressor  genes (e.g., p16) results in the activation of the cyclindependent  kinases (CDK4 and CDK6).	('CDK6', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('CDK6', 'Gene', '1021', (129, 133))	('Deregulation', 'Var', (0, 12))	('p16', 'Gene', '1029', (56, 59))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('cyclindependent', 'Enzyme', (94, 109))	('CDK4', 'Gene', (120, 124))	('tumour', 'Disease', (24, 30))	('CDK4', 'Gene', '1019', (120, 124))	('p16', 'Gene', (56, 59))	('activation', 'PosReg', (76, 86))
9696	29845782	This activation, in turn, hyper-phosphorylates pRb,  thereby causing the release of E2F transcription factors to  increased Ezh2 expression.	('expression', 'MPA', (129, 139))	('E2F transcription factors', 'MPA', (84, 109))	('increased', 'PosReg', (114, 123))	('pRb', 'Gene', '5925', (47, 50))	('pRb', 'Gene', (47, 50))	('Ezh2', 'Gene', (124, 128))	('release', 'MPA', (73, 80))	('Ezh2', 'Gene', '2146', (124, 128))	('causing', 'Reg', (61, 68))	('hyper-phosphorylates', 'Var', (26, 46))
9697	29845782	EZH2 is known to methylate  H3K27Me3 and H3K9Me3, possibly in the regions  upstream of tumour suppressor genes.	('tumour', 'Disease', (87, 93))	('EZH2', 'Gene', '2146', (0, 4))	('H3K27Me3', 'Var', (28, 36))	('EZH2', 'Gene', (0, 4))	('H3K9Me3', 'Var', (41, 48))	('methylate', 'Var', (17, 26))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
9711	29845782	The sequential  methylation of H3K9Me to H3K9Me2 and H3K9Me3 is  mediated by G9a (interactions with the C-terminal domain  of Snail) and Suv39H1 (via the SNAG domain of Snail)  respectively.	('G9a', 'Var', (77, 80))	('interactions', 'Interaction', (82, 94))	('Snail', 'Gene', '6615', (126, 131))	('Snail', 'Gene', (126, 131))	('Suv39H1', 'Gene', (137, 144))	('mediated', 'Reg', (65, 73))	('Suv39H1', 'Gene', '6839', (137, 144))	('Snail', 'Gene', '6615', (169, 174))	('Snail', 'Gene', (169, 174))	('H3K9Me3', 'Var', (53, 60))
9721	29845782	This HMT, in  turn, mono-methylates H4K20 and suppresses E-cadherin  expression, while a similar methylation event in the N-cadherin promoter activates it.	('mono-methylates', 'Var', (20, 35))	('N-cadherin', 'Gene', (122, 132))	('suppresses', 'NegReg', (46, 56))	('H4K20', 'Protein', (36, 41))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('N-cadherin', 'Gene', '1000', (122, 132))	('HMT', 'Gene', (5, 8))	('HMT', 'Gene', '56979', (5, 8))
9723	29845782	In specific,  homo-dimerization of TWIST leads to the activation  of N-cadherin, however, hetero-dimerization of this  transcription factor with Mi2/NuRD, MTA2, RbAp46,  Mi2 and HDAC2 proteins leads to suppression by the  formed complexes.	('homo-dimerization', 'MPA', (14, 31))	('RbAp46', 'Gene', '5931', (161, 167))	('RbAp46', 'Gene', (161, 167))	('TWIST', 'Gene', (35, 40))	('N-cadherin', 'Gene', '1000', (69, 79))	('HDAC2', 'Gene', (178, 183))	('HDAC2', 'Gene', '3066', (178, 183))	('activation', 'PosReg', (54, 64))	('N-cadherin', 'Gene', (69, 79))	('TWIST', 'Gene', '7291', (35, 40))	('hetero-dimerization', 'Var', (90, 109))	('MTA2', 'Gene', '9219', (155, 159))	('MTA2', 'Gene', (155, 159))	('suppression', 'NegReg', (202, 213))
9730	29845782	In both cases, EZH2-mediated trimethylation of  H3K27Me3 leads to local heterochromatisation as well  as DNMT1-mediated gene silencing.	('trimethylation', 'Var', (29, 43))	('local heterochromatisation', 'MPA', (66, 92))	('DNMT1', 'Gene', (105, 110))	('H3K27Me3', 'Protein', (48, 56))	('DNMT1', 'Gene', '1786', (105, 110))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('leads to', 'Reg', (57, 65))
9733	29845782	The section below outlines the links between hypermethylation  of the CpG islands in the promoter region  and silencing of the gene while bearing in mind that  multiple studies have reported DNMT1 and SNAIL1 to  be involved in the repression of E-cadherin expression.	('E-cadherin', 'Gene', (245, 255))	('SNAIL1', 'Gene', (201, 207))	('E-cadherin', 'Gene', '999', (245, 255))	('hypermethylation', 'Var', (45, 61))	('SNAIL1', 'Gene', '6615', (201, 207))	('DNMT1', 'Gene', (191, 196))	('silencing', 'MPA', (110, 119))	('DNMT1', 'Gene', '1786', (191, 196))	('involved', 'Reg', (215, 223))
9738	29845782	Hypomethylation and the possible consequent  constitutive expression of the JAK/STAT pathway has  been reported in CD44+/CD24 low putative BC stem cells.	('CD44', 'Gene', (115, 119))	('JAK/STAT pathway', 'Pathway', (76, 92))	('Hypomethylation', 'Var', (0, 15))	('CD24', 'Gene', '100133941', (121, 125))	('CD44', 'Gene', '960', (115, 119))	('CD24', 'Gene', (121, 125))
9739	29845782	Hypermethylation of cytosines in the regulatory  region of the E-cadherin gene has been observed in an  E-cadherin-negative BC cell line.	('E-cadherin', 'Gene', '999', (63, 73))	('Hypermethylation', 'Var', (0, 16))	('E-cadherin', 'Gene', '999', (104, 114))	('E-cadherin', 'Gene', (63, 73))	('E-cadherin', 'Gene', (104, 114))	('cytosines', 'Chemical', 'MESH:D003596', (20, 29))
9741	29845782	In a later study, it was again demonstrated  that E-cadherin methylation correlated with fibroblast- like morphology in BC cell lines.	('correlated', 'Reg', (73, 83))	('methylation', 'Var', (61, 72))	('E-cadherin', 'Gene', (50, 60))	('fibroblast- like morphology', 'CPA', (89, 116))	('E-cadherin', 'Gene', '999', (50, 60))
9754	29845782	Hypermethylation at the miR-200c-141 locus and a  concomitant increase in EMT features in an in vitro cellular  model provided evidence for the simultaneous occurrences  of these intermediate phenotypes.	('Hypermethylation', 'Var', (0, 16))	('EMT features in an in', 'CPA', (74, 95))	('miR-200c', 'Gene', (24, 32))	('miR-200c', 'Gene', '406985', (24, 32))	('increase', 'PosReg', (62, 70))
9757	29845782	These results were substantiated in clinical samples,  with hypermethylation at P1 linked to metastasis to the  lymph nodes, while P2 showed association with loss of  ER or PR.	('clinical samples', 'Species', '191496', (36, 52))	('metastasis to the  lymph nodes', 'CPA', (93, 123))	('hypermethylation', 'Var', (60, 76))	('linked to', 'Reg', (83, 92))	('loss', 'NegReg', (158, 162))
9779	29845782	There is a strong association between DNA hyper methylation and histone methylation-mediated loss of tumour suppressor gene expression.	('loss', 'NegReg', (93, 97))	('tumour', 'Disease', (101, 107))	('histone', 'Reg', (64, 71))	('DNA hyper methylation', 'Var', (38, 59))	('expression', 'MPA', (124, 134))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
9788	29845782	In all these cancers, epigenetic events may modulate the  CSC phenotype and a number of examples with respect to  this aspect are provided below.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('epigenetic events', 'Var', (22, 39))	('modulate', 'Reg', (44, 52))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Disease', (13, 20))	('CSC', 'Disease', (58, 61))
9791	29845782	The  endogenous negative regulator of Nodal (Lefty1-a  regulatory protein normally sequestered in the hESC  microenvironment) is not expressed in cancer cells  , thereby providing a plausible mechanism for  Lefty1-mediated epigenetic silencing-mediated  uncontrolled growth of cancer cells.	('epigenetic silencing-mediated', 'Var', (223, 252))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Lefty1', 'Gene', '10637', (207, 213))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('Lefty1', 'Gene', (207, 213))	('Lefty1', 'Gene', '10637', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Lefty1', 'Gene', (45, 51))
9793	29845782	In addition,  removal of the transactivating domain of GATA-3  can affect the reprogramming of chromatin without  altering its binding ability.	('removal', 'Var', (14, 21))	('transactivating domain', 'MPA', (29, 51))	('affect', 'Reg', (67, 73))	('GATA-3', 'Gene', '2625', (55, 61))	('GATA-3', 'Gene', (55, 61))	('reprogramming of chromatin', 'CPA', (78, 104))
9810	26366541	Tamoxifen also reduces recurrences among women whose DCIS expresses estrogen receptors, but like RT, does not reduce mortality, and can result in elevated risk of uterine cancer and venous thromboembolic events.	('result', 'Reg', (136, 142))	('uterine cancer', 'Phenotype', 'HP:0010784', (163, 177))	('thromboembolic events', 'Phenotype', 'HP:0001907', (189, 210))	('estrogen receptors', 'Protein', (68, 86))	('recurrences', 'CPA', (23, 34))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))	('venous thromboembolic', 'Disease', 'MESH:D054556', (182, 203))	('cancer', 'Disease', (171, 177))	('venous thromboembolic', 'Disease', (182, 203))	('DCIS expresses', 'Var', (53, 67))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('reduces', 'NegReg', (15, 22))	('women', 'Species', '9606', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
9818	26366541	Clinical, pathological, and treatment variables included were age at diagnosis, menopausal status (pre- or perimenopausal vs. postmenopausal), family history (at least one first or second degree family member with breast cancer), presentation (clinically palpable mass, nipple discharge or Paget's disease vs. radiologic), nuclear grade (categorized as non-high grade [including borderline cases focally reaching or approaching low grade DCIS, low grade, and intermediate grade] or high grade), number of excisions, margin width (categorized as positive [tumor on ink], close [<=2mm], >2-10mm [includes cases with margins described as widely clear], or >10mm [includes patients with no residual disease in the re-excision specimen]), RT, endocrine therapy, and date of definitive surgery.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('DCIS', 'Phenotype', 'HP:0030075', (438, 442))	("Paget's disease", 'Disease', 'MESH:C537701', (290, 305))	('tumor', 'Disease', 'MESH:D009369', (555, 560))	("Paget's disease", 'Disease', (290, 305))	('>10mm [', 'Var', (653, 660))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('menopausal status', 'Phenotype', 'HP:0008209', (80, 97))	('patients', 'Species', '9606', (669, 677))	('tumor', 'Phenotype', 'HP:0002664', (555, 560))	('breast cancer', 'Disease', (214, 227))	('tumor', 'Disease', (555, 560))
9827	26366541	To further explore various margin width thresholds among those receiving RT, we created multivariable models with margin width dichotomized into positive vs. tumor not on ink, <=2mm vs. >2mm, and <=10mm vs. >10mm, but found no significant difference (p=0.67, p=0.96, p=0.70, respectively) in risk of recurrence with any threshold.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('<=10mm', 'Var', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('<=2mm', 'Var', (176, 181))
9850	26366541	In a large, well-characterized population of women with DCIS, where numerous factors were controlled for, we have found that margin width is strongly associated with risk of recurrence for women undergoing BCS who do not receive RT.	('recurrence', 'Disease', (174, 184))	('margin width', 'Var', (125, 137))	('women', 'Species', '9606', (189, 194))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('women', 'Species', '9606', (45, 50))	('associated with', 'Reg', (150, 165))
9859	31289308	Thus, the presence of a DCIS component in patients with IDC is associated with favorable clinical characteristics and independently predicts improved OS.	('IDC', 'Gene', '4000', (56, 59))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('improved', 'PosReg', (141, 149))	('OS', 'Chemical', '-', (150, 152))	('patients', 'Species', '9606', (42, 50))	('presence', 'Var', (10, 18))	('IDC', 'Gene', (56, 59))
9883	31289308	Factors included patient age (<60 vs. >=60 years), race/ethnicity (white vs. non-white); Charlson-Deyo co-morbidity score (0 vs. >=1); clinical T stage (T1 vs. T2, T3, or T4) and N stage (N0 vs. N1, N2, or N3); ER (positive vs. negative), PR (positive vs. negative), and Her2 (negative vs. positive or unknown) receptor status; surgical type (partial mastectomy vs. mastectomy); and tumor grade (low/intermediate vs. high).	('N stage', 'CPA', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (383, 388))	('T1', 'Var', (153, 155))	('patient', 'Species', '9606', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('Her2', 'Gene', (271, 275))	('PR', 'Gene', '5241', (239, 241))	('tumor', 'Disease', (383, 388))	('ER', 'Gene', '2099', (211, 213))	('Her2', 'Gene', '2064', (271, 275))	('N0', 'Var', (188, 190))
9917	31289308	In the primary cohort, the presence of IDC + DCIS was associated with significantly improved OS compared to IDC alone on univariable analysis (5-year OS, 89.3% vs. 85.5, p < 0.001; hazard ratio [HR], 0.74; 95% CI, 0.73-0.75, p < 0.001) (Fig.	('IDC', 'Gene', '4000', (39, 42))	('IDC', 'Gene', (39, 42))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('OS', 'Chemical', '-', (93, 95))	('improved', 'PosReg', (84, 92))	('OS', 'Chemical', '-', (150, 152))	('IDC', 'Gene', '4000', (108, 111))	('IDC', 'Gene', (108, 111))	('presence', 'Var', (27, 35))
9929	31289308	4), with 5-year OS rates of 85.5%, 88.5%, and 90.0% for IDC alone, low DCIS, and extensive DCIS, respectively (p < 0.001 for all comparisons).	('low DCIS', 'Phenotype', 'HP:0200161', (67, 75))	('IDC', 'Gene', '4000', (56, 59))	('low DCIS', 'Var', (67, 75))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('OS', 'Chemical', '-', (16, 18))	('extensive', 'Var', (81, 90))	('IDC', 'Gene', (56, 59))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
9932	31289308	In this study we show that for patients with IDC, the presence of an accompanying DCIS component is associated with favorable prognostic features and confers a statistically significant improvement in OS.	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('presence', 'Var', (54, 62))	('improvement', 'PosReg', (186, 197))	('OS', 'Chemical', '-', (201, 203))	('IDC', 'Gene', '4000', (45, 48))	('patients', 'Species', '9606', (31, 39))	('IDC', 'Gene', (45, 48))
9956	31289308	These findings suggest that the presence of DCIS with IDC may be a marker of reduced aggressiveness, and could be incorporated as a prognostic feature in future treatment algorithms.	('IDC', 'Gene', '4000', (54, 57))	('IDC', 'Gene', (54, 57))	('aggressiveness', 'Disease', (85, 99))	('aggressiveness', 'Phenotype', 'HP:0000718', (85, 99))	('reduced', 'NegReg', (77, 84))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('aggressiveness', 'Disease', 'MESH:D001523', (85, 99))	('DCIS', 'Var', (44, 48))
9960	26908327	In BRCA1/2 mutation carriers of all ages (BRCA1=1219 and BRCA2=732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P>0.05).	('BRCA1', 'Gene', '672', (3, 8))	('BRCA1', 'Gene', '672', (42, 47))	('BRCA1/2', 'Gene', '672;675', (3, 10))	('increased', 'PosReg', (149, 158))	('BRCA1', 'Gene', (3, 8))	('BRCA2', 'Gene', (57, 62))	('BRCA1', 'Gene', (42, 47))	('BRCA1', 'Gene', '672', (170, 175))	('mutation', 'Var', (195, 203))	('BRCA2', 'Gene', (189, 194))	('BRCA2', 'Gene', '675', (57, 62))	('BRCA1', 'Gene', (170, 175))	('mutation', 'Var', (11, 19))	('BRCA1/2', 'Gene', (3, 10))	('BRCA2', 'Gene', '675', (189, 194))
9961	26908327	However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only.	('breast cancers', 'Disease', 'MESH:D001943', (74, 88))	('mutation', 'Var', (29, 37))	('breast cancers', 'Disease', (74, 88))	('women', 'Species', '9606', (12, 17))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('BRCA2', 'Gene', (23, 28))	('BRCA2', 'Gene', '675', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
9963	26908327	Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those <=40 years.	('BRCA2', 'Gene', (169, 174))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA2', 'Gene', '675', (169, 174))	('BRCA1', 'Gene', (84, 89))	('mutation', 'Var', (90, 98))
9965	26908327	Women with a BRCA1 or BRCA2 mutation have limited choices to prevent mortality resulting from their 40-80% lifetime risk for breast cancer.	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', (13, 18))	('BRCA2', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('mutation', 'Var', (28, 36))	('breast cancer', 'Disease', (125, 138))	('BRCA2', 'Gene', '675', (22, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('BRCA1', 'Gene', '672', (13, 18))
9971	26908327	Proper repair of DNA double-strand breaks that are caused by low-dose X-rays is impaired at any age in both BRCA1 and BRCA2 mutations carriers.	('repair', 'MPA', (7, 13))	('mutations', 'Var', (124, 133))	('impaired', 'NegReg', (80, 88))	('BRCA2', 'Gene', (118, 123))	('BRCA1', 'Gene', '672', (108, 113))	('rays', 'Species', '255564', (72, 76))	('BRCA1', 'Gene', (108, 113))	('BRCA2', 'Gene', '675', (118, 123))
9972	26908327	This makes BRCA1 and BRCA2 mutation carriers more susceptible than non-carriers, possibly also at older ages, to the cumulative effect of yearly mammograms.	('BRCA2', 'Gene', '675', (21, 26))	('susceptible', 'Reg', (50, 61))	('BRCA1', 'Gene', '672', (11, 16))	('mutation', 'Var', (27, 35))	('BRCA1', 'Gene', (11, 16))	('BRCA2', 'Gene', (21, 26))
9973	26908327	Given these potential disadvantages of mammography, it is important to balance the potential benefits and harms of mammography screening in BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', '672;675', (140, 147))	('mutation', 'Var', (148, 156))	('BRCA1/2', 'Gene', (140, 147))
9974	26908327	Hence, substantial early detection of breast cancer by mammography is needed to outweigh the potential harm of cancer induction in BRCA1/2 mutation carriers.	('mutation', 'Var', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('BRCA1/2', 'Gene', (131, 138))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', (38, 51))	('BRCA1/2', 'Gene', '672;675', (131, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (45, 51))
9975	26908327	We performed an individual patient data (IPD) meta-analysis from six prospective MRI screening studies to determine if mammography screening in BRCA1/2 mutation carriers in addition to MRI improves screening accuracy, and whether this effect differs between BRCA1 and BRCA2 gene mutation carriers or by different age groups.	('BRCA1/2', 'Gene', (144, 151))	('BRCA1', 'Gene', '672', (258, 263))	('screening accuracy', 'MPA', (198, 216))	('BRCA1', 'Gene', (144, 149))	('BRCA1/2', 'Gene', '672;675', (144, 151))	('BRCA2', 'Gene', '675', (268, 273))	('BRCA1', 'Gene', (258, 263))	('patient', 'Species', '9606', (27, 34))	('improves', 'PosReg', (189, 197))	('mutation', 'Var', (152, 160))	('BRCA2', 'Gene', (268, 273))	('BRCA1', 'Gene', '672', (144, 149))
9976	26908327	Studies were eligible if mammography and MRI breast cancer sensitivity and specificity were compared in women with a BRCA1/2 mutation.	('BRCA1/2', 'Gene', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('women', 'Species', '9606', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('BRCA1/2', 'Gene', '672;675', (117, 124))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('mutation', 'Var', (125, 133))
9977	26908327	The data were assembled and cross-checked with the original publications; inclusion criteria for analyses were women with a BRCA1/2 mutation, screened annually with both mammography and MRI.	('women', 'Species', '9606', (111, 116))	('mutation', 'Var', (132, 140))	('BRCA1/2', 'Gene', (124, 131))	('BRCA1/2', 'Gene', '672;675', (124, 131))
9992	26908327	The number of mammographic screens that would have been needed (NSN) to detect one breast cancer that was missed by MRI was calculated, and stratified according to BRCA mutation, age group and screening round (first or subsequent round).	('one breast', 'Phenotype', 'HP:0012813', (79, 89))	('mutation', 'Var', (169, 177))	('BRCA', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('BRCA', 'Gene', '672', (164, 168))
9993	26908327	The analyses were based on 1951 BRCA1/2 mutation carriers with 6085 woman-years of follow-up (Table 1).	('mutation', 'Var', (40, 48))	('BRCA1/2', 'Gene', (32, 39))	('BRCA1/2', 'Gene', '672;675', (32, 39))	('woman', 'Species', '9606', (68, 73))
9994	26908327	There was no significant difference in cancer risk between BRCA1 and BRCA2 mutation carriers.	('BRCA1', 'Gene', '672', (59, 64))	('BRCA2', 'Gene', '675', (69, 74))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('BRCA1', 'Gene', (59, 64))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('BRCA2', 'Gene', (69, 74))
9995	26908327	Five breast cancers were diagnosed before the age of 30 in BRCA1 mutation carriers, and none in BRCA2 mutation carriers.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('BRCA1', 'Gene', '672', (59, 64))	('breast cancers', 'Disease', 'MESH:D001943', (5, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('breast cancers', 'Disease', (5, 19))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', (59, 64))	('mutation', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (5, 19))	('BRCA2', 'Gene', (96, 101))
9997	26908327	In BRCA1 mutation carriers, there were no statistically significant differences in sensitivity and specificity between mammography and MRI combined compared with MRI alone.	('mutation', 'Var', (9, 17))	('BRCA1', 'Gene', (3, 8))	('BRCA1', 'Gene', '672', (3, 8))
9998	26908327	In BRCA2 carriers, there were no significant differences in sensitivity or specificity between combined mammography and MRI and MRI alone in all age groups.	('carriers', 'Var', (9, 17))	('BRCA2', 'Gene', (3, 8))	('BRCA2', 'Gene', '675', (3, 8))
9999	26908327	In BRCA1 carriers overall, adding mammography to MRI screening increased sensitivity by roughly 4-92.5% (Table 2) (P=0.553).	('BRCA1', 'Gene', '672', (3, 8))	('increased', 'PosReg', (63, 72))	('BRCA1', 'Gene', (3, 8))	('carriers', 'Var', (9, 17))	('sensitivity', 'MPA', (73, 84))
10002	26908327	In BRCA2 carriers, adding mammography to MRI screening increased sensitivity by 12.6-92.7% (Table 2) (P=0.154).	('increased', 'PosReg', (55, 64))	('carriers', 'Var', (9, 17))	('BRCA2', 'Gene', (3, 8))	('BRCA2', 'Gene', '675', (3, 8))
10006	26908327	For the first screening round, the NSN for mammography to detect one breast cancer not detected by MRI was 527 for women with a BRCA1 mutation and 94 for women with a BRCA2 mutation for all ages (Table 4).	('one breast', 'Phenotype', 'HP:0012813', (65, 75))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('mutation', 'Var', (134, 142))	('BRCA2', 'Gene', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('women', 'Species', '9606', (154, 159))	('BRCA1', 'Gene', '672', (128, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('BRCA2', 'Gene', '675', (167, 172))	('BRCA1', 'Gene', (128, 133))	('women', 'Species', '9606', (115, 120))
10007	26908327	For subsequent screening rounds, the NSN for mammography to detect an additional breast cancer for women with a BRCA1 mutation (717 screens) was roughly three times that for women with a BRCA2 mutation (231 screens).	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('BRCA2', 'Gene', (187, 192))	('women', 'Species', '9606', (174, 179))	('women', 'Species', '9606', (99, 104))	('BRCA1', 'Gene', '672', (112, 117))	('mutation', 'Var', (118, 126))	('BRCA2', 'Gene', '675', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA1', 'Gene', (112, 117))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
10009	26908327	Adding mammography to MRI screening in BRCA1 mutation carriers leads to a very modest increase in sensitivity of 3.9% among 112 breast cancers (P=0.553), and a small decrease in specificity (by 4%, P=0.154).	('sensitivity', 'MPA', (98, 109))	('increase', 'PosReg', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BRCA1', 'Gene', (39, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('mutation', 'Var', (45, 53))	('BRCA1', 'Gene', '672', (39, 44))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('decrease', 'NegReg', (166, 174))
10014	26908327	The contribution of mammography above MRI to screening sensitivity in the 72 BRCA2 mutation carriers was 12.6% (P>0.05).	('mutation', 'Var', (83, 91))	('BRCA2', 'Gene', (77, 82))	('BRCA2', 'Gene', '675', (77, 82))
10015	26908327	Additional mammography in BRCA2 mutation carriers also decreased the specificity.	('specificity', 'MPA', (69, 80))	('decreased', 'NegReg', (55, 64))	('BRCA2', 'Gene', (26, 31))	('mutation', 'Var', (32, 40))	('BRCA2', 'Gene', '675', (26, 31))
10016	26908327	Without mammography one-third of breast cancers would not have been detected in BRCA2 mutation carriers aged 40 years and younger, but this proportion was 9.3% in those older than 40 years.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('BRCA2', 'Gene', (80, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (33, 47))	('BRCA2', 'Gene', '675', (80, 85))	('breast cancers', 'Disease', 'MESH:D001943', (33, 47))	('breast cancers', 'Disease', (33, 47))	('mutation', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
10020	26908327	The proportion of DCIS is larger for women with a BRCA2 mutation than for women with a BRCA1 mutation, thus differences in histology distributions in BRCA-associated breast cancers may account for our findings.	('BRCA2', 'Gene', (50, 55))	('BRCA', 'Gene', (87, 91))	('BRCA', 'Gene', (150, 154))	('DCIS', 'Disease', (18, 22))	('BRCA', 'Gene', '672', (50, 54))	('BRCA2', 'Gene', '675', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('women', 'Species', '9606', (37, 42))	('BRCA1', 'Gene', '672', (87, 92))	('BRCA1', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancers', 'Disease', 'MESH:D001943', (166, 180))	('breast cancers', 'Disease', (166, 180))	('BRCA', 'Gene', (50, 54))	('mutation', 'Var', (56, 64))	('women', 'Species', '9606', (74, 79))	('BRCA', 'Gene', '672', (87, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('BRCA', 'Gene', '672', (150, 154))
10022	26908327	The modest additional value of digital-only mammography to current MRI screening of BRCA1 mutation carriers was recently shown in a retrospective study.	('mutation', 'Var', (90, 98))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA1', 'Gene', (84, 89))
10029	26908327	Two-fold increase in breast cancers in BRCA1/2 mutation carriers after exposure to 4 or more radiographs, compared with non-exposure, was significant below age 30 years (HR=1.9 (95% CI: 1.2-3.0), but not at 30-39 years.	('breast cancers', 'Phenotype', 'HP:0003002', (21, 35))	('breast cancers', 'Disease', 'MESH:D001943', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancers', 'Disease', (21, 35))	('mutation', 'Var', (47, 55))	('increase', 'PosReg', (9, 17))	('BRCA1/2', 'Gene', (39, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('BRCA1/2', 'Gene', '672;675', (39, 46))
10030	26908327	Two other studies did not demonstrate tumour induction in BRCA1/2 mutation carriers by screening mammography or low-dose contralateral irradiation from breast-conserving treatment.	('BRCA1/2', 'Gene', '672;675', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('mutation', 'Var', (66, 74))	('tumour', 'Disease', (38, 44))	('BRCA1/2', 'Gene', (58, 65))
10032	26908327	From two meta-analyses based on retrospective studies, the estimated cumulative risk of breast cancer by the age of 70 years vary from 57% (95% CI: 47-66%) to 65% (95% CI: 44-78) in women with a BRCA1 mutation and from 45% (95% CI: 31-56%) to 49% (95% CI: 40-57) in women with a BRCA2 mutation.	('BRCA1', 'Gene', '672', (195, 200))	('BRCA2', 'Gene', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1', 'Gene', (195, 200))	('women', 'Species', '9606', (266, 271))	('BRCA2', 'Gene', '675', (279, 284))	('women', 'Species', '9606', (182, 187))	('mutation', 'Var', (201, 209))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
10033	26908327	In this IPD meta-analysis, we combined IPD from six prospective studies, making this the largest analysis in the world of prospectively collected screening data on BRCA1/2 mutation carriers, although numbers are modest in some subgroups.	('mutation', 'Var', (172, 180))	('BRCA1/2', 'Gene', '672;675', (164, 171))	('BRCA1/2', 'Gene', (164, 171))
10035	26908327	Although data from six studies could not be included, this only resulted in ~716 women with BRCA1/2 mutations (36 breast cancers) not being included in the IPD.	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('women', 'Species', '9606', (81, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('BRCA1/2', 'Gene', (92, 99))	('breast cancers', 'Disease', 'MESH:D001943', (114, 128))	('breast cancers', 'Disease', (114, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('BRCA1/2', 'Gene', '672;675', (92, 99))
10037	26908327	Based on our findings, the additional detection from mammography in BRCA1 mutation carriers who receive MRI screening is minimal, and might not outweigh potential disadvantages (potential cancer induction by radiation, false-positive results).	('mutation', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA1', 'Gene', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('BRCA1', 'Gene', '672', (68, 73))
10038	26908327	It may be reasonable, on the basis of this collective evidence, to consider potential omission of mammography screening in BRCA1 mutation carriers or to open discussion on its potential omission given its limited contribution.	('BRCA1', 'Gene', '672', (123, 128))	('BRCA1', 'Gene', (123, 128))	('mammography', 'Disease', (98, 109))	('mutation', 'Var', (129, 137))
10039	26908327	In BRCA2 mutation carriers, the contribution of mammography above MRI is more evident.	('mutation', 'Var', (9, 17))	('carriers', 'Reg', (18, 26))	('BRCA2', 'Gene', (3, 8))	('BRCA2', 'Gene', '675', (3, 8))
10123	24886063	A combination of Otud6b, Stk39 and Lgals8 gave an AUC of 0.868 (95% CI 0.744-0.968, p < 0.001) for pre-diagnostic sera and 0.871 for sera derived from tumor bearing mice (95% CI 0.744-0.976, p < 0.001) with a sensitivity of 0.75 and specificity of 0.8.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Lgals8', 'Gene', (35, 41))	('Stk39', 'Var', (25, 30))	('Otud6b', 'Gene', (17, 23))
10159	24886063	The majority of patients with primary billiary cirrhosis have autoantibodies directed against Pdhx.	('Pdhx', 'Chemical', '-', (94, 98))	('cirrhosis', 'Phenotype', 'HP:0001394', (47, 56))	('primary billiary cirrhosis', 'Disease', 'MESH:D005355', (30, 56))	('patients', 'Species', '9606', (16, 24))	('Pdhx', 'Gene', (94, 98))	('primary billiary cirrhosis', 'Phenotype', 'HP:0002613', (30, 56))	('primary billiary cirrhosis', 'Disease', (30, 56))	('autoantibodies', 'Var', (62, 76))
10161	24886063	Antibodies to Lgals8 have been identified in a variety of autoimmune diseases including systemic lupus erythematosis and rheumatoid arthritis and may play a role in regulating autoimmune inflammation.	('autoimmune diseases', 'Disease', 'MESH:D001327', (58, 77))	('autoimmune inflammation', 'Disease', (176, 199))	('Antibodies', 'Var', (0, 10))	('systemic lupus erythematosis', 'Disease', 'MESH:D020945', (88, 116))	('identified', 'Reg', (31, 41))	('autoimmune diseases', 'Disease', (58, 77))	('rheumatoid arthritis', 'Disease', (121, 141))	('Lgals8', 'Gene', (14, 20))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (121, 141))	('autoimmune inflammation', 'Disease', 'MESH:D007249', (176, 199))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (58, 77))	('systemic lupus erythematosis', 'Phenotype', 'HP:0002725', (88, 116))	('systemic lupus erythematosis', 'Disease', (88, 116))	('play', 'Reg', (150, 154))	('arthritis', 'Phenotype', 'HP:0001369', (132, 141))	('autoimmune inflammation', 'Phenotype', 'HP:0002960', (176, 199))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (121, 141))	('autoimmune disease', 'Phenotype', 'HP:0002960', (58, 76))
10164	24886063	Stk39 is involved in cation-chloride transport and polymorphisms in this gene are associated with the development of hypertension.	('chloride', 'Chemical', 'MESH:D002712', (28, 36))	('associated with', 'Reg', (82, 97))	('hypertension', 'Disease', 'MESH:D006973', (117, 129))	('Stk39', 'Gene', (0, 5))	('hypertension', 'Disease', (117, 129))	('polymorphisms', 'Var', (51, 64))	('hypertension', 'Phenotype', 'HP:0000822', (117, 129))
10167	24886063	Mutations in Vps35 have been associated with the development of Parkinson's disease.	("Parkinson's disease", 'Disease', (64, 83))	('Vps35', 'Gene', '65114', (13, 18))	('Vps35', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	("Parkinson's disease", 'Disease', 'MESH:D010300', (64, 83))	('associated with', 'Reg', (29, 44))
10179	24886063	Indeed, several lines of evidence suggest that the presence of IgM antibodies will increase the secretion of IgG antibodies to greater levels than those achieved if IgM antibodies are not present.	('increase', 'PosReg', (83, 91))	('IgM', 'Gene', '16019', (165, 168))	('IgM', 'Gene', '16019', (63, 66))	('presence of IgM antibodies', 'Phenotype', 'HP:0003496', (51, 77))	('IgM', 'Gene', (165, 168))	('IgM', 'Gene', (63, 66))	('IgG', 'Gene', '16059', (109, 112))	('secretion', 'MPA', (96, 105))	('IgG antibodies', 'Phenotype', 'HP:0003237', (109, 123))	('IgG', 'Gene', (109, 112))	('presence', 'Var', (51, 59))
10269	30342556	proposed that modifications in gene polymorphisms related to solute transportation of mitochondria, immune response activation and transmembrane signaling are the possible explanation for the increased breast cancer risk.	('modifications', 'Var', (14, 27))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('solute transportation of mitochondria', 'MPA', (61, 98))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
10271	30342556	While for women who have the BRCA gene mutation, at least two first- or second-degree relatives with breast or ovarian cancer history and chest radiation history are recommended for mammography plus MRI screening annually.	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (101, 125))	('mutation', 'Var', (39, 47))	('BRCA', 'Gene', '672', (29, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('women', 'Species', '9606', (10, 15))	('breast or ovarian cancer', 'Disease', (101, 125))	('BRCA', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
10287	30342556	Although some disputes exist based on three large epidemiology studies, it was concluded that the risk of breast cancer increased with exposure to combination HRT.	('breast cancer', 'Disease', (106, 119))	('combination', 'Var', (147, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
10336	28099081	A nested case-control study of 1877 breast biopsy specimens from the Nurse's Health Study identified 13 cases of DCIS that were originally diagnosed as benign, of which 2 of 4 with low-grade, 2 of 6 with intermediate-grade, and 2 of 3 with high-grade DCIS developed ipsilateral invasive cancer a mean of 9 (range 4-18) years after the initial "benign" biopsy.	('ipsilateral invasive cancer', 'Disease', 'MESH:D009362', (266, 293))	('DCIS', 'Phenotype', 'HP:0030075', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('DCIS', 'Disease', (113, 117))	('ipsilateral invasive cancer', 'Disease', (266, 293))	('low-grade', 'Var', (181, 190))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
10344	28099081	However, the meta-analysis of the randomized trials demonstrated that in patients treated with lumpectomy alone, the 10-year risk of an IBTR was markedly higher in patients with positive vs. negative margins (43.8% vs. 26.0%); this was also true in patients receiving RT with a 10-year IBTR rate of 24.2% vs. 12.0% in patients with positive vs. negative margins.	('positive', 'Var', (178, 186))	('patients', 'Species', '9606', (318, 326))	('patients', 'Species', '9606', (249, 257))	('higher', 'PosReg', (154, 160))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (73, 81))
10372	28099081	They found that the benefit of tamoxifen was limited to the estrogen receptor positive group, and in this subset tamoxifen was associated with a 42% reduction in any breast event (p = 0.0015), a 47% reduction in any invasive breast cancer (p = 0.005), and a 32% reduction in any ipsilateral breast cancer (p = 0.07).	('reduction', 'NegReg', (149, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('breast event', 'Disease', (166, 178))	('tamoxifen', 'Var', (113, 122))	('invasive breast cancer', 'Disease', (216, 238))	('tamoxifen', 'Chemical', 'MESH:D013629', (113, 122))	('tamoxifen', 'Chemical', 'MESH:D013629', (31, 40))	('invasive breast cancer', 'Disease', 'MESH:D001943', (216, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('reduction', 'NegReg', (199, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('ipsilateral breast cancer', 'Disease', (279, 304))	('reduction', 'NegReg', (262, 271))	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (279, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
10378	28099081	In B-35, the 10-year breast cancer event rate was 6.9% among those randomized to anastrozole vs. 10.9% in the tamoxifen group, corresponding to a hazard ratio of 0.73 (p = 0.02) with anastrozole.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('anastrozole', 'Chemical', 'MESH:D000077384', (183, 194))	('breast cancer', 'Disease', (21, 34))	('anastrozole', 'Chemical', 'MESH:D000077384', (81, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('anastrozole', 'Var', (81, 92))
10455	15318938	Subcellular ARF expression was not associated with clinicopathological parameters, and although not an independent prognosticator, these preliminary findings suggest that cytoplasmic p14ARF might be associated with a better overall survival (P = 0.09; log rank).	('overall', 'MPA', (224, 231))	('better', 'PosReg', (217, 223))	('ARF', 'Disease', (12, 15))	('ARF', 'Disease', (186, 189))	('p14ARF', 'Gene', '1029', (183, 189))	('cytoplasmic', 'Var', (171, 182))	('ARF', 'Disease', 'MESH:D058186', (12, 15))	('p14ARF', 'Gene', (183, 189))	('ARF', 'Disease', 'MESH:D058186', (186, 189))
10456	15318938	The association between HER-2 positivity and nuclear p14ARF (P = 0.038), as well as nuclear Hdm2 (P = 0.019), reflects the in vitro findings of HER-2 interaction with the ARF/Hdm2 pathway.	('positivity', 'Var', (30, 40))	('ARF', 'Disease', (56, 59))	('interaction', 'Interaction', (150, 161))	('p14ARF', 'Gene', (53, 59))	('ARF', 'Disease', 'MESH:D058186', (171, 174))	('Hdm2', 'Gene', '4193', (92, 96))	('p14ARF', 'Gene', '1029', (53, 59))	('HER-2', 'Protein', (24, 29))	('ARF', 'Disease', (171, 174))	('Hdm2', 'Gene', (92, 96))	('ARF', 'Disease', 'MESH:D058186', (56, 59))	('Hdm2', 'Gene', '4193', (175, 179))	('Hdm2', 'Gene', (175, 179))
10457	15318938	Cytoplasmic p53 and Hdm2 expression might have biological implications, through an association of cytoplasmic p53 with increased tumour proliferation (P = 0.005), and an improved overall survival (P = 0.002, log rank) in cytoplasmic Hdm2-expressing tumours, that independently predict favourable overall survival (P = 0.02) and disease-free survival (P = 0.03).	('overall survival', 'CPA', (179, 195))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('Hdm2', 'Gene', '4193', (233, 237))	('tumours', 'Phenotype', 'HP:0002664', (249, 256))	('Hdm2', 'Gene', (233, 237))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('Hdm2', 'Gene', (20, 24))	('tumours', 'Disease', 'MESH:D009369', (249, 256))	('tumours', 'Disease', (249, 256))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('improved', 'PosReg', (170, 178))	('tumour', 'Disease', (129, 135))	('tumour', 'Disease', (249, 255))	('cytoplasmic p53', 'Var', (98, 113))	('increased', 'PosReg', (119, 128))	('Hdm2', 'Gene', '4193', (20, 24))
10461	15318938	The development and growth of breast cancers result from the inactivation of p53 or retinoblastoma (pRb) tumour suppressor proteins that regulate cell cycle control.	('inactivation', 'Var', (61, 73))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('pRb', 'Gene', '5925', (100, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('retinoblastoma', 'Disease', 'MESH:D012175', (84, 98))	('retinoblastoma', 'Disease', (84, 98))	('growth of breast cancers', 'Disease', 'MESH:D001943', (20, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('tumour', 'Disease', (105, 111))	('p53', 'Gene', (77, 80))	('result from', 'Reg', (45, 56))	('growth of breast cancers', 'Disease', (20, 44))	('development', 'CPA', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('retinoblastoma', 'Phenotype', 'HP:0009919', (84, 98))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('pRb', 'Gene', (100, 103))
10464	15318938	Similarly, p53 accumulates to transcriptionally activate the cyclin-dependent kinase inhibitor p21WAFI/CIPI, as well as its own negative regulator Hdm2 (human Mdm2; murine double minute 2), which terminates the p53 response.	('cyclin', 'Gene', '5111', (61, 67))	('Hdm2', 'Gene', (147, 151))	('Hdm2', 'Gene', '4193', (147, 151))	('Mdm2', 'Gene', '4193', (159, 163))	('activate', 'PosReg', (48, 56))	('cyclin', 'Gene', (61, 67))	('p53', 'Var', (11, 14))	('human', 'Species', '9606', (153, 158))	('murine', 'Species', '10090', (165, 171))	('p21WAFI/CIPI', 'Gene', (95, 107))	('Mdm2', 'Gene', (159, 163))
10484	15318938	p14ARF acts upstream of p53 and is subject to its negative feedback regulation, suggesting that p53 mutations or its inactivation by HDM2 amplification are often accompanied by overexpression of ARF.	('mutations', 'Var', (100, 109))	('HDM2', 'Gene', '4193', (133, 137))	('p53', 'Gene', (96, 99))	('HDM2', 'Gene', (133, 137))	('overexpression', 'PosReg', (177, 191))	('p14ARF', 'Gene', '1029', (0, 6))	('accompanied', 'Reg', (162, 173))	('ARF', 'Disease', 'MESH:D058186', (3, 6))	('p14ARF', 'Gene', (0, 6))	('ARF', 'Disease', 'MESH:D058186', (195, 198))	('ARF', 'Disease', (3, 6))	('ARF', 'Disease', (195, 198))
10485	15318938	p53-positive tumours are also likely to have sustained epistatic mutations such as HDM2 amplification or ARF loss.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('HDM2 amplification or ARF loss', 'Disease', 'MESH:D015431', (83, 113))	('p53-positive', 'Var', (0, 12))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('HDM2 amplification or ARF loss', 'Disease', (83, 113))
10487	15318938	Nuclear import and export is a feature of both p53 and Hdm2 with implications for their functional regulation, such that cytoplasmic p53 is associated with tumours with a poor prognosis.	('export', 'MPA', (19, 25))	('associated with', 'Reg', (140, 155))	('Hdm2', 'Gene', '4193', (55, 59))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('Hdm2', 'Gene', (55, 59))	('cytoplasmic p53', 'Var', (121, 136))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('Nuclear import', 'MPA', (0, 14))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
10502	15318938	Axillary lymphadenopathy was evaluable in 90 patients: 37 (41%) of the patients were lymph node negative, and 53 (59%) were node positive (N1 [mobile ipsilateral] or N2 [fixed ipsilateral]).	('lymphadenopathy', 'Phenotype', 'HP:0002716', (9, 24))	('Axillary lymphadenopathy', 'Phenotype', 'HP:0025289', (0, 24))	('patients', 'Species', '9606', (71, 79))	('Axillary lymphadenopathy', 'Disease', (0, 24))	('patients', 'Species', '9606', (45, 53))	('Axillary lymphadenopathy', 'Disease', 'MESH:D008206', (0, 24))	('N2 [', 'Var', (166, 170))
10520	15318938	Hdm2 expression was assessed with the mouse monoclonal antibody OP46 (Oncogene Research, CN Biosciences, Nottingham, UK) that detects C-terminal Hdm2 with specificity for the 90 kDa isoform.	('mouse', 'Species', '10090', (38, 43))	('C-terminal', 'Var', (134, 144))	('Hdm2', 'Gene', (0, 4))	('Hdm2', 'Gene', '4193', (145, 149))	('Hdm2', 'Gene', (145, 149))	('Hdm2', 'Gene', '4193', (0, 4))
10524	15318938	Breast carcinomas known to overexpress p53 with known TP53 gene mutations and protein accumulation were used as positive controls.	('carcinomas', 'Phenotype', 'HP:0030731', (7, 17))	('overexpress', 'PosReg', (27, 38))	('Breast carcinomas', 'Disease', (0, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('Breast carcinomas', 'Disease', 'MESH:D001943', (0, 17))	('TP53', 'Gene', '7157', (54, 58))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', (54, 58))	('Breast carcinomas', 'Phenotype', 'HP:0003002', (0, 17))
10540	15318938	For p14ARF, p53 and Hdm2, univariate and multivariate analyses were performed and adjusted for the NPI score and treatment received (tamoxifen/chemotherapy/none).	('p14ARF', 'Gene', '1029', (4, 10))	('p53', 'Var', (12, 15))	('tamoxifen', 'Chemical', 'MESH:D013629', (133, 142))	('Hdm2', 'Gene', (20, 24))	('p14ARF', 'Gene', (4, 10))	('Hdm2', 'Gene', '4193', (20, 24))
10589	15318938	Kaplan-Meier analyses of nuclear p53 subgroups (negative [0-2], weak/moderate [3-5] and strong [6-8]) showed a significant association between strong nuclear p53 expression and a reduced DFS (P = 0.05; log rank), although patient numbers were small for this group (data not shown).	('patient', 'Species', '9606', (222, 229))	('nuclear', 'Var', (150, 157))	('expression', 'MPA', (162, 172))	('DFS', 'MPA', (187, 190))	('reduced', 'NegReg', (179, 186))
10594	15318938	Kaplan-Meier survival curves showed that the presence of cytoplasmic Hdm2 (MQS >= 3 compared with MQS < 3) was associated with improved OS (P = 0.002) (Fig.	('Hdm2', 'Gene', '4193', (69, 73))	('cytoplasmic', 'Var', (57, 68))	('Hdm2', 'Gene', (69, 73))	('OS', 'Chemical', '-', (136, 138))	('presence', 'Var', (45, 53))	('improved', 'PosReg', (127, 135))
10595	15318938	p14ARF suppresses cancer cell growth, and several in vitro studies have reported its inhibition of Hdm2 to stabilise and activate p53, with a loss of ARF increasing p53 degradation.	('Hdm2', 'Gene', (99, 103))	('loss', 'Var', (142, 146))	('ARF', 'Disease', (150, 153))	('ARF', 'Disease', 'MESH:D058186', (3, 6))	('p14ARF', 'Gene', (0, 6))	('cancer', 'Disease', (18, 24))	('p53 degradation', 'MPA', (165, 180))	('inhibition', 'NegReg', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Hdm2', 'Gene', '4193', (99, 103))	('ARF', 'Disease', 'MESH:D058186', (150, 153))	('increasing', 'PosReg', (154, 164))	('activate', 'PosReg', (121, 129))	('suppresses', 'NegReg', (7, 17))	('ARF', 'Disease', (3, 6))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('p14ARF', 'Gene', '1029', (0, 6))	('p53', 'Protein', (130, 133))	('stabilise', 'MPA', (107, 116))
10610	15318938	Such observations might invoke an additional pathway of ARF regulation through changes in its subcellular localisation as for other tumour suppressors, such as p53 and p21WAF1/CIP1 [.	('ARF', 'Disease', (56, 59))	('tumour', 'Disease', (132, 138))	('p53', 'Var', (160, 163))	('subcellular localisation', 'MPA', (94, 118))	('p21WAF1/CIP1', 'Gene', '1026', (168, 180))	('invoke', 'Reg', (24, 30))	('p21WAF1/CIP1', 'Gene', (168, 180))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('changes', 'Reg', (79, 86))	('ARF', 'Disease', 'MESH:D058186', (56, 59))
10612	15318938	It is suggested that the upregulation of nuclear p14ARF expression is a consequence of cell cycle malfunction involving p53 and Hdm2.	('Hdm2', 'Gene', '4193', (128, 132))	('p14ARF', 'Gene', '1029', (49, 55))	('Hdm2', 'Gene', (128, 132))	('cell', 'Disease', (87, 91))	('expression', 'MPA', (56, 66))	('cell cycle malfunction', 'Phenotype', 'HP:0011018', (87, 109))	('p53', 'Var', (120, 123))	('p14ARF', 'Gene', (49, 55))	('nuclear', 'Protein', (41, 48))	('upregulation', 'PosReg', (25, 37))
10613	15318938	Increasing levels of nuclear ARF on immunohistochemistry are a measure of p53 inactivation by mutation, or by Hdm2 overexpression resulting in disruption of the p53-p14ARF negative feedback loop.	('Hdm2', 'Gene', '4193', (110, 114))	('ARF', 'Disease', 'MESH:D058186', (29, 32))	('disruption', 'MPA', (143, 153))	('Hdm2', 'Gene', (110, 114))	('p14ARF', 'Gene', (165, 171))	('p53', 'Gene', (74, 77))	('ARF', 'Disease', 'MESH:D058186', (168, 171))	('ARF', 'Disease', (29, 32))	('inactivation', 'NegReg', (78, 90))	('ARF', 'Disease', (168, 171))	('mutation', 'Var', (94, 102))	('p14ARF', 'Gene', '1029', (165, 171))
10615	15318938	Although p53 immunostaining is not necessarily tightly correlated with TP53 gene function, 57% (17 cases) of p53-positive tumours in this study strongly expressed ARF, reflecting similar in vivo evidence showing concomitant p14ARF mRNA expression and p53 immunostaining in breast cancers, with a similar relationship between increasing levels of ARF protein and p53 mutations in B cell lymphomas (Table 3).	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('B cell lymphomas', 'Disease', 'MESH:D016393', (379, 395))	('ARF', 'Disease', 'MESH:D058186', (346, 349))	('mutations', 'Var', (366, 375))	('lymphomas', 'Phenotype', 'HP:0002665', (386, 395))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ARF', 'Disease', 'MESH:D058186', (227, 230))	('tumours', 'Disease', (122, 129))	('breast cancers', 'Disease', 'MESH:D001943', (273, 287))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancers', 'Disease', (273, 287))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('TP53', 'Gene', '7157', (71, 75))	('breast cancers', 'Phenotype', 'HP:0003002', (273, 287))	('p14ARF', 'Gene', '1029', (224, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('ARF', 'Disease', (163, 166))	('ARF', 'Disease', (346, 349))	('ARF', 'Disease', (227, 230))	('B cell lymphomas', 'Disease', (379, 395))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (379, 395))	('p53', 'Gene', (362, 365))	('p14ARF', 'Gene', (224, 230))	('TP53', 'Gene', (71, 75))	('ARF', 'Disease', 'MESH:D058186', (163, 166))
10628	15318938	Not uncommonly in colorectal cell lines and primary tumours, in vivo inactivation of ARF by methylation is associated with increasing cytoplasmic Hdm2 expression, emphasising the importance of p14ARF in nuclear Hdm2 localisation.	('colorectal cell lines and primary tumours', 'Disease', 'MESH:D015179', (18, 59))	('methylation', 'Var', (92, 103))	('Hdm2', 'Gene', '4193', (146, 150))	('inactivation', 'NegReg', (69, 81))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('ARF', 'Disease', 'MESH:D058186', (85, 88))	('expression', 'MPA', (151, 161))	('increasing', 'PosReg', (123, 133))	('p14ARF', 'Gene', '1029', (193, 199))	('Hdm2', 'Gene', (146, 150))	('ARF', 'Disease', 'MESH:D058186', (196, 199))	('Hdm2', 'Gene', '4193', (211, 215))	('ARF', 'Disease', (85, 88))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('ARF', 'Disease', (196, 199))	('Hdm2', 'Gene', (211, 215))	('p14ARF', 'Gene', (193, 199))
10635	15318938	Variable p14ARF mRNA expression including both overexpression as well as decreased mRNA levels are reported to be significantly associated with poor prognostic criteria including p53 mutational status, peritumoural vessel invasion, lymph node metastases and negative progesterone receptors.	('p53', 'Gene', (179, 182))	('mRNA expression', 'MPA', (16, 31))	('mRNA levels', 'MPA', (83, 94))	('overexpression', 'PosReg', (47, 61))	('decreased', 'NegReg', (73, 82))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('p14ARF', 'Gene', '1029', (9, 15))	('mutational status', 'Var', (183, 200))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('metastases', 'Disease', (243, 253))	('p14ARF', 'Gene', (9, 15))	('tumour', 'Disease', (206, 212))	('metastases', 'Disease', 'MESH:D009362', (243, 253))
10637	15318938	We find no clear associations between ARF levels and prognostic parameters or outcome, although the presence of cytoplasmic p14ARF as opposed to its absence suggests a better outcome (Fig.	('ARF', 'Disease', (38, 41))	('p14ARF', 'Gene', '1029', (124, 130))	('ARF', 'Disease', 'MESH:D058186', (127, 130))	('better', 'PosReg', (168, 174))	('cytoplasmic', 'Var', (112, 123))	('p14ARF', 'Gene', (124, 130))	('ARF', 'Disease', 'MESH:D058186', (38, 41))	('ARF', 'Disease', (127, 130))
10640	15318938	In vitro, HER-2 promotes Hdm2-mediated p53 degradation through the inactivation of ARF, and HER-2 further enhances mammary tumorigenesis in ARF heterozygous mice.	('inactivation', 'Var', (67, 79))	('promotes', 'PosReg', (16, 24))	('ARF', 'Disease', (83, 86))	('mice', 'Species', '10090', (157, 161))	('Hdm2', 'Gene', (25, 29))	('mammary tumorigenesis', 'CPA', (115, 136))	('ARF', 'Disease', 'MESH:D058186', (140, 143))	('enhances', 'PosReg', (106, 114))	('ARF', 'Disease', (140, 143))	('ARF', 'Disease', 'MESH:D058186', (83, 86))	('Hdm2', 'Gene', '4193', (25, 29))
10643	15318938	Immunohistochemical p53 expression might detect up to 89% of TP53 point mutations in breast carcinoma specimens, although it does not always correlate with specific mutations in exons 5 to 9.	('to 9', 'Species', '1214577', (186, 190))	('breast carcinoma', 'Disease', (85, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('breast carcinoma', 'Disease', 'MESH:D001943', (85, 101))	('point mutations', 'Var', (66, 81))	('breast carcinoma', 'Phenotype', 'HP:0003002', (85, 101))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
10646	15318938	We found a significant association of cytoplasmic p53 with increased tumour proliferation in DCIS, suggesting the value of its further investigation in future studies.	('tumour', 'Disease', (69, 75))	('DCIS', 'Disease', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('cytoplasmic p53', 'Var', (38, 53))	('increased', 'PosReg', (59, 68))
10658	15318938	Increasingly, evidence suggests the importance of evaluating the subcellular localisation of checkpoint proteins to include p53, Hdm2 and p14ARF .	('p14ARF', 'Gene', '1029', (138, 144))	('Hdm2', 'Gene', '4193', (129, 133))	('p14ARF', 'Gene', (138, 144))	('Hdm2', 'Gene', (129, 133))	('p53', 'Var', (124, 127))
10671	24380073	In two Japanese cohort studies, high daily green tea intake among patients with breast cancer has been associated with a decrease in risk of recurrence and mortality.	('high daily green tea', 'Var', (32, 52))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('decrease', 'NegReg', (121, 129))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('recurrence', 'CPA', (141, 151))	('patients', 'Species', '9606', (66, 74))
10676	24380073	Strong experimental evidence shows that EGCG influences cell growth and inhibits cell proliferation and angiogenesis, and induces apoptosis of preneoplastic and neoplastic cells, inhibiting essential mechanisms of cancer cell survival in different organ sites of various animal models and cell lines.	('cell proliferation', 'CPA', (81, 99))	('EGCG', 'Chemical', 'MESH:C045651', (40, 44))	('cancer', 'Disease', (214, 220))	('EGCG', 'Var', (40, 44))	('inhibiting', 'NegReg', (179, 189))	('apoptosis', 'CPA', (130, 139))	('cell growth', 'CPA', (56, 67))	('induces', 'Reg', (122, 129))	('influences', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('inhibits', 'NegReg', (72, 80))	('angiogenesis', 'CPA', (104, 116))	('men', 'Species', '9606', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
10741	24380073	In breast cancer cells, green tea or EGCG, have been found to inhibit cell proliferation, induce apoptosis, and block angiogenesis in cell cultures through multiple signaling pathways.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('EGCG', 'Chemical', 'MESH:C045651', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('EGCG', 'Var', (37, 41))	('cell proliferation', 'CPA', (70, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('induce', 'PosReg', (90, 96))	('block', 'NegReg', (112, 117))	('inhibit', 'NegReg', (62, 69))	('apoptosis', 'CPA', (97, 106))	('angiogenesis', 'CPA', (118, 130))
10744	24380073	A study using the C3(1)/SV40 mouse model which more closely mimics the development and progression of human breast cancers found that administration of 0.5% Polyphenon E in drinking water inhibited mammary tumor growth.. Additional studies have suggested that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth in mice experiments, EGCG enhances tamoxifen-induced cellular apoptosis in ERalpha-negative MDA-MB-231, and inhibits proliferation of trastuzumab-resistant human breast cancer cells.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('men', 'Species', '9606', (392, 395))	('breast cancer', 'Phenotype', 'HP:0003002', (357, 370))	('breast cancer', 'Disease', 'MESH:D001943', (540, 553))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('breast cancer', 'Disease', (540, 553))	('tamoxifen', 'Chemical', 'MESH:D013629', (413, 422))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('breast cancer', 'Disease', 'MESH:D001943', (357, 370))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('breast cancer', 'Disease', (357, 370))	('tamoxifen-induced', 'MPA', (413, 430))	('mouse', 'Species', '10090', (29, 34))	('inhibits', 'NegReg', (486, 494))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('human', 'Species', '9606', (102, 107))	('tamoxifen', 'Chemical', 'MESH:D013629', (293, 302))	('suppressing', 'NegReg', (345, 356))	('enhances', 'PosReg', (404, 412))	('Polyphenon E', 'Chemical', '-', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (470, 480))	('cancer', 'Phenotype', 'HP:0002664', (547, 553))	('trastuzumab', 'Chemical', 'MESH:D000068878', (512, 523))	('water', 'Chemical', 'MESH:D014867', (182, 187))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('men', 'Species', '9606', (78, 81))	('mice', 'Species', '10090', (381, 385))	('EGCG', 'Var', (399, 403))	('tumor', 'Disease', (206, 211))	('proliferation', 'CPA', (495, 508))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('human', 'Species', '9606', (534, 539))	('breast cancer', 'Phenotype', 'HP:0003002', (540, 553))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('EGCG', 'Chemical', 'MESH:C045651', (399, 403))
10745	24380073	More recently, EGCG was found to reactivate ERalpha expression in ERalpha-negative MDA-MB-213 breast cancer cells via epigenetic mechanisms.	('ERalpha', 'Gene', (44, 51))	('EGCG', 'Chemical', 'MESH:C045651', (15, 19))	('epigenetic', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('MDA-MB-213', 'CellLine', 'CVCL:0062', (83, 93))
10749	24380073	Notwithstanding, the present study suggests that green tea supplementation may decrease proliferation of breast tissue although we found little evidence for its effect on apoptosis and angiogenesis.	('proliferation of breast tissue', 'CPA', (88, 118))	('supplementation', 'Var', (59, 74))	('decrease', 'NegReg', (79, 87))	('men', 'Species', '9606', (65, 68))
10765	24179491	In addition, the aberrant expression of various molecules of the cell cycle, including p21, p27 and p16, has been identified in BC precursor lesions.	('p27', 'Gene', '3429', (92, 95))	('p27', 'Gene', (92, 95))	('aberrant', 'Var', (17, 25))	('BC precursor lesions', 'Disease', (128, 148))	('p21', 'Gene', '1026', (87, 90))	('identified', 'Reg', (114, 124))	('p21', 'Gene', (87, 90))	('p16', 'Gene', (100, 103))	('BC', 'Phenotype', 'HP:0003002', (128, 130))	('p16', 'Gene', '1029', (100, 103))
10768	24179491	Moreover, Bcl-2 positivity has been identified to correlate with p53 negativity in normal breast tissue and several BC precursor lesions.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('negativity', 'NegReg', (69, 79))	('BC', 'Phenotype', 'HP:0003002', (116, 118))	('positivity', 'Var', (16, 26))	('Bcl-2', 'Gene', (10, 15))	('Bcl-2', 'Gene', '596', (10, 15))
10769	24179491	Bcl-2 expression is often also associated with Ki67 expression, in fact, high Ki67 expression, associated with negativity for Bcl-2, has been reported to correlate with the development of poorly-differentiated carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('high', 'Var', (73, 77))	('Ki67', 'Gene', (78, 82))	('carcinoma', 'Disease', (210, 219))	('expression', 'MPA', (83, 93))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', (126, 131))	('Bcl-2', 'Gene', '596', (126, 131))	('carcinoma', 'Disease', 'MESH:D002277', (210, 219))	('Bcl-2', 'Gene', '596', (0, 5))
10770	24179491	By contrast, alterations in p53, well described in invasive BCs, are present in DCIS only.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('alterations', 'Var', (13, 24))
10772	24179491	E-cadherin hypermethylation has been highlighted in DCIS and the methylation pattern of this gene is consistent with the hypothesis that DCIS represents an IDC precursor.	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('hypermethylation', 'Var', (11, 27))	('DCIS', 'Disease', (52, 56))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))
10790	32997179	Many of the UK screening programme performance measures are based on the Swedish Two County (STC) randomised controlled trial which demonstrated the importance of detecting small-grade 3 invasive cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('invasive cancers', 'Disease', 'MESH:D009362', (187, 203))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('small-grade', 'Var', (173, 184))	('invasive cancers', 'Disease', (187, 203))
10799	32997179	However, if we are to further improve performance and increase mortality reduction, we need to understand the limitations of current technology and the ability of new technology to detect small grade 3 cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('small grade', 'Var', (188, 199))	('mortality', 'Disease', 'MESH:D003643', (63, 72))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('mortality', 'Disease', (63, 72))
10843	32997179	For cancers with known size, the mean detection rate of < 15-mm invasive cancers was 0.46 per 1000 (SD 0.12) with a range of 0.22 to 0.87 per 1000.	('cancers', 'Disease', (73, 80))	('invasive cancers', 'Disease', 'MESH:D009362', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('invasive cancers', 'Disease', (64, 80))	('< 15-mm', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancers', 'Disease', (4, 11))
10851	32997179	In this retrospective observational study of the English Breast Screening Programme, we provide evidence of a relative lack of sensitivity for the detection of small grade 3 cancers estimated at only 26% of the sensitivity for small grade 1 tumours.	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('tumours', 'Phenotype', 'HP:0002664', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('small', 'Var', (160, 165))	('tumours', 'Disease', 'MESH:D009369', (241, 248))	('tumours', 'Disease', (241, 248))	('lack', 'NegReg', (119, 123))
10877	32997179	There has also been an increase in overall cancer detection by 14% with digital mammography, almost exclusively grade 1 and 2 invasive cancers, but no change in grade 3.	('cancer', 'Disease', (135, 141))	('invasive cancers', 'Disease', 'MESH:D009362', (126, 142))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Disease', (43, 49))	('digital', 'Var', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('increase', 'PosReg', (23, 31))	('invasive cancers', 'Disease', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
10952	31595577	Additional descriptors noted included: staining location (tumor, stroma, nucleus, cytoplasm); signal pattern (weak, medium, strong, dots [single, dual, multiple], clusters [cells or nuclei densely stained]).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('weak', 'Var', (110, 114))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
11082	21264977	Lymph nodes in FVB/N mice had a slightly lower SNR compared with C3 SV40 Tag mice (p=0.01), but were observed to be similar in size at 1.8+-0.3 mm and 1.8+-0.2 mm for FVB/N and C3 SV40 Tag mice, respectively.	('mice', 'Species', '10090', (77, 81))	('SNR', 'MPA', (47, 50))	('mice', 'Species', '10090', (21, 25))	('mice', 'Species', '10090', (189, 193))	('lower', 'NegReg', (41, 46))	('C3 SV40 Tag', 'Var', (177, 188))	('FVB/N', 'Var', (15, 20))
11103	21264977	Conspicuity of in situ and early invasive tumors may reflect large variations compared with normal tissue of relaxation parameters T1, T2* as well as proton density, where the phrase 'proton density' is used to refer to water protons that are detectable by MRI using standard imaging parameters (as opposed to solid-state MRI methods).	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('invasive tumors', 'Disease', (33, 48))	('variations', 'Var', (67, 77))	('water', 'Chemical', 'MESH:D014867', (220, 225))	('invasive tumors', 'Disease', 'MESH:D009369', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
11210	22295246	Those women harboring a BRCA mutation or a strong family history of breast cancer may be considered candidates for prophylactic bilateral mastectomy.	('mutation', 'Var', (29, 37))	('BRCA', 'Gene', '672', (24, 28))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('BRCA', 'Gene', (24, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('women', 'Species', '9606', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
11221	22295246	Early studies indicate that resection of a primary breast lesion may increase survival in the setting of limited metastasis.	('resection', 'Var', (28, 37))	('increase', 'PosReg', (69, 77))	('breast lesion', 'Disease', (51, 64))	('survival', 'MPA', (78, 86))	('breast lesion', 'Disease', 'MESH:D001941', (51, 64))
11262	26268945	Moreover, selective knockdown of IL-6 in CAFs, but not in DCIS cells, abrogated the migratory phenotype.	('abrogated', 'NegReg', (70, 79))	('IL-6', 'Gene', (33, 37))	('migratory phenotype', 'CPA', (84, 103))	('CAFs', 'Chemical', '-', (41, 45))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('IL-6', 'Gene', '3569', (33, 37))	('knockdown', 'Var', (20, 29))
11280	26268945	show that knockdown of IL-6 in an invasive variant of the MCF10A cells, MCF10A-H-RasV12, inhibited cell migration in a transwell assay, and inhibited growth in a xenograft mouse model.	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('MCF10A', 'CellLine', 'CVCL:0598', (72, 78))	('growth in a xenograft mouse model', 'CPA', (150, 183))	('mouse', 'Species', '10090', (172, 177))	('inhibited', 'NegReg', (89, 98))	('inhibited', 'NegReg', (140, 149))	('IL-6', 'Gene', (23, 27))	('cell migration in a transwell assay', 'CPA', (99, 134))	('IL-6', 'Gene', '3569', (23, 27))	('knockdown', 'Var', (10, 19))
11312	26268945	The protease inhibitors CA074Me and E64d (Sigma, St. Louis, MO) were used at a concentration of 10 muM.	('CA074Me', 'Chemical', 'MESH:C400541', (24, 31))	('E64d', 'Var', (36, 40))	('CA074Me', 'Var', (24, 31))	('E64d', 'Chemical', 'MESH:C108192', (36, 40))
11321	26268945	Our data show higher IL-6 mRNA levels in both MCF10.DCIS and SUM102 cell lines, as compared to the MCF10A breast epithelial cell line (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('MCF10A', 'CellLine', 'CVCL:0598', (99, 105))	('MCF10.DCIS', 'Var', (46, 56))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (46, 56))	('IL-6', 'Gene', (21, 25))	('IL-6', 'Gene', '3569', (21, 25))	('higher', 'PosReg', (14, 20))
11341	26268945	IL-6 levels in CAF40TKi lysates were significantly higher than in FB-NF-i lysates (Fig.	('IL-6', 'Gene', (0, 4))	('CAF40TKi', 'Var', (15, 23))	('higher', 'PosReg', (51, 57))	('CAF40TKi', 'Chemical', '-', (15, 23))	('IL-6', 'Gene', '3569', (0, 4))
11344	26268945	We found that in MCF10.DCIS:CAF40TKi co-cultures there was an increase in the average diameter and volume of the multicellular structures and a prominent formation of branch-like interconnections between the structures (Fig.	('MCF10.DCIS', 'Var', (17, 27))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (17, 27))	('CAF40TKi', 'Var', (28, 36))	('CAF40TKi', 'Chemical', '-', (28, 36))	('branch-like interconnections', 'CPA', (167, 195))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('increase', 'PosReg', (62, 70))
11349	26268945	We observed the presence of multiple invasive processes in SUM102:CAF co-cultures that were completely absent in cultures of the SUM102 cells alone (Additional file 8: Figure S5C and D, arrow, cf.	('CAF', 'Gene', (66, 69))	('CAF', 'Gene', '8850', (66, 69))	('SUM102', 'Var', (59, 65))
11353	26268945	Here we found that MCF10.DCIS spheroids formed attachments to CAFs and remained associated with them throughout an 8-day culture.	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('CAFs', 'Chemical', '-', (62, 66))	('MCF10.DCIS', 'Var', (19, 29))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (19, 29))	('attachments', 'CPA', (47, 58))	('associated', 'Interaction', (80, 90))
11376	26268945	We treated cultures with E64d, a cell permeable pan-cysteine protease inhibitor, and found a 30 - 40 % reduction of matrix degradation (Fig.	('matrix degradation', 'MPA', (116, 134))	('reduction', 'NegReg', (103, 112))	('E64d', 'Chemical', 'MESH:C108192', (25, 29))	('E64d', 'Var', (25, 29))
11377	26268945	We also treated cultures with the cell permeable cathepsin B/L inhibitor, CA074Me, and found a 60 - 70 % reduction in matrix degradation (Fig.	('matrix degradation', 'MPA', (118, 136))	('CA074Me', 'Var', (74, 81))	('CA074Me', 'Chemical', 'MESH:C400541', (74, 81))	('cathepsin B', 'Gene', (49, 60))	('reduction', 'NegReg', (105, 114))	('cathepsin B', 'Gene', '1508', (49, 60))
11378	26268945	CA074Me has previously been shown to be a more efficacious inhibitor against cathepsins B and L than is E64d.	('CA074Me', 'Var', (0, 7))	('cathepsins', 'Protein', (77, 87))	('E64d', 'Chemical', 'MESH:C108192', (104, 108))	('CA074Me', 'Chemical', 'MESH:C400541', (0, 7))
11381	26268945	To determine whether CAF-stimulated migration and interaction with MCF10.DCIS cells could be inhibited by blocking IL-6, we co-cultured MCF10.DCIS cells with two human breast carcinoma-associated fibroblast lines WS-12Ti or CAF40TKi, in the presence of IL-6 nAb or an isotype control antibody.	('IL-6', 'Gene', (253, 257))	('CAF', 'Gene', (21, 24))	('CAF40TKi', 'Chemical', '-', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('IL-6', 'Gene', '3569', (115, 119))	('breast carcinoma', 'Disease', 'MESH:D001943', (168, 184))	('CAF', 'Gene', '8850', (224, 227))	('IL-6', 'Gene', (115, 119))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('CAF', 'Gene', (224, 227))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (67, 77))	('MCF10.DCIS', 'Var', (136, 146))	('breast carcinoma', 'Phenotype', 'HP:0003002', (168, 184))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('human', 'Species', '9606', (162, 167))	('IL-6', 'Gene', '3569', (253, 257))	('breast carcinoma', 'Disease', (168, 184))	('CAF', 'Gene', '8850', (21, 24))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (136, 146))
11385	26268945	In CAF40TKi and MCF10.DCIS cells, we achieved greater than 50 % reduction in secreted IL-6 (Additional file 14: Figure S8A).	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('CAF40TKi', 'Var', (3, 11))	('IL-6', 'Gene', '3569', (86, 90))	('CAF40TKi', 'Chemical', '-', (3, 11))	('MCF10.DCIS', 'Var', (16, 26))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (16, 26))	('reduction', 'NegReg', (64, 73))	('IL-6', 'Gene', (86, 90))
11387	26268945	Knocking down CAF40TKi IL-6 expression in co-culture resulted in the formation of multicellular structures with uniform borders and few invasive processes (Additional file 14: Figure S8C).	('resulted in', 'Reg', (53, 64))	('CAF40TKi', 'Var', (14, 22))	('IL-6', 'Gene', (23, 27))	('Knocking down CAF40TKi', 'Var', (0, 22))	('IL-6', 'Gene', '3569', (23, 27))	('CAF40TKi', 'Chemical', '-', (14, 22))	('formation of multicellular structures', 'CPA', (69, 106))	('invasive processes', 'CPA', (136, 154))
11388	26268945	Co-culture with non-shRNA transduced CAF40TKi fibroblasts and shRNA-IL-6 transduced MCF10.DCIS cells showed greater MCF10.DCIS:CAF40TKi interaction and multicellular structure branching (Additional file 14: Figure S8D).	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('CAF40TKi', 'Chemical', '-', (37, 45))	('CAF40TKi', 'Var', (127, 135))	('MCF10.DCIS:CAF40TKi', 'Var', (116, 135))	('IL-6', 'Gene', (68, 72))	('CAF40TKi', 'Chemical', '-', (127, 135))	('greater', 'PosReg', (108, 115))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (84, 94))	('IL-6', 'Gene', '3569', (68, 72))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('multicellular structure branching', 'CPA', (152, 185))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (116, 126))
11407	26268945	An underlying mechanism for DCIS:CAF interaction, enhanced tumor cell proliferation, and migration was IL-6 signaling in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('IL-6', 'Gene', '3569', (103, 107))	('CAF', 'Gene', (33, 36))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CAF', 'Gene', '8850', (33, 36))	('tumor', 'Disease', (125, 130))	('enhanced', 'PosReg', (50, 58))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('DCIS', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('IL-6', 'Gene', (103, 107))	('migration', 'CPA', (89, 98))	('interaction', 'Interaction', (37, 48))
11414	26268945	This phenotype was primarily produced by the inhibition of CAF secreted IL-6 as shRNA knockdown of IL-6 in CAFs, but not in DCIS cells was able to replicate the phenotype.	('knockdown', 'Var', (86, 95))	('CAF', 'Gene', '8850', (107, 110))	('IL-6', 'Gene', '3569', (72, 76))	('IL-6', 'Gene', (99, 103))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('CAF', 'Gene', (59, 62))	('CAFs', 'Chemical', '-', (107, 111))	('IL-6', 'Gene', '3569', (99, 103))	('CAF', 'Gene', '8850', (59, 62))	('CAF', 'Gene', (107, 110))	('IL-6', 'Gene', (72, 76))
11416	26268945	A recent study suggests that tumor cell EMT is mediated through factors secreted from CAFs and that selective inhibition of TGFbeta1 is sufficient to reverse EMT associated gene expression.	('EMT', 'Gene', '3702', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('TGFbeta1', 'Gene', '7040', (124, 132))	('EMT', 'Gene', (40, 43))	('TGFbeta1', 'Gene', (124, 132))	('inhibition', 'Var', (110, 120))	('CAFs', 'Chemical', '-', (86, 90))	('EMT', 'Gene', '3702', (40, 43))	('EMT', 'Gene', (158, 161))
11440	23151501	Among these is an interesting study by Jang and colleagues described in a recent issue of Breast Cancer Research, which evaluated and compared the frequency of amplification of four oncogenes ( HER2, c-MYC, CCND1, and FGFR1) in large cohorts of pure DCIS (n = 175), in the DCIS component of IBC (n = 203), and in the corresponding IBC (n = 427).	('DCIS', 'Phenotype', 'HP:0030075', (250, 254))	('Breast Cancer', 'Disease', 'MESH:D001943', (90, 103))	('FGFR1', 'Gene', (218, 223))	('DCIS', 'Phenotype', 'HP:0030075', (273, 277))	('amplification', 'Var', (160, 173))	('IBC', 'Chemical', '-', (291, 294))	('CCND1', 'Gene', (207, 212))	('HER2', 'Gene', '2064', (194, 198))	('IBC', 'Disease', (291, 294))	('c-MYC', 'Gene', (200, 205))	('HER2', 'Gene', (194, 198))	('Breast Cancer', 'Phenotype', 'HP:0003002', (90, 103))	('c-MYC', 'Gene', '4609', (200, 205))	('Breast Cancer', 'Disease', (90, 103))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CCND1', 'Gene', '595', (207, 212))	('pure DCIS', 'Disease', (245, 254))	('IBC', 'Chemical', '-', (331, 334))
11446	23151501	In these studies, amplification of FGFR1 was associated with significantly reduced disease-free survival in patients with IBC (about 10% at 8 years), particularly in hormone-receptor-positive patients, although HER2, c-MYC, and CCND1 were not prognostic in this cohort.	('HER2', 'Gene', (211, 215))	('IBC', 'Chemical', '-', (122, 125))	('HER2', 'Gene', '2064', (211, 215))	('patients', 'Species', '9606', (192, 200))	('IBC', 'Disease', (122, 125))	('CCND1', 'Gene', (228, 233))	('reduced', 'NegReg', (75, 82))	('disease-free survival', 'CPA', (83, 104))	('CCND1', 'Gene', '595', (228, 233))	('c-MYC', 'Gene', '4609', (217, 222))	('FGFR1', 'Gene', (35, 40))	('patients', 'Species', '9606', (108, 116))	('amplification', 'Var', (18, 31))	('c-MYC', 'Gene', (217, 222))
11455	23151501	The study by Jang and colleagues provides additional evidence of an important role for FGFR1 amplification in the progression of IBC.	('amplification', 'Var', (93, 106))	('IBC', 'Disease', (129, 132))	('FGFR1', 'Gene', (87, 92))	('IBC', 'Chemical', '-', (129, 132))
11597	21234412	To our knowledge, this is the first reported case of multiple papillomatosis with DCIS of breast, along with incidental synchronous papillomatosis of contralateral breast with DCIS.	('DCIS', 'Var', (82, 86))	('papilloma', 'Phenotype', 'HP:0012740', (132, 141))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('synchronous papillomatosis of contralateral breast', 'Disease', 'MESH:D010212', (120, 170))	('multiple papillomatosis', 'Disease', 'MESH:D010212', (53, 76))	('multiple papillomatosis', 'Disease', (53, 76))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('papilloma', 'Phenotype', 'HP:0012740', (62, 71))	('synchronous papillomatosis of contralateral breast', 'Disease', (120, 170))
11654	21234412	We have not come across any previous reported case of multiple papillomatosis with DCIS of breast, along with incidental synchronous papillomatosis of contralateral breast with DCIS, which makes this case unique.	('papilloma', 'Phenotype', 'HP:0012740', (133, 142))	('synchronous papillomatosis of contralateral breast', 'Disease', (121, 171))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('DCIS', 'Var', (83, 87))	('papilloma', 'Phenotype', 'HP:0012740', (63, 72))	('multiple papillomatosis', 'Disease', 'MESH:D010212', (54, 77))	('multiple papillomatosis', 'Disease', (54, 77))	('synchronous papillomatosis of contralateral breast', 'Disease', 'MESH:D010212', (121, 171))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
11662	18237383	Two markers were significantly different between cases and controls on univariate analysis: strong COX-2 expression was associated with increased risk of recurrence, with 67% vs. 24% positivity in cases and controls p = 0.006; and nuclear expression of PPARgamma was associated with protection from recurrence with 4% vs. 27% positivity in cases and controls, p = 0.024.	('nuclear expression', 'Var', (231, 249))	('PPARgamma', 'Gene', (253, 262))	('PPARgamma', 'Gene', '5468', (253, 262))	('COX-2', 'Gene', (99, 104))	('expression', 'MPA', (105, 115))
11672	18237383	Overexpression of HER-2/neu in invasive carcinoma is correlated with decreased relapse-free and overall survival, and resistance to hormonal and cytotoxic therapy.	('invasive carcinoma', 'Disease', (31, 49))	('decreased', 'NegReg', (69, 78))	('HER-2/neu', 'Gene', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('Overexpression', 'Var', (0, 14))	('HER-2/neu', 'Gene', '2064', (18, 27))	('invasive carcinoma', 'Disease', 'MESH:D009361', (31, 49))
11726	18237383	Dual negativity for COX-2 and HER-2/neu was significantly associated with control status (17 of 27 controls were dual negative, p = 0.024).	('HER-2/neu', 'Gene', (30, 39))	('associated', 'Reg', (58, 68))	('control status', 'Disease', (74, 88))	('HER-2/neu', 'Gene', '2064', (30, 39))	('COX-2', 'Gene', (20, 25))	('Dual negativity', 'Var', (0, 15))
11732	18237383	The odds ratio for recurrence was 0.11 (95% CI 0.012-1.00, p = 0.050) indicating a protective effect of nuclear PPARgamma against recurrence.	('nuclear', 'Var', (104, 111))	('PPARgamma', 'Gene', '5468', (112, 121))	('PPARgamma', 'Gene', (112, 121))
11741	18237383	There were weaker, although significant associations of p53 positivity with ER and cyclin D1 positivity, which are of uncertain significance.	('positivity', 'Var', (60, 70))	('p53', 'Gene', (56, 59))	('positivity', 'MPA', (93, 103))	('p53', 'Gene', '7157', (56, 59))	('associations', 'Interaction', (40, 52))	('cyclin D1', 'Gene', '595', (83, 92))	('cyclin D1', 'Gene', (83, 92))
11743	18237383	The risk of recurrence associated with strong COX-2 positivity was independent of tumor size, margin status, estrogen receptor positivity, use of radiotherapy, and tamoxifen use.	('tamoxifen', 'Chemical', 'MESH:D013629', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('positivity', 'Var', (52, 62))	('COX-2', 'Enzyme', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('estrogen receptor', 'Gene', '2099', (109, 126))	('tumor', 'Disease', (82, 87))	('estrogen receptor', 'Gene', (109, 126))
11748	18237383	We found that roughly half of the ER positive DCIS lesions in our study overexpressed COX-2 protein, the rate limiting enzyme in prostaglandin synthesis.	('prostaglandin', 'Chemical', 'MESH:D011453', (129, 142))	('COX-2', 'Gene', (86, 91))	('overexpressed', 'Reg', (72, 85))	('lesions', 'Var', (51, 58))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('protein', 'Protein', (92, 99))
11762	18237383	Our study suggests that the presence of PPARgamma in DCIS may be protective against ipsilateral recurrence particularly in Grade 2 and 3 lesions.	('presence', 'Var', (28, 36))	('ipsilateral recurrence', 'CPA', (84, 106))	('PPARgamma', 'Gene', (40, 49))	('PPARgamma', 'Gene', '5468', (40, 49))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
11774	18237383	Evidence for a coordinated relationship between COX-2 and PPARgamma comes from studies that showing activation of PPARgamma suppresses transcriptional activation of COX-2 in cell culture models.	('suppresses', 'NegReg', (124, 134))	('PPARgamma', 'Gene', (114, 123))	('transcriptional activation', 'MPA', (135, 161))	('PPARgamma', 'Gene', '5468', (114, 123))	('activation', 'Var', (100, 110))	('PPARgamma', 'Gene', (58, 67))	('PPARgamma', 'Gene', '5468', (58, 67))
11782	18237383	However, we do see the expected inverse relationship between hormone receptor positivity and HER-2/neu positivity, which is highly significant for progesterone receptor, which tends to validate our HER-2/neu scoring.	('HER-2/neu', 'Gene', '2064', (198, 207))	('positivity', 'Var', (103, 113))	('HER-2/neu', 'Gene', (93, 102))	('progesterone receptor', 'Gene', '5241', (147, 168))	('HER-2/neu', 'Gene', (198, 207))	('inverse', 'NegReg', (32, 39))	('HER-2/neu', 'Gene', '2064', (93, 102))	('progesterone receptor', 'Gene', (147, 168))
11821	32957504	In breast cancer patients, increased TrkA phosphorylation has been described in malignant pleural effusions while phosphorylation of Tyr674/675 and activation of tyrosine kinase activity in the cytoplasmic domain of TrkA has been shown as a potential prognostic biomarker.	('malignant pleural effusions', 'Disease', 'MESH:D016066', (80, 107))	('activation', 'PosReg', (148, 158))	('TrkA', 'Gene', (37, 41))	('tyrosine kinase activity', 'MPA', (162, 186))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Tyr674/675', 'Var', (133, 143))	('TrkA', 'Gene', (216, 220))	('increased', 'PosReg', (27, 36))	('Tyr674', 'Chemical', '-', (133, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (162, 170))	('TrkA', 'Gene', '4914', (37, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (17, 25))	('malignant pleural effusions', 'Disease', (80, 107))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('phosphorylation', 'MPA', (42, 57))	('breast cancer', 'Disease', (3, 16))	('TrkA', 'Gene', '4914', (216, 220))	('phosphorylation', 'MPA', (114, 129))	('pleural effusions', 'Phenotype', 'HP:0002202', (90, 107))
11856	32957504	The results (Figure 1) indicated that NTRK1 gene expression was altered in 6% (52 cases) of breast tumours with 31 amplifications, 3 missense mutations, 13 mRNA upregulations and 5 mRNA downregulations (Figure 1A).	('NTRK1', 'Gene', (38, 43))	('mRNA', 'MPA', (156, 160))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('missense mutations', 'Var', (133, 151))	('breast tumours', 'Disease', 'MESH:D001943', (92, 106))	('expression', 'MPA', (49, 59))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('amplifications', 'Var', (115, 129))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('upregulations', 'PosReg', (161, 174))	('NTRK1', 'Gene', '4914', (38, 43))	('mRNA', 'MPA', (181, 185))	('altered', 'Reg', (64, 71))	('breast tumours', 'Disease', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('breast tumour', 'Phenotype', 'HP:0100013', (92, 105))	('N', 'Chemical', 'MESH:D009584', (183, 184))
11857	32957504	A total of 17% (14 cases) of basal (triple-negative) cancers had alterations within the NTRK1 gene (Figure 1B).	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('alterations', 'Var', (65, 76))	('NTRK1', 'Gene', '4914', (88, 93))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NTRK1', 'Gene', (88, 93))
11860	32957504	Overall patient survival, when considering all 825 cases of invasive breast cancers included in the PAM50 dataset, tended to be lower for cases with NTRK1 gene alterations as compared to cases with no alterations (Figure 1F), but the statistical significance was limited (log-rank test p-value = 0.07).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('NTRK1', 'Gene', '4914', (149, 154))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NTRK1', 'Gene', (149, 154))	('alterations', 'Var', (160, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('lower', 'NegReg', (128, 133))	('invasive breast cancers', 'Disease', (60, 83))	('patient', 'Species', '9606', (8, 15))	('invasive breast cancers', 'Disease', 'MESH:D001943', (60, 83))
11873	32957504	Log-linear modelling and subsequent analysis indicated that the odds of HER2 positivity increased by a factor of exp(0.56) = 1.75 (i.e., increased by 75%) in the presence of TrkA.	('TrkA', 'Gene', (174, 178))	('positivity', 'Var', (77, 87))	('TrkA', 'Gene', '4914', (174, 178))	('HER2', 'Protein', (72, 76))
11876	32957504	In addition, a higher molecular weight form of TrkA (~180 kDa), probably reflecting TrkA N-glycosylation, was also detected in SK-BR-3 and BT-474 cell lines.	('TrkA', 'Gene', '4914', (84, 88))	('TrkA', 'Gene', (84, 88))	('TrkA', 'Gene', '4914', (47, 51))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('TrkA', 'Gene', (47, 51))	('SK-BR-3', 'CellLine', 'CVCL:0033', (127, 134))	('~180 kDa', 'Var', (53, 61))
11881	32957504	The data show that HER2-positive breast cancer cells are sensitive to GNF-5837 and that viability is reduced in a dose-dependent manner for all cell lines: SK-BR-3 (IC50 = 2.59 microM, Figure 4A), BT-474 (IC50 = 4.66 microM, Figure 4B), MDA-MB-453 (IC50 = 4.69 microM, Figure 4C) and JIMT-1 (IC50 = 15.31 microM, Figure 4D).	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('GNF-5837', 'Var', (70, 78))	('SK-BR-3', 'CellLine', 'CVCL:0033', (156, 163))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (237, 247))	('JIMT-1', 'CellLine', 'CVCL:2077', (284, 290))	('reduced', 'NegReg', (101, 108))	('GNF-5837', 'Chemical', '-', (70, 78))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('viability', 'CPA', (88, 97))	('HER2-positive', 'Protein', (19, 32))	('breast cancer', 'Disease', (33, 46))
11884	32957504	Phosphorylated TrkA (Tyr490) and phospho-AKT (Ser473) were markedly decreased in response to GNF-5837, in a dose-dependent manner, and common to all HER2-positive cell lines (Figure 4E).	('AKT', 'Gene', (41, 44))	('decreased', 'NegReg', (68, 77))	('Tyr490', 'Chemical', '-', (21, 27))	('TrkA', 'Gene', (15, 19))	('TrkA', 'Gene', '4914', (15, 19))	('Ser473', 'Chemical', '-', (46, 52))	('GNF-5837', 'Gene', (93, 101))	('AKT', 'Gene', '207', (41, 44))	('GNF-5837', 'Chemical', '-', (93, 101))	('Tyr490', 'Var', (21, 27))
11886	32957504	However, GNF-5837 did not increase the cytotoxic effect of Herceptin in any of the tested cell lines (Figure 4A-E).	('GNF-5837', 'Chemical', '-', (9, 17))	('cytotoxic', 'MPA', (39, 48))	('Herceptin', 'Chemical', 'MESH:D000068878', (59, 68))	('GNF-5837', 'Var', (9, 17))
11894	32957504	Our analysis was performed on a larger and more diverse cohort of breast tumours (PAM50), including all molecular subtypes and HER2 status, however no statistically significant associations were found between TrkA (NTRK1) gene alterations and the clinicopathological parameters.	('NTRK1', 'Gene', '4914', (215, 220))	('TrkA', 'Gene', (209, 213))	('breast tumour', 'Phenotype', 'HP:0100013', (66, 79))	('breast tumours', 'Disease', (66, 80))	('NTRK1', 'Gene', (215, 220))	('TrkA', 'Gene', '4914', (209, 213))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('breast tumours', 'Disease', 'MESH:D001943', (66, 80))	('alterations', 'Var', (227, 238))
11908	32957504	In vitro and animal model experiments have previously shown that TrkA overexpression enhances growth and invasion of breast cancer cells through the activation of Erk1/2 and PI3K-AKT mediated signaling pathways.	('invasion', 'CPA', (105, 113))	('AKT', 'Gene', (179, 182))	('overexpression', 'Var', (70, 84))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('growth', 'CPA', (94, 100))	('Erk1/2', 'Gene', '5595;5594', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('enhances', 'PosReg', (85, 93))	('Erk1/2', 'Gene', (163, 169))	('AKT', 'Gene', '207', (179, 182))	('TrkA', 'Gene', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('TrkA', 'Gene', '4914', (65, 69))	('activation', 'PosReg', (149, 159))
11963	29712688	Furthermore, we have shown that antibody-coupled ICG (B7-H3-ICG), when binding to B7-H3 on breast cancer cells, becomes internalized into cells and released from the antibody, resulting in a distinct change in the ICG optical absorption spectrum.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('ICG', 'Chemical', 'MESH:D007208', (49, 52))	('change', 'Reg', (200, 206))	('ICG optical absorption spectrum', 'MPA', (214, 245))	('binding', 'Interaction', (71, 78))	('ICG', 'Chemical', 'MESH:D007208', (60, 63))	('ICG', 'Chemical', 'MESH:D007208', (214, 217))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('B7-H3', 'Var', (82, 87))
11967	29712688	The purpose of this study was to assess the sensitivity and specificity of photoacoustic and fluorescence molecular imaging of B7-H3-ICG in a transgenic murine model of breast cancer development to guide surgical resection of small foci of disease.	('murine', 'Species', '10090', (153, 159))	('transgenic', 'Species', '10090', (142, 152))	('B7-H3-ICG', 'Var', (127, 136))	('foci of disease', 'Disease', 'MESH:C565785', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('foci of disease', 'Disease', (232, 247))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))	('ICG', 'Chemical', 'MESH:D007208', (133, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
12038	29712688	Using this approach, B7-H3-targeted sPA performed well as an intraoperative technique and was able to distinguish between normal and hyperplastic tissue versus DCIS and invasive cancer with an AUC of 0.93.	('invasive cancer', 'Disease', 'MESH:D009362', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('DCIS', 'Disease', (160, 164))	('B7-H3-targeted', 'Var', (21, 35))	('sPA', 'Chemical', '-', (36, 39))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))	('rat', 'Species', '10116', (69, 72))	('invasive cancer', 'Disease', (169, 184))
12048	29712688	However, the sPA molecular imaging technique employed here reduced background signal from not only endogenous chromophores, but also B7-H3-ICG contrast agent that has not bound to its molecular target.	('reduced', 'NegReg', (59, 66))	('background signal', 'MPA', (67, 84))	('ICG', 'Chemical', 'MESH:D007208', (139, 142))	('sPA', 'Chemical', '-', (13, 16))	('B7-H3-ICG', 'Var', (133, 142))
12072	23741988	Invasive cancers are not necessarily from preformed in situ tumours : an alternative way of carcinogenesis from misplaced stem cells Cancers are thought to be the result of accumulated gene mutations in cells.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('Cancers', 'Disease', (133, 140))	('cancers', 'Disease', (9, 16))	('situ tumours', 'Disease', (55, 67))	('carcinogenesis', 'Disease', (92, 106))	('Cancers', 'Disease', 'MESH:D009369', (133, 140))	('Cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('situ tumours', 'Disease', 'MESH:D002278', (55, 67))	('gene mutations', 'Var', (185, 199))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
12093	23741988	This theory holds that epithelial cells accumulate gene mutations first, and then transformation occurs, followed by abnormal proliferation of the transformed cells in the epithelium, and further develop into a stage of what is called in situ carcinoma.	('situ carcinoma', 'Disease', 'MESH:D002278', (238, 252))	('mutations', 'Var', (56, 65))	('situ carcinoma', 'Disease', (238, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))
12105	23741988	2) and/or ageing, degeneration of BM, all these situations increase the chances of the stem cell invasion, and these accumulated invasions add up to the increased probability of developing cancer.	('invasions', 'CPA', (129, 138))	('add', 'Reg', (139, 142))	('cancer', 'Disease', (189, 195))	('stem cell invasion', 'CPA', (87, 105))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('degeneration', 'Var', (18, 30))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('increase', 'PosReg', (59, 67))
12109	23741988	The loss of functional mutation of p53, which checks for the accuracy of gene duplication, leads to increasing amounts of mutations, and the genomic instability of tumour.	('loss of functional', 'NegReg', (4, 22))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('mutation', 'Var', (23, 31))	('mutations', 'MPA', (122, 131))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('amounts', 'MPA', (111, 118))
12111	23741988	Thus, this novel SCMT carcinogenesis theory of stem cell misplacement explains better the gene mutation than SMT, which holds that gene mutation accumulation leads to the transformation of the epithelial cells.	('leads to', 'Reg', (158, 166))	('carcinogenesis', 'Disease', (22, 36))	('accumulation', 'PosReg', (145, 157))	('transformation', 'CPA', (171, 185))	('gene mutation', 'Var', (131, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
12152	23997758	In this study, the covariates are the dummy variables indicating group membership, so we define beta regression parameters as  Because of the one-to-one relationship between lambdaj and muj, betaj = 0 implies equal means between group j and the reference group p + 1, that is, lambdaj = lambdap+1 and muj = mup+1.	('mup+1', 'Gene', (307, 312))	('betaj = 0', 'Var', (191, 200))	('mup+1', 'Gene', '60386', (307, 312))
12169	21555376	We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration.	('increases', 'PosReg', (126, 135))	('overexpression', 'PosReg', (91, 105))	('silencing', 'Var', (145, 154))	('survivin', 'Gene', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('leptin-induced migration', 'CPA', (174, 198))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('leptin-induced migration', 'CPA', (21, 45))	('abrogates', 'NegReg', (164, 173))
12198	21555376	We also found that survivin is required for leptin-mediated migration of breast cancer cells, and that pharmacological inhibition of survivin can inhibit this early event of malignant progression.	('inhibit', 'NegReg', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('survivin', 'Gene', (133, 141))	('pharmacological inhibition', 'Var', (103, 129))
12256	21555376	Epidemiological studies have shown that high leptin levels are significantly associated with an increased breast tumor growth and metastasis.	('high', 'Var', (40, 44))	('breast tumor', 'Disease', (106, 118))	('increased', 'PosReg', (96, 105))	('high leptin levels', 'Phenotype', 'HP:0031793', (40, 58))	('breast tumor', 'Phenotype', 'HP:0100013', (106, 118))	('leptin', 'Protein', (45, 51))	('metastasis', 'CPA', (130, 140))	('breast tumor', 'Disease', 'MESH:D001943', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
12274	21555376	In particular, Notch1 signaling has emerged as a pivotal target in breast cancer with Notch1 receptors acting as survival factors promoting breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('Notch1', 'Var', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('promoting', 'PosReg', (130, 139))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
12278	21555376	To examine the direct role of Notch1 activation in survivin expression, we treated breast cancer cells with a specific GSI (gamma-secretase) inhibitor (LY411,575), and found that inhibition of Notch1 activation inhibits survivin expression (Figure 3D).	('survivin', 'Protein', (220, 228))	('LY411', 'Chemical', '-', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inhibition', 'Var', (179, 189))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('inhibits', 'NegReg', (211, 219))	('Notch1', 'Gene', (193, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('expression', 'MPA', (229, 239))
12297	21555376	To test this hypothesis, we modulated survivin expression in breast cancer cells by transfecting full-length wild-type-survivin and p-silencer-survivin plasmids (Figure 5B).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('survivin', 'Protein', (38, 46))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('p-silencer-survivin', 'Var', (132, 151))	('modulated', 'Reg', (28, 37))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
12307	21555376	These results collectively showed that leptin-induced survivin upregulation is required for leptin-induced migration of breast cancer cells, and that disruption of survivin expression using lovastatin might be a valid therapeutic approach to counter the effects of leptin on breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('survivin', 'Gene', (164, 172))	('breast cancer', 'Disease', (120, 133))	('disruption', 'Var', (150, 160))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('lovastatin', 'Chemical', 'MESH:D008148', (190, 200))	('breast cancer', 'Disease', (275, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('upregulation', 'PosReg', (63, 75))
12317	21555376	Thus, pharmacological inhibition of survivin may be a suitable strategy for treating metastatic breast cancer progressing in the presence of high leptin levels.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('pharmacological', 'Var', (6, 21))	('breast cancer', 'Disease', (96, 109))	('high leptin levels', 'Phenotype', 'HP:0031793', (141, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
12325	21555376	Importantly, inhibition of EGFR activity inhibits leptin-induced survivin upregulation.	('EGFR', 'Gene', '1956', (27, 31))	('survivin', 'Protein', (65, 73))	('EGFR', 'Gene', (27, 31))	('inhibits', 'NegReg', (41, 49))	('inhibition', 'Var', (13, 23))	('upregulation', 'PosReg', (74, 86))	('activity', 'MPA', (32, 40))	('leptin-induced', 'MPA', (50, 64))
12334	21555376	Activation of Notch1 not only cause mammary tumors in mice but it is also associated with poor prognosis for breast cancer development.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Disease', (109, 122))	('cause', 'Reg', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('Notch1', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Activation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mice', 'Species', '10090', (54, 58))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
12336	21555376	Interestingly, we found crosstalk between Notch1 and EGFR in breast cancer cells where EGFR silencing inhibits leptin-induced Notch1 expression thus showing direct upstream involvement of EGFR in leptin-mediated Notch1 upregulation.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('EGFR', 'Gene', '1956', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('silencing', 'Var', (92, 101))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (188, 192))	('leptin-induced Notch1 expression', 'MPA', (111, 143))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', (188, 192))	('inhibits', 'NegReg', (102, 110))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
12342	21555376	Survivin overexpression increases leptin-induced migration whereas silencing of survivin abrogates leptin-induced migration of breast cancer cells.	('increases', 'PosReg', (24, 33))	('increases leptin', 'Phenotype', 'HP:0031793', (24, 40))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('leptin-induced', 'MPA', (34, 48))	('Survivin', 'Protein', (0, 8))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('silencing', 'Var', (67, 76))	('abrogates', 'NegReg', (89, 98))	('survivin', 'Gene', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
12343	21555376	A recent study linked survivin expression in human melanocytes and melanoma cells with enhanced capacity for migration and showed that survivin knockdown impaired melanoma cell migration (McKenzie, et al.	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('impaired melanoma cell migration', 'Disease', (154, 186))	('melanoma', 'Disease', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('human', 'Species', '9606', (45, 50))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('enhanced', 'PosReg', (87, 95))	('survivin', 'Gene', (135, 143))	('knockdown', 'Var', (144, 153))	('impaired melanoma cell migration', 'Disease', 'MESH:D054081', (154, 186))
12349	21555376	Utilizing molecular antagonists to interfere with the survivin pathway is another approach that uses systemic administration of antisense oligonucleotides, ribozymes, or local administration of mutant survivin adenoviruses to inhibit endogenous survivin expression.	('endogenous', 'MPA', (234, 244))	('expression', 'MPA', (254, 264))	('survivin', 'Gene', (201, 209))	('mutant', 'Var', (194, 200))	('inhibit', 'NegReg', (226, 233))	('survivin', 'Protein', (245, 253))	('survivin pathway', 'Pathway', (54, 70))	('oligonucleotides', 'Chemical', 'MESH:D009841', (138, 154))
12356	21743488	In addition, we report up-regulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients.	('Notch', 'Gene', (40, 45))	('association', 'Interaction', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Notch', 'Gene', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('Notch', 'Gene', '31293', (40, 45))	('breast cancer', 'Disease', (224, 237))	('up-regulation', 'PosReg', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('expression levels', 'MPA', (149, 166))	('tumor', 'Disease', (205, 210))	('HER2', 'Protein', (74, 78))	('transgenic', 'Species', '10090', (79, 89))	('Notch', 'Gene', '31293', (188, 193))	('transgenic', 'Var', (79, 89))	('patients', 'Species', '9606', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
12360	21743488	One aggressive subtype, comprising 20-25% of all invasive ductal carcinomas, is characterized by amplification of the HER2 gene, resulting in overexpression of the encoded HER2 oncoprotein (also known as ERBB-2/Neu).	('ductal carcinomas', 'Disease', 'MESH:D044584', (58, 75))	('overexpression', 'PosReg', (142, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('amplification', 'Var', (97, 110))	('ERBB-2', 'Gene', (204, 210))	('Neu', 'Gene', (211, 214))	('ductal carcinomas', 'Disease', (58, 75))	('Neu', 'Gene', '2064', (211, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('HER2', 'Gene', (118, 122))	('HER2 oncoprotein', 'Protein', (172, 188))	('ERBB-2', 'Gene', '2064', (204, 210))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (58, 74))
12369	21743488	The family includes four conserved transmembrane receptors (Notch1 through Notch4) and five surfacelocalized ligands (Jagged1, Jagged2, Delta-like1 through Delta-like3), which play fundamental roles in self-renewal and proliferation of progenitor and adult stem cells of the mammary gland.	('proliferation', 'CPA', (219, 232))	('Notch4', 'Gene', (75, 81))	('Jagged1', 'Gene', (118, 125))	('Notch4', 'Gene', '4855', (75, 81))	('Delta-like3', 'Gene', '10683', (156, 167))	('Jagged1', 'Gene', '182', (118, 125))	('Delta-like3', 'Gene', (156, 167))	('Notch1', 'Var', (60, 66))	('Jagged2', 'Gene', '3714', (127, 134))	('Jagged2', 'Gene', (127, 134))
12403	21743488	Western blotting of cell lysates from spheroids confirmed that Notch3 and its active cleavage product, NICD, were expressed at higher levels in MCF10A-HER2 cells compared to MCF10A cells (Figure 2E), and fractionation indicated that both forms were present in the cytoplasm, but only NICD partitioned with the nuclear fraction of MCF10A-HER2 cells (Supplementary Figure S2).	('MCF10A-HER2', 'Var', (144, 155))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (144, 155))	('MCF10A', 'CellLine', 'CVCL:0598', (330, 336))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (330, 341))	('Notch3', 'Gene', (63, 69))	('higher', 'PosReg', (127, 133))	('MCF10A', 'CellLine', 'CVCL:0598', (174, 180))	('MCF10A', 'CellLine', 'CVCL:0598', (144, 150))
12405	21743488	Immunostaining localized Notch3 to the cytoplasm of MCF10A cells, but specifically detected a fraction of Notch3 within nuclei of MCF10A-HER2 cells (Figure 2F).	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('Notch3', 'Var', (106, 112))	('Notch3', 'Var', (25, 31))	('MCF10A', 'CellLine', 'CVCL:0598', (130, 136))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (130, 141))
12408	21743488	When analyzed in monolayers, Notch3 knockdown significantly decreased proliferation of MCF10A-HER2 cells, such that they displayed growth rates similar to MCF10A cells (Figure 3B).	('decreased', 'NegReg', (60, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (155, 161))	('MCF10A', 'CellLine', 'CVCL:0598', (87, 93))	('growth rates', 'MPA', (131, 143))	('proliferation', 'CPA', (70, 83))	('knockdown', 'Var', (36, 45))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (87, 98))	('Notch3', 'Gene', (29, 35))	('MCF10A-HER2', 'Gene', (87, 98))
12410	21743488	In agreement with the ability of HER2 to confer autonomous growth, MCF10A-HER2 cells formed large spheroids, with Notch3 knockdown significantly reducing both their number and size (Figure 3C).	('knockdown', 'Var', (121, 130))	('MCF10A-HER2', 'Gene', (67, 78))	('reducing', 'NegReg', (145, 153))	('Notch3', 'Gene', (114, 120))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (67, 78))
12412	21743488	Staining of spheroids at day 6 for the cleaved form of Caspase-3 revealed luminal activity of this apoptosis-executing protease in MCF10A spheroids, as well as in Notch3 knocked-down MCF10A-HER2 spheroids, in line with the notion that the Notch pathway enables HER2- overexpressors to evade anoikis (Figure 3D).	('Notch', 'Gene', '31293', (163, 168))	('Notch', 'Gene', '31293', (239, 244))	('MCF10A', 'CellLine', 'CVCL:0598', (131, 137))	('luminal activity', 'MPA', (74, 90))	('MCF10A', 'CellLine', 'CVCL:0598', (183, 189))	('Caspase-3', 'Gene', '836', (55, 64))	('Caspase-3', 'Gene', (55, 64))	('Notch', 'Gene', (163, 168))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (183, 194))	('Notch', 'Gene', (239, 244))	('knocked-down', 'Var', (170, 182))
12414	21743488	Along with Notch3 up-regulation, overexpression of HER2 up-regulates the ligand DLL1 (Figs.	('up-regulation', 'PosReg', (18, 31))	('DLL1', 'Gene', '28514', (80, 84))	('up-regulates', 'PosReg', (56, 68))	('Notch3', 'Gene', (11, 17))	('DLL1', 'Gene', (80, 84))	('overexpression', 'Var', (33, 47))	('HER2', 'Protein', (51, 55))
12419	21743488	Likewise, our analyses revealed much higher expression of both c-MYC and Cyclin D1 in MCF10A-HER2 spheroids, relative to MCF10A spheroids (Figure 4A), and immunoblotting confirmed these differences at the protein level (Figure 4B).	('Cyclin D1', 'Gene', (73, 82))	('MCF10A', 'CellLine', 'CVCL:0598', (86, 92))	('expression', 'MPA', (44, 54))	('MCF10A', 'CellLine', 'CVCL:0598', (121, 127))	('higher', 'PosReg', (37, 43))	('MCF10A-HER2', 'Var', (86, 97))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (86, 97))	('c-MYC', 'Gene', '4609', (63, 68))	('Cyclin D1', 'Gene', '595', (73, 82))	('c-MYC', 'Gene', (63, 68))
12421	21743488	In the same vein, immunoblot analysis confirmed that knockdown of Notch3 in MCF10A-HER2 cells decreased the expression of both Cyclin D1 and c-MYC (Figure 4C).	('knockdown', 'Var', (53, 62))	('c-MYC', 'Gene', (141, 146))	('Notch3', 'Gene', (66, 72))	('decreased', 'NegReg', (94, 103))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (76, 87))	('expression', 'MPA', (108, 118))	('Cyclin D1', 'Gene', '595', (127, 136))	('c-MYC', 'Gene', '4609', (141, 146))	('Cyclin D1', 'Gene', (127, 136))
12425	21743488	HES1 knockdown enhanced the expression of the lipid phosphatase PTEN, in line with previous reports, and accordingly diminished the activating phosphorylation of AKT on serine-473 (Figure 4E).	('HES1', 'Gene', '3280', (0, 4))	('AKT', 'Gene', '207', (162, 165))	('knockdown', 'Var', (5, 14))	('activating phosphorylation', 'MPA', (132, 158))	('expression', 'MPA', (28, 38))	('AKT', 'Gene', (162, 165))	('HES1', 'Gene', (0, 4))	('PTEN', 'Gene', (64, 68))	('diminished', 'NegReg', (117, 127))	('PTEN', 'Gene', '5728', (64, 68))	('serine', 'Chemical', 'MESH:D012694', (169, 175))	('enhanced', 'PosReg', (15, 23))
12431	21743488	Similarly, when applied on MCF10A-HER2 spheroids, pathwayspecific inhibitors targeting MEK (U0126), c-MYC (10058-F4) or PI3K-AKT (LY-294002) markedly enhanced Caspase-3 activation, resulting in significant inhibition of luminal filling (Supplementary Figures S5C and S5D).	('AKT', 'Gene', '207', (125, 128))	('enhanced', 'PosReg', (150, 158))	('c-MYC', 'Gene', (100, 105))	('activation', 'PosReg', (169, 179))	('U0126', 'Var', (92, 97))	('AKT', 'Gene', (125, 128))	('Caspase-3', 'Gene', (159, 168))	('LY-294002', 'Var', (130, 139))	('MEK', 'Gene', (87, 90))	('c-MYC', 'Gene', '4609', (100, 105))	('MCF10A-HER2', 'CellLine', 'CVCL:0U80', (27, 38))	('Caspase-3', 'Gene', '836', (159, 168))	('U0126', 'Chemical', 'MESH:C113580', (92, 97))	('MEK', 'Gene', '5609', (87, 90))	('10058-F4', 'Var', (107, 115))	('inhibition', 'NegReg', (206, 216))
12436	21743488	Indeed, hyperplastic lesions, which frequently develop in the mammary glands of MMTV-HER2/neu transgenic mice, exhibited homogeneous weak to moderate immunohistochemical staining for Notch3, which was accentuated in cells facing the ductal lumen (Figure 5A).	('transgenic mice', 'Species', '10090', (94, 109))	('MMTV', 'Species', '11757', (80, 84))	('hyperplastic lesions', 'CPA', (8, 28))	('MMTV-HER2/neu', 'Gene', (80, 93))	('Notch3', 'Var', (183, 189))
12441	21743488	Analyses of mammary tumors from two independent patient cohorts (approximately 100 patients per cohort) confirmed significant correlation between the phosphorylated, active form of HER2 (p1248HER2) and Notch3 (cohort 1: r=0.43, p=1.55E-05; cohort 2: r=0.23, p=2.58E-02; Figure 5B).	('p1248HER2', 'Var', (187, 196))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('correlation', 'Interaction', (126, 137))	('Notch3', 'Gene', (202, 208))	('patient', 'Species', '9606', (48, 55))	('patient', 'Species', '9606', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('patients', 'Species', '9606', (83, 91))
12443	21743488	Individual patientrelated data were available for the second cohort, for which subgroup analyses revealed correlation of Notch3 with levels of HER2 (r=0.31, p=3.16E-02) and p1248HER2 (r=0.34, p=1.80E-02) in 48 patients with poorly differentiated tumors.	('p1248HER2', 'Var', (173, 182))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('correlation', 'Interaction', (106, 117))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Notch3', 'Gene', (121, 127))	('patient', 'Species', '9606', (210, 217))	('patients', 'Species', '9606', (210, 218))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('HER2', 'Protein', (143, 147))	('tumors', 'Disease', (246, 252))
12444	21743488	However, no such correlation was observed in moderately or well-differentiated tumors (HER2 r=0.03, p1248HER2 r=0.18, p>5.00E-02 for both).	('HER2', 'Protein', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('p1248HER2', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
12451	21743488	Thus, ectopic activation of Notch signaling commits mammary stem cells to the luminal lineage, as well as enhances proliferation of luminal cells, leading ultimately to their transformation.	('Notch', 'Gene', (28, 33))	('mammary stem cells', 'CPA', (52, 70))	('proliferation', 'CPA', (115, 128))	('commits', 'PosReg', (44, 51))	('enhances', 'PosReg', (106, 114))	('Notch', 'Gene', '31293', (28, 33))	('transformation', 'CPA', (175, 189))	('ectopic activation', 'Var', (6, 24))
12452	21743488	On the other hand, inhibition of Notch signaling enhances self-renewal, rather than differentiation, of mammary stem cells.	('Notch', 'Gene', '31293', (33, 38))	('inhibition', 'Var', (19, 29))	('self-renewal', 'CPA', (58, 70))	('Notch', 'Gene', (33, 38))	('enhances', 'PosReg', (49, 57))
12454	21743488	Whereas in small cell lung cancer, Notch may act as a tumor suppressive pathway, gain-of-function mutations and a chromosomal translocation leading to constitutive activation of Notch1 were identified in human T-cell acute lymphoblastic leukemia, gene amplification of Notch3 was detected in ovarian cancer, and relatively low levels of the Notch antagonist Numb were noted in breast tumors.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (292, 306))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Notch', 'Gene', '31293', (341, 346))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (11, 33))	('tumor', 'Disease', (384, 389))	('Notch', 'Gene', (178, 183))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('Notch', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (384, 389))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (223, 245))	('Numb', 'Gene', '8650', (358, 362))	('tumors', 'Phenotype', 'HP:0002664', (384, 390))	('Notch', 'Gene', '31293', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('lymphoblastic leukemia', 'Disease', (223, 245))	('breast tumors', 'Disease', 'MESH:D001943', (377, 390))	('ovarian cancer', 'Disease', 'MESH:D010051', (292, 306))	('Notch', 'Gene', (341, 346))	('breast tumors', 'Disease', (377, 390))	('human', 'Species', '9606', (204, 209))	('small cell lung cancer', 'Disease', 'MESH:D055752', (11, 33))	('tumor', 'Phenotype', 'HP:0002664', (384, 389))	('Notch', 'Gene', '31293', (35, 40))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (210, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (217, 245))	('breast tumors', 'Phenotype', 'HP:0100013', (377, 390))	('small cell lung cancer', 'Disease', (11, 33))	('gain-of-function', 'PosReg', (81, 97))	('mutations', 'Var', (98, 107))	('Notch', 'Gene', '31293', (178, 183))	('Notch', 'Gene', (269, 274))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (223, 245))	('tumor', 'Disease', (54, 59))	('ovarian cancer', 'Disease', (292, 306))	('Numb', 'Gene', (358, 362))
12474	21743488	Mammary fat pads of HER-2/neu transgenic or wild type FVB mice (Jackson Laboratories) were processed as previously described.	('HER-2/neu', 'Gene', (20, 29))	('HER-2/neu', 'Gene', '13866', (20, 29))	('mice', 'Species', '10090', (58, 62))	('transgenic', 'Var', (30, 40))	('transgenic', 'Species', '10090', (30, 40))
12530	21654686	The random effects pooled estimate of COX-2 positivity was 53% (95% CI, 44-61; P=0.04) with evidence of moderate heterogeneity I2=60.1% (Figure 1).	('positivity', 'Var', (44, 54))	('COX-2', 'Gene', (38, 43))	('COX-2', 'Gene', '5743', (38, 43))
12558	21654686	Several studies have reported on COX-2 expression and disease recurrence in invasive breast cancer and have shown elevated levels of COX-2 expression to be associated with a more aggressive cancer and decreased survival.	('disease recurrence', 'CPA', (54, 72))	('levels', 'Var', (123, 129))	('COX-2', 'Gene', (133, 138))	('COX-2', 'Gene', '5743', (33, 38))	('elevated levels', 'Var', (114, 129))	('aggressive cancer', 'Disease', (179, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('invasive breast cancer', 'Disease', (76, 98))	('COX-2', 'Gene', '5743', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (39, 49))	('survival', 'CPA', (211, 219))	('invasive breast cancer', 'Disease', 'MESH:D001943', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('COX-2', 'Gene', (33, 38))	('decreased', 'NegReg', (201, 210))	('expression', 'MPA', (139, 149))	('associated with', 'Reg', (156, 171))	('aggressive cancer', 'Disease', 'MESH:D009369', (179, 196))
12560	21654686	However, few studies have provided follow-up information on the relationship between COX-2 positivity in DCIS and disease progression after treatment, and none have explored whether NSAID use modulates the risk of progression.	('men', 'Species', '9606', (145, 148))	('DCIS', 'Disease', (105, 109))	('COX-2', 'Gene', (85, 90))	('positivity', 'Var', (91, 101))	('COX-2', 'Gene', '5743', (85, 90))
12570	30531835	In vivo studies demonstrated that deletion of stromal Gas6 delays early stage progression and decreases tumor formation, while tumor growth in established tumors remains unaffected.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('early stage progression', 'CPA', (66, 89))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (104, 109))	('stromal Gas6', 'Gene', (46, 58))	('tumor', 'Disease', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('delays', 'NegReg', (59, 65))	('deletion', 'Var', (34, 42))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('decreases tumor', 'Disease', 'MESH:D009369', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('decreases tumor', 'Disease', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
12583	30531835	Although Gas6 can bind all three receptors, its affinity for Axl is ~100-1000 times higher than MerTK and Tyro3.	('Tyro3', 'Gene', (106, 111))	('Tyro3', 'Gene', '22174', (106, 111))	('Gas6', 'Var', (9, 13))	('MerTK', 'Gene', '17289', (96, 101))	('affinity', 'MPA', (48, 56))	('MerTK', 'Gene', (96, 101))	('higher', 'PosReg', (84, 90))	('bind', 'Interaction', (18, 22))
12588	30531835	Gas6 was shown to promote prostate cancer cell invasion, while Axl-induced breast cancer metastasis was shown to be Gas6-independent.	('Gas6', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', (26, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (75, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('breast cancer metastasis', 'Disease', (75, 99))	('promote', 'PosReg', (18, 25))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
12605	30531835	To determine which cell type was secreting Gas6 in PN1a lesions, we FACS-sorted macrophages (CD45+CD11b+F480+), T-cells (CD45+CD3+CD11b-), and CD45- cells (primarily containing epithelial cells) and performed qPCR.	('CD45+CD11b+F480+', 'Var', (93, 109))	('PN1', 'Gene', '20720', (51, 54))	('PN1', 'Gene', (51, 54))	('CD45+CD3+CD11b-', 'Var', (121, 136))
12616	30531835	In contrast, co-culture with Gas6-/- BMDMs resulted in primarily non-malignant structures indistinguishable from colonies formed by PN1a cells alone, with an intact basal layer marked by integrin alpha6 staining and CK14 expression.	('PN1', 'Gene', '20720', (132, 135))	('Gas6-/- BMDMs', 'Var', (29, 42))	('colon', 'Disease', (113, 118))	('integrin alpha6', 'Gene', '16403', (187, 202))	('non-malignant structures', 'CPA', (65, 89))	('integrin alpha6', 'Gene', (187, 202))	('CK14', 'Gene', (216, 220))	('CK14', 'Gene', '16664', (216, 220))	('PN1', 'Gene', (132, 135))	('colon', 'Disease', 'MESH:D015179', (113, 118))
12617	30531835	Quantification of non-malignant and tumor-like colonies showed a significant decrease in malignant structures in co-cultures with Gas6-/- BMDMs as compared to wildtype BMDMs (Figure 2b).	('colon', 'Disease', (47, 52))	('malignant structures', 'CPA', (89, 109))	('decrease', 'NegReg', (77, 85))	('Gas6-/- BMDMs', 'Var', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('colon', 'Disease', 'MESH:D015179', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
12626	30531835	Figure 3 shows a significant increase in tumor-like colonies in Gas6-treated cells as compared to vehicle-treated, mimicking PN1a cells that were co-cultured with wildtype BMDMs (Figure 3a,b).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('colon', 'Disease', 'MESH:D015179', (52, 57))	('increase', 'PosReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('colon', 'Disease', (52, 57))	('Gas6-treated', 'Var', (64, 76))	('PN1', 'Gene', (125, 128))	('PN1', 'Gene', '20720', (125, 128))
12627	30531835	Altered integrin alpha6 localization and increased pAxl expression was observed in Gas6-treated cells as compared to controls.	('increased', 'PosReg', (41, 50))	('Gas6-treated', 'Var', (83, 95))	('localization', 'MPA', (24, 36))	('pAxl', 'Chemical', '-', (51, 55))	('integrin alpha6', 'Gene', '16403', (8, 23))	('pAxl', 'Gene', (51, 55))	('integrin alpha6', 'Gene', (8, 23))	('expression', 'MPA', (56, 66))
12628	30531835	Quantification of tumor-like colonies showed a significant increase in pAxl+ cells as compared to pAxl- cells in malignant structures, suggesting a link between activated Axl and the malignant phenotype (Figure 3c).	('pAxl+', 'Var', (71, 76))	('increase', 'PosReg', (59, 67))	('tumor', 'Disease', (18, 23))	('colon', 'Disease', 'MESH:D015179', (29, 34))	('pAxl', 'Chemical', '-', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('pAxl', 'Chemical', '-', (71, 75))	('colon', 'Disease', (29, 34))
12630	30531835	Similar to the PN1a model, wildtype BMDMs induced a tumor-like phenotype, while co-culture with Gas6-/- BMDMs resulted in non-malignant colonies (Supplemental Figure 3b).	('PN1', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('colon', 'Disease', (136, 141))	('PN1', 'Gene', '20720', (15, 18))	('Gas6-/-', 'Var', (96, 103))	('colon', 'Disease', 'MESH:D015179', (136, 141))	('induced', 'Reg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
12642	30531835	In contrast, pAxl expression was basally-restricted in Gas6-/- BMDM co-cultured PN1a cells, consistent with the observed non-malignant phenotype.	('pAxl', 'Gene', (13, 17))	('PN1', 'Gene', '20720', (80, 83))	('expression', 'MPA', (18, 28))	('Gas6-/- BMDM', 'Var', (55, 67))	('pAxl', 'Chemical', '-', (13, 17))	('PN1', 'Gene', (80, 83))
12647	30531835	Gas6/Axl signal transduction has previously been shown to induce anti-apoptotic effects during tumor progression by activating a number of pathways, including AKT, STAT3, and NFkappaB [reviewed in ].	('activating', 'Reg', (116, 126))	('AKT', 'Gene', (159, 162))	('induce', 'PosReg', (58, 64))	('AKT', 'Gene', '11651', (159, 162))	('NFkappaB', 'Gene', (175, 183))	('NFkappaB', 'Gene', '18033', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('Gas6/Axl', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('anti-apoptotic effects', 'MPA', (65, 87))	('STAT3', 'Gene', '20848', (164, 169))	('tumor', 'Disease', (95, 100))	('STAT3', 'Gene', (164, 169))
12664	30531835	In a second cohort of mice, we addressed whether Gas6 deletion affected palpable tumor formation and growth.	('Gas6', 'Gene', (49, 53))	('deletion', 'Var', (54, 62))	('affected', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('growth', 'CPA', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Disease', (81, 86))
12675	30531835	Macrophage ablation at the pre-invasive stage caused a significant delay in early progression, decreased localized invasion, and a significant reduction in tumor formation.	('decreased', 'NegReg', (95, 104))	('delay', 'NegReg', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Macrophage', 'Protein', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('localized invasion', 'CPA', (105, 123))	('early progression', 'CPA', (76, 93))	('reduction', 'NegReg', (143, 152))	('tumor', 'Disease', (156, 161))	('ablation', 'Var', (11, 19))
12680	30531835	Our studies utilizing an established mouse model of MIN progression showed that deletion of stromal Gas6 in vivo delayed tumor formation, but had no effect on tumor growth once primary tumors were established (Figure 8).	('tumor', 'Disease', (185, 190))	('deletion', 'Var', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('mouse', 'Species', '10090', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('delayed', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
12692	30531835	High Gas6 expression in ovarian cancer, glioblastoma, and non-small cell lung cancer (NSCLC) was shown to predict poor overall survival.	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('non-small cell lung cancer', 'Disease', (58, 84))	('High', 'Var', (0, 4))	('NSCLC', 'Disease', (86, 91))	('Gas6', 'Protein', (5, 9))	('ovarian cancer', 'Disease', 'MESH:D010051', (24, 38))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('overall', 'MPA', (119, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('poor', 'NegReg', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ovarian cancer', 'Disease', (24, 38))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))	('glioblastoma', 'Disease', (40, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (24, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (58, 84))
12698	30531835	Furthermore, our in vivo studies showed that once tumors were established, growth was not altered by Gas6 deletion (Figure 8).	('growth', 'MPA', (75, 81))	('Gas6', 'Gene', (101, 105))	('deletion', 'Var', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))
12732	28239564	However, there are no available targeted therapies for patients with basal-like DCIS (BL-DCIS) tumors due to their frequent lack of endocrine receptors and HER2 amplification, rendering them potentially susceptible to recurrence.	('HER2', 'Gene', (156, 160))	('endocrine', 'Protein', (132, 141))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('HER2', 'Gene', '2064', (156, 160))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('basal-like DCIS', 'Disease', (69, 84))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('lack', 'NegReg', (124, 128))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('amplification', 'Var', (161, 174))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('patients', 'Species', '9606', (55, 63))	('tumors', 'Disease', (95, 101))
12736	28239564	We summarize recently discovered relevant molecular signaling alterations that promote the generation of CSCs in BL-DCIS and the progression of BL-DCIS to invasive breast cancer, as well as the influence of the tissue microenvironment on CSCs and the invasive transition.	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('BL-DCIS', 'Disease', (113, 120))	('CSCs', 'Disease', (105, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('invasive breast cancer', 'Disease', (155, 177))	('promote', 'PosReg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('alterations', 'Var', (62, 73))	('invasive breast cancer', 'Disease', 'MESH:D001943', (155, 177))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
12748	28239564	Basal-like breast cancers are more likely to occur in younger, African American women, and are associated with breast cancer susceptibility (BRCA) gene mutations.	('women', 'Species', '9606', (80, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('mutations', 'Var', (152, 161))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BRCA', 'Gene', (141, 145))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancers', 'Disease', (11, 25))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('BRCA', 'Gene', '672;675', (141, 145))	('associated', 'Reg', (95, 105))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
12749	28239564	They are characterized by high tumor grade, proliferation rate, frequency of recurrence, and the presence of p53 mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('high tumor', 'Disease', (26, 36))	('mutations', 'Var', (113, 122))	('presence', 'Reg', (97, 105))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('proliferation rate', 'CPA', (44, 62))	('high tumor', 'Disease', 'MESH:D009369', (26, 36))
12755	28239564	The remaining non-triple-negative basal-like breast cancers share similar gene expression profiles with TN-BLBC, but might have gained additional genetic and/or epigenetic aberrations due to increased genomic instability.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('epigenetic aberrations', 'Var', (161, 183))	('increased', 'PosReg', (191, 200))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('gained', 'PosReg', (128, 134))	('breast cancers', 'Disease', (45, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
12762	28239564	While the molecular mechanisms leading to immune tolerance are not fully understood, two lines of study indicate that inactivation of tumor suppressor p53 and activation of CUL4A E3 ubiquitin ligase are involved in failure of tumor immunosurveillance.	('activation', 'PosReg', (159, 169))	('p53', 'Gene', '7157', (151, 154))	('CUL4A', 'Gene', (173, 178))	('tumor', 'Disease', (134, 139))	('inactivation', 'Var', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CUL4A', 'Gene', '8451', (173, 178))	('p53', 'Gene', (151, 154))	('failure of tumor immunosurveillance', 'Disease', (215, 250))	('tumor', 'Disease', (226, 231))	('failure of tumor immunosurveillance', 'Disease', 'MESH:D009369', (215, 250))
12770	28239564	These findings suggest that the multistep drug-resistant progression in which cells undergo DNA endoreduplication, polyploidization, depolyploidization and then generation of clonogenic escape cells, can account for tumor relapse after initial efficient chemotherapy.	('tumor', 'Disease', (216, 221))	('account', 'Reg', (204, 211))	('polyploidization', 'Var', (115, 131))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('depolyploidization', 'Var', (133, 151))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
12772	28239564	Besides these mechanisms, genetic alterations to restore the function of DNA repair proteins (e.g., BRCA1, BRCA2, FANCA, etc.)	('FANCA', 'Gene', '2175', (114, 119))	('function', 'MPA', (61, 69))	('BRCA1', 'Gene', '672', (100, 105))	('FANCA', 'Gene', (114, 119))	('BRCA2', 'Gene', '675', (107, 112))	('restore', 'PosReg', (49, 56))	('BRCA1', 'Gene', (100, 105))	('genetic alterations', 'Var', (26, 45))	('BRCA2', 'Gene', (107, 112))
12774	28239564	In addition to these general resistance mechanisms, dysregulation of signal pathway regulators in basal-like breast cancers have recently been identified to be responsible for resistance to neoadjuvant chemotherapy and PARP inhibitor treatment.	('PARP', 'Gene', '142', (219, 223))	('breast cancers', 'Disease', 'MESH:D001943', (109, 123))	('breast cancers', 'Disease', (109, 123))	('responsible', 'Reg', (160, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('PARP', 'Gene', (219, 223))	('dysregulation', 'Var', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancers', 'Phenotype', 'HP:0003002', (109, 123))
12775	28239564	For example, basal-like breast cancers have low expression of dual specificity protein phosphatase 4 (DUSP4), which negatively regulates the Ras-ERK pathway, due to hypermethylation of the DUSP4 promoter.	('ERK', 'Gene', (145, 148))	('DUSP4', 'Gene', '1846', (102, 107))	('DUSP4', 'Gene', '1846', (189, 194))	('expression', 'MPA', (48, 58))	('dual specificity protein phosphatase 4', 'Gene', '1846', (62, 100))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('dual specificity protein phosphatase 4', 'Gene', (62, 100))	('hypermethylation', 'Var', (165, 181))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancers', 'Disease', 'MESH:D001943', (24, 38))	('breast cancers', 'Disease', (24, 38))	('DUSP4', 'Gene', (102, 107))	('DUSP4', 'Gene', (189, 194))	('low', 'NegReg', (44, 47))	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('regulates', 'Reg', (127, 136))	('negatively', 'NegReg', (116, 126))	('ERK', 'Gene', '5594', (145, 148))
12802	28239564	Enrichment of CSCs in breast cancer correlates with tumor aggressiveness, likely due to the characteristics described above.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('CSCs', 'Var', (14, 18))	('tumor aggressiveness', 'Disease', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('aggressiveness', 'Phenotype', 'HP:0000718', (58, 72))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (52, 72))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
12814	28239564	A population-based cohort has shown that patients with BL-DCIS have a higher risk for local recurrence and development into invasive cancer compared with other molecular subtypes, demonstrating the need for further molecular characterization.	('BL-DCIS', 'Var', (55, 62))	('local recurrence', 'CPA', (86, 102))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('patients', 'Species', '9606', (41, 49))	('invasive cancer', 'Disease', (124, 139))	('invasive cancer', 'Disease', 'MESH:D009362', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
12815	28239564	The BL-DCIS subtype is associated with unfavorable prognostic variables such as high-grade nuclei, mutant p53 overexpression and elevated Ki-67 index.	('p53', 'Gene', '7157', (106, 109))	('elevated', 'PosReg', (129, 137))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('Ki-67 index', 'CPA', (138, 149))	('BL-DCIS', 'Disease', (4, 11))	('mutant', 'Var', (99, 105))	('p53', 'Gene', (106, 109))	('high-grade nuclei', 'CPA', (80, 97))	('overexpression', 'PosReg', (110, 124))
12844	28239564	miRNAs have been extensively investigated in cancer and other diseases, and regulate a variety of physiological and pathological processes at the posttranscriptional level.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('regulate', 'Reg', (76, 84))	('cancer', 'Disease', (45, 51))	('miRNAs', 'Var', (0, 6))
12856	28239564	It is likely that aberrantly activated AIB1 assists other deregulated factors to promote the transition of BL-DCIS to BL-IDC.	('BL-DCIS', 'Disease', (107, 114))	('promote', 'PosReg', (81, 88))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('aberrantly activated', 'Var', (18, 38))	('AIB1', 'Gene', (39, 43))	('AIB1', 'Gene', '8202', (39, 43))
12860	28239564	Functional analysis showed that silencing of MT1-MMP in MCF10DCIS.COM cells impaired the ability of this DCIS tumor model to progress into infiltrating lesions in vivo.	('impaired', 'NegReg', (76, 84))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (56, 69))	('MT1-MMP', 'Gene', '4323', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('MT1-MMP', 'Gene', (45, 52))	('silencing', 'Var', (32, 41))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('progress into infiltrating lesions', 'CPA', (125, 159))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
12862	28239564	Their findings suggest that aberrant activation of the p63/MT1-MMP axis in DCIS may contribute to the progression of DCIS to high-grade basal-like breast cancers.	('contribute', 'Reg', (84, 94))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('breast cancers', 'Phenotype', 'HP:0003002', (147, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('MT1-MMP', 'Gene', '4323', (59, 66))	('activation', 'PosReg', (37, 47))	('breast cancers', 'Disease', (147, 161))	('breast cancers', 'Disease', 'MESH:D001943', (147, 161))	('p63', 'Gene', (55, 58))	('MT1-MMP', 'Gene', (59, 66))	('DCIS', 'Disease', (117, 121))	('aberrant', 'Var', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('p63', 'Gene', '8626', (55, 58))	('DCIS', 'Disease', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
12864	28239564	Therefore, their results imply that aberrant activation of the p63/MT1-MMP axis in basal CSCs is a potential mechanism to trigger the progression of BL-DCIS to BL-IDC.	('MT1-MMP', 'Gene', '4323', (67, 74))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('p63', 'Gene', (63, 66))	('p63', 'Gene', '8626', (63, 66))	('aberrant', 'Var', (36, 44))	('MT1-MMP', 'Gene', (67, 74))	('activation', 'PosReg', (45, 55))	('BL-DCIS', 'Disease', (149, 156))
12867	28239564	Loss of SIM2s enhances EMT in the mouse mammary gland, normal breast and breast cancer cell lines.	('mouse', 'Species', '10090', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('EMT', 'CPA', (23, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('enhances', 'PosReg', (14, 22))	('SIM2s', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))
12875	28239564	From our and other studies indicating that basal CSCs are the origin of the tumorigenic and invasive characteristics of MCF10DCIS.COM cells, it is likely that decreased expression of SIM2s promotes the development of basal CSCs in BL-DCIS and further reduction in its expression activates invasive features of CSCs to facilitate the invasive progression of BL-DCIS into invasive breast carcinoma.	('basal CSCs', 'CPA', (217, 227))	('activates', 'PosReg', (279, 288))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (370, 395))	('decreased expression', 'Var', (159, 179))	('breast carcinoma', 'Phenotype', 'HP:0003002', (379, 395))	('tumor', 'Disease', (76, 81))	('invasive features', 'CPA', (289, 306))	('promotes', 'PosReg', (189, 197))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('SIM2s', 'Gene', (183, 188))	('reduction', 'NegReg', (251, 260))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('invasive breast carcinoma', 'Disease', (370, 395))	('facilitate', 'PosReg', (318, 328))	('invasive progression', 'CPA', (333, 353))	('expression', 'Var', (169, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('DCIS', 'Phenotype', 'HP:0030075', (360, 364))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('expression', 'MPA', (268, 278))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (120, 133))
12877	28239564	Inhibition of key lipogenic enzymes results in suppression of tumorigenicity both in vitro and in vivo by blocking proliferation and inducing apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('proliferation', 'CPA', (115, 128))	('Inhibition', 'Var', (0, 10))	('lipogenic', 'Enzyme', (18, 27))	('apoptosis', 'CPA', (142, 151))	('suppression', 'NegReg', (47, 58))	('inducing', 'Reg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('blocking', 'NegReg', (106, 114))
12882	28239564	Overexpression of SREBP1 caused enhanced lipogenesis, cell growth and mammosphere formation.	('SREBP1', 'Gene', (18, 24))	('lipogenesis', 'MPA', (41, 52))	('cell growth', 'CPA', (54, 65))	('enhanced', 'PosReg', (32, 40))	('Overexpression', 'Var', (0, 14))	('mammosphere formation', 'CPA', (70, 91))	('SREBP1', 'Gene', '6720', (18, 24))
12895	28239564	High tumor heterogeneity correlates with poor prognosis due to its association with malignancies, recurrence, metastasis and anti-cancer drug resistance.	('malignancies', 'Disease', (84, 96))	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('High', 'Var', (0, 4))	('association', 'Interaction', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('metastasis', 'CPA', (110, 120))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('recurrence', 'Disease', (98, 108))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))
12896	28239564	Intratumor heterogeneity could result from an intrinsic stochasticity in gene expression and from genetic and/or heritable epigenetic differences among tumor cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('epigenetic', 'Var', (123, 133))	('result', 'Reg', (31, 37))	('tumor', 'Disease', (5, 10))
12916	28239564	BL-DCIS is an early stage breast cancer with a high risk of recurrence, and targeting it may prevent cancer recurrence and progression to invasive disease.	('breast cancer', 'Disease', (26, 39))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (101, 107))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('invasive disease', 'Disease', (138, 154))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('BL-DCIS', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('targeting', 'Var', (76, 85))	('invasive disease', 'Disease', 'MESH:D009362', (138, 154))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
12934	22484800	Thus, we sought to examine the impact of a DCIS diagnosis on QOL outcomes, by comparing women with DCIS, women with EIBC, and a comparison group of age-matched women without a history of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('women', 'Species', '9606', (88, 93))	('DCIS', 'Var', (99, 103))	('women', 'Species', '9606', (160, 165))	('women', 'Species', '9606', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('EIBC', 'Chemical', '-', (116, 120))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('breast cancer', 'Disease', (187, 200))
12938	22484800	We tested two hypotheses: (1) women with DCIS would report lower levels of QOL compared with controls but would report similar QOL compared with women with EIBC at baseline and (2) DCIS patients' QOL would improve during 2-year follow-up and approach levels similar to those of controls faster than EIBC patients.	('levels of QOL', 'MPA', (65, 78))	('EIBC', 'Chemical', '-', (299, 303))	('patients', 'Species', '9606', (304, 312))	('patients', 'Species', '9606', (186, 194))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('QOL', 'MPA', (196, 199))	('lower', 'NegReg', (59, 64))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('DCIS', 'Var', (181, 185))	('women', 'Species', '9606', (30, 35))	('improve', 'PosReg', (206, 213))	('EIBC', 'Chemical', '-', (156, 160))	('women', 'Species', '9606', (145, 150))	('DCIS', 'Disease', (41, 45))
12976	22484800	Moreover, EIBC patients reported worse energy/fatigue compared with DCIS patients at T3 (P = 0.0004).	('EIBC', 'Chemical', '-', (10, 14))	('patients', 'Species', '9606', (15, 23))	('fatigue', 'Disease', 'MESH:D005221', (46, 53))	('fatigue', 'Disease', (46, 53))	('worse', 'NegReg', (33, 38))	('fatigue', 'Phenotype', 'HP:0012378', (46, 53))	('EIBC', 'Var', (10, 14))	('patients', 'Species', '9606', (73, 81))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
13001	22484800	The rate of change in QOL domains was similar in DCIS and EIBC patients, except for social functioning; EIBC patients, whose social functioning was poorer than that of DCIS patients at T1, showed a greater rate of increase in social functioning after T2 than DCIS patients did.	('EIBC', 'Chemical', '-', (104, 108))	('patients', 'Species', '9606', (173, 181))	('social functioning', 'CPA', (226, 244))	('EIBC', 'Chemical', '-', (58, 62))	('patients', 'Species', '9606', (109, 117))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('increase', 'PosReg', (214, 222))	('patients', 'Species', '9606', (63, 71))	('patients', 'Species', '9606', (264, 272))	('DCIS', 'Phenotype', 'HP:0030075', (259, 263))	('EIBC', 'Var', (104, 108))
13007	22484800	Another study using these data observed clinically significant declines in social functioning and mental health in women diagnosed with DCIS < six months before the QOL assessment compared with controls, but incident invasive breast cancer cases were not included.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('invasive breast cancer', 'Disease', (217, 239))	('declines', 'Disease', (63, 71))	('social functioning', 'CPA', (75, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('declines', 'Disease', 'MESH:D060825', (63, 71))	('women', 'Species', '9606', (115, 120))	('invasive breast cancer', 'Disease', 'MESH:D001943', (217, 239))	('mental health', 'CPA', (98, 111))	('DCIS < six', 'Var', (136, 146))
13097	21139586	This identified the same three main groups: ER-, PR-, Her2+ and Bcl-2- (n=20); ER-, PR-, Her2- and Bcl-2- (n=9); ER+, PR+, Her2- and Bcl-2+ (n=43), confirming the robustness of the classification.	('PR', 'Gene', '5241', (49, 51))	('Her2', 'Gene', (54, 58))	('ER+', 'Disease', (113, 116))	('PR', 'Gene', '5241', (118, 120))	('Her2', 'Gene', (123, 127))	('PR', 'Gene', '5241', (84, 86))	('ER-', 'Var', (79, 82))	('Bcl-2', 'Gene', (133, 138))	('Her2', 'Gene', '2064', (54, 58))	('Bcl-2', 'Gene', '596', (133, 138))	('Her2', 'Gene', '2064', (123, 127))	('Bcl-2', 'Gene', (99, 104))	('Her2', 'Gene', (89, 93))	('Bcl-2', 'Gene', '596', (99, 104))	('Bcl-2', 'Gene', (64, 69))	('Her2', 'Gene', '2064', (89, 93))	('Bcl-2', 'Gene', '596', (64, 69))
13140	19732720	Overexpression of ErbB2 has been demonstrated to promote breast cancer invasion and metastasis.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('rat', 'Species', '10116', (40, 43))	('metastasis', 'CPA', (84, 94))	('ErbB2', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('promote', 'PosReg', (49, 56))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
13151	19732720	It is conceivable that deregulation of 14-3-3 may contribute to cancer development.	('contribute', 'Reg', (50, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('14-3-3', 'Protein', (39, 45))	('deregulation', 'Var', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
13177	19732720	We found that Src phosphorylation is specifically increased in the two ErbB2 overexpressing MCF10A sublines compared to the two ErbB2 low-expressing MCF10A sublines (Figure S3A, B).	('ErbB2', 'Gene', (71, 76))	('MCF10A', 'Var', (92, 98))	('MCF10A', 'CellLine', 'CVCL:0598', (149, 155))	('increased', 'PosReg', (50, 59))	('MCF10A', 'CellLine', 'CVCL:0598', (92, 98))	('overexpressing', 'PosReg', (77, 91))	('Src', 'Gene', (14, 17))	('Src', 'Gene', '6714', (14, 17))
13178	19732720	Moreover, treatment with a Src kinase inhibitor (Saracatinib, or AZD0530) significantly inhibited the motility of 10A.ErbB2 and 10A.ErbB2.zeta cells, while Rac1 and PI3K inhibitors had no significant effect (Figure S3C).	('Rac1', 'Gene', (156, 160))	('inhibited', 'NegReg', (88, 97))	('AZD0530', 'Var', (65, 72))	('AZD0530', 'Chemical', 'MESH:C515233', (65, 72))	('Saracatinib', 'Chemical', 'MESH:C515233', (49, 60))	('Src', 'Gene', (27, 30))	('Src', 'Gene', '6714', (27, 30))	('motility', 'CPA', (102, 110))	('Rac1', 'Gene', '5879', (156, 160))
13222	19732720	LY2109761 treatment reduced smad2/3 phosphorylation and total smad3, but had no significant effect on the phosphorylation of Akt (p-Akt) or p42-MAPK (p-P42) (Figure 5A).	('reduced', 'NegReg', (20, 27))	('Akt', 'Gene', '207', (125, 128))	('Akt', 'Gene', (125, 128))	('smad2/3', 'Gene', '4087;4088', (28, 35))	('smad3', 'Gene', (62, 67))	('Akt', 'Gene', (132, 135))	('smad2/3', 'Gene', (28, 35))	('LY2109761', 'Chemical', 'MESH:C530108', (0, 9))	('p42-MAPK', 'Gene', (140, 148))	('p42-MAPK', 'Gene', '5594;23552', (140, 148))	('Akt', 'Gene', '207', (132, 135))	('LY2109761', 'Var', (0, 9))	('smad3', 'Gene', '4088', (62, 67))
13223	19732720	More importantly, the invasive phenotype of 10A.ErbB2.zeta acini in 3D matrigel culture was dramatically inhibited by LY2109761 treatment compared to control treatment (Figure 5B, middle).	('LY2109761', 'Chemical', 'MESH:C530108', (118, 127))	('inhibited', 'NegReg', (105, 114))	('LY2109761 treatment', 'Var', (118, 137))	('invasive phenotype', 'CPA', (22, 40))
13224	19732720	In contrast, LY2109761 treatment had no significant impact on acini development and maintenance in the other MCF10A sublines (Figure S7).	('LY2109761 treatment', 'Var', (13, 32))	('acini development', 'CPA', (62, 79))	('MCF10A', 'CellLine', 'CVCL:0598', (109, 115))	('LY2109761', 'Chemical', 'MESH:C530108', (13, 22))
13225	19732720	Consistent with the partial reversal of EMT morphology of the cells in 2D culture and reduced invasiveness in 3D culture, there was increased epithelial protein expression, such as E-cadherin and alpha-catenin, after LY2109761 treatment.	('epithelial protein', 'Protein', (142, 160))	('LY2109761', 'Var', (217, 226))	('E-cadherin', 'Gene', (181, 191))	('increased', 'PosReg', (132, 141))	('LY2109761', 'Chemical', 'MESH:C530108', (217, 226))	('E-cadherin', 'Gene', '999', (181, 191))	('alpha-catenin', 'Protein', (196, 209))
13228	19732720	Inhibition of TGFbeta/Smads pathway by LY2109761 partially recovered E-cadherin expression that inhibited the invasion of 10A.ErbB2.zeta acini, indicating that E-cadherin loss was a key event in the gain of invasiveness during EMT.	('TGFbeta', 'Gene', '7040', (14, 21))	('E-cadherin', 'Gene', '999', (69, 79))	('LY2109761', 'Chemical', 'MESH:C530108', (39, 48))	('E-cadherin', 'Gene', (160, 170))	('E-cadherin', 'Gene', '999', (160, 170))	('TGFbeta', 'Gene', (14, 21))	('inhibited', 'NegReg', (96, 105))	('LY2109761', 'Var', (39, 48))	('E-cadherin', 'Gene', (69, 79))
13245	19732720	Mice injected with the TM15.14-3-3zeta cells definitely had more lung metastasis than mice with TM15.Vec cells (Figure 6C).	('lung metastasis', 'Disease', (65, 80))	('mice', 'Species', '10090', (86, 90))	('TM15.14-3-3zeta', 'Var', (23, 38))	('Mice', 'Species', '10090', (0, 4))	('lung metastasis', 'Disease', 'MESH:D009362', (65, 80))
13248	19732720	In addition, in this patient cohort, multivariate analysis demonstrated that co-overexpression of ErbB2 and 14-3-3zeta in breast tumors can predict poor prognosis (Table S3).	('ErbB2', 'Gene', (98, 103))	('breast tumors', 'Phenotype', 'HP:0100013', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patient', 'Species', '9606', (21, 28))	('breast tumors', 'Disease', 'MESH:D001943', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('breast tumors', 'Disease', (122, 135))	('rat', 'Species', '10116', (66, 69))	('co-overexpression', 'Var', (77, 94))
13249	19732720	Since a majority of these patients died of recurrent metastatic disease, these data indicated that breast cancers overexpressing both ErbB2 and 14-3-3zeta are more aggressive and have greater metastatic potential.	('breast cancers', 'Disease', 'MESH:D001943', (99, 113))	('breast cancers', 'Disease', (99, 113))	('ErbB2', 'Gene', (134, 139))	('overexpressing', 'Var', (114, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('patients', 'Species', '9606', (26, 34))	('greater', 'PosReg', (184, 191))	('metastatic potential', 'CPA', (192, 212))	('breast cancers', 'Phenotype', 'HP:0003002', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
13254	19732720	We found that ErbB2 overexpression alone promoted cell migration via Src activation, but not invasion, whereas 14-3-3zeta overexpression alone had no effect on cell motility but was sufficient to reduce cell-cell adhesion via inducing EMT.	('overexpression', 'Var', (20, 34))	('inducing', 'Reg', (226, 234))	('cell-cell adhesion', 'CPA', (203, 221))	('ErbB2', 'Gene', (14, 19))	('promoted', 'PosReg', (41, 49))	('reduce', 'NegReg', (196, 202))	('Src', 'Gene', (69, 72))	('Src', 'Gene', '6714', (69, 72))	('rat', 'Species', '10116', (58, 61))	('cell migration', 'CPA', (50, 64))	('EMT', 'CPA', (235, 238))	('reduce cell-cell adhesion', 'Phenotype', 'HP:0008352', (196, 221))
13256	19732720	Other genetic or epigenetic alterations that facilitate the loss/reduction of cell-cell adhesion, either by inducing EMT, like 14-3-3zeta, or by other mechanisms, may also promote the ErbB2-overexpressing DCIS to progress to IBC.	('IBC', 'Disease', (225, 228))	('inducing', 'PosReg', (108, 116))	('EMT', 'CPA', (117, 120))	('alterations', 'Var', (28, 39))	('progress', 'PosReg', (213, 221))	('rat', 'Species', '10116', (32, 35))	('loss/reduction', 'NegReg', (60, 74))	('promote', 'PosReg', (172, 179))	('ErbB2-overexpressing', 'Gene', (184, 204))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('cell-cell adhesion', 'Protein', (78, 96))	('epigenetic alterations', 'Var', (17, 39))	('IBC', 'Chemical', '-', (225, 228))
13262	19732720	In this study, we detected deregulation of EMT markers more frequently in DCIS overexpressing 14-3-3zeta and TbetaRI, which significantly associated with higher grade DCIS that had a greater risk of developing invasive recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('associated', 'Reg', (138, 148))	('TbetaRI', 'Gene', (109, 116))	('deregulation', 'MPA', (27, 39))	('overexpressing', 'Var', (79, 93))	('DCIS', 'Disease', (167, 171))	('TbetaRI', 'Gene', '7046', (109, 116))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
13288	19732720	Our findings that ErbB2 and 14-3-3zeta co-overexpression in DCIS predicts a higher risk of progression to IBC also provide molecular targets for designing combination therapies to intervene in DCIS progression.	('DCIS', 'Gene', (60, 64))	('IBC', 'Chemical', '-', (106, 109))	('IBC', 'Disease', (106, 109))	('ErbB2', 'Gene', (18, 23))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('co-overexpression', 'Var', (39, 56))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
13326	14710227	While the precise mechanisms remain uncertain, and are being elucidated, it is recognised that the modulated expression of ER and the initiation of apoptosis are important factors in the promotion of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('promotion', 'PosReg', (187, 196))	('modulated', 'Var', (99, 108))	('prostate cancer', 'Disease', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
13379	14710227	The mean percentage of hsp-27 expression was higher in DCIS (Figure 1G) when compared with HUT (P<0.001; Figure 2).	('expression', 'MPA', (30, 40))	('hsp-27', 'Gene', (23, 29))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('hsp-27', 'Gene', '3315', (23, 29))	('DCIS', 'Var', (55, 59))	('higher', 'PosReg', (45, 51))
13406	14710227	Since there is evidence that the expression of hsp-27 blocks apoptosis induced by a wide range of stimuli (Richards et al, 1996) and protects tumour cells against the apoptotic effects of TNF-alpha (Wang et al, 1996), a likely mechanism is by imparting resistance to apoptosis and then by maintaining those particular populations of epithelial cells of enhanced malignant potential.	('blocks', 'NegReg', (54, 60))	('tumour', 'Disease', (142, 148))	('apoptosis', 'CPA', (61, 70))	('TNF-alpha', 'Gene', (188, 197))	('hsp-27', 'Gene', (47, 53))	('expression', 'Var', (33, 43))	('hsp-27', 'Gene', '3315', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('TNF-alpha', 'Gene', '7124', (188, 197))
13444	29669162	Misclassifying early stage invasive breast cancer in outcomes research as DCIS may inflate mortality and recurrence estimates associated with DCIS, leading to possible erroneous conclusions about overtreatment as well as cost and benefits of treatment.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('invasive breast cancer', 'Disease', 'MESH:D001943', (27, 49))	('invasive breast cancer', 'Disease', (27, 49))	('mortality', 'MPA', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('inflate', 'NegReg', (83, 90))	('Misclassifying', 'Var', (0, 14))
13519	29669162	The ICD-10 code for malignant neoplasms of the breast is C50.xxx.	('neoplasms', 'Phenotype', 'HP:0002664', (30, 39))	('malignant neoplasms', 'Disease', (20, 39))	('malignant neoplasms', 'Disease', 'MESH:D009369', (20, 39))	('neoplasms of the breast', 'Phenotype', 'HP:0100013', (30, 53))	('C50.xxx', 'Var', (57, 64))
13532	26437339	We also investigated the role of miR-92 in fibroblasts in vitro and showed that down-regulation in normal fibroblasts enhances the invasion of breast cancer epithelial cells.	('enhances', 'PosReg', (118, 126))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('miR-92', 'Gene', (33, 39))	('invasion', 'CPA', (131, 139))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('down-regulation', 'Var', (80, 95))	('miR-92', 'Gene', '407047', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
13543	26437339	Our data support a functional role in fibroblasts where modification of miR-92 expression can influence the invasive capacity of breast cancer epithelial cells.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('invasive capacity of', 'CPA', (108, 128))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('influence', 'Reg', (94, 103))	('miR-92', 'Gene', (72, 78))	('modification', 'Var', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-92', 'Gene', '407047', (72, 78))
13547	26437339	MiRs of the miR-17-92 cluster, also described as Oncomir-1, are thought to act as oncogenes and have been shown to promote cell proliferation and reduce apoptosis in lung cancer and lymphoma.	('promote', 'PosReg', (115, 122))	('cell proliferation', 'CPA', (123, 141))	('lymphoma', 'Disease', (182, 190))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('miR-17-92', 'Gene', '407975', (12, 21))	('MiRs', 'Var', (0, 4))	('lymphoma', 'Disease', 'MESH:D008223', (182, 190))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('lung cancer', 'Disease', (166, 177))	('miR-17-92', 'Gene', (12, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('reduce', 'NegReg', (146, 152))	('apoptosis', 'CPA', (153, 162))
13551	26437339	found that high expression of miR-92 predicted better recurrence-free survival in breast cancer patients, an unexpected observation for a so-called onco-mir.	('breast cancer', 'Disease', (82, 95))	('better', 'PosReg', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('recurrence-free survival', 'CPA', (54, 78))	('miR-92', 'Gene', (30, 36))	('miR-92', 'Gene', '407047', (30, 36))	('patients', 'Species', '9606', (96, 104))	('high', 'Var', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
13571	26437339	MCF-7, MDA-MB-231, T47D, HB2, BT-474, MDA-MB-453, MDA-MB-468 and BT-20 cells were maintained in RPMI 1640 medium, supplemented with 5% or 10% heat-inactivated fetal bovine serum (FBS; both Invitrogen), in a 5% CO2 humidified incubator at 37 C. Bimonthly Mycoplasma checks (MycoAlert Mycoplasma detection assay, Lonza) were consistently negative and short tandem repeat profiles confirmed cell identity (last tested April 2014).	('HB2', 'Gene', (25, 28))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (50, 60))	('negative', 'NegReg', (336, 344))	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (7, 17))	('bovine', 'Species', '9913', (165, 171))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (38, 48))	('HB2', 'Gene', '3888', (25, 28))	('FBS', 'Disease', 'MESH:D005198', (179, 182))	('Bim', 'Gene', (244, 247))	('RPMI', 'Chemical', '-', (96, 100))	('Bim', 'Gene', '10018', (244, 247))	('short tandem repeat profiles', 'Var', (349, 377))	('T47D', 'CellLine', 'CVCL:0553', (19, 23))	('BT-20', 'CellLine', 'CVCL:0178', (65, 70))	('FBS', 'Disease', (179, 182))
13585	26437339	found that high expression of miR-92 was associated with better patient outcome we performed an in silico analysis using the BreastMark platform.	('miR-92', 'Gene', (30, 36))	('miR-92', 'Gene', '407047', (30, 36))	('patient', 'Species', '9606', (64, 71))	('high', 'Var', (11, 15))
13586	26437339	Similarly, we found those patients with luminal A breast cancers who expressed high levels of miR-92 had a better disease free survival (DFS) rate compared to patients expressing low levels (Fig 1); an observation not expected for a so-called onco-mir.	('miR-92', 'Gene', (94, 100))	('miR-92', 'Gene', '407047', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('better', 'PosReg', (107, 113))	('disease free survival', 'CPA', (114, 135))	('high levels', 'Var', (79, 90))	('patients', 'Species', '9606', (26, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (50, 64))	('luminal A breast cancers', 'Disease', (40, 64))	('patients', 'Species', '9606', (159, 167))
13610	26437339	We then used a Matrigel  invasion assay to assess effects of transfected NFs or CAFs on the invasive capacity of MCF7 and MDA-MB-231 breast cancer epithelial cells growing on Matrigel -coated membranes of Tranwell inserts placed in the dishes which contained the transfected fibroblasts.	('breast cancer', 'Disease', (133, 146))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (122, 132))	('MDA-MB-231', 'Gene', (122, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('CAF', 'Gene', '8850', (80, 83))	('MCF7', 'CellLine', 'CVCL:0031', (113, 117))	('transfected', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NFs', 'Gene', (73, 76))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('CAF', 'Gene', (80, 83))	('MCF7', 'Gene', (113, 117))
13612	26437339	Our data support a functional role for miR-92 in fibroblasts and show that low levels of miR-92 promote a more aggressive breast cancer phenotype in cell lines representing 2 different molecular subtypes of breast cancer suggesting that changes in expression of this molecule in NFs can directly impact upon the behaviour of breast cancer epithelial cells.	('breast cancer', 'Phenotype', 'HP:0003002', (325, 338))	('miR-92', 'Gene', '407047', (89, 95))	('impact', 'Reg', (296, 302))	('breast cancer', 'Disease', 'MESH:D001943', (325, 338))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (325, 338))	('miR-92', 'Gene', '407047', (39, 45))	('miR-92', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('miR-92', 'Gene', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (111, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('changes', 'Var', (237, 244))	('aggressive breast cancer', 'Disease', (111, 135))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Disease', (207, 220))
13635	26437339	Loss-of-heterozygosity (LOH) at the human genomic locus encoding the miR-17-92 cluster, 13q31.3, has been observed in several tumour types and a recent genome-wide analysis of copy number alterations in cancer revealed that this locus was deleted in 16.5% of ovarian cancers, 21.9% of breast cancers and 20% of melanomas.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('ovarian cancers', 'Phenotype', 'HP:0100615', (259, 274))	('miR-17-92', 'Gene', (69, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (285, 299))	('ovarian cancer', 'Phenotype', 'HP:0100615', (259, 273))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('melanomas', 'Disease', 'MESH:D008545', (311, 320))	('cancer', 'Disease', (292, 298))	('deleted', 'Var', (239, 246))	('miR-17-92', 'Gene', '407975', (69, 78))	('melanomas', 'Disease', (311, 320))	('cancer', 'Disease', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('ovarian cancers', 'Disease', (259, 274))	('ovarian cancers', 'Disease', 'MESH:D010051', (259, 274))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('Loss-of-heterozygosity', 'NegReg', (0, 22))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('melanomas', 'Phenotype', 'HP:0002861', (311, 320))	('tumour', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('breast cancers', 'Disease', 'MESH:D001943', (285, 299))	('breast cancers', 'Disease', (285, 299))	('human', 'Species', '9606', (36, 41))
13637	26437339	also found that expression of miR-92 was inversely associated with tumour grade in 144 cases of primary breast cancer and added independent prognostic information; patients with high levels of miR-92 had a better clinical outcome than patients with low levels.	('high levels', 'Var', (178, 189))	('primary breast cancer', 'Disease', 'MESH:D001943', (96, 117))	('miR-92', 'Gene', (193, 199))	('tumour', 'Disease', (67, 73))	('miR-92', 'Gene', '407047', (193, 199))	('primary breast cancer', 'Disease', (96, 117))	('patients', 'Species', '9606', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-92', 'Gene', (30, 36))	('miR-92', 'Gene', '407047', (30, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (164, 172))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
13661	26437339	Nevertheless, this demonstrates that loss of miR-92 expression may have a role in regulating adjacent epithelial cell phenotype, acting via the stroma.	('stroma', 'Disease', (144, 150))	('stroma', 'Disease', 'None', (144, 150))	('miR-92', 'Gene', (45, 51))	('loss', 'Var', (37, 41))	('miR-92', 'Gene', '407047', (45, 51))	('adjacent epithelial cell phenotype', 'CPA', (93, 127))
13673	26437339	Nevertheless, these observations are in accordance with our data, which suggest low levels of miR-92 are associated with enhanced invasion and a more aggressive tumour phenotype.	('miR-92', 'Gene', (94, 100))	('miR-92', 'Gene', '407047', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('invasion', 'CPA', (130, 138))	('enhanced', 'PosReg', (121, 129))	('aggressive tumour', 'Disease', 'MESH:D001523', (150, 167))	('low levels', 'Var', (80, 90))	('aggressive tumour', 'Disease', (150, 167))
13677	26437339	Experimentally, they also showed that knock-down of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival of breast cancer cells and suggest that regulation of tumour-stromal cross-talk through fibroblastic TGF-beta pathway may depend on fibroblast phenotype.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('increased', 'PosReg', (79, 88))	('clonogenic survival', 'CPA', (120, 139))	('TGFBR2', 'Gene', (52, 58))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('knock-down', 'Var', (38, 48))	('CAF', 'Gene', (62, 65))	('tumour-stromal cross-talk', 'Disease', (194, 219))	('tumour-stromal cross-talk', 'Disease', 'MESH:D020922', (194, 219))	('cell growth', 'CPA', (89, 100))	('TGFBR2', 'Gene', '7048', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('CAF', 'Gene', '8850', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
13680	26437339	Inhibition of BMPR2 has been shown to inhibit growth and viability of breast cancer cells.	('BMPR2', 'Gene', (14, 19))	('BMPR2', 'Gene', '659', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('inhibit', 'NegReg', (38, 45))
13681	26437339	found that BMPR2 had a tumour-suppressive function in mammary epithelia and microenvironment and suggest that disruption can accelerate mammary carcinoma metastases.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('carcinoma metastases', 'Disease', (144, 164))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('BMPR2', 'Gene', (11, 16))	('carcinoma metastases', 'Disease', 'MESH:D009362', (144, 164))	('tumour', 'Disease', (23, 29))	('BMPR2', 'Gene', '659', (11, 16))	('accelerate', 'PosReg', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (136, 153))	('disruption', 'Var', (110, 120))
13682	26437339	Finally, it is known that epigenetic mechanisms including DNA methylation and histone modification contribute to expression of some miRNAs, including those of the miR-17-92 cluster.	('histone modification', 'MPA', (78, 98))	('expression', 'MPA', (113, 123))	('miR-17-92', 'Gene', '407975', (163, 172))	('contribute', 'Reg', (99, 109))	('miR-17-92', 'Gene', (163, 172))	('DNA', 'Var', (58, 61))
13683	26437339	Epigenetic regulation of miRNA expression has been described in colorectal, breast and lung cancers.	('described', 'Reg', (51, 60))	('miRNA expression', 'Protein', (25, 41))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('breast and lung cancers', 'Disease', 'MESH:D001943', (76, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('Epigenetic regulation', 'Var', (0, 21))	('colorectal', 'Disease', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancers', 'Phenotype', 'HP:0100526', (87, 99))
13696	24887547	Recent large genomic studies have identified and confirmed numerous recurrent mutations and aneuploidies that stratify breast carcinomas across clinicopathologic features.	('aneuploidies', 'Var', (92, 104))	('breast carcinomas', 'Disease', 'MESH:D001943', (119, 136))	('breast carcinomas', 'Disease', (119, 136))	('breast carcinomas', 'Phenotype', 'HP:0003002', (119, 136))	('mutations', 'Var', (78, 87))	('stratify', 'Reg', (110, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))
13705	24887547	We found that early neoplasias have already acquired a significant number of genomic alterations: many of the early neoplasias studied possess hundreds of single nucleotide mutations and several chromosome aneuploidies.	('neoplasias', 'Disease', 'MESH:D009369', (20, 30))	('neoplasias', 'Phenotype', 'HP:0002664', (20, 30))	('neoplasia', 'Phenotype', 'HP:0002664', (20, 29))	('neoplasias', 'Disease', (116, 126))	('neoplasias', 'Disease', (20, 30))	('neoplasias', 'Phenotype', 'HP:0002664', (116, 126))	('single nucleotide mutations', 'Var', (155, 182))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('neoplasias', 'Disease', 'MESH:D009369', (116, 126))
13706	24887547	Many of these alterations are observed in both the patient's early neoplasia and associated invasive cancer in a significant fraction of instances (4 of 6 sequenced patients, 4 of 14 early neoplasias).	('alterations', 'Var', (14, 25))	('neoplasia', 'Phenotype', 'HP:0002664', (67, 76))	('neoplasia', 'Disease', 'MESH:D009369', (189, 198))	('invasive cancer', 'Disease', (92, 107))	('neoplasia', 'Phenotype', 'HP:0002664', (189, 198))	('patient', 'Species', '9606', (165, 172))	('neoplasia', 'Disease', (67, 76))	('neoplasias', 'Disease', 'MESH:D009369', (189, 199))	('neoplasias', 'Phenotype', 'HP:0002664', (189, 199))	('invasive cancer', 'Disease', 'MESH:D009362', (92, 107))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neoplasias', 'Disease', (189, 199))	('neoplasia', 'Disease', 'MESH:D009369', (67, 76))	('neoplasia', 'Disease', (189, 198))
13707	24887547	These findings indicate that a common ancestral clone develops mutations at a very early stage, before giving rise to both the early neoplasia and related cancer.	('mutations', 'Var', (63, 72))	('neoplasia', 'Disease', 'MESH:D009369', (133, 142))	('giving rise', 'Reg', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('neoplasia', 'Disease', (133, 142))	('neoplasia', 'Phenotype', 'HP:0002664', (133, 142))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
13708	24887547	While most of the single nucleotide variations were not shared between patients, gain of chromosome 1q and activating mutations in PIK3CA were observed recurrently in some of the early neoplasia samples.	('neoplasia', 'Disease', 'MESH:D009369', (185, 194))	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('patients', 'Species', '9606', (71, 79))	('mutations', 'Var', (118, 127))	('activating', 'PosReg', (107, 117))	('gain of', 'PosReg', (81, 88))	('neoplasia', 'Disease', (185, 194))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))
13709	24887547	A previous targeted study of cancer hotspot mutations also identified PIK3CA as a common mutation present in roughly half of early neoplasias, but not necessarily correlated with progression to invasive carcinoma.	('cancer', 'Disease', (29, 35))	('invasive carcinoma', 'Disease', 'MESH:D009361', (194, 212))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('neoplasias', 'Phenotype', 'HP:0002664', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('PIK3CA', 'Gene', (70, 76))	('invasive carcinoma', 'Disease', (194, 212))	('mutations', 'Var', (44, 53))	('neoplasias', 'Disease', 'MESH:D009369', (131, 141))	('neoplasias', 'Disease', (131, 141))	('PIK3CA', 'Gene', '5290', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))
13711	24887547	Given a shared origin for early neoplasias and the adjacent invasive cancer, the early neoplasia mutations identified thus far represent molecular events that may be important at this very early stage and suggest that further characterization of early neoplasias represents a unique and promising tool for uncovering additional alterations and elucidating the molecular mechanisms necessary for cancer initiation.	('neoplasias', 'Disease', (252, 262))	('mutations', 'Var', (97, 106))	('invasive cancer', 'Disease', (60, 75))	('neoplasia', 'Disease', 'MESH:D009369', (87, 96))	('invasive cancer', 'Disease', 'MESH:D009362', (60, 75))	('cancer', 'Disease', 'MESH:D009369', (395, 401))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('neoplasia', 'Disease', 'MESH:D009369', (32, 41))	('neoplasia', 'Disease', (87, 96))	('neoplasias', 'Disease', 'MESH:D009369', (32, 42))	('neoplasia', 'Disease', (32, 41))	('neoplasia', 'Disease', 'MESH:D009369', (252, 261))	('neoplasias', 'Disease', 'MESH:D009369', (252, 262))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('neoplasia', 'Disease', (252, 261))	('neoplasia', 'Phenotype', 'HP:0002664', (32, 41))	('neoplasias', 'Phenotype', 'HP:0002664', (32, 42))	('cancer', 'Disease', (395, 401))	('cancer', 'Disease', (69, 75))	('neoplasias', 'Disease', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('neoplasias', 'Phenotype', 'HP:0002664', (252, 262))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))
13749	24887547	Observing cancer gene alterations within early neoplasias indicates that these genes may be important for establishing some of the earliest changes necessary to transform normal cells into pre-cancerous cells.	('neoplasias', 'Disease', 'MESH:D009369', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('neoplasia', 'Phenotype', 'HP:0002664', (47, 56))	('neoplasias', 'Disease', (47, 57))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('alterations', 'Var', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('neoplasias', 'Phenotype', 'HP:0002664', (47, 57))	('cancer', 'Disease', (10, 16))
13757	24887547	Additionally, when early neoplasias with a PIK3CA mutation were compared to early neoplasias without an identifiable PIK3CA mutation (Table S1 in Additional file 1), no significant gene expression differences were identified between the two groups (data not shown).	('PIK3CA', 'Gene', '5290', (43, 49))	('neoplasias', 'Disease', 'MESH:D009369', (82, 92))	('neoplasias', 'Phenotype', 'HP:0002664', (82, 92))	('neoplasia', 'Phenotype', 'HP:0002664', (25, 34))	('neoplasias', 'Disease', (82, 92))	('neoplasias', 'Phenotype', 'HP:0002664', (25, 35))	('neoplasias', 'Disease', 'MESH:D009369', (25, 35))	('PIK3CA', 'Gene', (117, 123))	('neoplasias', 'Disease', (25, 35))	('PIK3CA', 'Gene', '5290', (117, 123))	('neoplasia', 'Phenotype', 'HP:0002664', (82, 91))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
13758	24887547	This suggests that while PIK3CA activating mutations may be important for generating early neoplasia, they may not be a prominent player in promoting the progression to cancer at this early stage, despite known PIK3CA-associated expression differences at the carcinoma stage.	('PIK3CA', 'Gene', (211, 217))	('cancer', 'Disease', (169, 175))	('PIK3CA', 'Gene', '5290', (211, 217))	('carcinoma', 'Disease', 'MESH:D002277', (259, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('PIK3CA', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('neoplasia', 'Disease', (91, 100))	('carcinoma', 'Disease', (259, 268))	('mutations', 'Var', (43, 52))	('PIK3CA', 'Gene', '5290', (25, 31))	('neoplasia', 'Phenotype', 'HP:0002664', (91, 100))	('neoplasia', 'Disease', 'MESH:D009369', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('expression', 'MPA', (229, 239))
13761	24887547	Two of ten early neoplasias showed a copy number gain of chromosome 1q when compared with chromosomes 2q and 3q (Table S8 in Additional file 1), yet amplified samples (n = 2) and wild-type samples (n = 8) were indistinguishable using gene expression classification with PAM (data not shown).	('neoplasia', 'Phenotype', 'HP:0002664', (17, 26))	('neoplasias', 'Disease', 'MESH:D009369', (17, 27))	('gain', 'PosReg', (49, 53))	('neoplasias', 'Phenotype', 'HP:0002664', (17, 27))	('copy number', 'Var', (37, 48))	('neoplasias', 'Disease', (17, 27))
13779	24887547	When 1,376 of the previously defined cancer-expressed lncRNAs were analyzed in this study, we observed similar fractions of lncRNA transcripts experiencing modified expression in early neoplasias relative to normal (4.4% lncRNAs up-regulated; 0.7% lncRNAs down-regulated; compared with 4.1% RefSeq genes up-regulated and 1.4% RefSeq genes down-regulated; Tables 1 and 2; Table S11 in Additional file 1), indicating no global enrichment for lncRNA modifications compared with RefSeq genes in this early stage of cancer development.	('lncRNA transcripts', 'Gene', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('down-regulated', 'NegReg', (256, 270))	('neoplasias', 'Disease', 'MESH:D009369', (185, 195))	('neoplasias', 'Phenotype', 'HP:0002664', (185, 195))	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (511, 517))	('cancer', 'Disease', 'MESH:D009369', (511, 517))	('neoplasias', 'Disease', (185, 195))	('up-regulated', 'PosReg', (229, 241))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (511, 517))	('up-regulated', 'PosReg', (304, 316))	('S11', 'Gene', (377, 380))	('S11', 'Gene', '6267', (377, 380))	('modified', 'Var', (156, 164))
13783	24887547	This suggests that transcript 13741 may have a role in the ER/FOXA1/GATA3 pathway being activated in early neoplasias and maintaining elevated levels within cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('GATA3', 'Gene', '2625', (68, 73))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('FOXA1', 'Gene', (62, 67))	('activated', 'PosReg', (88, 97))	('neoplasias', 'Disease', 'MESH:D009369', (107, 117))	('neoplasias', 'Phenotype', 'HP:0002664', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('elevated levels', 'MPA', (134, 149))	('neoplasias', 'Disease', (107, 117))	('cancer', 'Disease', (157, 163))	('transcript 13741', 'Var', (19, 35))	('FOXA1', 'Gene', '3169', (62, 67))	('GATA3', 'Gene', (68, 73))
13797	24887547	While we know which mutations, aneuploidies, and expression changes occur in carcinoma, we have little insight as to the dynamics of the genomic changes.	('carcinoma', 'Disease', (77, 86))	('changes', 'Reg', (60, 67))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('expression', 'MPA', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('aneuploidies', 'Var', (31, 43))	('mutations', 'Var', (20, 29))
13802	24887547	Our recent full-genome sequencing study of 31 samples from 6 patients, including 14 early neoplasias, provided the most complete picture to date of mutations and aneuploidies present within early neoplasias, and definitively established a genetic relationship between early neoplasias and the adjacent invasive cancer.	('neoplasia', 'Phenotype', 'HP:0002664', (196, 205))	('mutations', 'Var', (148, 157))	('neoplasia', 'Phenotype', 'HP:0002664', (274, 283))	('neoplasias', 'Phenotype', 'HP:0002664', (274, 284))	('neoplasias', 'Disease', (274, 284))	('neoplasias', 'Disease', 'MESH:D009369', (196, 206))	('neoplasias', 'Phenotype', 'HP:0002664', (196, 206))	('patients', 'Species', '9606', (61, 69))	('neoplasias', 'Disease', (196, 206))	('neoplasia', 'Phenotype', 'HP:0002664', (90, 99))	('neoplasias', 'Disease', 'MESH:D009369', (90, 100))	('neoplasias', 'Phenotype', 'HP:0002664', (90, 100))	('invasive cancer', 'Disease', (302, 317))	('neoplasias', 'Disease', (90, 100))	('invasive cancer', 'Disease', 'MESH:D009362', (302, 317))	('neoplasias', 'Disease', 'MESH:D009369', (274, 284))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
13803	24887547	Importantly, these cancer-associated early neoplasias have already acquired aneuploidies, common within breast cancer, and hundreds of mutations, suggesting that critical oncogenic events are occurring at this early stage.	('neoplasias', 'Disease', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('mutations', 'Var', (135, 144))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', (104, 117))	('aneuploidies', 'MPA', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('neoplasias', 'Phenotype', 'HP:0002664', (43, 53))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('neoplasia', 'Phenotype', 'HP:0002664', (43, 52))	('neoplasias', 'Disease', 'MESH:D009369', (43, 53))
13824	24887547	Work has suggested that GATA3 may act as a differentiation factor within breast cells that, when lost, typically through mutation, allows cancer progression.	('cancer', 'Disease', (138, 144))	('GATA3', 'Gene', '2625', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('allows', 'PosReg', (131, 137))	('mutation', 'Var', (121, 129))	('lost', 'NegReg', (97, 101))	('GATA3', 'Gene', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
13827	24887547	Activating mutations of PIK3CA are present in 36% of all breast cancers, significantly enriched within luminal A breast cancers (45%), and function by activating the PI3K/AKT pathway to alter a number of cellular processes, including cell proliferation, differentiation, and survival.	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', '5290', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('activating', 'PosReg', (151, 161))	('survival', 'CPA', (275, 283))	('A breast cancers', 'Disease', 'MESH:D001943', (111, 127))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cellular processes', 'CPA', (204, 222))	('AKT', 'Gene', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('breast cancers', 'Disease', (57, 71))	('PIK3CA', 'Gene', (24, 30))	('A breast cancers', 'Disease', (111, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cell proliferation', 'CPA', (234, 252))	('differentiation', 'CPA', (254, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('AKT', 'Gene', '207', (171, 174))	('alter', 'Reg', (186, 191))
13829	24887547	Transcript levels of PIK3CA were not significantly different between mutant and wild-type early neoplasias, and these two groups did not show any of the previously described transcriptional changes found in IDC.	('IDC', 'Gene', (207, 210))	('mutant', 'Var', (69, 75))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('PIK3CA', 'Gene', '5290', (21, 27))	('neoplasias', 'Phenotype', 'HP:0002664', (96, 106))	('PIK3CA', 'Gene', (21, 27))	('neoplasias', 'Disease', 'MESH:D009369', (96, 106))	('neoplasias', 'Disease', (96, 106))	('Transcript', 'MPA', (0, 10))	('IDC', 'Gene', '4000', (207, 210))
13833	24887547	Aneuploidy work in yeast has shown that copy number alterations of chromosome arms can effect gene expression globally and is not limited to genes on the effected chromosome.	('yeast', 'Species', '4932', (19, 24))	('effect', 'Reg', (87, 93))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('gene expression', 'MPA', (94, 109))	('copy number alterations', 'Var', (40, 63))	('Aneuploidy', 'Disease', (0, 10))
13888	24887547	Bacterial artificial chromosome (BAC) clones RP11-1044H13 (1q32) and RP11-1120 M18 (3q25) were obtained from the BACPAC Resources Centre (Children's Hospital Oakland Research Institute, Oakland, CA, USA), while clone CTD-2344 F21 (2q37) was from Invitrogen/Life Technologies.	('RP11-1044H13', 'Var', (45, 57))	('RP11-1120 M18', 'Var', (69, 82))	('Children', 'Species', '9606', (138, 146))
13914	24887547	Work was supported by the National Institutes of Health (CA129927 to RBW) and the California Breast Cancer Research Program (grants 15NB-0156 and 15IB-0123 to RBW).	('Breast Cancer', 'Phenotype', 'HP:0003002', (93, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Breast Cancer', 'Disease', (93, 106))	('CA129927', 'Var', (57, 65))	('Breast Cancer', 'Disease', 'MESH:D001943', (93, 106))
13932	19664271	NUCKS has been characterized as a cell cycle related protein that is synthesized in the M/G1 phase.	('M/G1', 'Var', (88, 92))	('M/G1', 'SUBSTITUTION', 'None', (88, 92))	('NUCKS', 'Gene', (0, 5))	('NUCKS', 'Gene', '64710', (0, 5))
13937	19664271	Furthermore, translational modifications of NUCKS revealed acetylation and methylation sites specific for breast cancer, resembling the data from core histones.	('modifications', 'Var', (27, 40))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('NUCKS', 'Gene', '64710', (44, 49))	('acetylation', 'MPA', (59, 70))	('methylation', 'MPA', (75, 86))	('NUCKS', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
13983	19664271	Actually, this finding was in full agreement with the immunohistochemical results from the corresponding IDC, grade III biopsies which stained for NUCKS with a score of +1, compared to most of the benign proliferations and grade II biopsies which stained with a score of +2 to +3.	('IDC', 'Gene', (105, 108))	('NUCKS', 'Gene', (147, 152))	('rat', 'Species', '10116', (211, 214))	('score of +1', 'Var', (160, 171))	('stained', 'Reg', (135, 142))	('NUCKS', 'Gene', '64710', (147, 152))	('IDC', 'Gene', '4000', (105, 108))
14005	19664271	On the contrary, high grade poor differentiated DCIS, like most of the IDC, grade III cases, exhibited weak to moderate NUCKS staining.	('rat', 'Species', '10116', (115, 118))	('IDC', 'Gene', (71, 74))	('poor', 'Var', (28, 32))	('DCIS', 'Phenotype', 'HP:0030075', (48, 52))	('NUCKS', 'Gene', '64710', (120, 125))	('IDC', 'Gene', '4000', (71, 74))	('NUCKS', 'Gene', (120, 125))
14007	19664271	NUCKS has been characterized as a cell cycle related protein synthesized during the M/G1 phase.	('NUCKS', 'Gene', (0, 5))	('NUCKS', 'Gene', '64710', (0, 5))	('M/G1', 'Var', (84, 88))	('M/G1', 'SUBSTITUTION', 'None', (84, 88))
14050	19664271	The signal was visualized with DAB chromogen (0.05% DAB, 0.024% H2O2 in PBS).	('0.05', 'Var', (46, 50))	('PBS', 'Chemical', '-', (72, 75))	('0.024%', 'Var', (57, 63))	('DAB', 'Chemical', 'MESH:C000469', (31, 34))	('H2O2', 'Chemical', 'MESH:D006861', (64, 68))	('DAB', 'Chemical', 'MESH:C000469', (52, 55))
14097	27538810	Re-excisions have the potential for added discomfort, surgical complications, compromise in cosmetic outcome, additional stress for patients and families, and increased health care costs, and have been associated with conversion to bilateral mastectomy.	('Re-excisions', 'Var', (0, 12))	('associated', 'Reg', (202, 212))	('patients', 'Species', '9606', (132, 140))
14109	27538810	The annual hazard rate for IBTR after lumpectomy alone was 8.1 % for those with positive margins compared to 3.3% for patients with negative margins, reduced by WBRT to 2.7% and 1.2%, respectively.	('positive margins', 'Var', (80, 96))	('IBTR', 'Disease', (27, 31))	('patients', 'Species', '9606', (118, 126))
14110	27538810	Positive margins were significantly associated with IBTR in a multivariate analysis of the long-term results of the European Organization for Research and Treatment of Cancer (EORTC) 10853 trial.	('IBTR', 'Disease', (52, 56))	('Positive margins', 'Var', (0, 16))	('Cancer', 'Disease', (168, 174))	('Cancer', 'Disease', 'MESH:D009369', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))
14120	27538810	In the Radiation Therapy Oncology Group (RTOG) 9804 trial where patients with small, mammographically detected low-to-intermediate grade DCIS and margins >= 3 mm were randomized to excision alone or excision plus WBRT, 7-year IBTR rates were 6.7% and 0.9% (p = .0003), respectively.	('DCIS', 'Disease', (137, 141))	('low-to-intermediate grade', 'Var', (111, 136))	('patients', 'Species', '9606', (64, 72))	('Oncology', 'Phenotype', 'HP:0002664', (25, 33))
14147	30588019	Risk factors for lymph node metastasis and the impact of adjuvant chemotherapy on ductal carcinoma in situ with microinvasion: a population-based study Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases.	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (152, 176))	('ductal carcinoma', 'Disease', 'MESH:D044584', (82, 98))	('microinvasion', 'Var', (182, 195))	('breast cancer', 'Disease', (226, 239))	('ductal carcinoma', 'Disease', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (82, 98))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 106))	('Ductal carcinoma', 'Disease', (152, 168))	('DCISM', 'Chemical', '-', (197, 202))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (152, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
14227	30588019	After univariate and multivariate analyses, HER2 status was an independent predictor for worse disease-free survival with a median follow-up of 31 months, and they suggested that chemotherapy and target therapy in patients with HER2-positive disease seemed to be reasonable.	('HER2-positive disease', 'Disease', (228, 249))	('worse', 'NegReg', (89, 94))	('disease-free survival', 'CPA', (95, 116))	('HER2', 'Gene', (228, 232))	('patients', 'Species', '9606', (214, 222))	('HER2-positive disease', 'Disease', 'MESH:D064726', (228, 249))	('HER2', 'Gene', '2064', (228, 232))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (44, 48))	('status', 'Var', (49, 55))
14248	19261255	Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response Abnormalities of chromosome 17, recognised over two decades ago to be important in tumorigenesis, often occur in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('occur', 'Reg', (192, 197))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (201, 214))	('Breast cancer', 'Disease', (0, 13))	('carcinogenesis', 'Disease', (48, 62))	('Abnormalities', 'Var', (88, 101))
14249	19261255	Changes of specific loci on chromosome 17 including ERBB2 amplification, P53 loss, BRCA1 loss, and TOP2A amplification or deletion are known to have important roles in breast-cancer pathophysiology.	('breast-cancer', 'Disease', (168, 181))	('TOP2A', 'Gene', (99, 104))	('BRCA1 loss', 'Disease', 'MESH:D015431', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('amplification', 'Var', (105, 118))	('breast-cancer', 'Disease', 'MESH:D001943', (168, 181))	('deletion', 'Var', (122, 130))	('ERBB2', 'Gene', '2064', (52, 57))	('TOP2A', 'Gene', '7153', (99, 104))	('BRCA1 loss', 'Disease', (83, 93))	('loss', 'NegReg', (77, 81))	('ERBB2', 'Gene', (52, 57))	('P53', 'Gene', (73, 76))	('amplification', 'Var', (58, 71))	('P53', 'Gene', '7157', (73, 76))
14250	19261255	Numerical aberrations of chromosome 17 are linked to breast-cancer initiation and progression, and possibly to treatment response.	('breast-cancer initiation', 'Disease', 'MESH:D001943', (53, 77))	('linked', 'Reg', (43, 49))	('Numerical aberrations', 'Var', (0, 21))	('breast-cancer initiation', 'Disease', (53, 77))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
14252	19261255	Reports are conflicting regarding the association of copy gain of chromosome 17 (polysomy 17) with strong ERBB2 protein expression in the absence of true ERBB2 gene amplification.	('expression', 'MPA', (120, 130))	('ERBB2', 'Gene', (154, 159))	('ERBB2', 'Gene', '2064', (106, 111))	('ERBB2', 'Gene', '2064', (154, 159))	('copy gain', 'Var', (53, 62))	('ERBB2', 'Gene', (106, 111))	('protein', 'Protein', (112, 119))
14256	19261255	Changes in the number of individual whole chromosomes (aneusomy) seems to indicate genetic instability and was first proposed to cause tumorigenesis in 1902.	('neu', 'Gene', '2064', (56, 59))	('cause', 'Reg', (129, 134))	('neu', 'Gene', (56, 59))	('Changes', 'Var', (0, 7))	('tumorigenesis', 'CPA', (135, 148))
14258	19261255	Abnormalities in chromosome 17 are common in breast cancer, including whole chromosome and gene-copy-number anomalies, allelic losses, and structural rearrangements shown by conventional cytogenetic and molecular cytogenetic techniques.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Abnormalities', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('gene-copy-number anomalies', 'Var', (91, 117))
14262	19261255	Distinct patterns of changes are associated with different clinicopathological features and gene-expression subtypes of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('changes', 'Var', (21, 28))
14264	19261255	The effect of polysomy 17 on expression of human epidermal-growth-factor receptor 2 (ERBB2) in ERBB2 non-amplified breast tumours is of particular interest (figure 1), as is its effect on treatment response to ERBB2-targeted therapies (eg, trastuzumab, lapatinib).	('lapatinib', 'Chemical', 'MESH:D000077341', (253, 262))	('epidermal-growth-factor receptor 2', 'Gene', (49, 83))	('epidermal-growth-factor receptor 2', 'Gene', '2064', (49, 83))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('ERBB2', 'Gene', '2064', (95, 100))	('ERBB2', 'Gene', (85, 90))	('human', 'Species', '9606', (43, 48))	('ERBB2', 'Gene', '2064', (85, 90))	('ERBB2', 'Gene', (95, 100))	('trastuzumab', 'Chemical', 'MESH:D000068878', (240, 251))	('breast tumour', 'Phenotype', 'HP:0100013', (115, 128))	('breast tumours', 'Disease', (115, 129))	('ERBB2', 'Gene', '2064', (210, 215))	('non-amplified', 'Var', (101, 114))	('ERBB2', 'Gene', (210, 215))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('breast tumours', 'Disease', 'MESH:D001943', (115, 129))
14277	19261255	ERBB2 and TOP2A are in close proximity on chromosome 17 (figure 3) and copy number changes together in many tumours.	('copy number', 'Var', (71, 82))	('tumours', 'Disease', (108, 115))	('TOP2A', 'Gene', '7153', (10, 15))	('TOP2A', 'Gene', (10, 15))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('changes', 'Reg', (83, 90))
14278	19261255	TOP2A is either amplified or deleted, with equal probability, in nearly 90% of ERBB2-amplified primary breast tumours.	('TOP2A', 'Gene', (0, 5))	('breast tumour', 'Phenotype', 'HP:0100013', (103, 116))	('ERBB2', 'Gene', (79, 84))	('breast tumours', 'Disease', (103, 117))	('ERBB2', 'Gene', '2064', (79, 84))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('TOP2A', 'Gene', '7153', (0, 5))	('deleted', 'Var', (29, 36))	('breast tumours', 'Disease', 'MESH:D001943', (103, 117))
14279	19261255	By contrast, TOP2A copy-number anomalies are rare in ERBB2 non-amplified tumours (<7%).	('TOP2A', 'Gene', (13, 18))	('ERBB2', 'Gene', '2064', (53, 58))	('tumours', 'Disease', (73, 80))	('non-amplified', 'Var', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('TOP2A', 'Gene', '7153', (13, 18))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('ERBB2', 'Gene', (53, 58))
14280	19261255	TOP2A deletion also affects tumours with polysomy 17, and so TOP2A deletion probably happens before polysomy.	('TOP2A', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('deletion', 'Var', (6, 14))	('TOP2A', 'Gene', '7153', (0, 5))	('tumours', 'Disease', (28, 35))	('affects', 'Reg', (20, 27))	('TOP2A', 'Gene', '7153', (61, 66))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('TOP2A', 'Gene', (61, 66))
14281	19261255	Furthermore, the presence of abnormalities in both ERBB2 and TOP2A might help to identify patients best suited to trastuzumab and anthracycline therapies.	('abnormalities', 'Var', (29, 42))	('trastuzumab', 'Chemical', 'MESH:D000068878', (114, 125))	('TOP2A', 'Gene', '7153', (61, 66))	('presence', 'Var', (17, 25))	('help', 'Reg', (73, 77))	('ERBB2', 'Gene', '2064', (51, 56))	('anthracycline', 'Chemical', 'MESH:D018943', (130, 143))	('ERBB2', 'Gene', (51, 56))	('TOP2A', 'Gene', (61, 66))	('patients', 'Species', '9606', (90, 98))
14282	19261255	Preliminary findings suggest that polysomy 17 affects response to trastuzumab.	('response to trastuzumab', 'MPA', (54, 77))	('trastuzumab', 'Chemical', 'MESH:D000068878', (66, 77))	('affects', 'Reg', (46, 53))	('polysomy 17', 'Var', (34, 45))
14283	19261255	Therefore, whole chromosome 17 copy-number anomalies might affect the clinical assessment and importance of ERBB2 and TOP2A amplification and protein expression.	('affect', 'Reg', (59, 65))	('copy-number anomalies', 'Var', (31, 52))	('TOP2A', 'Gene', '7153', (118, 123))	('clinical assessment', 'MPA', (70, 89))	('ERBB2', 'Gene', '2064', (108, 113))	('TOP2A', 'Gene', (118, 123))	('ERBB2', 'Gene', (108, 113))
14284	19261255	Although polysomy in chromosome 17 is associated with several diseases and cancers, in this Review we focus on breast cancer.	('associated', 'Reg', (38, 48))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('polysomy', 'Var', (9, 17))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
14295	19261255	For each method, different signal counts have been used as cut-offs, leading to large differences in the reported incidences of chromosome 17 aneusomy (tables 1 and 2).	('neu', 'Gene', '2064', (143, 146))	('chromosome', 'Var', (128, 138))	('neu', 'Gene', (143, 146))
14299	19261255	Several studies have examined the prevalence of changes in copy number of chromosome 17 in invasive breast cancer (tables 1 and 2).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasive breast cancer', 'Disease', 'MESH:D001943', (91, 113))	('copy number', 'Var', (59, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('invasive breast cancer', 'Disease', (91, 113))	('changes', 'Var', (48, 55))
14301	19261255	The range in prevalence values is a result of different types of material examined, different selection criteria (eg, ERBB2 immunohistochemical scores), and the varying methods used to define thresholds of disomy, monosomy, and polysomy as discussed above.	('disomy', 'Disease', (206, 212))	('ERBB2', 'Gene', (118, 123))	('disomy', 'Disease', 'MESH:D024182', (206, 212))	('monosomy', 'Var', (214, 222))	('polysomy', 'Var', (228, 236))	('ERBB2', 'Gene', '2064', (118, 123))
14304	19261255	The role of aneusomy 17 in non-invasive disease is supported by a study that found copy-number changes of chromosome 17 in 25 of 32 women with non-proliferative epithelium or hyperplasia with no evidence of invasive disease.	('non-proliferative epithelium', 'Disease', (143, 171))	('copy-number changes', 'Var', (83, 102))	('women', 'Species', '9606', (132, 137))	('hyperplasia', 'Disease', 'MESH:D006965', (175, 186))	('invasive disease', 'Disease', (31, 47))	('invasive disease', 'Disease', (207, 223))	('neu', 'Gene', '2064', (13, 16))	('hyperplasia', 'Disease', (175, 186))	('invasive disease', 'Disease', 'MESH:D009362', (31, 47))	('neu', 'Gene', (13, 16))	('invasive disease', 'Disease', 'MESH:D009362', (207, 223))
14309	19261255	Indeed, distinctive, but overlapping patterns of genetic instability are found in primary breast-tumours and adjacent uninvolved parenchyma.	('primary breast-tumours', 'Disease', 'MESH:D001943', (82, 104))	('primary breast-tumours', 'Disease', (82, 104))	('genetic', 'Var', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))
14310	19261255	Monosomy 17 seems to be more widespread than polysomy 17 in non-invasive and low grade in-situ carcinomas (tables 3 and 4).	('situ carcinomas', 'Disease', 'MESH:D002278', (90, 105))	('situ carcinomas', 'Disease', (90, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('Monosomy 17', 'Var', (0, 11))
14312	19261255	Additionally, monosomy is more common than polysomy in LCIS, suggesting that subsets of preinvasive breast neoplasia have divergent patterns of genetic instability.	('breast neoplasia', 'Disease', 'MESH:D009369', (100, 116))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('breast neoplasia', 'Disease', (100, 116))	('preinvasive breast neoplasia', 'Phenotype', 'HP:0003002', (88, 116))	('breast neoplasia', 'Phenotype', 'HP:0100013', (100, 116))	('monosomy', 'Var', (14, 22))
14313	19261255	Monosomy of chromosomes 7, 8, 16, and 17 is more common in grade I DCIS than in grade III DCIS tumours (29% [9/31 hybridisations] vs 4% [2/49 hybridisations]).	('Monosomy', 'Var', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('common', 'Reg', (49, 55))	('III DCIS tumours', 'Disease', 'MESH:D002285', (86, 102))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('grade I DCIS', 'Disease', (59, 71))	('grade I DCIS', 'Phenotype', 'HP:0011072', (59, 71))	('DCIS', 'Disease', (67, 71))	('III DCIS tumours', 'Disease', (86, 102))
14314	19261255	However, neoplasms of grade II DCIS had varied chromosome aneuploidy: disomy in 38% (24/63 hybridisations), monosomy in 26% (16/63 hybridisations), and polysomy in 36% (19/63 hybridisations) of specimens.	('disomy', 'Disease', (70, 76))	('disomy', 'Disease', 'MESH:D024182', (70, 76))	('polysomy', 'Var', (152, 160))	('neoplasms', 'Disease', (9, 18))	('neoplasms', 'Disease', 'MESH:D009369', (9, 18))	('chromosome aneuploidy', 'Disease', 'MESH:D000782', (47, 68))	('monosomy', 'Var', (108, 116))	('chromosome aneuploidy', 'Disease', (47, 68))	('neoplasms', 'Phenotype', 'HP:0002664', (9, 18))
14319	19261255	The development of trastuzumab, an ERBB2-targeted antibody, and findings that ERBB2 overexpression and gene amplification often predict its benefit, prompted numerous investigations of the relation between chromosome 17 monosomy and polysomy, ERBB2 amplification and non-amplification, and ERBB2 expression in invasive breast cancer (table 2).	('ERBB2', 'Gene', '2064', (78, 83))	('overexpression', 'PosReg', (84, 98))	('invasive breast cancer', 'Disease', 'MESH:D001943', (310, 332))	('ERBB2', 'Gene', (78, 83))	('ERBB2', 'Gene', (290, 295))	('ERBB2', 'Gene', '2064', (290, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (319, 332))	('invasive breast cancer', 'Disease', (310, 332))	('ERBB2', 'Gene', (243, 248))	('ERBB2', 'Gene', '2064', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('trastuzumab', 'Chemical', 'MESH:D000068878', (19, 30))	('polysomy', 'Var', (233, 241))
14320	19261255	Reported prevalences for chromosome 17 monosomy were typically less than 15%, irrespective of ERBB2 amplification.	('chromosome', 'Gene', (25, 35))	('ERBB2', 'Gene', '2064', (94, 99))	('ERBB2', 'Gene', (94, 99))	('monosomy', 'Var', (39, 47))
14322	19261255	Chromosome 17 polysomy was usually more prevalent in tumours with ERBB2 amplification (10% [1/10]-88% [7/8]) than in tumours without ERBB2 amplification (3 6% [1/28]-55% [33/60]).	('tumours', 'Disease', (117, 124))	('amplification', 'Var', (72, 85))	('ERBB2', 'Gene', (133, 138))	('polysomy', 'Var', (14, 22))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('prevalent', 'Reg', (40, 49))	('ERBB2', 'Gene', '2064', (66, 71))	('Chromosome', 'Var', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('ERBB2', 'Gene', (66, 71))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('ERBB2', 'Gene', '2064', (133, 138))
14323	19261255	In our N9831 clinical trial, we observed polysomy 17 in 58% (865/1488) of ERBB2 amplified tumours and in 36% (70/156) of ERBB2 non-amplified tumours.	('tumours', 'Disease', (141, 148))	('ERBB2', 'Gene', '2064', (74, 79))	('ERBB2', 'Gene', (74, 79))	('amplified', 'Var', (80, 89))	('polysomy 17', 'Var', (41, 52))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('N9831', 'CellLine', 'CVCL:D425', (7, 12))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('ERBB2', 'Gene', '2064', (121, 126))	('ERBB2', 'Gene', (121, 126))	('tumours', 'Disease', (90, 97))
14324	19261255	Because ERBB2 overexpression without gene amplification has been observed in up to 10% of breast tumours, several studies assessed the association between chromosome 17 polysomy and ERBB2 expression in tumours without ERBB2 amplification (tables 1 and 2).	('ERBB2', 'Gene', '2064', (218, 223))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('overexpression', 'PosReg', (14, 28))	('ERBB2', 'Gene', (8, 13))	('tumours', 'Disease', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('breast tumour', 'Phenotype', 'HP:0100013', (90, 103))	('polysomy', 'Var', (169, 177))	('ERBB2', 'Gene', (182, 187))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('breast tumours', 'Disease', 'MESH:D001943', (90, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('ERBB2', 'Gene', '2064', (8, 13))	('ERBB2', 'Gene', '2064', (182, 187))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('ERBB2', 'Gene', (218, 223))	('expression', 'MPA', (188, 198))	('breast tumours', 'Disease', (90, 104))	('tumours', 'Disease', (202, 209))
14325	19261255	Many studies suggest that, at least in a subset of breast carcinoma, increases in ERBB2 copy number that result from polysomy 17 can lead to protein overexpression in the absence of ERBB2 amplification.	('increases', 'PosReg', (69, 78))	('ERBB2', 'Gene', '2064', (82, 87))	('lead to', 'Reg', (133, 140))	('ERBB2', 'Gene', (82, 87))	('breast carcinoma', 'Disease', (51, 67))	('polysomy 17', 'Var', (117, 128))	('breast carcinoma', 'Disease', 'MESH:D001943', (51, 67))	('ERBB2', 'Gene', '2064', (182, 187))	('protein', 'MPA', (141, 148))	('ERBB2', 'Gene', (182, 187))	('copy', 'MPA', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('breast carcinoma', 'Phenotype', 'HP:0003002', (51, 67))	('overexpression', 'PosReg', (149, 163))
14326	19261255	Polysomy 17 is more common in non-amplified tumours with overexpression of ERBB2 (immunohistochemical [IHC] scores of 3+) than in tumours with no or low ERBB2 expression (IHC scores of 0-1+).	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('overexpression', 'PosReg', (57, 71))	('ERBB2', 'Gene', (75, 80))	('Polysomy 17', 'Var', (0, 11))	('ERBB2', 'Gene', '2064', (75, 80))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('tumours', 'Disease', (44, 51))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('ERBB2', 'Gene', '2064', (153, 158))	('common', 'Reg', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('ERBB2', 'Gene', (153, 158))
14327	19261255	In our N9831 study, among 156 patients with ERBB2 non-amplified tumours, there is an association between polysomy 17 and ERBB2 expression.	('ERBB2', 'Gene', (121, 126))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('ERBB2', 'Gene', '2064', (44, 49))	('expression', 'MPA', (127, 137))	('ERBB2', 'Gene', (44, 49))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('patients', 'Species', '9606', (30, 38))	('N9831', 'CellLine', 'CVCL:D425', (7, 12))	('ERBB2', 'Gene', '2064', (121, 126))	('polysomy 17', 'Var', (105, 116))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
14328	19261255	Breast tumours scored as IHC 2-3+ were more likely to be polysomic for chromosome 17 than tumours scored as 0-1+ (p<0 001).	('Breast tumours', 'Disease', 'MESH:D001943', (0, 14))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('IHC 2-3+', 'Var', (25, 33))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours', 'Disease', (7, 14))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))	('Breast tumours', 'Disease', (0, 14))
14330	19261255	Conversely, weak associations between ERBB2 expression and ERBB2 copy number have been observed in other studies of non-amplified tumours.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('expression', 'MPA', (44, 54))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('ERBB2', 'Gene', (59, 64))	('tumours', 'Disease', (130, 137))	('ERBB2', 'Gene', '2064', (59, 64))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('copy number', 'Var', (65, 76))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
14332	19261255	Molecular detection techniques (eg, reverse transcription PCR and isotopic in-situ hybridisation) showed that ERBB2 mRNA expression was not increased in nonamplified breast tumours with polysomy 17, and that amplification of ERBB2 resulted in increased ERBB2 expression, independent of chromosome 17 polysomy.	('breast tumours', 'Disease', 'MESH:D001943', (166, 180))	('ERBB2', 'Gene', '2064', (253, 258))	('ERBB2', 'Gene', '2064', (110, 115))	('ERBB2', 'Gene', (253, 258))	('amplification', 'Var', (208, 221))	('breast tumour', 'Phenotype', 'HP:0100013', (166, 179))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('ERBB2', 'Gene', '2064', (225, 230))	('increased', 'PosReg', (243, 252))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('expression', 'MPA', (259, 269))	('breast tumours', 'Disease', (166, 180))	('ERBB2', 'Gene', (110, 115))	('ERBB2', 'Gene', (225, 230))
14333	19261255	Therefore, in the absence of amplification, polysomy 17 does not seems to result in increased expression of ERBB2 mRNA.	('increased', 'PosReg', (84, 93))	('expression', 'MPA', (94, 104))	('ERBB2', 'Gene', '2064', (108, 113))	('polysomy 17', 'Var', (44, 55))	('ERBB2', 'Gene', (108, 113))
14334	19261255	In summary, whether chromosome 17 polysomy can cause of ERBB2 overexpression in the absence of true ERBB2 amplification is unclear.	('cause', 'Reg', (47, 52))	('ERBB2', 'Gene', '2064', (100, 105))	('ERBB2', 'Gene', '2064', (56, 61))	('overexpression', 'PosReg', (62, 76))	('ERBB2', 'Gene', (100, 105))	('ERBB2', 'Gene', (56, 61))	('polysomy', 'Var', (34, 42))
14335	19261255	Polysomy 17 might cause slight ERBB2 expression (IHC 2+) in instances of gene amplification with FISH ratio 2-4 or 4-6 ERBB2 copies.	('Polysomy 17', 'Var', (0, 11))	('ERBB2', 'Gene', (119, 124))	('ERBB2', 'Gene', '2064', (119, 124))	('cause', 'Reg', (18, 23))	('ERBB2', 'Gene', '2064', (31, 36))	('expression', 'MPA', (37, 47))	('ERBB2', 'Gene', (31, 36))
14336	19261255	An additive effect on gene dosage and protein expression has been seen in scenarios of high polysomy 17 (>=4 chromosome 17 signals per nuclei) with gene duplication or modest gene amplification (ERBB2/CEP17 ratio 2-3).	('ERBB2', 'Gene', (195, 200))	('high polysomy 17', 'Disease', (87, 103))	('ERBB2', 'Gene', '2064', (195, 200))	('gene duplication', 'Var', (148, 164))
14338	19261255	Polysomy 17 has been reported in 41-86% of ERBB2 non-amplified tumours scored as IHC 2+ or 3+.	('tumours', 'Disease', (63, 70))	('Polysomy 17', 'Var', (0, 11))	('ERBB2', 'Gene', '2064', (43, 48))	('ERBB2', 'Gene', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('non-amplified', 'Var', (49, 62))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
14339	19261255	Genomic aberrations recurrent in a specific type of cancer can be important prognostic markers for tumour progression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('Genomic aberrations', 'Var', (0, 19))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
14340	19261255	Because chromosome 17 copy-number alterations have been repeatedly identified in preinvasive and invasive lesions (table 3), aneusomy 17 is a predictor of cancer aggressiveness.	('copy-number alterations', 'Var', (22, 45))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (155, 176))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer aggressiveness', 'Disease', (155, 176))	('neu', 'Gene', '2064', (126, 129))	('aggressiveness', 'Phenotype', 'HP:0000718', (162, 176))	('neu', 'Gene', (126, 129))
14345	19261255	Results are also inconsistent regarding links between polysomy 17 and oestrogen-receptor positivity and tumour size.	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('links', 'Interaction', (40, 45))	('oestrogen-receptor', 'Protein', (70, 88))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('polysomy 17', 'Var', (54, 65))	('tumour', 'Disease', (104, 110))
14346	19261255	Polysomy 17 was found more often in invasive ductal carcinomas than in invasive lobular carcinomas by use of chromogenic in-situ hybridisation.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Polysomy 17', 'Var', (0, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (36, 62))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (71, 98))	('found', 'Reg', (16, 21))	('invasive ductal carcinomas', 'Disease', (36, 62))	('invasive lobular carcinomas', 'Disease', (71, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (80, 98))
14347	19261255	Overall, it seems that aberrations of chromosome 17 copy-number are associated with indicators of poor prognosis in certain groups of patients with breast cancer, and that these associations might be related to differences in the ERBB2 amplification status of the tumour.	('tumour', 'Disease', (264, 270))	('associated', 'Reg', (68, 78))	('ERBB2', 'Gene', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ERBB2', 'Gene', '2064', (230, 235))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('patients', 'Species', '9606', (134, 142))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Disease', (148, 161))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('chromosome 17', 'Gene', (38, 51))	('aberrations', 'Var', (23, 34))
14349	19261255	Results from several studies show that polysomy 17 is regularly seen in tumours with discrepant ERBB2 protein and gene copy number measurements.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('ERBB2', 'Gene', (96, 101))	('ERBB2', 'Gene', '2064', (96, 101))	('seen', 'Reg', (64, 68))	('tumours', 'Disease', (72, 79))	('polysomy 17', 'Var', (39, 50))
14350	19261255	Polysomy 17 (especially highly polysomic cases) seems to cause the inconsistency in ERBB2 amplification defined by gene-copy number versus amplification defined by the ratio of gene-copy number to chromosome-copy number.	('ERBB2', 'Gene', (84, 89))	('Polysomy 17', 'Var', (0, 11))	('gene-copy number', 'Var', (115, 131))	('amplification', 'MPA', (90, 103))	('ERBB2', 'Gene', '2064', (84, 89))
14354	19261255	Reports indicate chromosome correction (chromosome copy number normalisation) as the best method to adjust for ERBB2/neu pseudoamplification due to chromosome 17 polysomy.	('neu', 'Gene', '2064', (117, 120))	('neu', 'Gene', (117, 120))	('polysomy', 'Var', (162, 170))	('ERBB2', 'Gene', (111, 116))	('ERBB2', 'Gene', '2064', (111, 116))
14359	19261255	Preliminary findings suggest that patients with metastatic breast cancer with ERBB2 amplification and chromosome 17 monosomy did not respond to trastuzumab.	('ERBB2', 'Gene', '2064', (78, 83))	('trastuzumab', 'Chemical', 'MESH:D000068878', (144, 155))	('ERBB2', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('amplification', 'Var', (84, 97))	('monosomy', 'Var', (116, 124))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('patients', 'Species', '9606', (34, 42))
14360	19261255	Our results from N9831 further suggest that patients with primary breast cancer with ERBB2/CEP17 ratios greater than 15, most of whom displayed monosomy 17, did not benefit from adjuvant trastuzumab (hazard ratio 1 01).	('N9831', 'CellLine', 'CVCL:D425', (17, 22))	('patients', 'Species', '9606', (44, 52))	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('trastuzumab', 'Chemical', 'MESH:D000068878', (187, 198))	('breast cancer', 'Disease', (66, 79))	('ratios', 'Var', (97, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))
14361	19261255	This implies that aneusomy 17 might be more important in tumours with ERBB2 amplification (ratio greater than or equal to 2) and monosomy 17 (although rare), if gene dosage is the main mechanism of protein overexpression.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('neu', 'Gene', '2064', (19, 22))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumours', 'Disease', (57, 64))	('neu', 'Gene', (19, 22))	('ERBB2', 'Gene', '2064', (70, 75))	('ERBB2', 'Gene', (70, 75))	('monosomy 17', 'Var', (129, 140))	('amplification', 'Var', (76, 89))
14362	19261255	For patients with high ERBB2/CEP17 ratios and monosomy 17, precautions should be taken and absolute gene copy number might be unimportant because ratio alone might not be a reliable indicator of ERBB2 status.	('ERBB2', 'Gene', (23, 28))	('ERBB2', 'Gene', '2064', (23, 28))	('ERBB2', 'Gene', (195, 200))	('ERBB2', 'Gene', '2064', (195, 200))	('monosomy 17', 'Var', (46, 57))	('patients', 'Species', '9606', (4, 12))
14364	19261255	Some researchers hypothesised that polysomy 17 might not have predictive value for trastuzumab therapy and only tumours with true gene amplification respond to trastuzumab therapy.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('polysomy 17', 'Var', (35, 46))	('tumours', 'Disease', (112, 119))	('trastuzumab', 'Chemical', 'MESH:D000068878', (83, 94))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('trastuzumab', 'Chemical', 'MESH:D000068878', (160, 171))
14365	19261255	Findings from two studies suggested that that polysomy of chromosome 17 was associated with ERBB2 overexpression in absence of ERBB2 amplification, indicating that polysomy 17 possibly can be used in clinical assessment of ERBB2 status and treatment prediction for anti-ERBB2 therapies.	('ERBB2', 'Gene', '2064', (92, 97))	('ERBB2', 'Gene', (270, 275))	('ERBB2', 'Gene', (92, 97))	('ERBB2', 'Gene', '2064', (270, 275))	('overexpression', 'PosReg', (98, 112))	('polysomy', 'Var', (46, 54))	('ERBB2', 'Gene', '2064', (223, 228))	('associated', 'Reg', (76, 86))	('ERBB2', 'Gene', (127, 132))	('ERBB2', 'Gene', '2064', (127, 132))	('ERBB2', 'Gene', (223, 228))
14367	19261255	A subset analysis of the CALGB 9840 trial suggested that patients who were FISH-negative and had polysomy 17 (defined as greater than or equal to 2 2 centromere 17 signals) possibly responded to trastuzumab (p=0 048) but did not have significantly longer progression-free and overall survival.	('polysomy 17', 'Var', (97, 108))	('patients', 'Species', '9606', (57, 65))	('trastuzumab', 'Chemical', 'MESH:D000068878', (195, 206))	('responded to trastuzumab', 'MPA', (182, 206))
14369	19261255	These results could be interpreted to mean that polysomy 17 does not predict anti-ERBB2 treatment response, or that polysomy 17 is clinically important in the metastatic setting, but not in the adjuvant setting.	('polysomy', 'Var', (116, 124))	('ERBB2', 'Gene', '2064', (82, 87))	('ERBB2', 'Gene', (82, 87))
14370	19261255	In our N9831 adjuvant trastuzumab trial, we reported a benefit from trastuzumab for patients with ERBB2 amplified tumours (ratio >=2 0) with either polysomy 17 (hazard ratio 0 52) or normal chromosome 17 copy-number (0 37).	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('trastuzumab', 'Chemical', 'MESH:D000068878', (22, 33))	('tumours', 'Disease', (114, 121))	('trastuzumab', 'Chemical', 'MESH:D000068878', (68, 79))	('ERBB2', 'Gene', '2064', (98, 103))	('ERBB2', 'Gene', (98, 103))	('patients', 'Species', '9606', (84, 92))	('amplified', 'Var', (104, 113))	('benefit', 'PosReg', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('polysomy 17', 'Var', (148, 159))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('normal chromosome 17 copy-number', 'Var', (183, 215))	('N9831', 'CellLine', 'CVCL:D425', (7, 12))
14371	19261255	Also, the 423 patients who received chemotherapy alone and had ERBB2 amplified and polysomy 17 tumours had a longer 5-year disease-free survival rate (78%) than the 282 patients who received chemotherapy alone and had ERBB2 amplified and disomy 17 tumours (68%; p=0.04).	('disease-free survival rate', 'CPA', (123, 149))	('ERBB2', 'Gene', '2064', (218, 223))	('longer', 'PosReg', (109, 115))	('disomy 17 tumours', 'Disease', (238, 255))	('ERBB2', 'Gene', (63, 68))	('patients', 'Species', '9606', (14, 22))	('tumours', 'Disease', (248, 255))	('ERBB2', 'Gene', '2064', (63, 68))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('tumours', 'Disease', 'MESH:D009369', (248, 255))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('ERBB2', 'Gene', (218, 223))	('amplified', 'Var', (69, 78))	('patients', 'Species', '9606', (169, 177))	('disomy 17 tumours', 'Disease', 'MESH:D024182', (238, 255))
14372	19261255	Furthermore, our exploratory analyses showed that 5-year disease-free survival rate for patients treated with trastuzumab with ERBB2 normal (non-amplified and IHC 0-2+) tumours was 66% for those with polysomy 17 and 84% for disomy backgrounds.	('disease-free survival', 'CPA', (57, 78))	('disomy', 'Disease', (224, 230))	('disomy', 'Disease', 'MESH:D024182', (224, 230))	('tumours', 'Disease', (169, 176))	('patients', 'Species', '9606', (88, 96))	('trastuzumab', 'Chemical', 'MESH:D000068878', (110, 121))	('polysomy 17', 'Var', (200, 211))	('ERBB2', 'Gene', (127, 132))	('ERBB2', 'Gene', '2064', (127, 132))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', 'MESH:D009369', (169, 176))
14377	19261255	Accumulation of genomic and epigenomic aberrations enables the development of breast cancer pathophysiology.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('epigenomic aberrations', 'Var', (28, 50))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
14379	19261255	Abnormalities of chromosome 17 result in key changes in genes including ERBB2, BRCA1, P53, and TOP2A.	('BRCA1', 'Gene', '672', (79, 84))	('Abnormalities', 'Var', (0, 13))	('BRCA1', 'Gene', (79, 84))	('P53', 'Gene', (86, 89))	('changes', 'Reg', (45, 52))	('ERBB2', 'Gene', '2064', (72, 77))	('TOP2A', 'Gene', '7153', (95, 100))	('ERBB2', 'Gene', (72, 77))	('P53', 'Gene', '7157', (86, 89))	('TOP2A', 'Gene', (95, 100))
14381	19261255	Whole chromosome 17 copy-number alterations are also common in breast cancer, but their clinical relevance is much less defined.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('copy-number alterations', 'Var', (20, 43))	('common', 'Reg', (53, 59))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('Whole chromosome 17', 'Gene', (0, 19))
14385	19261255	Chromosome 17 monosomy is more common in non-invasive and preinvasive cancers than in invasive breast lesions.	('common', 'Reg', (31, 37))	('invasive breast lesions', 'Disease', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('non-invasive', 'Disease', (41, 53))	('Chromosome', 'Var', (0, 10))	('monosomy', 'Var', (14, 22))	('invasive breast lesions', 'Disease', 'MESH:D001941', (86, 109))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
14386	19261255	By contrast, chromosome 17 polysomy is more common in invasive than in non-invasive and preinvasive breast lesions.	('polysomy', 'Var', (27, 35))	('invasive breast lesions', 'Disease', 'MESH:D001941', (91, 114))	('invasive breast lesions', 'Disease', (91, 114))	('common', 'Reg', (44, 50))	('chromosome', 'Var', (13, 23))	('invasive', 'Disease', (54, 62))
14387	19261255	Polysomy of chromosome 17 is also common in cases with equivocal ERBB2 protein expression and ERBB2 gene amplification as well as in cases with discrepant ERBB2 protein and gene copy number measurements.	('Polysomy', 'Var', (0, 8))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (65, 70))	('protein', 'Protein', (71, 78))	('ERBB2', 'Gene', (155, 160))	('ERBB2', 'Gene', '2064', (155, 160))	('ERBB2', 'Gene', '2064', (94, 99))	('common', 'Reg', (34, 40))	('ERBB2', 'Gene', (94, 99))	('amplification', 'MPA', (105, 118))
14388	19261255	Furthermore, ERBB2 overexpression in invasive breast cancer typically results from ERBB2 amplification independent of polysomy 17.	('overexpression', 'PosReg', (19, 33))	('invasive breast cancer', 'Disease', 'MESH:D001943', (37, 59))	('ERBB2', 'Gene', '2064', (13, 18))	('ERBB2', 'Gene', (13, 18))	('ERBB2', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('invasive breast cancer', 'Disease', (37, 59))	('ERBB2', 'Gene', '2064', (83, 88))	('amplification', 'Var', (89, 102))	('results from', 'Reg', (70, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
14389	19261255	Polysomy 17 should be distinguished from true ERBB2 amplification by use of chromosome correction.	('ERBB2', 'Gene', (46, 51))	('ERBB2', 'Gene', '2064', (46, 51))	('Polysomy 17', 'Var', (0, 11))
14390	19261255	Tumours with polysomy 17 seem to be more similar to ERBB2-negative than to ERBB2-positive tumours.	('polysomy 17', 'Var', (13, 24))	('ERBB2-positive tumours', 'Disease', 'MESH:D009369', (75, 97))	('ERBB2', 'Gene', (75, 80))	('ERBB2', 'Gene', '2064', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('ERBB2', 'Gene', '2064', (52, 57))	('ERBB2', 'Gene', (52, 57))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('ERBB2-positive tumours', 'Disease', (75, 97))
14391	19261255	Polysomy 17 in the absence of ERBB2 amplification has not been associated with clinical characteristics of ERBB2-positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('Polysomy 17', 'Var', (0, 11))	('ERBB2', 'Gene', '2064', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('ERBB2', 'Gene', (30, 35))	('ERBB2', 'Gene', (107, 112))	('ERBB2', 'Gene', '2064', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
14399	32490124	Evaluation of breast screening strategies in a high risk breast and ovarian cancer clinic BRCA mutation carriers are more likely to be diagnosed with breast cancer compared to high-risk non-BRCA carriers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (57, 82))	('breast cancer', 'Disease', (150, 163))	('BRCA', 'Gene', '672', (190, 194))	('BRCA', 'Gene', '672', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('BRCA', 'Gene', (190, 194))	('BRCA', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
14401	32490124	In BRCA mutation carriers younger than 40, there were no MRI occult cancers found.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('mutation', 'Var', (8, 16))
14402	32490124	Recent data suggest that BRCA mutation carriers younger than 40 may not benefit from mammography in addition to MRI.	('mutation', 'Var', (30, 38))	('BRCA', 'Gene', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
14404	32490124	631 women comprised the study population; 496 patients had no known mutation (79%), 128 (20%) had a BRCA mutation, and 7 patients had other deleterious mutations.	('patients', 'Species', '9606', (46, 54))	('mutation', 'Var', (105, 113))	('BRCA', 'Gene', '672', (100, 104))	('BRCA', 'Gene', (100, 104))	('women', 'Species', '9606', (4, 9))	('patients', 'Species', '9606', (121, 129))
14405	32490124	BRCA mutation carriers were more likely to have cancers diagnosed after mammogram callbacks (p = 0.0046) and biopsies (p = 0.0026) compared to non-BRCA mutation carriers.	('cancers', 'Disease', (48, 55))	('BRCA', 'Gene', (147, 151))	('BRCA', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (147, 151))	('BRCA', 'Gene', '672', (0, 4))
14406	32490124	BRCA mutation carriers were also more likely to have cancers diagnosed after biopsies following screening MRI (p = 0.045).	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('BRCA', 'Gene', (0, 4))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
14408	32490124	Of the cancers diagnosed after abnormal MRI, 3 were DCIS; all 3 patients had a normal mammogram 4-6 months prior.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (64, 72))	('DCIS', 'Disease', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('MRI', 'Var', (40, 43))	('abnormal MRI', 'Var', (31, 43))
14413	32490124	Germline pathogenic variants in a variety of genes are associated with an increased lifetime risk of breast and gynecologic cancers.	('variants', 'Var', (20, 28))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('breast', 'Disease', (101, 107))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
14414	32490124	Patients with a pathogenic variant in BRCA1, for example, have a lifetime cumulative risk of 72% and 44% for developing breast and ovarian cancer, respectively; for BRCA2 carriers, those risks are 69% and 17%.	('BRCA2', 'Gene', '675', (165, 170))	('pathogenic', 'Reg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA1', 'Gene', (38, 43))	('Patients', 'Species', '9606', (0, 8))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (120, 145))	('BRCA2', 'Gene', (165, 170))	('variant', 'Var', (27, 34))	('BRCA1', 'Gene', '672', (38, 43))
14415	32490124	Although pathogenic variants in BRCA1 and BRCA2 account for the majority of hereditary breast and gynecologic cancers, pathogenic variants in a number of other high and moderate penetrance genes, including DNA mismatch repair genes, TP53, PALB2, ATM, CHEK2, BARD1, BRIP1, CDH1, NBN, NF1, PTEN, RAD51C, RAD51D, and STK11 have also been implicated.	('variants', 'Var', (20, 28))	('PALB2', 'Gene', '79728', (239, 244))	('CHEK2', 'Gene', (251, 256))	('STK11', 'Gene', (314, 319))	('RAD51C', 'Gene', '5889', (294, 300))	('ATM', 'Gene', (246, 249))	('variants', 'Var', (130, 138))	('BRIP1', 'Gene', (265, 270))	('CHEK2', 'Gene', '11200', (251, 256))	('NBN', 'Gene', (278, 281))	('BRCA2', 'Gene', '675', (42, 47))	('RAD51D', 'Gene', '5892', (302, 308))	('PTEN', 'Gene', (288, 292))	('NF1', 'Gene', '4763', (283, 286))	('RAD51C', 'Gene', (294, 300))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('hereditary breast and gynecologic cancers', 'Disease', 'MESH:D061325', (76, 117))	('STK11', 'Gene', '6794', (314, 319))	('TP53', 'Gene', (233, 237))	('NF1', 'Gene', (283, 286))	('BARD1', 'Gene', '580', (258, 263))	('CDH1', 'Gene', '999', (272, 276))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PTEN', 'Gene', '5728', (288, 292))	('BRCA1', 'Gene', '672', (32, 37))	('BARD1', 'Gene', (258, 263))	('BRCA1', 'Gene', (32, 37))	('CDH1', 'Gene', (272, 276))	('PALB2', 'Gene', (239, 244))	('BRIP1', 'Gene', '83990', (265, 270))	('ATM', 'Gene', '472', (246, 249))	('RAD51D', 'Gene', (302, 308))	('BRCA2', 'Gene', (42, 47))	('NBN', 'Gene', '4683', (278, 281))	('TP53', 'Gene', '7157', (233, 237))
14416	32490124	Recent improvements in knowledge and accessibility of genetic testing has enhanced the detection of hereditary breast and ovarian cancer variants, leading to more widespread use of high-risk screening tools and risk-reducing surgeries.	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (100, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('enhanced', 'PosReg', (74, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('variants', 'Var', (137, 145))
14418	32490124	The American Cancer Society specifically recommends that patients with germline pathogenic variants in BRCA 1 or 2 begin breast cancer screening with MRIs at 25 years old and that they add surveillance mammography at 30 years old.	('Cancer', 'Disease', (13, 19))	('patients', 'Species', '9606', (57, 65))	('BRCA 1 or 2', 'Gene', '672;675', (103, 114))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('variants', 'Var', (91, 99))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('BRCA 1 or 2', 'Gene', (103, 114))
14421	32490124	There are a number of studies that address breast cancer screening specifically in patents that carry a pathogenic variant in BRCA, but few assess broader high-risk populations.	('BRCA', 'Gene', '672', (126, 130))	('pathogenic', 'Reg', (104, 114))	('variant', 'Var', (115, 122))	('address breast cancer', 'Disease', 'MESH:D001943', (35, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('BRCA', 'Gene', (126, 130))	('address breast cancer', 'Disease', (35, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
14425	32490124	Patients followed in this clinic were deemed to be high risk if they carried a known genetic mutation, met clinical criteria for a potential hereditary cancer syndrome, had a first or second degree relative with ovarian cancer, or met high risk breast criteria (over 20-25% lifetime risk of breast cancer).	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('breast cancer', 'Disease', (291, 304))	('hereditary cancer syndrome', 'Disease', (141, 167))	('hereditary cancer syndrome', 'Disease', 'MESH:D061325', (141, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (212, 226))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutation', 'Var', (93, 101))	('ovarian cancer', 'Disease', (212, 226))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
14431	32490124	Characteristics of BRCA gene mutation carriers with screening-detected cancers were then examined granularly.	('mutation', 'Var', (29, 37))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('BRCA', 'Gene', '672', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('BRCA', 'Gene', (19, 23))
14432	32490124	Univariate analyses were used to compare baseline patient characteristics and breast cancer screening outcomes by BRCA mutation carrier status.	('mutation carrier', 'Var', (119, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('carrier', 'Var', (128, 135))	('BRCA', 'Gene', '672', (114, 118))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('BRCA', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('patient', 'Species', '9606', (50, 57))	('breast cancer', 'Disease', (78, 91))
14434	32490124	Six hundred thirty-one patients (46.8%) were deemed to be at high-risk for breast cancer; of the high-risk patients, 496 patients had no known pathogenic variant (79%), 128 (20%) had a pathogenic variant in BRCA1 or BRCA2, and 7 patients had other pathogenic variants in known breast cancer genes (1 TP53, 1 PALB2, 3 ATM, 2 CHEK2).	('patients', 'Species', '9606', (229, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('PALB2', 'Gene', (308, 313))	('CHEK2', 'Gene', '11200', (324, 329))	('ATM', 'Gene', '472', (317, 320))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', (300, 304))	('BRCA2', 'Gene', '675', (216, 221))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (277, 290))	('PALB2', 'Gene', '79728', (308, 313))	('pathogenic', 'Reg', (185, 195))	('patients', 'Species', '9606', (107, 115))	('ATM', 'Gene', (317, 320))	('TP53', 'Gene', '7157', (300, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('BRCA1', 'Gene', '672', (207, 212))	('variant', 'Var', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('patients', 'Species', '9606', (121, 129))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('BRCA1', 'Gene', (207, 212))	('breast cancer', 'Disease', (75, 88))	('CHEK2', 'Gene', (324, 329))	('BRCA2', 'Gene', (216, 221))
14436	32490124	Those with a known BRCA variants were more likely to have had genetic testing at our institution versus those who are not known to have a BRCA pathogenic variant (non-BRCA carriers) (30% vs 45%; p = 0.002).	('variants', 'Var', (24, 32))	('BRCA', 'Gene', '672', (138, 142))	('BRCA', 'Gene', (138, 142))	('BRCA', 'Gene', '672', (19, 23))	('BRCA', 'Gene', (19, 23))	('BRCA', 'Gene', '672', (167, 171))	('BRCA', 'Gene', (167, 171))
14438	32490124	Additionally, BRCA mutation carriers were more likely to undergo risk-reducing mastectomy (45% vs 14%; p < 0.001) and risk-reducing bilateral salpingo-oophorectomy (56% vs 8.9%; p < 0.001) compared to non-BRCA mutation carriers.	('mutation', 'Var', (19, 27))	('BRCA', 'Gene', '672', (14, 18))	('BRCA', 'Gene', (14, 18))	('mastectomy', 'Disease', (79, 89))	('BRCA', 'Gene', '672', (205, 209))	('BRCA', 'Gene', (205, 209))
14447	32490124	However, patients with a pathogenic variant in BRCA were more likely to have cancers diagnosed after mammogram callbacks (15% vs 3.8%; p = 0.0046) and biopsies (50% vs 13%; p = 0.0026) compared to non-BRCA mutation carriers.	('patients', 'Species', '9606', (9, 17))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('variant', 'Var', (36, 43))	('cancers', 'Disease', (77, 84))	('BRCA', 'Gene', '672', (201, 205))	('BRCA', 'Gene', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BRCA', 'Gene', '672', (47, 51))	('pathogenic', 'Reg', (25, 35))	('BRCA', 'Gene', (47, 51))
14448	32490124	BRCA mutation carriers were also more likely to have cancers diagnosed after biopsies following screening MRI (27% vs 11%; p = 0.045), but rates of MRI callbacks, biopsies, and cancers diagnosed after callbacks was not statistically significantly different between the two groups (all p > 0.05).	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('BRCA', 'Gene', (0, 4))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
14454	32490124	Women with BRCA mutations in our patient population were more likely to have breast cancers diagnosed after both MRI and mammogram compared to patients with family history alone.	('breast cancers', 'Disease', 'MESH:D001943', (77, 91))	('breast cancers', 'Disease', (77, 91))	('patient', 'Species', '9606', (33, 40))	('Women', 'Species', '9606', (0, 5))	('patient', 'Species', '9606', (143, 150))	('BRCA', 'Gene', '672', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('BRCA', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancers', 'Phenotype', 'HP:0003002', (77, 91))
14458	32490124	A recent study found the false positive recall rates following mammogram or MRI to be 22.2% and 26.3% in BRCA mutation carriers and others at increased risk without a mutation, respectively.	('BRCA', 'Gene', '672', (105, 109))	('mutation', 'Var', (110, 118))	('BRCA', 'Gene', (105, 109))
14459	32490124	This study aimed to look specifically at cancers diagnosed in BRCA mutation carriers under the age of 40 in light of recent literature that calls into question the added utility of screening mammography in this population.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutation', 'Var', (67, 75))	('BRCA', 'Gene', '672', (62, 66))	('BRCA', 'Gene', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
14463	32490124	This group found, in a population of BRCA mutation carriers, that 3 of 61 cancers were detected only on mammogram (with none in those younger than 40) and that the addition of mammogram to MRI resulted mostly in the detection of a small number of DCIS cases that were occult on MRI.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('mutation', 'Var', (42, 50))	('BRCA', 'Gene', '672', (37, 41))	('BRCA', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DCIS', 'Disease', (247, 251))
14464	32490124	A primary argument for utilizing mammography (in addition to MRI) in breast cancer screening for BRCA mutation carriers is that it is better than MRI for identifying DCIS.	('mutation', 'Var', (102, 110))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('BRCA', 'Gene', '672', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('BRCA', 'Gene', (97, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))
14467	32490124	These results are also supported by a meta-analysis of four breast cancer screening trials of high risk women that found only one invasive cancer detected by mammography alone in BRCA1 mutation carriers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('breast cancer', 'Disease', (60, 73))	('BRCA1', 'Gene', (179, 184))	('cancer', 'Disease', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutation', 'Var', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1', 'Gene', '672', (179, 184))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('women', 'Species', '9606', (104, 109))	('cancer', 'Disease', (139, 145))
14470	32490124	BRCA mutation carriers may be particularly susceptible to the cumulative effect of yearly mammograms, as they have impaired repair of the double-strand DNA breaks that are caused by low-dose X-rays.	('repair', 'MPA', (124, 130))	('BRCA', 'Gene', (0, 4))	('impaired', 'NegReg', (115, 123))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
14474	32490124	In conclusion, patients with a pathogenic variant in BRCA 1 or 2 were more likely to be diagnosed with breast cancer following all screening modalities compared to high-risk non-BRCA carriers.	('pathogenic', 'Reg', (31, 41))	('BRCA', 'Gene', '672', (53, 57))	('patients', 'Species', '9606', (15, 23))	('BRCA', 'Gene', '672', (178, 182))	('BRCA 1 or 2', 'Gene', (53, 64))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('BRCA', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('BRCA 1 or 2', 'Gene', '672;675', (53, 64))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('BRCA', 'Gene', (53, 57))	('variant', 'Var', (42, 49))
14476	32490124	In BRCA mutation carriers younger than 40 years old, there were no MRI occult cancers found.	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('mutation', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
14477	32490124	These findings begin to address the question of whether MRI alone is a reasonable breast cancer screening strategy for BRCA mutation carriers under 40 years old.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('mutation', 'Var', (124, 132))	('BRCA', 'Gene', '672', (119, 123))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('BRCA', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
14491	30527351	Mutations in tumor suppressor genes BRCA1 and BRCA2 are two genetic aberrations that predispose an individual to breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (13, 18))	('aberrations', 'Disease', (68, 79))	('BRCA1', 'Gene', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('BRCA2', 'Gene', (46, 51))	('breast cancer', 'Disease', (113, 126))	('aberrations', 'Disease', 'MESH:D002869', (68, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('BRCA2', 'Gene', '675', (46, 51))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('BRCA1', 'Gene', '672', (36, 41))	('predispose', 'Reg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
14494	30527351	In this report, we present two cases: 1) a 32-year-old trans woman with a family history of breast cancer and a germline BRCA2 mutation; and 2) a 29-year-old trans man with a strong family history of breast cancer who was incidentally diagnosed with ductal carcinoma in-situ (DCIS) upon chest reconstruction surgery.	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (250, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('ductal carcinoma in-situ', 'Disease', (250, 274))	('BRCA2', 'Gene', '675', (121, 126))	('woman', 'Species', '9606', (61, 66))	('man', 'Species', '9606', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (250, 266))	('breast cancer', 'Disease', (92, 105))	('ductal carcinoma in-situ', 'Disease', 'MESH:D002285', (250, 274))	('mutation', 'Var', (127, 135))	('man', 'Species', '9606', (164, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BRCA2', 'Gene', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
14500	30527351	The individual was determined to carry the same deleterious BRCA2 mutation.	('BRCA2', 'Gene', (60, 65))	('BRCA2', 'Gene', '675', (60, 65))	('mutation', 'Var', (66, 74))
14507	30527351	Given her family history and BRCA2 positivity, the individual opted for primary breast cancer risk reduction with bilateral skin sparing mastectomies.	('BRCA2', 'Gene', (29, 34))	('positivity', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('skin sparing', 'Phenotype', 'HP:0000973', (124, 136))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('BRCA2', 'Gene', '675', (29, 34))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
14548	30527351	The lifetime breast cancer risk for women is 12%, whereas 72% of women with a BRCA1 mutation and 69% of women with a BRCA2 mutation will develop breast cancer by the age of 80.	('women', 'Species', '9606', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA2', 'Gene', '675', (117, 122))	('BRCA1', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('women', 'Species', '9606', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('BRCA1', 'Gene', '672', (78, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('BRCA2', 'Gene', (117, 122))	('develop', 'PosReg', (137, 144))	('women', 'Species', '9606', (104, 109))	('mutation', 'Var', (84, 92))
14549	30527351	Male breast cancer cases are more often associated with BRCA2 than BRCA1 mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('Male breast cancer', 'Disease', (0, 18))	('BRCA2', 'Gene', '675', (56, 61))	('Male breast cancer', 'Disease', 'MESH:D018567', (0, 18))	('BRCA1', 'Gene', '672', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('associated', 'Reg', (40, 50))	('BRCA2', 'Gene', (56, 61))	('mutations', 'Var', (73, 82))	('BRCA1', 'Gene', (67, 72))
14550	30527351	Male BRCA2 carriers have a 6.8% lifetime risk compared to 0.1% in the normal male population.	('BRCA2', 'Gene', '675', (5, 10))	('carriers', 'Var', (11, 19))	('BRCA2', 'Gene', (5, 10))
14555	30527351	In the trans woman described here, it is reasonable to assume that the germline BRCA2 mutation puts her at a 6.8% risk for developing breast cancer, and her risk is possibly further increased by GAHT.	('breast cancer', 'Disease', (134, 147))	('BRCA2', 'Gene', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('woman', 'Species', '9606', (13, 18))	('BRCA2', 'Gene', '675', (80, 85))	('mutation', 'Var', (86, 94))	('GAHT', 'Chemical', '-', (195, 199))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
14558	30527351	BRCA2 mutation carriers are also at risk of developing pancreatic and prostate cancer.	('BRCA2', 'Gene', '675', (0, 5))	('pancreatic and prostate cancer', 'Disease', 'MESH:D010190', (55, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('mutation', 'Var', (6, 14))	('BRCA2', 'Gene', (0, 5))
14609	30527351	In this report we present two cases: a 32-year old trans woman with a family history of breast cancer and a germline BRCA2 mutation and a 29-year old trans man with a family history of male breast cancer who was incidentally diagnosed with ductal carcinoma in-situ (DCIS) upon chest reconstruction surgery.	('mutation', 'Var', (123, 131))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA2', 'Gene', (117, 122))	('male breast cancer', 'Disease', 'MESH:D018567', (185, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (240, 264))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ductal carcinoma in-situ', 'Disease', (240, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('man', 'Species', '9606', (156, 159))	('BRCA2', 'Gene', '675', (117, 122))	('male breast cancer', 'Disease', (185, 203))	('woman', 'Species', '9606', (57, 62))	('man', 'Species', '9606', (59, 62))	('ductal carcinoma in-situ', 'Disease', 'MESH:D002285', (240, 264))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (240, 256))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
14709	28343309	Breast cancer detection and tumor characteristics in BRCA1 and BRCA2 mutation carriers To describe imaging findings, detection rates and tumor characteristics of breast cancers in a large series of patients with BRCA1 and BRCA2 mutations to potentially streamline screening strategies.	('tumor', 'Disease', (28, 33))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('patients', 'Species', '9606', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancers', 'Disease', 'MESH:D001943', (162, 176))	('breast cancers', 'Disease', (162, 176))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('BRCA2', 'Gene', (63, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (162, 176))	('BRCA2', 'Gene', (222, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('BRCA2', 'Gene', '675', (63, 68))	('tumor', 'Disease', (137, 142))	('mutations', 'Var', (228, 237))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('BRCA2', 'Gene', '675', (222, 227))	('BRCA1', 'Gene', '672', (212, 217))	('BRCA1', 'Gene', (212, 217))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('BRCA1', 'Gene', '672', (53, 58))	('Breast cancer', 'Disease', (0, 13))	('BRCA1', 'Gene', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
14710	28343309	An IRB-approved, HIPAA-compliant retrospective analysis of 496 BRCA mutation carriers diagnosed with breast carcinoma from 1999-2013 was performed.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('BRCA', 'Gene', '672', (63, 67))	('breast carcinoma', 'Phenotype', 'HP:0003002', (101, 117))	('mutation', 'Var', (68, 76))	('BRCA', 'Gene', (63, 67))	('breast carcinoma', 'Disease', (101, 117))	('breast carcinoma', 'Disease', 'MESH:D001943', (101, 117))
14712	28343309	Tumors in BRCA1 mutation carriers exhibited significantly higher nuclear and histological grade compared to BRCA2 (p<0.001).	('BRCA2', 'Gene', (108, 113))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutation', 'Var', (16, 24))	('BRCA1', 'Gene', '672', (10, 15))	('BRCA2', 'Gene', '675', (108, 113))	('BRCA1', 'Gene', (10, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (58, 64))
14713	28343309	Triple-negative tumors were more frequent in BRCA1 mutation carriers, whereas hormone receptor positive tumors were more frequent in BRCA2 mutation carriers (p<0.001).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BRCA1', 'Gene', '672', (45, 50))	('hormone receptor', 'Gene', '3164', (78, 94))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('BRCA2', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (104, 110))	('BRCA1', 'Gene', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mutation', 'Var', (51, 59))	('BRCA2', 'Gene', '675', (133, 138))	('tumors', 'Disease', (16, 22))	('hormone receptor', 'Gene', (78, 94))
14714	28343309	BRCA2 mutation carriers more frequently presented with ductal carcinoma in situ (DCIS) alone 14% (35/246) and cancers more frequently exhibiting calcifications (p<0.001).	('BRCA2', 'Gene', '675', (0, 5))	('calcifications', 'Disease', 'MESH:D002114', (145, 159))	('cancers', 'Disease', (110, 117))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('calcifications', 'Disease', (145, 159))	('presented', 'Reg', (40, 49))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (55, 79))	('ductal carcinoma in situ', 'Disease', (55, 79))	('BRCA2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (55, 79))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
14715	28343309	Mammography detected fewer cancers in BRCA1 mutation carriers compared to BRCA2 (p=0.04): 81% (186/231) BRCA1 vs. 89% (212/237) BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutation', 'Var', (44, 52))	('BRCA2', 'Gene', (128, 133))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA2', 'Gene', (74, 79))	('BRCA1', 'Gene', (38, 43))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA1', 'Gene', (104, 109))	('BRCA2', 'Gene', '675', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('fewer', 'NegReg', (21, 26))	('BRCA1', 'Gene', '672', (38, 43))	('cancers', 'Disease', (27, 34))
14719	28343309	Breast cancers in BRCA1 mutation carriers are associated with more aggressive tumor characteristics compared to BRCA2 and are less well seen on mammography.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('BRCA1', 'Gene', '672', (18, 23))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('BRCA1', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('BRCA2', 'Gene', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('Breast cancers', 'Disease', (0, 14))	('mutation', 'Var', (24, 32))	('aggressive tumor', 'Disease', 'MESH:D001523', (67, 83))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('BRCA2', 'Gene', '675', (112, 117))	('aggressive tumor', 'Disease', (67, 83))
14721	28343309	Thus, the omission of mammography in BRCA1 mutation carriers screened with MRI can be considered.	('mutation', 'Var', (43, 51))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
14722	28343309	Patients with BRCA1 and BRCA2 mutations are genetically predisposed for developing breast cancer.	('BRCA1', 'Gene', '672', (14, 19))	('BRCA2', 'Gene', '675', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRCA1', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('predisposed', 'Reg', (56, 67))	('breast cancer', 'Disease', (83, 96))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('mutations', 'Var', (30, 39))	('BRCA2', 'Gene', (24, 29))
14729	28343309	BRCA1 carriers often present with more aggressive tumors, which are harder to detect and characterize on mammography (e.g., triple negative cancers).	('BRCA1', 'Gene', (0, 5))	('present', 'Reg', (21, 28))	('aggressive tumors', 'Disease', 'MESH:D001523', (39, 56))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('aggressive tumors', 'Disease', (39, 56))	('cancers', 'Disease', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('BRCA1', 'Gene', '672', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('carriers', 'Var', (6, 14))
14730	28343309	In contrast, BRCA2 carriers are more likely to present with ductal carcinoma in situ (DCIS), which often develops microcalcifications and is more likely to be detected on mammography.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (60, 84))	('ductal carcinoma in situ', 'Disease', (60, 84))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (60, 84))	('carriers', 'Var', (19, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('calcifications', 'Disease', 'MESH:D002114', (119, 133))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('calcifications', 'Disease', (119, 133))	('BRCA2', 'Gene', (13, 18))	('BRCA2', 'Gene', '675', (13, 18))
14731	28343309	In light of the limited sensitivity of mammography in mutation carriers particularly for those with the BRCA1 mutation and concern for potential radiation carcinogenesis, the possibility of eliminating mammography, particularly in younger women, has been suggested but not yet implemented.	('women', 'Species', '9606', (239, 244))	('BRCA1', 'Gene', (104, 109))	('mutation', 'Var', (110, 118))	('BRCA1', 'Gene', '672', (104, 109))
14732	28343309	The purpose of this study was to describe the imaging findings, detection rates and tumor characteristics of breast cancers in a large series of patients with BRCA1 and BRCA2 mutations to potentially streamline screening strategies.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('breast cancers', 'Disease', 'MESH:D001943', (109, 123))	('BRCA2', 'Gene', (169, 174))	('breast cancers', 'Disease', (109, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA1', 'Gene', '672', (159, 164))	('tumor', 'Disease', (84, 89))	('BRCA2', 'Gene', '675', (169, 174))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('mutations', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA1', 'Gene', (159, 164))	('breast cancers', 'Phenotype', 'HP:0003002', (109, 123))
14736	28343309	The study population therefore comprised 496 patients: 250 BRCA1 and 246 BRCA2 mutation carriers.	('BRCA2', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (73, 78))	('patients', 'Species', '9606', (45, 53))	('mutation', 'Var', (79, 87))	('BRCA1 and 2', 'Gene', '672;675', (59, 70))
14743	28343309	Mean was used to summarize the tumor size and the Wilcoxon test was used to compare the distribution of tumor size between BRCA1 and 2 mutation carriers.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (104, 109))	('BRCA1 and 2', 'Gene', '672;675', (123, 134))	('mutation', 'Var', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
14745	28343309	The population was evenly divided between BRCA1 50.4% (250/496) and BRCA2 mutation carriers 49.6% (246/496).	('BRCA1', 'Gene', '672', (42, 47))	('mutation', 'Var', (74, 82))	('BRCA2', 'Gene', '675', (68, 73))	('BRCA1', 'Gene', (42, 47))	('BRCA2', 'Gene', (68, 73))
14746	28343309	Age at diagnosis ranged from 24 to 82 years with a mean of 44.1 years in BRCA1 mutation carriers and 45.1 years in BRCA2 mutation carriers.	('BRCA2', 'Gene', (115, 120))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA2', 'Gene', '675', (115, 120))	('mutation', 'Var', (79, 87))	('BRCA1', 'Gene', (73, 78))
14750	28343309	BRCA1 mutation carriers more often had invasive ductal carcinomas and triple-negative tumors compared to BRCA2 mutation carriers who more often had hormone receptor positive tumors including invasive lobular carcinomas (p<0.001 for each comparison).	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (39, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('invasive lobular carcinomas', 'Disease', (191, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('BRCA2', 'Gene', (105, 110))	('hormone receptor', 'Gene', '3164', (148, 164))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (174, 180))	('invasive ductal carcinomas', 'Disease', (39, 65))	('tumors', 'Disease', (86, 92))	('BRCA2', 'Gene', '675', (105, 110))	('BRCA1', 'Gene', '672', (0, 5))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (200, 218))	('BRCA1', 'Gene', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('hormone receptor', 'Gene', (148, 164))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (191, 218))	('mutation', 'Var', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
14751	28343309	Tumors in BRCA1 mutation carriers were also associated with a significantly higher nuclear and histological grade (p<0.001).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutation', 'Var', (16, 24))	('BRCA1', 'Gene', '672', (10, 15))	('BRCA1', 'Gene', (10, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (76, 82))
14752	28343309	BRCA2 mutation carriers more frequently presented with DCIS alone, 15% (36/246), whereas BRCA1 mutation carriers presented with DCIS alone in 9% (23/250) (p=0.0026).	('BRCA2', 'Gene', '675', (0, 5))	('DCIS', 'Disease', (55, 59))	('presented', 'Reg', (40, 49))	('BRCA1', 'Gene', (89, 94))	('mutation', 'Var', (6, 14))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('BRCA2', 'Gene', (0, 5))	('BRCA1', 'Gene', '672', (89, 94))
14755	28343309	There was no statistically significant difference in the number of patients with positive axillary lymph nodes at time of diagnosis: 27% (59/218) BRCA1 mutation carriers vs. 35% (70/200) BRCA2 mutation carriers (p=0.08).	('patients', 'Species', '9606', (67, 75))	('BRCA2', 'Gene', (187, 192))	('BRCA1', 'Gene', '672', (146, 151))	('BRCA1', 'Gene', (146, 151))	('BRCA2', 'Gene', '675', (187, 192))	('mutation', 'Var', (152, 160))
14758	28343309	Of the patients who developed interval cancers, 28/43 (65%) were BRCA1 mutation carriers and 15/43 (35%) were BRCA2 mutation carriers.	('BRCA1', 'Gene', '672', (65, 70))	('interval cancers', 'Disease', (30, 46))	('BRCA2', 'Gene', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('mutation', 'Var', (71, 79))	('interval cancers', 'Disease', 'MESH:D009369', (30, 46))	('BRCA1', 'Gene', (65, 70))	('BRCA2', 'Gene', '675', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (7, 15))
14767	28343309	Mammography detected significantly fewer cancers in BRCA1 mutation carriers compared to BRCA2 mutation carriers (p= 0.011): 81% (186/231) BRCA1 vs. 89%% (212/237) BRCA2.	('fewer', 'NegReg', (35, 40))	('BRCA1', 'Gene', '672', (138, 143))	('BRCA2', 'Gene', (163, 168))	('BRCA1', 'Gene', '672', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('BRCA2', 'Gene', (88, 93))	('BRCA1', 'Gene', (138, 143))	('BRCA1', 'Gene', (52, 57))	('mutation', 'Var', (58, 66))	('BRCA2', 'Gene', '675', (163, 168))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('BRCA2', 'Gene', '675', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
14770	28343309	Detection of cancers by mammography in BRCA2 mutation patients was also not significantly different by age: 92% (73/79) of the cancers were detected on mammography in patients aged 40 years or younger and 88% (139/158) of the cancers in women over 40 years (p=0.04).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (127, 134))	('BRCA2', 'Gene', (39, 44))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (167, 175))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Disease', (226, 233))	('mutation', 'Var', (45, 53))	('BRCA2', 'Gene', '675', (39, 44))	('women', 'Species', '9606', (237, 242))	('cancers', 'Disease', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
14773	28343309	Cancers in BRCA2 carriers exhibited calcifications on mammography more frequently compared to BRCA1 carriers (p<0.001).	('BRCA2', 'Gene', '675', (11, 16))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('BRCA1', 'Gene', '672', (94, 99))	('calcifications', 'Disease', 'MESH:D002114', (36, 50))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('calcifications', 'Disease', (36, 50))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('BRCA1', 'Gene', (94, 99))	('carriers', 'Var', (17, 25))	('exhibited', 'Reg', (26, 35))	('BRCA2', 'Gene', (11, 16))
14774	28343309	Enhancement patterns on MRI did not significantly differ between BRCA1 and BRCA2 mutation carriers (p>0.05).	('BRCA1', 'Gene', '672', (65, 70))	('BRCA1', 'Gene', (65, 70))	('mutation', 'Var', (81, 89))	('BRCA2', 'Gene', (75, 80))	('BRCA2', 'Gene', '675', (75, 80))
14776	28343309	The most commonly recognized gene mutations are BRCA1 and BRCA2.	('BRCA1', 'Gene', '672', (48, 53))	('BRCA2', 'Gene', '675', (58, 63))	('BRCA1', 'Gene', (48, 53))	('BRCA2', 'Gene', (58, 63))	('mutations', 'Var', (34, 43))
14780	28343309	In our study, BRCA1 carriers were more likely to develop invasive ductal carcinomas with high nuclear and histological grade, and particularly triple negative cancers.	('cancers', 'Disease', (159, 166))	('BRCA1', 'Gene', '672', (14, 19))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (57, 83))	('develop', 'PosReg', (49, 56))	('BRCA1', 'Gene', (14, 19))	('invasive ductal carcinomas', 'Disease', (57, 83))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('carriers', 'Var', (20, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
14783	28343309	Hormone receptor positive tumors with a lower histological and nuclear grade were more frequently seen in BRCA2 mutation carriers.	('carriers', 'Reg', (121, 129))	('mutation', 'Var', (112, 120))	('BRCA2', 'Gene', '675', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Hormone receptor', 'Gene', '3164', (0, 16))	('BRCA2', 'Gene', (106, 111))	('Hormone receptor', 'Gene', (0, 16))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('seen', 'Reg', (98, 102))	('tumors', 'Disease', (26, 32))
14784	28343309	BRCA2 carriers were also more likely to present with pure DCIS or DCIS adjacent to their invasive cancers and more likely to have calcifications on mammography.	('BRCA2', 'Gene', '675', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pure DCIS', 'Disease', (53, 62))	('invasive cancers', 'Disease', 'MESH:D009362', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('DCIS', 'Disease', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('calcifications', 'Disease', (130, 144))	('invasive cancers', 'Disease', (89, 105))	('calcifications', 'Disease', 'MESH:D002114', (130, 144))	('BRCA2', 'Gene', (0, 5))	('carriers', 'Var', (6, 14))
14785	28343309	This study of 496 breast cancer patients carrying BRCA1 or BRCA2 mutations is, to our knowledge, the largest study describing the imaging and tumor characteristics in these patients.	('BRCA2', 'Gene', '675', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BRCA1', 'Gene', (50, 55))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('patients', 'Species', '9606', (173, 181))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('tumor', 'Disease', (142, 147))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('BRCA2', 'Gene', (59, 64))	('BRCA1', 'Gene', '672', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('mutations', 'Var', (65, 74))
14786	28343309	Our results are consistent with previous studies: MRI was equally sensitive in BRCA1 as well as BRCA2 mutation carriers with cancer detection of 99%.	('BRCA1', 'Gene', '672', (79, 84))	('mutation', 'Var', (102, 110))	('BRCA2', 'Gene', '675', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRCA1', 'Gene', (79, 84))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('BRCA2', 'Gene', (96, 101))
14787	28343309	On the other hand, mammography detected significantly fewer cancers in patients with BRCA1 mutation than in patients with BRCA2 mutation (81% vs. 89%) again likely due to lack of calcifications and higher incidence of aggressive tumors, which often present with benign mammographic features.	('mutation', 'Var', (91, 99))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('BRCA1', 'Gene', (85, 90))	('aggressive tumors', 'Disease', 'MESH:D001523', (218, 235))	('cancers', 'Disease', (60, 67))	('patients', 'Species', '9606', (71, 79))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('aggressive tumors', 'Disease', (218, 235))	('calcifications', 'Disease', (179, 193))	('BRCA2', 'Gene', (122, 127))	('fewer', 'NegReg', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('calcifications', 'Disease', 'MESH:D002114', (179, 193))	('patients', 'Species', '9606', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('BRCA1', 'Gene', '672', (85, 90))	('BRCA2', 'Gene', '675', (122, 127))
14792	28343309	Obdeijn focused on BRCA1 mutation carriers and found only 2 of 94 tumors detected by mammography alone and both were patients with DCIS over 40.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('BRCA1', 'Gene', '672', (19, 24))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('patients', 'Species', '9606', (117, 125))	('BRCA1', 'Gene', (19, 24))
14793	28343309	Heijnsdijk assessed a screening population of 1275 mutation carriers and found only one invasive tumor in the BRCA1 subgroup below the age of 40 detected by mammography alone.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRCA1', 'Gene', '672', (110, 115))	('BRCA1', 'Gene', (110, 115))	('invasive tumor', 'Disease', (88, 102))	('mutation', 'Var', (51, 59))	('invasive tumor', 'Disease', 'MESH:D009369', (88, 102))
14799	28343309	Rijnsburger demonstrated significantly better sensitivity of mammography in BRCA2 mutation carriers than BRCA1, due to the higher proportion of DCIS in that population.	('BRCA1', 'Gene', (105, 110))	('BRCA2', 'Gene', (76, 81))	('mammography', 'Disease', (61, 72))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('mutation', 'Var', (82, 90))	('BRCA1', 'Gene', '672', (105, 110))	('BRCA2', 'Gene', '675', (76, 81))	('sensitivity', 'MPA', (46, 57))	('better', 'PosReg', (39, 45))
14802	28343309	Our findings in this hitherto unparalleled large series of high risk patients with breast cancer add to and support prior evidence that mammography in BRCA1 mutation carriers adds minimal benefit to MRI.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRCA1', 'Gene', '672', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('mutation', 'Var', (157, 165))	('breast cancer', 'Disease', (83, 96))	('BRCA1', 'Gene', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('patients', 'Species', '9606', (69, 77))
14812	28343309	In conclusion, this study of breast imaging in 496 BRCA mutation carriers with breast cancer overall confirms data from multiple smaller studies: Breast cancers in BRCA1 mutation carriers are associated with more aggressive tumor characteristics compared to BRCA2 mutation carriers and BRCA2 mutation carriers are more likely to present with DCIS alone or DCIS adjacent to the invasive cancer.	('BRCA2', 'Gene', '675', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('DCIS', 'Phenotype', 'HP:0030075', (356, 360))	('BRCA1', 'Gene', (164, 169))	('breast cancer', 'Disease', (79, 92))	('invasive cancer', 'Disease', (377, 392))	('BRCA', 'Gene', (286, 290))	('aggressive tumor', 'Disease', (213, 229))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('invasive cancer', 'Disease', 'MESH:D009362', (377, 392))	('Breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('BRCA', 'Gene', '672', (164, 168))	('mutation', 'Var', (170, 178))	('BRCA2', 'Gene', (286, 291))	('BRCA', 'Gene', '672', (51, 55))	('BRCA', 'Gene', '672', (258, 262))	('Breast cancers', 'Disease', (146, 160))	('BRCA', 'Gene', (164, 168))	('BRCA', 'Gene', (51, 55))	('DCIS alone', 'Disease', (342, 352))	('BRCA', 'Gene', (258, 262))	('BRCA2', 'Gene', '675', (286, 291))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('BRCA2', 'Gene', (258, 263))	('DCIS', 'Disease', (356, 360))	('DCIS', 'Phenotype', 'HP:0030075', (342, 346))	('aggressive tumor', 'Disease', 'MESH:D001523', (213, 229))	('BRCA', 'Gene', '672', (286, 290))	('Breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('BRCA1', 'Gene', '672', (164, 169))
14813	28343309	MRI is very sensitive in both BRCA subgroups, whereas mammography detects more cancers in BRCA2 mutation carriers.	('cancers', 'Disease', (79, 86))	('BRCA2', 'Gene', (90, 95))	('BRCA', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carriers', 'Reg', (105, 113))	('mutation', 'Var', (96, 104))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('BRCA', 'Gene', '672', (30, 34))
14814	28343309	Similar to other studies, we demonstrated minimal benefit of mammography in BRCA1 mutation carriers and we believe that mammography could be omitted in those having screening MRI.	('mutation', 'Var', (82, 90))	('BRCA1', 'Gene', (76, 81))	('BRCA1', 'Gene', '672', (76, 81))
14816	28343309	Eliminating mammograms in BRCA1 mutation carriers would reduce radiation exposure in these potentially radiosensitive patients, spare additional potential anxiety from mammography examinations, and reduce costs without negatively affecting patient outcome.	('reduce', 'NegReg', (198, 204))	('anxiety', 'Disease', (155, 162))	('anxiety', 'Phenotype', 'HP:0000739', (155, 162))	('BRCA1', 'Gene', (26, 31))	('costs', 'MPA', (205, 210))	('patient', 'Species', '9606', (240, 247))	('reduce', 'NegReg', (56, 62))	('BRCA1', 'Gene', '672', (26, 31))	('anxiety', 'Disease', 'MESH:D001008', (155, 162))	('patient', 'Species', '9606', (118, 125))	('mutation', 'Var', (32, 40))	('patients', 'Species', '9606', (118, 126))
14824	28382094	Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001).	('high', 'Var', (29, 33))	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('HER2', 'Gene', '2064', (79, 83))	('breast cancers', 'Disease', (105, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('associated', 'Reg', (63, 73))	('TLE1', 'Gene', '7088', (34, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('TLE1', 'Gene', (34, 38))	('HER2', 'Gene', (79, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
14827	28382094	High TLE1 expression is significantly associated with the HER2+ and TNBC subtypes.	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('TLE1', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('TNBC', 'Disease', (68, 72))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))	('TLE1', 'Gene', '7088', (5, 9))
14852	28382094	Percentages of TLE1 positive tumor cells and staining intensity were calculated for each sample as follows, using a modified scoring method: 0, no staining or staining in <1% of the tumor cells; 1, staining in 1% to 10% of the cells (weak); 2, staining in 11% to 50% of the cells (moderate); and 3, staining in >50% of tumor cells (strong).	('tumor', 'Disease', (319, 324))	('staining', 'Var', (244, 252))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TLE1', 'Gene', (15, 19))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('TLE1', 'Gene', '7088', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
14861	28382094	Intrinsic subtypes were defined as previously described and categorized as follows: luminal A (ER+ and/or PR+, HER2-, Ki-67 <14%), luminal B (ER+ and/or PR+, HER2- and Ki-67 >=14%, or HER2+ and any Ki-67), HER2+ (ER-, PR-, HER2+), and TNBC (ER-, PR-, HER2-).	('ER', 'Gene', '2099', (185, 187))	('ER', 'Gene', '2099', (224, 226))	('HER2', 'Gene', '2064', (184, 188))	('ER', 'Gene', '2099', (159, 161))	('PR', 'Gene', '5241', (246, 248))	('>=14%', 'Var', (174, 179))	('ER', 'Gene', '2099', (207, 209))	('HER2', 'Gene', '2064', (206, 210))	('ER', 'Gene', '2099', (95, 97))	('ER', 'Gene', '2099', (213, 215))	('HER2', 'Gene', '2064', (223, 227))	('Ki-67 >=14%', 'Var', (168, 179))	('HER2', 'Gene', '2064', (111, 115))	('ER', 'Gene', '2099', (142, 144))	('Ki-67', 'Var', (198, 203))	('HER2', 'Gene', '2064', (158, 162))	('ER', 'Gene', '2099', (252, 254))	('HER2', 'Gene', '2064', (251, 255))	('HER2', 'Gene', (184, 188))	('PR', 'Gene', '5241', (218, 220))	('HER2', 'Gene', (206, 210))	('HER2', 'Gene', (223, 227))	('HER2', 'Gene', (111, 115))	('ER', 'Gene', '2099', (241, 243))	('PR', 'Gene', '5241', (153, 155))	('HER2', 'Gene', (158, 162))	('HER2', 'Gene', (251, 255))	('ER', 'Gene', '2099', (112, 114))	('PR', 'Gene', '5241', (106, 108))
14862	28382094	The chi-square test or Fisher exact test (when the number of cases in a category was <10) was used to analyze clinicopathological characteristics between TLE1 high and low expression.	('TLE1', 'Gene', '7088', (154, 158))	('low', 'NegReg', (168, 171))	('TLE1', 'Gene', (154, 158))	('high', 'Var', (159, 163))
14879	28382094	High TLE1 expression was significantly correlated with negative LN involvement (p=0.007) and high histologic grade (p<0.001) (Table 3).	('negative LN involvement', 'CPA', (55, 78))	('High', 'Var', (0, 4))	('TLE1', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('TLE1', 'Gene', '7088', (5, 9))
14906	28382094	Their findings indicated that TLE1 expression promotes tumor suppression in hepatocarcinogenesis through interaction with the NF-kappaB pathway as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NF-kappaB', 'Gene', '4790', (126, 135))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (76, 96))	('TLE1', 'Gene', '7088', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (55, 60))	('hepatocarcinogenesis', 'Disease', (76, 96))	('tumor', 'Disease', (149, 154))	('NF-kappaB', 'Gene', (126, 135))	('interaction', 'Interaction', (105, 116))	('TLE1', 'Gene', (30, 34))	('expression', 'Var', (35, 45))
14911	28382094	We also found that high expression of TLE1 is associated with high histologic grade, ER negativity, PR negativity, HER2 positivity, high Ki-67 labeling index, CK5/6 positivity, EGFR positivity, and positive p53 expression, which are poor prognostic clinicopathological features in breast cancer.	('p53', 'Gene', '7157', (207, 210))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('CK5/6', 'Gene', '3852', (159, 164))	('HER2', 'Gene', (115, 119))	('p53', 'Gene', (207, 210))	('high histologic grade', 'CPA', (62, 83))	('associated', 'Reg', (46, 56))	('ER', 'Gene', '2099', (85, 87))	('ER', 'Gene', '2099', (116, 118))	('EGFR', 'Gene', (177, 181))	('TLE1', 'Gene', (38, 42))	('positive', 'Var', (198, 206))	('PR', 'Gene', '5241', (100, 102))	('CK5/6', 'Gene', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('positivity', 'Var', (120, 130))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))	('high', 'Var', (19, 23))	('breast cancer', 'Disease', (281, 294))	('HER2', 'Gene', '2064', (115, 119))	('TLE1', 'Gene', '7088', (38, 42))	('EGFR', 'Gene', '1956', (177, 181))	('expression', 'MPA', (211, 221))
14912	28382094	However, high expression of TLE1 was also significantly correlated with negative LN metastasis, which is the most important positive prognostic factor in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('TLE1', 'Gene', (28, 32))	('high expression', 'Var', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('TLE1', 'Gene', '7088', (28, 32))	('negative LN metastasis', 'CPA', (72, 94))	('correlated', 'Reg', (56, 66))
14918	28382094	We recently reported that the expression of TLE1 in gastric cancer is associated with better clinicopathological features, such as good histologic grade, less frequent lymphatic or perineural invasion, intestinal type histology, early tumor stage, negative LN metastasis, and early pathologic stage.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('intestinal type histology', 'CPA', (202, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('expression', 'Var', (30, 40))	('less', 'CPA', (154, 158))	('tumor', 'Disease', (235, 240))	('TLE1', 'Gene', (44, 48))	('negative LN metastasis', 'CPA', (248, 270))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TLE1', 'Gene', '7088', (44, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
14919	28382094	Interestingly, we also found that expression of TLE1 in gastric cancer was significantly correlated with longer DFS and OS in univariate analysis, but not multivariate analysis.	('correlated', 'Reg', (89, 99))	('TLE1', 'Gene', (48, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('expression', 'Var', (34, 44))	('TLE1', 'Gene', '7088', (48, 52))	('gastric cancer', 'Disease', (56, 70))	('longer DFS', 'Disease', (105, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
15027	27599456	Targeted therapies against HER2 can successfully delay the progression of HER2-positive BC, but details of how this overexpression drives the disease are not fully understood.	('delay', 'NegReg', (49, 54))	('Targeted therapies', 'Var', (0, 18))	('HER2', 'Protein', (27, 31))	('expression', 'Species', '29278', (120, 130))
15034	27599456	Gene amplification and overexpression of this protein in breast cancers (BCs) predict poor disease outcome due to elevated metastatic potentials.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('breast cancers', 'Disease', (57, 71))	('overexpression', 'PosReg', (23, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('expression', 'Species', '29278', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('Gene amplification', 'Var', (0, 18))	('metastatic potentials', 'CPA', (123, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('elevated', 'PosReg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
15043	27599456	Surprisingly, these finger-like membrane structures were also observed in cells overexpressing signalling-incompetent HER2 mutants, suggesting membrane deformation is induced by the high cell-surface density of HER2 rather than by the receptor's signalling activities.	('HER2', 'Gene', (118, 122))	('rat', 'Species', '10116', (216, 219))	('mutants', 'Var', (123, 130))	('membrane', 'MPA', (143, 151))
15044	27599456	We found that this membrane deformation can reduce the area available for cell contacts with substrates or neighbouring cells.	('rat', 'Species', '10116', (98, 101))	('area available for cell contacts with substrates', 'CPA', (55, 103))	('deformation', 'Var', (28, 39))	('reduce', 'NegReg', (44, 50))
15045	27599456	These observations suggest that a non-canonical effect of HER2 overexpression exists that contributes to the disruption of epithelial characteristics exhibited in HER2 3+ BC cells, which is implicated in early-stage cancer progression.	('HER2', 'Var', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('expression', 'Species', '29278', (67, 77))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('epithelial characteristics', 'CPA', (123, 149))
15050	27599456	SK-BR-3 naturally overexpresses HER2 (3+) and its HER2 level was reduced (to ~ 1+) by partial small interfering RNA (siRNA) knockdown (siH2-SK-BR-3).	('knockdown', 'Var', (124, 133))	('HER2 level', 'MPA', (50, 60))	('reduced', 'NegReg', (65, 72))	('HER2', 'Protein', (32, 36))	('SK-BR-3', 'CellLine', 'CVCL:0033', (140, 147))	('overexpresses', 'PosReg', (18, 31))	('SK-BR-3', 'CellLine', 'CVCL:0033', (0, 7))
15052	27599456	Indeed, the elongated cluster patterns of HER2 were frequently observed in other high expressers (EFM-192A, BT-474 and KPL-4), were less frequent in mid expressers (MDA-MB-175-VII (1+) and MDA-MB-453 (2+)) and rarely observed in low expressers (BT-549, MDA-MB-436, MDA-MB-231X1.1 and MCF10DCIS.com).	('HER2', 'Protein', (42, 46))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (253, 263))	('MDA-MB-175-VII', 'Var', (165, 179))	('MDA-MB-231X1.1', 'CellLine', 'CVCL:0062', (265, 279))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (189, 199))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (284, 297))	('MDA-MB-175', 'CellLine', 'CVCL:1400', (165, 175))	('BT-549', 'CellLine', 'CVCL:1092', (245, 251))
15065	27599456	IQ values of the high intensity membrane regions were smaller (ie, more elongated) in MCF-7-HER2 than in MCF-7 cells (Supplementary Fig.	('MCF-7', 'CellLine', 'CVCL:0031', (105, 110))	('MCF-7', 'CellLine', 'CVCL:0031', (86, 91))	('IQ values', 'MPA', (0, 9))	('MCF-7-HER2', 'CellLine', 'CVCL:0U80', (86, 96))	('smaller', 'NegReg', (54, 61))	('more elongated', 'PosReg', (67, 81))	('MCF-7-HER2', 'Var', (86, 96))
15074	27599456	The FLS were also unrelated to caveolin-1 (cav1) mediated membrane tubulation (invagination) that only occurs after cav1 transfection in SK-BR-3 (ref.).	('caveolin-1', 'Gene', (31, 41))	('cav1', 'Gene', (116, 120))	('cav1', 'Gene', (43, 47))	('cav1', 'Gene', '857', (43, 47))	('cav1', 'Gene', '857', (116, 120))	('caveolin-1', 'Gene', '857', (31, 41))	('SK-BR-3', 'CellLine', 'CVCL:0033', (137, 144))	('membrane tubulation', 'CPA', (58, 77))	('transfection', 'Var', (121, 133))	('FLS', 'Chemical', '-', (4, 7))
15077	27599456	The three mutations were (i) a point mutation in the kinase domain that disrupts ATP binding (knHER2), (ii) phenylalanine substitutions for seven individual tyrosine auto-phosphorylation sites (7YFHER2), and (iii) deletion of the entire intracellular domain of the receptor (DeltaicdHER2).	('deletion', 'Var', (214, 222))	('phenylalanine', 'Chemical', 'MESH:D010649', (108, 121))	('ATP', 'Protein', (81, 84))	('phenylalanine substitutions', 'Var', (108, 135))	('disrupts', 'NegReg', (72, 80))	('tyrosine', 'Chemical', 'MESH:D014443', (157, 165))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))
15080	27599456	Surprisingly, all MCF-7 cells overexpressing these mutants and wtHER2 exhibited elongated and clustered location patterns of HER2s, while MCF-7-vctrl (transfectants of the control vector) showed random patterns (representative HER2 distributions in the stable and transient transfectants are respectively shown in Fig.	('MCF-7', 'CellLine', 'CVCL:0031', (18, 23))	('HER2s', 'Protein', (125, 130))	('MCF-7', 'CellLine', 'CVCL:0031', (138, 143))	('mutants', 'Var', (51, 58))
15115	27599456	Specifically, we speculated that the membrane deformation may reduce the surface area available to cells for interaction with either their surrounding substrates or neighbouring cells.	('deformation', 'Var', (46, 57))	('rat', 'Species', '10116', (156, 159))	('reduce', 'NegReg', (62, 68))	('surface area available', 'MPA', (73, 95))	('interaction', 'Interaction', (109, 120))
15125	27599456	However, in all high expressers of wtHER2 (MCF-7-wtHER2 and SK-BR-3) and the signalling-incompetent mutants (MCF-7-knHER2, and MCF-7-DeltaicdHER2), as well as lapatinib treated SK-BR-3, the cell-surface densities of small paxillin clusters in the central regions were significantly reduced compared with low expressers.	('MCF-7', 'CellLine', 'CVCL:0031', (109, 114))	('MCF-7-DeltaicdHER2', 'Var', (127, 145))	('SK-BR-3', 'CellLine', 'CVCL:0033', (177, 184))	('MCF-7', 'CellLine', 'CVCL:0031', (127, 132))	('reduced', 'NegReg', (282, 289))	('lapatinib', 'Chemical', 'MESH:D000077341', (159, 168))	('MCF-7-wtHER2', 'CellLine', 'CVCL:0U80', (43, 55))	('paxillin', 'Gene', '5829', (222, 230))	('SK-BR-3', 'CellLine', 'CVCL:0033', (60, 67))	('paxillin', 'Gene', (222, 230))	('MCF-7', 'CellLine', 'CVCL:0031', (43, 48))
15126	27599456	8d for IF images for paxillin in SK-BR-3 variants and Supplementary Fig.	('variants', 'Var', (41, 49))	('SK-BR-3', 'CellLine', 'CVCL:0033', (33, 40))	('SK-BR-3', 'Gene', (33, 40))	('paxillin', 'Gene', '5829', (21, 29))	('paxillin', 'Gene', (21, 29))
15131	27599456	We found the cell-surface coverage of paxillin was also reduced in high-expresser MCF-7-wtHER2 cells compared with MCF-7-ctrl cells, when these cells were grown on collagen (Supplementary Fig.	('paxillin', 'Gene', (38, 46))	('cell-surface coverage of', 'CPA', (13, 37))	('reduced', 'NegReg', (56, 63))	('MCF-7-wtHER2', 'Gene', (82, 94))	('MCF-7-wtHER2', 'CellLine', 'CVCL:0U80', (82, 94))	('MCF-7', 'CellLine', 'CVCL:0031', (115, 120))	('high-expresser', 'Var', (67, 81))	('paxillin', 'Gene', '5829', (38, 46))	('MCF-7', 'CellLine', 'CVCL:0031', (82, 87))
15147	27599456	This progression involves disruption of normal epithelial morphology and increased dissemination potential of tumour cells as a result of various genetic alterations.	('increased', 'PosReg', (73, 82))	('genetic alterations', 'Var', (146, 165))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('rat', 'Species', '10116', (158, 161))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
15148	27599456	HER2 overexpression in BCs is known to facilitate this progression.	('facilitate', 'PosReg', (39, 49))	('overexpression', 'Var', (5, 19))	('expression', 'Species', '29278', (9, 19))	('HER2', 'Protein', (0, 4))
15167	27599456	For transient transfection, wtHER2 (full length HER2) as well as knHER2 (K753M), 7YFHER2 (Y to F substitutions at Y877, Y1023, Y1139, Y1195, Y1221, Y1222 and Y1248), DeltaicdHER2 (HER2 intracellular domain truncation: 1-748aa), and DeltaecdHER2 (HER2 extracellular domain truncation: 639-1255aa) genes that were fused with N-terminal gD epitope tags were cloned into pRK5 expression vectors after site-directed mutagenesis.	('N-terminal gD epitope', 'Disease', (323, 344))	('expression vectors', 'Species', '29278', (372, 390))	('Y1139', 'Var', (127, 132))	('Y1222', 'Var', (148, 153))	('N-terminal gD epitope', 'Disease', 'OMIM:300855', (323, 344))	('Y1221', 'Var', (141, 146))	('K753M', 'Var', (73, 78))	('K753M', 'Mutation', 'p.K753M', (73, 78))	('Y1023', 'Var', (120, 125))	('Y1248', 'Var', (158, 163))	('Y1195', 'Var', (134, 139))
15173	27599456	Cell pools expressing HER2 or HER2 mutants were selected using puromycin (Clontech Laboratories, 0.75 mug ml-1 for MCF-7 and 1.5 mug ml-1 for DCIS.com transfectants).	('puromycin', 'Chemical', 'MESH:D011691', (63, 72))	('mutants', 'Var', (35, 42))	('MCF-7', 'CellLine', 'CVCL:0031', (115, 120))	('HER2', 'Protein', (22, 26))	('HER2', 'Protein', (30, 34))	('rat', 'Species', '10116', (87, 90))
15211	23304477	This recommendation is based on the difficult pathologic distinction between ADH and LG DCIS especially in settings of small tissue samples, and also the fact that ADH on CNB is associated with a high degree of upstaging to in situ and invasive cancer on subsequent excisions at published rates varying between 24 and 45%.	('ADH', 'Var', (164, 167))	('invasive cancer', 'Disease', 'MESH:D009362', (236, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('upstaging', 'PosReg', (211, 220))	('invasive cancer', 'Disease', (236, 251))
15228	20920311	TF was higher in women with 1) cancer (DCIS or invasive) vs. either no cancer (atypia or benign pathology, p = .048), or benign pathology (p = .018); and 2) abnormal (atypia or cancer) versus benign pathology (p = .016); and was more predictive of atypia or cancer in post- compared to premenopausal women.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('higher', 'PosReg', (7, 13))	('women', 'Species', '9606', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('abnormal', 'Var', (157, 165))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('atypia or cancer', 'Disease', 'MESH:D009369', (248, 264))	('cancer', 'Disease', (31, 37))	('women', 'Species', '9606', (300, 305))	('atypia', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('atypia', 'Disease', 'None', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('atypia or cancer', 'Disease', 'MESH:D009369', (167, 183))	('atypia or cancer', 'Disease', (248, 264))	('atypia', 'Disease', (248, 254))	('cancer', 'Disease', (258, 264))	('atypia', 'Disease', 'None', (248, 254))	('atypia or cancer', 'Disease', (167, 183))	('TF', 'Chemical', '-', (0, 2))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('atypia', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('atypia', 'Disease', 'None', (79, 85))
15234	20920311	Antibodies to TF and Tn have been used clinically as indicators of cancer and have been detected in primary breast cancer, lymph node, and metastatic tissue samples.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (115, 121))	('Antibodies', 'Var', (0, 10))	('Tn', 'Chemical', 'MESH:C009497', (21, 23))	('cancer', 'Disease', (67, 73))	('TF', 'Chemical', '-', (14, 16))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('detected', 'Reg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('breast cancer', 'Disease', (108, 121))
15265	20920311	The ND, ASF and OSM samples were incubated at 25 C for 2 h followed by a TTBS wash. Biotinylated secondary detection proteins, anti-TF antibody (0.625 mug/ml) or Tn binding Vicia villosa lectin (1 mug/mL) in 100 muL TBS, were added to the wells and incubated for 1 hr.	('muL', 'Gene', '4591', (212, 215))	('TTBS', 'Chemical', '-', (73, 77))	('muL', 'Gene', (212, 215))	('TF', 'Chemical', '-', (132, 134))	('TBS', 'Chemical', 'MESH:D013725', (74, 77))	('Tn', 'Chemical', 'MESH:C009497', (162, 164))	('Vicia villosa', 'Species', '3911', (173, 186))	('TBS', 'Chemical', 'MESH:D013725', (216, 219))	('0.625 mug/ml', 'Var', (145, 157))
15284	20920311	Median concentrations of TF and Tn were 7 and 3 fold higher, respectively (Figure 1), in women with atypical compared to those with usual hyperplasia (H).	('higher', 'PosReg', (53, 59))	('hyperplasia', 'Disease', (138, 149))	('TF', 'Chemical', '-', (25, 27))	('women', 'Species', '9606', (89, 94))	('hyperplasia', 'Disease', 'MESH:D006965', (138, 149))	('atypical', 'Var', (100, 108))	('Tn', 'Chemical', 'MESH:C009497', (32, 34))	('rat', 'Species', '10116', (14, 17))
15287	20920311	TF expression trended higher in women with DCIS compared to those with usual hyperplasia (p = .09) and normals (p = .07).	('TF', 'Chemical', '-', (0, 2))	('higher', 'PosReg', (22, 28))	('DCIS', 'Var', (43, 47))	('women', 'Species', '9606', (32, 37))	('expression', 'MPA', (3, 13))	('hyperplasia', 'Disease', (77, 88))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))
15288	20920311	Univariate analysis indicated that TF concentration was higher in women with abnormal (atypia or cancer) than benign pathology (p = .016, Table 1).	('TF concentration', 'MPA', (35, 51))	('TF', 'Chemical', '-', (35, 37))	('atypia or cancer', 'Disease', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('women', 'Species', '9606', (66, 71))	('higher', 'PosReg', (56, 62))	('abnormal', 'Var', (77, 85))	('atypia or cancer', 'Disease', 'MESH:D009369', (87, 103))	('rat', 'Species', '10116', (45, 48))
15296	20920311	Each of these models demonstrates that in post- but not premenopausal women, high TF (odds ratios (OR) ranging from 8.53-15.56) and increasing age are independent predictors of disease (p < .05), whereas Tn concentration was not an independent predictor of disease status.	('rat', 'Species', '10116', (91, 94))	('high', 'Var', (77, 81))	('disease', 'Disease', (177, 184))	('rat', 'Species', '10116', (214, 217))	('Tn', 'Chemical', 'MESH:C009497', (204, 206))	('women', 'Species', '9606', (70, 75))	('rat', 'Species', '10116', (28, 31))	('TF', 'Chemical', '-', (82, 84))
15412	31897326	Although several studies have suggested that DCIS is not important for defining pCR, other researchers argue that DCIS might lead to higher local recurrence risk for patients after NACT.	('DCIS', 'Var', (114, 118))	('local recurrence', 'CPA', (140, 156))	('patients', 'Species', '9606', (166, 174))
15440	31897326	In addition, patients with RCB-I were confirmed to have similar 5-year distant relapse rate as RCB-0 (5.4% and 2.4%, respectively), while patients with RCB-III showed poor prognosis with 5-year distant relapse rate of 53.6%.	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (138, 146))	('distant relapse', 'CPA', (71, 86))	('RCB-I', 'Var', (27, 32))
15461	31897326	built a prognostic model based on post-NACT node status, as well as Ki-67 expression level, and concluded that compared to low-risk (nodes negative and Ki-67 < 15%) and intermediate-risk (nodes positivity or Ki-67 >= 15%) patients, high-risk patients (nodes positive and Ki-67 >= 15%) show significantly higher probability of recurrence and death.	('Ki-67', 'Var', (271, 276))	('patients', 'Species', '9606', (222, 230))	('recurrence', 'CPA', (326, 336))	('patients', 'Species', '9606', (242, 250))
15467	31897326	demonstrated that patients with high Ki-67 level after two weeks of NET revealed an obviously lower RFS than those with low Ki-67 level (p = 0.004), while pre-treatment Ki-67 did not show any prognostic effect.	('RFS', 'MPA', (100, 103))	('high Ki-67', 'Var', (32, 42))	('lower', 'NegReg', (94, 99))	('patients', 'Species', '9606', (18, 26))	('Ki-67', 'Var', (37, 42))
15472	31897326	According to the results of The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial (n = 236, ER-positive), patients with PEPI = 0 showed a significantly lower recurrence rate than the patients in the PEPI > 0 group (3.7% vs. 14.4%, p = 0.014).	('Z1031A', 'SUBSTITUTION', 'None', (85, 91))	('Oncology', 'Phenotype', 'HP:0002664', (61, 69))	('lower', 'NegReg', (168, 173))	('ER', 'Gene', '2099', (108, 110))	('Z1031A', 'Var', (85, 91))	('patients', 'Species', '9606', (122, 130))	('PEPI = 0', 'Var', (136, 144))	('patients', 'Species', '9606', (199, 207))	('recurrence', 'MPA', (174, 184))
15483	31897326	A study investigated the prognostic value of TIL level before, during, and after NAC in HER2+ BC; results suggested that stromal TIL level > 25% in residual disease had an adverse prognostic efficacy.	('BC', 'Disease', 'MESH:D001943', (94, 96))	('TIL', 'Gene', '7096', (45, 48))	('TIL', 'Gene', (129, 132))	('HER2', 'Gene', (88, 92))	('> 25%', 'Var', (139, 144))	('HER2', 'Gene', '2064', (88, 92))	('TIL', 'Gene', (45, 48))	('TIL', 'Gene', '7096', (129, 132))
15508	31897326	demonstrated that high expression of PD-L1 in residual disease was an adverse prognostic indicator for RFS and OS, the effect of which was most significant in patients with TNBC.	('PD-L1', 'Gene', (37, 42))	('PD-L1', 'Gene', '29126', (37, 42))	('RFS', 'Disease', (103, 106))	('high', 'Var', (18, 22))	('BC', 'Disease', 'MESH:D001943', (175, 177))	('patients', 'Species', '9606', (159, 167))
15510	31897326	Recent studies have shown that high PD-L1 expression can attenuate the survival benefit derived from high TIL level following NACT in patients with TNBC.	('PD-L1', 'Gene', (36, 41))	('TIL', 'Gene', (106, 109))	('BC', 'Disease', 'MESH:D001943', (150, 152))	('patients', 'Species', '9606', (134, 142))	('PD-L1', 'Gene', '29126', (36, 41))	('attenuate', 'NegReg', (57, 66))	('high', 'Var', (31, 35))	('survival benefit', 'MPA', (71, 87))	('TIL', 'Gene', '7096', (106, 109))
15533	31897326	reported that the loss of HER2 amplification during NACT is related to a tendency toward higher risk of recurrence and death.	('HER2', 'Gene', (26, 30))	('loss', 'NegReg', (18, 22))	('HER2', 'Gene', '2064', (26, 30))	('amplification', 'Var', (31, 44))
15535	31897326	Nevertheless, other studies have confirmed that the rate of HER2 loss was higher for patients received NACT, while application of trastuzumab did not affect the HER2 loss rate.	('loss', 'NegReg', (65, 69))	('NACT', 'Var', (103, 107))	('HER2', 'Gene', (60, 64))	('HER2', 'Gene', '2064', (60, 64))	('patients', 'Species', '9606', (85, 93))	('HER2', 'Gene', (161, 165))	('HER2', 'Gene', '2064', (161, 165))
15542	31897326	They used 20% as the cut-off value to identify ER and PR expression changes and concluded that patients with absolute ER percentage changes >= 20% revealed high 5-year RFS and OS.	('high', 'PosReg', (156, 160))	('patients', 'Species', '9606', (95, 103))	('PR', 'Gene', '5241', (54, 56))	('ER', 'Gene', '2099', (118, 120))	('ER', 'Gene', '2099', (47, 49))	('RFS', 'MPA', (168, 171))	('changes', 'Var', (132, 139))
15546	31897326	Evidently, the DFS and OS decreased significantly in patients with HR changes after NACT who did not receive subsequent ET.	('DFS', 'MPA', (15, 18))	('patients', 'Species', '9606', (53, 61))	('changes', 'Var', (70, 77))	('decreased', 'NegReg', (26, 35))	('HR', 'Gene', '3164', (67, 69))
15549	31897326	Furthermore, other studies have suggested that the loss of HRs in residual tumor after NACT was associated with poor prognosis.	('loss', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('HR', 'Gene', '3164', (59, 61))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
15550	31897326	has concluded that switching to TNBC after NACT was an adverse prognostic indicator for poor DFS and OS.	('switching', 'Var', (19, 28))	('BC', 'Disease', 'MESH:D001943', (34, 36))	('poor DFS', 'Disease', (88, 96))	('DFS', 'Disease', (93, 96))
15557	31897326	On the contrary, patients showing HR-positive changes showed better DFS and OS than patients who consistently showed HR-negative status.	('better', 'PosReg', (61, 67))	('HR', 'Gene', '3164', (34, 36))	('changes', 'Var', (46, 53))	('patients', 'Species', '9606', (84, 92))	('HR', 'Gene', '3164', (117, 119))	('DFS', 'MPA', (68, 71))	('patients', 'Species', '9606', (17, 25))
15560	31897326	According to the results of the post-treatment repeated assessment, patients who are positive for HR or show HER2 amplification in either core-needle biopsy specimen or surgical sample should be administered further adjuvant targeted treatment to improve long-term outcome.	('amplification', 'Var', (114, 127))	('HR', 'Gene', '3164', (98, 100))	('improve', 'PosReg', (247, 254))	('HER2', 'Gene', (109, 113))	('positive', 'Reg', (85, 93))	('HER2', 'Gene', '2064', (109, 113))	('patients', 'Species', '9606', (68, 76))
15565	31897326	reported that the lymph node status provided significant prognostic information for OS and RFS, and that the predictive value was better for OS of luminal A, B, and HER2 BC, and for RFS in luminal B and HER2 BC.	('BC', 'Disease', 'MESH:D001943', (208, 210))	('BC', 'Disease', 'MESH:D001943', (170, 172))	('RFS', 'Var', (182, 185))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', (203, 207))	('HER2', 'Gene', '2064', (165, 169))	('HER2', 'Gene', '2064', (203, 207))
15584	31516751	Of the 604 patients, 20.03% (n = 121) and 31.95% (n = 193) were upstaged to DCIS with microinvasion (DCISM) and invasive breast cancer (IBC) on final pathology, respectively.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('invasive breast cancer', 'Disease', 'MESH:D001943', (112, 134))	('IBC', 'Chemical', '-', (136, 139))	('microinvasion', 'Var', (86, 99))	('DCIS', 'Disease', (76, 80))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('upstaged', 'PosReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('invasive breast cancer', 'Disease', (112, 134))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('cancer', 'Disease', (128, 134))
15597	30455948	Three types of high-molecular-weight cytokeratins (CKs) - CK5/6, CK14, and CK34betaE12 - were targeted.	('CK14', 'Gene', '3861', (65, 69))	('CK5/6', 'Gene', '3852', (58, 63))	('CK14', 'Gene', (65, 69))	('CK34betaE12 -', 'Var', (75, 88))	('CK5/6', 'Gene', (58, 63))
15599	30455948	Immunohistochemical analyses used antibodies to CK5/6, CK14, and CK34betaE12 to make the differential diagnosis of solid papillary carcinoma in situ versus IPUDH.	('CK5/6', 'Gene', (48, 53))	('IPUDH', 'Chemical', '-', (156, 161))	('solid papillary carcinoma in situ', 'Disease', (115, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('CK34betaE12', 'Var', (65, 76))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (131, 148))	('solid papillary carcinoma in situ', 'Disease', 'MESH:D002278', (115, 148))	('CK14', 'Gene', '3861', (55, 59))	('CK5/6', 'Gene', '3852', (48, 53))	('CK14', 'Gene', (55, 59))
15601	30455948	Immunohistochemical staining with CK34betaE12 antibody produced scores of 1-3 in all patients with solid papillary carcinoma and 3-5 in all patients with IPUDH.	('CK34betaE12', 'Var', (34, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('solid papillary carcinoma', 'Disease', (99, 124))	('IPUDH', 'Chemical', '-', (154, 159))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (140, 148))	('solid papillary carcinoma', 'Disease', 'MESH:D002291', (99, 124))
15602	30455948	In tissues from patients with IPUDH, significantly more cells were stained with CK34betaE12 than CK5/6 (p < 0.05) or CK14 (p < 0.05).	('CK14', 'Gene', (117, 121))	('IPUDH', 'Chemical', '-', (30, 35))	('CK34betaE12', 'Var', (80, 91))	('IPUDH', 'Disease', (30, 35))	('cells', 'CPA', (56, 61))	('more', 'PosReg', (51, 55))	('CK5/6', 'Gene', (97, 102))	('patients', 'Species', '9606', (16, 24))	('CK14', 'Gene', '3861', (117, 121))	('CK5/6', 'Gene', '3852', (97, 102))
15603	30455948	The immunoreactivity of CK5/6, CK14, and CK34betaE12 antibodies was useful to differentiate solid papillary carcinoma in situ from IPUDH.	('CK14', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('CK34betaE12', 'Var', (41, 52))	('IPUDH', 'Chemical', '-', (131, 136))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (108, 125))	('solid papillary carcinoma in situ', 'Disease', (92, 125))	('CK5/6', 'Gene', '3852', (24, 29))	('CK14', 'Gene', '3861', (31, 35))	('solid papillary carcinoma in situ', 'Disease', 'MESH:D002278', (92, 125))	('CK5/6', 'Gene', (24, 29))
15622	30455948	Immunohistochemical staining of paraffin-embedded tissue was performed using antibodies to the following: chromogranin A, synaptophysin, CK5/6, CK14, and CK34betaE12 (which recognizes CKs 1, 5, 10, and 14).	('CK5/6', 'Gene', (137, 142))	('CKs 1', 'Gene', '137529', (184, 189))	('chromogranin A', 'Gene', '1113', (106, 120))	('CK14', 'Gene', '3861', (144, 148))	('synaptophysin', 'Gene', (122, 135))	('paraffin', 'Chemical', 'MESH:D010232', (32, 40))	('CK5/6', 'Gene', '3852', (137, 142))	('synaptophysin', 'Gene', '6855', (122, 135))	('chromogranin A', 'Gene', (106, 120))	('CK14', 'Gene', (144, 148))	('CK34betaE12', 'Var', (154, 165))	('CKs 1', 'Gene', (184, 189))
15625	30455948	The final objective of this pilot study was to determine whether there was a difference between IPUDH and DCIS in the rate of positivity for each of the three antibodies (CK5/6, CK14, and CK34betaE12).	('CK14', 'Gene', (178, 182))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('CK5/6', 'Gene', '3852', (171, 176))	('CK14', 'Gene', '3861', (178, 182))	('IPUDH', 'Chemical', '-', (96, 101))	('CK5/6', 'Gene', (171, 176))	('CK34betaE12', 'Var', (188, 199))
15632	30455948	We immunohistochemically stained surgical specimens from 17 patients with SPC in situ (Figure 1(a) and (b)) and 18 patients with IPUDH (Figure 2(a)) using antibodies to CK5/6 (Figures 1(c) and 2(b)), CK14 (Figures 1(d) and 2(c)), and CK34betaE12 (Figures 1(e) and 2(d)), and compared the staining scores for each marker.	('patients', 'Species', '9606', (115, 123))	('CK5/6', 'Gene', '3852', (169, 174))	('CK14', 'Gene', (200, 204))	('CK34betaE12', 'Var', (234, 245))	('patients', 'Species', '9606', (60, 68))	('SPC', 'Chemical', '-', (74, 77))	('CK5/6', 'Gene', (169, 174))	('CK14', 'Gene', '3861', (200, 204))	('IPUDH', 'Chemical', '-', (129, 134))
15642	30455948	A comparison of the immunoreactivities to CK5/6, CK14, and CK34betaE12 between the 17 SPC in situ patients and the 18 IPUDH patients revealed significant differences (p < 0.05) distinguishing SPC in situ from IPUDH, as determined by Fisher's exact probability test using cutoff scores of 2 (see Tables 3 and 4).	('IPUDH', 'Chemical', '-', (118, 123))	('CK5/6', 'Gene', (42, 47))	('SPC', 'Chemical', '-', (86, 89))	('CK34betaE12', 'Var', (59, 70))	('differences', 'Reg', (154, 165))	('IPUDH', 'Chemical', '-', (209, 214))	('SPC', 'Disease', (192, 195))	('patients', 'Species', '9606', (98, 106))	('CK14', 'Gene', '3861', (49, 53))	('CK5/6', 'Gene', '3852', (42, 47))	('SPC', 'Chemical', '-', (192, 195))	('patients', 'Species', '9606', (124, 132))	('CK14', 'Gene', (49, 53))
15643	30455948	Comparison of immunoreactivities to CK5/6, CK14, and CK34betaE12 in the 17 SPC in situ patients showed no significant differences between CK5/6 and CK14, CK5/6 and CK34betaE12, or CK14 and CK34betaE12 (Figure 3).	('CK14', 'Gene', (148, 152))	('CK14', 'Gene', (180, 184))	('CK5/6', 'Gene', (138, 143))	('CK14', 'Gene', '3861', (43, 47))	('CK5/6', 'Gene', '3852', (138, 143))	('CK14', 'Gene', '3861', (180, 184))	('CK5/6', 'Gene', '3852', (36, 41))	('CK34betaE12', 'Var', (189, 200))	('CK5/6', 'Gene', '3852', (154, 159))	('CK14', 'Gene', (43, 47))	('SPC', 'Chemical', '-', (75, 78))	('CK14', 'Gene', '3861', (148, 152))	('CK5/6', 'Gene', (36, 41))	('patients', 'Species', '9606', (87, 95))	('CK5/6', 'Gene', (154, 159))	('CK34betaE12', 'Var', (164, 175))
15644	30455948	Comparison of the immunoreactivities to CK5/6, CK14, and CK34betaE12 in 18 IPUDH patients revealed significant differences between CK5/6 and CK34betaE12 and between CK14 and CK34betaE12, but not between CK5/6 and CK14 (Figure 4).	('CK5/6', 'Gene', (203, 208))	('CK14', 'Gene', '3861', (47, 51))	('IPUDH', 'Chemical', '-', (75, 80))	('CK34betaE12', 'Var', (141, 152))	('CK14', 'Gene', '3861', (165, 169))	('CK14', 'Gene', '3861', (213, 217))	('patients', 'Species', '9606', (81, 89))	('CK5/6', 'Gene', (131, 136))	('CK5/6', 'Gene', '3852', (40, 45))	('CK14', 'Gene', (47, 51))	('CK14', 'Gene', (165, 169))	('CK5/6', 'Gene', (40, 45))	('CK5/6', 'Gene', '3852', (203, 208))	('CK14', 'Gene', (213, 217))	('differences', 'Reg', (111, 122))	('CK5/6', 'Gene', '3852', (131, 136))
15646	30455948	In this study, CK5/6, CK14, and CK34betaE12 showed similar immunohistochemical staining patterns.	('CK14', 'Gene', '3861', (22, 26))	('CK5/6', 'Gene', '3852', (15, 20))	('CK5/6', 'Gene', (15, 20))	('CK14', 'Gene', (22, 26))	('CK34betaE12', 'Var', (32, 43))
15647	30455948	We observed no significant differences between tissues from patients with IPUDH and SPC in situ in the rates of immunoreactivity of antibodies to CK5/6, CK14, and CK34betaE12 (Table 4), although these antibodies are considered to be useful for differentiating between IPUDH and SPC in situ.	('IPUDH', 'Chemical', '-', (74, 79))	('SPC', 'Chemical', '-', (278, 281))	('CK5/6', 'Gene', (146, 151))	('patients', 'Species', '9606', (60, 68))	('CK14', 'Gene', (153, 157))	('CK34betaE12', 'Var', (163, 174))	('IPUDH', 'Chemical', '-', (268, 273))	('IPUDH', 'Disease', (268, 273))	('SPC', 'Chemical', '-', (84, 87))	('CK5/6', 'Gene', '3852', (146, 151))	('CK14', 'Gene', '3861', (153, 157))
15654	30455948	CK5/6, CK14, and CK34betaE12 stain proliferative cells diffusely (mosaic pattern) in ductal hyperplasia and duct papillomatosis.	('CK34betaE12', 'Var', (17, 28))	('papillomatosis', 'Disease', 'MESH:D010212', (113, 127))	('papilloma', 'Phenotype', 'HP:0012740', (113, 122))	('papillomatosis', 'Disease', (113, 127))	('CK5/6', 'Gene', '3852', (0, 5))	('CK14', 'Gene', '3861', (7, 11))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (85, 103))	('CK5/6', 'Gene', (0, 5))	('ductal hyperplasia', 'Disease', (85, 103))	('CK14', 'Gene', (7, 11))
15655	30455948	The rate of positive staining of tumor cells by CK34betaE12 is 60%-100% in ductal hyperplasia.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('CK34betaE12', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (75, 93))	('ductal hyperplasia', 'Disease', (75, 93))
15657	30455948	Several studies have reported that CK34betaE12 stains positively 0%-20% of tumor cells in tissue from DCIS patients.	('CK34betaE12', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Disease', (75, 80))	('DCIS', 'Disease', (102, 106))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
15659	30455948	We diagnosed SPC in situ and IPUDH histopathologically using the conventional criteria, and we calculated the sensitivities and specificities of staining with antibodies to CK5/6, CK14, and CK34betaE12 in determining the optimum cutoff scores.	('IPUDH', 'Chemical', '-', (29, 34))	('CK14', 'Gene', (180, 184))	('CK5/6', 'Gene', '3852', (173, 178))	('SPC', 'Disease', (13, 16))	('CK5/6', 'Gene', (173, 178))	('CK34betaE12', 'Var', (190, 201))	('SPC', 'Chemical', '-', (13, 16))	('CK14', 'Gene', '3861', (180, 184))
15665	30455948	using CK34betaE12 showed significant differences between intraductal papillary carcinomas including SPC in situ and IPUDH.	('SPC', 'Chemical', '-', (100, 103))	('differences', 'Reg', (37, 48))	('CK34betaE12', 'Var', (6, 17))	('IPUDH', 'Chemical', '-', (116, 121))	('IPUDH', 'Disease', (116, 121))	('intraductal papillary carcinomas', 'Disease', 'MESH:D002291', (57, 89))	('intraductal papillary carcinomas', 'Disease', (57, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('SPC in situ', 'Disease', (100, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))
15666	30455948	We think that the reason of slightly immunopositive for CK5/6, CK14, and CK34betaE12 in some SPCs may be including intraductal papilloma components.	('intraductal papilloma', 'Disease', (115, 136))	('CK5/6', 'Gene', '3852', (56, 61))	('CK5/6', 'Gene', (56, 61))	('SPC', 'Chemical', '-', (93, 96))	('CK34betaE12', 'Var', (73, 84))	('papilloma', 'Phenotype', 'HP:0012740', (127, 136))	('CK14', 'Gene', '3861', (63, 67))	('intraductal papilloma', 'Disease', 'MESH:D018300', (115, 136))	('CK14', 'Gene', (63, 67))
15668	30455948	In this study, CK34betaE12 stained significantly more cells than did antibodies to CK5/6 (p < 0.05) and CK14 (p < 0.05) in tissue from IPUDH patients.	('CK5/6', 'Gene', (83, 88))	('CK14', 'Gene', '3861', (104, 108))	('CK34betaE12', 'Var', (15, 26))	('more', 'PosReg', (49, 53))	('CK5/6', 'Gene', '3852', (83, 88))	('IPUDH', 'Chemical', '-', (135, 140))	('CK14', 'Gene', (104, 108))	('patients', 'Species', '9606', (141, 149))
15669	30455948	have reported no significant differences in positive-staining percentages between CK5/CK6 and CK34betaE12 for papilloma.	('CK5', 'Gene', (82, 85))	('papilloma', 'Disease', (110, 119))	('CK34betaE12', 'Var', (94, 105))	('papilloma', 'Disease', 'MESH:D010212', (110, 119))	('CK5', 'Gene', '3852', (82, 85))	('papilloma', 'Phenotype', 'HP:0012740', (110, 119))
15673	30455948	This suggests that CK1 and 10 immunopositivity may be important in diagnosing IPUDH.	('CK1', 'Species', '2498238', (19, 22))	('IPUDH', 'Chemical', '-', (78, 83))	('IPUDH', 'Disease', (78, 83))	('CK1', 'Var', (19, 22))
15680	30455948	The immunohistochemistry of HMWCKs (CK5/6, CK14, and CK34betaE12) usually yields negative results in SPC in situ, similar to the findings for usual DCIS.	('SPC', 'Disease', (101, 104))	('negative', 'NegReg', (81, 89))	('CK14', 'Gene', '3861', (43, 47))	('CK5/6', 'Gene', '3852', (36, 41))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('CK14', 'Gene', (43, 47))	('SPC', 'Chemical', '-', (101, 104))	('CK34betaE12', 'Var', (53, 64))	('CK5/6', 'Gene', (36, 41))
15681	30455948	We observed significant differences using different cutoff scores for staining by CK5/6, CK14, and CK34betaE12 (1%, 10%, and 33.3%, respectively).	('CK5/6', 'Gene', '3852', (82, 87))	('CK14', 'Gene', '3861', (89, 93))	('CK5/6', 'Gene', (82, 87))	('CK14', 'Gene', (89, 93))	('CK34betaE12', 'Var', (99, 110))
15682	30455948	We observed that CK34betaE12 stained significantly more cells than CK5/6 and CK14 in IPUDH.	('CK34betaE12', 'Var', (17, 28))	('CK14', 'Gene', '3861', (77, 81))	('IPUDH', 'Chemical', '-', (85, 90))	('CK5/6', 'Gene', '3852', (67, 72))	('more', 'PosReg', (51, 55))	('CK14', 'Gene', (77, 81))	('CK5/6', 'Gene', (67, 72))
15692	29669584	Type-0, type-1 or type-2 patterns halfway through NAC showed highest tumor reduction rates on pathology assessment, with > 50% tumor reduction in 90%, 78% and 65% of cases, respectively.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('NAC', 'Gene', (50, 53))	('type-2 patterns', 'Var', (18, 33))	('tumor reduction', 'Disease', (127, 142))	('tumor reduction', 'Disease', 'MESH:D009369', (127, 142))	('tumor reduction', 'Disease', (69, 84))	('tumor reduction', 'Disease', 'MESH:D009369', (69, 84))	('NAC', 'Gene', '6622', (50, 53))
15711	29669584	Previous research shows that triple negative breast tumors regress significantly more often as a shrinking mass than HER2 positive and ER positive/HER2 negative tumors.	('HER2', 'Gene', (117, 121))	('tumors', 'Disease', (161, 167))	('ER', 'Gene', '2099', (135, 137))	('HER2', 'Gene', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('shrinking', 'NegReg', (97, 106))	('ER', 'Gene', '2099', (118, 120))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('triple negative', 'Var', (29, 44))	('HER2', 'Gene', '2064', (117, 121))	('tumors', 'Disease', (52, 58))	('ER', 'Gene', '2099', (148, 150))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HER2', 'Gene', '2064', (147, 151))	('breast tumors', 'Disease', 'MESH:D001943', (45, 58))	('breast tumors', 'Disease', (45, 58))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('breast tumors', 'Phenotype', 'HP:0100013', (45, 58))
15753	29669584	< 50% or no regression in tumor cells) were categorized as non-responders, while patients with Pinder classification 1i-2ii (i.e.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patients', 'Species', '9606', (81, 89))	('< 50', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
15810	29669584	Tumors with a type-4 (stable disease) or type-5 response (progression) halfway through NAC had the lowest chances of tumor regression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('type-5', 'Var', (41, 47))	('tumor', 'Disease', (117, 122))	('Tumors', 'Disease', (0, 6))	('NAC', 'Gene', '6622', (87, 90))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('NAC', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
15903	32211582	We previously reported on the cost-effectiveness of using the Oncotype DX DCIS Score, a test that uses tumor biology to predict recurrence risk.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('Oncotype DX', 'Var', (62, 73))	('DCIS', 'Disease', (74, 78))	('DCIS', 'Disease', 'MESH:D002285', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
15937	21149333	Prevalence of BRCA1 and BRCA2 mutations in women with carcinoma in situ of the breast referred for genetic testing Carcinoma in situ (CIS) of the breast will account for 62,280 (24.5%) of new breast cancer diagnoses in 2009.	('BRCA1', 'Gene', '672', (14, 19))	('Carcinoma in situ', 'Disease', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Carcinoma in situ', 'Disease', 'MESH:D002278', (115, 132))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('BRCA2', 'Gene', '675', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Carcinoma in situ', 'Phenotype', 'HP:0030075', (115, 132))	('BRCA1', 'Gene', (14, 19))	('breast cancer', 'Disease', (192, 205))	('women', 'Species', '9606', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (54, 71))	('mutations', 'Var', (30, 39))	('carcinoma', 'Disease', (54, 63))	('Carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('BRCA2', 'Gene', (24, 29))
15938	21149333	Management guidelines for BRCA1/2 mutation carriers advise close follow-up, intensive screening, and consideration of prophylactic surgeries to lower cancer risk.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutation', 'Var', (34, 42))	('BRCA1/2', 'Gene', (26, 33))	('cancer', 'Disease', (150, 156))	('BRCA1/2', 'Gene', '672;675', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
15939	21149333	The prevalence of BRCA1/2 mutations in women with a history of CIS using comprehensive DNA sequencing and rearrangement testing has not been definitively documented.	('mutations', 'Var', (26, 35))	('women', 'Species', '9606', (39, 44))	('BRCA1/2', 'Gene', (18, 25))	('BRCA1/2', 'Gene', '672;675', (18, 25))
15940	21149333	The prevalence of mutations in non-Ashkenazi Jewish women with CIS was assessed by way of a cross-sectional analysis of the Myriad Genetic Laboratories, Inc. BRCA1/2 database.	('CIS', 'Disease', (63, 66))	('BRCA1/2', 'Gene', '672;675', (158, 165))	('BRCA1/2', 'Gene', (158, 165))	('women', 'Species', '9606', (52, 57))	('mutations', 'Var', (18, 27))
15942	21149333	For women without personal history of invasive cancer (CIS alone+CIS and any family history subgroups), those with early-onset CIS had a significantly increased risk of a BRCA1/2 mutation compared to women with late-onset disease (>=50 years)(OR 1.5, 95% CI 1.1-2.1).	('BRCA1/2', 'Gene', '672;675', (171, 178))	('women', 'Species', '9606', (200, 205))	('invasive cancer', 'Disease', (38, 53))	('late-onset disease', 'Disease', (211, 229))	('BRCA1/2', 'Gene', (171, 178))	('mutation', 'Var', (179, 187))	('women', 'Species', '9606', (4, 9))	('late-onset disease', 'Disease', 'MESH:D020518', (211, 229))	('invasive cancer', 'Disease', 'MESH:D009362', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
15945	21149333	When a family history of breast and/or ovarian cancer are also present, testing women with early-onset CIS may increase the likelihood of BRCA1/2 mutation detection, and the opportunity for carriers to consider additional cancer prevention strategies.	('breast and/or ovarian cancer', 'Disease', (25, 53))	('women', 'Species', '9606', (80, 85))	('increase', 'PosReg', (111, 119))	('BRCA1/2', 'Gene', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', (47, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('BRCA1/2', 'Gene', '672;675', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (146, 154))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (25, 53))
15951	21149333	Early studies from the Breast Cancer Linkage Consortium (BCLC) confirmed a lower prevalence of DCIS and a lower risk of DCIS associated with invasive breast cancer in BRCA1/2 mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lower', 'NegReg', (75, 80))	('Breast Cancer', 'Disease', (23, 36))	('BRCA1/2', 'Gene', '672;675', (167, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('Breast Cancer', 'Disease', 'MESH:D001943', (23, 36))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('mutation', 'Var', (175, 183))	('carriers', 'Reg', (184, 192))	('invasive breast cancer', 'Disease', (141, 163))	('BRCA1/2', 'Gene', (167, 174))	('Breast Cancer', 'Phenotype', 'HP:0003002', (23, 36))	('DCIS', 'Disease', (95, 99))	('invasive breast cancer', 'Disease', 'MESH:D001943', (141, 163))
15952	21149333	Among women referred for genetic risk assessment with a BRCAPRO mutation probability > 10%, DCIS prevalence estimates were comparable in BRCA1/2 mutation carriers vs mutation negative women.	('women', 'Species', '9606', (184, 189))	('BRCAPRO', 'Gene', (56, 63))	('women', 'Species', '9606', (6, 11))	('BRCA1/2', 'Gene', '672;675', (137, 144))	('BRCA1/2', 'Gene', (137, 144))	('mutation', 'Var', (145, 153))
15954	21149333	Pathologic studies of breast tissue from mutation carriers undergoing mastectomy have additionally supported a high prevalence of pre-malignant lesions including DCIS and LCIS in mutation carriers as well as high-risk mutation-negative women.	('women', 'Species', '9606', (236, 241))	('mutation', 'Var', (179, 187))	('LCIS', 'Disease', (171, 175))	('DCIS', 'Disease', (162, 166))
15955	21149333	The identification of a BRCA1/2 mutation has important implications for mutation carriers.	('BRCA1/2', 'Gene', '672;675', (24, 31))	('mutation', 'Var', (32, 40))	('BRCA1/2', 'Gene', (24, 31))
15956	21149333	Deleterious mutations in the BRCA1/2 genes are the principal cause of hereditary breast-ovarian cancer (HBOC).	('cause', 'Reg', (61, 66))	('hereditary breast-ovarian cancer', 'Disease', 'MESH:D061325', (70, 102))	('Deleterious mutations', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA1/2', 'Gene', (29, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('BRCA1/2', 'Gene', '672;675', (29, 36))	('hereditary breast-ovarian cancer', 'Disease', (70, 102))
15957	21149333	The lifetime risk of breast cancer in mutation carriers has been reported to be as high as 87%.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('mutation', 'Var', (38, 46))
15958	21149333	The risks of ovarian cancer (as high as 44% in mutation carriers by age 70) and contra-lateral breast cancer are also elevated.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('mutation', 'Var', (47, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('ovarian cancer', 'Disease', (13, 27))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
15960	21149333	Among the first 10,000 women undergoing genetic testing through Myriad, 13% of women diagnosed with CIS before the age of 50 had a deleterious (disease-causing) BRCA1/2 mutation.	('mutation', 'Var', (169, 177))	('women', 'Species', '9606', (23, 28))	('BRCA1/2', 'Gene', '672;675', (161, 168))	('women', 'Species', '9606', (79, 84))	('BRCA1/2', 'Gene', (161, 168))	('CIS', 'Disease', (100, 103))
15961	21149333	Here, we report the prevalence of deleterious BRCA1/2 mutations in women reporting CIS from a large sample of consecutive individuals referred for comprehensive BRCA1/2 genetic testing using DNA sequencing and rearrangement testing technology.	('CIS', 'Disease', (83, 86))	('women', 'Species', '9606', (67, 72))	('BRCA1/2', 'Gene', '672;675', (161, 168))	('BRCA1/2', 'Gene', (46, 53))	('mutations', 'Var', (54, 63))	('BRCA1/2', 'Gene', (161, 168))	('BRCA1/2', 'Gene', '672;675', (46, 53))
15962	21149333	Established in 1996, the Myriad BRCA1/2 clinical database organizes the personal and family cancer history and mutation data collected on all individuals tested for BRCA1 and BRCA2 mutations, and is supported by Myriad Genetic Laboratories (Myriad).	('BRCA1', 'Gene', (32, 37))	('BRCA1', 'Gene', (165, 170))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('BRCA1/2', 'Gene', (32, 39))	('BRCA2', 'Gene', (175, 180))	('mutations', 'Var', (181, 190))	('BRCA1', 'Gene', '672', (32, 37))	('BRCA1/2', 'Gene', '672;675', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA1', 'Gene', '672', (165, 170))	('BRCA2', 'Gene', '675', (175, 180))
15963	21149333	The database includes all individuals who have undergone testing, including those receiving: 1) full-sequence DNA analysis of the BRCA1/2 genes; 2) site-specific DNA testing for persons with a known familial mutation; 3) founder panel testing at three sites for two highly prevalent mutations in BRCA1 (187delAG and 5385insC) and one in BRCA2 (6174delT) found primarily in the Ashkenazi Jewish population.	('BRCA1', 'Gene', (130, 135))	('BRCA2', 'Gene', '675', (337, 342))	('persons', 'Species', '9606', (178, 185))	('BRCA1', 'Gene', '672', (296, 301))	('5385insC', 'Var', (316, 324))	('6174delT', 'Mutation', 'rs786204278', (344, 352))	('5385insC', 'Mutation', 'c.5385insC', (316, 324))	('BRCA1', 'Gene', (296, 301))	('BRCA1/2', 'Gene', (130, 137))	('BRCA2', 'Gene', (337, 342))	('187delAG', 'Mutation', 'c.187delAG', (303, 311))	('BRCA1', 'Gene', '672', (130, 135))	('187delAG', 'Var', (303, 311))	('BRCA1/2', 'Gene', '672;675', (130, 137))
15964	21149333	This database has been used in part to generate BRCA1/2 mutation and large genomic rearrangement prevalence estimates accessible by the public for clinical and research purposes.	('BRCA1/2', 'Gene', '672;675', (48, 55))	('mutation', 'Var', (56, 64))	('BRCA1/2', 'Gene', (48, 55))
15969	21149333	Full-sequence DNA analysis of BRCA1 and BRCA2 and break-point analysis for five common large genomic rearrangements in BRCA1 (exon13del3835bp, exon13ins6kb, exon14-20del26kb, exon22del510bp and exon8-9del7.1kb) were performed.	('BRCA1', 'Gene', (30, 35))	('9del7', 'Mutation', 'c.9del7', (200, 205))	('BRCA1', 'Gene', (119, 124))	('exon13ins6kb', 'Var', (143, 155))	('exon8-9del7.1kb', 'Var', (194, 209))	('exon22del510bp', 'Var', (175, 189))	('exon13del3835bp', 'Var', (126, 141))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (30, 35))	('exon14-20del26kb', 'Var', (157, 173))	('BRCA1', 'Gene', '672', (119, 124))	('BRCA2', 'Gene', '675', (40, 45))
15970	21149333	In a subset of severe risk women negative by full-sequence DNA analysis and rearrangement testing, additional testing for several rare BRCA1 and BRCA2 large gene deletions and rearrangements (BART ) using quantitative multiplex PCR was performed.	('BART', 'Gene', (192, 196))	('BRCA2', 'Gene', (145, 150))	('BRCA1', 'Gene', '672', (135, 140))	('BRCA2', 'Gene', '675', (145, 150))	('rearrangements', 'Var', (176, 190))	('BRCA1', 'Gene', (135, 140))	('BART', 'Gene', '23568', (192, 196))	('women', 'Species', '9606', (27, 32))
15971	21149333	Stringent primer design to avoid common sequence variants, interspersion of BRCA1 and BRCA2 amplicons to minimize the potential of contiguous artifacts, optimized chemistries for GC rich regions, and robust analytical software tools provide a sensitive assay that identifies BRCA1 and BRCA2 rearrangements The age at which subjects were diagnosed with CIS or invasive cancer was treated as a continuous variable.	('BRCA2', 'Gene', (86, 91))	('BRCA2', 'Gene', (285, 290))	('BRCA1', 'Gene', '672', (275, 280))	('CIS', 'Disease', (352, 355))	('variants', 'Var', (49, 57))	('BRCA2', 'Gene', '675', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('BRCA1', 'Gene', (275, 280))	('BRCA2', 'Gene', '675', (285, 290))	('BRCA1', 'Gene', '672', (76, 81))	('invasive cancer', 'Disease', (359, 374))	('BRCA1', 'Gene', (76, 81))	('rearrangements', 'Var', (291, 305))	('invasive cancer', 'Disease', 'MESH:D009362', (359, 374))
15972	21149333	The association of early vs late age of CIS diagnosis to BRCA1/2 mutation status was assessed by the chi2 test and reported as an odds ratio (OR).	('BRCA1/2', 'Gene', (57, 64))	('BRCA1/2', 'Gene', '672;675', (57, 64))	('mutation', 'Var', (65, 73))
15977	21149333	DNA full-sequence analysis of BRCA1/2 revealed deleterious mutations in 5.9% (428/7295) of all tested subjects with CIS (any reported CIS).	('BRCA1/2', 'Gene', '672;675', (30, 37))	('BRCA1/2', 'Gene', (30, 37))	('mutations', 'Var', (59, 68))
15979	21149333	The prevalence of CIS stratified by personal history, family history, and BRCA1/2 mutation status is presented in Table 1.	('mutation', 'Var', (82, 90))	('BRCA1/2', 'Gene', (74, 81))	('BRCA1/2', 'Gene', '672;675', (74, 81))
15981	21149333	Here, it can be seen that a personal history of CIS but no invasive cancer (CIS alone+CIS and any family history subgroups) is a less powerful predictor of carrying a BRCA1/2 mutation than a personal history of invasive cancer (no personal history of CIS) [OR 0.42 (95% CI 0.37-0.48)].	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BRCA1/2', 'Gene', '672;675', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('mutation', 'Var', (175, 183))	('invasive cancer', 'Disease', 'MESH:D009362', (211, 226))	('invasive cancer', 'Disease', (59, 74))	('BRCA1/2', 'Gene', (167, 174))	('invasive cancer', 'Disease', 'MESH:D009362', (59, 74))	('invasive cancer', 'Disease', (211, 226))
15982	21149333	The distribution of BRCA1/2 mutations in CIS (CIS alone+CIS and any family history subgroups) also differs from that of invasive breast cancer (no personal history of CIS), in that BRCA2 mutations are more prevalent in the former [OR 3.25 (95% CI 2.43-4.39)] (see Table 2).	('prevalent', 'Reg', (206, 215))	('BRCA2', 'Gene', '675', (181, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('invasive breast cancer', 'Disease', 'MESH:D001943', (120, 142))	('mutations', 'Var', (187, 196))	('mutations', 'Var', (28, 37))	('BRCA2', 'Gene', (181, 186))	('BRCA1/2', 'Gene', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('invasive breast cancer', 'Disease', (120, 142))
15985	21149333	Among women in the CIS alone+CIS and any family history subgroups (CIS and any personal history excluded), those with early-onset CIS had a significantly increased risk of a BRCA1/2 mutation compared to women with late-onset disease (>= 50 years)(OR 1.5, 95% CI 1.1-2.1).	('BRCA1/2', 'Gene', '672;675', (174, 181))	('late-onset disease', 'Disease', (214, 232))	('women', 'Species', '9606', (6, 11))	('late-onset disease', 'Disease', 'MESH:D020518', (214, 232))	('mutation', 'Var', (182, 190))	('women', 'Species', '9606', (203, 208))	('BRCA1/2', 'Gene', (174, 181))
15989	21149333	Forty-one (8.4%) were found to carry a BRCA1/2 mutation (all were tested for BRCA1/2 after the diagnosis of invasive breast cancer).	('mutation', 'Var', (47, 55))	('BRCA1/2', 'Gene', (77, 84))	('BRCA1/2', 'Gene', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('BRCA1/2', 'Gene', '672;675', (77, 84))	('BRCA1/2', 'Gene', '672;675', (39, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
15992	21149333	Claus et al reported BRCA1/2 mutation prevalence of 3.3% (12/369) in a population-based sample of women with DCIS from the Connecticut Tumor Registry.	('mutation', 'Var', (29, 37))	('BRCA1/2', 'Gene', '672;675', (21, 28))	('women', 'Species', '9606', (98, 103))	('Tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BRCA1/2', 'Gene', (21, 28))
15993	21149333	Carrier status was significantly associated with a personal history of ovarian cancer or early-onset breast cancer, and a family history of breast cancer in a first-degree relative, particularly when early-onset (OR 10.6, CI 3.0-37.0).	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('ovarian cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('associated', 'Reg', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('Carrier status', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
15995	21149333	Most importantly, the exclusion of Ashkenazi Jewish individuals from the current study, among whom BRCA1/2 mutations are more frequent due to the presence of three well-described founder mutations in the Ashkenazi population, would be expected to result in comparatively lower prevalence estimates than those of Claus et al.	('mutations', 'Var', (107, 116))	('prevalence', 'MPA', (277, 287))	('lower', 'NegReg', (271, 276))	('BRCA1/2', 'Gene', (99, 106))	('BRCA1/2', 'Gene', '672;675', (99, 106))
15996	21149333	The inability to confirm histology on all tested patients, allowing the exclusion of women with lobular carcinoma in situ, a pre-invasive pathology that has not been associated with BRCA1/2 mutations, or other non-DCIS histologies, would also be expected to result in lower prevalence estimates in our sample subgroups.	('lobular carcinoma in situ', 'Disease', (96, 121))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (96, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('BRCA1/2', 'Gene', '672;675', (182, 189))	('mutations', 'Var', (190, 199))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (104, 121))	('prevalence', 'MPA', (274, 284))	('lower', 'NegReg', (268, 273))	('women', 'Species', '9606', (85, 90))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (96, 121))	('patients', 'Species', '9606', (49, 57))	('BRCA1/2', 'Gene', (182, 189))
15999	21149333	In Hwang et al, breast cancer and risk factor related data on a cohort of women self- or physician-referred for genetic testing were examined retrospectively, and DCIS was identified more commonly among mutation carriers compared to non-carriers (37% vs 34%).	('breast cancer', 'Disease', (16, 29))	('women', 'Species', '9606', (74, 79))	('DCIS', 'Disease', (163, 167))	('mutation', 'Var', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
16000	21149333	In multivariate modeling, mutation carriers were found to have greater hazard for DCIS [1.45 (0.98-2.14)] and invasive cancer [1.60 (1.12-2.30)] compared to non-carriers.	('invasive cancer', 'Disease', 'MESH:D009362', (110, 125))	('mutation', 'Var', (26, 34))	('invasive cancer', 'Disease', (110, 125))	('DCIS', 'Disease', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
16001	21149333	Smith et al examined the relationship of DCIS to BRCA1/2 mutations through three non-overlapping groups ascertained through a large urban-based cancer center.	('BRCA1/2', 'Gene', '672;675', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BRCA1/2', 'Gene', (49, 56))
16005	21149333	In a heterogeneous clinical referral population tested for BRCA1/2 mutations, we demonstrate the contribution of various components of personal and family history of in situ and invasive cancer to the prevalence of BRCA1/2 mutations, and show that early-onset CIS (age of onset < 50 years) in a population unselected for family history is significantly associated (OR 1.5, 95% CI 1.1-2.1) with the presence of a deleterious mutation by full-sequence DNA testing.	('mutation', 'Var', (424, 432))	('mutations', 'Var', (223, 232))	('invasive cancer', 'Disease', (178, 193))	('BRCA1/2', 'Gene', '672;675', (59, 66))	('mutations', 'Var', (67, 76))	('BRCA1/2', 'Gene', (215, 222))	('invasive cancer', 'Disease', 'MESH:D009362', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('early-onset CIS', 'Disease', (248, 263))	('BRCA1/2', 'Gene', '672;675', (215, 222))	('BRCA1/2', 'Gene', (59, 66))
16008	21149333	While all patients with CIS are at increased risk for another breast cancer event, those with a BRCA1/2 mutation have a very high lifetime risk of breast cancer and also have a significantly elevated risk of ovarian cancer.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('ovarian cancer', 'Disease', (208, 222))	('BRCA1/2', 'Gene', '672;675', (96, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('mutation', 'Var', (104, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (208, 222))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BRCA1/2', 'Gene', (96, 103))	('ovarian cancer', 'Disease', 'MESH:D010051', (208, 222))
16009	21149333	Thus, the knowledge of a BRCA1/2 mutation is likely to significantly change the assessment of their risks for future cancers and the cancer prevention and risk reduction recommendations that would be considered.	('mutation', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRCA1/2', 'Gene', '672;675', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('change', 'Reg', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('BRCA1/2', 'Gene', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Disease', (117, 124))
16010	21149333	Women made aware of a germ-line BRCA1/2 mutation may consider several screening and prophylaxis options to lower their breast and/or ovarian cancer risk, including the use of magnetic resonance imaging (MRI) to screen for breast cancer, surgical prophylaxis options such as mastectomy or salpingo-oophorectomy, or chemoprevention (e.g.	('mutation', 'Var', (40, 48))	('breast cancer', 'Disease', (222, 235))	('salpingo-oophorectomy', 'Disease', (288, 309))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lower', 'NegReg', (107, 112))	('BRCA1/2', 'Gene', (32, 39))	('BRCA1/2', 'Gene', '672;675', (32, 39))	('breast and/or ovarian cancer', 'Disease', (119, 147))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (119, 147))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
16024	21149333	As would be expected, the likelihood of a woman with CIS carrying a BRCA1/2 mutation increases not only with a diagnosis of invasive breast cancer but also as family history strengthens and age of CIS diagnosis decreases, permitting counseling and testing resources to be targeted more effectively.	('BRCA1/2', 'Gene', '672;675', (68, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('invasive breast cancer', 'Disease', (124, 146))	('BRCA1/2', 'Gene', (68, 75))	('woman', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutation', 'Var', (76, 84))	('increases', 'PosReg', (85, 94))	('invasive breast cancer', 'Disease', 'MESH:D001943', (124, 146))
16027	21149333	CIS may be more strongly associated with BRCA2 mutations.	('BRCA2', 'Gene', (41, 46))	('BRCA2', 'Gene', '675', (41, 46))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (25, 35))
16029	21149333	Women reporting CIS preceding a diagnosis of invasive breast cancer represented a small portion of our sample, and we did not find a difference in the mean reported time interval between CIS and invasive cancer in mutation carriers versus non-carriers.	('Women', 'Species', '9606', (0, 5))	('invasive breast cancer', 'Disease', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutation carriers', 'Var', (214, 231))	('invasive cancer', 'Disease', (195, 210))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('invasive cancer', 'Disease', 'MESH:D009362', (195, 210))	('invasive breast cancer', 'Disease', 'MESH:D001943', (45, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
16030	21149333	Because CIS and invasive breast cancer diagnosis histories were collected independent of mutation status, this represents an interesting finding, but one that should not be over-interpreted, as these data cannot account for differential screening biases that may have existed in these two groups, affecting both the timing of each diagnosis and the duration of the time interval in between them.	('affecting', 'Reg', (297, 306))	('invasive breast cancer', 'Disease', 'MESH:D001943', (16, 38))	('mutation', 'Var', (89, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('invasive breast cancer', 'Disease', (16, 38))
16079	15812557	The majority of invasive cancers were of relatively small size with 37.8% <=10 mm in maximum dimension and 83.4% <=20 mm.	('invasive cancers', 'Disease', (16, 32))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('invasive cancers', 'Disease', 'MESH:D009362', (16, 32))	('<=10', 'Var', (74, 78))
16131	17986321	Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment.	('increased', 'PosReg', (87, 96))	('tetracycline', 'Chemical', 'MESH:D013752', (28, 40))	('tetracycline-induced', 'Var', (28, 48))	('IFN-gamma', 'Gene', '3458', (143, 152))	('IFN-gamma', 'Gene', (143, 152))
16139	17986321	Consequently, psoriasin expression was shown to correlate to increased survival and NFkappaB signaling.	('NFkappaB', 'Gene', (84, 92))	('NFkappaB', 'Gene', '4790', (84, 92))	('survival', 'CPA', (71, 79))	('increased', 'PosReg', (61, 70))	('expression', 'Var', (24, 34))	('psoriasin', 'Gene', (14, 23))
16166	17986321	Western blot analyses of cell lysate were produced with anti-psoriasin (mouse-Ab) (Imgenex, San Diego, CA, USA), anti-tubulin beta (mouse-Ab) (Neomarkers, Freemont, CA, USA), anti-Stat1alpha (mouse-Ab), anti-p-Stat1 (rabbit-Ab), anti-calgranulin A (mouse-Ab), anti-Caspase-3 (mouse-Ab) and anti-GAPDH (rabbit-Ab) (Santa Cruz Biotechnology, USA).	('anti-tubulin', 'Var', (113, 125))	('rabbit', 'Species', '9986', (302, 308))	('Stat1', 'Gene', (210, 215))	('Stat1', 'Gene', (180, 185))	('mouse', 'Species', '10090', (192, 197))	('Caspase-3', 'Gene', (265, 274))	('Stat1', 'Gene', '20846', (210, 215))	('anti-calgranulin', 'Var', (229, 245))	('mouse', 'Species', '10090', (72, 77))	('mouse', 'Species', '10090', (276, 281))	('Stat1', 'Gene', '20846', (180, 185))	('Caspase-3', 'Gene', '12367', (265, 274))	('mouse', 'Species', '10090', (132, 137))	('mouse', 'Species', '10090', (249, 254))	('rabbit', 'Species', '9986', (217, 223))	('GAPDH', 'Gene', '14433', (295, 300))	('GAPDH', 'Gene', (295, 300))
16202	17986321	Figure 5 shows that dnIkkbeta suppresses psoriasin induction and leads to the accumulation of the NFkappaB inhibitor IkappaBalpha.	('IkappaBalpha', 'Gene', '4792', (117, 129))	('IkappaBalpha', 'Gene', (117, 129))	('NFkappaB', 'Gene', (98, 106))	('suppresses', 'NegReg', (30, 40))	('NFkappaB', 'Gene', '4790', (98, 106))	('dnIkkbeta', 'Var', (20, 29))	('psoriasin', 'Protein', (41, 50))	('accumulation', 'PosReg', (78, 90))
16203	17986321	There was no difference in pro-caspase-3 level after dnIkkbeta expression and IFN-gamma treatment, suggesting that the reduction in the induction of psoriasin following the expression of dnIkkbeta and IFN-gamma is not due to increased apoptosis (Figure 5).	('induction', 'MPA', (136, 145))	('dnIkkbeta', 'Var', (187, 196))	('IFN-gamma', 'Gene', (201, 210))	('pro-caspase-3', 'Gene', (27, 40))	('IFN-gamma', 'Gene', '3458', (201, 210))	('pro-caspase-3', 'Gene', '836', (27, 40))	('IFN-gamma', 'Gene', '3458', (78, 87))	('IFN-gamma', 'Gene', (78, 87))	('reduction', 'NegReg', (119, 128))	('psoriasin', 'Protein', (149, 158))
16232	17986321	ROS thus lead to the endogenous production of psoriasin, which may contribute to apoptosis resistance in DCIS and psoriasis.	('ROS', 'Var', (0, 3))	('apoptosis resistance', 'CPA', (81, 101))	('endogenous', 'MPA', (21, 31))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('psoriasis', 'Disease', (114, 123))	('psoriasis', 'Disease', 'MESH:D011565', (114, 123))	('psoriasis', 'Phenotype', 'HP:0003765', (114, 123))	('DCIS', 'Disease', (105, 109))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('lead to', 'Reg', (9, 16))	('contribute', 'Reg', (67, 77))
16481	32448217	This suggests that for IDC in particular, BSGI is superior to ultrasound and mammography for the diagnosis of BI-RADS 4 category lesions, although this was less apparent for the diagnosis of DCIS lesions.	('DCIS lesions', 'Disease', 'MESH:D002285', (191, 203))	('BI-RADS', 'Var', (110, 117))	('IDC', 'Disease', (23, 26))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('DCIS lesions', 'Disease', (191, 203))
16512	32448217	Breast density is also strongly correlated with the risk of breast cancer.	('breast cancer', 'Disease', (60, 73))	('correlated', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('Breast', 'Var', (0, 6))
16516	32448217	reported on 93 cases of BI-RADS 4 breast lesions detected via mammography, with a positive rate of biopsy of 14%.	('breast lesions', 'Disease', 'MESH:D001943', (34, 48))	('breast lesions', 'Disease', (34, 48))	('BI-RADS', 'Var', (24, 31))
16564	31898097	In multivariable analysis, increased breast density (BIRADS C/D vs A/B) was significantly associated with increased hazard of breast cancer (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.52-3.88) whereas BMI was not.	('increased', 'PosReg', (27, 36))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('BIRADS C/D', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast density', 'CPA', (37, 51))
16578	31898097	Women were excluded if they had a known BRCA mutation, a prior or concurrent cancer (defined as cancer diagnosed within 6 months of LCIS diagnosis), pleomorphic LCIS, missing BMI or breast density values, or if they did not return for at least 1 follow-up appointment after their initial visit.	('Women', 'Species', '9606', (0, 5))	('pleomorphic LCIS', 'Disease', (149, 165))	('LCIS', 'Phenotype', 'HP:0030076', (161, 165))	('BMI', 'CPA', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BRCA', 'Gene', '672', (40, 44))	('LCIS', 'Phenotype', 'HP:0030076', (132, 136))	('mutation', 'Var', (45, 53))	('breast density values', 'CPA', (182, 203))	('BRCA', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (96, 102))	('missing', 'NegReg', (167, 174))
16599	31898097	Cancer-free probability, however, was significantly lower in patients with BIRADS C/D versus A/B breast density (p<0.001), with a 10-year CFS of 0.81 (95% CI 0.78-0.84) in patients with BIRADS C/D breast density as compared to a 10-year CFS of 0.89 (95% CI 0.85-0.94) in patients with BIRADS A/B breast density (Fig.	('a 10', 'Gene', '28870', (227, 231))	('a 10', 'Gene', (227, 231))	('a 10', 'Gene', '28870', (128, 132))	('a 10', 'Gene', (128, 132))	('lower', 'NegReg', (52, 57))	('patients', 'Species', '9606', (61, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('BIRADS C/D', 'Var', (186, 196))	('patients', 'Species', '9606', (271, 279))	('patients', 'Species', '9606', (172, 180))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('BIRADS C/D', 'Var', (75, 85))
16637	29114882	A comprehensive analysis of polymorphic variants in steroid hormone and insulin-like growth factor-1 metabolism and risk of in situ breast cancer: Results from the Breast and Prostate Cancer Cohort Consortium We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific.	('single nucleotide polymorphisms', 'Var', (251, 282))	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('steroid hormone', 'Chemical', 'MESH:D013256', (339, 354))	('insulin-like growth factor 1', 'Gene', '3479', (360, 388))	('breast cancer', 'Phenotype', 'HP:0003002', (402, 415))	('insulin-like growth factor-1', 'Gene', (72, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (175, 190))	('breast cancer', 'Disease', 'MESH:D001943', (402, 415))	('situ breast cancer', 'Disease', 'MESH:D000071960', (127, 145))	('breast cancer', 'Disease', (402, 415))	('steroid hormones', 'Chemical', 'MESH:D013256', (339, 355))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('steroid hormone', 'Chemical', 'MESH:D013256', (52, 67))	('association', 'Interaction', (225, 236))	('situ breast cancer', 'Disease', (127, 145))	('insulin-like growth factor 1', 'Gene', (360, 388))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('insulin-like growth factor-1', 'Gene', '3479', (72, 100))	('Breast and Prostate Cancer', 'Disease', 'MESH:D011471', (164, 190))
16643	29114882	However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein.	('the protein', 'Protein', (110, 121))	('rs10500204', 'Mutation', 'rs10500204', (57, 67))	('influence', 'Reg', (85, 94))	('protein', 'Protein', (114, 121))	('rs10500204', 'Var', (57, 67))	('binding', 'Interaction', (99, 106))
16648	29114882	A previous study conducted within the Million Women Study identified 2p-rs4666451 as being more strongly associated with BCIS risk than with invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (141, 157))	('BCIS risk', 'Disease', (121, 130))	('invasive disease', 'Disease', (141, 157))	('Women', 'Species', '9606', (46, 51))	('associated', 'Reg', (105, 115))	('rs4666451', 'Mutation', 'rs4666451', (72, 81))	('2p-rs4666451', 'Var', (69, 81))
16649	29114882	Additionally, a study within the Breast Cancer Association Consortium (BCAC) found that the SNP 5p12-rs10941679 was more strongly associated with DCIS and lower grade tumors.	('rs10941679', 'Mutation', 'rs10941679', (101, 111))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('DCIS', 'Disease', (146, 150))	('Breast Cancer', 'Disease', 'MESH:D001943', (33, 46))	('Breast Cancer', 'Disease', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Breast Cancer', 'Phenotype', 'HP:0003002', (33, 46))	('SNP', 'Var', (92, 95))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('associated', 'Reg', (130, 140))
16652	29114882	In a previous effort, we investigated 1,414 SNPs in 37 steroid hormone metabolism genes and 24 insulin-like growth factor 1 (IGF-I) pathway genes in relation to invasive BC susceptibility.	('IGF-I', 'Gene', (125, 130))	('insulin-like growth factor 1', 'Gene', '3479', (95, 123))	('invasive BC', 'Disease', (161, 172))	('SNPs', 'Var', (44, 48))	('steroid hormone metabolism genes', 'Gene', (55, 87))	('IGF-I', 'Gene', '3479', (125, 130))	('steroid hormone', 'Chemical', 'MESH:D013256', (55, 70))	('insulin-like growth factor 1', 'Gene', (95, 123))
16653	29114882	While only modest associations between the selected SNPs and BC were detected, there is convincing epidemiologic and molecular evidence that the concentrations of endogenous steroid hormones and IGF play a crucial role in modulating the risk of developing BC, and it is possible that genetic variants in those pathways could influence early and non-invasive as well as more advanced stages of disease development.	('modulating', 'Reg', (222, 232))	('steroid hormones', 'Chemical', 'MESH:D013256', (174, 190))	('genetic variants', 'Var', (284, 300))	('influence', 'Reg', (325, 334))
16659	29114882	These included the RegulomeDB (http://regulome.stanford.edu/), which was used to investigate possible regulatory effects of the identified alleles or of other alleles in the surrounding region, and HaploReg v4.1 which facilitated the identification of other SNPs in high LD with the variants in our study.	('v4.1', 'Gene', '28783', (207, 211))	('variants', 'Var', (283, 291))	('v4.1', 'Gene', (207, 211))
16660	29114882	The mean SNP call rate was 99.36%, with the lowest (98.55%) observed for rs10500204 and the highest (99.88%) for rs238112.	('lowest', 'NegReg', (44, 50))	('rs10500204', 'Var', (73, 83))	('rs238112', 'Mutation', 'rs238112', (113, 121))	('rs10500204', 'Mutation', 'rs10500204', (73, 83))	('SNP call rate', 'CPA', (9, 22))	('rs238112', 'Var', (113, 121))
16668	29114882	According to information derived from the RegulomeDB (http://regulome.stanford.edu/), rs10500204 is likely to affect binding (RegulomeDB score = 2b) of the following proteins: promyelocytic leukemia (PML), DNA-binding protein Ikaros (IKZF1), Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) and Max-interacting protein 1 (MXI1).	('rs10500204', 'Var', (86, 96))	('affect', 'Reg', (110, 116))	('binding', 'Interaction', (117, 124))	('IKZF1', 'Gene', (234, 239))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('Nuclear factor of activated T-cells, cytoplasmic 1', 'Gene', '4772', (242, 292))	('MXI1', 'Gene', (333, 337))	('rs10500204', 'Mutation', 'rs10500204', (86, 96))	('Max-interacting protein 1', 'Gene', '4601', (306, 331))	('DNA-binding protein Ikaros', 'Gene', '10320', (206, 232))	('promyelocytic leukemia (PML)', 'Gene', '5371', (176, 204))	('MXI1', 'Gene', '4601', (333, 337))	('IKZF1', 'Gene', '10320', (234, 239))	('Max-interacting protein 1', 'Gene', (306, 331))	('NFATC1', 'Gene', '4772', (294, 300))	('DNA-binding protein Ikaros', 'Gene', (206, 232))	('promyelocytic leukemia (PML', 'Gene', (176, 203))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (176, 198))	('NFATC1', 'Gene', (294, 300))
16669	29114882	Additionally, using HaploReg v4.1, 35 SNPs in moderate to high LD (R2 > 0.6) with rs10500204 were identified.	('v4.1', 'Gene', '28783', (29, 33))	('rs10500204', 'Mutation', 'rs10500204', (82, 92))	('v4.1', 'Gene', (29, 33))	('rs10500204', 'Var', (82, 92))
16670	29114882	Out of these 35 SNPs, HaploReg provided information on functionality for only four (rs3815902, rs2059806, rs3786681, rs6510956), and none of them appeared to be functionally related to BCIS.	('rs6510956', 'Mutation', 'rs6510956', (117, 126))	('rs6510956', 'Var', (117, 126))	('rs3815902', 'Mutation', 'rs3815902', (84, 93))	('rs2059806', 'Var', (95, 104))	('rs2059806', 'Mutation', 'rs2059806', (95, 104))	('rs3786681', 'Var', (106, 115))	('rs3815902', 'Var', (84, 93))	('rs3786681', 'Mutation', 'rs3786681', (106, 115))
16673	29114882	Mutations in this gene have been involved in insulin resistance as well as in several types of obesity related invasive cancers, such as colorectal, pancreatic, liver and BC.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('involved', 'Reg', (33, 41))	('liver', 'Disease', (161, 166))	('pancreatic', 'Disease', (149, 159))	('obesity', 'Disease', 'MESH:D009765', (95, 102))	('colorectal', 'Disease', 'MESH:D015179', (137, 147))	('obesity', 'Disease', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (120, 127))	('insulin', 'Gene', (45, 52))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('obesity', 'Phenotype', 'HP:0001513', (95, 102))	('colorectal', 'Disease', (137, 147))	('insulin resistance', 'Phenotype', 'HP:0000855', (45, 63))	('insulin', 'Gene', '3630', (45, 52))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))
16675	29114882	The SNP rs10500204 is located in an intron of the INSR gene and according to information found in the RegulomeDB, it likely affects binding of the PML protein.	('INSR', 'Gene', (50, 54))	('rs10500204', 'Var', (8, 18))	('PML', 'Gene', '5371', (147, 150))	('INSR', 'Gene', '3643', (50, 54))	('PML', 'Gene', (147, 150))	('binding', 'Interaction', (132, 139))	('rs10500204', 'Mutation', 'rs10500204', (8, 18))	('affects', 'Reg', (124, 131))
16676	29114882	Mutations in the PML gene have been related to various insulin resistance syndromes and the PML protein has been associated with tumor suppression in patients of acute PML and is also known to be a tumor suppressor and growth regulator in cancer.	('protein', 'Protein', (96, 103))	('insulin resistance', 'Phenotype', 'HP:0000855', (55, 73))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('PML', 'Gene', (168, 171))	('patients', 'Species', '9606', (150, 158))	('PML', 'Gene', (17, 20))	('tumor', 'Disease', (129, 134))	('related', 'Reg', (36, 43))	('PML', 'Gene', '5371', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (239, 245))	('insulin', 'Gene', '3630', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('PML', 'Gene', '5371', (168, 171))	('PML', 'Gene', '5371', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('PML', 'Gene', (92, 95))	('insulin', 'Gene', (55, 62))	('associated', 'Reg', (113, 123))
16678	29114882	Taken together, this information suggests a protective effect of the PML gene on tumorigenesis, and one might hypothesize that the A-allele of rs10500204 could decrease the effect of the PML gene while the minor allele (C) enhances the binding of PML to the INSR gene.	('decrease', 'NegReg', (160, 168))	('effect', 'MPA', (173, 179))	('PML', 'Gene', (187, 190))	('PML', 'Gene', '5371', (247, 250))	('INSR', 'Gene', '3643', (258, 262))	('rs10500204', 'Mutation', 'rs10500204', (143, 153))	('PML', 'Gene', '5371', (187, 190))	('PML', 'Gene', '5371', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('INSR', 'Gene', (258, 262))	('PML', 'Gene', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('enhances', 'PosReg', (223, 231))	('binding', 'Interaction', (236, 243))	('PML', 'Gene', (69, 72))	('rs10500204', 'Var', (143, 153))	('tumor', 'Disease', (81, 86))
16679	29114882	Our study focuses on selected SNPs in genes related to steroid hormone metabolism and IGF-1-pathways that are known to be involved in breast carcinogenesis.	('breast carcinogenesis', 'Disease', (134, 155))	('involved', 'Reg', (122, 130))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (134, 155))	('SNPs', 'Var', (30, 34))	('steroid hormone', 'Chemical', 'MESH:D013256', (55, 70))	('IGF-1', 'Gene', '3479', (86, 91))	('IGF-1', 'Gene', (86, 91))
16715	27704370	Patients with lobular carcinoma in situ, Paget's disease, known BRCA 1/2 mutation, multicentric disease, invasive carcinoma, or contraindications to radiotherapy were excluded from the study.	('lobular carcinoma', 'Disease', 'MESH:D018275', (14, 31))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('invasive carcinoma', 'Disease', 'MESH:D009361', (105, 123))	('lobular carcinoma', 'Disease', (14, 31))	('multicentric disease', 'Disease', 'MESH:C537372', (83, 103))	("Paget's disease", 'Disease', 'MESH:C537701', (41, 56))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('BRCA 1', 'Gene', (64, 70))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (22, 39))	('mutation', 'Var', (73, 81))	('invasive carcinoma', 'Disease', (105, 123))	('BRCA 1', 'Gene', '672', (64, 70))	("Paget's disease", 'Disease', (41, 56))	('multicentric disease', 'Disease', (83, 103))
16732	27704370	Notably, all patients with high DCIS Score results had post-assay recommendations for radiotherapy from both specialties.	('DCIS Score', 'Gene', (32, 42))	('patients', 'Species', '9606', (13, 21))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('high', 'Var', (27, 31))
16758	27704370	While an association between the DCIS Score assay and benefit from radiotherapy has not yet been shown, an initial analysis of the patient cohort in the Ontario study that had BCS plus radiotherapy showed a proportional reduction in local recurrence that translates to a smaller absolute benefit of radiotherapy for patients with low DCIS Score results relative to the absolute benefit for patients with high DCIS Score results.	('local recurrence', 'CPA', (233, 249))	('patients', 'Species', '9606', (390, 398))	('DCIS', 'Phenotype', 'HP:0030075', (409, 413))	('low DCIS', 'Phenotype', 'HP:0200161', (330, 338))	('DCIS', 'Phenotype', 'HP:0030075', (334, 338))	('reduction', 'NegReg', (220, 229))	('patient', 'Species', '9606', (316, 323))	('low', 'Var', (330, 333))	('DCIS', 'Gene', (334, 338))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('patients', 'Species', '9606', (316, 324))	('patient', 'Species', '9606', (390, 397))	('patient', 'Species', '9606', (131, 138))
16801	19824828	A proliferative growth advantage within FEA is postulated to spawn ADH, upon which additional molecular alterations give rise to the last preinvasive stage of breast cancer progression, DCIS.	('alterations', 'Var', (104, 115))	('give rise to', 'Reg', (116, 128))	('proliferative growth advantage', 'CPA', (2, 32))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
16841	19824828	performed a comparative genomic hybridization (CGH)-based analysis of DCIS and invasive carcinoma and revealed that losses of 16q were seen almost exclusively in low- and intermediate-grade DCIS, whereas a higher frequency of 1q gain and 11q loss was observed in intermediate-grade DCIS.	('invasive carcinoma', 'Disease', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('low-', 'Disease', (162, 166))	('losses', 'Var', (116, 122))	('loss', 'NegReg', (242, 246))	('DCIS', 'Phenotype', 'HP:0030075', (282, 286))	('16q', 'Protein', (126, 129))	('invasive carcinoma', 'Disease', 'MESH:D009361', (79, 97))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))
16842	19824828	Analysis of CGH data generated from synchronous and metachronous IDC and DCIS lesions revealed a near-identical pattern of genetic change supporting the direct precursor relationship between DCIS and IDC.	('IDC', 'Gene', (200, 203))	('lesions', 'Var', (78, 85))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('DCIS', 'Disease', (191, 195))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('IDC', 'Gene', '4000', (65, 68))	('IDC', 'Gene', (65, 68))	('IDC', 'Gene', '4000', (200, 203))
16847	19824828	A comprehensive study by O'Connell and colleagues who analyzed LOH in 399 preinvasive breast lesions, revealed LOH in at least 1 of 15 loci studied in 42% and 44% of ADH lesions from noncancerous and cancerous breasts, respectively.	('cancerous breasts', 'Disease', 'MESH:D001943', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('ADH lesions', 'Disease', 'MESH:D007177', (166, 177))	('cancerous breasts', 'Disease', (200, 217))	('ADH lesions', 'Disease', (166, 177))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('LOH', 'Var', (111, 114))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
16868	19824828	Although the study by Ma and colleagues did not identify gene-expression differences that are specific to the distinct preinvasive and invasive stages of breast cancer, unique gene-expression alterations have been associated with different tumors grades.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('gene-expression', 'MPA', (176, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('alterations', 'Var', (192, 203))	('associated', 'Reg', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
16877	19824828	Interestingly, these tumors share genetic changes with both classic ILCs and high-grade IDCs in the form of (a) 16q loss and 1q gain and (b) amplification of 17q12, respectively.	('amplification', 'Var', (141, 154))	('IDC', 'Gene', '4000', (88, 91))	('IDC', 'Gene', (88, 91))	('gain', 'PosReg', (128, 132))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('loss', 'NegReg', (116, 120))	('16q', 'CPA', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
16878	19824828	However, a recent comparative analysis of array CGH data demonstrated that the overall molecular features of pleomorphic ILC are more closely related to those observed in ILC than those seen in IDC, suggesting that pleomorphic ILCs share a common evolutionary association with classic ILC along the low-grade, ER-positive pathway of neoplastic development and that they do not represent high-grade IDCs.	('IDC', 'Gene', (194, 197))	('classic ILC', 'Disease', (277, 288))	('ER', 'Gene', '2099', (310, 312))	('IDC', 'Gene', '4000', (398, 401))	('IDC', 'Gene', (398, 401))	('pleomorphic ILCs', 'Var', (215, 231))	('IDC', 'Gene', '4000', (194, 197))
16887	19824828	As outlined above, comparative genomic and gene-expression analyses of the different stages of breast cancer suggest that breast carcinogenesis evolves along one of two distinct branched pathways of progression defined by tumor grade and loss of chromosome 16q (the two pathway model; see Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast carcinogenesis', 'Disease', (122, 143))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (122, 143))	('loss', 'Var', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
16913	19824828	Furthermore, in agreement with previous studies, the authors observed significant genetic alterations in the neoplastic epithelium of both preinvasive and invasive breast cancers.	('invasive breast cancers', 'Disease', (155, 178))	('preinvasive', 'Disease', (139, 150))	('invasive breast cancers', 'Disease', 'MESH:D001943', (155, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (109, 130))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('genetic alterations', 'Var', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
16919	19824828	Significant gene-expression changes in nonneoplastic stromal and myoepithelial cells, without obvious genetic alterations, suggest that epigenetic modifications may be responsible for alterations in these cells.	('myoepithelial', 'Disease', (65, 78))	('gene-expression', 'MPA', (12, 27))	('myoepithelial', 'Disease', 'MESH:D009208', (65, 78))	('epigenetic modifications', 'Var', (136, 160))	('changes', 'Reg', (28, 35))
16920	19824828	explored the possibility that epigenetic alterations underlie the relatively stable gene-expression phenotype observed in nonneoplastic stromal cells of preinvasive and invasive breast cancer samples.	('invasive breast cancer', 'Disease', 'MESH:D001943', (169, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('epigenetic alterations', 'Var', (30, 52))	('invasive breast cancer', 'Disease', (169, 191))
16923	19824828	Third, and most notably, similar to stromal epigenetic differences observed between normal breast and invasive breast cancer tissues, distinct recurrent epigenetic alterations were observed in DCIS-associated myoepithelial cells as compared with their normal counterparts.	('myoepithelial', 'Disease', 'MESH:D009208', (209, 222))	('epigenetic alterations', 'Var', (153, 175))	('DCIS-associated', 'Gene', (193, 208))	('invasive breast cancer', 'Disease', 'MESH:D001943', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('myoepithelial', 'Disease', (209, 222))	('invasive breast cancer', 'Disease', (102, 124))
16924	19824828	The latter finding strongly suggests that epigenetic changes in nonneoplastic myoepithelial cells play an important role in the establishment and maintenance of the abnormal tumor microenvironment in the preinvasive stage of breast cancer.	('epigenetic changes', 'Var', (42, 60))	('abnormal tumor', 'Disease', 'MESH:D009369', (165, 179))	('nonneoplastic myoepithelial', 'Disease', (64, 91))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('abnormal tumor', 'Phenotype', 'HP:0002664', (165, 179))	('nonneoplastic myoepithelial', 'Disease', 'MESH:D009208', (64, 91))	('abnormal tumor', 'Disease', (165, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))
16938	19824828	Phenotypic, genetic, and epigenetic changes have been detected in the neoplastic epithelium of the preinvasive DCIS stage of breast cancer progression.	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (70, 91))	('detected', 'Reg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('epigenetic', 'Var', (25, 35))
16946	19824828	First, the so called escape model emphasizes the role of neoplastic DCIS epithelial cells and proposes that genetic changes in combination with clonal selection give rise to a subpopulation of neoplastic cells with the ability to disrupt the myoepithelial layer, degrade the basement membrane of the duct, and invade into the surrounding stromal tissue.	('degrade', 'NegReg', (263, 270))	('disrupt', 'NegReg', (230, 237))	('changes', 'Var', (116, 123))	('myoepithelial', 'Disease', (242, 255))	('invade', 'CPA', (310, 316))	('basement membrane of the duct', 'CPA', (275, 304))	('myoepithelial', 'Disease', 'MESH:D009208', (242, 255))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
16947	19824828	The so called release model, however, hypothesizes that alterations in the in the DCIS microenvironment such as phenotypic alterations of myoepithelial, myofibroblastic and fibroblastic cells and infiltration of inflammatory cells lead to the degradation of the basement membrane with subsequent invasion of the neoplastic epithelial cells.	('myoepithelial', 'Disease', (138, 151))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('alterations', 'Var', (56, 67))	('myoepithelial', 'Disease', 'MESH:D009208', (138, 151))	('invasion of the neoplastic epithelial cells', 'CPA', (296, 339))	('degradation', 'MPA', (243, 254))
16948	19824828	Current evidence supports a combination of the two models, in which changes in both the neoplastic epithelial cells and the nonneoplastic myoepithelial and stromal cells result in a tumor microenvironmental signaling network that ultimately facilitates the transition from preinvasive to invasive breast cancer (Figure 7).	('nonneoplastic myoepithelial', 'Disease', (124, 151))	('result in', 'Reg', (170, 179))	('tumor', 'Disease', (182, 187))	('facilitates', 'PosReg', (241, 252))	('nonneoplastic myoepithelial', 'Disease', 'MESH:D009208', (124, 151))	('invasive breast cancer', 'Disease', 'MESH:D001943', (288, 310))	('changes', 'Var', (68, 75))	('preinvasive', 'Disease', (273, 284))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('invasive breast cancer', 'Disease', (288, 310))	('breast cancer', 'Phenotype', 'HP:0003002', (297, 310))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
16959	19824828	Theauthors demonstrated that DCIS with high p16 and/or high COX2 in the absence of cell proliferation reflects a normal protective stress-activation response, that and this phenotype is associated with disease-free progression.	('protective stress-activation response', 'MPA', (120, 157))	('p16', 'Gene', (44, 47))	('high', 'Var', (39, 43))	('COX2', 'Gene', (60, 64))	('COX2', 'Gene', '4513', (60, 64))	('p16', 'Gene', '1029', (44, 47))	('associated', 'Reg', (186, 196))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('DCIS', 'Disease', (29, 33))	('high', 'Var', (55, 59))
16960	19824828	However, DCIS with high p16 and/or high COX2 in the presence of high cellular proliferation was shown to reflect an abrogated (or abnormal) response to cellular stress, and this phenotype is associated progression of DCIS to invasive breast cancer.	('COX2', 'Gene', (40, 44))	('high', 'Var', (19, 23))	('p16', 'Gene', '1029', (24, 27))	('COX2', 'Gene', '4513', (40, 44))	('DCIS', 'Disease', (217, 221))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('p16', 'Gene', (24, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('invasive breast cancer', 'Disease', (225, 247))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('response to cellular stress', 'MPA', (140, 167))	('high', 'Var', (35, 39))	('invasive breast cancer', 'Disease', 'MESH:D001943', (225, 247))
16977	19824828	Distinct genetic, epigenetic and gene-expression alterations occur in breast epithelium at the transition from normal to preinvasive breast cancer.	('epigenetic', 'Var', (18, 28))	('alterations', 'Reg', (49, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('invasive breast cancer', 'Disease', (124, 146))	('gene-expression', 'MPA', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('invasive breast cancer', 'Disease', 'MESH:D001943', (124, 146))
17003	19824828	Clinically, it is well established that high- and low-grade tumors are associated with the highest and lowest rates of recurrence and the shortest and longest recurrence times.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('high-', 'Var', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
17111	19301119	LCIS is thought to increase the risk of developing invasive breast cancer by 3.0- to 4.2-fold, although it is often considered a marker of an increased risk of breast cancer rather than a precursor lesion.	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('LCIS', 'Phenotype', 'HP:0030076', (0, 4))	('invasive breast cancer', 'Disease', (51, 73))	('LCIS', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('invasive breast cancer', 'Disease', 'MESH:D001943', (51, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
17258	14735181	The tumour size distribution is somewhat less favourable, with 15 700 (13.5%) in situ tumours, 42 500 (36.7%) T1a or T1b tumours, and 56 700 (49.8%) T1c or T2+ tumours.	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumours', 'Disease', (160, 167))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (4, 10))	('tumour', 'Disease', (121, 127))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Disease', (86, 93))	('situ tumours', 'Disease', (81, 93))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (160, 166))	('tumour', 'Disease', (160, 166))	('situ tumours', 'Disease', 'MESH:D002278', (81, 93))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (86, 92))	('T1a', 'Var', (110, 113))
17435	26999810	For women aged 50 to 59 years having screening mammography, the proportions in each diagnostic category are 0.516 (benign nonproliferative), 0.133 (benign proliferative), 0.039 (atypia), 0.061 (DCIS), and 0.251 (invasive breast cancer).	('0.039', 'Var', (171, 176))	('invasive breast cancer', 'Disease', (212, 234))	('0.133', 'Var', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('women', 'Species', '9606', (4, 9))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))	('invasive breast cancer', 'Disease', 'MESH:D001943', (212, 234))	('0.061', 'Var', (187, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))
17444	27221361	The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('IBC', 'Chemical', '-', (119, 122))	('invasive breast cancer', 'Disease', 'MESH:D001943', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (127, 151))	('ductal carcinoma in situ', 'Disease', (127, 151))	('Z1072', 'Var', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (55, 60))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (127, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (127, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('invasive breast cancer', 'Disease', (95, 117))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))
17457	27221361	The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining IBC or ductal carcinoma in situ (DCIS) on pathological examination of the targeted lesion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('IBC', 'Disease', (95, 98))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (102, 126))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Z1072', 'Var', (24, 29))	('ductal carcinoma in situ', 'Disease', (102, 126))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (102, 118))	('tumor', 'Disease', (55, 60))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (102, 126))	('IBC', 'Chemical', '-', (95, 98))
17488	27221361	Of the 87 cancers treated with cryoablation and eligible for evaluation, central pathologic review revealed successful cryoablation in 66 (75.9 %) cancers and residual IBC and/or DCIS in 21 (24.1 %) cancers.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('IBC', 'Chemical', '-', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('IBC', 'Disease', (168, 171))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cryoablation', 'Var', (119, 131))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Disease', (147, 154))	('cancers', 'Disease', (199, 206))	('cancers', 'Disease', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))
17504	27221361	Cryoablation of fibroadenomas produces less pain and requires less anesthesia than surgical excision, and does not require removal of normal surrounding breast tissue.	('fibroadenomas', 'Disease', (16, 29))	('pain', 'Phenotype', 'HP:0012531', (44, 48))	('pain', 'Disease', 'MESH:D010146', (44, 48))	('pain', 'Disease', (44, 48))	('fibroadenomas', 'Disease', 'MESH:D018226', (16, 29))	('Cryoablation', 'Var', (0, 12))
17519	27221361	In Z1072, cryoablation was effective in 92 % of targeted lesions and there was 100 % ablation in all tumors <1.0 cm.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Z1072', 'Var', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
17562	19852801	It has been suggested that microcalcification on mammography is an independent predictor of malignancy at follow-up surgical excision in patients diagnosed with ADH at CNB.	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('microcalcification', 'Var', (27, 45))	('patients', 'Species', '9606', (137, 145))	('malignancy', 'Disease', (92, 102))
17607	33255263	In our previous paper it was shown that CP-OCT and C-OCE can be helpful in breast cancer margin identification, as well as for grading breast cancer subtypes.	('CP-OCT', 'Var', (40, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('breast cancer', 'Disease', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('C-OCE', 'Chemical', '-', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('C-OCE', 'Var', (51, 56))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('CP-OCT', 'Chemical', '-', (40, 46))
17704	33255263	Furthermore, we demonstrated the possibility to differentiate invasive low-aggressive breast cancer subtypez with a favorable prognosis from highly-aggressive breast cancer subtypes with a poor prognosis for treatment and the course of the disease (Se-83.5 +- 10.5%, Sp-93.5 +- 6.0%, Ac-87.8 +- 6.5% and Se-87.3 +- 13.8 +- 6.5%, Sp-98.0 +- 3.1%, Ac-89.5 +- 10.0%, respectively).	('invasive low-aggressive breast cancer', 'Disease', 'MESH:D001943', (62, 99))	('Ac-87.8', 'Var', (284, 291))	('Sp-98.0', 'Var', (329, 336))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (148, 172))	('invasive low-aggressive breast cancer', 'Disease', (62, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('aggressive breast cancer', 'Disease', (148, 172))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (75, 99))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Sp-93.5', 'Var', (267, 274))	('Se-87.3', 'Var', (304, 311))
17734	33255263	Even higher was the Ac of CP-OCT and C-OCE for the difference between non-tumorous breast tissue and highly-aggressive breast cancer (97.2 +- 2.8% and 98.3 +- 2.2%, respectively).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumorous breast tissue', 'Disease', (74, 96))	('C-OCE', 'Var', (37, 42))	('CP-OCT', 'Var', (26, 32))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (108, 132))	('aggressive breast cancer', 'Disease', (108, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('C-OCE', 'Chemical', '-', (37, 42))	('tumorous breast tissue', 'Disease', 'MESH:D001943', (74, 96))	('CP-OCT', 'Chemical', '-', (26, 32))
17741	33255263	Furthermore, the preformed study demonstrated high potential of CP-OCT and C-OCE for differentiating particular molecular-biological and morphological subtypes of breast cancer with assessment of the tumor aggressiveness, which is important for subsequent treatment selection.	('CP-OCT', 'Chemical', '-', (64, 70))	('CP-OCT', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor aggressiveness', 'Disease', (200, 220))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('C-OCE', 'Chemical', '-', (75, 80))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('aggressiveness', 'Phenotype', 'HP:0000718', (206, 220))	('breast cancer', 'Disease', (163, 176))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (200, 220))
17781	31514390	Other cellular components:for example, immune cells:play key roles in the evolution of a tumor (i.e., the presence of M2 macrophages accelerates tumor progression).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('accelerates', 'PosReg', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (145, 150))	('presence', 'Var', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
17789	31514390	The nature of these mutations differs for each cancer and in each individual.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
17898	31514390	For example, when Pbase was higher than Ptip, an invasive phenotype was favored (Figure 4c-ii).	('Pbase', 'Var', (18, 23))	('Ptip', 'Gene', (40, 44))	('Ptip', 'Gene', '22976', (40, 44))
17912	31514390	Clusters of cells in co-culture (HMF and MCF10-DCIS) affected the structure (physical appearance under the microscope) of the matrix significantly more than did monocultured MCF10-DCIS cells.	('HMF', 'Chemical', 'MESH:C073815', (33, 36))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('affected', 'Reg', (53, 61))	('structure', 'MPA', (66, 75))	('DCIS', 'Phenotype', 'HP:0030075', (180, 184))	('MCF10-DCIS', 'Var', (41, 51))
18032	31514390	Also, these results suggest that the in vivo size window for effective NP tumor uptake could be narrower than that referred in literature and mainly based on the enhanced permeability and retention (EPR) paradigm; indeed, NPs smaller than 100 nm in diameter could be more effective.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NPs', 'Var', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('enhanced', 'PosReg', (162, 170))	('tumor', 'Disease', (74, 79))
18091	30538501	Compared with the matched group, the PD group had more HER2 positivity (P<0.01) and hormone receptor negativity (P<0.01), and a worse outcome (Kaplan-Meier analysis, P<0.001 for disease-free survival and P=0.002 for overall survival).	('positivity', 'Var', (60, 70))	('hormone receptor', 'Gene', '3164', (84, 100))	('HER2', 'Gene', '2064', (55, 59))	('negativity', 'NegReg', (101, 111))	('hormone receptor', 'Gene', (84, 100))	('HER2', 'Gene', (55, 59))	('PD', 'Disease', 'MESH:D010300', (37, 39))	('more', 'PosReg', (50, 54))
18155	30538501	In addition, the adjusted HR for the overall 5-year survival (2.26) suggested that the presence of PD may independently confer a worse survival.	('PD', 'Disease', 'MESH:D010300', (99, 101))	('presence', 'Var', (87, 95))	('worse', 'NegReg', (129, 134))
18189	29344009	Breast cancer is increasing in younger women due to changes in life-style as well as those at high risk as carriers of mutations in high-penetrance genes.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('women', 'Species', '9606', (39, 44))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (119, 128))	('Breast cancer', 'Disease', (0, 13))
18207	29344009	Women at highest risk, accounting for 5-10% of cases, are those who inherit gene mutations, and have 10- to 30-fold higher chance of developing breast cancer during their lifetime compared to the general population.	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('gene mutations', 'Var', (76, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('inherit', 'Reg', (68, 75))
18208	29344009	Genetic predisposition can be identified initially through investigation of family history of the disease and confirmed by screening for predictive mutations associated with specific high-penetrance genes, such as the BRCA1, BRCA2, TP53 and PTEN genes.	('mutations', 'Var', (148, 157))	('PTEN', 'Gene', (241, 245))	('BRCA2', 'Gene', (225, 230))	('PTEN', 'Gene', '5728', (241, 245))	('BRCA2', 'Gene', '675', (225, 230))	('BRCA1', 'Gene', '672', (218, 223))	('TP53', 'Gene', '7157', (232, 236))	('TP53', 'Gene', (232, 236))	('BRCA1', 'Gene', (218, 223))
18250	29344009	It is therefore not surprising that a comprehensive review of breast cancer biomarkers in 2007 by the Update Committee of the American Society of Clinical Oncology failed to recommend any of the most promising candidates, including blood levels of CA 15-3 and CA 27.29 (both forms of mucin-1) for diagnosis, detection of recurrence, decisions on therapy or metastasis, or circulating truncated extracellular HER2 for detection of breast cancer.	('mucin-1', 'Gene', (284, 291))	('men', 'Species', '9606', (179, 182))	('mucin-1', 'Gene', '4582', (284, 291))	('circulating truncated', 'Var', (372, 393))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CA 15-3', 'Gene', (248, 255))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Disease', 'MESH:D001943', (430, 443))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (430, 443))	('cancer', 'Phenotype', 'HP:0002664', (437, 443))	('breast cancer', 'Disease', (62, 75))	('breast cancer', 'Disease', (430, 443))	('CA 15-3', 'Gene', '4582', (248, 255))	('Oncology', 'Phenotype', 'HP:0002664', (155, 163))	('HER2', 'Gene', (408, 412))	('HER2', 'Gene', '2064', (408, 412))
18366	21371080	In IDC, Fra-1 expression correlated with aggressive phenotype markers, including: high grade, oestrogen receptor negativity and human epidermal growth factor receptor 2 (HER-2) positivity (P = 0.001, 0.015 and 0.004, respectively), and marginally with the presence of metastasis (P = 0.07).	('epidermal growth factor receptor 2', 'Gene', (134, 168))	('epidermal growth factor receptor 2', 'Gene', '2064', (134, 168))	('HER-2', 'Gene', (170, 175))	('IDC', 'Gene', '4000', (3, 6))	('oestrogen receptor negativity', 'Protein', (94, 123))	('Fra-1', 'Gene', '8061', (8, 13))	('IDC', 'Gene', (3, 6))	('expression', 'MPA', (14, 24))	('Fra-1', 'Gene', (8, 13))	('human', 'Species', '9606', (128, 133))	('positivity', 'Var', (177, 187))	('HER-2', 'Gene', '2064', (170, 175))
18423	21371080	In contrast, a comparison between Fra-1 expression and clinico-pathological variables in IDC (Table 4) revealed an association between Fra-1 positivity and histological grade 2 or 3 tumours (P = 0.001), lack of ER expression (P = 0.015) and the presence of HER-2 overexpression (P < 0.004).	('Fra-1', 'Gene', (34, 39))	('overexpression', 'PosReg', (263, 277))	('IDC', 'Gene', '4000', (89, 92))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('IDC', 'Gene', (89, 92))	('lack', 'NegReg', (203, 207))	('Fra-1', 'Gene', (135, 140))	('Fra-1', 'Gene', '8061', (135, 140))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('positivity', 'Var', (141, 151))	('HER-2', 'Gene', '2064', (257, 262))	('tumours', 'Disease', 'MESH:D009369', (182, 189))	('tumours', 'Disease', (182, 189))	('HER-2', 'Gene', (257, 262))	('Fra-1', 'Gene', '8061', (34, 39))
18441	21371080	One might hypothesize that Fra-1 positivity in DCIS results from a growth response of tumour cells following transformation, and is therefore a consequence of malignancy.	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('Fra-1', 'Gene', (27, 32))	('growth', 'MPA', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('malignancy', 'Disease', 'MESH:D009369', (159, 169))	('malignancy', 'Disease', (159, 169))	('positivity', 'Var', (33, 43))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('results from', 'Reg', (52, 64))	('DCIS', 'Disease', (47, 51))	('tumour', 'Disease', (86, 92))	('Fra-1', 'Gene', '8061', (27, 32))
18455	21371080	In IDC, we noted an association of Fra-1 positivity with poor prognostic characteristics, including ER negativity, poor differentiation, and overexpression of HER-2, suggesting an association with aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (197, 215))	('Fra-1', 'Gene', '8061', (35, 40))	('HER-2', 'Gene', (159, 164))	('positivity', 'Var', (41, 51))	('aggressive disease', 'Disease', (197, 215))	('Fra-1', 'Gene', (35, 40))	('association', 'Interaction', (20, 31))	('IDC', 'Gene', '4000', (3, 6))	('IDC', 'Gene', (3, 6))	('poor', 'MPA', (115, 119))	('overexpression', 'PosReg', (141, 155))	('HER-2', 'Gene', '2064', (159, 164))
18457	21371080	It could be that, because of the lack of ER, other factors form complexes with Fra-1, and that changes in AP-1 composition, activation or nuclear retention may induce the expression of genes involved in the establishment of an aggressive phenotype.	('expression', 'MPA', (171, 181))	('Fra-1', 'Gene', (79, 84))	('AP-1', 'Gene', (106, 110))	('complexes', 'Interaction', (64, 73))	('changes', 'Var', (95, 102))	('genes', 'Gene', (185, 190))	('AP-1', 'Gene', '3725', (106, 110))	('nuclear retention', 'CPA', (138, 155))	('induce', 'PosReg', (160, 166))	('Fra-1', 'Gene', '8061', (79, 84))
18459	21371080	In agreement with this, one of the subgroups with the highest percentage of Fra-1 positivity (38.5%) is characterized by negativity for ER and PR and the presence of HER-2 overexpression.	('HER-2', 'Gene', (166, 171))	('positivity', 'Var', (82, 92))	('Fra-1', 'Gene', '8061', (76, 81))	('Fra-1', 'Gene', (76, 81))	('overexpression', 'PosReg', (172, 186))	('negativity', 'NegReg', (121, 131))	('HER-2', 'Gene', '2064', (166, 171))	('PR', 'Gene', '5241', (143, 145))
18463	21371080	The presence of Fra-1 in basal-like carcinomas was expected, as basal-like cultured cells such as MDA-MB 231, BT549, MDA 435S, MX1, BT20 and H5578T cells have been shown to pre-ferentially express Fra-1.	('H5578T', 'Var', (141, 147))	('MDA 435S', 'CellLine', 'CVCL:0417', (117, 125))	('BT549', 'CellLine', 'CVCL:1092', (110, 115))	('H5578T', 'SUBSTITUTION', 'None', (141, 147))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (98, 108))	('MX1', 'Gene', (127, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('Fra-1', 'Gene', (16, 21))	('Fra-1', 'Gene', '8061', (197, 202))	('Fra-1', 'Gene', '8061', (16, 21))	('carcinomas', 'Disease', 'MESH:D002277', (36, 46))	('MX1', 'Gene', '4599', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Fra-1', 'Gene', (197, 202))	('carcinomas', 'Disease', (36, 46))
18524	20981137	Nuclear grade has been found to be associated with both risk of DCIS recurrence, and progression to invasive carcinoma.	('invasive carcinoma', 'Disease', (100, 118))	('associated', 'Reg', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('DCIS recurrence', 'Disease', (64, 79))	('invasive carcinoma', 'Disease', 'MESH:D009361', (100, 118))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('Nuclear grade', 'Var', (0, 13))
18529	20981137	Several studies have compared DCIS to normal tissue, to invasive carcinoma, or to metastatic carcinoma from the same patient by gene expression, protein expression, microsatellite markers, loss of heterozygosity, gene amplification or deletion (CGH), and nuclear image features.	('gene amplification', 'Var', (213, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('loss of heterozygosity', 'Var', (189, 211))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('carcinoma', 'Disease', (65, 74))	('protein', 'Protein', (145, 152))	('invasive carcinoma', 'Disease', (56, 74))	('carcinoma', 'Disease', (93, 102))	('patient', 'Species', '9606', (117, 124))	('carcinoma', 'Disease', 'MESH:D002277', (65, 74))	('invasive carcinoma', 'Disease', 'MESH:D009361', (56, 74))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
18624	27527714	Re-excisions have the potential for added discomfort, surgical complications, compromise in cosmetic outcome, additional stress for patients and families, and increased health care costs and have been associated with conversion to bilateral mastectomy.	('Re-excisions', 'Var', (0, 12))	('patients', 'Species', '9606', (132, 140))	('associated', 'Reg', (201, 211))
18632	27527714	The annual hazard rate for IBTR after lumpectomy alone was 8.1 % for those with positive margins compared with 3.3% for patients with negative margins, reduced by WBRT to 2.7% and 1.2%, respectively.	('positive margins', 'Var', (80, 96))	('IBTR', 'Disease', (27, 31))	('patients', 'Species', '9606', (120, 128))
18680	19403546	To determine where in the progression sequence of ductal neoplasia angiogenesis first occurs, we examined markers of angiogenesis in normal ducts, usual and atypical hyperplasia, and low- and high-grade DCIS.	('ductal neoplasia', 'Disease', (50, 66))	('hyperplasia', 'Disease', (166, 177))	('DCIS', 'Phenotype', 'HP:0030075', (203, 207))	('low-', 'Var', (183, 187))	('neoplasia', 'Phenotype', 'HP:0002664', (57, 66))	('hyperplasia', 'Disease', 'MESH:D006965', (166, 177))	('usual', 'Disease', (147, 152))	('ductal neoplasia', 'Disease', 'MESH:D009369', (50, 66))
18693	19403546	Pretreatment was performed using Dako Target Retrieval Solution, a citrate buffer (pH 6) in a pressure cooker for 5 minutes for CD31 and CD105, and the pH 8.0 EDTA detection system for VEGF.	('CD105', 'Var', (137, 142))	('CD31', 'Gene', '5175', (128, 132))	('VEGF', 'Gene', '7422', (185, 189))	('EDTA', 'Chemical', 'MESH:D004492', (159, 163))	('citrate', 'Chemical', 'MESH:D019343', (67, 74))	('CD31', 'Gene', (128, 132))	('VEGF', 'Gene', (185, 189))
18941	30144784	Immunoblotting results show that Rap1Gap levels in MCF10.Ca1D cells (a model of invasive carcinoma) are reduced compared to those in MCF10.DCIS (a model of DCIS).	('MCF10.Ca1D', 'CellLine', 'CVCL:5555', (51, 61))	('MCF10.Ca1D', 'Var', (51, 61))	('reduced', 'NegReg', (104, 111))	('invasive carcinoma', 'Disease', (80, 98))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('Rap1Gap', 'Gene', (33, 40))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (133, 143))	('Rap1Gap', 'Gene', '5909', (33, 40))	('invasive carcinoma', 'Disease', 'MESH:D009361', (80, 98))
18962	30144784	Although a role for the loss of Rap1Gap in breast cancer progression has not previously been defined, there is strong evidence for its tumor-suppressive activities in other malignancies (including melanoma and thyroid, renal, pancreatic, and oropharyngeal cancers) through inhibition of proliferation, migration, invasion, and motility.	('loss', 'Var', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('motility', 'CPA', (327, 335))	('migration', 'CPA', (302, 311))	('pancreatic', 'Disease', 'MESH:D010195', (226, 236))	('invasion', 'CPA', (313, 321))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('oropharyngeal cancers', 'Disease', (242, 263))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('Rap1Gap', 'Gene', '5909', (32, 39))	('pancreatic', 'Disease', (226, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('inhibition', 'NegReg', (273, 283))	('tumor', 'Disease', (135, 140))	('Rap1Gap', 'Gene', (32, 39))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('malignancies', 'Disease', 'MESH:D009369', (173, 185))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('breast cancer', 'Disease', (43, 56))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (242, 263))	('malignancies', 'Disease', (173, 185))	('renal', 'Disease', (219, 224))	('thyroid', 'Disease', (210, 217))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))
18965	30144784	The second member of the series, MCF10.NeoT, was generated after transforming MCF10A via transfection with mutated T24 H-ras.	('H-ras', 'Gene', '3265', (119, 124))	('MCF10A', 'Gene', (78, 84))	('MCF10.NeoT', 'CellLine', 'CVCL:5554', (33, 43))	('mutated', 'Var', (107, 114))	('H-ras', 'Gene', (119, 124))	('MCF10A', 'CellLine', 'CVCL:0598', (78, 84))
18981	30144784	Tissue microarrays (TMAs) BR8011 (enriched for normal and DCIS tissues), BR487 (enriched for triple-negative or TN IDCs), and BR1504 (enriched for human epidermal growth factor receptor-2 or HER2, and estrogen/progesterone receptor or ER/PR expressing IDCs) were purchased from Biomax (Rockville, MD).	('epidermal growth factor receptor-2', 'Gene', (153, 187))	('BR1504', 'CellLine', 'CVCL:1V66', (126, 132))	('HER2', 'Gene', (191, 195))	('human', 'Species', '9606', (147, 152))	('progesterone receptor', 'Gene', (210, 231))	('progesterone receptor', 'Gene', '5241', (210, 231))	('HER2', 'Gene', '2064', (191, 195))	('epidermal growth factor receptor-2', 'Gene', '2064', (153, 187))	('TMAs', 'Chemical', '-', (20, 24))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('BR1504', 'Var', (126, 132))
19004	30144784	Thirty thousand MCF10.DCIS or MCF10.DCIS Rap1Gap shRNA cells were seeded in serum-free media on BD cell culture inserts (8-mum pore size; Franklin Lakes, NJ) that we precoated with 2 mg/ml Cultrex.	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('Rap1Gap', 'Gene', (41, 48))	('Rap1Gap', 'Gene', '5909', (41, 48))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (16, 26))	('MCF10.DCIS', 'Var', (30, 40))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (30, 40))
19011	30144784	In the progression series, MCF10A cells expressed very low levels of Rap1Gap; MCF10NeoT, a model of transformed breast epithelium, and MCF10.AT1, a model of atypical hyperplasia, expressed some Rap1Gap; MCF10.DCIS, a model of DCIS, expressed high levels of Rap1Gap as expected from the previous transcriptomic analysis; and MCF10.Ca1D, a model of IDC, expressed very low levels of Rap1Gap.	('MCF10A', 'CellLine', 'CVCL:0598', (27, 33))	('MCF10.Ca1D', 'CellLine', 'CVCL:5555', (324, 334))	('Rap1Gap', 'Gene', (69, 76))	('Rap1Gap', 'Gene', '5909', (257, 264))	('Rap1Gap', 'Gene', '5909', (194, 201))	('MCF10', 'CellLine', 'CVCL:5555', (135, 140))	('MCF10.DCIS', 'Var', (203, 213))	('DCIS', 'Phenotype', 'HP:0030075', (226, 230))	('Rap1Gap', 'Gene', (257, 264))	('hyperplasia', 'Disease', (166, 177))	('MCF10', 'CellLine', 'CVCL:5555', (78, 83))	('Rap1Gap', 'Gene', (194, 201))	('hyperplasia', 'Disease', 'MESH:D006965', (166, 177))	('AT1', 'Gene', (141, 144))	('MCF10', 'CellLine', 'CVCL:5555', (324, 329))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (203, 213))	('DCIS', 'Phenotype', 'HP:0030075', (209, 213))	('Rap1Gap', 'Gene', '5909', (381, 388))	('MCF10', 'CellLine', 'CVCL:5555', (203, 208))	('AT1', 'Gene', '185', (141, 144))	('Rap1Gap', 'Gene', (381, 388))	('Rap1Gap', 'Gene', '5909', (69, 76))	('MCF10', 'CellLine', 'CVCL:5555', (27, 32))
19019	30144784	When the IDC samples were separated into ER+/PR+, HER2+, and TN subtypes (Figure S1), we found that expression of Rap1Gap was significantly reduced in the ER+/PR+ IDC samples relative to DCIS and that there was a trend (not reaching significance) for a reduction in Rap1Gap expression in TN IDC relative to DCIS (Figure S1F).	('expression', 'MPA', (274, 284))	('HER2', 'Gene', (50, 54))	('HER2', 'Gene', '2064', (50, 54))	('reduction', 'NegReg', (253, 262))	('expression', 'MPA', (100, 110))	('DCIS', 'Phenotype', 'HP:0030075', (307, 311))	('Rap1Gap', 'Gene', (114, 121))	('Rap1Gap', 'Gene', (266, 273))	('Rap1Gap', 'Gene', '5909', (114, 121))	('ER+/PR+', 'Var', (155, 162))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('Rap1Gap', 'Gene', '5909', (266, 273))	('reduced', 'NegReg', (140, 147))
19035	30144784	We hypothesized that reduction in E-cadherin and fewer adherens junctions would be a consequence of Rap1Gap knockdown.	('knockdown', 'Var', (108, 117))	('fewer', 'NegReg', (49, 54))	('adherens', 'MPA', (55, 63))	('Rap1Gap', 'Gene', (100, 107))	('E-cadherin', 'Gene', (34, 44))	('E-cadherin', 'Gene', '999', (34, 44))	('Rap1Gap', 'Gene', '5909', (100, 107))	('reduction', 'NegReg', (21, 30))
19037	30144784	In addition to changed localization, expression of E-cadherin was also reduced following Rap1Gap knockdown (Figure 4B).	('Rap1Gap', 'Gene', (89, 96))	('knockdown', 'Var', (97, 106))	('reduced', 'NegReg', (71, 78))	('Rap1Gap', 'Gene', '5909', (89, 96))	('localization', 'MPA', (23, 35))	('expression', 'MPA', (37, 47))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))
19039	30144784	Reduction in E-cadherin following Rap1Gap knockdown was also observed in monolayer cultures.	('Rap1Gap', 'Gene', (34, 41))	('Rap1Gap', 'Gene', '5909', (34, 41))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('Reduction', 'NegReg', (0, 9))	('knockdown', 'Var', (42, 51))
19040	30144784	This localization of E-cadherin was reduced following knockdown of Rap1Gap.	('knockdown', 'Var', (54, 63))	('Rap1Gap', 'Gene', (67, 74))	('localization', 'MPA', (5, 17))	('reduced', 'NegReg', (36, 43))	('Rap1Gap', 'Gene', '5909', (67, 74))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))
19044	30144784	These images also show that the cortical actin rings that are found in MCF10.DCIS cells were lost following knockdown of Rap1Gap.	('knockdown', 'Var', (108, 117))	('Rap1Gap', 'Gene', (121, 128))	('lost', 'NegReg', (93, 97))	('Rap1Gap', 'Gene', '5909', (121, 128))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (71, 81))	('cortical actin rings', 'CPA', (32, 52))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
19045	30144784	In order to test whether loss of Rap1Gap would enhance the invasive capability of MCF10.DCIS cells, the ability of the cells to move through rBM was assayed.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (82, 92))	('enhance', 'PosReg', (47, 54))	('loss', 'Var', (25, 29))	('Rap1Gap', 'Gene', (33, 40))	('invasive capability', 'CPA', (59, 78))	('Rap1Gap', 'Gene', '5909', (33, 40))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
19046	30144784	We found a significant increase in the number of invading cells when Rap1Gap is silenced, compared to the control (Figure 5B, C).	('Rap1Gap', 'Gene', (69, 76))	('increase', 'PosReg', (23, 31))	('Rap1Gap', 'Gene', '5909', (69, 76))	('silenced', 'Var', (80, 88))
19047	30144784	Degradation of collagen IV (indicated by green fluorescence) was detected in the MCF10.DCIS Rap1Gap shRNA structures but not in control MCF10.DCIS structures (Figure S4).	('Degradation', 'MPA', (0, 11))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('MCF10.DCIS', 'Var', (81, 91))	('collagen IV', 'MPA', (15, 26))	('Rap1Gap', 'Gene', (92, 99))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (81, 91))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (136, 146))	('Rap1Gap', 'Gene', '5909', (92, 99))
19050	30144784	Our results (Figure 5C) show that silencing of Rap1Gap in MCF10.DCIS led to enhanced invasion.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (58, 68))	('Rap1Gap', 'Gene', '5909', (47, 54))	('invasion', 'CPA', (85, 93))	('enhanced', 'PosReg', (76, 84))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('silencing', 'Var', (34, 43))	('Rap1Gap', 'Gene', (47, 54))
19052	30144784	The immunoblotting results in Figure 6A show increased phosphorylation of ERK1/2 in MCF10.DCIS cells with silenced Rap1Gap expression.	('silenced', 'Var', (106, 114))	('increased', 'PosReg', (45, 54))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (84, 94))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('Rap1Gap', 'Gene', (115, 122))	('ERK1/2', 'Gene', (74, 80))	('phosphorylation', 'MPA', (55, 70))	('Rap1Gap', 'Gene', '5909', (115, 122))	('ERK1/2', 'Gene', '5595;5594', (74, 80))
19054	30144784	We also observed robust ERK1/2 activation in 3D cultures of MCF10.Ca1D cells compared to the control (a 14-fold increase).	('MCF10.Ca1D', 'CellLine', 'CVCL:5555', (60, 70))	('MCF10.Ca1D', 'Var', (60, 70))	('ERK1/2', 'Gene', (24, 30))	('activation', 'PosReg', (31, 41))	('ERK1/2', 'Gene', '5595;5594', (24, 30))
19062	30144784	Given that Rap1Gap is a negative regulator of Rap, we reasoned that knockdown of Rap1Gap would result in an increase in Rap activity and that reexpression of Rap1Gap would reverse that activation.	('Rap1Gap', 'Gene', '5909', (158, 165))	('increase', 'PosReg', (108, 116))	('Rap', 'Gene', '4043', (158, 161))	('Rap', 'Gene', '4043', (11, 14))	('Rap1Gap', 'Gene', (11, 18))	('Rap', 'Gene', '4043', (120, 123))	('Rap', 'Gene', (46, 49))	('Rap1Gap', 'Gene', '5909', (11, 18))	('Rap', 'Gene', (81, 84))	('knockdown', 'Var', (68, 77))	('Rap1Gap', 'Gene', '5909', (81, 88))	('Rap', 'Gene', '4043', (46, 49))	('Rap', 'Gene', (158, 161))	('Rap', 'Gene', (11, 14))	('Rap', 'Gene', (120, 123))	('Rap1Gap', 'Gene', (81, 88))	('Rap', 'Gene', '4043', (81, 84))	('Rap1Gap', 'Gene', (158, 165))
19063	30144784	As seen in Figure 7C, D, while modest Rap1 activity was observed in the control MCF10.DCIS cells, increased Rap1 activity was found in both of the MCF10.DCIS Rap1Gap shRNA lines (four- and five-fold, respectively, compared to the control cells) and in MCF10.Ca1D cells (a five-fold increase).	('MCF10.DCIS', 'Var', (147, 157))	('Rap1Gap', 'Gene', '5909', (158, 165))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (147, 157))	('MCF10.Ca1D', 'CellLine', 'CVCL:5555', (252, 262))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (80, 90))	('increased', 'PosReg', (98, 107))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('activity', 'MPA', (113, 121))	('Rap1', 'Gene', (108, 112))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('Rap1Gap', 'Gene', (158, 165))
19066	30144784	Given that knockdown of Rap1Gap led to Rap1 activation and subsequent acquisition of invasive phenotype, we investigated whether direct modulation of Rap1A activity would have similar effects.	('invasive phenotype', 'MPA', (85, 103))	('Rap1', 'Gene', (39, 43))	('Rap1A', 'Gene', (150, 155))	('acquisition', 'MPA', (70, 81))	('activation', 'PosReg', (44, 54))	('Rap1Gap', 'Gene', (24, 31))	('Rap1A', 'Gene', '5906', (150, 155))	('Rap1Gap', 'Gene', '5909', (24, 31))	('knockdown', 'Var', (11, 20))
19067	30144784	Transient transfection of GFP-tagged DN-Rap1A mutant (Rap1A-N17) in the kd2 line led to the appearance of cell-cell contacts in monolayer culture and clustering of cells (see Supplemental Figure S6).	('cell-cell contacts in monolayer culture', 'CPA', (106, 145))	('Rap1A', 'Gene', (54, 59))	('Rap1A', 'Gene', (40, 45))	('Rap1A', 'Gene', '5906', (54, 59))	('Rap1A', 'Gene', '5906', (40, 45))	('Rap1A-N17', 'Gene', '5906', (54, 63))	('clustering of cells', 'CPA', (150, 169))	('mutant', 'Var', (46, 52))	('Rap1A-N17', 'Gene', (54, 63))
19068	30144784	When grown in 3D (Figure 8), expression of DN-Rap1A mutant (Rap1A-N17) in the kd2 line led to a reversion of invasive phenotype and the reappearance of organized cortical rings and compact structure (Figure S7), similar to MCF10.DCIS.	('reversion', 'NegReg', (96, 105))	('Rap1A-N17', 'Gene', (60, 69))	('compact structure', 'CPA', (181, 198))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (223, 233))	('mutant', 'Var', (52, 58))	('Rap1A', 'Gene', (60, 65))	('Rap1A', 'Gene', '5906', (60, 65))	('cortical rings', 'Phenotype', 'HP:0009717', (162, 176))	('Rap1A-N17', 'Gene', '5906', (60, 69))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))	('invasive phenotype', 'CPA', (109, 127))	('Rap1A', 'Gene', '5906', (46, 51))	('Rap1A', 'Gene', (46, 51))	('reappearance', 'PosReg', (136, 148))
19070	30144784	The 3D structures, formed by the MCF10.DCIS cells when transfected with DA Rap1A mutant (Figure 8), lost their characteristic compact shape, displayed disorganization of the actin cytoskeleton, and grew invasive outgrowths, a phenotype that is reminiscent of the kd2 line (Figure 5).	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('Rap1A', 'Gene', (75, 80))	('compact', 'MPA', (126, 133))	('Rap1A', 'Gene', '5906', (75, 80))	('disorganization', 'MPA', (151, 166))	('lost', 'NegReg', (100, 104))	('grew invasive outgrowths', 'CPA', (198, 222))	('mutant', 'Var', (81, 87))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (33, 43))
19072	30144784	Our previous transcriptomic data revealed that Rap1Gap was upregulated in MCF10.DCIS and two other DCIS lines, SUM 225 (derived from a chest wall recurrence) and SUM 102 (a primary DCIS with microinvasion), compared to the nontransformed MCF10A cells.	('Rap1Gap', 'Gene', '5909', (47, 54))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('MCF10A', 'CellLine', 'CVCL:0598', (238, 244))	('upregulated', 'PosReg', (59, 70))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('MCF10.DCIS', 'Var', (74, 84))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (74, 84))	('Rap1Gap', 'Gene', (47, 54))
19073	30144784	Our immunoblotting analysis confirmed that Rap1Gap expression is high in MCF10.DCIS and SUM 225 cells but unexpectedly found low expression of Rap1Gap in SUM 102 cells.	('Rap1Gap', 'Gene', '5909', (43, 50))	('Rap1Gap', 'Gene', (143, 150))	('expression', 'MPA', (129, 139))	('Rap1Gap', 'Gene', '5909', (143, 150))	('MCF10.DCIS', 'Var', (73, 83))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (73, 83))	('expression', 'MPA', (51, 61))	('high', 'PosReg', (65, 69))	('Rap1Gap', 'Gene', (43, 50))
19080	30144784	Even though our staining analyses show reduced Rap1Gap in the ER+/PR+ IDCs compared to other subtypes, we found high Rap1Gap expression levels in two cell lines, MCF-7 and T47-D, that model luminal A, hormone-responsive disease.	('ER+/PR+ IDCs', 'Var', (62, 74))	('Rap1Gap', 'Gene', '5909', (47, 54))	('Rap1Gap', 'Gene', (117, 124))	('MCF-7', 'CellLine', 'CVCL:0031', (162, 167))	('expression levels', 'MPA', (125, 142))	('Rap1Gap', 'Gene', '5909', (117, 124))	('reduced', 'NegReg', (39, 46))	('luminal A', 'Disease', (190, 199))	('T47', 'CellLine', 'CVCL:3945', (172, 175))	('Rap1Gap', 'Gene', (47, 54))
19087	30144784	Thus, low levels of Rap1Gap may be particularly associated with the claudin low subset of TNBCs and thus be linked with acquisition of mesenchymal characteristics.	('Rap1Gap', 'Gene', (20, 27))	('associated', 'Reg', (48, 58))	('low levels', 'Var', (6, 16))	('Rap1Gap', 'Gene', '5909', (20, 27))	('claudin low', 'Disease', (68, 79))	('linked with', 'Reg', (108, 119))
19088	30144784	The Curtis Breast dataset shows a 2.4-fold increase in Rap1Gap mRNA expression in DCIS samples compared to normal breast tissue samples (Figure S8).	('DCIS', 'Var', (82, 86))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('Rap1Gap', 'Gene', (55, 62))	('Rap1Gap', 'Gene', '5909', (55, 62))	('Curtis', 'Disease', 'MESH:C537936', (4, 10))	('increase', 'PosReg', (43, 51))	('mRNA expression', 'MPA', (63, 78))	('Curtis', 'Disease', (4, 10))
19091	30144784	Our results (Figure 3, Figure 4, Figure 5, Figure 7) indicate that, upon silencing of Rap1Gap, MCF10.DCIS cells acquired phenotypic and behavioral characteristics that are reminiscent of the basal B cell lines BT549, MDA-MB-231, and Hs578T.	('silencing', 'Var', (73, 82))	('Rap1Gap', 'Gene', (86, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (217, 227))	('BT549', 'CellLine', 'CVCL:1092', (210, 215))	('Rap1Gap', 'Gene', '5909', (86, 93))	('behavioral characteristics', 'Phenotype', 'HP:0000708', (136, 162))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (95, 105))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))
19094	30144784	Here we demonstrated that silencing of Rap1Gap in MCF10.DCIS cells results in activation of ERK MAP kinase, reduced levels of E-cadherin, formation of invasive outgrowths (cytoskeletal remodeling), and a robust invasive capability.	('reduced', 'NegReg', (108, 115))	('invasive outgrowths', 'CPA', (151, 170))	('invasive capability', 'CPA', (211, 230))	('ERK', 'Gene', '5594', (92, 95))	('E-cadherin', 'Gene', (126, 136))	('E-cadherin', 'Gene', '999', (126, 136))	('ERK', 'Gene', (92, 95))	('activation', 'PosReg', (78, 88))	('silencing', 'Var', (26, 35))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (50, 60))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('Rap1Gap', 'Gene', (39, 46))	('Rap1Gap', 'Gene', '5909', (39, 46))
19095	30144784	These data are strongly supported by other studies which have previously reported that depletion of Rap1A in aggressive breast cancer cell line MDA-MB-231 reduces invasion in 3D Matrigel cultures.	('Rap1A', 'Gene', '5906', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (144, 154))	('reduces', 'NegReg', (155, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('invasion in 3D Matrigel cultures', 'CPA', (163, 195))	('depletion', 'Var', (87, 96))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (109, 133))	('Rap1A', 'Gene', (100, 105))	('aggressive breast cancer', 'Disease', (109, 133))
19104	30144784	Silencing of Rap1Gap in MCF10.DCIS cells led to increased ERK/MAPK phosphorylation in 3D models of DCIS.	('increased', 'PosReg', (48, 57))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (24, 34))	('Rap1Gap', 'Gene', '5909', (13, 20))	('Rap1Gap', 'Gene', (13, 20))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('MAPK', 'Gene', '5595;5594;5595', (62, 66))	('ERK', 'Gene', '5594', (58, 61))	('MAPK', 'Gene', (62, 66))	('ERK', 'Gene', (58, 61))	('Silencing', 'Var', (0, 9))
19118	30144784	Thus, although our data show that manipulation of Rap1A activity can phenocopy changes in Rap1Gap expression, it is possible that Rap1B and/or Rap2 might play a role in this system and could be the subject of further studies.	('Rap2', 'Gene', '5911', (143, 147))	('Rap1B', 'Gene', '5908', (130, 135))	('Rap1A', 'Gene', (50, 55))	('activity', 'MPA', (56, 64))	('Rap1B', 'Gene', (130, 135))	('Rap1Gap', 'Gene', (90, 97))	('Rap1A', 'Gene', '5906', (50, 55))	('Rap1Gap', 'Gene', '5909', (90, 97))	('Rap2', 'Gene', (143, 147))	('manipulation', 'Var', (34, 46))	('changes', 'Reg', (79, 86))	('expression', 'MPA', (98, 108))
19120	30144784	Thus, overall, we conclude that upregulation of Rap1Gap in MCF10.DCIS, through modulation of Rap activity, might serve as a tumor-suppressive attempt to prevent progression to IDC by reducing Ras-driven transformation.	('Rap', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('upregulation', 'PosReg', (32, 44))	('Rap', 'Gene', (93, 96))	('IDC', 'Disease', (176, 179))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (59, 69))	('tumor', 'Disease', (124, 129))	('Rap1Gap', 'Gene', (48, 55))	('Rap', 'Gene', '4043', (48, 51))	('Rap', 'Gene', '4043', (93, 96))	('reducing', 'NegReg', (183, 191))	('Rap1Gap', 'Gene', '5909', (48, 55))	('Ras-driven transformation', 'CPA', (192, 217))	('modulation', 'Var', (79, 89))
19124	30144784	Studies in various models, such as melanoma and thyroid and pancreatic cancers, show that Rap1Gap expression is lost at a higher frequency in more aggressive tumor types via promoter hypermethylation and/or loss of heterozygosity (LOH).	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('aggressive tumor', 'Disease', 'MESH:D001523', (147, 163))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('lost', 'NegReg', (112, 116))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Rap1Gap', 'Gene', (90, 97))	('loss', 'Var', (207, 211))	('Rap1Gap', 'Gene', '5909', (90, 97))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (60, 78))	('aggressive tumor', 'Disease', (147, 163))	('pancreatic cancers', 'Disease', 'MESH:D010190', (60, 78))	('pancreatic cancers', 'Disease', (60, 78))	('promoter hypermethylation', 'Var', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('expression', 'MPA', (98, 108))
19125	30144784	LOH for Rap1Gap leads to promotion of growth, survival, and invasion in pancreatic cancer models in vitro and in vivo .	('promotion', 'PosReg', (25, 34))	('invasion', 'CPA', (60, 68))	('LOH', 'Var', (0, 3))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('Rap1Gap', 'Gene', (8, 15))	('Rap1Gap', 'Gene', '5909', (8, 15))	('survival', 'CPA', (46, 54))	('growth', 'CPA', (38, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
19126	30144784	These findings are complemented by studies in prostate cancer that show evidence of cancer cell migration, invasion, and enhanced rate of tumor incidence in mouse xenograft models following Rap1 activation.	('Rap1', 'Gene', (190, 194))	('activation', 'Var', (195, 205))	('prostate cancer', 'Disease', (46, 61))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('tumor', 'Disease', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('enhanced', 'PosReg', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('invasion', 'CPA', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mouse', 'Species', '10090', (157, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('cancer', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
19133	30144784	Other studies have also shown that depletion of Rap1Gap in colon cancer cells induces increase in Src and focal adhesion kinase activation.	('colon cancer', 'Disease', (59, 71))	('increase', 'PosReg', (86, 94))	('Src', 'Gene', (98, 101))	('Src', 'Gene', '6714', (98, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('Rap1Gap', 'Gene', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Rap1Gap', 'Gene', '5909', (48, 55))	('activation', 'MPA', (128, 138))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('depletion', 'Var', (35, 44))
19143	30144784	Thus far, the majority of studies that have linked SIPA1 to breast cancer are analyses of single nucleotide polymorphisms and their correlation with breast cancer risk, incidence, metastasis, and poor prognosis and survival.	('SIPA1 to breast cancer', 'Disease', (51, 73))	('single nucleotide polymorphisms', 'Var', (90, 121))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('SIPA1 to breast cancer', 'Disease', 'MESH:D001943', (51, 73))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
19147	30144784	We have developed a model in which high expression of Rap1Gap may be limiting the premalignant progression of breast cancer at the DCIS stage, whereas subsequent reduction in Rap1Gap may act as a switch to an invasive phenotype.	('reduction', 'NegReg', (162, 171))	('limiting', 'NegReg', (69, 77))	('Rap1Gap', 'Gene', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Rap1Gap', 'Gene', '5909', (175, 182))	('high expression', 'Var', (35, 50))	('Rap1Gap', 'Gene', (54, 61))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('Rap1Gap', 'Gene', '5909', (54, 61))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
19151	25893591	Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression.	('ipsilateral breast tumors', 'Disease', 'MESH:D001943', (34, 59))	('ipsilateral breast tumors', 'Disease', (34, 59))	('breast tumors', 'Phenotype', 'HP:0100013', (85, 98))	('APBIb', 'Chemical', '-', (142, 147))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('contralateral breast tumors', 'Disease', (71, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('contralateral breast tumors', 'Disease', 'MESH:D001943', (71, 98))	('IBTs', 'Chemical', '-', (61, 65))	('patients', 'Species', '9606', (182, 190))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('CBTs', 'Chemical', '-', (100, 104))	('patients', 'Species', '9606', (128, 136))	('breast tumors', 'Phenotype', 'HP:0100013', (46, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('APBIb', 'Var', (142, 147))	('breast tumor', 'Phenotype', 'HP:0100013', (46, 58))
19155	25893591	Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR, 1.74; 95% CI, 1.06 to 2.85) but not CBTs (OR, 0.91; 95% CI, 0.59 to 1.41).	('APBIb', 'Var', (19, 24))	('CBTs', 'Chemical', '-', (125, 129))	('APBIb', 'Chemical', '-', (19, 24))	('IBTs', 'Chemical', '-', (79, 83))	('IBTs', 'Disease', (79, 83))
19161	25893591	However, APBIb could not irradiate cancer cells in the untargeted part of the breast and may result in increased local recurrence risk.	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('APBIb', 'Chemical', '-', (9, 14))	('irradiate cancer', 'Phenotype', 'HP:0010997', (25, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('result', 'Reg', (93, 99))	('APBIb', 'Var', (9, 14))	('local recurrence', 'CPA', (113, 129))
19226	25893591	Compared with WBI, APBIb was associated with a significantly higher risk of IBTs and a similar risk of CBTs during a median 46-month followup.	('APBIb', 'Var', (19, 24))	('IBTs', 'Chemical', '-', (76, 80))	('IBTs', 'Disease', (76, 80))	('APBIb', 'Chemical', '-', (19, 24))	('CBTs', 'Chemical', '-', (103, 107))
19256	25893591	In summary, APBIb was associated with a moderately increased IBT risk in DCIS patients during a median 46-month followup compared with WBI, while the absolute difference in the 5-year IBT rate was small.	('APBIb', 'Var', (12, 17))	('IBT', 'Disease', (61, 64))	('increased', 'PosReg', (51, 60))	('DCIS', 'Disease', (73, 77))	('IBT', 'Chemical', '-', (184, 187))	('patients', 'Species', '9606', (78, 86))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('APBIb', 'Chemical', '-', (12, 17))	('IBT', 'Chemical', '-', (61, 64))
19269	32671987	Across all mixed samples, we detected 23 variants previously described in cancer.	('cancer', 'Disease', (74, 80))	('variants', 'Var', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
19272	32671987	Most variants detected in invasive compartments were also found in the corresponding in situ cell compartment indicating a clonal relationship between the tumor stages.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('variants', 'Var', (5, 13))	('tumor', 'Disease', (155, 160))
19275	32671987	The lower number of potential driver variants found in pure DCIS compared with the in situ cell compartments of mixed tumors may imply that pure DCIS is captured earlier in the path of progression to invasive disease.	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))	('invasive disease', 'Disease', 'MESH:D009361', (200, 216))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('variants', 'Var', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('invasive disease', 'Disease', (200, 216))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
19313	32671987	Across all samples from mixed tumors we identified 23 different, potentially pathogenic variants in seven genes (AKT1, CDH1, CDKN2A, ERBB2, MET, PIK3CA, and TP53) (Suppl.	('TP53', 'Gene', (157, 161))	('pathogenic', 'Reg', (77, 87))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('MET', 'Gene', '79811', (140, 143))	('ERBB2', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PIK3CA', 'Gene', (145, 151))	('AKT1', 'Gene', '207', (113, 117))	('variants', 'Var', (88, 96))	('TP53', 'Gene', '7157', (157, 161))	('ERBB2', 'Gene', '2064', (133, 138))	('tumors', 'Disease', (30, 36))	('CDKN2A', 'Gene', (125, 131))	('AKT1', 'Gene', (113, 117))	('CDH1', 'Gene', '999', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('MET', 'Gene', (140, 143))	('CDH1', 'Gene', (119, 123))	('PIK3CA', 'Gene', '5290', (145, 151))	('CDKN2A', 'Gene', '1029', (125, 131))
19318	32671987	Across the samples from mixed tumors, five different PIK3CA variants were detected in 19 samples from 13 patients including one normal sample.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (105, 113))	('PIK3CA', 'Gene', '5290', (53, 59))	('detected', 'Reg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('variants', 'Var', (60, 68))	('PIK3CA', 'Gene', (53, 59))
19321	32671987	Interestingly, we found five different ERBB2 variants; two (p.D769H and p.V777L) resided in both the in situ and invasive tumor compartments of the same tumor.	('ERBB2', 'Gene', '2064', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('p.D769H', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('invasive tumor', 'Disease', 'MESH:D009361', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('p.V777L', 'Mutation', 'rs121913471', (72, 79))	('p.V777L', 'Var', (72, 79))	('invasive tumor', 'Disease', (113, 127))	('tumor', 'Disease', (122, 127))	('p.D769H', 'Mutation', 'rs121913468', (60, 67))	('ERBB2', 'Gene', (39, 44))
19322	32671987	Two other ERBB2 variants were found in a second tumor.	('tumor', 'Disease', (48, 53))	('ERBB2', 'Gene', (10, 15))	('ERBB2', 'Gene', '2064', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('variants', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
19323	32671987	One of these (p.D769Y) was found in both the in situ and invasive tumor compartments and the other (p.L755S) was found only in the in situ compartment.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p.L755S', 'Mutation', 'rs121913470', (100, 107))	('p.D769Y', 'Var', (14, 21))	('p.D769Y', 'Mutation', 'rs121913468', (14, 21))	('invasive tumor', 'Disease', 'MESH:D009361', (57, 71))	('invasive tumor', 'Disease', (57, 71))
19324	32671987	One ERBB2 variant (p.G776delinsAVGC) was found in a normal sample; however, none of the corresponding tumor cell compartments were successfully sequenced for this particular case.	('ERBB2', 'Gene', '2064', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ERBB2', 'Gene', (4, 9))	('p.G776delinsAVGC', 'Var', (19, 35))	('p.G776delinsAVGC', 'Mutation', 'p.776delinsG,AVGC', (19, 35))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
19325	32671987	Altogether, these findings demonstrate large intertumor heterogeneity in mutation pattern in synchronous DCIS and IBC and indicate that ERBB2 variants also are present early in tumorigenesis.	('tumor', 'Disease', (177, 182))	('ERBB2', 'Gene', '2064', (136, 141))	('variants', 'Var', (142, 150))	('ERBB2', 'Gene', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('IBC', 'Chemical', '-', (114, 117))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('IBC', 'Disease', (114, 117))	('tumor', 'Disease', (50, 55))
19326	32671987	In three tumors (UPP027, UPP208, and UPP244), normal epithelium was successfully sequenced in addition to invasive and in situ tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('UPP244', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('situ tumor', 'Disease', (122, 132))	('tumors', 'Disease', (9, 15))	('UPP027', 'Var', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('UPP208', 'Var', (25, 31))	('situ tumor', 'Disease', 'MESH:D002278', (122, 132))
19327	32671987	Two of these tumors (UPP027 and UPP208) carried only one variant each (PIK3CA:p.H1047R and TP53:p.A84fs, respectively) and none of the corresponding normal compartments carried these variants.	('UPP027', 'Var', (21, 27))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('TP53:p.A84fs', 'FRAMESHIFT', 'None', (91, 103))	('UPP208', 'Var', (32, 38))	('TP53:p.A84fs', 'Var', (91, 103))	('PIK3CA:p.H1047R', 'SUBSTITUTION', 'None', (71, 86))	('PIK3CA:p.H1047R', 'Var', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
19328	32671987	The last tumor with three samples (UPP244) carried two different variants; one of these (TP53:p.R175H) was found in both the in situ and invasive compartments, while the other (PIK3CA:p.H1047R) was found in the normal compartment at a frequency of 30%, absent in the in situ compartment and present at a very low frequency (3%) in the invasive compartment.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TP53:p.R175H', 'Var', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA:p.H1047R', 'SUBSTITUTION', 'None', (177, 192))	('PIK3CA:p.H1047R', 'Var', (177, 192))	('tumor', 'Disease', (9, 14))	('TP53:p.R175H', 'SUBSTITUTION', 'None', (89, 101))
19330	32671987	We found a significant association between PIK3CA variants and positive PR status (P = .039, Fisher's exact test), which has been previously noted.21, 22, 23 A similar association was not seen for ER (P = .44), however; the low number of samples in this study may have prevented the identification of any such association.	('PR', 'Gene', '5241', (72, 74))	('PIK3CA', 'Gene', '5290', (43, 49))	('ER', 'Gene', '2099', (197, 199))	('variants', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
19332	32671987	Three variants in three different tumors were detected; PIK3CA:p.C420R, PIK3CA:p.E542K, and TP53:p.R213X (Suppl.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('PIK3CA:p.E542K', 'Var', (72, 86))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('TP53:p.R213X', 'Var', (92, 104))	('TP53:p.R213X', 'SUBSTITUTION', 'None', (92, 104))	('PIK3CA:p.C420R', 'SUBSTITUTION', 'None', (56, 70))	('PIK3CA:p.C420R', 'Var', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PIK3CA:p.E542K', 'SUBSTITUTION', 'None', (72, 86))
19333	32671987	Two of these were not detected in any of the microdissected samples, while the third variant (PIK3CA:p.C420R) was found in one of the invasive tumor cell compartments, but was filtered out due to allele frequency below threshold.	('invasive tumor', 'Disease', 'MESH:D009361', (134, 148))	('PIK3CA:p.C420R', 'SUBSTITUTION', 'None', (94, 108))	('invasive tumor', 'Disease', (134, 148))	('PIK3CA:p.C420R', 'Var', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
19334	32671987	There was a notable difference in the number of variants across the 50 genes between in situ cell compartments from mixed tumors compared with pure DCIS.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('variants', 'Var', (48, 56))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
19336	32671987	However, the pure DCIS tumors were not subjected to microdissection before sequencing which may have lowered the allele frequency and compromised the detection of relevant variants.	('allele frequency', 'MPA', (113, 129))	('compromised', 'NegReg', (134, 145))	('detection', 'MPA', (150, 159))	('DCIS tumors', 'Disease', 'MESH:D002285', (18, 29))	('variants', 'Var', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('DCIS tumors', 'Disease', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('lowered', 'NegReg', (101, 108))
19337	32671987	Using this cut-off, 4/10 (40%) of the pure DCIS carry potentially pathogenic variants (Figure 2), however; comparison with the sequencing results from synchronous DCIS from mixed tumors is challenging when different thresholds are applied.	('variants', 'Var', (77, 85))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('pathogenic', 'Reg', (66, 76))
19338	32671987	Noticeably, none of the pure DCIS tumors carried the most common variant identified among the mixed tumors (PIK3CA:p.H1047R).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('DCIS tumors', 'Disease', 'MESH:D002285', (29, 40))	('PIK3CA:p.H1047R', 'SUBSTITUTION', 'None', (108, 123))	('PIK3CA:p.H1047R', 'Var', (108, 123))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('DCIS tumors', 'Disease', (29, 40))
19344	32671987	Previous sequencing studies have reported similar mutation profiles in DCIS and IBC, with PIK3CA, TP53, and GATA3 as the most commonly affected genes.8, 9, 10, 24, 26, 27, 28, 29, 30 However, different prevalence of PIK3CA variants has been observed between DCIS and IBC.	('DCIS', 'Disease', (258, 262))	('IBC', 'Chemical', '-', (267, 270))	('IBC', 'Disease', (267, 270))	('GATA3', 'Gene', (108, 113))	('variants', 'Var', (223, 231))	('GATA3', 'Gene', '2625', (108, 113))	('PIK3CA', 'Gene', (216, 222))	('DCIS', 'Phenotype', 'HP:0030075', (258, 262))	('PIK3CA', 'Gene', (90, 96))	('TP53', 'Gene', '7157', (98, 102))	('PIK3CA', 'Gene', '5290', (216, 222))	('PIK3CA', 'Gene', '5290', (90, 96))	('IBC', 'Chemical', '-', (80, 83))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('TP53', 'Gene', (98, 102))
19345	32671987	One study reported PIK3CA variants restricted to the in situ compartment in two cases of synchronous DCIS and IBC, while in a third case, a reduced frequency of a specific PIK3CA variant was found in invasive cells relative to the cells from the in situ compartment.	('PIK3CA', 'Gene', (19, 25))	('PIK3CA', 'Gene', '5290', (19, 25))	('PIK3CA', 'Gene', (172, 178))	('PIK3CA', 'Gene', '5290', (172, 178))	('IBC', 'Chemical', '-', (110, 113))	('variant', 'Var', (179, 186))	('IBC', 'Disease', (110, 113))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('variants', 'Var', (26, 34))
19346	32671987	9  In one tumor in our study, we found a PIK3CA variant in the in situ cells, and not in the invasive cell compartment, while in two tumors, we found a PIK3CA variant in the invasive cells while not in the corresponding in situ cell compartment.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('PIK3CA', 'Gene', '5290', (152, 158))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('PIK3CA', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('PIK3CA', 'Gene', '5290', (41, 47))	('PIK3CA', 'Gene', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('variant', 'Var', (48, 55))
19347	32671987	In our study, the sequencing panel did not include GATA3, so the high frequency of GATA3 variants previously found in DCIS could not be confirmed.	('variants', 'Var', (89, 97))	('GATA3', 'Gene', '2625', (83, 88))	('GATA3', 'Gene', (51, 56))	('GATA3', 'Gene', '2625', (51, 56))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('GATA3', 'Gene', (83, 88))
19351	32671987	Four of the samples with TP53 mutations in this study were included in a previous study of TP53 mutations in synchronous DCIS and IBC.	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', (25, 29))	('synchronous', 'Disease', (109, 120))	('IBC', 'Chemical', '-', (130, 133))	('IBC', 'Disease', (130, 133))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', '7157', (25, 29))	('mutations', 'Var', (96, 105))
19353	32671987	Although the number of cases included was small, we found that across the 50 cancer-relevant genes included in the panel, the spectrum of variants was similar between synchronous DCIS and IBC supporting earlier findings of a clonal relationship between the two tumor stages and a possible selection of subclones during tumor progression.	('tumor', 'Disease', (319, 324))	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('IBC', 'Chemical', '-', (188, 191))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('variants', 'Var', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
19432	28814131	Women were considered to have almost no risk of systemic recurrence if SEER data indicated stage 0 (DCIS); low risk of systemic recurrence (<10% risk of systemic recurrence) if SEER data indicated stage IA, estrogen receptor (ER)-positive, HER2-negative, tumor grade 1-2, and tumor genomic profiling with the 21-gene recurrence score (RS) either not done or RS 0-10 ; intermediate risk of systemic recurrence (<20% risk of systemic recurrence) if SEER data indicated stage IA, ER-positive, HER2-negative, tumor grade 1-2, and RS recurrence score >10; or stage IA, ER-positive, HER2-negative, and tumor grade 3+; or stage IB or IIA, ER-positive, HER2-negative, with any tumor grade and any RS status; or high risk of systemic recurrence (<40% risk of systemic recurrence) if SEER data indicated stage IIB, ER-negative, and/or HER2-positive.	('ER', 'Gene', '2099', (477, 479))	('Women', 'Species', '9606', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('ER', 'Gene', '2099', (73, 75))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('ER', 'Gene', '2099', (564, 566))	('tumor', 'Disease', (505, 510))	('tumor', 'Phenotype', 'HP:0002664', (596, 601))	('ER', 'Gene', '2099', (826, 828))	('estrogen receptor', 'Gene', '2099', (207, 224))	('HER2', 'Gene', (490, 494))	('systemic recurrence', 'Disease', (716, 735))	('HER2', 'Gene', (577, 581))	('tumor', 'Disease', 'MESH:D009369', (505, 510))	('ER', 'Gene', '2099', (491, 493))	('tumor', 'Disease', (669, 674))	('HER2', 'Gene', '2064', (825, 829))	('ER', 'Gene', '2099', (578, 580))	('HER2', 'Gene', (240, 244))	('tumor', 'Disease', 'MESH:D009369', (669, 674))	('HER2', 'Gene', (645, 649))	('ER', 'Gene', '2099', (776, 778))	('ER', 'Gene', '2099', (632, 634))	('tumor', 'Phenotype', 'HP:0002664', (505, 510))	('tumor', 'Disease', (255, 260))	('estrogen receptor', 'Gene', (207, 224))	('tumor', 'Disease', (276, 281))	('ER', 'Gene', '2099', (449, 451))	('tumor', 'Disease', (596, 601))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('HER2', 'Gene', '2064', (490, 494))	('tumor', 'Phenotype', 'HP:0002664', (669, 674))	('>10', 'Var', (546, 549))	('HER2', 'Gene', (825, 829))	('ER', 'Gene', '2099', (646, 648))	('ER', 'Gene', '2099', (226, 228))	('ER', 'Gene', '2099', (179, 181))	('ER', 'Gene', '2099', (241, 243))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('HER2', 'Gene', '2064', (577, 581))	('tumor', 'Disease', 'MESH:D009369', (596, 601))	('ER', 'Gene', '2099', (805, 807))	('HER2', 'Gene', '2064', (240, 244))	('HER2', 'Gene', '2064', (645, 649))
19518	27237323	Interestingly, cancer cells recurrently remain dependent on TWIST1 for their survival and/or proliferation, making TWIST1 their Achilles' heel.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('TWIST1', 'Var', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
19536	27237323	Nonetheless, homodimerization is privileged at low protein concentration (e.g., TWIST1 haploinsufficiency in Saethre-Chotzen patients), in the presence of ID HLH proteins which titrate E proteins, or following the phosphorylation of residues located in the helix I of TWIST1 (i.e., Thr121 and Ser123) by protein kinase A.	('patients', 'Species', '9606', (125, 133))	('Thr121', 'Var', (282, 288))	('haploinsufficiency', 'Disease', (87, 105))	('H', 'Gene', '9464', (160, 161))	('TWIST1', 'Gene', (80, 86))	('TWIST1', 'Gene', (268, 274))	('Ser123', 'Var', (293, 299))	('H', 'Gene', '9464', (158, 159))	('haploinsufficiency', 'Disease', 'MESH:D058495', (87, 105))	('low protein concentration', 'Phenotype', 'HP:0003075', (47, 72))	('E proteins', 'Protein', (185, 195))	('homodimer', 'Gene', '6647', (13, 22))	('homodimer', 'Gene', (13, 22))
19537	27237323	Point mutations preventing the posttranslational modification of these residues (TS121-123AA) or mimicking their constitutive phosphorylation (TS121-123ED) were demonstrated to functionally mimic the TWIST1 homodimer and heterodimer, respectively.	('heterodimer', 'Interaction', (221, 232))	('preventing', 'NegReg', (16, 26))	('homodimer', 'Gene', '6647', (207, 216))	('TS121-123ED', 'Var', (143, 154))	('TS121-123AA', 'Var', (81, 92))	('homodimer', 'Gene', (207, 216))	('posttranslational modification', 'MPA', (31, 61))	('mimic', 'Reg', (190, 195))
19541	27237323	Moreover, identifying the TWIST1 complex implicated in the escape from fail-safe program and upon which cancer cells are dependent for their proliferation and survival constitutes an essential step in the development of novel therapeutic strategies aiming at eradicating cancer cells through TWIST1 inactivation.	('TWIST1', 'Gene', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('inactivation', 'Var', (299, 311))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (104, 110))	('TWIST1', 'Gene', (26, 32))
19564	27237323	shRNA TWIST1 lentiviral particles were generated through the co-transfection of 293T cells with pLKO.1, pCMV DeltaR8.91 (gag-pop-Tat-Rev), and phCMVG-VSVG (env) expression constructs, and shRNA TWIST1 retroviral particles were generated through the transfection of HEK293GP cells with pSIREN and phCMVG-VSVG (env) expression constructs using the calcium phosphate precipitation technique.	('env', 'Gene', (156, 159))	('expression', 'Species', '29278', (161, 171))	('calcium phosphate', 'Chemical', 'MESH:C020243', (346, 363))	('env', 'Gene', '100616444', (309, 312))	('HEK293GP', 'CellLine', 'CVCL:E072', (265, 273))	('env', 'Gene', '100616444', (156, 159))	('293T', 'CellLine', 'CVCL:0063', (80, 84))	('DeltaR8', 'Var', (109, 116))	('expression', 'Species', '29278', (314, 324))	('env', 'Gene', (309, 312))	('DeltaR8', 'DELETION', 'None', (109, 116))
19566	27237323	Consequences of TWIST depletion on cell survival and proliferation were assessed in the absence of selection.	('depletion', 'Var', (22, 31))	('TWIST', 'Gene', '7291', (16, 21))	('TWIST', 'Gene', (16, 21))
19573	27237323	HEK293T cells were transfected with wild-type or mutant FLAG-tagged TWIST1 and/or MYC-tagged E12 expression constructs using the calcium-phosphate technique.	('TWIST1', 'Gene', (68, 74))	('mutant', 'Var', (49, 55))	('E12', 'Gene', '26767', (93, 96))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('expression', 'Species', '29278', (97, 107))	('E12', 'Gene', (93, 96))	('calcium-phosphate', 'Chemical', 'MESH:C020243', (129, 146))
19592	27237323	Cleavage of TWIST1 by caspase 3 was originally reported in apoptotic cells and was quickly followed by its proteasome-mediated degradation.	('Cleavage', 'Var', (0, 8))	('caspase 3', 'Gene', (22, 31))	('TWIST1', 'Gene', (12, 18))	('proteasome-mediated', 'MPA', (107, 126))	('caspase 3', 'Gene', '836', (22, 31))
19593	27237323	As the study progressed, additional mutants were generated including the T R154P~E heterodimer (hereafter named T RP~E) to confirm the need of the interaction between both partners to generate an active tethered heterodimer.	('T R154P~E', 'Var', (73, 82))	('R154P', 'Mutation', 'p.R154P', (75, 80))	('interaction', 'Interaction', (147, 158))
19594	27237323	The R154P mutation was previously reported to disrupt the TWIST1-E2A protein interaction, and this was herein confirmed by performing a co-immunoprecipitation assay (Figure S2A).	('R154P', 'Var', (4, 9))	('R154P', 'Mutation', 'p.R154P', (4, 9))	('E2A', 'Gene', (65, 68))	('disrupt', 'NegReg', (46, 53))	('E2A', 'Gene', '6929', (65, 68))	('interaction', 'Interaction', (77, 88))
19595	27237323	Insertion of this mutation into the T~E tethered dimer (T RP~E) did not have an impact on its nuclear sublocalization (Figure S2B) but, as anticipated, abrogated the ability of the fusion protein to activate the TWIST1-targeted vimentin (VIM) gene in a reporter assay (Figure S2C).	('VIM', 'Gene', (238, 241))	('abrogated', 'NegReg', (152, 161))	('TWIST1-targeted', 'Gene', (212, 227))	('activate', 'PosReg', (199, 207))	('vimentin', 'Gene', '7431', (228, 236))	('mutation', 'Var', (18, 26))	('VIM', 'Gene', '7431', (238, 241))	('Insertion', 'Var', (0, 9))	('vimentin', 'Gene', (228, 236))	('ability', 'MPA', (166, 173))
19597	27237323	The Lys145 residue plays a determining role in stabilizing TWIST1 complexes on the DNA by contributing to the establishment of the interhelical loops and by directly interacting with oxygen atoms of DNA bases.	('contributing', 'PosReg', (90, 102))	('interacting', 'Interaction', (166, 177))	('Lys145', 'Chemical', '-', (4, 10))	('TWIST1', 'Gene', (59, 65))	('interhelical loops', 'MPA', (131, 149))	('establishment', 'MPA', (110, 123))	('Lys145', 'Var', (4, 10))	('oxygen', 'Chemical', 'MESH:D010100', (183, 189))	('stabilizing', 'MPA', (47, 58))
19598	27237323	The K145E mutation thus affects the global structure of TWIST1 complexes and abrogates TWIST1 DNA binding properties .	('TWIST1 complexes', 'Protein', (56, 72))	('TWIST1', 'Protein', (87, 93))	('abrogates', 'NegReg', (77, 86))	('affects', 'Reg', (24, 31))	('K145E', 'Mutation', 'rs923386820', (4, 9))	('global structure', 'MPA', (36, 52))	('K145E', 'Var', (4, 9))
19604	27237323	To support this hypothesis, we observed that the disruption of the partner interaction through the insertion of the R154P point mutation in TWIST1 abolished T~E activity (Figure 1, C and D).	('TWIST1', 'Gene', (140, 146))	('R154P', 'Mutation', 'p.R154P', (116, 121))	('R154P point', 'Var', (116, 127))	('abolished', 'NegReg', (147, 156))	('T~E activity', 'MPA', (157, 169))	('partner interaction', 'Interaction', (67, 86))
19605	27237323	Indeed, ectopic TWIST1 was confirmed to immunoprecipitate the endogenous E12 protein (Figure S3).	('ectopic', 'Var', (8, 15))	('E12', 'Gene', '26767', (73, 76))	('E12', 'Gene', (73, 76))
19608	27237323	As an internal control, the insertion of the K145E mutation (T KE~T KE tethered dimer), described to abolish the TWIST1 DNA binding capability, annihilated its transactivation potential.	('annihilated', 'NegReg', (144, 155))	('transactivation potential', 'MPA', (160, 185))	('K145E', 'Mutation', 'rs923386820', (45, 50))	('K145E', 'Var', (45, 50))	('abolish', 'NegReg', (101, 108))	('TWIST1', 'Protein', (113, 119))
19616	27237323	To strengthen this result, we examined whether the ectopic expression of T~T or T~E in the absence of an oncogenic insult was sufficient to promote breast carcinogenesis, with an anticipated lower penetrance and extended latency to accumulate requested secondary events.	('T~T', 'Gene', (73, 76))	('ectopic expression', 'Var', (51, 69))	('expression', 'Species', '29278', (59, 69))	('promote', 'PosReg', (140, 147))	('T~E', 'Gene', (80, 83))	('breast carcinogenesis', 'Disease', (148, 169))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (148, 169))
19619	27237323	As shown in Figure 2, C-E, T~E-producing mice were found to develop breast carcinomas with a higher frequency (37.9%, n = 29) and a shorter latency than T~T-producing mice (18.1%, n = 14) and control littermates (6.2%, n = 16).	('breast carcinomas', 'Disease', (68, 85))	('mice', 'Species', '10090', (41, 45))	('breast carcinomas', 'Phenotype', 'HP:0003002', (68, 85))	('C-E', 'Var', (22, 25))	('breast carcinoma', 'Phenotype', 'HP:0003002', (68, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('develop', 'PosReg', (60, 67))	('mice', 'Species', '10090', (167, 171))	('breast carcinomas', 'Disease', 'MESH:D001943', (68, 85))
19624	27237323	Depletion in the TWIST1 and E2A proteins significantly reduced the number of dots detectable in the TWIST1-positive MDA-MB436 (8.8 +- 1.1 dots/cell to 4.9 +- 1.0 and 1.6 +- 1.5 dots/cell, respectively) and Hs578T (9.8 +- 3.1 dots/cell to 3.1 +- 1.9 and 2.2 +- 1.7 dots/cell, respectively), whereas the number of dots/cell remained < 1 in TWIST1-negative HMEC-hTERT cells (Figure S5).	('TWIST1', 'Gene', (17, 23))	('HMEC-hTERT cells', 'CellLine', 'CVCL:0307', (354, 370))	('reduced', 'NegReg', (55, 62))	('E2A', 'Gene', (28, 31))	('TWIST1-positive', 'Var', (100, 115))	('H', 'Gene', '9464', (206, 207))	('MDA-MB436', 'CellLine', 'CVCL:0623', (116, 125))	('H', 'Gene', '9464', (354, 355))	('E2A', 'Gene', '6929', (28, 31))
19639	27237323	Despite the limited number of mice examined, the absence of pathology observed when the homodimeric TWIST1 complex was combined with RAS demonstrated that T~T was less efficient than T~E in promoting tumor initiation in this context (G.W.	('less', 'NegReg', (163, 167))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor initiation', 'Disease', 'MESH:D009369', (200, 216))	('promoting', 'PosReg', (190, 199))	('homodimer', 'Gene', '6647', (88, 97))	('homodimer', 'Gene', (88, 97))	('tumor initiation', 'Disease', (200, 216))	('T~T', 'Var', (155, 158))
19641	27237323	The tendency of mice, ectopically expressing T~E in mammary epithelial cells, to spontaneously develop breast carcinoma with a higher frequency than their T~T counterparts and control littermates further supports this conclusion.	('breast carcinoma', 'Phenotype', 'HP:0003002', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('breast carcinoma', 'Disease', (103, 119))	('breast carcinoma', 'Disease', 'MESH:D001943', (103, 119))	('develop', 'PosReg', (95, 102))	('T~E', 'Var', (45, 48))	('mice', 'Species', '10090', (16, 20))
19650	27237323	Because the ectopic expression of the tethered dimer T~T did not affect breast cancer cell proliferation, it is possible that the homodimeric complex does not display transdominant negative properties, at least with regard to the functions and cellular models considered in this study.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('T~T', 'Var', (53, 56))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('homodimer', 'Gene', '6647', (130, 139))	('homodimer', 'Gene', (130, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('expression', 'Species', '29278', (20, 30))
19658	27237323	TWIST1 and TWIST2 were also shown to similarly downregulate RB and p53 pathways.	('TWIST1', 'Var', (0, 6))	('downregulate', 'NegReg', (47, 59))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('TWIST2', 'Gene', (11, 17))	('TWIST2', 'Gene', '117581', (11, 17))
19832	29212475	Women were excluded if they were pregnant, had a known BRCA 1/2 mutation or if they had a previous diagnosis of breast cancer, lobular carcinoma in situ or DCIS.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (127, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('Women', 'Species', '9606', (0, 5))	('mutation', 'Var', (64, 72))	('breast cancer', 'Disease', (112, 125))	('BRCA 1', 'Gene', (55, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (135, 152))	('DCIS', 'Disease', (156, 160))	('BRCA 1', 'Gene', '672', (55, 61))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (127, 152))	('lobular carcinoma in situ', 'Disease', (127, 152))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
19910	29212475	women with low grade DCIS and women with lower health literacy and the perceived involvement in treatment decision-making by women, nurses and physicians.	('lower', 'NegReg', (41, 46))	('women', 'Species', '9606', (30, 35))	('involvement', 'Reg', (81, 92))	('women', 'Species', '9606', (0, 5))	('low grade DCIS', 'Var', (11, 25))	('women', 'Species', '9606', (125, 130))
19924	23977052	Furthermore, knockdown of ERRgamma promoted the proliferation rate in ANG-deficient breast cancer cells.	('proliferation rate', 'CPA', (48, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('ERRgamma', 'Gene', '2104', (26, 34))	('promoted', 'PosReg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('deficient breast', 'Phenotype', 'HP:0003187', (74, 90))	('knockdown', 'Var', (13, 22))	('ERRgamma', 'Gene', (26, 34))	('ANG-deficient breast cancer', 'Disease', 'MESH:D001943', (70, 97))	('ANG-deficient breast cancer', 'Disease', (70, 97))
19932	23977052	Either inhibition of nuclear translocation by neomysin or mutagenesis at the nuclear localization sequence abolishes ANG-promoted cell proliferation.	('ANG', 'Gene', '283', (117, 120))	('nuclear translocation', 'MPA', (21, 42))	('mutagenesis', 'Var', (58, 69))	('ANG', 'Gene', (117, 120))	('inhibition', 'NegReg', (7, 17))	('cell proliferation', 'CPA', (130, 148))	('abolishes', 'NegReg', (107, 116))
19941	23977052	The inhibitory effect of ERRgamma on cancer cell proliferation was attributed to the induction of two cyclin-dependent kinase inhibitors p21WAF/CIP and p27KIP .	('ERRgamma', 'Gene', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('p27KIP', 'Var', (152, 158))	('cancer', 'Disease', (37, 43))	('inhibitory effect', 'NegReg', (4, 21))	('ERRgamma', 'Gene', '2104', (25, 33))	('CIP', 'Disease', (144, 147))	('CIP', 'Disease', 'MESH:D010259', (144, 147))	('cyclin-dependent', 'Enzyme', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
20001	23977052	Down-regulation of ANG did not influence the luciferase activities of null vector or ABSE-, but significantly increased the luciferase activity of ABSE+ (Fig.	('luciferase', 'Enzyme', (124, 134))	('Down-regulation', 'Var', (0, 15))	('increased', 'PosReg', (110, 119))	('ANG', 'Gene', '283', (19, 22))	('activity', 'MPA', (135, 143))	('ANG', 'Gene', (19, 22))
20008	23977052	Data showed that knockdown of ANG significantly increased H3K4me2 level and acetyl-H4 level at the ABSE region, but not the ERRgamma coding region or GAPDH promoter region (Fig.	('H3K4me2 level', 'MPA', (58, 71))	('increased', 'PosReg', (48, 57))	('ERRgamma', 'Gene', (124, 132))	('ANG', 'Gene', '283', (30, 33))	('acetyl-H4 level', 'MPA', (76, 91))	('ANG', 'Gene', (30, 33))	('ERRgamma', 'Gene', '2104', (124, 132))	('knockdown', 'Var', (17, 26))	('GAPDH', 'Gene', '2597', (150, 155))	('GAPDH', 'Gene', (150, 155))
20014	23977052	Knock down of ANG decreased cell proliferation rate.	('ANG', 'Gene', '283', (14, 17))	('ANG', 'Gene', (14, 17))	('decreased', 'NegReg', (18, 27))	('cell proliferation rate', 'CPA', (28, 51))	('Knock down', 'Var', (0, 10))
20015	23977052	However, the knock down of ERRgamma had almost no effect on cell proliferation, which might be because of the low expression level of ERRgamma in MCF-7 cells.	('cell proliferation', 'CPA', (60, 78))	('expression level', 'MPA', (114, 130))	('ERRgamma', 'Gene', '2104', (134, 142))	('MCF-7', 'CellLine', 'CVCL:0031', (146, 151))	('ERRgamma', 'Gene', '2104', (27, 35))	('knock down', 'Var', (13, 23))	('ERRgamma', 'Gene', (134, 142))	('ERRgamma', 'Gene', (27, 35))
20016	23977052	When both genes were silenced, the proliferation rate of MCF-7 cells increased significantly compared to ANG-deficient cells (Fig.	('silenced', 'Var', (21, 29))	('increased', 'PosReg', (69, 78))	('proliferation rate', 'CPA', (35, 53))	('ANG', 'Gene', '283', (105, 108))	('ANG', 'Gene', (105, 108))	('MCF-7', 'CellLine', 'CVCL:0031', (57, 62))
20022	23977052	Data showed that knock down of ANG enhanced the p21WAF1/CIP1 and p27KIP1 genes expression.	('p27KIP1', 'Gene', '1027', (65, 72))	('ANG', 'Gene', (31, 34))	('expression', 'MPA', (79, 89))	('p27KIP1', 'Gene', (65, 72))	('enhanced', 'PosReg', (35, 43))	('p21WAF1/CIP1', 'Gene', '1026', (48, 60))	('p21WAF1/CIP1', 'Gene', (48, 60))	('knock down', 'Var', (17, 27))	('ANG', 'Gene', '283', (31, 34))
20025	23977052	Knock down of ANG increased the occupations of ERRgamma and Pol II on the promoter regions (Fig.	('occupations', 'MPA', (32, 43))	('ANG', 'Gene', '283', (14, 17))	('ANG', 'Gene', (14, 17))	('increased', 'PosReg', (18, 27))	('Pol I', 'Gene', (60, 65))	('ERRgamma', 'Gene', '2104', (47, 55))	('Pol I', 'Gene', '11201', (60, 65))	('ERRgamma', 'Gene', (47, 55))	('Knock down', 'Var', (0, 10))
20037	23977052	We have reported previously that ANG binds to the CT repeats in rDNA region.	('binds', 'Interaction', (37, 42))	('CT repeats', 'Var', (50, 60))	('ANG', 'Gene', '283', (33, 36))	('ANG', 'Gene', (33, 36))
20051	23977052	Our data showed that ANG-promoted cell proliferation and inhibited the expression levels of p21WAF/CIP and p27KIP1 through ERRgamma, as knockdown of ERRgamma can increase the proliferation rate in ANG-deficient cells.	('increase', 'PosReg', (162, 170))	('ERRgamma', 'Gene', '2104', (123, 131))	('cell proliferation', 'CPA', (34, 52))	('inhibited', 'NegReg', (57, 66))	('ERRgamma', 'Gene', (149, 157))	('ANG', 'Gene', '283', (21, 24))	('CIP', 'Disease', 'MESH:D010259', (99, 102))	('p27KIP1', 'Gene', '1027', (107, 114))	('ANG', 'Gene', '283', (197, 200))	('ANG', 'Gene', (197, 200))	('knockdown', 'Var', (136, 145))	('ERRgamma', 'Gene', (123, 131))	('p27KIP1', 'Gene', (107, 114))	('proliferation rate', 'CPA', (175, 193))	('ANG', 'Gene', (21, 24))	('expression levels', 'MPA', (71, 88))	('ERRgamma', 'Gene', '2104', (149, 157))	('CIP', 'Disease', (99, 102))
20060	23977052	Our data showed that knockdown of ANG increased active gene markers H3K4me2 and acetyl-H4 at ABSE region, therefore the presence of ANG may induce heterochromatin formation, fasten the rDNA structure and consequently exclude the recruitment of transcriptional machineries.	('ANG', 'Gene', '283', (132, 135))	('induce', 'PosReg', (140, 146))	('rDNA structure', 'CPA', (185, 199))	('ANG', 'Gene', (34, 37))	('acetyl-H4', 'MPA', (80, 89))	('active gene', 'MPA', (48, 59))	('ANG', 'Gene', (132, 135))	('exclude', 'NegReg', (217, 224))	('recruitment', 'MPA', (229, 240))	('fasten', 'NegReg', (174, 180))	('presence', 'Var', (120, 128))	('heterochromatin', 'MPA', (147, 162))	('ANG', 'Gene', '283', (34, 37))	('increased', 'PosReg', (38, 47))	('H3K4me2', 'Protein', (68, 75))
20078	23513042	Risk factor models for BC have been developed for women at average population risk as well as those with increased risk due to cancer susceptibility gene mutations or family history of BC.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BC', 'Phenotype', 'HP:0003002', (23, 25))	('women', 'Species', '9606', (50, 55))	('mutations', 'Var', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('BC', 'Phenotype', 'HP:0003002', (185, 187))	('cancer', 'Disease', (127, 133))
20122	23513042	In the present study of 67,819 screening mammograms from PHBC women, we observed an overall cancer rate of 10.3/1000 screens within one year of screening, with an invasive BC rate of 7.7/1000 screens.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('BC', 'Phenotype', 'HP:0003002', (172, 174))	('PHBC', 'Chemical', '-', (57, 61))	('BC', 'Phenotype', 'HP:0003002', (59, 61))	('screens', 'Var', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('women', 'Species', '9606', (62, 67))
20155	33913277	A total of 890 women with BRCA mutation or family history of breast cancer and lifetime risk >= 20% are enrolled.	('BRCA', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('women', 'Species', '9606', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('mutation', 'Var', (31, 39))	('BRCA', 'Gene', '672', (26, 30))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
20164	33913277	Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is a highly sensitive modality for breast cancer detection and is recommended as a supplemental screening tool for women with BRCA mutations or a family history of breast cancer and a lifetime risk of over 20%.	('women', 'Species', '9606', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('BRCA', 'Gene', (191, 195))	('BRCA', 'Gene', '672', (191, 195))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Disease', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('mutations', 'Var', (196, 205))
20193	33913277	As there are no published studies on the sensitivity of DW MRI in the screening population among women at high risk, we estimated that the sensitivity of screening DW MRI for breast cancer detection would be 72.5%, which is approximately 80% of the sensitivity of DCE MRI (90%), based on previous studies.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('women', 'Species', '9606', (97, 102))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('DW MRI', 'Var', (164, 170))
20314	19635166	Despite the plausibility of our above explanation, which is clearly supported by the work of other investigators, that adjacent multifocal disease within the same quadrant of the affected breast may contribute to the occurrence of many failed BCS procedures, we can not rule out that some failed BCS procedures may result from suboptimal surgical resection margin assessment techniques that fail to recognized positive or close margins on the BCS specimen itself.	('result from', 'Reg', (315, 326))	('suboptimal', 'Var', (327, 337))	('BCS', 'Disease', (296, 299))	('multifocal disease', 'Disease', (128, 146))	('multifocal disease', 'Disease', 'None', (128, 146))
20349	28723330	Despite 5-year survival rates that approach 100% among patients with low-risk differentiated thyroid cancer, prostate cancer, and ductal carcinoma in situ (DCIS), diagnosis of one of these cancers often leads to a cascade of testing and treatment that isn't associated with longer survival but can cause harm (see Supplementary Appendix for a detailed definition of low-risk cancers).	('testing', 'MPA', (225, 232))	('men', 'Species', '9606', (320, 323))	('thyroid cancer', 'Disease', (93, 107))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (130, 154))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('ductal carcinoma in situ', 'Disease', (130, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (93, 107))	('diagnosis', 'Var', (163, 172))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('thyroid cancer', 'Phenotype', 'HP:0002890', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (130, 154))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('cancers', 'Disease', (189, 196))	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('prostate cancer', 'Disease', (109, 124))	('leads to', 'Reg', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('men', 'Species', '9606', (242, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (55, 63))	('cancers', 'Disease', (375, 382))
20414	28819437	In one study, accompanying DCIS was found to predict improved local recurrence-free survival in breast cancer patients; however, other studies have shown that, while the presence of concomitant DCIS is associated with favorable features, the prognosis is not altered.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('local recurrence-free survival', 'CPA', (62, 92))	('presence', 'Var', (170, 178))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('DCIS', 'Disease', (194, 198))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('improved', 'PosReg', (53, 61))	('patients', 'Species', '9606', (110, 118))
20417	28819437	Patients were selected for our study based on 3 criteria: 1) invasive tumor size <=0.5 cm (T1a) or >0.5 cm but <=1.0 cm (T1b); 2) the patient completed axillary staging and was negative for lymph node metastasis; and 3) the statuses of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were known.	('epidermal growth factor receptor 2', 'Gene', '2064', (298, 332))	('ER', 'Gene', '2099', (255, 257))	('T1a', 'Gene', '10630', (91, 94))	('invasive tumor', 'Disease', 'MESH:D009369', (61, 75))	('patient', 'Species', '9606', (134, 141))	('estrogen receptor', 'Gene', (236, 253))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('<=0.5', 'Var', (81, 86))	('epidermal growth factor receptor 2', 'Gene', (298, 332))	('T1a', 'Gene', (91, 94))	('Patients', 'Species', '9606', (0, 8))	('PR', 'Gene', '5241', (283, 285))	('HER2', 'Gene', (334, 338))	('progesterone receptor', 'Gene', (260, 281))	('human', 'Species', '9606', (292, 297))	('estrogen receptor', 'Gene', '2099', (236, 253))	('invasive tumor', 'Disease', (61, 75))	('progesterone receptor', 'Gene', '5241', (260, 281))	('ER', 'Gene', '2099', (335, 337))	('HER2', 'Gene', '2064', (334, 338))
20430	28819437	The chi-square test was used to determine differences in categorical predictor variables between patients with T1aN0 and T1bN0 breast cancer and between screening-detected and symptomatic T1a,bN0 breast cancer; a Mann-Whitney U test was utilized for continuous predictor variables.	('T1a', 'Gene', '10630', (111, 114))	('T1a', 'Gene', (111, 114))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (196, 209))	('breast cancer', 'Disease', (127, 140))	('T1a', 'Gene', '10630', (188, 191))	('T1a', 'Gene', (188, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('T1bN0', 'Var', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('patients', 'Species', '9606', (97, 105))
20439	28819437	On multivariate analysis, symptomatic T1a,bN0 patients were more likely to have large DCIS lesions (odds ratio [OR]: 2.00, p=0.043), be of younger age (OR: 3.61, p = 0.009), and to have undergone a mastectomy (OR: 2.16, p=0.006) when compared to their screening-detected counterparts (Table 3).	('patients', 'Species', '9606', (46, 54))	('bN0', 'Var', (42, 45))	('mastectomy', 'Disease', (198, 208))	('T1a', 'Gene', '10630', (38, 41))	('T1a', 'Gene', (38, 41))
20441	28819437	Univariate analysis showed that symptomatic tumors, large accompanying DCIS lesions, and HER2 positivity were significantly associated with worse DRFS.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('HER2', 'Gene', (89, 93))	('positivity', 'Var', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('worse DRFS', 'Disease', (140, 150))	('HER2', 'Gene', '2064', (89, 93))
20442	28819437	Tumors accompanied by large DCIS and those that were ER-negative, PR-negative, and HER2-positive resulted in significantly worse BCSS (Table 4).	('BCSS', 'CPA', (129, 133))	('ER', 'Gene', '2099', (84, 86))	('large', 'Var', (22, 27))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ER', 'Gene', '2099', (53, 55))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (83, 87))	('PR', 'Gene', '5241', (66, 68))
20459	28819437	We also found that symptomatic T1a,bN0 breast cancers are more likely to be associated with large DCIS lesions; large DCIS size was an independent prognostic factor in our multivariate analysis.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('large', 'Var', (92, 97))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', (39, 53))	('T1a', 'Gene', '10630', (31, 34))	('T1a', 'Gene', (31, 34))
20463	28819437	More recently, an analysis of >100,000 women with DCIS from the Surveillance, Epidemiology, and End Results (SEER) database revealed that larger DCIS lesions were found to be associated with worse BCSS rates.	('lesions', 'Var', (150, 157))	('DCIS', 'Gene', (145, 149))	('women', 'Species', '9606', (39, 44))	('ER', 'Gene', '2099', (111, 113))	('BCSS rates', 'CPA', (197, 207))
20475	28819437	In conclusion, symptomatic T1a,bN0 breast cancers are different from those detected by screening, and are associated with larger accompanying DCIS.	('bN0', 'Var', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('associated', 'Reg', (106, 116))	('breast cancers', 'Phenotype', 'HP:0003002', (35, 49))	('breast cancers', 'Disease', 'MESH:D001943', (35, 49))	('breast cancers', 'Disease', (35, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('T1a', 'Gene', '10630', (27, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('T1a', 'Gene', (27, 30))
20567	27315013	The relative risk of developing carcinoma following the identification of IDP in an excisional biopsy specimen was 2.01, comparable to the risk in patients with proliferative disease without atypia (1.90) .	('carcinoma', 'Disease', 'MESH:D002277', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('patients', 'Species', '9606', (147, 155))	('IDP', 'Var', (74, 77))	('carcinoma', 'Disease', (32, 41))
20579	27247546	High, intermediate and low NG of DCIS was significantly related to casting-type, crushed stone-like and powdery microcalcifications, respectively (P < 0.01).	('low NG', 'Var', (23, 29))	('casting-type', 'Disease', (67, 79))	('DCIS', 'Gene', (33, 37))	('NG', 'Chemical', '-', (27, 29))	('crushed stone-like', 'Disease', (81, 99))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('related', 'Reg', (56, 63))	('powdery microcalcifications', 'Disease', (104, 131))
20581	27247546	Comedonecrosis was significantly more common in high NG DCIS (P < 0.01).	('necrosis', 'Disease', (6, 14))	('necrosis', 'Disease', 'MESH:D009336', (6, 14))	('high NG DCIS', 'Var', (48, 60))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('NG', 'Chemical', '-', (53, 55))
20594	27247546	All of them fulfilled the study entering criteria: BIRADS category 4 or 5 microcalcifications without mass or architectural distortion, pure DCIS found on histological examination, lack of invasion or microinvasion (<= 1 mm in the longest diameter), absence of any other breast malignancy or border-line lesion.	('pure DCIS', 'Disease', (136, 145))	('breast malignancy', 'Disease', (271, 288))	('breast malignancy', 'Disease', 'MESH:D001943', (271, 288))	('microinvasion', 'CPA', (201, 214))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('microcalcifications', 'Disease', (74, 93))	('BIRADS', 'Var', (51, 57))
20612	27247546	In summary, high NG DCIS was most commonly related to casting-type microcalcifications while low NG DCIS most rarely.	('high NG', 'Var', (12, 19))	('casting-type microcalcifications', 'Disease', (54, 86))	('NG', 'Chemical', '-', (17, 19))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('related', 'Reg', (43, 50))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('NG', 'Chemical', '-', (97, 99))
20624	27247546	Grouped microcalcifications revealed low, intermediate and high NG DCIS in 45% (14), 39% (12), and 16% (5) of cases while regional microcalcifications in 27% (3), 27% (3), and 46% (5), respectively.	('intermediate', 'Var', (42, 54))	('low', 'Var', (37, 40))	('NG', 'Chemical', '-', (64, 66))	('high NG DCIS', 'Var', (59, 71))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
20627	27247546	Summarising, low NG DCIS was the most common in clustered microcalcifications and very rare in regional, where high NG DCIS was the most often, being found in nearly half of cases.	('NG', 'Chemical', '-', (116, 118))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('clustered microcalcifications', 'Disease', (48, 77))	('NG', 'Chemical', '-', (17, 19))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('low NG DCIS', 'Var', (13, 24))	('common', 'Reg', (38, 44))
20629	27247546	In 94% (17) of high NG DCIS the comedonecrosis was present, whereas in 47% (18) and 48% (34) of intermediate and low NG, respectively.	('necrosis', 'Disease', (38, 46))	('high NG', 'Var', (15, 22))	('NG', 'Chemical', '-', (20, 22))	('necrosis', 'Disease', 'MESH:D009336', (38, 46))	('comedo', 'Phenotype', 'HP:0025249', (32, 38))	('NG', 'Chemical', '-', (117, 119))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))
20631	27247546	In the group with comedonecrosis high, intermediate, and low NG DCIS were diagnosed in 25% (17), 26% (18), and 49% (34) of cases, respectively.	('comedo', 'Phenotype', 'HP:0025249', (18, 24))	('NG', 'Chemical', '-', (61, 63))	('necrosis', 'Disease', (24, 32))	('necrosis', 'Disease', 'MESH:D009336', (24, 32))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('low NG', 'Var', (57, 63))
20632	27247546	In summary, almost all the patients with high NG DCIS had comedonecrosis while just less than half of others.	('necrosis', 'Disease', 'MESH:D009336', (64, 72))	('high NG DCIS', 'Var', (41, 53))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('patients', 'Species', '9606', (27, 35))	('necrosis', 'Disease', (64, 72))	('comedo', 'Phenotype', 'HP:0025249', (58, 64))	('NG', 'Chemical', '-', (46, 48))
20635	27247546	Younger patients (50-60) had low, intermediate, and high NG DCIS in 57% (38), 28% (19), and 15% (10), while older women (61-69) in 55% (33), 32% (19), and 13% (8), respectively.	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))	('women', 'Species', '9606', (114, 119))	('low', 'NegReg', (29, 32))	('patients', 'Species', '9606', (8, 16))	('high NG DCIS', 'Var', (52, 64))	('NG', 'Chemical', '-', (57, 59))
20645	27247546	low/intermediate nuclear grade, absence of comedonecrosis) and eventually upgraded in the final examination of postoperative specimen.	('comedo', 'Phenotype', 'HP:0025249', (43, 49))	('necrosis', 'Disease', (49, 57))	('necrosis', 'Disease', 'MESH:D009336', (49, 57))	('low/intermediate', 'Var', (0, 16))
20646	27247546	It corresponds to our observation that low NG DCIS is usually found in clustered microcalcifications of crushed stone-like or powdery type whereas high NG DCIS is most common in casting type microcalcifications with regional distribution.	('high NG DCIS', 'Var', (147, 159))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('NG', 'Chemical', '-', (152, 154))	('found', 'Reg', (62, 67))	('NG', 'Chemical', '-', (43, 45))
20657	27247546	Histopathologically, HER2-positive DCIS and triple-negative DCIS were more commonly associated with high nuclear grade and comedonecrosis when compared to ER-positive DCIS.	('triple-negative', 'Var', (44, 59))	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('necrosis', 'Disease', 'MESH:D009336', (129, 137))	('high', 'Disease', (100, 104))	('DCIS', 'Gene', (60, 64))	('comedo', 'Phenotype', 'HP:0025249', (123, 129))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('associated', 'Reg', (84, 94))	('necrosis', 'Disease', (129, 137))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
20670	26630136	The advantages of VAB have been reported as a lower mistargeting rate and a lower underestimation rate of cancer, compared with a Tru-Cut biopsy using a 14-gauge needle.	('mistargeting', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('lower', 'NegReg', (46, 51))	('cancer', 'Disease', (106, 112))	('VAB', 'Chemical', '-', (18, 21))	('VAB', 'Var', (18, 21))
20708	26630136	Two of 7 palpable lesions were referred for rebiopsy and the remaining palpable lesion exhibited diffuse heterogeneity and calcifications on US (BI-RADS 4C and BI-RADS 4B, respectively).	('diffuse', 'MPA', (97, 104))	('calcification', 'Disease', (123, 136))	('calcification', 'Disease', 'MESH:D002114', (123, 136))	('BI-RADS', 'Var', (160, 167))	('RADS 4B', 'Phenotype', 'HP:0500055', (163, 170))
20719	26630136	Among them, 4 cases classified as BI-RADS 4B (n = 1) or 4C (n = 3) were upgraded to malignancy after rebiopsy.	('RADS 4B', 'Phenotype', 'HP:0500055', (37, 44))	('BI-RADS', 'Var', (34, 41))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('upgraded', 'Reg', (72, 80))	('malignancy', 'Disease', (84, 94))
20829	23851504	Conversely, loss of AIB1 expression in the mammary gland prevents RAS- or HER2-induced mammary tumor development.	('AIB1', 'Gene', (20, 24))	('HER2', 'Gene', (74, 78))	('p', 'Gene', '8202', (57, 58))	('RAS-', 'CPA', (66, 70))	('loss', 'Var', (12, 16))	('HER2', 'Gene', '2064', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p', 'Gene', '8202', (27, 28))	('tumor', 'Disease', (95, 100))	('p', 'Gene', '8202', (107, 108))
20859	23851504	AIB1 was also detected in the invasive lesions that developed from the MCFDCIS cells in vivo although the staining was less intense than in the DCIS lesions (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('detected', 'Reg', (14, 22))	('invasive lesions', 'CPA', (30, 46))	('MCFDCIS', 'Var', (71, 78))	('p', 'Gene', '8202', (58, 59))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
20878	23851504	The average spheroid size of MCFDCIS shAIB1-2 spheroids was also significantly smaller than MCFDCIS shCTRL and similar to the average size seen in MCF-10A (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('MCFDCIS shAIB1-2', 'Var', (29, 45))	('smaller', 'NegReg', (79, 86))	('p', 'Gene', '8202', (47, 48))	('p', 'Gene', '8202', (13, 14))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('MCF-10A', 'CellLine', 'CVCL:0598', (147, 154))
20882	23851504	Interestingly, in the MCFDCIS shAIB1 spheroids we observed Caspase 3-positive apoptotic cells especially in the center of the sphere (Fig.	('p', 'Gene', '8202', (69, 70))	('p', 'Gene', '8202', (38, 39))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('Caspase 3', 'Gene', (59, 68))	('p', 'Gene', '8202', (81, 82))	('p', 'Gene', '8202', (127, 128))	('Caspase 3', 'Gene', '836', (59, 68))	('p', 'Gene', '8202', (62, 63))	('p', 'Gene', '8202', (79, 80))	('MCFDCIS', 'Var', (22, 29))	('p', 'Gene', '8202', (96, 97))
20884	23851504	Changes in expression of these molecules have been associated with resumption of a more normal mammary acinar structure with the hollow lumen being created by increased apoptosis.	('p', 'Gene', '8202', (72, 73))	('p', 'Gene', '8202', (170, 171))	('associated', 'Reg', (51, 61))	('p', 'Gene', '8202', (13, 14))	('Changes', 'Var', (0, 7))	('p', 'Gene', '8202', (172, 173))
20886	23851504	We next determined if the loss of AIB1 in MCFDCIS cells could affect MCFDCIS tumor development in vivo.	('AIB1', 'Gene', (34, 38))	('affect', 'Reg', (62, 68))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('MCFDCIS', 'Disease', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('p', 'Gene', '8202', (89, 90))	('loss', 'Var', (26, 30))	('tumor', 'Disease', (77, 82))
20896	23851504	We also observed a decrease in the number of proliferative cells in the MCFDCIS AIB1 shRNA lesions as determined by the quantitation of overall PCNA staining (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('decrease', 'NegReg', (19, 27))	('PCNA', 'Gene', (144, 148))	('MCFDCIS AIB1', 'Var', (72, 84))	('PCNA', 'Gene', '5111', (144, 148))	('p', 'Gene', '8202', (45, 46))
20918	23851504	To determine if these expression changes impacted the population of BCIC, we FACS sorted MCFDCIS +/- AIB1 shRNA cells for CD24-/CD44+ (Fig.	('changes', 'Var', (33, 40))	('CD24', 'Gene', '100133941', (122, 126))	('p', 'Gene', '8202', (43, 44))	('CD24', 'Gene', (122, 126))	('p', 'Gene', '8202', (54, 55))	('p', 'Gene', '8202', (24, 25))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('p', 'Gene', '8202', (56, 57))
20920	23851504	Consistent with a loss of BCIC, the CD44 and CD49f levels were also significantly reduced in MCFDCIS AIB1shRNA cells (Fig.	('CD49f', 'Gene', '3655', (45, 50))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('CD44', 'MPA', (36, 40))	('MCFDCIS AIB1shRNA', 'Var', (93, 110))	('reduced', 'NegReg', (82, 89))	('CD49f', 'Gene', (45, 50))
20928	23851504	To determine if the changes in BCIC cell populations were observed after AIB1 reduction in vivo we stained MCFDCIS tumors obtained from the constitutive and conditional mouse models for CD44, CK18 and p63 expression (Fig.	('CK18', 'Var', (192, 196))	('p', 'Gene', '8202', (201, 202))	('p', 'Gene', '8202', (207, 208))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('p', 'Gene', '8202', (43, 44))	('reduction', 'NegReg', (78, 87))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mouse', 'Species', '10090', (169, 174))	('p', 'Gene', '8202', (41, 42))
20932	23851504	Interestingly, in the MCFDCIS AIB1 shRNA lesions, there was a gain in vivo in the CK18 staining, a marker of differentiated luminal epithelium (Fig.	('gain', 'PosReg', (62, 66))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('MCFDCIS AIB1', 'Var', (22, 34))	('p', 'Gene', '8202', (133, 134))	('CK18', 'Protein', (82, 86))
20935	23851504	In contrast, myoepithelial progenitor cells were significantly reduced in AIB1 shRNA, cells, indicated by loss of overall expression of alphaSMA mRNA in vitro (Fig.	('myoepithelial', 'Disease', 'MESH:D009208', (13, 26))	('p', 'Gene', '8202', (138, 139))	('AIB1', 'Var', (74, 78))	('reduced', 'NegReg', (63, 70))	('p', 'Gene', '8202', (124, 125))	('p', 'Gene', '8202', (17, 18))	('alphaSMA', 'Gene', (136, 144))	('loss', 'NegReg', (106, 110))	('p', 'Gene', '8202', (27, 28))	('alphaSMA', 'Gene', '11475', (136, 144))	('myoepithelial', 'Disease', (13, 26))
20938	23851504	In summary, the loss of AIB1 in MCFDCIS cells in vitro and in vivo reduces the BCIC and myoepithelial progenitor populations and also prevents the progression of the remaining luminal cells to invasive cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('AIB1', 'Gene', (24, 28))	('p', 'Gene', '8202', (115, 116))	('p', 'Gene', '8202', (92, 93))	('p', 'Gene', '8202', (102, 103))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('myoepithelial', 'Disease', (88, 101))	('p', 'Gene', '8202', (134, 135))	('p', 'Gene', '8202', (113, 114))	('loss', 'Var', (16, 20))	('myoepithelial', 'Disease', 'MESH:D009208', (88, 101))	('reduces', 'NegReg', (67, 74))	('cancer', 'Disease', (202, 208))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('p', 'Gene', '8202', (147, 148))	('BCIC and', 'MPA', (79, 87))
20939	23851504	cDNA array analysis of gene expression changes induced by loss of AIB1 in MCFDCIS cells indicated that NOTCH ligands (DLL1 and DLL3) were significantly downregulated (Table S1).	('DLL1', 'Gene', '28514', (118, 122))	('loss', 'Var', (58, 62))	('AIB1', 'Gene', (66, 70))	('p', 'Gene', '8202', (30, 31))	('DLL3', 'Gene', (127, 131))	('DLL1', 'Gene', (118, 122))	('downregulated', 'NegReg', (152, 165))	('DLL3', 'Gene', '10683', (127, 131))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
20947	23851504	Thus it was possible that changes in AIB1 levels were affecting HER2 and HER3 signaling and this in turn was altering expression of members of the NOTCH pathway.	('HER3', 'Gene', (73, 77))	('changes', 'Var', (26, 33))	('HER3', 'Gene', '2065', (73, 77))	('p', 'Gene', '8202', (153, 154))	('p', 'Gene', '8202', (12, 13))	('HER2', 'Gene', (64, 68))	('p', 'Gene', '8202', (120, 121))	('HER2', 'Gene', '2064', (64, 68))	('altering', 'Reg', (109, 117))	('affecting', 'Reg', (54, 63))
20952	23851504	Consistent with this, we demonstrated that HER2 mRNA and protein are upregulated in MCF-10A cells infected with lentivirus expressing AIB1 (Fig.	('AIB1', 'Var', (134, 138))	('p', 'Gene', '8202', (125, 126))	('HER2', 'Gene', (43, 47))	('p', 'Gene', '8202', (57, 58))	('HER2', 'Gene', '2064', (43, 47))	('MCF-10A', 'CellLine', 'CVCL:0598', (84, 91))	('p', 'Gene', '8202', (70, 71))
20958	23851504	While increased necrosis is often seen in the lumen of DCIS lesions in vivo, the necrosis we observed was more associated with the inability to sustain the DCIS cells thus inhibiting their progression to invasive lesions.	('invasive lesions', 'CPA', (204, 220))	('necrosis', 'Disease', 'MESH:D009336', (16, 24))	('inability', 'Var', (131, 140))	('increased necrosis', 'Phenotype', 'HP:0010885', (6, 24))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('inhibiting', 'NegReg', (172, 182))	('p', 'Gene', '8202', (189, 190))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('necrosis', 'Disease', (16, 24))	('necrosis', 'Disease', (81, 89))
20967	23851504	Since AIB1 is highly expressed in the patient DCIS samples that we have examined to date, and its loss prevents MCFDCIS invasive tumor development, we can conclude that AIB1 overexpression is necessary primarily for development and maintenance of DCIS through preserving the BCIC population, but further genetic changes are most likely necessary for the development of the invasive phenotype in a subset of DCIS.	('p', 'Gene', '8202', (360, 361))	('p', 'Gene', '8202', (202, 203))	('AIB1', 'Gene', (6, 10))	('p', 'Gene', '8202', (280, 281))	('invasive tumor', 'Disease', (120, 134))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('p', 'Gene', '8202', (103, 104))	('DCIS', 'Phenotype', 'HP:0030075', (247, 251))	('p', 'Gene', '8202', (389, 390))	('p', 'Gene', '8202', (382, 383))	('p', 'Gene', '8202', (23, 24))	('p', 'Gene', '8202', (222, 223))	('patient', 'Species', '9606', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('loss', 'Var', (98, 102))	('p', 'Gene', '8202', (38, 39))	('DCIS', 'Phenotype', 'HP:0030075', (407, 411))	('invasive tumor', 'Disease', 'MESH:D009369', (120, 134))	('p', 'Gene', '8202', (180, 181))	('p', 'Gene', '8202', (141, 142))	('AIB1', 'Gene', (169, 173))	('p', 'Gene', '8202', (54, 55))	('p', 'Gene', '8202', (260, 261))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('p', 'Gene', '8202', (282, 283))
20975	23851504	AIB1 is required for HER2 mediated mammary tumor formation in vivo and high levels of AIB1 and HER2 have been associated with worse prognosis and tamoxifen resistance in human breast cancer.	('p', 'Gene', '8202', (132, 133))	('high', 'Var', (71, 75))	('AIB1', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('HER2', 'Gene', (95, 99))	('associated with', 'Reg', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('HER2', 'Gene', '2064', (95, 99))	('human', 'Species', '9606', (170, 175))	('HER2', 'Gene', '2064', (21, 25))	('tamoxifen', 'Chemical', 'MESH:D013629', (146, 155))	('HER2', 'Gene', (21, 25))	('breast cancer', 'Disease', (176, 189))	('tumor', 'Disease', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('tamoxifen', 'MPA', (146, 155))
20978	23851504	In our gene expression analysis of +/-AIB1 in MCFDCIS cells in vitro, major changes in expression of HER family members HER1, 2 and HER3 were not observed.	('+/-AIB1', 'Var', (35, 42))	('HER3', 'Gene', (132, 136))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('HER3', 'Gene', '2065', (132, 136))	('HER1', 'Gene', (120, 124))	('p', 'Gene', '8202', (89, 90))	('p', 'Gene', '8202', (14, 15))	('HER1', 'Gene', '1956', (120, 124))
20980	23851504	HER2 signaling can regulate mammary stem cell renewal and loss of HER2 signaling controlled by loss of AIB1 could explain the significant loss of BCIC in vivo.	('loss', 'NegReg', (138, 142))	('HER2', 'Gene', '2064', (66, 70))	('AIB1', 'Gene', (103, 107))	('p', 'Gene', '8202', (116, 117))	('HER2', 'Gene', (0, 4))	('mammary stem cell renewal', 'CPA', (28, 53))	('BCIC', 'Disease', (146, 150))	('HER2', 'Gene', '2064', (0, 4))	('loss', 'Var', (95, 99))	('HER2', 'Gene', (66, 70))
20981	23851504	Interestingly, HER3 has recently been shown to play a role in maintaining luminal epithelium cells and loss of HER3 signaling causes a switch to mammary basal epithelium gene expression patterns.	('p', 'Gene', '8202', (186, 187))	('HER3', 'Gene', (111, 115))	('p', 'Gene', '8202', (177, 178))	('loss', 'Var', (103, 107))	('HER3', 'Gene', '2065', (111, 115))	('p', 'Gene', '8202', (160, 161))	('HER3', 'Gene', (15, 19))	('p', 'Gene', '8202', (47, 48))	('switch', 'Reg', (135, 141))	('HER3', 'Gene', '2065', (15, 19))	('p', 'Gene', '8202', (83, 84))
21012	23851504	MCFDCIS cells were stained with the following antibodies: anti-CD24-488, anti-CD44-PE, anti-CD49f-APC, anti-ESA-488, and anti-CD10-PE (BioLegend).	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('CD49f', 'Gene', (92, 97))	('anti-CD44-PE', 'Var', (73, 85))	('CD24', 'Gene', '100133941', (63, 67))	('CD24', 'Gene', (63, 67))	('CD49f', 'Gene', '3655', (92, 97))	('anti-ESA-488', 'Var', (103, 115))	('anti-CD10-PE', 'Var', (121, 133))
21026	23876597	Unexpectedly, mammary gland adenocarcinomas developed in BPA-exposed offspring by PND90.	('BPA', 'Chemical', 'MESH:C006780', (57, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('PND90', 'Var', (82, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (28, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('adenocarcinomas', 'Disease', (28, 43))
21036	23876597	Incomplete polymerization of BPA leads to leaching of the chemical and subsequent human exposure, as evidenced by the detection of BPA in human urine, serum, maternal and fetal plasma, amniotic fluid, placenta, and adipose tissue.	('BPA', 'Gene', (131, 134))	('leaching', 'MPA', (42, 50))	('Incomplete', 'Var', (0, 10))	('human', 'Species', '9606', (138, 143))	('BPA', 'Chemical', 'MESH:C006780', (131, 134))	('BPA', 'Chemical', 'MESH:C006780', (29, 32))	('human', 'Species', '9606', (82, 87))
21106	23876597	However, histological assessment of glands for ADH or DCIS showed that the incidence of ADH among glands from females exposed to all doses of BPA during both exposure periods ranged from 0 to 60% compared with no incidence (0%) in the vehicle controls (Table 3).	('BPA', 'Chemical', 'MESH:C006780', (142, 145))	('BPA', 'Gene', (142, 145))	('ADH', 'Disease', (88, 91))	('doses', 'Var', (133, 138))
21108	23876597	Four animals exhibited proliferative lesions in their mammary glands at PND90 and PND140 following either gestational-only or gestational/lactational exposure (Table 4): one lesion, diagnosed as a benign microfibroadenoma, in a mammary gland from a vehicle-exposed animal at PND140, and three lesions that were diagnosed as lobular alveolar hyperplasia in three different females, one each exposed to BPA0.25, BPA25, or BPA250.	('lobular alveolar hyperplasia', 'Disease', 'MESH:D018275', (324, 352))	('benign microfibroadenoma', 'Disease', (197, 221))	('BPA', 'Chemical', 'MESH:C006780', (401, 404))	('BPA', 'Chemical', 'MESH:C006780', (410, 413))	('lactation', 'Disease', (138, 147))	('BPA25', 'Var', (410, 415))	('BPA250', 'Chemical', '-', (420, 426))	('lactation', 'Disease', 'MESH:D007775', (138, 147))	('BPA25', 'Chemical', '-', (410, 415))	('rat', 'Species', '10116', (30, 33))	('alveolar hyperplasia', 'Phenotype', 'HP:0009085', (332, 352))	('BPA25', 'Chemical', '-', (420, 425))	('benign microfibroadenoma', 'Phenotype', 'HP:0010619', (197, 221))	('benign microfibroadenoma', 'Disease', 'MESH:D009369', (197, 221))	('PND140', 'Gene', (82, 88))	('BPA0.25', 'Var', (401, 408))	('lobular alveolar hyperplasia', 'Disease', (324, 352))	('BPA', 'Chemical', 'MESH:C006780', (420, 423))
21110	23876597	We detected tumors at PND90, PND140, and PND200 in animals exposed to BPA across all doses and exposure times.	('PND200', 'Var', (41, 47))	('PND140', 'Var', (29, 35))	('PND90', 'Var', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('BPA', 'Chemical', 'MESH:C006780', (70, 73))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
21111	23876597	A total of six mammary gland tumors were observed in females exposed perinatally to BPA at doses ranging from BPA0.25 to BPA250 (n = 230; Table 4).	('BPA', 'Chemical', 'MESH:C006780', (84, 87))	('BPA250', 'Chemical', '-', (121, 127))	('mammary gland', 'Disease', (15, 28))	('BPA0.25', 'Var', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BPA', 'Chemical', 'MESH:C006780', (110, 113))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('BPA', 'Chemical', 'MESH:C006780', (121, 124))	('tumors', 'Disease', (29, 35))	('BPA250', 'Var', (121, 127))
21117	23876597	In the BPA250 gestational exposure group, we detected significantly higher levels of unconjugated BPA in both dams and fetuses than in controls; these high levels were within the range of the levels detected in human serum (Table 1).	('BPA', 'Chemical', 'MESH:C006780', (98, 101))	('BPA', 'Chemical', 'MESH:C006780', (7, 10))	('gestational exposure', 'Phenotype', 'HP:0031437', (14, 34))	('higher', 'PosReg', (68, 74))	('human', 'Species', '9606', (211, 216))	('BPA250', 'Var', (7, 13))	('BPA250', 'Chemical', '-', (7, 13))
21126	23876597	The increase in BPA levels in the dams at PND10 and the significant decrease in BPA in the pups compared with fetuses could also be attributed to maternal grooming practices, as suggested for other chemicals.	('PND10', 'Var', (42, 47))	('decrease', 'NegReg', (68, 76))	('BPA', 'MPA', (80, 83))	('BPA levels', 'MPA', (16, 26))	('BPA', 'Chemical', 'MESH:C006780', (16, 19))	('BPA', 'Chemical', 'MESH:C006780', (80, 83))	('increase', 'PosReg', (4, 12))
21132	23876597	In the present study, nonneoplastic lesions diagnosed as lobular alveolar hyperplasia were observed in whole mounts of mammary glands at PND90 and PND140.	('alveolar hyperplasia', 'Phenotype', 'HP:0009085', (65, 85))	('nonneoplastic lesions', 'Disease', 'MESH:D004194', (22, 43))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (25, 43))	('nonneoplastic lesions', 'Disease', (22, 43))	('lobular alveolar hyperplasia', 'Disease', (57, 85))	('lobular alveolar hyperplasia', 'Disease', 'MESH:D018275', (57, 85))	('PND140', 'Var', (147, 153))
21134	23876597	A previous study showed that a single injection of the carcinogen N-nitrosomethylurea to postpubertal virgin female rats resulted in secretion of alpha-lactalbumin from lobular alveolar structures in the PND200 mammary gland.	('secretion', 'MPA', (133, 142))	('rats', 'Species', '10116', (116, 120))	('alpha-lactalbumin', 'Gene', (146, 163))	('alpha-lactalbumin', 'Gene', '24528', (146, 163))	('nitrosomethylurea', 'Chemical', 'MESH:D008770', (68, 85))	('N-nitrosomethylurea', 'Var', (66, 85))
21205	28902343	None-the-less, these findings suggest a potential role for Cx43 in normal human breast function and it follows that a disruption of normal Cx43 expression and function, potentially between luminal and basal cell populations or the surrounding stroma, could play a role in the development of human breast malignancy.	('Cx43', 'Gene', '2697', (139, 143))	('role', 'Reg', (264, 268))	('breast malignancy', 'Disease', (297, 314))	('disruption', 'Var', (118, 128))	('Cx43', 'Gene', (139, 143))	('expression', 'MPA', (144, 154))	('function', 'MPA', (159, 167))	('breast malignancy', 'Disease', 'MESH:D001943', (297, 314))	('Cx43', 'Gene', '2697', (59, 63))	('Cx43', 'Gene', (59, 63))	('play', 'Reg', (257, 261))	('human', 'Species', '9606', (74, 79))	('human', 'Species', '9606', (291, 296))
21222	28902343	Taken together, these observations suggest that loss of Cx43, and presumably GJIC regulated by Cx43, is a common feature of breast malignancies regardless of histological or receptor defined subtype.	('Cx43', 'Gene', (56, 60))	('loss', 'Var', (48, 52))	('breast malignancies regardless', 'Disease', (124, 154))	('Cx43', 'Gene', (95, 99))	('Cx43', 'Gene', '2697', (95, 99))	('breast malignancies regardless', 'Disease', 'MESH:D001943', (124, 154))	('Cx43', 'Gene', '2697', (56, 60))
21277	28902343	Many studies have questioned if the loss of GJIC between a potential cancer cell and normal cells is an alteration that leads to a cancer cell transformation.	('cancer', 'Disease', (131, 137))	('leads to', 'Reg', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('loss', 'Var', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (69, 75))
21302	28902343	The researchers developed an antiserum (SA226P) that strongly and selectively reacts with Cx43 phosphorylated on Serine (S) residues at amino acid positions 279 and 282 (S279/S282).	('Cx43', 'Gene', (90, 94))	('Serine', 'Chemical', 'MESH:D012694', (113, 119))	('SA226P', 'Chemical', '-', (40, 46))	('S279/S282', 'Var', (170, 179))	('Cx43', 'Gene', '2697', (90, 94))
21303	28902343	Previous studies showed that S279 and S282 are phosphorylated by MAPK signaling through ERK1/2.	('ERK1/2', 'Gene', (88, 94))	('S279', 'Var', (29, 33))	('ERK1/2', 'Gene', '5595;5594', (88, 94))	('S282', 'Var', (38, 42))
21306	28902343	In the normal breast, FCD and FA samples, the SA226P antiserum stained myoepithelial cells in all samples, which was predominantly cytoplasmic and diffuse.	('SA226P', 'Var', (46, 52))	('FCD', 'Disease', (22, 25))	('stained', 'Reg', (63, 70))	('SA226P', 'Chemical', '-', (46, 52))	('FCD', 'Phenotype', 'HP:0006552', (22, 25))	('FCD', 'Disease', 'MESH:C563256', (22, 25))
21311	28902343	While it is difficult to form any conclusions regarding the pan-Cx43 IHC results, the SA226P IHC results suggest that phosphorylation of Cx43 could vary between normal and malignant breast.	('SA226P', 'Chemical', '-', (86, 92))	('Cx43', 'Gene', '2697', (64, 68))	('Cx43', 'Gene', '2697', (137, 141))	('Cx43', 'Gene', (64, 68))	('Cx43', 'Gene', (137, 141))	('vary', 'Reg', (148, 152))	('SA226P', 'Var', (86, 92))
21313	28902343	These results showed that the intensity of the bands that reacted with the SA226P antiserum were high in normal breast but were somewhat decreased in papilloma and DCIS samples.	('intensity', 'MPA', (30, 39))	('SA226P', 'Var', (75, 81))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('papilloma', 'Phenotype', 'HP:0012740', (150, 159))	('SA226P', 'Chemical', '-', (75, 81))	('papilloma', 'Disease', (150, 159))	('decreased', 'NegReg', (137, 146))	('papilloma', 'Disease', 'MESH:D010212', (150, 159))
21339	28902343	Some debate still exists regarding the levels of expression of Cx43 in the malignant progression of breast cancer, however, it seems evident from the literature that loss of GJIC is integral to breast tumor formation.	('breast tumor', 'Disease', 'MESH:D001943', (194, 206))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('loss', 'Var', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('breast tumor', 'Disease', (194, 206))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('Cx43', 'Gene', '2697', (63, 67))	('Cx43', 'Gene', (63, 67))	('breast tumor', 'Phenotype', 'HP:0100013', (194, 206))
21340	28902343	As reviewed here, a general trend seems to be that loss of Cx43 GJIC is an early event in malignancy.	('loss', 'Var', (51, 55))	('malignancy', 'Disease', 'MESH:D009369', (90, 100))	('Cx43', 'Gene', '2697', (59, 63))	('malignancy', 'Disease', (90, 100))	('Cx43', 'Gene', (59, 63))
21362	25499596	Malignancy rate was associated with lesion size, washout kinetics and marked background enhancement of the breast parenchyma but was not associated with any clinical history characteristics.	('washout kinetics', 'MPA', (49, 65))	('background enhancement', 'MPA', (77, 99))	('lesion size', 'Var', (36, 47))	('Malignancy', 'Disease', (0, 10))	('Malignancy', 'Disease', 'MESH:D009369', (0, 10))
21401	25499596	There was a trend for a higher malignancy rate in masses with a spiculated margin (31% malignancy rate versus 7% and 8% in those with a smooth or irregular margin, respectively, p=0.05-0.06) and a lower malignancy rate in masses or foci with a high T2 signal (6% malignancy rate versus 20% in those with intermediate or low T2 signal, p=0.06).	('spiculated margin', 'Var', (64, 81))	('malignancy', 'Disease', 'MESH:D009369', (31, 41))	('malignancy', 'Disease', 'MESH:D009369', (203, 213))	('malignancy', 'Disease', (203, 213))	('malignancy', 'Disease', 'MESH:D009369', (87, 97))	('malignancy', 'Disease', 'MESH:D009369', (263, 273))	('higher', 'PosReg', (24, 30))	('malignancy', 'Disease', (31, 41))	('malignancy', 'Disease', (87, 97))	('malignancy', 'Disease', (263, 273))
21407	25499596	One patient with a BRCA2 gene mutation and new diagnosis of breast cancer planned for contralateral prophylactic mastectomy, but after the MRI-guided biopsy demonstrated a high risk lesion, a contralateral sentinel node dissection was also performed at the time of surgery.	('breast cancer', 'Disease', (60, 73))	('BRCA2', 'Gene', (19, 24))	('mutation', 'Var', (30, 38))	('patient', 'Species', '9606', (4, 11))	('BRCA2', 'Gene', '675', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
21428	25499596	Malignancy rate was associated with lesion size, washout kinetics and marked background enhancement of the breast parenchyma, confirming the suspicious nature of these findings.	('washout kinetics', 'MPA', (49, 65))	('background enhancement', 'MPA', (77, 99))	('lesion', 'Var', (36, 42))	('Malignancy', 'Disease', (0, 10))	('Malignancy', 'Disease', 'MESH:D009369', (0, 10))
21439	25149183	SLNB and ALND were associated with larger size and higher grade DCIS lesions.	('ALND', 'Disease', (9, 13))	('SLNB', 'Var', (0, 4))	('ALND', 'Chemical', '-', (9, 13))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('DCIS lesions', 'Disease', (64, 76))
21467	25149183	These results add support to the limited value of nodal staging in women with screen-detected DCIS and to recent guidelines that further restrict the indication for SLNB in DCIS, suggesting that clinicians consider SLNB when mastectomy is planned, in case of clinically evident mass lesions suggestive of invasive cancer, and in very large size DCIS (>5 cm.)	('invasive cancer', 'Disease', (305, 320))	('invasive cancer', 'Disease', 'MESH:D009362', (305, 320))	('women', 'Species', '9606', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))	('DCIS', 'Phenotype', 'HP:0030075', (345, 349))	('SLNB', 'Var', (215, 219))	('DCIS', 'Phenotype', 'HP:0030075', (173, 177))
21537	17453296	The excluded group of patients represented a relatively large proportion of low-grade DCIS according to the Van Nuys classification (p < .001) in comparison with the TMA group.	('TMA', 'Chemical', 'MESH:C071868', (166, 169))	('low-grade', 'Var', (76, 85))	('DCIS', 'Disease', (86, 90))	('patients', 'Species', '9606', (22, 30))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))
21544	17453296	Much data point out that poorly differentiated or high-grade DCIS lesions have a greater potential to progress to invasive disease than low-grade DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('invasive disease', 'Disease', (114, 130))	('progress', 'Reg', (102, 110))	('high-grade', 'Var', (50, 60))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('invasive disease', 'Disease', 'MESH:D009362', (114, 130))
21545	17453296	High grade is also an independent risk factor of local recurrence after lumpectomy for DCIS, and approximately 50% of these recurrences are invasive cancers.	('invasive cancers', 'Disease', 'MESH:D009362', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('local recurrence', 'CPA', (49, 65))	('invasive cancers', 'Disease', (140, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('High grade', 'Var', (0, 10))
21564	17453296	ER and PR positivity are related to low-grade DCIS, whereas p53 and cyclin D1 expression are associated with high grade.	('ER', 'Gene', '2099', (0, 2))	('low-grade DCIS', 'Disease', (36, 50))	('positivity', 'Var', (10, 20))	('associated', 'Reg', (93, 103))	('p53', 'Gene', (60, 63))	('cyclin D1', 'Gene', '595', (68, 77))	('p53', 'Gene', '7157', (60, 63))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('cyclin D1', 'Gene', (68, 77))	('PR', 'Gene', '5241', (7, 9))
21599	24639339	In our study, the diagnosis of LN was most often reserved for low nuclear grade, monotonous, discohesive epithelial proliferations involving sclerosing adenosis.	('adenosis', 'Disease', 'MESH:D005348', (152, 160))	('discohesive epithelial proliferations', 'Disease', (93, 130))	('monotonous', 'Disease', (81, 91))	('adenosis', 'Disease', (152, 160))	('low nuclear', 'Var', (62, 73))	('LN', 'Phenotype', 'HP:0030076', (31, 33))
21602	24639339	Patients with either pleomorphic LCIS, defined as LCIS with grade 2 or 3 nuclei, or florid LCIS with necrosis also were excluded from this study, as all patients in our institution diagnosed with variant LCIS are recommended to have excisional biopsies with negative margins.	('LCIS', 'Phenotype', 'HP:0030076', (91, 95))	('patients', 'Species', '9606', (153, 161))	('necrosis', 'Disease', (101, 109))	('Patients', 'Species', '9606', (0, 8))	('necrosis', 'Disease', 'MESH:D009336', (101, 109))	('LCIS', 'Phenotype', 'HP:0030076', (33, 37))	('variant', 'Var', (196, 203))	('LCIS', 'Phenotype', 'HP:0030076', (50, 54))	('LCIS', 'Phenotype', 'HP:0030076', (204, 208))	('LCIS', 'Gene', (204, 208))
21716	22583194	These findings provide additional evidence that an aberrant reactivity of myofibroblasts to endogenous or exogenous hormones is probably an important factor in the development of PASH.	('men', 'Species', '9606', (171, 174))	('reactivity', 'MPA', (60, 70))	('aberrant', 'Var', (51, 59))	('PASH', 'Disease', (179, 183))
21733	22583194	In our study we reported positivity for CD34 in all cases of PASH examined which is consistent with the findings in the literature and supports the myofibroblastic stromal origin of these lesions.	('PASH', 'Disease', (61, 65))	('positivity', 'Var', (25, 35))	('CD34', 'Gene', '947', (40, 44))	('CD34', 'Gene', (40, 44))
21850	19889214	In spite of the supporting evidence in the literature, the significance of circulating MMP-9 in prognosis and progression of breast cancer disease requires further clarification.	('MMP-9', 'Gene', '4318', (87, 92))	('MMP-9', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer disease', 'Disease', (125, 146))	('breast cancer disease', 'Disease', 'MESH:D001943', (125, 146))	('circulating', 'Var', (75, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
21861	19728082	The primary endpoint was Ki-67 (proliferation) reduction.	('Ki-67', 'Var', (25, 30))	('reduction', 'NegReg', (47, 56))	('Ki-67', 'Chemical', '-', (25, 30))
21874	19728082	However, the largest published cohort looking specifically at the impact of statin exposure on ER-negative tumors showed that the relative frequency of ER-negative breast cancers decreased in women taking lipophilic statins for more than a year (OR 0.63, 95% CI 0.43-0.92; P = 0.02).	('decreased', 'NegReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('tumors', 'Disease', (107, 113))	('breast cancers', 'Disease', (164, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('women', 'Species', '9606', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('lipophilic', 'Var', (205, 215))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
21881	19728082	We and others have shown that lipophilic statins inhibit growth of breast cancer tumor cell lines and breast cancer tumors in animal models.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (67, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lipophilic', 'Var', (30, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer tumors', 'Disease', 'MESH:D001943', (102, 122))	('breast cancer tumor', 'Disease', (67, 86))	('breast cancer tumor', 'Disease', 'MESH:D001943', (102, 121))	('growth', 'CPA', (57, 63))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (102, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast cancer tumors', 'Disease', (102, 122))	('inhibit', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer tumor', 'Disease', 'MESH:D001943', (67, 86))
21882	19728082	These findings indicate that lipophilic statins may inhibit breast cancer cell growth and that impact is highly dependent on tumor characteristics.	('breast cancer', 'Disease', (60, 73))	('inhibit', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lipophilic', 'Var', (29, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
21885	19728082	Taken together, data suggest that ER-negative breast cancer is the biologic subtype most likely to be affected by lipophilic statins, an impact that epidemiologic studies could miss.	('affected', 'Reg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('lipophilic', 'Var', (114, 124))	('breast cancer', 'Disease', (46, 59))
21924	19728082	Non-high grade tumors had a 0.3 percentage point decrease in tumor proliferation (P = 0.47).	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Non-high grade', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('decrease', 'NegReg', (49, 57))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumors', 'Disease', (15, 21))
21925	19728082	With respect to ER status, the change in Ki-67 index was not statistically significant (2.0% median reduction in ER-negative vs. 0.8% median reduction in ER positive, P = 0.56).	('reduction', 'NegReg', (100, 109))	('ER-negative', 'Var', (113, 124))	('Ki-67', 'Chemical', '-', (41, 46))
21991	19144122	Breast-cancer gene 2 (BRCA2) mutation had been identified in a maternal aunt recently on the exon 24 insertion called c9481_9482insA.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('c9481_9482insA', 'Var', (118, 132))	('Breast-cancer gene 2', 'Gene', '675', (0, 20))	('BRCA2', 'Gene', (22, 27))	('Breast-cancer gene 2', 'Gene', (0, 20))	('9482insA', 'Mutation', 'c.9482insA', (124, 132))	('BRCA2', 'Gene', '675', (22, 27))
21992	19144122	It was very likely that this patient was a carrier of this BRCA2 mutation, which poses a small risk for him to develop prostate cancer.	('patient', 'Species', '9606', (29, 36))	('BRCA2', 'Gene', '675', (59, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('develop', 'PosReg', (111, 118))	('prostate cancer', 'Disease', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutation', 'Var', (65, 73))	('BRCA2', 'Gene', (59, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))
22014	19144122	Between 4% and 40% of male breast cancers might result from autosomal dominant mutations, primarily BRCA1 or BRCA2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (115, 124))	('BRCA1', 'Gene', '672', (100, 105))	('male breast cancers', 'Disease', 'MESH:D018567', (22, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (27, 41))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', (109, 114))	('male breast cancers', 'Disease', (22, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('result from', 'Reg', (48, 59))	('BRCA2', 'Gene', '675', (109, 114))
22085	24511905	It should be acknowledged that borderline categories such as ADH and low-grade DCIS may be prone to diagnostic variability because of their innate lack of distinction from a biological perspective, despite their clinical utility as diagnostic categories.	('ADH', 'Disease', 'MESH:D007177', (61, 64))	('low-grade DCIS', 'Var', (69, 83))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('ADH', 'Disease', (61, 64))
22108	24146864	Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction.	('p16', 'Gene', '1029', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'Var', (26, 30))	('develop', 'PosReg', (86, 93))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('expression', 'MPA', (35, 45))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('aggressive breast cancers', 'Disease', (99, 124))	('p16', 'Gene', (31, 34))	('p53', 'Gene', '7157', (147, 150))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (99, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('p53', 'Gene', (147, 150))
22112	24146864	Cell-cycle deregulation can lead to uncontrolled cell growth and contribute to tumor formation.	('Cell-cycle', 'CPA', (0, 10))	('tumor', 'Disease', (79, 84))	('deregulation', 'Var', (11, 23))	('uncontrolled', 'MPA', (36, 48))	('lead to', 'Reg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('contribute', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
22113	24146864	Deregulated cell proliferation is characteristic of tumor cells, and gene mutations affecting control of the cell cycle are extremely common in human cancers, including breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('human', 'Species', '9606', (144, 149))	('gene mutations', 'Var', (69, 83))	('tumor', 'Disease', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('common', 'Reg', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cell proliferation', 'CPA', (12, 30))	('breast cancer', 'Disease', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
22117	24146864	Through inactivation of CDK 4 and 6, p16 prevents phosphorylation and inactivation of Rb family cell cycle regulators.	('phosphorylation', 'MPA', (50, 65))	('CDK 4 and 6', 'Gene', '1019;1021', (24, 35))	('inactivation', 'NegReg', (70, 82))	('prevents', 'NegReg', (41, 49))	('inactivation', 'Var', (8, 20))	('p16', 'Gene', '1029', (37, 40))	('p16', 'Gene', (37, 40))
22120	24146864	Disrupting p53 function, such as the inactivation that occurs in response to various p53 mutations and high-risk HPV E6 protein.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('inactivation', 'MPA', (37, 49))	('Disrupting', 'NegReg', (0, 10))	('mutations', 'Var', (89, 98))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('function', 'MPA', (15, 23))
22121	24146864	The proliferative advantage given by p53 inactivation and the ubiquitous expression of p53 explain why it is found to be mutated in almost every type of cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('inactivation', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))
22148	24146864	This was closely but not perfectly correlated with p53 mutations.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('mutations', 'Var', (55, 64))
22151	24146864	Tumors that were ER+ and/or PR+, and either HER2+ and/or high proliferation were considered luminal B tumors.	('ER+', 'Var', (17, 20))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('HER2', 'Gene', (44, 48))	('PR+', 'Var', (28, 31))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('HER2', 'Gene', '2064', (44, 48))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('high proliferation', 'CPA', (57, 75))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
22165	24146864	There were less tumor proliferation features was characteristic of patients who had low p16 expression (Table 2).	('p16', 'Gene', (88, 91))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('low', 'Var', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('p16', 'Gene', '1029', (88, 91))	('tumor', 'Disease', (16, 21))	('less', 'NegReg', (11, 15))
22173	24146864	Patients with high levels of p16 expression were found to be more likely to develop subsequent advanced breast cancer than patients with low p16 expression (Figure 3).	('p16', 'Gene', (29, 32))	('p16', 'Gene', '1029', (141, 144))	('high levels', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('patients', 'Species', '9606', (123, 131))	('p16', 'Gene', '1029', (29, 32))	('develop', 'PosReg', (76, 83))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (104, 117))	('p16', 'Gene', (141, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
22175	24146864	To determine the potential mechanism behind DCIS with high p16 expression and the propensity of these cases to develop advanced breast cancer, the p53 status of these cases was determined.	('p16', 'Gene', '1029', (59, 62))	('high', 'Var', (54, 58))	('develop', 'PosReg', (111, 118))	('expression', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('p16', 'Gene', (59, 62))	('p53', 'Gene', '7157', (147, 150))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('p53', 'Gene', (147, 150))
22176	24146864	Correlations with p16 expression and p53 aberrant overexpression (Figure 2).	('p16', 'Gene', '1029', (18, 21))	('aberrant', 'Var', (41, 49))	('overexpression', 'PosReg', (50, 64))	('p16', 'Gene', (18, 21))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))
22182	24146864	Because as p53 mutation is closely correlated with aberrant overexpression of p53, these results might indicate that the dysfunction of the p53 pathway chiefly occurs in triple-negative breast cancers.	('p53', 'Gene', (11, 14))	('mutation', 'Var', (15, 23))	('correlated', 'Reg', (35, 45))	('p53', 'Gene', '7157', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('breast cancers', 'Phenotype', 'HP:0003002', (186, 200))	('p53', 'Gene', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancers', 'Disease', 'MESH:D001943', (186, 200))	('breast cancers', 'Disease', (186, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('p53', 'Gene', '7157', (78, 81))	('p53', 'Gene', (140, 143))	('occurs', 'Reg', (160, 166))	('p53', 'Gene', '7157', (140, 143))
22225	33912731	E5194 patients had either low-or intermediate-grade DCIS with tumor <=2.5 cm or high-grade DCIS with tumor <=1 cm.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('E5194', 'Var', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (62, 67))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('low-or', 'Disease', (26, 32))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
22227	33912731	Patients who underwent lumpectomy between November 2011 and August 2014 with an available 12-gene DCIS Score result and who were consented to one of 2 IRB-approved protocols (NCT01185145 and NCT01185132) were identified in clinical practice; cases with any invasive (including microinvasive) disease were excluded.	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('DCIS Score', 'Gene', (98, 108))	('Patients', 'Species', '9606', (0, 8))	('NCT01185145', 'Var', (175, 186))	('NCT01185132', 'Var', (191, 202))
22234	33912731	The E5194-eligible patients tended to have smaller total DCIS span and larger margin size.	('smaller', 'NegReg', (43, 50))	('E5194-eligible', 'Var', (4, 18))	('patients', 'Species', '9606', (19, 27))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
22235	33912731	Median patient age at diagnosis in the E5194-ineligible cohort was higher, but the interquartile and overall ranges were similar.	('patient', 'Species', '9606', (7, 14))	('higher', 'PosReg', (67, 73))	('E5194-ineligible', 'Var', (39, 55))
22251	33912731	The benefit of radiation may also be greater in women older than age 50 than in younger women, although the simulated model suggests the survival benefit remains similar between the age groups, with radiation improving survival by 4 months in women aged 45 years and 5 months in women aged 60 years.	('women', 'Species', '9606', (88, 93))	('radiation', 'Var', (199, 208))	('women', 'Species', '9606', (243, 248))	('improving', 'PosReg', (209, 218))	('women', 'Species', '9606', (48, 53))	('women', 'Species', '9606', (279, 284))	('survival', 'MPA', (219, 227))
22258	26511265	At T2, chemotherapy (P < 0.001) and BCS (P < 0.001) were independently associated with worse QOL in adjusted linear regression, and the adverse effect of chemotherapy was prominent among patients who received BCS compared with those who received mastectomy (Pinteraction = 0.031).	('patients', 'Species', '9606', (187, 195))	('worse', 'NegReg', (87, 92))	('BCS', 'Var', (36, 39))	('QOL', 'MPA', (93, 96))	('BCS', 'Var', (209, 212))
22259	26511265	In the GEE model, QOL significantly improved over time among patients who received BCS (Ptrend = 0.047), mastectomy (Ptrend = 0.024), and chemotherapy (Ptrend < 0.001) but not among patients who did not receive chemotherapy (Ptrend = 0.720).	('patients', 'Species', '9606', (61, 69))	('chemotherapy', 'Var', (138, 150))	('QOL', 'MPA', (18, 21))	('improved', 'PosReg', (36, 44))	('patients', 'Species', '9606', (182, 190))	('mastectomy', 'Disease', (105, 115))
22291	26511265	At Time2, BCS (P < 0.001) and chemotherapy (P = 0.001) were associated with worse QOL, and the adverse effect of chemotherapy on QOL was more prominent among patients who received BCS than mastectomy (Pinteraction = 0.031).	('patients', 'Species', '9606', (158, 166))	('BCS', 'Var', (180, 183))	('QOL', 'MPA', (82, 85))	('BCS', 'Disease', (10, 13))
22297	26511265	QOL also improved significantly in patients who received chemotherapy, but not in patients who did not receive chemotherapy.	('chemotherapy', 'Var', (57, 69))	('patients', 'Species', '9606', (82, 90))	('QOL', 'MPA', (0, 3))	('improved', 'PosReg', (9, 17))	('patients', 'Species', '9606', (35, 43))
22298	26511265	Excluding DCIS patients, the 3-way interaction in the GEE model still was not significant (P = 0.96); QOL significantly improved for patients who received chemotherapy and mastectomy but not for patients who received BCS or who did not receive chemotherapy.	('improved', 'PosReg', (120, 128))	('patients', 'Species', '9606', (15, 23))	('QOL', 'MPA', (102, 105))	('chemotherapy', 'Var', (155, 167))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (195, 203))	('mastectomy', 'Var', (172, 182))
22333	31342393	After adjustment, breast-cancer-specific survival was significantly different between DCISM and the other two groups (DCIS: HR 0.59, CI 0.43-0.8; invasive: HR 1.43, CI 1.04-1.96).	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('breast-cancer', 'Disease', (18, 31))	('different', 'Reg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('HR', 'Gene', '3164', (124, 126))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('breast-cancer', 'Disease', 'MESH:D001943', (18, 31))	('DCISM', 'Var', (86, 91))	('HR', 'Gene', '3164', (156, 158))
22365	31342393	Although the majority of patients were node-negative for all groups, patients with DCISM were slightly more likely to have a higher N stage than those with invasive disease (7.5% vs. 5.7% N1 disease, 1.3% vs. 0.5% N2 disease; Table 1).	('invasive disease', 'Disease', 'MESH:D009361', (156, 172))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('N stage', 'CPA', (132, 139))	('DCISM', 'Var', (83, 88))	('patients', 'Species', '9606', (25, 33))	('invasive disease', 'Disease', (156, 172))	('patients', 'Species', '9606', (69, 77))
22367	31342393	Younger women with DCISM had a higher percentage of grade 3 (18-39 year: 30% vs. > 70 year: 15.6%) and HER2-positive tumors (18-39 year: 9.4% vs. > 70 year: 5.6%), whereas older women had higher proportions of node-negative (18-39 year: 80% vs. > 70 year: 92.8%), ER-positive (18-39 year: 65.6% vs. > 70 year: 74.9%), and PR-positive tumors (18-39 year: 53.1% vs. > 70 year: 58.8%; Supplemental Table 2).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('women', 'Species', '9606', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('ER', 'Gene', '2099', (104, 106))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ER', 'Gene', '2099', (264, 266))	('tumors', 'Disease', (334, 340))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('women', 'Species', '9606', (178, 183))	('HER2', 'Gene', '2064', (103, 107))	('PR', 'Gene', '5241', (322, 324))	('HER2', 'Gene', (103, 107))	('DCISM', 'Var', (19, 24))	('grade 3', 'CPA', (52, 59))
22375	31342393	However, the adjusted OS was not significantly different between DCISM and invasive disease (HR 0.98, CI 0.87-1.09, p = 0.66), whereas patients with DCIS had improved OS compared with DCISM (HR 0.84, CI 0.75-0.93, p < 0.001; Table 4).	('invasive disease', 'Disease', (75, 91))	('patients', 'Species', '9606', (135, 143))	('improved', 'PosReg', (158, 166))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('invasive disease', 'Disease', 'MESH:D009361', (75, 91))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('HR', 'Gene', '3164', (93, 95))	('HR', 'Gene', '3164', (191, 193))	('DCIS', 'Var', (149, 153))
22387	31342393	Furthermore, one of the largest studies comparing DCIS and DCISM demonstrated that DCISM was associated with more aggressive tumor biology.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('aggressive tumor', 'Disease', 'MESH:D001523', (114, 130))	('DCISM', 'Var', (83, 88))	('aggressive tumor', 'Disease', (114, 130))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
22390	31342393	Furthermore, previous studies have shown that DCIS on core needle biopsy is upstaged to invasive disease at the time of surgical excision in 15-20% of cases, and this may be related to the extent of disease on preoperative imaging.	('upstaged', 'PosReg', (76, 84))	('invasive disease', 'Disease', 'MESH:D009361', (88, 104))	('invasive disease', 'Disease', (88, 104))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('DCIS', 'Var', (46, 50))
22409	31342393	However, our study suggests that outcomes for women with DCISM more closely reflect those of small invasive cancers and thus may warrant comparable treatment.	('DCISM', 'Var', (57, 62))	('small invasive cancers', 'Disease', 'MESH:D055752', (93, 115))	('small invasive cancers', 'Disease', (93, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('women', 'Species', '9606', (46, 51))
22511	26318461	In a recent study, ACOSOG Z0011, in which patients with clinical T1-2 N0 M0 BC having a positive SN were randomized to have ALND or no further axillary surgery, results showed no trend toward a clinical benefit of ALND for patients with limited nodal disease.	('patients', 'Species', '9606', (223, 231))	('nodal disease', 'Disease', 'MESH:D013611', (245, 258))	('nodal disease', 'Disease', (245, 258))	('T1-2 N0 M0 BC', 'Var', (65, 78))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('patients', 'Species', '9606', (42, 50))
22521	22666571	Comparative analyses for implementing predictive markers in tumour biology show a multitude of genetic alterations in all the DCIS cases and propose distinct pathways in morphological evolution (poor, intermediate, and well).	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('tumour', 'Disease', (60, 66))	('genetic alterations', 'Var', (95, 114))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
22522	22666571	Poorly differentiated diseases displayed a higher frequency of amplifications (17q12, 11q13) and a higher average rate of genetic imbalances (40%) suggesting a developmental progression model for intraductal carcinoma.	('intraductal carcinoma', 'Disease', 'MESH:D002285', (196, 217))	('imbalances', 'Phenotype', 'HP:0002172', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('Poorly differentiated diseases', 'Disease', (0, 30))	('intraductal carcinoma', 'Disease', (196, 217))	('17q12', 'Var', (79, 84))
22524	22666571	The natural history of small, noncomedo, and low grade in situ lesions treated by biopsy alone has been evaluated in studies with long-term follow-up.	('comedo', 'Phenotype', 'HP:0025249', (33, 39))	('situ lesions', 'Disease', 'MESH:D002278', (58, 70))	('low grade', 'Var', (45, 54))	('situ lesions', 'Disease', (58, 70))
22538	22666571	Pathological classification combines high nuclear grade and comedo-type necrosis to predict clinical behavior and stratify disease into three groups: non-high-nuclear grade without comedo-type necrosis (Score  1), or with necrosis (Score  2) and high nuclear grade (Score  3).	('necrosis', 'Disease', 'MESH:D009336', (222, 230))	('necrosis', 'Disease', (72, 80))	('non-high-nuclear grade', 'Var', (150, 172))	('comedo', 'Phenotype', 'HP:0025249', (60, 66))	('necrosis', 'Disease', (193, 201))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('necrosis', 'Disease', (222, 230))	('necrosis', 'Disease', 'MESH:D009336', (193, 201))	('comedo', 'Phenotype', 'HP:0025249', (181, 187))
22553	22666571	Histopathologically, in DCIS a strong association was found between large nuclear size and comedonecrosis as independent significant predictors.	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('necrosis', 'Disease', (97, 105))	('comedo', 'Phenotype', 'HP:0025249', (91, 97))	('large nuclear', 'Var', (68, 81))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))
22562	22666571	The risk of a radical intervention is defined higher in some clinical scenarios like diffuse and suspicious-appearing microcalcifications, suboptimal tumor to breast size ratio with an unacceptable cosmetic results, the inability to obtain margin control by lumpectomy or reexcision(s).	('suboptimal', 'Var', (139, 149))	('diffuse', 'Disease', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
22600	22666571	Successful downscoring of a patient with a USC/VNPI or 10 or 11 could result in substantial reduction in the risk of local recurrence, perhaps changing a recommendation from mastectomy to radiation therapy.	('local recurrence', 'MPA', (117, 133))	('reduction', 'NegReg', (92, 101))	('patient', 'Species', '9606', (28, 35))	('changing', 'Reg', (143, 151))	('USC/VNPI', 'Var', (43, 51))
22615	22666571	Therefore, in patients diagnosed with DCIS on core biopsy examinations SLNB should be reserved for those at high risk of invasive disease, including patients with palpable lesions, DCIS larger than 40 mm, high nuclear grade, comedo morphology, necrosis or recurrent disease, or patients undergoing mastectomy where SLNB could not be postponed.	('invasive disease', 'Disease', 'MESH:D009362', (121, 137))	('patients', 'Species', '9606', (149, 157))	('necrosis', 'Disease', (244, 252))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('recurrent disease', 'CPA', (256, 273))	('comedo', 'Phenotype', 'HP:0025249', (225, 231))	('invasive disease', 'Disease', (121, 137))	('comedo morphology', 'CPA', (225, 242))	('necrosis', 'Disease', 'MESH:D009336', (244, 252))	('patients', 'Species', '9606', (278, 286))	('patients', 'Species', '9606', (14, 22))	('high nuclear', 'Var', (205, 217))
22616	22666571	Moreover axillary node involvement is higher with DCISM (5.1%) than that with DCIS (1.4%) and inadequate sampling could result in misdiagnosis and consequent under-treatment of patients.	('DCISM', 'Var', (50, 55))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('misdiagnosis', 'Disease', (130, 142))	('result', 'Reg', (120, 126))	('patients', 'Species', '9606', (177, 185))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('higher', 'PosReg', (38, 44))	('axillary node involvement', 'CPA', (9, 34))	('DCISM', 'Chemical', '-', (50, 55))
22641	18564426	Of these tumour size greater than 15 mm, intermediate or high nuclear grade, presence of comedo necrosis and intermediate or high VNPI scores were found to significantly increase the chance of patients receiving adjuvant RT.	('patients', 'Species', '9606', (193, 201))	('tumour', 'Disease', (9, 15))	('VNPI', 'Gene', (130, 134))	('necrosis', 'Disease', (96, 104))	('intermediate', 'Var', (41, 53))	('increase', 'PosReg', (170, 178))	('necrosis', 'Disease', 'MESH:D009336', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('comedo', 'Phenotype', 'HP:0025249', (89, 95))
22674	18564426	Taking these factors in to account and appreciating that the natural history of DCIS remains elusive, it is our opinion that RT should be reserved for those patients with high and possibly intermediate VNPI scores as it is in these groups that the benefit: risk ratio is likely to be highest.	('VNPI', 'Gene', (202, 206))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('scores', 'Var', (207, 213))	('patients', 'Species', '9606', (157, 165))
22694	24171825	We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).	('Triple Negative DCIS', 'Var', (180, 200))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('women', 'Species', '9606', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
22711	24171825	For HER2 gene amplification the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria for single HER2 probe testing was used (diploid, 1 to 2.5 copies/nucleus; polysomy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/nucleus; and high-level amplification >10 copies/nucleus) and for dual HER2/CHR17 probe testing (nonamplified ratio <1.8; equivocal ratio, 1.8 to 2.2; gene amplification, >2.2).	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', '2064', (168, 172))	('HER2', 'Gene', (413, 417))	('HER2', 'Gene', '2064', (128, 132))	('HER2', 'Gene', '2064', (413, 417))	('Oncology', 'Phenotype', 'HP:0002664', (61, 69))	('polysomy', 'Var', (231, 239))	('HER2', 'Gene', (4, 8))	('HER2', 'Gene', '2064', (4, 8))	('HER2', 'Gene', (168, 172))
22833	22376239	Increased nuclear-to-cytoplasmic ratio is also a marker of low differentiation, and when it is associated with variation in nuclear size between cancer cells the tumor gets a high score also in this element of the Nottingham grading system.	('cancer', 'Disease', (145, 151))	('nuclear-to-cytoplasmic', 'CPA', (10, 32))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('low differentiation', 'CPA', (59, 78))	('tumor', 'Disease', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('variation', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
22849	22376239	As a whole, DCIS may be seen as an intermediate step in the malignification process of tumors, and the typical hallmark trait of low differentiation in this form of neoplasia is the presence of comedo-type necrosis.	('necrosis', 'Disease', (206, 214))	('neoplasia', 'Disease', 'MESH:D009369', (165, 174))	('neoplasia', 'Phenotype', 'HP:0002664', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('comedo', 'Phenotype', 'HP:0025249', (194, 200))	('necrosis', 'Disease', 'MESH:D009336', (206, 214))	('low differentiation', 'Var', (129, 148))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('typical hallmark trait', 'Phenotype', 'HP:0000957', (103, 125))	('neoplasia', 'Disease', (165, 174))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
22896	19701073	LCIS lesions are further characterized by loss of expression of the adhesion molecule E-cadherin, most commonly due to mutation or deletion of CDH1 locus on chromosome 16q.	('mutation', 'Var', (119, 127))	('loss', 'NegReg', (42, 46))	('LCIS lesions', 'Disease', (0, 12))	('CDH1', 'Gene', (143, 147))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))	('expression', 'MPA', (50, 60))	('CDH1', 'Gene', '999', (143, 147))	('deletion', 'Var', (131, 139))
22901	19701073	Prior to its recognition, this lesion was probably most often classified as high grade DCIS due to the presence of nuclear pleomorphism and the frequent presence of comedo-type necrosis.	('necrosis', 'Disease', 'MESH:D009336', (177, 185))	('comedo', 'Phenotype', 'HP:0025249', (165, 171))	('nuclear pleomorphism', 'Var', (115, 135))	('necrosis', 'Disease', (177, 185))
22928	19701073	Therefore, HER2 positive cases in this study showed both 3+ staining and HER2 gene amplification.	('HER2', 'Gene', '2064', (73, 77))	('HER2', 'Gene', (73, 77))	('HER2', 'Gene', (11, 15))	('amplification', 'Var', (83, 96))	('3+ staining', 'Var', (57, 68))	('HER2', 'Gene', '2064', (11, 15))
22976	19701073	Overall, PLCIS and CLCIS shared similar genomic alterations: both groups were characterized by 1q gain (75% in PLCIS vs 69% in CLCIS) and 16q loss (85% vs 76%, for PLCIS and CLCIS respectively) (Figure 4).	('CLCIS', 'Chemical', '-', (127, 132))	('loss', 'NegReg', (142, 146))	('CLCIS', 'Chemical', '-', (19, 24))	('16q', 'Var', (138, 141))	('gain', 'PosReg', (98, 102))	('CLCIS', 'Chemical', '-', (174, 179))
22978	19701073	However, some genomic alterations were either only noted in the PLCIS but not the CLCIS such as amplification of HER2 gene at17q11.2-17q12 (10% vs 0%), gain of 16p (14% vs 0%), loss of 8p (5% vs 0%) or more prevalent in the PLCIS such as amplification of cyclin D1 gene at 11q13.3 (14% vs 5%).	('cyclin D1', 'Gene', (255, 264))	('amplification', 'Var', (238, 251))	('HER2', 'Gene', (113, 117))	('gain', 'PosReg', (152, 156))	('HER2', 'Gene', '2064', (113, 117))	('loss', 'Var', (177, 181))	('CLCIS', 'Chemical', '-', (82, 87))	('cyclin D1', 'Gene', '595', (255, 264))
22979	19701073	In addition to 1q gain and 16q loss, recurrent copy number changes for apocrine PLCIS included gains of 16p (36%) and 6p (15%), losses of 3q (22%), 11q (32%), 13q (25%) and 17p (45%), and amplification of cyclin D1 gene (3/8, 38%) and HER2 gene (2/8, 25%); for non apocrine PLCIS, no additional recurrent change was observed.	('losses', 'NegReg', (128, 134))	('loss', 'NegReg', (31, 35))	('gain', 'PosReg', (18, 22))	('cyclin D1', 'Gene', '595', (205, 214))	('HER2', 'Gene', (235, 239))	('apocrine', 'Disease', (71, 79))	('amplification', 'Var', (188, 201))	('cyclin D1', 'Gene', (205, 214))	('HER2', 'Gene', '2064', (235, 239))	('gains', 'PosReg', (95, 100))
22982	19701073	Specifically, apocrine PLCIS had significantly higher FGL (p=0.04), more whole chromosomes changes (p=0.04), more amplifications (p=0.02) and more chromosomes with amplifications (p=0.02) than CLCIS.	('chromosomes with', 'CPA', (147, 163))	('whole chromosomes changes', 'CPA', (73, 98))	('apocrine', 'Var', (14, 22))	('FGL', 'CPA', (54, 57))	('higher', 'PosReg', (47, 53))	('amplifications', 'MPA', (114, 128))	('CLCIS', 'Chemical', '-', (193, 198))
22993	19701073	We found that similar to CLCIS, PLCIS was characterized by 16q loss and 1q gain as well as abrogation of E-cadherin expression, suggesting a relationship between PLCIS and CLCIS.	('expression', 'MPA', (116, 126))	('CLCIS', 'Chemical', '-', (172, 177))	('CLCIS', 'Chemical', '-', (25, 30))	('E-cadherin', 'Gene', (105, 115))	('E-cadherin', 'Gene', '999', (105, 115))	('abrogation', 'NegReg', (91, 101))	('16q', 'Var', (59, 62))	('loss', 'NegReg', (63, 67))	('gain', 'PosReg', (75, 79))
23007	19701073	The majority of PLCIS in our study demonstrated 1q gain and 16q loss, a molecular signature for lobular carcinomas including CLCIS.	('lobular carcinomas', 'Disease', (96, 114))	('1q gain', 'Var', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('CLCIS', 'Chemical', '-', (125, 130))	('lobular carcinomas', 'Disease', 'MESH:D018275', (96, 114))	('loss', 'NegReg', (64, 68))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (96, 114))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (96, 113))	('16q', 'CPA', (60, 63))	('CLCIS', 'Disease', (125, 130))
23011	19701073	Alternatively, epigenetic alterations such as promoter methylation and/or histone deacetylation rather than genetic changes themselves may be the main mechanisms for alteration in the biomarker expression, and such changes would not be detected by aCGH analysis.	('histone deacetylation', 'MPA', (74, 95))	('biomarker expression', 'MPA', (184, 204))	('epigenetic alterations', 'Var', (15, 37))	('promoter methylation', 'MPA', (46, 66))	('alteration', 'Reg', (166, 176))	('CGH', 'Gene', (249, 252))	('CGH', 'Gene', '3342', (249, 252))
23013	19701073	Although there was no specific genomic pattern that distinguished apocrine PLCIS from non-apocrine PLCIS or CLCIS, some molecular changes were either only present or more prevalent in apocrine PLCIS, including amplification of 17q11.2-17q12 (the region harboring HER2 gene), amplification of 11q13.3 (the region containing cyclin D1 gene), gain of 16p, and losses of 3q, 11q, 13q and 17p.	('amplification', 'Var', (210, 223))	('amplification', 'Var', (275, 288))	('apocrine', 'Disease', (184, 192))	('17q11.2-17q12', 'Var', (227, 240))	('11q', 'Gene', (371, 374))	('cyclin D1', 'Gene', (323, 332))	('13q', 'Gene', (376, 379))	('HER2', 'Gene', (263, 267))	('CLCIS', 'Chemical', '-', (108, 113))	('HER2', 'Gene', '2064', (263, 267))	('losses', 'NegReg', (357, 363))	('11q13.3', 'Gene', (292, 299))	('16p', 'CPA', (348, 351))	('cyclin D1', 'Gene', '595', (323, 332))	('gain', 'PosReg', (340, 344))
23015	19701073	Furthermore, amplification of HER2 gene and loss of 13q (which harbors RB gene at 13q14.1-14.2) have also been noted in invasive pleomorphic lobular carcinoma but not in invasive classic lobular carcinoma.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (141, 158))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (187, 204))	('noted', 'Reg', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('13q', 'Gene', (52, 55))	('invasive classic lobular carcinoma', 'Disease', (170, 204))	('invasive pleomorphic lobular carcinoma', 'Disease', 'MESH:D018275', (120, 158))	('HER2', 'Gene', (30, 34))	('amplification', 'Var', (13, 26))	('loss', 'Var', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('HER2', 'Gene', '2064', (30, 34))	('invasive pleomorphic lobular carcinoma', 'Disease', (120, 158))	('invasive classic lobular carcinoma', 'Disease', 'MESH:D018275', (170, 204))
23017	19701073	This finding suggests that there is significant overlap in the pattern of genomic alteration among various LCIS types as defined by morphology and that there does not appear to be a particular genetic signature to define these LCIS subtypes, except the 1q gain and 16q loss for lobular neoplasia as a group.	('lobular neoplasia', 'Disease', 'MESH:D009369', (278, 295))	('neoplasia', 'Phenotype', 'HP:0002664', (286, 295))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (278, 295))	('lobular neoplasia', 'Disease', (278, 295))	('16q loss', 'Var', (265, 273))
23054	24936466	Spontaneous dwarf rats, which bear a loss-of-function mutation in GH, have deficient alveolar development that can be rescued by GH reinfusion.	('mutation', 'Var', (54, 62))	('loss-of-function', 'NegReg', (37, 53))	('deficient alveolar', 'Disease', 'MESH:D002282', (75, 93))	('rats', 'Species', '10116', (18, 22))	('deficient alveolar', 'Phenotype', 'HP:0006329', (75, 93))	('deficient alveolar', 'Disease', (75, 93))
23056	24936466	In humans, mutations affecting the expression and function of the GH receptor (GHR) are collectively known as Laron syndrome (LS).	('GH receptor', 'Gene', '2690', (66, 77))	('mutations affecting', 'Var', (11, 30))	('GHR', 'Gene', (79, 82))	('Laron syndrome', 'Disease', (110, 124))	('GH receptor', 'Gene', (66, 77))	('humans', 'Species', '9606', (3, 9))	('Laron syndrome', 'Disease', 'MESH:D046150', (110, 124))	('function', 'MPA', (50, 58))
23068	24936466	We also showed that inhibition of GH signaling halts the growth of a patient-derived breast cancer xenografted in immunodeficient mice.	('mice', 'Species', '10090', (130, 134))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('halts', 'NegReg', (47, 52))	('inhibition', 'Var', (20, 30))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('growth', 'CPA', (57, 63))	('immunodeficient', 'Disease', 'MESH:D007153', (114, 129))	('immunodeficient', 'Disease', (114, 129))	('patient', 'Species', '9606', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
23088	24936466	The sorted CD49f+EpCAM+GHR+ cells generated predominantly luminal colonies (90%) and CD49f-EpCAM+GHR+ cells generated mixed, luminal, and myoepithelial colonies (data not shown).	('myoepithelial colonies', 'Disease', 'MESH:D009208', (138, 160))	('myoepithelial colonies', 'Disease', (138, 160))	('mixed', 'CPA', (118, 123))	('luminal', 'CPA', (125, 132))	('luminal colonies', 'CPA', (58, 74))	('CD49f-EpCAM+GHR+', 'Var', (85, 101))
23135	24936466	ALDH1A1+ cells appeared to be overlapping or juxtaposed with GHR in both normal areas adjacent to the DCIS lesions and within the DCIS lesions (Figures 6F-6N; Figure S5).	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))	('ALDH1A1', 'Gene', '216', (0, 7))	('lesions', 'Var', (107, 114))	('ALDH1A1', 'Gene', (0, 7))	('DCIS', 'Disease', (102, 106))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
23141	24936466	This xenograft was established from a triple-negative breast cancer; therefore, inhibition of GH may be effective in this subtype of breast cancers as well.	('breast cancer', 'Disease', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('breast cancers', 'Disease', 'MESH:D001943', (133, 147))	('breast cancers', 'Disease', (133, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('inhibition', 'Var', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))
23182	24936466	For assessing GH mRNA level, cells were treated for 1 or 4 hr with P4, E2, E2+P4 with or without ICI 182.780, RU486.	('E2+P4', 'Var', (75, 80))	('RU486', 'Var', (110, 115))	('E2+P4', 'Chemical', '-', (75, 80))
23190	22295212	High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy.	('HER2', 'Gene', '2064', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('overexpression', 'PosReg', (61, 75))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('high Ki67', 'Var', (50, 59))	('Ki67', 'Chemical', '-', (55, 59))	('aneuploidy', 'Disease', (101, 111))	('tumors', 'Disease', (11, 17))	('p53', 'Gene', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('p53', 'Gene', '7157', (88, 91))	('lower', 'NegReg', (22, 27))	('HER2', 'Gene', (79, 83))	('aneuploidy', 'Disease', 'MESH:D000782', (101, 111))
23191	22295212	Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA.	('HER2', 'Gene', '2064', (14, 18))	('IBCA', 'Disease', (97, 101))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('prevalent', 'Reg', (84, 93))	('triple negative', 'Var', (59, 74))	('HER2', 'Gene', (14, 18))	('pDCIS', 'Disease', (48, 53))	('common', 'Reg', (38, 44))
23192	22295212	In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes.	('triple', 'Disease', (25, 31))	('lum', 'Gene', '4060', (137, 140))	('aneuploidy', 'Disease', (114, 124))	('HER2', 'Gene', (16, 20))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('HER2', 'Gene', '2064', (16, 20))	('overexpression', 'PosReg', (83, 97))	('aneuploidy', 'Disease', 'MESH:D000782', (114, 124))	('lum', 'Gene', (137, 140))	('ki67', 'Var', (77, 81))	('DNA', 'CPA', (110, 113))
23232	22295212	The two-way ANOVA with Bonferroni post hoc test was used for comparing Ki67 in the different subtypes of pDCIS and IBCA using the Prism 5 software (Graphpad Software Inc, San Diego, Calif, USA).	('Ki67', 'Var', (71, 75))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('pDCIS', 'Disease', (105, 110))	('IBCA', 'Disease', (115, 119))	('Calif', 'Gene', (182, 187))	('Calif', 'Gene', '9337', (182, 187))	('Ki67', 'Chemical', '-', (71, 75))
23240	22295212	Comedo necrosis was present in 75% (27/36) of HER2 positive cases compared to 67% (55/82) in HER2 negative (67.0%), P = 0.51.	('HER2', 'Gene', '2064', (93, 97))	('HER2', 'Gene', (46, 50))	('HER2', 'Gene', '2064', (46, 50))	('necrosis', 'Disease', (7, 15))	('positive', 'Var', (51, 59))	('necrosis', 'Disease', 'MESH:D009336', (7, 15))	('Comedo', 'Phenotype', 'HP:0025249', (0, 6))	('HER2', 'Gene', (93, 97))	('Comedo', 'Disease', (0, 6))
23243	22295212	Overexpression of p53 was also more frequent in high-grade Pdcis, compared to low grade (P = 0.002).	('p53', 'Gene', '7157', (18, 21))	('p53', 'Gene', (18, 21))	('high-grade Pdcis', 'Disease', (48, 64))	('Overexpression', 'Var', (0, 14))
23248	22295212	Grade 1 and 2 IBCA, 29/34 (85.2%) had diploid DNA, and 35/66 (53.0%) of grade 3 tumors were aneuploid (P = 0.0002).	('IBCA', 'Disease', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('diploid DNA', 'Var', (38, 49))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
23254	22295212	Similar association was seen in the IBCA group; luminal tumors were mostly diploid, 30/66 (45.4%), and non luminal subtypes were frequently aneuploid/multiploid, 28/33 (84.8%), P = 0.0035.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lum', 'Gene', (48, 51))	('lum', 'Gene', (107, 110))	('luminal tumors', 'Disease', 'MESH:D009369', (48, 62))	('aneuploid/multiploid', 'Var', (140, 160))	('lum', 'Gene', '4060', (48, 51))	('IBCA', 'Disease', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('luminal tumors', 'Disease', (48, 62))	('lum', 'Gene', '4060', (107, 110))
23269	22295212	Additionally, these tumors were frequently diploid compared to nonluminal tumors.	('luminal tumors', 'Disease', 'MESH:D009369', (66, 80))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('luminal tumors', 'Disease', (66, 80))	('diploid', 'Var', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
23293	22295212	The increased rate of detection of high-grade DCIS by screening mammography may also contribute to the higher prevalence of HER2-positive pDCIS.	('pDCIS', 'Disease', (138, 143))	('high-grade', 'Var', (35, 45))	('HER2', 'Gene', '2064', (124, 128))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('HER2', 'Gene', (124, 128))
23306	22295212	showed significantly higher Ki67 in invasive ductal carcinoma compared to those associated with DCIS.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (36, 61))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('Ki67', 'Chemical', '-', (28, 32))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (45, 61))	('Ki67', 'Var', (28, 32))	('invasive ductal carcinoma', 'Disease', (36, 61))	('higher', 'PosReg', (21, 27))
23312	22295212	We have demonstrated for the first time the relationship between proliferation and molecular subtypes of both pDCIS and IBCA using Ki67 expression by routine IHC.	('pDCIS', 'Disease', (110, 115))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('IBCA', 'Disease', (120, 124))	('Ki67', 'Var', (131, 135))	('Ki67', 'Chemical', '-', (131, 135))
23313	22295212	Additionally, the Ki67 indices in the luminal-HER2, HER2, and triple negative subtypes of IBCA were significantly higher compared to similar subtypes of pDCIS.	('lum', 'Gene', (38, 41))	('HER2', 'Gene', (46, 50))	('HER2', 'Gene', '2064', (52, 56))	('HER2', 'Gene', '2064', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('IBCA', 'Disease', (90, 94))	('Ki67', 'Var', (18, 22))	('Ki67', 'Chemical', '-', (18, 22))	('lum', 'Gene', '4060', (38, 41))	('higher', 'PosReg', (114, 120))	('HER2', 'Gene', (52, 56))
23326	32909943	We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels.	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('SOX11+DCIS', 'Var', (14, 24))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('metastasize', 'CPA', (38, 49))	('tumour', 'Disease', (25, 31))
23330	32909943	SOX11 expression in invasive breast cancer is associated with increased distant metastasis formation.	('SOX11', 'Gene', (0, 5))	('increased', 'PosReg', (62, 71))	('expression', 'Species', '29278', (6, 16))	('distant metastasis formation', 'CPA', (72, 100))	('invasive breast cancer', 'Disease', 'MESH:D001943', (20, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('expression', 'Var', (6, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('invasive breast cancer', 'Disease', (20, 42))
23338	32909943	These findings led us to hypothesise that reactivation of embryonic mammary developmental programmes mediated by SOX11 in postnatal breast epithelial cells would promote invasive progression of pre-invasive DCIS breast lesions and acquisition of features associated with poor patient outcome, including formation of distant metastasis.	('invasive DCIS breast lesions', 'Disease', (198, 226))	('invasive DCIS breast lesions', 'Disease', 'MESH:D001943', (198, 226))	('invasive progression', 'CPA', (170, 190))	('promote', 'PosReg', (162, 169))	('distant metastasis', 'CPA', (316, 334))	('SOX11', 'Gene', (113, 118))	('patient', 'Species', '9606', (276, 283))	('reactivation', 'Var', (42, 54))
23354	32909943	We assessed the expression of markers associated with mammary epithelial and mesenchymal states in iEV and iSOX11 as well as non-induced (denoted ni) niEV and niSOX11 DCIS cells.	('niSOX11 DCIS', 'Var', (159, 171))	('iEV', 'Disease', (99, 102))	('expression', 'MPA', (16, 26))	('expression', 'Species', '29278', (16, 26))
23358	32909943	These results show that SOX11 expression leads to a reduction of larger spheroids formed from DCIS.com cells and increased formation of smaller spheroids that retain label.	('label', 'MPA', (166, 171))	('SOX11', 'Gene', (24, 29))	('DCIS.com', 'CellLine', 'CVCL:5552', (94, 102))	('expression', 'Var', (30, 40))	('larger spheroids formed', 'CPA', (65, 88))	('expression', 'Species', '29278', (30, 40))	('DCIS.com', 'Gene', (94, 102))	('reduction', 'NegReg', (52, 61))
23361	32909943	To explore whether sustained reactivation of SOX11 promotes tumour progression, we assessed features of iSOX11 spheroids.	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('SOX11', 'Gene', (45, 50))	('tumour', 'Disease', (60, 66))	('reactivation', 'Var', (29, 41))	('promotes', 'PosReg', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
23363	32909943	Despite their smaller volume, tumours originated from cells with high SOX11 levels displayed greater bioluminescence than control tumours, suggesting iSOX11 tumours contained more viable cells (Figure 2G).	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('SOX11', 'Gene', (70, 75))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('more', 'PosReg', (175, 179))	('greater', 'PosReg', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('tumours', 'Disease', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (157, 164))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('high', 'Var', (65, 69))	('bioluminescence', 'MPA', (101, 116))	('tumours', 'Disease', (157, 164))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
23365	32909943	Larger necrotic and CC3+ (apoptotic) areas were observed in the EV tumour tumours and niSOX11 tumours when compared to the iSOX11 tumours, which showed little central necrosis and fewer CC3+ cells (Figure 2H).	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('necrosis', 'Disease', 'MESH:D009336', (167, 175))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('necrosis', 'Disease', (167, 175))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('niSOX11', 'Var', (86, 93))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('EV tumour tumours', 'Disease', (64, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('EV tumour tumours', 'Disease', 'MESH:D009369', (64, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumours', 'Disease', (94, 101))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('necrotic', 'Disease', (7, 15))	('tumours', 'Disease', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('necrotic', 'Disease', 'MESH:D009336', (7, 15))
23369	32909943	When injected directly into the mammary duct, iSOX11 DCIS cells formed slightly larger tumours, with similar bioluminescence levels as iEV tumours, which indicates the microenvironment highly influences behaviour of SOX11+ tumour cells (Figure 2I-K).	('tumour', 'Disease', (87, 93))	('influences', 'Reg', (192, 202))	('tumours', 'Disease', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('tumour', 'Disease', (139, 145))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('iSOX11 DCIS', 'Var', (46, 57))	('tumours', 'Disease', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('iEV tumours', 'Disease', 'MESH:D009369', (135, 146))	('tumour', 'Disease', (223, 229))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('iEV tumours', 'Disease', (135, 146))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
23370	32909943	A greater proportion of mammary tumours formed from iSOX11 cells expressed moderate to high levels of ALDH1 (6/6) compared to control tumours (1/8).	('iSOX11', 'Var', (52, 58))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('tumours', 'Disease', (32, 39))	('tumours', 'Disease', 'MESH:D009369', (134, 141))	('tumours', 'Disease', (134, 141))	('ALDH1', 'Gene', (102, 107))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('ALDH1', 'Gene', '216', (102, 107))
23383	32909943	We found many SOX11+ breast cancer cell lines express high levels of MEX3A or TUBB3 compared to DCIS.com cell line (Figure 3G).	('SOX11+', 'Var', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('MEX3A', 'MPA', (69, 74))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('DCIS.com', 'CellLine', 'CVCL:5552', (96, 104))	('TUBB3', 'Gene', (78, 83))	('TUBB3', 'Gene', '10381', (78, 83))
23386	32909943	To explore whether sustained reactivation of SOX11 promotes tumour progression, we injected luciferase-tagged iEV and iSOX11 cells into the mammary fat pad.	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('reactivation', 'Var', (29, 41))
23390	32909943	It was noted that the frequencies of mice with lung metastasis were similar, but a significant reduction of iSOX11 DCIS cells accumulated in the lungs was observed when compared to mice engrafted with iEV cells when quantified by IVIS (Figure 4C-D).	('mice', 'Species', '10090', (181, 185))	('reduction', 'NegReg', (95, 104))	('iSOX11', 'Var', (108, 114))	('mice', 'Species', '10090', (37, 41))
23392	32909943	SOX11 expression in primary breast cancer is associated with increased metastasis formation at distant sites (Figure 4E).	('SOX11', 'Gene', (0, 5))	('expression', 'Species', '29278', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('metastasis formation at distant sites', 'CPA', (71, 108))	('increased', 'PosReg', (61, 70))	('expression', 'Var', (6, 16))
23394	32909943	SOX11 amplification and overexpression has been detected in breast cancer brain metastasis in patients with ER-, ER+, and BRCA1-/- tumours in a recent study that comprehensively profiled a small number of cases (Figure 4:figure supplement 1; ).	('SOX11', 'Gene', (0, 5))	('BRCA1', 'Gene', '672', (122, 127))	('BRCA1', 'Gene', (122, 127))	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('patients', 'Species', '9606', (94, 102))	('expression', 'Species', '29278', (28, 38))	('detected', 'Reg', (48, 56))	('tumours', 'Disease', (131, 138))	('ER', 'Gene', '2069', (113, 115))	('overexpression', 'PosReg', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer brain metastasis', 'Disease', 'MESH:D001943', (60, 90))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer brain metastasis', 'Disease', (60, 90))	('amplification', 'Var', (6, 19))	('ER', 'Gene', '2069', (108, 110))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
23399	32909943	After xenografting iSOX11Br cells into the tail vein, mice that had been fed normal chow had a greater metastatic burden in the lungs compared to mice fed DOX-containing chow to induce SOX11 expression, similar to results observed using the parental iSOX11 DCIS cell line (Figure 5B-D).	('iSOX11Br', 'Var', (19, 27))	('DOX', 'Chemical', 'MESH:D004318', (155, 158))	('metastatic burden in the lungs', 'CPA', (103, 133))	('mice', 'Species', '10090', (146, 150))	('expression', 'Species', '29278', (191, 201))	('mice', 'Species', '10090', (54, 58))	('xenografting', 'Var', (6, 18))
23400	32909943	After intracranial injections of iSOX11Br cells, higher levels of bioluminescence were detected in the brains of mice fed DOX chow (Figure 5E).	('levels of bioluminescence', 'MPA', (56, 81))	('DOX', 'Chemical', 'MESH:D004318', (122, 125))	('iSOX11Br cells', 'Var', (33, 47))	('mice', 'Species', '10090', (113, 117))	('higher', 'PosReg', (49, 55))
23402	32909943	These results indicate that iSOX11Br cells have a colonisation and growth advantage in the brain compared to that niSOX11Br cells lacking SOX11 expression.	('growth advantage', 'CPA', (67, 83))	('colonisation', 'CPA', (50, 62))	('iSOX11Br', 'Var', (28, 36))	('expression', 'Species', '29278', (144, 154))
23404	32909943	Using DOX-inducible lentiviral vectors containing shRNAs to SOX11 and control non-targeting shRNAs, reductions in SOX11 levels were obtained, as well as decreases of TUBB3, MEX3A, GPC2, MPK4, OLFM2, ST6GALNAC5, and NCAD levels and an increase in SERPINA3 in CAL-148 cells after SOX11 knockdown when compared to control (Figure 6A).	('DOX', 'Chemical', 'MESH:D004318', (6, 9))	('CAL-148', 'CellLine', 'CVCL:1106', (258, 265))	('TUBB3', 'Gene', '10381', (166, 171))	('OLFM2', 'Gene', (192, 197))	('NCAD levels', 'MPA', (215, 226))	('ST6GALNAC5', 'MPA', (199, 209))	('reductions', 'NegReg', (100, 110))	('GPC2', 'Gene', (180, 184))	('SOX11', 'Gene', (278, 283))	('MPK4', 'MPA', (186, 190))	('GPC2', 'Gene', '221914', (180, 184))	('OLFM2', 'Gene', '93145', (192, 197))	('increase', 'PosReg', (234, 242))	('decreases', 'NegReg', (153, 162))	('MEX3A', 'MPA', (173, 178))	('SERPINA3', 'Gene', (246, 254))	('SOX11', 'MPA', (114, 119))	('TUBB3', 'Gene', (166, 171))	('knockdown', 'Var', (284, 293))	('SERPINA3', 'Gene', '12', (246, 254))
23405	32909943	Reduced levels of SOX11, MEX3A and TUBB3 protein were detected after SOX11 knockdown (Figure 6B).	('SOX11', 'Gene', (69, 74))	('TUBB3', 'Gene', (35, 40))	('levels', 'MPA', (8, 14))	('Reduced', 'NegReg', (0, 7))	('TUBB3', 'Gene', '10381', (35, 40))	('knockdown', 'Var', (75, 84))
23406	32909943	Cell viability assays detected greater cell numbers after SOX11 knockdown in CAL-148 cells, compared to control cells (Figure 6C).	('SOX11', 'Gene', (58, 63))	('greater', 'PosReg', (31, 38))	('cell numbers', 'CPA', (39, 51))	('knockdown', 'Var', (64, 73))	('CAL-148', 'CellLine', 'CVCL:1106', (77, 84))
23417	32909943	Due to MEX3A's established links with regulation of both EMT and proliferation of intestinal and various types of cancer cells, we knocked down MEX3A in ER- BT-20, CAL-148 and HCC1187 breast cancer cells to determine if MEX3A regulates similar processes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('ER', 'Gene', '2069', (153, 155))	('CAL-148', 'CellLine', 'CVCL:1106', (164, 171))	('knocked', 'Var', (131, 138))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('MEX3A', 'Gene', (144, 149))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('HCC1187', 'CellLine', 'CVCL:1247', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('cancer', 'Disease', (114, 120))
23419	32909943	An increase in cell numbers were observed after knockdown of MEX3A in both CAL-148 and HCC1187 cells grown in 2D or 3D (Figure 8C-D).	('MEX3A', 'Gene', (61, 66))	('HCC1187', 'CellLine', 'CVCL:1247', (87, 94))	('cell numbers', 'CPA', (15, 27))	('CAL-148', 'CellLine', 'CVCL:1106', (75, 82))	('increase', 'PosReg', (3, 11))	('knockdown', 'Var', (48, 57))
23424	32909943	CAL-148 cells normally form aggregates when grown in 2D culture conditions and after MEX3A knockdown, CAL-148 cells displayed a reduced ability to form aggregates and an acquired ability to adhere to plastic (Figure 8G).	('CAL-148', 'CellLine', 'CVCL:1106', (102, 109))	('reduced', 'NegReg', (128, 135))	('CAL-148', 'CellLine', 'CVCL:1106', (0, 7))	('MEX3A', 'Gene', (85, 90))	('knockdown', 'Var', (91, 100))	('CAL-148', 'Gene', (102, 109))	('adhere', 'CPA', (190, 196))
23425	32909943	After MEX3A knockdown, CAL-148 cells displayed increased expression of E-CADHERIN and EPCAM (Figure 8H).	('expression', 'MPA', (57, 67))	('MEX3A', 'Gene', (6, 11))	('knockdown', 'Var', (12, 21))	('increased', 'PosReg', (47, 56))	('EPCAM', 'Gene', (86, 91))	('E-CADHERIN', 'Gene', '999', (71, 81))	('expression', 'Species', '29278', (57, 67))	('E-CADHERIN', 'Gene', (71, 81))	('EPCAM', 'Gene', '17075', (86, 91))	('CAL-148', 'CellLine', 'CVCL:1106', (23, 30))
23426	32909943	BT-20 and HCC1187 cells lack expression of E-CADHERIN but showed an increase in EPCAM levels after MEX3A knockdown (Figure 8:figure supplement 2).	('EPCAM', 'Gene', '17075', (80, 85))	('HCC1187', 'CellLine', 'CVCL:1247', (10, 17))	('MEX3A', 'Gene', (99, 104))	('knockdown', 'Var', (105, 114))	('increase', 'PosReg', (68, 76))	('E-CADHERIN', 'Gene', (43, 53))	('expression', 'Species', '29278', (29, 39))	('E-CADHERIN', 'Gene', '999', (43, 53))	('EPCAM', 'Gene', (80, 85))
23445	32909943	A significant association of SOX11 and N-CADHERIN (CDH2) expression is also observed in genomic analyses across six cancer types, suggesting that mesenchymal pathways may be activated by SOX11 in both normal and cancer cells.	('mesenchymal pathways', 'CPA', (146, 166))	('SOX11', 'Var', (187, 192))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('N-CADHERIN', 'Gene', '1000', (39, 49))	('expression', 'Species', '29278', (57, 67))	('N-CADHERIN', 'Gene', (39, 49))	('activated', 'PosReg', (174, 183))	('CDH2', 'Gene', (51, 55))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CDH2', 'Gene', '1000', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
23465	32909943	Together, these data suggest that patients whose DCIS and primary breast cancers express high levels of SOX11 are among a high-risk metastasis subgroup that should be considered for aggressive therapies in neo-adjuvant settings.	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('DCIS', 'Disease', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancers', 'Disease', 'MESH:D001943', (66, 80))	('SOX11', 'Gene', (104, 109))	('breast cancers', 'Disease', (66, 80))	('high', 'Var', (89, 93))	('patients', 'Species', '9606', (34, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
23516	32909943	Essential revisions: 1) Controls are lacking or inappropriate in some figures and need to be amended - for example, please justify the use of the pooled control lines in Figure 3, provide blots for SOX11 in all control lines, provide a blot for TUBB3 knockdown etc.	('TUBB3', 'Gene', '10381', (245, 250))	('knockdown', 'Var', (251, 260))	('TUBB3', 'Gene', (245, 250))
23519	32909943	3) The authors need to show a western blot for TUBB3 knockdown in Figure 7.	('knockdown', 'Var', (53, 62))	('TUBB3', 'Gene', '10381', (47, 52))	('TUBB3', 'Gene', (47, 52))
23528	32909943	10.7554/eLife.58374.sa2 Essential revisions: 1) Controls are lacking or inappropriate in some figures and need to be amended - for example, please justify the use of the pooled control lines in Figure 3, provide blots for SOX11 in all control lines, provide a blot for TUBB3 knockdown etc.	('sa2', 'Chemical', '-', (20, 23))	('knockdown', 'Var', (275, 284))	('TUBB3', 'Gene', (269, 274))	('TUBB3', 'Gene', '10381', (269, 274))
23530	32909943	Blots of SOX11 are shown in Figure 3G and we have provided a blot for TUBB3 knockdown Figure 7A and blots for MEX3A knockdown are included in Figure 8:figure supplement 2.	('TUBB3', 'Gene', (70, 75))	('TUBB3', 'Gene', '10381', (70, 75))	('knockdown', 'Var', (76, 85))
23540	32909943	We have included the western blot showing TUBB3 knockdown in Figure 7A.	('TUBB3', 'Gene', (42, 47))	('TUBB3', 'Gene', '10381', (42, 47))	('knockdown', 'Var', (48, 57))
23551	31352554	The role of MRI in the evaluation and management of patients with pathological nipple discharge The aim of this study was to determine the ability of MRI to identify and assess the extent of disease in patients with pathological nipple discharge (PND) with an occult malignancy not evident on standard pre-operative evaluation with mammography and ultrasound.	('nipple discharge', 'Disease', (229, 245))	('occult malignancy', 'Disease', 'MESH:D009382', (260, 277))	('pathological', 'Var', (216, 228))	('patients', 'Species', '9606', (202, 210))	('occult malignancy', 'Disease', (260, 277))	('patients', 'Species', '9606', (52, 60))
23589	31352554	Two patients had invasive lobular carcinoma with adjacent DCIS and one patient had a benign papilloma on microdochectomy but the MRI showed an area with grade 2 invasive ductal carcinoma and low grade DCIS in the ipsilateral breast (Table 1).	('invasive ductal carcinoma', 'Disease', (161, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (17, 43))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (170, 186))	('invasive ductal carcinoma', 'Disease', 'MESH:D044584', (161, 186))	('papilloma', 'Phenotype', 'HP:0012740', (92, 101))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (26, 43))	('patient', 'Species', '9606', (4, 11))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('papilloma', 'Disease', (92, 101))	('patients', 'Species', '9606', (4, 12))	('low grade', 'Var', (191, 200))	('papilloma', 'Disease', 'MESH:D010212', (92, 101))	('DCIS', 'Phenotype', 'HP:0030075', (201, 205))	('patient', 'Species', '9606', (71, 78))	('invasive lobular carcinoma', 'Disease', (17, 43))
23629	31352554	One could speculate that in this subgroup of patients DCIS is diagnosed prior to the development of microcalcifications due to the presence of PND and that the same pathophysiologic changes that result in nipple discharge allow its identification through a different modality with the use of MRI.	('presence', 'Var', (131, 139))	('patients', 'Species', '9606', (45, 53))	('DCIS', 'Disease', (54, 58))	('nipple discharge', 'Disease', (205, 221))	('PND', 'Gene', (143, 146))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))
23634	30154229	Intensive surveillance with bi-annual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer.	('downstages', 'NegReg', (91, 101))	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('BRCA1', 'Gene', (119, 124))	('BRCA1', 'Gene', '672', (119, 124))	('women', 'Species', '9606', (178, 183))	('carriers', 'Reg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('mutation', 'Var', (125, 133))
23636	30154229	Eligible participants had a cumulative lifetime breast cancer risk >= 20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene.	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('mutation', 'Var', (114, 122))	('participants', 'Species', '9606', (9, 21))	('positive', 'Reg', (88, 96))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
23643	30154229	The number of recalls and biopsies needed to detect one cancer by bi-annual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively.	('BRCA1/2', 'Gene', '672;675', (172, 179))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA1', 'Gene', '672', (172, 177))	('BRCA2', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRCA1', 'Gene', (100, 105))	('BRCA1', 'Gene', (172, 177))	('BRCA2', 'Gene', '675', (132, 137))	('carriers', 'Var', (106, 114))	('BRCA1/2', 'Gene', (172, 179))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
23647	30154229	The American Cancer Society and other organizations have published guidelines that recommend annual MRI in conjunction with annual MG for a well-defined category of high-risk women including: carriers of damaging mutations in breast cancer susceptibility genes and their untested first-degree relatives, women with a lifetime breast cancer risk >20% as defined by risk-prediction models, and women with prior history of chest radiation between the ages of 10 and 30 years.	('breast cancer', 'Phenotype', 'HP:0003002', (326, 339))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('breast cancer', 'Disease', (326, 339))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('women', 'Species', '9606', (304, 309))	('breast cancer', 'Disease', 'MESH:D001943', (326, 339))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('women', 'Species', '9606', (175, 180))	('carriers', 'Reg', (192, 200))	('mutations', 'Var', (213, 222))	('women', 'Species', '9606', (392, 397))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
23678	30154229	157 (53.2%; including two patients with mutations in two genes) carried a pathogenic mutation in at least one breast cancer susceptibility gene: 75 BRCA1, 61 BRCA2, 10 CHEK2, 4 CDH1, 3 PALB2, 2 ATM, 1 TP53, 1 PTEN, 1 NBN, and 1 BRIP1.	('ATM', 'Gene', (194, 197))	('mutation', 'Var', (85, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('mutations', 'Var', (40, 49))	('TP53', 'Gene', (201, 205))	('carried', 'Reg', (64, 71))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('BRIP1', 'Gene', '83990', (228, 233))	('BRCA2', 'Gene', (158, 163))	('breast cancer', 'Disease', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CHEK2', 'Gene', (168, 173))	('ATM', 'Gene', '472', (194, 197))	('pathogenic', 'Reg', (74, 84))	('PALB2', 'Gene', (185, 190))	('CDH1', 'Gene', '999', (177, 181))	('BRCA2', 'Gene', '675', (158, 163))	('one breast', 'Phenotype', 'HP:0012813', (106, 116))	('CHEK2', 'Gene', '11200', (168, 173))	('BRCA1', 'Gene', '672', (148, 153))	('TP53', 'Gene', '7157', (201, 205))	('BRIP1', 'Gene', (228, 233))	('PALB2', 'Gene', '79728', (185, 190))	('patients', 'Species', '9606', (26, 34))	('BRCA1', 'Gene', (148, 153))	('CDH1', 'Gene', (177, 181))	('PTEN, 1 NBN, and 1', 'Gene', '5728', (209, 227))
23679	30154229	There were no statistically significant differences in number of screening episodes between mutation carriers, patients with previous breast cancer, and other women.	('mutation', 'Var', (92, 100))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('women', 'Species', '9606', (159, 164))	('patients', 'Species', '9606', (111, 119))
23681	30154229	Fifteen of the total occurred in patients with mutations (11 BRCA1, 3 BRCA2, 1 CDH1).	('BRCA1', 'Gene', (61, 66))	('patients', 'Species', '9606', (33, 41))	('CDH1', 'Gene', (79, 83))	('BRCA2', 'Gene', '675', (70, 75))	('CDH1', 'Gene', '999', (79, 83))	('mutations', 'Var', (47, 56))	('occurred', 'Reg', (21, 29))	('BRCA1', 'Gene', '672', (61, 66))	('BRCA2', 'Gene', (70, 75))
23684	30154229	MRI missed one high grade DCIS in a BRCA1 mutation carrier measuring 0.5 cm that was seen on MG and one intermediate grade DCIS measuring 1.7 cm that was found incidentally (4 months after MRI and 2 months before next scheduled MRI/MG visit) in a prophylactic mastectomy specimen from a 36-year-old BRCA2 mutation carrier.	('BRCA1', 'Gene', (36, 41))	('mutation', 'Var', (305, 313))	('BRCA2', 'Gene', '675', (299, 304))	('BRCA1', 'Gene', '672', (36, 41))	('BRCA2', 'Gene', (299, 304))
23689	30154229	Of note, all three screening-detected, high-grade DCIS were diagnosed in BRCA1 mutation carriers.	('diagnosed', 'Reg', (60, 69))	('BRCA1', 'Gene', '672', (73, 78))	('carriers', 'Reg', (88, 96))	('mutation', 'Var', (79, 87))	('BRCA1', 'Gene', (73, 78))
23692	30154229	Except for a CDH1 mutation carrier who developed a low-grade invasive lobular carcinoma with associated LCIS, all other invasive cancers were ductal and moderate-to-high-grade.	('CDH1', 'Gene', '999', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('invasive cancers', 'Disease', 'MESH:D009362', (120, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('invasive cancers', 'Disease', (120, 136))	('LCIS', 'Disease', (104, 108))	('invasive lobular carcinoma', 'Disease', (61, 87))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (61, 87))	('mutation', 'Var', (18, 26))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (70, 87))	('CDH1', 'Gene', (13, 17))
23695	30154229	Of note, for BRCA1 mutation carriers, the screening yield was excellent with 2.8 recalls and 1.7 biopsies to detect one cancer using bi-annual MRI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutation', 'Var', (19, 27))	('BRCA1', 'Gene', (13, 18))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('BRCA1', 'Gene', '672', (13, 18))
23696	30154229	This is in contrast to 12.0 recalls and 8.0 biopsies for one cancer detected in BRCA2 mutation carriers, and 11.7 recalls and 5.0 biopsies for one cancer detected in other women.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('BRCA2', 'Gene', (80, 85))	('cancer', 'Disease', (61, 67))	('BRCA2', 'Gene', '675', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutation', 'Var', (86, 94))	('cancer', 'Disease', (147, 153))	('women', 'Species', '9606', (172, 177))
23698	30154229	Eleven of the 75 BRCA1 mutation carriers developed breast cancers, yielding an incidence rate of 3.65 per 100 person-years (95% CI: 1.82-6.53) that was significantly higher than that in women without BRCA1 mutations (Figure 3B, p=0.0005).	('BRCA1', 'Gene', '672', (17, 22))	('higher', 'PosReg', (166, 172))	('women', 'Species', '9606', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutation', 'Var', (23, 31))	('breast cancers', 'Phenotype', 'HP:0003002', (51, 65))	('BRCA1', 'Gene', (17, 22))	('BRCA1', 'Gene', '672', (200, 205))	('person', 'Species', '9606', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('breast cancers', 'Disease', 'MESH:D001943', (51, 65))	('breast cancers', 'Disease', (51, 65))	('BRCA1', 'Gene', (200, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))
23701	30154229	This is the first report on a prospective cohort of genetically defined high-risk women undergoing intensive surveillance with MRI every 6 months in conjunction with clinical breast examinations and annual MG. Thirteen invasive cancers and four DCIS were diagnosed, predominantly in BRCA1 mutation carriers (65%).	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('women', 'Species', '9606', (82, 87))	('invasive cancers', 'Disease', 'MESH:D009362', (219, 235))	('BRCA1', 'Gene', '672', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('DCIS', 'Disease', (245, 249))	('invasive cancers', 'Disease', (219, 235))	('mutation', 'Var', (289, 297))	('BRCA1', 'Gene', (283, 288))
23704	30154229	There were too few cancers in BRCA2 mutation carriers to make definitive conclusions about benefit of bi-annual MRI.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('BRCA2', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutation', 'Var', (36, 44))	('BRCA2', 'Gene', '675', (30, 35))
23705	30154229	Diagnosing breast cancer at an early and treatable stage is crucial for improving outcomes for young women with breast cancer due to inherited mutations.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('women', 'Species', '9606', (101, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (143, 152))
23709	30154229	Previous studies of combined annual MRI and MG in high-risk patients with long-term follow-up, specifically in BRCA1 and BRCA2 carriers, detected breast cancers at more advanced stages, including approximately 15% cancers with nodal involvement and 5% interval cancers.	('cancers', 'Disease', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('carriers', 'Var', (127, 135))	('BRCA2', 'Gene', '675', (121, 126))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('detected', 'Reg', (137, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('breast cancers', 'Disease', (146, 160))	('cancers', 'Disease', (261, 268))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancers', 'Disease', (214, 221))	('BRCA1', 'Gene', '672', (111, 116))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('BRCA1', 'Gene', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('BRCA2', 'Gene', (121, 126))
23715	30154229	Most significant is the exceedingly high cancer yield in BRCA1 mutation carriers where we only needed 1.7 biopsies to diagnose 1 cancer in comparison to 8.0 and 5.0 biopsies for BRCA2 carriers and non-BRCA mutation carriers, respectively.	('BRCA1', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('BRCA', 'Gene', '672', (178, 182))	('BRCA', 'Gene', (178, 182))	('BRCA', 'Gene', '672', (201, 205))	('cancer', 'Disease', (129, 135))	('mutation', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('BRCA', 'Gene', (201, 205))	('BRCA2', 'Gene', (178, 183))	('BRCA1', 'Gene', '672', (57, 62))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('BRCA', 'Gene', '672', (57, 61))	('BRCA', 'Gene', (57, 61))	('BRCA2', 'Gene', '675', (178, 183))
23716	30154229	Thus, similar sensitivity/specificity, a higher positive predictive value, and a lower false-positive biopsy rate in women with mutations in BRCA1 compared to other groups, suggest that this screening strategy may be more beneficial to BRCA1 mutation carriers.	('BRCA1', 'Gene', (236, 241))	('lower', 'NegReg', (81, 86))	('mutations', 'Var', (128, 137))	('BRCA1', 'Gene', '672', (141, 146))	('BRCA1', 'Gene', (141, 146))	('BRCA1', 'Gene', '672', (236, 241))	('women', 'Species', '9606', (117, 122))
23731	30154229	Lastly, with improved understanding of penetrance of pathogenic mutations in breast cancer susceptibility genes such as BRCA1 and BRCA2, the cost-effectiveness of population screening to identify all mutation carriers, preferably by age 30 years, as well as the benefit of intensive surveillance coupled with primary prevention protocols deserve further evaluation.	('breast cancer', 'Disease', (77, 90))	('BRCA1', 'Gene', (120, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('BRCA2', 'Gene', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (64, 73))	('BRCA1', 'Gene', '672', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('BRCA2', 'Gene', '675', (130, 135))
23831	21127880	It has been suggested that the conflicting reports on HER2 positivity affecting MRI accuracy may be attributed to the use of trastuzumab; in the study showing increased accuracy trastuzumab was used.	('trastuzumab', 'Chemical', 'MESH:D000068878', (178, 189))	('HER2', 'Gene', (54, 58))	('positivity', 'Var', (59, 69))	('MRI accuracy', 'MPA', (80, 92))	('HER2', 'Gene', '2064', (54, 58))	('trastuzumab', 'Chemical', 'MESH:D000068878', (125, 136))
23839	21127880	Univariate analyses showed that HER2 positivity was a strong predictive factor of pCR at baseline.	('HER2', 'Gene', (32, 36))	('CR', 'Chemical', '-', (83, 85))	('HER2', 'Gene', '2064', (32, 36))	('positivity', 'Var', (37, 47))	('pCR', 'Disease', (82, 85))
23923	33755692	Family history was also associated with breast cancer (aHR, 1.67; 95% CI: 1.41, 1.98).	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('associated', 'Reg', (24, 34))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Family history', 'Var', (0, 14))
23970	33755692	aHR Adjusted hazard ratio AUC Area under the receiving operating characteristic curve BI-RADS Breast Imaging Reporting and Data System BBD Benign breast disease DCIS Ductal carcinoma in situ E/O Expected to observed SNPs Single Nucleotide Polymorphisms 95%CI 95% Confidence intervals 10.1371/journal.pone.0248930.r001 Bowles Erin J A This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.	('Benign breast disease', 'Disease', (139, 160))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (166, 190))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('Ductal carcinoma', 'Disease', (166, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('Benign breast disease', 'Disease', 'MESH:D001943', (139, 160))	('10.1371/journal.pone.0248930.r001', 'Var', (284, 317))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (166, 182))
24026	33755692	In addition, in our cohort only 59% of cancers after a lesion appear in the same breast (ipsilateral), and in the case of other recognized papers such as the Hartmann study of benign breast disease (Hartmann L, Sellers T, Frost MH et al.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('lesion', 'Var', (55, 61))	('benign breast disease', 'Disease', 'MESH:D001943', (176, 197))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('benign breast disease', 'Disease', (176, 197))
24213	33437197	In the Erasmus cohort, radiosensitive patients treated with radiotherapy had better 5-year metastasis-free survival than patients with radiation-resistant tumours (77% vs 64%, p=0.0409), with no differences in patients who did not receive RT (80% vs 81%, p=0.9425).	('better', 'PosReg', (77, 83))	('radiotherapy', 'Var', (60, 72))	('radiation-resistant tumours', 'Disease', (135, 162))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('radiation-resistant tumours', 'Disease', 'MESH:D009381', (135, 162))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (38, 46))	('metastasis-free survival', 'CPA', (91, 115))	('patients', 'Species', '9606', (121, 129))
24228	33437197	For healthy tissues - at least in some organs - the gene profile could influence up to 80% of radiosensitivity and, therefore, the associated toxicity.	('influence', 'Reg', (71, 80))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('radiosensitivity', 'CPA', (94, 110))	('toxicity', 'Disease', (142, 150))	('gene profile', 'Var', (52, 64))
24231	33437197	Mutations in the ATM (ataxia-telangiectasia mutated) gene were among the first to be evaluated for their possible association with tissue radiosensitivity.	('ATM (ataxia-telangiectasia mutated', 'Gene', '472', (17, 51))	('tissue radiosensitivity', 'Phenotype', 'HP:0010997', (131, 154))	('telangiectasia', 'Phenotype', 'HP:0001009', (29, 43))	('association', 'Interaction', (114, 125))	('Mutations', 'Var', (0, 9))	('tissue radiosensitivity', 'CPA', (131, 154))	('ataxia', 'Phenotype', 'HP:0001251', (22, 28))
24233	33437197	It has been shown that patients with a truncated mutation in both copies of the ATM gene are likely to develop significant radiation-induced toxicity, and it is precise that these patients who develop ataxia-telangiectasia syndrome.	('ATM', 'Gene', (80, 83))	('develop', 'PosReg', (103, 110))	('patients', 'Species', '9606', (23, 31))	('telangiectasia', 'Phenotype', 'HP:0001009', (208, 222))	('ataxia-telangiectasia syndrome', 'Disease', 'MESH:D001260', (201, 231))	('truncated mutation in', 'Var', (39, 60))	('ATM', 'Gene', '472', (80, 83))	('develop', 'PosReg', (193, 200))	('toxicity', 'Disease', 'MESH:D064420', (141, 149))	('toxicity', 'Disease', (141, 149))	('ataxia', 'Phenotype', 'HP:0001251', (201, 207))	('patients', 'Species', '9606', (180, 188))	('ataxia-telangiectasia syndrome', 'Disease', (201, 231))
24234	33437197	The SNP rs1801516 (c.5557G> A, p.Asp1853Asn) is among the ATM SNPs that have been most thoroughly investigated.	('c.5557G> A', 'Mutation', 'rs1801516', (19, 29))	('rs1801516', 'Mutation', 'rs1801516', (8, 17))	('ATM', 'Gene', (58, 61))	('p.Asp1853Asn', 'Mutation', 'rs1801516', (31, 43))	('ATM', 'Gene', '472', (58, 61))	('c.5557G> A', 'Var', (19, 29))
24236	33437197	Andreassen et al., on behalf of the International Radiogenomics Consortium, conducted an individual patient data meta-analysis to assess the relationship between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients from 17 different cohorts (breast cancer, n=2759; prostate cancer, n=2697), concluding that there is an association between the ATM rs1801516 Asn allele and increased risk of radiation-induced toxicity (odds ratio of approximately 1.5 for acute toxicity and 1.2 for late toxicity).	('prostate cancer', 'Disease', (235, 250))	('toxicity', 'Disease', 'MESH:D064420', (453, 461))	('ATM', 'Gene', '472', (166, 169))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('toxicity', 'Disease', 'MESH:D064420', (188, 196))	('toxicity', 'Disease', 'MESH:D064420', (531, 539))	('rs1801516', 'Mutation', 'rs1801516', (392, 401))	('association', 'Interaction', (364, 375))	('toxicity', 'Disease', 'MESH:D064420', (505, 513))	('ATM', 'Gene', (388, 391))	('prostate cancer', 'Disease', 'MESH:D011471', (310, 325))	('toxicity', 'Disease', (453, 461))	('rs1801516', 'Mutation', 'rs1801516', (170, 179))	('prostate cancer', 'Phenotype', 'HP:0012125', (310, 325))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (224, 250))	('prostate cancer', 'Disease', (310, 325))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ATM', 'Gene', (166, 169))	('toxicity', 'Disease', (531, 539))	('toxicity', 'Disease', (188, 196))	('patient', 'Species', '9606', (251, 258))	('toxicity', 'Disease', (505, 513))	('patient', 'Species', '9606', (100, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('rs1801516', 'Var', (392, 401))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('ATM', 'Gene', '472', (388, 391))	('breast cancer', 'Disease', (287, 300))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))
24285	23098066	Univariate analysis of the risk of local recurrence was performed, by means of Fisher's exact test, to determine which of the following parameters were associated with local control: patient age (subdivided into 3 groups: <= 40, between 41-69 and >= 70 years), tumour size (< 10 mm, 10-30 mm, > 30 mm), nuclear grade (G1, G2, G3), surgical technique (quadrantectomy vs. tumorectomy vs. wide excision) and boost administration (yes vs. no).	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('< 10 mm', 'Var', (274, 281))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('G1', 'Var', (318, 320))	('patient', 'Species', '9606', (183, 190))	('tumour', 'Disease', (261, 267))	('G3', 'Var', (326, 328))
24362	28113244	We demonstrate that variations in the environmental niche can produce intraductal cancers independent of genetic changes in the resident cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('variations', 'Var', (20, 30))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('intraductal cancers', 'Disease', (70, 89))	('produce', 'Reg', (62, 69))	('intraductal cancers', 'Disease', 'MESH:D002285', (70, 89))
24477	28113244	The buildup of DS, emanating from the mutant cells and diffusing into the surrounding tissue, creates an ever expanding niche which induces dedifferentiation in the pre-existing fully differentiated cells propagating the large highly stem core.	('mutant', 'Var', (38, 44))	('DS', 'Chemical', '-', (15, 17))	('induces', 'Reg', (132, 139))	('dedifferentiation', 'CPA', (140, 157))
24627	30002750	Moreover, the finding of ADH may affect the risk of breast cancer development to a lesser degree than previously reported.	('ADH', 'Var', (25, 28))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('affect', 'Reg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
24646	30002750	In our study, the presence of the lesion in both US and MMG was an independent predictive factor for malignancy.	('presence', 'Var', (18, 26))	('malignancy', 'Disease', (101, 111))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))
24675	22852075	Other factors include nulliparity or late age at first birth, late menopause, and obesity in postmenopausal women.	('women', 'Species', '9606', (108, 113))	('obesity', 'Phenotype', 'HP:0001513', (82, 89))	('obesity in postmenopausal women', 'Phenotype', 'HP:0008209', (82, 113))	('obesity', 'Disease', 'MESH:D009765', (82, 89))	('late menopause', 'Phenotype', 'HP:0008209', (62, 76))	('obesity', 'Disease', (82, 89))	('nulliparity', 'Var', (22, 33))
24764	20856894	We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS.	('CD10', 'Gene', '4311', (34, 38))	('MEC', 'Gene', '56477', (53, 56))	('basement membrane disruption', 'CPA', (90, 118))	('MEC', 'Gene', (53, 56))	('DCIS', 'Disease', (159, 163))	('relapse', 'Disease', (148, 155))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('loss', 'Var', (26, 30))	('CD10', 'Gene', (34, 38))
24833	20856894	In the groups of patients treated by lumpectomy or lumpectomy plus radiotherapy, none of the patients with high CD10 mRNA (N = 17/77) experienced a relapse (p = 1.6E-02) (figure 2.C).	('patients', 'Species', '9606', (17, 25))	('CD10', 'Gene', (112, 116))	('high', 'Var', (107, 111))	('CD10', 'Gene', '4311', (112, 116))	('patients', 'Species', '9606', (93, 101))
24856	20856894	All the patients with relapsing tumors were distributed into one of two groups: either a group with high VNPI scores representative of high tumor stage, or one with low CD10 expression reflecting at least some MEC layer alterations.	('VNPI scores', 'Gene', (105, 116))	('patients', 'Species', '9606', (8, 16))	('CD10', 'Gene', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('high', 'Var', (100, 104))	('CD10', 'Gene', '4311', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('MEC', 'Gene', '56477', (210, 213))	('MEC', 'Gene', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (140, 145))
24857	20856894	Both characteristics - tumor stage and low CD10 expression - seem to be necessary for predicting relapse, which highlights the importance of assessing intrinsic DCIS properties as well as the surrounding microenvironment.	('relapse', 'CPA', (97, 104))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('expression', 'MPA', (48, 58))	('low', 'Var', (39, 42))	('CD10', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CD10', 'Gene', '4311', (43, 47))	('tumor', 'Disease', (23, 28))
24909	15083182	Indeed, a closer association was found between the nuclear pleomorphism score for the recurrent invasive carcinoma and the original DCIS grade (kappa=0.396 and 0.485, respectively).	('nuclear pleomorphism score', 'Var', (51, 77))	('invasive carcinoma', 'Disease', (96, 114))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('invasive carcinoma', 'Disease', 'MESH:D009361', (96, 114))
24913	15083182	Both of these studies add strength to the theory that the recurrent lesions following excision of DCIS are closely related to the original disease and almost certainly represent re-growth of residual tumour.	('original disease', 'Disease', (130, 146))	('tumour', 'Disease', (200, 206))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('original disease', 'Disease', 'MESH:D014717', (130, 146))	('DCIS', 'Gene', (98, 102))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('excision', 'Var', (86, 94))	('tumour', 'Disease', 'MESH:D009369', (200, 206))
24915	15083182	However, patients with poorly differentiated DCIS had a significantly higher risk of developing distant metastases and of death, which must reflect the higher grade of invasive carcinomas associated with this type of DCIS.	('invasive carcinomas', 'Disease', (168, 187))	('DCIS', 'Disease', (45, 49))	('invasive carcinomas', 'Disease', 'MESH:D009361', (168, 187))	('patients', 'Species', '9606', (9, 17))	('metastases', 'Disease', (104, 114))	('death', 'Disease', 'MESH:D003643', (122, 127))	('death', 'Disease', (122, 127))	('poorly differentiated', 'Var', (23, 44))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))
24935	24687377	Cancer/testis antigens (CTAs) are a group of tumor-associated antigens that have normal expression in the adult testis, but aberrant expression in several cancer types, particularly advanced cancers with stem cell-like characteristics.	('expression', 'MPA', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', (191, 198))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('aberrant', 'Var', (124, 132))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
24943	24687377	However, the mechanism by which MAGEC2 results in more aggressive tumors that are likely to metastasize remains unclear, and further investigations into the role and mechanism of MAGEC2 in breast cancer are needed.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('MAGEC2', 'Var', (32, 38))	('aggressive tumors', 'Disease', (55, 72))	('results in', 'Reg', (39, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('aggressive tumors', 'Disease', 'MESH:D001523', (55, 72))	('more', 'PosReg', (50, 54))
25009	22509805	Co-injection of MCF10DCIS cells with either normal human fibroblasts, invasive breast CAFs, or fibroblasts from rheumatoid arthritis resulted in invasive carcinomas, whereas co-injection with myoepithelial cells resulted in ductal carcinoma in situ (DCIS).	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('resulted in', 'Reg', (133, 144))	('human', 'Species', '9606', (51, 56))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (224, 248))	('myoepithelial', 'Disease', 'MESH:D009208', (192, 205))	('invasive carcinomas', 'Disease', 'MESH:D009361', (145, 164))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (112, 132))	('ductal carcinoma in situ', 'Disease', (224, 248))	('MCF10DCIS', 'Var', (16, 25))	('DCIS', 'Phenotype', 'HP:0030075', (250, 254))	('invasive breast CAFs', 'Disease', (70, 90))	('arthritis', 'Phenotype', 'HP:0001369', (123, 132))	('invasive carcinomas', 'Disease', (145, 164))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (16, 25))	('rheumatoid arthritis', 'Disease', (112, 132))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (224, 248))	('myoepithelial', 'Disease', (192, 205))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
25010	22509805	Interestingly, triple injections of MCF10DCIS with myoepithelial cells and fibroblasts/CAFs formed small tumors with DCIS histology, indicating that myoepithelial cells exert a tumor-suppressive effect which cannot be overcome by fibroblasts.	('small tumors', 'Disease', (99, 111))	('small tumors', 'Disease', 'MESH:D058405', (99, 111))	('tumor', 'Disease', (105, 110))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('myoepithelial', 'Disease', (51, 64))	('myoepithelial', 'Disease', (149, 162))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('myoepithelial', 'Disease', 'MESH:D009208', (51, 64))	('myoepithelial', 'Disease', 'MESH:D009208', (149, 162))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (36, 45))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('MCF10DCIS', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (177, 182))
25013	22509805	MCF10DCIS cultures including HGF-expressing fibroblasts, or conditioned medium from these fibroblasts, showed a more invasive growth pattern than cultures without, or with control fibroblasts.	('HGF', 'Gene', '3082', (29, 32))	('invasive growth pattern', 'CPA', (117, 140))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS', 'Var', (0, 9))	('HGF', 'Gene', (29, 32))
25017	22509805	Recent studies have demonstrated how modulation of these properties can act as a promoter of tumor progression and have also started to uncover the signaling pathways that are involved in conveying the mechanical alterations into changes of cell phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('promoter', 'PosReg', (81, 89))	('tumor', 'Disease', (93, 98))	('modulation', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25023	22509805	Together these findings indicate modulation of extracellular matrix stiffness as a potential mechanism whereby fibroblasts can regulate tumor initiation and progression.	('tumor initiation', 'Disease', (136, 152))	('regulate', 'Reg', (127, 135))	('modulation', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor initiation', 'Disease', 'MESH:D009369', (136, 152))
25036	22509805	High reporter gene activity was also associated with high expression of colon CSC markers like CD133+, CD166+/CD44+, and up-regulation of the c-Met receptor.	('CD133+', 'Var', (95, 101))	('c-Met', 'Gene', (142, 147))	('up-regulation', 'PosReg', (121, 134))	('expression', 'MPA', (58, 68))	('c-Met', 'Gene', '4233', (142, 147))	('CD44', 'Gene', '960', (110, 114))	('activity', 'MPA', (19, 27))	('colon CSC', 'Disease', (72, 81))	('CD44', 'Gene', (110, 114))	('colon CSC', 'Disease', 'MESH:D015179', (72, 81))
25037	22509805	Importantly, CAF-induced CSCs showed higher clonogenicity and increased tumor-forming capacity in subcutaneous xenograft mouse models.	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('clonogenicity', 'CPA', (44, 57))	('higher', 'PosReg', (37, 43))	('tumor', 'Disease', (72, 77))	('mouse', 'Species', '10090', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('CAF-induced', 'Var', (13, 24))
25038	22509805	HGF was implied as a key mediator of this process since the Wnt-reporter-stimulatory activity of myofibroblast conditioned medium was blocked by neutralizing HGF antibodies.	('Wnt', 'Gene', '7474', (60, 63))	('HGF', 'Gene', (158, 161))	('Wnt', 'Gene', (60, 63))	('HGF', 'Gene', (0, 3))	('HGF', 'Gene', '3082', (158, 161))	('HGF', 'Gene', '3082', (0, 3))	('neutralizing', 'Var', (145, 157))
25057	22509805	Implied pathways ultimately affecting actomyosin contractility, include the receptor gp130-IL6ST, JAK1, and rho-kinases.	('actomyosin contractility', 'MPA', (38, 62))	('gp130-IL6ST', 'Var', (85, 96))	('JAK1', 'Gene', (98, 102))	('affecting', 'Reg', (28, 37))	('JAK1', 'Gene', '3716', (98, 102))
25064	22509805	LOX was previously known to cross-link collagens and elastins in the ECM but had also been associated with increased breast cancer cell invasion in vitro.	('collagens', 'Protein', (39, 48))	('elastins', 'Protein', (53, 61))	('increased', 'PosReg', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('cross-link', 'Reg', (28, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('LOX', 'Var', (0, 3))
25065	22509805	In a mouse model of breast cancer, inhibition of LOX reduced cancer cell motility and invasiveness and prevented metastasis.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('prevented', 'NegReg', (103, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('reduced', 'NegReg', (53, 60))	('cancer cell motility and invasiveness', 'Disease', 'MESH:D009362', (61, 98))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('metastasis', 'CPA', (113, 123))	('mouse', 'Species', '10090', (5, 10))	('inhibition', 'Var', (35, 45))
25068	22509805	The niche-promoting effects of LOX include cross-linking of collagen IV that recruits first myeloid cells and then bone-marrow-derived cells and tumor cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('niche-promoting effects', 'CPA', (4, 27))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cross-linking', 'Var', (43, 56))	('tumor', 'Disease', (145, 150))
25081	22509805	This group recently used the orthotopic 4T1 breast cancer model to show that depletion of S100A4 cells reduced the metastatic area, increased apoptosis in metastases, and reduced CD31 staining.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('4T1', 'CellLine', 'CVCL:0125', (40, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('depletion', 'Var', (77, 86))	('reduced', 'NegReg', (103, 110))	('breast cancer', 'Disease', (44, 57))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('increased', 'PosReg', (132, 141))	('CD31', 'Gene', (179, 183))	('reduced', 'NegReg', (171, 178))	('metastatic area', 'CPA', (115, 130))	('S100A4', 'Gene', (90, 96))	('CD31', 'Gene', '5175', (179, 183))	('metastases', 'Disease', (155, 165))
25157	20429922	One patient carrying BRCA-1 gene mutation had bilateral prophylactic mastectomies with normal histology.	('BRCA-1', 'Gene', '672', (21, 27))	('mutation', 'Var', (33, 41))	('patient', 'Species', '9606', (4, 11))	('BRCA-1', 'Gene', (21, 27))
25177	20429922	Significant capsule formation was observed in approximately 85% (23/27) of patients who had either prior RT or PMR, which was substantially greater than the 13% (13/100) for those patients who had not received any RT.	('greater', 'PosReg', (140, 147))	('patients', 'Species', '9606', (75, 83))	('PMR', 'Var', (111, 114))	('capsule formation', 'CPA', (12, 29))	('patients', 'Species', '9606', (180, 188))
25211	20429922	However, PMR has been shown to reduce LR and improve survival for patients with four or more involved regional lymph nodes or tumours >5 cm.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('lymph nodes or tumours', 'Disease', 'MESH:D000072717', (111, 133))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('lymph nodes or tumours', 'Disease', (111, 133))	('survival', 'MPA', (53, 61))	('PMR', 'Var', (9, 12))	('improve', 'PosReg', (45, 52))	('reduce', 'NegReg', (31, 37))	('patients', 'Species', '9606', (66, 74))
25242	27681435	Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas Estrogen receptor alpha-positive luminal tumors are the most frequent subtype of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Tumor Growth', 'CPA', (48, 60))	('luminal tumors', 'Disease', (147, 161))	('Carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('Estrogen receptor alpha', 'Gene', '2099', (114, 137))	('Estrogen receptor alpha', 'Gene', (114, 137))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Carcinomas', 'Disease', 'MESH:D002277', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('breast cancer', 'Disease', (195, 208))	('Promote', 'PosReg', (40, 47))	('Prolactin Receptor', 'Gene', '19116', (11, 29))	('Carcinomas', 'Disease', (103, 113))	('luminal tumors', 'Disease', 'MESH:D009369', (147, 161))	('Murine', 'Species', '10090', (64, 70))	('Prolactin Receptor', 'Gene', (11, 29))	('Mutations', 'Var', (30, 39))	('Estrogen Receptor-Alpha', 'Gene', (71, 94))	('Estrogen Receptor-Alpha', 'Gene', '13982', (71, 94))
25245	27681435	This investigation identified somatic truncating mutations affecting the prolactin receptor (Prlr) in all tumor and no normal samples.	('prolactin receptor', 'Gene', (73, 91))	('prolactin receptor', 'Gene', '5618', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('truncating mutations', 'Var', (38, 58))	('Prlr', 'Gene', (93, 97))	('tumor', 'Disease', (106, 111))
25246	27681435	Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating this is an early event in tumorigenesis.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('precancerous lesions', 'Disease', 'MESH:D011230', (65, 85))	('precancerous lesions', 'Disease', (65, 85))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
25247	27681435	Functional evaluation of these heterozygous mutations in Stat1-/- mouse embryonic fibroblasts showed that co-expression of truncated and wild type Prlr led to aberrant Stat3 and Stat5 activation downstream of the receptor, cellular transformation in vitro and tumor formation in vivo.	('tumor', 'Disease', (260, 265))	('activation', 'PosReg', (184, 194))	('mouse', 'Species', '10090', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('Prlr', 'Gene', (147, 151))	('cellular transformation', 'CPA', (223, 246))	('Stat5', 'MPA', (178, 183))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))
25248	27681435	In conclusion, truncating mutations of Prlr promote tumor growth in a model of human ERalpha+ breast cancer and warrant further investigation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('truncating mutations', 'Var', (15, 35))	('promote', 'PosReg', (44, 51))	('human', 'Species', '9606', (79, 84))	('Prlr', 'Gene', (39, 43))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('breast cancer', 'Disease', (94, 107))
25257	27681435	Our analysis revealed relatively few copy number variation (CNV) events in primary Stat1-/- mammary tumors, but a point mutation rate consistent with that observed in human breast cancers.	('copy number variation', 'Var', (37, 58))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancers', 'Phenotype', 'HP:0003002', (173, 187))	('point mutation', 'Var', (114, 128))	('breast cancers', 'Disease', 'MESH:D001943', (173, 187))	('breast cancers', 'Disease', (173, 187))	('human', 'Species', '9606', (167, 172))
25258	27681435	A number of key genes reported in human cohorts were also mutated in the Stat1-/- mammary tumors including Trp53, Brca1, Mll3 and the Arid family.	('Mll3', 'Gene', '58508', (121, 125))	('Brca1', 'Gene', '672', (114, 119))	('human', 'Species', '9606', (34, 39))	('Mll3', 'Gene', (121, 125))	('Trp53', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Trp53', 'Gene', '7157', (107, 112))	('Brca1', 'Gene', (114, 119))	('mutated', 'Var', (58, 65))
25259	27681435	Strikingly, we identified a truncating mutation hotspot within the prolactin receptor (Prlr) with mutations affecting 100% of the Stat1-/- mammary tumor samples and 0% of control samples examined.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('prolactin receptor', 'Gene', '5618', (67, 85))	('prolactin receptor', 'Gene', (67, 85))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Prlr', 'Gene', (87, 91))	('affecting', 'Reg', (108, 117))	('Stat1-/-', 'Disease', (130, 138))
25260	27681435	Co-expression of full-length and truncated Prlr in immortalized Stat1-/- mouse embryonic fibroblasts (MEFs) led to activation of the downstream oncogenic substrates Stat3 and Stat5, transformation of MEFs in vitro, and tumor formation in mice.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Stat3', 'MPA', (165, 170))	('activation', 'PosReg', (115, 125))	('transformation', 'CPA', (182, 196))	('tumor', 'Disease', (219, 224))	('Prlr', 'Gene', (43, 47))	('MEFs', 'CellLine', 'CVCL:9115', (102, 106))	('truncated', 'Var', (33, 42))	('mouse', 'Species', '10090', (73, 78))	('Stat5', 'MPA', (175, 180))	('mice', 'Species', '10090', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('MEFs', 'CellLine', 'CVCL:9115', (200, 204))
25261	27681435	In a discovery set of 22 Stat1-/- tumor samples, using whole genome sequencing (WGS), we detected over 10,112 single nucleotide variants (SNVs) and 3,331 insertions and deletions (indels) within or near coding regions of known genes.	('insertions', 'Var', (154, 164))	('tumor', 'Disease', (34, 39))	('single nucleotide variants', 'Var', (110, 136))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('deletions', 'Var', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
25262	27681435	The 1,858 mutations occurred in 1,649 genes with 139 recurrently mutated genes (occurring in two or more samples) across all 22 tumors (Table 1 and Table S2).	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('mutations', 'Var', (10, 19))	('occurred', 'Reg', (20, 28))
25264	27681435	Beyond the Prlr gene, mutations were observed in many of the same key genes and pathways reported previously for human breast and ovarian cancer, including Trp53, DNA repair genes (Brca1, Rad50, Rfc2, Poln, and Polr2a), chromatin modifiers (Arid1a and Arid1b), transcription factors (Zfp335, Zfp523, Zfp119a, Zfp119b), and kinases and phosphatases (Ptprb, Pik3r2, Pik3cd, Mapk7 and Src).	('Zfp335', 'Var', (284, 290))	('Polr2a', 'Gene', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Poln', 'Gene', (201, 205))	('Zfp119a', 'Var', (300, 307))	('Pik3cd', 'Gene', '5293', (364, 370))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (119, 144))	('Src', 'Gene', '6714', (382, 385))	('human', 'Species', '9606', (113, 118))	('Pik3r2', 'Gene', (356, 362))	('Pik3r2', 'Gene', '5296', (356, 362))	('Polr2a', 'Gene', '5430', (211, 217))	('Brca1', 'Gene', '672', (181, 186))	('Rad50', 'Gene', '10111', (188, 193))	('Mapk7', 'Gene', (372, 377))	('Arid1a', 'Gene', '8289', (241, 247))	('Rfc2', 'Gene', (195, 199))	('Rad50', 'Gene', (188, 193))	('Ptprb', 'Gene', (349, 354))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))	('Ptprb', 'Gene', '5787', (349, 354))	('Zfp119b', 'Var', (309, 316))	('Rfc2', 'Gene', '5982', (195, 199))	('Zfp523', 'Gene', (292, 298))	('mutations', 'Var', (22, 31))	('Trp53', 'Gene', (156, 161))	('Pik3cd', 'Gene', (364, 370))	('Mapk7', 'Gene', '5598', (372, 377))	('Brca1', 'Gene', (181, 186))	('Trp53', 'Gene', '7157', (156, 161))	('Arid1b', 'Gene', (252, 258))	('Arid1b', 'Gene', '57492', (252, 258))	('Poln', 'Gene', '353497', (201, 205))	('Arid1a', 'Gene', (241, 247))	('Src', 'Gene', (382, 385))	('Zfp523', 'Gene', '7629', (292, 298))
25265	27681435	Other mutations of note were in Ip6k2, which encodes a protein that affects the growth suppressive and apoptotic activities of interferon-beta in ovarian cancers; Tiam1, which is a t-lymphoma invasion and metastasis-inducing protein; and Esrrg, which encodes the estrogen-related receptor gamma protein.	('apoptotic activities', 'CPA', (103, 123))	('growth suppressive', 'CPA', (80, 98))	('Esrrg', 'Gene', (238, 243))	('t-lymphoma', 'Phenotype', 'HP:0012190', (181, 191))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('ovarian cancers', 'Phenotype', 'HP:0100615', (146, 161))	('interferon-beta', 'Gene', '3456', (127, 142))	('Esrrg', 'Gene', '2104', (238, 243))	('affects', 'Reg', (68, 75))	('Ip6k2', 'Gene', '51447', (32, 37))	('mutations', 'Var', (6, 15))	('interferon-beta', 'Gene', (127, 142))	('Tiam1', 'Gene', (163, 168))	('lymphoma', 'Disease', (183, 191))	('estrogen-related receptor gamma', 'Gene', (263, 294))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('lymphoma', 'Disease', 'MESH:D008223', (183, 191))	('ovarian cancers', 'Disease', (146, 161))	('ovarian cancers', 'Disease', 'MESH:D010051', (146, 161))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('estrogen-related receptor gamma', 'Gene', '2104', (263, 294))	('Tiam1', 'Gene', '7074', (163, 168))	('Ip6k2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
25268	27681435	Despite this, we compared our cohort to mutations frequently observed in human luminal breast cancers by identifying genes mutated at >5% frequency in the human TCGA luminal A and B cohort (n=699).	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('human', 'Species', '9606', (155, 160))	('human', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('luminal breast cancers', 'Disease', 'MESH:D001943', (79, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('mutated', 'Var', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('luminal breast cancers', 'Disease', (79, 101))
25269	27681435	We observed Trp53 and Mll3 mutations at frequencies comparable to the human dataset with 14% vs 16% and 18% vs 8%, respectively (Figure S1).	('mutations', 'Var', (27, 36))	('Trp53', 'Gene', '7157', (12, 17))	('human', 'Species', '9606', (70, 75))	('Mll3', 'Gene', '58508', (22, 26))	('Trp53', 'Gene', (12, 17))	('Mll3', 'Gene', (22, 26))
25270	27681435	The lack of Pik3ca and Map3k1 mutations is perhaps expected in the context of Prlr truncation (see below) given that their activity is downstream of Prlr and therefore activating mutations in these genes may not be required for tumor formation.	('Map3k1', 'Gene', '4214', (23, 29))	('Pik3ca', 'Gene', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Pik3ca', 'Gene', '5290', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (228, 233))	('Map3k1', 'Gene', (23, 29))	('activity', 'MPA', (123, 131))
25276	27681435	Prlr mutations were not observed in any matched normal tails (0/17), wild type mammary glands (0/10), or tumor-free Stat1-/- mammary glands (0/5).	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Prlr', 'Gene', (0, 4))	('tumor', 'Disease', (105, 110))
25277	27681435	Our alignment and variant calling pipelines and further manual inspection of WGS data for the Prlr region revealed Prlr mutations in a total of 21/22 tumors (Table 2 and Appendix 1).	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('Prlr', 'Gene', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutations', 'Var', (120, 129))
25278	27681435	Only the TAC246 tumor sample had no evidence of a Prlr mutation in the initial discovery WGS dataset.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (16, 21))	('mutation', 'Var', (55, 63))
25280	27681435	Sequence traces consistent with the WGS mutations were confirmed for 19 of 21 tumors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (40, 49))
25281	27681435	MiSeq sequencing of a formalin-fixed paraffin-embedded (FFPE) sample from the TAC246 tumor identified a Prlr mutation in this sample that was missed in the original discovery set by WGS (giving a sensitivity of 95.5% for the ~30x WGS approach of detecting Prlr mutations).	('tumor', 'Disease', (85, 90))	('formalin', 'Chemical', 'MESH:D005557', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Prlr', 'Gene', (104, 108))	('paraffin', 'Chemical', 'MESH:D010232', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutation', 'Var', (109, 117))
25285	27681435	Prlr mutations were observed in all additional tumors and none of the non-tumor samples (Figure S2).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('non-tumor', 'Disease', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (5, 14))	('Prlr', 'Gene', (0, 4))	('non-tumor', 'Disease', 'MESH:D009369', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('observed', 'Reg', (20, 28))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
25286	27681435	In order to determine whether Prlr mutations are an early tumor-initiating event, ductal carcinoma in situ (DCIS) components were identified from FFPE blocks of additional Stat1-/- mammary glands.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (82, 106))	('ductal carcinoma in situ', 'Disease', (82, 106))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (82, 98))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 106))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('mutations', 'Var', (35, 44))
25288	27681435	These results suggest that mutations in the Prlr allele and activation of the Prlr pathway are an early event during tumorigenesis of Stat1-/- mammary epithelial cells.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Prlr', 'Gene', (44, 48))	('tumor', 'Disease', (117, 122))	('activation', 'PosReg', (60, 70))	('Prlr pathway', 'Pathway', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
25290	27681435	Examination of WGS data showed that nearly all Prlr mutations, except for the SSM1 tumor cell line, appeared to be heterozygous.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SSM1', 'Gene', (78, 82))	('tumor', 'Disease', (83, 88))	('SSM1', 'Gene', '20829', (78, 82))	('Prlr', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
25292	27681435	Since all but one of the observed Prlr mutations in primary Stat1-/- mammary tumors occurred in one of two alleles and all of the primary tumors examined so far displayed constitutive Prlr pathway activation, we hypothesized that heterodimers of full-length (FL) and truncated (T) Prlr may be the cause of constitutive Prlr activation and thus the tumorigenic phenotype of the Stat1-/- mammary epithelial cells.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('heterodimers', 'Var', (230, 242))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('primary tumors', 'Disease', 'MESH:D009369', (130, 144))	('Prlr', 'Gene', (281, 285))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Prlr', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('activation', 'PosReg', (324, 334))	('tumors', 'Disease', (138, 144))	('tumor', 'Disease', (348, 353))	('tumor', 'Disease', (77, 82))	('primary tumors', 'Disease', (130, 144))
25293	27681435	Endogenous expression of the FL and T Prlr isoforms was verified in Stat1-/- mammary tumor cell lines (SSM1, SSM2 and SSM3) harboring these mutations by immunoprecipitation and Western blotting (Figure S5A).	('S5A', 'Gene', (202, 205))	('tumor', 'Disease', (85, 90))	('S5A', 'Gene', '5710', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('SSM1', 'Gene', '20829', (103, 107))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SSM1', 'Gene', (103, 107))
25294	27681435	In contrast to the SSM2 and SSM3 tumor cell lines, which are heterozygous for the mutation, the SSM1 tumor cell line was homozygous (Table 2 and Figure S5A) and failed to display constitutive Prlr-Jak2-Stat3/5 signaling.	('mutation', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('S5A', 'Gene', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('S5A', 'Gene', '5710', (152, 155))	('SSM1', 'Gene', (96, 100))	('SSM1', 'Gene', '20829', (96, 100))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
25298	27681435	Cells expressing FL and T Prlr developed significantly more colonies than control MEFs (p = 0.0013), or those expressing FL alone (p = 0.0013) or T alone (p = 0.0015) when plated in soft agar (Figure 3B and Figure S5C).	('MEFs', 'CellLine', 'CVCL:9115', (82, 86))	('T Prlr', 'Var', (24, 30))	('agar', 'Chemical', 'MESH:D000362', (187, 191))	('more', 'PosReg', (55, 59))	('colonies', 'CPA', (60, 68))
25300	27681435	Tumor formation also occurred more quickly in mice that received FL/T expressing MEFs than FL alone (p=0.03), T alone (p=0.0001), vector alone (p=0.0005), or MEFs alone (p=0.0001; Figure S5D).	('Tumor formation', 'CPA', (0, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MEFs', 'Var', (81, 85))	('MEFs', 'CellLine', 'CVCL:9115', (81, 85))	('MEFs', 'CellLine', 'CVCL:9115', (158, 162))	('mice', 'Species', '10090', (46, 50))
25301	27681435	FL/T expressing MEFs formed tumors at a frequency similar to the Kras expressing positive control (p = 1.0), although at a significantly slower rate (p<0.0001).	('FL/T', 'Var', (0, 4))	('MEFs', 'CellLine', 'CVCL:9115', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
25303	27681435	To assess the prevalence of PRLR mutations in human breast cancers, we examined human breast cancer exome sequence data from 991 patients made publicly available through the TCGA data portal.	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('patients', 'Species', '9606', (129, 137))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (33, 42))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancers', 'Disease', (52, 66))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('human', 'Species', '9606', (46, 51))	('human', 'Species', '9606', (80, 85))	('PRLR', 'Gene', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer', 'Disease', (86, 99))	('PRLR', 'Gene', '5618', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
25305	27681435	One of these mutations, an indel (L360fs), causes a truncating mutation in the human PRLR exon 10 (ENST00000382002, Ensembl v70_37), analogous to that observed in the mouse Stat1-/- mammary tumors.	('human', 'Species', '9606', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('PRLR', 'Gene', (85, 89))	('L360fs', 'Mutation', 'p.L360fsX', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PRLR', 'Gene', '5618', (85, 89))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('L360fs', 'Var', (34, 40))	('tumors', 'Disease', (190, 196))	('truncating mutation', 'MPA', (52, 71))	('causes', 'Reg', (43, 49))	('mouse', 'Species', '10090', (167, 172))
25306	27681435	Manual review of alignment data for this exon identified 4 additional truncating indels at E313fs (2/47 reads), L315fs (2/44), L360fs (35/42) and K460fs (3/100) from samples TCGA-B6-A0X7, TCGA-A2-A04R, TCGA-AC-A3EH and TCGA-AR-A5QQ, respectively.	('K460fs', 'Mutation', 'p.K460fsX', (146, 152))	('K460fs', 'Var', (146, 152))	('E313fs', 'Mutation', 'p.E313fsX', (91, 97))	('L315fs', 'Mutation', 'p.L315fsX', (112, 118))	('L315fs', 'Var', (112, 118))	('L360fs', 'Mutation', 'p.L360fsX', (127, 133))	('E313fs', 'Var', (91, 97))	('A04R', 'Mutation', 'p.A04R', (196, 200))	('L360fs', 'Var', (127, 133))
25307	27681435	L360fs, E313fs and L315fs were found in luminal subtype breast cancers whereas K460fs was in a basal breast cancer.	('E313fs', 'Var', (8, 14))	('L360fs', 'Mutation', 'p.L360fsX', (0, 6))	('L315fs', 'Mutation', 'p.L315fsX', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('luminal subtype breast cancers', 'Disease', (40, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('luminal subtype breast cancers', 'Disease', 'MESH:D001943', (40, 70))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('K460fs', 'Mutation', 'p.K460fsX', (79, 85))	('breast cancer', 'Disease', (101, 114))	('E313fs', 'Mutation', 'p.E313fsX', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('K460fs', 'Var', (79, 85))	('found', 'Reg', (31, 36))	('L360fs', 'Var', (0, 6))	('breast cancers', 'Phenotype', 'HP:0003002', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('L315fs', 'Var', (19, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))
25308	27681435	The Exome Aggregation Consortium (ExAC) reports only 4 individuals with rare (allele frequency < 0.00001) germline truncating mutations in PRLR at A597fs, N568fs, S27*, and W180*.	('PRLR', 'Gene', (139, 143))	('W180*', 'Var', (173, 178))	('PRLR', 'Gene', '5618', (139, 143))	('S27*', 'SUBSTITUTION', 'None', (163, 167))	('N568fs', 'Var', (155, 161))	('A597fs', 'Mutation', 'p.A597fsX', (147, 153))	('N568fs', 'Mutation', 'p.N568fsX', (155, 161))	('A597fs', 'Var', (147, 153))	('W180*', 'SUBSTITUTION', 'None', (173, 178))	('S27*', 'Var', (163, 167))
25309	27681435	There are currently 8 to 10 reported complete protein-coding transcript isoforms for human PRLR according to Ensembl (ENSG00000113494, release 79), UCSC (PRLR, GRCh37/hg19) and UniProt (P16471, Entry version 175) that can be broadly grouped as long, intermediate and short PRLR isoforms (Figure S6 and Table S6).	('PRLR', 'Gene', (273, 277))	('PRLR', 'Gene', '5618', (91, 95))	('PRLR', 'Gene', (91, 95))	('PRLR', 'Gene', '5618', (273, 277))	('PRLR', 'Gene', '5618', (154, 158))	('PRLR', 'Gene', (154, 158))	('P16471', 'Var', (186, 192))	('human', 'Species', '9606', (85, 90))
25310	27681435	We investigated the possibility of an increase in the expression of truncated (T) (i.e., short) PRLR relative to full-length (FL) (i.e., long) PRLR in human ERalpha+ luminal breast cancer.	('expression', 'MPA', (54, 64))	('increase', 'PosReg', (38, 46))	('truncated', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PRLR', 'Gene', (143, 147))	('human', 'Species', '9606', (151, 156))	('luminal breast cancer', 'Disease', (166, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('PRLR', 'Gene', '5618', (143, 147))	('PRLR', 'Gene', (96, 100))	('PRLR', 'Gene', '5618', (96, 100))	('luminal breast cancer', 'Disease', 'MESH:D001943', (166, 187))
25319	27681435	These data indicate that there may be a preferential usage of the truncated PRLR isoform in tumor cells with reduced STAT1 expression among ERalpha+ luminal breast cancers.	('PRLR', 'Gene', '5618', (76, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('luminal breast cancers', 'Disease', (149, 171))	('STAT1', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('tumor', 'Disease', (92, 97))	('truncated', 'Var', (66, 75))	('STAT1', 'Gene', '6772', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('reduced', 'NegReg', (109, 116))	('luminal breast cancers', 'Disease', 'MESH:D001943', (149, 171))	('PRLR', 'Gene', (76, 80))
25320	27681435	In this study, we identified recurrent gene mutations that were associated with the tumorigenic landscape of ERalpha+ Stat1-/- luminal mammary gland tumors.	('associated', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (84, 89))	('tumors', 'Disease', (149, 155))	('ERalpha+', 'Gene', (109, 117))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
25322	27681435	Our study also revealed a potential mechanism whereby ERalpha+ luminal breast cancer initiates and progresses.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('luminal breast cancer', 'Disease', (63, 84))	('luminal breast cancer', 'Disease', 'MESH:D001943', (63, 84))	('ERalpha+', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
25323	27681435	Loss of Stat1 expression in mammary cells favors acquisition of mutations in an 85 base pair hotspot of exon 10 of the Prlr gene (ENSMUST00000124470), resulting in a truncation of the cytoplasmic tail of the prolactin receptor (Prlr).	('prolactin receptor', 'Gene', (208, 226))	('prolactin receptor', 'Gene', '5618', (208, 226))	('Prlr', 'Gene', (119, 123))	('Stat1', 'Gene', (8, 13))	('mutations', 'Var', (64, 73))	('truncation', 'MPA', (166, 176))
25329	27681435	There is also support for an association between PRLR allelic variations and breast cancer risk.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('allelic variations', 'Var', (54, 72))	('PRLR', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PRLR', 'Gene', '5618', (49, 53))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
25330	27681435	In lobular neoplasia, amplification of PRLR may also be important for pathogenesis and progression.	('important', 'Reg', (56, 65))	('PRLR', 'Gene', '5618', (39, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (11, 20))	('PRLR', 'Gene', (39, 43))	('amplification', 'Var', (22, 35))	('lobular neoplasia', 'Disease', (3, 20))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (3, 20))	('lobular neoplasia', 'Disease', 'MESH:D009369', (3, 20))
25333	27681435	We have also shown that loss of Stat1 expression results in unopposed Prlr signaling, promotes expansion of mammary luminal progenitor cells, leads to development of ductal carcinoma in situ (DCIS) and finally to invasive mammary carcinomas.	('loss', 'Var', (24, 28))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (166, 182))	('DCIS', 'Phenotype', 'HP:0030075', (192, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (230, 240))	('unopposed Prlr signaling', 'MPA', (60, 84))	('carcinomas', 'Disease', (230, 240))	('carcinomas', 'Disease', 'MESH:D002277', (230, 240))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (166, 190))	('Stat1', 'Gene', (32, 37))	('invasive', 'Disease', (213, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('leads to', 'Reg', (142, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('promotes', 'PosReg', (86, 94))	('expansion', 'CPA', (95, 104))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (166, 190))	('ductal carcinoma in situ', 'Disease', (166, 190))
25341	27681435	Prlr truncation and Stat3/5 activation were also observed in DCIS in Stat1-/- mammary glands, indicating that persistent Prlr signaling mediated by Prlr mutations was an early tumorigenic event.	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('Prlr signaling', 'MPA', (121, 135))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (153, 162))	('tumor', 'Disease', (176, 181))	('Prlr', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
25342	27681435	These results suggest that FL/T PRLR heterodimers could contribute to ERalpha+ breast cancer development in patients with normal PRL levels due to the intrinsic ability of the heterodimers to signal without ligand stimulation.	('PRLR', 'Gene', '5618', (32, 36))	('FL/T', 'Var', (27, 31))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('patients', 'Species', '9606', (108, 116))	('contribute', 'Reg', (56, 66))	('PRLR', 'Gene', (32, 36))
25358	27681435	It is possible that PRLR truncation may occur as other types of genomic alterations such as larger scale deletions, gene fusions, or translocations that are not easily detected from TCGA exome or RNA-seq data.	('deletions', 'Var', (105, 114))	('PRLR', 'Gene', (20, 24))	('PRLR', 'Gene', '5618', (20, 24))	('translocations', 'Var', (133, 147))	('gene fusions', 'Var', (116, 128))	('occur', 'Reg', (40, 45))
25364	27681435	Our analyses compared all of the known short isoforms (S1a, S1b, Delta4 S1b, DeltaS4-Delta7/11, Delta7/11, DeltaS1) to the full-length isoform and observed a significant increase in expression of the short isoforms over full-length Prlr in STAT1-low luminal but not basal breast cancer.	('STAT1', 'Gene', (240, 245))	('DeltaS1', 'DELETION', 'None', (107, 114))	('expression', 'MPA', (182, 192))	('DeltaS4', 'Var', (77, 84))	('Delta4 S1b', 'Var', (65, 75))	('STAT1', 'Gene', '6772', (240, 245))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('increase', 'PosReg', (170, 178))	('DeltaS4', 'DELETION', 'None', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancer', 'Disease', (272, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('DeltaS1', 'Var', (107, 114))
25369	27681435	However, these experiments were performed using MEFs rather than the primary cell of origin and future studies should assess the tumorigenic property of Prlr heterodimers in Stat1-/- mammary epithelial cells (MECs) with endogenous levels of Jak2.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MEFs', 'CellLine', 'CVCL:9115', (48, 52))	('tumor', 'Disease', (129, 134))	('heterodimers', 'Var', (158, 170))
25370	27681435	Phosphorylation of Ser349 on Prlr recruits the b-TrCP ubiquitin-protein ligase.	('Phosphorylation', 'MPA', (0, 15))	('b-TrCP', 'Protein', (47, 53))	('Ser349', 'Chemical', '-', (19, 25))	('Ser349', 'Var', (19, 25))
25372	27681435	Consistent with this hypothesis, phosphorylation on Ser349 is diminished in human breast cancer cell lines, leading to an increase in Prlr expression levels.	('breast cancer', 'Disease', (82, 95))	('phosphorylation', 'MPA', (33, 48))	('Prlr expression levels', 'MPA', (134, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('Ser349', 'Chemical', '-', (52, 58))	('diminished', 'NegReg', (62, 72))	('human', 'Species', '9606', (76, 81))	('Ser349', 'Var', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('increase', 'PosReg', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
25373	27681435	In addition, although FL Prlr and the truncated S1b isoform have similar binding affinity to growth hormone, the level of specific binding by S1b is significantly higher than that of FL Prlr on COS-1 or HEK293 cells transfected with either isoform.	('HEK293', 'CellLine', 'CVCL:0045', (203, 209))	('binding', 'Interaction', (73, 80))	('S1b', 'Var', (142, 145))	('binding', 'Interaction', (131, 138))	('higher', 'PosReg', (163, 169))
25375	27681435	For example, LFA102, an anti-PRLR antibody, blocks PRLR pathway activation by either inhibiting PRLR dimerization or locking the PRLR dimer in an inactive conformation without affecting PRL ligand binding.	('PRLR', 'Gene', '5618', (29, 33))	('PRLR', 'Gene', (129, 133))	('LFA102', 'Var', (13, 19))	('blocks', 'NegReg', (44, 50))	('PRLR', 'Gene', '5618', (129, 133))	('activation', 'MPA', (64, 74))	('dimerization', 'MPA', (101, 113))	('inhibiting', 'NegReg', (85, 95))	('PRLR', 'Gene', (51, 55))	('PRLR', 'Gene', (96, 100))	('PRLR', 'Gene', '5618', (51, 55))	('PRLR', 'Gene', '5618', (96, 100))	('PRLR', 'Gene', (29, 33))
25376	27681435	Since truncated PRLR expression is preferentially increased in ERalpha+ breast cancer and FL/T PRLR heterodimers display constitutive activation as shown in our current study, it would be of interest to examine whether LFA102 is able to block heterodimerization of full-length and truncated PRLR in future studies.	('heterodimers', 'MPA', (100, 112))	('truncated', 'Var', (6, 15))	('PRLR', 'Gene', (16, 20))	('PRLR', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PRLR', 'Gene', '5618', (16, 20))	('PRLR', 'Gene', (291, 295))	('PRLR', 'Gene', '5618', (95, 99))	('increased', 'PosReg', (50, 59))	('expression', 'MPA', (21, 31))	('PRLR', 'Gene', '5618', (291, 295))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('heterodimerization', 'MPA', (243, 261))	('breast cancer', 'Disease', (72, 85))	('FL/T', 'Gene', (90, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
25380	27681435	Stat1-/- mammary gland adenocarcinomas have been previously characterized in our laboratory.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('adenocarcinomas', 'Disease', (23, 38))	('Stat1-/-', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('adenocarcinomas', 'Disease', 'MESH:D000230', (23, 38))
25398	27681435	Based on the region in which truncating Prlr mutations were observed in the discovery set (chr15:10258139-10258195; mm9) two sets of primers were designed to encompass this region with approximately 50 or 100 bp additional flanking sequence on each side, respectively (Table S10 and Supplemental Experimental Procedures).	('mutations', 'Var', (45, 54))	('Prlr', 'Gene', (40, 44))	('chr15:10258139-10258195', 'STRUCTURAL_ABNORMALITY', 'None', (91, 114))
25400	27681435	We performed Sanger sequencing as described above on the original 22 tumor samples to validate Prlr variants that were called from WGS data and to extend the Prlr findings to 10 additional tumors and 35 non-tumor samples (Figure 1 and Figure S2).	('non-tumor', 'Disease', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (69, 74))	('variants', 'Var', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('non-tumor', 'Disease', 'MESH:D009369', (203, 212))	('Prlr', 'Gene', (95, 99))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
25425	27681435	Female NCr nude mice (Taconic) were implanted with 1 x106 of immortalized Stat1-/- MEFs expressing Jak2 alone, FL Prlr/Jak2, T Prlr/Jak2, FL/T Prlr/Jak2 or Kras in 100 microl vehicle.	('MEFs', 'CellLine', 'CVCL:9115', (83, 87))	('nude mice', 'Species', '10090', (11, 20))	('Jak2', 'Gene', (99, 103))	('FL/T', 'Var', (138, 142))
25430	27681435	Fisher's exact test was used to compare tumor formation in each group of nude mice implanted with Stat1-/- MEFs to the FL/T expressing group.	('Stat1-/- MEFs', 'Var', (98, 111))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MEFs', 'CellLine', 'CVCL:9115', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('nude mice', 'Species', '10090', (73, 82))
25479	23088337	Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('breast cancer', 'Disease', (130, 143))	('patients', 'Species', '9606', (33, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('CTC', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Presence', 'Var', (0, 8))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('associated', 'Reg', (92, 102))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))
25485	23088337	The presence of micrometastases in bone marrow of breast cancer patients is associated with an increased risk for disease recurrence and death.	('bone marrow of breast cancer', 'Disease', 'MESH:D001855', (35, 63))	('patients', 'Species', '9606', (64, 72))	('death', 'Disease', 'MESH:D003643', (137, 142))	('death', 'Disease', (137, 142))	('bone marrow of breast cancer', 'Disease', (35, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('disease recurrence', 'CPA', (114, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('micrometastases', 'Var', (16, 31))
25487	23088337	For CTC detection a validated method is available and several studies have demonstrated that the presence of CTC in patients with metastatic breast cancer is associated with a significantly shorter progression-free and overall survival.	('overall survival', 'CPA', (219, 235))	('presence', 'Var', (97, 105))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('CTC', 'Gene', (109, 112))	('breast cancer', 'Disease', (141, 154))	('shorter', 'NegReg', (190, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
25553	23088337	Detection of tumor cells in the blood is an attractive alternative as a validated method is available and the presence of CTC in breast cancer patients with metastatic disease has shown to be an independent prognostic factor for progression-free and overall survival.	('breast cancer', 'Disease', (129, 142))	('tumor', 'Disease', (13, 18))	('presence', 'Var', (110, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('CTC', 'Gene', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
25566	23088337	Even though a background was observed in the control group, the presence of CTC in 30 ml of preoperatively drawn blood of patients with non-metastatic breast cancer was associated with a higher risk of recurrence and breast cancer-related death as compared to patients without CTC.	('death', 'Disease', (239, 244))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('patients', 'Species', '9606', (260, 268))	('presence', 'Var', (64, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('patients', 'Species', '9606', (122, 130))	('breast cancer', 'Disease', (151, 164))	('recurrence', 'CPA', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('death', 'Disease', 'MESH:D003643', (239, 244))
25579	23088337	Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death and distant disease-free survival, but not for overall recurrence-free survival.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('breast cancer', 'Disease', (130, 143))	('patients', 'Species', '9606', (33, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('distant disease-free survival', 'CPA', (162, 191))	('CTC', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Presence', 'Var', (0, 8))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))
25601	30145750	Similarly, immunohistochemical analysis of DCIS show expression of multiple histologic grades as well as different levels of biomarker expression, including ER, PR, HER2 and Ki67, within the same patient DCIS suggesting that DCIS exhibit similar intra-tumoral heterogeneity as IDC.	('Ki67', 'Var', (174, 178))	('IDC', 'Gene', '4000', (277, 280))	('IDC', 'Gene', (277, 280))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('patient', 'Species', '9606', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('DCIS', 'Phenotype', 'HP:0030075', (225, 229))	('tumor', 'Disease', (252, 257))	('DCIS', 'Phenotype', 'HP:0030075', (204, 208))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
25602	30145750	Indeed, there was a significant correlation between a mutation in p53 and DCIS intratumoral heterogeneity.	('mutation', 'Var', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('rat', 'Species', '10116', (82, 85))	('DCIS', 'Disease', (74, 78))	('p53', 'Gene', (66, 69))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
25662	30145750	Although variants of the MMTV-Neu models display different tumor latencies (3-6 months), likely due to differences in transgene expression and integration sites, mammary lesions develop atypical hyperplasias and focal or multifocal tumors with varying degrees of lung metastasis.	('hyperplasias', 'Disease', 'MESH:D006965', (195, 207))	('tumor', 'Disease', (59, 64))	('lung metastasis', 'Disease', 'MESH:D009362', (263, 278))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('lung metastasis', 'Disease', (263, 278))	('multifocal tumors', 'Disease', 'None', (221, 238))	('variants', 'Var', (9, 17))	('tumor', 'Disease', (232, 237))	('MMTV', 'Species', '11757', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('rat', 'Species', '10116', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('multifocal tumors', 'Disease', (221, 238))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('develop', 'PosReg', (178, 185))	('Neu', 'Gene', (30, 33))	('mammary lesions', 'Disease', (162, 177))	('Neu', 'Gene', '13866', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('hyperplasias', 'Disease', (195, 207))
25663	30145750	The hyperplasias that develop in various ErbB2 transgenic models have been shown to share common cytological features with human DCIS.	('hyperplasias', 'Disease', 'MESH:D006965', (4, 16))	('human', 'Species', '9606', (123, 128))	('transgenic', 'Species', '10090', (47, 57))	('ErbB2', 'Gene', (41, 46))	('transgenic', 'Var', (47, 57))	('hyperplasias', 'Disease', (4, 16))	('DCIS', 'Phenotype', 'HP:0030075', (129, 133))
25666	30145750	Genetic alterations in erbb2 occur frequently in high grade DCIS, but whether the progression of MMTV-Neu-induced hyperplasias accurately mimics human HER2+ DCIS progression has yet to be determined.	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (131, 134))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('hyperplasias', 'Disease', (114, 126))	('rat', 'Species', '10116', (12, 15))	('MMTV', 'Species', '11757', (97, 101))	('high', 'Disease', (49, 53))	('hyperplasias', 'Disease', 'MESH:D006965', (114, 126))	('Neu', 'Gene', (102, 105))	('Neu', 'Gene', '13866', (102, 105))	('human', 'Species', '9606', (145, 150))	('erbb2', 'Gene', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
25677	30145750	Female mice initially show normal ductal development, progress to ductal atypia by 6-8 weeks of age (low grade MIN), high grade MIN (similar to DCIS) by 12-14 weeks, and invasive cancer by 16 weeks or later.	('high grade MIN', 'Var', (117, 131))	('invasive cancer', 'Disease', 'MESH:D009362', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('mice', 'Species', '10090', (7, 11))	('ductal', 'Disease', (66, 72))	('invasive cancer', 'Disease', (170, 185))	('ductal development', 'CPA', (34, 52))	('progress', 'PosReg', (54, 62))
25679	30145750	Unlike MMTV-PyMT- and MMTV-Neu-induced lesions, SV40 T antigen-driven models appear to represent DH rather than HAN, forming solid nests of poorly differentiated cells that may originate within the terminal ducts of the mammary gland, where the transgene is expressed.	('DH', 'Disease', 'MESH:D065630', (97, 99))	('SV40 T', 'Var', (48, 54))	('Neu', 'Gene', (27, 30))	('Neu', 'Gene', '13866', (27, 30))	('MMTV', 'Species', '11757', (22, 26))	('rat', 'Species', '10116', (100, 103))	('MMTV', 'Species', '11757', (7, 11))
25681	30145750	These findings are corroborated by early gene expression profiling of human breast lesions from ADH, DCIS and IDC in which the majority of genetic alterations important for tumor progression occurred by the ADH stage, and persisted throughout progression.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('DH', 'Disease', 'MESH:D065630', (97, 99))	('breast lesions', 'Disease', (76, 90))	('occurred', 'Reg', (191, 199))	('genetic alterations', 'Var', (139, 158))	('DH', 'Disease', 'MESH:D065630', (208, 210))	('rat', 'Species', '10116', (26, 29))	('human', 'Species', '9606', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('IDC', 'Gene', '4000', (110, 113))	('rat', 'Species', '10116', (151, 154))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('IDC', 'Gene', (110, 113))
25683	30145750	TP53 is the most frequently mutated gene in breast cancer, with genetic alterations in about 30% of breast cancers, predominantly of the basal subtype.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('rat', 'Species', '10116', (76, 79))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', (44, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancers', 'Disease', (100, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('genetic alterations', 'Var', (64, 83))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
25692	30145750	Unlike lesions induced by chemical carcinogens or in C(3)1Tag mice, the p53-/- premalignant lesions are ovarian hormone-dependent, a characteristic unique to this model.	('ovarian', 'Disease', (104, 111))	('mice', 'Species', '10090', (62, 66))	('p53-/-', 'Var', (72, 78))
25722	30145750	The MIND model supports intraductal growth of epithelial cells derived from a variety of human premalignant and malignant lesions including hyperplasias, subtypes of DCIS, subtypes of invasive ductal carcinoma and normal mammary epithelial cells from BRCA mutation carriers (Behbod, F unpublished results).	('BRCA', 'Gene', '672', (251, 255))	('human', 'Species', '9606', (89, 94))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (193, 209))	('BRCA', 'Gene', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('mutation', 'Var', (256, 264))	('invasive ductal carcinoma', 'Disease', (184, 209))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('hyperplasias', 'Disease', (140, 152))	('hyperplasias', 'Disease', 'MESH:D006965', (140, 152))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (184, 209))
25831	24978026	Breast tissue sections were stained with standard clinical receptor markers, ER, PR, and HER2, as well as three promising DCIS risk biomarkers (Ki-67, p16 and p53).	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('Ki-67', 'Var', (144, 149))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('ER', 'Gene', '2099', (90, 92))	('p16', 'Gene', (151, 154))	('clinical', 'Species', '191496', (50, 58))	('ER', 'Gene', '2099', (77, 79))	('HER2', 'Gene', (89, 93))	('PR', 'Gene', '5241', (81, 83))	('HER2', 'Gene', '2064', (89, 93))	('p16', 'Gene', '1029', (151, 154))	('DCIS', 'Disease', (122, 126))
25837	24978026	K4007 and K4011, respectively).	('K4007', 'Var', (0, 5))	('K4011', 'Chemical', '-', (10, 15))	('K4011', 'Var', (10, 15))	('K4007', 'Chemical', '-', (0, 5))
25845	24978026	For p53 staining only lesions containing cells with very strongly stained nuclei, which was indicative of mutant p53, were assigned a numeric score; all other lesions were considered as expressing wild type p53 (score 0).	('mutant', 'Var', (106, 112))	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('p53', 'Gene', (4, 7))
25846	24978026	If strong nuclear staining (indicating mutant p53) was observed, lesions were given a numeric score as follows: 1-10% positive cells (scored as 1), 11-75% positive cells (scored as 2), and >75% positive cells (scored as 3).	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', (46, 49))	('mutant', 'Var', (39, 45))
25848	24978026	Staining intensity for ER, PR, HER2, Ki-67, p53, p16, p63 and Cleaved Caspase-3 are demonstrated in Figure S1 in File S1.	('HER2', 'Gene', '2064', (31, 35))	('p63', 'Gene', '8626', (54, 57))	('Cleaved', 'Var', (62, 69))	('p16', 'Gene', (49, 52))	('Caspase-3', 'Gene', (70, 79))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('p16', 'Gene', '1029', (49, 52))	('Ki-67', 'Var', (37, 42))	('ER', 'Gene', '2099', (32, 34))	('ER', 'Gene', '2099', (23, 25))	('HER2', 'Gene', (31, 35))	('p63', 'Gene', (54, 57))	('PR', 'Gene', '5241', (27, 29))
25875	24978026	Lesions with p53 mutations, as indicated by the dark brown staining (Figure S1 in File S1), were also more likely to be ER- (P = 3.2x10-8).	('p53', 'Gene', '7157', (13, 16))	('mutations', 'Var', (17, 26))	('ER', 'Gene', '2099', (120, 122))	('p53', 'Gene', (13, 16))
25878	24978026	As shown in Table S2 in File S2, there is a positive correlation between Ki67 and Cleaved Caspase-3 staining (P<5x10-7).	('Cleaved Caspase-3', 'MPA', (82, 99))	('Ki67', 'Var', (73, 77))	('Ki67', 'Chemical', '-', (73, 77))
25886	24978026	This result indicates that those patients with a high level of marker heterogeneity may be more likely to have more aggressive or metastatic cancers that are difficult to treat.	('patients', 'Species', '9606', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('marker heterogeneity', 'Var', (63, 83))	('cancers', 'Disease', (141, 148))
25894	24978026	We then tested if any breast cancer markers, Ki-67, p16 or p53, have significant distribution differences among DCIS subgroups.	('tested', 'Reg', (8, 14))	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('breast cancer', 'Disease', (22, 35))	('p16', 'Gene', '1029', (52, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Ki-67', 'Var', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('p16', 'Gene', (52, 55))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
25899	24978026	A gradual improvement in AUC was observed with the inclusion of Ki67, either alone or in conjunction with p53 and/or p16, with the best performing model being that containing all markers [AUC = 0.82, 95% CI: (0.78,0.86)].	('improvement', 'PosReg', (10, 21))	('p53', 'Gene', '7157', (106, 109))	('Ki67', 'Chemical', '-', (64, 68))	('p16', 'Gene', '1029', (117, 120))	('AUC', 'MPA', (25, 28))	('p16', 'Gene', (117, 120))	('p53', 'Gene', (106, 109))	('Ki67', 'Var', (64, 68))
25907	24978026	Consistent with the breast cancer progression model of Welling and Jensen, results from the present study suggest that some (epi)genetic changes must arise in an early precursor cell and are inherited by daughter cells that become increasingly abnormal as they mature (i.e.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('changes', 'Var', (137, 144))
25910	24978026	Only those lesions with more aggressive characteristics, including but not limited to, high proliferation rate (high Ki-67), gain of mutant p53, and loss of the tumor suppressor p16, are favorable for breast cancer progression.	('loss of the tumor', 'Disease', 'MESH:D009369', (149, 166))	('p16', 'Gene', '1029', (178, 181))	('gain', 'PosReg', (125, 129))	('p16', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('high proliferation rate', 'CPA', (87, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (201, 214))	('mutant', 'Var', (133, 139))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('loss of the tumor', 'Disease', (149, 166))
25911	24978026	This data therefore suggests that those individuals with a heterogeneous DCIS cell population combined with high levels of Ki-67, increased mutant p53, and low p16 should be clinically managed more aggressively.	('p16', 'Gene', (160, 163))	('p16', 'Gene', '1029', (160, 163))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('p53', 'Gene', '7157', (147, 150))	('increased', 'PosReg', (130, 139))	('clinical', 'Species', '191496', (174, 182))	('low', 'NegReg', (156, 159))	('mutant', 'Var', (140, 146))	('p53', 'Gene', (147, 150))
25993	29295986	Following previous work, we found that in MMTV-HER2 early lesions there is a sub-population of HER2+/P-p38lo/P-ATF2lo/TWISThi/E-cadherinlo disseminating cancer cells that reach distant organs and initiate metastasis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('MMTV', 'Species', '11757', (42, 46))	('cancer', 'Disease', (153, 159))	('metastasis', 'CPA', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HER2+/P-p38lo/P-ATF2lo/TWISThi/E-cadherinlo', 'Var', (95, 138))
26006	29295986	Here we show that the branching morphogenesis program is altered by oncogenes early in cancer development.	('cancer', 'Disease', (87, 93))	('oncogenes', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('branching morphogenesis program', 'CPA', (22, 53))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('altered', 'Reg', (57, 64))
26026	29295986	The loss of E-cadherin junctions in Comma-1D cells induced by Raw264.7 macrophages was reversed by the addition of DKK1, an inhibitor of canonical Wnt signaling, to the co-cultures (Fig.	('Wnt', 'Gene', '7471;22408;22416;54361;7474;22418', (147, 150))	('Raw264.7', 'CellLine', 'CVCL:0493', (62, 70))	('Wnt', 'Gene', (147, 150))	('E-cadherin junctions', 'Protein', (12, 32))	('loss', 'NegReg', (4, 8))	('DKK1', 'Var', (115, 119))
26042	29295986	CSF1R blockade led to the depletion of tissue-resident CD11b+/F4/80+/Gr1- macrophages compared to PBS-treated and IgG-treated animals (Supplementary Fig.	('IgG', 'Gene', '16059', (114, 117))	('IgG', 'Gene', (114, 117))	('F4/80+', 'Gene', (62, 68))	('depletion of', 'MPA', (26, 38))	('blockade', 'Var', (6, 14))	('CSF1R', 'Gene', (0, 5))	('PBS', 'Chemical', '-', (98, 101))	('F4/80+', 'Gene', '13733', (62, 68))
26063	29295986	CSF1R blockade during early stages also caused a statistically significant (p = 0.039) decrease in the number of metachronous metastases per mouse (Fig.	('mouse', 'Species', '10090', (141, 146))	('metastases', 'Disease', (126, 136))	('blockade', 'Var', (6, 14))	('decrease', 'NegReg', (87, 95))	('CSF1R', 'Gene', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
26089	29295986	Q-RT-PCR of RNA isolated from FACS-sorted monocytes, macrophages, neutrophils, and HER2+ cancer cells during early stages of progression confirmed the CCL2 production by HER2+ early lesions (Supplementary Fig.	('CCL2 production', 'MPA', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('HER2+', 'Var', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
26096	29295986	However, systemic CCR2 inhibition did not reduce the number of early circulating cancer cells (eCCCs) (Fig.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('inhibition', 'Var', (23, 33))	('cancer', 'Disease', (81, 87))	('CCR2', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
26104	29295986	Additionally, within the same patient, individual lesions with high macrophage numbers had lower E-cadherin levels (Supplementary Fig.	('lower', 'NegReg', (91, 96))	('patient', 'Species', '9606', (30, 37))	('E-cadherin levels', 'MPA', (97, 114))	('high macrophage numbers', 'Var', (63, 86))
26107	29295986	Quantification of intra-lesion macrophages in HER2- or HER2+ DCIS lesions revealed no differences (Supplementary Fig.	('intra-lesion', 'Disease', 'MESH:D051437', (18, 30))	('HER2+', 'Var', (55, 60))	('HER2-', 'Var', (46, 51))	('intra-lesion', 'Disease', (18, 30))
26154	29295986	For CCR2 blockade, mice were either treated with 2 mg/kg of RS504393 (Tocris Bioscience) or vehicle control (dimethyl sulfoxide (DMSO)) daily by intraperitoneal injections for 14 days or by injection of 1 mg/kg RS504393 into the fat pad for 5 days.	('RS504393', 'Chemical', 'MESH:C579117', (211, 219))	('DMSO', 'Chemical', 'MESH:D004121', (129, 133))	('CCR2', 'Gene', (4, 8))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (109, 127))	('RS504393', 'Var', (60, 68))	('Tocris Bioscience', 'Disease', (70, 87))	('Tocris Bioscience', 'Disease', 'None', (70, 87))	('mice', 'Species', '10090', (19, 23))	('RS504393', 'Chemical', 'MESH:C579117', (60, 68))
26202	29295986	For inhibitory treatments, 5-day-old acini cultures were treated for 24 h with 1 muM lapatinib (LC Laboratories), 2 muM IKK inhibitor (generous gift from Dr. Albert Baldwin), 1 muM CCR2 inhibitor RS504393 (Tocris Bioscience) or DMSO as vehicle control.	('DMSO', 'Chemical', 'MESH:D004121', (228, 232))	('rat', 'Species', '10116', (103, 106))	('muM', 'Gene', (116, 119))	('RS504393', 'Chemical', 'MESH:C579117', (196, 204))	('muM', 'Gene', '56925', (177, 180))	('muM', 'Gene', '56925', (81, 84))	('Tocris Bioscience', 'Disease', (206, 223))	('Tocris Bioscience', 'Disease', 'None', (206, 223))	('RS504393', 'Var', (196, 204))	('muM', 'Gene', (177, 180))	('lapatinib', 'Chemical', 'MESH:D000077341', (85, 94))	('muM', 'Gene', '56925', (116, 119))	('muM', 'Gene', (81, 84))
26240	31842685	For example, epigenetic readers MDB3 and MeCP2 show preferential specificity for 5hmC, and both have important roles in transcriptional regulation.	('5hmC', 'Disease', (81, 85))	('MDB3', 'Gene', (32, 36))	('specificity', 'MPA', (65, 76))	('epigenetic readers', 'Var', (13, 31))	('5hmC', 'Chemical', 'MESH:C011865', (81, 85))	('MeCP2', 'Gene', '4204', (41, 46))	('roles', 'Reg', (111, 116))	('MeCP2', 'Gene', (41, 46))
26246	31842685	Emerging evidence also suggests dysregulation of 5hmC abundance may actively contribute to human cancer2.	('dysregulation', 'Var', (32, 45))	('cancer', 'Disease', (97, 103))	('contribute', 'Reg', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('5hmC', 'Chemical', 'MESH:C011865', (49, 53))	('5hmC', 'Protein', (49, 53))	('human', 'Species', '9606', (91, 96))
26247	31842685	Global reduction of 5hmC is observed among cancers of diverse tissues, including breast cancer, and maintenance of 5hmC protects against characteristic cancer-associated CpG island hypermethylation.	('cancer', 'Disease', (88, 94))	('breast cancer', 'Disease', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('hypermethylation', 'Var', (181, 197))	('CpG', 'Var', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('5hmC', 'Chemical', 'MESH:C011865', (20, 24))	('5hmC', 'Chemical', 'MESH:C011865', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('reduction', 'NegReg', (7, 16))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
26251	31842685	Collectively, these observations suggest dysregulation of 5hmC may contribute to breast cancer: however, the detailed reference maps of 5hmC in normal breast tissues required to test this hypothesis are not yet available.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))	('dysregulation', 'Var', (41, 54))	('5hmC', 'Chemical', 'MESH:C011865', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('5hmC', 'Chemical', 'MESH:C011865', (58, 62))	('contribute', 'Reg', (67, 77))
26267	31842685	Variation in cell-type composition of heterogeneous tissues is known to be a potential confounder in epigenomic studies and could impact 5hmC levels.	('5hmC levels', 'MPA', (137, 148))	('Variation', 'Var', (0, 9))	('impact', 'Reg', (130, 136))	('5hmC', 'Chemical', 'MESH:C011865', (137, 141))
26288	31842685	cg16398761 (C14orf43/ELM2), cg25252585 (FXYDY), and cg04403423 (ATP1A1) represented the three individual CpG loci with the most abundant 5hmC (median beta-values 0.310, 0.296, and 0.294 (Figure 2(b))), respectively.	('ATP1A1', 'Gene', '476', (64, 70))	('C14orf43', 'Gene', (12, 20))	('cg25252585', 'Chemical', '-', (28, 38))	('ATP1A1', 'Gene', (64, 70))	('cg25252585', 'Var', (28, 38))	('cg04403423', 'Var', (52, 62))	('5hmC', 'Chemical', 'MESH:C011865', (137, 141))	('cg16398761', 'Var', (0, 10))	('C14orf43', 'Gene', '91748', (12, 20))
26301	31842685	Among repetitive DNA elements, 5hmC demonstrated a significant enrichment at SINE and LINE elements, as well as a depletion among low complexity and simple repeats (Supplementary Figure 5).	('5hmC', 'Chemical', 'MESH:C011865', (31, 35))	('SINE', 'Var', (77, 81))	('simple repeats', 'Var', (149, 163))	('low complexity', 'Var', (130, 144))
26305	31842685	In contrast, all seven regions associated with transcriptional inactivity were strongly depleted for 5hmC (Figure 3(c)).	('5hmC', 'Chemical', 'MESH:C011865', (101, 105))	('5hmC', 'Var', (101, 105))	('depleted', 'NegReg', (88, 96))
26316	31842685	Enrichment was also observed for several molecular function gene sets related to binding and activity of TGF-beta (Supplementary Data 5), supporting the observation that five of the high 5hmC CpGs were located within the gene body of TGFBR2 (Supplementary Data 5).	('5hmC', 'Chemical', 'MESH:C011865', (187, 191))	('TGFBR2', 'Gene', (234, 240))	('TGF-beta', 'Gene', (105, 113))	('CpGs', 'Var', (192, 196))	('TGFBR2', 'Gene', '7048', (234, 240))	('TGF-beta', 'Gene', '7039', (105, 113))
26321	31842685	We observed a significant positive enrichment for genes associated with high 5hmC loci among transcripts assigned to the 'high' expression group (OR, 2.1; 95% CI, 1.95-2.27; P-value, 2.1E-11; Supplementary Table 2).	('5hmC', 'Chemical', 'MESH:C011865', (77, 81))	('high', 'Var', (72, 76))	('5hmC', 'Gene', (77, 81))
26325	31842685	Among the most statistically significant correlations were those of cg23267550 and cg01915609 with RAB32 expression for both 5hmC and 5mC (Figure 4(d,e)).	('5hmC', 'Chemical', 'MESH:C011865', (125, 129))	('RAB32', 'Gene', '10981', (99, 104))	('RAB32', 'Gene', (99, 104))	('cg01915609', 'Var', (83, 93))	('5mC', 'Chemical', 'MESH:D044503', (134, 137))	('correlations', 'Interaction', (41, 53))	('expression', 'MPA', (105, 115))	('cg23267550', 'Var', (68, 78))
26336	31842685	Epigenetic deregulation is an early event in carcinogenesis.	('carcinogenesis', 'Disease', (45, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('Epigenetic deregulation', 'Var', (0, 23))
26338	31842685	To assess the potential contribution of 5hmC to breast carcinogenesis, we utilized available data describing regulatory regions present in variant human mammary epithelial cells (vHMECs), proliferative clones of HMECs that invariably result during cell culture, and share several phenotypes with premalignant breast cancers.	('premalignant breast cancers', 'Disease', 'MESH:D001943', (296, 323))	('breast carcinogenesis', 'Disease', 'MESH:D001943', (48, 69))	('breast cancers', 'Phenotype', 'HP:0003002', (309, 323))	('human', 'Species', '9606', (147, 152))	('variant', 'Var', (139, 146))	('5hmC', 'Chemical', 'MESH:C011865', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('premalignant breast cancers', 'Disease', (296, 323))	('breast carcinogenesis', 'Disease', (48, 69))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))
26339	31842685	Specifically, we identified chromatin states (defined using the core 15-state ChromHMM model) that were non-overlapping between parental HMECs and variant HMECs (that is, chromatin states lost or gained during the progression from HMEC to vHMEC).	('gained', 'PosReg', (196, 202))	('variant HMECs', 'CellLine', 'CVCL:0307', (147, 160))	('variant', 'Var', (147, 154))	('chromatin states', 'MPA', (171, 187))	('lost', 'NegReg', (188, 192))
26345	31842685	These data suggest sites with high 5hmC in normal breast tissue are enriched among regions of transcriptionally active chromatin that may become altered during transformation, indicating dysregulation of 5hmC abundance at these loci may contribute to this process.	('dysregulation', 'Var', (187, 200))	('contribute', 'Reg', (237, 247))	('5hmC', 'Chemical', 'MESH:C011865', (35, 39))	('5hmC', 'Chemical', 'MESH:C011865', (204, 208))
26356	31842685	In the comparison of DCIS to normal DNA methylation analysis, high 5hmC CpG sites identified in normal breast again had a distribution of P-values significantly lower than randomly selected CpGs (P= 0.017, Table 3, Supplementary Figure 11).	('lower', 'NegReg', (161, 166))	('5hmC', 'Chemical', 'MESH:C011865', (67, 71))	('sites', 'Var', (76, 81))
26357	31842685	Together these results suggest 5hmC dysregulation may contribute to breast cancer development, and an appreciable fraction of the changes may occur early in the carcinogenic process.	('dysregulation', 'Var', (36, 49))	('5hmC', 'Chemical', 'MESH:C011865', (31, 35))	('carcinogenic', 'Disease', 'MESH:D063646', (161, 173))	('5hmC', 'Gene', (31, 35))	('contribute', 'Reg', (54, 64))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('carcinogenic', 'Disease', (161, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
26363	31842685	Furthermore, we provide evidence suggesting deregulation of 5hmC at these loci may contribute to breast carcinogenesis.	('breast carcinogenesis', 'Disease', 'MESH:D001943', (97, 118))	('5hmC', 'Chemical', 'MESH:C011865', (60, 64))	('5hmC', 'Protein', (60, 64))	('breast carcinogenesis', 'Disease', (97, 118))	('deregulation', 'Var', (44, 56))	('contribute', 'Reg', (83, 93))
26377	31842685	Mobilization of repetitive DNA elements due to loss of 5mC is known to contribute to carcinogenic processes, therefore understanding the function of 5hmC during these processes is required to more completely understand the roles of repetitive elements in cancer.	('5hmC', 'Chemical', 'MESH:C011865', (149, 153))	('5mC', 'Chemical', 'MESH:D044503', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('contribute', 'Reg', (71, 81))	('carcinogenic', 'Disease', 'MESH:D063646', (85, 97))	('5mC', 'Protein', (55, 58))	('carcinogenic', 'Disease', (85, 97))	('loss', 'Var', (47, 51))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('Mobilization', 'MPA', (0, 12))
26384	31842685	Emerging evidence suggests changes in 5hmC abundance regulates oncogenic processes in cancer, as has been observed in pancreatic ductal adenocarcinoma, glioblastoma, and breast tumor initiating cells.	('breast tumor', 'Phenotype', 'HP:0100013', (170, 182))	('regulates', 'Reg', (53, 62))	('breast tumor', 'Disease', (170, 182))	('oncogenic processes', 'CPA', (63, 82))	('changes', 'Var', (27, 34))	('5hmC', 'Chemical', 'MESH:C011865', (38, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('cancer', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (118, 150))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('glioblastoma', 'Disease', (152, 164))	('pancreatic ductal adenocarcinoma', 'Disease', (118, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('breast tumor', 'Disease', 'MESH:D001943', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('5hmC', 'Protein', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (118, 150))
26385	31842685	The identification of several oncogenes and tumor suppressor genes associated with several CpG loci with abundant 5hmC in normal breast tissues supports the hypothesis that deregulation of 5hmC could contribute to oncogenic processes.	('5hmC', 'Chemical', 'MESH:C011865', (114, 118))	('CpG', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('deregulation', 'Var', (173, 185))	('oncogenic processes', 'CPA', (214, 233))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('5hmC', 'Chemical', 'MESH:C011865', (189, 193))	('tumor', 'Disease', (44, 49))	('contribute', 'Reg', (200, 210))
26389	31842685	Recently, downregulation of Sept9_i2 via promoter hypermethylation was observed in breast cancer cell lines, suggesting potential tumor suppressive functions.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('Sept9_i2', 'Gene', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('downregulation', 'NegReg', (10, 24))	('promoter hypermethylation', 'Var', (41, 66))	('tumor', 'Disease', (130, 135))
26397	31842685	Furthermore, our observation that the high 5hmC CpGs identified in this cohort are enriched among differentially methylated loci between normal and malignant tissue from several intrinsic breast cancer subtypes, as well as differentially methylated loci between normal and pre-invasive tissues (ductal carcinoma in-situ), supports the hypothesis that alterations in 5hmC contribute to breast cancer pathogenesis, and that a portion of these alterations may occur in early stages of carcinogenesis.	('alterations', 'Var', (351, 362))	('carcinogenesis', 'Disease', 'MESH:D063646', (482, 496))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('ductal carcinoma', 'Disease', 'MESH:D044584', (295, 311))	('carcinogenesis', 'Disease', (482, 496))	('ductal carcinoma', 'Disease', (295, 311))	('breast cancer', 'Disease', (188, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('breast cancer', 'Disease', 'MESH:D001943', (385, 398))	('5hmC', 'Chemical', 'MESH:C011865', (366, 370))	('5hmC', 'Chemical', 'MESH:C011865', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('breast cancer', 'Disease', (385, 398))	('contribute', 'Reg', (371, 381))	('breast cancer', 'Phenotype', 'HP:0003002', (385, 398))	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (295, 319))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
26407	31842685	Additionally, we provide evidence that dysregulation of 5hmC in breast tissue may contribute to carcinogenesis.	('5hmC', 'Chemical', 'MESH:C011865', (56, 60))	('dysregulation', 'Var', (39, 52))	('5hmC', 'Protein', (56, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('contribute', 'Reg', (82, 92))	('carcinogenesis', 'Disease', (96, 110))
26425	31842685	The GenomicRanges R/Bioconductor package was used to construct contingency tables describing the overlap between genomic coordinates of high 5hmC CpGs and the described transcriptional features, stratified by CpG island context.	('high', 'Var', (136, 140))	('CpGs', 'Gene', (146, 150))	('5hmC', 'Chemical', 'MESH:C011865', (141, 145))
26432	31842685	Enrichment for transcripts associated with high 5hmC CpG loci, among highly expressed genes, was tested using a Fisher's exact test.	('5hmC', 'Gene', (48, 52))	('5hmC', 'Chemical', 'MESH:C011865', (48, 52))	('high', 'Var', (43, 47))
26440	32182822	Loss of Y-Chromosome during Male Breast Carcinogenesis Loss of Y-chromosome (LOY) is associated with increased cancer mortality in males.	('Loss', 'Var', (55, 59))	('Male Breast Carcinogenesis', 'Disease', (28, 54))	('cancer mortality', 'Disease', (111, 127))	('cancer mortality', 'Disease', 'MESH:D003643', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Male Breast Carcinogenesis', 'Disease', 'MESH:D018567', (28, 54))
26450	32182822	Loss of Y-chromosome (LOY) has previously been described in several solid tumors, including esophageal carcinoma, pancreatic cancer, urothelial bladder cancer, colorectal cancer, and prostate cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('colorectal cancer', 'Disease', (160, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (92, 112))	('Y-chromosome', 'Protein', (8, 20))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (133, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (183, 198))	('prostate cancer', 'Phenotype', 'HP:0012125', (183, 198))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('esophageal carcinoma', 'Disease', (92, 112))	('prostate cancer', 'Disease', (183, 198))	('urothelial bladder cancer', 'Disease', (133, 158))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (92, 112))	('pancreatic cancer', 'Disease', (114, 131))	('tumors', 'Disease', (74, 80))
26452	32182822	They suggested that LOY could lead to the loss of a candidate tumor suppressor gene (TMSB4Y), resulting in increased cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('increased', 'PosReg', (107, 116))	('TMSB4Y', 'Gene', (85, 91))	('tumor', 'Disease', (62, 67))	('cell proliferation', 'CPA', (117, 135))	('TMSB4Y', 'Gene', '9087', (85, 91))	('LOY', 'Var', (20, 23))	('loss', 'NegReg', (42, 46))
26454	32182822	In the peripheral blood of males, LOY has been reported to be associated with an increased risk of all-cause mortality and non-hematological cancer mortality.	('mortality', 'Disease', (148, 157))	('mortality', 'Disease', 'MESH:D003643', (109, 118))	('cancer mortality', 'Disease', (141, 157))	('cancer mortality', 'Disease', 'MESH:D003643', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('hematological cancer', 'Phenotype', 'HP:0004377', (127, 147))	('mortality', 'Disease', 'MESH:D003643', (148, 157))	('mortality', 'Disease', (109, 118))	('LOY', 'Var', (34, 37))
26482	32182822	Additionally, the presence of LOY in peripheral blood was also recently associated with all-cause mortality and non-hematological cancer mortality.	('presence', 'Var', (18, 26))	('hematological cancer', 'Phenotype', 'HP:0004377', (116, 136))	('all-cause', 'Disease', (88, 97))	('mortality', 'Disease', (137, 146))	('mortality', 'Disease', (98, 107))	('associated', 'Reg', (72, 82))	('LOY', 'Var', (30, 33))	('cancer mortality', 'Disease', (130, 146))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer mortality', 'Disease', 'MESH:D003643', (130, 146))	('mortality', 'Disease', 'MESH:D003643', (98, 107))	('mortality', 'Disease', 'MESH:D003643', (137, 146))
26487	32182822	This early role for LOY in male carcinogenesis was also previously suggested by Wong and colleagues.	('male carcinogenesis', 'Disease', 'MESH:D018567', (27, 46))	('male carcinogenesis', 'Disease', (27, 46))	('LOY', 'Var', (20, 23))
26488	32182822	Using a functional assay, they showed that clonal LOY contributes to breast carcinogenesis through the deletion of a Y-chromosome expressed tumor suppressor gene.	('breast carcinogenesis', 'Disease', 'MESH:D001943', (69, 90))	('tumor', 'Disease', (140, 145))	('breast carcinogenesis', 'Disease', (69, 90))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deletion', 'Var', (103, 111))
26489	32182822	Together with our data, showing an early LOY, this suggests that LOY might contribute to male breast carcinogenesis through dysregulation of the cell proliferation and differentiation mechanism.	('contribute', 'Reg', (75, 85))	('male breast carcinogenesis', 'Disease', (89, 115))	('cell proliferation', 'CPA', (145, 163))	('male breast carcinogenesis', 'Disease', 'MESH:D018567', (89, 115))	('LOY', 'Var', (65, 68))
26505	32182822	Selected cores were manually scored using Inform (Akoya biosciences, Malborough, MA, USA), whereby LOY was defined as the absence of Y-chromosome in at least 75% of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('LOY', 'Var', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
26518	27553211	In contrast, short hairpin RNA-mediated knockdown of TBX3 in the 21MT-1 cells resulted in smaller colonies, with a more regular, less dispersed (less infiltrative) morphology.	('MT-1', 'CellLine', 'CVCL:6F14', (67, 71))	('more', 'PosReg', (115, 119))	('TBX3', 'Gene', (53, 57))	('knockdown', 'Var', (40, 49))	('smaller', 'NegReg', (90, 97))	('less dispersed', 'CPA', (129, 143))	('colonies', 'CPA', (98, 106))
26519	27553211	Array profiling of the 21NT TBX3 iso1 and iso2 transfectants showed that there are common alterations in expression of several genes involved in signal transduction, cell cycle control/cell survival, epithelial-mesenchymal transition and invasiveness.	('transfectants', 'Var', (47, 60))	('alterations', 'Reg', (90, 101))	('iso1', 'Gene', (33, 37))	('invasiveness', 'CPA', (238, 250))	('epithelial-mesenchymal', 'CPA', (200, 222))	('expression', 'Species', '29278', (105, 115))	('cell cycle', 'CPA', (166, 176))	('expression', 'MPA', (105, 115))	('TBX3', 'Gene', (28, 32))	('iso1', 'Gene', '10209', (33, 37))
26520	27553211	Overall, these results indicate that TBX3 (isoform 1 or 2) expression can promote progression in a model of early breast cancer by altering cell properties involved in cell survival/colony formation and invasiveness, as well as key regulatory and EMT/invasiveness-related gene expressions.	('cell properties', 'MPA', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('promote', 'PosReg', (74, 81))	('TBX3', 'Gene', (37, 41))	('expression', 'Species', '29278', (59, 69))	('altering', 'Reg', (131, 139))	('expression', 'Species', '29278', (277, 287))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('expression', 'Var', (59, 69))	('breast cancer', 'Disease', (114, 127))
26526	27553211	In humans, Ulnar-mammary syndrome, a congenital autosomal dominant disorder, is caused by mutations that result in haploinsufficiency of TBX3 and is characterized by upper-limb anomalies and mammary gland hypoplasia.	('congenital autosomal dominant disorder', 'Disease', 'MESH:D009358', (37, 75))	('caused by', 'Reg', (80, 89))	('mutations', 'Var', (90, 99))	('upper-limb anomalies', 'Disease', (166, 186))	('Ulnar-mammary syndrome', 'Disease', (11, 33))	('haploinsufficiency of TBX3', 'Disease', (115, 141))	('limb anomalies', 'Phenotype', 'HP:0040064', (172, 186))	('gland hypoplasia', 'Disease', (199, 215))	('humans', 'Species', '9606', (3, 9))	('haploinsufficiency of TBX3', 'Disease', 'MESH:D058495', (115, 141))	('gland hypoplasia', 'Disease', 'MESH:D010900', (199, 215))	('upper-limb anomalies', 'Disease', 'MESH:D038062', (166, 186))	('upper-limb anomalies', 'Phenotype', 'HP:0002817', (166, 186))	('congenital autosomal dominant disorder', 'Disease', (37, 75))
26534	27553211	The TBX3iso2 variant has an extra 20 amino acids, encoded by exon 2a, inserted into the T-box domain.	('TBX3iso2', 'Gene', '6926', (4, 12))	('variant', 'Var', (13, 20))	('TBX3iso2', 'Gene', (4, 12))
26561	27553211	The TBX3 shRNA lentivirus particles generated were used to knockdown TBX3 in the 21MT-1 cell line and Luciferase shRNA was used a negative control.	('knockdown', 'Var', (59, 68))	('MT-1', 'CellLine', 'CVCL:6F14', (83, 87))	('TBX3', 'Gene', (69, 73))
26580	27553211	RNA was isolated from TBX3iso1 and TBX3iso2 transfectants, as well as vector controls, using the RNeasy Mini Kit (Qiagen).	('iso1', 'Gene', '10209', (26, 30))	('TBX3iso', 'Gene', (35, 42))	('transfectants', 'Var', (44, 57))	('TBX3iso2', 'Gene', '6926', (35, 43))	('TBX3iso', 'Gene', '6926', (22, 29))	('iso1', 'Gene', (26, 30))	('TBX3iso', 'Gene', (22, 29))	('TBX3iso', 'Gene', '6926', (35, 42))	('TBX3iso2', 'Gene', (35, 43))
26589	27553211	Similarly, both TBX3iso1 and TBX3iso2 were found to be expressed at higher levels in 21MT-1 than in 21PT or 21NT cells (Fig.	('TBX3iso', 'Gene', '6926', (16, 23))	('TBX3iso', 'Gene', '6926', (29, 36))	('TBX3iso2', 'Gene', (29, 37))	('TBX3iso', 'Gene', (16, 23))	('higher', 'PosReg', (68, 74))	('TBX3iso', 'Gene', (29, 36))	('iso1', 'Gene', '10209', (20, 24))	('MT-1', 'CellLine', 'CVCL:6F14', (87, 91))	('21MT-1', 'Var', (85, 91))	('TBX3iso2', 'Gene', '6926', (29, 37))	('iso1', 'Gene', (20, 24))
26594	27553211	Total TBX3 mRNA was increased (at least 6-fold) in both 21NT + TBX3iso1 and 21NT + TBX3iso2 transfectants (Fig.	('TBX3', 'Gene', (6, 10))	('increased', 'PosReg', (20, 29))	('TBX3iso', 'Gene', (63, 70))	('TBX3iso', 'Gene', (83, 90))	('transfectants', 'Var', (92, 105))	('TBX3iso2', 'Gene', '6926', (83, 91))	('TBX3iso2', 'Gene', (83, 91))	('TBX3iso', 'Gene', '6926', (63, 70))	('TBX3iso', 'Gene', '6926', (83, 90))
26598	27553211	TBX3 overexpression increased the colony formation of the 21NT cells in a 3D Matrigel system from 55 % for the empty vector controls to 66 % for the 21NT + TBX3iso1 cells and 63 % for the 21NT + TBX3iso2 cells (Fig.	('increased', 'PosReg', (20, 29))	('TBX3iso', 'Gene', '6926', (156, 163))	('TBX3iso2', 'Gene', '6926', (195, 203))	('iso1', 'Gene', (160, 164))	('TBX3iso', 'Gene', (156, 163))	('expression', 'Species', '29278', (9, 19))	('overexpression', 'Var', (5, 19))	('TBX3iso', 'Gene', '6926', (195, 202))	('TBX3', 'Gene', (0, 4))	('colony formation of', 'CPA', (34, 53))	('TBX3iso2', 'Gene', (195, 203))	('iso1', 'Gene', '10209', (160, 164))	('TBX3iso', 'Gene', (195, 202))
26600	27553211	TBX3 overexpression also increased the number of nuclei per colony after 9 days from 34 nuclei per colony for the empty vector control to 97 nuclei per colony for the 21NT + TBX3iso1 cells and 89 nuclei per colony for the 21NT + TBX3iso2 cells (Fig.	('TBX3iso', 'Gene', '6926', (229, 236))	('increased', 'PosReg', (25, 34))	('TBX3iso2', 'Gene', (229, 237))	('TBX3iso', 'Gene', '6926', (174, 181))	('iso1', 'Gene', '10209', (178, 182))	('expression', 'Species', '29278', (9, 19))	('TBX3iso', 'Gene', (229, 236))	('TBX3iso', 'Gene', (174, 181))	('TBX3', 'Gene', (0, 4))	('overexpression', 'Var', (5, 19))	('TBX3iso2', 'Gene', '6926', (229, 237))	('iso1', 'Gene', (178, 182))
26602	27553211	3g) expression for both TBX3iso1 and TBX3iso2 transfectants vs. the negative control, resulting in an increase in the proliferation to apoptosis (Ki67/cleaved caspase 3) ratio for both TBX3 transfectants (Fig.	('TBX3iso', 'Gene', (24, 31))	('expression', 'Species', '29278', (4, 14))	('TBX3iso', 'Gene', '6926', (37, 44))	('Ki67', 'Gene', '17345', (146, 150))	('proliferation', 'CPA', (118, 131))	('TBX3iso2', 'Gene', (37, 45))	('TBX3iso', 'Gene', '6926', (24, 31))	('TBX3iso', 'Gene', (37, 44))	('increase', 'PosReg', (102, 110))	('TBX3iso2', 'Gene', '6926', (37, 45))	('transfectants', 'Var', (46, 59))	('Ki67', 'Gene', (146, 150))	('TBX3', 'Gene', (185, 189))
26604	27553211	TBX3 (iso1 and iso2) overexpression increased the 21NT cell's ability to both migrate over gelatin (Fig.	('expression', 'Species', '29278', (25, 35))	('overexpression', 'Var', (21, 35))	('iso1', 'Gene', '10209', (6, 10))	('increased', 'PosReg', (36, 45))	('TBX3', 'Gene', (0, 4))	('iso1', 'Gene', (6, 10))
26625	27553211	As we saw no difference in functional effect, our analysis here was focused on gene expression alterations occurring in common between the two isoforms, which could potentially explain characteristics of the more aggressive phenotype seen in both TBX3iso1 and TBX3iso2 transfectants.	('TBX3iso2', 'Gene', '6926', (260, 268))	('TBX3iso', 'Gene', '6926', (260, 267))	('iso1', 'Gene', '10209', (251, 255))	('TBX3iso', 'Gene', '6926', (247, 254))	('expression', 'Species', '29278', (84, 94))	('transfectants', 'Var', (269, 282))	('TBX3iso', 'Gene', (260, 267))	('TBX3iso2', 'Gene', (260, 268))	('iso1', 'Gene', (251, 255))	('TBX3iso', 'Gene', (247, 254))
26627	27553211	Gene expression profiling of the TBX3 transfectants in our study showed altered expression of several genes potentially involved in these processes in both TBX3iso1 and TBX3iso2 transfected cells (i.e.	('TBX3iso', 'Gene', '6926', (156, 163))	('altered', 'Reg', (72, 79))	('TBX3', 'Gene', (33, 37))	('TBX3iso', 'Gene', (169, 176))	('TBX3iso2', 'Gene', (169, 177))	('TBX3iso', 'Gene', (156, 163))	('transfectants', 'Var', (38, 51))	('expression', 'Species', '29278', (80, 90))	('expression', 'MPA', (80, 90))	('TBX3iso2', 'Gene', '6926', (169, 177))	('TBX3iso', 'Gene', '6926', (169, 176))	('expression', 'Species', '29278', (5, 15))
26631	27553211	Another prominent aspect of the altered phenotype seen with both TBX3iso1 and TBX3iso2 transfectants of 21NT cells was a more irregular/dispersed colony morphology in 3D Matrigel, with increased cellular invasiveness in transwell assays, suggestive of an EMT effect.	('TBX3iso2', 'Gene', '6926', (78, 86))	('TBX3iso', 'Gene', (65, 72))	('cellular invasiveness in transwell assays', 'CPA', (195, 236))	('TBX3iso', 'Gene', '6926', (78, 85))	('TBX3iso2', 'Gene', (78, 86))	('transfectants', 'Var', (87, 100))	('iso1', 'Gene', '10209', (69, 73))	('TBX3iso', 'Gene', '6926', (65, 72))	('TBX3iso', 'Gene', (78, 85))	('more', 'PosReg', (121, 125))	('increased', 'PosReg', (185, 194))	('iso1', 'Gene', (69, 73))
26636	27553211	In addition, knockdown of TBX3 in invasive (21MT-1) cells can revert them to a less aggressive phenotype, with less potential for 3D growth and a less infiltrative phenotype.	('TBX3', 'Gene', (26, 30))	('less aggressive phenotype', 'MPA', (79, 104))	('MT-1', 'CellLine', 'CVCL:6F14', (46, 50))	('knockdown', 'Var', (13, 22))	('less infiltrative phenotype', 'CPA', (146, 173))	('less', 'NegReg', (111, 115))
26642	27553211	The recent finding that TBX3 alterations may be key driver mutations in breast cancer, and the suggestion that altered (probably increased) TBX3 function may be associated with at least some cases of familial breast cancer, adds particular significance to the potential of TBX3 as an important regulator of breast cancer progression, and added urgency to a better understanding of its role in the malignancy of breast cancer.	('associated', 'Reg', (161, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (411, 424))	('alterations', 'Var', (29, 40))	('altered', 'Var', (111, 118))	('TBX3', 'Gene', (140, 144))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (307, 320))	('breast cancer', 'Disease', (72, 85))	('function', 'MPA', (145, 153))	('added urgency', 'Phenotype', 'HP:0000012', (338, 351))	('breast cancer', 'Disease', 'MESH:D001943', (411, 424))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', 'MESH:D001943', (307, 320))	('increased', 'PosReg', (129, 138))	('breast cancer', 'Disease', (307, 320))	('malignancy of breast cancer', 'Disease', 'MESH:D001943', (397, 424))	('familial breast cancer', 'Disease', 'MESH:D001943', (200, 222))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('familial breast cancer', 'Disease', (200, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('TBX3', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (418, 424))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('malignancy of breast cancer', 'Disease', (397, 424))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('malignancy of breast', 'Phenotype', 'HP:0100013', (397, 417))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
26712	28199152	The spectrum of microcalcification features that could represent DCIS as reflected in the BI-RADS lexicon covers a rather large associated likelihood of malignancy, ranging from 13% for coarse heterogeneous to nearly 70% for fine linear or fine-linear branching microcalcifications.	('calcification', 'Disease', (21, 34))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('calcification', 'Disease', 'MESH:D002114', (267, 280))	('malignancy', 'Disease', 'MESH:D009369', (153, 163))	('fine linear', 'Var', (225, 236))	('malignancy', 'Disease', (153, 163))	('calcification', 'Disease', (267, 280))	('fine-linear branching', 'Var', (240, 261))	('calcification', 'Disease', 'MESH:D002114', (21, 34))
26758	12927036	Although it is clear that LCIS is not an obligate precursor to invasive lobular carcinoma, many studies have shown that a proportion of women with LCIS go on to develop invasive carcinoma, with a risk of 6.9 times to about 12 times that of women without LCIS.	('develop', 'PosReg', (161, 168))	('invasive lobular carcinoma', 'Disease', (63, 89))	('LCIS', 'Phenotype', 'HP:0030076', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('LCIS', 'Phenotype', 'HP:0030076', (147, 151))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (63, 89))	('LCIS', 'Phenotype', 'HP:0030076', (254, 258))	('invasive carcinoma', 'Disease', (169, 187))	('LCIS', 'Var', (147, 151))	('women', 'Species', '9606', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('women', 'Species', '9606', (240, 245))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (72, 89))	('invasive carcinoma', 'Disease', 'MESH:D009361', (169, 187))
26761	12927036	Data accumulated from nine separate studies revealed that 15% of 172 patients diagnosed with LCIS developed invasive carcinoma in the ipsilateral breast, and 9.3% of 204 patients developed invasive carcinoma in the contralateral breast.	('patients', 'Species', '9606', (170, 178))	('invasive carcinoma', 'Disease', (189, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('patients', 'Species', '9606', (69, 77))	('invasive carcinoma', 'Disease', (108, 126))	('LCIS', 'Phenotype', 'HP:0030076', (93, 97))	('invasive carcinoma', 'Disease', 'MESH:D009361', (189, 207))	('LCIS', 'Var', (93, 97))	('developed', 'Reg', (98, 107))	('invasive carcinoma', 'Disease', 'MESH:D009361', (108, 126))
26776	33824323	Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('influences', 'Reg', (186, 196))	('tumor', 'Disease', (39, 44))	('mutations', 'Var', (217, 226))
26788	33824323	The heterogeneous collection of tens of thousands of somatic alterations may be classified into drivers (conferring advantageous, cancerous phenotypes to neoplastic cells) and passengers (neutral, nearly-neutral, or slightly deleterious mutations).	('cancerous', 'Disease', 'MESH:D009369', (130, 139))	('cancerous', 'Disease', (130, 139))	('alterations', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('advantageous', 'PosReg', (116, 128))
26789	33824323	Highly deleterious mutations are subject to negative selection and are removed from the population, while moderately deleterious mutations can evade purifying selection to remain present in an evolving tumor under selection pressure, a process known as "hitchhiking" with the sweeping driver clone.	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('mutations', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (202, 207))
26794	33824323	This evolutionary bottleneck establishes key driver mutations in the invasive parental clone, which are the ubiquitous mutations measured during the neutral phase of tumor growth.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))
26806	33824323	Cells begin each simulation with a single driver mutation, where each subsequent driver increases the birth rate (i.e., multiplicative epistasis) by a factor of a fitness advantage parameter, sd.	('fitness', 'Disease', 'MESH:D012640', (163, 170))	('mutation', 'Var', (49, 57))	('birth rate', 'CPA', (102, 112))	('increases', 'PosReg', (88, 97))	('fitness', 'Disease', (163, 170))
26818	33824323	Conversely, "Darwinian" tumors sweep each new driver mutation through the population, resulting in a vertical trajectory (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutation', 'Var', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('vertical trajectory', 'MPA', (101, 120))
26839	33824323	3g-l; see 'Methods') by performing 10,000 stochastic simulations for a range of driver mutation rates (mud   [10-7, 1]) and fitness (sd   [10-3, 10]).	('fitness', 'Disease', 'MESH:D012640', (124, 131))	('mutation', 'Var', (87, 95))	('fitness', 'Disease', (124, 131))
26853	33824323	Neutral evolution has previously been quantified using the distribution of the cumulative number of mutations in the tumor with respect to inverse allelic frequency (1/f power-law distribution).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (100, 109))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
26876	33824323	where a driver mutation is a rare event with confers a fitness advantage to birth rate known as sd and a passenger mutation is a relatively common event that confers some fitness penalty, sp.	('fitness', 'Disease', (55, 62))	('mutation', 'Var', (15, 23))	('fitness', 'Disease', 'MESH:D012640', (55, 62))	('advantage', 'PosReg', (63, 72))	('fitness', 'Disease', (171, 178))	('fitness', 'Disease', 'MESH:D012640', (171, 178))
26880	33824323	Model parameterizations were performed by simulating 10,000 stochastic realizations of the mathematical model for a range of driver mutation rates (mud   [10-8, 1]) and fitness (sd   [10-3, 10]), with constant passenger fitness (sp = 10-3) and rate (mup = Tpmu = 10610-8 = 10-2) and spatial location (z = 75%).	('fitness', 'Disease', (169, 176))	('fitness', 'Disease', 'MESH:D012640', (169, 176))	('mutation', 'Var', (132, 140))	('fitness', 'Disease', (220, 227))	('fitness', 'Disease', 'MESH:D012640', (220, 227))
26898	28604616	The impact of these variations has functional implications as they dictate the specificity of multivalent glycan binding.	('variations', 'Var', (20, 30))	('glycan', 'Chemical', 'MESH:D011134', (106, 112))	('dictate', 'Reg', (67, 74))	('specificity', 'MPA', (79, 90))	('binding', 'Interaction', (113, 120))
26923	28604616	Although glycan structures present in glycoproteins are known to have N and O linked oligosaccharides, desialylation of the glycan can result in an increase or decrease in lectin binding affinity.	('decrease', 'NegReg', (160, 168))	('increase', 'PosReg', (148, 156))	('N and O linked oligosaccharides', 'Chemical', '-', (70, 101))	('lectin binding affinity', 'Interaction', (172, 195))	('glycan', 'Chemical', 'MESH:D011134', (124, 130))	('glycan', 'Chemical', 'MESH:D011134', (9, 15))	('desialylation', 'Var', (103, 116))
26945	28604616	Retroviruses, such as HIV, have a surface covered by highly glycosylated virally-encoded glycoproteins, e.g., gp120 (that contains high mannose and/or hybrid glycans) and gp41.	('mannose', 'Chemical', 'MESH:D008358', (136, 143))	('HIV', 'Species', '12721', (22, 25))	('gp41', 'Var', (171, 175))	('gp120', 'Gene', (110, 115))	('glycans', 'Chemical', 'MESH:D011134', (158, 165))	('gp120', 'Gene', '155971', (110, 115))	('high mannose', 'Protein', (131, 143))	('hybrid glycans', 'Protein', (151, 165))
26967	28604616	GS II mutant lectins lacking the ability to bind carbohydrates displayed sensitivity to proteolysis by digestive enzymes with a consequent loss of toxicity.	('carbohydrates', 'Chemical', 'MESH:D002241', (49, 62))	('mutant', 'Var', (6, 12))	('lectins', 'Protein', (13, 20))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('loss', 'NegReg', (139, 143))	('sensitivity', 'Reg', (73, 84))	('proteolysis', 'MPA', (88, 99))	('GS', 'Disease', 'MESH:D011125', (0, 2))
27079	33435265	In a multivariate analysis including subtype, tumor size, grade, mitotic index, and Ki67 index, only BC subtype (luminal/TNBC/HER2-positive) and Ki67 were significantly associated with pCR.	('pCR', 'Disease', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BC', 'Phenotype', 'HP:0003002', (101, 103))	('BC', 'Phenotype', 'HP:0003002', (123, 125))	('tumor', 'Disease', (46, 51))	('HER2', 'Gene', (126, 130))	('associated with', 'Reg', (169, 184))	('Ki67', 'Var', (145, 149))	('HER2', 'Gene', '2064', (126, 130))	('luminal', 'Chemical', 'MESH:D010634', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
27117	33435265	In univariate analysis, the baseline clinical and pathological factors significantly associated with higher pCR rates were (Table 4): TNBC or HER2-positive BC subtype, high grade, high mitotic index and Ki67 >= 20.	('HER2', 'Gene', (142, 146))	('BC', 'Phenotype', 'HP:0003002', (156, 158))	('higher', 'PosReg', (101, 107))	('HER2', 'Gene', '2064', (142, 146))	('BC', 'Phenotype', 'HP:0003002', (136, 138))	('TNBC', 'Disease', (134, 138))	('pCR', 'Disease', (108, 111))	('high grade', 'CPA', (168, 178))	('high mitotic index', 'CPA', (180, 198))	('Ki67 >= 20', 'Var', (203, 213))
27118	33435265	In a multivariable logistic regression analysis including subtype, tumor size, grade, mitotic index and Ki67 index, only subtype and Ki67 were significantly associated with pCR.	('Ki67', 'Var', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('associated with', 'Reg', (157, 172))	('pCR', 'Disease', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
27120	33435265	Indeed, the pCR rate was 20.4% in cases of DCIS on the pre-NAC biopsy vs. 25.7% for cases with no DCIS on the pre-NAC biopsy (OR = 0.74 (95% CI: 0.52-1.06), p = 0.1).	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('DCIS', 'Var', (43, 47))	('NAC', 'Chemical', '-', (59, 62))	('NAC', 'Chemical', '-', (114, 117))	('pCR', 'Disease', (12, 15))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
27142	33435265	found that the presence of DCIS associated with HER2-positive breast cancer was an independent negative predictor of pCR after NAC (OR = 0.42 (95% CI 0.2-0.9), p = 0.0027).	('HER2', 'Gene', '2064', (48, 52))	('NAC', 'Chemical', '-', (127, 130))	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('pCR', 'Disease', (117, 120))	('presence', 'Var', (15, 23))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('DCIS', 'Gene', (27, 31))	('HER2', 'Gene', (48, 52))	('negative', 'NegReg', (95, 103))
27207	18723155	To be eligible for the study, patients are required to be asymptomatic, have either heterogeneously dense or extremely dense breast parenchyma and have an increased risk for breast cancer as defined by at least one of the following risk factors: a personal history of breast cancer; a family history of one first-degree relative with breast cancer; a family history of two second-degree relatives with breast cancer; a known BRCA mutation; a personal history of lobular carcinoma in situ, atypical ductal hyperplasia, or atypical papilloma; an estimated five-year risk of breast cancer >= 1.7% or an estimated lifetime risk of breast cancer >= 20% as calculated by the Gail model.	('breast cancer', 'Disease', (572, 585))	('lobular carcinoma', 'Disease', (462, 479))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (498, 516))	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('papilloma', 'Disease', (530, 539))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('papilloma', 'Disease', 'MESH:D010212', (530, 539))	('breast cancer', 'Disease', 'MESH:D001943', (334, 347))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('breast cancer', 'Disease', (334, 347))	('breast cancer', 'Disease', 'MESH:D001943', (627, 640))	('BRCA', 'Gene', '672', (425, 429))	('papilloma', 'Phenotype', 'HP:0012740', (530, 539))	('breast cancer', 'Disease', (627, 640))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('breast cancer', 'Disease', (174, 187))	('breast parenchyma', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('breast parenchyma', 'Disease', 'MESH:D010195', (125, 142))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('mutation', 'Var', (430, 438))	('breast cancer', 'Phenotype', 'HP:0003002', (402, 415))	('patients', 'Species', '9606', (30, 38))	('breast cancer', 'Disease', (268, 281))	('breast cancer', 'Phenotype', 'HP:0003002', (334, 347))	('cancer', 'Phenotype', 'HP:0002664', (579, 585))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (462, 479))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (470, 487))	('BRCA', 'Gene', (425, 429))	('ductal hyperplasia', 'Disease', (498, 516))	('breast cancer', 'Disease', 'MESH:D001943', (402, 415))	('breast cancer', 'Disease', (402, 415))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (462, 487))	('breast cancer', 'Phenotype', 'HP:0003002', (572, 585))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('lobular carcinoma', 'Disease', 'MESH:D018275', (462, 479))	('breast cancer', 'Disease', 'MESH:D001943', (572, 585))	('carcinoma', 'Phenotype', 'HP:0030731', (470, 479))
27262	34001017	The radiomics models were developed to predict the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53 by using combination of multiple feature selection and classifiers.	('p53', 'Gene', (181, 184))	('HER2', 'Gene', (159, 163))	('p53', 'Gene', '7157', (181, 184))	('Ki67', 'Chemical', '-', (166, 170))	('epidermal growth factor receptor 2', 'Gene', '2064', (123, 157))	('HER2', 'Gene', '2064', (159, 163))	('epidermal growth factor receptor 2', 'Gene', (123, 157))	('estrogen receptor', 'Gene', (65, 82))	('human', 'Species', '9606', (117, 122))	('estrogen receptor', 'Gene', '2099', (65, 82))	('PR', 'Gene', '5241', (112, 114))	('p16', 'Gene', (172, 175))	('ER', 'Gene', '2099', (84, 86))	('ER', 'Gene', '2099', (160, 162))	('Ki67', 'Var', (166, 170))	('progesterone receptor', 'Gene', '5241', (89, 110))	('progesterone receptor', 'Gene', (89, 110))	('p16', 'Gene', '1029', (172, 175))
27271	34001017	Some studies have shown that some molecular biomarkers were important indicators for predicting biological behavior and judging follow-up treatment in patients with DCIS, such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53.	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('human', 'Species', '9606', (231, 236))	('p53', 'Gene', '7157', (295, 298))	('estrogen receptor', 'Gene', (179, 196))	('HER2', 'Gene', (273, 277))	('progesterone receptor', 'Gene', (203, 224))	('p53', 'Gene', (295, 298))	('ER', 'Gene', '2099', (198, 200))	('epidermal growth factor receptor 2', 'Gene', '2064', (237, 271))	('p16', 'Gene', (286, 289))	('ER', 'Gene', '2099', (274, 276))	('PR', 'Gene', '5241', (226, 228))	('p16', 'Gene', '1029', (286, 289))	('estrogen receptor', 'Gene', '2099', (179, 196))	('epidermal growth factor receptor 2', 'Gene', (237, 271))	('patients', 'Species', '9606', (151, 159))	('HER2', 'Gene', '2064', (273, 277))	('Ki67', 'Chemical', '-', (280, 284))	('Ki67', 'Var', (280, 284))	('progesterone receptor', 'Gene', '5241', (203, 224))
27282	34001017	Impaired function of p53, such as p53 mutation, can lead to uncontrolled proliferation of damaged cells.	('Impaired', 'NegReg', (0, 8))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p53', 'Gene', '7157', (21, 24))	('lead to', 'Reg', (52, 59))	('mutation', 'Var', (38, 46))	('function', 'MPA', (9, 17))	('uncontrolled proliferation of damaged cells', 'CPA', (60, 103))	('p53', 'Gene', (21, 24))
27300	34001017	The IHC (ER, PR, HER2, Ki67, p16, and p53) conformed to the diagnositic criteria of the department pathology in this hospital, and were classified as positive or negative.	('p16', 'Gene', (29, 32))	('Ki67', 'Var', (23, 27))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('ER', 'Gene', '2099', (18, 20))	('HER2', 'Gene', (17, 21))	('p16', 'Gene', '1029', (29, 32))	('HER2', 'Gene', '2064', (17, 21))	('ER', 'Gene', '2099', (9, 11))	('PR', 'Gene', '5241', (13, 15))	('Ki67', 'Chemical', '-', (23, 27))
27312	34001017	The correlation clustering heatmaps among 5234 features of each molecular biomarkers (ER, PR, HER2, Ki67, p16, and p53) were shown in Fig.	('PR', 'Gene', '5241', (90, 92))	('HER2', 'Gene', '2064', (94, 98))	('ER', 'Gene', '2099', (86, 88))	('Ki67', 'Var', (100, 104))	('p16', 'Gene', (106, 109))	('Ki67', 'Chemical', '-', (100, 104))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('p16', 'Gene', '1029', (106, 109))	('ER', 'Gene', '2099', (95, 97))	('HER2', 'Gene', (94, 98))
27313	34001017	A list of 18 feature importance methods were obtained, and the combination feature selection methods for optimal modeling results of each molecular biomarkers were as follows: Spearman0.75 + Statistical Test + RF, Spearman0.75 + Statistical Test + RF, Spearman0.75 + LASSO, Spearman0.75 + Statistical Test + RF, Spearman0.75 + Statistical Test + SVM-RFE, and Spearman0.85 + SVM-RFE.	('Spearman0.75 + Statistical Test + SVM-RFE', 'Var', (312, 353))	('LASSO', 'Chemical', '-', (267, 272))	('Spearman0.75 + Statistical Test + RF', 'Var', (274, 310))	('Spearman0.85 + SVM-RFE', 'Var', (359, 381))
27324	34001017	demonstrated that high Ki67 expression was an independent predictor of postoperative recurrence in patients with DCIS.	('expression', 'MPA', (28, 38))	('Ki67', 'Protein', (23, 27))	('patients', 'Species', '9606', (99, 107))	('high', 'Var', (18, 22))	('postoperative', 'CPA', (71, 84))	('DCIS', 'Disease', (113, 117))	('Ki67', 'Chemical', '-', (23, 27))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
27403	33350734	In the DCISM cohort, 13 (5.3%) patients had lymph node metastasis, and the DCISM group had significantly worse RFS than the DCIS group, with 11 patients (4.64%) experiencing relapse and 6 patients experiencing ipsilateral lymph node metastasis.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('DCISM', 'Var', (75, 80))	('DCISM', 'Chemical', '-', (7, 12))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('RFS', 'MPA', (111, 114))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (144, 152))	('lymph node metastasis', 'CPA', (44, 65))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('DCISM', 'Chemical', '-', (75, 80))	('patients', 'Species', '9606', (31, 39))	('worse', 'NegReg', (105, 110))	('experiencing', 'Reg', (161, 173))	('had', 'Reg', (40, 43))
27436	29426360	In all these applications, MRI has yielded consistently higher sensitivity and increased cancer detection rates compared with digital mammography (DM).	('increased', 'PosReg', (79, 88))	('MRI', 'Var', (27, 30))	('sensitivity', 'MPA', (63, 74))	('DM', 'Disease', 'MESH:D009223', (147, 149))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('higher', 'PosReg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
27437	29426360	Such false-positive diagnoses add to the overall cost of screening because they necessitate additional workup by imaging or biopsy, may cause physical harm because of additional morbidity associated with biopsy procedures, and may cause emotional harm because they may generate breast cancer anxiety in the patient.	('false-positive', 'Var', (5, 19))	('breast cancer anxiety', 'Disease', (278, 299))	('anxiety', 'Phenotype', 'HP:0000739', (292, 299))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('breast cancer anxiety', 'Disease', 'MESH:D001008', (278, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('patient', 'Species', '9606', (307, 314))	('cause', 'Reg', (231, 236))	('generate', 'Reg', (269, 277))
27461	29426360	Only if, after this workup, the final diagnosis was BI-RADS 4 or 5, did the patient proceed to undergo mammographic (DM- or DBT-guided) vacuum biopsy or DM/DBT-guided needle localization.	('DM', 'Disease', 'MESH:D009223', (153, 155))	('DBT', 'Gene', (156, 159))	('DBT', 'Gene', '1629', (156, 159))	('BI-RADS 4', 'Var', (52, 61))	('DM', 'Disease', 'MESH:D009223', (117, 119))	('patient', 'Species', '9606', (76, 83))	('DM/DBT', 'Gene', '1629', (153, 159))	('DM/DBT', 'Gene', (153, 159))	('DBT', 'Gene', (124, 127))	('DBT', 'Gene', '1629', (124, 127))
27497	29426360	The second most important reason for false-positive diagnosis based on MRI was complex proliferative tissue changes (48 of 202; 23.8%), whereas with DM/DBT, the second most important reason was simple proliferative changes (51 of 195; 25.2%).	('DM/DBT', 'Gene', '1629', (149, 155))	('MRI', 'Var', (71, 74))	('DM/DBT', 'Gene', (149, 155))
27508	29426360	Yet, the distribution of histological tissue types, especially the prevalence of atypical proliferation or of high-risk lesions in general, will greatly depend on the individual woman's risk of breast cancer.	('atypical', 'Var', (81, 89))	('woman', 'Species', '9606', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('depend', 'Reg', (153, 159))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
27513	29426360	As evidenced by common patterns of genomic additions and deletions, breast cancer progression is a biological continuum, starting from normal breast tissue via flat epithelial atypia, ADH, to DCIS, and then to invasive breast cancer.	('deletions', 'Var', (57, 66))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('flat epithelial atypia', 'Disease', (160, 182))	('breast cancer', 'Disease', (68, 81))	('breast cancer', 'Disease', (219, 232))	('flat epithelial atypia', 'Disease', 'MESH:D005413', (160, 182))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
27541	29108304	Patients treated by RT and RT + tamoxifen also exhibited a significantly lower risk of IBC compared with control group (OR=0.55, 95%CrI: 0.37-0.82; OR=0.42, 95%CrI: 0.18-0.99).	('RT +', 'Var', (27, 31))	('RT + tamoxifen', 'Chemical', '-', (27, 41))	('Patients', 'Species', '9606', (0, 8))	('IBC', 'Disease', (87, 90))	('lower', 'NegReg', (73, 78))
27560	29108304	Although anastrozole and tamoxifen have similar side effects and toxicity, patients treated by anastrozole exhibited fewer thromboembolic events compared to those treated by tamoxifen.	('thromboembolic', 'Disease', 'MESH:D013923', (123, 137))	('thromboembolic events', 'Phenotype', 'HP:0001907', (123, 144))	('fewer', 'NegReg', (117, 122))	('toxicity', 'Disease', 'MESH:D064420', (65, 73))	('patients', 'Species', '9606', (75, 83))	('toxicity', 'Disease', (65, 73))	('anastrozole', 'Chemical', 'MESH:D000077384', (9, 20))	('tamoxifen', 'Chemical', 'MESH:D013629', (174, 183))	('anastrozole', 'Chemical', 'MESH:D000077384', (95, 106))	('thromboembolic', 'Disease', (123, 137))	('tamoxifen', 'Chemical', 'MESH:D013629', (25, 34))	('anastrozole', 'Var', (95, 106))
27562	29108304	In addition, patients treated with anastrozole were associated with fewer cases of deep-vein thrombosis, hot flush, endometrial cancer and stroke compared with those treated by tamoxifen.	('stroke', 'Disease', 'MESH:D020521', (139, 145))	('tamoxifen', 'Chemical', 'MESH:D013629', (177, 186))	('deep-vein thrombosis', 'Disease', (83, 103))	('patients', 'Species', '9606', (13, 21))	('flush', 'Disease', 'MESH:D005483', (109, 114))	('stroke', 'Disease', (139, 145))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('flush', 'Phenotype', 'HP:0031284', (109, 114))	('anastrozole', 'Var', (35, 46))	('endometrial cancer', 'Disease', (116, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('fewer', 'NegReg', (68, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (116, 134))	('vein thrombosis', 'Phenotype', 'HP:0004936', (88, 103))	('deep-vein thrombosis', 'Phenotype', 'HP:0002625', (83, 103))	('anastrozole', 'Chemical', 'MESH:D000077384', (35, 46))	('deep-vein thrombosis', 'Disease', 'MESH:D020246', (83, 103))	('flush', 'Disease', (109, 114))	('stroke', 'Phenotype', 'HP:0001297', (139, 145))
27571	29108304	Patients treated by RT, and RT + tamoxifen were associated with a significantly decreased risk of LC compared to the control group (RT: OR = 0.54, 95% CrI = 0.40-0.73; RT + Tamoxifen: OR = 0.41, 95% CrI = 0.19-0.90).	('RT + tamoxifen', 'Chemical', '-', (28, 42))	('Tamoxifen', 'Chemical', 'MESH:D013629', (173, 182))	('decreased', 'NegReg', (80, 89))	('Patients', 'Species', '9606', (0, 8))	('RT + tamoxifen', 'Var', (28, 42))
27572	29108304	Similarly, RT and RT + tamoxifen were associated with a lower risk of IBC compared to the control group (OR = 0.55, 95%CrI = 0.37-0.82; OR = 0.42, 95%CrI = 0.18-0.99, respectively).	('lower', 'NegReg', (56, 61))	('IBC', 'Disease', (70, 73))	('RT + tamoxifen', 'Var', (18, 32))	('RT + tamoxifen', 'Chemical', '-', (18, 32))
27574	29108304	Moreover, patients with RT+ tamoxifen also exhibited a lower risk of LC compared with tamoxifen alone (OR = 0.28, 95% CrI = 0.10-0.68).	('tamoxifen', 'Chemical', 'MESH:D013629', (28, 37))	('lower', 'NegReg', (55, 60))	('patients', 'Species', '9606', (10, 18))	('tamoxifen', 'Chemical', 'MESH:D013629', (86, 95))	('RT+ tamoxifen', 'Var', (24, 37))
27581	29108304	Moreover, RT + anastrozole and RT + tamoxifen were also associated with lower risk of M and CBC, which was confirmed by previous studies.	('RT + tamoxifen', 'Chemical', '-', (31, 45))	('RT +', 'Var', (31, 35))	('RT + anastrozole', 'Chemical', '-', (10, 26))	('lower', 'NegReg', (72, 77))	('RT + anastrozole', 'Var', (10, 26))
27591	29108304	For instance, a randomized double-blinded trial (NSABP B-35) suggested that anastrozole significantly improved the breast cancer-free interval in DCIS patients under the age of 60 compared to the tamoxifen group, while another study reported no significant difference in the risk of overall recurrence between the anastrozole and tamoxifen group.	('tamoxifen', 'Chemical', 'MESH:D013629', (196, 205))	('anastrozole', 'Chemical', 'MESH:D000077384', (314, 325))	('patients', 'Species', '9606', (151, 159))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('anastrozole', 'Var', (76, 87))	('tamoxifen', 'Chemical', 'MESH:D013629', (330, 339))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('improved', 'PosReg', (102, 110))	('anastrozole', 'Chemical', 'MESH:D000077384', (76, 87))
27617	33001307	Further, unsatisfactory image quality, positioning, or inadequate assessment at recall may cause a cancer to be missed.	('cause', 'Reg', (91, 96))	('unsatisfactory', 'Var', (9, 23))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('missed', 'Disease', (112, 118))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
27660	33001307	We observed 21% (20/97) for ILC among distortions, compared with 7% (54/777) for masses and 2% (5/242) for calcifications.	('calcification', 'Disease', 'MESH:D002114', (107, 120))	('ILC', 'Disease', (28, 31))	('distortions', 'Var', (38, 49))	('calcification', 'Disease', (107, 120))
27661	33001307	Among invasive cancers, distortions were associated with the lowest percentage of histological grade 3 tumors (8%, 7/92) and calcifications were associated with the highest (41%, 39/94).	('calcification', 'Disease', 'MESH:D002114', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lowest', 'NegReg', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('invasive cancers', 'Disease', 'MESH:D009362', (6, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('calcification', 'Disease', (125, 138))	('invasive cancers', 'Disease', (6, 22))	('distortions', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
27683	33001307	The larger tumor diameter and higher percentage of tumors with low/intermediate histological grade among distortions may be related to the increased frequency of ILC among distortions.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('ILC', 'Disease', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (51, 56))	('distortions', 'Var', (105, 116))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('larger', 'PosReg', (4, 10))
27710	30657766	Interestingly, when lapatinib resistant lines MDA-MB-453 and JIMT-1 were tested, it was found that the presence of Th1 cytokines appeared to enhance sensitivity for lapatinib-induced metabolic suppression and induction of apoptotic cell death, nearly abrogating drug resistance.	('lapatinib', 'Chemical', 'MESH:D000077341', (20, 29))	('Th1', 'Gene', '51497', (115, 118))	('presence', 'Var', (103, 111))	('apoptotic cell death', 'CPA', (222, 242))	('metabolic suppression', 'MPA', (183, 204))	('enhance', 'PosReg', (141, 148))	('drug resistance', 'Phenotype', 'HP:0020174', (262, 277))	('abrogating', 'NegReg', (251, 261))	('sensitivity', 'MPA', (149, 160))	('JIMT-1', 'CellLine', 'CVCL:2077', (61, 67))	('Th1', 'Gene', (115, 118))	('lapatinib', 'Chemical', 'MESH:D000077341', (165, 174))	('drug resistance', 'MPA', (262, 277))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (46, 56))
27719	30657766	In addition, immunohistochemical studies revealed heavy infiltrates of both CD4pos T cells and CD20pos B cells to the areas of disease, but relatively fewer CD8pos T cells, suggesting a central role for helper T cells in anti-tumor immunity.	('CD20pos', 'Var', (95, 102))	('CD8', 'Gene', (157, 160))	('CD4', 'Gene', (76, 79))	('CD8', 'Gene', '925', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('infiltrates', 'PosReg', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CD4', 'Gene', '920', (76, 79))	('tumor', 'Disease', (226, 231))
27793	30657766	However, when HER-3 dimerizes with either HER-2, or to a lesser extent EGFR, its catalytic tail is activated through cross-phosphorylation and becomes a potent oncogenic driver.	('catalytic tail', 'MPA', (81, 95))	('activated', 'PosReg', (99, 108))	('dimerizes', 'Var', (20, 29))	('HER-2', 'Gene', '2064', (42, 47))	('cross-phosphorylation', 'Var', (117, 138))	('EGFR', 'Gene', '1956', (71, 75))	('HER-3', 'Gene', '2065', (14, 19))	('HER-2', 'Gene', (42, 47))	('HER-3', 'Gene', (14, 19))	('EGFR', 'Gene', (71, 75))
27866	30657766	Our in vitro data shows that the presence of Th1 cytokines can lower by several fold the amount of lapatinib necessary to achieve the same level of tumor killing.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('lower', 'NegReg', (63, 68))	('Th1', 'Gene', (45, 48))	('tumor', 'Disease', (148, 153))	('presence', 'Var', (33, 41))	('amount of lapatinib', 'MPA', (89, 108))	('Th1', 'Gene', '51497', (45, 48))	('lapatinib', 'Chemical', 'MESH:D000077341', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
27911	25369150	In Table 4, the odds of BCS versus mastectomy among women < 65 years of age were higher for increasing year of age (OR = 1.01, p=0.031), black race/ethnicity (OR = 1.24, p=0.043), private health insurance (OR = 1.37, p=0.023), and receipt of breast surgery in a CoC approved facility (OR = 1.26, p=0.028).	('BCS', 'Gene', '617', (24, 27))	('women', 'Species', '9606', (52, 57))	('BCS', 'Gene', (24, 27))	('black race/ethnicity', 'Var', (137, 157))
27919	25369150	Among women aged 65 years and older, the odds of RT following BCS were lower with increased year of age (OR= 0.88, p < 0.001), Hispanic ethnicity (OR= 0.40, p= 0.012), and having moderate/severe comorbidity (OR= 0.52, p=0.012).	('BCS', 'Gene', (62, 65))	('Hispanic ethnicity', 'Var', (127, 145))	('women', 'Species', '9606', (6, 11))	('BCS', 'Gene', '617', (62, 65))	('lower', 'NegReg', (71, 76))
27922	25369150	From the ROC analysis, the two most common deviations from guidelines were omission of RT when the surgical approach was BCS, and lymph node dissection.	('omission', 'Var', (75, 83))	('BCS', 'Gene', (121, 124))	('BCS', 'Gene', '617', (121, 124))	('lymph node dissection', 'CPA', (130, 151))
27955	24481326	Esr1, Ccdn1, prolactin, TGFalpha, AIB1, Espl1, and Wnt1 over-expression, Pik3ca gain of function, as well as loss of p53 or loss of Stat1 are associated with ER+ mammary cancer.	('loss', 'NegReg', (124, 128))	('cancer', 'Disease', (170, 176))	('loss', 'Var', (109, 113))	('Wnt1', 'Gene', '22408', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Pik3ca', 'Gene', '18706', (73, 79))	('Espl1', 'Gene', (40, 45))	('p53', 'Protein', (117, 120))	('Ccdn1', 'Gene', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Wnt1', 'Gene', (51, 55))	('gain of function', 'PosReg', (80, 96))	('AIB1', 'Gene', (34, 38))	('Pik3ca', 'Gene', (73, 79))	('Stat1', 'Gene', (132, 137))	('over-expression', 'PosReg', (56, 71))	('Espl1', 'Gene', '105988', (40, 45))	('Stat1', 'Gene', '20846', (132, 137))	('TGFalpha', 'Gene', (24, 32))	('AIB1', 'Gene', '76960', (34, 38))
27972	24481326	In both women and mice deregulated estrogen signaling can result in increased proliferation of the mammary ductal epithelium leading to cancer progression.	('estrogen', 'Protein', (35, 43))	('deregulated', 'Var', (23, 34))	('women', 'Species', '9606', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('rat', 'Species', '10116', (85, 88))	('mice', 'Species', '10090', (18, 22))	('cancer', 'Disease', (136, 142))	('proliferation', 'CPA', (78, 91))	('increased', 'PosReg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
27979	24481326	The second type exhibits ER+ mammary cancer as a result of genetic aberrations of other molecules within the estrogen-signaling pathway (Table 1B).	('genetic aberrations', 'Var', (59, 78))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
27981	24481326	The fourth type results from exposure to a chemical carcinogen in combination with genetic aberrations of other molecules within the estrogen-signaling pathway (Table 1D).	('rat', 'Species', '10116', (95, 98))	('results from', 'Reg', (16, 28))	('genetic aberrations', 'Var', (83, 102))
28010	24481326	In contrast in the 'tet-on' system a mutated tetracycline responsive transactivator protein is expressed that binds a tetracycline responsive promoter only when it is bound to a tetracycline compound such as doxycycline.	('tet', 'Chemical', 'MESH:C010349', (178, 181))	('binds', 'Interaction', (110, 115))	('tet', 'Chemical', 'MESH:C010349', (118, 121))	('tetracycline', 'Chemical', 'MESH:D013752', (118, 130))	('doxycycline', 'Chemical', 'MESH:D004318', (208, 219))	('tet', 'Chemical', 'MESH:C010349', (45, 48))	('tet', 'Chemical', 'MESH:C010349', (20, 23))	('tetracycline', 'Chemical', 'MESH:D013752', (178, 190))	('mutated', 'Var', (37, 44))	('tetracycline', 'Chemical', 'MESH:D013752', (45, 57))
28013	24481326	The adenocarcinomas that develop in the tet-op-Esr1MMTV-tTA/tet-op-SV40-TAg mice histologically model human ER+ ductal adenocarcinoma.	('adenocarcinomas', 'Disease', 'MESH:D000230', (4, 19))	('tet', 'Chemical', 'MESH:C010349', (40, 43))	('tet-op-Esr1MMTV-tTA/tet-op-SV40-TAg', 'Var', (40, 75))	('tet', 'Chemical', 'MESH:C010349', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('tTA', 'Chemical', '-', (56, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('adenocarcinomas', 'Disease', (4, 19))	('mice', 'Species', '10090', (76, 80))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (112, 133))	('ductal adenocarcinoma', 'Disease', (112, 133))	('human', 'Species', '9606', (102, 107))
28015	24481326	Half of the invasive adenocarcinomas that appear are ERalpha+ and neither cancer prevalence nor percentage of ERalpha+ adenocarcinoma are altered by low-dose DMBA exposure, loss of the Stat5a gene or coincident cyclin D1 over-expression.	('adenocarcinoma', 'Disease', (119, 133))	('cancer', 'Disease', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Stat5a', 'Gene', '20850', (185, 191))	('adenocarcinoma', 'Disease', (21, 35))	('invasive adenocarcinomas', 'Disease', 'MESH:D000230', (12, 36))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('loss', 'Var', (173, 177))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('invasive adenocarcinomas', 'Disease', (12, 36))	('DMBA', 'Chemical', 'MESH:D015127', (158, 162))	('Stat5a', 'Gene', (185, 191))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('cyclin D1', 'Gene', '12443', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cyclin D1', 'Gene', (211, 220))	('over-expression', 'PosReg', (221, 236))
28019	24481326	Loss of one copy of p53 significantly increases preneoplasia prevalence but not cancer.	('p53', 'Gene', (20, 23))	('increases', 'PosReg', (38, 47))	('Loss of one', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('preneoplasia', 'Disease', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('preneoplasia', 'Disease', 'None', (48, 60))	('cancer', 'Disease', (80, 86))
28023	24481326	The higher rates of preneoplasia and cancer development in Tet-op-Esr1MMTV-rtTA as compared to Tet-op-Esr1MMTV-tTA mice is correlated with a significantly higher percentage of mammary epithelial cells demonstrating targeted transgene expression.	('preneoplasia', 'Disease', (20, 32))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Tet', 'Chemical', 'MESH:C010349', (59, 62))	('rat', 'Species', '10116', (208, 211))	('cancer', 'Disease', (37, 43))	('Tet', 'Chemical', 'MESH:C010349', (95, 98))	('higher', 'PosReg', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('preneoplasia', 'Disease', 'None', (20, 32))	('rat', 'Species', '10116', (11, 14))	('tTA', 'Chemical', '-', (76, 79))	('mice', 'Species', '10090', (115, 119))	('higher', 'PosReg', (155, 161))	('tTA', 'Chemical', '-', (111, 114))	('Tet-op-Esr1MMTV-rtTA', 'Var', (59, 79))
28030	24481326	Loss of the BReast CAncer 1, early-onset 1 (BRCA1) gene is a genetic risk factor for development of breast cancer.	('BRCA1', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BReast CAncer', 'Phenotype', 'HP:0003002', (12, 25))	('BReast CAncer 1, early-onset 1', 'Gene', '12189', (12, 42))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('CAncer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', (100, 113))	('Loss', 'Var', (0, 4))
28031	24481326	A high percentage of women born with deleterious mutations in the BRCA1 gene will develop breast cancer by age 70.	('mutations', 'Var', (49, 58))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('BRCA1', 'Gene', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('women', 'Species', '9606', (21, 26))	('develop', 'PosReg', (82, 89))
28032	24481326	The predilection for cancer development in estrogen responsive tissues in women carrying BRCA1 mutations may be related to the ability of BRCA1 to down-regulate activity of ERalpha.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('down-regulate', 'NegReg', (147, 160))	('women', 'Species', '9606', (74, 79))	('BRCA1', 'Gene', (89, 94))	('ERalpha', 'Protein', (173, 180))	('cancer', 'Disease', (21, 27))	('mutations', 'Var', (95, 104))	('activity', 'MPA', (161, 169))
28033	24481326	Tet-op-Esr1MMTV-rtTA mice were mated to mice with genetically engineered conditional deletion of exon 11 of the Brca1 gene in mammary epithelial cells to generate Tet-op-Esr1MMTV-rtTA/Brca1 floxed exon 11 (f11)/f11/MMTV-Cre for testing the impact of ERalpha overexpression on cancer development initiated by loss of BRCA1 function.	('Tet', 'Chemical', 'MESH:C010349', (0, 3))	('MMTV', 'Gene', '17826', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('mice', 'Species', '10090', (21, 25))	('MMTV', 'Gene', '17826', (215, 219))	('rat', 'Species', '10116', (158, 161))	('MMTV', 'Gene', (174, 178))	('Tet', 'Chemical', 'MESH:C010349', (163, 166))	('Brca1', 'Gene', (184, 189))	('tTA', 'Chemical', '-', (180, 183))	('MMTV', 'Gene', '17826', (174, 178))	('Brca1', 'Gene', (112, 117))	('cancer', 'Disease', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('deletion', 'Var', (85, 93))	('mice', 'Species', '10090', (40, 44))	('Brca1', 'Gene', '12189', (184, 189))	('MMTV', 'Gene', (11, 15))	('Brca1', 'Gene', '12189', (112, 117))	('tTA', 'Chemical', '-', (17, 20))	('MMTV', 'Gene', (215, 219))	('loss', 'NegReg', (308, 312))
28066	24481326	Mutations in the p53 gene are reported in 20-23% of ER positive breast cancer and are reported to negatively impact response to anti-hormonal therapy.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('reported', 'Reg', (30, 38))	('impact', 'Reg', (109, 115))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('p53', 'Gene', (17, 20))	('response to anti-hormonal therapy', 'MPA', (116, 149))	('breast cancer', 'Disease', (64, 77))
28069	24481326	However, In vivo, p53 deficient mice have been shown to develop ER+ tumors indicating that p53 is not required for ER expression.	('p53', 'Gene', (18, 21))	('tumors', 'Disease', (68, 74))	('deficient', 'Var', (22, 31))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('develop', 'PosReg', (56, 63))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
28071	24481326	Expression of a p53 R270H mutant allele targeted to mammary epithelium and activated during pregnancy using a WAP-Cre transgene generates a mouse model in which mammary cancers appeared in 87% of the mice with a mean latency of five months following activation of Cre recombination during pregnancy.	('mouse', 'Species', '10090', (140, 145))	('cancers', 'Disease', (169, 176))	('rat', 'Species', '10116', (132, 135))	('WAP', 'Gene', (110, 113))	('WAP', 'Gene', '22373', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mice', 'Species', '10090', (200, 204))	('R270H', 'Mutation', 'rs55819519', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('p53 R270H', 'Var', (16, 25))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
28074	24481326	In another model, the WAP-cre transgene is used to delete both copies of p53 in mammary epithelium.	('delete', 'Var', (51, 57))	('WAP', 'Gene', '22373', (22, 25))	('WAP', 'Gene', (22, 25))	('p53', 'Gene', (73, 76))
28078	24481326	In contrast, if an MMTV-Cre transgene is used to execute the p53 deletion, none of the mammary cancers that develop are ER+, whether they are parous or virgin.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('MMTV', 'Gene', (19, 23))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('MMTV', 'Gene', '17826', (19, 23))	('p53', 'Gene', (61, 64))	('deletion', 'Var', (65, 73))
28079	24481326	A third p53-related model developed in BALB/c mice uses implants of mammary epithelium from eight-week-old female mice with germ-line loss of p53 that are placed into the cleared mammary fat pads of three week old mice to generate a mouse model of human DCIS.	('p53', 'Gene', (142, 145))	('human', 'Species', '9606', (248, 253))	('mouse', 'Species', '10090', (233, 238))	('mice', 'Species', '10090', (46, 50))	('mice', 'Species', '10090', (114, 118))	('rat', 'Species', '10116', (226, 229))	('mice', 'Species', '10090', (214, 218))	('loss', 'Var', (134, 138))
28093	24481326	TGFalpha expression can be found in 50-70% of human breast tumors and has been found to be downregulated by tamoxifen in ER+/PR+ breast cancers.	('downregulated', 'NegReg', (91, 104))	('ER+/PR+', 'Var', (121, 128))	('breast cancers', 'Disease', 'MESH:D001943', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancers', 'Disease', (129, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('TGFalpha', 'Gene', (0, 8))	('breast tumors', 'Phenotype', 'HP:0100013', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (46, 51))	('expression', 'MPA', (9, 19))	('tamoxifen', 'Chemical', 'MESH:D013629', (108, 117))	('breast tumors', 'Disease', 'MESH:D001943', (52, 65))	('breast cancers', 'Phenotype', 'HP:0003002', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast tumors', 'Disease', (52, 65))
28095	24481326	Genetically engineered FVB/N mice that over-express TGFalpha in mammary epithelial cells due to an Nrl-TGFalpha transgene will develop ER+ mammary cancers (Table 1B).	('develop', 'PosReg', (127, 134))	('transgene', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('TGFalpha', 'Gene', (52, 60))	('cancers', 'Disease', (147, 154))	('mice', 'Species', '10090', (29, 33))	('over-express', 'PosReg', (39, 51))	('Nrl-TGFalpha', 'Gene', (99, 111))
28103	24481326	Both mammary preneoplasia and tumors are reported to demonstrate high levels of the phosphorylated forms of Insulin Growth Factor-I Receptor, the p70S6 kinase, and phospho-S6 ribosomal protein.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('rat', 'Species', '10116', (60, 63))	('phosphorylated', 'MPA', (84, 98))	('p70S6 kinase', 'MPA', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('phospho-S6', 'Var', (164, 174))	('preneoplasia and tumors', 'Disease', 'MESH:D009369', (13, 36))	('Insulin', 'Protein', (108, 115))
28115	24481326	Activating mutations in the PIK3CA gene occur in between one quarter and one third of human breast cancers with 40% of these mutations located to the kinase domain.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('PIK3CA', 'Gene', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('human', 'Species', '9606', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('PIK3CA', 'Gene', '5290', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
28119	24481326	Loss of one p53 allele increases the percentage of Pik3caH1047R/p53f/+/MMTV-CreNLST mice demonstrating mammary tumors to 80% by approximately 10 months of age.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MMTV', 'Gene', (71, 75))	('tumors', 'Disease', (111, 117))	('p53', 'Gene', (12, 15))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('MMTV', 'Gene', '17826', (71, 75))	('rat', 'Species', '10116', (96, 99))	('Loss', 'Var', (0, 4))	('mice', 'Species', '10090', (84, 88))
28133	24481326	Localization of AKT1 to the membrane through myristoylation generates a mouse model with constitutive AKT activation.	('AKT', 'Gene', '11651', (16, 19))	('mouse', 'Species', '10090', (72, 77))	('AKT', 'Gene', '11651', (102, 105))	('rat', 'Species', '10116', (64, 67))	('AKT', 'Gene', (16, 19))	('AKT1', 'Gene', '11651', (16, 20))	('myristoylation', 'Var', (45, 59))	('AKT', 'Gene', (102, 105))	('AKT1', 'Gene', (16, 20))
28154	24481326	Another approach to developing more sophisticated models reflective of individual ER+ breast cancer sub-types will be to combine transgenic Esr1 expression with other genetic manipulations as was accomplished for both TAg expression and loss of Brca1/p53.	('Brca1', 'Gene', '12189', (245, 250))	('loss', 'Var', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('Esr1', 'Gene', (140, 144))	('transgenic', 'Species', '10090', (129, 139))	('breast cancer', 'Disease', (86, 99))	('Brca1', 'Gene', (245, 250))
28155	24481326	For example combining Tet-op-Esr1MMTV-rtTA mice with a mouse model of ErbB2/HER2 mutation could generate a model for Luminal B ER+ breast cancer.	('mice', 'Species', '10090', (43, 47))	('Tet', 'Chemical', 'MESH:C010349', (22, 25))	('HER2', 'Gene', (76, 80))	('tTA', 'Chemical', '-', (39, 42))	('MMTV', 'Gene', (33, 37))	('mutation', 'Var', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mouse', 'Species', '10090', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('ErbB2', 'Gene', (70, 75))	('MMTV', 'Gene', '17826', (33, 37))	('HER2', 'Gene', '13866', (76, 80))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('rat', 'Species', '10116', (100, 103))	('ErbB2', 'Gene', '13866', (70, 75))
28156	24481326	Although joining Esr1 over-expression with germ-line p53 haploinsufficiency did not accelerate tumor development, combining p53R270H/+/WAP-Cre with Tet-op-Esr1MMTV-rtTA mice might be more potent as mutant p53 R270H has more molecular impact than simple reduction of p53 expression levels.	('haploinsufficiency', 'Disease', 'MESH:D058495', (57, 75))	('MMTV', 'Gene', (159, 163))	('MMTV', 'Gene', '17826', (159, 163))	('WAP', 'Gene', (135, 138))	('haploinsufficiency', 'Disease', (57, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tTA', 'Chemical', '-', (165, 168))	('Tet', 'Chemical', 'MESH:C010349', (148, 151))	('p53 R270H', 'Var', (205, 214))	('mice', 'Species', '10090', (169, 173))	('WAP', 'Gene', '22373', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('R270H', 'Mutation', 'rs55819519', (209, 214))	('R270H', 'Mutation', 'rs55819519', (127, 132))	('tumor', 'Disease', (95, 100))	('rat', 'Species', '10116', (90, 93))
28157	24481326	Moreover, a model with mutant p53 would be translationally relevant for breast cancers carrying somatic p53 mutation in contrast to the germ-line insufficiency model that more closely parallels Li-Fraumeni syndrome.	('p53', 'Gene', (104, 107))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (194, 214))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('p53', 'Gene', (30, 33))	('Li-Fraumeni syndrome', 'Disease', (194, 214))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutation', 'Var', (108, 116))	('insufficiency', 'Disease', 'MESH:D000309', (146, 159))	('mutant', 'Var', (23, 29))	('insufficiency', 'Disease', (146, 159))
28159	24481326	Loss of Stat1 accelerates mammary cancer development in MMTV-Neu-IRES-Cre mice.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MMTV', 'Gene', (56, 60))	('MMTV', 'Gene', '17826', (56, 60))	('Neu', 'Gene', (61, 64))	('Stat1', 'Gene', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Neu', 'Gene', '13866', (61, 64))	('Stat1', 'Gene', '20846', (8, 13))	('cancer', 'Disease', (34, 40))	('accelerates', 'PosReg', (14, 25))	('rat', 'Species', '10116', (20, 23))	('mice', 'Species', '10090', (74, 78))	('Loss', 'Var', (0, 4))
28160	24481326	If loss of Stat1 in Tet-op-Esr1MMTV-rtTA mice accelerated cancer development to under 12 months, this would be a more tractable model for further study of luminal type breast cancer.	('rat', 'Species', '10116', (52, 55))	('loss', 'Var', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tTA', 'Chemical', '-', (37, 40))	('Stat1', 'Gene', '20846', (11, 16))	('Tet', 'Chemical', 'MESH:C010349', (20, 23))	('accelerated', 'PosReg', (46, 57))	('mice', 'Species', '10090', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('luminal type breast cancer', 'Disease', 'MESH:D001943', (155, 181))	('cancer', 'Disease', (58, 64))	('Stat1', 'Gene', (11, 16))	('luminal type breast cancer', 'Disease', (155, 181))
28162	31875548	miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC).	('Breast Cancer', 'Disease', 'MESH:D001943', (93, 106))	('increased', 'PosReg', (158, 167))	('Activates', 'PosReg', (13, 22))	('expression', 'MPA', (168, 178))	('Breast Cancer', 'Phenotype', 'HP:0003002', (93, 106))	('miRNA551b-3p', 'Var', (0, 12))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('microRNA 551b-3p', 'Var', (182, 198))	('Breast Cancer', 'Disease', (93, 106))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('Oncostatin Signaling Module', 'Pathway', (26, 53))	('breast cancer', 'Disease', (231, 244))
28163	31875548	Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription.	('IPO8', 'Gene', (96, 100))	('STAT3', 'Gene', '6774', (116, 121))	('miR551b-3p', 'Var', (29, 39))	('activates', 'PosReg', (106, 115))	('IPO8', 'Gene', '10526', (96, 100))	('STAT3', 'Gene', (116, 121))	('importin-8', 'Gene', '10526', (84, 94))	('importin-8', 'Gene', (84, 94))
28164	31875548	As a consequence, miR551b upregulates the expression of Oncostatin M receptor (OSMR) and interleukin-31 receptor-alpha (IL31RA) as well as their ligands Oncostatin-M (OSM) and interleukin 31 (IL31) through STAT3 transcription.	('OSMR', 'Gene', '9180', (79, 83))	('Oncostatin-M', 'Gene', '5008', (153, 165))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('STAT3', 'Gene', (206, 211))	('upregulates', 'PosReg', (26, 37))	('interleukin-31 receptor-alpha', 'Gene', (89, 118))	('Oncostatin M receptor', 'Gene', (56, 77))	('interleukin 31', 'Gene', '386653', (176, 190))	('expression', 'MPA', (42, 52))	('interleukin-31 receptor-alpha', 'Gene', '133396', (89, 118))	('miR551b', 'Var', (18, 25))	('Oncostatin M receptor', 'Gene', '9180', (56, 77))	('interleukin 31', 'Gene', (176, 190))	('IL31RA', 'Gene', '133396', (120, 126))	('Oncostatin-M', 'Gene', (153, 165))	('STAT3', 'Gene', '6774', (206, 211))	('OSMR', 'Gene', (79, 83))	('IL31RA', 'Gene', (120, 126))
28165	31875548	We defined this set of genes induced by miR551b-3p as "Oncostatin signaling module", which provides oncogenic addictions in cancer cells.	('miR551b-3p', 'Var', (40, 50))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
28167	31875548	Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of OSM signaling module, and reduced tumor growth as well as migration and invasion of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('anti-miR551b-3p', 'Var', (35, 50))	('reduced', 'NegReg', (51, 58))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('reduced', 'NegReg', (103, 110))	('breast cancer', 'Disease', (161, 174))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('expression', 'MPA', (63, 73))	('tumor', 'Disease', (111, 116))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('miR551b', 'Var', (22, 29))	('OSM', 'Protein', (77, 80))	('invasion', 'CPA', (149, 157))
28169	31875548	miR551b is part of the 3q26.2 chromosomal locus, which is frequently amplified in breast cancer as well as in multiple other cancer lineages, including cervical, head and neck, and prostate cancers.	('breast cancer', 'Disease', (82, 95))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('prostate cancers', 'Disease', 'MESH:D011471', (181, 197))	('miR551b', 'Var', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('prostate cancers', 'Phenotype', 'HP:0012125', (181, 197))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cervical', 'Disease', (152, 160))	('prostate cancers', 'Disease', (181, 197))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
28170	31875548	We found that miR551b directly activates transcription via RNA activation (RNAa) to increase transcription of the signal transducer and activator of transcription factor 3 (STAT3) oncogene.	('activates', 'PosReg', (31, 40))	('transcription', 'MPA', (41, 54))	('STAT3', 'Gene', '6774', (173, 178))	('miR551b', 'Var', (14, 21))	('transcription', 'MPA', (93, 106))	('STAT3', 'Gene', (173, 178))	('increase', 'PosReg', (84, 92))	('signal transducer and activator of transcription factor 3', 'Gene', '6774', (114, 171))
28174	31875548	We have shown that miR551b-3p interacts with promoter sequences of STAT3 to facilitate the recruitment of RNA-polymerase-II and TWIST1 transcription factor, increasing STAT3 transcription.	('si', 'Chemical', 'MESH:D012825', (163, 165))	('RNA-polymerase-II', 'Protein', (106, 123))	('STAT3', 'Gene', '6774', (67, 72))	('facilitate', 'PosReg', (76, 86))	('increasing', 'PosReg', (157, 167))	('STAT3', 'Gene', (67, 72))	('TWIST1', 'Gene', (128, 134))	('recruitment', 'MPA', (91, 102))	('STAT3', 'Gene', '6774', (168, 173))	('TWIST1', 'Gene', '7291', (128, 134))	('miR551b-3p', 'Var', (19, 29))	('STAT3', 'Gene', (168, 173))
28175	31875548	While our previous study identified miR551b as a key mediator of STAT3 transcription through RNAa, it did not elucidate the functional consequences of the miR551b-STAT3 signaling cascade.	('STAT3', 'Gene', '6774', (163, 168))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('STAT3', 'Gene', (163, 168))	('STAT3', 'Gene', '6774', (65, 70))	('miR551b', 'Var', (36, 43))	('STAT3', 'Gene', (65, 70))
28182	31875548	However, the role of miR551b-mediated upregulation of Oncostatin gene module in basal-like breast cancers have not been well understood.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('miR551b-mediated', 'Var', (21, 37))	('breast cancers', 'Phenotype', 'HP:0003002', (91, 105))	('breast cancers', 'Disease', 'MESH:D001943', (91, 105))	('upregulation', 'PosReg', (38, 50))	('breast cancers', 'Disease', (91, 105))	('Oncostatin gene module', 'Gene', (54, 76))
28183	31875548	In this study, we uncover the mechanism how mature microRNA-551b-3p translocated to the nucleus and upregulates OSM gene module for breast cancer progression.	('OSM gene module', 'Gene', (112, 127))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('microRNA-551b-3p', 'Var', (51, 67))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('upregulates', 'PosReg', (100, 111))
28188	31875548	Our results show that miR551b-3p increased the proliferation (Figures-1A) and clonogenic potential of both MCF10A and MDA-MB-231 cells (Figures-1B and S1B) as well as promoted the migration and invasion of both MCF10A and MDA-MB-231 cells (Figures-1C).	('clonogenic potential', 'CPA', (78, 98))	('MCF10A', 'CellLine', 'CVCL:0598', (107, 113))	('invasion', 'CPA', (194, 202))	('promoted', 'PosReg', (167, 175))	('migration', 'CPA', (180, 189))	('si', 'Chemical', 'MESH:D012825', (198, 200))	('increased', 'PosReg', (33, 42))	('miR551b-3p', 'Var', (22, 32))	('MCF10A', 'CellLine', 'CVCL:0598', (211, 217))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (118, 128))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (222, 232))	('proliferation', 'CPA', (47, 60))
28189	31875548	Furthermore, miR551b increased the wound healing ability of MCF10A and MDA-MB-231 cells (Figures-1D) and increased the levels of Vimentin and N-cadherin and reduced the levels of E-cadherin (Figures-1E and 1F; and see Figures-S1C for miRNA expression).	('wound healing ability', 'CPA', (35, 56))	('miR551b', 'Var', (13, 20))	('increased', 'PosReg', (21, 30))	('N-cadherin', 'Gene', '1000', (142, 152))	('si', 'Chemical', 'MESH:D012825', (246, 248))	('E-cadherin', 'Gene', (179, 189))	('E-cadherin', 'Gene', '999', (179, 189))	('MCF10A', 'CellLine', 'CVCL:0598', (60, 66))	('Vimentin', 'Gene', (129, 137))	('increased', 'PosReg', (105, 114))	('N-cadherin', 'Gene', (142, 152))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (71, 81))	('Vimentin', 'Gene', '7431', (129, 137))	('reduced', 'NegReg', (157, 164))
28191	31875548	Importantly, miR551b-3p increased the number and size of spheroids and the invasion of MDA-MB-231 tumor spheroids (Figures-1G and S1D).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('invasion', 'CPA', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('increased', 'PosReg', (24, 33))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('miR551b-3p', 'Var', (13, 23))
28193	31875548	Complementing these findings, we found that miR551b-3p upregulates expression of CD44, and c-Kit, and downregulates expression of CD24 and E-cadherin (Figures-1H).	('E-cadherin', 'Gene', (139, 149))	('expression', 'MPA', (116, 126))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('c-Kit', 'Gene', (91, 96))	('downregulates', 'NegReg', (102, 115))	('CD44', 'Gene', '960', (81, 85))	('c-Kit', 'Gene', '3815', (91, 96))	('CD24', 'Gene', '100133941', (130, 134))	('E-cadherin', 'Gene', '999', (139, 149))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('CD44', 'Gene', (81, 85))	('CD24', 'Gene', (130, 134))	('expression', 'MPA', (67, 77))	('miR551b-3p', 'Var', (44, 54))	('upregulates', 'PosReg', (55, 66))
28194	31875548	To determine if miR551b induce the TNBC characteristics like mesenchymal properties and cancer stemness in luminal breast cancer cells, we overexpressed miR551b-3p in a luminal cell line MCF-7 and found that the gain of miR551b-3p in MCF-7 cells, increased the levels of Vimentin, N-Cadherin and reduced the levels of E-Cadherin (Figure-S1E).	('E-Cadherin', 'Gene', (318, 328))	('N-Cadherin', 'Gene', '1000', (281, 291))	('reduced', 'NegReg', (296, 303))	('Vimentin', 'Gene', '7431', (271, 279))	('MCF-7', 'CellLine', 'CVCL:0031', (234, 239))	('miR551b-3p', 'Var', (220, 230))	('cancer stemness in luminal breast cancer', 'Disease', (88, 128))	('E-Cadherin', 'Gene', '999', (318, 328))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('levels', 'MPA', (261, 267))	('N-Cadherin', 'Gene', (281, 291))	('cancer stemness in luminal breast cancer', 'Disease', 'MESH:D001943', (88, 128))	('MCF-7', 'CellLine', 'CVCL:0031', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Vimentin', 'Gene', (271, 279))	('increased', 'PosReg', (247, 256))	('gain', 'PosReg', (212, 216))
28195	31875548	We also found that miR551b-3p upregulated the expression of CD44 and downregulated CD24, which demonstrates the acquisition of the characteristics of cancer stemness in MCF-7 cells (Figure-S1F).	('CD44', 'Gene', '960', (60, 64))	('miR551b-3p', 'Var', (19, 29))	('cancer stemness', 'Disease', 'MESH:D009369', (150, 165))	('upregulated', 'PosReg', (30, 41))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('CD44', 'Gene', (60, 64))	('downregulated', 'NegReg', (69, 82))	('cancer stemness', 'Disease', (150, 165))	('MCF-7', 'CellLine', 'CVCL:0031', (169, 174))	('CD24', 'Gene', (83, 87))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('expression', 'MPA', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('CD24', 'Gene', '100133941', (83, 87))
28197	31875548	Consistent with the finding that miR551b-3p confers oncogenic properties, knockdown of miR551b-3p reduced proliferation and colony forming activity of MDA-MB-231 cells (Figures-2A to 2C and see S2A for miR551b-3p expression).	('colony forming activity', 'CPA', (124, 147))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (151, 161))	('miR551b-3p', 'Var', (87, 97))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('reduced', 'NegReg', (98, 105))	('proliferation', 'CPA', (106, 119))
28198	31875548	Furthermore, anti-miR551b-3p promotes apoptosis in MDA-MB-231 cells (Figure-2D).	('apoptosis', 'CPA', (38, 47))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('anti-miR551b-3p', 'Var', (13, 28))	('promotes', 'PosReg', (29, 37))
28199	31875548	In parallel to anti-proliferative and pro-apoptotic effects of anti-miR551b-3p, we found that anti-miR551b-3p reduced migration and invasion of MDA-MB-231 and HCC-1806RR cells (Figures-2E, 2F and S2B).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (144, 154))	('reduced', 'NegReg', (110, 117))	('anti-miR551b-3p', 'Var', (94, 109))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('HCC-1806RR', 'CellLine', 'CVCL:1258', (159, 169))	('migration', 'CPA', (118, 127))	('invasion', 'CPA', (132, 140))
28200	31875548	Anti-miR551b-3p also reduced the number and size of MDA-MB-231 spheroids in both non-adherent and adherent conditions and HCC-1806RR spheroids in non-adherent conditions (Figures-2G, S2C and S2D).	('reduced', 'NegReg', (21, 28))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('MDA-MB-231', 'Gene', (52, 62))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('Anti-miR551b-3p', 'Var', (0, 15))	('HCC-1806RR', 'CellLine', 'CVCL:1258', (122, 132))
28201	31875548	We also noticed that anti-miR551b reduced the expression of vimentin and N-cadherin, and increased the expression of E-cadherin in both MDA-MB-231 and HCC-1806RR cell lines, which expresses high levels of miR551b-3p (Figures-2H, 2I and S2E),and decreased stem cell characteristics as displayed by decreased levels of CD44 and c-Kit, and increased levels of CD24 in both MDA-MB-231 and HCC-1806RR cell lines (Figures-2J and S2F).	('stem cell characteristics', 'CPA', (255, 280))	('reduced', 'NegReg', (34, 41))	('increased', 'PosReg', (337, 346))	('HCC-1806RR', 'CellLine', 'CVCL:1258', (151, 161))	('expression', 'MPA', (103, 113))	('CD24', 'Gene', '100133941', (357, 361))	('miR551b-3p', 'Var', (205, 215))	('decreased', 'NegReg', (245, 254))	('CD44', 'Gene', '960', (317, 321))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (136, 146))	('CD44', 'Gene', (317, 321))	('levels', 'MPA', (307, 313))	('c-Kit', 'Gene', '3815', (326, 331))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('N-cadherin', 'Gene', (73, 83))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('increased', 'PosReg', (89, 98))	('expression', 'MPA', (46, 56))	('N-cadherin', 'Gene', '1000', (73, 83))	('c-Kit', 'Gene', (326, 331))	('anti-miR551b', 'Var', (21, 33))	('HCC-1806RR', 'CellLine', 'CVCL:1258', (385, 395))	('CD24', 'Gene', (357, 361))	('vimentin', 'Gene', '7431', (60, 68))	('decreased', 'NegReg', (297, 306))	('vimentin', 'Gene', (60, 68))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (370, 380))
28202	31875548	To explore the mechanisms by which miR551b-3p mediates its effects in TNBC, we assessed the changes in protein expression resulting from miR551b-3p expression in MDA-MB-231 cells, using reverse phase protein array (RPPA) as described before.	('miR551b-3p', 'Var', (137, 147))	('protein expression', 'MPA', (103, 121))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (162, 172))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('si', 'Chemical', 'MESH:D012825', (181, 183))
28203	31875548	We found that miR551b-3p upregulated both total and phospho-STAT3 (Y705) proteins, supporting that STAT3 is the key target of miR551b-3p in breast cancer cells (Figure-3A).	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('miR551b-3p', 'Var', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('STAT3', 'Gene', '6774', (99, 104))	('upregulated', 'PosReg', (25, 36))	('STAT3', 'Gene', '6774', (60, 65))	('STAT3', 'Gene', (60, 65))	('STAT3', 'Gene', (99, 104))	('miR551b-3p', 'Var', (126, 136))
28204	31875548	Furthermore, miR551b-3p increased PI3K and AKT signaling while downregulating RAS/MAPK signaling and decreasing levels of phosphorylated S6 protein (Figures-3A and S3A).	('si', 'Chemical', 'MESH:D012825', (87, 89))	('decreasing', 'NegReg', (101, 111))	('MAPK', 'Gene', '26413', (82, 86))	('AKT', 'Gene', '207', (43, 46))	('downregulating', 'NegReg', (63, 77))	('MAPK', 'Gene', (82, 86))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('PI3K', 'Pathway', (34, 38))	('AKT', 'Gene', (43, 46))	('levels of phosphorylated S6 protein', 'MPA', (112, 147))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('increased', 'PosReg', (24, 33))	('miR551b-3p', 'Var', (13, 23))
28205	31875548	These findings support the contention that increased PI3K and AKT signaling together with decreased levels of RAS/MAPK signaling by miR551b-3p constitute an important oncogenic mechanism in tumor cells.	('AKT', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('decreased', 'NegReg', (90, 99))	('miR551b-3p', 'Var', (132, 142))	('tumor', 'Disease', (190, 195))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('increased', 'PosReg', (43, 52))	('AKT', 'Gene', '207', (62, 65))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('MAPK', 'Gene', (114, 118))	('MAPK', 'Gene', '26413', (114, 118))
28206	31875548	miR551b-3p is located at the 3q26.2 locus, and the miR551b copy-gain is present in ~27% breast cancer patients and miR551b is amplified in ~3.5% breast cancer patients in the TCGA breast cancer data set (Table-S1).	('miR551b', 'Var', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('patients', 'Species', '9606', (102, 110))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('miR551b', 'Var', (115, 122))	('breast cancer', 'Disease', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (159, 167))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
28207	31875548	Our analysis using TCGA breast cancer data further showed that breast cancer samples exhibit miR551b amplification express high levels of STAT3 mRNA (Figure-S3B) and miR551b-3p expression is correlated with STAT3 and phospho-STAT3 (Y705) levels in breast cancer samples, particularly in the basal-like subtype (Figures-3B, 3C and S3C).	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Disease', (24, 37))	('STAT3', 'Gene', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('si', 'Chemical', 'MESH:D012825', (183, 185))	('STAT3', 'Gene', '6774', (207, 212))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('miR551b-3p', 'Var', (166, 176))	('STAT3', 'Gene', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('STAT3', 'Gene', (225, 230))	('miR551b', 'Gene', (93, 100))	('correlated', 'Reg', (191, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('STAT3', 'Gene', '6774', (138, 143))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('STAT3', 'Gene', '6774', (225, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('breast cancer', 'Disease', (248, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))
28208	31875548	In conjunction with our previous findings in ovarian cancer, our data demonstrate that miR551b-3p appears to regulate total and phospho-STAT3 in breast cancer cells, where miR551b-3p could be a major contributor to the functional effects of STAT3.	('STAT3', 'Gene', (241, 246))	('regulate', 'Reg', (109, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('miR551b-3p', 'Var', (87, 97))	('ovarian cancer', 'Disease', (45, 59))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('STAT3', 'Gene', '6774', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', (145, 158))	('STAT3', 'Gene', '6774', (241, 246))	('STAT3', 'Gene', (136, 141))
28209	31875548	Next, we determined if there is an association between miR551b-3p and STAT3 in the set of breast cancer cell lines, in which we have determined the expression of miR551b (see Figure-S1A) and found that those cell lines expressing high levels of miR551b-3p also express high levels of STAT3 and phosphorylated form of STAT3 (S727 and Y705) (Figure-S3D).	('STAT3', 'Gene', (317, 322))	('STAT3', 'Gene', (70, 75))	('STAT3', 'Gene', '6774', (284, 289))	('si', 'Chemical', 'MESH:D012825', (225, 227))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('miR551b-3p', 'Var', (245, 255))	('S727', 'Var', (324, 328))	('STAT3', 'Gene', '6774', (70, 75))	('STAT3', 'Gene', (284, 289))	('breast cancer', 'Disease', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('STAT3', 'Gene', '6774', (317, 322))	('phosphorylated', 'MPA', (294, 308))	('Y705', 'Var', (333, 337))
28210	31875548	Our correlation coefficient analysis between the expression of miR551b-3p and the levels of STAT3, pSTAT3 (Y705), or pSTAT3 (S727) again confirm a positive correlation between miR551b-3p vs STAT3 proteins (Pearson correlation coefficient [r] > 0.7) (Figure-S3D and S3E).	('si', 'Chemical', 'MESH:D012825', (149, 151))	('STAT3', 'Gene', (100, 105))	('miR551b-3p', 'Var', (63, 73))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('STAT3', 'Gene', '6774', (190, 195))	('miR551b-3p', 'Var', (176, 186))	('STAT3', 'Gene', '6774', (118, 123))	('STAT3', 'Gene', '6774', (92, 97))	('STAT3', 'Gene', (190, 195))	('STAT3', 'Gene', (118, 123))	('STAT3', 'Gene', (92, 97))	('STAT3', 'Gene', '6774', (100, 105))	('si', 'Chemical', 'MESH:D012825', (55, 57))
28214	31875548	Taken together, our data suggests that miR551b-3p could act through a gene module consisting of OSM, OSMR, IL31, IL31RA, IL6ST, JAK1, and JAK2.	('IL31RA', 'Gene', (113, 119))	('OSMR', 'Gene', '9180', (101, 105))	('OSMR', 'Gene', (101, 105))	('IL6ST', 'Gene', (121, 126))	('JAK1', 'Gene', '3716', (128, 132))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('JAK2', 'Gene', '3717', (138, 142))	('miR551b-3p', 'Var', (39, 49))	('IL31RA', 'Gene', '133396', (113, 119))	('IL6ST', 'Gene', '3572', (121, 126))	('JAK1', 'Gene', (128, 132))	('JAK2', 'Gene', (138, 142))
28215	31875548	Importantly miR551b-3p upregulated the expression of OSM, OSMR, IL31, IL31RA, and IL6ST, which we define as the OSM gene module and that anti-miR551b-3p reduces expression of these components at both mRNA and protein levels (Figures-3E to 3H and Figures-S3G).	('IL31RA', 'Gene', '133396', (70, 76))	('upregulated', 'PosReg', (23, 34))	('OSMR', 'Gene', '9180', (58, 62))	('IL6ST', 'Gene', '3572', (82, 87))	('expression', 'MPA', (161, 171))	('IL31', 'Gene', (64, 68))	('IL31RA', 'Gene', (70, 76))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('reduces', 'NegReg', (153, 160))	('miR551b-3p', 'Var', (12, 22))	('OSM', 'Gene', (53, 56))	('IL6ST', 'Gene', (82, 87))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('anti-miR551b-3p', 'Var', (137, 152))	('OSMR', 'Gene', (58, 62))
28217	31875548	Thus, we quantified the secreted levels of OSM and IL31 by ELISA and found that miR551b-3p increased the levels of both OSM and IL31 in supernatants of MCF10A and MDA-MB-231 cells (Figures-3I-3J).	('MCF10A', 'CellLine', 'CVCL:0598', (152, 158))	('miR551b-3p', 'Var', (80, 90))	('levels', 'MPA', (105, 111))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (163, 173))	('increased', 'PosReg', (91, 100))
28218	31875548	Conversely, anti-miR551b-3p reduced the levels of OSM and IL31 in MDA-MB-231 cells (Figure-S3H).	('reduced', 'NegReg', (28, 35))	('levels of OSM', 'MPA', (40, 53))	('IL31', 'MPA', (58, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('anti-miR551b-3p', 'Var', (12, 27))
28219	31875548	OSM or IL31 also induced the phosphorylation of JAK1 (Y-1034/1035), JAK2 (Y-1008) and STAT3 (S-727 and Y-705) in breast cancer cells (Figure-3K).	('JAK2', 'Gene', '3717', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('S-727', 'Var', (93, 98))	('STAT3', 'Gene', (86, 91))	('JAK1', 'Gene', '3716', (48, 52))	('breast cancer', 'Disease', (113, 126))	('JAK2', 'Gene', (68, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('STAT3', 'Gene', '6774', (86, 91))	('Y-1034/1035', 'Var', (54, 65))	('Y-1008', 'Var', (74, 80))	('IL31', 'Gene', (7, 11))	('JAK1', 'Gene', (48, 52))	('phosphorylation', 'MPA', (29, 44))
28220	31875548	We further determined the effects of OSM and IL31 on phosphorylation of STAT3 in comparison with IL6, which is a known stimulator of STAT3 phosphorylation and found that OSM induced the phosphorylation of STAT3 at Y705 and S727 residues markedly higher than IL-6 and IL-31 and persistent for prolonged period (Figures-S3I and S3J).	('IL-6', 'Gene', '3569', (258, 262))	('STAT3', 'Gene', (72, 77))	('higher', 'PosReg', (246, 252))	('IL-31', 'Gene', '386653', (267, 272))	('S727', 'Var', (223, 227))	('STAT3', 'Gene', '6774', (205, 210))	('si', 'Chemical', 'MESH:D012825', (280, 282))	('STAT3', 'Gene', '6774', (133, 138))	('Y705', 'Var', (214, 218))	('STAT3', 'Gene', (205, 210))	('STAT3', 'Gene', (133, 138))	('IL6', 'Gene', '3569', (97, 100))	('IL-31', 'Gene', (267, 272))	('si', 'Chemical', 'MESH:D012825', (230, 232))	('IL6', 'Gene', (97, 100))	('phosphorylation', 'MPA', (186, 201))	('IL-6', 'Gene', (258, 262))	('STAT3', 'Gene', '6774', (72, 77))
28221	31875548	We have shown that miR551b-3p interacts with STAT3 promoter in the nucleus and activates STAT3 transcription previously.	('STAT3', 'Gene', (45, 50))	('interacts', 'Interaction', (30, 39))	('STAT3', 'Gene', '6774', (89, 94))	('STAT3', 'Gene', (89, 94))	('miR551b-3p', 'Var', (19, 29))	('activates', 'PosReg', (79, 88))	('STAT3', 'Gene', '6774', (45, 50))
28222	31875548	To determine if mature miR551b-3p is present in the nucleus and is required for transcriptional activation, we have performed qPCR to quantitate the expression of miR551b-3p in the nuclear and cytoplasmic fractions in breast cancer cell lines.	('breast cancer', 'Disease', (218, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('miR551b-3p', 'Var', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('si', 'Chemical', 'MESH:D012825', (155, 157))
28224	31875548	Our in situ hybridization also shows increased levels of mature miR551b-3p in the nucleus of MDAMB-231 and HCC-1806RR cells compared to MCF7 and MCF10A, which express low levels of miR551b exhibited less amount of miR551b-3p in the nucleus (Figures-4A, S4B and S4C).	('S4C', 'Mutation', 'p.S4C', (261, 264))	('miR551b', 'Var', (181, 188))	('HCC-1806RR', 'CellLine', 'CVCL:1258', (107, 117))	('MCF10A', 'CellLine', 'CVCL:0598', (145, 151))	('MDAMB-231', 'CellLine', 'CVCL:0062', (93, 102))	('levels', 'MPA', (47, 53))	('increased', 'PosReg', (37, 46))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('MCF7', 'CellLine', 'CVCL:0031', (136, 140))	('miR551b-3p', 'Var', (64, 74))
28225	31875548	Importantly, the overexpression of miR551b3p in MDA-MB231 leads to the increased expression of miR551b-3p in both cytoplasmic and nuclear fractions compared to the cells transfected with control miRNA (Figure S4D).	('si', 'Chemical', 'MESH:D012825', (87, 89))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('MDA-MB231', 'CellLine', 'CVCL:0062', (48, 57))	('miR551b3p', 'Var', (35, 44))	('miR551b-3p', 'Var', (95, 105))	('increased', 'PosReg', (71, 80))	('overexpression', 'PosReg', (17, 31))	('MDA-MB231', 'Gene', (48, 57))	('expression', 'MPA', (81, 91))
28226	31875548	In conjunction with previous studies from us and others, the mutation in the STAT3 promoter sequences (Mutant #2, and #3), which is complementary to the 5' sequences of miR551b-3p and the deletion of non-complementary loop in the STAT3 promoter (Mutant #4) abolished miR551b-3p induced promoter activity (Figures-4B and 4C).	('promoter activity', 'MPA', (286, 303))	('mutation', 'Var', (61, 69))	('abolished', 'NegReg', (257, 266))	('STAT3', 'Gene', '6774', (230, 235))	('deletion', 'Var', (188, 196))	('STAT3', 'Gene', '6774', (77, 82))	('miR551b-3p', 'Var', (267, 277))	('STAT3', 'Gene', (230, 235))	('STAT3', 'Gene', (77, 82))
28227	31875548	We also noticed that mutations in STAT3 promoter complementary towards 3'sequences of miR551b-3p (Mutant #1) reduced the miR551b-3p-induced promoter activity about 30%, whereas other mutations as described above reduced the promoter activity more than 75% compared to the luciferase activity induced by miR551b-3p in the cells were transfected with wild type STAT3 promoter.	('STAT3', 'Gene', (34, 39))	('miR551b-3p-induced promoter activity', 'MPA', (121, 157))	('STAT3', 'Gene', (359, 364))	('STAT3', 'Gene', '6774', (34, 39))	('miR551b-3p', 'Gene', (86, 96))	('reduced', 'NegReg', (109, 116))	('promoter activity', 'MPA', (224, 241))	('STAT3', 'Gene', '6774', (359, 364))	('mutations', 'Var', (21, 30))
28228	31875548	Collectively, our results suggest that the sequences 5'GCGACCCAUACUUGGU3' in miR551b-3p is critical for the interaction of miR551b-3p with STAT3 promoter for STAT3 transcription.	('STAT3', 'Gene', '6774', (139, 144))	('STAT3', 'Gene', (139, 144))	('interaction', 'Interaction', (108, 119))	('STAT3', 'Gene', '6774', (158, 163))	('miR551b-3p', 'Var', (123, 133))	('STAT3', 'Gene', (158, 163))	('miR551b-3p', 'Gene', (77, 87))
28229	31875548	To visualize the translocation of miR551b to the nucleus, we have used the 5' Cy3-labelled wild type miR551b-3p (5'-GCGACCCAUACUUGGUUUCAG-3') or mutated miR551b-3p, in which UUGGUUU sequence in miR551b-3p mutated to CCAUCGG and transfected into MDA-MB-231 cells.	('Cy3', 'Chemical', '-', (78, 81))	('miR551b-3p', 'Gene', (194, 204))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (245, 255))	('mutated', 'Var', (205, 212))
28230	31875548	Taken together, our results show that UUGGUUU sequence in miR551b-3p is important for its nuclear translocation and the 5'GCGACCCAUACUUGGU3' sequence in miR551b-3p is important for STAT3 transcriptional activation.	('miR551b-3p', 'Var', (58, 68))	('STAT3', 'Gene', (181, 186))	('STAT3', 'Gene', '6774', (181, 186))
28231	31875548	To further validate the nuclear translocation of miR551b-3p in miR551b genetic knockout model, we deleted miR-551b in a TNBC subtype Hs578T breast cancer cells using CRISPR/Cas9 vectors and the deletion of miR551b is confirmed using gel electrophoresis of the DNA fragment encompassing miR551b amplified using target specific primers and Sanger sequencing (Figures S4E to S4G).	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('miR-551b', 'Gene', (106, 114))	('miR-551b', 'Gene', '693136', (106, 114))	('si', 'Chemical', 'MESH:D012825', (228, 230))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('si', 'Chemical', 'MESH:D012825', (249, 251))	('miR551b', 'Gene', (286, 293))	('si', 'Chemical', 'MESH:D012825', (305, 307))	('Hs578T', 'CellLine', 'CVCL:0332', (133, 139))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('si', 'Chemical', 'MESH:D012825', (281, 283))	('deleted', 'Var', (98, 105))
28234	31875548	To further support our results on the nuclear translocation of mature miR551b-3p in the WT and miR551b-KO Hs578T cells, we performed RNA in situ hybridization in a cancer cell line exhibits homozygous deletion of miR551b, which did not show any presence of mature miR551b-3p in the cytoplasm or in nucleus (Figure S4J and S4K).	('deletion', 'Var', (201, 209))	('miR551b', 'Gene', (213, 220))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('S4K', 'Mutation', 'p.S4K', (322, 325))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('Hs578T', 'CellLine', 'CVCL:0332', (106, 112))
28238	31875548	miR or mutated miR551b-3p is enriched in the nuclear fraction, when we purified IPO8 bound miRNAs from the nuclear extract (Figure-4F).	('miR551b-3p', 'Var', (15, 25))	('mutated miR551b-3p', 'Var', (7, 25))	('IPO8', 'Gene', (80, 84))	('IPO8', 'Gene', '10526', (80, 84))
28240	31875548	Next, we determined the IPO8 levels in a set of breast cancer cell lines and found that TNBC cells express high levels of IPO8 (Figures- S5A and S5B), which also express high levels of STAT3 and miR551b-3p (Figures- S1A and S3D).	('IPO8', 'Gene', (122, 126))	('IPO8', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('IPO8', 'Gene', '10526', (122, 126))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('S5B', 'Gene', '5711', (145, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('IPO8', 'Gene', '10526', (24, 28))	('breast cancer', 'Disease', (48, 61))	('STAT3', 'Gene', '6774', (185, 190))	('S5B', 'Gene', (145, 148))	('miR551b-3p', 'Var', (195, 205))	('STAT3', 'Gene', (185, 190))
28242	31875548	We used IPO9 as a control to confirm if there is specificity between the interaction of miR551b-3p with IPO8.	('interaction', 'Interaction', (73, 84))	('IPO8', 'Gene', (104, 108))	('IPO9', 'Gene', (8, 12))	('miR551b-3p', 'Var', (88, 98))	('IPO8', 'Gene', '10526', (104, 108))	('IPO9', 'Gene', '55705', (8, 12))
28243	31875548	This assay demonstrated that the loss of IPO8 expression but not the loss of IPO9 reduced the enrichment of miR551b in the nuclear fractions of cells, that were transfected with miR551b (Figures-4H and S5C to S5D).	('IPO9', 'Gene', '55705', (77, 81))	('IPO8', 'Gene', (41, 45))	('miR551b', 'Var', (108, 115))	('IPO8', 'Gene', '10526', (41, 45))	('IPO9', 'Gene', (77, 81))	('loss', 'Var', (33, 37))	('enrichment', 'MPA', (94, 104))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('reduced', 'NegReg', (82, 89))	('miR551b', 'Var', (178, 185))
28244	31875548	In conjunction with our qPCR assays in Fig-4H, our immunofluorescence assay also shows that the loss of IPO8 but not the loss of IPO9 disrupted the translocation of miR551b-3p to the nucleus (Figures-4I and 4J).	('miR551b-3p', 'Var', (165, 175))	('loss', 'Var', (96, 100))	('IPO9', 'Gene', (129, 133))	('disrupted', 'NegReg', (134, 143))	('IPO8', 'Gene', (104, 108))	('IPO8', 'Gene', '10526', (104, 108))	('translocation', 'MPA', (148, 161))	('IPO9', 'Gene', '55705', (129, 133))
28245	31875548	Next, we determined the interaction between miR551b-3p and importin-8 by assessing the co-localization of Cy-3 labelled miR551b-3p with IPO8 in immunofluorescence assay and found that miR551b-3p co-localized with IPO8 in the cytoplasm (orange) and in the nucleus (cyan) (Figure-S5E).	('IPO8', 'Gene', (136, 140))	('Cy-', 'Chemical', 'MESH:D003545', (106, 109))	('IPO8', 'Gene', (213, 217))	('IPO8', 'Gene', '10526', (136, 140))	('miR551b-3p', 'Var', (184, 194))	('importin-8', 'Gene', (59, 69))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('importin-8', 'Gene', '10526', (59, 69))	('IPO8', 'Gene', '10526', (213, 217))
28248	31875548	Next, we performed the rescue experiment, where we introduced the miR551b-3p expression in the miR551b-KO Hs578T cells, which were pre-transfected with IPO8 siRNAs or control siRNAs to prove the exogenous miR551b requires IPO8-mediated nuclear translocation to upregulate STAT3 expression.	('IPO8', 'Gene', (222, 226))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('IPO8', 'Gene', '10526', (152, 156))	('IPO8', 'Gene', '10526', (222, 226))	('si', 'Chemical', 'MESH:D012825', (284, 286))	('IPO8', 'Gene', (152, 156))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('miR551b', 'Var', (205, 212))	('Hs578T', 'CellLine', 'CVCL:0332', (106, 112))	('STAT3', 'Gene', '6774', (272, 277))	('upregulate', 'PosReg', (261, 271))	('STAT3', 'Gene', (272, 277))	('si', 'Chemical', 'MESH:D012825', (83, 85))
28249	31875548	In this assay, we found that the gain of expression of miR551b rescued the proliferation and spheroid forming ability of miR551b-KO-Hs578T cells, which was disrupted by the loss of miR551b (Figure S6G and S6H).	('gain of expression', 'PosReg', (33, 51))	('miR551b', 'Gene', (181, 188))	('miR551b-KO-Hs578T', 'Var', (121, 138))	('Hs578T', 'CellLine', 'CVCL:0332', (132, 138))	('miR551b', 'Gene', (55, 62))	('loss', 'Var', (173, 177))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('rescued', 'PosReg', (63, 70))	('spheroid forming ability', 'CPA', (93, 117))	('S6H', 'Mutation', 'p.S6H', (205, 208))	('proliferation', 'CPA', (75, 88))
28250	31875548	Importantly, the knock down of importin-8 (IPO8) but not the IPO-9 abrogated the nuclear translocation of miR551b and miR551b -induced STAT3 induction and subsequent increase in proliferation and spheroid forming ability of miR551b-KO-Hs578T cells, which was disrupted by the loss of miR551b (Figure S5G to S5K).	('IPO-9', 'Gene', '55705', (61, 66))	('IPO-9', 'Gene', (61, 66))	('increase', 'PosReg', (166, 174))	('STAT3', 'Gene', (135, 140))	('IPO8', 'Gene', '10526', (43, 47))	('loss', 'Var', (276, 280))	('STAT3', 'Gene', '6774', (135, 140))	('Hs578T', 'CellLine', 'CVCL:0332', (235, 241))	('miR551b', 'Gene', (118, 125))	('miR551b-KO-Hs578T', 'Var', (224, 241))	('miR551b', 'Var', (284, 291))	('IPO8', 'Gene', (43, 47))	('spheroid forming ability', 'CPA', (196, 220))	('abrogated', 'NegReg', (67, 76))	('importin-8', 'Gene', (31, 41))	('nuclear translocation', 'MPA', (81, 102))	('proliferation', 'CPA', (178, 191))	('importin-8', 'Gene', '10526', (31, 41))	('knock down', 'Var', (17, 27))	('miR551b', 'Gene', (106, 113))
28251	31875548	Taken together, our results demonstrate that the interaction of IPO8 to miR551b-3p-AGO complex translocate to the nucleus and the sequence complementarity between miR551b-3p and STAT3 promoter allows the binding of miR551b-3p on STAT3 promoter.	('STAT3', 'Gene', '6774', (229, 234))	('IPO8', 'Gene', '10526', (64, 68))	('translocate', 'MPA', (95, 106))	('interaction', 'Interaction', (49, 60))	('STAT3', 'Gene', (229, 234))	('miR551b-3p', 'Var', (163, 173))	('binding', 'Interaction', (204, 211))	('STAT3', 'Gene', '6774', (178, 183))	('IPO8', 'Gene', (64, 68))	('STAT3', 'Gene', (178, 183))
28252	31875548	Importantly, this interaction of miR551b-3p with STAT3 promoter improve the occupancy of TWIST1 transcription factor and RNA-Pol-II to the transcription initiation site for STAT3 transcription (Figure-4K).	('TWIST1', 'Gene', (89, 95))	('TWIST1', 'Gene', '7291', (89, 95))	('improve', 'PosReg', (64, 71))	('STAT3', 'Gene', (49, 54))	('STAT3', 'Gene', '6774', (173, 178))	('interaction', 'Interaction', (18, 29))	('STAT3', 'Gene', (173, 178))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('occupancy', 'MPA', (76, 85))	('miR551b-3p', 'Var', (33, 43))	('STAT3', 'Gene', '6774', (49, 54))
28254	31875548	To further interrogate if STAT3 is critical for the expression of the OSM gene module, we transfected miR551b-3p into breast cancer cells that had been transfected separately with two different STAT3 siRNAs.	('STAT3', 'Gene', '6774', (194, 199))	('STAT3', 'Gene', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('STAT3', 'Gene', '6774', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('STAT3', 'Gene', (26, 31))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('miR551b-3p', 'Var', (102, 112))
28256	31875548	Importantly, our results showed that loss of STAT3 expression abolished miR551b-induced OSMR, IL6ST, and IL31RA at both the transcript (Figure-5A) and protein level (Figure-5B).	('miR551b-induced', 'Var', (72, 87))	('abolished', 'NegReg', (62, 71))	('STAT3', 'Gene', (45, 50))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('IL6ST', 'Gene', (94, 99))	('OSMR', 'Gene', (88, 92))	('IL31RA', 'Gene', '133396', (105, 111))	('OSMR', 'Gene', '9180', (88, 92))	('loss', 'Var', (37, 41))	('IL6ST', 'Gene', '3572', (94, 99))	('IL31RA', 'Gene', (105, 111))	('STAT3', 'Gene', '6774', (45, 50))
28258	31875548	Our results showed that loss of STAT3 abolished miR551b-induced increase in the expression of OSM and IL31 in both MDA-MB-231 and MCF10A cell lines (Figures-5C and S6A).	('loss', 'Var', (24, 28))	('abolished', 'NegReg', (38, 47))	('OSM', 'Gene', (94, 97))	('STAT3', 'Gene', '6774', (32, 37))	('STAT3', 'Gene', (32, 37))	('IL31', 'Gene', (102, 106))	('increase', 'PosReg', (64, 72))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (115, 125))	('MCF10A', 'CellLine', 'CVCL:0598', (130, 136))	('expression', 'MPA', (80, 90))	('miR551b-induced', 'Var', (48, 63))	('si', 'Chemical', 'MESH:D012825', (86, 88))
28259	31875548	To investigate whether miR551b induces STAT3-mediated transcription of OSM family genes, we performed chromatin immunoprecipitation (ChIP), targeting STAT3 protein.	('STAT3', 'Gene', '6774', (39, 44))	('induces', 'Reg', (31, 38))	('STAT3', 'Gene', '6774', (150, 155))	('STAT3', 'Gene', (39, 44))	('STAT3', 'Gene', (150, 155))	('miR551b', 'Var', (23, 30))
28260	31875548	This approach showed that miR551b-3p treatment enriched STAT3 on promoters of the OSM gene module, including the promoters of OSMR, OSM, IL31RA, IL31, and IL6ST (Figure-5D and Figure-S6B).	('OSMR', 'Gene', '9180', (126, 130))	('OSM gene module', 'Gene', (82, 97))	('STAT3', 'Gene', (56, 61))	('IL6ST', 'Gene', (155, 160))	('STAT3', 'Gene', '6774', (56, 61))	('IL31RA', 'Gene', '133396', (137, 143))	('miR551b-3p', 'Var', (26, 36))	('IL6ST', 'Gene', '3572', (155, 160))	('OSMR', 'Gene', (126, 130))	('IL31RA', 'Gene', (137, 143))
28263	31875548	This result supports the notion that chemokines such as OSM or IL31 produced by STAT3 could activate STAT3 for prolonged periods contributing to transcription of OSM, OSMR, IL6ST, IL31, and IL31R.	('STAT3', 'Gene', '6774', (101, 106))	('IL31', 'Var', (180, 184))	('STAT3', 'Gene', '6774', (80, 85))	('OSM', 'Gene', (162, 165))	('STAT3', 'Gene', (101, 106))	('STAT3', 'Gene', (80, 85))	('transcription', 'MPA', (145, 158))	('OSMR', 'Gene', (167, 171))	('IL6ST', 'Gene', (173, 178))	('OSMR', 'Gene', '9180', (167, 171))	('IL6ST', 'Gene', '3572', (173, 178))	('IL31R', 'Var', (190, 195))
28264	31875548	Thus miR551b-3p-mediated activation of STAT3 promotes transcription of OSM gene module, more importantly, for autocrine regulation of OSM family gene expression.	('miR551b-3p-mediated', 'Var', (5, 24))	('expression', 'MPA', (150, 160))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('activation', 'PosReg', (25, 35))	('STAT3', 'Gene', '6774', (39, 44))	('autocrine regulation', 'MPA', (110, 130))	('promotes', 'PosReg', (45, 53))	('STAT3', 'Gene', (39, 44))	('transcription', 'MPA', (54, 67))	('OSM gene module', 'Gene', (71, 86))
28265	31875548	As our data implied that OSM and IL31 are effectors of miR551b-3p in cancer, we next determined their effects on MDA-MB-231 breast cancer cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('miR551b-3p', 'Var', (55, 65))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (113, 123))	('cancer', 'Disease', (69, 75))
28270	31875548	Importantly, OSM and IL31 induced phosphorylation of STAT3 (Y705).	('Y705', 'Var', (60, 64))	('STAT3', 'Gene', '6774', (53, 58))	('STAT3', 'Gene', (53, 58))	('phosphorylation', 'MPA', (34, 49))
28281	31875548	We next used an orthotopic mouse model of breast cancer to explore the therapeutic potential of targeting miR551b-3p to inhibit breast cancer growth.	('miR551b-3p', 'Var', (106, 116))	('mouse', 'Species', '10090', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('inhibit', 'NegReg', (120, 127))	('breast cancer', 'Disease', (42, 55))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
28282	31875548	After encapsulating anti-miR551b-3p or control anti-miR into neutral nanoliposomes (1,2-dioleoyl-sn-glycero-3-phosphotidylcholine-DOPC), we injected them intraperitoneally into athymic female nude mice bearing MDMB231 breast cancer cells orthotopically (Figure-7A).	('breast cancer', 'Disease', (218, 231))	('anti-miR551b-3p', 'Var', (20, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('1,2-dioleoyl-sn-glycero-3-phosphotidylcholine', 'Chemical', '-', (84, 129))	('MDMB231', 'CellLine', 'CVCL:L524', (210, 217))	('DOPC', 'Chemical', '-', (130, 134))	('nude mice', 'Species', '10090', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))
28284	31875548	As expected, anti-miR551b-3p also reduced the expression of miR551b-3p (Figure-7E) and key effectors, including STAT3, OSMR, and IL6ST (Figures-7F and 7G).	('reduced', 'NegReg', (34, 41))	('miR551b-3p', 'Gene', (60, 70))	('IL6ST', 'Gene', '3572', (129, 134))	('STAT3', 'Gene', '6774', (112, 117))	('OSMR', 'Gene', (119, 123))	('anti-miR551b-3p', 'Var', (13, 28))	('STAT3', 'Gene', (112, 117))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('IL6ST', 'Gene', (129, 134))	('expression', 'MPA', (46, 56))	('OSMR', 'Gene', '9180', (119, 123))
28285	31875548	In conjunction, the treatment with anti-miR551b-3p reduced the expression of cellular proliferation marker Ki67 and upregulated the levels of apoptotic marker cleaved caspase-3 in vivo (Figure-7H).	('anti-miR551b-3p', 'Var', (35, 50))	('reduced', 'NegReg', (51, 58))	('upregulated', 'PosReg', (116, 127))	('Ki67', 'Gene', '17345', (107, 111))	('levels of apoptotic marker cleaved caspase-3', 'MPA', (132, 176))	('Ki67', 'Gene', (107, 111))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('expression of cellular proliferation', 'MPA', (63, 99))
28286	31875548	We also noticed that anti-miR551b-3p decreased the levels of vimentin and N-cadherin; and increased the levels of E-cadherin in tumor tissues and reduced secreted levels of OSM and IL31 (Figures- 7G and 7I).	('E-cadherin', 'Gene', (114, 124))	('N-cadherin', 'Gene', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('E-cadherin', 'Gene', '999', (114, 124))	('increased', 'PosReg', (90, 99))	('N-cadherin', 'Gene', '1000', (74, 84))	('reduced', 'NegReg', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('secreted levels of OSM', 'MPA', (154, 176))	('vimentin', 'Gene', '7431', (61, 69))	('tumor', 'Disease', (128, 133))	('vimentin', 'Gene', (61, 69))	('decreased', 'NegReg', (37, 46))	('anti-miR551b-3p', 'Var', (21, 36))
28287	31875548	It is noteworthy that the delivery of anti-miR551b-3p encapsulated in neutral nanolipsome did not make any unfavorable toxic effects in mice as indicated by significant changes in the levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), loss in body weight or toxicity induced damages in kidney, liver, lung heart, brain and spleen, (Figures S7A to S7D).	('body weight', 'CPA', (277, 288))	('mice', 'Species', '10090', (136, 140))	('ALT', 'Gene', (263, 266))	('alanine aminotransferase', 'Gene', (237, 261))	('loss', 'NegReg', (269, 273))	('aspartate aminotransferase', 'Gene', '235504', (200, 226))	('aspartate aminotransferase', 'Gene', (200, 226))	('alanine aminotransferase', 'Gene', '76282', (237, 261))	('toxicity', 'Disease', 'MESH:D064420', (292, 300))	('ALT', 'Gene', '76282', (263, 266))	('kidney', 'MPA', (320, 326))	('toxicity', 'Disease', (292, 300))	('AST', 'Gene', '235504', (228, 231))	('AST', 'Gene', (228, 231))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (194, 226))	('anti-miR551b-3p', 'Var', (38, 53))
28288	31875548	To further determine the effects of anti-miR551b-3p we observed due to the specific inhibition of miR551b but not through other non-specific targets, we prepared MDA-MB-231 cells stably knockdown of miR551b using small hairpin loop expressing anti-miR sequences or scrambled sequences and selected clone#3, in which miR551b expression is reduced more than 90% compared to the control for further studies (Figure-S8A and S8B) and also reduced the sphere forming capacity of MDA-MB-231 cells ~90% consistently in the serial dilutions (Figure-S8C) along with loss of characteristics of cancer stem cell markers evidenced by the loss of expression of CD44 and c-KIT and gain in the levels of CD24 (Figure-S8D).	('cancer', 'Phenotype', 'HP:0002664', (583, 589))	('si', 'Chemical', 'MESH:D012825', (208, 210))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (162, 172))	('si', 'Chemical', 'MESH:D012825', (238, 240))	('c-KIT', 'Gene', (656, 661))	('CD24', 'Gene', (688, 692))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (473, 483))	('miR551b', 'Var', (199, 206))	('miR551b', 'Var', (316, 323))	('cancer', 'Disease', 'MESH:D009369', (583, 589))	('c-KIT', 'Gene', '3815', (656, 661))	('characteristics', 'CPA', (564, 579))	('sphere forming capacity', 'CPA', (446, 469))	('gain', 'PosReg', (666, 670))	('levels', 'MPA', (678, 684))	('loss', 'NegReg', (556, 560))	('expression', 'MPA', (633, 643))	('CD44', 'Gene', '960', (647, 651))	('si', 'Chemical', 'MESH:D012825', (330, 332))	('CD44', 'Gene', (647, 651))	('reduced', 'NegReg', (338, 345))	('CD24', 'Gene', '100133941', (688, 692))	('si', 'Chemical', 'MESH:D012825', (498, 500))	('reduced', 'NegReg', (434, 441))	('cancer', 'Disease', (583, 589))	('si', 'Chemical', 'MESH:D012825', (639, 641))	('loss', 'NegReg', (625, 629))
28290	31875548	In our 3D culture assay, we found that the stable knockdown of miR551b-3p in MDA-MB-231 cells reduced the size and number of 3D colonies in matrigel significantly.	('si', 'Chemical', 'MESH:D012825', (149, 151))	('miR551b-3p', 'Var', (63, 73))	('reduced', 'NegReg', (94, 101))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (77, 87))
28291	31875548	We also found that the transfections of anti-miR551b-3p reduced the cell viability, spheroid size and number of 3D colonies of MDA-MB-231-sh-control-miR cells.	('cell viability', 'CPA', (68, 82))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (127, 137))	('reduced', 'NegReg', (56, 63))	('anti-miR551b-3p', 'Var', (40, 55))	('spheroid size', 'CPA', (84, 97))
28292	31875548	In contrast, transfections of anti-miR551b-3p in MDA-MB-231-sh-miR551b cells, did not have any effect on the cell viability, spheroid size and number of 3D colonies and miR551b-3p expression in miR551b-3p stable knockdown cells (Figure-S8E to S8G).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (49, 59))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('anti-miR551b-3p', 'Var', (30, 45))	('miR551b-3p', 'Gene', (169, 179))	('si', 'Chemical', 'MESH:D012825', (186, 188))
28293	31875548	Next, we employed the orthotopic breast cancer model, in which we injected the MDA-MB-231 control cells or MDA-MB-231-sh-miR551b (miR551b stable knockdown) cells in the mammary fat pad of nude mice.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (79, 89))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('MDA-MB-231-sh-miR551b', 'Var', (107, 128))	('nude mice', 'Species', '10090', (188, 197))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
28296	31875548	In conjunction with our results in 3D culture model, we found that the loss of miR551b-3p using sh-RNA vector reduced the tumor growth more than 70% and reduced the tumor volume on 5th week onwards until the termination of the study ~80% as compared to the group of mice bearing MDA-MB-231-control-shRNA cells.	('reduced', 'NegReg', (110, 117))	('reduced', 'NegReg', (153, 160))	('miR551b-3p', 'Gene', (79, 89))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (279, 289))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('loss', 'Var', (71, 75))	('mice', 'Species', '10090', (266, 270))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (165, 170))
28297	31875548	Importantly, we noticed that the delivery of anti-miR551b-3p in the group of mice bearing MDA-MB-231-control-shRNA reduced the tumor growth ~60% and reduced tumor volume on 5th week onwards until the termination of the study ~70%, which is comparable to the genetic loss of miR551b-3p using sh-RNA vectors.	('tumor', 'Disease', (157, 162))	('mice', 'Species', '10090', (77, 81))	('anti-miR551b-3p', 'Var', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('MDA-MB-231-control-shRNA', 'Var', (90, 114))	('reduced', 'NegReg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('reduced', 'NegReg', (149, 156))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('si', 'Chemical', 'MESH:D012825', (286, 288))
28298	31875548	In contrast, we did not find any effect on tumor growth or tumor volume by the delivery of anti-miR551b-3p encapsulated nanoliposomes in the mice bearing MDA-MB-231-sh-miR551b tumors (Figures-S9A to S9D).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('anti-miR551b-3p', 'Var', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
28299	31875548	While the treatment with anti-miR551b-3p reduced the expression of cellular proliferation marker Ki67 and upregulated the levels of cleaved caspase-3 in the mice bearing MDA-MB-231 sh-control tumors; anti-miR551b-3p did not make any significant change in the levels of Ki67 and cleaved caspase-3 in the group of mice bearing MDA-MB-231sh-miR551b-3p tumors (Figure-S9E).	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('mice', 'Species', '10090', (157, 161))	('tumors', 'Disease', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('reduced', 'NegReg', (41, 48))	('tumors', 'Disease', (349, 355))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('Ki67', 'Gene', '17345', (97, 101))	('MDA-MB-231sh-miR551b-3p', 'Var', (325, 348))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (170, 180))	('mice', 'Species', '10090', (312, 316))	('Ki67', 'Gene', (269, 273))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('levels of cleaved caspase-3', 'MPA', (122, 149))	('upregulated', 'PosReg', (106, 117))	('expression', 'MPA', (53, 63))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (325, 335))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Ki67', 'Gene', '17345', (269, 273))	('si', 'Chemical', 'MESH:D012825', (233, 235))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Ki67', 'Gene', (97, 101))
28300	31875548	Taken together, our results demonstrate that the ant-tumor effect of anti-miR551b mediated is not through any other targets other than specific inhibition of miR551b.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('anti-miR551b', 'Var', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
28303	31875548	Our data demonstrate that miR551b-3p located in 3q26.2 locus, provides growth and proliferative advantages to cancer cells.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miR551b-3p', 'Var', (26, 36))	('proliferative advantages', 'CPA', (82, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
28305	31875548	In addition to the proliferative effects, miR551b-3p, and its effector OSM gene module, and STAT3 transcription factor induce several molecular switches that could contribute to the migration and invasion of breast cancer cells.	('migration', 'CPA', (182, 191))	('miR551b-3p', 'Var', (42, 52))	('invasion', 'CPA', (196, 204))	('STAT3', 'Gene', '6774', (92, 97))	('contribute', 'Reg', (164, 174))	('STAT3', 'Gene', (92, 97))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('induce', 'Reg', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('molecular switches', 'MPA', (134, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
28306	31875548	We found that mature miR551b-3p translocates from the cytoplasm to nucleus with the aid of IPO8 to interact with STAT3 promoter.	('IPO8', 'Gene', (91, 95))	('translocates', 'MPA', (32, 44))	('miR551b-3p', 'Var', (21, 31))	('IPO8', 'Gene', '10526', (91, 95))	('STAT3', 'Gene', '6774', (113, 118))	('STAT3', 'Gene', (113, 118))	('interact', 'Interaction', (99, 107))
28310	31875548	Constitutive activation of STAT3 has been reported in various cancers, thus STAT3 could be exploited as a target for cancer therapy in the patients, whose tumors express high levels of miR551b-3p.	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('STAT3', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (155, 161))	('miR551b-3p', 'Var', (185, 195))	('STAT3', 'Gene', '6774', (76, 81))	('STAT3', 'Gene', (27, 32))	('activation', 'PosReg', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('STAT3', 'Gene', '6774', (27, 32))
28312	31875548	Recent developments in the small molecule inhibitors yielded into new generation STAT3 inhibitors like PG-S3-001 which is derived from the SH-4-54 class of STAT3 inhibitors as well as inhibitors like SF-1-066, BP-1-102, and BP-5-087 demonstrated superior pharmacokinetic properties for cancer therapy and treatment without severe toxicity and off target effects.	('BP-5-087', 'Chemical', 'MESH:C000597560', (224, 232))	('SF-1-066', 'Var', (200, 208))	('BP-5-087', 'Var', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('STAT3', 'Gene', '6774', (81, 86))	('STAT3', 'Gene', '6774', (156, 161))	('SF-1-066', 'Chemical', 'MESH:C000595191', (200, 208))	('toxicity', 'Disease', (330, 338))	('BP-1-102', 'Var', (210, 218))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('PG-S3', 'Gene', (103, 108))	('STAT3', 'Gene', (156, 161))	('cancer', 'Disease', (286, 292))	('STAT3', 'Gene', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('BP-1-102', 'Chemical', 'MESH:C000595192', (210, 218))	('PG-S3', 'Gene', '25809', (103, 108))	('pharmacokinetic properties', 'MPA', (255, 281))
28316	31875548	Overexpression of growth factor family genes or their mutations are important mechanisms for aberrant activation of growth factor signaling, which enhance the robustness of oncogenic signaling.	('si', 'Chemical', 'MESH:D012825', (183, 185))	('growth factor signaling', 'Pathway', (116, 139))	('oncogenic signaling', 'CPA', (173, 192))	('enhance', 'PosReg', (147, 154))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('mutations', 'Var', (54, 63))	('activation', 'PosReg', (102, 112))	('robustness', 'MPA', (159, 169))	('growth factor family genes', 'Gene', (18, 44))	('si', 'Chemical', 'MESH:D012825', (10, 12))
28318	31875548	Our in vitro and clinical data supports the notion that upregulated levels of OSM and IL31, which are mediated by miR551b-3p, not only promotes the proliferation of tumor cells, which also facilitate the transition of tumor cells towards mesenchymal traits for invasion and metastasis.	('si', 'Chemical', 'MESH:D012825', (208, 210))	('proliferation', 'CPA', (148, 161))	('facilitate', 'PosReg', (189, 199))	('si', 'Chemical', 'MESH:D012825', (281, 283))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('miR551b-3p', 'Var', (114, 124))	('transition', 'CPA', (204, 214))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promotes', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (218, 223))	('si', 'Chemical', 'MESH:D012825', (265, 267))	('upregulated', 'PosReg', (56, 67))	('tumor', 'Disease', (165, 170))
28320	31875548	In this regard, we propose that targeting OSM gene module will be effective approach to treat a subset of patients, whose tumors express miR551b-3p or STAT3 or both.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('miR551b-3p', 'Var', (137, 147))	('STAT3', 'Gene', (151, 156))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('STAT3', 'Gene', '6774', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
28321	31875548	The OSM signaling module we identified as the downstream effect of miR551b-3p, is comprised of ligands (OSM and IL31), their receptors (OSMR, and IL31RA), and the STAT3 transcription factor are regulated through an autocrine mechanism (Figure-7J).	('OSM', 'MPA', (4, 7))	('STAT3', 'Gene', '6774', (163, 168))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('STAT3', 'Gene', (163, 168))	('IL31RA', 'Gene', '133396', (146, 152))	('IL31RA', 'Gene', (146, 152))	('miR551b-3p', 'Var', (67, 77))	('OSMR', 'Gene', '9180', (136, 140))	('OSMR', 'Gene', (136, 140))
28328	31875548	Many of nano-liposome encapsulated RNAi strategies have entered in the clinic trials for a number of cancers, suggesting that targeting miR551b-3p with anti-microRNAs warrants further exploration as a novel therapy to inhibit STAT3 and OSM signaling module in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('si', 'Chemical', 'MESH:D012825', (240, 242))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('breast cancer', 'Disease', (260, 273))	('cancers', 'Disease', (101, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('inhibit', 'NegReg', (218, 225))	('STAT3', 'Gene', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('STAT3', 'Gene', '6774', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR551b-3p', 'Var', (136, 146))
28332	31875548	For both studies, as a therapeutic approach, MDA-MB-231 tumor cells or MDA-MB-231 shmiRNA tumor bearing mice were randomly divided in two groups (n = 7/group) after seven days of tumor cell injection and treated with (150 mug/kg body weight) control anti-mirRNA or anti-miR551b-3p (encapsulated in neutral DOPC nanoliposomes) in 100mul PBS intraperitoneally twice in a week as indicated.	('anti-miR551b-3p', 'Var', (265, 280))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DOPC', 'Chemical', '-', (306, 310))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('PBS', 'Chemical', 'MESH:D007854', (336, 339))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (90, 95))	('mice', 'Species', '10090', (104, 108))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MDA-MB-231', 'Var', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (179, 184))
28349	31875548	Deletion of miR551b in Hs578T cells was validated by Synthego via Sanger sequencing of the PCR amplified edited fragment using the primers F: CCCCTGAGTTATATTTGCTGGTTCTTAC R: CCCATTGGAACAGAAATGCAATATAATC and gel electrophoresis after extracting the genomic DNA.	('si', 'Chemical', 'MESH:D012825', (122, 124))	('Hs578T', 'CellLine', 'CVCL:0332', (23, 29))	('miR551b', 'Gene', (12, 19))	('si', 'Chemical', 'MESH:D012825', (223, 225))	('Deletion', 'Var', (0, 8))
28362	31875548	The effect of miR551b on cellular motility was analyzed by carrying out cell migration and invasion assay as described earlier.	('cell migration', 'CPA', (72, 86))	('miR551b', 'Var', (14, 21))	('si', 'Chemical', 'MESH:D012825', (95, 97))
28371	31875548	For in vitro limiting dilution assay, spheroid cultures from MDA-MB-231 cells stably knockdown with shmiR551b and shcontrol miRNA were suspended as mentioned previously at 1, 10, 100, 1000, 10,000 cells per well.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))	('knockdown', 'Var', (85, 94))	('shmiR551b', 'Gene', (100, 109))
28425	31875548	For each well, 100 ng of wild type (WT) STAT3 promoter or mutant STAT3 promoter cloned in Renila Luciferase reporter vector pLight (Active Motif, Carlsbad, CA) was co-transfected along with 7 nM control miRNA or miR551b using Lipofectamine 2000.	('mutant', 'Var', (58, 64))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (226, 244))	('STAT3', 'Gene', '6774', (40, 45))	('STAT3', 'Gene', '6774', (65, 70))	('STAT3', 'Gene', (40, 45))	('STAT3', 'Gene', (65, 70))
28433	31875548	RNA-FISH was used to identify the nuclear and cytoplasmic localization of miR551b-3p in breast cancer cells.	('miR551b-3p', 'Var', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
28489	31962001	Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05).	('high grade', 'Var', (81, 91))	('HER2', 'Gene', '2064', (121, 125))	('PAR2', 'Gene', '2150', (35, 39))	('PAR2', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TF', 'Gene', '2152', (11, 13))	('high Ki67', 'Var', (70, 79))	('HER2', 'Gene', '2064', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('thrombin', 'Gene', (15, 23))	('PAR1', 'Gene', '2149', (25, 29))	('cancers', 'Disease', (57, 64))	('increased', 'PosReg', (44, 53))	('HER2', 'Gene', (121, 125))	('ER', 'Gene', '2099', (101, 103))	('ER', 'Gene', '2099', (93, 95))	('PAR1', 'Gene', (25, 29))	('thrombin', 'Gene', '2147', (15, 23))	('ER', 'Gene', '2099', (122, 124))	('HER2', 'Gene', (111, 115))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('ER', 'Gene', '2099', (112, 114))
28492	31962001	On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (>=3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT.	('reduced', 'NegReg', (57, 64))	('>=3.2', 'Var', (125, 130))	('plasma TAT', 'MPA', (113, 123))	('OS', 'Chemical', '-', (65, 67))
28530	31962001	Fibroblast expression of TF, thrombin, PAR1, and PAR2 were increased in cancers with high Ki67 (all P <= .002, Figure 3) and higher grade disease (grade 1 vs 3, all P < .001, Figure 3).	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('PAR2', 'Gene', '2150', (49, 53))	('PAR1', 'Gene', (39, 43))	('PAR1', 'Gene', '2149', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('thrombin', 'Gene', (29, 37))	('PAR2', 'Gene', (49, 53))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('high Ki67', 'Var', (85, 94))	('TF', 'Gene', '2152', (25, 27))	('cancers', 'Disease', (72, 79))	('increased', 'PosReg', (59, 68))	('thrombin', 'Gene', '2147', (29, 37))
28532	31962001	HER2 positivity was associated with increased fibroblast expression of TF (P = .01), thrombin (P = .002), and PAR2 (P = .001, Figure 4).	('positivity', 'Var', (5, 15))	('PAR2', 'Gene', '2150', (110, 114))	('fibroblast expression', 'MPA', (46, 67))	('thrombin', 'Gene', '2147', (85, 93))	('increased fibroblast expression of TF', 'Phenotype', 'HP:0410157', (36, 73))	('PAR2', 'Gene', (110, 114))	('increased', 'PosReg', (36, 45))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('thrombin', 'Gene', (85, 93))	('TF', 'Gene', '2152', (71, 73))
28537	31962001	In invasive cancer, on univariate analysis, fibroblast TF expression was associated with reduced OS (P = .02) and DFS (P = .04).	('DFS', 'CPA', (114, 117))	('invasive cancer', 'Disease', (3, 18))	('OS', 'Chemical', '-', (97, 99))	('expression', 'Var', (58, 68))	('invasive cancer', 'Disease', 'MESH:D009362', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('reduced', 'NegReg', (89, 96))	('TF', 'Gene', '2152', (55, 57))
28547	31962001	On multivariate analysis, pre-operative plasma TAT was associated with reduced OS (HR 3.26, CI:1.16-3.1, P = .02) with a high plasma TAT (>=3.2 ng/mL) associated with greater than three-fold mortality risk compared to low plasma TAT (<3.2 ng/mL) (Figure 5, Appendix D).	('>=3.2 ng/mL', 'Var', (138, 149))	('reduced', 'NegReg', (71, 78))	('OS', 'Chemical', '-', (79, 81))
28607	30342538	We therefore designed 3 independent experiments to assess the impact of non-neoplastic surrounding tissue on gene expression, in particular adipose tissue and DCIS as well as variations in TCC.	('TCC', 'Chemical', '-', (189, 192))	('variations', 'Var', (175, 185))	('TCC', 'Gene', (189, 192))
28662	30342538	The question whether multigene risk predictors are sensitive or not to variations of TCC is hence related to factors like test design and gene-specific ratios of tumor-vs-normal expression.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('TCC', 'Chemical', '-', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('variations', 'Var', (71, 81))
28671	30342538	Others have previously shown that the mean RNA recovery from DCIS was substantially lower than that of invasive tumor of similar volume.	('invasive tumor', 'Disease', (103, 117))	('DCIS', 'Var', (61, 65))	('invasive tumor', 'Disease', 'MESH:D009369', (103, 117))	('RNA recovery', 'MPA', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('lower', 'NegReg', (84, 89))
28674	30342538	Eventually, whether surrounding adipose tissue, normal tissue adjacent to tumor or admixed DCIS, the RT-qPCR signal is dominated by the invasive tumor component, allowing for consistent calculations in whole sections with up to 60% DCIS and in a TCC range of 20-100%.	('DCIS', 'Var', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TCC', 'Chemical', '-', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (74, 79))	('invasive tumor', 'Disease', 'MESH:D009369', (136, 150))	('invasive tumor', 'Disease', (136, 150))
28709	33199800	As might be expected, increasing lesion size was associated with a greater likelihood of patients undergoing mastectomy, with 80% of patients with DCIS >40 mm treated by mastectomy, compared to 19% of those with DCIS <40 mm in size.	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (89, 97))	('DCIS >40 mm', 'Var', (147, 158))	('mastectomy', 'Disease', (109, 119))
28711	33199800	Breast-conserving surgery (BCS) was the preferred mode of surgical treatment across all DCIS grades, but mastectomy was more common in patients with high-grade DCIS (36%) compared to those with low-grade DCIS (15%) (Chi2 170.9, df = 1, p < 0.0001).	('patients', 'Species', '9606', (135, 143))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))	('Breast-conserving', 'Disease', (0, 17))	('high-grade DCIS', 'Var', (149, 164))	('mastectomy', 'Disease', (105, 115))	('DCIS', 'Phenotype', 'HP:0030075', (204, 208))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
28731	33199800	Overall, 377/5753 (6.6%) patients with high-grade DCIS had an ipsilateral recurrence compared with 210/2550 (8.2%) with intermediate-grade DCIS and 73/868 (8.4%) with low-grade disease.	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('high-grade', 'Var', (39, 49))	('DCIS', 'Disease', (50, 54))	('patients', 'Species', '9606', (25, 33))	('ipsilateral recurrence', 'CPA', (62, 84))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))
28756	33199800	In a further 111 patients, both ADH and lobular in situ neoplasia were present along with the DCIS, again more commonly seen with low-grade DCIS (4% of low-grade DCIS cases) than in intermediate- (1%) or high-grade disease (<1%).	('situ neoplasia', 'Disease', (51, 65))	('neoplasia', 'Phenotype', 'HP:0002664', (56, 65))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))	('patients', 'Species', '9606', (17, 25))	('lobular in situ neoplasia', 'Phenotype', 'HP:0030076', (40, 65))	('low-grade', 'Var', (130, 139))	('situ neoplasia', 'Disease', 'MESH:D002278', (51, 65))
28758	33199800	The co-existence of differing grades of DCIS in an individual patient has been described, and some even believe that 'poorly differentiated' DCIS may evolve from 'well-differentiated' DCIS by randomly acquiring genetic defects, although this is not widely accepted.	('patient', 'Species', '9606', (62, 69))	("'poorly differentiated' DCIS", 'Disease', (117, 145))	('genetic defects', 'Var', (211, 226))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))
28768	33199800	In the cohort with extended follow-up (9191 patients), it is intriguing that a higher rate of subsequent in situ and invasive carcinoma is noted following a primary diagnosis of either low- or intermediate-grade DCIS compared with high-grade disease.	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('patients', 'Species', '9606', (44, 52))	('invasive carcinoma', 'Disease', (117, 135))	('low-', 'Var', (185, 189))	('in situ', 'Disease', (105, 112))	('intermediate-grade', 'Var', (193, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('invasive carcinoma', 'Disease', 'MESH:D009361', (117, 135))
28770	33199800	However, when analysis is limited to the majority of patients who have undergone BCS (7934, 86% of patients) the ipsilateral recurrence rates are 9.2, 9.7 and 9.8%, respectively, for high, intermediate- and low-grade DCIS (with invasive recurrence frequencies of 4.9, 6.7 and 6.7%, respectively).	('patients', 'Species', '9606', (53, 61))	('DCIS', 'Disease', (217, 221))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('high', 'Disease', (183, 187))	('patients', 'Species', '9606', (99, 107))	('low-grade', 'Var', (207, 216))
28772	33199800	The differences may also be influenced by the ability to determine DCIS size and especially completeness of excision more accurately in high-grade DCIS, due to a greater proportion of ducts associated with microcalcification when compared to low-grade DCIS in which a greater proportion of the area is non-calcific.	('calcification', 'Disease', 'MESH:D002114', (211, 224))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('calcification', 'Disease', (211, 224))	('high-grade', 'Var', (136, 146))	('associated with', 'Reg', (190, 205))	('ducts', 'Disease', (184, 189))	('DCIS', 'Phenotype', 'HP:0030075', (252, 256))
28808	29558872	For instance, there is now sufficient evidence that chemotherapy regimens employing anthracyclines and taxanes lead to higher pCR rates in triple-negative tumors compared to estrogen and progesterone receptor-positive subtypes of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('anthracyclines', 'Chemical', 'MESH:D018943', (84, 98))	('taxanes', 'Chemical', 'MESH:D043823', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('breast cancer', 'Disease', (230, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('higher', 'PosReg', (119, 125))	('progesterone receptor', 'Gene', (187, 208))	('tumors', 'Disease', (155, 161))	('pCR', 'CPA', (126, 129))	('progesterone receptor', 'Gene', '5241', (187, 208))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('anthracyclines', 'Var', (84, 98))
28814	29558872	Moreover, high lymphocyte infiltration correlates with higher pCR rates as well as with better patient prognosis.	('pCR', 'Disease', (62, 65))	('patient', 'Species', '9606', (95, 102))	('high', 'Var', (10, 14))	('higher', 'PosReg', (55, 61))	('high lymphocyte', 'Phenotype', 'HP:0100827', (10, 25))
28880	29558872	Different chemotherapeutic agents have been described to stimulate antitumor immune responses; among them, cyclophosphamide, anthracyclines, and taxanes have been demonstrated to stimulate T cell proliferation, activate NK cells, deplete circulating regulatory T cells (Treg), and inhibit Treg infiltration into tumor tissues.	('stimulate', 'PosReg', (57, 66))	('anthracyclines', 'Var', (125, 139))	('taxanes', 'Var', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('activate', 'PosReg', (211, 219))	('tumor', 'Disease', (312, 317))	('anthracyclines', 'Chemical', 'MESH:D018943', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('cyclophosphamide', 'Var', (107, 123))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (107, 123))	('stimulate', 'PosReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('NK cells', 'CPA', (220, 228))	('T cell proliferation', 'CPA', (189, 209))	('tumor', 'Disease', (71, 76))	('taxanes', 'Chemical', 'MESH:D043823', (145, 152))	('deplete', 'NegReg', (230, 237))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('inhibit', 'NegReg', (281, 288))
28916	28262971	Two independent studies showed that Maspin global knockout is embryonically lethal.	('Maspin', 'Gene', (36, 42))	('global knockout', 'Var', (43, 58))	('ies', 'Chemical', 'MESH:D015019', (20, 23))
28945	28262971	Conversely, cytoplasmic staining of maspin was associated with ER and PR negativity, high cell cycle S-phase fraction and aneuploidy.	('maspin', 'Gene', (36, 42))	('PR', 'Gene', '5241', (70, 72))	('aneuploidy', 'Disease', 'MESH:D000782', (122, 132))	('high cell cycle S-phase fraction', 'CPA', (85, 117))	('cytoplasmic staining', 'Var', (12, 32))	('aneuploidy', 'Disease', (122, 132))	('associated', 'Reg', (47, 57))
28957	28262971	This finding is not entirely surprising as a significant fraction of triple negative breast cancer bears significant resemblance to that of stem-like basal cells, which may reside in the maspin-positive myoepithelial layer.	('myoepithelial', 'Disease', (203, 216))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('myoepithelial', 'Disease', 'MESH:D009208', (203, 216))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('triple negative', 'Var', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
28962	28262971	Despite the biphasic maspin differential expression in breast tumor progression, the 60 human breast cancer cell lines included in the National Cancer Institute (NCI) for anticancer drug screening (NCI60/NCBI profile: GDS4296/204855_at/) lost maspin expression.	('cancer', 'Disease', (175, 181))	('human', 'Species', '9606', (88, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast tumor', 'Disease', 'MESH:D001943', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lost', 'NegReg', (238, 242))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast tumor', 'Phenotype', 'HP:0100013', (55, 67))	('maspin', 'Protein', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('breast tumor', 'Disease', (55, 67))	('Cancer', 'Disease', (144, 150))	('maspin', 'Protein', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (144, 150))	('GDS4296/204855_at/', 'Var', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('expression', 'MPA', (250, 260))
28965	28262971	When the Maspin gene is conditionally knocked out in oogenesis by Zp3-Cre mediated recombination, the virgin mammary glands of the resulting animals display myoepithelial hyperplasia and increased mammary duct branching while the luminal epithelial cell morphology remains largely unchanged.	('myoepithelial hyperplasia', 'Disease', (157, 182))	('Zp3', 'Gene', '7784', (66, 69))	('mammary duct branching', 'CPA', (197, 219))	('myoepithelial hyperplasia', 'Disease', 'MESH:D009208', (157, 182))	('Zp3', 'Gene', (66, 69))	('Maspin', 'Gene', (9, 15))	('knocked out', 'Var', (38, 49))	('increased', 'PosReg', (187, 196))
28976	28262971	Since the first report that ectopically expressed maspin inhibits breast tumor cell invasion in vitro and blocks tumor metastasis in vivo, preclinical evidence with established mammary epithelial cell lines in vivo and in vitro demonstrates that the collective function of maspin is to support the differentiated phenotype of epithelial cells, which includes polarized and stable organization through cell-cell and cell-matrix interaction, the sensitivity to contact-inhibition of proliferation, strong defense against stress and lack of invasiveness.	('breast tumor', 'Disease', 'MESH:D001943', (66, 78))	('polarized', 'CPA', (359, 368))	('ectopically expressed', 'Var', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('blocks tumor metastasis', 'Disease', (106, 129))	('breast tumor', 'Disease', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('breast tumor', 'Phenotype', 'HP:0100013', (66, 78))	('maspin', 'Gene', (50, 56))	('blocks tumor metastasis', 'Disease', 'MESH:D009362', (106, 129))	('inhibits', 'NegReg', (57, 65))
28979	28262971	In contrast to the acini formation by the parental MCF-10A and scrambled siRNA-transfected control (NC1), maspin knock-down clones (siMas8 and siMas11) were more proliferative, formed disorganized cellular aggregates with increased infiltration into the Matrigel (Figure 1,).	('knock-down', 'Var', (113, 123))	('formed', 'Reg', (177, 183))	('proliferative', 'CPA', (162, 175))	('maspin', 'Gene', (106, 112))	('MCF-10A', 'CellLine', 'CVCL:0598', (51, 58))	('more', 'PosReg', (157, 161))	('increased', 'PosReg', (222, 231))	('disorganized cellular aggregates', 'CPA', (184, 216))	('infiltration into the Matrigel', 'CPA', (232, 262))
28981	28262971	These data are consistent with the observation that maspin re-expression in prostate tumor cells DU145 rendered epithelial acini formation in an in vivo xenograft model for tumor bone metastasis and in an organotypic 3D collagen I model system.	('DU145', 'CellLine', 'CVCL:0105', (97, 102))	('prostate tumor', 'Phenotype', 'HP:0100787', (76, 90))	('tumor bone metastasis', 'Disease', (173, 194))	('epithelial acini formation', 'CPA', (112, 138))	('maspin', 'Gene', (52, 58))	('prostate tumor', 'Disease', 'MESH:D011471', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor bone metastasis', 'Disease', 'MESH:D009362', (173, 194))	('re-expression', 'Var', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('prostate tumor', 'Disease', (76, 90))
28982	28262971	Moreover, these results are in agreement with a previous report that maspin re-expression in prostate tumor cells averts stemness.	('prostate tumor', 'Phenotype', 'HP:0100787', (93, 107))	('re-expression', 'Var', (76, 89))	('prostate tumor', 'Disease', 'MESH:D011471', (93, 107))	('stemness', 'CPA', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('maspin', 'Protein', (69, 75))	('averts', 'NegReg', (114, 120))	('prostate tumor', 'Disease', (93, 107))
28992	28262971	In the third study, we showed that amino acid D346 in maspin is critical for its translocation from the nucleus to the cytoplasm in prostate cancer cells.	('D346', 'Chemical', 'MESH:C030860', (46, 50))	('prostate cancer', 'Disease', (132, 147))	('maspin', 'Gene', (54, 60))	('translocation', 'MPA', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('amino acid D346', 'Var', (35, 50))
28993	28262971	Conservative site-directed substation of Asp346 (D346) by Glu (E) (MaspinD346E) rendered maspin exclusively nuclear.	('Glu', 'Chemical', 'MESH:D018698', (58, 61))	('D346', 'Chemical', 'MESH:C030860', (73, 77))	('Asp346', 'Chemical', '-', (41, 47))	('nuclear', 'MPA', (108, 115))	('D346', 'Chemical', 'MESH:C030860', (49, 53))	('Asp346 (D346', 'Var', (41, 53))
28994	28262971	In 3D Matrigel and Collagen I matrices, infection of SUM159 triple negative breast anaplastic tumor cells by adenovirus encoding for wild-type maspin (MaspinWT) or for the D346E mutation (MaspinD346E) reverted those cells to a better differentiated state with a highly organized structures, relative to control cells infected with empty vector adenovirus (MaspinEV), (Figure 2).	('infection', 'Disease', (40, 49))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('D346E', 'Var', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('D346E', 'Mutation', 'p.D346E', (194, 199))	('reverted', 'PosReg', (201, 209))	('breast anaplastic tumor', 'Disease', 'MESH:D001943', (76, 99))	('D346E', 'Mutation', 'p.D346E', (172, 177))	('breast anaplastic tumor', 'Disease', (76, 99))
29005	28262971	We have shown that substitution of R340 by Ala (A) abolished the maspin interaction with pro-uPA.	('uPA', 'Gene', '5328', (93, 96))	('interaction', 'Interaction', (72, 83))	('substitution', 'Var', (19, 31))	('R340 by Ala', 'Mutation', 'p.R340A', (35, 46))	('abolished', 'NegReg', (51, 60))	('maspin', 'Protein', (65, 71))	('uPA', 'Gene', (93, 96))
29010	28262971	The exposed maspin RCL with R340 at the center appears to act as a natural cap to block the entry of HDAC1 substrates.	('HDAC1', 'Gene', (101, 106))	('R340', 'Var', (28, 32))	('entry', 'MPA', (92, 97))	('HDAC1', 'Gene', '3065', (101, 106))
29011	28262971	In addition, mutation of 86 amino acids located between amino acids 139 and 225 of maspin diminished the adhesion of MCF- 10A cells to their own ECM, and may encompass the binding site to integrin beta1.	('MCF- 10A', 'CellLine', 'CVCL:0598', (117, 125))	('binding', 'Interaction', (172, 179))	('mutation', 'Var', (13, 21))	('integrin beta1', 'Gene', (188, 202))	('maspin', 'Gene', (83, 89))	('integrin beta1', 'Gene', '3688', (188, 202))	('adhesion', 'MPA', (105, 113))	('diminished', 'NegReg', (90, 100))
29013	28262971	Conservative substitution of D346 by E rendered maspin exclusively nuclear and increased the maspin interaction with HDAC1 in tumor cells that otherwise expressed maspin predominantly in the cytoplasm.	('increased', 'PosReg', (79, 88))	('D346', 'Chemical', 'MESH:C030860', (29, 33))	('interaction', 'Interaction', (100, 111))	('HDAC1', 'Gene', '3065', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('HDAC1', 'Gene', (117, 122))	('maspin', 'Protein', (93, 99))	('D346', 'Var', (29, 33))	('tumor', 'Disease', (126, 131))
29014	28262971	The current experimental evidence supports a working model that D346 may be involved in the interaction with a nuclear protein that may be down regulated in tumor progression.	('tumor', 'Disease', (157, 162))	('D346', 'Var', (64, 68))	('down regulated', 'NegReg', (139, 153))	('D346', 'Chemical', 'MESH:C030860', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('nuclear protein', 'Protein', (111, 126))	('involved', 'Reg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('interaction', 'Interaction', (92, 103))
29017	28262971	While inhibition of tyrosine phosphatases increased maspin protein levels and leads to its cytoplasmic accumulation, epidermal growth factor receptor (EGFR) signaling is shown to lead to maspin tyrosine phosphorylation and increase maspin nuclear localization in MCF-10A cells.	('increase', 'PosReg', (223, 231))	('epidermal growth factor receptor', 'Gene', (117, 149))	('epidermal growth factor receptor', 'Gene', '1956', (117, 149))	('lead to', 'Reg', (179, 186))	('maspin', 'Protein', (52, 58))	('tyrosine phosphorylation', 'MPA', (194, 218))	('maspin', 'Protein', (187, 193))	('increased', 'PosReg', (42, 51))	('tyrosine', 'Chemical', 'MESH:D014443', (20, 28))	('EGFR', 'Gene', (151, 155))	('tyrosine', 'Chemical', 'MESH:D014443', (194, 202))	('phosphatases increased', 'Phenotype', 'HP:0003155', (29, 51))	('maspin', 'Protein', (232, 238))	('tyrosine phosphatases increased', 'Phenotype', 'HP:0003231', (20, 51))	('cytoplasmic accumulation', 'MPA', (91, 115))	('inhibition', 'Var', (6, 16))	('nuclear localization', 'MPA', (239, 259))	('MCF-10A', 'CellLine', 'CVCL:0598', (263, 270))	('EGFR', 'Gene', '1956', (151, 155))
29093	19538464	The levels of hsa-mir-299-5p was determined as 2-DeltaDeltaCtx 100% wherein DeltaDeltaCt =DeltaCtbreast cancer-DeltaCtNormal Breast or DeltaDeltaCt =DeltaCtSFC-DeltaCtadherent.	('DeltaDeltaCt', 'Var', (135, 147))	('-299-5p', 'Chemical', '-', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('hsa-mir-299', 'Gene', '407023', (14, 25))	('hsa-mir-299', 'Gene', (14, 25))	('DeltaDeltaCt', 'Var', (76, 88))
29108	19538464	In order to monitor the effect of OPN on tumour growth, cells were transfected with OPN shRNA (NM636) or universal scrambled-sequence cloned into pSUPER using Lipofectamine 2000 (Invitrogen).	('tumour growth', 'Disease', (41, 54))	('OPN', 'Gene', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour growth', 'Disease', 'MESH:D006130', (41, 54))	('OPN', 'Gene', '6696', (84, 87))	('NM636', 'Var', (95, 100))	('OPN', 'Gene', (84, 87))	('OPN', 'Gene', '6696', (34, 37))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (159, 177))
29120	19538464	Overall, the rate of tumour formation by the adherent MCF10DCIS.com cells was significantly slower than the DCIS-SFC cells (P= 0.02).	('MCF10DCIS.com', 'Var', (54, 67))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Disease', (21, 27))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (54, 67))	('slower', 'NegReg', (92, 98))
29137	19538464	We previously published that abrogating OPN expression greatly reduced the tumorigenicity of aggressive, metastatic human breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('reduced', 'NegReg', (63, 70))	('abrogating', 'Var', (29, 39))	('OPN', 'Gene', '6696', (40, 43))	('expression', 'Protein', (44, 54))	('OPN', 'Gene', (40, 43))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('human', 'Species', '9606', (116, 121))
29138	19538464	When the secreted OPN was squelched by the addition of a neutralizing anti-OPN antibody, the SFCs proliferated significantly slower compared to the cells with an isotype control antibody added.	('OPN', 'Gene', '6696', (18, 21))	('neutralizing', 'Var', (57, 69))	('OPN', 'Gene', '6696', (75, 78))	('OPN', 'Gene', (18, 21))	('slower', 'NegReg', (125, 131))	('proliferated', 'CPA', (98, 110))	('OPN', 'Gene', (75, 78))
29139	19538464	In the presence of an anti-OPN antibody the proliferation rate of MCF7- SFC and MCF10DCIS- SFC was reduced to 40% (P < 0.001) and 60% (P < 0.005) respectively of the untreated cells.	('OPN', 'Gene', (27, 30))	('MCF7', 'CellLine', 'CVCL:0031', (66, 70))	('MCF10DCIS-', 'Var', (80, 90))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (80, 89))	('proliferation rate', 'CPA', (44, 62))	('MCF7-', 'Var', (66, 71))	('reduced', 'NegReg', (99, 106))	('OPN', 'Gene', '6696', (27, 30))
29143	19538464	In order to determine if the increased expression of OPN contributed towards the growth advantage of the tumour, we injected 50,000 spheroid-enriched cells from MCF10DCIS.com cells (DCIS- SFC) that were transfected with either the shRNA to OPN or a universal scrambled-sequence control (Fig.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('OPN', 'Gene', '6696', (240, 243))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (161, 174))	('MCF10DCIS.com', 'Var', (161, 174))	('tumour', 'Disease', (105, 111))	('OPN', 'Gene', (240, 243))	('OPN', 'Gene', '6696', (53, 56))	('OPN', 'Gene', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
29144	19538464	The MCF10DCIS- SFC transfected with shRNA to OPN (DCIS- SFC + OPN shRNA) showed significant (P= 0.03) retardation in the tumour growth rate compared to MCF10DCIS- SFC transfected with scrambled-sequence shRNA (DCIS- SFC + Scr shRNA).	('OPN', 'Gene', (62, 65))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (152, 161))	('OPN', 'Gene', '6696', (45, 48))	('MCF10DCIS-', 'Var', (4, 14))	('OPN', 'Gene', (45, 48))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour growth', 'Disease', (121, 134))	('retardation', 'Disease', (102, 113))	('tumour growth', 'Disease', 'MESH:D006130', (121, 134))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (4, 13))	('retardation', 'Disease', 'MESH:D008607', (102, 113))	('OPN', 'Gene', '6696', (62, 65))
29145	19538464	While the MCF10DCIS- SFC + Scr shRNA group attained an average size of 9 mm in just 30 days, the MCF10DCIS- SFC + OPN shRNA tumours attained 8 mm average size after 38 days (Fig.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (97, 106))	('OPN', 'Gene', '6696', (114, 117))	('OPN', 'Gene', (114, 117))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('MCF10DCIS- SFC', 'Var', (97, 111))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (10, 19))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
29146	19538464	Thus, transfecting shRNA to OPN resulted in a ~30% slower growth rate of the MCF10DCIS- SFC.	('OPN', 'Gene', '6696', (28, 31))	('transfecting', 'Var', (6, 18))	('OPN', 'Gene', (28, 31))	('slower', 'NegReg', (51, 57))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (77, 86))	('growth rate', 'MPA', (58, 69))
29150	19538464	Moreover, silencing of OPN from malignant breast cancer cells negatively impacted their tumorigenic potential.	('negatively', 'NegReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('tumorigenic potential', 'CPA', (88, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('OPN', 'Gene', '6696', (23, 26))	('OPN', 'Gene', (23, 26))	('silencing', 'Var', (10, 19))
29157	19538464	This suggests that removal of OPN interfered with the ability of the SFCs to maintain the spheroid structure and to adapt to nutrient limitation.	('spheroid structure', 'CPA', (90, 108))	('adapt', 'MPA', (116, 121))	('OPN', 'Gene', '6696', (30, 33))	('OPN', 'Gene', (30, 33))	('removal', 'Var', (19, 26))	('interfered', 'NegReg', (34, 44))
29195	19538464	As the cancer cells acquire self-sufficiency and undergo uncontrolled proliferation, due to genetic changes within or as a result of changes in the microenvironment, the niche gets transformed into a microenvironment that favours proliferation and growth.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('favours', 'PosReg', (222, 229))	('growth', 'CPA', (248, 254))	('changes', 'Reg', (133, 140))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('changes', 'Var', (100, 107))	('proliferation', 'CPA', (230, 243))	('self-sufficiency', 'CPA', (28, 44))
29202	19538464	As a component of the secretome of cancer cells, OPN interacts with cell surface via integrins and CD44 variants and can act as a medium for cell adhesion.	('integrins', 'Protein', (85, 94))	('OPN', 'Gene', '6696', (49, 52))	('CD44', 'Gene', '960', (99, 103))	('OPN', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('interacts', 'Interaction', (53, 62))	('variants', 'Var', (104, 112))	('CD44', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
29225	19538464	The gain-of-OPN expression permits the spheroid forming breast cancer cells to metamorphose into vascular structures that support a lumen, thereby highlighting their role in tumour angiogenesis.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('expression', 'Var', (16, 26))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('OPN', 'Gene', '6696', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('OPN', 'Gene', (12, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('metamorphose', 'CPA', (79, 91))
29247	30795637	Therefore, this study sought to examine the acute postoperative complication rates in breast cancer patients who underwent PM, M, M + I, M + MF, and OPS.	('M + I', 'Var', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('patients', 'Species', '9606', (100, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('M + MF', 'Var', (137, 143))
29253	30795637	After October 2015, ICD Tenth Edition replaced the previous system of classification, and patients with IvBC or DCIS were classified under the appropriate ICD-10 codes: D05, D5.1-D05.99 (DCIS), and IvBC (C50).	('D5.1-D05.99', 'Var', (174, 185))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('IvBC', 'Chemical', '-', (104, 108))	('ICD Tenth Edition', 'Disease', 'OMIM:252500', (20, 37))	('ICD Tenth Edition', 'Disease', (20, 37))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('IvBC', 'Chemical', '-', (198, 202))	('patients', 'Species', '9606', (90, 98))	('D05', 'Var', (169, 172))
29256	30795637	Each patient was categorized as: underweight (BMI < 18.5), normal (BMI 18.5-25), overweight (BMI 25-30) or obese (BMI > 30).	('obese', 'Disease', (107, 112))	('patient', 'Species', '9606', (5, 12))	('overweight', 'Phenotype', 'HP:0025502', (81, 91))	('obese', 'Disease', 'MESH:D009765', (107, 112))	('BMI 25-30', 'Var', (93, 102))
29257	30795637	NSQIP defines patients at risk for bleeding due to any condition with deficiency of clotting elements (Vitamin K deficiency, hemophilia's, thrombocytopenia, or on chronic anticoagulation other than aspirin).	('bleeding', 'Disease', (35, 43))	('aspirin', 'Chemical', 'MESH:D001241', (198, 205))	('deficiency', 'Var', (113, 123))	('thrombocytopenia', 'Disease', 'MESH:D013921', (139, 155))	('deficiency of clotting', 'Disease', (70, 92))	('hemophilia', 'Disease', (125, 135))	('deficiency of clotting', 'Disease', 'MESH:D013927', (70, 92))	('Vitamin K', 'Chemical', 'MESH:D014812', (103, 112))	('deficiency of clotting', 'Phenotype', 'HP:0001928', (70, 92))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (139, 155))	('bleeding', 'Disease', 'MESH:D006470', (35, 43))	('thrombocytopenia', 'Disease', (139, 155))	("hemophilia's", 'Disease', 'MESH:D006467', (125, 137))	('patients', 'Species', '9606', (14, 22))
29268	30795637	Compared to other groups, the M + I group had the highest incidence of younger patients and a lower incidence of the following preoperative indicators: lower ASA class, fewer open wound infections or systemic infections within 48 hours of surgery, and fewer prior operations in the last 30 days.	('ASA class', 'MPA', (158, 167))	('fewer', 'NegReg', (169, 174))	('infections', 'Disease', (186, 196))	('ASA', 'Chemical', '-', (158, 161))	('M + I', 'Var', (30, 35))	('infections', 'Disease', 'MESH:D007239', (209, 219))	('systemic infections', 'Disease', 'MESH:D034721', (200, 219))	('lower', 'NegReg', (152, 157))	('systemic infections', 'Disease', (200, 219))	('patients', 'Species', '9606', (79, 87))	('wound infections', 'Phenotype', 'HP:0001581', (180, 196))	('infections', 'Disease', (209, 219))	('infections', 'Disease', 'MESH:D007239', (186, 196))
29269	30795637	Wound, infectious, respiratory, bleeding and thromboembolic complications were highest in the M + MF group.	('bleeding', 'Disease', 'MESH:D006470', (32, 40))	('bleeding', 'Disease', (32, 40))	('infectious', 'CPA', (7, 17))	('Wound', 'CPA', (0, 5))	('thromboembolic complications', 'Disease', (45, 73))	('respiratory', 'CPA', (19, 30))	('M + MF', 'Var', (94, 100))	('thromboembolic complications', 'Disease', 'MESH:D013923', (45, 73))	('thromboembolic complications', 'Phenotype', 'HP:0001907', (45, 73))
29273	30795637	Factors in the unadjusted analysis most likely associated with any complication were: outpatient surgery, increased BMI, smoking, M + R, OPS, ASA Class, increasing operative time, PMH of diabetics, renal failure, angina, CHF, COPD and HTN.	('angina', 'Disease', 'MESH:D000787', (213, 219))	('renal failure', 'Phenotype', 'HP:0000083', (198, 211))	('associated', 'Reg', (47, 57))	('BMI', 'Disease', (116, 119))	('increased BMI', 'Phenotype', 'HP:0031418', (106, 119))	('renal failure', 'Disease', 'MESH:D051437', (198, 211))	('angina', 'Disease', (213, 219))	('renal failure', 'Disease', (198, 211))	('COPD', 'Disease', 'MESH:D029424', (226, 230))	('diabetics', 'Disease', (187, 196))	('COPD', 'Disease', (226, 230))	('CHF', 'Disease', (221, 224))	('M + R', 'Var', (130, 135))	('diabetics', 'Disease', 'MESH:D003920', (187, 196))	('outpatient', 'Species', '9606', (86, 96))	('outpatient surgery', 'Disease', (86, 104))	('ASA', 'Chemical', '-', (142, 145))	('HTN', 'Phenotype', 'HP:0000822', (235, 238))	('CHF', 'Disease', 'MESH:D006333', (221, 224))
29289	30795637	PMH of angina was associated with a two-fold risk of wound complications (p = 0.003) and cardiac complications risk 5.20x (p = 0.03).	('wound complications', 'CPA', (53, 72))	('angina', 'Disease', (7, 13))	('cardiac complications', 'Disease', 'MESH:D005117', (89, 110))	('angina', 'Disease', 'MESH:D000787', (7, 13))	('cardiac complications', 'Disease', (89, 110))	('PMH', 'Var', (0, 3))
29294	30795637	There was a 10-fold increase for bleeding complications in the M + MF group (<0.0001).	('bleeding complications', 'Disease', 'MESH:D006470', (33, 55))	('bleeding complications', 'Disease', (33, 55))	('M + MF', 'Var', (63, 69))	('increase', 'PosReg', (20, 28))
29305	30795637	The occurrence of a bleeding complication was 4.34% in M + MF, followed by 1.2% in M, 0.63% in M + I and 0.38% in OPS.	('bleeding', 'Disease', 'MESH:D006470', (20, 28))	('M + I', 'Var', (95, 100))	('bleeding', 'Disease', (20, 28))	('M + MF', 'Var', (55, 61))
29306	30795637	Overall, our analysis relates to and expands on previously published data demonstrating that patients undergoing OPS had the lowest complication rates when compared to patients undergoing M alone or M with any reconstructive procedure.	('complication', 'CPA', (132, 144))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (93, 101))	('OPS', 'Var', (113, 116))
29319	30795637	For example, HTN increased odds two-fold (p = 0.003) for cardiac complications as did angina 5x (p = 0.03) and underweight BMI 3x (p = 0.02).	('HTN', 'Phenotype', 'HP:0000822', (13, 16))	('HTN', 'Var', (13, 16))	('cardiac complications', 'Disease', (57, 78))	('underweight BMI', 'Phenotype', 'HP:0045082', (111, 126))	('angina', 'Disease', (86, 92))	('cardiac complications', 'Disease', 'MESH:D005117', (57, 78))	('angina', 'Disease', 'MESH:D000787', (86, 92))
29321	30795637	Similarly, PMH of renal failure exaggerated renal complications ten-fold (p = 0.03) as did other comorbidities such as CHF, bleeding disorders and recent weight loss (albeit to a lesser extent).	('weight loss', 'Disease', (154, 165))	('renal complications', 'Disease', (44, 63))	('renal failure', 'Phenotype', 'HP:0000083', (18, 31))	('weight loss', 'Phenotype', 'HP:0001824', (154, 165))	('exaggerated', 'PosReg', (32, 43))	('renal complications', 'Disease', 'MESH:D007674', (44, 63))	('renal failure', 'Disease', 'MESH:D051437', (18, 31))	('PMH', 'Var', (11, 14))	('weight loss', 'Disease', 'MESH:D015431', (154, 165))	('bleeding disorders', 'Disease', (124, 142))	('bleeding disorders', 'Disease', 'MESH:D006470', (124, 142))	('CHF', 'Disease', (119, 122))	('renal failure', 'Disease', (18, 31))	('CHF', 'Disease', 'MESH:D006333', (119, 122))
29338	28690657	Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes Immortality is an essential characteristic of cancer cells; a recent transcriptomic study of epithelial cell immortalization has linked epigenetic silencing of the long noncoding RNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) to this process.	('MORT', 'Gene', '100128252', (24, 28))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('epigenetic silencing', 'Var', (265, 285))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Mortal Obligate RNA Transcript', 'Gene', (312, 342))	('MORT', 'Gene', (24, 28))	('Breast Tumor', 'Phenotype', 'HP:0100013', (107, 119))	('Tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MORT', 'Gene', '100128252', (344, 348))	('alias ZNF667-AS1', 'Disease', (350, 366))	('alias ZNF667-AS1', 'Disease', 'OMIM:607277', (350, 366))	('Mortal Obligate RNA Transcript', 'Gene', '100128252', (312, 342))	('MORT', 'Gene', (344, 348))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
29340	28690657	Results show that MORT silencing is an early epigenetic event in human carcinogenesis, likely occurring near the point where premalignant cells gain immortality; this epigenetic silencing is maintained throughout malignant transformation and metastatic growth.	('human', 'Species', '9606', (65, 70))	('MORT', 'Gene', '100128252', (18, 22))	('carcinogenesis', 'Disease', (71, 85))	('silencing', 'Var', (23, 32))	('MORT', 'Gene', (18, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
29341	28690657	Additional associations between MORT loss and clinical and molecular features of breast tumors showed that silencing of MORT occurs predominantly in luminal, receptor-positive breast cancer; is associated with overexpression of CCND1 and mutations of GATA3; and is negatively correlated with TP53 mutations.	('MORT', 'Gene', (120, 124))	('TP53', 'Gene', (292, 296))	('breast tumors', 'Disease', 'MESH:D001943', (81, 94))	('breast tumors', 'Disease', (81, 94))	('breast tumors', 'Phenotype', 'HP:0100013', (81, 94))	('negatively', 'NegReg', (265, 275))	('breast tumor', 'Phenotype', 'HP:0100013', (81, 93))	('mutations', 'Var', (238, 247))	('silencing', 'MPA', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MORT', 'Gene', '100128252', (32, 36))	('overexpression', 'PosReg', (210, 224))	('MORT', 'Gene', '100128252', (120, 124))	('luminal', 'Disease', (149, 156))	('TP53', 'Gene', '7157', (292, 296))	('GATA3', 'Gene', '2625', (251, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('CCND1', 'Gene', '595', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('GATA3', 'Gene', (251, 256))	('mutations', 'Var', (297, 306))	('CCND1', 'Gene', (228, 233))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('breast cancer', 'Disease', (176, 189))	('MORT', 'Gene', (32, 36))
29343	28690657	Immortality is an essential characteristic of cancer cells; our recent transcriptomic study of in vitro immortalization of human mammary epithelial cells (HMEC) reported on the epigenetic silencing of the long noncoding RNA (lncRNA) Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) during the transition of the cells from mortal to immortal.	('Mortal Obligate RNA Transcript', 'Gene', '100128252', (233, 263))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('MORT', 'Gene', '100128252', (265, 269))	('human', 'Species', '9606', (123, 128))	('alias ZNF667-AS1', 'Disease', 'OMIM:607277', (271, 287))	('epigenetic silencing', 'Var', (177, 197))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Mortal Obligate RNA Transcript', 'Gene', (233, 263))	('alias ZNF667-AS1', 'Disease', (271, 287))	('MORT', 'Gene', (265, 269))
29346	28690657	Since a large fraction of clinical carcinoma in situ lesions:including ductal carcinoma in situ (DCIS) :show evidence of immortality in the absence of a frank malignancy, it is predicted that the epigenetic silencing of MORT is a common feature of this premalignant state.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('carcinoma', 'Disease', (35, 44))	('malignancy', 'Disease', (159, 169))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (71, 95))	('epigenetic silencing', 'Var', (196, 216))	('situ lesions', 'Disease', (48, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('MORT', 'Gene', (220, 224))	('carcinoma', 'Disease', (78, 87))	('situ lesions', 'Disease', 'MESH:D002278', (48, 60))	('ductal carcinoma in situ', 'Disease', (71, 95))	('carcinoma', 'Disease', 'MESH:D002277', (35, 44))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (35, 52))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('MORT', 'Gene', '100128252', (220, 224))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (71, 95))	('carcinoma', 'Disease', 'MESH:D002277', (78, 87))	('malignancy', 'Disease', 'MESH:D009369', (159, 169))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (78, 95))
29349	28690657	Consistent with previous laboratory studies, our data analysis shows that DNA methylation-mediated silencing of MORT is found in both breast DCIS and colonic adenomas; this moves the timing of MORT epigenetic silencing further back to clinical premalignant conditions.	('colonic adenomas', 'Disease', (150, 166))	('MORT', 'Gene', (112, 116))	('methylation-mediated', 'Var', (78, 98))	('MORT', 'Gene', '100128252', (193, 197))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('silencing', 'NegReg', (99, 108))	('colonic adenomas', 'Disease', 'MESH:D000236', (150, 166))	('MORT', 'Gene', '100128252', (112, 116))	('MORT', 'Gene', (193, 197))	('breast DCIS', 'Disease', (134, 145))
29350	28690657	The epigenetic silencing of MORT in premalignancy is maintained throughout progression towards the invasive and metastatic disease; no evidence was found for genetic mechanisms of MORT silencing.	('MORT', 'Gene', '100128252', (28, 32))	('epigenetic silencing', 'Var', (4, 24))	('MORT', 'Gene', '100128252', (180, 184))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('MORT', 'Gene', (28, 32))	('invasive and', 'Disease', (99, 111))	('malignancy', 'Disease', (39, 49))	('MORT', 'Gene', (180, 184))
29351	28690657	The DNA methylation-mediated silencing of MORT is significantly associated with luminal, receptor positive breast cancer; in contrast, basal triple negative breast cancers do not generally display MORT methylation or gene silencing.	('silencing', 'NegReg', (29, 38))	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('breast cancers', 'Disease', (157, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('DNA', 'Var', (4, 7))	('associated', 'Reg', (64, 74))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('MORT', 'Gene', '100128252', (42, 46))	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('MORT', 'Gene', (197, 201))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('luminal', 'Disease', (80, 87))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('methylation-mediated', 'Var', (8, 28))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MORT', 'Gene', (42, 46))	('MORT', 'Gene', '100128252', (197, 201))
29352	28690657	These early epigenetic events and the cellular mechanisms that they influence may provide new targets for cancer prevention or treatment.	('epigenetic events', 'Var', (12, 29))	('influence', 'Reg', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
29356	28690657	In addition to TCGA, further Illumina HumanMethylation450 datasets for breast (GSE60185, GSE66313, and GSE58999) and colon (GSE48684 and GSE77954) cancer samples were downloaded from Gene Expression Omnibus (GEO).	('GSE66313', 'Var', (89, 97))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('GSE60185', 'Var', (79, 87))	('GSE58999', 'Var', (103, 111))	('breast', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('GSE77954', 'Var', (137, 145))	('GSE48684', 'Var', (124, 132))
29359	28690657	We have previously reported that MORT is epigenetically silenced by DNA methylation in breast cancer and 14 out of 16 other common human tumors investigated.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('human', 'Species', '9606', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epigenetically', 'Var', (41, 55))	('breast cancer', 'Disease', (87, 100))	('MORT', 'Gene', '100128252', (33, 37))	('DNA methylation', 'Var', (68, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('MORT', 'Gene', (33, 37))
29369	28690657	Figure 2A presents analysis performed to assess whether gene deletion is an additional mechanism of MORT loss in cancer, in addition to aberrant DNA methylation.	('MORT', 'Gene', '100128252', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('gene deletion', 'Var', (56, 69))	('MORT', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
29370	28690657	The results show that MORT loss rarely occurs due to gene deletion (Figure 2A).	('MORT', 'Gene', '100128252', (22, 26))	('MORT', 'Gene', (22, 26))	('gene deletion', 'Var', (53, 66))
29371	28690657	MORT loss is therefore predominantly due to epigenetic silencing and increased DNA methylation of the MORT promoter; MORT promoter methylation is a good indicator of MORT silencing that could be used as a surrogate for MORT loss in samples where expression data are not available.	('MORT', 'Gene', '100128252', (219, 223))	('MORT', 'Gene', '100128252', (0, 4))	('increased', 'PosReg', (69, 78))	('MORT', 'Gene', (102, 106))	('MORT', 'Gene', '100128252', (117, 121))	('MORT', 'Gene', (0, 4))	('MORT', 'Gene', '100128252', (166, 170))	('MORT', 'Gene', (219, 223))	('DNA', 'MPA', (79, 82))	('MORT', 'Gene', (117, 121))	('MORT', 'Gene', '100128252', (102, 106))	('epigenetic silencing', 'Var', (44, 64))	('MORT', 'Gene', (166, 170))
29372	28690657	When we tested the association between MORT methylation and clinical variables, we found a strong link between MORT methylation and the presence of hormone receptors.	('tested', 'Reg', (8, 14))	('MORT', 'Gene', (39, 43))	('presence', 'Reg', (136, 144))	('MORT', 'Gene', '100128252', (111, 115))	('methylation', 'Var', (116, 127))	('hormone receptors', 'Protein', (148, 165))	('MORT', 'Gene', '100128252', (39, 43))	('MORT', 'Gene', (111, 115))
29375	28690657	These data predict that MORT is predominantly silenced in luminal breast cancers; indeed, when we classified the breast tumors into subtypes according to PAM50, luminal B, luminal A, and human epidermal growth factor receptor 2 (HER2)-enriched tumors had a large proportion of MORT methylation, while basal-like tumors showed no significant difference in MORT methylation or expression compared to normal control samples (Figure 2F, Supplementary Figure 2E, available online).	('tumors', 'Disease', (312, 318))	('tumors', 'Disease', (120, 126))	('breast tumor', 'Phenotype', 'HP:0100013', (113, 125))	('MORT', 'Gene', (24, 28))	('breast tumors', 'Disease', 'MESH:D001943', (113, 126))	('epidermal growth factor receptor 2', 'Gene', '2064', (193, 227))	('breast tumors', 'Disease', (113, 126))	('luminal breast cancers', 'Disease', (58, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('breast tumors', 'Phenotype', 'HP:0100013', (113, 126))	('MORT', 'Gene', (277, 281))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('HER2', 'Gene', '2064', (229, 233))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('MORT', 'Gene', (355, 359))	('epidermal growth factor receptor 2', 'Gene', (193, 227))	('MORT', 'Gene', '100128252', (24, 28))	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumors', 'Disease', (244, 250))	('luminal breast cancers', 'Disease', 'MESH:D001943', (58, 80))	('MORT', 'Gene', '100128252', (277, 281))	('methylation', 'Var', (282, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('basal-like tumors', 'Phenotype', 'HP:0002671', (301, 318))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('HER2', 'Gene', (229, 233))	('MORT', 'Gene', '100128252', (355, 359))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('human', 'Species', '9606', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
29378	28690657	Together, these results indicate that epigenetic silencing of MORT occurs predominantly in luminal, receptor-positive breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('MORT', 'Gene', '100128252', (62, 66))	('epigenetic silencing', 'Var', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('MORT', 'Gene', (62, 66))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('breast cancers', 'Disease', (118, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
29384	28690657	Finally, we analyzed the links between MORT methylation and mutations in 23 genes frequently mutated in breast cancer.	('MORT', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('MORT', 'Gene', '100128252', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('mutations', 'Var', (60, 69))
29385	28690657	Mutations in two of these genes were strongly linked to the level of MORT methylation.	('MORT', 'Gene', (69, 73))	('MORT', 'Gene', '100128252', (69, 73))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (46, 52))
29386	28690657	Mutation of TP53 is negatively correlated to MORT methylation (Figure 2I):tumors carrying a TP53 mutation usually have normal levels of MORT (Supplementary Figure 2G, available online).	('mutation', 'Var', (97, 105))	('MORT', 'Gene', (136, 140))	('MORT', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TP53', 'Gene', '7157', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', (12, 16))	('MORT', 'Gene', '100128252', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('MORT', 'Gene', '100128252', (45, 49))	('tumors', 'Disease', (74, 80))
29387	28690657	GATA3 is frequently mutated in tumors that have reduced MORT expression (Supplementary Figure 2H, available online):there is a positive correlation between GATA3 mutation and MORT methylation (Figure 2J).	('GATA3', 'Gene', '2625', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('MORT', 'Gene', (175, 179))	('MORT', 'Gene', '100128252', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('GATA3', 'Gene', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('GATA3', 'Gene', (0, 5))	('mutation', 'Var', (162, 170))	('MORT', 'Gene', (56, 60))	('MORT', 'Gene', '100128252', (175, 179))	('GATA3', 'Gene', '2625', (156, 161))
29388	28690657	This is consistent with evidence showing that TP53 mutations are enriched in basal-like triple negative tumors, while GATA3 mutations are found predominantly in luminal tumors.	('luminal tumors', 'Disease', 'MESH:D009369', (161, 175))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('GATA3', 'Gene', (118, 123))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('TP53', 'Gene', (46, 50))	('luminal tumors', 'Disease', (161, 175))	('GATA3', 'Gene', '2625', (118, 123))	('tumors', 'Disease', (169, 175))
29390	28690657	The lack of MORT silencing in basal tumors that frequently carry TP53 mutations indicates that MORT might act in a pathway that requires functional TP53, as the cells with nonfunctional TP53 can "afford" to express MORT and become immortal.	('MORT', 'Gene', (215, 219))	('MORT', 'Gene', (12, 16))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('MORT', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (186, 190))	('basal tumors', 'Phenotype', 'HP:0002671', (30, 42))	('basal tumors', 'Disease', 'MESH:D002280', (30, 42))	('MORT', 'Gene', '100128252', (215, 219))	('MORT', 'Gene', '100128252', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('TP53', 'Gene', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('MORT', 'Gene', '100128252', (95, 99))	('basal tumors', 'Disease', (30, 42))
29391	28690657	The dissociation between TP53 mutations and MORT silencing is consistent with the in vitro immortalization model used in the discovery of MORT, where the immortal HMEC retained wild-type TP53.	('MORT', 'Gene', (44, 48))	('TP53', 'Gene', (25, 29))	('MORT', 'Gene', '100128252', (138, 142))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', (187, 191))	('mutations', 'Var', (30, 39))	('MORT', 'Gene', (138, 142))	('MORT', 'Gene', '100128252', (44, 48))	('TP53', 'Gene', '7157', (25, 29))
29392	28690657	Overall, our analysis found that, as predicted from the in vitro model of HMEC immortalization, aberrant methylation of the MORT CpG island promoter occurs early in human breast carcinogenesis, likely at or near the point where premalignant cells gain immortality; this epigenetic silencing is maintained throughout malignant transformation and metastatic growth.	('human', 'Species', '9606', (165, 170))	('breast carcinogenesis', 'Disease', (171, 192))	('MORT', 'Gene', '100128252', (124, 128))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (171, 192))	('aberrant', 'Var', (96, 104))	('MORT', 'Gene', (124, 128))	('methylation', 'MPA', (105, 116))	('gain', 'PosReg', (247, 251))
29397	25223380	In ductal carcinoma in situ, multiple groups have shown that dysregulation of the RB pathway is critically associated with recurrence and disease progression.	('RB pathway', 'Pathway', (82, 92))	('dysregulation', 'Var', (61, 74))	('associated', 'Reg', (107, 117))	('RB', 'Chemical', 'MESH:D012413', (82, 84))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (3, 27))	('ductal carcinoma in situ', 'Disease', (3, 27))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
29406	25223380	Loss of heterozygosity at the Rb1 locus represents the seminal basis for the development of retinoblastoma, and was the basis through which the gene encoding RB was identified.	('Loss of heterozygosity', 'Var', (0, 22))	('RB', 'Chemical', 'MESH:D012413', (158, 160))	('Rb1', 'Gene', (30, 33))	('retinoblastoma', 'Gene', (92, 106))	('retinoblastoma', 'Phenotype', 'HP:0009919', (92, 106))	('retinoblastoma', 'Gene', '5925', (92, 106))
29415	25223380	The biochemical importance of these processes was demonstrated using mutants of RB that cannot be phosphorylated and are potent inhibitors of cell cycle progression in the vast majority of tumor cells.	('tumor', 'Disease', (189, 194))	('cell cycle progression', 'CPA', (142, 164))	('mutants', 'Var', (69, 76))	('inhibitors', 'NegReg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('RB', 'Chemical', 'MESH:D012413', (80, 82))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
29416	25223380	Furthermore, the CDK4/6 inhibitor p16ink4a is dependent on RB for function in suppressing cell cycle progression and inducing senescence.	('cell cycle progression', 'CPA', (90, 112))	('suppressing', 'NegReg', (78, 89))	('p16ink4a', 'Var', (34, 42))	('inducing', 'Reg', (117, 125))	('senescence', 'CPA', (126, 136))	('RB', 'Chemical', 'MESH:D012413', (59, 61))
29417	25223380	Together, the pathway of CDK4/6, RB, and p16ink4a define the proximal RB pathway (Figure 1).	('RB', 'Chemical', 'MESH:D012413', (33, 35))	('proximal RB pathway', 'Pathway', (61, 80))	('p16ink4a', 'Var', (41, 49))	('RB', 'Chemical', 'MESH:D012413', (70, 72))	('CDK4/6', 'Gene', (25, 31))
29419	25223380	For example, tumors with loss of p16ink4a will retain wild-type RB, while tumors mutant for RB will express p16ink4a at very high levels (Figure 2).	('p16ink4a', 'Var', (33, 41))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('RB', 'Chemical', 'MESH:D012413', (64, 66))	('RB', 'Chemical', 'MESH:D012413', (92, 94))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('loss', 'NegReg', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('p16ink4a', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
29422	25223380	p16ink4a and RB are members of gene families, and compensatory mechanisms can mitigate the effects of loss of these tumor suppressors in specific settings, most notably in mouse models.	('mouse', 'Species', '10090', (172, 177))	('p16ink4a', 'Var', (0, 8))	('RB', 'Chemical', 'MESH:D012413', (13, 15))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
29428	25223380	Estrogen receptor (ER)-positive breast cancers generally exhibit deregulation of the kinase components CDK4/6 as a result of aberrant cyclin D1 expression or amplification.	('Estrogen receptor', 'Gene', '2099', (0, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('expression', 'MPA', (144, 154))	('cyclin D1', 'Protein', (134, 143))	('amplification', 'MPA', (158, 171))	('Estrogen receptor', 'Gene', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('aberrant', 'Var', (125, 133))	('breast cancers', 'Phenotype', 'HP:0003002', (32, 46))	('deregulation', 'MPA', (65, 77))	('breast cancers', 'Disease', 'MESH:D001943', (32, 46))	('CDK4/6', 'Gene', (103, 109))	('breast cancers', 'Disease', (32, 46))
29431	25223380	In spite of these generalities, one should note that any breast cancer can exhibit loss of RB, loss of p16ink4a, or amplification of cyclin D1; there is thus the opportunity to evaluate how these events impinge on the underlying biology of disease and the prognostic and therapeutic implications in the clinic.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('impinge', 'Reg', (203, 210))	('RB', 'Chemical', 'MESH:D012413', (91, 93))	('amplification', 'Var', (116, 129))	('cyclin D1', 'Gene', (133, 142))	('loss', 'NegReg', (95, 99))	('p16ink4a', 'Protein', (103, 111))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('loss', 'NegReg', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
29439	25223380	For example, high levels of p16ink4a in benign Nevi are believed to contribute to potent suppression of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('p16ink4a', 'Var', (28, 36))	('Nevi', 'Phenotype', 'HP:0003764', (47, 51))	('suppression', 'NegReg', (89, 100))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
29440	25223380	Such a combination of markers (high p16ink4a and high proliferation) is indicative of the loss of RB.	('RB', 'Chemical', 'MESH:D012413', (98, 100))	('loss', 'NegReg', (90, 94))	('high p16ink4a', 'Var', (31, 44))	('p16ink4a', 'Var', (36, 44))
29441	25223380	This is supported by a multitude of studies showing that p16ink4a levels are very high in tumors that have lost RB by mutation or through the action of viral oncoproteins.	('p16ink4a', 'Var', (57, 65))	('RB', 'Chemical', 'MESH:D012413', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('mutation', 'Var', (118, 126))
29442	25223380	Furthermore, only through the loss of RB can the cytostatic effect of p16ink4a be bypassed.	('p16ink4a', 'Var', (70, 78))	('RB', 'Chemical', 'MESH:D012413', (38, 40))	('loss', 'NegReg', (30, 34))
29444	25223380	The prognostic significance of RB-pathway deregulation is significant in multivariate models, and is true both as a single marker and in combination with other determinants of DCIS biology, including Her2 levels, Cox2 levels, and PTEN levels.	('PTEN', 'Gene', '5728', (230, 234))	('Her2', 'Gene', (200, 204))	('deregulation', 'Var', (42, 54))	('RB-pathway', 'Gene', (31, 41))	('Her2', 'Gene', '2064', (200, 204))	('Cox2', 'Gene', '4513', (213, 217))	('Cox2', 'Gene', (213, 217))	('RB', 'Chemical', 'MESH:D012413', (31, 33))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('PTEN', 'Gene', (230, 234))
29448	25223380	Particularly in a variety of breast cancer models, knockdown of RB led to altered morphology and the expression of specific markers of EMT (for example, vimentin).	('RB', 'Chemical', 'MESH:D012413', (64, 66))	('vimentin', 'Gene', '7431', (153, 161))	('vimentin', 'Gene', (153, 161))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('morphology', 'CPA', (82, 92))	('altered', 'Reg', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('expression', 'MPA', (101, 111))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('knockdown', 'Var', (51, 60))
29450	25223380	Similarly, in mouse models it was observed that tumors which arise with Rb1 deletion are particularly characterized by aspects of EMT.	('deletion', 'Var', (76, 84))	('Rb1', 'Gene', (72, 75))	('mouse', 'Species', '10090', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
29456	25223380	For example, cases of DCIS that are p16ink4a high and RB deficient would be expected to have the most benefit from adjuvant radiation therapy.	('RB deficient', 'Disease', (54, 66))	('p16ink4a high', 'Var', (36, 49))	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('RB deficient', 'Disease', 'MESH:D012175', (54, 66))	('DCIS', 'Disease', (22, 26))
29464	25223380	As mentioned above, ER-positive breast cancer is dominated by deregulation of CDK4/6 that is driven by amplication or overexpression of cyclin D1 (Figure 4).	('breast cancer', 'Disease', (32, 45))	('overexpression', 'PosReg', (118, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('CDK4/6', 'Gene', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('amplication', 'Var', (103, 114))	('deregulation', 'MPA', (62, 74))
29466	25223380	What is clearly without contention is that breast cancers which harbor deregulated expression of RB/E2F target genes are associated with poor prognosis.	('breast cancers', 'Disease', 'MESH:D001943', (43, 57))	('RB', 'Chemical', 'MESH:D012413', (97, 99))	('breast cancers', 'Disease', (43, 57))	('deregulated', 'Var', (71, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('RB/E2F', 'Gene', (97, 103))	('expression', 'MPA', (83, 93))	('breast cancers', 'Phenotype', 'HP:0003002', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
29468	25223380	An example is shown in Figure 5, where deregulation of an RB/E2F signature differentiates luminal A and luminal B breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RB/E2F signature', 'Gene', (58, 74))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('luminal A', 'Disease', (90, 99))	('RB', 'Chemical', 'MESH:D012413', (58, 60))	('deregulation', 'Var', (39, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('differentiates', 'Reg', (75, 89))
29469	25223380	Simple analysis of TCGA datasets indicates that luminal B cancers are over-represented for cyclin D1 amplification and loss of p16ink4a or RB relative to luminal A breast cancer (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('amplification', 'Var', (101, 114))	('luminal A breast cancer', 'Disease', 'MESH:D001943', (154, 177))	('over-represented', 'PosReg', (70, 86))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('luminal A breast cancer', 'Disease', (154, 177))	('p16ink4a', 'Protein', (127, 135))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('loss', 'NegReg', (119, 123))	('cancers', 'Disease', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('RB', 'Chemical', 'MESH:D012413', (139, 141))	('cyclin D1', 'Protein', (91, 100))
29470	25223380	Deregulation of the RB pathway thus does seem to associate with more aggressive tumor behavior in ER-positive breast cancer.	('RB pathway', 'Pathway', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('associate', 'Reg', (49, 58))	('aggressive tumor', 'Disease', 'MESH:D001523', (69, 85))	('RB', 'Chemical', 'MESH:D012413', (20, 22))	('aggressive tumor', 'Disease', (69, 85))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
29471	25223380	Consistent with this point, perturbation of the RB pathway has been shown to lead to more aggressive/rapid tumor growth in preclinical models.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('more', 'PosReg', (85, 89))	('RB pathway', 'Pathway', (48, 58))	('RB', 'Chemical', 'MESH:D012413', (48, 50))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('perturbation', 'Var', (28, 40))
29477	25223380	Deregulation of RB/E2F activity is thus, in effect, used clinically to estimate the risk of recurrence.	('RB', 'Chemical', 'MESH:D012413', (16, 18))	('activity', 'MPA', (23, 31))	('RB/E2F', 'Protein', (16, 22))	('Deregulation', 'Var', (0, 12))
29479	25223380	Knowledge that deregulation of the RB pathway is associated with rapid recurrence with endocrine therapy is born out in multiple studies.	('RB', 'Chemical', 'MESH:D012413', (35, 37))	('associated', 'Reg', (49, 59))	('deregulation', 'Var', (15, 27))	('RB pathway', 'Pathway', (35, 45))
29481	25223380	Similarly, perturbation of the RB pathway through multiple mechanisms can blunt the sensitivity to endocrine therapies and can help facilitate the development of resistance.	('sensitivity to endocrine therapies', 'MPA', (84, 118))	('blunt', 'NegReg', (74, 79))	('RB pathway', 'Pathway', (31, 41))	('facilitate', 'PosReg', (132, 142))	('RB', 'Chemical', 'MESH:D012413', (31, 33))	('development of resistance', 'MPA', (147, 172))	('perturbation', 'Var', (11, 23))
29482	25223380	While important and demonstrating that downstream aberration of the RB pathway can bypass the response to endocrine therapy, loss of RB or cyclin D1 amplification does not represent the principle basis for acquired resistance in preclinical models.	('aberration', 'Var', (50, 60))	('RB pathway', 'Pathway', (68, 78))	('loss', 'Var', (125, 129))	('RB', 'Chemical', 'MESH:D012413', (68, 70))	('RB', 'Chemical', 'MESH:D012413', (133, 135))
29483	25223380	Typically, deregulation of oncogenic signaling molecules will drive the aberrant activation of cyclin D1 and RB phosphorylation independent of ER.	('phosphorylation', 'MPA', (112, 127))	('RB', 'Chemical', 'MESH:D012413', (109, 111))	('deregulation', 'Var', (11, 23))	('activation', 'PosReg', (81, 91))	('cyclin D1', 'Protein', (95, 104))
29500	25223380	Parallel investigation has shown that Her2-positive models are sensitive to CDK4/6 inhibitors in preclinical models; interestingly, in such models CDK4/6 inhibition not only prevents proliferation but also limits the invasive potential of such models.	('limits', 'NegReg', (206, 212))	('CDK4/6', 'Protein', (147, 153))	('inhibition', 'Var', (154, 164))	('prevents', 'NegReg', (174, 182))	('proliferation', 'CPA', (183, 196))	('invasive potential of such models', 'CPA', (217, 250))	('Her2', 'Gene', (38, 42))	('Her2', 'Gene', '2064', (38, 42))
29528	25223380	For example, while ~20% of DCIS are RB-negative and express high levels of p16ink4a, there is no indication as to how RB protein expression is lost.	('RB', 'Chemical', 'MESH:D012413', (36, 38))	('lost', 'NegReg', (143, 147))	('p16ink4a', 'Var', (75, 83))	('expression', 'MPA', (129, 139))	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('RB', 'Chemical', 'MESH:D012413', (118, 120))
29536	25223380	Deregulated RB/E2F target genes (for example, OncotypeDX) inform aggressive treatment with adjuvant chemotherapy.	('Deregulated', 'Var', (0, 11))	('RB', 'Chemical', 'MESH:D012413', (12, 14))	('RB/E2F', 'Gene', (12, 18))
29569	18366696	In addition, a link between activating mutations in oncogenes and inflammation has been recently reported, as activation of Ras proto-oncogenes in cancer results in up-regulation of the inflammatory cytokine IL-8, which, in turn, acts as a chemokine and in turn promotes tumor associated inflammation, angiogenesis and eventually tumor growth.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('IL-8', 'Gene', (208, 212))	('mutations', 'Var', (39, 48))	('inflammation', 'Disease', 'MESH:D007249', (288, 300))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('up-regulation', 'PosReg', (165, 178))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))	('angiogenesis', 'CPA', (302, 314))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (271, 276))	('inflammation', 'Disease', (288, 300))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('IL-8', 'Gene', '3576', (208, 212))	('activation', 'PosReg', (110, 120))	('inflammation', 'Disease', (66, 78))	('Ras', 'Gene', (124, 127))	('promotes', 'PosReg', (262, 270))	('cancer', 'Disease', (147, 153))
29620	18366696	Cleavage occurs in the Golgi; blockage of protein transport from the endoplasmic reticulum to the Golgi apparatus abrogated APRIL processing, whereas inhibition of post-Golgi transport, does not interfere with APRIL cleavage, but block secretion of processed APRIL.	('rat', 'Species', '10116', (108, 111))	('protein', 'Protein', (42, 49))	('abrogated', 'NegReg', (114, 123))	('APRIL processing', 'MPA', (124, 140))	('secretion of processed APRIL', 'MPA', (236, 264))	('blockage', 'Var', (30, 38))	('block', 'NegReg', (230, 235))
29738	24268788	Compared with lumpectomy alone, brachytherapy achieved a more modest reduction in adjusted risk (hazard ratio [HR], 0.61; 95% CI, 0.40-0.94) than achieved with EBRT (HR, 0.22; 95% CI, 0.18-0.28).	('brachytherapy', 'Var', (32, 45))	('reduction', 'NegReg', (69, 78))	('adjusted risk', 'MPA', (82, 95))	('EBRT', 'Chemical', '-', (160, 164))
29742	24268788	In this study era, brachytherapy showed lesser breast-preservation benefit compared with EBRT.	('EBRT', 'Chemical', '-', (89, 93))	('brachytherapy', 'Var', (19, 32))	('breast-preservation', 'CPA', (47, 66))
29778	24268788	Patients treated with brachytherapy, in comparison with lumpectomy alone and EBRT, were more likely to have a tumor size of 2.0 cm or less, ER-positive receptor status, non-high-grade histology, and negative axillary lymph nodes and were more likely to undergo axillary surgery but were less likely to have DCIS (P<.001 for all comparisons) and less likely than patients treated with EBRT to receive chemotherapy (P<.001) (Table 1).	('patients', 'Species', '9606', (362, 370))	('undergo', 'Reg', (253, 260))	('EBRT', 'Chemical', '-', (77, 81))	('axillary surgery', 'CPA', (261, 277))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('DCIS', 'Disease', (307, 311))	('EBRT', 'Chemical', '-', (384, 388))	('Patients', 'Species', '9606', (0, 8))	('DCIS', 'Phenotype', 'HP:0030075', (307, 311))	('brachytherapy', 'Var', (22, 35))	('non-high-grade histology', 'Var', (169, 193))	('ER', 'Gene', '2099', (140, 142))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
29781	24268788	On adjusted analysis, compared with lumpectomy alone as the referent (hazard ratio [HR], 1.00), both brachytherapy (HR, 0.61; 95% CI, 0.40-0.94; P=.02) and EBRT (HR, 0.22; 95% CI, 0.18-0.28; P<.001) were associated with lower subsequent mastectomy risks.	('brachytherapy', 'Var', (101, 114))	('mastectomy', 'Disease', (237, 247))	('EBRT', 'Var', (156, 160))	('lower', 'NegReg', (220, 225))	('P=.02', 'Gene', (145, 150))	('P=.02', 'Gene', '7178', (145, 150))	('EBRT', 'Chemical', '-', (156, 160))
29782	24268788	However, compared with brachytherapy as the referent, EBRT maintained the lowest subsequent mastectomy risk (HR, 0.37; 95% CI, 0.24-0.55; P<.001).	('EBRT', 'Var', (54, 58))	('lowest', 'NegReg', (74, 80))	('EBRT', 'Chemical', '-', (54, 58))	('mastectomy', 'Disease', (92, 102))
29783	24268788	Other predictors of subsequent mastectomy included ER-negative status, large tumor size, T4 stage, and high grade (Table 3).	('ER', 'Gene', '2099', (51, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mastectomy', 'Disease', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('high', 'Var', (103, 107))	('tumor', 'Disease', (77, 82))	('T4 stage', 'CPA', (89, 97))
29796	24268788	Specifically, the 5-year cumulative incidence of subsequent mastectomy was 1.6% (95% CI, 0.7%-3.5%) for brachytherapy versus 0.8% (95% CI, 0.6%-1.1%) for EBRT in suitable patients, as compared with 5.4% (95% CI, 2.5%-11.6%) versus 2.2% (95% CI, 1.7%-2.8%) in cautionary patients and with 3.6% (95% CI, 1.3%-9.4%) versus 1.6% (95% CI, 1.3%-2.0%) in unsuitable patients (Table 2).	('mastectomy', 'Disease', (60, 70))	('patients', 'Species', '9606', (270, 278))	('brachytherapy', 'Var', (104, 117))	('EBRT', 'Chemical', '-', (154, 158))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (359, 367))
29802	24268788	Within 1 year of diagnosis, the frequency of postoperative infections was 9.9% (95% CI, 9.2%-10.5%) for lumpectomy alone, 16.5% (95% CI, 14.5%-18.5%) for brachytherapy, and 11.4% (95% CI, 11.0%-11.8%) for EBRT (P<.001 for each pair-wise comparison) (Table 3).	('lumpectomy', 'Disease', (104, 114))	('postoperative infections', 'Disease', 'MESH:D010149', (45, 69))	('EBRT', 'Chemical', '-', (205, 209))	('postoperative infections', 'Disease', (45, 69))	('brachytherapy', 'Var', (154, 167))
29803	24268788	On adjusted analysis, compared with lumpectomy alone as the referent, brachytherapy was associated with an increased postoperative infection risk (RR, 1.54; 95% CI, 1.33-1.77; P<.001), but EBRT showed no difference (RR, 1.03; 95% CI, 0.94-1.11; P<.001) (Table E5).	('postoperative infection', 'Disease', 'MESH:D010149', (117, 140))	('brachytherapy', 'Var', (70, 83))	('EBRT', 'Chemical', '-', (189, 193))	('postoperative infection', 'Disease', (117, 140))
29804	24268788	The frequency of noninfectious postoperative complications was 6.0% (95% CI, 5.5%-6.5%) for lumpectomy alone, 18.7% (95% CI, 16.6%-20.8%) for brachytherapy, and 9.5% (95% CI, 9.1%-9.8%) for EBRT (P<.001 for each pair-wise comparison) (Table 3).	('brachytherapy', 'Var', (142, 155))	('lumpectomy', 'Disease', (92, 102))	('EBRT', 'Chemical', '-', (190, 194))
29805	24268788	After adjustment, compared with lumpectomy alone as the referent, brachytherapy was associated with an increased noninfectious complication risk (RR, 2.81; 95% CI, 2.43-3.24; P<.001), as was EBRT (RR, 1.37; 95% CI, 1.24-1.52; P<.001) (Table E5).	('EBRT', 'Chemical', '-', (191, 195))	('brachytherapy', 'Var', (66, 79))	('noninfectious complication', 'Disease', (113, 139))
29806	24268788	Brachytherapy was associated with a higher 5-year cumulative incidence of breast pain (22.9%; 95% CI, 20.2%-25.7%) compared with lumpectomy alone (11.2%; 95% CI, 10.5%-12.0%) or EBRT (16.7%; 95% CI, 16.2%-17.2%) (P<.001 for both comparisons).	('Brachytherapy', 'Var', (0, 13))	('pain', 'Phenotype', 'HP:0012531', (81, 85))	('breast pain', 'Disease', 'MESH:D059373', (74, 85))	('EBRT', 'Chemical', '-', (178, 182))	('breast pain', 'Disease', (74, 85))
29807	24268788	Brachytherapy was associated with a higher cumulative incidence of fat necrosis (15.3%; 95% CI, 13.0%-17.9%) compared with lumpectomy alone (5.3%; 95% CI, 4.8%-5.8%) or EBRT (7.7%; 95% CI, 7.3%-8.0%) (P<.001 for both comparisons).	('EBRT', 'Chemical', '-', (169, 173))	('Brachytherapy', 'Var', (0, 13))	('fat necrosis', 'Disease', 'MESH:D005218', (67, 79))	('fat necrosis', 'Disease', (67, 79))	('fat necrosis', 'Phenotype', 'HP:0010885', (67, 79))
29809	24268788	In this cohort of older patients, for invasive breast cancer, brachytherapy was associated with an improved likelihood of breast preservation compared with lumpectomy alone but with a lesser magnitude of benefit compared with EBRT.	('invasive breast cancer', 'Disease', (38, 60))	('brachytherapy', 'Var', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('EBRT', 'Chemical', '-', (226, 230))	('invasive breast cancer', 'Disease', 'MESH:D001943', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('patients', 'Species', '9606', (24, 32))	('breast', 'Disease', (122, 128))
29811	24268788	As practiced in this era, brachytherapy was associated with increased postoperative and local toxicity risks.	('postoperative', 'CPA', (70, 83))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('toxicity', 'Disease', (94, 102))	('brachytherapy', 'Var', (26, 39))
29813	24268788	Previous randomized and population-based studies established a 70% local control benefit for adjuvant EBRT compared with lumpectomy alone for invasive breast cancer, consistent with the magnitude of subsequent mastectomy benefit for EBRT reported in our analysis.	('invasive breast cancer', 'Disease', (142, 164))	('EBRT', 'Gene', (102, 106))	('EBRT', 'Chemical', '-', (102, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('local', 'MPA', (67, 72))	('adjuvant', 'Var', (93, 101))	('EBRT', 'Chemical', '-', (233, 237))	('invasive breast cancer', 'Disease', 'MESH:D001943', (142, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
29837	26540569	Breast cancer (BC) is promoted by the interplay of hereditary and environmental risk factors that cause progressive accumulation of genetic and epigenetic changes in breast cells, e.g.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('BC', 'Phenotype', 'HP:0003002', (15, 17))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('epigenetic changes', 'Var', (144, 162))	('Breast cancer', 'Disease', (0, 13))
29848	26540569	The rationale behind this approach is that cancer-associated gene and protein changes can lead to oxidative stress, with different cell membranes causing disease-specific VOCs exuded into the blood.	('protein', 'Protein', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('changes', 'Var', (78, 85))	('oxidative stress', 'Phenotype', 'HP:0025464', (98, 114))	('causing', 'Reg', (146, 153))	('oxidative stress', 'MPA', (98, 114))	('gene', 'Protein', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lead to', 'Reg', (90, 97))
29897	26540569	ROS molecules may also enhance the activity of a large and diverse group of mixed oxidase enzymes (i.e.	('activity', 'MPA', (35, 43))	('ROS molecules', 'Var', (0, 13))	('mixed oxidase enzymes', 'Enzyme', (76, 97))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('enhance', 'PosReg', (23, 30))
29903	26540569	It is also important to note that dimethyl ester carbonic acid was under the LOD for healthy volunteers, benign states, HER2, Luminal A and Luminal B sub-classification, but was found to have discriminatory power for HER2+ comparisons when the DFA model was applied (Table 2; and SI, Table S2).	('HER2', 'Gene', (120, 124))	('dimethyl ester carbonic acid', 'Chemical', '-', (34, 62))	('dimethyl', 'Var', (34, 42))	('HER2', 'Gene', '2064', (120, 124))	('SI', 'Disease', 'None', (280, 282))	('HER2', 'Gene', (217, 221))	('HER2', 'Gene', '2064', (217, 221))
29951	25610697	Unfortunately, there are several long-term complications of breast restoration with prosthetic implants, such as rippling, capsular contracture, implant malposition, bottoming out, implant exposure, and symmastia.	('bottoming out', 'Disease', (166, 179))	('contracture', 'Disease', (132, 143))	('rippling', 'Disease', (113, 121))	('implant exposure', 'Disease', (181, 197))	('capsular', 'Disease', (123, 131))	('contracture', 'Disease', 'MESH:D003286', (132, 143))	('symmastia', 'Disease', (203, 212))	('breast', 'Disease', (60, 66))	('contracture', 'Phenotype', 'HP:0001371', (132, 143))	('malposition', 'Var', (153, 164))
30005	18813261	Finally, radiotherapy after breast-conserving surgery and after mastectomy in selected high-risk patients has been shown to improve not only loco-regional control, but also long-term survival (5% reduction in 15-year breast cancer mortality).	('radiotherapy', 'Var', (9, 21))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('improve', 'PosReg', (124, 131))	('loco-regional control', 'CPA', (141, 162))	('reduction', 'NegReg', (196, 205))	('patients', 'Species', '9606', (97, 105))
30019	18813261	Women of higher socioeconomic status are also at increased risk of developing invasive breast cancer due to differing reproductive behaviours of aetiological significance, for example, late age at first birth, low parity, and low breastfeeding rates.	('Women', 'Species', '9606', (0, 5))	('invasive breast cancer', 'Disease', 'MESH:D001943', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breastfeeding rates', 'CPA', (230, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('low', 'Var', (210, 213))	('invasive breast cancer', 'Disease', (78, 100))
30095	28649658	However, this model was uninformative with respect to differential drug sensitivity because both the outer and niche-associated tumor cells were insensitive to lapatinib, possibly due to a H1047R PIK3CA mutation, which has been shown to limit the effectiveness of lapatinib (Supplementary Fig.	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('lapatinib', 'Chemical', 'MESH:D000077341', (264, 273))	('drug sensitivity', 'Phenotype', 'HP:0020174', (67, 83))	('PIK3CA', 'Gene', (196, 202))	('H1047R', 'Mutation', 'rs121913279', (189, 195))	('PIK3CA', 'Gene', '5290', (196, 202))	('lapatinib', 'Chemical', 'MESH:D000077341', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('effectiveness', 'MPA', (247, 260))	('H1047R', 'Var', (189, 195))
30108	28649658	Mice bearing SUM225 DCIS-like tumors (n = 4-5 mice per group) were pre-treated with either vehicle or lapatinib [200 mg/kg/day per os (p.o.)]	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('lapatinib', 'Chemical', 'MESH:D000077341', (102, 111))	('Mice', 'Species', '10090', (0, 4))	('SUM225', 'Var', (13, 19))
30124	28649658	Analyses of the tissue sections by H&E in parallel with HER2 IHC indicated that T-DM1 treatment induced extensive cell death within the inner tumor cell layers as well as large sections of the outer, protected tumor cell population (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (142, 147))	('DM1', 'Gene', (82, 85))	('tumor', 'Disease', (210, 215))	('H&E', 'Chemical', '-', (35, 38))	('extensive cell', 'CPA', (104, 118))	('death within the inner tumor', 'Disease', 'MESH:D001929', (119, 147))	('that', 'Var', (75, 79))	('DM1', 'Gene', '1760', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('death within the inner tumor', 'Disease', (119, 147))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
30127	28649658	We found that HER2 blockade in combination with a BCL-2/XL inhibitor reduced the niche-protected population.	('niche-protected population', 'CPA', (81, 107))	('BCL-2', 'Gene', (50, 55))	('blockade', 'Var', (19, 27))	('reduced', 'NegReg', (69, 76))	('HER2', 'Protein', (14, 18))	('BCL-2', 'Gene', '596', (50, 55))
30138	28649658	The adaptive response demonstrated here could facilitate the acquisition of additional genetic alterations in proliferating tumor cells that may lead to the generation of stably resistant tumor cells that can survive and proliferate in an niche-independent fashion.	('tumor', 'Disease', (188, 193))	('genetic alterations', 'Var', (87, 106))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('proliferate', 'CPA', (221, 232))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('lead to', 'Reg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
30144	28649658	Indeed, in a mouse prostate non-invasive tumor model induced by PTEN deletion, outer tumor cells only were preserved in mice treated with mTOR inhibitors and residual tumor cells were BCL2-positive.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (85, 90))	('mouse', 'Species', '10090', (13, 18))	('mice', 'Species', '10090', (120, 124))	('tumor', 'Disease', (41, 46))	('PTEN', 'Gene', '19211', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PTEN', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('deletion', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (167, 172))
30190	30728717	For breast cancer specific survival (BCSS), the HR of the IDC group (P-value for trend = .04) increased along with increasing parity and was worse than nulliparous patients, and the HR of the DCIS-IDC group increased but was better than nulliparous patients (P-value for trend = .02).	('DCIS', 'Phenotype', 'HP:0030075', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('patients', 'Species', '9606', (249, 257))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('increased', 'PosReg', (94, 103))	('breast cancer', 'Disease', (4, 17))	('patients', 'Species', '9606', (164, 172))	('parity', 'Var', (126, 132))
30194	30728717	High parity-related all-cause death risk is proposed to be related to an increased risk of cardiovascular diseases among women.	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (91, 114))	('death', 'Disease', 'MESH:D003643', (30, 35))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (91, 114))	('death', 'Disease', (30, 35))	('High parity-related', 'Var', (0, 19))	('cardiovascular diseases', 'Disease', (91, 114))	('women', 'Species', '9606', (121, 126))
30202	30728717	First is progression from DCIS to IDC as a convergent phenotype, where several combinations of somatic genetic and/or epigenetic aberrations result in the acquisition of the biological properties required for cancer cells to progress from in situ to invasive cancer.	('result in', 'Reg', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('invasive cancer', 'Disease', (250, 265))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('epigenetic aberrations', 'Var', (118, 140))	('invasive cancer', 'Disease', 'MESH:D009362', (250, 265))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Disease', (209, 215))	('progress', 'PosReg', (225, 233))	('cancer', 'Disease', (259, 265))
30205	30728717	Reproductive factors could make epigenetic aberrations on mammary carcinogenesis.	('carcinogenesis', 'Disease', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('epigenetic aberrations', 'Var', (32, 54))
30244	30728717	Although the HRs of the DCIS-IDC group were less than nulliparous patients, the higher the number of children, the greater the risk of BCSS (P-value for trend = .02) (Table 4) Any AFB increased HR of BCSS in both DCIS groups and IDC groups, and decreased HR of BCSS in DCIS-IDC group.	('children', 'Species', '9606', (101, 109))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('increased', 'PosReg', (184, 193))	('DCIS', 'Phenotype', 'HP:0030075', (269, 273))	('BCSS', 'CPA', (200, 204))	('AFB', 'Chemical', '-', (180, 183))	('AFB', 'Var', (180, 183))	('patients', 'Species', '9606', (66, 74))
30246	30728717	In general, parity in women has been known to have a dual, non-linear effect on life span, and less than three births is associated with a higher survival than more than three births or nulliparous status.	('women', 'Species', '9606', (22, 27))	('survival', 'MPA', (146, 154))	('higher', 'PosReg', (139, 145))	('less than three', 'Var', (95, 110))
30259	30728717	An evolutionary bottleneck model has been supported by several reports that have identified additional copy number alterations and mutations in IDC regions of patients with synchronous DCIS that were absent in DCIS regions.	('IDC regions', 'Gene', (144, 155))	('mutations', 'Var', (131, 140))	('DCIS', 'Phenotype', 'HP:0030075', (210, 214))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('copy number alterations', 'Var', (103, 126))	('patients', 'Species', '9606', (159, 167))
30261	30728717	With the development of next-generation sequencing technologies, many of these studies have identified concordant and discordant mutations in patients with synchronous DCIS-IDC.	('DCIS-IDC', 'Disease', (168, 176))	('mutations', 'Var', (129, 138))	('patients', 'Species', '9606', (142, 150))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))
30303	30056557	Of potential relevance is that Natrajan and colleagues have reported that the MCF10 series harbors relevant driver alterations that are also seen in primary breast cancers (e.g., PIK3CA).	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('primary breast cancers', 'Disease', (149, 171))	('primary breast cancers', 'Disease', 'MESH:D001943', (149, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('MCF10', 'Gene', (78, 83))	('MCF10', 'CellLine', 'CVCL:5555', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('alterations', 'Var', (115, 126))	('PIK3CA', 'Gene', (179, 185))	('PIK3CA', 'Gene', '5290', (179, 185))
30311	30056557	SUM102PT is also an ER-negative/PR-negative/HER2-negative DCIS cell line (https://sumlineknowledgebase.com/?page_id=1181).	('SUM102PT', 'Var', (0, 8))	('DCIS', 'Disease', (58, 62))	('DCIS', 'Disease', 'MESH:D002285', (58, 62))
30314	30056557	SUM102PT is classified as a basal-like model of DCIS with micro-invasion and has been studied in both 3D culture and nude mice.	('DCIS', 'Disease', (48, 52))	('SUM102PT', 'Var', (0, 8))	('nude mice', 'Species', '10090', (117, 126))	('DCIS', 'Disease', 'MESH:D002285', (48, 52))
30318	30056557	This positivity is also reported to increase the rate of upstaging to invasive breast cancer as compared to HER2-negative DCIS.	('positivity', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('invasive breast cancer', 'Disease', (70, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('DCIS', 'Disease', 'MESH:D002285', (122, 126))	('invasive breast cancer', 'Disease', 'MESH:D001943', (70, 92))	('DCIS', 'Disease', (122, 126))
30321	30056557	Notably, SUM225 forms dysplastic structures in both 3D culture models and in vivo in an intraductal mouse model.	('SUM225', 'Var', (9, 15))	('dysplastic', 'Disease', (22, 32))	('mouse', 'Species', '10090', (100, 105))	('dysplastic', 'Disease', 'MESH:D004416', (22, 32))
30330	30056557	Of these, ETCC006 (and to a lesser degree ETCC010) resembled the original lesion the closest with regard to expression of pan-cytokeratin, cytokeratin-19, vimentin, estrogen receptor alpha/beta, and progesterone receptor.	('vimentin', 'Gene', (155, 163))	('cytokeratin-19', 'Gene', '3880', (139, 153))	('pan-cytokeratin', 'Protein', (122, 137))	('ETCC006', 'Var', (10, 17))	('estrogen receptor alpha/beta, and progesterone receptor', 'Gene', '5241;2099', (165, 220))	('cytokeratin-19', 'Gene', (139, 153))	('vimentin', 'Gene', '7431', (155, 163))
30333	30056557	In contrast, ETCC006, ETCC007, ETCC010 and ETCC011 all showed tumor growth after 50 days.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ETCC010', 'Var', (31, 38))	('tumor', 'Disease', (62, 67))	('ETCC011', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
30337	30056557	In a more recent paper, they analyzed the effect of modulating SIM2s expression on DCIS progression.	('modulating', 'Var', (52, 62))	('DCIS', 'Disease', 'MESH:D002285', (83, 87))	('SIM2s', 'Gene', (63, 68))	('DCIS', 'Disease', (83, 87))
30339	30056557	found that stable knockdown of SIM2s in MCF10DCIS.com cells results in an increase in proliferation and invasiveness.	('knockdown', 'Var', (18, 27))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (40, 53))	('invasiveness', 'CPA', (104, 116))	('proliferation', 'CPA', (86, 99))	('increase', 'PosReg', (74, 82))	('SIM2s', 'Gene', (31, 36))
30340	30056557	Contradictory changes in expression of several matrix metal-loproteinases (MMPs) are observed in xenografts generated from the cells in which SIM2s expression had been manipulated.	('MMPs', 'Gene', (75, 79))	('expression', 'MPA', (25, 35))	('manipulated', 'Var', (168, 179))	('SIM2s', 'Gene', (142, 147))	('MMPs', 'Gene', '4312;4318', (75, 79))	('changes', 'Reg', (14, 21))
30342	30056557	Porter and colleagues concluded that SIM2s may play a role in breast cancer progression, and that expression of the protein can promote tumor differentiation.	('expression', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('promote', 'PosReg', (128, 135))	('tumor', 'Disease', (136, 141))	('SIM2s', 'Gene', (37, 42))
30357	30056557	To recapitulate this environment, SUM102PT was co-cultured with HGF-expressing fibroblasts.	('HGF', 'Gene', (64, 67))	('SUM102PT', 'Var', (34, 42))	('HGF', 'Gene', '3082', (64, 67))
30362	30056557	Zhou and colleagues have reported that co-culturing adipocytes with either of the two DCIS cell lines, MCF10DCIS.com or SUM102PT, results in increased migration.	('migration', 'CPA', (151, 160))	('DCIS', 'Disease', 'MESH:D002285', (108, 112))	('increased', 'PosReg', (141, 150))	('SUM102PT', 'Var', (120, 128))	('DCIS', 'Disease', (108, 112))	('DCIS', 'Disease', (86, 90))	('DCIS', 'Disease', 'MESH:D002285', (86, 90))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (103, 116))
30363	30056557	They also observed a more aggressive phenotype of MCF10DCIS.com, characterized by enhanced invasiveness and increased tumor growth in vivo.	('MCF10DCIS.com', 'Var', (50, 63))	('enhanced', 'PosReg', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('increased', 'PosReg', (108, 117))	('invasiveness', 'CPA', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (50, 63))
30375	30056557	Through proteomic screening of acid-adapted and acid-naive MCF-7 breast cancer cells, they found that lysosome-associated membrane protein-2 (LAMP2) expression is significantly increased with adaption.	('lysosome-associated membrane protein-2', 'Gene', '3920', (102, 140))	('LAMP2', 'Gene', (142, 147))	('LAMP2', 'Gene', '3920', (142, 147))	('lysosome-associated membrane protein-2', 'Gene', (102, 140))	('MCF-7', 'CellLine', 'CVCL:0031', (59, 64))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('increased', 'PosReg', (177, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('expression', 'MPA', (149, 159))	('adaption', 'Var', (192, 200))
30403	30056557	who reported that high expression of G3BP2, which regulates initiation of breast cancer, is associated with poor survival of breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('G3BP2', 'Gene', (37, 42))	('initiation of breast cancer', 'Disease', (60, 87))	('patients', 'Species', '9606', (139, 147))	('initiation of breast cancer', 'Disease', 'MESH:D001943', (60, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('high expression', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('G3BP2', 'Gene', '9908', (37, 42))
30404	30056557	Studies on DCIS progression have focused on two different hypotheses for the acquisition of invasiveness that characterizes the transition from DCIS to IDC: 1) molecular and genetic alterations in the DCIS cells or 2) alterations resulting from cross-talk between DCIS cells and their microenvironment including matrices as discussed above or stromal cells and pathochemical factors as discussed below (see "3D DCIS cultures: analyses of interactions with tumor microenvironment").	('tumor', 'Disease', 'MESH:D009369', (456, 461))	('DCIS', 'Disease', (264, 268))	('DCIS', 'Disease', (11, 15))	('IDC', 'Disease', 'MESH:D044584', (152, 155))	('DCIS', 'Disease', 'MESH:D002285', (264, 268))	('DCIS', 'Disease', 'MESH:D002285', (11, 15))	('DCIS', 'Disease', 'MESH:D002285', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (456, 461))	('IDC', 'Disease', (152, 155))	('DCIS', 'Disease', (201, 205))	('tumor', 'Disease', (456, 461))	('alterations', 'Var', (218, 229))	('DCIS', 'Disease', 'MESH:D002285', (411, 415))	('DCIS', 'Disease', (411, 415))	('DCIS', 'Disease', (144, 148))	('DCIS', 'Disease', 'MESH:D002285', (144, 148))
30405	30056557	Profiling of DCIS patient samples has revealed significant changes in gene expression in association with the transition to IDC, similarities in gene expression and mutation in epithelial cells from in situ and invasive regions, and both changes and similarities.	('IDC', 'Disease', (124, 127))	('IDC', 'Disease', 'MESH:D044584', (124, 127))	('transition', 'Disease', (110, 120))	('mutation', 'Var', (165, 173))	('changes', 'Reg', (59, 66))	('gene expression', 'MPA', (70, 85))	('patient', 'Species', '9606', (18, 25))	('DCIS', 'Disease', 'MESH:D002285', (13, 17))	('DCIS', 'Disease', (13, 17))
30413	30056557	Secretion of CCL20/MIP-3alpha increases in 3D rBM mono-cultures of MCF10 variants from atypical hyperplastic to DCIS and remains high in the isogenic IDC cell line.	('MCF10', 'Gene', (67, 72))	('variants', 'Var', (73, 81))	('MCF10', 'CellLine', 'CVCL:5555', (67, 72))	('CCL20', 'Gene', (13, 18))	('MIP-3alpha', 'Gene', (19, 29))	('IDC', 'Disease', (150, 153))	('IDC', 'Disease', 'MESH:D044584', (150, 153))	('CCL20', 'Gene', '6364', (13, 18))	('Secretion', 'MPA', (0, 9))	('DCIS', 'Disease', (112, 116))	('DCIS', 'Disease', 'MESH:D002285', (112, 116))	('MIP-3alpha', 'Gene', '6364', (19, 29))
30426	30056557	have shown that another protease inhibitor, i.e., stefin A, an inhibitor of cysteine cathepsins, is abundant in MEPs and that stefin A suppresses DCIS invasion, an inhibitory effect reliant on cathepsin B.	('suppresses', 'NegReg', (135, 145))	('cathepsin B', 'Gene', '1508', (193, 204))	('stefin A', 'Var', (126, 134))	('DCIS', 'Disease', (146, 150))	('DCIS', 'Disease', 'MESH:D002285', (146, 150))	('cathepsin B', 'Gene', (193, 204))
30443	30056557	CXCR2 is implicated in breast cancer progression as targeting CXCR2 in mouse mammary carcinoma models enhances responses to chemotherapy and inhibits tumor growth, angiogenesis, and lung metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('CXCR2', 'Gene', '12765', (0, 5))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('lung metastasis', 'Disease', 'MESH:D009362', (182, 197))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('mouse', 'Species', '10090', (71, 76))	('breast cancer', 'Disease', (23, 36))	('inhibits', 'NegReg', (141, 149))	('responses to chemotherapy', 'MPA', (111, 136))	('lung metastasis', 'Disease', (182, 197))	('CXCR2', 'Gene', '12765', (62, 67))	('CXCR2', 'Gene', (0, 5))	('enhances', 'PosReg', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (77, 94))	('tumor', 'Disease', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('carcinoma', 'Disease', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('targeting', 'Var', (52, 61))	('CXCR2', 'Gene', (62, 67))	('angiogenesis', 'CPA', (164, 176))
30551	28274272	Screen detection was associated with lower all-cause mortality (HR = 0.85, 95% CI = 0.73-0.98); when we additionally accounted for the occurrence of invasive breast cancer the magnitude of this effect remained similar (HR = 0.86, 95% CI = 0.75-1.00).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('invasive breast cancer', 'Disease', (149, 171))	('Screen detection', 'Var', (0, 16))	('lower', 'NegReg', (37, 42))	('all-cause mortality', 'MPA', (43, 62))	('invasive breast cancer', 'Disease', 'MESH:D001943', (149, 171))
30602	28274272	In the supplementary analysis, we found that women with interval DCIS tended to have higher risk of ipsilateral invasive breast cancer than women with screen-detected DCIS (HR 1.64; 95% CI 0.99-2.72), whereas the risk of contralateral invasive breast cancer was similar (HR 1.01; 95% CI 0.61-1.67) (Additional file 5).	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('interval DCIS', 'Var', (56, 69))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('contralateral invasive breast cancer', 'Disease', 'MESH:D001943', (221, 257))	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (100, 134))	('women', 'Species', '9606', (140, 145))	('ipsilateral invasive breast cancer', 'Disease', (100, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('contralateral invasive breast cancer', 'Disease', (221, 257))	('women', 'Species', '9606', (45, 50))
30625	28274272	reported a higher risk of ipsilateral invasive breast cancer in symptomatic DCIS, which was comparable to the higher risk in non-screening-related DCIS in our study (HR = 1.38, 95% CI = 1.12-1.63 and HR = 1.33, 95% CI = 1.04-1.70, respectively).	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (26, 60))	('ipsilateral invasive breast cancer', 'Disease', (26, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DCIS', 'Var', (76, 80))
30631	28274272	As high breast density is associated with decreased mammographic accuracy and increased risk of breast cancer, it might be hypothesized that women with screen-detected DCIS have relatively low breast density and therefore confer a lower risk of subsequent breast cancer as compared with women with interval DCIS.	('breast cancer', 'Disease', (256, 269))	('decreased', 'NegReg', (42, 51))	('women', 'Species', '9606', (287, 292))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('DCIS', 'Phenotype', 'HP:0030075', (307, 311))	('breast cancer', 'Disease', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mammographic accuracy', 'CPA', (52, 73))	('lower', 'NegReg', (231, 236))	('breast', 'MPA', (193, 199))	('women', 'Species', '9606', (141, 146))	('low', 'NegReg', (189, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('DCIS', 'Var', (168, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('high breast density', 'Phenotype', 'HP:0010313', (3, 22))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
30652	22424533	In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings.	('Ki67', 'Var', (86, 90))	('ER', 'Gene', '2099', (104, 106))	('HR-positive tumours', 'Disease', (3, 22))	('aggressiveness of the tumour', 'Disease', 'MESH:D001523', (28, 56))	('Ki67', 'Chemical', '-', (86, 90))	('HR-positive tumours', 'Disease', 'MESH:D009369', (3, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (28, 42))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('aggressiveness of the tumour', 'Disease', (28, 56))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
30660	22424533	Due to the limitations of the molecular systems, current clinical practice of breast cancer therapy is largely based upon conventional clinical and pathologic criteria, including mainly tumour stage (T), lymph node involvement (N), histological grade (G), expression of hormone receptors (HR), and hyper-expression and amplification of human epidermal growth factor receptor 2 (HER2) in the tumour tissue.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('lymph node involvement', 'Disease', (204, 226))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('HR', 'Gene', '3164', (289, 291))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('HER2', 'Gene', (378, 382))	('epidermal growth factor receptor 2', 'Gene', '2064', (342, 376))	('breast cancer', 'Disease', (78, 91))	('tumour', 'Disease', (186, 192))	('hormone receptors', 'Gene', '3164', (270, 287))	('hyper-expression', 'Var', (298, 314))	('epidermal growth factor receptor 2', 'Gene', (342, 376))	('tumour', 'Phenotype', 'HP:0002664', (391, 397))	('tumour', 'Disease', 'MESH:D009369', (391, 397))	('amplification', 'Var', (319, 332))	('tumour', 'Disease', (391, 397))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hormone receptors', 'Gene', (270, 287))	('HER2', 'Gene', '2064', (378, 382))	('human', 'Species', '9606', (336, 341))
30675	22424533	Immunohistochemistry for ER, PR, HER2, AR, Ki67, p53, p16, BCL2, SATB1 and HIF-1alpha was performed using the SP1, 1E2 and 4B5 (Ventana), SP107 (Spring), MIB-1 (DAKO), DO-7 (Novocastra), E6H4 (CINtec), 124 (DAKO), EPR3895 and EP1215Y (Epitomics) antibodies, respectively.	('BCL2', 'Gene', '596', (59, 63))	('HIF-1alpha', 'Gene', '3091', (75, 85))	('MIB-1', 'Gene', (154, 159))	('p53', 'Gene', '7157', (49, 52))	('ER', 'Gene', '2099', (25, 27))	('SATB1', 'Gene', (65, 70))	('HER2', 'Gene', '2064', (33, 37))	('SP107', 'Var', (138, 143))	('MIB-1', 'Gene', '57534', (154, 159))	('SP1, 1E2 and 4B5', 'Gene', '6667', (110, 126))	('p53', 'Gene', (49, 52))	('SATB1', 'Gene', '6304', (65, 70))	('BCL2', 'Gene', (59, 63))	('HIF-1alpha', 'Gene', (75, 85))	('EP1215Y', 'Var', (226, 233))	('HER2', 'Gene', (33, 37))	('AR', 'Gene', '367', (39, 41))	('E6H4', 'Var', (187, 191))	('EPR3895', 'Var', (214, 221))	('ER', 'Gene', '2099', (34, 36))	('p16', 'Gene', (54, 57))	('p16', 'Gene', '1029', (54, 57))	('Ki67', 'Chemical', '-', (43, 47))
30689	22424533	Since the intrinsic subtypes were subdivided based on the visual evaluation of the IHC images, the DA results on ER, PR, HER2, and Ki67 do not strictly correspond to the conventional cut-off values used for the definition of intrinsic subtypes.	('HER2', 'Gene', '2064', (121, 125))	('ER', 'Gene', '2099', (113, 115))	('Ki67', 'Var', (131, 135))	('ER', 'Gene', '2099', (122, 124))	('Ki67', 'Chemical', '-', (131, 135))	('HER2', 'Gene', (121, 125))
30690	22424533	Factor analysis was performed on 109 patients with a complete set of 10 IHC markers: ER, PR, AR, HER2, BCL2, Ki67, HIF-1alpha, SATB1, p53, and p16.	('HER2', 'Gene', (97, 101))	('Ki67', 'Var', (109, 113))	('ER', 'Gene', '2099', (98, 100))	('HIF-1alpha', 'Gene', '3091', (115, 125))	('AR', 'Gene', '367', (93, 95))	('BCL2', 'Gene', '596', (103, 107))	('HER2', 'Gene', '2064', (97, 101))	('p53', 'Gene', '7157', (134, 137))	('HIF-1alpha', 'Gene', (115, 125))	('patients', 'Species', '9606', (37, 45))	('SATB1', 'Gene', (127, 132))	('p16', 'Gene', (143, 146))	('SATB1', 'Gene', '6304', (127, 132))	('BCL2', 'Gene', (103, 107))	('ER', 'Gene', '2099', (85, 87))	('p53', 'Gene', (134, 137))	('Ki67', 'Chemical', '-', (109, 113))	('p16', 'Gene', '1029', (143, 146))
30732	22424533	We found that major factor of the IHC profile variation in the ductal breast carcinoma was characterized by a strong inverse relation between the expression of hormone receptors (ER, PR, AR) along with anti-apoptotic marker BCL2, on one side, and Ki67 (proliferation) and HIF-1alpha (hypoxic stress, angiogenesis, see below), on the other side.	('ductal breast carcinoma', 'Disease', (63, 86))	('ductal breast carcinoma', 'Disease', 'MESH:D018270', (63, 86))	('BCL2', 'Gene', '596', (224, 228))	('ER', 'Gene', '2099', (179, 181))	('breast carcinoma', 'Phenotype', 'HP:0003002', (70, 86))	('Ki67', 'Chemical', '-', (247, 251))	('AR', 'Gene', '367', (187, 189))	('HIF-1alpha', 'Gene', '3091', (272, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('BCL2', 'Gene', (224, 228))	('hormone receptors', 'Gene', '3164', (160, 177))	('hypoxic stress', 'Disease', 'MESH:D004194', (284, 298))	('hypoxic stress', 'Disease', (284, 298))	('variation', 'Var', (46, 55))	('hormone receptors', 'Gene', (160, 177))	('inverse', 'NegReg', (117, 124))	('expression', 'MPA', (146, 156))	('HIF-1alpha', 'Gene', (272, 282))
30743	22424533	In addition, our data suggest that inclusion of HIF-1alpha into this integrated index of the disease aggressiveness might bring more accuracy to this potential prognostic indicator.	('HIF-1alpha', 'Gene', (48, 58))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('accuracy', 'MPA', (133, 141))	('HIF-1alpha', 'Gene', '3091', (48, 58))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('inclusion', 'Var', (35, 44))	('aggressiveness', 'Disease', (101, 115))
30764	22424533	In particular, the expression levels of SATB1 mRNA in 2058 breast cancer samples were not related to disease-free survival among ER negative cancers, however, high SATB1 expression among ER positive tumours showed beneficial prognosis; nevertheless, even in ER positive cancer no independent prognostic value in multivariate analysis with standard parameters was observed.	('SATB1', 'Gene', '6304', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('high', 'Var', (159, 163))	('expression', 'MPA', (170, 180))	('cancer', 'Disease', (270, 276))	('beneficial', 'PosReg', (214, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumours', 'Disease', (199, 206))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancers', 'Disease', (141, 148))	('cancer', 'Disease', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('SATB1', 'Gene', (40, 45))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('breast cancer', 'Disease', (59, 72))	('ER', 'Gene', '2099', (187, 189))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('ER', 'Gene', '2099', (258, 260))	('SATB1', 'Gene', '6304', (40, 45))	('SATB1', 'Gene', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('ER', 'Gene', '2099', (129, 131))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancer', 'Disease', (66, 72))
30786	22424533	AR expression has been reported as a marker of better prognosis in Triple-negative breast cancer, however, our findings warn that this effect may be caused by the confounding effect due to the inverse relation between AR and Ki67 with p16.	('p16', 'Gene', (235, 238))	('better', 'PosReg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AR', 'Gene', '367', (218, 220))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('p16', 'Gene', '1029', (235, 238))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Ki67', 'Var', (225, 229))	('Ki67', 'Chemical', '-', (225, 229))	('AR', 'Gene', '367', (0, 2))
30792	22424533	In HR-positive tumours, the aggressiveness of the tumour is best reflected by the combination of Ki67 and ER, rather than Ki67 and BCL2.	('ER', 'Gene', '2099', (106, 108))	('aggressiveness of the tumour', 'Disease', (28, 56))	('BCL2', 'Gene', '596', (131, 135))	('aggressiveness of the tumour', 'Disease', 'MESH:D001523', (28, 56))	('HR-positive tumours', 'Disease', (3, 22))	('HR-positive tumours', 'Disease', 'MESH:D009369', (3, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (28, 42))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('Ki67', 'Var', (97, 101))	('BCL2', 'Gene', (131, 135))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
30806	28879558	Therefore, misclassification and misdiagnosis reduce the clinical effectiveness of breast cancer screening and increase potential harms to women.	('women', 'Species', '9606', (139, 144))	('increase', 'PosReg', (111, 119))	('reduce', 'NegReg', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('misdiagnosis', 'Var', (33, 45))	('misclassification', 'Var', (11, 28))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('clinical effectiveness', 'MPA', (57, 79))
30862	25666939	In Japanese patients, when both invasive carcinoma and DCIS were combined, the 10-year IBTR rates were reported to be 8.5 % after partial resection plus irradiation and 17.2 % after partial resection alone.	('patients', 'Species', '9606', (12, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinoma', 'Disease', (41, 50))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('partial resection', 'Var', (130, 147))	('carcinoma', 'Disease', 'MESH:D002277', (41, 50))
30864	25666939	On the other hand, a 10-year IBTR rate after partial resection for DCIS was reported to be only 3.3 % after surgical therapy alone in a study conducted in a Japanese institute that treated a large number of patients.	('DCIS', 'Disease', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('patients', 'Species', '9606', (207, 215))	('partial resection', 'Var', (45, 62))
30987	22908098	Margin assessment is critical for local disease control because positive margins have been associated with an increased probability of local recurrence and mortality, resulting in a 20-40% re-excision rate.	('mortality', 'CPA', (156, 165))	('local disease', 'Disease', 'MESH:D012594', (34, 47))	('local disease', 'Disease', (34, 47))	('local recurrence', 'CPA', (135, 151))	('positive', 'Var', (64, 72))
31016	31549321	High nuclear grade and microinvasion were also associated with risk of LRR, and these factors, as well as close/positive margins, were more prevalent in younger women.	('High', 'Var', (0, 4))	('LRR', 'Disease', (71, 74))	('women', 'Species', '9606', (161, 166))	('microinvasion', 'CPA', (23, 36))
31034	28169313	DOT overcomes some of the drawbacks of conventional diagnostic modalities, such as X-ray mammography (XMMG), ultrasonography (US), and magnetic resonance imaging (MRI): XMMG is associated with ionizing radiation and has lower diagnostic sensitivity for dense breast tissue; the results of US depend greatly on instrumental performance and the examiner's skill; and MRI requires the use of contrast medium, which is not suitable for mass screening or repeated examination.	('w', 'Chemical', 'MESH:D014414', (29, 30))	('w', 'Chemical', 'MESH:D014414', (406, 407))	('ionizing radiation', 'Disease', (193, 211))	('w', 'Chemical', 'MESH:D014414', (222, 223))	('lower', 'NegReg', (220, 225))	('XMMG', 'Var', (169, 173))	('diagnostic sensitivity', 'MPA', (226, 248))	('ionizing radiation', 'Disease', 'MESH:D004194', (193, 211))	('w', 'Chemical', 'MESH:D014414', (188, 189))
31239	25667101	High DDR2 was associated with high tumor grade (p=0.002), triple negative subtype (TNBC) (p<0.0001), and worse survival (p=0.037).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('triple negative subtype', 'Disease', (58, 81))	('High', 'Var', (0, 4))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('DDR2', 'Gene', (5, 9))	('tumor', 'Disease', (35, 40))
31240	25667101	We discovered a novel concordant deregulation of DDR expression, with a DDR1Low/DDR2High profile significantly associated with TNBC, compared to luminal tumors (p=0.012), and with worse overall survival.	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('DDR', 'MPA', (49, 52))	('luminal tumors', 'Disease', 'MESH:D009369', (145, 159))	('associated', 'Reg', (111, 121))	('deregulation', 'MPA', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('DDR1Low/DDR2High', 'Var', (72, 88))	('TNBC', 'Disease', (127, 131))	('luminal tumors', 'Disease', (145, 159))
31241	25667101	A DDR1Low/DDR2High protein profile is associated with TNBC, and may identify invasive carcinomas with worse prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('associated', 'Reg', (38, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('BC', 'Phenotype', 'HP:0003002', (56, 58))	('invasive carcinomas', 'Disease', (77, 96))	('invasive carcinomas', 'Disease', 'MESH:D009361', (77, 96))	('TNBC', 'Disease', (54, 58))	('DDR1Low/DDR2High', 'Var', (2, 18))
31243	25667101	In normal breast tissues, high mammographic density, which is partly due to increased fibrillar collagen deposition, is associated with a two-fold increased risk of breast cancer development.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('high', 'Var', (26, 30))	('increased', 'PosReg', (76, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('fibrillar', 'MPA', (86, 95))	('increased fibrillar collagen deposition', 'Phenotype', 'HP:0032208', (76, 115))
31252	25667101	DDR1 knockdown in mice causes abnormal mammary gland development and leads to lactation deficiency, suggesting a key role for DDR1 in mammary gland function.	('causes', 'Reg', (23, 29))	('knockdown', 'Var', (5, 14))	('leads to', 'Reg', (69, 77))	('mice', 'Species', '10090', (18, 22))	('mammary gland development', 'CPA', (39, 64))	('lactation deficiency', 'Disease', (78, 98))	('lactation deficiency', 'Disease', 'MESH:D007775', (78, 98))	('DDR1', 'Gene', (0, 4))
31255	25667101	In contrast to DDR1, no evidence of an abnormal or dysfunctional mammary gland phenotype has been reported in DDR2 deficient mice.	('dysfunctional', 'Disease', 'MESH:D006331', (51, 64))	('mice', 'Species', '10090', (125, 129))	('dysfunctional', 'Disease', (51, 64))	('deficient', 'Var', (115, 124))	('DDR2', 'Gene', (110, 114))
31258	25667101	Consistently, targeting these receptors restored MEK inhibitor sensitivity.	('restored', 'PosReg', (40, 48))	('targeting', 'Var', (14, 23))	('MEK', 'Gene', (49, 52))	('MEK', 'Gene', '5609', (49, 52))
31278	25667101	Slides were incubated for 1.5 hours at room temperature with one of the following antibodies: anti-DDR1 (Santa Cruz Biotechnology, Cat#SC-532, 1:425), anti-DDR2 (R&D Systems, Cat#MAB2538, 1:75), anti-Snail1, anti-Slug (Cell Signaling, Cat# 3895, 1:800, and Cat#9585, 1:100), anti- E-Cadherin (BD Biosciences, Cat# 610182, 1:5000), an antibody cocktail containing anti-CD44 (Abcam, Cat# AB51037, 1:500) and anti-CD24 (Biocare Medical, Cat# CM323, 1:120), or anti-ALDH-1 (BD Biosciences, Cat# 611194, 1:6000).	('ALDH-1', 'Gene', (462, 468))	('Slug', 'Gene', '6591', (213, 217))	('E-Cadherin', 'Gene', (281, 291))	('and', 'Var', (402, 405))	('CD24', 'Gene', '100133941', (411, 415))	('CD24', 'Gene', (411, 415))	('Slug', 'Gene', (213, 217))	('E-Cadherin', 'Gene', '999', (281, 291))	('CD44', 'Gene', '960', (368, 372))	('ALDH-1', 'Gene', '216', (462, 468))	('Snail1', 'Gene', (200, 206))	('containing', 'Var', (352, 362))	('CD44', 'Gene', (368, 372))	('Snail1', 'Gene', '6615', (200, 206))
31305	25667101	Moreover, we found equal distribution of high and low DDR1 expressing tumors within the luminal and TNBC subtypes (Figure 3).	('low', 'NegReg', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BC', 'Phenotype', 'HP:0003002', (102, 104))	('DDR1', 'Gene', (54, 58))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('high', 'Var', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
31306	25667101	In contrast, high DDR2 expression was significantly associated with higher histological grade (p=0.002), negative estrogen and progesterone receptor (ER and PR) status, negative HER2/neu overexpression (p<0.0001, p=0.0005, and p=0.01, respectively, Table 2), and with the TNBC subtype in which the majority of cases displayed high DDR2 expression (Figure 3, Chi Square test p<0.0001).	('overexpression', 'PosReg', (187, 201))	('histological grade', 'CPA', (75, 93))	('neu', 'Gene', (183, 186))	('HER2', 'Gene', '2064', (178, 182))	('high', 'Var', (13, 17))	('BC', 'Phenotype', 'HP:0003002', (274, 276))	('progesterone receptor', 'Gene', '5241', (127, 148))	('higher', 'PosReg', (68, 74))	('HER2', 'Gene', (178, 182))	('progesterone receptor', 'Gene', (127, 148))	('DDR2', 'Gene', (18, 22))	('neu', 'Gene', '2064', (183, 186))	('expression', 'MPA', (23, 33))
31308	25667101	DDR1Low/DDR2High expression is significantly associated with TNBC compared to luminal and HER2 subtypes (p=0.012).	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', '2064', (90, 94))	('associated', 'Reg', (45, 55))	('BC', 'Phenotype', 'HP:0003002', (63, 65))	('TNBC', 'Disease', (61, 65))	('DDR1Low/DDR2High expression', 'Var', (0, 27))
31311	25667101	Kaplan Meier survival analyses showed that patients with tumors expressing high DDR2 had a significantly worse overall survival than those expressing low DDR2 after initial surgical treatment (Kaplan Meier, log rank p=0.037, Figure 4A).	('overall survival', 'MPA', (111, 127))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('worse', 'NegReg', (105, 110))	('high DDR2', 'Var', (75, 84))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
31312	25667101	The median survival for patients with tumors expressing high and low DDR2 levels was 7.2 years vs. 11.0 years (Log rank p=0.037).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('high', 'Var', (56, 60))	('low', 'NegReg', (65, 68))	('patients', 'Species', '9606', (24, 32))	('DDR2', 'Gene', (69, 73))
31314	25667101	The median survival for patients with tumors expressing DDR1Low/DDR2High levels was 6.4 years and, by contrast 10.8 years for patients with tumors without this phenotype (Log rank p=0.007).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('DDR1Low/DDR2High', 'Var', (56, 72))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (24, 32))
31315	25667101	The 10-year overall survival for patients with DDR1Low/DDR2High tumors was 35% compared to 55%, for those without this phenotype.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', (64, 70))	('DDR1Low/DDR2High', 'Var', (47, 63))	('patients', 'Species', '9606', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
31316	25667101	DDR1Low/DDR2High was able to predict survival independently of tumor size, TNBC phenotype, and lymphovascular invasion, with a hazard ratio of 1.73 and a 95% confidence interval of 1.13-2.63, p=0.011.	('tumor', 'Disease', (63, 68))	('BC', 'Phenotype', 'HP:0003002', (77, 79))	('DDR1Low/DDR2High', 'Var', (0, 16))	('predict', 'Reg', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
31317	25667101	Collectively, these data show that DDR2 protein is associated with survival in patients with breast cancer and that when considered in association with DDR1 protein levels, the DDR1Low/DDR2 High profile may be an independent predictor of outcome.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('DDR2', 'Gene', (35, 39))	('DDR1Low/DDR2 High', 'Var', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('associated', 'Reg', (51, 61))	('breast cancer', 'Disease', (93, 106))	('patients', 'Species', '9606', (79, 87))	('protein', 'Protein', (40, 47))
31321	25667101	The invasive carcinomas in our cohort displayed almost an equal distribution of tumors expressing either high or reduced DDR1 protein.	('high', 'Var', (105, 109))	('DDR1', 'Gene', (121, 125))	('protein', 'Protein', (126, 133))	('invasive carcinomas', 'Disease', (4, 23))	('invasive carcinomas', 'Disease', 'MESH:D009361', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('reduced', 'NegReg', (113, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))
31322	25667101	Our statistical analyses did not reveal any significant association between high or low DDR1 protein expression and the histopathological features of the tumors.	('tumors', 'Disease', (154, 160))	('low', 'NegReg', (84, 87))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('protein', 'Protein', (93, 100))	('DDR1', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('high', 'Var', (76, 80))
31323	25667101	Based on the reported experimental evidence, it is possible that variations in DDR1 expression may be a reflection of the complex effects that DDR1 elicits in breast cancer cells, from tumor suppressive to tumor promoter in a context dependent manner.	('tumor', 'Disease', (185, 190))	('DDR1', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (206, 211))	('variations', 'Var', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('DDR1', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
31327	25667101	Thus, MT1-MMP-mediated cleavage of the receptor ectodomain may hinder the tumor suppressive effects of DDR1 during breast cancer progression.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MT1-MMP', 'Gene', '4323', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MT1-MMP', 'Gene', (6, 13))	('hinder', 'NegReg', (63, 69))	('tumor', 'Disease', (74, 79))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('cleavage', 'Var', (23, 31))
31329	25667101	High DDR1 expression may also play a role in breast cancer cell proliferation and/or survival.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('High', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('survival', 'CPA', (85, 93))	('expression', 'MPA', (10, 20))	('breast cancer', 'Disease', (45, 58))	('play', 'Reg', (30, 34))	('DDR1', 'Gene', (5, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
31338	25667101	We found that high DDR2 protein levels were significantly associated with high tumor grade, a measure of tumor differentiation and indicator of poor patient outcome, TNBC, and with worse survival compared to low DDR2 protein.	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('DDR2 protein', 'Protein', (19, 31))	('high', 'Var', (14, 18))	('BC', 'Phenotype', 'HP:0003002', (168, 170))	('patient', 'Species', '9606', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
31339	25667101	These data further validate the reported association between high levels of DDR2 messenger RNA with higher risk of relapse in breast cancer, as well as the reported association between DDR2 gene amplified copy number and worse survival.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('relapse', 'Disease', (115, 122))	('high levels', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('DDR2', 'Protein', (76, 80))	('DDR2', 'Gene', (185, 189))
31346	22472881	Mitochondrial D310 mutations in the early development of breast cancer The role of mitochondrial DNA (mtDNA) mutations in the development of breast cancer is largely unknown.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (19, 28))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('Mitochondrial D310', 'Gene', (0, 18))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('early development of breast', 'Phenotype', 'HP:0010314', (36, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
31347	22472881	In this study, we investigated the frequency and pattern of mutations in the D310 region, the most commonly mutated region in mtDNA, in a series of breast lesions.	('breast lesions', 'Disease', 'MESH:D001941', (148, 162))	('D310', 'Var', (77, 81))	('D310', 'Chemical', '-', (77, 81))	('breast lesions', 'Disease', (148, 162))
31348	22472881	Using capillary electrophoresis, we genotyped the D310 sequence of neoplastic epithelial cells from 23 patients with synchronous ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), 26 patients with IDC only and 29 patients with DCIS only.	('patients', 'Species', '9606', (201, 209))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (129, 153))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (129, 145))	('patients', 'Species', '9606', (231, 239))	('D310', 'Chemical', '-', (50, 54))	('ductal carcinoma in situ', 'Disease', (129, 153))	('D310', 'Var', (50, 54))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (129, 153))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (174, 190))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (165, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('patients', 'Species', '9606', (103, 111))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (136, 153))	('invasive ductal carcinoma', 'Disease', (165, 190))	('synchronous ductal carcinoma', 'Disease', 'MESH:D009378', (117, 145))	('synchronous ductal carcinoma', 'Disease', (117, 145))
31349	22472881	A majority of DCIS (68.4%) and IDC (71.4%) lesions harbour different D310 sequences compared with their matched normal control.	('D310', 'Chemical', '-', (69, 73))	('IDC', 'Disease', (31, 34))	('D310 sequences', 'Var', (69, 83))	('DCIS', 'Disease', (14, 18))
31350	22472881	Specific D310 sequences were more frequently identified in tumour samples (77.1% of DCIS and 75.5% of IDC) compared with normal tissues (35.3% of normal; P<0.0001).	('D310', 'Chemical', '-', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('D310 sequences', 'Var', (9, 23))	('DCIS', 'Disease', (84, 88))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
31351	22472881	In five cases, histologically normal tissue adjacent to tumour was found to share D310 sequences with the tumour, while normal tissue taken further away did not.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('D310', 'Chemical', '-', (82, 86))	('tumour', 'Disease', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('D310 sequences', 'Var', (82, 96))	('tumour', 'Disease', (56, 62))
31352	22472881	Although D310 alterations do not seem to be related to DCIS progression, they were found in histologically normal cells adjacent to tumour.	('tumour', 'Disease', (132, 138))	('D310 alterations', 'Var', (9, 25))	('D310', 'Chemical', '-', (9, 13))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))
31353	22472881	This suggests a field of genetically altered cells, thus D310 mutations could represent a potential marker for the clonal expansion of premalignant breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('premalignant breast cancer', 'Disease', 'MESH:D001943', (135, 161))	('D310', 'Chemical', '-', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('premalignant breast cancer', 'Disease', (135, 161))	('D310 mutations', 'Var', (57, 71))
31357	22472881	It has been proposed that DCIS harbouring 17q22.24 gains are associated with a higher risk of progression to invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (109, 125))	('17q22.24', 'Var', (42, 50))	('invasive disease', 'Disease', (109, 125))	('gains', 'PosReg', (51, 56))
31358	22472881	An important link has been made between p53 mutations and DCIS of high histological grade.	('mutations', 'Var', (44, 53))	('DCIS', 'Disease', (58, 62))	('p53', 'Gene', '7157', (40, 43))	('p53', 'Gene', (40, 43))
31359	22472881	P53 missense mutations occur at highest frequency in high-grade DCIS, but not in areas of hyperplasia or normal breast epithelium, suggesting that p53 mutations occur before the development of IDC.	('hyperplasia', 'Disease', (90, 101))	('IDC', 'Disease', (193, 196))	('hyperplasia', 'Disease', 'MESH:D006965', (90, 101))	('missense mutations', 'Var', (4, 22))	('P53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (147, 150))	('P53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (147, 150))
31360	22472881	Recently, mitochondrial DNA (mtDNA) depletion- and mutation-induced oxidative stress have been shown to be linked to increased tumourigenicity and an invasive phenotype, suggesting that mtDNA mutations may serve as markers for cancer progression.	('oxidative', 'MPA', (68, 77))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('increased', 'PosReg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('depletion-', 'Var', (36, 46))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('invasive phenotype', 'CPA', (150, 168))	('cancer', 'Disease', (227, 233))	('mutation-induced', 'Var', (51, 67))	('tumour', 'Disease', (127, 133))	('mutations', 'Var', (192, 201))
31362	22472881	To date, mtDNA mutations have been detected in fine-needle aspirates and bodily fluids of cancer patients.	('detected', 'Reg', (35, 43))	('mtDNA', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('patients', 'Species', '9606', (97, 105))
31363	22472881	Many mtDNA mutations have been described in various forms of cancer, most of them in the regulatory region or D-loop, the replication origin for the heavy strand of mtDNA.	('mutations', 'Var', (11, 20))	('described', 'Reg', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('mtDNA', 'Gene', (5, 10))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
31364	22472881	Within the D-loop, the majority of mutations occur within a poly-C repeat stretch termed D310.	('poly-C', 'Chemical', 'MESH:D011066', (60, 66))	('occur', 'Reg', (45, 50))	('mutations', 'Var', (35, 44))	('D310', 'Chemical', '-', (89, 93))	('D310', 'Var', (89, 93))
31365	22472881	D310 mutations are highly prevalent in human tumours, including gastric, colorectal, bladder, lung, gallbladder, and breast cancers.	('D310 mutations', 'Var', (0, 14))	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('gallbladder', 'Disease', (100, 111))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('bladder', 'Disease', (85, 92))	('prevalent', 'Reg', (26, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('D310', 'Chemical', '-', (0, 4))	('colorectal', 'Disease', (73, 83))	('human', 'Species', '9606', (39, 44))	('gastric', 'Disease', (64, 71))	('lung', 'Disease', (94, 98))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('colorectal', 'Disease', 'MESH:D015179', (73, 83))	('tumours', 'Disease', (45, 52))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))
31367	22472881	In breast cancer, mutations in the D-loop have been associated with clinicopathological data, such as poor disease-free survival, later onset age, and estrogen and progesterone receptor-negative tumours.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('progesterone receptor', 'Gene', '5241', (164, 185))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('associated', 'Reg', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('tumours', 'Disease', (195, 202))	('progesterone receptor', 'Gene', (164, 185))	('mutations', 'Var', (18, 27))
31368	22472881	However, questions still remain as to at which stage of breast cancer these D310 mutations occur, and whether they can be used as a marker for breast cancer progression.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('D310', 'Var', (76, 80))	('breast cancer', 'Disease', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('D310', 'Chemical', '-', (76, 80))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
31369	22472881	Mutations in the D310 region have been used to track clonal growth of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('D310', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
31371	22472881	A recent study examining D310 mutations in head and neck carcinoma indicated that normal tissues adjacent to tumour had a propensity towards expansion/deletion of this region similar to cancerous tissues.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('cancerous', 'Disease', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('D310 mutations', 'Var', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('expansion/deletion', 'Var', (141, 159))	('tumour', 'Disease', (109, 115))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (43, 66))	('cancerous', 'Disease', 'MESH:D009369', (186, 195))	('neck carcinoma', 'Disease', (52, 66))	('neck carcinoma', 'Disease', 'MESH:D006258', (52, 66))	('D310', 'Chemical', '-', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
31372	22472881	These mutations can be used as markers of clonal growth of precancerous cells.	('cancerous', 'Disease', 'MESH:D009369', (62, 71))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancerous', 'Disease', (62, 71))
31373	22472881	It remains to be seen whether D310 mutations may be used as a marker for clonal growth in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('D310', 'Chemical', '-', (30, 34))	('D310 mutations', 'Var', (30, 44))
31374	22472881	The aims of our study were therefore to evaluate the frequency of mtDNA D310 mutation in tumour adjacent normal tissues and tumour tissues of breast cancer patients, and to assess the relationship between the D310 mutations and the progression of pre-invasive to invasive breast carcinoma.	('mutation', 'Var', (77, 85))	('tumour tissues of breast cancer', 'Disease', 'MESH:D009369', (124, 155))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('breast carcinoma', 'Disease', 'MESH:D001943', (272, 288))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('tumour', 'Disease', (124, 130))	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('D310', 'Chemical', '-', (72, 76))	('mtDNA D310', 'Gene', (66, 76))	('breast carcinoma', 'Phenotype', 'HP:0003002', (272, 288))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast carcinoma', 'Disease', (272, 288))	('pre-invasive', 'Disease', (247, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('D310', 'Var', (209, 213))	('tumour tissues of breast cancer', 'Disease', (124, 155))	('D310', 'Chemical', '-', (209, 213))
31390	22472881	A chi2 test was used to compare the distributions of D310 polymorphism in histologically normal and tumour samples.	('D310 polymorphism', 'Var', (53, 70))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('D310', 'Chemical', '-', (53, 57))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))
31397	22472881	Insertion or deletion of cytosine(s) occurred at approximately similar frequency, and was not significantly different between tumour samples (P> 0.05).	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('cytosine', 'Gene', (25, 33))	('deletion', 'Var', (13, 21))	('tumour', 'Disease', (126, 132))	('cytosine', 'Chemical', 'MESH:D003596', (25, 33))	('Insertion', 'Var', (0, 9))
31398	22472881	We subsequently analysed the genotype of the D310 sequence in mtDNA extracted from 48 cases of pre-invasive breast cancer (29 cases from patients with DCIS only and 19 cases from patients with synchronous DCIS and IDC) and 49 cases of invasive breast cancer (26 cases from patients with IDC only and 23 cases from patients with DCIS and IDC).	('invasive breast cancer', 'Disease', (99, 121))	('patients', 'Species', '9606', (314, 322))	('patients', 'Species', '9606', (273, 281))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('invasive breast cancer', 'Disease', 'MESH:D001943', (235, 257))	('invasive breast cancer', 'Disease', 'MESH:D001943', (99, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('patients', 'Species', '9606', (179, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('D310', 'Var', (45, 49))	('invasive breast cancer', 'Disease', (235, 257))	('D310', 'Chemical', '-', (45, 49))
31399	22472881	We compared the distributions of D310 sequences extracted from tumour tissues to sequences extracted from normal tissue controls.	('D310 sequences', 'Var', (33, 47))	('D310', 'Chemical', '-', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Disease', (63, 69))
31401	22472881	For the purpose of this study, D310 sequences C6TC6 to C11TC6 were therefore termed as C6 to C11, according to the number of cytosine residues.	('C11', 'Gene', (55, 58))	('cytosine', 'Chemical', 'MESH:D003596', (125, 133))	('D310', 'Chemical', '-', (31, 35))	('C11', 'Gene', (93, 96))	('D310 sequences C6TC6', 'Var', (31, 51))	('C6TC6', 'Var', (46, 51))	('TC6', 'CellLine', 'CVCL:6A95', (58, 61))	('C11', 'Gene', '51728', (55, 58))	('TC6', 'CellLine', 'CVCL:6A95', (48, 51))	('C11', 'Gene', '51728', (93, 96))
31409	22472881	The distribution of D310 sequences did not differ significantly between DCIS samples from synchronous DCIS and IDC cases, and DCIS only cases (P=0.59, Figure 3).	('D310', 'Var', (20, 24))	('D310', 'Chemical', '-', (20, 24))	('DCIS', 'Disease', (102, 106))	('IDC', 'Disease', (111, 114))
31410	22472881	In addition, the frequency of somatic mutations (any D310 sequences in tumour that differed from sequences of the matched normal tissue) was similar in DCIS samples from synchronous DCIS and IDC cases and pure DCIS cases (P>0.05, Supplementary Table 3).	('tumour', 'Disease', (71, 77))	('DCIS', 'Disease', (182, 186))	('IDC', 'Disease', (191, 194))	('D310', 'Chemical', '-', (53, 57))	('DCIS', 'Disease', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('D310 sequences', 'Var', (53, 67))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
31421	22472881	Mitochondrial DNA (mtDNA) mutations are highly prevalent in many cancers including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (83, 96))	('mutations', 'Var', (26, 35))	('prevalent', 'Reg', (47, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
31423	22472881	In breast cancer tissue, 72% of all D-loop mutations occur in the D310 region, whereas in fine-needle aspirates from breast cancer patients, 58% of D-loop mutations occur in the D310 region.	('patients', 'Species', '9606', (131, 139))	('D310', 'Chemical', '-', (66, 70))	('D310', 'Chemical', '-', (178, 182))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('D-loop', 'Gene', (36, 42))	('breast cancer', 'Disease', (117, 130))	('mutations', 'Var', (43, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))
31424	22472881	In a previous study, D310 mutations have been found, along with three other mitochondrial mutations, in 0% (0/4) of pre-invasive (DCIS) and 34.1% (15/44) of invasive (IDC) breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('D310 mutations', 'Var', (21, 35))	('breast cancers', 'Disease', 'MESH:D001943', (172, 186))	('breast cancers', 'Disease', (172, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('D310', 'Chemical', '-', (21, 25))
31425	22472881	In this study, the prevalence of D310 somatic mutations was investigated in a larger sample size of pre-invasive breast cancer, and our results demonstrated for the first time that these mutations occurred early in the development of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('D310', 'Var', (33, 37))	('breast cancer', 'Disease', (234, 247))	('occurred', 'Reg', (197, 205))	('invasive breast cancer', 'Disease', (104, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('D310', 'Chemical', '-', (33, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('invasive breast cancer', 'Disease', 'MESH:D001943', (104, 126))
31428	22472881	These mutation frequencies were similar to those reported in other types of cancers: 61.5% (8/13) of squamous cell carcinoma in situ of the head and neck and 70% (10/14) of lung cancers harboured a D-loop mutation.	('carcinoma in situ of the head and neck', 'Phenotype', 'HP:0012288', (115, 153))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancers', 'Phenotype', 'HP:0100526', (173, 185))	('cancers', 'Disease', (76, 83))	('D-loop mutation', 'Var', (198, 213))	('squamous cell carcinoma', 'Disease', (101, 124))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (115, 132))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('harboured', 'Reg', (186, 195))	('lung cancers', 'Disease', 'MESH:D008175', (173, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('cancers', 'Disease', (178, 185))	('lung cancers', 'Disease', (173, 185))
31429	22472881	In these studies, mutation was scored by comparing D310 sequences from tumour and corresponding normal tissue/ blood samples, similar to our work.	('D310 sequences', 'Var', (51, 65))	('tumour', 'Disease', (71, 77))	('D310', 'Chemical', '-', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
31430	22472881	In this study, we did not find a correlation between the frequency of D310 mutations in breast cancer and the degree of dysplasia (DCIS and IDC cases have a similar frequency of mutations).	('D310', 'Chemical', '-', (70, 74))	('dysplasia', 'Disease', (120, 129))	('D310 mutations', 'Var', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('dysplasia', 'Disease', 'MESH:D004476', (120, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
31433	22472881	Taken together, these results show that D310 mutations likely occurred before DCIS transformation to IDC; perhaps during the transformation of atypical ductal hyperplasia to DCIS.	('hyperplasia', 'Disease', (159, 170))	('D310 mutations', 'Var', (40, 54))	('D310', 'Chemical', '-', (40, 44))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('DCIS', 'Disease', (78, 82))
31434	22472881	Thus, the timing of events explains the lack of association between D310 mutations and DCIS progression.	('D310 mutations', 'Var', (68, 82))	('DCIS progression', 'Disease', (87, 103))	('D310', 'Chemical', '-', (68, 72))
31435	22472881	As D310 mutations occur at high frequency in pre-malignant lesions, it is important to consider whether they have a causative role in breast carcinogenesis.	('breast carcinogenesis', 'Disease', 'MESH:D063646', (134, 155))	('D310 mutations', 'Var', (3, 17))	('breast carcinogenesis', 'Disease', (134, 155))	('D310', 'Chemical', '-', (3, 7))
31436	22472881	Interestingly, associations have been made between D310 mutations and poor disease-free survival, a late onset age, and estrogen and progesterone-negative breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('poor disease-free survival', 'CPA', (70, 96))	('D310 mutations', 'Var', (51, 65))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('associations', 'Interaction', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('D310', 'Chemical', '-', (51, 55))
31439	22472881	D310 mutations most likely resulted from a combination of oxidative stress, low efficiency of the mtDNA mismatch repair mechanism, and poor proof reading by polymerase gamma.	('poor', 'NegReg', (135, 139))	('resulted from', 'Reg', (27, 40))	('D310 mutations', 'Var', (0, 14))	('proof reading', 'MPA', (140, 153))	('mtDNA', 'Gene', (98, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (58, 74))	('D310', 'Chemical', '-', (0, 4))	('low', 'NegReg', (76, 79))
31443	22472881	It is therefore plausible that D310 mutations promote the early development of breast cancer by depleting mtDNA content in cells, thus altering energy metabolism and promoting genetic instability.	('promote', 'PosReg', (46, 53))	('depleting', 'NegReg', (96, 105))	('D310', 'Chemical', '-', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('early development of breast', 'Phenotype', 'HP:0010314', (58, 85))	('promoting', 'PosReg', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('D310 mutations', 'Var', (31, 45))	('breast cancer', 'Disease', (79, 92))	('energy metabolism', 'MPA', (144, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('altering', 'Reg', (135, 143))	('genetic instability', 'MPA', (176, 195))	('mtDNA content in', 'MPA', (106, 122))
31445	22472881	Finally, field cancerisation has been observed in breast cancer and it is a postulated explanation for the occurrence of D310 mutations in normal epithelium adjacent to tumours.	('D310', 'Gene', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('D310', 'Chemical', '-', (121, 125))	('tumours', 'Disease', (169, 176))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (57, 63))	('tumours', 'Disease', 'MESH:D009369', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('mutations', 'Var', (126, 135))	('observed', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (50, 63))
31446	22472881	First introduced by) 'field cancerisation' is now commonly used to describe the occurrence of genetic and epigenetic alterations in normal tissues surrounding an area of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('epigenetic alterations', 'Var', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
31450	22472881	When measured under the microscope, histologically normal, but D310 mutant containing, tissues were found at an average distance of 1.08+-1.0 mm from tumours, a significantly shorter distance in comparison with normal tissues that did not display D310 mutations (2.64+-0.93 mm).	('D310', 'Chemical', '-', (63, 67))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('D310 mutant containing', 'Var', (63, 85))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('D310', 'Chemical', '-', (247, 251))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
31452	22472881	This interpretation is corroborated by the fact that in these cases, all of the mutant alleles in adjacent histologically normal tissues are conserved in the matched tumours, but not in another set of normal tissues taken this time at least 2 cm away from tumour.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (166, 172))	('tumours', 'Disease', (166, 173))	('tumour', 'Disease', (256, 262))	('mutant', 'Var', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (166, 173))
31454	22472881	In gallbladder carcinoma, and head and neck carcinoma, identical D310 sequences to tumour tissues have been found in 86% (19/22) and 37.5% (3/8) of microdissected epithelial tissues adjacent to tumour tissue, respectively.	('tumour', 'Disease', (83, 89))	('D310 sequences', 'Var', (65, 79))	('neck carcinoma', 'Disease', (39, 53))	('tumour', 'Disease', (194, 200))	('neck carcinoma', 'Disease', 'MESH:D006258', (39, 53))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (3, 24))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('gallbladder carcinoma', 'Disease', (3, 24))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('D310', 'Chemical', '-', (65, 69))
31455	22472881	Thus, as demonstrated in this study and others, D310 mutations in mtDNA can function as a marker of clonality and be used to define a field of genetic abnormality.	('mtDNA', 'Gene', (66, 71))	('D310', 'Chemical', '-', (48, 52))	('D310 mutations', 'Var', (48, 62))	('genetic abnormality', 'Disease', 'MESH:D030342', (143, 162))	('genetic abnormality', 'Disease', (143, 162))
31456	22472881	As it has been suggested that local normal remnants of a field may develop into cancer after removal of the primary tumour site, further investigation is warranted to examine whether D310 mutations in adjacent normal tissue is associated with tumour recurrence.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('D310', 'Chemical', '-', (183, 187))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('associated', 'Reg', (227, 237))	('tumour', 'Disease', (116, 122))	('tumour', 'Disease', 'MESH:D009369', (243, 249))	('tumour', 'Disease', (243, 249))	('D310 mutations', 'Var', (183, 197))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('develop', 'Reg', (67, 74))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (80, 86))
31457	22472881	In conclusion, our study has showed that mitochondrial D310 mutations are an early genetic event in the carcinogenesis of breast cancer, and probably occur before DCIS transitioning to IDC.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('D310', 'Chemical', '-', (55, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('carcinogenesis of breast cancer', 'Disease', (104, 135))	('D310 mutations', 'Var', (55, 69))	('carcinogenesis of breast cancer', 'Disease', 'MESH:D063646', (104, 135))	('mitochondrial', 'Gene', (41, 54))
31459	22472881	Given the abundance of mtDNA in each cell, and the success of identifying mtDNA mutations in fine-needle aspirates and bodily fluids of cancer patients, D310 mutation assessment may become a convenient biomarker to apply in clinical settings.	('mutations', 'Var', (80, 89))	('mtDNA', 'Gene', (74, 79))	('D310', 'Chemical', '-', (153, 157))	('D310', 'Var', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
31479	20412586	It was postulated, based on epidemiological studies, that the risk for breast cancer ranges from 1.5-2, 4-5, and 8-10, respectively, for women diagnosed with UH, ADH, and DCIS.	('breast cancer', 'Disease', (71, 84))	('UH', 'Chemical', '-', (158, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('ADH', 'Var', (162, 165))	('women', 'Species', '9606', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
31498	20412586	Approximately 15-20% of breast cancers have amplification of the HER-2/neu gene or over-expression of its protein product.	('protein', 'Protein', (106, 113))	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancers', 'Disease', 'MESH:D001943', (24, 38))	('breast cancers', 'Disease', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('over-expression', 'PosReg', (83, 98))	('HER-2/neu', 'Gene', (65, 74))	('amplification', 'Var', (44, 57))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('HER-2/neu', 'Gene', '2064', (65, 74))
31565	20412586	A regression model is fitted as Ki67 in tumors (% value) = 0.038 + 0.609 * Ki67 in IEL (% value).	('Ki67', 'Chemical', '-', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('IEL', 'Disease', (83, 86))	('Ki67', 'Chemical', '-', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('Ki67', 'Var', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
31626	16796758	The association of mammographic density with ductal carcinoma in situ of the breast: the Multiethnic Cohort It is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('breast cancer', 'Disease', (197, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ductal carcinoma', 'Disease', 'MESH:D044584', (45, 61))	('women', 'Species', '9606', (136, 141))	('high', 'Var', (147, 151))	('ductal carcinoma', 'Disease', (45, 61))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (45, 69))	('women', 'Species', '9606', (220, 225))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))
31637	16796758	Several case-control studies have confirmed that mammographic density is associated with risk for breast cancer; women with high breast density have a three-fold to six-fold greater risk for developing breast cancer than women with low breast density.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('high breast density', 'Phenotype', 'HP:0010313', (124, 143))	('breast cancer', 'Disease', (98, 111))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('women', 'Species', '9606', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('high', 'Var', (124, 128))	('women', 'Species', '9606', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
31688	16796758	Although it is known that some breast DCIS lesions will develop into invasive breast cancers, and that DCIS is often found near invasive breast cancer lesions, it remains problematic to distinguish DCIS lesions that may progress to invasive breast cancer from those that may not.	('invasive breast cancer', 'Disease', 'MESH:D001943', (128, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('progress', 'PosReg', (220, 228))	('invasive breast cancers', 'Disease', 'MESH:D001943', (69, 92))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('develop', 'Reg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (78, 92))	('invasive breast cancers', 'Disease', (69, 92))	('lesions', 'Var', (43, 50))	('invasive breast cancer lesions', 'Disease', 'MESH:D001943', (128, 158))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('CIS', 'Phenotype', 'HP:0030075', (104, 107))	('invasive breast cancer', 'Disease', 'MESH:D001943', (69, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('CIS', 'Phenotype', 'HP:0030075', (199, 202))	('invasive breast cancer', 'Disease', (232, 254))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('invasive breast cancer', 'Disease', 'MESH:D001943', (232, 254))	('CIS', 'Phenotype', 'HP:0030075', (39, 42))	('invasive breast cancer lesions', 'Disease', (128, 158))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))
31691	16796758	Established invasive breast cancer risk factors shown to be consistently associated with breast CIS include family history of breast cancer, low BMI among premenopausal women, and nulliparity.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('women', 'Species', '9606', (169, 174))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('invasive breast cancer', 'Disease', 'MESH:D001943', (12, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('associated', 'Reg', (73, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('invasive breast cancer', 'Disease', (12, 34))	('CIS', 'Phenotype', 'HP:0030075', (96, 99))	('low BMI', 'Phenotype', 'HP:0045082', (141, 148))	('nulliparity', 'Var', (180, 191))	('breast CIS', 'Disease', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
31693	16796758	Our study and other reports mentioned above indicate that mammographic density is associated with breast CIS and with invasive breast cancer.	('mammographic density', 'Var', (58, 78))	('invasive breast cancer', 'Disease', 'MESH:D001943', (118, 140))	('associated', 'Reg', (82, 92))	('CIS', 'Phenotype', 'HP:0030075', (105, 108))	('breast CIS', 'Disease', (98, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('invasive breast cancer', 'Disease', (118, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
31708	30659022	Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis.	('NODAL expression', 'MPA', (23, 39))	('decreased tumor', 'Disease', (79, 94))	('MNK1', 'Gene', (8, 12))	('decreased tumor', 'Disease', 'MESH:D009369', (79, 94))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('IDC', 'Gene', '4000', (59, 62))	('IDC', 'Gene', (59, 62))	('inhibited', 'NegReg', (41, 50))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
31712	30659022	In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('IDC', 'Gene', '4000', (21, 24))	('microinvasion', 'Var', (39, 52))	('IDC', 'Gene', (21, 24))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('clinical samples', 'Species', '191496', (3, 19))	('higher', 'PosReg', (63, 69))	('levels of phospho-MNK1', 'MPA', (70, 92))
31713	30659022	Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease.	('MNK1', 'Gene', (54, 58))	('inhibitors', 'Var', (59, 69))	('invasive disease', 'Disease', (101, 117))	('invasive disease', 'Disease', 'MESH:D009362', (101, 117))
31714	30659022	These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.	('clinical', 'Species', '191496', (96, 104))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (67, 83))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (169, 193))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (169, 185))	('MNK1', 'Gene', (120, 124))	('ductal carcinoma', 'Disease', 'MESH:D044584', (206, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (197, 222))	('ductal carcinoma', 'Disease', 'MESH:D044584', (169, 185))	('ductal carcinoma', 'Disease', (169, 185))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (206, 222))	('invasive ductal carcinoma', 'Disease', (197, 222))	('ductal carcinoma', 'Disease', 'MESH:D044584', (67, 83))	('delay', 'NegReg', (139, 144))	('ductal carcinoma', 'Disease', (67, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('inhibitors', 'Var', (125, 135))
31720	30659022	The best characterized function of MNK1/2 is to phosphorylate eukaryotic initiation factor 4E (eIF4E) at Ser209.	('Ser209', 'Var', (105, 111))	('eukaryotic initiation factor 4E', 'Gene', (62, 93))	('Ser209', 'Chemical', '-', (105, 111))	('eIF4E', 'Gene', (95, 100))	('eIF4E', 'Gene', '13684', (95, 100))	('eukaryotic initiation factor 4E', 'Gene', '13684', (62, 93))	('MNK1/2', 'Gene', (35, 41))
31725	30659022	Finally, lack of MNK1 decreases the oncogenic potential of leukemia, gliomas, melanoma, ovarian cancer, and malignant peripheral nerve sheath tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gliomas', 'Disease', (69, 76))	('MNK1', 'Gene', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('decreases', 'NegReg', (22, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (108, 148))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('ovarian cancer', 'Disease', (88, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('oncogenic potential', 'CPA', (36, 55))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (108, 148))	('leukemia', 'Disease', 'MESH:D007938', (59, 67))	('leukemia', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('malignant peripheral nerve sheath tumors', 'Disease', (108, 148))	('lack', 'Var', (9, 13))
31760	30659022	Briefly, human and mouse tumor sections were stained for p63, MNK1, p-MNK1, NODAL, VIMEN-TIN, p-histone H3, Ki67, and cleaved caspase-3 and counter-stained with 20% Harris-modified hematoxylin (Thermo Fisher Scientific).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('VIMEN-TIN', 'Gene', (83, 92))	('Ki67', 'Gene', '17345', (108, 112))	('hematoxylin', 'Chemical', 'MESH:D006416', (181, 192))	('human', 'Species', '9606', (9, 14))	('VIMEN-TIN', 'Gene', '22352', (83, 92))	('p-MNK1', 'Var', (68, 74))	('mouse', 'Species', '10090', (19, 24))	('p63', 'Gene', '22061', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('p63', 'Gene', (57, 60))	('Ki67', 'Gene', (108, 112))	('p-histone', 'Chemical', '-', (94, 103))
31779	30659022	Thus, our results show that increased expression of phospho-MNK1 and MNK1 occurs in a larger percentage of high-grade DCIS/IDC samples, compared with low-grade DCIS specimens.	('increased', 'PosReg', (28, 37))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('IDC', 'Gene', '4000', (123, 126))	('expression', 'MPA', (38, 48))	('IDC', 'Gene', (123, 126))	('phospho-MNK1', 'Var', (52, 64))	('MNK1', 'Gene', (69, 73))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))
31794	30659022	Although not statistically significant, mice that had received MNK1-KO cells showed a trend toward better overall survival, than those animals that were implanted with CTL cells (Fig.	('better', 'PosReg', (99, 105))	('mice', 'Species', '10090', (40, 44))	('MNK1-KO cells', 'Var', (63, 76))
31795	30659022	Furthermore, 80% of mice that received CTL cells had relapsed metastatic disease, while no mice that received MNK1- KO cells had metastasis (Fig.	('mice', 'Species', '10090', (91, 95))	('CTL cells', 'Var', (39, 48))	('mice', 'Species', '10090', (20, 24))	('relapsed metastatic disease', 'CPA', (53, 80))
31805	30659022	Unlike the lack of proliferative advantage observed in 2D culture, caMNK1-expressing tumors were larger compared with pBABE control expressing tumors (Fig.	('caMNK1-expressing', 'Var', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
31810	30659022	In addition, 6 of the 10 mice injected with caMNK1 cells have tumors with central necrosis, while only 2 of 10 mice injected with pBABE cells present with tumors with central necrosis (Fig.	('caMNK1', 'Var', (44, 50))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('necrosis', 'Disease', 'MESH:D009336', (175, 183))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (111, 115))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('necrosis', 'Disease', (82, 90))	('necrosis', 'Disease', (175, 183))
31813	30659022	Tumor formation in the orthotopic mammary fat pad was significantly increased in mice injected with caMNK1 cells compared with those injected with the control pBABE cells (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (81, 85))	('Tumor formation in the orthotopic mammary fat pad', 'CPA', (0, 49))	('caMNK1 cells', 'Var', (100, 112))	('increased', 'PosReg', (68, 77))
31814	30659022	We further interrogated whether the increase in tumor formation associated with caMNK1 expression was due to an increase in proliferation or a decrease in apoptosis.	('expression', 'Var', (87, 97))	('tumor', 'Disease', (48, 53))	('decrease', 'NegReg', (143, 151))	('increase', 'PosReg', (36, 44))	('increase', 'PosReg', (112, 120))	('caMNK1', 'Gene', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('apoptosis', 'CPA', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
31818	30659022	These data suggest that caMNK1-derived tumors are larger than their pBABE counterparts, due to an evasion of apoptotic cell death.	('apoptotic', 'CPA', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('evasion', 'MPA', (98, 105))	('caMNK1-derived', 'Var', (24, 38))	('tumors', 'Disease', (39, 45))
31819	30659022	Cumulatively, the data presented here demonstrate that modulation of MNK1 influences the DCIS to IDC transition in vivo.	('influences', 'Reg', (74, 84))	('MNK1', 'Gene', (69, 73))	('modulation', 'Var', (55, 65))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('IDC', 'Gene', '4000', (97, 100))	('IDC', 'Gene', (97, 100))
31830	30659022	Moreover, we determined whether depletion of MNK1 could reduce the tumor-initiating cell subpopulation by performing FACS analysis for CD44hi/ CD24lo populations in the MCFDCIS.com cells knocked out for MNK1.	('FACS', 'Gene', (117, 121))	('depletion', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('FACS', 'Gene', '14081', (117, 121))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('CD24', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MNK1', 'Gene', (45, 49))	('reduce', 'NegReg', (56, 62))	('CD24', 'Gene', '12484', (143, 147))	('tumor', 'Disease', (67, 72))	('MNK1', 'Gene', (203, 207))	('MCFDCIS.com', 'CellLine', 'CVCL:5552', (169, 180))
31834	30659022	Similar to our results in DCIS cells, depleting MNK1 in 66cl4 cells using CRISPR-Cas9 technology, and by siRNA in MB-MDA-468 cells, caused these cells to express less NODAL (Supplementary Fig.	('less', 'NegReg', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('depleting', 'Var', (38, 47))	('MNK1', 'Gene', (48, 52))	('NODAL', 'MPA', (167, 172))	('MB-MDA-468', 'CellLine', 'CVCL:0419', (114, 124))
31835	30659022	Similarly, concomitant with the reduced NODAL levels observed when we silence MNK1 in MDA-MB-468 cells, their invasion is also impaired (Supplementary Fig.	('silence', 'Var', (70, 77))	('MNK1', 'Gene', (78, 82))	('NODAL levels', 'MPA', (40, 52))	('impaired', 'NegReg', (127, 135))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (86, 96))	('invasion', 'MPA', (110, 118))
31839	30659022	S3I, the caMNK1-expressing cells have an increased tumor-initiating capability, compared with their pBABE control counterparts.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('increased', 'PosReg', (41, 50))	('tumor', 'Disease', (51, 56))	('caMNK1-expressing', 'Var', (9, 26))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
31859	30659022	Furthermore, xenografts from the SEL201 group showed a reduced percentage of IDC (10% of tumors) compared with the vehicle group (87.5% of tumors; Fig.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('IDC', 'Gene', (77, 80))	('reduced', 'NegReg', (55, 62))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('IDC', 'Gene', '4000', (77, 80))	('SEL201', 'Var', (33, 39))
31860	30659022	Consistent with our previous work, SEL201 showed no overt systemic toxicity, as evidenced by body weight (Supplementary Fig.	('body weight', 'CPA', (93, 104))	('SEL201', 'Var', (35, 41))	('toxicity', 'Disease', (67, 75))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))
31863	30659022	SEL201 also inhibits colony formation of SUM225 cells in vitro, and slows down the transition from DCIS to IDC in the SUM225 intraductal model of DCIS (Supplementary Fig.	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('transition', 'MPA', (83, 93))	('SEL201', 'Var', (0, 6))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('slows down', 'NegReg', (68, 78))	('colony formation', 'CPA', (21, 37))	('inhibits', 'NegReg', (12, 20))	('IDC', 'Gene', '4000', (107, 110))	('IDC', 'Gene', (107, 110))
31864	30659022	In summary, our results provide evidence to show the feasibility of inhibiting MNK1 to slow the conversion of DCIS to IDC.	('conversion', 'MPA', (96, 106))	('inhibiting', 'Var', (68, 78))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('MNK1', 'Gene', (79, 83))	('slow', 'NegReg', (87, 91))	('IDC', 'Gene', '4000', (118, 121))	('IDC', 'Gene', (118, 121))
31872	30659022	Similar results were previously shown in response to Twist1 expression, which induces a partial EMT and dedifferentiation toward "sternness".	('dedifferentiation', 'CPA', (104, 121))	('EMT', 'Gene', (96, 99))	('Twist1', 'Gene', '22160', (53, 59))	('induces', 'Reg', (78, 85))	('expression', 'Var', (60, 70))	('Twist1', 'Gene', (53, 59))	('EMT', 'Gene', '16428', (96, 99))
31900	24678379	However, there are other demographic characteristics of particular relevance to Mississippi, and these too may result in a worsened overall impact due to breast cancer mortality rates.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('Mississippi', 'Var', (80, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))
31925	24678379	One group has observed more extensive CpG island methylation in the promoters of the RASSF1A, RARbeta2 and CDH13 loci in tumors taken from women of African versus European ancestry.	('RASSF1A', 'Gene', (85, 92))	('women', 'Species', '9606', (139, 144))	('CDH13', 'Gene', '1012', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('RARbeta2', 'Gene', (94, 102))	('RASSF1A', 'Gene', '11186', (85, 92))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('methylation', 'Var', (49, 60))	('CDH13', 'Gene', (107, 112))
31926	24678379	Methylational silencing of tumor suppressor genes commonly occurs through such mechanisms.	('tumor', 'Disease', (27, 32))	('Methylational silencing', 'Var', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
32002	20466998	Deregulated estrogen receptor alpha and p53 heterozygosity collaborate in the development of mammary hyperplasia Both increased Estrogen Receptor (ER)alpha expression and germline disruption of one p53 allele increase breast cancer risk in women.	('increased', 'PosReg', (118, 127))	('p53', 'Gene', '22059', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('expression', 'MPA', (156, 166))	('heterozygosity', 'Var', (44, 58))	('p53', 'Gene', (40, 43))	('estrogen receptor', 'Gene', (12, 29))	('increased Estrogen Receptor', 'Phenotype', 'HP:0025134', (118, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('hyperplasia', 'Disease', (101, 112))	('Estrogen Receptor', 'Gene', '2099', (128, 145))	('p53', 'Gene', (198, 201))	('hyperplasia', 'Disease', 'MESH:D006965', (101, 112))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('Estrogen Receptor', 'Gene', (128, 145))	('increase', 'PosReg', (209, 217))	('breast cancer', 'Disease', (218, 231))	('germline', 'Var', (171, 179))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (93, 112))	('p53', 'Gene', '22059', (40, 43))	('women', 'Species', '9606', (240, 245))	('estrogen receptor', 'Gene', '2099', (12, 29))
32003	20466998	Genetically engineered mouse models of deregulated ERalpha expression and p53 haploinsufficiency were used to investigate similarities and differences of each genetic lesion alone and in combination on mammary preneoplasia development.	('haploinsufficiency', 'Disease', 'MESH:D058495', (78, 96))	('preneoplasia', 'Disease', (210, 222))	('deregulated', 'Var', (39, 50))	('p53', 'Gene', (74, 77))	('ERalpha', 'Protein', (51, 58))	('haploinsufficiency', 'Disease', (78, 96))	('mouse', 'Species', '10090', (23, 28))	('genetic lesion', 'Disease', (159, 173))	('preneoplasia', 'Disease', 'None', (210, 222))	('genetic lesion', 'Disease', 'MESH:D020022', (159, 173))
32004	20466998	Each genetic lesion independently and in combination led to development of age-dependent preneoplasia but the highest prevalence was found in compound mice with increased ERalpha expression coupled with p53 heterozygosity.	('genetic lesion', 'Disease', (5, 19))	('genetic lesion', 'Disease', 'MESH:D020022', (5, 19))	('preneoplasia', 'Disease', (89, 101))	('mice', 'Species', '10090', (151, 155))	('ERalpha', 'Protein', (171, 178))	('preneoplasia', 'Disease', 'None', (89, 101))	('increased', 'PosReg', (161, 170))	('p53 heterozygosity', 'Var', (203, 221))	('heterozygosity', 'Var', (207, 221))
32006	20466998	The highest levels of cell proliferation were found in compound mice, but increased levels were also found with either increased ERalpha expression or p53 heterozygosity.	('ERalpha', 'Protein', (129, 136))	('p53 heterozygosity', 'Var', (151, 169))	('mice', 'Species', '10090', (64, 68))	('increased', 'PosReg', (119, 128))	('cell proliferation', 'CPA', (22, 40))
32007	20466998	Mice with increased ERalpha expression showed predicted higher levels of nuclear localized ERalpha, but this was attenuated in compound mice in association with a relative increase in Src phosphorylation.	('mice', 'Species', '10090', (136, 140))	('increase', 'PosReg', (172, 180))	('ERalpha', 'Gene', (20, 27))	('nuclear localized', 'MPA', (73, 90))	('expression', 'Var', (28, 38))	('Mice', 'Species', '10090', (0, 4))	('Src', 'Gene', '20779', (184, 187))	('higher', 'PosReg', (56, 62))	('Src', 'Gene', (184, 187))	('increased', 'PosReg', (10, 19))
32008	20466998	Parity protection was limited to p53 heterozygous mice and not found in mice with increased ERalpha alone.	('mice', 'Species', '10090', (50, 54))	('mice', 'Species', '10090', (72, 76))	('p53', 'Var', (33, 36))	('Parity', 'CPA', (0, 6))
32009	20466998	In summary, increased and deregulated ERalpha collaborates with p53 heterozygosity in increasing the risk of mammary preneoplasia development.	('deregulated', 'Var', (26, 37))	('preneoplasia', 'Disease', 'None', (117, 129))	('ERalpha', 'Gene', (38, 45))	('preneoplasia', 'Disease', (117, 129))
32012	20466998	Breast cancer is associated with somatic genetic and epigenetic alterations in the breast tissue such as tumor suppressor gene mutation or other molecular changes that compromise their function.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('epigenetic alterations', 'Var', (53, 75))	('mutation', 'Var', (127, 135))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('function', 'MPA', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Breast cancer', 'Disease', (0, 13))	('tumor', 'Disease', (105, 110))
32014	20466998	Alterations to p53 are commonly detected in primary human breast tumors, reported in 30-40% of human breast cancers and about 25% of all preinvasive DCIS lesions.	('human', 'Species', '9606', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Alterations', 'Var', (0, 11))	('human', 'Species', '9606', (52, 57))	('p53', 'Gene', (15, 18))	('breast tumors', 'Phenotype', 'HP:0100013', (58, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('breast tumors', 'Disease', 'MESH:D001943', (58, 71))	('breast cancers', 'Disease', (101, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast tumors', 'Disease', (58, 71))
32015	20466998	Disruption of p53 function may be involved in earlier rather than later stages of breast cancer progression such as initiation of breast carcinogenesis and impaired differentiation of DCIS.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('p53', 'Gene', (14, 17))	('involved', 'Reg', (34, 42))	('initiation of breast carcinogenesis', 'Disease', 'MESH:D063646', (116, 151))	('initiation of breast carcinogenesis', 'Disease', (116, 151))	('impaired differentiation', 'CPA', (156, 180))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('Disruption', 'Var', (0, 10))
32017	20466998	In cancers, loss or mutation of p53 is correlated with increased aggressiveness, poor prognosis and chemotherapy resistance.	('chemotherapy resistance', 'CPA', (100, 123))	('mutation', 'Var', (20, 28))	('loss', 'NegReg', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('p53', 'Gene', (32, 35))	('cancers', 'Disease', (3, 10))	('poor prognosis', 'CPA', (81, 95))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('increased aggressiveness', 'Disease', 'MESH:D001523', (55, 79))	('increased aggressiveness', 'Disease', (55, 79))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
32018	20466998	In addition to p53 somatic mutation in sporadic cancers, germline mutation of one allele of this gene in humans causes an inborn predisposition to cancer known as Li-Fraumeni syndrome where early-onset female breast cancer is the most prevalent tumor type.	('causes', 'Reg', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('germline mutation', 'Var', (57, 74))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Li-Fraumeni syndrome', 'Disease', (163, 183))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('inborn', 'Disease', 'MESH:D030342', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (163, 183))	('cancers', 'Disease', (48, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('humans', 'Species', '9606', (105, 111))	('breast cancer', 'Disease', (209, 222))	('inborn', 'Disease', (122, 128))	('cancer', 'Disease', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
32021	20466998	Increased ERalpha expression in normal breast epithelium is found in conjunction with breast cancer, leading to the concept that loss of the normal regulatory mechanisms that control expression levels of ERalpha in normal breast epithelium may increase the risk for the development of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('increase', 'Reg', (244, 252))	('loss', 'Var', (129, 133))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('breast cancer', 'Disease', (86, 99))	('breast cancer', 'Disease', (285, 298))	('ERalpha', 'Gene', (204, 211))
32022	20466998	Increased and deregulated ERalpha expression in the mammary epithelial cells of transgenic mice (CERM) results in the development of ductal carcinoma in situ and increased cell proliferation.	('transgenic mice', 'Species', '10090', (80, 95))	('ductal carcinoma', 'Disease', 'MESH:D044584', (133, 149))	('ERalpha', 'Protein', (26, 33))	('increased', 'PosReg', (162, 171))	('ductal carcinoma', 'Disease', (133, 149))	('cell proliferation', 'CPA', (172, 190))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (133, 157))	('carcinoma in situ', 'Disease', 'MESH:D002278', (140, 157))	('deregulated', 'Var', (14, 25))	('carcinoma in situ', 'Disease', (140, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
32027	20466998	Human breast cancers with p53 mutations are more frequently ER-negative.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancers', 'Phenotype', 'HP:0003002', (6, 20))	('breast cancers', 'Disease', 'MESH:D001943', (6, 20))	('breast cancers', 'Disease', (6, 20))	('p53', 'Gene', (26, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('mutations', 'Var', (30, 39))
32028	20466998	In serial transplant studies, absence of p53 in mammary epithelium is associated with DCIS lesions and invasive cancer that progress from an ERalpha-positive to ERalpha-negative state.	('absence', 'Var', (30, 37))	('invasive cancer', 'Disease', (103, 118))	('associated', 'Reg', (70, 80))	('DCIS lesions', 'Disease', (86, 98))	('p53', 'Protein', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('invasive cancer', 'Disease', 'MESH:D009362', (103, 118))
32029	20466998	c-Src phosphorylation has been shown to stimulate ERalpha ubiquitylation and proteasome-dependent degradation and p53 has been reported to down-regulate some Src functions.	('Src', 'Gene', '20779', (158, 161))	('Src', 'Gene', (158, 161))	('stimulate', 'PosReg', (40, 49))	('ERalpha ubiquitylation', 'MPA', (50, 72))	('c-Src', 'Gene', (0, 5))	('down-regulate', 'NegReg', (139, 152))	('Src', 'Gene', '20779', (2, 5))	('c-Src', 'Gene', '6714', (0, 5))	('p53', 'Var', (114, 117))	('phosphorylation', 'Var', (6, 21))	('Src', 'Gene', (2, 5))	('proteasome-dependent degradation', 'MPA', (77, 109))
32030	20466998	The effects of loss of p53 and ERalpha deregulation on cell proliferation and apoptosis during in vivo carcinogenesis have been previously studied independently.	('apoptosis', 'CPA', (78, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('ERalpha', 'Gene', (31, 38))	('cell proliferation', 'CPA', (55, 73))	('loss', 'Var', (15, 19))	('p53', 'Gene', (23, 26))	('deregulation', 'Var', (39, 51))	('carcinogenesis', 'Disease', (103, 117))
32031	20466998	Indeed, loss of p53 activity disrupts apoptosis and accelerates the appearance of tumors, and increases cell proliferation levels while deregulated ERalpha increases cell proliferation and the prevalence of DH/DCIS.	('activity', 'MPA', (20, 28))	('p53', 'Protein', (16, 19))	('tumors', 'Disease', (82, 88))	('DH', 'Disease', 'MESH:D065630', (207, 209))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('apoptosis', 'CPA', (38, 47))	('cell', 'MPA', (104, 108))	('increases', 'PosReg', (94, 103))	('increases', 'PosReg', (156, 165))	('cell proliferation', 'CPA', (166, 184))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('loss', 'Var', (8, 12))	('accelerates', 'PosReg', (52, 63))	('disrupts', 'NegReg', (29, 37))	('ERalpha', 'Protein', (148, 155))
32032	20466998	Studies in mouse models have shown that loss of p53 has a different impact in the susceptibility of mammary tumor development depending on the strain.	('p53', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mouse', 'Species', '10090', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('impact', 'Reg', (68, 74))	('loss', 'Var', (40, 44))
32033	20466998	C57BL/6 p53+/- mice are relatively resistant to mammary tumor development as compared to BALB/cJ.	('C57BL/6 p53+/-', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('resistant', 'NegReg', (35, 44))	('p53+/-', 'Var', (8, 14))	('tumor', 'Disease', (56, 61))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
32034	20466998	The objective of this study was to utilize genetically engineered mouse models to investigate the impact of the combination of deregulated ERalpha and p53 haploinsufficiency and compare this to each factor alone in age-dependent mammary preneoplasia development, impact on cell proliferation and apoptosis, expression of regulatory proteins including ERalpha, and parity protection.	('haploinsufficiency', 'Disease', (155, 173))	('impact', 'Reg', (263, 269))	('preneoplasia', 'Disease', (237, 249))	('apoptosis', 'CPA', (296, 305))	('deregulated', 'Var', (127, 138))	('mouse', 'Species', '10090', (66, 71))	('haploinsufficiency', 'Disease', 'MESH:D058495', (155, 173))	('preneoplasia', 'Disease', 'None', (237, 249))	('cell proliferation', 'CPA', (273, 291))	('ERalpha', 'Gene', (139, 146))	('p53', 'Gene', (151, 154))
32036	20466998	Molecular studies revealed that only p53 heterozygosity impacted AKT activation and p27 expression while only the combination of deregulated ERalpha and p53 haploinsufficiency increased ERK1/2 and c-Src activation in association with decreased expression levels of ERalpha.	('p27', 'Gene', (84, 87))	('decreased', 'NegReg', (234, 243))	('increased', 'PosReg', (176, 185))	('expression levels', 'MPA', (244, 261))	('AKT', 'Gene', (65, 68))	('c-Src', 'Gene', (197, 202))	('ERalpha', 'Gene', (141, 148))	('ERK1/2', 'Gene', (186, 192))	('c-Src', 'Gene', '6714', (197, 202))	('haploinsufficiency', 'Disease', (157, 175))	('haploinsufficiency', 'Disease', 'MESH:D058495', (157, 175))	('p53', 'Gene', (153, 156))	('heterozygosity', 'Var', (41, 55))	('AKT', 'Gene', '11651', (65, 68))	('activation', 'PosReg', (203, 213))	('expression', 'MPA', (88, 98))	('ERK1/2', 'Gene', '26417;26413', (186, 192))	('activation', 'PosReg', (69, 79))
32038	20466998	Mice carrying a transgene composed of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) linked to sequences encoding the tetracycline responsive reverse transactivator (rtTA) for "tet-on" gene regulation and a transgene composed of the tetracycline operator (tet-op) promoter linked to sequences encoding murine ERalpha [MMTV-rtTA/tet-op- ERalpha (CERM)] mice were bred to mice carrying a homozygous p53 mutation (Jackson Laboratory, Bar Harbor, ME) to generate experimental CERM, p53+/- and compound CERM/p53+/- mice.	('mice', 'Species', '10090', (525, 529))	('mice', 'Species', '10090', (367, 371))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MMTV', 'Species', '11757', (90, 94))	('mouse mammary tumor virus', 'Species', '11757', (42, 67))	('mice', 'Species', '10090', (385, 389))	('mutation', 'Var', (416, 424))	('murine', 'Species', '10090', (317, 323))	('Mice', 'Species', '10090', (0, 4))	('p53', 'Gene', (412, 415))	('MMTV', 'Species', '11757', (333, 337))
32061	20466998	Primary antibodies included phospho-p44/42 MAPK (E10), p44/42 MAPK, phospho-Akt (D9E), Akt (C67E7), and p27 Kip1.	('p44', 'Gene', (36, 39))	('Akt', 'Gene', (87, 90))	('p27 Kip1', 'Gene', '12576', (104, 112))	('p27 Kip1', 'Gene', (104, 112))	('p44', 'Gene', '22059', (36, 39))	('Akt', 'Gene', (76, 79))	('Akt', 'Gene', '11651', (76, 79))	('p44', 'Gene', '22059', (55, 58))	('p44', 'Gene', (55, 58))	('Akt', 'Gene', '11651', (87, 90))	('C67E7', 'Var', (92, 97))
32062	20466998	Secondary antibodies included rabbit anti-goat sc-2768 and anti-mouse sc-2005 (Santa Cruz Biotechnology) and anti-rabbit (GE Healthcare Bio-Sciences).	('sc-2005', 'Gene', (70, 77))	('rabbit', 'Species', '9986', (114, 120))	('anti-mouse', 'Var', (59, 69))	('anti-rabbit', 'Var', (109, 120))	('rabbit', 'Species', '9986', (30, 36))	('goat', 'Species', '9925', (42, 46))	('mouse', 'Species', '10090', (64, 69))
32066	20466998	To test the relationship between age and mammary preneoplasia development secondary to p53 deficiency and/or deregulated ERalpha expression, HAN (Fig.	('preneoplasia', 'Disease', (49, 61))	('deficiency', 'Var', (91, 101))	('deregulated', 'Var', (109, 120))	('p53', 'Gene', (87, 90))	('preneoplasia', 'Disease', 'None', (49, 61))	('secondary', 'Reg', (74, 83))	('ERalpha', 'Protein', (121, 128))
32070	20466998	By 12 months of age HAN prevalence was significantly increased in CERM/p53+/- mice as compared to the 4 and 8-month timepoints (71% vs. 0%, P<=0.0001; and 71% vs. 20%, P<=0.008, respectively).	('HAN', 'MPA', (20, 23))	('increased', 'PosReg', (53, 62))	('mice', 'Species', '10090', (78, 82))	('CERM/p53+/-', 'Var', (66, 77))
32074	20466998	Like HAN prevalence, by 12 months of age DH/DCIS prevalence was increased in CERM/p53+/- mice as compared to 8 months of age (60% vs. 40%).	('CERM/p53+/-', 'Var', (77, 88))	('mice', 'Species', '10090', (89, 93))	('DH', 'Disease', 'MESH:D065630', (41, 43))	('increased', 'PosReg', (64, 73))
32076	20466998	In summary, while all mice showed an increase in HAN and DH/DCIS prevalence with age, the combination of deregulated ERalpha and p53 deficiency demonstrated the highest prevalence and most significant increases in age-related preneoplasia development as compared to either deregulated ERalpha or p53 deficiency alone.	('preneoplasia', 'Disease', (226, 238))	('deregulated', 'Var', (105, 116))	('deficiency', 'Var', (133, 143))	('DH', 'Disease', 'MESH:D065630', (57, 59))	('increases', 'PosReg', (201, 210))	('ERalpha', 'Gene', (117, 124))	('p53', 'Gene', (129, 132))	('preneoplasia', 'Disease', 'None', (226, 238))	('mice', 'Species', '10090', (22, 26))
32078	20466998	The combination of deregulated ERalpha and p53 deficiency showed the highest PI (41+-1%) as compared to 24+-1%, 23+-3% and 0.4+-0.3, respectively, in CERM, p53+/- and WT mice (all P<=0.0004).	('deregulated', 'Var', (19, 30))	('ERalpha', 'Gene', (31, 38))	('p53', 'Gene', (43, 46))	('mice', 'Species', '10090', (170, 174))	('deficiency', 'Var', (47, 57))
32079	20466998	The AI was lowest in CERM/p53+/- (0.06+-0.04%) mice but all three experimental genotypes (CERM: 0.19+-0.08%; p53+/-: 0.12+-0.06%) were significantly lower than WT mice (0.66+-0.06%) (all P<=0.0009).	('lower', 'NegReg', (149, 154))	('mice', 'Species', '10090', (163, 167))	('mice', 'Species', '10090', (47, 51))	('p53+/-: 0.12+-0.06', 'Var', (109, 127))
32080	20466998	In summary, while all three experimental genotypes demonstrated abnormal apoptotic and proliferation rates, the mice with both deregulated ERalpha and p53 deficiency demonstrated the most abnormal parameters.	('deregulated', 'Var', (127, 138))	('apoptotic', 'CPA', (73, 82))	('deficiency', 'Var', (155, 165))	('ERalpha', 'Gene', (139, 146))	('p53', 'Gene', (151, 154))	('mice', 'Species', '10090', (112, 116))
32081	20466998	At 12 months of age, all three experimental genotypes demonstrated increased levels of ERK1/2 activation, however only mice with p53 heterozygosity (CERM/p53+/- and p53+/-) showed increased AKT activation and decreased p27 expression (Fig.	('ERK1/2', 'Gene', '26417;26413', (87, 93))	('p53+/-', 'Var', (165, 171))	('mice', 'Species', '10090', (119, 123))	('p27', 'Protein', (219, 222))	('activation', 'PosReg', (194, 204))	('p53', 'Var', (129, 132))	('increased', 'PosReg', (180, 189))	('AKT', 'Gene', '11651', (190, 193))	('ERK1/2', 'Gene', (87, 93))	('AKT', 'Gene', (190, 193))	('decreased', 'NegReg', (209, 218))
32085	20466998	While the mean percentage of nuclear-localized ERalpha was significantly decreased in CERM/p53+/- (6.9+-0.3%), as compared to CERM mice (P<=0.0001), nuclear-localized PgR was increased in both CERM/p53+/- (16.5+-1.8%) and CERM (13.9+-0.4%) as compared to p53+/- (9.1+-0.1%) and control (9.7+-1.0%) mice (all P<=0.02) (Fig.	('CERM/p53+/-', 'Var', (193, 204))	('mice', 'Species', '10090', (298, 302))	('decreased', 'NegReg', (73, 82))	('nuclear-localized', 'MPA', (29, 46))	('nuclear-localized', 'MPA', (149, 166))	('mice', 'Species', '10090', (131, 135))	('PgR', 'Gene', '18667', (167, 170))	('CERM/p53+/-', 'Var', (86, 97))	('increased', 'PosReg', (175, 184))	('PgR', 'Gene', (167, 170))
32090	20466998	p-Src scores were significantly higher in CERM/p53+/- (3.8+-0.3) as compared to CERM (1.8+-0.3), p53+/- (1.8+-0.5), and WT (1.3+-0.3) mice (Fig.	('mice', 'Species', '10090', (134, 138))	('higher', 'PosReg', (32, 38))	('Src', 'Gene', '20779', (2, 5))	('CERM/p53+/-', 'Var', (42, 53))	('Src', 'Gene', (2, 5))
32091	20466998	In summary, the changes in proliferation and apoptotic rates were accompanied by expression changes in apoptosis and proliferation-related proteins with changes in p53, phospho-AKT and p27 associated with p53 heterozygosity.	('AKT', 'Gene', '11651', (177, 180))	('changes', 'Reg', (16, 23))	('changes', 'Reg', (92, 99))	('proliferation', 'CPA', (27, 40))	('p27', 'Protein', (185, 188))	('p53', 'Gene', (205, 208))	('apoptotic rates', 'CPA', (45, 60))	('heterozygosity', 'Var', (209, 223))	('AKT', 'Gene', (177, 180))	('p53', 'Protein', (164, 167))	('proliferation-related', 'CPA', (117, 138))	('apoptosis', 'CPA', (103, 112))	('changes', 'Reg', (153, 160))
32094	20466998	Parous p53+/- mice showed a significant absence of HAN development following serial pregnancy that was not seen in CERM mice (P<0.03) or other genotype.	('absence', 'NegReg', (40, 47))	('p53+/-', 'Var', (7, 13))	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (14, 18))	('HAN development', 'CPA', (51, 66))
32097	20466998	In summary, parity was associated with a reduction in preneoplasia only in cohorts where p53 haploinsufficiency played a role.	('haploinsufficiency', 'Disease', (93, 111))	('preneoplasia only', 'Disease', (54, 71))	('parity', 'Var', (12, 18))	('haploinsufficiency', 'Disease', 'MESH:D058495', (93, 111))	('preneoplasia only', 'Disease', 'MESH:D054331', (54, 71))	('reduction', 'NegReg', (41, 50))
32098	20466998	This in vivo study demonstrated that deregulated ERalpha and p53 have independent and collaborating roles in the genesis of mammary preneoplasia.	('deregulated', 'Var', (37, 48))	('preneoplasia', 'Disease', (132, 144))	('p53', 'Protein', (61, 64))	('ERalpha', 'Protein', (49, 56))	('preneoplasia', 'Disease', 'None', (132, 144))
32100	20466998	Instructive aspects of the study were the focus on p53 heterozygosity as compared to complete loss of p53, comparison of two types of proliferative lesions (DH/DCIS and HANs), and investigation of the impact of both age and parity on prevalence of preneoplasia.	('DH', 'Disease', 'MESH:D065630', (157, 159))	('preneoplasia', 'Disease', 'None', (248, 260))	('heterozygosity', 'Var', (55, 69))	('preneoplasia', 'Disease', (248, 260))
32104	20466998	Changes in AKT activation were limited to either the p53 heterozygous mice or the combination.	('AKT', 'Gene', (11, 14))	('activation', 'PosReg', (15, 25))	('p53', 'Var', (53, 56))	('mice', 'Species', '10090', (70, 74))	('AKT', 'Gene', '11651', (11, 14))
32108	20466998	The cell cycle inhibitor p27 has been referred to as a candidate tumor suppressor and the presence of functional p53 correlates with p27 expression in human breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('expression', 'MPA', (137, 147))	('presence', 'Var', (90, 98))	('breast cancer', 'Disease', (157, 170))	('tumor', 'Disease', (65, 70))	('p27', 'Gene', (133, 136))	('human', 'Species', '9606', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('p53', 'Gene', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
32112	20466998	Our results showed decreased levels of p27 protein in the p53 deficient mice.	('decreased', 'NegReg', (19, 28))	('p27 protein', 'Protein', (39, 50))	('levels', 'MPA', (29, 35))	('deficient', 'Var', (62, 71))	('mice', 'Species', '10090', (72, 76))	('p53', 'Gene', (58, 61))
32114	20466998	As reported previously, the mice with deregulated ERalpha in this study showed an approximately two-fold increase in mammary epithelial cells with nuclear localized ERalpha.	('ERalpha', 'Gene', (165, 172))	('deregulated', 'Var', (38, 49))	('mice', 'Species', '10090', (28, 32))	('increase', 'PosReg', (105, 113))	('ERalpha', 'Gene', (50, 57))	('mammary', 'CPA', (117, 124))
32117	20466998	The highest levels of the activated p-Src (Tyr416) were found with the combination of deregulated ERalpha and p53 deficiency while expression of the ERalpha down stream gene PgR was maintained.	('ERalpha', 'Gene', (98, 105))	('p53', 'Gene', (110, 113))	('deregulated', 'Var', (86, 97))	('Src', 'Gene', '20779', (38, 41))	('PgR', 'Gene', '18667', (174, 177))	('Src', 'Gene', (38, 41))	('Tyr416', 'Chemical', '-', (43, 49))	('PgR', 'Gene', (174, 177))	('deficiency', 'Var', (114, 124))
32124	20466998	A noticeable decrease in preneoplasia in p53 deficient mice but not in mice with deregulated ERalpha alone or WT mice was found, suggesting a possible protective effect of pregnancy in mice with disease initiated by loss of p53 function.	('mice', 'Species', '10090', (71, 75))	('p53', 'Gene', (224, 227))	('preneoplasia', 'Disease', (25, 37))	('decrease', 'NegReg', (13, 21))	('mice', 'Species', '10090', (185, 189))	('mice', 'Species', '10090', (55, 59))	('deficient', 'Var', (45, 54))	('loss', 'NegReg', (216, 220))	('preneoplasia', 'Disease', 'None', (25, 37))	('mice', 'Species', '10090', (113, 117))	('p53', 'Gene', (41, 44))
32126	20466998	The fact that preneoplasia was not prevented by parity in either the mice with deregulated ERalpha alone or the WT mice suggests that not all risk factors associated with increased breast cancer risk can be reduced by pregnancy.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('preneoplasia', 'Disease', (14, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer', 'Disease', (181, 194))	('mice', 'Species', '10090', (69, 73))	('deregulated', 'Var', (79, 90))	('ERalpha', 'Gene', (91, 98))	('mice', 'Species', '10090', (115, 119))	('preneoplasia', 'Disease', 'None', (14, 26))
32130	28062852	Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to a highly selective reduction in the cellular levels of a v-SNARE (Vamp8).	('Rab17', 'Gene', '64284', (87, 92))	('knockdown', 'Var', (74, 83))	('v-SNARE', 'Gene', (159, 166))	('v-SNARE', 'Gene', '10490', (159, 166))	('reduction', 'NegReg', (121, 130))	('Rab17', 'Gene', (87, 92))
32147	28062852	It is already known that Rab25, a Rab11 GTPase whose expression is largely restricted to epithelia, is often lost in breast cancer, and deletion of Rab25 accelerates tumorigenesis in a mouse model of colon cancer.	('mouse', 'Species', '10090', (185, 190))	('Rab11', 'Gene', '8766', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Rab25', 'Gene', (148, 153))	('accelerates', 'PosReg', (154, 165))	('colon cancer', 'Disease', (200, 212))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('Rab11', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('deletion', 'Var', (136, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (200, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('lost', 'NegReg', (109, 113))	('tumorigenesis', 'CPA', (166, 179))	('colon cancer', 'Disease', 'MESH:D015179', (200, 212))
32157	28062852	Prominent amongst these proteins was neuropilin-2 (NRP2), which moves from endosomes to the plasma membrane following Rab17 depletion.	('NRP2', 'Gene', (51, 55))	('Rab17', 'Gene', (118, 123))	('NRP2', 'Gene', '8828', (51, 55))	('Rab17', 'Gene', '64284', (118, 123))	('neuropilin-2', 'Gene', (37, 49))	('depletion', 'Var', (124, 133))	('neuropilin-2', 'Gene', '8828', (37, 49))
32165	28062852	To search for these, we knocked down Rab17  and performed a SILAC-based global proteomic MS analysis.	('Rab17', 'Gene', '64284', (37, 42))	('knocked', 'Var', (24, 31))	('Rab17', 'Gene', (37, 42))	('SILAC', 'Chemical', '-', (60, 65))
32168	28062852	We confirmed this result by knocking down Rab17 in MDA-MB-231 cells using either a single small interfering (si)RNA oligonucleotide or pooled siRNAs, followed by western blotting (Fig.	('oligonucleotide', 'Chemical', 'MESH:D009841', (116, 131))	('Rab17', 'Gene', '64284', (42, 47))	('knocking', 'Var', (28, 36))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('Rab17', 'Gene', (42, 47))
32169	28062852	Moreover, this analysis indicated that levels of Vamp3 and Vamp7 (the most closely related Vamps to Vamp8) were unaffected by knockdown of Rab17 (Fig.	('Rab17', 'Gene', (139, 144))	('Vamp3', 'Gene', (49, 54))	('Vamp7', 'Gene', '6845', (59, 64))	('Rab17', 'Gene', '64284', (139, 144))	('Vamp7', 'Gene', (59, 64))	('Vamp3', 'Gene', '9341', (49, 54))	('knockdown', 'Var', (126, 135))
32170	28062852	Furthermore, since Rab17 knockdown suppressed Vamp8 protein but not levels of its mRNA, we conclude that Rab17 controls Vamp8 expression post-transcriptionally .	('Vamp8', 'Gene', (120, 125))	('protein', 'Protein', (52, 59))	('Rab17', 'Gene', (19, 24))	('Rab17', 'Gene', '64284', (19, 24))	('suppressed', 'NegReg', (35, 45))	('Rab17', 'Gene', (105, 110))	('Rab17', 'Gene', '64284', (105, 110))	('knockdown', 'Var', (25, 34))	('Vamp8', 'Gene', (46, 51))
32174	28062852	Knockdown of ERK2 led to increased levels of Rab17 mRNA and Vamp8 protein (Fig.	('Rab17', 'Gene', (45, 50))	('ERK2', 'Gene', (13, 17))	('increased', 'PosReg', (25, 34))	('Vamp8', 'Protein', (60, 65))	('Knockdown', 'Var', (0, 9))	('Rab17', 'Gene', '64284', (45, 50))	('levels of', 'MPA', (35, 44))	('ERK2', 'Gene', '5594', (13, 17))
32188	28062852	1, we observed a reduction in Vamp8 levels following Rab17 knockdown.	('Rab17', 'Gene', (53, 58))	('Rab17', 'Gene', '64284', (53, 58))	('knockdown', 'Var', (59, 68))	('Vamp8 levels', 'MPA', (30, 42))	('reduction', 'NegReg', (17, 26))
32192	28062852	Initially, we investigated the consequences of knocking down Rab17 or Vamp8 on the ability of MDA-MB-231 cells to invade into plugs of Matrigel that had been supplemented with fibronectin.	('fibronectin', 'Gene', '2335', (176, 187))	('Rab17', 'Gene', '64284', (61, 66))	('fibronectin', 'Gene', (176, 187))	('Rab17', 'Gene', (61, 66))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (94, 104))	('Vamp8', 'Gene', (70, 75))	('knocking down', 'Var', (47, 60))
32193	28062852	siRNA-mediated knockdown of Rab17 increased invasiveness of MDA-MB-231 cells.	('Rab17', 'Gene', '64284', (28, 33))	('knockdown', 'Var', (15, 24))	('invasiveness', 'CPA', (44, 56))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))	('increased', 'PosReg', (34, 43))	('Rab17', 'Gene', (28, 33))
32194	28062852	Interestingly, siRNA knockdown of Vamp8 also promoted invasiveness into Matrigel plugs, consistent with the view that Vamp8 is functionally linked to Rab17 (Fig.	('Vamp8', 'Gene', (34, 39))	('promoted', 'PosReg', (45, 53))	('Rab17', 'Gene', (150, 155))	('invasiveness into Matrigel plugs', 'CPA', (54, 86))	('knockdown', 'Var', (21, 30))	('Rab17', 'Gene', '64284', (150, 155))
32203	28062852	Consistently, immunofluorescence staining for beta4 integrin and laminin-V indicated that siRNA knockdown of Rab17 or Vamp8 drove substantial disruption of the basement membrane surrounding the comedo-like structure, allowing MCF10DCIS.com cells to migrate out of the organoid (Fig.	('knockdown', 'Var', (96, 105))	('Vamp8', 'Gene', (118, 123))	('comedo', 'Phenotype', 'HP:0025249', (194, 200))	('disruption', 'MPA', (142, 152))	('migrate', 'CPA', (249, 256))	('Rab17', 'Gene', (109, 114))	('Rab17', 'Gene', '64284', (109, 114))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (226, 239))
32205	28062852	Finally, combined knockdown of Rab17 and Vamp8 did not increase the disruption of sphericity that was evoked by knockdown of these proteins individually, consistent with Rab17 and Vamp8 operating in the same signalling axis .	('knockdown', 'Var', (18, 27))	('disruption', 'MPA', (68, 78))	('Rab17', 'Gene', (31, 36))	('Rab17', 'Gene', '64284', (31, 36))	('Rab17', 'Gene', (170, 175))	('Rab17', 'Gene', '64284', (170, 175))	('knockdown', 'Var', (112, 121))
32228	28062852	We then looked for proteins whose relative abundance between surface and endosomal compartments was reproducibly (in the forward and reverse experiments) influenced by Rab17 knockdown.	('Rab17', 'Gene', '64284', (168, 173))	('abundance', 'MPA', (43, 52))	('influenced', 'Reg', (154, 164))	('knockdown', 'Var', (174, 183))	('Rab17', 'Gene', (168, 173))
32229	28062852	We categorised these according to whether their abundance was coordinately or differentially regulated at the cell surface and the endosome by Rab17 knockdown.	('Rab17', 'Gene', '64284', (143, 148))	('Rab17', 'Gene', (143, 148))	('knockdown', 'Var', (149, 158))
32230	28062852	The largest category constituted those proteins whose abundance was co-ordinately increased in the surface proteome and the internalised proteome by Rab17 knockdown (upper-right quadrant in Fig.	('knockdown', 'Var', (155, 164))	('internalised proteome', 'MPA', (124, 145))	('surface proteome', 'MPA', (99, 115))	('abundance', 'MPA', (54, 63))	('Rab17', 'Gene', (149, 154))	('Rab17', 'Gene', '64284', (149, 154))	('increased', 'PosReg', (82, 91))
32233	28062852	proteins that were distributed differently between the cell surface and endosomes following siRNA knockdown of Rab17.	('Rab17', 'Gene', (111, 116))	('Rab17', 'Gene', '64284', (111, 116))	('knockdown', 'Var', (98, 107))
32234	28062852	We, therefore, focussed our attention on those proteins whose abundance moved in opposite directions in the surface proteome and internalised proteome following Rab17 knockdown (upper-left quadrant in Fig.	('knockdown', 'Var', (167, 176))	('abundance', 'MPA', (62, 71))	('Rab17', 'Gene', '64284', (161, 166))	('Rab17', 'Gene', (161, 166))
32235	28062852	Interestingly, this analysis revealed neuropilin-2 (NRP2), which is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), to be the protein whose surface expression was most significantly increased (1.5-fold) at the cell surface and reduced (1.2-fold) in the internalised proteome when Rab17 was silenced (Fig.	('vascular endothelial growth factor', 'Gene', (102, 136))	('silenced', 'Var', (319, 327))	('neuropilin-2', 'Gene', (38, 50))	('internalised proteome', 'MPA', (282, 303))	('NRP2', 'Gene', (52, 56))	('vascular endothelial growth factor', 'Gene', '7422', (102, 136))	('neuropilin-2', 'Gene', '8828', (38, 50))	('surface expression', 'MPA', (169, 187))	('increased', 'PosReg', (211, 220))	('VEGF', 'Gene', '7422', (138, 142))	('NRP2', 'Gene', '8828', (52, 56))	('reduced', 'NegReg', (256, 263))	('Rab17', 'Gene', (309, 314))	('Rab17', 'Gene', '64284', (309, 314))	('VEGF', 'Gene', (138, 142))
32236	28062852	Western blotting confirmed that siRNA knockdown of Rab17 increased the quantity of NRP2 at the cell surface and decreased the endosomal pool of NRP2, whilst its total cellular content remained unchanged (Fig.	('NRP2', 'Gene', (144, 148))	('Rab17', 'Gene', (51, 56))	('Rab17', 'Gene', '64284', (51, 56))	('NRP2', 'Gene', (83, 87))	('NRP2', 'Gene', '8828', (144, 148))	('quantity', 'MPA', (71, 79))	('NRP2', 'Gene', '8828', (83, 87))	('increased', 'PosReg', (57, 66))	('decreased', 'NegReg', (112, 121))	('knockdown', 'Var', (38, 47))
32237	28062852	Furthermore, we found that knockdown of Vamp8 evoked similar alterations to the plasma membrane and endosomal distribution of NRP2 to that elicited by knockdown of Rab17 (Fig.	('knockdown', 'Var', (27, 36))	('NRP2', 'Gene', (126, 130))	('endosomal distribution', 'MPA', (100, 122))	('NRP2', 'Gene', '8828', (126, 130))	('Vamp8', 'Gene', (40, 45))	('alterations', 'Reg', (61, 72))	('Rab17', 'Gene', (164, 169))	('Rab17', 'Gene', '64284', (164, 169))
32238	28062852	Our proteomic analysis indicated that NRP2 redistributes from endosomes to the cell surface following Rab17 knockdown, suggesting that the endosomal trafficking of this receptor is regulated by Rab17 and Vamp8.	('knockdown', 'Var', (108, 117))	('NRP2', 'Gene', (38, 42))	('Rab17', 'Gene', (194, 199))	('NRP2', 'Gene', '8828', (38, 42))	('redistributes', 'Reg', (43, 56))	('Rab17', 'Gene', '64284', (194, 199))	('Rab17', 'Gene', (102, 107))	('endosomal trafficking', 'MPA', (139, 160))	('Rab17', 'Gene', '64284', (102, 107))
32239	28062852	To visualise the trafficking of NRP2, we transfected MDA-MB-231 cells with GFP-tagged NRP2 in combination with the late endosomal marker mCherry-Lamp1 and performed fluorescence live-cell imaging followed by quantitative vesicle tracking.	('GFP-tagged', 'Var', (75, 85))	('NRP2', 'Gene', (86, 90))	('NRP2', 'Gene', (32, 36))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (53, 63))	('Lamp1', 'Gene', '3916', (145, 150))	('Lamp1', 'Gene', (145, 150))	('NRP2', 'Gene', '8828', (86, 90))	('NRP2', 'Gene', '8828', (32, 36))
32242	28062852	By contrast, following knockdown of either Rab17 or Vamp8, the number of smaller NRP2-positive vesicles increased dramatically (>70% of structures being less than 2 mum2), and quantitative tracking analysis indicated that the speed of their movement significantly increased (Fig.	('increased', 'PosReg', (264, 273))	('increased', 'PosReg', (104, 113))	('NRP2', 'Gene', '8828', (81, 85))	('knockdown', 'Var', (23, 32))	('Rab17', 'Gene', (43, 48))	('Rab17', 'Gene', '64284', (43, 48))	('Vamp8', 'Gene', (52, 57))	('NRP2', 'Gene', (81, 85))
32243	28062852	Moreover, the population of smaller vesicles that was evoked by knockdown of Rab17 or Vamp8 still overlapped substantially with Lamp1-containing structures.	('Rab17', 'Gene', (77, 82))	('Rab17', 'Gene', '64284', (77, 82))	('knockdown', 'Var', (64, 73))	('Vamp8', 'Gene', (86, 91))	('Lamp1', 'Gene', '3916', (128, 133))	('Lamp1', 'Gene', (128, 133))
32246	28062852	Our MS analysis indicated that NRP2 redistributes from endosomes to the cell surface following Rab17 knockdown, suggesting that this receptor is a pro-invasive cargo whose recycling is opposed by Rab17 and Vamp8.	('Rab17', 'Gene', '64284', (196, 201))	('NRP2', 'Gene', (31, 35))	('knockdown', 'Var', (101, 110))	('NRP2', 'Gene', '8828', (31, 35))	('Rab17', 'Gene', (95, 100))	('Rab17', 'Gene', '64284', (95, 100))	('Rab17', 'Gene', (196, 201))
32247	28062852	We, therefore, provoked breast cancer cell invasiveness by knocking down Rab17 or Vamp8 and tested the requirement for NRP2 in this.	('provoked', 'Reg', (15, 23))	('breast cancer cell invasiveness', 'Disease', 'MESH:D001943', (24, 55))	('Vamp8', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('knocking', 'Var', (59, 67))	('tested', 'Reg', (92, 98))	('NRP2', 'Gene', '8828', (119, 123))	('breast cancer cell invasiveness', 'Disease', (24, 55))	('Rab17', 'Gene', (73, 78))	('Rab17', 'Gene', '64284', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('NRP2', 'Gene', (119, 123))
32249	28062852	However, siRNA knockdown of NRP2 (using either a SMARTPool siRNA or an individual siRNA sequence) opposed the ability of Rab17 and Vamp8 knockdown to drive basement membrane degradation and to disrupt acinar sphericity (Fig.	('knockdown', 'Var', (15, 24))	('disrupt', 'Reg', (193, 200))	('Rab17', 'Gene', (121, 126))	('Rab17', 'Gene', '64284', (121, 126))	('drive', 'PosReg', (150, 155))	('basement membrane degradation', 'CPA', (156, 185))	('NRP2', 'Gene', (28, 32))	('knockdown', 'Var', (137, 146))	('acinar', 'MPA', (201, 207))	('opposed', 'NegReg', (98, 105))	('NRP2', 'Gene', '8828', (28, 32))	('ability', 'MPA', (110, 117))
32250	28062852	Consistently, we found that knockdown of NRP2 completely opposed the ability of both Rab17 and Vamp8 knockdown to drive invasion of MDA-MB-231 cells into Matrigel plugs (Fig.	('NRP2', 'Gene', (41, 45))	('Vamp8', 'Gene', (95, 100))	('NRP2', 'Gene', '8828', (41, 45))	('ability', 'MPA', (69, 76))	('invasion', 'CPA', (120, 128))	('opposed', 'NegReg', (57, 64))	('knockdown', 'Var', (28, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))	('Rab17', 'Gene', (85, 90))	('Rab17', 'Gene', '64284', (85, 90))	('drive', 'PosReg', (114, 119))	('knockdown', 'Var', (101, 110))
32256	28062852	Moreover, because Vamp8 is the only component of the proteome that is significantly altered following Rab17 knockdown, the relationship between this GTPase and Vamp8 stability is likely to be highly selective.	('knockdown', 'Var', (108, 117))	('Rab17', 'Gene', (102, 107))	('Rab17', 'Gene', '64284', (102, 107))	('altered', 'Reg', (84, 91))
32271	28062852	The receptor whose distribution was most significantly altered by Rab17 knockdown was NRP2.	('Rab17', 'Gene', (66, 71))	('Rab17', 'Gene', '64284', (66, 71))	('altered', 'Reg', (55, 62))	('NRP2', 'Gene', (86, 90))	('distribution', 'MPA', (19, 31))	('NRP2', 'Gene', '8828', (86, 90))	('knockdown', 'Var', (72, 81))
32285	28062852	GFP-NRP2 in pCMV6-AC-GFP was from Amsbio (MG223943), and GFP-Vamp8 was a gift from Thierry Galli (Institut Jaques Monod, Paris, France) [Addgene plasmid #42311 ].	('NRP2', 'Gene', '8828', (4, 8))	('MG223943', 'Var', (42, 50))	('NRP2', 'Gene', (4, 8))
32286	28062852	SILAC-labelled MDA-MB-231 cells were obtained by culturing in SILAC-DMEM lacking arginine and lysine (Life Technologies) supplemented with L-arginine and L-lysine (SILAC light) (Sigma-Aldrich) or [13C6][15N4] L-arginine and [13C6] [15N2] L-lysine (SILAC heavy; Cambridge Isotope Laboratories, Tewksbury, MA).	('[13C6][15N4] L-arginine', 'Var', (196, 219))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (15, 25))	('SILAC', 'Chemical', '-', (0, 5))	('SILAC', 'Chemical', '-', (248, 253))	('Isotope Laboratories', 'Disease', 'MESH:D007757', (271, 291))	('SILAC', 'Chemical', '-', (164, 169))	('Isotope Laboratories', 'Disease', (271, 291))	('[13C6] [15N2] L-lysine', 'Var', (224, 246))	('SILAC', 'Chemical', '-', (62, 67))
32295	28062852	Site-directed mutagenesis was performed using QuikChange Lightning kit (Agilent) to create GST-Rab17Q77L (forward 5'-TGTGGTACTTCTTCCAGGCCAGCTGTGTCC-3' and reverse 5'-GGACACAGCTGGCCTGGAGAAGTACCACA-3'), and the two rescue vectors resistant to Rab17 si-#1, GFP-Rab17 T81C_C84G_C87A_G90T (forward 5'-GCCAAGCTGGACTTACCAACTGACCCGCTTCCCAGGAGAACCAG-3', reverse 5'-CTGGTTCTCCTGGGAAGCGGGTCAGTTGGTAAGTCCAGCTTGGC-3') and GFP-Vamp8 resistant to Vamp8 si-#2 C234T_T237G_C240A_C243T (forward 5'-CTGGTGGAAGAACGTGAAGATGATTGTTCTGATATGTGTGATTGTTTTTATCATCATCCTCTTC-3', reverse 5'-GAAGAGGATGATGATAAAAACAATCACACATATCAGAACAATCATCTTCACGTTCTTCCACCAG-3').	('Rab17', 'Gene', (241, 246))	('Rab17', 'Gene', '64284', (241, 246))	('Rab17', 'Gene', '64284', (258, 263))	('C87A', 'Mutation', 'c.87C>A', (274, 278))	('C234T', 'Mutation', 'rs749265757', (444, 449))	('C243T', 'Mutation', 'rs369917659', (462, 467))	('T81C', 'Mutation', 'rs1249597015', (264, 268))	('T237G', 'Mutation', 'c.237T>G', (450, 455))	('C84G', 'Mutation', 'c.84C>G', (269, 273))	('C234T_T237G_C240A_C243T', 'Var', (444, 467))	('G90T', 'Mutation', 'c.90G>T', (279, 283))	('Rab17', 'Gene', (95, 100))	('Rab17', 'Gene', '64284', (95, 100))	('Rab17', 'Gene', (258, 263))	('C240A', 'Mutation', 'c.240C>A', (456, 461))
32301	28062852	For the proteome analysis of cells that had been silenced for Rab17, proteins were trypsin-digested using the filter-aid sample preparation (FASP) method, and 50 microg of peptides were separated by using strong anion exchange chromatography on StageTip as previously described.	('Rab17', 'Gene', '64284', (62, 67))	('silenced', 'Var', (49, 57))	('Rab17', 'Gene', (62, 67))
32306	28062852	To identify differentially trafficked proteins upon Rab17 knockdown, proteins belonging to the 1st or 3rd quartiles of the SILAC ratio distribution of the forward and reverse experiments were considered.	('SILAC', 'Chemical', '-', (123, 128))	('Rab17', 'Gene', (52, 57))	('knockdown', 'Var', (58, 67))	('Rab17', 'Gene', '64284', (52, 57))
32336	22675624	High-grade DCIS which is oestrogen receptor (ER) and progesterone receptor (PR) negative is significantly associated with HER2 and p53 positivity.	('associated', 'Reg', (106, 116))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('progesterone receptor', 'Gene', (53, 74))	('positivity', 'Var', (135, 145))	('progesterone receptor', 'Gene', '5241', (53, 74))	('HER2', 'Protein', (122, 126))
32337	22675624	HER2 overexpression represents an aggressive biological subtype of DCIS, correlating with high grade, p53 expression, and hormone receptor negativity.	('hormone receptor', 'Gene', (122, 138))	('hormone receptor', 'Gene', '3164', (122, 138))	('p53', 'Var', (102, 105))	('overexpression', 'PosReg', (5, 19))	('HER2', 'Protein', (0, 4))
32338	22675624	Hormone receptor positivity has been associated with low-grade DCIS.	('low-grade DCIS', 'Disease', (53, 67))	('positivity', 'Var', (17, 27))	('Hormone receptor', 'Gene', '3164', (0, 16))	('associated', 'Reg', (37, 47))	('Hormone receptor', 'Gene', (0, 16))
32404	22655186	The major advantage on local control was noted in cases of DCIS with necrosis, comedocarcinoma, high nuclear grade, and positive or "close" margins.	('DCIS', 'Disease', (59, 63))	('necrosis', 'Disease', (69, 77))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('advantage', 'PosReg', (10, 19))	('local control', 'CPA', (23, 36))	('high nuclear', 'Var', (96, 108))	('necrosis', 'Disease', 'MESH:D009336', (69, 77))	('comedocarcinoma', 'Disease', (79, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('comedocarcinoma', 'Disease', 'None', (79, 94))	('comedo', 'Phenotype', 'HP:0025249', (79, 85))
32418	22655186	In the multivariate analysis of the prognostic factors, young age (<=40 years), symptomatically detected DCIS, high nuclear grade (G2-3), solid/comedo or cribriform growth pattern, and the absence of free margins were associated with an increased risk of LR.	('solid/comedo or cribriform growth pattern', 'CPA', (138, 179))	('DCIS', 'Disease', (105, 109))	('comedo', 'Phenotype', 'HP:0025249', (144, 150))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('LR', 'Chemical', '-', (255, 257))	('high', 'Var', (111, 115))
32426	22655186	In a previous study that had investigated the histopathologic risk factors for LR by a slide revision of 2 cohort cases from the trial, high nuclear grade and necrosis were associated to a major local relapse risk.	('LR', 'Chemical', '-', (79, 81))	('necrosis', 'Disease', (159, 167))	('associated to', 'Reg', (173, 186))	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('high nuclear grade', 'Var', (136, 154))	('local relapse', 'CPA', (195, 208))
32454	22655186	The most frequently reported factors associated with a higher risk of LR are high nuclear grade, comedo necrosis, and larger tumor size.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('high', 'Var', (77, 81))	('necrosis', 'Disease', (104, 112))	('comedo', 'Phenotype', 'HP:0025249', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('LR', 'Chemical', '-', (70, 72))
32460	22655186	In this study, comedo architecture and nuclear grade 3 had a significantly higher 5-year LR rate; the difference, however, was no longer statistically significant at 10 years.	('comedo architecture', 'CPA', (15, 34))	('higher', 'PosReg', (75, 81))	('comedo', 'Phenotype', 'HP:0025249', (15, 21))	('LR', 'Chemical', '-', (89, 91))	('nuclear grade 3', 'Var', (39, 54))
32521	18765527	The human cathepsin gene family is composed of 11 members [cathepsins B (CTSB), C, H, F (CTSF), K (CTSK), L (CTSL), O, S, V, W, and X/Z] each with their unique as well as overlapping function as revealed by the phenotype of mutant mice deficient for individual genes or their combination.	('CTSL', 'Gene', '1514', (109, 113))	('mutant', 'Var', (224, 230))	('CTSF', 'Gene', '8722', (89, 93))	('human', 'Species', '9606', (4, 9))	('CTSB', 'Gene', (73, 77))	('CTSL', 'Gene', (109, 113))	('CTSF', 'Gene', (89, 93))	('cathepsins B', 'Gene', (59, 71))	('mice', 'Species', '10090', (231, 235))	('CTSB', 'Gene', '1508', (73, 77))	('cathepsins B', 'Gene', '1508', (59, 71))
32524	18765527	Inhibition of cathepsin activity appears to be a promising therapeutic approach for the treatment of metastatic disease and inhibition of tumor progression.	('cathepsin activity', 'Protein', (14, 32))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('metastatic disease', 'Disease', (101, 119))
32531	18765527	Its receptor is still unknown, but CXCL14 has been shown to be a chemoattractant for monocytes, B cells, and dendritic cells and has also been implicated to play a role in the regulation of tumor cell growth, angiogenesis, and activation of NK cells.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('play', 'Reg', (157, 161))	('tumor', 'Disease', (190, 195))	('angiogenesis', 'CPA', (209, 221))	('CXCL14', 'Var', (35, 41))	('NK cells', 'CPA', (241, 249))
32534	18765527	Associated with its potential role in obesity, CXCL14 was also shown to be induced by growth hormone, insulin-like growth factor, and insulin in hepatocytes and to enhance insulin-dependent glucose uptake in adipocytes.	('enhance', 'PosReg', (164, 171))	('insulin', 'Gene', (134, 141))	('obesity', 'Phenotype', 'HP:0001513', (38, 45))	('CXCL14', 'Var', (47, 53))	('glucose', 'Chemical', 'MESH:D005947', (190, 197))	('insulin', 'Gene', '3630', (134, 141))	('insulin', 'Gene', (102, 109))	('insulin', 'Gene', (172, 179))	('obesity', 'Disease', 'MESH:D009765', (38, 45))	('insulin', 'Gene', '3630', (102, 109))	('insulin', 'Gene', '3630', (172, 179))	('obesity', 'Disease', (38, 45))
32537	18765527	Thus, CXCL14 may contribute to breast tumorigenesis via multiple different mechanisms including both autocrine and paracrine effects.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('breast tumor', 'Disease', (31, 43))	('contribute', 'Reg', (17, 27))	('breast tumor', 'Phenotype', 'HP:0100013', (31, 43))	('CXCL14', 'Var', (6, 12))	('breast tumor', 'Disease', 'MESH:D001943', (31, 43))
32548	18765527	Thus, inhibition of CTSK activity may decrease the risk of breast tumor progression and should be explored further in clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast tumor', 'Disease', (59, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (59, 71))	('decrease', 'NegReg', (38, 46))	('CTSK', 'Protein', (20, 24))	('inhibition', 'Var', (6, 16))	('breast tumor', 'Disease', 'MESH:D001943', (59, 71))	('activity', 'MPA', (25, 33))
32564	18765527	The expression levels were analyzed blindly and independently by breast pathologists and classified into -, +, ++, and +++ following a previously validated scoring schema.	('schema', 'Disease', (164, 170))	('schema', 'Disease', 'None', (164, 170))	('+++', 'Var', (119, 122))
32589	18765527	Besides cathepsins, several cysteine protease inhibitors including cystatin C were also up-regulated in DCIS-associated myoepithelial cells and myofibroblasts raising the possibility that alterations in cysteine protease balance in epithelial and various stromal cells composing the microenvironment may contribute to breast tumor progression by promoting invasion.	('cystatin C', 'Gene', (67, 77))	('cystatin C', 'Gene', '1471', (67, 77))	('contribute', 'Reg', (304, 314))	('breast tumor', 'Phenotype', 'HP:0100013', (318, 330))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('invasion', 'CPA', (356, 364))	('breast tumor', 'Disease', 'MESH:D001943', (318, 330))	('up-regulated', 'PosReg', (88, 100))	('cysteine protease', 'Enzyme', (28, 45))	('cathepsins', 'MPA', (8, 18))	('alterations', 'Var', (188, 199))	('promoting', 'PosReg', (346, 355))	('breast tumor', 'Disease', (318, 330))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))
32623	18765527	Next, we compared CTSK expression levels (divided into the four categories: -, +, ++, and +++) between interlobular stroma and intralobular stroma within tissue samples from the same patient (Table 1C).	('patient', 'Species', '9606', (183, 190))	('stroma and intralobular stroma', 'Disease', 'None', (116, 146))	('CTSK expression', 'MPA', (18, 33))	('+++', 'Var', (90, 93))
32633	18765527	When using the Fisher's exact test to assess the relationships between CTSK expression levels and tumor and patient characteristics, T stage (P = 0.02) and estrogen receptor (ER) status (P = 0.05) were significantly associated with CTSK positivity (Supplementary Table S3).	('ER', 'Gene', '2099', (175, 177))	('T stage', 'CPA', (133, 140))	('positivity', 'Var', (237, 247))	('estrogen receptor', 'Gene', (156, 173))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('estrogen receptor', 'Gene', '2099', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CTSK', 'Gene', (232, 236))	('patient', 'Species', '9606', (108, 115))	('tumor', 'Disease', (98, 103))
32710	28286675	Corresponding numbers for DCIS with crushed stone calcifications were HER2+/ER- lesions in 18%, HER2-/ER- lesions in 7%, and ER+ lesions in 75% of the cases and for DCIS with architectural distortion they were HER2+/ER- lesions in 8%, HER2-/ER- lesions in 19%, and ER+ lesions in 73%.	('HER2', 'Gene', (210, 214))	('HER2', 'Gene', (70, 74))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('HER2', 'Gene', '2064', (70, 74))	('HER2', 'Gene', (235, 239))	('HER2', 'Gene', '2064', (210, 214))	('HER2', 'Gene', '2064', (235, 239))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (96, 100))	('DCIS', 'Disease', (26, 30))	('ER+ lesions', 'Var', (125, 136))
32712	28286675	The 44 DCIS showing histopathological neoductgenesis were HER2+/ER- lesions in 55% of the cases, HER2-/ER- in 10%, and ER+ in 35% of the cases while DCIS without signs of neoductgenesis were HER2+/ER- in 15%, HER2-/ER- in 9%, and ER+ in 76% of the cases.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', (191, 195))	('HER2', 'Gene', '2064', (97, 101))	('HER2', 'Gene', '2064', (191, 195))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('HER2', 'Gene', (209, 213))	('ER+', 'Var', (119, 122))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (209, 213))	('HER2', 'Gene', '2064', (58, 62))
32717	28286675	Our aim was to include DCIS cases with mammographic casting type calcifications, histopathological signs of neoductgenesis, and high Tn-C expression in a model trying to identify lesions with a worse prognosis.	('Tn-C', 'Gene', '3371', (133, 137))	('expression', 'MPA', (138, 148))	('high', 'Var', (128, 132))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('Tn-C', 'Gene', (133, 137))
32725	28286675	HER2 expression, for example, has been related to a higher risk of recurrence but it seems like it only relates to in situ IBE.	('HER2', 'Gene', '2064', (0, 4))	('expression', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))	('IBE', 'Chemical', '-', (123, 126))
32799	26295657	Studies from Ireland, the Netherlands, and Norway have reported increased cancer detection rates with digital while studies from Spain, the United Kingdom, and the U.S. show similar cancer detection rates for digital and film.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('digital', 'Var', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (182, 188))	('increased', 'PosReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
32811	26295657	We do not believe this is the case because mammographically DCIS has a less than 10% chance of being associated with a subsequent invasive cancer in 10 years and most subsequent invasive cancers are not aggressive as the interval cancers in our study.	('invasive cancers', 'Disease', 'MESH:D009362', (178, 194))	('invasive cancer', 'Disease', (130, 145))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('invasive cancer', 'Disease', 'MESH:D009362', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('invasive cancers', 'Disease', (178, 194))	('invasive cancer', 'Disease', 'MESH:D009362', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('interval cancers', 'Disease', (221, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('mammographically DCIS', 'Var', (43, 64))	('associated', 'Reg', (101, 111))	('interval cancers', 'Disease', 'MESH:D009369', (221, 237))
32828	23437403	LDH-B promoter methylation was identified in T-47D and MCF7 cells, and in 25/ 25 cases of breast cancer tissues, but not in 5/ 5 cases of normal breast tissues.	('methylation', 'Var', (15, 26))	('LDH-B', 'Gene', '3945', (0, 5))	('T-47D', 'CellLine', 'CVCL:0553', (45, 50))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('LDH-B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('MCF7', 'CellLine', 'CVCL:0031', (55, 59))
32850	23437403	Tumour cells have been shown to undergo aerobic glycolysis following oncogene activation (myc, ras, AKT), and tumour suppressor (p53, VHL) gene inactivation, which act to upregulate Hypoxia-Inducible Factor 1 alpha (HIF-1alpha) levels.	('HIF-1alpha', 'Gene', (216, 226))	('VHL', 'Gene', '7428', (134, 137))	('AKT', 'Gene', (100, 103))	('aerobic glycolysis', 'MPA', (40, 58))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('upregulate', 'PosReg', (171, 181))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('AKT', 'Gene', '207', (100, 103))	('VHL', 'Gene', (134, 137))	('HIF-1alpha', 'Gene', '3091', (216, 226))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('Hypoxia-Inducible Factor 1 alpha', 'Gene', '3091', (182, 214))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))	('Hypoxia-Inducible Factor 1 alpha', 'Gene', (182, 214))	('gene inactivation', 'Var', (139, 156))
32899	23437403	In mammals, DNA methylation of cytosine residues located at 5' to guanine residues (CpG sites), represents a major epigenetic mechanism for regulating gene expression, including X-chromosome inactivation and genomic imprinting.	('guanine', 'Chemical', 'MESH:D006147', (66, 73))	('regulating', 'Reg', (140, 150))	('gene expression', 'MPA', (151, 166))	('cytosine', 'Chemical', 'MESH:D003596', (31, 39))	('X-chromosome', 'Var', (178, 190))	('methylation', 'Var', (16, 27))
32921	23437403	Our current study has shown for the first time in human breast cancer that loss of expression of the LDH-B subunit may occur at an early (DCIS) stage, and occurs in a high frequency of breast cancers, with the underlying mechanism likely to involve methylation of the LDH-B promoter.	('LDH-B', 'Gene', (101, 106))	('methylation', 'Var', (249, 260))	('LDH-B', 'Gene', (268, 273))	('breast cancers', 'Disease', 'MESH:D001943', (185, 199))	('breast cancers', 'Disease', (185, 199))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('loss of expression', 'NegReg', (75, 93))	('LDH-B', 'Gene', '3945', (268, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('human', 'Species', '9606', (50, 55))	('breast cancers', 'Phenotype', 'HP:0003002', (185, 199))	('LDH-B', 'Gene', '3945', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
32931	23437403	For instance, silencing the expression of LDH-A has been shown to decrease cellular proliferation and tumourigenic ability of breast cancer cells, and furthermore LDH-A has been shown to be involved in tumour progression.	('silencing', 'Var', (14, 23))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('LDH-A', 'Gene', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('LDH-A', 'Gene', '3939', (163, 168))	('breast cancer', 'Disease', (126, 139))	('cellular proliferation', 'CPA', (75, 97))	('LDH-A', 'Gene', (163, 168))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('decrease', 'NegReg', (66, 74))	('tumour', 'Disease', (202, 208))	('LDH-A', 'Gene', '3939', (42, 47))	('involved', 'Reg', (190, 198))
32933	23437403	Thus, it has been reported that the non-invasive MCF7 cells have a much lower aerobic glucose consumption rate compared with the highly invasive MDA-MB-231 breast cancer cell line.	('glucose consumption', 'Disease', 'MESH:D014397', (86, 105))	('non-invasive MCF7', 'Var', (36, 53))	('glucose consumption', 'Disease', (86, 105))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (145, 155))	('lower', 'NegReg', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('MCF7', 'CellLine', 'CVCL:0031', (49, 53))
32934	23437403	Although this finding is in line with our data where we found that during conditions of normoxia, lactate levels were higher in the highly invasive MDA-MB-436 cells compared with MCF7 cells, we did not expect this finding based on the LDH isoenzyme profiles observed in these cells.	('higher', 'PosReg', (118, 124))	('LDH', 'Gene', '3939;3945;3948', (235, 238))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (148, 158))	('lactate', 'Chemical', 'MESH:D019344', (98, 105))	('lactate levels', 'MPA', (98, 112))	('MCF7', 'CellLine', 'CVCL:0031', (179, 183))	('MDA-MB-436', 'Var', (148, 158))	('LDH', 'Gene', (235, 238))
32948	23437403	Furthermore, a low pH has been shown to stimulate in vitro invasion and in vivo metastasis of cancer cells.	('low pH', 'Var', (15, 21))	('stimulate', 'PosReg', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('invasion', 'CPA', (59, 67))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
32956	23437403	Targeting the remaining LDH-A subunit with therapeutic agents, specifically in those tumours with an absent or decreased expression of LDH-B is expected to lead to a greater cell death, as this is expected to inhibit all cellular LDH activity, and lead to a depletion of the NAD+ stock necessary for self-sufficient glycolysis to occur.	('self-sufficient glycolysis', 'MPA', (300, 326))	('lead', 'Reg', (156, 160))	('LDH-A', 'Gene', '3939', (24, 29))	('LDH-A', 'Gene', (24, 29))	('LDH', 'Gene', (230, 233))	('LDH', 'Gene', (24, 27))	('decreased', 'NegReg', (111, 120))	('LDH', 'Gene', (135, 138))	('NAD+', 'Chemical', 'MESH:D009243', (275, 279))	('cell death', 'CPA', (174, 184))	('Targeting', 'Var', (0, 9))	('inhibit', 'NegReg', (209, 216))	('tumours', 'Disease', (85, 92))	('lead to', 'Reg', (248, 255))	('depletion of the NAD+ stock necessary', 'MPA', (258, 295))	('activity', 'MPA', (234, 242))	('LDH-B', 'Gene', (135, 140))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('LDH', 'Gene', '3939;3945;3948', (230, 233))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('LDH', 'Gene', '3939;3945;3948', (24, 27))	('LDH', 'Gene', '3939;3945;3948', (135, 138))	('LDH-B', 'Gene', '3945', (135, 140))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
32961	23437403	Future efforts should therefore be focused on developing non-toxic and highly specific small molecule inhibitors of the LDH-A subunit, in order to block glycolysis, particularly in those tumours which have absent or decreased expression of the LDH-B subunit, thus, 'cutting-off' a major pathway used by breast and other cancer cells for their energy production.	('LDH-A', 'Gene', (120, 125))	('glycolysis', 'MPA', (153, 163))	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('decreased', 'NegReg', (216, 225))	('block', 'NegReg', (147, 152))	('tumours', 'Disease', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('inhibitors', 'Var', (102, 112))	('LDH-B', 'Gene', '3945', (244, 249))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('LDH-B', 'Gene', (244, 249))	("'cutting-off'", 'NegReg', (265, 278))	('LDH-A', 'Gene', '3939', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('cancer', 'Disease', (320, 326))
32968	25261293	The CBT risk was significantly increased among black (RR 1.21; 95 % CI 1.08-1.36) and Asian/PI (RR 1.16; 95 % CI 1.02-1.31) women compared with white women.	('RR 1', 'Gene', '6240', (96, 100))	('increased', 'PosReg', (31, 40))	('CBT', 'Disease', (4, 7))	('Asian/PI', 'Var', (86, 94))	('women', 'Species', '9606', (150, 155))	('RR 1', 'Gene', (96, 100))	('RR 1', 'Gene', '6240', (54, 58))	('RR 1', 'Gene', (54, 58))	('women', 'Species', '9606', (124, 129))
33013	25261293	Hispanic ethnicity was associated with ipsilateral DCIS (RR 1.33; 95 % CI 1.02-1.72), but not with invasive IBT (RR 1.13; 95 % CI 0.96-1.34).	('IBT', 'Chemical', '-', (108, 111))	('RR 1', 'Gene', (57, 61))	('Hispanic ethnicity', 'Var', (0, 18))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('RR 1', 'Gene', '6240', (113, 117))	('RR 1', 'Gene', '6240', (57, 61))	('RR 1', 'Gene', (113, 117))	('ipsilateral DCIS', 'Disease', (39, 55))
33019	25261293	The multivariable-adjusted CBT risk was significantly increased among black (RR 1.21; 95 % CI 1.08-1.36) and Asian/PI, especially Filipino (Supplement Table 2), women (RR 1.16; 95 % CI 1.02-1.31) compared to their white counterparts.	('RR 1', 'Gene', (77, 81))	('RR 1', 'Gene', '6240', (168, 172))	('CBT', 'Disease', (27, 30))	('women', 'Species', '9606', (161, 166))	('increased', 'PosReg', (54, 63))	('RR 1', 'Gene', (168, 172))	('Asian/PI', 'Var', (109, 117))	('RR 1', 'Gene', '6240', (77, 81))
33022	25261293	In contrast, Asian/PI patients had significantly higher risk for contralateral DCIS (RR 1.59; 95 % CI 1.30-1.95) but not for invasive CBT (RR 0.96; 95 % CI 0.82-1.13) (Table 4).	('RR 1', 'Gene', (85, 89))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('patients', 'Species', '9606', (22, 30))	('Asian/PI', 'Var', (13, 21))	('contralateral DCIS', 'Disease', (65, 83))	('RR 1', 'Gene', '6240', (85, 89))
33037	25261293	In the current study, black race was associated with 46 % increased risk for IBTs and 21 % increased risk for CBTs after adjustment for pathologic factors, age and year of diagnosis of first DCIS, registry, and treatment.	('CBTs', 'Disease', (110, 114))	('black race', 'Var', (22, 32))	('IBTs', 'Chemical', '-', (77, 81))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('IBTs', 'Disease', (77, 81))	('CBTs', 'Chemical', 'MESH:C044169', (110, 114))
33054	25261293	The current study with more racial minority women found that Hispanic ethnicity was associated with significantly increased risk for IBTs but not for CBTs.	('IBTs', 'Chemical', '-', (133, 137))	('women', 'Species', '9606', (44, 49))	('IBTs', 'Disease', (133, 137))	('CBTs', 'Chemical', 'MESH:C044169', (150, 154))	('Hispanic ethnicity', 'Var', (61, 79))
33069	25261293	However, black race was associated with longer waiting time for and lower probabilities of completing radiotherapy following BCS.	('black race', 'Var', (9, 19))	('BCS', 'Gene', '617', (125, 128))	('BCS', 'Gene', (125, 128))	('lower', 'NegReg', (68, 73))
33081	28928852	This article describes detailed multidisciplinary practices including extensive preoperative/intraoperative pathologic/histologic image-guided assessment of margins, offering some patients with small low/intermediate grade DCIS no RT, the use/magnitude of radiation boost tailoring to margin width, and endocrine therapy for ER-positive DCIS.	('DCIS', 'Disease', (223, 227))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('DCIS', 'Phenotype', 'HP:0030075', (337, 341))	('low/intermediate grade', 'Var', (200, 222))	('patients', 'Species', '9606', (180, 188))
33113	28928852	For patients who did not receive RT, those with margins < 2 mm were significantly more likely to develop a LRR than those with margins >= 2 mm (10-year LRR 30.9% vs. 5.4%, respectively; p=0.003; Figure 1b).	('margins < 2 mm', 'Var', (48, 62))	('LRR', 'Disease', (107, 110))	('patients', 'Species', '9606', (4, 12))	('develop', 'PosReg', (97, 104))
33114	28928852	Thus, in our contemporary multidisciplinary practice, for patients with < 2 mm margins receiving adjuvant radiation therapy, there is no detectable significant difference in locoregional recurrence when compared to patients with >= 2mm margins.	('patients', 'Species', '9606', (58, 66))	('locoregional recurrence', 'CPA', (174, 197))	('< 2 mm', 'Var', (72, 78))	('patients', 'Species', '9606', (215, 223))
33168	28928852	Although adherence to treatment was relatively low and similar among both treatment arms (67%), there were significant differences in adverse events, where patients who received anastrozole had more musculoskeletal events including fractures and osteoporosis, while those who received tamoxifen had more vasomotor, gynecological and thromboembolic events.	('patients', 'Species', '9606', (156, 164))	('thromboembolic', 'Disease', 'MESH:D013923', (333, 347))	('musculoskeletal', 'Disease', (199, 214))	('fractures', 'Disease', (232, 241))	('thromboembolic events', 'Phenotype', 'HP:0001907', (333, 354))	('vasomotor', 'MPA', (304, 313))	('anastrozole', 'Var', (178, 189))	('gynecological', 'Disease', (315, 328))	('osteoporosis', 'Disease', 'MESH:D010024', (246, 258))	('osteoporosis', 'Disease', (246, 258))	('fractures', 'Disease', 'MESH:D050723', (232, 241))	('thromboembolic', 'Disease', (333, 347))	('anastrozole', 'Chemical', 'MESH:D000077384', (178, 189))	('tamoxifen', 'Chemical', 'MESH:D013629', (285, 294))	('osteoporosis', 'Phenotype', 'HP:0000939', (246, 258))
33174	28928852	In our updated analysis, approximately 57% of patients with ER-positive DCIS take endocrine therapy following BCS for DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('patients', 'Species', '9606', (46, 54))	('DCIS', 'Disease', (72, 76))	('take', 'Reg', (77, 81))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('ER-positive', 'Var', (60, 71))
33205	26353381	Hence, the variation of the copy number of a (set of) gene(s) can be used as a measure of progression of a cancer cell with respect to the healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variation', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('copy number', 'Var', (28, 39))	('cancer', 'Disease', (107, 113))
33257	26353381	Also in this case, the doubling-loss event can be considered as a possible source of progression of the carcinoma, being located in several internal vertices of corresponding predictions.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Disease', 'MESH:D002277', (104, 113))	('carcinoma', 'Disease', (104, 113))	('doubling-loss', 'Var', (23, 36))
33263	26353381	Specifically, in this dataset progression of the carcinoma seems to be caused by iterated increments of COX2 over time, which seems to be associated with variation in the copy number of CDH1.	('carcinoma', 'Disease', 'MESH:D002277', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('variation', 'Var', (154, 163))	('copy number', 'Var', (171, 182))	('carcinoma', 'Disease', (49, 58))	('caused', 'Reg', (71, 77))	('associated', 'Reg', (138, 148))	('CDH1', 'Gene', (186, 190))	('COX2', 'Gene', (104, 108))	('CDH1', 'Gene', '999', (186, 190))	('COX2', 'Gene', '5743', (104, 108))
33270	26353381	For each random arborescence T, we simulated the progression of tumor cells by randomly choosing on each arc (i, j) of T the type of mutation on vertex j (namely, copy number increment, copy number decrement and pure doubling) and the genes involved in the mutation.	('copy number', 'Var', (186, 197))	('tumor', 'Disease', (64, 69))	('increment', 'PosReg', (175, 184))	('pure', 'MPA', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('copy number', 'Var', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
33271	26353381	If the selected type of mutation is a pure doubling, then the copy numbers of all genes (but TP53) of vertex j are doubled and the copy number of TP53 is increased by 1 unit.	('TP53', 'Gene', '7157', (146, 150))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (146, 150))	('TP53', 'Gene', (93, 97))	('mutation', 'Var', (24, 32))	('copy numbers', 'MPA', (62, 74))
33282	26353381	In particular suggesting that developing effective therapies may require considering both the current spectrum of driver mutations in a tumor and the mutator phenotype by which it is generating diversity.	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('mutations', 'Var', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (136, 141))
33288	26215578	Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival.	('EREG', 'Var', (187, 191))	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (117, 126))	('promotes', 'PosReg', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))
33290	26215578	In comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity.	('FGF', 'Gene', '2258;2247;2258', (201, 204))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (65, 74))	('MCF10DCIS', 'Var', (65, 74))	('EREG', 'Gene', (45, 49))	('EGF', 'Gene', (25, 28))	('MCF10A', 'CellLine', 'CVCL:0598', (95, 101))	('induced', 'PosReg', (54, 61))	('EGF', 'Gene', '1950', (25, 28))	('expression', 'MPA', (128, 138))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('MCF10A', 'CellLine', 'CVCL:0598', (106, 112))	('FGF', 'Gene', (201, 204))
33291	26215578	Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (27, 36))	('MCF10DCIS', 'Var', (27, 36))	('reduced', 'NegReg', (108, 115))	('EREG', 'Protein', (8, 12))	('decreased tumor', 'Disease', 'MESH:D009369', (50, 65))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('decreased tumor', 'Disease', (50, 65))	('cell survival', 'CPA', (116, 129))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))
33292	26215578	Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents.	('cell survival', 'CPA', (68, 81))	('EREG', 'Gene', (54, 58))	('enhanced', 'PosReg', (59, 67))	('MCF10A', 'CellLine', 'CVCL:0598', (26, 32))	('exogenous', 'Var', (44, 53))
33295	26215578	EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples.	('MMP-1', 'Gene', (84, 89))	('DCIS', 'Disease', (20, 24))	('induced', 'Reg', (9, 16))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('lesions', 'Var', (25, 32))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('MMP-1', 'Gene', '4312', (84, 89))	('EREG', 'Disease', (0, 4))
33301	26215578	Aberrant activation of the ErbB family of growth factor receptors and their downstream signaling pathways has been implicated in breast cancer initiation and maintenance.	('implicated', 'Reg', (115, 125))	('activation', 'PosReg', (9, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('Aberrant', 'Var', (0, 8))	('breast cancer initiation', 'Disease', (129, 153))	('ErbB', 'Gene', '1956', (27, 31))	('ErbB', 'Gene', (27, 31))	('breast cancer initiation', 'Disease', 'MESH:D001943', (129, 153))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
33302	26215578	Activation of ErbB receptors in cancer occurs through various mechanisms, including mutation, amplification and regulation of epidermal growth factor (EGF)-family ligands and cross-talk with other signaling pathways.	('amplification', 'Var', (94, 107))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cross-talk', 'Reg', (175, 185))	('EGF', 'Gene', (151, 154))	('regulation', 'MPA', (112, 122))	('epidermal', 'Protein', (126, 135))	('Activation', 'PosReg', (0, 10))	('ErbB', 'Gene', '1956', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('ErbB', 'Gene', (14, 18))	('EGF', 'Gene', '1950', (151, 154))	('mutation', 'Var', (84, 92))
33310	26215578	Furthermore, high levels of MMP-1 expression are associated with poor prognosis and increased risk of bone metastasis in breast cancer patients.	('bone metastasis', 'Disease', (102, 117))	('high levels', 'Var', (13, 24))	('patients', 'Species', '9606', (135, 143))	('expression', 'MPA', (34, 44))	('MMP-1', 'Gene', '4312', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('MMP-1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('bone metastasis', 'Disease', 'MESH:D009362', (102, 117))
33314	26215578	Finally, we demonstrate that loss of EREG expression in transformed breast cancer cells leads to reduced tumor growth in vivo, which is associated with increased tumor cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('increased', 'PosReg', (152, 161))	('tumor', 'Disease', (162, 167))	('EREG', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('breast cancer', 'Disease', (68, 81))	('reduced', 'NegReg', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('loss', 'Var', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
33322	26215578	AREG and HB-EGF were increased approximately 8-fold in the MCF10DCIS cells compared with MCF10A cells (Fig.	('increased', 'PosReg', (21, 30))	('HB-EGF', 'Gene', '1839', (9, 15))	('HB-EGF', 'Gene', (9, 15))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (59, 68))	('AREG', 'Gene', '374', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('MCF10A', 'CellLine', 'CVCL:0598', (89, 95))	('AREG', 'Gene', (0, 4))	('MCF10DCIS', 'Var', (59, 68))
33323	26215578	However, EREG expression levels were found to be increased over 100-fold in MCF10DCIS cells compared with MCF10A cells (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('expression levels', 'MPA', (14, 31))	('EREG', 'Gene', (9, 13))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (76, 85))	('increased', 'PosReg', (49, 58))	('MCF10DCIS', 'Var', (76, 85))	('MCF10A', 'CellLine', 'CVCL:0598', (106, 112))
33324	26215578	1b, a significant increase in EREG was found in conditioned media obtained from MCF10DCIS cells compared with media from MCF10A cells.	('increase', 'PosReg', (18, 26))	('MCF10A', 'CellLine', 'CVCL:0598', (121, 127))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('EREG', 'MPA', (30, 34))	('MCF10DCIS', 'Var', (80, 89))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (80, 89))
33326	26215578	EREG was found to be highest in the MCF10DCIS and SUM225 cells, compared with the other cell lines (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('EREG', 'MPA', (0, 4))	('highest', 'Reg', (21, 28))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (36, 45))	('MCF10DCIS', 'Var', (36, 45))	('SUM225', 'CellLine', 'CVCL:5593', (50, 56))
33333	26215578	Of the 22 ligands examined, two were found to be increased in MCF10DCIS cells more than 2-fold, including FGF-2, which was increased 13-fold (Fig.	('increased', 'PosReg', (123, 132))	('MCF10DCIS', 'Var', (62, 71))	('increased', 'PosReg', (49, 58))	('FGF-2', 'Gene', '2247', (106, 111))	('FGF-2', 'Gene', (106, 111))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (62, 71))
33336	26215578	Based on the finding that EREG expression is significantly enhanced in MCF10DCIS compared with MCF10A cells, further studies were performed to determine the contributions of EREG to MCF10DCIS tumor growth.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (182, 191))	('tumor', 'Disease', (192, 197))	('EREG', 'Gene', (26, 30))	('enhanced', 'PosReg', (59, 67))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (71, 80))	('expression', 'MPA', (31, 41))	('MCF10DCIS', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('MCF10A', 'CellLine', 'CVCL:0598', (95, 101))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
33338	26215578	Effects of EREG knock-down on growth of MCF10DCIS cells were initially evaluated in three-dimensional culture.	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (40, 49))	('EREG', 'Gene', (11, 15))	('knock-down', 'Var', (16, 26))
33341	26215578	To assess the effects of loss of EREG expression on tumor growth, MCF10DCIS cells expressing either non-targeting shRNA or EREG shRNA were implanted subcutaneously into nude mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (66, 75))	('EREG', 'Var', (123, 127))	('nude mice', 'Species', '10090', (169, 178))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
33344	26215578	Despite this reduction in tumor size, the histologic appearance of both control and EREG knockdown tumors was similar (Fig.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('EREG', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('knockdown', 'Var', (89, 98))	('reduction', 'NegReg', (13, 22))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (99, 105))
33348	26215578	Overall, no single morphologic characteristic could reliably differentiate control from EREG knockdown tumors, and the appearance was highly consistent with previously published reports of the MCF10DCIS xenograft tumors.	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('EREG', 'Gene', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (193, 202))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))
33349	26215578	Despite the morphologic similarity based on H&E staining, immunoblot analysis of tumor lysates demonstrated that loss of EREG was associated with decreased phosphorylation of EGFR (Fig.	('that', 'Var', (108, 112))	('EGFR', 'Gene', (175, 179))	('with', 'NegReg', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('EGFR', 'Gene', '1956', (175, 179))	('decreased', 'MPA', (146, 155))	('tumor', 'Disease', (81, 86))
33362	26215578	Treatment of MCF10A and MCF10AT cells with rhEREG led to increased expression of MMP-1 gene expression and protein expression, with a stronger induction in MMP-1 protein observed in the MCF10AT cells (Fig.	('MMP-1', 'Gene', '4312', (81, 86))	('MCF10AT', 'Var', (186, 193))	('MMP-1', 'Gene', (156, 161))	('MMP-1', 'Gene', (81, 86))	('MCF10A', 'CellLine', 'CVCL:0598', (186, 192))	('MCF10A', 'CellLine', 'CVCL:0598', (13, 19))	('protein expression', 'MPA', (107, 125))	('MCF10A', 'CellLine', 'CVCL:0598', (24, 30))	('increased', 'PosReg', (57, 66))	('expression', 'MPA', (67, 77))	('MMP-1', 'Gene', '4312', (156, 161))	('expression', 'MPA', (92, 102))
33368	26215578	Furthermore, MMP-1 knockdown in MCF10A cells abrogated the ability of rhEREG treatment to prevent doxorubicin-induced apoptosis as evidenced by increased levels of caspase-3 cleavage (Fig.	('abrogated', 'NegReg', (45, 54))	('MMP-1', 'Gene', '4312', (13, 18))	('caspase-3', 'Gene', '836', (164, 173))	('knockdown', 'Var', (19, 28))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('MMP-1', 'Gene', (13, 18))	('prevent', 'NegReg', (90, 97))	('MCF10A', 'CellLine', 'CVCL:0598', (32, 38))	('caspase-3', 'Gene', (164, 173))	('doxorubicin-induced', 'MPA', (98, 117))	('increased', 'PosReg', (144, 153))
33371	26215578	Increased gene and protein expression of MMP-1 was found in MCF10DCIS cells compared with MCF10A cells (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (90, 96))	('MMP-1', 'Gene', '4312', (41, 46))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('Increased', 'PosReg', (0, 9))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (60, 69))	('MMP-1', 'Gene', (41, 46))	('MCF10DCIS', 'Var', (60, 69))
33380	26215578	Based on findings in which EREG was found to be highly upregulated in MCF10DCIS cells in comparison with MCF10A cells, the studies described here focus on determining the potential contributions of EREG to early stages of breast tumor formation.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('breast tumor', 'Phenotype', 'HP:0100013', (222, 234))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('MCF10DCIS', 'Var', (70, 79))	('breast tumor', 'Disease', 'MESH:D001943', (222, 234))	('MCF10A', 'CellLine', 'CVCL:0598', (105, 111))	('upregulated', 'PosReg', (55, 66))	('EREG', 'Gene', (27, 31))	('breast tumor', 'Disease', (222, 234))
33384	26215578	Based on the finding that EREG was enhanced in MCF10DCIS cells, initial studies were performed to identify mechanisms driving enhanced EREG expression.	('expression', 'MPA', (140, 150))	('enhanced', 'PosReg', (126, 134))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('enhanced', 'PosReg', (35, 43))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (47, 56))	('EREG', 'CPA', (26, 30))	('MCF10DCIS', 'Var', (47, 56))	('EREG', 'MPA', (135, 139))
33392	26215578	While it is possible that the reduction in tumor volume solely reflects an overall decrease in EGF ligand concentration within the tumor, it is also possible that EREG has distinct effects on tumor growth than the other ligands.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('EGF', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EGF', 'Gene', '1950', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (131, 136))	('decrease', 'NegReg', (83, 91))	('reduction', 'NegReg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (43, 48))	('EREG', 'Var', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
33398	26215578	The results from these studies suggest that early stage tumor cells produce increased levels of EREG, and that exogenous EREG is capable of enhancing survival of epithelial cells even in the presence of serum and additional EGF ligand in the context of 3D culture.	('EREG', 'Gene', (121, 125))	('EGF', 'Gene', '1950', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('exogenous', 'Var', (111, 120))	('levels', 'MPA', (86, 92))	('survival', 'CPA', (150, 158))	('increased', 'PosReg', (76, 85))	('enhancing', 'PosReg', (140, 149))	('tumor', 'Disease', (56, 61))	('EREG', 'MPA', (96, 100))	('EGF', 'Gene', (224, 227))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
33400	26215578	EREG was found to significantly enhance survival of non-transformed epithelial cells, leading to a possible model in which high levels of EREG in the developing tumor microenvironment may enhance tumorigenic properties of surrounding normal epithelium in a paracrine manner.	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('EREG', 'Var', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('enhance', 'PosReg', (32, 39))	('tumor', 'Disease', (161, 166))	('enhance', 'PosReg', (188, 195))
33414	26215578	The following antibodies were used for immunoblotting: phospho-FRS2alpha (3861), GAPDH (2118), beta-tubulin (2146) pEGFR (2234) and cleaved caspase 3 (9661) (Cell Signaling, Danvers, MA).	('GAPDH', 'Gene', (81, 86))	('2118', 'Var', (88, 92))	('caspase 3', 'Protein', (140, 149))	('3861', 'Var', (74, 78))	('FRS2alpha', 'Gene', (63, 72))	('cleaved', 'Var', (132, 139))	('beta-tubulin', 'Protein', (95, 107))	('GAPDH', 'Gene', '2597', (81, 86))	('FRS2alpha', 'Gene', '10818', (63, 72))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('9661', 'Var', (151, 155))
33423	26215578	MCF10DCIS cells expressing non-targeting shRNA or shRNAs specific for EREG were plated into Matrigel in the same media used for the MCF10A cells and allowed to establish for 4 days.	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10A', 'CellLine', 'CVCL:0598', (132, 138))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('shRNAs', 'Gene', (50, 56))	('non-targeting', 'Var', (27, 40))
33433	26215578	FOXN1Nu athymic nude mice (Harlan Laboratories, Indianapolis, IN) were injected subcutaneously with MCF10DCIS expressing non-targeting or EREG shRNA (50,000 cells in 50 mul of 50 % Matrigel).	('non-targeting', 'Var', (121, 134))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (100, 109))	('Harlan Laboratories', 'Disease', 'MESH:D007757', (27, 46))	('nude mice', 'Species', '10090', (16, 25))	('FOXN1', 'Gene', (0, 5))	('MCF10DCIS', 'Gene', (100, 109))	('FOXN1', 'Gene', '15218', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('Harlan Laboratories', 'Disease', (27, 46))
33434	26215578	Subcutaneous injections were performed rather than orthotopic transplantation due to the need for consistent detection of early tumors (100 mm3) prior to shRNA induction by doxycycline.	('100 mm3', 'Var', (136, 143))	('doxycycline', 'Chemical', 'MESH:D004318', (173, 184))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
33436	26215578	Once tumors reached 100 mm3, mice were given 2 g/kg doxycycline in the chow (Harlan Laboratories) to induce EREG knockdown.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('doxycycline', 'Chemical', 'MESH:D004318', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Harlan Laboratories', 'Disease', (77, 96))	('EREG', 'Gene', (108, 112))	('knockdown', 'Var', (113, 122))	('mice', 'Species', '10090', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('Harlan Laboratories', 'Disease', 'MESH:D007757', (77, 96))
33577	31871887	Upgrading BI-RADS in Malignant Masses PA/US resulted in downgrading 34.5% of benign masses (from BI-RADS 4A or higher to BI-RADS 3 or 2, or from BIRADS 3 to BI-RADS 2).	('PA', 'Chemical', '-', (38, 40))	('benign masses', 'CPA', (77, 90))	('BI-RADS', 'Var', (10, 17))	('downgrading', 'NegReg', (56, 67))
33581	31871887	Diagnostic performance PA/US resulted in upgrading 47.0% of malignant masses classified as BI-RADS 3 with US to BI-RADS 4A or higher.	('PA/US', 'Var', (23, 28))	('upgrading', 'PosReg', (41, 50))	('malignant masses', 'CPA', (60, 76))	('PA', 'Chemical', '-', (23, 25))
33587	31871887	The aim of the Dutch study was focused on assessing the ability of PA/US to assist in downgrading benign masses classified as BI-RADS 4A and 4B to BI-RADS 3 or 2.	('PA', 'Chemical', '-', (67, 69))	('benign masses', 'Disease', (98, 111))	('BI-RADS', 'Var', (126, 133))	('downgrading', 'NegReg', (86, 97))
33861	31871887	Due to the spatially variant fluence phi(r) the PA signal at depth is not directly proportional to mua(r) but is dependent on mua(r)phi(r), with phi(r) itself depending on mua (mus and the anisotropy g).	('PA signal', 'MPA', (48, 57))	('phi', 'Var', (37, 40))	('PA', 'Chemical', '-', (48, 50))
34026	28777142	Altered protein products caused by the genetic mutations in cancer cells can function as neoantigens, eliciting an immune response against a perceived "foreign" cell.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('genetic mutations', 'Var', (39, 56))	('protein', 'Protein', (8, 15))	('cancer', 'Disease', (60, 66))	('immune response against a perceived "foreign" cell', 'MPA', (115, 165))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('eliciting', 'Reg', (102, 111))
34067	28777142	Many potentially useful biomarkers such as the Ki67 proliferative index in breast cancer suffer from a plethora of non-comparable methods, which affects the level of evidence that can be obtained and prevents uniform clinical implementation.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('Ki67', 'Var', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('affects', 'Reg', (145, 152))	('plethora', 'Phenotype', 'HP:0001050', (103, 111))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
34089	28777142	In addition, the presence of TILs in post-treatment specimens with residual disease appears to confer a better prognosis than those showing an absence of TILs.	('TIL', 'Gene', (29, 32))	('TIL', 'Gene', (154, 157))	('presence', 'Var', (17, 25))	('TIL', 'Gene', '7096', (154, 157))	('TIL', 'Gene', '7096', (29, 32))
34184	28777142	The tumor types with high average mutation load such as melanoma and non-small cell lung carcinoma, as well as the most highly mutated individual tumors within these types, appear to respond better to immunotherapy, however the mutational load does not necessarily correlate with the expression of immune-related genes in the tumor or the effector T cell infiltrate.	('tumor', 'Disease', (4, 9))	('non-small cell lung carcinoma', 'Disease', (69, 98))	('tumor', 'Disease', (146, 151))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (73, 98))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (69, 98))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumors', 'Disease', (146, 152))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (69, 98))
34238	26520874	On mammography, 14 out of 17 (82%) participants with DCIS and 14 out of 22 (64%) with benign micro-calcifications had heterogeneously dense or dense breast parenchyma.	('DCIS', 'Var', (53, 57))	('breast parenchyma', 'Disease', 'MESH:D010195', (149, 166))	('participants', 'Species', '9606', (35, 47))	('breast parenchyma', 'Disease', (149, 166))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
34268	26520874	We have shown that malignant micro-calcifications due to DCIS show significantly greater enhancement and conspicuity than benign calcifications on CEbCT.	('DCIS', 'Var', (57, 61))	('CEbCT', 'Chemical', '-', (147, 152))	('calcifications on CEbCT', 'Phenotype', 'HP:0002514', (129, 152))	('greater enhancement', 'PosReg', (81, 100))	('conspicuity', 'CPA', (105, 116))	('malignant micro-calcifications', 'CPA', (19, 49))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
34306	19491436	The conductivity at 10 kHz varied by 8.3% about the mean of the cancer tissue (0.145 +- 0.012 S m-1) and by 34.8% about the mean for the fibrocystic samples (0.068 +- 0.024 S m-1).	('fibrocystic', 'Disease', 'MESH:D005348', (137, 148))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('conductivity', 'MPA', (4, 16))	('fibrocystic', 'Disease', (137, 148))	('0.145 +- 0.012', 'Var', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
34363	21466711	The right breast lesion in case 11 showed MLL with DCIS at additional resection, while the left lesion showed MLL with ADH.	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('DCIS', 'Var', (51, 55))	('MLL', 'Gene', (42, 45))	('MLL', 'Gene', '4297', (42, 45))	('MLL', 'Gene', (110, 113))	('MLL', 'Gene', '4297', (110, 113))
34367	21466711	The additional resection performed in case 9 revealed MLL with DCIS.	('MLL', 'Gene', '4297', (54, 57))	('DCIS', 'Var', (63, 67))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('MLL', 'Gene', (54, 57))
34395	28491135	The mutation and neo-antigen load progressively decreased from ICR4 to ICR1 but could not explain immune phenotypic differences.	('ICR4', 'Gene', '3391', (63, 67))	('ICR1', 'Gene', '3388', (71, 75))	('ICR4', 'Gene', (63, 67))	('decreased', 'NegReg', (48, 57))	('mutation', 'Var', (4, 12))	('ICR1', 'Gene', (71, 75))	('neo-antigen load', 'MPA', (17, 33))
34396	28491135	Mutations of TP53 were enriched in the immune favourable phenotype (ICR4).	('TP53', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('ICR4', 'Gene', '3391', (68, 72))	('immune favourable', 'Disease', (39, 56))	('TP53', 'Gene', '7157', (13, 17))	('ICR4', 'Gene', (68, 72))
34397	28491135	Instead, the presence of MAP3K1 and MAP2K4 mutations were closely associated with an immune unfavourable phenotype (ICR1).	('ICR1', 'Gene', '3388', (116, 120))	('associated', 'Reg', (66, 76))	('MAP3K1', 'Gene', (25, 31))	('MAP2K4', 'Gene', '6416', (36, 42))	('MAP2K4', 'Gene', (36, 42))	('ICR1', 'Gene', (116, 120))	('mutations', 'Var', (43, 52))	('immune unfavourable phenotype', 'Disease', (85, 114))	('presence', 'Var', (13, 21))	('MAP3K1', 'Gene', '4214', (25, 31))
34398	28491135	These findings suggest that mutational-driven deregulation of MAPK pathways is linked to the negative regulation of intratumoural immune response in BC.	('mutational-driven deregulation', 'Var', (28, 58))	('linked', 'Reg', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('deregulation', 'Var', (46, 58))	('MAPK pathways', 'Pathway', (62, 75))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))
34402	28491135	Regarding de-escalating and escalating in radiotherapy (RT), as stated by P Poortmans, it is necessary to consider the life expectancy of patients, comorbidities, define the tumour risk (stage, biology) and share decision-making benefits/risks with patients.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (249, 257))	('tumour', 'Disease', (174, 180))	('de-escalating', 'Var', (10, 23))	('patients', 'Species', '9606', (138, 146))	('radiotherapy', 'Disease', (42, 54))
34413	28491135	Many trials have studied the effects of postoperative radiotherapy after breast-conserving surgery in patients with DCIS, and they have shown that radiotherapy halves the risk of ipsilateral events without, however, having any significant effect on breast cancer mortality (SweDCIS, RTOG9804).	('breast cancer', 'Disease', (249, 262))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('patients', 'Species', '9606', (102, 110))	('ipsilateral events', 'MPA', (179, 197))	('halves', 'NegReg', (160, 166))	('radiotherapy', 'Var', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))
34426	28491135	Application of this model allowed the identification of additional tumours with alteration of BRCA1 or BRCA2, which could have selective therapeutic sensitivity to PARP inhibition.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('additional tumours', 'Disease', 'MESH:D009369', (56, 74))	('BRCA2', 'Gene', '675', (103, 108))	('BRCA1', 'Gene', '672', (94, 99))	('PARP', 'Gene', (164, 168))	('additional tumours', 'Disease', (56, 74))	('BRCA1', 'Gene', (94, 99))	('PARP', 'Gene', '142', (164, 168))	('alteration', 'Var', (80, 90))	('BRCA2', 'Gene', (103, 108))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
34429	28491135	An example is represented by Taselisib which has enhanced potency in P13CA mutant models because it uniquely degrades mutant p110a protein, and it continues to be investigated in ongoing clinical trials (Sandpiper); SOLAR-1 is another phase III study that is underway and investigates the role of another P13Kalfa inhibitor, alpelisib.	('degrades', 'NegReg', (109, 117))	('enhanced', 'PosReg', (49, 57))	('alpelisib', 'Chemical', 'MESH:C585539', (325, 334))	('P13K', 'Mutation', 'p.P13K', (305, 309))	('potency', 'MPA', (58, 65))	('Taselisib', 'Chemical', 'MESH:C582924', (29, 38))	('mutant', 'Var', (118, 124))	('mutant', 'Var', (75, 81))	('Sandpiper', 'Species', '320702', (204, 213))	('P13CA', 'Gene', (69, 74))
34432	28491135	LR Yates, based on current evidence, stated that most driver alterations in the primary tumour denote a subclone origin of aggressive clinical behaviour such as those seeding metastatic dissemination or treatment resistance.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('alterations', 'Var', (61, 72))	('treatment resistance', 'CPA', (203, 223))	('seeding', 'Reg', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (123, 152))
34437	28491135	Remarkable recent examples of this include ESR1 mutations that result within the setting of aromatic inhibitor treatment.	('ESR1', 'Gene', (43, 47))	('ESR1', 'Gene', '2099', (43, 47))	('mutations', 'Var', (48, 57))	('result', 'Reg', (63, 69))
34438	28491135	Among all, we can quote mutation of PIK3CA associable with sensitivity to alpha-selective PI3K inhibitors, mutations of AKT1, and ERBB2 associable with sensitivity to AZD5363, and neratinib, and mutations of BRCA2 linked with sensitivity to poly ADP ribose polymerase (PARP) inhibitors.	('mutations', 'Var', (107, 116))	('poly ADP ribose polymerase', 'Gene', (241, 267))	('AKT1', 'Gene', (120, 124))	('PARP', 'Gene', '142', (269, 273))	('ERBB2', 'Gene', '2064', (130, 135))	('ERBB2', 'Gene', (130, 135))	('PIK3CA', 'Gene', '5290', (36, 42))	('BRCA2', 'Gene', (208, 213))	('mutations', 'Var', (195, 204))	('mutation', 'Var', (24, 32))	('AZD5363', 'Chemical', 'MESH:C575618', (167, 174))	('BRCA2', 'Gene', '675', (208, 213))	('PARP', 'Gene', (269, 273))	('PIK3CA', 'Gene', (36, 42))	('AKT1', 'Gene', '207', (120, 124))	('poly ADP ribose polymerase', 'Gene', '142', (241, 267))	('neratinib', 'Chemical', 'MESH:C487932', (180, 189))
34450	28491135	Some tumours present resistance to this approach because of for example, mutations in PIK3CA or low levels of HER-2.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('HER-2', 'Gene', '2064', (110, 115))	('HER-2', 'Gene', (110, 115))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('PIK3CA', 'Gene', (86, 92))	('tumours', 'Disease', (5, 12))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('PIK3CA', 'Gene', '5290', (86, 92))	('mutations', 'Var', (73, 82))
34452	28491135	Regarding this topic, I Krop, discussed mutations in the gene encoding ER (ESR1) which are associated with resistance to AI.	('ESR1', 'Gene', (75, 79))	('ESR1', 'Gene', '2099', (75, 79))	('mutations', 'Var', (40, 49))	('ER', 'Gene', '2099', (71, 73))	('associated', 'Reg', (91, 101))
34456	28491135	BC with mutations in the gene encoding HER-2/ERBB2 may be susceptible to potentiate HER-2-kinase inhibitors such as neratinib.	('HER-2', 'Gene', '2064', (39, 44))	('HER-2', 'Gene', (84, 89))	('HER-2', 'Gene', '2064', (84, 89))	('HER-2', 'Gene', (39, 44))	('neratinib', 'Chemical', 'MESH:C487932', (116, 125))	('mutations', 'Var', (8, 17))	('ERBB2', 'Gene', '2064', (45, 50))	('ERBB2', 'Gene', (45, 50))	('potentiate', 'MPA', (73, 83))
34458	28491135	Genomic analyses have revealed that TNBC has genomic instability with a loss of function in gatekeeper genes and the amplification of oncogenes resulting in tumour growth, adaption to treatment, and drug resistance.	('tumour growth', 'Disease', (157, 170))	('adaption to treatment', 'CPA', (172, 193))	('drug resistance', 'CPA', (199, 214))	('drug resistance', 'Phenotype', 'HP:0020174', (199, 214))	('tumour growth', 'Disease', 'MESH:D006130', (157, 170))	('gatekeeper', 'Species', '111938', (92, 102))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('loss of function', 'NegReg', (72, 88))	('TNBC', 'Gene', (36, 40))	('amplification', 'Var', (117, 130))
34502	28491135	Z1031A, ALTERNATE and P024 seem to show the advantages of using AI in neo-adjuvant setting as presented by M Ellis.	('ER', 'Gene', '2099', (11, 13))	('Z1031A', 'Var', (0, 6))	('Z1031A', 'SUBSTITUTION', 'None', (0, 6))	('P024', 'Var', (22, 26))
34511	28491135	Individual trials and meta-analysis suggest that AI treatment, as either initial or sequential therapy, reduces recurrence risk compared to five years of TAM alone.	('AI treatment', 'Var', (49, 61))	('recurrence risk', 'MPA', (112, 127))	('reduces', 'NegReg', (104, 111))	('TAM', 'Chemical', 'MESH:D013629', (154, 157))
34532	28491135	In FinHER, for every 10% increase in stromal tumour infiltrating lymphocytes in the TNBC subset, there was a nearly 25% improvement in DFS; and in CALGB 40603 pCR was highly associated with activated immune gene signatures.	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('activated immune gene signatures', 'MPA', (190, 222))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('40603 pCR', 'Var', (153, 162))	('improvement', 'PosReg', (120, 131))	('increase', 'PosReg', (25, 33))	('DFS', 'MPA', (135, 138))	('tumour', 'Disease', (45, 51))	('ER', 'Gene', '2099', (7, 9))
34539	28491135	First of all, bisphosphonates prevent bone reabsorption, secondly they prevent reduction in bone mineral density and the risk of fractures resulting from oestrogen (or androgen) deprivation in cancer therapies, and lastly they reduce bone recurrence and improve survival in postmenopausal women with non-metastatic breast cancer (no significant effects on non-breast cancer deaths, contralateral breast cancer, or loco-regional recurrence).	('women', 'Species', '9606', (289, 294))	('bone mineral density', 'CPA', (92, 112))	('deprivation', 'NegReg', (178, 189))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('cancer', 'Disease', (193, 199))	('bone reabsorption', 'CPA', (38, 55))	('survival', 'CPA', (262, 270))	('improve', 'PosReg', (254, 261))	('cancer', 'Disease', (367, 373))	('breast cancer', 'Disease', 'MESH:D001943', (396, 409))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (396, 409))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('fractures', 'Disease', (129, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('fractures', 'Disease', 'MESH:D050723', (129, 138))	('reduce', 'NegReg', (227, 233))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (403, 409))	('breast cancer', 'Disease', (315, 328))	('bone recurrence', 'CPA', (234, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (360, 373))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('non-breast cancer deaths, contralateral breast cancer', 'Disease', 'MESH:D001943', (356, 409))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('bisphosphonates', 'Chemical', 'MESH:D004164', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('bone reabsorption', 'Phenotype', 'HP:0002797', (38, 55))	('bisphosphonates', 'Var', (14, 29))	('reduction', 'NegReg', (79, 88))	('breast cancer', 'Disease', 'MESH:D001943', (360, 373))	('breast cancer', 'Disease', (360, 373))	('breast cancer', 'Phenotype', 'HP:0003002', (396, 409))	('cancer', 'Disease', 'MESH:D009369', (403, 409))
34635	18780960	Analysis of the histologic slides confirmed that many stages of the development of mammary carcinoma were present in the specimens, including DCIS, small invasive tumors (<3 mm) and large tumors (<3 mm).	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (83, 100))	('invasive tumors', 'Disease', (154, 169))	('<3', 'Var', (171, 173))	('DCIS', 'Disease', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('invasive tumors', 'Disease', 'MESH:D009369', (154, 169))	('carcinoma', 'Disease', (91, 100))
34706	16361123	The most common gene mutations are BRCA1 and BRCA2.	('BRCA2', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (45, 50))	('common', 'Reg', (9, 15))	('BRCA1', 'Gene', '672', (35, 40))	('BRCA1', 'Gene', (35, 40))	('mutations', 'Var', (21, 30))
34730	16361123	The most common gene mutations are the BRCA 1 and BRCA 2.	('BRCA 1', 'Gene', (39, 45))	('BRCA 1', 'Gene', '672', (39, 45))	('BRCA 2', 'Gene', '675', (50, 56))	('BRCA 2', 'Gene', (50, 56))	('mutations', 'Var', (21, 30))
34731	16361123	In 1990, Hall and co-workers identified chromosome 17 q 21 as the location of a susceptibility gene for early onset breast cancer, now known as the BRCA 1 gene mutation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('mutation', 'Var', (160, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('BRCA 1', 'Gene', (148, 154))	('BRCA 1', 'Gene', '672', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
34732	16361123	Shortly after that Narod described a linkage between the genetic marker D17 S 74 on 17 q 21 and ovarian cancer.	('D17 S 74', 'Var', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('linkage', 'Interaction', (37, 44))	('D17 S', 'Mutation', 'p.D17S', (72, 77))	('ovarian cancer', 'Disease', (96, 110))
34734	16361123	Mutations in the BRCA 1 are most commonly seen in Russia, followed by Israel and Italy.	('BRCA 1', 'Gene', '672', (17, 23))	('seen', 'Reg', (42, 46))	('Russia', 'Disease', (50, 56))	('Mutations', 'Var', (0, 9))	('BRCA 1', 'Gene', (17, 23))
34735	16361123	Women who are carriers of the BRCA 1 gene mutation have a lifetime risk (LTR) for developing breast cancer of approximately 80%.	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('mutation', 'Var', (42, 50))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('BRCA 1', 'Gene', '672', (30, 36))	('BRCA 1', 'Gene', (30, 36))	('carriers', 'Reg', (14, 22))
34740	16361123	Approximately 35% of all inherited breast cancers are caused by the BRCA 2 mutation, first identified by Wooster et al..	('BRCA 2', 'Gene', '675', (68, 74))	('BRCA 2', 'Gene', (68, 74))	('caused by', 'Reg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (35, 49))	('mutation', 'Var', (75, 83))	('breast cancers', 'Disease', 'MESH:D001943', (35, 49))	('breast cancers', 'Disease', (35, 49))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
34741	16361123	They also described a linkage between BRCA 2 mutation and male breast cancer.	('BRCA 2', 'Gene', '675', (38, 44))	('male breast cancer', 'Disease', 'MESH:D018567', (58, 76))	('BRCA 2', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('male breast cancer', 'Disease', (58, 76))	('linkage', 'Interaction', (22, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('mutation', 'Var', (45, 53))
34746	16361123	The BRCA 2 mutation is associated with a 6% LTR of male breast cancer, which means a 100-fold increase over the general male population.	('male breast cancer', 'Disease', 'MESH:D018567', (51, 69))	('BRCA 2', 'Gene', '675', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRCA 2', 'Gene', (4, 10))	('male breast cancer', 'Disease', (51, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('mutation', 'Var', (11, 19))
34748	16361123	For both the BRCA 1 and BRCA 2 mutation carriers, the LTR for a contralateral breast cancer is about 65%.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('BRCA 2', 'Gene', '675', (24, 30))	('BRCA 2', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('BRCA 1', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('BRCA 1', 'Gene', '672', (13, 19))
34800	16361123	However, in the group of carriers of BRCA 1/2 the incidence of malignancy was 26.5 per 1000 women.	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('women', 'Species', '9606', (92, 97))	('malignancy', 'Disease', (63, 73))	('BRCA 1', 'Gene', (37, 43))	('BRCA 1', 'Gene', '672', (37, 43))	('carriers', 'Var', (25, 33))
34804	16361123	The negative node status was also better in the MRISK group than in both control groups with 21.4% compared to 52.4 and 56.4%, respectively.	('MRISK', 'Chemical', '-', (48, 53))	('better', 'PosReg', (34, 40))	('MRISK', 'Var', (48, 53))	('negative node status', 'CPA', (4, 24))
34856	31156298	(2) Relative contraindications: 1) Pregnant or breast-feeding; 2) Severe heart, liver, or kidney dysfunction; allergy to iodine-based contrast materials; 4) Unable to lie flat for at least 15 min; incontinence; claustrophobia; 5) Increased intracranial pressure due to brain metastases.	('metastases', 'Disease', (275, 285))	('intracranial pressure', 'MPA', (240, 261))	('Increased intracranial pressure', 'Phenotype', 'HP:0002516', (230, 261))	('claustrophobia', 'Disease', 'MESH:D010698', (211, 225))	('kidney dysfunction', 'Phenotype', 'HP:0000083', (90, 108))	('iodine', 'Chemical', 'MESH:D007455', (121, 127))	('allergy to iodine-based contrast', 'Phenotype', 'HP:0012394', (110, 142))	('allergy', 'Disease', 'MESH:D004342', (110, 117))	('Increased', 'PosReg', (230, 239))	('kidney dysfunction', 'Disease', 'MESH:D007674', (90, 108))	('claustrophobia', 'Phenotype', 'HP:0025253', (211, 225))	('incontinence', 'Disease', (197, 209))	('claustrophobia', 'Disease', (211, 225))	('allergy', 'Disease', (110, 117))	('incontinence', 'Disease', 'MESH:D014549', (197, 209))	('allergy', 'Phenotype', 'HP:0012393', (110, 117))	('metastases', 'Disease', 'MESH:D009362', (275, 285))	('kidney dysfunction', 'Disease', (90, 108))	('Unable', 'Var', (157, 163))	('heart', 'Disease', (73, 78))	('liver', 'Disease', (80, 85))
34932	31156298	HER-2 positivity is defined by more than 10% of cells showing strong membrane staining (3+), and/or in situ hybridization detects HER-2 gene amplification (single copy HER-2 gene >6 or HER-2/CEP17 ratio >2.0).	('single copy', 'Var', (156, 167))	('HER-2', 'Gene', '2064', (130, 135))	('HER-2', 'Gene', (130, 135))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('HER-2', 'Gene', '2064', (168, 173))	('HER-2', 'Gene', (185, 190))	('HER-2', 'Gene', '2064', (185, 190))	('HER-2', 'Gene', (168, 173))
34952	31156298	(2) DCIS DCIS is believed to be the precursor to invasive ductal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('invasive ductal carcinoma', 'Disease', (49, 74))	('DCIS', 'Var', (4, 8))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (58, 74))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (49, 74))
35017	31156298	If not trial are eligible, patients over 50 years with unifocal T1N0 invasive ducal carcinomas, ER positive, no lymphovascular invasion and adequate negative surgical margins may consider APBI.	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('carcinomas', 'Disease', 'MESH:D002277', (84, 94))	('patients', 'Species', '9606', (27, 35))	('carcinomas', 'Disease', (84, 94))	('T1N0', 'Var', (64, 68))
35018	31156298	Patients with small (less than 2 cm) low-grade DCIS and adequate negative surgical margins may also consider APBI.	('DCIS', 'Disease', (47, 51))	('APBI', 'Disease', (109, 113))	('Patients', 'Species', '9606', (0, 8))	('low-grade', 'Var', (37, 46))
35109	31156298	However, for patients with high-risk factors (hormone receptor negative, high-grade, high Ki-67), trastuzumab may be considered.	('trastuzumab', 'Chemical', 'MESH:D000068878', (98, 109))	('patients', 'Species', '9606', (13, 21))	('high-grade', 'Var', (73, 83))	('Ki-67', 'Gene', (90, 95))	('hormone receptor', 'Gene', (46, 62))	('hormone receptor', 'Gene', '3164', (46, 62))
35190	29898744	Using a 4T1.2 syngeneic mouse model of breast cancer, we found that mice bearing 4T1.2-shOSM tumors with knocked down tumor expression of OSM had reduced CTCs, decreased lung metastatic burden, and increased survival compared with mice bearing control tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('mouse', 'Species', '10090', (24, 29))	('OSM', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('reduced', 'NegReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('decreased', 'NegReg', (160, 169))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', (252, 257))	('knocked down', 'Var', (105, 117))	('breast cancer', 'Disease', (39, 52))	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('OSM tumors', 'Disease', (89, 99))	('hOSM', 'Gene', '5008', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('CTCs', 'MPA', (154, 158))	('tumors', 'Disease', (252, 258))	('OSM tumors', 'Disease', 'MESH:D009369', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mice', 'Species', '10090', (231, 235))	('tumors', 'Disease', (93, 99))	('hOSM', 'Gene', (88, 92))	('lung metastatic burden', 'CPA', (170, 192))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Disease', (93, 98))	('increased', 'PosReg', (198, 207))	('tumor', 'Disease', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('survival', 'CPA', (208, 216))	('decreased lung', 'Phenotype', 'HP:0002089', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
35194	29898744	Therefore, early therapeutic inhibition of OSM in patients with breast cancer may prevent breast cancer metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('prevent', 'NegReg', (82, 89))	('patients', 'Species', '9606', (50, 58))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (90, 114))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer metastasis', 'Disease', (90, 114))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('inhibition', 'Var', (29, 39))	('breast cancer', 'Disease', (64, 77))
35237	29898744	The lysates were then run on a PathScan  Phospho-Stat3 (Tyr705) Sandwich ELISA in accordance with the manufacturer's instructions (catalogue number 7146; Cell Signaling Technology).	('Tyr705', 'Chemical', '-', (56, 62))	('Stat3', 'Gene', '20848', (49, 54))	('Tyr705', 'Var', (56, 62))	('Stat3', 'Gene', (49, 54))
35291	29898744	Although there is some indication that the expression of OSM is greater in ER+ and HER2+ breast cancer tissue samples, cell lines representing these subtypes have poor tumorigenic and metastatic capacity in vivo.	('poor', 'NegReg', (163, 167))	('ER+', 'Disease', (75, 78))	('tumor', 'Disease', (168, 173))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('HER2+', 'Var', (83, 88))	('OSM', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('expression', 'MPA', (43, 53))	('greater', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
35333	29898744	In animals that received rhOSM injections, there was a fourfold increase in the number of CTCs per 100 mul of mouse blood compared with animals that did not receive OSM (Fig.	('mouse', 'Species', '10090', (110, 115))	('CTCs', 'CPA', (90, 94))	('increase', 'PosReg', (64, 72))	('injections', 'Var', (31, 41))	('hOSM', 'Gene', '5008', (26, 30))	('hOSM', 'Gene', (26, 30))
35335	29898744	To use an immunocompetent mouse model, we employed two highly metastatic 4T1.2 mouse mammary tumor cell lines exhibiting knockdown expression of OSM in a syngeneic, orthotopic model of breast cancer.	('knockdown', 'Var', (121, 130))	('mouse', 'Species', '10090', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('tumor', 'Disease', (93, 98))	('breast cancer', 'Disease', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('mouse', 'Species', '10090', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
35356	29898744	There was no statistical difference in the survival time between mice injected intracardially with 4T1.2-shLacZ versus 4T1.2-shOSM2 cells (Fig.	('4T1.2-shLacZ', 'Var', (99, 111))	('hOSM', 'Gene', '5008', (126, 130))	('hOSM', 'Gene', (126, 130))	('mice', 'Species', '10090', (65, 69))
35359	29898744	To determine if knocking out OSM in the whole organism affects CTC numbers in the 4T1.2 mouse model, wild-type and OSM-KO BALB/c mice were orthotopically injected with either 4T1.2-shLacZ or 4T1.2-shOSM2 cells.	('knocking out', 'Var', (16, 28))	('hOSM', 'Gene', '5008', (198, 202))	('OSM', 'Gene', (29, 32))	('CTC', 'MPA', (63, 66))	('mouse', 'Species', '10090', (88, 93))	('hOSM', 'Gene', (198, 202))	('mice', 'Species', '10090', (129, 133))
35377	29898744	Despite the differences between the systems used in our study, our results were consistent in that suppression of OSM reduced metastasis in BALB/c mice and injection of recombinant hOSM or TET-induced hOSM expression in MDATO/OSM cells increased human breast tumor metastasis in athymic mice.	('hOSM', 'Gene', (181, 185))	('mice', 'Species', '10090', (147, 151))	('hOSM', 'Gene', '5008', (201, 205))	('OSM', 'Gene', (114, 117))	('breast tumor', 'Phenotype', 'HP:0100013', (252, 264))	('reduced', 'NegReg', (118, 125))	('suppression', 'Var', (99, 110))	('breast tumor metastasis', 'Disease', 'MESH:D009362', (252, 275))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('hOSM', 'Gene', (201, 205))	('metastasis', 'CPA', (126, 136))	('human', 'Species', '9606', (246, 251))	('breast tumor metastasis', 'Disease', (252, 275))	('increased', 'PosReg', (236, 245))	('hOSM', 'Gene', '5008', (181, 185))	('mice', 'Species', '10090', (287, 291))	('TET', 'Chemical', 'MESH:D013752', (189, 192))
35385	29898744	Interestingly, TET has been shown to actually reduce tumor cell growth and aggressiveness, but this effect was not seen in our studies.	('reduce', 'NegReg', (46, 52))	('aggressiveness', 'Phenotype', 'HP:0000718', (75, 89))	('TET', 'Chemical', 'MESH:D013752', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('aggressiveness', 'Disease', 'MESH:D001523', (75, 89))	('TET', 'Var', (15, 18))	('aggressiveness', 'Disease', (75, 89))
35396	29898744	Increased CTC numbers have been linked clinically to enhanced metastatic burden in patients and a reduced 5-year survival rate.	('Increased CTC', 'Phenotype', 'HP:0003236', (0, 13))	('5-year survival rate', 'CPA', (106, 126))	('reduced', 'NegReg', (98, 105))	('patients', 'Species', '9606', (83, 91))	('CTC numbers', 'Var', (10, 21))	('metastatic burden', 'CPA', (62, 79))	('enhanced', 'PosReg', (53, 61))
35417	29898744	Specifically, OSM increases tumor cell migration, detachment, and invasion, supporting the idea that OSM operates in the preintravasation steps of metastasis.	('detachment', 'CPA', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('increases tumor', 'Disease', (18, 33))	('invasion', 'CPA', (66, 74))	('OSM', 'Var', (14, 17))	('increases tumor', 'Disease', 'MESH:D009369', (18, 33))
35418	29898744	Inhibition of OSM and/or OSMR has demonstrated antitumor effects and has recently been receiving increased attention as a possible cancer therapy.	('cancer', 'Disease', (131, 137))	('OSM', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Inhibition', 'Var', (0, 10))	('OSMR', 'Gene', (25, 29))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
35460	28371110	The differences in the percentages of ER and HER2 positivity between non-HNG and HNG groups were statistically significant (p<=0.001).	('HER2', 'Gene', (45, 49))	('ER', 'Gene', '2099', (46, 48))	('HER2', 'Gene', '2064', (45, 49))	('positivity', 'Var', (50, 60))	('ER', 'Gene', '2099', (38, 40))
35464	28371110	In total, 17 of 57 significant metrics were identified in the heterogeneity analysis of HER2 positive versus HER2 negative DCIS (Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('HER2', 'Gene', (109, 113))	('HER2', 'Gene', (88, 92))	('HER2', 'Gene', '2064', (109, 113))	('HER2', 'Gene', '2064', (88, 92))	('positive', 'Var', (93, 101))
35476	28371110	Four metrics analyzing signal intensity values - minimal, maximum, mean, and median intensity - showed an average lower pixel intensity in HER2 positive DCIS compared to HER2 negative disease.	('HER2', 'Gene', (170, 174))	('HER2', 'Gene', '2064', (170, 174))	('HER2', 'Gene', (139, 143))	('positive', 'Var', (144, 152))	('HER2', 'Gene', '2064', (139, 143))	('lower', 'NegReg', (114, 119))	('pixel intensity', 'MPA', (120, 135))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))
35478	28371110	Positive association of HER2 amplification with periductal neovascularization has also been reported.	('periductal neovascularization', 'Disease', (48, 77))	('HER2', 'Gene', '2064', (24, 28))	('amplification', 'Var', (29, 42))	('HER2', 'Gene', (24, 28))
35481	28371110	HER2 amplification is strongly associated with HNG, and as mentioned above, HNG DCIS is independently associated with increased recurrence and progression to invasive disease.	('associated', 'Reg', (102, 112))	('invasive disease', 'Disease', (158, 174))	('amplification', 'Var', (5, 18))	('associated', 'Reg', (31, 41))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('HER2', 'Gene', (0, 4))	('invasive disease', 'Disease', 'MESH:D009362', (158, 174))	('HNG', 'Disease', (47, 50))	('HER2', 'Gene', '2064', (0, 4))	('HNG', 'Gene', (76, 79))
35482	28371110	Two thirds of the imaging biomarkers that correlated with HER2 amplification were identified on the first post-contrast or subtracted first post-contrast sequences.	('HER2', 'Gene', (58, 62))	('amplification', 'Var', (63, 76))	('HER2', 'Gene', '2064', (58, 62))
35558	26291517	Therefore, patients with MRI lesions are at baseline higher risk for breast cancer than patients with mammographic lesions.	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('patients', 'Species', '9606', (88, 96))	('MRI lesions', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('patients', 'Species', '9606', (11, 19))
35583	25146004	DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.	('DNA', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('alterations', 'Var', (16, 27))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('methylation alterations', 'Var', (4, 27))
35587	25146004	In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations.	('gene expression', 'MPA', (46, 61))	('associated', 'Reg', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('DNA', 'Var', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
35590	25146004	Epigenetic marks (and DNA methylation in particular) are known to be deregulated in cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Epigenetic marks', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
35591	25146004	DNA methylation patterns are also associated with histopathological parameters such as hormone receptor status, TP53 mutation status, histologic grade, stage, and survival time.	('associated', 'Reg', (34, 44))	('mutation status', 'Var', (117, 132))	('TP53', 'Gene', '7157', (112, 116))	('methylation patterns', 'Var', (4, 24))	('TP53', 'Gene', (112, 116))
35597	25146004	Epigenetic studies of breast tissue report aberrant methylation levels already present in benign neoplastic breast lesions such as columnar cell lesions and ductal hyperplasia.	('ductal hyperplasia', 'Disease', (157, 175))	('neoplastic breast lesions', 'Phenotype', 'HP:0100013', (97, 122))	('benign neoplastic breast lesions', 'Disease', 'MESH:D001941', (90, 122))	('methylation levels', 'MPA', (52, 70))	('columnar cell lesions', 'Disease', (131, 152))	('benign neoplastic breast lesions', 'Disease', (90, 122))	('aberrant', 'Var', (43, 51))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (157, 175))
35598	25146004	Studies of benign or premalignant tumors from a variety of organs have revealed that some of these lesions have epigenetic characteristics that separate them both from normal tissue and from the malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('epigenetic', 'Var', (112, 122))	('premalignant tumors', 'Disease', 'MESH:D009369', (21, 40))	('malignant tumors', 'Disease', (195, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('malignant tumors', 'Disease', 'MESH:D018198', (195, 211))	('premalignant tumors', 'Disease', (21, 40))	('malignant tumors', 'Disease', 'MESH:D018198', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
35600	25146004	Taken together, these data suggest that epigenetic changes occur early in cancer development and as such have great potential as biomarkers in addition to increase our biological understanding of progression of cancer.	('increase', 'PosReg', (155, 163))	('epigenetic changes', 'Var', (40, 58))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
35617	25146004	A high degree of CpG methylation deregulation during neoplastic transformation may have important implications for a better understanding of breast cancer progression.	('methylation deregulation', 'Var', (21, 45))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('CpG', 'Protein', (17, 20))	('breast cancer', 'Disease', (141, 154))	('implications', 'Reg', (98, 110))	('deregulation', 'Var', (33, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
35630	25146004	Multivariable Cox proportional hazard models were calculated for the patients in the training set (n = 176) as well as patients in the TCGA validation (n = 583) adjusting for estrogen receptor (ER) status, TP53 mutation status (only training set), T status, and lymph node status.	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('estrogen receptor', 'Gene', (175, 192))	('estrogen receptor', 'Gene', '2099', (175, 192))	('patients', 'Species', '9606', (119, 127))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('patients', 'Species', '9606', (69, 77))	('ER', 'Gene', '2099', (194, 196))	('mutation', 'Var', (211, 219))
35645	25146004	Our observation that extensive epigenetic alterations occur early in cancer progression has been reported for other cancer types, including colorectal cancer.	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('epigenetic alterations', 'Var', (31, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('cancer', 'Disease', (69, 75))
35646	25146004	For example, studies using the HumanMethylation450 assay reported that precancerous adenomas demonstrate heterogeneity similar to invasive tumors, and that aberrant DNA methylation occurs early in colorectal cancer formation.	('heterogeneity', 'MPA', (105, 118))	('precancerous adenomas', 'Disease', 'MESH:D011230', (71, 92))	('colorectal cancer', 'Disease', (197, 214))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('invasive tumors', 'Disease', (130, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('precancerous adenomas', 'Disease', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('aberrant', 'Var', (156, 164))	('invasive tumors', 'Disease', 'MESH:D009369', (130, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
35649	25146004	Future studies are needed to define the mechanistic effects that DNA methylation and other epigenetic marks may have on early development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DNA methylation', 'Var', (65, 80))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
35653	25146004	Similar findings have been reported in chronic lymphocytic leukemia and support that promoter hypermethylation is an important mechanism for gene silencing, while DNA methylation elsewhere may have more complex functions that are yet to be fully understood.	('chronic lymphocytic leukemia', 'Disease', (39, 67))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('promoter hypermethylation', 'Var', (85, 110))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (39, 67))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (39, 67))	('silencing', 'NegReg', (146, 155))
35663	25146004	In the present study, high methylation levels of CpGs in TBX5 were associated with lower expression levels of TBX5 and adverse prognosis.	('high methylation levels', 'MPA', (22, 45))	('TBX5', 'Gene', '6910', (57, 61))	('lower', 'NegReg', (83, 88))	('TBX5', 'Gene', (57, 61))	('TBX5', 'Gene', '6910', (110, 114))	('TBX5', 'Gene', (110, 114))	('expression levels', 'MPA', (89, 106))	('CpGs', 'Var', (49, 53))
35666	25146004	Some genes in the survival signature have also been associated with functions related to motility and invasion: EPN3 over-expression has been shown to promote cancer cell invasion, MACF1 has been shown to be involved in cell mobility and steering by interactions with HER2, and CSNK1G2 is thought to modulate the activity of metastasis-associated MTA1 while itself a target of ER.	('EPN3', 'Gene', (112, 116))	('cell mobility', 'CPA', (220, 233))	('MACF1', 'Gene', '23499', (181, 186))	('involved', 'Reg', (208, 216))	('MTA1', 'Gene', (347, 351))	('cancer', 'Disease', (159, 165))	('MTA1', 'Gene', '9112', (347, 351))	('ER', 'Gene', '2099', (269, 271))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MACF1', 'Gene', (181, 186))	('promote', 'PosReg', (151, 158))	('metastasis-associated', 'Disease', (325, 346))	('HER2', 'Gene', '2064', (268, 272))	('over-expression', 'Var', (117, 132))	('CSNK1G2', 'Gene', (278, 285))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('ER', 'Gene', '2099', (377, 379))	('CSNK1G2', 'Gene', '1455', (278, 285))	('activity', 'MPA', (313, 321))	('interactions', 'Interaction', (250, 262))	('HER2', 'Gene', (268, 272))	('EPN3', 'Gene', '55040', (112, 116))	('modulate', 'Reg', (300, 308))
35693	31666931	T-helper 1-type cytokines induce apoptosis and loss of HER-family oncodriver expression in murine and human breast cancer cells A recent neoadjuvant vaccine trial for early breast cancer induced strong Th1 immunity against the HER-2 oncodriver, complete pathologic responses in 18% of subjects, and for many individuals, dramatically reduced HER-2 expression on residual disease.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('HER-family oncodriver', 'Gene', (55, 76))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('reduced', 'NegReg', (334, 341))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('HER-2', 'Protein', (342, 347))	('murine', 'Species', '10090', (91, 97))	('Th1 immunity', 'CPA', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('loss', 'Var', (47, 51))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('expression', 'MPA', (348, 358))	('human', 'Species', '9606', (102, 107))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (173, 186))
35721	31666931	Indeed, a recent manuscript showed that the paired combination of IFN-gamma and TNF-alpha could induce a state of permanent growth arrest in some murine and human cancer cells consistent with senescence.	('murine', 'Species', '10090', (146, 152))	('growth arrest', 'CPA', (124, 137))	('growth arrest', 'Phenotype', 'HP:0001510', (124, 137))	('IFN-gamma', 'Gene', (66, 75))	('human', 'Species', '9606', (157, 162))	('combination', 'Var', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TNF-alpha', 'Gene', (80, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
35722	31666931	We therefore hypothesized that the combination of IFN-gamma and TNF-alpha could replicate, in vitro, the observed anti-breast tumor effects of DC1 vaccination, including induced cell death with associated loss of HER-2 expression.	('breast tumor', 'Phenotype', 'HP:0100013', (119, 131))	('expression', 'MPA', (219, 229))	('loss', 'NegReg', (205, 209))	('cell death', 'CPA', (178, 188))	('breast tumor', 'Disease', 'MESH:D061325', (119, 131))	('DC1', 'Gene', (143, 146))	('HER-2', 'Protein', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast tumor', 'Disease', (119, 131))	('vaccination', 'Var', (147, 158))
35723	31666931	We show in the present studies that the combination of these cytokines can indeed induce in a number of HER family-expressing murine and human breast cancer lines apoptosis, as well as a strong suppression of HER expression, both of which are associated with the activation of caspase-3.	('apoptosis', 'CPA', (163, 172))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('induce', 'Reg', (82, 88))	('human', 'Species', '9606', (137, 142))	('expression', 'MPA', (213, 223))	('HER', 'Protein', (209, 212))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('murine', 'Species', '10090', (126, 132))	('suppression', 'NegReg', (194, 205))	('combination', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
35732	31666931	It was evident via histogram analysis that the incorporation of labeled nucleotide was increased for cytokine-treated TUBO cells (dark histogram traces) compared with untreated cells (light histogram traces).	('increased', 'PosReg', (87, 96))	('cytokine-treated', 'Var', (101, 117))	('rat', 'Species', '10116', (54, 57))	('incorporation of labeled nucleotide', 'MPA', (47, 82))
35738	31666931	After 5 hours, cells were harvested, extracted, proteins separated via SDS-PAGE and analyzed via Western Blot for expression of pro-caspase 3 (32kDa form), activated caspase3(17kDa form) and beta-actin (loading control).	('activated', 'PosReg', (156, 165))	('pro-caspase 3', 'Gene', (128, 141))	('beta-actin', 'Gene', '728378', (191, 201))	('caspase3', 'Gene', (166, 174))	('beta-actin', 'Gene', (191, 201))	('pro-caspase 3', 'Gene', '836', (128, 141))	('SDS', 'Chemical', 'MESH:C032259', (71, 74))	('rat', 'Species', '10116', (61, 64))	('caspase3', 'Gene', '836', (166, 174))	('32kDa', 'Var', (143, 148))
35741	31666931	We demonstrated in the previous experiments that the combination of IFN-gamma and TNF-alpha was capable of inducing apoptotic cell death in rHER-2pos cell lines, confirming the first part of our hypothesis that soluble factors secreted by Th1 cells could account for the clinical effects of DC1 vaccination.	('inducing', 'PosReg', (107, 115))	('apoptotic cell death', 'CPA', (116, 136))	('combination', 'Var', (53, 64))	('TNF-alpha', 'Gene', (82, 91))	('rat', 'Species', '10116', (10, 13))
35759	31666931	Interestingly, PAC-1 also induced loss of HER-2 expression in TUBO and SKBR3 cells comparable to that caused by Th1 cytokine exposure, and also elicited a similar loss of HER-3 in MDA-MB-468 cells (Figure 7A lower panels), suggesting caspase 3 activation precedes HER loss.	('caspase 3', 'Gene', '836', (234, 243))	('loss', 'NegReg', (163, 167))	('expression', 'MPA', (48, 58))	('HER-2', 'Protein', (42, 47))	('PAC', 'Phenotype', 'HP:0006699', (15, 18))	('HER-3', 'Protein', (171, 176))	('loss', 'NegReg', (34, 38))	('PAC-1', 'Var', (15, 20))	('caspase 3', 'Gene', (234, 243))
35767	31666931	Interestingly, this immunity is diminished in patients with early HER-2pos breast cancer (DCIS), and further depressed, sometimes to the point of non-detection, in patients with more advanced invasive HER-2pos tumors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (46, 54))	('breast cancer', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('patients', 'Species', '9606', (164, 172))	('depressed', 'NegReg', (109, 118))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('diminished', 'NegReg', (32, 42))	('HER-2pos', 'Var', (66, 74))
35780	31666931	As normal cells transform into cancerous ones, changes in gene expression can trigger immune responses capable of destroying all of the altered cells, protecting the body.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('trigger', 'Reg', (78, 85))	('changes', 'Var', (47, 54))	('cancerous', 'Disease', 'MESH:D009369', (31, 40))	('gene', 'Gene', (58, 62))	('As', 'Chemical', 'None', (0, 2))	('cancerous', 'Disease', (31, 40))
35784	31666931	In our previously-published clinical trial we used HER-2 peptide-pulsed, IL-12-secreting dendritic cells as vehicles for vaccinating against an early form of HER-2pos breast cancer.	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('HER-2pos', 'Var', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
35787	31666931	However, a possible alternate interpretation is that elimination of HER-2 expression is deleterious in the estrogen receptor-negative (ERneg) patient subpopulation, because the resulting ERneg/HER-2neg phenotype is by definition "triple-negative", and part of a subset of tumors considered notoriously difficult to treat, since there are currrently fewer targeted treatment options for this phenotype.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('HER-2', 'Protein', (68, 73))	('estrogen', 'Chemical', 'MESH:D004967', (107, 115))	('patient', 'Species', '9606', (142, 149))	('ERneg/HER-2neg', 'Var', (187, 201))
35854	15535853	Certain lesions are widely acknowledged to have significant premalignant potential, including atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia, and their more advanced counterparts ductal carcinoma in situ (DCIS) and lobular carcinoma in situ, respectively.	('atypical', 'Var', (132, 140))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (103, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('ductal hyperplasia', 'Disease', (103, 121))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (206, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (141, 160))	('lobular hyperplasia', 'Disease', (141, 160))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (235, 260))	('ductal carcinoma', 'Disease', 'MESH:D044584', (199, 215))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (243, 260))	('ductal carcinoma', 'Disease', (199, 215))	('DCIS', 'Phenotype', 'HP:0030075', (225, 229))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (199, 223))	('lobular carcinoma', 'Disease', 'MESH:D018275', (235, 252))	('lobular carcinoma', 'Disease', (235, 252))
35861	15535853	In fact, ER-negative IBCs are often histologically high-grade, rapidly proliferating tumors.	('tumors', 'Disease', (85, 91))	('IBCs', 'Disease', (21, 25))	('ER-negative', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
35866	15535853	Reducing estrogen by oophorectomy in high-risk carriers of BRCA1 mutations greatly reduces the overall incidence of IBC, including ER-negative tumors, which indirectly argues that ER-dependent or otherwise estrogen-dependent pathways give rise to ER-negative disease.	('BRCA1', 'Gene', '672', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('ER-negative', 'Disease', (247, 258))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('BRCA1', 'Gene', (59, 64))	('IBC', 'Disease', (116, 119))	('reduces', 'NegReg', (83, 90))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mutations', 'Var', (65, 74))
35871	15535853	These examples are associated with relatively advanced stages of breast cancer evolution (DCIS or beyond) with prominent genetic instability and diversity, which could result in the loss of ER expression.	('loss', 'NegReg', (182, 186))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('ER expression', 'MPA', (190, 203))	('genetic instability', 'Var', (121, 140))
35881	15535853	The majority of available evidence suggests that most breast cancers, including ER-negative breast cancers, arise from ER-positive or otherwise estrogen-responsive progenitor cells through potentially reversible epigenetic mechanisms.	('breast cancers', 'Disease', (54, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('arise from', 'Reg', (108, 118))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('epigenetic', 'Var', (212, 222))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
35890	23756858	These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.	('inhibit', 'NegReg', (121, 128))	('inhibitors', 'Var', (101, 111))	('ER', 'Gene', '2099', (165, 167))	('oestrogen actions', 'MPA', (129, 146))	('deprivation', 'NegReg', (196, 207))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
35938	23756858	The median with min-max value of intratumoral estrone concentration was 0.23 (0-1.1) pg g-1 in DCIS tissues treated with letrozole, which was significantly lower (0.0003-fold and P=0.0008) than that without the therapy (76.5 (11.9-159.3) pg g-1) (Figure 1A).	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('letrozole', 'Chemical', 'MESH:D000077289', (121, 130))	('estrone', 'Chemical', 'MESH:D004970', (46, 53))	('lower', 'NegReg', (156, 161))	('letrozole', 'Var', (121, 130))
35940	23756858	On the other hand, androstenedione level of DCIS was not significantly different (P=0.75) between letrozole-treated (586 (228-3563) pg g-1) and untreated (687 (128-4864) pg g-1) groups in this study (Figure 1C).	('586 (228-3563) pg g-1', 'Var', (117, 138))	('androstenedione level', 'MPA', (19, 40))	('androstenedione', 'Chemical', 'MESH:D000735', (19, 34))	('letrozole', 'Chemical', 'MESH:D000077289', (98, 107))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
35993	23756858	In summary, intratumoral concentrations of estrogens were significantly lower in DCIS tissues treated with letrozole compared with those without the therapy, and a great majority of oestrogen-induced genes showed lower expression levels in DCIS tissues after the therapy.	('oestrogen-induced genes', 'Gene', (182, 205))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('lower', 'NegReg', (213, 218))	('expression levels', 'MPA', (219, 236))	('lower in DCIS', 'Phenotype', 'HP:0200161', (72, 85))	('DCIS', 'Phenotype', 'HP:0030075', (240, 244))	('letrozole', 'Chemical', 'MESH:D000077289', (107, 116))	('lower', 'NegReg', (72, 77))	('letrozole', 'Var', (107, 116))
35995	23756858	These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors may potently inhibit the oestrogen-mediated growth and/or progression in postmenopausal ER-positive DCIS cases through rapid deprivation of intratumoral estrogens.	('progression', 'CPA', (170, 181))	('inhibitors', 'Var', (101, 111))	('inhibit', 'NegReg', (125, 132))	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('deprivation', 'NegReg', (237, 248))	('ER', 'Gene', '2099', (200, 202))	('oestrogen-mediated growth', 'CPA', (137, 162))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))
36082	30854249	The approach taken by the STRAT-AP assay is backed by evidence in several cancers that deregulation of key signalling pathways (for example, PI3K, FAK, Rho-ROCK and MAPK) is responsible for disease-relevant molecular and cellular phenotypes, including changes in cytoskeletal dynamics, migration velocity and membrane fluctuations, which are central to tumorigenesis and metastasis.	('rat', 'Species', '10116', (289, 292))	('membrane fluctuations', 'MPA', (309, 330))	('changes', 'Reg', (252, 259))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('deregulation', 'Var', (87, 99))	('PI3K', 'Var', (141, 145))	('FAK', 'Gene', (147, 150))	('cancers', 'Disease', (74, 81))	('MAPK', 'Disease', (165, 169))	('FAK', 'Gene', '5747', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('migration velocity', 'CPA', (286, 304))	('cytoskeletal dynamics', 'MPA', (263, 284))
36105	30854249	GAPP predicts both overall tumour aggressiveness and metastatic potential, with high sensitivity and specificity for prostate cancer and breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('breast cancer', 'Disease', (137, 150))	('predicts', 'Reg', (5, 13))	('GAPP', 'Var', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('GAPP', 'Chemical', '-', (0, 4))	('tumour aggressiveness', 'Disease', (27, 48))	('metastatic potential', 'CPA', (53, 73))	('aggressiveness', 'Phenotype', 'HP:0000718', (34, 48))	('prostate cancer', 'Disease', (117, 132))	('tumour aggressiveness', 'Disease', 'MESH:D001523', (27, 48))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
36116	30854249	The conditions for the inclusion of prostate cancer samples were male patients from 40 to 80 years of age; all races; the patient is willing to participate and has signed the written informed-consent form; patients with Gleason score 6, 7,8, 9 or 10; patients undergoing radical prostatectomy; patients with known clinical outcomes.	('patients', 'Species', '9606', (70, 78))	('patient', 'Species', '9606', (294, 301))	('prostate cancer', 'Disease', (36, 51))	('Gleason score 6', 'Var', (220, 235))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('patient', 'Species', '9606', (122, 129))	('patient', 'Species', '9606', (206, 213))	('patients', 'Species', '9606', (294, 302))	('patient', 'Species', '9606', (251, 258))	('patient', 'Species', '9606', (70, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (36, 51))	('patients', 'Species', '9606', (206, 214))	('patients', 'Species', '9606', (251, 259))	('prostate cancer', 'Phenotype', 'HP:0012125', (36, 51))
36139	30854249	Alternatively, laminin may also be used as a protein coating to promote adhesion and survival, albeit less efficiently, as the engagement of pro-growth integrins facilitates the adhesion and survival of primary biopsy cells in 2D culture systems.	('engagement', 'Var', (127, 137))	('promote', 'PosReg', (64, 71))	('adhesion', 'CPA', (72, 80))	('survival', 'CPA', (85, 93))	('facilitates', 'PosReg', (162, 173))	('men', 'Species', '9606', (133, 136))	('survival', 'CPA', (191, 199))	('adhesion', 'CPA', (178, 186))
36155	30854249	All images were captured using a Nikon TE-2000 system and Nikon Elements software with a Nikon CFI Plan Apo Lambda x20, 0.75 numerical aperture, 1.0 mm working-distance DIC objective (MRD00205) and exposure time of 100 ms for live-cell imaging, and a Nikon CFI Plan Fluor x40, 0.75 numerical aperture Eco glass objective (MRH00401), exposure times of 500 ms and Nikon filter sets, C-FL GFP HC HISN zero shift filter set (96362), C-FL Texas Red HC HISN zero shift filter set (96365), C-FL CY5 HC HISN zero shift filter set (96366) for fluorescence imaging.	('HC HISN', 'Disease', 'MESH:D003556', (492, 499))	('C-FL', 'Gene', (483, 487))	('HC HISN', 'Disease', 'MESH:D003556', (390, 397))	('C-FL', 'Gene', '1072', (429, 433))	('C-FL', 'Gene', (381, 385))	('C-FL', 'Gene', (429, 433))	('96366', 'Var', (523, 528))	('HC HISN', 'Disease', 'MESH:D003556', (444, 451))	('men', 'Species', '9606', (67, 70))	('HC HISN', 'Disease', (492, 499))	('C-FL', 'Gene', '1072', (483, 487))	('HC HISN', 'Disease', (390, 397))	('HC HISN', 'Disease', (444, 451))	('C-FL', 'Gene', '1072', (381, 385))	('96365', 'Var', (475, 480))
36181	30061623	Our results highlight the dichotomous effects of estrogen on tumor progression and suggest that, in contrast to its established role in promoting growth of ER+ tumors, estrogen has a significant role in suppressing invasion through actin cytoskeletal remodeling.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('invasion', 'CPA', (215, 223))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('suppressing', 'NegReg', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (61, 66))	('estrogen', 'Var', (168, 176))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
36185	30061623	Moreover, large-scale clinical trials designed to look at the effects of hormone replacement therapy (HRT) on breast cancer incidence in postmenopausal women revealed that HRT increased the risk of breast cancer.	('women', 'Species', '9606', (152, 157))	('HRT', 'Var', (172, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('clinical', 'Species', '191496', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('breast cancer', 'Disease', (198, 211))
36186	30061623	Interestingly, HRT did not reduce the locoregional recurrence rate, suggesting that under HRT, recurrent tumors are able to develop and grow locally at the initial tumor site but are less prone to disseminate and metastasize to distant sites.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('HRT', 'Var', (90, 93))	('grow', 'CPA', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (105, 110))
36199	30061623	Moreover, tumors with LII <=7 microm (denoted as LII low) were associated with foldfold less LN dissemination than tumors with LII >=9 microm (denoted as LII high) (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('less', 'NegReg', (88, 92))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('LII <=7 microm', 'Var', (22, 36))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('LN dissemination', 'CPA', (93, 109))
36210	30061623	This analysis showed a marked decrease in the number and speed of membrane ruffles in E2-treated MCF7 cells, as compared to control (Fig.	('MCF7', 'CellLine', 'CVCL:0031', (97, 101))	('decrease', 'NegReg', (30, 38))	('E2-treated', 'Var', (86, 96))
36265	30061623	Our study raises the question of whether inhibiting ER could potentially down-regulate EVL and aggravate tumor invasion and dissemination of these recurrent tumors.	('tumor', 'Disease', (157, 162))	('aggravate', 'PosReg', (95, 104))	('inhibiting', 'Var', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('EVL', 'Protein', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('down-regulate', 'NegReg', (73, 86))	('dissemination', 'CPA', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (105, 110))
36287	30061623	The following plasmids from this paper have been deposited to Addgene: pLenti CMV-MRLC1-mRuby2-IRES-PuroR (#103031), Lifeact-iRFP670 (#103032), pLenti Lifeact-iRFP670-BlastR (#84385), pLenti Lifeact-eGFP-BlastR (#84383), pENTR CMVie-Lifeact-iRFP670 L1-R5 (#84390), pENTR CMVie-Lifeact-EGFP L1-R5 (#84391), pLenti Dest BlastR R1-R2 (#84574), and pLenti Dest PuroR R1-R2 (#84575).	('#84391', 'Var', (297, 303))	('#84390', 'Var', (256, 262))	('MRLC1', 'Gene', (82, 87))	('#103031', 'Var', (107, 114))	('#84574', 'Var', (332, 338))	('MRLC1', 'Gene', '10398', (82, 87))	('#84383', 'Var', (212, 218))	('#103032', 'Var', (134, 141))	('#84385', 'Var', (175, 181))
36534	22375924	We show that the expression of DYX1C1 in breast cancer is associated with several clinicopathological parameters and that loss of DYX1C1 correlates with a more aggressive disease, in turn indicating that DYX1C1 is a potential prognostic biomarker in breast cancer.	('aggressive disease', 'Disease', 'MESH:D001523', (160, 178))	('DYX1C1', 'Gene', (130, 136))	('breast cancer', 'Disease', (250, 263))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('associated', 'Reg', (58, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('aggressive disease', 'Disease', (160, 178))	('breast cancer', 'Disease', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('DYX1C1', 'Gene', (31, 37))	('loss', 'Var', (122, 126))	('breast cancer', 'Disease', 'MESH:D001943', (250, 263))
36550	22375924	By using in utero siRNA, knocking down DYX1C1 in the developing mice brain, the migration of neurons was halted.	('halted', 'NegReg', (105, 111))	('knocking down', 'Var', (25, 38))	('migration of neurons', 'CPA', (80, 100))	('mice', 'Species', '10090', (64, 68))	('DYX1C1', 'Gene', (39, 45))
36551	22375924	Furthermore, data from our group indicate that when DYX1C1 is overexpressed in the neuroblastoma cell line SH-SY5Y, the motility of the cells increased (unpublished data).	('motility of the cells', 'CPA', (120, 141))	('DYX1C1', 'Var', (52, 58))	('neuroblastoma', 'Phenotype', 'HP:0003006', (83, 96))	('increased', 'PosReg', (142, 151))	('overexpressed', 'PosReg', (62, 75))	('neuroblastoma', 'Disease', 'MESH:D009447', (83, 96))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (107, 114))	('neuroblastoma', 'Disease', (83, 96))
36568	22375924	DYX1C1 expression was examined by TaqMan assay (Hs00370049_m1) and GAPDH TaqMan assay (Hs99999905_m1) was used for normalization (Applied Biosystems).	('DYX1C1', 'Gene', (0, 6))	('GAPDH', 'Gene', (67, 72))	('Hs00370049_m1', 'Var', (48, 61))	('GAPDH', 'Gene', '2597', (67, 72))
36615	22375924	According to this cut-off, 196 (88.7%) tumors were scored as expressing DYX1C1 and 25 (11.3%) did not express the protein (Figure 4).	('tumors', 'Disease', (39, 45))	('DYX1C1', 'Var', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
36617	22375924	In the Cox proportional hazards survival model (adjusting for age at diagnosis, ER, PR, grade, and lymph node status) from primary breast cancer diagnosis to death or censoring at end of follow-up, patients with a low DYX1C1 status had a statistically significant increased risk of mortality compared with patients with high DYX1C1 status (Hazard ratio [HR] 3.44, CI 95% 1.84-6.42).	('DYX1C1', 'Gene', (218, 224))	('Cox', 'Gene', '1351', (7, 10))	('patients', 'Species', '9606', (198, 206))	('death', 'Disease', 'MESH:D003643', (158, 163))	('low', 'Var', (214, 217))	('Cox', 'Gene', (7, 10))	('death', 'Disease', (158, 163))	('ER', 'Gene', '2099', (80, 82))	('PR', 'Gene', '5241', (84, 86))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('patients', 'Species', '9606', (306, 314))
36624	22375924	The pathological mechanisms leading to malignant transformation of normal mammary epithelium are not fully understood, however mutations of tumor suppressor gene TP53 and amplification of ERBB2 are common genetic alterations.	('TP53', 'Gene', '7157', (162, 166))	('ERBB2', 'Gene', '2064', (188, 193))	('TP53', 'Gene', (162, 166))	('ERBB2', 'Gene', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('amplification', 'Var', (171, 184))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', (140, 145))
36629	22375924	DCIS is generally considered as a premalignant lesion, and women with DCIS are at higher risk of developing invasive ductal carcinoma.	('DCIS', 'Disease', (0, 4))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('invasive ductal carcinoma', 'Disease', (108, 133))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('women', 'Species', '9606', (59, 64))	('DCIS', 'Var', (70, 74))
36637	22375924	As DYX1C1 has been shown to interact as a chaperone with ERalpha and also regulate its expression, higher levels of DYX1C1 protein, which could be a result of increased transcription of DYX1C1, could perhaps influence the levels of ERalpha and, consequently, affect the response to the anti-estrogen treatment of the patient.	('influence', 'Reg', (208, 217))	('ERalpha', 'Gene', '2099', (57, 64))	('ERalpha', 'Gene', (57, 64))	('response', 'MPA', (270, 278))	('higher', 'PosReg', (99, 105))	('regulate', 'Reg', (74, 82))	('affect', 'Reg', (259, 265))	('increased', 'PosReg', (159, 168))	('levels', 'MPA', (222, 228))	('expression', 'MPA', (87, 97))	('DYX1C1', 'Var', (116, 122))	('DYX1C1', 'Gene', (186, 192))	('ERalpha', 'Gene', (232, 239))	('patient', 'Species', '9606', (317, 324))	('ERalpha', 'Gene', '2099', (232, 239))
36651	22375924	Reelin, another protein important in neuronal migration in the brain, was recently shown to be epigenetically silenced in breast cancer compared with normal mammary tissue.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('Reelin', 'Gene', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('Reelin', 'Gene', '5649', (0, 6))	('epigenetically silenced', 'Var', (95, 118))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
36680	21858221	BHP demonstrated significantly improved immunohistochemical detection of phosphorylated proteins ERK Thr202/Tyr204, GSK3-alpha/beta Ser21/Ser9, p38-MAPK Thr180/Tyr182, eIF4G Ser1108 and Acetyl-CoA Carboxylase Ser79.	('Thr202/Tyr204', 'Var', (101, 114))	('Thr180', 'Chemical', '-', (153, 159))	('eIF4G', 'Gene', '1981', (168, 173))	('p38', 'Gene', '1432', (144, 147))	('Ser21', 'Chemical', '-', (132, 137))	('ERK', 'Gene', '5594', (97, 100))	('GSK3-alpha', 'Gene', (116, 126))	('Ser79', 'Chemical', '-', (209, 214))	('improved', 'PosReg', (31, 39))	('Ser1108', 'Chemical', '-', (174, 181))	('Tyr204', 'Chemical', '-', (108, 114))	('immunohistochemical detection', 'MPA', (40, 69))	('Thr202', 'Chemical', '-', (101, 107))	('Ser9', 'Chemical', '-', (138, 142))	('ERK', 'Gene', (97, 100))	('Thr180/Tyr182', 'Var', (153, 166))	('GSK3-alpha', 'Gene', '2931', (116, 126))	('BHP', 'Chemical', '-', (0, 3))	('p38', 'Gene', (144, 147))	('eIF4G', 'Gene', (168, 173))	('Tyr182', 'Chemical', '-', (160, 166))
36750	21858221	Nuclear structures (nuclear membrane, chromatin and nucleoli) were better preserved by BHP.	('Nuclear structures', 'CPA', (0, 18))	('BHP', 'Chemical', '-', (87, 90))	('BHP', 'Var', (87, 90))
36777	21858221	We further evaluated the preservation of antigenicity for 6 labile phosphorylated proteins that are of special relevance to cancer biology: ERK Thr202/Tyr204, GSK3 alpha/beta Ser21/Ser9, p38 MAPK Thr180/Tyr182, eIF4G Ser1108, Acetyl-CoA Carboxylase Ser79 and Bcl-2 Ser70 (Figure 11A (data for Bcl-2 not shown), Table S6, Text S1).	('p38', 'Gene', (187, 190))	('Bcl-2', 'Gene', (259, 264))	('Bcl-2', 'Gene', (293, 298))	('Ser79', 'Chemical', '-', (249, 254))	('Tyr204', 'Chemical', '-', (151, 157))	('Ser9', 'Chemical', '-', (181, 185))	('ERK', 'Gene', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('GSK3 alpha', 'Gene', '2931', (159, 169))	('Tyr182', 'Chemical', '-', (203, 209))	('Thr180/Tyr182', 'Var', (196, 209))	('Bcl-2', 'Gene', '596', (259, 264))	('Bcl-2', 'Gene', '596', (293, 298))	('p38', 'Gene', '1432', (187, 190))	('eIF4G', 'Gene', (211, 216))	('Ser21', 'Chemical', '-', (175, 180))	('GSK3 alpha', 'Gene', (159, 169))	('Thr180', 'Chemical', '-', (196, 202))	('eIF4G', 'Gene', '1981', (211, 216))	('cancer', 'Disease', (124, 130))	('Thr202', 'Chemical', '-', (144, 150))	('Ser1108', 'Chemical', '-', (217, 224))	('Ser70', 'Chemical', '-', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ERK', 'Gene', '5594', (140, 143))
36779	21858221	In the cases of phospho-ERK Thr202/Tyr204 in human colon cancer, phospho-GSK3 alpha/beta Ser21/Ser9 in human DCIS, phospho-p38 MAPK Thr180/Tyr182 in mouse brain cortex and phospho-acetyl-CoA carboxylase Ser79 in mouse brain hippocampus, staining was virtually absent in formalin fixed samples, but clearly visible in matched BHP fixed tissue.	('Ser79', 'Chemical', '-', (203, 208))	('p38', 'Gene', (123, 126))	('Ser9', 'Chemical', '-', (95, 99))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('GSK3 alpha', 'Gene', '2931', (73, 83))	('mouse', 'Species', '10090', (212, 217))	('Thr202', 'Chemical', '-', (28, 34))	('human', 'Species', '9606', (103, 108))	('Tyr182', 'Chemical', '-', (139, 145))	('formalin', 'Chemical', 'MESH:D005557', (270, 278))	('Thr180/Tyr182', 'Var', (132, 145))	('mouse', 'Species', '10090', (149, 154))	('ERK', 'Gene', '5594', (24, 27))	('colon cancer', 'Disease', (51, 63))	('Ser21', 'Chemical', '-', (89, 94))	('BHP', 'Chemical', '-', (325, 328))	('p38', 'Gene', '1432', (123, 126))	('Tyr204', 'Chemical', '-', (35, 41))	('GSK3 alpha', 'Gene', (73, 83))	('ERK', 'Gene', (24, 27))	('Thr180', 'Chemical', '-', (132, 138))	('human', 'Species', '9606', (45, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))
36789	21858221	These deficiencies of formalin are more than tissue-based penetration related issues as we have shown that formalin failed to preserve an EGF induced increase in the phosphorylation of EGFR Tyr1068 in suspension cells that are likely immediately fixed, thus indicating inadequate retention of phosphorylation due to the slow inhibition of phosphatase enzymes (Figure 5).	('formalin', 'Chemical', 'MESH:D005557', (107, 115))	('EGF', 'Gene', '1950', (138, 141))	('Tyr1068', 'Chemical', '-', (190, 197))	('EGFR', 'Gene', (185, 189))	('formalin', 'Chemical', 'MESH:D005557', (22, 30))	('EGF', 'Gene', (185, 188))	('EGF', 'Gene', (138, 141))	('Tyr1068', 'Var', (190, 197))	('phosphorylation', 'MPA', (166, 181))	('EGF', 'Gene', '1950', (185, 188))	('EGFR', 'Gene', '1956', (185, 189))
36801	21858221	Supporting a direct effect of formalin fixation on phosphoprotein signaling, we found that an EGF-induced phosphorylation peak of EGFR Tyr1068 in U266 cells suspended in formalin, was not adequately preserved (Figure 5).	('U266', 'CellLine', 'CVCL:0566', (146, 150))	('formalin', 'Chemical', 'MESH:D005557', (170, 178))	('EGF', 'Gene', '1950', (94, 97))	('phosphorylation peak', 'MPA', (106, 126))	('Tyr1068', 'Chemical', '-', (135, 142))	('EGF', 'Gene', (130, 133))	('EGF', 'Gene', (94, 97))	('formalin', 'Chemical', 'MESH:D005557', (30, 38))	('EGF', 'Gene', '1950', (130, 133))	('Tyr1068', 'Var', (135, 142))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
36803	21858221	This speed of phosphatase inhibition translated directly into the preservation of the expected increase in EGFR Tyr1068 phosphorylation after EGF stimulation of U266 cells.	('EGF', 'Gene', '1950', (107, 110))	('Tyr1068', 'Var', (112, 119))	('EGFR', 'Gene', '1956', (107, 111))	('EGF', 'Gene', '1950', (142, 145))	('Tyr1068', 'Chemical', '-', (112, 119))	('increase', 'PosReg', (95, 103))	('EGFR', 'Gene', (107, 111))	('U266', 'CellLine', 'CVCL:0566', (161, 165))	('EGF', 'Gene', (142, 145))	('EGF', 'Gene', (107, 110))
36865	21858221	To measure unstimulated levels of phospho-epidermal growth factor receptor (EGFR) Tyr1068, 200 microL of cell suspension was spun at 800 x g for 3 minutes and washed with phosphate buffered saline without calcium or magnesium (PBS) (Gibco).	('calcium', 'Chemical', 'MESH:D002118', (205, 212))	('PBS', 'Disease', (227, 230))	('phosphate buffered saline', 'Chemical', '-', (171, 196))	('EGFR', 'Gene', '1956', (76, 80))	('Tyr1068', 'Chemical', '-', (82, 89))	('phospho-epidermal growth factor receptor', 'Gene', '1956', (34, 74))	('magnesium', 'Chemical', 'MESH:D008274', (216, 225))	('EGFR', 'Gene', (76, 80))	('phospho-epidermal growth factor receptor', 'Gene', (34, 74))	('Tyr1068', 'Var', (82, 89))	('PBS', 'Disease', 'MESH:D011535', (227, 230))
36999	29568299	Specifically, better prognosis was observed for high B-cell/low IL-8 group in both untreated (P = 0.001) and post- chemotherapy patients (P = 0.05).	('IL-8', 'Gene', '3576', (64, 68))	('IL-8', 'Gene', (64, 68))	('better', 'PosReg', (14, 20))	('high B-cell/low', 'Var', (48, 63))	('patients', 'Species', '9606', (128, 136))
37011	29568299	Interestingly, TILs in the metastatic lesions displayed a similar arrangement as their matched primary tumors (PT), containing CD4+ T cells being most abundant followed by CD8+ T cells and CD20+ B cells.	('primary tumors', 'Disease', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumors', 'Disease', 'MESH:D009369', (95, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('CD20', 'Gene', '54474', (189, 193))	('CD20', 'Gene', (189, 193))	('CD8', 'Gene', (172, 175))	('CD8', 'Gene', '925', (172, 175))	('CD4+ T cells', 'Var', (127, 139))
37035	29568299	The transfer also resulted in the induction of tumor-specific T-cell immunity as measured by cytotoxicity and the productions of cytokine interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor.	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (165, 213))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('productions of cytokine interferon', 'MPA', (114, 148))	('transfer', 'Var', (4, 12))	('cytotoxicity', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (165, 213))	('tumor', 'Disease', (47, 52))
37040	29568299	Antibodies binding to tumor antigens may induce powerful antitumor response, underscoring the essential roles of TIL-B in the BC environment.	('Antibodies', 'Var', (0, 10))	('BC', 'Phenotype', 'HP:0003002', (126, 128))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('induce', 'PosReg', (41, 47))	('TIL-B', 'Chemical', '-', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (61, 66))
37051	29568299	A typical type of B220+CD25hiCD69hiMHC-IIhi B-cell subset could promote lung metastases of BC, which secrete cytokine transforming growth factor (TGF)-beta and IL-10.	('BC', 'Phenotype', 'HP:0003002', (91, 93))	('promote', 'PosReg', (64, 71))	('secrete', 'MPA', (101, 108))	('metastases', 'Disease', (77, 87))	('transforming growth factor (TGF)-beta', 'Gene', '7040', (118, 155))	('B220+CD25hiCD69hiMHC-IIhi', 'Var', (18, 43))	('metastases', 'Disease', 'MESH:D009362', (77, 87))
37057	29568299	Within the tumor environment, purified TIL-B were reported to suppress the proliferation of CD4+, CD8+, and CD4+CD25- T cells, as well as NK proliferation in response to IL-15.	('suppress', 'NegReg', (62, 70))	('IL-15', 'Gene', '3600', (170, 175))	('CD8', 'Gene', (98, 101))	('TIL-B', 'Chemical', '-', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('IL-15', 'Gene', (170, 175))	('CD8', 'Gene', '925', (98, 101))	('NK proliferation', 'CPA', (138, 154))	('TIL-B', 'Gene', (39, 44))	('proliferation', 'CPA', (75, 88))	('CD4+CD25-', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
37060	29568299	In addition, a decreased number of CD4+CD25+FoxP3+ Tregs was noted in the spleen of BCDM and TDLN relative to wide-type mice.	('CD4+CD25+FoxP3+', 'Var', (35, 50))	('mice', 'Species', '10090', (120, 124))	('decreased', 'NegReg', (15, 24))	('BC', 'Phenotype', 'HP:0003002', (84, 86))
37076	29568299	Specifically, PD-L1 expression was associated with higher TILs density including CD19+ B cells.	('higher', 'PosReg', (51, 57))	('expression', 'Var', (20, 30))	('CD19', 'Gene', (81, 85))	('PD-L1', 'Gene', (14, 19))	('CD19', 'Gene', '930', (81, 85))	('TILs density', 'CPA', (58, 70))
37087	29568299	High Blimp1 expression tends to trigger BC cell invasion and metastasis formation.	('Blimp1', 'Gene', (5, 11))	('Blimp1', 'Gene', '639', (5, 11))	('High', 'Var', (0, 4))	('metastasis formation', 'CPA', (61, 81))	('BC', 'Phenotype', 'HP:0003002', (40, 42))	('trigger', 'PosReg', (32, 39))	('BC cell invasion', 'CPA', (40, 56))
37099	26955804	Overexpression of Mortalin was closely correlated with histological grade, clinical stage, lymph node metastasis, lower disease free survival (DFS) and overall survival (OS) rates of patients with breast cancer.	('Mortalin', 'Gene', (18, 26))	('breast cancer', 'Disease', (197, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('overall survival', 'CPA', (152, 168))	('lymph node metastasis', 'CPA', (91, 112))	('lower', 'NegReg', (114, 119))	('Overexpression', 'Var', (0, 14))	('clinical', 'Species', '191496', (75, 83))	('disease free survival', 'CPA', (120, 141))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('patients', 'Species', '9606', (183, 191))
37127	26955804	After washing with PBS, the cells were counterstained with DAPI (C1006, Beyotime, Shanghai, China), and the coverslips were mounted with an Anti fade Mounting Medium (P0126, Beyotime, Shanghai, China).	('P0126', 'Var', (167, 172))	('C1006', 'Var', (65, 70))	('PBS', 'Chemical', 'MESH:D007854', (19, 22))	('DAPI', 'Chemical', 'MESH:C007293', (59, 63))
37149	26955804	To further substantiate the importance of high Mortalin expression in breast cancer progression, we analyzed DFS and OS of 155 breast cancer cases using the Kaplan-Meier method, and found that patients with high Mortalin expression had lower DFS and OS than those with low Mortalin expression (both P < 0.0001) (Fig.	('lower', 'NegReg', (236, 241))	('patients', 'Species', '9606', (193, 201))	('high Mortalin', 'Var', (207, 220))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('DFS', 'MPA', (242, 245))
37150	26955804	Additionally, breast cancer patients with high Mortalin expression had decreased DFS and OS compared to those with low Mortalin expression in either Early stage cases (P = 0.043, P = 0.042 respectively) or late-stage cases (P = 0.008, P = 0.010 respectively) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('high Mortalin expression', 'Var', (42, 66))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('DFS', 'CPA', (81, 84))	('patients', 'Species', '9606', (28, 36))	('decreased', 'NegReg', (71, 80))
37151	26955804	Similarly, the patients with high Mortalin expression had decreased DFS and OS compared to those with low Mortalin expression in either LN metastasis (-) cases (P = 0.003, P = 0.005 respectively) or LN metastasis (+) cases (P = 0.035, P = 0.029 respectively) (Fig.	('high', 'Var', (29, 33))	('patients', 'Species', '9606', (15, 23))	('DFS', 'MPA', (68, 71))	('expression', 'Var', (43, 53))	('decreased', 'NegReg', (58, 67))	('Mortalin', 'Gene', (34, 42))
37156	26955804	Moreover, it has multiple functions contributing to continued proliferation of cancer cells, including mitochondrial-biogenesis, ATP production, anti-apoptosis, chaperoning, inactivation of tumor suppressor p53 and PI3K/AKT activities.	('AKT', 'Gene', (220, 223))	('ATP', 'Chemical', 'MESH:D000255', (129, 132))	('inactivation', 'Var', (174, 186))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mitochondrial-biogenesis', 'MPA', (103, 127))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('anti-apoptosis', 'MPA', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('tumor', 'Disease', (190, 195))	('AKT', 'Gene', '207', (220, 223))	('ATP production', 'MPA', (129, 143))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('chaperoning', 'MPA', (161, 172))
37165	26955804	Furthermore, the presence of Mortalin in breast cancer is also significantly associated with histological grade, LN metastasis and clinical stage, the three critical prognostic factors indicative of poor outcomes and cancer recurrence in breast cancer patients.	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (48, 54))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('breast cancer', 'Disease', (238, 251))	('LN metastasis', 'CPA', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (252, 260))	('Mortalin', 'Gene', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('associated', 'Reg', (77, 87))	('cancer', 'Disease', (245, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('clinical stage', 'CPA', (131, 145))	('breast cancer', 'Disease', (41, 54))	('clinical', 'Species', '191496', (131, 139))	('cancer', 'Disease', (217, 223))	('histological grade', 'CPA', (93, 111))	('presence', 'Var', (17, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
37172	26955804	found that expression of Mortalin was notably higher in the SMMC 7721 (a liver-derived tumor cell line) than in a normal liver cell line.	('SMMC', 'Var', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('higher', 'PosReg', (46, 52))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', (87, 92))	('Mortalin', 'Gene', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
37173	26955804	showed that human HepG2 cells lacked mortalin-p53 interaction and were resistant to apoptosis, but cell apoptosis was significantly increased by Mortalin shRNA transfection.	('transfection', 'Var', (160, 172))	('cell apoptosis', 'CPA', (99, 113))	('p53', 'Gene', (46, 49))	('Mortalin shRNA transfection', 'Var', (145, 172))	('increased', 'PosReg', (132, 141))	('p53', 'Gene', '7157', (46, 49))	('interaction', 'Interaction', (50, 61))	('human', 'Species', '9606', (12, 17))	('HepG2', 'CellLine', 'CVCL:0027', (18, 23))
37174	26955804	also showed the conclusions that low expression of Mortalin was able to inhibit EMT, decrease tumor progression and lose the metastasis-inducing capability.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('decrease', 'NegReg', (85, 93))	('EMT', 'Gene', (80, 83))	('lose', 'NegReg', (116, 120))	('EMT', 'Gene', '3702', (80, 83))	('inhibit', 'NegReg', (72, 79))	('low expression', 'Var', (33, 47))	('metastasis-inducing capability', 'CPA', (125, 155))	('Mortalin', 'Gene', (51, 59))
37191	30154547	In general, tumors are associated with different genetic and epigenetic events resulting in a change of gene expression.	('epigenetic', 'Var', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('change', 'Reg', (94, 100))	('tumors', 'Disease', (12, 18))	('gene expression', 'MPA', (104, 119))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
37200	30154547	In the present study, we found that deregulated levels of exosomal miR-16, miR-30b and miR-93 were most significantly associated with BC receptor status, BC recurrence and DCIS, respectively.	('deregulated', 'MPA', (36, 47))	('DCIS', 'Disease', (172, 176))	('BC', 'Phenotype', 'HP:0003002', (134, 136))	('exosomal', 'MPA', (58, 66))	('BC', 'Phenotype', 'HP:0003002', (154, 156))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('miR-30b', 'Gene', '407030', (75, 82))	('BC receptor status', 'Disease', (134, 152))	('miR-30b', 'Gene', (75, 82))	('miR-93', 'Gene', '407051', (87, 93))	('miR-93', 'Gene', (87, 93))	('associated', 'Reg', (118, 128))	('miR-16', 'Var', (67, 73))	('BC recurrence', 'Disease', (154, 167))
37246	30154547	They found MWs of 25 kDa for non-glycosylated, 35 kDa for lower-glycosylated and above 50 kDa for higher-glycosylated CD63.	('lower-glycosylated', 'Var', (58, 76))	('CD63', 'Gene', '967', (118, 122))	('CD63', 'Gene', (118, 122))
37294	30154547	In conclusion, our findings show a specific packaging of miR-16, miR-30b and miR-93 into exosomes from BC and DCIS patients.	('miR-30b', 'Gene', (65, 72))	('patients', 'Species', '9606', (115, 123))	('DCIS', 'Disease', (110, 114))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('BC', 'Phenotype', 'HP:0003002', (103, 105))	('miR-16', 'Var', (57, 63))	('miR-93', 'Gene', '407051', (77, 83))	('miR-30b', 'Gene', '407030', (65, 72))	('miR-93', 'Gene', (77, 83))
37331	30154547	The obtained data of the miRNA expression levels were calculated by the DeltaCt method as follows: DeltaCt = mean value Ct (reference cel-miR-39 + miR-484) - mean value Ct (miRNA of interest).	('miR-484', 'Gene', '619553', (147, 154))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (147, 150))	('miR', 'Gene', (25, 28))	('DeltaCt', 'Var', (99, 106))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('miR-484', 'Gene', (147, 154))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', (173, 176))
37347	26866475	In addition, NCT increases the chances of successful breast-conservation surgery, facilitates tumor biology research, and most importantly, provides information about prognosis.	('facilitates', 'PosReg', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('increases', 'PosReg', (17, 26))	('NCT', 'Var', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('breast-conservation surgery', 'CPA', (53, 80))
37371	26866475	HER2 was considered positive with immunohistochemistry scores of 3+ or gene amplification by FISH.	('HER2', 'Gene', '2064', (0, 4))	('gene amplification', 'Var', (71, 89))	('HER2', 'Gene', (0, 4))
37385	26866475	Patients with ypT0 were more likely to have ER-negative, PR-negative, and HER2-negative tumors.	('ypT0', 'Var', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('HER2', 'Gene', (74, 78))	('HER2', 'Gene', '2064', (74, 78))	('PR', 'Gene', '5241', (57, 59))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('ER-negative', 'CPA', (44, 55))
37386	26866475	Therefore, triple-negative breast cancer was significantly more common in the ypT0 group.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('ypT0', 'Var', (78, 82))
37387	26866475	Breast-conservation surgeries were more frequently performed in patients with ypT0.	('patients', 'Species', '9606', (64, 72))	('ypT0', 'Var', (78, 82))	('Breast-conservation', 'Disease', (0, 19))
37393	26866475	Round shape of the main lesion, posterior enhancement, and sonographic absence of calcifications were more frequently observed in patients with ypT0.	('patients', 'Species', '9606', (130, 138))	('calcification', 'Disease', 'MESH:D002114', (82, 95))	('posterior enhancement', 'CPA', (32, 53))	('calcification', 'Disease', (82, 95))	('ypT0', 'Var', (144, 148))
37424	26866475	In the present study, univariate analyses demonstrated that round shape on baseline sonographic analyses, posterior features, sonographic absence of calcification, and complete response after NCT were associated with a higher possibility of ypT0.	('ypT0', 'CPA', (241, 245))	('calcification', 'Disease', (149, 162))	('calcification', 'Disease', 'MESH:D002114', (149, 162))	('round', 'Var', (60, 65))
37464	29417425	The current study includes women diagnosed with ductal carcinoma (ICD-O codes 8201, 8230, 8500, 8501, 8503, 8507, 8521-8523, and 8543).	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('ductal carcinoma', 'Disease', 'MESH:D044584', (48, 64))	('ductal carcinoma', 'Disease', (48, 64))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (48, 64))	('women', 'Species', '9606', (27, 32))	('8521-8523', 'Var', (114, 123))
37542	28416734	Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('luminal breast cancer', 'Disease', 'MESH:D001943', (102, 123))	('associated', 'Reg', (86, 96))	('high', 'Var', (59, 63))	('luminal breast cancer', 'Disease', (102, 123))	('AT1R', 'Gene', (64, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
37550	28416734	Given the importance of these processes in cancer, the inhibition of AT1R could offer a beneficial complementary treatment.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('AT1R', 'Protein', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('inhibition', 'Var', (55, 65))
37605	28416734	There were no differences in cells positive for CD3, B220 or F480 in Losartan versus untreated mammary tumours, reflecting no changes in the recruitment of lymphocytes or tumour-associated macrophages (TAMs).	('TAMs', 'Chemical', '-', (202, 206))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('mammary tumours', 'Disease', (95, 110))	('F480', 'Var', (61, 65))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('B220', 'Var', (53, 57))	('tumour', 'Disease', (171, 177))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('mammary tumours', 'Disease', 'MESH:D001943', (95, 110))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('tumour', 'Disease', (103, 109))	('Losartan', 'Chemical', 'MESH:D019808', (69, 77))
37606	28416734	The use of ARBs as a potential breast cancer therapy would be predicted to have maximal success in patients with tumors expressing AT1R.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('AT1R', 'Var', (131, 135))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('patients', 'Species', '9606', (99, 107))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
37609	28416734	Frozen tumor tissue sections were probed with 125I-[Sar1, Ile8]AngII, and co-incubated with unlabeled AngII, Losartan or PD123,319 (an inhibitor for AT2R, a functionally distinct isoform of AT1R).	('tumor', 'Disease', (7, 12))	('AT2R', 'Gene', (149, 153))	('Losartan', 'Chemical', 'MESH:D019808', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('PD123', 'Chemical', '-', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('125I-[', 'Var', (46, 52))
37610	28416734	Competitive inhibition of binding was observed with unlabeled AngII and Losartan (Figure 4a), indicating detectable AT1R, but not AT2R, in tumor and normal tissue.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Losartan', 'Chemical', 'MESH:D019808', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('AT1R', 'Var', (116, 120))
37630	28416734	Our analysis of the TCGA database is confirmatory that high AGTR1 expression is associated with luminal breast cancer and inversely correlated to HER2 expression.	('AGTR1', 'Gene', '185', (60, 65))	('HER2', 'Gene', '2064', (146, 150))	('luminal breast cancer', 'Disease', 'MESH:D001943', (96, 117))	('expression', 'MPA', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('luminal breast cancer', 'Disease', (96, 117))	('expression', 'MPA', (66, 76))	('associated', 'Reg', (80, 90))	('high', 'Var', (55, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('AGTR1', 'Gene', (60, 65))	('HER2', 'Gene', (146, 150))
37645	28416734	The importance of AT1R function on mammary gland morphogenesis during normal development and pregnancy has been characterised by Nahmod and colleagues using mice deficient in either, or both, of the two different murine angiotensin receptors (AT1A or AT1B) and with the administration of Irbesartan, an ARB.	('Irbesartan', 'Chemical', 'MESH:D000077405', (288, 298))	('AT1B', 'Gene', (251, 255))	('mice', 'Species', '10090', (157, 161))	('AT1A', 'Gene', '11607', (243, 247))	('murine', 'Species', '10090', (213, 219))	('deficient', 'Var', (162, 171))	('AT1A', 'Gene', (243, 247))	('AT1B', 'Gene', '11608', (251, 255))
37650	28416734	AT1R inhibition has proven to reduce inflammation in hypertension, as well as LPS-induced inflammation, via the reduction of IL-1beta, IL-6 and TNFalpha levels.	('AT1R', 'Gene', (0, 4))	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('LPS', 'Chemical', 'MESH:D008070', (78, 81))	('inhibition', 'Var', (5, 15))	('hypertension', 'Disease', (53, 65))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('inflammation', 'Disease', (90, 102))	('IL-1beta', 'MPA', (125, 133))	('hypertension', 'Phenotype', 'HP:0000822', (53, 65))	('reduce', 'NegReg', (30, 36))	('TNFalpha levels', 'MPA', (144, 159))	('reduction', 'NegReg', (112, 121))	('inflammation', 'Disease', (37, 49))	('hypertension', 'Disease', 'MESH:D006973', (53, 65))
37672	28416734	In conclusion, our findings indicate a specific role of AT1R inhibition in delaying the occurrence and progression of invasive breast cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (118, 140))	('delaying', 'NegReg', (75, 83))	('inhibition', 'Var', (61, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('invasive breast cancer', 'Disease', (118, 140))	('AT1R', 'Protein', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('progression', 'CPA', (103, 114))
37696	28416734	mRNA was quantified using TaqMan probes (AT1aR: Mm01957722_s1, RN18S: Mm03928990_g1) and Taqman Gene Expression Master Mix (Life Technologies) on the ABI Prism 7900-HT Real-time PCR system.	('AT1aR', 'Gene', (41, 46))	('AT1aR', 'Gene', '185', (41, 46))	('Mix', 'Gene', (119, 122))	('Mix', 'Gene', '83881', (119, 122))	('Mm01957722_s1', 'Var', (48, 61))
37702	28416734	Tissues were then incubated overnight at 4 C with the primary antibody of interest including: alphaSMA (Abcam ab5694, 1:200), Ki67 (Abcam ab833, 1:400 and Thermoscientific (SP6), 1:200), E-cadherin (BD610182, 1:300), F480 (in-house Ludwig antibody, 1:200, trypsin antigen retrieval), Cleaved Caspase 3 (Cell Signalling #2215, 1:300), phosphoSTAT3 (Cell Signalling #2215, 1:200) and ERalpha (Santa Cruz sc-542, 1:200).	('Ki67', 'Chemical', '-', (126, 130))	('Abcam ab833', 'Var', (132, 143))	('SMA', 'Gene', '6606', (99, 102))	('ERalpha', 'Gene', (382, 389))	('BD610182', 'Var', (199, 207))	('ERalpha', 'Gene', '2099', (382, 389))	('SMA', 'Gene', (99, 102))
37714	28416734	The assay entailed incubation of 5 mul of tumor lysate with CaptSure donor and acceptor beads coated with antibodies against the phospho-Tyr705-epitope and the distal STAT3alpha and STAT3beta (NP_644805 and NP_998827).	('Tyr705', 'Chemical', '-', (137, 143))	('NP_644805', 'Var', (193, 202))	('tumor', 'Disease', (42, 47))	('NP_998827', 'Var', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('donor', 'Species', '9606', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
37717	28416734	20 mum frozen sections of tumor and normal breast tissue sections were incubated with 0.2 pCi/ml 125I[Sar1, Ile8] Angiotensin II (AngII) (90 pmol/L, ProSearch, Australia) to determine total receptor binding, 10 mmol/L PD123319 (AT2R isotype blocker) to show AT1R specific binding, and/or Losartan to show AT1R binding or 1 mmol/L unlabelled Ang II (Sigma, Australia) to show nonspecific binding.	('PD123', 'Chemical', '-', (218, 223))	('AT1R', 'Protein', (305, 309))	('AT1R specific', 'Protein', (258, 271))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PD123319', 'Var', (218, 226))	('Losartan', 'Chemical', 'MESH:D019808', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
37734	21058923	Identifying alterations associated with multiple cancers and central to cancer progression is imperative to improve diagnosis and treatment.	('associated', 'Reg', (24, 34))	('alterations', 'Var', (12, 23))	('multiple cancers', 'Disease', (40, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('multiple cancers', 'Disease', 'MESH:D009369', (40, 56))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', (72, 78))
37746	21058923	Many 14-3-3 interacting proteins contain one or more of these motifs; however, a broad range of substitutions, such as phospho-threonine, can be found in other proteins.	('phospho-threonine', 'Var', (119, 136))	('phospho-threonine', 'Chemical', 'MESH:D010769', (119, 136))	('14-3-3 interacting proteins', 'Protein', (5, 32))
37747	21058923	Phosphorylation of the threonine 232 residue in 14-3-3 zeta and tau can disrupt 14-3-3 binding by altering the conformation of the C-terminal tail.	('conformation of the C-terminal tail', 'MPA', (111, 146))	('disrupt', 'NegReg', (72, 79))	('14-3-3', 'Protein', (80, 86))	('Phosphorylation', 'Var', (0, 15))	('binding', 'Interaction', (87, 94))	('14-3-3 zeta', 'Gene', '7534', (48, 59))	('threonine', 'Chemical', 'MESH:D013912', (23, 32))	('14-3-3 zeta', 'Gene', (48, 59))	('altering', 'Reg', (98, 106))
37760	21058923	Single nucleotide polymorphisms in the 14-3-3tau gene from soft tissue sarcoma (STS) patients were associated with an early onset of disease and an increased risk of tumor-related death in STS patients.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('patients', 'Species', '9606', (193, 201))	('STS', 'Phenotype', 'HP:0030448', (80, 83))	('STS', 'Phenotype', 'HP:0030448', (189, 192))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('sarcoma', 'Disease', 'MESH:D012509', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (85, 93))	('sarcoma', 'Disease', (71, 78))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (59, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('14-3-3tau', 'Gene', (39, 48))	('associated', 'Reg', (99, 109))
37761	21058923	Additionally, knockdown of 14-3-3beta with antisense induced apoptosis in cancer cell lines; whereas, 14-3-3beta overexpression contributed to transformation.	('apoptosis', 'CPA', (61, 70))	('14-3-3beta', 'Chemical', '-', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('antisense', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('14-3-3beta', 'Chemical', '-', (102, 112))
37771	21058923	Mutation of the 14-3-3 binding site in IGF1R blocked colony formation in a soft agar assay and reduced the tumorigenicity in mice, suggesting 14-3-3zeta and/or beta may contribute to IGF1R mediated transformation.	('IGF1R', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('colony formation in a soft agar assay', 'CPA', (53, 90))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Mutation', 'Var', (0, 8))	('mice', 'Species', '10090', (125, 129))	('reduced', 'NegReg', (95, 102))	('blocked', 'NegReg', (45, 52))	('contribute', 'Reg', (169, 179))
37779	21058923	In lung cancer, knockdown of 14-3-3zeta sensitized cells to stress-induced apoptosis and enhanced cell adhesion and cell-cell contacts; two activities that are frequently being suppressed in cancer development.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('enhanced', 'PosReg', (89, 97))	('cancer', 'Disease', (8, 14))	('lung cancer', 'Disease', (3, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('knockdown', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cell adhesion', 'CPA', (98, 111))	('sensitized', 'Reg', (40, 50))
37780	21058923	Similarly, knockdown of 14-3-3zeta was sufficient to restore the sensitivity of lung cancer cells to anoikis and impair their anchorage-independent growth.	('impair', 'NegReg', (113, 119))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('anchorage-independent growth', 'CPA', (126, 154))	('sensitivity', 'MPA', (65, 76))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('restore', 'PosReg', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('knockdown', 'Var', (11, 20))
37792	21058923	Ectopic expression of p53 restored luminal apoptosis in 14-3-3zeta overexpressing MECs.	('luminal apoptosis', 'MPA', (35, 52))	('restored', 'PosReg', (26, 34))	('MEC', 'Gene', '56477', (82, 85))	('p53', 'Gene', (22, 25))	('Ectopic expression', 'Var', (0, 18))	('MEC', 'Gene', (82, 85))	('p53', 'Gene', '7157', (22, 25))
37793	21058923	Furthermore, 14-3-3zeta overexpression was found to be a "second hit" in a subset of ErbB2-overexpressing DCIS lesions facilitating the transition from non-invasive DCIS into life-threatening invasive breast cancer.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('invasive breast cancer', 'Disease', (192, 214))	('ErbB2', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('invasive breast cancer', 'Disease', 'MESH:D001943', (192, 214))	('ErbB2', 'Gene', '2064', (85, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('lesions', 'Var', (111, 118))	('non-invasive DCIS', 'Disease', (152, 169))
37805	21058923	Interestingly, HNOSCC patients having overexpression of both 14-3-3sigma and 14-3-3zeta had a significantly decreased median disease-free survival compared to patients showing no overexpression of these two proteins.	('14-3-3sigma', 'Gene', (61, 72))	('HNOSCC', 'Disease', (15, 21))	('14-3-3sigma', 'Gene', '2810', (61, 72))	('patients', 'Species', '9606', (22, 30))	('decreased', 'NegReg', (108, 117))	('overexpression', 'PosReg', (38, 52))	('disease-free survival', 'CPA', (125, 146))	('14-3-3zeta', 'Var', (77, 87))	('patients', 'Species', '9606', (159, 167))
37816	21058923	Several studies in different cancer types suggest that increased gene copy numbers of YWHAZ may be associated with increased protein expression of 14-3-3zeta.	('YWHAZ', 'Gene', (86, 91))	('gene copy numbers', 'Var', (65, 82))	('cancer', 'Disease', (29, 35))	('YWHAZ', 'Gene', '7534', (86, 91))	('increased', 'PosReg', (115, 124))	('protein expression', 'MPA', (125, 143))	('increased', 'PosReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
37818	21058923	Of the ten genes in this region, two genes, YWHAZ and POLR2K, were found to have a strong correlation between high copy numbers and high gene expression.	('POLR2K', 'Gene', (54, 60))	('high gene expression', 'MPA', (132, 152))	('YWHAZ', 'Gene', '7534', (44, 49))	('YWHAZ', 'Gene', (44, 49))	('high', 'Var', (110, 114))	('POLR2K', 'Gene', '5440', (54, 60))
37821	21058923	Similarly, amplification and chromosome 8 polysomy contributes to increased YWHAZ gene copy numbers in breast cancer.	('polysomy', 'Var', (42, 50))	('YWHAZ', 'Gene', (76, 81))	('increased', 'PosReg', (66, 75))	('YWHAZ', 'Gene', '7534', (76, 81))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('amplification', 'Var', (11, 24))
37823	21058923	Another recent study in breast cancer found that amplification of the chromosomal 8q22 region contained 12 genes, including YWHAZ, associated with metastatic recurrence.	('amplification', 'Var', (49, 62))	('YWHAZ', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('metastatic recurrence', 'Disease', (147, 168))	('YWHAZ', 'Gene', '7534', (124, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))	('associated with', 'Reg', (131, 146))
37824	21058923	Amplification of 8q22 was correlated with increased expression of the 12 genes and was found to be a strong independent prognostic factor for breast cancer recurrence.	('increased', 'PosReg', (42, 51))	('8q22', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('expression', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))
37825	21058923	These studies suggest amplification may be a common mechanism leading to 14-3-3zeta overexpression in multiple cancers, although mechanisms independent of increased gene copy number, such as modulation of 14-3-3zeta gene transcription, protein translation, or RNA and protein stability may also contribute to increased 14-3-3zeta expression.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('overexpression', 'PosReg', (84, 98))	('multiple cancers', 'Disease', 'MESH:D009369', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('expression', 'MPA', (330, 340))	('protein', 'Protein', (268, 275))	('amplification', 'Var', (22, 35))	('RNA', 'MPA', (260, 263))	('modulation', 'Var', (191, 201))	('multiple cancers', 'Disease', (102, 118))	('leading', 'Reg', (62, 69))	('increased', 'PosReg', (309, 318))
37832	21058923	High expression of two tamoxifen stimulated genes, YWHAZ/14-3-3zeta and LOC441453, were found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive breast cancers, suggesting 14-3-3zeta overexpression may contribute to tamoxifen resistance.	('tamoxifen', 'Chemical', 'MESH:D013629', (23, 32))	('YWHAZ', 'Gene', '7534', (51, 56))	('YWHAZ', 'Gene', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('contribute', 'Reg', (258, 268))	('disease', 'Disease', (126, 133))	('tamoxifen', 'Chemical', 'MESH:D013629', (272, 281))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancers', 'Phenotype', 'HP:0003002', (201, 215))	('women', 'Species', '9606', (178, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (155, 164))	('breast cancers', 'Disease', 'MESH:D001943', (201, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancers', 'Disease', (201, 215))	('LOC441453', 'Var', (72, 81))
37833	21058923	Additionally, amplification of 8q22 was associated with the increased expression of 12 genes in this region and chemo resistance in breast cancer.	('amplification', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('8q22', 'Gene', (31, 35))	('expression', 'MPA', (70, 80))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('increased', 'PosReg', (60, 69))	('chemo resistance', 'CPA', (112, 128))
37834	21058923	8q22 amplification led to overexpression of 8q22 genes in tumor tissue, which was associated with poor prognosis in untreated cases and increased disease recurrence despite adjuvant chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('8q22', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('overexpression', 'PosReg', (26, 40))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increased', 'PosReg', (136, 145))	('disease recurrence', 'CPA', (146, 164))	('8q22 genes', 'Gene', (44, 54))
37836	21058923	The increased sensitivity was specifically to anthracyclines but not cisplatin or paclitaxel.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('anthracyclines', 'Chemical', 'MESH:D018943', (46, 60))	('sensitivity', 'MPA', (14, 25))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('anthracyclines', 'Var', (46, 60))
37841	21058923	Increased expression of 14-3-3zeta was also detected in patients with DLBCL, and 14-3-3zeta may lead to CHOP resistance in these patients.	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (129, 137))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('lead to', 'Reg', (96, 103))	('CHOP', 'Gene', '1649', (104, 108))	('DLBCL', 'Disease', (70, 75))	('14-3-3zeta', 'Var', (81, 91))	('CHOP', 'Gene', (104, 108))
37849	21058923	In lung cancer, 14-3-3zeta knockdown by siRNA increased the sensitivity to cisplatin both in vitro and in vivo.	('knockdown', 'Var', (27, 36))	('lung cancer', 'Disease', (3, 14))	('increased', 'PosReg', (46, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('sensitivity to cisplatin', 'MPA', (60, 84))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))
37851	21058923	Several other studies in multiple cancer types have shown that knock down of 14-3-3zeta via antisense or siRNA is effective at reducing tumor growth and sensitizing cancer cells to apoptosis inducing agents.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('sensitizing', 'Reg', (153, 164))	('knock down', 'Var', (63, 73))	('reducing', 'NegReg', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('antisense', 'Var', (92, 101))	('multiple cancer', 'Disease', (25, 40))	('siRNA', 'MPA', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('apoptosis', 'CPA', (181, 190))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('14-3-3zeta', 'Gene', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('multiple cancer', 'Disease', 'MESH:D009369', (25, 40))
37852	21058923	These studies suggest using siRNA or antisense RNA to knockdown 14-3-3zeta expression in tumors may be a potential therapeutic strategy; however, the clinical feasibility of using siRNA or anti-sense as therapies is still a challenge that needs to be met.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('knockdown', 'Var', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('14-3-3zeta', 'Gene', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
37855	21058923	In BCR-ABL transformed cells the R18 dimer effectively induced apoptosis, in part through liberation and reactivation of FOXO3a but not by disrupting 14-3-3/BCR-ABL association or BCR-ABL tyrosine kinase activity.	('BCR-ABL', 'Gene', (180, 187))	('BCR-ABL', 'Gene', '25', (180, 187))	('reactivation', 'MPA', (105, 117))	('FOXO3a', 'Gene', '2309', (121, 127))	('BCR-ABL', 'Gene', (3, 10))	('BCR-ABL', 'Gene', '25', (3, 10))	('BCR-ABL', 'Gene', (157, 164))	('liberation', 'MPA', (90, 100))	('apoptosis', 'CPA', (63, 72))	('FOXO3a', 'Gene', (121, 127))	('BCR-ABL', 'Gene', '25', (157, 164))	('induced', 'Reg', (55, 62))	('R18 dimer', 'Var', (33, 42))
37856	21058923	Furthermore, cells expressing imatinib-resistant BCR-ABL mutants were more susceptible to apoptosis by R18 alone or in combination with signaling pathway inhibitors.	('susceptible', 'Reg', (75, 86))	('apoptosis', 'CPA', (90, 99))	('BCR-ABL', 'Gene', (49, 56))	('imatinib', 'Chemical', 'MESH:D000068877', (30, 38))	('mutants', 'Var', (57, 64))	('BCR-ABL', 'Gene', '25', (49, 56))
37857	21058923	Similarly, glioma cell lines showed increased apoptosis in vitro following knockdown of 14-3-3 via siRNA or inhibition via difopein.	('14-3-3', 'Gene', (88, 94))	('apoptosis', 'CPA', (46, 55))	('inhibition', 'NegReg', (108, 118))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('knockdown', 'Var', (75, 84))	('glioma', 'Disease', (11, 17))
37859	21058923	While R18/difopein is an effective inhibitor of 14-3-3 target binding, it is a global inhibitor of 14-3-3 and is not specific to any isoform, such as 14-3-3 zeta.	('binding', 'Interaction', (62, 69))	('14-3-3 zeta', 'Gene', '7534', (150, 161))	('R18/difopein', 'Var', (6, 18))	('14-3-3 zeta', 'Gene', (150, 161))
37862	21058923	In contrast, knockdown of 14-3-3zeta reduced tumor growth and sensitized cells to chemotherapeutic agents.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('sensitized', 'Reg', (62, 72))	('tumor', 'Disease', (45, 50))	('reduced', 'NegReg', (37, 44))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
37868	21058923	Gene amplification may be a common mechanism leading to 14-3-3zeta overexpression in multiple cancers.	('14-3-3zeta', 'Protein', (56, 66))	('multiple cancers', 'Disease', 'MESH:D009369', (85, 101))	('overexpression', 'PosReg', (67, 81))	('Gene amplification', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('multiple cancers', 'Disease', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))
37873	21058923	Many studies have shown that 14-3-3zeta regulates central pathways critical for maintenance of the transformed phenotype and 14-3-3zeta overexpression may activate or enhance numerous pathways that contribute to cancer development and progression.	('enhance', 'PosReg', (167, 174))	('regulates', 'Reg', (40, 49))	('activate', 'PosReg', (155, 163))	('14-3-3zeta overexpression', 'Var', (125, 150))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('overexpression', 'Var', (136, 150))	('central pathways', 'Pathway', (50, 66))	('pathways', 'Pathway', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
37877	21058923	In addition, the tumor profile of mice infected with a Polyomavirus middle T antigen (MT) mutant defective in 14-3-3 binding showed a striking deficiency in the induction of salivary gland tumors but not other tumor types.	('mutant', 'Var', (90, 96))	('binding', 'Interaction', (117, 124))	('salivary gland tumors', 'Disease', 'MESH:D012468', (174, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('defective', 'NegReg', (97, 106))	('14-3-3', 'Protein', (110, 116))	('tumor', 'Disease', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (34, 38))	('Polyomavirus middle T', 'Disease', (55, 76))	('deficiency', 'NegReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (174, 195))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('Polyomavirus middle T', 'Disease', 'MESH:D020244', (55, 76))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('salivary gland tumors', 'Disease', (174, 195))
37904	21058923	Overexpression of 14-3-3zeta is associated with diverse cancer types and regulates pathways that promote cancer initiation and progression.	('cancer initiation', 'Disease', 'MESH:D009369', (105, 122))	('cancer initiation', 'Disease', (105, 122))	('cancer', 'Disease', (105, 111))	('progression', 'CPA', (127, 138))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pathways', 'Pathway', (83, 91))	('Overexpression', 'Var', (0, 14))	('regulates', 'Reg', (73, 82))	('associated', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('promote', 'PosReg', (97, 104))
37905	21058923	14-3-3zeta overexpression and gene amplification are correlated with poor prognosis and chemoresistance in cancer patients.	('14-3-3zeta', 'Protein', (0, 10))	('poor prognosis', 'CPA', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('chemoresistance', 'CPA', (88, 103))	('gene amplification', 'Var', (30, 48))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (114, 122))	('overexpression', 'PosReg', (11, 25))	('cancer', 'Disease', (107, 113))
37926	17848911	The planned use of adjuvant RT also showed a strong relationship with VNPI, increasing from 27.1% for tumours with a score of 3 or 4, to 68.2% for tumours with a score of 5, 6 or 7 and 79.5% for tumours with a score of 8 or 9 (Table 1).	('VNPI', 'Disease', (70, 74))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('score', 'Var', (117, 122))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('tumours', 'Disease', (147, 154))	('increasing', 'PosReg', (76, 86))	('tumours', 'Disease', (102, 109))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
37977	29722170	In the ICD-O-3, the codes are defined as follows: code 8500 (ductal carcinoma), code 8540 (mammary Paget disease), code 8541 (Paget disease with infiltrating ductal carcinoma), and code 8543 (Paget disease with intraductal carcinoma).	('code 8543', 'Var', (181, 190))	('ductal carcinoma', 'Disease', 'MESH:D044584', (61, 77))	('ductal carcinoma', 'Disease', (61, 77))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (61, 77))	('ductal carcinoma', 'Disease', 'MESH:D044584', (216, 232))	('ductal carcinoma', 'Disease', 'MESH:D044584', (158, 174))	('ductal carcinoma', 'Disease', (158, 174))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (216, 232))	('code 8500', 'Var', (50, 59))	('intraductal carcinoma', 'Disease', (211, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('code 8541', 'Var', (115, 124))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (158, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('intraductal carcinoma', 'Disease', 'MESH:D002285', (211, 232))	('code 8540', 'Var', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
38070	24520039	In addition, low dose BPA exposure on the early differentiation stage of mammary epithelial cells has been associated with possible cancer risk in the in vitro model of human embryonic stem cell.	('cancer', 'Disease', (132, 138))	('associated', 'Reg', (107, 117))	('low dose', 'Var', (13, 21))	('exposure', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (169, 174))	('BPA', 'Chemical', 'MESH:C006780', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
38074	24520039	Modulation of oncogenes and tumor suppressors has been shown to increase MaSC self-renewal suggesting that alteration of MaSC frequency and function may lead to transformation and tumorigenesis.	('transformation', 'CPA', (161, 175))	('Modulation', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('increase', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('alteration', 'Var', (107, 117))	('MaSC self-renewal', 'CPA', (73, 90))	('oncogenes', 'Protein', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('lead to', 'Reg', (153, 160))
38166	24520039	Consistent with this observation, breast tissue from BRCA1 mutation carriers generally showed an increase in LPs relative to the total epithelial cells.	('increase', 'PosReg', (97, 105))	('LPs', 'CPA', (109, 112))	('mutation', 'Var', (59, 67))	('BRCA1', 'Gene', '12189', (53, 58))	('LPs', 'Chemical', '-', (109, 112))	('BRCA1', 'Gene', (53, 58))
38168	24520039	These findings indicate a possible correlation between increased LPs in mammary epithelium and mammary gland transformation potential.	('LPs', 'Var', (65, 68))	('LPs', 'Chemical', '-', (65, 68))	('mammary gland transformation potential', 'CPA', (95, 133))	('increased LPs', 'Phenotype', 'HP:0003141', (55, 68))
38213	23604310	Further, we showed that exon skip and intron retention are predominant splice events in breast cancer.	('exon skip', 'Var', (24, 33))	('intron', 'MPA', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
38219	23604310	The process of generating novel cancer-specific isoforms is driven by alterations at several layers such as alternative pre-RNAs, promoter usage, and splicing and polyadenylation that alters coding regions and consequently, the function of the resulting proteins.	('alterations', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('proteins', 'Protein', (254, 262))	('cancer', 'Disease', (32, 38))	('alters', 'Reg', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('polyadenylation', 'Var', (163, 178))	('coding regions', 'MPA', (191, 205))	('function', 'MPA', (228, 236))
38228	23604310	Recent studies have identified specific variants of TP53, SYK, BRCA1, and MUC1 in breast cancer, as well as splice variants of many genes that play important functional roles in tumor progression.	('breast cancer', 'Disease', (82, 95))	('tumor', 'Disease', (178, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('TP53', 'Gene', '7157', (52, 56))	('BRCA1', 'Gene', (63, 68))	('MUC1', 'Gene', (74, 78))	('SYK', 'Gene', (58, 61))	('TP53', 'Gene', (52, 56))	('MUC1', 'Gene', '4582', (74, 78))	('SYK', 'Gene', '6850', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('variants', 'Var', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('BRCA1', 'Gene', '672', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
38238	23604310	To detect the TNBC, non-TNBC and HER2-positive breast cancer-specific splice events such as exon skip, exon inclusion, transcript start and termination and intron retention, we employed a direct exon model comparison analysis as well as multivariate analysis.	('HER2-positive breast cancer', 'Disease', (33, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('transcript', 'MPA', (119, 129))	('exon', 'Var', (103, 107))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (33, 60))	('exon skip', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
38253	23604310	The distribution of the differentially spliced transcripts for the three cancer types is shown on Supplemental Figure 8; from them, 322, 246 and 368 isoforms are almost exclusively expressed in TNBC, non-TNBC and HER2-positive breast cancer samples, respectively, and are not present in NBS (Supplemental Files 8-10).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('HER2-positive breast cancer', 'Disease', (213, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (213, 240))	('TNBC', 'Var', (194, 198))
38262	23604310	Aberrant splicing and cancer specific splice variants represent emerging cancer biomarkers.	('splice variants', 'Var', (38, 53))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Aberrant splicing', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
38285	23604310	Intron retention and exon skipping appear to be the most predominant splice events in all three breast cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('exon skipping', 'Var', (21, 34))	('Intron retention', 'Var', (0, 16))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('predominant', 'Reg', (57, 68))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
38293	23604310	In both cases, a suggested mechanism of action is through overexpression in the cancer cells of functional protein, which is suppressed in the NBS through a mechanism of exon exclusion.	('functional protein', 'Protein', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('overexpression', 'PosReg', (58, 72))	('exon', 'Var', (170, 174))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
38321	23604310	Cancer specific splice variants of genes that control the cell proliferation and DNA damage (e.g.	('Cancer', 'Disease', (0, 6))	('splice variants', 'Var', (16, 31))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
38339	23604310	Our datasets highlighted multiple genes that are regulated through differential promoter usage or promoter switch in a cancer subtype specific manner.	('promoter switch', 'Var', (98, 113))	('differential promoter usage', 'Var', (67, 94))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
38355	23604310	Additionally, for consistency checking and independent validation we used an in-house built program (http://genomics.jhu.edu/software/ASproFile/) to compare the exon models between isoforms assembled with the program cufflinks for the normal and cancer samples (as mentioned earlier, only the isoforms that are similar to reference and isoforms that comprise novel splice junctions were considered), and determine the splicing differences indicative of exon inclusion, exclusion, alternative 5', 3', and intron retention events.	('cancer', 'Disease', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('exon', 'Var', (453, 457))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
38408	27708222	Interestingly, in agreement with our previous findings, we also detected a preferential decrease in gene expression in the early stage of DCIS progression, which suggests that the invasion capability that is manifested in epithelial tumor cells in the early phase of the process may be enhanced by the inactivation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('decrease', 'NegReg', (88, 96))	('epithelial tumor', 'Disease', (222, 238))	('tumor', 'Disease', (233, 238))	('invasion capability', 'CPA', (180, 199))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('epithelial tumor', 'Phenotype', 'HP:0031492', (222, 238))	('inactivation', 'Var', (302, 314))	('enhanced', 'PosReg', (286, 294))	('epithelial tumor', 'Disease', 'MESH:D002277', (222, 238))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('gene expression', 'MPA', (100, 115))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
38412	27708222	Both genes are associated with players in important cancer-related pathways, including p38 MAPK, PI3K, ERK1/2, JNK and TGF-beta.	('MAPK', 'Gene', (91, 95))	('MAPK', 'Gene', '5595;5594;5595', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('JNK', 'Gene', (111, 114))	('ERK1/2', 'Gene', (103, 109))	('ERK1/2', 'Gene', '5595;5594', (103, 109))	('TGF-beta', 'Gene', '7040', (119, 127))	('JNK', 'Gene', '5599', (111, 114))	('associated', 'Reg', (15, 25))	('TGF-beta', 'Gene', (119, 127))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('PI3K', 'Disease', (97, 101))	('p38', 'Var', (87, 90))
38419	27708222	RARRES3 is thought to act as a tumor suppressor or growth regulator that suppresses metastasis; it has also been associated with the modulation of the acylation status of Wnt proteins to suppress EMT and cancer stem cell properties.	('cancer', 'Disease', (204, 210))	('EMT', 'Gene', (196, 199))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EMT', 'Gene', '3702', (196, 199))	('suppress', 'NegReg', (187, 195))	('tumor', 'Disease', (31, 36))	('RARRES3', 'Gene', (0, 7))	('metastasis', 'CPA', (84, 94))	('RARRES3', 'Gene', '5920', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('acylation status', 'MPA', (151, 167))	('modulation', 'Var', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('associated', 'Reg', (113, 123))	('suppresses', 'NegReg', (73, 83))
38423	27708222	Evidences show that inactivation of INPP1 leads to a reduction in glycolytic intermediates; this reduction impairs cancer cell motility, invasiveness, and tumorigenicity via a complex feed-forward mechanism.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('INPP1', 'Gene', '3628', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('inactivation', 'Var', (20, 32))	('reduction', 'NegReg', (53, 62))	('glycolytic intermediates', 'MPA', (66, 90))	('tumor', 'Disease', (155, 160))	('INPP1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('reduction impairs cancer', 'Disease', (97, 121))	('invasiveness', 'CPA', (137, 149))	('reduction impairs cancer', 'Disease', 'MESH:D009422', (97, 121))
38431	27708222	More recently, polymorphisms in the POSTN gene have been associated with breast cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('POSTN', 'Gene', '10631', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('POSTN', 'Gene', (36, 41))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('polymorphisms', 'Var', (15, 28))	('associated', 'Reg', (57, 67))
38743	31015465	Cancer has historically been thought of as a genetic disease, with tumors arising from genetic mutations in DNA.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('DNA', 'Gene', (108, 111))	('genetic disease', 'Disease', 'MESH:D030342', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('genetic disease', 'Disease', (45, 60))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic mutations', 'Var', (87, 104))	('tumors', 'Disease', (67, 73))
38766	31015465	All plasmids in this study have been banked in Addgene using the following ID numbers: pLenti-GAL4 (121514), pLenti-sgYAP-2 (121423), pLenti-sgYAP-10 (121424), pLenti-sgSTAT3-1 (121425), pLenti-EGFP (121426), and pLenti-STAT3-linker-EGFP (121427).	('GAL4', 'Gene', '3960', (94, 98))	('STAT3', 'Gene', '6774', (169, 174))	('121423', 'Var', (125, 131))	('YAP', 'Gene', '10413', (118, 121))	('STAT3', 'Gene', (220, 225))	('STAT3', 'Gene', (169, 174))	('STAT3', 'Gene', '6774', (220, 225))	('121425', 'Var', (178, 184))	('121426', 'Var', (200, 206))	('YAP', 'Gene', '10413', (143, 146))	('YAP', 'Gene', (118, 121))	('121514', 'Var', (100, 106))	('YAP', 'Gene', (143, 146))	('GAL4', 'Gene', (94, 98))	('121424', 'Var', (151, 157))
38887	24829621	Luminal tumors are ER and PR-positive whereas HER2-positive tumors arise from overexpression or amplification of the EGFR family of receptor tyrosine kinases, particularly HER2 (also called ErbB2, neu).	('amplification', 'Var', (96, 109))	('neu', 'Gene', '2064', (197, 200))	('ER', 'Gene', '2099', (47, 49))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('neu', 'Gene', (197, 200))	('overexpression', 'PosReg', (78, 92))	('ER', 'Gene', '2099', (173, 175))	('PR', 'Gene', '5241', (26, 28))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('ER', 'Gene', '2099', (19, 21))	('tumors', 'Disease', (60, 66))
38892	24829621	ER and its ligand estrogen are key regulators in breast cancer carcinogenesis, and modulation of the receptor or reduction of estrogen are strategies for reduction of breast cancer risk.	('ER', 'Gene', '2099', (0, 2))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('breast cancer carcinogenesis', 'Disease', (49, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('reduction of breast cancer', 'Disease', (154, 180))	('modulation', 'Var', (83, 93))	('reduction of breast cancer', 'Disease', 'MESH:D001943', (154, 180))	('reduction', 'NegReg', (113, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('rat', 'Species', '10116', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer carcinogenesis', 'Disease', 'MESH:D063646', (49, 77))
38931	24829621	Results from phase II studies suggest that E75, in particular when administered in the adjuvant setting, prevents disease recurrence among selected high-risk patients.	('patients', 'Species', '9606', (158, 166))	('E75', 'Var', (43, 46))	('prevents', 'NegReg', (105, 113))	('disease recurrence', 'CPA', (114, 132))
38952	24829621	Moreover, concerns about rare serious toxicity, cardiovascular toxicity associated with COX-2 inhibitors, and other known potential side effects of treatment with NSAIDS, for example gastrointestinal bleeding and perforation, should be taken into account before routine implementation of NSAIDS as chemoprevention for breast cancer.	('cardiovascular toxicity', 'Disease', 'MESH:D002318', (48, 71))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (183, 208))	('toxicity', 'Disease', 'MESH:D064420', (63, 71))	('cardiovascular toxicity', 'Disease', (48, 71))	('COX-2', 'Gene', '5743', (88, 93))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (63, 71))	('men', 'Species', '9606', (153, 156))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (183, 208))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('gastrointestinal bleeding', 'Disease', (183, 208))	('inhibitors', 'Var', (94, 104))	('toxicity', 'Disease', (38, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (318, 331))	('men', 'Species', '9606', (275, 278))	('COX-2', 'Gene', (88, 93))	('rat', 'Species', '10116', (218, 221))	('breast cancer', 'Disease', 'MESH:D001943', (318, 331))	('breast cancer', 'Disease', (318, 331))
38956	24829621	Upon disruption of mitochondrial complex I, AMP/ATP and ADP/ATP ratios are increased which activates AMPK (Fig.	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('AMPK', 'MPA', (101, 105))	('ADP', 'Chemical', 'MESH:D000244', (56, 59))	('AMP', 'Chemical', 'MESH:D000249', (101, 104))	('disruption', 'Var', (5, 15))	('AMP', 'Chemical', 'MESH:D000249', (44, 47))	('rat', 'Species', '10116', (64, 67))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('AMP/ATP', 'MPA', (44, 51))	('increased', 'PosReg', (75, 84))	('mitochondrial', 'Protein', (19, 32))	('ADP/ATP ratios', 'MPA', (56, 70))
38961	24829621	Moreover, other retrospective studies have demonstrated that metformin, in particular, reduces the risk of breast cancer compared with other antidiabetic therapy (e.g., insulin, alpha-glucosidase inhibitors, prandial glucose regulators, sulfonylureas, thiazolidinediones).	('thiazolidinediones', 'Chemical', 'MESH:D045162', (252, 270))	('insulin', 'Gene', '3630', (169, 176))	('metformin', 'Chemical', 'MESH:D008687', (61, 70))	('rat', 'Species', '10116', (50, 53))	('reduces', 'NegReg', (87, 94))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('sulfonylureas', 'Chemical', 'MESH:D013453', (237, 250))	('breast cancer', 'Disease', (107, 120))	('glucose', 'Chemical', 'MESH:D005947', (217, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('alpha-glucosidase', 'Gene', '6476', (178, 195))	('metformin', 'Var', (61, 70))	('alpha-glucosidase', 'Gene', (178, 195))	('insulin', 'Gene', (169, 176))
38979	24829621	After a median follow-up of eight years, fenretinide treatment did not reduce the incidence of second breast cancers overall; when given to premenopausal women, however, fenretinide resulted in significant (38 %) reduction of the risk of second breast cancers (Table 2).	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('men', 'Species', '9606', (143, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (102, 116))	('fenretinide', 'Chemical', 'MESH:D017313', (170, 181))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('fenretinide', 'Chemical', 'MESH:D017313', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('breast cancers', 'Disease', 'MESH:D001943', (245, 259))	('breast cancers', 'Disease', (245, 259))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancers', 'Disease', 'MESH:D001943', (102, 116))	('breast cancers', 'Disease', (102, 116))	('men', 'Species', '9606', (156, 159))	('fenretinide', 'Var', (170, 181))	('women', 'Species', '9606', (154, 159))	('breast cancers', 'Phenotype', 'HP:0003002', (245, 259))	('reduction', 'NegReg', (213, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('men', 'Species', '9606', (58, 61))
38981	24829621	bexarotene and LG100268) activate RXR without activating RAR nuclear receptors.	('RXR', 'Gene', (34, 37))	('activate', 'PosReg', (25, 33))	('RAR', 'Gene', '5914', (57, 60))	('LG100268', 'Chemical', 'MESH:C095104', (15, 23))	('RXR', 'Gene', '6256', (34, 37))	('LG100268', 'Var', (15, 23))	('bexarotene', 'Chemical', 'MESH:D000077610', (0, 10))	('RAR', 'Gene', (57, 60))
38989	24829621	Our laboratory has previously shown that the rexinoid LG100268 can prevent ER-negative/HER2 positive mammary tumors in preclinical mouse models and delay TNBC development.	('TNBC development', 'CPA', (154, 170))	('rat', 'Species', '10116', (8, 11))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('rexinoid', 'Chemical', '-', (45, 53))	('mouse', 'Species', '10090', (131, 136))	('men', 'Species', '9606', (166, 169))	('ER', 'Gene', '2099', (75, 77))	('delay', 'NegReg', (148, 153))	('LG100268', 'Chemical', 'MESH:C095104', (54, 62))	('ER', 'Gene', '2099', (88, 90))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('prevent', 'NegReg', (67, 74))	('tumors', 'Disease', (109, 115))	('LG100268', 'Var', (54, 62))
38990	24829621	Moreover, combination therapy using LG100268 and a synthetic triterpenoid, CDDO-methyl amide, synergistically suppressed ER-negative/HER2 positive mammary tumors (Table 1).	('ER', 'Gene', '2099', (121, 123))	('CDDO-methyl amide', 'Chemical', 'MESH:C530803', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('LG100268', 'Chemical', 'MESH:C095104', (36, 44))	('triterpenoid', 'Chemical', '-', (61, 73))	('ER', 'Gene', '2099', (134, 136))	('suppressed', 'NegReg', (110, 120))	('LG100268', 'Var', (36, 44))
39005	24829621	Inhibition of PARP-1 is a promising approach for targeted prevention of breast cancer, especially among women with deleterious BRCA mutations.	('PARP-1', 'Gene', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA', 'Gene', '672', (127, 131))	('PARP-1', 'Gene', '142', (14, 20))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA', 'Gene', (127, 131))	('women', 'Species', '9606', (104, 109))
39010	24829621	However, PARP inhibitors may be found to be useful for cancer prevention in the future, considering approximately 55 to 65 % of BRCA1 mutation carriers will develop breast cancer by age 70 years.	('PARP', 'Gene', (9, 13))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('PARP', 'Gene', '142', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutation', 'Var', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('BRCA1', 'Gene', '672', (128, 133))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (55, 61))	('BRCA1', 'Gene', (128, 133))	('develop', 'PosReg', (157, 164))
39083	19197974	HER-2 positive cancer has been found to have more multiple mass lesions than its HER-2 negative counterparts (57% vs. 15%).	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('HER-2', 'Gene', '2064', (81, 86))	('positive', 'Var', (6, 14))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', (81, 86))	('HER-2', 'Gene', '2064', (0, 5))	('multiple mass lesions', 'CPA', (50, 71))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
39090	19197974	Spiculated margins are usually associated with IDC and less commonly with tubular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('associated', 'Reg', (31, 41))	('Spiculated', 'Var', (0, 10))	('tubular carcinoma', 'Disease', (74, 91))	('IDC', 'Disease', (47, 50))	('tubular carcinoma', 'Disease', 'MESH:D000230', (74, 91))
39109	19197974	Among the non-mass-like enhancement patterns, stippled enhancement is most frequently associated with benign lesions and has a 25% incidence of malignancy while homogenous, heterogeneous and clumped enhancement have a higher cancer likelihood of 67%, 53%-69%, and 60%-88%, respectively.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('malignancy', 'Disease', (144, 154))	('cancer', 'Disease', (225, 231))	('associated', 'Reg', (86, 96))	('benign lesions', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('stippled enhancement', 'Var', (46, 66))	('malignancy', 'Disease', 'MESH:D009369', (144, 154))
39264	25714649	High nuclear grade nonsignificantly increased the risk of DCIS patients having LIR from the pooled result of the RCTs (HR=1.33; 95% CI 0.86-1.79).	('High nuclear grade', 'Var', (0, 18))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('LIR', 'Disease', (79, 82))	('patients', 'Species', '9606', (63, 71))
39265	25714649	However, according to results from observational studies, the high nuclear grade nonsignificantly decreased the risk of DCIS patients having LIR (HR=0.97; 95% CI 0.75-1.19).	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('DCIS', 'Disease', (120, 124))	('decreased', 'NegReg', (98, 107))	('LIR', 'Disease', (141, 144))	('high nuclear grade', 'Var', (62, 80))	('patients', 'Species', '9606', (125, 133))
39281	25714649	A decade later, further suggested that multifocality and nonscreening detection were associated with a higher risk of ipsilateral breast tumor recurrence.	('breast tumor', 'Phenotype', 'HP:0100013', (130, 142))	('ipsilateral breast tumor', 'Disease', (118, 142))	('nonscreening detection', 'Var', (57, 79))	('ipsilateral breast tumor', 'Disease', 'MESH:D001943', (118, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('multifocality', 'Var', (39, 52))
39307	25365327	To our knowledge, only two reports of 3-T breast MRI in patients with suspicious microcalcifications were reported, which stated 3-T MRI increases the diagnostic value in patients with microcalcifications.	('patients', 'Species', '9606', (56, 64))	('3-T', 'Var', (129, 132))	('patients', 'Species', '9606', (171, 179))	('diagnostic value', 'MPA', (151, 167))	('increases', 'PosReg', (137, 146))
39354	23548208	Basal or basal-like breast carcinomas express p63, CK5, CK6, CK14 and CK17 proteins that are typically expressed in myoepithelial cells of the mammary epithelium, while luminal tumors rarely or only transitionally express basal cytokeratins.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('breast carcinomas', 'Phenotype', 'HP:0003002', (20, 37))	('CK5', 'Gene', (51, 54))	('myoepithelial', 'Disease', (116, 129))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('CK17', 'Gene', '3872', (70, 74))	('breast carcinoma', 'Phenotype', 'HP:0003002', (20, 36))	('CK6', 'Var', (56, 59))	('p63', 'Gene', (46, 49))	('p63', 'Gene', '8626', (46, 49))	('CK5', 'Gene', '3852', (51, 54))	('CK14', 'Gene', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CK17', 'Gene', (70, 74))	('myoepithelial', 'Disease', 'MESH:D009208', (116, 129))	('breast carcinomas', 'Disease', 'MESH:D001943', (20, 37))	('Basal', 'Disease', (0, 5))	('breast carcinomas', 'Disease', (20, 37))	('CK14', 'Gene', '3861', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))
39423	23548208	p63 is a classic myoepithelial marker that outlines the myoepithelium of the normal breast; however, expansion of p63+ cells in basal-like breast cancer occurs from differentiation of precursors that give rise to the myoepithelial lineage or from precursors that are scattered at the basal and luminal areas of the ducts.	('myoepithelial', 'Disease', (217, 230))	('myoepithelial', 'Disease', (17, 30))	('myoepithelial', 'Disease', 'MESH:D009208', (217, 230))	('p63', 'Gene', (0, 3))	('myoepithelial', 'Disease', 'MESH:D009208', (17, 30))	('p63', 'Gene', (114, 117))	('p63', 'Gene', '8626', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('p63', 'Gene', '8626', (114, 117))	('expansion', 'Var', (101, 110))
39429	23548208	In this case, expansion of these cells could give rise to atypical p63/Her2-expressing basal-like carcinoma.	('give rise to', 'Reg', (45, 57))	('carcinoma', 'Disease', 'MESH:D002277', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Her2', 'Gene', (71, 75))	('Her2', 'Gene', '2064', (71, 75))	('p63', 'Gene', (67, 70))	('expansion', 'Var', (14, 23))	('carcinoma', 'Disease', (98, 107))	('p63', 'Gene', '8626', (67, 70))
39430	23548208	In such an event, coexpression of p63 and Her2 could potentially direct novel or modified gene expression programs that could further contribute to tumor heterogeneity.	('Her2', 'Gene', '2064', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p63', 'Gene', (34, 37))	('tumor', 'Disease', (148, 153))	('modified', 'Reg', (81, 89))	('contribute', 'Reg', (134, 144))	('p63', 'Gene', '8626', (34, 37))	('direct', 'Reg', (65, 71))	('Her2', 'Gene', (42, 46))	('coexpression', 'Var', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('gene', 'Gene', (90, 94))
39435	23548208	Among the various subtypes of DCIS, comedo-DCIS is associated with high nuclear grade, aneuploidy, higher proliferation rates, and Her2/neu gene amplification or protein overexpression, ER negativity, and clinically aggressive behavior.	('amplification', 'Var', (145, 158))	('comedo-DCIS', 'Disease', (36, 47))	('aneuploidy', 'Disease', (87, 97))	('higher', 'PosReg', (99, 105))	('comedo', 'Phenotype', 'HP:0025249', (36, 42))	('clinically', 'CPA', (205, 215))	('Her2/neu', 'Gene', (131, 139))	('ER', 'Gene', '2099', (186, 188))	('aggressive behavior', 'Phenotype', 'HP:0000718', (216, 235))	('protein', 'Protein', (162, 169))	('DCIS', 'Chemical', '-', (43, 47))	('aneuploidy', 'Disease', 'MESH:D000782', (87, 97))	('DCIS', 'Chemical', '-', (30, 34))	('overexpression', 'PosReg', (170, 184))	('Her2/neu', 'Gene', '2064', (131, 139))
39440	23548208	Based on our data we propose that similar to "DCIS", triple negative breast cancer is not a single disease that is identifiable by triple negativity for ER/PgR/Her2/neu, and positivity for EGFR and CK5 expression, but rather are dynamic entities that may be generated in varying proportions or as transitional intermediates in the heterogeneous milieu of the breast tumor.	('breast tumor', 'Disease', 'MESH:D001943', (359, 371))	('positivity', 'Var', (174, 184))	('PgR', 'Gene', '5241', (156, 159))	('Her2/neu', 'Gene', (160, 168))	('CK5', 'Gene', '3852', (198, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast tumor', 'Phenotype', 'HP:0100013', (359, 371))	('EGFR', 'Gene', '1956', (189, 193))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('breast tumor', 'Disease', (359, 371))	('breast cancer', 'Disease', (69, 82))	('Her2/neu', 'Gene', '2064', (160, 168))	('PgR', 'Gene', (156, 159))	('CK5', 'Gene', (198, 201))	('DCIS', 'Chemical', '-', (46, 50))	('EGFR', 'Gene', (189, 193))	('ER', 'Gene', '2099', (153, 155))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))
39450	23548208	Anonymized DCIS breast tumor sections from 17 comedo-DCIS with microinvasion or recurrence and 12 noncomedo-DCIS with microinvasion or recurrence were acquired after protocol review and approval by the Wayne State University Human Investigation Committee.	('microinvasion', 'Var', (63, 76))	('breast tumor', 'Disease', 'MESH:D001943', (16, 28))	('DCIS', 'Chemical', '-', (53, 57))	('comedo', 'Phenotype', 'HP:0025249', (46, 52))	('comedo', 'Phenotype', 'HP:0025249', (101, 107))	('breast tumor', 'Phenotype', 'HP:0100013', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast tumor', 'Disease', (16, 28))	('Human', 'Species', '9606', (225, 230))	('DCIS', 'Chemical', '-', (108, 112))	('DCIS', 'Chemical', '-', (11, 15))
39454	23548208	The antibodies used for immunohistochemistry and/or immunofluorescence were: anti-p63 (Santa Cruz), anti-CK5 (Dako), anti-Her2 (clone CB11, Life Technologies), anti-EGFR (Cell Signaling), anti-type IV collagen (Dako), anti-ER and anti-PgR (Dako).	('EGFR', 'Gene', (165, 169))	('CK5', 'Gene', (105, 108))	('ER', 'Gene', '2099', (223, 225))	('p63', 'Gene', '8626', (82, 85))	('Her2', 'Gene', (122, 126))	('CK5', 'Gene', '3852', (105, 108))	('PgR', 'Gene', (235, 238))	('PgR', 'Gene', '5241', (235, 238))	('Her2', 'Gene', '2064', (122, 126))	('p63', 'Gene', (82, 85))	('EGFR', 'Gene', '1956', (165, 169))	('anti-type', 'Var', (188, 197))
39569	24691501	Administration of BXL0124 maintained the critical myoepithelial cell layer as well as basement membrane, and animals treated with BXL0124 showed a 43% reduction in tumor volume by week 4.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('BXL0124', 'Chemical', 'MESH:C552206', (130, 137))	('tumor', 'Disease', (164, 169))	('BXL0124', 'Var', (130, 137))	('myoepithelial', 'Disease', (50, 63))	('myoepithelial', 'Disease', 'MESH:D009208', (50, 63))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('BXL0124', 'Chemical', 'MESH:C552206', (18, 25))	('reduction', 'NegReg', (151, 160))
39571	24691501	In addition, the BXL0124 treatment reduced the mRNA levels of matrix metalloproteinases (MMPs) starting at week 3, contributing to the inhibition of invasive transition.	('inhibition', 'NegReg', (135, 145))	('reduced', 'NegReg', (35, 42))	('MMPs', 'Gene', '4313;4318;4323;4324;4325', (89, 93))	('BXL0124', 'Chemical', 'MESH:C552206', (17, 24))	('mRNA levels of', 'MPA', (47, 61))	('MMPs', 'Gene', (89, 93))	('BXL0124', 'Var', (17, 24))	('invasive transition', 'CPA', (149, 168))
39598	24691501	In this report, we investigated the effects of BXL0124 treatment on MCF10DCIS.com xenografts, and found that BXL0124 maintained the integrity of critical structures related to non-cancerous breast lesions which are typically lost during the progression to malignant disease.	('critical structures', 'MPA', (145, 164))	('non-cancerous breast lesions', 'Disease', 'MESH:D001943', (176, 204))	('malignant disease', 'Disease', 'MESH:D009369', (256, 273))	('BXL0124', 'Chemical', 'MESH:C552206', (109, 116))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('BXL0124', 'Chemical', 'MESH:C552206', (47, 54))	('malignant disease', 'Disease', (256, 273))	('BXL0124', 'Var', (109, 116))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('non-cancerous breast lesions', 'Disease', (176, 204))	('integrity', 'MPA', (132, 141))	('maintained', 'Reg', (117, 127))
39619	24691501	For immunofluorescence staining, the slides were blocked in 10% goat serum, and then incubated sequentially overnight at 4 C with the combination of primary antibodies to smooth muscle actin (SMA) (1:200, Abcam, ab5694, Cambridge, MA), laminin 5 (1:50, Santa Cruz Biotechnology, sc13587, Santa Cruz, CA), pancytokeratin (panCK) (1:50, Dako, M3515, Carpinteria, CA) and TO-PRO-3 iodide nuclear antibody (Invitrogen, 1muM).	('muM', 'Gene', '56925', (416, 419))	('1:200', 'Var', (198, 203))	('goat', 'Species', '9925', (64, 68))	('muM', 'Gene', (416, 419))	('PRO', 'Chemical', 'MESH:D011392', (372, 375))	('SMA', 'Chemical', '-', (192, 195))
39635	24691501	Animals treated with BXL0124 showed a reduction in average tumor volume over the first 3 weeks and significant repression was observed by week 4 with a 43% reduction in tumor size (p < 0.05) (Fig.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('reduction', 'NegReg', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BXL0124', 'Chemical', 'MESH:C552206', (21, 28))	('tumor', 'Disease', (169, 174))	('BXL0124', 'Var', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('reduction', 'NegReg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
39639	24691501	The tumors treated with BXL0124 formed DCIS lesions by week 3 and unlike control tumors, maintained these DCIS lesions through week 4, showing approximately 30% invasive histology (p < 0.05) (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('BXL0124', 'Chemical', 'MESH:C552206', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('BXL0124', 'Var', (24, 31))
39641	24691501	The cell proliferation in MCF10DCIS.com tumors remained relatively low through week 3.	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (26, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('MCF10DCIS.com', 'Var', (26, 39))	('cell proliferation', 'CPA', (4, 22))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('low', 'NegReg', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
39643	24691501	Treatment with BXL0124 showed a significant decrease in PCNA levels compared to the control at week 4 (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (15, 22))	('PCNA', 'Gene', '5111', (56, 60))	('decrease', 'NegReg', (44, 52))	('BXL0124', 'Var', (15, 22))	('PCNA', 'Gene', (56, 60))
39650	24691501	However, treatment with BXL0124 not only maintained DCIS histology but also retained VDR levels at week 4 (Fig.	('VDR levels', 'MPA', (85, 95))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('DCIS histology', 'MPA', (52, 66))	('BXL0124', 'Chemical', 'MESH:C552206', (24, 31))	('BXL0124', 'Var', (24, 31))
39657	24691501	There was a gradual establishment of the myoepithelial cell layer starting at week 2, fully forming around the epithelial cells in both the control and BXL0124 treated group by week 3 (Fig.	('myoepithelial', 'Disease', (41, 54))	('BXL0124', 'Var', (152, 159))	('myoepithelial', 'Disease', 'MESH:D009208', (41, 54))	('BXL0124', 'Chemical', 'MESH:C552206', (152, 159))
39665	24691501	Consequently, we assessed the mRNA levels of specific MMPs in MCF10DCIS.com tumor xenografts at weeks 3 and 4.	('MMPs', 'Gene', '4313;4318;4323;4324;4325', (54, 58))	('MMPs', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (62, 75))	('MCF10DCIS.com', 'Var', (62, 75))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
39666	24691501	Analysis of MCF10DCIS.com tumors showed a significant decrease in the mRNA levels of MMP2, 9, 14, and 15 upon BXL0124 treatment at week 3 while MMP16 did not change (Fig.	('decrease', 'NegReg', (54, 62))	('BXL0124', 'Var', (110, 117))	('MMP16', 'Gene', (144, 149))	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('MMP2', 'Gene', '4313', (85, 89))	('MMP16', 'Gene', '4325', (144, 149))	('BXL0124', 'Chemical', 'MESH:C552206', (110, 117))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (12, 25))	('tumors', 'Disease', (26, 32))	('MMP2', 'Gene', (85, 89))
39668	24691501	These observations suggest that reduction of MMP expression by BXL0124 contributes to the inhibition of transition from DCIS to invasive carcinomas.	('inhibition', 'NegReg', (90, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('MMP', 'Protein', (45, 48))	('transition', 'CPA', (104, 114))	('invasive carcinomas', 'Disease', (128, 147))	('reduction', 'NegReg', (32, 41))	('invasive carcinomas', 'Disease', 'MESH:D009361', (128, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('BXL0124', 'Chemical', 'MESH:C552206', (63, 70))	('BXL0124', 'Var', (63, 70))
39677	24691501	BXL0124 does not seem to affect the rate of formation of the myoepithelial layer (Fig.	('myoepithelial', 'Disease', 'MESH:D009208', (61, 74))	('BXL0124', 'Var', (0, 7))	('BXL0124', 'Chemical', 'MESH:C552206', (0, 7))	('myoepithelial', 'Disease', (61, 74))
39679	24691501	Week 4), suggesting that BXL0124 inhibits the transition from DCIS to invasive carcinoma.	('DCIS', 'Disease', (62, 66))	('invasive carcinoma', 'Disease', (70, 88))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('BXL0124', 'Chemical', 'MESH:C552206', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('inhibits', 'NegReg', (33, 41))	('BXL0124', 'Var', (25, 32))	('invasive carcinoma', 'Disease', 'MESH:D009361', (70, 88))
39690	24691501	This suggests that the down-regulation of MMPs by BXL0124 treatment could play a major role in the preservation of DCIS histology.	('BXL0124', 'Chemical', 'MESH:C552206', (50, 57))	('BXL0124', 'Var', (50, 57))	('down-regulation', 'NegReg', (23, 38))	('MMPs', 'Gene', '4313;4318;4323;4324;4325', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('MMPs', 'Gene', (42, 46))
39692	24691501	The significant reduction of the proliferation rate in tumors from BXL0124 treated animals at week 4 demonstrates the potential of BXL0124 to slow the growth of DCIS epithelial cells.	('BXL0124', 'Var', (131, 138))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('reduction', 'NegReg', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('proliferation rate', 'CPA', (33, 51))	('growth of DCIS epithelial cells', 'CPA', (151, 182))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('slow', 'NegReg', (142, 146))	('BXL0124', 'Chemical', 'MESH:C552206', (131, 138))	('BXL0124', 'Chemical', 'MESH:C552206', (67, 74))
39695	24691501	In our study, the BXL0124 treatment not only maintained the integrity of the DCIS structure, but also retained VDR levels in the epithelial cells (Fig.	('integrity', 'MPA', (60, 69))	('BXL0124', 'Var', (18, 25))	('VDR levels', 'MPA', (111, 121))	('BXL0124', 'Chemical', 'MESH:C552206', (18, 25))	('retained', 'Reg', (102, 110))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
39696	24691501	VDR protein levels were higher in BXL0124 treated group when compared to the control group at week 4.	('BXL0124', 'Chemical', 'MESH:C552206', (34, 41))	('BXL0124', 'Var', (34, 41))	('VDR protein levels', 'MPA', (0, 18))	('higher', 'PosReg', (24, 30))
39700	24691501	This further suggests that BXL0124 does not act directly on the myoepithelial cell layer but may exert its anti-tumor effects through a paracrine mechanism from the luminal cells.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('BXL0124', 'Chemical', 'MESH:C552206', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('myoepithelial', 'Disease', (64, 77))	('tumor', 'Disease', (112, 117))	('myoepithelial', 'Disease', 'MESH:D009208', (64, 77))	('BXL0124', 'Var', (27, 34))
39705	24691501	In the present study, BXL0124 inhibited the progression of DCIS to IDC by maintaining the integrity of the myoepithelial cell layer and basement membrane.	('DCIS', 'Disease', (59, 63))	('myoepithelial', 'Disease', (107, 120))	('BXL0124', 'Chemical', 'MESH:C552206', (22, 29))	('IDC', 'Disease', (67, 70))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('inhibited', 'NegReg', (30, 39))	('BXL0124', 'Var', (22, 29))	('maintaining', 'PosReg', (74, 85))	('myoepithelial', 'Disease', 'MESH:D009208', (107, 120))	('integrity', 'MPA', (90, 99))
39795	31062495	Clinicopathological factors were collected based on the index DCIS, including age at diagnosis ( 49 or  50), menopausal status, family history, presentation (clinical or radiological), nuclear grade (low or high/intermediate), size ( 20 mm or  21 mm), ER, and HER2 status, and use of adjuvant treatment (RT, endocrine therapy) for the index DCIS.	('low', 'Var', (200, 203))	('HER2', 'Gene', (260, 264))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('DCIS', 'Phenotype', 'HP:0030075', (341, 345))	('HER2', 'Gene', '2064', (260, 264))	('menopausal status', 'Phenotype', 'HP:0008209', (109, 126))
39940	17164758	Underexpression of the FHIT gene has frequently been linked to human cancer including breast cancer (Pekarsky et al, 2002).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (63, 68))	('FHIT', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('linked', 'Reg', (53, 59))	('Underexpression', 'Var', (0, 15))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
39949	17164758	Our results show that underexpression of FHIT may have some use as a marker of breast disease progression in BBD.	('underexpression', 'Var', (22, 37))	('breast disease', 'Disease', (79, 93))	('FHIT', 'Protein', (41, 45))	('breast disease', 'Disease', 'MESH:D001941', (79, 93))
39970	17164758	Incorporation of Cy3- or Cy5-UTP (Perkin-Elmer Life and Analytical Sciences) was carried out during the IVT stage of the final amplification half-cycle using MEGAscript reagents (Ambion Inc., Cambridgeshire, UK) in accordance with the manufacturer's instructions and the amplified RNA (aRNA) purified using Arcturus Paradise kit reagents.	('Arcturus Paradise', 'Phenotype', 'HP:0001084', (307, 324))	('Cy5-UTP', 'Var', (25, 32))	('Cy3-', 'Var', (17, 21))	('Ca', 'Phenotype', 'HP:0002664', (192, 194))	('Cy3- or Cy5-UTP', 'Chemical', '-', (17, 32))
40008	17164758	Two of three lesions with FHIT underexpression and five of five lesions with normal FHIT expression progressed subsequently to invasive breast cancer, but the difference was not significant (P=0.375).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('invasive breast cancer', 'Disease', (127, 149))	('FHIT', 'Gene', (26, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('underexpression', 'Var', (31, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (127, 149))	('progressed', 'PosReg', (100, 110))
40015	17164758	Loss of BRCA1 is associated with a more aggressive phenotype in sporadic breast cancer (Jarvis et al, 1998; Taylor et al, 1998) and concomitant loss of FHIT and BRCA1 alleles has also been reported in a number of repair-deficient cancers including breast cancer and ovarian cancers (Wilson et al, 1999; Turner et al, 2002; Santos et al, 2004).	('Wilson', 'Disease', (283, 289))	('deficient cancers', 'Disease', 'MESH:D009369', (220, 237))	('deficient cancers', 'Disease', (220, 237))	('BRCA1', 'Gene', '672', (161, 166))	('BRCA1', 'Gene', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('ovarian cancers', 'Disease', (266, 281))	('ovarian cancers', 'Disease', 'MESH:D010051', (266, 281))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('BRCA1', 'Gene', '672', (8, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (64, 86))	('Loss', 'Var', (0, 4))	('BRCA1', 'Gene', (8, 13))	('FHIT', 'Gene', (152, 156))	('loss', 'NegReg', (144, 148))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (248, 261))	('sporadic breast cancer', 'Disease', (64, 86))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('ovarian cancers', 'Phenotype', 'HP:0100615', (266, 281))	('Wilson', 'Disease', 'MESH:D006527', (283, 289))
40018	17164758	In contrast, underexpression of FHIT was associated with lesions with increasing severity (chi2trend=114.31), including four out of 12 DCIS and 14 out of 34 invasive carcinomas.	('invasive carcinomas', 'Disease', (157, 176))	('invasive carcinomas', 'Disease', 'MESH:D009361', (157, 176))	('FHIT', 'Protein', (32, 36))	('underexpression', 'Var', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('DCIS', 'Disease', (135, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))
40063	28068382	In this context, the time delay resulting from preoperative MRI in our study, while statistically significant, is unlikely to have a definite negative impact on patient survival, and may potentially benefit surgical management, as previously discussed.	('benefit', 'Reg', (199, 206))	('MRI', 'Var', (60, 63))	('surgical management', 'CPA', (207, 226))	('patient', 'Species', '9606', (161, 168))
40085	26375517	Alterations in protease activity, involving members of all five major classes of endopeptidases [i.e., aspartic, cysteine, matrix metalloproteinases (MMPs), serine, and threonine proteases], are associated with malignant progression including tumor angiogenesis, invasion and metastasis [for review see Refs.	('associated', 'Reg', (195, 205))	('activity', 'MPA', (24, 32))	('invasion', 'CPA', (263, 271))	('serine', 'Chemical', 'MESH:D012694', (157, 163))	('Alterations', 'Var', (0, 11))	('MMPs', 'Gene', '4312;4313;4314;4317;4320;4323', (150, 154))	('threonine', 'Chemical', 'MESH:D013912', (169, 178))	('MMPs', 'Gene', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cysteine', 'Chemical', 'MESH:D003545', (113, 121))	('metastasis [', 'CPA', (276, 288))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('malignant progression', 'CPA', (211, 232))	('tumor', 'Disease', (243, 248))
40089	26375517	There are several different mechanisms by which proteolysis can be increased during malignant progression including aberrant localization of proteases, gene amplification, increased mRNA stability, altered expression or stability of endogenous inhibitors, and increased acidity at tumor margins leading to pH dependent protease activation.	('proteolysis', 'MPA', (48, 59))	('stability', 'MPA', (220, 229))	('increased', 'PosReg', (172, 181))	('mRNA stability', 'MPA', (182, 196))	('expression', 'MPA', (206, 216))	('activation', 'PosReg', (328, 338))	('localization', 'MPA', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('increased', 'PosReg', (67, 76))	('pH dependent protease', 'Enzyme', (306, 327))	('acidity', 'MPA', (270, 277))	('altered', 'Reg', (198, 205))	('gene amplification', 'Var', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('increased', 'PosReg', (260, 269))	('tumor', 'Disease', (281, 286))
40092	26375517	Moreover, alterations in ion pumps/exchangers such as the V-ATPase proton pumps, which can be found in the plasma membrane, and NHE-1, the sodium-hydrogen ion exchanger, can contribute to the acidification of the tumor microenvironment.	('tumor', 'Disease', (213, 218))	('ion pumps/exchangers', 'MPA', (25, 45))	('acidification', 'MPA', (192, 205))	('alterations', 'Var', (10, 21))	('NHE-1', 'Gene', (128, 133))	('NHE-1', 'Gene', '6548', (128, 133))	('contribute', 'Reg', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('hydrogen', 'Chemical', 'MESH:D006859', (146, 154))	('V-ATPase proton pumps', 'MPA', (58, 79))	('sodium', 'Chemical', 'MESH:D012964', (139, 145))
40096	26375517	Gillies and colleagues have hypothesized that acidification of the tumor microenvironment promotes tumor invasion and metastasis by stimulating stromal remodeling.	('stimulating', 'Reg', (132, 143))	('tumor', 'Disease', (99, 104))	('metastasis', 'CPA', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('acidification', 'Var', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (67, 72))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('stromal remodeling', 'CPA', (144, 162))
40102	26375517	Using a murine window chamber model, we have shown that neutralizing the acidic pH of the tumor microenvironment with sodium bicarbonate can reduce the invasive potential of tumors.	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (118, 136))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('reduce', 'NegReg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('sodium bicarbonate', 'MPA', (118, 136))	('neutralizing', 'Var', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('murine', 'Species', '10090', (8, 14))
40142	26375517	In breast cancer animal models, GB123 tagged with Cy5 and GB137 with near-infrared fluorescent tags reached a maximal signal to background ratio in 6 h and the signal then lasted for an extended period.	('Cy5', 'Var', (50, 53))	('GB137', 'Gene', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('Cy5', 'Chemical', 'MESH:C085321', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('GB123', 'Chemical', '-', (32, 37))	('GB123', 'Gene', (32, 37))
40143	26375517	Edgington and coworkers demonstrated optical imaging of apoptosis by caspases-3 and -7 with ABPs, AB50-Cy5 and tAB50-Cy5, in mouse xenograft models bearing human colorectal tumor cells.	('colorectal tumor', 'Disease', (162, 178))	('AB50-Cy5', 'Chemical', 'MESH:C573545', (112, 120))	('AB50-Cy5', 'Chemical', 'MESH:C573545', (98, 106))	('colorectal tumor', 'Disease', 'MESH:D015179', (162, 178))	('AB50-Cy5', 'Var', (98, 106))	('mouse', 'Species', '10090', (125, 130))	('ABPs', 'Gene', (92, 96))	('caspases-3 and -7', 'Gene', '12367;12369', (69, 86))	('tAB50-Cy5', 'Chemical', '-', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('apoptosis', 'CPA', (56, 65))	('human', 'Species', '9606', (156, 161))
40146	26375517	Nonetheless, ABPs have been shown to have a minimal effect on cysteine cathepsin activity in vivo, likely due to the low doses used for imaging.	('cysteine cathepsin activity', 'MPA', (62, 89))	('ABPs', 'Var', (13, 17))	('cysteine', 'Chemical', 'MESH:D003545', (62, 70))
40159	26375517	Many proteases are redirected to the plasma membrane and/or secreted into the tumor microenvironment of cancers, yet changes in trafficking of proteases may not necessarily increase proteolytic activity unless other factors, including proper localization of protease receptors and activators (such as uPAR and MMP14), the absence of endogenous protease inhibitors [such as tissue inhibitor of metalloproteinases (TIMPs) and serpins], and pericellular acidification also occur.	('MMP14', 'Gene', (310, 315))	('uPAR', 'Gene', (301, 305))	('serpins', 'Protein', (424, 431))	('pericellular acidification', 'CPA', (438, 464))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('proteolytic', 'MPA', (182, 193))	('uPAR', 'Gene', '5329', (301, 305))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (78, 83))	('MMP14', 'Gene', '4323', (310, 315))	('cancers', 'Disease', (104, 111))	('changes', 'Var', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
40172	26375517	When the isogenic MCF-10A progression series of cell lines, c-H-ras transformed MCF10AneoT and non-invasive MCF10AT1, were analyzed under the same conditions, they formed simple duct-like structures with no central lumens and multi-acinar structures, which are typical of in vivo-like phenotypes of benign hyperplastic and atypical hyperplastic lesions, respectively.	('MCF10', 'CellLine', 'CVCL:5555', (108, 113))	('MCF10', 'CellLine', 'CVCL:5555', (80, 85))	('c-H-ras', 'Gene', '3265', (60, 67))	('MCF-10A', 'CellLine', 'CVCL:0598', (18, 25))	('c-H-ras', 'Gene', (60, 67))	('MCF10AneoT', 'Var', (80, 90))
40178	26375517	These results are consistent with the fact that acidity generated within the tumor microenvironment enhances tumor invasion in vivo by inducing secretion of active cathepsin B.	('cathepsin B', 'Protein', (164, 175))	('acidity', 'Var', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('inducing', 'PosReg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('secretion of active', 'MPA', (144, 163))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('enhances', 'PosReg', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (109, 114))
40181	26375517	Co-culturing of MCF10.DCIS cells in MAME models with mammary fibroblasts overexpressing stromal-derived hepatocyte growth factor (HGF) (MF:HGF) or in the presence of conditioned media from the fibroblasts results in increased invasiveness and development of invasive outgrowths by the MCF10.DCIS cells.	('HGF', 'Gene', (130, 133))	('HGF', 'Gene', '3082', (139, 142))	('MCF10.DCIS', 'Var', (285, 295))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (285, 295))	('hepatocyte growth factor', 'Gene', (104, 128))	('HGF', 'Gene', '3082', (130, 133))	('development of invasive outgrowths', 'CPA', (243, 277))	('MCF10.DCIS', 'Var', (16, 26))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (16, 26))	('hepatocyte growth factor', 'Gene', '3082', (104, 128))	('HGF', 'Gene', (139, 142))	('invasiveness', 'CPA', (226, 238))	('increased', 'PosReg', (216, 225))
40215	26375517	In addition, we have used MAME avatars to demonstrate the ability of neutralizing antibodies to interleukin 6 to reduce the invasive phenotype of tumor cells; this is a class of antibodies that have been FDA-approved for treatment of Castleman's disease.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	("Castleman's disease", 'Disease', (234, 253))	('reduce', 'NegReg', (113, 119))	('tumor', 'Disease', (146, 151))	('antibodies', 'Var', (82, 92))	('interleukin 6', 'Gene', (96, 109))	("Castleman's disease", 'Disease', 'MESH:C536362', (234, 253))	('neutralizing antibodies', 'Var', (69, 92))	('interleukin 6', 'Gene', '3569', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
40246	24830599	Aside from cancer diagnoses, screening mammography may also lead to false-positive examinations, which result in further imaging and/or biopsy.	('examinations', 'MPA', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('false-positive', 'Var', (68, 82))	('result', 'Reg', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
40289	24830599	For example, both atypical ductal and lobular hyperplasia are associated with an increased cancer risk (2.5-fold for atypical ductal hyperplasia and > 5-fold for atypical lobular hyperplasia).	('lobular hyperplasia', 'Disease', (38, 57))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (171, 190))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (38, 57))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('atypical ductal', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (126, 144))	('ductal hyperplasia', 'Disease', (126, 144))	('lobular hyperplasia', 'Disease', (171, 190))
40335	21296703	Data from recent immunophenotypic and molecular genetic studies support the notion that both ADH and all forms of DCIS represent intraepithelial neoplasias characterized by morphological changes that result from clonal alterations in genes and thus carry a risk of variable magnitudes for invasion and metastasis.	('ADH', 'Disease', (93, 96))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('neoplasias', 'Phenotype', 'HP:0002664', (145, 155))	('intraepithelial neoplasias', 'Disease', (129, 155))	('DCIS', 'Disease', (114, 118))	('genes', 'Protein', (234, 239))	('intraepithelial neoplasias', 'Disease', 'MESH:D019048', (129, 155))	('alterations', 'Var', (219, 230))	('invasion', 'CPA', (289, 297))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (129, 155))
40345	21296703	Once identified as actionable, determining the true subtype of a lesion on percutaneous biopsy does not change initial patient management much, whereas misclassifying UDH as an actionable lesion or vice versa may have severe consequences.	('patient', 'Species', '9606', (119, 126))	('misclassifying', 'Var', (152, 166))	('UDH', 'Disease', (167, 170))	('UDH', 'Chemical', '-', (167, 170))
40408	31719063	Recent data from the National Health and Nutrition Examination Survey (NHANES) showed that higher AL was significantly associated with increased breast cancer risk among Black women; however, this association was null among White women.	('higher', 'Var', (91, 97))	('increased', 'PosReg', (135, 144))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('women', 'Species', '9606', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('women', 'Species', '9606', (176, 181))
40446	31719063	Biomarkers which only contributed to AL measure 1 included HDL, abnormal LDL and/or total cholesterol, and triglycerides.	('triglycerides', 'Chemical', 'MESH:D014280', (107, 120))	('abnormal LDL', 'Phenotype', 'HP:0031886', (64, 76))	('total cholesterol', 'MPA', (84, 101))	('abnormal', 'Var', (64, 72))	('cholesterol', 'Chemical', 'MESH:D002784', (90, 101))	('triglycerides', 'MPA', (107, 120))	('HDL', 'Disease', (59, 62))
40462	31719063	Emerging evidence has led to the supposition that higher AL possibly contributes to increased risks of mortality among Black women, which is likely due to more aggressive phenotypes in this group.	('mortality', 'Disease', 'MESH:D003643', (103, 112))	('women', 'Species', '9606', (125, 130))	('higher', 'Var', (50, 56))	('mortality', 'Disease', (103, 112))
40486	31719063	To date, only one published study has discussed the impact of AL on health outcomes in Black women at the cellular level, suggesting that epigenetic changes, namely DNA methylation, alterations on covalent histone modifications, aberrant changes in expression of miRNA and long non-coding RNA, play important roles.	('expression', 'MPA', (249, 259))	('changes', 'Reg', (238, 245))	('long non-coding RNA', 'Protein', (273, 292))	('covalent histone modifications', 'MPA', (197, 227))	('miRNA', 'Protein', (263, 268))	('DNA', 'Disease', (165, 168))	('aberrant', 'Var', (229, 237))	('women', 'Species', '9606', (93, 98))	('alterations', 'Reg', (182, 193))
40491	31719063	We will address this concern in future analysis with a much larger sample size, and also explore the associations of interest with additional breast tumor features that are indicative of more aggressive breast cancer clinicopathology (e.g., high Ki67 proliferation marker, HER2+ status, triple-negative breast cancer subtype).	('high Ki67', 'Var', (241, 250))	('breast tumor', 'Disease', 'MESH:D001943', (142, 154))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('breast tumor', 'Disease', (142, 154))	('HER2', 'Gene', (273, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('HER2', 'Gene', '2064', (273, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('breast tumor', 'Phenotype', 'HP:0100013', (142, 154))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (192, 216))	('aggressive breast cancer', 'Disease', (192, 216))
40567	27042159	C3(1)-Tag mice develop tumors due to T antigen (Tag) under the control of the rat prostatic steroid binding protein C3(1) gene.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('mice', 'Species', '10090', (10, 14))	('rat', 'Species', '10116', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('T antigen', 'Var', (37, 46))
40568	27042159	It is well-established that at 8 weeks old, C3(1)-Tag mice develop ADH.	('mice', 'Species', '10090', (54, 58))	('develop', 'PosReg', (59, 66))	('C3(1)-Tag', 'Var', (44, 53))	('ADH', 'CPA', (67, 70))
40588	27042159	The 4 kinases decreased by HFD included 5'-AMP-activated protein kinase catalytic subunit alpha-2 (AAPK2, Prkaa2), interleukin-1 receptor-associated kinase 1 (IRAK1, Irak1), fructosamine-3-kinase (FN3 K, Fn3 k), and epithelial discoidin domain-containing receptor 1 (DDR1, Ddr1) in unaffected mammary glands (Additional file 4a).	('kinases', 'Enzyme', (6, 13))	('FN3 K', 'Gene', '63828', (197, 202))	('fructosamine-3-kinase', 'Gene', (174, 195))	('interleukin-1 receptor-associated kinase 1', 'Gene', '16179', (115, 157))	('Prkaa2', 'Gene', '108079', (106, 112))	("5'-AMP-activated protein kinase catalytic subunit alpha-2", 'Gene', '108079', (40, 97))	('fructosamine-3-kinase', 'Gene', '63828', (174, 195))	('Irak1', 'Gene', (166, 171))	('Irak1', 'Gene', '16179', (166, 171))	('interleukin-1 receptor-associated kinase 1', 'Gene', (115, 157))	('Fn3 k', 'Gene', (204, 209))	('epithelial discoidin domain-containing receptor 1', 'Gene', (216, 265))	('FN3 K', 'Gene', (197, 202))	('decreased', 'NegReg', (14, 23))	('IRAK1', 'Gene', (159, 164))	('IRAK1', 'Gene', '16179', (159, 164))	('Prkaa2', 'Gene', (106, 112))	('DDR1', 'Gene', '12305', (267, 271))	('Ddr1', 'Gene', '12305', (273, 277))	('DDR1', 'Gene', (267, 271))	('epithelial discoidin domain-containing receptor 1', 'Gene', '12305', (216, 265))	('Ddr1', 'Gene', (273, 277))	('Fn3 k', 'Gene', '63828', (204, 209))	('HFD', 'Var', (27, 30))
40592	27042159	When directly comparing activity of kinases from unaffected mammary glands isolated from mice on HFD versus diet switch groups, several important kinases were discovered to be regulated by HFD and inversely regulated by weight loss (Fig.	('weight loss', 'Disease', 'MESH:D015431', (220, 231))	('mice', 'Species', '10090', (89, 93))	('weight loss', 'Disease', (220, 231))	('weight loss', 'Phenotype', 'HP:0001824', (220, 231))	('regulated', 'Reg', (176, 185))	('HFD', 'Var', (189, 192))
40633	27042159	An important upstream regulator of PKC-alpha was demonstrated to be the second most potently upregulated kinase by HFD and dramatically reduced by weight loss, the serine/threonine-protein kinase D1 (KPCD1, Prkd1), also known as PKD1.	('rat', 'Species', '10116', (56, 59))	('Prkd1', 'Gene', '18760', (207, 212))	('weight loss', 'Disease', (147, 158))	('PKC-alpha', 'Gene', (35, 44))	('HFD', 'Var', (115, 118))	('weight loss', 'Phenotype', 'HP:0001824', (147, 158))	('protein kinase D1', 'Gene', (181, 198))	('reduced', 'NegReg', (136, 143))	('protein kinase D1', 'Gene', '5587', (181, 198))	('upregulated', 'PosReg', (93, 104))	('Prkd1', 'Gene', (207, 212))	('PKC-alpha', 'Gene', '18750', (35, 44))	('weight loss', 'Disease', 'MESH:D015431', (147, 158))
40634	27042159	PKD1 has been shown to increase cell proliferation in breast, prostate, salivary tumors and pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancers', 'Disease', 'MESH:D010190', (92, 110))	('pancreatic cancers', 'Disease', (92, 110))	('salivary tumors', 'Disease', (72, 87))	('salivary tumors', 'Phenotype', 'HP:0100684', (72, 87))	('PKD1', 'Var', (0, 4))	('rat', 'Species', '10116', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('prostate', 'Disease', (62, 70))	('increase', 'PosReg', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast', 'Disease', (54, 60))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cell proliferation', 'CPA', (32, 50))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (92, 110))	('salivary tumors', 'Disease', 'MESH:D008949', (72, 87))
40635	27042159	PKD1 also reduced serum- and anchorage-dependence for proliferation and survival in vitro and drove tumorigenesis in xenograft models of mammary tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('serum- and', 'MPA', (18, 28))	('reduced', 'NegReg', (10, 17))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PKD1', 'Var', (0, 4))	('tumors', 'Disease', (145, 151))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Disease', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('survival', 'CPA', (72, 80))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('drove', 'Reg', (94, 99))
40636	27042159	demonstrated that PKD1 is expressed in cells of the unaffected mammary gland, and is necessary for preventing epithelial-to-mesenchymal transition and invasive carcinoma.	('invasive carcinoma', 'Disease', (151, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PKD1', 'Var', (18, 22))	('rat', 'Species', '10116', (7, 10))	('invasive carcinoma', 'Disease', 'MESH:D009361', (151, 169))	('preventing', 'NegReg', (99, 109))
40641	27042159	PKA activity was also increased by HFD and decreased by weight loss.	('HFD', 'Var', (35, 38))	('PKA', 'Gene', '18749', (0, 3))	('PKA', 'Gene', (0, 3))	('weight loss', 'Disease', 'MESH:D015431', (56, 67))	('increased', 'PosReg', (22, 31))	('weight loss', 'Disease', (56, 67))	('decreased', 'NegReg', (43, 52))	('weight loss', 'Phenotype', 'HP:0001824', (56, 67))
40645	27042159	MEK3 is increased by mutant p53, and led to cell proliferation and survival through increased oncogene RAS expression, as well as activation of p38alpha (MAPK14).	('p53', 'Gene', (28, 31))	('MAPK14', 'Gene', (154, 160))	('MEK3', 'Gene', (0, 4))	('survival', 'CPA', (67, 75))	('p38alpha', 'Gene', (144, 152))	('cell proliferation', 'CPA', (44, 62))	('mutant', 'Var', (21, 27))	('rat', 'Species', '10116', (56, 59))	('RAS', 'Gene', (103, 106))	('activation', 'PosReg', (130, 140))	('expression', 'MPA', (107, 117))	('p53', 'Gene', '22060', (28, 31))	('p38alpha', 'Gene', '26416', (144, 152))	('increased', 'PosReg', (8, 17))	('increased', 'PosReg', (84, 93))	('MAPK14', 'Gene', '26416', (154, 160))
40646	27042159	Inhibition of MEK3 led to reduction in cell proliferation and apoptosis, and knockdown of MEK3 led to reduced cell viability as well as increased susceptibility to chemotherapeutic agents in vitro and in vivo.	('MEK3', 'Gene', (14, 18))	('cell viability', 'CPA', (110, 124))	('knockdown', 'Var', (77, 86))	('reduction', 'NegReg', (26, 35))	('MEK3', 'Gene', (90, 94))	('susceptibility', 'MPA', (146, 160))	('apoptosis', 'CPA', (62, 71))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (136, 145))	('cell proliferation', 'CPA', (39, 57))	('reduced', 'NegReg', (102, 109))	('rat', 'Species', '10116', (51, 54))
40649	27042159	A final kinase moderately but significantly up-regulated by HFD and down-regulated by weight loss was the serine/threonine protein kinase unc-51 like kinase 3, ULK3 (Ulk3).	('unc-51 like kinase 3', 'Gene', '71742', (138, 158))	('unc-51 like kinase 3', 'Gene', (138, 158))	('down-regulated', 'NegReg', (68, 82))	('ULK3', 'Gene', (160, 164))	('Ulk3', 'Gene', '71742', (166, 170))	('weight loss', 'Disease', 'MESH:D015431', (86, 97))	('rat', 'Species', '10116', (19, 22))	('weight loss', 'Disease', (86, 97))	('up-regulated', 'PosReg', (44, 56))	('weight loss', 'Phenotype', 'HP:0001824', (86, 97))	('ULK3', 'Gene', '71742', (160, 164))	('HFD', 'Var', (60, 63))	('Ulk3', 'Gene', (166, 170))
40660	27042159	Importantly, metformin can inhibit cell growth in basal-like cancer cells.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('metformin', 'Var', (13, 22))	('cancer', 'Disease', (61, 67))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('inhibit', 'NegReg', (27, 34))
40666	27042159	One-third of US adults are obese and two-thirds are overweight, underscoring a critical need to reduce breast cancer risk, especially triple negative breast cancers (TNBC) that are significantly associated with obesity.	('obesity', 'Disease', (211, 218))	('triple negative', 'Var', (134, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('TNBC', 'Disease', (166, 170))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('obese', 'Disease', 'MESH:D009765', (27, 32))	('breast cancer', 'Disease', (103, 116))	('obesity', 'Disease', 'MESH:D009765', (211, 218))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('overweight', 'Phenotype', 'HP:0025502', (52, 62))	('obesity', 'Phenotype', 'HP:0001513', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancers', 'Disease', 'MESH:D001943', (150, 164))	('breast cancers', 'Disease', (150, 164))	('TNBC', 'Disease', 'None', (166, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('reduce', 'NegReg', (96, 102))	('breast cancers', 'Phenotype', 'HP:0003002', (150, 164))	('obese', 'Disease', (27, 32))
40709	32195332	CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (57, 63))	('mutation', 'Var', (64, 72))	('PIK3CA', 'Gene', (57, 63))	('activating', 'PosReg', (46, 56))	('pure IDP', 'Disease', (17, 25))
40711	32195332	In contrast to pure IDP, PIK3CA mutations were absent from clonal cases.	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (25, 31))	('PIK3CA', 'Gene', (25, 31))
40713	32195332	The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.	('PIK3CA', 'Gene', '5290', (15, 21))	('carcinoma', 'Disease', 'MESH:D002277', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('clinical', 'Species', '191496', (74, 82))	('mutations', 'Var', (22, 31))	('carcinoma', 'Disease', (137, 146))	('PIK3CA', 'Gene', (15, 21))	('patients', 'Species', '9606', (97, 105))
40716	32195332	There are only a few low resolution cytogenetics studies evaluating copy number alterations (CNA) in benign IDP (not associated with carcinoma) but none included atypical IDP.	('copy number alterations', 'Var', (68, 91))	('benign IDP', 'Disease', (101, 111))	('carcinoma', 'Disease', 'MESH:D002277', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('carcinoma', 'Disease', (133, 142))
40717	32195332	Focused somatic mutation studies have showed a high prevalence of PIK3CA mutations and AKT1 pathway activation in both benign and atypical IDP, but interestingly not in papillary carcinoma (PC).	('benign', 'Disease', (119, 125))	('AKT1', 'Gene', '207', (87, 91))	('papillary carcinoma', 'Disease', (169, 188))	('PIK3CA', 'Gene', (66, 72))	('AKT1', 'Gene', (87, 91))	('papillary carcinoma', 'Disease', 'MESH:D002291', (169, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('atypical IDP', 'Disease', (130, 142))	('activation', 'PosReg', (100, 110))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))
40721	32195332	In addition to their unknown biology, recent studies suggested that the rate of developing subsequent ipsilateral breast cancer following diagnosis of atypical IDP is higher (13.2% in 8 years) than after benign IDP (5.8%).	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ipsilateral breast cancer', 'Disease', (102, 127))	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (102, 127))	('atypical IDP', 'Var', (151, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))
40731	32195332	The most prevalent CN changes were chromosome X loss (partial or full; 3/24 cases, 13%), followed by 16q loss (2/24 cases, 8%), and 7q loss (partial/full arm; 2/24 cases, 8%) (Table 1).	('7q loss', 'Var', (132, 139))	('loss', 'NegReg', (105, 109))	('16q', 'CPA', (101, 104))	('X loss', 'Disease', (46, 52))	('X loss', 'Disease', 'MESH:D015431', (46, 52))	('chromosome', 'Var', (35, 45))
40743	32195332	No other recurrent somatic mutations were found in the pure IDP cohort; however, single cases had known cancer hotspot mutations in ERBB3 (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ERBB3', 'Gene', '2065', (132, 137))	('ERBB3', 'Gene', (132, 137))	('mutations', 'Var', (119, 128))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
40744	32195332	2) and HRAS, and a missense mutation in SPEN (Fig.	('HRAS', 'Gene', (7, 11))	('SPEN', 'Gene', (40, 44))	('missense mutation', 'Var', (19, 36))	('SPEN', 'Gene', '23013', (40, 44))	('HRAS', 'Gene', '3265', (7, 11))
40745	32195332	One case (P4) carried both PIK3R3 and TP53 variants, both with low allelic frequencies (<0.1); however, these could not be validated by Sanger sequencing due to unavailability of DNA.	('TP53', 'Gene', (38, 42))	('PIK3R3', 'Gene', '8503', (27, 33))	('PIK3R3', 'Gene', (27, 33))	('variants', 'Var', (43, 51))	('TP53', 'Gene', '7157', (38, 42))
40746	32195332	Interestingly, this case also carried PIK3CA and SPEN variants at higher allele frequencies (0.17, 0.52, respectively, Supplementary Table 2), suggesting that a subclone(s) had arisen carrying the PIK3R3 and TP53 mutations.	('PIK3R3', 'Gene', (197, 203))	('PIK3CA', 'Gene', (38, 44))	('SPEN', 'Gene', '23013', (49, 53))	('PIK3CA', 'Gene', '5290', (38, 44))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))	('mutations', 'Var', (213, 222))	('SPEN', 'Gene', (49, 53))	('PIK3R3', 'Gene', '8503', (197, 203))
40758	32195332	9); and (3) a shared 1q gain along with a PIK3R1 deletion (case S9, Supplementary Table 2, Fig.	('gain', 'PosReg', (24, 28))	('PIK3R1', 'Gene', '5295', (42, 48))	('deletion', 'Var', (49, 57))	('PIK3R1', 'Gene', (42, 48))
40767	32195332	One of the non-clonal cases (S18) had a PIK3CA mutation only in the IDP component (p.H1047R).	('PIK3CA', 'Gene', (40, 46))	('p.H1047R', 'Var', (83, 91))	('PIK3CA', 'Gene', '5290', (40, 46))	('S18', 'Gene', (29, 32))	('p.H1047R', 'Mutation', 'rs121913279', (83, 91))	('S18', 'Gene', '6222', (29, 32))
40768	32195332	Taken together, PIK3CA mutations were found in 2 of 6 non-clonal IDP and 0/7 clonal IDP, compared to 9/13 in pure IDP.	('PIK3CA', 'Gene', '5290', (16, 22))	('to 9', 'Species', '1214577', (98, 102))	('mutations', 'Var', (23, 32))	('found', 'Reg', (38, 43))	('PIK3CA', 'Gene', (16, 22))
40771	32195332	5f, p = 0.04, Mann-Whitney test) with almost no CN change, whereas clonal IDP had a significantly higher FGA than pure IDP (p = 0.0002, Mann-Whitney test).	('clonal IDP', 'Var', (67, 77))	('higher', 'PosReg', (98, 104))	('FGA', 'Gene', (105, 108))	('FGA', 'Gene', '2243', (105, 108))
40775	32195332	In contrast, gains on 17q, 8q, 1q and loss of 16q, 22q, partial or full arm X, 10q were seen in both clonal IDP and synchronous carcinoma, and are also common alterations in DCIS/IDC.	('synchronous carcinoma', 'Disease', 'MESH:D009378', (116, 137))	('clonal IDP', 'Disease', (101, 111))	('synchronous carcinoma', 'Disease', (116, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('IDC', 'Gene', '4000', (179, 182))	('IDC', 'Gene', (179, 182))	('partial', 'Var', (56, 63))	('gains', 'PosReg', (13, 18))	('loss', 'NegReg', (38, 42))
40777	32195332	Moreover, for the cases with available mutation and CN data, a significant difference was observed between pure and clonal cases with the absence of PIK3CA mutation together with the presence of any CN event (Fig.	('PIK3CA', 'Gene', (149, 155))	('absence', 'NegReg', (138, 145))	('PIK3CA', 'Gene', '5290', (149, 155))	('mutation', 'Var', (156, 164))
40778	32195332	Interestingly, while the clonal IDP components lacked PIK3CA activating mutations, 6/11 cases did harbour at least one change that could affect the PIK3CA/AKT1 pathway including deletion in PIK3R1 (n = 2), AKT1 mutation (n = 1), CN gain of PIK3CA (n = 2), loss of PTEN (n = 1) or even gain of EGFR (n = 1).	('EGFR', 'Gene', '1956', (293, 297))	('AKT1', 'Gene', (206, 210))	('PIK3R1', 'Gene', '5295', (190, 196))	('PIK3CA', 'Gene', '5290', (240, 246))	('PIK3CA', 'Gene', (148, 154))	('AKT1', 'Gene', '207', (155, 159))	('gain', 'PosReg', (232, 236))	('PTEN', 'Gene', (264, 268))	('gain', 'PosReg', (285, 289))	('PIK3CA', 'Gene', '5290', (54, 60))	('EGFR', 'Gene', (293, 297))	('PIK3CA', 'Gene', (240, 246))	('loss', 'NegReg', (256, 260))	('deletion', 'Var', (178, 186))	('AKT1', 'Gene', (155, 159))	('PIK3R1', 'Gene', (190, 196))	('affect', 'Reg', (137, 143))	('PIK3CA', 'Gene', '5290', (148, 154))	('PTEN', 'Gene', '5728', (264, 268))	('AKT1', 'Gene', '207', (206, 210))	('mutation', 'Var', (211, 219))	('PIK3CA', 'Gene', (54, 60))
40788	32195332	Clonal IDP cases could be distinguished from non-clonal and pure IDP by the presence of specific CN events, particularly 16q loss, 1q gain and 11q loss, which are alterations commonly identified in PC and ductal carcinoma.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (205, 221))	('loss', 'NegReg', (125, 129))	('11q', 'CPA', (143, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('ductal carcinoma', 'Disease', 'MESH:D044584', (205, 221))	('ductal carcinoma', 'Disease', (205, 221))	('16q', 'Var', (121, 124))	('gain', 'PosReg', (134, 138))
40789	32195332	The origin of the carcinomas in cases that were not clonal to the IDPs remain unknown although it is possible that the coexisting lesions do have a common etiology, but through genetic or epigenetic processes not detected in our targeted assay.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('carcinomas', 'Disease', (18, 28))	('carcinomas', 'Disease', 'MESH:D002277', (18, 28))	('epigenetic', 'Var', (188, 198))
40792	32195332	Our study confirms and extends the findings of previous studies showing that while PIK3CA mutation is common in both benign and atypical pure IDPs, they are rare in PC or IDC that arise in the context of IDP.	('IDC', 'Gene', '4000', (171, 174))	('PIK3CA', 'Gene', '5290', (83, 89))	('IDC', 'Gene', (171, 174))	('PIK3CA', 'Gene', (83, 89))	('common', 'Reg', (102, 108))	('mutation', 'Var', (90, 98))
40793	32195332	It is unclear whether the lack of PIK3CA mutations in the clonal IDP/carcinomas is by chance due to the limited cases (n = 6) or reflects an intrinsic biological difference in carcinoma arising from an IDP.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('carcinomas', 'Disease', 'MESH:D002277', (69, 79))	('carcinoma', 'Disease', (69, 78))	('carcinomas', 'Disease', (69, 79))	('carcinoma', 'Disease', (176, 185))	('PIK3CA', 'Gene', '5290', (34, 40))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinoma', 'Disease', 'MESH:D002277', (176, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
40794	32195332	PIK3CA mutation is very common in ductal carcinoma, but as an initiating driver of proliferation in IDPs may lead to an evolutionary dead-end, lacking malignant potential.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lacking', 'NegReg', (143, 150))	('ductal carcinoma', 'Disease', 'MESH:D044584', (34, 50))	('PIK3CA', 'Gene', (0, 6))	('ductal carcinoma', 'Disease', (34, 50))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (34, 50))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))
40795	32195332	also reported that PIK3CA mutation in various early breast lesions could provide only an advantage for cellular proliferation, instead of driving towards carcinogenesis, due to the lack of clonal PIK3CA mutations in carcinoma components compared to synchronous neoplastic lesions.	('carcinoma component', 'Disease', 'MESH:C562869', (216, 235))	('PIK3CA', 'Gene', (19, 25))	('lack', 'NegReg', (181, 185))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (261, 279))	('PIK3CA', 'Gene', '5290', (19, 25))	('breast lesions', 'Disease', (52, 66))	('mutation', 'Var', (26, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('PIK3CA', 'Gene', (196, 202))	('synchronous neoplastic lesions', 'Disease', (249, 279))	('mutations', 'Var', (203, 212))	('carcinogenesis', 'Disease', (154, 168))	('PIK3CA', 'Gene', '5290', (196, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('carcinoma component', 'Disease', (216, 235))	('breast lesions', 'Disease', 'MESH:D001941', (52, 66))	('synchronous neoplastic lesions', 'Disease', 'MESH:D009378', (249, 279))	('cellular proliferation', 'CPA', (103, 125))
40796	32195332	This paradox remains to be explained, but is supported by the identification of PIK3CA mutations, particularly in the kinase domain, in overgrowth syndromes that lack any malignant transformation.	('overgrowth', 'Phenotype', 'HP:0001548', (136, 146))	('overgrowth syndromes', 'Disease', (136, 156))	('PIK3CA', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (80, 86))	('mutations', 'Var', (87, 96))
40798	32195332	Consequently, the absence of CN events (1q gain/16q loss/11q loss) as well as the presence of PIK3CA mutation in IDPs diagnosed in core biopsy irrespective of histopathological features (benign/atypia) or symptoms have the potential to be a biomarker of a low risk malignant potential lesion.	('1q gain/16q', 'Var', (40, 51))	('presence', 'Var', (82, 90))	('PIK3CA', 'Gene', (94, 100))	('mutation', 'Var', (101, 109))	('PIK3CA', 'Gene', '5290', (94, 100))
40824	32195332	A low DNA input library preparation protocol was used for all samples using the NEBNext  UltraTM II DNA Library Prep Kit (NEB E7645S/L, New England BioLabs  Inc., Ipswich, MA, USA) as described.	('E7645S', 'Var', (126, 132))	('Prep', 'Gene', (112, 116))	('E7645S', 'SUBSTITUTION', 'None', (126, 132))	('Prep', 'Gene', '5550', (112, 116))
40830	32195332	Additional samples were screened for PIK3CA variants in exons 9 and 20.	('PIK3CA', 'Gene', '5290', (37, 43))	('variants', 'Var', (44, 52))	('PIK3CA', 'Gene', (37, 43))
40840	32195332	Here, n = number of shared mutations in IDP and DCIS/IDC components and fk = the percentage of breast carcinomas from TCGA dataset harbouring a given mutation.	('mutations', 'Var', (27, 36))	('IDC', 'Gene', '4000', (53, 56))	('breast carcinomas', 'Disease', (95, 112))	('IDC', 'Gene', (53, 56))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))
40843	32195332	CNA segments were exported from Nexus and the percentage of genome altered by copy number in base pairs resolution or the weighted fraction of the genome altered (FGA) was calculated.	('FGA', 'Gene', '2243', (163, 166))	('copy number', 'Var', (78, 89))	('FGA', 'Gene', (163, 166))
40851	32195332	; Providing access to clinical samples: G.B.M., E.A.R., S.B.F., A.R.G.	('G.B.M.', 'Var', (40, 46))	('clinical samples', 'Species', '191496', (22, 38))	('S.B.F.', 'Var', (56, 62))
40856	25879521	Women eligible for chemoprevention with antiestrogens had a 5-year predicted breast cancer risk according to the Gail model of >=1.67%, history of lobular or ductal carcinoma in situ (LCIS/DCIS), and/or BRCA mutation.	('breast cancer', 'Disease', (77, 90))	('mutation', 'Var', (208, 216))	('Women', 'Species', '9606', (0, 5))	('BRCA', 'Gene', '672', (203, 207))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (158, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('BRCA', 'Gene', (203, 207))	('ductal carcinoma in situ', 'Disease', (158, 182))	('lobular or ductal carcinoma in situ', 'Phenotype', 'HP:0030076', (147, 182))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (158, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
40859	25879521	Women were grouped based upon their highest category of breast cancer risk (in descending order):  BRCA mutation carriers (3%), DCIS (40%), LCIS (22%), and 5-year Gail risk >=1.67% (36%).	('Women', 'Species', '9606', (0, 5))	('BRCA', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('mutation', 'Var', (104, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('BRCA', 'Gene', '672', (99, 103))
40885	25879521	High-risk is defined as a woman with either a family history of breast cancer, personal history of atypical ductal or lobular hyperplasia (ADH/ALH), lobular or ductal carcinoma in situ (LCIS/DCIS), or known deleterious BRCA1 or BRCA2 mutation.	('BRCA1', 'Gene', '672', (219, 224))	('mutation', 'Var', (234, 242))	('BRCA1', 'Gene', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (160, 184))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lobular or ductal carcinoma in situ', 'Phenotype', 'HP:0030076', (149, 184))	('ductal carcinoma in situ', 'Disease', (160, 184))	('BRCA2', 'Gene', (228, 233))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('lobular hyperplasia', 'Disease', (118, 137))	('lobular or', 'Disease', (149, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (160, 184))	('ADH', 'Disease', 'MESH:D007177', (139, 142))	('woman', 'Species', '9606', (26, 31))	('ADH', 'Disease', (139, 142))	('BRCA2', 'Gene', '675', (228, 233))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (118, 137))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
40887	25879521	We determined antiestrogen eligibility based upon current guidelines for breast cancer chemoprevention, which include a 5-year predicted Gail risk >=1.67%, history of LCIS, known BRCA mutation carrier status, or history of estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) DCIS.	('BRCA', 'Gene', (179, 183))	('BRCA', 'Gene', '672', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('progesterone receptor', 'Gene', (263, 284))	('progesterone receptor', 'Gene', '5241', (263, 284))	('breast cancer', 'Disease', (73, 86))	('DCIS', 'Phenotype', 'HP:0030075', (300, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('LCIS', 'Disease', (167, 171))	('mutation', 'Var', (184, 192))
40895	25879521	Women were grouped based upon their highest category of breast cancer risk (in descending order): BRCA mutation, DCIS, LCIS, and 5-year Gail risk >=1.67%.	('BRCA', 'Gene', (98, 102))	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('BRCA', 'Gene', '672', (98, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('DCIS', 'Disease', (113, 117))	('mutation', 'Var', (103, 111))	('breast cancer', 'Disease', (56, 69))	('LCIS', 'Disease', (119, 123))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
40902	25879521	We used the same model criteria for our secondary analysis among women in the primary prevention setting, those with either a 5-year Gail risk >=1.67% or LCIS/BRCA mutation.	('women', 'Species', '9606', (65, 70))	('mutation', 'Var', (164, 172))	('BRCA', 'Gene', (159, 163))	('BRCA', 'Gene', '672', (159, 163))
40909	25879521	The main reasons for antiestrogen ineligibility included 5-year Gail risk <1.67% (40%), age younger than 35 years without LCIS, DCIS or a BRCA mutation (24%), history of ER- and PR- DCIS (17%), opting for bilateral mastectomies (11%), or medical contraindications to an antiestrogen (8%).	('BRCA', 'Gene', '672', (138, 142))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('mutation', 'Var', (143, 151))	('BRCA', 'Gene', (138, 142))	('ER- and', 'Disease', (170, 177))
40917	25879521	In multivariable analysis (Table 2), we found that women with a 5-year Gail risk >=1.67% or LCIS/BRCA mutation had about a 20% lower likelihood of antiestrogen use compared to women with DCIS (RR=0.82, 95% CI=0.70-0.96 and RR=0.84, 95% CI=0.70-1.02, respectively).	('antiestrogen use', 'MPA', (147, 163))	('mutation', 'Var', (102, 110))	('BRCA', 'Gene', '672', (97, 101))	('lower', 'NegReg', (127, 132))	('BRCA', 'Gene', (97, 101))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('women', 'Species', '9606', (176, 181))	('women', 'Species', '9606', (51, 56))
40919	25879521	Among women with LCIS, a BRCA mutation, ADH/ALH, or 5-year Gail risk >=1.67%, 37% of women eligible for an antiestrogen had past or current antiestrogen use.	('BRCA', 'Gene', (25, 29))	('ADH', 'Disease', 'MESH:D007177', (40, 43))	('mutation', 'Var', (30, 38))	('ADH', 'Disease', (40, 43))	('women', 'Species', '9606', (6, 11))	('women', 'Species', '9606', (85, 90))	('LCIS', 'Disease', (17, 21))	('BRCA', 'Gene', '672', (25, 29))
40926	25879521	At our breast center, we found that antiestrogen use among women with DCIS was 73% compared to about 38% in the primary prevention setting.	('antiestrogen', 'Protein', (36, 48))	('DCIS', 'Var', (70, 74))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('women', 'Species', '9606', (59, 64))
40971	31054033	In univariate analysis, we confirmed patients with serum sLeX >8 U/ml have a significantly shorter progression free survival (PFS) (P=0.0074) and overall survival (OS (P=0.0003).	('progression free survival', 'CPA', (99, 124))	('serum sLeX >8 U/ml', 'Var', (51, 69))	('overall survival', 'CPA', (146, 162))	('patients', 'Species', '9606', (37, 45))	('shorter', 'NegReg', (91, 98))
40972	31054033	Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P=0.001 and P<0.001, respectively) and PFS (P=0.010 and P<0.001, respectively).	('MCP-1', 'Gene', (36, 41))	('MCP-1', 'Gene', '6347', (36, 41))	('IP-10', 'Gene', '3627', (46, 51))	('IP-10', 'Gene', (46, 51))	('shorter', 'NegReg', (56, 63))	('high serum', 'Var', (25, 35))	('patients', 'Species', '9606', (11, 19))	('PFS', 'CPA', (107, 110))
40982	31054033	Aberrant expression of sLeX is associated with tumor formation and metastasis and the level of sLeX was found to be elevated in the sera of patients with metastatic breast cancers (MBC) and correlated with metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('elevated', 'PosReg', (116, 124))	('breast cancers', 'Disease', 'MESH:D001943', (165, 179))	('breast cancers', 'Disease', (165, 179))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Aberrant', 'Var', (0, 8))	('breast cancers', 'Phenotype', 'HP:0003002', (165, 179))	('associated', 'Reg', (31, 41))	('patients', 'Species', '9606', (140, 148))	('correlated', 'Reg', (190, 200))	('metastasis', 'CPA', (67, 77))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Disease', (47, 52))	('MBC', 'Disease', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('sLeX', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('MBC', 'Disease', 'MESH:D001943', (181, 184))
40993	31054033	Abnormal expression of sLeX has attracted much attention because of its function in cancer cell extravasation, mimicking a molecular mechanism involved in leukocyte extravasation.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('sLeX', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Abnormal', 'Var', (0, 8))
40997	31054033	This retrospective study was approved by the MD Anderson Institutional Review Board (IRB) as LAB09-0347 for the evaluation of patients with non-invasive DCIS, invasive breast cancer (MBC), and healthy donors (HD) who have participated in previous diagnostic protocols at MDACC (IRB approved as LAB09-049, 2005-0243, ID02-052, 2006-1072, ID02-458, LAB03-0479, LAB05-0083, ID99-231, LAB08-0231, and LAB08-0199).	('LAB05-0083', 'Var', (359, 369))	('LAB03-0479', 'Var', (347, 357))	('MBC', 'Disease', (183, 186))	('invasive breast cancer', 'Disease', (159, 181))	('non-invasive DCIS', 'Disease', (140, 157))	('ID99-231', 'Var', (371, 379))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('HD', 'Disease', 'MESH:D006816', (209, 211))	('patients', 'Species', '9606', (126, 134))	('invasive breast cancer', 'Disease', 'MESH:D001943', (159, 181))	('MBC', 'Disease', 'MESH:D001943', (183, 186))	('LAB08-0231', 'Var', (381, 391))	('LAB08-0199', 'Var', (397, 407))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
41033	31054033	The full cohort of non-MBC patients (including IBC) with serum sLeX >= 8.0 U/ml had a trend towards shorter PFS (P = 0.07) and significantly shorter OS (P = 0.0047) (Figure 3 bottom) compared to patients with serum sLeX <8.0 U/ml.	('MBC', 'Disease', 'MESH:D001943', (23, 26))	('shorter', 'NegReg', (141, 148))	('PFS', 'MPA', (108, 111))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (195, 203))	('MBC', 'Disease', (23, 26))	('serum sLeX >= 8.0 U/ml', 'Var', (57, 79))
41035	31054033	There were 3 deaths, all in patients with serum sLeX >=8.0 U/ml (log-rank P = 0.0003).	('patients', 'Species', '9606', (28, 36))	('deaths', 'Disease', 'MESH:D003643', (13, 19))	('serum', 'Var', (42, 47))	('deaths', 'Disease', (13, 19))
41038	31054033	Multicovariate Cox models indicate that adjusted for the presence of metastasis (MBC vs non-MBC) and hormonal receptor status (positive vs negative), sLeX (>=8U/ml vs <8U/ml) was a significant factor associated with OS (HR=2.985, 95% CI 1.563 - 5.698, p=0.0009), as well as MCP-1 (HR=1.001, p=0.0003) and IP-10 (HR=1.001, p=0.0357, Table 4).	('metastasis', 'CPA', (69, 79))	('>=8U/ml', 'Var', (156, 163))	('MBC', 'Disease', 'MESH:D001943', (81, 84))	('IP-10', 'Gene', '3627', (305, 310))	('MCP-1', 'Gene', (274, 279))	('MBC', 'Disease', 'MESH:D001943', (92, 95))	('MCP-1', 'Gene', '6347', (274, 279))	('MBC', 'Disease', (81, 84))	('associated', 'Reg', (200, 210))	('MBC', 'Disease', (92, 95))	('IP-10', 'Gene', (305, 310))
41039	31054033	Furthermore, adjusting for metastatic disease, sLeX (>=8U/ml vs <8U/ml) was associated with shorter PFS time (HR=1.653, 95% CI:0.977 - 2.795, p=0.0609), as well as IP-10 (HR=1.001, p=0.0017, Table 5).	('>=8U/ml', 'Var', (53, 60))	('IP-10', 'Gene', (164, 169))	('PFS time', 'MPA', (100, 108))	('IP-10', 'Gene', '3627', (164, 169))	('shorter', 'NegReg', (92, 99))
41042	31054033	Combining serum sLeX, MCP-1 and IP-10 into a single prognostic factor, patients with positive serum levels for all three had significantly worse OS and PFS compared to patients that were negative for all 3 or positive for any of the three (both P<0.0001, Figure 4 bottom).	('IP-10', 'Gene', '3627', (32, 37))	('positive serum levels', 'Var', (85, 106))	('patients', 'Species', '9606', (71, 79))	('all 3', 'Gene', (200, 205))	('MCP-1', 'Gene', '6347', (22, 27))	('all 3', 'Gene', '5079', (200, 205))	('worse', 'NegReg', (139, 144))	('IP-10', 'Gene', (32, 37))	('patients', 'Species', '9606', (168, 176))	('PFS', 'CPA', (152, 155))	('MCP-1', 'Gene', (22, 27))
41052	31054033	We also observed that patients with a high serum sLeX have a significantly shorter survival (both PFS and OS) compared with patients with lower serum sLeX.	('high serum', 'Var', (38, 48))	('patients', 'Species', '9606', (22, 30))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (124, 132))	('survival', 'MPA', (83, 91))
41078	31054033	Therefore, the hazard associated with a change on the order of the difference observed between mean non-MBC IP-10 (302 pg/ml) and MBC IP-10 (558 pg/ml) would be more substantive 1.292 (1.001 256) and the hazard associated with a 1 mg/ml difference would be 2.7 or 2.8.	('IP-10', 'Gene', (134, 139))	('MBC', 'Disease', (104, 107))	('IP-10', 'Gene', '3627', (134, 139))	('MBC', 'Disease', 'MESH:D001943', (130, 133))	('IP-10', 'Gene', (108, 113))	('302', 'Var', (115, 118))	('MBC', 'Disease', 'MESH:D001943', (104, 107))	('MBC', 'Disease', (130, 133))	('IP-10', 'Gene', '3627', (108, 113))
41140	29579131	Mammography screening for women aged 55-59 years was estimated to gain 289 life years per 100,000 women and resulted in an ICER of US$4,405.44 when compared to no screening.	('gain', 'PosReg', (66, 70))	('women', 'Species', '9606', (98, 103))	('women', 'Species', '9606', (26, 31))	('Mammography', 'Gene', (0, 11))	('screening', 'Var', (12, 21))
41191	29285036	HER2 positivity was associated with increased IBTR in these patients.	('positivity', 'Var', (5, 15))	('IBTR', 'Disease', (46, 50))	('patients', 'Species', '9606', (60, 68))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
41196	29285036	However, even those patients with small tumors of <=2.5 cm in size of low-to-intermediate grade had a significant recurrence risk as follows: the 12-year ipsilateral breast event rate was 14.4% in a study by the Eastern Cooperative Oncology Group (ECOG), and the 10-year local recurrence rate was 15.6% in a study by the Dana-Farber group.	('Oncology', 'Phenotype', 'HP:0002664', (232, 240))	('small tumors', 'Disease', (34, 46))	('ipsilateral breast event', 'Disease', (154, 178))	('small tumors', 'Disease', 'MESH:D058405', (34, 46))	('patients', 'Species', '9606', (20, 28))	('low-to-intermediate grade', 'Var', (70, 95))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
41234	29285036	In addition, HER2 positivity was associated with increased IBTR in these patients.	('increased', 'PosReg', (49, 58))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('IBTR', 'Disease', (59, 63))	('HER2', 'Gene', '2064', (13, 17))	('patients', 'Species', '9606', (73, 81))
41261	29285036	In our study, when the 90 patients with unknown or equivocal HER2 status were excluded, HER2 positivity was associated with a significantly higher IBTR rate.	('HER2', 'Gene', (88, 92))	('higher', 'PosReg', (140, 146))	('patients', 'Species', '9606', (26, 34))	('HER2', 'Gene', '2064', (88, 92))	('positivity', 'Var', (93, 103))	('HER2', 'Gene', (61, 65))	('HER2', 'Gene', '2064', (61, 65))	('IBTR', 'CPA', (147, 151))
41273	27059373	FGFR3 mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ~61%; high-grade, ~11%).	('bladder cancer', 'Disease', 'MESH:D001749', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('decrease', 'NegReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('bladder cancer', 'Disease', (19, 33))	('FGFR3', 'Gene', (0, 5))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
41274	27059373	"Driver" mutations also occur in nonmalignant settings: TP53 mutations in synovial tissue from rheumatoid arthritis and FGFR3 mutations in seborrheic keratosis.	('FGFR3', 'Gene', (120, 125))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (95, 115))	('seborrheic keratosis', 'Disease', (139, 159))	('mutations', 'Var', (61, 70))	('rheumatoid arthritis', 'Disease', (95, 115))	('TP53', 'Gene', (56, 60))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (139, 159))	('mutations', 'Var', (126, 135))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (95, 115))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (139, 159))	('arthritis', 'Phenotype', 'HP:0001369', (106, 115))
41276	27059373	Putative driver mutations can also be germline and associated with increased cancer risk (eg, germline RAS or TP53 alterations), but germline FGFR3 or NF2 abnormalities do not predispose to malignancy.	('TP53', 'Gene', (110, 114))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('mutations', 'Var', (16, 25))	('associated', 'Reg', (51, 61))	('NF2', 'Gene', '4771', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('malignancy', 'Disease', (190, 200))	('NF2', 'Gene', (151, 154))
41280	27059373	Other alterations, termed genetic "drivers", are implicated in pathways crucial to the ability of cancer cells to grow and survive.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('implicated', 'Reg', (49, 59))
41282	27059373	Overall, a basic premise in oncology is that, via the process of clonal selection, driver mutations are rare in benign conditions, variably present in premalignancy (depending on severity and cancer risk), and most frequent in advanced cancer.	('mutations', 'Var', (90, 99))	('frequent', 'Reg', (215, 223))	('premalignancy', 'Disease', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('oncology', 'Phenotype', 'HP:0002664', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('premalignancy', 'Disease', 'None', (151, 164))
41285	27059373	In this review, we describe an emerging body of literature indicating that genomic drivers, considered a hallmark of specific cancers, can also be found in benign conditions and in premalignant lesions, sometimes at frequencies higher than in the corresponding tumors (Table 1), and discuss the implications of these findings for current theories of carcinogenesis and designing prevention strategies.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('genomic', 'Var', (75, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (350, 364))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('carcinogenesis', 'Disease', (350, 364))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))
41287	27059373	Mutations in the BRAF gene, especially the V600E mutation, lead to constitutive activation of the MAP kinase pathway and increase in growth signals.	('increase', 'PosReg', (121, 129))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('growth signals', 'MPA', (133, 147))	('BRAF', 'Gene', (17, 21))	('MAP kinase pathway', 'Pathway', (98, 116))	('V600E', 'Var', (43, 48))	('activation', 'PosReg', (80, 90))
41289	27059373	BRAF mutations are clinically important targets because they are sensitive to BRAF or MAP kinase-ERK kinase (MEK) inhibitors.	('mutations', 'Var', (5, 14))	('MAP kinase-ERK kinase', 'Gene', '5609', (86, 107))	('clinical', 'Species', '191496', (19, 27))	('BRAF', 'Gene', (0, 4))	('MEK', 'Gene', (109, 112))	('MEK', 'Gene', '5609', (109, 112))	('MAP kinase-ERK kinase', 'Gene', (86, 107))
41290	27059373	The BRAF V600E mutation has been identified in 40% to 45% of metastatic melanomas in prospective studies with comprehensive interrogation.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('V600E', 'Var', (9, 14))	('melanomas', 'Disease', (72, 81))	('BRAF', 'Gene', (4, 8))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
41291	27059373	This mutation is considered an oncogenic driver, and melanomas bearing these BRAF V600E alterations have excellent responses to BRAF inhibitors such as vemurafenib or dabrafenib; these responses are entirely comparable with the most effective single-agent, oncogene-targeted therapies in non-small lung cancer (EGFR and ALK inhibitors in patients with corresponding actionable alterations).	('melanomas', 'Disease', (53, 62))	('small lung', 'Phenotype', 'HP:0002089', (292, 302))	('responses', 'MPA', (115, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('dabrafenib', 'Chemical', 'MESH:C561627', (167, 177))	('non-small lung cancer', 'Disease', 'MESH:D002289', (288, 309))	('patients', 'Species', '9606', (338, 346))	('ALK', 'Gene', '238', (320, 323))	('V600E', 'Mutation', 'rs113488022', (82, 87))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('V600E alterations', 'Var', (82, 99))	('vemurafenib', 'Chemical', 'MESH:D000077484', (152, 163))	('ALK', 'Gene', (320, 323))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('BRAF', 'Gene', (77, 81))	('alterations', 'Var', (88, 99))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (288, 309))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('non-small lung cancer', 'Disease', (288, 309))
41292	27059373	The BRAF V600E mutation is very common in benign melanocytic nevi, being discernible in 70% to 88% of such lesions.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('benign melanocytic nevi', 'Disease', (42, 65))	('nevi', 'Phenotype', 'HP:0003764', (61, 65))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (49, 65))
41294	27059373	Thus, BRAF mutations are considered to be one of the earliest events in melanoma development.	('mutations', 'Var', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Disease', (72, 80))	('BRAF', 'Gene', (6, 10))
41297	27059373	If BRAF mutations were a strong driver for melanoma development, one would assume they would be more commonly seen in patients with melanoma than in its benign counterpart.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('mutations', 'Var', (8, 17))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('BRAF', 'Gene', (3, 7))	('patients', 'Species', '9606', (118, 126))
41298	27059373	Because approximately 50% of patients with melanoma with BRAF mutations respond to BRAF or MEK inhibitors, there is no doubt that these melanomas depend on the MAP kinase pathway, but whether oncogenic BRAF itself is sufficient to sustain oncogenic MAP kinase signaling is an open question.	('patients', 'Species', '9606', (29, 37))	('melanomas depend', 'Disease', (136, 152))	('mutations', 'Var', (62, 71))	('respond', 'Reg', (72, 79))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('BRAF', 'Gene', (57, 61))	('melanoma', 'Disease', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('melanomas depend', 'Disease', 'MESH:D008545', (136, 152))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))	('BRAF', 'Gene', (83, 87))
41299	27059373	A variety of changes have been reported in preexisting, previously stable melanocytic nevi in patients receiving BRAF inhibitors, including increased pigmentation and involution.	('pigmentation', 'Disease', (150, 162))	('inhibitors', 'Var', (118, 128))	('patients', 'Species', '9606', (94, 102))	('nevi', 'Phenotype', 'HP:0003764', (86, 90))	('involution', 'Disease', (167, 177))	('BRAF', 'Gene', (113, 117))	('increased pigmentation', 'Phenotype', 'HP:0000953', (140, 162))	('melanocytic nevi', 'Disease', (74, 90))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (74, 90))	('increased', 'PosReg', (140, 149))	('pigmentation', 'Disease', 'MESH:D010859', (150, 162))
41301	27059373	However, it may be that even in dormant melanocytic nevi BRAF inhibitors increase expression of microphthalmia-associated transcription factor (MITF), with several consequences including upregulation of pigmentation pathways.	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('upregulation', 'PosReg', (187, 199))	('increase', 'PosReg', (73, 81))	('expression', 'MPA', (82, 92))	('pigmentation', 'Disease', (203, 215))	('microphthalmia-associated transcription factor', 'Gene', (96, 142))	('pigmentation', 'Disease', 'MESH:D010859', (203, 215))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (40, 56))	('MITF', 'Gene', '4286', (144, 148))	('MITF', 'Gene', (144, 148))	('inhibitors', 'Var', (62, 72))	('microphthalmia', 'Phenotype', 'HP:0000568', (96, 110))	('microphthalmia-associated transcription factor', 'Gene', '4286', (96, 142))
41303	27059373	observed development of new dysplastic nevi or new primary melanomas when patients were treated with vemurafenib for melanomas with BRAF V600E mutations.	('BRAF', 'Gene', (132, 136))	('melanomas', 'Disease', 'MESH:D008545', (117, 126))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (28, 43))	('melanomas', 'Disease', (59, 68))	('patients', 'Species', '9606', (74, 82))	('V600E mutations', 'Var', (137, 152))	('melanomas', 'Disease', (117, 126))	('V600E', 'Mutation', 'rs113488022', (137, 142))	('vemurafenib', 'Chemical', 'MESH:D000077484', (101, 112))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('nevi', 'Phenotype', 'HP:0003764', (39, 43))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('dysplastic nevi', 'Disease', (28, 43))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))	('dysplastic nevi', 'Disease', 'MESH:D004416', (28, 43))
41304	27059373	Some melanocytic nevi that were newly developed or had morphological changes observed in patients with melanoma receiving BRAF inhibitor therapy for metastatic BRAF V600E-disease have activating NRAS mutations (not BRAF) and are thought to arise as a consequence of the well-described triggering effect that these agents can have on RAS-activated premalignant lesions.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('mutations', 'Var', (200, 209))	('melanocytic nevi', 'Disease', (5, 21))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (5, 21))	('activating', 'PosReg', (184, 194))	('V600E-disease', 'Var', (165, 178))	('patients', 'Species', '9606', (89, 97))	('NRAS', 'Gene', (195, 199))	('V600E', 'Mutation', 'rs113488022', (165, 170))	('nevi', 'Phenotype', 'HP:0003764', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
41308	27059373	In support of both theories, investigation of activated ERK in melanocytic nevi by immunohistochemistry consistently demonstrates low levels of MAP kinase pathway activation (whereas it is uniformly elevated in BRAF V600E metastatic melanomas).	('MAP kinase pathway', 'Pathway', (144, 162))	('activation', 'MPA', (163, 173))	('melanomas', 'Disease', (233, 242))	('V600E', 'Mutation', 'rs113488022', (216, 221))	('BRAF', 'Var', (211, 215))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanomas', 'Phenotype', 'HP:0002861', (233, 242))	('elevated', 'PosReg', (199, 207))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('melanomas', 'Disease', 'MESH:D008545', (233, 242))	('melanocytic nevi', 'Disease', (63, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (63, 79))
41309	27059373	In an effort to clarify possible BRAF codrivers, experimental models have been generated with genetic manipulation of tumor suppressors known to be altered in invasive and metastatic melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('melanomas', 'Disease', (183, 192))	('genetic manipulation', 'Var', (94, 114))
41310	27059373	showed that BRAF V600E-mutated zebrafish developed patches of ectopic melanocytes; however, when TP53 was also deleted, zebrafish rapidly developed invasive melanomas.	('zebrafish', 'Species', '7955', (120, 129))	('invasive melanomas', 'Disease', 'MESH:D008545', (148, 166))	('developed', 'PosReg', (138, 147))	('zebrafish', 'Species', '7955', (31, 40))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('TP53', 'Gene', (97, 101))	('V600E-mutated', 'Var', (17, 30))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('invasive melanomas', 'Disease', (148, 166))
41311	27059373	Using the same BRAF V600E-mutant/TP53-deficient zebrafish model, Kaufman et al.	('V600E-mutant/TP53-deficient', 'Var', (20, 47))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('zebrafish', 'Species', '7955', (48, 57))	('BRAF', 'Var', (15, 19))
41314	27059373	In mouse models in which BRAF V600E was conditionally expressed in melanocytes, melanocytic proliferations were observed with histologic features of melanoma, but invasive melanomas did not develop.	('BRAF V600E', 'Var', (25, 35))	('invasive melanomas', 'Disease', 'MESH:D008545', (163, 181))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('mouse', 'Species', '10090', (3, 8))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (80, 106))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('melanocytic proliferations', 'Disease', (80, 106))	('invasive melanomas', 'Disease', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('melanoma', 'Disease', (172, 180))
41316	27059373	Another phenomenon of interest in unraveling some of these questions is the intriguing observation that stably transducing the "oncogene" BRAF V600E into melanocytes leads to blockage of cellular proliferation and to an increase in cellular senescence, despite phosphorylation of the downstream effector ERK.	('cellular senescence', 'MPA', (232, 251))	('cellular proliferation', 'CPA', (187, 209))	('BRAF V600E', 'Var', (138, 148))	('blockage', 'NegReg', (175, 183))	('V600E', 'Mutation', 'rs113488022', (143, 148))	('increase', 'PosReg', (220, 228))
41317	27059373	This finding contrasts with the transforming effect of BRAF V600E when introduced into p16-null melanocytes (p16 being one of two tumor suppressor gene products of CDKN2A).	('p16', 'Gene', (109, 112))	('p16', 'Gene', '1029', (87, 90))	('BRAF', 'Var', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CDKN2A', 'Gene', (164, 170))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('p16', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p16', 'Gene', '1029', (109, 112))	('CDKN2A', 'Gene', '1029', (164, 170))	('tumor', 'Disease', (130, 135))
41318	27059373	The presence of insulin-like growth factor binding protein 7 (IGFBP7) was initially considered to be involved in BRAF V600E-mediated oncogene-induced senescence in melanocytic nevi and melanoma, but this observation has not been validated.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (164, 180))	('senescence', 'MPA', (150, 160))	('nevi', 'Phenotype', 'HP:0003764', (176, 180))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('melanocytic nevi', 'Disease', (164, 180))	('IGFBP7', 'Gene', '3490', (62, 68))	('insulin-like growth factor binding protein 7', 'Gene', (16, 60))	('involved', 'Reg', (101, 109))	('BRAF', 'Var', (113, 117))	('insulin-like growth factor binding protein 7', 'Gene', '3490', (16, 60))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('IGFBP7', 'Gene', (62, 68))
41319	27059373	A genome-wide investigation of differentially expressed genes in BRAF V600E melanocytic nevi compared with melanocytic nevi with BRAF wild-type revealed consistent upregulation of CDKN2A, CDKN1C, and MITF.	('melanocytic nevi', 'Disease', (76, 92))	('MITF', 'Gene', (200, 204))	('CDKN2A', 'Gene', '1029', (180, 186))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (107, 123))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (76, 92))	('BRAF V600E', 'Var', (65, 75))	('CDKN1C', 'Gene', '1028', (188, 194))	('nevi', 'Phenotype', 'HP:0003764', (88, 92))	('CDKN1C', 'Gene', (188, 194))	('nevi', 'Phenotype', 'HP:0003764', (119, 123))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('CDKN2A', 'Gene', (180, 186))	('upregulation', 'PosReg', (164, 176))	('MITF', 'Gene', '4286', (200, 204))
41323	27059373	It remains puzzling that BRAF mutations are less commonly seen in melanoma than in melanocytic or dysplastic nevi.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanocytic or dysplastic', 'Disease', 'MESH:D009508', (83, 108))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('dysplastic nevi', 'Disease', (98, 113))	('melanocytic or dysplastic nevi', 'Phenotype', 'HP:0000995', (83, 113))	('nevi', 'Phenotype', 'HP:0003764', (109, 113))	('dysplastic nevi', 'Disease', 'MESH:D004416', (98, 113))	('mutations', 'Var', (30, 39))	('BRAF', 'Gene', (25, 29))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (98, 113))	('melanocytic or dysplastic', 'Disease', (83, 108))
41324	27059373	Recent descriptive and functional analysis suggest that alterations of CDKN2A/B, PTEN, CDK4, CCND1, ERBB4, and AKT, known to occur in human melanomas with high frequency, facilitate relief of oncogene-induced senescence, leading to selection of these melanocytic nevi during malignant evolution.	('melanomas', 'Disease', (140, 149))	('AKT', 'Gene', (111, 114))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('CDKN2A/B', 'Gene', (71, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (251, 267))	('AKT', 'Gene', '207', (111, 114))	('human', 'Species', '9606', (134, 139))	('CCND1', 'Gene', '595', (93, 98))	('melanocytic nevi', 'Disease', (251, 267))	('ERBB4', 'Gene', '2066', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('PTEN', 'Gene', (81, 85))	('ERBB4', 'Gene', (100, 105))	('CDK4', 'Gene', (87, 91))	('CCND1', 'Gene', (93, 98))	('alterations', 'Var', (56, 67))	('CDKN2A/B', 'Gene', '1029;1030', (71, 79))	('nevi', 'Phenotype', 'HP:0003764', (263, 267))	('PTEN', 'Gene', '5728', (81, 85))	('facilitate', 'PosReg', (171, 181))	('CDK4', 'Gene', '1019', (87, 91))	('relief', 'MPA', (182, 188))
41325	27059373	However, the cooperation of these aforementioned alterations with BRAF V600E to hyperactive the MAP kinase pathway has not been established.	('V600E', 'Mutation', 'rs113488022', (71, 76))	('hyperactive the MAP', 'Disease', (80, 99))	('hyperactive the MAP', 'Disease', 'MESH:D006948', (80, 99))	('BRAF V600E', 'Var', (66, 76))
41328	27059373	The frequency of aberrations in each RAS gene differs depending on the underlying malignancy.	('RAS gene', 'Gene', (37, 45))	('malignancy', 'Disease', 'MESH:D009369', (82, 92))	('aberrations', 'Var', (17, 28))	('malignancy', 'Disease', (82, 92))
41330	27059373	NRAS (notably Q61) aberrations have been associated with several tumors including melanoma (18%-28%), multiple myeloma (20%), and thyroid carcinoma (9%).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (130, 147))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('aberrations', 'Var', (19, 30))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('NRAS', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (130, 147))	('multiple myeloma', 'Phenotype', 'HP:0006775', (102, 118))	('thyroid carcinoma', 'Disease', (130, 147))	('multiple myeloma', 'Disease', 'MESH:D009101', (102, 118))	('multiple myeloma', 'Disease', (102, 118))
41331	27059373	HRAS (G12, G13 and Q61) mutations are not as frequent when compared with KRAS or NRAS mutations; however, they have been reported in various cancer types including bladder urothelial carcinoma (1%-6%), head and neck squamous cell carcinoma (5%), and thyroid carcinoma (4%).	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('mutations', 'Var', (24, 33))	('KRAS', 'Gene', '3845', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (250, 267))	('reported', 'Reg', (121, 129))	('thyroid carcinoma', 'Disease', (250, 267))	('bladder urothelial carcinoma', 'Disease', (164, 192))	('cancer', 'Disease', (141, 147))	('KRAS', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (164, 192))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (250, 267))	('neck squamous cell carcinoma', 'Disease', (211, 239))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (211, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('HRAS', 'Gene', '3265', (0, 4))	('HRAS', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
41332	27059373	RAS mutations confer resistance to EGFR inhibitors in advanced colorectal and non-small cell lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal', 'Disease', (63, 73))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (78, 105))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (78, 105))	('RAS', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('EGFR', 'Gene', (35, 39))	('non-small cell lung cancers', 'Disease', (78, 105))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (82, 105))	('colorectal', 'Disease', 'MESH:D015179', (63, 73))	('resistance', 'MPA', (21, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (78, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (82, 104))	('mutations', 'Var', (4, 13))	('lung cancers', 'Phenotype', 'HP:0100526', (93, 105))
41333	27059373	To date, there are no effective therapies to directly overcome RAS mutations although multiple studies are ongoing, including application of agents targeting signals downstream of RAS (eg, MEK), screening compounds for synthetic lethality, identifying drugs that effectively interfere with RAS membrane localization, and the development of direct RAS inhibitors.	('RAS', 'Protein', (290, 293))	('MEK', 'Gene', (189, 192))	('mutations', 'Var', (67, 76))	('MEK', 'Gene', '5609', (189, 192))	('interfere', 'NegReg', (275, 284))
41335	27059373	Examples include progression of pancreatic premalignancy (intraepithelial neoplasia) driven by KRAS mutation, followed by inactivation of tumor suppressor genes CDKN2A and finally the inactivation of TP53 and deletion of SMAD4.	('SMAD4', 'Gene', (221, 226))	('tumor', 'Disease', (138, 143))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (58, 83))	('neoplasia', 'Phenotype', 'HP:0002664', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('inactivation', 'NegReg', (122, 134))	('SMAD4', 'Gene', '4089', (221, 226))	('CDKN2A', 'Gene', (161, 167))	('intraepithelial neoplasia', 'Disease', (58, 83))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('TP53', 'Gene', (200, 204))	('inactivation', 'Var', (184, 196))	('CDKN2A', 'Gene', '1029', (161, 167))	('KRAS', 'Gene', '3845', (95, 99))	('mutation', 'Var', (100, 108))	('deletion', 'Var', (209, 217))	('pancreatic premalignancy', 'Disease', (32, 56))	('pancreatic premalignancy', 'Disease', 'MESH:D010195', (32, 56))	('KRAS', 'Gene', (95, 99))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (58, 83))
41336	27059373	Similarly, the development of the colorectal adenoma-cancer neoplastic sequence is also attributed to a stepwise accumulation of mutations identified in premalignant adenomas, including those in the APC, KRAS, and TP53 genes.	('colorectal adenoma-cancer neoplastic', 'Disease', 'MESH:D015179', (34, 70))	('adenomas', 'Disease', (166, 174))	('colorectal adenoma-cancer neoplastic', 'Disease', (34, 70))	('mutations', 'Var', (129, 138))	('APC', 'Disease', 'MESH:D011125', (199, 202))	('KRAS', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KRAS', 'Gene', '3845', (204, 208))	('APC', 'Disease', (199, 202))	('TP53', 'Gene', (214, 218))	('adenomas', 'Disease', 'MESH:D000236', (166, 174))
41337	27059373	Although NRAS mutations are not as frequent when compared with the example of BRAF mutations (found in the majority of melanocytic nevi), the NRAS Q61K mutation is discerned in 6% to 14% of benign melanocytic nevi.	('benign melanocytic nevi', 'Disease', (190, 213))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (197, 213))	('Q61K', 'Mutation', 'rs121913254', (147, 151))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (119, 135))	('NRAS Q61K', 'Var', (142, 151))	('nevi', 'Phenotype', 'HP:0003764', (209, 213))
41338	27059373	Considering that the presence of NRAS mutation in melanoma is somewhat higher (18%-28%) than in melanocytic nevi, it is speculated that NRAS mutations are one of the driver mutations for melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('nevi', 'Phenotype', 'HP:0003764', (108, 112))	('NRAS', 'Gene', (33, 37))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('mutation', 'Var', (38, 46))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (96, 112))
41339	27059373	Interestingly, NRAS mutations (Q61K or Q61R) are detected in 70% to 95% of cases of congenital melanocytic nevi (benign melanocytic proliferation that develops in utero), which have a 465-fold increase risk of developing melanoma.	('detected', 'Reg', (49, 57))	('Q61R', 'Var', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Disease', (221, 229))	('nevi', 'Phenotype', 'HP:0003764', (107, 111))	('NRAS', 'Gene', (15, 19))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('Q61R', 'Mutation', 'rs11554290', (39, 43))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (95, 111))	('congenital melanocytic', 'Disease', (84, 106))	('congenital melanocytic', 'Disease', 'MESH:C536819', (84, 106))	('Q61K', 'Mutation', 'rs121913254', (31, 35))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (84, 111))
41341	27059373	The higher melanoma risk observed in patients with congenital melanocytic nevi suggests that length of time that NRAS mutations are harbored may be a factor in susceptibility to cancer development.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('congenital melanocytic', 'Disease', (51, 73))	('patients', 'Species', '9606', (37, 45))	('mutations', 'Var', (118, 127))	('NRAS', 'Gene', (113, 117))	('nevi', 'Phenotype', 'HP:0003764', (74, 78))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('congenital melanocytic', 'Disease', 'MESH:C536819', (51, 73))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (51, 78))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
41342	27059373	Congenital RAS mutations are associated with RASopathies, which are a group of genetic developmental disorders affected by increased RAS-MAPK signaling.	('RASopathies', 'Disease', (45, 56))	('mutations', 'Var', (15, 24))	('RASopathies', 'Disease', 'None', (45, 56))	('genetic developmental disorders', 'Disease', (79, 110))	('genetic developmental disorders', 'Disease', 'MESH:D030342', (79, 110))	('associated', 'Reg', (29, 39))	('Congenital', 'Disease', (0, 10))
41343	27059373	Although full detail of RASopathies is beyond the scope of this review and has been extensively described elsewhere, some of the syndromes associated with germline mutations in this pathway include Noonan syndrome (PTPN11 and KRAS mutations), LEOPARD syndrome (PTPN11 and RAF1 mutations), neurofibromatosis type 1 (NF1 mutation), Costello syndrome (HRAS mutation), and cardio-facio-cutaneous syndrome (BRAF, MAP2K1 and 2, KRAS mutations).	('KRAS', 'Gene', '3845', (226, 230))	('RASopathies', 'Disease', (24, 35))	('cardio-facio-cutaneous syndrome', 'Disease', (369, 400))	('Costello syndrome', 'Disease', 'MESH:D056685', (330, 347))	('NF1', 'Gene', '4763', (315, 318))	('KRAS', 'Gene', (226, 230))	('Costello syndrome', 'Disease', (330, 347))	('KRAS', 'Gene', '3845', (422, 426))	('NF1', 'Gene', (315, 318))	('KRAS', 'Gene', (422, 426))	('neurofibromatosis type 1', 'Gene', (289, 313))	('Noonan syndrome', 'Disease', (198, 213))	('cardio-facio-cutaneous syndrome', 'Disease', 'MESH:C535579', (369, 400))	('LEOPARD syndrome', 'Disease', 'MESH:D044542', (243, 259))	('RASopathies', 'Disease', 'None', (24, 35))	('HRAS', 'Gene', '3265', (349, 353))	('mutations', 'Var', (164, 173))	('HRAS', 'Gene', (349, 353))	('neurofibroma', 'Phenotype', 'HP:0001067', (289, 301))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (289, 306))	('Noonan syndrome', 'Disease', 'MESH:D009634', (198, 213))	('neurofibromatosis type 1', 'Gene', '4763', (289, 313))	('LEOPARD syndrome', 'Disease', (243, 259))
41348	27059373	GNAQ-activating mutations lead to an increase in MAP kinase pathway signals.	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (16, 25))	('MAP kinase pathway', 'Pathway', (49, 67))	('increase', 'PosReg', (37, 45))	('GNAQ', 'Gene', (0, 4))
41349	27059373	Interestingly, they are found in about 88% of Sturge-Weber syndrome (GNAQ R183Q).	('Sturge-Weber syndrome', 'Disease', (46, 67))	('GNAQ', 'Gene', '2776', (69, 73))	('R183Q', 'Var', (74, 79))	('Weber syndrome', 'Phenotype', 'HP:0002277', (53, 67))	('R183Q', 'Mutation', 'rs397514698', (74, 79))	('GNAQ', 'Gene', (69, 73))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (46, 67))
41352	27059373	Mutations in GNAQ are also found in patients with cancer.	('cancer', 'Disease', (50, 56))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('found', 'Reg', (27, 32))	('GNAQ', 'Gene', '2776', (13, 17))
41353	27059373	For instance, GNAQ alterations are frequent in uveal melanoma, with a minority (3%-6%) harboring R183Q, while GNAQ Q209L is detected in 22% to 45% of patients (Table 1).	('R183Q', 'Var', (97, 102))	('GNAQ', 'Gene', '2776', (14, 18))	('R183Q', 'Mutation', 'rs397514698', (97, 102))	('GNAQ', 'Gene', '2776', (110, 114))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('Q209L', 'Mutation', 'rs121913492', (115, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('patients', 'Species', '9606', (150, 158))	('GNAQ', 'Gene', (14, 18))	('GNAQ', 'Gene', (110, 114))	('uveal melanoma', 'Disease', (47, 61))	('frequent', 'Reg', (35, 43))
41354	27059373	The reason that Sturge-Weber patients do not develop cancer may be because the GNAQ mutations they harbor develop as a consequence of somatic mosaicism and, hence, are not found in all body cells.	('patients', 'Species', '9606', (29, 37))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GNAQ', 'Gene', '2776', (79, 83))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GNAQ', 'Gene', (79, 83))
41356	27059373	Hence, mutations in GNAQ may require specific tissue contexts to produce cancer.	('produce', 'Reg', (65, 72))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('GNAQ', 'Gene', '2776', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('GNAQ', 'Gene', (20, 24))	('mutations', 'Var', (7, 16))
41364	27059373	Radiation therapy was more effective in HER2 overexpressing DCIS, both in reducing ipsilateral DCIS and invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('HER2', 'Gene', (40, 44))	('HER2', 'Gene', '2064', (40, 44))	('ipsilateral DCIS', 'Disease', (83, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('invasive breast cancer', 'Disease', (104, 126))	('invasive breast cancer', 'Disease', 'MESH:D001943', (104, 126))	('overexpressing', 'Var', (45, 59))	('reducing', 'NegReg', (74, 82))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
41367	27059373	FGFR3 aberrations are found in multiple tumor types, most commonly being described in urothelial bladder cancer and some reports in cervical cancer.	('cervical cancer', 'Disease', (132, 147))	('multiple tumor', 'Disease', 'MESH:D009369', (31, 45))	('aberrations', 'Var', (6, 17))	('cervical cancer', 'Disease', 'MESH:D002583', (132, 147))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (86, 111))	('described', 'Reg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FGFR3', 'Gene', (0, 5))	('found', 'Reg', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('urothelial bladder cancer', 'Disease', (86, 111))	('multiple tumor', 'Disease', (31, 45))
41368	27059373	Aberrations include FGFR3 R248C, S249C, and G372C in cancer (Table 1).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('FGFR3', 'Gene', (20, 25))	('G372C', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('S249C', 'Var', (33, 38))	('R248C', 'Var', (26, 31))	('G372C', 'Mutation', 'rs121913479', (44, 49))	('S249C', 'Mutation', 'rs121913483', (33, 38))	('R248C', 'Mutation', 'rs121913482', (26, 31))
41369	27059373	However, the frequency of FGFR3 mutations in bladder cancer paradoxically decreases with advanced and higher-grade tumors (frequency of FGFR3 mutations in TaG1 tumor: ~61%, TaG2: ~58%, TaG3: ~34%, T1G3: ~17%, T2-T4, high-grade tumors: ~11%).	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('mutations', 'Var', (142, 151))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (32, 41))	('decreases', 'NegReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TaG1', 'Gene', '6900', (155, 159))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (160, 165))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))	('FGFR3', 'Gene', (26, 31))	('FGFR3', 'Gene', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('TaG1', 'Gene', (155, 159))
41371	27059373	FGFR3-activating mutations have been reported in 18% to 85% of seborrheic keratoses; these are benign lesions with no risk of cancer (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FGFR3-activating', 'Gene', (0, 16))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (63, 83))	('seborrheic keratoses', 'Disease', (63, 83))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (63, 83))	('mutations', 'Var', (17, 26))
41372	27059373	The wide range of frequency of FGFR3 mutations may be because of different patient characteristics, locations of the seborrheic keratoses that were biopsied (seborrheic keratoses from head and neck had a higher frequency of FGFR3 mutations when compared with the ones from the trunk and extremities), and experimental designs.	('seborrheic keratoses', 'Disease', 'MESH:D017492', (117, 137))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (158, 178))	('seborrheic keratoses', 'Disease', (158, 178))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (230, 239))	('FGFR3', 'Gene', (224, 229))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (117, 137))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (158, 178))	('seborrheic keratoses', 'Disease', (117, 137))	('FGFR3', 'Gene', (31, 36))	('patient', 'Species', '9606', (75, 82))
41373	27059373	Similarly, 33% of epidermal nevi harbor FGFR3 R248C mutation.	('nevi', 'Phenotype', 'HP:0003764', (28, 32))	('FGFR3', 'Gene', (40, 45))	('R248C', 'Var', (46, 51))	('R248C', 'Mutation', 'rs121913482', (46, 51))	('epidermal nevi', 'Phenotype', 'HP:0010816', (18, 32))	('epidermal nevi', 'Disease', (18, 32))
41374	27059373	Some of the specific FGFR3 mutations, including R248C, S249C, and G372C alterations, are also found in urothelial bladder and cervical cancers while others are not (Table 1).	('found', 'Reg', (94, 99))	('urothelial bladder and cervical cancers', 'Disease', 'MESH:D001749', (103, 142))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('G372C', 'Mutation', 'rs121913479', (66, 71))	('R248C', 'Mutation', 'rs121913482', (48, 53))	('FGFR3', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('S249C', 'Var', (55, 60))	('G372C alterations', 'Var', (66, 83))	('S249C', 'Mutation', 'rs121913483', (55, 60))	('R248C', 'Var', (48, 53))
41375	27059373	evaluated keratinocyte cell lines transduced with either FGFR3 wild-type or the R248C mutation and showed that FGFR3-mutant keratinocytes had lower levels of apoptosis and enhanced phosphorylation of ERK1/2 when compared with wild-type controls.	('R248C', 'Var', (80, 85))	('enhanced', 'PosReg', (172, 180))	('ERK1/2', 'Gene', (200, 206))	('FGFR3-mutant', 'Gene', (111, 123))	('ERK1/2', 'Gene', '5595;5594', (200, 206))	('lower', 'NegReg', (142, 147))	('phosphorylation', 'MPA', (181, 196))	('apoptosis', 'CPA', (158, 167))	('R248C', 'Mutation', 'rs121913482', (80, 85))
41376	27059373	Furthermore, in clinical samples of seborrheic keratosis, there were no differences in Ki-67 expression between wild-type and FGFR3-mutant samples, suggesting that FGFR3 may not contribute to proliferation in seborrheic keratosis.	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (209, 229))	('FGFR3-mutant', 'Gene', (126, 138))	('FGFR3-mutant', 'Var', (126, 138))	('Ki-67', 'Protein', (87, 92))	('clinical samples', 'Species', '191496', (16, 32))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (209, 229))	('seborrheic keratosis', 'Disease', (36, 56))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (36, 56))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (36, 56))	('seborrheic keratosis', 'Disease', (209, 229))
41377	27059373	FGFR3 germline mutations have an inhibitory impact on bone growth that leads to dwarfism syndromes, with mutations identical to those discerned in some cancers and seborrheic keratoses (eg, R248C and S249C).	('bone growth', 'CPA', (54, 65))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('R248C', 'Var', (190, 195))	('FGFR3', 'Gene', (0, 5))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (164, 184))	('S249C', 'Var', (200, 205))	('seborrheic keratoses', 'Disease', (164, 184))	('dwarfism', 'Phenotype', 'HP:0003510', (80, 88))	('dwarfism syndromes', 'Disease', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('R248C', 'Mutation', 'rs121913482', (190, 195))	('S249C', 'Mutation', 'rs121913483', (200, 205))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (164, 184))	('leads to', 'Reg', (71, 79))
41378	27059373	FGFR3 inhibitor exposure restored dwarf mice harboring FGFR3 mutations to a normal phenotype.	('mice', 'Species', '10090', (40, 44))	('mutations', 'Var', (61, 70))	('FGFR3', 'Gene', (55, 60))
41379	27059373	Although patients with dwarfism syndromes have decreased life expectancy (average 10 years shorter), mainly because of heart disease-related mortality, these patients have no documented increased incidence of cancer or of seborrheic keratoses.	('patients', 'Species', '9606', (9, 17))	('dwarfism', 'Phenotype', 'HP:0003510', (23, 31))	('dwarfism syndromes', 'Var', (23, 41))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (222, 242))	('seborrheic keratoses', 'Disease', (222, 242))	('heart disease', 'Disease', (119, 132))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (222, 242))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('heart disease', 'Disease', 'MESH:D006331', (119, 132))	('life expectancy', 'CPA', (57, 72))	('cancer', 'Disease', (209, 215))	('patients', 'Species', '9606', (158, 166))	('shorter', 'NegReg', (91, 98))	('decreased', 'NegReg', (47, 56))
41380	27059373	Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are found in diverse malignancies.	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (13, 33))	('found', 'Reg', (97, 102))	('PIK3CA', 'Gene', '5290', (85, 91))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('Mutations', 'Var', (0, 9))	('malignancies', 'Disease', (114, 126))	('PIK3CA', 'Gene', (85, 91))
41381	27059373	Tumors harboring PIK3CA mutations may respond to PI3K/Akt/mTOR inhibitors, confirming the PIK3CA oncogenic role.	('mTOR', 'Gene', (58, 62))	('respond', 'MPA', (38, 45))	('Akt', 'Gene', '207', (54, 57))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('Akt', 'Gene', (54, 57))	('Tumors', 'Disease', (0, 6))	('PIK3CA', 'Gene', (90, 96))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', '5290', (90, 96))	('mTOR', 'Gene', '2475', (58, 62))
41382	27059373	PIK3CA mutations are also detected in a subset of benign epidermal nevi and seborrheic keratoses (Table 1).	('seborrheic keratoses', 'Disease', 'MESH:D017492', (76, 96))	('PIK3CA', 'Gene', (0, 6))	('epidermal nevi', 'Phenotype', 'HP:0010816', (57, 71))	('PIK3CA', 'Gene', '5290', (0, 6))	('nevi', 'Phenotype', 'HP:0003764', (67, 71))	('benign epidermal nevi', 'Disease', (50, 71))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (76, 96))	('seborrheic keratoses', 'Disease', (76, 96))	('detected', 'Reg', (26, 34))	('mutations', 'Var', (7, 16))
41384	27059373	Certain PIK3CA anomalies, including E542K, E545K, and H1047R mutations, have been found in multiple cancer types including colon, breast, and bladder cancer.	('H1047R', 'Var', (54, 60))	('found', 'Reg', (82, 87))	('anomalies', 'Disease', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('H1047R', 'Mutation', 'rs121913279', (54, 60))	('PIK3CA', 'Gene', '5290', (8, 14))	('colon', 'Disease', (123, 128))	('cancer', 'Disease', (150, 156))	('breast', 'Disease', (130, 136))	('E542K', 'Mutation', 'rs121913273', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('E545K', 'Mutation', 'rs104886003', (43, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('E542K', 'Var', (36, 41))	('cancer', 'Disease', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('PIK3CA', 'Gene', (8, 14))	('anomalies', 'Disease', 'MESH:D000014', (15, 24))	('E545K', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (150, 156))
41385	27059373	It has been reported that PIK3CA mutations predict response to treatment with combination regimens that include a PI3K/AKT/mammalian target of rapamycin (mTOR) inhibitor.	('mammalian target of rapamycin', 'Gene', '2475', (123, 152))	('mammalian target of rapamycin', 'Gene', (123, 152))	('PIK3CA', 'Gene', '5290', (26, 32))	('AKT', 'Gene', (119, 122))	('AKT', 'Gene', '207', (119, 122))	('mutations', 'Var', (33, 42))	('predict', 'Reg', (43, 50))	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', '2475', (154, 158))	('PIK3CA', 'Gene', (26, 32))
41390	27059373	Similar to the FGFR3 and BRAF mutation story, PIK3CA-activating alterations are implicated in the pathogenesis of seborrheic keratosis (~16%) and epidermal nevi (~27%), with mutations identical to those found in certain malignancies (includes E542K, E545K, and H1047R).	('E545K', 'Var', (250, 255))	('PIK3CA', 'Gene', '5290', (46, 52))	('seborrheic keratosis', 'Disease', (114, 134))	('implicated', 'Reg', (80, 90))	('H1047R', 'Var', (261, 267))	('E542K', 'Mutation', 'rs121913273', (243, 248))	('malignancies', 'Disease', 'MESH:D009369', (220, 232))	('H1047R', 'Mutation', 'rs121913279', (261, 267))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (114, 134))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('malignancies', 'Disease', (220, 232))	('epidermal nevi', 'Phenotype', 'HP:0010816', (146, 160))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (114, 134))	('epidermal nevi', 'Disease', (146, 160))	('E542K', 'Var', (243, 248))	('E545K', 'Mutation', 'rs104886003', (250, 255))	('PIK3CA', 'Gene', (46, 52))
41391	27059373	PIK3CA-activating alterations are also reported in patients with fibroadipose hyperplasia, which is a syndrome of nonmalignant progressive segmental overgrowth of fibrous and adipose tissue, where 90% of patients were found to have either PIK3CA H1047R or H1047L mutations, and in hemimegalencephaly (HME), characterized by nonmalignant overgrowth of either one of the two cerebral hemispheres, as well as other brain malformations.	('HME', 'Phenotype', 'HP:0007206', (301, 304))	('overgrowth', 'Phenotype', 'HP:0001548', (149, 159))	('patients', 'Species', '9606', (204, 212))	('PIK3CA', 'Gene', '5290', (239, 245))	('overgrowth', 'Phenotype', 'HP:0001548', (337, 347))	('hemimegalencephaly', 'Disease', 'MESH:D065705', (281, 299))	('hyperplasia', 'Disease', (78, 89))	('patients', 'Species', '9606', (51, 59))	('PIK3CA', 'Gene', '5290', (0, 6))	('H1047L', 'Mutation', 'rs121913279', (256, 262))	('hyperplasia', 'Disease', 'MESH:D006965', (78, 89))	('brain malformations', 'Phenotype', 'HP:0012443', (412, 431))	('hemimegalencephaly', 'Phenotype', 'HP:0007206', (281, 299))	('brain malformations', 'Disease', (412, 431))	('PIK3CA', 'Gene', (239, 245))	('H1047R', 'Var', (246, 252))	('brain malformations', 'Disease', 'MESH:D000014', (412, 431))	('PIK3CA', 'Gene', (0, 6))	('H1047L mutations', 'Var', (256, 272))	('H1047R', 'Mutation', 'rs121913279', (246, 252))	('hemimegalencephaly', 'Disease', (281, 299))
41392	27059373	Although PIK3CA mutations are uncommon in melanoma (~1%-3%) or basal cell and squamous cell carcinoma of skin, they are found in 9% to 18% of other solid tumors (Table 1).	('melanoma', 'Disease', (42, 50))	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinoma of skin', 'Phenotype', 'HP:0008069', (92, 109))	('mutations', 'Var', (16, 25))	('found', 'Reg', (120, 125))	('solid tumors', 'Disease', (148, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('PIK3CA', 'Gene', (9, 15))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('PIK3CA', 'Gene', '5290', (9, 15))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
41393	27059373	In the context of the PI3K/Akt/mTOR pathway, AKT1-activating mutations, which are found in diverse malignancies, are also reported in seborrheic keratoses (E17K: 2%).	('AKT1', 'Gene', '207', (45, 49))	('mTOR', 'Gene', (31, 35))	('AKT1', 'Gene', (45, 49))	('mTOR', 'Gene', '2475', (31, 35))	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (134, 154))	('malignancies', 'Disease', (99, 111))	('E17K', 'Mutation', 'rs121434592', (156, 160))	('seborrheic keratoses', 'Disease', (134, 154))	('mutations', 'Var', (61, 70))	('Akt', 'Gene', '207', (27, 30))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (134, 154))	('Akt', 'Gene', (27, 30))	('malignancies', 'Disease', 'MESH:D009369', (99, 111))
41395	27059373	Fusion of ALK with different genomic partners leads constitutively to activation and drives tumorigenesis.	('ALK', 'Gene', '238', (10, 13))	('Fusion', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('ALK', 'Gene', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('activation', 'PosReg', (70, 80))
41397	27059373	Interestingly, ALK rearrangement is also reported in patients with benign inflammatory myofibroblastic tumors (Table 1).	('ALK', 'Gene', (15, 18))	('reported', 'Reg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (74, 109))	('ALK', 'Gene', '238', (15, 18))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (87, 109))	('inflammatory myofibroblastic tumors', 'Disease', (74, 109))	('rearrangement', 'Var', (19, 32))
41398	27059373	ALK rearrangement has been described in a variety of tumors, including anaplastic large cell lymphoma (NPM-ALK: 60%-80%, TPM3-ALK: 12%-18%), lung adenocarcinoma (EML4-ALK: 3%-7%), and breast cancer (EML4-ALK: 0%-2.4%).	('ALK', 'Gene', '238', (126, 129))	('rearrangement', 'Var', (4, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('ALK', 'Gene', (126, 129))	('ALK', 'Gene', '238', (204, 207))	('TPM3', 'Gene', '7170', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('ALK', 'Gene', (204, 207))	('ALK', 'Gene', '238', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EML4', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('EML4', 'Gene', '27436', (162, 166))	('ALK', 'Gene', (107, 110))	('tumors', 'Disease', (53, 59))	('TPM3', 'Gene', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('described', 'Reg', (27, 36))	('cell lymphoma', 'Disease', (88, 101))	('cell lymphoma', 'Phenotype', 'HP:0012191', (88, 101))	('ALK', 'Gene', '238', (167, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (71, 101))	('ALK', 'Gene', '238', (0, 3))	('lung adenocarcinoma', 'Disease', (141, 160))	('cell lymphoma', 'Disease', 'MESH:D016399', (88, 101))	('ALK', 'Gene', (167, 170))	('EML4', 'Gene', (199, 203))	('ALK', 'Gene', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('EML4', 'Gene', '27436', (199, 203))	('breast cancer', 'Disease', (184, 197))
41400	27059373	Interestingly, about half of inflammatory myofibroblastic tumors harbor rearrangements in the ALK locus (TPM3 or TPM4-ALK), leading to aberrant ALK signaling.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ALK', 'Gene', '238', (94, 97))	('inflammatory myofibroblastic tumors', 'Disease', 'MESH:D009369', (29, 64))	('ALK', 'Gene', '238', (144, 147))	('TPM3', 'Gene', (105, 109))	('TPM3', 'Gene', '7170', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('inflammatory myofibroblastic tumors', 'Disease', (29, 64))	('rearrangements', 'Var', (72, 86))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (42, 64))	('ALK', 'Gene', '238', (118, 121))	('ALK', 'Gene', (144, 147))	('TPM4', 'Gene', '7171', (113, 117))	('ALK', 'Gene', (94, 97))	('TPM4', 'Gene', (113, 117))	('ALK', 'Gene', (118, 121))
41405	27059373	Despite the strong association between TP53 abnormalities and malignancy, mutations in this gene have also been described in benign diseases as below (Table 1).	('malignancy', 'Disease', 'MESH:D009369', (62, 72))	('benign diseases', 'Disease', (125, 140))	('malignancy', 'Disease', (62, 72))	('mutations', 'Var', (74, 83))	('described', 'Reg', (112, 121))	('abnormalities', 'Var', (44, 57))	('TP53', 'Gene', (39, 43))
41406	27059373	TP53 mutations can result in both gain of function and loss of function; the latter is mostly associated with a dominant-negative effect over wild-type p53.	('TP53', 'Gene', (0, 4))	('loss', 'NegReg', (55, 59))	('gain', 'PosReg', (34, 38))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('mutations', 'Var', (5, 14))
41407	27059373	Mutations are especially frequent in serous ovarian (95% of patients) and serous endometrial carcinomas (89%).	('serous endometrial carcinomas', 'Disease', (74, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (74, 103))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (74, 103))	('patients', 'Species', '9606', (60, 68))	('frequent', 'Reg', (25, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('Mutations', 'Var', (0, 9))	('serous ovarian', 'Disease', 'MESH:D010051', (37, 51))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (81, 103))	('serous ovarian', 'Disease', (37, 51))
41408	27059373	Furthermore, patients with germline TP53 mutations have Li-Fraumeni syndrome that is associated with a high incidence of cancer.	('mutations', 'Var', (41, 50))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('germline', 'Var', (27, 35))	('patients', 'Species', '9606', (13, 21))	('Li-Fraumeni syndrome', 'Disease', (56, 76))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('TP53', 'Gene', (36, 40))	('cancer', 'Disease', (121, 127))
41410	27059373	It has been documented that 17% to 46% of synovial tissues from patients with rheumatoid arthritis had alterations in TP53 that are identical to the mutations seen in malignancies (eg, H193Y, E224fs, N239S); these mutations were not observed in patients with osteoarthritis.	('H193Y', 'Var', (185, 190))	('patients', 'Species', '9606', (245, 253))	('alterations', 'Reg', (103, 114))	('E224fs', 'Mutation', 'p.E224fsX', (192, 198))	('osteoarthritis', 'Disease', 'MESH:D010003', (259, 273))	('TP53', 'Gene', (118, 122))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (78, 98))	('malignancies', 'Disease', 'MESH:D009369', (167, 179))	('malignancies', 'Disease', (167, 179))	('N239S', 'Mutation', 'rs1057519999', (200, 205))	('E224fs', 'Var', (192, 198))	('H193Y', 'Mutation', 'rs876658468', (185, 190))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (78, 98))	('osteoarthritis', 'Phenotype', 'HP:0002758', (259, 273))	('osteoarthritis', 'Disease', (259, 273))	('arthritis', 'Phenotype', 'HP:0001369', (264, 273))	('arthritis', 'Phenotype', 'HP:0001369', (89, 98))	('N239S)', 'Var', (200, 206))	('patients', 'Species', '9606', (64, 72))	('rheumatoid arthritis', 'Disease', (78, 98))
41411	27059373	followed four patients with TP53-mutated rheumatoid arthritis for two years and none developed signs of malignancy.	('rheumatoid arthritis', 'Disease', (41, 61))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (41, 61))	('arthritis', 'Phenotype', 'HP:0001369', (52, 61))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('TP53-mutated', 'Var', (28, 40))	('malignancy', 'Disease', (104, 114))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (41, 61))	('patients', 'Species', '9606', (14, 22))
41413	27059373	Although the role of TP53 mutation in the pathogenesis of rheumatoid arthritis remains to be fully clarified, in vitro and in vivo work shows that inactivation of TP53 in synovial cells leads to stimulation of metalloproteinase and cytokines, which are in turn associated with enhanced proliferation and invasiveness of synoviocytes.	('TP53', 'Gene', (21, 25))	('enhanced', 'PosReg', (277, 285))	('inactivation', 'Var', (147, 159))	('mutation', 'Var', (26, 34))	('rheumatoid arthritis', 'Disease', (58, 78))	('stimulation', 'PosReg', (195, 206))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (58, 78))	('proliferation', 'CPA', (286, 299))	('metalloproteinase', 'Enzyme', (210, 227))	('cytokines', 'MPA', (232, 241))	('arthritis', 'Phenotype', 'HP:0001369', (69, 78))	('TP53', 'Gene', (163, 167))	('invasiveness', 'CPA', (304, 316))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (58, 78))
41414	27059373	Further, Angelo and colleagues reported that mutated TP53 leads to interleukin-6 (IL-6) overexpression, at least in part by modulating specific transcription factor binding to the IL-6 promoter.	('interleukin-6', 'Gene', (67, 80))	('IL-6', 'Gene', (180, 184))	('overexpression', 'PosReg', (88, 102))	('interleukin-6', 'Gene', '3569', (67, 80))	('binding', 'Interaction', (165, 172))	('IL-6', 'Gene', '3569', (180, 184))	('specific transcription factor', 'MPA', (135, 164))	('leads to', 'Reg', (58, 66))	('modulating', 'Reg', (124, 134))	('IL-6', 'Gene', (82, 86))	('mutated', 'Var', (45, 52))	('IL-6', 'Gene', '3569', (82, 86))	('TP53', 'Gene', (53, 57))
41417	27059373	Mutations in germline TP53 are associated with the Li-Fraumeni syndrome, a rare disorder that greatly increases the risk of developing several types of cancer (breast cancer, sarcomas, brain tumors, leukemias, and adrenocortical carcinomas), particularly in children and young adults.	('sarcomas', 'Disease', (175, 183))	('leukemia', 'Phenotype', 'HP:0001909', (199, 207))	('cancer', 'Disease', (167, 173))	('brain tumors', 'Disease', 'MESH:D001932', (185, 197))	('brain tumors', 'Phenotype', 'HP:0030692', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('leukemias', 'Disease', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('TP53', 'Gene', (22, 26))	('cancer', 'Disease', (152, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (214, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('associated', 'Reg', (31, 41))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('adrenocortical carcinomas', 'Disease', (214, 239))	('brain tumors', 'Disease', (185, 197))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('Li-Fraumeni syndrome', 'Disease', (51, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (214, 239))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (51, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('leukemias', 'Disease', 'MESH:D007938', (199, 208))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('leukemias', 'Phenotype', 'HP:0001909', (199, 208))	('sarcomas', 'Disease', 'MESH:D012509', (175, 183))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (160, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (175, 183))	('children', 'Species', '9606', (258, 266))
41418	27059373	Aberrations in cyclin-dependent kinase (CDK) pathways disrupt cell cycle restriction and contribute to genomic instability and tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('genomic instability', 'CPA', (103, 122))	('contribute', 'Reg', (89, 99))	('Aberrations', 'Var', (0, 11))	('disrupt', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cell cycle restriction', 'CPA', (62, 84))
41421	27059373	Loss or inactivating mutations of CDKN2A can lead to alteration in CDK pathway and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('alteration', 'Reg', (53, 63))	('inactivating mutations', 'Var', (8, 30))	('Loss', 'NegReg', (0, 4))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('CDK pathway', 'Pathway', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
41422	27059373	Aberrations in CDKN2A (mostly loss or hypermethylation) have been observed in about 19% of patients with diverse malignancies and have been associated with poor clinical outcome.	('observed', 'Reg', (66, 74))	('associated', 'Reg', (140, 150))	('patients', 'Species', '9606', (91, 99))	('CDKN2A', 'Gene', (15, 21))	('mostly loss', 'Disease', 'MESH:D015431', (23, 34))	('malignancies', 'Disease', (113, 125))	('CDKN2A', 'Gene', '1029', (15, 21))	('hypermethylation', 'MPA', (38, 54))	('Aberrations', 'Var', (0, 11))	('clinical', 'Species', '191496', (161, 169))	('mostly loss', 'Disease', (23, 34))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
41423	27059373	Aberration in CDKN2A is observed in multiple premalignant conditions, including pancreatic intraepithelial neoplasia (42%), colorectal adenomas (34%), and Barrett's esophagus (33%).	('CDKN2A', 'Gene', '1029', (14, 20))	('colorectal adenomas', 'Disease', (124, 143))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (80, 116))	("Barrett's esophagus", 'Disease', (155, 174))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (91, 116))	('pancreatic intraepithelial neoplasia', 'Disease', (80, 116))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (155, 174))	('colorectal adenomas', 'Disease', 'MESH:D015179', (124, 143))	('observed', 'Reg', (24, 32))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (155, 174))	('Aberration', 'Var', (0, 10))	('CDKN2A', 'Gene', (14, 20))
41424	27059373	recently reported that aberration of CDKN2A was a late event in melanoma development, exclusively observed in patients with invasive melanoma and not associated with precursor skin lesions that were commonly associated with BRAF or HRAS aberrations.	('aberration', 'Var', (23, 33))	('CDKN2A', 'Gene', (37, 43))	('invasive melanoma', 'Disease', 'MESH:D008545', (124, 141))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('HRAS aberrations', 'Disease', (232, 248))	('melanoma', 'Disease', (64, 72))	('CDKN2A', 'Gene', '1029', (37, 43))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('observed', 'Reg', (98, 106))	('melanoma', 'Disease', (133, 141))	('HRAS aberrations', 'Disease', 'MESH:D002869', (232, 248))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('invasive melanoma', 'Disease', (124, 141))	('patients', 'Species', '9606', (110, 118))
41425	27059373	The latter observations suggest that CDKN2A aberrations are critical for melanoma development (Figure 1).	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('aberrations', 'Var', (44, 55))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
41427	27059373	CDKN2A germline mutations increase the risk of melanoma and pancreatic cancer, and possibly sarcoma, breast, and esophageal cancers.	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('esophageal cancers', 'Disease', (113, 131))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('pancreatic cancer', 'Disease', (60, 77))	('sarcoma', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast', 'Disease', (101, 107))	('esophageal cancers', 'Disease', 'MESH:D004938', (113, 131))	('germline', 'Var', (7, 15))	('CDKN2A', 'Gene', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('increase', 'PosReg', (26, 34))	('CDKN2A', 'Gene', '1029', (0, 6))
41431	27059373	NF1 mutations are considered to be mutually exclusive with NRAS or BRAF mutations, suggesting their dedicated role in the RAS-MAPK pathway.	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (0, 3))	('RAS-MAPK pathway', 'Pathway', (122, 138))
41432	27059373	Preclinical studies suggest that NF1 mutations are potentially targetable with mTOR inhibitors such as everolimus or MEK inhibitors such as trametinib, or by combining both mTOR and MEK inhibitors, and that suppression of signals downstream of RAS with MEK and/or mTOR is capable of controlling tumorigenesis.	('MEK', 'Gene', '5609', (253, 256))	('MEK', 'Gene', (182, 185))	('NF1', 'Gene', (33, 36))	('mTOR', 'Gene', '2475', (173, 177))	('suppression', 'NegReg', (207, 218))	('MEK', 'Gene', '5609', (117, 120))	('MEK', 'Gene', (253, 256))	('mTOR', 'Gene', (264, 268))	('trametinib', 'Chemical', 'MESH:C560077', (140, 150))	('MEK', 'Gene', (117, 120))	('everolimus', 'Chemical', 'MESH:D000068338', (103, 113))	('tumor', 'Disease', (295, 300))	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (37, 46))	('mTOR', 'Gene', '2475', (79, 83))	('MEK', 'Gene', '5609', (182, 185))	('NF1', 'Gene', '4763', (33, 36))	('mTOR', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('clinical', 'Species', '191496', (3, 11))
41442	27059373	Thus, inactivating mutations of NF2 lead to increases in PI3K and RAS-MAPK signaling.	('PI3K', 'Pathway', (57, 61))	('NF2', 'Gene', (32, 35))	('RAS-MAPK signaling', 'Pathway', (66, 84))	('NF2', 'Gene', '4771', (32, 35))	('increases', 'PosReg', (44, 53))	('inactivating mutations', 'Var', (6, 28))
41444	27059373	These malignancies are, however, not increased in patients with germline NF2 mutations.	('patients', 'Species', '9606', (50, 58))	('malignancies', 'Disease', 'MESH:D009369', (6, 18))	('NF2', 'Gene', (73, 76))	('mutations', 'Var', (77, 86))	('malignancies', 'Disease', (6, 18))	('NF2', 'Gene', '4771', (73, 76))
41447	27059373	As mentioned, some sporadic cases of these neoplasms harbor somatic NF2 mutations.	('mutations', 'Var', (72, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('NF2', 'Gene', '4771', (68, 71))	('neoplasms', 'Disease', 'MESH:D009369', (43, 52))	('neoplasms', 'Disease', (43, 52))	('NF2', 'Gene', (68, 71))
41450	27059373	Indeed, germline alterations in NF2 are more likely to be nonsense or frameshift mutations while missense mutations are more frequently found in sporadic cancers when compared with patients with neurofibromatosis type 2.	('neurofibroma', 'Phenotype', 'HP:0001067', (195, 207))	('sporadic cancers', 'Disease', (145, 161))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (195, 212))	('neurofibromatosis type 2', 'Gene', (195, 219))	('frameshift mutations', 'Var', (70, 90))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('germline alterations', 'Var', (8, 28))	('NF2', 'Gene', (32, 35))	('patients', 'Species', '9606', (181, 189))	('NF2', 'Gene', '4771', (32, 35))	('neurofibromatosis type 2', 'Gene', '4771', (195, 219))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('sporadic cancers', 'Disease', 'MESH:D009369', (145, 161))	('missense mutations', 'Var', (97, 115))	('nonsense', 'Var', (58, 66))
41451	27059373	However, this explanation is not complete because there is overlap between the germline NF2 mutations and those found in NF2-bearing sporadic cancers.	('NF2', 'Gene', '4771', (88, 91))	('sporadic cancers', 'Disease', 'MESH:D009369', (133, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NF2', 'Gene', (121, 124))	('sporadic cancers', 'Disease', (133, 149))	('mutations', 'Var', (92, 101))	('NF2', 'Gene', (88, 91))	('NF2', 'Gene', '4771', (121, 124))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
41452	27059373	Further investigation is required to understand the mechanisms of NF2 mutations and tumorigenesis, which may lead to the identification of novel approaches targeting NF2 in both patients with neurofibromatosis type 2 and in sporadic cancers with this mutation.	('neurofibromatosis type 2', 'Gene', (192, 216))	('NF2', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('NF2', 'Gene', '4771', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patients', 'Species', '9606', (178, 186))	('NF2', 'Gene', (166, 169))	('neurofibromatosis type 2', 'Gene', '4771', (192, 216))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (192, 209))	('tumor', 'Disease', (84, 89))	('sporadic cancers', 'Disease', 'MESH:D009369', (224, 240))	('NF2', 'Gene', '4771', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('sporadic cancers', 'Disease', (224, 240))	('neurofibroma', 'Phenotype', 'HP:0001067', (192, 204))
41453	27059373	reported a patient with neurofibromatosis type 2 and multiple neoplasms (meningioma, ependymoma and schwannomas) that showed regression when treated with an mTOR inhibitor-containing regimen (and it is known that NF2 mutations activate the mTOR pathway).	('NF2', 'Gene', '4771', (213, 216))	('multiple neoplasms', 'Disease', (53, 71))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (24, 41))	('NF2', 'Gene', (213, 216))	('neurofibromatosis type 2', 'Gene', '4771', (24, 48))	('neurofibroma', 'Phenotype', 'HP:0001067', (24, 36))	('mTOR', 'Gene', (240, 244))	('activate', 'PosReg', (227, 235))	('multiple neoplasms', 'Disease', 'MESH:D009378', (53, 71))	('ependymoma', 'Phenotype', 'HP:0002888', (85, 95))	('ependymoma and schwannomas', 'Disease', 'MESH:D004806', (85, 111))	('meningioma', 'Disease', (73, 83))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('mTOR', 'Gene', '2475', (240, 244))	('schwannoma', 'Phenotype', 'HP:0100008', (100, 110))	('mTOR', 'Gene', (157, 161))	('meningioma', 'Disease', 'MESH:D008577', (73, 83))	('neurofibromatosis type 2', 'Gene', (24, 48))	('patient', 'Species', '9606', (11, 18))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))	('schwannomas', 'Phenotype', 'HP:0100008', (100, 111))	('mutations', 'Var', (217, 226))	('mTOR', 'Gene', '2475', (157, 161))
41457	27059373	Of interest in this regard, activating EGFR mutations, present in about 20% of lung adenocarcinoma (and associated with dramatic responses to EGFR inhibitors), have been reported to be a very early genetic driver in the development of this subset of lung cancer, detected in 43% of histologically normal epithelium surrounding (within and adjacent to) EGFR-mutant lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lung cancer', 'Disease', (250, 261))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('activating', 'PosReg', (28, 38))	('lung cancer', 'Disease', (364, 375))	('lung cancer', 'Phenotype', 'HP:0100526', (364, 375))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('mutations', 'Var', (44, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', (39, 43))	('lung cancer', 'Disease', 'MESH:D008175', (364, 375))	('lung adenocarcinoma', 'Disease', (79, 98))
41458	27059373	No mutation was seen in normal lung tissues when lung adenocarcinoma did not harbor EGFR mutation.	('lung adenocarcinoma', 'Disease', (49, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (49, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('mutation', 'Var', (89, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('EGFR', 'Gene', (84, 88))
41459	27059373	Preclinical models with mice carrying doxycycline-inducible, lung-specific, mutant EGFR transgenes (L858R or L747-S752 deletion mutation) showed that the EGFR mutation is sufficient for lung cancer development and necessary for tumor maintenance (withdrawal of doxycycline led to tumor regression).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('EGFR', 'Gene', (83, 87))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('L858R', 'Mutation', 'rs121434568', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('EGFR', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('L747-S752 deletion mutation', 'Var', (109, 136))	('mutation', 'Var', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (280, 285))	('L858R', 'Var', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('doxycycline', 'Chemical', 'MESH:D004318', (38, 49))	('lung cancer', 'Disease', (186, 197))	('doxycycline', 'Chemical', 'MESH:D004318', (261, 272))	('mice', 'Species', '10090', (24, 28))	('mutant', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (228, 233))	('clinical', 'Species', '191496', (3, 11))
41460	27059373	Also of relevance to prevention, ultra-deep sequencing of 74 cancer genes in 234 biopsies of sun-exposed eyelid epidermis revealed two to six mutations per megabase per cell, similar to that seen in many malignancies.	('malignancies', 'Disease', (204, 216))	('mutations', 'Var', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('sun-exposed eyelid', 'Phenotype', 'HP:0012470', (93, 111))	('exposed eyelid epidermis', 'Phenotype', 'HP:0009755', (97, 121))	('cancer', 'Disease', (61, 67))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
41461	27059373	The most common mutations were in the NOTCH1/2 and FAT1 genes.	('common', 'Reg', (9, 15))	('mutations', 'Var', (16, 25))	('NOTCH1/2', 'Gene', '4851;4853', (38, 46))	('FAT1', 'Gene', '2195', (51, 55))	('NOTCH1/2', 'Gene', (38, 46))	('FAT1', 'Gene', (51, 55))
41462	27059373	NOTCH1 driver mutations have also been detected in oral premalignancy.	('oral premalignancy', 'Disease', (51, 69))	('detected', 'Reg', (39, 47))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('oral premalignancy', 'Disease', 'MESH:D020820', (51, 69))	('mutations', 'Var', (14, 23))
41463	27059373	Cyclin D1 amplification was one of the first genetic drivers identified in upper aerodigestive tract with severe dysplasia, and Izzo et al.	('Cyclin D1', 'Gene', '595', (0, 9))	('dysplasia', 'Disease', (113, 122))	('amplification', 'Var', (10, 23))	('Cyclin D1', 'Gene', (0, 9))	('dysplasia', 'Disease', 'MESH:D004476', (113, 122))
41465	27059373	Data from lung squamous cell carcinoma and recently in lung squamous premalignancy identified 3q26.33-3q29 (including SOX2) amplification/overexpression as a genetic driver in this setting.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (10, 38))	('lung squamous premalignancy', 'Disease', (55, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 38))	('3q26.33-3q29', 'Var', (94, 106))	('SOX2', 'Gene', '6657', (118, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('lung squamous cell carcinoma', 'Disease', (10, 38))	('SOX2', 'Gene', (118, 122))	('lung squamous premalignancy', 'Disease', 'MESH:D002294', (55, 82))	('amplification/overexpression', 'PosReg', (124, 152))	('amplification/overexpression', 'Var', (124, 152))	('squamous premalignancy', 'Phenotype', 'HP:0002860', (60, 82))
41470	27059373	Although the focus of this paper is on solid tumors, somatic and germline driver mutations have also been well described in some hematologic disorders (eg, germline ETV6 mutations in familial thrombocytopenia and diverse hematologic malignancies; and somatic JAK2 mutations in myeloproliferative disorders).	('solid tumors', 'Disease', (39, 51))	('mutations', 'Var', (264, 273))	('hematologic malignancies', 'Disease', (221, 245))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (277, 305))	('familial thrombocytopenia', 'Disease', 'MESH:D013921', (183, 208))	('mutations', 'Var', (81, 90))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (192, 208))	('ETV6', 'Gene', (165, 169))	('hematologic malignancies', 'Disease', 'MESH:D019337', (221, 245))	('myeloproliferative disorders', 'Disease', (277, 305))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('familial thrombocytopenia', 'Disease', (183, 208))	('solid tumors', 'Disease', 'MESH:D009369', (39, 51))	('hematologic disorders', 'Disease', (129, 150))	('JAK2', 'Gene', '3717', (259, 263))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('hematologic disorders', 'Disease', 'MESH:D006402', (129, 150))	('JAK2', 'Gene', (259, 263))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (277, 305))	('mutations', 'Var', (170, 179))	('hematologic disorders', 'Phenotype', 'HP:0001871', (129, 150))	('ETV6', 'Gene', '2120', (165, 169))
41478	27059373	First, despite classic theories of clonal selection of driver alterations in the progression from benign lesions to premalignancy to malignancy, there appear to be important exceptions.	('premalignancy to malignancy', 'Disease', 'MESH:D009369', (116, 143))	('alterations', 'Var', (62, 73))	('premalignancy to malignancy', 'Disease', (116, 143))
41479	27059373	These include BRAF V600E mutations, which are paradoxically more common in benign melanocytic nevi (~80% mutation rate) than in dysplastic nevi (~60%) or melanoma (~40%-45%); HER2, which is more frequently overexpressed in patients with ductal carcinoma in situ (~27%-56% of cases) when compared with its malignant counterpart, invasive breast cancer (~11%-20%); and FGFR3 mutations, which decrease in frequency with grade of bladder cancer (low-grade tumors, ~61% of cases; high-grade, ~11%) (Table 1).	('dysplastic nevi', 'Phenotype', 'HP:0001062', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('HER2', 'Gene', '2064', (175, 179))	('tumors', 'Disease', (452, 458))	('mutations', 'Var', (25, 34))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (237, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (337, 350))	('invasive breast cancer', 'Disease', (328, 350))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('BRAF', 'Gene', (14, 18))	('mutations', 'Var', (373, 382))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('tumors', 'Disease', 'MESH:D009369', (452, 458))	('dysplastic nevi', 'Disease', (128, 143))	('invasive breast cancer', 'Disease', 'MESH:D001943', (328, 350))	('nevi', 'Phenotype', 'HP:0003764', (139, 143))	('ductal carcinoma in situ', 'Disease', (237, 261))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('HER2', 'Gene', (175, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (426, 440))	('bladder cancer', 'Disease', (426, 440))	('dysplastic nevi', 'Disease', 'MESH:D004416', (128, 143))	('benign melanocytic nevi', 'Disease', (75, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (426, 440))	('FGFR3', 'Gene', (367, 372))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (237, 261))	('tumors', 'Phenotype', 'HP:0002664', (452, 458))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (82, 98))	('patients', 'Species', '9606', (223, 231))
41482	27059373	For instance, TP53 mutations are amongst the most common underlying tumor suppressor gene alterations across tumor types.	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (109, 114))
41484	27059373	Similarly, identical FGFR3-activating mutations that are seen in solid tumors are also found in benign conditions, such as seborrheic keratoses, with no malignant potential.	('seborrheic keratoses', 'Phenotype', 'HP:0031287', (123, 143))	('seborrheic keratoses', 'Disease', (123, 143))	('FGFR3-activating', 'Gene', (21, 37))	('solid tumors', 'Disease', (65, 77))	('seborrheic keratoses', 'Disease', 'MESH:D017492', (123, 143))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))	('mutations', 'Var', (38, 47))
41485	27059373	In some cases, such as Li-Fraumeni syndrome, whose hallmark is germline TP53 mutations, affected individuals are clearly predisposed to a variety of malignancies.	('malignancies', 'Disease', (149, 161))	('predisposed', 'Reg', (121, 132))	('TP53', 'Gene', (72, 76))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (23, 43))	('mutations', 'Var', (77, 86))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('Li-Fraumeni syndrome', 'Disease', (23, 43))
41486	27059373	However, in other cases, such as dwarfism syndromes whose germline FGFR3 alterations are identical to those found to be drivers in their somatic form, there is no documented increase in cancer in individuals harboring the germline abnormality.	('FGFR3', 'Gene', (67, 72))	('alterations', 'Var', (73, 84))	('dwarfism', 'Phenotype', 'HP:0003510', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('dwarfism', 'Disease', (33, 41))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
41487	27059373	In summary, the observation of presumed genomic drivers at high frequency in some benign and premalignant lesions, as well as in germline conditions without an increased incidence of cancer, suggests that the functional impact of a gene alteration may be context dependent, with the attendant genomic landscape as well as the tissue and developmental setting being germane.	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gene alteration', 'Var', (232, 247))	('benign', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
41490	27059373	Are there underlying intact tumor suppressors in benign conditions that prevent driver mutations from promoting tumorigenesis?	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promoting', 'PosReg', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (87, 96))
41491	27059373	Can we reliably use genomic alterations as a screening tool for early detection of cancer or as a marker for prevention or treatment response such as with liquid biopsies?	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('genomic alterations', 'Var', (20, 39))	('cancer', 'Disease', (83, 89))
41492	27059373	Finally, the role of certain driver mutations in tumor initiation and premalignancy, rather than progression and malignancy, merits exploration.	('malignancy', 'Disease', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('mutations', 'Var', (36, 45))	('malignancy', 'Disease', (73, 83))	('tumor initiation and premalignancy', 'Disease', 'MESH:D009369', (49, 83))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))
41573	22067528	Furthermore, DCIS often unfolds the TDLU externalizing the once intralobular stroma.	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))	('DCIS', 'Var', (13, 17))	('intralobular stroma', 'Disease', (64, 83))	('intralobular stroma', 'Disease', 'None', (64, 83))
41589	22067528	The stroma of normal mammary gland contains many CD34 positive fibroblasts/fibrocytes and the presence of stromal positive CD34 fibroblasts has been shown to be associated with benign lesions.	('associated', 'Reg', (161, 171))	('presence', 'Var', (94, 102))	('benign lesions', 'Disease', (177, 191))	('CD34', 'Gene', (123, 127))	('CD34', 'Gene', '947', (49, 53))	('CD34', 'Gene', '947', (123, 127))	('CD34', 'Gene', (49, 53))
41630	19800453	We report three cases of sub-clinical cardiac depression associated with HER-2/neu targeted vaccination and discuss the implications of this finding.	('targeted vaccination', 'Var', (83, 103))	('HER-2/neu', 'Protein', (73, 82))	('depression', 'Phenotype', 'HP:0000716', (46, 56))	('cardiac depression', 'Disease', 'MESH:D000275', (38, 56))	('cardiac depression', 'Disease', (38, 56))	('associated', 'Reg', (57, 67))
41640	19800453	The dendritic cells of HLA-A2pos subjects were additionally pulsed with two HLA-A2-binding peptides (369-377 and 689-697) shown previously to stimulate CD8pos T cells.	('369-377', 'Var', (101, 108))	('stimulate', 'PosReg', (142, 151))	('CD8', 'Gene', (152, 155))	('689-697', 'Var', (113, 120))	('CD8', 'Gene', '925', (152, 155))
41665	19800453	Of the 3 patients exhibiting declines in cardiac ejection fraction, 08012-09 had only blood derived CD4 T cell response, 08012-08 had both blood and sentinel lymph node CD4 T cell reactivity, and 08012-26 had only lymph node reactivity (Table II.).	('declines', 'Disease', 'MESH:D060825', (29, 37))	('patients', 'Species', '9606', (9, 17))	('CD4', 'Gene', (100, 103))	('CD4', 'Gene', (169, 172))	('CD4', 'Gene', '920', (100, 103))	('CD4 T cell reactivity', 'Phenotype', 'HP:0005407', (169, 190))	('declines', 'Disease', (29, 37))	('CD4', 'Gene', '920', (169, 172))	('08012-09', 'Var', (68, 76))	('08012-08', 'Var', (121, 129))
41686	19800453	Inhibition of HER-2 signaling is implicated as a central mechanism of trastuzumab-related cardiotoxicity.	('cardiotoxicity', 'Disease', 'MESH:D066126', (90, 104))	('trastuzumab', 'Chemical', 'MESH:D000068878', (70, 81))	('HER-2', 'Protein', (14, 19))	('Inhibition', 'Var', (0, 10))	('cardiotoxicity', 'Disease', (90, 104))
41706	19800453	While all patients demonstrated pre-vaccination antibodies, only a small subset showed declines in ejection fraction post vaccination.	('declines', 'Disease', (87, 95))	('ejection fraction', 'MPA', (99, 116))	('antibodies', 'Var', (48, 58))	('patients', 'Species', '9606', (10, 18))	('declines', 'Disease', 'MESH:D060825', (87, 95))
41827	30528340	2 and 6. it is clearly seen that for fixed duct radius, tumor clusters elongate more with larger cell-membrane adhesion, which is consistent with the results we observed above.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('fixed', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('larger', 'PosReg', (90, 96))
41828	30528340	With smaller contact angle theta (e.g., theta <= 90 ) tumor clusters advance faster with small duct radius, because small duct radius increases the availability of nutrients to the tumor cells.	('small', 'Var', (89, 94))	('availability of nutrients', 'MPA', (148, 173))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('increases', 'PosReg', (134, 143))	('tumor', 'Disease', (54, 59))	('advance', 'PosReg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('g., theta', 'Species', '55529', (36, 45))	('small', 'Var', (116, 121))
41855	30528340	The results demonstrate that enhanced membrane deformability promotes tumor growth and tumor calcification and that the mammographic and pathologic tumor sizes are linearly correlated with small duct radius or weak cell-BM adhesion as predicted by using an agent-based model that does not account for the deformability of the basement membrane and the active forces that the membrane imparts on the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (399, 404))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('membrane deformability', 'CPA', (38, 60))	('promotes', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (399, 404))	('tumor calcification', 'Disease', 'MESH:D002114', (87, 106))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor calcification', 'Disease', (87, 106))	('enhanced', 'PosReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('small', 'Var', (189, 194))
41856	30528340	However, quadratically correlated between the sizes of the the mammographic and pathologic tumor clusters is predicted for those with large duct radius and strong cell-BM adhesion (e.g., theta = 170 , 180 ).	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('large duct', 'Var', (134, 144))	('g., theta', 'Species', '55529', (183, 192))	('cell-BM adhesion', 'CPA', (163, 179))	('tumor', 'Disease', (91, 96))
41866	22252965	DCIS have been shown to constitute bona fide non-obligate precursors of invasive breast cancer based on the observations that if untreated, up to 39% of low grade DCIS progress to invasive carcinomas, and that DCIS and invasive breast cancers arising in the same quadrant of the breast share similar histological features, gene expression profiles and gene copy number aberrations.	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('invasive breast cancers', 'Disease', 'MESH:D001943', (219, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('invasive breast cancer', 'Disease', (72, 94))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('invasive breast cancer', 'Disease', 'MESH:D001943', (219, 241))	('breast cancers', 'Phenotype', 'HP:0003002', (228, 242))	('low grade', 'Var', (153, 162))	('invasive carcinomas', 'Disease', (180, 199))	('invasive carcinomas', 'Disease', 'MESH:D009361', (180, 199))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('invasive breast cancer', 'Disease', 'MESH:D001943', (72, 94))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('invasive breast cancers', 'Disease', (219, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
41872	22252965	Given the evidence to suggest that genetic differences may exist between matched DCIS and IDC samples, we hypothesised that in some cases, progression may be mediated by selection of a subpopulation of cancer cells or by acquisition of new aberrations, including gene copy number aberrations or gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('gene mutations', 'Var', (295, 309))	('cancer', 'Disease', (202, 208))	('gene copy number aberrations', 'Var', (263, 291))
41873	22252965	The aims of this study were to determine if matched DCIS and adjacent invasive carcinomas from the same patient (and the same histological block) harbour distinct patterns of copy number aberrations or mutations in known cancer genes.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('invasive carcinomas', 'Disease', (70, 89))	('invasive carcinomas', 'Disease', 'MESH:D009361', (70, 89))	('cancer', 'Disease', (221, 227))	('patient', 'Species', '9606', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('copy number aberrations', 'Var', (175, 198))	('mutations', 'Var', (202, 211))
41887	22252965	DNA from each component of 12 out of 13 breast cancer samples included in this study was subjected to mutation screening to detect 238 mutations in 19 oncogenes using the OncoCarta Panel v1.0 (Sequenom Inc., San Diego, CA) as previously described.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('oncogenes', 'Gene', (151, 160))
41889	22252965	After exclusion of regions mapping to known copy number polymorphisms (http://projects.tcag.ca/variation/), aCGH analysis demonstrated that in situ and invasive components harboured similar numbers of copy number aberrations (mean of 12.6%, range of 1.0%-28.4% vs mean of 10.1%, range of 1.0%-27.1%, respectively, of BACs showing either gains, losses or amplifications; Student's t test, p = 0.498).	('losses', 'NegReg', (344, 350))	('BACs', 'Gene', (317, 321))	('amplifications', 'Var', (354, 368))	('BACs', 'Gene', '10998', (317, 321))	('gains', 'PosReg', (337, 342))
41901	22252965	To determine if in situ and invasive breast cancers harbour distinct patterns of mutations in known cancer genes, 12 paired samples were subjected to Sequenom mutational profiling using the Oncocarta v1.0 panel as previously described.	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancers', 'Disease', (28, 51))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('invasive breast cancers', 'Disease', 'MESH:D001943', (28, 51))	('breast cancers', 'Phenotype', 'HP:0003002', (37, 51))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
41902	22252965	PIK3CA mutations were identified in 6/12 cases (50%), consistent with previous reports that PIK3CA mutations are common in ER-positive luminal cancers and in DCIS (Supplementary Table S5).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('mutations', 'Var', (99, 108))	('luminal cancers', 'Disease', 'MESH:D009369', (135, 150))	('common', 'Reg', (113, 119))	('PIK3CA', 'Gene', (92, 98))	('luminal cancers', 'Disease', (135, 150))	('DCIS', 'Disease', (158, 162))
41903	22252965	In a grouped comparison, considering only if a component was positive or negative for PIK3CA mutations (rather than the frequency of the mutant allele), no significant difference was identified in the frequency of mutations between DCIS and adjacent invasive carcinomas (Fisher's exact test, p=0.68).	('mutations', 'Var', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('PIK3CA', 'Gene', (86, 92))	('invasive carcinomas', 'Disease', (250, 269))	('invasive carcinomas', 'Disease', 'MESH:D009361', (250, 269))
41904	22252965	In three of these cases (Cases 3, 8, and 10), the mutant allele frequency was similar in the in situ and invasive components (c.1633G>A, p.545E>K, range 19.2-54.2%, Figure 4A).	('p.545E>K', 'Mutation', 'rs104886003', (137, 145))	('p.545E>K', 'Var', (137, 145))	('c.1633G>A', 'Var', (126, 135))	('c.1633G>A', 'Mutation', 'rs104886003', (126, 135))
41905	22252965	In the remaining three cases, the mutant allele frequency was higher in the in situ than in the invasive component (Cases 2 and 12 with c.1624G>A, p.542E>K, and Case 5 with c.3140A>G, p.1047H>R, range 11.5-48.8%, Figures 4B and 4C).	('p.1047H>R', 'Mutation', 'rs121913279', (184, 193))	('p.542E>K', 'Mutation', 'rs121913273', (147, 155))	('c.3140A>G', 'Var', (173, 182))	('c.1624G>A', 'Var', (136, 145))	('higher', 'PosReg', (62, 68))	('c.1624G>A', 'Mutation', 'rs121913273', (136, 145))	('c.3140A>G', 'Mutation', 'rs121913279', (173, 182))	('p.542E>K', 'Var', (147, 155))
41906	22252965	In fact, in two of these cases (Case 12 harbouring an E542K mutation, and Case 5 an H1047R mutation), the PIK3CA mutation was absent from the invasive component.	('H1047R', 'Var', (84, 90))	('PIK3CA', 'Gene', (106, 112))	('E542K', 'Var', (54, 59))	('H1047R', 'Mutation', 'rs121913279', (84, 90))	('E542K', 'Mutation', 'rs121913273', (54, 59))
41907	22252965	Sanger sequencing analysis of the same DNA samples confirmed all E545K PIK3CA mutations and 2 out of 3 E542K PIK3CA mutations.	('E542K', 'Mutation', 'rs121913273', (103, 108))	('E545K', 'Var', (65, 70))	('E545K', 'Mutation', 'rs104886003', (65, 70))	('PIK3CA', 'Gene', (71, 77))
41908	22252965	One of the E542K PIK3CA mutations and the H1047R PIK3CA mutation were not validated by Sanger sequencing (Supplementary Table S5).	('E542K', 'Mutation', 'rs121913273', (11, 16))	('PIK3CA', 'Gene', (17, 23))	('H1047R', 'Mutation', 'rs121913279', (42, 48))	('PIK3CA', 'Gene', (49, 55))	('H1047R', 'Var', (42, 48))	('E542K', 'Var', (11, 16))
41909	22252965	21% E542K PIK3CA mutation in Case 12) or below the threshold of mutation detection (i.e.	('E542K', 'Var', (4, 9))	('PIK3CA', 'Gene', (10, 16))	('E542K', 'Mutation', 'rs121913273', (4, 9))
41910	22252965	11.5% H1047R PIK3CA mutation in Case 5).	('H1047R', 'Mutation', 'rs121913279', (6, 12))	('H1047R', 'Var', (6, 12))	('PIK3CA', 'Gene', (13, 19))
41911	22252965	Despite the very low allelic frequency of the H1047R mutation in Case 5, a small peak representing an A to a G base change consistent with the H1047R mutation can be identified (Figure 4C).	('H1047R', 'Mutation', 'rs121913279', (143, 149))	('H1047R', 'Var', (46, 52))	('A to', 'MPA', (102, 106))	('H1047R', 'Var', (143, 149))	('H1047R', 'Mutation', 'rs121913279', (46, 52))
41912	22252965	Taken together, these data confirm previous observations that PIK3CA mutations are an early event in breast cancer, are frequently found in ER-positive DCIS, and suggest PIK3CA mutations are unlikely to play a role in progression from DCIS to invasive breast cancer.	('invasive breast cancer', 'Disease', (243, 265))	('mutations', 'Var', (69, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('PIK3CA', 'Gene', (62, 68))	('invasive breast cancer', 'Disease', 'MESH:D001943', (243, 265))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
41920	22252965	In the absence of a common denominator in the form of gene copy number aberrations or mutations in known cancer genes, the analyses performed would not be able to identify statistically significant changes.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gene copy number aberrations', 'Var', (54, 82))
41921	22252965	It is also possible that genetic aberrations other than gene copy number changes or mutations in known cancer genes (e.g.	('mutations', 'Var', (84, 93))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
41923	22252965	Here we performed the most comprehensive profiling for mutations in known cancer genes in matched DCIS and adjacent invasive breast carcinomas.	('invasive breast carcinomas', 'Disease', (116, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('mutations', 'Var', (55, 64))	('breast carcinoma', 'Phenotype', 'HP:0003002', (125, 141))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('cancer', 'Disease', (74, 80))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (116, 142))	('breast carcinomas', 'Phenotype', 'HP:0003002', (125, 142))	('DCIS', 'Disease', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
41924	22252965	In agreement with Miron et al., we observed differences in the presence of PIK3CA mutations between the DCIS and adjacent invasive carcinoma.	('PIK3CA', 'Gene', (75, 81))	('differences', 'Reg', (44, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('invasive carcinoma', 'Disease', 'MESH:D009361', (122, 140))	('mutations', 'Var', (82, 91))	('invasive carcinoma', 'Disease', (122, 140))
41925	22252965	mutant vs non-mutant) between DCIS and adjacent invasive breast cancer was observed as previously reported, quantitative differences were observed in that the clones harbouring a PIK3CA mutation were more prevalent in the DCIS than in the adjacent invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (248, 266))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('invasive breast cancer', 'Disease', (48, 70))	('prevalent', 'Reg', (205, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('invasive carcinoma', 'Disease', (248, 266))	('PIK3CA', 'Gene', (179, 185))	('invasive breast cancer', 'Disease', 'MESH:D001943', (48, 70))	('DCIS', 'Disease', (222, 226))	('mutation', 'Var', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
41927	22252965	In fact, in two of the cases reported by Kalinsky et al., quantitative changes in the prevalence of PIK3CA mutations from DCIS to invasive carcinoma were also observed.	('mutations', 'Var', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('invasive carcinoma', 'Disease', 'MESH:D009361', (130, 148))	('PIK3CA', 'Gene', (100, 106))	('invasive carcinoma', 'Disease', (130, 148))	('DCIS', 'Disease', (122, 126))
41928	22252965	Alternative hypotheses for our findings include the possibility i) that in some breast cancers, PIK3CA mutations may not be driver events due to other epistatic interactions (e.g.	('mutations', 'Var', (103, 112))	('breast cancers', 'Phenotype', 'HP:0003002', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PIK3CA', 'Gene', (96, 102))	('breast cancers', 'Disease', 'MESH:D001943', (80, 94))	('breast cancers', 'Disease', (80, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
41930	22252965	In this context, other genetic or epigenetic alterations may confer an advantage for a subclone of cancer cells to be able to progress to invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('advantage', 'PosReg', (71, 80))	('invasive breast cancer', 'Disease', (138, 160))	('progress', 'PosReg', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (99, 105))	('epigenetic alterations', 'Var', (34, 56))	('invasive breast cancer', 'Disease', 'MESH:D001943', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
41931	22252965	Although phenotypic heterogeneity in regards to the expression of multiple immunohistochemical markers in DCIS and genetic differences between unmatched DCIS and invasive breast cancers have been previously documented, the finding of genetic heterogeneity for selected amplifications between synchronously diagnosed matched DCIS and invasive breast cancers is novel, but not entirely surprising.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('invasive breast cancers', 'Disease', (162, 185))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('invasive breast cancers', 'Disease', 'MESH:D001943', (162, 185))	('DCIS', 'Disease', (324, 328))	('amplifications', 'Var', (269, 283))	('invasive breast cancers', 'Disease', (333, 356))	('breast cancers', 'Phenotype', 'HP:0003002', (342, 356))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('invasive breast cancers', 'Disease', 'MESH:D001943', (333, 356))
41939	22252965	progression from DCIS to invasive cancer may be caused by a large constellation of genetic and/ or epigenetic aberrations, and/ or be mediated by the microenvironment).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('invasive cancer', 'Disease', (25, 40))	('epigenetic aberrations', 'Var', (99, 121))	('invasive cancer', 'Disease', 'MESH:D009362', (25, 40))	('DCIS', 'Disease', (17, 21))	('caused by', 'Reg', (48, 57))
41948	26347357	Imprinting methylation status also has the potential to contribute to the development of improved screening and treatment strategies for women with, or at risk of, breast cancer.	('methylation status', 'Var', (11, 29))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast cancer', 'Disease', (164, 177))	('women', 'Species', '9606', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
41955	26347357	A common observation in human breast cancers, and many other tumour types, is epigenetic change, including altered methylation of DNA.	('epigenetic change', 'Var', (78, 95))	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancers', 'Disease', (30, 44))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('human', 'Species', '9606', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('tumour', 'Disease', (61, 67))	('altered', 'Reg', (107, 114))	('methylation', 'MPA', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('DNA', 'Protein', (130, 133))
41956	26347357	There is an increasing interest in the role of epigenetics as a potential mechanism linking environmental exposures to cancer risk and as a non-genetic explanation for cancer heritability.	('epigenetics', 'Var', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
41957	26347357	Aberrant DNA methylation has been reported in breast tumours for a number of genes involved in apoptosis, cell cycle control and DNA repair.	('reported', 'Reg', (34, 42))	('Aberrant', 'Var', (0, 8))	('breast tumours', 'Disease', 'MESH:D001943', (46, 60))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('breast tumours', 'Disease', (46, 60))
41958	26347357	One class of epigenetic mark with particular relevance to cancer is imprinting; the epigenetic marking of genes in a parent-of-origin specific manner within the germ cells.	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('epigenetic', 'Var', (84, 94))
41960	26347357	A number of imprinted genes are known tumour suppressors or oncogenes, and loss of imprinting is a hallmark of many cancers.	('hallmark of many cancers', 'Disease', (99, 123))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (99, 123))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Disease', (38, 44))	('loss', 'Var', (75, 79))
41964	26347357	DNA methylation changes in blood have been reported in breast cancer and in relation to the pathological characteristics of breast cancer including histological type, tumour size and receptor status.	('changes', 'Reg', (16, 23))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('methylation', 'Var', (4, 15))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('breast cancer', 'Disease', (55, 68))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
41966	26347357	Six germ line DMRs, identified to regulate the associated imprinted gene regions, were chosen for pyrosequencing analysis: PLAGL1/ZAC1 [OMIM 603044], H19 [OMIM 103280], KvDMR [OMIM 604115], RB1 [OMIM 614041], SNRPN [OMIM 18227] and PEG3 [OMIM 601483].	('DMRs', 'Chemical', '-', (14, 18))	('PEG3', 'Gene', '5178', (232, 236))	('PLAGL1', 'Gene', '5325', (123, 129))	('SNRPN', 'Gene', '6638', (209, 214))	('PEG3', 'Gene', (232, 236))	('RB1', 'Gene', (190, 193))	('[OMIM 614041]', 'Var', (194, 207))	('[OMIM 603044]', 'Var', (135, 148))	('ZAC1', 'Gene', '5325', (130, 134))	('ZAC1', 'Gene', (130, 134))	('H19', 'Gene', '283120', (150, 153))	('H19', 'Gene', (150, 153))	('RB1', 'Gene', '5925', (190, 193))	('PLAGL1', 'Gene', (123, 129))	('SNRPN', 'Gene', (209, 214))
41985	26347357	Increased KvDMR-ICR2 methylation was associated with an elevated risk of DCIS (odds ratio = 1.395; 95 % CI 1.190, 1.635; p < 0.001).	('DCIS', 'Disease', (73, 77))	('KvDMR-ICR2', 'Gene', '7051', (10, 20))	('KvDMR-ICR2', 'Gene', (10, 20))	('methylation', 'Var', (21, 32))
41987	26347357	Risk of DCIS decreased with increasing PLAGL1/ZAC1 methylation (odds ratio = 0.905; 95 % CI 0.833, 0.982; p = 0.017) (Table 3).	('decreased', 'NegReg', (13, 22))	('ZAC1', 'Gene', (46, 50))	('ZAC1', 'Gene', '5325', (46, 50))	('PLAGL1', 'Gene', (39, 45))	('DCIS', 'Disease', (8, 12))	('methylation', 'Var', (51, 62))	('PLAGL1', 'Gene', '5325', (39, 45))
41989	26347357	Further statistical analysis showed that PLAGL1/ZAC1 methylation was inversely correlated with KVDMR-ICR2 (correlation coefficient = -0.290; p < 0.001).	('PLAGL1', 'Gene', (41, 47))	('correlated', 'Interaction', (79, 89))	('ZAC1', 'Gene', '5325', (48, 52))	('ZAC1', 'Gene', (48, 52))	('PLAGL1', 'Gene', '5325', (41, 47))	('inversely', 'NegReg', (69, 78))	('KVDMR-ICR2', 'Gene', (95, 105))	('KVDMR-ICR2', 'Gene', '7051', (95, 105))	('methylation', 'Var', (53, 64))
41996	26347357	Increased KvDMR-ICR2 methylation appeared to be associated with oestrogen receptor (ER) positive status, after adjustment for breast cancer type (odds ratio = 1.197; 95 % CI 1.032, 1.389; p = 0.018).	('KvDMR-ICR2', 'Gene', (10, 20))	('KvDMR-ICR2', 'Gene', '7051', (10, 20))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('oestrogen', 'Protein', (64, 73))	('breast cancer', 'Disease', (126, 139))	('methylation', 'Var', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
42002	26347357	Studies have confirmed correlation of PEG3 methylation between multiple tissue types, including blood and normal breast tissue and that cancerous breast tumours have increased methylation compared to benign breast tumours.	('cancerous breast tumours', 'Disease', (136, 160))	('benign breast tumours', 'Disease', 'MESH:D001943', (200, 221))	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('methylation', 'Var', (43, 54))	('increased', 'PosReg', (166, 175))	('PEG3', 'Gene', '5178', (38, 42))	('cancerous breast tumours', 'Disease', 'MESH:D009369', (136, 160))	('methylation', 'MPA', (176, 187))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('benign breast tumours', 'Disease', (200, 221))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PEG3', 'Gene', (38, 42))
42003	26347357	PEG3 encodes a Kruppel-type zinc-finger protein which regulates the tumour necrosis factor (TNF) response, of which dysregulation is commonly implicated in cancer [OMIM 601483].	('TNF', 'Gene', '7124', (92, 95))	('tumour necrosis factor', 'Gene', (68, 90))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('dysregulation', 'Var', (116, 129))	('cancer', 'Disease', (156, 162))	('implicated', 'Reg', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumour necrosis factor', 'Gene', '7124', (68, 90))	('PEG3', 'Gene', '5178', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('TNF', 'Gene', (92, 95))	('PEG3', 'Gene', (0, 4))	('regulates', 'Reg', (54, 63))
42004	26347357	Aberrant PEG3 methylation in blood samples of women with breast cancer has recently been reported but this analysis only highlighted the frequency of extreme outliers for PEG3 methylation, rather than the more subtle changes in average methylation reported here.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('Aberrant', 'Var', (0, 8))	('PEG3', 'Gene', (9, 13))	('PEG3', 'Gene', '5178', (171, 175))	('PEG3', 'Gene', (171, 175))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('PEG3', 'Gene', '5178', (9, 13))	('women', 'Species', '9606', (46, 51))
42013	26347357	The risk of progression is estimated at 25-50 % for women with low-grade DCIS and 75 % for women with high-grade DCIS.	('DCIS', 'Disease', (73, 77))	('women', 'Species', '9606', (52, 57))	('women', 'Species', '9606', (91, 96))	('low-grade', 'Var', (63, 72))
42015	26347357	Increased KvDMR-ICR2 methylation and decreased PLAGL1/ZAC1 methylation were linked with increasing risk of DCIS compared to both controls and IDC cases.	('methylation', 'MPA', (59, 70))	('PLAGL1', 'Gene', '5325', (47, 53))	('KvDMR-ICR2', 'Gene', (10, 20))	('KvDMR-ICR2', 'Gene', '7051', (10, 20))	('DCIS', 'Disease', (107, 111))	('ZAC1', 'Gene', (54, 58))	('methylation', 'Var', (21, 32))	('IDC', 'Gene', '4000', (142, 145))	('Increased', 'PosReg', (0, 9))	('ZAC1', 'Gene', '5325', (54, 58))	('PLAGL1', 'Gene', (47, 53))	('IDC', 'Gene', (142, 145))	('decreased', 'NegReg', (37, 46))
42021	26347357	Altered KvDMR-ICR2 methylation, as observed within this study, may influence breast cancer risk through an effect on CDKN1C or KCNQ1OT1.	('breast cancer', 'Disease', (77, 90))	('effect', 'Reg', (107, 113))	('methylation', 'Var', (19, 30))	('influence', 'Reg', (67, 76))	('KCNQ1OT1', 'Gene', '10984', (127, 135))	('KvDMR-ICR2', 'Gene', (8, 18))	('CDKN1C', 'Gene', '1028', (117, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('KCNQ1OT1', 'Gene', (127, 135))	('KvDMR-ICR2', 'Gene', '7051', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('CDKN1C', 'Gene', (117, 123))
42024	26347357	This is based on the idea that widespread changes in normal tissues precede the development of the disease and increase the risk of transition to cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('changes', 'Var', (42, 49))
42039	26347357	Imprinted gene methylation is particularly interesting to consider as these provide potential mechanistic routes to early life influences and non-genetic heritability of breast cancer.	('methylation', 'Var', (15, 26))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
42047	26347357	Only European Caucasians were included in the study and women with known family history of BRCA1/2 mutations and those which have been identified at an increased risk of breast cancer were excluded from the analysis.	('BRCA1/2', 'Gene', (91, 98))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('mutations', 'Var', (99, 108))	('BRCA1/2', 'Gene', '672;675', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('women', 'Species', '9606', (56, 61))
42073	24658685	Cell-to-cell heterogeneity has been described in solid tumors, and heterogeneity within carcinoma cell lines has been associated with drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (134, 149))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('drug resistance', 'MPA', (134, 149))	('solid tumors', 'Disease', (49, 61))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('carcinoma', 'Disease', (88, 97))	('associated', 'Reg', (118, 128))	('solid tumors', 'Disease', 'MESH:D009369', (49, 61))	('heterogeneity', 'Var', (67, 80))
42081	24658685	Disruption of TNC inhibits intraductal outgrowth of basal-like breast cancer cells in vivo, suggesting a functional role for the circuit during premalignancy.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('inhibits', 'NegReg', (18, 26))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('TNC', 'Gene', '3371', (14, 17))	('breast cancer', 'Disease', (63, 76))	('TNC', 'Gene', (14, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('Disruption', 'Var', (0, 10))
42102	24658685	Ectopic TGFBR3 expression reciprocally inhibited JUND expression (P = 0.022, one-sided t test; Fig.	('expression', 'Var', (15, 25))	('JUND expression', 'MPA', (49, 64))	('inhibited', 'NegReg', (39, 48))	('TGFBR3', 'Gene', '21814', (8, 14))	('expression', 'Species', '29278', (15, 25))	('TGFBR3', 'Gene', (8, 14))	('Ectopic', 'Var', (0, 7))	('expression', 'Species', '29278', (54, 64))
42104	24658685	Mutual TGFBR3-JUND antagonism creates a double-negative (positive) feedback loop, which can establish two distinct molecular states.	('TGFBR3', 'Gene', '21814', (7, 13))	('TGFBR3', 'Gene', (7, 13))	('antagonism', 'Var', (19, 29))
42122	24658685	The first group was enriched for JUND-associated genes (P = 6.6 x 10-5, hypergeometric test), including KRT5, and was most-highly expressed in ER--HER2- breast cancer, which contains the basal-like subtype.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('JUND-associated genes', 'Gene', (33, 54))	('KRT5', 'Gene', (104, 108))	('KRT5', 'Gene', '3852', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('most-highly', 'PosReg', (118, 129))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('ER--HER2-', 'Var', (143, 152))	('breast cancer', 'Disease', (153, 166))
42154	24658685	KRT5 levels increased with two type I keratin partners (KRT14 and KRT15; Supplementary Fig.	('KRT15', 'Var', (66, 71))	('KRT14', 'Var', (56, 61))	('KRT5', 'Gene', (0, 4))	('increased', 'PosReg', (12, 21))	('KRT5', 'Gene', '3852', (0, 4))
42157	24658685	Although ectopic expression of JunD left the induction of KRT5 protein unaltered (Supplementary Fig.	('ectopic expression', 'Var', (9, 27))	('expression', 'Species', '29278', (17, 27))	('KRT5', 'Gene', (58, 62))	('induction of', 'MPA', (45, 57))	('JunD', 'Gene', (31, 35))	('KRT5', 'Gene', '3852', (58, 62))
42158	24658685	Conversely, JUND knockdown accelerated keratinization and augmented it, with KRT5K cells apparent as early as 8 hr (P = 2.4 x 10-4 and 8.7 x 10-4, two-sided t test; Fig.	('keratinization', 'MPA', (39, 53))	('KRT5', 'Gene', (77, 81))	('augmented', 'PosReg', (58, 67))	('KRT5', 'Gene', '3852', (77, 81))	('accelerated', 'PosReg', (27, 38))	('knockdown', 'Var', (17, 26))
42174	24658685	To reconstitute p-RPS6, we inducibly overexpressed a constitutively active S6K (E389-DeltaCT) mutant  (Supplementary Fig.	('RPS6', 'Gene', '6194', (18, 22))	('RPS6', 'Gene', (18, 22))	('E389-DeltaCT', 'Var', (80, 92))	('S6K', 'Gene', (75, 78))	('E389-DeltaCT', 'Mutation', 'p.389delCT', (80, 92))
42178	24658685	Thus, loss of p-RPS6 is a critical trigger for detachment-induced keratinization of basal-like breast epithelial cells.	('RPS6', 'Gene', (16, 20))	('loss', 'Var', (6, 10))	('breast epithelia', 'Disease', 'MESH:D001943', (95, 111))	('RPS6', 'Gene', '6194', (16, 20))	('breast epithelia', 'Disease', (95, 111))
42179	24658685	Keratinization provided an appealing mechanism for the JUND-KRT5 anticorrelation observed in inner cells and CC regions of basal-like breast cancer (Fig.	('JUND-KRT5', 'Var', (55, 64))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
42213	24658685	TNC knockdown significantly increased the percentage of KRT5+ cells (P = 0.0014, two-sided t test; Fig.	('increased', 'PosReg', (28, 37))	('TNC', 'Gene', '3371', (0, 3))	('KRT5', 'Gene', '3852', (56, 60))	('TNC', 'Gene', (0, 3))	('KRT5', 'Gene', (56, 60))	('knockdown', 'Var', (4, 13))
42214	24658685	Two days after injection, we observed comparable bioluminescence in ducts injected with TNC knockdown cells compared to uninduced controls (Supplementary Fig.	('bioluminescence', 'MPA', (49, 64))	('TNC', 'Gene', '3371', (88, 91))	('TNC', 'Gene', (88, 91))	('knockdown cells', 'Var', (92, 107))
42215	24658685	At 21 days, however, colonization frequency was significantly inhibited by TNC knockdown (P = 0.049, Fisher's exact test; Fig.	('inhibited', 'NegReg', (62, 71))	('TNC', 'Gene', '3371', (75, 78))	('colonization frequency', 'CPA', (21, 43))	('knockdown', 'Var', (79, 88))	('TNC', 'Gene', (75, 78))
42229	24658685	There also appears to be a critical posttranscriptional component regulated by phosphorylation of RPS6.	('RPS6', 'Gene', '6194', (98, 102))	('RPS6', 'Gene', (98, 102))	('phosphorylation', 'Var', (79, 94))
42248	24658685	The human TRIPZ lentiviral inducible shRPS6 constructs V3THS_333416 (#1) and V3THS_333414 (#2) and the shTNC construct V2THS_133229 (Ref. )	('human', 'Species', '9606', (4, 9))	('RPS6', 'Gene', '6194', (39, 43))	('TNC', 'Gene', '3371', (105, 108))	('V3THS_333414', 'Var', (77, 89))	('V3THS_333416', 'Var', (55, 67))	('RPS6', 'Gene', (39, 43))	('TNC', 'Gene', (105, 108))
42311	24658685	8g), which were assessed by two-way ANOVA for an interaction between TNC knockdown and the frequencies of early-vs.-late apoptosis.	('TNC', 'Gene', (69, 72))	('TNC', 'Gene', '3371', (69, 72))	('knockdown', 'Var', (73, 82))
42330	21934681	However, YKL-40 lacks chitinase/hydrolase activity due to mutation of an essential glutamic acid to leucine in the chitinase-3-like catalytic domain.	('activity', 'MPA', (42, 50))	('leucine', 'Chemical', 'MESH:D007930', (100, 107))	('chitinase/hydrolase', 'Enzyme', (22, 41))	('mutation', 'Var', (58, 66))	('YKL-40', 'Gene', '1116', (9, 15))	('glutamic acid', 'Chemical', 'MESH:D018698', (83, 96))	('lacks', 'NegReg', (16, 21))	('YKL-40', 'Gene', (9, 15))
42532	27581127	Previously, we discovered numerous hotspot PIK3CA mutations in proliferative breast lesions.	('PIK3CA', 'Gene', '5290', (43, 49))	('breast lesions', 'Disease', 'MESH:D001941', (77, 91))	('mutations', 'Var', (50, 59))	('breast lesions', 'Disease', (77, 91))	('PIK3CA', 'Gene', (43, 49))
42534	27581127	We identified PI3K phosphosignaling network signatures in columnar cell change (CCL), usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS) and IBC in 29 lesions of known PIK3CA genotype from 10 human breast specimens using a hyperspectral-based multiplexed tissue imaging platform (MTIP) to simultaneously quantitate PI3K/MAPK pathway targets (pAKT473, pAKT308, pPRAS40, pS6, and pERK) in FFPE tissue, with single cell resolution.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (118, 142))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (125, 142))	('PIK3CA', 'Gene', (181, 187))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (92, 110))	('pAKT473', 'Var', (355, 362))	('pAKT308', 'Var', (364, 371))	('pS6', 'Gene', '338413', (382, 385))	('UDH', 'Chemical', '-', (112, 115))	('pERK', 'Gene', '9451', (391, 395))	('pERK', 'Gene', (391, 395))	('MTIP', 'Chemical', '-', (293, 297))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('ductal hyperplasia', 'Disease', (92, 110))	('PIK3CA', 'Gene', '5290', (181, 187))	('CCL', 'Chemical', '-', (80, 83))	('human', 'Species', '9606', (205, 210))	('ductal carcinoma in situ', 'Disease', (118, 142))	('pPRAS40', 'Var', (373, 380))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('pS6', 'Gene', (382, 385))
42537	27581127	Further, 5 UDH/CCL lesions across different patients had a common phosphosignature at the epithelial-stromal interface (possible myoepithelial cells) that was distinct from both the adjacent lesional epithelium, and distinct from adjacent stroma.	('lesions', 'Var', (19, 26))	('UDH/CCL', 'Disease', (11, 18))	('patients', 'Species', '9606', (44, 52))	('UDH', 'Chemical', '-', (11, 14))	('myoepithelial', 'Disease', (129, 142))	('CCL', 'Chemical', '-', (15, 18))	('myoepithelial', 'Disease', 'MESH:D009208', (129, 142))
42540	27581127	Numerous studies have demonstrated that well over half of breast cancers have genetic changes in components of the phosphatidylinositol-3-kinase (PI3K) signaling cascade, predicted to result in pathway activation.	('breast cancers', 'Phenotype', 'HP:0003002', (58, 72))	('phosphatidylinositol-3-kinase', 'Gene', (115, 144))	('phosphatidylinositol-3-kinase', 'Gene', '5290', (115, 144))	('breast cancers', 'Disease', 'MESH:D001943', (58, 72))	('breast cancers', 'Disease', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('genetic changes', 'Var', (78, 93))
42541	27581127	These genomic changes include amplification, mutation or activation of receptor tyrosine kinases (HER2, EGFR), mutation or amplification of the catalytic subunit (PIK3CA), mutation of amplification of AKT1, or loss of inhibition, impacting the PIK3R1 regulatory subunit, or phosphatase and tensin homolog (PTEN) function.	('mutation', 'Var', (172, 180))	('PIK3R1', 'Gene', (244, 250))	('PIK3CA', 'Gene', (163, 169))	('loss', 'NegReg', (210, 214))	('PTEN', 'Gene', (306, 310))	('EGFR', 'Gene', (104, 108))	('amplification', 'Gene', (184, 197))	('activation', 'PosReg', (57, 67))	('HER2', 'Gene', (98, 102))	('AKT1', 'Gene', '207', (201, 205))	('impacting', 'NegReg', (230, 239))	('amplification', 'PosReg', (123, 136))	('PTEN', 'Gene', '5728', (306, 310))	('PIK3R1', 'Gene', '5295', (244, 250))	('AKT1', 'Gene', (201, 205))	('inhibition', 'MPA', (218, 228))	('mutation', 'Var', (111, 119))	('PIK3CA', 'Gene', '5290', (163, 169))	('EGFR', 'Gene', '1956', (104, 108))	('amplification', 'Disease', (30, 43))	('mutation', 'Var', (45, 53))	('HER2', 'Gene', '2064', (98, 102))	('function', 'MPA', (312, 320))
42542	27581127	Activating 'hotspot' point mutations in PIK3CA are present in about 25% of invasive breast cancers, and are even further enriched in luminal-A cancers including invasive lobular carcinoma.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('PIK3CA', 'Gene', (40, 46))	('luminal-A cancers', 'Disease', 'MESH:D009369', (133, 150))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('PIK3CA', 'Gene', '5290', (40, 46))	('point mutations', 'Var', (21, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (84, 98))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('invasive breast cancers', 'Disease', (75, 98))	('lobular carcinoma', 'Disease', 'MESH:D018275', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	("Activating 'hotspot'", 'PosReg', (0, 20))	('luminal-A cancers', 'Disease', (133, 150))	('invasive breast cancers', 'Disease', 'MESH:D001943', (75, 98))	('lobular carcinoma', 'Disease', (170, 187))
42543	27581127	Accumulating data from a number of different studies shows that concurrent invasive and in-situ breast carcinoma (ductal carcinoma in-situ, DCIS) in the same patient frequently harbor identical PIK3CA mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutations', 'Var', (201, 210))	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (114, 138))	('situ breast carcinoma', 'Disease', (91, 112))	('invasive', 'Disease', (75, 83))	('harbor', 'Reg', (177, 183))	('patient', 'Species', '9606', (158, 165))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('situ breast carcinoma', 'Disease', 'MESH:D000071960', (91, 112))	('ductal carcinoma', 'Disease', 'MESH:D044584', (114, 130))	('ductal carcinoma', 'Disease', (114, 130))	('breast carcinoma', 'Phenotype', 'HP:0003002', (96, 112))	('PIK3CA', 'Gene', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PIK3CA', 'Gene', '5290', (194, 200))
42544	27581127	This observation fits the prevailing notion of DCIS as direct precursor of invasive breast cancer, and furthers the concept of activating PIK3CA mutations as a potential 'driver' of breast carcinogenesis.	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('fits', 'Disease', (17, 21))	('mutations', 'Var', (145, 154))	('activating', 'PosReg', (127, 137))	('breast carcinogenesis', 'Disease', (182, 203))	('invasive breast cancer', 'Disease', 'MESH:D001943', (75, 97))	('fits', 'Disease', 'MESH:D012640', (17, 21))	('PIK3CA', 'Gene', (138, 144))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (182, 203))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('invasive breast cancer', 'Disease', (75, 97))	('PIK3CA', 'Gene', '5290', (138, 144))
42545	27581127	Further, we and others have recently shown that PIK3CA mutations are present in both 'benign' and 'atypical' proliferative breast lesions.	('breast lesions', 'Disease', (123, 137))	('mutations', 'Var', (55, 64))	('PIK3CA', 'Gene', (48, 54))	("'benign'", 'Disease', (85, 93))	('present', 'Reg', (69, 76))	('breast lesions', 'Disease', 'MESH:D001941', (123, 137))	('PIK3CA', 'Gene', '5290', (48, 54))
42546	27581127	However, the PIK3CA mutation status of these proliferative breast lesions was frequently different than that of concurrent invasive carcinoma sampled from the same tissue specimen.	('PIK3CA', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('breast lesions', 'Disease', (59, 73))	('mutation', 'Var', (20, 28))	('PIK3CA', 'Gene', '5290', (13, 19))	('breast lesions', 'Disease', 'MESH:D001941', (59, 73))	('invasive carcinoma', 'Disease', 'MESH:D009361', (123, 141))	('invasive carcinoma', 'Disease', (123, 141))	('different', 'Reg', (89, 98))
42547	27581127	For example, ten patients with PIK3CA-wild type (WT) carcinoma each had PIK3CA exon-20 mutated proliferative lesions present in the same breast tissue specimen.	('mutated', 'Var', (87, 94))	('carcinoma', 'Disease', 'MESH:D002277', (53, 62))	('PIK3CA', 'Gene', (72, 78))	('PIK3CA', 'Gene', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('patients', 'Species', '9606', (17, 25))	('PIK3CA', 'Gene', '5290', (31, 37))	('PIK3CA', 'Gene', '5290', (72, 78))	('carcinoma', 'Disease', (53, 62))
42548	27581127	Activating PIK3CA mutations have been shown to evoke downstream PI3K network signaling that fuels cellular transformation and cancer growth in vitro, but their in vivo activity within lesional tissue is more difficult to establish, in light of intra-network inhibitory feedback loops or inter-network cross-talk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Activating', 'PosReg', (0, 10))	('evoke', 'Reg', (47, 52))	('cancer', 'Disease', (126, 132))	('PIK3CA', 'Gene', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('PIK3CA', 'Gene', '5290', (11, 17))	('cellular transformation', 'CPA', (98, 121))	('mutations', 'Var', (18, 27))
42549	27581127	Given the high prevalence of mutations and potential impact of PIK3CA mutation on downstream signaling in breast epithelial proliferation/neoplasia, we sought to capture the spatial nature of PI3K network signaling and its relationship with PIK3CA mutations in proliferative breast lesions.	('PIK3CA', 'Gene', '5290', (241, 247))	('breast lesions', 'Disease', (275, 289))	('neoplasia', 'Disease', 'MESH:D009369', (138, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('mutations', 'Var', (29, 38))	('PIK3CA', 'Gene', (241, 247))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('breast lesions', 'Disease', 'MESH:D001941', (275, 289))	('mutation', 'Var', (70, 78))	('neoplasia', 'Disease', (138, 147))
42550	27581127	To do this, we used MTIP, a new multiplexed hyperspectral tissue imaging platform to identify and map the location of phosphorylated PI3K network signaling nodes (pAKT1 (308, 473), pPRAS40, pS6, and pERK) and identify distinct PI3K network signatures.	('pPRAS40', 'Var', (181, 188))	('AKT1', 'Gene', '207', (164, 168))	('pS6', 'Gene', '338413', (190, 193))	('MTIP', 'Chemical', '-', (20, 24))	('pERK', 'Gene', '9451', (199, 203))	('AKT1', 'Gene', (164, 168))	('pERK', 'Gene', (199, 203))	('pS6', 'Gene', (190, 193))
42555	27581127	DNA was screened for a large panel of hotspot mutations as previously described, including 58 substitutions in 34 codons of the PIK3CA gene; point mutations were confirmed by sequencing.	('PIK3CA', 'Gene', (128, 134))	('substitutions', 'Var', (94, 107))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', '5290', (128, 134))
42556	27581127	From this cohort, 29 lesions from 10 patients were selected for image analysis, based on availability of multiple lesions (up to 4) with different PIK3CA mutations from the same patient (Table 1).	('patient', 'Species', '9606', (37, 44))	('patients', 'Species', '9606', (37, 45))	('patient', 'Species', '9606', (178, 185))	('PIK3CA', 'Gene', (147, 153))	('PIK3CA', 'Gene', '5290', (147, 153))	('mutations', 'Var', (154, 163))
42560	27581127	FFPE specimens were incubated with a a cocktail of hapten-conjugated primary antibodies (pS6:BF, pAKT S473:DIG, pPRAS40:NP, pERK 1/2:NCA, pAKT T308:DNP at 5, 15, 20, 30, 12.5 mug/mL) at 37 C for 32 minutes.	('pS6', 'Gene', '338413', (89, 92))	('pERK 1/2:NCA', 'Gene', '4680', (124, 136))	('pPRAS40:NP', 'Var', (112, 122))	('pERK 1/2:NCA', 'Gene', (124, 136))	('pS6', 'Gene', (89, 92))
42561	27581127	Following the primary antibody incubation step, samples were incubated with secondary anti-hapten antibody quantum dot (QD) conjugates (anti-BF:QD525, anti-DIG:QD565, anti-NP:QD605l, anti-NCA:QD625, anti-DNP:QD655 at 40, 50, 70, 40, and 30 nM concentrations respectively) at 37 C for 32 minutes.	('anti-NP:QD605l', 'Var', (167, 181))	('anti-DNP:QD655', 'Var', (199, 213))	('anti-DIG:QD565', 'Var', (151, 165))	('NCA', 'Gene', (188, 191))	('NCA', 'Gene', '4680', (188, 191))	('anti-BF:QD525', 'Var', (136, 149))
42569	27581127	Multiplexed phopshoantibody staining and spectral imaging of phosphoactivated protein species (pAKT473, pAKT308, pPRAS40, pS6, and pERK) was performed on the cohort (see Methods).	('pS6', 'Gene', (122, 125))	('pS6', 'Gene', '338413', (122, 125))	('pAKT473', 'Var', (95, 102))	('pERK', 'Gene', (131, 135))	('pPRAS40', 'Var', (113, 120))	('pERK', 'Gene', '9451', (131, 135))	('pAKT308', 'Var', (104, 111))
42577	27581127	For example, lesions with the PIK3CA exon 20 H1047R mutation, coded in yellow in the rightmost column of Figure 2, were spaced throughout the dendrogram tree.	('H1047R', 'Mutation', 'rs121913279', (45, 51))	('PIK3CA', 'Gene', (30, 36))	('H1047R', 'Var', (45, 51))	('PIK3CA', 'Gene', '5290', (30, 36))
42579	27581127	We did, however, find similarity in PI3K/MAPK signatures at the epithelial-stroma interface in 5 CCL lesions across different patients with different genotypes: PIK3CA E545K and H1047R (epithelial-stromal interface signatures are denoted by an asterisk, as described above and shown in Figure 1B and Figure 2).	('H1047R', 'Mutation', 'rs121913279', (178, 184))	('E545K', 'Mutation', 'rs104886003', (168, 173))	('E545K', 'Var', (168, 173))	('PIK3CA', 'Gene', (161, 167))	('CCL', 'Chemical', '-', (97, 100))	('PIK3CA', 'Gene', '5290', (161, 167))	('H1047R', 'Var', (178, 184))	('patients', 'Species', '9606', (126, 134))
42603	27581127	Nevertheless, there was one recurring PI3K signature, which was seen in 5 proliferative, non-invasive breast lesions at the epithelial-stromal interface (Figure 1b, Figure 2).	('breast lesions', 'Disease', (102, 116))	('breast lesions', 'Disease', 'MESH:D001941', (102, 116))	('proliferative', 'Disease', (74, 87))	('PI3K', 'Var', (38, 42))
42618	33753731	DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10-46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression.	('expression', 'MPA', (26, 36))	('COX-2', 'Gene', (224, 229))	('high', 'Var', (15, 19))	('COX-2', 'Gene', '4513', (224, 229))	('iIBC', 'Disease', (163, 167))	('smaller adipocyte', 'Phenotype', 'HP:0040063', (193, 210))	('iIBC', 'Chemical', '-', (163, 167))	('large breast', 'Phenotype', 'HP:0010313', (41, 53))	('COX-2', 'Gene', '4513', (20, 25))	('women', 'Species', '9606', (182, 187))	('COX-2', 'Gene', (20, 25))
42619	33753731	Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC.	('Large breast', 'Phenotype', 'HP:0010313', (0, 12))	('iIBC', 'Chemical', '-', (113, 117))	('iIBC', 'Disease', (113, 117))	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('COX-2', 'Gene', (43, 48))	('COX-2', 'Gene', '4513', (43, 48))	('associated', 'Reg', (71, 81))
42654	33753731	Women with an adipocyte area75th within the highest quartile had a 2.75-fold (95% CI = 1.25-6.05) increased risk for subsequent iIBC compared to women with an adipocyte area75th within the lowest quartile.	('iIBC', 'Chemical', '-', (128, 132))	('Women', 'Species', '9606', (0, 5))	('iIBC', 'Disease', (128, 132))	('adipocyte area75th', 'Var', (14, 32))	('women', 'Species', '9606', (145, 150))
42658	33753731	In the presence of high COX-2 expression, adipocyte area75th remained an independent predictor of subsequent iIBC.	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('iIBC', 'Disease', (109, 113))	('iIBC', 'Chemical', '-', (109, 113))	('adipocyte area75th', 'MPA', (42, 60))	('COX-2', 'Gene', '4513', (24, 29))	('COX-2', 'Gene', (24, 29))
42659	33753731	Women with an adipocyte area75th within the highest quartile had a 3.05-fold (95% CI = 1.32-7.05) increased risk for subsequent iIBC compared to women with an adipocyte area75th within the lowest quartile, while COX-2 was an independent predictor for iIBC in the presence of adipocyte area75th (OR 4.33, 95% CI 1.79-10.5).	('iIBC', 'Chemical', '-', (128, 132))	('Women', 'Species', '9606', (0, 5))	('iIBC', 'Disease', (128, 132))	('COX-2', 'Gene', '4513', (212, 217))	('adipocyte area75th', 'Var', (14, 32))	('iIBC', 'Chemical', '-', (251, 255))	('COX-2', 'Gene', (212, 217))	('women', 'Species', '9606', (145, 150))
42661	33753731	The risk of subsequent iIBC in DCIS patients with high COX-2 expression and an adipocyte area75th within the highest quartile was 12 times higher than in DCIS patients with low COX-2 expression and an smaller (quartile 1-3) adipocyte area75th (OR 12.0, 95% CI = 3.10-46.3, Table 3).	('COX-2', 'Gene', (55, 60))	('patients', 'Species', '9606', (36, 44))	('DCIS', 'Disease', (31, 35))	('COX-2', 'Gene', '4513', (177, 182))	('higher', 'PosReg', (139, 145))	('iIBC', 'Disease', (23, 27))	('COX-2', 'Gene', (177, 182))	('iIBC', 'Chemical', '-', (23, 27))	('patients', 'Species', '9606', (159, 167))	('COX-2', 'Gene', '4513', (55, 60))	('high', 'Var', (50, 54))
42669	33753731	DCIS with high COX-2 expression, a cytoplasmic enzyme involved in prostaglandin synthesis, was also associated with iIBC risk, as we previously showed.	('COX-2', 'Gene', '4513', (15, 20))	('iIBC', 'Disease', (116, 120))	('expression', 'MPA', (21, 31))	('associated', 'Reg', (100, 110))	('COX-2', 'Gene', (15, 20))	('iIBC', 'Chemical', '-', (116, 120))	('high', 'Var', (10, 14))	('prostaglandin', 'Chemical', 'MESH:D011453', (66, 79))
42699	33753731	Patients with an adipocyte area75thq4/COX-2high DCIS lesions when treated with BCS alone, had a 12-fold increased risk for subsequent iIBC compared to adipocyte area75thq1-3/COX-2low DCIS lesions, and thus may benefit from more careful monitoring during follow-up.	('DCIS lesions', 'Disease', 'MESH:D002285', (183, 195))	('DCIS lesions', 'Disease', (183, 195))	('Patients', 'Species', '9606', (0, 8))	('DCIS lesions', 'Disease', (48, 60))	('COX-2', 'Gene', '4513', (174, 179))	('COX-2', 'Gene', '4513', (38, 43))	('iIBC', 'Chemical', '-', (134, 138))	('iIBC', 'Disease', (134, 138))	('adipocyte', 'Var', (17, 26))	('COX-2', 'Gene', (174, 179))	('COX-2', 'Gene', (38, 43))	('DCIS lesions', 'Disease', 'MESH:D002285', (48, 60))
42770	33409073	Positive margins are frustrating to patients and providers alike and are associated with an increase in re-operations, mastectomy rates, medical and radiation treatments all of which are difficult for the patients and expensive for the health care systems.	('mastectomy', 'Disease', (119, 129))	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (36, 44))	('medical', 'CPA', (137, 144))	('re-operations', 'CPA', (104, 117))	('increase', 'PosReg', (92, 100))	('Positive', 'Var', (0, 8))
42940	26542585	LCIS was initially considered to be a form of mammary carcinoma and, as such, was treated with mastectomy; however, long-term results of clinical follow-up studies suggested that LCIS and ALH represented markers of generalized increased breast cancer risk, not true precursor lesions, and surgery fell out of favor.	('LCIS', 'Phenotype', 'HP:0030076', (179, 183))	('increased', 'PosReg', (227, 236))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('LCIS', 'Phenotype', 'HP:0030076', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('LCIS', 'Var', (179, 183))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (46, 63))	('breast cancer', 'Disease', (237, 250))	('carcinoma', 'Disease', (54, 63))	('ALH', 'Var', (188, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))
42976	26542585	In conclusion, in this prospective multi-institutional study of patients with BIRADS 4 or lower concordant lesions with LN on core biopsy, we found a very low upgrade rate to invasive cancer or DCIS on excision.	('patients', 'Species', '9606', (64, 72))	('BIRADS', 'Var', (78, 84))	('invasive cancer', 'Disease', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('LN', 'Phenotype', 'HP:0030076', (120, 122))	('DCIS', 'Disease', (194, 198))	('invasive cancer', 'Disease', 'MESH:D009362', (175, 190))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))
42986	21776373	Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis.	('Breast Cancer', 'Disease', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinogenesis', 'Disease', (201, 215))	('Breast Cancer', 'Phenotype', 'HP:0003002', (86, 99))	('human', 'Species', '9606', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('Aberrant methylation', 'Var', (100, 120))	('carcinogenesis', 'Disease', 'MESH:D063646', (201, 215))	('Breast Cancer', 'Disease', 'MESH:D001943', (86, 99))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))
42991	21776373	Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Promoter methylation', 'Var', (0, 20))	('tumor', 'Disease', (43, 48))	('detected', 'Reg', (25, 33))
42992	21776373	Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer.	('GSTP1', 'Gene', '2950', (100, 105))	('invasive breast cancer', 'Disease', 'MESH:D001943', (193, 215))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('RASSF1', 'Gene', '11186', (20, 26))	('APC', 'Disease', (82, 85))	('Hypermethylation', 'Var', (0, 16))	('GSTP1', 'Gene', (100, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('invasive breast cancer', 'Disease', (193, 215))	('RASSF1', 'Gene', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
42994	21776373	DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.	('preneoplasia to invasive breast cancer', 'Disease', (120, 158))	('preneoplasia to invasive breast cancer', 'Disease', 'MESH:D001943', (120, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('hypermethylation', 'Var', (4, 20))
42997	21776373	Such alterations are thought to contribute to the neoplastic process by transcriptional silencing of tumor suppressor gene expression and by increasing the rate of genetic mutation.	('contribute', 'Reg', (32, 42))	('expression', 'MPA', (123, 133))	('genetic', 'MPA', (164, 171))	('transcriptional', 'Var', (72, 87))	('tumor', 'Disease', (101, 106))	('neoplastic process', 'Phenotype', 'HP:0002664', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('neoplastic process', 'CPA', (50, 68))	('alterations', 'Var', (5, 16))	('increasing', 'PosReg', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
42998	21776373	The potential that aberrant methylation may be pharmacologically reversible offers additional treatment opportunities for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('aberrant methylation', 'Var', (19, 39))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
43004	21776373	Aberrant methylation of APC was noted in 12/17 cases with evidence of a progression continuum from normal to benign to invasive breast cancer in Case 3, benign to CIS to tumor in Case 2 (Figure 1C-1E), benign (papilloma) to tumor in Case 5, and DCIS to tumor in Cases 9, 15, and 18.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (170, 175))	('invasive breast cancer', 'Disease', 'MESH:D001943', (119, 141))	('APC', 'Disease', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('papilloma', 'Disease', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (224, 229))	('papilloma', 'Disease', 'MESH:D010212', (210, 219))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Disease', (253, 258))	('papilloma', 'Phenotype', 'HP:0012740', (210, 219))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('DCIS', 'Phenotype', 'HP:0030075', (245, 249))	('invasive breast cancer', 'Disease', (119, 141))	('benign', 'Disease', (202, 208))
43006	21776373	Methylation of TIMP3 in 4/17 cases linked normal and benign (ALH) lesions in Case 7, and DCIS and tumor lesions in Case 15.	('DCIS', 'Disease', (89, 93))	('TIMP3', 'Gene', (15, 20))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('Methylation', 'Var', (0, 11))	('tumor lesions', 'Disease', 'MESH:D051437', (98, 111))	('TIMP3', 'Gene', '7078', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor lesions', 'Disease', (98, 111))
43007	21776373	Aberrant methylation of CDKN2B and ESR1 in 4/17 cases, connected benign (ALH) and tumor lesions in Case 7.	('tumor lesions', 'Disease', (82, 95))	('Aberrant', 'Var', (0, 8))	('ESR1', 'Gene', '2099', (35, 39))	('tumor lesions', 'Disease', 'MESH:D051437', (82, 95))	('CDKN2B', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ESR1', 'Gene', (35, 39))	('methylation', 'MPA', (9, 20))	('CDKN2B', 'Gene', '1030', (24, 30))	('connected', 'Reg', (55, 64))
43009	21776373	MSP for APC, GSTP1 and RASSF1, performed in Cases 1, 2, 3 and 5 (Table 1, Figure 2) confirmed aberrant methylation of APC detected by MS-MLPA for Case 1 (tumor), Case 2 (LCIS and tumor) and Case 3 (tumor block 6 and 10).	('tumor block', 'Disease', (198, 209))	('GSTP1', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('APC', 'Disease', 'MESH:D011125', (118, 121))	('MS-MLPA', 'Chemical', '-', (134, 141))	('APC', 'Disease', (118, 121))	('tumor', 'Disease', (154, 159))	('RASSF1', 'Gene', '11186', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('RASSF1', 'Gene', (23, 29))	('LCIS', 'Phenotype', 'HP:0030076', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor block', 'Disease', 'MESH:D006327', (198, 209))	('APC', 'Disease', (8, 11))	('tumor', 'Disease', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('aberrant', 'Var', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('methylation', 'MPA', (103, 114))	('APC', 'Disease', 'MESH:D011125', (8, 11))	('GSTP1', 'Gene', '2950', (13, 18))	('tumor', 'Disease', (179, 184))
43011	21776373	MSP confirmed aberrant methylation of GSTP1 for Case 3 (tumor block 10) and lack of methylation in Case 5 tumor block 2, indicated by MS-MLPA.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor block', 'Disease', 'MESH:D006327', (106, 117))	('tumor block 2', 'Disease', (106, 119))	('GSTP1', 'Gene', (38, 43))	('tumor block 2', 'Disease', 'MESH:D006327', (106, 119))	('aberrant', 'Var', (14, 22))	('tumor block', 'Disease', (56, 67))	('methylation', 'MPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('GSTP1', 'Gene', '2950', (38, 43))	('tumor block', 'Disease', 'MESH:D006327', (56, 67))	('MS-MLPA', 'Chemical', '-', (134, 141))	('methylation', 'MPA', (23, 34))
43015	21776373	Additional RASSF1 methylation was detected by MSP in Case 2 (ALH), Case 3 (normal and hyperplasia) and Case 5 (normal and tumor block 2).	('detected', 'Reg', (34, 42))	('hyperplasia', 'Disease', (86, 97))	('tumor block 2', 'Disease', (122, 135))	('RASSF1', 'Gene', '11186', (11, 17))	('hyperplasia', 'Disease', 'MESH:D006965', (86, 97))	('tumor block 2', 'Disease', 'MESH:D006327', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('methylation', 'Var', (18, 29))	('RASSF1', 'Gene', (11, 17))
43016	21776373	Promoter region hypermethylation is known to be an early event in carcinogenesis.	('carcinogenesis', 'Disease', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('hypermethylation', 'Var', (16, 32))
43017	21776373	The consequence of CpG island hypermethylation, especially for those islands associated with tumor suppressor gene promoters is the loss of tumor suppressor function, which contributes to tumorigenesis.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('loss', 'NegReg', (132, 136))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('hypermethylation', 'Var', (30, 46))	('tumor', 'Disease', (140, 145))
43018	21776373	Clonal epigenetic alterations in benign and precancerous lesions may reflect biological peculiarities pertinent to tumor behavior.	('tumor behavior', 'Disease', 'MESH:D001523', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('precancerous lesions', 'Disease', 'MESH:D011230', (44, 64))	('reflect', 'Reg', (69, 76))	('precancerous lesions', 'Disease', (44, 64))	('tumor behavior', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('epigenetic alterations', 'Var', (7, 29))
43020	21776373	Our previous studies have demonstrated that epigenetic events of DNA hypermethylation underlie the pathogenesis of benign sinonasal and laryngeal papillomas, including establishing a monoclonal origin for recurrent respiratory papillomas (RRP).	('papilloma', 'Phenotype', 'HP:0012740', (146, 155))	('benign sinonasal', 'Disease', (115, 131))	('underlie', 'Reg', (86, 94))	('respiratory papillomas', 'Disease', 'MESH:D012131', (215, 237))	('epigenetic events', 'Var', (44, 61))	('papillomas', 'Phenotype', 'HP:0012740', (227, 237))	('respiratory papillomas', 'Disease', (215, 237))	('laryngeal papillomas', 'Disease', (136, 156))	('papilloma', 'Phenotype', 'HP:0012740', (227, 236))	('papillomas', 'Phenotype', 'HP:0012740', (146, 156))	('laryngeal papillomas', 'Disease', 'MESH:C535297', (136, 156))
43021	21776373	This study underscores promoter hypermethylation as an early event in the pathogenesis of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('promoter hypermethylation', 'Var', (23, 48))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))
43022	21776373	Aberrant methylation in normal breast epithelium or benign lesions from four cases with progression implicated TP73, TIMP3, CDKN2B, ESR1, APC, GSTP1 and RASSF1 as early events.	('ESR1', 'Gene', '2099', (132, 136))	('RASSF1', 'Gene', '11186', (153, 159))	('CDKN2B', 'Gene', '1030', (124, 130))	('RASSF1', 'Gene', (153, 159))	('ESR1', 'Gene', (132, 136))	('TP73', 'Gene', '7161', (111, 115))	('GSTP1', 'Gene', (143, 148))	('TP73', 'Gene', (111, 115))	('Aberrant methylation', 'Var', (0, 20))	('APC', 'Disease', 'MESH:D011125', (138, 141))	('APC', 'Disease', (138, 141))	('GSTP1', 'Gene', '2950', (143, 148))	('TIMP3', 'Gene', '7078', (117, 122))	('TIMP3', 'Gene', (117, 122))	('CDKN2B', 'Gene', (124, 130))
43023	21776373	RASSF1 was most frequently methylated (14/17) cases followed by APC (12/17) cases and GSTP1 in 9/17 cases.	('GSTP1', 'Gene', '2950', (86, 91))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('methylated', 'Var', (27, 37))	('APC', 'Disease', (64, 67))	('RASSF1', 'Gene', '11186', (0, 6))	('GSTP1', 'Gene', (86, 91))	('RASSF1', 'Gene', (0, 6))
43024	21776373	Methylation of RASSF1A and APC was reported to occur more frequently in benign samples from high risk women (determined by the Gail model) than in samples from low or intermediate risk women and was associated with epidemiologic markers of increased breast cancer risk.	('breast cancer', 'Disease', (250, 263))	('associated', 'Reg', (199, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('RASSF1A', 'Gene', '11186', (15, 22))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('women', 'Species', '9606', (102, 107))	('APC', 'Disease', (27, 30))	('women', 'Species', '9606', (185, 190))	('RASSF1A', 'Gene', (15, 22))	('breast cancer', 'Disease', 'MESH:D001943', (250, 263))
43025	21776373	RASSF1A methylation has been highly correlated with breast cancer risk, atypical cytology and benign breast disease requiring biopsy.	('benign breast disease', 'Disease', 'MESH:D001941', (94, 115))	('RASSF1A', 'Gene', (0, 7))	('benign breast disease', 'Disease', (94, 115))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('correlated', 'Reg', (36, 46))	('RASSF1A', 'Gene', '11186', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('methylation', 'Var', (8, 19))
43028	21776373	Methylation of RASSF1A leads to accumulation of cyclin D1 and may represent one mechanism for overriding cell cycle control under conditions of increased cell cycle pressure.	('cyclin D1', 'Gene', (48, 57))	('RASSF1A', 'Gene', '11186', (15, 22))	('Methylation', 'Var', (0, 11))	('accumulation', 'PosReg', (32, 44))	('RASSF1A', 'Gene', (15, 22))	('cyclin D1', 'Gene', '595', (48, 57))
43029	21776373	showed that the RASSF1A promoter was methylated in all epithelial hyperplasia and papilloma samples and in 83% of ductal carcinoma samples in situ, suggesting methylation of RASSF1A as a new marker for nonphysiological epithelial proliferation in the breast.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('epithelial hyperplasia', 'Disease', (55, 77))	('papilloma', 'Phenotype', 'HP:0012740', (82, 91))	('RASSF1A', 'Gene', '11186', (174, 181))	('papilloma', 'Disease', (82, 91))	('ductal carcinoma', 'Disease', 'MESH:D044584', (114, 130))	('RASSF1A', 'Gene', (16, 23))	('ductal carcinoma', 'Disease', (114, 130))	('methylation', 'Var', (159, 170))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (55, 77))	('papilloma', 'Disease', 'MESH:D010212', (82, 91))	('RASSF1A', 'Gene', '11186', (16, 23))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (114, 130))	('RASSF1A', 'Gene', (174, 181))
43031	21776373	Genetic and epigenetic alterations in APC (adenomatosis polyposis coli), a tumor suppressor gene originally implicated in colon cancer have been reported in other malignancies including breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancers', 'Disease', 'MESH:D001943', (186, 200))	('breast cancers', 'Disease', (186, 200))	('tumor', 'Disease', (75, 80))	('epigenetic alterations', 'Var', (12, 34))	('breast cancers', 'Phenotype', 'HP:0003002', (186, 200))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('APC', 'Disease', 'MESH:D011125', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('reported', 'Reg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('APC', 'Disease', (38, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('malignancies', 'Disease', 'MESH:D009369', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('colon cancer', 'Disease', (122, 134))	('adenomatosis polyposis coli', 'Phenotype', 'HP:0005227', (43, 70))	('malignancies', 'Disease', (163, 175))	('adenomatosis polyposis coli', 'Disease', 'MESH:D011125', (43, 70))	('Genetic', 'Var', (0, 7))	('adenomatosis polyposis coli', 'Disease', (43, 70))
43033	21776373	demonstrated that APC gene methylation correlated positively with TNM staging and negatively with protein expression suggesting a role in the development of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('TNM', 'Gene', '10178', (66, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('methylation', 'Var', (27, 38))	('APC', 'Disease', 'MESH:D011125', (18, 21))	('TNM', 'Gene', (66, 69))	('APC', 'Disease', (18, 21))	('protein expression', 'MPA', (98, 116))	('negatively', 'NegReg', (82, 92))
43037	21776373	The pi-class of glutathione S-transferase enzymes has been associated with preneoplastic and neoplastic changes.	('preneoplastic', 'CPA', (75, 88))	('glutathione S-transferase enzymes', 'Enzyme', (16, 49))	('neoplastic changes', 'Phenotype', 'HP:0002664', (93, 111))	('associated', 'Reg', (59, 69))	('glutathione', 'Chemical', 'MESH:D005978', (16, 27))	('pi-class', 'Var', (4, 12))
43038	21776373	Inactivation of GSTP1 by promoter hypermethylation is characteristic of steroid related neoplasms such as breast, liver, and prostate cancers.	('prostate cancers', 'Disease', (125, 141))	('breast', 'Disease', (106, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('GSTP1', 'Gene', '2950', (16, 21))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('prostate cancers', 'Disease', 'MESH:D011471', (125, 141))	('neoplasms', 'Disease', 'MESH:D009369', (88, 97))	('prostate cancers', 'Phenotype', 'HP:0012125', (125, 141))	('neoplasms', 'Disease', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('liver', 'Disease', (114, 119))	('Inactivation', 'Var', (0, 12))	('GSTP1', 'Gene', (16, 21))	('promoter hypermethylation', 'Var', (25, 50))
43040	21776373	In our cohort, nine of 17 cases demonstrated aberrant methylation of GSTP1 and in three cases (Cases 3, 5, 7) a transformation continuum from benign to invasive carcinoma was evident.	('invasive carcinoma', 'Disease', 'MESH:D009361', (152, 170))	('aberrant', 'Var', (45, 53))	('GSTP1', 'Gene', (69, 74))	('invasive carcinoma', 'Disease', (152, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('methylation', 'MPA', (54, 65))	('GSTP1', 'Gene', '2950', (69, 74))
43053	21776373	Given the lack of circulating tumor markers, particularly tumor associated antigens, and a dearth of reliable genetic markers for diagnosis of early breast cancer, methylation changes, which often precede apparent malignant changes, have potential utility in the early diagnosis of cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('methylation changes', 'Var', (164, 183))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('utility', 'Reg', (248, 255))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('malignant changes', 'Phenotype', 'HP:0002664', (214, 231))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Disease', (282, 288))	('tumor', 'Disease', (30, 35))
43068	21776373	In this study, aberrant methylation of RASSF1, APC and GSTP1 were both frequent as well as early events in the progression continuum from normal to benign to invasive cancer and support a monoclonal transformation continuum to breast cancer progression.	('RASSF1', 'Gene', '11186', (39, 45))	('aberrant methylation', 'Var', (15, 35))	('APC', 'Disease', 'MESH:D011125', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('RASSF1', 'Gene', (39, 45))	('invasive cancer', 'Disease', (158, 173))	('frequent', 'Reg', (71, 79))	('APC', 'Disease', (47, 50))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('GSTP1', 'Gene', (55, 60))	('invasive cancer', 'Disease', 'MESH:D009362', (158, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('breast cancer', 'Disease', (227, 240))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('GSTP1', 'Gene', '2950', (55, 60))
43069	21776373	Identifying epigenetic alterations in a precancerous lesion may lead to the discovery of biomarkers that add to the knowledge of risk assessment and early detection, and may provide molecular targets for chemopreventive interventions.	('lead to', 'Reg', (64, 71))	('precancerous lesion', 'Disease', (40, 59))	('epigenetic alterations', 'Var', (12, 34))	('precancerous lesion', 'Disease', 'MESH:D011230', (40, 59))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
43100	30338425	A follow-up retrospective analysis of the histological features and characteristics of breast cancers in the hormone-treated vs. placebo groups of the WHI trial suggest that CEE combined with MPA increased the number and size of invasive breast tumors.	('increased', 'PosReg', (196, 205))	('CEE', 'Var', (174, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('breast tumor', 'Phenotype', 'HP:0100013', (238, 250))	('breast cancers', 'Disease', 'MESH:D001943', (87, 101))	('invasive breast tumors', 'Disease', 'MESH:D001943', (229, 251))	('breast cancers', 'Disease', (87, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('breast tumors', 'Phenotype', 'HP:0100013', (238, 251))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('invasive breast tumors', 'Disease', (229, 251))
43101	30338425	This was attributed to an increase in cell proliferative cycles and breast epithelium density observed with prolonged use of CEE + MPA.	('rat', 'Species', '10116', (50, 53))	('cell proliferative cycles', 'CPA', (38, 63))	('breast epithelium density', 'CPA', (68, 93))	('CEE', 'Var', (125, 128))	('increase', 'PosReg', (26, 34))
43124	30338425	These data suggest co-targeting COX-2 and aromatase may have a benefit with long-term treatment regimens in patients with pure ER+ DCIS.	('patients', 'Species', '9606', (108, 116))	('COX-2', 'Enzyme', (32, 37))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('aromatase', 'Gene', (42, 51))	('co-targeting', 'Var', (19, 31))	('aromatase', 'Gene', '1588', (42, 51))	('ER', 'Gene', '2099', (127, 129))
43130	30338425	Clinical studies have also observed that ER and PR are upregulated in HELUs (early lesion precursors) and that Ki67 is significantly increased compared to normal terminal ductal lobular units (TDLU).	('ER', 'Gene', '2099', (41, 43))	('Ki67', 'Var', (111, 115))	('HELUs', 'Disease', (70, 75))	('upregulated', 'PosReg', (55, 66))	('increased', 'PosReg', (133, 142))	('PR', 'Gene', '5241', (48, 50))
43172	30338425	Using this transplant method, spontaneous adenocarcinomas of ductal origin arise from the loss of p53 and progress through ductal hyperplasia and DCIS before becoming invasive breast cancer.	('ductal hyperplasia', 'Disease', (123, 141))	('adenocarcinomas', 'Disease', 'MESH:D000230', (42, 57))	('DCIS', 'Disease', (146, 150))	('loss', 'Var', (90, 94))	('adenocarcinomas', 'Disease', (42, 57))	('p53', 'Protein', (98, 101))	('invasive breast cancer', 'Disease', 'MESH:D001943', (167, 189))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('progress', 'Reg', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('invasive breast cancer', 'Disease', (167, 189))
43186	30338425	A GEM model that spontaneously develops ER+/PR+ tumors as a result of targeted disruption of the STAT1 gene has been reported.	('tumors', 'Disease', (48, 54))	('STAT1', 'Gene', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('disruption', 'Var', (79, 89))	('PR', 'Gene', '5241', (44, 46))	('ER', 'Gene', '2099', (40, 42))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
43190	30338425	More recently, a transgenic mouse line was developed that conditionally expresses an activating mutation in Ki-RasG12V in mammary epithelium after lactation by use of the beta lactoglobulin promoter.	('activating', 'PosReg', (85, 95))	('mouse', 'Species', '10090', (28, 33))	('Ki-RasG12V', 'Gene', (108, 118))	('mutation', 'Var', (96, 104))	('transgenic', 'Species', '10090', (17, 27))
43213	30338425	In the DCIS.COM PR-B+ cell line, R5020 stimulated a robust set of unique genes compared to the PR-A cell line (Fig.	('PR-B', 'Gene', (16, 20))	('stimulated', 'PosReg', (39, 49))	('R5020', 'Var', (33, 38))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('PR', 'Gene', '5241', (16, 18))	('PR', 'Gene', '5241', (95, 97))	('PR-B', 'Gene', '5925', (16, 20))	('DCIS.COM', 'CellLine', 'CVCL:5552', (7, 15))
43220	30338425	R5020 treatment of PR-B+ cells negatively correlated with an EMT gene signature, whereas E2 treatment of the ER + PR-B+ cells did not.	('EMT', 'Gene', '3702', (61, 64))	('negatively', 'NegReg', (31, 41))	('ER', 'Gene', '2099', (109, 111))	('PR-B', 'Gene', '5925', (19, 23))	('PR-B', 'Gene', '5925', (114, 118))	('R5020', 'Var', (0, 5))	('PR-B', 'Gene', (19, 23))	('PR-B', 'Gene', (114, 118))	('EMT', 'Gene', (61, 64))
43224	30338425	Knock-down of NEMO in ER+/PR+ DCIS.COM cells prior to intraductal xenografting increased invasive progression of DCIS lesions in vivo, implicating NEMO as a potential tumor suppressor regulated by E2 and P4 in the transition of DCIS to IBC.	('increased', 'PosReg', (79, 88))	('invasive progression', 'CPA', (89, 109))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('NEMO', 'Gene', (147, 151))	('DCIS', 'Gene', (113, 117))	('NEMO', 'Gene', '8517', (147, 151))	('NEMO', 'Gene', (14, 18))	('PR', 'Gene', '5241', (26, 28))	('NEMO', 'Gene', '8517', (14, 18))	('DCIS.COM', 'CellLine', 'CVCL:5552', (30, 38))	('ER', 'Gene', '2099', (22, 24))	('IBC', 'Chemical', '-', (236, 239))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('lesions', 'Var', (118, 125))	('DCIS', 'Phenotype', 'HP:0030075', (228, 232))	('tumor', 'Disease', (167, 172))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
43248	29441334	The underestimation rate was significantly higher in patients with SUVmax >2.65 (P < 0.001), over the moderate enhanced uptake on visual analysis (P < 0.001).	('enhanced uptake', 'PosReg', (111, 126))	('patients', 'Species', '9606', (53, 61))	('higher', 'PosReg', (43, 49))	('underestimation', 'MPA', (4, 19))	('SUVmax', 'Var', (67, 73))
43273	29441334	The SUVmax was significantly higher in the patients who had symptoms, palpable masses (P = 0.001, P < 0.001), a lesion over 2 cm in size (P < 0.001), and BI-RAD category 5 (P = 0.049).	('higher', 'PosReg', (29, 35))	('lesion', 'Var', (112, 118))	('patients', 'Species', '9606', (43, 51))	('SUVmax', 'MPA', (4, 10))
43276	29441334	The underestimation rate was significantly higher in patients with a SUVmax > 2.65 (P < 0.001), over moderate enhanced uptake on visual analysis (P < 0.001), and positive axillary FDG uptake (P = 0.032) (Table 4).	('patients', 'Species', '9606', (53, 61))	('higher', 'PosReg', (43, 49))	('FDG', 'Chemical', 'MESH:D019788', (180, 183))	('enhanced', 'PosReg', (110, 118))	('SUVmax', 'Var', (69, 75))	('uptake', 'MPA', (119, 125))	('underestimation', 'MPA', (4, 19))
43280	29441334	The underestimation rate was significantly higher in patients with a SUVmax > 2.65 and patients with over moderate uptake and positive axillary FDG uptake on visual analysis.	('patients', 'Species', '9606', (53, 61))	('higher', 'PosReg', (43, 49))	('SUVmax', 'Var', (69, 75))	('patients', 'Species', '9606', (87, 95))	('FDG', 'Chemical', 'MESH:D019788', (144, 147))
43286	29441334	A higher underestimation rate was significantly related to symptoms, lesion palpability, thin biopsy devices, high BI-RADS scores, high nuclear grades, and comedo necrosis.	('BI-RADS', 'MPA', (115, 122))	('comedo', 'Phenotype', 'HP:0025249', (156, 162))	('necrosis', 'Disease', (163, 171))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))	('high', 'Var', (131, 135))
43294	29441334	Previous studies have revealed that the high level of SUVmax was significantly associated with large tumor size, lymph node involvement, high nuclear grade, lymphovascular invasion, negative hormone receptor status, and positive HER2 status in IBC patients.	('high', 'Var', (40, 44))	('associated', 'Reg', (79, 89))	('high nuclear grade', 'CPA', (137, 155))	('HER2', 'Gene', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('SUVmax', 'Gene', (54, 60))	('HER2', 'Gene', '2064', (229, 233))	('lymph node involvement', 'CPA', (113, 135))	('lymphovascular invasion', 'CPA', (157, 180))	('patients', 'Species', '9606', (248, 256))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
43310	29662076	RAB35 is sufficient to induce recurrent and polarized CDRs that travel as propagating waves, thus behaving as an excitable system that can be biased to control cell steering.	('CDRs', 'MPA', (54, 58))	('RAB35', 'Var', (0, 5))	('induce', 'Reg', (23, 29))	('CDRs', 'Chemical', '-', (54, 58))
43323	29662076	Additional important factors in the formation of CDRs are lipid kinases, and specifically PI3K as both pharmacologically or genetic inhibition of this enzyme abrogate their formation by preventing the generation of phosphatidylinositol-3,4,5-phosphates important for the recruitment of membrane binding, curvature sensitive Bin-Amphiphysin-Rvs (BAR)-containing proteins as well as to activate RAC1 GEFs, including TIAM1 (refs. )	('TIAM1', 'Gene', '7074', (414, 419))	('activate', 'PosReg', (384, 392))	('preventing', 'NegReg', (186, 196))	('RAC1', 'Gene', (393, 397))	('generation', 'MPA', (201, 211))	('lipid', 'Chemical', 'MESH:D008055', (58, 63))	('phosphatidylinositol-3,4,5-phosphates', 'Chemical', '-', (215, 252))	('CDRs', 'Chemical', '-', (49, 53))	('PI3K', 'Var', (90, 94))	('abrogate', 'NegReg', (158, 166))	('TIAM1', 'Gene', (414, 419))	('inhibition', 'Var', (132, 142))
43341	29662076	The top regulator of CDRs included, as expected, the beta isoform of the PDGF receptor, and few RAB GTPases, among which RAB35, the silencing of which resulted in one of the most robust inhibition of CDRs formation (Fig.	('inhibition', 'NegReg', (186, 196))	('silencing', 'Var', (132, 141))	('RAB', 'Gene', (96, 99))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('CDRs', 'Chemical', '-', (21, 25))	('RAB', 'Gene', (121, 124))	('CDRs', 'Chemical', '-', (200, 204))	('RAB', 'Gene', '3267', (96, 99))	('CDRs formation', 'CPA', (200, 214))	('RAB', 'Gene', '3267', (121, 124))
43342	29662076	The silencing of RAB35, RAB8A and RAB8B resulted in a robust and reproducible decreased in CDR activity, thus corroborating the validity of the primary screen and providing evidence that RAB35 is the main regulator of CDR formation among the mammalian RAB protein family (Fig.	('RAB', 'Gene', (17, 20))	('RAB8B', 'Gene', '51762', (34, 39))	('RAB8B', 'Gene', (34, 39))	('RAB', 'Gene', '3267', (187, 190))	('RAB', 'Gene', '3267', (252, 255))	('RAB', 'Gene', (34, 37))	('mammalian', 'Species', '9606', (242, 251))	('RAB', 'Gene', (24, 27))	('RAB', 'Gene', (187, 190))	('RAB8A', 'Gene', '4218', (24, 29))	('RAB', 'Gene', '3267', (17, 20))	('CDR activity', 'MPA', (91, 103))	('RAB8A', 'Gene', (24, 29))	('RAB', 'Gene', (252, 255))	('decreased', 'NegReg', (78, 87))	('RAB', 'Gene', '3267', (24, 27))	('silencing', 'Var', (4, 13))	('RAB', 'Gene', '3267', (34, 37))
43351	29662076	Silencing of RAB35 in these cells severely decreased CDRs formation as compared to scrambled-transfected cells (Supplementary Figure 1E), indicating that RAB35 is a critical regulator of CDR formation in response to different growth factor-dependent signalling pathways.	('CDRs', 'Chemical', '-', (53, 57))	('CDRs formation', 'MPA', (53, 67))	('RAB35', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (43, 52))
43362	29662076	RAB35-expressing, but not control cells, form multiple CDRs in the absence of any added growth factor and these structures precede the extension of lamellipodia with a lag phase of about 105'' (Fig.	('extension of lamellipodia', 'CPA', (135, 160))	('CDRs', 'Chemical', '-', (55, 59))	('RAB35-expressing', 'Var', (0, 16))
43363	29662076	We further exploited the ability of RAB35 to induce a constitutive wave of recurrent multiple CDRs to characterize their overall dynamics and kinematics in more details and relate it to the extension of membrane protrusions.	('CDRs', 'Chemical', '-', (94, 98))	('RAB35', 'Var', (36, 41))	('induce', 'Reg', (45, 51))
43367	29662076	If CDRs are indeed bona fide, excitable, steering devices, their perturbation should impair directional motility, particularly toward growth factors known to induce robustly their formation right at the onset of chemotaxis.	('impair', 'NegReg', (85, 91))	('perturbation', 'Var', (65, 77))	('CDRs', 'Chemical', '-', (3, 7))	('directional motility', 'CPA', (92, 112))
43372	29662076	These latter observations are consistent with the possibility that multiple and short-lived CDRs are induced by the expression of the transgene, leading to cells that frequently change the direction of their protrusions and motion, and cannot persistently move in a biased direction.	('CDRs', 'Chemical', '-', (92, 96))	('direction', 'MPA', (189, 198))	('transgene', 'Var', (134, 143))	('change', 'Reg', (178, 184))
43385	29662076	This cell line is an oncogenic variant of MCF-10A that is widely used to recapitulate the transition from an in situ ductal to an invasive breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('breast carcinoma', 'Disease', 'MESH:D001943', (139, 155))	('MCF-10A', 'CellLine', 'CVCL:0598', (42, 49))	('breast carcinoma', 'Phenotype', 'HP:0003002', (139, 155))	('MCF-10A', 'Gene', (42, 49))	('breast carcinoma', 'Disease', (139, 155))	('variant', 'Var', (31, 38))
43387	29662076	Ablation of RAB35 profoundly affected the chemotactic migratory ability of MCF10.DCIS.com cells (Fig.	('affected', 'Reg', (29, 37))	('MCF10.DCIS.com', 'CellLine', 'CVCL:5552', (75, 89))	('Ablation', 'Var', (0, 8))	('chemotactic migratory ability', 'CPA', (42, 71))	('RAB35', 'Gene', (12, 17))
43391	29662076	The addition of HGF in the presence of collagen type I is known to trigger an invasive programme, characterized by the outgrowths of multicellular structures that expand from the regular contour of the spheroids.	('addition', 'Var', (4, 12))	('HGF', 'Gene', '3082', (16, 19))	('outgrowths of multicellular structures', 'CPA', (119, 157))	('trigger', 'Reg', (67, 74))	('invasive programme', 'CPA', (78, 96))	('HGF', 'Gene', (16, 19))
43394	29662076	However, no difference in either total PDGFRB or surface amounts could be found following silencing (Supplementary Figure 2A) or ectopic up-regulation (Supplementary Figure 2B) of RAB35.	('RAB35', 'Gene', (180, 185))	('silencing', 'Var', (90, 99))	('PDGFRB', 'Gene', '5159', (39, 45))	('up-regulation', 'PosReg', (137, 150))	('PDGFRB', 'Gene', (39, 45))
43399	29662076	On the contrary, silencing of Rab5 or Rac1 genes nearly completely abrogated RAB35-induced CDRs (Fig.	('RAB35-induced', 'Gene', (77, 90))	('Rab5', 'Gene', '5868', (30, 34))	('CDRs', 'Chemical', '-', (91, 95))	('Rab5', 'Gene', (30, 34))	('abrogated', 'NegReg', (67, 76))	('Rac1', 'Gene', (38, 42))	('Rac1', 'Gene', '5879', (38, 42))	('silencing', 'Var', (17, 26))
43403	29662076	The resulting CDR score showed that the genetic ablation of p85 isoforms was the sole manipulation able to phenocopy the loss of RAB35 (Fig.	('p85', 'Gene', '5295', (60, 63))	('p85', 'Gene', (60, 63))	('loss', 'Var', (121, 125))	('RAB35', 'Gene', (129, 134))
43405	29662076	Treatment of PDGF-stimulated with LY294002 or the more specific GDC-0941 PI3K inhibitors, the efficacy of which was tested by measuring the phosphorylation levels of the PI3K target and effector protein AKT, severely abrogated the formation of CDRs (Supplementary Figure 3A-B).	('LY294002', 'Var', (34, 42))	('phosphorylation', 'MPA', (140, 155))	('formation of CDRs', 'MPA', (231, 248))	('AKT', 'Gene', (203, 206))	('GDC-0941', 'Chemical', 'MESH:C532162', (64, 72))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('CDRs', 'Chemical', '-', (244, 248))	('AKT', 'Gene', '207', (203, 206))	('abrogated', 'NegReg', (217, 226))
43406	29662076	Inhibition of AKT with MK-2206 had, instead, no effect on PDGF-induced CDRs formation nor on macropinocytosis (Supplementary Figure 3C).	('CDRs', 'Chemical', '-', (71, 75))	('AKT', 'Gene', (14, 17))	('CDRs formation', 'MPA', (71, 85))	('MK-2206', 'Var', (23, 30))	('macropinocytosis', 'MPA', (93, 109))	('MK-2206', 'Chemical', 'MESH:C548887', (23, 30))	('AKT', 'Gene', '207', (14, 17))	('PDGF-induced', 'Gene', (58, 70))
43408	29662076	We corroborated the latter findings using MEF-KO for p85alpha and beta.	('MEF', 'Gene', (42, 45))	('p85alpha', 'Var', (53, 61))	('MEF', 'Gene', '2000', (42, 45))
43412	29662076	Indeed, while we were working on this project, RAB35 was identified as a critical and direct activator of the p85/PI3K-AKT pathway, shown to directly interact with the regulatory p85alpha subunit and to mediate, through this pathway, cell transformation.	('cell transformation', 'CPA', (234, 253))	('p85', 'Gene', (179, 182))	('p85', 'Gene', '5295', (110, 113))	('AKT', 'Gene', '207', (119, 122))	('p85', 'Gene', (110, 113))	('RAB35', 'Var', (47, 52))	('mediate', 'Reg', (203, 210))	('AKT', 'Gene', (119, 122))	('interact', 'Interaction', (150, 158))	('p85', 'Gene', '5295', (179, 182))
43413	29662076	In agreement with this latter finding, we found that silencing of RAB35 reduced significantly the phosphorylation of AKT in response to PDGF stimulation, without affecting PDGFR phosphorylation status, and PDGFR-dependent MAPK activity (Fig.	('PDGFR', 'Gene', (206, 211))	('MAPK', 'Gene', (222, 226))	('reduced', 'NegReg', (72, 79))	('PDGFR', 'Gene', '5159', (172, 177))	('phosphorylation', 'MPA', (98, 113))	('PDGFR', 'Gene', '5159', (206, 211))	('MAPK', 'Gene', '5595;5594;5595', (222, 226))	('AKT', 'Gene', '207', (117, 120))	('activity', 'MPA', (227, 235))	('AKT', 'Gene', (117, 120))	('silencing', 'Var', (53, 62))	('RAB35', 'Gene', (66, 71))	('response', 'MPA', (124, 132))	('PDGFR', 'Gene', (172, 177))
43414	29662076	We also showed that the ectopic expression of RAB35, in doxycycline-stimulated MEF pSLIK-HA-RAB35 cells cultured in growing conditions without addition of growth factors, caused the hyper-activation of AKT signalling without affecting the phosphorylation levels of other transducers (Fig.	('RAB35', 'Gene', (46, 51))	('AKT', 'Gene', (202, 205))	('doxycycline', 'Chemical', 'MESH:D004318', (56, 67))	('MEF', 'Gene', '2000', (79, 82))	('MEF', 'Gene', (79, 82))	('AKT', 'Gene', '207', (202, 205))	('ectopic expression', 'Var', (24, 42))	('hyper-activation', 'PosReg', (182, 198))
43415	29662076	Importantly, wild-type RAB35, but not an inactive dominant-negative RAB35S22N mutant, associated with endogenous p85alpha, whereas dominant active RAB35 interacted with p85alpha in a constitutive growth factors-independent fashion (Fig.	('associated', 'Interaction', (86, 96))	('endogenous p85alpha', 'MPA', (102, 121))	('RAB35S22N', 'Var', (68, 77))	('S22N', 'Mutation', 'p.S22N', (73, 77))
43417	29662076	Consistent, with this notion a dominant-negative RAB35S22N mutant abrogated PDGF-induced CDRs formation and directional migration (Supplementary Figure 3D), whereas two recently identified activated, tumour-associated RAB35 mutants, RAB35A151T and F161L, promoted CDRs formation and elevated AKT phosphorylation in the absence of growth factor stimulation (Supplementary Figure 3E and Movie 16).	('AKT', 'Gene', (292, 295))	('PDGF-induced', 'Gene', (76, 88))	('elevated', 'PosReg', (283, 291))	('F161L', 'Var', (248, 253))	('CDRs formation', 'CPA', (264, 278))	('F161L', 'Mutation', 'rs1181410011', (248, 253))	('CDRs formation', 'CPA', (89, 103))	('RAB35', 'Gene', (218, 223))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('CDRs', 'Chemical', '-', (264, 268))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('directional migration', 'CPA', (108, 129))	('AKT', 'Gene', '207', (292, 295))	('tumour', 'Disease', (200, 206))	('CDRs', 'Chemical', '-', (89, 93))	('abrogated', 'NegReg', (66, 75))	('RAB35S22N mutant', 'Var', (49, 65))	('RAB35A151T', 'Var', (233, 243))	('promoted', 'PosReg', (255, 263))
43421	29662076	These latter results indicate that deregulation of the levels of this GTPase may be positively selected in a subset of prostate tumours.	('prostate tumours', 'Disease', (119, 135))	('levels', 'MPA', (55, 61))	('deregulation', 'Var', (35, 47))	('prostate tumours', 'Disease', 'MESH:D011471', (119, 135))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('GTPase', 'Protein', (70, 76))
43424	29662076	Here, we provide evidence that the small RAB35 GTPase is necessary and sufficient to control the formation of CDRs and promote their oscillating, recurrent dynamic behaviours (Fig.	('GTP', 'Chemical', 'MESH:D006160', (47, 50))	('oscillating', 'MPA', (133, 144))	('promote', 'PosReg', (119, 126))	('GTPase', 'Protein', (47, 53))	('CDRs', 'Chemical', '-', (110, 114))	('formation', 'MPA', (97, 106))	('RAB35', 'Var', (41, 46))
43425	29662076	We showed that the elevation of RAB35 is sufficient to induce the formation of multiple CDRs that expand centrifugally, travel along elongated protrusions, frequently in the form of oscillating waves, that precede or accompany the extension of lamellipodia protrusions.	('elevation', 'Var', (19, 28))	('induce', 'Reg', (55, 61))	('CDRs', 'Chemical', '-', (88, 92))	('RAB35', 'Gene', (32, 37))
43435	29662076	Consistently, two somatic RAB35 mutations found in human tumours generate alleles that constitutively activate PI3K/AKT signalling, suppress apoptosis and transform cells in a PI3K-dependent manner.	('activate', 'PosReg', (102, 110))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('suppress', 'NegReg', (132, 140))	('RAB35', 'Gene', (26, 31))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('human', 'Species', '9606', (51, 56))	('tumours', 'Disease', (57, 64))	('mutations', 'Var', (32, 41))	('AKT', 'Gene', '207', (116, 119))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('transform', 'Reg', (155, 164))	('apoptosis', 'CPA', (141, 150))	('AKT', 'Gene', (116, 119))
43436	29662076	Our finding indicates that RAB35 and the oncogenic-associated mutant forms are also implicated in CDR formation and chemotactic migration in a AKT-independent, but PI3K-dependent fashion.	('CDR formation', 'CPA', (98, 111))	('mutant', 'Var', (62, 68))	('AKT', 'Gene', (143, 146))	('implicated', 'Reg', (84, 94))	('AKT', 'Gene', '207', (143, 146))	('chemotactic migration', 'CPA', (116, 137))	('RAB35', 'Gene', (27, 32))
43437	29662076	These results argue that certain tumours might specifically exploit and select for alterations of RAB35 also to increase their invasiveness and ability to navigate through complex interstitial environment.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('alterations', 'Var', (83, 94))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('increase', 'PosReg', (112, 120))	('RAB35 also', 'Gene', (98, 108))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('invasiveness', 'CPA', (127, 139))
43438	29662076	This process has recently emerged as a major scavenging route for proteinaceous material and lipid sources in order to refill the amino acid pools, fuel mitochondrial metabolism and lipid biosynthesis, particularly in tumours bearing KRAS or PI3K activating mutations, ultimately enabling survival in a nutrient-deprived tumour microenvironment.	('PI3K', 'Gene', (242, 246))	('tumours bearing KRAS', 'Disease', 'MESH:C565129', (218, 238))	('tumour', 'Disease', 'MESH:D009369', (321, 327))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('lipid', 'Chemical', 'MESH:D008055', (182, 187))	('lipid biosynthesis', 'MPA', (182, 200))	('tumour', 'Disease', (321, 327))	('tumour', 'Disease', (218, 224))	('fuel mitochondrial metabolism', 'MPA', (148, 177))	('amino acid pools', 'MPA', (130, 146))	('lipid', 'Chemical', 'MESH:D008055', (93, 98))	('activating mutations', 'Var', (247, 267))	('enabling', 'PosReg', (280, 288))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('tumour', 'Phenotype', 'HP:0002664', (321, 327))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumours bearing KRAS', 'Disease', (218, 238))
43445	29662076	siRNA oligos targeting human RAB35 (siRNA IDs: s21707; s21708; s21709) and RAB35 GEFs and Effectors were purchased from Ambion (siRNA IDs: s105812; s116366; s87812; s103715; s115827; s97565; s95591; s101197; s233383; s65847).	('s21708; s21709', 'Var', (55, 69))	('s115827; s97565; s95591; s101197; s233383; s65847', 'Var', (174, 223))	('s116366; s87812', 'Var', (148, 163))	('human', 'Species', '9606', (23, 28))
43447	29662076	Mouse monoclonal antibodies anti-phospho-ERK1-2 (Thr202/Tyr204, #9106 dilution 1:200), anti-ERK1-2 (#9102, dilution 1:500), rabbit monoclonal antibodies anti-phospho-AKT (Ser473, #4058, dilution 1:1000), anti-phospho-PDGFRB (Tyr1009, #3124, dilution 1:500), anti-PDGFRB (#4564, dilution 1:500) and the rabbit polyclonal antibody anti-AKT (#9272, dilution 1:500) were purchased from Cell Signaling.	('Tyr1009', 'Var', (225, 232))	('PDGFRB', 'Gene', (217, 223))	('rabbit', 'Species', '9986', (302, 308))	('ERK1-2', 'Gene', (41, 47))	('AKT', 'Gene', (334, 337))	('AKT', 'Gene', '207', (166, 169))	('rabbit', 'Species', '9986', (124, 130))	('ERK1-2', 'Gene', '5595;5594', (41, 47))	('PDGFRB', 'Gene', '5159', (263, 269))	('AKT', 'Gene', (166, 169))	('PDGFRB', 'Gene', (263, 269))	('ERK1-2', 'Gene', (92, 98))	('Mouse', 'Species', '10090', (0, 5))	('AKT', 'Gene', '207', (334, 337))	('ERK1-2', 'Gene', '5595;5594', (92, 98))	('PDGFRB', 'Gene', '5159', (217, 223))
43451	29662076	Mouse monoclonal antibodies raised against alpha-tubulin (#T5168) or Vinculin (#V9131) and the rabbit polyclonal anti-GFP antibody (#SAB4301138) were from Sigma-Aldrich and they were all used at 1:500 dilution.	('#T5168', 'Var', (58, 64))	('rabbit', 'Species', '9986', (95, 101))	('Vinculin', 'Gene', (69, 77))	('Vinculin', 'Gene', '7414', (69, 77))	('alpha-tubulin', 'Protein', (43, 56))	('Mouse', 'Species', '10090', (0, 5))	('#V9131', 'Var', (79, 85))
43454	29662076	Cy3-secondary antibodies from Jackson ImmunoResearch (#711-165-152, #715-165-150, dilution 1:400), Dapi (#D-1306) and AlexaFluor 488 (#A-11055, #A-21202) were from Thermo Fisher Scientific.	('#D-1306', 'Var', (105, 112))	('#A-11055', 'Var', (134, 142))	('AlexaFluor 488', 'Chemical', '-', (118, 132))	('Cy3', 'Chemical', '-', (0, 3))	('#715-165-150', 'Var', (68, 80))	('Dapi', 'Chemical', 'MESH:C007293', (99, 103))	('#711-165-152', 'Var', (54, 66))
43455	29662076	FITC-conjugated Phalloidin (#P5282), LY294002 (#L9908), Doxycycline Hyclate (#D9891) and Fibronectin (#F1056) were from Sigma-Aldrich.	('Fibronectin', 'Gene', '2335', (89, 100))	('LY294002 (#L9908', 'Var', (37, 53))	('#L9908', 'Var', (47, 53))	('Fibronectin', 'Gene', (89, 100))	('Phalloidin', 'Chemical', 'MESH:D010590', (16, 26))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('#F1056', 'Var', (102, 108))	('Doxycycline Hyclate', 'Chemical', 'MESH:D004318', (56, 75))	('#D9891', 'Var', (77, 83))	('#P5282', 'Var', (28, 34))	('FITC', 'Chemical', 'MESH:D016650', (0, 4))
43456	29662076	The MK-2206 (#11593) and GDC-0941 (#11600) were from Cayman Chemical.	('#11593', 'Var', (13, 19))	('GDC-0941', 'Chemical', 'MESH:C532162', (25, 33))	('#11600', 'Var', (35, 41))	('MK-2206', 'Chemical', 'MESH:C548887', (4, 11))
43458	29662076	Human Recombinant PDGF-BB (#GRF-10694) was from Immunological Sciences; Human Recombinant HGF (#CYT-244) from Prospec; Human Recombinant EGF (#BPS-90201-3) from Vinci-Biochem; Human Insulin (#11376497001) from Roche; Hydrocortisone (#H0888-1G) from Sigma-Aldrich.	('Human', 'Species', '9606', (0, 5))	('Human', 'Species', '9606', (119, 124))	('EGF', 'Gene', (137, 140))	('Human', 'Species', '9606', (72, 77))	('#11376497001', 'Var', (191, 203))	('Human', 'Species', '9606', (176, 181))	('HGF', 'Gene', (90, 93))	('EGF', 'Gene', '1950', (137, 140))	('HGF', 'Gene', '3082', (90, 93))	('Hydrocortisone', 'Chemical', 'MESH:D006854', (217, 231))
43459	29662076	Lipofectamine RNAiMAX (#13778030) and Lipofectamin 2000 (#11668019) were from Thermo Fisher Scientific.	('#11668019', 'Var', (57, 66))	('#13778030', 'Var', (23, 32))	('Lipofectamine', 'Chemical', 'MESH:C086724', (0, 13))	('Lipofectamin', 'Chemical', '-', (0, 12))	('Lipofectamin', 'Chemical', '-', (38, 50))
43463	29662076	MEFs were derived from embryos of p85alpha-/- and p85beta-/- and wild-type mice (129XC57BL/6).	('MEFs', 'CellLine', 'CVCL:9115', (0, 4))	('mice', 'Species', '10090', (75, 79))	('p85alpha-/-', 'Var', (34, 45))	('p85beta-/-', 'Var', (50, 60))
43466	29662076	MEFs p85alpha-/-p85beta-/- were reconstituted by expressing a p85alpha construct.	('p85alpha-/-p85beta-/-', 'Var', (5, 26))	('MEFs', 'CellLine', 'CVCL:9115', (0, 4))	('p85alpha', 'Var', (62, 70))
43487	29662076	More specifically, we included: siRNAs targeting Plk1 and Incenp, two genes involved in mitotic segregation, the knock down of which results in obvious morphologically altered nuclei, as transfection efficiency controls; scrambled sequences targeting no endogenous genes in the mouse genome and thus not affecting CDR formation (siEGFP), and Pdgfrb silencing oligos, which abrogate CDRs, as negative and positive controls, respectively.	('Plk1', 'Gene', '18817', (49, 53))	('Pdgfrb', 'Gene', (342, 348))	('mouse', 'Species', '10090', (278, 283))	('EGF', 'Gene', '1950', (331, 334))	('Plk1', 'Gene', (49, 53))	('CDRs', 'Chemical', '-', (382, 386))	('silencing', 'Var', (349, 358))	('EGF', 'Gene', (331, 334))
43501	29662076	Primer assay IDs were: GAPDH, Hs99999905_m1 and Mm99999915_g1; RAB35, Hs00199284_m1 and Mm01204416_m1; PDGFRB, Mm00435546_m1; RAB8a, Mm00445684_m1; RAB8b, Mm00557812_m1; RAB5a, mm01278246_m1; RAB5b, mm00834147_g1; RAB5c, mm00659190_m1; RAC1, mm01201653_mh; DENND1a, Mm00620186_m1; DENND1b, Mm01285090_m1; DENND1c, Mm01227405_m1; DENND6b, Mm01308059_m1; FLCN, Mm00840973_m1; OCRL, Mm00623482_m1; RUSC2, Mm01349595_m1; ACAP2, Mm01342334_m1; MICAL1, Mm00506780_m1; MICALL1, Mm01300206_m1; FSCN, mm00456046_m1.	('RAB5c', 'Gene', '5878', (214, 219))	('DENND1a', 'Gene', '57706', (257, 264))	('Mm00506780_m1', 'Var', (447, 460))	('mm00456046_m1', 'Var', (492, 505))	('MICAL1', 'Gene', '64780', (439, 445))	('RAB5a', 'Gene', '5868', (170, 175))	('DENND6b', 'Gene', (329, 336))	('Mm00840973_m1', 'Var', (359, 372))	('OCRL', 'Gene', (374, 378))	('MICALL1', 'Gene', (462, 469))	('MICALL1', 'Gene', '85377', (462, 469))	('RAB5a', 'Gene', (170, 175))	('RUSC2', 'Gene', (395, 400))	('RAB8b', 'Gene', (148, 153))	('FLCN', 'Gene', '201163', (353, 357))	('MICAL1', 'Gene', (439, 445))	('DENND1b', 'Gene', (281, 288))	('FLCN', 'Gene', (353, 357))	('RUSC2', 'Gene', '9853', (395, 400))	('Mm01227405_m1', 'Var', (314, 327))	('DENND1b', 'Gene', '163486', (281, 288))	('RAB5b', 'Gene', '5869', (192, 197))	('OCRL', 'Gene', '4952', (374, 378))	('RAB8a', 'Gene', (126, 131))	('ACAP2', 'Gene', '23527', (417, 422))	('DENND1c', 'Gene', '79958', (305, 312))	('PDGFRB', 'Gene', '5159', (103, 109))	('RAB5b', 'Gene', (192, 197))	('Mm01349595_m1', 'Var', (402, 415))	('Mm01342334_m1', 'Var', (424, 437))	('PDGFRB', 'Gene', (103, 109))	('DENND1c', 'Gene', (305, 312))	('RAB8a', 'Gene', '4218', (126, 131))	('Mm01300206_m1', 'Var', (471, 484))	('DENND1a', 'Gene', (257, 264))	('RAB5c', 'Gene', (214, 219))	('ACAP2', 'Gene', (417, 422))	('DENND6b', 'Gene', '414918', (329, 336))	('RAB8b', 'Gene', '51762', (148, 153))
43609	27560937	DCIS accompanying invasive carcinoma group was associated with HER2 positivity and lymph node metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('positivity', 'Var', (68, 78))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('invasive carcinoma', 'Disease', (18, 36))	('HER2', 'Gene', (63, 67))	('invasive carcinoma', 'Disease', 'MESH:D009361', (18, 36))	('associated', 'Reg', (47, 57))	('HER2', 'Gene', '2064', (63, 67))	('lymph node metastasis', 'CPA', (83, 104))
43623	27560937	Our HR-MAS 1H NMR spectroscopy analysis found several metabolite markers (GPC/PC ratio, m-Ins, Ala, and Suc) that differed between pure DCIS and DCIS accompanying invasive carcinoma.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('GPC', 'Chemical', 'MESH:D005997', (74, 77))	('pure DCIS', 'Var', (131, 140))	('1H', 'Chemical', '-', (11, 13))	('invasive carcinoma', 'Disease', (163, 181))	('PC', 'Chemical', 'MESH:D010767', (75, 77))	('Ala', 'Chemical', 'MESH:D000409', (95, 98))	('PC', 'Chemical', 'MESH:D010767', (78, 80))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('differed', 'Reg', (114, 122))	('Suc', 'Chemical', 'MESH:D019802', (104, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('invasive carcinoma', 'Disease', 'MESH:D009361', (163, 181))	('m-Ins', 'Chemical', 'MESH:D007294', (88, 93))
43749	21443808	HER2/neu amplification or over- expression has been shown to be associated with higher grades of tumor and poorer prognosis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('over- expression', 'PosReg', (26, 42))	('amplification', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('HER2/neu', 'Gene', '2064', (0, 8))	('HER2/neu', 'Gene', (0, 8))
43751	21443808	It has been demonstrated that some percentage of breast cancers with mutations in p53 tumor suppressor gene are associated with clinical aggressiveness.	('mutations', 'Var', (69, 78))	('aggressiveness', 'Disease', 'MESH:D001523', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (49, 63))	('breast cancers', 'Disease', 'MESH:D001943', (49, 63))	('aggressiveness', 'Disease', (137, 151))	('breast cancers', 'Disease', (49, 63))	('rat', 'Species', '10116', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('aggressiveness', 'Phenotype', 'HP:0000718', (137, 151))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('associated', 'Reg', (112, 122))
43757	21443808	Hormone receptors positivity also correlate with absence of p53 mutation and inversely with the presence of epidermal growth factor receptor.	('mutation', 'Var', (64, 72))	('positivity', 'Reg', (18, 28))	('p53', 'Gene', (60, 63))	('Hormone receptors', 'Protein', (0, 17))	('epidermal growth factor receptor', 'Gene', (108, 140))	('absence', 'NegReg', (49, 56))	('p53', 'Gene', '7157', (60, 63))	('epidermal growth factor receptor', 'Gene', '1956', (108, 140))
43763	21443808	Ultimately, these changes drive tumorigenesis through the coordinated phosphorylation of proteins, cell-cycle progression and metabolism, and transcription factors that regulate the expression of genes involved in these processes.	('changes', 'Var', (18, 25))	('drive', 'Reg', (26, 31))	('expression', 'MPA', (182, 192))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cell-cycle progression', 'CPA', (99, 121))	('phosphorylation', 'MPA', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('metabolism', 'CPA', (126, 136))	('tumor', 'Disease', (32, 37))	('proteins', 'Protein', (89, 97))
43764	21443808	The mutations that cause cancer is produced by complex interactions between environmental and inherited factors.	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))
43766	21443808	Defective P53 tumor suppressor gene, could allow abnormal cells to proliferate, resulting ultimately in cancer.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rat', 'Species', '10116', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('P53', 'Gene', (10, 13))	('Defective', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('P53', 'Gene', '7157', (10, 13))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('allow', 'Reg', (43, 48))	('resulting ultimately in', 'Reg', (80, 103))
43767	21443808	As many as 50% of all human tumors are associated with P53 mutations.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('associated', 'Reg', (39, 49))	('mutations', 'Var', (59, 68))	('P53', 'Gene', (55, 58))	('human', 'Species', '9606', (22, 27))	('P53', 'Gene', '7157', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
43819	21443808	It is also possible that, when gene alterations occur in breast cancer, high proliferation rates are found irrespective of the presence of invasion and that other molecular alterations are involved in the development of breast cancer, Accordingly, the degree of differentiation does not contribute to the increase of the expression of both markers, though it may reflect the possible role of other pathways by which the tumor is advancing independently from the increase in signaling pathways of both HER2/neu and p53 genes.	('breast cancer', 'Disease', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('alterations', 'Var', (36, 47))	('rat', 'Species', '10116', (40, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('HER2/neu', 'Gene', '2064', (501, 509))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('breast cancer', 'Disease', (220, 233))	('p53', 'Gene', '7157', (514, 517))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (84, 87))	('tumor', 'Disease', (420, 425))	('p53', 'Gene', (514, 517))	('HER2/neu', 'Gene', (501, 509))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('rat', 'Species', '10116', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
43820	21443808	Thus, introducing a new line of treatment which include a genetic modulation of the signaling pathway may alter the prognosis of breast cancer patients which clearly requires further attention in future research and medical follow up.	('breast cancer', 'Disease', (129, 142))	('genetic modulation', 'Var', (58, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('alter', 'Reg', (106, 111))	('patients', 'Species', '9606', (143, 151))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
43825	21443808	The present work confirms previous findings that combined alteration in the expression of HER-2/neu and p53, are linked to accelerated tumor progression and a poor prognosis.	('p53', 'Gene', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('p53', 'Gene', '7157', (104, 107))	('rat', 'Species', '10116', (129, 132))	('accelerated', 'PosReg', (123, 134))	('tumor', 'Disease', (135, 140))	('alteration', 'Var', (58, 68))	('HER-2/neu', 'Gene', (90, 99))	('rat', 'Species', '10116', (62, 65))	('linked', 'Reg', (113, 119))	('HER-2/neu', 'Gene', '2064', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
43923	25849106	We present here a review of lobular carcinoma, paying particular attention to the morphological and immunophenotypic features of pre-invasive and invasive lesions, the importance of E-cadherin dysfunction in tumour biology, transcriptomics, genomics and diagnostic aspects that aid patient management.	('E-cadherin', 'Gene', '999', (182, 192))	('lobular carcinoma', 'Disease', 'MESH:D018275', (28, 45))	('tumour', 'Disease', (208, 214))	('lobular carcinoma', 'Disease', (28, 45))	('E-cadherin', 'Gene', (182, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('patient', 'Species', '9606', (282, 289))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (28, 45))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('dysfunction', 'Var', (193, 204))	('tumour', 'Disease', 'MESH:D009369', (208, 214))
43937	25849106	Furthermore, while several studies report that morphological variants are aggressive subtypes associated with poor outcome, particularly relative to classic type, evidence suggests that a nuclear pleomorphism score of 3 (which would indicate a classification of PLC), in an overall grade 2 tumour does not add prognostic value, the most important discriminator being overall grade and/or mitotic count.	('tumour', 'Disease', 'MESH:D009369', (290, 296))	('tumour', 'Disease', (290, 296))	('associated', 'Reg', (94, 104))	('variants', 'Var', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))
43946	25849106	Pleomorphic ILCs, on the other hand, are more likely to exhibit HER2 amplification (in 35 to 80% of cases) and p53 expression and the proliferation index is typically higher.	('proliferation index', 'CPA', (134, 153))	('higher', 'PosReg', (167, 173))	('amplification', 'MPA', (69, 82))	('p53', 'Gene', (111, 114))	('HER2', 'Gene', (64, 68))	('p53', 'Gene', '7157', (111, 114))	('expression', 'MPA', (115, 125))	('HER2', 'Gene', '2064', (64, 68))	('Pleomorphic', 'Var', (0, 11))
43947	25849106	The characteristic discohesive growth pattern of ILC is the result of the dysregulation of cell-cell adhesion properties, primarily driven by the targeted disruption of the cell adhesion molecule E-cadherin.	('E-cadherin', 'Gene', (196, 206))	('discohesive growth pattern', 'CPA', (19, 45))	('E-cadherin', 'Gene', '999', (196, 206))	('cell-cell adhesion properties', 'CPA', (91, 120))	('disruption', 'Var', (155, 165))
43953	25849106	In contrast, approximately 90% of LNs and ILCs, including variants, completely lack E-cadherin protein expression.	('variants', 'Var', (58, 66))	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('lack', 'NegReg', (79, 83))
43958	25849106	The E-cadherin-catenin complex may be dysfunctional in these cases due to the presence of CDH1 gene mutation (see below) or aberrant/loss of expression of the catenin binding proteins, which may be detected using beta-catenin and p120-catenin immunohistochemistry.	('dysfunctional', 'Reg', (38, 51))	('beta-catenin', 'Gene', '1499', (213, 225))	('aberrant/loss', 'NegReg', (124, 137))	('CDH1', 'Gene', (90, 94))	('mutation', 'Var', (100, 108))	('p120-catenin', 'Gene', (230, 242))	('CDH1', 'Gene', '999', (90, 94))	('catenin binding proteins', 'Protein', (159, 183))	('expression', 'MPA', (141, 151))	('E-cadherin', 'Gene', (4, 14))	('E-cadherin', 'Gene', '999', (4, 14))	('p120-catenin', 'Gene', '1500', (230, 242))	('beta-catenin', 'Gene', (213, 225))
43959	25849106	E-cadherin deregulation occurs in the earliest morphological stage of lobular tumourigenesis (that is, ALH) and is frequently and irreversibly driven by genomic alterations targeting its gene, CDH1 (located at chromosome 16q22.1).	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('deregulation', 'Var', (11, 23))	('CDH1', 'Gene', (193, 197))	('tumour', 'Disease', (78, 84))	('CDH1', 'Gene', '999', (193, 197))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))	('ALH', 'Chemical', '-', (103, 106))
43960	25849106	Molecularly, the patterns of E-cadherin loss often follow Knudsen's two hit hypothesis for a classic tumour suppressor gene, involving CDH1 mutation, gene methylation and/or loss of heterozygosity in the region of 16q22.1 (frequently involving the whole chromosomal arm).	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('tumour', 'Disease', (101, 107))	('loss of heterozygosity', 'Var', (174, 196))	('mutation', 'Var', (140, 148))	('CDH1', 'Gene', (135, 139))	('methylation', 'Var', (155, 166))	('loss', 'NegReg', (40, 44))	('CDH1', 'Gene', '999', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
43961	25849106	Promoter hypermethylation and concomitant down-regulation of CDH1 expression has been reported in 21 to 77% of ILCs and the detection of methylated CDH1 promoter sequences in adjacent normal tissues and in LN implies that this is an early hit.	('CDH1', 'Gene', '999', (61, 65))	('CDH1', 'Gene', (148, 152))	('expression', 'MPA', (66, 76))	('CDH1', 'Gene', '999', (148, 152))	('down-regulation', 'NegReg', (42, 57))	('CDH1', 'Gene', (61, 65))	('Promoter hypermethylation', 'Var', (0, 25))	('ILCs', 'Disease', (111, 115))
43962	25849106	The somatic copy number loss of 16q in ILC and ER-positive, low-grade IC-NST is extremely frequent, suggesting these tumours share a common pathway of evolution.	('tumours', 'Disease', (117, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('copy number loss of 16q', 'Var', (12, 35))	('IC-NST', 'Disease', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('tumours', 'Disease', 'MESH:D009369', (117, 124))
43963	25849106	We reviewed the DNA copy number status at the CDH1 gene locus in the 153 lobular tumours from The Cancer Genome Atlas (TCGA) data resource and this revealed that 12.4% of tumours show a diploid copy number; 84.3% show a single copy loss and 3.3% show a putative homozygous deletion.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('diploid copy number', 'Var', (186, 205))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('CDH1', 'Gene', (46, 50))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('tumours', 'Disease', (81, 88))	('lobular tumours', 'Disease', (73, 88))	('lobular tumours', 'Disease', 'MESH:D018275', (73, 88))	('single copy', 'Var', (220, 231))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (171, 178))	('CDH1', 'Gene', '999', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
43966	25849106	Identical CDH1 genetic mutations have been detected in LCIS and in their adjacent invasive counterpart, which is a key finding implicating LCIS as a direct (but non-obligate) precursor for ILC.	('mutations', 'Var', (23, 32))	('CDH1', 'Gene', (10, 14))	('CDH1', 'Gene', '999', (10, 14))
43967	25849106	Further to this, CDH1 mutations were detected in LCIS, although, surprisingly, no mutations were found in adjacent, microdissected ALH lesions.	('CDH1', 'Gene', '999', (17, 21))	('ALH', 'Chemical', '-', (131, 134))	('LCIS', 'Disease', (49, 53))	('detected', 'Reg', (37, 45))	('mutations', 'Var', (22, 31))	('CDH1', 'Gene', (17, 21))
43968	25849106	The reported frequency of CDH1 mutation and loss of heterozygosity is unexpectedly discrepant between studies (from 30 to 80%).	('loss', 'NegReg', (44, 48))	('CDH1', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('CDH1', 'Gene', '999', (26, 30))
43969	25849106	For example, TCGA reported from an exome sequencing strategy (that is, enriching for exons only) that CDH1 mutations were very common (30/36; 83%) within the lobular histological subtype and, expectedly, corresponded with low E-cadherin expression.	('CDH1', 'Gene', '999', (102, 106))	('mutations', 'Var', (107, 116))	('low', 'NegReg', (222, 225))	('expression', 'MPA', (237, 247))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('CDH1', 'Gene', (102, 106))
43970	25849106	TCGA resource has now made comprehensive 'omic data available for 958 breast cancers through the cBioPortal and in an investigation of these data we identified CDH1 mutations in 78 out of 155 ILCs (50%).	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('breast cancers', 'Phenotype', 'HP:0003002', (70, 84))	('CDH1', 'Gene', (160, 164))	('breast cancers', 'Disease', 'MESH:D001943', (70, 84))	('ILCs', 'Disease', (192, 196))	('breast cancers', 'Disease', (70, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (165, 174))	('CDH1', 'Gene', '999', (160, 164))
43971	25849106	This latter figure is supported by an independent exome sequencing study of ER-positive tumours in the clinical context of aromatase inhibitor response, where they identified CDH1 mutation in 20 out of 40 ILCs.	('CDH1', 'Gene', '999', (175, 179))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('mutation', 'Var', (180, 188))	('CDH1', 'Gene', (175, 179))	('identified', 'Reg', (164, 174))
43972	25849106	Mutations in CDH1 have also been identified in other types of epithelial cancers, most notably in diffuse gastric carcinomas, which have a very similar infiltrative growth pattern to ILC of the breast.	('CDH1', 'Gene', '999', (13, 17))	('ILC of the breast', 'Disease', (183, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('gastric carcinomas', 'Disease', 'MESH:D013274', (106, 124))	('gastric carcinomas', 'Disease', (106, 124))	('epithelial cancers', 'Disease', 'MESH:D000077216', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (33, 43))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (106, 123))	('CDH1', 'Gene', (13, 17))	('epithelial cancers', 'Disease', (62, 80))
43973	25849106	Hereditary diffuse gastric carcinoma is sometimes caused by a germline mutation in CDH1 and mutation carriers have an increased risk for developing ILC.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('CDH1', 'Gene', (83, 87))	('caused by', 'Reg', (50, 59))	('ILC', 'Disease', (148, 151))	('gastric carcinoma', 'Disease', (19, 36))	('CDH1', 'Gene', '999', (83, 87))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (19, 36))	('gastric carcinoma', 'Disease', 'MESH:D013274', (19, 36))	('germline mutation', 'Var', (62, 79))
43975	25849106	Despite E-cadherin being the obvious candidate for such a predisposition, early work suggested CDH1 germline variants are rare in familial lobular breast cancer but do account for some cases of bilateral ILC.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('CDH1', 'Gene', '999', (95, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (139, 160))	('familial lobular breast cancer', 'Disease', (130, 160))	('familial lobular breast cancer', 'Disease', 'MESH:D013274', (130, 160))	('bilateral ILC', 'Disease', (194, 207))	('account', 'Reg', (168, 175))	('variants', 'Var', (109, 117))	('CDH1', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
43977	25849106	Animal models of hereditary diffuse gastric cancer and lobular breast cancer provide additional support for this concept, whereby CDH1 germline deficiency in combination with a second hit (carcinogen treatment or TP53 mutation) is sufficient to initiate disease development.	('CDH1', 'Gene', '999', (130, 134))	('deficiency', 'Disease', 'MESH:D007153', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('lobular breast cancer', 'Disease', (55, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (17, 50))	('lobular breast cancer', 'Disease', 'MESH:D013274', (55, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('TP53', 'Gene', '7157', (213, 217))	('hereditary diffuse gastric cancer', 'Disease', (17, 50))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (55, 76))	('germline', 'Var', (135, 143))	('deficiency', 'Disease', (144, 154))	('CDH1', 'Gene', (130, 134))
43978	25849106	The loss of E-cadherin is also associated with the process of epithelial to mesenchymal transition (EMT) where cells lose polarity and adhesion to become more migratory and invasive during embryonic morphogenesis and wound healing.	('E-cadherin', 'Gene', (12, 22))	('epithelial to mesenchymal transition', 'Disease', (62, 98))	('adhesion', 'CPA', (135, 143))	('E-cadherin', 'Gene', '999', (12, 22))	('more', 'PosReg', (154, 158))	('invasive', 'CPA', (173, 181))	('associated', 'Reg', (31, 41))	('polarity', 'CPA', (122, 130))	('lose', 'NegReg', (117, 121))	('loss', 'Var', (4, 8))
43998	25849106	The key alterations identified more recently by aCGH in classic LCIS, florid/extensive LCIS and PLCIS are 1q gain and 16q loss, with increased genomic complexity observed in the latter two groups of lesions, including loss of 8p, 11q and 17p and amplifications at 11q13 (CCND1) and 17q12 (ERBB2).	('CCND1', 'Gene', '595', (271, 276))	('ERBB2', 'Gene', '2064', (289, 294))	('classic LCIS', 'Disease', (56, 68))	('loss', 'Var', (218, 222))	('16q', 'CPA', (118, 121))	('florid/extensive', 'Disease', (70, 86))	('CGH', 'Gene', '3342', (49, 52))	('loss', 'NegReg', (122, 126))	('gain', 'PosReg', (109, 113))	('CCND1', 'Gene', (271, 276))	('CGH', 'Gene', (49, 52))	('ERBB2', 'Gene', (289, 294))	('amplifications', 'Var', (246, 260))
43999	25849106	Other recurrent alterations include losses at 8p23-p21, 11q14.1-q25, and 13q, gains of 8q and 16p, and high-level amplifications at 1q32, 8p12-p11.2, and 11q13.	('p21', 'Gene', (51, 54))	('p11', 'Gene', (143, 146))	('p21', 'Gene', '644914', (51, 54))	('losses', 'NegReg', (36, 42))	('gains', 'PosReg', (78, 83))	('p11', 'Gene', '6281', (143, 146))	('amplifications', 'Var', (114, 128))
44002	25849106	As mentioned above, PLC contains a similar profile of chromosomal change, although there is increased complexity and additional amplifications are present - 8q24 (MYC), 17q12 (ERBB2/Her2) and 20q13, which are usually considered to be archetypal changes of high-grade ductal tumours.	('MYC', 'Gene', '4609', (163, 166))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('tumours', 'Phenotype', 'HP:0002664', (274, 281))	('20q13', 'Var', (192, 197))	('ductal tumours', 'Disease', (267, 281))	('MYC', 'Gene', (163, 166))	('ERBB2', 'Gene', '2064', (176, 181))	('Her2', 'Gene', (182, 186))	('ERBB2', 'Gene', (176, 181))	('Her2', 'Gene', '2064', (182, 186))	('ductal tumours', 'Disease', 'MESH:D044584', (267, 281))
44006	25849106	Similarly, tumours in IntClust 8 also harbour a high frequency of 1q + and 16q-, but also 16p+.	('16q-', 'Var', (75, 79))	('1q +', 'Var', (66, 70))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('16p+', 'Var', (90, 94))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))
44007	25849106	Conversely, tumours in IntClust 4 showed infrequent 1q + and 16q-.	('16q-', 'Var', (61, 65))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
44012	25849106	Beyond the highly recurrent mutations in CDH1 and PIK3CA, which for PIK3CA the mutation rate is similar to that observed overall in ER-positive breast cancers, there is a paucity of recurrent driver mutations in this tumour type (Table 1), supporting the idea that heterogeneity within and between tumours is complex.	('tumours', 'Phenotype', 'HP:0002664', (298, 305))	('PIK3CA', 'Gene', '5290', (50, 56))	('tumours', 'Disease', 'MESH:D009369', (298, 305))	('mutations', 'Var', (199, 208))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('PIK3CA', 'Gene', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (298, 304))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (298, 304))	('tumour', 'Disease', (217, 223))	('tumour', 'Disease', (298, 304))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('PIK3CA', 'Gene', (50, 56))	('CDH1', 'Gene', '999', (41, 45))	('breast cancers', 'Disease', 'MESH:D001943', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancers', 'Disease', (144, 158))	('CDH1', 'Gene', (41, 45))	('mutations', 'Var', (28, 37))	('breast cancers', 'Phenotype', 'HP:0003002', (144, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('PIK3CA', 'Gene', '5290', (68, 74))	('tumours', 'Disease', (298, 305))
44014	25849106	This study sequenced a pleural effusion metastasis and matched primary ILC diagnosed 9 years earlier and found that 5 somatic mutations (of a possible 32 defined for the metastasis) were present in the primary tumour, a telling comment on the degree of clonal evolution occurring during progression from primary clone to metastasis.	('pleural effusion', 'Phenotype', 'HP:0002202', (23, 39))	('pleural effusion metastasis', 'Disease', 'MESH:D010996', (23, 50))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('pleural effusion metastasis', 'Disease', (23, 50))	('mutations', 'Var', (126, 135))	('tumour', 'Disease', (210, 216))
44015	25849106	This patient also had an ERBB2 mutation, as did 2 of 192 ILCs in their validation set.	('ERBB2', 'Gene', (25, 30))	('ERBB2', 'Gene', '2064', (25, 30))	('patient', 'Species', '9606', (5, 12))	('mutation', 'Var', (31, 39))
44017	25849106	Consulting the cBioPortal for an updated data review, 6 of 155 ILCs (3.9%) harboured an ERBB2 mutation.	('ERBB2', 'Gene', '2064', (88, 93))	('ERBB2', 'Gene', (88, 93))	('mutation', 'Var', (94, 102))
44018	25849106	Interestingly, in a massively parallel, targeted amplicon sequencing of 'actionable cancer genes' in ILC post-treatment relapse (that is, recurrence or metastasis), Ross and colleagues reported HER2/ERBB2 genetic alterations in 6 of 22 (27%) cases, including 4 mutations, one gene fusion and one amplification.	('mutations', 'Var', (261, 270))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('ILC', 'Disease', (101, 104))	('cancer', 'Disease', (84, 90))	('reported', 'Reg', (185, 193))	('HER2', 'Gene', '2064', (194, 198))	('ERBB2', 'Gene', '2064', (199, 204))	('HER2', 'Gene', (194, 198))	('genetic alterations', 'Var', (205, 224))	('ERBB2', 'Gene', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
44032	25849106	The somatic mutation profile of a tumour may contribute to this; for example, tumours harbouring or acquiring driver mutations in ESR1 or ERBB2 or amplifications at 8p12 (FGFR1) or 11q13 (CCND1) may be less responsive to targeted endocrine therapy.	('ESR1', 'Gene', (130, 134))	('mutations', 'Var', (117, 126))	('CCND1', 'Gene', '595', (188, 193))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('FGFR1', 'Gene', (171, 176))	('FGFR1', 'Gene', '2260', (171, 176))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumour', 'Disease', (78, 84))	('tumour', 'Disease', (34, 40))	('tumours', 'Disease', (78, 85))	('ERBB2', 'Gene', '2064', (138, 143))	('ESR1', 'Gene', '2099', (130, 134))	('ERBB2', 'Gene', (138, 143))	('CCND1', 'Gene', (188, 193))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
44035	25849106	Recent research has also shown that PIK3CA mutations are selected for during progression from the primary ILC tumour to a local recurrence but not through to dissemination of distant metastases.	('metastases', 'Disease', (183, 193))	('PIK3CA', 'Gene', '5290', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (43, 52))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('PIK3CA', 'Gene', (36, 42))	('tumour', 'Disease', (110, 116))
44047	22461506	Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia.	('lacking', 'NegReg', (99, 106))	('proliferation', 'CPA', (10, 23))	('Neu', 'Gene', (80, 83))	('MMTV-HER2', 'Var', (61, 70))	('hyperplasia', 'Disease', (156, 167))	('inhibiting', 'NegReg', (119, 129))	('Neu', 'Gene', '13866', (80, 83))	('Decreased', 'NegReg', (0, 9))	('ErbB3', 'Gene', (107, 112))	('apoptosis', 'CPA', (38, 47))	('MMTV', 'Species', '11757', (75, 79))	('MMTV', 'Species', '11757', (61, 65))	('hyperplasia', 'Disease', 'MESH:D006965', (156, 167))	('rat', 'Species', '10116', (17, 20))	('mammary glands lacking', 'Phenotype', 'HP:0100783', (84, 106))
44048	22461506	Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('transgenic', 'Species', '10090', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('decreased', 'NegReg', (142, 151))	('tumor', 'Disease', (125, 130))	('ErbB3', 'Gene', (176, 181))	('ablation', 'Var', (182, 190))
44050	22461506	In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in preneoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of preexisting HER2-overexpressing tumors, and improved tumor response to the HER2 tyrosine kinase inhibitor lapatinib.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('p44', 'Gene', (44, 47))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('impaired', 'NegReg', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('loss', 'Var', (13, 17))	('lapatinib', 'Chemical', 'MESH:D000077341', (260, 269))	('decreased growth', 'Phenotype', 'HP:0001510', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('ErbB3', 'Gene', (21, 26))	('Akt', 'Gene', (36, 39))	('improved', 'PosReg', (198, 206))	('tyrosine', 'Chemical', 'MESH:D014443', (234, 242))	('decreased', 'NegReg', (134, 143))	('Akt', 'Gene', '11651', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('growth', 'MPA', (144, 150))	('p44', 'Gene', '26417', (44, 47))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (186, 192))
44051	22461506	These events were rescued by reexpression of ErbB3, but were only partially rescued by ErbB36F, an ErbB3 mutant harboring six tyrosine-to-phenylalanine mutations that block its interaction with phosphatidyl inositol 3-kinase.	('phenylalanine', 'Chemical', 'MESH:D010649', (138, 151))	('tyrosine', 'Chemical', 'MESH:D014443', (126, 134))	('ErbB3', 'Gene', (99, 104))	('interaction', 'Interaction', (177, 188))	('mutant', 'Var', (105, 111))
44054	22461506	Aberrant regulation of ErbB receptor tyrosine kinases is common in human cancers.	('cancers', 'Disease', (73, 80))	('Aberrant', 'Var', (0, 8))	('ErbB receptor tyrosine kinases', 'Enzyme', (23, 53))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tyrosine', 'Chemical', 'MESH:D014443', (37, 45))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
44060	22461506	These studies would predict that therapeutic combinations targeting ErbB2 and ErbB3 would improve outcome in ERBB2/HER2-amplified breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancers', 'Disease', 'MESH:D001943', (130, 144))	('breast cancers', 'Disease', (130, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('ErbB2', 'Gene', (68, 73))	('combinations', 'Var', (45, 57))	('ERBB2/HER2-amplified', 'Gene', (109, 129))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('improve', 'PosReg', (90, 97))	('breast cancers', 'Phenotype', 'HP:0003002', (130, 144))	('ErbB3', 'Gene', (78, 83))
44063	22461506	It is important to understand what supports the transition of ErbB2+ DCIS to invasive, metastatic breast cancers.	('breast cancers', 'Disease', (98, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('invasive', 'Disease', (77, 85))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('ErbB2+ DCIS', 'Var', (62, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancers', 'Disease', 'MESH:D001943', (98, 112))
44065	22461506	These studies revealed that the formation of ErbB2-mediated hyperplasias, DCIS, adenocarcinomas, and distant metastatic lesions were substantially decreased upon ErbB3 ablation.	('decreased', 'NegReg', (147, 156))	('DCIS', 'Disease', (74, 78))	('adenocarcinomas', 'Disease', 'MESH:D000230', (80, 95))	('hyperplasias', 'Disease', (60, 72))	('ErbB3', 'Gene', (162, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('distant metastatic lesions', 'CPA', (101, 127))	('adenocarcinomas', 'Disease', (80, 95))	('ablation', 'Var', (168, 176))	('hyperplasias', 'Disease', 'MESH:D006965', (60, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
44066	22461506	Inducible ErbB3 ablation in preexisting ErbB2-overexpressing tumors improved lapatinib-mediated growth inhibition.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ErbB3', 'Gene', (10, 15))	('lapatinib-mediated growth inhibition', 'MPA', (77, 113))	('ablation', 'Var', (16, 24))	('ErbB2-overexpressing', 'Gene', (40, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('lapatinib', 'Chemical', 'MESH:D000077341', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('improved', 'PosReg', (68, 76))
44068	22461506	These signaling events were rescued by ErbB3 reexpression, but only partially rescued by ErbB36F, a mutant ErbB3 isoform incapable of interacting with p85.	('ErbB36F', 'Var', (89, 96))	('p85', 'Gene', (151, 154))	('p85', 'Gene', '21981', (151, 154))
44077	22461506	ErbB3FL/FL, MMTV-Cre, MMTV-rtTA, TetOp-Cre, MMTV-Neu, MMTV-HER2, and MMTV-NIC mice have been previously described.	('MMTV', 'Species', '11757', (69, 73))	('ErbB3FL/FL', 'Var', (0, 10))	('MMTV', 'Species', '11757', (12, 16))	('MMTV', 'Species', '11757', (54, 58))	('MMTV', 'Species', '11757', (44, 48))	('MMTV', 'Species', '11757', (22, 26))	('Neu', 'Gene', (49, 52))	('Neu', 'Gene', '13866', (49, 52))	('mice', 'Species', '10090', (78, 82))
44078	22461506	ErbB3FL/FL X MMTV-Cre is referred to herein as ErbB3MMTV-KO, ErbB3FL/FL X MMTV-rtTA X TetOp-Cre as ErbB3DOX-KO, and ErbB3FL/FL X MMTV-Neu as NiB3.	('MMTV', 'Species', '11757', (52, 56))	('Neu', 'Gene', (134, 137))	('DOX', 'Chemical', 'MESH:D004318', (104, 107))	('ErbB3FL/FL X', 'Var', (116, 128))	('Neu', 'Gene', '13866', (134, 137))	('MMTV', 'Species', '11757', (129, 133))	('MMTV', 'Species', '11757', (74, 78))	('MMTV', 'Species', '11757', (13, 17))	('ErbB3FL/FL', 'Var', (61, 71))
44090	22461506	The following primary antibodies were used: ErbB3 (C-17, Santa Cruz Biotechnology; 1:2,000), alpha-actin (Sigma-Aldrich; 1:5,000), Y1197 P-ErbB3, p85, AKT, and S473 P-Akt (Cell Signaling Technology; 1:1,000.	('AKT', 'Gene', (151, 154))	('S473 P', 'Mutation', 'p.S473P', (160, 166))	('Y1197 P-ErbB3', 'Var', (131, 144))	('C-17', 'Gene', (51, 55))	('Akt', 'Gene', '11651', (167, 170))	('AKT', 'Gene', '11651', (151, 154))	('p85', 'Gene', (146, 149))	('Akt', 'Gene', (167, 170))	('p85', 'Gene', '21981', (146, 149))	('C-17', 'Gene', '231162', (51, 55))
44105	22461506	Inhibition of ErbB2/HER2-driven hyperplasia was maintained in ErbB3MMTV-KO X MMTV-HER2 mammary glands through 27 weeks of age (Fig.	('ErbB3MMTV-KO X', 'Var', (62, 76))	('hyperplasia', 'Disease', (32, 43))	('MMTV', 'Species', '11757', (67, 71))	('MMTV', 'Species', '11757', (77, 81))	('hyperplasia', 'Disease', 'MESH:D006965', (32, 43))
44106	22461506	However, focal neoplasias were present in ErbB3MMTV-KO X MMTV-HER2 mammary glands, even in the context of suppressed hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (117, 128))	('neoplasias', 'Disease', (15, 25))	('neoplasias', 'Phenotype', 'HP:0002664', (15, 25))	('MMTV', 'Species', '11757', (57, 61))	('MMTV', 'Species', '11757', (47, 51))	('neoplasia', 'Phenotype', 'HP:0002664', (15, 24))	('neoplasias', 'Disease', 'MESH:D009369', (15, 25))	('hyperplasia', 'Disease', (117, 128))	('ErbB3MMTV-KO X MMTV-HER2', 'Var', (42, 66))
44107	22461506	Average tumor latency was statistically similar in ErbB3MMTV-KO X MMTV-HER2 mice and ErbB3FL/+ X MMTV-HER2 mice (P > 0.05, log-rank test; Fig.	('MMTV', 'Species', '11757', (66, 70))	('MMTV', 'Species', '11757', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MMTV', 'Species', '11757', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mice', 'Species', '10090', (76, 80))	('mice', 'Species', '10090', (107, 111))	('tumor', 'Disease', (8, 13))	('ErbB3MMTV-KO X MMTV-HER2', 'Var', (51, 75))
44114	22461506	Whole-mount beta-galactosidase staining revealed numerous ErbB3MMTV-KO X MMTV-HER2 X Rosa26 MECs lacking beta-galactosidase (Fig.	('MMTV', 'Species', '11757', (73, 77))	('beta-galactosidase', 'Gene', (12, 30))	('beta-galactosidase', 'Gene', '12091', (12, 30))	('Rosa26', 'Gene', '14910', (85, 91))	('ErbB3MMTV-KO', 'Var', (58, 70))	('beta-galactosidase', 'Gene', (105, 123))	('beta-galactosidase', 'Gene', '12091', (105, 123))	('Rosa26', 'Gene', (85, 91))	('lacking', 'NegReg', (97, 104))	('MMTV', 'Species', '11757', (63, 67))
44116	22461506	S2), although the average number of MMTV-HER2 tumors per mouse was not different between ErbB3MMTV-KO and ErbB3FL/+mice, the tumor distribution was (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ErbB3MMTV-KO', 'Var', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (46, 51))	('MMTV-HER2 tumors', 'Disease', 'MESH:D009369', (36, 52))	('tumor', 'Disease', (125, 130))	('MMTV-HER2 tumors', 'Disease', (36, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mice', 'Species', '10090', (115, 119))	('mouse', 'Species', '10090', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
44117	22461506	Ninety percent of all ErbB3FL/+ X MMTV-HER2 mice occurred in thoracic mammary glands (9 of 10 mice), but occurred at a lesser frequency in ErbB3MMTV-KO X MMTV-HER2 (5 of 13), but cervical and inguinal mammary tumors occurred with higher frequency.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('ErbB3FL/+ X MMTV-HER2', 'Var', (22, 43))	('mice', 'Species', '10090', (44, 48))	('mice', 'Species', '10090', (94, 98))	('ErbB3MMTV-KO', 'Var', (139, 151))	('MMTV', 'Species', '11757', (144, 148))	('MMTV', 'Species', '11757', (34, 38))	('MMTV', 'Species', '11757', (154, 158))	('occurred', 'Reg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
44121	22461506	Mammary glands harvested from 12-week-old virgin female NIC mice revealed ErbB2-induced diffuse hyperplasia and focal neoplasia in ErbB3FL/+ X NIC samples, but not ErbB3FL/+ X NIC (Fig.	('neoplasia', 'Disease', (118, 127))	('hyperplasia', 'Disease', 'MESH:D006965', (96, 107))	('ErbB3FL/+ X NIC', 'Var', (131, 146))	('neoplasia', 'Disease', 'MESH:D009369', (118, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (118, 127))	('mice', 'Species', '10090', (60, 64))	('hyperplasia', 'Disease', (96, 107))	('ErbB2-induced', 'Gene', (74, 87))
44122	22461506	Cell proliferation in ErbB3FL/FL X NIC mammary glands was decreased as compared with ErbB3FL/+ X NIC, whereas cell death was increased.	('increased', 'PosReg', (125, 134))	('rat', 'Species', '10116', (12, 15))	('decreased', 'NegReg', (58, 67))	('ErbB3FL/FL X', 'Var', (22, 34))	('cell death', 'CPA', (110, 120))	('Cell proliferation', 'CPA', (0, 18))
44125	22461506	However, 2 of 15 ErbB3FL/FL X NIC mice developed DCIS that were too small for detection by manual palpation, but were detected at necropsy at 180 days.	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('ErbB3FL/FL', 'Var', (17, 27))	('DCIS', 'Disease', (49, 53))	('mice', 'Species', '10090', (34, 38))
44127	22461506	Western blot analysis showed loss of ErbB3 expression in ErbB3FL/FL X NIC whole tissue lysates, which did not affect Akt phosphorylation at S473, but drastically reduced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK).	('p44', 'Gene', '26417', (189, 192))	('Akt', 'Gene', (117, 120))	('reduced', 'NegReg', (162, 169))	('loss', 'NegReg', (29, 33))	('Akt', 'Gene', '11651', (117, 120))	('p44', 'Gene', (189, 192))	('ErbB3', 'Gene', (37, 42))	('ErbB3FL/FL', 'Var', (57, 67))	('phosphorylation', 'MPA', (170, 185))
44128	22461506	Palpable mammary tumors were evident in 7 of 8 ErbB3+/+ X NIC mice, and in 7 of 8 ErbB3FL/+ X NIC mice, occurring with similar average tumor latencies (Fig.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('ErbB3+/+ X NIC', 'Var', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mice', 'Species', '10090', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
44129	22461506	Average total tumor burden per mouse was decreased in ErbB3FL/FL X NIC mice as compared with ErbB3+/+ X NIC and ErbB3FL/+ X NIC (Fig.	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', (14, 19))	('decreased', 'NegReg', (41, 50))	('ErbB3FL/FL X NIC', 'Var', (54, 70))	('mouse', 'Species', '10090', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
44131	22461506	Therefore, ErbB3 ablation greatly decreases progression of ErbB2+ premalignant lesions to metastatic breast cancers.	('decreases', 'NegReg', (34, 43))	('progression', 'MPA', (44, 55))	('ErbB3', 'Gene', (11, 16))	('ablation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast cancers', 'Disease', (101, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
44145	22461506	Next, NiB3 cells (with endogenous ErbB3 still intact) were infected with pMSCV-based retroviral particles encoding WT rat ErbB3 (ErbB3WT), or mutant rat ErbB3 in which tyrosine-to-phenylalanine mutations were introduced into the 6 PI3K interaction motifs of ErbB3 (ErbB36F; ref.).	('rat', 'Species', '10116', (149, 152))	('tyrosine', 'Chemical', 'MESH:D014443', (168, 176))	('rat', 'Species', '10116', (118, 121))	('phenylalanine', 'Chemical', 'MESH:D010649', (180, 193))	('mutant', 'Var', (142, 148))	('ErbB3', 'Gene', (153, 158))	('tyrosine-to-phenylalanine mutations', 'Var', (168, 203))
44146	22461506	Pools of puromycin-resistant cells were infected with Ad.Cre to remove endogenous ErbB3, leaving expression of ErbB3WT or ErbB36F (Fig.	('ErbB36F', 'Var', (122, 129))	('puromycin', 'Chemical', 'MESH:D011691', (9, 18))	('ErbB3WT', 'Var', (111, 118))
44148	22461506	Akt phosphorylation was also substantially reduced but not eliminated in NiB3 vector (i.e., ErbB3 deficient) and NiB3-ErbB36Fcells, consistent with the idea that ErbB3 facilitates PI3K activation in ErbB2-overexpressing cells, but that ErbB2 retains alternative mechanisms to activate the PI3K/Akt signaling pathway outside of ErbB3, as previously reported.	('NiB3 vector', 'Var', (73, 84))	('PI3K', 'Pathway', (180, 184))	('Akt', 'Gene', '11651', (294, 297))	('Akt', 'Gene', (294, 297))	('Akt', 'Gene', '11651', (0, 3))	('activation', 'PosReg', (185, 195))	('activate', 'PosReg', (276, 284))	('reduced', 'NegReg', (43, 50))	('Akt', 'Gene', (0, 3))	('NiB3-ErbB36Fcells', 'Var', (113, 130))
44149	22461506	Interestingly, we found that Erk1/2 MAPK phosphorylation was lost in cells lacking ErbB3, but was restored in cells expressing either ErbB3WT or ErbB36F, suggesting that ErbB3 is required for ErbB2-induced MAPK activation through mechanisms that do not involve tyrosine phosphorylation at these 6 residues.	('lost', 'NegReg', (61, 65))	('Erk1/2', 'Gene', '26417;26413', (29, 35))	('ErbB3WT', 'Var', (134, 141))	('phosphorylation', 'MPA', (41, 56))	('ErbB36F', 'Var', (145, 152))	('Erk1/2', 'Gene', (29, 35))	('tyrosine', 'Chemical', 'MESH:D014443', (261, 269))
44151	22461506	Importantly, coprecipitation of p85 with ErbB3 was eliminated in ErbB36F-expressing cells, despite the presence of tyrosine phosphorylated ErbB3, confirming that ErbB3-PI3K interactions were disrupted.	('tyrosine', 'MPA', (115, 123))	('p85', 'Gene', '21981', (32, 35))	('tyrosine', 'Chemical', 'MESH:D014443', (115, 123))	('ErbB36F-expressing', 'Var', (65, 83))	('presence', 'Reg', (103, 111))	('p85', 'Gene', (32, 35))	('eliminated', 'NegReg', (51, 61))	('ErbB3', 'Gene', (139, 144))	('coprecipitation', 'MPA', (13, 28))	('interactions', 'Interaction', (173, 185))
44152	22461506	In long-term colony assays, Ad.Cre-infected NiB3 cells expressing ErbB36F were more sensitive to lapatinib-induced growth inhibition than ErbB3WT-expressing cells (Fig.	('sensitive', 'MPA', (84, 93))	('lapatinib-induced growth inhibition', 'MPA', (97, 132))	('lapatinib', 'Chemical', 'MESH:D000077341', (97, 106))	('ErbB36F', 'Var', (66, 73))
44156	22461506	We carried out orthotopic transplant of NiB3-ErbB3WT and NiB3-ErbB36F into contralateral mammary fat pads of mice, using a protocol in which Ad.Cre eliminated endogenous ErbB3 ex vivo, 7 days before tumor inoculation.	('tumor', 'Disease', (199, 204))	('NiB3-ErbB36F', 'Var', (57, 69))	('endogenous', 'MPA', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mice', 'Species', '10090', (109, 113))	('ErbB3', 'Gene', (170, 175))
44159	22461506	Relative levels of cell proliferation (as measured by mitotic index) in tumors harvested 1 hour after the final treatment were not statistically different in NiB3-ErbB36F and NiB3-ErbB3WT tumors (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('NiB3-ErbB36F', 'Var', (158, 170))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('NiB3-ErbB3WT tumors', 'Disease', (175, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('NiB3-ErbB3WT tumors', 'Disease', 'MESH:D009369', (175, 194))	('rat', 'Species', '10116', (31, 34))
44166	22461506	However, clinical success of ErbB2 inhibitors is limited by tumor resistance to these inhibitors.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibitors', 'Var', (35, 45))	('tumor', 'Disease', (60, 65))	('ErbB2', 'Gene', (29, 34))
44169	22461506	Our results suggest that complete ablation of ErbB3 decreases growth and survival of ErbB2-expressing mammary tumors in mice.	('mice', 'Species', '10090', (120, 124))	('decreases', 'NegReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('survival', 'CPA', (73, 81))	('tumors', 'Disease', (110, 116))	('growth', 'MPA', (62, 68))	('ErbB2-expressing', 'Gene', (85, 101))	('ErbB3', 'Gene', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ablation', 'Var', (34, 42))	('decreases growth', 'Phenotype', 'HP:0001510', (52, 68))
44171	22461506	Although genetic ErbB3 ablation decreased tumor growth as a single therapeutic strategy (Fig.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('rat', 'Species', '10116', (81, 84))	('ErbB3', 'Gene', (17, 22))	('ablation', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('decreased', 'NegReg', (32, 41))
44174	22461506	The observation that genetic ErbB3 ablation effectively limits tumor cell growth as a single-agent strategy is consistent with previous reports that siRNA sequences targeting ErbB3 decreased growth of ERBB2/HER2-amplified breast cell lines and the hormone-independent growth of MCF-7 cells.	('tumor', 'Disease', (63, 68))	('limits', 'NegReg', (56, 62))	('ErbB3', 'Gene', (175, 180))	('growth', 'MPA', (191, 197))	('rat', 'Species', '10116', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MCF-7', 'CellLine', 'CVCL:0031', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('hormone-independent growth', 'CPA', (248, 274))	('decreased growth', 'Phenotype', 'HP:0001510', (181, 197))	('ErbB3', 'Gene', (29, 34))	('ablation', 'Var', (35, 43))	('decreased', 'NegReg', (181, 190))
44175	22461506	Furthermore, genetic ablation of ErbB3, or treatment of mice with EZN-3920, an antisense oligonucleotide that was used to knock down ErbB3 in vivo, decreased PI3K signaling and tumor growth in the MMTV-PyVmT model of breast cancer.	('PI3K signaling', 'Pathway', (158, 172))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('EZN-3920', 'Chemical', '-', (66, 74))	('genetic ablation', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('decreased', 'NegReg', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('oligonucleotide', 'Chemical', 'MESH:D009841', (89, 104))	('mice', 'Species', '10090', (56, 60))	('MMTV', 'Species', '11757', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('knock down', 'Var', (122, 132))	('tumor', 'Disease', (177, 182))	('ErbB3', 'Gene', (133, 138))	('ErbB3', 'Gene', (33, 38))
44209	25713984	Th1 immune response both destroys the current disease and provides immunologic memory to protect against recurrence or progression because of IFN-gamma associated inflammatory cytokines which are necessary for enhanced function of antigen presenting cells, epitope spreading, activation of the CD8+ T cells and immunologic memory.	('destroys', 'NegReg', (25, 33))	('CD8', 'Gene', '925', (294, 297))	('CD8', 'Gene', (294, 297))	('epitope', 'Var', (257, 264))
44212	25713984	Furthermore, MHC class II epitopes from the same protein can either stimulate a predominantly IFN-gamma Th1 or IL-10 Th2 response and inclusion of any Th2 epitopes in a vaccine prevents the antitumor immune response.	('IL-10', 'Gene', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('prevents', 'NegReg', (177, 185))	('inclusion', 'Var', (134, 143))	('stimulate', 'PosReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IL-10', 'Gene', '3586', (111, 116))	('MHC', 'Gene', (13, 16))	('tumor', 'Disease', (194, 199))	('MHC', 'Gene', '3107', (13, 16))	('epitopes', 'Var', (26, 34))	('predominantly IFN-gamma Th1', 'MPA', (80, 107))
44224	25713984	The tumors that did develop in the multiantigen-vaccinated mice were slower growing and demonstrated increased CD8+ T-cell tumor infiltration as compared with control-vaccinated mice (p = 0.003).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (59, 63))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mice', 'Species', '10090', (178, 182))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('slower', 'NegReg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD8', 'Gene', (111, 114))	('multiantigen-vaccinated', 'Var', (35, 58))	('CD8', 'Gene', '925', (111, 114))
44226	25713984	The protection was CD4+ mediated and depletion of the CD4+ T cells caused loss of the tumor inhibitory effect (p = 0.013).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('depletion', 'Var', (37, 46))	('tumor', 'Disease', (86, 91))	('loss', 'NegReg', (74, 78))	('CD4', 'Gene', (54, 57))	('CD4', 'Gene', (19, 22))	('CD4', 'Gene', '920', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('CD4', 'Gene', '920', (54, 57))
44237	23652305	DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential.	('breast cancer', 'Disease', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('malignant potential', 'CPA', (118, 137))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('hypermethylation', 'Var', (4, 20))
44244	23652305	DNA hypermethylation is recognised as an important epigenetic aberrancy contributing to the development of several types of cancer, including breast cancer.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('contributing', 'Reg', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('hypermethylation', 'Var', (4, 20))
44249	23652305	In DCIS and IDC, we also assessed the relation of aberrant methylation and established predictors in breast cancer, such as oestrogen receptor (ER), progesterone receptor (PR), HER2 and histological grade.	('PR', 'Gene', '5241', (172, 174))	('aberrant methylation', 'Var', (50, 70))	('progesterone receptor', 'Gene', (149, 170))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('HER2', 'Gene', (177, 181))	('progesterone receptor', 'Gene', '5241', (149, 170))	('HER2', 'Gene', '2064', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
44290	23652305	Increased MI of RARbeta2 was associated with HER2 amplification in DCIS (P=0.046).	('amplification', 'Var', (50, 63))	('RARbeta2', 'Gene', (16, 24))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
44291	23652305	Methylation Indexpanel was significantly higher in ER-negative DCIS lesions (P=0.01).	('DCIS', 'Disease', (63, 67))	('ER-negative', 'Var', (51, 62))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('Methylation Indexpanel', 'MPA', (0, 22))	('higher', 'PosReg', (41, 47))	('Indexpanel', 'Chemical', '-', (12, 22))
44292	23652305	A trend existed towards increased MIpanel in PR-negative DCIS (P=0.11) and HER2-positive DCIS (P=0.10).	('PR', 'Gene', '5241', (45, 47))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('HER2', 'Gene', (75, 79))	('MIpanel', 'Chemical', '-', (34, 41))	('HER2', 'Gene', '2064', (75, 79))	('MIpanel', 'Var', (34, 41))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
44293	23652305	In IDC, MINT31 MI was also increased in ER-negative tumours as compared with ER-positive tumours (P=0.046).	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('increased', 'PosReg', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('MINT31 MI', 'Var', (8, 17))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
44294	23652305	In addition, MINT31 MI was higher in tumours with amplification of HER2 (P=0.014).	('amplification', 'Var', (50, 63))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('HER2', 'Gene', (67, 71))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('HER2', 'Gene', '2064', (67, 71))	('higher', 'PosReg', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('MINT31', 'Gene', (13, 19))
44298	23652305	Fewer studies have looked into methylation aberrancies and the pattern of their occurrence during breast cancer longitudinal progression.	('breast cancer longitudinal', 'Disease', (98, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer longitudinal', 'Disease', 'MESH:D001943', (98, 124))	('methylation', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
44299	23652305	A study indicating the importance of methylation aberrancies in early malignant transformation showed methylation of p16 to be a key factor in the earliest onset of premalignant programmes, even in normal-appearing epithelial cells.	('methylation', 'Var', (102, 113))	('premalignant programmes', 'Disease', (165, 188))	('p16', 'Gene', '1029', (117, 120))	('p16', 'Gene', (117, 120))
44303	23652305	This study demonstrates the occurrence of methylation aberrancies during the key developmental steps of ductal breast cancer.	('occurrence', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('aberrancies', 'Var', (54, 65))	('methylation aberrancies', 'Var', (42, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('ductal breast cancer', 'Disease', (104, 124))	('ductal breast cancer', 'Disease', 'MESH:D001943', (104, 124))
44304	23652305	Our data show that hypermethylation of MINT17 and RARbeta2 marks the transition from proliferative epithelial hyperplasia towards atypia, occurring especially during transition from DH to ADH.	('hyperplasia', 'Disease', (110, 121))	('RARbeta2', 'Gene', (50, 58))	('hyperplasia', 'Disease', 'MESH:D006965', (110, 121))	('MINT17', 'Gene', (39, 45))	('hypermethylation', 'Var', (19, 35))	('DH', 'Disease', 'MESH:D065630', (182, 184))	('DH', 'Disease', 'MESH:D065630', (189, 191))
44305	23652305	In our study, RASSF1A hypermethylation was an early marker of proliferative development, signalling the transition from normal epithelia towards DH.	('RASSF1A', 'Gene', '11186', (14, 21))	('RASSF1A', 'Gene', (14, 21))	('DH', 'Disease', 'MESH:D065630', (145, 147))	('hypermethylation', 'Var', (22, 38))
44307	23652305	Interestingly, we showed that aberrant methylation was associated with unfavourable lesion characteristics in DCIS with known ER, PR and HER2.	('DCIS', 'Disease', (110, 114))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('aberrant methylation', 'Var', (30, 50))	('associated', 'Reg', (55, 65))	('HER2', 'Gene', (137, 141))	('PR', 'Gene', '5241', (130, 132))	('HER2', 'Gene', '2064', (137, 141))
44308	23652305	Methylation Indexpanel was also associated with ER negativity in DCIS but not in IDC.	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('associated', 'Reg', (32, 42))	('ER negativity', 'MPA', (48, 61))	('Indexpanel', 'Chemical', '-', (12, 22))	('Methylation Indexpanel', 'Var', (0, 22))
44309	23652305	Our previous study demonstrated association 'Methylation-High' or 'Meth-H' phenotype with ER positivity in IDC.	("'Meth-H", 'PosReg', (66, 73))	('IDC', 'Disease', (107, 110))	('Meth-H', 'Chemical', '-', (67, 73))	('ER positivity', 'Disease', (90, 103))	("'Methylation-High'", 'Var', (44, 62))
44315	23652305	The association of aberrant methylation and hormone receptor expression in DCIS is novel and warrants exploration of precancer analysis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('aberrant methylation', 'Var', (19, 39))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('DCIS', 'Disease', (75, 79))	('hormone receptor', 'Gene', (44, 60))	('expression', 'MPA', (61, 71))	('hormone receptor', 'Gene', '3164', (44, 60))
44316	23652305	Our data illustrate that aberrant methylation is an important event in the development of ductal breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('aberrant methylation', 'Var', (25, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('ductal breast cancer', 'Disease', (90, 110))	('ductal breast cancer', 'Disease', 'MESH:D001943', (90, 110))
44318	23652305	Methylation aberrancies may provide a therapeutic target in patients with premalignant lesions.	('aberrancies', 'Var', (12, 23))	('Methylation aberrancies', 'Var', (0, 23))	('patients', 'Species', '9606', (60, 68))
44322	23652305	Epigenetic aberrancies occur frequently in breast cancer, and may be candidates.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('Epigenetic aberrancies', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
44323	23652305	This study showed that aberrant methylation of a panel of four biomarkers occurs in the early stages of breast cancer development.	('occurs', 'Reg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('methylation', 'MPA', (32, 43))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('aberrant', 'Var', (23, 31))
44324	23652305	Targeting aberrant methylation may provide an opportunity to modulate cancer risk in the earliest stages of cancer development, at the transformation towards atypia.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('modulate', 'Reg', (61, 69))	('aberrant methylation', 'Var', (10, 30))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
44325	23652305	Whether aberrant methylation in premalignant breast lesions infers a greater risk for disease progression and, eventually, the development of invasive disease, is a question that merits further research in a larger well clinically annotated cohort of patients.	('disease progression', 'CPA', (86, 105))	('invasive disease', 'Disease', (142, 158))	('patients', 'Species', '9606', (251, 259))	('invasive disease', 'Disease', 'MESH:D009362', (142, 158))	('aberrant methylation', 'Var', (8, 28))
44377	26512815	Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS, invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity.	('BC', 'Phenotype', 'HP:0003002', (162, 164))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('invasive disease', 'Disease', (115, 131))	('Cancer', 'Disease', (0, 6))	('BC', 'Phenotype', 'HP:0003002', (185, 187))	('DCIS', 'Disease', (109, 113))	('tumor', 'Disease', (133, 138))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('HER2', 'Gene', (210, 214))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('HER2', 'Gene', '2064', (210, 214))	('positivity', 'Var', (215, 225))	('invasive disease', 'Disease', 'MESH:D009362', (115, 131))
44504	23056988	There have been associations with the BRCA2 gene mutation in many cases of male breast carcinoma.	('male breast carcinoma', 'Disease', 'MESH:D018567', (75, 96))	('BRCA2', 'Gene', '675', (38, 43))	('breast carcinoma', 'Phenotype', 'HP:0003002', (80, 96))	('man', 'Species', '9606', (61, 64))	('associations', 'Interaction', (16, 28))	('mutation', 'Var', (49, 57))	('BRCA2', 'Gene', (38, 43))	('male breast carcinoma', 'Disease', (75, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
44520	20461020	In two cross-sectional studies, patients receiving mastectomy regardless of breast reconstruction reported greater problems with sexual attractiveness compared with patients receiving BCS, and patients with breast reconstruction reported less sexual activity and sexual responsiveness compared with patients having BCS or mastectomy without reconstruction in patients with locally advanced breast cancer.	('problems', 'NegReg', (115, 123))	('sexual activity', 'CPA', (243, 258))	('sexual responsiveness', 'CPA', (263, 284))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (32, 40))	('less', 'NegReg', (238, 242))	('patients', 'Species', '9606', (359, 367))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('breast reconstruction', 'Var', (207, 228))	('sexual activity', 'Phenotype', 'HP:0030214', (243, 258))	('problems with sexual', 'Phenotype', 'HP:0030214', (115, 135))	('sexual attractiveness', 'Disease', (129, 150))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (299, 307))	('breast cancer', 'Disease', 'MESH:D001943', (390, 403))	('breast cancer', 'Phenotype', 'HP:0003002', (390, 403))	('sexual attractiveness', 'Disease', 'MESH:D012735', (129, 150))	('breast cancer', 'Disease', (390, 403))
44585	20461020	Patients who received a mastectomy reported more sexual problems on the 9-item measure and more problems with sexual attractiveness at all interviews than patients who received BCS (each P < 0.05); problems with sexual interest/enjoyment differed significantly by type of surgery only at T4 (P = 0.032).	('sexual problems', 'CPA', (49, 64))	('problems with sexual', 'Phenotype', 'HP:0030214', (96, 116))	('more', 'PosReg', (44, 48))	('sexual attractiveness', 'Disease', (110, 131))	('problems', 'Reg', (96, 104))	('Patients', 'Species', '9606', (0, 8))	('mastectomy', 'Var', (24, 34))	('patients', 'Species', '9606', (155, 163))	('sexual attractiveness', 'Disease', 'MESH:D012735', (110, 131))	('problems with sexual', 'Phenotype', 'HP:0030214', (198, 218))	('sexual interest', 'Phenotype', 'HP:0030214', (212, 227))	('sexual problems', 'Phenotype', 'HP:0030214', (49, 64))
44627	20461020	Our findings also showed that patients who received mastectomy were more likely to report more problems on the 9-item sexual-problems measure two years later, but they did not differ in perceived problems with sexual attractiveness at the first interview compared with patients who received BCS.	('problems with sexual', 'Phenotype', 'HP:0030214', (196, 216))	('sexual attractiveness', 'Disease', (210, 231))	('sexual attractiveness', 'Disease', 'MESH:D012735', (210, 231))	('problems', 'MPA', (95, 103))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (269, 277))	('mastectomy', 'Var', (52, 62))
44656	19844232	Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells.	('silencing', 'Var', (93, 102))	('motility', 'CPA', (38, 46))	('MCF-7', 'CellLine', 'CVCL:0031', (164, 169))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (171, 181))	('Snail', 'Gene', '6615', (18, 23))	('Snail', 'Gene', (18, 23))	('migratory propensity', 'CPA', (140, 160))	('rat', 'Species', '10116', (143, 146))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (186, 196))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (67, 77))	('T-47D', 'CellLine', 'CVCL:0553', (57, 62))	('increased', 'PosReg', (24, 33))	('decreased', 'NegReg', (130, 139))	('MCF-7', 'CellLine', 'CVCL:0031', (50, 55))
44667	19844232	Overexpression of Snail has been reported to be a sufficient inducer of EMT as well as being predictor for an aggressive tumour phenotype (Cano et al, 2000).	('aggressive tumour', 'Disease', 'MESH:D001523', (110, 127))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('EMT', 'CPA', (72, 75))	('Snail', 'Gene', '6615', (18, 23))	('Snail', 'Gene', (18, 23))	('aggressive tumour', 'Disease', (110, 127))	('Overexpression', 'Var', (0, 14))
44669	19844232	Kurrey et al (2005) reported ectopic Snail or Slug expression to result in induction of EMT in an ovarian carcinoma cell line, with enhanced motility and invasiveness, loss of expression of epithelial markers and increased expression of vimentin.	('induction', 'PosReg', (75, 84))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (98, 115))	('ovarian carcinoma', 'Disease', (98, 115))	('expression', 'MPA', (176, 186))	('Slug', 'Gene', (46, 50))	('invasiveness', 'CPA', (154, 166))	('expression', 'MPA', (223, 233))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (98, 115))	('epithelial', 'Protein', (190, 200))	('Snail', 'Gene', '6615', (37, 42))	('motility', 'CPA', (141, 149))	('Slug', 'Gene', '6591', (46, 50))	('enhanced', 'PosReg', (132, 140))	('loss', 'NegReg', (168, 172))	('ectopic', 'Var', (29, 36))	('vimentin', 'Gene', '7431', (237, 245))	('vimentin', 'Gene', (237, 245))	('EMT', 'CPA', (88, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('Snail', 'Gene', (37, 42))	('increased', 'PosReg', (213, 222))
44686	19844232	Finally, nuclear expression of Snail was shown to be associated with higher grade and high proliferation rate in primary breast cancer.	('higher grade', 'CPA', (69, 81))	('rat', 'Species', '10116', (105, 108))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('rat', 'Species', '10116', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high proliferation rate', 'CPA', (86, 109))	('associated', 'Reg', (53, 63))	('breast cancer', 'Disease', (121, 134))	('Snail', 'Gene', (31, 36))	('Snail', 'Gene', '6615', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('nuclear expression', 'Var', (9, 27))
44768	19844232	Moreover, silencing of Snail expression in MCF-7, MDA-MB-468 and MDA-MB-231 decreased cell migration significantly, whereas no effect of the knockdown was observed in T-47D cells (Figure 3D and E).	('Snail', 'Gene', '6615', (23, 28))	('rat', 'Species', '10116', (94, 97))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (50, 60))	('decreased', 'NegReg', (76, 85))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (65, 75))	('cell migration', 'CPA', (86, 100))	('T-47D', 'CellLine', 'CVCL:0553', (167, 172))	('Snail', 'Gene', (23, 28))	('MCF-7', 'CellLine', 'CVCL:0031', (43, 48))	('silencing', 'Var', (10, 19))
44773	19844232	However, motility of hypoxic cells transfected with siRNA against Snail was in contrast not significantly decreased due to the knockdown, relative to control-transfected hypoxic cells (Figure 3F).	('decreased', 'NegReg', (106, 115))	('motility', 'CPA', (9, 17))	('Snail', 'Gene', (66, 71))	('Snail', 'Gene', '6615', (66, 71))	('knockdown', 'Var', (127, 136))
44788	19844232	We continued by investigating the expression of Snail in a model system of hypoxia in vivo, non-invasive DCIS; DCIS lesions are often presented with areas of central necrosis where hypoxic tumour cells are surrounding the necrotic zone.	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('necrotic', 'Disease', 'MESH:D009336', (222, 230))	('hypoxic tumour', 'Disease', 'MESH:D009369', (181, 195))	('lesions', 'Var', (116, 123))	('hypoxic tumour', 'Disease', (181, 195))	('necrosis', 'Disease', (166, 174))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('Snail', 'Gene', '6615', (48, 53))	('Snail', 'Gene', (48, 53))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('necrotic', 'Disease', (222, 230))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('necrosis', 'Disease', 'MESH:D009336', (166, 174))
44807	19844232	A Snail mutant exhibiting mutations in these phosphorylation motifs was shown to be much more stable and resided exclusively in the nucleus, suggesting that only Snail that is unable to interact with and become phosphorylated by GSK-3beta is able to induce EMT in breast cancer cells.	('EMT', 'CPA', (257, 260))	('Snail', 'Gene', '6615', (2, 7))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('GSK-3beta', 'Gene', '2932', (229, 238))	('GSK-3beta', 'Gene', (229, 238))	('breast cancer', 'Disease', (264, 277))	('mutations', 'Var', (26, 35))	('Snail', 'Gene', '6615', (162, 167))	('Snail', 'Gene', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('induce', 'PosReg', (250, 256))	('Snail', 'Gene', (2, 7))
44808	19844232	Interestingly, when screening for mutations in the two consensus motifs of Snail, no mutations could be identified, indicating that the upstream signalling is the crucial mechanism determining the function of Snail.	('Snail', 'Gene', '6615', (75, 80))	('Snail', 'Gene', (75, 80))	('Snail', 'Gene', (209, 214))	('Snail', 'Gene', '6615', (209, 214))	('mutations', 'Var', (34, 43))
44810	19844232	Pak1 phosphorylation of Snail promotes nuclear accumulation and transcription repression activity of the E-cadherin gene in breast cancer cells, and hence induction of EMT (Yang et al, 2005).	('promotes', 'PosReg', (30, 38))	('Snail', 'Gene', (24, 29))	('phosphorylation', 'Var', (5, 20))	('E-cadherin', 'Gene', (105, 115))	('Pak1', 'Gene', '5058', (0, 4))	('E-cadherin', 'Gene', '999', (105, 115))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('induction', 'PosReg', (155, 164))	('Snail', 'Gene', '6615', (24, 29))	('nuclear accumulation', 'MPA', (39, 59))	('Pak1', 'Gene', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EMT', 'CPA', (168, 171))	('transcription', 'MPA', (64, 77))
44821	19844232	Knocking down Snail resulted in significant reduction of the migratory capacity of MCF-7, MDA-MB-468 and MDA-MB-231 cells.	('migratory capacity', 'CPA', (61, 79))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('Snail', 'Gene', (14, 19))	('rat', 'Species', '10116', (64, 67))	('reduction', 'NegReg', (44, 53))	('Snail', 'Gene', '6615', (14, 19))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (105, 115))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (90, 100))	('Knocking', 'Var', (0, 8))
44822	19844232	The mechanism behind this shift in migration can again not be explained by regulation of E-cadherin or vimentin, since expression of neither of the two proteins was significantly changed by Snail silencing.	('vimentin', 'Gene', '7431', (103, 111))	('expression', 'MPA', (119, 129))	('vimentin', 'Gene', (103, 111))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('rat', 'Species', '10116', (38, 41))	('Snail', 'Gene', '6615', (190, 195))	('Snail', 'Gene', (190, 195))	('silencing', 'Var', (196, 205))	('changed', 'Reg', (179, 186))
44827	19844232	Presence of nuclear Snail predicted a tumour phenotype displaying a more poorly differentiated histology and increased proliferation rate in premenopausal breast cancer, confirming the previously reported link between EMT and clinical aggressiveness (Cano et al, 2000; Blanco et al, 2002).	('aggressiveness', 'Disease', (235, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (141, 168))	('Snail', 'Gene', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('aggressiveness', 'Phenotype', 'HP:0000718', (235, 249))	('Snail', 'Gene', '6615', (20, 25))	('rat', 'Species', '10116', (133, 136))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('rat', 'Species', '10116', (126, 129))	('tumour', 'Disease', (38, 44))	('increased', 'PosReg', (109, 118))	('aggressiveness', 'Disease', 'MESH:D001523', (235, 249))	('Presence', 'Var', (0, 8))	('proliferation rate', 'CPA', (119, 137))
44833	19844232	The ER-MTA3-E-cadherin pathway has emerged as a novel pathway in the regulation of ER signalling, and allelic alterations in these genes have been reported to be associated with both tumour-promoting and antitumour mechanisms (Cheng et al, 2001; Fearon, 2003).	('allelic alterations', 'Var', (102, 121))	('E-cadherin', 'Gene', (12, 22))	('rat', 'Species', '10116', (114, 117))	('tumour', 'Disease', (183, 189))	('tumour', 'Disease', (208, 214))	('E-cadherin', 'Gene', '999', (12, 22))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (208, 214))
44836	19844232	Moreover, aetiological factors such as, for example, age at first full-term pregnancy, affects the importance of Snail as a susceptibility marker, and single-nucleotide polymorphism (SNP) of Snail has been shown to be of importance for the oestrogen-related risk factor in relation to breast cancer risk (Yu et al, 2006).	('Snail', 'Gene', '6615', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('single-nucleotide polymorphism', 'Var', (151, 181))	('Snail', 'Gene', '6615', (113, 118))	('Snail', 'Gene', (113, 118))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('breast cancer', 'Disease', (285, 298))	('Snail', 'Gene', (191, 196))
44838	19844232	Silencing of either Snail or Slug caused reversion of the mesenchymal-like phenotype, and in addition treatment with the oestrogen antagonist ICI was shown to overcome the inhibitory effect of E2 on E-cadherin transcription, suggesting a crucial role for oestrogen and its receptor in EMT-dependent tumour progression.	('mesenchymal-like phenotype', 'CPA', (58, 84))	('Snail', 'Gene', (20, 25))	('Snail', 'Gene', '6615', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('E-cadherin', 'Gene', (199, 209))	('Slug', 'Gene', '6591', (29, 33))	('E-cadherin', 'Gene', '999', (199, 209))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('Silencing', 'Var', (0, 9))	('Slug', 'Gene', (29, 33))	('tumour', 'Disease', (299, 305))
44839	19844232	Interestingly, in the same study it was also demonstrated that presence of ERbeta had an opposing effect on ERalpha, in the context of EMT regulation, inhibiting the ERalpha-induced EMT (Park et al, 2008).	('presence', 'Var', (63, 71))	('rat', 'Species', '10116', (52, 55))	('ERbeta', 'Gene', '2100', (75, 81))	('ERalpha', 'Gene', (108, 115))	('ERalpha', 'Gene', '2099', (108, 115))	('inhibiting', 'NegReg', (151, 161))	('ERbeta', 'Gene', (75, 81))	('ERalpha', 'Gene', '2099', (166, 173))	('ERalpha', 'Gene', (166, 173))
44844	19844232	In tumours with nuclear Snail expression, tamoxifen might exert its effect by inhibiting the function of Snail, as described previously for the antagonist ICI.	('nuclear', 'Var', (16, 23))	('Snail', 'Gene', '6615', (105, 110))	('Snail', 'Gene', (105, 110))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('Snail', 'Gene', (24, 29))	('inhibiting', 'NegReg', (78, 88))	('Snail', 'Gene', '6615', (24, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (42, 51))	('function', 'MPA', (93, 101))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))
44928	32691390	Several regression grading systems have been introduced which are based on prognostic markers such as tumor size (in one or more dimensions), change in cellularity, presence of DCIS, presence of regression or metastasis in lymph nodes and the size of lymph node metastasis.	('cellularity', 'MPA', (152, 163))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('DCIS', 'Protein', (177, 181))	('change', 'Reg', (142, 148))	('metastasis', 'CPA', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('regression', 'CPA', (195, 205))	('presence', 'Var', (165, 173))
44930	32691390	Although the presence of residual DCIS has been reported to convey a worse prognosis than complete absence of in situ and invasive carcinoma, there was no significant difference between OS and DFS estimates of ypT0ypN0 and ypTisypN0.	('ypT0ypN0', 'Var', (210, 218))	('DCIS', 'Disease', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('invasive carcinoma', 'Disease', 'MESH:D009361', (122, 140))	('presence', 'Var', (13, 21))	('invasive carcinoma', 'Disease', (122, 140))
44931	32691390	Our findings regarding the prognostic impact of pCR are in keeping with those of others, since patients with pCR had a favorable prognosis (both in DFS and OS) compared to patients having partial regression.	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (95, 103))	('DFS', 'Disease', (148, 151))	('pCR', 'Var', (109, 112))
44959	27914000	Moreover, the ECM mediates communication between the epithelial and stromal cells, and perturbations in this process can lead to breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('perturbations', 'Var', (87, 100))	('lead to', 'Reg', (121, 128))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
44997	27914000	While it is being increasingly recognized that altered ECM stiffness contributes, in part, to tumor progression, we will now highlight some of the mechanisms underlying this process.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ECM stiffness', 'MPA', (55, 68))	('tumor', 'Disease', (94, 99))	('contributes', 'Reg', (69, 80))	('altered', 'Var', (47, 54))
45013	27914000	Recently, it was shown that a collagen-dense breast tumor environment recruits tumor-associated neutrophils (TANs) due to altered cytokine signaling, and depletion of TANs reduces metastasis in a stiffness-dependent manner.	('TANs', 'Chemical', '-', (109, 113))	('breast tumor', 'Disease', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('metastasis', 'CPA', (180, 190))	('TANs', 'Chemical', '-', (167, 171))	('tumor', 'Disease', (79, 84))	('reduces', 'NegReg', (172, 179))	('tumor', 'Disease', (52, 57))	('depletion', 'Var', (154, 163))	('breast tumor', 'Phenotype', 'HP:0100013', (45, 57))	('breast tumor', 'Disease', 'MESH:D001943', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cytokine signaling', 'MPA', (130, 148))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('altered', 'Reg', (122, 129))
45034	27914000	In mice models of breast cancer, the CD11b+ Ly6Chigh MDSCs recruited to the pre-metastatic lung secrete the ECM proteoglycan versican, which facilitates mesenchymal-to-epithelial transition of breast tumor cells, enhances their proliferation, and accelerates metastases.	('breast tumor', 'Disease', 'MESH:D001943', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('metastases', 'Disease', (259, 269))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('mesenchymal-to-epithelial transition', 'CPA', (153, 189))	('accelerates', 'PosReg', (247, 258))	('mice', 'Species', '10090', (3, 7))	('facilitates', 'PosReg', (141, 152))	('breast tumor', 'Disease', (193, 205))	('CD11b+ Ly6Chigh', 'Var', (37, 52))	('breast cancer', 'Disease', (18, 31))	('proliferation', 'CPA', (228, 241))	('enhances', 'PosReg', (213, 221))	('metastases', 'Disease', 'MESH:D009362', (259, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('breast tumor', 'Phenotype', 'HP:0100013', (193, 205))
45035	27914000	Importantly, knockdown of versican significantly decreases the metastatic burden in the lung and versican is found to be upregulated more so in metastatic lungs of patients compared to healthy controls, implicating the importance of ECM in creating a tumor-hospitable niche.	('versican', 'Gene', (97, 105))	('tumor', 'Disease', (251, 256))	('decreases', 'NegReg', (49, 58))	('versican', 'Gene', (26, 34))	('upregulated', 'PosReg', (121, 132))	('metastatic burden in the lung', 'CPA', (63, 92))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('patients', 'Species', '9606', (164, 172))	('knockdown', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
45037	27914000	The CD11b+ Gb1+ MDSCs recruited to the pre-metastatic sites adhere to the remodeled ECM and secrete matrix metalloproteinases (MMPs), which degrade the matrix collagen releasing collagen IV peptides.	('Gb1', 'Gene', '2550', (11, 14))	('CD11b+', 'Var', (4, 10))	('matrix collagen releasing collagen IV peptides', 'MPA', (152, 198))	('degrade', 'NegReg', (140, 147))	('Gb1', 'Gene', (11, 14))
45043	27914000	The interaction between fibronectin and alpha4beta1 is essential for formation of VEGFR1+ HPC clusters, and inhibition of these clusters prevents metastasis.	('fibronectin', 'Gene', (24, 35))	('interaction', 'Interaction', (4, 15))	('VEGFR1', 'Gene', (82, 88))	('metastasis', 'CPA', (146, 156))	('prevents', 'NegReg', (137, 145))	('fibronectin', 'Gene', '2335', (24, 35))	('inhibition', 'Var', (108, 118))	('VEGFR1', 'Gene', '2321', (82, 88))
45057	27914000	S100A4+ fibroblasts mediate stromal tenascin C deposition in the lung and metastatic outgrowth of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('S100A4+', 'Var', (0, 7))	('tenascin C', 'Gene', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tenascin C', 'Gene', '3371', (36, 46))	('metastatic outgrowth', 'CPA', (74, 94))
45059	27914000	The disruption of interactions between the tumor cell integrins and the newly created ECM of the secondary site prevents acquisition of stem-like phenotype and limits metastatic tumor growth.	('tumor', 'Disease', (178, 183))	('acquisition', 'CPA', (121, 132))	('prevents', 'NegReg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('interactions', 'Interaction', (18, 30))	('limits', 'NegReg', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('disruption', 'Var', (4, 14))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
45102	27914000	In pre-clinical models, normalizing the tumor stroma through the inhibition of TGF-beta signaling decreases collagen deposition and increases vascular permeability, significantly slowing down tumor growth and enhancing therapeutic response.	('TGF-beta', 'Gene', (79, 87))	('tumor', 'Disease', (192, 197))	('tumor stroma', 'Disease', (40, 52))	('collagen deposition', 'MPA', (108, 127))	('enhancing', 'PosReg', (209, 218))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('therapeutic response', 'CPA', (219, 239))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('slowing down', 'NegReg', (179, 191))	('increases', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('inhibition', 'Var', (65, 75))	('decreases', 'NegReg', (98, 107))	('tumor stroma', 'Disease', 'MESH:D009369', (40, 52))	('tumor', 'Disease', (40, 45))	('vascular permeability', 'MPA', (142, 163))	('TGF-beta', 'Gene', '7040', (79, 87))
45109	27914000	Novel approaches of depleting copper with tetrathiomolybdate in phase I and phase II clinical trials decrease lung metastasis, LOX activity, and collagen cross-linking in high-risk breast cancer patients.	('lung metastasis', 'Disease', (110, 125))	('depleting', 'Var', (20, 29))	('lung metastasis', 'Disease', 'MESH:D009362', (110, 125))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('decrease lung', 'Phenotype', 'HP:0002089', (101, 114))	('collagen cross-linking', 'CPA', (145, 167))	('tetrathiomolybdate', 'Chemical', 'MESH:C020809', (42, 60))	('breast cancer', 'Disease', (181, 194))	('patients', 'Species', '9606', (195, 203))	('copper', 'Chemical', 'MESH:D003300', (30, 36))	('decrease', 'NegReg', (101, 109))	('LOX activity', 'MPA', (127, 139))
45134	21336636	Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 accounting for about 5% of all breast cancers.	('BRCA1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancers', 'Disease', 'MESH:D001943', (129, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('breast cancers', 'Disease', (129, 143))	('caused by', 'Reg', (33, 42))	('breast cancers', 'Phenotype', 'HP:0003002', (14, 28))	('BRCA2', 'Gene', (92, 97))	('breast cancers', 'Disease', 'MESH:D001943', (14, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('mutations', 'Var', (43, 52))	('breast cancers', 'Disease', (14, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA2', 'Gene', '675', (92, 97))	('breast cancers', 'Phenotype', 'HP:0003002', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
45138	21336636	Furthermore, we will focus on the histology, the immunophenotype and genotype of breast cancers caused by mutations in BRCA1 and BRCA2 genes and the other high or moderate penetrance breast cancer susceptibility genes.	('caused', 'Reg', (96, 102))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('breast cancers', 'Disease', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('BRCA1', 'Gene', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('BRCA2', 'Gene', (129, 134))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('BRCA2', 'Gene', '675', (129, 134))	('mutations', 'Var', (106, 115))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('breast cancer', 'Disease', (183, 196))	('BRCA1', 'Gene', '672', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
45146	21336636	With the knowledge of today, only in about 5% of all the breast cancer cases, the disease will occur as part of a hereditary cancer susceptibility syndrome, caused by mutations in high penetrance susceptibility genes.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('hereditary cancer', 'Disease', 'MESH:D009369', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('caused by', 'Reg', (157, 166))	('mutations', 'Var', (167, 176))	('hereditary cancer', 'Disease', (114, 131))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
45147	21336636	A substantial proportion of hereditary breast cancers, about 16%, can be attributed to germline mutations in either of the BRCA (breast cancer 1 and 2) early onset genes.	('hereditary breast cancers', 'Disease', 'MESH:D001943', (28, 53))	('BRCA', 'Gene', (123, 127))	('attributed', 'Reg', (73, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('hereditary breast cancers', 'Disease', (28, 53))	('breast cancer 1 and 2', 'Gene', '672', (129, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('germline mutations', 'Var', (87, 105))	('BRCA', 'Gene', '672', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
45159	21336636	At the same time, families with high frequencies of male breast cancer were found to carry the BRCA2 mutation.	('BRCA2', 'Gene', '675', (95, 100))	('male breast cancer', 'Disease', 'MESH:D018567', (52, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('male breast cancer', 'Disease', (52, 70))	('high frequencies of male breast', 'Phenotype', 'HP:0000771', (32, 63))	('BRCA2', 'Gene', (95, 100))	('mutation', 'Var', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
45160	21336636	Carriers of the BRCA1 and BRCA2 mutations do not only develop breast cancer and ovarian cancer but also bear an increased risk for developing Fallopian tube, colon, melanoma, prostate and pancreatic cancer.	('prostate', 'Disease', (175, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('BRCA2', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('mutations', 'Var', (32, 41))	('breast cancer', 'Disease', (62, 75))	('develop', 'PosReg', (54, 61))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('melanoma', 'Disease', (165, 173))	('BRCA2', 'Gene', '675', (26, 31))	('Fallopian tube', 'Disease', (142, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('BRCA1', 'Gene', '672', (16, 21))	('BRCA1', 'Gene', (16, 21))	('ovarian cancer', 'Disease', (80, 94))	('colon', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
45165	21336636	Mutations in the RING finger domain inactivate BRCA E3 ligase and have an effect on the other tumor suppressor activities of BRCA1.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('inactivate', 'NegReg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BRCA', 'Gene', '672', (125, 129))	('BRCA1', 'Gene', '672', (125, 130))	('tumor', 'Disease', (94, 99))	('BRCA', 'Gene', (125, 129))	('Mutations', 'Var', (0, 9))	('BRCA1', 'Gene', (125, 130))	('effect', 'Reg', (74, 80))	('BRCA', 'Gene', '672', (47, 51))	('BRCA', 'Gene', (47, 51))
45192	21336636	The Breast Cancer Information Core (BIC) database has recorded 1,639 and 1,853 distinct mutations, polymorphisms and variants in the BRCA1 and BRCA2 genes, respectively (data 2010).	('BRCA2', 'Gene', '675', (143, 148))	('Breast Cancer', 'Phenotype', 'HP:0003002', (4, 17))	('polymorphisms', 'Var', (99, 112))	('Breast Cancer', 'Disease', (4, 17))	('mutations', 'Var', (88, 97))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('variants', 'Var', (117, 125))	('BRCA1', 'Gene', '672', (133, 138))	('Breast Cancer', 'Disease', 'MESH:D001943', (4, 17))	('BRCA2', 'Gene', (143, 148))	('BRCA1', 'Gene', (133, 138))
45193	21336636	Most mutations found in the breast and ovarian cancer families are predicted to truncate the protein product, which will lead to shortened and non-functional BRCA1 and BRCA2 proteins.	('non-functional', 'NegReg', (143, 157))	('BRCA2', 'Gene', '675', (168, 173))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (28, 53))	('BRCA1', 'Gene', (158, 163))	('protein', 'Protein', (93, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))	('mutations', 'Var', (5, 14))	('proteins', 'Protein', (174, 182))	('truncate', 'NegReg', (80, 88))	('BRCA2', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('shortened', 'NegReg', (129, 138))	('BRCA1', 'Gene', '672', (158, 163))
45194	21336636	These mutations will cover approximately 70% of the BRCA1 mutations and 90% of the BRCA2 mutations in linked families, as estimated by the Breast Cancer Linkage Consortium (BCLC).	('mutations', 'Var', (58, 67))	('BRCA1', 'Gene', '672', (52, 57))	('BRCA2', 'Gene', '675', (83, 88))	('Breast Cancer', 'Disease', 'MESH:D001943', (139, 152))	('BRCA1', 'Gene', (52, 57))	('Breast Cancer', 'Phenotype', 'HP:0003002', (139, 152))	('mutations', 'Var', (89, 98))	('Breast Cancer', 'Disease', (139, 152))	('BRCA2', 'Gene', (83, 88))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))
45195	21336636	Large-scale rearrangements including insertions, deletions or duplications of more than 500 kb of DNA have also been identified.	('DNA', 'Gene', (98, 101))	('deletions', 'Var', (49, 58))	('duplications', 'Var', (62, 74))	('insertions', 'Var', (37, 47))	('men', 'Species', '9606', (21, 24))
45198	21336636	According to the BIC database, approximately half of the unique BRCA1 and BRCA2 variants detected (excluding common polymorphisms) are missense variants of unknown pathogenic potential, termed "unclassified variants".	('BRCA1', 'Gene', '672', (64, 69))	('BRCA1', 'Gene', (64, 69))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('variants', 'Var', (80, 88))
45199	21336636	For the others, the subtle alteration might not alter the function of the protein and there might also be insufficient information about the family history to classify these unclassified variants as cancer predisposing changes.	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('variants', 'Var', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (199, 205))
45200	21336636	It has been stated that a new approach is needed to improve the association between these unclassified variants and breast cancer risk, and that using histopathology data of tumors from carries of an unclassified variant could be helpful.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('variants', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('association', 'Interaction', (64, 75))
45207	21336636	However, certain mutations in BRCA1 and BRCA2 have been observed to be common in specific populations.	('BRCA1', 'Gene', (30, 35))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (30, 35))	('mutations', 'Var', (17, 26))	('BRCA2', 'Gene', '675', (40, 45))
45208	21336636	Such founder mutations in BRCA1 and BRCA2 have been described in French Canadian, Swedes, Icelandic women, Norwegians, Finns, Dutch women, Russians, Japanese women and African Americans.	('women', 'Species', '9606', (132, 137))	('BRCA1', 'Gene', (26, 31))	('BRCA2', 'Gene', (36, 41))	('BRCA2', 'Gene', '675', (36, 41))	('women', 'Species', '9606', (158, 163))	('BRCA1', 'Gene', '672', (26, 31))	('mutations', 'Var', (13, 22))	('women', 'Species', '9606', (100, 105))
45209	21336636	Three founder mutations are very commonly found in the Ashkenazi Jewish population, the 185delAG and 5382insC in BRCA1 and 6147delT in BRCA2.	('BRCA2', 'Gene', (135, 140))	('5382insC', 'Mutation', 'c.5382insC', (101, 109))	('BRCA1', 'Gene', (113, 118))	('6147delT', 'Var', (123, 131))	('185delAG', 'Mutation', 'c.185delAG', (88, 96))	('6147delT', 'Mutation', 'c.6147delT', (123, 131))	('BRCA2', 'Gene', '675', (135, 140))	('5382insC', 'Var', (101, 109))	('185delAG', 'Var', (88, 96))	('BRCA1', 'Gene', '672', (113, 118))
45212	21336636	In Ashkenazi Jewish women with breast cancer, the 185delAG mutation in BRCA1 is found in 20%.	('BRCA1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('185delAG', 'Mutation', 'c.185delAG', (50, 58))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('women', 'Species', '9606', (20, 25))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('185delAG', 'Var', (50, 58))	('BRCA1', 'Gene', '672', (71, 76))
45214	21336636	In Iceland, a single BRCA2 mutation 999del5 has been identified and is present in the majority of familial breast cancer cases in this population.	('BRCA2', 'Gene', '675', (21, 26))	('999del5', 'Mutation', 'c.999del5', (36, 43))	('familial breast cancer', 'Disease', 'MESH:D001943', (98, 120))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('familial breast cancer', 'Disease', (98, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('BRCA2', 'Gene', (21, 26))
45218	21336636	The remaining histological types of breast cancer occur about equally in BRCA1 mutation associated tumors and in sporadic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('BRCA1', 'Gene', '672', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('sporadic breast cancer', 'Disease', (113, 135))	('mutation', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA1', 'Gene', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('tumors', 'Disease', (99, 105))
45221	21336636	When considering the age of onset of these BRCA1 mutation carriers, less than 50 years of age compared to age above 50 years, significant differences in grade (higher) and in percentage of medullary type (more cases), of breast cancer are seen in the younger population.	('BRCA1', 'Gene', (43, 48))	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('BRCA1', 'Gene', '672', (43, 48))	('breast cancer', 'Disease', (221, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))
45222	21336636	With regard to pre-invasive breast lesions, it has initially been reported that ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are seen less frequently in BRCA1 mutation carriers, being 41% and 2% respectively versus 56% and 6% in non-carriers.	('BRCA1', 'Gene', (177, 182))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (80, 96))	('LCIS', 'Phenotype', 'HP:0030076', (143, 147))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (87, 104))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (124, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (80, 104))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (116, 141))	('mutation', 'Var', (183, 191))	('BRCA1', 'Gene', '672', (177, 182))	('ductal carcinoma', 'Disease', 'MESH:D044584', (80, 96))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (116, 141))	('ductal carcinoma', 'Disease', (80, 96))	('lobular carcinoma in situ', 'Disease', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
45224	21336636	Studies investigating the occurrence of premalignant lesions in prophylactic mastectomies of BRCA1 mutation carriers usually showed more frequent occurrence of premalignant lesions.	('BRCA1', 'Gene', '672', (93, 98))	('BRCA1', 'Gene', (93, 98))	('mutation', 'Var', (99, 107))
45227	21336636	The immunophenotype of the BRCA1 mutation related breast cancers (Table 2) is first of all characterized by a low expression of the estrogen receptor alpha (ERalpha).	('estrogen receptor alpha', 'Gene', (132, 155))	('ERalpha', 'Gene', (157, 164))	('mutation', 'Var', (33, 41))	('BRCA1', 'Gene', '672', (27, 32))	('estrogen receptor alpha', 'Gene', '2099', (132, 155))	('ERalpha', 'Gene', '2099', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('BRCA1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (114, 124))	('breast cancers', 'Phenotype', 'HP:0003002', (50, 64))	('low', 'NegReg', (110, 113))	('breast cancers', 'Disease', 'MESH:D001943', (50, 64))	('breast cancers', 'Disease', (50, 64))
45229	21336636	Subsequent reports confirmed this observation and in addition described a significant relationship between low ERalpha on the one hand and high grade and an earlier age of onset on the other.	('ERalpha', 'Gene', '2099', (111, 118))	('high grade', 'CPA', (139, 149))	('ERalpha', 'Gene', (111, 118))	('low', 'Var', (107, 110))
45230	21336636	In contrast, overexpression of estrogen receptor beta (ERbeta) is seen in breast cancers of BRCA1 mutation carriers.	('breast cancers', 'Disease', 'MESH:D001943', (74, 88))	('breast cancers', 'Disease', (74, 88))	('estrogen receptor beta', 'Gene', (31, 53))	('mutation', 'Var', (98, 106))	('ERbeta', 'Gene', (55, 61))	('estrogen receptor beta', 'Gene', '2100', (31, 53))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('overexpression', 'PosReg', (13, 27))	('BRCA1', 'Gene', '672', (92, 97))	('ERbeta', 'Gene', '2100', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('BRCA1', 'Gene', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
45233	21336636	Furthermore, HER-2/neu amplifications among BRCA1 tumors have only rarely been reported.	('BRCA1 tumors', 'Disease', 'MESH:D009369', (44, 56))	('HER-2/neu', 'Gene', (13, 22))	('HER-2/neu', 'Gene', '2064', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('amplifications', 'Var', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('BRCA1 tumors', 'Disease', (44, 56))
45237	21336636	Also the expression of p27Kip1 is very low in BRCA1 related breast cancers and this is seen together with high levels of cyclin E. Mutations in the TP53 gene are seen in 30%-77% of BRCA1 tumors whereas they are only present in about 20% of sporadic controls.	('TP53', 'Gene', (148, 152))	('BRCA1 tumors', 'Disease', 'MESH:D009369', (181, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('breast cancers', 'Disease', (60, 74))	('p27Kip1', 'Gene', (23, 30))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('p27Kip1', 'Gene', '1027', (23, 30))	('BRCA1', 'Gene', '672', (46, 51))	('TP53', 'Gene', '7157', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('BRCA1', 'Gene', (46, 51))	('BRCA1', 'Gene', '672', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('BRCA1', 'Gene', (181, 186))	('BRCA1 tumors', 'Disease', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Mutations', 'Var', (131, 140))
45239	21336636	Furthermore, the distribution of the TP53 mutations might be influenced by the BRCA1 and BRCA2 genes.	('BRCA2', 'Gene', '675', (89, 94))	('BRCA1', 'Gene', '672', (79, 84))	('influenced', 'Reg', (61, 71))	('BRCA1', 'Gene', (79, 84))	('BRCA2', 'Gene', (89, 94))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
45255	21336636	Promotor hypermethylation of tumor suppressor genes has been shown to be somewhat less abundant in BRCA1 germline mutation related breast cancers, although it is still clearly higher than in normal tissue.	('germline mutation', 'Var', (105, 122))	('higher', 'Reg', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BRCA1', 'Gene', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('breast cancers', 'Phenotype', 'HP:0003002', (131, 145))	('less', 'NegReg', (82, 86))	('breast cancers', 'Disease', 'MESH:D001943', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancers', 'Disease', (131, 145))	('tumor', 'Disease', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('BRCA1', 'Gene', '672', (99, 104))
45264	21336636	With regard to pre-invasive breast lesions it has been described that DCIS and LCIS in BRCA2 mutation carriers occur in the same frequency, 52% and 3% respectively compared to 56% and 6% in control individuals.	('BRCA2', 'Gene', '675', (87, 92))	('LCIS', 'Phenotype', 'HP:0030076', (79, 83))	('LCIS', 'Disease', (79, 83))	('DCIS', 'Disease', (70, 74))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('mutation', 'Var', (93, 101))	('BRCA2', 'Gene', (87, 92))
45288	21336636	Looking more specifically at the molecular genetics, BRCA2 related breast cancers show patterns of chromosomal copy-number gains and losses that are not found in sporadic controls.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('chromosomal copy-number gains', 'Var', (99, 128))	('BRCA2', 'Gene', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (67, 81))	('losses', 'NegReg', (133, 139))	('BRCA2', 'Gene', '675', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancers', 'Disease', 'MESH:D001943', (67, 81))	('breast cancers', 'Disease', (67, 81))
45289	21336636	Copy number changes more frequently occurring in BRCA2 related breast cancers are gains of 8q, 17q22-q24 and 20q13 and loss of 8p, 6q, 11q and 13q, see Table 3.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('17q22-q24', 'Var', (95, 104))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('BRCA2', 'Gene', '675', (49, 54))	('gains', 'PosReg', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('breast cancers', 'Disease', (63, 77))	('loss', 'NegReg', (119, 123))	('BRCA2', 'Gene', (49, 54))
45295	21336636	Most mutations are point mutations leading to proteins defective for sequence-specific DNA binding and activation of p53 responsive genes.	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('DNA binding', 'Interaction', (87, 98))	('proteins', 'Protein', (46, 54))	('mutations', 'Var', (5, 14))	('activation', 'PosReg', (103, 113))
45297	21336636	In BRCA1 or BRCA2 deficient cells changes were seen at TP53 codons that are not the mutation hotspots.	('BRCA1', 'Gene', '672', (3, 8))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('BRCA2', 'Gene', (12, 17))	('BRCA1', 'Gene', (3, 8))	('changes', 'Reg', (34, 41))	('BRCA2', 'Gene', '675', (12, 17))	('deficient', 'Var', (18, 27))
45298	21336636	Structural modelling showed that most of these p53 non-hot spot aminoacids are distributed in a region of the protein on the opposite side of the p53 DNA-binding surface in these BRCA1 or BRCA2 deficient cells.	('BRCA1', 'Gene', '672', (179, 184))	('BRCA2', 'Gene', '675', (188, 193))	('BRCA1', 'Gene', (179, 184))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('BRCA2', 'Gene', (188, 193))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('deficient', 'Var', (194, 203))
45299	21336636	Breast cancers with these TP53 non-hot spot mutations were associated with a significantly better prognosis when compared with TP53 mutations in conserved or structural domains.	('TP53', 'Gene', (26, 30))	('non-hot spot mutations', 'Var', (31, 53))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('mutations', 'Var', (44, 53))	('Breast cancers', 'Disease', (0, 14))	('TP53', 'Gene', '7157', (26, 30))	('TP53', 'Gene', '7157', (127, 131))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('TP53', 'Gene', (127, 131))
45300	21336636	Preliminary data suggest that BRCA1 or BRCA2 mutations influence the distribution of the TP53 mutations and the way of carcinogenesis, but additional studies must be performed to support this.	('BRCA1', 'Gene', (30, 35))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', (89, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (119, 133))	('TP53', 'Gene', '7157', (89, 93))	('mutations', 'Var', (94, 103))	('BRCA2', 'Gene', (39, 44))	('carcinogenesis', 'Disease', (119, 133))	('BRCA2', 'Gene', '675', (39, 44))	('BRCA1', 'Gene', '672', (30, 35))	('influence', 'Reg', (55, 64))
45302	21336636	Mutations in CHEK2 were originally thought to result in the Li-Fraumeni syndrome or in a Li-Fraumeni-like syndrome (mentioned above and described in Table 1), since the first CHEK2 mutations were found in these Li-Fraumeni families.	('CHEK2', 'Gene', (13, 18))	('men', 'Species', '9606', (218, 221))	('CHEK2', 'Gene', '11200', (13, 18))	('men', 'Species', '9606', (96, 99))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (89, 114))	('Mutations', 'Var', (0, 9))	('Li-Fraumeni syndrome', 'Disease', (60, 80))	('Li-Fraumeni', 'Disease', (211, 222))	('Li-Fraumeni', 'Disease', (60, 71))	('CHEK2', 'Gene', (175, 180))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (60, 80))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (211, 222))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (60, 71))	('CHEK2', 'Gene', '11200', (175, 180))	('Li-Fraumeni', 'Disease', (89, 100))	('result in', 'Reg', (46, 55))	('men', 'Species', '9606', (67, 70))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (89, 100))	('Li-Fraumeni-like syndrome', 'Disease', (89, 114))	('men', 'Species', '9606', (116, 119))
45303	21336636	More recent studies question this association, following the identification of the 1000delC and 1157T CHEK2 germline variants among breast cancer patients that otherwise show no signs of Li-Fraumeni like features.	('1000delC', 'Var', (83, 91))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (187, 198))	('CHEK2', 'Gene', '11200', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('1000delC', 'Mutation', 'c.1000delC', (83, 91))	('Li-Fraumeni', 'Disease', (187, 198))	('breast cancer', 'Disease', (132, 145))	('patients', 'Species', '9606', (146, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('CHEK2', 'Gene', (102, 107))
45309	21336636	Biallelic mutations in this gene are linked to the rare human autosomal recessive disorder called ataxia teleangiectasia (AT), causing a variety of somatic disorders as described in Table 1.	('Biallelic mutations', 'Var', (0, 19))	('causing', 'Reg', (127, 134))	('ataxia', 'Phenotype', 'HP:0001251', (98, 104))	('ataxia teleangiectasia', 'Disease', (98, 120))	('human', 'Species', '9606', (56, 61))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (62, 90))	('AT', 'Disease', 'None', (122, 124))	('autosomal recessive disorder', 'Disease', (62, 90))	('linked', 'Reg', (37, 43))	('somatic disorders', 'Disease', (148, 165))	('ataxia teleangiectasia', 'Disease', 'MESH:D001259', (98, 120))	('somatic disorders', 'Disease', 'MESH:D013001', (148, 165))
45310	21336636	A heterozygous mutation of ATM does not lead to the AT phenotype but carriers have a two to five fold risk of breast cancer (Table 1).	('AT', 'Disease', 'None', (27, 29))	('AT', 'Disease', 'None', (52, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('ATM', 'Gene', (27, 30))	('heterozygous mutation', 'Var', (2, 23))	('ATM', 'Gene', '472', (27, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
45312	21336636	Familial diffuse gastric cancer, an autosomal dominant cancer syndrome is caused by mutations in the CDH1 gene and affected women are predisposed to lobular breast cancer.	('lobular breast cancer', 'Disease', 'MESH:D013274', (149, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('caused by', 'Reg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (149, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (17, 31))	('CDH1', 'Gene', (101, 105))	('mutations', 'Var', (84, 93))	('CDH1', 'Gene', '999', (101, 105))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (36, 61))	('autosomal dominant cancer', 'Disease', (36, 61))	('gastric cancer', 'Disease', (17, 31))	('lobular breast cancer', 'Disease', (149, 170))	('women', 'Species', '9606', (124, 129))
45316	21336636	Germline mutations in PTEN can lead to a rare autosomal dominant inherited cancer syndrome, Cowden disease, characterized by a high risk of breast-, thyroid- and endometrial carcinomas and hamartomas.	('Germline mutations', 'Var', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('hamartomas', 'Phenotype', 'HP:0010566', (189, 199))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (162, 184))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lead to', 'Reg', (31, 38))	('PTEN', 'Gene', (22, 26))	('endometrial carcinomas and hamartomas', 'Disease', 'MESH:D016889', (162, 199))	('autosomal dominant inherited cancer syndrome', 'Disease', 'MESH:D009386', (46, 90))	('PTEN', 'Gene', '5728', (22, 26))	('autosomal dominant inherited cancer syndrome', 'Disease', (46, 90))	('Cowden disease', 'Disease', 'MESH:D006223', (92, 106))	('breast-', 'Disease', (140, 147))	('Cowden disease', 'Disease', (92, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))
45317	21336636	Mutations in PTEN also cause the related syndrome, Bannayan-Riley-Rivalcaba syndrome, see for more details Table 1.	('Bannayan-Riley-Rivalcaba syndrome', 'Disease', (51, 84))	('Bannayan-Riley-Rivalcaba syndrome', 'Disease', 'MESH:D006223', (51, 84))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('cause', 'Reg', (23, 28))
45323	21336636	The estimated prevalence of the most common mutation is very low and the breast cancer risk conferred by a NBS1 mutation is estimated to be low.	('mutation', 'Var', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('NBS1', 'Gene', '4683', (107, 111))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('NBS1', 'Gene', (107, 111))
45325	21336636	Mutations in FANCJ (=BRIP1) and FANCN (= PALB2) are associated with a two fold increased risk of breast cancer.	('FA', 'Phenotype', 'HP:0001994', (13, 15))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PALB2', 'Gene', '79728', (41, 46))	('BRIP1', 'Gene', '83990', (21, 26))	('associated', 'Reg', (52, 62))	('FANCN', 'Gene', '79728', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('Mutations', 'Var', (0, 9))	('FANCJ', 'Gene', (13, 18))	('FANCJ', 'Gene', '83990', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('FA', 'Phenotype', 'HP:0001994', (32, 34))	('breast cancer', 'Disease', (97, 110))	('PALB2', 'Gene', (41, 46))	('BRIP1', 'Gene', (21, 26))	('FANCN', 'Gene', (32, 37))
45334	21336636	These breast cancers develop as a consequence of mutations in different moderate to low penetrance genes, like the genes mentioned earlier (see Table 1), or in genes yet to be discovered.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (49, 58))	('men', 'Species', '9606', (121, 124))	('breast cancers', 'Phenotype', 'HP:0003002', (6, 20))	('breast cancers', 'Disease', 'MESH:D001943', (6, 20))	('breast cancers', 'Disease', (6, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))
45339	21336636	Morphologic and immunophenotypic studies of breast cancer in patients with a CHEK2 mutation has yielded conflicting results, largely due to the limited cases of breast cancers that have been found being related to this mutation.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (161, 175))	('breast cancer', 'Disease', (44, 57))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancers', 'Disease', 'MESH:D001943', (161, 175))	('mutation', 'Var', (83, 91))	('breast cancers', 'Disease', (161, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('CHEK2', 'Gene', '11200', (77, 82))	('CHEK2', 'Gene', (77, 82))
45341	21336636	Breast cancer in patients with a U157T mutation has been associated with an increased incidence of lobular carcinomas as has been described earlier.	('lobular carcinomas', 'Disease', 'MESH:D018275', (99, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (99, 117))	('patients', 'Species', '9606', (17, 25))	('lobular carcinomas', 'Disease', (99, 117))	('Breast cancer', 'Disease', (0, 13))	('U157T', 'Var', (33, 38))
45345	21336636	Prophylactic bilateral mastectomy reduces the risk of breast cancer by almost 100% in mutation carriers.	('breast cancer', 'Disease', (54, 67))	('reduces', 'NegReg', (34, 41))	('mutation', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
45346	21336636	In view of the additional high lifetime risk of ovarian cancer, especially in BRCA1 mutation carriers, these women are strongly advised to undergo BSO including the removal of the Fallopian tubes at the completion of childbearing.	('carriers', 'Reg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('women', 'Species', '9606', (109, 114))	('BRCA1', 'Gene', '672', (78, 83))	('ovarian cancer', 'Disease', (48, 62))	('BRCA1', 'Gene', (78, 83))	('mutation', 'Var', (84, 92))
45347	21336636	Preliminary results from one study suggests that the use of hormone therapy in postmenopausal women with a BRCA1 mutation was associated with a decreased risk of breast cancer.	('women', 'Species', '9606', (94, 99))	('mutation', 'Var', (113, 121))	('men', 'Species', '9606', (96, 99))	('decreased', 'NegReg', (144, 153))	('BRCA1', 'Gene', '672', (107, 112))	('men', 'Species', '9606', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA1', 'Gene', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))
45349	21336636	Due to the important role of the BRCA genes in DNA repair it could be expected that DNA cross linking agents, like cisplatin and mitomycine-c, would have an effect especially in those diseases that occur as a consequence of mutated and therefore dysfunctional BRCA1 and BRCA2 genes.	('mutated', 'Var', (224, 231))	('mitomycine-c', 'Chemical', 'MESH:D016685', (129, 141))	('BRCA', 'Gene', (260, 264))	('diseases', 'Disease', (184, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('BRCA2', 'Gene', (270, 275))	('dysfunctional BRCA1', 'Disease', (246, 265))	('BRCA', 'Gene', '672', (33, 37))	('BRCA', 'Gene', '672', (270, 274))	('BRCA', 'Gene', (33, 37))	('BRCA', 'Gene', (270, 274))	('BRCA', 'Gene', '672', (260, 264))	('BRCA2', 'Gene', '675', (270, 275))	('dysfunctional BRCA1', 'Disease', 'OMIM:604370', (246, 265))
45350	21336636	Higher tumor responses to platinum based chemotherapy have indeed been observed in patients with BRCA1 mutated ovarian cancers when compared with the effects observed in non hereditary ovarian cancer.	('mutated', 'Var', (103, 110))	('hereditary ovarian cancer', 'Disease', 'MESH:D061325', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('ovarian cancers', 'Disease', (111, 126))	('hereditary ovarian cancer', 'Disease', (174, 199))	('ovarian cancers', 'Disease', 'MESH:D010051', (111, 126))	('BRCA1', 'Gene', '672', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))	('BRCA1', 'Gene', (97, 102))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('ovarian cancers', 'Phenotype', 'HP:0100615', (111, 126))	('tumor', 'Disease', (7, 12))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('Higher', 'PosReg', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
45354	21336636	The absence of PARP leads to spontaneous single strand breaks which collapse replication forks into double strand breaks, triggering homologous recombination for repair.	('collapse', 'NegReg', (68, 76))	('triggering', 'Reg', (122, 132))	('replication forks', 'MPA', (77, 94))	('PARP', 'Gene', '142', (15, 19))	('single strand breaks', 'MPA', (41, 61))	('absence', 'Var', (4, 11))	('homologous recombination', 'MPA', (133, 157))	('PARP', 'Gene', (15, 19))
45355	21336636	However, with the loss of functional BRCA1 or BRCA2, cells will be sensitized to inhibit PARP activity, apparently leading to the persistence of the DNA lesions which are usually repaired by homologous recombination.	('BRCA2', 'Gene', (46, 51))	('DNA lesions', 'MPA', (149, 160))	('PARP', 'Gene', (89, 93))	('BRCA2', 'Gene', '675', (46, 51))	('BRCA1', 'Gene', '672', (37, 42))	('PARP', 'Gene', '142', (89, 93))	('loss of functional', 'Var', (18, 36))	('BRCA1', 'Gene', (37, 42))
45364	21336636	More studies should be performed on morphological, immunohistochemical and molecular characterization of BRCA2 related breast cancers, breast cancers caused by unclassified variants of BRCA1 and BRCA2, and breast cancers caused by other breast cancer susceptibility genes to gain insight into the development of these breast cancers, and to subsequently be able to offer clues for diagnosis and new therapeutic approaches.	('BRCA2', 'Gene', '675', (195, 200))	('breast cancers', 'Phenotype', 'HP:0003002', (206, 220))	('BRCA2', 'Gene', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('men', 'Species', '9606', (304, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('BRCA1', 'Gene', '672', (185, 190))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (325, 332))	('BRCA1', 'Gene', (185, 190))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('breast cancer', 'Disease', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('BRCA2', 'Gene', '675', (105, 110))	('breast cancers', 'Disease', 'MESH:D001943', (318, 332))	('breast cancers', 'Disease', (318, 332))	('caused', 'Reg', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('breast cancers', 'Phenotype', 'HP:0003002', (318, 332))	('breast cancers', 'Disease', (135, 149))	('BRCA2', 'Gene', (195, 200))	('breast cancers', 'Disease', 'MESH:D001943', (119, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (318, 331))	('breast cancers', 'Disease', (119, 133))	('breast cancers', 'Disease', 'MESH:D001943', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('breast cancers', 'Disease', (206, 220))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('variants', 'Var', (173, 181))	('breast cancer', 'Disease', 'MESH:D001943', (318, 331))	('breast cancers', 'Phenotype', 'HP:0003002', (119, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
45383	32352029	Additionally, METABRIC revealed that a significantly higher proportion of basal (25.8%) and luminal A (24.9%) breast cancers exhibited BCL9 genomic amplification (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('basal', 'Disease', (74, 79))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('breast cancers', 'Disease', 'MESH:D001943', (110, 124))	('breast cancers', 'Disease', (110, 124))	('luminal', 'Chemical', 'MESH:D010634', (92, 99))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('BCL9 genomic amplification', 'Var', (135, 161))
45385	32352029	Taken together, these results suggest that aberrant elevated expression of BCL9 in breast cancers is driven by BCL9 genomic amplification and/or promoter hypomethylation.	('genomic amplification', 'Var', (116, 137))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('promoter hypomethylation', 'Var', (145, 169))	('BCL9', 'Gene', (111, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BCL9', 'Gene', (75, 79))	('expression', 'MPA', (61, 71))	('elevated', 'PosReg', (52, 60))
45390	32352029	The data showed highest BCL9 expression in MCF7 and DCIS.COM but moderate expression in SUM225 compared to MCF10A, 293 T, CCH1 or T47D (Supplementary Fig.	('expression', 'MPA', (74, 84))	('T47D', 'Var', (130, 134))	('MCF10A', 'CellLine', 'CVCL:0598', (107, 113))	('SUM225', 'Var', (88, 94))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('MCF7', 'CellLine', 'CVCL:0031', (43, 47))	('BCL9 expression', 'MPA', (24, 39))	('293 T', 'CellLine', 'CVCL:0063', (115, 120))	('T47D', 'CellLine', 'CVCL:0553', (130, 134))
45393	32352029	We compared RPPA results in DCIS.COM and SUM225 cell lines, which expressed knockdown of BCL9 (BCL9-KD) and non-silencing (NS) controls (Supplementary Fig.	('BCL9', 'Gene', (89, 93))	('knockdown', 'Var', (76, 85))	('BCL9-KD', 'Gene', '607', (95, 102))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('BCL9-KD', 'Gene', (95, 102))
45394	32352029	RPPA analysis revealed that BCL9 KD resulted in downregulation of a number of oncoproteins including p-AKT, p-EGFR, p-p70S6K, integrin beta3, p-Src, p-STAT3, and p-mTOR (Supplementary Fig.	('p-STAT3', 'MPA', (149, 156))	('AKT', 'Gene', '207', (103, 106))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('Src', 'Gene', (144, 147))	('AKT', 'Gene', (103, 106))	('BCL9 KD', 'Var', (28, 35))	('integrin beta3', 'Gene', (126, 140))	('downregulation', 'NegReg', (48, 62))	('mTOR', 'Gene', '2475', (164, 168))	('Src', 'Gene', '6714', (144, 147))	('integrin beta3', 'Gene', '3690', (126, 140))	('p70S6K', 'Gene', (118, 124))	('mTOR', 'Gene', (164, 168))	('p70S6K', 'Gene', '6198', (118, 124))	('oncoproteins', 'Protein', (78, 90))
45399	32352029	PLA was also used in 293 T cells transfected with BCL9 (OE) and either beta-catenin, non-mutated wild-type (WT)-STAT3, constitutively active (CA)-STAT3, phosphorylation mutants Y705F-STAT3 or S727A-STAT3.	('Y705F-STAT3', 'Var', (177, 188))	('Y705F', 'Mutation', 'p.Y705F', (177, 182))	('S727A-STAT3', 'Var', (192, 203))	('S727A', 'Mutation', 'p.S727A', (192, 197))	('293 T', 'CellLine', 'CVCL:0063', (21, 26))
45412	32352029	Based on these results we propose that BCL9 KD resulted downregulation in transcription of a number of enhancer associated target genes involved in DCIS malignancy (Supplementary data 2).	('BCL9 KD', 'Var', (39, 46))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('downregulation', 'NegReg', (56, 70))	('DCIS malignancy', 'Disease', (148, 163))	('DCIS malignancy', 'Disease', 'MESH:D002285', (148, 163))	('transcription', 'MPA', (74, 87))
45427	32352029	A significant association was found between alphaVbeta3 knockdown and a reduction in total number of lesions, the number of invasive lesions, and the number of invasive areas (Fig.	('reduction', 'NegReg', (72, 81))	('invasive lesions', 'Disease', 'MESH:D009361', (124, 140))	('invasive lesions', 'Disease', (124, 140))	('beta3', 'Gene', (50, 55))	('beta3', 'Gene', '10312', (50, 55))	('knockdown', 'Var', (56, 65))
45450	32352029	5d, e, there was a significant loss of integrin alphaVbeta3 and MMP16 expression and colocalization in BCL9 KD compared to control DCIS xenografts.	('colocalization', 'MPA', (85, 99))	('MMP16', 'Gene', (64, 69))	('loss', 'NegReg', (31, 35))	('integrin alphaVbeta3', 'Gene', (39, 59))	('MMP16', 'Gene', '4325', (64, 69))	('expression', 'MPA', (70, 80))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('BCL9 KD', 'Var', (103, 110))	('integrin alphaVbeta3', 'Gene', '3685', (39, 59))
45470	32352029	Constitutive Y705STAT3 and PS-727-STAT3 have been observed in many types of cancers including breast cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('observed', 'Reg', (50, 58))	('cancers', 'Disease', (101, 108))	('breast cancers', 'Phenotype', 'HP:0003002', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PS-727-STAT3', 'Var', (27, 39))	('Y705STAT3', 'Var', (13, 22))	('breast cancers', 'Disease', 'MESH:D001943', (94, 108))	('breast cancers', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))
45482	32352029	Our studies further validated these findings since silencing of integrin alphaVbeta3 in our basal type DCIS.COM cells led to in vivo inhibition of invasion.	('silencing', 'Var', (51, 60))	('integrin alphaVbeta3', 'Gene', (64, 84))	('invasion', 'CPA', (147, 155))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('inhibition', 'NegReg', (133, 143))	('integrin alphaVbeta3', 'Gene', '3685', (64, 84))
45496	32352029	Therefore, high co-expression of MMP16 and integrin alphavbeta3 could serve as an indication of poor prognosis in breast cancer patients and disruption of the binding between these two proteins is a possibility for prevention of DCIS invasive progression.	('MMP16', 'Gene', '4325', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('integrin alphavbeta3', 'Gene', (43, 63))	('binding', 'Interaction', (159, 166))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('DCIS', 'Disease', (229, 233))	('MMP16', 'Gene', (33, 38))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))	('disruption', 'Var', (141, 151))	('patients', 'Species', '9606', (128, 136))	('integrin alphavbeta3', 'Gene', '3685', (43, 63))	('breast cancer', 'Disease', (114, 127))
45503	32352029	We also propose that in breast cancers with aberrant BCL9 expression, BCL9, through the regulation of enhancers may result the expression of multiple oncogenic targets to drive DCIS malignancy (Model: Supplementary Fig.	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('result', 'Reg', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancers', 'Disease', 'MESH:D001943', (24, 38))	('expression', 'MPA', (127, 137))	('breast cancers', 'Disease', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('DCIS malignancy', 'Disease', (177, 192))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('BCL9', 'Gene', (53, 57))	('aberrant', 'Var', (44, 52))	('DCIS malignancy', 'Disease', 'MESH:D002285', (177, 192))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
45555	31546097	MCs are associated with 90-95% of all ductal carcinoma in situ (DCIS) cases as well as some high risk invasive cancers.	('invasive cancers', 'Disease', 'MESH:D009362', (102, 118))	('MCs', 'Var', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ductal carcinoma', 'Disease', 'MESH:D044584', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ductal carcinoma', 'Disease', (38, 54))	('invasive cancers', 'Disease', (102, 118))	('associated', 'Reg', (8, 18))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (38, 54))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (38, 62))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
45556	31546097	The presence of MCs in invasive ductal carcinoma (IDC) patients positively correlates with tumor aggressiveness as indicated by greater tumor volume, increased lymph node involvement, and decreased 8-year patient survival.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (32, 48))	('increased', 'PosReg', (150, 159))	('invasive ductal carcinoma', 'Disease', (23, 48))	('tumor aggressiveness', 'Disease', (91, 111))	('tumor', 'Disease', (91, 96))	('lymph node involvement', 'CPA', (160, 182))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('increased lymph node involvement', 'Phenotype', 'HP:0002716', (150, 182))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (205, 212))	('tumor', 'Disease', (136, 141))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (91, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('MCs', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('presence', 'Var', (4, 12))	('IDC', 'Gene', '4000', (50, 53))	('decreased', 'NegReg', (188, 197))	('IDC', 'Gene', (50, 53))	('greater', 'PosReg', (128, 135))	('8-year patient survival', 'CPA', (198, 221))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('patients', 'Species', '9606', (55, 63))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (23, 48))
45561	31546097	Collectively, these observations suggest that HA MCs may actively promote tumor progression and consequently, increase metastatic potential.	('increase', 'PosReg', (110, 118))	('HA MCs', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('promote', 'PosReg', (66, 73))	('metastatic potential', 'CPA', (119, 139))	('tumor', 'Disease', (74, 79))	('HA', 'Chemical', 'MESH:D017886', (46, 48))
45578	31546097	Human mammary epithelial cell lines from the MCF10A cell line series - MCF10A, MCF10DCIS.com, and MCF10CA1a (Karmanos Institute) - were cultured in 1:1 DMEM/F12 (Gibco) supplemented with 5% horse serum (Invitrogen), 1% penicillin/streptomycin (Gibco), 10 mug/ml insulin (Sigma), 0.5 mug/ml hydrocortisone (Sigma), 100 ng/ml cholera toxin (Sigma), and 20 ng/ml EGF (Millipore).	('insulin', 'Gene', '3630', (262, 269))	('Human', 'Species', '9606', (0, 5))	('MCF10A', 'CellLine', 'CVCL:0598', (45, 51))	('MCF10CA1a', 'Var', (98, 107))	('MCF10A', 'CellLine', 'CVCL:0598', (71, 77))	('MCF10', 'CellLine', 'CVCL:5555', (98, 103))	('EGF', 'Gene', (360, 363))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (79, 92))	('MCF10', 'CellLine', 'CVCL:5555', (71, 76))	('penicillin', 'Chemical', 'MESH:D010406', (219, 229))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('DMEM', 'Chemical', '-', (152, 156))	('MCF10', 'CellLine', 'CVCL:5555', (79, 84))	('EGF', 'Gene', '1950', (360, 363))	('insulin', 'Gene', (262, 269))	('streptomycin', 'Chemical', 'MESH:D013307', (230, 242))	('MCF10', 'CellLine', 'CVCL:5555', (45, 50))
45626	31546097	Taken together, these analyses point to a potential link between the presence of mammographically-detected MCs in tumorigenic breast tissue and the upregulation of IL-8.	('presence', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('upregulation', 'PosReg', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MCs', 'Gene', (107, 110))	('IL-8', 'Protein', (164, 168))	('tumor', 'Disease', (114, 119))
45627	31546097	To more directly investigate how the progression of breast cancer influences responses to HA mineral, we cultured three isogenically matched MCF10 cell lines - normal MCF10A (10A), premalignant MCF10DCIS.com (DCIS), and metastatic MCF10CA1a (CA1a) - in mineral-containing scaffolds and used non-mineral-containing scaffolds as controls.	('MCF10', 'CellLine', 'CVCL:5555', (141, 146))	('MCF10', 'CellLine', 'CVCL:5555', (194, 199))	('MCF10CA1a', 'Var', (231, 240))	('MCF10', 'CellLine', 'CVCL:5555', (231, 236))	('DCIS', 'Phenotype', 'HP:0030075', (209, 213))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('MCF10', 'CellLine', 'CVCL:5555', (167, 172))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('HA', 'Chemical', 'MESH:D017886', (90, 92))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MCF10A', 'CellLine', 'CVCL:0598', (167, 173))	('influences', 'Reg', (66, 76))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (194, 207))
45676	31546097	In contrast, non-transformed MCF10A cells did not exhibit increased IL-8 secretion in the HA-scaffolds, which raises the possibility that MCs may be pro-malignant but may not induce cancerous transformation without additional genetic or environmental drivers.	('pro-malignant', 'CPA', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('MCs', 'Var', (138, 141))	('MCF10A', 'CellLine', 'CVCL:0598', (29, 35))	('cancerous', 'Disease', 'MESH:D009369', (182, 191))	('HA', 'Chemical', 'MESH:D017886', (90, 92))	('secretion', 'MPA', (73, 82))	('cancerous', 'Disease', (182, 191))	('induce', 'Reg', (175, 181))
45685	31546097	Although alphavbeta3 integrin expression levels have not been characterized in the MCF10 cell line series, integrin-mediated signaling events appear to play a more critical role in the transformed MCF10DCIS versus the non-transformed MCF10A cells.	('MCF10A', 'CellLine', 'CVCL:0598', (234, 240))	('DCIS', 'Phenotype', 'HP:0030075', (202, 206))	('MCF10', 'CellLine', 'CVCL:5555', (197, 202))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (197, 206))	('MCF10DCIS', 'Var', (197, 206))	('MCF10', 'CellLine', 'CVCL:5555', (234, 239))	('integrin-mediated signaling', 'MPA', (107, 134))	('MCF10', 'CellLine', 'CVCL:5555', (83, 88))
45686	31546097	Relative to MCF10A, MCF10DCIS cells possess high levels of the activated, phosphorylated forms of ERK and AKT, which are key to integrin-mediated signal transduction that can stimulate the expression of chemokines such as IL-8.	('AKT', 'Gene', (106, 109))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('ERK', 'Gene', '5594', (98, 101))	('stimulate', 'PosReg', (175, 184))	('expression', 'MPA', (189, 199))	('MCF10A', 'CellLine', 'CVCL:0598', (12, 18))	('ERK', 'Gene', (98, 101))	('AKT', 'Gene', '207', (106, 109))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (20, 29))	('MCF10DCIS', 'Var', (20, 29))
45689	31546097	In contrast to MCF10A, MCF10DCIS cells express the alternative isoform CD44v.	('CD44', 'Gene', '960', (71, 75))	('CD44', 'Gene', (71, 75))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('MCF10A', 'CellLine', 'CVCL:0598', (15, 21))	('MCF10DCIS', 'Var', (23, 32))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (23, 32))
45701	31546097	This observation supports the idea that HA-mediated changes in phenotypic state may in fact persist across multiple generations and result in more invasive cell colonies even after initial exposure to HA mineral, which often presents heterogeneously in breast tissue.	('result in', 'Reg', (132, 141))	('invasive cell colonies', 'CPA', (147, 169))	('HA', 'Chemical', 'MESH:D017886', (201, 203))	('more', 'PosReg', (142, 146))	('HA', 'Chemical', 'MESH:D017886', (40, 42))	('changes', 'Var', (52, 59))
45785	26391857	In this single institution prospective study we found that the use of FFDM plus DBT resulted in a significant decrease in recall rates during baseline screening mammography.	('DBT', 'Gene', (80, 83))	('FFDM', 'Chemical', '-', (70, 74))	('FFDM', 'Var', (70, 74))	('decrease', 'NegReg', (110, 118))	('recall rates', 'MPA', (122, 134))
45853	24083544	Furthermore, family history was significantly associated with an increased risk of breast cancer with negative (OR = 2.60, 95% CI = 1.42 to 4.75, P = 0.002) and positive lymph nodes (OR = 2.07, 95% CI = 1.05 to 4.08, P = 0.036).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('positive lymph nodes', 'Var', (161, 181))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('family history', 'Var', (13, 27))
45993	21314937	It is known that alterations in RR levels can have significant effects on the biological properties of cells, including tumour promotion and tumour progression.	('effects', 'Reg', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('biological properties of cells', 'CPA', (78, 108))	('tumour', 'Disease', (120, 126))	('RR', 'Chemical', '-', (32, 34))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour', 'Disease', (141, 147))	('alterations', 'Var', (17, 28))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
46043	17722985	Typically in early tumorigenesis, cells incur a breakdown of the DNA replication machinery that results in an accumulation of genomic aberrations in the form of duplications, deletions, translocations, and other genomic alterations.	('duplications', 'MPA', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('breakdown', 'NegReg', (48, 57))	('deletions', 'Var', (175, 184))	('translocations', 'Var', (186, 200))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('accumulation', 'PosReg', (110, 122))	('tumor', 'Disease', (19, 24))	('genomic aberrations', 'MPA', (126, 145))
46055	17722985	In cancer cells, aberrations can turn on or off various pathways necessary for tumor development and survival.	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('turn', 'Reg', (33, 37))	('cancer', 'Disease', (3, 9))	('pathways', 'Pathway', (56, 64))	('aberrations', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
46085	17722985	In DCIS and invasive ductal carcinoma, Chromosome 8 has been shown to contain a large deletion on the 8p arm and many gains on the 8q arm.	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (12, 37))	('DCIS', 'Disease', (3, 7))	('gains', 'PosReg', (118, 123))	('invasive ductal carcinoma', 'Disease', (12, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('deletion', 'Var', (86, 94))
46088	17722985	Recently, a study examining Chromosome 8 in invasive ductal carcinoma cell lines using high resolution Chromosome 8-specific tiling arrays was able to detect these same regions of deletion on the 8q arm.	('deletion', 'Var', (180, 188))	('invasive ductal carcinoma', 'Disease', (44, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (44, 69))
46091	17722985	In addition to localizing the deletion of CDH1 (p' = 0.0028), we were able to identify many high-confidence deletions in the 16q arm (Figure S3).	('deletion', 'Var', (30, 38))	('CDH1', 'Gene', '999', (42, 46))	('CDH1', 'Gene', (42, 46))	('deletions', 'Var', (108, 117))
46116	17722985	The promise of aCGH is the ability to detect copy number aberrations with accuracy and high resolution.	('CGH', 'Gene', (16, 19))	('CGH', 'Gene', '3342', (16, 19))	('copy number aberrations', 'Var', (45, 68))
46151	29902386	Between 1986 and 1998, 1,410 patients were randomized to one of three arms that were all delivered over five weeks: CF-WBI (50 Gy in 25 fractions) or two HF-WBI arms (42.9 Gy in 13 fractions or 39 Gy in 13 fractions, each delivered every other day).	('patients', 'Species', '9606', (29, 37))	('HF-WBI arms', 'Disease', 'MESH:D001134', (154, 165))	('42.9 Gy', 'Var', (167, 174))	('HF-WBI arms', 'Disease', (154, 165))
46157	29902386	Eligibility criteria included T1-2 N0 M0 invasive cancers in patients who underwent BCS with negative margins on ink.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('invasive cancers', 'Disease', 'MESH:D009362', (41, 57))	('patients', 'Species', '9606', (61, 69))	('invasive cancers', 'Disease', (41, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('T1-2 N0', 'Var', (30, 37))
46164	29902386	Between 1999 and 2002, 2,236 patients were randomized to one of three arms that were all delivered over five weeks: CF-WBI (50 Gy in 25 fractions) or two HF-WBI arms (41.6 Gy in 13 fractions or 39 Gy in 13 fractions, each delivered every other day).	('patients', 'Species', '9606', (29, 37))	('41.6 Gy', 'Var', (167, 174))	('HF-WBI arms', 'Disease', 'MESH:D001134', (154, 165))	('HF-WBI arms', 'Disease', (154, 165))
46167	29902386	At 10 years, breast induration, edema, and telangiectasias were significantly reduced in the 39 Gy arm compared to the 50 Gy arm, while there were no significant differences between the 41.6 Gy and 50 Gy arm.	('telangiectasias', 'Disease', (43, 58))	('telangiectasias', 'Disease', 'MESH:D013684', (43, 58))	('edema', 'Disease', 'MESH:D004487', (32, 37))	('edema', 'Phenotype', 'HP:0000969', (32, 37))	('breast induration', 'CPA', (13, 30))	('reduced', 'NegReg', (78, 85))	('39 Gy', 'Var', (93, 98))	('edema', 'Disease', (32, 37))
46171	29902386	At 10 years, breast shrinkage, telangiectasias, and edema were significantly reduced in the 40 Gy arm compared to the 50 Gy arm, while there were no significant differences in breast induration, shoulder stiffness, or arm edema.	('edema', 'Disease', 'MESH:D004487', (52, 57))	('edema', 'Phenotype', 'HP:0000969', (52, 57))	('shoulder', 'CPA', (195, 203))	('shoulder stiffness', 'Phenotype', 'HP:0009742', (195, 213))	('edema', 'Disease', 'MESH:D004487', (222, 227))	('edema', 'Disease', (52, 57))	('edema', 'Phenotype', 'HP:0000969', (222, 227))	('telangiectasias', 'Disease', (31, 46))	('reduced', 'NegReg', (77, 84))	('telangiectasias', 'Disease', 'MESH:D013684', (31, 46))	('breast shrinkage', 'CPA', (13, 29))	('edema', 'Disease', (222, 227))	('40 Gy', 'Var', (92, 97))
46176	29902386	From 2004 to 2007, 915 patients were randomized to one of three dose regimens: CF-WBI (50 Gy in 25 fractions) or one of two HF-WBI arms (30 Gy or 28.5 Gy in five once-weekly fractions of 6 Gy or 5.7 Gy, respectively).	('patients', 'Species', '9606', (23, 31))	('HF-WBI arms', 'Disease', (124, 135))	('HF-WBI arms', 'Disease', 'MESH:D001134', (124, 135))	('30 Gy', 'Var', (137, 142))
46177	29902386	Two-year and three-year breast cosmesis was significantly worse for the 30 Gy arm compared to the 50 Gy arm (p<0.001) but there were no significant differences between the 28.5 Gy and 50 Gy arms.	('30 Gy', 'Var', (72, 77))	('breast cosmesis', 'Disease', (24, 39))	('breast cosmesis', 'Disease', 'MESH:D001943', (24, 39))	('worse', 'NegReg', (58, 63))
46185	29902386	Overall acute grade two (47% vs. 78%, p<0.001) and grade three (0% vs. 5%, p=0.01) toxicities were lower with HF-WBI compared to CF-WBI, with significantly lower individual components of fatigue, pruritus, breast pain, dermatitis, and hyperpigmentation.	('breast pain', 'Disease', 'MESH:D059373', (206, 217))	('hyperpigmentation', 'Disease', 'MESH:D017495', (235, 252))	('breast pain', 'Disease', (206, 217))	('toxicities', 'Disease', 'MESH:D064420', (83, 93))	('pruritus', 'Phenotype', 'HP:0000989', (196, 204))	('lower', 'NegReg', (156, 161))	('lower', 'NegReg', (99, 104))	('toxicities', 'Disease', (83, 93))	('pruritus', 'Disease', (196, 204))	('pruritus', 'Disease', 'MESH:D011537', (196, 204))	('fatigue', 'Disease', (187, 194))	('fatigue', 'Phenotype', 'HP:0012378', (187, 194))	('dermatitis', 'Disease', 'MESH:D003872', (219, 229))	('dermatitis', 'Disease', (219, 229))	('pain', 'Phenotype', 'HP:0012531', (213, 217))	('dermatitis', 'Phenotype', 'HP:0011123', (219, 229))	('hyperpigmentation', 'Disease', (235, 252))	('fatigue', 'Disease', 'MESH:D005221', (187, 194))	('HF-WBI', 'Var', (110, 116))
46197	29902386	None of the major trials reported on acute toxicity; however, in the MDACC trial, overall acute grade two and three effects were significantly reduced with HF-WBI as compared to CF-WBI, and several patient-reported functional outcomes were improved at six months.	('toxicity', 'Disease', (43, 51))	('improved', 'PosReg', (240, 248))	('reduced', 'NegReg', (143, 150))	('patient', 'Species', '9606', (198, 205))	('HF-WBI', 'Var', (156, 162))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))
46198	29902386	Additionally, in a prospective observational study of 2,309 patients, patients who received HF-WBI had significantly lower physician-assessed moist desquamation (6.6% vs. 28.5%, p<0.001) and any grade two or higher dermatitis (27.4% vs. 62.6%, p< 0.001) compared to those who received CF-WBI.	('patients', 'Species', '9606', (70, 78))	('desquamation', 'Phenotype', 'HP:0040189', (148, 160))	('patients', 'Species', '9606', (60, 68))	('lower', 'NegReg', (117, 122))	('dermatitis', 'Disease', 'MESH:D003872', (215, 225))	('dermatitis', 'Disease', (215, 225))	('moist desquamation', 'MPA', (142, 160))	('HF-WBI', 'Var', (92, 98))	('dermatitis', 'Phenotype', 'HP:0011123', (215, 225))	('grade two', 'Disease', (195, 204))
46199	29902386	Patient-reported metrics demonstrated significantly lower pain, burning/stinging, swelling, and fatigue in those receiving HF-WBI compared to CF-WBI.	('swelling', 'CPA', (82, 90))	('pain', 'Disease', 'MESH:D010146', (58, 62))	('HF-WBI', 'Var', (123, 129))	('fatigue', 'Disease', (96, 103))	('pain', 'Disease', (58, 62))	('fatigue', 'Phenotype', 'HP:0012378', (96, 103))	('lower', 'NegReg', (52, 57))	('fatigue', 'Disease', 'MESH:D005221', (96, 103))	('burning/stinging', 'CPA', (64, 80))	('pain', 'Phenotype', 'HP:0012531', (58, 62))	('Patient', 'Species', '9606', (0, 7))
46222	29902386	The OCOG trial was notable for its sub-group analysis showing that for high-grade tumors, 10-year cumulative local recurrence was 15.6% in the HF-WBI arm compared to 4.7% in the CF-WBI arm (HR=3.08, 95% CI: 1.22-7.76).	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('HF-WBI', 'Var', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('local recurrence', 'CPA', (109, 125))	('OCOG', 'Chemical', '-', (4, 8))
46229	29902386	In subgroup analysis of those who received a boost, there was no difference in local recurrence at 10 years (HR=0.99, 95% CI: 0.76-1.29) and there was less moderate or marked breast changes in patients randomized to HF-WBI compared to CF-WBI (HR=0.86, 95% CI: 0.76-0.96).	('local recurrence', 'CPA', (79, 95))	('patients', 'Species', '9606', (193, 201))	('breast changes', 'CPA', (175, 189))	('HF-WBI', 'Var', (216, 222))
46235	29902386	Additionally, the MDACC trial, which used three-dimensional planning, did not demonstrate higher acute side effects in patients in the upper quartile of breast central axis separation or body mass index receiving HF-WBI as compared to CF-WBI, demonstrating the safety of HF-WBI in patients with large breasts.	('HF-WBI', 'Var', (213, 219))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (281, 289))	('breast central axis separation', 'Disease', (153, 183))	('large breasts', 'Phenotype', 'HP:0010313', (295, 308))	('breast central axis separation', 'Disease', 'MESH:C566610', (153, 183))
46313	29902386	Large prospective, randomized phase III trials have demonstrated that hypofractionated treatment results in equivalent tumor controls, better or improved acute and late toxicity, and better or improved breast cosmesis compared to conventionally-fractionated regimens for early-stage breast cancer.	('hypofractionated', 'Var', (70, 86))	('breast cancer', 'Disease', (283, 296))	('breast cosmesis', 'Disease', (202, 217))	('acute', 'MPA', (154, 159))	('breast cancer', 'Disease', 'MESH:D001943', (283, 296))	('equivalent tumor', 'Disease', (108, 124))	('breast cosmesis', 'Disease', 'MESH:D001943', (202, 217))	('improved', 'PosReg', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('improved', 'PosReg', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('toxicity', 'Disease', 'MESH:D064420', (169, 177))	('toxicity', 'Disease', (169, 177))	('equivalent tumor', 'Disease', 'MESH:D064386', (108, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (283, 296))
46410	20871992	All examinations were interpreted according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) with BI-RADS 4 and above treated as suspicious for malignancy.	('BI-RADS 4', 'Var', (137, 146))	('malignancy', 'Disease', (183, 193))	('malignancy', 'Disease', 'MESH:D009369', (183, 193))
46529	20871992	The other reasons for declining an MRI in consecutive order were time constraints, financial concern, no physician referral, lack of interest, medically intolerant to MRI, refusal of intravenous injection, probable additional biopsy procedures as a result of an MRI, scheduling constraints within a patient's menstrual cycle and their hormonal status, travel, gadolinium-related risks or allergies, and finally unknown reasons.	('gadolinium', 'Chemical', 'MESH:D005682', (360, 370))	('allergies', 'Disease', 'MESH:D004342', (388, 397))	('allergies', 'Phenotype', 'HP:0012393', (388, 397))	('MRI', 'Var', (262, 265))	('allergies', 'Disease', (388, 397))	('patient', 'Species', '9606', (299, 306))
46577	22361634	Nuclear staining was scored for ER, PR, Ki67, p53, p21, cyclin D1, and membranous staining for HER2/neu oncoprotein, and both nuclear and cytoplasmic staining were scored for calgranulin and psoriasin.	('p21', 'Gene', (51, 54))	('p53', 'Gene', (46, 49))	('p21', 'Gene', '644914', (51, 54))	('HER2/neu', 'Gene', '2064', (95, 103))	('p53', 'Gene', '7157', (46, 49))	('HER2/neu', 'Gene', (95, 103))	('PR', 'Gene', '5241', (36, 38))	('cyclin D1', 'Gene', '595', (56, 65))	('Ki67', 'Var', (40, 44))	('cyclin D1', 'Gene', (56, 65))
46594	22361634	Hazard ratios for HER2/neu, ER status and PR status represent a change in the risk for positive compared with the negative status.	('ER status', 'Var', (28, 37))	('HER2/neu', 'Gene', '2064', (18, 26))	('HER2/neu', 'Gene', (18, 26))	('PR', 'Gene', '5241', (42, 44))
46617	22361634	Overall, a third (31%) of women with HER2/neu+/Ki67+ DCIS developed local recurrence following breast-conserving therapy compared to 16% (26/162) with different biomarker profiles.	('DCIS', 'Var', (53, 57))	('local recurrence', 'CPA', (68, 84))	('women', 'Species', '9606', (26, 31))	('HER2/neu', 'Gene', '2064', (37, 45))	('HER2/neu', 'Gene', (37, 45))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
46735	33634620	The predictors of upstaging to an invasive lesion are a large DCIS lesion, palpable tumor, mass-forming lesion detected during mammography, lack of hormone receptor expression, high nuclear grade, diagnosis via core-needle biopsy, and the non-cribriform subtype.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('high', 'Var', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('hormone receptor', 'Protein', (148, 164))	('lack', 'Var', (140, 144))	('palpable', 'Disease', (75, 83))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('tumor', 'Disease', (84, 89))	('DCIS lesion', 'Disease', 'MESH:D002285', (62, 73))	('DCIS lesion', 'Disease', (62, 73))
46746	33634620	The KCD-7 code for DCIS is D05.1, and that for invasive breast carcinoma is C50.9.	('breast carcinoma', 'Phenotype', 'HP:0003002', (56, 72))	('invasive breast carcinoma', 'Disease', (47, 72))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('C50.9', 'Var', (76, 81))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (47, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
46747	33634620	Patients who had both D05.1 and C50.9 codes simultaneously prior to curative breast and axillary surgery were excluded from the study.	('Patients', 'Species', '9606', (0, 8))	('D05.1', 'Var', (22, 27))	('C50.9', 'Var', (32, 37))
46749	33634620	We categorized patients as having undergone BCS (N7121, N7122, or N7133) or TM (N7131 or N7134).	('N7122', 'Var', (56, 61))	('patients', 'Species', '9606', (15, 23))	('N7121', 'Var', (49, 54))	('N7131', 'Var', (80, 85))	('N7133', 'Var', (66, 71))
46751	33634620	The SLNB group was defined based on the codes for axillary surgery (P2121, P2123, or P2124), and axillary dissection (AD) was identified based on the related code (P2122).	('P2124', 'Var', (85, 90))	('P2123', 'Var', (75, 80))	('AD', 'Chemical', '-', (118, 120))	('P2121', 'Var', (68, 73))
46758	33634620	Among these, 2,874 patients (60.49%) underwent breast surgery (N7121, N7122, N7133, N7135, or N7131), and we identified 2,085 DCIS patients who fulfilled the inclusion criteria (Figure 1).	('N7122', 'Var', (70, 75))	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (19, 27))	('N7131', 'Var', (94, 99))	('N7133', 'Var', (77, 82))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('N7135', 'Var', (84, 89))	('breast surgery', 'Disease', (47, 61))	('N7121', 'Var', (63, 68))
46763	33634620	Although the sample size was extremely small, the likelihood of AD was higher in low-volume hospitals (< 100 and < 50 DCIS operations per year) than for other hospitals (OR, 2.628; 95% CI, 1.642-4.205 and OR, 3.255; 95% CI, 2.203-4.808, respectively).	('higher', 'PosReg', (71, 77))	('AD', 'Chemical', '-', (64, 66))	('AD', 'Disease', (64, 66))	('< 100', 'Var', (103, 108))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))
46783	33634620	The predictors of upstaging to an invasive lesion are large DCIS lesion, palpable tumor, mass-forming lesion detected during mammography, lack of hormone receptor expression, high nuclear grade, a diagnosis via core-needle biopsy, and the non-cribriform subtype.	('hormone receptor', 'Protein', (146, 162))	('DCIS lesion', 'Disease', 'MESH:D002285', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('high', 'Var', (175, 179))	('DCIS lesion', 'Disease', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lack', 'Var', (138, 142))	('tumor', 'Disease', (82, 87))	('palpable', 'Disease', (73, 81))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
46793	33634620	The study reported that AD was performed to achieve the final diagnosis in 5% of the women who underwent BCS for DCIS, versus in almost 20% among women who underwent a mastectomy.	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))	('women', 'Species', '9606', (85, 90))	('DCIS', 'Disease', (113, 117))	('BCS', 'Var', (105, 108))	('AD', 'Chemical', '-', (24, 26))	('women', 'Species', '9606', (146, 151))
46820	24523870	We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival.	('poorer', 'NegReg', (175, 181))	('expression', 'MPA', (34, 44))	('Syk interacting', 'Gene', (125, 140))	('mutations', 'Var', (105, 114))	('Syk', 'Protein', (30, 33))	('reduction', 'NegReg', (17, 26))	('patient', 'Species', '9606', (190, 197))
46822	24523870	In normal or cancerous mammary epithelial cells, the presence of Syk suppresses malignant growth characteristics including proliferation and invasive cell migration and its loss induces invasion and metastasis.	('malignant growth characteristics', 'CPA', (80, 112))	('induces', 'Reg', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancerous', 'Disease', 'MESH:D009369', (13, 22))	('Syk', 'Gene', (65, 68))	('presence', 'Var', (53, 61))	('loss', 'NegReg', (173, 177))	('cancerous', 'Disease', (13, 22))	('suppresses', 'NegReg', (69, 79))
46825	24523870	SYK loss has been attributed to hypermethylation of the promoter in breast cancer tissues and its loss is associated with increased cellular invasiveness.	('cellular invasiveness', 'CPA', (132, 153))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('SYK', 'Gene', (0, 3))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('loss', 'NegReg', (98, 102))	('hypermethylation', 'Var', (32, 48))	('increased', 'PosReg', (122, 131))	('loss', 'NegReg', (4, 8))
46826	24523870	Hypermethylation of the SYK promoter is associated with lower SYK mRNA and poor prognosis and metastasis in various cancers including breast, lung, pancreatic, urinary bladder cancers, mesothelioma, and melanoma; in vitro experiments confirm that re-expression of SYK by transfection or inhibitors of hypermethylation reverses the invasive and metastatic phenotype ( and for review).	('pancreatic', 'Disease', 'MESH:D010195', (148, 158))	('urinary bladder cancers', 'Disease', (160, 183))	('inhibitors', 'Var', (287, 297))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('cancers', 'Disease', (176, 183))	('bladder cancers', 'Phenotype', 'HP:0009725', (168, 183))	('mesothelioma', 'Disease', (185, 197))	('pancreatic', 'Disease', (148, 158))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('SYK', 'Gene', (264, 267))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('hypermethylation', 'Var', (301, 317))	('lower', 'NegReg', (56, 61))	('urinary bladder cancers', 'Disease', 'MESH:D001749', (160, 183))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))
46830	24523870	Recently, several studies have identified SNPs and somatic mutations of SYK associated with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('associated', 'Reg', (76, 86))	('SNPs', 'Var', (42, 46))	('SYK', 'Gene', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
46831	24523870	Examination of heterozygotic SYK knockdown mice and derivatives of these mice revealed that loss of a single SYK allele was sufficient to reduce Syk protein levels by about half.	('mice', 'Species', '10090', (43, 47))	('SYK', 'Gene', (109, 112))	('mice', 'Species', '10090', (73, 77))	('loss', 'Var', (92, 96))	('Syk protein levels', 'MPA', (145, 163))	('reduce', 'NegReg', (138, 144))
46834	24523870	In the same study, transient or stable Syk knockdown in a non-transformed human epithelial cell line MCF10A had the same effects; proliferation and invasion were enhanced.	('knockdown', 'Var', (43, 52))	('MCF10A', 'CellLine', 'CVCL:0598', (101, 107))	('enhanced', 'PosReg', (162, 170))	('proliferation', 'CPA', (130, 143))	('human', 'Species', '9606', (74, 79))	('Syk', 'Gene', (39, 42))	('invasion', 'CPA', (148, 156))
46836	24523870	SYK is located on human chromosome 9q22.2 and interestingly, allelic loss on chromosome 9q22 is associated with lymph node metastasis in primary breast cancer.	('allelic loss', 'Var', (61, 73))	('associated with', 'Reg', (96, 111))	('human', 'Species', '9606', (18, 23))	('lymph node metastasis', 'CPA', (112, 133))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
46838	24523870	To determine whether allelic loss of SYK might be associated with breast cancer invasion and progression in patient samples, we performed fluorescent in situ hybridization (FISH) to detect SYK alleles in a dual color FISH protocol.	('invasion', 'CPA', (80, 88))	('SYK', 'Gene', (37, 40))	('allelic loss', 'Var', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('patient', 'Species', '9606', (108, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('associated', 'Reg', (50, 60))
46839	24523870	The rationale for this includes the previous observation that single allelic loss of SYK in a mouse model led to enhanced invasion, proliferation, and tumor formation in the mammary gland; Syk knockdown in cells results in an epithelial-to-mesenchymal (EMT)-like transition with enhanced invasiveness; and Syk re-expression in breast cancer cell lines prevents tumor growth and metastasis in mouse models.	('enhanced', 'PosReg', (279, 287))	('tumor', 'Disease', (361, 366))	('invasiveness', 'CPA', (288, 300))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('invasion', 'CPA', (122, 130))	('mouse', 'Species', '10090', (94, 99))	('loss', 'Var', (77, 81))	('EMT', 'Gene', '16428', (253, 256))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('mouse', 'Species', '10090', (392, 397))	('knockdown', 'Var', (193, 202))	('proliferation', 'CPA', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (327, 340))	('EMT', 'Gene', (253, 256))	('SYK', 'Gene', (85, 88))	('Syk', 'Gene', (189, 192))	('prevents', 'NegReg', (352, 360))	('tumor', 'Disease', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (327, 340))	('breast cancer', 'Disease', (327, 340))	('enhanced', 'PosReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
46840	24523870	Thus, SYK allelic loss in human DCIS, particularly in combination with hypermethylation and silencing might result in invasive breast disease ultimately leading to metastasis.	('result in', 'Reg', (108, 117))	('leading to', 'Reg', (153, 163))	('invasive breast disease', 'Disease', 'MESH:D001941', (118, 141))	('silencing', 'Var', (92, 101))	('invasive breast disease', 'Phenotype', 'HP:0003002', (118, 141))	('SYK', 'Gene', (6, 9))	('metastasis', 'CPA', (164, 174))	('invasive breast disease', 'Disease', (118, 141))	('human', 'Species', '9606', (26, 31))
46841	24523870	If so, SYK status in DCIS tissues might provide a powerful prognostic tool, identifying women most likely to progress to invasive carcinoma.	('invasive carcinoma', 'Disease', (121, 139))	('women', 'Species', '9606', (88, 93))	('SYK status', 'Var', (7, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('invasive carcinoma', 'Disease', 'MESH:D009361', (121, 139))
46852	24523870	The Bacterial Artificial Chromosome (BAC) clones, RP11367F29, and RP1183L6 which span the SYK gene region at 9q22.2, were obtained from the BAC/PAC Resource at Children's Hospital Oakland Research Institute (Oakland, CA) for development of a FISH probe.	('RP11367F29', 'Var', (50, 60))	('Children', 'Species', '9606', (160, 168))	('PAC', 'Phenotype', 'HP:0006699', (144, 147))	('RP1183L6 which', 'Var', (66, 80))
46872	24523870	The mean methylation level of the control DNAs were 2.32% for the non-methylated DNA, 70.54% for the methylated DNA, and 4.70% for the normal human DNA.	('methylation level', 'MPA', (9, 26))	('methylated', 'Var', (101, 111))	('human', 'Species', '9606', (142, 147))
46884	24523870	Previously, we determined genes that were up- or down-regulated by SYK siRNA knockdown (> = 1.5 fold) in MCF10A cells cultured on collagen I fibrillar matrices.	('SYK siRNA', 'Gene', (67, 76))	('down-regulated', 'NegReg', (49, 63))	('up-', 'PosReg', (42, 45))	('knockdown', 'Var', (77, 86))	('MCF10A', 'CellLine', 'CVCL:0598', (105, 111))
46895	24523870	In order to examine whether protein loss occurred in parallel with loss of mRNA as previously reported, and whether loss was associated with methylation and/or allelic SYK gene loss, adjacent tissue sections were double labeled with anti-Syk and anti-pan keratin antibodies and then counterstained with DAPI for immunofluorescence confocal microscopy.	('protein', 'Protein', (28, 35))	('SYK', 'Gene', (168, 171))	('loss', 'NegReg', (36, 40))	('DAPI', 'Chemical', 'MESH:C007293', (303, 307))	('loss', 'NegReg', (177, 181))	('mRNA', 'MPA', (75, 79))	('loss', 'NegReg', (67, 71))	('methylation', 'Var', (141, 152))
46898	24523870	We used cBioPortal tools to access copy number and mutations for SYK in this large breast cancer study and to develop a method to discriminate between immune infiltrated invasive breast cancers and cases depleted of immune infiltration so that mRNA and protein values would more accurately reflect epithelial cells (see Methods).	('mutations', 'Var', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('large breast', 'Phenotype', 'HP:0010313', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('invasive breast cancers', 'Disease', (170, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (83, 96))	('SYK', 'Gene', (65, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('invasive breast cancers', 'Disease', 'MESH:D001943', (170, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (179, 193))
46900	24523870	Using the immune depleted subset or using a subset of 696 IDC only cases, we found that only two mutations in SYK were present, one of which would likely have an effect on function, namely A146G (data not shown).	('effect', 'Reg', (162, 168))	('function', 'MPA', (172, 180))	('A146G', 'Var', (189, 194))	('A146G', 'Mutation', 'c.146A>G', (189, 194))	('SYK', 'Gene', (110, 113))
46901	24523870	Putative copy number loss described as heterozygotic loss (HetLoss) occurs in 26.2% of the immune depleted cases (Figure 5A, 6B) and in 29.3% of IDC cases (Figure 6A).	('heterozygotic loss', 'Disease', 'MESH:C535338', (39, 57))	('heterozygotic loss', 'Disease', (39, 57))	('copy number loss', 'Var', (9, 25))
46902	24523870	As described previously, the SYK promoter is methylated in invasive breast cancers; and, methylation values were correlated with reduction in SYK mRNA levels in immune depleted cases (Figure 5B); similarly protein levels were positively associated with SYK mRNA levels (Figure 5C).	('SYK mRNA levels', 'MPA', (142, 157))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('reduction', 'NegReg', (129, 138))	('invasive breast cancers', 'Disease', 'MESH:D001943', (59, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('methylation', 'Var', (89, 100))	('SYK mRNA levels', 'MPA', (253, 268))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))	('invasive breast cancers', 'Disease', (59, 82))
46905	24523870	We queried 696 cases (IDC) from the provisional breast cancer study using mutations and copy number and found that overall survival times estimated in a Kaplan-Meier plot with SYK were not significantly different between affected and unaffected cases where affected cases were less than 1% of the total (plot not shown, Logrank test P-value 0.619806).	('copy number', 'Var', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (74, 83))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))
46917	24523870	Of the 9 genes for which the percent of cases altered for the 55 Gene Set was greater than 4.5% (CN, copy number and MUT, mutations) (Figure 8A), all had increased average copy number (Figure 8B); of those, 2 were from genes whose mRNA was down-regulated by SYK siRNA (ADAM15 and ECT2) and 7 were from genes whose mRNA was up-regulated by SYK siRNA (SPRR1A, RAB11FIP1, MUC1, RHOD, and SPTBN2).	('ECT2', 'Gene', '1894', (280, 284))	('SPTBN2', 'Gene', '6712', (385, 391))	('down-regulated', 'NegReg', (240, 254))	('copy number', 'MPA', (172, 183))	('RAB11FIP1', 'Gene', '80223', (358, 367))	('ECT2', 'Gene', (280, 284))	('ADAM15', 'Gene', '8751', (269, 275))	('SPTBN2', 'Gene', (385, 391))	('up-regulated', 'PosReg', (323, 335))	('ADAM15', 'Gene', (269, 275))	('increased', 'PosReg', (154, 163))	('SPRR1A', 'Gene', (350, 356))	('MUC1', 'Gene', (369, 373))	('MUC1', 'Gene', '4582', (369, 373))	('RAB11FIP1', 'Gene', (358, 367))	('RHOD', 'Gene', '29984', (375, 379))	('mutations', 'Var', (122, 131))	('SPRR1A', 'Gene', '6698', (350, 356))	('RHOD', 'Gene', (375, 379))
46922	24523870	This graphic illustration of genes versus patients with amplifications in red, mutations in green, and deletions in blue reveals the pattern of one or more alterations per affected patient (Figure S3A).	('blue', 'Gene', (116, 120))	('patient', 'Species', '9606', (181, 188))	('deletions', 'Var', (103, 112))	('patient', 'Species', '9606', (42, 49))	('patients', 'Species', '9606', (42, 50))	('mutations', 'Var', (79, 88))
46927	24523870	A two gene comparison using cBioPortal for copy number of SYK and CTNNAL1 resulted in a positive correlation in IDC patients for these two genes (Figure S4B).	('copy', 'Var', (43, 47))	('patients', 'Species', '9606', (116, 124))	('SYK', 'Gene', (58, 61))	('CTNNAL1', 'Gene', '8727', (66, 73))	('IDC', 'Disease', (112, 115))	('CTNNAL1', 'Gene', (66, 73))
46939	24523870	We conclude that SYK copy number changes reflect the overall genomic instability in the tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('SYK', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('copy number changes', 'Var', (21, 40))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
46941	24523870	To parse out the effects of the additional 4 genes (CDH1, CTTN, SRC, and TP53), Kaplan-Meier curves were generated revealing significant Logrank p-values of 0.004582 and 0.006403 for the 51 Gene Set and 4 Gene Set, respectively, with associated reductions in the survival plateaus (Figure 11B-C).	('TP53', 'Gene', '7157', (73, 77))	('reductions', 'NegReg', (245, 255))	('CTTN', 'Gene', '2017', (58, 62))	('CDH1', 'Gene', (52, 56))	('survival plateaus', 'CPA', (263, 280))	('SRC', 'Gene', '6714', (64, 67))	('TP53', 'Gene', (73, 77))	('CDH1', 'Gene', '999', (52, 56))	('SRC', 'Gene', (64, 67))	('0.006403', 'Var', (170, 178))	('CTTN', 'Gene', (58, 62))	('0.004582', 'Var', (157, 165))	('p-values', 'Var', (145, 153))
46943	24523870	Thus, in this preliminary study of DCIS, there appears to be a strong association of SYK allelic loss in DCIS tissues with adjacent invasive breast cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (132, 154))	('SYK', 'Gene', (85, 88))	('allelic loss', 'Var', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('invasive breast cancer', 'Disease', (132, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
46947	24523870	We conclude that Syk-regulated genes represent an epithelial biological network for restraint of motility and invasion that contribute to suppressing metastasis; in turn, loss of this restraint due to genomic instability or loss of Syk expression decreases overall survival of breast cancer patients.	('decreases', 'NegReg', (247, 256))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('overall', 'MPA', (257, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('loss', 'NegReg', (224, 228))	('breast cancer', 'Disease', (277, 290))	('patients', 'Species', '9606', (291, 299))	('metastasis', 'CPA', (150, 160))	('Syk', 'Gene', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('suppressing', 'NegReg', (138, 149))	('loss', 'NegReg', (171, 175))	('genomic instability', 'Var', (201, 220))
46957	24523870	Even so, the progression series of MCF10A cell lines shows a loss of Syk in the DCIS.COM line compared with MCF10A; and Syk knockdown in either cell line results in increased proliferation and invasion characteristics.	('knockdown', 'Var', (124, 133))	('Syk', 'Gene', (120, 123))	('MCF10A', 'CellLine', 'CVCL:0598', (35, 41))	('Syk', 'Protein', (69, 72))	('MCF10A', 'CellLine', 'CVCL:0598', (108, 114))	('invasion characteristics', 'CPA', (193, 217))	('loss', 'NegReg', (61, 65))	('increased', 'PosReg', (165, 174))	('proliferation', 'CPA', (175, 188))
46959	24523870	Interestingly, ESR1 protein and phosphoS118 ESR1 (ERalpha or estrogen receptor 1) are decreased in cases where alterations in the 55 Gene Set are present (Table S4).	('ESR1', 'Gene', '2099', (15, 19))	('alterations', 'Var', (111, 122))	('ESR1', 'Gene', '2099', (44, 48))	('ERalpha or estrogen receptor 1', 'Gene', (50, 80))	('decreased', 'NegReg', (86, 95))	('ERalpha or estrogen receptor 1', 'Gene', '2099', (50, 80))	('ESR1', 'Gene', (15, 19))	('phosphoS118', 'Var', (32, 43))	('ESR1', 'Gene', (44, 48))
46960	24523870	That these tumors are more aggressive is also suggested by recent data using anti-phospho S118 ESR1 to identify cases where the ERalpha pathway is active; mutation of this site leads to more aggressive cell behavior in MCF7 breast cancer cells ( and references therein).	('MCF7 breast cancer', 'Disease', (219, 237))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (219, 237))	('ESR1', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('tumors', 'Disease', (11, 17))	('ESR1', 'Gene', '2099', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('ERalpha', 'Gene', (128, 135))	('aggressive cell behavior', 'CPA', (191, 215))	('mutation', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('ERalpha', 'Gene', '2099', (128, 135))	('more', 'PosReg', (186, 190))
46964	24523870	Specifically, we found earlier that the cell surface expression of invadopodia genes of an integrin heterodimer, alpha6beta1 (CD49f, ITGA6/ITGB1), adhesion receptor CD44, and matrix-degrading protease, MT1-MMP (MMP14), are directly regulated by SYK; SYK knockdown results in their increased expression at the cell surface coupled with the formation of invadopodia and consequent cell invasion.	('SYK', 'Gene', (250, 253))	('expression', 'MPA', (291, 301))	('MMP14', 'Gene', '4323', (211, 216))	('ITGA6', 'Gene', (133, 138))	('ITGB1', 'Gene', '3688', (139, 144))	('MT1-MMP', 'Gene', (202, 209))	('MMP14', 'Gene', (211, 216))	('MT1-MMP', 'Gene', '4323', (202, 209))	('CD44', 'Gene', '960', (165, 169))	('CD49f', 'Gene', (126, 131))	('cell invasion', 'CPA', (379, 392))	('ITGB1', 'Gene', (139, 144))	('CD44', 'Gene', (165, 169))	('knockdown', 'Var', (254, 263))	('increased', 'PosReg', (281, 290))	('CD49f', 'Gene', '3655', (126, 131))	('ITGA6', 'Gene', '3655', (133, 138))
46966	24523870	ADAM15, up-regulated following SYK knockdown in MCF10A cells, was identified in this study as frequently altered in copy number.	('knockdown', 'Var', (35, 44))	('ADAM15', 'Gene', '8751', (0, 6))	('up-regulated', 'PosReg', (8, 20))	('altered', 'Reg', (105, 112))	('MCF10A', 'CellLine', 'CVCL:0598', (48, 54))	('ADAM15', 'Gene', (0, 6))
46967	24523870	ADAM15 functions in invadopodia by binding TKS5, a Src substrate; variants contribute to mammary cell carcinoma, and increased copy number was found to lead to formation of multiple variants.	('cell carcinoma', 'Disease', (97, 111))	('contribute to', 'Reg', (75, 88))	('cell carcinoma', 'Disease', 'MESH:C538614', (97, 111))	('variants', 'Var', (66, 74))	('Src', 'Gene', (51, 54))	('Src', 'Gene', '6714', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TKS5', 'Gene', '9644', (43, 47))	('ADAM15', 'Gene', '8751', (0, 6))	('TKS5', 'Gene', (43, 47))	('ADAM15', 'Gene', (0, 6))
46977	24523870	However, we demonstrated that heterozygotic SYK is associated with reduction in SYK mRNA compared with diploid cases in breast cancer cases without immune filtration.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('SYK mRNA', 'MPA', (80, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('reduction', 'NegReg', (67, 76))	('heterozygotic SYK', 'Var', (30, 47))
46978	24523870	This gene set powerfully predicted poorer patient outcome when copy number and mutational alterations of one or more of these genes occurred.	('occurred', 'Reg', (132, 140))	('mutational alterations', 'Var', (79, 101))	('predicted', 'Reg', (25, 34))	('patient', 'Species', '9606', (42, 49))	('copy number', 'Var', (63, 74))
46979	24523870	In summary, we propose two mechanisms whereby SYK loss together with mutations and copy number changes in the 55 Gene Set results in poorer overall survival of patients.	('mutations', 'Var', (69, 78))	('poorer', 'NegReg', (133, 139))	('patients', 'Species', '9606', (160, 168))	('loss', 'NegReg', (50, 54))	('overall', 'MPA', (140, 147))	('copy number changes', 'Var', (83, 102))	('SYK', 'Gene', (46, 49))
46984	23457626	Lapatinb reduced acini size and mammosphere formation in SUM225, whereas mammosphere formation and Notch1 activity were increased in MCF10DCIS.com.	('Notch1', 'Gene', '4851', (99, 105))	('MCF10DCIS.com', 'Var', (133, 146))	('reduced', 'NegReg', (9, 16))	('acini size', 'CPA', (17, 27))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('mammosphere formation', 'CPA', (73, 94))	('Notch1', 'Gene', (99, 105))	('increased', 'PosReg', (120, 129))	('mammosphere formation', 'CPA', (32, 53))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (133, 146))
46988	23457626	We report for the first time that cross talk between the two pathways in DCIS occurs regardless of ErbB2 receptor status and inhibition of Notch and ErbB1/2 was more efficacious than either alone.	('cross talk', 'Reg', (34, 44))	('DCIS', 'Disease', (73, 77))	('ErbB2', 'Gene', (99, 104))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('ErbB2', 'Gene', '2064', (99, 104))	('inhibition', 'Var', (125, 135))
46996	23457626	Recent data indicate that in trastuzumab resistant BT474 cells treatment with either trastuzumab or a dual ErbB1/ErbB2 receptor tyrosine kinase inhibitor, 4557W, causes an increase in Notch1 activity.	('ErbB1', 'Gene', (107, 112))	('increase', 'PosReg', (172, 180))	('4557W', 'Var', (155, 160))	('Notch1', 'Gene', (184, 190))	('ErbB2', 'Gene', (113, 118))	('activity', 'MPA', (191, 199))	('Notch1', 'Gene', '4851', (184, 190))	('ErbB2', 'Gene', '2064', (113, 118))	('ErbB1', 'Gene', '1956', (107, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (29, 40))	('trastuzumab', 'Chemical', 'MESH:D000068878', (85, 96))
47004	23457626	Notch3 siRNA was sufficient to reverse the lumen filled ErbB2 phenotype through induction of apoptosis, indicating that Notch signalling plays a role in the anoikis resistance in ErbB2 overexpressing cells.	('ErbB2', 'Gene', (179, 184))	('lumen filled', 'MPA', (43, 55))	('anoikis resistance', 'CPA', (157, 175))	('Notch3', 'Var', (0, 6))	('ErbB2', 'Gene', (56, 61))	('ErbB2', 'Gene', '2064', (179, 184))	('ErbB2', 'Gene', '2064', (56, 61))
47013	23457626	The number of acini did not change after treatment with either inhibitor however the size of DCIS acini was reduced by 25% in the MCF10DCIS.com cells at 10 microM DAPT (p<=0.0001) and no reduction was seen in the SUM225 cell line (Figure 1A&C).	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (130, 143))	('reduced', 'NegReg', (108, 115))	('MCF10DCIS.com', 'Var', (130, 143))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('size', 'MPA', (85, 89))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('DAPT', 'Chemical', '-', (163, 167))
47025	23457626	In MCF10DCIS.com cells, combined treatment caused a further reduction in acini size of 27% (p = 0.023) and 50% (p<0.0001) compared to DAPT 10 microM (p<0.001) or 0.1 microM lapatinib (p = 0.012) treatment alone respectively.	('acini size', 'CPA', (73, 83))	('DAPT', 'Chemical', '-', (134, 138))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (3, 16))	('reduction', 'NegReg', (60, 69))	('lapatinib', 'Chemical', 'MESH:D000077341', (173, 182))	('MCF10DCIS.com', 'Var', (3, 16))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))
47043	23457626	However Western blotting did not indicate a marked reduction in the cleaved form of Notch1 or the down stream target Hes-1 in Sum225 mammospheres compared to the DCIS.com mammospheres (Figure 3).	('Notch1', 'Gene', (84, 90))	('cleaved form', 'MPA', (68, 80))	('Hes-1', 'Gene', '3280', (117, 122))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('Sum225', 'Var', (126, 132))	('Notch1', 'Gene', '4851', (84, 90))	('Hes-1', 'Gene', (117, 122))
47048	23457626	Increased full length Notch1 has been reported in HCC-1896 and MDA MB 231 (ErbB2 normal) cells after treatment with the ErbB1/2 inhibitor, gefitinib and ErbB2 inhibition caused increased Notch1 receptor activity in ErbB2 overexpressing cell lines.	('ErbB2', 'Gene', (215, 220))	('HCC-1896', 'CellLine', 'CVCL:9H91', (50, 58))	('ErbB2', 'Gene', '2064', (153, 158))	('ErbB2', 'Gene', (75, 80))	('ErbB2', 'Gene', '2064', (215, 220))	('MDA MB 231', 'CellLine', 'CVCL:0062', (63, 73))	('Notch1', 'Gene', (187, 193))	('increased', 'PosReg', (177, 186))	('ErbB2', 'Gene', '2064', (75, 80))	('Notch1', 'Gene', (22, 28))	('gefitinib', 'Chemical', 'MESH:D000077156', (139, 148))	('Notch1', 'Gene', '4851', (187, 193))	('ErbB2', 'Gene', (153, 158))	('inhibition', 'Var', (159, 169))	('Notch1', 'Gene', '4851', (22, 28))	('activity', 'MPA', (203, 211))
47050	23457626	The combination of DAPT and lapatinib showed an additive reduction in both size of acini and mammosphere formation in the MCF10DCIS.com and the SUM225 cells (Figure 4).	('DAPT', 'Chemical', '-', (19, 23))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (122, 135))	('size of acini', 'CPA', (75, 88))	('reduction', 'NegReg', (57, 66))	('MCF10DCIS.com', 'Var', (122, 135))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))	('mammosphere formation', 'CPA', (93, 114))	('lapatinib', 'Chemical', 'MESH:D000077341', (28, 37))
47058	23457626	Other studies suggest a reduction in cell survival after combined treatment with Notch and ErbB2 inhibitors via a reduction in AKT activity and this is consistent with our findings.	('ErbB2', 'Gene', (91, 96))	('reduction', 'NegReg', (114, 123))	('ErbB2', 'Gene', '2064', (91, 96))	('AKT', 'Gene', '207', (127, 130))	('cell survival', 'CPA', (37, 50))	('reduction', 'NegReg', (24, 33))	('AKT', 'Gene', (127, 130))	('Notch', 'Gene', (81, 86))	('inhibitors', 'Var', (97, 107))
47061	23457626	CSC activity and acini formation of both cell lines and primary DCIS samples was reduced to a greater extent with combination treatment than with either inhibitor alone, regardless of ErbB2 receptor status.	('ErbB2', 'Gene', '2064', (184, 189))	('acini formation', 'CPA', (17, 32))	('CSC activity', 'CPA', (0, 12))	('combination', 'Var', (114, 125))	('reduced', 'NegReg', (81, 88))	('ErbB2', 'Gene', (184, 189))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))
47081	16280055	A common missense variant in BRCA2 predisposes to early onset breast cancer Mutations in the BRCA2 gene are one of the two major causes of hereditary breast cancer.	('Mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (139, 163))	('causes', 'Reg', (129, 135))	('BRCA2', 'Gene', '675', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA2', 'Gene', (29, 34))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA2', 'Gene', (93, 98))	('missense variant', 'Var', (9, 25))	('hereditary breast cancer', 'Disease', (139, 163))	('predisposes', 'Reg', (35, 46))
47082	16280055	Protein-truncating mutations of BRCA2 are usually deleterious and increase the risk of breast cancer up to 80% over a lifetime.	('BRCA2', 'Gene', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('increase', 'Reg', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('BRCA2', 'Gene', '675', (32, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('Protein-truncating mutations', 'Var', (0, 28))
47083	16280055	A few missense mutations in BRCA2 are believed to have a similarly high penetrance, apart from more common neutral polymorphisms.	('BRCA2', 'Gene', '675', (28, 33))	('missense mutations', 'Var', (6, 24))	('BRCA2', 'Gene', (28, 33))
47084	16280055	For a deleterious variant, one would expect a greater allele frequency in breast cancer cases than in ethnic-matched controls.	('breast cancer', 'Disease', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('variant', 'Var', (18, 25))
47085	16280055	We genotyped 3,241 cases of breast cancer diagnosed at under 51 years of age, unselected for family history, from 18 hospitals throughout Poland and 2,791 ethnic-matched controls for a single BRCA2 C5972T variant.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('C5972T', 'SUBSTITUTION', 'None', (198, 204))	('breast cancer', 'Disease', (28, 41))	('BRCA2', 'Gene', (192, 197))	('C5972T', 'Var', (198, 204))	('BRCA2', 'Gene', '675', (192, 197))
47087	16280055	The overall odds ratio for breast cancer in women with a single copy of the BRCA2 C5972T variant was 1.1 (p = 0.7); however, the effect was significant for patients diagnosed at or before age 40 (OR = 1.4; p = 0.04).	('patients', 'Species', '9606', (156, 164))	('C5972T', 'SUBSTITUTION', 'None', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('BRCA2', 'Gene', (76, 81))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('C5972T', 'Var', (82, 88))	('women', 'Species', '9606', (44, 49))	('BRCA2', 'Gene', '675', (76, 81))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))
47088	16280055	We reviewed the association between the BRCA2 variant in different histologic subgroups and found the effect most pronounced in women who had ductal carcinoma in situ (DCIS) with micro-invasion (OR = 2.8; p < 0.0001).	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (142, 166))	('women', 'Species', '9606', (128, 133))	('variant', 'Var', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('BRCA2', 'Gene', (40, 45))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (142, 166))	('ductal carcinoma in situ', 'Disease', (142, 166))	('BRCA2', 'Gene', '675', (40, 45))
47089	16280055	The BRCA2 C5972T allele is a common variant in Poland that increases the risk of DCIS with micro-invasion.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('micro-invasion', 'CPA', (91, 105))	('C5972T', 'Mutation', 'g.5972C>T', (10, 16))	('C5972T', 'Var', (10, 16))	('BRCA2', 'Gene', (4, 9))	('DCIS', 'Disease', (81, 85))	('BRCA2', 'Gene', '675', (4, 9))
47092	16280055	If the penetrance of the missense variant is low, however, then the association may be missed if only a small number of cancers is studied and the variant may falsely be classified as a neutral polymorphism.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('missense', 'Var', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
47095	16280055	There are a few common variant alleles in BRCA2 in Poland; one of these (C5972T) changes the amino acid sequence of BRCA2 from threonine to methionine at codon 1915.	('BRCA2', 'Gene', '675', (42, 47))	('threonine to methionine at codon 1915', 'Mutation', 'rs4987117', (127, 164))	('changes', 'Reg', (81, 88))	('BRCA2', 'Gene', (116, 121))	('C5972T', 'Mutation', 'g.5972C>T', (73, 79))	('amino', 'MPA', (93, 98))	('BRCA2', 'Gene', (42, 47))	('BRCA2', 'Gene', '675', (116, 121))	('C5972T', 'Var', (73, 79))
47097	16280055	We sought to determine whether this common missense BRCA2 variant plays a role in breast cancer susceptibility.	('BRCA2', 'Gene', (52, 57))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BRCA2', 'Gene', '675', (52, 57))	('missense', 'Var', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
47106	16280055	The C5972T variant (Thr1915Met) was analyzed by restriction fragment length polymorphism PCR using b5972F (5'-CTC TCT AGA TAA TGA TGA ATG ATG CA) and b5972R (5'-CCA AAC TAA CAT CAC AAG GTG) primers.	('C5972T', 'SUBSTITUTION', 'None', (4, 10))	('b5972F', 'Var', (99, 105))	('b5972R', 'Var', (150, 156))	('Thr1915Met', 'SUBSTITUTION', 'None', (20, 30))	('C5972T', 'Var', (4, 10))	('Thr1915Met', 'Var', (20, 30))
47109	16280055	A fragment of BRCA2 exon 11 was amplified by PCR using b5972F/b5972R primers.	('BRCA2', 'Gene', (14, 19))	('b5972F/b5972R', 'Var', (55, 68))	('BRCA2', 'Gene', '675', (14, 19))
47111	16280055	All breast cancer patients were tested as described previously for three mutations (5382insC, C61G, 4153delA) representing 80% to 90% of all high-risk BRCA1 changes in Poland.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('4153delA', 'Var', (100, 108))	('BRCA1', 'Gene', '672', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('5382insC', 'Mutation', 'c.5382insC', (84, 92))	('breast cancer', 'Disease', (4, 17))	('C61G', 'Var', (94, 98))	('BRCA1', 'Gene', (151, 156))	('C61G', 'Mutation', 'rs28897672', (94, 98))	('4153delA', 'Mutation', 'c.4153delA', (100, 108))	('patients', 'Species', '9606', (18, 26))	('5382insC', 'Var', (84, 92))
47114	16280055	The C5972T variant was detected in 8.3% of unselected breast cancer patients diagnosed at age 40 years or below, in 5.7% of cases diagnosed from age 41 to 50 years, and in 5.8% of Polish controls.	('breast cancer', 'Disease', (54, 67))	('C5972T', 'SUBSTITUTION', 'None', (4, 10))	('patients', 'Species', '9606', (68, 76))	('C5972T', 'Var', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
47115	16280055	The overall OR for breast cancer with a C5972T mutation was 1.1 (95% CI: 0.8-1.3); however, in women less than 40 years old the OR was 1.4 (95% CI: 1.0 - 1.9) (Table 1).	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('C5972T', 'Mutation', 'g.5972C>T', (40, 46))	('C5972T', 'Var', (40, 46))	('women', 'Species', '9606', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('breast cancer', 'Disease', (19, 32))
47120	16280055	We then explored the characteristics of the breast cancers that were identified in women with the BRCA2 C5972T allele (Table 2) and compared them with tumors in women without the predisposing allele (women with BRCA1 mutations were excluded from all comparisons and women who received pre-operative chemotherapy were excluded from the histological comparisons).	('women', 'Species', '9606', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('BRCA1', 'Gene', '672', (211, 216))	('BRCA2', 'Gene', '675', (98, 103))	('BRCA1', 'Gene', (211, 216))	('breast cancers', 'Disease', 'MESH:D001943', (44, 58))	('breast cancers', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('breast cancers', 'Phenotype', 'HP:0003002', (44, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('C5972T', 'Var', (104, 110))	('women', 'Species', '9606', (83, 88))	('women', 'Species', '9606', (266, 271))	('C5972T', 'Mutation', 'g.5972C>T', (104, 110))	('women', 'Species', '9606', (161, 166))	('BRCA2', 'Gene', (98, 103))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))
47121	16280055	Women with the BRCA2 variant were more likely to have bilateral cancer (5% versus 3%) or multifocal cancer (30% versus 23%) but these differences were not statistically significant.	('bilateral cancer', 'Disease', 'MESH:D009369', (54, 70))	('Women', 'Species', '9606', (0, 5))	('BRCA2', 'Gene', (15, 20))	('multifocal cancer', 'Phenotype', 'HP:0006625', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bilateral cancer', 'Disease', (54, 70))	('variant', 'Var', (21, 28))	('multifocal cancer', 'Disease', 'None', (89, 106))	('BRCA2', 'Gene', '675', (15, 20))	('multifocal cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
47123	16280055	Among the 5972C/T heterozygotes, 18 of 103 tumors were predominantly intraductal (17%), compared to 7% in 5972C/C breast cancer patients (OR = 2.82; p <= 0.0001; 95% CI: 1.6-4.8).	('C breast cancer', 'Disease', 'MESH:D001943', (112, 127))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('5972C/T', 'Mutation', 'g.5972C>T', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('to 7', 'Species', '1214577', (97, 101))	('5972C/T', 'Var', (10, 17))	('tumors', 'Disease', (43, 49))	('C breast cancer', 'Disease', (112, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('patients', 'Species', '9606', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
47124	16280055	A heterozygous BRCA2 variant was present in 13% of the women with predominantly intraductal cancer.	('women', 'Species', '9606', (55, 60))	('intraductal cancer', 'Disease', 'MESH:D002285', (80, 98))	('BRCA2', 'Gene', (15, 20))	('variant', 'Var', (21, 28))	('BRCA2', 'Gene', '675', (15, 20))	('intraductal cancer', 'Disease', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
47125	16280055	Compared to the population controls, the OR for intraductal cancer given a (heterozygous) form of BRCA2 variant was 2.5 (p = 0.0005; 95% CI: 1.5-4.1).	('intraductal cancer', 'Disease', 'MESH:D002285', (48, 66))	('intraductal cancer', 'Disease', (48, 66))	('BRCA2', 'Gene', (98, 103))	('BRCA2', 'Gene', '675', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('variant', 'Var', (104, 111))
47127	16280055	The C5972T allele of the BRCA2 gene appears to be over-represented in women with early onset breast cancer in Poland compared to controls.	('BRCA2', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA2', 'Gene', '675', (25, 30))	('over-represented', 'PosReg', (50, 66))	('C5972T', 'Mutation', 'g.5972C>T', (4, 10))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('C5972T', 'Var', (4, 10))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('women', 'Species', '9606', (70, 75))
47128	16280055	Although the effect was modest in the overall data set, it was stronger for women who had predominantly intraductal breast cancer and for women who were homozygous for the variant allele.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('intraductal breast cancer', 'Disease', (104, 129))	('variant', 'Var', (172, 179))	('women', 'Species', '9606', (138, 143))	('women', 'Species', '9606', (76, 81))	('intraductal breast cancer', 'Disease', 'MESH:D001943', (104, 129))
47132	16280055	Our data set did not include cases of DCIS alone and we were unable to assess the effect of the BRCA2 C5972T allele in women with predominantly invasive cancer and associated DCIS.	('invasive cancer', 'Disease', (144, 159))	('C5972T', 'Mutation', 'g.5972C>T', (102, 108))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('BRCA2', 'Gene', '675', (96, 101))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('C5972T', 'Var', (102, 108))	('invasive cancer', 'Disease', 'MESH:D009362', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('women', 'Species', '9606', (119, 124))	('BRCA2', 'Gene', (96, 101))	('DCIS', 'Disease', (175, 179))
47137	16280055	In one family with a germline BRCA2 mutation, three cases of invasive breast cancer and one case of DCIS were observed.	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('BRCA2', 'Gene', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasive breast cancer', 'Disease', (61, 83))	('mutation', 'Var', (36, 44))	('BRCA2', 'Gene', '675', (30, 35))
47139	16280055	The authors suggest that DCIS and LOH in the BRCA2 locus may be common early steps in the development of invasive breast cancer in BRCA2 carriers.	('BRCA2', 'Gene', (131, 136))	('BRCA2', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (45, 50))	('LOH', 'Var', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('invasive breast cancer', 'Disease', 'MESH:D001943', (105, 127))	('DCIS', 'Var', (25, 29))	('BRCA2', 'Gene', '675', (131, 136))	('carriers', 'Var', (137, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('invasive breast cancer', 'Disease', (105, 127))
47141	16280055	In support of this hypothesis are our observations of a greater breast cancer risk in women with two inherited 5972T variants and a lower frequency of positive family history among 5972C/T heterozygotes.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('5972T', 'Var', (111, 116))	('5972C/T', 'Mutation', 'g.5972C>T', (181, 188))	('greater', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('women', 'Species', '9606', (86, 91))	('breast cancer', 'Disease', (64, 77))
47142	16280055	This may be explained by the modest association of the examined variant with breast cancer risk and probable recessive pattern of inheritance (the highest OR values were observed in homozygotes, all of them with negative breast cancer family history).	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('variant', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('association', 'Interaction', (36, 47))	('breast cancer', 'Disease', (221, 234))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))
47143	16280055	Actually, at least some of the 5972C/T heterozygotes may be compound heterozygotes, with the second allele being another BRCA2 variant.	('5972C/T', 'Var', (31, 38))	('5972C/T', 'Mutation', 'g.5972C>T', (31, 38))	('BRCA2', 'Gene', (121, 126))	('BRCA2', 'Gene', '675', (121, 126))
47145	16280055	Few other deleterious missense variants in BRCA2 have been identified.	('missense variants', 'Var', (22, 39))	('BRCA2', 'Gene', (43, 48))	('BRCA2', 'Gene', '675', (43, 48))
47146	16280055	The HH genotype of the non-conservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3-fold to 1.5-fold increase in the risk of both breast and ovarian cancer, but there have been negative studies as well.	('ovarian cancer', 'Phenotype', 'HP:0100615', (199, 213))	('BRCA2', 'Gene', (90, 95))	('BRCA2', 'Gene', '675', (90, 95))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (188, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('N372H', 'Mutation', 'rs144848', (77, 82))	('N372H', 'Var', (77, 82))	('increase', 'PosReg', (159, 167))
47150	16280055	The heterozygosity of the BRCA2 C5972T variant appears to be a neutral polymorphism in women above the age of 40 but may be deleterious prior to age 40.	('C5972T', 'Var', (32, 38))	('BRCA2', 'Gene', (26, 31))	('C5972T', 'SUBSTITUTION', 'None', (32, 38))	('women', 'Species', '9606', (87, 92))	('BRCA2', 'Gene', '675', (26, 31))
47157	31623646	Sensitivity was high, about 80%, in women with BI-RADS density score 1 and MTR markers 1 or 2.	('MTR markers', 'Gene', (75, 86))	('BI-RADS', 'Var', (47, 54))	('women', 'Species', '9606', (36, 41))
47158	31623646	Sensitivity was low, 67%, in women with BI-RADS density score 2 and MTR marker 4.	('BI-RADS', 'Var', (40, 47))	('women', 'Species', '9606', (29, 34))	('MTR marker', 'Gene', (68, 78))
47159	31623646	For women with BI-RADS density scores 3 and 4, the already low sensitivity was further decreased for women with MTR marker 4.	('BI-RADS', 'Var', (15, 22))	('women', 'Species', '9606', (4, 9))	('women', 'Species', '9606', (101, 106))	('decreased', 'NegReg', (87, 96))
47189	31623646	The BI-RADS density score and the MTR marker were highly correlated with the majority of women with BI-RADS density score 1 having MTR marker 1 and the majority of women with BI-RADS density score 4 having MTR marker 4, p < 0.00001 (Table 1 and Fig.	('MTR', 'Gene', (131, 134))	('BI-RADS density score 1', 'Var', (100, 123))	('women', 'Species', '9606', (164, 169))	('women', 'Species', '9606', (89, 94))
47191	31623646	Sensitivity decreased from 78% (95% CI, 69-85) for women with BI-RADS density score 1 to 47% (95% CI, 30-65) for women with BI-RADS density score 4.	('Sensitivity', 'MPA', (0, 11))	('women', 'Species', '9606', (113, 118))	('decreased', 'NegReg', (12, 21))	('BI-RADS density score 1', 'Var', (62, 85))	('women', 'Species', '9606', (51, 56))
47200	31623646	Among women with dense breasts, the sensitivity was also particularly low for women with a heterogenous texture: 61% for BI-RADS density score 3 and MTR marker 4, and 41% for BI-RADS density score 4 and MTR marker 4.	('women', 'Species', '9606', (78, 83))	('MTR', 'Gene', (149, 152))	('women', 'Species', '9606', (6, 11))	('BI-RADS density score 4', 'Var', (175, 198))	('BI-RADS density score 3', 'Var', (121, 144))
47204	31623646	The US Breast Cancer Surveillance Consortium (BCSC) from 2002 to 2011 showed for women aged 50-59 years, the sensitivity vary from 89.6% for women with BI-RADS density score 1 to 71.3% for women with BI-RADS density score 4; the numbers for women aged 60-69 years were 92.5% and 65.5%, respectively.	('women', 'Species', '9606', (141, 146))	('women', 'Species', '9606', (81, 86))	('Breast Cancer', 'Phenotype', 'HP:0003002', (7, 20))	('Breast Cancer', 'Disease', (7, 20))	('BI-RADS', 'Var', (200, 207))	('women', 'Species', '9606', (189, 194))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BI-RADS density score', 'Var', (152, 173))	('women', 'Species', '9606', (241, 246))	('Breast Cancer', 'Disease', 'MESH:D001943', (7, 20))
47207	31623646	In crude terms, 5 out of 100 women with BI-RADS density score 1, who turned out to be free of breast cancer, were recalled for extra examinations, while this was the case for 10 out of 100 for women with BI-RADS density scores 2-4.	('women', 'Species', '9606', (29, 34))	('women', 'Species', '9606', (193, 198))	('BI-RADS density score 1', 'Var', (40, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
47228	27456031	Importantly, numerous studies have shown that DCE-MRI of the breast is a far more sensitive screening modality than FFDM or US in the detection of clinically occult breast cancer in women at greatly increased lifetime risk, especially those with BRCA mutations, with most studies showing a doubling of the cancer detection rate with breast MRI and little additional benefit from mammography.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('DCE', 'Chemical', 'MESH:C024565', (46, 49))	('mutations', 'Var', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('women', 'Species', '9606', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('BRCA', 'Gene', '672', (246, 250))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('BRCA', 'Gene', (246, 250))	('cancer', 'Disease', (306, 312))
47230	27456031	Specifically, the evidence suggests that use of preoperative breast MRI in patients with breast cancer results in increased mastectomy rates or larger wide local excisions with, at the same time, no reduction in the incidence of positive surgical margins (necessitating re-excision) nor, ultimately, in ipsilateral in-breast local recurrence.	('mastectomy rates', 'CPA', (124, 140))	('breast MRI', 'Var', (61, 71))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('positive surgical margins', 'CPA', (229, 254))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('increased', 'PosReg', (114, 123))	('patients', 'Species', '9606', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('reduction', 'NegReg', (199, 208))
47231	27456031	Similarly, though there is good evidence of stage shift as a result of the use of breast MRI for screening of high-risk women, it remains to be seen whether the increased cancer detection rate with breast MRI in high risk women translates into improvements in breast cancer-specific mortality, at least in the BRCA 1 population.	('breast MRI', 'Var', (198, 208))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('breast cancer', 'Disease', (260, 273))	('women', 'Species', '9606', (222, 227))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('BRCA 1', 'Gene', (310, 316))	('cancer', 'Disease', (171, 177))	('women', 'Species', '9606', (120, 125))	('BRCA 1', 'Gene', '672', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('increased', 'PosReg', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('improvements', 'PosReg', (244, 256))
47274	27456031	BI-RADS 4 lesions have a probability of malignancy of between 5-95 % and thus constitute a bit of a dumping ground; but importantly, these lesions should not be left alone.	('BI-RADS', 'Var', (0, 7))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('malignancy', 'Disease', (40, 50))
47280	27456031	Finally, BI-RADS 5 lesions have a greater than 95 % chance of malignancy.	('BI-RADS 5 lesions', 'Var', (9, 26))	('malignancy', 'Disease', (62, 72))	('malignancy', 'Disease', 'MESH:D009369', (62, 72))
47295	27456031	There are instances where I pursue indeterminate findings much more aggressively; namely in the case of women with BRCA mutations undergoing screening MRI, especially if there is a known or suspected BRCA 1 mutation.	('BRCA 1', 'Gene', (200, 206))	('BRCA', 'Gene', '672', (200, 204))	('BRCA 1', 'Gene', '672', (200, 206))	('BRCA', 'Gene', '672', (115, 119))	('BRCA', 'Gene', (200, 204))	('BRCA', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('women', 'Species', '9606', (104, 109))
47338	25112586	Prior surgery (p = 0.132) and focal asymmetric density (p = 0.077) were included by stepwise regression due to their predictive ability of invasive cancer, despite being non-significant.	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('invasive cancer', 'Disease', (139, 154))	('invasive cancer', 'Disease', 'MESH:D009362', (139, 154))	('focal asymmetric density', 'Var', (30, 54))
47346	25112586	Clinically, misclassifying invasive cancer as DCIS is a more serious error (defined as a false negative) than misclassifying DCIS as an invasive cancer (defined as a false positive).	('invasive cancer', 'Disease', (136, 151))	('invasive cancer', 'Disease', 'MESH:D009362', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('invasive cancer', 'Disease', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('invasive cancer', 'Disease', 'MESH:D009362', (27, 42))	('misclassifying', 'Var', (12, 26))
47366	25112586	Breast density has previously been shown to be a strong risk factor for both invasive cancer and DCIS compared to women without cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('women', 'Species', '9606', (114, 119))	('invasive cancer', 'Disease', (77, 92))	('invasive cancer', 'Disease', 'MESH:D009362', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DCIS', 'Disease', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Breast density', 'Var', (0, 14))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', (128, 134))
47381	28894698	Furthermore, breast cancer-specific survival was identical between patients with low-grade DCIS who did and did not undergo surgery.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (67, 75))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('low-grade', 'Var', (81, 90))
47402	28894698	We observed a better breast cancer-specific survival (BCSS) among patients who underwent surgery for high-grade DCIS, compared to patients with high-grade DCIS who did not undergo surgery at a median follow-up of 72 months from diagnosis.	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-grade DCIS', 'Var', (101, 116))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('better', 'PosReg', (14, 20))	('patients', 'Species', '9606', (130, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('patients', 'Species', '9606', (66, 74))
47404	28894698	Among patients with low-grade DCIS, the weighted 10-year BCSS rates were 98.6% after surgery and 98.8% among patients who did not undergo surgery.	('low-grade', 'Var', (20, 29))	('patients', 'Species', '9606', (109, 117))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('patients', 'Species', '9606', (6, 14))	('DCIS', 'Disease', (30, 34))
47435	23577021	We propose a paradigm shift: direct interrogation of lncRNAs in the molecular characterization of DCIS subtypes, including the idea that lncRNAs may be the trigger for progression from in situ to invasive cancer.	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('invasive cancer', 'Disease', (196, 211))	('lncRNAs', 'Var', (137, 144))	('invasive cancer', 'Disease', 'MESH:D009362', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))
47448	23577021	Sense-antisense mRNAlncRNA gene pairs affect several tumor suppressors which are cis-regulated by antisense lncRNAs transcribed from the same locus, including p15 and p21 (Lipovich et al.,).	('p21', 'Gene', '644914', (167, 170))	('pairs', 'Var', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('p15', 'Gene', (159, 162))	('p15', 'Gene', '1030', (159, 162))	('affect', 'Reg', (38, 44))	('tumor', 'Disease', (53, 58))	('p21', 'Gene', (167, 170))
47450	23577021	Highly Upregulated in Liver Cancer (HULC), identified as the most-upregulated gene in an HCC microarray study of 7000 genes, is a canonically spliced, polyadenylated lncRNA whose knockdown in a cell line induces CDK8 and a tumor suppressor candidate (Panzitt et al.,).	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('HULC', 'Gene', (36, 40))	('Liver Cancer', 'Disease', 'MESH:D006528', (22, 34))	('Liver Cancer', 'Phenotype', 'HP:0002896', (22, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('knockdown', 'Var', (179, 188))	('HULC', 'Gene', '728655', (36, 40))	('Liver Cancer', 'Disease', (22, 34))	('CDK8', 'Gene', (212, 216))	('Upregulated', 'PosReg', (7, 18))	('induces', 'PosReg', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('CDK8', 'Gene', '1024', (212, 216))
47476	23216911	Patients with DCIS and DCIS-Mi were younger than those with IDC (P = 0.007).	('DCIS', 'Disease', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('DCIS-Mi', 'Chemical', '-', (23, 30))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('DCIS-Mi', 'Var', (23, 30))
47478	23216911	The incidence of IDC with node-positive was significantly higher than it in DCIS and DCIS-Mi (P <0.001).	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('higher', 'PosReg', (58, 64))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('node-positive', 'Var', (26, 39))	('IDC', 'Disease', (17, 20))	('DCIS-Mi', 'Chemical', '-', (85, 92))
47482	23216911	The incidence of the first performance of ultrasound (catheter winded and nodular mass) and mammography (nodular mass) had significantly difference among patients with DCIS, DCIS-Mi, and IDC (P <0.001).	('DCIS-Mi', 'Chemical', '-', (174, 181))	('DCIS', 'Phenotype', 'HP:0030075', (174, 178))	('difference', 'Reg', (137, 147))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('patients', 'Species', '9606', (154, 162))	('DCIS', 'Var', (168, 172))	('mammography', 'CPA', (92, 103))
47514	23216911	Patients with DCIS and DCIS-Mi were significantly younger than those with IDC (P = 0.007).	('DCIS', 'Disease', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('DCIS-Mi', 'Chemical', '-', (23, 30))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('DCIS-Mi', 'Var', (23, 30))
47515	23216911	Patients with DCIS and DCIS-Mi were more often found to have the status of premenopausal when compare to those with IDC (P <=0.001).	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('DCIS', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('DCIS-Mi', 'Chemical', '-', (23, 30))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('DCIS-Mi', 'Var', (23, 30))
47517	23216911	We also observed that the number of status of Her2 expressed positive in patients with DCIS and DCIS-Mi was higher than in those with IDC (P <0.001) but we found that the tumor size and family history of breast cancer in a first-degree relative seemed to have no difference in the three groups (P >0.05).	('Her2', 'Gene', (46, 50))	('DCIS-Mi', 'Chemical', '-', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('DCIS-Mi', 'Var', (96, 103))	('Her2', 'Gene', '2064', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('tumor', 'Disease', (171, 176))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('breast cancer', 'Disease', (204, 217))	('patients', 'Species', '9606', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))
47521	23216911	The incidence of nipple discharge was similar in the patients with DCIS, DCIS-Mi, and IDC groups (P = 0.51), but DCIS and DCIS-Mi was mainly yellow discharge, IDC was mainly bloody.	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('patients', 'Species', '9606', (53, 61))	('DCIS-Mi', 'Chemical', '-', (122, 129))	('DCIS-Mi', 'Var', (122, 129))	('yellow discharge', 'Phenotype', 'HP:0040321', (141, 157))	('DCIS-Mi', 'Chemical', '-', (73, 80))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('DCIS', 'Disease', (113, 117))	('yellow', 'Disease', (141, 147))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
47636	31562602	After adjustment, characteristics independently associated with increased TTS included Black and Asian race, Hispanic ethnicity, lack of high school diploma, metropolitan setting, greater treating facility distance, transfers of care, and increased Charlson comorbidity score, among others (Table 1).	('TTS', 'Disease', (74, 77))	('diploma', 'Disease', (149, 156))	('increased', 'PosReg', (239, 248))	('increased', 'PosReg', (64, 73))	('diploma', 'Disease', 'None', (149, 156))	('Hispanic ethnicity', 'Var', (109, 127))
47683	30361873	Annual breast surgery trends changed as follows: PM 46.3-46.1% (p = 0.21), M 35.8-26.4% (p = 0.001), M+R 15.9-23.0% (p = 0.03), and OS 1.8-4.42% (p = 0.001).	('breast surgery', 'Disease', (7, 21))	('M+R', 'Var', (101, 104))	('OS', 'Chemical', '-', (132, 134))
47705	30361873	After October 2015, ICD tenth edition replaced the previous system of classification, and patients with IBC or DCIS were classified under the appropriate ICD-10 codes: D05, D5.1-D05.99 (DCIS), and IBC (C50).	('ICD tenth edition', 'Disease', 'OMIM:252500', (20, 37))	('D05', 'Var', (168, 171))	('ICD tenth edition', 'Disease', (20, 37))	('IBC', 'Chemical', '-', (104, 107))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('IBC', 'Disease', (104, 107))	('D5.1-D05.99', 'Var', (173, 184))	('patients', 'Species', '9606', (90, 98))	('IBC', 'Chemical', '-', (197, 200))
47805	28491319	Linear, branching mammographic microcalcifications, or clumped NMLE on MRI, associated with a synchronous ipsilateral invasive malignancy, both highly predictive of DCIS on imaging, could represent the unusual possibility of concomitant LVI rather than DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (253, 257))	('DCIS', 'Disease', (165, 169))	('clumped NMLE', 'Var', (55, 67))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('synchronous ipsilateral invasive malignancy', 'Disease', (94, 137))	('synchronous ipsilateral invasive malignancy', 'Disease', 'MESH:D009378', (94, 137))	('LVI', 'Chemical', '-', (237, 240))	('LVI', 'Disease', (237, 240))
47812	27835884	The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC.	('COX-2', 'Gene', '5743', (25, 30))	('expression', 'MPA', (31, 41))	('mutational', 'Var', (99, 109))	('PIK3CA', 'Gene', (92, 98))	('COX-2', 'Gene', (25, 30))
47813	27835884	The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('celecoxib', 'Chemical', 'MESH:D000068579', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutated', 'Var', (113, 120))	('tested', 'Reg', (42, 48))	('tumor', 'Disease', (8, 13))
47815	27835884	Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations.	('patients', 'Species', '9606', (139, 147))	('expression level', 'MPA', (84, 100))	('COX-2', 'Gene', (78, 83))	('COX-2', 'Gene', '5743', (78, 83))	('better', 'PosReg', (49, 55))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))	('Metastasis-free survival', 'CPA', (0, 24))
47817	27835884	Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Celecoxib', 'Chemical', 'MESH:D000068579', (0, 9))	('mutated', 'Var', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PDX', 'Disease', (65, 68))	('PIK3CA mutated', 'Var', (50, 64))	('tumor', 'Disease', (32, 37))
47820	27835884	Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX.	('tumor', 'Disease', (4, 9))	('celecoxib', 'Chemical', 'MESH:D000068579', (22, 31))	('PIK3CA mutated', 'Var', (49, 63))	('PDX', 'Disease', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
47821	27835884	These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy.	('celecoxib', 'Chemical', 'MESH:D000068579', (81, 90))	('mutation', 'Var', (34, 42))	('PIK3CA', 'Gene', (27, 33))
47850	27835884	Other studies confirmed the benefit of aspirin treatment on overall survival in PIK3CA mutated colorectal cancer.	('aspirin', 'Chemical', 'MESH:D001241', (39, 46))	('mutated', 'Var', (87, 94))	('colorectal cancer', 'Disease', (95, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('PIK3CA', 'Gene', (80, 86))	('overall survival', 'MPA', (60, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
47851	27835884	As PIK3CA mutations are reported in 10-40% of BCs we hypothesized that mutated-PIK3CA breast tumor expressing COX-2 could benefit from treatment with a COX-2 inhibitor such as celecoxib.	('COX-2', 'Gene', (152, 157))	('breast tumor', 'Disease', 'MESH:D001943', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('COX-2', 'Gene', (110, 115))	('mutated-PIK3CA', 'Var', (71, 85))	('COX-2', 'Gene', '5743', (110, 115))	('COX-2', 'Gene', '5743', (152, 157))	('breast tumor', 'Disease', (86, 98))	('celecoxib', 'Chemical', 'MESH:D000068579', (176, 185))	('breast tumor', 'Phenotype', 'HP:0100013', (86, 98))	('benefit', 'PosReg', (122, 129))
47852	27835884	In the present study we first evaluated COX-2 expression levels and prognostic value according to the PIK3CA mutational status in a large retrospective cohort of BC patients.	('PIK3CA', 'Gene', (102, 108))	('expression levels', 'MPA', (46, 63))	('COX-2', 'Gene', (40, 45))	('COX-2', 'Gene', '5743', (40, 45))	('mutational', 'Var', (109, 119))	('patients', 'Species', '9606', (165, 173))
47863	27835884	These data show a good correlation between the COX-2 mRNA and the COX-2 protein expression levels except for two cases (2/26, 8%) of primary tumor (3395 and 5015).	('primary tumor', 'Disease', 'MESH:D009369', (133, 146))	('COX-2', 'Gene', (66, 71))	('COX-2', 'Gene', '5743', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tween', 'Chemical', 'MESH:D011136', (37, 42))	('COX-2', 'Gene', (47, 52))	('3395', 'Var', (148, 152))	('COX-2', 'Gene', '5743', (47, 52))	('primary tumor', 'Disease', (133, 146))
47864	27835884	Technical difficulties prevented us from accurately determine the percent of positive cells and intensity of the staining in particular histological types of breast carcinomas like ductal carcinoma in situ (6189), neuroendocrine carcinoma (6602) and metaplastic carcinoma (HBCx-60).	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('breast carcinomas like ductal carcinoma', 'Disease', 'MESH:D018270', (158, 197))	('metaplastic carcinoma', 'Disease', 'MESH:D002277', (250, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (181, 205))	('ductal carcinoma in situ', 'Disease', (181, 205))	('breast carcinoma', 'Phenotype', 'HP:0003002', (158, 174))	('breast carcinomas like ductal carcinoma', 'Disease', (158, 197))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (214, 238))	('breast carcinomas', 'Phenotype', 'HP:0003002', (158, 175))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (181, 205))	('neuroendocrine carcinoma', 'Disease', (214, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('6602', 'Var', (240, 244))	('metaplastic carcinoma', 'Disease', (250, 271))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (214, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))
47869	27835884	PIK3CA mutations were detected in 33% of patients (148/446).	('detected', 'Reg', (22, 30))	('patients', 'Species', '9606', (41, 49))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
47870	27835884	COX-2 mRNA level was tightly linked to EGFR mRNA levels (p<10-4) and to PIK3CA mutations (p<10-4) (Table 3).	('p<10-4', 'Gene', (90, 96))	('p<10-4', 'Gene', '4820', (57, 63))	('COX-2', 'Gene', '5743', (0, 5))	('mRNA level', 'MPA', (6, 16))	('linked', 'Reg', (29, 35))	('PIK3CA', 'Gene', (72, 78))	('p<10-4', 'Gene', (57, 63))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('p<10-4', 'Gene', '4820', (90, 96))	('COX-2', 'Gene', (0, 5))	('mutations', 'Var', (79, 88))
47871	27835884	SBR grade (p=1.5.10-4), lymph node status (p=1.9.10-3), tumor size (p=1.4.10-5), ER (p=8.4.10-6) and PR (p=8.6.10-6) status as well as PIK3CA mutations (p=0.02) all had prognostic value as measured by the 5-years MFS.	('mutations', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PR', 'Gene', '5241', (101, 103))	('tumor', 'Disease', (56, 61))	('PIK3CA', 'Gene', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
47877	27835884	Independently of the subtype of BC and adjuvant treatment received (chemotherapy, hormone therapy, both or none) MFS was significantly better in patients with high COX-2 expression (p=0.007, HR 1.560 [1.130-2.153]) (Figure 2A) and in patients with PIK3CA mutations (p=0.02, HR 1.455 [1.058-2.002]) (Figure 2B).	('patients', 'Species', '9606', (145, 153))	('expression', 'MPA', (170, 180))	('MFS', 'MPA', (113, 116))	('better', 'PosReg', (135, 141))	('patients', 'Species', '9606', (234, 242))	('PIK3CA', 'Gene', (248, 254))	('COX-2', 'Gene', (164, 169))	('COX-2', 'Gene', '5743', (164, 169))	('high', 'Var', (159, 163))	('mutations', 'Var', (255, 264))
47879	27835884	However in the PIK3CA wild-type patients' subgroup MFS was significantly better in patients with high COX-2 expression as compared to patients with low COX-2 expression (p=0.01, HR 1.617 [1.113-2.350]) (Figure 2C).	('COX-2', 'Gene', '5743', (102, 107))	('COX-2', 'Gene', (152, 157))	('MFS', 'MPA', (51, 54))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (83, 91))	('COX-2', 'Gene', '5743', (152, 157))	('patients', 'Species', '9606', (134, 142))	('COX-2', 'Gene', (102, 107))	('expression', 'MPA', (108, 118))	('better', 'PosReg', (73, 79))	('high', 'Var', (97, 101))
47880	27835884	Interestingly, the same result was observed in HR+ tumors where PIK3CA mutations are clearly associated with good prognosis (p=0.0004, HR 2.377 [1.473-3.835]).	('PIK3CA', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HR+ tumors', 'Disease', (47, 57))	('HR+ tumors', 'Disease', 'MESH:D009369', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (71, 80))
47881	27835884	Patients with high COX-2 expression and PIK3CA wild-type had a similar MFS as PIK3CA mutated patients (p=0.07, HR 1.717 [0.9458-3.116]) (Figure 2D).	('COX-2', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('COX-2', 'Gene', '5743', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (93, 101))
47884	27835884	COX-2 expression and PIK3CA mutational status did not impact overall survival (OS) in this cohort with very long follow-up (Supplementary Figure S2).	('mutational status', 'Var', (28, 45))	('impact', 'Reg', (54, 60))	('PIK3CA', 'Gene', (21, 27))	('overall survival', 'MPA', (61, 77))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
47885	27835884	In the TCGA validation set, high COX-2 expression was associated with a better DFS (p=0.0014, HR 2.206 [1.356-3.587]) and PIK3CA mutations did not have prognostic impact on DFS (Supplementary Figures S3A and S3B).	('PIK3CA', 'Gene', (122, 128))	('mutations', 'Var', (129, 138))	('COX-2', 'Gene', (33, 38))	('COX-2', 'Gene', '5743', (33, 38))	('DFS', 'MPA', (79, 82))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))
47886	27835884	After combination of these two parameters, COX-2 expression level did not have prognostic impact in PIK3CA wild-type patients but high COX-2 level expression was associated with a better DFS among mutated patients (p=0.0007, HR 4.667 [1.917-11.36]) (Supplementary Figure 3C).	('patients', 'Species', '9606', (205, 213))	('COX-2', 'Gene', (135, 140))	('high', 'Var', (130, 134))	('COX-2', 'Gene', '5743', (135, 140))	('COX-2', 'Gene', (43, 48))	('mutated', 'Var', (197, 204))	('better', 'PosReg', (180, 186))	('COX-2', 'Gene', '5743', (43, 48))	('patients', 'Species', '9606', (117, 125))	('DFS', 'MPA', (187, 190))
47887	27835884	In the luminal subtype, high COX-2 expression was associated with a better DFS (p=0.012, HR 2.682 [1.243-5.785]) and PIK3CA mutations did not have prognostic impact on DFS (data not shown).	('COX-2', 'Gene', (29, 34))	('expression', 'MPA', (35, 45))	('PIK3CA', 'Gene', (117, 123))	('COX-2', 'Gene', '5743', (29, 34))	('high', 'Var', (24, 28))	('DFS', 'MPA', (75, 78))
47888	27835884	Among PIK3CA wild-type patients, high COX-2 patients had a better DFS than low COX-2 patients (p=0.012, HR 3.206 [1.287-7.984]) (Supplementary Figure S3D).	('COX-2', 'Gene', '5743', (79, 84))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (23, 31))	('PIK3CA', 'Gene', (6, 12))	('better', 'PosReg', (59, 65))	('DFS', 'MPA', (66, 69))	('patients', 'Species', '9606', (85, 93))	('COX-2', 'Gene', (79, 84))	('COX-2', 'Gene', (38, 43))	('COX-2', 'Gene', '5743', (38, 43))
47891	27835884	Among wild-type PIK3CA patients, high COX-2 patients had a better overall survival than low COX-2 patients (p=0.018, HR 2.183 [1.146-4.157]).	('overall survival', 'MPA', (66, 82))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (23, 31))	('COX-2', 'Gene', (92, 97))	('patients', 'Species', '9606', (98, 106))	('better', 'PosReg', (59, 65))	('COX-2', 'Gene', '5743', (92, 97))	('COX-2', 'Gene', (38, 43))	('COX-2', 'Gene', '5743', (38, 43))
47893	27835884	In the luminal subtype, high COX-2 expression was associated with a better OS (p=0.0051, HR 1.831 [0.999-3.357]) and PIK3CA mutations did not have a prognostic impact on OS (data not shown).	('COX-2', 'Gene', (29, 34))	('expression', 'MPA', (35, 45))	('COX-2', 'Gene', '5743', (29, 34))	('PIK3CA', 'Gene', (117, 123))	('high', 'Var', (24, 28))
47894	27835884	Among mutated PIK3CA patients, high COX-2 patients had a better overall survival than low COX-2 patients (p=0.023, HR 3.206 [1.177-8.734]) (Supplementary Figure S4D).	('COX-2', 'Gene', (90, 95))	('COX-2', 'Gene', '5743', (90, 95))	('overall survival', 'MPA', (64, 80))	('COX-2', 'Gene', (36, 41))	('patients', 'Species', '9606', (21, 29))	('COX-2', 'Gene', '5743', (36, 41))	('PIK3CA', 'Gene', (14, 20))	('patients', 'Species', '9606', (96, 104))	('better', 'PosReg', (57, 63))	('patients', 'Species', '9606', (42, 50))	('mutated', 'Var', (6, 13))
47897	27835884	In the PIK3CA mutated TNBC PDX model (HBCx-4B) a significant reduction in tumor volume (RTV) was observed in mice receiving celecoxib as compared to control mice from day 22 (p=0.03) and until the end of the experiment (day 61, TGI=57%, p=0.01) (Figure 4A).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('reduction', 'NegReg', (61, 70))	('PIK3CA', 'Var', (7, 13))	('TNBC', 'Chemical', '-', (22, 26))	('celecoxib', 'Chemical', 'MESH:D000068579', (124, 133))	('tumor', 'Disease', (74, 79))	('mice', 'Species', '10090', (109, 113))	('TNBC', 'Gene', (22, 26))
47898	27835884	These results clearly showed that celecoxib induced a significant antitumor effect in tumors expressing COX-2 and harboring a PIK3CA mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (133, 141))	('PIK3CA', 'Gene', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('COX-2', 'Gene', (104, 109))	('COX-2', 'Gene', '5743', (104, 109))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (70, 75))	('celecoxib', 'Chemical', 'MESH:D000068579', (34, 43))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
47915	27835884	More importantly the under-expression of COX-2 is an independent pejorative prognostic factor.	('under-expression', 'Var', (21, 37))	('COX-2', 'Gene', (41, 46))	('COX-2', 'Gene', '5743', (41, 46))
47916	27835884	Low COX-2 and PIK3CA wild-type status was identified as the worse prognostic factor for MFS in our cohort and confirmed for DFS in an independent validation set.	('MFS', 'Disease', (88, 91))	('COX-2', 'Gene', (4, 9))	('PIK3CA', 'Gene', (14, 20))	('COX-2', 'Gene', '5743', (4, 9))	('Low', 'Var', (0, 3))
47935	27835884	COX-2 positivity was significantly correlated with high grade, negative ER, high Ki67, luminal B and triple-negative tumors.	('correlated', 'Reg', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('luminal', 'Disease', (87, 94))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('positivity', 'Var', (6, 16))	('negative', 'NegReg', (63, 71))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('high grade', 'CPA', (51, 61))
47937	27835884	Under-expression of COX-2 transcript was associated with poor prognosis and HR status but was not with other classical criteria like high grade, tumor size or lymph node status.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Under-expression', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('poor prognosis', 'CPA', (57, 71))	('tumor', 'Disease', (145, 150))	('COX-2', 'Gene', (20, 25))	('COX-2', 'Gene', '5743', (20, 25))
47938	27835884	Multivariate analysis showed that COX-2 under-expression, high grade, higher tumor size and lymph node involvement were predictive of poor prognosis.	('lymph node', 'CPA', (92, 102))	('COX-2', 'Gene', '5743', (34, 39))	('high grade', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('under-expression', 'Var', (40, 56))	('COX-2', 'Gene', (34, 39))	('tumor', 'Disease', (77, 82))
47939	27835884	COX-2 under-expression should be thus considered as an independent poor prognostic factor.	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('under-expression', 'Var', (6, 22))
47941	27835884	High COX-2 expression is significantly correlated with better OS of PIK3CA wild-type and mutated patients in the TCGA cohort but this result was not observed in our BC cohort with a longer median follow-up delay (8.6 years for the Curie cohort versus 28.9 months for the TCGA cohort).	('PIK3CA', 'Gene', (68, 74))	('High', 'Var', (0, 4))	('COX-2', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('COX-2', 'Gene', '5743', (5, 10))	('better', 'PosReg', (55, 61))	('mutated', 'Var', (89, 96))	('patients', 'Species', '9606', (97, 105))
47943	27835884	in colorectal cancer, our in vivo PDX experiments showed that celecoxib antitumoral effect was restricted to PIK3CA mutated breast tumors.	('PIK3CA', 'Gene', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('breast tumors', 'Disease', 'MESH:D001943', (124, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('celecoxib', 'Chemical', 'MESH:D000068579', (62, 71))	('colorectal cancer', 'Disease', (3, 20))	('breast tumors', 'Phenotype', 'HP:0100013', (124, 137))	('breast tumor', 'Phenotype', 'HP:0100013', (124, 136))	('mutated', 'Var', (116, 123))	('breast tumors', 'Disease', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
47946	27835884	Eventually, new prospective trials combining celecoxib with hormone therapy or chemotherapy may screen patients for tumor PIK3CA mutations to confirm its predictive value.	('PIK3CA', 'Gene', (122, 128))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('celecoxib', 'Chemical', 'MESH:D000068579', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('patients', 'Species', '9606', (103, 111))	('tumor', 'Disease', (116, 121))
47949	27835884	There were two non-responders tumors in our PIK3CA mutated PDX model.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutated', 'Var', (51, 58))
47953	27835884	In conclusion, treatment with celecoxib may be an additional therapeutic option for patients with BCs expressing COX-2 protein and mutated for PIK3CA whatever the level of cox-2 mRNA expression.	('cox-2', 'Gene', (172, 177))	('patients', 'Species', '9606', (84, 92))	('celecoxib', 'Chemical', 'MESH:D000068579', (30, 39))	('mutated', 'Var', (131, 138))	('PIK3CA', 'Gene', (143, 149))	('COX-2', 'Gene', (113, 118))	('cox-2', 'Gene', '5743', (172, 177))	('protein', 'Protein', (119, 126))	('COX-2', 'Gene', '5743', (113, 118))
47955	27835884	Noteworthy, PIK3CA mutation screening and COX-2 IHC staining are very easy to implement in diagnostic laboratory and could be used routinely for patient selection.	('COX-2', 'Gene', '5743', (42, 47))	('mutation', 'Var', (19, 27))	('patient', 'Species', '9606', (145, 152))	('COX-2', 'Gene', (42, 47))	('PIK3CA', 'Gene', (12, 18))
47979	27835884	Proteins were separated by SDS-PAGE and then electrophoretically transferred into nitrocellulose membrane and probed using the following primary antibodies: anti-GAPDH (V18 clone, 1/20000) purchased from Santa Cruz Biotechnology, anti-COX-2 (12282, 1/1000), anti-phospho Serin 473-AKT (4060, 1/2000), anti-PTEN (9552, 1/2000), anti-INPP4B (14543, 1/2000) and anti-phospho-S6 ribosomal protein (2211, 1/8000) purchased from Cell Signaling Technology (Ozyme).	('AKT', 'Gene', (281, 284))	('INPP4B', 'Gene', '8821', (332, 338))	('PTEN', 'Gene', (306, 310))	('INPP4B', 'Gene', (332, 338))	('PTEN', 'Gene', '5728', (306, 310))	('GAPDH', 'Gene', '2597', (162, 167))	('GAPDH', 'Gene', (162, 167))	('COX-2', 'Gene', (235, 240))	('COX-2', 'Gene', '5743', (235, 240))	('AKT', 'Gene', '207', (281, 284))	('14543', 'Var', (340, 345))
47989	27835884	The effect of celecoxib (purchased from Pfizer) was evaluated in two PDX: HBCx-4B which presents a PIK3CA mutation and HBCx-52, wild-type for this gene, both expressing COX-2.	('PIK3CA', 'Var', (99, 105))	('COX-2', 'Gene', (169, 174))	('celecoxib', 'Chemical', 'MESH:D000068579', (14, 23))	('COX-2', 'Gene', '5743', (169, 174))
48001	30150038	Forty-nine women (BRCA-1/2 mutation carriers and women with >20% lifetime risk) were diagnosed with breast cancer within our high-risk screening program.	('women', 'Species', '9606', (49, 54))	('diagnosed', 'Reg', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA-1/2', 'Gene', (18, 26))	('mutation', 'Var', (27, 35))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('women', 'Species', '9606', (11, 16))	('breast cancer', 'Disease', (100, 113))	('BRCA-1/2', 'Gene', '672;675', (18, 26))
48018	30150038	In addition to the annual triple-modality screening rounds, ultrasound examinations were offered every six months to BRCA mutation carriers.	('mutation', 'Var', (122, 130))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', '672', (117, 121))
48029	30150038	In BRCA-1 mutation carriers, invasive cancers were exclusively TNBC (100%, 9/9 P<0.01).	('invasive cancers', 'Disease', (29, 45))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutation', 'Var', (10, 18))	('carriers', 'Reg', (19, 27))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('BRCA-1', 'Gene', (3, 9))	('BRCA-1', 'Gene', '672', (3, 9))	('invasive cancers', 'Disease', 'MESH:D009362', (29, 45))	('TNBC', 'Chemical', '-', (63, 67))
48030	30150038	BRCA-1 mutation carriers presented mainly with high-grade tumors (G3) for both DCIS (18% 2/11;P>0.5) and invasive carcinomas (81%, 9/11;P=0.012).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('DCIS', 'Disease', (79, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('invasive carcinomas', 'Disease', (105, 124))	('mutation', 'Var', (7, 15))	('invasive carcinomas', 'Disease', 'MESH:D009361', (105, 124))	('BRCA-1', 'Gene', (0, 6))	('BRCA-1', 'Gene', '672', (0, 6))
48031	30150038	BRCA-2 mutation carriers presented more frequently with DCIS (5/9; 56%;P>0.5).	('DCIS', 'Disease', (56, 60))	('BRCA-2', 'Gene', '675', (0, 6))	('mutation', 'Var', (7, 15))	('BRCA-2', 'Gene', (0, 6))
48044	30150038	On MRI, 100% (11/11) of cancers with the BRCA-1 mutation were detected, which was more often than with MG, 60% (6/11), or US, 60% (6/11), P=0.022.	('BRCA-1', 'Gene', '672', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('mutation', 'Var', (48, 56))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('BRCA-1', 'Gene', (41, 47))
48048	30150038	On MRI, all cancers (100%, 9/9) were detected, which was significantly more often than with MG, 56% (5/9, P=0.029), or US, 44% (4/9, P=0.010) (Figure 3).	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('MRI', 'Var', (3, 6))	('cancers', 'Disease', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
48083	30150038	BRCA-1 mutation carriers often present with higher grade and TNBC compared to non-carriers, with rates of TNBC ranging from 50%-88%.	('TNBC', 'Chemical', '-', (61, 65))	('TNBC', 'Chemical', '-', (106, 110))	('mutation', 'Var', (7, 15))	('TNBC', 'Disease', (61, 65))	('BRCA-1', 'Gene', (0, 6))	('BRCA-1', 'Gene', '672', (0, 6))
48092	30150038	found microcalcifications in 50% of cancers in their patients with a BRCA-2 mutation.	('patients', 'Species', '9606', (53, 61))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('calcification', 'Disease', (11, 24))	('cancers', 'Disease', (36, 43))	('BRCA-2', 'Gene', (69, 75))	('BRCA-2', 'Gene', '675', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutation', 'Var', (76, 84))	('calcification', 'Disease', 'MESH:D002114', (11, 24))
48093	30150038	In our study, BRCA-2 carriers were also more likely to present with pure DCIS or DCIS associated with invasive cancer, confirming previous results.	('pure DCIS', 'Disease', (68, 77))	('invasive cancer', 'Disease', (102, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carriers', 'Var', (21, 29))	('associated', 'Reg', (86, 96))	('BRCA-2', 'Gene', (14, 20))	('invasive cancer', 'Disease', 'MESH:D009362', (102, 117))	('BRCA-2', 'Gene', '675', (14, 20))	('DCIS', 'Disease', (81, 85))
48095	30150038	found, in a population of 93 BRCA-1 mutation-carriers, a sensitivity of 93.6% for MRI alone, with no additional value for mammography in MRI screening for women below the age of 40.	('women', 'Species', '9606', (155, 160))	('mutation-carriers', 'Var', (36, 53))	('BRCA-1', 'Gene', (29, 35))	('BRCA-1', 'Gene', '672', (29, 35))
48099	30150038	reported that patients with BRCA mutations exhibited benign morphologic features more frequently, yet kinetic analysis of these masses revealed malignant curves.	('BRCA', 'Gene', '672', (28, 32))	('patients', 'Species', '9606', (14, 22))	('BRCA', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
48108	30150038	This supports data from Schrading et al., who showed that BRCA-1 mutation carriers tend to develop cancers in the posterior part of the breast.	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('develop', 'PosReg', (91, 98))	('mutation', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BRCA-1', 'Gene', (58, 64))	('BRCA-1', 'Gene', '672', (58, 64))
48143	24025166	Even prior to senescence, the aging process and patient-to-patient variation affects gene expression, as shown by quantitative reverse transcription PCR in Additional file 1.	('affects', 'Reg', (77, 84))	('gene expression', 'MPA', (85, 100))	('patient', 'Species', '9606', (59, 66))	('patient', 'Species', '9606', (48, 55))	('P', 'Chemical', 'MESH:D010758', (149, 150))	('variation', 'Var', (67, 76))
48151	24025166	We used the Agilent Quick Amp labeling kit and protocol to synthesize Cy3-labeled reference from Stratagene Universal Human Reference spiked at 1:1,000 with MCF7 RNA and 1:1,000 with ME16C RNA to increase expression of breast cancer genes.	('Cy3', 'Chemical', '-', (70, 73))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('Amp', 'Chemical', 'MESH:D000249', (26, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('breast cancer', 'Disease', (219, 232))	('ME16C RNA', 'Var', (183, 192))	('MCF7', 'CellLine', 'CVCL:0031', (157, 161))	('Human', 'Species', '9606', (118, 123))	('increase', 'PosReg', (196, 204))	('expression', 'MPA', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
48167	24025166	The blots were probed with antibodies against the receptor MET (#8198S; Cell Signaling, Beverly, MA, USA), HGFalpha chain (sc-166724; Santa Cruz, Dallas, TX, USA) and beta-actin (#4967; Cell Signaling, Beverly, MA, USA).	('#4967;', 'Var', (179, 185))	('beta-actin', 'Protein', (167, 177))	('HGFalpha', 'Gene', '3083', (107, 115))	('#8198S', 'Var', (64, 70))	('HGFalpha', 'Gene', (107, 115))	('sc-166724', 'Var', (123, 132))
48170	24025166	The relative quantity of HGF (Hs00300159_m1, ABI catalogue number 4331182) and MET (Hs01565584_m1, ABI catalogue number 4331182) mRNA was assayed by quantitative PCR using an ABI 7900HT machine (Life Technologies, Carlsbad, CA, USA).	('HGF', 'Gene', (25, 28))	('Hs00300159_m1', 'Var', (30, 43))	('HGF', 'Gene', '3082', (25, 28))	('Hs01565584_m1', 'Var', (84, 97))	('P', 'Chemical', 'MESH:D010758', (162, 163))
48200	24025166	Using this regression equation, independent estimates of k were obtained for MCF10A and MCF10DCIS in coculture with and without anti-HGF antibody.	('HGF', 'Gene', (133, 136))	('MCF10A', 'Gene', (77, 83))	('HGF', 'Gene', '3082', (133, 136))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (88, 97))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('MCF10A', 'CellLine', 'CVCL:0598', (77, 83))	('MCF10DCIS', 'Var', (88, 97))
48203	24025166	Two-tailed t tests were performed to determine statistical differences between lumen size (by OCT measurement in 3D morphogenesis assay) of MCF10A and MCF10DCIS, with and without anti-HGF.	('HGF', 'Gene', '3082', (184, 187))	('MCF10DCIS', 'Var', (151, 160))	('MCF10A', 'Var', (140, 146))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('MCF10A', 'CellLine', 'CVCL:0598', (140, 146))	('HGF', 'Gene', (184, 187))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (151, 160))
48204	24025166	A chi-square analysis was performed comparing the presence of apoptosis (yes/no) and lumen (yes/no) in the 3D morphogenesis in MCF10A, MCF10DCIS and MCF10DCIS + anti-HGF cocultures.	('HGF', 'Gene', '3082', (166, 169))	('MCF10A', 'CellLine', 'CVCL:0598', (127, 133))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (149, 158))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (135, 144))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('MCF10DCIS', 'Var', (135, 144))	('MCF10A', 'Var', (127, 133))	('HGF', 'Gene', (166, 169))
48206	24025166	One set of genes was particularly upregulated in MCF10DCIS cells, and not in MCF10A or MCF10AT cells (gray bar in Figure 1A).	('MCF10DCIS', 'Var', (49, 58))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (49, 58))	('MCF10A', 'CellLine', 'CVCL:0598', (87, 93))	('upregulated', 'PosReg', (34, 45))	('MCF10A', 'CellLine', 'CVCL:0598', (77, 83))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))
48211	24025166	MCF10DCIS cells had a high basal-like interaction score (Figure 1B), similar to that of the invasive basal-like breast cancer cell line SUM149.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('SUM149', 'CellLine', 'CVCL:3422', (136, 142))	('breast cancer', 'Disease', (112, 125))	('basal-like interaction score', 'MPA', (27, 55))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
48214	24025166	A striking increase in the number of cytokines expressed occurred in the MCF10DCIS cocultures, with a total of 62 cytokines upregulated by more than 1.5-fold.	('increase', 'PosReg', (11, 19))	('MCF10DCIS', 'Var', (73, 82))	('number of cytokines expressed', 'MPA', (27, 56))	('upregulated', 'PosReg', (124, 135))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (73, 82))
48215	24025166	In contrast, MCF10A and MCF10AT cocultures each upregulated only a small number of cytokines (Table 1; a full list of cytokines and their fold-change relative to monoculture is provided in Additional file 4).	('MCF10A', 'Var', (13, 19))	('MCF10A', 'CellLine', 'CVCL:0598', (24, 30))	('upregulated', 'PosReg', (48, 59))	('MCF10A', 'CellLine', 'CVCL:0598', (13, 19))	('MCF10AT', 'Var', (24, 31))	('cytokines', 'MPA', (83, 92))
48216	24025166	The most highly upregulated cytokine in DCIS cocultures was HGF, which increased monotonically from MCF10A to MCF10AT1 to MCF10DCIS and was upregulated more than 80-fold in MCF10DCIS and 70-fold in MCF10AT1 direct cocultures (Figure 2A).	('upregulated', 'PosReg', (16, 27))	('MCF10A', 'CellLine', 'CVCL:0598', (100, 106))	('MCF10A', 'CellLine', 'CVCL:0598', (110, 116))	('HGF', 'Gene', '3082', (60, 63))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('upregulated', 'PosReg', (140, 151))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (173, 182))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))	('MCF10A', 'Var', (100, 106))	('increased', 'PosReg', (71, 80))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (122, 131))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('HGF', 'Gene', (60, 63))
48224	24025166	HAI-1 was more highly expressed in MCF10A cocultures, and is associated with lower HGF secreted protein by cytokine array analysis.	('lower', 'NegReg', (77, 82))	('MCF10A', 'CellLine', 'CVCL:0598', (35, 41))	('HAI-1', 'Gene', '6692', (0, 5))	('MCF10A', 'Var', (35, 41))	('HGF', 'Gene', (83, 86))	('HAI-1', 'Gene', (0, 5))	('HGF', 'Gene', '3082', (83, 86))
48229	24025166	This effect was not observed (in MCF10A) or markedly diminished (in MCF10AT1) in the other two cell lines of the series.	('MCF10A', 'CellLine', 'CVCL:0598', (68, 74))	('diminished', 'NegReg', (53, 63))	('MCF10AT1', 'Var', (68, 76))	('MCF10A', 'CellLine', 'CVCL:0598', (33, 39))
48230	24025166	The interaction of MCF10DCIS cells with RMF in coculture thus stimulates an increase in HGF secretion and a concomitant increase in epithelial HGF receptor, MET, expression.	('HGF receptor', 'Gene', (143, 155))	('HGF receptor', 'Gene', '4233', (143, 155))	('interaction', 'Interaction', (4, 15))	('increase', 'PosReg', (76, 84))	('HGF', 'Gene', '3082', (88, 91))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (19, 28))	('HGF', 'Gene', (143, 146))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('epithelial', 'MPA', (132, 142))	('MCF10DCIS', 'Var', (19, 28))	('MET', 'MPA', (157, 160))	('expression', 'MPA', (162, 172))	('HGF', 'Gene', '3082', (143, 146))	('increase', 'PosReg', (120, 128))	('HGF', 'Gene', (88, 91))
48241	24025166	While our coculture results show that HGF signaling is already present at the DCIS stage, the importance of this pathway in survival illustrates that the dysregulation of the HGF pathway persists in invasive basal-like tumors and contributes to their progression.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('HGF', 'Gene', (175, 178))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('dysregulation', 'Var', (154, 167))	('contributes', 'Reg', (230, 241))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('HGF', 'Gene', (38, 41))	('HGF', 'Gene', '3082', (175, 178))	('basal-like tumors', 'Phenotype', 'HP:0002671', (208, 225))	('HGF', 'Gene', '3082', (38, 41))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))
48243	24025166	In light of our current data illustrating that (1) MCF10DCIS:RMF cocultures have high basal-like interaction scores, (2) that HGF was secreted/active in MCF10DCIS cocultures, and (3) that HGF signaling is over-represented among invasive basal-like tumors and is prognostic of overall survival, we used HGF-targeted antibodies to study the role of HGF in the basal-like interaction score and functional morphogenic coculture assays.	('MCF10DCIS', 'Var', (51, 60))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('tumors', 'Disease', (248, 254))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (51, 60))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (153, 162))	('over-represented', 'PosReg', (205, 221))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('HGF', 'Gene', '3082', (302, 305))	('HGF', 'Gene', '3082', (188, 191))	('HGF', 'Gene', '3082', (126, 129))	('HGF', 'Gene', (302, 305))	('HGF', 'Gene', '3082', (347, 350))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('HGF', 'Gene', (188, 191))	('HGF', 'Gene', (126, 129))	('basal-like tumors', 'Phenotype', 'HP:0002671', (237, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('HGF', 'Gene', (347, 350))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))
48249	24025166	Using this as a metric, we performed 3D cocultures of MCF10A and MCF10DCIS with RMFs in a Matrigel -collagen mix for 2 weeks.	('RMFs', 'Var', (80, 84))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (65, 74))	('MCF10DCIS', 'Var', (65, 74))	('MCF10A', 'CellLine', 'CVCL:0598', (54, 60))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))
48254	24025166	As shown in Figure 4B, the number of structures without a lumen is high in MCF10A cocultures, and similar in the MCF10DCIS cocultures treated with anti-HGF, whereas the untreated MCF10DCIS cocultures have progressed to form a lumen (Additional file 7; P = 0.0007).	('HGF', 'Gene', '3082', (152, 155))	('cocultures', 'Var', (82, 92))	('MCF10A cocultures', 'Var', (75, 92))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (179, 188))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (113, 122))	('MCF10A', 'CellLine', 'CVCL:0598', (75, 81))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('HGF', 'Gene', (152, 155))	('P', 'Chemical', 'MESH:D010758', (252, 253))
48255	24025166	These differences cannot be attributable to differences in proliferation rates of the cell lines, because the PDTs (in two-dimensional indirect cocultures) are very similar; PDTs of MCF10A and MCF10DCIS in coculture with RMF are 21.3 and 21.5 hours, respectively.	('P', 'Chemical', 'MESH:D010758', (174, 175))	('MCF10A', 'Var', (182, 188))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (193, 202))	('MCF10DCIS', 'Var', (193, 202))	('P', 'Chemical', 'MESH:D010758', (110, 111))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('MCF10A', 'CellLine', 'CVCL:0598', (182, 188))
48260	24025166	Figure 4C shows that, as expected, apoptosis was greater in the cocultures of MCF10A compared with MCF10DCIS cocultures and that treatment with anti-HGF antibody restores MCF10 apoptosis levels to those more similar to MCF10A (Additional file 8; P = 0.0450053).	('restores', 'PosReg', (162, 170))	('P', 'Chemical', 'MESH:D010758', (246, 247))	('greater', 'PosReg', (49, 56))	('apoptosis levels', 'MPA', (177, 193))	('MCF10A', 'Var', (78, 84))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('HGF', 'Gene', '3082', (149, 152))	('MCF10', 'CellLine', 'CVCL:5555', (78, 83))	('MCF10', 'Gene', (171, 176))	('MCF10', 'CellLine', 'CVCL:5555', (171, 176))	('MCF10', 'CellLine', 'CVCL:5555', (99, 104))	('HGF', 'Gene', (149, 152))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (99, 108))	('MCF10', 'CellLine', 'CVCL:5555', (219, 224))	('MCF10A', 'CellLine', 'CVCL:0598', (78, 84))	('MCF10A', 'CellLine', 'CVCL:0598', (219, 225))	('apoptosis', 'CPA', (35, 44))
48268	24025166	Similarly increased malignant potential has been observed in xenograft models with MCF10DCIS, which also preserve stromal interactions.	('MCF10DCIS', 'Var', (83, 92))	('malignant potential', 'CPA', (20, 39))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (83, 92))	('increased', 'PosReg', (10, 19))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
48277	24025166	Mouse models with overexpression of MET induce basal-like tumors with signatures of WNT and epithelial to mesenchymal transition, suggesting that this pathway's importance in tumor biology is conserved across species.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (175, 180))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('basal-like tumors', 'Phenotype', 'HP:0002671', (47, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('MET', 'Var', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Mouse', 'Species', '10090', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('overexpression', 'PosReg', (18, 32))
48280	24025166	In the developing mammary duct, deletion of epithelial MET inhibits ductal branching; and in adult glands, HGF is critical for tubulogenesis.	('epithelial MET', 'Gene', (44, 58))	('deletion', 'Var', (32, 40))	('inhibits', 'NegReg', (59, 67))	('ductal branching', 'CPA', (68, 84))	('HGF', 'Gene', (107, 110))	('HGF', 'Gene', '3082', (107, 110))
48285	24025166	Their study concluded that an imbalance in MET expression between the tumor and the surrounding normal tissue is associated with aggressive DCIS phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('associated', 'Reg', (113, 123))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('tumor', 'Disease', (70, 75))	('MET expression', 'MPA', (43, 57))	('imbalance', 'Var', (30, 39))	('imbalance', 'Phenotype', 'HP:0002172', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('aggressive DCIS phenotypes', 'Disease', (129, 155))
48335	32540554	CESM may decrease FNs especially for women with dense breasts.	('women', 'Species', '9606', (37, 42))	('FNs', 'Disease', (18, 21))	('dense breasts', 'Disease', (48, 61))	('CESM', 'Var', (0, 4))	('decrease', 'NegReg', (9, 17))
48363	27287780	After propensity score matching, preoperative MRI use was significantly associated with a higher synchronous CBC detection rate (108.6 vs. 29.7 per 1,000 person-years; hazard ratio [HR]=3.65; p <.001) with no significant differences in subsequent CBC rate (6.7 vs. 6.8 per 1,000 person-years; HR=0.90; p=.71).	('person', 'Species', '9606', (279, 285))	('MRI', 'Var', (46, 49))	('person', 'Species', '9606', (154, 160))	('higher', 'PosReg', (90, 96))	('synchronous', 'MPA', (97, 108))
48364	27287780	The 6-year cumulative incidence of any CBC (in situ plus invasive) remained significantly higher among women undergoing MRI, compared with those not undergoing MRI (9% vs. 4%, p<.001).	('MRI', 'Var', (120, 123))	('CBC', 'Disease', (39, 42))	('situ plus invasive', 'Disease', (47, 65))	('higher', 'PosReg', (90, 96))	('women', 'Species', '9606', (103, 108))	('situ plus invasive', 'Disease', 'MESH:D002278', (47, 65))
48365	27287780	Women undergoing MRI also had a higher incidence of invasive CBC (4% vs. 3%, p=.04).	('Women', 'Species', '9606', (0, 5))	('invasive CBC', 'Disease', (52, 64))	('MRI', 'Var', (17, 20))
48368	27287780	Patients with DCIS generally do not die from breast cancer unless they have subsequent invasive breast cancer, such as ipsilateral recurrence and new ipsilateral or contralateral breast cancer.	('contralateral breast cancer', 'Disease', 'MESH:D001943', (165, 192))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ipsilateral recurrence', 'Disease', (119, 141))	('invasive breast cancer', 'Disease', (87, 109))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('contralateral breast cancer', 'Disease', (165, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('DCIS', 'Var', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (45, 58))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
48403	27287780	In the propensity-score matched cohort (3,315 women with 12,562 person-years of follow-up; median follow-up: 44 months), women who received MRI had a higher rate of overall CBC occurrence, compared with women who did not receive MRI (19.7 vs. 9.6 per 1,000 person-years; HR 2.11; 95% CI 1.53 to 2.92; Table 2).	('person', 'Species', '9606', (257, 263))	('CBC', 'Disease', (173, 176))	('MRI', 'Var', (140, 143))	('person', 'Species', '9606', (64, 70))	('women', 'Species', '9606', (203, 208))	('women', 'Species', '9606', (46, 51))	('women', 'Species', '9606', (121, 126))
48406	27287780	Women who underwent MRI were more likely to have synchronous invasive stage I CBCs (46.0 vs. 12.5 per 1,000 person-years; HR 3.79; 95% CI 1.94 to 7.40), compared with women who did not receive MRI.	('Women', 'Species', '9606', (0, 5))	('to 7', 'Species', '1214577', (143, 147))	('person', 'Species', '9606', (108, 114))	('MRI', 'Var', (20, 23))	('women', 'Species', '9606', (167, 172))	('synchronous', 'Disease', (49, 60))
48414	27287780	After 6 years of follow-up, cumulative CBC incidence (both in situ and invasive) for women receiving MRI was approximately two times that of women who did not receive MRI (9% vs. 4%; p<.001).	('women', 'Species', '9606', (141, 146))	('CBC', 'Disease', (39, 42))	('MRI', 'Var', (101, 104))	('women', 'Species', '9606', (85, 90))
48415	27287780	Similarly, the 6-year cumulative incidence of invasive CBC remained higher among women receiving MRI than among women who did not receive MRI (4% vs. 3%; p=.04; Figure 2B).	('women', 'Species', '9606', (81, 86))	('women', 'Species', '9606', (112, 117))	('higher', 'PosReg', (68, 74))	('MRI', 'Var', (97, 100))	('invasive CBC', 'Disease', (46, 58))
48567	24755315	These variations will result in temporal variations in estrogen concentration which could alter ER expression.	('estrogen concentration', 'MPA', (55, 77))	('ER', 'Gene', '2099', (96, 98))	('variations', 'Var', (6, 16))	('result', 'Reg', (22, 28))	('alter', 'Reg', (90, 95))
48662	21847387	VABB diminishes the histological underestimation rates, compared to core-needle biopsy, because VABB produces heavier and larger specimens with more contiguous sampling and a higher retrieval rate of calcification.	('VABB', 'Var', (96, 100))	('calcification', 'Disease', 'MESH:D002114', (200, 213))	('retrieval', 'CPA', (182, 191))	('calcification', 'Disease', (200, 213))	('VABB', 'Chemical', '-', (0, 4))	('VABB', 'Chemical', '-', (96, 100))
48701	21847387	Above all, VABB reduces the time between detection and diagnosis, which is very important for patient reassurance.	('time between detection', 'MPA', (28, 50))	('VABB', 'Var', (11, 15))	('reduces', 'NegReg', (16, 23))	('patient', 'Species', '9606', (94, 101))	('VABB', 'Chemical', '-', (11, 15))
48710	32633727	The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions.	('mice', 'Species', '10090', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('expression', 'MPA', (34, 44))	('prevented', 'NegReg', (220, 229))	('inhibition', 'Var', (188, 198))	('STAT5a', 'Gene', (101, 107))	('elevated', 'PosReg', (25, 33))	('Signal Transducer and Activator of Transcription 5a', 'Gene', '20850', (48, 99))
48727	32633727	Conversely, transgenic overexpression of a constitutively activated STAT5a mutant or its upstream JAK2 activator was sufficient to cause tumor formation in the mammary glands of mice.	('overexpression', 'PosReg', (23, 37))	('tumor', 'Disease', (137, 142))	('transgenic', 'Species', '10090', (12, 22))	('mice', 'Species', '10090', (178, 182))	('JAK2', 'Gene', (98, 102))	('JAK2', 'Gene', '16452', (98, 102))	('cause', 'Reg', (131, 136))	('mutant', 'Var', (75, 81))	('STAT5a', 'Gene', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
48730	32633727	STAT5a was also shown to promote the progression of human atypical ductal hyperplasia (ADH), a precursor of DCIS.	('STAT5a', 'Var', (0, 6))	('human', 'Species', '9606', (52, 57))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (67, 85))	('ductal hyperplasia', 'Disease', (67, 85))	('promote', 'PosReg', (25, 32))
48733	32633727	Herein, our current report establishes that phosphorylated STAT5a (Y694) expression is significantly upregulated in the epithelia of DCIS lesions in Cav-1 KO mice following estrogen treatment, compared to wild-type (WT) mice.	('STAT5a', 'Gene', (59, 65))	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('Y694', 'Var', (67, 71))	('DCIS lesion', 'Disease', 'MESH:D002285', (133, 144))	('mice', 'Species', '10090', (158, 162))	('mice', 'Species', '10090', (220, 224))	('expression', 'MPA', (73, 83))	('DCIS lesion', 'Disease', (133, 144))	('upregulated', 'PosReg', (101, 112))
48734	32633727	Functionaly, STAT5a deletion in Cav-1 KO mice prevented mammary ductal branching and foci (DCIS-like lesion) formation, reduced the accumulation of PCNA positive epithelial cells, and maintained mammary ductal integrity by exhibiting both normal basement membrane and smooth muscle actin (myoepithelial) layer following estrogen treatment, suggesting that STAT5a could also play a role in invasion.	('maintained', 'PosReg', (184, 194))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('mammary ductal integrity', 'CPA', (195, 219))	('mice', 'Species', '10090', (41, 45))	('mammary ductal branching', 'CPA', (56, 80))	('deletion', 'Var', (20, 28))	('STAT5a', 'Gene', (13, 19))	('prevented', 'NegReg', (46, 55))	('accumulation', 'MPA', (132, 144))	('PCNA positive epithelial', 'MPA', (148, 172))	('reduced', 'NegReg', (120, 127))
48739	32633727	A similar protocol was utilized to examine if STAT5a was induced during this process and how its deletion could affect DCIS formation in these mice.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('DCIS formation', 'CPA', (119, 133))	('affect', 'Reg', (112, 118))	('deletion', 'Var', (97, 105))	('mice', 'Species', '10090', (143, 147))
48743	32633727	A homozygous deletion of STAT5a in Cav-1 KO mice was sufficient to significantly reduce the development of mammary branching compared to Cav-1 KO mice (1.5-fold, p<0.01, n=7-8), but still significantly higher than the WT group (1.9-fold, p<0.01, n=8-9) (Figure 2B: left panel).	('reduce', 'NegReg', (81, 87))	('development of mammary branching', 'CPA', (92, 124))	('deletion', 'Var', (13, 21))	('mice', 'Species', '10090', (146, 150))	('higher', 'PosReg', (202, 208))	('mice', 'Species', '10090', (44, 48))	('STAT5a', 'Gene', (25, 31))
48746	32633727	The increased level of PCNA nuclear expression observed in Cav-1 KO compared to WT mammary glands (middle panel) was reduced by a homozygous deletion of STAT5a in Cav-1 KO mice.	('reduced', 'NegReg', (117, 124))	('deletion', 'Var', (141, 149))	('STAT5a', 'Gene', (153, 159))	('mice', 'Species', '10090', (172, 176))
48747	32633727	Given the reported involvement of STAT5a in driving the progression of solid tumors, we sought to examine closer whether a STAT5a deletion could restore mammary duct structural integrity in Cav-1 KO mice treated with estrogen.	('mammary duct structural integrity', 'CPA', (153, 186))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mice', 'Species', '10090', (199, 203))	('restore', 'PosReg', (145, 152))	('deletion', 'Var', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('STAT5a', 'Gene', (123, 129))
48749	32633727	To assess how STAT5a deletion affected the histological morphology of the mammary ducts in Cav-1 KO mice, we first stained WT, Cav-1 KO, and Cav-1/STAT5a dKO mammary glands with Masson's Trichrome histochemical stain, which highlights collagen layers surrounding the outside of the mammary ducts (Figure 4A).	('mice', 'Species', '10090', (100, 104))	('affected', 'Reg', (30, 38))	('STAT5a', 'Gene', (14, 20))	('deletion', 'Var', (21, 29))
48756	32633727	This was further confirmed by western blotting (Figure 5B), where densitometry analysis demonstrated a significant increase in phosphorylated STAT5a (Y694) expression in STAT5a overexpressor cells in comparison to empty vector control cells (11.3-fold, p<0.01, n=3) (Figure 5C).	('rat', 'Species', '10116', (95, 98))	('increase', 'PosReg', (115, 123))	('expression', 'MPA', (156, 166))	('overexpressor', 'Var', (177, 190))	('phosphorylated', 'MPA', (127, 141))
48783	32633727	For example, STAT5a expression was predictive of increased overall survival and response to endocrine therapy in ER-positive human invasive breast cancer.	('STAT5a expression', 'Var', (13, 30))	('invasive breast cancer', 'Disease', 'MESH:D001943', (131, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('increased', 'PosReg', (49, 58))	('invasive breast cancer', 'Disease', (131, 153))	('human', 'Species', '9606', (125, 130))	('expression', 'Var', (20, 30))	('ER', 'Gene', '2099', (113, 115))	('overall survival', 'CPA', (59, 75))
48784	32633727	In addition, in vitro experiments demonstrated that STAT5a inhibited the invasion of well-differentiated ER positive human T-47D cells and poorly differentiated ER negative human BT-20 cells.	('T-47D', 'CellLine', 'CVCL:0553', (123, 128))	('ER', 'Gene', '2099', (161, 163))	('human', 'Species', '9606', (117, 122))	('inhibited', 'NegReg', (59, 68))	('rat', 'Species', '10116', (41, 44))	('human', 'Species', '9606', (173, 178))	('BT-20', 'CellLine', 'CVCL:0178', (179, 184))	('invasion', 'CPA', (73, 81))	('ER', 'Gene', '2099', (105, 107))	('STAT5a', 'Var', (52, 58))
48786	32633727	Although our study demonstrates STAT5a as a key factor during DCIS formation in vivo and which also stimulates pro-invasive properties in a DCIS model in vitro, more studies will be warented to fully undertand its biological role in early cancer progression.	('pro-invasive properties', 'MPA', (111, 134))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('rat', 'Species', '10116', (26, 29))	('STAT5a', 'Var', (32, 38))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('cancer', 'Disease', (239, 245))	('stimulates', 'PosReg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
48793	32633727	Important future experiments will focus on overexpressing a traditional nuclear ER-alpha (66KDa) in MCF10DCIS.com and assess whether STAT5a will maintain its pro-invasive properties and/or knocking down ER-alpha 36.	('ER-alpha', 'Gene', (80, 88))	('ER-alpha', 'Gene', '2099', (203, 211))	('knocking', 'Var', (189, 197))	('pro-invasive', 'MPA', (158, 170))	('ER-alpha', 'Gene', '2099', (80, 88))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (100, 113))	('ER-alpha', 'Gene', (203, 211))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))
48794	32633727	Interestingly, a previous study showed that in a model of traditional nuclear ER-alpha-66 overexpression, a deletion of STAT5a did not prevent chemically-induced tumors in the presence of estrogen, which could also hint at the importance of the ER subtypes to fully understand the role of this transcription factor.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ER-alpha', 'Gene', (78, 86))	('hint', 'Gene', '3094', (215, 219))	('hint', 'Gene', (215, 219))	('STAT5a', 'Gene', (120, 126))	('ER', 'Gene', '2099', (245, 247))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('ER-alpha', 'Gene', '2099', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('ER', 'Gene', '2099', (78, 80))	('deletion', 'Var', (108, 116))
48808	32633727	To our knowledge, no studies have yet correlated the levels of STAT5a, especially the Y694 phosphorylated form, to histological grades of DCIS and invasive potential in vivo or in patients.	('DCIS', 'Disease', (138, 142))	('invasive potential', 'CPA', (147, 165))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('Y694 phosphorylated', 'Var', (86, 105))	('patients', 'Species', '9606', (180, 188))
48812	32633727	In summary, whether phosphorylated STAT5a (Y694) could serve as a clinical biomarker and potential target to help treat Cav-1-depleted DCIS population at greater risk of progressing to IBC remains a future avenue for further exploration.	('Y694', 'Var', (43, 47))	('IBC', 'Disease', (185, 188))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('rat', 'Species', '10116', (230, 233))	('Cav-1-depleted', 'Gene', (120, 134))
48852	32633727	The MCF10DCIS.com cell line was cultured in phenol-free DMEM/F12 medium (Cat#21041025, ThermoFisher Scientific, Waltham, MA) supplemented with 5.26% charcoal-stripped horse serum (Cat#NC9058780, ThermoFisher Scientific, Waltham, MA), 1.05mM calcium chloride (Cat#21115-100ML, Sigma-Aldrich, St. Louis, MO), and 10mM HEPES (Cat#15630080, ThermoFisher Scientific, Waltham, MA).	('Cat#15630080', 'Var', (323, 335))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (4, 17))	('phenol', 'Chemical', 'MESH:D019800', (44, 50))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('Cat#NC9058780', 'Var', (180, 193))
48853	32633727	293T cells (Cat#CRL-3216, ATCC, Manassas, VA) were cultured in DMEM medium (Cat#11965118) supplemented with 10% fetal bovine serum (FBS) (Cat#16140071) and 1% penicillin/streptomycin (Cat#15140163) (ThermoFisher Scientific, Waltham, MA).	('penicillin', 'Chemical', 'MESH:D010406', (159, 169))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('Cat#16140071', 'Var', (138, 150))	('DMEM medium', 'Chemical', '-', (63, 74))	('streptomycin', 'Chemical', 'MESH:D013307', (170, 182))	('Cat#15140163', 'Var', (184, 196))	('Cat#11965118', 'Var', (76, 88))
48873	32633727	Samples were homogenized in RIPA lysis buffer (50mM Tris pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 0.5% deoxycholate, 0.1% SDS) supplemented with complete mini protease inhibitor cocktail (Cat#NC0969110, Roche Diagnostics, Basel, Switzerland) and phosphatase inhibitor cocktail (Cat#78428, ThermoFisher Scientific, Waltham, MA).	('Cat#NC0969110', 'Var', (185, 198))	('Tris', 'Chemical', '-', (52, 56))	('RIPA lysis buffer', 'Chemical', '-', (28, 45))	('SDS', 'Chemical', 'MESH:D012967', (119, 122))	('NaCl', 'Chemical', 'MESH:D012965', (72, 76))	('Nonidet P-40', 'Chemical', 'MESH:C010615', (81, 93))	('Cat#78428', 'Var', (275, 284))	('deoxycholate', 'Chemical', 'MESH:D003840', (100, 112))
48894	28584621	A core needle biopsy (CNB) was performed, and pathologic analysis revealed low-grade DCIS in solid and cribriform patterns in a background of complex fibroadenoma (Fig.	('low-grade', 'Var', (75, 84))	('fibroadenoma', 'Disease', 'MESH:D018226', (150, 162))	('fibroadenoma', 'Disease', (150, 162))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))
48971	25537958	For women diagnosed with breast cancer during follow-up, we describe the characteristics of the breast tumors including extent of disease (in-situ versus invasive), and, among invasive cancers, late stage (IIB-IV), grade, size (<10, 10-19, or >=20 mm), and nodal status.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast tumors', 'Disease', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('invasive cancers', 'Disease', 'MESH:D009362', (176, 192))	('breast cancer', 'Disease', (25, 38))	('women', 'Species', '9606', (4, 9))	('breast tumors', 'Phenotype', 'HP:0100013', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('<10', 'Var', (228, 231))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('invasive cancers', 'Disease', (176, 192))	('breast tumors', 'Disease', 'MESH:D001943', (96, 109))
49020	25257856	Detection of ductal carcinoma in situ (DCIS) significantly increased with FFDM (0.05 % vs 0.09 %; p = 0.010), along with the proportion of small invasive cancers (<20 mm) (69.37 % vs 78.90 %; p = 0.040).	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (13, 37))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('ductal carcinoma in situ', 'Disease', (13, 37))	('FFDM', 'Chemical', '-', (74, 78))	('small invasive cancers', 'Disease', 'MESH:D055752', (139, 161))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (13, 37))	('small invasive cancers', 'Disease', (139, 161))	('FFDM', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('increased', 'PosReg', (59, 68))
49021	25257856	The false-positive rate decreased with FFDM (4.79 % vs 3.38 %; p < 0.001) without differences in the cancer detection rate (0.42 % vs 0.43 %; p = 0.685) or in the interval cancer rate (0.14 % vs 0.14 %; p = 0.816).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('decreased', 'NegReg', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (101, 107))	('interval cancer', 'Disease', (163, 178))	('FFDM', 'Chemical', '-', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('interval cancer', 'Disease', 'MESH:D009369', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('FFDM', 'Var', (39, 43))	('cancer', 'Disease', (172, 178))
49080	25257856	In DCIS, the percentage of high-grade tumours was higher in those detected with FFDM than with SFM, although this difference was not statistically significant (60.34 % vs. 51.22 %, respectively; p = 0.581).	('tumours', 'Disease', (38, 45))	('higher', 'PosReg', (50, 56))	('FFDM', 'Var', (80, 84))	('FFDM', 'Chemical', '-', (80, 84))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (38, 45))
49113	25257856	Some studies have described a reduction in PPV after the introduction of FFDM, whereas others, including ours, have shown an increase, especially in successive screenings.	('PPV', 'MPA', (43, 46))	('reduction', 'NegReg', (30, 39))	('FFDM', 'Var', (73, 77))	('FFDM', 'Chemical', '-', (73, 77))
49211	20006623	Finally in the Discussion section, we analyze the changes in morphological subtype with variations in the parameters that most strongly affect biomechanical forces: intra-ductal pressure, cellular proliferation, and apoptosis.	('si', 'Chemical', 'MESH:D012825', (222, 224))	('apoptosis', 'CPA', (216, 225))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('cellular proliferation', 'CPA', (188, 210))	('variations', 'Var', (88, 98))	('intra-ductal', 'MPA', (165, 177))
49406	14612904	Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence In situ carcinoma of the breast has been a more frequent observation since the introduction of mammography screening, now accounting for up to 20% of all mammographically detected breast malignancies, compared to a few percent in the prescreening era (Rosner et al, 1980; Ringberg et al, 1991; Ernster et al, 2002) As with invasive breast cancer, noninvasive breast lesions appear to be heterogenous in nature and the relationship between preinvasive and invasive disease is not yet fully clarified.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cyclin D1', 'Gene', '595', (115, 124))	('breast malignancies', 'Disease', (341, 360))	('invasive disease', 'Disease', 'MESH:D009362', (616, 632))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('breast lesions', 'Disease', (520, 534))	('situ carcinoma of the breast', 'Disease', (164, 192))	('breast malignancies', 'Disease', 'MESH:D001943', (341, 360))	('situ carcinoma of the breast', 'Disease', 'MESH:D000071960', (164, 192))	('ductal carcinoma', 'Disease', 'MESH:D044584', (58, 74))	('invasive disease', 'Disease', (616, 632))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (58, 82))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (169, 192))	('low', 'Var', (111, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (493, 506))	('invasive breast cancer', 'Disease', (484, 506))	('cyclin D1', 'Gene', (115, 124))	('invasive breast cancer', 'Disease', 'MESH:D001943', (484, 506))	('ductal carcinoma', 'Disease', (58, 74))	('breast lesions', 'Disease', 'MESH:D001941', (520, 534))
49413	14612904	Invasive breast cancers overexpressing cyclin D1 are predominantly oestrogen receptor (OR)-positive, whereas cyclin E high tumours in contrast are OR-negative and often p27 low as well as p53- and pRb-inactivated (Nielsen et al, 1999; Loden et al, 2002).	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('pRb', 'Gene', '5925', (197, 200))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('oestrogen receptor', 'Protein', (67, 85))	('cyclin D1', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancers', 'Disease', 'MESH:D001943', (9, 23))	('E high tumours', 'Disease', (116, 130))	('breast cancers', 'Disease', (9, 23))	('p53', 'Gene', '7157', (188, 191))	('low', 'NegReg', (173, 176))	('breast cancers', 'Phenotype', 'HP:0003002', (9, 23))	('p27', 'Gene', '3429', (169, 172))	('p53', 'Gene', (188, 191))	('p27', 'Gene', (169, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('pRb', 'Gene', (197, 200))	('E high tumours', 'Disease', 'MESH:D016751', (116, 130))
49414	14612904	It is obvious that certain genetic alterations are clustered in breast cancer and it is likely that these changes also are found in preinvasive forms of breast cancer such as DCIS.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('genetic alterations', 'Var', (27, 46))	('breast cancer', 'Disease', (64, 77))	('DCIS', 'Disease', (175, 179))
49415	14612904	In the present study, we wanted to determine the expression of various cell cycle regulating proteins in a series of DCIS cases arranged in a tissue microarray (TMA) and to delineate potential clusters of aberrations in cyclin D1, cyclin E, p27 and p16 and their associations to local recurrence.	('p16', 'Gene', (249, 252))	('p27', 'Gene', '3429', (241, 244))	('p27', 'Gene', (241, 244))	('aberrations', 'Var', (205, 216))	('cyclin', 'Gene', (231, 237))	('p16', 'Gene', '1029', (249, 252))	('associations', 'Interaction', (263, 275))	('cyclin', 'Gene', (220, 226))	('local recurrence', 'Disease', (279, 295))
49421	14612904	All tumours have earlier been reevaluated regarding histopathological features and sets of clinicopathological parameters and tumour biological factors have also been reported (OR, PgR, c-erb-B-2, bcl-2, p53, DNA ploidy status and Ki-67) (Ringberg et al, 2001).	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('Ki-67', 'Var', (231, 236))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('c-erb-B-2', 'Gene', (186, 195))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('c-erb-B-2', 'Gene', '2064', (186, 195))	('bcl-2', 'Gene', (197, 202))	('PgR', 'Gene', (181, 184))	('DNA ploidy status', 'Var', (209, 226))	('p53', 'Gene', '7157', (204, 207))	('Ki-67', 'Chemical', '-', (231, 236))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('bcl-2', 'Gene', '596', (197, 202))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('p53', 'Gene', (204, 207))	('tumour', 'Disease', (126, 132))	('PgR', 'Gene', '5241', (181, 184))	('tumours', 'Disease', (4, 11))
49424	14612904	The following antibodies were used: Cyclin D1 (1 : 1000 M1755, Dako, Denmark), Ki-67, (1 : 200, M0722, DAKO, Denmark), cyclin E (1 : 100 HE12, Santa Cruz, CA, USA), p16 (1 : 200, BD PharMingen, San Jose, CA, USA), p27Kip 1 antibody (1 : 200, DAKO, Denmark).	('p27Kip 1', 'Gene', '1027', (214, 222))	('1 : 100 HE12', 'Var', (129, 141))	('p16', 'Gene', (165, 168))	('Ki-67', 'Chemical', '-', (79, 84))	('1 : 200', 'Var', (87, 94))	('p27Kip 1', 'Gene', (214, 222))	('p16', 'Gene', '1029', (165, 168))
49436	14612904	Cell cycle aberrations will presumably increase the proliferation in tumours and we therefore characterised the proliferation in the DCIS material using Ki-67 as a marker.	('aberrations', 'Var', (11, 22))	('tumours', 'Disease', (69, 76))	('proliferation', 'CPA', (52, 65))	('Cell cycle', 'CPA', (0, 10))	('increase', 'PosReg', (39, 47))	('Cell cycle aberrations', 'Phenotype', 'HP:0011018', (0, 22))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('Ki-67', 'Chemical', '-', (153, 158))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
49437	14612904	Like others, we have earlier observed striking associations between various aberrations in cell cycle regulatory proteins in invasive breast carcinomas (Nielsen et al, 1999).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('aberrations', 'Var', (76, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('breast carcinomas', 'Phenotype', 'HP:0003002', (134, 151))	('aberrations in cell cycle', 'Phenotype', 'HP:0011018', (76, 101))	('cell', 'Protein', (91, 95))	('invasive breast carcinomas', 'Disease', (125, 151))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (125, 151))
49440	14612904	As also shown in Figure 3B, this pattern is similar to previous data obtained from Western blot analyses of invasive breast carcinomas (Nielsen et al, 1997), suggesting that the relation between aberrations in these two cell cycle regulatory proteins is comparable in DCIS and invasive carcinomas.	('aberrations', 'Var', (195, 206))	('invasive carcinomas', 'Disease', 'MESH:D009361', (277, 296))	('invasive carcinomas', 'Disease', (277, 296))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (108, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('DCIS', 'Disease', (268, 272))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('invasive breast carcinomas', 'Disease', (108, 134))	('breast carcinomas', 'Phenotype', 'HP:0003002', (117, 134))
49461	14612904	Most studies delineating the prognostic importance for cyclin D1 overexpression in breast cancer have been performed using invasive tumours and the results are diverging: some studies indicate that cyclin D1 overexpression is associated with a negative clinical outcome (Ohta et al, 1997; Kenny et al, 1999), some show no prognostic significance (Michalides et al, 1996; van Diest et al, 1997), while others report a better prognosis for cyclin D1 high tumours (Gillett et al, 1996; Hwang et al, 2003).	('invasive tumours', 'Disease', (123, 139))	('high tumours', 'Disease', (448, 460))	('cyclin', 'Var', (198, 204))	('overexpression', 'PosReg', (208, 222))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (453, 459))	('cyclin D1', 'Gene', (438, 447))	('breast cancer', 'Disease', (83, 96))	('invasive tumours', 'Disease', 'MESH:D009361', (123, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumours', 'Phenotype', 'HP:0002664', (453, 460))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('high tumours', 'Disease', 'MESH:D009369', (448, 460))
49479	29532340	Of these 122 cases, 91 (75%) had pure RS on CNB while 31 (25%) had associated atypia or HRL.	('atypia or HRL', 'Disease', (78, 91))	('pure RS', 'Var', (33, 40))	('RS', 'Chemical', '-', (38, 40))	('CNB', 'Gene', (44, 47))	('atypia or HRL', 'Disease', 'MESH:C563273', (78, 91))
49514	29532340	Of the 31 patients with RS and atypia on image-guided CNB, 26 (84%) of the patients had an excisional biopsy and none of these patients were diagnosed with a breast cancer on the excisional biopsy (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('patients', 'Species', '9606', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('RS', 'Chemical', '-', (24, 26))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (10, 18))	('atypia', 'Var', (31, 37))
49630	24188089	Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55-64 and >=65 years (Page-interaction = 0.02).	('Women', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (65, 89))	('women', 'Species', '9606', (109, 114))	('high MD', 'Var', (26, 33))	('ductal carcinoma in situ', 'Disease', (65, 89))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (65, 89))
49669	24188089	Low MD (that is, 0 to 10%) was not significantly associated with a reduced risk of tumors <1.1 cm compared with the referent category MD 11 to 25%; however, for tumors >1.1 cm, low MD was significantly associated with lower risk (ORs: 0.31 to 0.60) (Figure 1; see also Table S3 in Additional file 2).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('low', 'Var', (177, 180))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
49673	24188089	For women aged <55 years, a stronger association was observed for ER-negative disease (OR: 2.84, 95% confidence interval: 1.83, 4.40) versus ER-positive disease (OR: 1.96; 95% confidence interval: 1.56, 2.45) for MD 51% + versus MD 11 to 25% (Pheterogeneity = 0.09), while associations for women aged >=55 years were nonstatistically significantly stronger for ER-positive tumors versus ER-negative tumors.	('ER', 'Gene', '2099', (387, 389))	('ER', 'Gene', '2099', (141, 143))	('ER', 'Gene', '2099', (66, 68))	('tumors', 'Disease', (373, 379))	('tumors', 'Disease', 'MESH:D009369', (399, 405))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('ER', 'Gene', '2099', (361, 363))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('women', 'Species', '9606', (290, 295))	('women', 'Species', '9606', (4, 9))	('tumors', 'Disease', (399, 405))	('MD 51% +', 'Var', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('tumors', 'Phenotype', 'HP:0002664', (399, 405))
49718	24188089	This work was supported in part by the National Institutes of Health, National Cancer Institute (R01 CA140286, R01 CA128931, P50 CA58207, P50 CA116201, R01 CA97396, R01 CA 122340, P01 CA087969, R01 CA050385, R01 CA124865, and R01 CA131332), the Breast Cancer Research Foundation and the Department of Defense (DAMD 17-00-1-033).	('Cancer', 'Disease', (252, 258))	('P50 CA116201', 'Var', (138, 150))	('P50 CA58207', 'Var', (125, 136))	('CA97396', 'Var', (156, 163))	('CA087969', 'Chemical', '-', (184, 192))	('R01 CA131332', 'Var', (226, 238))	('R01 CA 122340', 'Var', (165, 178))	('R01 CA128931', 'Var', (111, 123))	('Cancer', 'Disease', 'MESH:D009369', (79, 85))	('R01 CA124865', 'Var', (208, 220))	('R01 CA97396', 'Var', (152, 163))	('Cancer', 'Disease', 'MESH:D009369', (252, 258))	('R01 CA050385', 'Var', (194, 206))	('CA124865', 'Chemical', '-', (212, 220))	('CA97396', 'Chemical', '-', (156, 163))	('CA128931', 'Chemical', '-', (115, 123))	('Breast Cancer', 'Disease', 'MESH:D001943', (245, 258))	('CA116201', 'Chemical', '-', (142, 150))	('R01 CA140286', 'Var', (97, 109))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Breast Cancer', 'Disease', (245, 258))	('CA58207', 'Chemical', '-', (129, 136))	('Cancer', 'Disease', (79, 85))	('Breast Cancer', 'Phenotype', 'HP:0003002', (245, 258))	('P01 CA087969', 'Var', (180, 192))	('CA050385', 'Chemical', '-', (198, 206))
49722	22887771	Differential Copy Number Aberrations in Novel Candidate Genes Associated with Progression from In Situ to Invasive Ductal Carcinoma of the Breast Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease.	('Associated', 'Reg', (62, 72))	('Carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Situ to Invasive Ductal Carcinoma', 'Disease', 'MESH:D002285', (98, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (177, 201))	('Carcinoma of the Breast', 'Phenotype', 'HP:0100013', (122, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('Situ to Invasive Ductal Carcinoma', 'Disease', (98, 131))	('Ductal Carcinoma', 'Phenotype', 'HP:0030075', (115, 131))	('Differential Copy Number Aberrations', 'Var', (0, 36))	('intraductal carcinomas of the breast give rise to stromally invasive disease', 'Disease', 'MESH:D002285', (165, 241))
49727	22887771	Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions.	('PD versus MD lesions', 'Disease', 'MESH:D010300', (74, 94))	('PD versus MD lesions', 'Disease', (74, 94))	('Copy number changes', 'Var', (0, 19))
49739	22887771	We hypothesized that alterations in the genome of the intraductal tumor cells play a major role in determining whether a particular epithelial neoplasm will interact with its microenvironment in a way that enables the tumor cells to break through the basement membrane and invade the stroma.	('epithelial neoplasm', 'Disease', 'MESH:D002277', (132, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('enables', 'Reg', (206, 213))	('intraductal tumor', 'Disease', 'MESH:D002285', (54, 71))	('tumor', 'Disease', (66, 71))	('break through', 'CPA', (233, 246))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('epithelial neoplasm', 'Phenotype', 'HP:0031492', (132, 151))	('intraductal tumor', 'Disease', (54, 71))	('epithelial neoplasm', 'Disease', (132, 151))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (218, 223))	('invade', 'CPA', (273, 279))	('alterations', 'Var', (21, 32))
49741	22887771	Our approach included whole genome profiling of highly enriched neoplastic cell populations microdissected from LGDCIS lesions with and without associated invasive carcinoma using high density comparative genomic hybridization (CGH) microarrays, identifying differential copy number gains or losses in indolent (without evidence of invasion) versus aggressive neoplasms (that had progressed to invasive carcinoma), and validating copy number changes in candidate genes by quantitative PCR (qPCR).	('neoplasms', 'Disease', 'MESH:D009369', (360, 369))	('neoplasms', 'Disease', (360, 369))	('invasive carcinoma', 'Disease', (394, 412))	('neoplasm', 'Phenotype', 'HP:0002664', (360, 368))	('copy', 'Var', (430, 434))	('gains', 'PosReg', (283, 288))	('invasive carcinoma', 'Disease', (155, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (403, 412))	('copy number', 'Var', (271, 282))	('neoplasms', 'Phenotype', 'HP:0002664', (360, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('invasive carcinoma', 'Disease', 'MESH:D009361', (394, 412))	('losses', 'NegReg', (292, 298))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('invasive carcinoma', 'Disease', 'MESH:D009361', (155, 173))
49760	22887771	One mug of male control and the tumor DNA (1-5 mug of BioScore product) was random primer labeled with Cy3 and Cy5 respectively, using a BioArray CGH Labeling System (Enzo Life Sciences, Farmingdale, NY) as previously described.	('Cy5', 'Var', (111, 114))	('Cy5', 'Chemical', 'MESH:C085321', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Cy3', 'Var', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('Cy3', 'Chemical', '-', (103, 106))
49770	22887771	Comparative qPCR experiments were performed to confirm the differential copy number changes of 19 candidate genes from 16 regions on 13 chromosomal arms that were differentially amplified or deleted in PD versus MD lesions.	('PD versus MD lesions', 'Disease', 'MESH:D010300', (202, 222))	('PD versus MD lesions', 'Disease', (202, 222))	('deleted', 'Var', (191, 198))	('copy number changes', 'Var', (72, 91))
49776	22887771	Frequencies of copy number losses (L), normal (N) and gains (G) observed in patients with indolent (PD) and aggressive DCIS (MD) were reported as contingency tables, and association to DCIS progression was assessed using Fisher's exact test.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('patients', 'Species', '9606', (76, 84))	('copy number', 'Var', (15, 26))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('gains', 'PosReg', (54, 59))	('aggressive DCIS', 'Disease', (108, 123))	('losses', 'NegReg', (27, 33))
49777	22887771	A score of +1 was assigned to copy number losses for nuclear receptor corepressor 2/silencing mediator of retinoid and thyroid hormone receptor (NCOR2/SMRT), nuclear receptor subfamily 4 group A member 1/Nur77 orphan receptor TR3 (NR4A1/NUR77/TR3), dynein light chain roadblock-type 2/dynein cytoplasmic light polypeptide 2B (DYNLRB2/DNLC2B), suppression of tumerogenicity 13/Hsp70 interacting protein (ST13/HIP), uroplakin 3A (UPK3A) and cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1), and for copy number gains in Grb2-related adapter protein 2 (GRAP2) and TATA box binding protein-associated factor 1C (TAF1C).	('TAF1C', 'Gene', (614, 619))	('UPK3A', 'Gene', (428, 433))	('roadblock-type 2/dynein cytoplasmic light polypeptide 2B', 'Gene', '83657', (268, 324))	('nuclear receptor subfamily 4 group A member 1', 'Gene', '3164', (158, 203))	('copy number', 'Var', (503, 514))	('NR4A1', 'Gene', (231, 236))	('uroplakin 3A', 'Gene', '7380', (414, 426))	('Nur77', 'Gene', (204, 209))	('DNLC2B', 'Gene', '83657', (334, 340))	('cadherin EGF LAG seven-pass G-type receptor 1', 'Gene', '9620', (439, 484))	('DNLC2B', 'Gene', (334, 340))	('TR3', 'Gene', '3164', (243, 246))	('UPK3A', 'Gene', '7380', (428, 433))	('TR3', 'Gene', '3164', (226, 229))	('Nur77', 'Gene', '3164', (204, 209))	('GRAP2', 'Gene', (556, 561))	('gains', 'PosReg', (515, 520))	('SMRT', 'Gene', '9612', (151, 155))	('NR4A1', 'Gene', '3164', (231, 236))	('DYNLRB2', 'Gene', '83657', (326, 333))	('TR3', 'Gene', (243, 246))	('TR3', 'Gene', (226, 229))	('cadherin EGF LAG seven-pass G-type receptor 1', 'Gene', (439, 484))	('DYNLRB2', 'Gene', (326, 333))	('suppression of tumerogenicity 13/Hsp70 interacting protein', 'Gene', '6767', (343, 401))	('TATA box binding protein-associated factor 1C', 'Gene', (567, 612))	('TAF1C', 'Gene', '9013', (614, 619))	('TATA box binding protein-associated factor 1C', 'Gene', '9013', (567, 612))	('SMRT', 'Gene', (151, 155))	('nuclear receptor subfamily 4 group A member 1', 'Gene', (158, 203))	('NCOR2', 'Gene', (145, 150))	('NUR77', 'Gene', (237, 242))	('Grb2-related adapter protein 2', 'Gene', (524, 554))	('NCOR2', 'Gene', '9612', (145, 150))	('NUR77', 'Gene', '3164', (237, 242))	('Grb2-related adapter protein 2', 'Gene', '9402', (524, 554))	('GRAP2', 'Gene', '9402', (556, 561))	('CELSR1', 'Gene', '9620', (486, 492))	('ST13/HIP', 'Gene', (403, 411))	('CELSR1', 'Gene', (486, 492))	('uroplakin 3A', 'Gene', (414, 426))	('ST13/HIP', 'Gene', '6767', (403, 411))
49778	22887771	Pure low grade DCIS lesions without an invasive component (PD) had a higher average frequency of DNA copy number changes compared to mixed DCIS (MD) that had progressed to invasive carcinoma (Table 2, P = 0.047 for difference in total fractional copy number aberrations (CNAs)).	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('invasive carcinoma', 'Disease', (172, 190))	('changes', 'Var', (113, 120))	('DNA copy number', 'Gene', (97, 112))	('DCIS', 'Disease', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('invasive carcinoma', 'Disease', 'MESH:D009361', (172, 190))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))
49784	22887771	There were no significant differences in the distribution of chromosomal copy number changes between mixed DCIS (MD) and invasive carcinomas (MI) (Figure 2).	('invasive carcinomas', 'Disease', (121, 140))	('invasive carcinomas', 'Disease', 'MESH:D009361', (121, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('chromosomal copy number changes', 'Var', (61, 92))	('mixed DCIS', 'Disease', (101, 111))
49787	22887771	CELSR1 and UPK3A (both on 22q13.31) were more commonly amplified in PD, while GRAP2 showed more common gains in MD.	('amplified', 'Var', (55, 64))	('GRAP2', 'Gene', (78, 83))	('GRAP2', 'Gene', '9402', (78, 83))	('UPK3A', 'Gene', '7380', (11, 16))	('UPK3A', 'Gene', (11, 16))	('CELSR1', 'Gene', '9620', (0, 6))	('CELSR1', 'Gene', (0, 6))
49792	22887771	For the eight confirmed candidate genes showing differential copy number changes in PD versus MD lesions by qPCR, we explored whether a combination of all or some of these genes may have greater discriminatory power.	('copy number changes', 'Var', (61, 80))	('PD versus MD lesions', 'Disease', (84, 104))	('PD versus MD lesions', 'Disease', 'MESH:D010300', (84, 104))
49807	22887771	Interestingly, we found that many of the chromosomal aberrations more commonly seen in PD lesions were copy number gains, suggesting the novel concept that, at the molecular level, LGDCIS without the propensity to progress are dead end lesions that may be characterized by amplification and possible activation of invasion suppressor genes.	('PD lesions', 'Disease', (87, 97))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (41, 64))	('DCIS', 'Phenotype', 'HP:0030075', (183, 187))	('PD lesions', 'Disease', 'MESH:D010300', (87, 97))	('copy', 'Var', (103, 107))
49828	22887771	The transcription co-factor TAF1C (on 16q24.1) was more commonly deleted in pure DCIS lesions.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('TAF1C', 'Gene', (28, 33))	('deleted', 'Var', (65, 72))	('pure DCIS lesions', 'Disease', (76, 93))	('TAF1C', 'Gene', '9013', (28, 33))
49834	22887771	This finding may be somewhat analogous to the well documented presence of both amplifications and deletions in the topoisomerase IIalpha gene in breast tumors.	('breast tumors', 'Disease', 'MESH:D001943', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('breast tumors', 'Disease', (145, 158))	('breast tumor', 'Phenotype', 'HP:0100013', (145, 157))	('breast tumors', 'Phenotype', 'HP:0100013', (145, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('deletions', 'Var', (98, 107))
49874	26215193	Although studies have shown that local recurrence at 5 years is more common in patients with high-grade DCIS, these differences do not persist with longer follow-up.	('local recurrence', 'CPA', (33, 49))	('DCIS', 'Disease', (104, 108))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('high-grade', 'Var', (93, 103))	('patients', 'Species', '9606', (79, 87))
49957	25490766	Although relatively less work has focused on the evaluation of breast biopsies with benign pathological diagnoses, nuclear morphometry in benign proliferative lesions has been associated with the subsequent development of breast cancer.	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('nuclear morphometry', 'Var', (115, 134))	('associated with', 'Reg', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
49961	25490766	Our study demonstrates that models comprised of relatively small sets of quantitative nuclear features can achieve high accuracy for the classification of UDH vs. DCIS and low grade vs high grade DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (196, 200))	('UDH', 'Chemical', '-', (155, 158))	('low grade', 'Var', (172, 181))	('DCIS', 'Disease', (163, 167))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('UDH', 'Disease', (155, 158))
49969	21375733	Twenty-nine miRNA and 420 mRNA were aberrantly expressed between HN and DCIS.	('aberrantly', 'Var', (36, 46))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
49973	21375733	Augmentation of CBX7 by knockdown of miR-182 expression, in turn, positively regulated the expression of E-cadherin, a key protein involved in maintaining normal epithelial cell morphology, which is commonly lost during neoplastic progression.	('expression', 'MPA', (91, 101))	('miR-182', 'Gene', (37, 44))	('regulated', 'Reg', (77, 86))	('E-cadherin', 'Gene', (105, 115))	('CBX7', 'Gene', (16, 20))	('E-cadherin', 'Gene', '999', (105, 115))	('miR-182', 'Gene', '406958', (37, 44))	('CBX7', 'Gene', '23492', (16, 20))	('knockdown', 'Var', (24, 33))	('epithelia', 'Disease', 'None', (162, 171))	('epithelia', 'Disease', (162, 171))
49975	21375733	Further, we demonstrate that altered miRNA expression can modulate gene expression changes that characterize these early cancers.	('cancers', 'Disease', (121, 128))	('miR', 'Gene', '220972', (37, 40))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('miR', 'Gene', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gene expression changes', 'MPA', (67, 90))	('altered', 'Var', (29, 36))	('modulate', 'Reg', (58, 66))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
49976	21375733	We conclude that miRNA dysregulation likely plays a substantial role in early breast cancer development.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('dysregulation', 'Var', (23, 36))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
50020	21375733	qRT-PCR was performed by diluting RT product in 2x Universal PCR MasterMix and 20x TaqMan Gene Expression Assay for each gene to be measured: chromobox homolog 7 (CBX7) (Hs00980916_g1), docking protein 4 (DOK4) (Hs00902919_g1), early growth response 1 (EGR1) (Hs00152928_m1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (4333764F), mediator of ErbB2-driven cell motility (MEMO1) (Hs00831646_uH), N-myristoyltransferase 2 (NMT2) (Hs01013924_g1) and nuclear receptor-interacting protein 1 (NRIP1/RIP140) (Hs00942766_s1).	('chromobox homolog 7', 'Gene', (142, 161))	('DOK4', 'Gene', (205, 209))	('N-myristoyltransferase 2', 'Gene', (401, 425))	('GAPDH', 'Gene', '2597', (318, 323))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (276, 316))	('EGR1', 'Gene', (253, 257))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (276, 316))	('RIP140', 'Gene', (499, 505))	('EGR1', 'Gene', '1958', (253, 257))	('N-myristoyltransferase 2', 'Gene', '9397', (401, 425))	('CBX7', 'Gene', (163, 167))	('chromobox homolog 7', 'Gene', '23492', (142, 161))	('NRIP1', 'Gene', '8204', (493, 498))	('Hs00152928_m1', 'Var', (260, 273))	('docking protein 4', 'Gene', (186, 203))	('DOK4', 'Gene', '55715', (205, 209))	('early growth response 1', 'Gene', (228, 251))	('ErbB2', 'Gene', '2064', (349, 354))	('GAPDH', 'Gene', (318, 323))	('NMT2', 'Gene', '9397', (427, 431))	('Hs01013924_g1', 'Var', (434, 447))	('MEMO1', 'Gene', '51072', (377, 382))	('CBX7', 'Gene', '23492', (163, 167))	('NRIP1', 'Gene', (493, 498))	('early growth response 1', 'Gene', '1958', (228, 251))	('receptor-interacting protein 1', 'Gene', '8737', (461, 491))	('ErbB2', 'Gene', (349, 354))	('MEMO1', 'Gene', (377, 382))	('Hs00831646_uH', 'Var', (385, 398))	('docking protein 4', 'Gene', '55715', (186, 203))	('receptor-interacting protein 1', 'Gene', (461, 491))	('RIP140', 'Gene', '8204', (499, 505))	('NMT2', 'Gene', (427, 431))	('Hs00902919_g1', 'Var', (212, 225))
50024	21375733	The membrane was incubated with primary antibodies against CBX7 (ab21873; Abcam, Cambridge, MA, USA), E-cadherin (610181; BD Biosciences, San Jose, CA, USA) and beta-actin (A5441; Sigma-Aldrich).	('E-cadherin', 'Gene', (102, 112))	('beta-actin', 'Gene', '728378', (161, 171))	('610181;', 'Var', (114, 121))	('E-cadherin', 'Gene', '999', (102, 112))	('CBX7', 'Gene', (59, 63))	('beta-actin', 'Gene', (161, 171))	('CBX7', 'Gene', '23492', (59, 63))
50045	21375733	Of the 29 miRNA dysregulated in DCIS compared to HN, 18 (62%) of 29 are implicated in IBC and concordant with the reported changes in expression.	('dysregulated', 'Var', (16, 28))	('miR', 'Gene', '220972', (10, 13))	('IBC', 'Disease', (86, 89))	('miR', 'Gene', (10, 13))	('implicated', 'Reg', (72, 82))
50079	21375733	It has been suggested that the loss of CBX7 expression may influence the invasiveness of epithelial cancers by promoting an epithelial-to-mesenchymal transition.	('epithelia', 'Disease', (124, 133))	('invasiveness of epithelial cancers', 'Disease', 'MESH:D000077216', (73, 107))	('CBX7', 'Gene', (39, 43))	('loss', 'Var', (31, 35))	('promoting', 'PosReg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('epithelia', 'Disease', 'None', (89, 98))	('epithelia', 'Disease', (89, 98))	('influence', 'Reg', (59, 68))	('CBX7', 'Gene', '23492', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('invasiveness of epithelial cancers', 'Disease', (73, 107))	('epithelia', 'Disease', 'None', (124, 133))
50109	21375733	We found that with modulation of miR-125b, miR-182 and miR-183 expression, we obtained results that suggest these miRNA do regulate the expression of their predicted target genes.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('expression', 'MPA', (136, 146))	('miR-183', 'Gene', '406959', (55, 62))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('regulate', 'Reg', (123, 131))	('miR-182', 'Gene', (43, 50))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (55, 58))	('miR', 'Gene', (114, 117))	('miR-182', 'Gene', '406958', (43, 50))	('modulation', 'Var', (19, 29))	('miR-183', 'Gene', (55, 62))
50116	21375733	Furthermore, in future studies, combined modulation of miR-125b, miR-182 and/or miR-183, as well as other miRNA altered in DCIS, may be effective in reversing the forward progression to IBC.	('IBC', 'Disease', (186, 189))	('modulation', 'Var', (41, 51))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '220972', (80, 83))	('miR-183', 'Gene', (80, 87))	('forward progression', 'CPA', (163, 182))	('miR', 'Gene', (106, 109))	('miR-183', 'Gene', '406959', (80, 87))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', '220972', (65, 68))	('miR-182', 'Gene', (65, 72))	('miR', 'Gene', (65, 68))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('reversing', 'NegReg', (149, 158))	('miR-182', 'Gene', '406958', (65, 72))
50134	31468162	Wilcoxon rank sum test or Fisher's exact test were performed to compare kinetic parameters, volume, diameter, age, and BI-RADS morphological descriptors between subcentimeter carcinomas and benign lesions.	('age', 'Gene', '5973', (110, 113))	('carcinomas', 'Disease', 'MESH:D009369', (175, 185))	('age', 'Gene', (110, 113))	('subcentimeter', 'Var', (161, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('carcinomas', 'Disease', (175, 185))
50156	31468162	Conventional DCE-MR images were acquired using a 3D fat-suppressed T1-weighted volume imaging breast assessment (VIBRANT) sequence composed of one pre-contrast and three post-contrast phases labeled as Pre-CE, Post-CE1, Post-CE2 and Post-CE3 (Figure 2).	('Post-CE3', 'Var', (233, 241))	('CE1', 'Gene', '1066', (215, 218))	('age', 'Gene', '5973', (22, 25))	('CE2', 'Gene', '8824', (225, 228))	('breast assessment', 'Disease', (94, 111))	('CE1', 'Gene', (215, 218))	('CE2', 'Gene', (225, 228))	('age', 'Gene', (22, 25))	('DCE', 'Chemical', '-', (13, 16))
50217	31468162	SER is a conventional DCE-MRI derived parameter that indicates the delayed phase kinetic assessment in BI-RADS: persistent, SER <91; plateau, 91 <= SER <= 111; and washout, 111 < SER, SER was significantly different between carcinomas and benign lesions in both the Subcentimeter C4&5 Group and the Reference Group.	('carcinomas', 'Disease', 'MESH:D009369', (224, 234))	('SER', 'Chemical', '-', (0, 3))	('SER', 'Chemical', '-', (179, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('different', 'Reg', (206, 215))	('carcinomas', 'Disease', (224, 234))	('SER', 'Chemical', '-', (124, 127))	('SER <91', 'Var', (124, 131))	('SER', 'Chemical', '-', (148, 151))	('SER', 'Chemical', '-', (184, 187))	('DCE', 'Chemical', '-', (22, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
50260	30608397	In addition, Her-2/Neu was considered overexpressed when staining 3+ or 2+ with FISH amplification, negative if value was 0, 1+ or 2+ without FISH amplification.	('overexpressed', 'PosReg', (38, 51))	('Her-2/Neu', 'Gene', '2064', (13, 22))	('Her-2/Neu', 'Gene', (13, 22))	('staining 3+', 'Var', (57, 68))
50288	30608397	In particular, considering the model with non surgical therapy adjustment (adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant hormonal therapy), as in Table 4B, DFS was significantly influenced by DCISM, clinical suspicion of a palpable lesion, and tumor grading >=2.	('DCISM', 'Var', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('influenced', 'Reg', (191, 201))	('DCISM', 'Chemical', '-', (205, 210))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('DFS', 'MPA', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (257, 262))
50303	30608397	While taking into account tumor characteristics, DCISM resulted in a higher prevalence of less favorable prognostic factors, including basal-like subtype (available only in a minority of DCIS or DCISM, due to missing data), high nuclear grading, high proliferation index, comedo-like necrosis, multifocality/multicentricity, and bunched axillary nodes.	('high nuclear grading', 'CPA', (224, 244))	('basal-like', 'Disease', (135, 145))	('necrosis', 'Disease', 'MESH:D009336', (284, 292))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('DCISM', 'Chemical', '-', (49, 54))	('comedo', 'Phenotype', 'HP:0025249', (272, 278))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('necrosis', 'Disease', (284, 292))	('bunched axillary nodes', 'CPA', (329, 351))	('DCISM', 'Var', (49, 54))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('DCISM', 'Chemical', '-', (195, 200))	('multifocality/multicentricity', 'CPA', (294, 323))	('high proliferation index', 'CPA', (246, 270))
50317	30608397	In our study, we found DCISM to be a risk factor for nodal metastases or ITCs, and older age or postmenopausal status to be protective factors.	('nodal metastases', 'Disease', 'MESH:D009362', (53, 69))	('DCISM', 'Var', (23, 28))	('postmenopausal status', 'Phenotype', 'HP:0008209', (96, 117))	('DCISM', 'Chemical', '-', (23, 28))	('nodal metastases', 'Disease', (53, 69))	('ITCs', 'Disease', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))
50342	30111989	Studies confirm that the Notch pathway has a major participation in breast cancer progression through overexpression and/or abnormal genetic type expression of the notch receptors and ligands that determine angiogenesis.	('participation in breast cancer', 'Disease', (51, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('overexpression', 'PosReg', (102, 116))	('abnormal', 'Var', (124, 132))	('participation in breast cancer', 'Disease', 'MESH:D001943', (51, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Notch pathway', 'Pathway', (25, 38))
50347	30111989	Studies revealed that aberrant Notch signaling induces mammary gland carcinoma in transgenic mice and, a few years later, Notch was also detected in human breast cancer predisposing to play a major role in breast cancer development due to its participation in cell proliferation, differentiation, and apoptosis.	('aberrant', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('induces', 'Reg', (47, 54))	('Notch signaling', 'Gene', (31, 46))	('carcinoma', 'Disease', (69, 78))	('breast cancer', 'Disease', (206, 219))	('human', 'Species', '9606', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('transgenic mice', 'Species', '10090', (82, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
50350	30111989	One in 400 women is found to be positive to BRCA mutation and the average cumulative cancer risk in those women by the age of 70 years ranges from 45% to 65% for breast cancer.	('mutation', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA', 'Gene', '672', (44, 48))	('positive', 'Reg', (32, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('BRCA', 'Gene', (44, 48))	('breast cancer', 'Disease', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
50365	30111989	The appearance of abnormal vessels and the insufficient tumor growth are also related to the correlation between the Dll-4 expression and the VEGF molecule in "tip" and "stalk" cell; blockade of the VEGF action on neoplastic structure downregulates Dll-4 expression.	('insufficient tumor', 'Disease', (43, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('abnormal vessels', 'Phenotype', 'HP:0002597', (18, 34))	('Dll-4', 'Gene', (249, 254))	('expression', 'MPA', (255, 265))	('neoplastic structure', 'Phenotype', 'HP:0002664', (214, 234))	('insufficient tumor', 'Disease', 'MESH:D000309', (43, 61))	('blockade', 'Var', (183, 191))	('downregulates', 'NegReg', (235, 248))
50371	30111989	Deregulation of the Dll-4 ligand has a negative impact on vessel formation; new vessels are indeed being constructed but their functional ability is restricted; this fact results in impaired tumor growth.	('restricted', 'NegReg', (149, 159))	('Deregulation', 'Var', (0, 12))	('vessel formation', 'CPA', (58, 74))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('impaired tumor', 'Disease', 'MESH:D015417', (182, 196))	('impaired tumor', 'Disease', (182, 196))
50379	30111989	According to their results, ER(+) and/or PR(+) combined to HER2(-) (Luminal A or B subtype) mainly reveal high expression of Notch-4 but revealed, without statistical significance, low levels of Notch-1 and -3.	('expression', 'MPA', (111, 121))	('Notch-4', 'Var', (125, 132))	('HER2', 'Gene', (59, 63))	('Notch-1 and -3', 'Gene', '4851;4854', (195, 209))
50381	30111989	Among the Notch receptors, Notch-3 and Notch-4 seem to have eminent role in normal breast growth, even though Notch-4 demonstrates increased activity (upregulation) in the neoplastic tumor vasculature.	('increased', 'PosReg', (131, 140))	('activity', 'MPA', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('breast growth', 'CPA', (83, 96))	('Notch-4', 'Var', (110, 117))	('neoplastic tumor', 'Disease', (172, 188))	('neoplastic tumor', 'Disease', 'MESH:D009369', (172, 188))
50382	30111989	(2008) showed that Notch-1 and Notch-3 NICD were expressed in various carcinogenic breast gland cellular lines enhancing the results of Callahan and Raafat.	('carcinogenic breast', 'Disease', 'MESH:D001943', (70, 89))	('Callahan', 'CPA', (136, 144))	('enhancing', 'PosReg', (111, 120))	('Notch-3', 'Var', (31, 38))	('carcinogenic breast', 'Disease', (70, 89))
50383	30111989	The overexpressed type of Notch-2 receptor seems to be connected to improved patient clinical outcome; the presence of Notch-2 represents decreased tumor dissemination.	('Notch-2', 'Gene', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('presence', 'Var', (107, 115))	('decreased', 'NegReg', (138, 147))	('tumor dissemination', 'Disease', 'MESH:D009103', (148, 167))	('tumor dissemination', 'Disease', (148, 167))
50388	30111989	Aberrant Notch signaling expression seems to participate in both preinvasive ductal carcinoma in situ and metastatic mammary neoplasm, whereas the number of the overexpressed Notch receptors was increased.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (77, 101))	('Aberrant', 'Var', (0, 8))	('metastatic mammary neoplasm', 'Disease', (106, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('neoplasm', 'Phenotype', 'HP:0002664', (125, 133))	('Notch signaling', 'Gene', (9, 24))	('participate', 'Reg', (45, 56))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (77, 101))	('ductal carcinoma in situ', 'Disease', (77, 101))
50393	30111989	experimented on mice mammary tumor virus-induced neoplasms and identified Notch-4 to be the potent oncogene; Notch-4 changes the mammary epithelium towards the carcinogenic type.	('carcinogenic type', 'Disease', 'MESH:D063646', (160, 177))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('Notch-4', 'Var', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('carcinogenic type', 'Disease', (160, 177))	('changes', 'Reg', (117, 124))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))
50399	30111989	presented a study, where authors reported that estradiol decreases Notch transcriptional activity in breast cancer cells via an estrogen receptor (ER) alpha, while in the presence or absence of estradiol, Notch-1 activates ERalpha-dependent transcriptions.	('Notch transcriptional activity', 'MPA', (67, 97))	('estrogen receptor (ER) alpha', 'Gene', (128, 156))	('estrogen receptor (ER) alpha', 'Gene', '2099', (128, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Notch-1', 'Var', (205, 212))	('estradiol decreases', 'Phenotype', 'HP:0008214', (47, 66))	('activates', 'PosReg', (213, 222))	('decreases', 'NegReg', (57, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('ERalpha-dependent', 'Enzyme', (223, 240))
50404	30111989	Jagged-1 deletion caused deficits in vascular smooth muscle and fatal vascular defects, inhibiting sprouting angiogenesis, while Dll-4 blockade inhibits tumor growth, resulting in increased but dysfunctional angiogenesis, with other studies complementing an increased efficacy on the adjuvant chemotherapy when combined to anti-Dll-4 factors.	('sprouting angiogenesis', 'CPA', (99, 121))	('tumor growth', 'CPA', (153, 165))	('inhibits', 'NegReg', (144, 152))	('Jagged-1', 'Gene', (0, 8))	('deletion', 'Var', (9, 17))	('vascular smooth muscle', 'CPA', (37, 59))	('increased', 'PosReg', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('vascular defects', 'Disease', 'MESH:D000783', (70, 86))	('deficits', 'NegReg', (25, 33))	('vascular defects', 'Disease', (70, 86))	('but', 'CPA', (190, 193))	('inhibiting', 'NegReg', (88, 98))
50409	30111989	Another gamma-secretase inhibitor, Z-Leu-Leu-Nle-CHO, was proven to cause cell death even at minimum concentrations inhibiting proteosomal function unlike DAPT (GSI IX) and L685,458 (GSI X) inhibitors.	('inhibiting', 'NegReg', (116, 126))	('proteosomal function', 'MPA', (127, 147))	('Z-Leu-Leu-Nle-CHO', 'Var', (35, 52))	('cause', 'Reg', (68, 73))	('CHO', 'CellLine', 'CVCL:0213', (49, 52))	('DAPT', 'Chemical', '-', (155, 159))	('GSI IX', 'Chemical', '-', (161, 167))
50417	30111989	studied the involvement of Notch in stem cells of breast ductal carcinoma in situ (DCIS) by examining accumulation of NICD and Notch-4 intracellular domain and the expression of Hes1 in DCIS tissue.	('Hes1', 'Gene', '3280', (178, 182))	('accumulation', 'MPA', (102, 114))	('Notch-4', 'Var', (127, 134))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (57, 81))	('Hes1', 'Gene', (178, 182))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('breast ductal carcinoma in situ', 'Disease', (50, 81))	('breast ductal carcinoma in situ', 'Disease', 'MESH:D002285', (50, 81))	('NICD', 'MPA', (118, 122))
50419	30111989	Harrison et al., both in 2010 and 2013, also supported that self-renewal of BCSC is regulated by Notch signaling and added that Notch-4 knockdown has a more significant impact than Notch1 in BCSC and that Notch inhibitors operate downstream of oestrogen in the regulation of ER-negative cancer stem cells by blocking their activity and reducing their frequency.	('Notch1', 'Gene', (181, 187))	('reducing', 'NegReg', (336, 344))	('activity', 'MPA', (323, 331))	('Notch1', 'Gene', '4851', (181, 187))	('knockdown', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('blocking', 'NegReg', (308, 316))	('frequency', 'MPA', (351, 360))	('Notch-4', 'Gene', (128, 135))
50465	29271113	Palpable breast lumps on physical examination, receiving pre-operative MRI, tumor size >1 cm on final pathology, median-grade tumor, and high-grade tumor were all predictive factors of axillary evaluation.	('high-grade', 'Var', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('breast lump', 'Phenotype', 'HP:0032408', (9, 20))	('breast lumps', 'Disease', (9, 21))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('breast lumps', 'Phenotype', 'HP:0032408', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('axillary evaluation', 'Disease', (185, 204))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (126, 131))
50538	24202240	Preclinical studies have shown that trastuzumab enhances radiosensitivity of HER2-expressing cancer cells in xenograft models and cell lines with no detrimental effect on HER2-normal cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('HER2', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HER2', 'Gene', (171, 175))	('trastuzumab', 'Var', (36, 47))	('HER2', 'Gene', '2064', (77, 81))	('HER2', 'Gene', '2064', (171, 175))	('enhances', 'PosReg', (48, 56))	('radiosensitivity', 'MPA', (57, 73))	('trastuzumab', 'Chemical', 'MESH:D000068878', (36, 47))
50604	24202240	Our results may support the recent progression model of breast cancer suggesting that high-grade DCIS evolves to high-grade invasive carcinomas, and low-grade DCIS precipitates to low-grade invasive carcinomas, a concept supported by recent genetic studies.	('high-grade', 'Var', (86, 96))	('invasive carcinomas', 'Disease', (190, 209))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('invasive carcinomas', 'Disease', (124, 143))	('invasive carcinomas', 'Disease', 'MESH:D009361', (124, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('low-grade', 'Var', (149, 158))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('breast cancer', 'Disease', (56, 69))	('invasive carcinomas', 'Disease', 'MESH:D009361', (190, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
50608	24202240	The updated guidelines consider cases with ratios of >=2 to be positive for HER2 amplification.	('HER2', 'Gene', '2064', (76, 80))	('amplification', 'Var', (81, 94))	('HER2', 'Gene', (76, 80))
50616	24202240	Analysis of HER2 status in a study sample of over 1,428 DCIS cases reported here provides for the first time a more accurate estimate of incidence of HER2 positivity in DCIS lesions, which are being image detected and are of high grade (Table 1).	('HER2', 'Gene', (12, 16))	('positivity', 'Var', (155, 165))	('HER2', 'Gene', '2064', (12, 16))	('HER2', 'Gene', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('HER2', 'Gene', '2064', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (169, 173))	('DCIS lesions', 'Disease', (169, 181))
50673	29514679	Based on the simulation results, cost-effectiveness acceptability curves were presented to the uncertainty in the ICUR caused by variations in parameters such as the attendance, compliance with referral for diagnostic tests, incidence (Please see Additional file 1: Figure S1) and positivity for stage I disease.	('stage I disease', 'Disease', (296, 311))	('positivity', 'Var', (281, 291))	('variations', 'Var', (129, 139))	('CU', 'Chemical', 'MESH:D003300', (115, 117))
50782	31786415	Women who have had DCIS have an increased risk of both ipsilateral and contralateral invasive recurrence, and a recent meta-analysis further showed that African American (AA) women treated for DCIS had a significantly higher risk of invasive recurrence than white women.	('Women', 'Species', '9606', (0, 5))	('invasive recurrence', 'CPA', (233, 252))	('women', 'Species', '9606', (175, 180))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('contralateral invasive recurrence', 'CPA', (71, 104))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('women', 'Species', '9606', (264, 269))	('DCIS', 'Var', (193, 197))
50839	31786415	Low BMI in adolescence and early adulthood is a well-established risk factor for invasive breast cancer, while postmenopausal obesity is consistently associated with increased risk of ER+ invasive breast cancer.	('associated', 'Reg', (150, 160))	('invasive breast cancer', 'Disease', (188, 210))	('Low BMI', 'Var', (0, 7))	('Low BMI', 'Phenotype', 'HP:0045082', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('obesity', 'Phenotype', 'HP:0001513', (126, 133))	('ER', 'Gene', '2099', (184, 186))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('obesity', 'Disease', 'MESH:D009765', (126, 133))	('invasive breast cancer', 'Disease', 'MESH:D001943', (81, 103))	('invasive breast cancer', 'Disease', 'MESH:D001943', (188, 210))	('postmenopausal obesity', 'Phenotype', 'HP:0008209', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('obesity', 'Disease', (126, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('invasive breast cancer', 'Disease', (81, 103))
50850	31786415	In a prior analysis in AMBER, which included the BWHS, CBCS, WCHS, and the Multiethnic Cohort Study, heavy alcohol consumption (>=14 drinks/week) was associated with an increased risk of invasive breast cancer, similar to studies in women of European ancestry.	('invasive breast cancer', 'Disease', 'MESH:D001943', (187, 209))	('heavy alcohol consumption', 'Var', (101, 126))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (101, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('invasive breast cancer', 'Disease', (187, 209))	('ER', 'Gene', '2099', (26, 28))	('women', 'Species', '9606', (233, 238))	('alcohol', 'Chemical', 'MESH:D000438', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
50875	27113214	EZH2 expression was inversely related to the status of ER and PR (Chi-square, p < 0.001), and it was significantly associated with HER2 positivity, high proliferative index, and high histologic grade (Chi-square, p < 0.05).	('positivity', 'Var', (136, 146))	('expression', 'MPA', (5, 15))	('EZH2', 'Gene', '2146', (0, 4))	('high proliferative index', 'CPA', (148, 172))	('HER2', 'Gene', (131, 135))	('EZH2', 'Gene', (0, 4))	('ER', 'Gene', '2099', (55, 57))	('HER2', 'Gene', '2064', (131, 135))	('associated', 'Reg', (115, 125))	('high histologic grade', 'CPA', (178, 199))	('inversely', 'NegReg', (20, 29))	('ER', 'Gene', '2099', (132, 134))	('PR', 'Gene', '5241', (62, 64))
50882	27113214	EZH2 overexpression is associated aggressive pathologic features including high nuclear grade, high proliferative index, and positivity of HER2 of breast carcinoma.	('high nuclear grade', 'CPA', (75, 93))	('EZH2', 'Gene', '2146', (0, 4))	('breast carcinoma', 'Disease', (147, 163))	('HER2', 'Gene', (139, 143))	('EZH2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (139, 143))	('overexpression', 'PosReg', (5, 19))	('breast carcinoma', 'Disease', 'MESH:D001943', (147, 163))	('positivity', 'Var', (125, 135))	('high proliferative index', 'CPA', (95, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('breast carcinoma', 'Phenotype', 'HP:0003002', (147, 163))
50890	27113214	There are studies suggesting that EZH2 probably plays an important role in carcinogenesis of breast carcinoma, and high expression of EZH2 was associated with triple-negative breast carcinoma.	('associated', 'Reg', (143, 153))	('carcinogenesis of breast carcinoma', 'Disease', 'MESH:D063646', (75, 109))	('EZH2', 'Gene', '2146', (134, 138))	('EZH2', 'Gene', '2146', (34, 38))	('breast carcinoma', 'Disease', (175, 191))	('breast carcinoma', 'Phenotype', 'HP:0003002', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('EZH2', 'Gene', (34, 38))	('EZH2', 'Gene', (134, 138))	('breast carcinoma', 'Disease', 'MESH:D001943', (175, 191))	('breast carcinoma', 'Disease', 'MESH:D001943', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('breast carcinoma', 'Phenotype', 'HP:0003002', (175, 191))	('carcinogenesis of breast carcinoma', 'Disease', (75, 109))	('high expression', 'Var', (115, 130))
50894	27113214	only reported high EZH2 expression was associated with high histologic grade, locally advanced cancers, and presence of distant metastatic disease of breast carcinoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (150, 166))	('locally advanced', 'CPA', (78, 94))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('metastatic disease of breast', 'Phenotype', 'HP:0100013', (128, 156))	('cancers', 'Disease', (95, 102))	('breast carcinoma', 'Phenotype', 'HP:0003002', (150, 166))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('high', 'Var', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('associated', 'Reg', (39, 49))	('EZH2', 'Gene', '2146', (19, 23))	('high histologic grade', 'CPA', (55, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast carcinoma', 'Disease', (150, 166))	('EZH2', 'Gene', (19, 23))	('distant metastatic disease', 'CPA', (120, 146))
50977	27113214	We found that EZH2 is significantly overexpressed in high-grade triple-negative breast carcinoma: 90.9 % (50/55) of triple-negative breast carcinoma showed overexpression of EZH2 with a multiplicative score of intensity and percentage >3, and 88 % (44/50) among them showed homogeneously strong overexpression in 90 ~ 100 % tumor cells with a multiplicative score of 9 (Table 2).	('breast carcinoma', 'Phenotype', 'HP:0003002', (132, 148))	('EZH2', 'Gene', (174, 178))	('triple-negative', 'Var', (116, 131))	('overexpression', 'PosReg', (156, 170))	('EZH2', 'Gene', '2146', (174, 178))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('tumor', 'Disease', (324, 329))	('breast carcinoma', 'Phenotype', 'HP:0003002', (80, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('breast carcinoma', 'Disease', (132, 148))	('breast carcinoma', 'Disease', 'MESH:D001943', (132, 148))	('breast carcinoma', 'Disease', 'MESH:D001943', (80, 96))	('breast carcinoma', 'Disease', (80, 96))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
50979	27113214	We found that EZH2 expression in breast carcinoma was significantly associated with tumor cell proliferation: 87.3 % (69/79) of breast carcinoma with high Ki67 index (>30 %) showed high EZH2 levels, whereas only 25.7 % (19/74) invasive breast carcinoma with a low Ki67 index (<14 %) showed EZH2 overexpression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (227, 252))	('Ki67', 'Gene', '17345', (155, 159))	('breast carcinoma', 'Phenotype', 'HP:0003002', (236, 252))	('breast carcinoma', 'Disease', 'MESH:D001943', (128, 144))	('breast carcinoma', 'Disease', 'MESH:D001943', (33, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Ki67', 'Gene', '17345', (264, 268))	('high', 'Var', (150, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('invasive breast carcinoma', 'Disease', (227, 252))	('breast carcinoma', 'Phenotype', 'HP:0003002', (128, 144))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('breast carcinoma', 'Phenotype', 'HP:0003002', (33, 49))	('breast carcinoma', 'Disease', (128, 144))	('EZH2', 'Gene', '2146', (290, 294))	('breast carcinoma', 'Disease', (33, 49))	('Ki67', 'Gene', (155, 159))	('EZH2', 'Gene', (290, 294))	('breast carcinoma', 'Disease', 'MESH:D001943', (236, 252))	('tumor', 'Disease', (84, 89))	('EZH2', 'Gene', (186, 190))	('EZH2', 'Gene', '2146', (186, 190))	('Ki67', 'Gene', (264, 268))
50994	27113214	Furthermore, the highest level of EZH2 expression was observed in high nuclear grade triple-negative DCIS, which is consistent with the clinical evolution of DCIS, as it is widely accepted that high nuclear grade DCIS is associated with higher rate of recurrence than low and intermediate nuclear grade DCIS.	('recurrence', 'MPA', (252, 262))	('high nuclear grade', 'Var', (194, 212))	('EZH2', 'Gene', (34, 38))	('EZH2', 'Gene', '2146', (34, 38))
51152	16078997	Wrensch and colleagues have observed in a prospective trial that NAF production and NAF atypia in a screening population are associated with an increased risk of breast cancer.	('NAF', 'Var', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated with', 'Reg', (125, 140))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))
51197	33605547	Multivariate logistic analysis further showed that positive sTn expression and accompanying mass were statistically significant independent risk factors for malignant nipple fluid.	('Tn', 'Gene', '7123', (61, 63))	('malignant nipple fluid', 'Disease', (157, 179))	('positive', 'Var', (51, 59))
51210	33605547	Aberrant O-glycosylation can play a pivotal role in cancer development, progression, angiogenesis and metastasis.	('O-glycosylation', 'Protein', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Aberrant', 'Var', (0, 8))	('play', 'Reg', (29, 33))	('angiogenesis', 'CPA', (85, 97))	('metastasis', 'CPA', (102, 112))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
51215	33605547	Marja Leivonen et al 13  documented the expression of sTn was associated with larger tumor size and ER/PR negativity.	('tumor', 'Disease', (85, 90))	('ER/PR negativity', 'Disease', (100, 116))	('expression', 'Var', (40, 50))	('Tn', 'Gene', '7123', (55, 57))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
51250	33605547	The HER-2 amplification, which we evaluated by fluorescence in situ hybridization or IHC of IDC samples, was correlated with sTn expression in our series (p = 0.039, Table 2).	('HER-2', 'Gene', '2064', (4, 9))	('correlated', 'Reg', (109, 119))	('amplification', 'Var', (10, 23))	('Tn', 'Gene', '7123', (126, 128))	('HER-2', 'Gene', (4, 9))
51251	33605547	Fifteen of 24 cases (62.5%) with sTn expression had positive HER-2 amplification, indicating a more aggressive behavior in IDC.	('aggressive behavior', 'Phenotype', 'HP:0000718', (100, 119))	('amplification', 'Var', (67, 80))	('HER-2', 'Gene', '2064', (61, 66))	('HER-2', 'Gene', (61, 66))	('IDC', 'Disease', (123, 126))	('aggressive behavior', 'CPA', (100, 119))	('Tn', 'Gene', '7123', (34, 36))
51259	33605547	16  One mechanism that may result in O-linked glycoproteins carrying truncated Tn and sTn glycans is the inactivation or lack of expression of Cosmc.	('Cosmc', 'Gene', '29071', (143, 148))	('truncated', 'Var', (69, 78))	('Tn', 'Gene', '7123', (87, 89))	('Tn', 'Gene', '7123', (79, 81))	('sTn glycans', 'Chemical', '-', (86, 97))	('Cosmc', 'Gene', (143, 148))	('O-linked', 'Protein', (37, 45))
51274	33605547	Twenty-four cases harbored HER-2 amplification, including 15 sTn-positive and 9 sTn-negative neoplasms.	('Tn', 'Gene', '7123', (62, 64))	('neoplasms', 'Disease', 'MESH:D009369', (93, 102))	('amplification', 'Var', (33, 46))	('neoplasms', 'Disease', (93, 102))	('Tn', 'Gene', '7123', (81, 83))	('HER-2', 'Gene', '2064', (27, 32))	('neoplasms', 'Phenotype', 'HP:0002664', (93, 102))	('HER-2', 'Gene', (27, 32))
51305	30157721	Electroporation, or electropermeabilization, may be a novel approach for treating invasive ductal carcinoma because electroporation of the plasma membrane of living cells increases the uptake of nonpermeant or poorly permeant molecules once the cells had been exposed to short and strong electric pulses.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (91, 107))	('treating invasive ductal carcinoma', 'Disease', 'MESH:D018270', (73, 107))	('electroporation', 'Var', (116, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('uptake of nonpermeant or poorly permeant molecules', 'MPA', (185, 235))	('increases', 'PosReg', (171, 180))	('treating invasive ductal carcinoma', 'Disease', (73, 107))
51341	30157721	Variation in distance among the electrodes was proposed to fulfill a complete coverage of the tumors in the 3 patients according to their particular dimensions and geometries.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('Variation', 'Var', (0, 9))	('patients', 'Species', '9606', (110, 118))
51344	30157721	Needles' diameter in all arrays was 1.2 mm, and their active length varied depending on the tumor size as shown in Table 2, where C-P refers to the distance from the intratumoral-central electrode to the peripheral electrodes, P-P refers to the distance between peripheral electrodes only, and D refers to the distance between electrodes forming diagonals.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('C-P', 'Var', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('P-P', 'Var', (227, 230))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
51385	30157721	Contrary to the results obtained for patient 1 with the array 4Di1, 4-needle diamond configuration in any of the sets, that is, 4Di1, 4Di2, and 4Di3, resulted in the least effective arrays for the treatment of the target lesions even if the voltage was increased to the maximum value (3000 V) provided by current electroporation systems.	('patient', 'Species', '9606', (37, 44))	('least', 'NegReg', (166, 171))	('arrays', 'MPA', (182, 188))	('4Di2', 'Var', (134, 138))	('4Di1', 'Var', (128, 132))
51395	30157721	Drug resistance contribution through activation of multiple drug resistance pumps due to low-drug concentration if multiple ECT sessions are required and inflammatory response associated with necrosis achieved in irreversibly electroporated regions.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('low-drug', 'Var', (89, 97))	('Drug resistance', 'MPA', (0, 15))	('activation', 'PosReg', (37, 47))	('necrosis', 'Disease', 'MESH:D009336', (192, 200))	('low-drug concentration', 'Phenotype', 'HP:0020171', (89, 111))	('necrosis', 'Disease', (192, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))
51413	22489268	However, in a recent publication by Fisher and colleagues, micropapillary DCIS was found to be associated with both ipsilateral and contralateral recurrence of malignancy in a statistically significant number of cases.	('malignancy', 'Disease', (160, 170))	('micropapillary', 'Var', (59, 73))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('associated', 'Reg', (95, 105))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
51429	22489268	Overall, a micropapillary pattern was seen in 40/157 (25%), a cribriform component in 78/157 (50%), a solid component in 113/157 (72%), and macropapillary (encysted papillary carcinoma) in 3 (1.9%) of the DCIS cases (Table 2).	('encysted papillary carcinoma', 'Disease', (156, 184))	('encysted papillary carcinoma', 'Disease', 'MESH:D002291', (156, 184))	('macropapillary', 'Var', (140, 154))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))
51439	22489268	The authors concluded that although nuclear grade may significantly influence the biological behaviour of micropapillary ductal carcinoma in situ, micropapillary growth pattern represents a risk factor for local recurrence after breast-conserving surgery.	('local', 'Disease', (206, 211))	('micropapillary ductal carcinoma', 'Disease', (106, 137))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (121, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('micropapillary growth pattern', 'Var', (147, 176))	('influence', 'Reg', (68, 77))	('biological', 'MPA', (82, 92))	('micropapillary ductal carcinoma', 'Disease', 'MESH:D044584', (106, 137))
51444	22489268	This may mean that those cases of low grade DCIS that may have a certain genetic makeup will maintain an indolent course, whereas the more aggressive ones will undergo the changes described above and assume a mixed growth pattern with comedonecrosis.	('undergo', 'Reg', (160, 167))	('low grade', 'Var', (34, 43))	('necrosis', 'Disease', (241, 249))	('assume', 'Reg', (200, 206))	('comedo', 'Phenotype', 'HP:0025249', (235, 241))	('necrosis', 'Disease', 'MESH:D009336', (241, 249))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
51455	21980430	Our results show that kin17 expression was markedly increased in clinical breast tumors and was associated with tumor grade, Ki-67 expression, p53 mutation status and progesterone receptor expression, which were assessed in a clinicopathologic characteristics review.	('breast tumors', 'Phenotype', 'HP:0100013', (74, 87))	('breast tumor', 'Phenotype', 'HP:0100013', (74, 86))	('associated', 'Reg', (96, 106))	('p53', 'Gene', '7157', (143, 146))	('increased', 'PosReg', (52, 61))	('progesterone receptor', 'Gene', '5241', (167, 188))	('tumor', 'Disease', (112, 117))	('progesterone receptor', 'Gene', (167, 188))	('p53', 'Gene', (143, 146))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Ki-67', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('breast tumors', 'Disease', (74, 87))	('expression', 'MPA', (28, 38))	('breast tumors', 'Disease', 'MESH:D001943', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('kin17', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutation status', 'Var', (147, 162))	('clinical', 'Species', '191496', (65, 73))
51497	21980430	In addition, we also found a significant association between kin17 expression and progesterone receptor (PR) expression (p = 0.046) as well as p53 mutation status (p = 0.017).	('p53', 'Gene', '7157', (143, 146))	('PR', 'Gene', '5241', (105, 107))	('kin17', 'Gene', (61, 66))	('p53', 'Gene', (143, 146))	('progesterone receptor', 'Gene', (82, 103))	('progesterone receptor', 'Gene', '5241', (82, 103))	('mutation status', 'Var', (147, 162))
51498	21980430	In order to analyze the effects of kin17 on proliferative and morphogenic phenotypes of breast epithelial cells and breast cancer cells, we knocked down endogenous kin17 in MDA-MB-231 (Figure 2A) and BT474 cells (Figure 2B) with siRNA_kin17.	('kin17', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('knocked', 'Var', (140, 147))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (173, 183))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
51499	21980430	Kin17 knockdown significantly inhibited the proliferation of MDA-MB-231 (p<0.01) and BT474 cells (p<0.05), however, had little effect on the proliferation of MCF-10A cells (Figure S3).	('inhibited', 'NegReg', (30, 39))	('Kin17', 'Gene', '22944', (0, 5))	('Kin17', 'Gene', (0, 5))	('MCF-10A', 'CellLine', 'CVCL:0598', (158, 165))	('knockdown', 'Var', (6, 15))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))	('proliferation', 'CPA', (44, 57))
51500	21980430	After knockdown of kin17, the colony number in soft agar was decreased by 2.0 fold in MDA-MB-231 and 2.7 fold in BT474 cells (p<0.05 and p<0.01, respectively).	('colony number in soft agar', 'CPA', (30, 56))	('decreased', 'NegReg', (61, 70))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (86, 96))	('agar', 'Chemical', 'MESH:D000362', (52, 56))	('kin17', 'Gene', (19, 24))	('knockdown', 'Var', (6, 15))
51505	21980430	Our results showed that the proliferative rate of MCF-10Amock was similar to parental cells.	('proliferative', 'CPA', (28, 41))	('MCF-10Amock', 'Var', (50, 61))	('MCF-10A', 'CellLine', 'CVCL:0598', (50, 57))
51506	21980430	While MCF-10Akin17 cells showed a higher proliferative capacity, as determined by the EdU retention assay, compared to MCF-10Amockcells in 2-dimensional (2-D) cultures (Figure 2C and Figure 2E).	('MCF-10Akin17', 'CellLine', 'CVCL:5555', (6, 18))	('MCF-10A', 'CellLine', 'CVCL:0598', (6, 13))	('EdU', 'Chemical', 'MESH:C031086', (86, 89))	('higher', 'PosReg', (34, 40))	('MCF-10Akin17', 'Var', (6, 18))	('proliferative capacity', 'CPA', (41, 63))	('MCF-10A', 'CellLine', 'CVCL:0598', (119, 126))
51512	21980430	While kin17 knockdown decreased ERK1/2 autophosphorylation and cyclin D1 expression in BT474 cells.	('autophosphorylation', 'MPA', (39, 58))	('knockdown', 'Var', (12, 21))	('expression', 'MPA', (73, 83))	('ERK1/2', 'Gene', (32, 38))	('ERK1/2', 'Gene', '5595;5594', (32, 38))	('cyclin D1', 'Gene', '595', (63, 72))	('kin17', 'Gene', (6, 11))	('cyclin D1', 'Gene', (63, 72))	('decreased', 'NegReg', (22, 31))
51514	21980430	DNA damage is elevated in cancer cells due to carcinogenic exposure, telomere shortening and hypoxia.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('elevated', 'PosReg', (14, 22))	('telomere shortening', 'Var', (69, 88))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('carcinogenic', 'Disease', 'MESH:D063646', (46, 58))	('carcinogenic', 'Disease', (46, 58))	('hypoxia', 'Disease', (93, 100))	('DNA damage', 'MPA', (0, 10))
51515	21980430	An increased number of DNA lesions results in cell cycle arrest and cell death due to the activation of DNA damage repair pathways.	('DNA damage repair pathways', 'Pathway', (104, 130))	('activation', 'PosReg', (90, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (46, 63))	('lesions', 'Var', (27, 34))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('arrest', 'Disease', (57, 63))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', (73, 78))
51517	21980430	In this study, knockdown of kin17 resulted in DNA damage in both MCF-10A and BT474 cells.	('kin17', 'Gene', (28, 33))	('knockdown', 'Var', (15, 24))	('DNA damage', 'MPA', (46, 56))	('MCF-10A', 'CellLine', 'CVCL:0598', (65, 72))	('resulted in', 'Reg', (34, 45))
51518	21980430	However, more DNA damage was detected in the BT474 than in the MCF-10A cells after kin17 was knocked down (Figure 3A).	('kin17', 'Gene', (83, 88))	('MCF-10A', 'CellLine', 'CVCL:0598', (63, 70))	('knocked down', 'Var', (93, 105))	('BT474', 'Var', (45, 50))	('DNA damage', 'MPA', (14, 24))
51520	21980430	The main forms of DNA damage induced by ADM are DNA double-strand breaks, DNA single strand breaks, alkali labile sites, and ADM-DNA adducts.	('adducts', 'Interaction', (133, 140))	('ADM', 'Chemical', 'MESH:D004317', (40, 43))	('single strand breaks', 'Var', (78, 98))	('alkali labile sites', 'MPA', (100, 119))	('ADM', 'Chemical', 'MESH:D004317', (125, 128))
51527	21980430	To determine if kin17 plays a role in the increased cell proliferation caused by EGF, we knocked down kin17 and then stimulated cells with EGF.	('increased', 'PosReg', (42, 51))	('EGF', 'Gene', (139, 142))	('EGF', 'Gene', (81, 84))	('cell proliferation', 'CPA', (52, 70))	('EGF', 'Gene', '1950', (139, 142))	('EGF', 'Gene', '1950', (81, 84))	('knocked', 'Var', (89, 96))	('kin17', 'Gene', (102, 107))
51531	21980430	Previous work has shown that human fibroblasts immortalized with SV40 have an elevated level of kin17 protein compared to normal diploid human fibroblasts.	('human', 'Species', '9606', (137, 142))	('level', 'MPA', (87, 92))	('elevated', 'PosReg', (78, 86))	('human', 'Species', '9606', (29, 34))	('kin17 protein', 'Protein', (96, 109))	('SV40', 'Var', (65, 69))
51546	21980430	Our results showed that knockdown of kin17 in breast cancer cells inhibited DNA replication, aggravated DNA damage and blocked cells in the S phase of the cell cycle.	('DNA damage', 'MPA', (104, 114))	('aggravated', 'PosReg', (93, 103))	('breast cancer', 'Disease', (46, 59))	('cells in the S phase of the cell cycle', 'CPA', (127, 165))	('blocked', 'NegReg', (119, 126))	('kin17', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('inhibited', 'NegReg', (66, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('DNA replication', 'MPA', (76, 91))	('knockdown', 'Var', (24, 33))
51549	21980430	Cyclin D1 is one of the key regulators of the G1/S transition, and gene amplification or overexpression of cyclin D1 is associated with cell growth and tumorigenesis in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cyclin D1', 'Gene', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('associated with', 'Reg', (120, 135))	('Cyclin D1', 'Gene', '595', (0, 9))	('cell growth', 'CPA', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('overexpression', 'PosReg', (89, 103))	('tumor', 'Disease', (152, 157))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('gene amplification', 'Var', (67, 85))	('Cyclin D1', 'Gene', (0, 9))	('cyclin D1', 'Gene', '595', (107, 116))	('breast cancer', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
51551	21980430	We found that kin17 increased cyclin D1 protein expression and constitutive phosphorylation of ERK1/2 in MCF-10A and BT474 cells.	('increased', 'PosReg', (20, 29))	('constitutive phosphorylation', 'MPA', (63, 91))	('cyclin D1', 'Gene', '595', (30, 39))	('ERK1/2', 'Gene', (95, 101))	('kin17', 'Var', (14, 19))	('cyclin D1', 'Gene', (30, 39))	('MCF-10A', 'CellLine', 'CVCL:0598', (105, 112))	('ERK1/2', 'Gene', '5595;5594', (95, 101))
51554	21980430	p53 mutations have been identified in many types of cancer, and such mutations serve as the most powerful prognostic markers in breast cancer.	('p53', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('p53', 'Gene', '7157', (0, 3))	('cancer', 'Disease', (135, 141))	('identified', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('mutations', 'Var', (4, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (52, 58))
51555	21980430	A significant association between increased kin17 expression and p53 mutations in our study would strongly suggest that kin17 is involved in breast cancer progression.	('mutations', 'Var', (69, 78))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('involved', 'Reg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('kin17', 'Gene', (44, 49))	('increased', 'PosReg', (34, 43))	('expression', 'MPA', (50, 60))
51568	21980430	Moreover, silencing kin17 expression inhibited proliferation signaling initiated by EGF.	('proliferation signaling', 'CPA', (47, 70))	('EGF', 'Gene', (84, 87))	('inhibited', 'NegReg', (37, 46))	('EGF', 'Gene', '1950', (84, 87))	('kin17', 'Gene', (20, 25))	('silencing', 'Var', (10, 19))
51569	21980430	Thus, we proposed that combination of kin17 knocking down with ADM treatment would reduce the dose of ADM, so as to lessen the drug resistance and toxicity of ADM in conventional treatment.	('drug resistance', 'Phenotype', 'HP:0020174', (127, 142))	('dose', 'MPA', (94, 98))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('lessen', 'NegReg', (116, 122))	('ADM', 'Chemical', 'MESH:D004317', (102, 105))	('drug resistance', 'MPA', (127, 142))	('ADM', 'Chemical', 'MESH:D004317', (63, 66))	('reduce', 'NegReg', (83, 89))	('ADM', 'Chemical', 'MESH:D004317', (159, 162))	('knocking down', 'Var', (44, 57))	('kin17', 'Gene', (38, 43))
51570	21980430	In addition, kin17 knockdown displayed weak inhibition on proliferation of MCF-10A, and kin17 silencing showed little effect on ERK1/2 autophosphorylation, cyclin D1 expression and chemosensitivity to ADM in MCF-10A cells.	('silencing', 'NegReg', (94, 103))	('ADM', 'Chemical', 'MESH:D004317', (201, 204))	('proliferation', 'CPA', (58, 71))	('cyclin D1', 'Gene', (156, 165))	('cyclin D1', 'Gene', '595', (156, 165))	('knockdown', 'Var', (19, 28))	('ERK1/2', 'Gene', (128, 134))	('ERK1/2', 'Gene', '5595;5594', (128, 134))	('inhibition', 'NegReg', (44, 54))	('kin17', 'Gene', (88, 93))	('MCF-10A', 'CellLine', 'CVCL:0598', (75, 82))	('MCF-10A', 'CellLine', 'CVCL:0598', (208, 215))	('expression', 'MPA', (166, 176))	('kin17', 'Gene', (13, 18))	('autophosphorylation', 'MPA', (135, 154))
51653	21122101	Invasive cancers with an ultrasound size <15 mm had an average mean elasticity of 109 kPa, compared with an average value for lesions >= 15 mm of 167 kPa.	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('Invasive cancers', 'Disease', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('<15 mm', 'Var', (41, 47))	('Invasive cancers', 'Disease', 'MESH:D009362', (0, 16))	('elasticity', 'MPA', (68, 78))
51677	19383888	Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2.	('HER2', 'Gene', '2064', (132, 136))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('overexpressing', 'Var', (50, 64))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))	('Invasive', 'Disease', (0, 8))	('HER2', 'Gene', (132, 136))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
51709	19383888	Univariate analysis revealed significant associations between invasion and high nuclear grade, HER2 overexpression, and tumor size of >3 cm (Table 1).	('high nuclear', 'Var', (75, 87))	('HER2', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('HER2', 'Gene', '2064', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('overexpression', 'PosReg', (100, 114))	('tumor', 'Disease', (120, 125))
51710	19383888	Of these associations, only that with HER2 overexpression remained significant after multivariate adjustment (Table 2); specifically, DCIS lesions that overexpressed HER2 were over 6 times as likely to be associated with invasive disease than were DCIS lesions in which HER2 overexpression was not present (odds ratio, 6.4; P = 0.01).	('lesions', 'Var', (139, 146))	('HER2', 'Gene', (166, 170))	('HER2', 'Gene', (270, 274))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('HER2', 'Gene', '2064', (166, 170))	('HER2', 'Gene', '2064', (270, 274))	('overexpressed', 'PosReg', (152, 165))	('invasive disease', 'Disease', (221, 237))	('DCIS', 'Phenotype', 'HP:0030075', (248, 252))	('associated with', 'Reg', (205, 220))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))	('invasive disease', 'Disease', 'MESH:D009362', (221, 237))
51714	19383888	Invasive disease was seen in association with HER2 positive DCIS in 8 of 23 cases (35%) and with luminal B DCIS in 7 of 17 cases (41%).	('positive DCIS', 'Var', (51, 64))	('HER2', 'Gene', (46, 50))	('Invasive disease', 'Disease', (0, 16))	('HER2', 'Gene', '2064', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
51736	19536326	DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples.	('DEAR1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('missense mutations', 'Var', (6, 24))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('HD', 'Disease', 'MESH:D006816', (50, 52))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('p', 'Gene', '387572', (111, 112))
51737	19536326	Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutation', 'Var', (88, 96))	('breast cancer', 'Disease', (102, 115))	('p', 'Gene', '387572', (210, 211))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('p', 'Gene', '387572', (33, 34))	('p', 'Gene', '387572', (78, 79))	('invasive breast cancer', 'Disease', (166, 188))	('initiated', 'PosReg', (190, 199))	('tissue architecture', 'CPA', (286, 305))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('invasive breast cancer', 'Disease', 'MESH:D001943', (166, 188))	('restored', 'PosReg', (277, 285))
51738	19536326	Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation.	('p', 'Gene', '387572', (285, 286))	('mutated', 'Var', (159, 166))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('human', 'Species', '9606', (42, 47))	('loss', 'NegReg', (245, 249))	('breast cancer', 'Disease', (123, 136))	('p', 'Gene', '387572', (287, 288))	('p', 'Gene', '387572', (215, 216))	('rat', 'Species', '10116', (204, 207))	('tissue architecture', 'CPA', (224, 243))	('p', 'Gene', '387572', (57, 58))	('p', 'Gene', '387572', (266, 267))	('p', 'Gene', '387572', (85, 86))	('p', 'Gene', '387572', (254, 255))	('apical basal polarity', 'Phenotype', 'HP:0032176', (253, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('DEAR1', 'Gene', (167, 172))
51740	19536326	Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('p', 'Gene', '387572', (225, 226))	('p', 'Gene', '387572', (314, 315))	('p', 'Gene', '387572', (187, 188))	('breast cancer', 'Disease', (99, 112))	('p', 'Gene', '387572', (9, 10))	('rat', 'Species', '10116', (338, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('p', 'Gene', '387572', (287, 288))	('p', 'Gene', '387572', (78, 79))	('genetic alteration', 'Var', (45, 63))	('DEAR1', 'Gene', (90, 95))	('early-onset disease', 'Disease', (354, 373))	('rat', 'Species', '10116', (57, 60))	('p', 'Gene', '387572', (20, 21))	('loss of', 'NegReg', (68, 75))	('p', 'Gene', '387572', (306, 307))
51753	19536326	In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.	('p', 'Gene', '387572', (166, 167))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('deletion', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('women', 'Species', '9606', (199, 204))	('altered', 'Reg', (67, 74))	('p', 'Gene', '387572', (179, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('mutations', 'Var', (79, 88))
51757	19536326	Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes).	('missense mutations', 'Var', (46, 64))	('function', 'MPA', (113, 121))	('p', 'Gene', '387572', (210, 211))	('p', 'Gene', '387572', (135, 136))	('p', 'Gene', '387572', (163, 164))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('human', 'Species', '9606', (182, 187))	('lost', 'NegReg', (151, 155))	('breast tumors', 'Phenotype', 'HP:0100013', (18, 31))	('breast tumor', 'Phenotype', 'HP:0100013', (18, 30))	('breast tumors', 'Disease', 'MESH:D001943', (18, 31))	('breast tumors', 'Disease', (18, 31))	('DEAR1', 'Gene', (40, 45))
51758	19536326	To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('p', 'Gene', '387572', (54, 55))	('mutation', 'Var', (121, 129))	('DEAR1', 'Gene', (133, 138))	('DEAR1', 'Gene', (78, 83))	('p', 'Gene', '387572', (72, 73))
51762	19536326	Finally, the researchers report that DEAR1 expression (detected "immunohistochemically") was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('reduced', 'NegReg', (210, 217))	('women', 'Species', '9606', (112, 117))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('breast cancer', 'Disease', 'MESH:D001943', (302, 315))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Disease', (302, 315))	('p', 'Gene', '387572', (335, 336))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('breast cancer', 'Disease', (277, 290))	('DEAR1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('local recurrence-free survival', 'CPA', (218, 248))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('p', 'Gene', '387572', (45, 46))	('lost', 'NegReg', (104, 108))	('loss', 'Var', (169, 173))	('p', 'Gene', '387572', (321, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('p', 'Gene', '387572', (185, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (302, 315))	('DEAR1', 'Gene', (177, 182))	('p', 'Gene', '387572', (27, 28))
51763	19536326	These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer.	('loss of', 'NegReg', (52, 59))	('rat', 'Species', '10116', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('genetic alteration', 'Var', (29, 47))	('DEAR1', 'Gene', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('p', 'Gene', '387572', (62, 63))	('breast cancer', 'Disease', (94, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))
51835	19536326	LOH within Chromosome 1p has been shown to predict poor prognosis in node-negative breast cancers, and allelic deletions in the 1p36 and 1p32 region have been found to correlate with poor survival.	('p', 'Gene', '387572', (56, 57))	('p', 'Gene', '387572', (51, 52))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('LOH', 'Var', (0, 3))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', (83, 97))	('p', 'Gene', '387572', (183, 184))	('p', 'Gene', '387572', (23, 24))	('p', 'Gene', '387572', (43, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('p', 'Gene', '387572', (129, 130))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('allelic deletions', 'Var', (103, 120))	('p', 'Gene', '387572', (138, 139))
51843	19536326	DEAR1 is essentially identical (98%) to mouse and rat sequences (NP_835211 [Mus musculus] and XP_232757 [Rattus norvegicus]) (Figure S3) as well as RBCC/TRIM proteins from diverse species, including Xenopus laevis XNF7 (33% identity) and TRIM39 (32% identity in mouse, rat, and human).	('TRIM39', 'Gene', (238, 244))	('mouse', 'Species', '10090', (262, 267))	('XNF7', 'Gene', (214, 218))	('Xenopus laevis', 'Species', '8355', (199, 213))	('rat', 'Species', '10116', (269, 272))	('mouse', 'Species', '10090', (40, 45))	('TRIM39', 'Gene', '432113', (238, 244))	('human', 'Species', '9606', (278, 283))	('p', 'Gene', '387572', (181, 182))	('p', 'Gene', '387572', (158, 159))	('XNF7', 'Gene', '397856', (214, 218))	('Mus musculus', 'Species', '10090', (76, 88))	('p', 'Gene', '387572', (203, 204))	('NP_835211', 'Var', (65, 74))	('RBCC', 'Gene', '51127', (148, 152))	('Rattus norvegicus', 'Species', '10116', (105, 122))	('rat', 'Species', '10116', (50, 53))	('XP_232757', 'Var', (94, 103))	('RBCC', 'Gene', (148, 152))
51858	19536326	All of the cell lines in the 21T series contained identical nonconservative missense mutations in exon 3 within codon 187 (CGG TGG, R187W) in the coiled-coil domain not observed in 136 normal alleles or the SNP database (Figure 3A, Table S1).	('R187W', 'Mutation', 'rs377504881', (132, 137))	('CGG', 'Gene', (123, 126))	('coiled-coil domain', 'MPA', (146, 164))	('R187W', 'Var', (132, 137))
51859	19536326	The mammary epithelial cell strain (H16N-2) derived from normal breast epithelium of the same patient as the 21T series lines, did not contain the codon 187 mutation, indicating that the genetic alteration in the 21T series is not a rare polymorphism, but rather a tumor-derived mutational event (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('p', 'Gene', '387572', (94, 95))	('p', 'Gene', '387572', (245, 246))	('p', 'Gene', '387572', (238, 239))	('rat', 'Species', '10116', (256, 259))	('tumor', 'Disease', (265, 270))	('H16N', 'Var', (36, 40))	('patient', 'Species', '9606', (94, 101))	('p', 'Gene', '387572', (13, 14))	('rat', 'Species', '10116', (199, 202))	('H16N', 'SUBSTITUTION', 'None', (36, 40))	('genetic alteration', 'Var', (187, 205))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('p', 'Gene', '387572', (72, 73))
51860	19536326	The R187W mutation falls between the two coils of the coiled-coil domain based on Parcoil (http://paircoil.lcs.mit.edu/cgi-bin/paircoil) and therefore might be predicted to affect protein binding to DEAR1.	('falls', 'Phenotype', 'HP:0002527', (19, 24))	('binding', 'Interaction', (188, 195))	('p', 'Gene', '387572', (180, 181))	('p', 'Gene', '387572', (94, 95))	('affect', 'Reg', (173, 179))	('p', 'Gene', '387572', (98, 99))	('p', 'Gene', '387572', (160, 161))	('R187W', 'Mutation', 'rs377504881', (4, 9))	('R187W', 'Var', (4, 9))	('p', 'Gene', '387572', (127, 128))	('DEAR1', 'Protein', (199, 204))
51863	19536326	Sequence analysis of 55 primary breast tumors obtained from The University of Texas M. D. Anderson Cancer tumor bank revealed that 13% contained genetic alterations in DEAR1, including three missense mutations, three intronic alterations, and a silent mutation not observed in screening controls or the SNP database (Table S2).	('breast tumors', 'Phenotype', 'HP:0100013', (32, 45))	('intronic alterations', 'Var', (217, 237))	('genetic alterations', 'Var', (145, 164))	('DEAR1', 'Gene', (168, 173))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast tumors', 'Disease', 'MESH:D001943', (32, 45))	('Cancer tumor', 'Disease', 'MESH:D009369', (99, 111))	('breast tumors', 'Disease', (32, 45))	('Cancer tumor', 'Disease', (99, 111))	('rat', 'Species', '10116', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p', 'Gene', '387572', (24, 25))	('breast tumor', 'Phenotype', 'HP:0100013', (32, 44))	('rat', 'Species', '10116', (230, 233))	('missense mutations', 'Var', (191, 209))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
51865	19536326	Two missense mutations were identified in later-onset breast tumor samples, both affecting exon 5 (GTC ATC, V473I and GTC ATC, V350I) (Table S2) and present in both tumor and adjacent normal samples but not in controls or the SNP database.	('p', 'Gene', '387572', (70, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (54, 66))	('p', 'Gene', '387572', (149, 150))	('affecting', 'Reg', (81, 90))	('V350I', 'Mutation', 'rs771712820', (127, 132))	('p', 'Gene', '387572', (194, 195))	('breast tumor', 'Disease', 'MESH:D001943', (54, 66))	('V473I', 'Mutation', 'rs61737100', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('V473I', 'Var', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('breast tumor', 'Disease', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('V350I', 'Var', (127, 132))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (165, 170))
51866	19536326	In addition, the exon 5 mutation was not observed in normal lymph node from the same individual whose tumor contained the codon 473 mutation, indicating that the sequence alteration in the tumor was a somatic mutation of the DEAR1 sequence (Figure 3B).	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('alteration', 'Var', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('rat', 'Species', '10116', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('p', 'Gene', '387572', (63, 64))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
51872	19536326	Subsequent PMA detected a deletion of both the CHD5 and p73 genes, which lie distal to DEAR1 in Chromosome 1p, suggestive of a terminal deletion of one allele with a breakpoint within the DEAR1 promoter, which then resulted in LOH encompassing two distal candidate tumor suppressors on Chromosome 1p (Figure 3E).	('deletion', 'Var', (26, 34))	('deletion', 'Var', (136, 144))	('PMA', 'Chemical', '-', (11, 14))	('p', 'Gene', '387572', (56, 57))	('tumor', 'Disease', (265, 270))	('CHD5', 'Gene', '26038', (47, 51))	('LOH', 'NegReg', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('p', 'Gene', '387572', (236, 237))	('p', 'Gene', '387572', (171, 172))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('p', 'Gene', '387572', (108, 109))	('p73', 'Gene', '7161', (56, 59))	('p73', 'Gene', (56, 59))	('p', 'Gene', '387572', (194, 195))	('p', 'Gene', '387572', (273, 274))	('p', 'Gene', '387572', (274, 275))	('CHD5', 'Gene', (47, 51))	('p', 'Gene', '387572', (298, 299))
51875	19536326	Additionally, because PMA detected heterozygous deletion of distal genes to DEAR1, and genomic PCR detected the HD limited to the DEAR1 promoter and exon 1, our results are consistent with a microdeletion in one allele and a terminal deletion with a breakpoint in the promoter of DEAR1 in the second allele, thereby deleting the entire DEAR1 coding region as well as the distal arm (Figure 3D).	('DEAR1', 'Gene', (336, 341))	('microdeletion', 'Var', (191, 204))	('deletion', 'NegReg', (48, 56))	('PMA', 'Chemical', '-', (22, 25))	('deleting', 'NegReg', (316, 324))	('HD', 'Disease', 'MESH:D006816', (112, 114))	('p', 'Gene', '387572', (136, 137))	('p', 'Gene', '387572', (268, 269))	('p', 'Gene', '387572', (255, 256))	('DEAR1', 'Gene', (280, 285))
51877	19536326	In order to determine if the mutations in DEAR1 are important to the genesis or progression of breast cancer and are not mere "passenger" mutations, we performed functional assays.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('p', 'Gene', '387572', (80, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('DEAR1', 'Gene', (42, 47))	('p', 'Gene', '387572', (152, 153))	('mutations', 'Var', (29, 38))	('p', 'Gene', '387572', (54, 55))	('p', 'Gene', '387572', (127, 128))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
51878	19536326	To determine the effect of genetic complementation of the missense mutation affecting codon 187 in the breast cancer progression model as well as in a breast tumor sample, full-length DEAR1 wild type and R187W mutant cDNA were introduced into 21MT to generate stable transfectants.	('p', 'Gene', '387572', (117, 118))	('breast tumor', 'Disease', (151, 163))	('missense mutation', 'Var', (58, 75))	('R187W', 'Mutation', 'rs377504881', (204, 209))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('R187W', 'Var', (204, 209))	('breast tumor', 'Phenotype', 'HP:0100013', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('p', 'Gene', '387572', (197, 198))	('codon 187', 'Gene', (86, 95))	('rat', 'Species', '10116', (255, 258))	('p', 'Gene', '387572', (167, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('breast tumor', 'Disease', 'MESH:D001943', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('p', 'Gene', '387572', (38, 39))
51880	19536326	cDNA sequencing confirmed expression of predominant wild-type DEAR1 transcripts in 21MT/J and 21MT/L transfectants and as well as the R187W mutant transcripts in control 21MT/Delta (unpublished data).	('p', 'Gene', '387572', (76, 77))	('p', 'Gene', '387572', (155, 156))	('p', 'Gene', '387572', (184, 185))	('DEAR1', 'Gene', (62, 67))	('p', 'Gene', '387572', (40, 41))	('R187W', 'Mutation', 'rs377504881', (134, 139))	('R187W', 'Var', (134, 139))	('p', 'Gene', '387572', (28, 29))	('p', 'Gene', '387572', (59, 60))
51884	19536326	Introduction of the tumor-associated R187W missense mutation in 21MT/Delta also resulted in a similar percentage of large, irregularly shaped multiacinar structures as observed in 21MT cells (Figure 4B).	('R187W missense', 'Var', (37, 51))	('R187W', 'Mutation', 'rs377504881', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('p', 'Gene', '387572', (102, 103))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('p', 'Gene', '387572', (138, 139))	('tumor', 'Disease', (20, 25))
51889	19536326	Similarly, transfectant 21MT/Delta containing the codon 187 missense mutation resulted in structures (median, 128.5 microm; interquartile range, 88.9 to 176.0 microm; range, 38.1 to 304.6 microm; n = 50), which by size and morphology closely resembled 21MT cells in basement membrane culture and were significantly different from DEAR1 wild-type transfectants (p<0.0001).	('p', 'Gene', '387572', (361, 362))	('resulted', 'Reg', (78, 86))	('p', 'Gene', '387572', (226, 227))	('p', 'Gene', '387572', (343, 344))	('missense mutation', 'Var', (60, 77))
51892	19536326	In contrast to 21MT and 21MT/Delta, E-cadherin staining in wild-type DEAR1 transfectants was properly localized at cell-cell contacts.	('p', 'Gene', '387572', (93, 94))	('p', 'Gene', '387572', (96, 97))	('transfectants', 'Var', (75, 88))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('p', 'Gene', '387572', (66, 67))
51896	19536326	Thus, the introduction of wild-type DEAR1 resulted in restoration of normal epithelial acinar architecture, a reinitiation of apicobasal polarity, and a clearing of luminal space, providing evidence for the role of DEAR1 in the dominant regulation of acinar morphogenesis and indicating that the 21MT missense mutant phenotype could be rescued by the introduction of wild-type DEAR1.	('introduction', 'Var', (10, 22))	('DEAR1', 'Var', (36, 41))	('p', 'Gene', '387572', (180, 181))	('p', 'Gene', '387572', (324, 325))	('p', 'Gene', '387572', (33, 34))	('p', 'Gene', '387572', (77, 78))	('p', 'Gene', '387572', (137, 138))	('p', 'Gene', '387572', (374, 375))	('p', 'Gene', '387572', (174, 175))	('rat', 'Species', '10116', (59, 62))	('p', 'Gene', '387572', (261, 262))	('p', 'Gene', '387572', (127, 128))	('p', 'Gene', '387572', (317, 318))
51897	19536326	Similar results were obtained by transient transfection of DEAR1 into MCF-7, which has very low to undetectable DEAR1 expression (Figure 2C), in which transient expression of DEAR1 could partially restore acinar morphogenesis in this cell line (Figure S6).	('DEAR1', 'Var', (175, 180))	('p', 'Gene', '387572', (163, 164))	('p', 'Gene', '387572', (187, 188))	('MCF-7', 'CellLine', 'CVCL:0031', (70, 75))	('p', 'Gene', '387572', (215, 216))	('p', 'Gene', '387572', (120, 121))	('restore', 'PosReg', (197, 204))	('DEAR1', 'Gene', (112, 117))
51905	19536326	Because both DEAR1 mutations and a homozygous deletion were observed in primary tumors from young women, and because we herein demonstrate the functional importance of complementation of a tumor-derived mutation and in vitro silencing of the gene, these data indicate that DEAR1 is involved in the underlying genetic etiology of early-onset breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast cancer', 'Disease', 'MESH:D001943', (341, 354))	('tumors', 'Disease', (80, 86))	('breast cancer', 'Disease', (341, 354))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('p', 'Gene', '387572', (72, 73))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('rat', 'Species', '10116', (134, 137))	('DEAR1', 'Gene', (13, 18))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('p', 'Gene', '387572', (171, 172))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (189, 194))	('women', 'Species', '9606', (98, 103))	('involved', 'Reg', (282, 290))	('p', 'Gene', '387572', (156, 157))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (341, 354))
51916	19536326	Furthermore, loss of DEAR1 expression correlated significantly with loss of progesterone receptor expression and with the triple-negative phenotype (ER-, PR-, HER-2-) of breast cancers (r = 0.21, p = 0.0362), a subgroup common in BRCA1 mutation carriers and identified by gene expression profiling as breast cancers of poor prognosis and for which few treatment options exist (Table 1).	('mutation', 'Var', (236, 244))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('HER-2', 'Gene', (159, 164))	('progesterone receptor', 'Gene', (76, 97))	('p', 'Gene', '387572', (145, 146))	('progesterone receptor', 'Gene', '5241', (76, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (301, 314))	('p', 'Gene', '387572', (288, 289))	('loss', 'NegReg', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('p', 'Gene', '387572', (319, 320))	('breast cancers', 'Disease', 'MESH:D001943', (170, 184))	('breast cancers', 'Disease', (170, 184))	('p', 'Gene', '387572', (279, 280))	('breast cancers', 'Phenotype', 'HP:0003002', (170, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('BRCA1', 'Gene', '672', (230, 235))	('p', 'Gene', '387572', (93, 94))	('p', 'Gene', '387572', (125, 126))	('BRCA1', 'Gene', (230, 235))	('p', 'Gene', '387572', (324, 325))	('p', 'Gene', '387572', (29, 30))	('cancers', 'Phenotype', 'HP:0002664', (308, 315))	('DEAR1', 'Gene', (21, 26))	('p', 'Gene', '387572', (363, 364))	('p', 'Gene', '387572', (196, 197))	('breast cancers', 'Disease', 'MESH:D001943', (301, 315))	('p', 'Gene', '387572', (138, 139))	('p', 'Gene', '387572', (100, 101))	('breast cancers', 'Disease', (301, 315))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('p', 'Gene', '387572', (76, 77))	('p', 'Gene', '387572', (218, 219))	('breast cancers', 'Phenotype', 'HP:0003002', (301, 315))	('loss', 'NegReg', (13, 17))	('HER-2', 'Gene', '2064', (159, 164))
51918	19536326	Although loss of DEAR1 expression did not correlate with distant metastasis or survival in this young cohort of women with early stage breast cancer, loss of DEAR1 expression on immunohistochemical staining significantly predicted local recurrence.	('p', 'Gene', '387572', (25, 26))	('loss', 'Var', (150, 154))	('p', 'Gene', '387572', (166, 167))	('DEAR1', 'Gene', (158, 163))	('p', 'Gene', '387572', (221, 222))	('women', 'Species', '9606', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('local recurrence', 'CPA', (231, 247))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
51923	19536326	DEAR1 undergoes mutation and deletion in breast cancer.	('deletion', 'Var', (29, 37))	('DEAR1', 'Gene', (0, 5))	('mutation', 'Var', (16, 24))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))
51924	19536326	Furthermore, by complementation of a somatic tumor-derived missense mutation, wild-type DEAR1 restored acinar structures that, by size, polarity, and presence of luminal apoptosis, resembled normal mammary acini grown under similar conditions.	('missense mutation', 'Var', (59, 76))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('acinar structures', 'MPA', (103, 120))	('p', 'Gene', '387572', (173, 174))	('tumor', 'Disease', (45, 50))	('p', 'Gene', '387572', (19, 20))	('p', 'Gene', '387572', (85, 86))	('p', 'Gene', '387572', (150, 151))	('p', 'Gene', '387572', (136, 137))	('restored', 'PosReg', (94, 102))	('p', 'Gene', '387572', (171, 172))	('DEAR1', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
51925	19536326	Stable knockdown of DEAR1 in immortalized HMECs recapitulated the phenotype in 21MT cells with disruption of tissue architecture, loss of polarity, and lumen formation, indicating that DEAR1 is required for normal acinar morphogenesis in 3D culture.	('p', 'Gene', '387572', (66, 67))	('DEAR1', 'Gene', (20, 25))	('p', 'Gene', '387572', (73, 74))	('loss', 'NegReg', (130, 134))	('knockdown', 'Var', (7, 16))	('p', 'Gene', '387572', (224, 225))	('p', 'Gene', '387572', (138, 139))	('p', 'Gene', '387572', (52, 53))	('p', 'Gene', '387572', (100, 101))
51929	19536326	To date, mutations in RBCC/TRIM family members have been shown to be causal in hereditary disorders of development, including mutation of MUL in mulibrey nanism, an autosomal recessive disorder involving defective development of several mesodermal tissues and MID1, in X-linked Opitz/GBBB syndrome, an inherited disorder primarily affecting midline structures as well as PYRIN/MARENOSTRIN, which is specifically mutated in familial Mediterranean fever.	('X-linked Opitz/GBBB syndrome', 'Disease', (269, 297))	('X-linked Opitz/GBBB syndrome', 'Disease', 'MESH:C567932', (269, 297))	('inherited disorder', 'Disease', (302, 320))	('mutations', 'Var', (9, 18))	('hereditary disorders', 'Disease', (79, 99))	('familial Mediterranean fever', 'Disease', (423, 451))	('MID1', 'Gene', (260, 264))	('p', 'Gene', '387572', (279, 280))	('MARENOSTRIN', 'Gene', (377, 388))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (165, 193))	('autosomal recessive disorder', 'Disease', (165, 193))	('hereditary disorders', 'Disease', 'MESH:D030342', (79, 99))	('PYRIN', 'Gene', '4210', (371, 376))	('familial Mediterranean fever', 'Disease', 'MESH:D010505', (423, 451))	('inherited disorder', 'Disease', 'MESH:D030342', (302, 320))	('MUL', 'Gene', (138, 141))	('p', 'Gene', '387572', (109, 110))	('PYRIN', 'Gene', (371, 376))	('MID1', 'Gene', '4281', (260, 264))	('p', 'Gene', '387572', (220, 221))	('p', 'Gene', '387572', (400, 401))	('mutation', 'Var', (126, 134))	('p', 'Gene', '387572', (321, 322))	('MARENOSTRIN', 'Gene', '4210', (377, 388))	('RBCC', 'Gene', '51127', (22, 26))	('fever', 'Phenotype', 'HP:0001945', (446, 451))	('RBCC', 'Gene', (22, 26))
51934	19536326	Thus, although it is experimentally feasible to phenotypically alter the ECM and the growth of tumor cells in vivo and in vitro, we now have genotypically complemented a tumor-associated mutation, indicating that replacement of a single gene can restore epithelial differentiation despite multiple genetic abnormalities in a breast cancer cell line and, furthermore, that DEAR1 is a dominant regulator of an important pathway to tumorigenesis in early-onset breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (325, 338))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p', 'Gene', '387572', (48, 49))	('breast cancer', 'Disease', 'MESH:D001943', (325, 338))	('p', 'Gene', '387572', (255, 256))	('breast cancer', 'Disease', (325, 338))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (458, 471))	('p', 'Gene', '387572', (215, 216))	('p', 'Gene', '387572', (23, 24))	('p', 'Gene', '387572', (294, 295))	('p', 'Gene', '387572', (158, 159))	('breast cancer', 'Disease', 'MESH:D001943', (458, 471))	('genetic abnormalities', 'Disease', 'MESH:D030342', (298, 319))	('breast cancer', 'Disease', (458, 471))	('tumor', 'Disease', (429, 434))	('p', 'Gene', '387572', (55, 56))	('p', 'Gene', '387572', (410, 411))	('genetic abnormalities', 'Disease', (298, 319))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('p', 'Gene', '387572', (284, 285))	('tumor', 'Disease', 'MESH:D009369', (429, 434))	('p', 'Gene', '387572', (418, 419))	('tumor', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (465, 471))	('mutation', 'Var', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))	('restore', 'PosReg', (246, 253))	('p', 'Gene', '387572', (147, 148))
51941	19536326	Our results in 3D culture suggest that there is no discernible difference in Ki67 staining of acini in the DEAR1 knockdown HMECs compared with wild-type HMECs, suggesting that DEAR1 mediates its effects more by regulation of polarity than by proliferation, although additional experimentation will be required to dissect the pathways regulated by DEAR1.	('p', 'Gene', '387572', (279, 280))	('p', 'Gene', '387572', (225, 226))	('p', 'Gene', '387572', (132, 133))	('DEAR1', 'Gene', (107, 112))	('p', 'Gene', '387572', (242, 243))	('rat', 'Species', '10116', (249, 252))	('p', 'Gene', '387572', (325, 326))	('p', 'Gene', '387572', (150, 151))	('knockdown', 'Var', (113, 122))
51946	19536326	CHD5 maps to a region associated with LOH in epithelial tumors, as well as brain tumors and hematopoietic neoplasms, suggesting that CHD5 is a critical player in many types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('brain tumors', 'Disease', 'MESH:D001932', (75, 87))	('brain tumors', 'Phenotype', 'HP:0030692', (75, 87))	('p', 'Gene', '387572', (169, 170))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('epithelial tumors', 'Disease', (45, 62))	('epithelial tumors', 'Disease', 'MESH:D002277', (45, 62))	('CHD5', 'Gene', '26038', (0, 4))	('p', 'Gene', '387572', (152, 153))	('neoplasms', 'Phenotype', 'HP:0002664', (106, 115))	('brain tumors', 'Disease', (75, 87))	('CHD5', 'Gene', '26038', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('p', 'Gene', '387572', (7, 8))	('p', 'Gene', '387572', (46, 47))	('LOH', 'Var', (38, 41))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (92, 115))	('p', 'Gene', '387572', (109, 110))	('CHD5', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (92, 115))	('p', 'Gene', '387572', (98, 99))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CHD5', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', (176, 182))	('hematopoietic neoplasms', 'Disease', (92, 115))
51947	19536326	Interestingly, in the breast tumor sample showing HD for DEAR1, one copy of Chromosome 1p contains a microdeletion of DEAR1, while the second copy deletes the entire short arm, including CHD5, but the breakpoint for the deletion lies within DEAR1.	('p', 'Gene', '387572', (206, 207))	('p', 'Gene', '387572', (70, 71))	('short arm', 'Phenotype', 'HP:0009824', (166, 175))	('CHD5', 'Gene', '26038', (187, 191))	('breast tumor', 'Phenotype', 'HP:0100013', (22, 34))	('CHD5', 'Gene', (187, 191))	('deletes', 'NegReg', (147, 154))	('p', 'Gene', '387572', (88, 89))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('HD', 'Disease', 'MESH:D006816', (50, 52))	('p', 'Gene', '387572', (144, 145))	('breast tumor', 'Disease', 'MESH:D001943', (22, 34))	('HD', 'Disease', 'MESH:D006816', (188, 190))	('DEAR1', 'Gene', (118, 123))	('breast tumor', 'Disease', (22, 34))	('microdeletion', 'Var', (101, 114))	('p', 'Gene', '387572', (38, 39))
51948	19536326	CHD5 maps to a genomic interval associated with LOH in late-stage tumors; thus, the finding that DEAR1 seems to play a role in the earliest stages of breast tumorigenesis would suggest a mechanism for mutation or deletion of DEAR1 as an initiating event that could lead to the LOH for distal Chromosome 1p loci and thus haploinsufficiency of CHD5.	('LOH', 'NegReg', (277, 280))	('p', 'Gene', '387572', (112, 113))	('CHD5', 'Gene', '26038', (342, 346))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutation', 'Var', (201, 209))	('CHD5', 'Gene', '26038', (0, 4))	('lead to', 'Reg', (265, 272))	('haploinsufficiency of CHD5', 'Disease', 'MESH:D058495', (320, 346))	('deletion', 'Var', (213, 221))	('breast tumor', 'Disease', 'MESH:D001943', (150, 162))	('p', 'Gene', '387572', (7, 8))	('late-stage tumors', 'Disease', 'MESH:D062706', (55, 72))	('breast tumor', 'Phenotype', 'HP:0100013', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('p', 'Gene', '387572', (322, 323))	('CHD5', 'Gene', (342, 346))	('DEAR1', 'Gene', (225, 230))	('CHD5', 'Gene', (0, 4))	('haploinsufficiency of CHD5', 'Disease', (320, 346))	('breast tumor', 'Disease', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p', 'Gene', '387572', (304, 305))	('late-stage tumors', 'Disease', (55, 72))
51949	19536326	The present study also describes the potential clinical significance of DEAR1 genetic alteration and loss of expression in breast tumorigenesis.	('p', 'Gene', '387572', (111, 112))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('genetic alteration', 'Var', (78, 96))	('DEAR1', 'Gene', (72, 77))	('p', 'Gene', '387572', (37, 38))	('breast tumor', 'Disease', 'MESH:D001943', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p', 'Gene', '387572', (4, 5))	('breast tumor', 'Disease', (123, 135))	('rat', 'Species', '10116', (90, 93))
51951	19536326	Our data indicate that DEAR1 mutation and loss of function play a role in early-onset disease.	('mutation', 'Var', (29, 37))	('early-onset disease', 'Disease', (74, 93))	('loss of function', 'NegReg', (42, 58))	('DEAR1', 'Gene', (23, 28))	('p', 'Gene', '387572', (59, 60))
51956	19536326	Thus, it is a formal possibility that DEAR1 loss of function and mutation might play an important role in germline predisposition to breast cancer or that DEAR1 lies in a critical genetic pathway involved in both inherited and sporadic breast cancer.	('p', 'Gene', '387572', (90, 91))	('breast cancer', 'Disease', (236, 249))	('breast cancer', 'Disease', (133, 146))	('p', 'Gene', '387572', (115, 116))	('DEAR1', 'Gene', (38, 43))	('p', 'Gene', '387572', (80, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('p', 'Gene', '387572', (228, 229))	('p', 'Gene', '387572', (21, 22))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('mutation', 'Var', (65, 73))	('p', 'Gene', '387572', (188, 189))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('p', 'Gene', '387572', (121, 122))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('loss of function', 'NegReg', (44, 60))
51966	19536326	DCIS ductal carcinoma in situ DHPLC denaturing high-performance liquid chromatography DIC differential interference contrast ECM extracellular matrix FISH fluorescence in situ hybridization HD homozygous deletion HMEC human mammary epithelial cell LOH loss of heterozygosity PMA pyrosequencing-based methylation analysis TRIM tripartite motif	('ductal carcinoma', 'Disease', (5, 21))	('p', 'Gene', '387572', (279, 280))	('HMEC', 'Gene', (213, 217))	('HD', 'Disease', 'MESH:D006816', (190, 192))	('PMA', 'Chemical', '-', (275, 278))	('deletion', 'Var', (204, 212))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (5, 29))	('p', 'Gene', '387572', (82, 83))	('p', 'Gene', '387572', (329, 330))	('human', 'Species', '9606', (218, 223))	('p', 'Gene', '387572', (233, 234))	('loss of heterozygosity', 'NegReg', (252, 274))	('DHPLC', 'Chemical', '-', (30, 35))	('p', 'Gene', '387572', (52, 53))	('ductal carcinoma', 'Disease', 'MESH:D044584', (5, 21))
52005	29107353	A recent study showed that anisotropy in 2D shear-wave elastography is an indicator of breast cancer.	('anisotropy', 'Var', (27, 37))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('2D shear-wave elastography', 'MPA', (41, 67))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
52015	29107353	The size of a breast lesion measured with CEUS is larger than that measured with conventional ultrasound.	('CEUS', 'Var', (42, 46))	('breast lesion', 'Disease', (14, 27))	('breast lesion', 'Disease', 'MESH:D001941', (14, 27))
52085	29107353	Sakamoto considered that the higher falsenegative rate of US-VAB for MRI-detected lesions (26%) than for US detected lesions (7.4%) was caused by the difficulties in MRI-US correlation, and which indicates the need for MRI-guided biopsy.	('falsenegative', 'MPA', (36, 49))	('VAB', 'Chemical', '-', (61, 64))	('US-VAB', 'Var', (58, 64))
52111	29107353	Mammographic screening results in a highly significant decrease in breast cancer-specific mortality.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('decrease', 'NegReg', (55, 63))	('Mammographic screening', 'Var', (0, 22))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
52140	29107353	Annual screening with MRI and mammography improves metastasis-free survival in women with BRCA1 mutation or a familial predisposition.	('BRCA1', 'Gene', '672', (90, 95))	('metastasis-free survival', 'CPA', (51, 75))	('mutation', 'Var', (96, 104))	('BRCA1', 'Gene', (90, 95))	('improves', 'PosReg', (42, 50))	('women', 'Species', '9606', (79, 84))
52176	29107353	The patient-based SE and SP of FDG PET/CT were 96% and 89%, respectively.While the SE was similar to that in their previous study using FDG PET alone, the SP was significantly higher for PET/CT.	('SP', 'Chemical', 'MESH:C000604007', (25, 27))	('SE', 'Chemical', '-', (18, 20))	('SP', 'Chemical', 'MESH:C000604007', (155, 157))	('patient', 'Species', '9606', (4, 11))	('FDG', 'Gene', '23583', (136, 139))	('FDG', 'Gene', '23583', (31, 34))	('FDG', 'Gene', (136, 139))	('higher', 'PosReg', (176, 182))	('PET/CT', 'Var', (187, 193))	('FDG', 'Gene', (31, 34))	('SE', 'Chemical', '-', (83, 85))
52242	19829939	Tsuda et al reported that loss of heterozygosity (LOH) on chromosome 16q was a useful marker for intracystic papillary carcinoma, since intraductal papilloma showed no LOH.	('loss of heterozygosity', 'Var', (26, 48))	('papilloma', 'Phenotype', 'HP:0012740', (148, 157))	('intraductal papilloma', 'Disease', 'MESH:D018300', (136, 157))	('intraductal papilloma', 'Disease', (136, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('intracystic papillary carcinoma', 'Disease', (97, 128))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (97, 128))
52257	19829939	CNB core needle biopsy DCIS ductal carcinoma in situ IPC intracystic papillary carcinoma LOH loss of heterozygosity MRI magnetic resonance imaging	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (28, 52))	('loss', 'Var', (93, 97))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (28, 52))	('ductal carcinoma in situ', 'Disease', (28, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (57, 88))	('intracystic papillary carcinoma', 'Disease', (57, 88))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))
52261	32267247	The alteration of this signalling becomes, in a first phase, a ductal carcinoma in situ (DCIS), and in a second, an infiltrating ductal carcinoma (Figure 1).	('ductal carcinoma', 'Disease', 'MESH:D044584', (129, 145))	('ductal carcinoma', 'Disease', (129, 145))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (129, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('alteration', 'Var', (4, 14))	('ductal carcinoma', 'Disease', 'MESH:D044584', (63, 79))	('ductal carcinoma in situ', 'Disease', (63, 87))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (63, 87))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (63, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (63, 87))
52262	32267247	At present, it is not yet entirely clear how DCIS transforms into an infiltrating carcinoma, although the presence of mutations in the BRCA1, BRCA2, PTEN and PT53 genes is a known cause.	('BRCA2', 'Gene', (142, 147))	('carcinoma', 'Disease', 'MESH:D009369', (82, 91))	('PT53', 'Gene', (158, 162))	('BRCA1', 'Gene', '672', (135, 140))	('PTEN', 'Gene', (149, 153))	('mutations', 'Var', (118, 127))	('BRCA2', 'Gene', '675', (142, 147))	('PTEN', 'Gene', '5728', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('BRCA1', 'Gene', (135, 140))	('carcinoma', 'Disease', (82, 91))
52301	27771840	However, the presence of DCIS reflects increased risk for invasive breast cancer, as 11-19% of women with DCIS develop a second breast cancer within 10 years of diagnosis, with similar rates 10 or more years after diagnosis.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('invasive breast cancer', 'Disease', (58, 80))	('DCIS', 'Var', (106, 110))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('women', 'Species', '9606', (95, 100))	('invasive breast cancer', 'Disease', 'MESH:D001943', (58, 80))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
52416	27639373	Ten-year data from these studies (Royal Marsden trial, Canadian trial, and the START A and B trials) demonstrated that hypofractionation is associated to equivalent or improved outcomes (both local and distant disease control), toxicity, cosmesis, and cost-effectiveness.	('improved', 'PosReg', (168, 176))	('hypofractionation', 'Var', (119, 136))	('toxicity', 'Disease', 'MESH:D064420', (228, 236))	('toxicity', 'Disease', (228, 236))
52470	27639373	At the last follow-up, given the small number of G1 toxicity, the correlation decreased to p = 0.014, keeping however the same trend (PTV_WB volumes of 646 +- 36 and 1104 +- 198 cm3 for no and mild toxicity, respectively).	('PTV', 'Chemical', '-', (134, 137))	('1104 +- 198 cm3', 'Var', (166, 181))	('toxicity', 'Disease', 'MESH:D064420', (52, 60))	('toxicity', 'Disease', (52, 60))	('toxicity', 'Disease', 'MESH:D064420', (198, 206))	('toxicity', 'Disease', (198, 206))
52536	18384688	Furthermore, it has been proposed that carcinogenesis does not result from epithelial or stromal mutations alone, but rather from the loss or breakdown of biological structures induced by perturbed stromal-epithelial interactions.	('perturbed', 'Var', (188, 197))	('carcinogenesis', 'Disease', (39, 53))	('breakdown', 'NegReg', (142, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('biological structures', 'MPA', (155, 176))	('loss', 'NegReg', (134, 138))
52563	18384688	A dramatic decrease of CD34 expression of fibroblasts and acquisition of SMA was mostly observed around ducts harboring DCIS-I and DCIS-H. Interestingly, in four cases of DCIS-I and three cases of DCIS-H a homogenous pattern of staining was observed with fibroblasts being strongly positive to both CD34 and SMA.	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('CD34', 'Gene', (23, 27))	('CD34', 'Gene', '947', (23, 27))	('DCIS-I', 'Var', (171, 177))	('SMA', 'Chemical', '-', (308, 311))	('SMA', 'Chemical', '-', (73, 76))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('CD34', 'Gene', (299, 303))	('CD34', 'Gene', '947', (299, 303))
52564	18384688	Taking into consideration the fact that, in DCIS-I and DCIS-H, the SMA positivity index was higher, while the CD34 positivity index was lower than the rest groups of study (Table 2), it was necessary to define whether this difference was of significance.	('SMA', 'Chemical', '-', (67, 70))	('higher', 'PosReg', (92, 98))	('DCIS-I', 'Var', (44, 50))	('SMA positivity index', 'MPA', (67, 87))	('DCIS-H', 'Var', (55, 61))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('CD34', 'Gene', '947', (110, 114))	('CD34', 'Gene', (110, 114))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
52566	18384688	On the contrary both SMA and CD34 expression patterns were revealed significantly different on DCIS-I and DCIS-H when compared to normal breast tissue samples.	('DCIS-H', 'Var', (106, 112))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('expression', 'MPA', (34, 44))	('CD34', 'Gene', (29, 33))	('CD34', 'Gene', '947', (29, 33))	('DCIS-I', 'Var', (95, 101))	('SMA', 'Chemical', '-', (21, 24))	('different', 'Reg', (82, 91))
52571	18384688	The evaluation of angiogenesis with anti-CD31 antibody revealed that high microvessel counts were strongly associated with DCIS-I and DCIS-H, with a mean of 140 +- 32 and 146 +- 38 respectively and to a lesser extent with DCIS-L, ADH, FA, LCIS and ALH (mean values 121 +- 13, 119 +- 10, 114 +- 9, 111 +- 7 and 109 +- 5 respectively).	('DCIS', 'Phenotype', 'HP:0030075', (222, 226))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('DCIS-I', 'Var', (123, 129))	('LCIS', 'Phenotype', 'HP:0030076', (239, 243))	('CD31', 'Gene', '5175', (41, 45))	('associated', 'Interaction', (107, 117))	('CD31', 'Gene', (41, 45))	('DCIS-H', 'Var', (134, 140))	('ALH', 'Chemical', '-', (248, 251))
52578	18384688	Another group of investigators also supports the concept of stromal-epithelial interactions in the development and progression of mammary neoplasia but in their study the genetic alterations of the stromal cells were found to precede genotypic changes in the epithelial cells.	('neoplasia', 'Disease', 'MESH:D009369', (138, 147))	('genetic alterations', 'Var', (171, 190))	('neoplasia', 'Disease', (138, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))
52624	28890755	For the four way classification (UDH, Low-DCIS, Medium-DCIS, High-DCIS), the difference is by 6% in accuracy, 8% in micro-AUC, and 19% in macro-AUC.	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('High-DCIS', 'Var', (61, 70))	('Medium-DCIS', 'Var', (48, 59))	('UDH', 'Chemical', '-', (33, 36))	('Low-DCIS', 'Var', (38, 46))
52705	25634748	This has been associated with a progressive decline in the rate of underestimation ofmalignancy associated with the presence of RS alone on NCB.	('malignancy', 'Disease', (85, 95))	('decline', 'NegReg', (44, 51))	('presence', 'Var', (116, 124))	('RS', 'Chemical', '-', (128, 130))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))
52721	25634748	On multivariate analysis, there was no additional risk associated with the presence of RS when the data were adjusted for the presence of either proliferative disease or atypical hyperplasia.	('RS', 'Chemical', '-', (87, 89))	('presence', 'Var', (75, 83))	('proliferative disease', 'Disease', (145, 166))	('proliferative disease', 'Disease', 'MESH:D018630', (145, 166))	('atypical hyperplasia', 'Disease', (170, 190))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (170, 190))
52889	24948027	Our findings show a low degree of inter-observer diagnostic agreement between generalist pathologists and a specialist in breast pathology with regard to CCL without atypia and pleomorphic LCIS, moderate agreement for FEA, ADH, and low-grade, intermediate, and microinvasive DCIS, and good agreement for high-grade DCIS, ALH, and LCIS.	('DCIS', 'Phenotype', 'HP:0030075', (315, 319))	('ALH', 'Chemical', '-', (321, 324))	('DCIS', 'Phenotype', 'HP:0030075', (275, 279))	('LCIS', 'Phenotype', 'HP:0030076', (330, 334))	('LCIS', 'Phenotype', 'HP:0030076', (189, 193))	('ALH', 'Disease', (321, 324))	('microinvasive', 'Var', (261, 274))	('low-grade', 'Var', (232, 241))	('CCL', 'Chemical', '-', (154, 157))
52907	16778390	This model has gained persuasiveness by virtue of a pioneering study using loss of heterozygosity (LOH) analysis on the continua from the normal tissue, through potential precursors of breast cancer, to invasive cancer.	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('invasive cancer', 'Disease', (203, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('invasive cancer', 'Disease', 'MESH:D009362', (203, 218))	('loss', 'Var', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
52939	16778390	IDC with RBNG 1 or 2 was arbitrarily defined as non-high grade IDC, and the patients with non-high grade IDC were classified as Group II.	('patients', 'Species', '9606', (76, 84))	('IDC', 'Gene', (105, 108))	('IDC', 'Gene', '4000', (0, 3))	('non-high', 'Disease', (48, 56))	('IDC', 'Gene', '4000', (63, 66))	('RBNG 1', 'Var', (9, 15))	('IDC', 'Gene', (0, 3))	('IDC', 'Gene', (63, 66))	('IDC', 'Gene', '4000', (105, 108))
52940	16778390	IDC with RBNG 3 was defined as high grade IDC, and the patients with high grade IDC were classified as Group III.	('IDC', 'Gene', (80, 83))	('IDC', 'Gene', '4000', (0, 3))	('RBNG 3', 'Var', (9, 15))	('IDC', 'Gene', '4000', (42, 45))	('IDC', 'Gene', (42, 45))	('IDC', 'Gene', (0, 3))	('patients', 'Species', '9606', (55, 63))	('IDC', 'Gene', '4000', (80, 83))
52960	16778390	In Group II, the subgroup of patients with PR positive showed statistically better survival function than the subgroup with PR negative (p=0.025), while no significant difference in survival function existed between the subgroups in either Group I or III.	('PR positive', 'Var', (43, 54))	('better', 'PosReg', (76, 82))	('patients', 'Species', '9606', (29, 37))	('survival function', 'CPA', (83, 100))
52962	16778390	The subgroup with c-erbB-2 positive had worse prognosis than that with c-erbB-2 negative in Group III (p=0.035), but not in Group I (p= 0.167) or II (p=0.180).	('c-erbB-2', 'Gene', (71, 79))	('positive', 'Var', (27, 35))	('c-erbB-2', 'Gene', (18, 26))	('c-erbB-2', 'Gene', '2064', (18, 26))	('c-erbB-2', 'Gene', '2064', (71, 79))
52964	16778390	Within Group II, the subgroup of patients who received tamoxifen showed significantly better survival function than the subgroup of the patients who had not received it (p=0.018), while no difference in survival function existed between the two subgroups within either Group I or III (Fig.	('patients', 'Species', '9606', (33, 41))	('tamoxifen', 'Var', (55, 64))	('better', 'PosReg', (86, 92))	('patients', 'Species', '9606', (136, 144))	('survival function', 'CPA', (93, 110))	('tamoxifen', 'Chemical', 'MESH:D013629', (55, 64))
52967	16778390	The mechanism is that distinct series of genetic alterations result in heterogeneous phenotypes of breast cancer.	('genetic alterations', 'Var', (41, 60))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('result in', 'Reg', (61, 70))	('heterogeneous phenotypes', 'MPA', (71, 95))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
52969	16778390	When cancers clustered by certain series of genetic alterations express identical biological characteristics including their clinical outcome, this mechanism could be exclusively accepted.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('genetic alterations', 'Var', (44, 63))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
52973	16778390	In the view of diachrony, however, details of genetic alterations in cancer change with progression in some breast cancers.	('cancer', 'Disease', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('genetic alterations', 'Var', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('change', 'Reg', (76, 82))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (69, 75))
52974	16778390	Furthermore, the genetic alterations in a clone tend to increase substantially from DCIS to IDC.	('increase', 'PosReg', (56, 64))	('IDC', 'Gene', '4000', (92, 95))	('IDC', 'Gene', (92, 95))	('DCIS', 'Disease', (84, 88))	('genetic alterations', 'Var', (17, 36))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))
52994	16778390	First, the frequency of premenopausal women was remarkably higher in Group III (82.9%) compared to both Group I (64.3%) and II (67.6%), even though the mean age was similar in all three groups.	('higher', 'PosReg', (59, 65))	('women', 'Species', '9606', (38, 43))	('premenopausal', 'Var', (24, 37))
53063	25250628	According to the ROC analysis, the area under the curve for 99mTc-3P4-RGD2 SMM (area = 0.851) was higher than that for 99mTc-MIBI SMM (area = 0.781), but the statistical difference was not significant.	('higher', 'PosReg', (98, 104))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (119, 129))	('99mTc-3P4-RGD2 SMM', 'Var', (60, 78))
53065	25250628	The T/NT ratio of 99mTc-3P4-RGD2 SMM was significantly higher than that of 99mTc-MIBI SMM.	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (75, 85))	('99mTc-3P4-RGD2 SMM', 'Var', (18, 36))	('T/NT', 'MPA', (4, 8))	('higher', 'PosReg', (55, 61))
53082	25250628	In this study, we compare the diagnostic value of 99mTc-3P4-RGD2 SMM with 99mTc-MIBI SMM for the detection of breast cancer by receiver operating characteristic (ROC) curve analysis.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (74, 84))	('99mTc-3P4-RGD2', 'Var', (50, 64))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
53093	25250628	Regions of interest (ROIs) were drawn around the tumor and an area of normal breast tissue in the same breast on lateral images and used to determine the tumor to non-tumor ratios (T/NT) of 99mTc-3P4-RGD2 and 99mTc-MIBI.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('99mTc-3P4-RGD2', 'Var', (190, 204))	('99mTc-MIBI', 'Var', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('non-tumor', 'Disease', (163, 172))	('tumor', 'Disease', (49, 54))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (209, 219))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('non-tumor', 'Disease', 'MESH:D009369', (163, 172))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (154, 159))
53102	25250628	In 99mTc-3P4-RGD2 SMM, the T/NT of breast cancer was 3.54+-1.51 and that of benign lesions was 1.83+-0.98.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('99mTc-3P4-RGD2 SMM', 'Var', (3, 21))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
53107	25250628	One patient with ductal carcinoma in situ (DCIS) in the long axis diameter of 2.2 cm was clear detected by 99mTc-3P4-RGD2 SMM, but not with 99mTc-MIBI SMM (Fig.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (24, 41))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (140, 150))	('patient', 'Species', '9606', (4, 11))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (17, 41))	('ductal carcinoma in situ', 'Disease', (17, 41))	('99mTc-3P4-RGD2 SMM', 'Var', (107, 125))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (17, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
53110	25250628	The fibroadenoma with mastitis was also false positive in 99mTc-3P4-RGD2 SMM (Fig.	('fibroadenoma', 'Disease', 'MESH:D018226', (4, 16))	('mastitis', 'Disease', (22, 30))	('fibroadenoma', 'Disease', (4, 16))	('99mTc-3P4-RGD2 SMM', 'Var', (58, 76))	('mastitis', 'Disease', 'MESH:D008413', (22, 30))	('fibroadenoma with mastitis', 'Phenotype', 'HP:0010619', (4, 30))
53111	25250628	ROC analyses were performed to determine the optimal cut-off values of both 99mTc-3P4-RGD2 and 99mTc-MIBI SMM T/NT for the detection of malignant breast cancer.	('99mTc-3P4-RGD2', 'Var', (76, 90))	('99mTc-MIBI SMM', 'Var', (95, 109))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (95, 105))	('malignant breast cancer', 'Disease', 'MESH:D001943', (136, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('malignant breast cancer', 'Disease', (136, 159))
53118	25250628	In this present study, to differentiate benign from malignant lesions, ROC analyses were performed to determine the optimal cut-off values of T/NT of 99mTc-3P4-RGD2 and 99mTc-MIBI SMM.	('99mTc-MIBI SMM', 'Var', (169, 183))	('99mTc-3P4-RGD2', 'Var', (150, 164))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (169, 179))
53120	25250628	The sensitivities reported in this study for 99mTc-3P4-RGD2 SMM are comparable with our previous reports; however the specificity is slightly higher than previous studies, which may be due to the low total number of benign breast lesions.	('benign breast lesions', 'Disease', (216, 237))	('benign breast lesions', 'Disease', 'MESH:D001941', (216, 237))	('specificity', 'MPA', (118, 129))	('99mTc-3P4-RGD2', 'Var', (45, 59))	('higher', 'PosReg', (142, 148))
53122	25250628	Although the sensitivity, specificity and accuracy of 99mTc-3P4-RGD2 SMM was slightly superior to that of 99mTc-MIBI SMM in this study, the difference was not statistically significant.	('superior', 'PosReg', (86, 94))	('99mTc-3P4-RGD2 SMM', 'Var', (54, 72))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (106, 116))
53123	25250628	The area under the curve of 99mTc-3P4-RGD2 SMM was slightly larger than that of 99mTc-MIBI SMM, although this difference was also not significant.	('99mTc-3P4-RGD2 SMM', 'Var', (28, 46))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (80, 90))	('larger', 'PosReg', (60, 66))	('area', 'MPA', (4, 8))
53134	25250628	The true positive result with 99mTc-3P4-RGD2 SMM in this common malignant tumor may be an advantage of RGD targeting.	('99mTc-3P4-RGD2 SMM', 'Var', (30, 48))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('malignant tumor', 'Disease', (64, 79))	('malignant tumor', 'Disease', 'MESH:D018198', (64, 79))
53140	25250628	Previous studies have also shown that the integrin alphavbeta3 can exist on neutrophils, monocytes, and vascular smooth muscle cells, which can be the main reason for the false positive result using 99mTc-3P4-RGD2 SMM.	('99mTc-3P4-RGD2', 'Var', (199, 213))	('integrin alphavbeta3', 'Gene', '3685', (42, 62))	('integrin alphavbeta3', 'Gene', (42, 62))
53142	25250628	The uptake of 99mTc-3P4-RGD2 in breast cancer was higher than that of 99mTc-MIBI.	('breast cancer', 'Disease', (32, 45))	('99mTc-3P4-RGD2', 'Var', (14, 28))	('higher', 'PosReg', (50, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('99mTc-MIBI', 'Chemical', 'MESH:C000607999', (70, 80))	('uptake', 'MPA', (4, 10))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
53156	12927043	Mammographic density is a risk factor for breast cancer and is attributed to alterations in the composition of breast tissue.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('Mammographic', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))
53157	12927043	Furthermore, although breast cancer is a direct manifestation of alterations in the expression of multiple genes and cellular pathways within the breast epithelial cell, it is now recognized that perturbations in stromal-epithelial interactions might also influence tumorigenesis and progression through direct effects on growth factor pathways and indirect effects mediated through cell adhesion and structure.	('alterations', 'Reg', (65, 76))	('breast cancer', 'Disease', (22, 35))	('progression', 'CPA', (284, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('influence', 'Reg', (256, 265))	('tumorigenesis', 'CPA', (266, 279))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('growth factor pathways', 'Pathway', (322, 344))	('perturbations', 'Var', (196, 209))	('effects', 'Reg', (311, 318))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
53159	12927043	We have also shown that the small leucine-rich proteoglycans (SLRPs) lumican and decorin are a highly abundant component of breast tissue stroma and that altered expression of stromal proteins is associated with tumour progression and outcome.	('lumican', 'Gene', (69, 76))	('outcome', 'CPA', (235, 242))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('breast tissue stroma', 'Disease', (124, 144))	('associated with', 'Reg', (196, 211))	('lumican', 'Gene', '4060', (69, 76))	('decorin', 'Gene', (81, 88))	('breast tissue stroma', 'Disease', 'MESH:D001943', (124, 144))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('expression', 'MPA', (162, 172))	('tumour', 'Disease', (212, 218))	('altered', 'Var', (154, 161))	('decorin', 'Gene', '1634', (81, 88))
53186	12927043	Recent studies have shown that both stromal architecture and composition can exert an important influence on normal epithelial biology, and somatic mutations can be identified in the stromal compartment of breast tumours independently of mutations in the neoplastic epithelium.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (148, 157))	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (255, 276))	('tumours', 'Phenotype', 'HP:0002664', (213, 220))	('breast tumours', 'Disease', (206, 220))	('influence', 'Reg', (96, 105))	('breast tumours', 'Disease', 'MESH:D001943', (206, 220))
53194	12927043	The levels of expression of these SLRPs are correlated when compared within non-neoplastic or within neoplastic tissues, and low levels of both SLRPs are associated with poor outcome in primary invasive tumours.	('low', 'Var', (125, 128))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('primary invasive tumours', 'Disease', 'MESH:D009361', (186, 210))	('associated', 'Reg', (154, 164))	('primary invasive tumours', 'Disease', (186, 210))
53196	12927043	The principal factors determining SLRP expression in breast are not known, although the expression of insulin-like growth factor (IGF) has been implicated as a risk factor for breast cancer and is also known to be associated with mammographic density in premenopausal women.	('SLRP', 'Gene', (34, 38))	('expression', 'Var', (88, 98))	('IGF', 'Gene', (130, 133))	('risk factor', 'Reg', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('implicated', 'Reg', (144, 154))	('breast cancer', 'Disease', (176, 189))	('associated', 'Reg', (214, 224))	('women', 'Species', '9606', (268, 273))
53223	21124756	found that women with atypia on biopsy had 5.3 times the risk of developing invasive disease compared with women with nonproliferative lesions on biopsy.	('atypia', 'Var', (22, 28))	('invasive disease', 'Disease', (76, 92))	('women', 'Species', '9606', (11, 16))	('women', 'Species', '9606', (107, 112))	('invasive disease', 'Disease', 'MESH:D009362', (76, 92))
53225	21124756	used periareolar fine needle aspiration to assess women for the presence of atypia and found that 15% of women with an elevated Gail risk and atypia developed cancer compared with 4% of women with similar Gail risk but no atypia.	('cancer', 'Disease', (159, 165))	('women', 'Species', '9606', (186, 191))	('aspiration', 'Phenotype', 'HP:0002835', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('women', 'Species', '9606', (105, 110))	('women', 'Species', '9606', (50, 55))	('developed', 'PosReg', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('atypia', 'Var', (142, 148))
53238	21124756	Some investigators have used fluorescence in situ hybridization (FISH) to detect genomic abnormalities by identifying aneusomy of chromosomes within ductal lavage cells, as changes in copy numbers of chromosomes 1, 8, 11, and 17 have been shown to be associated with both preinvasive and invasive breast lesions.	('copy numbers', 'Var', (184, 196))	('invasive breast lesions', 'Disease', 'MESH:D001941', (288, 311))	('associated', 'Reg', (251, 261))	('invasive breast lesions', 'Disease', (288, 311))	('changes', 'Var', (173, 180))	('preinvasive', 'Disease', (272, 283))
53243	21124756	Others have shown that evaluation of methylation may also have more sensitivity for cancer detection than cytology: Krassenstein et al.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('methylation', 'Var', (37, 48))	('cancer', 'Disease', (84, 90))
53300	26686313	The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen.	('symptoms', 'Disease', (330, 338))	('strokes', 'Disease', 'MESH:D020521', (255, 262))	('muscle spasm', 'Disease', 'MESH:D013035', (289, 301))	('deep vein thromboses', 'Disease', 'MESH:D020246', (364, 384))	('anastrozole', 'Var', (268, 279))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('more fractures', 'Phenotype', 'HP:0002757', (188, 202))	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('tamoxifen', 'Chemical', 'MESH:D013629', (102, 111))	('deep vein thromboses', 'Disease', (364, 384))	('cancers', 'Disease', (318, 325))	('strokes', 'Disease', (255, 262))	('muscle spasm', 'Phenotype', 'HP:0003394', (289, 301))	('women', 'Species', '9606', (14, 19))	('women', 'Species', '9606', (86, 91))	('vasomotor symptoms', 'Phenotype', 'HP:0025637', (340, 358))	('fractures', 'Disease', (193, 202))	('anastrozole', 'Chemical', 'MESH:D000077384', (268, 279))	('women', 'Species', '9606', (118, 123))	('deep vein thromboses', 'Phenotype', 'HP:0002625', (364, 384))	('more', 'PosReg', (188, 192))	('muscle spasm', 'Disease', (289, 301))	('fractures', 'Disease', 'MESH:D050723', (193, 202))	('hypercholesterolaemia', 'Disease', 'None', (228, 249))	('anastrozole', 'Chemical', 'MESH:D000077384', (68, 79))	('vein thromboses', 'Phenotype', 'HP:0004936', (369, 384))	('hypercholesterolaemia', 'Disease', (228, 249))	('cancers', 'Disease', 'MESH:D009369', (318, 325))	('vasomotor symptoms', 'Disease', (340, 358))	('tamoxifen', 'Chemical', 'MESH:D013629', (390, 399))	('musculoskeletal events', 'Disease', (204, 226))	('strokes', 'Phenotype', 'HP:0001297', (255, 262))
53310	26686313	Retrospective evaluation of oestrogen receptors (ER) and progesterone receptors (PgR) in 732 patients from the original study showed that tamoxifen reduced subsequent breast cancer events by 51% for women with ER-positive DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (222, 226))	('ER-positive', 'Var', (210, 221))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('reduced', 'NegReg', (148, 155))	('PgR', 'Gene', (81, 84))	('PgR', 'Gene', '5241', (81, 84))	('women', 'Species', '9606', (199, 204))	('tamoxifen', 'Chemical', 'MESH:D013629', (138, 147))	('progesterone receptors', 'Gene', '5241', (57, 79))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (93, 101))	('progesterone receptors', 'Gene', (57, 79))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
53356	26686313	Median DCIS major diameter was 13 mm (IQR 7-22), median clear margin distance was 5 mm (IQR 2-10), and most women had either intermediate-grade (1224; 42%) or high-grade (1129; 38%) tumours.	('women', 'Species', '9606', (108, 113))	('1224', 'Var', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('high-grade', 'CPA', (159, 169))	('tumours', 'Disease', 'MESH:D009369', (182, 189))	('tumours', 'Disease', (182, 189))
53374	26686313	Hypercholesterolaemia was furthermore significantly more common in women receiving anastrozole compared with those receiving tamoxifen, probably as a result of the cholesterol-reducing effects of tamoxifen.	('anastrozole', 'Chemical', 'MESH:D000077384', (83, 94))	('cholesterol', 'Chemical', 'MESH:D002784', (5, 16))	('Hypercholesterolaemia', 'Disease', (0, 21))	('women', 'Species', '9606', (67, 72))	('Hypercholesterolaemia', 'Disease', 'None', (0, 21))	('tamoxifen', 'Chemical', 'MESH:D013629', (196, 205))	('cholesterol', 'Chemical', 'MESH:D002784', (164, 175))	('anastrozole', 'Var', (83, 94))	('common', 'Reg', (57, 63))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))
53403	26686313	A decrease of colorectal cancer has been reported in users of menopausal hormone therapy; although a small increase was reported in ATAC (39 cases with anastrozole vs 31 with tamoxifen), a lower risk was seen in IBIS-II prevention (three with anastrozole vs 11 with tamoxifen), so the role of aromatase inhibitors in affecting risk of colorectal cancer remains uncertain.	('tamoxifen', 'Chemical', 'MESH:D013629', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colorectal cancer', 'Disease', (335, 352))	('anastrozole', 'Chemical', 'MESH:D000077384', (152, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (175, 184))	('anastrozole', 'Chemical', 'MESH:D000077384', (243, 254))	('colorectal cancer', 'Disease', (14, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (335, 352))	('IBIS-I', 'Chemical', '-', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('anastrozole', 'Var', (152, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (335, 352))
53497	32454928	Figure 2 shows representative MPM images and corresponding H&E images of the microstructure of normal breast tissue, ADH, low-grade DCIS, and high-grade DCIS-MI.	('DCIS-MI', 'Disease', (153, 160))	('DCIS-MI', 'Disease', 'MESH:D002285', (153, 160))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('and', 'Var', (138, 141))	('H&E', 'Chemical', 'MESH:D006371', (59, 62))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))
53504	32454928	The MPM images (Figure 2(c)) of low-grade DCIS showed details of the hyperplastic epithelial cells that showed exactly the same details as the H&E image (Figure 2(g)).	('low-grade', 'Var', (32, 41))	('H&E', 'Chemical', 'MESH:D006371', (143, 146))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('DCIS', 'Disease', (42, 46))
53509	32454928	Comparing MPM images of normal breast tissue and early stages of breast ductal carcinoma, including ADH, low-grade DCIS, and high-grade DCIS-MI, MPM-identifiable features are summarized and shown in Table 1.	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('high-grade', 'Var', (125, 135))	('breast ductal carcinoma', 'Disease', (65, 88))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (72, 88))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (65, 88))	('DCIS-MI', 'Disease', (136, 143))	('DCIS-MI', 'Disease', 'MESH:D002285', (136, 143))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('ADH', 'Disease', (100, 103))	('breast ductal carcinoma', 'Disease', 'MESH:D001943', (65, 88))
53513	32454928	Specifically, the nuclear area was 16.12 +- 3.10 mum2 in normal breast tissue, 25.75 +- 5.62 mum2 in ADH, 27.10 +- 5.28 mum2 in low-grade DCIS, and 82.25 +- 22.76 mum2 in high-grade DCIS-MI.	('mum2', 'Gene', (120, 124))	('mum2', 'Gene', '58485', (120, 124))	('mum2', 'Gene', (49, 53))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('low-grade', 'Var', (128, 137))	('mum2', 'Gene', (93, 97))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('mum2', 'Gene', '58485', (49, 53))	('mum2', 'Gene', (163, 167))	('mum2', 'Gene', '58485', (93, 97))	('mum2', 'Gene', '58485', (163, 167))	('DCIS-MI', 'Disease', (182, 189))	('DCIS-MI', 'Disease', 'MESH:D002285', (182, 189))
53514	32454928	The mean and SD of the collagen density were 0.86 +- 0.06 for normal breast tissue, 0.67 +- 0.09 for ADH, 0.57 +- 0.137 for low-grade DCIS, and 0.42 +- 0.162 for high-grade DCIS-MI.	('DCIS-MI', 'Disease', (173, 180))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('low-grade', 'Var', (124, 133))	('DCIS-MI', 'Disease', 'MESH:D002285', (173, 180))	('0.57 +- 0.137', 'Var', (106, 119))	('DCIS', 'Phenotype', 'HP:0030075', (173, 177))
53582	31807966	HAp is an enigmatic material, that can accommodate multiple substitutional ions, which affects the crystallographic properties determined using X-ray diffraction (XRD) techniques.	('HAp', 'Gene', (0, 3))	('substitutional', 'Var', (60, 74))	('HAp', 'Gene', '5915', (0, 3))
53585	31807966	Numerous substitutions into the HAp lattice have been observed.	('HAp', 'Gene', (32, 35))	('substitutions', 'Var', (9, 22))	('HAp', 'Gene', '5915', (32, 35))
53596	31807966	For example, A- and B-type carbonate substitution have complementary effects on the crystallographic 'a' and 'c' lattice parameters.	('carbonate', 'Chemical', 'MESH:D002254', (27, 36))	('substitution', 'Var', (37, 49))	('effects', 'Reg', (69, 76))
53624	31807966	The relative difference between benign and in-situ calcifications for the <00l>, <hk0> and < 0 k0> directions are similar (25%, 22% and 27%), while the difference between in-situ and invasive is smaller than the difference between benign and in-situ in all three cases.	('calcification', 'Disease', 'MESH:D002114', (51, 64))	('calcification', 'Disease', (51, 64))	('< 0 k0>', 'Var', (91, 98))
53625	31807966	However, the percentage difference between in-situ and invasive calcifications is more pronounced in the <0 k0> and < hk0> directions (23% and 19%) compared to the <00l> (11%) direction.	('invasive calcification', 'Disease', (55, 77))	('<0 k0>', 'Var', (105, 111))	('< hk0>', 'Var', (116, 122))	('invasive calcification', 'Disease', 'MESH:D002114', (55, 77))
53658	31807966	A-type carbonate substitutions increase the apatite 'a' axis due to CO3 having a significantly greater ionic radius than OH.	('CO3', 'Gene', (68, 71))	('substitutions', 'Var', (17, 30))	('carbonate', 'Chemical', 'MESH:D002254', (7, 16))	('CO3', 'Chemical', '-', (68, 71))	('ionic radius', 'MPA', (103, 115))	("a' axis", 'Species', '30531', (53, 60))	("apatite 'a' axis", 'CPA', (44, 60))	('greater', 'PosReg', (95, 102))	('increase', 'PosReg', (31, 39))
53660	31807966	In addition, A-type carbonate substitutions decreases the 'c' axis and B-type increases the 'c' axis.	("c' axis", 'Species', '30531', (93, 100))	('carbonate', 'Chemical', 'MESH:D002254', (20, 29))	("'c' axis", 'MPA', (92, 100))	('substitutions', 'Var', (30, 43))	('increases', 'PosReg', (78, 87))	('decreases', 'NegReg', (44, 53))	("c' axis", 'Species', '30531', (59, 66))
53672	31807966	For example, the presence of hydroxyapatite in mammary cell lines has been shown to upregulate matrix metalloproteinases which are key proteins in the degradation of the basement membrane, enhance mitogenesis, and induce the production of interleukins (ILs).	('matrix', 'Protein', (95, 101))	('upregulate', 'PosReg', (84, 94))	('hydroxyapatite', 'Chemical', 'MESH:D017886', (29, 43))	('enhance', 'PosReg', (189, 196))	('induce', 'PosReg', (214, 220))	('presence', 'Var', (17, 25))	('production', 'MPA', (225, 235))	('mitogenesis', 'MPA', (197, 208))
53674	31807966	Moreover, the substitution of ions such as carbonate into the hydroxyapatite lattice can affect crystal morphology, meaning that the microstructure of microcalcifications potentially has the ability to impact downstream effectors and hence tumour virulence characteristics.	('calcification', 'Disease', 'MESH:D002114', (156, 169))	('carbonate', 'Chemical', 'MESH:D002254', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour virulence', 'Disease', 'MESH:D009369', (240, 256))	('tumour virulence', 'Disease', (240, 256))	('impact', 'Reg', (202, 208))	('calcification', 'Disease', (156, 169))	('crystal', 'MPA', (96, 103))	('substitution', 'Var', (14, 26))	('affect', 'Reg', (89, 95))	('hydroxyapatite', 'Chemical', 'MESH:D017886', (62, 76))
53677	31807966	Secondly, the data suggests that a combination of A-type and B-type substituted carbonate is found in breast microcalcifications, and it is the ratio of these two types that is specifically related to tissue type.	('breast', 'Disease', (102, 108))	('calcification', 'Disease', 'MESH:D002114', (114, 127))	('calcification', 'Disease', (114, 127))	('carbonate', 'Chemical', 'MESH:D002254', (80, 89))	('B-type', 'Var', (61, 67))
53679	31807966	These differences may have a multitude of impacts on the propagation of tumour characteristics through interactions with the microenvironment.	('differences', 'Var', (6, 17))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('have', 'Reg', (22, 26))	('interactions', 'Interaction', (103, 115))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('impacts', 'Reg', (42, 49))	('tumour', 'Disease', (72, 78))
53691	28652380	Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes.	('breast tumors', 'Disease', 'MESH:D001943', (72, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('HER2', 'Gene', '2064', (66, 70))	('breast tumor', 'Phenotype', 'HP:0100013', (72, 84))	('breast tumors', 'Disease', (72, 85))	('clinical', 'Species', '191496', (111, 119))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('ERBB2', 'Gene', (49, 54))	('breast tumors', 'Phenotype', 'HP:0100013', (72, 85))	('ERBB2', 'Gene', '2064', (49, 54))	('Co-amplification', 'Var', (0, 16))	('HER2', 'Gene', (66, 70))
53705	28652380	We also characterized genetic alterations in cancer cells that might impact the tumor immune microenvironment and disease progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('disease progression', 'CPA', (114, 133))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('genetic alterations', 'Var', (22, 41))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('impact', 'Reg', (69, 75))	('cancer', 'Disease', (45, 51))
53709	28652380	We analyzed normal breast tissues from nulliparous and parous women, including BRCA1 and BRCA2 mutation carriers, as well as DCIS and IDCs of different subtypes (Supplementary Table S1).	('BRCA2', 'Gene', '675', (89, 94))	('BRCA1', 'Gene', '672', (79, 84))	('BRCA1', 'Gene', (79, 84))	('BRCA2', 'Gene', (89, 94))	('women', 'Species', '9606', (62, 67))	('mutation', 'Var', (95, 103))
53712	28652380	This latter result is potentially interesting in light of recent findings in animal models showing that gammadeltaT cells promote breast cancer metastasis via their recruitment of neutrophils.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('promote', 'PosReg', (122, 129))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('gammadeltaT', 'Var', (104, 115))
53763	28652380	S4A), and TCR clonotype diversity measured by the Shannon index was significantly (p=0.03) higher in DCIS compared to IDCs (Fig.	('higher', 'PosReg', (91, 97))	('TCR', 'Gene', '6962', (10, 13))	('DCIS', 'Var', (101, 105))	('TCR', 'Gene', (10, 13))
53773	28652380	We found a positive correlation between exhausted and cytotoxic gene signatures in both MIKI67high and MKI67low T cells, which was expected as these markers are commonly co-expressed in the same T cell population and exhaustion is usually due to chronic activation.	('MKI67', 'Gene', (103, 108))	('MIKI67high', 'Var', (88, 98))	('cytotoxic gene signatures', 'MPA', (54, 79))	('MKI67', 'Gene', '4288', (103, 108))
53797	28652380	Testing of ten TN IDC revealed CD274 copy number gain and PD-L1 overexpression in 3/10 cases, whereas none of the ten TN DCIS showed gain of this locus and had relatively low expression of PD-L1 (Fig.	('CD274', 'Gene', (31, 36))	('PD-L1', 'Gene', '29126', (58, 63))	('gain', 'PosReg', (49, 53))	('copy number', 'Var', (37, 48))	('overexpression', 'PosReg', (64, 78))	('CD274', 'Gene', '29126', (31, 36))	('PD-L1', 'Gene', (58, 63))	('PD-L1', 'Gene', (189, 194))	('PD-L1', 'Gene', '29126', (189, 194))
53798	28652380	These results suggest that a possible mechanism for the in situ to invasive breast carcinoma transition in TN through the selection for tumor cells with higher expression of PD-L1 due to increased copy number for CD274.	('expression', 'MPA', (160, 170))	('copy number', 'Var', (197, 208))	('higher', 'PosReg', (153, 159))	('invasive breast carcinoma', 'Disease', (67, 92))	('CD274', 'Gene', '29126', (213, 218))	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PD-L1', 'Gene', (174, 179))	('increased', 'PosReg', (187, 196))	('CD274', 'Gene', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (67, 92))	('tumor', 'Disease', (136, 141))	('PD-L1', 'Gene', '29126', (174, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
53808	28652380	Next, we developed a multicolor FISH assay to evaluate both the 17q12 CC and ERBB2 copy number gain in HER2+ IDCs and DCIS at the single cell level (Fig.	('ERBB2', 'Gene', '2064', (77, 82))	('ERBB2', 'Gene', (77, 82))	('copy number', 'Var', (83, 94))	('HER2', 'Gene', '2064', (103, 107))	('HER2', 'Gene', (103, 107))	('17q12 CC', 'Var', (64, 72))	('gain', 'PosReg', (95, 99))
53833	28652380	TIGIT+ T cells were more common in DCIS than in IDC, especially in TN subtype, whereas the expression of PD-L1 was almost undetectable in DCIS tumor epithelial cells but increased to higher levels in IDC with the amplification of the CD274 locus encoding PD-L1 in a subset (~30%) of the cases.	('PD-L1', 'Gene', '29126', (255, 260))	('tumor', 'Disease', (143, 148))	('PD-L1', 'Gene', (105, 110))	('amplification', 'Var', (213, 226))	('CD274', 'Gene', '29126', (234, 239))	('increased', 'PosReg', (170, 179))	('IDC', 'Disease', (200, 203))	('DCIS', 'Disease', (35, 39))	('PD-L1', 'Gene', '29126', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('CD274', 'Gene', (234, 239))	('PD-L1', 'Gene', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
53843	28652380	We have also found evidence for co-evolution of cancer cells and leukocytes as exemplified by the negative association between the co-amplification of 17q12 chemokine cluster with ERBB2 in HER2+ breast tumors and presence of activated T cells within tumors.	('cancer', 'Disease', (48, 54))	('HER2', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ERBB2', 'Gene', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('HER2', 'Gene', '2064', (189, 193))	('co-amplification', 'Var', (131, 147))	('negative', 'NegReg', (98, 106))	('17q12', 'Gene', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('breast tumors', 'Disease', 'MESH:D001943', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('ERBB2', 'Gene', '2064', (180, 185))	('breast tumors', 'Disease', (195, 208))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('T cells within tumors', 'Disease', (235, 256))	('breast tumors', 'Phenotype', 'HP:0100013', (195, 208))	('breast tumor', 'Phenotype', 'HP:0100013', (195, 207))	('T cells within tumors', 'Disease', 'MESH:D001929', (235, 256))
53844	28652380	This co-amplification was more common in PAM50 luminal HER2+ IDCs compared to PAM50 HER2-enriched subset that may reflect different evolutionary paths for luminal, commonly ER+, and non-luminal ER- HER2+ tumors.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('HER2', 'Gene', (84, 88))	('HER2', 'Gene', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('HER2', 'Gene', '2064', (84, 88))	('HER2', 'Gene', '2064', (198, 202))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (55, 59))	('PAM50', 'Var', (41, 46))
53845	28652380	Interestingly, the copy number gain was relatively low in a subset of luminal HER2+ tumors for both ERBB2 and the CC locus, which could imply higher intratumor heterogeneity in these tumors that can contribute to their lower response rate to HER2-targeted therapies.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', (183, 189))	('tumor', 'Disease', (154, 159))	('HER2', 'Gene', (242, 246))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('HER2', 'Gene', '2064', (78, 82))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', (183, 188))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ERBB2', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('HER2', 'Gene', '2064', (242, 246))	('copy number gain', 'Var', (19, 35))	('HER2', 'Gene', (78, 82))	('tumor', 'Disease', (84, 89))	('low', 'NegReg', (51, 54))	('ERBB2', 'Gene', '2064', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
53886	28652380	The association between the probability of a cell carrying the 17q12 chemokine cluster (CC) amplification and ERBB2 amplification (together with the cell type (DCIS or IDC cells) in the DCIS/IDC cohorts) was estimated using logistic hierarchical model (or logistic mixed effects regression) to account for the correlation of cells within each sample and of samples within each patient.	('amplification', 'Var', (92, 105))	('ERBB2', 'Gene', (110, 115))	('patient', 'Species', '9606', (377, 384))	('ERBB2', 'Gene', '2064', (110, 115))
53984	32493768	Gene set enrichment analysis (GSEA) was performed to identify functional ontologies that were enriched in the murine and human proteomic datasets upon DCIS progression to IBC (Fig.	('IBC', 'Disease', (171, 174))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('DCIS', 'Var', (151, 155))	('human', 'Species', '9606', (121, 126))	('GSEA', 'Chemical', '-', (30, 34))	('murine', 'Species', '10090', (110, 116))
54011	32493768	MIF was found to be exclusively upregulated in the human MCF10DCIS.com cells at 10w post-injection but not in the mouse stromal cells .	('MIF', 'Gene', (0, 3))	('MCF10DCIS.com', 'Var', (57, 70))	('human', 'Species', '9606', (51, 56))	('mouse', 'Species', '10090', (114, 119))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (57, 70))	('upregulated', 'PosReg', (32, 43))
54070	28006062	Benign Breast Disease in White/Caucasian American and African American Women and Subsequent Triple Negative Breast Cancer African American (AA) women have a two-fold higher incidence of breast cancers that are negative for estrogen receptor, progesterone receptor and HER2/neu (triple negative breast cancer, TNBC) compared with White/Caucasian Americans (WA).	('breast cancer', 'Disease', (294, 307))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('Breast Cancer', 'Disease', 'MESH:D001943', (108, 121))	('progesterone receptor', 'Gene', (242, 263))	('progesterone receptor', 'Gene', '5241', (242, 263))	('women', 'Species', '9606', (144, 149))	('breast cancers', 'Disease', 'MESH:D001943', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancers', 'Disease', (186, 200))	('Breast Cancer', 'Disease', (108, 121))	('Women', 'Species', '9606', (71, 76))	('higher', 'PosReg', (166, 172))	('HER2/neu', 'Gene', (268, 276))	('estrogen receptor', 'Gene', '2099', (223, 240))	('breast cancers', 'Phenotype', 'HP:0003002', (186, 200))	('Breast Cancer', 'Phenotype', 'HP:0003002', (108, 121))	('African', 'Var', (122, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('Benign Breast Disease', 'Disease', (0, 21))	('HER2/neu', 'Gene', '2064', (268, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))	('estrogen receptor', 'Gene', (223, 240))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))
54098	28006062	Immunohistochemistry for HER2/neu staining was performed using the HerceptTest (DAKO, Glostrup, Denmark), an FDA-approved clinical test that qualitatively identifies by light microscopy p185 HER2 overexpression in breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('HER2', 'Gene', (191, 195))	('HER2', 'Gene', '2064', (191, 195))	('p185', 'Var', (186, 190))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('HER2', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('HER2/neu', 'Gene', '2064', (25, 33))	('overexpression', 'PosReg', (196, 210))	('HER2', 'Gene', '2064', (25, 29))	('breast cancer', 'Disease', (214, 227))	('HER2/neu', 'Gene', (25, 33))
54137	28006062	Multiple pregnancies, for example, reduce the likelihood of developing ER-positive breast cancer, but several studies reveal that multiparity increases the risk of TNBC.	('multiparity', 'Var', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('Multiple pregnancies', 'Phenotype', 'HP:0001622', (0, 20))	('breast cancer', 'Disease', (83, 96))	('ER', 'Gene', '2099', (71, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('TNBC', 'Disease', (164, 168))
54174	28859163	High levels of C35 mRNA expression in primary breast cancer are associated with HER2 gene amplification, and hallmarks of transformation, including invasion into collagen matrix, colony growth in soft agar, and formation of large acinar structures in three-dimensional cell cultures.	('associated', 'Reg', (64, 74))	('HER2', 'Protein', (80, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('colony growth in soft agar', 'CPA', (179, 205))	('C35', 'Gene', '84299', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('C35', 'Gene', (15, 18))	('breast cancer', 'Disease', (46, 59))	('invasion into', 'CPA', (148, 161))	('amplification', 'Var', (90, 103))
54176	28859163	Recent studies have shown that the viability of breast carcinoma cells could be affected by various agents, such as factors secreted by osteo-differentiating mesenchymal stem cells, oxidized gamma-tocotrienol, marine-derived fungus clonostachys rosea, inhibition of glucose transporter 4 (GLUT4), fucoxanthin and fucoxanthinol, and knockdown of human RNA helicase DDX3.	('fungus clonostachys rosea', 'Disease', 'MESH:D017515', (225, 250))	('affected', 'Reg', (80, 88))	('GLUT4', 'Gene', (289, 294))	('fucoxanthinol', 'Protein', (313, 326))	('fungus clonostachys rosea', 'Disease', (225, 250))	('glucose', 'Chemical', 'MESH:D005947', (266, 273))	('breast carcinoma', 'Disease', 'MESH:D001943', (48, 64))	('human RNA helicase', 'Protein', (345, 363))	('GLUT4', 'Gene', '6517', (289, 294))	('DDX3', 'Gene', (364, 368))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('gamma-tocotrienol', 'Chemical', 'MESH:C013649', (191, 208))	('breast carcinoma', 'Phenotype', 'HP:0003002', (48, 64))	('inhibition', 'Var', (252, 262))	('fucoxanthin', 'Chemical', 'MESH:C025164', (297, 308))	('DDX3', 'Gene', '1654', (364, 368))	('human', 'Species', '9606', (345, 350))	('viability', 'CPA', (35, 44))	('breast carcinoma', 'Disease', (48, 64))	('fucoxanthinol', 'Chemical', 'MESH:C483031', (313, 326))	('knockdown', 'Var', (332, 341))	('fucoxanthin', 'Chemical', 'MESH:C025164', (313, 324))
54181	28859163	Amplification or over-expression of HER2 plays an important role in the development and progression of aggressive types of breast cancer.	('over-expression', 'PosReg', (17, 32))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('HER2', 'Protein', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
54262	28549415	Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors.	('PAD2', 'Gene', (118, 122))	('ductal carcinoma', 'Disease', 'MESH:D044584', (23, 39))	('xenograft tumors', 'Disease', 'MESH:D009369', (195, 211))	('inhibition', 'Var', (74, 84))	('ductal carcinoma', 'Disease', (23, 39))	('peptidylarginine deiminase 2', 'Gene', '18600', (88, 116))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (23, 47))	('basement', 'MPA', (164, 172))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (23, 39))	('peptidylarginine deiminase 2', 'Gene', (88, 116))	('activity', 'MPA', (135, 143))	('xenograft tumors', 'Disease', (195, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('mouse', 'Species', '10090', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('maintain', 'Reg', (155, 163))
54267	28549415	Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells.	('alters', 'Reg', (85, 91))	('inhibition suppresses', 'NegReg', (44, 65))	('cell migration', 'CPA', (66, 80))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (110, 123))	('depletion', 'Var', (31, 40))
54268	28549415	In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin.	('Rac1', 'Gene', '5879', (114, 118))	('expression', 'MPA', (57, 67))	('RhoA', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('Rac1', 'Gene', (114, 118))	('depletion', 'Var', (32, 41))	('RhoA', 'Gene', '387', (108, 112))	('Cdc42', 'Gene', (124, 129))	('PAD2', 'Gene', (27, 31))	('suppresses', 'NegReg', (42, 52))	('E-cadherin', 'Gene', (264, 274))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('increase', 'PosReg', (226, 234))	('mesenchymal to epithelial-like transition', 'CPA', (150, 191))	('E-cadherin', 'Gene', '999', (264, 274))	('promotes', 'PosReg', (139, 147))	('Cdc42', 'Gene', '998', (124, 129))
54288	28549415	have also shown that ectopic expression of PAD4 results in inhibition of tumor cell growth.	('inhibition', 'NegReg', (59, 69))	('PAD4', 'Gene', '23569', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('PAD4', 'Gene', (43, 47))	('ectopic expression', 'Var', (21, 39))
54293	28549415	The following antibodies were used: anti-PAD2 (12110-1-AP, Proteintech), anti-E-cadherin (ab1518, Abcam), anti-RhoA (2117, Cell Signaling), anti-Rac1 (05-389, Millipore), anti-Cdc42 (07-1466, Millipore), anti-pan-Citrulline (07-377, Millipore; ab6464, Abcam), and anti-beta-actin (ab8227, Abcam) antibodies.	('Rac1', 'Gene', (145, 149))	('RhoA', 'Gene', (111, 115))	('ab6464', 'Var', (244, 250))	('P', 'Chemical', 'MESH:D010758', (59, 60))	('RhoA', 'Gene', '387', (111, 115))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('Cdc42', 'Gene', (176, 181))	('E-cadherin', 'Gene', (78, 88))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('Citrulline', 'Chemical', 'MESH:D002956', (213, 223))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('E-cadherin', 'Gene', '999', (78, 88))	('Cdc42', 'Gene', '998', (176, 181))	('Rac1', 'Gene', '5879', (145, 149))	('beta-actin', 'Gene', (269, 279))	('beta-actin', 'Gene', '728378', (269, 279))
54304	28549415	The membranes were blocked in either 5% milk (for anti-E-cadherin, anti-RhoA, anti-Rac1, anti-Cdc42, and anti-beta-actin) or 3% BSA (for anti-PAD2) at room temperature and were incubated overnight with primary antibodies diluted in TBST at 4  C using the following antibody concentrations: anti-PAD2 (1:1000), anti-E-cadherin (1:1000), anti-RhoA (1:1000), anti-Rac1 (1:1000), and anti-Cdc42 (1:1000) antibodies.	('E-cadherin', 'Gene', (55, 65))	('beta-actin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (55, 65))	('RhoA', 'Gene', (341, 345))	('RhoA', 'Gene', (72, 76))	('E-cadherin', 'Gene', (315, 325))	('E-cadherin', 'Gene', '999', (315, 325))	('1:1000', 'Var', (392, 398))	('Cdc42', 'Gene', '998', (94, 99))	('S', 'Chemical', 'MESH:D013455', (234, 235))	('1:1000', 'Var', (367, 373))	('Cdc42', 'Gene', (385, 390))	('RhoA', 'Gene', '387', (72, 76))	('RhoA', 'Gene', '387', (341, 345))	('Rac1', 'Gene', (83, 87))	('beta-actin', 'Gene', '728378', (110, 120))	('1:1000', 'Var', (347, 353))	('Rac1', 'Gene', (361, 365))	('Cdc42', 'Gene', '998', (385, 390))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('Cdc42', 'Gene', (94, 99))	('Rac1', 'Gene', '5879', (83, 87))	('Rac1', 'Gene', '5879', (361, 365))
54341	28549415	Using a wound healing assay, we found that depletion of PAD2 in MCF10DCIS.com cells inhibited cell migration, with a 39% reduction in migration in the PAD2-depleted cells compared to the scrambled shRNA cell line (Fig.	('depletion', 'Var', (43, 52))	('cell migration', 'CPA', (94, 108))	('migration', 'CPA', (134, 143))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (64, 77))	('reduction', 'NegReg', (121, 130))	('inhibited', 'NegReg', (84, 93))
54352	28549415	These observations suggest that PAD2 depletion may lead to the upregulation of cell-cell adhesion molecules, such as E-cadherin.	('depletion', 'Var', (37, 46))	('E-cadherin', 'Gene', (117, 127))	('PAD2', 'Gene', (32, 36))	('cell-cell adhesion molecules', 'Protein', (79, 107))	('upregulation', 'PosReg', (63, 75))	('E-cadherin', 'Gene', '999', (117, 127))
54353	28549415	We tested this hypothesis and found that depletion of PAD2 upregulates the expression of E-cadherin by approximately 5-fold (Fig.	('PAD2', 'Gene', (54, 58))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('depletion', 'Var', (41, 50))	('upregulates', 'PosReg', (59, 70))	('expression', 'MPA', (75, 85))
54354	28549415	Given that EGF signaling plays an important role in cancer cell polarization and migration, we tested whether EGF may regulate PAD2 expression and activity and whether modulation of PAD2 activity may affect EGF-induced cell migration.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('affect', 'Reg', (200, 206))	('tested', 'Reg', (95, 101))	('PAD2', 'Gene', (127, 131))	('EGF-induced cell migration', 'CPA', (207, 233))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('regulate', 'Reg', (118, 126))	('expression', 'MPA', (132, 142))	('activity', 'MPA', (147, 155))	('modulation', 'Var', (168, 178))
54362	28549415	Immunofluorescence analysis supported our qRT-PCR results as we found that E-cadherin levels appeared to be higher in the BB-Cl-Amidine treated cells than control cells (Fig.	('E-cadherin', 'Gene', (75, 85))	('BB-Cl-Amidine', 'Chemical', '-', (122, 135))	('P', 'Chemical', 'MESH:D010758', (46, 47))	('E-cadherin', 'Gene', '999', (75, 85))	('BB-Cl-Amidine', 'Var', (122, 135))	('higher', 'PosReg', (108, 114))
54368	28549415	We find that E-cadherin expression appears to be strongly upregulated in the Cl-Amidine treated group compared to the control group (Fig.	('expression', 'MPA', (24, 34))	('Cl-Amidine', 'Var', (77, 87))	('upregulated', 'PosReg', (58, 69))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('Cl-Amidine', 'Chemical', 'MESH:C558727', (77, 87))
54370	28549415	We found that when the organoids were treated with 0.5 muM BB-Cl-Amidine, there was a striking reduction in EGF-induced ductal elongation (Fig.	('BB-Cl-Amidine', 'Var', (59, 72))	('muM', 'Gene', '56925', (55, 58))	('muM', 'Gene', (55, 58))	('BB-Cl-Amidine', 'Chemical', '-', (59, 72))	('reduction', 'NegReg', (95, 104))	('EGF-induced', 'Gene', (108, 119))
54376	28549415	In mouse xenograft models of breast cancer, we have previously shown that systemic treatment with the PAD inhibitor, Cl-Amidine, resulted in increased tumoral basement membrane integrity compared to tumors from mice treated with vehicle alone.	('tumor', 'Disease', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('Cl-Amidine', 'Chemical', 'MESH:C558727', (117, 127))	('mouse', 'Species', '10090', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('increased', 'PosReg', (141, 150))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('mice', 'Species', '10090', (211, 215))	('Cl-Amidine', 'Var', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
54377	28549415	In this study, we show that PAD2 depletion or inhibition suppresses tumor cell migration, alters tumor cell morphology, and suppresses the expression of the cytoskeletal regulatory proteins: RhoA, Rac1, and Cdc42.	('suppresses', 'NegReg', (124, 134))	('Cdc42', 'Gene', '998', (207, 212))	('RhoA', 'Gene', '387', (191, 195))	('tumor', 'Disease', (68, 73))	('suppresses', 'NegReg', (57, 67))	('Rac1', 'Gene', (197, 201))	('tumor', 'Disease', (97, 102))	('PAD2', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('alters', 'Reg', (90, 96))	('cytoskeletal regulatory proteins', 'MPA', (157, 189))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('depletion', 'Var', (33, 42))	('Cdc42', 'Gene', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inhibition', 'Var', (46, 56))	('Rac1', 'Gene', '5879', (197, 201))	('RhoA', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'MPA', (139, 149))
54380	28549415	In support of this hypothesis, we found that E-cadherin expression is upregulated in MCF10DCIS cells following PAD2 depletion.	('depletion', 'Var', (116, 125))	('expression', 'MPA', (56, 66))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (85, 94))	('upregulated', 'PosReg', (70, 81))	('MCF10DCIS', 'Var', (85, 94))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
54384	28549415	Taken together, these results suggest that the EGF-induced nuclear targeting of PAD2 may lead to PAD2-mediated upregulation of genes involved in tumor cell migration.	('nuclear targeting', 'Var', (59, 76))	('upregulation', 'PosReg', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('genes', 'MPA', (127, 132))	('PAD2-mediated', 'Gene', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('PAD2', 'Gene', (80, 84))
54385	28549415	Since we observed that PAD2 was upregulated after EGF treatment, we then tested whether inhibition of PAD2 can suppress EGF-mediated cell migration.	('EGF-mediated cell migration', 'CPA', (120, 147))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('tested', 'Reg', (73, 79))	('suppress', 'NegReg', (111, 119))	('PAD2', 'Gene', (23, 27))	('PAD2', 'Gene', (102, 106))	('inhibition', 'Var', (88, 98))	('upregulated', 'PosReg', (32, 43))
54386	28549415	Outcomes from our in vitro and in vivo studies support this prediction as they found that BB-Cl-Amidine suppressed EGF-induced tumor cell migration and invasion.	('invasion', 'CPA', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('BB-Cl-Amidine', 'Var', (90, 103))	('EGF-induced', 'Protein', (115, 126))	('suppressed', 'NegReg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('BB-Cl-Amidine', 'Chemical', '-', (90, 103))
54396	28549415	In addition, we found that PAD2 depletion suppresses the expression of Rho GTPases (RhoA, Rac1, and Cdc42), which are known to be involved in actin-mediated cell migration.	('expression', 'MPA', (57, 67))	('Rho GTPases', 'Gene', (71, 82))	('Rho GTPases', 'Gene', '387', (71, 82))	('depletion', 'Var', (32, 41))	('Cdc42', 'Gene', (100, 105))	('RhoA', 'Gene', (84, 88))	('suppresses', 'NegReg', (42, 52))	('PAD2', 'Gene', (27, 31))	('RhoA', 'Gene', '387', (84, 88))	('Cdc42', 'Gene', '998', (100, 105))	('Rac1', 'Gene', (90, 94))	('Rac1', 'Gene', '5879', (90, 94))	('actin', 'Gene', (142, 147))	('actin', 'Gene', '728378;60', (142, 147))
54398	28549415	In vivo, we found that treatment of MCF10DCIS.com xenograft tumors with PAD inhibitors upregulate E-cadherin expression and that EGF-induced cell migration upregulates PAD2 expression and activity.	('expression', 'MPA', (109, 119))	('upregulates', 'PosReg', (156, 167))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('xenograft tumors', 'Disease', 'MESH:D009369', (50, 66))	('cell migration', 'CPA', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PAD2', 'Gene', (168, 172))	('activity', 'MPA', (188, 196))	('PAD', 'Gene', (72, 75))	('inhibitors', 'Var', (76, 86))	('expression', 'MPA', (173, 183))	('xenograft tumors', 'Disease', (50, 66))	('upregulate', 'PosReg', (87, 97))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (36, 49))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
54553	18351348	The results confirmed that mechanical FUS ablation resulted in a systemic anti-tumour immune response and that the response is related to dendritic cell activation.	('FUS', 'Chemical', '-', (38, 41))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('ablation', 'Var', (42, 50))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
54616	25593980	There was a significant correlation of HER2 positivity with marked (4+) CD8+ lymphocytic infiltration (P=0.0075).	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (39, 43))	('CD8', 'Gene', (72, 75))	('positivity', 'Var', (44, 54))	('CD8', 'Gene', '925', (72, 75))
54617	25593980	A marginally significant association of MAGEA positivity with high CD8+ lymphocytic infiltration was also observed (P=0.0545).	('positivity', 'Var', (46, 56))	('MAGEA', 'Gene', (40, 45))	('CD8', 'Gene', (67, 70))	('CD8', 'Gene', '925', (67, 70))
54660	25593980	Infiltrating CD8+ cells, demonstrated by IHC using C8/144B antibody, were evaluated by two pathologists (SS and AMN) who were blinded to the clinical characteristics and outcomes of the patients.	('CD8', 'Gene', (13, 16))	('clinical', 'Species', '191496', (141, 149))	('CD8', 'Gene', '925', (13, 16))	('AMN', 'Disease', 'MESH:D000326', (112, 115))	('C8/144B', 'Var', (51, 58))	('AMN', 'Disease', (112, 115))	('patients', 'Species', '9606', (186, 194))
54667	29661250	The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion.	('knockdown', 'Var', (80, 89))	('IDH1', 'Gene', '3417', (28, 32))	('IDH1', 'Gene', (75, 79))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('IDH1', 'Gene', '3417', (75, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('IDH1', 'Gene', (28, 32))
54672	29661250	Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('IDH1', 'Gene', '3417', (74, 78))	('Cox', 'Gene', (13, 16))	('shorter', 'NegReg', (145, 152))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('shorter', 'NegReg', (203, 210))	('breast cancer', 'Disease', (292, 305))	('disease-free survival', 'CPA', (211, 232))	('snail', 'Gene', '6615', (88, 93))	('DSS', 'Gene', (153, 156))	('high', 'Var', (83, 87))	('expression', 'MPA', (94, 104))	('low', 'NegReg', (70, 73))	('IDH1', 'Gene', (74, 78))	('DSS', 'Gene', '5376', (153, 156))	('snail', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('patients', 'Species', '9606', (278, 286))	('Cox', 'Gene', '1351', (13, 16))
54683	29661250	reported that IDH1 mutations contribute to tumorigenesis by modulating the stabilization of hypoxia-inducible factor (HIF)-1.	('contribute', 'Reg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('hypoxia-inducible factor (HIF)-1', 'Gene', '3091', (92, 124))	('IDH1', 'Gene', (14, 18))	('tumor', 'Disease', (43, 48))	('modulating', 'Reg', (60, 70))	('IDH1', 'Gene', '3417', (14, 18))
54684	29661250	In addition, IDH1/2 mutations have frequently resulted in the accumulation of D-2-hydroxygluarate, which blocks TET-induced cytosine 5-hydroxymethylation, resulting in increased global DNA hypermethylation.	('D-2-hydroxygluarate', 'MPA', (78, 97))	('blocks', 'NegReg', (105, 111))	('resulted in', 'Reg', (46, 57))	('TET-induced cytosine 5-hydroxymethylation', 'MPA', (112, 153))	('increased', 'PosReg', (168, 177))	('TET', 'Chemical', '-', (112, 115))	('accumulation', 'PosReg', (62, 74))	('IDH1', 'Gene', (13, 17))	('D-2-hydroxygluarate', 'Chemical', '-', (78, 97))	('IDH1', 'Gene', '3417', (13, 17))	('global DNA hypermethylation', 'MPA', (178, 205))	('cytosine', 'Chemical', 'MESH:D003596', (124, 132))	('mutations', 'Var', (20, 29))
54685	29661250	In acute myeloid leukemia, IDH1/2 mutations are closely associated with poor prognosis.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('associated', 'Reg', (56, 66))	('acute myeloid leukemia', 'Disease', (3, 25))	('IDH1', 'Gene', (27, 31))	('mutations', 'Var', (34, 43))	('IDH1', 'Gene', '3417', (27, 31))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
54686	29661250	On the other hand, the low frequency of IDH1/2 mutations has been reported in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (40, 44))	('mutations', 'Var', (47, 56))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
54688	29661250	In this study, we first reported that the IDH1 is downregulated in breast cancer and depletion of IDH1 in breast cancer cells results in accelerating breast cancer migration and invasion activities by activating snail expression.	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('depletion', 'Var', (85, 94))	('snail', 'Gene', (212, 217))	('IDH1', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (98, 102))	('downregulated', 'NegReg', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('IDH1', 'Gene', '3417', (42, 46))	('accelerating', 'PosReg', (137, 149))	('breast cancer', 'Disease', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('invasion activities', 'CPA', (178, 197))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Disease', (67, 80))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('snail', 'Gene', '6615', (212, 217))	('breast cancer', 'Disease', (106, 119))	('IDH1', 'Gene', (98, 102))	('activating', 'PosReg', (201, 211))
54747	29661250	Furthermore, high IDH1 expression levels were significantly correlated with human epidermal growth factor receptor (HER)-positive human breast cancer (p = 0.046), whereas no difference was observed in estrogen receptor (ER) and progesterone receptor (PR) status (Additional file 3: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('epidermal growth factor receptor', 'Gene', (82, 114))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('high', 'Var', (13, 17))	('IDH1', 'Gene', '3417', (18, 22))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('human', 'Species', '9606', (76, 81))	('progesterone receptor', 'Gene', (228, 249))	('progesterone receptor', 'Gene', '5241', (228, 249))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('correlated', 'Reg', (60, 70))	('expression levels', 'MPA', (23, 40))	('IDH1', 'Gene', (18, 22))	('human', 'Species', '9606', (130, 135))
54752	29661250	In addition, several studies have showed that the IHC antibody raised against mutant IDH1 protein with R132H mutation can specifically recognize this mutant protein in the tumor tissues using immunochemistry staining (IHC).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('R132H', 'Var', (103, 108))	('tumor', 'Disease', (172, 177))	('protein', 'Protein', (90, 97))	('R132H', 'Mutation', 'rs121913500', (103, 108))	('IDH1', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('IDH1', 'Gene', '3417', (85, 89))
54753	29661250	Therefore, we examined the presence of R132H mutant IDH1 in breast cancer tissues using the IHC approach, and this mutation was absent in breast cancer tissue from the 309 women (data not shown).	('breast cancer', 'Disease', (60, 73))	('IDH1', 'Gene', '3417', (52, 56))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('R132H', 'Var', (39, 44))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', (138, 151))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('women', 'Species', '9606', (172, 177))	('IDH1', 'Gene', (52, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
54755	29661250	A number of studies have reported that dysfunction of miRNA is often the cause of the aberrant expression of cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('dysfunction', 'Var', (39, 50))	('cancer', 'Disease', (109, 115))	('miRNA', 'Protein', (54, 59))	('aberrant expression', 'MPA', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (73, 78))
54764	29661250	We further constructed the wild-type IDH1 full-length 3'UTR, the mutant IDH1 3'UTR with mutated miR-32-5p binding site and with mutated miR-92-3p binding site respectively into the pMIR reporter vector and performed luciferase reporter assays in MDA-MB-231 cells (Fig.	('miR-32-5p', 'Gene', (96, 105))	('IDH1', 'Gene', (72, 76))	('mutant', 'Var', (65, 71))	('IDH1', 'Gene', '3417', (72, 76))	('IDH1', 'Gene', (37, 41))	('miR-92', 'Gene', (136, 142))	('miR-92', 'Gene', '407047', (136, 142))	('mutated', 'Var', (88, 95))	('miR-32-5p', 'Gene', '442899', (96, 105))	('IDH1', 'Gene', '3417', (37, 41))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (246, 256))
54776	29661250	The growth ability of MDA-MB-231 cells was not significantly affected after IDH1 knockdown (Fig.	('IDH1', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (22, 32))	('IDH1', 'Gene', '3417', (76, 80))
54777	29661250	However, the wound healing assay indicated that IDH1 knockdown significantly increased the migration ability of MDA-B-231 cells (Fig.	('migration ability', 'CPA', (91, 108))	('IDH1', 'Gene', '3417', (48, 52))	('MDA-B-231', 'CellLine', 'CVCL:0062', (112, 121))	('knockdown', 'Var', (53, 62))	('increased', 'PosReg', (77, 86))	('IDH1', 'Gene', (48, 52))
54778	29661250	Furthermore, the invasion ability of MDA-MB-231 cells significantly increased after IDH1 knockdown (p < 0.001; Fig.	('invasion ability', 'CPA', (17, 33))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (37, 47))	('knockdown', 'Var', (89, 98))	('increased', 'PosReg', (68, 77))
54782	29661250	Similar results also were observed in HS578T and BT549 cells with IDH1 knockdown (Additional file 8: Figure S4).	('BT549', 'CellLine', 'CVCL:1092', (49, 54))	('IDH1', 'Gene', '3417', (66, 70))	('IDH1', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))
54784	29661250	As depicted in Additional file 9: Figure S5, the knockdown of IDH1 can significantly accelerate the migration ability of MCF7 cells through increased snail and twist expression (Additional file 9: Figure S5b and c).	('snail', 'Gene', '6615', (150, 155))	('knockdown', 'Var', (49, 58))	('MCF7', 'CellLine', 'CVCL:0031', (121, 125))	('accelerate', 'PosReg', (85, 95))	('IDH1', 'Gene', '3417', (62, 66))	('snail', 'Gene', (150, 155))	('IDH1', 'Gene', (62, 66))	('migration ability of MCF7 cells', 'CPA', (100, 131))	('increased', 'PosReg', (140, 149))
54785	29661250	In contrast to MDA-MB-231 cells, the proliferation of MCF7 was promoted after IDH1 knockdown (Additional file 9: Figure S5d), which suggested that the role of IDH1 in MCF7 cell proliferation might be slightly different in breast cancer cells with different subtypes.	('breast cancer', 'Disease', (222, 235))	('IDH1', 'Gene', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('IDH1', 'Gene', (78, 82))	('IDH1', 'Gene', '3417', (159, 163))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (15, 25))	('MCF7', 'CellLine', 'CVCL:0031', (54, 58))	('IDH1', 'Gene', '3417', (78, 82))	('MCF7', 'CellLine', 'CVCL:0031', (167, 171))	('proliferation', 'CPA', (37, 50))	('promoted', 'PosReg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('knockdown', 'Var', (83, 92))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
54786	29661250	Our present study revealed that IDH1 knockdown significantly increased the migration and invasion ability of breast cancer cells by triggering their EMT.	('EMT', 'CPA', (149, 152))	('invasion ability', 'CPA', (89, 105))	('breast cancer', 'Disease', (109, 122))	('IDH1', 'Gene', (32, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('knockdown', 'Var', (37, 46))	('IDH1', 'Gene', '3417', (32, 36))	('increased', 'PosReg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('migration', 'CPA', (75, 84))	('triggering', 'Reg', (132, 142))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
54788	29661250	Pathway enrichment analysis revealed that IDH1 knockdown significantly altered cancer-related pathways such as the mitogen-activated protein kinase (MAPK), peroxisome proliferator-activated receptor signaling pathways, regulation of cell adhesion, and cell migration (Additional file 10: Figure S6).	('IDH1', 'Gene', '3417', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('altered', 'Reg', (71, 78))	('knockdown', 'Var', (47, 56))	('IDH1', 'Gene', (42, 46))	('cell migration', 'CPA', (252, 266))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
54789	29661250	Mutant IDH1 can reportedly influence the activity of MAPK signaling in melanoma cells.	('IDH1', 'Gene', '3417', (7, 11))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('MAPK signaling', 'Pathway', (53, 67))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('influence', 'Reg', (27, 36))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('activity', 'MPA', (41, 49))
54791	29661250	Based on the previous evidence, we examined whether IDH1 knockdown could potentially accelerate the invasion ability of breast cancer cells through MAPK-HIF-1a/NFkB signaling (Additional file 10: Figure S6b).	('IDH1', 'Gene', '3417', (52, 56))	('accelerate', 'PosReg', (85, 95))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('invasion ability', 'CPA', (100, 116))	('knockdown', 'Var', (57, 66))	('HIF-1a', 'Gene', '3091', (153, 159))	('HIF-1a', 'Gene', (153, 159))	('IDH1', 'Gene', (52, 56))
54792	29661250	5a-c, MAPK signaling was activated in IDH1 knockdown MDA-MB-231 cells and thus promoted cell invasion.	('IDH1', 'Gene', '3417', (38, 42))	('MAPK', 'Gene', (6, 10))	('knockdown', 'Var', (43, 52))	('promoted', 'PosReg', (79, 87))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (53, 63))	('cell invasion', 'CPA', (88, 101))	('IDH1', 'Gene', (38, 42))	('activated', 'PosReg', (25, 34))
54793	29661250	Treatment of U0126, the inhibitor of MAPK signaling, abolished IDH1 knockdown-induced cell invasion (Fig.	('IDH1', 'Gene', '3417', (63, 67))	('cell invasion', 'CPA', (86, 99))	('knockdown-induced', 'Var', (68, 85))	('abolished', 'NegReg', (53, 62))	('IDH1', 'Gene', (63, 67))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))
54794	29661250	5b and c), implying that the effect of IDH1 knockdown on the promotion of cell invasion may be attributed to MAPK signaling.	('IDH1', 'Gene', (39, 43))	('IDH1', 'Gene', '3417', (39, 43))	('promotion', 'PosReg', (61, 70))	('knockdown', 'Var', (44, 53))	('cell invasion', 'CPA', (74, 87))
54796	29661250	The reporter assay showed that both HIF-1alpha and NFkB signaling were activated in IDH1 knockdown cells.	('NFkB signaling', 'MPA', (51, 65))	('activated', 'PosReg', (71, 80))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('IDH1', 'Gene', (84, 88))	('HIF-1alpha', 'Gene', (36, 46))	('IDH1', 'Gene', '3417', (84, 88))	('knockdown', 'Var', (89, 98))
54797	29661250	Meanwhile, the activation of HIF-1alpha and NFkB signaling induced by IDH1 knockdown was abolished in the presence of U0126 (Fig.	('activation', 'PosReg', (15, 25))	('IDH1', 'Gene', '3417', (70, 74))	('HIF-1alpha', 'Gene', '3091', (29, 39))	('HIF-1alpha', 'Gene', (29, 39))	('knockdown', 'Var', (75, 84))	('U0126', 'Chemical', 'MESH:C113580', (118, 123))	('abolished', 'NegReg', (89, 98))	('IDH1', 'Gene', (70, 74))
54799	29661250	We subsequently investigated the molecular mechanism underlying the IDH1 knockdown-mediated upregulation of HIF1alpha.	('knockdown-mediated', 'Var', (73, 91))	('IDH1', 'Gene', (68, 72))	('upregulation', 'PosReg', (92, 104))	('HIF1alpha', 'Gene', (108, 117))	('IDH1', 'Gene', '3417', (68, 72))	('HIF1alpha', 'Gene', '3091', (108, 117))
54800	29661250	First, we examined whether the elevated HIF1alpha expression upon IDH1 depletion was regulated at the mRNA level.	('IDH1', 'Gene', '3417', (66, 70))	('HIF1alpha', 'Gene', (40, 49))	('depletion', 'Var', (71, 80))	('HIF1alpha', 'Gene', '3091', (40, 49))	('elevated', 'PosReg', (31, 39))	('IDH1', 'Gene', (66, 70))	('expression', 'MPA', (50, 60))
54801	29661250	Quantitative reverse transcription polymerase chain reaction (qRT-PCR) indicated that IDH1 depletion caused a slight decrease in HIF1alpha mRNA (Fig.	('IDH1', 'Gene', (86, 90))	('depletion', 'Var', (91, 100))	('HIF1alpha', 'Gene', '3091', (129, 138))	('IDH1', 'Gene', '3417', (86, 90))	('decrease', 'NegReg', (117, 125))	('HIF1alpha', 'Gene', (129, 138))
54808	29661250	IDH1 is the major cellular enzyme responsible for catalyzing isocitrate into alpha-KG in the tricarboxylic acid (TCA) cycle, therefore, we hypothesized that IDH1 depletion caused a reduction in the cellular level of alpha-KG to impair the activity of PHD2, leading to the stabilization of HIF1alpha proteins under normoxic conditions.	('activity', 'MPA', (239, 247))	('PHD2', 'Gene', (251, 255))	('impair', 'NegReg', (228, 234))	('depletion', 'Var', (162, 171))	('IDH1', 'Gene', (0, 4))	('HIF1alpha', 'Gene', '3091', (289, 298))	('TCA', 'Chemical', 'MESH:D014233', (113, 116))	('PHD2', 'Gene', '54583', (251, 255))	('IDH1', 'Gene', (157, 161))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (93, 111))	('HIF1alpha', 'Gene', (289, 298))	('IDH1', 'Gene', '3417', (0, 4))	('alpha-KG', 'Chemical', '-', (77, 85))	('isocitrate', 'Chemical', 'MESH:C034219', (61, 71))	('IDH1', 'Gene', '3417', (157, 161))	('cellular level', 'MPA', (198, 212))	('reduction', 'NegReg', (181, 190))	('stabilization', 'MPA', (272, 285))	('alpha-KG', 'Chemical', '-', (216, 224))
54812	29661250	Taken together, these results indicated that IDH1 depletion resulted in a low level of cellular alpha-KG, which in turn impaired the activity of the alpha-KG-dependent enzyme PHD2, ultimately leading to the accumulation of HIF1alpha protein.	('IDH1', 'Gene', '3417', (45, 49))	('alpha-KG', 'Chemical', '-', (96, 104))	('low', 'NegReg', (74, 77))	('alpha-KG', 'Chemical', '-', (149, 157))	('HIF1alpha', 'Gene', (223, 232))	('PHD2', 'Gene', (175, 179))	('impaired', 'NegReg', (120, 128))	('leading to', 'Reg', (192, 202))	('accumulation', 'PosReg', (207, 219))	('HIF1alpha', 'Gene', '3091', (223, 232))	('PHD2', 'Gene', '54583', (175, 179))	('activity', 'MPA', (133, 141))	('IDH1', 'Gene', (45, 49))	('depletion', 'Var', (50, 59))
54821	29661250	Furthermore, depletion of IDH1 in breast cancer cells results in accelerating breast cancer migration and invasion activities by activating snail expression (Fig.	('invasion activities', 'CPA', (106, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('snail', 'Gene', '6615', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('IDH1', 'Gene', (26, 30))	('depletion', 'Var', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('accelerating', 'PosReg', (65, 77))	('snail', 'Gene', (140, 145))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('IDH1', 'Gene', '3417', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('activating', 'PosReg', (129, 139))
54827	29661250	Studies have revealed that IDH1 and IDH2 mutations promote global hypermethylation with concomitant reductions in 5hmC levels.	('IDH2', 'Gene', (36, 40))	('mutations', 'Var', (41, 50))	('IDH2', 'Gene', '3418', (36, 40))	('global hypermethylation', 'MPA', (59, 82))	('5hmC', 'Chemical', '-', (114, 118))	('5hmC levels', 'MPA', (114, 125))	('promote', 'PosReg', (51, 58))	('IDH1', 'Gene', (27, 31))	('IDH1', 'Gene', '3417', (27, 31))	('reductions', 'NegReg', (100, 110))
54837	29661250	A study has shown that the siRNA knockdown of either IDH1 or IDH2 can significantly reduce the proliferative capacity of a glioblastoma cell line expressing both wild-type IDH1 and IDH2.	('reduce', 'NegReg', (84, 90))	('glioblastoma', 'Disease', (123, 135))	('IDH1', 'Gene', '3417', (172, 176))	('knockdown', 'Var', (33, 42))	('IDH1', 'Gene', (53, 57))	('IDH2', 'Gene', (181, 185))	('IDH2', 'Gene', (61, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('IDH1', 'Gene', '3417', (53, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('IDH2', 'Gene', '3418', (61, 65))	('IDH1', 'Gene', (172, 176))	('IDH2', 'Gene', '3418', (181, 185))
54838	29661250	suggested that the attenuation of IDH family gene expression may protect the skin from ultraviolet (UV)-B-mediated damage by inducing the apoptosis of UV-damaged cells.	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('attenuation', 'Var', (19, 30))	('inducing', 'PosReg', (125, 133))	('apoptosis', 'CPA', (138, 147))
54841	29661250	Furthermore, the siRNA knockdown of IDH1 can promote the invasion ability of breast cancer cells, suggesting that IDH1 acts as a tumor suppressor in breast cancer progression.	('breast cancer', 'Disease', (77, 90))	('IDH1', 'Gene', (36, 40))	('IDH1', 'Gene', (114, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('knockdown', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IDH1', 'Gene', '3417', (114, 118))	('promote', 'PosReg', (45, 52))	('IDH1', 'Gene', '3417', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (129, 134))	('breast cancer', 'Disease', (149, 162))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
54850	29661250	IDH1 mutants can play a dominant negative role in wild-type IDH1 functions, resulting in the increased phosphorylation of MAPK and signal transducer and activator of transcription 3 in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('signal transducer and activator of transcription 3', 'Gene', '6774', (131, 181))	('IDH1', 'Gene', (60, 64))	('increased', 'PosReg', (93, 102))	('MAPK', 'Protein', (122, 126))	('mutants', 'Var', (5, 12))	('phosphorylation', 'MPA', (103, 118))	('IDH1', 'Gene', '3417', (60, 64))	('IDH1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('IDH1', 'Gene', '3417', (0, 4))
54851	29661250	reported that IDH1 mutants can activate the hypoxia pathway by preventing HIF-1alpha degradation through prolyl hydroxylase activation in glioma cells.	('preventing', 'NegReg', (63, 73))	('glioma', 'Disease', (138, 144))	('hypoxia', 'Disease', (44, 51))	('activate', 'PosReg', (31, 39))	('HIF-1alpha', 'Gene', '3091', (74, 84))	('hypoxia', 'Disease', 'MESH:D000860', (44, 51))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('mutants', 'Var', (19, 26))	('HIF-1alpha', 'Gene', (74, 84))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('IDH1', 'Gene', (14, 18))	('prolyl hydroxylase activation', 'MPA', (105, 134))	('IDH1', 'Gene', '3417', (14, 18))
54853	29661250	In the present study, we demonstrated that IDH1 depletion in breast cancer cells led to an increase in the HIF1alpha protein level to promote cell migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('promote', 'PosReg', (134, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('invasion', 'CPA', (161, 169))	('increase', 'PosReg', (91, 99))	('cell migration', 'CPA', (142, 156))	('HIF1alpha', 'Gene', (107, 116))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))	('depletion', 'Var', (48, 57))	('HIF1alpha', 'Gene', '3091', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
54855	29661250	Our mechanistic study demonstrated that IDH1 depletion led to a decrease in intracellular alpha-KG, which in turn stabilized HIF1alpha (Fig.	('decrease', 'NegReg', (64, 72))	('IDH1', 'Gene', (40, 44))	('alpha-KG', 'Chemical', '-', (90, 98))	('intracellular', 'MPA', (76, 89))	('HIF1alpha', 'Gene', '3091', (125, 134))	('IDH1', 'Gene', '3417', (40, 44))	('HIF1alpha', 'Gene', (125, 134))	('stabilized', 'PosReg', (114, 124))	('depletion', 'Var', (45, 54))
54860	29661250	We provide a novel insight that miR-32-5p and miR-92b-3p dysregulation results in IDH1 depletion.	('miR-92b-3', 'Gene', (46, 55))	('dysregulation', 'Var', (57, 70))	('miR-32-5p', 'Gene', '442899', (32, 41))	('results in', 'Reg', (71, 81))	('miR-32-5p', 'Gene', (32, 41))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('depletion', 'MPA', (87, 96))	('miR-92b-3', 'Gene', '407047', (46, 55))
54861	29661250	Low IDH1 expression levels can promote the migration and invasion abilities of breast cancer cells by activating snail expression.	('expression', 'MPA', (119, 129))	('IDH1', 'Gene', '3417', (4, 8))	('snail', 'Gene', '6615', (113, 118))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('activating', 'PosReg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('expression levels', 'MPA', (9, 26))	('promote', 'PosReg', (31, 38))	('snail', 'Gene', (113, 118))	('IDH1', 'Gene', (4, 8))	('migration', 'CPA', (43, 52))	('invasion abilities', 'CPA', (57, 75))	('Low', 'Var', (0, 3))
54874	23083134	Phosphorylated ERK1/2 was detected in 58/80 (72.5%) IBDC tissues, and was associated with higher TNM stage and lymph node metastasis, but not patient age or tumor size.	('tumor', 'Disease', (157, 162))	('Phosphorylated', 'Var', (0, 14))	('lymph node metastasis', 'CPA', (111, 132))	('IBDC', 'Chemical', '-', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('TNM', 'Gene', '10178', (97, 100))	('ERK1/2', 'Gene', (15, 21))	('patient', 'Species', '9606', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('higher', 'PosReg', (90, 96))	('TNM', 'Gene', (97, 100))	('associated', 'Reg', (74, 84))
54887	23083134	To date, several MAP3Ks and MAP2Ks have been identified that regulate the ERK signaling pathway, including the MAP3Ks Raf and Mos, and the MAP2Ks, MAPK/ERK kinase 1 (MEK1) and MEK2.	('MEK1', 'Gene', (166, 170))	('MAP3Ks', 'Var', (111, 117))	('Raf', 'Gene', (118, 121))	('ERK', 'Gene', '5594', (152, 155))	('MAPK/ERK kinase 1', 'Gene', '5604', (147, 164))	('ERK', 'Gene', '5594', (74, 77))	('MAPK/ERK kinase 1', 'Gene', (147, 164))	('regulate', 'Reg', (61, 69))	('ERK', 'Gene', (152, 155))	('ERK', 'Gene', (74, 77))	('Raf', 'Gene', '22882', (118, 121))	('MEK2', 'Gene', '5605', (176, 180))	('Mos', 'CPA', (126, 129))	('MEK2', 'Gene', (176, 180))	('MEK1', 'Gene', '5604', (166, 170))
54944	23083134	The Transwell migration assay revealed that EGF increased the migration and invasion of the cells; however, EGF-induced BT474 cell migration and invasion were significantly attenuated in a dose-dependent manner by the knockdown of ERK1/2 using 50-200 nM ERK1/2 siRNA (Figures 2C, E and F).	('migration', 'CPA', (62, 71))	('EGF', 'Gene', (44, 47))	('EGF', 'Gene', '1950', (108, 111))	('knockdown', 'Var', (218, 227))	('BT474', 'CellLine', 'CVCL:0179', (120, 125))	('EGF', 'Gene', '1950', (44, 47))	('attenuated', 'NegReg', (173, 183))	('EGF', 'Gene', (108, 111))	('BT474', 'Gene', (120, 125))	('invasion', 'CPA', (145, 153))	('invasion of the cells', 'CPA', (76, 97))
54945	23083134	Similarly, U0126 significantly decreased EGF-induced cell migration and invasion in a dose-dependent manner (Figures 2E and F).	('U0126', 'Chemical', 'MESH:C113580', (11, 16))	('decreased', 'NegReg', (31, 40))	('EGF', 'Gene', (41, 44))	('U0126', 'Var', (11, 16))	('invasion', 'CPA', (72, 80))	('EGF', 'Gene', '1950', (41, 44))
54954	23083134	Transwell assays demonstrated that knockdown of ERK1/2 expression using siRNAs attenuated IL-1beta-induced cell migration and invasion in a dose-dependent manner (Figures 2E and F).	('attenuated', 'NegReg', (79, 89))	('knockdown', 'Var', (35, 44))	('ERK1/2', 'Gene', (48, 54))	('IL-1beta', 'Gene', '3553', (90, 98))	('cell migration', 'CPA', (107, 121))	('invasion', 'CPA', (126, 134))	('IL-1beta', 'Gene', (90, 98))
54955	23083134	The MEK/ERK inhibitor U0126 also significantly inhibited IL-1beta-induced BT474 cell migration and invasion (Figures 2E and F), indicating that IL-1beta-induced IBDC cell metastasis are dependent on the MEK/ERK signaling pathway, and also that ERK1/2 contributes to inflammatory factor-associated IBDC cell migration and invasion.	('ERK', 'Gene', (244, 247))	('invasion', 'CPA', (321, 329))	('BT474', 'Gene', (74, 79))	('U0126', 'Chemical', 'MESH:C113580', (22, 27))	('IBDC', 'Chemical', '-', (297, 301))	('ERK', 'Gene', '5594', (8, 11))	('IBDC', 'Chemical', '-', (161, 165))	('ERK', 'Gene', '5594', (207, 210))	('U0126', 'Var', (22, 27))	('MEK', 'Gene', '5609', (4, 7))	('MEK', 'Gene', '5609', (203, 206))	('invasion', 'CPA', (99, 107))	('ERK', 'Gene', (8, 11))	('MEK', 'Gene', (203, 206))	('ERK', 'Gene', (207, 210))	('IL-1beta', 'Gene', '3553', (57, 65))	('MEK', 'Gene', (4, 7))	('IL-1beta', 'Gene', '3553', (144, 152))	('ERK', 'Gene', '5594', (244, 247))	('IBDC', 'Disease', (297, 301))	('BT474', 'CellLine', 'CVCL:0179', (74, 79))	('inhibited', 'NegReg', (47, 56))	('IL-1beta', 'Gene', (57, 65))	('IL-1beta', 'Gene', (144, 152))
54965	23083134	The knockdown of ERK1/2 by siRNA or the inhibition of ERK1/2 activation by U0126 significantly reduced EGF-induced MMP-9 mRNA and protein expression in a dose-dependent manner (P < 0.05 compared with control siRNA or untransfected cells, independent sample t-test), and attenuated the EGF-induced increase in MMP-9 activity (Figures 3A to F, and H, respectively).	('ERK1/2', 'Gene', (17, 23))	('U0126', 'Chemical', 'MESH:C113580', (75, 80))	('EGF', 'Gene', '1950', (285, 288))	('MMP-9', 'Gene', (309, 314))	('EGF', 'Gene', '1950', (103, 106))	('U0126', 'Var', (75, 80))	('MMP-9', 'Gene', '4318', (115, 120))	('reduced', 'NegReg', (95, 102))	('inhibition', 'NegReg', (40, 50))	('MMP-9', 'Gene', (115, 120))	('EGF', 'Gene', (285, 288))	('ERK1/2', 'Gene', (54, 60))	('attenuated', 'NegReg', (270, 280))	('EGF', 'Gene', (103, 106))	('knockdown', 'Var', (4, 13))	('MMP-9', 'Gene', '4318', (309, 314))
54971	23083134	The knockdown of ERK1/2 by siRNA significantly reduced both EGF- and IL-1beta-induced AP-1 activation in a dose-dependent manner (P < 0.05 compared with control siRNA, independent sample t-test).	('ERK1/2', 'Gene', (17, 23))	('EGF', 'Gene', (60, 63))	('AP-1', 'Gene', '2353', (86, 90))	('EGF', 'Gene', '1950', (60, 63))	('IL-1beta', 'Gene', '3553', (69, 77))	('siRNA', 'Gene', (27, 32))	('IL-1beta', 'Gene', (69, 77))	('knockdown', 'Var', (4, 13))	('AP-1', 'Gene', (86, 90))	('reduced', 'NegReg', (47, 54))
54990	23083134	Importantly, we also demonstrated for the first time that IL-1beta also enhanced IBDC cell migration and invasion, and the presence of EGF and IL-1beta synergistically increased IBDC cell migration and invasion via the ERK1/2 pathway.	('invasion', 'CPA', (105, 113))	('EGF', 'Gene', (135, 138))	('ERK1/2 pathway', 'Pathway', (219, 233))	('increased', 'PosReg', (168, 177))	('IBDC cell migration', 'CPA', (81, 100))	('IL-1beta', 'Gene', '3553', (58, 66))	('EGF', 'Gene', '1950', (135, 138))	('IBDC', 'Chemical', '-', (178, 182))	('IBDC cell migration', 'CPA', (178, 197))	('IL-1beta', 'Gene', (143, 151))	('IL-1beta', 'Gene', '3553', (143, 151))	('presence', 'Var', (123, 131))	('enhanced', 'PosReg', (72, 80))	('invasion', 'CPA', (202, 210))	('IL-1beta', 'Gene', (58, 66))	('IBDC', 'Chemical', '-', (81, 85))
55008	29653745	The significance of PTEN mutations resulting in variable PTEN expression and their impact on prognosis of breast cancer is not well established.	('mutations', 'Var', (25, 34))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('expression', 'MPA', (62, 72))	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', '5728', (57, 61))	('PTEN', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PTEN', 'Gene', '5728', (20, 24))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
55021	29653745	Luminal B breast cancers are mitotically active with Ki-67>=14% and may express Her-2.	('Her-2', 'Gene', '2064', (80, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (10, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('express', 'Reg', (72, 79))	('Her-2', 'Gene', (80, 85))	('breast cancers', 'Disease', (10, 24))	('breast cancers', 'Disease', 'MESH:D001943', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('Ki-67', 'Var', (53, 58))	('mitotically', 'CPA', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
55057	29653745	Luminal A was characterized by strong expression of ER and PR (H-score >=200), HER2 negativity, and Ki-67 proliferation <14%.	('PR', 'Gene', '5241', (59, 61))	('negativity', 'Var', (84, 94))	('HER2', 'Gene', '2064', (79, 83))	('ER', 'Gene', '2099', (52, 54))	('ER', 'Gene', '2099', (80, 82))	('HER2', 'Gene', (79, 83))
55058	29653745	Luminal B was characterized by Ki-67 >= 14% and HER2-negative or HER2 positive.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', '2064', (65, 69))	('Ki-67 >= 14%', 'Var', (31, 43))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', (65, 69))
55096	29653745	MK-2206, an AKT inhibitor, was associated with increased toxicity at different doses.	('toxicity', 'Disease', (57, 65))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('AKT', 'Gene', '207', (12, 15))	('AKT', 'Gene', (12, 15))	('MK-2206', 'Var', (0, 7))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
55100	29653745	The activation of downstream signaling pathway secondary to loss of PTEN results in trastuzumab resistance.	('trastuzumab', 'Chemical', 'MESH:D000068878', (84, 95))	('downstream signaling pathway', 'Pathway', (18, 46))	('PTEN', 'Gene', (68, 72))	('loss', 'Var', (60, 64))	('PTEN', 'Gene', '5728', (68, 72))	('trastuzumab resistance', 'MPA', (84, 106))	('activation', 'PosReg', (4, 14))
55103	29653745	Germline mutations in PTEN predisposes to multiorgan system carcinogenesis (Breast, Endometrial, Thyroid) and multiple hamartomatous polyps in the gastrointestinal tract known as Cowden syndrome.	('Germline mutations', 'Var', (0, 18))	('polyps in the gastrointestinal tract', 'Phenotype', 'HP:0200008', (133, 169))	('predisposes to', 'Reg', (27, 41))	('hamartomatous polyps in the gastrointestinal tract', 'Disease', (119, 169))	('Cowden syndrome', 'Disease', 'MESH:D006223', (179, 194))	('hamartomatous polyps', 'Phenotype', 'HP:0004390', (119, 139))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('Endometrial', 'Disease', (84, 95))	('Cowden syndrome', 'Disease', (179, 194))	('hamartomatous polyps in the gastrointestinal tract', 'Disease', 'MESH:D011127', (119, 169))	('system carcinogenesis', 'Disease', 'MESH:D063646', (53, 74))	('system carcinogenesis', 'Disease', (53, 74))
55112	23812984	Phylogenetic analysis of multiprobe fluorescence in situ hybridization data from tumor cell populations Motivation: Development and progression of solid tumors can be attributed to a process of mutations, which typically includes changes in the number of copies of genes or genomic regions.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('solid tumors', 'Disease', (147, 159))	('mutations', 'Var', (194, 203))	('changes', 'Reg', (230, 237))	('attributed', 'Reg', (167, 177))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (81, 86))
55120	23812984	Recent studies of genetic variation in solid tumors have revealed massive intratumor heterogeneity in the spectrum of genomic changes within single tumors.	('solid tumors', 'Disease', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (79, 84))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('solid tumors', 'Disease', 'MESH:D009369', (39, 51))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('genetic variation', 'Var', (18, 35))
55187	23812984	As with the CC data, the table consistently shows significant P-values, which again may indicate differences in the evolutionary processes at different stages of tumor development.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('P-values', 'Var', (62, 70))	('CC', 'Phenotype', 'HP:0002664', (12, 14))
55192	23812984	Loss of DBC2 and CDH1 is part of a dominant imbalance clone reported in where it is inferred that cells with this imbalance clone have a growth advantage in DCIS and IDC.	('DBC2', 'Gene', '23221', (8, 12))	('CDH1', 'Gene', '999', (17, 21))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('BC', 'Phenotype', 'HP:0003002', (9, 11))	('imbalance', 'Phenotype', 'HP:0002172', (114, 123))	('growth advantage', 'CPA', (137, 153))	('DCIS', 'CPA', (157, 161))	('CDH1', 'Gene', (17, 21))	('imbalance', 'Phenotype', 'HP:0002172', (44, 53))	('Loss', 'Var', (0, 4))	('DBC2', 'Gene', (8, 12))
55197	23812984	The discrepancy appears to be due to one case, in which 90% of cells in IDC show ZNF217 deletion.	('deletion', 'Var', (88, 96))	('ZNF217', 'Gene', (81, 87))	('ZNF217', 'Gene', '7764', (81, 87))
55213	23812984	Deletion of CDH1 was also reported in, and was selected here in the Edge Count case.	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))	('Deletion', 'Var', (0, 8))
55285	28941977	Risk of a second ipsilateral event was > 5-fold and > 2-fold lower within 2 years and 5 years of initial DCIS diagnosis, respectively, in women who received BCS + RT compared with BCS alone; and overall survival was 3-fold higher in women who received BCS + RT.	('lower', 'NegReg', (61, 66))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('BCS + RT', 'Var', (157, 165))	('higher', 'PosReg', (223, 229))	('women', 'Species', '9606', (138, 143))	('women', 'Species', '9606', (233, 238))
55298	28941977	Studies have also shown that there is no difference in survival between women overall treated with BCS + RT versus MTX for women with early stage breast cancer.	('BCS + RT', 'Var', (99, 107))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('women', 'Species', '9606', (123, 128))	('MTX', 'Gene', '4580', (115, 118))	('women', 'Species', '9606', (72, 77))	('MTX', 'Gene', (115, 118))
55314	28941977	Tumor characteristics included tumor grade (low grade, high grade, or unknown), tumor size (<=15 mm, > 15 mm, or unknown size), tumor histology (comedo or other histology), estrogen receptor status, and progesterone receptor status, all obtained from the SEER data.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('progesterone receptor', 'Gene', '5241', (203, 224))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('comedo', 'Phenotype', 'HP:0025249', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Tumor', 'Disease', (0, 5))	('tumor', 'Disease', (31, 36))	('<=15', 'Var', (92, 96))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('estrogen receptor', 'Gene', '2099', (173, 190))	('estrogen receptor', 'Gene', (173, 190))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('progesterone receptor', 'Gene', (203, 224))
55321	28941977	The greatest proportion of patients underwent BCS + RT (36.1%) followed by MTX without CPM (25.8%), then BCS alone (22.2%), and MTX with CPM (15.8%).	('MTX', 'Gene', (75, 78))	('BCS', 'Var', (46, 49))	('patients', 'Species', '9606', (27, 35))	('MTX', 'Gene', '4580', (128, 131))	('MTX', 'Gene', (128, 131))	('MTX', 'Gene', '4580', (75, 78))
55325	28941977	Young women who got BCS alone were more likely to have a second ipsilateral breast tumor compared with women who received BCS + RT, at 2 years as well as at 5 years after DCIS diagnosis (hazard ratio [HR], 5.36; 94% CI, 2.02-14.3; P = .0008 and HR, 2.46; 95% CI, 1.47-4.11; P = .0006, respectively), after adjusting for year of diagnosis, race, registry region, tumor grade, histology, size, and hormone receptor status (Table 3).	('BCS', 'Var', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('breast tumor', 'Disease', 'MESH:D001943', (76, 88))	('breast tumor', 'Phenotype', 'HP:0100013', (76, 88))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('breast tumor', 'Disease', (76, 88))	('women', 'Species', '9606', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor', 'Disease', (362, 367))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('women', 'Species', '9606', (103, 108))
55328	28941977	There was also no significant difference in overall survival in young women who received MTX with CPM compared with without CPM (data not shown).	('MTX', 'Gene', (89, 92))	('MTX', 'Gene', '4580', (89, 92))	('CPM', 'Var', (98, 101))	('women', 'Species', '9606', (70, 75))
55330	28941977	The trends in treatment patterns among young women diagnosed with DCIS observed in our study are different than in a previous analysis of women of all age groups, which reported that the greatest proportion opted for BCS + RT (43%), followed by BCS alone (26.5%), unilateral MTX (23.8%), and MTX with CPM (4.5%).	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('MTX', 'Gene', (275, 278))	('MTX', 'Gene', (292, 295))	('MTX', 'Gene', '4580', (275, 278))	('MTX', 'Gene', '4580', (292, 295))	('BCS + RT', 'Var', (217, 225))	('women', 'Species', '9606', (138, 143))	('women', 'Species', '9606', (45, 50))
55334	28941977	An unexpected finding was that women with tumors > 15 mm were less likely to get MTX with CPM than MTX without CPM compared with women with tumors up to 15 mm.	('MTX', 'Gene', '4580', (99, 102))	('MTX', 'Gene', (81, 84))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('MTX', 'Gene', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('women', 'Species', '9606', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('CPM', 'Var', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('less', 'NegReg', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('women', 'Species', '9606', (31, 36))	('MTX', 'Gene', '4580', (81, 84))
55337	28941977	Consistent with previous studies, which showed that women of all ages diagnosed with DCIS who got RT had a 60% decreased risk of second ipsilateral event compared with women who got BCS alone, our data also showed that young women with DCIS who got BCS + RT also had a > 5-fold and > 2-fold lower risk of a second ipsilateral event within 2 years and 5 years of initial DCIS diagnosis, respectively.	('DCIS', 'Phenotype', 'HP:0030075', (236, 240))	('women', 'Species', '9606', (168, 173))	('BCS + RT', 'Var', (249, 257))	('women', 'Species', '9606', (225, 230))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('DCIS', 'Phenotype', 'HP:0030075', (370, 374))	('decreased', 'NegReg', (111, 120))	('DCIS', 'Disease', (236, 240))	('women', 'Species', '9606', (52, 57))	('lower', 'NegReg', (291, 296))
55339	28941977	Although our data indicate that, after adjusting for potential confounders, young women who received BCS alone were more than 3-fold likely to die compared with women who received BCS + RT, there does not appear to be a survival benefit associated with undergoing MTX with or without CPM over BCS + RT.	('women', 'Species', '9606', (82, 87))	('women', 'Species', '9606', (161, 166))	('MTX', 'Gene', '4580', (264, 267))	('BCS', 'Var', (101, 104))	('MTX', 'Gene', (264, 267))
55358	28941977	Previous studies have also shown that there are no differences in survival between women treated with BCS + RT versus MTX for women overall with early stage breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('BCS + RT', 'Var', (102, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('women', 'Species', '9606', (126, 131))	('MTX', 'Gene', (118, 121))	('MTX', 'Gene', '4580', (118, 121))	('women', 'Species', '9606', (83, 88))
55360	28941977	Overall survival in young women with DCIS who received BCS + RT was significantly higher compared with BCS alone.	('women', 'Species', '9606', (26, 31))	('BCS', 'Var', (55, 58))	('higher', 'PosReg', (82, 88))	('DCIS', 'Disease', (37, 41))	('Overall survival', 'MPA', (0, 16))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
55427	27349894	We found that cases with discordant ER and PR status between cores had significantly lower median tumor cellularity, but that tumor cellularity was similar in cases with concordant and discordant HER2 status (Table 1).	('discordant', 'Var', (25, 35))	('lower', 'NegReg', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('HER2', 'Gene', (196, 200))	('PR', 'Gene', '5241', (43, 45))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ER', 'Gene', '2099', (197, 199))	('ER', 'Gene', '2099', (36, 38))	('HER2', 'Gene', '2064', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (126, 131))
55440	27349894	Therefore, admixture of tumor and DCIS and/or benign epithelium can potentially lead to tumor biomarker misclassification by automated analysis if biomarker status is discordant between tumor and nontumor tissues.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('lead to', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (24, 29))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (88, 93))	('admixture', 'Var', (11, 20))
55499	22488610	In these studies which included primarily cases of low grade DCIS, up to 40% of women were diagnosed with invasive cancer in the ipsilateral breast with follow-up of more than 30 years.	('women', 'Species', '9606', (80, 85))	('diagnosed', 'Reg', (91, 100))	('invasive cancer', 'Disease', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('invasive cancer', 'Disease', 'MESH:D009362', (106, 121))	('low', 'Var', (51, 54))
55572	22488610	However, there are no data at this point to suggest that a name change will have an effect on risk perceptions, anxiety/distress or decision-making.	('anxiety', 'Disease', 'MESH:D001008', (112, 119))	('name change', 'Var', (59, 70))	('effect', 'Reg', (84, 90))	('anxiety', 'Phenotype', 'HP:0000739', (112, 119))	('anxiety', 'Disease', (112, 119))	('risk perceptions', 'MPA', (94, 110))	('decision-making', 'CPA', (132, 147))
55578	22488610	In summary, while a change in terminology may be worthy of consideration in the future, there are no data to support the contention that a name change at the present time will reduce observer variability in diagnosis, reduce patient anxiety or assist patients and clinicians in choosing among the various treatment options for DCIS which will be the same regardless of the terminology used.	('reduce', 'NegReg', (218, 224))	('observer variability', 'MPA', (183, 203))	('change', 'Var', (144, 150))	('assist', 'Reg', (244, 250))	('diagnosis', 'MPA', (207, 216))	('DCIS', 'Disease', (327, 331))	('patient', 'Species', '9606', (251, 258))	('anxiety', 'Disease', 'MESH:D001008', (233, 240))	('reduce', 'NegReg', (176, 182))	('patients', 'Species', '9606', (251, 259))	('patient', 'Species', '9606', (225, 232))	('anxiety', 'Phenotype', 'HP:0000739', (233, 240))	('anxiety', 'Disease', (233, 240))
55586	22488610	In the future, we seek to (1) evaluate the process by which other diseases made nomenclature changes and to determine the extent to which communication influenced implementation and quality of life of the patients; and, (2) obtain information from other countries including Italy where recent nomenclature changes have been adopted on the resulting effects of the changes on risk perceptions, psychosocial outcomes and decision-making.	('patients', 'Species', '9606', (205, 213))	('psychosocial', 'Disease', 'MESH:C535569', (393, 405))	('psychosocial', 'Disease', (393, 405))	('changes', 'Var', (93, 100))
55621	31902979	Microarray analysis helps in genetic alteration that might be  responsible for cancerous alterations by calculating genes expression values for the respective disease under study.The study schema is given in (Figure 1) The breast cancer-specific microarray data sets were downloaded from GEO (Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/) database with the accession id GSE21422  and GSE5764.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancerous', 'Disease', 'MESH:D009369', (79, 88))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('GSE5764', 'Var', (397, 404))	('breast cancer', 'Disease', (223, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancerous', 'Disease', (79, 88))
55644	31902979	Some of the identified DEGs were found to be directly related to breast cancer.	('related', 'Reg', (54, 61))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('DEGs', 'Var', (23, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))
55654	10604741	Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type We analysed the involvement of known and putative tumour suppressor- and oncogene loci in ductal carcinoma in situ (DCIS) by microsatellite analysis (LOH), Southern blotting and comparative genomic hybridization (CGH).	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (70, 94))	('ductal carcinoma', 'Disease', 'MESH:D044584', (239, 255))	('ductal carcinoma in situ', 'Disease', (239, 263))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (239, 263))	('alterations', 'Var', (8, 19))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (239, 263))	('tumour', 'Disease', (199, 205))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (246, 263))	('ductal carcinoma', 'Disease', 'MESH:D044584', (70, 86))	('DCIS', 'Phenotype', 'HP:0030075', (265, 269))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (77, 94))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (70, 94))	('ductal carcinoma in situ', 'Disease', (70, 94))
55657	10604741	In conclusion, our data indicates that inactivation of a yet unknown tumour suppressor gene on chromosome 16q is implicated in the development of most well and intermediately differentiated DCIS whereas amplification and inactivation of various genes on chromosome 17 are implicated in the development of poorly differentiated DCIS.	('tumour', 'Disease', (69, 75))	('implicated', 'Reg', (113, 123))	('DCIS', 'Phenotype', 'HP:0030075', (327, 331))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('inactivation', 'Var', (39, 51))
55682	25729425	Genetically modified mice with tissue-specific deletion of BRCA1 or BRCA2 in mammary epithelium spontaneously develop breast cancer which closely mimics the disease in humans.	('mice', 'Species', '10090', (21, 25))	('BRCA1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('develop', 'Reg', (110, 117))	('deletion', 'Var', (47, 55))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('humans', 'Species', '9606', (168, 174))	('BRCA2', 'Gene', (68, 73))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
55685	25729425	PARP1 inhibition leads to unrepaired single-strand DNA breaks that eventually turn into double-strand breaks that also cannot be repaired due to failure of BRCA1 or BRCA2 and lead to cell death.	('failure', 'Disease', 'MESH:D017093', (145, 152))	('failure', 'Disease', (145, 152))	('double-strand', 'MPA', (88, 101))	('single-strand DNA breaks', 'MPA', (37, 61))	('inhibition', 'Var', (6, 16))	('BRCA2', 'Gene', (165, 170))	('turn', 'Reg', (78, 82))	('PARP1', 'Gene', (0, 5))	('BRCA1', 'Gene', (156, 161))	('PARP1', 'Gene', '142', (0, 5))
55688	25729425	However, subsequent pre-clinical study reported that indeed inactivation of P-glycoprotein increased the long-term response of BRCA-deficient breast cancer to olaparib, but these tumours eventually acquired resistance to the therapy.	('BRCA-deficient breast cancer', 'Disease', 'MESH:D001943', (127, 155))	('response', 'MPA', (115, 123))	('P-glycoprotein', 'Gene', '5243', (76, 90))	('P-glycoprotein', 'Gene', (76, 90))	('deficient breast', 'Phenotype', 'HP:0003187', (132, 148))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('olaparib', 'Chemical', 'MESH:C531550', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumours', 'Disease', (179, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('BRCA-deficient breast cancer', 'Disease', (127, 155))	('tumours', 'Disease', 'MESH:D009369', (179, 186))	('acquired', 'Reg', (198, 206))	('increased', 'PosReg', (91, 100))	('inactivation', 'Var', (60, 72))
55800	24382996	Data from the MammoSite Registry Trial demonstrated that negative ER status was the only variable, associated with IBTR in patients with invasive carcinoma (OR 4.01, P = 0.003).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('IBTR', 'Disease', (115, 119))	('ER', 'Gene', '2099', (66, 68))	('patients', 'Species', '9606', (123, 131))	('negative', 'Var', (57, 65))	('invasive carcinoma', 'Disease', 'MESH:D009361', (137, 155))	('invasive carcinoma', 'Disease', (137, 155))
55807	24382996	The higher IBTR rate among ER negative patients in our study may be explained by the finding of a BRCA mutation in one of the 3 ER negative patients that recurred.	('BRCA', 'Gene', (98, 102))	('ER', 'Gene', '2099', (27, 29))	('patients', 'Species', '9606', (39, 47))	('ER', 'Gene', '2099', (128, 130))	('patients', 'Species', '9606', (140, 148))	('mutation', 'Var', (103, 111))	('BRCA', 'Gene', '672', (98, 102))
56035	27048417	We defined HER2 positivity as having an immunohistochemistry score of 3+ or a positive fluorescence in situ hybridization result.	('HER2', 'Gene', (11, 15))	('positivity', 'Var', (16, 26))	('HER2', 'Gene', '2064', (11, 15))
56050	27048417	Similarly, the prevalence of M-positives tumors was highest in self-detected cases.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('M-positives', 'Var', (29, 40))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))
56090	27048417	The relatively higher frequency of breast cancers positive for BRCA1/2 mutations in Japan (27.2 %) may result in different age distributions compared to other countries.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (35, 49))	('breast cancers', 'Disease', 'MESH:D001943', (35, 49))	('BRCA1/2', 'Gene', '672;675', (63, 70))	('breast cancers', 'Disease', (35, 49))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('positive', 'Reg', (50, 58))	('BRCA1/2', 'Gene', (63, 70))
56110	32397691	The contributions of BRCA1/2 mutations to breast cancer incidence are expected to differ between Asians and Caucasians, and the different genetic backgrounds among races are likely to influence the breast cancer phenotypes.	('BRCA1/2', 'Gene', '672;675', (21, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (29, 38))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('BRCA1/2', 'Gene', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('influence', 'Reg', (184, 193))	('breast cancer', 'Disease', (198, 211))
56114	32397691	Genetic predisposition is one of the major risk factors in breast cancer which constitutes 5%-10% of all breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('breast cancers', 'Disease', (105, 119))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('Genetic', 'Var', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
56115	32397691	About 20%-40% of inherited breast cancers are attributed to deleterious mutations in the breast cancer-associated genes BRCA1 and BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (72, 81))	('inherited breast cancers', 'Disease', 'MESH:D061325', (17, 41))	('attributed', 'Reg', (46, 56))	('BRCA1', 'Gene', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (27, 41))	('breast cancer', 'Disease', (89, 102))	('inherited breast cancers', 'Disease', (17, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('BRCA2', 'Gene', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('BRCA1', 'Gene', '672', (120, 125))	('BRCA2', 'Gene', '675', (130, 135))
56118	32397691	BRCA1/2 germline mutations are more common in patients with a family history of breast or ovarian cancer, personal history of breast cancer at young age, or triple-negative phenotype (for BRCA1 only).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('germline mutations', 'Var', (8, 26))	('BRCA1', 'Gene', (0, 5))	('patients', 'Species', '9606', (46, 54))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('BRCA1', 'Gene', (188, 193))	('breast or ovarian cancer', 'Disease', 'MESH:D001943', (80, 104))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('common', 'Reg', (36, 42))	('breast or ovarian cancer', 'Disease', (80, 104))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1/2', 'Gene', (0, 7))	('BRCA1', 'Gene', '672', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
56122	32397691	Thus, the contributions of BRCA1/2 germline mutations to breast cancer incidence are expected to differ between Asians and Caucasians.	('BRCA1/2', 'Gene', (27, 34))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('BRCA1/2', 'Gene', '672;675', (27, 34))	('germline', 'Var', (35, 43))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
56125	32397691	The reported prevalence of BRCA1/2 germline mutations in Asian patients with familial breast cancer ranges from 8.0% to 31.8% and in those with early-onset breast cancers from 2.8% to 21.4%.	('BRCA1/2', 'Gene', (27, 34))	('BRCA1/2', 'Gene', '672;675', (27, 34))	('familial breast cancer', 'Disease', 'MESH:D001943', (77, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('patients', 'Species', '9606', (63, 71))	('familial breast cancer', 'Disease', (77, 99))	('germline mutations', 'Var', (35, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('breast cancers', 'Disease', (156, 170))
56126	32397691	The prevalence of BRCA1/2 mutations in familial breast cancer in Asians is similar to that of African and Hispanic Americans but lower than Ashkenazi-Jews and North Americans of Caucasian descent.	('BRCA1/2', 'Gene', (18, 25))	('familial breast cancer', 'Disease', 'MESH:D001943', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('BRCA1/2', 'Gene', '672;675', (18, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('mutations', 'Var', (26, 35))	('familial breast cancer', 'Disease', (39, 61))	('lower', 'NegReg', (129, 134))
56127	32397691	The prevalence of BRCA1/2 mutations in early-onset breast cancer in Asians is similar to that of Caucasians and African Americans.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA1/2', 'Gene', (18, 25))	('BRCA1/2', 'Gene', '672;675', (18, 25))	('mutations', 'Var', (26, 35))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
56128	32397691	It has been reported that BRCA2 mutations have a higher incidence in Asians with the exception of Indians and Pakistanis, whereas BRCA1 mutations are more prominent in other ethnicities.	('BRCA1', 'Gene', (130, 135))	('Asians', 'Disease', (69, 75))	('BRCA2', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('BRCA1', 'Gene', '672', (130, 135))	('BRCA2', 'Gene', '675', (26, 31))
56129	32397691	In a recent study from a Chinese cohort, BRCA mutations were identified in 9.1% of cases with at least one risk factor for hereditary breast cancer, 3.5% of sporadic patients, and 0.38% of healthy controls.	('BRCA', 'Gene', (41, 45))	('hereditary breast cancer', 'Disease', (123, 147))	('mutations', 'Var', (46, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (166, 174))	('hereditary breast cancer', 'Disease', 'MESH:D061325', (123, 147))	('BRCA', 'Gene', '672', (41, 45))
56130	32397691	In Western countries, the estimated cumulative risk of breast cancer to the age of 70 years in BRCA1 and BRCA2 mutation carriers ranges from 72%-87% and 71%-84%, respectively.	('BRCA1', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BRCA2', 'Gene', (105, 110))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('mutation', 'Var', (111, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('BRCA1', 'Gene', '672', (95, 100))	('BRCA2', 'Gene', '675', (105, 110))
56131	32397691	The estimated cumulative risk of breast cancer to the age of 70 years is 72.1%-66.3% and 78%-80% for BRCA1 and BRCA2 mutation carriers in Korea and Japan, respectively.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('BRCA2', 'Gene', (111, 116))	('BRCA1', 'Gene', '672', (101, 106))	('BRCA2', 'Gene', '675', (111, 116))	('BRCA1', 'Gene', (101, 106))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('mutation', 'Var', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
56133	32397691	However, as chemotherapeutic regimens are becoming increasingly tumor-specific, it is possible that patients with BRCA mutations will be treated differently in the future.	('tumor', 'Disease', (64, 69))	('BRCA', 'Gene', '672', (114, 118))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('BRCA', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
56134	32397691	Recently, for example, various clinical trials have investigated polyadenosine diphosphate-ribose polymerase (PARP) inhibitor treatment for advanced breast cancer patients with germline BRCA1/2 mutation.	('mutation', 'Var', (194, 202))	('patients', 'Species', '9606', (163, 171))	('polyadenosine diphosphate-ribose polymerase', 'Gene', '142', (65, 108))	('BRCA1/2', 'Gene', (186, 193))	('PARP', 'Gene', (110, 114))	('polyadenosine diphosphate-ribose polymerase', 'Gene', (65, 108))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('BRCA1/2', 'Gene', '672;675', (186, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))	('PARP', 'Gene', '142', (110, 114))
56137	32397691	Most studies on Asian patients have focused on the incidence and prevalence of BRCA mutation in high-risk women and their families, and few studies have investigated the clinicopathological features of BRCA-associated breast cancer.	('breast cancer', 'Disease', (218, 231))	('BRCA', 'Gene', '672', (79, 83))	('BRCA', 'Gene', (202, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('BRCA', 'Gene', (79, 83))	('patients', 'Species', '9606', (22, 30))	('women', 'Species', '9606', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('BRCA', 'Gene', '672', (202, 206))	('mutation', 'Var', (84, 92))
56139	32397691	As opposed to sporadic breast cancers, breast cancers with mutations in high-penetrance susceptibility genes display distinctive clinical features: younger age at diagnosis, higher incidence of bilateral breast cancer, and association with other cancers including ovarian, colon, prostate, pancreatic, endometrial, and male breast cancers and sarcomas.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (14, 37))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('pancreatic', 'Disease', 'MESH:D010195', (290, 300))	('higher', 'PosReg', (174, 180))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('breast cancers', 'Phenotype', 'HP:0003002', (324, 338))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))	('endometrial', 'Disease', (302, 313))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (331, 338))	('cancers', 'Disease', (246, 253))	('ovarian, colon', 'Disease', 'MESH:D010051', (264, 278))	('pancreatic', 'Disease', (290, 300))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (194, 217))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('sporadic breast cancers', 'Disease', (14, 37))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (46, 53))	('cancers', 'Disease', (30, 37))	('male breast cancers', 'Disease', 'MESH:D018567', (319, 338))	('sarcomas', 'Disease', 'MESH:D012509', (343, 351))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (59, 68))	('male breast cancers', 'Disease', (319, 338))	('breast cancers', 'Disease', (39, 53))	('bilateral breast cancer', 'Disease', (194, 217))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', 'MESH:D001943', (23, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (343, 351))	('sarcomas', 'Disease', (343, 351))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('cancers', 'Disease', (331, 338))	('association', 'Interaction', (223, 234))	('prostate', 'Disease', (280, 288))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('breast cancers', 'Disease', 'MESH:D001943', (324, 338))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
56141	32397691	BRCA1 mutations are observed in 6% to 16% of breast cancers diagnosed before the age of 36 years, while BRCA2 mutations account for a similar to the smaller or similar percentage in such young patients.	('patients', 'Species', '9606', (193, 201))	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('BRCA2', 'Gene', '675', (104, 109))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('breast cancers', 'Disease', (45, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('observed', 'Reg', (20, 28))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (6, 15))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
56143	32397691	A multicenter study of 457 Ashkenazi-Jewish women with breast cancer reported that three founder mutations in BRCA1 and BRCA2 were found in over 40% of breast cancers diagnosed before age 40.	('mutations', 'Var', (97, 106))	('found', 'Reg', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BRCA1', 'Gene', '672', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('women', 'Species', '9606', (44, 49))	('BRCA2', 'Gene', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (152, 166))	('BRCA1', 'Gene', (110, 115))	('breast cancers', 'Disease', 'MESH:D001943', (152, 166))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('BRCA2', 'Gene', '675', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('breast cancers', 'Disease', (152, 166))
56145	32397691	A family history of ovarian or breast cancer, especially the number of first-degree relatives with breast cancer diagnosed before age 50, was an important predictor of BRCA1 and BRCA2 germline mutations in both affected and unaffected Ashkenazi-Jewish individuals.	('BRCA1', 'Gene', '672', (168, 173))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('BRCA1', 'Gene', (168, 173))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('BRCA2', 'Gene', (178, 183))	('ovarian or breast cancer', 'Disease', 'MESH:D001943', (20, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('ovarian or breast cancer', 'Disease', (20, 44))	('germline mutations', 'Var', (184, 202))	('BRCA2', 'Gene', '675', (178, 183))
56147	32397691	It has been reported that in Korea, approximately 50% of breast cancer patients with BRCA1/2 mutations were younger than 40 years of age.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (71, 79))	('BRCA1/2', 'Gene', (85, 92))	('BRCA1/2', 'Gene', '672;675', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
56148	32397691	In a Chinese cohort, the mean age at breast cancer diagnosis in BRCA1/2 mutation carriers was 39-45 years, and 56.2% of BRCA1 mutation carriers and 33.3% of BRCA2 mutation carriers were diagnosed with breast cancer before the age of 40 years compared with only 16.4% of non-carriers.	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('mutation', 'Var', (163, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('diagnosed with', 'Reg', (186, 200))	('BRCA2', 'Gene', (157, 162))	('BRCA1/2', 'Gene', (64, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('BRCA1', 'Gene', '672', (120, 125))	('breast cancer', 'Disease', (37, 50))	('BRCA1', 'Gene', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('mutation', 'Var', (72, 80))	('breast cancer', 'Disease', (201, 214))	('BRCA2', 'Gene', '675', (157, 162))	('BRCA1/2', 'Gene', '672;675', (64, 71))	('BRCA1', 'Gene', '672', (64, 69))	('BRCA1', 'Gene', (64, 69))	('mutation', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
56149	32397691	In a Japanese cohort, BRCA1/2 mutation carriers were significantly younger at the time of diagnosis compared with non-carriers.	('mutation', 'Var', (30, 38))	('BRCA1/2', 'Gene', (22, 29))	('BRCA1/2', 'Gene', '672;675', (22, 29))
56150	32397691	A study from the Philippines reported that two-thirds of the Philippino breast cancer patients with BRCA1/2 mutations were under 45 years of age.	('BRCA1/2', 'Gene', (100, 107))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA1/2', 'Gene', '672;675', (100, 107))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('patients', 'Species', '9606', (86, 94))
56151	32397691	Patients with BRCA1/2 mutations have higher incidences of contralateral and second ipsilateral primary breast cancers.	('BRCA1/2', 'Gene', (14, 21))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('breast cancers', 'Disease', (103, 117))	('BRCA1/2', 'Gene', '672;675', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('mutations', 'Var', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))
56152	32397691	BRCA1/2 mutation carriers diagnosed with breast cancer have a long-term risk of developing a contralateral tumor as high as 60% to 70%.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('mutation', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('BRCA1/2', 'Gene', (0, 7))
56154	32397691	BRCA1/2 mutations were found in 22.1% (15/68) of bilateral breast cancer patients in Korea.	('BRCA1/2', 'Gene', '672;675', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bilateral breast cancer', 'Disease', (49, 72))	('mutations', 'Var', (8, 17))	('patients', 'Species', '9606', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (49, 72))	('BRCA1/2', 'Gene', (0, 7))
56158	32397691	However, in a recent large study on Chinese population, there was no difference in tumor size among BRCA1 carriers, BRCA2 carriers, and non-carriers.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BRCA1', 'Gene', '672', (100, 105))	('tumor', 'Disease', (83, 88))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', (116, 121))	('carriers', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('BRCA2', 'Gene', '675', (116, 121))
56159	32397691	Regarding lymph node status, several studies have shown that there was a tendency for BRCA1 mutation carriers to have a higher percentage of lymph node-negative tumors compared with controls.	('BRCA1', 'Gene', '672', (86, 91))	('mutation', 'Var', (92, 100))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('BRCA1', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
56160	32397691	Earlier Chinese and Japanese cohort studies reported no differences in nodal status between BRCA1/2 mutation carriers and non-carriers.	('mutation', 'Var', (100, 108))	('nodal', 'Gene', (71, 76))	('nodal', 'Gene', '4838', (71, 76))	('BRCA1/2', 'Gene', (92, 99))	('BRCA1/2', 'Gene', '672;675', (92, 99))
56161	32397691	However, a recent Chinese study reported a significantly higher rate of lymph node metastasis in BRCA2 mutation carriers compared with BRCA1 carriers and non-carriers.	('BRCA2', 'Gene', (97, 102))	('mutation carriers', 'Var', (103, 120))	('higher', 'PosReg', (57, 63))	('BRCA1', 'Gene', '672', (135, 140))	('BRCA2', 'Gene', '675', (97, 102))	('carriers', 'Var', (112, 120))	('BRCA1', 'Gene', (135, 140))	('lymph node metastasis', 'CPA', (72, 93))
56162	32397691	The reported clinical outcomes of BRCA1/2 mutation carriers and non-carriers with breast cancer have been inconsistent.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BRCA1/2', 'Gene', '672;675', (34, 41))	('mutation', 'Var', (42, 50))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('BRCA1/2', 'Gene', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
56163	32397691	Some studies observed significantly worse survival in BRCA mutation carriers compared with sporadic breast cancer patients, whereas other studies have reported similar outcomes between BRCA mutation carriers and non-carriers.	('survival', 'MPA', (42, 50))	('BRCA', 'Gene', '672', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA', 'Gene', (185, 189))	('carriers', 'Var', (68, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('sporadic breast cancer', 'Disease', (91, 113))	('mutation carriers', 'Var', (59, 76))	('BRCA', 'Gene', '672', (54, 58))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (91, 113))	('patients', 'Species', '9606', (114, 122))	('worse', 'NegReg', (36, 41))	('BRCA', 'Gene', (54, 58))
56165	32397691	A large population-based study reported that 10-year survival rates were similar between BRCA mutation carriers and non-carriers.	('mutation', 'Var', (94, 102))	('BRCA', 'Gene', (89, 93))	('BRCA', 'Gene', '672', (89, 93))
56167	32397691	However, a meta-analysis assessing the effect of BRCA1/2 mutations on survival by Lee et al.	('BRCA1/2', 'Gene', '672;675', (49, 56))	('mutations', 'Var', (57, 66))	('BRCA1/2', 'Gene', (49, 56))
56168	32397691	concluded that BRCA1, but not BRCA2, mutation decreases short-term and long-term overall survivals and short-term progression-free survival.	('mutation', 'Var', (37, 45))	('BRCA1', 'Gene', '672', (15, 20))	('decreases', 'NegReg', (46, 55))	('BRCA2', 'Gene', (30, 35))	('overall survivals', 'CPA', (81, 98))	('BRCA1', 'Gene', (15, 20))	('BRCA2', 'Gene', '675', (30, 35))
56169	32397691	The majority of these results were from Western studies, and there have been few reports comparing the clinical outcomes of BRCA mutation carriers and non-carriers in Asian patients.	('BRCA', 'Gene', (124, 128))	('BRCA', 'Gene', '672', (124, 128))	('patients', 'Species', '9606', (173, 181))	('mutation', 'Var', (129, 137))
56170	32397691	In a Chinese cohort, BRCA1/2 mutation was not associated with breast cancer-specific survival, and BRCA1 mutation was not proven as an independent prognostic factor.	('mutation', 'Var', (29, 37))	('BRCA1/2', 'Gene', '672;675', (21, 28))	('BRCA1', 'Gene', '672', (21, 26))	('BRCA1', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1', 'Gene', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRCA1/2', 'Gene', (21, 28))	('BRCA1', 'Gene', '672', (99, 104))
56171	32397691	Another large Chinese cohort study reported no difference in disease-free survival among BRCA1 carriers, BRCA2 carriers, and non-carriers.	('BRCA1', 'Gene', (89, 94))	('BRCA2', 'Gene', (105, 110))	('carriers', 'Var', (95, 103))	('BRCA2', 'Gene', '675', (105, 110))	('BRCA1', 'Gene', '672', (89, 94))
56172	32397691	General opinion seems to be that BRCA1/2 mutation carriers and non-carriers have a similar prognosis.	('mutation', 'Var', (41, 49))	('BRCA1/2', 'Gene', '672;675', (33, 40))	('BRCA1/2', 'Gene', (33, 40))
56173	32397691	It remains inconclusive whether BRCA mutation carriers are more likely to develop local recurrence than non-carriers.	('local recurrence', 'CPA', (82, 98))	('mutation', 'Var', (37, 45))	('BRCA', 'Gene', '672', (32, 36))	('BRCA', 'Gene', (32, 36))	('develop', 'PosReg', (74, 81))
56174	32397691	Some studies have reported similar rates of local recurrence between BRCA mutation carriers and non-carriers while others have observed more frequent ipsilateral breast cancer recurrence among BRCA mutation carriers.	('mutation', 'Var', (74, 82))	('BRCA', 'Gene', '672', (69, 73))	('BRCA', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('BRCA', 'Gene', (193, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))
56175	32397691	The most common histological subtype in hereditary breast cancers is invasive ductal carcinoma-not otherwise specified, and this type of breast cancer seems to be more frequent in BRCA1/2 mutation carriers than in non-carriers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (69, 94))	('BRCA1/2', 'Gene', '672;675', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('invasive ductal carcinoma', 'Disease', (69, 94))	('hereditary breast cancers', 'Disease', 'MESH:D061325', (40, 65))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (78, 94))	('hereditary breast cancers', 'Disease', (40, 65))	('frequent', 'Reg', (168, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (51, 65))	('common', 'Reg', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('mutation', 'Var', (188, 196))	('BRCA1/2', 'Gene', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))
56177	32397691	In a report by the Breast Cancer Linkage Consortium (BCLC), which is the most extensive series on the histological features of BRCA-associated breast cancer, BRCA1 mutation carriers were found to have a higher incidence of medullary or atypical medullary carcinomas (13%) than BRCA2 carriers (3%) and non-carriers (2%).	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('Breast Cancer', 'Disease', 'MESH:D001943', (19, 32))	('mutation', 'Var', (164, 172))	('BRCA', 'Gene', (277, 281))	('Breast Cancer', 'Disease', (19, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinomas', 'Disease', 'MESH:D009369', (255, 265))	('BRCA', 'Gene', (158, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('BRCA2', 'Gene', (277, 282))	('Breast Cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('medullary or', 'Disease', (223, 235))	('BRCA', 'Gene', '672', (127, 131))	('BRCA2', 'Gene', '675', (277, 282))	('BRCA1', 'Gene', '672', (158, 163))	('BRCA1', 'Gene', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('carcinomas', 'Disease', (255, 265))	('BRCA', 'Gene', (127, 131))	('BRCA', 'Gene', '672', (277, 281))	('BRCA', 'Gene', '672', (158, 162))
56181	32397691	found that pleomorphic lobular carcinomas and extensive intraductal carcinomas were more frequent in BRCA2 mutation carriers.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (23, 40))	('BRCA2', 'Gene', (101, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('pleomorphic lobular carcinomas', 'Disease', 'MESH:D018275', (11, 41))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (61, 77))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (23, 41))	('pleomorphic lobular carcinomas', 'Disease', (11, 41))	('BRCA2', 'Gene', '675', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('ductal carcinomas', 'Disease', 'MESH:D044584', (61, 78))	('carriers', 'Reg', (116, 124))	('frequent', 'Reg', (89, 97))	('ductal carcinomas', 'Disease', (61, 78))	('mutation', 'Var', (107, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
56189	32397691	The incidence of grade III tumors has been reported to range from 66% to 84% in BRCA1 mutation carriers and 30% to 40% in sporadic controls.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('III tumors', 'Disease', (23, 33))	('carriers', 'Reg', (95, 103))	('BRCA1', 'Gene', '672', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('BRCA1', 'Gene', (80, 85))	('mutation', 'Var', (86, 94))	('III tumors', 'Disease', 'MESH:D009369', (23, 33))
56199	32397691	reported that the rate of ER negativity in tumors of BRCA1 carriers, BRCA2 carriers, and non-carriers among Chinese patients was 71.2%, 27.1%, and 42.8%, respectively.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA2', 'Gene', '675', (69, 74))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BRCA1', 'Gene', '672', (53, 58))	('carriers', 'Var', (75, 83))	('ER', 'Gene', '2099', (26, 28))	('tumors', 'Disease', (43, 49))	('BRCA2', 'Gene', (69, 74))	('BRCA1', 'Gene', (53, 58))	('carriers', 'Var', (59, 67))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
56204	32397691	reported the rate of PR negativity in tumors of BRCA1 carriers, BRCA2 carriers, and non-carriers as 71.2%, 31.8%, and 47.7%, respectively.	('BRCA2', 'Gene', '675', (64, 69))	('BRCA1', 'Gene', '672', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('BRCA1', 'Gene', (48, 53))	('carriers', 'Var', (54, 62))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('BRCA2', 'Gene', (64, 69))	('PR', 'Gene', '5241', (21, 23))
56210	32397691	The low incidence of HER2/neu amplification in BRCA1-associated carcinomas may be due to physical codeletion of one HER2/neu allele and nearby sequences during the loss of heterozygosity at the BRCA1 locus as suggested in one study.	('carcinomas', 'Disease', (64, 74))	('BRCA1', 'Gene', (47, 52))	('neu', 'Gene', (121, 124))	('neu', 'Gene', '2064', (26, 29))	('amplification', 'Var', (30, 43))	('neu', 'Gene', (26, 29))	('HER2', 'Gene', (116, 120))	('carcinomas', 'Disease', 'MESH:D009369', (64, 74))	('BRCA1', 'Gene', '672', (194, 199))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', '2064', (116, 120))	('HER2', 'Gene', (21, 25))	('BRCA1', 'Gene', '672', (47, 52))	('BRCA1', 'Gene', (194, 199))	('neu', 'Gene', '2064', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
56213	32397691	Most studies have shown a significantly higher frequency (57% to 75%) of the triple-negative phenotype among BRCA1 mutation carriers (Fig.	('mutation', 'Var', (115, 123))	('BRCA1', 'Gene', '672', (109, 114))	('BRCA1', 'Gene', (109, 114))	('higher', 'PosReg', (40, 46))
56214	32397691	The incidence of BRCA1 mutations in TNBC patients has been reported to be 7.5% to 15.6%.	('BRCA1', 'Gene', '672', (17, 22))	('BRCA1', 'Gene', (17, 22))	('TNBC', 'Disease', (36, 40))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (23, 32))
56215	32397691	evaluated the prevalence of BRCA1/2 mutations in 207 TNBC patients and reported that deleterious BRCA1/2 mutations were present in 15.4% of patients with BRCA1 in 11.1% and BRCA2 in 4.3% of patients.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1/2', 'Gene', (28, 35))	('BRCA1', 'Gene', (154, 159))	('BRCA1/2', 'Gene', (97, 104))	('patients', 'Species', '9606', (190, 198))	('BRCA2', 'Gene', (173, 178))	('BRCA1', 'Gene', (28, 33))	('BRCA1/2', 'Gene', '672;675', (28, 35))	('BRCA1', 'Gene', '672', (97, 102))	('mutations', 'Var', (36, 45))	('mutations', 'Var', (105, 114))	('BRCA2', 'Gene', '675', (173, 178))	('patients', 'Species', '9606', (140, 148))	('BRCA1', 'Gene', (97, 102))	('BRCA1/2', 'Gene', '672;675', (97, 104))	('patients', 'Species', '9606', (58, 66))	('BRCA1', 'Gene', '672', (154, 159))
56217	32397691	A higher incidence of the triple-negative phenotype (50% to 100%) among Asian patients with BRCA1 mutations has also been reported.	('mutations', 'Var', (98, 107))	('patients', 'Species', '9606', (78, 86))	('BRCA1', 'Gene', '672', (92, 97))	('BRCA1', 'Gene', (92, 97))
56218	32397691	The reported incidence of BRCA1 mutation among Asian patients with TNBC is 9.4% to 36.8%.	('patients', 'Species', '9606', (53, 61))	('mutation', 'Var', (32, 40))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA1', 'Gene', (26, 31))
56219	32397691	A recent Chinese cohort study reported the rate of triple-negative phenotype in BRCA1 carriers, BRCA2 carriers, and non-carriers was 61.6%, 23.9%, and 33.1%, respectively.	('carriers', 'Var', (86, 94))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', '672', (80, 85))	('carriers', 'Var', (102, 110))	('BRCA1', 'Gene', (80, 85))	('BRCA2', 'Gene', (96, 101))
56220	32397691	The rate of BRCA1 mutation among patients with TNBC was 11.1%.	('patients', 'Species', '9606', (33, 41))	('mutation', 'Var', (18, 26))	('BRCA1', 'Gene', '672', (12, 17))	('BRCA1', 'Gene', (12, 17))
56224	32397691	Ductal carcinoma in situ (DCIS) around the invasive lesion is reported to be less common in BRCA1 mutation carriers than in controls.	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (0, 16))	('mutation', 'Var', (98, 106))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (7, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('invasive lesion', 'Disease', (43, 58))	('BRCA1', 'Gene', '672', (92, 97))	('invasive lesion', 'Disease', 'MESH:D009361', (43, 58))	('Ductal carcinoma', 'Disease', (0, 16))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 24))	('BRCA1', 'Gene', (92, 97))
56226	32397691	In the BCLC study, BRCA1 mutation carriers showed less DCIS around the invasive cancer compared to controls (41% vs. 56%, p = .001).	('invasive cancer', 'Disease', (71, 86))	('less', 'NegReg', (50, 54))	('invasive cancer', 'Disease', 'MESH:D009362', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutation', 'Var', (25, 33))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCIS', 'MPA', (55, 59))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA1', 'Gene', (19, 24))
56228	32397691	BRCA1 and BRCA2 mutations were found in three (0.8%) and nine (2.4%) of 369 DCIS cases, respectively.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (10, 15))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (16, 25))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('BRCA2', 'Gene', (10, 15))	('found', 'Reg', (31, 36))
56229	32397691	Prophylactic mastectomy specimens have been used to investigate the different stages of breast cancer development in BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('BRCA1/2', 'Gene', '672;675', (117, 124))	('carriers', 'Reg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('mutation', 'Var', (125, 133))
56230	32397691	assessed prophylactic mastectomy specimens of 67 women who had an extremely high genetic risk of breast cancer (66% of patients were BRCA1 or BRCA2 mutation carriers) and reported that one or more types of high-risk histopathological lesions, such as DCIS, LCIS, atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH), were present in 57% of the women.	('hyperplasia', 'Disease', 'MESH:D006965', (319, 330))	('hyperplasia', 'Disease', (279, 290))	('LCIS', 'Disease', (257, 261))	('DCIS', 'Phenotype', 'HP:0030075', (251, 255))	('hyperplasia', 'Disease', 'MESH:D006965', (279, 290))	('women', 'Species', '9606', (49, 54))	('BRCA2', 'Gene', (142, 147))	('women', 'Species', '9606', (365, 370))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('LCIS', 'Phenotype', 'HP:0030076', (257, 261))	('BRCA2', 'Gene', '675', (142, 147))	('BRCA1', 'Gene', '672', (133, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('BRCA1', 'Gene', (133, 138))	('DCIS', 'Disease', (251, 255))	('patients', 'Species', '9606', (119, 127))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Disease', (97, 110))	('hyperplasia', 'Disease', (319, 330))	('mutation', 'Var', (148, 156))
56231	32397691	also reported that lesions with risks of developing subsequent malignancy (DCIS, LCIS, ADH, and ALH) are more common in prophylactic mastectomy specimens from women with BRCA mutations than in autopsy specimens from unaffected women of unknown genetic predisposition.	('LCIS', 'Phenotype', 'HP:0030076', (81, 85))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('LCIS', 'Disease', (81, 85))	('ADH', 'Disease', (87, 90))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('BRCA', 'Gene', '672', (170, 174))	('malignancy', 'Disease', (63, 73))	('BRCA', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('women', 'Species', '9606', (227, 232))	('women', 'Species', '9606', (159, 164))
56232	32397691	evaluated therapeutic mastectomy and prophylactic mastectomy specimens from high-risk women with or without BRCA1/2 mutations.	('BRCA1/2', 'Gene', (108, 115))	('BRCA1/2', 'Gene', '672;675', (108, 115))	('mutations', 'Var', (116, 125))	('women', 'Species', '9606', (86, 91))
56233	32397691	They observed that proliferative fibrocystic changes were less prevalent in BRCA1/2 mutation carriers (7%) than controls (25%) and non-carriers with a family history of breast cancer (22%-33%).	('BRCA1/2', 'Gene', (76, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('proliferative fibrocystic changes', 'Disease', (19, 52))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('fibrocystic changes', 'Phenotype', 'HP:0006552', (33, 52))	('breast cancer', 'Disease', (169, 182))	('less', 'NegReg', (58, 62))	('mutation', 'Var', (84, 92))
56234	32397691	However, the prevalence of DCIS was not different among the groups (50%-60%), and invasive carcinomas were of higher grade in the BRCA1/2 mutation carriers compared with controls and non-carriers.	('invasive carcinomas', 'Disease', (82, 101))	('BRCA1/2', 'Gene', '672;675', (130, 137))	('invasive carcinomas', 'Disease', 'MESH:D009361', (82, 101))	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('BRCA1/2', 'Gene', (130, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('higher', 'PosReg', (110, 116))	('carriers', 'Var', (147, 155))	('mutation carriers', 'Var', (138, 155))
56236	32397691	The comprehensive pathology data of 4,325 BRCA1 and 2,568 BRCA2 mutation carriers were reported in 2012 from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), the most extensive collaborative study of BRCA1 and BRCA2 mutation carriers.	('BRCA1', 'Gene', '672', (42, 47))	('BRCA2', 'Gene', '675', (226, 231))	('BRCA1/2', 'Gene', '672;675', (157, 164))	('mutation', 'Var', (64, 72))	('BRCA1', 'Gene', (157, 162))	('BRCA1', 'Gene', (216, 221))	('BRCA2', 'Gene', '675', (58, 63))	('BRCA1', 'Gene', (42, 47))	('BRCA2', 'Gene', (226, 231))	('BRCA1/2', 'Gene', (157, 164))	('BRCA2', 'Gene', (58, 63))	('BRCA1', 'Gene', '672', (157, 162))	('BRCA1', 'Gene', '672', (216, 221))	('BRCA1 and 2', 'Gene', '672;675', (42, 53))
56237	32397691	In both BRCA1 and BRCA2 carriers diagnosed with breast cancer, invasive ductal carcinoma of no special type was the predominant histologic subtype.	('carriers', 'Var', (24, 32))	('BRCA2', 'Gene', '675', (18, 23))	('invasive ductal carcinoma', 'Disease', (63, 88))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (63, 88))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (72, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('BRCA1', 'Gene', '672', (8, 13))	('breast cancer', 'Disease', (48, 61))	('BRCA2', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('BRCA1', 'Gene', (8, 13))	('diagnosed', 'Reg', (33, 42))
56239	32397691	As for receptor status, 78%, 79%, 90%, and 69% of tumors diagnosed in BRCA1 carriers were ER-negative, PR-negative, HER2-negative, and triple-negative, respectively, whereas 23%, 36%, 87%, and 16% of tumors from BRCA2 carriers were ER-negative, PR-negative, HER2-negative, and triple-negative.	('PR', 'Gene', '5241', (103, 105))	('HER2', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('HER2', 'Gene', (258, 262))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('ER', 'Gene', '2099', (117, 119))	('ER', 'Gene', '2099', (259, 261))	('PR', 'Gene', '5241', (245, 247))	('BRCA2', 'Gene', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('HER2', 'Gene', '2064', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('HER2', 'Gene', '2064', (258, 262))	('BRCA2', 'Gene', '675', (212, 217))	('carriers', 'Var', (76, 84))	('BRCA1', 'Gene', '672', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ER', 'Gene', '2099', (90, 92))	('ER', 'Gene', '2099', (232, 234))	('BRCA1', 'Gene', (70, 75))	('tumors', 'Disease', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
56245	32397691	Among 226 high-risk Hong Kong Chinese women, 28 women (12.4%) carried BRCA mutations (BRCA1 mutation, 11 patients; BRCA2 mutations, 17 patients), and 55.6% of these carriers were diagnosed with breast cancer before age 40 compared with 36.0% of non-carriers (p = .05).	('patients', 'Species', '9606', (135, 143))	('mutation', 'Var', (92, 100))	('BRCA', 'Gene', '672', (86, 90))	('BRCA', 'Gene', '672', (70, 74))	('BRCA2', 'Gene', '675', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('women', 'Species', '9606', (48, 53))	('diagnosed', 'Reg', (179, 188))	('BRCA', 'Gene', '672', (115, 119))	('BRCA', 'Gene', (86, 90))	('women', 'Species', '9606', (38, 43))	('BRCA', 'Gene', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('patients', 'Species', '9606', (105, 113))	('BRCA', 'Gene', (115, 119))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('BRCA2', 'Gene', (115, 120))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA1', 'Gene', (86, 91))	('mutations', 'Var', (75, 84))
56246	32397691	BRCA mutation carriers were more likely to have a family history of breast and ovarian cancers, high-grade cancers, and TNBCs.	('cancers', 'Disease', (87, 94))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('BRCA', 'Gene', (0, 4))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('TNBCs', 'Disease', (120, 125))	('ovarian cancers', 'Phenotype', 'HP:0100615', (79, 94))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (68, 94))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
56248	32397691	ER-negative cancer was significantly associated with BRCA1 mutations, especially in patients under 40 years of age.	('ER', 'Gene', '2099', (0, 2))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('patients', 'Species', '9606', (84, 92))	('cancer', 'Disease', (12, 18))	('BRCA1', 'Gene', '672', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('associated', 'Reg', (37, 47))	('mutations', 'Var', (59, 68))	('BRCA1', 'Gene', (53, 58))
56249	32397691	compared the characteristics of breast cancers from 181 BRCA1/2 mutation carriers cases (80 patients with BRCA1 mutation and 101 patients with BRCA2 mutation) and 55,387 sporadic breast cancers from the Korean Breast Cancer Registry.	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('breast cancers', 'Disease', 'MESH:D001943', (179, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))	('BRCA1', 'Gene', '672', (106, 111))	('Breast Cancer', 'Disease', 'MESH:D001943', (210, 223))	('breast cancers', 'Phenotype', 'HP:0003002', (179, 193))	('BRCA1', 'Gene', (106, 111))	('patients', 'Species', '9606', (92, 100))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (170, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Breast Cancer', 'Disease', (210, 223))	('BRCA2', 'Gene', (143, 148))	('mutation', 'Var', (64, 72))	('mutation', 'Var', (112, 120))	('BRCA1', 'Gene', '672', (56, 61))	('patients', 'Species', '9606', (129, 137))	('BRCA1/2', 'Gene', (56, 63))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('Breast Cancer', 'Phenotype', 'HP:0003002', (210, 223))	('BRCA1', 'Gene', (56, 61))	('breast cancers', 'Disease', 'MESH:D001943', (32, 46))	('breast cancers', 'Disease', (32, 46))	('BRCA2', 'Gene', '675', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('BRCA1/2', 'Gene', '672;675', (56, 63))	('sporadic breast cancers', 'Disease', (170, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (32, 46))
56250	32397691	In this report, median patient age was significantly lower in the BRCA1 and BRCA2 mutation groups than in the registry group (37 years and 41 years vs. 48 years; p < .001 for both).	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', (76, 81))	('mutation', 'Var', (82, 90))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (76, 81))	('lower', 'NegReg', (53, 58))	('patient', 'Species', '9606', (23, 30))
56259	32397691	reported the prevalence of BRCA mutation and features of BRCA-associated breast cancer in Chinese patients by using next-generation sequencing on 2,991 breast cancer patients and 1,043 healthy individuals as controls.	('BRCA', 'Gene', (27, 31))	('BRCA', 'Gene', '672', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('patients', 'Species', '9606', (98, 106))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Disease', (152, 165))	('BRCA', 'Gene', '672', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('mutation', 'Var', (32, 40))	('BRCA', 'Gene', (57, 61))	('patients', 'Species', '9606', (166, 174))
56260	32397691	BRCA mutations were present in 9.1% (232/2,560) of patients with at least one risk factor for hereditary breast cancer compared to 3.5% (15/431) in sporadic patients and 0.38% (4/1,043) in healthy controls.	('hereditary breast cancer', 'Disease', 'MESH:D061325', (94, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('BRCA', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (157, 165))	('hereditary breast cancer', 'Disease', (94, 118))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BRCA', 'Gene', '672', (0, 4))
56261	32397691	Family history of breast/ovarian cancer, young age, negative HER2, high Ki-67 index, and high tumor grade were associated with BRCA mutations.	('breast/ovarian cancer', 'Disease', 'MESH:D001943', (18, 39))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BRCA', 'Gene', '672', (127, 131))	('mutations', 'Var', (132, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('associated', 'Reg', (111, 121))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('HER2', 'Gene', (61, 65))	('Ki-67', 'CPA', (72, 77))	('negative', 'NegReg', (52, 60))	('HER2', 'Gene', '2064', (61, 65))	('breast/ovarian cancer', 'Disease', (18, 39))	('BRCA', 'Gene', (127, 131))
56262	32397691	BRCA1 carriers were more likely to be ER- or PR-negative than BRCA1 non-carriers, whereas BRCA2-mutated breast cancers were more likely to be ER- or PR-positive.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('PR', 'Gene', '5241', (45, 47))	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', (90, 95))	('BRCA1', 'Gene', '672', (62, 67))	('PR', 'Gene', '5241', (149, 151))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ER', 'Gene', '2099', (142, 144))	('BRCA2', 'Gene', '675', (90, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (104, 118))	('BRCA1', 'Gene', (62, 67))	('breast cancers', 'Disease', 'MESH:D001943', (104, 118))	('breast cancers', 'Disease', (104, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('BRCA1', 'Gene', '672', (0, 5))	('carriers', 'Var', (6, 14))	('ER', 'Gene', '2099', (38, 40))
56263	32397691	BRCA1-mutated patients also presented a higher stage at the time of diagnosis, and BRCA2 mutation carriers showed more positive lymph nodes.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (83, 88))	('stage', 'MPA', (47, 52))	('higher', 'PosReg', (40, 46))	('mutation', 'Var', (89, 97))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA2', 'Gene', (83, 88))	('patients', 'Species', '9606', (14, 22))
56264	32397691	There were no differences in disease-free survival among BRCA1 carriers, BRCA2 carriers, and non-carriers.	('BRCA1', 'Gene', (57, 62))	('carriers', 'Var', (63, 71))	('BRCA2', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (73, 78))	('BRCA1', 'Gene', '672', (57, 62))
56265	32397691	However, among the non-TNBC patients, BRCA2 mutation carriers showed decreased disease-free survival compared to BRCA2 mutation non-carriers (hazard ratio, 1.892; 95% confidence interval, 1.132 to 3.161; p = .013).	('mutation', 'Var', (44, 52))	('BRCA2', 'Gene', '675', (38, 43))	('decreased', 'NegReg', (69, 78))	('disease-free survival', 'CPA', (79, 100))	('BRCA2', 'Gene', (113, 118))	('BRCA2', 'Gene', (38, 43))	('patients', 'Species', '9606', (28, 36))	('BRCA2', 'Gene', '675', (113, 118))
56270	32397691	Lifestyle modifiers of breast cancer and estimated penetrance of BRCA mutations in Asians may become clearer with the groups' efforts.	('breast cancer', 'Disease', (23, 36))	('mutations', 'Var', (70, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('BRCA', 'Gene', (65, 69))	('BRCA', 'Gene', '672', (65, 69))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
56277	32397691	Medullary carcinomas are also more frequent in BRCA1 mutation carriers.	('BRCA1', 'Gene', (47, 52))	('carcinomas', 'Disease', 'MESH:D009369', (10, 20))	('mutation', 'Var', (53, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('carcinomas', 'Disease', (10, 20))	('BRCA1', 'Gene', '672', (47, 52))	('frequent', 'Reg', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('carriers', 'Reg', (62, 70))
56310	29178258	IER had higher sensitivity (80.6% vs 75.5%) and specificity (55.8% vs 48.1%) than washout curves for positive nodes, higher specificity (48.1% vs 36.5%) and positive predictive value (70.2% vs 66.7%) for high ki-67, and excellent inter-observer agreement (ICC=0.82).	('higher', 'PosReg', (117, 123))	('ki-67', 'Protein', (209, 214))	('ER', 'Gene', '2099', (1, 3))	('higher', 'PosReg', (8, 14))	('high', 'Var', (204, 208))
56338	29178258	Medical records were reviewed for clinical-pathological data including size, tumor receptor expression (estrogen receptor (ER), progesterone receptor (PR) and HER2 positivity, ki-67, pathology-proven axillary metastases, Oncotype DX score (Genomic Health, Redwood City, CA), and tumor stage.	('HER2', 'Gene', (159, 163))	('metastases', 'Disease', 'MESH:D009362', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('HER2', 'Gene', '2064', (159, 163))	('positivity', 'Var', (164, 174))	('tumor', 'Disease', (279, 284))	('Redwood', 'Species', '28980', (256, 263))	('estrogen receptor', 'Gene', (104, 121))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ER', 'Gene', '2099', (160, 162))	('estrogen receptor', 'Gene', '2099', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('metastases', 'Disease', (209, 219))	('tumor', 'Disease', (77, 82))	('ER', 'Gene', '2099', (123, 125))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
56356	29178258	Overall, IER was significantly higher in invasive cancer than in DCIS (both readers, p<0.001), and higher for invasive cancers and high-grade DCIS when compared to low and intermediate grade DCIS (both readers, p<0.001; Figure 2).	('invasive cancer', 'Disease', 'MESH:D009362', (110, 125))	('ER', 'Gene', '2099', (10, 12))	('high-grade', 'Var', (131, 141))	('higher', 'PosReg', (99, 105))	('invasive cancers', 'Disease', 'MESH:D009362', (110, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('invasive cancer', 'Disease', (41, 56))	('invasive cancers', 'Disease', (110, 126))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('invasive cancer', 'Disease', 'MESH:D009362', (41, 56))	('higher', 'PosReg', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
56364	29178258	IER AUC was significant for each of the four tested clinical factors: biopsy-proven metastatic axillary nodes (AUC 0.720), invasive cancer (AUC 0.798), biologically relevant cancer (AUC 0.797) and high ki-67 (AUC 0.672, all p<0.001).	('cancer', 'Disease', (132, 138))	('invasive cancer', 'Disease', (123, 138))	('invasive cancer', 'Disease', 'MESH:D009362', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('high ki-67', 'Var', (197, 207))	('ER', 'Gene', '2099', (1, 3))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
56366	29178258	IER was less sensitive (60.9% vs 64.7%) but equally specific (88.2%) for biologically relevant cancers, and less sensitive (78.4% vs 81.5%) for high ki-67 but more specific (48.1% vs 36.5%).	('high ki-67', 'Var', (144, 154))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('ER', 'Gene', '2099', (1, 3))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
56382	29178258	IER in our study also correlated with high ki-67, a marker of cell proliferation, and with node-positive invasive cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('invasive cancers', 'Disease', (105, 121))	('ki-67', 'Protein', (43, 48))	('high', 'Var', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ER', 'Gene', '2099', (1, 3))	('invasive cancers', 'Disease', 'MESH:D009362', (105, 121))
56383	29178258	Similar to HER2+ and TNBC, high ki-67 and positive axillary nodes at time of diagnosis are associated with rapid local spread, decreased time to recurrence, and decreased disease-free survival.	('disease-free survival', 'CPA', (171, 192))	('decreased', 'NegReg', (127, 136))	('decreased', 'NegReg', (161, 170))	('high ki-67', 'Var', (27, 37))	('time to recurrence', 'CPA', (137, 155))	('HER2', 'Gene', (11, 15))	('HER2', 'Gene', '2064', (11, 15))
56388	29178258	IER also offers higher specificity and positive predictive value for lesions with high ki-67.	('higher', 'PosReg', (16, 22))	('specificity', 'MPA', (23, 34))	('high', 'Var', (82, 86))	('ki-67', 'Gene', (87, 92))	('ER', 'Gene', '2099', (1, 3))
56460	33618160	Since 2003, BI-RADS has suggested the use of BI-RADS 4 category subdivisions to provide improved stratification of likelihood of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('BI-RADS', 'Var', (45, 52))	('malignancy', 'Disease', (129, 139))
56469	33618160	In a subset of four studies investigating BI-RADS 4 calcifications, an NPV for malignant lesions of 92% was reported and the rate of avoidable biopsies was not assessed.	('calcification', 'Disease', 'MESH:D002114', (52, 65))	('malignant lesions', 'Disease', (79, 96))	('calcification', 'Disease', (52, 65))	('BI-RADS', 'Var', (42, 49))	('malignant lesions', 'Disease', 'MESH:D009369', (79, 96))
56481	33618160	In conclusion, this meta-analysis generally supports the feasibility of CE-MRI of the breast to downgrade BI-RADS 4 mammographic microcalcifications and therefore avoid unnecessary stereotactic biopsies.	('calcification', 'Disease', (134, 147))	('calcification', 'Disease', 'MESH:D002114', (134, 147))	('CE-MRI', 'Var', (72, 78))	('downgrade', 'NegReg', (96, 105))
56485	30987214	We identified significant differences in aligners' performance: HISAT2 was prone to misalign reads to retrogene genomic loci, STAR generated more precise alignments, especially for early neoplasia samples.	('STAR', 'Gene', '6770', (126, 130))	('neoplasia', 'Disease', (187, 196))	('STAR', 'Gene', (126, 130))	('misalign', 'Var', (84, 92))	('precise alignments', 'MPA', (146, 164))	('neoplasia', 'Phenotype', 'HP:0002664', (187, 196))	('neoplasia', 'Disease', 'MESH:D009369', (187, 196))	('more', 'PosReg', (141, 145))
56498	30987214	After the read is completely aligned, STAR joins the two or more "seeds" together and scores the aligned reads based on a user-defined penalty for mismatches, insertions, and deletions.	('STAR', 'Gene', '6770', (38, 42))	('deletions', 'Var', (175, 184))	('STAR', 'Gene', (38, 42))	('insertions', 'Var', (159, 169))	('mismatches', 'Var', (147, 157))
56516	30987214	Between the two aligners tested, HISAT2 consistently had significantly higher amounts of reads aligned to pseudogenes when compared to STAR (Figure 5A).	('higher', 'PosReg', (71, 77))	('STAR', 'Gene', (135, 139))	('STAR', 'Gene', '6770', (135, 139))	('HISAT2', 'Var', (33, 39))
56521	30987214	Differential expression analysis using DESeq2 on pairwise comparisons of STAR alignments revealed 255 transcripts having LFC > 1 and 177 genes with LFC < 1 in normal versus atypia comparisons.	('STAR', 'Gene', (73, 77))	('STAR', 'Gene', '6770', (73, 77))	('LFC > 1', 'Var', (121, 128))
56553	27716309	While telomere shortening represents a mitotic clock and has been associated with increased cancer risk, these associations have, however, been largely inconsistent and only obtained in surrogate tissues such as blood.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('telomere shortening', 'Var', (6, 25))	('associated', 'Reg', (66, 76))	('telomere shortening', 'Phenotype', 'HP:0031413', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
56554	27716309	A recently identified mutational clock-like signature may also approximate a mitotic clock but has not yet been applied to cancer risk prediction.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mitotic clock', 'MPA', (77, 90))	('approximate', 'MPA', (63, 74))	('mutational', 'Var', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
56556	27716309	Indeed, clonal genetic and copy number variation mosaicism has already been associated with the future risk of hematological cancers, and DNAm variability in normal cervical cells has been shown to predict the prospective risk of cervical cancer.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hematological cancers', 'Disease', 'MESH:D009369', (111, 132))	('associated', 'Reg', (76, 86))	('copy number variation mosaicism', 'Var', (27, 58))	('cervical cancer', 'Disease', (230, 245))	('hematological cancers', 'Disease', (111, 132))	('cervical cancer', 'Disease', 'MESH:D002583', (230, 245))	('clonal genetic', 'Var', (8, 22))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
56564	27716309	To this end, we analyzed Illumina 450 k data from a cohort of healthy individuals spanning a wide age range of over 70 years, obtained from purified cells sorted using FACS and representing three different blood cell subtypes (CD4+ T cells, CD14+/CD16- monocytes, and CD19+ B cells) and encompassing 151 independent samples ("Methods").	('CD16', 'Gene', '2214', (247, 251))	('CD4+ T', 'Var', (227, 233))	('CD14', 'Gene', (241, 245))	('CD16', 'Gene', (247, 251))	('CD19', 'Gene', (268, 272))	('CD14', 'Gene', '929', (241, 245))	('CD19', 'Gene', '930', (268, 272))
56600	27716309	That the pcgtAge score could discriminate normal tissue containing such field defects from the normal tissue of age-matched cancer-free women (AUC of 0.66, 95 % CI 0.55-0.77) suggests that epiTOC may serve to assess the risk of neoplastic transformation of normal tissue.	('cancer', 'Disease', (124, 130))	('women', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('defects', 'Var', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
56613	27716309	Importantly, our work has further exposed a subtle difference between promoter CpGs that undergo age-associated hypermethylation from those that undergo hypomethylation, with the analogous model based on age-hypomethylated sites not correlating with the mitotic index in cancer tissue and correspondingly not exhibiting a consistent acceleration in cancer.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('hypermethylation', 'Var', (112, 128))	('cancer', 'Disease', (271, 277))
56614	27716309	In fact, whereas the model based on hypomethylation also correlated with the number of stem cell divisions per stem cell in normal tissues, as well as with exposure to smoking in normal buccal tissue, it is intriguing that no consistent associations were found in cancer or preinvasive cancer lesions.	('cancer lesions', 'Disease', 'MESH:D009062', (286, 300))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer lesions', 'Disease', (286, 300))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('correlated', 'Reg', (57, 67))	('stem cell divisions per stem cell', 'CPA', (87, 120))	('hypomethylation', 'Var', (36, 51))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', (264, 270))
56616	27716309	It will be important for future studies to try to understand this deep and subtle asymmetry between age-associated hyper- and hypomethylation in relation to the changes seen in cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('hypomethylation', 'Var', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
56633	27716309	Both models together are highly consistent with an overarching "phase transition" model of oncogenesis, in which epigenetic clonal mosaicism is maximal before cancer emerges.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('epigenetic clonal', 'Var', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))
56640	27716309	3 above is independent of the sample s; hence, one can write for the cancer risk: and so, if pcgtAge(s1,x) > pcgtAge(s2,x), then the cancer risk (CR) of sample s1 is also greater than that of s2: CR(s1,x) > CR(s2,x).	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CR', 'Chemical', '-', (146, 148))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('pcgtAge(s1,x', 'Var', (93, 105))	('cancer', 'Disease', (133, 139))	('CR', 'Chemical', '-', (207, 209))	('CR', 'Chemical', '-', (196, 198))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (69, 75))
56667	23328585	In vivo binding specificity studies (n=26 tumors) showed that ultrasound imaging signal was significantly higher (P<0.001) using MBVEGFR2 compared to non-targeted microbubbles and imaging signal significantly decreased (P<0.001) by blocking antibodies.	('MBVEGFR2', 'Var', (129, 137))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('higher', 'PosReg', (106, 112))	('binding', 'Interaction', (8, 15))	('ultrasound imaging signal', 'MPA', (62, 87))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('decreased', 'NegReg', (209, 218))
56714	23328585	Following intravenous administration of MBVEGFR2, in vivo ultrasound imaging signal obtained from breast cancers was significantly higher (P<0.001) compared to the signal obtained after MBControl administration (Figure 2).	('breast cancers', 'Disease', (98, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('MBVEGFR2', 'Var', (40, 48))	('rat', 'Species', '10116', (204, 207))	('breast cancers', 'Disease', 'MESH:D001943', (98, 112))	('rat', 'Species', '10116', (30, 33))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('higher', 'PosReg', (131, 137))
56802	22116632	These experiments were optimized and performed as described previously with the following alterations: 15microg of each of the 3 pairs of biological replicates of ERalpha(+) and ERalpha(-) cell extracts were labeled with 200 pmoles of either Cy3 or Cy5.	('ERalpha', 'Gene', (178, 185))	('Cy5', 'Var', (249, 252))	('Cy3', 'Chemical', '-', (242, 245))	('ERalpha', 'Gene', '2099', (178, 185))	('Cy5', 'Chemical', 'MESH:C085321', (249, 252))	('ERalpha', 'Gene', (163, 170))	('Cy3', 'Protein', (242, 245))	('ERalpha', 'Gene', '2099', (163, 170))
56816	22116632	TYK2 knock-down and protein extraction were performed as described previously.	('TYK2', 'Gene', '7297', (0, 4))	('knock-down', 'Var', (5, 15))	('TYK2', 'Gene', (0, 4))
56817	22116632	Migration of TYK2 knocked-down MCF-10A ERalpha (+) breast epithelial cells versus control were assessed by measuring the movement of cells into a scrape, "wound assay".	('MCF-10A', 'Gene', (31, 38))	('knocked-down', 'Var', (18, 30))	('TYK2', 'Gene', '7297', (13, 17))	('MCF-10A ERalpha', 'CellLine', 'CVCL:0598', (31, 46))	('TYK2', 'Gene', (13, 17))
56819	22116632	Matrigel invasion assay (chemoinvasion) of TYK2 knocked-down MCF-10A cells was assessed using BD Fluoroblok inserts (8microm pore size, 24 well format, BD Biosciences) and EGF as chemoattractant.	('MCF-10A', 'CellLine', 'CVCL:0598', (61, 68))	('EGF', 'Gene', (172, 175))	('Matrigel invasion assay', 'CPA', (0, 23))	('TYK2', 'Gene', '7297', (43, 47))	('knocked-down', 'Var', (48, 60))	('TYK2', 'Gene', (43, 47))	('EGF', 'Gene', '1950', (172, 175))
56824	22116632	A 1:1 ratio of collagen gel and TYK2 knocked-down MCF-10A or control cells were added on top of the pre-set layer at time t = 0 min and incubated at 37 C. Complete media was added at time t = 30 min.	('knocked-down', 'Var', (37, 49))	('TYK2', 'Gene', (32, 36))	('TYK2', 'Gene', '7297', (32, 36))	('MCF-10A', 'CellLine', 'CVCL:0598', (50, 57))	('MCF-10A', 'Gene', (50, 57))
56833	22116632	Fifteen microg of proteins from each of the 6 samples were labeled with Cy3 or Cy5 fluorophores.	('Cy3', 'Chemical', '-', (72, 75))	('proteins', 'Protein', (18, 26))	('Cy3', 'Var', (72, 75))	('Cy5', 'Var', (79, 82))	('Cy5', 'Chemical', 'MESH:C085321', (79, 82))
56856	22116632	A general diagram in figure 5 revealed that TYK2 levels were lowest in N1, T2N1/2M0, Stage IIIa, ERalpha(-) breast cancers and highest in normal, benign, and triple(+) breast cancers (one-way ANOVA; P < 0.0001).	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('TYK2', 'Gene', '7297', (44, 48))	('ERalpha', 'Gene', (97, 104))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('Stage IIIa', 'Disease', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lowest', 'NegReg', (61, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ERalpha', 'Gene', '2099', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancers', 'Disease', 'MESH:D001943', (168, 182))	('breast cancers', 'Disease', (168, 182))	('T2N1/2M0', 'Var', (75, 83))	('breast cancers', 'Phenotype', 'HP:0003002', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('TYK2', 'Gene', (44, 48))
56857	22116632	TYK2 knock-down in MCF-10A cells neither affected the levels of ERalpha expression (Fig.	('TYK2', 'Gene', '7297', (0, 4))	('ERalpha', 'Gene', (64, 71))	('knock-down', 'Var', (5, 15))	('TYK2', 'Gene', (0, 4))	('ERalpha', 'Gene', '2099', (64, 71))	('levels', 'MPA', (54, 60))	('MCF-10A', 'CellLine', 'CVCL:0598', (19, 26))
56858	22116632	Some of the initially seeded cells died and most of the cells showed an aggregated morphology in both TYK2 knock-down MCF-10A and control cells.	('knock-down', 'Var', (107, 117))	('MCF-10A', 'CellLine', 'CVCL:0598', (118, 125))	('TYK2', 'Gene', '7297', (102, 106))	('aggregated morphology', 'CPA', (72, 93))	('TYK2', 'Gene', (102, 106))
56859	22116632	Changes in migration and invasion due to TYK2 knock-down were analyzed using a scratch/wound assay and Boyden chamber assay, respectively.	('TYK2', 'Gene', (41, 45))	('migration', 'CPA', (11, 20))	('invasion', 'CPA', (25, 33))	('knock-down', 'Var', (46, 56))	('TYK2', 'Gene', '7297', (41, 45))
56860	22116632	The rate of gap closure of the monolayer decreased by 11.93% at 4 hrs and by 31.08% at 8 hrs in TYK2 knock-down MCF-10A when compared to control cells (Fig.	('TYK2', 'Gene', (96, 100))	('decreased', 'NegReg', (41, 50))	('gap closure of the monolayer', 'CPA', (12, 40))	('TYK2', 'Gene', '7297', (96, 100))	('MCF-10A', 'CellLine', 'CVCL:0598', (112, 119))	('knock-down', 'Var', (101, 111))
56861	22116632	In the Boyden chamber Matrigel invasion (chemoinvasion) assay, knockdown of TYK2 caused a 31.76% decrease in chemoinvasion of mammary epithelial cells (p < 0.05) (Fig.	('TYK2', 'Gene', '7297', (76, 80))	('TYK2', 'Gene', (76, 80))	('decrease', 'NegReg', (97, 105))	('chemoinvasion of mammary epithelial cells', 'MPA', (109, 150))	('knockdown', 'Var', (63, 72))
56893	22116632	We performed morphology, migration, and cell invasion assays in MCF-10A ERalpha(+) breast cells following TYK2 knockdown.	('cell invasion', 'CPA', (40, 53))	('TYK2', 'Gene', (106, 110))	('knockdown', 'Var', (111, 120))	('migration', 'CPA', (25, 34))	('MCF-10A ERalpha', 'CellLine', 'CVCL:0598', (64, 79))	('TYK2', 'Gene', '7297', (106, 110))
56895	22116632	Contrary to the role it plays in the ERalpha(-) de-differentiated cells, TYK2 knock-down in MCF-10A ERalpha(+) mammary epithelial cells caused a statistically significant decrease in migration and chemo-invasion pointing that the role of TYK2 is not independent and that other members of the jak/STAT pathway are involved in the initiation of invasion.	('ERalpha', 'Gene', '2099', (37, 44))	('TYK2', 'Gene', '7297', (73, 77))	('ERalpha', 'Gene', (37, 44))	('knock-down', 'Var', (78, 88))	('decrease', 'NegReg', (171, 179))	('TYK2', 'Gene', (73, 77))	('migration', 'CPA', (183, 192))	('MCF-10A ERalpha', 'CellLine', 'CVCL:0598', (92, 107))	('ERalpha', 'Gene', (100, 107))	('TYK2', 'Gene', '7297', (238, 242))	('ERalpha', 'Gene', '2099', (100, 107))	('TYK2', 'Gene', (238, 242))
56905	21816844	Preclinical studies of HER family-targeting drugs in mammary carcinogenesis demonstrate suppression of 1) ER-negative tumors in HER2-overexpressing mouse strains, 2) ER-negative tumors in mutant-BRCA1/p53+/- mice, and 3) ER-positive tumors in the methylnitrosourea (MNU) rat model; tumors arising in both the MNU and mutant-BRCA1/p53+/- models lack HER2 overexpression.	('methylnitrosourea', 'Chemical', 'MESH:D008770', (247, 264))	('mutant-BRCA1/p53+/-', 'Var', (317, 336))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('carcinogenesis', 'Disease', (61, 75))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutant-BRCA1/p53+/-', 'Var', (188, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))	('MNU', 'Chemical', 'MESH:D008770', (309, 312))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mouse', 'Species', '10090', (148, 153))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Disease', (282, 288))	('MNU', 'Chemical', 'MESH:D008770', (266, 269))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('mice', 'Species', '10090', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('rat', 'Species', '10116', (83, 86))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('rat', 'Species', '10116', (271, 274))
56919	21816844	Dysregulated expression and activity of HER-family members is prevalent in human neoplasia.	('activity', 'MPA', (28, 36))	('expression', 'MPA', (13, 23))	('neoplasia', 'Disease', (81, 90))	('Dysregulated', 'Var', (0, 12))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('human', 'Species', '9606', (75, 80))	('neoplasia', 'Disease', 'MESH:D009369', (81, 90))
56922	21816844	The humanized monoclonal antibody trastuzumab (Herceptin) was the first agent developed for HER2 targeting and has dramatically improved outcomes among women with HER2-positive (defined by HER2 overexpression and/or amplification) breast cancer.	('women', 'Species', '9606', (152, 157))	('trastuzumab', 'Chemical', 'MESH:D000068878', (34, 45))	('human', 'Species', '9606', (4, 9))	('overexpression', 'PosReg', (194, 208))	('outcomes', 'MPA', (137, 145))	('improved', 'PosReg', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('HER2-positive', 'Var', (163, 176))	('Herceptin', 'Chemical', 'MESH:D000068878', (47, 56))	('breast cancer', 'Disease', (231, 244))
56938	21816844	Two subsequent studies examined the EGFR inhibitor gefitinib in the FVB MMTV/neu and BALB/c MMTV/neuT mouse models of breast cancer, in which tumor formation is driven by expression of the wild-type (in the FVB MMTV/neu model) or mutationally activated (in the BALB/c MMTV/neuT model) rat HER2 homolog.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MMTV', 'Species', '11757', (268, 272))	('MMTV', 'Species', '11757', (72, 76))	('gefitinib', 'Chemical', 'MESH:D000077156', (51, 60))	('tumor', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mouse', 'Species', '10090', (102, 107))	('MMTV', 'Species', '11757', (211, 215))	('MMTV', 'Species', '11757', (92, 96))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('EGFR', 'Gene', (36, 40))	('breast cancer', 'Disease', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('mutationally', 'Var', (230, 242))	('rat', 'Species', '10116', (285, 288))
56949	21816844	All of the studies discussed above utilized HER2-overexpressing mouse strains, a rational choice based on a predicted model in which ErbB inhibitors suppress HER2 signaling via modulation of EGFR-HER2 heterodimers.	('suppress', 'NegReg', (149, 157))	('ErbB', 'Gene', (133, 137))	('rat', 'Species', '10116', (81, 84))	('EGFR-HER2', 'Gene', (191, 200))	('EGFR-HER2', 'Gene', '13649;13866', (191, 200))	('heterodimers', 'Interaction', (201, 213))	('HER2 signaling', 'MPA', (158, 172))	('inhibitors', 'Var', (138, 148))	('mouse', 'Species', '10090', (64, 69))
56962	21816844	This group found that EGFR expression increased in cultured mammary epithelial cells in response to small-interfering RNA (siRNA)-mediated BRCA1 depletion, particularly in the subset expressing the putative stem cell marker aldehyde dehydrogenase 1 (ALDH1).	('aldehyde dehydrogenase 1', 'Gene', (224, 248))	('aldehyde dehydrogenase 1', 'Gene', '216', (224, 248))	('BRCA1', 'Gene', (139, 144))	('expression', 'MPA', (27, 37))	('ALDH1', 'Gene', (250, 255))	('depletion', 'Var', (145, 154))	('ALDH1', 'Gene', '216', (250, 255))	('increased', 'PosReg', (38, 47))	('EGFR', 'Gene', (22, 26))
56963	21816844	Corresponding EGFR upregulation occurred in the acini of BRCA1-deficient mammary glands from MMTV/Cre, BRCA1flox/flox/p53+/- mice.	('MMTV', 'Species', '11757', (93, 97))	('deficient mammary glands', 'Phenotype', 'HP:0100783', (63, 87))	('mice', 'Species', '10090', (125, 129))	('upregulation', 'PosReg', (19, 31))	('BRCA1-deficient', 'Disease', (57, 72))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (57, 72))	('BRCA1flox/flox/p53+/-', 'Var', (103, 124))
56967	21816844	This study suggests the exciting possibility that EGFR inhibition may be a viable strategy for reducing ER-negative breast cancer risk in carriers of mutant-BRCA1 alleles.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('rat', 'Species', '10116', (84, 87))	('mutant-BRCA1', 'Gene', (150, 162))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('mutant-BRCA1', 'Var', (150, 162))
57000	21816844	These results suggest that HER2-positive, ER-negative tumors are more sensitive (versus HER2-positive, ER-positive tumors) to lapatinib, as is supported by some evidence from the therapeutic setting.	('lapatinib', 'Chemical', 'MESH:D000077341', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('more', 'PosReg', (65, 69))	('HER2-positive', 'Var', (27, 40))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('sensitive', 'MPA', (70, 79))	('tumors', 'Disease', (54, 60))
57012	21816844	Indeed, the NSABP is currently testing trastuzumab in an ongoing phase III trial in women with HER2-positive DCIS (NSABP B-43, NCT00769379), and investigators at M. D. Anderson Cancer Center are conducting a phase II multi-center pre-surgical trial of lapatinib in patients with EGFR- or HER2-positive DCIS (NCT00555152).	('HER2-positive', 'Var', (288, 301))	('Cancer', 'Disease', 'MESH:D009369', (177, 183))	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (84, 89))	('patients', 'Species', '9606', (265, 273))	('lapatinib', 'Chemical', 'MESH:D000077341', (252, 261))	('Cancer', 'Disease', (177, 183))	('trastuzumab', 'Chemical', 'MESH:D000068878', (39, 50))
57018	21816844	Risk models integrating family history, breast density, target-tissue markers, and germline changes (e.g., BRCA mutations and single-nucleotide polymorphisms) are helping to identify high breast-cancer risk.	('BRCA', 'Gene', '672', (107, 111))	('breast-cancer', 'Disease', 'MESH:D001943', (188, 201))	('BRCA', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('single-nucleotide polymorphisms', 'Var', (126, 157))	('rat', 'Species', '10116', (17, 20))	('breast-cancer', 'Disease', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
57093	19137376	The calculated probabilities for the different cases were: C11 pn = 0.97, C12 pn = 0.83, C15 pn = 0.56, and C19 pn = 0.64.	('C15', 'Gene', '51316', (89, 92))	('C19 pn', 'Var', (108, 114))	('C11', 'Gene', '1109', (59, 62))	('C12', 'Var', (74, 77))	('C15', 'Gene', (89, 92))	('C11', 'Gene', (59, 62))
57101	19137376	The calculated probabilities of missing the tumor for the different cases were: C11 pn = 0.97, C15 pn = 0.56, and C19 pn = 0.64.	('C15', 'Gene', '51316', (95, 98))	('C11', 'Gene', '1109', (80, 83))	('C19 pn', 'Var', (114, 120))	('C11', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('C15', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
57169	31827233	CCR2 knockdown in breast cancer cells inhibited tumor growth and invasion without significantly affecting the immune and angiogenic microenvironments.	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('knockdown', 'Var', (5, 14))	('breast cancer', 'Disease', (18, 31))	('CCR2', 'Gene', (0, 4))	('inhibited', 'NegReg', (38, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
57179	31827233	CCR2 knockdown inhibited mammary tumor growth, and according to H&E stain, inhibited tumor invasion and stromal reactivity (Figures 1C-D).	('tumor', 'Disease', (85, 90))	('inhibited', 'NegReg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('knockdown', 'Var', (5, 14))	('H&E', 'Chemical', 'MESH:D006371', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('CCR2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
57180	31827233	CCR2 knockdown decreased tumor cell proliferation (Figures 1E).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('knockdown', 'Var', (5, 14))	('rat', 'Species', '10116', (43, 46))	('CCR2', 'Gene', (0, 4))	('decreased tumor', 'Disease', (15, 30))	('decreased tumor', 'Disease', 'MESH:D002303', (15, 30))
57182	31827233	CCR2 knockdown increased numbers of overall and activated CD8+ T cells but not CD4+ T cells (Figure 2D-E).	('CD8', 'Gene', (58, 61))	('CD4', 'Gene', (79, 82))	('knockdown', 'Var', (5, 14))	('CD4', 'Gene', '920', (79, 82))	('CCR2', 'Gene', (0, 4))	('increased', 'PosReg', (15, 24))	('CD8', 'Gene', '925', (58, 61))	('activated', 'PosReg', (48, 57))
57184	31827233	Overall, CCR2 knockdown in PyVmT mammary tumors inhibited mammary tumor growth and invasion, decreased M2 macrophages, elevated cytotoxic T cells and decreased angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (41, 47))	('angiogenesis', 'CPA', (160, 172))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('P', 'Chemical', 'MESH:D010758', (27, 28))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('decreased', 'NegReg', (150, 159))	('CCR2', 'Gene', (9, 13))	('tumor', 'Disease', (41, 46))	('M2 macrophages', 'MPA', (103, 117))	('elevated', 'PosReg', (119, 127))	('decreased', 'NegReg', (93, 102))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cytotoxic T cells', 'CPA', (128, 145))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('knockdown', 'Var', (14, 23))
57192	31827233	CCR2 deficiency in PyVmT and DCIS.com cells elevated CD154 expression but did not affect CCL2 expression (Figure 4A-C, Supplemental Figure 4A-B).	('CD154', 'Gene', (53, 58))	('deficiency', 'Var', (5, 15))	('elevated', 'PosReg', (44, 52))	('DCIS.com', 'CellLine', 'CVCL:5552', (29, 37))	('expression', 'MPA', (59, 69))	('P', 'Chemical', 'MESH:D010758', (19, 20))
57193	31827233	CCR2 knockdown did not affect proliferation (Figure 4D) but inhibited wound closure migration, which was rescued with CD154 antibody neutralization (Figure 4E, Supplemental Figure 4C), and with CD154 shRNA knockdown (Figure 4F-G).	('CD154', 'Gene', (118, 123))	('knockdown', 'Var', (5, 14))	('wound closure migration', 'CPA', (70, 93))	('rat', 'Species', '10116', (37, 40))	('CCR2', 'Gene', (0, 4))	('inhibited', 'NegReg', (60, 69))	('inhibited wound closure', 'Phenotype', 'HP:0001058', (60, 83))	('N', 'Chemical', 'MESH:D009584', (203, 204))	('neutralization', 'Var', (133, 147))	('rat', 'Species', '10116', (87, 90))
57195	31827233	CCL2 knockdown in CCR2 expressing mammary carcinoma cells inhibited cell migration but not cell proliferation (Figure 5A-C, Supplemental Figure 4D-E).	('cell migration', 'CPA', (68, 82))	('rat', 'Species', '10116', (103, 106))	('rat', 'Species', '10116', (76, 79))	('carcinoma', 'Disease', (42, 51))	('knockdown', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('carcinoma', 'Disease', 'MESH:D009369', (42, 51))	('inhibited', 'NegReg', (58, 67))	('CCR2', 'Gene', (18, 22))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (34, 51))
57196	31827233	CCL2 knockdown did not affect wound closure in CCR2-deficient cells, confirming specificity for CCL2/CCR2 signaling in mammary carcinoma cells (Figure 5D).	('carcinoma', 'Disease', (127, 136))	('knockdown', 'Var', (5, 14))	('carcinoma', 'Disease', 'MESH:D009369', (127, 136))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (119, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
57200	31827233	CCR2 knockout in DCIS.com cells or CCR2 siRNA knockdown in PyVmT cells increased CD154 expression corresponding to increased NFATc1 and NF-KappaB activity (Supplemental Figure 5A).	('CCR2', 'Gene', (35, 39))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('NF-KappaB', 'Gene', '4790', (136, 145))	('CD154', 'Gene', (81, 86))	('knockdown', 'Var', (46, 55))	('increased', 'PosReg', (115, 124))	('activity', 'MPA', (146, 154))	('P', 'Chemical', 'MESH:D010758', (59, 60))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('expression', 'MPA', (87, 97))	('NFATc1', 'Gene', (125, 131))	('NFATc1', 'Gene', '4772', (125, 131))	('DCIS.com', 'CellLine', 'CVCL:5552', (17, 25))	('increased', 'PosReg', (71, 80))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('NF-KappaB', 'Gene', (136, 145))
57203	31827233	Bay11-7082 decreased NFATc1 expression, consistent with studies showing that NF-KappaB regulates NFATc1 expression and activity.	('Bay11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('NF-KappaB', 'Gene', '4790', (77, 86))	('decreased', 'NegReg', (11, 20))	('NFATc1', 'Gene', (21, 27))	('NFATc1', 'Gene', '4772', (21, 27))	('expression', 'MPA', (104, 114))	('activity', 'MPA', (119, 127))	('NFATc1', 'Gene', '4772', (97, 103))	('NF-KappaB', 'Gene', (77, 86))	('Bay11-7082', 'Var', (0, 10))	('NFATc1', 'Gene', (97, 103))
57214	31827233	CCL2 knockdown in PyVmT cells inhibited endothelial cell invasion, which was rescued with CCL2 treatment (Figure 6A).	('CCL2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (30, 39))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('endothelial cell invasion', 'CPA', (40, 65))
57220	31827233	PyVmT cells induced robust macrophage recruitment, which was decreased with CCR2 knockdown.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('knockdown', 'Var', (81, 90))	('CCR2', 'Gene', (76, 80))	('macrophage recruitment', 'CPA', (27, 49))
57222	31827233	CCL2 knockdown in PyVmT cells inhibited macrophage recruitment, which was not rescued with recombinant CCL2 treatment (Figure 6B).	('CCL2', 'Gene', (0, 4))	('macrophage recruitment', 'CPA', (40, 62))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (30, 39))	('P', 'Chemical', 'MESH:D010758', (18, 19))
57225	31827233	Arginase I expression was rescued with CD154 antibody neutralization and with CD154 knockdown in PyVmT cells.	('CD154', 'Gene', (39, 44))	('Arginase I', 'Gene', (0, 10))	('rescued', 'PosReg', (26, 33))	('CD154', 'Gene', (78, 83))	('expression', 'MPA', (11, 21))	('knockdown', 'Var', (84, 93))	('Arginase I', 'Gene', '11846', (0, 10))	('neutralization', 'Var', (54, 68))	('P', 'Chemical', 'MESH:D010758', (97, 98))
57229	31827233	CCR2 knockdown in PyVmT cells reduced tumor cell proliferation, associated with decreased macrophage recruitment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('rat', 'Species', '10116', (56, 59))	('knockdown', 'Var', (5, 14))	('CCR2', 'Gene', (0, 4))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('decreased', 'NegReg', (80, 89))	('macrophage recruitment', 'CPA', (90, 112))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('reduced', 'NegReg', (30, 37))
57231	31827233	CCL2 knockdown in PyVmT cells inhibited macrophage-mediated tumor cell proliferation.	('CCL2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('rat', 'Species', '10116', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
57235	31827233	CCR2 knockdown in PyVmT cells in co-cultures inhibited tumor cell invasion, which was rescued with CD154 antibody neutralization, and with CD154 shRNA knockdown.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('knockdown', 'Var', (5, 14))	('CCR2', 'Gene', (0, 4))	('tumor', 'Disease', (55, 60))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('inhibited', 'NegReg', (45, 54))
57236	31827233	CCL2 knockdown in PyVmT cells inhibited tumor cell invasion, which was rescued with CCL2 treatment (Figure 7B).	('CCL2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
57272	31827233	As breast tumors are often poor in T cell infiltrates, targeting CCR2 could restore an immunogenic microenvironment by preventing tumor cell cooption of endothelium and macrophages.	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('immunogenic microenvironment', 'MPA', (87, 115))	('breast tumors', 'Phenotype', 'HP:0100013', (3, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('breast tumor', 'Phenotype', 'HP:0100013', (3, 15))	('breast tumors', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('restore', 'PosReg', (76, 83))	('preventing', 'NegReg', (119, 129))	('CCR2', 'Gene', (65, 69))	('breast tumors', 'Disease', (3, 16))	('targeting', 'Var', (55, 64))	('rat', 'Species', '10116', (48, 51))
57279	31827233	Thus, targeting CCR2 could have wide reaching effects on cancer that could be translated to the clinic.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('CCR2', 'Gene', (16, 20))	('cancer', 'Disease', (57, 63))	('targeting', 'Var', (6, 15))	('effects', 'Reg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
57302	31827233	Cells were serum starved for 24 hours and scratched in DMEM/1% FBS with or without 3 mug/ml CD154, 1 mug/ml anti-CD154 (BD Biosciences cat no.552559) or control mouse IgG (Millipore cat no.12-371).	('DMEM', 'Chemical', '-', (55, 59))	('CD154', 'Var', (92, 97))	('rat', 'Species', '10116', (44, 47))	('anti-CD154', 'Var', (108, 118))	('mouse', 'Species', '10090', (161, 166))
57306	31827233	CD154 expression was detected using anti-CD154 (BD Biosciences cat no.552559) and rabbit biotinylated antibodies bound to streptavidin-peroxidase (Vector Laboratories, cat no.PK-6100).	('anti-CD154', 'Var', (36, 46))	('P', 'Chemical', 'MESH:D010758', (175, 176))	('expression', 'MPA', (6, 16))	('CD154', 'Gene', (0, 5))	('rat', 'Species', '10116', (158, 161))
57320	31827233	The following chemicals were obtained: Cyclosporin A (TCI Chemical cat no.C2408), Bay11-7082 (Enzo cat no.E1279), PP2 (Tocris cat no.1407), Go 6983 (Cayman Chemical cat no.13311), INCB3284 (Cayman Chemical cat no.1163).	('C2408', 'Chemical', '-', (74, 79))	('TCI', 'Gene', '6947', (54, 57))	('TCI', 'Gene', (54, 57))	('INCB3284', 'Chemical', 'MESH:C000595924', (180, 188))	('Cyclosporin A', 'Chemical', 'MESH:D016572', (39, 52))	('PP2', 'Gene', (114, 117))	('PP2', 'Gene', '4888', (114, 117))	('E1279', 'Chemical', '-', (106, 111))	('Go 6983', 'Chemical', 'MESH:C465664', (140, 147))	('Bay11-7082', 'Chemical', 'MESH:C434003', (82, 92))	('Bay11-7082', 'Var', (82, 92))
57393	21840986	In summary, while gain of both ERalpha and aromatase activate abnormal growth pathways in the mammary gland, aromatase induced a wider range of abnormalities that was associated with a higher prevalence of mammary preneoplasia and cancer progression.	('mammary preneoplasia', 'Disease', 'MESH:D015674', (206, 226))	('aromatase', 'Var', (109, 118))	('associated with', 'Reg', (167, 182))	('growth pathways', 'Pathway', (71, 86))	('preneoplasia and cancer', 'Disease', 'MESH:D009369', (214, 237))	('mammary preneoplasia', 'Disease', (206, 226))	('abnormal growth', 'Phenotype', 'HP:0001507', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
57404	21840986	Deregulated estrogen and progesterone signaling contributes to breast cancer pathophysiology.	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('progesterone', 'Chemical', 'MESH:D011374', (25, 37))
57414	21840986	In the first transgenic mouse model of mammary-targeted aromatase, murine aromatase produced mammary gland hyperplasia.	('mouse', 'Species', '10090', (24, 29))	('hyperplasia', 'Disease', (107, 118))	('mammary gland hyperplasia', 'Phenotype', 'HP:0010313', (93, 118))	('murine', 'Species', '10090', (67, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (107, 118))	('murine aromatase', 'Var', (67, 83))	('transgenic', 'Species', '10090', (13, 23))
57432	21840986	Real-Time PCR Taqman Gene Expression Assays (ABI Prism 7700): COX-2 (Ptgs2) (Mm01307329_m1), PR (Pgr) (Mn00435625_m1), Pgr-b isoform (forward: TGGACTCAGGTCCCTTCCAA, reverse: CGTCCAGGGAGATCGGTATAGG, reporter: ACGTGTCGTCTGTAGTCTC), RANKL [TNF ligand superfamily member 11 (Tnfsf11)](Mm01313944_g1), wingless-related MMTV integration site 4 (Wnt4) (Mm01194003_m1), amphiregulin (Areg) (Mm00437583_m1), c-myc (myelocytomatosis oncogene) (Myc) (Mm00487804_m1), cyclin D1 (Ccnd1) (Mm00432360_m1), Erbb2 (Mm0065854_m1), and eukaryotic 18s rRNA (Hs99999901_s1).	('Areg', 'Gene', (376, 380))	('Mm00487804_m1', 'Var', (440, 453))	('cyclin D1', 'Gene', (456, 465))	('Wnt4', 'Gene', '22417', (339, 343))	('amphiregulin', 'Gene', (362, 374))	('Ccnd1', 'Gene', '12443', (467, 472))	('myc', 'Gene', '17869', (401, 404))	('amphiregulin', 'Gene', '11839', (362, 374))	('Ptgs2', 'Gene', '19225', (69, 74))	('Tnfsf11', 'Gene', '21943', (271, 278))	('myc', 'Gene', (401, 404))	('COX-2', 'Gene', (62, 67))	('Pgr', 'Gene', (97, 100))	('PR', 'Gene', '18667', (93, 95))	('Pgr', 'Gene', (119, 122))	('Mm01194003_m1', 'Var', (346, 359))	('Myc', 'Gene', (434, 437))	('wingless-related MMTV integration site 4', 'Gene', '22417', (297, 337))	('Pgr', 'Gene', '18667', (97, 100))	('Hs99999901_s1', 'Var', (538, 551))	('myelocytomatosis oncogene', 'Disease', (406, 431))	('Ptgs2', 'Gene', (69, 74))	('Erbb2', 'Gene', '13866', (491, 496))	('myelocytomatosis oncogene', 'Disease', 'MESH:D000074723', (406, 431))	('Areg', 'Gene', '11839', (376, 380))	('Pgr', 'Gene', '18667', (119, 122))	('Mm00432360_m1', 'Var', (475, 488))	('Myc', 'Gene', '17869', (434, 437))	('Wnt4', 'Gene', (339, 343))	('Mm00437583_m1', 'Var', (383, 396))	('Mm0065854_m1', 'Var', (498, 510))	('COX-2', 'Gene', '17709', (62, 67))	('cyclin D1', 'Gene', '12443', (456, 465))	('Erbb2', 'Gene', (491, 496))	('wingless-related MMTV integration site 4', 'Gene', (297, 337))	('Tnfsf11', 'Gene', (271, 278))	('Ccnd1', 'Gene', (467, 472))
57439	21840986	Primary antibodies: ERalpha (sc-542); PR (sc-538); Her2/Neu (sc-284); E-Cadherin (sc-7870); Cyclin E (sc-481); CDK2 (sc-163); E2F-1 (sc-193); Retinoblastoma (Rb) (sc-50) (Santa Cruz Biotechnology, Inc.), CA; p-STAT3 (D3A7); STAT3 (#9132); p-STAT5 (C11C5); STAT5 (#9363); p-Rb (Ser807/811) (Cell Signaling Technology, Inc., MA); aromatase antibody Ab677: a gift from Dr. Dean B. Evans, Novartis, Basel, Switzerland; KI-67 (RTU-Ki67-MM1) (Novocastra, UK); Cyclin D1 (RM-9104-S) (Thermo Scientific, CA); COX-2 (#160126) (Cayman Chemical, MI).	('sc-50', 'Species', '1010616', (163, 168))	('STAT5', 'Gene', (241, 246))	('CDK2', 'Gene', '12566', (111, 115))	('STAT3', 'Gene', (224, 229))	('#160126', 'Var', (508, 515))	('E2F-1', 'Gene', (126, 131))	('RTU-Ki67-MM1', 'Gene', (422, 434))	('p-Rb', 'Gene', '18667', (271, 275))	('STAT5', 'Gene', (256, 261))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (142, 156))	('Her2', 'Gene', '13866', (51, 55))	('KI-67', 'Gene', '17345', (415, 420))	('STAT5', 'Gene', '20850', (241, 246))	('E-Cadherin', 'Gene', '12550', (70, 80))	('STAT3', 'Gene', '20848', (210, 215))	('RTU-Ki67-MM1', 'Gene', '17345', (422, 434))	('Cyclin D1', 'Gene', '12443', (454, 463))	('STAT5', 'Gene', '20850', (256, 261))	('CDK2', 'Gene', (111, 115))	('Her2', 'Gene', (51, 55))	('COX-2', 'Gene', '17709', (501, 506))	('E-Cadherin', 'Gene', (70, 80))	('p-Rb', 'Gene', (271, 275))	('STAT3', 'Gene', '20848', (224, 229))	('Novartis', 'Disease', 'None', (385, 393))	('Novartis', 'Disease', (385, 393))	('Retinoblastoma', 'Disease', 'MESH:D012175', (142, 156))	('STAT3', 'Gene', (210, 215))	('Retinoblastoma', 'Disease', (142, 156))	('E2F-1', 'Gene', '13555', (126, 131))	('PR', 'Gene', '18667', (38, 40))	('Cyclin D1', 'Gene', (454, 463))	('KI-67', 'Gene', (415, 420))	('COX-2', 'Gene', (501, 506))
57459	21840986	Aromatase expression resulted in a higher prevalence of diffuse ductal disease (47%) as compared to ERalpha over-expression (6%, P<0.0001) (Fig.	('Aromatase', 'Gene', (0, 9))	('diffuse ductal disease', 'Disease', (56, 78))	('Aromatase', 'Gene', '13075', (0, 9))	('diffuse ductal disease', 'Disease', 'MESH:D044584', (56, 78))	('expression', 'Var', (10, 20))
57467	21840986	Serum 17beta-estradiol levels were increased over three-fold in the mice exposed to 17beta-estradiol while no significant differences were found between non-exposed WT, CERM and Arom mice (Fig.	('mice', 'Species', '10090', (68, 72))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (6, 22))	('increased', 'PosReg', (35, 44))	('17beta-estradiol', 'Var', (84, 100))	('mice', 'Species', '10090', (183, 187))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (84, 100))	('Serum 17beta-estradiol levels', 'MPA', (0, 29))
57482	21840986	The proliferative index (PI) was highest in Arom (21 +- 1%) as compared to CERM (12.5 +- 0.9) and WT (2.2 +- 0.3) mice (Fig.	('Arom', 'Var', (44, 48))	('mice', 'Species', '10090', (114, 118))	('proliferative index', 'CPA', (4, 23))
57486	21840986	Arom mice also demonstrated a statistically significant increase in nuclear localized p-Rb protein (44 +- 5%) as compared to CERM (19.9+-0.9%) and WT (8+-2%) mice.	('p-Rb', 'Gene', '18667', (86, 90))	('increase', 'PosReg', (56, 64))	('nuclear localized', 'MPA', (68, 85))	('mice', 'Species', '10090', (158, 162))	('p-Rb', 'Gene', (86, 90))	('mice', 'Species', '10090', (5, 9))	('Arom', 'Var', (0, 4))
57487	21840986	Phosphorylation of Rb leads to release of E2F-1, which in turn facilitates the transcription of genes necessary for entry into the S phase of the cell cycle.	('transcription of genes', 'MPA', (79, 101))	('Phosphorylation', 'Var', (0, 15))	('facilitates', 'PosReg', (63, 74))	('E2F-1', 'Gene', (42, 47))	('E2F-1', 'Gene', '13555', (42, 47))	('release', 'MPA', (31, 38))
57491	21840986	In contrast, relative levels of p-ERK1/2, p-IGFR, p-STAT3 and p-STAT5 were increased in both Arom and CERM mice.	('STAT5', 'Gene', (64, 69))	('p-ERK1/2', 'Var', (32, 40))	('STAT3', 'Gene', (52, 57))	('STAT5', 'Gene', '20850', (64, 69))	('p-IGFR', 'Var', (42, 48))	('mice', 'Species', '10090', (107, 111))	('increased', 'PosReg', (75, 84))	('STAT3', 'Gene', '20848', (52, 57))
57495	21840986	The ERalpha antagonist ICI 182,780 resulted in a modest regression of the mammary gland ductal tree in both CERM and Arom mice with no changes in DH incidence (Fig.	('mice', 'Species', '10090', (122, 126))	('DH', 'Disease', 'MESH:D065630', (146, 148))	('ICI', 'Chemical', '-', (23, 26))	('ICI', 'Var', (23, 26))	('regression', 'NegReg', (56, 66))
57502	21840986	Differences in activation of downstream signaling pathways were correlated with a higher prevalence of preneoplasia and cancer in mice with mammary-targeted aromatase expression as compared to ERalpha over-expression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mice', 'Species', '10090', (130, 134))	('activation', 'PosReg', (15, 25))	('downstream signaling pathways', 'Pathway', (29, 58))	('preneoplasia and cancer', 'Disease', 'MESH:D009369', (103, 126))	('expression', 'Var', (167, 177))	('mammary-targeted', 'Var', (140, 156))
57506	21840986	In women, DH and DCIS lesions in the breast are associated with increased risk of invasive breast cancer development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('invasive breast cancer', 'Disease', (82, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('invasive breast cancer', 'Disease', 'MESH:D001943', (82, 104))	('DCIS lesions', 'Var', (17, 29))	('women', 'Species', '9606', (3, 8))	('DH', 'Disease', 'MESH:D065630', (10, 12))
57508	21840986	Our investigations identified local aromatase expression as a more potent inducer of DH, HANs, and invasive cancers than ERalpha over-expression.	('expression', 'Var', (46, 56))	('local aromatase', 'Protein', (30, 45))	('invasive cancers', 'Disease', (99, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('DH', 'Disease', 'MESH:D065630', (85, 87))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('inducer', 'PosReg', (74, 81))	('invasive cancers', 'Disease', 'MESH:D009362', (99, 115))	('HANs', 'Disease', (89, 93))
57526	21840986	Rates of mammary epithelial cell proliferation were higher in Arom mice as compared to CERM mice.	('mice', 'Species', '10090', (67, 71))	('Arom', 'Var', (62, 66))	('higher', 'PosReg', (52, 58))	('mammary epithelial cell proliferation', 'CPA', (9, 46))	('mice', 'Species', '10090', (92, 96))
57529	21840986	E2F-1 deregulation may be involved in the progression of breast cancer because its expression levels are higher in DCIS and invasive cancers then in the normal breast.	('breast cancer', 'Disease', (57, 70))	('involved', 'Reg', (26, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('deregulation', 'Var', (6, 18))	('higher', 'PosReg', (105, 111))	('expression levels', 'MPA', (83, 100))	('E2F-1', 'Gene', (0, 5))	('invasive cancers', 'Disease', 'MESH:D009362', (124, 140))	('E2F-1', 'Gene', '13555', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('DCIS', 'Disease', (115, 119))	('invasive cancers', 'Disease', (124, 140))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
57554	32020054	Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC while overexpression is sufficient to increase growth in nulliparous hosts.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('decreases tumor', 'Disease', 'MESH:D002303', (59, 74))	('BC', 'Phenotype', 'HP:0003002', (98, 100))	('silencing', 'Var', (39, 48))	('decreases tumor', 'Disease', (59, 74))	('SEMA7A', 'Gene', (52, 58))	('PPBC', 'Chemical', '-', (96, 100))
57557	32020054	Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts.	('co-expression', 'Var', (22, 35))	('COX-2', 'Gene', (46, 51))	('COX-2', 'Gene', '5743', (46, 51))	('FN', 'Gene', '2335', (52, 54))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patient', 'Species', '9606', (100, 107))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
57563	32020054	Since the MCF10DCIS model initially resembles ductal carcinoma in situ (DCIS), which progresses to ER/PR/HER2 negative invasive ductal carcinoma (IDC), we utilized this model to show accelerated tumor growth and progression to IDC in postpartum hosts.	('MCF10DCIS', 'Var', (10, 19))	('accelerated', 'PosReg', (183, 194))	('tumor', 'Disease', (195, 200))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (46, 70))	('ductal carcinoma', 'Disease', 'MESH:D044584', (128, 144))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (10, 19))	('ductal carcinoma', 'Disease', (46, 62))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (46, 62))	('HER2', 'Gene', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('ductal carcinoma', 'Disease', 'MESH:D044584', (46, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (119, 144))	('HER2', 'Gene', '2064', (105, 109))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('invasive ductal carcinoma', 'Disease', (119, 144))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (128, 144))
57571	32020054	Furthermore, we propose a cell-autonomous pro-invasive and survival role for SEMA7A that is mediated through fibronectin (FN), epithelial-to-mesenchymal transition (EMT) and downstream pro-survival signaling via phosphorylation of AKT.	('FN', 'Gene', '2335', (122, 124))	('fibronectin', 'Gene', '2335', (109, 120))	('AKT', 'Gene', '207', (231, 234))	('fibronectin', 'Gene', (109, 120))	('phosphorylation', 'Var', (212, 227))	('AKT', 'Gene', (231, 234))	('epithelial-to-mesenchymal transition', 'CPA', (127, 163))
57575	32020054	We observed that silencing of SEMA7A is sufficient to decrease tumor growth in postpartum hosts despite some of the tumors regaining expression of SEMA7A protein (Figure1A; SFigure1B).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'MPA', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('decrease tumor', 'Disease', 'MESH:D002303', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SEMA7A', 'Gene', (30, 36))	('decrease tumor', 'Disease', (54, 68))	('regaining', 'PosReg', (123, 132))	('silencing', 'Var', (17, 26))
57576	32020054	Harvested tumors (H&E stained sections) were scored for invasion at 5 weeks post-injection, when the majority of postpartum tumors are normally invasive (SFigure1C), and 33% of the SEMA7A-KD were invasive compared to 86% in the controls.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('the', 'Var', (177, 180))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
57577	32020054	Further, 56% of tumors in the SEMA7A-KD group maintained evidence of DCIS versus 12.5% controls (Figure1B).	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SEMA7A-KD', 'Var', (30, 39))	('DCIS', 'MPA', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))
57597	32020054	To understand additional SEMA7A mediated changes to the TME, we performed an unbiased mass spectrometry analysis of conditioned medias from ex vivo tumors derived from SEMA7A-KD or control cells.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SEMA7A-KD', 'Var', (168, 177))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (148, 154))
57603	32020054	Furthermore, immunoblot analysis of MCF10DCIS SEMA7A-OE cells reveals decreased E-cadherin and increased vimentin expression, markers of epithelial and mesenchymal cells, respectively (SFigure5F).	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('vimentin', 'Gene', '7431', (105, 113))	('decreased', 'NegReg', (70, 79))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (36, 45))	('vimentin', 'Gene', (105, 113))	('MCF10DCIS', 'Var', (36, 45))	('expression', 'MPA', (114, 124))	('increased', 'PosReg', (95, 104))
57607	32020054	Additionally, analysis of cell death in real time confirmed that SEMA7A-KD MDA-MB-231 cells exhibit increases in cell death via activation of apoptotic signaling (Figure6C).	('MDA-MB-231', 'Gene', (75, 85))	('apoptotic signaling', 'Pathway', (142, 161))	('activation', 'PosReg', (128, 138))	('cell death', 'CPA', (113, 123))	('SEMA7A-KD', 'Var', (65, 74))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))
57608	32020054	One known pro-survival mechanism co-opted by tumors to block activation of caspase cleavage is activation of pro-survival kinase AKT and we observed decreased levels of phosphorylated AKT via immunoblot for pS473 in SEMA7A-KD and a corresponding increase in levels in SEMA7A OE cells (Figure6D&SFigure6G).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('pS473', 'Var', (207, 212))	('levels', 'MPA', (159, 165))	('AKT', 'Gene', '207', (184, 187))	('tumors', 'Disease', (45, 51))	('AKT', 'Gene', '207', (129, 132))	('phosphorylated', 'MPA', (169, 183))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('increase', 'PosReg', (246, 254))	('AKT', 'Gene', (184, 187))	('decreased', 'NegReg', (149, 158))	('AKT', 'Gene', (129, 132))	('levels', 'MPA', (258, 264))
57619	32020054	However, co-expression of COX-2, SEMA7A, and FN1 increases risk for metastasis in ER-BC patients, with 5 year DMFS rates approaching 70% by both KmPlot and GOBO (Gene expression-based Outcome for Breast cancer Online or GOBO) analysis (Figure7B&C).	('SEMA7A', 'Var', (33, 39))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('Breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('patients', 'Species', '9606', (88, 96))	('Breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('FN1', 'Gene', '2335', (45, 48))	('COX-2', 'Gene', (26, 31))	('metastasis', 'CPA', (68, 78))	('COX-2', 'Gene', '5743', (26, 31))	('FN1', 'Gene', (45, 48))	('Breast cancer', 'Disease', (196, 209))	('co-expression', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
57628	32020054	We support this claim by showing a that co-expression of COX-2, SEMA7A, and FN correlates with distant metastasis formation in BC patients.	('co-expression', 'Var', (40, 53))	('COX-2', 'Gene', (57, 62))	('BC', 'Phenotype', 'HP:0003002', (127, 129))	('patients', 'Species', '9606', (130, 138))	('distant metastasis formation', 'CPA', (95, 123))	('COX-2', 'Gene', '5743', (57, 62))	('SEMA7A', 'Gene', (64, 70))	('FN', 'Gene', '2335', (76, 78))
57632	32020054	During fibrosis and in response to TGFbeta, SEMA7A activates AKT signaling, which results in upregulation of collagen and FN in a beta1-integrin dependent manner.	('upregulation', 'PosReg', (93, 105))	('beta1-integrin', 'Gene', (130, 144))	('FN', 'Gene', '2335', (122, 124))	('activates', 'PosReg', (51, 60))	('beta1-integrin', 'Gene', '3688', (130, 144))	('SEMA7A', 'Var', (44, 50))	('AKT', 'Gene', '207', (61, 64))	('fibrosis', 'Disease', 'MESH:D005355', (7, 15))	('fibrosis', 'Disease', (7, 15))	('AKT', 'Gene', (61, 64))
57640	32020054	Moreover, one major limitation of our current study is investigation of this mechanism only in ER- models, which is supported, in part, by our patient dataset studies showing that SEMA7A expression invokes a higher risk for metastasis in ER- breast cancers compared to all breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('expression', 'Var', (187, 197))	('metastasis', 'CPA', (224, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('patient', 'Species', '9606', (143, 150))	('SEMA7A', 'Protein', (180, 186))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('breast cancers', 'Disease', (242, 256))	('breast cancers', 'Phenotype', 'HP:0003002', (242, 256))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('breast cancers', 'Disease', 'MESH:D001943', (242, 256))	('breast cancer', 'Disease', (273, 286))
57656	32020054	If direct targeting of SEMA7A is not feasible, SEMA7A activates downstream targets such as FAK, Src, and ERK, for which targeted therapies are available.	('FAK', 'Gene', (91, 94))	('FAK', 'Gene', '5747', (91, 94))	('ERK', 'Gene', '5594', (105, 108))	('SEMA7A', 'Var', (47, 53))	('activates', 'PosReg', (54, 63))	('Src', 'Gene', (96, 99))	('ERK', 'Gene', (105, 108))	('Src', 'Gene', '6714', (96, 99))
57782	30848037	reported that increased Cho levels in 100 women with BIRADS 4-6 lesions had a sensitivity of 68.42% and specificity of 93.10%, diffusion restriction had a sensitivity of 90.79% and specificity of 89.66%, and evaluation of DCE-MRI enhancement curve characteristics had a sensitivity of 45.05% and specificity of 72.41%.	('increased', 'PosReg', (14, 23))	('Cho levels', 'MPA', (24, 34))	('diffusion', 'MPA', (127, 136))	('DCE', 'Gene', (222, 225))	('DCE', 'Gene', '1718', (222, 225))	('women', 'Species', '9606', (42, 47))	('BIRADS', 'Var', (53, 59))	('Cho', 'Chemical', 'MESH:D002794', (24, 27))
57818	30848037	However, the glycerophosphocholine/phosphocholine ratio as well as the concentrations of myo-inositol and succinate was significantly higher in the pure DCIS than in DCIS without an invasive component.	('phosphocholine', 'Chemical', 'MESH:D010767', (35, 49))	('myo-inositol', 'Chemical', 'MESH:D007294', (89, 101))	('higher', 'PosReg', (134, 140))	('glycerophosphocholine/phosphocholine ratio', 'MPA', (13, 55))	('pure', 'Var', (148, 152))	('glycerophosphocholine', 'Chemical', 'MESH:D005997', (13, 34))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('succinate', 'Chemical', 'MESH:D019802', (106, 115))	('phosphocholine', 'Chemical', 'MESH:D010767', (20, 34))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))
57886	30848037	The authors concluded that mpMRI with three parameters increases the diagnostic accuracy of breast cancer, compared with DCE-MRI alone and MP MRI with two parameters, and should be considered for future implementation in breast cancer care Recently, the concept of multiparametric imaging has been extended to ultra-high-field MRI.	('diagnostic', 'MPA', (69, 79))	('mpMRI', 'Var', (27, 32))	('DCE', 'Gene', '1718', (121, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('DCE', 'Gene', (121, 124))	('increases', 'PosReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
57903	28589368	The estimated 10-year risk of invasive breast cancer or DCIS in our cohort of ~ 1600 women who did not receive chemoprevention was 17.3% after ADH, 20.7% after ALH, and 26.0% after severe ADH.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('ADH', 'Var', (143, 146))	('ALH', 'Chemical', '-', (160, 163))	('invasive breast cancer', 'Disease', 'MESH:D001943', (30, 52))	('DCIS', 'Disease', (56, 60))	('women', 'Species', '9606', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('invasive breast cancer', 'Disease', (30, 52))
57964	28589368	As such, it is reasonable to state that any woman over age 35 and younger than 75 diagnosed with ADH, severe ADH, or ALH, regardless of their age group, has an equivalent risk of developing either invasive breast cancer or DCIS of 7.6% (95% CI 5.9-9.3%) at 5 years, 25.1%(20.7-29.2%) at 10 years, and 40.1% at 15 years.	('developing', 'PosReg', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('invasive breast cancer', 'Disease', 'MESH:D001943', (197, 219))	('DCIS', 'Disease', (223, 227))	('ADH', 'Disease', (97, 100))	('woman', 'Species', '9606', (44, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('invasive breast cancer', 'Disease', (197, 219))	('severe', 'Var', (102, 108))	('ALH', 'Chemical', '-', (117, 120))
57978	25092160	Extent of Microinvasion in Ductal Carcinoma In Situ Is Not Associated with Sentinel Lymph Node Metastases DCIS with microinvasion (DCISM) is a rare diagnosis with a good prognosis.	('microinvasion', 'Var', (116, 129))	('Ductal Carcinoma', 'Disease', (27, 43))	('Metastases', 'Disease', (95, 105))	('Ductal Carcinoma', 'Disease', 'MESH:D044584', (27, 43))	('Carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('DCISM', 'Chemical', '-', (131, 136))	('Metastases', 'Disease', 'MESH:D009362', (95, 105))	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (27, 51))
57996	25092160	Small, single-institution studies have suggested that the extent of microinvasion on histologic examination may be predictive of an increased risk for sentinel lymph node metastases.	('sentinel lymph node metastases', 'Disease', 'MESH:D009362', (151, 181))	('microinvasion', 'Var', (68, 81))	('sentinel lymph node metastases', 'Disease', (151, 181))
58020	25092160	Patients with multiple foci of microinvasion were more likely to have poor prognostic features of the primary tumor, including a significantly higher incidence of poorly differentiated tumors and tumors negative for estrogen and progesterone receptors, and positive for HER2 receptor, though in many cases, the invasive carcinoma was too small to assess these factors (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (320, 329))	('tumor', 'Disease', (196, 201))	('positive', 'Reg', (257, 265))	('microinvasion', 'Var', (31, 44))	('HER2', 'Gene', '2064', (270, 274))	('higher', 'PosReg', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('HER2', 'Gene', (270, 274))	('progesterone receptor', 'Gene', (229, 250))	('progesterone receptor', 'Gene', '5241', (229, 250))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('invasive carcinoma', 'Disease', (311, 329))	('invasive carcinoma', 'Disease', 'MESH:D009361', (311, 329))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', (110, 115))	('tumors and tumors', 'Disease', 'MESH:D009369', (185, 202))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
58050	25092160	In our population, the presence of >=2 foci of microinvasion was associated with more poorly differentiated disease, and was more likely to be hormone receptor (HR) negative and HER2 positive, though, interestingly, none of the patients who were HR negative and had a negative SLNB received chemotherapy.	('hormone receptor', 'Gene', '3164', (143, 159))	('SLN', 'Gene', (277, 280))	('HER2', 'Gene', '2064', (178, 182))	('HR', 'Gene', '3164', (246, 248))	('patients', 'Species', '9606', (228, 236))	('HR', 'Gene', '3164', (161, 163))	('SLN', 'Gene', '6588', (277, 280))	('poorly differentiated disease', 'Disease', (86, 115))	('HER2', 'Gene', (178, 182))	('microinvasion', 'Var', (47, 60))	('hormone receptor', 'Gene', (143, 159))
58069	22988495	Adjuvant therapy is tailored based on the molecular profile of the neoplasm and can include aromatase inhibitors, anti-estrogen, anti-progesterone (or a combination of antiestrogen and antiprogesterone), and HER2 neu suppression therapy.	('aromatase inhibitors', 'Protein', (92, 112))	('progesterone', 'Chemical', 'MESH:D011374', (189, 201))	('HER2', 'Gene', (208, 212))	('HER2', 'Gene', '2064', (208, 212))	('anti-progesterone', 'Var', (129, 146))	('neu', 'Gene', '2064', (213, 216))	('neoplasm', 'Disease', (67, 75))	('progesterone', 'Chemical', 'MESH:D011374', (134, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (67, 75))	('neu', 'Gene', (213, 216))	('suppression', 'NegReg', (217, 228))	('neoplasm', 'Disease', 'MESH:D009369', (67, 75))
58094	22988495	Nulliparity or women who had a late pregnancy (after 30 years of age) also had a higher incidence of DCIS.	('women', 'Species', '9606', (15, 20))	('DCIS', 'Disease', (101, 105))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('Nulliparity', 'Var', (0, 11))	('late pregnancy', 'Phenotype', 'HP:0001622', (31, 45))
58104	22988495	In the LIFT study of older postmenopausal women with low bone mineral density, breast cancer risk was decreased in the group receiving Tibolone compared with placebo; however, the study was terminated early due to an increased incidence of stroke.	('Tibolone', 'Chemical', 'MESH:C027385', (135, 143))	('low bone mineral density', 'Phenotype', 'HP:0004349', (53, 77))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('Tibolone', 'Var', (135, 143))	('stroke', 'Phenotype', 'HP:0001297', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('women', 'Species', '9606', (42, 47))	('stroke', 'Disease', (240, 246))	('stroke', 'Disease', 'MESH:D020521', (240, 246))	('decreased', 'NegReg', (102, 111))
58108	22988495	Obesity and increases in BMI by 25% are also risk factors for breast cancer.	('increases', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('Obesity', 'Disease', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('breast cancer', 'Disease', (62, 75))	('BMI', 'MPA', (25, 28))
58127	22988495	The detection rate was higher with digital mammography than film mammography in women between the ages of 60 and 69 years (89.5% versus.	('digital', 'Var', (35, 42))	('women', 'Species', '9606', (80, 85))	('higher', 'PosReg', (23, 29))	('detection', 'MPA', (4, 13))
58160	22988495	Mutated p53 (a tumor suppressor gene) is expressed by about 25% of DCIS.	('p53', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('p53', 'Gene', '7157', (8, 11))	('tumor', 'Disease', (15, 20))	('Mutated', 'Var', (0, 7))
58163	22988495	Inherited differences in AR CAG length might influence the transition from DCIS to invasive carcinoma, perhaps by modulating the function of AR in breast tissue.	('function', 'MPA', (129, 137))	('invasive carcinoma', 'Disease', (83, 101))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('differences', 'Var', (10, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('modulating', 'Reg', (114, 124))	('influence', 'Reg', (45, 54))	('DCIS', 'Disease', (75, 79))	('AR', 'Gene', '367', (25, 27))	('invasive carcinoma', 'Disease', 'MESH:D009361', (83, 101))	('AR', 'Gene', '367', (141, 143))
58188	22988495	Patients with either low or intermediate risk, with tumors measuring 2.5 cm or smaller or high-grade or DCIS 1 cm or smaller who had microscopic margins of 3 mm or wider, were eligible for study.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('high-grade', 'Var', (90, 100))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('Patients', 'Species', '9606', (0, 8))	('DCIS 1 cm', 'Var', (104, 113))
58189	22988495	During the 6.2 years of followup, the 5-year rate of cancer recurrence and related morbidity was 6.1% in patients with low or intermediaterisk, and 15.3% in the high-grade DCIS group.	('intermediaterisk', 'Var', (126, 142))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('low', 'Var', (119, 122))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
58204	22988495	The value of genetic testing for BRCA1 and BRCA 2 mutation is its ability to reduce the number of women who develop breast cancer and the number of women who die of disease.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('reduce', 'NegReg', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('women', 'Species', '9606', (98, 103))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('BRCA1', 'Gene', '672', (33, 38))	('BRCA 2', 'Gene', '675', (43, 49))	('BRCA 2', 'Gene', (43, 49))	('BRCA1', 'Gene', (33, 38))	('women', 'Species', '9606', (148, 153))	('mutation', 'Var', (50, 58))
58205	22988495	Patients with BRCA1 and BRCA2 mutations have several options for breast cancer prevention.	('BRCA1', 'Gene', '672', (14, 19))	('BRCA2', 'Gene', '675', (24, 29))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('BRCA1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (30, 39))	('BRCA2', 'Gene', (24, 29))
58208	22988495	Though prophylactic total mastectomy offers the best protection against developing breast cancer in BRCA1 and BRCA 2 mutation carriers, one study in Canada showed that the majority of women with BRCA1/2 mutations are unwilling to undergo such a radical surgical procedure.	('BRCA1', 'Gene', '672', (195, 200))	('BRCA1/2', 'Gene', (195, 202))	('women', 'Species', '9606', (184, 189))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA1/2', 'Gene', '672;675', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRCA1', 'Gene', (195, 200))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('BRCA1', 'Gene', (100, 105))	('breast cancer', 'Disease', (83, 96))	('BRCA 2', 'Gene', '675', (110, 116))	('BRCA 2', 'Gene', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('mutation', 'Var', (117, 125))	('mutations', 'Var', (203, 212))
58224	22988495	There is one laboratory study in progress that is evaluating inhibition of p38 kinase as a chemopreventive measure for ER-breast tumors.	('p38', 'Gene', '1432', (75, 78))	('breast tumors', 'Phenotype', 'HP:0100013', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('inhibition', 'Var', (61, 71))	('ER-breast tumors', 'Disease', 'MESH:D001943', (119, 135))	('p38', 'Gene', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ER-breast tumors', 'Disease', (119, 135))
58227	22988495	Rexinoid LG100268 has been shown in animal models to be an effective chemopreventive agent for prevention of preinvasive neoplasm of the breast with minimal toxicity.	('toxicity', 'Disease', 'MESH:D064420', (157, 165))	('neoplasm of the breast', 'Phenotype', 'HP:0100013', (121, 143))	('toxicity', 'Disease', (157, 165))	('neoplasm', 'Disease', (121, 129))	('Rexinoid', 'Chemical', '-', (0, 8))	('neoplasm', 'Disease', 'MESH:D009369', (121, 129))	('LG100268', 'Chemical', 'MESH:C095104', (9, 17))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('LG100268', 'Var', (9, 17))
58264	19318480	Quantitation of TMEM may be a useful new prognostic marker for breast cancer patients.	('Quantitation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('patients', 'Species', '9606', (77, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('TMEM', 'Gene', (16, 20))	('TMEM', 'Chemical', '-', (16, 20))
58288	19318480	In murine mammary tumors resulting from the expression of the PyMT oncogene in wild-type mice with intact macrophage numbers and function, carcinoma cells, when associated with macrophages, show an invasive phenotype with increased motility.	('carcinoma cell', 'Disease', (139, 153))	('mice', 'Species', '10090', (89, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('expression', 'Var', (44, 54))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('murine', 'Species', '10090', (3, 9))	('motility', 'CPA', (232, 240))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('carcinoma cell', 'Disease', 'MESH:C538614', (139, 153))	('increased', 'PosReg', (222, 231))	('PyMT', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
58471	21785684	Four of the nine patients whose HNB tissues showed low-grade molecular abnormality on microarray had the final pathologic diagnosis of IDC, 4 had only DCIS, and 1 had mucinous carcinoma.	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (167, 185))	('IDC', 'Gene', (135, 138))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (167, 185))	('mucinous carcinoma', 'Disease', (167, 185))	('patients', 'Species', '9606', (17, 25))	('IDC', 'Gene', '4000', (135, 138))	('low-grade molecular abnormality', 'Var', (51, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
58485	21785684	While the majority of cases in HNB tissues with low-grade molecular abnormality had MCM2 index of 1-2%, 2 of the cases (Case #s 9 and 14) (Table 4) had higher MCM2 indices (12% and 8%, resp.	('MCM2', 'Gene', '4171', (84, 88))	('MCM2', 'Gene', (159, 163))	('s 9 and 14', 'Gene', '6203;6208', (126, 136))	('MCM2', 'Gene', (84, 88))	('low-grade molecular abnormality', 'Var', (48, 79))	('MCM2', 'Gene', '4171', (159, 163))
58511	21785684	found a threefold increase in allelic imbalance (AI) in histologically normal breast tissue from sporadic breast cancer patients and BRCA1 gene mutation carriers as compared to women who underwent reduction mammoplasty, suggesting that these genetic abnormalities may be contributing to the risk of development of malignancy.	('increase', 'PosReg', (18, 26))	('contributing', 'Reg', (271, 283))	('sporadic breast cancer', 'Disease', (97, 119))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (97, 119))	('women', 'Species', '9606', (177, 182))	('genetic abnormalities', 'Disease', (242, 263))	('malignancy', 'Disease', 'MESH:D009369', (314, 324))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('allelic imbalance', 'MPA', (30, 47))	('mutation', 'Var', (144, 152))	('BRCA1', 'Gene', '672', (133, 138))	('patients', 'Species', '9606', (120, 128))	('malignancy', 'Disease', (314, 324))	('BRCA1', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('genetic abnormalities', 'Disease', 'MESH:D030342', (242, 263))	('imbalance', 'Phenotype', 'HP:0002172', (38, 47))
58513	21785684	These findings provide further support to the "cancer field effect" concept recognizing the presence of genetically aberrant cells that may represent high risk cell populations within the histologically normal breast tissues.	('genetically aberrant', 'Var', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
58515	21785684	Using specific epigenetic biomarkers, we have previously mapped a number of DNA methylation changes in histologically normal breast tissues as a potential explanation as to why histologically normal breast tissues are at risk for local recurrence after surgical therapy for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('breast cancer', 'Disease', (274, 287))	('changes', 'Var', (92, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('local recurrence', 'CPA', (230, 246))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
58527	21785684	Recent evidence suggests that amplification or deletion of TOP2A gene may account for sensitivity or resistance to topo II-inhibitor (anthracycline) therapy in breast cancer.	('TOP2A', 'Gene', (59, 64))	('resistance', 'MPA', (101, 111))	('topo', 'Chemical', 'MESH:C044965', (115, 119))	('sensitivity', 'MPA', (86, 97))	('amplification', 'Var', (30, 43))	('account', 'Reg', (74, 81))	('deletion', 'Var', (47, 55))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('anthracycline', 'Chemical', 'MESH:D018943', (134, 147))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('TOP2A', 'Gene', '7153', (59, 64))
58532	21785684	Since amplification of TOP2A gene leads to the overexpression of the TOP2A protein and better response to anthracycline therapy, while deletion of TOP2A gene leads to marked reduction in the expression of TOP2A protein and primary chemoresistance to TOP2 inhibitor drugs, our findings in histologically normal breast tissues, if clinically validated in larger series of histologically normal and benign breast tissues, may have potential implications for future chemopreventive trials in patients with various atypical and pre-malignant breast lesions.	('deletion', 'Var', (135, 143))	('TOP2A', 'Gene', '7153', (69, 74))	('overexpression', 'PosReg', (47, 61))	('TOP2A', 'Gene', (147, 152))	('TOP2A', 'Gene', (69, 74))	('TOP2A', 'Gene', '7153', (23, 28))	('TOP2A', 'Gene', '7153', (205, 210))	('patients', 'Species', '9606', (488, 496))	('amplification', 'Var', (6, 19))	('malignant breast lesions', 'Phenotype', 'HP:0100013', (527, 551))	('TOP2A', 'Gene', '7153', (147, 152))	('reduction', 'NegReg', (174, 183))	('TOP2A', 'Gene', (23, 28))	('anthracycline', 'Chemical', 'MESH:D018943', (106, 119))	('TOP2A', 'Gene', (205, 210))	('expression', 'MPA', (191, 201))
58556	21785684	BUB1B protein is a mitotic checkpoint kinase required for cell mitotic divisions following severe cell damage or mutation.	('mutation', 'Var', (113, 121))	('BUB1B', 'Gene', (0, 5))	('BUB1B', 'Gene', '701', (0, 5))
58588	30992681	For invasive BC, mastectomy rates were higher for lobular, multifocal, >=20 mm, Her2-positive tumors and diffuse positive margins and lower for age >50 years and during the last period.	('Her2', 'Gene', (80, 84))	('lower', 'NegReg', (134, 139))	('higher', 'PosReg', (39, 45))	('invasive BC', 'Disease', (4, 15))	('Her2', 'Gene', '2064', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mastectomy', 'Disease', (17, 27))	('multifocal', 'Var', (59, 69))	('>=20 mm', 'Var', (71, 78))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
58602	30992681	In the multivariate analysis for DCIS, tumor size >=20 mm increased reoperation rate and age >50 years, P2-3 periods, and tumor localization (upper superior quadrant and external superior and inferior quadrants) decreased reoperation rates (Table 2).	('decreased', 'NegReg', (212, 221))	('increased', 'PosReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('reoperation', 'CPA', (68, 79))	('>=20', 'Var', (50, 54))	('reoperation', 'CPA', (222, 233))	('P2-3', 'Gene', '7178', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('P2-3', 'Gene', (104, 108))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (122, 127))
58605	30992681	For DCIS, the mastectomy rate was higher for grade 2 tumors and tumor sizes >=20 mm (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('>=20', 'Var', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mastectomy', 'Disease', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('higher', 'Reg', (34, 40))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumors', 'Disease', (53, 59))
58606	30992681	For invasive BC, the mastectomy rate was higher for lobular tumors, bifocal or multifocal tumors, tumor sizes >=20 mm, Her2-positive tumors, and diffuse positive margins and lower for age >50 years and patients treated during the last period (Table 5).	('lobular tumors', 'Disease', 'MESH:D018275', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Her2', 'Gene', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('lobular tumors', 'Disease', (52, 66))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('invasive BC', 'Disease', (4, 15))	('multifocal tumors', 'Disease', 'None', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('patients', 'Species', '9606', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('multifocal tumors', 'Disease', (79, 96))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (133, 138))	('tumors', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('mastectomy', 'Disease', (21, 31))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('bifocal', 'Disease', (68, 75))	('tumors', 'Disease', (90, 96))	('Her2', 'Gene', '2064', (119, 123))	('higher', 'PosReg', (41, 47))	('>=20', 'Var', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
58649	32466799	Moreover, several studies have shown that these parameters present higher or comparable accuracy to Breast Imaging Reporting and Data System (BI-RADS) delayed phase kinetic curve assessment, suggesting that ultrafast DCE-MRI in the very early phase may substitute for the standard DCE-MRI delayed phase.	('DCE', 'Gene', '1718', (217, 220))	('DCE', 'Gene', (217, 220))	('DCE', 'Gene', '1718', (281, 284))	('ultrafast', 'Var', (207, 216))	('DCE', 'Gene', (281, 284))
58691	32466799	Triple negative or HER2 type presented significantly shorter BAT than luminal type (P < 0.001) (Fig.	('luminal', 'Chemical', 'MESH:D010634', (70, 77))	('HER2', 'Gene', (19, 23))	('HER2', 'Gene', '2064', (19, 23))	('BAT', 'MPA', (61, 64))	('Triple negative', 'Var', (0, 15))	('shorter', 'NegReg', (53, 60))
58979	30678480	In conclusion, the results of our study showed that CESM resulted in an only minute improvement in sensitivity and NPV at the predefined cut-off point, with the measurement error in the assessment of disease extent being slightly reduced compared to FFDM.	('CESM', 'Var', (52, 56))	('NPV', 'MPA', (115, 118))	('FFDM', 'Chemical', '-', (250, 254))	('improvement', 'PosReg', (84, 95))	('sensitivity', 'MPA', (99, 110))
59007	28285537	Between 1972 and 1974, 380 women with node-positive breast cancer were randomly assigned to receive either L-phenylalanine mustard (L-PAM) or placebo following primary breast cancer surgery in the NSABP B-05 trial.	('L-phenylalanine mustard', 'Chemical', 'MESH:D008558', (107, 130))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('L-PAM', 'Chemical', 'MESH:D008558', (132, 137))	('breast cancer', 'Disease', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('L-phenylalanine', 'Var', (107, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('women', 'Species', '9606', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
59019	28285537	The OlympiA trial [NSABP B-55/Breast International Group (BIG) 6-13] is a global indication study evaluating the effectiveness of olaparib in patients with a BRCA mutation and stage II or III breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('BRCA', 'Gene', (158, 162))	('olaparib', 'Chemical', 'MESH:C531550', (130, 138))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('patients', 'Species', '9606', (142, 150))	('mutation', 'Var', (163, 171))
59131	27683209	Calcifications were inversely associated with hormone receptor-negative (vs. positive, OR=0.73, 95%CI 0.57-0.93), >35mm (vs. <=8mm, OR=0.47, 95%CI 0.37-0.61), and lobular (vs. ductal, OR=0.39, 95%CI 0.22-0.69) tumors.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('Calcifications', 'Disease', (0, 14))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('hormone receptor', 'Gene', (46, 62))	('hormone receptor', 'Gene', '3164', (46, 62))	('>35mm', 'Var', (114, 119))
59133	27683209	The association with tumor size was strongest for BI-RADS 3 and 4 (P-heterogeneity<0.01).	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('BI-RADS', 'Var', (50, 57))	('tumor', 'Disease', (21, 26))
59152	27683209	We hypothesized that BI-RADS 4 (suspicious) and 5 (highly suggestive of malignancy) calcifications would be more strongly associated with poor prognostic factors compared with BI-RADS 2 (benign) or 3 (probably benign) calcifications.	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('calcification', 'Disease', 'MESH:D002114', (84, 97))	('malignancy', 'Disease', (72, 82))	('calcification', 'Disease', 'MESH:D002114', (218, 231))	('BI-RADS 4', 'Var', (21, 30))	('calcification', 'Disease', (84, 97))	('calcification', 'Disease', (218, 231))
59197	27683209	For example, there was a more than two-fold association between the presence of BI-RADS 2, 3, and 5 calcifications and intermediate or high tumor grade (vs. low grade), but the association between BI-RADS 4 and intermediate or high grade was closer to the null.	('intermediate', 'CPA', (119, 131))	('calcification', 'Disease', 'MESH:D002114', (100, 113))	('high tumor', 'Disease', (135, 145))	('calcification', 'Disease', (100, 113))	('high tumor', 'Disease', 'MESH:D009369', (135, 145))	('presence', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BI-RADS 2', 'Gene', (80, 89))
59216	27683209	The association between BI-RADS 4 and 5 calcifications and the presence of an in situ component in addition to the invasive tumor was one of the strongest we observed.	('calcification', 'Disease', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BI-RADS', 'Var', (24, 31))	('invasive tumor', 'Disease', 'MESH:D009369', (115, 129))	('invasive tumor', 'Disease', (115, 129))	('calcification', 'Disease', 'MESH:D002114', (40, 53))
59219	27683209	On one hand, studies suggest that the presence of DCIS or LCIS with an invasive tumor either has no effect on recurrence or is a predictor of good prognosis.	('presence', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('LCIS', 'Phenotype', 'HP:0030076', (58, 62))	('invasive tumor', 'Disease', (71, 85))	('DCIS', 'Disease', (50, 54))	('LCIS', 'Gene', (58, 62))	('invasive tumor', 'Disease', 'MESH:D009369', (71, 85))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
59237	24386264	Prognostic Significance of Deregulated Dicer Expression in Breast Cancer Dicer, an RNase III-type endonuclease, is the key enzyme involved in RNA interference and microRNA pathways.	('Breast Cancer', 'Phenotype', 'HP:0003002', (59, 72))	('Deregulated', 'Var', (27, 38))	('Dicer', 'Gene', '23405', (73, 78))	('Dicer', 'Gene', (73, 78))	('Dicer', 'Gene', '23405', (39, 44))	('Breast Cancer', 'Disease', (59, 72))	('Dicer', 'Gene', (39, 44))	('Expression', 'MPA', (45, 55))	('RNase III', 'Gene', (83, 92))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RNase III', 'Gene', '29102', (83, 92))	('Breast Cancer', 'Disease', 'MESH:D001943', (59, 72))
59238	24386264	Aberrant expression of Dicer is reported in several human cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aberrant', 'Var', (0, 8))	('Dicer', 'Gene', '23405', (23, 28))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Dicer', 'Gene', (23, 28))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('reported', 'Reg', (32, 40))	('cancers', 'Disease', (58, 65))
59244	24386264	Dicer expression was increased in nodal metastases compared to primary tumours (p<0.001); and was associated with ER negativity (p<0.001), HER2 positivity (p<0.001), high Ki67 labeling index (p<0.001) and expression of basal-like biomarkers (p = 0.002).	('increased', 'PosReg', (21, 30))	('nodal metastases', 'Disease', (34, 50))	('HER2', 'Gene', (139, 143))	('positivity', 'Var', (144, 154))	('expression', 'MPA', (6, 16))	('primary tumours', 'Disease', 'MESH:D009369', (63, 78))	('HER2', 'Gene', '2064', (139, 143))	('nodal metastases', 'Disease', 'MESH:D009362', (34, 50))	('primary tumours', 'Disease', (63, 78))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('associated', 'Reg', (98, 108))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
59245	24386264	Dicer positivity was more frequent in the HER2 overexpressing (p<0.001) and basal-like (p = 0.002) subtypes compared to luminal A subtype.	('HER2', 'Gene', '2064', (42, 46))	('positivity', 'Var', (6, 16))	('overexpressing', 'PosReg', (47, 61))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('HER2', 'Gene', (42, 46))
59246	24386264	Dicer expression was associated with reduced overall survival (OS) on univariate analysis (p = 0.058) and remained an independent predictor of OS on multivariate analysis (HR 2.84, 95% CI 1.43-5.62, p = 0.003), with nodal status (HR 2.61, 95% CI 1.18-5.80, p = 0.018) and PR (HR 0.28, 95% CI 0.13-0.59, p = 0.001).	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('reduced', 'NegReg', (37, 44))	('expression', 'Var', (6, 16))	('overall survival', 'MPA', (45, 61))	('PR', 'Gene', '5241', (272, 274))
59248	24386264	Deregulated Dicer expression is associated with aggressive tumour characteristics and is an independent prognostic factor for OS.	('aggressive tumour', 'Disease', (48, 65))	('Deregulated', 'Var', (0, 11))	('Dicer', 'Gene', '23405', (12, 17))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('Dicer', 'Gene', (12, 17))	('expression', 'MPA', (18, 28))	('associated', 'Reg', (32, 42))	('aggressive tumour', 'Disease', 'MESH:D001523', (48, 65))
59254	24386264	Deregulation of miRNAs is associated with a broad range of human diseases including cancers and miRNAs have been shown to be critically involved in control of cell survival and cell death decisions.	('human', 'Species', '9606', (59, 64))	('miRNAs', 'Protein', (16, 22))	('Deregulation', 'Var', (0, 12))	('involved', 'Reg', (136, 144))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('associated', 'Reg', (26, 36))
59257	24386264	For example, inactivating mutations have been reported in exportin-5 (XPO5) and TAR RNA-binding protein (TRBP2) in sporadic and hereditary colon carcinomas with microsatellite instability.	('TRBP2', 'Gene', (105, 110))	('inactivating mutations', 'Var', (13, 35))	('XPO5', 'Gene', (70, 74))	('XPO5', 'Gene', '57510', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('hereditary colon carcinomas', 'Disease', (128, 155))	('TRBP2', 'Gene', '6895', (105, 110))	('RNA-binding protein', 'Gene', '27303', (84, 103))	('RNA-binding protein', 'Gene', (84, 103))	('exportin-5', 'Gene', '57510', (58, 68))	('exportin-5', 'Gene', (58, 68))	('microsatellite instability', 'Var', (161, 187))	('hereditary colon carcinomas', 'Disease', 'MESH:D015179', (128, 155))
59258	24386264	Germline-inactivating mutations in Dicer have been shown to contribute significantly to familial pleuropulmonaryblastoma, cystic nephroma, ovarian Sertoli-Leydig tumour and intraocular medulloepithelioma.	('Dicer', 'Gene', '23405', (35, 40))	('Dicer', 'Gene', (35, 40))	('intraocular medulloepithelioma', 'Disease', 'MESH:D008527', (173, 203))	('familial pleuropulmonaryblastoma', 'Phenotype', 'HP:0100528', (88, 120))	('contribute', 'Reg', (60, 70))	('medulloepithelioma', 'Phenotype', 'HP:0030071', (185, 203))	('Leydig tumour', 'Phenotype', 'HP:0100618', (155, 168))	('familial pleuropulmonaryblastoma, cystic nephroma, ovarian Sertoli-Leydig tumour', 'Disease', 'MESH:D018310', (88, 168))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('Germline-inactivating mutations', 'Var', (0, 31))	('Sertoli-Leydig tumour', 'Phenotype', 'HP:0100619', (147, 168))	('intraocular medulloepithelioma', 'Disease', (173, 203))
59259	24386264	Analysis of eight tumours from Dicer mutation-positive patients showed there was no loss of the wild-type allele in any tumour.	('Dicer', 'Gene', '23405', (31, 36))	('Dicer', 'Gene', (31, 36))	('tumours', 'Disease', (18, 25))	('mutation-positive', 'Var', (37, 54))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Disease', (120, 126))	('patients', 'Species', '9606', (55, 63))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumours', 'Disease', 'MESH:D009369', (18, 25))	('tumour', 'Disease', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
59262	24386264	Furthermore, analysis of Dicer copy number using data from Cancer Genome Project at the Sanger Institute revealed hemizygous deletions of DICER1 in 27% (207/761) of tumours derived from tissues of diverse origins such as central nervous system, lung, pancreas, soft tissues, breast and bone and hemizygous deletion of Dicer was also observed in approximately 37% of breast cancers.	('Dicer', 'Gene', '23405', (25, 30))	('Dicer', 'Gene', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('pancreas', 'Disease', (251, 259))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast', 'Disease', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (373, 380))	('DICER1', 'Gene', '23405', (138, 144))	('lung', 'Disease', (245, 249))	('breast cancers', 'Disease', 'MESH:D001943', (366, 380))	('breast cancers', 'Disease', (366, 380))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('DICER1', 'Gene', (138, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (366, 380))	('tumours', 'Disease', (165, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (366, 379))	('Dicer', 'Gene', '23405', (318, 323))	('Dicer', 'Gene', (318, 323))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('deletions', 'Var', (125, 134))
59269	24386264	We demonstrate herein that deregulated Dicer expression is significantly associated with several adverse clinical features such as ER negativity, Ki67 labelling index and expression of basal markers.	('Dicer', 'Gene', '23405', (39, 44))	('clinical', 'Species', '191496', (105, 113))	('Dicer', 'Gene', (39, 44))	('deregulated', 'Var', (27, 38))	('associated', 'Reg', (73, 83))	('expression', 'MPA', (45, 55))	('ER negativity', 'Disease', (131, 144))
59270	24386264	We report that deregulated Dicer expression is associated with poor overall survival in IBC and is associated with a reduced disease free survival in the HER2 overexpressing subtype of breast cancer.	('Dicer', 'Gene', (27, 32))	('deregulated', 'Var', (15, 26))	('IBC', 'Chemical', '-', (88, 91))	('IBC', 'Disease', (88, 91))	('disease free survival', 'CPA', (125, 146))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('reduced', 'NegReg', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('breast cancer', 'Disease', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('HER2', 'Gene', (154, 158))	('poor', 'NegReg', (63, 67))	('HER2', 'Gene', '2064', (154, 158))	('Dicer', 'Gene', '23405', (27, 32))
59280	24386264	Nuclear staining for ER, PR, p53 and Ki67 was scored as positive with a cut-off of 10%.	('Ki67', 'Var', (37, 41))	('PR', 'Gene', '5241', (25, 27))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', (29, 32))
59316	24386264	There was a significant association between Dicer positivity and HER2 overexpression (estimate of difference in proportions of 20.3%) and Ki67 labelling index.	('HER2', 'Gene', '2064', (65, 69))	('Dicer', 'Gene', '23405', (44, 49))	('positivity', 'Var', (50, 60))	('Dicer', 'Gene', (44, 49))	('overexpression', 'PosReg', (70, 84))	('HER2', 'Gene', (65, 69))
59317	24386264	Dicer positivity was also associated with expression of basal-like biomarker EGFR and, in the analysis of breast cancer subtypes, luminal A subtype showed a significantly lower proportion of Dicer positive patients than basal-like and HER2 overexpressing subtypes.	('luminal A', 'Disease', (130, 139))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('HER2', 'Gene', (235, 239))	('positivity', 'Var', (6, 16))	('expression', 'MPA', (42, 52))	('Dicer', 'Gene', '23405', (191, 196))	('HER2', 'Gene', '2064', (235, 239))	('Dicer', 'Gene', (191, 196))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('EGFR', 'Gene', '1956', (77, 81))	('patients', 'Species', '9606', (206, 214))	('EGFR', 'Gene', (77, 81))	('lower', 'NegReg', (171, 176))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
59319	24386264	Cox regression revealed that Dicer positivity was associated with an increased likelihood of death of 1.55 (CI: 0.98-2.45) compared with Dicer negativity (p = 0.061).	('Dicer', 'Gene', '23405', (29, 34))	('Dicer', 'Gene', (29, 34))	('positivity', 'Var', (35, 45))	('death', 'Disease', (93, 98))	('Dicer', 'Gene', '23405', (137, 142))	('Dicer', 'Gene', (137, 142))
59321	24386264	In the final model, selected using variable selection, Dicer expression was associated with an increased likelihood of death from breast cancer by a factor of 2.84 (HR, 2.84; 95% CI, 1.43-5.62; p = 0.003) adjusting for lymph node status and PR status (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('Dicer', 'Gene', '23405', (55, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('Dicer', 'Gene', (55, 60))	('expression', 'Var', (61, 71))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('PR', 'Gene', '5241', (241, 243))
59328	24386264	Although the number of cases and events at extended follow up are small, we observed a better prognosis for DFS with high Dicer expression compared to low or negative Dicer expression in the HER2 overexpressing subgroup (p = 0.0376) (Figure 5b).	('HER2', 'Gene', (191, 195))	('HER2', 'Gene', '2064', (191, 195))	('Dicer', 'Gene', '23405', (122, 127))	('Dicer', 'Gene', '23405', (167, 172))	('Dicer', 'Gene', (122, 127))	('Dicer', 'Gene', (167, 172))	('high', 'Var', (117, 121))
59330	24386264	Again, there was a significant association between high Dicer expression and the HER2 overexpressing compared to the luminal A subtype (chi2 = 8.31, p = 0.004); and high Dicer expression was more common in HER2 positive (chi2 = 4.29, p = 0.04) and EGFR positive (chi2 = 4.73, p = 0.03) compared to HER2 and EGFR negative cases respectively.	('Dicer', 'Gene', '23405', (56, 61))	('Dicer', 'Gene', (56, 61))	('EGFR', 'Gene', '1956', (248, 252))	('overexpressing', 'PosReg', (86, 100))	('Dicer', 'Gene', '23405', (170, 175))	('Dicer', 'Gene', (170, 175))	('EGFR', 'Gene', '1956', (307, 311))	('EGFR', 'Gene', (248, 252))	('EGFR', 'Gene', (307, 311))	('HER2', 'Gene', (298, 302))	('HER2', 'Gene', (81, 85))	('high', 'Var', (165, 169))	('HER2', 'Gene', '2064', (81, 85))	('HER2', 'Gene', (206, 210))	('HER2', 'Gene', '2064', (298, 302))	('HER2', 'Gene', '2064', (206, 210))
59334	24386264	Dicer expression was associated with features of aggressive disease and was a predictor of reduced OS that was independent of clinico-pathological variables, steroid hormone and HER2 receptor status in the entire series.	('aggressive disease', 'Disease', (49, 67))	('associated', 'Reg', (21, 31))	('Dicer', 'Gene', '23405', (0, 5))	('reduced', 'NegReg', (91, 98))	('Dicer', 'Gene', (0, 5))	('aggressive disease', 'Disease', 'MESH:D001523', (49, 67))	('HER2', 'Gene', (178, 182))	('expression', 'Var', (6, 16))	('HER2', 'Gene', '2064', (178, 182))
59343	24386264	found an association between increased Dicer protein expression and both nodal metastasis and high Ki67 proliferation index, while Faggad et al.	('nodal metastasis', 'CPA', (73, 89))	('Dicer', 'Gene', '23405', (39, 44))	('Dicer', 'Gene', (39, 44))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (53, 63))	('high', 'Var', (94, 98))
59345	24386264	Similarly, both low and high Dicer protein expression were associated with and adverse features and/or outcome in colorectal cancer.	('low', 'Var', (16, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('Dicer', 'Gene', '23405', (29, 34))	('Dicer', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('associated', 'Reg', (59, 69))	('high', 'Var', (24, 28))	('colorectal cancer', 'Disease', (114, 131))	('expression', 'MPA', (43, 53))
59352	24386264	The pattern of Dicer expression in that study however conflicts both with data from our study, where Dicer positivity was associated with aggressive phenotypic features (high Ki67, ER negativity, basal phenotype and with reduced OS) and also with the data from Grelier et al.	('Dicer', 'Gene', '23405', (101, 106))	('Dicer', 'Gene', (101, 106))	('high Ki67', 'Var', (170, 179))	('Dicer', 'Gene', '23405', (15, 20))	('Dicer', 'Gene', (15, 20))	('positivity', 'Var', (107, 117))
59355	24386264	Thus, Dicer deregulation may be site specific and its role may differ in different tumours and in different subtypes.	('tumours', 'Disease', (83, 90))	('deregulation', 'Var', (12, 24))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('Dicer', 'Gene', '23405', (6, 11))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('Dicer', 'Gene', (6, 11))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
59356	24386264	This is supported by functional studies where knockdown of Dicer expression rendered MDAMB-231 and MDA-MB-436 cells significantly more invasive, while knockdown of Dicer in MCF-7 cells led to G1 arrest and increase sensitivity to cisplatin suggesting that the effects of Dicer on development and progression of cancer are context-dependent.	('Dicer', 'Gene', '23405', (271, 276))	('Dicer', 'Gene', (271, 276))	('more', 'PosReg', (130, 134))	('cancer', 'Disease', (311, 317))	('cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('arrest', 'Disease', (195, 201))	('Dicer', 'Gene', '23405', (164, 169))	('MCF-7', 'CellLine', 'CVCL:0031', (173, 178))	('Dicer', 'Gene', '23405', (59, 64))	('Dicer', 'Gene', (164, 169))	('Dicer', 'Gene', (59, 64))	('invasive', 'CPA', (135, 143))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('arrest', 'Disease', 'MESH:D006323', (195, 201))	('MDAMB-231', 'CellLine', 'CVCL:0062', (85, 94))	('knockdown', 'Var', (46, 55))	('sensitivity to cisplatin', 'MPA', (215, 239))	('increase', 'PosReg', (206, 214))
59372	24386264	Dicer mRNA was lower in cell lines that underwent epithelial to mesenchymal transition (EMT) and down-regulation of Dicer protein by miR-103/107 was shown to be associated with EMT and metastasis.	('protein', 'Protein', (122, 129))	('epithelial to mesenchymal transition', 'CPA', (50, 86))	('down-regulation', 'NegReg', (97, 112))	('EMT', 'CPA', (177, 180))	('miR-103/107', 'Var', (133, 144))	('Dicer', 'Gene', '23405', (116, 121))	('Dicer', 'Gene', (116, 121))	('Dicer', 'Gene', '23405', (0, 5))	('Dicer', 'Gene', (0, 5))	('lower', 'NegReg', (15, 20))
59387	23469238	When necrosis was found in association with grade 2 or 3 DCIS, the decrease in CD34 expression was higher than in lesions without necrosis and that independently of the grade of DCIS (p<0.05).	('DCIS', 'Var', (57, 61))	('decrease', 'NegReg', (67, 75))	('necrosis', 'Disease', 'MESH:D009336', (130, 138))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('CD34', 'Gene', '947', (79, 83))	('necrosis', 'Disease', (5, 13))	('grade 2', 'Var', (44, 51))	('expression', 'MPA', (84, 94))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('CD34', 'Gene', (79, 83))	('necrosis', 'Disease', 'MESH:D009336', (5, 13))	('necrosis', 'Disease', (130, 138))
59439	23469238	These data indicate a strong negative association between the presence of CD34 fibrocytes and the malignancy of ductal breast lesions.	('malignancy of ductal breast lesions', 'Disease', (98, 133))	('CD34', 'Gene', (74, 78))	('CD34', 'Gene', '947', (74, 78))	('malignancy of ductal breast lesions', 'Disease', 'MESH:D018270', (98, 133))	('negative', 'NegReg', (29, 37))	('presence', 'Var', (62, 70))
59446	23469238	Therefore, modulation of the expression of CD34 could be one explanation of the role of necrosis in tumor invasion.	('necrosis', 'Disease', 'MESH:D009336', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('modulation', 'Var', (11, 21))	('tumor', 'Disease', (100, 105))	('CD34', 'Gene', (43, 47))	('CD34', 'Gene', '947', (43, 47))	('necrosis', 'Disease', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
59462	23469238	This raises the possibility that loss of CD34 may be related to invasive potential at least in ductal lesions.	('ductal lesions', 'Disease', (95, 109))	('related', 'Reg', (53, 60))	('invasive potential', 'Disease', (64, 82))	('CD34', 'Gene', (41, 45))	('loss', 'Var', (33, 37))	('CD34', 'Gene', '947', (41, 45))
59465	29511964	Dose-Dependent Effect of Mammographic Breast Density on the Risk of Contralateral Breast Cancer Increased mammographic breast density is a significant risk factor for breast cancer.	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('Contralateral Breast Cancer', 'Disease', (68, 95))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Contralateral Breast Cancer', 'Disease', 'MESH:D001943', (68, 95))	('mammographic breast density', 'Var', (106, 133))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Breast Cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
59476	29511964	Even though some patients diagnosed with unilateral BC indeed have a high risk of developing CBC, for example, those carrying BRCA mutations or having family history of BC, majority of women have much lower risk of developing CBC due to increasing use of effective adjuvant therapies, which has a protective effect on the healthy contralateral breast.	('BRCA', 'Gene', '672', (126, 130))	('CBC', 'Disease', (93, 96))	('mutations', 'Var', (131, 140))	('BRCA', 'Gene', (126, 130))	('women', 'Species', '9606', (185, 190))	('patients', 'Species', '9606', (17, 25))	('BC', 'Phenotype', 'HP:0003002', (227, 229))	('BC', 'Phenotype', 'HP:0003002', (52, 54))	('BC', 'Phenotype', 'HP:0003002', (94, 96))	('BC', 'Phenotype', 'HP:0003002', (169, 171))
59478	29511964	In particular, carrying BRCA 1/2 mutations, younger age at first BC diagnosis, and having family history of BC are associated with higher risks of CBC while getting hormonal therapy for first breast cancer is associated with a lower risk of CBC.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (192, 205))	('BRCA 1/2', 'Gene', '672;675', (24, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('mutations', 'Var', (33, 42))	('BC', 'Phenotype', 'HP:0003002', (65, 67))	('BC', 'Phenotype', 'HP:0003002', (108, 110))	('CBC', 'Disease', (147, 150))	('BC', 'Phenotype', 'HP:0003002', (242, 244))	('BRCA 1/2', 'Gene', (24, 32))	('BC', 'Phenotype', 'HP:0003002', (148, 150))
59562	23588746	Computer-aided detection was also associated with greater adjusted odds that an invasive tumor was smaller than 1 cm in diameter and had negative lymph node status.	('smaller', 'NegReg', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Computer-aided', 'Var', (0, 14))	('invasive', 'Disease', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
59613	23588746	Meanwhile, CAD-associated ORs for diagnostic testing among women without breast cancer were greater among the stratum of digital mammography than among film mammography.	('digital mammography', 'Var', (121, 140))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('diagnostic testing', 'MPA', (34, 52))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('women', 'Species', '9606', (59, 64))
59667	33675490	Thus, invasive recurrences among patients initially treated with BCS were more frequently clinical stage I compared to those originally treated with mastectomy.	('BCS', 'Var', (65, 68))	('clinical', 'Disease', (90, 98))	('patients', 'Species', '9606', (33, 41))	('invasive recurrences', 'CPA', (6, 26))
59673	33675490	While initial surgical therapy was not associated with recurrence patterns, we found that the presence of necrosis and multifocal DCIS were significantly associated with shorter time to regional recurrence, after adjusting for initial surgery type and adjuvant treatment.	('necrosis', 'Disease', (106, 114))	('multifocal', 'Var', (119, 129))	('necrosis', 'Disease', 'MESH:D009336', (106, 114))	('shorter', 'NegReg', (170, 177))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
59697	33675490	P30 CA008748 to Memorial Sloan Kettering Cancer Center.	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('P30 CA008748', 'Var', (0, 12))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Disease', (41, 47))
59727	22736444	Patients of Hispanic and Asian/Pacific Islander descent were significantly younger (median ages 50 and 52 years, respectively) than white and African American patients (median ages 55 and 56 years, respectively, P< 0.001, Table 1).	('Hispanic', 'Var', (12, 20))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (159, 167))	('Asian/Pacific Islander descent', 'Var', (25, 55))
59788	22736444	Indeed, previous studies have shown a 3.3% to 27% prevalence of BRCA1/BRCA2 mutations in women diagnosed with DCIS  and these patients have an elevated lifetime risk of developing invasive breast cancer.	('BRCA1', 'Gene', '672', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (76, 85))	('BRCA2', 'Gene', '675', (70, 75))	('BRCA1', 'Gene', (64, 69))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('invasive breast cancer', 'Disease', (180, 202))	('women', 'Species', '9606', (89, 94))	('patients', 'Species', '9606', (126, 134))	('BRCA2', 'Gene', (70, 75))	('invasive breast cancer', 'Disease', 'MESH:D001943', (180, 202))
59862	14726638	Some surgeons have suggested that BI-RADS 4 lesions should be surgically excised, though in our study group, the positive biopsy rate for calcifications of this grade was 31.8% (48/151).	('BI-RADS', 'Var', (34, 41))	('calcification', 'Disease', 'MESH:D002114', (138, 151))	('calcification', 'Disease', (138, 151))
59872	14726638	An earlier study noted that amorphous calcifications portended higher failure rates at stereotactic biopsy, even with a vacuum-assisted device.	('amorphous', 'Var', (28, 37))	('calcification', 'Disease', (38, 51))	('vacuum-assisted device', 'Phenotype', 'HP:0011412', (120, 142))	('calcification', 'Disease', 'MESH:D002114', (38, 51))	('failure', 'CPA', (70, 77))
59884	14726638	In conclusion, although stereotactic biopsy can be reliably employed for the evaluation of calcifications observed at mammography, long-term follow-up showed that when the predominant mammographic finding was non-mass calcifications and the most commonly diagnosed cancer was DCIS, the sensitivity of SCNB was 82%.	('DCIS', 'Disease', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('calcification', 'Disease', 'MESH:D002114', (218, 231))	('calcification', 'Disease', 'MESH:D002114', (91, 104))	('DCIS', 'Phenotype', 'HP:0030075', (276, 280))	('non-mass', 'Var', (209, 217))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('calcification', 'Disease', (91, 104))	('calcification', 'Disease', (218, 231))
59891	27475843	It is well-established that AREG production increases in response to binding of ER alpha in the TEB epithelium, that ER- mice fail to initiate pubertal mammary gland development in response to hormonal signaling at the onset of puberty, and that loss of AREG results in gross stunting in pubertal mammary gland development.	('stunting', 'NegReg', (276, 284))	('ER alpha', 'Gene', (80, 88))	('ER alpha', 'Gene', '13982', (80, 88))	('binding', 'Interaction', (69, 76))	('mice', 'Species', '10090', (121, 125))	('AREG', 'MPA', (28, 32))	('loss', 'Var', (246, 250))	('onset of puberty', 'Phenotype', 'HP:0000826', (219, 235))	('increases', 'PosReg', (44, 53))	('AREG', 'Gene', (254, 258))	('pubertal mammary gland development', 'CPA', (288, 322))
59914	27475843	For both ER+ and ER- phenotypes, proliferation may only occur if they are not entering necrosis or apoptosis.	('ER-', 'Var', (17, 20))	('necrosis', 'Disease', 'MESH:D009336', (87, 95))	('ER+', 'Var', (9, 12))	('necrosis', 'Disease', (87, 95))
59985	27511848	In our cohort of predominantly overweight and obese patients with early-stage breast cancer receiving breast conservation therapy, BMI >33.2 kg/m2 was significantly associated with local-regional recurrence (Fig.	('obese', 'Disease', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('local-regional recurrence', 'CPA', (181, 206))	('associated with', 'Reg', (165, 180))	('patients', 'Species', '9606', (52, 60))	('BMI', 'Var', (131, 134))	('overweight', 'Phenotype', 'HP:0025502', (31, 41))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('obese', 'Disease', 'MESH:D009765', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
60013	27511848	Data from this cohort of predominantly overweight, early stage breast cancer patients receiving breast conservation surgery and whole breast irradiation suggest that higher body mass index may increase the rate of local-regional recurrence.	('local-regional recurrence', 'CPA', (214, 239))	('overweight', 'Phenotype', 'HP:0025502', (39, 49))	('increase', 'PosReg', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('patients', 'Species', '9606', (77, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('higher body mass index', 'Var', (166, 188))
60039	26868906	From these three samples, the distribution of several detected lipid species [m/z 706.5, PC (30:0); m/z 718.6, PC(32:0) or PE(35:0); m/z 724.5, PE(34:1); m/z 730.5, PC(32:2)] was found to be homogeneous in the ion images, and all of the ions that could distinguish breast cancer tissue from normal breast tissue or benign breast tissue were determined by AFAI-MSI.	('PC', 'Chemical', 'MESH:D010713', (165, 167))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('PE', 'Chemical', 'MESH:C483858', (144, 146))	('PE', 'Chemical', 'MESH:C483858', (123, 125))	('lipid', 'Chemical', 'MESH:D008055', (63, 68))	('PC', 'Chemical', 'MESH:D010713', (89, 91))	('PC', 'Chemical', 'MESH:D010713', (111, 113))	('breast cancer', 'Disease', 'MESH:D001943', (265, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (265, 278))	('m/z 718.6', 'Var', (100, 109))	('breast cancer', 'Disease', (265, 278))
60045	26868906	The ion maps of four representative ions [m/z 706.5, PC(30:0); m/z 718.6, PC(32:0) or PE(35:0); m/z 724.5, PE(34:1); and m/z 730.5, PC(32:2)] are present.	('m/z 724.5', 'Var', (96, 105))	('m/z 718.6', 'Var', (63, 72))	('PE', 'Chemical', 'MESH:C483858', (107, 109))	('PC', 'Chemical', 'MESH:D010713', (132, 134))	('PE', 'Chemical', 'MESH:C483858', (86, 88))	('PC', 'Chemical', 'MESH:D010713', (53, 55))	('PC', 'Chemical', 'MESH:D010713', (74, 76))	('[m/z 706.5', 'Var', (41, 51))	('m/z 730.5', 'Var', (121, 130))
60052	26868906	Figure 2B shows that N6 is characterized by high relative abundances of the ions [m/z 782.6, [PC(34:1)+Na]+; m/z 808.6, [PC(36:2)+Na]+; m/z 810.6, [PC(36:1)+Na]+; and m/z 813.6, SM(42:2)], which is in agreement with the histopathological evaluation of an H&E-stained serial tissue section, this sample was diagnosed as medium-grade IDC.	('m/z 810.6', 'Var', (136, 145))	('[PC(34:1)+Na]+; m/z 808.6', 'Var', (93, 118))	('m/z 813.6', 'Var', (167, 176))	('H&E', 'Chemical', '-', (255, 258))	('PC', 'Chemical', 'MESH:D010713', (121, 123))	('PC', 'Chemical', 'MESH:D010713', (94, 96))	('PC', 'Chemical', 'MESH:D010713', (148, 150))	('SM', 'Chemical', 'MESH:D013109', (178, 180))	('[m/z 782.6', 'Var', (81, 91))
60054	26868906	1C,D: m/z 295.2, FA(18:2); m/z 311.2, octadecanoids; m/z 327.2, FA(22:6); and m/z 329.2, FA(22:5).	('octadecanoids', 'Chemical', '-', (38, 51))	('m/z 295.2', 'Var', (6, 15))	('m/z 329.2', 'Var', (78, 87))	('m/z 311.2', 'Var', (27, 36))	('m/z 327.2', 'Var', (53, 62))	('octadecanoids', 'MPA', (38, 51))
60065	26868906	We not only found m/z 700-900 phospholipid profiles but also noted abundant free fatty acids (m/z 100-500) in this case.	('free fatty acids', 'Chemical', 'MESH:D005230', (76, 92))	('m/z 100-500', 'Var', (94, 105))	('free fatty acids', 'MPA', (76, 92))	('phospholipid', 'Chemical', 'MESH:D010743', (30, 42))	('m/z 700-900', 'Var', (18, 29))	('phospholipid profiles', 'MPA', (30, 51))
60092	26868906	Accumulating evidence suggests that molecular changes in lipids are a widespread phenomenon in malignant tumor cells.	('malignant tumor', 'Disease', 'MESH:D018198', (95, 110))	('lipids', 'Chemical', 'MESH:D008055', (57, 63))	('molecular changes', 'Var', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('malignant tumor', 'Disease', (95, 110))
60138	22911365	In women undergoing MRI, average weight of excision at definitive surgery was 49.5 g, while in women who did not undergo MRI, average weight of excision at definitive surgery was 48.7 g. Our data show that MRI does not significantly decrease reexcision rates or conversion to mastectomy after attempted breast-conservation surgery.	('MRI', 'Var', (206, 209))	('reexcision rates', 'CPA', (242, 258))	('decrease', 'NegReg', (233, 241))	('women', 'Species', '9606', (95, 100))	('women', 'Species', '9606', (3, 8))	('mastectomy', 'Disease', (276, 286))
60195	22911365	In our cohort, 2/154 women who underwent MRI for DCIS were ultimately diagnosed with higher-stage contralateral cancers (both stage I) as a result of the MRI.	('MRI', 'Var', (154, 157))	('contralateral cancers', 'Disease', 'MESH:D009369', (98, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('women', 'Species', '9606', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('contralateral cancers', 'Disease', (98, 119))
60208	17060931	Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer.	('epithelial cancers', 'Disease', 'MESH:D000077216', (235, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('c-Src', 'Gene', (152, 157))	('c-SRC', 'Gene', '6714', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('positivity', 'Var', (107, 117))	('c-SRC', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('human', 'Species', '9606', (229, 234))	('HER2', 'Gene', '2064', (102, 106))	('c-Src', 'Gene', '6714', (152, 157))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (19, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('Activated', 'PosReg', (0, 9))	('Overexpression', 'PosReg', (118, 132))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('activity', 'MPA', (140, 148))	('associated with', 'Reg', (190, 205))	('tumour', 'Disease', (65, 71))	('ductal carcinoma', 'Disease', (19, 35))	('high proliferation', 'CPA', (79, 97))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('breast cancer', 'Disease', (264, 277))	('epithelial cancers', 'Disease', (235, 253))	('HER2', 'Gene', (102, 106))	('ductal carcinoma', 'Disease', 'MESH:D044584', (19, 35))
60211	17060931	High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation.	('tumour', 'Disease', (69, 75))	('c-Src', 'Gene', '6714', (25, 30))	('comedo', 'Phenotype', 'HP:0025249', (83, 89))	('necrosis', 'Disease', (90, 98))	('positivity', 'Var', (52, 62))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('epithelial proliferation', 'CPA', (112, 136))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('HER2', 'Protein', (47, 51))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('elevated', 'PosReg', (103, 111))	('c-Src', 'Gene', (25, 30))
60212	17060931	In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011).	('c-Src', 'Gene', (39, 44))	('c-Src', 'Gene', '6714', (39, 44))	('high', 'Var', (24, 28))	('recurrence-free survival', 'CPA', (73, 97))	('lower', 'NegReg', (67, 72))
60224	17060931	mAb Clone 28 recognizes an epitope adjacent to Tyrosine 530 in the C terminal regulatory domain of activated c-Src (Kawakatsu et al, 1996).	('c-Src', 'Gene', (109, 114))	('Tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('c-Src', 'Gene', '6714', (109, 114))	('Tyrosine 530', 'Var', (47, 59))
60243	17060931	High levels of activated c-Src in DCIS was associated with HER2 positivity (P<0.0005), high tumour nuclear grade (P<0.0005), the presence of comedo necrosis (P=0.001) and high Ki67 scores (P=0.025), but not with ER status (P=0.973), tumour size (P=0.403) and EGFR/HER1 expression (P=0.507).	('c-Src', 'Gene', '6714', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('positivity', 'Var', (64, 74))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('HER1', 'Gene', '1956', (264, 268))	('tumour', 'Disease', (92, 98))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('necrosis', 'Disease', (148, 156))	('EGFR', 'Gene', '1956', (259, 263))	('tumour', 'Disease', (233, 239))	('comedo', 'Phenotype', 'HP:0025249', (141, 147))	('necrosis', 'Disease', 'MESH:D009336', (148, 156))	('EGFR', 'Gene', (259, 263))	('HER1', 'Gene', (264, 268))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('HER2', 'Protein', (59, 63))	('c-Src', 'Gene', (25, 30))
60247	17060931	Other factors including HER2 status, Ki67, tumour nuclear grade, margin status and patient age were also significant predictors of disease recurrence (Table 2).	('HER2', 'Protein', (24, 28))	('Ki67', 'Var', (37, 41))	('tumour', 'Disease', (43, 49))	('patient', 'Species', '9606', (83, 90))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
60258	17060931	Furthermore, high expression of activated c-Src correlated with significantly lower recurrence-free survival at 5 years.	('c-Src', 'Gene', (42, 47))	('high', 'Var', (13, 17))	('recurrence-free survival at 5 years', 'CPA', (84, 119))	('c-Src', 'Gene', '6714', (42, 47))	('lower', 'NegReg', (78, 83))
60262	17060931	However, highly expressed activated c-Src was also seen in HER2 negative DCIS thus HER2 independent pathways for activation must exist.	('HER2', 'Var', (59, 63))	('activated', 'PosReg', (26, 35))	('c-Src', 'Gene', (36, 41))	('c-Src', 'Gene', '6714', (36, 41))	('negative', 'NegReg', (64, 72))
60315	33935708	The deficiency of dietary selenium increases the risk of various diseases including cancer development.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('deficiency', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('selenium', 'Gene', (26, 34))	('selenium', 'Gene', '6713', (26, 34))	('men', 'Species', '9606', (98, 101))
60334	33935708	Immunohistochemical stains for LCIS and its variants have exhibited a complete or partial loss of cell-cell adhesion protein epithelial-Cadherin (E-cadherin) expression and the presence of p120 cytoplasmic catenin which is considered as the positive marker for LCIS.	('epithelial-Cadherin', 'Gene', '999', (125, 144))	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('loss', 'NegReg', (90, 94))	('expression', 'MPA', (158, 168))	('p120', 'Gene', '1500', (189, 193))	('epithelial-Cadherin', 'Gene', (125, 144))	('LCIS', 'Gene', (31, 35))	('p120', 'Gene', (189, 193))	('variants', 'Var', (44, 52))	('presence', 'Reg', (177, 185))
60373	33935708	GPx2, GPx3 modulate carcinogenesis and peroxidation in case of low glutathione respectively.	('modulate', 'Reg', (11, 19))	('GPx2', 'Gene', '2877', (0, 4))	('GPx2', 'Gene', (0, 4))	('carcinogenesis', 'Disease', 'MESH:D063646', (20, 34))	('GPx3', 'Gene', (6, 10))	('carcinogenesis', 'Disease', (20, 34))	('peroxidation', 'MPA', (39, 51))	('low', 'Var', (63, 66))	('glutathione', 'Chemical', 'MESH:D005978', (67, 78))	('GPx3', 'Gene', '2878', (6, 10))	('low glutathione', 'Phenotype', 'HP:0003343', (63, 78))
60380	33935708	This increases the obesity-induced oxidative stress causing DNA damage leading to modified bases or mutations in tumor suppressor genes, a critical factor in carcinogenesis.	('tumor', 'Disease', (113, 118))	('mutations', 'Var', (100, 109))	('obesity', 'Disease', 'MESH:D009765', (19, 26))	('obesity', 'Disease', (19, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('modified', 'Var', (82, 90))	('DNA damage', 'MPA', (60, 70))	('oxidative stress', 'Phenotype', 'HP:0025464', (35, 51))	('increases', 'PosReg', (5, 14))	('carcinogenesis', 'Disease', (158, 172))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('obesity', 'Phenotype', 'HP:0001513', (19, 26))	('oxidative stress', 'MPA', (35, 51))
60392	33935708	Inhibition of TrxR reduces the reduced Trx thus increasing the oxidized Trx in the cells which binds to a number of apoptosis regulating proteins thus promoting apoptosis.	('Trx', 'Gene', '7295', (14, 17))	('promoting', 'PosReg', (151, 160))	('Trx', 'Gene', '7295', (72, 75))	('Trx', 'Gene', (14, 17))	('Trx', 'Gene', (72, 75))	('apoptosis', 'CPA', (161, 170))	('increasing', 'PosReg', (48, 58))	('Inhibition', 'Var', (0, 10))	('Trx', 'Gene', '7295', (39, 42))	('binds', 'Interaction', (95, 100))	('Trx', 'Gene', (39, 42))	('oxidized', 'MPA', (63, 71))
60405	33935708	Polymorphisms in selenoproteins are associated with variations in protein levels and pose a cancer risk to the system.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('variations', 'Reg', (52, 62))	('selenoprotein', 'Gene', '93684', (17, 30))	('selenoprotein', 'Gene', (17, 30))	('associated', 'Reg', (36, 46))	('protein levels', 'MPA', (66, 80))
60426	33935708	Methylselenol, a metabolite of selenium, upregulates natural killer group 2 member D (NKG2D) ligands on the surface of the tumor cells which are then recognized and eliminated by the CD8+ T cells also expressing NKG2D.	('NKG2D', 'Gene', (212, 217))	('NKG2D', 'Gene', '22914', (86, 91))	('tumor', 'Disease', (123, 128))	('Methylselenol', 'Chemical', 'MESH:C019003', (0, 13))	('CD8', 'Gene', '925', (183, 186))	('NKG2D', 'Gene', (86, 91))	('Methylselenol', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('upregulates', 'PosReg', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('CD8', 'Gene', (183, 186))	('NKG2D', 'Gene', '22914', (212, 217))	('selenium', 'Gene', (31, 39))	('natural killer group 2 member D', 'Gene', '22914', (53, 84))	('selenium', 'Gene', '6713', (31, 39))	('natural killer group 2 member D', 'Gene', (53, 84))
60436	33935708	In specific, MSA inhibits the STAT dimer and the PII and PI.4 promoters of the CYP19A1 gene that transforms androgens to estrogens.	('inhibits', 'NegReg', (17, 25))	('MSA', 'Var', (13, 16))	('CYP19A1', 'Gene', (79, 86))	('transforms', 'MPA', (97, 107))	('STAT dimer', 'MPA', (30, 40))	('MSA', 'Chemical', 'MESH:C008493', (13, 16))	('CYP19A1', 'Gene', '1588', (79, 86))
60442	33935708	Increased inactivation of the promitogenic and prosurvival PKC epsilon isoenzyme resulted in reduced cell growth and increased apoptosis and has also been shown to enhance insulin sensitivity.	('enhance', 'PosReg', (164, 171))	('increased', 'PosReg', (117, 126))	('cell growth', 'CPA', (101, 112))	('PKC epsilon', 'Gene', (59, 70))	('inactivation', 'Var', (10, 22))	('reduced', 'NegReg', (93, 100))	('enhance insulin sensitivity', 'Phenotype', 'HP:0000855', (164, 191))	('apoptosis', 'CPA', (127, 136))	('insulin', 'Gene', (172, 179))	('PKC epsilon', 'Gene', '5581', (59, 70))	('insulin', 'Gene', '3630', (172, 179))
60465	33935708	The cancerous cell has the property of cell invasion by amoeboid cell movement which is acquired by inhibition of beta1-integrin leading to collective to amoeboid transition (CAT) or by inhibition of proteases leading to mesenchymal to amoeboid transition (MAT).	('mesenchymal to amoeboid transition', 'CPA', (221, 255))	('inhibition', 'NegReg', (186, 196))	('cancerous', 'Disease', 'MESH:D009369', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('beta1-integrin', 'Gene', '3688', (114, 128))	('inhibition', 'Var', (100, 110))	('beta1-integrin', 'Gene', (114, 128))	('men', 'Species', '9606', (74, 77))	('cancerous', 'Disease', (4, 13))	('collective to amoeboid transition', 'CPA', (140, 173))
60486	33935708	Particularly SeMet increases the redox status of cancer cells by increasing the expression of uncoupling protein 2 (UCP2) and redox enzymes and also reducing oxidative damage to proteins and lipids.	('SeMet', 'Var', (13, 18))	('reducing', 'NegReg', (149, 157))	('UCP2', 'Gene', '7351', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('SeMet', 'Chemical', 'MESH:D012645', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('redox status', 'MPA', (33, 45))	('increases', 'PosReg', (19, 28))	('lipids', 'Chemical', 'MESH:D008055', (191, 197))	('increasing', 'PosReg', (65, 75))	('expression', 'MPA', (80, 90))	('UCP2', 'Gene', (116, 120))	('uncoupling protein 2', 'Gene', '7351', (94, 114))	('cancer', 'Disease', (49, 55))	('uncoupling protein 2', 'Gene', (94, 114))
60487	33935708	In contrast to this, selenocysteine decreased the antioxidant enzyme and UCP2 protein expression, thereby increasing the ROS production and decreasing the viability of breast cancer cells.	('UCP2', 'Gene', (73, 77))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('decreasing', 'NegReg', (140, 150))	('selenocysteine', 'Var', (21, 35))	('breast cancer', 'Disease', (168, 181))	('viability', 'CPA', (155, 164))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('expression', 'MPA', (86, 96))	('UCP2', 'Gene', '7351', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('ROS production', 'MPA', (121, 135))	('increasing', 'PosReg', (106, 116))	('antioxidant', 'Enzyme', (50, 61))	('selenocysteine', 'Chemical', 'MESH:D017279', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('decreased', 'NegReg', (36, 45))
60490	33935708	Nonetheless, some studies have reported that UCP2 expression confers a pro-survival advantage for cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'Var', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('UCP2', 'Gene', '7351', (45, 49))	('cancer', 'Disease', (98, 104))	('pro-survival advantage', 'CPA', (71, 93))	('UCP2', 'Gene', (45, 49))
60508	33935708	GSH depletion induces oxidative stress-induced necroptosis owing to pharmacological inhibition.	('depletion', 'Var', (4, 13))	('induces', 'Reg', (14, 21))	('oxidative stress-induced necroptosis', 'MPA', (22, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (22, 38))	('GSH', 'Chemical', '-', (0, 3))
60510	33935708	However, the mechanism of RSL3-induced ferroptosis is not by depleting GSH but by inactivating GPX4.	('ferroptosis', 'Disease', (39, 50))	('GPX4', 'Gene', (95, 99))	('GPX4', 'Gene', '2879', (95, 99))	('inactivating', 'NegReg', (82, 94))	('GSH', 'Chemical', '-', (71, 74))	('RSL3', 'Chemical', '-', (26, 30))	('RSL3-induced', 'Var', (26, 38))	('GSH', 'MPA', (71, 74))
60511	33935708	GPX4 silencing sensitizes RSL3-induced ferroptosis cells that are followed by lipid ROS accumulation.	('GPX4', 'Gene', (0, 4))	('GPX4', 'Gene', '2879', (0, 4))	('silencing', 'Var', (5, 14))	('RSL3', 'Chemical', '-', (26, 30))	('lipid', 'Chemical', 'MESH:D008055', (78, 83))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
60634	26686957	With B-35 we report a further decrease in events, particularly contralateral IBC, in postmenopausal women <60 years.	('decrease', 'NegReg', (30, 38))	('B-35', 'Var', (5, 9))	('women', 'Species', '9606', (100, 105))
60766	22607447	The assessments reported in our previous study are shown (with permission) in Table 1, including the number of cases in the following categories: inadequate cases, C1 + G1 (benign) and E1 + J1 (malignant); indeterminate cases, C3 + G3 (benign) and E3 + J3 (malignant); false-negative cases, E2 + J2; and false positive cases, C5 + G5.	('C1 + G1 (benign) and E1 + J1 (malignant); indeterminate cases, C3 + G3', 'Gene', '28950', (164, 234))	('C5 + G5', 'Var', (326, 333))	('E3 + J3', 'Var', (248, 255))	('E2 + J2', 'Var', (291, 298))
60866	17147824	For each sample, two arrays were utilized in a dye-swap pair format, in which the experimental sample and reference sample are each labeled separately with cyanine 3 and cyanine 5, respectively, and combined for the first array, and then labeled in the reverse and combined for the second array.	('cyanine', 'Var', (156, 163))	('cyanine 5', 'Chemical', '-', (170, 179))	('cyanine 3', 'Chemical', '-', (156, 165))	('cyanine', 'Var', (170, 177))
60885	17147824	Ovarian ablation decreased the average MIN-O size and delayed palpable tumor development, but with various degrees of statistical significance in each line.	('decreased', 'NegReg', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('MIN-O size', 'CPA', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('delayed palpable', 'Phenotype', 'HP:0000270', (54, 70))	('tumor', 'Disease', (71, 76))	('ablation', 'Var', (8, 16))	('delayed', 'NegReg', (54, 61))
60898	17147824	The most common gain associated with the tumor transformation was the whole chromosome gain of chromosome 15 (4 out of 14 tumors) (Figure 1D).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('14 tumors', 'Disease', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('whole chromosome gain', 'Var', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (122, 127))	('gain', 'PosReg', (16, 20))	('14 tumors', 'Disease', 'MESH:C567448', (119, 128))
60902	17147824	Other regions that were found to have deletions in one MIN-O/tumor pair were 12A, 16C2, and 3D-E1.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (61, 66))	('deletions', 'Var', (38, 47))
60903	17147824	Also, the deletion of a small region in 19D was found in a single tumor.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('deletion', 'Var', (10, 18))
60905	17147824	Another area of interest was duplication of 11E1 found in one tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('11E1', 'Gene', (44, 48))	('duplication', 'Var', (29, 40))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
60919	17147824	When expression of genes on chromosome 2 from the MIN-O lines with whole chromosome gains (8w-B and 4w-4) were compared to those from the lines with normal chromosome number (4w-11 and 8w-D), 60 probes had significantly higher expression (p < 0.01) in 8w-B and 4w-4 MIN-Os, while only 5 probes had significantly lower expression, when compared to 4w-11 and 8w-D MIN-Os (Table 5).	('4w-', 'Chemical', '-', (347, 350))	('expression', 'MPA', (227, 237))	('probes', 'Var', (195, 201))	('4w-', 'Chemical', '-', (175, 178))	('higher', 'PosReg', (220, 226))	('4w-', 'Chemical', '-', (261, 264))	('4w-', 'Chemical', '-', (100, 103))
60925	17147824	The genes in these regions are: Hspa12b, 1700037H04Rik, Spef1, Cenpb, cdc25b, 2310035K24Rik, D430028G21Rik, Pank2, Rnf24, Smox, Adra1d, 1600014E20Rik, Prnp, Rassf2, Slc23a2, on chromosome 2; Trim2, 6330505N24Rik, on chromosome 3; and 2810410M20Rik on chromosome 17.	('Adra1d', 'Gene', (128, 134))	('cdc25b', 'Gene', (70, 76))	('1600014E20Rik', 'Gene', (136, 149))	('Trim2', 'Gene', '80890', (191, 196))	('Adra1d', 'Gene', '11550', (128, 134))	('1700037H04Rik', 'Var', (41, 54))	('Slc23a2', 'Gene', (165, 172))	('2310035K24Rik', 'Var', (78, 91))	('Rassf2', 'Gene', '215653', (157, 163))	('Prnp', 'Gene', (151, 155))	('1600014E20Rik', 'Gene', '71995', (136, 149))	('Rassf2', 'Gene', (157, 163))	('cdc25b', 'Gene', '12531', (70, 76))	('Pank2', 'Gene', '74450', (108, 113))	('Spef1', 'Gene', (56, 61))	('Trim2', 'Gene', (191, 196))	('D430028G21Rik', 'Var', (93, 106))	('2810410M20Rik', 'Gene', '66310', (234, 247))	('Pank2', 'Gene', (108, 113))	('Slc23a2', 'Gene', '54338', (165, 172))	('Cenpb', 'Gene', (63, 68))	('Hspa12b', 'Gene', '72630', (32, 39))	('Hspa12b', 'Gene', (32, 39))	('Smox', 'Gene', '228608', (122, 126))	('Smox', 'Gene', (122, 126))	('Prnp', 'Gene', '19122', (151, 155))	('Cenpb', 'Gene', '12616', (63, 68))	('Spef1', 'Gene', '70997', (56, 61))	('2810410M20Rik', 'Gene', (234, 247))	('Rnf24', 'Gene', '51902', (115, 120))	('Rnf24', 'Gene', (115, 120))
60926	17147824	The deleted regions in 3E and 17E were covered by only one probe each (104207_at for 6330505N24 and 98886_at for 2810410M20Rik).	('2810410M20Rik', 'Gene', (113, 126))	('104207_at for 6330505N24', 'Var', (71, 95))	('2810410M20Rik', 'Gene', '66310', (113, 126))
60953	17147824	Moreover, the expression of cyp19a1, an aromatase which catalyzes essential reactions for estrogen biosynthesis, is also slightly but statistically significantly higher in the 8w-B and 8w-D lines (fold change = 1.07, p = 0.0068).	('8w-B', 'Var', (176, 180))	('higher', 'PosReg', (162, 168))	('cyp19a1', 'Gene', '13075', (28, 35))	('expression', 'MPA', (14, 24))	('cyp19a1', 'Gene', (28, 35))
60961	17147824	The finding that the MIN-Os already have the major genomic and expression changes that have previously been associated with tumorigenesis is consistent with observations in human breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (179, 192))	('tumor', 'Disease', (124, 129))	('changes', 'Var', (74, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('human', 'Species', '9606', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
60971	17147824	Moreover, for the other two areas of deletion, the losses of DNA were confirmed to span the same areas in the MIN-Os and the tumors.	('DNA', 'Gene', (61, 64))	('losses', 'NegReg', (51, 57))	('deletion', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))
60974	17147824	These studies have identified regions of frequent copy number changes in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('copy number changes', 'Var', (50, 69))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
60975	17147824	For example, ErbB2 amplicon on 17q21 is amplified in 20-30% of breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ErbB2', 'Gene', (13, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('amplicon on', 'Var', (19, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('ErbB2', 'Gene', '13866', (13, 18))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('breast cancers', 'Disease', (63, 77))	('amplified', 'Var', (40, 49))
60976	17147824	Frequent copy number changes of certain chromosome regions are associated with BRCA1 and BRCA2 tumors, and they can be classified by the genomic copy number alterations.	('BRCA1 and BRCA2 tumors', 'Disease', 'OMIM:604370', (79, 101))	('copy number changes', 'Var', (9, 28))	('associated', 'Reg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
60977	17147824	has shown that breast tumors can be classified into three subtypes based on the copy number alteration phenotypes.	('breast tumors', 'Disease', 'MESH:D001943', (15, 28))	('breast tumors', 'Disease', (15, 28))	('copy number alteration', 'Var', (80, 102))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('breast tumors', 'Phenotype', 'HP:0100013', (15, 28))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
60987	17147824	Since major molecular changes had occurred in the MIN-Os, tumors developed from the MIN-Os had surprisingly small genetic differences from the corresponding MIN-O tissues.	('MIN-Os', 'Var', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))
60995	17147824	Overexpression of AurkA is associated with cancer, including human DCIS.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('human DCIS', 'Disease', (61, 71))	('cancer', 'Disease', (43, 49))	('associated', 'Reg', (27, 37))	('AurkA', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('human', 'Species', '9606', (61, 66))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
61004	17147824	It is believed that changes in apoptotic tumor cell death pattern affect the tumor microenvironment and the associated immune response.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('affect', 'Reg', (66, 72))	('tumor', 'Disease', (41, 46))	('immune response', 'CPA', (119, 134))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('changes', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (77, 82))
61023	17147824	Dysregulation of these genes seems to draw a picture of increase ER and estrogen activities in these MIN-Os.	('Dysregulation', 'Var', (0, 13))	('ER', 'Gene', '13982', (65, 67))	('increase', 'PosReg', (56, 64))
61040	25959051	Mouse studies further suggest that the aberrant mechanics in cancerous tissue contributes to tumor aggression and compromises treatment efficacy.	('contributes', 'Reg', (78, 89))	('compromises', 'NegReg', (114, 125))	('tumor aggression', 'Disease', 'MESH:D001523', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('treatment efficacy', 'CPA', (126, 144))	('aggression', 'Phenotype', 'HP:0000718', (99, 109))	('cancerous', 'Disease', 'MESH:D009369', (61, 70))	('cancerous', 'Disease', (61, 70))	('Mouse', 'Species', '10090', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('aberrant mechanics', 'Var', (39, 57))	('tumor aggression', 'Disease', (93, 109))
61049	25959051	Collagen abundance in the primary breast tumor is also a significant risk factor for patient mortality.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('breast tumor', 'Disease', (34, 46))	('patient', 'Species', '9606', (85, 92))	('breast tumor', 'Phenotype', 'HP:0100013', (34, 46))	('breast tumor', 'Disease', 'MESH:D001943', (34, 46))	('Collagen', 'Var', (0, 8))
61050	25959051	Indeed, breast cancer patients with high levels of the collagen cross-linker lysyl oxidase (LOX) have a higher probability of developing metastatic lesions.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('metastatic lesions', 'CPA', (137, 155))	('high', 'Var', (36, 40))	('lysyl oxidase', 'Gene', (77, 90))	('LOX', 'Gene', (92, 95))	('lysyl oxidase', 'Gene', '4015', (77, 90))	('patients', 'Species', '9606', (22, 30))	('LOX', 'Gene', '4015', (92, 95))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
61051	25959051	Because collagen stiffness increases as a function of concentration, fiber width and with LOX-mediated cross-linking these findings imply that ECM stiffness promotes malignancy and enhances tumor aggression in breast cancer patients.	('tumor aggression', 'Disease', (190, 206))	('tumor aggression', 'Disease', 'MESH:D001523', (190, 206))	('LOX', 'Gene', '4015', (90, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('promotes', 'PosReg', (157, 165))	('LOX', 'Gene', (90, 93))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('rat', 'Species', '10116', (61, 64))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('aggression', 'Phenotype', 'HP:0000718', (196, 206))	('breast cancer', 'Disease', (210, 223))	('patients', 'Species', '9606', (224, 232))	('enhances', 'PosReg', (181, 189))	('ECM stiffness', 'Var', (143, 156))	('malignancy', 'Disease', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
61068	25959051	Second harmonics generation (SHG) imaging using two-photon microscopy additionally revealed that the collagen fibers surrounding the DCIS lesions were more linearized, as compared to the collagens associated with the adjacent normal breast tissue, and that these linearized collagens appeared thicker in the stroma within the tissue regions contained the transformed IDC (Figure 1A; fourth panel).	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('IDC', 'Gene', '4000', (367, 370))	('more', 'PosReg', (151, 155))	('IDC', 'Gene', (367, 370))	('lesions', 'Var', (138, 145))	('rat', 'Species', '10116', (21, 24))	('thicker', 'PosReg', (293, 300))
61096	25959051	Moreover, AFM indentation indicated that the invasive front in the higher grant Her2+ and TNBCs were significantly stiffer than the less aggressive luminal breast tumors.	('breast tumor', 'Phenotype', 'HP:0100013', (156, 168))	('Her2', 'Gene', (80, 84))	('aggressive luminal breast tumors', 'Disease', 'MESH:D001943', (137, 169))	('invasive front', 'CPA', (45, 59))	('Her2', 'Gene', '2064', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TNBCs', 'Var', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('aggressive luminal breast tumors', 'Disease', (137, 169))	('breast tumors', 'Phenotype', 'HP:0100013', (156, 169))
61097	25959051	Furthermore, analysis of immunofluorescence images of the invasive front of the luminal A, luminal B, Her2+ and TNBC biopsied tissue revealed that the cells within the more aggressive tumor subtypes (Her2+, TNBC) had the highest levels of activated beta1 integrin (Activated beta1 integrin) and FAK (pY397FAK) and were more contractile (pS19MLC) indicating they were likely more mechanically activated (Figure 6A; images quantified in bar graphs shown in B).	('beta1 integrin', 'Gene', '3688', (275, 289))	('Her2', 'Gene', (200, 204))	('FAK', 'Gene', '5747', (305, 308))	('activated', 'PosReg', (239, 248))	('FAK', 'Gene', (305, 308))	('beta1 integrin', 'Gene', '3688', (249, 263))	('FAK', 'Gene', '5747', (295, 298))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('beta1 integrin', 'Gene', (275, 289))	('Her2', 'Gene', '2064', (200, 204))	('Her2', 'Gene', (102, 106))	('aggressive tumor', 'Disease', 'MESH:D001523', (173, 189))	('FAK', 'Gene', (295, 298))	('TNBC', 'Var', (207, 211))	('beta1 integrin', 'Gene', (249, 263))	('Her2', 'Gene', '2064', (102, 106))	('aggressive tumor', 'Disease', (173, 189))	('contractile', 'CPA', (324, 335))
61143	25959051	Rotation of the top polarizer (rotation angle theta) results in a sinusoidal modulation of the light intensity at each pixel: where, phi is the principal axis and delta is the phase retardance (in radian) defined by The polarizer stage steps in 4  per step with a total of 200 .	('Rotation', 'Var', (0, 8))	('sinusoidal modulation', 'MPA', (66, 87))	('retardance', 'Disease', (182, 192))	('retardance', 'Disease', 'MESH:D008607', (182, 192))	('phi', 'Var', (133, 136))	('rotation angle theta', 'Disease', (31, 51))	('rotation angle theta', 'Disease', 'MESH:D009069', (31, 51))
61218	32994388	In accordance with the description of the method, the average values were determined for the differences between DeltaMG, DeltaCESM, DeltaMG%, and DeltaCESM% versus the HP measurement for the pre-defined subgroups (carcinoma type in CNB, grading, biological subtype).	('CESM', 'Chemical', '-', (152, 156))	('carcinoma', 'Disease', 'MESH:D009369', (215, 224))	('DeltaCESM%', 'Var', (147, 157))	('CESM', 'Chemical', '-', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('DeltaMG%', 'Var', (133, 141))	('carcinoma', 'Disease', (215, 224))
61317	26251627	Similarly, multifocal breast cancer is likely a risk factor for regional IBTR, conceivably because a negative surgical margin could be reported by bisecting breast tissue separating two distinct islands of tumor cells and therefore leaving disease in the breast.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('tumor', 'Disease', (206, 211))	('bisecting', 'Var', (147, 156))	('leaving', 'Reg', (232, 239))	('multifocal breast cancer', 'Disease', (11, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('multifocal breast cancer', 'Disease', 'None', (11, 35))	('multifocal breast cancer', 'Phenotype', 'HP:0006625', (11, 35))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
61319	26251627	An EIC not only increases the total tumor diameter but has been shown to predict for residual disease after lumpectomy in older mastectomy series.	('predict', 'Reg', (73, 80))	('EIC', 'Var', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('residual disease', 'Disease', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('increases', 'PosReg', (16, 25))	('tumor', 'Disease', (36, 41))
61374	26251627	McHaffie et al demonstrated that women with DCIS or age 50-59 as their only "cautionary" risk factor that otherwise would have met "suitable" criteria had excellent locoregional control compared with other "cautionary" patient factors.	('patient', 'Species', '9606', (219, 226))	('women', 'Species', '9606', (33, 38))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('locoregional control', 'CPA', (165, 185))	('DCIS', 'Var', (44, 48))
61440	18837981	In addition, apoptotic index, Ki-67 index, and positive Bcl-2 immunolabeling tended to be higher in DCIS-Mi than in DCIS.	('apoptotic index', 'CPA', (13, 28))	('Bcl-2', 'Gene', (56, 61))	('Bcl-2', 'Gene', '596', (56, 61))	('DCIS-Mi', 'Chemical', '-', (100, 107))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('DCIS-Mi', 'Var', (100, 107))	('higher', 'PosReg', (90, 96))	('Ki-67 index', 'CPA', (30, 41))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
61442	18837981	Compared with DCIS, DCIS-Mi is characterized by a slightly elevated cell proliferation capacity and enhanced apoptosis within the intraductal lesion, both of which are thought to promote the formation of cell necrotic foci.	('necrotic foci', 'Disease', (209, 222))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('DCIS-Mi', 'Var', (20, 27))	('enhanced', 'PosReg', (100, 108))	('apoptosis', 'CPA', (109, 118))	('promote', 'PosReg', (179, 186))	('DCIS-Mi', 'Chemical', '-', (20, 27))	('elevated', 'PosReg', (59, 67))	('cell proliferation capacity', 'CPA', (68, 95))	('necrotic foci', 'Disease', 'MESH:C565785', (209, 222))
61490	18837981	There was no difference in nuclear grade between the two groups but a necrotic focus was found at a significantly higher frequency in DCIS-Mi (85.7%) than in DCIS (51.9%) (P = 0.0017).	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('necrotic', 'Disease', (70, 78))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('necrotic', 'Disease', 'MESH:D009336', (70, 78))	('DCIS-Mi', 'Chemical', '-', (134, 141))	('DCIS-Mi', 'Var', (134, 141))
61491	18837981	According to the Van Nuys classification, which evaluates both nuclear grade and necrosis, the grade of malignancy was significantly higher in DCIS-Mi (14.3%, Grade 1) than in DCIS (48.1%, Grade 1) (P = 0.0017, Grade 1 vs. Grade 2 and 3) (Table 2).	('DCIS-Mi', 'Chemical', '-', (143, 150))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('DCIS-Mi', 'Var', (143, 150))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('higher', 'PosReg', (133, 139))	('malignancy', 'Disease', (104, 114))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('necrosis', 'Disease', (81, 89))
61493	18837981	The Ki-67 index tended to be higher in DCIS-Mi (22.8 +- 2.0%) than in DCIS (17.9 +- 1.5%), although the difference was not statistically significant (P = 0.052) (Table 3).	('higher', 'PosReg', (29, 35))	('DCIS-Mi', 'Chemical', '-', (39, 46))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('DCIS-Mi', 'Var', (39, 46))	('Ki-67', 'Gene', (4, 9))
61495	18837981	Apoptotic index tended to be higher in DCIS-Mi (0.29 +- 0.06%) than in DCIS (0.17 +- 0.04%) (P = 0.082).	('higher', 'PosReg', (29, 35))	('DCIS-Mi', 'Chemical', '-', (39, 46))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('Apoptotic index', 'CPA', (0, 15))	('DCIS-Mi', 'Var', (39, 46))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
61496	18837981	The expression of Bax, a promoting factor of apoptosis, was significantly higher in DCIS-Mi (96.4%) than in DCIS (71.2%) (P = 0.0028).	('higher', 'PosReg', (74, 80))	('Bax', 'Gene', '581', (18, 21))	('expression', 'MPA', (4, 14))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('DCIS-Mi', 'Chemical', '-', (84, 91))	('Bax', 'Gene', (18, 21))	('DCIS-Mi', 'Var', (84, 91))
61506	18837981	The important result obtained from our analysis of apoptosis-related factors was that the positive rate of survivin expression was significantly higher in DCIS-Mi than in DCIS (P = 0.0048).	('expression', 'MPA', (116, 126))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('survivin', 'Protein', (107, 115))	('DCIS-Mi', 'Chemical', '-', (155, 162))	('DCIS-Mi', 'Var', (155, 162))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('higher', 'PosReg', (145, 151))
61509	18837981	Previous reports have shown that, in invasive ductal carcinoma of the breast, survivin expression is significantly higher in the invasive foci than in the intraductal components and that high nuclear expression of survivin in the invasive foci is associated with a higher risk of recurrence and mortality.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (46, 62))	('invasive ductal carcinoma of the breast', 'Disease', 'MESH:D018270', (37, 76))	('high nuclear', 'Var', (187, 199))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (53, 76))	('invasive ductal carcinoma of the breast', 'Disease', (37, 76))	('expression', 'MPA', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('higher', 'PosReg', (115, 121))	('survivin', 'Protein', (78, 86))
61514	18837981	In our present results, the Bax expression was significantly higher (P = 0.0028) and the Bcl-2 expression tended to be slightly higher (P = 0.071) in DCIS-Mi compared with DCIS.	('DCIS-Mi', 'Chemical', '-', (150, 157))	('DCIS-Mi', 'Var', (150, 157))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('higher', 'PosReg', (61, 67))	('Bax', 'Gene', '581', (28, 31))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('Bax', 'Gene', (28, 31))	('Bcl-2', 'Gene', (89, 94))	('expression', 'MPA', (32, 42))	('Bcl-2', 'Gene', '596', (89, 94))	('higher', 'PosReg', (128, 134))	('expression', 'MPA', (95, 105))
61517	18837981	In our present study, we also found a tendency for higher apoptotic and Ki-67 indices in DCIS-Mi relative to DCIS.	('DCIS-Mi', 'Chemical', '-', (89, 96))	('DCIS-Mi', 'Var', (89, 96))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('apoptotic', 'CPA', (58, 67))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('higher', 'PosReg', (51, 57))	('Ki-67 indices', 'CPA', (72, 85))
61520	18837981	Taken together, it has been suggested that both cell proliferation and apoptosis are enhanced in DCIS-Mi as compared to DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('apoptosis', 'CPA', (71, 80))	('enhanced', 'PosReg', (85, 93))	('cell proliferation', 'CPA', (48, 66))	('DCIS-Mi', 'Chemical', '-', (97, 104))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('DCIS-Mi', 'Var', (97, 104))
61521	18837981	Furthermore, multivariate analysis for apoptosis-related factors affecting invasion, identified the presence of necrosis (P = 0.017) and high survivin expression (P = 0.044) as statistically significant factors.	('necrosis', 'Disease', 'MESH:D009336', (112, 120))	('survivin', 'Protein', (142, 150))	('high', 'Var', (137, 141))	('expression', 'MPA', (151, 161))	('necrosis', 'Disease', (112, 120))
61525	18837981	These results revealed that, compared to DCIS, DCIS-Mi is histologically associated with necrotic focus more commonly, and with a significantly higher expression of apoptosis-related factors, including survivin and Bax.	('necrotic', 'Disease', (89, 97))	('DCIS-Mi', 'Chemical', '-', (47, 54))	('DCIS-Mi', 'Var', (47, 54))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('Bax', 'Gene', (215, 218))	('necrotic', 'Disease', 'MESH:D009336', (89, 97))	('expression', 'MPA', (151, 161))	('higher', 'PosReg', (144, 150))	('Bax', 'Gene', '581', (215, 218))	('associated with', 'Reg', (73, 88))	('survivin', 'Protein', (202, 210))
61526	18837981	In other words, DCIS-Mi is characterized by a slightly elevated cell proliferation ability and a tendency for enhanced apoptosis, which could increase cell death and subsequently promote the formation of necrotic foci.	('death', 'Disease', 'MESH:D003643', (156, 161))	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('death', 'Disease', (156, 161))	('increase', 'PosReg', (142, 150))	('promote', 'PosReg', (179, 186))	('necrotic foci', 'Disease', 'MESH:C565785', (204, 217))	('enhanced', 'PosReg', (110, 118))	('necrotic foci', 'Disease', (204, 217))	('cell proliferation ability', 'CPA', (64, 90))	('apoptosis', 'CPA', (119, 128))	('DCIS-Mi', 'Chemical', '-', (16, 23))	('elevated', 'PosReg', (55, 63))	('DCIS-Mi', 'Var', (16, 23))
61528	18837981	Compared with DCIS, DCIS-Mi is characterized by a slightly elevated cell proliferation capacity and enhanced apoptosis within the intraductal lesion, which are thought to promote the formation of cell necrotic foci.	('necrotic foci', 'Disease', 'MESH:C565785', (201, 214))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('necrotic foci', 'Disease', (201, 214))	('DCIS-Mi', 'Var', (20, 27))	('apoptosis', 'CPA', (109, 118))	('enhanced', 'PosReg', (100, 108))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('DCIS-Mi', 'Chemical', '-', (20, 27))	('elevated', 'PosReg', (59, 67))	('cell proliferation capacity', 'CPA', (68, 95))
61558	30675210	The knockdown of PKC-zeta decreased the nuclear translocation of beta-Catenin which ultimately leads to reduced colorectal cell proliferation and metastasis.	('reduced', 'NegReg', (104, 111))	('PKC-zeta', 'Gene', '5590', (17, 25))	('PKC-zeta', 'Gene', (17, 25))	('beta-Catenin', 'Gene', '1499', (65, 77))	('colorectal', 'Disease', (112, 122))	('beta-Catenin', 'Gene', (65, 77))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (26, 35))	('nuclear translocation of', 'MPA', (40, 64))
61559	30675210	These data were further supported by another investigation performed by Wu et al, which determined that inhibition of PKC-zeta in breast cancer cell lines decreased adhesion and actin polymerization.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('adhesion', 'CPA', (165, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('PKC-zeta', 'Gene', '5590', (118, 126))	('decreased', 'NegReg', (155, 164))	('actin polymerization', 'CPA', (178, 198))	('PKC-zeta', 'Gene', (118, 126))	('inhibition', 'Var', (104, 114))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
61639	30675210	When compared to the control, PKC-zeta knockdown decreased the invasion of breast cancer cells by 60% and was significant (Student's t-test P<0.05, one-way ANOVA Tukey HSD P-value 0.0029646, P<0.01; Scheffe P-value 0.0049622, P<0.01; Bonferroni P-value 0.0040067, P<0.01 and Holm P-value 0.0040067, P<0.01) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('PKC-zeta', 'Gene', (30, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('HSD', 'Disease', (168, 171))	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (49, 58))	('HSD', 'Disease', 'OMIM:143095', (168, 171))	('PKC-zeta', 'Gene', '5590', (30, 38))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
61641	30675210	Moreover, MDA-MB-231 breast cancer cells were fixed and stained with phalloidin probe to visualize the impacts of PRKCZ gene silencing on F-actin organization.	('phalloidin', 'Chemical', 'MESH:D010590', (69, 79))	('PRKCZ', 'Gene', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('F-actin', 'MPA', (138, 145))	('breast cancer', 'Disease', (21, 34))	('PRKCZ', 'Gene', '5590', (114, 119))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (10, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('gene', 'Var', (120, 124))
61642	30675210	The silencing of PRKCZ caused the reorganization of F-actin around the cell cytoskeleton (Fig.	('PRKCZ', 'Gene', (17, 22))	('F-actin around the', 'MPA', (52, 70))	('PRKCZ', 'Gene', '5590', (17, 22))	('silencing', 'Var', (4, 13))	('reorganization', 'Reg', (34, 48))
61645	30675210	Likewise, Paul et al concluded that the depletion of PKC-zeta reduced the invasive behaviors of MDA-MB-231 cells by upregulating epithelial markers such as Zonula occludens-1 (ZO-1) and E-cadherin.	('E-cadherin', 'Gene', (186, 196))	('PKC-zeta', 'Gene', (53, 61))	('E-cadherin', 'Gene', '999', (186, 196))	('upregulating', 'PosReg', (116, 128))	('depletion', 'Var', (40, 49))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (96, 106))	('invasive behaviors of MDA-MB-231 cells', 'CPA', (74, 112))	('ZO-1', 'Gene', '7082', (176, 180))	('Zonula occludens-1', 'Gene', '7082', (156, 174))	('PKC-zeta', 'Gene', '5590', (53, 61))	('epithelial', 'MPA', (129, 139))	('ZO-1', 'Gene', (176, 180))	('Zonula occludens-1', 'Gene', (156, 174))	('reduced', 'NegReg', (62, 69))
61655	30675210	However, previous studies illustrated an increase in E-cadherin levels in PKC-zeta knockdown MDA-MB-231 cells.	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('knockdown', 'Var', (83, 92))	('PKC-zeta', 'Gene', '5590', (74, 82))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('increase', 'PosReg', (41, 49))	('PKC-zeta', 'Gene', (74, 82))
61668	30675210	We found that the knockdown of PKC-zeta by siPRKCZ reduced the invasion of MDA-MB-231 breast cancer cells by 60% (P<0.05) when compared to control (Fig.	('knockdown', 'Var', (18, 27))	('PRKCZ', 'Gene', (45, 50))	('PKC-zeta', 'Gene', '5590', (31, 39))	('reduced', 'NegReg', (51, 58))	('PRKCZ', 'Gene', '5590', (45, 50))	('PKC-zeta', 'Gene', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))
61686	31856858	Lastly, the rates for 10-year overall survival and disease-free survival were significantly lower in patients with positive NEDD4 staining than those in BC patients with negative NEDD4 staining BC (P = 0.0024 and P = 0.0011, respectively).	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (101, 109))	('BC', 'Phenotype', 'HP:0003002', (194, 196))	('NEDD4', 'Gene', (124, 129))	('disease-free survival', 'CPA', (51, 72))	('BC', 'Phenotype', 'HP:0003002', (153, 155))	('positive', 'Var', (115, 123))	('lower', 'NegReg', (92, 97))	('overall survival', 'CPA', (30, 46))
61703	31856858	In addition, aberrant NEDD4 expression has been implicated in pathogenesis and is associated with an adverse prognosis in gastric cardia adenocarcinoma tumors.	('associated', 'Reg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('expression', 'MPA', (28, 38))	('NEDD4', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('gastric cardia adenocarcinoma tumors', 'Disease', (122, 158))	('implicated', 'Reg', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('gastric cardia adenocarcinoma tumors', 'Disease', 'MESH:D004938', (122, 158))	('aberrant', 'Var', (13, 21))
61754	31856858	Data for GSE20685 (microarray-based molecular subtyping of breast cancer) was acquired through Oncomine.com NEDD4 has a role in promoting the growth of hepatocellular and bladder cancer cell lines.	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Oncomine', 'Chemical', '-', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('bladder cancer', 'Disease', (171, 185))	('GS', 'Disease', 'MESH:D011125', (9, 11))	('NEDD4', 'Gene', (108, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('promoting', 'PosReg', (128, 137))	('Oncomine.com', 'Var', (95, 107))	('hepatocellular', 'Disease', (152, 166))	('growth', 'MPA', (142, 148))
61755	31856858	NEDD4 was first knocked down by two independent siRNAs in five BC cell lines: luminal A (MCF7, T47D), luminal B (ZR-75-1), and TNBC (MDA-MB-231, BT549; Fig.	('knocked', 'Var', (16, 23))	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('BT549', 'CellLine', 'CVCL:1092', (145, 150))	('BC', 'Phenotype', 'HP:0003002', (63, 65))	('luminal', 'Chemical', 'MESH:D010634', (78, 85))	('MCF7', 'CellLine', 'CVCL:0031', (89, 93))	('luminal', 'Chemical', 'MESH:D010634', (102, 109))	('NEDD4', 'Gene', (0, 5))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (133, 143))	('T47D', 'CellLine', 'CVCL:0553', (95, 99))
61777	31856858	High NEDD4-expressing BC was associated with a large tumor size (chi2 = 8.973, P = 0.030) and a high incidence of lymph node invasion (chi2 = 10.111, P = 0.001; Table 1).	('NEDD4-expressing', 'Gene', (5, 21))	('BC', 'Phenotype', 'HP:0003002', (22, 24))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('lymph node invasion', 'CPA', (114, 133))
61778	31856858	In addition, high NEDD4 expression correlated with an ER-positive status (chi2 = 4.451, P = 0.035) and a PR-positive status (chi2 = 5.197, P = 0.023; Table 1).	('NEDD4', 'Gene', (18, 23))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('PR', 'Gene', '5241', (105, 107))	('ER', 'Gene', '2099', (54, 56))
61807	31856858	These results clearly show that patients with NEDD4-positive staining BC in stages II and III had a lower survival rate during follow-up, suggesting that NEDD4 expression may be a feasible index for predicting a poor survival rate in patients with BC.	('patients', 'Species', '9606', (32, 40))	('NEDD4-positive staining', 'Var', (46, 69))	('lower', 'NegReg', (100, 105))	('patients', 'Species', '9606', (234, 242))	('BC', 'Phenotype', 'HP:0003002', (248, 250))	('BC', 'Phenotype', 'HP:0003002', (70, 72))	('survival rate', 'CPA', (106, 119))
61810	31856858	NEDD4 expression was associated with a low OS rate in patients who received adjuvant therapy (Fig.	('patients', 'Species', '9606', (54, 62))	('expression', 'Var', (6, 16))	('NEDD4', 'Gene', (0, 5))
61811	31856858	Interestingly, a statistical correlation between NEDD4 expression and OS was not found in ER-positive breast tumors (Additional file 5: Figure S4a, P = 0.0865), while high NEDD4 expression was associated with a lower OS rate in ER-negative patients (Additional file 5: Figure S4b, P = 0.0204).	('breast tumors', 'Phenotype', 'HP:0100013', (102, 115))	('NEDD4', 'Gene', (172, 177))	('expression', 'MPA', (178, 188))	('high', 'Var', (167, 171))	('ER', 'Gene', '2099', (90, 92))	('breast tumors', 'Disease', 'MESH:D001943', (102, 115))	('OS rate', 'MPA', (217, 224))	('breast tumor', 'Phenotype', 'HP:0100013', (102, 114))	('breast tumors', 'Disease', (102, 115))	('ER', 'Gene', '2099', (228, 230))	('patients', 'Species', '9606', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lower', 'NegReg', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
61814	31856858	In support of our results, analyses of the 327 BC patient samples in GSE20685 revealed that NEDD4 mRNA expression is highly prognostic of OS (P = 0.04835) and distant metastasis-free survival (P = 0.0033) in the ER-negative patient population (Additional file 6: Figure S5c,d).	('ER', 'Gene', '2099', (212, 214))	('GS', 'Disease', 'MESH:D011125', (69, 71))	('BC', 'Phenotype', 'HP:0003002', (47, 49))	('patient', 'Species', '9606', (224, 231))	('mRNA expression', 'Var', (98, 113))	('distant metastasis-free survival', 'CPA', (159, 191))	('NEDD4', 'Gene', (92, 97))	('patient', 'Species', '9606', (50, 57))	('prognostic', 'Reg', (124, 134))
61821	31856858	NEDD4 expression is an independent predictive factor for OS and DFS, particularly in BC patients with invaded lymph node metastasis.	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('DFS', 'Disease', (64, 67))	('patients', 'Species', '9606', (88, 96))	('expression', 'Var', (6, 16))	('NEDD4', 'Gene', (0, 5))
61829	31856858	Seventy-five percent (60/80) of NEDD4-positive BC samples stained positively for p-AktSer473 whereas it was only 26.5% (18/68) in NEDD4-negative BC samples (Fig.	('p-AktSer473', 'Var', (81, 92))	('BC', 'Phenotype', 'HP:0003002', (47, 49))	('NEDD4-positive', 'Gene', (32, 46))	('stained positively', 'Reg', (58, 76))	('BC', 'Phenotype', 'HP:0003002', (145, 147))	('AktSer473', 'Chemical', '-', (83, 92))
61831	31856858	In support of the results obtained from IHC staining, knocked down NEDD4 led to decreased IGF-1R and p-AktSer473, even in the T47D cells that harbor an activating PI3K mutation that is constitutively active (Fig.	('T47D', 'CellLine', 'CVCL:0553', (126, 130))	('knocked down', 'Var', (54, 66))	('AktSer473', 'Chemical', '-', (103, 112))	('decreased', 'NegReg', (80, 89))	('PI3K', 'Var', (163, 167))	('decreased IGF', 'Phenotype', 'HP:0002850', (80, 93))	('NEDD4', 'Gene', (67, 72))	('p-AktSer473', 'MPA', (101, 112))	('activating', 'PosReg', (152, 162))	('IGF-1R', 'Gene', (90, 96))	('IGF-1R', 'Gene', '3480', (90, 96))
61845	31856858	In our study, we found that high NEDD4 expression was associated with a poor post-surgery prognosis in patients with BC, as reflected by their OS and DFS.	('BC', 'Phenotype', 'HP:0003002', (117, 119))	('NEDD4', 'Gene', (33, 38))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (103, 111))
61847	31856858	We also found that NEDD4 expression is an independent factor for a poor prognosis along with two well-known predictive factors, tumor grade, and nodal status (Table 2 (a, b)) but independent from established prognostic factors such as tumor size, margin status, and menstruation status.	('nodal', 'Gene', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('nodal', 'Gene', '4838', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (235, 240))	('NEDD4', 'Gene', (19, 24))	('tumor', 'Disease', (128, 133))	('expression', 'Var', (25, 35))
61849	31856858	An analysis of GSE20685 indicated that high NEDD4 expression is associated with lower distant metastasis-free survival in women with ER-negative BC (Additional file 6: Figure S5d).	('ER', 'Gene', '2099', (133, 135))	('high', 'Var', (39, 43))	('women', 'Species', '9606', (122, 127))	('GS', 'Disease', 'MESH:D011125', (15, 17))	('lower', 'NegReg', (80, 85))	('distant metastasis-free survival', 'CPA', (86, 118))	('BC', 'Phenotype', 'HP:0003002', (145, 147))	('NEDD4', 'Gene', (44, 49))	('expression', 'MPA', (50, 60))
61852	31856858	NEDD4 expression is associated with lower OS in a subset of ER-negative patients.	('expression', 'Var', (6, 16))	('ER', 'Gene', '2099', (60, 62))	('lower OS', 'Disease', (36, 44))	('NEDD4', 'Gene', (0, 5))	('patients', 'Species', '9606', (72, 80))
61864	31856858	Our results suggest that NEDD4 may promote BC growth and progression via an IGF-1R/Akt pathway, even in the cells that harbor an activating PI3K mutation.	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('Akt', 'Gene', (83, 86))	('NEDD4', 'Gene', (25, 30))	('promote', 'PosReg', (35, 42))	('IGF-1R', 'Gene', (76, 82))	('Akt', 'Gene', '207', (83, 86))	('BC growth', 'CPA', (43, 52))	('progression', 'CPA', (57, 68))	('IGF-1R', 'Gene', '3480', (76, 82))	('mutation', 'Var', (145, 153))
61880	31856858	Lastly, the roles of NEDD4 in the DNA damage response may contribute to the poor prognosis of patients with BC showing a high expression of NEDD4.	('roles', 'Reg', (12, 17))	('patients', 'Species', '9606', (94, 102))	('NEDD4', 'Gene', (21, 26))	('high expression', 'Var', (121, 136))	('BC', 'Phenotype', 'HP:0003002', (108, 110))	('NEDD4', 'Gene', (140, 145))
61881	31856858	It has been demonstrated that loss of NEDD4 increased the percentage of G1-arrested cells following a DNA-damaging insult and reduced the cell growth rate, which depends on p53, an important factor of the DNA damage response.	('cell growth rate', 'CPA', (138, 154))	('NEDD4', 'Gene', (38, 43))	('arrest', 'Disease', 'MESH:D006323', (75, 81))	('increased', 'PosReg', (44, 53))	('arrest', 'Disease', (75, 81))	('loss', 'Var', (30, 34))	('reduced', 'NegReg', (126, 133))
61890	31856858	The work described was supported by a National Natural Science Foundation of China grant (31571452 and 31271503), a Guangdong Provincial Natural Science Foundation of China grant (S2012010008368), a startup fund from The First Affiliated Hospital of Sun Yat-sen University and scholarships from the Chinese Scholarship Council (to Z. Ma), and a startup fund from The Ohio State University Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center (to J. Zhang).	('Cancer', 'Disease', 'MESH:D009369', (419, 425))	('Cancer', 'Phenotype', 'HP:0002664', (419, 425))	('Cancer', 'Disease', (419, 425))	('31271503', 'Var', (103, 111))
61965	31217628	Over 90% of the St. Gallen panelists recommend the use of multigene signatures for patients with a T1/2 tumour without lymph node involvement (93.6%), but a majority also recommend it for those with T3N0 tumours (74.5%) as well as independent of the T stage for patients with 1 - 3 positive nodes (78.7%).	('multigene', 'Var', (58, 67))	('tumour', 'Disease', (204, 210))	('tumours', 'Disease', 'MESH:D009369', (204, 211))	('tumours', 'Disease', (204, 211))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('T3N0', 'Var', (199, 203))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (262, 270))	('tumour', 'Disease', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
62029	31217628	Likewise the German expert group does not agree with the majority vote of the panelists (67.3%) to limit the neoadjuvant use of platinum to patients with a BRCA mutation.	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('mutation', 'Var', (161, 169))	('BRCA', 'Gene', '672', (156, 160))	('BRCA', 'Gene', (156, 160))	('patients', 'Species', '9606', (140, 148))
62031	31217628	The BRCA mutation increases the chemotherapy sensitivity of the tumour, however not in particular the sensitivity to platinum  .	('mutation', 'Var', (9, 17))	('BRCA', 'Gene', '672', (4, 8))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('increases', 'PosReg', (18, 27))	('BRCA', 'Gene', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('chemotherapy sensitivity', 'MPA', (32, 56))
62081	31217628	Here, the St. Gallen panelists (85.4%) and the German experts recommend genetic testing if the patient is under 60 years of age at first diagnosis.	('patient', 'Species', '9606', (95, 102))	('genetic testing', 'Var', (72, 87))	('und', 'Gene', '7373', (106, 109))	('und', 'Gene', (106, 109))
62363	19773762	Forty-eight per cent of women with koilocytosis alone in cervical epithelial cells may develop cervical intraepithelial neoplasia (Evans-Jones et al, 1985).	('develop', 'PosReg', (87, 94))	('koilocytosis', 'Var', (35, 47))	('neoplasia', 'Phenotype', 'HP:0002664', (120, 129))	('women', 'Species', '9606', (24, 29))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (95, 129))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (95, 129))	('cervical intraepithelial neoplasia', 'Disease', (95, 129))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (104, 129))
62368	19773762	E6 and E7 oncoproteins work in concert to disrupt cell cycle regulation and stimulate cell cycle progression by binding and inhibiting the p53 and p110RB tumour suppressor genes, respectively, thereby inducing the proliferation of infected basal cells, which facilitates replication of the viral genome.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('binding', 'Interaction', (112, 119))	('basal cells', 'CPA', (240, 251))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('disrupt', 'NegReg', (42, 49))	('cell cycle progression', 'CPA', (86, 108))	('inducing', 'NegReg', (201, 209))	('tumour', 'Disease', (154, 160))	('proliferation', 'CPA', (214, 227))	('p53', 'Gene', (139, 142))	('inhibiting', 'NegReg', (124, 134))	('p110RB', 'Var', (147, 153))	('p53', 'Gene', '7157', (139, 142))	('cell', 'MPA', (50, 54))	('stimulate', 'PosReg', (76, 85))
62370	19773762	E7-induced degradation of p110RB often results in a reciprocal overexpression of the cyclin-dependent kinase inhibitor p16INK4A, although this is further complicated with increasing cancer stage.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('p110RB', 'Var', (26, 32))	('p16INK4A', 'Gene', (119, 127))	('results in', 'Reg', (39, 49))	('E7-induced', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('p16INK4A', 'Gene', '1029', (119, 127))	('cancer', 'Disease', (182, 188))	('overexpression', 'PosReg', (63, 77))
62376	19773762	Putative koilocytes have been identified in HPV 6/11-associated benign laryngeal papillomas (Martins et al, 2008), high-risk HPV 16-associated malignant oesophageal lesions (Miller et al, 1997), high-risk HPV 11-associated conjunctival papilloma (Minchiotti et al, 2006), HPV 6/11-associated benign ductal papillomas of the salivary glands (Haberland-Carrodeguas et al, 2003), and high-risk HPV 16 in bladder cancers (Aggarwal et al, 2009).	('high-risk', 'Var', (381, 390))	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('benign laryngeal papillomas', 'Disease', (64, 91))	('HPV', 'Species', '10566', (125, 128))	('HPV', 'Species', '10566', (44, 47))	('papillomas of the salivary glands', 'Disease', (306, 339))	('papillomas', 'Phenotype', 'HP:0012740', (81, 91))	('papilloma', 'Phenotype', 'HP:0012740', (236, 245))	('bladder cancers', 'Disease', 'MESH:D001749', (401, 416))	('HPV 16', 'Gene', (391, 397))	('HPV 16', 'Species', '333760', (391, 397))	('bladder cancers', 'Disease', (401, 416))	('papilloma', 'Phenotype', 'HP:0012740', (306, 315))	('HPV', 'Species', '10566', (391, 394))	('papillomas of the salivary glands', 'Disease', 'MESH:D012466', (306, 339))	('HPV', 'Species', '10566', (272, 275))	('HPV 11', 'Species', '10580', (205, 211))	('conjunctival papilloma', 'Disease', 'MESH:D003229', (223, 245))	('malignant oesophageal lesions', 'Disease', 'MESH:D009369', (143, 172))	('HPV 16', 'Species', '333760', (125, 131))	('conjunctival papilloma', 'Disease', (223, 245))	('benign laryngeal papillomas', 'Disease', 'MESH:C535297', (64, 91))	('malignant oesophageal lesions', 'Disease', (143, 172))	('HPV', 'Species', '10566', (205, 208))	('papilloma', 'Phenotype', 'HP:0012740', (81, 90))	('papillomas', 'Phenotype', 'HP:0012740', (306, 316))	('HPV 6/11-associated', 'Gene', (44, 63))	('cancers', 'Phenotype', 'HP:0002664', (409, 416))	('HPV 16-associated', 'Gene', (125, 142))	('bladder cancers', 'Phenotype', 'HP:0009725', (401, 416))	('HPV 6/11-associated', 'Gene', (272, 291))
62377	19773762	These associations between the presence of HPVs and koilocytosis are in addition to their well-established associations in anogenital cancers (Boon and Kok, 1985).	('anogenital cancers', 'Disease', (123, 141))	('associations', 'Interaction', (6, 18))	('koilocytosis', 'Disease', (52, 64))	('anogenital cancers', 'Disease', 'MESH:D009369', (123, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('HPVs', 'Gene', (43, 47))	('HPV', 'Species', '10566', (43, 46))	('presence', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
62385	19773762	We based simplified histological definitions of koilocytosis on those established by Reid et al (1982) as follows:  We compared the breast cancer and normal breast specimens that contained koilocytes with cervical cancer specimens that also contained koilocytes.	('cervical cancer', 'Disease', 'MESH:D002583', (205, 220))	('cervical cancer', 'Disease', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('koilocytes', 'Var', (189, 199))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
62410	19773762	Therefore, it should not be assumed that the presence of koilocytosis in normal breast tissues commonly leads to breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('leads to', 'Reg', (104, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('presence', 'Var', (45, 53))
62425	11250725	More recently the transgenic and knockout technologies have yielded mouse strains with specific genetic alternations or deficiencies that result in breast cancer development.	('mouse', 'Species', '10090', (68, 73))	('deficiencies', 'Var', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('result in', 'Reg', (138, 147))
62429	11250725	Furthermore, although they may show how gene alterations can effect cancer development, they do not necessarily reflect how they do so under the 'normal' conditions of maturation, endocrinologic change and environmental exposures that occur during the long preclinical period during which a woman passes from being at risk to developing breast cancer.	('alterations', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (344, 350))	('woman', 'Species', '9606', (291, 296))	('gene alterations', 'Var', (40, 56))	('breast cancer', 'Disease', 'MESH:D001943', (337, 350))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('breast cancer', 'Disease', (337, 350))	('effect', 'Reg', (61, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (337, 350))	('rat', 'Species', '10116', (172, 175))	('cancer', 'Disease', (68, 74))	('rat', 'Species', '10116', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('endocrinologic change', 'Phenotype', 'HP:0000818', (180, 201))
62443	11250725	In contrast to MCF10A cells, MCF10AneoT cells form persistent lesions in immunodeficient mice when 1 x 107 cells suspended in Matrigel are inoculated subcutaneously.	('mice', 'Species', '10090', (89, 93))	('MCF10A', 'CellLine', 'CVCL:0598', (29, 35))	('MCF10AneoT', 'Var', (29, 39))	('MCF10A', 'CellLine', 'CVCL:0598', (15, 21))	('MCF10AneoT', 'CellLine', 'CVCL:5554', (29, 39))	('immunodeficient', 'Disease', 'MESH:D007153', (73, 88))	('immunodeficient', 'Disease', (73, 88))
62448	11250725	Although it may be argued that the presence of mutant Ha-ras gene, a rare mutational event in human breast cancers, may have contributed to the transformation process by initiation and/or selection of a subpopulation of MCF10A cells, the presence of mutant Ha-ras is clearly not sufficient for histologic progression of MCF10AT cells.	('MCF10A', 'CellLine', 'CVCL:0598', (320, 326))	('MCF10A', 'CellLine', 'CVCL:0598', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Ha-ras', 'Gene', (257, 263))	('contributed', 'Reg', (125, 136))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('Ha-ras', 'Gene', (54, 60))	('breast cancers', 'Disease', (100, 114))	('human', 'Species', '9606', (94, 99))	('mutant', 'Var', (250, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('mutant', 'Var', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
62449	11250725	Indeed, MCF10AneoT clones that express high levels of protein encoded by mutant Ha-ras have been shown to lack the ability to form lesions.	('mutant', 'Var', (73, 79))	('lack', 'NegReg', (106, 110))	('Ha-ras', 'Gene', (80, 86))	('MCF10AneoT', 'CellLine', 'CVCL:5554', (8, 18))
62451	11250725	An important feature that distinguishes MCF10AT cells from parental MCF10A cells is the presence of a functional wild-type estrogen receptor (ER).	('MCF10AT', 'Var', (40, 47))	('estrogen receptor', 'Gene', (123, 140))	('estrogen receptor', 'Gene', '2099', (123, 140))	('ER', 'Gene', '2099', (142, 144))	('MCF10A', 'CellLine', 'CVCL:0598', (40, 46))	('MCF10A', 'CellLine', 'CVCL:0598', (68, 74))
62458	11250725	However, serial trocar passage of small pieces of MCF10AT lesions have yielded tumorigenic variants that produce heterogeneous tumors with prominent areas of DCIS and invasive carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumors', 'Disease', (127, 133))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('invasive carcinoma', 'Disease', 'MESH:D009361', (167, 185))	('produce', 'Reg', (105, 112))	('variants', 'Var', (91, 99))	('invasive carcinoma', 'Disease', (167, 185))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('MCF10AT lesions', 'Disease', (50, 65))	('MCF10AT lesions', 'Disease', 'MESH:D051437', (50, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
62459	11250725	One of the 14 clones derived from this variant reproducibly generates tumors with predominant comedo DCIS (MCF10DCIS.com) within a few weeks.	('comedo', 'Phenotype', 'HP:0025249', (94, 100))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (107, 120))	('variant', 'Var', (39, 46))	('tumors', 'Disease', (70, 76))	('rat', 'Species', '10116', (64, 67))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('comedo DCIS', 'Disease', (94, 105))
62461	11250725	The absence of commitment to a single pathway of cancer, and its easy manipulability by hormonal agents, render the MCF10AT xenograft model the only currently available human model that has been shown to exhibit the histologic stigmata identified in women who are at high risk for developing breast cancer, and furthermore to undergo preneoplastic and neoplastic progression in vivo.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('undergo', 'Reg', (326, 333))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('MCF10AT', 'Var', (116, 123))	('women', 'Species', '9606', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Disease', (292, 305))	('human', 'Species', '9606', (169, 174))	('MCF10A', 'CellLine', 'CVCL:0598', (116, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (49, 55))
62512	30652620	A number of factors from medical records:including age, lesion size, number of biopsies, and history of breast cancer:were associated with lesion upgrade.	('associated', 'Reg', (123, 133))	('lesion upgrade', 'Var', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
62585	26689336	High-risk women are those considered with a BRCA gene mutation or who are untested first-degree relatives of a BRCA carrier, a history of chest irradiation between the ages of 10-30 years for lymphomas and other tumors, and women with 20% or greater lifetime risk of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('mutation', 'Var', (54, 62))	('lymphomas', 'Disease', 'MESH:D008223', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('BRCA', 'Gene', '672', (111, 115))	('lymphomas', 'Phenotype', 'HP:0002665', (192, 201))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('BRCA', 'Gene', (111, 115))	('women', 'Species', '9606', (10, 15))	('BRCA', 'Gene', '672', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('BRCA', 'Gene', (44, 48))	('lymphomas', 'Disease', (192, 201))	('breast cancer', 'Disease', (267, 280))	('women', 'Species', '9606', (224, 229))
62627	26689336	Consideration for BPM has tended to focus on women at high risk as determined by the presence of mutations of BRCA 1 or 2 genes, which are associated with increased risk of breast cancer, or by statistical models of risk estimation, such as the Gail model.	('mutations', 'Var', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('BRCA 1', 'Gene', (110, 116))	('BRCA 1', 'Gene', '672', (110, 116))	('associated', 'Reg', (139, 149))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('women', 'Species', '9606', (45, 50))	('breast cancer', 'Disease', (173, 186))
62628	26689336	A number of case series and retrospective cohort studies indicate that BPM reduces in approximately 90% the incidence of breast cancer in high-risk patients.	('patients', 'Species', '9606', (148, 156))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('BPM', 'Var', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('reduces', 'NegReg', (75, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
62629	26689336	One of these studies, including 639 women at high and moderate risk of breast cancer, reported 81-94% reduction in the risk of dying from breast cancer following BPM after a median follow-up of 14 years.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('BPM', 'Var', (162, 165))	('women', 'Species', '9606', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('reduction', 'NegReg', (102, 111))	('breast cancer', 'Disease', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
62644	26689336	Positive margins, defined as 'ink on tumor', are associated with more than a twofold increase in the risk of ipsilateral breast tumor recurrence (IBTR).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ipsilateral breast tumor', 'Disease', 'MESH:D001943', (109, 133))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ipsilateral breast tumor', 'Disease', (109, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (128, 133))	('Positive', 'Var', (0, 8))	('breast tumor', 'Phenotype', 'HP:0100013', (121, 133))
62664	26689336	Recent data from the ACOSOG Z1071 trial demonstrated that triple-negative and Her-2-positive breast cancers had the highest rates of pCR (38.2 and 45.4%, respectively; p <0.001) and BCS (46.8 and 43%, respectively; p = 0.019) after neoadjuvant chemotherapy compared with luminal tumors (pCR: 11.4%; BCS: 34.5%).	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('luminal tumors', 'Disease', 'MESH:D009369', (271, 285))	('BCS', 'Disease', (182, 185))	('triple-negative', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('pCR', 'Disease', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancers', 'Disease', 'MESH:D001943', (93, 107))	('breast cancers', 'Disease', (93, 107))	('luminal tumors', 'Disease', (271, 285))	('Her-2-positive', 'Gene', (78, 92))
62765	24000981	Due to its "en face" acquisition of the images, FF-OCT offers better lateral resolution than conventional OCT.	('lateral resolution', 'CPA', (69, 87))	('FF-OCT', 'Chemical', '-', (48, 54))	('FF-OCT', 'Var', (48, 54))
62771	24000981	If images are acquired before this warm up time is complete, field illumination may be inhomogeneous and slight mechanical misalignments may produce artifacts on the images, visible as broad lines on Figure 5B.	('produce', 'Reg', (141, 148))	('misalignments', 'Var', (123, 136))	('men', 'Species', '9606', (131, 134))	('artifacts', 'MPA', (149, 158))
62836	24000981	Part 2: Distinction between benign/normal and malignant tissue: After gaining an understanding of the appearance of normal morphological features of human breast tissue in our images, we next focused on discerning what aberrations of these morphological features in our images would allow characterization of the tissue as benign/normal or malignant.	('human', 'Species', '9606', (149, 154))	('aberrations', 'Var', (219, 230))	('allow', 'Reg', (283, 288))
62909	23304479	These studies identified a number of independent predictors of local recurrence including age less than 40 years, microcalcifications on mammography, palpable tumors, large tumors, multi-centricity, presence of DCIS or lobular histology, and lymphovascular invasion.	('lymphovascular invasion', 'CPA', (242, 265))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('calcifications', 'Disease', 'MESH:D002114', (119, 133))	('tumors', 'Disease', (173, 179))	('multi-centricity', 'Var', (181, 197))	('calcifications', 'Disease', (119, 133))	('local', 'CPA', (63, 68))	('large', 'Disease', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
62934	23304479	In this study, the correlation between MRI and tumor size was found to be significantly higher; however, no significant difference was found in between-group analysis of the incidence of margin involvement with MRI versus without MRI (30% versus 24.7%, P = 0.414, resp.).	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('MRI', 'Var', (211, 214))
62940	23304479	In HER2 amplified tumors, the use of HER2-targeted agents was associated with a less accurate MRI prediction of residual tumor extent.	('HER2', 'Gene', '2064', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (18, 23))	('HER2', 'Gene', (37, 41))	('tumor', 'Disease', (121, 126))	('HER2', 'Gene', '2064', (37, 41))	('amplified', 'Var', (8, 17))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('HER2', 'Gene', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
63036	22482059	A common diagnostic feature of breast cancer progression from in situ to invasive tumor is the aberration of the fully differentiated myoepithelial cell layer suggesting that dissolution of the myoepithelial cell layer is an absolute prerequisite for tumor invasion.	('myoepithelial', 'Disease', 'MESH:D009208', (134, 147))	('aberration', 'Var', (95, 105))	('tumor', 'Disease', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('myoepithelial', 'Disease', (194, 207))	('invasive tumor', 'Disease', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('invasive tumor', 'Disease', 'MESH:D009369', (73, 87))	('breast cancer', 'Disease', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('myoepithelial', 'Disease', 'MESH:D009208', (194, 207))	('tumor', 'Disease', (82, 87))	('myoepithelial', 'Disease', (134, 147))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
63062	22482059	Il-6 depletion from adipocytes inhibited the invasion and migration of breast tumor cells.	('depletion', 'Var', (5, 14))	('breast tumor', 'Phenotype', 'HP:0100013', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('breast tumor', 'Disease', 'MESH:D001943', (71, 83))	('Il-6', 'Gene', '3569', (0, 4))	('inhibited', 'NegReg', (31, 40))	('breast tumor', 'Disease', (71, 83))	('Il-6', 'Gene', (0, 4))
63115	22482059	The authors found that macrophage ablation dramatically decreased the number of tumor cells observable in the lungs.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('macrophage', 'CPA', (23, 33))	('decreased', 'NegReg', (56, 65))	('tumor', 'Disease', (80, 85))	('ablation', 'Var', (34, 42))
63133	22482059	Mice deficient in FSP-1 exhibited a significant reduction in tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Mice', 'Species', '10090', (0, 4))	('FSP-1', 'Gene', (18, 23))	('reduction', 'NegReg', (48, 57))	('tumor', 'Disease', (61, 66))	('deficient', 'Var', (5, 14))
63145	22482059	Inhibition of VEGFR1+ BMDCs either during primary tumor or after the formation of premetastatic niche caused the prevention of endothelial cell migration and metastasis.	('VEGFR1', 'Gene', '2321', (14, 20))	('VEGFR1', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Inhibition', 'Var', (0, 10))	('prevention', 'NegReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
63149	22482059	Colony stimulating factor-1 (CSF-1) deletion caused failure in macrophage homing to the malignant stroma that was associated with attenuated angiogenic responses, decreased neoplastic progression and inhibition of pulmonary metastasis.	('failure', 'NegReg', (52, 59))	('pulmonary metastasis', 'CPA', (214, 234))	('malignant stroma', 'Disease', (88, 104))	('inhibition', 'NegReg', (200, 210))	('deletion', 'Var', (36, 44))	('Colony stimulating factor-1', 'Gene', '1435', (0, 27))	('CSF-1', 'Gene', (29, 34))	('neoplastic progression', 'CPA', (173, 195))	('Colony stimulating factor-1', 'Gene', (0, 27))	('angiogenic responses', 'CPA', (141, 161))	('decreased', 'NegReg', (163, 172))	('CSF-1', 'Gene', '1435', (29, 34))	('malignant stroma', 'Disease', 'MESH:D009369', (88, 104))	('attenuated', 'NegReg', (130, 140))
63173	22482059	demonstrated that the selective neutralization of host-derived bone-derived placental growth factor (PlGF) by anti-mouse alphaPlGF reduced the engraftment of tumor cells in the bone, inhibited their interaction with matrix components, reduced the incidence, number, and size of bone metastases, and preserved bone therefore inhibiting both the progression of metastasis and the settlement of tumor in the bone.	('interaction', 'Interaction', (199, 210))	('bone metastases', 'Disease', 'MESH:D009362', (278, 293))	('PlGF', 'Gene', (126, 130))	('tumor', 'Disease', (392, 397))	('reduced', 'NegReg', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PlGF', 'Gene', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('bone metastases', 'Disease', (278, 293))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('neutralization', 'Var', (32, 46))	('mouse', 'Species', '10090', (115, 120))	('placental growth factor', 'Gene', (76, 99))	('incidence', 'CPA', (247, 256))	('PlGF', 'Gene', '5228', (126, 130))	('inhibited', 'NegReg', (183, 192))	('tumor', 'Disease', (158, 163))	('tumor in the bone', 'Phenotype', 'HP:0010622', (392, 409))	('PlGF', 'Gene', '5228', (101, 105))	('progression of metastasis', 'CPA', (344, 369))	('anti-mouse', 'Var', (110, 120))	('reduced', 'NegReg', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('placental growth factor', 'Gene', '5228', (76, 99))	('inhibiting', 'NegReg', (324, 334))
63189	32377564	For the cases that will never progress to invasive disease, overtreatment of DCIS comes with its own morbidity risks and represents a large, and potentially unnecessary, burden on the US medical system.	('invasive disease', 'Disease', (42, 58))	('overtreatment', 'Var', (60, 73))	('invasive disease', 'Disease', 'MESH:D009361', (42, 58))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
63221	32377564	Previously, B7-H3 has been shown by us and others to be expressed in numerous cancer types including breast, and is generally considered to be correlated with poorer outcomes.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('expressed', 'Reg', (56, 65))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('B7-H3', 'Var', (12, 17))	('breast', 'Disease', (101, 107))	('correlated', 'Reg', (143, 153))
63234	32377564	Direct correlation between imaging signal and histological stage (normal vs. DCIS) was determined, and photoacoustic molecular imaging was able to differentiate B7-H3-ICG accumulation within small (<1 mm) foci of DCIS from normal murine mammary glands with an AUC of 0.93.	('accumulation', 'PosReg', (171, 183))	('B7-H3-ICG', 'Var', (161, 170))	('DCIS', 'Disease', (213, 217))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('murine', 'Species', '10090', (230, 236))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
63280	20028875	Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits.	('COX-2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastrointestinal complications', 'Phenotype', 'HP:0004798', (141, 171))	('cardiovascular and gastrointestinal complications', 'Disease', 'MESH:D002318', (122, 171))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('inhibitors', 'Var', (15, 25))
63281	20028875	In variant human mammary epithelial cells that have silenced p16 (vHMEC), double strand DNA damage or telomere malfunction results in a p53-and activin A-dependent induction of COX-2 and continued proliferation.	('human', 'Species', '9606', (11, 16))	('malfunction', 'Var', (111, 122))	('COX-2', 'Protein', (177, 182))	('p16', 'Gene', (61, 64))	('rat', 'Species', '10116', (204, 207))	('induction', 'PosReg', (164, 173))	('vHMEC', 'Chemical', '-', (66, 71))	('silenced', 'Var', (52, 60))	('double strand DNA damage', 'Var', (74, 98))	('p16', 'Gene', '1029', (61, 64))
63282	20028875	In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest.	('p16', 'Gene', (57, 60))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('induces', 'Reg', (72, 79))	('cell cycle arrest', 'CPA', (80, 97))	('telomere malfunction', 'Var', (13, 33))	('p16', 'Gene', '1029', (57, 60))
63284	20028875	These data demonstrate that DNA damage and telomere malfunction can have both cell autonomous and cell non-autonomous consequences and provides a novel mechanism for the propagation of tumorigenesis.	('tumor', 'Disease', (185, 190))	('rat', 'Species', '10116', (18, 21))	('malfunction', 'Var', (52, 63))	('telomere', 'Protein', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
63289	20028875	For example, high COX-2 in benign atypical hyperplasia lesions is associated with increased risk of developing breast cancer.	('high', 'Var', (13, 17))	('hyperplasia lesions', 'Disease', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('hyperplasia lesions', 'Disease', 'MESH:D006965', (43, 62))	('breast cancer', 'Disease', (111, 124))	('COX-2', 'Gene', (18, 23))
63291	20028875	In combination with p16/Rb pathway malfunction, high COX-2 expression predicts progression of pre-invasive ductal carcinoma in situ (DCIS) lesions to invasive ductal carcinoma (IDC) .	('invasive ductal carcinoma', 'Disease', (150, 175))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (107, 123))	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('p16', 'Gene', (20, 23))	('COX-2', 'Gene', (53, 58))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (98, 123))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (150, 175))	('expression', 'MPA', (59, 69))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (107, 131))	('ductal carcinoma in situ', 'Disease', (107, 131))	('high', 'Var', (48, 52))	('p16', 'Gene', '1029', (20, 23))	('invasive ductal carcinoma', 'Disease', (98, 123))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (107, 131))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (159, 175))
63296	20028875	the inhibition of COX-2 in the vasculature decreases the vasodilator PGI2, without reducing COX-1-dependent vasoconstrictive thromboxanes.	('COX-1', 'Gene', (92, 97))	('PGI2', 'Chemical', 'MESH:D011464', (69, 73))	('inhibition', 'Var', (4, 14))	('vasodilator PGI2', 'MPA', (57, 73))	('COX-1', 'Gene', '4512', (92, 97))	('decreases', 'NegReg', (43, 52))	('COX-2', 'Gene', (18, 23))	('thromboxanes', 'Chemical', 'MESH:D013931', (125, 137))
63297	20028875	Decreasing COX-2 expression in a single cell type might mitigate these side effects; for instance, loss of COX-2 in breast epithelial cells could reduce breast cancer incidence and progression without inducing the complications associated with NSAIDS or coxibs.	('COX-2', 'Gene', (107, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('progression', 'CPA', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('loss', 'Var', (99, 103))	('reduce', 'NegReg', (146, 152))	('breast cancer', 'Disease', (153, 166))
63308	20028875	Primer-probe sets for COX-2 (Hs00153133), TRF2 (Hs00194619), hTERT (Hs00162669), activin A/inhibin A (Hs00170103), ATM (HS00175892), p53 (Hs99999147) and p21 (Hs00355782) were obtained from ABI.	('ATM', 'Gene', (115, 118))	('HS00175892', 'Var', (120, 130))	('Hs00355782', 'Var', (159, 169))	('TRF2', 'Gene', '7014', (42, 46))	('Hs00170103', 'Var', (102, 112))	('TRF2', 'Gene', (42, 46))	('ATM', 'Gene', '472', (115, 118))	('Hs00162669', 'Var', (68, 78))	('hTERT', 'Gene', '7015', (61, 66))	('Hs00194619', 'Var', (48, 58))	('Hs00153133', 'Var', (29, 39))	('Hs99999147', 'Var', (138, 148))	('hTERT', 'Gene', (61, 66))
63330	20028875	However, the magnitude of induction was lower and of shorter duration following exposure to UVC compared to etoposide, suggesting that double-strand DNA (dsDNA) breaks are more potent and sustained inducers of COX-2 in vHMEC than single-strand DNA (ssDNA) breaks.	('COX-2', 'Gene', (210, 215))	('etoposide', 'Chemical', 'MESH:D005047', (108, 117))	('double-strand DNA', 'Var', (135, 152))	('vHMEC', 'Chemical', '-', (219, 224))	('inducers', 'PosReg', (198, 206))	('breaks', 'Var', (161, 167))	('rat', 'Species', '10116', (63, 66))
63332	20028875	We hypothesized that telomere malfunction, a type of dsDNA damage, which occurs early and nearly universally in epithelial cancers, might also induce COX-2.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('induce', 'PosReg', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('epithelial cancers', 'Disease', (112, 130))	('telomere malfunction', 'Var', (21, 41))	('COX-2', 'Disease', (150, 155))	('epithelial cancers', 'Disease', 'MESH:D000077216', (112, 130))
63333	20028875	Based on a report showing that inhibition of DNA-PK kinase activity by NU7026 resulted in telomere malfunction, we tested the effect of this treatment (0.055umol/ml NU7026) on COX-2 expression in vHMEC.	('inhibition', 'NegReg', (31, 41))	('NU7026', 'Chemical', 'MESH:C479235', (165, 171))	('DNA-PK', 'Gene', (45, 51))	('telomere malfunction', 'MPA', (90, 110))	('vHMEC', 'Chemical', '-', (196, 201))	('DNA-PK', 'Gene', '5591', (45, 51))	('NU7026', 'Chemical', 'MESH:C479235', (71, 77))	('NU7026', 'Var', (71, 77))	('tested', 'Reg', (115, 121))
63334	20028875	Subsequent kinetic experiments demonstrated that treatment with NU7026 also resulted in a biphasic induction of COX-2 mRNA with peak expression at 6 (1.5-fold) and 48 hours (4.32-fold).	('expression', 'MPA', (133, 143))	('induction', 'MPA', (99, 108))	('mRNA', 'MPA', (118, 122))	('COX-2', 'Gene', (112, 117))	('rat', 'Species', '10116', (38, 41))	('NU7026', 'Chemical', 'MESH:C479235', (64, 70))	('NU7026', 'Var', (64, 70))
63337	20028875	Consistent with previous reports, TRF2 overexpression, to levels observed in cancer cell lines and tissues, induced telomere malfunction and a > 6-fold increase in abnormal metaphase spreads including duplications, deletions, translocations and chromosome breaks (p<0.0001).	('TRF2', 'Gene', '7014', (34, 38))	('overexpression', 'PosReg', (39, 53))	('duplications', 'CPA', (201, 213))	('TRF2', 'Gene', (34, 38))	('abnormal metaphase spreads', 'CPA', (164, 190))	('deletions', 'Var', (215, 224))	('translocations', 'CPA', (226, 240))	('increase', 'PosReg', (152, 160))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('chromosome breaks', 'CPA', (245, 262))	('telomere', 'CPA', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('chromosome breaks', 'Phenotype', 'HP:0040012', (245, 262))
63340	20028875	Mean COX-2 mRNA and protein levels increased ~3-fold in vHMEC overexpressing TRF2 (TRF2-vHMEC) compared to vector (p=0.01, Figure 1C, 2B).	('increased', 'PosReg', (35, 44))	('TRF2', 'Gene', '7014', (83, 87))	('TRF2', 'Gene', (83, 87))	('TRF2-vHMEC', 'Gene', (83, 93))	('vHMEC', 'Chemical', '-', (56, 61))	('TRF2-vHMEC', 'Gene', '7014', (83, 93))	('TRF2', 'Gene', '7014', (77, 81))	('TRF2', 'Gene', (77, 81))	('vHMEC', 'Chemical', '-', (88, 93))	('overexpressing', 'Var', (62, 76))
63350	20028875	Exposure to 0.02 or 0.04 muM SB203580 reduced mean COX-2 mRNA levels by 49% and 71% (p=0.007), respectively, in TRF2-vHMEC.	('SB203580', 'Var', (29, 37))	('TRF2-vHMEC', 'Gene', (112, 122))	('reduced', 'NegReg', (38, 45))	('COX-2 mRNA levels', 'MPA', (51, 68))	('TRF2-vHMEC', 'Gene', '7014', (112, 122))	('SB203580', 'Chemical', 'MESH:C093642', (29, 37))
63351	20028875	Correspondingly, COX-2 and phospho-p38 protein levels were decreased following exposure to SB203580, demonstrating that phospho-p38 was indeed necessary for TRF2 to induce COX-2 in vHMEC.	('SB203580', 'Var', (91, 99))	('rat', 'Species', '10116', (108, 111))	('vHMEC', 'Chemical', '-', (181, 186))	('decreased', 'NegReg', (59, 68))	('p38', 'Gene', (128, 131))	('TRF2', 'Gene', (157, 161))	('p38', 'Gene', '1432', (35, 38))	('p38', 'Gene', '1432', (128, 131))	('SB203580', 'Chemical', 'MESH:C093642', (91, 99))	('TRF2', 'Gene', '7014', (157, 161))	('p38', 'Gene', (35, 38))
63358	20028875	Similarly, treatment with NU7026, which induces telomere malfunction, increased activin A mRNA and protein levels (Figure 3A).	('NU7026', 'Chemical', 'MESH:C479235', (26, 32))	('NU7026', 'Var', (26, 32))	('telomere malfunction', 'MPA', (48, 68))	('increased', 'PosReg', (70, 79))
63360	20028875	However, activin A levels were greater in vHMEC treated with etoposide or NU7026 than with UVC.	('vHMEC', 'Disease', (42, 47))	('vHMEC', 'Chemical', '-', (42, 47))	('greater', 'PosReg', (31, 38))	('etoposide', 'Chemical', 'MESH:D005047', (61, 70))	('activin A levels', 'MPA', (9, 25))	('NU7026', 'Chemical', 'MESH:C479235', (74, 80))	('NU7026', 'Var', (74, 80))
63364	20028875	In contrast, mean COX-2 mRNA levels decreased 46% in TRF2-vHMEC expressing activin A shRNA compared to TRF2-vHMEC expressing pGL3 (p=0.002).	('TRF2-vHMEC', 'Gene', (53, 63))	('TRF2-vHMEC', 'Gene', '7014', (103, 113))	('pGL3', 'Gene', (125, 129))	('COX-2 mRNA levels', 'MPA', (18, 35))	('TRF2-vHMEC', 'Gene', '7014', (53, 63))	('TRF2-vHMEC', 'Gene', (103, 113))	('pGL3', 'Gene', '6391', (125, 129))	('activin A shRNA', 'Var', (75, 90))	('decreased', 'NegReg', (36, 45))
63371	20028875	ATM or p53 silencing decreased basal levels of COX-2 mRNA, activin A mRNA and activin protein in vHMEC by 40%, 41%, 53% and 42%, 36%, 61%, respectively, compared to control shRNA (Figure 4C).	('silencing', 'Var', (11, 20))	('activin', 'Gene', '83729', (59, 66))	('decreased', 'NegReg', (21, 30))	('activin', 'Gene', (78, 85))	('ATM', 'Gene', (0, 3))	('vHMEC', 'Chemical', '-', (97, 102))	('activin', 'Gene', (59, 66))	('activin', 'Gene', '83729', (78, 85))	('p53', 'Gene', (7, 10))	('ATM', 'Gene', '472', (0, 3))
63380	20028875	However, TRF2-HMEC also up-regulated p16 and p21 (Figure 5B), displayed flattened vacuolated morphology, entered growth arrest (Figure 5C) and exhibited a decreased fraction of cells in S-phase (Supplemental Figure 4), all phenotypes consistent with senescence.	('p16', 'Gene', (37, 40))	('up-regulated', 'PosReg', (24, 36))	('entered growth arrest', 'Disease', 'MESH:D006323', (105, 126))	('S-phase', 'CPA', (186, 193))	('TRF2', 'Gene', '7014', (9, 13))	('TRF2', 'Gene', (9, 13))	('decreased', 'NegReg', (155, 164))	('p16', 'Gene', '1029', (37, 40))	('growth arrest', 'Phenotype', 'HP:0001510', (113, 126))	('entered growth arrest', 'Disease', (105, 126))	('p21', 'Var', (45, 48))
63387	20028875	DCIS lesions with high gammaH2AX, TRF2 or COX-2 expression had lower telomere content than those with low gammaH2AX, TRF2 or COX-2 expression (p=0.001, p=0.001, p=0.001, respectively).	('TRF2', 'Gene', '7014', (34, 38))	('TRF2', 'Gene', (34, 38))	('TRF2', 'Gene', '7014', (117, 121))	('lower', 'NegReg', (63, 68))	('lower telomere content', 'Phenotype', 'HP:0031413', (63, 85))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('gammaH2AX', 'Chemical', '-', (23, 32))	('gammaH2AX', 'Var', (23, 32))	('TRF2', 'Gene', (117, 121))	('gammaH2AX', 'Chemical', '-', (106, 115))	('high gammaH2AX', 'Var', (18, 32))	('COX-2', 'Gene', (42, 47))	('telomere', 'MPA', (69, 77))
63389	20028875	Thus, our findings in vitro are recapitulated in vivo: DNA damage induced by telomere malfunction and characterized by low telomere content, high gammaH2AX and high TRF2 expression, are associated with increased activin A and COX-2 expression.	('high', 'Var', (160, 164))	('TRF2', 'Gene', '7014', (165, 169))	('increased', 'PosReg', (202, 211))	('TRF2', 'Gene', (165, 169))	('low', 'NegReg', (119, 122))	('telomere content', 'MPA', (123, 139))	('low telomere content', 'Phenotype', 'HP:0031413', (119, 139))	('gammaH2AX', 'Chemical', '-', (146, 155))	('activin', 'Protein', (212, 219))	('gammaH2AX', 'Protein', (146, 155))	('expression', 'MPA', (232, 242))	('high', 'Var', (141, 145))	('expression', 'MPA', (170, 180))	('COX-2', 'Enzyme', (226, 231))
63390	20028875	Here we show for the first time that dsDNA damage and telomere malfunction in human breast epithelial cells results in a p53- and activin A-dependent COX-2 induction.	('malfunction', 'Var', (63, 74))	('p53-', 'MPA', (121, 125))	('COX-2', 'Enzyme', (150, 155))	('induction', 'PosReg', (156, 165))	('human', 'Species', '9606', (78, 83))	('telomere', 'Gene', (54, 62))
63410	20028875	Inhibiting activin A, either through induction of physiological regulators (follistatin, inhibin A or follistatin-related protein FLRG) or use of inhibitors (SB432542 or type I and II receptor antibodies), is an attractive therapeutic approach to ablate the COX-2 overexpression triggered by DNA damage, although side effects of such therapies remain to be investigated.	('FLRG', 'Gene', (130, 134))	('Inhibiting', 'Var', (0, 10))	('activin A', 'Protein', (11, 20))	('FLRG', 'Gene', '10272', (130, 134))	('ablate', 'NegReg', (247, 253))	('overexpression', 'PosReg', (264, 278))	('SB432542', 'Chemical', '-', (158, 166))	('COX-2', 'Gene', (258, 263))
63412	20028875	p53 or p16/Rb), DNA damage generates genomic instability and, consequently, may result in random loss of tumor suppressors, gain of oncogenes and clonal expansion.	('loss', 'NegReg', (97, 101))	('genomic instability', 'MPA', (37, 56))	('gain', 'PosReg', (124, 128))	('DNA', 'Var', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p16', 'Gene', (7, 10))	('oncogenes', 'CPA', (132, 141))	('p53', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('clonal expansion', 'CPA', (146, 162))	('p16', 'Gene', '1029', (7, 10))	('rat', 'Species', '10116', (31, 34))
63413	20028875	Thus, DNA damage indirectly contributes to tumorigenesis through generation of genomic instability.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('genomic instability', 'MPA', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('contributes', 'Reg', (28, 39))	('tumor', 'Disease', (43, 48))	('DNA', 'Var', (6, 9))	('rat', 'Species', '10116', (69, 72))
63415	20028875	Since activin A and the prostaglandins are secreted, DNA damage in one cell could drive tumorigenic phenotypes in an adjacent p16-compromised precursor cell or lead to proliferative arrest in an adjacent p16-intact cell.	('lead to', 'Reg', (160, 167))	('drive', 'PosReg', (82, 87))	('proliferative arrest', 'CPA', (168, 188))	('p16', 'Gene', '1029', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('prostaglandins', 'Chemical', 'MESH:D011453', (24, 38))	('p16', 'Gene', (126, 129))	('p16', 'Gene', '1029', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('DNA', 'Var', (53, 56))	('rat', 'Species', '10116', (175, 178))	('tumor', 'Disease', (88, 93))	('activin', 'Protein', (6, 13))	('p16', 'Gene', (204, 207))
63440	27630987	Epigenetic changes within neoplastic cells could account for the lack of significant changes in the genetic code between MINO and tumor.	('MIN', 'Disease', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('Epigenetic changes', 'Var', (0, 18))	('MIN', 'Disease', 'None', (121, 124))
63480	27630987	The equations used to calculate buffer capacity are = -52.95pHi + 400 for nMEC, = -38.55pHi + 293 for Met1, and = -29.01pHi + 227 for MINO.	('Met1', 'Gene', (102, 106))	('nMEC', 'MPA', (74, 78))	('MIN', 'Disease', 'None', (134, 137))	('MIN', 'Disease', (134, 137))	('= -29.01pHi + 227', 'Var', (112, 129))	('Met1', 'Gene', '3004', (102, 106))
63495	27630987	2-NBDG treated suspensions of cells were stained with 4',6-diamidino-2-phenylindole (DAPI), CD45, TER119 and CD31 (Semerad et al.,; Christopher and Link,) and sorted on a FACS Aria flow cytometer (BD Biosciences).	('TER119', 'Var', (98, 104))	('CD31', 'Gene', (109, 113))	('CD45', 'Gene', (92, 96))	('CD31', 'Gene', '5175', (109, 113))	('2-NBDG', 'Chemical', 'MESH:C098340', (0, 6))	("4',6-diamidino-2-phenylindole", 'Chemical', 'MESH:C007293', (54, 83))	('CD45', 'Gene', '5788', (92, 96))	('DAPI', 'Chemical', 'MESH:C007293', (85, 89))
63530	27630987	Met1 cancer cells have a higher rate of proton production than nMEC (Figure 4A), as measured by the rate of intracellular acidification during the sodium washout experiments where proton extrusion was blocked by inhibiting NHE1 in nominally bicarb-free medium.	('Met1', 'Gene', '3004', (0, 4))	('bicarb', 'Chemical', 'MESH:D017693', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('inhibiting', 'Var', (212, 222))	('NHE1', 'Gene', (223, 227))	('cancer', 'Disease', (5, 11))	('proton production', 'MPA', (40, 57))	('sodium', 'Chemical', 'MESH:D012964', (147, 153))	('Met1', 'Gene', (0, 4))	('higher', 'PosReg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
63573	27630987	The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fcell.2016.00093 Mino Mammary Intraepithelial Neoplasia Outgrowth Nmec Normal Mammary Epithelial Cells.	('Mino', 'Var', (132, 136))	('Intraepithelial Neoplasia', 'Disease', 'MESH:D019048', (145, 170))	('Intraepithelial Neoplasia', 'Phenotype', 'HP:0032187', (145, 170))	('Neoplasia', 'Phenotype', 'HP:0002664', (161, 170))	('Intraepithelial Neoplasia', 'Disease', (145, 170))
63577	25811878	Although some phenotypic adaptations to this cyclic hypoxia are likely reversible, we hypothesize that some adaptations may become fixed through mutations promoted by hypoxia-induced genomic instability.	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('mutations', 'Var', (145, 154))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', (52, 59))
63584	25811878	As cancer cells progress, they undergo an evolutionary process during which genetic or epigenetic changes accumulate leading to progressively aggressive phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('epigenetic changes', 'Var', (87, 105))	('cancer', 'Disease', 'MESH:D009369', (3, 9))
63590	25811878	In vitro studies have shown that hypoxia selects for cells carrying mutations in p53 such that minor populations engineered to carry nonfunctional alleles of TP53 eventually overtake populations wild-type for TP53, which can lead to apoptosis resistance.	('overtake', 'PosReg', (174, 182))	('TP53', 'Gene', '7157', (158, 162))	('lead to', 'Reg', (225, 232))	('TP53', 'Gene', (158, 162))	('TP53', 'Gene', (209, 213))	('hypoxia', 'Disease', (33, 40))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('apoptosis resistance', 'CPA', (233, 253))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('mutations', 'Var', (68, 77))	('TP53', 'Gene', '7157', (209, 213))
63609	25811878	Changes in oxygen tensions have been shown to inflict genotoxic stress upon cells and inhibit cell proliferation.	('genotoxic stress', 'MPA', (54, 70))	('oxygen', 'Chemical', 'MESH:D010100', (11, 17))	('Changes', 'Var', (0, 7))	('inhibit', 'NegReg', (86, 93))	('cell proliferation', 'CPA', (94, 112))	('inflict', 'Reg', (46, 53))
63626	25811878	Despite the heterogeneity of phenotypes, as a group the IH-selected cells were significantly more resistant to etoposide killing than were the non-selected variants (p<0.0001).	('IH-selected', 'Var', (56, 67))	('resistant to etoposide killing', 'MPA', (98, 128))	('etoposide', 'Chemical', 'MESH:D005047', (111, 120))
63658	25811878	These cells were chosen because they carry functional alleles of CDH1, but have mutant p53.	('CDH1', 'Gene', (65, 69))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('mutant', 'Var', (80, 86))	('CDH1', 'Gene', '999', (65, 69))
63662	25811878	The G245S p53 mutation in this cell line is generally considered to be inactive.	('G245S', 'Mutation', 'rs28934575', (4, 9))	('G245S', 'Var', (4, 9))	('p53', 'Gene', (10, 13))	('p53', 'Gene', '7157', (10, 13))
63682	25811878	Additionally, we detected an increase in CA-IX mRNA and protein levels in IH-selected clones relative to passage controls (S9 Fig.).	('CA-IX', 'Gene', '768', (41, 46))	('IH-selected', 'Var', (74, 85))	('CA-IX', 'Gene', (41, 46))	('increase', 'PosReg', (29, 37))
63716	25811878	One possible explanation is that loss of E-cadherin promotes invasion, thus allowing cells to move to regions that are more well-oxygenated.	('oxygen', 'Chemical', 'MESH:D010100', (129, 135))	('allowing', 'Reg', (76, 84))	('invasion', 'CPA', (61, 69))	('promotes', 'PosReg', (52, 60))	('loss', 'Var', (33, 37))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))
63730	25811878	Four mice were injected in the right (R) flank with MCF10A-IH clone 4, and on the left (F) flank with non selected MCF10A clone 4.	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('clone 4', 'Gene', (122, 129))	('clone 4', 'Gene', (62, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (115, 121))	('MCF10A-IH', 'Var', (52, 61))	('clone 4', 'Gene', '22116', (122, 129))	('clone 4', 'Gene', '22116', (62, 69))	('mice', 'Species', '10090', (5, 9))
63843	23213495	Skripenova and Layfield found residual invasive carcinoma in greater than 25% of patients with margins less than 2 mm while only 16% had residual invasive carcinoma when the margin was greater than 2 mm.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('invasive carcinoma', 'Disease', 'MESH:D009361', (146, 164))	('invasive carcinoma', 'Disease', 'MESH:D009361', (39, 57))	('Skripenova', 'Chemical', '-', (0, 10))	('less than 2 mm', 'Var', (103, 117))	('patients', 'Species', '9606', (81, 89))	('invasive carcinoma', 'Disease', (146, 164))	('invasive carcinoma', 'Disease', (39, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
63851	23213495	Studies have consistently shown that patients with extensive DCIS in the primary excision are at significantly higher risk for residual tumor than those without such extensive DCIS.	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('extensive DCIS', 'Var', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
63856	23213495	Schwartz's group found micropapillary to be associated with multicentricity (86%) and comedocarcinoma more likely to be associated with microinvasive DCIS (53%).	('associated', 'Reg', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('microinvasive DCIS', 'Disease', (136, 154))	('multicentricity', 'Disease', (60, 75))	('comedocarcinoma', 'Disease', (86, 101))	('comedocarcinoma', 'Disease', 'None', (86, 101))	('micropapillary', 'Var', (23, 37))
64018	26769139	High levels of Treg are more common in ER- carcinomas, and predicts horter progression free and overall survival.	('common', 'Reg', (29, 35))	('High levels', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('ER', 'Gene', '2099', (39, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('carcinomas', 'Disease', 'MESH:D002277', (43, 53))	('carcinomas', 'Disease', (43, 53))	('predicts', 'Reg', (59, 67))
64019	26769139	In addition, relative to luminal A cancers, triple negative breast carcinomas tend to harbor tumor infiltrating lymphocytes with the T helper type 2 phenotype thought to promote tumor growth.	('breast carcinomas tend to harbor tumor', 'Disease', (60, 98))	('tumor', 'Disease', (178, 183))	('triple negative', 'Var', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('breast carcinomas', 'Phenotype', 'HP:0003002', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('A cancers', 'Disease', (33, 42))	('tumor', 'Disease', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('breast carcinoma', 'Phenotype', 'HP:0003002', (60, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('A cancers', 'Disease', 'MESH:D009369', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('breast carcinomas tend to harbor tumor', 'Disease', 'MESH:D001943', (60, 98))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('promote', 'PosReg', (170, 177))
64028	26769139	In one study, PD-L1 expression was associated with improved clinical outcomes, however a separate study reported an association with negative clinical outcomes.	('clinical', 'MPA', (60, 68))	('PD-L1', 'Gene', '29126', (14, 19))	('improved', 'PosReg', (51, 59))	('expression', 'Var', (20, 30))	('PD-L1', 'Gene', (14, 19))
64045	26769139	790-4423, Ventana Medical Systems Inc, Tucson, AZ), CD8 (mouse monoclonal, clone C8/C8144B, catalogue no.	('C8144B', 'Var', (84, 90))	('C8144B', 'SUBSTITUTION', 'None', (84, 90))	('CD8', 'Gene', (52, 55))	('mouse', 'Species', '10090', (57, 62))	('CD8', 'Gene', '925', (52, 55))
64070	26769139	ER+ DCIS and DCIS in older patients tended to have lower tumor infiltrating lymphocyte density scores than ER- DCIS o r DCIS in younger patients(p = 0.	('ER', 'Gene', '2099', (0, 2))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('DCIS', 'Var', (13, 17))	('ER', 'Gene', '2099', (107, 109))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('DCIS', 'Phenotype', 'HP:0030075', (4, 8))	('lower', 'NegReg', (51, 56))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (136, 144))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
64096	26769139	Both PD-L1+ and PD -L1- DCIS had similar CD8/FoxP3 ratios.	('FoxP3', 'Gene', '50943', (45, 50))	('PD-L1', 'Gene', (5, 10))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('CD8', 'Gene', (41, 44))	('FoxP3', 'Gene', (45, 50))	('PD-L1', 'Gene', '29126', (5, 10))	('CD8', 'Gene', '925', (41, 44))	('PD -L1- DCIS', 'Var', (16, 28))
64100	26769139	Second, while DCIS carcinoma cells do not express cell surface PD-L1 in this study, the majority of DCIS -associated tumor infiltrating lymphocytes are PD -L1+.	('PD -L1+', 'Var', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('DCIS', 'Disease', (100, 104))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('tumor', 'Disease', (117, 122))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('PD-L1', 'Gene', (63, 68))	('carcinoma', 'Disease', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('PD-L1', 'Gene', '29126', (63, 68))
64114	26769139	Nuclear grade 2-3 DCIS is associated with tumor infiltrating lymphocytephenotypes similar to those seen in invasive breast carcinomas .	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (107, 133))	('Nuclear grade 2-3', 'Var', (0, 17))	('tumor', 'Disease', (42, 47))	('breast carcinomas', 'Phenotype', 'HP:0003002', (116, 133))	('breast carcinoma', 'Phenotype', 'HP:0003002', (116, 132))	('invasive breast carcinomas', 'Disease', (107, 133))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
64173	24713637	The same cut-off value (i.e., BI-RADS 1 and 2 for benign lesions and BI-RADS 3-5 for malignant lesions) was used to calculate the reliability using kappa statistics.	('malignant lesion', 'Disease', 'MESH:D009369', (85, 101))	('BI-RADS', 'Var', (69, 76))	('malignant lesion', 'Disease', (85, 101))
64203	24713637	In this study, the BI-RADS MRI cut-off value for malignancy was set at BI-RADS 3, because in our hospital, many BI-RADS 3 patients are referred for biopsy.	('malignancy', 'Disease', 'MESH:D009369', (49, 59))	('patients', 'Species', '9606', (122, 130))	('malignancy', 'Disease', (49, 59))	('BI-RADS 3', 'Var', (112, 121))
64259	32426228	Finally, since the hemoglobin distribution in the specimen may be affected by excision, it may not be a reliable indicator of malignancy.	('malignancy', 'Disease', (126, 136))	('hemoglobin distribution', 'MPA', (19, 42))	('affected', 'Reg', (66, 74))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('excision', 'Var', (78, 86))
64367	26970122	Intriguingly, the SRC gene was detected in normal, uninfected avian tissue, unequivocally demonstrating that the origins of cancer are within us and that, in most cases, it is our own cellular genome that accumulates sufficient alterations to eventually lead to cancer.	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', (124, 130))	('alterations', 'Var', (228, 239))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lead to', 'Reg', (254, 261))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
64374	26970122	We know that whether from an underlying genetic predisposition, endogenous processes in the cell, bacterial or viral infection, and/or other exogenous factors such as sun, tobacco, certain chemical, or radiation exposure, it is our own cellular genome that collects enough genetic alterations to eventually transform a normal cell to a malignant one.	('viral infection', 'Disease', 'MESH:D001102', (111, 126))	('tobacco', 'Species', '4097', (172, 179))	('genetic alterations', 'Var', (273, 292))	('viral infection', 'Disease', (111, 126))	('transform', 'Reg', (307, 316))
64406	26970122	One suggested mechanism for this undesirable association is the increase in acid production resulting from H pylori eradication, which leads in turn to an increase in esophageal adenocarcinoma.	('increase', 'PosReg', (155, 163))	('eradication', 'Var', (116, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (167, 192))	('pylori', 'Species', '210', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('esophageal adenocarcinoma', 'Disease', (167, 192))	('H pylori', 'Gene', (107, 115))	('increase', 'PosReg', (64, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (167, 192))	('acid production', 'MPA', (76, 91))
64443	26970122	In exploring these mutations, Vogelstein and colleagues have proposed a model for distinguishing the mutations "driving" the development of cancer from the mutations that are merely "passenger" or bystander mutations.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
64447	26970122	Indeed, the ability to identify actionable mutations that inform novel treatment options has been transformative to the approach to cancer treatment.	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
64451	26970122	In addition, KRAS mutations are detected in 14% of precursor adenoma lesions compared with 47% of colorectal cancers, making it highly likely that the actionable information we discern from these mutations in cancer will be different in premalignant conditions.	('colorectal cancers', 'Disease', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('detected', 'Reg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (209, 215))	('adenoma lesions', 'Disease', (61, 76))	('adenoma lesions', 'Disease', 'MESH:D000236', (61, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))	('mutations', 'Var', (18, 27))
64454	26970122	In addition, a low Ki-67 LI was associated with a 3% cumulative incidence of breast cancer at 10 years, compared with 14% in those with a high Ki-67 LI.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('low Ki-67 LI', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
64457	26970122	For example, short-term administration of lapatinib, which targets mutant epidermal growth factor receptor (EGFR), was found to decrease cell proliferation in ductal intraepithelial neoplasia while, in mice, lapatinib prevented the development of estrogen receptor-positive mammary tumors.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (166, 191))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('lapatinib', 'Chemical', 'MESH:D000077341', (42, 51))	('mice', 'Species', '10090', (202, 206))	('neoplasia', 'Phenotype', 'HP:0002664', (182, 191))	('tumors', 'Disease', (282, 288))	('EGFR', 'Gene', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('ductal intraepithelial neoplasia', 'Disease', 'MESH:D019048', (159, 191))	('lapatinib', 'Chemical', 'MESH:D000077341', (208, 217))	('mutant', 'Var', (67, 73))	('decrease', 'NegReg', (128, 136))	('epidermal growth factor receptor', 'Gene', (74, 106))	('epidermal growth factor receptor', 'Gene', '13649', (74, 106))	('ductal intraepithelial neoplasia', 'Disease', (159, 191))
64461	26970122	This concept posits that:for some cancers:activating oncogenic mutations occur during the course of the disease that confer a survival advantage to cancer cells.	('cancer', 'Disease', (148, 154))	('mutations', 'Var', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('activating', 'PosReg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('survival advantage', 'CPA', (126, 144))
64462	26970122	Identifying and targeting these mutations should, therefore, lead to death in cancer cells.	('lead to', 'Reg', (61, 68))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (32, 41))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
64463	26970122	A striking example of this is the BCR-ABL translocation in chronic myelogenous leukemia (CML).	('chronic myelogenous leukemia', 'Disease', (59, 87))	('CML', 'Disease', 'MESH:D015464', (89, 92))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (59, 87))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (59, 87))	('translocation', 'Var', (42, 55))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('CML', 'Phenotype', 'HP:0005506', (89, 92))	('BCR-ABL', 'Gene', '25', (34, 41))	('CML', 'Disease', (89, 92))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (67, 87))	('BCR-ABL', 'Gene', (34, 41))
64467	26970122	When individuals with CML develop resistance to these drugs, it is due to secondary mutations in BCR-ABL, not compensation by another pathway, suggesting that CML is addicted to the specific BCR-ABL oncogene and not evolving to become reliant on altered signaling from other molecules.	('BCR-ABL', 'Gene', (191, 198))	('BCR-ABL', 'Gene', '25', (191, 198))	('BCR-ABL', 'Gene', (97, 104))	('BCR-ABL', 'Gene', '25', (97, 104))	('CML', 'Disease', (22, 25))	('resistance', 'MPA', (34, 44))	('mutations', 'Var', (84, 93))	('CML', 'Disease', 'MESH:D015464', (159, 162))	('CML', 'Phenotype', 'HP:0005506', (159, 162))	('CML', 'Disease', 'MESH:D015464', (22, 25))	('CML', 'Disease', (159, 162))	('CML', 'Phenotype', 'HP:0005506', (22, 25))
64468	26970122	In CML, the BCR-ABL mutation is the initiating genetic change in the course of the disease, providing an early marker and target for intervention.	('CML', 'Disease', 'MESH:D015464', (3, 6))	('BCR-ABL', 'Gene', '25', (12, 19))	('mutation', 'Var', (20, 28))	('CML', 'Phenotype', 'HP:0005506', (3, 6))	('CML', 'Disease', (3, 6))	('BCR-ABL', 'Gene', (12, 19))
64472	26970122	What this suggests is that the cellular context, timing, and order of genetic mutations are key components classifying a lesion as benign, premalignant or cancerous.	('cancerous', 'Disease', (155, 164))	('cancerous', 'Disease', 'MESH:D009369', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (78, 87))
64474	26970122	There is the possibility of pushing the boundaries of technology even further to detect circulating tumor cells sloughed off from developing lesions, and to merge that with next generation sequencing to detect specific mutations that can portend a developing malignant tumor.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('malignant tumor', 'Disease', 'MESH:D018198', (259, 274))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (269, 274))	('malignant tumor', 'Disease', (259, 274))	('mutations', 'Var', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
64477	26970122	And if so, can we detect such mutations in biopsies or stool samples and use them to predict which patients are at high risk of developing cancer?	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', (139, 145))
64478	26970122	Can we study prostatic intraepithelial neoplasia and identify mutations that confidently predict disease progression?	('prostatic intraepithelial neoplasia', 'Disease', (13, 48))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (13, 48))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (23, 48))	('predict', 'Reg', (89, 96))	('neoplasia', 'Phenotype', 'HP:0002664', (39, 48))	('mutations', 'Var', (62, 71))
64485	26970122	Moreover, analagous to how these mutations are used to guide treatment for cancer, perhaps they can be used to "treat" premalignant conditions.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (33, 42))
64489	26970122	For example, we have resolved that obesity is associated with triple-negative breast cancer, HPV is associated with a specific mutation pattern in head and neck cancer, benzene exposure leads to a distinct gene expression signature in acute myelogenous leukemia (AML) and aflatoxin exposure is associated with R249S TP53 mutations in human hepatocellular carcinomas.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (235, 261))	('TP53', 'Gene', (316, 320))	('HPV', 'Species', '10566', (93, 96))	('benzene', 'Chemical', 'MESH:D001554', (169, 176))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('obesity', 'Disease', (35, 42))	('breast cancer', 'Disease', (78, 91))	('leukemia', 'Phenotype', 'HP:0001909', (253, 261))	('head and neck cancer', 'Phenotype', 'HP:0012288', (147, 167))	('acute myelogenous leukemia', 'Disease', (235, 261))	('AML', 'Disease', 'MESH:D015470', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('neck cancer', 'Disease', 'MESH:D006258', (156, 167))	('human', 'Species', '9606', (334, 339))	('neck cancer', 'Disease', (156, 167))	('AML', 'Phenotype', 'HP:0004808', (263, 266))	('AML', 'Disease', (263, 266))	('obesity', 'Disease', 'MESH:D009765', (35, 42))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (340, 365))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (241, 261))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (235, 261))	('R249S', 'Mutation', 'rs28934571', (310, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('aflatoxin', 'Chemical', 'MESH:D000348', (272, 281))	('carcinomas', 'Phenotype', 'HP:0030731', (355, 365))	('TP53', 'Gene', '7157', (316, 320))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (340, 365))	('obesity', 'Phenotype', 'HP:0001513', (35, 42))	('hepatocellular carcinomas', 'Disease', (340, 365))	('R249S', 'Var', (310, 315))
64524	26970122	Leibowitz and colleagues have shown that NSAIDs prevent CRC by inducing the cell death of normal intestinal stem cells that have acquired mutations and lost functional APC.	('death', 'Disease', 'MESH:D003643', (81, 86))	('CRC', 'Disease', (56, 59))	('inducing', 'Reg', (63, 71))	('death', 'Disease', (81, 86))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('mutations', 'Var', (138, 147))
64549	26970122	Understanding how the environment and our lifestyles impact epigenetic inheritance, and the extent to which it exists, could have significant implications for how we think about the molecular basis for cancer prevention.	('impact', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('implications', 'Reg', (142, 154))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('epigenetic inheritance', 'Var', (60, 82))
64568	26970122	Familial cases of cancer comprise, on average, 5%-10% of the total cancer burden in the population.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Familial', 'Var', (0, 8))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
64569	26970122	Among the best-known genetic susceptibility mutations are those arising in the BRCA1 and BRCA2 genes.	('BRCA2', 'Gene', '675', (89, 94))	('BRCA1', 'Gene', '672', (79, 84))	('BRCA1', 'Gene', (79, 84))	('mutations', 'Var', (44, 53))	('BRCA2', 'Gene', (89, 94))
64572	26970122	However, it has been estimated that 50% of BRCA1/2 mutation carriers could be missed using these criteria.	('BRCA1/2', 'Gene', (43, 50))	('BRCA1/2', 'Gene', '672;675', (43, 50))	('mutation', 'Var', (51, 59))
64573	26970122	Among those with no family history, the lifetime risk of developing cancer by age 80 years is 83% in BRCA1 carriers and 76% in BRCA2 carriers, in itself a potential argument for more widespread genetic testing for BRCA1 and BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BRCA2', 'Gene', '675', (127, 132))	('carriers', 'Var', (107, 115))	('BRCA1', 'Gene', '672', (101, 106))	('BRCA2', 'Gene', '675', (224, 229))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('BRCA1', 'Gene', (101, 106))	('BRCA1', 'Gene', '672', (214, 219))	('cancer', 'Disease', (68, 74))	('BRCA2', 'Gene', (127, 132))	('BRCA1', 'Gene', (214, 219))	('BRCA2', 'Gene', (224, 229))
64574	26970122	For mutations that confer a high likelihood of breast or ovarian cancer development, there are prevention strategies an individual can take.	('breast or ovarian cancer', 'Disease', (47, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (47, 71))	('mutations', 'Var', (4, 13))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))
64575	26970122	Similar to BRCA mutation carriers, individuals that carry germline mutations in TP53 carry a high lifetime risk of cancer development, including osteosarcoma, leukemia and soft tissue sarcoma.	('leukemia', 'Disease', (159, 167))	('leukemia', 'Disease', 'MESH:D007938', (159, 167))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TP53', 'Gene', '7157', (80, 84))	('BRCA', 'Gene', '672', (11, 15))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (172, 191))	('osteosarcoma', 'Disease', (145, 157))	('germline mutations', 'Var', (58, 76))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (172, 191))	('cancer', 'Disease', (115, 121))	('soft tissue sarcoma', 'Disease', (172, 191))	('BRCA', 'Gene', (11, 15))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TP53', 'Gene', (80, 84))
64578	26970122	TP53 and BRCA1/2 mutations are examples characterized by single high-penetrance genetic mutations, making cancer prevention interventions and recommendations possible.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('BRCA1/2', 'Gene', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('BRCA1/2', 'Gene', '672;675', (9, 16))	('cancer', 'Disease', (106, 112))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
64580	26970122	Many susceptibility mutations have been identified from GWAS studies, and unlike BRCA1 and BRCA2, most of the mutations identified are estimated to have small effect sizes on disease risk.	('BRCA1', 'Gene', (81, 86))	('mutations', 'Var', (110, 119))	('BRCA2', 'Gene', (91, 96))	('BRCA2', 'Gene', '675', (91, 96))	('BRCA1', 'Gene', '672', (81, 86))	('mutations', 'Var', (20, 29))
64584	26970122	While cancer screening with mammography or colonoscopy can lead to the early detection of a malignant or premalignant condition and genomic analysis of a cancer can lead to actionable mutations that guide treatment options, genetic testing of the population or high-risk individuals leads to the discovery of a predisposition to cancer.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (184, 193))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('genetic', 'Var', (224, 231))	('lead to', 'Reg', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (6, 12))
64588	26970122	PALB2 (partner and localizer of BRCA2) mutations, for example, are associated with a 35% cumulative risk of breast cancer by age 70 years.	('BRCA2', 'Gene', (32, 37))	('PALB2', 'Gene', '79728', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (39, 48))	('PALB2', 'Gene', (0, 5))	('associated', 'Reg', (67, 77))	('BRCA2', 'Gene', '675', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
64589	26970122	However, in the case of BRCA1/2:while additional mutations have been discovered:some of them are exceedingly rare and the associations with risk of breast cancer are currently unknown.	('mutations', 'Var', (49, 58))	('BRCA1/2', 'Gene', '672;675', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('BRCA1/2', 'Gene', (24, 31))
64590	26970122	If applied to premalignant conditions in a systematic way, whole genome sequencing to detect somatic (as well as germline) mutations could lead to the identification of both known and unknown actionable mutations and, at present, there are scant guidelines for patients and doctors regarding how to deal with such information.	('patients', 'Species', '9606', (261, 269))	('lead to', 'Reg', (139, 146))	('mutations', 'Var', (123, 132))	('mutations', 'Var', (203, 212))
64591	26970122	However, screening for susceptibility to cancer by looking at mutations in TP53 and BRCA1/2 has been successful due to the high penetrance of these genes in terms of lifetime risk of cancer, and the net benefits of screening might be more difficult to translate to findings from GWAS or whole genome sequencing studies.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('BRCA1/2', 'Gene', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (41, 47))	('TP53', 'Gene', (75, 79))	('BRCA1/2', 'Gene', '672;675', (84, 91))	('TP53', 'Gene', '7157', (75, 79))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
64633	22778939	The consideration for postmastectomy RT should be based on an individualized risk evaluating surgical technique used, presence of BRCA mutation, grade and extent of tumor, and proximity of lesion to the margin of resection.	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('BRCA', 'Gene', '672', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutation', 'Var', (135, 143))	('BRCA', 'Gene', (130, 134))	('tumor', 'Disease', (165, 170))
64650	22778939	Future research exploring the risk of relapse based on presence or absence of BRCA mutations and potential contribution of molecular breast cancer biomarkers including Oncotype Dx, HOXB-13, and others yet to be defined may guide the individual risk categorization for local relapse and accordingly the role for adjuvant therapies.	('HOXB-13', 'Gene', '10481', (181, 188))	('mutations', 'Var', (83, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('local relapse', 'Disease', (268, 281))	('HOXB-13', 'Gene', (181, 188))	('BRCA', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('absence', 'NegReg', (67, 74))
64664	32578065	In The Netherlands, resection margin status for patients with invasive breast cancer is defined as free (no ink on tumor), focally positive (<= 4 mm ink on tumor), or more than focally positive (> 4 mm ink on tumor).	('tumor', 'Disease', (209, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('invasive breast cancer', 'Disease', (62, 84))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('<= 4', 'Var', (141, 145))	('invasive breast cancer', 'Disease', 'MESH:D001943', (62, 84))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
64697	32578065	In addition, single seed localization was associated with a smaller DCIS diameter (p < 0.001) and the highest percentage of patients with a resection margin >= 2.0 mm (p = 0.001) compared with multiple seed localization.	('age', 'Gene', '5973', (117, 120))	('single seed', 'Var', (13, 24))	('DCIS diameter', 'MPA', (68, 81))	('age', 'Gene', (117, 120))	('smaller', 'NegReg', (60, 67))	('patients', 'Species', '9606', (124, 132))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
64720	32156290	Identification of key differentially expressed genes and gene mutations in breast ductal carcinoma in situ using RNA-seq analysis The aim of this study was to identify the key differentially expressed genes (DEGs) and high-risk gene mutations in breast ductal carcinoma in situ (DCIS).	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (75, 98))	('breast ductal carcinoma', 'Disease', 'MESH:D001943', (246, 269))	('breast ductal carcinoma', 'Disease', 'MESH:D001943', (75, 98))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (253, 269))	('DCIS', 'Phenotype', 'HP:0030075', (279, 283))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (82, 98))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (253, 277))	('breast ductal carcinoma', 'Disease', (75, 98))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('breast ductal carcinoma', 'Disease', (246, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('mutations', 'Var', (233, 242))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (246, 269))
64734	32156290	Furthermore, gene mutations in DCIS have also been associated with the progression of DCIS; these include BRCA1/2 deleterious mutation, somatic mutations in AKT1, PIK3CA, and TP53, and hypermethylation of HOXA5 and SOX genes.	('DCIS', 'Gene', (31, 35))	('TP53', 'Gene', (175, 179))	('mutations', 'Var', (18, 27))	('TP53', 'Gene', '7157', (175, 179))	('BRCA1/2', 'Gene', '672;675', (106, 113))	('AKT1', 'Gene', (157, 161))	('DCIS', 'Disease', (86, 90))	('HOXA5', 'Gene', '3202', (205, 210))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('associated', 'Reg', (51, 61))	('PIK3CA', 'Gene', (163, 169))	('HOXA5', 'Gene', (205, 210))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('mutations', 'Var', (144, 153))	('BRCA1/2', 'Gene', (106, 113))	('PIK3CA', 'Gene', '5290', (163, 169))	('AKT1', 'Gene', '207', (157, 161))	('hypermethylation', 'Var', (185, 201))
64737	32156290	The RNA-seq data GSE36863 were downloaded from the database of Gene Expression Omnibus (GEO), including three DCIS samples (DCIS cell lines MCF10.DCIS (GSM903304), Sum102 (GSM903305), and Sum22 (GSM903306)), and one normal control sample (mammary epithelial cell MCF10A (GSM903303)).	('MCF10A', 'CellLine', 'CVCL:0598', (263, 269))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('GSM903305', 'Var', (172, 181))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('GSM903304', 'Var', (152, 161))	('MCF10.DCIS', 'CellLine', 'CVCL:5555', (140, 150))
64754	32156290	For example, the enrichment of positively regulated tumor necrosis factor production was most significant in Sum102, while the enrichment of second-messenger-mediated signaling was more common in Sum225 and MCF10.DCIS cell lines.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Sum102', 'Var', (109, 115))	('tumor necrosis', 'Disease', 'MESH:D009336', (52, 66))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('tumor necrosis', 'Disease', (52, 66))	('MCF10.DCIS', 'CellLine', 'CVCL:5555', (207, 217))
64755	32156290	Through VENN analysis, we detected 603 upregulated and 1043 downregulated DEGs overlapping in the three cancer cell lines (Fig.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('upregulated', 'PosReg', (39, 50))	('DEGs', 'Var', (74, 78))	('downregulated', 'NegReg', (60, 73))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
64763	32156290	Base mutations located in chr1:161332189 and chr1:27190350 led to missense mutations in SDHC and SFN, respectively.	('SFN', 'Gene', '2810', (97, 100))	('missense mutations', 'Var', (66, 84))	('SFN', 'Gene', (97, 100))	('SDHC', 'Gene', (88, 92))	('SDHC', 'Gene', '6391', (88, 92))
64765	32156290	SDHC mutations occurred in Sum102 and Sum225 cell lines at the same mutant site, as well as SFN.	('occurred', 'Reg', (15, 23))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('SFN', 'Gene', '2810', (92, 95))	('SFN', 'Gene', (92, 95))
64766	32156290	RWDD4 and SEPT7 mutations occurred in both MCF10.DCIS and Sum102 cell lines.	('SEPT7', 'Gene', '989', (10, 15))	('RWDD4', 'Gene', '201965', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('mutations', 'Var', (16, 25))	('SEPT7', 'Gene', (10, 15))	('RWDD4', 'Gene', (0, 5))	('MCF10.DCIS', 'CellLine', 'CVCL:5555', (43, 53))	('occurred', 'Reg', (26, 34))
64771	32156290	A previous study had reported that some homeobox genes, such as HOXB13, TLX1, and HNF1B, were hypermethylated in the early stages of breast cancer.	('TLX1', 'Gene', '3195', (72, 76))	('hypermethylated', 'Var', (94, 109))	('TLX1', 'Gene', (72, 76))	('breast cancer', 'Disease', (133, 146))	('HOXB13', 'Gene', '10481', (64, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('HNF1B', 'Gene', '6928', (82, 87))	('HOXB13', 'Gene', (64, 70))	('HNF1B', 'Gene', (82, 87))	('homeobox genes', 'Gene', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
64773	32156290	In addition, DCIS is closely associated with the silencing of HOXA2.	('silencing', 'Var', (49, 58))	('HOXA2', 'Gene', (62, 67))	('HOXA2', 'Gene', '3199', (62, 67))	('associated', 'Reg', (29, 39))	('DCIS', 'Disease', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
64792	32156290	The knockdown of RWDD4 inhibits transitional cell carcinoma (TCC), cell proliferation, migration, and invasion.	('migration', 'CPA', (87, 96))	('RWDD4', 'Gene', '201965', (17, 22))	('carcinoma', 'Disease', 'MESH:D002277', (50, 59))	('TCC', 'Phenotype', 'HP:0006740', (61, 64))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (32, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('invasion', 'CPA', (102, 110))	('carcinoma', 'Disease', (50, 59))	('RWDD4', 'Gene', (17, 22))	('cell proliferation', 'CPA', (67, 85))	('knockdown', 'Var', (4, 13))	('inhibits', 'NegReg', (23, 31))
64793	32156290	However, no study has revealed RWDD4 mutations in DCIS so far.	('DCIS', 'Gene', (50, 54))	('RWDD4', 'Gene', '201965', (31, 36))	('mutations', 'Var', (37, 46))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('RWDD4', 'Gene', (31, 36))
64795	32156290	SDHC mutation has been confirmed to be associated with various cancers, such as kidney cancer, gastrointestinal stromal tumors, pheochromocytoma, and head and neck paraganglioma.	('associated', 'Reg', (39, 49))	('neck paraganglioma', 'Disease', (159, 177))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (95, 126))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (95, 126))	('kidney cancer', 'Disease', 'MESH:D007680', (80, 93))	('SDHC', 'Gene', '6391', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('neck paraganglioma', 'Disease', 'MESH:D010235', (159, 177))	('pheochromocytoma', 'Disease', 'MESH:D010673', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('paraganglioma', 'Phenotype', 'HP:0002668', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (80, 93))	('kidney cancer', 'Disease', (80, 93))	('gastrointestinal stromal tumors', 'Disease', (95, 126))	('pheochromocytoma', 'Disease', (128, 144))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (128, 144))	('SDHC', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutation', 'Var', (5, 13))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
64797	32156290	SDHB and SDHD variants are highly related to the increased prevalence of breast cancers.	('SDHD', 'Gene', (9, 13))	('SDHD', 'Gene', '6392', (9, 13))	('variants', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('SDHB', 'Gene', '6390', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('related', 'Reg', (34, 41))	('SDHB', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
64801	32156290	Therefore, we speculated that the SDHC mutation might be closely related to the progression of DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('mutation', 'Var', (39, 47))	('SDHC', 'Gene', (34, 38))	('SDHC', 'Gene', '6391', (34, 38))	('related', 'Reg', (65, 72))	('DCIS', 'Disease', (95, 99))
64811	32156290	ALDH5A1 Aldehyde dehydrogenase 5A1 BDC Breast ductal carcinoma BP Biological process CC Cellular component DAVID The Database for Annotation, Visualization and Integrated Discovery DCIS Ductal carcinoma in situ DEGs Differentially expressed genes GEO Gene Expression Omnibus IDC Invasive ductal carcinomas MF Molecular function NCBI National Center for Biotechnology Information SNPs Single nucleotide polymorphisms SNVs Single nucleotide variations TAGs Tumor-associated genes TF Transcription factor TSGs Tumor suppressor genes CZ conceived the research, acquired the data and drafted the manuscript.	('ALDH5A1', 'Gene', (0, 7))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (295, 305))	('ALDH5A1', 'Gene', '7915', (0, 7))	('Tumor', 'Phenotype', 'HP:0002664', (507, 512))	('IDC', 'Disease', (275, 278))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (46, 62))	('Invasive ductal carcinomas', 'Disease', (279, 305))	('Single nucleotide polymorphisms', 'Var', (384, 415))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (186, 210))	('Breast ductal carcinoma', 'Disease', 'MESH:D001943', (39, 62))	('BDC', 'Disease', 'MESH:D001943', (35, 38))	('Tumor', 'Phenotype', 'HP:0002664', (455, 460))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Ductal carcinoma in situ', 'Disease', (186, 210))	('IDC', 'Disease', 'MESH:D044584', (275, 278))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (288, 304))	('BDC', 'Disease', (35, 38))	('Breast ductal carcinoma', 'Disease', (39, 62))	('Single nucleotide variations', 'Var', (421, 449))	('Breast ductal carcinoma', 'Phenotype', 'HP:0003002', (39, 62))	('BDC', 'Phenotype', 'HP:0003002', (35, 38))	('Ductal carcinoma in situ', 'Disease', 'MESH:D002285', (186, 210))	('Invasive ductal carcinomas', 'Disease', 'MESH:D044584', (279, 305))
64960	18928525	The findings of the present study might have been influenced by the small number of pure DCIS, which retain very specific characteristic, such as high grade and HER2 positivity.	('positivity', 'Var', (166, 176))	('HER2', 'Gene', (161, 165))	('HER2', 'Gene', '2064', (161, 165))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))
64973	31450928	Statistical significant increase was found in methylation status of GSTP1 promotor gene in BC cases than that in control group, (60% of patients samples had methylated GSTP1 promotor vs only 6.7% of controls) (p= >0.001).	('increase', 'PosReg', (24, 32))	('GSTP1', 'Gene', '2950', (68, 73))	('GSTP1', 'Gene', (168, 173))	('GSTP1', 'Gene', (68, 73))	('methylated', 'Var', (157, 167))	('patients', 'Species', '9606', (136, 144))	('GSTP1', 'Gene', '2950', (168, 173))	('methylation status', 'MPA', (46, 64))
64976	31450928	Also GSTP1 promotor methylation was 2.4 times higher in Her2 positive cases than either ER or PR positive cases.	('GSTP1', 'Gene', (5, 10))	('positive', 'Var', (61, 69))	('higher', 'PosReg', (46, 52))	('Her2', 'Gene', '2064', (56, 60))	('GSTP1', 'Gene', '2950', (5, 10))	('Her2', 'Gene', (56, 60))
64984	31450928	Variable genetic modifications have been found to affect the function of GSTP1 gene as mutations and polymorphism.	('GSTP1', 'Gene', '2950', (73, 78))	('function', 'MPA', (61, 69))	('polymorphism', 'Var', (101, 113))	('affect', 'Reg', (50, 56))	('GSTP1', 'Gene', (73, 78))	('mutations', 'Var', (87, 96))
64985	31450928	In addition different epigenetic modifications in GSTP1 have been identified which include DNA methylation, histone modification, nucleosome positioning, chromosomal looping and non coding RNAs (Fazzari and Greally , 2004).	('DNA methylation', 'MPA', (91, 106))	('chromosomal looping', 'CPA', (154, 173))	('non coding RNAs', 'Var', (178, 193))	('GSTP1', 'Gene', '2950', (50, 55))	('histone modification', 'MPA', (108, 128))	('nucleosome', 'MPA', (130, 140))	('GSTP1', 'Gene', (50, 55))
64986	31450928	Epigenetic silencing of GSTP1 gene expression which is induced by promotor methylation has been found to be implicated in the pathogenesis of different types of cancers (Allocati et al., 2018).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('methylation', 'Var', (75, 86))	('GSTP1', 'Gene', (24, 29))	('GSTP1', 'Gene', '2950', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('Epigenetic silencing', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('implicated', 'Reg', (108, 118))
64987	31450928	It was found that methylation of the promotor regions of several genes, including known tumor suppressor genes (as GSTP1 and Breast cancer type 1 (BRCA1) and Ras-association domain family (RASSF), results in the subsequent failure to express their functional proteins as DNA methylation may impede the binding of transcriptional regulators to the gene (Jin et al., 2012 ; Sheng et al., 2017).	('GSTP1', 'Gene', '2950', (115, 120))	('express', 'MPA', (234, 241))	('BRCA1', 'Gene', '672', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('DNA methylation', 'Var', (271, 286))	('binding', 'Interaction', (302, 309))	('impede', 'NegReg', (291, 297))	('BRCA1', 'Gene', (147, 152))	('Breast cancer type 1', 'Gene', '672', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('functional', 'MPA', (248, 258))	('Breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('GSTP1', 'Gene', (115, 120))	('methylation', 'Var', (18, 29))	('Breast cancer type 1', 'Gene', (125, 145))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('failure', 'NegReg', (223, 230))
64988	31450928	Aberrant methylation of the GSTP1 has been reported to occur in different types of cancer including those of liver (Huang et al., 2011), prostate (Yang and Park, 2012), hematological malignancies (Karius et al., 2011) and breast (Brooks et al., 2009; Pongtheerat et al., 2011).	('hematological malignancies', 'Phenotype', 'HP:0004377', (169, 195))	('Aberrant', 'Var', (0, 8))	('liver', 'Disease', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate', 'Disease', (137, 145))	('GSTP1', 'Gene', (28, 33))	('occur', 'Reg', (55, 60))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('malignancies', 'Disease', (183, 195))	('breast', 'Disease', (222, 228))	('methylation', 'MPA', (9, 20))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('GSTP1', 'Gene', '2950', (28, 33))	('cancer', 'Disease', (83, 89))
65001	31450928	Breast cancer biopsies showed statistical significant increase in the methylation status of GSTP1 promotor region than that of normal control biopsies with p= <0.001 and OR= 21.0 which denotes that the odds of finding the GSTP1 promotor region methylated in breast cancer tissues was 21 times the odds of finding control tissues methylated (Table 1 ).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('methylation status', 'MPA', (70, 88))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('GSTP1', 'Gene', '2950', (222, 227))	('increase', 'PosReg', (54, 62))	('GSTP1', 'Gene', '2950', (92, 97))	('breast cancer', 'Disease', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('methylated', 'Var', (244, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('Breast cancer', 'Disease', (0, 13))	('GSTP1', 'Gene', (222, 227))	('GSTP1', 'Gene', (92, 97))
65004	31450928	Also no significant association between the clinicopathological factors that are risky for breast cancer (menopausal state, multiparity, grade, stage and Her2) and the presence of methylation of GSTP1 promotor.	('menopausal state', 'Phenotype', 'HP:0008209', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('GSTP1', 'Gene', (195, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('Her2', 'Gene', (154, 158))	('GSTP1', 'Gene', '2950', (195, 200))	('Her2', 'Gene', '2064', (154, 158))	('methylation', 'Var', (180, 191))	('presence', 'Var', (168, 176))
65005	31450928	However, postmenopausal ladies were two times at risk to have methylated GSTP1 promotor than premenopausal ladies as OR was 2.167.	('GSTP1', 'Gene', '2950', (73, 78))	('postmenopausal ladies', 'Phenotype', 'HP:0008209', (9, 30))	('premenopausal ladies', 'Phenotype', 'HP:0008209', (93, 113))	('methylated', 'Var', (62, 72))	('GSTP1', 'Gene', (73, 78))
65006	31450928	Besides patients with Grade III tumor were 3 times at risk of having methylated promotor region than patients with Grade II tumor as OR was 3.059.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('methylated', 'Var', (69, 79))	('tumor', 'Disease', (32, 37))	('patients', 'Species', '9606', (8, 16))
65007	31450928	In addition, the hormonal status of the tumor tissues showed also no statistical significant relation , however OR in Her2 positive cases was 2.4, denoting that cases with Her2 positivity were more than two times at risk of having methylation in GSTP1 promotor (Table 2).	('Her2', 'Gene', (118, 122))	('GSTP1', 'Gene', '2950', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Her2', 'Gene', '2064', (118, 122))	('methylation', 'MPA', (231, 242))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('GSTP1', 'Gene', (246, 251))	('Her2', 'Gene', (172, 176))	('positivity', 'Var', (177, 187))	('Her2', 'Gene', '2064', (172, 176))
65013	31450928	The presence of methylation in GSTP1 promotor region was also correlated with the histopathological and prognostic parameters.	('GSTP1', 'Gene', '2950', (31, 36))	('GSTP1', 'Gene', (31, 36))	('presence', 'Var', (4, 12))	('methylation', 'Var', (16, 27))	('correlated', 'Reg', (62, 72))
65014	31450928	The big Odd's ratio {(OR)= 21.0, 95% confidence interval (CI) = 2.474 - 178.220} denoted that the odds of finding the GSTP1 promotor region methylated in breast cancer tissues is 21 times the odds of finding normal control tissues methylated.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('methylated', 'Var', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('GSTP1', 'Gene', '2950', (118, 123))	('Odd', 'Gene', '130497', (8, 11))	('GSTP1', 'Gene', (118, 123))	('Odd', 'Gene', (8, 11))
65016	31450928	In accordance with our study, Wu et al., (2016) and Bhat et al., ( 2017) found that significantly high frequency of the promotor methylation of GSTP1 gene in breast cancer cases (p <= 0.001) when compared to the promotor hypermethylation profile of the normal tissues, and significantly hypermethylation of GSTP1 promotor region in breast cancer (BC) as compared with Begnin Breast Disease (BBD) and controls ( p=0.010.	('breast cancer', 'Disease', 'MESH:D001943', (332, 345))	('GSTP1', 'Gene', '2950', (307, 312))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('hypermethylation', 'PosReg', (287, 303))	('breast cancer', 'Phenotype', 'HP:0003002', (332, 345))	('breast cancer', 'Disease', (332, 345))	('methylation', 'Var', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('GSTP1', 'Gene', (144, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('high', 'PosReg', (98, 102))	('GSTP1', 'Gene', '2950', (144, 149))	('GSTP1', 'Gene', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))
65021	31450928	The relation between GSTP1 methylation and gene expression was shown in several studies as Bhat et al., (2017) stated that epigenetic silencing of the GSTP1 gene by CpG promotor hypermethylation is associated with the significant loss of the protein expression.	('GSTP1', 'Gene', '2950', (151, 156))	('GSTP1', 'Gene', (151, 156))	('GSTP1', 'Gene', (21, 26))	('epigenetic', 'Var', (123, 133))	('GSTP1', 'Gene', '2950', (21, 26))	('protein expression', 'MPA', (242, 260))	('hypermethylation', 'Var', (178, 194))	('loss', 'NegReg', (230, 234))
65022	31450928	This conclusion was also consistent with Fang et al., (2015) who clarified in their meta-analysis that GSTP1 gene promotor hypemethylation occurs more in breast cancer and thus may lead to cancer progression through inactivation of GSTP1 expression.	('inactivation', 'NegReg', (216, 228))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('GSTP1', 'Gene', '2950', (232, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('hypemethylation', 'Var', (123, 138))	('lead to', 'Reg', (181, 188))	('GSTP1', 'Gene', '2950', (103, 108))	('GSTP1', 'Gene', (232, 237))	('GSTP1', 'Gene', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('expression', 'MPA', (238, 248))	('cancer', 'Disease', (189, 195))
65023	31450928	We found that there was no significant difference in the frequency of GSTP1 promotor methylation between pre and postmenopausal cases (p= 0.317).	('methylation', 'Var', (85, 96))	('GSTP1', 'Gene', (70, 75))	('GSTP1', 'Gene', '2950', (70, 75))
65024	31450928	However, the OR was 2.167 which denoted that postmenopausal ladies were twice at risk to have methylated GSTP1 promotor than premenopausal cases.	('methylated', 'Var', (94, 104))	('GSTP1', 'Gene', '2950', (105, 110))	('GSTP1', 'Gene', (105, 110))	('postmenopausal ladies', 'Phenotype', 'HP:0008209', (45, 66))
65027	31450928	Also Lasabova et al., (2010) and Wu et al., (2016) found no association between methylation status of the promotor region GSTP1 and tumor size.	('GSTP1', 'Gene', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('GSTP1', 'Gene', '2950', (122, 127))	('methylation', 'Var', (80, 91))
65028	31450928	On the other hand Myake et al., (2013) found that methylation status was related to larger tumor more than smaller tumor thus leading to worse prognosis (p=0.044).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('methylation status', 'Var', (50, 68))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
65029	31450928	No statistical significant association between lymph node metastasis and GSTP1 methylation status was present in our study.	('GSTP1', 'Gene', '2950', (73, 78))	('GSTP1', 'Gene', (73, 78))	('lymph node metastasis', 'CPA', (47, 68))	('methylation status', 'Var', (79, 97))
65030	31450928	On the contrary, Bhat et al., (2017) found that most of patients with methylated GSTP1 promotor region tumors had positive lymph node metastasis (p = <0.001).	('patients', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('GSTP1', 'Gene', '2950', (81, 86))	('methylated', 'Var', (70, 80))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('positive lymph node metastasis', 'CPA', (114, 144))	('GSTP1', 'Gene', (81, 86))
65031	31450928	Also, Lasabova et al., (2010) study showed a significant association between GSTP1 promotor region hypermethylation and lymph node metastasis (p = 0.0142).	('GSTP1', 'Gene', (77, 82))	('GSTP1', 'Gene', '2950', (77, 82))	('hypermethylation', 'Var', (99, 115))	('lymph node metastasis', 'CPA', (120, 141))
65032	31450928	The present study also revealed that Grade III tumor patients are 3 times at risk of having methylated GSTP1 promotor region than Grade II tumor patients as the OR was 3.059.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('GSTP1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('GSTP1', 'Gene', '2950', (103, 108))	('methylated', 'Var', (92, 102))	('tumor', 'Disease', (47, 52))
65033	31450928	Also 80% of Grade III tumor patients had methylated promotor region of GSTP1 while only 43.3% of Grade II tumor had unmethylated GSTP1 promotor.	('GSTP1', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('GSTP1', 'Gene', '2950', (129, 134))	('GSTP1', 'Gene', '2950', (71, 76))	('methylated', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('GSTP1', 'Gene', (129, 134))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Disease', (106, 111))
65037	31450928	On the contrary, many studies concluded that there was statistical association between GSTP1 gene methylation and tumor stage as Fang et al., (2015) who found that level of GSTP1 methylation increased significantly (p=0.039) in late-stage compared to the early stage breast carcinomas.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('methylation', 'MPA', (179, 190))	('GSTP1', 'Gene', '2950', (173, 178))	('breast carcinomas', 'Phenotype', 'HP:0003002', (267, 284))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation', 'Var', (98, 109))	('GSTP1', 'Gene', (87, 92))	('breast carcinoma', 'Phenotype', 'HP:0003002', (267, 283))	('tumor', 'Disease', (114, 119))	('increased', 'PosReg', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('carcinomas', 'Phenotype', 'HP:0030731', (274, 284))	('GSTP1', 'Gene', (173, 178))	('breast carcinomas', 'Disease', 'MESH:D001943', (267, 284))	('GSTP1', 'Gene', '2950', (87, 92))	('breast carcinomas', 'Disease', (267, 284))
65038	31450928	They suggested that breast cancer patients with GSTP1 promotor hypermethylation may have a phenotype with more biological aggressiveness.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('aggressiveness', 'Disease', (122, 136))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('hypermethylation', 'Var', (63, 79))	('breast cancer', 'Disease', (20, 33))	('GSTP1', 'Gene', (48, 53))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('patients', 'Species', '9606', (34, 42))	('aggressiveness', 'Disease', 'MESH:D001523', (122, 136))	('GSTP1', 'Gene', '2950', (48, 53))
65041	31450928	They suggested the role of GSTP1 promotor methylation in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('GSTP1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('GSTP1', 'Gene', '2950', (27, 32))	('methylation', 'Var', (42, 53))
65043	31450928	Regarding hormonal status and its association with GSTP1 promotor methylation, 87.5% of ER negative patients had methylated promotor region of GSTP1, while 88.9% of PR negative had methylated GSTP1 promotor region and 75% of Her 2 positive patients had methylation in promotor region of GSTP1 cases.	('GSTP1', 'Gene', '2950', (51, 56))	('methylation', 'Var', (253, 264))	('methylated', 'Var', (113, 123))	('methylated', 'Var', (181, 191))	('GSTP1', 'Gene', (192, 197))	('GSTP1', 'Gene', (143, 148))	('GSTP1', 'Gene', '2950', (287, 292))	('patients', 'Species', '9606', (100, 108))	('GSTP1', 'Gene', '2950', (192, 197))	('GSTP1', 'Gene', (51, 56))	('patients', 'Species', '9606', (240, 248))	('GSTP1', 'Gene', '2950', (143, 148))	('Her 2', 'Gene', '2064', (225, 230))	('Her 2', 'Gene', (225, 230))	('GSTP1', 'Gene', (287, 292))
65046	31450928	This may be explained by inhibition of GSTP1 gene expression which can add to the decrease of its capability to detoxify estrogen due to GSTP1 promotor methylation (Callahan et al., 2016).	('GSTP1', 'Gene', '2950', (39, 44))	('decrease', 'NegReg', (82, 90))	('GSTP1', 'Gene', (137, 142))	('GSTP1', 'Gene', '2950', (137, 142))	('GSTP1', 'Gene', (39, 44))	('capability', 'MPA', (98, 108))	('methylation', 'Var', (152, 163))	('detoxify estrogen', 'MPA', (112, 129))
65050	31450928	In addition, 75% of cases with HER2 positive showed methylation in GSTP1 promotor region.	('HER2', 'Gene', '2064', (31, 35))	('GSTP1', 'Gene', '2950', (67, 72))	('methylation', 'Var', (52, 63))	('HER2', 'Gene', (31, 35))	('GSTP1', 'Gene', (67, 72))
65051	31450928	The current work, also reported that all cases with Her2 enriched tumors had methylated GSTP1 promotor region and 75% of cases with triple negative tumors had methylated GSTP1 promotor region.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Her2', 'Gene', '2064', (52, 56))	('GSTP1', 'Gene', '2950', (170, 175))	('GSTP1', 'Gene', '2950', (88, 93))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('GSTP1', 'Gene', (170, 175))	('Her2', 'Gene', (52, 56))	('GSTP1', 'Gene', (88, 93))	('methylated', 'Var', (77, 87))
65052	31450928	But 52.2 % of cases with Luminal A tumors and 50% of cases with Luminal B tumors had methylated GSTP1 promotor region.	('Luminal', 'Chemical', 'MESH:D010634', (64, 71))	('B tumors', 'Disease', 'MESH:D006509', (72, 80))	('methylated', 'Var', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('GSTP1', 'Gene', (96, 101))	('Luminal', 'Chemical', 'MESH:D010634', (25, 32))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (35, 41))	('B tumors', 'Disease', (72, 80))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('GSTP1', 'Gene', '2950', (96, 101))	('tumors', 'Disease', (74, 80))
65053	31450928	This led to non significance statistical association between the BC molecular types and GSTP1 promotor hypermethylation.	('hypermethylation', 'Var', (103, 119))	('GSTP1', 'Gene', '2950', (88, 93))	('GSTP1', 'Gene', (88, 93))
65057	31450928	In conclusion, since our results revealed the significant hypermethylation in GSTP1 promotor in BC tissues than that in normal tissues, this may suggest the possible role of GSTP1 promotor hypermethylation in the pathogenesis of BC in Egyptian females.	('hypermethylation', 'Var', (189, 205))	('hypermethylation', 'Var', (58, 74))	('GSTP1', 'Gene', (174, 179))	('GSTP1', 'Gene', '2950', (78, 83))	('GSTP1', 'Gene', '2950', (174, 179))	('GSTP1', 'Gene', (78, 83))
65064	23318431	Inhibition of these pathways, as well as inhibition of reactive oxygen species (ROS) with antioxidants, prevents IR-induced invasion.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (55, 78))	('Inhibition', 'Var', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('prevents', 'NegReg', (104, 112))	('IR-induced invasion', 'CPA', (113, 132))
65084	23318431	Similar to ErbB2, 14-3-3zeta overexpression can confer luminal filling in vitro, but does not lead to invasion.	('luminal filling', 'CPA', (55, 70))	('14-3-3zeta', 'Gene', (18, 28))	('overexpression', 'Var', (29, 43))	('ErbB2', 'Gene', (11, 16))	('14-3-3zeta', 'Gene', '7534', (18, 28))	('ErbB2', 'Gene', '2064', (11, 16))
65088	23318431	Culture of the immortalized human mammary epithelial cell line, MCF10A, in reconstituted basement membrane (for example, Matrigel) leads to the formation of polarized, hollow, acinar-like structures, with properties similar to normal mammary ducts; transduction of MCF10A cells with ErbB2 results in the generation of disorganized, filled, DCIS-like structures that remain non-invasive when cultured in reconstituted basement membrane.	('MCF10A', 'CellLine', 'CVCL:0598', (265, 271))	('disorganized', 'CPA', (318, 330))	('ErbB2', 'Gene', '2064', (283, 288))	('human', 'Species', '9606', (28, 33))	('MCF10A', 'CellLine', 'CVCL:0598', (64, 70))	('MCF10A', 'Gene', (265, 271))	('transduction', 'Var', (249, 261))	('ErbB2', 'Gene', (283, 288))
65091	23318431	Inhibition of ErbB2, Src, Akt or FoxM1 prevents IR-mediated invasion.	('FoxM1', 'Gene', '2305', (33, 38))	('FoxM1', 'Gene', (33, 38))	('Akt', 'Gene', '207', (26, 29))	('Src', 'Gene', (21, 24))	('prevents', 'NegReg', (39, 47))	('ErbB2', 'Gene', (14, 19))	('Src', 'Gene', '6714', (21, 24))	('Akt', 'Gene', (26, 29))	('IR-mediated invasion', 'CPA', (48, 68))	('Inhibition', 'Var', (0, 10))	('ErbB2', 'Gene', '2064', (14, 19))
65130	23318431	Consistent with a role for Src in activation of ErbB2 and promotion of IR-induced invasion, inhibition of Src with PP2 diminished ErbB2 phosphorylation in response to IR (Figure 3b).	('inhibition', 'Var', (92, 102))	('phosphorylation', 'MPA', (136, 151))	('ErbB2', 'Gene', (130, 135))	('Src', 'Gene', (106, 109))	('Src', 'Gene', (27, 30))	('diminished', 'NegReg', (119, 129))	('ErbB2', 'Gene', (48, 53))	('response to IR', 'MPA', (155, 169))	('Src', 'Gene', '6714', (106, 109))	('ErbB2', 'Gene', '2064', (130, 135))	('Src', 'Gene', '6714', (27, 30))	('PP2', 'Gene', (115, 118))	('PP2', 'Gene', '4888', (115, 118))	('ErbB2', 'Gene', '2064', (48, 53))
65132	23318431	Inhibition of Src and EGFR were also able to abolish IR-induced invasion (Figures 3c and d).	('abolish', 'NegReg', (45, 52))	('IR-induced invasion', 'CPA', (53, 72))	('Inhibition', 'Var', (0, 10))	('Src', 'Gene', (14, 17))	('EGFR', 'Gene', '1956', (22, 26))	('Src', 'Gene', '6714', (14, 17))	('EGFR', 'Gene', (22, 26))
65134	23318431	Both MAPK/ERK and PI3K/AKT pathways are known to be activated downstream of ErbB2 phosphorylation.	('MAPK', 'Gene', (5, 9))	('ErbB2', 'Gene', '2064', (76, 81))	('AKT', 'Gene', '207', (23, 26))	('phosphorylation', 'Var', (82, 97))	('ERK', 'Gene', '5594', (10, 13))	('AKT', 'Gene', (23, 26))	('ErbB2', 'Gene', (76, 81))	('ERK', 'Gene', (10, 13))	('MAPK', 'Gene', '5595;5594;5595', (5, 9))
65137	23318431	Inhibition of PI3K with LY294002 reduced relative invasion 4.9-fold compared with dimethylsulphoxide treatment as measured by transwell invasion assay, significantly more than the MEK inhibitor U0126, which reduced relative invasion 1.6-fold (Figure 4b).	('LY294002', 'Var', (24, 32))	('dimethylsulphoxide', 'Chemical', 'MESH:D004121', (82, 100))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('MEK', 'Gene', (180, 183))	('U0126', 'Chemical', 'MESH:C113580', (194, 199))	('MEK', 'Gene', '5609', (180, 183))	('reduced', 'NegReg', (33, 40))	('relative invasion', 'CPA', (41, 58))	('PI3K', 'Pathway', (14, 18))
65138	23318431	Compared with dimethylsulphoxide-treated irradiated MCF10A-ErbB2 with 45.1% invasive structures, only 3.24% of irradiated LY294002 treated structures became invasive, as compared with 25.2% of irradiated U0126-treated structures (Figure 4c).	('MCF10A-ErbB2', 'Gene', (52, 64))	('LY294002', 'Chemical', 'MESH:C085911', (122, 130))	('U0126', 'Chemical', 'MESH:C113580', (204, 209))	('dimethylsulphoxide', 'Chemical', 'MESH:D004121', (14, 32))	('invasive', 'CPA', (157, 165))	('MCF10A-ErbB2', 'Gene', '2064', (52, 64))	('LY294002', 'Var', (122, 130))
65140	23318431	Thus, PI3K/Akt is a critical pathway activated by IR-induced ErbB2 phosphorylation that promotes invasion.	('promotes', 'PosReg', (88, 96))	('Akt', 'Gene', (11, 14))	('ErbB2', 'Gene', (61, 66))	('phosphorylation', 'Var', (67, 82))	('Akt', 'Gene', '207', (11, 14))	('ErbB2', 'Gene', '2064', (61, 66))	('invasion', 'CPA', (97, 105))
65155	23318431	However, irradiation significantly increased relative invasion through transwell chambers (Figure 5e) and in 3D culture (Figure 5f) Results with MCF10A-FoxM1 cells suggest that expression of FoxM1 in the absence of ErbB2 is capable of driving IR-induced invasion.	('ErbB2', 'Gene', (215, 220))	('FoxM1', 'Gene', (191, 196))	('MCF10A', 'CellLine', 'CVCL:0598', (145, 151))	('expression', 'Var', (177, 187))	('ErbB2', 'Gene', '2064', (215, 220))	('FoxM1', 'Gene', '2305', (152, 157))	('IR-induced invasion', 'CPA', (243, 262))	('FoxM1', 'Gene', (152, 157))	('FoxM1', 'Gene', '2305', (191, 196))
65162	23318431	Coexpression of the regulatory protein 14-3-3zeta with ErbB2 was previously shown to promote DCIS progression to an invasive lesion, and recently has been shown to have an upstream regulatory function on FoxM1.	('FoxM1', 'Gene', (204, 209))	('14-3-3zeta', 'Gene', '7534', (39, 49))	('ErbB2', 'Gene', '2064', (55, 60))	('promote', 'PosReg', (85, 92))	('Coexpression', 'Var', (0, 12))	('14-3-3zeta', 'Gene', (39, 49))	('ErbB2', 'Gene', (55, 60))	('DCIS progression to an invasive lesion', 'CPA', (93, 131))	('FoxM1', 'Gene', '2305', (204, 209))
65171	23318431	Inhibition of 14-3-3zeta prevented invasion of MCF10A-ErbB2 cells in response to IR, in both transwell invasion assays (Figure 7a) and 3D culture (Figure 7b).	('MCF10A-ErbB2', 'Gene', (47, 59))	('14-3-3zeta', 'Gene', (14, 24))	('prevented', 'NegReg', (25, 34))	('MCF10A-ErbB2', 'Gene', '2064', (47, 59))	('invasion', 'CPA', (35, 43))	('Inhibition', 'Var', (0, 10))	('response to IR', 'MPA', (69, 83))	('14-3-3zeta', 'Gene', '7534', (14, 24))
65183	23318431	As evidenced by our results, expression of all three may increase the invasive potential of premalignant cells and may drive progression to malignancy in response to IR or increased oxidative stress.	('expression', 'Var', (29, 39))	('drive', 'Reg', (119, 124))	('response to IR', 'MPA', (154, 168))	('oxidative stress', 'Phenotype', 'HP:0025464', (182, 198))	('invasive potential of premalignant cells', 'CPA', (70, 110))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (172, 198))	('increase', 'PosReg', (57, 65))	('oxidative stress', 'MPA', (182, 198))	('malignancy', 'Disease', 'MESH:D009369', (140, 150))	('malignancy', 'Disease', (140, 150))
65184	23318431	Coexpression of 14-3-3zeta and ErbB2 has previously been associated with the presence of microinvasion in the clinical samples of DCIS, as well as with higher rates of recurrence and death in inflammatory breast cancer.	('death', 'Disease', (183, 188))	('14-3-3zeta', 'Gene', '7534', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('clinical samples', 'Species', '191496', (110, 126))	('inflammatory breast cancer', 'Disease', (192, 218))	('microinvasion', 'MPA', (89, 102))	('14-3-3zeta', 'Gene', (16, 26))	('death', 'Disease', 'MESH:D003643', (183, 188))	('ErbB2', 'Gene', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('Coexpression', 'Var', (0, 12))	('inflammatory breast cancer', 'Disease', 'MESH:D058922', (192, 218))	('associated', 'Reg', (57, 67))	('ErbB2', 'Gene', '2064', (31, 36))
65189	23318431	In addition, our data suggest that mere expression of ErbB2, FoxM1 and 14-3-3zeta is not sufficient for invasion, but rather primes the cell for an invasive response to stress.	('ErbB2', 'Gene', (54, 59))	('expression', 'Var', (40, 50))	('FoxM1 and 14-3-3zeta', 'Gene', '2305;7534', (61, 81))	('ErbB2', 'Gene', '2064', (54, 59))	('primes', 'PosReg', (125, 131))	('invasive response', 'CPA', (148, 165))
65211	23318431	Thus, ErbB2, FoxM1 and 14-3-3zeta, may be an important set of markers for determining treatment strategy in DCIS patients, and furthermore that targeting 14-3-3zeta and/or the kinase activity of ErbB2 in conjunction with radiotherapy may further decrease the risk of malignant progression of DCIS.	('decrease', 'NegReg', (246, 254))	('DCIS', 'Disease', (292, 296))	('kinase activity', 'MPA', (176, 191))	('malignant progression', 'CPA', (267, 288))	('ErbB2', 'Gene', (6, 11))	('FoxM1 and 14-3-3zeta', 'Gene', '2305;7534', (13, 33))	('14-3-3zeta', 'Gene', '7534', (23, 33))	('DCIS', 'Disease', (108, 112))	('ErbB2', 'Gene', (195, 200))	('targeting', 'Var', (144, 153))	('patients', 'Species', '9606', (113, 121))	('14-3-3zeta', 'Gene', '7534', (154, 164))	('14-3-3zeta', 'Gene', (154, 164))	('ErbB2', 'Gene', '2064', (6, 11))	('ErbB2', 'Gene', '2064', (195, 200))	('14-3-3zeta', 'Gene', (23, 33))
65221	23318431	RNA interference against FoxM1 and 14-3-3zeta was performed using two independent lentiviral pLKO.1-puromycin shRNA sequences each from The RNA interference Consortium (TRC) TRC-hs1.0 lentiviral shRNA library (FoxM1: Thermo Scientific, TRCN0000015543 and TRCN0000015544; 14-3-3zeta: Sigma-Aldrich, TRCN0000029404 and TRCN0000029405).	('14-3-3zeta', 'Gene', (271, 281))	('1-puromycin', 'Chemical', '-', (98, 109))	('14-3-3zeta', 'Gene', (35, 45))	('FoxM1 and 14-3-3zeta', 'Gene', '2305;7534', (25, 45))	('TRCN0000029404', 'Var', (298, 312))	('14-3-3zeta', 'Gene', '7534', (271, 281))	('FoxM1', 'Gene', '2305', (25, 30))	('FoxM1', 'Gene', '2305', (210, 215))	('FoxM1', 'Gene', (25, 30))	('14-3-3zeta', 'Gene', '7534', (35, 45))	('FoxM1', 'Gene', (210, 215))
65231	23318431	Antibodies against phophorylated-ErbB2 (Y877), ErbB2, EGFR, phosphorylated Src (Y416), Src, phosphorylated Akt (S473), Akt and MMP2 were obtained from Cell Signaling (Danvers, MA, USA).	('Akt', 'Gene', '207', (119, 122))	('ErbB2', 'Gene', '2064', (33, 38))	('EGFR', 'Gene', '1956', (54, 58))	('Src', 'Gene', (87, 90))	('ErbB2', 'Gene', '2064', (47, 52))	('S473', 'Var', (112, 116))	('Src', 'Gene', '6714', (87, 90))	('ErbB2', 'Gene', (33, 38))	('MMP2', 'Gene', (127, 131))	('Src', 'Gene', (75, 78))	('Akt', 'Gene', (107, 110))	('Y416', 'Var', (80, 84))	('Y877', 'Var', (40, 44))	('Akt', 'Gene', '207', (107, 110))	('EGFR', 'Gene', (54, 58))	('Src', 'Gene', '6714', (75, 78))	('ErbB2', 'Gene', (47, 52))	('MMP2', 'Gene', '4313', (127, 131))	('Akt', 'Gene', (119, 122))
65232	23318431	Antibodies against phosphorylated Erk 1/2 (T185/Y187) and total Erk were obtained from Invitrogen and Promega (Madison, WI, USA), respectively.	('Erk', 'Gene', '5594', (64, 67))	('Erk', 'Gene', '5594', (34, 37))	('Erk', 'Gene', (64, 67))	('T185/Y187', 'Var', (43, 52))	('Erk 1/2', 'Gene', '5595;5594', (34, 41))	('Erk', 'Gene', (34, 37))	('Erk 1/2', 'Gene', (34, 41))
65238	23318431	Two hundred and fifty nanogram total RNA was added to Stratagene Brilliant II quantitative real time - PCR master mix with primer/probe sets from Applied Biosystems (PP1A: Hs99999904_m1; MMP2: Hs00234422_m1; FOXM1: Hs01073586_m1; cyclophillin A: Hs99999904_m1; LDHA: Hs00855332_g1.	('MMP2', 'Gene', '4313', (187, 191))	('LDHA', 'Gene', (261, 265))	('FOXM1', 'Gene', (208, 213))	('Brilliant II', 'Chemical', '-', (65, 77))	('Hs01073586_m1', 'Var', (215, 228))	('FOXM1', 'Gene', '2305', (208, 213))	('Hs99999904_m1', 'Var', (172, 185))	('LDHA', 'Gene', '3939', (261, 265))	('MMP2', 'Gene', (187, 191))	('PP1A', 'Gene', (166, 170))	('Hs00234422_m1', 'Var', (193, 206))	('PP1A', 'Gene', '5499', (166, 170))	('Hs99999904_m1', 'Var', (246, 259))
65346	22429463	Our preliminary estimate of the hazard ratio (HR) associated with Active (compared to Inactive) microenvironment was approximately 2.5, which is substantial considering that established genomic phenotypes such as p53 mutation status and Cyclin E overexpression have HRs near two.	('overexpression', 'PosReg', (246, 260))	('p53', 'Gene', '7157', (213, 216))	('p53', 'Gene', (213, 216))	('Cyclin E', 'Enzyme', (237, 245))	('mutation status', 'Var', (217, 232))
65417	20727142	Our hypothesis is that LIN is most likely not just a risk factor, but a precursor lesion to invasive cancer, and that LIN at the surgical margin may have a significantly higher recurrence rate over clear margins on BCT.	('higher', 'PosReg', (170, 176))	('recurrence', 'CPA', (177, 187))	('lesion to invasive cancer', 'Disease', (82, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('LIN', 'Disease', (23, 26))	('LIN', 'Var', (118, 121))	('lesion to invasive cancer', 'Disease', 'MESH:D009362', (82, 107))
65421	20727142	Our terminology composed of ALH, and LCIS which were the classic type, LCIS with distension and comedo necrosis with nuclear grade 2 and pleomorphic LCIS with nuclear grade 3.	('nuclear grade 2', 'Var', (117, 132))	('comedo', 'Phenotype', 'HP:0025249', (96, 102))	('necrosis', 'Disease', (103, 111))	('necrosis', 'Disease', 'MESH:D009336', (103, 111))	('LCIS', 'Phenotype', 'HP:0030076', (149, 153))	('LCIS', 'Phenotype', 'HP:0030076', (37, 41))	('LCIS', 'Phenotype', 'HP:0030076', (71, 75))
65465	20727142	Their study showed a trend towards an increased local recurrence rate with positive margins for LCIS only and this seems limited to women greater than 50-years of age.	('women', 'Species', '9606', (132, 137))	('LCIS', 'Disease', (96, 100))	('positive', 'Var', (75, 83))	('LCIS', 'Phenotype', 'HP:0030076', (96, 100))	('local recurrence', 'CPA', (48, 64))
65467	20727142	studied whether or not LCIS at the margin would increase local recurrence in patients treated with breast-conserving therapy.	('local recurrence', 'CPA', (57, 73))	('LCIS', 'Var', (23, 27))	('patients', 'Species', '9606', (77, 85))	('LCIS', 'Phenotype', 'HP:0030076', (23, 27))	('increase', 'PosReg', (48, 56))
65469	20727142	Jolly et al., on the contrary, found that the presence of LCIS was associated with a higher incidence ipsilateral recurrence; 14% with LCIS at the margin when compared to 7% without LCIS at the margin from a patient sample of 56 with a median of 8.7 years follow up.	('patient', 'Species', '9606', (208, 215))	('LCIS', 'Phenotype', 'HP:0030076', (182, 186))	('to 7', 'Species', '1214577', (168, 172))	('LCIS', 'Phenotype', 'HP:0030076', (58, 62))	('LCIS at', 'Var', (135, 142))	('LCIS', 'Gene', (58, 62))	('LCIS', 'Phenotype', 'HP:0030076', (135, 139))
65498	20030867	Previous studies by the Lisanti group have shown that caveolin-1 is downregulated in fibroblasts during transformation and that recombinant expression of caveolin-1 in oncogenically transformed cells abrogates anchorage-independent growth, therefore biologically underpinning the observations in breast tumour stroma.	('breast tumour stroma', 'Disease', (296, 316))	('breast tumour stroma', 'Disease', 'MESH:D001943', (296, 316))	('abrogates', 'NegReg', (200, 209))	('downregulated', 'NegReg', (68, 81))	('breast tumour', 'Phenotype', 'HP:0100013', (296, 309))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('anchorage-independent growth', 'CPA', (210, 238))	('caveolin-1', 'Gene', (154, 164))	('caveolin-1', 'Gene', (54, 64))	('caveolin-1', 'Gene', '857', (154, 164))	('caveolin-1', 'Gene', '857', (54, 64))	('recombinant expression', 'Var', (128, 150))
65523	34007958	Furthermore, our data suggests that loss of CK5 prior to invasive stage causes decreased levels of Zinc finger protein SNAI2 (SLUG), a key regulator of the mammary epithelial cell lineage determination.	('CK5', 'Gene', (44, 47))	('SNAI2', 'Gene', '6591', (119, 124))	('SNAI2', 'Gene', (119, 124))	('decreased', 'NegReg', (79, 88))	('decreased levels of Zinc', 'Phenotype', 'HP:0031831', (79, 103))	('loss', 'Var', (36, 40))	('CK5', 'Gene', '3852', (44, 47))	('levels', 'MPA', (89, 95))
65546	34007958	Recently, loss of alpha-SMA was also shown to compromise the barrier made by ME cells, suggesting that the ME layer acts as a mechanical barrier and that the contractile potential, mediated by alpha-SMA, is important for its protective function.	('loss', 'Var', (10, 14))	('alpha-SMA', 'Gene', '58', (193, 202))	('alpha-SMA', 'Gene', (193, 202))	('ME', 'Chemical', '-', (107, 109))	('alpha-SMA', 'Gene', '58', (18, 27))	('ME', 'Chemical', '-', (77, 79))	('alpha-SMA', 'Gene', (18, 27))
65556	34007958	Furthermore, our cell biological experiments with primary canine mammary epithelial cells and the human mammary epithelial cell line showed that the loss of CK5, and to a lesser extent CK14, from the basal progenitor population affected maturation of the progenitors into functional, contractile ME cells.	('ME', 'Chemical', '-', (296, 298))	('affected', 'Reg', (228, 236))	('loss', 'Var', (149, 153))	('CK5', 'Gene', (157, 160))	('CK14', 'Gene', '3861', (185, 189))	('maturation', 'CPA', (237, 247))	('canine', 'Species', '9615', (58, 64))	('CK5', 'Gene', '3852', (157, 160))	('human', 'Species', '9606', (98, 103))	('CK14', 'Gene', (185, 189))
65558	34007958	Importantly, loss of CK5 was associated with downregulation of transcriptional repressor Zinc finger protein SNAI2 (SLUG), an important regulator of the mammary epithelial cell lineage determination.	('SNAI2', 'Gene', '6591', (109, 114))	('SNAI2', 'Gene', (109, 114))	('CK5', 'Gene', (21, 24))	('downregulation', 'NegReg', (45, 59))	('loss', 'Var', (13, 17))	('CK5', 'Gene', '3852', (21, 24))
65584	34007958	To further explore whether the loss of these specific CKs could affect the morphology of 3D structures by impacting the epithelial differentiation process, we isolated the CD49f+ EpCAM- population, enriched for basal progenitors, from the MCF10A cell line (Figures S4C-S4E).	('CK', 'Gene', '51727', (54, 56))	('impacting', 'Reg', (106, 115))	('EpCAM', 'Gene', '4072', (179, 184))	('loss', 'Var', (31, 35))	('CD49f', 'Gene', '3655', (172, 177))	('epithelial differentiation process', 'CPA', (120, 154))	('MCF10A', 'CellLine', 'CVCL:0598', (239, 245))	('EpCAM', 'Gene', (179, 184))	('affect', 'Reg', (64, 70))	('CD49f', 'Gene', (172, 177))
65585	34007958	These progenitor cells were targeted by lentiviral-based RNA interference to knock down CK5 and CK14 (Figures S4F, S4G, and S5A).	('CK5', 'Gene', (88, 91))	('CK14', 'Gene', '3861', (96, 100))	('knock', 'Var', (77, 82))	('CK5', 'Gene', '3852', (88, 91))	('S4G', 'Mutation', 'p.S4G', (115, 118))	('CK14', 'Gene', (96, 100))
65586	34007958	Similar to siRNA experiments these knock down (KD) cells in a 3D environment formed larger mammospheres with abnormal morphology (Figures 2F,S5B, and S5C).	('S5C', 'Mutation', 'p.S5C', (150, 153))	('S5B', 'Gene', (141, 144))	('knock down', 'Var', (35, 45))	('S5B', 'Gene', '5711', (141, 144))
65598	34007958	These results suggest that CK5 has a major role in the maturation process of ME cells, the loss of CK5 leading to a differentiation bias toward the CK18+ luminal epithelial cell type.	('CK5', 'Gene', (99, 102))	('CK18', 'Gene', (148, 152))	('CK5', 'Gene', (27, 30))	('differentiation bias', 'CPA', (116, 136))	('loss', 'Var', (91, 95))	('CK5', 'Gene', '3852', (99, 102))	('ME', 'Chemical', '-', (77, 79))	('CK18', 'Gene', '3875', (148, 152))	('leading to', 'Reg', (103, 113))	('CK5', 'Gene', '3852', (27, 30))	('luminal', 'Chemical', 'MESH:D010634', (154, 161))
65601	34007958	As CK5, and to a lesser extent CK14, were found to affect the maturation of ME cells, we wanted to assess whether loss of these proteins could also impact the resistance of the ME layer through cell adhesive structures.	('impact', 'Reg', (148, 154))	('CK14', 'Gene', (31, 35))	('affect', 'Reg', (51, 57))	('ME', 'Chemical', '-', (76, 78))	('CK5', 'Gene', (3, 6))	('loss', 'Var', (114, 118))	('maturation of ME cells', 'CPA', (62, 84))	('ME', 'Chemical', '-', (177, 179))	('CK14', 'Gene', '3861', (31, 35))	('CK5', 'Gene', '3852', (3, 6))
65603	34007958	Both markers were significantly decreased upon loss of CK5, while loss of CK14 did not seem to play a role in maintaining their levels (Figures 4A and 4B).	('CK14', 'Gene', '3861', (74, 78))	('CK5', 'Gene', '3852', (55, 58))	('CK14', 'Gene', (74, 78))	('loss', 'Var', (47, 51))	('CK5', 'Gene', (55, 58))	('decreased', 'NegReg', (32, 41))
65619	34007958	These results act as additional proof for the observations that loss of CK5 not only impacts the mechanical features of the basal layer but also leads to loss of protective basement membrane possibly through impaired maturation of myoepithelial cells.	('protective basement membrane', 'CPA', (162, 190))	('impacts', 'Reg', (85, 92))	('impaired', 'NegReg', (208, 216))	('CK5', 'Gene', '3852', (72, 75))	('mechanical features of the basal layer', 'CPA', (97, 135))	('loss', 'Var', (64, 68))	('CK5', 'Gene', (72, 75))	('loss', 'NegReg', (154, 158))	('maturation', 'CPA', (217, 227))
65622	34007958	In line with these observations, the level of E-cadherin, a known target for SLUG-mediated repression, was slightly upregulated upon depletion of CK5 (Figures 6C and 6D).	('E-cadherin', 'Gene', (46, 56))	('CK5', 'Gene', '3852', (146, 149))	('depletion', 'Var', (133, 142))	('E-cadherin', 'Gene', '999', (46, 56))	('upregulated', 'PosReg', (116, 127))	('CK5', 'Gene', (146, 149))
65626	34007958	These data indicate that the loss of CK5 may lead to differentiation bias in the mammary progenitors through regulation of SLUG levels.	('CK5', 'Gene', (37, 40))	('differentiation bias in the mammary progenitors', 'CPA', (53, 100))	('lead to', 'Reg', (45, 52))	('loss', 'Var', (29, 33))	('CK5', 'Gene', '3852', (37, 40))	('regulation', 'MPA', (109, 119))	('SLUG levels', 'MPA', (123, 134))
65644	34007958	Loss of CK14 had in our studies only a slight effect on these ME cell markers (Figures 3 andS6) and, as it is known to heterodimerize with CK5, this slight effect could possibly also go through CK5.	('CK5', 'Gene', (194, 197))	('CK14', 'Gene', '3861', (8, 12))	('CK5', 'Gene', (139, 142))	('ME', 'Chemical', '-', (62, 64))	('CK14', 'Gene', (8, 12))	('CK5', 'Gene', '3852', (194, 197))	('heterodimerize', 'MPA', (119, 133))	('CK5', 'Gene', '3852', (139, 142))	('ME cell markers', 'CPA', (62, 77))	('Loss', 'Var', (0, 4))
65645	34007958	Additionally, ME-specific cell-cell junction proteins P-cadherin and Dsg3 were downregulated upon loss of CK5, causing deficiency in the maintenance of intact epithelial structures (Figure 4).	('Dsg3', 'Gene', '1830', (69, 73))	('cadherin', 'Gene', (56, 64))	('deficiency', 'Disease', 'MESH:D007153', (119, 129))	('ME', 'Chemical', '-', (14, 16))	('Dsg3', 'Gene', (69, 73))	('cadherin', 'Gene', '999;1001', (56, 64))	('CK5', 'Gene', (106, 109))	('downregulated', 'NegReg', (79, 92))	('loss', 'Var', (98, 102))	('CK5', 'Gene', '3852', (106, 109))	('deficiency', 'Disease', (119, 129))
65648	34007958	Loss of CK5 from the basal progenitors thus affects the compliance, contractility, and integrity of the epithelial junctions, clearly leading to loss of ME barrier function.	('compliance', 'MPA', (56, 66))	('ME barrier', 'MPA', (153, 163))	('affects', 'Reg', (44, 51))	('CK5', 'Gene', '3852', (8, 11))	('contractility', 'CPA', (68, 81))	('integrity', 'MPA', (87, 96))	('loss', 'NegReg', (145, 149))	('ME', 'Chemical', '-', (153, 155))	('CK5', 'Gene', (8, 11))	('Loss', 'Var', (0, 4))
65649	34007958	Interestingly, loss of alpha-SMA from the ME cells also led to downregulation of CK5, vimentin, and Dsg3, indicating a regulatory feedback loop mechanism in between CK5 positive stem/progenitor cells and mature ME cells (Figures 4G,S6F and S6G).	('CK5', 'Gene', '3852', (165, 168))	('ME', 'Chemical', '-', (42, 44))	('CK5', 'Gene', (81, 84))	('vimentin', 'Gene', '7431', (86, 94))	('alpha-SMA', 'Gene', '58', (23, 32))	('Dsg3', 'Gene', (100, 104))	('vimentin', 'Gene', (86, 94))	('alpha-SMA', 'Gene', (23, 32))	('loss', 'Var', (15, 19))	('CK5', 'Gene', (165, 168))	('CK5', 'Gene', '3852', (81, 84))	('ME', 'Chemical', '-', (211, 213))	('downregulation', 'NegReg', (63, 77))	('Dsg3', 'Gene', '1830', (100, 104))
65661	34007958	Moreover, we observed that E-cadherin, a target for SLUG-mediated repression, was upregulated upon depletion of CK5 (Figures 6C,6D,S8D, and S8E).	('CK5', 'Gene', '3852', (112, 115))	('CK5', 'Gene', (112, 115))	('upregulated', 'PosReg', (82, 93))	('depletion', 'Var', (99, 108))	('S8D', 'Mutation', 'p.S8D', (131, 134))	('S8E', 'Mutation', 'p.S8E', (140, 143))	('E-cadherin', 'Gene', (27, 37))	('E-cadherin', 'Gene', '999', (27, 37))
65663	34007958	As SLUG clearly plays a role in the maintenance of basal-like state and represses luminal lineage differentiation, loss of CK5 could conceivably cause the differentiation bias via regulation of SLUG.	('differentiation bias', 'CPA', (155, 175))	('CK5', 'Gene', (123, 126))	('represses', 'NegReg', (72, 81))	('loss', 'Var', (115, 119))	('CK5', 'Gene', '3852', (123, 126))	('cause', 'Reg', (145, 150))	('luminal lineage differentiation', 'CPA', (82, 113))	('luminal', 'Chemical', 'MESH:D010634', (82, 89))	('regulation', 'MPA', (180, 190))
65685	26290094	Micro-optical computed tomography and nuclear morphometry was used to compare variations between human breast cell lines and found that nuclear volumes increased from normal to metastatic breast cells and that nuclei of abnormal cells contained more nucleoli.	('increased', 'PosReg', (152, 161))	('abnormal', 'Var', (220, 228))	('human', 'Species', '9606', (97, 102))	('nuclear volumes', 'CPA', (136, 151))
65774	26290094	Despite this variation, leave-one-out cross-validation of the CART model yields similar performance to the original model suggesting that our algorithm may generalize to an independent data set.	('variation', 'Var', (13, 22))	('CART', 'Gene', (62, 66))	('CART', 'Gene', '9607', (62, 66))
65820	22685640	Ultimately, 9 of 43 (21%) high-risk DCIS patients with a positive SLN, and 9 of 470 (2%) of all high-risk DCIS patients were upstaged to stage 1 or stage 2 (AJCC 6th Edition) as a direct result of SLNB.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('upstaged', 'PosReg', (125, 133))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('SLN', 'Gene', (66, 69))	('patients', 'Species', '9606', (41, 49))	('DCIS', 'Disease', (36, 40))	('SLNB', 'Var', (197, 201))	('patients', 'Species', '9606', (111, 119))
65911	22685640	For women with a higher volume of disease near the margin, radiotherapy is associated with a greater risk reduction of IBTR.	('IBTR', 'Disease', (119, 123))	('reduction', 'NegReg', (106, 115))	('women', 'Species', '9606', (4, 9))	('IBTR', 'Chemical', '-', (119, 123))	('radiotherapy', 'Var', (59, 71))
65930	20501858	Depletion of CD151 suppressed growth of HB2 cells, a non-tumourigenic breast epithelial cell line, in 3-D extracellular matrices (ECM) and in Matrigel-based xenografts.	('HB2', 'Gene', '3888', (40, 43))	('tumour', 'Disease', (57, 63))	('suppressed', 'NegReg', (19, 29))	('growth', 'MPA', (30, 36))	('Depletion', 'Var', (0, 9))	('CD151', 'Gene', (13, 18))	('HB2', 'Gene', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
65943	20501858	We and others have found that whilst depletion of CD151 diminished growth of tumour cells in immunocompromised animals, cell proliferation under standard conditions was not affected.	('depletion', 'Var', (37, 46))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('CD151', 'Gene', (50, 55))	('diminished', 'NegReg', (56, 66))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
65948	20501858	By knocking down expression of CD151 in HB2 cells, a non-tumourigenic mammary epithelial cell line, we found that this tetraspanin controls proliferation of cells in vivo (mouse xenografts) and in 3-D extracellular matrix (ECM).	('proliferation', 'CPA', (140, 153))	('HB2', 'Gene', '3888', (40, 43))	('tumour', 'Disease', (57, 63))	('knocking', 'Var', (3, 11))	('CD151', 'Gene', (31, 36))	('mouse', 'Species', '10090', (172, 177))	('controls', 'Reg', (131, 139))	('HB2', 'Gene', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
65954	20501858	HB2/CD151rec and HB2/CD151-QRD cell lines were established after transfections of HB2/CD151(-) cells with constructs encoding shRNA-resistant wild-type and QRD194-196 INF mutant of CD151.	('HB2', 'Gene', (0, 3))	('QRD194-196 INF mutant', 'Var', (156, 177))	('HB2', 'Gene', '3888', (82, 85))	('HB2', 'Gene', '3888', (0, 3))	('HB2', 'Gene', '3888', (17, 20))	('CD151', 'Gene', (181, 186))	('HB2', 'Gene', (82, 85))	('HB2', 'Gene', (17, 20))
65985	20501858	These results suggested that differences in growth of HB2/CD151(+) and HB2/CD151(-) cells in vivo are due to the effect of CD151 on cell proliferation rather than apoptosis.	('HB2', 'Gene', '3888', (54, 57))	('growth', 'MPA', (44, 50))	('HB2', 'Gene', (54, 57))	('HB2', 'Gene', (71, 74))	('CD151', 'Var', (123, 128))	('cell proliferation', 'CPA', (132, 150))	('HB2', 'Gene', '3888', (71, 74))
65989	20501858	Interestingly, although expression of the CD151-QRD mutant in CD151-negative cells has effectively restored their colony-forming potential in 3-D ECM, HB2/CD151-QRD aggregates appeared distinctly different from either CD151(+) or CD151(-) colonies.	('restored', 'PosReg', (99, 107))	('mutant', 'Var', (52, 58))	('HB2', 'Gene', '3888', (151, 154))	('colony-forming potential', 'CPA', (114, 138))	('CD151-QRD', 'Gene', (42, 51))	('HB2', 'Gene', (151, 154))
65993	20501858	Whilst the ability of HB2/alpha3beta1(-) cells to grow in 3-D ECM was severely compromised, depletion of alpha6(-) integrins had no apparent effect on the plating efficiency and morphology of the colonies formed by HB2 cells (Fig.3).	('HB2', 'Gene', '3888', (215, 218))	('depletion', 'Var', (92, 101))	('alpha6', 'Gene', '14399', (105, 111))	('3beta1', 'Gene', (31, 37))	('alpha6', 'Gene', (105, 111))	('3beta1', 'Gene', '18368', (31, 37))	('HB2', 'Gene', (22, 25))	('HB2', 'Gene', (215, 218))	('plating efficiency', 'CPA', (155, 173))	('HB2', 'Gene', '3888', (22, 25))
66003	20501858	Next we investigated whether CD151-dependent relocalisation of alpha3beta1 can be linked to changes in secretion and/or deposition of Ln-332 or Ln-511/Ln-521, known laminin substrates for this integrin.	('3beta1', 'Gene', '18368', (68, 74))	('3beta1', 'Gene', (68, 74))	('changes', 'Reg', (92, 99))	('CD151-dependent', 'Gene', (29, 44))	('secretion', 'MPA', (103, 112))	('deposition', 'MPA', (120, 130))	('relocalisation', 'MPA', (45, 59))	('Ln-511/Ln-521', 'Var', (144, 157))
66018	20501858	To examine whether decrease in the levels of active ERK1/2 and c-Akt were sufficient to inhibit growth in 3-D ECM and change the phenotypic pattern of colonies, we cultured the control HB2/CD151(+) cells in the presence of U0126 and LY29004, widely used inhibitors of Erk1/2 and PI3-K/c-Akt signalling pathways, respectively.	('U0126', 'Chemical', 'MESH:C113580', (223, 228))	('Akt', 'Gene', (65, 68))	('ERK1/2', 'Gene', (52, 58))	('decrease', 'NegReg', (19, 27))	('HB2', 'Gene', (185, 188))	('Erk1/2', 'Gene', '26417;26413', (268, 274))	('LY29004', 'Chemical', '-', (233, 240))	('inhibit', 'NegReg', (88, 95))	('HB2', 'Gene', '3888', (185, 188))	('Akt', 'Gene', '11651', (287, 290))	('Erk1/2', 'Gene', (268, 274))	('growth', 'MPA', (96, 102))	('U0126', 'Var', (223, 228))	('Akt', 'Gene', (287, 290))	('change', 'Reg', (118, 124))	('Akt', 'Gene', '11651', (65, 68))	('ERK1/2', 'Gene', '26417;26413', (52, 58))	('LY29004', 'Var', (233, 240))
66025	20501858	In this report we described a new cellular model for mammary ductal carcinoma in situ (DCIS) and showed that tetraspanin CD151 is likely to play an important role in the development of this disease.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (61, 85))	('ductal carcinoma in situ', 'Disease', (61, 85))	('tetraspanin CD151', 'Chemical', '-', (109, 126))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (61, 77))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (61, 85))	('tetraspanin CD151', 'Var', (109, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('CD151', 'Var', (121, 126))
66030	20501858	Importantly, our report and an earlier study, which was focussed on tetraspanin CD81 in T-cells, have shown that co-stimulatory activities of tetraspanins are linked to activation of Erk1/2.	('CD81', 'Gene', (80, 84))	('T-cells', 'CellLine', 'CVCL:2G67', (88, 95))	('activation', 'PosReg', (169, 179))	('Erk1/2', 'Gene', '26417;26413', (183, 189))	('co-stimulatory', 'MPA', (113, 127))	('CD81', 'Gene', '12520', (80, 84))	('tetraspanins', 'Var', (142, 154))	('Erk1/2', 'Gene', (183, 189))
66037	20501858	Therefore, it is possible that CD151 depletion results in refining GTP CDC42.	('CDC42', 'Gene', '12540', (71, 76))	('CDC42', 'Gene', (71, 76))	('depletion', 'Var', (37, 46))	('CD151', 'Gene', (31, 36))	('refining', 'MPA', (58, 66))	('GTP', 'Chemical', 'MESH:D006160', (67, 70))	('results', 'Reg', (47, 54))
66040	20501858	It is important to emphasise that despite the prominent effect of CD151 removal on repositioning Golgi, polarization of HB2 cells in 3-D Matrigel was incomplete.	('removal', 'Var', (72, 79))	('CD151', 'Gene', (66, 71))	('HB2', 'Gene', '3888', (120, 123))	('HB2', 'Gene', (120, 123))
66043	20501858	The fact that the elevated expression CD151 is specifically associated with high grade forms of DCIS (which is characterised by a high level of proliferation and inhibition of apoptosis), further supports the physiological relevance of our findings linking function of CD151 with proliferation of HB2 cells in 3-D ECM.	('CD151', 'Gene', (269, 274))	('HB2', 'Gene', '3888', (297, 300))	('HB2', 'Gene', (297, 300))	('function', 'Var', (257, 265))	('elevated', 'PosReg', (18, 26))	('CD151', 'Gene', (38, 43))	('associated', 'Reg', (60, 70))
66053	31214858	Tools employed a median of 2.0 labels (range 1.0 to 5.0) for DCIS, most frequently non-invasive breast cancer (29, 74.4%), abnormal cells (14, 35.9%), pre-cancer (14, 35.9%), and early form of breast cancer (13, 33.3%).	('breast cancer', 'Disease', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('abnormal', 'Var', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (155, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('invasive breast cancer', 'Disease', (87, 109))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('early form', 'Disease', (179, 189))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('cancer', 'Disease', (200, 206))
66161	30506111	68 participants gave answers for upgrade to DCIS: < 5%: 15 (22%); < 10%: 40 (59%); < 15%: 9 (13%); and < 20%: 4 (6%).	('< 10%', 'Var', (66, 71))	('< 15%', 'Var', (83, 88))	('participants', 'Species', '9606', (3, 15))
66201	30506111	The underlying rationale is that in contrast to LCIS and ALH, 25-60% of cases with LN (B5a category) variants on CNB/VAB are found to upgrade to carcinoma on excision.	('VAB', 'Chemical', '-', (117, 120))	('carcinoma', 'Disease', 'MESH:D002277', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('CNB/VAB', 'Gene', (113, 120))	('variants', 'Var', (101, 109))	('carcinoma', 'Disease', (145, 154))	('upgrade', 'PosReg', (134, 141))
66204	30506111	ALH/LCIS has to be considered as both, a risk factor and a non-obligate precursor of invasive breast carcinoma conferring an 8 to 10 times relative risk compared to the general population.	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (85, 110))	('breast carcinoma', 'Phenotype', 'HP:0003002', (94, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('invasive breast carcinoma', 'Disease', (85, 110))	('ALH/LCIS', 'Var', (0, 8))
66263	27195180	However, analysis by lesion type showed a statistically significant increase in reader shape (Delta =11.34, P = 0.013) and margin (Delta =9.93, P = 0.023) visualization confidence with DBCT versus dxDM for masses and significant decrease in reader morphology (Delta = -29.95, P = 0.001) and distribution (Delta = -28.62, P = 0.002) visualization confidence for calcifications.	('decrease', 'NegReg', (229, 237))	('calcification', 'Disease', 'MESH:D002114', (361, 374))	('increase', 'PosReg', (68, 76))	('DBCT', 'Chemical', '-', (185, 189))	('calcification', 'Disease', (361, 374))	('DBCT', 'Var', (185, 189))
66423	25133091	All patients with high risk VNPI scores underwent postoperative RT, whereas those with low and intermediate VNPI scores underwent postoperative RT at the discretion of the surgeon.	('patients', 'Species', '9606', (4, 12))	('VNPI', 'Gene', (28, 32))	('scores', 'Var', (33, 39))
66457	25133091	An evaluation of 132 patients with DCIS treated with BCS without (n = 33) or with (n = 99) whole-breast RT found an absolute difference of about 8.5% in rates of local recurrence in patients with ER-negative and ER-positive DCIS (Roka et al.	('DCIS', 'Phenotype', 'HP:0030075', (224, 228))	('patients', 'Species', '9606', (21, 29))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('local recurrence', 'CPA', (162, 178))	('patients', 'Species', '9606', (182, 190))	('ER-positive', 'Var', (212, 223))	('ER-negative', 'Var', (196, 207))
66463	25133091	The finding that all recurrences were in patients with ER-negative DCIS indicates that recurrences are due to biologic characteristics of the tumor associated with ER negativity, not with RT.	('ER negativity', 'Var', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('patients', 'Species', '9606', (41, 49))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
66467	25133091	Patients with large, high grade, ER-negative DCIS may require TM, whereas those with ER-positive DCIS may be treated with BCS plus RT.	('DCIS', 'Disease', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('Patients', 'Species', '9606', (0, 8))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('ER-negative', 'Var', (33, 44))
66486	22309790	The retrospective cohort included 310 patients with 312 tumors of T1-T2N0-N1micM0 invasive ductal carcinoma (IDC), ILC, or Tis (DCIS) treated with APBI via external beam.	('invasive ductal carcinoma', 'Disease', (82, 107))	('APBI', 'Chemical', '-', (147, 151))	('ILC', 'Disease', (115, 118))	('T1-T2N0-N1micM0', 'Var', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (82, 107))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (38, 46))
66507	22309790	Between November 1, 2002, and June 30, 2009, 339 patients with 341 tumors of T1-T2N0-N1micM0 IDC, ILC, or Tis (DCIS) were treated with APBI via external beam at four facilities of the NorthShore University HealthSystem.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('T1-T2N0-N1micM0', 'Var', (77, 92))	('APBI', 'Chemical', '-', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (49, 57))	('tumors', 'Disease', (67, 73))
66617	19920274	Number of mammograms, breast cancer mortality reduction or life years gained [LYG] (vs. no screening), false positives, unnecessary biopsies and over-diagnosis.	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('mammograms', 'Disease', (10, 20))	('false positives', 'Var', (103, 118))	('breast cancer mortality reduction', 'Disease', (22, 55))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('life years gained', 'CPA', (59, 76))	('breast cancer mortality reduction', 'Disease', 'MESH:D001943', (22, 55))
66680	19920274	The models also do not capture differences in outcomes among certain risk sub-groups, such as women with BRCA 1 or 2 genetic susceptibility mutations, those who are healthier or sicker than average or African-American women who appear to have more disease at younger ages than Whites.	('women', 'Species', '9606', (94, 99))	('women', 'Species', '9606', (218, 223))	('BRCA 1', 'Gene', (105, 111))	('mutations', 'Var', (140, 149))	('BRCA 1', 'Gene', '672', (105, 111))
66685	19223547	Silencing of TMS1/ASC promotes resistance to anoikis in breast epithelial cells Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact.	('promotes', 'PosReg', (22, 30))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (80, 104))	('ASC', 'Gene', (18, 21))	('resistance to anoikis', 'MPA', (31, 52))	('Ductal carcinoma', 'Disease', (80, 96))	('TMS1', 'Gene', '29108', (13, 17))	('ASC', 'Gene', '29108', (18, 21))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (80, 96))	('Silencing', 'Var', (0, 9))	('TMS1', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
66687	19223547	Epigenetic silencing of TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown.	('TMS1', 'Gene', (137, 141))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('TMS1', 'Gene', '29108', (137, 141))	('TMS1', 'Gene', (24, 28))	('carcinogenesis', 'Disease', (167, 181))	('breast', 'Disease', (84, 90))	('TMS1', 'Gene', '29108', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('observed', 'Reg', (38, 46))	('human', 'Species', '9606', (78, 83))	('silencing', 'NegReg', (142, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (167, 181))
66690	19223547	siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of ERK and an impaired ability to upregulate the BH3-only protein Bim.	('Bim', 'Gene', '10018', (169, 172))	('knockdown', 'Var', (15, 24))	('activation', 'PosReg', (92, 102))	('TMS1', 'Gene', (28, 32))	('leads to', 'Reg', (33, 41))	('upregulate', 'PosReg', (137, 147))	('ERK', 'Gene', '5594', (106, 109))	('TMS1', 'Gene', '29108', (28, 32))	('Bim', 'Gene', (169, 172))	('ERK', 'Gene', (106, 109))	('anoikis', 'Disease', (42, 49))
66692	19223547	These data demonstrate a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development.	('breast cancer', 'Disease', (243, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('TMS1', 'Gene', '29108', (113, 117))	('silencing', 'Var', (100, 109))	('allowing', 'Reg', (173, 181))	('contribute', 'Reg', (122, 132))	('TMS1', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('TMS1', 'Gene', '29108', (49, 53))	('promotion', 'PosReg', (61, 70))	('TMS1', 'Gene', (113, 117))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('anoikis', 'CPA', (74, 81))
66702	19223547	Upregulation of the caspase-8 inhibitor c-Flip has been observed in many transformed cell lines that are resistant to anoikis and inhibition of c-Flip in these cells restores sensitivity to anoikis.	('Upregulation', 'PosReg', (0, 12))	('sensitivity to anoikis', 'MPA', (175, 197))	('caspase-8', 'Gene', (20, 29))	('inhibition', 'Var', (130, 140))	('caspase-8', 'Gene', '841', (20, 29))	('c-Flip', 'Gene', '8837', (40, 46))	('c-Flip', 'Gene', (40, 46))	('c-Flip', 'Gene', '8837', (144, 150))	('c-Flip', 'Gene', (144, 150))	('restores', 'PosReg', (166, 174))
66705	19223547	Although the precise function of TMS1 in apoptosis is unclear, overexpression or forced oligomerization of TMS1 in epithelial cells is sufficient to induce apoptosis via a mechanism that is dependent on caspase-8.	('caspase-8', 'Gene', (203, 212))	('caspase-8', 'Gene', '841', (203, 212))	('TMS1', 'Gene', '29108', (33, 37))	('TMS1', 'Gene', (107, 111))	('induce', 'PosReg', (149, 155))	('oligomerization', 'Var', (88, 103))	('TMS1', 'Gene', (33, 37))	('TMS1', 'Gene', '29108', (107, 111))	('apoptosis', 'CPA', (156, 165))	('overexpression', 'PosReg', (63, 77))
66707	19223547	Importantly, TMS1 is subject to aberrant DNA methylation and epigenetic silencing in a number of different tumor types, suggesting that loss of TMS1 confers a survival advantage to tumor cells.	('tumor', 'Disease', (181, 186))	('TMS1', 'Gene', (144, 148))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('TMS1', 'Gene', '29108', (13, 17))	('survival advantage', 'CPA', (159, 177))	('TMS1', 'Gene', '29108', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('loss', 'Var', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('TMS1', 'Gene', (13, 17))
66708	19223547	However, the mechanism by which silencing of TMS1 contributes to carcinogenesis remains unclear.	('TMS1', 'Gene', (45, 49))	('TMS1', 'Gene', '29108', (45, 49))	('silencing', 'Var', (32, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('contributes', 'Reg', (50, 61))	('carcinogenesis', 'Disease', (65, 79))
66721	19223547	TMS1 is a proapoptotic protein that is subject to epigenetic silencing in a significant proportion of breast and other cancers.	('breast', 'Disease', (102, 108))	('TMS1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('TMS1', 'Gene', '29108', (0, 4))	('epigenetic silencing', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
66731	19223547	whether loss of TMS1 in certain DCIS lesions ultimately gives rise to invasive ductal carcinomas lacking TMS1 expression).	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('TMS1', 'Gene', '29108', (16, 20))	('TMS1', 'Gene', '29108', (105, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('gives rise to', 'Reg', (56, 69))	('loss', 'Var', (8, 12))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (70, 96))	('TMS1', 'Gene', (105, 109))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (79, 95))	('invasive ductal carcinomas', 'Disease', (70, 96))	('TMS1', 'Gene', (16, 20))
66732	19223547	Nevertheless, the data are suggestive that loss of TMS1 accompanies the transition from DCIS to invasive carcinoma during the progression of breast cancer.	('TMS1', 'Gene', (51, 55))	('invasive carcinoma', 'Disease', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TMS1', 'Gene', '29108', (51, 55))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('DCIS', 'Disease', (88, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('loss', 'Var', (43, 47))	('invasive carcinoma', 'Disease', 'MESH:D009361', (96, 114))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
66738	19223547	In contrast, neither expression of a dominant-negative IkappaB, siRNA-mediated knockdown of NF-kappaB nor chemical inhibition of JNK had any impact on suspension-induced upregulation of TMS1 (Figure 2C, D and data not shown), indicating that upregulation of TMS1 occurs independently of these pathways.	('NF-kappaB', 'Gene', (92, 101))	('NF-kappaB', 'Gene', '4790', (92, 101))	('upregulation', 'PosReg', (170, 182))	('TMS1', 'Gene', (258, 262))	('JNK', 'Gene', (129, 132))	('JNK', 'Gene', '5599', (129, 132))	('TMS1', 'Gene', (186, 190))	('TMS1', 'Gene', '29108', (258, 262))	('knockdown', 'Var', (79, 88))	('TMS1', 'Gene', '29108', (186, 190))
66739	19223547	We next determined the impact of TMS1 silencing on the apoptotic response to detachment in MCF10A cells.	('TMS1', 'Gene', (33, 37))	('MCF10A', 'CellLine', 'CVCL:0598', (91, 97))	('silencing', 'Var', (38, 47))	('TMS1', 'Gene', '29108', (33, 37))
66742	19223547	Strikingly, knockdown of TMS1 led to a significant delay in the apoptotic events associated with anoikis.	('TMS1', 'Gene', (25, 29))	('anoikis', 'Disease', (97, 104))	('knockdown', 'Var', (12, 21))	('TMS1', 'Gene', '29108', (25, 29))	('apoptotic events', 'CPA', (64, 80))	('delay', 'NegReg', (51, 56))
66744	19223547	Consistent with the observed delay in PARP cleavage, knockdown of TMS1 in MCF10A cells conferred a ~2-fold protection from cell death after 24 hours in suspension (Figure 3B).	('PARP', 'Gene', '1302', (38, 42))	('cell death', 'CPA', (123, 133))	('knockdown', 'Var', (53, 62))	('TMS1', 'Gene', (66, 70))	('PARP', 'Gene', (38, 42))	('MCF10A', 'CellLine', 'CVCL:0598', (74, 80))	('TMS1', 'Gene', '29108', (66, 70))
66745	19223547	This degree of protection is similar to previous reports describing the impact of Bim knockdown on detachment-induced apoptosis in breast epithelial cells.	('Bim', 'Gene', (82, 85))	('knockdown', 'Var', (86, 95))	('Bim', 'Gene', '10018', (82, 85))
66748	19223547	Strikingly, both the magnitude and timing of Bim protein accumulation were significantly inhibited in TMS1 knockdown cells (Figure 3A).	('knockdown', 'Var', (107, 116))	('inhibited', 'NegReg', (89, 98))	('TMS1', 'Gene', '29108', (102, 106))	('Bim', 'Gene', (45, 48))	('Bim', 'Gene', '10018', (45, 48))	('TMS1', 'Gene', (102, 106))
66749	19223547	The impact of TMS1 knockdown was specific, as a similar delay in apoptotic events (caspase-8 cleavage, PARP cleavage) and inhibition of Bim upregulation were observed when MCF10A cells were transfected with a second independent siRNA targeting TMS1 (Supplemental Figure 2), but not when transfected with siRNAs targeting lamin a/c or caspase-1 (data not shown).	('caspase-8', 'Gene', (83, 92))	('caspase-1', 'Gene', (334, 343))	('TMS1', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('apoptotic', 'CPA', (65, 74))	('TMS1', 'Gene', (244, 248))	('Bim', 'Gene', (136, 139))	('PARP', 'Gene', (103, 107))	('delay', 'NegReg', (56, 61))	('Bim', 'Gene', '10018', (136, 139))	('TMS1', 'Gene', '29108', (244, 248))	('PARP', 'Gene', '1302', (103, 107))	('caspase-8', 'Gene', '841', (83, 92))	('TMS1', 'Gene', '29108', (14, 18))	('caspase-1', 'Gene', '834', (334, 343))	('lamin a/c', 'Gene', '4000', (321, 330))	('lamin a/c', 'Gene', (321, 330))	('MCF10A', 'CellLine', 'CVCL:0598', (172, 178))
66750	19223547	Taken together, these data illustrate that caspase-8 cleavage, PARP cleavage and Bim upregulation are severely inhibited in cells lacking TMS1 expression, and that loss of TMS1 confers resistance to anoikis.	('Bim', 'Gene', (81, 84))	('cleavage', 'MPA', (53, 61))	('loss', 'Var', (164, 168))	('cleavage', 'MPA', (68, 76))	('Bim', 'Gene', '10018', (81, 84))	('expression', 'MPA', (143, 153))	('resistance', 'CPA', (185, 195))	('TMS1', 'Gene', '29108', (138, 142))	('PARP', 'Gene', '1302', (63, 67))	('PARP', 'Gene', (63, 67))	('TMS1', 'Gene', (172, 176))	('TMS1', 'Gene', (138, 142))	('upregulation', 'PosReg', (85, 97))	('inhibited', 'NegReg', (111, 120))	('TMS1', 'Gene', '29108', (172, 176))	('caspase-8', 'Gene', (43, 52))	('lacking', 'NegReg', (130, 137))	('caspase-8', 'Gene', '841', (43, 52))
66757	19223547	Again, knockdown of TMS1 severely inhibited the induction of BimEL expression (Figure 4A).	('Bim', 'Gene', (61, 64))	('TMS1', 'Gene', (20, 24))	('Bim', 'Gene', '10018', (61, 64))	('inhibited', 'NegReg', (34, 43))	('TMS1', 'Gene', '29108', (20, 24))	('induction', 'MPA', (48, 57))	('knockdown', 'Var', (7, 16))
66761	19223547	Detachment and a shift to fresh serum-containing medium led to a stimulation of ERK phosphorylation that was both greater in magnitude and persisted longer in TMS1 knockdown cells compared to control cells (Figure 4B).	('TMS1', 'Gene', '29108', (159, 163))	('ERK', 'Gene', '5594', (80, 83))	('ERK', 'Gene', (80, 83))	('stimulation', 'PosReg', (65, 76))	('TMS1', 'Gene', (159, 163))	('knockdown', 'Var', (164, 173))
66763	19223547	Taken together these data suggest that TMS1 acts upstream of Bim and that the resistance to anoikis observed in TMS1 knockdown cells may be, in part, due to the inhibition of Bim induction.	('TMS1', 'Gene', (112, 116))	('Bim', 'Gene', (175, 178))	('Bim', 'Gene', (61, 64))	('TMS1', 'Gene', '29108', (39, 43))	('Bim', 'Gene', '10018', (61, 64))	('TMS1', 'Gene', '29108', (112, 116))	('Bim', 'Gene', '10018', (175, 178))	('resistance to anoikis', 'CPA', (78, 99))	('inhibition', 'NegReg', (161, 171))	('TMS1', 'Gene', (39, 43))	('knockdown', 'Var', (117, 126))
66765	19223547	As shown above, knockdown of TMS1 inhibited both the upregulation of BimEL protein and apoptosis after 24 hours in suspension (Figure 4C).	('TMS1', 'Gene', '29108', (29, 33))	('inhibited', 'NegReg', (34, 43))	('knockdown', 'Var', (16, 25))	('upregulation', 'PosReg', (53, 65))	('Bim', 'Gene', (69, 72))	('apoptosis', 'CPA', (87, 96))	('Bim', 'Gene', '10018', (69, 72))	('TMS1', 'Gene', (29, 33))
66769	19223547	As expected, overexpression of Bcl2 blocked detachment-induced apoptosis (as indicated by the reduction in PARP cleavage), but again had no impact on detachment induced upregulation of TMS1 or Bim, nor on the delayed upregulation of Bim and inhibition of PARP cleavage afforded by TMS1 knockdown (Figure 4D).	('TMS1', 'Gene', (281, 285))	('knockdown', 'Var', (286, 295))	('PARP', 'Gene', '1302', (255, 259))	('reduction', 'NegReg', (94, 103))	('upregulation', 'PosReg', (169, 181))	('TMS1', 'Gene', (185, 189))	('Bim', 'Gene', (233, 236))	('PARP', 'Gene', (255, 259))	('TMS1', 'Gene', '29108', (281, 285))	('Bim', 'Gene', '10018', (233, 236))	('Bcl2', 'Gene', (31, 35))	('TMS1', 'Gene', '29108', (185, 189))	('PARP', 'Gene', '1302', (107, 111))	('apoptosis', 'CPA', (63, 72))	('Bim', 'Gene', (193, 196))	('PARP', 'Gene', (107, 111))	('Bcl2', 'Gene', '596', (31, 35))	('Bim', 'Gene', '10018', (193, 196))
66773	19223547	We provide evidence that loss of TMS1 expression promotes resistance to anoikis, which may be mediated at least in part by the inhibition of detachment-induced upregulation of BimEL.	('resistance to anoikis', 'CPA', (58, 79))	('loss', 'Var', (25, 29))	('upregulation', 'PosReg', (160, 172))	('promotes', 'PosReg', (49, 57))	('Bim', 'Gene', (176, 179))	('TMS1', 'Gene', (33, 37))	('Bim', 'Gene', '10018', (176, 179))	('TMS1', 'Gene', '29108', (33, 37))
66777	19223547	These data suggest that TMS1 acts upstream of Bim, and may act as a link between loss of integrin signaling and the onset of anoikis, such that in the absence of TMS1, survival signaling through the MAPK/ERK pathway persists even in the absence of matrix attachments.	('survival signaling', 'MPA', (168, 186))	('ERK', 'Gene', '5594', (204, 207))	('MAPK', 'Gene', '5595;5594;5595', (199, 203))	('TMS1', 'Gene', (24, 28))	('MAPK', 'Gene', (199, 203))	('integrin', 'MPA', (89, 97))	('TMS1', 'Gene', (162, 166))	('ERK', 'Gene', (204, 207))	('TMS1', 'Gene', '29108', (24, 28))	('absence', 'Var', (151, 158))	('TMS1', 'Gene', '29108', (162, 166))	('Bim', 'Gene', (46, 49))	('Bim', 'Gene', '10018', (46, 49))
66778	19223547	In previous work, we and others have shown that TMS1 overexpression or forced oligomerization induces apoptosis, and that TMS1-induced apoptosis is dependent on caspase-8.	('apoptosis', 'CPA', (102, 111))	('overexpression', 'PosReg', (53, 67))	('caspase-8', 'Gene', '841', (161, 170))	('TMS1', 'Gene', '29108', (122, 126))	('forced', 'Var', (71, 77))	('TMS1', 'Gene', (48, 52))	('induces', 'Reg', (94, 101))	('TMS1', 'Gene', '29108', (48, 52))	('caspase-8', 'Gene', (161, 170))	('TMS1', 'Gene', (122, 126))
66787	19223547	TMS1 is upregulated following detachment of the breast epithelial cells, and siRNA-mediated knockdown of TMS1 causes these cells to be resistant to anoikis.	('TMS1', 'Gene', '29108', (105, 109))	('TMS1', 'Gene', (0, 4))	('knockdown', 'Var', (92, 101))	('resistant', 'CPA', (135, 144))	('TMS1', 'Gene', '29108', (0, 4))	('TMS1', 'Gene', (105, 109))	('upregulated', 'PosReg', (8, 19))
66790	19223547	Together, our data illustrate that the epigenetic silencing of TMS1 observed in breast cancer and other tumor types might contribute to the progression of carcinomas by allowing epithelial cells to bypass anoikis.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('contribute', 'Reg', (122, 132))	('carcinomas', 'Disease', (155, 165))	('TMS1', 'Gene', (63, 67))	('tumor', 'Disease', (104, 109))	('allowing', 'Reg', (169, 177))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinomas', 'Disease', 'MESH:D002277', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', (80, 93))	('TMS1', 'Gene', '29108', (63, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('epigenetic silencing', 'Var', (39, 59))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
66799	19754954	In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP.	('CHOP', 'Gene', (118, 122))	('CA-ErbB2', 'Var', (34, 42))	('down-regulated', 'NegReg', (80, 94))	('CHOP', 'Gene', '1649', (118, 122))
66801	19754954	However, inhibition of eIF2alpha dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth.	('eIF2alpha', 'Gene', '83939', (23, 32))	('MMTV', 'Species', '11757', (122, 126))	('inhibit', 'NegReg', (85, 92))	('salubrinal', 'Chemical', 'MESH:C496827', (56, 66))	('Neu', 'Gene', (127, 130))	('Neu', 'Gene', '2064', (127, 130))	('deregulation', 'CPA', (139, 151))	('dephosphorylation', 'MPA', (33, 50))	('eIF2alpha', 'Gene', (23, 32))	('inhibition', 'Var', (9, 19))
66814	19754954	Phosphorylation of the alpha subunit of eIF2 at Ser-51 sequesters it in an inactive GDP-bound complex with its GTP-exchange factor, eIF2B, resulting in attenuation of translation initiation.	('attenuation', 'NegReg', (152, 163))	('eIF2', 'Gene', '8894', (132, 136))	('Ser', 'Chemical', 'MESH:D012694', (48, 51))	('Phosphorylation', 'Var', (0, 15))	('eIF2B', 'Gene', '8894', (132, 137))	('eIF2', 'Gene', '8894', (40, 44))	('eIF2', 'Gene', (132, 136))	('GTP', 'Chemical', 'MESH:D006160', (111, 114))	('eIF2', 'Gene', (40, 44))	('GDP', 'Chemical', 'MESH:D006153', (84, 87))	('eIF2B', 'Gene', (132, 137))	('translation initiation', 'MPA', (167, 189))
66820	19754954	For example, ErbB2 can enhance c-Myc protein synthesis and increase Src translation via the Akt/mTOR/4EBP-1 pathway.	('mTOR', 'Gene', (96, 100))	('Src', 'Gene', (68, 71))	('Src', 'Gene', '6714', (68, 71))	('Akt', 'Gene', '207', (92, 95))	('c-Myc', 'Gene', (31, 36))	('4EBP-1', 'Gene', (101, 107))	('Akt', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (96, 100))	('4EBP-1', 'Gene', '1978', (101, 107))	('ErbB2', 'Var', (13, 18))	('enhance', 'PosReg', (23, 30))	('c-Myc', 'Gene', '4609', (31, 36))	('increase', 'PosReg', (59, 67))
66829	19754954	The CA-ErbB2 form has a single point mutation in the trans-membrane domain of the receptor, which results in a Val to Glu substitution at position 664 and increased transforming capacity compared to the wild-type receptor.	('increased', 'PosReg', (155, 164))	('Val to Glu', 'MPA', (111, 121))	('transforming capacity', 'CPA', (165, 186))	('substitution', 'Var', (122, 134))	('Val to Glu substitution at position 664', 'Mutation', 'p.V664E', (111, 150))
66834	19754954	Still ErbB2 phosphorylation at residues pTy1221/1222 was strong (Fig.	('phosphorylation', 'MPA', (12, 27))	('pTy1221', 'Chemical', '-', (40, 47))	('pTy1221/1222', 'Var', (40, 52))	('ErbB2', 'Gene', (6, 11))
66849	19754954	We conclude that increased ErbB2 signaling while not affecting basal phosphorylation of PERK and eIF2alpha or ATF4 expression, appears to downregulate CHOP expression in the more invasive structures induced by CA-ErbB2.	('increased', 'PosReg', (17, 26))	('ATF4', 'Gene', '468', (110, 114))	('eIF2alpha', 'Gene', (97, 106))	('CHOP', 'Gene', '1649', (151, 155))	('PERK', 'Gene', (88, 92))	('downregulate', 'NegReg', (138, 150))	('CA-ErbB2', 'Var', (210, 218))	('CHOP', 'Gene', (151, 155))	('eIF2alpha', 'Gene', '83939', (97, 106))	('ATF4', 'Gene', (110, 114))	('ErbB2', 'MPA', (27, 32))	('PERK', 'Gene', '9451', (88, 92))
66901	19754954	In CA-ErbB2-expressing cells this mutant oncogene appears to block apoptosis and this associates with less CHOP induction.	('apoptosis', 'CPA', (67, 76))	('less', 'NegReg', (102, 106))	('CHOP', 'Gene', '1649', (107, 111))	('block', 'NegReg', (61, 66))	('mutant', 'Var', (34, 40))	('CHOP', 'Gene', (107, 111))
66933	19754954	The decrease in cyclin D1 levels in CA-ErbB2 cells was also of a lower magnitude compared to Wt-ErbB2, suggesting that the growth arrest was not entirely dependent on down-regulation of this cell cycle protein.	('cyclin D1', 'Gene', '595', (16, 25))	('lower', 'NegReg', (65, 70))	('growth arrest', 'Disease', (123, 136))	('decrease', 'NegReg', (4, 12))	('cyclin D1', 'Gene', (16, 25))	('growth arrest', 'Disease', 'MESH:D006323', (123, 136))	('growth arrest', 'Phenotype', 'HP:0001510', (123, 136))	('CA-ErbB2', 'Var', (36, 44))
66936	19754954	It will be important to determine whether phospho-mimetic mutants of eIF2alpha or the use of the FV2E-PERK fusion protein also generate the same effects as salubrinal.	('eIF2alpha', 'Gene', (69, 78))	('rat', 'Species', '10116', (131, 134))	('eIF2alpha', 'Gene', '83939', (69, 78))	('PERK', 'Gene', (102, 106))	('mutants', 'Var', (58, 65))	('salubrinal', 'Chemical', 'MESH:C496827', (156, 166))	('PERK', 'Gene', '9451', (102, 106))
66937	19754954	We recently showed that chronic inhibition of eIF2alpha phosphorylation by PERK dominant negative mutants in MCF10A cells results in acinar deregulation and hyperplastic benign growth in vivo .	('PERK', 'Gene', '9451', (75, 79))	('MCF10A', 'Gene', (109, 115))	('hyperplastic benign growth', 'CPA', (157, 183))	('inhibition', 'NegReg', (32, 42))	('negative', 'NegReg', (89, 97))	('mutants', 'Var', (98, 105))	('eIF2alpha', 'Gene', (46, 55))	('acinar deregulation', 'CPA', (133, 152))	('MCF10A', 'CellLine', 'CVCL:0598', (109, 115))	('phosphorylation', 'MPA', (56, 71))	('PERK', 'Gene', (75, 79))	('eIF2alpha', 'Gene', '83939', (46, 55))
66938	19754954	Thus, perturbations that ablate the growth inhibitory function of PERK-eIF2alpha signaling can favor benign tumor formation.	('ablate', 'Var', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('eIF2alpha', 'Gene', '83939', (71, 80))	('PERK', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('growth inhibitory function', 'MPA', (36, 62))	('PERK', 'Gene', '9451', (66, 70))	('perturbations', 'Var', (6, 19))	('tumor', 'Disease', (108, 113))	('eIF2alpha', 'Gene', (71, 80))	('favor', 'PosReg', (95, 100))
66951	19754954	This and the fact that salubrinal or more powerful derivates like Sal003 do not appear to have significant toxicities in murine models may warrant further investigation into whether Salubrinal or similar molecules that target GADD34-PP1C could be used to treat breast cancers with amplified ErbB2.	('toxicities', 'Disease', (107, 117))	('ErbB2', 'Gene', (291, 296))	('salubrinal', 'Chemical', 'MESH:C496827', (23, 33))	('breast cancers', 'Phenotype', 'HP:0003002', (261, 275))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('breast cancers', 'Disease', 'MESH:D001943', (261, 275))	('toxicities', 'Disease', 'MESH:D064420', (107, 117))	('breast cancers', 'Disease', (261, 275))	('PP1C', 'Gene', '5501', (233, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (261, 274))	('PP1C', 'Gene', (233, 237))	('Salubrinal', 'Chemical', 'MESH:C496827', (182, 192))	('amplified', 'Var', (281, 290))	('murine', 'Species', '10090', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))
66957	19754954	Anti-phospho-ErbB2 (pTy1221/1222), anti-phospho- and total PERK (P-Thr 980) and eIF2alpha (P-Ser 51), anti-phospho-Akt (Ser473), cyclin D1 and anti-cleaved caspase-3 were from Cell Signaling (Danvers, MA).	('Akt', 'Gene', '207', (115, 118))	('Ser', 'Chemical', 'MESH:D012694', (120, 123))	('pTy1221', 'Chemical', '-', (20, 27))	('PERK', 'Gene', '9451', (59, 63))	('Akt', 'Gene', (115, 118))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('Ser473', 'Var', (120, 126))	('cyclin D1 and anti-cleaved caspase-3', 'Gene', '595', (129, 165))	('eIF2alpha', 'Gene', (80, 89))	('Ser473', 'Chemical', '-', (120, 126))	('eIF2alpha', 'Gene', '83939', (80, 89))	('Thr', 'Chemical', 'MESH:D013912', (67, 70))	('PERK', 'Gene', (59, 63))	('pTy1221/1222', 'Var', (20, 32))
66958	19754954	Anti-total ErbB2 and anti-total Erk 1 was from BD Biosciences.	('Erk 1', 'Gene', (32, 37))	('anti-total', 'Var', (21, 31))	('Erk 1', 'Gene', '5595', (32, 37))
66959	19754954	Anti-ATF4, anti-CHOP/GADD153 (sc-575), anti-GADD34 and anti-phospho-Erk 1/2 were from Santa Cruz Biotechnology (Santa Cruz, CA).	('CHOP', 'Gene', '1649', (16, 20))	('ATF4', 'Gene', (5, 9))	('GADD153', 'Gene', (21, 28))	('CHOP', 'Gene', (16, 20))	('ATF4', 'Gene', '468', (5, 9))	('anti-GADD34', 'Var', (39, 50))	('GADD153', 'Gene', '1649', (21, 28))
66990	25403959	Our preliminary data from the Wisconsin In Situ Cohort suggests that DCIS patients treated with BCS may have better physical function and fewer physical role limitations, compared to women treated with mastectomy.	('BCS', 'Var', (96, 99))	('fewer', 'NegReg', (138, 143))	('women', 'Species', '9606', (183, 188))	('patients', 'Species', '9606', (74, 82))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('physical role limitations', 'CPA', (144, 169))	('better', 'PosReg', (109, 115))	('physical function', 'CPA', (116, 133))
66998	25403959	As a petroleum-derived product, plastic production is associated with habitat destruction, soil erosion, chemical contamination of land and water, human health and safety risks for oil workers and neighboring communities, and social justice issues related to oil drilling and extraction.	('water', 'Chemical', 'MESH:D014867', (140, 145))	('associated', 'Reg', (54, 64))	('plastic production', 'Var', (32, 50))	('human', 'Species', '9606', (147, 152))
67068	23778408	EGFR positivity, which is associated with positivity for basal cytokeratins and negativity for estrogen receptor and HER2, defines basal-like breast cancers for other authors.	('HER2', 'Gene', (117, 121))	('positivity', 'Var', (5, 15))	('EGFR', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (142, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancers', 'Disease', 'MESH:D001943', (142, 156))	('breast cancers', 'Disease', (142, 156))	('estrogen receptor', 'Gene', (95, 112))	('EGFR', 'Gene', '1956', (0, 4))	('estrogen receptor', 'Gene', '2099', (95, 112))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
67069	23778408	EGFR gene amplification and/or high EGFR expression are biological predictors of poor prognosis in breast carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('EGFR', 'Gene', (0, 4))	('breast carcinomas', 'Disease', 'MESH:D001943', (99, 116))	('breast carcinomas', 'Disease', (99, 116))	('expression', 'MPA', (41, 51))	('breast carcinoma', 'Phenotype', 'HP:0003002', (99, 115))	('breast carcinomas', 'Phenotype', 'HP:0003002', (99, 116))	('EGFR', 'Gene', '1956', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('amplification', 'Var', (10, 23))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (0, 4))
67076	23778408	Our data showed an increased frequency of the HER2 phenotype in pure high-grade DCIS, which is consistent with previous studies demonstrating a higher prevalence of HER2 protein overexpression and gene amplification among DCIS in comparison to invasive breast cancers and suggesting that HER2/neu gene amplification is inversely related to invasive progression in DCIS patients.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('invasive breast cancers', 'Disease', (244, 267))	('neu', 'Gene', (293, 296))	('HER2', 'Gene', (46, 50))	('neu', 'Gene', '2064', (293, 296))	('patients', 'Species', '9606', (369, 377))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('HER2', 'Gene', '2064', (46, 50))	('HER2', 'Gene', (288, 292))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('invasive breast cancers', 'Disease', 'MESH:D001943', (244, 267))	('overexpression', 'PosReg', (178, 192))	('HER2', 'Gene', '2064', (288, 292))	('invasive progression', 'Disease', (340, 360))	('gene amplification', 'Var', (197, 215))	('HER2', 'Gene', (165, 169))	('breast cancers', 'Phenotype', 'HP:0003002', (253, 267))	('HER2', 'Gene', '2064', (165, 169))
67121	16677423	The outcome of the invasive disease differed markedly between the grades, however, with the risk of distant metastasis and death being significantly higher in recurrences secondary to high-grade DCIS.	('DCIS', 'Disease', (195, 199))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('invasive disease', 'Disease', 'MESH:D009362', (19, 35))	('invasive disease', 'Disease', (19, 35))	('high-grade', 'Var', (184, 194))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (123, 128))	('higher', 'PosReg', (149, 155))	('distant metastasis', 'CPA', (100, 118))
67124	16677423	Betsill and colleagues reported on the outcome of 10 patients with low-grade DCIS treated with biopsy alone with a mean follow-up of 21.6 years, and found that 7 had developed invasive carcinoma at an average interval of 9.7 years (range of 7 to 30 years).	('patients', 'Species', '9606', (53, 61))	('invasive carcinoma', 'Disease', (176, 194))	('developed', 'PosReg', (166, 175))	('low-grade', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('invasive carcinoma', 'Disease', 'MESH:D009361', (176, 194))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
67134	16677423	Ringberg and colleagues found high Ki-67, high p53 and reduced bcl-2 to be associated with recurrence in univariate analysis, although in multivariate analysis including tumour grade and growth pattern none reached statistical significance.	('bcl-2', 'Gene', (63, 68))	('reduced', 'NegReg', (55, 62))	('tumour', 'Disease', (170, 176))	('p53', 'Gene', '7157', (47, 50))	('Ki-67', 'Var', (35, 40))	('recurrence', 'Disease', (91, 101))	('bcl-2', 'Gene', '596', (63, 68))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('p53', 'Gene', (47, 50))	('high Ki-67', 'Var', (30, 40))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
67135	16677423	This is largely in agreement with other reports that show a relationship between grade of DCIS and biological factors, such as p53 mutation.	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))	('mutation', 'Var', (131, 139))
67154	32437426	The B-categories from CNB/VAB were as follows: B2 42.2 percent (n = 856), B3 4.5 percent (n = 91), B5a 5.7 percent (n = 115), and B5b 47.6 percent (n = 967).	('VAB', 'Chemical', '-', (26, 29))	('B5a', 'Var', (99, 102))	('B5b', 'Var', (130, 133))
67171	32437426	Lee et al, found that the B3 rate was higher in screening program compared to symptomatic patients (7.3 percent vs 2 percent).	('screening program', 'Var', (48, 65))	('patients', 'Species', '9606', (90, 98))	('higher', 'PosReg', (38, 44))
67227	32093026	The acquired changes might remain in the tissue even after tumor removal and may contribute to tumor relapse.	('tumor', 'Disease', (59, 64))	('contribute', 'Reg', (81, 91))	('changes', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (95, 100))
67246	32093026	Herein, we performed a detailed comparison of the functional properties of MSCs from the following four origins in healthy donors and breast cancer patients to determine the influence of malignancy on normal stromal precursors: (1) the first MSC group was isolated from the breast adipose tissue of healthy donors undergoing planned aesthetic breast surgery; (2) the second group comprised MSCs from cancer patient breast adipose tissue adjacent to pre-malignant lesions; (3) the third group was MSCs obtained from adipose tissue of breast cancer patients diagnosed with invasive tumor type and (4) this group contained tissue similar to that in the third group but also harboring the BRCA gene mutation.	('mutation', 'Var', (695, 703))	('cancer', 'Disease', (400, 406))	('donor', 'Species', '9606', (307, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('donor', 'Species', '9606', (123, 128))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('cancer', 'Disease', (540, 546))	('patients', 'Species', '9606', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (580, 585))	('breast cancer', 'Disease', (134, 147))	('malignancy', 'Disease', 'MESH:D009369', (187, 197))	('cancer', 'Phenotype', 'HP:0002664', (540, 546))	('BRCA', 'Gene', '672', (685, 689))	('patient', 'Species', '9606', (547, 554))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (400, 406))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('invasive tumor type', 'Disease', (571, 590))	('malignancy', 'Disease', (187, 197))	('patient', 'Species', '9606', (148, 155))	('BRCA', 'Gene', (685, 689))	('breast cancer', 'Phenotype', 'HP:0003002', (533, 546))	('cancer', 'Disease', 'MESH:D009369', (540, 546))	('invasive tumor type', 'Disease', 'MESH:D009361', (571, 590))	('breast cancer', 'Disease', 'MESH:D001943', (533, 546))	('breast cancer', 'Disease', (533, 546))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('patient', 'Species', '9606', (407, 414))	('patients', 'Species', '9606', (547, 555))
67249	32093026	Mesenchymal stromal cells were isolated from the breast adipose tissue of four different donor groups: Group No.1 MSC-H (n = 9), isolated from breast adipose tissue of healthy donors, Group No.2 MSC-DCIS (n = 2), isolated from adipose tissue adjacent to pre-malignant lesions, Group No.3 MSC-CA (n = 24), isolated from adipose tissue adjacent to malignant lesions, and Group No.4 MSC-BRCA+ (n = 6), isolated from adipose tissue adjacent to malignant lesions harboring the BRCA gene mutation.	('BRCA', 'Gene', (384, 388))	('mutation', 'Var', (482, 490))	('BRCA', 'Gene', '672', (472, 476))	('donor', 'Species', '9606', (89, 94))	('BRCA', 'Gene', (472, 476))	('donor', 'Species', '9606', (176, 181))	('BRCA', 'Gene', '672', (384, 388))
67263	32093026	The expression of CD90, CD105, CD14, CD20, CD34 and CD45 was assessed by BD FACSCanto  II Flow cytometer (Becton Dickinson, USA) equipped with the FacsDiva program, and the data were then analyzed by FCS Express program.	('CD90', 'Gene', '7070', (18, 22))	('CD20', 'Gene', (37, 41))	('CD45', 'Gene', (52, 56))	('CD105', 'Var', (24, 29))	('CD90', 'Gene', (18, 22))	('CD34', 'Gene', (43, 47))	('CD34', 'Gene', '947', (43, 47))	('CD45', 'Gene', '5788', (52, 56))	('CD14', 'Gene', (31, 35))	('CD14', 'Gene', '929', (31, 35))	('CD20', 'Gene', '54474', (37, 41))
67288	32093026	Endogenous peroxidase was blocked by 5 min of incubation with FLEX peroxidase Block (DAKO), and sections were then incubated with primary antibodies, anti-human Ki67 MIB-1, anti-human Vimentin or anti-human smooth muscle actin (alphaSMA) for 20 min at RT (FLEX, DAKO).	('Ki67', 'Chemical', '-', (161, 165))	('human', 'Species', '9606', (178, 183))	('human', 'Species', '9606', (155, 160))	('MIB-1', 'Gene', (166, 171))	('human', 'Species', '9606', (201, 206))	('anti-human Ki67', 'Var', (150, 165))
67295	32093026	MSCs were positive for CD90, CD105 and CD73 (>95%), but did not express CD14, CD20, CD34 and CD45 markers, as expected (<5% positive cells, representative sample in Figure 2A).	('CD20', 'Gene', (78, 82))	('CD73', 'Gene', (39, 43))	('CD34', 'Gene', '947', (84, 88))	('CD45', 'Gene', (93, 97))	('CD34', 'Gene', (84, 88))	('positive', 'Reg', (10, 18))	('CD73', 'Gene', '4907', (39, 43))	('CD90', 'Gene', '7070', (23, 27))	('CD45', 'Gene', '5788', (93, 97))	('CD105', 'Var', (29, 34))	('CD14', 'Gene', (72, 76))	('CD90', 'Gene', (23, 27))	('CD14', 'Gene', '929', (72, 76))	('CD20', 'Gene', '54474', (78, 82))
67310	32093026	However, if these tumor-caused changes are permanently retained in MSCs, such altered MSCs may later contribute to (or even cause) tumor recurrence.	('contribute to', 'Reg', (101, 114))	('changes', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('cause', 'Reg', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
67312	32093026	As the molecular interplay between IGF1 and leptin, as well as its association with the pathogenesis of breast cancer, was shown previously, we have also analyzed the level of leptin which was significantly decreased in the group of MSC-CA (Figure 5B).	('leptin', 'Gene', '3952', (44, 50))	('IGF1', 'Gene', '3479', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('IGF1', 'Gene', (35, 39))	('leptin', 'Gene', (44, 50))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('MSC-CA', 'Var', (233, 239))	('breast cancer', 'Disease', (104, 117))	('leptin', 'Gene', '3952', (176, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('decreased', 'NegReg', (207, 216))	('leptin', 'Gene', (176, 182))
67313	32093026	After observing that the secretion of analyzed factors was decreased in cancer patient-derived MSCs, we were intrigued to see whether MSC-CA generally release less cytokines compared to MSC-H.	('less', 'NegReg', (159, 163))	('decreased', 'NegReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MSC-CA', 'Var', (134, 140))	('release', 'MPA', (151, 158))	('patient', 'Species', '9606', (79, 86))	('cytokines', 'MPA', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('secretion of', 'MPA', (25, 37))	('cancer', 'Disease', (72, 78))
67321	32093026	Although in NLR-T47D co-culture the spheroid size was bigger, the structure was less compact, and the luminescent assay showed significantly less ATP in all MSC groups (Figure 7B left).	('less', 'NegReg', (141, 145))	('NLR-T47D', 'Var', (12, 20))	('ATP', 'CPA', (146, 149))	('spheroid size', 'CPA', (36, 49))	('ATP', 'Chemical', 'MESH:D000255', (146, 149))
67377	32093026	While the collective migration of tumor cells was combined with high Ki67 and VIM positivity in the invasive front, the cell invasion differed in tumor cells co-injected with MSC-DCIS compared to MSC-CA.	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('VIM', 'Gene', '7431', (78, 81))	('differed', 'Reg', (134, 142))	('Ki67', 'Chemical', '-', (69, 73))	('tumor', 'Disease', (146, 151))	('Ki67', 'Var', (69, 73))	('VIM', 'Gene', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('MSC-DCIS', 'Var', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cell invasion', 'CPA', (120, 133))
67391	26078038	In common with invasive breast cancer, ductal carcinoma in situ exhibits many genomic changes, predominantly copy number alterations.	('ductal carcinoma', 'Disease', 'MESH:D044584', (39, 55))	('ductal carcinoma', 'Disease', (39, 55))	('invasive breast cancer', 'Disease', 'MESH:D001943', (15, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (39, 63))	('invasive breast cancer', 'Disease', (15, 37))	('copy number alterations', 'Var', (109, 132))
67392	26078038	Although studies have revealed the genomic heterogeneity within individual ductal carcinoma in situ lesions and the association of certain copy number alterations with nuclear grade, none of the genomic changes defined so far is consistently associated with invasive transformation or recurrence risk in pure ductal carcinoma in situ.	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('association', 'Interaction', (116, 127))	('carcinoma in situ lesions', 'Disease', 'MESH:D002278', (82, 107))	('ductal carcinoma', 'Disease', 'MESH:D044584', (75, 91))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (75, 99))	('ductal carcinoma', 'Disease', (75, 91))	('invasive transformation', 'CPA', (258, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('copy number alterations', 'Var', (139, 162))	('ductal carcinoma', 'Disease', 'MESH:D044584', (309, 325))	('carcinoma in situ lesions', 'Disease', (82, 107))	('ductal carcinoma', 'Disease', (309, 325))	('associated with', 'Reg', (242, 257))	('recurrence', 'CPA', (285, 295))	('changes', 'Var', (203, 210))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (309, 333))
67396	26078038	Clinical and histopathological features associated with increased risk of ipsilateral recurrence include young patient age, symptomatic tumour detection, tumour multifocality, large tumour size, involved surgical margins, high nuclear grade, and presence of comedo necrosis.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('necrosis', 'Disease', (265, 273))	('tumour multifocality', 'Disease', (154, 174))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour multifocality', 'Disease', 'None', (154, 174))	('high', 'Var', (222, 226))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Disease', (136, 142))	('tumour', 'Disease', (154, 160))	('necrosis', 'Disease', 'MESH:D009336', (265, 273))	('patient', 'Species', '9606', (111, 118))	('tumour', 'Disease', (182, 188))	('comedo', 'Phenotype', 'HP:0025249', (258, 264))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
67398	26078038	Breast cancer not only is driven by somatic point mutations and epigenetic alterations but also characterised by extensive copy number changes, and these large-scale alterations are likely to be informative of its biology in addition to clinico-histopathological features and expression profiles.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('epigenetic alterations', 'Var', (64, 86))	('driven', 'Reg', (26, 32))	('copy number changes', 'Var', (123, 142))	('Breast cancer', 'Disease', (0, 13))
67402	26078038	Genome-wide approaches used in studying DCIS include chromosomal comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), single-nucleotide polymorphism (SNP)-based arrays, and massively parallel sequencing (MPS).	('single-nucleotide polymorphism', 'Var', (154, 184))	('MPS', 'Disease', (240, 243))	('MPS', 'Disease', 'MESH:D009084', (240, 243))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))
67406	26078038	MPS allows the simultaneous detection of genomic events at multiple loci in a high-throughput manner and not only can identify point mutations but can provide accurate copy number and, in the case of whole-genome sequencing, chromosomal translocation information as well.	('MPS', 'Disease', (0, 3))	('MPS', 'Disease', 'MESH:D009084', (0, 3))	('point mutations', 'Var', (127, 142))
67413	26078038	In terms of individual genes, MYC (8q24) and ERBB2 (17q12) amplifications have been associated with high nuclear grade and with other features suggestive of a more aggressive phenotype such as high Ki-67 index and micropapillary and comedo growth patterns, respectively.	('high Ki-67 index', 'CPA', (193, 209))	('MYC', 'Gene', '4609', (30, 33))	('ERBB2', 'Gene', (45, 50))	('amplifications', 'Var', (59, 73))	('high nuclear grade', 'CPA', (100, 118))	('comedo', 'Phenotype', 'HP:0025249', (233, 239))	('associated', 'Reg', (84, 94))	('ERBB2', 'Gene', '2064', (45, 50))	('MYC', 'Gene', (30, 33))
67414	26078038	Copy number alterations of CCNE1 (19q12) and AURKA (20q13) have been reported to occur exclusively in high-grade DCIS, while the 11q13 amplicon, frequently present in high-grade DCIS, contains the known oncogene CCND1 (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))	('AURKA', 'Gene', '6790', (45, 50))	('AURKA', 'Gene', (45, 50))	('Copy number alterations', 'Var', (0, 23))	('CCNE1', 'Gene', '898', (27, 32))	('CCNE1', 'Gene', (27, 32))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('CCND1', 'Gene', (212, 217))	('high-grade DCIS', 'Disease', (102, 117))	('occur', 'Reg', (81, 86))	('CCND1', 'Gene', '595', (212, 217))
67417	26078038	This study identified specific regions of gain (17q) and losses (3p, 4p, 4q, and 8p) in HER2-amplified DCIS and specific regions of gain (1q, 8p, and 17q) and loss (16q) in luminal-subtype DCIS.	('gain', 'PosReg', (42, 46))	('DCIS', 'Disease', (103, 107))	('1q', 'Var', (138, 140))	('HER2', 'Gene', (88, 92))	('losses', 'NegReg', (57, 63))	('loss', 'NegReg', (159, 163))	('gain', 'PosReg', (132, 136))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('HER2', 'Gene', '2064', (88, 92))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))
67418	26078038	They also classified DCIS cases into categories based on the type and degree of copy number alterations, similar to that proposed in invasive carcinomas.	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('copy number alterations', 'Var', (80, 103))	('invasive carcinomas', 'Disease', (133, 152))	('invasive carcinomas', 'Disease', 'MESH:D009361', (133, 152))
67419	26078038	Tumours were characterized by (i) few copy number changes apart from 1q gain and 16q loss (classified as '1q/16q'), (ii) tumours with many low-level copy number alterations (labelled 'complex'), and (iii) tumours with recurrent amplifications in addition to low-level copy number alterations ('mixed amplifiers').	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('low-level copy number alterations', 'Var', (139, 172))	('tumours', 'Disease', (121, 128))	('tumours', 'Disease', (205, 212))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('gain', 'PosReg', (72, 76))	('loss', 'NegReg', (85, 89))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
67424	26078038	However, given that many of the alterations in low-grade DCIS are in common with invasive carcinoma, this seems unlikely.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('invasive carcinoma', 'Disease', 'MESH:D009361', (81, 99))	('alterations', 'Var', (32, 43))	('low-grade', 'Var', (47, 56))	('invasive carcinoma', 'Disease', (81, 99))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
67426	26078038	Thus, reduced detection sensitivity may be a technical reason for lower levels of copy number alterations in invasive breast cancer compared with DCIS.	('copy number alterations', 'Var', (82, 105))	('detection sensitivity', 'MPA', (14, 35))	('reduced', 'NegReg', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lower', 'NegReg', (66, 71))	('invasive breast cancer', 'Disease', 'MESH:D001943', (109, 131))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('invasive breast cancer', 'Disease', (109, 131))
67430	26078038	In addition, exclusive regions of copy number gain (5q, 16p, 19q, and 20) and copy number loss (3q, 6q, 8p, and 11q) were also identified in the invasive component as well as a region of exclusive copy number loss (17q11.2) in DCIS.	('copy number loss', 'Disease', 'MESH:D016388', (197, 213))	('copy number loss', 'Disease', (78, 94))	('copy number loss', 'Disease', 'MESH:D016388', (78, 94))	('5q', 'Var', (52, 54))	('copy number gain', 'Disease', (34, 50))	('DCIS', 'Phenotype', 'HP:0030075', (227, 231))	('copy number gain', 'Disease', 'MESH:D015430', (34, 50))	('copy number loss', 'Disease', (197, 213))	('3q', 'Var', (96, 98))
67432	26078038	Similarly, genomic differences between DCIS and invasive carcinoma components may indicate genetic changes important in determining invasion but could also be due to clonal heterogeneity and ongoing genetic evolution.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('invasive carcinoma', 'Disease', (48, 66))	('genomic differences', 'Var', (11, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('invasive carcinoma', 'Disease', 'MESH:D009361', (48, 66))
67433	26078038	Copy number alterations of specific genes reported to be associated with disease progression include those whose protein products regulate the cell cycle (CCND1) or transcription (MYC) or function as receptor tyrosine kinases (ERBB2 and FGFR1) (Fig.	('MYC', 'Gene', '4609', (180, 183))	('transcription', 'MPA', (165, 178))	('cell cycle', 'CPA', (143, 153))	('regulate', 'Reg', (130, 138))	('Copy number alterations', 'Var', (0, 23))	('CCND1', 'Gene', '595', (155, 160))	('ERBB2', 'Gene', '2064', (227, 232))	('MYC', 'Gene', (180, 183))	('FGFR1', 'Gene', (237, 242))	('FGFR1', 'Gene', '2260', (237, 242))	('ERBB2', 'Gene', (227, 232))	('CCND1', 'Gene', (155, 160))
67440	26078038	Mu and colleagues (2011) also identified CCND1 amplification in invasive carcinoma which was absent in matched adjacent DCIS in three of 16 (18.8 %) cases.	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('CCND1', 'Gene', '595', (41, 46))	('invasive carcinoma', 'Disease', 'MESH:D009361', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('amplification', 'Var', (47, 60))	('invasive carcinoma', 'Disease', (64, 82))	('CCND1', 'Gene', (41, 46))
67443	26078038	Although a previous smaller study (n = 39) revealed no difference in FGFR1 copy number between mixed DCIS and matched invasive carcinoma, Jang and colleagues (2012) examined a large cohort of pure DCIS (n = 175), mixed DCIS (n = 203), and invasive carcinoma (n = 427) by FISH and reported that FGFR1 amplification (defined as average copy number of more than 6.0 or FGFR1-to-centromeric enumeration probe ratio of more than 2.2) was not only significantly more frequent in invasive carcinoma compared with pure DCIS (12.5 % versus 6.0 %, P = 0.020) but also more frequent in invasive carcinoma compared with matched adjacent DCIS (P = 0.031), suggesting a role of FGFR1 amplification in the transition from non-invasive to invasive disease.	('FGFR1', 'Gene', '2260', (664, 669))	('DCIS', 'Phenotype', 'HP:0030075', (625, 629))	('FGFR1', 'Gene', (366, 371))	('invasive carcinoma', 'Disease', (118, 136))	('invasive carcinoma', 'Disease', 'MESH:D009361', (239, 257))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('invasive carcinoma', 'Disease', 'MESH:D009361', (118, 136))	('FGFR1', 'Gene', (294, 299))	('invasive carcinoma', 'Disease', (575, 593))	('DCIS', 'Phenotype', 'HP:0030075', (219, 223))	('FGFR1', 'Gene', (69, 74))	('invasive carcinoma', 'Disease', (473, 491))	('FGFR1', 'Gene', (664, 669))	('invasive carcinoma', 'Disease', 'MESH:D009361', (575, 593))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('amplification', 'Var', (670, 683))	('DCIS', 'Phenotype', 'HP:0030075', (511, 515))	('invasive disease', 'Disease', 'MESH:D009362', (723, 739))	('frequent', 'Reg', (563, 571))	('FGFR1', 'Gene', '2260', (366, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (482, 491))	('invasive carcinoma', 'Disease', 'MESH:D009361', (473, 491))	('carcinoma', 'Phenotype', 'HP:0030731', (584, 593))	('invasive disease', 'Disease', (723, 739))	('FGFR1', 'Gene', '2260', (294, 299))	('FGFR1', 'Gene', '2260', (69, 74))	('invasive carcinoma', 'Disease', (239, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
67446	26078038	Studies examining copy number alterations in matched pairs of mixed DCIS and invasive carcinoma have also shed light onto the high degree of intra-tumoural genomic heterogeneity of DCIS.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('intra-tumoural', 'Disease', (141, 155))	('invasive carcinoma', 'Disease', 'MESH:D009361', (77, 95))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('copy number alterations', 'Var', (18, 41))	('intra-tumoural', 'Disease', 'MESH:D009369', (141, 155))	('invasive carcinoma', 'Disease', (77, 95))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
67461	26078038	PIK3CA mutations are believed to be early events in the development of breast cancer.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('mutations', 'Var', (7, 16))
67462	26078038	A higher frequency of PIK3CA mutations in mixed DCIS (8 out of 33, 24 %) than in pure DCIS (0 out of 31) has been reported in a specific group of high-grade, estrogen receptor-positive, HER2-negative DCIS cases.	('PIK3CA', 'Gene', '5290', (22, 28))	('HER2', 'Gene', (186, 190))	('mutations', 'Var', (29, 38))	('HER2', 'Gene', '2064', (186, 190))	('DCIS', 'Phenotype', 'HP:0030075', (48, 52))	('DCIS', 'Disease', (200, 204))	('DCIS', 'Phenotype', 'HP:0030075', (200, 204))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('PIK3CA', 'Gene', (22, 28))
67463	26078038	However, Miron and colleagues (2010) reported the frequency of PIK3CA activating mutations to be 30 % in pure DCIS (61 out of 202 cases) and mixed DCIS (29 out of 97 cases) and 29 % in invasive carcinoma (35 out of 120 cases).	('pure DCIS', 'Disease', (105, 114))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('activating', 'PosReg', (70, 80))	('mixed DCIS', 'Disease', (141, 151))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('mutations', 'Var', (81, 90))	('invasive carcinoma', 'Disease', 'MESH:D009361', (185, 203))	('invasive carcinoma', 'Disease', (185, 203))
67465	26078038	In addition, Johnson and colleagues (2012) identified PIK3CA mutations in 8 out of 21 (38.1 %) matched mixed DCIS-invasive tumours; however, in two of these cases, the mutation was present in the DCIS component only.	('DCIS', 'Phenotype', 'HP:0030075', (196, 200))	('DCIS-invasive tumours', 'Disease', (109, 130))	('PIK3CA', 'Gene', '5290', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (61, 70))	('DCIS-invasive tumours', 'Disease', 'MESH:D002285', (109, 130))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('PIK3CA', 'Gene', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
67466	26078038	These findings suggest that PIK3CA mutations are not positively selected in the transition from in situ to invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (107, 123))	('PIK3CA', 'Gene', (28, 34))	('invasive disease', 'Disease', (107, 123))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutations', 'Var', (35, 44))
67467	26078038	Although AKT1 mutations are rare in invasive breast cancer (approximately 2 %) (TCGA), activating AKT1 exon 2 mutations were observed in the in situ component of two of three breast tumours exhibiting the mutation in the invasive component in one study and in three of six papillomas harbouring DCIS in another study.	('breast tumours', 'Disease', (175, 189))	('papillomas', 'Disease', (273, 283))	('activating', 'PosReg', (87, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('invasive breast cancer', 'Disease', (36, 58))	('mutations', 'Var', (14, 23))	('AKT1', 'Gene', '207', (98, 102))	('mutations', 'Var', (110, 119))	('invasive breast cancer', 'Disease', 'MESH:D001943', (36, 58))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('breast tumours', 'Disease', 'MESH:D001943', (175, 189))	('AKT1', 'Gene', '207', (9, 13))	('AKT1', 'Gene', (98, 102))	('DCIS', 'Phenotype', 'HP:0030075', (295, 299))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('papillomas', 'Disease', 'MESH:D010212', (273, 283))	('AKT1', 'Gene', (9, 13))	('papillomas', 'Phenotype', 'HP:0012740', (273, 283))
67468	26078038	Similar to invasive breast cancers, no coexistent PIK3CA mutations were detected in tumours with AKT1 mutations consistent with their role within the same pathway.	('breast cancers', 'Phenotype', 'HP:0003002', (20, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('PIK3CA', 'Gene', '5290', (50, 56))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('invasive breast cancers', 'Disease', 'MESH:D001943', (11, 34))	('tumours', 'Disease', (84, 91))	('AKT1', 'Gene', '207', (97, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('AKT1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('PIK3CA', 'Gene', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('invasive breast cancers', 'Disease', (11, 34))
67469	26078038	TP53 mutations in exons 4 to 11 have been reported in 10 % to 37 % of pure DCIS cases and 20 % to 33 % of mixed DCIS cases and associated with high nuclear grade and HER2 subtype.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('TP53', 'Gene', '7157', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (127, 137))	('HER2', 'Gene', (166, 170))	('high nuclear grade', 'CPA', (143, 161))	('HER2', 'Gene', '2064', (166, 170))	('reported', 'Reg', (42, 50))	('mutations', 'Var', (5, 14))	('pure DCIS', 'Disease', (70, 79))
67470	26078038	The presence of TP53 mutations also appears to be an early event in breast cancer development and not specifically associated with in situ-to-invasive transition.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('TP53', 'Gene', '7157', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('presence', 'Var', (4, 12))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
67471	26078038	Translocations of two genes previously associated with increased oncogenic activity, MAST2 and NOTCH1, were identified by FISH in one study in 4 out of 115 (3.5 %) and 2 out of 115 (1.7 %) mixed DCIS cases, respectively, but these translocations were not observed in 170 cases of pure DCIS.	('Translocations', 'Var', (0, 14))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('MAST2', 'Gene', (85, 90))	('NOTCH1', 'Gene', '4851', (95, 101))	('NOTCH1', 'Gene', (95, 101))	('mixed DCIS', 'Disease', (189, 199))	('DCIS', 'Phenotype', 'HP:0030075', (285, 289))	('MAST2', 'Gene', '23139', (85, 90))
67472	26078038	However, structural rearrangements in DCIS may be more frequent than currently realized given the relatively frequent occurrence of such events in invasive breast cancers and breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('invasive breast cancers', 'Disease', 'MESH:D001943', (147, 170))	('breast cancer', 'Disease', (175, 188))	('structural rearrangements', 'Var', (9, 34))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('DCIS', 'Gene', (38, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('invasive breast cancers', 'Disease', (147, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
67477	26078038	Genomic alterations in DCIS lesions could be informative of outcome by being markers of a certain relationship between the malignant cells and the tumour microenvironment permissive to local recurrence or by reflecting the genetic instability of the local breast field.	('reflecting', 'Reg', (208, 218))	('DCIS lesions', 'Gene', (23, 35))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('alterations', 'Var', (8, 19))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', (147, 153))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))
67478	26078038	aCGH array comparative genomic hybridization BAC Bacterial artificial chromosome bp base pairs CGH Comparative genomic hybridisation DCIS Ductal carcinoma in situ ddPCR droplet digital polymerase chain reaction FFPE Formalin-fixed paraffin-embedded FISH Fluorescence in situ hybridisation LOH Loss of heterozygosity MIP Molecular inversion probe MPS Massively parallel sequencing qPCR quantitative polymerase chain reaction SNP Single-nucleotide polymorphism TCGA The cancer genome Atlas	('cancer', 'Disease', (468, 474))	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('Formalin', 'Chemical', 'MESH:D005557', (216, 224))	('Ductal carcinoma', 'Disease', (138, 154))	('cancer', 'Phenotype', 'HP:0002664', (468, 474))	('paraffin', 'Chemical', 'MESH:D010232', (231, 239))	('MPS', 'Disease', 'MESH:D009084', (346, 349))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (138, 154))	('Single-nucleotide polymorphism', 'Var', (428, 458))	('cancer', 'Disease', 'MESH:D009369', (468, 474))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (138, 162))	('MPS', 'Disease', (346, 349))
67500	23986868	In a study based on data collected from 1648 patients through a breast cancer screening program in Melbourne, Kurniawan has identified mammographic microcalcifications (P < 0.0001), presence of DCIS (P < 0.0001), high tumor grade, multifocal disease, and lobular histology (P = 0.005) as factors correlated with positive margins.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('mammographic', 'Disease', (135, 147))	('multifocal disease', 'Disease', (231, 249))	('multifocal disease', 'Disease', 'None', (231, 249))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (64, 77))	('presence', 'Var', (182, 190))
67505	23986868	reported in a retrospective study of 291 women with DCIS who underwent BCS 10-year actuarial LRRs of 28%, 21%, and 19% for SM <1 mm, 1-9 mm, and >=10 mm, respectively, without radiotherapy; these LRRs were reduced by radiotherapy.	('1-9 mm', 'Var', (133, 139))	('SM <1 mm', 'Var', (123, 131))	('women', 'Species', '9606', (41, 46))	('>=10 mm', 'Var', (145, 152))
67559	23986868	Of note, Jatoi has responded that, while systemic therapies may improve control on early local recurrences, late recurrences are more frequent among patients treated with BCS than those treated with mastectomy.	('improve', 'PosReg', (64, 71))	('patients', 'Species', '9606', (149, 157))	('BCS', 'Var', (171, 174))	('control', 'MPA', (72, 79))
67650	28104942	This is similar to our study where non-mass enhancement was more likely to be associated with luminal cancers, in keeping with higher incidence of DCIS associated with them.	('associated', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-mass enhancement', 'Var', (35, 55))	('luminal cancers', 'Disease', 'MESH:D009369', (94, 109))	('luminal cancers', 'Disease', (94, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))
67728	32883000	It was shown that CDC42 depletion in epithelial cells in suspension did not affect entosis.	('entosis', 'Disease', (83, 90))	('CDC42', 'Gene', '998', (18, 23))	('depletion', 'Var', (24, 33))	('CDC42', 'Gene', (18, 23))	('entosis', 'Disease', 'None', (83, 90))
67762	32883000	Entosis in cancer cells cultured in vitro, induced by the loss of 4.1N, was associated with cancer cell resistance to cell death.	('Entosis', 'CPA', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('loss', 'Var', (58, 62))	('4.1N', 'Protein', (66, 70))	('associated', 'Reg', (76, 86))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (11, 17))
67763	32883000	Even though the authors did not calculate entotic figures in specimens, it could be concluded that loss of 4.1N protein induced entosis in vitro and was associated with worse prognosis in vivo.	('loss of', 'Var', (99, 106))	('entosis', 'Disease', 'None', (128, 135))	('4.1N protein', 'Protein', (107, 119))	('entosis', 'Disease', (128, 135))
67769	32883000	Moreover, methylselenoesters induce death of inner entotic cells of Panc-1 pancreatic cancer cells, through downregulation of CDC42 and beta1-integrin (CD29).	('beta1-integrin', 'Gene', (136, 150))	('CD29', 'Gene', (152, 156))	('Panc-1', 'CellLine', 'CVCL:0480', (68, 74))	('CDC42', 'Gene', '998', (126, 131))	('inner entotic cells', 'CPA', (45, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('CDC42', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('CD29', 'Gene', '3688', (152, 156))	('methylselenoesters', 'Var', (10, 28))	('pancreatic cancer', 'Disease', (75, 92))	('downregulation', 'NegReg', (108, 122))	('beta1-integrin', 'Gene', '3688', (136, 150))
67834	28415634	Retrospective evaluation of the 732 patients demonstrated that tamoxifen was associated with a 51% reduction in subsequent breast cancer for women with ER-positive DCIS, but no effect in ER-negative patients.	('women', 'Species', '9606', (141, 146))	('patients', 'Species', '9606', (36, 44))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('ER-positive', 'Var', (152, 163))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('tamoxifen', 'Chemical', 'MESH:D013629', (63, 72))	('reduction', 'NegReg', (99, 108))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
67857	28415634	The aggregated results of these studies indicated that, anastrozole was associated with a significantly improved RFS than tamoxifen (HR = 0.86, 95%CI: 0.76-0.98; P = 0.024) (Figure 4).	('anastrozole', 'Chemical', 'MESH:D000077384', (56, 67))	('RFS', 'Chemical', '-', (113, 116))	('improved', 'PosReg', (104, 112))	('tamoxifen', 'Chemical', 'MESH:D013629', (122, 131))	('RFS', 'MPA', (113, 116))	('anastrozole', 'Var', (56, 67))
67860	28415634	The pooled results suggested that patients with breast cancer who were treated with anastrozole had a higher ORR than those treated with tamoxifen (RR = 1.21, 95% CI: 1.05-1.39; P = 0.009) (Figure 6).	('ORR', 'MPA', (109, 112))	('tamoxifen', 'Chemical', 'MESH:D013629', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('anastrozole', 'Chemical', 'MESH:D000077384', (84, 95))	('breast cancer', 'Disease', (48, 61))	('patients', 'Species', '9606', (34, 42))	('anastrozole', 'Var', (84, 95))
67863	28415634	The pooled results demonstrated that, compared with tamoxifen, anastrozole was associated with a significantly higher incidence of arthralgia (RR = 1.55, 95%CI: 1.20-1.99; P = 0.001), bone pain (RR = 1.31, 95%CI: 1.05-1.62; P = 0.015), but a lower incidence of vaginal bleeding (RR = 0.51, 95%CI: 0.28-0.93; P = 0.029), vaginal discharge (RR = 0.31, 95%CI: 0.12-0.82; P = 0.017), and thromboembolic events (RR = 0.39, 95%CI: 0.28-0.55; P < 0.001).	('thromboembolic events', 'Phenotype', 'HP:0001907', (384, 405))	('anastrozole', 'Chemical', 'MESH:D000077384', (63, 74))	('bone pain', 'Disease', 'MESH:D010146', (184, 193))	('arthralgia', 'Disease', 'MESH:D018771', (131, 141))	('anastrozole', 'Var', (63, 74))	('arthralgia', 'Disease', (131, 141))	('thromboembolic', 'Disease', (384, 398))	('bone pain', 'Disease', (184, 193))	('arthralgia', 'Phenotype', 'HP:0002829', (131, 141))	('vaginal bleeding', 'Disease', (261, 277))	('tamoxifen', 'Chemical', 'MESH:D013629', (52, 61))	('vaginal bleeding', 'Disease', 'MESH:D014592', (261, 277))	('bone pain', 'Phenotype', 'HP:0002653', (184, 193))	('vaginal discharge', 'Disease', (320, 337))	('pain', 'Phenotype', 'HP:0012531', (189, 193))	('thromboembolic', 'Disease', 'MESH:D013923', (384, 398))
67871	28415634	Their results suggested that, compared with continuing on tamoxifen, switching to anastrozole was associated with a significant improvements in DFS (HR = 0.59, 95%CI: 0.48-0.74; P < 0.001), event-free survival (HR = 0.55, 95%CI: 0.42-0.71; P < 0.001), and distant RFS (HR = 0.61, 95%CI: 0.45-0.83; P = 0.002).	('DFS', 'CPA', (144, 147))	('improvements', 'PosReg', (128, 140))	('switching', 'Var', (69, 78))	('tamoxifen', 'Chemical', 'MESH:D013629', (58, 67))	('distant RFS', 'CPA', (256, 267))	('anastrozole', 'Chemical', 'MESH:D000077384', (82, 93))	('RFS', 'Chemical', '-', (264, 267))	('event-free survival', 'CPA', (190, 209))
67894	28415634	According to the previous studies, DCIS had been recognized as a precursor of invasive cancer, and patients with DCIS was more likely to develop invasive breast cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('invasive cancer', 'Disease', (78, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('invasive breast cancer', 'Disease', (145, 167))	('DCIS', 'Var', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (99, 107))	('DCIS', 'Disease', (35, 39))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('invasive cancer', 'Disease', 'MESH:D009362', (78, 93))	('develop', 'PosReg', (137, 144))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
67915	28415634	Patients treated with anastrozole had a significantly fewer vaginal bleeding, vaginal discharge, and thromboembolic events than did those treated with tamoxifen.	('thromboembolic', 'Disease', (101, 115))	('vaginal bleeding', 'Disease', (60, 76))	('vaginal', 'CPA', (78, 85))	('anastrozole', 'Chemical', 'MESH:D000077384', (22, 33))	('vaginal bleeding', 'Disease', 'MESH:D014592', (60, 76))	('thromboembolic events', 'Phenotype', 'HP:0001907', (101, 122))	('Patients', 'Species', '9606', (0, 8))	('tamoxifen', 'Chemical', 'MESH:D013629', (151, 160))	('fewer', 'NegReg', (54, 59))	('thromboembolic', 'Disease', 'MESH:D013923', (101, 115))	('anastrozole', 'Var', (22, 33))
67979	25264427	In addition, the population doubling rates of the derived cell lines are similar to that of untransformed ETCC001, while ETCC008 and ETCC011 have distinct faster doubling rate compared to ETCC001.	('ETCC008', 'Var', (121, 128))	('rat', 'Species', '10116', (37, 40))	('faster', 'PosReg', (155, 161))	('rat', 'Species', '10116', (171, 174))	('ETCC011', 'Gene', (133, 140))
67982	25264427	All hTERT-transfected cells formed colonies in the soft agar with ETCC006 and ETCC007 forming the highest number of colonies (Figures 2C and D).	('hTERT', 'Gene', (4, 9))	('ETCC006', 'Var', (66, 73))	('agar', 'Chemical', 'MESH:D000362', (56, 60))	('hTERT', 'Gene', '7015', (4, 9))	('ETCC007', 'Var', (78, 85))
67992	25264427	Genetic changes of selected cancer causal gene are shown in Table 1.	('cancer', 'Disease', (28, 34))	('Genetic changes', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
67996	25264427	There were gene loss and/or LOH of TP53 (17p13) and copy number neutral LOH in MAP2K4 (17p11) in all cell lines except ETCC008.	('MAP2K4', 'Gene', (79, 85))	('copy number neutral', 'Var', (52, 71))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('loss', 'NegReg', (16, 20))	('LOH', 'NegReg', (28, 31))	('LOH', 'NegReg', (72, 75))	('MAP2K4', 'Gene', '6416', (79, 85))
67997	25264427	Copy number neutral LOH in BRCA1 (17q21) is observed in ETCC007, ETCC010 and ETCC011.	('BRCA1', 'Gene', '672', (27, 32))	('Copy number neutral LOH', 'Var', (0, 23))	('BRCA1', 'Gene', (27, 32))
68002	25264427	Mice injected with ETCC011 and ETCC007 exhibited overall good acceptance (8/8) and take rate (100%) whereas the animals injected with ETCC010 and ETCC006 exhibited lower take rate of 87.5% (7/8) and 75% (6/8) respectively.	('take', 'CPA', (83, 87))	('ETCC007', 'Var', (31, 38))	('rat', 'Species', '10116', (88, 91))	('ETCC011', 'Var', (19, 26))	('rat', 'Species', '10116', (175, 178))	('Mice', 'Species', '10090', (0, 4))
68020	25264427	Transfection of these cells with hTERT are found to extend cell division to over 250 population doublings.	('hTERT', 'Gene', '7015', (33, 38))	('extend', 'PosReg', (52, 58))	('Transfection', 'Var', (0, 12))	('cell division', 'CPA', (59, 72))	('hTERT', 'Gene', (33, 38))
68028	25264427	Even though MCF7 and T47D express both ER and PR, they are of metastatic origin and are derived from lung pleural effusion.	('metastatic', 'CPA', (62, 72))	('MCF7', 'Gene', (12, 16))	('lung pleural effusion', 'Disease', 'MESH:D010996', (101, 122))	('pleural effusion', 'Phenotype', 'HP:0002202', (106, 122))	('T47D', 'Var', (21, 25))	('ER', 'Gene', '2099', (39, 41))	('MCF7', 'CellLine', 'CVCL:0031', (12, 16))	('PR', 'Gene', '5241', (46, 48))	('T47', 'CellLine', 'CVCL:3945', (21, 24))	('lung pleural effusion', 'Disease', (101, 122))
68034	25264427	LOH on the X-chromosome have been reported to be associated with human breast cancer and other cancers.	('breast cancer', 'Disease', (71, 84))	('human', 'Species', '9606', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('LOH', 'Var', (0, 3))	('other cancers', 'Disease', 'MESH:D009369', (89, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('associated', 'Reg', (49, 59))	('other cancers', 'Disease', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
68036	25264427	The loss of the BRCA1 wild-type allele inherited from the unaffected parent through LOH represents the event that initiates the tumorigenesis process observed in primary breast and ovarian tumors.	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (170, 195))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('BRCA1', 'Gene', '672', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (128, 133))	('ovarian tumors', 'Phenotype', 'HP:0100615', (181, 195))	('BRCA1', 'Gene', (16, 21))	('loss', 'Var', (4, 8))
68037	25264427	We have observed BRCA1 copy number neutral LOH in three of the derived cell lines.	('BRCA1', 'Gene', '672', (17, 22))	('BRCA1', 'Gene', (17, 22))	('copy number neutral LOH', 'Var', (23, 46))
68038	25264427	Besides BRCA1, other important cancer causal genes on chromosome 17 such as TP53, MAP2K4, ERBB2 and PRKAR1A are all observed to have loss or copy number neutral LOH in these cell lines.	('PRKAR1A', 'Gene', '5573', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TP53', 'Gene', '7157', (76, 80))	('copy number neutral', 'Var', (141, 160))	('loss', 'NegReg', (133, 137))	('BRCA1', 'Gene', '672', (8, 13))	('TP53', 'Gene', (76, 80))	('PRKAR1A', 'Gene', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('ERBB2', 'Gene', '2064', (90, 95))	('MAP2K4', 'Gene', (82, 88))	('MAP2K4', 'Gene', '6416', (82, 88))	('cancer', 'Disease', (31, 37))	('ERBB2', 'Gene', (90, 95))	('BRCA1', 'Gene', (8, 13))
68039	25264427	Deletions of functional copies of MAP2K4 and BRCA1 have also been reported in several breast cancer cell lines.	('MAP2K4', 'Gene', '6416', (34, 40))	('BRCA1', 'Gene', '672', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('reported', 'Reg', (66, 74))	('BRCA1', 'Gene', (45, 50))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('MAP2K4', 'Gene', (34, 40))	('Deletions', 'Var', (0, 9))
68226	28765364	This model is composed of three cell lines: (1) normal immortalized breast epithelial cells (MCF10A), (2) premalignant H-Ras transformed MCF10A variants (MCF10AT cell line) that are tumorigenic as xenografts, and (3) tumorigenic and invasive MCF10A variants (MCF10DCIS.COM cell line).	('variants', 'Var', (144, 152))	('MCF10A', 'Gene', (242, 248))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (182, 187))	('MCF10A', 'Gene', (137, 143))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (259, 272))	('MCF10A', 'CellLine', 'CVCL:0598', (93, 99))	('DCIS', 'Phenotype', 'HP:0030075', (264, 268))	('MCF10A', 'CellLine', 'CVCL:0598', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('MCF10A', 'CellLine', 'CVCL:0598', (137, 143))	('MCF10A', 'CellLine', 'CVCL:0598', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('variants', 'Var', (249, 257))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
68231	28765364	Importantly, DCIS.COM colonies displayed higher filopodia density and longer filopodia than MCF10A colonies regardless of the composition of the microenvironment (Fig.	('filopodia density', 'CPA', (48, 65))	('longer filopodia', 'CPA', (70, 86))	('MCF10A', 'CellLine', 'CVCL:0598', (92, 98))	('DCIS.COM', 'CellLine', 'CVCL:5552', (13, 21))	('higher', 'PosReg', (41, 47))	('DCIS.COM', 'Var', (13, 21))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
68236	28765364	As filopodia formation appeared to be different in MCF10A and DCIS.COM cells (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (51, 57))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('MCF10A', 'Var', (51, 57))	('DCIS.COM', 'CellLine', 'CVCL:5552', (62, 70))	('filopodia formation', 'CPA', (3, 22))
68243	28765364	Using FiloQuant and TrackMate, we found that DCIS.COM cells generate a higher proportion of stable filopodia (>3 min lifetime) compared with MCF10A cells regardless of the composition of the microenvironment (Fig.	('DCIS.COM', 'Var', (45, 53))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('rat', 'Species', '10116', (64, 67))	('stable filopodia', 'CPA', (92, 108))	('DCIS.COM', 'CellLine', 'CVCL:5552', (45, 53))	('MCF10A', 'CellLine', 'CVCL:0598', (141, 147))
68245	28765364	We demonstrate that the higher density of long filopodia displayed by DCIS.COM cells appears to correlate with enhanced ability to invade through Matrigel and collagen (Fig.	('DCIS.COM', 'CellLine', 'CVCL:5552', (70, 78))	('DCIS.COM', 'Var', (70, 78))	('enhanced', 'PosReg', (111, 119))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('rat', 'Species', '10116', (10, 13))
68247	28765364	As filopodia formation (density and length) are particularly enhanced in DCIS.COM cells compared with normal MCF10A breast epithelial cells (Figs.	('enhanced', 'PosReg', (61, 69))	('DCIS.COM', 'Var', (73, 81))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('MCF10A', 'CellLine', 'CVCL:0598', (109, 115))	('DCIS.COM', 'CellLine', 'CVCL:5552', (73, 81))	('filopodia formation', 'CPA', (3, 22))
68252	28765364	Strikingly, DCIS.COM spheroids displayed very prominent edge filopodia at days 7 and 14 after plating compared with MCF10A or MCF10AT spheroids (Fig.	('edge filopodia', 'CPA', (56, 70))	('DCIS.COM', 'CellLine', 'CVCL:5552', (12, 20))	('MCF10A', 'CellLine', 'CVCL:0598', (116, 122))	('DCIS.COM', 'Var', (12, 20))	('MCF10A', 'CellLine', 'CVCL:0598', (126, 132))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))
68468	28692660	For MDA-MB-231 cells, it was revealed that OdDHL has two mechanisms to decrease the cell number.	('OdDHL', 'Var', (43, 48))	('cell number', 'CPA', (84, 95))	('decrease', 'NegReg', (71, 79))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (4, 14))
68475	28692660	The fact that OdDHL triggers necrosis as opposed to apoptosis in malignant cells is not surprising, as bacteria are known to induce necrosis.	('necrosis', 'Disease', (132, 140))	('OdDHL', 'Var', (14, 19))	('necrosis', 'Disease', (29, 37))	('necrosis', 'Disease', 'MESH:D009336', (132, 140))	('necrosis', 'Disease', 'MESH:D009336', (29, 37))
68476	28692660	However, the fact that OdDHL may reduce apoptosis and necrosis for non-malignant cells under a stressful microenvironment (i.e.	('reduce', 'NegReg', (33, 39))	('apoptosis', 'CPA', (40, 49))	('necrosis', 'Disease', (54, 62))	('OdDHL', 'Var', (23, 28))	('necrosis', 'Disease', 'MESH:D009336', (54, 62))
68483	28692660	The MCF-DCIS.com cells exhibited increased apoptosis and necrosis in the 2D/normoxia condition, which would have worked in concert with decreased proliferation in this condition leading to the reduced viability observed (Fig 4).	('apoptosis', 'CPA', (43, 52))	('rat', 'Species', '10116', (153, 156))	('MCF-DCIS.com', 'CellLine', 'CVCL:5552', (4, 16))	('necrosis', 'Disease', (57, 65))	('MCF-DCIS.com', 'Var', (4, 16))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
68489	28692660	Future studies investigating the possible role of tumor microenvironmental microbiota should establish if, as is suggested here, OdDHL suppresses highly malignant phenotypes.	('suppresses', 'NegReg', (135, 145))	('highly malignant phenotypes', 'MPA', (146, 173))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('OdDHL', 'Var', (129, 134))	('tumor', 'Disease', (50, 55))
68490	28692660	In addition, further experiments should extend the study of non-malignant and pre-malignant cell types to establish if, as seems to be the case for MCF-10A cells, OdDHL increases the survival of these cells in the presence of tumor microenvironmental stressors.	('MCF-10A', 'CellLine', 'CVCL:0598', (148, 155))	('increases', 'PosReg', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('OdDHL', 'Var', (163, 168))	('survival', 'CPA', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))
68491	28692660	Finally, although we show that OdDHL decreases breast viability through inhibition of proliferation as well as cell type and culture condition dependent induction of apoptosis and/or necrosis, future work should establish the cell signaling pathways associated with the differential responses to OdDHL.	('necrosis', 'Disease', (183, 191))	('proliferation', 'CPA', (86, 99))	('breast viability', 'CPA', (47, 63))	('OdDHL', 'Var', (31, 36))	('necrosis', 'Disease', 'MESH:D009336', (183, 191))	('decreases', 'NegReg', (37, 46))	('apoptosis', 'CPA', (166, 175))	('inhibition', 'NegReg', (72, 82))	('rat', 'Species', '10116', (93, 96))
68540	25781441	Confidence intervals accounted for both within- and between-participant variability by employing variance estimates of the form {var(ratep) + [avg(ratep) x (1 - avg(ratep))]/nc}/np, for which avg(ratep) is the average rate among pathologists, var(ratep) is the sample variance of rates among pathologists, nc is the number of cases interpreted by each pathologist, and np is the number of pathologists.	('avg', 'Var', (192, 195))	('participant', 'Species', '9606', (60, 71))	('var', 'Var', (243, 246))
68619	22577534	Escaped from proliferation control as a consequence of genetic and epigenetic alterations in genes involved in cell-fate decision, these ER-positive progenitor cells should generate cells constitutively expressing estrogen receptor.	('epigenetic alterations', 'Var', (67, 89))	('estrogen receptor', 'Gene', (214, 231))	('estrogen receptor', 'Gene', '2099', (214, 231))
68632	22577534	This gene encodes for cytochrome P450 (better known as aromatase), the enzyme that catalyzes the conversion from circulating and rostenedione to estrone or testosterone to estradiol, and its presence should support the hypothesis of a very early activation of an autocrine production of estrogen.	('aromatase', 'Gene', (55, 64))	('estrone', 'Chemical', 'MESH:D004970', (145, 152))	('rostenedione', 'Chemical', '-', (129, 141))	('estradiol', 'Chemical', 'MESH:D004958', (172, 181))	('aromatase', 'Gene', '1588', (55, 64))	('presence', 'Var', (191, 199))	('cytochrome P450', 'Enzyme', (22, 37))	('testosterone', 'Chemical', 'MESH:D013739', (156, 168))
68639	22577534	Notably, these alterations in gene expression did not result in a progressive mesenchymal transition but rather in a terminally differentiated luminal phenotype, in agreement with the model according to which ER-positive invasive breast cancer derives from ER-positive progenitor cells.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('invasive breast cancer', 'Disease', (221, 243))	('alterations', 'Var', (15, 26))	('invasive breast cancer', 'Disease', 'MESH:D001943', (221, 243))
68691	23664839	The IBIS model adds BRCA1/2 genetic status, age at menopause, and hormone replacement therapy, which are all potential risk factors not included in the GAIL model.	('IBIS', 'Chemical', '-', (4, 8))	('men', 'Species', '9606', (51, 54))	('age at menopause', 'Phenotype', 'HP:0008209', (44, 60))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('men', 'Species', '9606', (81, 84))	('genetic status', 'Var', (28, 42))	('BRCA1/2', 'Gene', (20, 27))
68713	23664839	Furthermore, in a case-control study, a large reduction in adjusted overall risk for invasive breast cancer (OR=0.4, 95% CI= 0.3-0.6) was observed with NSAID use.	('invasive breast cancer', 'Disease', (85, 107))	('reduction', 'NegReg', (46, 55))	('NSAID use', 'Var', (152, 161))	('invasive breast cancer', 'Disease', 'MESH:D001943', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))
68719	23664839	Finally, in a case control study of 1162 women with DCIS, an association between COX-2/p16/Ki67 triple positivity in DCIS lesions and subsequent invasive disease was observed.	('triple positivity', 'Var', (96, 113))	('invasive disease', 'Disease', 'MESH:D009362', (145, 161))	('p16', 'Gene', '1029', (87, 90))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('DCIS lesions', 'Disease', (117, 129))	('p16', 'Gene', (87, 90))	('invasive disease', 'Disease', (145, 161))	('women', 'Species', '9606', (41, 46))
68756	23664839	In this model, inhibition of COX-2, via NSAID administration during the two week period of murine postpartum involution, reduced mammary gland collagen deposition, decreased tumor COX-2 expression, and blocked tumor cell growth and invasion.	('tumor', 'Disease', (174, 179))	('decreased', 'NegReg', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('COX-2', 'Gene', (29, 34))	('invasion', 'CPA', (232, 240))	('reduced', 'NegReg', (121, 128))	('mammary gland collagen deposition', 'CPA', (129, 162))	('tumor', 'Disease', (210, 215))	('murine', 'Species', '10090', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('blocked', 'NegReg', (202, 209))	('expression', 'MPA', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('inhibition', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
68786	23664839	Importantly, metformin's anti-cancer activity is likely mediated, in part, through modification of the tumor microenvironment, as metformin treatment improves glucose control, and decreases circulating glucose, lipids, and pro-inflammatory cytokines available to the developing tumor.	('lipids', 'MPA', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('men', 'Species', '9606', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('decreases', 'NegReg', (180, 189))	('improves', 'PosReg', (150, 158))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('circulating glucose', 'MPA', (190, 209))	('metformin', 'Var', (130, 139))	('men', 'Species', '9606', (121, 124))	('metformin', 'Chemical', 'MESH:D008687', (130, 139))	('lipids', 'Chemical', 'MESH:D008055', (211, 217))	('glucose', 'Chemical', 'MESH:D005947', (202, 209))	('tumor', 'Disease', (278, 283))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', (30, 36))	('glucose control', 'MPA', (159, 174))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('glucose', 'Chemical', 'MESH:D005947', (159, 166))
68803	17244359	Tissue microarray analysis revealed strong positive staining of tumour cells for syndecan-1 in 72%, E-cadherin in 67.8% and c-met in 48.6% of DCIS.	('syndecan-1', 'Gene', (81, 91))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('syndecan-1', 'Gene', '6382', (81, 91))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))	('c-met', 'Var', (124, 129))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
68819	17244359	Moreover, ribozyme targeting of c-met in mammary cancer cells reduced mammary cancer and tumour-associated angiogenesis in a xenograft model.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('ribozyme targeting', 'Var', (10, 28))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (89, 95))	('c-met', 'Gene', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (49, 55))	('reduced', 'NegReg', (62, 69))
68820	17244359	To mobilize its full transforming potential in breast cancer, c-met appears to depend on coactivating factors, such as overexpression of additional proto-oncogenes (MYC, RON), or beta4 integrin activity.	('MYC', 'Gene', (165, 168))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('RON', 'Gene', (170, 173))	('overexpression', 'PosReg', (119, 133))	('RON', 'Gene', '4486', (170, 173))	('MYC', 'Gene', '4609', (165, 168))	('beta4', 'Gene', '10381', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('c-met', 'Var', (62, 67))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('beta4', 'Gene', (179, 184))
68865	17244359	Staining results for c-met, Sdc1 and E-cad were correlated with each other and with the expression of angiogenic and lymphangiogenic markers, as well as with ER, PR and HER2 status.	('correlated', 'Reg', (48, 58))	('PR', 'Gene', '5241', (162, 164))	('Sdc1', 'Gene', (28, 32))	('c-met', 'Var', (21, 26))
68874	17244359	Similar levels of Sdc1 expression were observed in MCF-7 and MDA-MB468 cells, but Sdc1 mRNA expression was significantly lower (P < 0.001) in MDA-MB231 cells than in MDA-MB468 cells.	('MDA-MB231', 'CellLine', 'CVCL:0062', (142, 151))	('MDA-MB231', 'Var', (142, 151))	('MDA-MB468', 'CellLine', 'CVCL:0419', (166, 175))	('MDA-MB468', 'CellLine', 'CVCL:0419', (61, 70))	('MCF-7', 'CellLine', 'CVCL:0031', (51, 56))	('lower', 'NegReg', (121, 126))	('Sdc1', 'Gene', (82, 86))	('mRNA expression', 'MPA', (87, 102))
68875	17244359	With increasing de-differentiation and higher metastatic potential (MCF-7 < MDA-MB468 < MDA-MB231), a significant decrease in E-cad mRNA expression was observed (Figure 2b).	('MCF-7', 'CellLine', 'CVCL:0031', (68, 73))	('MDA-MB468', 'CellLine', 'CVCL:0419', (76, 85))	('higher', 'PosReg', (39, 45))	('metastatic potential', 'CPA', (46, 66))	('MDA-MB231', 'CellLine', 'CVCL:0062', (88, 97))	('MDA-MB231', 'Var', (88, 97))	('de-differentiation', 'CPA', (16, 34))	('E-cad', 'CPA', (126, 131))	('decrease', 'NegReg', (114, 122))
68880	17244359	Based on a four-tiered scale, moderate to strong positive staining of tumour cells was observed for Sdc1 in 108 out of 150 (72%), for c-met in 69 out of 142 (48.6%) and for E-cad in 101 out of 149 (67.8%) evaluable DCIS samples.	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('c-met', 'Var', (134, 139))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('DCIS', 'Phenotype', 'HP:0030075', (215, 219))	('Sdc1', 'Gene', (100, 104))
68898	17244359	In this study we characterized coexpression of the functionally linked prognostic markers Sdc1, E-cad and c-met in 200 DCIS using TMA technology and in different human breast cancer cell lines.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('Sdc1', 'Gene', (90, 94))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', (168, 181))	('c-met', 'Var', (106, 111))	('human', 'Species', '9606', (162, 167))	('TMA', 'Chemical', '-', (130, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
68907	17244359	In addition, coordinated overexpression of c-met and the oncogene RON is observed in MBA-MB231 but not in MCF-7 cells.	('MCF-7', 'CellLine', 'CVCL:0031', (106, 111))	('RON', 'Gene', (66, 69))	('RON', 'Gene', '4486', (66, 69))	('MBA-MB231', 'Var', (85, 94))	('MBA-MB231', 'CellLine', 'CVCL:0062', (85, 94))	('c-met', 'Protein', (43, 48))	('overexpression', 'PosReg', (25, 39))
68924	17244359	Ribozyme targeting of c-met in mammary cancer cells reduced mammary cancer and tumour-associated angiogenesis in a xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Ribozyme', 'Var', (0, 8))	('cancer', 'Disease', (39, 45))	('reduced', 'NegReg', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('c-met', 'Gene', (22, 27))	('cancer', 'Disease', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
68939	17244359	In DCIS, coexpression of ET receptors, E-cad, c-met and Sdc1 may constitute a specific expression signature indicative of the transition of an early stage to later stages of tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('Sdc1', 'Gene', (56, 60))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('ET receptors', 'Protein', (25, 37))	('tumour', 'Disease', (174, 180))	('E-cad', 'Protein', (39, 44))	('c-met', 'Var', (46, 51))
68941	17244359	Inhibitors of tyrosine kinases, of the endothelin axis, of heparan sulphate-modulated signalling and of angiogenesis are currently being evaluated in clinical trials or have already found their way into cancer therapies.	('heparan sulphate-modulated signalling', 'MPA', (59, 96))	('heparan sulphate', 'Chemical', 'MESH:D006497', (59, 75))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('angiogenesis', 'CPA', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
69115	24867535	With a median follow-up time of five years, hypo-fractionated breast RT with concurrent boost results in a five year cumulative incidence rate of ipsilateral breast tumor recurrence of 0.82% (95%CI: 0.65-1.04).	('hypo-fractionated', 'Var', (44, 61))	('ipsilateral breast tumor', 'Disease', (146, 170))	('breast tumor', 'Phenotype', 'HP:0100013', (158, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ipsilateral breast tumor', 'Disease', 'MESH:D001943', (146, 170))
69117	24867535	Currently available evidence supports the equivalence of hypo-fractionated breast RT to standard fractionation breast RT in patients with T1-2N0 disease, and in patients who do not require treatment with chemotherapy.	('T1-2N0 disease', 'Disease', (138, 152))	('T1-2N0 disease', 'Disease', 'MESH:C538397', (138, 152))	('hypo-fractionated', 'Var', (57, 74))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (124, 132))
69128	17362521	Clinical implications and utility of field cancerization Cancer begins with multiple cumulative epigenetic and genetic alterations that sequencially transform a cell, or a group of cells in a particular organ.	('Cancer', 'Disease', (57, 63))	('epigenetic', 'Var', (96, 106))	('Cancer', 'Disease', 'MESH:D009369', (57, 63))	('genetic alterations', 'Var', (111, 130))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('transform', 'Reg', (149, 158))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
69142	17362521	In a more extensive histopathologic review of 783 oral cancer patients, Slaughter and colleagues then used the term field cancerization to describe the existence of generalized carcinogen induced early genetic changes in the epithelium from which multiple independent lesions occur, leading to the development of multifocal tumors.	('multifocal tumors', 'Disease', (313, 330))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('multifocal tumors', 'Disease', 'None', (313, 330))	('men', 'Species', '9606', (305, 308))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('oral cancer', 'Disease', 'MESH:D009062', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('changes', 'Var', (210, 217))	('patients', 'Species', '9606', (62, 70))	('oral cancer', 'Disease', (50, 61))	('cancer', 'Disease', (55, 61))
69148	17362521	Alternatively, does an early genetic event occur simultaneously in a group of cells such that subsequent genetic lesions drive some cells towards malignancy?	('drive', 'Reg', (121, 126))	('malignancy', 'Disease', (146, 156))	('genetic lesions', 'Var', (105, 120))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))
69149	17362521	Is it also plausible that some field changes are created during organogenesis when some altered cells proliferate to generate a vast area of preconditioned epithelial surface, such that subsequent genetic lesions in some cells result in multiple cancers?	('result in', 'Reg', (227, 236))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('multiple cancers', 'Disease', (237, 253))	('genetic lesions', 'Var', (197, 212))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('multiple cancers', 'Disease', 'MESH:D009369', (237, 253))
69158	17362521	Epigenetic gene silencing, chromosomal anomalies, LOH, DNA sequence analysis for SNP and mutation detection, altered gene expression (transcripts and proteins), and mitochondrial genome changes have all been demonstrated in both precancerous lesions and normal appearing cells close to tumors.	('chromosomal anomalies', 'Disease', (27, 48))	('changes', 'Reg', (186, 193))	('mitochondrial genome', 'CPA', (165, 185))	('precancerous lesions', 'Disease', 'MESH:D011230', (229, 249))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('precancerous lesions', 'Disease', (229, 249))	('Epigenetic gene', 'Var', (0, 15))	('tumors', 'Disease', (286, 292))	('mutation', 'Var', (89, 97))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('altered', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (27, 48))
69161	17362521	If well characterized, such early molecular alterations could have great value in risk assessment, early cancer detection, monitoring of disease progression, and chemoprevention.	('men', 'Species', '9606', (93, 96))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('alterations', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
69165	17362521	In addition, leakage of ROS into the nucleus can cause mutations in nuclear genes that could initiate the malignant process.	('initiate', 'Reg', (93, 101))	('mutations', 'Var', (55, 64))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('nuclear genes', 'Gene', (68, 81))	('ROS', 'Protein', (24, 27))	('cause', 'Reg', (49, 54))	('leakage', 'MPA', (13, 20))
69166	17362521	It is thus likely that the modest mtDNA molecule might sustain early genetic damage, and thus an even earlier biomarker indicative of field cancerization compared to nuclear genomic alterations that have been extensively studied.	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mtDNA', 'Var', (34, 39))	('genetic damage', 'Disease', 'MESH:D030342', (69, 83))	('genetic damage', 'Disease', (69, 83))
69177	17362521	Profiling of mucosa from 73 healthy individuals, 113 HNSCC, 99 tumor-distant, and 18 tumor-adjacent discovered that 72% of tumor-adjacent and 27.3% of tumor-distance samples harbored aberrant protein profiles indicative of field cancerization.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('tumor', 'Disease', (151, 156))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('aberrant', 'Var', (183, 191))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
69180	17362521	A role for geneomic alterations in stromal tissue in modulating the development of HNSCC was recently provided.	('HNSCC', 'Disease', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('men', 'Species', '9606', (75, 78))	('stroma', 'Disease', (35, 41))	('geneomic alterations', 'Var', (11, 31))	('stroma', 'Disease', 'None', (35, 41))	('modulating', 'Reg', (53, 63))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
69185	17362521	Notably, these mutations increased with increasing severity of dysplasia, suggesting acquired mitochondrial genome alterations might drive or indicate disease progression.	('drive', 'Reg', (133, 138))	('increased', 'PosReg', (25, 34))	('mitochondrial genome', 'Gene', (94, 114))	('dysplasia', 'Disease', 'MESH:D004476', (63, 72))	('mutations', 'Var', (15, 24))	('alterations', 'Var', (115, 126))	('indicate', 'Reg', (142, 150))	('dysplasia', 'Disease', (63, 72))
69191	17362521	Interestingly, precancerous lesions had higher levels of the deletion than cancerous tissue, and in both cases, the adjacent submucosal stroma harbored more deletions than the lesions.	('precancerous lesions', 'Disease', 'MESH:D011230', (15, 35))	('cancerous', 'Disease', (18, 27))	('cancerous', 'Disease', 'MESH:D009369', (75, 84))	('submucosal stroma', 'Disease', (125, 142))	('deletions', 'Var', (157, 166))	('deletion', 'Var', (61, 69))	('precancerous lesions', 'Disease', (15, 35))	('cancerous', 'Disease', 'MESH:D009369', (18, 27))	('submucosal stroma', 'Disease', 'MESH:C563509', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancerous', 'Disease', (75, 84))	('levels', 'MPA', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
69195	17362521	sampled tissues from the entire tracheobronchial tree of one individual who had 50-pack-years of smoking history without lung cancer, for p53 mutation analysis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('p53', 'Gene', (138, 141))	('p53', 'Gene', '7157', (138, 141))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('mutation analysis', 'Var', (142, 159))
69200	17362521	More recently, LOH, especially at chromosome 12p12 was demonstrated in normal bronchial epithelium of long-term smokers, and deletion hotspots at two chromosomal regions (2q35-q36, 12p12p13) were observed in non-small cell lung cancer (NSCLC) and matched normal bronchial epithelial cells.	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('cell lung cancer', 'Disease', (218, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (236, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('2q35-q36', 'Var', (171, 179))	('cell lung cancer', 'Disease', 'MESH:D008175', (218, 234))	('12p12p13', 'Var', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (208, 234))	('NSCLC', 'Disease', (236, 241))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (212, 234))	('deletion', 'Var', (125, 133))
69201	17362521	This suggests LOH could indicate susceptibility to or potential presence of cancer and may be a hallmark of progression of apparently phenotypically normal pre-neoplastic cells to cancer.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('LOH', 'Var', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (180, 186))
69205	17362521	Using p53 mutation as a clonal marker, Prevo et al.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('mutation', 'Var', (10, 18))
69211	17362521	Indeed, mutant p16 clones could expand to involve about 17 cm of the esophagus.	('p16', 'Gene', (15, 18))	('mutant', 'Var', (8, 14))	('p16', 'Gene', '1029', (15, 18))
69212	17362521	Epigenetic gene silencing of APC, CDH1, ESR1 and p16 has been studied in Barrett's esophagus.	('APC', 'Disease', 'MESH:D011125', (29, 32))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (73, 92))	('APC', 'Disease', (29, 32))	('CDH1', 'Gene', '999', (34, 38))	('ESR1', 'Gene', '2099', (40, 44))	('Barrett', 'Disease', (73, 80))	('p16', 'Gene', (49, 52))	('ESR1', 'Gene', (40, 44))	('Epigenetic gene silencing', 'Var', (0, 25))	('p16', 'Gene', '1029', (49, 52))	('CDH1', 'Gene', (34, 38))
69213	17362521	Hypermethylation in large contiguous fields were observed, further confirming molecular field cancerization in Barrett's metaplasia.	('Hypermethylation', 'Var', (0, 16))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (111, 131))	("Barrett's metaplasia", 'Disease', (111, 131))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
69214	17362521	In a prospective study where 267 patients were followed, it was demonstrated that clone sizes (which is an index of clones multiplied by the length of Barretts's segment they occupied) with p53 LOH and ploidy, were a better predictor of progression towards adenocarcinoma.	('men', 'Species', '9606', (165, 168))	('LOH', 'NegReg', (194, 197))	('ploidy', 'Var', (202, 208))	('patients', 'Species', '9606', (33, 41))	('p53', 'Gene', (190, 193))	('adenocarcinoma', 'Disease', (257, 271))	('p53', 'Gene', '7157', (190, 193))	('adenocarcinoma', 'Disease', 'MESH:D000230', (257, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	("Barretts's segment", 'Phenotype', 'HP:0100580', (151, 169))
69223	17362521	Epigenetic silencing via CpG island hypermethylation of LIMS1, a gene involved in cell dispersion has been demonstrated in 53% of gastric cancers.	('gastric cancers', 'Disease', (130, 145))	('gastric cancers', 'Phenotype', 'HP:0012126', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('Epigenetic silencing', 'Var', (0, 20))	('CpG island hypermethylation', 'Var', (25, 52))	('LIMS1', 'Gene', '3987', (56, 61))	('LIMS1', 'Gene', (56, 61))	('gastric cancers', 'Disease', 'MESH:D013274', (130, 145))
69224	17362521	Interestingly, LIMS1 methylation was observed in normal-appearing gastric tissue suggesting that this could be an early genetic event in the development of gastric neoplasia.	('LIMS1', 'Gene', (15, 20))	('gastric neoplasia', 'Disease', 'MESH:D009369', (156, 173))	('gastric neoplasia', 'Disease', (156, 173))	('men', 'Species', '9606', (148, 151))	('methylation', 'Var', (21, 32))	('gastric neoplasia', 'Phenotype', 'HP:0006753', (156, 173))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))	('LIMS1', 'Gene', '3987', (15, 20))
69230	17362521	In this well designed study, methylation in tumors was observed to be associated with methylation in normal adjacent mucosa, and normal appearing colorectal mucosa located 10 cm away from tumors were methylated in 10/13 tumors.	('methylation', 'Var', (29, 40))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', (188, 194))	('colorectal', 'Disease', (146, 156))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('methylation', 'MPA', (86, 97))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Disease', (220, 226))	('associated', 'Reg', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('colorectal', 'Disease', 'MESH:D015179', (146, 156))
69231	17362521	Normal mucosa located 1 cm from tumor margin was more likely to be hypermethylated than those 10 cm away.	('tumor', 'Disease', (32, 37))	('hypermethylated', 'Var', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))
69232	17362521	Epigenetic silencing of MGMT thus creates a preconditioned genetic field from which colorectal tumors develop.	('MGMT', 'Gene', '4255', (24, 28))	('colorectal tumors', 'Disease', (84, 101))	('colorectal tumors', 'Disease', 'MESH:D015179', (84, 101))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('MGMT', 'Gene', (24, 28))
69233	17362521	Indeed, epigenetic events are proving to be useful biomarkers of the molecular process leading to colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('epigenetic events', 'Var', (8, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
69241	17362521	Different skin neoplasms are associated with signature gene mutations and alterations in gene expression.	('neoplasms', 'Phenotype', 'HP:0002664', (15, 24))	('skin neoplasms', 'Disease', (10, 24))	('alterations', 'Reg', (74, 85))	('skin neoplasms', 'Phenotype', 'HP:0008069', (10, 24))	('neoplasm', 'Phenotype', 'HP:0002664', (15, 23))	('skin neoplasms', 'Disease', 'MESH:D012878', (10, 24))	('mutations', 'Var', (60, 69))
69242	17362521	Precursor lesions such as actinic keratosis (AK) is associated with p53 mutations (and moderately increased p16 expression); squamous cell carcinoma (SCC) is associated with p53 mutations, increased p16 expression, activation of the mitogenic ras pathway, reduced expression of FasR (CD95-R) and increased expression of FasL; and basal cell carcinoma (BCC) is associated with mutations in PTCH (from the sonic hedgehog pathway) and p53.	('p53', 'Gene', (432, 435))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (330, 350))	('p16', 'Gene', '1029', (108, 111))	('BCC', 'Phenotype', 'HP:0002671', (352, 355))	('AK', 'Phenotype', 'HP:0025127', (45, 47))	('expression', 'MPA', (264, 274))	('reduced', 'NegReg', (256, 263))	('p53', 'Gene', '7157', (174, 177))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))	('mitogenic ras pathway', 'Pathway', (233, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('mutations', 'Var', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (330, 350))	('FasL', 'Gene', (320, 324))	('actinic keratosis', 'Disease', 'MESH:D055623', (26, 43))	('FasL', 'Gene', '356', (320, 324))	('p53', 'Gene', (174, 177))	('PTCH', 'Gene', (389, 393))	('increased', 'PosReg', (296, 305))	('actinic keratosis', 'Phenotype', 'HP:0025127', (26, 43))	('basal cell carcinoma', 'Disease', (330, 350))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 148))	('activation', 'PosReg', (215, 225))	('actinic keratosis', 'Disease', (26, 43))	('p16', 'Gene', (199, 202))	('p53', 'Gene', '7157', (68, 71))	('p16', 'Gene', '1029', (199, 202))	('p53', 'Gene', '7157', (432, 435))	('mutations', 'Var', (376, 385))	('expression', 'MPA', (203, 213))	('squamous cell carcinoma', 'Disease', (125, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('expression', 'MPA', (306, 316))	('p53', 'Gene', (68, 71))	('p16', 'Gene', (108, 111))	('mutations', 'Var', (178, 187))	('PTCH', 'Gene', '5727', (389, 393))	('increased', 'PosReg', (189, 198))
69245	17362521	As described above, mutations in p53 are common in skin cancer and as such have been used as biomarkers of clonality in the skin.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('skin cancer', 'Disease', (51, 62))	('mutations', 'Var', (20, 29))	('skin cancer', 'Disease', 'MESH:D012878', (51, 62))	('common', 'Reg', (41, 47))
69246	17362521	In one study, p53 mutations were present in non-melanoma skin cancer (NMSC) as well as the normal appearing peri-lesional skin of 8 patients.	('non-melanoma skin cancer', 'Disease', (44, 68))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('skin cancer', 'Phenotype', 'HP:0008069', (57, 68))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (44, 68))	('present', 'Reg', (33, 40))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (18, 27))
69247	17362521	studied the clonal evolution and spread of p53 mutant keratinocytes arising from the dermal-epidermal junctions and hair follicles.	('p53', 'Gene', '7157', (43, 46))	('mutant', 'Var', (47, 53))	('p53', 'Gene', (43, 46))
69249	17362521	In a study of 69 tumors, p53 mutations were present in 54% of cases.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
69252	17362521	In NMSC, both tumors and the normal tissue adjacent to tumor (i.e., peri-lesional skin) contained homoplasmic UV-induced mtDNA mutations.	('contained', 'Reg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mtDNA', 'Gene', (121, 126))	('tumor', 'Disease', (14, 19))	('NMSC', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (14, 20))	('tumor', 'Disease', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
69254	17362521	This is important when one considers that the majority of studies involving nuclear DNA damage and skin cancer/skin disease often use peri-lesional skin as a control tissue.	('skin cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('nuclear', 'Var', (76, 83))	('skin cancer', 'Disease', 'MESH:D012878', (99, 110))	('skin disease', 'Phenotype', 'HP:0000951', (111, 123))	('skin disease', 'Disease', (111, 123))	('skin cancer', 'Phenotype', 'HP:0008069', (99, 110))	('skin disease', 'Disease', 'MESH:D012871', (111, 123))
69255	17362521	Whereas D310 abnormalities were infrequent in normal samples, they increased in frequency in dysplastic lesions and normal appearing tissue adjacent to a tumor.	('abnormalities', 'Var', (13, 26))	('dysplastic lesions', 'Disease', (93, 111))	('dysplastic lesions', 'Disease', 'MESH:D021782', (93, 111))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('increased', 'PosReg', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('D310 abnormalities', 'Var', (8, 26))	('tumor', 'Disease', (154, 159))
69257	17362521	Whole organ mapping of bladder cancer fields has been studied using a combination of LOH, p53 mutation and fluorescence in situ hybridization (FISH) analysis.	('p53', 'Gene', (90, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('p53', 'Gene', '7157', (90, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('mutation', 'Var', (94, 102))
69275	17362521	Epigenetic gene silencing in breast cancer has been studied.	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('Epigenetic gene silencing', 'Var', (0, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
69281	17362521	Genomic instability, gene expression studies and analysis of mitochondrial genome alterations have recently been reported to show field cancerization in prostate cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (162, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Genomic instability', 'Var', (0, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('alterations', 'Var', (82, 93))	('mitochondrial genome', 'Gene', (61, 81))	('prostate cancer', 'Disease', (153, 168))
69282	17362521	Methylation in GSTP1 and RARbeta2 was present in prostate cancer, adjacent stroma and adjacent normal glands close to tumor and were absent in normal epithelia from benign prostatic hyperplasia.	('prostatic hyperplasia', 'Disease', (172, 193))	('prostatic hyperplasia', 'Disease', 'MESH:D011470', (172, 193))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('stroma', 'Disease', 'None', (75, 81))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('Methylation', 'Var', (0, 11))	('GSTP1', 'Gene', '2950', (15, 20))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (165, 193))	('present', 'Reg', (38, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('RARbeta2', 'Gene', (25, 33))	('GSTP1', 'Gene', (15, 20))	('prostate cancer', 'Disease', (49, 64))	('stroma', 'Disease', (75, 81))
69289	17362521	In any particular individual, ERG, ETV1, and ETV4 were either over-expressed or not expressed in all samples, suggesting alteration in these genes could be early events in prostate cancer evolution.	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('ETV4', 'Gene', (45, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('over-expressed', 'PosReg', (62, 76))	('alteration', 'Var', (121, 131))	('ETV4', 'Gene', '2118', (45, 49))	('ETV1', 'Gene', (35, 39))	('ERG', 'Gene', '2078', (30, 33))	('prostate cancer', 'Disease', (172, 187))	('ETV1', 'Gene', '2115', (35, 39))	('ERG', 'Gene', (30, 33))
69295	17362521	Although not directly questioned, the concept of field cancerization is indicated in a number of mtDNA mutation studies of prostate cancers.	('cancer', 'Disease', (132, 138))	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('mtDNA', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('prostate cancers', 'Phenotype', 'HP:0012125', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancers', 'Disease', (123, 139))	('mutation', 'Var', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancer', 'Disease', (55, 61))	('prostate cancers', 'Disease', 'MESH:D011471', (123, 139))
69296	17362521	Mutations in the mitochondrial genome were present in a co-existing precursor lesion, PIN and matched tumor.	('PIN', 'Gene', '8655', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Mutations', 'Var', (0, 9))	('mitochondrial genome', 'Gene', (17, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('PIN', 'Gene', (86, 89))
69299	17362521	MtDNA mutation load in tumors and matched normal appearing glands were identical and these were significantly different from those obtained from age-matched control individuals without cancer.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutation', 'Var', (6, 14))	('different', 'Reg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MtDNA', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
69300	17362521	In a follow-up study, a single large scale mtDNA deletion associated with prostate cancer was observed to increase in frequency in normal appearing glands adjacent to a tumor.	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('prostate cancer', 'Disease', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mtDNA', 'Gene', (43, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('tumor', 'Disease', (169, 174))	('deletion', 'Var', (49, 57))	('increase', 'PosReg', (106, 114))
69304	17362521	Likely, distinct genetic alterations in a preconditioned epithelium may lead to BOTs and serous carcinomas independently.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('serous carcinomas', 'Disease', 'MESH:D018284', (89, 106))	('BOTs', 'Disease', (80, 84))	('serous carcinomas', 'Disease', (89, 106))	('lead to', 'Reg', (72, 79))	('genetic alterations', 'Var', (17, 36))
69307	17362521	High frequency of promoter methylation of CDKC2A and MGMT were found in both endometrial and ovarian carcinomas, suggesting the epigenetic silencing of these genes could be an early event in the development of these synchronous cancers.	('CDKC2A', 'Gene', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('men', 'Species', '9606', (202, 205))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (93, 110))	('synchronous cancers', 'Disease', (216, 235))	('promoter', 'MPA', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('endometrial and ovarian carcinomas', 'Disease', 'MESH:D016889', (77, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('epigenetic silencing', 'Var', (128, 148))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('MGMT', 'Gene', (53, 57))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (93, 111))	('MGMT', 'Gene', '4255', (53, 57))	('synchronous cancers', 'Disease', 'MESH:D009378', (216, 235))
69310	17362521	Mutations in K-ras are early important events in pancreatic ductal carcinoma and non-neoplastic pancreatic ductal lesions.	('non-neoplastic pancreatic ductal lesions', 'Disease', (81, 121))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (60, 76))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (49, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Mutations', 'Var', (0, 9))	('non-neoplastic pancreatic ductal lesions', 'Disease', 'MESH:D010190', (81, 121))	('K-ras', 'Gene', (13, 18))	('pancreatic ductal carcinoma', 'Disease', (49, 76))	('K-ras', 'Gene', '3845', (13, 18))
69312	17362521	Microdissected tumors and associated ductal hyperplastic tissue from 37 patients for K-ras mutation and X-chromosome inactivation analyses demonstrated distinct genomic abnormalities in hyperplasia as well as pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (209, 226))	('mutation', 'Var', (91, 99))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (209, 226))	('K-ras', 'Gene', (85, 90))	('genomic abnormalities in hyperplasia', 'Disease', (161, 197))	('K-ras', 'Gene', '3845', (85, 90))	('genomic abnormalities in hyperplasia', 'Disease', 'MESH:D006965', (161, 197))	('pancreatic cancer', 'Disease', (209, 226))	('tumors', 'Disease', (15, 21))	('patients', 'Species', '9606', (72, 80))
69313	17362521	This study concluded that polyclonal multicentric pancreatic cancers originate form epithelium with early genetic changes.	('pancreatic cancers', 'Disease', (50, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('pancreatic cancers', 'Disease', 'MESH:D010190', (50, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('polyclonal', 'Var', (26, 36))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
69314	17362521	In a study of microdissected samples from 20 intraductal papillary-mucinous tumors (IPMT) and 7 ductal adenocarcinoma, K-ras mutations were noted in 66.7% of peri-tumoral tissue and 62.5% of separate IPMT lesions, and at least one identical mutation was observed in the tumor and peritumoral tissue in all IPMT patients with those lesions.	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('papillary-mucinous tumors', 'Disease', 'MESH:D000077779', (57, 82))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('ductal adenocarcinoma', 'Disease', (96, 117))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('papillary-mucinous tumors', 'Disease', (57, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('K-ras', 'Gene', '3845', (119, 124))	('noted', 'Reg', (140, 145))	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('IPMT', 'Disease', (306, 310))	('tumor', 'Disease', (270, 275))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (96, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('patients', 'Species', '9606', (311, 319))	('K-ras', 'Gene', (119, 124))	('tumor', 'Disease', (284, 289))
69315	17362521	K-ras mutation as a marker of disease progression has been demonstrated.	('K-ras', 'Gene', '3845', (0, 5))	('mutation', 'Var', (6, 14))	('K-ras', 'Gene', (0, 5))
69316	17362521	Analysis of 46 different histologic grades of IPMT from 16 patients and 9 with ductal adenocarcinoma reveal an increased frequency of K-ras mutation from 16.7% in normal epithelium and papillary hyperplasia, to 57.1% in high grade dysplasia, carcinoma in situ and invasive cancer.	('papillary hyperplasia', 'Disease', 'MESH:D006965', (185, 206))	('carcinoma in situ', 'Disease', 'MESH:D002278', (242, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('dysplasia', 'Disease', (231, 240))	('ductal adenocarcinoma', 'Disease', (79, 100))	('carcinoma in situ', 'Disease', (242, 259))	('mutation', 'Var', (140, 148))	('dysplasia', 'Disease', 'MESH:D004476', (231, 240))	('invasive cancer', 'Disease', 'MESH:D009362', (264, 279))	('K-ras', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('patients', 'Species', '9606', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (242, 259))	('invasive cancer', 'Disease', (264, 279))	('K-ras', 'Gene', '3845', (134, 139))	('papillary hyperplasia', 'Disease', (185, 206))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (79, 100))
69320	17362521	Heteroplasmy is an early indicator of disease, and in oncology, this could probably be an indicator of field cancerization.	('oncology', 'Phenotype', 'HP:0002664', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('Heteroplasmy', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
69323	17362521	A heteroplasmic mtDNA mutation in MDS was observed to increase with disease evolution until the final stage of AML when the mutant copy became homoplasmic.	('AML', 'Disease', 'MESH:D015470', (111, 114))	('MDS', 'Phenotype', 'HP:0002863', (34, 37))	('mutation', 'Var', (22, 30))	('AML', 'Disease', (111, 114))	('increase', 'PosReg', (54, 62))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('MDS', 'Disease', (34, 37))	('MDS', 'Disease', 'MESH:D009190', (34, 37))
69324	17362521	This sequencing data was confirmed using restriction digest analysis by showing that the mtDNA mutation load positively correlated with progression from MDS to AML.	('AML', 'Disease', 'MESH:D015470', (160, 163))	('mutation load', 'Var', (95, 108))	('correlated with', 'Reg', (120, 135))	('AML', 'Disease', (160, 163))	('MDS', 'Disease', (153, 156))	('MDS', 'Disease', 'MESH:D009190', (153, 156))	('MDS', 'Phenotype', 'HP:0002863', (153, 156))	('AML', 'Phenotype', 'HP:0004808', (160, 163))	('mtDNA', 'Gene', (89, 94))
69327	17362521	Mutations in p53 were present in 20/24 cases, with chromosomal loses and allelic imbalances in several other tumor samples.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Mutations', 'Var', (0, 9))	('imbalance', 'Phenotype', 'HP:0002172', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('p53', 'Gene', (13, 16))	('present', 'Reg', (22, 29))	('p53', 'Gene', '7157', (13, 16))	('tumor', 'Disease', (109, 114))	('imbalances', 'Phenotype', 'HP:0002172', (81, 91))
69328	17362521	In a separate series, mtDNA was used as a clonal marker for GC, and consistent band losses were observed in all tumor samples from two individuals, one of who also had p53 mutations.	('mutations', 'Var', (172, 181))	('losses', 'NegReg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('p53', 'Gene', '7157', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (168, 171))
69335	17362521	Obviously this will lead to erroneous mutations being associated with the disease processes, since the adjacent normal tissue in a cancerization field may sustain somatic mtDNA mutations as well.	('cancer', 'Disease', (131, 137))	('erroneous mutations', 'Var', (28, 47))	('mutations', 'Var', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mtDNA', 'Gene', (171, 176))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (54, 64))
69344	17362521	Indeed, epigenetic gene silencing through promoter hypermethylation and transcriptional repression of several tumor-associated genes is an early event in several cancers including breast, prostate, colorectal, gastric, and ovarian cancers.	('transcriptional', 'MPA', (72, 87))	('cancers', 'Disease', (162, 169))	('promoter hypermethylation', 'Var', (42, 67))	('gastric', 'Disease', (210, 217))	('breast', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('epigenetic gene silencing', 'Var', (8, 33))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('colorectal', 'Disease', (198, 208))	('cancers', 'Disease', (231, 238))	('prostate', 'Disease', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ovarian cancers', 'Phenotype', 'HP:0100615', (223, 238))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('colorectal', 'Disease', 'MESH:D015179', (198, 208))	('ovarian cancer', 'Phenotype', 'HP:0100615', (223, 237))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('tumor', 'Disease', (110, 115))	('ovarian cancers', 'Disease', (223, 238))	('ovarian cancers', 'Disease', 'MESH:D010051', (223, 238))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
69347	17362521	For instance, genetic changes preceding breast cancer development might be detectable in nipple aspirate fluids.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('genetic changes', 'Var', (14, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('men', 'Species', '9606', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
69373	17362521	Comprehensive high-throughput analyses for the discovery of early and relevant genetic changes that extend across global networks and represent modular alterations of multiple targets (or surrogates) of terminal histologically differentiated stages of cancer subtypes will be essential for early detection, risk assessment and primary chemoprevention.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('genetic changes', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('men', 'Species', '9606', (318, 321))
69387	29279850	The model suggests a tumor is most likely to start with a mutated cell.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutated cell', 'Var', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
69402	29279850	Copy number variation is segment loss or duplication of genome sequence ranging from kilo bases (Kb) to mega bases (Mb) in size, which covers 360 Mb and encompasses hundreds of genes, disease loci, and functional elements.	('Copy number variation', 'Var', (0, 21))	('segment loss', 'Disease', (25, 37))	('segment loss', 'Disease', 'MESH:C537538', (25, 37))	('duplication', 'Var', (41, 52))
69403	29279850	CNVs affect gene expressions in human cell-lines, which also play a major role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('gene expressions', 'MPA', (12, 28))	('affect', 'Reg', (5, 11))	('human', 'Species', '9606', (32, 37))	('CNVs', 'Var', (0, 4))
69405	29279850	Some tumor progression analysis tools combine VAFs of SNVs and population frequencies of structure variations to reconstruct subclonal composition and tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('variations', 'Var', (99, 109))
69408	29279850	Li and Xie propose a software package called PyLOH to deconvolve the mixture of normal and tumor cells using copy number alterations and LOH information.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('copy number alterations', 'Var', (109, 132))
69411	29279850	obtain robust high-resolution copy number profiles by sequencing a single cell and infer about the evolution and spread of cancer by examining multiple cells from the same cancer with the Euclidean metric.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('copy', 'Var', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (172, 178))
69417	29279850	The cervical cancer dataset contains the copy number profiles of four genes, and breast cancer dataset is up to eight genes.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cervical cancer', 'Disease', (4, 19))	('cervical cancer', 'Disease', 'MESH:D002583', (4, 19))	('copy number', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
69422	29279850	Randomly select two different individuals Xp1,G, Xp2,G to produce the mutant individual Vi,G corresponding to individual Xi,G aswhere xp1,Gj - xp2,Gj is difference vector and scaling factor lambda is a positive control parameter of difference vector.	('Xp1', 'Gene', (42, 45))	('Gj - xp2', 'Var', (138, 146))	('xp1', 'Gene', (134, 137))	('Xp1', 'Gene', '7507', (42, 45))	('mutant', 'Var', (70, 76))	('xp1', 'Gene', '7507', (134, 137))
69426	29279850	For each individual Xi,G, randomly select two different individuals Xp1,G, Xp2,G to produce the mutant individual Vi,G as follows: For the jth candidate Steiner node, if individuals Xp1,G, Xp2,G have the same choice, the mutant individual yields xp1,Gj or xp2,Gj; otherwise it directly derives from Xi,G.	('xp1', 'Gene', '7507', (246, 249))	('Xp1', 'Gene', (68, 71))	('mutant', 'Var', (221, 227))	('xp1', 'Gene', (246, 249))	('Xp1', 'Gene', (182, 185))	('Xp1', 'Gene', '7507', (68, 71))	('Xp1', 'Gene', '7507', (182, 185))
69539	28103572	In our study, most patients with "mammographic calcifications" presented with the indicated malignant calcifications graded at least BI-RADS 4A on mammography, which were also pathologically validated before or after the PM.	('BI-RADS 4A', 'Var', (133, 143))	('patients', 'Species', '9606', (19, 27))	('presented', 'Reg', (63, 72))	('calcification', 'Disease', 'MESH:D002114', (102, 115))	('calcification', 'Disease', 'MESH:D002114', (47, 60))	('calcification', 'Disease', (102, 115))	('calcification', 'Disease', (47, 60))
69553	28143474	Instead, substantial numbers of women believe they are at considerable risk of a new contralateral primary, and CPM improves their likelihood of survival.	('improves', 'PosReg', (116, 124))	('CPM', 'Var', (112, 115))	('survival', 'CPA', (145, 153))	('women', 'Species', '9606', (32, 37))
69610	28143474	Further, they believe that CPM improves their long-term outcomes even though the medical evidence does not support this belief (except for women with BRCA mutations).	('women', 'Species', '9606', (139, 144))	('BRCA', 'Gene', (150, 154))	('CPM', 'Var', (27, 30))	('improves', 'PosReg', (31, 39))	('BRCA', 'Gene', '672', (150, 154))	('long-term', 'MPA', (46, 55))
69661	24207116	A mismatch between patients' desired and actual level of involvement in decision-making has been found to result in lower levels of satisfaction with the decision-making process and greater regret of treatment choice, particularly among Spanish-speaking Latinas.	('lower', 'NegReg', (116, 121))	('mismatch', 'Var', (2, 10))	('patients', 'Species', '9606', (19, 27))	('regret', 'CPA', (190, 196))
69740	23216981	Luminal A (ER positive (ER+) and/or PR positive (PR+), Her2 negative (Her2-)) with ki67<14%, luminal B (ER + and/or PR+ with ki67>14%, Her2 positive or negative (Her2+/-), Her2+/ER - subtype (Her2+, ER-, PR-) and basal-like (ER-, PR-, Her2-, Cytokeratin 5/6 positive (CK5/6+) and/or Her1+ (EGFR)).	('Her1', 'Gene', '1956', (283, 287))	('Her2', 'Gene', '2064', (135, 139))	('ER', 'Gene', '2099', (104, 106))	('ki67', 'Var', (125, 129))	('Her2', 'Gene', (55, 59))	('Her2', 'Gene', (135, 139))	('ER', 'Gene', '2099', (24, 26))	('ki67', 'Var', (83, 87))	('Her2', 'Gene', '2064', (70, 74))	('CK5/6+', 'Gene', (268, 274))	('EGFR', 'Gene', '1956', (290, 294))	('Her2', 'Gene', '2064', (235, 239))	('Cytokeratin 5', 'Gene', (242, 255))	('Her2', 'Gene', (70, 74))	('Her2', 'Gene', '2064', (172, 176))	('Her2', 'Gene', '2064', (162, 166))	('Cytokeratin 5', 'Gene', '3852', (242, 255))	('Her2', 'Gene', (235, 239))	('Her1', 'Gene', (283, 287))	('CK5/6+)', 'Gene', '3852', (268, 275))	('Her2', 'Gene', '2064', (192, 196))	('Her2', 'Gene', (172, 176))	('Her2', 'Gene', (162, 166))	('ER', 'Gene', '2099', (178, 180))	('ER', 'Gene', '2099', (11, 13))	('Her2', 'Gene', (192, 196))	('ER', 'Gene', '2099', (225, 227))	('EGFR', 'Gene', (290, 294))	('ER', 'Gene', '2099', (199, 201))	('Her2', 'Gene', '2064', (55, 59))
69754	23216981	Immunohistochemical surrogate biomarkers of molecular classification Immunohistochemical subtypes were defined as follows: Luminal A (ER + and/or PR+, Her2-, KI67<14%), luminal B (ER + and/or PR+, Her2+/-, Ki67>14%), basal-like (ER-, PR-, Her2-, and CK5/6+, CK14+), Her2+/ER-, and unclassified subtype (negative for all markers) (Table 1).	('ER', 'Gene', '2099', (272, 274))	('Her2', 'Gene', (266, 270))	('Her2', 'Gene', (197, 201))	('Her2', 'Gene', (239, 243))	('Her2', 'Gene', '2064', (266, 270))	('Ki67>', 'Var', (206, 211))	('ER', 'Gene', '2099', (180, 182))	('CK5/6+', 'Gene', (250, 256))	('Her2', 'Gene', (151, 155))	('Her2', 'Gene', '2064', (197, 201))	('Her2', 'Gene', '2064', (239, 243))	('CK14', 'Gene', '3861', (258, 262))	('ER', 'Gene', '2099', (134, 136))	('ER', 'Gene', '2099', (229, 231))	('CK5/6+', 'Gene', '3852', (250, 256))	('Her2', 'Gene', '2064', (151, 155))	('CK14', 'Gene', (258, 262))
69786	23216981	Arvydas and al reported a series of tissue microarrays of 109 patients with breast ductal carcinoma, were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1alpha, SATB1, p53, and p16).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('SATB1', 'Gene', (185, 190))	('HIF-1alpha', 'Gene', (173, 183))	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (76, 99))	('ER', 'Gene', '2099', (152, 154))	('p16', 'Gene', (201, 204))	('p53', 'Gene', (192, 195))	('patients', 'Species', '9606', (62, 70))	('HER2', 'Gene', '2064', (151, 155))	('ER', 'Gene', '2099', (143, 145))	('SATB1', 'Gene', '6304', (185, 190))	('p16', 'Gene', '1029', (201, 204))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (76, 99))	('BCL2', 'Gene', '596', (167, 171))	('breast ductal carcinoma', 'Disease', (76, 99))	('Ki67', 'Var', (157, 161))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (83, 99))	('HER2', 'Gene', (151, 155))	('HIF-1alpha', 'Gene', '3091', (173, 183))	('BCL2', 'Gene', (167, 171))	('p53', 'Gene', '7157', (192, 195))
30792	23216981	In HR-positive tumours, the aggressiveness of the tumour is best reflected by the combination of Ki67 and ER, rather than Ki67 and BCL2.	('ER', 'Gene', '2099', (106, 108))	('aggressiveness of the tumour', 'Disease', (28, 56))	('BCL2', 'Gene', '596', (131, 135))	('aggressiveness of the tumour', 'Disease', 'MESH:D001523', (28, 56))	('HR-positive tumours', 'Disease', (3, 22))	('HR-positive tumours', 'Disease', 'MESH:D009369', (3, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (28, 42))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('Ki67', 'Var', (97, 101))	('BCL2', 'Gene', (131, 135))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
69801	23216981	Overexpression of the protein and/or amplification of the HER2 gene have been reported in approximately 20 to 30% of breast cancers, similar to what was found in our patients (24,7%).	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancers', 'Disease', (117, 131))	('amplification', 'Var', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('protein', 'Protein', (22, 29))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('HER2', 'Gene', (58, 62))	('patients', 'Species', '9606', (166, 174))	('HER2', 'Gene', '2064', (58, 62))
69810	23216981	EGFR gene mutations are infrequent in breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (38, 52))	('EGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancers', 'Disease', 'MESH:D001943', (38, 52))	('breast cancers', 'Disease', (38, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', '1956', (0, 4))
69811	23216981	This suggested that EGFR mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy for breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('EGFR', 'Gene', (20, 24))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('breast cancers', 'Disease', (118, 132))	('EGFR', 'Gene', '1956', (20, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
69821	23216981	In the patients with LIN 3 (equivalent to LCIS), the frequency of association with IDC and ILC was 23% and 86%, respectively.	('LIN', 'Var', (21, 24))	('IDC', 'Disease', (83, 86))	('association', 'Interaction', (66, 77))	('ILC', 'Disease', (91, 94))	('patients', 'Species', '9606', (7, 15))
69830	23216981	Otherwise, Smac immunoscore was prevalent in HER2 positive group than negative group (P < 0.0001).	('positive', 'Var', (50, 58))	('prevalent', 'Reg', (32, 41))	('Smac', 'Gene', '56616', (11, 15))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))	('Smac', 'Gene', (11, 15))
69882	16234825	The 5-year LR-free survival in patients treated with BCS, was 91% in patients who had been treated according to the guidelines and 73% in patients who had not been treated so (log rank 4.77, P=0.029; Figure 1B).	('LR-free survival', 'CPA', (11, 27))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (69, 77))	('BCS', 'Var', (53, 56))	('patients', 'Species', '9606', (138, 146))
69898	16234825	Deviation from the guidelines automatically results in under- or overtreatment of patients.	('overtreatment', 'PosReg', (65, 78))	('Deviation', 'Var', (0, 9))	('under-', 'NegReg', (55, 61))	('patients', 'Species', '9606', (82, 90))
69914	31980967	A Cox proportional-hazards model was used to estimate the effect of age group, including adjustment for tumor subtype [hormone receptor [HR]+/HER2-, HER2+, triple-negative (TN)].	('HER2', 'Gene', (142, 146))	('hormone receptor', 'Gene', (119, 135))	('HER2', 'Gene', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('HER2', 'Gene', '2064', (142, 146))	('HER2', 'Gene', '2064', (149, 153))	('tumor', 'Disease', (104, 109))	('triple-negative', 'Var', (156, 171))	('hormone receptor', 'Gene', '3164', (119, 135))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
69933	31980967	Patients were categorized as DCIS if their ICD-O-3 behavior code was two (meaning 'in situ') and they were pT0/IS, pN0, and pM0/X if pathologic data were available, or cT0/IS, cN0, and cM0 if pathologic data were not available.	('pT0/IS', 'Var', (107, 113))	('pN0', 'Var', (115, 118))	('Patients', 'Species', '9606', (0, 8))	('cT0/IS', 'Var', (168, 174))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))
69935	31980967	Invasive patients with pM1 or cM1 were categorized as metastatic, and all other invasive patients were categorized as invasive non-metastatic.	('pM1', 'Var', (23, 26))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (89, 97))	('cM1', 'Var', (30, 33))
69974	31980967	compared genomic aberrations among 780 young and elderly breast cancer patients in The Cancer Genome Atlas dataset; older patients had more somatic mutations and copy number variations, while younger patients had higher expression of gene signatures related to proliferation, stem cell features, and endocrine resistance.	('breast cancer', 'Disease', (57, 70))	('copy number variations', 'Var', (162, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('patients', 'Species', '9606', (200, 208))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (71, 79))	('expression', 'MPA', (220, 230))	('higher', 'PosReg', (213, 219))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Disease', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
69988	31980967	found that the breast cancer-specific mortality was greater in young women (age <= 35 years) with DCIS when compared to older women, suggesting that death in the elderly is likely related to causes other than breast cancer.	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('DCIS', 'Var', (98, 102))	('mortality', 'Disease', 'MESH:D003643', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (209, 222))	('greater', 'PosReg', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('women', 'Species', '9606', (126, 131))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('mortality', 'Disease', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('women', 'Species', '9606', (69, 74))	('death', 'Disease', 'MESH:D003643', (149, 154))	('death', 'Disease', (149, 154))
70069	15226768	Group I (n=20) consisted of non-high-grade DCIS without comedo-type necrosis, group II (n=16) of non-high-grade DCIS with comedo-type necrosis and group III (n=24) of high-grade DCIS, irrespective of comedo-type necrosis.	('non-high-grade', 'Var', (97, 111))	('comedo', 'Phenotype', 'HP:0025249', (200, 206))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('necrosis', 'Disease', 'MESH:D009336', (68, 76))	('necrosis', 'Disease', 'MESH:D009336', (212, 220))	('necrosis', 'Disease', 'MESH:D009336', (134, 142))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('comedo', 'Phenotype', 'HP:0025249', (122, 128))	('necrosis', 'Disease', (212, 220))	('necrosis', 'Disease', (134, 142))	('necrosis', 'Disease', (68, 76))	('comedo', 'Phenotype', 'HP:0025249', (56, 62))
70078	15226768	In each case negative controls were performed by substituting nonimmune antibodies (IgG) for mAb #3936, pAb HU277 and mAb IID7, respectively.	('mAb #3936', 'Var', (93, 102))	('pAb HU277', 'Var', (104, 113))	('pAb', 'Chemical', '-', (104, 107))	('HU277', 'Chemical', '-', (108, 113))
70101	15226768	With no exception, MEs, tumour cells, macrophages, fibroblasts and endothelial cells showed a positive reaction with the antisense probe (Figure 2G and H).	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('MEs', 'Chemical', 'MESH:C004550', (19, 22))	('antisense', 'Var', (121, 130))
70105	15226768	In 56 of the cases (18 grade 1; 14 grade 2; 24 grade 3) MEs were stained by mAb IID7, 41 of those specimens (15 grade 1; 12 grade 2; 14 grade 3) reacted with pAb HU277 and 39 of those (14 grade 1; 11 grade 2; 14 grade 3) showed immunoreactivity of MEs with mAb #3936 (Figures 1A, B and 2C, D).	('pAb HU277', 'Var', (158, 167))	('mAb', 'Gene', (76, 79))	('MEs', 'Chemical', 'MESH:C004550', (248, 251))	('reacted', 'Reg', (145, 152))	('HU277', 'Chemical', '-', (162, 167))	('MEs', 'Chemical', 'MESH:C004550', (56, 59))	('pAb', 'Chemical', '-', (158, 161))
70112	15226768	In 10 of the tissue sections, normal epithelial cells stained with mAb IID7 (Figure 1D), and in seven cases, epithelial cells showed a positive immunoreaction using pAb HU277.	('pAb', 'Chemical', '-', (165, 168))	('mAb IID7', 'Var', (67, 75))	('pAb HU277', 'Var', (165, 174))	('HU277', 'Chemical', '-', (169, 174))
70113	15226768	Endothelial cells of normal breast tissue stained with mAb IID7 (7 specimens) and pAb HU277 (4 specimens).	('mAb', 'Gene', (55, 58))	('pAb HU277', 'Var', (82, 91))	('pAb', 'Chemical', '-', (82, 85))	('HU277', 'Chemical', '-', (86, 91))
70165	33488713	In this study, the percentage of patients detected on screening, diagnosed at <=50 years of age, with tumor size <=2.0 cm, and with low-intermediate grade was 39.4%, 56.7%, 72.6%, and 77.4%, respectively, as compared to 50-80%, 20-30%, 70-90%, and 40-60% in published reports from western countries.	('age', 'Gene', (92, 95))	('<=2.0', 'Var', (113, 118))	('age', 'Gene', '5973', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('age', 'Gene', '5973', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('age', 'Gene', (26, 29))
70185	33080708	HER2 amplification was detected in focal regions of the atypical intraductal component by fluorescence in situ hybridization (FISH), which resulted in a diagnosis of AME with ductal carcinoma in situ.	('AME', 'Disease', (166, 169))	('amplification', 'Var', (5, 18))	('ductal carcinoma', 'Disease', 'MESH:D044584', (175, 191))	('ductal carcinoma', 'Disease', (175, 191))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (175, 199))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))
70193	33080708	In this case, human epidermal growth factor receptor 2 fluorescence in situ hybridization (HER2 FISH) demonstrated amplification of the HER2 gene in the atypical ductal component, which resulted in a diagnosis of AME with ductal carcinoma in situ (DCIS).	('epidermal growth factor receptor 2', 'Gene', '2064', (20, 54))	('ductal carcinoma', 'Disease', 'MESH:D044584', (222, 238))	('amplification', 'Var', (115, 128))	('ductal carcinoma', 'Disease', (222, 238))	('epidermal growth factor receptor 2', 'Gene', (20, 54))	('human', 'Species', '9606', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (222, 246))	('DCIS', 'Phenotype', 'HP:0030075', (248, 252))	('AME', 'Disease', (213, 216))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', (136, 140))	('HER2', 'Gene', '2064', (91, 95))	('HER2', 'Gene', '2064', (136, 140))	('resulted in', 'Reg', (186, 197))
70234	33080708	ER-positive AME exhibited phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) or RAC-alpha serine/threonine-protein kinase (AKT1)-activating mutations, whereas ER-negative AME expressed recurrent GTPase HRas (HRAS) mutations, which co-occurred with PIK3CA or phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1) mutations.	('HRAS', 'Gene', (238, 242))	('PIK3CA', 'Gene', '5290', (278, 284))	('PIK3CA', 'Gene', (99, 105))	('ER', 'Gene', '2099', (0, 2))	('RAC-alpha serine/threonine-protein kinase', 'Gene', (110, 151))	('phosphatidylinositol 3-kinase regulatory subunit alpha', 'Gene', '5295', (288, 342))	('GTPase HRas', 'Gene', '3265', (225, 236))	('PIK3R1', 'Gene', (344, 350))	('mutations', 'Var', (244, 253))	('ER', 'Gene', '2099', (189, 191))	('GTPase HRas', 'Gene', (225, 236))	('RAC-alpha serine/threonine-protein kinase', 'Gene', '207', (110, 151))	('PIK3CA', 'Gene', (278, 284))	('AKT1', 'Gene', '207', (153, 157))	('phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha', 'Gene', '5290', (26, 97))	('mutations', 'Var', (170, 179))	('PIK3CA', 'Gene', '5290', (99, 105))	('HRAS', 'Gene', '3265', (238, 242))	('PIK3R1', 'Gene', '5295', (344, 350))	('AKT1', 'Gene', (153, 157))
70236	33080708	AMEs and their respective carcinomatous or metastatic components displayed HRAS Q61 hot-spot mutations, PIK3CA mutations, PIK3R1 mutations, and cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletions, whereas telomerase reverse transcriptase (TERT) promoter mutations might constitute early or late events in the development and/or progression of AME.	('telomerase reverse transcriptase', 'Gene', '7015', (220, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (144, 180))	('PIK3CA', 'Gene', '5290', (104, 110))	('AME', 'Disease', (358, 361))	('PIK3R1', 'Gene', (122, 128))	('mutations', 'Var', (111, 120))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (144, 180))	('HRAS', 'Gene', '3265', (75, 79))	('HRAS', 'Gene', (75, 79))	('mutations', 'Var', (93, 102))	('PIK3CA', 'Gene', (104, 110))	('CDKN2A', 'Gene', (182, 188))	('PIK3R1', 'Gene', '5295', (122, 128))	('telomerase reverse transcriptase', 'Gene', (220, 252))	('carcinomatous', 'Disease', (26, 39))	('mutations', 'Var', (129, 138))	('TERT', 'Gene', (254, 258))	('TERT', 'Gene', '7015', (254, 258))	('CDKN2A', 'Gene', '1029', (182, 188))	('carcinomatous', 'Disease', 'MESH:D055756', (26, 39))
70288	31276247	For example, in one study, triple-negative breast cancers demonstrated increased heterogeneity at peak contrast enhancement (a static texture feature), but also increased homogeneity over time (a textural kinetic feature), when compared with other lesion types.	('breast cancers', 'Disease', 'MESH:D001943', (43, 57))	('breast cancers', 'Disease', (43, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('heterogeneity', 'MPA', (81, 94))	('homogeneity', 'MPA', (171, 182))	('peak contrast enhancement', 'MPA', (98, 123))	('triple-negative', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('increased', 'PosReg', (71, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (43, 57))	('increased', 'PosReg', (161, 170))
70312	31276247	For example, nuclear grade is an important clinical factor, as high nuclear grade DCIS has a different prognosis than low and intermediate nuclear grade DCIS, and is more likely to progress to invasive cancer.	('invasive cancer', 'Disease', 'MESH:D009362', (193, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('high nuclear grade', 'Var', (63, 81))	('progress', 'PosReg', (181, 189))	('invasive cancer', 'Disease', (193, 208))
70323	31276247	Radiomics features from DCE-MRI have been used to demonstrate that tumors with high Ki-67 expression are larger and more homogeneous than those with low expression, and to demonstrate that imaging features of intratumoral subregions are more predictive than whole-tumor features.	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('homogeneous', 'MPA', (121, 132))	('high', 'Var', (79, 83))	('tumor', 'Disease', (67, 72))	('DCE', 'Gene', '1718', (24, 27))	('tumoral', 'Disease', (214, 221))	('tumor', 'Disease', (264, 269))	('tumoral', 'Disease', 'MESH:D009369', (214, 221))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('expression', 'Var', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Ki-67', 'Gene', (84, 89))	('tumor', 'Disease', (214, 219))	('tumors', 'Disease', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('DCE', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('more', 'PosReg', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
70324	31276247	A study showing that a classifier based on T2-MR features was better able to predict Ki-67 status, compared than one with DCE-MR features, suggesting that additional work needs to be done regarding which MR sequences would result in best feature selection.	('DCE', 'Gene', '1718', (122, 125))	('DCE', 'Gene', (122, 125))	('Ki-67', 'Var', (85, 90))
70354	31276247	Fan et al found that fusing intratumoral and peritumoral characteristics increased prediction accuracy.	('fusing', 'Var', (21, 27))	('increased', 'PosReg', (73, 82))	('tumoral', 'Disease', (33, 40))	('tumoral', 'Disease', 'MESH:D009369', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumoral', 'Disease', (49, 56))	('tumoral', 'Disease', 'MESH:D009369', (49, 56))	('prediction', 'MPA', (83, 93))
70410	30390667	Furthermore, most of the lesions upgraded from radial scar are ductal carcinoma in situ (DCIS) or low grade ductal or tubular type.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (63, 87))	('ductal carcinoma in situ', 'Disease', (63, 87))	('scar', 'Phenotype', 'HP:0100699', (54, 58))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (63, 87))	('low grade', 'Var', (98, 107))
70412	30390667	reported an upgrade rate to invasive carcinoma of less than 1% at surgical excision of radial scar, with or without associated high risk lesions, and also revealed that the radiologic appearances of a mass or architectural distortion on mammography or ultrasound (US) are more likely to be upgraded than calcifications.	('invasive carcinoma', 'Disease', (28, 46))	('mass', 'Disease', (201, 205))	('calcification', 'Disease', 'MESH:D002114', (304, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('scar', 'Phenotype', 'HP:0100699', (94, 98))	('invasive carcinoma', 'Disease', 'MESH:D009361', (28, 46))	('calcification', 'Disease', (304, 317))	('architectural distortion', 'Var', (209, 233))
70462	27122132	The hormone receptor negativity was strong independent predictive factors for IBTR in both DCIS and invasive breast cancer.	('hormone receptor', 'Gene', (4, 20))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('IBTR', 'Disease', (78, 82))	('hormone receptor', 'Gene', '3164', (4, 20))	('invasive breast cancer', 'Disease', (100, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('negativity', 'Var', (21, 31))	('IBTR', 'Chemical', '-', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('invasive breast cancer', 'Disease', 'MESH:D001943', (100, 122))	('DCIS', 'Disease', (91, 95))
70465	27122132	The hormone receptor negativity was revealed as independent predictive factor for IBTR after BCS in both DCIS and invasive cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hormone receptor', 'Gene', (4, 20))	('hormone receptor', 'Gene', '3164', (4, 20))	('IBTR', 'Chemical', '-', (82, 86))	('DCIS', 'Disease', (105, 109))	('negativity', 'Var', (21, 31))	('invasive cancer', 'Disease', (114, 129))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('invasive cancer', 'Disease', 'MESH:D009362', (114, 129))
70473	27122132	Positive margin status, human epidermal growth factor receptor 2 (HER-2) positivity, young age, in situ lesions around the tumor, triple-negative subtype, and lymphovascular invasion (LVI) of tumors are known as predictive factors for the development of IBTR after BCS.	('tumors', 'Disease', (192, 198))	('lymphovascular invasion', 'CPA', (159, 182))	('tumor', 'Disease', (123, 128))	('human', 'Species', '9606', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (192, 197))	('situ lesions', 'Disease', (99, 111))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('IBTR', 'Disease', (254, 258))	('HER-2', 'Gene', '2064', (66, 71))	('IBTR', 'Chemical', '-', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('HER-2', 'Gene', (66, 71))	('epidermal growth factor receptor 2', 'Gene', '2064', (30, 64))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('situ lesions', 'Disease', 'MESH:D002278', (99, 111))	('positivity', 'Var', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('epidermal growth factor receptor 2', 'Gene', (30, 64))
70483	27122132	Clinicopathologic features of the recurrent tumor including LVI, high-grade histology, high Ki-67 index, close/positive margins, and estrogen receptor (ER) negativity are predictive factors for poor OS after IBTR.	('negativity', 'Var', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('LVI', 'Disease', (60, 63))	('ER', 'Gene', '2099', (152, 154))	('IBTR', 'Chemical', '-', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('estrogen receptor', 'Gene', (133, 150))	('estrogen receptor', 'Gene', '2099', (133, 150))	('poor OS', 'Disease', (194, 201))	('tumor', 'Disease', (44, 49))
70528	27122132	By univariate analysis, positive resection margin status and ER and PR negativity were associated with IBTR in DCIS patients.	('IBTR', 'Chemical', '-', (103, 107))	('negativity', 'Var', (71, 81))	('patients', 'Species', '9606', (116, 124))	('DCIS', 'Disease', (111, 115))	('ER', 'Gene', '2099', (61, 63))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('PR', 'Gene', '5241', (68, 70))	('IBTR', 'Disease', (103, 107))
70542	27122132	And, the 5-year distant metastasis-free survival of patients with IBTR was inferior to those without (63.3 vs. 96.5 %).	('distant metastasis-free survival', 'CPA', (16, 48))	('IBTR', 'Chemical', '-', (66, 70))	('inferior', 'NegReg', (75, 83))	('IBTR', 'Var', (66, 70))	('patients', 'Species', '9606', (52, 60))
70544	27122132	LN positivity, advanced stage, and experience of IBTR were associated with poor OS and distant metastasis on univariate analysis.	('poor', 'Disease', (75, 79))	('distant metastasis', 'CPA', (87, 105))	('LN positivity', 'Var', (0, 13))	('IBTR', 'Chemical', '-', (49, 53))
70559	27122132	Although we had a small study population, multiplicity, young age, and extensive intraductal component (EIC), LVI, and HER-2 positivity showed little or no clinical significance as predictive factors for IBTR in this study.	('IBTR', 'Disease', (204, 208))	('positivity', 'Var', (125, 135))	('IBTR', 'Chemical', '-', (204, 208))	('HER-2', 'Gene', '2064', (119, 124))	('HER-2', 'Gene', (119, 124))
70571	27122132	Despite our small study population and the small number of events, these results are consistent with the findings of NSABP B-06, which showed that patients treated with radiation remained with low IBTR as compared to those receiving no radiation through 9 years of follow-up, regardless of age, nodal status, and tumor size.	('tumor', 'Disease', (313, 318))	('patients', 'Species', '9606', (147, 155))	('IBTR', 'Chemical', '-', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('IBTR', 'MPA', (197, 201))	('radiation', 'Var', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
70593	27122132	In addition, clinicopathologic features of the recurrent tumor including LVI, high-grade histology, high Ki-67 index, close/positive margins, and ER negativity are known as predictive factors of poor OS after IBTR.	('poor OS', 'Disease', (195, 202))	('LVI', 'Disease', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('high', 'Var', (100, 104))	('ER', 'Gene', '2099', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Ki-67 index', 'Protein', (105, 116))	('high-grade', 'Var', (78, 88))	('tumor', 'Disease', (57, 62))	('IBTR', 'Chemical', '-', (209, 213))
70609	23704974	Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells.	('consequences', 'Reg', (211, 223))	('impacts', 'Reg', (22, 29))	('tumor', 'Disease', (137, 142))	('integrity', 'MPA', (34, 43))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('damage', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
70617	23704974	Firstly, the long and highly variable timespan over which oncogenic mutations accumulate to result in cancer makes longitudinal study of transformation nearly impossible.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('result in', 'Reg', (92, 101))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (68, 77))
70625	23704974	a mutation inactivating a tumor suppressor).	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutation inactivating', 'Var', (2, 23))
70644	23704974	It has also been demonstrated as a tumor suppressor, whose disruption is considered an early event in breast oncogenesis.	('breast', 'Disease', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('disruption', 'Var', (59, 69))
70645	23704974	Interestingly, the vast majority of mutations that result in ER+ tumors in human models produce ER- tumors in mouse models; this is not true of RUNX3 +/- mice, which spontaneously develop ER+ mammary tumors.	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ER+', 'Gene', (61, 64))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (100, 106))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (65, 71))	('mouse', 'Species', '10090', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (200, 206))	('ER-', 'Disease', (96, 99))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
70662	23704974	Known genetic predispositions for developing breast cancer, notably the effect of the TP53 and BRCA1 mutations, primarily affects the pre-menopausal population.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRCA1', 'Gene', (95, 100))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (86, 90))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('TP53', 'Gene', (86, 90))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('BRCA1', 'Gene', '672', (95, 100))
70664	23704974	Simulations were run in both the wild-type condition and a selected set of known oncogenic mutations: TP53, Myc and BRCA1, where single copies of each of these genes were altered at the initiation of each simulation run (n-individual simulations = 500 in each group, with N-groups = 3).	('BRCA1', 'Gene', (116, 121))	('TP53', 'Gene', (102, 106))	('Myc', 'Gene', '4609', (108, 111))	('mutations', 'Var', (91, 100))	('Myc', 'Gene', (108, 111))	('BRCA1', 'Gene', '672', (116, 121))	('TP53', 'Gene', '7157', (102, 106))	('altered', 'Reg', (171, 178))
70682	23704974	Specifically, the generation of cancer in the DEABM required mutated cells to divide, and in the DEABM, given its rules at that stage of development, ER+ cells could not divide.	('DEABM', 'Chemical', '-', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('DEABM', 'Chemical', '-', (46, 51))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutated', 'Var', (61, 68))
70696	23704974	Similarly, the hyper-activity of the proto-oncogene Myc resulted in over 2-fold increase in cumulative risk to 8.6 (range 6.4 to 10.8)% under the same conditions (Figure 6).	('increase', 'PosReg', (80, 88))	('hyper-activity', 'Var', (15, 29))	('Myc', 'Gene', '4609', (52, 55))	('Myc', 'Gene', (52, 55))	('cumulative', 'MPA', (92, 102))
70698	23704974	Because women with a germline mutation in BRCA1 have such a drastically increased incidence in breast cancer risk, this mutation afforded the opportunity to examine how the DEABM would perform in reproducing cumulative risk of breast cancer over time.	('BRCA1', 'Gene', '672', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('women', 'Species', '9606', (8, 13))	('DEABM', 'Chemical', '-', (173, 178))	('BRCA1', 'Gene', (42, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('breast cancer', 'Disease', (227, 240))	('germline mutation', 'Var', (21, 38))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
70699	23704974	As such, a single germline copy of BRCA1 was disabled in the DEABM to simulate a familial germline BRCA1 mutation.	('mutation', 'Var', (105, 113))	('BRCA1', 'Gene', (99, 104))	('BRCA1', 'Gene', '672', (35, 40))	('DEABM', 'Chemical', '-', (61, 66))	('BRCA1', 'Gene', (35, 40))	('BRCA1', 'Gene', '672', (99, 104))
70701	23704974	In addition, the longitudinal cumulative incidence over time predicted by the DEABM was comparable to previously assessed risk in populations with germline BRCA1 mutation (Figure 7B), demonstrating the ability of the DEABM to plausibly reproduce the incidences of invasive breast cancer in both wild-type/sporadic and BRCA1 mutant populations.	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('invasive breast cancer', 'Disease', (264, 286))	('mutant', 'Var', (324, 330))	('DEABM', 'Chemical', '-', (78, 83))	('BRCA1', 'Gene', '672', (156, 161))	('BRCA1', 'Gene', '672', (318, 323))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('invasive breast cancer', 'Disease', 'MESH:D001943', (264, 286))	('mutation', 'Var', (162, 170))	('DEABM', 'Chemical', '-', (217, 222))	('BRCA1', 'Gene', (156, 161))	('BRCA1', 'Gene', (318, 323))
70702	23704974	Additionally, in terms of recapitulating ER status in these simulated populations, ~65% (range 59-71%) of the simulated breast cancers in the wild-type/sporadic population were ER+ (Figure 8A).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancers', 'Disease', 'MESH:D001943', (120, 134))	('breast cancers', 'Disease', (120, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('ER+', 'Var', (177, 180))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('breast cancers', 'Phenotype', 'HP:0003002', (120, 134))
70703	23704974	In comparison, a survey of the literature suggests that ~68% (range 60-77%) of premenopausal breast tumors are ER+.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('breast tumors', 'Disease', (93, 106))	('ER+', 'Var', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast tumors', 'Phenotype', 'HP:0100013', (93, 106))	('breast tumor', 'Phenotype', 'HP:0100013', (93, 105))	('breast tumors', 'Disease', 'MESH:D001943', (93, 106))
70705	23704974	Similarly, in the BRCA1 mutant population the DEABM shows that only ~38% (range 29-44%) of tumors generated were ER+ (Figure 8B), in concordance to published incidences of ER+ BRCA1 mutant tumors of ~36% (range 19-52%).	('mutant', 'Var', (24, 30))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('BRCA1', 'Gene', '672', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('DEABM', 'Chemical', '-', (46, 51))	('BRCA1', 'Gene', '672', (176, 181))	('BRCA1', 'Gene', (18, 23))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BRCA1', 'Gene', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
70709	23704974	More importantly, these findings suggest a class of pre-pre-cancerous mutations that may set the stage for subsequent oncogene activation/tumor suppressor loss.	('loss', 'NegReg', (155, 159))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancerous', 'Disease', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('oncogene', 'Protein', (118, 126))	('cancerous', 'Disease', 'MESH:D009369', (60, 69))
70724	23704974	With respect to the generation of malignancy, the DEABM recapitulated cancer incidences in both sporadic cancer and BRCA1 mutant simulations.	('BRCA1', 'Gene', (116, 121))	('malignancy', 'Disease', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('DEABM', 'Chemical', '-', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('BRCA1', 'Gene', '672', (116, 121))	('malignancy', 'Disease', 'MESH:D009369', (34, 44))	('cancer', 'Disease', (70, 76))	('mutant', 'Var', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
70725	23704974	Furthermore, the DEABM simulations of BRCA1 mutant patients demonstrated a timeline of cumulative breast cancer risk comparable to that reported in the literature.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('BRCA1', 'Gene', (38, 43))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutant', 'Var', (44, 50))	('DEABM', 'Chemical', '-', (17, 22))	('BRCA1', 'Gene', '672', (38, 43))
70745	23704974	As a result, in the DEABM the loss of RUNX3 expression leads to an expanded ER+ population by allowing ER+ luminal cells to express c-Met and to receive proliferative stimulus via associated HGF signaling from nearby fibroblasts, i.e.	('ER+ population', 'CPA', (76, 90))	('RUNX3', 'Gene', (38, 43))	('HGF', 'Gene', '3082', (191, 194))	('allowing', 'Reg', (94, 102))	('c-Met', 'Gene', (132, 137))	('receive proliferative stimulus', 'MPA', (145, 175))	('DEABM', 'Chemical', '-', (20, 25))	('c-Met', 'Gene', '4233', (132, 137))	('HGF', 'Gene', (191, 194))	('loss', 'Var', (30, 34))
70748	23704974	RUNX3 expression is also significantly lower in ER+ mammary ductal carcinomas (versus ER- cancers, see Figure 8), suggesting that dysregulation of RUNX3 does play a role in the preference for ER+ breast tumorigenesis.	('cancers', 'Disease', (90, 97))	('breast tumor', 'Disease', (196, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('dysregulation', 'Var', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'MPA', (6, 16))	('ductal carcinomas', 'Disease', 'MESH:D044584', (60, 77))	('breast tumor', 'Phenotype', 'HP:0100013', (196, 208))	('ductal carcinomas', 'Disease', (60, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('breast tumor', 'Disease', 'MESH:D001943', (196, 208))	('lower', 'NegReg', (39, 44))	('RUNX3', 'Gene', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
70754	23704974	The generation of largely ER- tumors with BRCA1 mutant DEABM simulations further supports our hypothesis.	('DEABM', 'Chemical', '-', (55, 60))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('BRCA1', 'Gene', '672', (42, 47))	('mutant', 'Var', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('BRCA1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
70755	23704974	It is well known that the overwhelming majority of people with germline BRCA1 mutations develop basal-like (triple-negative) breast cancer.	('develop', 'Reg', (88, 95))	('BRCA1', 'Gene', '672', (72, 77))	('people', 'Species', '9606', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA1', 'Gene', (72, 77))	('germline', 'Var', (63, 71))	('mutations', 'Var', (78, 87))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
70757	23704974	The ability of the model to mimic clinical rates of tumor ER-status so closely, particularly with regard to a mutation in a single gene (BRCA1) demonstrates the potential benefit and utility of model-aided hypothesis generation and evaluation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BRCA1', 'Gene', '672', (137, 142))	('tumor', 'Disease', (52, 57))	('BRCA1', 'Gene', (137, 142))	('aid', 'Gene', '57379', (200, 203))	('mutation', 'Var', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('aid', 'Gene', (200, 203))
70760	23704974	For instance, the enrichment for non-silent TP53 mutations in ER- breast cancer subtypes may potentially play a significant role in the selected generation of ER- cancers.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('play', 'Reg', (105, 109))	('mutations', 'Var', (49, 58))	('non-silent', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('TP53', 'Gene', '7157', (44, 48))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('TP53', 'Gene', (44, 48))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
70769	23704974	We assert that agent-based modeling could assist in this contextualization, by enhancing the investigation, understanding and categorization the multiple possible trajectories resulting from multiple sets of possible mutations into groups or classes of functional tumor phenotypes, with prognostic and therapeutic implications.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('functional tumor', 'Disease', (253, 269))	('enhancing', 'PosReg', (79, 88))	('functional tumor', 'Disease', 'MESH:D009369', (253, 269))	('mutations', 'Var', (217, 226))
70771	23704974	The innovation of such models is to provide a platform in which oncogenesis can be tracked across a series of identified mutations that progress from precancerous states to, ultimately, invasive cancer.	('invasive cancer', 'Disease', 'MESH:D009362', (186, 201))	('mutations', 'Var', (121, 130))	('cancerous', 'Disease', (153, 162))	('progress', 'PosReg', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancerous', 'Disease', 'MESH:D009369', (153, 162))	('invasive cancer', 'Disease', (186, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
70776	23704974	Description of the simulation experiments include those intended to first test the validity of the DEABM in terms of effectively reproducing normal breast cell population dynamics in response to different normal hormone patterns (cyclical menses and pregnancy) without introducing mutations, then introducing mutations in order to validate the ability of the DEABM to reproduce recognized incidences of breast cancer development.	('DEABM', 'Chemical', '-', (359, 364))	('DEABM', 'Chemical', '-', (99, 104))	('breast cancer', 'Disease', 'MESH:D001943', (403, 416))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('mutations', 'Var', (309, 318))	('breast cancer', 'Disease', (403, 416))	('breast cancer', 'Phenotype', 'HP:0003002', (403, 416))
70780	23704974	This allows the DEABM to represent some degree of spatial plausibility and constraint while representing the interactions and subsequent behaviors of the cellular populations as they accumulate mutations and start to exhibit behaviors that shift them from the healthy dynamic steady state.	('exhibit', 'Reg', (217, 224))	('mutations', 'Var', (194, 203))	('DEABM', 'Chemical', '-', (16, 21))	('accumulate', 'PosReg', (183, 193))
70801	23704974	Mutations: Mutations of E-cadherin delay the initiation of apoptosis due to failure of adherence (see corresponding section below in Luminal Cells for more details).	('failure', 'NegReg', (76, 83))	('adherence', 'CPA', (87, 96))	('delay', 'NegReg', (35, 40))	('apoptosis', 'CPA', (59, 68))	('E-cadherin', 'Gene', (24, 34))	('Mutations', 'Var', (11, 20))	('E-cadherin', 'Gene', '999', (24, 34))
70830	23704974	At baseline, Myc is suppressed, and mutations lead to loss of its suppression.	('Myc', 'Gene', (13, 16))	('suppression', 'MPA', (66, 77))	('loss', 'NegReg', (54, 58))	('mutations', 'Var', (36, 45))	('Myc', 'Gene', '4609', (13, 16))
70832	23704974	Mutations that lead to loss of control of MMPs remove the movement restriction on proliferative cells and allow mutated cells to grow beyond the basement membrane   BRCA1: BRCA1 is involved in DNA repair, entry into senescence and the expression of ER.	('movement restriction', 'MPA', (58, 78))	('BRCA1', 'Gene', (165, 170))	('BRCA1', 'Gene', '672', (172, 177))	('movement restriction', 'Phenotype', 'HP:0100022', (58, 78))	('MMPs', 'Gene', '4313;4314;8510', (42, 46))	('BRCA1', 'Gene', (172, 177))	('involved', 'Reg', (181, 189))	('Mutations', 'Var', (0, 9))	('MMPs', 'Gene', (42, 46))	('BRCA1', 'Gene', '672', (165, 170))
70838	23704974	Both p53 and BRCA1 are needed for this full capacity to manifest; a reduction in either's gene levels through mutation lead to some degree of decreased ability to repair its DNA-integrity.	('BRCA1', 'Gene', (13, 18))	('gene levels', 'MPA', (90, 101))	('decreased', 'NegReg', (142, 151))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('mutation', 'Var', (110, 118))	('reduction', 'NegReg', (68, 77))	('BRCA1', 'Gene', '672', (13, 18))
70841	23704974	There is a probability that some of these mutations will affect one of the 8 focus genes/functional modules noted above, but since the large proportion of mutations would occur in genes not significant to the current focus of the DEABM, the probability of acquiring a mutation to one of the 8 focus genes is relatively low.	('DEABM', 'Chemical', '-', (230, 235))	('mutations', 'Var', (42, 51))	('mutations', 'Var', (155, 164))	('affect', 'Reg', (57, 63))
70843	23704974	Cancer, in the DEABM, emerges when a lineage of cells acquire a series of mutations that allow overgrowth and invasion.	('overgrowth', 'Phenotype', 'HP:0001548', (95, 105))	('DEABM', 'Chemical', '-', (15, 20))	('mutations', 'Var', (74, 83))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('invasion', 'CPA', (110, 118))	('overgrowth', 'CPA', (95, 105))
70880	22078026	These data imply that epigenetic modifications are at least in part responsible for the altered phenotype of cells composing the microenvironment in breast cancer.	('responsible', 'Reg', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))	('epigenetic modifications', 'Var', (22, 46))
70897	22078026	One possibility is that they are derived from native interstitial fibroblasts whose phenotype has been modified by persistent aberrant signaling from neighboring tumor epithelial cells.	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('aberrant', 'Var', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
70906	22078026	Abnormal physical characteristics of breast tumors, such as abnormal collagen cross-linking resulting in ECM stiffening, also contribute to progression.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('breast tumor', 'Phenotype', 'HP:0100013', (37, 49))	('breast tumors', 'Disease', 'MESH:D001943', (37, 50))	('contribute', 'Reg', (126, 136))	('breast tumors', 'Disease', (37, 50))	('collagen cross-linking', 'MPA', (69, 91))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('abnormal collagen', 'Phenotype', 'HP:0008271', (60, 77))	('ECM', 'MPA', (105, 108))	('abnormal', 'Var', (60, 68))	('breast tumors', 'Phenotype', 'HP:0100013', (37, 50))
70944	22078026	In DCIS, patients with tumors expressing low levels of CD10 (a myoepithelial cell surface marker) had a higher risk of local relapse.	('CD10', 'Gene', (55, 59))	('patients', 'Species', '9606', (9, 17))	('tumors', 'Disease', (23, 29))	('CD10', 'Gene', '4311', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('low levels', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('local relapse', 'CPA', (119, 132))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
70970	22078026	Inhibition of TAM recruitment by several approaches increased the efficacy of chemotherapy by decreasing tumor development and metastasis in a CD8+ T cell-dependent manner.	('TAM', 'Protein', (14, 17))	('decreasing', 'NegReg', (94, 104))	('increased', 'PosReg', (52, 61))	('CD8', 'Gene', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CD8', 'Gene', '925', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('chemotherapy', 'CPA', (78, 90))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (105, 110))	('TAM', 'Chemical', '-', (14, 17))	('metastasis', 'CPA', (127, 137))
70972	22078026	Inhibition of TAMs promotes CD8+ T-cell recruitment and is associated with increased antitumor immunity.	('promotes', 'PosReg', (19, 27))	('TAMs', 'Gene', (14, 18))	('TAMs', 'Chemical', '-', (14, 18))	('CD8', 'Gene', (28, 31))	('CD8', 'Gene', '925', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
70981	22078026	Interestingly, metronomic therapies have been implicated in inhibiting angiogenesis, promoting a beneficial immune response and tumor dormancy.	('metronomic therapies', 'Var', (15, 35))	('inhibiting', 'NegReg', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('angiogenesis', 'CPA', (71, 83))	('beneficial', 'PosReg', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('promoting', 'PosReg', (85, 94))
70983	22078026	Just as the epigenetic changes identified in tumors possibly arise from chronic exposure to pro-tumorigenic signals derived from malignant epithelium, one could postulate a similar affect from chronic exposure to anti-neoplastic agents.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('arise', 'Reg', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('epigenetic changes', 'Var', (12, 30))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
70993	22078026	Furthermore, the epigenetic modifications that contribute to phenotypic alterations, while inheritable, are reversible, and there is mounting interest in 'normalizing' the altered stroma, thereby abrogating its tumor-supporting role.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	("'normalizing", 'PosReg', (154, 166))	('epigenetic modifications', 'Var', (17, 41))	('abrogating', 'NegReg', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))
71016	21113352	Patients having DCIS with microinvasion may present with axillary lymph node metastases, whereas DCIS patients without microinvasion usually do not present with axillary metastases.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('axillary metastases', 'Disease', (161, 180))	('patients', 'Species', '9606', (102, 110))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('metastases', 'Disease', (77, 87))	('metastases', 'Disease', (170, 180))	('Patients', 'Species', '9606', (0, 8))	('axillary metastases', 'Disease', 'MESH:D009362', (161, 180))	('metastases', 'Disease', 'MESH:D009362', (170, 180))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('DCIS', 'Disease', (16, 20))	('present', 'Reg', (44, 51))	('microinvasion', 'Var', (26, 39))
71043	33532348	Especially, clitoriacetal (C19H18O9) is the major component that can be detected in the root part which demonstrates antipyretic, anti-inflammatory, and antioxidant activities [Figure 1].	('clitoriacetal', 'Chemical', 'MESH:C052364', (12, 25))	('anti-inflammatory', 'MPA', (130, 147))	('antipyretic', 'MPA', (117, 128))	('C19H18O9', 'Var', (27, 35))	('antioxidant activities', 'MPA', (153, 175))
71123	30383678	While the expression of HER-2 in DCIS with microinvasion (56.4%) was significantly higher than in DCIS (36.6%, P = .01).	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('expression', 'MPA', (10, 20))	('HER-2', 'Gene', '2064', (24, 29))	('microinvasion', 'Var', (43, 56))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('higher', 'PosReg', (83, 89))	('HER-2', 'Gene', (24, 29))
71124	30383678	Furthermore, DCIS with microinvasion was significantly more likely to have aggressive subtype (Triple-negative and HER2-enriched tumors, P = .005).	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('HER2-enriched tumors', 'Disease', 'MESH:D009369', (115, 135))	('HER2-enriched tumors', 'Disease', (115, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('aggressive subtype', 'Disease', (75, 93))	('microinvasion', 'Var', (23, 36))	('DCIS', 'Disease', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
71149	30383678	HER-2 positivity was considered as score 3+ by IHC or FISH positive, whereas cases with score 0 to 1+ or 2+ without FISH positive were regarded as negative.	('positivity', 'Var', (6, 16))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))
71160	30383678	HER-2 amplification was demonstrated in 36.6% of DCIS.	('DCIS', 'Disease', (49, 53))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('amplification', 'Var', (6, 19))
71161	30383678	Interestingly, the HER-2 expression in DCIS with microinvasion (56.4%) was significantly high than in DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('HER-2', 'Gene', '2064', (19, 24))	('expression', 'MPA', (25, 35))	('HER-2', 'Gene', (19, 24))	('microinvasion', 'Var', (49, 62))	('high', 'PosReg', (89, 93))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
71168	30383678	In patients with microinvasion, the most commonly seen component in the background was high-grade DCIS, and it is very unusual in low-grade disease.	('microinvasion', 'Var', (17, 30))	('patients', 'Species', '9606', (3, 11))	('high-grade DCIS', 'Disease', (87, 102))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))
71170	30383678	In this study, we found that there was significant difference between patients with DCIS and DCIS with microinvasion in nuclear grade.	('patients', 'Species', '9606', (70, 78))	('microinvasion', 'Var', (103, 116))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('DCIS', 'Disease', (84, 88))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))
71189	30383678	Patients with DCIS with microinvasion in our study were significantly more likely to have HER-2-enriched and Triple-negative tumors or less likely Luminal A and Luminal B type tumors than patients with DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('patients', 'Species', '9606', (188, 196))	('DCIS', 'Phenotype', 'HP:0030075', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('Patients', 'Species', '9606', (0, 8))	('less', 'NegReg', (135, 139))	('type tumors', 'Disease', (171, 182))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HER-2', 'Gene', (90, 95))	('HER-2', 'Gene', '2064', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('microinvasion', 'Var', (24, 37))	('DCIS', 'Disease', (14, 18))	('tumors', 'Disease', (176, 182))	('type tumors', 'Disease', 'MESH:D009369', (171, 182))
71190	30383678	Triple-negative and HER2-positive tumors are both known to be aggressive phenotypes.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('Triple-negative', 'Var', (0, 15))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', '2064', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
71281	26545402	Women with DCIS are four times more likely to develop invasive breast cancer than the general population.	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('invasive breast cancer', 'Disease', 'MESH:D001943', (54, 76))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('develop', 'PosReg', (46, 53))	('DCIS', 'Var', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('invasive breast cancer', 'Disease', (54, 76))
71356	26078587	Breast cancer develops from the progressive accumulation of mutations in "driver" genes, which confer a proliferative advantage to the cells.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (60, 69))	('Breast cancer', 'Disease', (0, 13))	('proliferative advantage', 'CPA', (104, 127))
71357	26078587	Clonal expansion of these cells results in an enlarging field of "cancerized" cells with increased susceptibility to the acquisition of additional mutations and increased risk for breast cancer.	('mutations', 'Var', (147, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Clonal', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('enlarging', 'PosReg', (46, 55))
71359	26078587	Importantly, analysis of normal at-risk breast tissue has identified cytologic and molecular abnormalities indicative of breast carcinogenesis, which correlate with increased risk for breast cancer, including atypical epithelial cells, DNA methylation, loss of heterozygosity/allelic imbalance, accumulation of p53 protein, aneuploidy, and overexpression of epidermal growth factor receptor.	('breast carcinogenesis', 'Disease', 'MESH:D063646', (121, 142))	('accumulation', 'PosReg', (295, 307))	('aneuploidy', 'Disease', (324, 334))	('DNA methylation', 'Var', (236, 251))	('imbalance', 'Phenotype', 'HP:0002172', (284, 293))	('epidermal growth factor receptor', 'Gene', (358, 390))	('p53', 'Gene', (311, 314))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('breast carcinogenesis', 'Disease', (121, 142))	('p53', 'Gene', '7157', (311, 314))	('loss', 'Var', (253, 257))	('overexpression', 'PosReg', (340, 354))	('aneuploidy', 'Disease', 'MESH:D000782', (324, 334))	('breast cancer', 'Disease', (184, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('protein', 'Protein', (315, 322))	('epidermal growth factor receptor', 'Gene', '1956', (358, 390))
71478	25128694	However, cardiovascular mortality, including both cardiovascular and cerebrovascular diseases, was lower for DCIS patients, with a standardized mortality ratio of 0.77 (95% CI = 0.67 to 0.89) (Table 3).	('DCIS', 'Var', (109, 113))	('lower', 'NegReg', (99, 104))	('cardiovascular', 'Disease', (9, 23))	('cardiovascular and cerebrovascular diseases', 'Disease', 'MESH:D002318', (50, 93))	('patients', 'Species', '9606', (114, 122))
71483	25128694	Although non-statistically significant, risks of cardiovascular mortality, IHD, congestive heart failure, and cardiovascular surgical interventions tended to be lower for patients treated with radiotherapy to the left breast than for patients irradiated to the right breast.	('lower', 'NegReg', (161, 166))	('congestive heart failure', 'Disease', (80, 104))	('radiotherapy', 'Var', (193, 205))	('cardiovascular', 'Disease', (49, 63))	('IHD', 'Disease', 'None', (75, 78))	('patients', 'Species', '9606', (171, 179))	('IHD', 'Disease', (75, 78))	('patients', 'Species', '9606', (234, 242))	('congestive heart failure', 'Disease', 'MESH:D006333', (80, 104))	('congestive heart failure', 'Phenotype', 'HP:0001635', (80, 104))
71484	25128694	Conversely, risks of valvular dysfunction and arrhythmia were somewhat higher, although not statistically significantly, for left-sided vs right-sided radiotherapy.	('valvular dysfunction', 'Disease', 'MESH:D006349', (21, 41))	('arrhythmia', 'Disease', (46, 56))	('arrhythmia', 'Phenotype', 'HP:0011675', (46, 56))	('left-sided', 'Var', (125, 135))	('valvular dysfunction', 'Disease', (21, 41))	('arrhythmia', 'Disease', 'MESH:D001145', (46, 56))
71526	12927038	These studies were supported by analogy with mouse mammary tumour models and by epidemiological studies, which showed that the risk for breast cancer increased with the rate of proliferation and atypia in breast biopsies.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('atypia', 'Var', (195, 201))	('mouse', 'Species', '10090', (45, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
71536	12927038	ADH in the presently used nomenclature is viewed as a risk factor for and not as a direct precursor of invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('ADH', 'Var', (0, 3))	('invasive breast cancer', 'Disease', (103, 125))	('invasive breast cancer', 'Disease', 'MESH:D001943', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
71605	12927038	A good example of the presence of a specific genetic alteration in a specific type of intraductal proliferation is the inactivation of E-cadherin in lobular neoplasia.	('lobular neoplasia', 'Phenotype', 'HP:0030076', (149, 166))	('lobular neoplasia', 'Disease', (149, 166))	('inactivation', 'Var', (119, 131))	('lobular neoplasia', 'Disease', 'MESH:D009369', (149, 166))	('neoplasia', 'Phenotype', 'HP:0002664', (157, 166))	('E-cadherin', 'Gene', (135, 145))	('E-cadherin', 'Gene', '999', (135, 145))
71666	21135965	Interestingly, we observed that fibroblast migration into the epithelial compartment was inhibited in the presence of DCIS cells (Fig.	('inhibited', 'NegReg', (89, 98))	('DCIS', 'Var', (118, 122))	('rat', 'Species', '10116', (46, 49))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))
71681	21135965	For instance, Provenzano et al have shown that alignment of collagen perpendicular to the tumor-explant boundary promotes local invasion of mammary epithelial cells.	('promotes', 'PosReg', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('alignment', 'Var', (47, 56))	('local invasion of mammary epithelial cells', 'CPA', (122, 164))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
71753	20689613	The Nottingham grading system has clinical utility in determining patient risk and outcome:patients with low-grade carcinomas have ~95% five-year survival compared to just 50% in patients with high-grade disease.	('patients', 'Species', '9606', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('patient', 'Species', '9606', (179, 186))	('patient', 'Species', '9606', (66, 73))	('carcinomas', 'Disease', (115, 125))	('patients', 'Species', '9606', (179, 187))	('low-grade', 'Var', (105, 114))	('patient', 'Species', '9606', (91, 98))
71762	20689613	For example, Roylance et al observed distinct genomic differences between grade I and grade III breast tumors; in particular, loss of chromosome 16q was significantly more frequent in grade I (65%) compared to grade III (16%) tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('breast tumors', 'Disease', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('breast tumor', 'Phenotype', 'HP:0100013', (96, 108))	('breast tumors', 'Phenotype', 'HP:0100013', (96, 109))	('loss of chromosome', 'Var', (126, 144))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('breast tumors', 'Disease', 'MESH:D001943', (96, 109))
71764	20689613	Since the initial models of disease progression were published, a number of studies examining levels and patterns of genomic variation in breast carcinomas have supported the hypothesis that low-grade and high-grade tumors represent separate genetic diseases, based largely on observations that the frequency of alterations at chromosome 16q was significantly higher in low-grade tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumors', 'Disease', (380, 386))	('tumors', 'Disease', 'MESH:D009369', (380, 386))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('genetic diseases', 'Disease', 'MESH:D030342', (242, 258))	('genetic diseases', 'Disease', (242, 258))	('tumors', 'Disease', (216, 222))	('breast carcinomas', 'Disease', 'MESH:D001943', (138, 155))	('breast carcinomas', 'Disease', (138, 155))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('higher', 'Reg', (360, 366))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('breast carcinomas', 'Phenotype', 'HP:0003002', (138, 155))	('alterations', 'Var', (312, 323))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))
71766	20689613	Likewise, microsatellite-based data from our own group showed significantly higher levels of AI at chromosome 16q11-q22 in low-grade compared to high-grade breast carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('breast carcinomas', 'Disease', 'MESH:D001943', (156, 173))	('low-grade', 'Disease', (123, 132))	('breast carcinomas', 'Disease', (156, 173))	('higher', 'PosReg', (76, 82))	('breast carcinomas', 'Phenotype', 'HP:0003002', (156, 173))	('AI at chromosome 16q11-q22', 'Var', (93, 119))
71768	20689613	Only proximal markers (D16S409 and D16S2624) on 16q had a higher frequency of AI in grade 1 versus grade 3 tumors, suggesting that changes in the 16q11-q22 region are critical in the development of low-grade disease (Fig.	('D16S2624', 'CellLine', 'CVCL:B072', (35, 43))	('D16S409', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('low-grade disease', 'Disease', (198, 215))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('D16S2624', 'Var', (35, 43))
71775	20689613	Tumors with reduced tubule formation (score = 3) showed higher levels of AI at chromosomal regions 11q23 and 13q12, those with high levels of nuclear atypia had frequent alterations at 9p21, 11q23, 13q14, 17p13, and 17q12, and carcinomas with high mitotic counts were commonly altered at 1p36, 11q23, and 13q14.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('11q23', 'Var', (191, 196))	('carcinomas', 'Disease', (227, 237))	('tubule formation', 'CPA', (20, 36))	('carcinomas', 'Disease', 'MESH:D002277', (227, 237))	('reduced', 'NegReg', (12, 19))	('alterations', 'Reg', (170, 181))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (56, 62))	('altered', 'Reg', (277, 284))	('9p21', 'Var', (185, 189))
71776	20689613	Alterations at 11q23 are common in breast tumors showing reduced tubule formation, high nuclear atypia, and high mitotic counts, suggesting that this is an early genetic change in the development of poorly-differentiated breast tumors; however, alterations at other chromosomal regions in poorly-differentiated tumors may specifically influence cell structure, nuclear morphology, and cellular proliferation.	('tumors', 'Disease', (311, 317))	('breast tumors', 'Disease', (35, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('Alterations', 'Var', (0, 11))	('influence', 'Reg', (335, 344))	('nuclear morphology', 'CPA', (361, 379))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('breast tumors', 'Disease', 'MESH:D001943', (221, 234))	('breast tumors', 'Disease', (221, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('breast tumors', 'Phenotype', 'HP:0100013', (221, 234))	('breast tumor', 'Phenotype', 'HP:0100013', (221, 233))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cellular proliferation', 'CPA', (385, 407))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('tumors', 'Disease', (42, 48))	('cell structure', 'CPA', (345, 359))	('breast tumor', 'Phenotype', 'HP:0100013', (35, 47))	('alterations', 'Var', (245, 256))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('breast tumors', 'Disease', 'MESH:D001943', (35, 48))
71780	20689613	In contrast, high-grade (poorly-differentiated) invasive tumors did not show significantly higher levels of AI than grade 3 DCIS, but AI events at specific chromosomal regions (1p36 and 11q23) were significantly more frequent in high-grade invasive tumors compared to high-grade DCIS.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('invasive tumors', 'Disease', 'MESH:D009369', (48, 63))	('invasive tumors', 'Disease', 'MESH:D009369', (240, 255))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('1p36', 'Var', (177, 181))	('frequent', 'Reg', (217, 225))	('invasive tumors', 'Disease', (240, 255))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('invasive tumors', 'Disease', (48, 63))
71782	20689613	Likewise, increased levels of AI at 1p36 and 11q23 in high-grade carcinomas suggest that these chromosomal regions may harbor genes associated with invasiveness.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('AI at', 'Var', (30, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('carcinomas', 'Disease', (65, 75))	('carcinomas', 'Disease', 'MESH:D002277', (65, 75))	('11q23', 'Gene', (45, 50))	('increased', 'PosReg', (10, 19))
71783	20689613	Stratification of low-grade and high-grade breast carcinomas into separate molecular diseases is based on the high frequency of alterations observed for chromosome 16 in low-grade tumors and a low frequency of 16q alterations in high-grade tumors.	('breast carcinomas', 'Disease', (43, 60))	('chromosome 16', 'Gene', (153, 166))	('alterations', 'Var', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('breast carcinomas', 'Phenotype', 'HP:0003002', (43, 60))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('breast carcinomas', 'Disease', 'MESH:D001943', (43, 60))
71784	20689613	The majority of low-grade tumors showed large deletions of 16q, while high-grade tumors were more frequently characterized by multiple, small chromosomal alterations, including copy number gains in this region.	('16q', 'Gene', (59, 62))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('copy number gains', 'Var', (177, 194))	('deletions', 'Var', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors', 'Disease', (26, 32))
71785	20689613	Based on this data, and the identification of copy number gains not previously detected, Roylance et al suggest that loss of chromosome 16q is an early event in the development of low-grade tumors, and postulate that high-grade carcinomas evolve from low-grade tumors by the accumulation of subsequent chromosomal alterations, such as small breaks and amplifications.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('loss', 'Var', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('small', 'CPA', (335, 340))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('carcinomas', 'Disease', (228, 238))	('carcinomas', 'Disease', 'MESH:D002277', (228, 238))	('tumors', 'Disease', (190, 196))	('amplifications', 'Var', (352, 366))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
71795	20689613	Further studies of genomic alterations in breast tumors of different histological grades have shown that although genetic changes were more frequent in grade 3 tumors, alterations of one specific chromosomal region (16q) were significantly lower (P < 0.01) in high-grade (26%) compared to intermediate-grade (54%) tumors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high-grade', 'Disease', (260, 270))	('breast tumors', 'Phenotype', 'HP:0100013', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (49, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (42, 54))	('tumors', 'Disease', (160, 166))	('lower', 'NegReg', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('alterations', 'Var', (168, 179))	('16q', 'Gene', (216, 219))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumors', 'Disease', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('breast tumors', 'Disease', (42, 55))	('breast tumors', 'Disease', 'MESH:D001943', (42, 55))
71796	20689613	Thus it appears that intermediate-grade carcinomas may represent a mixture of histological characteristics and may develop along two independent genetic pathways, one characterized by loss of chromosome 16q, few genomic alterations, and high rates of diploidy, while the other pathway is characterized by high homology with high-grade tumors.	('tumors', 'Disease', (335, 341))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('loss', 'NegReg', (184, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('diploidy', 'Var', (251, 259))	('carcinomas', 'Disease', (40, 50))
71806	20689613	Survival outcomes for the G2a and G2b groups were similar to those in patients with grade 1 and grade 3 tumors, respectively.	('patients', 'Species', '9606', (70, 78))	('G2a', 'Gene', '29933', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('G2b', 'Var', (34, 37))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('G2a', 'Gene', (26, 29))
71841	17683614	20-40% have amplification of the Her2 gene which is a marker of increased recurrence rates and poorer prognosis.	('Her2', 'Gene', '2064', (33, 37))	('increased', 'PosReg', (64, 73))	('Her2', 'Gene', (33, 37))	('amplification', 'Var', (12, 25))
71874	17683614	We find that RBSK, Homo sapiens cDNA FLJ12924 fis, clone NT2RP2004709 and CRIP1 are up-regulated in the LG group, and EYA2, ANXA1, RUNX3, DKFZp762A227, GPRC5B are down-regulated in the LG group.	('RBSK', 'Gene', (13, 17))	('GPRC5B', 'Gene', '51704', (152, 158))	('EYA2', 'Gene', (118, 122))	('ANXA1', 'Gene', (124, 129))	('CRIP1', 'Gene', (74, 79))	('EYA2', 'Gene', '2139', (118, 122))	('RUNX3', 'Gene', '864', (131, 136))	('Homo sapiens', 'Species', '9606', (19, 31))	('up-regulated', 'PosReg', (84, 96))	('RUNX3', 'Gene', (131, 136))	('FLJ12924', 'Var', (37, 45))	('GPRC5B', 'Gene', (152, 158))	('RBSK', 'Gene', '64080', (13, 17))	('ANXA1', 'Gene', '301', (124, 129))	('CRIP1', 'Gene', '1396', (74, 79))
71880	17683614	The ER and Her2 status suggest that both LG1 and LG2 are Luminals in the standard nomenclature, with LG2 presenting more aggressive features than LG1.	('Her2', 'Gene', '2064', (11, 15))	('Her2', 'Gene', (11, 15))	('LG2', 'Var', (101, 104))
71887	17683614	This suggests the possibility that patients in the HG3 subgroup might have a re-arrangement or deletion of genes around the Her2 gene leading to loss of regulation or function for these genes which might explain why only 15% of HG3 patients are Her2+, while 53% are Her2- and 15% are undetermined.	('HG3', 'Gene', (51, 54))	('Her2', 'Gene', (245, 249))	('function', 'MPA', (167, 175))	('loss of', 'NegReg', (145, 152))	('deletion', 'Var', (95, 103))	('regulation', 'MPA', (153, 163))	('Her2', 'Gene', (266, 270))	('patients', 'Species', '9606', (232, 240))	('HG3', 'Gene', (228, 231))	('Her2', 'Gene', '2064', (124, 128))	('Her2', 'Gene', '2064', (266, 270))	('Her2', 'Gene', '2064', (245, 249))	('HG3', 'Gene', '339039', (51, 54))	('patients', 'Species', '9606', (35, 43))	('Her2', 'Gene', (124, 128))	('HG3', 'Gene', '339039', (228, 231))
71890	17683614	Mutations in this gene have been associated with the development of various types of tumors.	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('associated with', 'Reg', (33, 48))
71896	17683614	The FDR values for the genes in Figure 5 are 0.6 for LG, 0.2 for HG and for the genes in Figure 6 are 0.02 for LG1, 0.2 for LG2, 0.2 for HG1, 0.5 for HG2, 0.06 for HG3 and 0.002 for HG4.	('HG4', 'Gene', '353512', (182, 185))	('HG3', 'Gene', '339039', (164, 167))	('HG2', 'Gene', (150, 153))	('HG4', 'Gene', (182, 185))	('HG1', 'Gene', (137, 140))	('HG3', 'Gene', (164, 167))	('HG2', 'Gene', '283955', (150, 153))	('0.06', 'Var', (155, 159))	('HG1', 'Gene', '339044', (137, 140))
72005	27616890	The clinicopathological significance of RUNX3 hypermethylation and mRNA expression in human breast cancer, a meta-analysis Aberrant promoter methylation of RUNX3 has been reported in several tumors including human breast cancer (BC).	('reported', 'Reg', (171, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('RUNX3', 'Gene', '864', (156, 161))	('RUNX3', 'Gene', (40, 45))	('tumors', 'Disease', (191, 197))	('human', 'Species', '9606', (208, 213))	('breast cancer', 'Disease', (214, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('promoter', 'MPA', (132, 140))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Disease', (92, 105))	('human', 'Species', '9606', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('RUNX3', 'Gene', (156, 161))	('RUNX3', 'Gene', '864', (40, 45))	('Aberrant', 'Var', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
72006	27616890	However, the association between RUNX3 hypermethylation and incidence of BC remains elusive.	('RUNX3', 'Gene', (33, 38))	('hypermethylation', 'Var', (39, 55))	('RUNX3', 'Gene', '864', (33, 38))
72010	27616890	We also determined that RUNX3 hypermethylation was significantly higher in ER positive BC than in ER negative BC.	('RUNX3', 'Gene', '864', (24, 29))	('RUNX3', 'Gene', (24, 29))	('hypermethylation', 'MPA', (30, 46))	('higher', 'PosReg', (65, 71))	('ER positive', 'Var', (75, 86))
72011	27616890	In addition, high RUNX3 mRNA expression was found to be correlated with better overall survival and relapse-free survival for all BC patients.	('relapse-free survival', 'CPA', (100, 121))	('RUNX3', 'Gene', (18, 23))	('overall survival', 'CPA', (79, 95))	('high', 'Var', (13, 17))	('RUNX3', 'Gene', '864', (18, 23))	('patients', 'Species', '9606', (133, 141))	('better', 'PosReg', (72, 78))	('mRNA expression', 'MPA', (24, 39))
72012	27616890	Our results strongly support that RUNX3 hypermethylation may play an important role in BC incidence.	('hypermethylation', 'Var', (40, 56))	('RUNX3', 'Gene', (34, 39))	('RUNX3', 'Gene', '864', (34, 39))
72013	27616890	RUNX3 methylation is a valuable early biomarker for the diagnosis of BC.	('methylation', 'Var', (6, 17))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
72014	27616890	Further large-scale studies will provide more insight into the role of RUNX3 hypermethylation in the carcinogenesis and clinical diagnosis of BC patients.	('patients', 'Species', '9606', (145, 153))	('carcinogenesis', 'Disease', (101, 115))	('RUNX3', 'Gene', '864', (71, 76))	('RUNX3', 'Gene', (71, 76))	('hypermethylation', 'Var', (77, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))
72025	27616890	RUNX3 was first reported as a tumor suppressor because of the causal link between the loss of RUNX3 and gastric carcinogenesis.	('loss', 'Var', (86, 90))	('RUNX3', 'Gene', (0, 5))	('gastric carcinogenesis', 'Disease', (104, 126))	('RUNX3', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (104, 126))	('RUNX3', 'Gene', '864', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('RUNX3', 'Gene', '864', (0, 5))
72030	27616890	In addition, it remains elusive whether or not RUNX3 gene hypermethylation is correlated with the early stage of BC.	('hypermethylation', 'Var', (58, 74))	('RUNX3', 'Gene', '864', (47, 52))	('RUNX3', 'Gene', (47, 52))	('correlated', 'Reg', (78, 88))
72031	27616890	In this study, we performed a meta-analysis to determine the effects of RUNX3 hypermethylation on the incidence of BC.	('RUNX3', 'Gene', (72, 77))	('RUNX3', 'Gene', '864', (72, 77))	('hypermethylation', 'Var', (78, 94))
72039	27616890	The pooled frequency of RUNX3 hyper-methylation and 95% CIs were estimated.	('hyper-methylation', 'Var', (30, 47))	('RUNX3', 'Gene', '864', (24, 29))	('RUNX3', 'Gene', (24, 29))
72046	27616890	The pooled OR from four studies including 207 ER positive BC and 146 ER negative BC is shown in Figure 4 (OR =8.16, 95% CI =4.53-14.71, z score=6.99, P<0.00001, I2=43%, P=0.15), indicating that RUNX3 hypermethylation was significantly higher in ER positive BC than in ER negative BC.	('hypermethylation', 'MPA', (200, 216))	('higher', 'PosReg', (235, 241))	('RUNX3', 'Gene', '864', (194, 199))	('RUNX3', 'Gene', (194, 199))	('ER positive', 'Var', (245, 256))
72048	27616890	High RUNX3 mRNA expression was found to be correlated with better overall survival (OS) for all BC patients followed for 20 years (Figure 6A, hazard ratio 0.78, P=0.037).	('overall survival', 'MPA', (66, 82))	('High', 'Var', (0, 4))	('mRNA expression', 'MPA', (11, 26))	('better', 'PosReg', (59, 65))	('patients', 'Species', '9606', (99, 107))	('RUNX3', 'Gene', (5, 10))	('RUNX3', 'Gene', '864', (5, 10))
72049	27616890	In addition, high RUNX3 mRNA expression was also found to be correlated with better relapse-free survival (RFS) for all BC patients followed for 20 years (Figure 6B, hazard ratio 0.8, P=0.00013).	('better', 'PosReg', (77, 83))	('relapse-free survival', 'CPA', (84, 105))	('RUNX3', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('RUNX3', 'Gene', '864', (18, 23))	('patients', 'Species', '9606', (123, 131))	('mRNA expression', 'MPA', (24, 39))
72054	27616890	RUNX3 hypermethylation plays an important role during normal development and tumorigenesis in several types of tumors including BC.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('hypermethylation', 'Var', (6, 22))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
72059	27616890	The results from the current study indicated that the hypermethylation rate of RUNX3 gene is an early event during BC carcinogenesis.	('RUNX3', 'Gene', '864', (79, 84))	('carcinogenesis', 'Disease', (118, 132))	('hypermethylation rate', 'Var', (54, 75))	('RUNX3', 'Gene', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))
72060	27616890	Thus, RUNX3 methylation is a valuable early detection biomarker for the diagnosis of BC.	('methylation', 'Var', (12, 23))	('RUNX3', 'Gene', (6, 11))	('RUNX3', 'Gene', '864', (6, 11))
72061	27616890	Epigenetic alterations, particularly aber rant DNA methylation, one of the best-characterized epigenetic modifications, contribute to tumor initiation and progression.	('tumor initiation', 'Disease', (134, 150))	('contribute', 'Reg', (120, 130))	('tumor initiation', 'Disease', 'MESH:D009369', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('aber rant DNA methylation', 'Var', (37, 62))
72066	27616890	Numerous studies have supported that RUNX3 is a suppressor and is inactivated in BC by protein mislocalization, reduced copy number, hemizygous deletion, and gene hypermethylation.	('gene hypermethylation', 'Var', (158, 179))	('inactivated', 'NegReg', (66, 77))	('protein', 'Protein', (87, 94))	('mislocalization', 'Var', (95, 110))	('RUNX3', 'Gene', '864', (37, 42))	('reduced', 'NegReg', (112, 119))	('RUNX3', 'Gene', (37, 42))	('copy', 'MPA', (120, 124))
72067	27616890	Based on this meta-analysis, we may conclude that RUNX3 hypermethylation in BC tends to indicate higher incidence of BC, its inactivation could contribute to tumor initiation and progression.	('higher', 'PosReg', (97, 103))	('tumor initiation', 'Disease', (158, 174))	('hypermethylation', 'Var', (56, 72))	('contribute', 'Reg', (144, 154))	('RUNX3', 'Gene', '864', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RUNX3', 'Gene', (50, 55))	('tumor initiation', 'Disease', 'MESH:D009369', (158, 174))
72070	27616890	Therefore, RUNX3 methylation could contribute to the development of BC by modulating ER signaling pathway.	('RUNX3', 'Gene', '864', (11, 16))	('RUNX3', 'Gene', (11, 16))	('methylation', 'Var', (17, 28))	('ER signaling pathway', 'Pathway', (85, 105))	('modulating', 'Reg', (74, 84))	('contribute', 'Reg', (35, 45))
72073	27616890	High RUNX3 mRNA expression was found to be correlated with better OS for all BC patients followed for 20 years, hazard ratio 0.78, P=0.037.	('patients', 'Species', '9606', (80, 88))	('High', 'Var', (0, 4))	('better OS', 'Disease', (59, 68))	('mRNA expression', 'MPA', (11, 26))	('RUNX3', 'Gene', (5, 10))	('RUNX3', 'Gene', '864', (5, 10))
72074	27616890	In addition, high RUNX3 mRNA expression was also found to be correlated with better RFS for all BC patients followed for 20 years, hazard ratio 0.8, P=0.00013.	('better', 'PosReg', (77, 83))	('RUNX3', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('RUNX3', 'Gene', '864', (18, 23))	('RFS', 'MPA', (84, 87))	('patients', 'Species', '9606', (99, 107))
72076	27616890	The frequency of RUNX3 methylation is associated with ER status in patients with BC.	('RUNX3', 'Gene', (17, 22))	('associated', 'Reg', (38, 48))	('patients', 'Species', '9606', (67, 75))	('methylation', 'Var', (23, 34))	('RUNX3', 'Gene', '864', (17, 22))	('ER status', 'Disease', (54, 63))
72077	27616890	In addition, high RUNX3 mRNA expression was found to be correlated with better OS and RFS for all BC patients.	('patients', 'Species', '9606', (101, 109))	('RUNX3', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('RUNX3', 'Gene', '864', (18, 23))	('better', 'PosReg', (72, 78))	('RFS', 'CPA', (86, 89))
72101	23077445	The probability of malignancy in our experience was higher for non-mass lesion type and for washout and plateau kinetics.	('washout', 'MPA', (92, 99))	('non-mass lesion type', 'Var', (63, 83))	('malignancy', 'Disease', (19, 29))	('malignancy', 'Disease', 'MESH:D009369', (19, 29))
72165	31307644	Multifocal disease, nonmass enhancement lesion, or greater background parenchymal enhancement on preoperative breast MRI were significantly associated with positive or close margins.	('positive', 'CPA', (156, 164))	('associated', 'Reg', (140, 150))	('Multifocal disease', 'Disease', 'MESH:D000080364', (0, 18))	('nonmass', 'Var', (20, 27))	('background parenchymal enhancement', 'MPA', (59, 93))	('Multifocal disease', 'Disease', (0, 18))
72206	31307644	The lesion size on MRI was significantly larger in patients with close/positive margins compared to those with negative margins (mean, 2.3 cm; range, 0.6-6.3 cm vs mean, 1.6 cm; range, 0.3-6.4 cm, respectively; p = 0.002) (Table 2).	('larger', 'PosReg', (41, 47))	('close/positive margins', 'Var', (65, 87))	('patients', 'Species', '9606', (51, 59))
72322	19920187	In agreement with the in vitro findings, co-injection with HGF-secreting fibroblasts increased invasiveness of MCF10.DCIS xenografts in SCID mice.	('MCF10.DCIS', 'Var', (111, 121))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (111, 121))	('SCID', 'Disease', (136, 140))	('SCID', 'Disease', 'MESH:D053632', (136, 140))	('invasiveness', 'CPA', (95, 107))	('mice', 'Species', '10090', (141, 145))	('increased', 'PosReg', (85, 94))
72330	19920187	Higher levels of HGF and c-Met staining in DCIS are associated with other aggressive tumor markers including comedo histology, high nuclear grade, p53 positivity, and bcl-2 negativity.	('bcl-2', 'Gene', (167, 172))	('HGF', 'Protein', (17, 20))	('c-Met', 'Gene', (25, 30))	('aggressive tumor', 'Disease', (74, 90))	('c-Met', 'Gene', '4233', (25, 30))	('high', 'Var', (127, 131))	('positivity', 'Var', (151, 161))	('associated', 'Reg', (52, 62))	('bcl-2', 'Gene', '596', (167, 172))	('comedo', 'Phenotype', 'HP:0025249', (109, 115))	('comedo histology', 'Disease', (109, 125))	('p53', 'Gene', '7157', (147, 150))	('aggressive tumor', 'Disease', 'MESH:D001523', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p53', 'Gene', (147, 150))
72341	19920187	Where indicated, concentrated, conditioned media from fibroblasts, 100 ng/ml recombinant HGF (rHGF; R&D, Minneapolis, MN), 2 muM SU11274 (Calbiochem, San Diego, CA) or rHGF plus SU11274 were added to culture media.	('rHGF', 'Gene', '24446', (94, 98))	('rHGF', 'Gene', (94, 98))	('SU11274', 'Chemical', 'MESH:C478479', (129, 136))	('SU11274', 'Chemical', 'MESH:C478479', (178, 185))	('MN', 'CellLine', 'CVCL:U508', (118, 120))	('muM', 'Var', (125, 128))	('rHGF', 'Gene', '24446', (168, 172))	('rHGF', 'Gene', (168, 172))
72357	19920187	We had previously established by immunoblot analysis of conditioned media from MCF10.DCIS, MF and MF:HGF cells that only the MF:HGF cells secreted HGF (105-210 ng/ml; n = 3; data not shown).	('HGF', 'Protein', (147, 150))	('MCF10.DCIS', 'Var', (79, 89))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (79, 89))
72361	19920187	1A), but many of the MCF10.DCIS structures exhibited 'invasive outgrowths' consisting of two or more cells migrating into the surrounding extracellular matrix (Fig.	("'invasive outgrowths'", 'CPA', (53, 74))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (21, 31))	('MCF10.DCIS', 'Var', (21, 31))
72363	19920187	In co-cultures of MF:HGF and MCF10.DCIS cells, a significantly higher percentage of 3D structures were found to display invasive outgrowths than did MCF10.DCIS cells alone or MCF10.DCIS cells in co-culture with MF cells (Fig.	('invasive outgrowths', 'CPA', (120, 139))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (149, 159))	('MCF10.DCIS', 'Var', (29, 39))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (29, 39))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (175, 185))
72371	19920187	Consequently after 9 days, there were fewer 3D structures in cultures incubated with MF CM or MF:HGF CM than in control cultures (270 +- 40 and 231 +- 22, respectively, as compared to 325 +- 17; mean +- SEM).	('3D structures', 'CPA', (44, 57))	('MF CM', 'Disease', (85, 90))	('MF CM', 'Disease', 'MESH:D009202', (85, 90))	('fewer', 'NegReg', (38, 43))	('MF:HGF CM', 'Var', (94, 103))
72373	19920187	Degradation of DQ-collagen IV by MCF10.DCIS cells was significantly increased by MF:HGF CM (~2.5 fold; Fig.	('Degradation', 'MPA', (0, 11))	('increased', 'PosReg', (68, 77))	('MF:HGF CM', 'Var', (81, 90))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (33, 43))
72375	19920187	Live imaging revealed a dramatic increase in degradation products surrounding the MCF10.DCIS structures that had been incubated with MF:HGF CM (Fig.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (82, 92))	('MF', 'Var', (133, 135))	('degradation products', 'MPA', (45, 65))	('increase', 'PosReg', (33, 41))	('MCF10.DCIS', 'Var', (82, 92))
72377	19920187	Small molecule inhibitors that compete for ATP binding, such as SU11274, inhibit c-Met phosphorylation.	('ATP', 'Chemical', 'MESH:D000255', (43, 46))	('SU11274', 'Var', (64, 71))	('SU11274', 'Chemical', 'MESH:C478479', (64, 71))	('c-Met', 'Gene', (81, 86))	('c-Met', 'Gene', '4233', (81, 86))	('inhibit', 'NegReg', (73, 80))
72379	19920187	To detect activation of c-Met, we immunoblotted cell lysates using antibodies specific for the double phosphorylation at phosphoepitopes Y1234/Y1235 of c-Met.	('c-Met', 'Gene', (24, 29))	('c-Met', 'Gene', '4233', (24, 29))	('c-Met', 'Gene', (152, 157))	('Y1234/Y1235', 'Var', (137, 148))	('c-Met', 'Gene', '4233', (152, 157))
72380	19920187	Following MF:HGF CM treatment, we observed a sustained phosphorylation of c-Met in both MCF10.DCIS and SUM102 DCIS lines and SU11274 abrogated the phosphorylation (Fig.	('SU11274', 'Var', (125, 132))	('phosphorylation', 'MPA', (147, 162))	('MCF10.DCIS', 'Var', (88, 98))	('c-Met', 'Gene', (74, 79))	('c-Met', 'Gene', '4233', (74, 79))	('abrogated', 'NegReg', (133, 142))	('phosphorylation', 'MPA', (55, 70))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (88, 98))	('SU11274', 'Chemical', 'MESH:C478479', (125, 132))	('SUM102 DCIS', 'Var', (103, 114))
72381	19920187	SU11274 also significantly decreased the development of invasive outgrowths induced when MCF10.DCIS cells were co-cultured with HGF-expressing fibroblasts (Suppl.	('development of invasive outgrowths', 'CPA', (41, 75))	('MCF10.DCIS', 'Gene', (89, 99))	('decreased', 'NegReg', (27, 36))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (89, 99))
72385	19920187	Cultures treated with MF:HGF CM exhibited increased levels of uPA and uPAR in cell lysates and conditioned media as compared to controls and SU11274 abrogated those increases in the MCF10.DCIS cells and partially in the SUM102 cells (Fig.	('increased', 'PosReg', (42, 51))	('uPA', 'Gene', '5328', (70, 73))	('uPAR', 'Gene', '5329', (70, 74))	('MF:HGF CM', 'Var', (22, 31))	('uPA', 'Gene', (62, 65))	('SU11274', 'Chemical', 'MESH:C478479', (141, 148))	('uPA', 'Gene', '5328', (62, 65))	('uPAR', 'Gene', (70, 74))	('SU11274', 'Var', (141, 148))	('uPA', 'Gene', (70, 73))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (182, 192))
72387	19920187	MF:HGF CM stimulated invasive outgrowths, invasion and degradation of DQ-collagen IV by MCF10.DCIS cells, consistent with an involvement of HGF.	('degradation of DQ-collagen IV', 'MPA', (55, 84))	('invasive outgrowths', 'CPA', (21, 40))	('MCF10.DCIS', 'Var', (88, 98))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (88, 98))	('invasion', 'CPA', (42, 50))
72389	19920187	Both MCF10.DCIS and SUM102 cell lines formed dysplastic 3D structures with few structures exhibiting invasive outgrowths in the presence of the DMSO vehicle control (Control) or SU11274 (I).	('dysplastic', 'Disease', 'MESH:D004416', (45, 55))	('SU11274', 'Var', (178, 185))	('DMSO', 'Chemical', 'MESH:D004121', (144, 148))	('dysplastic', 'Disease', (45, 55))	('SU11274', 'Chemical', 'MESH:C478479', (178, 185))	('MCF10.DCIS', 'Var', (5, 15))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (5, 15))
72392	19920187	Stimulation of c-Met appeared to be responsible for the increase of invasive outgrowths since rHGF did not increase the percentage of structures with invasive outgrowths in the presence of SU11274 (Fig.	('rHGF', 'Gene', '24446', (94, 98))	('invasive outgrowths', 'CPA', (68, 87))	('rHGF', 'Gene', (94, 98))	('c-Met', 'Gene', (15, 20))	('SU11274', 'Var', (189, 196))	('SU11274', 'Chemical', 'MESH:C478479', (189, 196))	('c-Met', 'Gene', '4233', (15, 20))
72394	19920187	Since expression of uPA and uPAR was increased in 3D rBM cultures treated with MF:HGF CM (Fig.	('uPAR', 'Gene', '5329', (28, 32))	('expression', 'MPA', (6, 16))	('MF:HGF', 'Var', (79, 85))	('uPAR', 'Gene', (28, 32))	('increased', 'PosReg', (37, 46))	('uPA', 'Gene', (28, 31))	('uPA', 'Gene', (20, 23))	('uPA', 'Gene', '5328', (20, 23))	('uPA', 'Gene', '5328', (28, 31))
72402	19920187	rHGF increased the intensity of peripheral degradation products associated with MCF10.DCIS and SUM102 3D cultures (Fig.	('MCF10.DCIS', 'Var', (80, 90))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (80, 90))	('rHGF', 'Gene', '24446', (0, 4))	('peripheral degradation products', 'MPA', (32, 63))	('intensity', 'MPA', (19, 28))	('rHGF increased', 'Phenotype', 'HP:0030269', (0, 14))	('rHGF', 'Gene', (0, 4))
72407	19920187	Tumor take was similar among the 3 groups of mice (n=8 per group), yet the median wet weight of the tumors was greatest in mice coinjected with DCIS cells and MF:HGF (680 mg; range: 70-869 mg), as compared to DCIS cells alone (99 mg; range: 66-124 mg) and those coinjected with DCIS cells and MF (171 mg; range: 90-502 mg).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (45, 49))	('wet weight', 'CPA', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('DCIS cells', 'Var', (144, 154))	('mice', 'Species', '10090', (123, 127))
72416	19920187	In MCF10.DCIS cells, MAPK/ERK activity is elevated, whereas in SUM102 cells, EGFR is elevated and EGFR ligands are secreted.	('EGFR', 'Gene', (98, 102))	('MCF10.DCIS', 'Var', (3, 13))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (3, 13))	('ERK', 'Gene', '5594', (26, 29))	('ERK', 'Gene', (26, 29))	('elevated', 'PosReg', (85, 93))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', '1956', (98, 102))	('elevated', 'PosReg', (42, 50))	('EGFR', 'Gene', (77, 81))	('activity', 'MPA', (30, 38))
72420	19920187	We suggest that there may be interaction between c-Met signaling and aberrant ErbB2 signaling in the DCIS cell lines.	('c-Met', 'Gene', (49, 54))	('c-Met', 'Gene', '4233', (49, 54))	('ErbB2', 'Gene', '2064', (78, 83))	('aberrant', 'Var', (69, 77))	('interaction', 'Interaction', (29, 40))	('ErbB2', 'Gene', (78, 83))
72423	19920187	Our results would thus be consistent with ErbB2 related alterations in MCF10.DCIS and SUM102 cells interacting with HGF/c-Met signaling to promote development of large dysplastic structures and invasive outgrowths.	('dysplastic', 'Disease', (168, 178))	('promote', 'PosReg', (139, 146))	('alterations', 'Var', (56, 67))	('dysplastic', 'Disease', 'MESH:D004416', (168, 178))	('SUM102', 'Gene', (86, 92))	('ErbB2', 'Gene', (42, 47))	('ErbB2', 'Gene', '2064', (42, 47))	('c-Met', 'Gene', (120, 125))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (71, 81))	('c-Met', 'Gene', '4233', (120, 125))	('MCF10.DCIS', 'Gene', (71, 81))	('invasive outgrowths', 'CPA', (194, 213))
72430	23184082	The penetrance of ductal carcinoma in situ among BRCA1 and BRCA2 mutation carriers Ductal carcinoma in situ (DCIS) is a precancerous lesion of the female breast and is strongly suspected to be a precursor of invasive breast cancer (IBC).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BRCA2', 'Gene', '675', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ductal carcinoma', 'Disease', 'MESH:D044584', (18, 34))	('precancerous lesion', 'Disease', (120, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutation', 'Var', (65, 73))	('precancerous lesion', 'Disease', 'MESH:D011230', (120, 139))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (83, 107))	('BRCA1', 'Gene', '672', (49, 54))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (90, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('invasive breast cancer', 'Disease', (208, 230))	('BRCA1', 'Gene', (49, 54))	('BRCA2', 'Gene', (59, 64))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (18, 42))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (25, 42))	('invasive breast cancer', 'Disease', 'MESH:D001943', (208, 230))	('Ductal carcinoma', 'Disease', (83, 99))	('lesion of the female breast', 'Phenotype', 'HP:0100013', (133, 160))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (83, 99))	('ductal carcinoma', 'Disease', (18, 34))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))
72432	23184082	to the general population, we obtain a lifetime risk for carriers of a deleterious mutation of either BRCA1 or BRCA2 of 6.21 % (95 % CI 6.09-6.33 %).	('BRCA2', 'Gene', (111, 116))	('BRCA1', 'Gene', (102, 107))	('BRCA2', 'Gene', '675', (111, 116))	('carriers', 'Reg', (57, 65))	('mutation', 'Var', (83, 91))	('BRCA1', 'Gene', '672', (102, 107))
72433	23184082	The increase in lifetime risk of DCIS for a BRCA mutation carrier compared to a non-carrier is therefore about six-fold.	('mutation', 'Var', (49, 57))	('DCIS', 'Disease', (33, 37))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))
72434	23184082	Our quantification is directly relevant to the identification and genetic counseling of BRCA mutation carriers, and emphasizes the potential importance of including information on diagnoses of DCIS in counseling of individuals who are at familial risk for breast cancer.	('breast cancer', 'Disease', (256, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('BRCA', 'Gene', '672', (88, 92))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('mutation', 'Var', (93, 101))	('BRCA', 'Gene', (88, 92))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
72435	23184082	All these factors can contribute to a more specific and targeted prevention, potentially reducing the impact of IBC among BRCA mutation carriers.	('BRCA', 'Gene', '672', (122, 126))	('mutation', 'Var', (127, 135))	('BRCA', 'Gene', (122, 126))	('reducing', 'NegReg', (89, 97))
72436	23184082	Deleterious germline mutations in the BRCA1 and BRCA2 genes are known to cause an increase in the rate of invasive breast cancer (IBC).	('increase', 'Reg', (82, 90))	('germline mutations', 'Var', (12, 30))	('BRCA2', 'Gene', '675', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('BRCA1', 'Gene', (38, 43))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA1', 'Gene', '672', (38, 43))	('BRCA2', 'Gene', (48, 53))	('invasive breast cancer', 'Disease', (106, 128))
72438	23184082	To address this question, here we combine information from the SEER registry with a retrospective study that tested DCIS cases for BRCA status, to obtain estimates of the absolute risk for DCIS among BRCA mutation carriers.	('BRCA', 'Gene', '672', (200, 204))	('BRCA', 'Gene', '672', (131, 135))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('BRCA', 'Gene', (200, 204))	('BRCA', 'Gene', (131, 135))	('mutation', 'Var', (205, 213))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
72440	23184082	Thus, our results have direct implications for the efficient identification, genetic counseling and clinical management of carriers of BRCA1 and BRCA2 mutation.	('BRCA2', 'Gene', (145, 150))	('BRCA1', 'Gene', '672', (135, 140))	('BRCA2', 'Gene', '675', (145, 150))	('mutation', 'Var', (151, 159))	('carriers', 'Reg', (123, 131))	('BRCA1', 'Gene', (135, 140))
72443	23184082	study which estimates BRCA1 and BRCA2 mutation prevalence among women diagnosed with non-invasive carcinoma of the breast.	('BRCA2', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('women', 'Species', '9606', (64, 69))	('carcinoma of the breast', 'Disease', 'MESH:D001943', (98, 121))	('BRCA1', 'Gene', '672', (22, 27))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (98, 121))	('BRCA2', 'Gene', '675', (32, 37))	('mutation', 'Var', (38, 46))	('carcinoma of the breast', 'Disease', (98, 121))	('BRCA1', 'Gene', (22, 27))
72445	23184082	Consistently with Claus et al., we will consider "deleterious" mutations in the BRCA1/2 to be those which are commonly known to have an association with the disease, not including variants of unknown significance.	('mutations', 'Var', (63, 72))	('BRCA1/2', 'Gene', '672;675', (80, 87))	('BRCA1/2', 'Gene', (80, 87))	('association', 'Interaction', (136, 147))
72448	23184082	All available participants in the initial study were subsequently recontacted for testing for mutations in BRCA1 and BRCA2 genes.	('BRCA1', 'Gene', '672', (107, 112))	('BRCA2', 'Gene', '675', (117, 122))	('mutations', 'Var', (94, 103))	('BRCA1', 'Gene', (107, 112))	('participants', 'Species', '9606', (14, 26))	('BRCA2', 'Gene', (117, 122))
72454	23184082	We use B to denote the presence of a germline mutation in either BRCA1 or BRCA2.	('BRCA1', 'Gene', '672', (65, 70))	('germline mutation', 'Var', (37, 54))	('BRCA2', 'Gene', (74, 79))	('BRCA1', 'Gene', (65, 70))	('BRCA2', 'Gene', '675', (74, 79))
72456	23184082	We estimate the lifetime risk of DCIS among carriers of BRCA1 or BRCA2 mutations to be 6.21 % (95 % bootstrap CI 6.09-6.33 %).	('BRCA2', 'Gene', '675', (65, 70))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA1', 'Gene', (56, 61))	('DCIS', 'Disease', (33, 37))	('mutations', 'Var', (71, 80))	('BRCA2', 'Gene', (65, 70))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))
72461	28940516	We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium.	('CCO deficiency', 'Disease', (91, 105))	('clonal expansions', 'Var', (47, 64))	('CCO deficiency', 'Disease', 'MESH:D020512', (91, 105))	('occur', 'Reg', (159, 164))	('human', 'Species', '9606', (33, 38))
72474	28940516	To determine the location of stem cells within the human mammary epithelium, we have used a lineage tracing technique where mitochondrial DNA (mtDNA) mutations act as a marker of clonal expansion 13.	('human', 'Species', '9606', (51, 56))	('mtDNA', 'Gene', (143, 148))	('mutations', 'Var', (150, 159))
72475	28940516	Mutant cells are identified by the deficiency of the mitochondrial enzyme cytochrome c oxidase (CCO).	('Mutant', 'Var', (0, 6))	('cytochrome c', 'Gene', (74, 86))	('deficiency', 'NegReg', (35, 45))	('cytochrome c', 'Gene', '54205', (74, 86))
72476	28940516	MtDNA mutations accumulate within normal tissue stem cells and increase in frequency with age, reaching homoplasmy or detectable levels of heteroplasmy in mid to late life 15.	('heteroplasmy', 'Disease', (139, 151))	('heteroplasmy', 'Disease', 'None', (139, 151))	('MtDNA', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
72478	28940516	Furthermore, somatic mtDNA mutations are neutral, conferring no selective advantage or disadvantage permitting analysis of steady-state clonal competition within the normal human mammary gland 19.	('mutations', 'Var', (27, 36))	('mtDNA', 'Gene', (21, 26))	('human', 'Species', '9606', (173, 178))
72503	28940516	All microdissected cells from CCO-deficient areas contained the same mtDNA mutation (3127G > A), which was not present in the surrounding CCO-proficient cells, demonstrating a clonal expansion (Figure 2F).	('3127G > A', 'Mutation', 'g.3127G>A', (85, 94))	('mtDNA', 'Gene', (69, 74))	('3127G > A', 'Var', (85, 94))
72509	28940516	Figure 4A-L shows CCO-deficient epithelial cells in serial sections of normal adult breast co-localized with alphaSMA-positive myoepithelial cells and CK18-positive luminal epithelial cells.	('CK18', 'Gene', (151, 155))	('myoepithelial', 'Disease', 'MESH:D009208', (127, 140))	('CK18', 'Gene', '3875', (151, 155))	('CCO-deficient', 'Var', (18, 31))	('myoepithelial', 'Disease', (127, 140))
72517	28940516	Areas containing CCO-deficient cells, which were clonal for mtDNA mutations, were found in the normal adult human mammary epithelium and were shown to contain cells of both luminal and myoepithelial lineages, thus demonstrating that both mammary lineages derive from a long-lived and multipotent progenitor cell.	('mutations', 'Var', (66, 75))	('myoepithelial', 'Disease', 'MESH:D009208', (185, 198))	('human', 'Species', '9606', (108, 113))	('mtDNA', 'Gene', (60, 65))	('myoepithelial', 'Disease', (185, 198))
72518	28940516	It has been shown previously that the accrual of a sufficient burden of somatic mutations which result in CCO deficiency may take a considerable period of time (almost 40 years in the human colon) 29.	('mutations', 'Var', (80, 89))	('CCO deficiency', 'Disease', (106, 120))	('CCO deficiency', 'Disease', 'MESH:D020512', (106, 120))	('human', 'Species', '9606', (184, 189))	('result', 'Reg', (96, 102))
72958	24281072	It is well documented in the Lewis-lung model that removal of the primary tumor will reduce angiogenesis inhibitors and it is known that after surgery a sharp spike in angiogenesis stimulators and growth factors occurs to aid in wound healing.	('aid', 'Gene', (222, 225))	('angiogenesis stimulators', 'MPA', (168, 192))	('removal', 'Var', (51, 58))	('Lewis-lung', 'Disease', (29, 39))	('Lewis-lung', 'Disease', 'MESH:D018827', (29, 39))	('reduce', 'NegReg', (85, 91))	('angiogenesis inhibitors', 'MPA', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('primary tumor', 'Disease', (66, 79))	('men', 'Species', '9606', (15, 18))	('wound healing', 'CPA', (229, 242))	('aid', 'Gene', '57379', (222, 225))	('primary tumor', 'Disease', 'MESH:D009369', (66, 79))
73025	24281072	The concept was supported by studies on the effect of partial hepatectomy, sham hepatectomy and observation on the development of hepatic metastases.	('hepatic metastases', 'Disease', 'MESH:D009362', (130, 148))	('partial', 'Var', (54, 61))	('hepatic metastases', 'Disease', (130, 148))	('men', 'Species', '9606', (122, 125))
73026	24281072	In animals subjected to repeated laparotomies with partial hepatectomy, sham hepatectomy, liver manipulation and chemical hepatic injury, the incidence of metastasis progressively increased to virtually 100%.	('metastasis', 'CPA', (155, 165))	('increased', 'PosReg', (180, 189))	('partial hepatectomy', 'Var', (51, 70))	('man', 'Species', '9606', (96, 99))	('hepatic injury', 'Disease', (122, 136))	('hepatic injury', 'Disease', 'MESH:D056486', (122, 136))
73087	24281072	Looking at cancer from the GRN dynamics approach, we may conceive that a rewiring of the network architecture by genetic or epigenetic changes may reshape the attractor landscape, hence allowing the cell to acquire new, self-stabilizing gene expression programs still preserving basic cellular functions.	('rewiring', 'Reg', (73, 81))	('genetic', 'Var', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('reshape', 'Reg', (147, 154))	('attractor landscape', 'MPA', (159, 178))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('epigenetic changes', 'Var', (124, 142))
73156	19847566	In a T1 invasive cancer scenario, 11% of surgeons endorsed margins of tumor not touching ink (TNTI), 42% of 1-2mm, 28% of >=5mm, and 19% >1cm as precluding re-excision.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('invasive cancer', 'Disease', 'MESH:D009362', (8, 23))	('TNTI', 'Chemical', '-', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('>1cm', 'Var', (137, 141))	('tumor', 'Disease', (70, 75))	('invasive cancer', 'Disease', (8, 23))	('1-2mm', 'Var', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
73186	19847566	In the invasive scenario, the mean surgeon ages for those who selected margin widths of tumor not touching ink, > 1-2 mm and > 5 mm were 53.7+/- 10 years, 50.7 +/- 10 years, and 52.4 +/- 10 years, respectively.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('> 1-2 mm', 'Var', (112, 120))	('> 5 mm', 'Var', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
73267	19152687	A selective inhibitor for the hepatocyte growth factor (HGF) receptor, c-met, (100 nM, PHA 665752, Tocris) and/or a broad spectrum MMP inhibitor (10 muM, GM6001, Chemicon, Millipore, Watford, UK) was included in the media at D1 with additional inhibitor added at D3 and D5.	('c-met', 'Gene', '4233', (71, 76))	('MMP', 'Gene', '4313;4314;4318;4320;4322', (131, 134))	('hepatocyte growth factor', 'Gene', '3082', (30, 54))	('muM', 'Gene', '56925', (149, 152))	('c-met', 'Gene', (71, 76))	('GM6001', 'Chemical', 'MESH:C078131', (154, 160))	('muM', 'Gene', (149, 152))	('HGF', 'Gene', (56, 59))	('MMP', 'Gene', (131, 134))	('100', 'Var', (79, 82))	('hepatocyte growth factor', 'Gene', (30, 54))	('HGF', 'Gene', '3082', (56, 59))
73314	19152687	Inhibitors to either the HGF receptor (c-met) and a broad spectrum MMP inhibitor were incorporated into MCF7/myoepithelial/TAF cultures, either alone or in combination, and the frequency of co-unit formation was assessed in comparison to vehicle-only controls (n = 3 for each condition).	('myoepithelial', 'Disease', 'MESH:D009208', (109, 122))	('HGF receptor', 'Gene', (25, 37))	('HGF receptor', 'Gene', '4233', (25, 37))	('c-met', 'Gene', (39, 44))	('Inhibitors', 'Var', (0, 10))	('TAF', 'Gene', '129685', (123, 126))	('MMP', 'Gene', (67, 70))	('myoepithelial', 'Disease', (109, 122))	('c-met', 'Gene', '4233', (39, 44))	('MCF7', 'CellLine', 'CVCL:0031', (104, 108))	('MMP', 'Gene', '4313;4314;4318;4320;4322', (67, 70))	('TAF', 'Gene', (123, 126))
73315	19152687	The presence of the c-met inhibitor significantly increased the average number of co-units from two in the control group to 4.5 (p = 0.016).	('presence', 'Var', (4, 12))	('c-met', 'Gene', (20, 25))	('increased', 'PosReg', (50, 59))	('c-met', 'Gene', '4233', (20, 25))
73326	19152687	We obtained cell lines generated from luminal, myoepithelial and fibroblast populations isolated in a similar fashion to our primary cells and immortalised by transduction with SV40 large T antigen.	('myoepithelial', 'Disease', 'MESH:D009208', (47, 60))	('myoepithelial', 'Disease', (47, 60))	('SV40', 'Var', (177, 181))
73330	19152687	Homing has been shown to be dependant on spatial specificity determined by desmosomal proteins and can be disrupted using peptides to myoepithelial specific desmoglein-3 and desmocollin (Dsc) 3.	('desmocollin (Dsc) 3', 'Gene', (174, 193))	('myoepithelial', 'Disease', 'MESH:D009208', (134, 147))	('desmocollin (Dsc) 3', 'Gene', '1825', (174, 193))	('desmoglein-3', 'Gene', '1830', (157, 169))	('peptides', 'Var', (122, 130))	('Homing', 'CPA', (0, 6))	('myoepithelial', 'Disease', (134, 147))	('desmoglein-3', 'Gene', (157, 169))
73534	28108837	There was a trend towards more BI-RADS category B and less category C women among inconclusive cases, though this was not statistically significant (Fig.	('less', 'NegReg', (54, 58))	('BI-RADS category', 'Var', (31, 47))	('women', 'Species', '9606', (70, 75))
73557	21892261	The hazard ratio for recurrence for HER2/neu positive DCIS was 1.927 (confidence interval 1.016-3.653) compared to HER2 negative DCIS.	('positive DCIS', 'Var', (45, 58))	('HER2', 'Gene', (115, 119))	('HER2/neu', 'Gene', '2064', (36, 44))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (115, 119))	('HER2/neu', 'Gene', (36, 44))	('HER2', 'Gene', '2064', (36, 40))
73606	21892261	HER2/neu oncoprotein overexpression or gene amplification was positive in 45% and 42.9% in cases that recurred as DCIS or invasive cancer respectively, but only in 26.1% of cases that never recurred (p = 0.04).	('oncoprotein', 'Protein', (9, 20))	('invasive cancer', 'Disease', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('overexpression', 'PosReg', (21, 35))	('DCIS', 'Disease', (114, 118))	('HER2/neu', 'Gene', '2064', (0, 8))	('gene amplification', 'Var', (39, 57))	('invasive cancer', 'Disease', 'MESH:D009362', (122, 137))	('HER2/neu', 'Gene', (0, 8))
73609	21892261	Correlation analysis revealed significant associations between ER-negativity, HER2/neu overexpression, MIB1, p53, p21, calgranulin and psoriasin positivity and high tumor grade (p < 0.01).	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('p21', 'Gene', (114, 117))	('calgranulin', 'Protein', (119, 130))	('ER', 'Gene', '2099', (63, 65))	('MIB1', 'Gene', '57534', (103, 107))	('p21', 'Gene', '644914', (114, 117))	('ER', 'Gene', '2099', (79, 81))	('positivity', 'Var', (145, 155))	('high tumor', 'Disease', (160, 170))	('HER2/neu', 'Gene', '2064', (78, 86))	('high tumor', 'Disease', 'MESH:D009369', (160, 170))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('overexpression', 'PosReg', (87, 101))	('MIB1', 'Gene', (103, 107))	('HER2/neu', 'Gene', (78, 86))	('psoriasin', 'Protein', (135, 144))
73610	21892261	Comedo necrosis correlated with PR-negativity, HER2/neu overexpression, MIB1 positivity and p53 positivity (p < 0.01).	('Comedo', 'Phenotype', 'HP:0025249', (0, 6))	('necrosis', 'Disease', (7, 15))	('HER2/neu', 'Gene', '2064', (47, 55))	('PR', 'Gene', '5241', (32, 34))	('MIB1', 'Gene', '57534', (72, 76))	('p53', 'Gene', (92, 95))	('necrosis', 'Disease', 'MESH:D009336', (7, 15))	('overexpression', 'PosReg', (56, 70))	('HER2/neu', 'Gene', (47, 55))	('p53', 'Gene', '7157', (92, 95))	('positivity', 'Var', (77, 87))	('MIB1', 'Gene', (72, 76))
73618	21892261	The hazard ratio for recurrence for HER2 positive DCIS is 1.927 (confidence interval 1.016-3.653) compared to HER2 negative DCIS.	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('HER2', 'Gene', (110, 114))	('positive DCIS', 'Var', (41, 54))	('HER2', 'Gene', '2064', (110, 114))
73637	21892261	In an Australian nested case-control study, both nuclear grade and extensive necrosis were significant predictors of recurrence.	('nuclear grade', 'Var', (49, 62))	('necrosis', 'Disease', (77, 85))	('necrosis', 'Disease', 'MESH:D009336', (77, 85))
73641	21892261	described overexpression and amplification of HER-2/neu in carcinoma-in-situ; but did not correlate it with prognosis in his study.	('carcinoma-in-situ', 'Disease', 'MESH:D002278', (59, 76))	('amplification', 'Var', (29, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('HER-2/neu', 'Gene', (46, 55))	('overexpression', 'PosReg', (10, 24))	('HER-2/neu', 'Gene', '2064', (46, 55))	('carcinoma-in-situ', 'Disease', (59, 76))
73648	21892261	Our findings are in line with one case-control study that found a significant association between HER2/neu positivity and increased risk for recurrence.	('HER2/neu', 'Gene', '2064', (98, 106))	('HER2/neu', 'Gene', (98, 106))	('positivity', 'Var', (107, 117))
73652	21892261	Other studies showed that HER2/neu positivity correlated with high tumor grade and comedo necrosis, p53 accumulation, and was inversely related to ER, PR and bcl-2 expression, but was not found to be an independent prognostic factor.	('high tumor', 'Disease', (62, 72))	('comedo', 'Phenotype', 'HP:0025249', (83, 89))	('ER', 'Gene', '2099', (27, 29))	('bcl-2', 'Gene', (158, 163))	('necrosis', 'Disease', (90, 98))	('ER', 'Gene', '2099', (147, 149))	('expression', 'MPA', (164, 174))	('high tumor', 'Disease', 'MESH:D009369', (62, 72))	('positivity', 'Var', (35, 45))	('accumulation', 'PosReg', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('bcl-2', 'Gene', '596', (158, 163))	('p53', 'Gene', '7157', (100, 103))	('HER2/neu', 'Gene', '2064', (26, 34))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('HER2/neu', 'Gene', (26, 34))	('PR', 'Gene', '5241', (151, 153))	('p53', 'Gene', (100, 103))
73655	21892261	Gene amplification was detected in 9.5% of the benign specimens and was associated with increased risk of invasive breast cancer.	('associated', 'Reg', (72, 82))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('Gene amplification', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('invasive breast cancer', 'Disease', (106, 128))
73666	21892261	In the present study, calgranulin B (S100A9) another member of the S100 family of proteins, was significantly associated with high nuclear grade, psoriasin positivity and HER2/neu overexpression and was inversely associated with ER and PR.	('ER', 'Gene', '2099', (172, 174))	('calgranulin B', 'Gene', '6280', (22, 35))	('overexpression', 'PosReg', (180, 194))	('S100A9', 'Gene', '6280', (37, 43))	('associated', 'Reg', (110, 120))	('HER2/neu', 'Gene', '2064', (171, 179))	('high', 'Var', (126, 130))	('PR', 'Gene', '5241', (236, 238))	('positivity', 'Var', (156, 166))	('psoriasin', 'Protein', (146, 155))	('ER', 'Gene', '2099', (229, 231))	('HER2/neu', 'Gene', (171, 179))	('calgranulin B', 'Gene', (22, 35))	('S100A9', 'Gene', (37, 43))
73714	24147085	Some imaging and pathological variables that were essential for this study had not been (fully) documented for the COBRA and COBRA 2000 study: maximum lesion diameter, lobular cancerization, presence of necrosis and presence of microinvasion (defined as the extension of cancer cells beyond the basement membrane into the adjacent tissues with no focus more than 0.1 cm in greatest dimension).	('lobular', 'Disease', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('presence', 'Reg', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('necrosis', 'Disease', 'MESH:D009336', (203, 211))	('microinvasion', 'Var', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (271, 277))	('necrosis', 'Disease', (203, 211))
73728	24147085	The mean predicted probability was 0.34 in women with DCIS underestimation and 0.27 in women without DCIS underestimation, resulting in an absolute difference of 0.07 (discrimination slope).	('underestimation', 'Var', (59, 74))	('women', 'Species', '9606', (43, 48))	('DCIS', 'Disease', (54, 58))	('women', 'Species', '9606', (87, 92))
73742	24147085	In the multivariable model, the predictors mammographic lesion size, radiological classification, DCIS histological grade, necrosis, lobular cancerization, and microinvasion were found to have a positive association with DCIS underestimation.	('lobular', 'Disease', (133, 140))	('necrosis', 'Disease', 'MESH:D009336', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DCIS underestimation', 'Disease', (221, 241))	('microinvasion', 'Var', (160, 173))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('necrosis', 'Disease', (123, 131))	('cancer', 'Disease', (141, 147))
73762	19741276	Specifically, inhomogenous broadening of the water resonance will increase signal in off-peak components, and can be used as a source of MR contrast.	('increase', 'PosReg', (66, 74))	('water', 'Chemical', 'MESH:D014867', (45, 50))	('signal in off-peak components', 'MPA', (75, 104))	('inhomogenous broadening', 'Var', (14, 37))
73765	19741276	In the present work, FCIs of 32 patients are evaluated, and the presence of spatially correlated variations in water resonance structure is correlated to biopsy results and BIRADS rating.	('patients', 'Species', '9606', (32, 40))	('water resonance structure', 'MPA', (111, 136))	('FCIs', 'Chemical', '-', (21, 25))	('variations', 'Var', (97, 107))	('water', 'Chemical', 'MESH:D014867', (111, 116))
73795	19741276	Inhomogeneously broadened voxels will have higher intensity FCIDelta than voxels with Lorentzian water lineshapes.	('higher', 'PosReg', (43, 49))	('Inhomogeneously', 'Var', (0, 15))	('intensity FCIDelta', 'MPA', (50, 68))	('water', 'Chemical', 'MESH:D014867', (97, 102))	('FCI', 'Chemical', '-', (60, 63))
73834	19741276	Off-resonance water signal is the result of local microscopic (sub-voxel) variations in magnetic susceptibility - which could be produced at the boundaries of blood vessels, microcalcifications, and other anatomic boundaries.	('Off-resonance water signal', 'MPA', (0, 26))	('water', 'Chemical', 'MESH:D014867', (14, 19))	('magnetic susceptibility -', 'MPA', (88, 113))	('variations', 'Var', (74, 84))
73961	25265904	IDC patients also showed significant association between nuclear Ep-ICD expression and reduced disease-free survival (p < 0.001; Figure 3B).	('ICD', 'Gene', '79158', (68, 71))	('disease-free survival', 'CPA', (95, 116))	('reduced', 'NegReg', (87, 94))	('IDC', 'Gene', '4000', (0, 3))	('nuclear', 'Var', (57, 64))	('IDC', 'Gene', (0, 3))	('patients', 'Species', '9606', (4, 12))	('ICD', 'Gene', (68, 71))
73992	25265904	The in vitro studies on functional role of EpCAM in breast cancer cell lines demonstrated that transfection of EpCAM resulted in increased nuclear accumulation of beta-catenin in MDA-MB-231EpCAM and upregulated Wnt reporter assay activity in Hs578TEpCAM cells suggesting activation of Wnt pathway.	('EpCAM', 'Gene', (248, 253))	('transfection', 'Var', (95, 107))	('EpCAM', 'Gene', '4072', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('EpCAM', 'Gene', (111, 116))	('nuclear accumulation', 'MPA', (139, 159))	('Wnt reporter', 'Pathway', (211, 223))	('increased', 'PosReg', (129, 138))	('EpCAM', 'Gene', '4072', (111, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('EpCAM', 'Gene', (189, 194))	('EpCAM', 'Gene', '4072', (189, 194))	('beta-catenin', 'Gene', (163, 175))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Disease', (52, 65))	('beta-catenin', 'Gene', '1499', (163, 175))	('EpCAM', 'Gene', (43, 48))	('upregulated', 'PosReg', (199, 210))	('Wnt pathway', 'Pathway', (285, 296))	('EpCAM', 'Gene', '4072', (43, 48))
73999	25265904	The prevalence of the full length EpCAM and Ep-ICD in a variety of human cancers has been recently reported using tissue microarrays suggesting loss of membranous EpEx is a common event in human epithelial cancers and the ratio of EpEx and Ep-ICD is dependent on the tumor.	('loss', 'Var', (144, 148))	('ICD', 'Gene', '79158', (47, 50))	('EpCAM', 'Gene', '4072', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('ICD', 'Gene', '79158', (243, 246))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('ICD', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('human', 'Species', '9606', (189, 194))	('epithelial cancers', 'Disease', (195, 213))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('ICD', 'Gene', (243, 246))	('epithelial cancers', 'Disease', 'MESH:D000077216', (195, 213))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('tumor', 'Disease', (267, 272))	('human', 'Species', '9606', (67, 72))	('EpCAM', 'Gene', (34, 39))
74001	25265904	Future studies evaluating the prognostic and predictive role of these variants in human cancers, especially in patients treated with Ep-CAM specific antibodies are warranted.	('Ep-CAM', 'Gene', '4072', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('variants', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Ep-CAM', 'Gene', (133, 139))	('human', 'Species', '9606', (82, 87))	('patients', 'Species', '9606', (111, 119))
74006	25265904	At the same time the absence of nuclear Ep-ICD in early stage breast cancer patients also has the potential to help avoid over-treatment, sparing these patients the harmful side effects of aggressive therapies and reducing health care costs upon validation in future studies.	('ICD', 'Gene', '79158', (43, 46))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('sparing', 'NegReg', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('absence', 'Var', (21, 28))	('breast cancer', 'Disease', (62, 75))	('patients', 'Species', '9606', (152, 160))	('ICD', 'Gene', (43, 46))
74023	29786129	Reoperations negatively impact patient care by delaying the initiation and completion of adjuvant therapies, increasing health care costs, diminishing aesthetic outcomes, contributing to increased infection rates, and exacerbating patient-specific psychological stressors.	('patient care', 'CPA', (31, 43))	('health care costs', 'CPA', (120, 137))	('delaying', 'NegReg', (47, 55))	('increasing', 'PosReg', (109, 119))	('infection rates', 'CPA', (197, 212))	('diminishing', 'NegReg', (139, 150))	('impact', 'Reg', (24, 30))	('exacerbating', 'PosReg', (218, 230))	('patient', 'Species', '9606', (31, 38))	('increased', 'PosReg', (187, 196))	('aesthetic', 'MPA', (151, 160))	('negatively', 'NegReg', (13, 23))	('patient', 'Species', '9606', (231, 238))	('Reoperations', 'Var', (0, 12))
74065	21483040	Gerosuppressant Metformin: less is more Further expanding the major findings of the landmark study by Harrison and colleagues showing that late-life pharmacological inhibition of the enzyme mammalian Target Of Rapamycin (mTOR) -a conserved integrator of nutrient and growth factor signaling- is sufficient to significantly extend lifespan in mice on rapamycin feeding, Selman and colleagues have recently revealed that loss of the ribosomal S6 protein kinase S6K1 -a downstream target and effector of mTOR- can similarly provide health and longevity effects without detrimental effects when targeted pharmacologically.	('mice', 'Species', '10090', (342, 346))	('loss', 'Var', (419, 423))	('rat', 'Species', '10116', (245, 248))	('mammalian Target Of Rapamycin', 'Gene', (190, 219))	('ribosomal S6 protein kinase S6K1', 'Enzyme', (431, 463))	('mammalian Target Of Rapamycin', 'Gene', '2475', (190, 219))	('inhibition', 'Var', (165, 175))
74066	21483040	As previously observed in calorie restriction (CR)-related interventions that similarly delayed aging in Caenorhabditis elegans, rodents and rhesus monkeys, long-lived S6K1 knockout animals exhibit a reduced body size.	('body size', 'CPA', (208, 217))	('knockout', 'Var', (173, 181))	('reduced', 'NegReg', (200, 207))	('S6K1', 'Gene', (168, 172))	('Caenorhabditis elegans', 'Species', '6239', (105, 127))	('rhesus monkeys', 'Species', '9544', (141, 155))	('CR', 'Chemical', '-', (47, 49))
74069	21483040	activation of AMPK and inhibition of mTOR/S6K1 leading to extensive activation of autophagic catabolism) aimed to slow-down cellular division-dependent accumulation of genomic damage.	('inhibition', 'Var', (23, 33))	('AMPK', 'Gene', '5563', (14, 18))	('slow-down', 'NegReg', (114, 123))	('activation', 'PosReg', (68, 78))	('mTOR/S6K1', 'Gene', (37, 46))	('AMPK', 'Gene', (14, 18))	('cellular division-dependent accumulation', 'CPA', (124, 164))
74071	21483040	If activation of AMPK (and/or inhibition of mTOR/S6K1) constitutes the best metabolic response to avoid that a normal growth rate would compromise somatic integrity in progeroid animals, it is reasonable to suggest that the occurrence of AMPK upregulation upon loss of S6K1 would lead also to reductions in cell growth/division rates in order to avoid that bioenergetic stresses might trigger cell death.	('rat', 'Species', '10116', (125, 128))	('reductions', 'NegReg', (293, 303))	('AMPK', 'Gene', (238, 242))	('loss', 'Var', (261, 265))	('cell growth/division rates', 'CPA', (307, 333))	('death', 'Disease', 'MESH:D003643', (398, 403))	('death', 'Disease', (398, 403))	('rat', 'Species', '10116', (328, 331))	('AMPK', 'Gene', (17, 21))	('upregulation', 'PosReg', (243, 255))	('S6K1', 'Gene', (269, 273))	('AMPK', 'Gene', '5563', (238, 242))	('AMPK', 'Gene', '5563', (17, 21))
74085	21483040	In vitro studies have suggested that metformin might molecularly recapitulate most of the pro-longevity effects occurring upon loss of S6K1.	('pro-longevity', 'CPA', (90, 103))	('loss', 'Var', (127, 131))	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('S6K1', 'Gene', (135, 139))
74087	21483040	Despite overall reduction in global mRNA translation in response to metformin-induced dephosphorylation of S6K1, metformin treatment triggers a complex transcriptional program that includes upregulation of genes coding for several aminoacyl-tRNA synthetases and RNA helicases, which might account for yet to be determined metformin-regulated mechanisms of differential translation with respect to specific mRNAs.	('metformin', 'Var', (113, 122))	('response', 'MPA', (56, 64))	('metformin', 'Chemical', 'MESH:D008687', (322, 331))	('global mRNA translation', 'MPA', (29, 52))	('RNA helicases', 'Protein', (262, 275))	('metformin', 'Chemical', 'MESH:D008687', (113, 122))	('reduction', 'NegReg', (16, 25))	('upregulation', 'PosReg', (190, 202))	('dephosphorylation', 'MPA', (86, 103))	('S6K1', 'Gene', (107, 111))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))
74088	21483040	A similar mechanism has been suggested by Selman and colleagues to explain the occurrence of AMPK protein upregulation upon loss of S6K1.	('AMPK', 'Gene', (93, 97))	('loss', 'Var', (124, 128))	('S6K1', 'Gene', (132, 136))	('AMPK', 'Gene', '5563', (93, 97))	('upregulation', 'PosReg', (106, 118))
74092	21483040	Inactivation of the Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, has been recently shown to decrease reprogramming efficiency and leads to genomic instability in iPS cells.	('genomic instability', 'CPA', (203, 222))	('ATM', 'Gene', '472', (51, 54))	('Ataxia-telangiectasia mutated', 'Gene', '472', (20, 49))	('reprogramming efficiency', 'CPA', (165, 189))	('leads to', 'Reg', (194, 202))	('Ataxia', 'Phenotype', 'HP:0001251', (20, 26))	('Ataxia-telangiectasia mutated', 'Gene', (20, 49))	('decrease', 'NegReg', (156, 164))	('ATM', 'Gene', (51, 54))	('Inactivation', 'Var', (0, 12))	('telangiectasia', 'Phenotype', 'HP:0001009', (27, 41))
74096	21483040	Metformin's ability to enhance the epithelial behavior of cancer cells not only may occur through transcriptional inhibition of the "E-cadherin repressor interactome" (thus enhancing the expression of the metastasis suppressor protein E-cadherin at cell-cell junctions) but also by epigenetically preserving the differentiated phenotype of human epithelia via upregulation of the microRNA let-7a, a crucial regulator of CSC maintenance and point at connection between EMT and CSC formation.	('microRNA', 'Protein', (380, 388))	('human', 'Species', '9606', (340, 345))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('epithelial behavior', 'CPA', (35, 54))	('E-cadherin', 'Gene', (235, 245))	('E-cadherin', 'Gene', (133, 143))	('cancer', 'Disease', (58, 64))	('epigenetically', 'Var', (282, 296))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('E-cadherin', 'Gene', '999', (235, 245))	('E-cadherin', 'Gene', '999', (133, 143))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('expression', 'MPA', (187, 197))	('upregulation', 'PosReg', (360, 372))	('enhancing', 'PosReg', (173, 182))	('enhance', 'PosReg', (23, 30))
74110	21483040	Metformin was found to extend the mean lifespan of the longest-living animals (i.e.	('Metformin', 'Var', (0, 9))	('extend', 'PosReg', (23, 29))	('mean lifespan', 'CPA', (34, 47))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))
74119	21483040	In contrast, if started late in life, metformin treatment appears to significantly reduce (by 13%) the mean lifespan of tumor-free mice.	('metformin', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('metformin', 'Chemical', 'MESH:D008687', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mice', 'Species', '10090', (131, 135))	('reduce', 'NegReg', (83, 89))	('tumor', 'Disease', (120, 125))
74125	21483040	dose and/or time), a recently conducted retrospective study has reported an impressive 56% decrease in breast cancer risk among diabetic receiving metformin compared with diabetics treated with other therapies.	('diabetic', 'Disease', 'MESH:D003920', (171, 179))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('metformin', 'Var', (147, 156))	('diabetic', 'Disease', (171, 179))	('breast cancer', 'Disease', (103, 116))	('diabetic', 'Disease', 'MESH:D003920', (128, 136))	('diabetics', 'Disease', (171, 180))	('metformin', 'Chemical', 'MESH:D008687', (147, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('diabetic', 'Disease', (128, 136))	('diabetics', 'Disease', 'MESH:D003920', (171, 180))	('decrease', 'NegReg', (91, 99))
74128	21483040	neu-N transgenic mouse model of mammary cancer) strains of rodents, metformin's ability to prolong lifespan without affecting cancer in non-cancer-prone strain of rodents (e. g. SHR) may suggest that metformin can prolong life (and delay aging) by mechanisms unrelated to its ability to suppress cancer.	('mouse', 'Species', '10090', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (40, 46))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))	('metformin', 'Var', (200, 209))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('delay', 'NegReg', (232, 237))	('metformin', 'Chemical', 'MESH:D008687', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (140, 146))	('non-cancer', 'Disease', 'MESH:D009369', (136, 146))	('prolong', 'PosReg', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('non-cancer', 'Disease', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('transgenic', 'Species', '10090', (6, 16))	('cancer', 'Disease', (296, 302))
74134	21483040	Treatment of neu-N transgenic mice with the semi-synthetic inhibitor of FASN activity C75 has been found to significantly delay mammary tumor development (i.e.	('C75', 'Var', (86, 89))	('delay', 'NegReg', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('transgenic mice', 'Species', '10090', (19, 34))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
74135	21483040	solely 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days compared to 50% in the vehicle control animals) and complete prevention of the disease in some neu-N animals.	('carcinoma', 'Disease', (64, 73))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (56, 73))	('developed', 'PosReg', (46, 55))	('transgenic mice', 'Species', '10090', (30, 45))	('carcinoma', 'Disease', 'MESH:D002277', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('C75-treated', 'Var', (18, 29))
74155	21483040	In Anisimov's experiments, however, metformin treatment was found to significantly decrease body temperature when its administration started at the age of 3 and 9 months but it failed to significantly affect levels of serum cholesterol, triglycerides, glucose and insulin.	('triglycerides', 'Chemical', 'MESH:D014280', (237, 250))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('body temperature', 'MPA', (92, 108))	('rat', 'Species', '10116', (126, 129))	('decrease', 'NegReg', (83, 91))	('cholesterol', 'Chemical', 'MESH:D002784', (224, 235))	('rat', 'Species', '10116', (102, 105))	('triglycerides', 'MPA', (237, 250))	('glucose and insulin', 'Disease', 'MESH:D007333', (252, 271))	('metformin', 'Var', (36, 45))
74161	21483040	In this regard, an ideal scenario relates to genetic susceptibility to breast and ovarian cancer in women arising from a mutation in the BRCA1 gene, which is one of the most widespread genetic diseases.	('susceptibility', 'Reg', (53, 67))	('genetic diseases', 'Disease', 'MESH:D030342', (185, 201))	('BRCA1', 'Gene', '672', (137, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('women', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRCA1', 'Gene', (137, 142))	('mutation', 'Var', (121, 129))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (71, 96))	('genetic diseases', 'Disease', (185, 201))
74162	21483040	Women with a mutation have a 65% risk of developing breast cancer before age 70.	('Women', 'Species', '9606', (0, 5))	('mutation', 'Var', (13, 21))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
74163	21483040	Breast and ovarian cancers linked to mutations in BRCA1 are likely one of the main genetically-related causes of death in middle-age women and can be therefore regarded as important deleterious mutations in old age mortality.	('Breast and ovarian cancers', 'Disease', 'MESH:D010051', (0, 26))	('linked', 'Reg', (27, 33))	('BRCA1', 'Gene', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('women', 'Species', '9606', (133, 138))	('death', 'Disease', 'MESH:D003643', (113, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('death', 'Disease', (113, 118))	('mutations', 'Var', (37, 46))	('ovarian cancers', 'Phenotype', 'HP:0100615', (11, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('BRCA1', 'Gene', '672', (50, 55))
74164	21483040	Indeed, when all BRCA1 mutations are taken together, the prevalence of breast and ovarian cancer linked to the BRCA1 locus is one of the highest among late-onset diseases.	('BRCA1', 'Gene', '672', (17, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRCA1', 'Gene', (17, 22))	('BRCA1', 'Gene', '672', (111, 116))	('mutations', 'Var', (23, 32))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (71, 96))	('BRCA1', 'Gene', (111, 116))
74168	21483040	breast cancer in BRCA1 carriers) and that, therefore, alleles under negative selection small enough to be traded-off for a positive effect at younger ages (e.g.	('BRCA1', 'Gene', '672', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('BRCA1', 'Gene', (17, 22))	('breast cancer', 'Disease', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('carriers', 'Var', (23, 31))
74173	21483040	On the one hand, specific sequences of BRCA1 have been found to play a crucial role in longevity because their alteration results in the development of aging-like phenotypes including growth retardation and skin abnormalities.	('skin abnormalities', 'Disease', 'MESH:D012868', (207, 225))	('rat', 'Species', '10116', (115, 118))	('skin abnormalities', 'Phenotype', 'HP:0000951', (207, 225))	('growth retardation', 'Phenotype', 'HP:0001510', (184, 202))	('results in', 'Reg', (122, 132))	('BRCA1', 'Gene', '672', (39, 44))	('skin abnormalities', 'Disease', (207, 225))	('growth retardation', 'Disease', 'MESH:D006130', (184, 202))	('alteration', 'Var', (111, 121))	('growth retardation', 'Disease', (184, 202))	('BRCA1', 'Gene', (39, 44))
74176	21483040	Because BRCA1 selectively inhibits aromatase expression and thus local, pro-tumorigenic estrogen production in breast adipose fibroblasts, breast adipose stromal cells and breast malignant epithelial cells, metformin's ability to concurrently inhibit IGF-1, endogenous lipogenesis and aromatase expression must be carefully evaluated on its impact against the "endocrine-genotoxic liberation" that occurs upon transfer from the wild-type to the mutant BRCA1.	('inhibits', 'NegReg', (26, 34))	('metformin', 'Chemical', 'MESH:D008687', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('aromatase', 'MPA', (35, 44))	('tumor', 'Disease', (76, 81))	('BRCA1', 'Gene', '672', (8, 13))	('inhibit', 'NegReg', (243, 250))	('mutant', 'Var', (445, 451))	('BRCA1', 'Gene', '672', (452, 457))	('IGF-1', 'Gene', '3479', (251, 256))	('IGF-1', 'Gene', (251, 256))	('rat', 'Species', '10116', (385, 388))	('BRCA1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('BRCA1', 'Gene', (452, 457))
74177	21483040	Further studies are warranted to evaluate if metformin treatment significantly modifies cancer risk due to deleterious BRCA1 gene mutations to decrease middle-age women mortality and/or late-onset familial cancer.	('familial cancer', 'Disease', 'MESH:D009369', (197, 212))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('women', 'Species', '9606', (163, 168))	('decrease', 'NegReg', (143, 151))	('BRCA1', 'Gene', (119, 124))	('mutations', 'Var', (130, 139))	('familial cancer', 'Disease', (197, 212))	('middle-age women mortality', 'CPA', (152, 178))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('modifies', 'Reg', (79, 87))	('BRCA1', 'Gene', '672', (119, 124))
74184	21483040	When some of theses hallmarks of senescent cells were qualitatively assessed in skin fibroblasts from SHR mice, metformin treatment was found to reduce the number of SAHF foci, the average nuclei area, and the nuclei accumulation of gammaH2AX compared to untreated control skin fibroblasts.	('gammaH2AX', 'Gene', (233, 242))	('SAHF foci', 'Disease', 'MESH:C565785', (166, 175))	('mice', 'Species', '10090', (106, 110))	('nuclei accumulation', 'CPA', (210, 229))	('metformin', 'Chemical', 'MESH:D008687', (112, 121))	('SAHF foci', 'Disease', (166, 175))	('gammaH2AX', 'Gene', '15270', (233, 242))	('reduce', 'NegReg', (145, 151))	('metformin', 'Var', (112, 121))
74191	21483040	Although it cannot be excluded that metformin treatment may actively inhibit production of new senescent cells (thus decreasing their "normal" frequency of accumulation in aging tissues) the fact that senescent cells are turned over slowly strongly suggests that metformin may enhance immune system responsiveness to senescent cells (thus increasing their "normal" clearance rate in aging tissues).	('metformin', 'Chemical', 'MESH:D008687', (263, 272))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('increasing', 'PosReg', (339, 349))	('immune', 'CPA', (285, 291))	('clearance', 'CPA', (365, 374))	('decreasing', 'NegReg', (117, 127))	('metformin', 'Var', (263, 272))	('rat', 'Species', '10116', (375, 378))	('inhibit', 'NegReg', (69, 76))	('enhance', 'PosReg', (277, 284))
74198	21483040	rapamycin has immunostimulatory effects on the generation of memory CD8 T cells, and c.) metformin itself enhances CD8 T-cell memory.	('CD8', 'Gene', '925', (115, 118))	('CD8', 'Gene', (68, 71))	('CD8', 'Gene', '925', (68, 71))	('metformin', 'Chemical', 'MESH:D008687', (89, 98))	('c.', 'Var', (85, 87))	('enhances', 'PosReg', (106, 114))	('CD8', 'Gene', (115, 118))	('rat', 'Species', '10116', (51, 54))
74199	21483040	Indeed, metformin-induced alteration in fatty acid metabolism during development of memory CD8 T cells has been found to considerable improve the efficacy of an anti-cancer vaccine.	('CD8', 'Gene', (91, 94))	('metformin', 'Chemical', 'MESH:D008687', (8, 17))	('improve', 'PosReg', (134, 141))	('cancer', 'Disease', (166, 172))	('CD8', 'Gene', '925', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('fatty acid metabolism', 'MPA', (40, 61))	('alteration', 'Var', (26, 36))	('rat', 'Species', '10116', (30, 33))	('fatty acid', 'Chemical', 'MESH:D005227', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('efficacy', 'MPA', (146, 154))
74204	21483040	by inactivating p53) causes a significant acceleration in the development of human tumors whereas the senescence response in established malignant states is associated with tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('acceleration', 'PosReg', (42, 54))	('tumor', 'Disease', (83, 88))	('p53', 'Gene', (16, 19))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('p53', 'Gene', '7157', (16, 19))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('inactivating', 'Var', (3, 15))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('rat', 'Species', '10116', (48, 51))	('human', 'Species', '9606', (77, 82))
74229	21483040	Landmark studies of Lin et al and Campaner et al have recently found that the inhibition of the activity of cyclin dependent kinases (CDKs) plays a significant role in establishing protective cellular senescence; particularly, inhibition of CDK2 activity appears to be critical to lower the bar for triggering senescence in tumor cells.	('CDKs', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('CDK2', 'Gene', (241, 245))	('tumor', 'Disease', (324, 329))	('CDKs', 'Gene', '1017', (134, 138))	('inhibition', 'Var', (227, 237))	('activity', 'MPA', (246, 254))	('CDK2', 'Gene', '1017', (241, 245))	('bar', 'MPA', (291, 294))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
74235	21483040	pharmacological and small inhibitory RNA-targeted ablation of FASN lipogenic activity -a well recognized metformin's molecular target- causes a dramatic down-regulation of Skp2 to promote a prominent accumulation of p27Kip1.	('p27Kip1', 'Gene', '1027', (216, 223))	('down-regulation', 'NegReg', (153, 168))	('Skp2', 'Gene', (172, 176))	('ablation', 'Var', (50, 58))	('metformin', 'Chemical', 'MESH:D008687', (105, 114))	('p27Kip1', 'Gene', (216, 223))	('accumulation', 'PosReg', (200, 212))	('promote', 'PosReg', (180, 187))
74237	21483040	As reported by Lin et al, Skp2 inactivation on its own failed to induce cellular senescence; however, aberrant proto-oncogenic signals as well as inactivation of tumor suppressor genes triggered a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (162, 167))	('inactivation', 'Var', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('mice', 'Species', '10090', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('aberrant', 'Var', (102, 110))
74238	21483040	It would be relevant to evaluate whether metformin co-exposure may favour the "accelerated senescence" triggered in normal cells by the expression of mutant Ras or Raf (oncogene-induced senescence) and by some other forms of supraphysiological mitogenic signaling getting stuck irrespective of senescence-inhibiting adaptations (e.g.	('favour', 'PosReg', (67, 73))	('rat', 'Species', '10116', (85, 88))	('Raf', 'Gene', (164, 167))	('metformin', 'Chemical', 'MESH:D008687', (41, 50))	('Ras', 'Gene', (157, 160))	('mutant', 'Var', (150, 156))	('Raf', 'Gene', '22882', (164, 167))
74239	21483040	inactivation of p53).	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (16, 19))	('inactivation', 'Var', (0, 12))
74263	21483040	It is tempting to suggest that chronic exposure to sub-clinical doses of metformin institutes an autonomously-driven feedback regulatory loop of intermediary metabolism which ignores numerous & tissue-specific gero-promoting signaling to such a degree that it can significantly extend lifespan and postpone tumor formation.	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('metformin', 'Var', (73, 82))	('extend', 'CPA', (278, 284))	('tumor', 'Disease', (307, 312))	('metformin', 'Chemical', 'MESH:D008687', (73, 82))	('significantly', 'PosReg', (264, 277))
74266	21483040	Indeed, pharmacological activation of AMPK or inhibition of mTOR prevented age-associated pathologies induced by loss of sestrins.	('sestrins', 'Protein', (121, 129))	('inhibition', 'NegReg', (46, 56))	('AMPK', 'Gene', '5563', (38, 42))	('prevented', 'NegReg', (65, 74))	('loss', 'Var', (113, 117))	('AMPK', 'Gene', (38, 42))	('mTOR', 'Gene', (60, 64))	('age-associated pathologies', 'Disease', (75, 101))	('sestrin', 'Chemical', '-', (121, 128))
74272	18681966	Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('stimulate', 'PosReg', (309, 318))	('cytotoxicity', 'Disease', (128, 140))	('chemotherapy-induced apoptosis', 'CPA', (355, 385))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Prolactin receptor', 'Gene', '5618', (0, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Prolactin receptor', 'Gene', (0, 18))	('growth', 'CPA', (325, 331))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('breast cancer', 'Disease', (195, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('reduces', 'NegReg', (30, 37))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))	('breast cancer', 'Disease', (266, 279))	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('antagonism', 'Var', (19, 29))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('breast cancer', 'Disease', (65, 78))	('clonogenic capacity', 'CPA', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('potentiates', 'PosReg', (89, 100))
74277	18681966	Delta1-9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel.	('Delta1-9', 'Var', (0, 8))	('paclitaxel', 'Chemical', 'MESH:D017239', (139, 149))	('doxorubicin', 'Chemical', 'MESH:D004317', (123, 134))	('cytotoxic effects', 'CPA', (102, 119))	('potentiated', 'PosReg', (86, 97))
74283	18681966	Exogenous prolactin has been shown to induce the proliferation, survival, migration and invasion of breast cancer cell lines in vitro and to increase the clonogenicity of primary human breast cancer samples in soft agar.	('clonogenicity', 'CPA', (154, 167))	('Exogenous', 'Var', (0, 9))	('survival', 'CPA', (64, 72))	('human', 'Species', '9606', (179, 184))	('invasion', 'CPA', (88, 96))	('induce', 'PosReg', (38, 44))	('increase', 'PosReg', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('proliferation', 'CPA', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', (185, 198))	('migration', 'CPA', (74, 83))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('agar', 'Chemical', 'MESH:D000362', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
74289	18681966	This corroborates preclinical data in breast and ovarian cancers and myeloma in which exogenous prolactin reduced the apoptotic response to commonly used cytotoxic agents.	('exogenous', 'Var', (86, 95))	('prolactin reduced', 'Phenotype', 'HP:0008202', (96, 113))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (38, 64))	('myeloma', 'Disease', 'MESH:D009101', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ovarian cancers', 'Phenotype', 'HP:0100615', (49, 64))	('myeloma', 'Disease', (69, 76))	('reduced', 'NegReg', (106, 113))
74290	18681966	Furthermore, breast cancer cell lines engineered to overexpress autocrine prolactin are resistant to taxane-mediated cell death both in vitro and in tumour xenografts in vivo .	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('taxane', 'Chemical', 'MESH:C080625', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (13, 26))	('resistant', 'CPA', (88, 97))	('overexpress', 'PosReg', (52, 63))	('autocrine', 'Var', (64, 73))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))
74295	18681966	Neutralising prolactin antibodies have been shown to inhibit MCF-7 and T47Dco cell growth by 20% to 85% and to increase cell death twofold to threefold; however, no in vivo data have been reported on this approach.	('increase', 'PosReg', (111, 119))	('inhibit', 'NegReg', (53, 60))	('antibodies', 'Var', (23, 33))	('cell death', 'CPA', (120, 130))	('prolactin', 'Protein', (13, 22))	('MCF-7', 'CPA', (61, 66))	('T47D', 'CellLine', 'CVCL:0553', (71, 75))	('MCF-7', 'CellLine', 'CVCL:0031', (61, 66))
74296	18681966	In the latter study, prolactin neutralisation also resulted in additive augmentation of the apoptotic effects of exogenous ceramide.	('augmentation', 'PosReg', (72, 84))	('prolactin', 'Protein', (21, 30))	('ceramide', 'Chemical', 'MESH:D002518', (123, 131))	('apoptotic', 'CPA', (92, 101))	('neutralisation', 'Var', (31, 45))
74297	18681966	The human PRLR antagonist G129R-hPRL was developed by site-directed mutagenesis, with the substitution of glycine for arginine at position 129 in the third alpha helix.	('glycine', 'Var', (106, 113))	('human', 'Species', '9606', (4, 9))	('hPRL', 'Gene', (32, 36))	('glycine for arginine at position 129', 'Mutation', 'p.R129G', (106, 142))	('PRLR', 'Gene', (10, 14))	('hPRL', 'Gene', '5617', (32, 36))	('G129R', 'Mutation', 'p.G129R', (26, 31))	('PRLR', 'Gene', '5618', (10, 14))	('substitution', 'Var', (90, 102))
74298	18681966	This mutation sterically hinders the sequential dimerisation and subsequent activation of the PRLR, but notably reduces the PRLR binding affinity 10-fold.	('sequential dimerisation', 'MPA', (37, 60))	('reduces', 'NegReg', (112, 119))	('activation', 'MPA', (76, 86))	('PRLR', 'Gene', (124, 128))	('PRLR', 'Gene', (94, 98))	('hinders', 'NegReg', (25, 32))	('PRLR', 'Gene', '5618', (124, 128))	('PRLR', 'Gene', '5618', (94, 98))	('mutation', 'Var', (5, 13))
74301	18681966	The single G129R mutation does not remove all agonist activity, however, as demonstrated by high sensitivity assays in vitro and in the prostate gland in vivo, where G129R-hPRL was overexpressed using the metallothionein promoter.	('G129R', 'Mutation', 'p.G129R', (166, 171))	('hPRL', 'Gene', '5617', (172, 176))	('agonist activity', 'MPA', (46, 62))	('hPRL', 'Gene', (172, 176))	('G129R', 'Var', (11, 16))	('G129R', 'Mutation', 'p.G129R', (11, 16))
74303	18681966	Further modification of G129R by its N-terminal truncation results in a 'pure' PRLR antagonist, Delta1-9 G129R-hPRL (Delta1-9), which is devoid of any agonist activity.	('G129R', 'Mutation', 'p.G129R', (24, 29))	('hPRL', 'Gene', '5617', (111, 115))	('PRLR', 'Gene', (79, 83))	('G129R', 'Mutation', 'p.G129R', (105, 110))	('PRLR', 'Gene', '5618', (79, 83))	('Delta1-9', 'Var', (96, 104))	('G129R', 'Var', (24, 29))	('hPRL', 'Gene', (111, 115))
74304	18681966	Coinjection of female Balb-c/J mice with Delta1-9 and exogenous prolactin reduced the prolactin-induced activation of STAT3 and STAT5 but only at an antagonist/prolactin ratio of 100:1.	('activation', 'PosReg', (104, 114))	('STAT5', 'Gene', '20850', (128, 133))	('prolactin-induced', 'MPA', (86, 103))	('STAT3', 'Gene', '20848', (118, 123))	('prolactin reduced', 'Phenotype', 'HP:0008202', (64, 81))	('STAT3', 'Gene', (118, 123))	('mice', 'Species', '10090', (31, 35))	('STAT5', 'Gene', (128, 133))	('reduced', 'NegReg', (74, 81))	('Delta1-9', 'Var', (41, 49))
74306	18681966	No further data are published on Delta1-9 in breast cancer, however it has been shown to induce apoptosis in prostate cancer cell lines by antagonising autocrine prolactin-mediated janus kinase 2 (JAK2)/STAT5A/B signalling.	('STAT5A', 'Gene', (203, 209))	('JAK2', 'Gene', '3717', (197, 201))	('induce', 'PosReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('prostate cancer', 'Disease', (109, 124))	('STAT5A', 'Gene', '6776', (203, 209))	('JAK2', 'Gene', (197, 201))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('janus kinase 2', 'Gene', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Delta1-9', 'Var', (33, 41))	('janus kinase 2', 'Gene', '3717', (181, 195))	('breast cancer', 'Disease', (45, 58))	('apoptosis', 'CPA', (96, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('antagonising', 'NegReg', (139, 151))
74308	18681966	Although ineffective at inhibiting breast cancer cell line growth in monolayer culture as a single agent, Delta1-9 significantly augmented the cytotoxic effects of doxorubicin and paclitaxel.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('paclitaxel', 'Chemical', 'MESH:D017239', (180, 190))	('doxorubicin', 'Chemical', 'MESH:D004317', (164, 175))	('augmented', 'PosReg', (129, 138))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('Delta1-9', 'Var', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('cytotoxic effects', 'CPA', (143, 160))
74310	18681966	In addition, we demonstrate for the first time that prolactin receptor antagonism markedly inhibited the colony forming efficiency of cell lines and primary cancers in vitro.	('prolactin receptor', 'Gene', '5618', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('antagonism', 'Var', (71, 81))	('primary cancers', 'Disease', (149, 164))	('inhibited', 'NegReg', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('primary cancers', 'Disease', 'MESH:D009369', (149, 164))	('prolactin receptor', 'Gene', (52, 70))
74346	18681966	In the development of the growth hormone receptor antagonist Peg-Visomant (Somavert ), this need was overcome by further engineering the site 1 binding site, with eight additional amino acid substitutions, restoring the receptor binding affinity to that of native growth hormone.	('restoring', 'PosReg', (206, 215))	('Peg-Visomant', 'Chemical', 'MESH:C406545', (61, 73))	('receptor', 'MPA', (220, 228))	('substitutions', 'Var', (191, 204))	('binding', 'Interaction', (229, 236))
74354	18681966	In serum-free medium, the MCF-7 cell number declined over 5 days in culture and, in contrast to the findings above, Delta1-9 induced further significant reductions in the MCF-7 cell number of 5% to 10% over controls, at concentrations >10 ng/ml (Figure 2a).	('MCF-7', 'CellLine', 'CVCL:0031', (26, 31))	('MCF-7', 'CellLine', 'CVCL:0031', (171, 176))	('reductions', 'NegReg', (153, 163))	('Delta1-9', 'Var', (116, 124))	('MCF-7 cell number', 'CPA', (171, 188))
74355	18681966	Using RT-PCR, a time-dependent increase in prolactin mRNA expression was seen in response to serum starvation, leading to the hypothesis that autocrine prolactin is produced to promote survival of breast cancer cells under conditions of stress, and that its antagonism reduces cell survival (Figure 2b).	('breast cancer', 'Disease', (197, 210))	('promote', 'PosReg', (177, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('reduces', 'NegReg', (269, 276))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('antagonism', 'Var', (258, 268))	('increase in prolactin', 'Phenotype', 'HP:0000870', (31, 52))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('mRNA expression', 'MPA', (53, 68))	('cell survival', 'CPA', (277, 290))
74361	18681966	We next examined whether Delta1-9 potentiated the effects of doxorubicin, and of the microtubule stabilising agent paclitaxel, on cell number.	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('potentiated', 'PosReg', (34, 45))	('Delta1-9', 'Var', (25, 33))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))
74364	18681966	Coculture with Delta1-9 significantly reduced the cell number by 10% to 15% compared with cells grown in control medium, irrespective of the initial doxorubicin pulse duration.	('cell number', 'CPA', (50, 61))	('doxorubicin', 'Chemical', 'MESH:D004317', (149, 160))	('Delta1-9', 'Var', (15, 23))	('reduced', 'NegReg', (38, 45))
74373	18681966	The addition of 1,000 ng/ml Delta1-9 to the doxorubicin further reduced the CFE, resulting in a 94% reduction compared with controls (P < 0.01) and an 84% reduction compared with doxorubicin treatment alone (P < 0.01).	('reduction', 'NegReg', (100, 109))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('doxorubicin', 'Chemical', 'MESH:D004317', (179, 190))	('reduction', 'NegReg', (155, 164))	('reduced', 'NegReg', (64, 71))	('Delta1-9', 'Var', (28, 36))	('CFE', 'Disease', (76, 79))
74375	18681966	In contrast, incorporation of Delta1-9 into both layers of the agar resulted in a marked, dose-dependent reduction in the MCF-7 CFE (Figure 4b).	('MCF-7', 'Gene', (122, 127))	('incorporation', 'Var', (13, 26))	('MCF-7', 'CellLine', 'CVCL:0031', (122, 127))	('agar', 'Chemical', 'MESH:D000362', (63, 67))	('reduction', 'NegReg', (105, 114))	('Delta1-9', 'Var', (30, 38))
74378	18681966	This dramatic effect of PRLR antagonism in clonogenic cells but not in a monolayer culture suggests the presence of a subpopulation of clonogenic cells with increased dependence upon autocrine/paracrine prolactin signalling compared with their nonclonogenic counterparts.	('PRLR', 'Gene', (24, 28))	('PRLR', 'Gene', '5618', (24, 28))	('antagonism', 'Var', (29, 39))
74384	18681966	Only one other group has reported data on clonogenic assays and prolactin in breast cancer cells; in their hands, prolactin increased the CFE by up to 25%.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('increased', 'PosReg', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CFE', 'CPA', (138, 141))	('prolactin', 'Var', (114, 123))	('prolactin increased', 'Phenotype', 'HP:0000870', (114, 133))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
74400	18681966	In contrast to its lack of effect in monolayer culture, PRLR antagonism with Delta1-9 profoundly inhibits colony formation of both breast cancer cell lines and primary tumour samples.	('Delta1-9', 'Gene', (77, 85))	('antagonism', 'Var', (61, 71))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('inhibits', 'NegReg', (97, 105))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colony formation', 'CPA', (106, 122))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('tumour', 'Disease', (168, 174))	('breast cancer', 'Disease', (131, 144))	('PRLR', 'Gene', (56, 60))	('PRLR', 'Gene', '5618', (56, 60))
74437	26992816	Of those 88 patients (age ranged 28-76 years; mean 50 years), 64% of women with CPM had some degree of increased risk for developing breast cancer: 19 (34%) patients were previously tested positive for BRCA mutation; seven (12%) patients had prior history chest radiation; and 30 (54%) patients had family history of breast cancer in 1st degree relatives.	('patients', 'Species', '9606', (229, 237))	('patients', 'Species', '9606', (12, 20))	('BRCA', 'Gene', (202, 206))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('CPM', 'Disease', (80, 83))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('patients', 'Species', '9606', (157, 165))	('breast cancer', 'Disease', (317, 330))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutation', 'Var', (207, 215))	('women', 'Species', '9606', (69, 74))	('BRCA', 'Gene', '672', (202, 206))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('patients', 'Species', '9606', (286, 294))
74462	26992816	However, accordantly to a prior study 26 young women perceived of greater risk of breast cancer as well as patients with high-risk factors as mutation carries, prior history of chest radiation and family history of breast cancer which could influence the decision maker of CPM.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer', 'Disease', (215, 228))	('mutation carries', 'Var', (142, 158))	('women', 'Species', '9606', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('influence', 'Reg', (241, 250))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('patients', 'Species', '9606', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
74488	25606594	In contrast, alpha6beta4 integrin is not essential for proper branching morphogenesis in vivo, although in mice lacking alpha6beta4 integrin the rapid advancement of end buds generates a fragile glandular epithelium due to deficiencies in cell-BM adhesion, exacerbated in tissue areas of shear stress.	('beta4', 'Gene', '10381', (126, 131))	('fragile glandular', 'Disease', 'MESH:D002277', (187, 204))	('cell-BM adhesion', 'CPA', (239, 255))	('fragile glandular', 'Disease', (187, 204))	('beta4', 'Gene', '10381', (19, 24))	('mice', 'Species', '10090', (107, 111))	('deficiencies', 'NegReg', (223, 235))	('beta4', 'Gene', (19, 24))	('lacking', 'Var', (112, 119))	('beta4', 'Gene', (126, 131))
74489	25606594	On the other hand, in immortalized normal breast cell lines such as MCF10A, alpha6beta4 integrin is determinant in the formation of hemidesmosomes, and their disruption impedes branching morphogenesis.	('disruption', 'Var', (158, 168))	('impedes', 'NegReg', (169, 176))	('beta4', 'Gene', '10381', (82, 87))	('branching morphogenesis', 'CPA', (177, 200))	('MCF10A', 'CellLine', 'CVCL:0598', (68, 74))	('beta4', 'Gene', (82, 87))
74494	25606594	Integrin alpha6beta4 is critical for the basal polarity in three-dimensional cultured HMT-3522-S1 cells and alteration of this integrin signaling leads to the formation of disorganized colonies and the loss of polarity.	('disorganized colonies', 'CPA', (172, 193))	('beta4', 'Gene', '10381', (15, 20))	('leads to', 'Reg', (146, 154))	('beta4', 'Gene', (15, 20))	('alteration', 'Var', (108, 118))	('HMT-3522-S1', 'CellLine', 'CVCL:2499', (86, 97))	('loss', 'NegReg', (202, 206))
74497	25606594	In mammary epithelial cells cultured on the BM matrix, the deletion of beta1 disrupts focal adhesion and impedes acini formation with a reduction of tyrosine phosphorylation in focal adhesion kinase (FAK) and paxillin.	('impedes', 'NegReg', (105, 112))	('focal adhesion kinase', 'Gene', (177, 198))	('disrupts', 'NegReg', (77, 85))	('tyrosine', 'Chemical', 'MESH:D014443', (149, 157))	('acini formation', 'CPA', (113, 128))	('paxillin', 'Protein', (209, 217))	('beta1', 'Gene', (71, 76))	('focal adhesion', 'CPA', (86, 100))	('reduction', 'NegReg', (136, 145))	('focal adhesion kinase', 'Gene', '5747', (177, 198))	('tyrosine phosphorylation', 'MPA', (149, 173))	('deletion', 'Var', (59, 67))
74499	25606594	beta1 is essential in the alveogenesis process, as demonstrated by deleting the integrin in the mouse mammary gland, leading to defects in alveolar development, milk production and integrity of epithelial structures.	('defects', 'NegReg', (128, 135))	('deleting', 'Var', (67, 75))	('integrity of epithelial', 'CPA', (181, 204))	('mouse', 'Species', '10090', (96, 101))	('milk production', 'CPA', (161, 176))	('integrin', 'Protein', (80, 88))	('alveolar development', 'CPA', (139, 159))
74514	25606594	In patients with invasive breast cancer, high beta1 integrin expression was found to be associated with significantly shorter overall and disease-free survival,.	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('invasive breast cancer', 'Disease', (17, 39))	('high', 'Var', (41, 45))	('beta1 integrin', 'Gene', '3688', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('shorter', 'NegReg', (118, 125))	('overall', 'CPA', (126, 133))	('invasive breast cancer', 'Disease', 'MESH:D001943', (17, 39))	('disease-free survival', 'CPA', (138, 159))	('patients', 'Species', '9606', (3, 11))	('beta1 integrin', 'Gene', (46, 60))	('expression', 'MPA', (61, 71))
74521	25606594	On the other hand, transfecting normal HMT-3522-S1 cells with beta4 mutant, deleted in the cytoplasmatic tail, in competition with the endogeneous wild-type beta4 integrin, disrupts the hemidesmosome formation and perturbs the cytoskeleton organization and BM-directed tissue polarity.	('beta4', 'Gene', (157, 162))	('perturbs', 'NegReg', (214, 222))	('beta4', 'Gene', '10381', (62, 67))	('hemidesmosome formation', 'CPA', (186, 209))	('BM-directed tissue polarity', 'CPA', (257, 284))	('beta4', 'Gene', (62, 67))	('HMT-3522-S1', 'CellLine', 'CVCL:2499', (39, 50))	('beta4', 'Gene', '10381', (157, 162))	('cytoskeleton organization', 'CPA', (227, 252))	('disrupts', 'NegReg', (173, 181))	('mutant', 'Var', (68, 74))
74524	25606594	Ablation of beta1 in the mammary epithelium severely impaired breast tumor formation and beta1-integrin-deficient mice show a dramatic reduction in the number of hyperplastic mammary lesions.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('beta1-integrin', 'Gene', (89, 103))	('reduction', 'NegReg', (135, 144))	('Ablation', 'Var', (0, 8))	('impaired breast tumor', 'Disease', 'MESH:D009422', (53, 74))	('breast tumor', 'Phenotype', 'HP:0100013', (62, 74))	('mice', 'Species', '10090', (114, 118))	('beta1-integrin', 'Gene', '3688', (89, 103))	('impaired breast tumor', 'Disease', (53, 74))
74526	25606594	On the other hand, the targeted disruption of FAK function in the mammary epithelium impairs mammary tumor development, and FAK-deficient cells form hyperplastic lesions with a reduced proliferative potential.	('FAK', 'Gene', (46, 49))	('impairs', 'NegReg', (85, 92))	('disruption', 'Var', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('hyperplastic lesions', 'CPA', (149, 169))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
74527	25606594	In mouse mammary tumor virus (MMTV)/ErbB2 mice, conditioned deletion of beta1 in mammary epithelial cells resulted in a significant 33-day delay in the induction of mammary tumors and an increase in the number of apoptotic cells, indicating the importance of beta1 in mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mouse mammary tumor virus', 'Species', '11757', (3, 28))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('MMTV', 'Species', '11757', (30, 34))	('delay', 'NegReg', (139, 144))	('increase', 'PosReg', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('tumor', 'Disease', (17, 22))	('deletion', 'Var', (60, 68))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', (173, 178))	('beta1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
74530	25606594	Moreover, ILK expression has an impact on ErbB2-driven mammary tumor onset, and disruption of ILK inhibits proliferation and invasion and sensitizes ErbB2 tumor cells to apoptotic cell death.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (63, 68))	('ILK', 'Gene', (94, 97))	('impact', 'Reg', (32, 38))	('sensitizes', 'Reg', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('apoptotic cell', 'CPA', (170, 184))	('proliferation', 'CPA', (107, 120))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ILK', 'Gene', (10, 13))	('disruption', 'Var', (80, 90))	('inhibits', 'NegReg', (98, 106))	('invasion', 'CPA', (125, 133))
74532	25606594	Deletion of the beta4 signaling domain in these mice suppressed the ErbB2-driven mammary gland tumorigenesis.	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('beta4', 'Gene', '10381', (16, 21))	('beta4', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ErbB2-driven', 'Gene', (68, 80))	('suppressed', 'NegReg', (53, 63))	('tumor', 'Disease', (95, 100))	('Deletion', 'Var', (0, 8))
74535	25606594	beta1-deficient 4 T1 cells, stimulated with TGFbeta, show an actin cytoskeleton architecture with epithelial features, compared with the elongated morphologies and stress fibers of the parental cells that were treated with TGFbeta.	('actin cytoskeleton', 'MPA', (61, 79))	('T1', 'CellLine', 'CVCL:M858', (18, 20))	('TGFbeta', 'Var', (44, 51))
74548	25606594	This vessel co-option, and subsequent micro-metastatic perivascular growth, was attenuated in glioblastoma with inhibitory anti-beta1 monoclonal antibodies and by knocking out beta1.	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('knocking out', 'Var', (163, 175))	('micro-metastatic perivascular growth', 'CPA', (38, 74))	('attenuated', 'NegReg', (80, 90))	('beta1', 'Protein', (176, 181))	('glioblastoma', 'Disease', (94, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))	('anti-beta1', 'Protein', (123, 133))
74551	25606594	Recently, cross-talk between P-cadherin and the alpha6beta4 signaling pathway has been established and the properties of P-cadherin in inducing stem cell and invasive behavior in basal-like breast cancer cell lines has been ascribed to its cooperation with alpha6beta4.	('beta4', 'Gene', '10381', (263, 268))	('inducing', 'PosReg', (135, 143))	('P-cadherin', 'Var', (121, 131))	('beta4', 'Gene', (54, 59))	('cooperation', 'Interaction', (240, 251))	('beta4', 'Gene', (263, 268))	('beta4', 'Gene', '10381', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
74555	25606594	In the HMT-3522-T4-2 cells, EGFR and beta1 are upregulated, and inhibition of EGFR or beta1 by blocking antibodies and other inhibitors induces downregulation of EGFR expression and phosphorylation in parallel with the reversion of breast tumor cells to a phenotypically normal morphology.	('breast tumor', 'Phenotype', 'HP:0100013', (232, 244))	('EGFR', 'Gene', '1956', (28, 32))	('upregulated', 'PosReg', (47, 58))	('EGFR', 'Gene', '1956', (162, 166))	('beta1', 'Gene', (37, 42))	('EGFR', 'Gene', (162, 166))	('EGFR', 'Gene', (28, 32))	('inhibition', 'Var', (64, 74))	('phosphorylation', 'MPA', (182, 197))	('downregulation', 'NegReg', (144, 158))	('breast tumor', 'Disease', 'MESH:D001943', (232, 244))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('HMT-3522-T4-2', 'CellLine', 'CVCL:2501', (7, 20))	('breast tumor', 'Disease', (232, 244))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('expression', 'MPA', (167, 177))
74563	25606594	Of clinical relevance, blocking beta1 with the blocking antibody AIIB2 restores the growth inhibitory effects of both trastuzumab and lapatinib individually or of the lapatinib and trastuzumab combination.	('blocking', 'Var', (23, 31))	('trastuzumab', 'Chemical', 'MESH:D000068878', (181, 192))	('beta1', 'Protein', (32, 37))	('growth inhibitory effects', 'MPA', (84, 109))	('restores', 'PosReg', (71, 79))	('AIIB2', 'Gene', (65, 70))	('trastuzumab', 'Chemical', 'MESH:D000068878', (118, 129))	('lapatinib', 'Chemical', 'MESH:D000077341', (167, 176))	('lapatinib', 'Chemical', 'MESH:D000077341', (134, 143))
74570	25606594	However, deletion of the beta4 signaling domain improves the efficacy of anti-RTK therapy.	('RTK', 'Gene', '5979', (78, 81))	('beta4', 'Gene', '10381', (25, 30))	('deletion', 'Var', (9, 17))	('beta4', 'Gene', (25, 30))	('efficacy', 'MPA', (61, 69))	('RTK', 'Gene', (78, 81))	('improves', 'PosReg', (48, 56))
74588	25606594	Deregulation of these pathways, from ECM to transcription factors, alters cell adhesion and the integrity of the tissues and organs and contributes to invasiveness, breast cancer progression and therapy resistance.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('alters', 'Reg', (67, 73))	('therapy resistance', 'CPA', (195, 213))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('Deregulation', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('cell adhesion', 'CPA', (74, 87))	('contributes to', 'Reg', (136, 150))	('invasiveness', 'CPA', (151, 163))
74736	33888841	Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK.	('phospho-p42/44MAPK', 'Var', (208, 226))	('breast lesions', 'Disease', (162, 176))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('breast lesions', 'Disease', 'MESH:D001943', (162, 176))	('hDCIS.01', 'CellLine', 'CVCL:5552', (37, 45))	('phospho-SMAD3', 'Var', (190, 203))
74751	33888841	Knockdown or antibody neutralization of CCL2 in breast xenograft models inhibits infiltration of CCR2+ macrophages and reduces tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('infiltration of', 'CPA', (81, 96))	('tumor', 'Disease', (127, 132))	('neutralization', 'Var', (22, 36))	('inhibits', 'NegReg', (72, 80))	('antibody', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CCL2', 'Gene', (40, 44))	('reduces', 'NegReg', (119, 126))
74762	33888841	Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we demonstrated that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK.	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('breast lesions', 'Disease', (170, 184))	('breast lesions', 'Disease', 'MESH:D001943', (170, 184))	('phospho-p42/44MAPK', 'Var', (216, 234))	('hDCIS.01', 'CellLine', 'CVCL:5552', (37, 45))	('phospho-SMAD3', 'Var', (198, 211))
74782	33888841	9520), phospho-p42/44MAPK Thr202/Thr204 (Cell Signaling Technology cat no.	('Thr202/Thr204', 'Var', (26, 39))	('Thr202', 'Chemical', '-', (26, 32))	('Thr204', 'Chemical', '-', (33, 39))	('phospho-p42/44MAPK', 'Var', (7, 25))
74816	33888841	Breast lesions showing higher CCR2 expression (IC-031317 and IC-022316) did not show significant differences in growth and invasion of breast lesions compared to those with relatively low CCR2 expression (IC-041717-1) (Fig.	('IC-022316', 'Var', (61, 70))	('CCR2', 'Gene', (30, 34))	('breast lesions', 'Disease', (135, 149))	('breast lesions', 'Disease', 'MESH:D001943', (135, 149))	('IC-031317', 'Var', (47, 56))
74822	33888841	CCL2 delivery was associated with a significant increase in the growth and invasion of IC-031317 and IC-022316 breast lesions, which had high CCR2 expression (Fig.	('invasion', 'CPA', (75, 83))	('expression', 'MPA', (147, 157))	('IC-022316 breast lesions', 'Disease', 'MESH:D001943', (101, 125))	('IC-031317', 'Var', (87, 96))	('IC-022316 breast lesions', 'Disease', (101, 125))	('growth', 'CPA', (64, 70))	('CCR2', 'Gene', (142, 146))	('increase', 'PosReg', (48, 56))
74824	33888841	Overall, DCIS cases IC-031317 and IC-022316, which showed higher CCR2 expression, formed more invasive breast lesions with CCL2 treatment, compared to IC-041717-1, which showed low CCR2 expression.	('IC-031317', 'Var', (20, 29))	('breast lesions', 'Disease', (103, 117))	('IC-022316', 'Var', (34, 43))	('breast lesions', 'Disease', 'MESH:D001943', (103, 117))	('expression', 'MPA', (70, 80))	('higher', 'PosReg', (58, 64))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('CCR2', 'Gene', (65, 69))
74827	33888841	Cells enriched for CCR2 expression formed breast lesions at earlier times, compared to control parental cells (Fig.	('expression', 'Var', (24, 34))	('CCR2', 'Gene', (19, 23))	('breast lesions', 'Disease', (42, 56))	('breast lesions', 'Disease', 'MESH:D001943', (42, 56))
74828	33888841	Additionally, tissues enriched for CCR2+ displayed a significantly higher percentage of invasive lesions compared to parental (Fig.	('invasive lesions', 'Disease', (88, 104))	('invasive lesions', 'Disease', 'MESH:D009361', (88, 104))	('higher', 'PosReg', (67, 73))	('CCR2+', 'Var', (35, 40))
74829	33888841	These data indicated that the CCR2+ breast carcinoma cells were associated with increased proliferation and formation of invasive breast carcinomas.	('breast carcinoma', 'Disease', 'MESH:D001943', (36, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('breast carcinoma', 'Disease', 'MESH:D001943', (130, 146))	('breast carcinoma', 'Phenotype', 'HP:0003002', (36, 52))	('proliferation', 'CPA', (90, 103))	('increased', 'PosReg', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('breast carcinomas', 'Phenotype', 'HP:0003002', (130, 147))	('invasive breast carcinomas', 'Disease', 'MESH:D001943', (121, 147))	('breast carcinoma', 'Phenotype', 'HP:0003002', (130, 146))	('invasive breast carcinomas', 'Disease', (121, 147))	('CCR2+', 'Var', (30, 35))	('formation', 'CPA', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('breast carcinoma', 'Disease', (36, 52))
74832	33888841	Overall, these data indicated that ductal carcinomas with high CCR2 expression were associated with increased invasiveness and increased expression of CCL2, phospho-SMAD3 and phospho-p42/44MAPK.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('carcinomas', 'Disease', (42, 52))	('invasiveness', 'CPA', (110, 122))	('expression', 'MPA', (137, 147))	('increased', 'PosReg', (100, 109))	('CCL2', 'Gene', (151, 155))	('CCR2', 'Gene', (63, 67))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (35, 51))	('high', 'Var', (58, 62))	('carcinomas', 'Disease', 'MESH:D009369', (42, 52))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
74839	33888841	Overall, these studies demonstrate that CCR2 antagonists impair CCL2/CCR2 mediated growth and signaling of breast cancer cells in vitro.	('antagonists', 'Var', (45, 56))	('CCR2', 'Gene', (40, 44))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('impair', 'NegReg', (57, 63))	('CCL2/CCR2', 'Gene', (64, 73))
74841	33888841	Through analysis of patient derived breast tissues and mouse models of DCIS, we showed that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK proteins were associated with invasive breast ductal carcinomas.	('CCL2', 'Gene', (106, 110))	('invasive breast ductal carcinomas', 'Disease', (185, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('CCR2', 'Gene', (112, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('phospho-p42/44MAPK', 'Var', (136, 154))	('mouse', 'Species', '10090', (55, 60))	('associated', 'Reg', (169, 179))	('patient', 'Species', '9606', (20, 27))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('invasive breast ductal carcinomas', 'Disease', 'MESH:D001943', (185, 218))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (201, 217))
74846	33888841	Furthermore, SMAD3 cooperation with p42/44MAPK was found to be important in CCL2/CCR2 mediated breast cancer cell survival and motility.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('CCL2/CCR2', 'Gene', (76, 85))	('p42/44MAPK', 'Var', (36, 46))	('motility', 'CPA', (127, 135))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
74847	33888841	Here, phospho-SMAD3 expression was associated with increased CCL2 and CCR2 levels, and increased growth and invasion of patient derived lesions (IC-031317, IC-022316) and hDCIS.01 breast lesions in mice.	('increased', 'PosReg', (87, 96))	('hDCIS.01', 'CellLine', 'CVCL:5552', (171, 179))	('increased', 'PosReg', (51, 60))	('patient', 'Species', '9606', (120, 127))	('breast lesions', 'Disease', (180, 194))	('growth', 'CPA', (97, 103))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('phospho-SMAD3', 'Var', (6, 19))	('breast lesions', 'Disease', 'MESH:D001943', (180, 194))	('mice', 'Species', '10090', (198, 202))	('invasion', 'CPA', (108, 116))
74883	30647841	On the other hand, several studies have proposed two separate pathways of progression which are characterized by 16q loss (in low grade tumors) and second by amplification of 11q13 and 17q1.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('loss', 'NegReg', (117, 121))	('16q', 'Gene', (113, 116))	('11q13', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('amplification', 'Var', (158, 171))
74889	30647841	These studies identified gene expression signatures or other kinds of genetic alterations such as epigenetic signatures, loss of heterozygosity and allelic imbalance resulting from the development of malignancy.	('epigenetic', 'MPA', (98, 108))	('allelic', 'MPA', (148, 155))	('imbalance', 'Phenotype', 'HP:0002172', (156, 165))	('malignancy', 'Disease', 'MESH:D009369', (200, 210))	('loss of heterozygosity', 'Var', (121, 143))	('malignancy', 'Disease', (200, 210))
74900	30647841	Genes related to response to oxidative stress (GO:0006979), mitotic cell cycle process (GO:1903047), extracellular matrix organization (GO:0030198), focal adhesion (ko04510), epithelial cell proliferation (GO:0050673) and regulation of cell migration (GO:0030334) were enriched in IDC.	('epithelial cell proliferation', 'CPA', (175, 204))	('mitotic cell cycle process', 'CPA', (60, 86))	('GO:0030334', 'Var', (252, 262))	('ko04510', 'Var', (165, 172))	('GO:0050673', 'Var', (206, 216))	('IDC', 'Gene', '4000', (281, 284))	('IDC', 'Gene', (281, 284))	('extracellular matrix organization', 'CPA', (101, 134))	('focal adhesion', 'CPA', (149, 163))	('GO:0030198', 'Var', (136, 146))	('oxidative stress', 'Phenotype', 'HP:0025464', (29, 45))
74913	30647841	Particularly, ncRNAs such as SNORD115, SNORD116, SNORD114, SNORD113, SNORD78 and miR205 were highlighted in this study.	('SNORD116', 'Gene', '692236', (39, 47))	('SNORD114', 'Gene', (49, 57))	('SNORD115', 'Gene', '692218', (29, 37))	('miR205', 'Gene', '406988', (81, 87))	('SNORD113', 'Var', (59, 67))	('SNORD78', 'Gene', '692198', (69, 76))	('SNORD116', 'Gene', (39, 47))	('miR205', 'Gene', (81, 87))	('SNORD78', 'Gene', (69, 76))	('SNORD114', 'Gene', '692217', (49, 57))	('SNORD115', 'Gene', (29, 37))
74922	30647841	The quantitative analysis of DCIS lesions differentiating them from ADH lesions is based on the presence of a homogenous population in at least two membrane bound spaces with a size of more than 2mm, making the identification difficult.	('lesions', 'Var', (34, 41))	('ADH lesion', 'Disease', 'MESH:D007177', (68, 78))	('DCIS', 'Disease', (29, 33))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('ADH lesion', 'Disease', (68, 78))
74934	30647841	Deregulation of sno-RNA expression has been seen in many cancers.	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('sno-RNA expression', 'Protein', (16, 34))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
74991	30647841	Two biological replicates of each MCF10A (normal/benign), MCF10AT (ADH), MCF10DCIS (DCIS) and MCF10CA1a (IDC) cells were used for analyses.	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('MCF10', 'CellLine', 'CVCL:5555', (94, 99))	('MCF10DCIS', 'Var', (73, 82))	('IDC', 'Gene', (105, 108))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('MCF10', 'CellLine', 'CVCL:5555', (34, 39))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (73, 82))	('MCF10A', 'CellLine', 'CVCL:0598', (34, 40))	('MCF10', 'CellLine', 'CVCL:5555', (58, 63))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('IDC', 'Gene', '4000', (105, 108))	('MCF10', 'CellLine', 'CVCL:5555', (73, 78))
75003	28335433	Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control).	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('invasive breast cancer', 'Disease', (180, 202))	('miR-455-5p', 'Var', (81, 91))	('women', 'Species', '9606', (144, 149))	('miR-29a', 'Gene', (36, 43))	('invasive breast cancer', 'Disease', 'MESH:D001943', (180, 202))	('miR-375', 'Gene', '494324', (54, 61))	('miR-184', 'Gene', '406960', (63, 70))	('women', 'Species', '9606', (215, 220))	('miR-375', 'Gene', (54, 61))	('miR-363', 'Gene', (72, 79))	('miR-221', 'Gene', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('invasive breast cancer', 'Disease', (241, 263))	('miR-363', 'Gene', '574031', (72, 79))	('miR-221', 'Gene', '407006', (45, 52))	('invasive breast cancer', 'Disease', 'MESH:D001943', (241, 263))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('miR-184', 'Gene', (63, 70))	('miR-29a', 'Gene', '407021', (36, 43))
75004	28335433	Dysregulation of their expression has been associated with many diseases and suggested to play important roles in the initiation and progression of a variety of human malignancies.	('human', 'Species', '9606', (161, 166))	('malignancies', 'Disease', 'MESH:D009369', (167, 179))	('Dysregulation', 'Var', (0, 13))	('diseases', 'Disease', (64, 72))	('malignancies', 'Disease', (167, 179))	('associated', 'Reg', (43, 53))	('expression', 'MPA', (23, 33))
75025	28335433	Each of these libraries included a matched DCIS case-control sample pair (Figure 4A, I607Y and I607G; 12-year-old specimens) that was run in duplicate.	('I607G', 'Mutation', 'p.I607G', (95, 100))	('I607Y', 'Mutation', 'p.I607Y', (85, 90))	('I607G', 'Var', (95, 100))	('I607Y', 'Var', (85, 90))
75026	28335433	Additionally, the PCA plot in Figure 4C shows that specimens I607Y and I607G from the three different libraries clustered well together, indicating that our optimized method is reliable for reproducing libraries containing the same FFPE RNA samples.	('I607G', 'Var', (71, 76))	('I607Y', 'Var', (61, 66))	('I607G', 'Mutation', 'p.I607G', (71, 76))	('I607Y', 'Mutation', 'p.I607Y', (61, 66))
75028	28335433	Our statistical analyses of libraries #1a, 2 and 3 initially identified a list of 20 miRNAs with significant differential expression between DCIS cases and controls (p-value < 0.05), of which the top 12 miRNAs (miR-29a, miR-126-3p, miR-101, miR-221, miR-375, miR-18a, miR-184, miR-363, miR-20b, miR-455-5p, miR-1270 and miR-597) are displayed in a heat map (Figure 5A).	('expression', 'MPA', (122, 132))	('miR-20b', 'Gene', (286, 293))	('miR-363', 'Gene', '574031', (277, 284))	('miR-184', 'Gene', (268, 275))	('miR-126-3p', 'Gene', (220, 230))	('miR-1270', 'Gene', (307, 315))	('miR-455-5p', 'Var', (295, 305))	('miR-18a', 'Gene', (259, 266))	('miR-597', 'Gene', (320, 327))	('miR-126-3p', 'Gene', '100302148', (220, 230))	('miR-1270', 'Gene', '100302179', (307, 315))	('miR-101', 'Var', (232, 239))	('miR-597', 'Gene', '693182', (320, 327))	('miR-20b', 'Gene', '574032', (286, 293))	('miR-375', 'Gene', '494324', (250, 257))	('miR-18a', 'Gene', '406953', (259, 266))	('miR-184', 'Gene', '406960', (268, 275))	('miR-375', 'Gene', (250, 257))	('miR-221', 'Gene', (241, 248))	('miR-221', 'Gene', '407006', (241, 248))	('miR-363', 'Gene', (277, 284))	('miR-29a', 'Gene', '407021', (211, 218))	('miR-29a', 'Gene', (211, 218))
75029	28335433	Of those top twelve differentially-expressed miRNAs, six retained statistical significance after adjustment for multiple testing (Figure 5B, miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p).	('miR-363', 'Gene', '574031', (177, 184))	('miR-221', 'Gene', '407006', (150, 157))	('miR-363', 'Gene', (177, 184))	('miR-375', 'Gene', (159, 166))	('miR-455-5p', 'Var', (186, 196))	('miR-29a', 'Gene', (141, 148))	('miR-29a', 'Gene', '407021', (141, 148))	('miR-221', 'Gene', (150, 157))	('miR-375', 'Gene', '494324', (159, 166))	('miR-184', 'Gene', '406960', (168, 175))	('miR-184', 'Gene', (168, 175))
75035	28335433	Secondly, due to the introduction and amplification of gamma-32ATP-labeled size markers with the libraries during the pilot PCR reaction, which affected the output due to lower RNA input and quality, the digestion by the restriction enzyme PmeI to remove these radio-labeled primers was omitted.	('gamma-32ATP', 'Chemical', '-', (55, 66))	('output', 'MPA', (157, 163))	('quality', 'MPA', (191, 198))	('gamma-32ATP-labeled', 'Var', (55, 74))	('RNA input', 'MPA', (177, 186))	('affected', 'Reg', (144, 152))	('lower', 'NegReg', (171, 176))
75036	28335433	We evaluated the performance of our modified approach using gold standard matched fresh/frozen and FFPE human tissues/cells and demonstrated that FFPE RNA provides high quality miRNA expression data relative to its matched fresh/frozen counterpart, when using NGS.	('human', 'Species', '9606', (104, 109))	('miRNA expression data', 'MPA', (177, 198))	('FFPE', 'Var', (146, 150))
75041	28335433	Our sequencing analyses revealed that six miRNAs retained significance after adjustment for multiple testing, namely miR-29a, miR-221, miR-375, miR-184, miR-363 and miR-455-5p, of which two miRNAs, namely miR-375 and miR-363, were further validated by qPCR.	('miR-184', 'Gene', (144, 151))	('miR-363', 'Gene', (153, 160))	('miR-375', 'Gene', '494324', (135, 142))	('miR-375', 'Gene', '494324', (205, 212))	('miR-363', 'Gene', '574031', (217, 224))	('miR-375', 'Gene', (205, 212))	('miR-29a', 'Gene', (117, 124))	('miR-221', 'Gene', '407006', (126, 133))	('miR-29a', 'Gene', '407021', (117, 124))	('miR-184', 'Gene', '406960', (144, 151))	('miR-375', 'Gene', (135, 142))	('miR-363', 'Gene', (217, 224))	('miR-363', 'Gene', '574031', (153, 160))	('miR-221', 'Gene', (126, 133))	('miR-455-5p', 'Var', (165, 175))
75064	28335433	For ligation of the 3' barcoded adapters, we made the 10x RNA ligase buffer (without ATP), which contained 343 muL Ambion  nuclease-free water (not DEPC-treated) (AM9932, Thermo Fisher Scientific), 500 muL UltraPure  1M Tris-HCl Buffer pH 7.5 (15567027, Thermo Fisher Scientific), 100 muL Ambion  1M MgCl2 (AM9530G, Thermo Fisher Scientific), 50 muL 20 mg/mL BSA, acetylated (B8894, Sigma-Aldrich, St. Louis, MO, USA) and 7 muL 14 M 2-mercaptoethanol (O3446I, Thermo Fisher Scientific).	('ATP', 'Chemical', 'MESH:D000255', (85, 88))	('muL', 'Gene', '4591', (346, 349))	('muL', 'Gene', (424, 427))	('muL', 'Gene', '4591', (202, 205))	('15567027', 'Var', (244, 252))	('Tris', 'Chemical', '-', (220, 224))	('muL', 'Gene', (346, 349))	('muL', 'Gene', '4591', (285, 288))	('B8894', 'Var', (376, 381))	('water', 'Chemical', 'MESH:D014867', (137, 142))	('muL', 'Gene', (202, 205))	('muL', 'Gene', '4591', (111, 114))	('muL', 'Gene', '4591', (424, 427))	('ethanol', 'Chemical', 'MESH:D000431', (443, 450))	('muL', 'Gene', (285, 288))	('muL', 'Gene', (111, 114))
75067	28335433	After deactivation of the enzyme at 90  C for 1 min and the addition of 1.2 muL of Glycoblue mix (1 muL Glycoblue  Coprecipitant (15 mg/mL) (AM9516, Thermo Fisher Scientific) in 26 muL NaCl (5M) (AM9579, Thermo Fisher Scientific)) and 63 muL 100% ethanol to each tube, all 18 reactions were pooled in a Fisherbrand  siliconized low-retention microcentrifuge tube (02-681-331, Thermo Fisher Scientific) and incubated on ice for 1 h after gentle mixing.	('mix', 'Gene', (93, 96))	('mix', 'Gene', '83881', (444, 447))	('muL', 'Gene', '4591', (100, 103))	('muL', 'Gene', '4591', (181, 184))	('mix', 'Gene', (444, 447))	('muL', 'Gene', (181, 184))	('muL', 'Gene', '4591', (238, 241))	('deactivation', 'Var', (6, 18))	('muL', 'Gene', '4591', (76, 79))	('NaCl', 'Chemical', 'MESH:D012965', (185, 189))	('muL', 'Gene', (100, 103))	('mix', 'Gene', '83881', (93, 96))	('muL', 'Gene', (238, 241))	('ethanol', 'Chemical', 'MESH:D000431', (247, 254))	('muL', 'Gene', (76, 79))
75072	28335433	The excised gel piece was subjected to a gel breaker (3388-100, IST Engineering, Milpitas, CA, USA), and 300 muL NaCl (400 mM) were added to it and the tube incubated on a thermomixer at 1100 rpm at 4  C, overnight.	('muL', 'Gene', (109, 112))	('mix', 'Gene', '83881', (178, 181))	('mix', 'Gene', (178, 181))	('3388-100', 'Var', (54, 62))	('muL', 'Gene', '4591', (109, 112))	('NaCl', 'Chemical', 'MESH:D012965', (113, 117))
75122	25527189	Expression of a single additional oncogene, PIK3CA-H1047R, converted the cells into invasive cancer cells.	('converted', 'Reg', (59, 68))	('PIK3CA-H1047R', 'Var', (44, 57))	('invasive cancer', 'Disease', 'MESH:D009362', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('H1047R', 'Mutation', 'rs121913279', (51, 57))	('invasive cancer', 'Disease', (84, 99))
75123	25527189	The resulting tumors were ERalpha+, Ki67+ luminal B adenocarcinomas that were resistant to treatment with fulvestrant.	('Ki67+', 'Var', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('adenocarcinomas', 'Disease', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('Ki67', 'Chemical', '-', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('fulvestrant', 'Chemical', 'MESH:D000077267', (106, 117))
75138	25527189	Introduction of a single additional activated oncogene, PIK3CA-H1047R, converted them into ERalpha + invasive ductal adenocarcinomas.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('invasive ductal adenocarcinomas', 'Disease', 'MESH:D018270', (101, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('PIK3CA-H1047R', 'Var', (56, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('invasive ductal adenocarcinomas', 'Disease', (101, 132))
75148	25527189	The membranes were blocked with 5% fat-free milk powder in 150 mM NaCl, 50 mM Tris-HCL pH 8.0, 0.1% Tween-20 (TBST) and incubated overnight at 4 C with the following antibodies: TERT (Y182), PI3K p110alpha (04-399), DeltaN-p63 (p40 - PC373), GATA3 (09-076) (Millipore); BMI1 (D20B7), keratin 18 (DC10), cyclin D1 (DCS6), myc (D84C12), AKT (9272), phospho-AKT-T308 (4056/244 F9), ERBB3 (4754) (Cell Signaling Technology); FOXA1 (Ab55-178) (Abcam); AGR2 (1C3), tubulin (B-5-1-2) (Sigma); keratin 14 (LL002, gift from Birgit Lane); ERalpha (Ab-16, RB-1493) (ThermoScientific); p53 (D01, gift from David Lane).	('myc', 'Gene', '4609', (321, 324))	('FOXA1', 'Gene', '3169', (421, 426))	('AKT', 'Gene', '207', (335, 338))	('ERBB3', 'Gene', '2065', (379, 384))	('myc', 'Gene', (321, 324))	('keratin 18', 'Gene', '3875', (284, 294))	('FOXA1', 'Gene', (421, 426))	('cyclin D1', 'Gene', '595', (303, 312))	('p53', 'Var', (574, 577))	('p40', 'Gene', '5594', (228, 231))	('DC10', 'Gene', (296, 300))	('DC10', 'Gene', '26269', (296, 300))	('AKT', 'Gene', (355, 358))	('p40', 'Gene', (228, 231))	('keratin 18', 'Gene', (284, 294))	('RB-1493', 'CellLine', 'CVCL:1M67', (545, 552))	('AGR2', 'Gene', (447, 451))	('GATA3', 'Gene', '2625', (242, 247))	('ERBB3', 'Gene', (379, 384))	('TBST', 'Chemical', '-', (110, 114))	('AKT', 'Gene', (335, 338))	('AGR2', 'Gene', '10551', (447, 451))	('AKT', 'Gene', '207', (355, 358))	('GATA3', 'Gene', (242, 247))	('tubulin (B-5-1-2', 'Gene', '6431', (459, 475))	('cyclin D1', 'Gene', (303, 312))
75186	25527189	Western blotting showed that the switch from EGF to AREG and NRG1 in svWIT decreased the level of EGFR receptor tail phosphorylation despite an increase in the amount of the protein (Figure 6A), consistent with weaker activation of EGFR and decreased receptor turnover.	('EGFR', 'Gene', (98, 102))	('level', 'MPA', (89, 94))	('NRG1', 'Gene', (61, 65))	('switch', 'Var', (33, 39))	('tail phosphorylation', 'MPA', (112, 132))	('decreased', 'NegReg', (75, 84))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (232, 236))	('increase', 'PosReg', (144, 152))	('amount of the protein', 'MPA', (160, 181))
75187	25527189	Western blotting of the cells in pWIT showed that they express keratin 14 and DeltaN-p63alpha strongly, confirming the suggestion from the flow cytometry data that at least one of the populations in pWIT is myoepithelial or squamous.	('myoepithelial', 'Disease', (207, 220))	('myoepithelial', 'Disease', 'MESH:D009208', (207, 220))	('DeltaN-p63alpha', 'Var', (78, 93))	('keratin 14', 'Protein', (63, 73))	('DeltaN-p63alpha', 'Chemical', '-', (78, 93))
75193	25527189	To transform them fully, they were infected with lentiviruses expressing PIK3CA-H1047R and a small hairpin RNA (shp53) targeting TP53.	('PIK3CA-H1047R', 'Var', (73, 86))	('TP53', 'Gene', (129, 133))	('H1047R', 'Mutation', 'rs121913279', (80, 86))	('TP53', 'Gene', '7157', (129, 133))
75196	25527189	Interestingly, the breakpoint on 3p21 truncates PBRM1 (BAF180), a known breast cancer tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BAF180', 'Gene', (55, 61))	('p21', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BAF180', 'Gene', '55193', (55, 61))	('p21', 'Gene', '644914', (34, 37))	('breakpoint', 'Var', (19, 29))	('PBRM1', 'Gene', (48, 53))	('breast cancer tumor', 'Disease', 'MESH:D001943', (72, 91))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (72, 91))	('truncates', 'Var', (38, 47))	('PBRM1', 'Gene', '55193', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('breast cancer tumor', 'Disease', (72, 91))
75198	25527189	Only the cells transduced with both the shp53 and the PIK3CA vectors could form progressively growing tumors (Figure 4A; the images of mice show how the data were collected, the graph shows fluorescence normalized to the value one week after injection).	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mice', 'Species', '10090', (135, 139))	('shp53', 'Var', (40, 45))	('fluorescence', 'MPA', (190, 202))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PIK3CA', 'Gene', (54, 60))
75219	25527189	Interestingly, the cells were positive for ERalpha and Ki67 but negative for PGR (Figure 8C; the PGR stain is negative relative to controls cells on the same section).	('positive', 'Reg', (30, 38))	('PGR', 'Gene', (97, 100))	('Ki67', 'Chemical', '-', (55, 59))	('ERalpha', 'Protein', (43, 50))	('PGR', 'Gene', '5241', (97, 100))	('Ki67', 'Var', (55, 59))	('PGR', 'Gene', (77, 80))	('PGR', 'Gene', '5241', (77, 80))	('negative', 'NegReg', (64, 72))
75228	25527189	Immunohistochemistry showed that the level of ERalpha was lower in the tumors that received fulvestrant than in the vehicle-treated controls (Figure 3D), confirming that the drug had reached its target in vivo.	('lower', 'NegReg', (58, 63))	('fulvestrant', 'Var', (92, 103))	('ERalpha', 'MPA', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('fulvestrant', 'Chemical', 'MESH:D000077267', (92, 103))	('tumors', 'Disease', (71, 77))	('level', 'MPA', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
75233	25527189	The logic behind their approach is that subtle differences in signaling proteins create a species barrier that prevents human myoepithelial cells from communicating properly with mouse fibroblasts.	('mouse', 'Species', '10090', (179, 184))	('myoepithelial', 'Disease', 'MESH:D009208', (126, 139))	('communicating', 'MPA', (151, 164))	('human', 'Species', '9606', (120, 125))	('subtle differences', 'Var', (40, 58))	('myoepithelial', 'Disease', (126, 139))	('prevents', 'NegReg', (111, 119))
75243	25527189	All of the human cells expressed ERalpha, and many expressed Ki67, but they did not express PGR, FOXA1 or GATA3 (Figure 12C&D), consistent with their in vitro profile.	('ERalpha', 'Protein', (33, 40))	('Ki67', 'Var', (61, 65))	('Ki67', 'Chemical', '-', (61, 65))	('human', 'Species', '9606', (11, 16))	('expressed', 'Reg', (51, 60))	('FOXA1', 'Gene', (97, 102))	('PGR', 'Gene', (92, 95))	('GATA3', 'Gene', (106, 111))	('FOXA1', 'Gene', '3169', (97, 102))	('GATA3', 'Gene', '2625', (106, 111))	('PGR', 'Gene', '5241', (92, 95))
75246	25527189	Taken together, the data suggest that the cells immortalized by the TERT, BMI1, CCND1, MYC and shp53 transgenes may be precursors of hormone sensing or secretory cells trapped at the luminal progenitor stage.	('BMI1', 'Gene', (74, 78))	('TERT', 'Gene', (68, 72))	('CCND1', 'Gene', (80, 85))	('shp53', 'Gene', (95, 100))	('MYC', 'Gene', (87, 90))	('CCND1', 'Gene', '595', (80, 85))	('transgenes', 'Var', (101, 111))
75247	25527189	We have shown that genetically defined human mammary epithelial cells expressing multiple oncogenes can form a morphologically normal luminal layer in the mouse mammary gland, and that expression of a single additional activated oncogene, PIK3CA-H1047R, is sufficient to convert them into invasive ERalpha + adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('PIK3CA-H1047R', 'Var', (239, 252))	('adenocarcinoma', 'Disease', (308, 322))	('mouse', 'Species', '10090', (155, 160))	('adenocarcinoma', 'Disease', 'MESH:D000230', (308, 322))	('H1047R', 'Mutation', 'rs121913279', (246, 252))	('convert', 'Reg', (271, 278))	('human', 'Species', '9606', (39, 44))
75253	25527189	Third, deletion of Erbb3 in mice leads to loss of the luminal layer and expansion of the basal/myoepithelial layer.	('expansion', 'CPA', (72, 81))	('myoepithelial', 'Disease', 'MESH:D009208', (95, 108))	('Erbb3', 'Gene', (19, 24))	('mice', 'Species', '10090', (28, 32))	('luminal layer', 'CPA', (54, 67))	('myoepithelial', 'Disease', (95, 108))	('Erbb3', 'Gene', '13867', (19, 24))	('deletion', 'Var', (7, 15))	('loss', 'NegReg', (42, 46))
75257	25527189	Furthermore, our cell lines established in AREG/NRG1 medium grow poorly if transferred back into EGF medium, suggesting that the AREG/NRG1 combination not only prevents overgrowth of a confused myoepithelial population but also favors the growth of luminal cells.	('prevents', 'NegReg', (160, 168))	('favors', 'PosReg', (228, 234))	('myoepithelial', 'Disease', (194, 207))	('AREG/NRG1', 'Gene', (129, 138))	('growth of luminal cells', 'CPA', (239, 262))	('overgrowth', 'CPA', (169, 179))	('myoepithelial', 'Disease', 'MESH:D009208', (194, 207))	('combination', 'Var', (139, 150))	('overgrowth', 'Phenotype', 'HP:0001548', (169, 179))
75259	25527189	The striking feature of PI3K-induced mouse models is the extent to which they express ERalpha, despite their unpromising histology.	('PI3K-induced', 'Var', (24, 36))	('mouse', 'Species', '10090', (37, 42))	('ERalpha', 'Protein', (86, 93))
75262	25527189	In addition to the above arguments, the rationale for using CCND1, PI3K-H1047R, MYC, TERT, BMI1 and sh-p53 was based on genomic data in luminal breast cancer and on past experience with mammary transformation protocols.	('luminal breast cancer', 'Disease', 'MESH:D001943', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('H1047R', 'Mutation', 'rs121913279', (72, 78))	('PI3K-H1047R', 'Var', (67, 78))	('CCND1', 'Gene', (60, 65))	('luminal breast cancer', 'Disease', (136, 157))	('CCND1', 'Gene', '595', (60, 65))
75263	25527189	According to the TCGA consortium, PIK3CA mutations are seen in 45% of luminal A and 29% of luminal B tumors; TP53 mutations are seen in 29% of luminal B tumors .	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('seen', 'Reg', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('TP53', 'Gene', '7157', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('luminal A', 'Disease', (70, 79))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('TP53', 'Gene', (109, 113))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Disease', (101, 107))
75265	25527189	After silencing of p53, the cells from the XS11 mammoplasty acquired a deletion on 3p21 starting within PBRM1, the gene encoding the BAF180 subunit of the PBAF ATP-dependent chromatin-remodeling complex.	('deletion', 'Var', (71, 79))	('BAF180', 'Gene', (133, 139))	('p53', 'Gene', (19, 22))	('ATP', 'Chemical', 'MESH:D000255', (160, 163))	('PBRM1', 'Gene', (104, 109))	('BAF180', 'Gene', '55193', (133, 139))	('p21', 'Gene', (84, 87))	('silencing', 'Var', (6, 15))	('p21', 'Gene', '644914', (84, 87))	('PBRM1', 'Gene', '55193', (104, 109))
75266	25527189	Truncating mutations, as seen here, have previously been described in breast cancer, where they reduce p21 induction by TGFbeta and p53.	('Truncating mutations', 'Var', (0, 20))	('p21', 'Gene', (103, 106))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('p21', 'Gene', '644914', (103, 106))	('reduce', 'NegReg', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
75267	25527189	We have not performed CGH on multiple independently derived cell lines so we can not say whether this change is absolutely required for transformation with CCND1, PI3K-H1047R, MYC, TERT, BMI1 and sh-p53, but it seems unlikely.	('CCND1', 'Gene', '595', (156, 161))	('H1047R', 'Mutation', 'rs121913279', (168, 174))	('PI3K-H1047R', 'Var', (163, 174))	('CCND1', 'Gene', (156, 161))
75269	25527189	CCND1 and mutant PIK3CA can confer resistance to endocrine therapy in cell lines but the relationship between PIK3CA mutation and the response to endocrine therapy is hotly debated.	('mutant', 'Var', (10, 16))	('PIK3CA', 'Gene', (17, 23))	('CCND1', 'Gene', (0, 5))	('PIK3CA', 'Gene', (110, 116))	('CCND1', 'Gene', '595', (0, 5))	('resistance', 'MPA', (35, 45))
75270	25527189	Paradoxically, PIK3CA mutations are associated with a gene signature of low mTORC1 signaling and better outcomes in ERalpha + breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('mTORC1', 'Gene', '382056', (76, 82))	('mutations', 'Var', (22, 31))	('mTORC1', 'Gene', (76, 82))	('low', 'NegReg', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('PIK3CA', 'Gene', (15, 21))
75272	25527189	The 4G-shp53 cells have a growth advantage over the murine luminal cells they replace but, apart from being bigger than murine luminal cells, they are normal in appearance.	('murine', 'Species', '10090', (52, 58))	('4G-shp53', 'Var', (4, 12))	('murine', 'Species', '10090', (120, 126))	('growth advantage', 'CPA', (26, 42))
75275	25527189	Alternatively, the fact that occasional human cells bordering the necrotic core of the largest DCIS lesions expressed p63 suggests that squamous differentiation may be a cell autonomous effect that normal myoepithelial cells prevent through release of a diffusible factor.	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('p63', 'Var', (118, 121))	('necrotic', 'Disease', (66, 74))	('myoepithelial', 'Disease', (205, 218))	('squamous differentiation', 'Disease', (136, 160))	('myoepithelial', 'Disease', 'MESH:D009208', (205, 218))	('release', 'MPA', (241, 248))	('necrotic', 'Disease', 'MESH:D009336', (66, 74))	('human', 'Species', '9606', (40, 45))
75294	25527189	In conclusion, we have shown that by altering the balance of EGFR family signaling in favor of ERBB3/ERBB4 we can prevent squamous metaplasia of mammary epithelial cells in vitro, that human cells with multiple defined oncogenic changes can replace the luminal cell layer in the mouse mammary gland with a morphologically normal luminal layer of human cells, and that addition of a single activated oncogene, mutant PIK3CA, is sufficient to convert these cells into invasive ERalpha + adenocarcinoma cells.	('ERBB3', 'Gene', (95, 100))	('human', 'Species', '9606', (185, 190))	('convert', 'Reg', (441, 448))	('mutant', 'Var', (409, 415))	('PIK3CA', 'Gene', (416, 422))	('squamous metaplasia', 'Disease', (122, 141))	('adenocarcinoma', 'Disease', (485, 499))	('mouse', 'Species', '10090', (279, 284))	('ERBB4', 'Gene', '2066', (101, 106))	('human', 'Species', '9606', (346, 351))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (122, 141))	('squamous metaplasia', 'Disease', 'MESH:D008679', (122, 141))	('EGFR', 'Gene', '1956', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('adenocarcinoma', 'Disease', 'MESH:D000230', (485, 499))	('ERBB4', 'Gene', (101, 106))	('ERBB3', 'Gene', '2065', (95, 100))	('EGFR', 'Gene', (61, 65))
75299	23412907	Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (69, 78))	('Sulf-2', 'Gene', (13, 19))	('cell death', 'CPA', (55, 65))	('Silencing', 'Var', (0, 9))	('matrix detachment', 'CPA', (29, 46))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
75301	23412907	Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Sulf-2 levels', 'MPA', (191, 204))	('MCF10DCIS', 'Var', (51, 60))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('reduced', 'NegReg', (117, 124))	('reduced', 'NegReg', (183, 190))	('tumor', 'Disease', (125, 130))	('Bortezomib', 'Chemical', 'MESH:D000069286', (27, 37))	('mouse', 'Species', '10090', (80, 85))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('apoptosis', 'CPA', (152, 161))
75351	23412907	To further evaluate the role of Sulf-2 on survival upon matrix detachment, we subjected NTC and Sulf-2 knockdown clones to matrix detachment for 24 h followed by their transfer to adhesive polystyrene plates.	('polystyrene', 'Chemical', 'MESH:D011137', (189, 200))	('Sulf-2', 'Gene', (96, 102))	('NTC', 'Gene', (88, 91))	('knockdown', 'Var', (103, 112))
75384	23412907	ShRNA mediated Sulf-2 knockdown in MCF10DCIS cells resulted in increased matrix detachment induced cell death as revealed by increased PARP cleavage and decreased survival.	('PARP cleavage', 'CPA', (135, 148))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (35, 44))	('increased', 'PosReg', (63, 72))	('increased', 'PosReg', (125, 134))	('cell death', 'CPA', (99, 109))	('knockdown', 'Var', (22, 31))	('decreased', 'NegReg', (153, 162))	('matrix detachment', 'CPA', (73, 90))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('survival', 'CPA', (163, 171))
75387	23412907	We identified that proteasomal inhibitors such as MG132, Lactacystine and bortezomib attenuated Sulf-2 expression in several breast cancer cell lines.	('bortezomib', 'Chemical', 'MESH:D000069286', (74, 84))	('expression', 'MPA', (103, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('Lactacystine', 'Chemical', '-', (57, 69))	('breast cancer', 'Disease', (125, 138))	('Sulf-2', 'Gene', (96, 102))	('MG132', 'Var', (50, 55))	('attenuated', 'NegReg', (85, 95))	('MG132', 'Chemical', 'MESH:C072553', (50, 55))
75389	23412907	Although it is likely that the effects elicited by bortezomib are predominantly due to its impact on proteasomal inhibition, bortezomib might affect several key signaling pathways thereby leading to decreased tumor growth apart from its effect on Sulf-2.	('decreased tumor', 'Disease', (199, 214))	('affect', 'Reg', (142, 148))	('key signaling pathways', 'Pathway', (157, 179))	('bortezomib', 'Chemical', 'MESH:D000069286', (51, 61))	('proteasomal inhibition', 'MPA', (101, 123))	('bortezomib', 'Chemical', 'MESH:D000069286', (125, 135))	('decreased tumor', 'Disease', 'MESH:D009369', (199, 214))	('bortezomib', 'Var', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
75446	27620353	Its role as a tumor-suppressor gene has been adequately substantiated, and PTEN hypermethylation has been demonstrated in familial and sporadic cancers.	('familial', 'Disease', (122, 130))	('tumor', 'Disease', (14, 19))	('sporadic cancers', 'Disease', (135, 151))	('hypermethylation', 'Var', (80, 96))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('PTEN', 'Gene', (75, 79))	('PTEN', 'Gene', '5728', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('demonstrated', 'Reg', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('sporadic cancers', 'Disease', 'MESH:D009369', (135, 151))
75449	27620353	The pooled OR, 22.30, 95% confidential intervals, CI = 1.98-251.51, P = 0.01, which demonstrates that loss of PTEN expression by hypermethylation plays a critical role in the early tumorigenesis of ductal carcinoma in situ (DCIS).	('PTEN', 'Gene', '5728', (110, 114))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (198, 222))	('tumor', 'Disease', (181, 186))	('ductal carcinoma in situ', 'Disease', (198, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (198, 222))	('expression', 'MPA', (115, 125))	('loss', 'NegReg', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('hypermethylation', 'Var', (129, 145))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('PTEN', 'Gene', (110, 114))
75450	27620353	In addition, PTEN hypermethylation also is detected in invasive ductal carcinomas (IDCs) and is significantly higher than in normal controls, OR = 23.32, 95% CI = 10.43-52.13, P < 0.00001.	('hypermethylation', 'Var', (18, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('PTEN', 'Gene', (13, 17))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (55, 81))	('higher', 'PosReg', (110, 116))	('PTEN', 'Gene', '5728', (13, 17))	('invasive ductal carcinomas', 'Disease', (55, 81))
75451	27620353	Further analysis did not show significant correlation between PTEN hypermethylation and the progression of breast cancer, estrogen receptor (ER), progesterone receptor (PgR), as well as HER2 status.	('PTEN', 'Gene', (62, 66))	('estrogen receptor', 'Gene', '2099', (122, 139))	('ER', 'Gene', '2099', (141, 143))	('HER2', 'Gene', (186, 190))	('PgR', 'Gene', (169, 172))	('progesterone receptor', 'Gene', (146, 167))	('PTEN', 'Gene', '5728', (62, 66))	('PgR', 'Gene', '5241', (169, 172))	('HER2', 'Gene', '2064', (186, 190))	('progesterone receptor', 'Gene', '5241', (146, 167))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('ER', 'Gene', '2099', (187, 189))	('hypermethylation', 'Var', (67, 83))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('estrogen receptor', 'Gene', (122, 139))
75452	27620353	These results indicate the PTEN hypermethylation is significantly associated with both DCIS and IDCs.	('DCIS', 'Disease', (87, 91))	('associated', 'Reg', (66, 76))	('hypermethylation', 'Var', (32, 48))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('IDCs', 'Disease', (96, 100))
75453	27620353	The detection of PTEN hypermethylation could be an early tumorigenesis marker for breast cancer patients.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('hypermethylation', 'Var', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PTEN', 'Gene', (17, 21))	('patients', 'Species', '9606', (96, 104))	('PTEN', 'Gene', '5728', (17, 21))	('tumor', 'Disease', (57, 62))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
75455	27620353	Breast cancer develops as a stepwise accumulation of genetic changes (point mutations, deletions, and gene amplifications) leading to oncogene activation or tumor suppressor gene inactivation.	('tumor', 'Disease', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('oncogene', 'Protein', (134, 142))	('deletions', 'Var', (87, 96))	('gene amplifications', 'Var', (102, 121))	('activation', 'PosReg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Breast cancer', 'Disease', (0, 13))
75456	27620353	In addition to genetic alterations, breast cancer progression is also controlled by epigenetic modifications such as DNA methylation, histone acetylation and nucleosomal remodeling.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('histone acetylation', 'MPA', (134, 153))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('controlled', 'Reg', (70, 80))	('DNA methylation', 'Var', (117, 132))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
75463	27620353	Reduced expression of PTEN in breast cancer may result from PTEN gene as mutation, deletion and methylation.	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('Reduced', 'NegReg', (0, 7))	('PTEN', 'Gene', (60, 64))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (60, 64))	('methylation', 'Var', (96, 107))	('expression', 'MPA', (8, 18))	('deletion', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutation', 'Var', (73, 81))
75467	27620353	They solidified that PTEN inactivation is associated with unfavorable overall survival and disease-free survival.	('PTEN', 'Gene', '5728', (21, 25))	('disease-free survival', 'CPA', (91, 112))	('inactivation', 'Var', (26, 38))	('PTEN', 'Gene', (21, 25))
75470	27620353	Keywords used to search relevant publications included: "breast cancer", "breast tumor", and "breast carcinoma", "methylation", "hypermethylation", "epigenetic changes", " phosphatase and tensin honolog", and "PTEN".	('PTEN', 'Gene', '5728', (210, 214))	('breast cancer', 'Disease', (57, 70))	('breast tumor', 'Phenotype', 'HP:0100013', (74, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('breast carcinoma', 'Phenotype', 'HP:0003002', (94, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('breast tumor', 'Disease', 'MESH:D001943', (74, 86))	('PTEN', 'Gene', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast tumor', 'Disease', (74, 86))	('breast carcinoma', 'Disease', 'MESH:D001943', (94, 110))	('breast carcinoma', 'Disease', (94, 110))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('epigenetic changes', 'Var', (149, 167))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
75473	27620353	The following data were extracted from each study: (1) bibliographic data including the first author name, year of publication, and country; (2) data on clinicopathological characteristics including number of cases, sample source, age, state of disease, histology, ER status, PR status and HER2 status; (3) methylation detection methods, methylation rate, and/or expression, and follow up.	('HER2', 'Gene', (290, 294))	('ER', 'Gene', '2099', (265, 267))	('HER2', 'Gene', '2064', (290, 294))	('ER', 'Gene', '2099', (291, 293))	('methylation', 'Var', (307, 318))	('methylation', 'Var', (338, 349))
75474	27620353	The pooled rate of PTEN hypermethylation and 95% confidence intervals (95% CI) from different studies were combined to obtain a summary estimate.	('hypermethylation', 'Var', (24, 40))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))
75485	27620353	2A (odds ratios, OR = 22.30, 95% confidential intervals, CI = 1.98-251.51, P = 0.01), which demonstrates that loss of PTEN expression by hypermethylation plays a critical role in the early tumorigenesis of DCIS.	('DCIS', 'Disease', (206, 210))	('loss', 'NegReg', (110, 114))	('tumor', 'Disease', (189, 194))	('expression', 'MPA', (123, 133))	('PTEN', 'Gene', '5728', (118, 122))	('PTEN', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('hypermethylation', 'Var', (137, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
75486	27620353	In addition, PTEN hypermethylation also is detected in IDCs and is significantly higher than in normal controls (OR = 23.32, 95% CI = 10.43-52.13, P < 0.00001), as shown in Fig.	('hypermethylation', 'Var', (18, 34))	('higher', 'PosReg', (81, 87))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('IDCs', 'Disease', (55, 59))
75488	27620353	We then determined 540 breast cancer patients pooled in 4 studies to evaluate the role of inactivation of PTEN via hypermethylation in the progression of breast cancer.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('patients', 'Species', '9606', (37, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('hypermethylation', 'Var', (115, 131))	('PTEN', 'Gene', (106, 110))	('inactivation', 'Var', (90, 102))	('PTEN', 'Gene', '5728', (106, 110))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
75489	27620353	3, aberrant PTEN hypermethylation is not significantly higher in advanced stage of breast cancer (III) than that in early staged breast cancer (I & II), OR = 0.87, 95% CI = 0.20-3.72, P = 0.85.	('higher', 'Reg', (55, 61))	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('aberrant', 'Var', (3, 11))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('PTEN', 'Gene', (12, 16))	('breast cancer', 'Disease', (83, 96))	('PTEN', 'Gene', '5728', (12, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
75490	27620353	These results indicate that the inactivation of PTEN gene by hypermethylation may not play an important role in breast cancer progression from initial stage to advanced stage.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('PTEN', 'Gene', (48, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('PTEN', 'Gene', '5728', (48, 52))	('breast cancer', 'Disease', (112, 125))	('hypermethylation', 'Var', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
75499	27620353	Genetic changes of PTEN, such as mutations and deletion, and/or epigenetic alterations are often observed in a variety of cancers.	('observed', 'Reg', (97, 105))	('PTEN', 'Gene', (19, 23))	('mutations', 'Var', (33, 42))	('epigenetic alterations', 'Var', (64, 86))	('PTEN', 'Gene', '5728', (19, 23))	('deletion', 'Var', (47, 55))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
75501	27620353	Recent findings from Hamamoto's group showed that SMYD2-mediated PTEN methylation at lysine 313 increased phosphorylation at serine 380 of PTEN, consequently inactivated PTEN and activated AKT activity and promoted cell growth and proliferation.	('activated', 'PosReg', (179, 188))	('promoted', 'PosReg', (206, 214))	('methylation', 'Var', (70, 81))	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('AKT', 'Gene', (189, 192))	('PTEN', 'Gene', (170, 174))	('PTEN', 'Gene', (139, 143))	('cell growth', 'CPA', (215, 226))	('inactivated', 'NegReg', (158, 169))	('PTEN', 'Gene', (65, 69))	('SMYD2', 'Gene', (50, 55))	('PTEN', 'Gene', '5728', (170, 174))	('PTEN', 'Gene', '5728', (139, 143))	('phosphorylation at serine 380', 'MPA', (106, 135))	('SMYD2', 'Gene', '56950', (50, 55))	('AKT', 'Gene', '207', (189, 192))	('increased', 'PosReg', (96, 105))	('PTEN', 'Gene', '5728', (65, 69))	('serine', 'Chemical', 'MESH:D012694', (125, 131))	('activity', 'MPA', (193, 201))	('proliferation', 'CPA', (231, 244))
75502	27620353	The loss of PTEN expression through hypermethylation plays an important role in the formation of both DCIS and IDCs, 2) PTEN hypermethylation does not contribute to the progression of breast cancer, 3) No correlation with PTEN hypermethylation was found for hormone receptor status and HER2 status.	('HER2', 'Gene', '2064', (286, 290))	('hormone receptor', 'Gene', '3164', (258, 274))	('expression', 'MPA', (17, 27))	('hormone receptor', 'Gene', (258, 274))	('hypermethylation', 'Var', (36, 52))	('PTEN', 'Gene', (12, 16))	('PTEN', 'Gene', (222, 226))	('PTEN', 'Gene', '5728', (12, 16))	('PTEN', 'Gene', (120, 124))	('PTEN', 'Gene', '5728', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('PTEN', 'Gene', '5728', (120, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('loss', 'NegReg', (4, 8))	('breast cancer, 3', 'Gene', '60500', (184, 200))	('HER2', 'Gene', (286, 290))
75504	27620353	The case of PTEN methylation in breast cancer fits into the latter scenario, which showed no difference in PTEN methylation frequency in DCIS and IDC.	('PTEN', 'Gene', (107, 111))	('breast cancer fits', 'Disease', 'MESH:D001943', (32, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('PTEN', 'Gene', '5728', (107, 111))	('methylation', 'Var', (17, 28))	('PTEN', 'Gene', (12, 16))	('PTEN', 'Gene', '5728', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer fits', 'Disease', (32, 50))
75506	27620353	Our current meta-analysis on PTEN methylation in breast cancer implied that PTEN methylation is an early tumorigenic marker for breast cancer and stays positive and stable through the whole process of malignancy from very early to advanced stage.	('methylation', 'Var', (81, 92))	('malignancy', 'Disease', (201, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', (29, 33))	('malignancy', 'Disease', 'MESH:D009369', (201, 211))	('PTEN', 'Gene', '5728', (29, 33))	('PTEN', 'Gene', '5728', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('tumor', 'Disease', (105, 110))
75507	27620353	Only one study investigated the prognostic significance of PTEN hypermethylation in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('hypermethylation', 'Var', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))	('breast cancer', 'Disease', (84, 97))
75511	27620353	In contrast to the data from mRNA expression, a group in China recently conducted a meta-analysis to assess the association of PTEN negativity by immunohistochemistry method with overall survival and disease-free survival.	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))	('negativity', 'Var', (132, 142))
75512	27620353	They found that PTEN negativity was significantly associated with unfavourable prognosis in terms of overall survival in breast cancer although the association of PTEN negativity and disease-free survival was not validated by their study.	('PTEN', 'Gene', (163, 167))	('PTEN', 'Gene', '5728', (163, 167))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('PTEN', 'Gene', (16, 20))	('negativity', 'Var', (21, 31))	('breast cancer', 'Disease', (121, 134))	('PTEN', 'Gene', '5728', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('associated', 'Reg', (50, 60))
75513	27620353	In conclusion, the meta-analysis demonstrated that PTEN could be an early tumorigenesis marker for breast cancer, whether PTEN methylation with negative protein expression (not only mRNA expression) was probably associated with poor survival status needs more clinical cohort studies to confirm.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('negative', 'NegReg', (144, 152))	('breast cancer', 'Disease', (99, 112))	('methylation', 'Var', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('protein expression', 'MPA', (153, 171))	('PTEN', 'Gene', '5728', (122, 126))	('tumor', 'Disease', (74, 79))	('PTEN', 'Gene', (122, 126))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
75514	27620353	The association between phosphatase and tensin homolog hypermethylation and patients with breast cancer, a meta-analysis and literature review.	('patients', 'Species', '9606', (76, 84))	('hypermethylation', 'Var', (55, 71))	('association', 'Interaction', (4, 15))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))
75563	26311223	We used core biopsies of healthy breast tissue donated to Komen Tissue Bank as a source of normal breast because of documented aberrant histologic characteristics in >85% of breast tissues obtained from reduction mammoplasty or tumor-adjacent normal tissues.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('aberrant', 'Var', (127, 135))
75617	26311223	In fact, cells from the BRCA1 mutant-4 sample were predominantly CD49f-/EpCAM+ and CD271-/EpCAM+ .	('BRCA1', 'Gene', '672', (24, 29))	('CD49f', 'Gene', '3655', (65, 70))	('EpCAM', 'Gene', (72, 77))	('EpCAM', 'Gene', (90, 95))	('CD271', 'Gene', '4804', (83, 88))	('BRCA1', 'Gene', (24, 29))	('EpCAM', 'Gene', '4072', (72, 77))	('CD271', 'Gene', (83, 88))	('mutant-4', 'Var', (30, 38))	('EpCAM', 'Gene', '4072', (90, 95))	('CD49f', 'Gene', (65, 70))
75619	26311223	A specific BRCA1 mutation is less likely to be responsible for this discrepancy because Pathania et al.	('BRCA1', 'Gene', (11, 16))	('mutation', 'Var', (17, 25))	('BRCA1', 'Gene', '672', (11, 16))
75620	26311223	evaluated cells from 14 types of BRCA1 mutations and did not observe differences in CD49f, CD44 and EpCAM expression profiles.	('EpCAM', 'Gene', (100, 105))	('CD49f', 'Gene', (84, 89))	('CD44', 'Gene', '960', (91, 95))	('mutations', 'Var', (39, 48))	('CD49f', 'Gene', '3655', (84, 89))	('EpCAM', 'Gene', '4072', (100, 105))	('BRCA1', 'Gene', '672', (33, 38))	('CD44', 'Gene', (91, 95))	('BRCA1', 'Gene', (33, 38))
75630	26311223	Note that the DNA from a limited number of tumor cells was subjected to copy number variation analysis using the NanoString Technology nCounter Cancer CNV v2 code set to confirm genomic aberration in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('copy number variation', 'Var', (72, 93))	('tumor', 'Disease', (43, 48))
75638	26311223	Tumor cells displayed mature features, as most of the tumor cells were CD49flow/EpCAM+, CD271-/EpCAM+, and EpCAMhigh/Jam-Ahigh (Figure S11A).	('CD49f', 'Gene', '3655', (71, 76))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EpCAM', 'Gene', (107, 112))	('EpCAM', 'Gene', (80, 85))	('CD271', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CD49f', 'Gene', (71, 76))	('EpCAM', 'Gene', '4072', (107, 112))	('Jam-A', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EpCAM', 'Gene', (95, 100))	('EpCAM', 'Gene', '4072', (80, 85))	('S11A', 'Var', (135, 139))	('tumor', 'Disease', (54, 59))	('Jam-A', 'Gene', '50848', (117, 122))	('CD271', 'Gene', '4804', (88, 93))	('S11A', 'SUBSTITUTION', 'None', (135, 139))	('EpCAM', 'Gene', '4072', (95, 100))
75640	26311223	Tumor cells were predominantly CD44+/CD24- and CD49f+/EpCAM+ (Figure S11B).	('EpCAM', 'Gene', '4072', (54, 59))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD24', 'Gene', '100133941', (37, 41))	('CD24', 'Gene', (37, 41))	('CD49f', 'Gene', (47, 52))	('S11B', 'Var', (69, 73))	('S11B', 'SUBSTITUTION', 'None', (69, 73))	('CD49f', 'Gene', '3655', (47, 52))	('CD44', 'Gene', '960', (31, 35))	('EpCAM', 'Gene', (54, 59))	('CD44', 'Gene', (31, 35))
75666	26311223	Thus, cancer-specific aberrations contribute to phenotypic changes in the cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('aberrations', 'Var', (22, 33))	('cancer', 'Disease', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
75685	26311223	Mechanistically, elevated levels of PROCR+/EpCAM- cells in AA could be related to haplotypes of this gene; there are four haplotypes and H1 among them is associated with increased levels of membrane associated PROCR.	('levels of membrane associated PROCR', 'MPA', (180, 215))	('increased', 'PosReg', (170, 179))	('haplotypes', 'Var', (122, 132))	('EpCAM', 'Gene', (43, 48))	('PROCR+', 'Gene', (36, 42))	('PROCR+', 'Gene', '10544', (36, 42))	('EpCAM', 'Gene', '4072', (43, 48))
75687	26311223	Recent studies with limited number of samples showed a defect in luminal progenitor commitment and accumulation of stem cells among BRCA1 mutants, which was mechanistically linked to stabilized EMT-associated Slug protein.	('Slug', 'Gene', '6591', (209, 213))	('mutants', 'Var', (138, 145))	('defect', 'NegReg', (55, 61))	('luminal progenitor commitment', 'CPA', (65, 94))	('Slug', 'Gene', (209, 213))	('BRCA1', 'Gene', '672', (132, 137))	('BRCA1', 'Gene', (132, 137))	('accumulation', 'PosReg', (99, 111))
75688	26311223	However, another study failed to observe elevated Slug in BRCA1 mutant cells.	('BRCA1', 'Gene', (58, 63))	('Slug', 'Gene', '6591', (50, 54))	('Slug', 'Gene', (50, 54))	('mutant', 'Var', (64, 70))	('BRCA1', 'Gene', '672', (58, 63))
75692	26311223	Our results differ from other reports, which showed elevated ALDEFLUOR+ cells upon BRCA1 knockdown in human breast cancer or epithelial cell lines and in mouse mammary epithelial cells.	('mouse', 'Species', '10090', (154, 159))	('BRCA1', 'Gene', '672', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA1', 'Gene', (83, 88))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('knockdown', 'Var', (89, 98))	('human', 'Species', '9606', (102, 107))	('ALDEFLUOR+ cells', 'MPA', (61, 77))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('elevated', 'PosReg', (52, 60))
75693	26311223	Reasons for this discrepancy are unknown but could be related to differences in source of cells (cell lines versus primary cells) and experimental conditions (knockdown versus the presence of mutant BRCA1 proteins).	('mutant', 'Var', (192, 198))	('BRCA1', 'Gene', '672', (199, 204))	('BRCA1', 'Gene', (199, 204))	('proteins', 'Protein', (205, 213))
75741	23729641	However, this is a laborious and unwieldy process (that also does not provide the required level of accuracy as detailed below), which can be simplified by devising a single algorithm to simultaneously detect microcalcifications and diagnose the associated breast lesion(s).	('breast lesion', 'Disease', (257, 270))	('breast lesion', 'Disease', 'MESH:D001941', (257, 270))	('microcalcifications', 'Var', (209, 228))
75750	23729641	First, a single-step SVM Raman algorithm was constructed to simultaneously detect microcalcifications and diagnose the associated breast lesion(s).	('microcalcifications', 'Var', (82, 101))	('breast lesion', 'Disease', (130, 143))	('breast lesion', 'Disease', 'MESH:D001941', (130, 143))
75820	23300877	High-grade DCIS is associated with a high risk of progression to invasive breast cancer.	('invasive breast cancer', 'Disease', (65, 87))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('High-grade', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasive breast cancer', 'Disease', 'MESH:D001943', (65, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
75830	23300877	It has been shown that CD24 is a marker of tumor aggressiveness and that the expression of CD24 promotes breast cancer development.	('CD24', 'Gene', '100133941', (23, 27))	('CD24', 'Gene', (23, 27))	('CD24', 'Gene', '100133941', (91, 95))	('tumor aggressiveness', 'Disease', (43, 63))	('expression', 'Var', (77, 87))	('promotes', 'PosReg', (96, 104))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (43, 63))	('CD24', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
75839	23300877	MCF10A cells in confluence were treated, every other day for ten days, with N-acetyl-cysteine (NAC) (10 mM), caffeic acid phenethyl ester (CAPE) (50 microM), Tyrphostin (10 microM), U73122 (10 microM), Wortmannin (50 nM) and DMSO (diluents control), all purchased from Sigma-Aldrich (St Louis, USA), or infected with dominant negative IKK-beta (dnIKKB) adenoviral vector.	('DMSO', 'Chemical', 'MESH:D004121', (225, 229))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('Tyrphostin', 'Chemical', 'MESH:D020032', (158, 168))	('NAC', 'Chemical', 'MESH:D000111', (95, 98))	('Wortmannin', 'Chemical', 'MESH:D000077191', (202, 212))	('IKK-beta', 'Gene', (335, 343))	('U73122', 'Var', (182, 188))	('IKK-beta', 'Gene', '3551', (335, 343))	('U73122', 'Chemical', 'MESH:C060229', (182, 188))
75865	23300877	Likewise, cells treated with inhibitors of NF-kappaB, CAPE (Figure 3B) and dn-IKKB (Figure 3C) did not upregulate the expression of psoriasin and CD24.	('dn-IKKB', 'Var', (75, 82))	('upregulate', 'PosReg', (103, 113))	('expression', 'MPA', (118, 128))	('CD24', 'Gene', '100133941', (146, 150))	('CD24', 'Gene', (146, 150))	('psoriasin', 'Protein', (132, 141))
75868	23300877	The slightly reduced psoriasin expression in response to treatment with U73122 (Figure 3 D) and Tyrphostin (Figure 3E) may also depend on the high dose of DMSO used.	('DMSO', 'Chemical', 'MESH:D004121', (155, 159))	('U73122', 'Chemical', 'MESH:C060229', (72, 78))	('Tyrphostin', 'Chemical', 'MESH:D020032', (96, 106))	('psoriasin', 'Protein', (21, 30))	('expression', 'MPA', (31, 41))	('U73122', 'Var', (72, 78))	('reduced', 'NegReg', (13, 20))
75873	23300877	The downregulation of psoriasin expression was confirmed in MCF10A Pso-shRNA (Figure 4A) and Pso-siRNA (Figure 4C) compared with C-shRNA and C-siRNA, in suspension culture.	('MCF10A', 'Var', (60, 66))	('psoriasin', 'Gene', (22, 31))	('MCF10A', 'CellLine', 'CVCL:0598', (60, 66))	('downregulation', 'NegReg', (4, 18))	('expression', 'MPA', (32, 42))
75899	23300877	We have previously shown that psoriasin expression is induced by ROS and downregulated by treatment with the antioxidants Bcl-2 and NAC.	('expression', 'MPA', (40, 50))	('NAC', 'Chemical', 'MESH:D000111', (132, 135))	('induced', 'Reg', (54, 61))	('psoriasin', 'Disease', (30, 39))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('ROS', 'Var', (65, 68))	('downregulated', 'NegReg', (73, 86))	('Bcl-2', 'Gene', (122, 127))	('Bcl-2', 'Gene', '596', (122, 127))
75916	23300877	Changes in and the dysregulation of the interactions between epithelial cells and the ECM generate signals for pathologic processes, such as breast tumor formation.	('dysregulation', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('breast tumor', 'Disease', 'MESH:D001943', (141, 153))	('breast tumor', 'Disease', (141, 153))	('signals', 'Reg', (99, 106))	('interactions', 'Interaction', (40, 52))	('breast tumor', 'Phenotype', 'HP:0100013', (141, 153))
75977	22130160	The next day, DCs were pulsed with 6 HER-2/neu MHC class II promiscuous-binding peptides (42-56, 98-114, 328-345, 776-790, 927-941, 1166-1180).	('927-941', 'Var', (123, 130))	('HER-2/neu', 'Gene', '2064', (37, 46))	('328-345', 'Var', (105, 112))	('HER-2/neu', 'Gene', (37, 46))	('42-56', 'Var', (90, 95))
75995	22130160	Autologous DCs were pulsed with HER-2/neu p369-377 or p689-697 at 10mug/ml 2h prior to harvest.	('HER-2/neu', 'Gene', '2064', (32, 41))	('2h', 'Chemical', 'MESH:D003903', (75, 77))	('p369-377', 'Var', (42, 50))	('p689-697', 'Var', (54, 62))	('HER-2/neu', 'Gene', (32, 41))
76009	22130160	There were 13 HLA A2pos subjects that received ICAIT DC pulsed with additional HLA-A2 binding peptides (369-377 and 689-697), each potentially capable of sensitizing CD8pos T cells.	('689-697', 'Var', (116, 123))	('ICAIT DC', 'Chemical', '-', (47, 55))	('CD8', 'Gene', (166, 169))	('CD8', 'Gene', '925', (166, 169))	('369-377', 'Var', (104, 111))
76015	22130160	One of these subjects had evidence of tumor recognition prior to vaccination 080102-09 (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('080102-09', 'Var', (77, 86))
76091	21161341	Furthermore, the lifetime risk of subsequently developing invasive breast cancer (relative risk, RR) increases in a progressive fashion according to the histological subtype of benign disease: women with PDWA have RR of 1.3-1.9, women with atypical hyperplasia have RR of 3.5-5.3, and women with DCIS have RR of 10-11.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('invasive breast cancer', 'Disease', (58, 80))	('PDWA', 'Var', (204, 208))	('women', 'Species', '9606', (229, 234))	('benign disease', 'Disease', (177, 191))	('benign disease', 'Disease', 'MESH:D009369', (177, 191))	('women', 'Species', '9606', (193, 198))	('atypical hyperplasia', 'Disease', (240, 260))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (240, 260))	('invasive breast cancer', 'Disease', 'MESH:D001943', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('women', 'Species', '9606', (285, 290))
76103	21161341	Both DCIS and invasive cancer are histologically and biologically diverse, composed of many different subtypes; in high grade DCIS the myoepithelial cell layer and the BM become discontinuous, with proliferation of fibroblasts, increased angiogenesis, and infiltration of lymphocytes.	('invasive cancer', 'Disease', 'MESH:D009362', (14, 29))	('DCIS', 'Disease', (126, 130))	('invasive cancer', 'Disease', (14, 29))	('infiltration', 'CPA', (256, 268))	('increased', 'PosReg', (228, 237))	('high grade', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('angiogenesis', 'CPA', (238, 250))
76106	21161341	In support of this possibility, biopsies of breast tissue removed prophylactically from BRCA1/2 carriers were found to contain various proliferative benign lesions including atypia in over 50% of cases.	('atypia', 'Disease', (174, 180))	('carriers', 'Var', (96, 104))	('proliferative benign lesions', 'CPA', (135, 163))	('BRCA1/2', 'Gene', (88, 95))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('contain', 'Reg', (119, 126))
76125	21161341	Inhibition of COX-2 completely blocked the increased growth of tumors with co-injected fibroblasts and inhibited transition from DCIS to invasive cancer.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('growth', 'MPA', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('invasive cancer', 'Disease', (137, 152))	('inhibited', 'NegReg', (103, 112))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Inhibition', 'Var', (0, 10))	('invasive cancer', 'Disease', 'MESH:D009362', (137, 152))	('COX-2', 'Gene', '4513', (14, 19))	('blocked', 'NegReg', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('COX-2', 'Gene', (14, 19))
76149	21161341	These were higher grade tumors, progesterone and estrogen receptor negative, and positive for TP53 mutations, with survival prognosis varying between the cancer subsets.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('estrogen receptor', 'Gene', (49, 66))	('tumors', 'Disease', (24, 30))	('positive', 'Reg', (81, 89))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('estrogen receptor', 'Gene', '2099', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('TP53', 'Gene', '7157', (94, 98))	('cancer', 'Disease', (154, 160))	('TP53', 'Gene', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
76155	21161341	Also supporting the concept that the epithelial cells of DCIS and IBC are very similar in their gene expression characteristics, a recent study has demonstrated that the MCF10DCIS cells are able to spontaneously progress into IBC-like cells, although normal myoepithelial cells are able to block this progression.	('MCF10DCIS', 'Var', (170, 179))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (170, 179))	('progress', 'PosReg', (212, 220))	('IBC-like', 'Disease', (226, 234))
76156	21161341	Although gene expression changes were found in all cell types, genetic alterations, analyzed using single nucleotide polymorphism (SNP) arrays, were only detected in epithelial cancer cells, which suggested that the underlying processes were likely due to epigenetic regulation rather than genetic mutations.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('epigenetic regulation', 'Var', (256, 277))	('changes', 'Reg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('epithelial cancer', 'Phenotype', 'HP:0031492', (166, 183))
76164	21161341	ADH atypical ductal hyperplasia ALH atypical lobular hyperplasia BBD benign breast disease BM basement membrane CAF carcinoma-associated fibroblast CSF-1 colony stimulating factor-1 CTGF connective tissue growth factor DCIS ductal carcinoma in situ DTF desmoid-type fibromatosis ECM extracellular matrix IBC invasive breast carcinoma IHC immunohistochemistry LCIS lobular carcinoma in situ LCM laser capture microdissection PDWA proliferative disease without atypia RR relative risk SAGE serial analysis of gene expression SFT solitary fibrous tumor SNP single nucleotide polymorphism TDLU terminal duct lobular unit	('ECM', 'Gene', '22915', (279, 282))	('carcinoma', 'Disease', 'MESH:D002277', (324, 333))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (364, 389))	('ALH', 'Chemical', '-', (32, 35))	('carcinoma in situ', 'Disease', 'MESH:D002278', (372, 389))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (45, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Disease', 'MESH:D002277', (116, 125))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (224, 248))	('carcinoma', 'Disease', (231, 240))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (13, 31))	('benign breast disease', 'Disease', (69, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (372, 381))	('lobular carcinoma', 'Disease', 'MESH:D018275', (364, 381))	('carcinoma', 'Disease', (372, 381))	('lobular carcinoma', 'Disease', (364, 381))	('CSF-1', 'Gene', '1435', (148, 153))	('ductal carcinoma in situ', 'Disease', (224, 248))	('TDLU', 'Chemical', '-', (585, 589))	('breast carcinoma', 'Disease', 'MESH:D001943', (317, 333))	('desmoid-type fibromatosis', 'Disease', (253, 278))	('carcinoma in situ', 'Disease', (372, 389))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('carcinoma', 'Disease', 'MESH:D002277', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (544, 549))	('carcinoma', 'Disease', (324, 333))	('ECM', 'Gene', (279, 282))	('CAF', 'Chemical', '-', (112, 115))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (231, 248))	('single nucleotide polymorphism', 'Var', (554, 584))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (224, 248))	('benign breast disease', 'Disease', 'MESH:D001941', (69, 90))	('ductal hyperplasia', 'Disease', (13, 31))	('carcinoma', 'Disease', (116, 125))	('desmoid-type fibromatosis', 'Disease', 'MESH:C535944', (253, 278))	('carcinoma in situ', 'Disease', 'MESH:D002278', (231, 248))	('carcinoma', 'Disease', 'MESH:D002277', (372, 381))	('breast carcinoma', 'Phenotype', 'HP:0003002', (317, 333))	('fibrous tumor', 'Disease', 'MESH:D054364', (536, 549))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (372, 389))	('lobular hyperplasia', 'Disease', (45, 64))	('breast carcinoma', 'Disease', (317, 333))	('fibrous tumor', 'Disease', (536, 549))	('CSF-1', 'Gene', (148, 153))
76210	20740500	To identify phenotype modifications of effector lymphocytes involved in trastuzumab-mediated cytotoxicity, as well as the frequency of effector natural killer (NK) and T cell populations among PBMCs 4x105 of the PBMCs prepared for use in the ADCC assay were left in parallel cultures with unlabeled MDA-MB-361 target cells at an effector-to-target ratio of 25:1 in the presence of 20% autologous serum or trastuzumab (10 mug/ml) or in their absence (negative control), in otherwise identical culture conditions of ADCC assay.	('trastuzumab', 'Gene', (405, 416))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('trastuzumab', 'Chemical', 'MESH:D000068878', (405, 416))	('MDA-MB-361', 'CellLine', 'CVCL:0620', (299, 309))	('trastuzumab', 'Chemical', 'MESH:D000068878', (72, 83))	('cytotoxicity', 'Disease', (93, 105))	('10 mug/ml', 'Var', (418, 427))
76214	20740500	The peptides, which are designated by the position of the first amino acid (Pool I: p98, p369, p927; Pool II: p776, p62, p77; Pool III: p83, p88, p350; Pool IV: p976, p42, p688; and Pool V: p971, p1166) were all class II peptides that have been previously described.	('p62', 'Gene', '23636', (116, 119))	('p927', 'Var', (95, 99))	('p369', 'Var', (89, 93))	('p42', 'Gene', '23552', (167, 170))	('p98', 'Var', (84, 87))	('p62', 'Gene', (116, 119))	('p1166', 'Var', (196, 201))	('p350', 'Gene', (146, 150))	('p971', 'Var', (190, 194))	('p350', 'Gene', '5591', (146, 150))	('p42', 'Gene', (167, 170))	('p83', 'Gene', '23221', (136, 139))	('p83', 'Gene', (136, 139))	('p776', 'Var', (110, 114))	('p688', 'Var', (172, 176))	('p976', 'Var', (161, 165))	('p77', 'Var', (121, 124))	('p88', 'Var', (141, 144))
76228	20740500	Overall, 24 (35%) patients had lesions with overexpression or amplification of HER2.	('HER2', 'Gene', '2064', (79, 83))	('overexpression', 'PosReg', (44, 58))	('patients', 'Species', '9606', (18, 26))	('amplification', 'Var', (62, 75))	('HER2', 'Gene', (79, 83))
76281	20740500	In vitro, blockade of the HER2 receptor results in upregulation of the cell cycle inhibitor p27, which can inhibit cyclin E/cdk2 complexes resulting in a G1 cell cycle arrest, with a concomitant reduction in proliferation.	('inhibit', 'NegReg', (107, 114))	('upregulation', 'PosReg', (51, 63))	('p27', 'Gene', (92, 95))	('cdk2', 'Gene', (124, 128))	('cdk2', 'Gene', '1017', (124, 128))	('arrest', 'Disease', (168, 174))	('blockade', 'Var', (10, 18))	('HER2', 'Gene', (26, 30))	('proliferation', 'CPA', (208, 221))	('p27', 'Gene', '51014', (92, 95))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (157, 174))	('reduction', 'NegReg', (195, 204))	('HER2', 'Gene', '2064', (26, 30))	('arrest', 'Disease', 'MESH:D006323', (168, 174))
76314	20740500	The rationale for utilizing trastuzumab concurrently with radiation for HER2-overexpressing DCIS is that trastuzumab radiosensitizes only cells that overexpress HER2 and therefore will enhance the radiation sensitivity of carcinoma more than surrounding healthy tissues.	('HER2', 'Gene', (72, 76))	('HER2', 'Gene', '2064', (72, 76))	('radiosensitizes', 'NegReg', (117, 132))	('radiation sensitivity', 'CPA', (197, 218))	('enhance', 'PosReg', (185, 192))	('carcinoma', 'Disease', 'MESH:D002277', (222, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('HER2', 'Gene', (161, 165))	('trastuzumab', 'Chemical', 'MESH:D000068878', (28, 39))	('trastuzumab', 'Var', (105, 116))	('HER2', 'Gene', '2064', (161, 165))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('trastuzumab', 'Chemical', 'MESH:D000068878', (105, 116))	('carcinoma', 'Disease', (222, 231))
76341	31121489	While a variety of environmental and socioeconomic risk factors have been identified, studies have shown that physical exercise reduces the risk of breast cancer mortality by upwards of 45% by limiting aggressiveness, as well as reducing the risk of getting diagnosed with breast cancer by 14%.	('physical', 'Var', (110, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('aggressiveness', 'Disease', 'MESH:D001523', (202, 216))	('limiting', 'NegReg', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('reduces', 'NegReg', (128, 135))	('aggressiveness', 'Disease', (202, 216))	('breast cancer', 'Disease', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (202, 216))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('reducing', 'NegReg', (229, 237))	('breast cancer', 'Disease', (273, 286))
76377	31121489	Significant weight changes were observed between the exercise and control groups for both the FVB/NJ and SV40 Tag mice.	('SV40', 'Var', (105, 109))	('mice', 'Species', '10090', (114, 118))	('weight changes', 'CPA', (12, 26))
76380	31121489	Tissue oxygenation and perfusion measurements were analyzed between the FVB/NJ and SV40 Tag mice, as well as among the exercise and control subgroups of each mouse line.	('SV40', 'Var', (83, 87))	('mouse', 'Species', '10090', (158, 163))	('oxygen', 'Chemical', 'MESH:D010100', (7, 13))	('FVB/NJ', 'Var', (72, 78))	('mice', 'Species', '10090', (92, 96))
76385	31121489	In comparing the exercise and control groups of the SV40 Tag mice, average weekly values were higher for the exercise group than the control group, although this was not statistically significant (-6.51 +- 26.17% vs. 17.26 +- 25.06%, P = 0.037).	('mice', 'Species', '10090', (61, 65))	('SV40 Tag', 'Var', (52, 60))	('higher', 'PosReg', (94, 100))
76387	31121489	Although there was no statistical difference between the tumor volumes in the exercise and control groups, the exercise group exhibited slower tumor growth than compared to the control group at the early time points (0.38 +- 1.29 mm3 vs. 0.88 +- 1.28 mm3, P = 0.21, Figure 5).	('slower', 'NegReg', (136, 142))	('tumor', 'Disease', (143, 148))	('exercise', 'Var', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
76388	31121489	Furthermore, the exercise mice survived an average of 3 weeks longer than those who had no exercise available (26 weeks vs. 23 weeks, P = 0.014; Figure 6).	('longer', 'PosReg', (62, 68))	('exercise', 'Var', (17, 25))	('mice', 'Species', '10090', (26, 30))
76392	31121489	Additionally, studies have found that exercise helps reduce the risk of breast cancer occurrence, as well as reducing the risk of death post-diagnosis.	('exercise', 'Var', (38, 46))	('reduce', 'NegReg', (53, 59))	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('reducing', 'NegReg', (109, 117))
76400	31121489	that exercise has no effect on perfusion as there were no differences between the FVB/NJ and SV40 Tag mice nor their subgroups (P > .2).	('mice', 'Species', '10090', (102, 106))	('perfusion', 'MPA', (31, 40))	('SV40', 'Var', (93, 97))
76403	31121489	The average tumor size was lower in the exercise group than in the control group (Figure 5).	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lower', 'NegReg', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('exercise', 'Var', (40, 48))	('tumor', 'Disease', (12, 17))
76421	28261300	In a meta-analysis of 8 randomized clinical trials comprising over 600,000 women, Gotzsche and Nielsen evaluated that performing mammography in women in the 50 to 69 age group, over a 2- or 3-year interval, reduced mortality from BC by approximately 10% to 25%.	('women', 'Species', '9606', (75, 80))	('BC', 'Phenotype', 'HP:0003002', (230, 232))	('reduced', 'NegReg', (207, 214))	('mammography', 'Gene', (129, 140))	('mortality', 'MPA', (215, 224))	('performing', 'Var', (118, 128))	('women', 'Species', '9606', (144, 149))
76441	28261300	More patients with tumors up to 2 cm were found in the NBCSP group, whereas more patients with tumors from 2 to 5 cm and with pT4 were recorded in the group not participating in the NBCSP (pT1 - 64.3% vs. 53.3%, p = 0.006; pT2 - 27.8% vs. 37.2%, p = 0.012; pT4 - 1.4% vs. 3.3%, p = 0.874).	('tumors', 'Disease', (19, 25))	('NBCSP', 'Var', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('patients', 'Species', '9606', (5, 13))	('pT1', 'Gene', (189, 192))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BC', 'Phenotype', 'HP:0003002', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('pT1', 'Gene', '58492', (189, 192))	('BC', 'Phenotype', 'HP:0003002', (183, 185))	('tumors', 'Disease', (95, 101))
76446	28261300	A meta-analysis of 8 randomized trials, published by Autier, showed a linear correlation between the reduction in advanced cancers and increase in survival rate due to MBCS.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('reduction', 'NegReg', (101, 110))	('increase', 'PosReg', (135, 143))	('survival', 'CPA', (147, 155))	('MBCS', 'Var', (168, 172))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('BC', 'Phenotype', 'HP:0003002', (169, 171))
76452	28261300	Kalager observed a reduction in mortality in a group of women participating in MBCS, as well as in a group not participating in MBCS, in Norway (7.2/100 000 vs. 4.8/100 000, respectively), and thus concluded that screening was only responsible for about 33% of the reduction in mortality.	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('reduction', 'NegReg', (19, 28))	('MBCS', 'Var', (79, 83))	('mortality', 'MPA', (32, 41))	('BC', 'Phenotype', 'HP:0003002', (80, 82))	('women', 'Species', '9606', (56, 61))
76469	28261300	In comparison to other countries, the results obtained in the NBCSP should be considered unsatisfactory; in the UK the percentage of tumors < 20 mm was 78.4%, in Norway and the USA it was 84%, and in Canada in the years 1980 to 1985 the percentage was 60%.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('< 20 mm', 'Var', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('BC', 'Phenotype', 'HP:0003002', (63, 65))
76493	26916154	False-positive results are a concern of mammographic screening as they might cause distress, anxiety, and other psychological problems to the women 1, 2.	('cause', 'Reg', (77, 82))	('anxiety', 'Disease', (93, 100))	('anxiety', 'Phenotype', 'HP:0000739', (93, 100))	('False-positive', 'Var', (0, 14))	('distress', 'Disease', (83, 91))	('anxiety', 'Disease', 'MESH:D001008', (93, 100))	('women', 'Species', '9606', (142, 147))
76549	26916154	Women with a false-positive result at first screen had a lower risk of breast cancer compared with women with a false-positive result at later screens (first screen: RR = 1.86; 95% CI: 1.77-1.96; second screen: RR = 2.16; 95% CI: 1.98-2.35; third screen or more: RR = 2.42; 95% CI: 2.21-2.64).	('breast cancer', 'Disease', (71, 84))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('false-positive', 'Var', (13, 27))	('women', 'Species', '9606', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('lower', 'NegReg', (57, 62))
76554	26916154	The results excluding women with at least one irregular screening participation (n = 174,134) showed a similarly increased risk of screen-detected breast cancer in women with false-positive results (RR = 2.00; 95% CI: 1.91-2.09) compared to women with false-positive results in the full database analyses.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('women', 'Species', '9606', (22, 27))	('breast cancer', 'Disease', (147, 160))	('women', 'Species', '9606', (164, 169))	('women', 'Species', '9606', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('false-positive results', 'Var', (175, 197))
76574	26916154	The highest risk of screen-detected cancer was found in the screening test immediately following a false-positive result, and decreased gradually with the number of screens since false-positive result.	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (36, 42))	('false-positive', 'Var', (99, 113))	('cancer', 'Disease', 'MESH:D009369', (36, 42))
76588	26916154	False-positive results are likely to increase not only the risk of screen detected cancers but also the risk of clinically diagnosed breast cancers, which would have been desirable to analyze 16.	('False-positive results', 'Var', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('breast cancers', 'Disease', 'MESH:D001943', (133, 147))	('breast cancers', 'Disease', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('increase', 'PosReg', (37, 45))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))	('cancers', 'Disease', (83, 90))
76751	22733916	A malignancy coded as BI-RADS category 4A, 4B, 4C, or 5 was considered a true-positive and a benign or high-risk lesion coded as BI-RADS category 1, 2, or 3 was considered a true-negative.	('RADS category 4A', 'Phenotype', 'HP:0500054', (25, 41))	('BI-RADS category', 'Var', (22, 38))	('malignancy', 'Disease', (2, 12))	('malignancy', 'Disease', 'MESH:D009369', (2, 12))
76762	22733916	Cysts were present in more than 37% of participants in ACRIN 6666 in year 1 and more than 47% of participants over the 3 years of screening ultrasound, with the largest cyst 8 mm or smaller in 70% of the women with cysts.	('ACRIN 6666', 'Var', (55, 65))	('women', 'Species', '9606', (204, 209))	('participants', 'Species', '9606', (39, 51))	('Cysts', 'Disease', (0, 5))	('participants', 'Species', '9606', (97, 109))
76801	30139236	Mutations in this gene are associated with lung and breast cancer (Sobral-Leite et al., 2017).	('lung and breast cancer', 'Disease', 'MESH:D001943', (43, 65))	('associated', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
76813	30139236	Anti-RAGE antibody (A11): sc- 80652 RAGE Antibody (A11) is a mouse monoclonal IgG2a provided at 200 mug/ml, raised against a truncated extracellular domain of RAGE of human origin (Santa Cruz Biotechnology, USA).	('A11', 'Gene', (51, 54))	('A11', 'Gene', '28874', (51, 54))	('sc- 80652', 'Var', (26, 35))	('mouse', 'Species', '10090', (61, 66))	('A11', 'Gene', (20, 23))	('human', 'Species', '9606', (167, 172))	('A11', 'Gene', '28874', (20, 23))
76860	30139236	Among the different types of BC, triple negative BC (TNBC) (ER-, PR-, and HER2-) has been associated the most with poor prognosis and survival due to early metastasis to other organs and a lack of clinically established targeted therapies.	('poor', 'NegReg', (115, 119))	('triple negative', 'Var', (33, 48))	('HER2', 'Gene', (74, 78))	('TNBC', 'Disease', 'None', (53, 57))	('HER2', 'Gene', '2064', (74, 78))	('TNBC', 'Disease', (53, 57))
76870	30139236	We found also that, the intensity and score of RAGE expression were higher in lymph node metastatic deposits of high grade invasive breast cancer compared to the same parameters in case of low grade invasive breast cancer with statistical significance (p<0.05 and p<0.01 respectively).	('invasive breast cancer', 'Disease', (199, 221))	('high grade', 'Var', (112, 122))	('intensity', 'MPA', (24, 33))	('score', 'MPA', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('higher', 'PosReg', (68, 74))	('invasive breast cancer', 'Disease', 'MESH:D001943', (123, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('invasive breast cancer', 'Disease', 'MESH:D001943', (199, 221))	('lymph node metastatic deposits', 'CPA', (78, 108))	('RAGE expression', 'MPA', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('invasive breast cancer', 'Disease', (123, 145))
76877	30139236	Dysregulation of EGFR pathways by overexpression or constitutive activation can promote tumor processes including angiogenesis and metastasis and is associated with poor prognosis in many human malignancies (Salomon et a., 1995; Lurje and Lenz, 2009; Martinazzi et al.,1993).	('malignancies', 'Disease', (194, 206))	('human', 'Species', '9606', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Dysregulation', 'Var', (0, 13))	('overexpression', 'PosReg', (34, 48))	('angiogenesis', 'CPA', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EGFR', 'Gene', '1956', (17, 21))	('malignancies', 'Disease', 'MESH:D009369', (194, 206))	('tumor', 'Disease', (88, 93))	('activation', 'PosReg', (65, 75))	('promote', 'PosReg', (80, 87))	('EGFR', 'Gene', (17, 21))
76892	30139236	We compared primary tumors with their corresponding metastatic lesions, and found that there were no significant differences in the expression of Ki67 between them, which is same with studies carried out by Tawfik et al., (2015), but different from studies have found greater expression of Ki67 in metastatic tumors compared with primary tumors (Park et al., 2007; Buxant et al., 2002; Tokes et al., 2015).	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('primary tumors', 'Disease', 'MESH:D009369', (330, 344))	('primary tumors', 'Disease', 'MESH:D009369', (12, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (309, 315))	('greater', 'PosReg', (268, 275))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('tumors', 'Disease', (338, 344))	('expression', 'MPA', (276, 286))	('Ki67', 'Var', (290, 294))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('primary tumors', 'Disease', (330, 344))	('tumors', 'Disease', 'MESH:D009369', (338, 344))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
76893	30139236	That Ki67 expression is useful in metastatic tumors but not in primary tumors has been reported (Park et al., 2007).	('primary tumors', 'Disease', 'MESH:D009369', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('primary tumors', 'Disease', (63, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', (71, 77))	('Ki67', 'Var', (5, 9))
76894	30139236	Interestingly, it was demonstrated that a high Ki67 in ALN but not in breast is significantly associated with shorter patient survival, sug gesting that patients with higher Ki67 level in LN metastases might require more aggressive therapy and closer clinical monitoring of their disease.	('Ki67', 'Var', (47, 51))	('sug', 'Chemical', '-', (136, 139))	('patients', 'Species', '9606', (153, 161))	('shorter', 'NegReg', (110, 117))	('metastases', 'Disease', (191, 201))	('patient survival', 'CPA', (118, 134))	('patient', 'Species', '9606', (153, 160))	('metastases', 'Disease', 'MESH:D009362', (191, 201))	('patient', 'Species', '9606', (118, 125))	('ALN', 'Chemical', '-', (55, 58))
76898	25400950	Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis.	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('desmoplastic reaction', 'Disease', (122, 143))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Disease', (271, 277))	('calcification', 'Disease', 'MESH:D002114', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('tenascin-C', 'Gene', (174, 184))	('cancer', 'Disease', (7, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (306, 319))	('TN-C', 'Gene', '3371', (186, 190))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('tenascin-C', 'Gene', '3371', (174, 184))	('high grade', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('TN-C', 'Gene', (186, 190))	('calcification', 'Disease', (45, 58))	('breast cancer', 'Disease', 'MESH:D001943', (306, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('overexpression', 'PosReg', (192, 206))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('breast cancer', 'Disease', (306, 319))	('desmoplastic reaction', 'Disease', 'MESH:D004342', (122, 143))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('breast cancer', 'Disease', (264, 277))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('cancer', 'Disease', (313, 319))
76980	20531416	In invasive breast carcinomas, Mb expression was associated with better histological tumour differentiation according to BRE grading (correlation coefficient (cc)=-0.116; P=0.001).	('breast carcinomas', 'Phenotype', 'HP:0003002', (12, 29))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('invasive breast carcinomas', 'Disease', (3, 29))	('tumour', 'Disease', (85, 91))	('expression', 'Var', (34, 44))	('better', 'PosReg', (65, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (3, 29))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
76985	20531416	High Mb expression was also significantly associated with longer overall patient survival (5-year survival rate of Mb-positive cases was 83% vs 75% in Mb-negative cases, Figure 2A), but lost significance in a multivariate Cox analysis that included pT, pN, BRE-grade, ERalpha and Mb (not shown).	('High', 'Var', (0, 4))	('patient survival', 'CPA', (73, 89))	('longer', 'PosReg', (58, 64))	('patient', 'Species', '9606', (73, 80))	('ERalpha', 'Gene', '2099', (268, 275))	('expression', 'MPA', (8, 18))	('ERalpha', 'Gene', (268, 275))
77015	20531416	We therefore conclude that Mb is de novo expressed in breast cancer cells, although rare cases of so-called metaplastic carcinomas of the breast might exist in which Mb positivity stems from the rabdomyogenous differentiation of the cells (Jamieson and Rudland, 1990; Yang et al, 2003).	('breast cancer', 'Disease', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('positivity', 'Var', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('stems from', 'Reg', (180, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('carcinomas', 'Disease', (120, 130))	('carcinomas', 'Disease', 'MESH:D002277', (120, 130))	('metaplastic carcinomas of the breast', 'Phenotype', 'HP:0100013', (108, 144))
77050	20531416	The authors assume that these beneficial outcomes of Mb overexpressing tumours result primarily from the reduction of tumour hypoxia (Galluzzo et al, 2009).	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('tumour hypoxia', 'Disease', (118, 132))	('tumours', 'Disease', (71, 78))	('reduction', 'NegReg', (105, 114))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour hypoxia', 'Disease', 'MESH:D000860', (118, 132))	('overexpressing', 'Var', (56, 70))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
77059	20531416	According to Flogel et al (2005), lack of Mb in the heart of knockout mice leads to a biochemical shift in cardiac substrate utilisation from FA to glucose oxidation, which, not only corresponds to an adaptive reduction in O2 consumption for the equimolar production of ATP but also implicates the protein in providing FA substrates for the mitochondrial beta-oxidation breakdown in vivo.	('O2 consumption for', 'MPA', (223, 241))	('glucose oxidation', 'Disease', 'MESH:D004194', (148, 165))	('cardiac substrate utilisation', 'MPA', (107, 136))	('glucose oxidation', 'Disease', (148, 165))	('mice', 'Species', '10090', (70, 74))	('lack', 'Var', (34, 38))	('O2', 'Chemical', 'MESH:D010100', (223, 225))	('reduction', 'NegReg', (210, 219))	('ATP', 'Chemical', 'MESH:D000255', (270, 273))	('implicates', 'Reg', (283, 293))
77075	16646977	The increased breast cancer risk associated with increased mammographic densities may simply be a reflection of increased epithelial cell numbers.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mammographic densities', 'Var', (59, 81))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))
77081	16646977	Li and colleagues also found in their much larger study (n = 236) of 'random' breast tissue collected from normal women by Bartow and colleagues in their autopsy study of accidental deaths in New Mexico that women with high mammographic density had greater amounts of epithelial tissue (as measured by area of epithelial nuclear staining) and the result was highly statistically significant.	('greater', 'PosReg', (249, 256))	('women', 'Species', '9606', (114, 119))	('high', 'Var', (219, 223))	('women', 'Species', '9606', (208, 213))
77093	16646977	Similarly, on the null hypothesis of no association between MIB1 positivity as a proportion of epithelial cells and the CT density of the local tissue, the expected value of the n's is simply proportional to the related t's, so that, for example, the expected value of nH is (nL + nM + nH) x tH/(tL + tM + tH).	('MIB1', 'Gene', (60, 64))	('nL + nM + nH) x tH/(tL + tM + tH', 'Var', (276, 308))	('MIB1', 'Gene', '57534', (60, 64))
77108	16646977	These results suggest that the increasing breast cancer risk associated with increasing mammographic density might be simply a reflection of more breast epithelial tissue.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mammographic density', 'Var', (88, 108))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))
77229	32238387	Based on a comprehensive meta-analysis of all prior publications, African-American race, premenopausal status, detection by palpation, high histologic grade, involved margins, and high p16 expression are all significantly associated with risk of invasive recurrence.	('invasive', 'Disease', (246, 254))	('premenopausal status', 'Phenotype', 'HP:0008209', (89, 109))	('p16', 'Gene', (185, 188))	('expression', 'MPA', (189, 199))	('associated', 'Reg', (222, 232))	('high', 'Var', (180, 184))	('p16', 'Gene', '1029', (185, 188))
77234	32238387	PIK3CA mutations, more common in ER+ luminal cases, are sometimes discordant between IDC and adjacent DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))	('PIK3CA', 'Gene', (0, 6))	('IDC', 'Disease', (85, 88))	('PIK3CA', 'Gene', '5290', (0, 6))	('luminal', 'Chemical', 'MESH:D010634', (37, 44))	('mutations', 'Var', (7, 16))
77235	32238387	Comparing genomic copy number profiles of IDC and adjacent synchronous DCIS at single cell resolution complemented with exome sequencing confirmed known copy number alterations in breast cancer and revealed many shared clones between in situ and invasive regions of the same tumor, suggesting a multiclonal invasion model.	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('copy number alterations', 'Var', (153, 176))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
77248	32238387	Similarly, the relative proportion of macrophages (Mphi) increases in HER2+ and triple-negative IDC compared to DCIS, while the fraction of dendritic cells (DCs) decreases as tumors progress.	('tumors', 'Disease', (175, 181))	('HER2', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('HER2', 'Gene', '2064', (70, 74))	('triple-negative', 'Var', (80, 95))	('increases', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
77255	32238387	Mphi can also have pro- or antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('Mphi', 'Var', (0, 4))	('pro-', 'CPA', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
77262	32238387	DCIS with microinvasion or adjacent to IDC have higher TIL density compared to pure DCIS, with CD8+, CD4+ and CD38+ cells being more common in adjacent DCIS lesions.	('CD38', 'Gene', (110, 114))	('microinvasion', 'Var', (10, 23))	('CD8', 'Gene', '925', (95, 98))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('TIL', 'Gene', '7096', (55, 58))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('CD4', 'Gene', (101, 104))	('CD38', 'Gene', '952', (110, 114))	('higher', 'PosReg', (48, 54))	('CD4', 'Gene', '920', (101, 104))	('TIL', 'Gene', (55, 58))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('CD8', 'Gene', (95, 98))
77279	32238387	In HER2+ pure DCIS and IDC, amplification of ERBB2 associates with co-amplification of this CC, which inversely correlates with the frequency of intratumoral GZMB+CD8+ T cells.	('HER2', 'Gene', '2064', (3, 7))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('GZMB', 'Gene', '3002', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('GZMB', 'Gene', (158, 162))	('CD8', 'Gene', '925', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('ERBB2', 'Gene', '2064', (45, 50))	('CD8', 'Gene', (163, 166))	('ERBB2', 'Gene', (45, 50))	('HER2', 'Gene', (3, 7))	('tumor', 'Disease', (150, 155))	('amplification', 'Var', (28, 41))
77297	32238387	In the adjuvant setting, vaccination against HER-2 resulted in no tumor recurrences after a 34-month period.	('HER-2', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('HER-2', 'Gene', '2064', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('vaccination', 'Var', (25, 36))
77300	32238387	For example, targeting TAMs may lift immunosuppression on effector cells and reestablish Mphi antitumor effects.	('TAMs', 'Chemical', '-', (23, 27))	('immunosuppression', 'MPA', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('TAMs', 'Gene', (23, 27))	('targeting', 'Var', (13, 22))	('tumor', 'Disease', (98, 103))	('lift', 'PosReg', (32, 36))
77303	32238387	For example, inhibition of class IIA HDACs in luminal B breast cancer increased the efficacy and durability of immune checkpoint inhibitor and chemotherapy, while neutralization of the Macrophage Receptor With Collagenous Structure (MARCO) on a subset of inflammatory TAMs inhibited tumor metastasis.	('neutralization', 'Var', (163, 177))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('efficacy', 'MPA', (84, 92))	('increased', 'PosReg', (70, 79))	('durability', 'CPA', (97, 107))	('Macrophage Receptor With Collagenous Structure', 'Gene', (185, 231))	('inhibited', 'NegReg', (273, 282))	('TAMs', 'Chemical', '-', (268, 272))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('immune checkpoint inhibitor', 'MPA', (111, 138))	('MARCO', 'Gene', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('MARCO', 'Gene', '8685', (233, 238))	('Macrophage Receptor With Collagenous Structure', 'Gene', '8685', (185, 231))	('luminal B breast cancer', 'Disease', (46, 69))	('luminal B breast cancer', 'Disease', 'MESH:D001943', (46, 69))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (283, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))
77398	29708782	We further excluded tumors with DCIS to assess wheth-er the presence of DCIS, which is not considered when determining pathologic CR by pathologic assessment, reduced the accuracy for predicting pathologic CR by preoperative measurements.	('CR', 'Chemical', '-', (206, 208))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('DCIS', 'Gene', (72, 76))	('reduced', 'NegReg', (159, 166))	('presence', 'Var', (60, 68))	('CR', 'Chemical', '-', (130, 132))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))
77451	31053611	Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness.	('GP130', 'Gene', (44, 49))	('depleting', 'Var', (34, 43))	('obesity-augmented TNBC stemness', 'Disease', (75, 106))	('TNBC', 'Gene', (53, 57))	('Deleting', 'Var', (0, 8))	('Nox2', 'Gene', '13058', (9, 13))	('obesity', 'Phenotype', 'HP:0001513', (75, 82))	('obesity-augmented TNBC stemness', 'Disease', 'MESH:D009765', (75, 106))	('Nox2', 'Gene', (9, 13))	('attenuates', 'NegReg', (64, 74))
77476	31053611	As previously reported, DIO increased the total tumor burden in C3(1)-TAg mice (Fig.	('increased', 'PosReg', (28, 37))	('DIO', 'Var', (24, 27))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
77486	31053611	At this time, murine E0771 or Py8119 TNBC cells were injected at limiting dilutions into mammary fat pads of lean or obese mice, diets were continued, and their tumor-initiating potential was assessed using a limiting dilution assay.	('E0771', 'Var', (21, 26))	('TNBC', 'Gene', (37, 41))	('murine', 'Species', '10090', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('obese', 'Disease', 'MESH:D009765', (117, 122))	('Py8119', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('obese', 'Disease', (117, 122))	('mice', 'Species', '10090', (123, 127))
77487	31053611	We found that DIO decreased the number of E0771 or Py8119 cells required to form tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('E0771', 'Var', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Py8119 cells', 'Var', (51, 63))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
77492	31053611	At this time, we injected E0771 or Py8119 cells into mammary fat, continued diet feeding, and quantified tumor incidence over a 7-wk period.	('Py8119', 'Var', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('E0771', 'Var', (26, 31))	('tumor', 'Disease', (105, 110))
77493	31053611	Short-term preexposure to HFD did not support increased E0771 or Py8119 tumor formation (Fig.	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('E0771', 'Var', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))
77500	31053611	To begin to test this hypothesis, we determined whether DIO could increase the number of mammary fat ATMs and/or their pro-inflammatory cytokine expression in female C57BL/6 mice fed the HFD for 12 wk.	('increase', 'PosReg', (66, 74))	('DIO', 'Var', (56, 59))	('pro-inflammatory cytokine expression', 'MPA', (119, 155))	('mice', 'Species', '10090', (174, 178))
77501	31053611	Although DIO substantially increased mammary adipose tissue mass, the percentage of CD45+ immune cells, ATMs (defined as CD11b+F4/80+), and CD4+ and CD8+ T cells in the stromal vascular cells (SVCs) were not increased (Fig.	('F4/80', 'Gene', '13733', (127, 132))	('adipose', 'Gene', '230796', (45, 52))	('F4/80', 'Gene', (127, 132))	('increased', 'PosReg', (27, 36))	('DIO', 'Var', (9, 12))	('adipose', 'Gene', (45, 52))	('CD8', 'Gene', (149, 152))	('CD8', 'Gene', '925', (149, 152))
77505	31053611	Thus, although DIO did not induce mATM accumulation in mice, it did increase ATM inflammation in mammary fat; the latter observation is similar to what has been widely reported in visceral fat depots.	('DIO', 'Var', (15, 18))	('mice', 'Species', '10090', (55, 59))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('increase', 'PosReg', (68, 76))
77509	31053611	Obese mATM media also induced tumorsphere formation of E0771 and M6C cells (derived from C3(1)-TAg mice), and this effect was maintained in serially passaged tumorspheres in the absence of continued exposure to ATM media (Fig.	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('mice', 'Species', '10090', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('M6C', 'CellLine', 'CVCL:4538', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('E0771', 'Var', (55, 60))	('induced', 'Reg', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
77517	31053611	First, we compared mATMs from lean and obese female C57BL/6 mice for the expression of markers diagnostic of the M1 (Cd40, Cd38) and MMe (Cd36, Plin2) phenotypes.	('Cd38', 'Gene', '12494', (123, 127))	('Cd36', 'Var', (138, 142))	('Cd36', 'Species', '42374', (138, 142))	('obese', 'Disease', (39, 44))	('Cd40', 'Gene', '21939', (117, 121))	('Cd38', 'Gene', (123, 127))	('Plin2', 'Gene', (144, 149))	('Cd40', 'Gene', (117, 121))	('mice', 'Species', '10090', (60, 64))	('Plin2', 'Gene', '101055843', (144, 149))	('obese', 'Disease', 'MESH:D009765', (39, 44))
77522	31053611	MMe media also promoted tumorsphere formation in E0771 and M6C cells (Fig.	('promoted', 'PosReg', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('M6C', 'CellLine', 'CVCL:4538', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('E0771', 'Var', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))
77523	31053611	S3) and tumor-initiating potential of E0771 cells in vivo (Fig.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('E0771', 'Var', (38, 43))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))
77526	31053611	We first determined whether deleting NOX2 (Cybb-/-) in in vitro-derived MMe macrophages could diminish their ability to promote TNBC stem-like properties.	('Cybb', 'Gene', (43, 47))	('Cybb', 'Gene', '13058', (43, 47))	('diminish', 'NegReg', (94, 102))	('promote', 'PosReg', (120, 127))	('TNBC stem-like properties', 'CPA', (128, 153))	('deleting', 'Var', (28, 36))	('NOX2', 'Gene', (37, 41))	('NOX2', 'Gene', '13058', (37, 41))
77527	31053611	As previously described, deleting Nox2 lowered inflammatory cytokine expression in MMe macrophages (Fig.	('lowered', 'NegReg', (39, 46))	('Nox2', 'Gene', '13058', (34, 38))	('deleting', 'Var', (25, 33))	('Nox2', 'Gene', (34, 38))	('inflammatory cytokine expression', 'MPA', (47, 79))	('lowered inflammatory cytokine', 'Phenotype', 'HP:0012648', (39, 68))
77528	31053611	Moreover, deleting Nox2 in MMe macrophages attenuated their ability to induce stem cell-associated marker expression and tumorsphere formation in E0771 cells in vitro (Figs.	('Nox2', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('deleting', 'Var', (10, 18))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('attenuated', 'NegReg', (43, 53))	('induce', 'PosReg', (71, 77))	('Nox2', 'Gene', '13058', (19, 23))
77539	31053611	Two lines of evidence based on deleting Nox2 in myeloid cells implicated MMe macrophages in promoting TNBC tumor formation.	('TNBC tumor', 'Disease', 'MESH:D009369', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('promoting', 'PosReg', (92, 101))	('deleting', 'Var', (31, 39))	('TNBC tumor', 'Disease', (102, 112))	('Nox2', 'Gene', '13058', (40, 44))	('Nox2', 'Gene', (40, 44))
77540	31053611	First, deleting Nox2 from mATMs decreased their ability to promote stem cell marker expression and tumorsphere formation in E0771 cells (Fig.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('Nox2', 'Gene', (16, 20))	('stem cell marker', 'CPA', (67, 83))	('promote', 'PosReg', (59, 66))	('deleting', 'Var', (7, 15))	('ability', 'MPA', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Nox2', 'Gene', '13058', (16, 20))	('decreased', 'NegReg', (32, 41))	('tumors', 'Disease', (99, 105))
77541	31053611	Second, deleting Nox2 from myeloid cells decreased tumor incidence in obese mice injected with E0771 or Py8119 cells (Fig.	('Nox2', 'Gene', '13058', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Nox2', 'Gene', (17, 21))	('decreased', 'NegReg', (41, 50))	('tumor', 'Disease', (51, 56))	('obese', 'Disease', 'MESH:D009765', (70, 75))	('mice', 'Species', '10090', (76, 80))	('deleting', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('obese', 'Disease', (70, 75))
77542	31053611	This decreased tumor incidence was not absolute, which may be explained by (1) the slight increases in body weight, mammary fat mass, and mATM number in mNox2-/- mice and (2) the inability of Nox2 deletion to completely block the induction of stem-like properties in TNBC cells.	('Nox2', 'Gene', '13058', (192, 196))	('body weight', 'CPA', (103, 114))	('deletion', 'Var', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Nox2', 'Gene', '13058', (154, 158))	('Nox2', 'Gene', (192, 196))	('Nox2', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('increases', 'PosReg', (90, 99))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Disease', (15, 20))	('mATM number', 'CPA', (138, 149))	('mNox2', 'Gene', '13058', (153, 158))	('decreased', 'NegReg', (5, 14))	('mNox2', 'Gene', (153, 158))	('mammary fat', 'CPA', (116, 127))
77546	31053611	Moreover, treating E0771 or M6C cells with obese mATM-conditioned media induced STAT3 phosphorylation (Fig.	('M6C', 'CellLine', 'CVCL:4538', (28, 31))	('obese', 'Disease', 'MESH:D009765', (43, 48))	('obese', 'Disease', (43, 48))	('E0771', 'Var', (19, 24))	('STAT3 phosphorylation', 'MPA', (80, 101))
77549	31053611	In vitro-derived MMe macrophages similarly up-regulated the expression of all GP130 ligands tested, and their media also induced STAT3 phosphorylation in E0771 and M6C cells in a GP130-dependent manner (Fig.	('expression', 'MPA', (60, 70))	('up-regulated', 'PosReg', (43, 55))	('M6C', 'CellLine', 'CVCL:4538', (164, 167))	('E0771', 'Var', (154, 159))	('STAT3 phosphorylation', 'MPA', (129, 150))	('GP130', 'Gene', (78, 83))	('induced', 'Reg', (121, 128))
77551	31053611	We treated obese mATM media with inactivating antibodies against IL-6, IL-11, OSM, LIF, or CTF1, alone or in combination, and monitored effects on STAT3 phosphorylation in E0771 cells.	('IL-11', 'Gene', (71, 76))	('STAT3 phosphorylation', 'MPA', (147, 168))	('IL-11', 'Gene', '16156', (71, 76))	('CTF1', 'Gene', (91, 95))	('inactivating antibodies', 'Var', (33, 56))	('LIF', 'Gene', (83, 86))	('obese', 'Disease', 'MESH:D009765', (11, 16))	('IL-6', 'Gene', (65, 69))	('IL-6', 'Gene', '16193', (65, 69))	('obese', 'Disease', (11, 16))
77556	31053611	However, we cannot rule out a contribution from other factors, since IL-6 neutralization did not completely abrogate the MMe macrophage-induced stem cell phenotype.	('MMe macrophage-induced stem cell phenotype', 'CPA', (121, 163))	('abrogate', 'NegReg', (108, 116))	('neutralization', 'Var', (74, 88))	('IL-6', 'Gene', (69, 73))	('IL-6', 'Gene', '16193', (69, 73))
77559	31053611	We found that knocking down GP130 attenuated the ability of obese mATM media to induce STAT3 phosphorylation and increase stem cell marker expression in E0771 cells (Fig.	('knocking down', 'Var', (14, 27))	('obese', 'Disease', 'MESH:D009765', (60, 65))	('GP130', 'Gene', (28, 33))	('STAT3 phosphorylation', 'MPA', (87, 108))	('obese', 'Disease', (60, 65))	('induce', 'PosReg', (80, 86))	('increase', 'PosReg', (113, 121))	('stem cell marker', 'CPA', (122, 138))	('attenuated', 'NegReg', (34, 44))
77560	31053611	We further explored whether GP130 signaling was required for DIO to promote the tumor-initiation potential of TNBC cells in vivo by injecting short hairpin (sh)-control or sh-Gp130 E0771 cells into obese female mice and monitoring tumor incidence.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('promote', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('obese', 'Disease', (198, 203))	('sh-Gp130', 'Var', (172, 180))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (231, 236))	('mice', 'Species', '10090', (211, 215))	('obese', 'Disease', 'MESH:D009765', (198, 203))
77571	31053611	Indeed, our previous studies showed that excessive FFAs leads to lipid accumulation in MMe macrophages, which attenuates TLR2-dependent inflammatory cytokine expression and induces lipid metabolism genes (e.g., Cd36 and Plin2) through PPARgamma and P62 activation.	('TLR2-dependent inflammatory cytokine expression', 'MPA', (121, 168))	('Cd36', 'Species', '42374', (211, 215))	('lipid accumulation', 'MPA', (65, 83))	('induces', 'PosReg', (173, 180))	('FFAs', 'Var', (51, 55))	('P62', 'Gene', (249, 252))	('attenuates', 'NegReg', (110, 120))	('PPARgamma', 'Protein', (235, 244))	('lipid metabolism genes', 'MPA', (181, 203))	('Cd36', 'Gene', (211, 215))	('Plin2', 'Gene', (220, 225))	('Plin2', 'Gene', '101055843', (220, 225))
77572	31053611	Importantly, we found that weight loss eliminated the increased tumor-forming capability of E0771 cells during obesity (Fig.	('eliminated', 'NegReg', (39, 49))	('tumor', 'Disease', (64, 69))	('obesity', 'Disease', (111, 118))	('weight loss', 'Disease', (27, 38))	('increased', 'PosReg', (54, 63))	('obesity', 'Phenotype', 'HP:0001513', (111, 118))	('weight loss', 'Phenotype', 'HP:0001824', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('E0771', 'Var', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('weight loss', 'Disease', 'MESH:D015431', (27, 38))	('obesity', 'Disease', 'MESH:D009765', (111, 118))
77577	31053611	The number of ATMs (defined as CD45+CD11b+CD14+) in the SVC from mammary fat was significantly elevated in obese women relative to nonobese women (Fig.	('obese', 'Disease', (107, 112))	('CD45+CD11b+CD14+', 'Var', (31, 47))	('obese', 'Disease', 'MESH:D009765', (134, 139))	('elevated', 'PosReg', (95, 103))	('obese', 'Disease', (134, 139))	('women', 'Species', '9606', (140, 145))	('obese', 'Disease', 'MESH:D009765', (107, 112))	('women', 'Species', '9606', (113, 118))
77584	31053611	Second, we determined whether human mATMs could signal through GP130 to promote human TNBC cell stem-like properties.	('human', 'Species', '9606', (30, 35))	('GP130', 'Var', (63, 68))	('promote', 'PosReg', (72, 79))	('human', 'Species', '9606', (80, 85))	('human TNBC cell stem-like properties', 'CPA', (80, 116))
77592	31053611	Tissue microarrays (TMAs) were obtained from lean (BMI <25 kg/m2, n = 8), overweight (BMI 25-30 kg/m2, n = 9), and obese (BMI >30 kg/m2, n = 9) patients.	('obese', 'Disease', (115, 120))	('overweight', 'Phenotype', 'HP:0025502', (74, 84))	('TMAs', 'Disease', (20, 24))	('TMAs', 'Disease', 'None', (20, 24))	('patients', 'Species', '9606', (144, 152))	('BMI 25-30 kg/m2', 'Var', (86, 101))	('obese', 'Disease', 'MESH:D009765', (115, 120))
77598	31053611	Third, we show that ablating Nox2, a gene required for MMe macrophage polarization, attenuated the ability of obese mATMs to promote TNBC stemness in vitro, and the ability of obesity to promote TNBC tumor formation in vivo.	('obesity', 'Disease', (176, 183))	('promote', 'PosReg', (187, 194))	('TNBC tumor', 'Disease', 'MESH:D009369', (195, 205))	('obese mATMs', 'Disease', 'MESH:D009765', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ablating', 'Var', (20, 28))	('TNBC stemness', 'Disease', 'MESH:D020295', (133, 146))	('TNBC tumor', 'Disease', (195, 205))	('obese mATMs', 'Disease', (110, 121))	('attenuated', 'NegReg', (84, 94))	('TNBC stemness', 'Disease', (133, 146))	('obesity', 'Phenotype', 'HP:0001513', (176, 183))	('Nox2', 'Gene', '13058', (29, 33))	('obesity', 'Disease', 'MESH:D009765', (176, 183))	('promote', 'PosReg', (125, 132))	('Nox2', 'Gene', (29, 33))
77605	31053611	These stem-like properties may be activated by mutation of key genes or epigenetic regulators in cancer cells, or by signals from the tumor microenvironment.	('cancer', 'Disease', (97, 103))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('activated', 'PosReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('epigenetic', 'Var', (72, 82))	('tumor', 'Disease', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
77611	31053611	Importantly, disabling this MMe-GP130-stemness pathway (by deleting Nox2 in macrophages or attenuating Gp130 in TNBC cells) did not completely block increased tumor formation during obesity.	('Nox2', 'Gene', (68, 72))	('obesity', 'Phenotype', 'HP:0001513', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('disabling', 'Var', (13, 22))	('attenuating', 'NegReg', (91, 102))	('obesity', 'Disease', 'MESH:D009765', (182, 189))	('tumor', 'Disease', (159, 164))	('Gp130', 'MPA', (103, 108))	('obesity', 'Disease', (182, 189))	('Nox2', 'Gene', '13058', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('deleting', 'NegReg', (59, 67))
77615	31053611	More generally, our findings reinforce the idea that tumorigenesis is regulated both by intrinsic properties of cancer cells (i.e., genetic alterations) and by the tissue-specific niche in which the tumor develops.	('tumor', 'Disease', (199, 204))	('genetic alterations', 'Var', (132, 151))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
77624	31053611	NOX2 inhibitors such as gp91sd-tat may be an attractive approach for attenuating MMe macrophage inflammation in obesity-driven TNBC.	('attenuating', 'NegReg', (69, 80))	('gp91sd-tat', 'Var', (24, 34))	('NOX2', 'Gene', (0, 4))	('obesity', 'Disease', 'MESH:D009765', (112, 119))	('NOX2', 'Gene', '13058', (0, 4))	('obesity', 'Disease', (112, 119))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('TNBC', 'Disease', (127, 131))	('inflammation', 'Disease', (96, 108))	('obesity', 'Phenotype', 'HP:0001513', (112, 119))
77665	31053611	E0771, M6C, or SUM159PT cells were plated at 500 cells/well of a ultra-low attachment 12-well plate (Corning) in standard mammosphere media comprising DMEM-F12 supplemented with fibroblast growth factor (20 ng/ml; GoldBio), epidermal growth factor (20 ng/ml; GoldBio), heparin (4 mg/ml; Sigma-Aldrich) and B27 supplement (Life Technologies).	('M6C', 'CellLine', 'CVCL:4538', (7, 10))	('epidermal growth factor', 'Gene', (224, 247))	('B27', 'Gene', (306, 309))	('B27', 'Gene', '56246', (306, 309))	('epidermal growth factor', 'Gene', '1950', (224, 247))	('heparin', 'Chemical', 'MESH:D006493', (269, 276))	('E0771', 'Var', (0, 5))
77674	31053611	Virus particles were packaged, E0771 and SUM159PT cells were infected, and infected cells were selected for by treatment with puromycin.	('SUM159PT', 'Var', (41, 49))	('E0771', 'Var', (31, 36))	('puromycin', 'Chemical', 'MESH:D011691', (126, 135))
77675	31053611	Antibodies for flow-cytometric measurements of murine cells were CD90, CD45, CD11b, CD206, CD14, CD36, CD38, CD319, F4/80, CD3, CD4, and CD8 (BD Biosciences), ABCA1 (Novus Biologicals), and CD24 (Biolegend).	('CD24', 'Gene', (190, 194))	('murine', 'Species', '10090', (47, 53))	('F4/80', 'Gene', (116, 121))	('CD3', 'Var', (123, 126))	('CD31', 'Gene', '18613', (109, 113))	('CD38', 'Gene', (103, 107))	('CD24', 'Gene', '12484', (190, 194))	('CD8', 'Gene', (137, 140))	('CD38', 'Gene', '12494', (103, 107))	('CD90', 'Gene', '21838', (65, 69))	('CD90', 'Gene', (65, 69))	('CD31', 'Gene', (109, 113))	('CD14', 'Var', (91, 95))	('CD11b', 'Var', (77, 82))	('CD45', 'Var', (71, 75))	('CD4', 'Var', (128, 131))	('CD206', 'Var', (84, 89))	('CD8', 'Gene', '925', (137, 140))	('CD36', 'Species', '42374', (97, 101))	('CD36', 'Var', (97, 101))	('F4/80', 'Gene', '13733', (116, 121))	('ABCA1', 'Gene', (159, 164))
77676	31053611	Antibodies for flow-cytometric measurements of human cells were CD45, CD11b, CD206, CD14, CD36, CD38, CD319 (BD Biosciences), and ABCA1 (Novus Biologicals).	('CD38', 'Gene', (96, 100))	('CD45', 'Var', (64, 68))	('ABCA1', 'Gene', (130, 135))	('CD36', 'Var', (90, 94))	('CD31', 'Gene', '18613', (102, 106))	('CD11b', 'Var', (70, 75))	('CD38', 'Gene', '12494', (96, 100))	('CD31', 'Gene', (102, 106))	('CD36', 'Species', '42374', (90, 94))	('CD206', 'Var', (77, 82))	('human', 'Species', '9606', (47, 52))	('CD14', 'Var', (84, 88))
77681	31053611	S2 shows that DIO decreases the latency of E0771 and Py8119 tumors.	('decreases', 'NegReg', (18, 27))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('latency', 'MPA', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('E0771', 'Var', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
77686	33263939	JPs harbored clonal somatic PIK3CA hotspot mutations in two cases.	('PIK3CA', 'Gene', (28, 34))	('mutations', 'Var', (43, 52))	('hotspot', 'PosReg', (35, 42))	('PIK3CA', 'Gene', '5290', (28, 34))
77687	33263939	In the JP with coexisting DCIS and IDC-NST, these lesions were clonally related to the associated JP, sharing a clonal PIK3CA E542K somatic hotspot mutation.	('E542K', 'Var', (126, 131))	('PIK3CA', 'Gene', '5290', (119, 125))	('E542K', 'Mutation', 'rs121913273', (126, 131))	('PIK3CA', 'Gene', (119, 125))
77693	33263939	Recently, Guillet et al reported recurrent PIK3CA or AKT1 hotspot mutations in benign JP lesions in the first published study of the molecular features of JP, expanding the spectrum of benign breast lesions with these mutations [3].	('mutations', 'Var', (66, 75))	('benign breast lesions', 'Disease', (185, 206))	('AKT1', 'Gene', (53, 57))	('PIK3CA', 'Gene', '5290', (43, 49))	('AKT1', 'Gene', '207', (53, 57))	('benign breast lesions', 'Disease', 'MESH:D001943', (185, 206))	('PIK3CA', 'Gene', (43, 49))
77715	33263939	We identified somatic clonal PIK3CA hotspot mutations in cases JuP2 (H1047R) and JuP3 (E542K).	('JuP', 'Gene', '3728', (81, 84))	('E542K', 'Mutation', 'rs121913273', (87, 92))	('H1047R', 'Mutation', 'rs121913279', (69, 75))	('JuP', 'Gene', (63, 66))	('JuP', 'Gene', '3728', (63, 66))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('JuP', 'Gene', (81, 84))	('E542K', 'Var', (87, 92))	('H1047R', 'Var', (69, 75))
77716	33263939	Interestingly, JuP1 was found to harbor a germline PIK3CA I391M variant, whose significance is uncertain.	('I391M', 'Var', (58, 63))	('I391M', 'Mutation', 'rs2230461', (58, 63))	('PIK3CA', 'Gene', (51, 57))	('JuP', 'Gene', (15, 18))	('PIK3CA', 'Gene', '5290', (51, 57))	('JuP', 'Gene', '3728', (15, 18))
77721	33263939	We observed that the DCIS and IDC-NST of JuP3 were clonally related to adjacent JP and shared a clonal PIK3CA E542K hotspot mutation and CES1 (S12A) and SMG1 (R420Q) missense mutations (Figure 3B,C).	('E542K', 'Var', (110, 115))	('JuP', 'Gene', (41, 44))	('CES1', 'Gene', (137, 141))	('S12A', 'SUBSTITUTION', 'None', (143, 147))	('SMG1', 'Gene', (153, 157))	('S12A', 'Var', (143, 147))	('JuP', 'Gene', '3728', (41, 44))	('PIK3CA', 'Gene', (103, 109))	('R420Q', 'Mutation', 'rs1402627879', (159, 164))	('CES1', 'Gene', '1066', (137, 141))	('E542K', 'Mutation', 'rs121913273', (110, 115))	('SMG1', 'Gene', '23049', (153, 157))	('PIK3CA', 'Gene', '5290', (103, 109))
77722	33263939	DCIS and IDC-NST shared 29 synonymous and nonsynonymous mutations not seen in JP, including a truncating mutation in the chromatin remodeling gene ARID1A, missense mutations in KMT2C and PIK3CB, and an E14K hotspot mutation affecting NUP93, a nucleoporin implicated in cell migration [29] (Figure 3B,C).	('NUP93', 'Gene', (234, 239))	('E14K', 'Mutation', 'rs528073782', (202, 206))	('nucleoporin', 'Gene', '729857', (243, 254))	('KMT2C', 'Gene', (177, 182))	('ARID1A', 'Gene', '8289', (147, 153))	('E14K', 'Var', (202, 206))	('ARID1A', 'Gene', (147, 153))	('KMT2C', 'Gene', '58508', (177, 182))	('PIK3CB', 'Gene', (187, 193))	('missense mutations', 'Var', (155, 173))	('nucleoporin', 'Gene', (243, 254))	('PIK3CB', 'Gene', '5291', (187, 193))	('NUP93', 'Gene', '9688', (234, 239))
77725	33263939	The DCIS and IDC-NST from JuP3, however, displayed a greater number of mutations than benign JP as well as a greater mutational signature 2 exposure (DCIS: 55%; IDC-NST: 64%), suggesting that the development of carcinoma in this case might be associated with an increase in APOBEC mutagenesis (Figure 3D).	('APOBEC', 'Gene', (274, 280))	('carcinoma', 'Disease', 'MESH:D009369', (211, 220))	('JuP', 'Gene', '3728', (26, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('mutations', 'Var', (71, 80))	('carcinoma', 'Disease', (211, 220))	('JuP', 'Gene', (26, 29))
77726	33263939	Here we provide evidence that JP shows recurrent PIK3CA mutations, and that it may constitute the substrate from which DCIS and invasive breast cancers develop, given that we documented clonal relatedness between JP and associated carcinoma.	('breast cancers', 'Phenotype', 'HP:0003002', (137, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('mutations', 'Var', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('invasive breast cancers', 'Disease', (128, 151))	('invasive breast cancers', 'Disease', 'MESH:D001943', (128, 151))	('carcinoma', 'Disease', (231, 240))	('PIK3CA', 'Gene', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('PIK3CA', 'Gene', '5290', (49, 55))	('DCIS', 'Disease', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Disease', 'MESH:D009369', (231, 240))
77727	33263939	Mutations in the PI3K-AKT pathway, which are commonly seen in invasive breast carcinoma, have also been identified in a variety of benign proliferative epithelial lesions, including papillary neoplasms, usual ductal hyperplasia, and columnar cell change, among others [30, 31].	('columnar cell change', 'Disease', (233, 253))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (62, 87))	('neoplasms', 'Phenotype', 'HP:0002664', (192, 201))	('hyperplasia', 'Disease', 'MESH:D006965', (216, 227))	('AKT', 'Gene', '207', (22, 25))	('identified', 'Reg', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('papillary neoplasms', 'Disease', 'MESH:D002291', (182, 201))	('breast carcinoma', 'Phenotype', 'HP:0003002', (71, 87))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', (22, 25))	('invasive breast carcinoma', 'Disease', (62, 87))	('hyperplasia', 'Disease', (216, 227))	('papillary neoplasms', 'Disease', (182, 201))
77728	33263939	WES analysis of the proliferative components of JP resulted in the identification of clonal PIK3CA hotspot mutations in 2 of 3 cases studied.	('PIK3CA', 'Gene', (92, 98))	('mutations', 'Var', (107, 116))	('PIK3CA', 'Gene', '5290', (92, 98))
77729	33263939	We also observed a germline PIK3CA variant affecting the C2 domain in the third case.	('affecting', 'Reg', (43, 52))	('C2 domain', 'MPA', (57, 66))	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('variant', 'Var', (35, 42))
77730	33263939	Although mutations affecting the C2 domain of PIK3CA have been reported to increase its kinase activity [32], the I391M germline mutation has a frequency of 6% in the normal population.	('PIK3CA', 'Gene', '5290', (46, 52))	('mutations', 'Var', (9, 18))	('kinase activity', 'MPA', (88, 103))	('increase', 'PosReg', (75, 83))	('I391M', 'Var', (114, 119))	('I391M', 'Mutation', 'rs2230461', (114, 119))	('PIK3CA', 'Gene', (46, 52))
77731	33263939	Our study confirms the findings of Guillet et al [3], who recently reported PIK3CA and AKT1 mutations in 5 of 10 and 2 of 10 cases of JP, respectively.	('AKT1', 'Gene', '207', (87, 91))	('AKT1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', (76, 82))	('reported', 'Reg', (67, 75))	('PIK3CA', 'Gene', '5290', (76, 82))
77732	33263939	Nonetheless, these studies expand the spectrum of benign breast lesions harboring mutations affecting PI3K-AKT pathway-related genes to include JP.	('AKT', 'Gene', (107, 110))	('benign breast lesions', 'Disease', 'MESH:D001943', (50, 71))	('benign breast lesions', 'Disease', (50, 71))	('mutations', 'Var', (82, 91))	('AKT', 'Gene', '207', (107, 110))
77734	33263939	Patients with Cowden syndrome, caused by a germline PTEN mutation, develop hamartomatous lesions and are at risk of multiple cancers [33].	('hamartomatous lesions', 'Disease', 'MESH:C563621', (75, 96))	('mutation', 'Var', (57, 65))	('germline', 'Var', (43, 51))	('multiple cancers', 'Disease', 'MESH:D009369', (116, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('PTEN', 'Gene', (52, 56))	('PTEN', 'Gene', '5728', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cowden syndrome', 'Disease', 'MESH:D006223', (14, 29))	('Patients', 'Species', '9606', (0, 8))	('develop', 'PosReg', (67, 74))	('multiple cancers', 'Disease', (116, 132))	('hamartomatous lesions', 'Disease', (75, 96))	('Cowden syndrome', 'Disease', (14, 29))	('caused by', 'Reg', (31, 40))
77735	33263939	Proteus syndrome, characterized by progressive asymmetric growth of multiple tissue types, is caused by somatic mosaicism for an activating AKT1 mutation [34].	('asymmetric growth', 'Phenotype', 'HP:0100555', (47, 64))	('mutation', 'Var', (145, 153))	('AKT1', 'Gene', '207', (140, 144))	('Proteus syndrome', 'Disease', 'MESH:D016715', (0, 16))	('AKT1', 'Gene', (140, 144))	('Proteus syndrome', 'Disease', (0, 16))	('activating', 'PosReg', (129, 139))
77736	33263939	Our study not only confirms the presence of PIK3CA hotspot mutations in JP, but also expands our understanding of the molecular relationship between JP and breast cancer, given that here we demonstrated in one case the presence of a clonal E542K PIK3CA hotspot mutation shared by separate components of JP, DCIS, and IDC-NST.	('PIK3CA', 'Gene', (44, 50))	('PIK3CA', 'Gene', '5290', (246, 252))	('E542K', 'Mutation', 'rs121913273', (240, 245))	('PIK3CA', 'Gene', '5290', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('mutations', 'Var', (59, 68))	('E542K', 'Var', (240, 245))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('PIK3CA', 'Gene', (246, 252))
77739	33263939	Classic lobular carcinomas are usually ER-positive/HER2-negative tumors driven by CDH1 alterations and PIK3CA mutations [36], whereas secretory carcinoma is a low-grade triple-negative breast cancer with a recurrent ETV6-NTRK3 fusion gene and is not driven by PI3K pathway alterations [37].	('NTRK3', 'Gene', '4916', (221, 226))	('ER', 'Gene', '2099', (39, 41))	('NTRK3', 'Gene', (221, 226))	('tumors', 'Disease', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('HER2', 'Gene', (51, 55))	('PIK3CA', 'Gene', '5290', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('carcinoma', 'Disease', (144, 153))	('Classic lobular carcinomas', 'Disease', 'MESH:D018275', (0, 26))	('ETV6', 'Gene', '2120', (216, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('carcinoma', 'Disease', (16, 25))	('CDH1', 'Gene', '999', (82, 86))	('mutations', 'Var', (110, 119))	('ER', 'Gene', '2099', (52, 54))	('Classic lobular carcinomas', 'Disease', (0, 26))	('PIK3CA', 'Gene', (103, 109))	('carcinoma', 'Disease', 'MESH:D009369', (144, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('HER2', 'Gene', '2064', (51, 55))	('CDH1', 'Gene', (82, 86))	('ETV6', 'Gene', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (8, 26))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (8, 25))	('carcinoma', 'Disease', 'MESH:D009369', (16, 25))	('alterations', 'Var', (87, 98))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('driven by', 'Reg', (72, 81))	('breast cancer', 'Disease', (185, 198))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
77742	33263939	Our observations suggest that APOBEC mutational processes might underpin the evolution of JP to the associated DCIS and IDC-NST components, in a way akin to the shifts from aging-related signatures to APOBEC-related mutagenesis in the progression from lobular carcinoma in situ to invasive lobular cancer [7] and from primary tumors to metastasis [38].	('tumors', 'Disease', (326, 332))	('APOBEC', 'Gene', (30, 36))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (252, 269))	('lobular carcinoma', 'Disease', (252, 269))	('invasive lobular cancer', 'Disease', (281, 304))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('mutational', 'Var', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (281, 304))	('underpin', 'Reg', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (252, 277))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (260, 277))	('lobular carcinoma', 'Disease', 'MESH:D018275', (252, 269))	('lobular cancer', 'Phenotype', 'HP:0030076', (290, 304))	('mutagenesis', 'Var', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
77745	33263939	Despite these limitations, here we confirm the presence of recurrent PIK3CA mutations in JP and provide evidence that JP and coexisting carcinoma are clonally related, further expanding our understanding of the relationship between JP and breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))	('mutations', 'Var', (76, 85))	('breast cancer', 'Disease', (239, 252))	('carcinoma', 'Disease', 'MESH:D009369', (136, 145))	('PIK3CA', 'Gene', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('PIK3CA', 'Gene', '5290', (69, 75))	('carcinoma', 'Disease', (136, 145))
77827	22970156	In contrast, DCIS displaying 'tube-like' architectures would most likely have developed resistance to apoptosis, such as through alterations in p53.	('resistance to apoptosis', 'CPA', (88, 111))	('alterations', 'Var', (129, 140))	('p53', 'Gene', (144, 147))	('p53', 'Gene', '7157', (144, 147))
77838	19930682	YB-1-specific Mab F-E2G5 associates with conformational binding epitopes mapping to two domains within the N-terminal half of the protein and detects nuclear YB-1 protein by immunohistochemistry in paraffin-embedded breast cancer tissues.	('conformational binding', 'MPA', (41, 63))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('F-E2G5', 'Var', (18, 24))	('protein', 'Protein', (163, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('YB-1', 'Gene', (158, 162))	('paraffin', 'Chemical', 'MESH:D010232', (198, 206))
77841	19930682	We observed a close correlation between nuclear YB-1 detection and absence of progesterone receptor expression (p = 0.002), indicating that nuclear YB-1 detection marks a specific subgroup of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('nuclear', 'Var', (140, 147))	('progesterone receptor', 'Gene', (78, 99))	('progesterone receptor', 'Gene', '5241', (78, 99))
77843	19930682	Monoclonal YB-1 antibody F-E2G5 should be of great value for prospective studies to validate YB-1 as a novel biomarker suitable to optimize breast cancer treatment.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('F-E2G5', 'Var', (25, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('YB-1', 'Gene', (93, 97))
77845	19930682	A recent study confirmed the unfavorable outcome of patients with YB-1 expression in breast cancer tissue with a large cohort of 4049 cases over an observation period of 20 years, which reached statistical significance in nearly all subgroups.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('expression', 'Var', (71, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('YB-1', 'Gene', (66, 70))	('patients', 'Species', '9606', (52, 60))
77855	19930682	Knock-down of YB-1 completely abrogated the proliferative effect of Twist, emphasizing the fundamental role that YB-1 plays for the EGF receptor axis.	('EGF', 'Gene', (132, 135))	('Twist', 'Gene', '7291', (68, 73))	('EGF', 'Gene', '1950', (132, 135))	('Knock-down', 'Var', (0, 10))	('Twist', 'Gene', (68, 73))	('proliferative', 'CPA', (44, 57))	('YB-1', 'Gene', (14, 18))	('abrogated', 'NegReg', (30, 39))	('rat', 'Species', '10116', (51, 54))
77856	19930682	Furthermore, serine 102 of YB-1 protein is a direct target of protein kinases B (AKT) and RSK, both of which are signaling cascades involved in cell transformation, proliferation and anchorage-independent growth.	('serine', 'Chemical', 'MESH:D012694', (13, 19))	('AKT', 'Gene', '207', (81, 84))	('RSK', 'Gene', (90, 93))	('serine 102', 'Var', (13, 23))	('protein', 'Protein', (32, 39))	('AKT', 'Gene', (81, 84))	('YB-1', 'Gene', (27, 31))	('rat', 'Species', '10116', (172, 175))	('protein', 'Pathway', (62, 69))	('RSK', 'Gene', '6196', (90, 93))
77899	19930682	The regression coefficients beta1, beta2, ..., betaq give the change in the response variable corresponding to a unit change in the appropriate explanatory variable, conditional on the other variables remaining constant.	('beta2', 'Gene', '4760', (35, 40))	('betaq', 'Var', (47, 52))	('beta1', 'Gene', (28, 33))	('beta2', 'Gene', (35, 40))	('beta1', 'Gene', '10678', (28, 33))
77900	19930682	In a first approach the F-E2G5 antibody was examined for its substrate specificity by western blot analysis using cell extracts from HEK293 cells expressing GFP, YB-1-GFP or YB-1(21-147)-GFP proteins.	('GFP', 'Var', (157, 160))	('HEK293', 'CellLine', 'CVCL:0045', (133, 139))	('YB-1(21-147)-GFP proteins', 'Var', (174, 199))	('YB-1-GFP', 'Gene', '4904', (162, 170))	('YB-1-GFP', 'Gene', (162, 170))	('rat', 'Species', '10116', (66, 69))
77913	19930682	From these results it is concluded that monoclonal F-E2G5 antibody has the propensity to immunoprecipitate YB-1-GFP as well as endogenous YB-1 protein, however, detection by means of immunoblotting with the utilized polyclonal anti-YB-1 antibody is susceptible to the chosen buffer conditions.	('F-E2G5', 'Var', (51, 57))	('YB-1-GFP', 'Gene', (107, 115))	('YB-1-GFP', 'Gene', '4904', (107, 115))
77925	19930682	These were compared by Kaplan Meier analysis between invasive breast tumours with nuclear YB-1 expression versus all other invasive breast tumours exhibiting no nuclear expression (Figure 5).	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('breast tumours', 'Disease', 'MESH:D001943', (132, 146))	('nuclear', 'Var', (82, 89))	('expression', 'Var', (95, 105))	('breast tumours', 'Disease', (62, 76))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('breast tumours', 'Disease', (132, 146))	('breast tumours', 'Disease', 'MESH:D001943', (62, 76))	('YB-1', 'Gene', (90, 94))
77926	19930682	Patients with nuclear YB-1 expression in the tumor had an estimated mean OS of 90 months (95% confidence interval (CI): 72-109 months) compared to 117 months (95% CI: 108-126 months) in patients with absent nuclear YB-1 immunoreactivity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('YB-1', 'Gene', (22, 26))	('tumor', 'Disease', (45, 50))	('Patients', 'Species', '9606', (0, 8))	('nuclear', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('patients', 'Species', '9606', (186, 194))
77927	19930682	Nuclear YB-1 detection also correlated with tumor stage (p = 0.004), higher (G2/G3) histological grade (p = 0.011) and negativity of progesterone receptor status (p = 0.002) (Table 1).	('YB-1', 'Gene', (8, 12))	('negativity', 'Var', (119, 129))	('progesterone receptor', 'Gene', '5241', (133, 154))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('progesterone receptor', 'Gene', (133, 154))	('higher', 'PosReg', (69, 75))	('tumor', 'Disease', (44, 49))
77942	19930682	Thus, it is conceivable that a sensitive detection system and valid predictive testing must include such information, which is also reiterated by the observation of nuclear YB-1 being associated with P-glycoprotein expression and drug resistance.	('YB-1', 'Gene', (173, 177))	('drug resistance', 'CPA', (230, 245))	('drug resistance', 'Phenotype', 'HP:0020174', (230, 245))	('P-glycoprotein', 'Gene', '5243', (200, 214))	('P-glycoprotein', 'Gene', (200, 214))	('rat', 'Species', '10116', (137, 140))	('nuclear', 'Var', (165, 172))	('associated', 'Reg', (184, 194))
77952	19930682	Concordantly with these observations, nuclear expression of YB-1 in invasive breast cancer was significantly associated with overall survival (p = 0.0046).	('invasive breast cancer', 'Disease', (68, 90))	('associated', 'Reg', (109, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('YB-1', 'Gene', (60, 64))	('overall', 'MPA', (125, 132))	('nuclear expression', 'Var', (38, 56))	('invasive breast cancer', 'Disease', 'MESH:D001943', (68, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
77954	19930682	So far we are the first group that describes a correlation between nuclear YB-1 expression and increased tumor grading (p = 0.011) and tumor stage (p = 0.004) in breast cancer.	('nuclear', 'Var', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('YB-1', 'Gene', (75, 79))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('expression', 'MPA', (80, 90))	('breast cancer', 'Disease', (162, 175))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
77955	19930682	In non-small lung cancer and ovarian cancer and by applying polyclonal antibodies, other groups described an apparent link between YB-1 positivity in the nucleus and tumor staging.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('positivity', 'Var', (136, 146))	('YB-1', 'Gene', (131, 135))	('ovarian cancer', 'Disease', (29, 43))	('non-small lung cancer', 'Disease', 'MESH:D002289', (3, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('non-small lung cancer', 'Disease', (3, 24))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (29, 43))	('small lung', 'Phenotype', 'HP:0002089', (7, 17))
77957	19930682	A further finding of our study is the highly significant correlation between nuclear YB-1 expression and negativity of the progesterone receptor status (p = 0.002), which has not been described so far.	('progesterone receptor', 'Gene', (123, 144))	('progesterone receptor', 'Gene', '5241', (123, 144))	('nuclear', 'Var', (77, 84))	('YB-1', 'Gene', (85, 89))	('expression', 'MPA', (90, 100))	('negativity', 'MPA', (105, 115))
78045	22410125	Xenografts were established by injecting NTC and HSulf-2 deficient MCF10DCIS cells in mouse mammary fat pads.	('deficient', 'Var', (57, 66))	('HSulf-2', 'Gene', '55959', (49, 56))	('HSulf-2', 'Gene', (49, 56))	('mouse', 'Species', '10090', (86, 91))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (67, 76))
78072	22410125	Antibodies used in these studies are anti-alpha-tubulin (Sigma, St. Louis, MO, USA), anti-Bnip3, anti-Bim EL, anti-cleaved PARP, anti- cleaved caspase 3, (Cell Signaling, Boston, MA, USA) anti-MMP-2, anti-MMP-9 and anti-MMP-14 antibodies (Chemicon, Billerica, MA, USA).	('anti-MMP-9', 'Var', (200, 210))	('MMP-14', 'Gene', (220, 226))	('MMP-14', 'Gene', '4323', (220, 226))
78110	22410125	Our in vivo data clearly suggest that HSulf-2 depletion resulted in decreased tumor volume and increased necrotic areas in H&E staining (Figure 2).	('depletion', 'Var', (46, 55))	('HSulf-2', 'Gene', '55959', (38, 45))	('HSulf-2', 'Gene', (38, 45))	('H&E', 'Chemical', 'MESH:D006371', (123, 126))	('decreased tumor', 'Disease', 'MESH:D009369', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('necrotic', 'Disease', (105, 113))	('increased', 'PosReg', (95, 104))	('necrotic', 'Disease', 'MESH:D009336', (105, 113))	('decreased tumor', 'Disease', (68, 83))
78113	22410125	Our data revealed that HSulf-2 depletion resulted in a higher degree of apoptotic positive areas (TUNEL positive, FITC labeled) in the xenografts as compared to NTC at Week 5 and notably at Week 7 (Figure 5A, panel 1).	('FITC', 'Chemical', 'MESH:D016650', (114, 118))	('apoptotic positive areas', 'CPA', (72, 96))	('HSulf-2', 'Gene', '55959', (23, 30))	('depletion', 'Var', (31, 40))	('HSulf-2', 'Gene', (23, 30))
78116	22410125	These data suggest that HSulf-2 knockdown resulted in increased apoptosis in the center of ductal lesions.	('HSulf-2', 'Gene', '55959', (24, 31))	('HSulf-2', 'Gene', (24, 31))	('apoptosis', 'CPA', (64, 73))	('knockdown', 'Var', (32, 41))	('increased', 'PosReg', (54, 63))
78117	22410125	We noted two major effects of HSulf-2 depletion on mouse derived xenografts: a) increased luminal apoptosis and b) decreased basement membrane breakdown.	('luminal apoptosis', 'CPA', (90, 107))	('increased', 'PosReg', (80, 89))	('mouse', 'Species', '10090', (51, 56))	('depletion', 'Var', (38, 47))	('decreased', 'NegReg', (115, 124))	('basement membrane breakdown', 'CPA', (125, 152))	('HSulf-2', 'Gene', '55959', (30, 37))	('HSulf-2', 'Gene', (30, 37))
78118	22410125	Our observation that HSulf-2 knockdown resulted in decreased breakdown of basement membrane even at Week 7 of tumor growth indicated that HSulf-2 presence might be critical for basement membrane (BM) breakdown.	('HSulf-2', 'Gene', (21, 28))	('HSulf-2', 'Gene', '55959', (138, 145))	('knockdown', 'Var', (29, 38))	('HSulf-2', 'Gene', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('decreased', 'NegReg', (51, 60))	('HSulf-2', 'Gene', '55959', (21, 28))	('breakdown of basement membrane', 'MPA', (61, 91))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
78128	22410125	By utilizing mouse mammary fat pad injections to evaluate the impact of HSulf-2 depleted MCF10DCIS cells on tumor growth, we found that HSulf-2 knockdown significantly attenuated tumor size, promoted apoptosis and retained comedo lesions for a longer period of time.	('HSulf-2', 'Gene', '55959', (72, 79))	('promoted', 'PosReg', (191, 199))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('HSulf-2', 'Gene', (136, 143))	('attenuated', 'NegReg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('HSulf-2', 'Gene', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (89, 98))	('comedo lesions', 'CPA', (223, 237))	('comedo', 'Phenotype', 'HP:0025249', (223, 229))	('mouse', 'Species', '10090', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('knockdown', 'Var', (144, 153))	('apoptosis', 'CPA', (200, 209))	('retained comedo', 'Phenotype', 'HP:0025250', (214, 229))	('HSulf-2', 'Gene', '55959', (136, 143))	('tumor', 'Disease', (179, 184))
78130	22410125	This indicates that loss of HSulf-2 selectively renders inner luminal cells of comedo lesions to undergo apoptosis presumably due to the tumor microenvironment resulting in culmination of the apoptotic program, which triggers spontaneous apoptosis in comedo lesions.	('HSulf-2', 'Gene', '55959', (28, 35))	('loss', 'Var', (20, 24))	('tumor', 'Disease', (137, 142))	('HSulf-2', 'Gene', (28, 35))	('apoptosis', 'CPA', (105, 114))	('renders', 'Reg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('comedo', 'Phenotype', 'HP:0025249', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('comedo', 'Phenotype', 'HP:0025249', (79, 85))
78134	22410125	Importantly, HSulf-2 silencing attenuated transition from DCIS to IDC by limiting MMP-9 expression and activities required for basement membrane degradation.	('HSulf-2', 'Gene', (13, 20))	('DCIS', 'Disease', (58, 62))	('limiting', 'NegReg', (73, 81))	('attenuated', 'NegReg', (31, 41))	('HSulf-2', 'Gene', '55959', (13, 20))	('activities required', 'MPA', (103, 122))	('expression', 'MPA', (88, 98))	('silencing', 'Var', (21, 30))	('MMP-9', 'Protein', (82, 87))
78137	22410125	Our in vivo data show that HSulf-2 depletion markedly attenuates tumor growth.	('HSulf-2', 'Gene', (27, 34))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('attenuates', 'NegReg', (54, 64))	('depletion', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('HSulf-2', 'Gene', '55959', (27, 34))
78142	22410125	This could be explained in several ways: a) it can be postulated that cells in the center of comedo lesions are often highly hypoxic and have a decreased supply of nutrients and b) these cells are separated from extracellular matrix protein of basement membrane and, hence, lack adhesion, and that HSulf-2 knockdown further sensitizes these cells to apoptosis due to lack of survival signals (growth factor and adhesion mediated).	('HSulf-2', 'Gene', (298, 305))	('sensitizes', 'Reg', (324, 334))	('adhesion', 'CPA', (279, 287))	('decreased', 'NegReg', (144, 153))	('knockdown', 'Var', (306, 315))	('survival signals', 'CPA', (375, 391))	('comedo', 'Phenotype', 'HP:0025249', (93, 99))	('apoptosis', 'CPA', (350, 359))	('hypoxic', 'Disease', (125, 132))	('hypoxic', 'Disease', 'MESH:D000860', (125, 132))	('HSulf-2', 'Gene', '55959', (298, 305))	('lack', 'NegReg', (274, 278))	('lack', 'NegReg', (367, 371))	('supply of nutrients', 'MPA', (154, 173))
78156	22410125	Additionally, we propose that therapeutic targeting of HSulf-2 could lead to improved clinical outcome in patients with breast cancer Silencing of heparan sulfatase 2 attenuates breast cancer growth and inhibits basement membrane disruption in a matrix metalloprotease dependent process.	('sulfatase 2', 'Gene', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('inhibits', 'NegReg', (203, 211))	('HSulf-2', 'Gene', '55959', (55, 62))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('HSulf-2', 'Gene', (55, 62))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('breast cancer', 'Disease', (178, 191))	('patients', 'Species', '9606', (106, 114))	('sulfatase 2', 'Gene', '55959', (155, 166))	('attenuates', 'NegReg', (167, 177))	('Silencing', 'Var', (134, 143))	('basement membrane disruption', 'CPA', (212, 240))
78224	18043578	Moinfar et al (2003) reported a higher rate of AR expression in especially low-grade DCIS as opposed to high-grade DCIS, although others did not find a correlation between AR expression and grade (Selim et al, 2002).	('AR', 'Gene', '367', (172, 174))	('low-grade', 'Var', (75, 84))	('AR', 'Gene', '367', (47, 49))	('higher', 'PosReg', (32, 38))
78228	18043578	The absence of Her2 overexpression in normal ducts and atypical ductal hyperplasia, and the frequent of Her2 amplification found in DCIS suggests that Her2 alterations are an early event in the pathway of development of Her2-positive invasive carcinomas.	('Her2', 'Gene', (15, 19))	('Her2', 'Gene', '2064', (104, 108))	('invasive carcinomas', 'Disease', (234, 253))	('invasive carcinomas', 'Disease', 'MESH:D009361', (234, 253))	('alterations', 'Var', (156, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('Her2', 'Gene', '2064', (15, 19))	('Her2', 'Gene', (151, 155))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (64, 82))	('Her2', 'Gene', (220, 224))	('ductal hyperplasia', 'Disease', (64, 82))	('Her2', 'Gene', (104, 108))	('Her2', 'Gene', '2064', (220, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (243, 253))	('Her2', 'Gene', '2064', (151, 155))
78231	18043578	Moreover, the mammographic detection of poorly differentiated Her2-positive DCIS often occurs at an early stage due to the conspicuous microcalcifications.	('Her2', 'Gene', (62, 66))	('poorly', 'Var', (40, 46))	('Her2', 'Gene', '2064', (62, 66))
78238	18043578	This is in keeping with the absence of basal-like in situ lesions in preventive mastectomy specimens of BRCA1 carriers, which are prone to develop basal-like tumours (Hoogerbrugge et al, 2003).	('carriers', 'Var', (110, 118))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('basal-like tumours', 'Phenotype', 'HP:0002671', (147, 165))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('BRCA1', 'Gene', '672', (104, 109))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('BRCA1', 'Gene', (104, 109))	('tumours', 'Disease', (158, 165))	('develop', 'PosReg', (139, 146))	('basal-like in situ lesions', 'Phenotype', 'HP:0002671', (39, 65))
78261	32050925	Myriad's hereditary cancer tests were done by Myriad Genetic Laboratories, Inc. (Salt Lake City, Utah, USA) through observations of deleterious mutations, as published by Frank et al..	('hereditary cancer', 'Disease', 'MESH:D009386', (9, 26))	('mutations', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hereditary cancer', 'Disease', (9, 26))
78294	32050925	Epigenetic alterations may contribute to BC progression by transcriptionally silencing specific tumor suppressor genes, which could explain the loss of expression that we observed.	('Epigenetic alterations', 'Var', (0, 22))	('transcriptionally', 'MPA', (59, 76))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('BC', 'Phenotype', 'HP:0003002', (41, 43))	('contribute', 'Reg', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('BC', 'Disease', 'MESH:D001943', (41, 43))
78308	32050925	We propose that downregulation favors DCIS progression.	('downregulation', 'Var', (16, 30))	('DCIS', 'Disease', (38, 42))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('DCIS', 'Disease', 'MESH:D002285', (38, 42))
78314	32050925	The progression from DCIS to invasive BC is a complex process, being possible that DCIS of distinct molecular phenotypes progress to invasive BC through the acquisition of distinct genetic or epigenetic hits.	('BC', 'Disease', 'MESH:D001943', (142, 144))	('DCIS', 'Disease', (21, 25))	('DCIS', 'Disease', (83, 87))	('DCIS', 'Disease', 'MESH:D002285', (83, 87))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('BC', 'Phenotype', 'HP:0003002', (38, 40))	('BC', 'Disease', 'MESH:D001943', (38, 40))	('progress', 'PosReg', (121, 129))	('epigenetic hits', 'Var', (192, 207))	('BC', 'Phenotype', 'HP:0003002', (142, 144))	('DCIS', 'Disease', 'MESH:D002285', (21, 25))
78335	30386176	We identified two AIF1 isoforms, AIF1v1 and AIF1v3, which were differentially expressed between affected and unaffected sisters from families with high risk of BC with no deleterious BRCA1/BRCA2 mutations (BRCAX).	('BC', 'Phenotype', 'HP:0003002', (160, 162))	('BRCAX', 'Gene', '60500', (206, 211))	('BRCA1', 'Gene', '672', (183, 188))	('BRCA2', 'Gene', (189, 194))	('mutations', 'Var', (195, 204))	('BRCA1', 'Gene', (183, 188))	('BRCAX', 'Gene', (206, 211))	('BRCA2', 'Gene', '675', (189, 194))
78356	30386176	AIF1 can increase IL-6, IL-10, and IL-12 production in the RAW 264.7 macrophage cell line stimulated with lipopolysaccharides.	('RAW 264.7', 'CellLine', 'CVCL:0493', (59, 68))	('increase', 'PosReg', (9, 17))	('IL-10', 'Gene', '16153', (24, 29))	('IL-10', 'Gene', (24, 29))	('increase IL-6', 'Phenotype', 'HP:0030783', (9, 22))	('IL-6', 'MPA', (18, 22))	('lipopolysaccharides', 'Chemical', 'MESH:D008070', (106, 125))	('IL-12 production', 'MPA', (35, 51))	('AIF1', 'Var', (0, 4))
78358	30386176	Furthermore, AIF1v3 may promote BC proliferation through activation of the NF-kappaB/cyclin D1 pathway.	('BC', 'Phenotype', 'HP:0003002', (32, 34))	('activation', 'PosReg', (57, 67))	('AIF1v3', 'Var', (13, 19))	('NF-kappaB', 'Gene', (75, 84))	('cyclin D1', 'Gene', '595', (85, 94))	('BC proliferation', 'CPA', (32, 48))	('cyclin D1', 'Gene', (85, 94))	('promote', 'PosReg', (24, 31))	('rat', 'Species', '10116', (42, 45))	('NF-kappaB', 'Gene', '4790', (75, 84))
78359	30386176	Additional studies have shown that AIF1v3 may promote BC cell migration via the upregulation of TNFalpha-mediated activation of the p38-MAPK signaling pathway and may increase the resistance of BC cells to cisplatin.	('activation', 'PosReg', (114, 124))	('promote', 'PosReg', (46, 53))	('TNFalpha', 'Gene', (96, 104))	('BC cell migration', 'CPA', (54, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('rat', 'Species', '10116', (65, 68))	('BC', 'Phenotype', 'HP:0003002', (194, 196))	('upregulation', 'PosReg', (80, 92))	('p38', 'Gene', (132, 135))	('BC', 'Phenotype', 'HP:0003002', (54, 56))	('TNFalpha', 'Gene', '7124', (96, 104))	('increase', 'PosReg', (167, 175))	('AIF1v3', 'Var', (35, 41))	('p38', 'Gene', '1432', (132, 135))	('resistance', 'MPA', (180, 190))
78417	30386176	Protocols for MCF7 transfection and E1/E2 treatment, steroid extraction and 1D thin layer chromatography measurements, and crystal violet assay for determining viability of cultured cells are described in Additional file 3: Additional methods.	('MCF7', 'CellLine', 'CVCL:0031', (14, 18))	('transfection', 'Var', (19, 31))	('E1/E2', 'Gene', (36, 41))	('MCF7', 'Gene', (14, 18))	('crystal violet', 'Chemical', 'MESH:D005840', (123, 137))	('steroid', 'Chemical', 'MESH:D013256', (53, 60))	('E1/E2', 'Gene', '6080', (36, 41))
78431	30386176	A decrease in cell viability was also observed in transfected MCF7 cells with AIF1v1 as compared to controls (Additional file 6: Figure S4A, B).	('MCF7', 'CellLine', 'CVCL:0031', (62, 66))	('cell viability', 'CPA', (14, 28))	('decrease', 'NegReg', (2, 10))	('AIF1v1', 'Var', (78, 84))
78445	30386176	In general, all patients in the high AIF1v1 expression group had a high KM score while 80% of patients in med and low groups had a low KM score.	('high', 'Var', (32, 36))	('patients', 'Species', '9606', (94, 102))	('AIF1v1', 'Gene', (37, 43))	('patients', 'Species', '9606', (16, 24))	('KM score', 'MPA', (72, 80))
78450	30386176	Overall, BC patients with high AIF1v1 breast adipose expression had more cell infiltrate at the invasive margin (KM score) and a significantly higher number of infiltrating immune cells consisting predominantly of lymphocytes, both in the peri and intra-tumoral regions.	('cell infiltrate at the invasive margin', 'CPA', (73, 111))	('patients', 'Species', '9606', (12, 20))	('infiltrating immune cells', 'CPA', (160, 185))	('intra-tumoral', 'Disease', (248, 261))	('high', 'Var', (26, 30))	('more', 'PosReg', (68, 72))	('rat', 'Species', '10116', (166, 169))	('rat', 'Species', '10116', (84, 87))	('BC', 'Phenotype', 'HP:0003002', (9, 11))	('breast adipose', 'MPA', (38, 52))	('higher', 'PosReg', (143, 149))	('intra-tumoral', 'Disease', 'MESH:D009369', (248, 261))	('AIF1v1', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
78467	30386176	Cells transfected with AIF1v1 showed reduced cell viability, in agreement with a previous study with AIF1 in pancreatic cells.	('cell viability', 'CPA', (45, 59))	('pancreatic', 'Disease', 'MESH:D010195', (109, 119))	('pancreatic', 'Disease', (109, 119))	('AIF1v1', 'Var', (23, 29))	('reduced', 'NegReg', (37, 44))
78469	30386176	Two previous studies demonstrated that AIF1v3 in transfected human BC cell lines could promote BC cell proliferation via the NF-kappaB pathway and enhance cell migration by activation of p38-MAPK pathway suggesting a possible role in BC progression.	('rat', 'Species', '10116', (163, 166))	('AIF1v3', 'Var', (39, 45))	('rat', 'Species', '10116', (110, 113))	('BC', 'Phenotype', 'HP:0003002', (95, 97))	('p38', 'Gene', '1432', (187, 190))	('BC', 'Phenotype', 'HP:0003002', (67, 69))	('enhance', 'PosReg', (147, 154))	('p38', 'Gene', (187, 190))	('activation', 'PosReg', (173, 183))	('BC cell proliferation', 'CPA', (95, 116))	('cell migration', 'CPA', (155, 169))	('NF-kappaB', 'Gene', '4790', (125, 134))	('BC', 'Phenotype', 'HP:0003002', (234, 236))	('promote', 'PosReg', (87, 94))	('human', 'Species', '9606', (61, 66))	('rat', 'Species', '10116', (28, 31))	('NF-kappaB', 'Gene', (125, 134))
78485	30386176	Our assessment of the tumor inflammatory cells infiltrate in breast tumors showed that adipose AIF1v1 was associated with the number of lymphocytes infiltrating breast tumors in both the peri and intra-tumoral regions and total number of plasma cells, which allow us to confirm our previous hypothesis.	('intra-tumoral', 'Disease', (196, 209))	('associated', 'Reg', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('breast tumors', 'Phenotype', 'HP:0100013', (161, 174))	('breast tumor', 'Phenotype', 'HP:0100013', (161, 173))	('tumor', 'Disease', (68, 73))	('adipose', 'Var', (87, 94))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('intra-tumoral', 'Disease', 'MESH:D009369', (196, 209))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (168, 173))	('rat', 'Species', '10116', (154, 157))	('breast tumors', 'Disease', 'MESH:D001943', (61, 74))	('AIF1v1', 'Gene', (95, 101))	('rat', 'Species', '10116', (53, 56))	('breast tumors', 'Disease', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('breast tumors', 'Phenotype', 'HP:0100013', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('breast tumor', 'Phenotype', 'HP:0100013', (61, 73))	('breast tumors', 'Disease', (161, 174))	('breast tumors', 'Disease', 'MESH:D001943', (161, 174))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
78575	26984519	Moreover, some of these miRNAs were also found to be differentially expressed between breast cancer patients and normal controls in other biological fluids such as serum (miR-23b, -133b, -181a, 338-3p, -625), and plasma (miR-200a).	('338-3p', 'Var', (194, 200))	('miR-23b', 'Gene', '407011', (171, 178))	('miR-23b', 'Gene', (171, 178))	('differentially expressed', 'Reg', (53, 77))	('miR', 'Gene', (171, 174))	('miR', 'Gene', '220972', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('miR', 'Gene', '220972', (24, 27))	('patients', 'Species', '9606', (100, 108))	('miR', 'Gene', (24, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('miR-200a', 'Gene', (221, 229))	('breast cancer', 'Disease', (86, 99))	('miR-200a', 'Gene', '406983', (221, 229))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (221, 224))
78586	26984519	Furthermore, some of these miRs were also found differentially expressed in various biological fluids of breast cancer patients compared to normal controls, such as miR-484 and miR-301a in serum, miR-144 and miR-301a in blood, and let-7a in breast milk.	('miR-144', 'Gene', (196, 203))	('miR-484', 'Gene', '619553', (165, 172))	('miR', 'Gene', (196, 199))	('miR', 'Gene', '220972', (27, 30))	('breast milk', 'Disease', (241, 252))	('miR', 'Gene', (165, 168))	('miR', 'Gene', '220972', (177, 180))	('miR-484', 'Gene', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR', 'Gene', (27, 30))	('miR-301a', 'Gene', (177, 185))	('miR-301a', 'Gene', (208, 216))	('miR', 'Gene', (177, 180))	('miR', 'Gene', '220972', (208, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('miR-144', 'Gene', '406936', (196, 203))	('miR-301a', 'Gene', '407027', (177, 185))	('miR-301a', 'Gene', '407027', (208, 216))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('miR', 'Gene', (208, 211))	('miR', 'Gene', '220972', (196, 199))	('patients', 'Species', '9606', (119, 127))	('let-7a', 'Var', (231, 237))	('miR', 'Gene', '220972', (165, 168))	('breast milk', 'Disease', 'MESH:D016269', (241, 252))
78657	12237770	Four of the 29 eligible non-entered patients treated with LE+RT developed a local recurrence (4-year local recurrence-free interval 74%), compared to 12 of 133 of the LE+RT group in the trial (4-year local recurrence-free interval 98%) (s.e.=13.4, P=0.075) (Table 4).	('LE+RT', 'Var', (58, 63))	('patients', 'Species', '9606', (36, 44))	('local recurrence', 'CPA', (76, 92))
78658	12237770	When all non-entered patients - eligible and ineligible - are grouped together, those non-entered patients treated with LE+RT had a significantly worse 4-years local recurrence-free interval compared to those randomised for LE+RT (83 vs 98%, s.e.=6.9, P=0.031).	('local recurrence-free interval', 'CPA', (160, 190))	('worse', 'NegReg', (146, 151))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (21, 29))	('LE+RT', 'Var', (120, 125))
78693	12237770	This may explain why the 4-year local recurrence rates in the non-entered patients treated with LE+RT are relatively high compared to the patients in the trial treated with LE+RT.	('LE+RT', 'Var', (96, 101))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (138, 146))	('local recurrence', 'CPA', (32, 48))
78702	12237770	Randomised patients treated with LE+RT had better 4-year local recurrence-free rates than those treated with LE+RT outside the trial.	('patients', 'Species', '9606', (11, 19))	('local recurrence-free rates', 'CPA', (57, 84))	('LE+RT', 'Var', (33, 38))
78768	11953822	We therefore felt that it was reasonable to hypothesize that changes in periductal vascularity may precede the development of invasive carcinoma in DCIS.	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('invasive carcinoma', 'Disease', 'MESH:D009361', (126, 144))	('changes', 'Var', (61, 68))	('invasive carcinoma', 'Disease', (126, 144))
78846	30497437	1b, c) confirmed that our experimental model of low oxygen availability is effective in inducing the hypoxia-related intracellular signalling in MCF10DCIS.	('hypoxia', 'Disease', (101, 108))	('low oxygen availability', 'Phenotype', 'HP:0012418', (48, 71))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('MCF10DCIS', 'Var', (145, 154))	('oxygen', 'Chemical', 'MESH:D010100', (52, 58))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (145, 154))	('inducing', 'Reg', (88, 96))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))
78850	30497437	2b, MCF10DCIS cells express both proteins and 96 h of culture under low oxygen induced a significant reduction of the epithelial marker E-cadherin and a strong increase of the mesenchymal marker Vimentin.	('MCF10DCIS', 'Var', (4, 13))	('reduction', 'NegReg', (101, 110))	('mesenchymal', 'CPA', (176, 187))	('Vimentin', 'Gene', '7431', (195, 203))	('E-cadherin', 'Gene', (136, 146))	('increase', 'PosReg', (160, 168))	('E-cadherin', 'Gene', '999', (136, 146))	('epithelial marker', 'MPA', (118, 135))	('oxygen', 'Chemical', 'MESH:D010100', (72, 78))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (4, 13))	('Vimentin', 'Gene', (195, 203))
78851	30497437	To assess if the hypoxia-related modifications of morphology and of EMT markers are sufficient to increase migration and/or invasion of MCF10DCIS cells, the Real-Time Cell Analyzer system was used, allowing to demonstrate that 96 h of hypoxia induced a significant increase of the migration capability but had no effect on the invasive properties of this cell line (Fig.	('migration', 'CPA', (107, 116))	('hypoxia', 'Disease', 'MESH:D000860', (235, 242))	('hypoxia', 'Disease', (235, 242))	('hypoxia', 'Disease', (17, 24))	('hypoxia', 'Disease', 'MESH:D000860', (17, 24))	('modifications', 'Var', (33, 46))	('increase', 'PosReg', (98, 106))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (136, 145))	('invasion', 'CPA', (124, 132))	('migration capability', 'CPA', (281, 301))	('increase', 'PosReg', (265, 273))
78874	30497437	MCF10DCIS were then cultured for 96 h under low oxygen and both PLC-beta2 mRNA and protein amount were evaluated.	('PLC-beta2', 'Gene', (64, 73))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('oxygen', 'Chemical', 'MESH:D010100', (48, 54))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('PLC-beta2', 'Gene', '5330', (64, 73))	('MCF10DCIS', 'Var', (0, 9))
78878	30497437	As determined by flow cytometry, the number of MCF10DCIS cells expressing CD133 at surface level markedly increased as a consequence of the silencing of PLC-beta2 during ATRA administration (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('PLC-beta2', 'Gene', '5330', (153, 162))	('CD133', 'Gene', (74, 79))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (47, 56))	('CD133', 'Gene', '8842', (74, 79))	('PLC-beta2', 'Gene', (153, 162))	('increased', 'PosReg', (106, 115))	('ATRA', 'Chemical', 'MESH:D014212', (170, 174))	('silencing', 'Var', (140, 149))
78882	30497437	Accordingly, in breast cancer as in many other solid cancers, low oxygen availability is associated with a clinically aggressive tumor behavior.	('associated', 'Reg', (89, 99))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('breast cancer', 'Disease', (16, 29))	('low oxygen availability', 'Phenotype', 'HP:0012418', (62, 85))	('solid cancers', 'Disease', (47, 60))	('solid cancers', 'Disease', 'MESH:D009369', (47, 60))	('aggressive tumor', 'Disease', 'MESH:D001523', (118, 134))	('oxygen', 'Chemical', 'MESH:D010100', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('low', 'Var', (62, 65))	('aggressive tumor', 'Disease', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
78885	30497437	This study was therefore planned to investigate the role of low oxygenation on malignant properties of MCF10DCIS cells, one of the very few established models of DCIS that, in immunocompromised mice, resulted in rapidly growing lesions that are predominantly high-grade comedo ductal carcinoma in situ.	('oxygen', 'Chemical', 'MESH:D010100', (64, 70))	('MCF10DCIS', 'Var', (103, 112))	('grade comedo', 'Phenotype', 'HP:0025250', (264, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('low oxygenation', 'Phenotype', 'HP:0012418', (60, 75))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (277, 293))	('carcinoma in situ', 'Disease', (284, 301))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (277, 301))	('comedo', 'Phenotype', 'HP:0025249', (270, 276))	('resulted in', 'Reg', (200, 211))	('mice', 'Species', '10090', (194, 198))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (103, 112))	('carcinoma in situ', 'Disease', 'MESH:D002278', (284, 301))
78913	25572327	When contemplating an effective approach to cancer prevention, vaccines offer unique advantages over other more standard approaches: First, once appropriately stimulated, antigen specific T-cells will travel to all sites of disease and eradicate cells bearing the proteins to which the T-cells have been primed by vaccination.	('proteins', 'Protein', (264, 272))	('eradicate', 'NegReg', (236, 245))	('cells', 'MPA', (246, 251))	('cancer', 'Disease', (44, 50))	('antigen', 'Var', (171, 178))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
79002	25572327	Also T-cells will travel to any site in the body where cancer occurs and eliminate cells that have begun to express the aberrant protein against which the T-cell was primed.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('aberrant', 'Var', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))
79015	33924033	Several studies have demonstrated good sensitivity and specificity in DWI combining b-value sequences and the apparent diffusion coefficient (ADC) map in the detection of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('DWI', 'Var', (70, 73))	('apparent', 'MPA', (110, 118))
79052	21761347	Transient expression of aurora-A promoter deletion mutants in luciferase constructs identified a GATA binding sequence motif as a functional regulatory element in ERalpha-positive breast cancer cells.	('GATA', 'Gene', '55278', (97, 101))	('aurora-A', 'Gene', (24, 32))	('mutants', 'Var', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('ERalpha', 'Gene', (163, 170))	('aurora-A', 'Gene', '6790', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('ERalpha', 'Gene', '2099', (163, 170))	('deletion mutants', 'Var', (42, 58))	('GATA', 'Gene', (97, 101))
79054	21761347	Anti-GATA-3 antibody generated a supershifted complex.	('supershifted complex', 'MPA', (33, 53))	('Anti-GATA-3', 'Var', (0, 11))	('rat', 'Species', '10116', (25, 28))
79056	21761347	Ectopic expression of GATA-3 resulted in elevated expression of Aurora-A in both ERalpha-positive and negative cells while siRNA-mediated silencing led to downregulation of endogenous Aurora-A in ERalpha-positive cells.	('Aurora-A', 'Gene', (64, 72))	('ERalpha', 'Gene', '2099', (81, 88))	('ERalpha', 'Gene', (81, 88))	('ERalpha', 'Gene', '2099', (196, 203))	('ERalpha', 'Gene', (196, 203))	('Ectopic expression', 'Var', (0, 18))	('endogenous', 'MPA', (173, 183))	('elevated', 'PosReg', (41, 49))	('downregulation', 'NegReg', (155, 169))	('GATA-3', 'Gene', (22, 28))	('expression', 'MPA', (50, 60))
79077	21761347	This question gained credence in light of the recently published evidence of E2-mediating Aurora-A overexpression in a rat model of breast cancer.	('overexpression', 'PosReg', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rat', 'Species', '10116', (119, 122))	('E2-mediating', 'Var', (77, 89))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('Aurora-A', 'Gene', (90, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
79089	21761347	1a, the results showed higher luciferase activity in BT474 (ERalpha+) than in HMLE (ERalpha-) cells, indicating that transcription factor(s) specifically expressed in an ERalpha+ cell line positively regulated the activity of the aurora-A promoter.	('ERalpha', 'Gene', '2099', (84, 91))	('ERalpha', 'Gene', (170, 177))	('regulated', 'Reg', (200, 209))	('aurora-A', 'Gene', (230, 238))	('BT474', 'Var', (53, 58))	('ERalpha', 'Gene', '2099', (60, 67))	('BT474', 'CellLine', 'CVCL:0179', (53, 58))	('luciferase', 'Enzyme', (30, 40))	('higher', 'PosReg', (23, 29))	('activity', 'MPA', (214, 222))	('aurora-A', 'Gene', '6790', (230, 238))	('ERalpha', 'Gene', '2099', (170, 177))	('ERalpha', 'Gene', (84, 91))	('activity', 'MPA', (41, 49))	('ERalpha', 'Gene', (60, 67))
79090	21761347	To identify the cis-element(s) and respective trans-factor (s) responsible for activation of AURKA gene promoter in ERalpha+ breast cancer cells, we examined the luciferase activities of promoter constructs with deletion to -415, -189, and -75 bp from the transcription initiation site.	('ERalpha', 'Gene', (116, 123))	('AURKA', 'Gene', (93, 98))	('ERalpha', 'Gene', '2099', (116, 123))	('activities', 'MPA', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('deletion to -415', 'Var', (212, 228))	('breast cancer', 'Disease', (125, 138))	('activation', 'PosReg', (79, 89))	('luciferase', 'Enzyme', (162, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('AURKA', 'Gene', '6790', (93, 98))
79091	21761347	Deletion to -189 detected high promoter activity in BT474 cells compared to those of HMLE cells.	('promoter activity', 'MPA', (31, 48))	('BT474', 'CellLine', 'CVCL:0179', (52, 57))	('Deletion', 'Var', (0, 8))
79104	21761347	Next, we determined whether knock down of GATA-3 expression by small interference RNA (siRNA) reduced the promoter activity of the AURKA gene in GATA-3-positive cell lines.	('AURKA', 'Gene', '6790', (131, 136))	('GATA-3', 'Gene', (42, 48))	('reduced', 'NegReg', (94, 101))	('AURKA', 'Gene', (131, 136))	('promoter activity', 'MPA', (106, 123))	('knock down', 'Var', (28, 38))
79133	21761347	While there is a strong correlation of high GATA-3 expression with the luminal A subtype of breast cancers, in addition to being an excellent predictor of ERalpha status, low GATA-3 expression is a predictor of poor clinical outcome, high tumor grade, and positive lymph node status.	('high tumor', 'Disease', (234, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('expression', 'MPA', (182, 192))	('high tumor', 'Disease', 'MESH:D009369', (234, 244))	('ERalpha', 'Gene', (155, 162))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('GATA-3', 'Gene', (175, 181))	('low', 'Var', (171, 174))	('ERalpha', 'Gene', '2099', (155, 162))	('expression', 'MPA', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('GATA-3', 'Gene', (44, 50))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
79138	21761347	Therefore, it is likely that aberrant expression of the GATA-3 gene regulatory network in ERalpha+ mammary epithelial cells leads to deregulated expression of Aurora-A, predisposing the normal epithelium to acquire centrosome anomalies and CIN associated with development of naturally occurring breast tumors in humans and also in the experimental models of mammary carcinogenesis in rats.	('CIN', 'Phenotype', 'HP:0040012', (240, 243))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('GATA-3', 'Gene', (56, 62))	('breast tumors', 'Disease', 'MESH:D001943', (295, 308))	('breast tumors', 'Disease', (295, 308))	('ERalpha', 'Gene', '2099', (90, 97))	('CIN', 'Disease', 'MESH:D007674', (240, 243))	('breast tumors', 'Phenotype', 'HP:0100013', (295, 308))	('rats', 'Species', '10116', (384, 388))	('deregulated expression', 'MPA', (133, 155))	('breast tumor', 'Phenotype', 'HP:0100013', (295, 307))	('CIN', 'Disease', (240, 243))	('carcinogenesis', 'Disease', (366, 380))	('associated', 'Reg', (244, 254))	('Aurora-A', 'Gene', (159, 167))	('aberrant', 'Var', (29, 37))	('carcinogenesis', 'Disease', 'MESH:D063646', (366, 380))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('ERalpha', 'Gene', (90, 97))	('humans', 'Species', '9606', (312, 318))
79149	21761347	Briefly, 1 mug of full-length or deletion constructs of an Aurora-A promoter (-1486~-75) in pGL3 vector (kindly provided by Dr. Ishigatsubo) were cotransfected with 100 ng of renilla luciferase reporter plasmid, a transfection efficiency control.	('pGL3', 'Gene', '6391', (92, 96))	('pGL3', 'Gene', (92, 96))	('deletion', 'Var', (33, 41))	('-1486~-75', 'Var', (78, 87))
79185	23053659	The hospitals at which patients were treated were characterized by location (urban, rural), region of the country (northeast, mid-west, west, south), size (<400 beds, 400-600 beds, and >600 beds) and teaching status (teaching, non-teaching).	('patients', 'Species', '9606', (23, 31))	('<400 beds', 'Var', (156, 165))	('400-600 beds', 'Var', (167, 179))
79202	23053659	Immediate reconstruction was significantly less likely for women of black race (OR 0.68; 95 %CI 0.64-0.72), single marital status (OR 0.76, 95 %CI 0.72-0.80), rural hospital location (OR 0.46; 95 %CI 0.43-0.49), and >2 co-morbid conditions (OR 0.55 95 %CI 0.53-0.57).	('single marital status', 'Var', (108, 129))	('women', 'Species', '9606', (59, 64))	('less', 'NegReg', (43, 47))
79356	33049922	LINC00885 silencing in breast cancer lines overexpressing this lncRNA leads to downregulation of proliferation related transcripts such as EREG, CMYC, CCND1 and to significant decrease in cell migration and motility.	('breast cancer', 'Disease', (23, 36))	('EREG', 'Gene', (139, 143))	('CMYC', 'Gene', (145, 149))	('CMYC', 'Gene', '4609', (145, 149))	('CCND1', 'Gene', '595', (151, 156))	('LINC00885', 'Gene', (0, 9))	('LINC00885', 'Gene', '401109', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('motility', 'CPA', (207, 215))	('EREG', 'Gene', '2069', (139, 143))	('downregulation', 'NegReg', (79, 93))	('decrease', 'NegReg', (176, 184))	('CCND1', 'Gene', (151, 156))	('silencing', 'Var', (10, 19))
79357	33049922	TCGA-BRCA data analyses show an association between high LINC00885 expression and worse overall survival in patients with primary invasive breast carcinomas (p = 0.024), suggesting that the pro-tumorigenic effects of LINC00885 overexpression persist post-invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('invasive breast carcinomas', 'Disease', (130, 156))	('breast carcinomas', 'Phenotype', 'HP:0003002', (139, 156))	('LINC00885', 'Gene', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('overall survival', 'MPA', (88, 104))	('LINC00885', 'Gene', (217, 226))	('LINC00885', 'Gene', '401109', (217, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('high', 'Var', (52, 56))	('expression', 'MPA', (67, 77))	('patients', 'Species', '9606', (108, 116))	('LINC00885', 'Gene', '401109', (57, 66))	('invasive breast carcinomas', 'Disease', 'MESH:D001943', (130, 156))
79375	33049922	Overall, we obtained strong evidence to propose this long non-coding RNA as a new oncogene associated with early breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('long non-coding RNA', 'Var', (53, 72))	('associated', 'Reg', (91, 101))
79384	33049922	Interestingly, copy number alteration (CNA) analysis of the CCLE dataset showed LINC00885 gene amplification (at chr3q29 locus) in 11% of human cancer cell lines (100 out of 881) (Supplementary Figure S1a).	('copy', 'Var', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('human', 'Species', '9606', (138, 143))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('LINC00885', 'Gene', '401109', (80, 89))	('LINC00885', 'Gene', (80, 89))	('amplification', 'PosReg', (95, 108))
79385	33049922	T47D was the breast cancer cell line most affected by LINC00885 gene amplification among others (Supplementary Figure S1b).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('T47D', 'CellLine', 'CVCL:0553', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('LINC00885', 'Gene', '401109', (54, 63))	('amplification', 'Var', (69, 82))	('LINC00885', 'Gene', (54, 63))
79387	33049922	Tumor-specific up-regulation of some genes can be attributed to aberrant DNA amplification, a phenomenon frequently found in solid tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('aberrant DNA amplification', 'Var', (64, 90))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('up-regulation', 'PosReg', (15, 28))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
79399	33049922	As shown in Figure 1e, Kaplan-Meier analysis revealed that the subgroup of patients with high LINC00885 expression is associated with a shorter overall survival (median survival = 10 years) compared with those with low expression (median survival = 18 years) (p = 0.024).	('patients', 'Species', '9606', (75, 83))	('high', 'Var', (89, 93))	('expression', 'MPA', (104, 114))	('overall survival', 'MPA', (144, 160))	('LINC00885', 'Gene', '401109', (94, 103))	('LINC00885', 'Gene', (94, 103))	('shorter', 'NegReg', (136, 143))
79411	33049922	Furthermore, MCF10A were also characterized by effects on 3D growth in matrigel.	('MCF10A', 'CellLine', 'CVCL:0598', (13, 19))	('effects', 'Reg', (47, 54))	('3D growth in matrigel', 'CPA', (58, 79))	('MCF10A', 'Var', (13, 19))
79414	33049922	Normal and DCIS cells stably transduced for LINC00885 overexpression display increased motility in the in vitro wound-healing assay compared with control cells (p < 0.01) (Figure 4a).	('LINC00885', 'Gene', (44, 53))	('LINC00885', 'Gene', '401109', (44, 53))	('increased', 'PosReg', (77, 86))	('overexpression', 'Var', (54, 68))	('motility in the in vitro wound-healing assay', 'CPA', (87, 131))
79419	33049922	LINC00885 depletion in MCF7 and T47D cells significantly decreased the wound closure rate compared to non-target controls (p < 0.05, Figure 5b,c) corroborating the gain-of-function studies.	('wound closure rate', 'CPA', (71, 89))	('MCF7', 'Gene', (23, 27))	('LINC00885', 'Gene', (0, 9))	('LINC00885', 'Gene', '401109', (0, 9))	('depletion', 'Var', (10, 19))	('MCF7', 'CellLine', 'CVCL:0031', (23, 27))	('T47D', 'CellLine', 'CVCL:0553', (32, 36))	('decreased', 'NegReg', (57, 66))
79446	33049922	The MCF10AT series of cell lines was originally transformed by HRAS (p.Gly12Val).	('HRAS', 'Gene', (63, 67))	('p.Gly12Val', 'Var', (69, 79))	('MCF10AT', 'Gene', (4, 11))	('p.Gly12Val', 'Mutation', 'rs104894230', (69, 79))	('MCF10A', 'CellLine', 'CVCL:0598', (4, 10))	('HRAS', 'Gene', '3265', (63, 67))
79487	33049922	In conclusion, the described results indicate that LINC00885 overexpression induces premalignant phenotypic changes in normal breast epithelial and DCIS cells by increasing cell proliferation, motility, and migration, and altering 3D growth.	('altering', 'Reg', (222, 230))	('3D growth', 'CPA', (231, 240))	('increasing', 'PosReg', (162, 172))	('migration', 'CPA', (207, 216))	('motility', 'CPA', (193, 201))	('LINC00885', 'Gene', '401109', (51, 60))	('LINC00885', 'Gene', (51, 60))	('cell proliferation', 'CPA', (173, 191))	('overexpression', 'Var', (61, 75))
79495	33049922	DCIS Ductal carcinoma in situ  lincRNA Long-intergenic RNA  CNA Copy number alteration  DEG Differentially expressed genes	('Differentially expressed', 'MPA', (92, 116))	('Copy number alteration', 'Var', (64, 86))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (5, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('Ductal carcinoma', 'Disease', (5, 21))	('DEG', 'Chemical', '-', (88, 91))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (5, 21))	('RNA  CNA', 'Gene', (55, 63))
79510	32096852	The invasive-cancer-detection-rate was 11.8 per 1000 women [95% CI 7.4-18.8] for AB-MR versus 4.8 per 1000 women [95% CI 2.4-10.0] for DBT, a difference of 7 per 1000 women [95% CI for the difference 2.2-11.6] (exact McNemar p=0.002).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('women', 'Species', '9606', (53, 58))	('AB-MR', 'Var', (81, 86))	('women', 'Species', '9606', (167, 172))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('women', 'Species', '9606', (107, 112))
79511	32096852	For detection of invasive cancer and DCIS, for AB-MR versus DBT, sensitivity was 95.7% [95% CI 79.0-99.2] versus 39.1% [95% CI 22.2-59.2] (p=0.001).	('AB-MR', 'Var', (47, 52))	('invasive cancer', 'Disease', (17, 32))	('invasive cancer', 'Disease', 'MESH:D009362', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DCIS', 'Disease', (37, 41))
79512	32096852	Among women with dense breasts undergoing screening, AB-MR, compared with DBT, was associated with a significantly higher rate of invasive breast-cancer detection.	('AB-MR', 'Var', (53, 58))	('invasive breast-cancer', 'Disease', 'MESH:D001943', (130, 152))	('women', 'Species', '9606', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('invasive breast-cancer', 'Disease', (130, 152))
79556	32096852	AB-MR detected the invasive cancer in all 17 women, and DBT in 7 women, yielding an invasive-cancer-detection-rate of 11.8 per 1000 women [95% CI 7.4-18.8] for AB-MR versus 4.8 per 1000 women [95% CI 2.4-10.0] for DBT, a difference of 7 per 1000 women [95% CI for the difference 2.2-11.6] (p=0.002).	('women', 'Species', '9606', (186, 191))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('invasive cancer', 'Disease', (19, 34))	('women', 'Species', '9606', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('AB-MR', 'Var', (160, 165))	('women', 'Species', '9606', (246, 251))	('invasive cancer', 'Disease', 'MESH:D009362', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('women', 'Species', '9606', (65, 70))	('cancer', 'Disease', (28, 34))	('women', 'Species', '9606', (45, 50))
79564	32096852	AB-MR identified cancer in 22 of the 23 women with cancer, DBT in 9 women, for an overall cancer detection rate of 15.2 per 1000 women (22/1444) [95% CI 10.1-23.0] for AB-MR versus 6.2 per 1000 women (9/1444) [95% CI 3.3-11.8] for DBT (p=0.001) (Figure 2).	('women', 'Species', '9606', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('women', 'Species', '9606', (129, 134))	('women', 'Species', '9606', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('women', 'Species', '9606', (68, 73))	('AB-MR', 'Var', (168, 173))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
79575	32096852	In this study on the performance of AB-MR for routine breast-cancer screening of average risk women with dense breasts, AB-MR was associated with a significantly higher invasive-breast-cancer detection rate compared with DBT, also referred to as 3D-mammography.	('women', 'Species', '9606', (94, 99))	('invasive-breast-cancer', 'Disease', (169, 191))	('breast-cancer', 'Disease', (178, 191))	('higher', 'PosReg', (162, 168))	('breast-cancer', 'Disease', 'MESH:D001943', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('invasive-breast-cancer', 'Disease', 'MESH:D001943', (169, 191))	('AB-MR', 'Var', (120, 125))	('breast-cancer', 'Disease', (54, 67))	('breast-cancer', 'Disease', 'MESH:D001943', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
79611	32096852	Among women with dense breasts undergoing screening, AB-MR, compared with DBT, was associated with a significantly higher rate of invasive-breast-cancer detection.	('AB-MR', 'Var', (53, 58))	('invasive-breast-cancer', 'Disease', (130, 152))	('invasive-breast-cancer', 'Disease', 'MESH:D001943', (130, 152))	('women', 'Species', '9606', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
79613	32096852	This cross-sectional study with longitudinal follow up included 1444 women who underwent both AB-MR and DBT, interpreted independently, AB-MR detected significantly more invasive cancers (17 patients; 11.8 per 1000 women) than DBT (7 patients; 4.8 per 1000 women).	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('AB-MR', 'Var', (136, 141))	('women', 'Species', '9606', (215, 220))	('patients', 'Species', '9606', (234, 242))	('invasive cancers', 'Disease', 'MESH:D009362', (170, 186))	('women', 'Species', '9606', (257, 262))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('women', 'Species', '9606', (69, 74))	('invasive cancers', 'Disease', (170, 186))
79615	32096852	Among women with dense breasts undergoing screening, AB-MR was associated with a significantly higher rate of invasive-cancer-detection than DBT.	('AB-MR', 'Var', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('women', 'Species', '9606', (6, 11))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
79751	26229606	The "suitable group" is patients aged 60 years or older, without BRCA1/2 mutation, with unicentric and clinically unifocal tumour of size less than or equal to 2 cm, excised with negative margin of at least 2 mm, with no evidence of lymphovascular invasion and no evidence of lymph node involvement, oestrogen receptor positive, invasive ductal or other favourable subtypes.	('BRCA1', 'Gene', '672', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('invasive ductal', 'CPA', (329, 344))	('BRCA1', 'Gene', (65, 70))	('tumour', 'Disease', (123, 129))	('oestrogen', 'Protein', (300, 309))	('patients', 'Species', '9606', (24, 32))	('mutation', 'Var', (73, 81))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
79758	18270717	Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated.	('mutation', 'Var', (53, 61))	('BRCA', 'Gene', '672', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('BRCA2', 'Gene', '675', (42, 47))	('Breast tumor', 'Disease', 'MESH:D001943', (0, 12))	('BRCA', 'Gene', (117, 121))	('BRCA2', 'Gene', (127, 132))	('Breast tumor', 'Phenotype', 'HP:0100013', (0, 12))	('BRCA', 'Gene', '672', (42, 46))	('BRCA', 'Gene', '672', (32, 36))	('BRCA', 'Gene', '672', (152, 156))	('BRCA1', 'Gene', '672', (32, 37))	('BRCA', 'Gene', '672', (127, 131))	('BRCA1', 'Gene', (32, 37))	('BRCA2', 'Gene', '675', (127, 132))	('BRCA1', 'Gene', '672', (117, 122))	('MC', 'Chemical', 'MESH:D008748', (157, 159))	('Breast tumor', 'Disease', (0, 12))	('BRCA', 'Gene', (42, 46))	('BRCA1', 'Gene', (117, 122))	('BRCA', 'Gene', (32, 36))	('BRCA', 'Gene', (152, 156))	('BRCA2', 'Gene', (42, 47))	('BRCA', 'Gene', (127, 131))
79765	18270717	BRCA1 and BRCA2 are the most well known gene mutations responsible for an increased risk for developing breast cancer.	('BRCA1', 'Gene', (0, 5))	('BRCA2', 'Gene', '675', (10, 15))	('mutations', 'Var', (45, 54))	('BRCA1', 'Gene', '672', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('BRCA2', 'Gene', (10, 15))
79821	18270717	described in their mammographic study on BRCA1 and BRCA2 mutation carriers a sensitivity of 64% for the detection of a tumor in the original reports.	('mutation', 'Var', (57, 65))	('tumor', 'Disease', (119, 124))	('BRCA1', 'Gene', '672', (41, 46))	('BRCA2', 'Gene', (51, 56))	('BRCA1', 'Gene', (41, 46))	('BRCA2', 'Gene', '675', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
79836	18270717	found in the screening of 1,909 women with an increased risk for developing breast cancer, including 358 carriers of germ-line mutations, that MRI missed five cases of DCIS that were detected on mammography, with six noninvasive tumors detected in total in the study.	('women', 'Species', '9606', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('tumors', 'Disease', (229, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('mutations', 'Var', (127, 136))	('tumors', 'Disease', 'MESH:D009369', (229, 235))
79844	18270717	This is in agreement with Tilanus et al., who also found the mitotic count to be significantly higher in tumors found in gene mutation carriers.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('higher', 'PosReg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mitotic count', 'CPA', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('gene mutation', 'Var', (121, 134))
79974	15104794	All the cases of DCIS had clusters <500 mm2 (P = 0.03), while only 2 cases of invasive cancer were associated with <500 mm2 clusters.	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('invasive cancer', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('invasive cancer', 'Disease', 'MESH:D009362', (78, 93))	('<500 mm2', 'Var', (35, 43))	('DCIS', 'Disease', (17, 21))
80057	29312887	The Copenhagen group conducted a subgroup analysis of post-treatment pain in their enrolled TARGIT-A cohort (n = 244) conducted using patient reported outcomes data, and found that persistent pain was reported in 34% of WBRT patients compared with 25% of IORT patients.	('patient', 'Species', '9606', (260, 267))	('pain', 'Disease', 'MESH:D010146', (69, 73))	('pain', 'Disease', (69, 73))	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (260, 268))	('persistent pain', 'Phenotype', 'HP:0012532', (181, 196))	('pain', 'Phenotype', 'HP:0012531', (192, 196))	('WBRT', 'Var', (220, 224))	('pain', 'Phenotype', 'HP:0012531', (69, 73))	('patient', 'Species', '9606', (225, 232))	('pain', 'Disease', 'MESH:D010146', (192, 196))	('patient', 'Species', '9606', (134, 141))	('pain', 'Disease', (192, 196))
80170	28960259	On multivariable analysis, after adjustment for clinicopathologic and treatment factors significantly associated with IBTR on univariate analysis (menopausal status, clinical versus radiologic presentation, use of endocrine therapy), as well as factors that varied between RT timing groups (menopausal status, necrosis, endocrine therapy, RT dose), delay in RT initiation remained a significant risk factor for IBTR (Table 4, overall P < 0.02).	('IBTR', 'Disease', (118, 122))	('menopausal status', 'Phenotype', 'HP:0008209', (291, 308))	('menopausal status', 'Phenotype', 'HP:0008209', (147, 164))	('necrosis', 'Disease', (310, 318))	('IBTR', 'Disease', (411, 415))	('delay', 'Var', (349, 354))	('necrosis', 'Disease', 'MESH:D009336', (310, 318))
80179	28960259	While the literature shows that positive margins are associated with a higher risk of IBTR, we have previously demonstrated that positive or close margins were not associated with IBTR in this population of women undergoing adjuvant RT after BCS for DCIS (P = 0.95).	('DCIS', 'Phenotype', 'HP:0030075', (250, 254))	('IBTR', 'Disease', (86, 90))	('women', 'Species', '9606', (207, 212))	('positive', 'Var', (32, 40))	('IBTR', 'Disease', (180, 184))
80183	28960259	In addition to the known clinicopathologic and treatment factors associated with increased risk of IBTR among women with DCIS, such as premenopausal status and lack of adjuvant endocrine therapy, delay in RT initiation of more than 12 weeks appears to be associated with worse outcomes.	('delay', 'Var', (196, 201))	('DCIS', 'Disease', (121, 125))	('premenopausal status', 'Phenotype', 'HP:0008209', (135, 155))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('IBTR', 'Disease', (99, 103))	('menopausal status', 'Phenotype', 'HP:0008209', (138, 155))	('women', 'Species', '9606', (110, 115))
80188	28960259	Delay in RT also has been shown to be associated with breast cancer-specific survival among patients with invasive breast cancer.	('breast cancer', 'Disease', (54, 67))	('associated', 'Reg', (38, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('patients', 'Species', '9606', (92, 100))	('Delay', 'Var', (0, 5))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('invasive breast cancer', 'Disease', (106, 128))
80342	27577080	In chemotherapy and trastuzumab-naive DCIS-Mi patients, human epidermal growth factor receptor2 (HER2) positivity (HR=21.8, 95%CI, 1.7-286.8, P=0.019) were independent predictor of worse DFS on multivariate analysis.	('human epidermal growth factor receptor2', 'Gene', (56, 95))	('HER2', 'Gene', (97, 101))	('patients', 'Species', '9606', (46, 54))	('worse DFS', 'Disease', (181, 190))	('HER2', 'Gene', '2064', (97, 101))	('positivity', 'Var', (103, 113))	('DCIS-Mi', 'Chemical', '-', (38, 45))	('human epidermal growth factor receptor2', 'Gene', '2064', (56, 95))	('trastuzumab', 'Chemical', 'MESH:D000068878', (20, 31))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))
80349	27577080	However, the natural history of cancer cells progression from DCIS to DCIS-Mi, and finally to invasive ductal carcinoma (IDC) remains unclear, and DCIS-Mi may represent the interim stage in the evolutionary progress from DCIS to IDC.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (94, 119))	('DCIS-Mi', 'Chemical', '-', (147, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('DCIS-Mi', 'Var', (147, 154))	('cancer', 'Disease', (32, 38))	('DCIS-Mi', 'Chemical', '-', (70, 77))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('invasive ductal carcinoma', 'Disease', (94, 119))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (103, 119))	('DCIS', 'Phenotype', 'HP:0030075', (221, 225))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))
80367	27577080	Patients with DCIS-Mi had significantly worse DFS when compared with DCIS patients (P=0.009), and no statistical significant difference was found between DCIS-Mi and DCIS-T1a groups (P=0.13, Figure 1).	('DCIS-Mi', 'Chemical', '-', (154, 161))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('patients', 'Species', '9606', (74, 82))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('DCIS-Mi', 'Chemical', '-', (14, 21))	('DCIS-Mi', 'Var', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('T1a', 'Chemical', '-', (171, 174))	('DFS', 'MPA', (46, 49))	('worse', 'NegReg', (40, 45))
80372	27577080	In the remaining 68 patients, young age, multifocality and HER2 positivity were significantly associated with poorer DFS.	('HER2', 'Gene', '2064', (59, 63))	('positivity', 'Var', (64, 74))	('patients', 'Species', '9606', (20, 28))	('HER2', 'Gene', (59, 63))
80382	27577080	Meanwhile, triple-negative subtype was more prevalent in DCIS-Mi and DCIS-T1a, whereas HER2-positive tumors were predominantly more frequent in DCIS-Mi than both DCIS and DCIS-T1a.	('T1a', 'Chemical', '-', (176, 179))	('DCIS-Mi', 'Disease', (57, 64))	('DCIS-Mi', 'Chemical', '-', (57, 64))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('triple-negative', 'Var', (11, 26))	('DCIS-T1a', 'Disease', (69, 77))	('T1a', 'Chemical', '-', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('DCIS-Mi', 'Chemical', '-', (144, 151))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('HER2-positive tumors', 'Disease', (87, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('prevalent', 'Reg', (44, 53))	('HER2-positive tumors', 'Disease', 'MESH:D009369', (87, 107))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
80385	27577080	We found that multifocality is associated with a worse survival in chemotherapy and trastuzumab-naive patients, though statistically insignificant in multivariate regression model.	('trastuzumab', 'Chemical', 'MESH:D000068878', (84, 95))	('patients', 'Species', '9606', (102, 110))	('multifocality', 'Var', (14, 27))	('worse', 'NegReg', (49, 54))
80409	27577080	HER2 positivity was considered as HER2 3+ by IHC or positive on FISH, whereas cases with 0 to 1+ or 2+ without FISH positivity were regarded as negative.	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', (34, 38))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', '2064', (34, 38))
80471	24119786	In the total mastectomy specimen, low-grade DCIS was identified in a 1-cm area around the biopsy site of the papilloma and farther away from the biopsy site showed ADH.	('low-grade', 'Var', (34, 43))	('papilloma', 'Phenotype', 'HP:0012740', (109, 118))	('ADH', 'Disease', 'MESH:D007177', (164, 167))	('ADH', 'Disease', (164, 167))	('DCIS', 'Disease', (44, 48))	('papilloma', 'Disease', (109, 118))	('papilloma', 'Disease', 'MESH:D010212', (109, 118))
80498	24119786	Although the presence of atypia such as ADH or atypical lobular hyperplasia at excision may prompt the consideration of chemoprevention, the significance of such findings on reducing the mortality and morbidity of patients is not clear enough to warrant excision.	('patients', 'Species', '9606', (214, 222))	('ADH', 'Disease', 'MESH:D007177', (40, 43))	('ADH', 'Disease', (40, 43))	('atypical', 'Var', (47, 55))	('lobular hyperplasia', 'Disease', (56, 75))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (56, 75))
80504	24119786	One study that included largely BPs without atypia that were identified on ultrasound-guided CNB found that the presence of microcalcifications on histologic slides of the CNB specimens was associated with upgrade to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('malignancy', 'Disease', (217, 227))	('upgrade', 'CPA', (206, 213))	('presence', 'Var', (112, 120))	('calcification', 'Disease', 'MESH:D002114', (129, 142))	('BP', 'Chemical', '-', (32, 34))	('associated', 'Reg', (190, 200))	('calcification', 'Disease', (129, 142))
80548	29928417	The results demonstrated that the DNA of HPV16 E7 was detected in 30.5% of the samples, and that HPV16 E7 promoted the proliferation of breast cancer cells in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('HPV16 E7', 'Var', (97, 105))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('promoted', 'PosReg', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('HPV16', 'Species', '333760', (41, 46))	('HPV16', 'Species', '333760', (97, 102))	('proliferation', 'CPA', (119, 132))
80549	29928417	Additionally, HPV16 E7-mediated proliferation of breast cancer cells was suppressed in response to treatment with cyclooxygenase-2 (COX-2)-specific small interfering RNA and celecoxib.	('cyclooxygenase-2', 'Gene', '29527', (114, 130))	('suppressed', 'NegReg', (73, 83))	('cyclooxygenase-2', 'Gene', (114, 130))	('COX-2', 'Gene', (132, 137))	('E7-mediated', 'Var', (20, 31))	('small interfering', 'Var', (148, 165))	('celecoxib', 'Chemical', 'MESH:D000068579', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('COX-2', 'Gene', '5743', (132, 137))	('HPV16', 'Species', '333760', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('HPV16', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
80555	29928417	The integration of the DNA of HPV16 into host cells promotes a constitutive high expression of E7 oncoprotein, leading to carcinogenesis in vivo.	('leading to', 'Reg', (111, 121))	('integration', 'Var', (4, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('HPV16', 'Species', '333760', (30, 35))	('carcinogenesis', 'Disease', (122, 136))	('HPV16', 'Gene', (30, 35))	('E7 oncoprotein', 'Protein', (95, 109))	('promotes', 'PosReg', (52, 60))
80560	29928417	Additionally, novel therapeutic targets for HPV16 E7-mediated cancer were investigated.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HPV16', 'Species', '333760', (44, 49))	('HPV16', 'Gene', (44, 49))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('E7-mediated', 'Var', (50, 61))
80563	29928417	Several reports have demonstrated that the suppression of COX-2 by selective inhibitors has antiviral effects on viral agents, including herpes simplex virus, avian influenza A (H5N1) and hepatitis C virus.	('inhibitors', 'Var', (77, 87))	('herpes simplex virus', 'Disease', (137, 157))	('hepatitis C virus', 'Species', '11103', (188, 205))	('avian influenza A', 'Disease', (159, 176))	('hepatitis C virus', 'Disease', (188, 205))	('antiviral effects', 'MPA', (92, 109))	('H5N1', 'Species', '102793', (178, 182))	('suppression', 'NegReg', (43, 54))	('hepatitis', 'Phenotype', 'HP:0012115', (188, 197))	('herpes simplex', 'Phenotype', 'HP:0012302', (137, 151))	('COX-2', 'Gene', (58, 63))	('COX-2', 'Gene', '5743', (58, 63))
80566	29928417	However, it remains unknown whether the upregulation of COX-2 results from HPV E7-mediated progression in breast carcinoma.	('COX-2', 'Gene', '5743', (56, 61))	('breast carcinoma', 'Disease', 'MESH:D001943', (106, 122))	('breast carcinoma', 'Disease', (106, 122))	('upregulation', 'PosReg', (40, 52))	('E7-mediated', 'Var', (79, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('HPV', 'Gene', (75, 78))	('COX-2', 'Gene', (56, 61))
80575	29928417	The sections were dried at room temperature and digested with Proteinase K (Qiagen GmbH, Hilden, Germany) overnight at 56 C. The following day, the samples were incubated for 1 h at 90 C to inactivate Proteinase K and total DNA was extracted from paraffin-embedded tissues using QIAamp DNA FFPE Tissue kit (Qiagen GmbH), according to the manufacturer's protocol.	('paraffin', 'Chemical', 'MESH:D010232', (247, 255))	('Proteinase', 'Enzyme', (201, 211))	('inactivate', 'Var', (190, 200))
80629	29928417	The expression level of COX-2 DNA in HPV16 E7-positive samples was significantly increased compared with that in HPV16 E7-negative samples (Fig.	('expression level', 'MPA', (4, 20))	('HPV16', 'Gene', (37, 42))	('HPV16', 'Species', '333760', (37, 42))	('HPV16', 'Species', '333760', (113, 118))	('increased', 'PosReg', (81, 90))	('E7-positive', 'Var', (43, 54))	('COX-2', 'Gene', (24, 29))	('COX-2', 'Gene', '5743', (24, 29))
80643	29928417	In the present study, the expression of HPV16 E7 DNA was detected in patients with invasive breast ductal carcinoma from North China.	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (92, 115))	('HPV16', 'Species', '333760', (40, 45))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (99, 115))	('invasive breast ductal carcinoma', 'Disease', 'MESH:D018270', (83, 115))	('HPV16', 'Gene', (40, 45))	('invasive breast ductal carcinoma', 'Disease', (83, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('E7 DNA', 'Var', (46, 52))	('patients', 'Species', '9606', (69, 77))
80645	29928417	Previous studies demonstrated that infection with HPV16 E7 increased the proliferation of breast cancer cells.	('proliferation', 'CPA', (73, 86))	('HPV16', 'Gene', (50, 55))	('HPV16', 'Species', '333760', (50, 55))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('increased', 'PosReg', (59, 68))	('infection', 'Var', (35, 44))
80646	29928417	The results of the present study demonstrated that the expression of COX-2 in HPV16 E7-positive samples was increased compared with that in HPV16 E7-negative samples, suggesting that the expression of COX-2 may be upregulated by the expression of HPV16 E7.	('upregulated', 'PosReg', (214, 225))	('HPV16', 'Species', '333760', (78, 83))	('COX-2', 'Gene', '5743', (69, 74))	('HPV16', 'Gene', (78, 83))	('increased', 'PosReg', (108, 117))	('COX-2', 'Gene', (201, 206))	('HPV16', 'Species', '333760', (140, 145))	('expression', 'MPA', (55, 65))	('HPV16', 'Gene', (247, 252))	('HPV16', 'Species', '333760', (247, 252))	('COX-2', 'Gene', '5743', (201, 206))	('expression', 'MPA', (187, 197))	('E7-positive', 'Var', (84, 95))	('COX-2', 'Gene', (69, 74))
80654	29928417	Recently, it has been demonstrated that celecoxib prevented carcinogenesis, delayed cancer progression and enhanced the efficacy of conventional cancer therapies, including chemotherapy and radiation therapy.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('efficacy', 'CPA', (120, 128))	('celecoxib', 'Var', (40, 49))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('enhanced', 'PosReg', (107, 115))	('carcinogenesis', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prevented', 'NegReg', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('celecoxib', 'Chemical', 'MESH:D000068579', (40, 49))
80663	29928417	It has been reported that celecoxib-treated HPV16+/- animals showed a lower incidence of epidermal dysplasia compared with untreated mice.	('epidermal dysplasia', 'Disease', 'MESH:D004814', (89, 108))	('mice', 'Species', '10090', (133, 137))	('HPV16', 'Species', '333760', (44, 49))	('lower', 'NegReg', (70, 75))	('HPV16+/-', 'Var', (44, 52))	('epidermal dysplasia', 'Disease', (89, 108))	('celecoxib', 'Chemical', 'MESH:D000068579', (26, 35))
80664	29928417	Additionally, celecoxib was reported to significantly decrease breast tumor volume in rats.	('decrease', 'NegReg', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('breast tumor', 'Disease', (63, 75))	('celecoxib', 'Chemical', 'MESH:D000068579', (14, 23))	('breast tumor', 'Phenotype', 'HP:0100013', (63, 75))	('celecoxib', 'Var', (14, 23))	('rats', 'Species', '10116', (86, 90))	('breast tumor', 'Disease', 'MESH:D001943', (63, 75))
80668	29928417	Therefore, the present study may provide a potent therapeutic target for HPV16 E7-associated breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('E7-associated', 'Var', (79, 92))	('HPV16', 'Species', '333760', (73, 78))	('HPV16', 'Gene', (73, 78))
80685	27324944	Further, emerging evidence suggests that infection with Fusobacterium nucleatum, a common member of the oropharyngeal flora and a pathogenic agent involved in gingival and periodontal disease, is associated with the development of human colorectal cancer.	('Fusobacterium nucleatum', 'Species', '851', (56, 79))	('periodontal disease', 'Disease', (172, 191))	('associated with', 'Reg', (196, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('gingival', 'Disease', (159, 167))	('periodontal disease', 'Disease', 'MESH:D010510', (172, 191))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('infection', 'Disease', (41, 50))	('infection', 'Disease', 'MESH:D007239', (41, 50))	('colorectal cancer', 'Disease', (237, 254))	('Fusobacterium', 'Var', (56, 69))	('human', 'Species', '9606', (231, 236))	('periodontal disease', 'Phenotype', 'HP:0000704', (172, 191))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))	('gingival', 'Disease', 'MESH:D005891', (159, 167))
80724	27324944	The pathway "flavone and flavonol biosynthesis (ko00944)" produced the lowest p-value (Kruskal-Wallis test, adjusted p-value = 0.066) (Fig.	('lowest', 'NegReg', (71, 77))	('ko00944', 'Var', (48, 55))	('flavone', 'Chemical', 'MESH:C043562', (13, 20))	('p-value', 'MPA', (78, 85))	('flavonol', 'Chemical', 'MESH:C041477', (25, 33))
80737	27324944	Polycyclic aromatic hydrocarbons have been associated with breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('Polycyclic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('associated', 'Reg', (43, 53))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))
80749	27324944	In a rat model for breast cancer, inhibition of Beta-Glucuronidase with calcium D-glucarate reduces breast cancer incidence by lowering endogenous levels of estradiol.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('Beta-Glucuronidase', 'Enzyme', (48, 66))	('endogenous levels of estradiol', 'MPA', (136, 166))	('inhibition', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lowering', 'NegReg', (127, 135))	('estradiol', 'Chemical', 'MESH:D004958', (157, 166))	('rat', 'Species', '10116', (5, 8))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('calcium D-glucarate', 'Chemical', 'MESH:D005937', (72, 91))	('breast cancer', 'Disease', (100, 113))	('rat', 'Species', '10116', (87, 90))	('reduces', 'NegReg', (92, 99))	('breast cancer', 'Disease', (19, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))
80813	21586611	For example, over-expression/knockdown of several miRNAs, including miR-10b, miR-9, miR-31, miR-126 and miR-335, was shown to play a role in metastasis.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', '220972', (92, 95))	('over-expression/knockdown', 'Var', (13, 38))	('miR-126', 'Gene', (92, 99))	('miR-335', 'Gene', '442904', (104, 111))	('miR', 'Gene', '220972', (50, 53))	('metastasis', 'CPA', (141, 151))	('miR', 'Gene', (84, 87))	('miR', 'Gene', (68, 71))	('miR-10b', 'Gene', (68, 75))	('miR', 'Gene', (92, 95))	('over-expression/knockdown', 'PosReg', (13, 38))	('miR-31', 'Gene', (84, 90))	('miR', 'Gene', '220972', (104, 107))	('miR-126', 'Gene', '406913', (92, 99))	('miR-335', 'Gene', (104, 111))	('miR', 'Gene', (50, 53))	('miR-10b', 'Gene', '406903', (68, 75))	('miR', 'Gene', (104, 107))	('miR', 'Gene', '220972', (77, 80))	('miR-31', 'Gene', '407035', (84, 90))
80850	21586611	Table S2); these reads were mapped to the genome allowing one mismatch/insertion/deletion and then to our non-coding RNA and miRNA databases allowing up to two mismatches or one insertion/deletion.	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))	('mismatch/insertion/deletion', 'Var', (62, 89))
80873	21586611	Normal breast samples clustered together, close to a small group of ER- and HER2-positive tumors characterized by lower expression of sf-miR-21(1) and higher expression of sf-miR-22(1) compared to the remainder of tumor samples.	('HER2-positive tumors', 'Disease', 'MESH:D009369', (76, 96))	('sf-miR-21', 'Var', (134, 143))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('expression', 'MPA', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('higher', 'PosReg', (151, 157))	('ER', 'Gene', '2099', (77, 79))	('lower', 'NegReg', (114, 119))	('tumor', 'Disease', (214, 219))	('miR-22', 'Gene', '407004', (175, 181))	('ER', 'Gene', '2099', (68, 70))	('miR-22', 'Gene', (175, 181))	('HER2-positive tumors', 'Disease', (76, 96))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
80902	21586611	Sequence-specific biases in the efficiency of cDNA library preparation can distort the representation of individual miRNAs by number of sequence read counts in a reproducible manner.	('representation', 'MPA', (87, 101))	('biases', 'Var', (18, 24))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))	('distort', 'Reg', (75, 82))
80904	21586611	This analysis did not show an over-representation above the median rf >5-fold for any of the miRNAs meeting our analysis cutoff, but did show under-representation >5-fold for miR-193a, miR-193b, miR-26b, 29c and miR-30b.	('under-representation', 'NegReg', (142, 162))	('miR', 'Gene', '220972', (195, 198))	('miR', 'Gene', (212, 215))	('miR-193a', 'Gene', (175, 183))	('29c', 'Var', (204, 207))	('miR-193a', 'Gene', '406968', (175, 183))	('miR-193b', 'Gene', '574455', (185, 193))	('miR', 'Gene', (93, 96))	('miR', 'Gene', (195, 198))	('miR', 'Gene', '220972', (185, 188))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', '220972', (175, 178))	('miR', 'Gene', (185, 188))	('miR-26b', 'Gene', '407017', (195, 202))	('miR-193b', 'Gene', (185, 193))	('miR', 'Gene', (175, 178))	('miR', 'Gene', '220972', (212, 215))	('miR-26b', 'Gene', (195, 202))	('miR-30b', 'Gene', '407030', (212, 219))	('miR-30b', 'Gene', (212, 219))
80914	21586611	Based on analysis of deep-sequencing data from a pool of 770 synthetic miRNAs (Hafner, unpublished data), 10% or higher variation frequency guaranteed that 98% of the identified variations were not random events due to sequencing errors, but likely due to mis-mapping between miRNAs similar in sequence.	('miR', 'Gene', (71, 74))	('variations', 'Var', (178, 188))	('miR', 'Gene', '220972', (276, 279))	('miR', 'Gene', (276, 279))	('miR', 'Gene', '220972', (71, 74))
80915	21586611	We identified 144 distinct nucleotide variations located within 117 mature and star miRNA sequences.	('nucleotide variations', 'Var', (27, 48))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))
80916	21586611	109 variations occurred in the last two positions of the predominant mature sequence read, likely representing instances of untemplated 3' terminal addition that were insufficiently repressed by our computational approach of not considering the 3' most nucleotide (102 variations represented changes into A or U) (Suppl.	('insufficiently', 'Disease', 'MESH:D000309', (167, 181))	('insufficiently', 'Disease', (167, 181))	('variations', 'Var', (269, 279))	('changes', 'Reg', (292, 299))
80918	21586611	The most common of the 35 variations observed in the mature and star miRNA sequences were A to G, likely representing A to I RNA editing by dsRNA-specific adenosine deaminases.	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('variations', 'Var', (26, 36))
80921	21586611	We detected two known SNPs (SNPdb version 131) in lowly abundant miR-196a-2* and miR-146a which have been studied in the context of breast cancer risk (rs11614913 and rs2910164).	('miR-146a', 'Gene', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs11614913', 'Var', (152, 162))	('miR-196a-2', 'Gene', (65, 75))	('miR-196a-2', 'Gene', '406973', (65, 75))	('rs2910164', 'Mutation', 'rs2910164', (167, 176))	('rs2910164', 'Var', (167, 176))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('miR-146a', 'Gene', '406938', (81, 89))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('rs11614913', 'Mutation', 'rs11614913', (152, 162))
80922	21586611	rs2910164 (C5G) was detected in five carcinomas, while rs11614913 (C18T) was detected in 39 samples including one normal breast sample and three cell lines.	('rs11614913', 'Var', (55, 65))	('C18T', 'Mutation', 'rs11614913', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('carcinomas', 'Disease', 'MESH:D002277', (37, 47))	('rs2910164', 'Var', (0, 9))	('rs2910164', 'Mutation', 'rs2910164', (0, 9))	('carcinomas', 'Disease', (37, 47))	('rs11614913', 'Mutation', 'rs11614913', (55, 65))
80944	21586611	miRNA nucleotide variations are implicated in tumorigenesis; however, evidence for their significance is limited.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('miRNA nucleotide', 'Chemical', '-', (0, 16))	('implicated', 'Reg', (32, 42))	('tumor', 'Disease', (46, 51))	('miRNA nucleotide variations', 'Var', (0, 27))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
81038	29736009	First, while most studies defined dense breasts as those with at least heterogeneous density (>=50% fibroglandular tissue), a handful of studies reported data for women with at least scattered density (25-49% fibroglandular tissue) where the risk of breast cancer is generally lower and mammography tends to be more sensitive.	('breast cancer', 'Disease', (250, 263))	('women', 'Species', '9606', (163, 168))	('25-49% fibroglandular', 'Var', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('breast cancer', 'Disease', 'MESH:D001943', (250, 263))	('lower', 'NegReg', (277, 282))
81039	29736009	The inclusion of women with scattered density appears to have slightly diluted the beneficial effect of the ultrasound (proportion of cancers detected by ultrasound 0.23 with BI-RADS 2-4 vs. 0.31 with BI-RADS 3-4).	('BI-RADS', 'Var', (175, 182))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('women', 'Species', '9606', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
81053	25624778	Expression Distribution of Cancer Stem Cells, Epithelial to Mesenchymal Transition, and Telomerase Activity in Breast Cancer and Their Association with Clinicopathologic Characteristics A total of 167 surgically resected primary invasive breast carcinomas and 63 metastatic lymph node lesions were analyzed for immunohistochemical (IHC) localization of the CD44+CD24-low breast cancer stem cell (CSC) markers, epithelial to mesenchymal transition (EMT) markers, and telomerase activity by double-staining IHC technique, in formalin-fixed, paraffin-embedded tissue, the results were validated by double-staining immunofluorescent and flow cytometry techniques.	('breast cancer', 'Disease', 'MESH:D001943', (371, 384))	('breast carcinoma', 'Phenotype', 'HP:0003002', (238, 254))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('breast cancer', 'Disease', (371, 384))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (229, 255))	('breast carcinomas', 'Phenotype', 'HP:0003002', (238, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (371, 384))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Breast Cancer', 'Phenotype', 'HP:0003002', (111, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CD44+CD24-low', 'Var', (357, 370))	('invasive breast carcinomas', 'Disease', (229, 255))	('Breast Cancer', 'Disease', (111, 124))	('formalin', 'Chemical', 'MESH:D005557', (523, 531))	('paraffin', 'Chemical', 'MESH:D010232', (539, 547))	('Breast Cancer', 'Disease', 'MESH:D001943', (111, 124))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
81054	25624778	The results showed that CSCs with CD44+CD24-low phenotype were significantly increased in node-positive tumors, high-grade tumors, and ductal carcinoma in situ (DCIS).	('ductal carcinoma', 'Phenotype', 'HP:0030075', (135, 151))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (135, 159))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (142, 159))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('CD44+CD24-low', 'Var', (34, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('increased', 'PosReg', (77, 86))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (135, 159))	('ductal carcinoma in situ', 'Disease', (135, 159))
81057	25624778	Increased numbers of both CSCs of CD44+CD24-low phenotype and cells underwent EMT in DCIS lesion might be an initial step in the stromal invasion and propagation of breast cancer, and occurrence of EMT in the breast tumor associated with high prevalence of CSCs, promoting tumor invasiveness and metastasis.	('breast tumor', 'Disease', (209, 221))	('metastasis', 'CPA', (296, 306))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('breast tumor', 'Phenotype', 'HP:0100013', (209, 221))	('CD44+CD24-low', 'Var', (34, 47))	('tumor invasiveness', 'Disease', (273, 291))	('promoting', 'PosReg', (263, 272))	('breast tumor', 'Disease', 'MESH:D001943', (209, 221))	('CSCs', 'Disease', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor invasiveness', 'Disease', 'MESH:D009369', (273, 291))
81076	25624778	In the present study, we try to analyze these CSCs (CD44+CD24-low) in different variants of primary human breast carcinoma using double-staining immunohistochemistry (IHC) and immu-nofluorescence (IF) and to correlate the presence of CSCs in associated metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('breast carcinoma', 'Disease', 'MESH:D001943', (106, 122))	('breast carcinoma', 'Disease', (106, 122))	('human', 'Species', '9606', (100, 105))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('CD44+CD24-low', 'Var', (52, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))
81080	25624778	Telomerase is an enzyme complex consisting of a human telomerase reverse transcriptase catalytic subunit (hTERT) and human telomerase RNA component for adding TTAGGG repeats to the end of the chromosome to maintain the length of the telomere.	('human', 'Species', '9606', (117, 122))	('human', 'Species', '9606', (48, 53))	('hTERT', 'Gene', '7015', (106, 111))	('length', 'MPA', (219, 225))	('maintain', 'Reg', (206, 214))	('TTAGGG repeats', 'Var', (159, 173))	('hTERT', 'Gene', (106, 111))
81090	25624778	Recent findings suggest that isolated CSC populations of CD44+CD24-low phenotype also exhibit telomerase activity and short telom-ere lengths similar to the parental cancer cell line.	('exhibit', 'Reg', (86, 93))	('CD44+CD24-low', 'Var', (57, 70))	('telomerase', 'Enzyme', (94, 104))	('parental cancer', 'Disease', 'MESH:D063129', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('parental cancer', 'Disease', (157, 172))
81101	25624778	demonstrated that CD44+CD24-low breast CSC signatures could be generated from CD44lowCD24+ nontumorigenic mammary epithelial cells.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('breast CSC signatures', 'CPA', (32, 53))	('CD44lowCD24+', 'Var', (78, 90))
81103	25624778	further demonstrated that the induction of non-tumorigenic, immortalized human mammary epithelial cells into EMT phenotype resulted in the loss of epithelial marker and the gain of mesenchymal markers concomitant with the acquisition of CD44+CD24low expression pattern and increased mammosphereforming ability as well as tumor-initiating capacity.	('mammosphereforming ability', 'CPA', (283, 309))	('mesenchymal markers', 'CPA', (181, 200))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('loss', 'NegReg', (139, 143))	('CD44+CD24low', 'Var', (237, 249))	('epithelial marker', 'Protein', (147, 164))	('human', 'Species', '9606', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('increased', 'PosReg', (273, 282))	('EMT', 'CPA', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (321, 326))	('gain', 'PosReg', (173, 177))	('expression', 'MPA', (250, 260))	('tumor', 'Disease', (47, 52))
81104	25624778	Whereas, isolated CD44+CD24low stem-like cells from normal and neoplastic human mammary cells exhibited a mesenchymal morphology and expressed mesenchymal markers such as vimentin and fibronectin.	('fibronectin', 'Gene', '2335', (184, 195))	('exhibited', 'Reg', (94, 103))	('CD44+CD24low', 'Var', (18, 30))	('fibronectin', 'Gene', (184, 195))	('vimentin', 'Protein', (171, 179))	('human', 'Species', '9606', (74, 79))	('mesenchymal morphology', 'CPA', (106, 128))	('expressed', 'Reg', (133, 142))
81106	25624778	Interestingly, the resulting mesenchymal tumor cells had a CD44+CD24low phenotype with the ability to reestablish an epithelial tumor.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CD44+CD24low', 'Var', (59, 71))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('epithelial tumor', 'Disease', (117, 133))	('tumor', 'Disease', (128, 133))	('epithelial tumor', 'Phenotype', 'HP:0031492', (117, 133))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('epithelial tumor', 'Disease', 'MESH:D002277', (117, 133))
81107	25624778	also found that the induction of EMT in transformed HMLER breast cancer cells by shRNA-mediated knock-down of E-cadherin expression displayed an increased population of CD44+CD24low, and these cells exhibited a ~100-fold enhanced mammosphere-forming ability compared to their epithelial phenotypic cells.	('E-cadherin', 'Protein', (110, 120))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('increased', 'PosReg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('knock-down', 'Var', (96, 106))	('EMT', 'CPA', (33, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('enhanced', 'PosReg', (221, 229))	('mammosphere-forming ability', 'CPA', (230, 257))	('CD44+CD24low', 'MPA', (169, 181))
81128	25624778	By using Dako Envision G 2 Doublestain System, Rabbit/Mouse (DAB+/Permanent Red), Code K5361, all cases that expressed CD44 were subjected for double-staining protocol to identify the CSCs (CD44+CD24-low) phenotype, while all the cases having vimentin-positive tumor cells and E-cadherin-negative tumor cells were subjected to double-staining protocol to identify the EMT phenomena.	('DAB', 'Chemical', 'MESH:C000469', (61, 64))	('CD44', 'Var', (119, 123))	('tumor', 'Disease', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('Rabbit', 'Species', '9986', (47, 53))	('Mouse', 'Species', '10090', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('tumor', 'Disease', (297, 302))
81145	25624778	to prepare single-cell suspension from FFPES was carried out as follows:  To evaluate and control the reliability of the CD44 and CD24 single staining, and immunohistochemical double staining of CSCs, a flow cytometric analysis with the same primary antibodies was performed in more than 10% of all cases, including 16 positive cases comprising CD44+CD24-low phenotypic tumor cells showing variable proportion of CSCs (CD44+CD24-low phenotype) and 4 negative cases devoid of any CSCs expressing CD44+CD24-low phenotype.	('PE', 'Chemical', '-', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('CD44+CD24-low', 'Var', (419, 432))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('CD44+CD24-low', 'Var', (345, 358))	('tumor', 'Disease', (370, 375))
81149	25624778	CD44+CD24-low subpopulation tumor cell was detected in the in situ carcinomas and in the invasive tumor cells as well as in the metastatic lymph node lesions and in the normal epithelium, when the latter were observable in the examined sections.	('situ carcinomas', 'Disease', 'MESH:D002278', (62, 77))	('tumor', 'Disease', (28, 33))	('situ carcinomas', 'Disease', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CD44+CD24-low', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (98, 103))	('invasive tumor', 'Disease', 'MESH:D009369', (89, 103))	('invasive tumor', 'Disease', (89, 103))
81151	25624778	Overall, in 167 cases of invasive breast carcinoma, CD44+CD24-low sub-population tumor cells were expressed in 73.7% (123/167).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (25, 50))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CD44+CD24-low', 'Var', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('invasive breast carcinoma', 'Disease', (25, 50))	('breast carcinoma', 'Phenotype', 'HP:0003002', (34, 50))	('tumor', 'Disease', (81, 86))
81158	25624778	The association between the CSC prevalence and classic prognostic factors, or independent variable and other clinicopathologic breast cancer parameters show that the CSC phenotype CD44+CD24-low is significantly correlated with tumor size.	('tumor', 'Disease', (227, 232))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('correlated', 'Reg', (211, 221))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('CD44+CD24-low', 'Var', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
81160	25624778	The CSC phenotype CD44+CD24-low was significantly increased in node-positive tumors (P < 0.0001).	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('increased', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD44+CD24-low', 'Var', (18, 31))
81164	25624778	CSCs, as determined by the phenotypic expression of CD44+CD24-low, were detected in 63 instances of primary invasive breast cancer and their metastatic lymph node lesions from the same patient.	('detected', 'Reg', (72, 80))	('patient', 'Species', '9606', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('CD44+CD24-low', 'Var', (52, 65))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
81200	25624778	It appeared that 91.4% (42/46) of the cases of invasive tumor that expressed EMT changes coincided with CSCs of CD44+CD24-low phenotype, but only 34%(42/123) of cases that showed CSCs co-expressed EMT changes, indicating that the occurrence of EMT phenomena was usually accompanied by the co- existence of CSCs of CD44+CD24-low phenotype.	('CD44+CD24-low', 'Var', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('invasive tumor', 'Disease', 'MESH:D009369', (47, 61))	('invasive tumor', 'Disease', (47, 61))
81205	25624778	In contrast to this notion, a previous hypothesis claimed that all tumor cell populations have the capacity to become tumorigenic through accumulation of mutations.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (154, 163))
81211	25624778	The present study demonstrates that the prevalence of breast CSC phenotype CD44+CD24-low was 73.7% (123/167) of all the tumors; in concordance with a previous study, Honeth et al.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('CD44+CD24-low', 'Var', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast CSC', 'Disease', (54, 64))
81212	25624778	demonstrating the CSC phenotype CD44+CD24-low in all their breast cancer samples.	('CD44+CD24-low', 'Var', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))
81216	25624778	reported that CD44+CD24-low breast cancer was not associated with clinical outcome, while Ricardo et al.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('CD44+CD24-low', 'Var', (14, 27))
81219	25624778	Breast cancer cells with CD44+CD24-low subpopulations express higher levels of proinvasive genes and have highly invasive properties.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('invasive properties', 'CPA', (113, 132))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('higher', 'PosReg', (62, 68))	('CD44+CD24-low', 'Var', (25, 38))	('levels of proinvasive genes', 'MPA', (69, 96))	('Breast cancer', 'Disease', (0, 13))
81226	25624778	who reported that there was no significant correlation between CD44+CD24-low tumor cell prevalence and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CD44+CD24-low', 'Var', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
81232	25624778	who found high percentages of CD44+CD24-low tumor cells in metastatic and recurrent lesion.	('CD44+CD24-low', 'Var', (30, 43))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
81266	25624778	We hypothesize that vimentin expression in breast carcinoma may be due to one of the following:  Cancer cells that have undergone EMT reportedly display the CD44+CD24-low phenotype.	('expression', 'Reg', (29, 39))	('breast carcinoma', 'Disease', (43, 59))	('breast carcinoma', 'Disease', 'MESH:D001943', (43, 59))	('CD44+CD24-low', 'Var', (157, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('breast carcinoma', 'Phenotype', 'HP:0003002', (43, 59))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('vimentin', 'Protein', (20, 28))
81275	25624778	CD44+CD24-low phenotype tumor cells seem to be related to CSCs with certain levels of differentiation and are confined to a distinct molecular subclass of breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('CSCs', 'Disease', (58, 62))	('tumor', 'Disease', (24, 29))	('CD44+CD24-low', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('related', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
81276	25624778	Because we failed to detect breast CSCs in about 30% (44/167) of the cases, these findings suggest that tumor-initiating properties are not wholly confined to CD44+CD24-low cells and other new biomarkers need to be identified.	('CD44+CD24-low', 'Var', (159, 172))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
81279	25624778	It is worthy to suggest that breast CSCs of CD44+CD24-low phenotype should be included in future validation studies as a prognostic marker in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('CD44+CD24-low', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))
81280	25624778	Estimating the frequency of breast CSCs in different variants of breast cancer can predict the clinical course of the disease and give prognostic clues for different variants of breast cancer.	('predict', 'Reg', (83, 90))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancer', 'Disease', (178, 191))	('variants', 'Var', (53, 61))
81285	25624778	Estimation of the frequency of CSCs and telomerase activity in different variants of breast cancer can predict the clinical course of the disease and give prognostic clues for different variants of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('breast cancer', 'Disease', (85, 98))	('predict', 'Reg', (103, 110))	('variants', 'Var', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', (198, 211))
81292	25624778	Our findings suggest that the increased proportion and prevalence of tumor cells with CD44+CD24-low and vimentin+/E-cadherin- phenotype in DCIS and metastatic lesions may play an important role in tumor invasiveness and aggressiveness, in addition to being a higher metastatic risk of the breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('aggressiveness', 'Disease', 'MESH:D001523', (220, 234))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('tumor', 'Disease', (69, 74))	('tumor invasiveness', 'Disease', (197, 215))	('tumor invasiveness', 'Disease', 'MESH:D009369', (197, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (289, 302))	('breast cancer', 'Disease', 'MESH:D001943', (289, 302))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('aggressiveness', 'Disease', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('breast cancer', 'Disease', (289, 302))	('CD44+CD24-low', 'Var', (86, 99))	('aggressiveness', 'Phenotype', 'HP:0000718', (220, 234))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (197, 202))
81300	23418461	In contrast, SnoN expression in the stroma is highly upregulated in the infiltrating inflammatory cells in high-grade esophageal and ovarian tumor samples, suggesting that SnoN may potentially promote malignant progression through modulating the tumor microenvironment in these tumor types.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('malignant progression', 'CPA', (201, 222))	('promote', 'PosReg', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('ovarian tumor', 'Phenotype', 'HP:0100615', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('SnoN', 'Var', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('expression', 'MPA', (18, 28))	('modulating', 'Reg', (231, 241))	('ovarian tumor', 'Disease', (133, 146))	('tumor', 'Disease', (278, 283))	('ovarian tumor', 'Disease', 'MESH:D010051', (133, 146))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('SnoN', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (141, 146))	('upregulated', 'PosReg', (53, 64))
81302	23418461	However, in human cancer cell lines with amplification of the snoN gene, a strong correlation between increased SnoN copy number and inactivation of p53 was detected, suggesting that the tumor suppressor SnoN-p53 pathway must be inactivated, either through downregulation of SnoN or inactivation of p53, in order to allow cancer cell to proliferate and survive.	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('tumor', 'Disease', (187, 192))	('cancer', 'Disease', (18, 24))	('inactivation', 'Var', (283, 295))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('p53', 'Gene', '7157', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('amplification', 'Var', (41, 54))	('p53', 'Gene', '7157', (299, 302))	('p53', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (322, 328))	('downregulation', 'NegReg', (257, 271))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('p53', 'Gene', '7157', (209, 212))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('p53', 'Gene', (299, 302))	('SnoN', 'Gene', (275, 279))	('human', 'Species', '9606', (12, 17))	('p53', 'Gene', (209, 212))
81323	23418461	In this report, we examined SnoN expression in four types of normal human tissues and matching cancer tissues of various clinical stages of malignancy to assess whether alterations of SnoN expression correlate with tumor malignancy and/or status of p53 inactivation.	('alterations', 'Var', (169, 180))	('human', 'Species', '9606', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('malignancy', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (95, 101))	('tumor malignancy', 'Disease', (215, 231))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('malignancy', 'Disease', 'MESH:D009369', (221, 231))	('SnoN', 'Gene', (184, 188))	('p53', 'Gene', (249, 252))	('p53', 'Gene', '7157', (249, 252))	('malignancy', 'Disease', (221, 231))	('inactivation', 'Var', (253, 265))	('tumor malignancy', 'Disease', 'MESH:D018198', (215, 231))	('malignancy', 'Disease', (140, 150))
81330	23418461	By examining the location and levels of SnoN expression in these tissues, we hope to gain a better understanding of the functions that SnoN play during tumorigenesis in both the epithelium and stromal environment and how this may correlate with p53 inactivation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', (245, 248))	('tumor', 'Disease', (152, 157))	('p53', 'Gene', '7157', (245, 248))	('inactivation', 'Var', (249, 261))
81359	23418461	For analysis of potential association of TP53 mutation and SKIL amplification, we performed data mining of the Novartis cell line encyclopedia (CLE) that contains 947 human cancer cell lines, in which copy numbers and mutations of SnoN (SKIL) and p53 genes have been characterized using Affymetrix SNP6 microarray or RNAseq.	('TP53', 'Gene', '7157', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('TP53', 'Gene', (41, 45))	('SKIL', 'Gene', '6498', (237, 241))	('Novartis cell line encyclopedia', 'Disease', (111, 142))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (218, 227))	('human', 'Species', '9606', (167, 172))	('SKIL', 'Gene', (59, 63))	('p53', 'Gene', '7157', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('SKIL', 'Gene', (237, 241))	('Novartis cell line encyclopedia', 'Disease', 'MESH:C538614', (111, 142))	('SnoN', 'Gene', (231, 235))	('SKIL', 'Gene', '6498', (59, 63))	('p53', 'Gene', (247, 250))
81394	23418461	The model further predicts that in order for tumor cells to overcome the tumor suppressive activity of the SnoN-p53 pathway, they have to either inactivate p53 or delete SnoN.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('delete', 'Var', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (45, 50))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (73, 78))	('p53', 'Gene', (112, 115))	('SnoN', 'Gene', (170, 174))	('inactivate', 'NegReg', (145, 155))	('p53', 'Gene', '7157', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
81398	23418461	We analyzed 914 cancer cell lines in the Novartis cell line encyclopedia (CLE), in which copy numbers and mutations of SnoN and p53 genes were characterized using Affymetrix SNP6 microarray or RNAseq technology, to determine whether samples with increased copy number of the SnoN gene also tend to show inactivation of p53 as indicated by a loss of p53 copy number or the presence of known inactivating mutations.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p53', 'Gene', '7157', (319, 322))	('copy number', 'Var', (256, 267))	('SnoN', 'Gene', (275, 279))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('inactivation', 'NegReg', (303, 315))	('loss', 'NegReg', (341, 345))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('Novartis cell line encyclopedia', 'Disease', 'MESH:C538614', (41, 72))	('copy number', 'MPA', (353, 364))	('increased', 'PosReg', (246, 255))	('p53', 'Gene', (349, 352))	('p53', 'Gene', (319, 322))	('p53', 'Gene', '7157', (349, 352))	('Novartis cell line encyclopedia', 'Disease', (41, 72))
81399	23418461	Based on the mutation status of p53, we classified cell lines into mutant or wild type, and copy number of SnoN were compared among these two groups.	('p53', 'Gene', (32, 35))	('mutation', 'Var', (13, 21))	('p53', 'Gene', '7157', (32, 35))
81400	23418461	As shown in Figure 6A, we identified significant enrichment of SnoN amplification events in p53 mutant or p53 deleted cell lines (p value: 7.25E-009), indicating a potential association between the two genetic events.	('p53', 'Gene', '7157', (106, 109))	('SnoN amplification', 'MPA', (63, 81))	('mutant', 'Var', (96, 102))	('deleted', 'Var', (110, 117))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))	('p53', 'Gene', (106, 109))
81402	23418461	A striking correlation between the frequency of p53 mutation and the frequency of SnoN amplification was detected (The Pearson's correlation coefficient was 0.7), where the lineages with higher incidence of p53 mutation tended to have higher incidence of SnoN amplification (Figure 6B).	('p53', 'Gene', (48, 51))	('SnoN amplification', 'MPA', (255, 273))	('p53', 'Gene', '7157', (48, 51))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('mutation', 'Var', (211, 219))
81411	23418461	Together our study suggests that SnoN is likely to play a tumor suppressor role in the initial stages of human cancer development, and inactivation of this pathway by targeting either SnoN itself or p53 is necessary for malignant progression.	('human', 'Species', '9606', (105, 110))	('tumor', 'Disease', (58, 63))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('SnoN', 'Gene', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('inactivation', 'Var', (135, 147))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
81428	23418461	Interestingly, the cancers of esophagus and ovary tend to harbor 3q26 amplification and show SnoN copy number increases, and they also display a stronger increase in stroma SnoN levels.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('SnoN copy number', 'MPA', (93, 109))	('increases', 'PosReg', (110, 119))	('cancers of esophagus and ovary', 'Disease', 'MESH:D004938', (19, 49))	('stroma', 'MPA', (166, 172))	('3q26', 'Protein', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('increase', 'PosReg', (154, 162))	('amplification', 'Var', (70, 83))
81434	23418461	Thus, tissues or cells that show elevated SnoN expression (either due to gene amplification or other means) may cease proliferation due to p53-mediated senescence or cell cycle arrest.	('elevated', 'PosReg', (33, 41))	('cease', 'NegReg', (112, 117))	('gene amplification', 'Var', (73, 91))	('SnoN', 'Gene', (42, 46))	('cell cycle arrest', 'CPA', (166, 183))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (166, 183))
81435	23418461	Malignant cells have to overcome this barrier in order to maintain their survival and expansion and may do so by either inactivating/deleting SnoN itself or any downstream steps in the SnoN-p53 pathway.	('inactivating/deleting', 'NegReg', (120, 141))	('SnoN', 'Gene', (142, 146))	('p53', 'Gene', '7157', (190, 193))	('p53', 'Gene', (190, 193))	('inactivating/deleting', 'Var', (120, 141))
81457	22091428	The remaining 37 cases, representing 19.7% of the ER/PgR-negative carcinomas and 5.2% of the total group of breast carcinomas, were the subject of ER/PgR status of DCIS that occurs in association with ER/PR-negative invasive breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (108, 124))	('breast carcinomas', 'Phenotype', 'HP:0003002', (108, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (216, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('carcinomas', 'Disease', 'MESH:D002277', (115, 125))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('breast carcinoma', 'Phenotype', 'HP:0003002', (225, 241))	('invasive breast carcinoma', 'Disease', (216, 241))	('carcinomas', 'Disease', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('breast carcinomas', 'Disease', 'MESH:D001943', (108, 125))	('breast carcinomas', 'Disease', (108, 125))	('ER/PgR', 'Var', (147, 153))
81511	20160274	We contrasted patients' perceived risk-of-recurrence categories with their calculated risk categories, creating four accuracy-of-perceived-risk categories: underestimated (perceived < calculated risk), accurate (patient's perceived risk fell in the same category as her calculated risk), overestimated (perceived > calculated risk), or uncertain (patients reported not knowing their risk).	('patient', 'Species', '9606', (212, 219))	('overestimated', 'PosReg', (288, 301))	('perceived > calculated', 'Var', (303, 325))	('patient', 'Species', '9606', (14, 21))	('patient', 'Species', '9606', (347, 354))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (347, 355))	('underestimated', 'NegReg', (156, 170))
81530	20160274	The role of higher perceived risk in motivating screening mammography in women without a history of breast cancer suggests that underestimating one's risk of recurrence might contribute to being less likely to receive post-treatment surveillance mammography in African American patients compared with white survivors.	('women', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('less', 'NegReg', (195, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('underestimating', 'Var', (128, 143))	('breast cancer', 'Disease', (100, 113))	('patients', 'Species', '9606', (278, 286))
81531	20160274	Although DCIS patients generally have a lower risk of recurrence after treatment and only about 1% die from breast cancer, DCIS patients were more likely than EIBC patients to overestimate their risk of recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('DCIS', 'Var', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EIBC', 'Chemical', '-', (159, 163))	('patients', 'Species', '9606', (164, 172))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (14, 22))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
81608	22655185	A recent overview of the randomized trials of radiotherapy in DCIS showed that radiotherapy reduced the absolute 10-year risk of ipsilateral recurrent DCIS by 8.4% and of ipsilateral invasive cancer by 8.5% (both P < 0.00001).	('ipsilateral recurrent DCIS', 'Disease', (129, 155))	('invasive cancer', 'Disease', 'MESH:D009362', (183, 198))	('ipsilateral invasive cancer', 'Disease', 'MESH:D009362', (171, 198))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('radiotherapy', 'Var', (79, 91))	('reduced', 'NegReg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ipsilateral invasive cancer', 'Disease', (171, 198))
81619	29133591	CCR2 overexpression increased SUM225 breast cancer survival and invasion associated with accumulation of CCL2 expressing fibroblasts.	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('accumulation', 'PosReg', (89, 101))	('invasion', 'CPA', (64, 72))	('CCL2', 'Gene', '6347', (105, 109))	('CCR2', 'Gene', (0, 4))	('overexpression increased', 'PosReg', (5, 29))	('SUM225', 'Var', (30, 36))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('CCL2', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
81627	29133591	Estrogen receptor (ER), Her2, Ki67, p16 and Cox2 are associated with disease recurrence but not with development of invasive breast cancer.	('Estrogen receptor', 'Gene', '2099', (0, 17))	('disease recurrence', 'Disease', (69, 87))	('Ki67', 'Var', (30, 34))	('Cox2', 'Gene', '4513', (44, 48))	('invasive breast cancer', 'Disease', 'MESH:D001943', (116, 138))	('Cox2', 'Gene', (44, 48))	('p16', 'Gene', '1029', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Estrogen receptor', 'Gene', (0, 17))	('Her2', 'Gene', (24, 28))	('associated', 'Reg', (53, 63))	('ER', 'Gene', '2099', (19, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('invasive breast cancer', 'Disease', (116, 138))	('p16', 'Gene', (36, 39))	('Her2', 'Gene', '2064', (24, 28))
81652	29133591	To generate lentivirus, 3.33 mug of PMD2G (Addgene cat no.12260), 6.66 mug PDPAX2 (Addgene cat no.12259) and 10 mug target vectors were co-transfected in HEK-293T cells using Lipofectamine 2000 (ThermoFisher cat no.	('PMD2G', 'Var', (36, 41))	('HEK-293T', 'CellLine', 'CVCL:0063', (154, 162))	('Lipofectamine', 'Chemical', 'MESH:C086724', (175, 188))	('rat', 'Species', '10116', (7, 10))	('PDPAX2', 'Gene', (75, 81))
81672	29133591	Endogenous peroxidases were quenched in PBS/60 % methanol/3% H2O2, blocked in PBS/3% FBS, and incubated with primary antibodies (1:100) overnight at 4 C: collagen IV (Novus Biologicals NB120-6586SS), cleaved caspase-3 Asp175 (Cell Signaling Technology cat no.	('FBS', 'Disease', 'MESH:D005198', (85, 88))	('caspase-3', 'Gene', (208, 217))	('PBS', 'Disease', 'MESH:D011535', (40, 43))	('cleaved', 'Var', (200, 207))	('quenched', 'NegReg', (28, 36))	('Endogenous', 'Enzyme', (0, 10))	('PBS', 'Disease', (40, 43))	('FBS', 'Disease', (85, 88))	('PBS', 'Disease', 'MESH:D011535', (78, 81))	('PBS', 'Disease', (78, 81))	('caspase-3', 'Gene', '836', (208, 217))
81712	29133591	A1110501), washed in PBS and incubated with anti-CCR2-PE for 1 hour on ice.	('PBS', 'Disease', 'MESH:D011535', (21, 24))	('PBS', 'Disease', (21, 24))	('A1110501', 'Var', (0, 8))
81725	29133591	By flow cytometry, CCR2 expression was significantly lower in SUM225 cells compared to DCIS.com breast cancer cells (Figure 1A).	('CCR2', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (24, 34))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('lower', 'NegReg', (53, 58))	('SUM225', 'Var', (62, 68))
81736	29133591	CCR2 overexpression was also associated with increased cell proliferation and decreased apoptosis as indicated by Ki67 and cleaved caspase-3 staining (Figure 1D-E).	('apoptosis', 'CPA', (88, 97))	('rat', 'Species', '10116', (67, 70))	('caspase-3', 'Gene', (131, 140))	('increased', 'PosReg', (45, 54))	('caspase-3', 'Gene', '836', (131, 140))	('CCR2', 'Gene', (0, 4))	('cell proliferation', 'CPA', (55, 73))	('decreased', 'NegReg', (78, 87))	('overexpression', 'Var', (5, 19))
81738	29133591	CCR2 knockdown (CCR2-KD) decreased mammary tissue tumor growth compared to control shRNA expressing xenografts (Figure 2B).	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CCR2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
81741	29133591	CCR2 KD was also associated with decreased tumor cell proliferation and increased apoptosis (Figure 2D-E).	('CCR2 KD', 'Var', (0, 7))	('increased', 'PosReg', (72, 81))	('apoptosis', 'CPA', (82, 91))	('decreased tumor', 'Disease', 'MESH:D009369', (33, 48))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('decreased tumor', 'Disease', (33, 48))
81747	29133591	There were no significant changes in VWF8 or F4/80 expression with CCR2 overexpression or knockdown (Supplemental Figure S4A-B).	('knockdown', 'Var', (90, 99))	('F4/80', 'Gene', (45, 50))	('CCR2', 'Gene', (67, 71))	('F4/80', 'Gene', '13733', (45, 50))	('expression', 'MPA', (51, 61))	('VWF', 'Gene', '7450', (37, 40))	('overexpression', 'PosReg', (72, 86))	('VWF', 'Gene', (37, 40))
81751	29133591	These data indicate that CCR2 overexpression or knockdown is associated with changes in CCL2 expressing fibroblasts in the DCIS stroma.	('changes', 'Reg', (77, 84))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('overexpression', 'PosReg', (30, 44))	('CCR2', 'Gene', (25, 29))	('CCL2', 'Gene', '6347', (88, 92))	('CCL2', 'Gene', (88, 92))	('knockdown', 'Var', (48, 57))
81760	29133591	CCR2 deficient DCIS.com cells co-grafted with 1213-249 fibroblasts showed a significant 20% decrease in tumor mass compared to fibroblasts co-grafted with control DCIS.com cells (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('decrease', 'NegReg', (92, 100))	('tumor', 'Disease', (104, 109))	('CCR2', 'Gene', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('deficient', 'Var', (5, 14))
81765	29133591	CCR2 deficient cells co-grafted with fibroblasts showed a reduction in tumor invasion, characterized by more cohesive tumors and a clearer delineation between tumor and kidney tissues (Figure 5C).	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CCR2', 'Gene', (0, 4))	('cohesive tumors', 'Disease', 'MESH:D009369', (109, 124))	('tumor', 'Disease', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('cohesive tumors', 'Disease', (109, 124))	('more', 'PosReg', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('reduction', 'NegReg', (58, 67))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('deficient', 'Var', (5, 14))
81768	29133591	These studies indicate that CCR2 knockdown in DCIS.com breast cancer cells inhibits fibroblast-mediated tumor growth and invasion.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('knockdown', 'Var', (33, 42))	('tumor', 'Disease', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('CCR2', 'Gene', (28, 32))	('breast cancer', 'Disease', (55, 68))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('inhibits', 'NegReg', (75, 83))
81789	29133591	However, whereas CCR2 knockdown significantly affected mammary tumor mass, CCR2 overexpression did not.	('tumor', 'Disease', (63, 68))	('CCR2', 'Gene', (17, 21))	('knockdown', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('affected', 'Reg', (46, 54))
81819	27756325	In 2D culture, breast cancer cells expressing high levels of MT1-MMP were capable of widespread ECM degradation and TIMP-2-mediated proMMP-2 activation, but were not the most migratory.	('MMP-2', 'Gene', '4313', (135, 140))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('MMP-2', 'Gene', (135, 140))	('MT1-MMP', 'Var', (61, 68))	('breast cancer', 'Disease', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
81820	27756325	In 3D culture, MCF-7 breast cancer cells expressing low levels of MT1-MMP demonstrated an invasive protrusive phenotype, whereas cells expressing high levels of MT1-MMP demonstrated loss of colony structure and cell fragment release.	('loss', 'NegReg', (182, 186))	('MT1-MMP', 'Var', (66, 73))	('cell fragment release', 'CPA', (211, 232))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (15, 34))	('MCF-7 breast cancer', 'Disease', (15, 34))	('colony structure', 'CPA', (190, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('invasive protrusive phenotype', 'CPA', (90, 119))
81821	27756325	Similarly, in vivo analysis demonstrated increased tumourigenecity and metastatic capability for cells expressing low levels of MT1-MMP, whereas cells expressing high levels were devoid of these qualities despite the production of functional MT1-MMP protein.	('increased', 'PosReg', (41, 50))	('MT1-MMP', 'Var', (128, 135))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('metastatic capability', 'CPA', (71, 92))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
81822	27756325	This study demonstrates that excessive ECM degradation mediated by high levels of MT1-MMP is not associated with cell migration and tumourigenesis, while low levels of MT1-MMP promote invasion and vascularization in vivo.	('tumour', 'Disease', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('MT1-MMP', 'Var', (82, 89))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('promote', 'PosReg', (176, 183))
81828	27756325	As a result of its proteolytic activity, MT1-MMP can cleave ECM and non-ECM substrates, and participates in activation of the pro-forms of MMP-2 and MMP-9.	('MT1-MMP', 'Var', (41, 48))	('proteolytic', 'MPA', (19, 30))	('MMP-2', 'Gene', '4313', (139, 144))	('MMP-9', 'Gene', '4318', (149, 154))	('MMP-9', 'Gene', (149, 154))	('MMP-2', 'Gene', (139, 144))	('activation', 'PosReg', (108, 118))
81829	27756325	MT1-MMP also signals through the ERK and AKT pathways and mediates HIF-1alpha stabilization via non-proteolytic mechanisms.	('HIF-1alpha', 'Gene', '3091', (67, 77))	('stabilization', 'MPA', (78, 91))	('HIF-1alpha', 'Gene', (67, 77))	('AKT', 'Gene', '207', (41, 44))	('signals', 'Reg', (13, 20))	('AKT', 'Gene', (41, 44))	('MT1-MMP', 'Var', (0, 7))
81830	27756325	Moreover, it has been shown that MT1-MMP overexpression also increases the migratory ability of breast cancer cells independent of its proteolytic activity.	('migratory ability', 'CPA', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('MT1-MMP', 'Var', (33, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('increases', 'PosReg', (61, 70))
81832	27756325	However, reported data reveal contradictions regarding the requirement for TIMP-2 in increasing migratory potential, as some report the necessity for TIMP-2 to increase migration of cancer cells overexpressing MT1-MMP, whereas others did not using similar cell models.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('MT1-MMP', 'Var', (210, 217))	('migration', 'CPA', (169, 178))	('increase', 'PosReg', (160, 168))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('migratory potential', 'CPA', (96, 115))	('cancer', 'Disease', (182, 188))
81836	27756325	These observations are consistent across platforms, both ex vivo with 3D cell culture, and with in vivo tumourigenesis and cancer cell extravasation assays, which all demonstrate that low MT1-MMP expression is optimal to induce a protrusive phenotype, increased invasiveness and metastatic capability in vivo.	('protrusive phenotype', 'CPA', (230, 250))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('invasiveness', 'CPA', (262, 274))	('MT1-MMP', 'Protein', (188, 195))	('low', 'Var', (184, 187))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (123, 129))	('increased', 'PosReg', (252, 261))	('induce', 'PosReg', (221, 227))	('metastatic capability', 'CPA', (279, 300))	('tumour', 'Disease', (104, 110))
81841	27756325	Human MT1-MMP (sc116990), TIMP-2 (sc118083) and MMP-2 (sc321560) cDNA clones were purchased from Origene and subcloned into the vector pcDNA 3.3 (Thermo Fisher).	('Human', 'Species', '9606', (0, 5))	('sc118083', 'Var', (34, 42))	('MMP-2', 'Gene', (48, 53))	('MMP-2', 'Gene', '4313', (48, 53))	('sc321560', 'Var', (55, 63))	('sc116990', 'Var', (15, 23))
81844	27756325	For immunoblot analysis, the following primary antibodies were used: MT1-MMP (1:1000, AB6004, Millipore); MT1-MMP (1:1000, AB51074, Abcam); Phospho-ERK1/2 (1:2000, D13.14.4E), ERK1/2 (1:2000, 137 F5) (Cell Signaling Technology); TIMP-2 (1:1000, 3A4), beta-Actin (1:1000, C4), and phospho-histone-3 (PH3) (1:5000, C1513) (Santa Cruz).	('beta-Actin', 'Gene', (251, 261))	('1:5000', 'Var', (305, 311))	('beta-Actin', 'Gene', '11461', (251, 261))	('1:1000', 'Var', (263, 269))	('C1513', 'Var', (313, 318))
81889	27756325	Gelatin zymography analysis demonstrated that MCF-7 cells transiently transfected with MT1-MMP are capable of activating proMMP-2 after 24 h of incubation with MMP-2 CM, as shown by the transition to the intermediate and active isoforms of MMP-2.	('MMP-2', 'Gene', (160, 165))	('MMP-2', 'Gene', '4313', (124, 129))	('MT1-MMP', 'Var', (87, 94))	('MMP-2', 'Gene', '4313', (160, 165))	('MMP-2', 'Gene', (240, 245))	('activating', 'MPA', (110, 120))	('MCF-7', 'CellLine', 'CVCL:0031', (46, 51))	('active', 'MPA', (221, 227))	('transition', 'MPA', (186, 196))	('MMP-2', 'Gene', (124, 129))	('MMP-2', 'Gene', '4313', (240, 245))
81890	27756325	Parental MCF-7 cells, which do not secrete endogenous proMMP-2, did not increase MMP-2 production after transfection with MT1-MMP, as determined by gelatin zymography (Fig.	('MMP-2', 'Gene', (57, 62))	('MMP-2', 'Gene', '4313', (57, 62))	('MMP-2', 'Gene', '4313', (81, 86))	('MCF-7', 'CellLine', 'CVCL:0031', (9, 14))	('MT1-MMP', 'Var', (122, 129))	('MMP-2', 'Gene', (81, 86))
81903	27756325	A low percentage of MT1-MMP C3 cells (~1.5 %) showed ECM degradation, and a higher percentage (~3 %) showed a cytoplasmic MT1-MMP signal, although these amounts were non-significantly different than parental MCF-7 cells.	('MT1-MMP', 'Var', (20, 27))	('ECM', 'MPA', (53, 56))	('cytoplasmic MT1-MMP signal', 'MPA', (110, 136))	('MCF-7', 'CellLine', 'CVCL:0031', (208, 213))
81907	27756325	Additionally, the pattern of ECM degradation and cytoplasmic MT1-MMP protein in MDA-MB 231 cells is most consistent with those of C3 cells, suggesting that cells that express low levels of MT1-MMP acquire invasive capabilities, despite reports that suggest high levels of MT1-MMP are typically needed for such phenotypes.	('MDA-MB 231', 'CellLine', 'CVCL:0062', (80, 90))	('invasive capabilities', 'CPA', (205, 226))	('MT1-MMP', 'Var', (189, 196))	('acquire', 'PosReg', (197, 204))
81914	27756325	Taken together, this analysis confirmed the functionality of our TIMP-2/ALA + TIMP-2 CMs and demonstrated how MCF-7 cells producing high levels of MT1-MMP protein follow the well-defined mechanism described for MT1-MMP/TIMP2 mediated activation of proMMP-2.	('TIMP2', 'Gene', (219, 224))	('MMP-2', 'Gene', (251, 256))	('ALA', 'Chemical', 'MESH:D000409', (72, 75))	('MCF-7', 'CellLine', 'CVCL:0031', (110, 115))	('MMP-2', 'Gene', '4313', (251, 256))	('MT1-MMP', 'Var', (147, 154))	('TIMP2', 'Gene', '7077', (219, 224))
81923	27756325	Migration was then examined using transwell assays where the cells were incubated in SF media containing TIMP-2 and ALA + TIMP-2 CMs in the upper compartment and allowed to migrate towards the lower compartment containing 10 % FBS.	('TIMP-2', 'Var', (105, 111))	('FBS', 'Disease', 'MESH:D005198', (227, 230))	('ALA', 'Chemical', 'MESH:D000409', (116, 119))	('FBS', 'Disease', (227, 230))
81924	27756325	TIMP-2 CM caused a significant increase in the number of migrated C2 and C3 cells, while ALA + TIMP-2 CM also caused a significant increase in the number migrated C3 cells (Fig.	('ALA', 'Chemical', 'MESH:D000409', (89, 92))	('increase', 'PosReg', (131, 139))	('TIMP-2 CM', 'Var', (0, 9))	('increase', 'PosReg', (31, 39))
81928	27756325	Migration of these C3 cell line variants were assayed during incubation in SF media containing TIMP-2 or ALA + TIMP-2 CM, or ALA + TIMP-2 CM along with the ERK inhibitor U0126 (10 muM).	('U0126', 'Chemical', 'MESH:C113580', (170, 175))	('muM', 'Gene', '56925', (180, 183))	('ALA', 'Chemical', 'MESH:D000409', (125, 128))	('ALA', 'Var', (125, 128))	('muM', 'Gene', (180, 183))	('ALA', 'Chemical', 'MESH:D000409', (105, 108))	('ALA', 'Var', (105, 108))
81935	27756325	Viability measurements of the C3 knockdown variants demonstrated that MT1-MMP is responsible for enhanced viability during SF incubation as C3 SH 2 cells, which are MT1-MMP deficient similar to parental MCF-7 cells, are less viable than other cell lines at day 6, and show the same viability as MCF-7 cells at day 9.	('MCF-7', 'CellLine', 'CVCL:0031', (203, 208))	('viability', 'MPA', (106, 115))	('enhanced', 'PosReg', (97, 105))	('variants', 'Var', (43, 51))	('MCF-7', 'CellLine', 'CVCL:0031', (295, 300))
81941	27756325	Furin inhibitor (which would inhibit intracellular activation of MT1-MMP) showed a non-significant dose dependent decrease in the viability of cells expressing MT1-MMP, a trend not seen in MCF-7 parental cells, indicating that high levels of pro-MT1-MMP likely negatively mediated viability.	('viability', 'CPA', (130, 139))	('MCF-7', 'CellLine', 'CVCL:0031', (189, 194))	('negatively', 'NegReg', (261, 271))	('Furin', 'Gene', '5045', (0, 5))	('Furin', 'Gene', (0, 5))	('MT1-MMP', 'Var', (160, 167))	('decrease', 'NegReg', (114, 122))
81951	27756325	C1 cells, which express the highest level of MT1-MMP and are the least migratory under control conditions, markedly improved their migratory potential during BB94 incubation as 73 % of cells migrated more than 25 mum (compared to 53 % in control conditions).	('MT1-MMP', 'Var', (45, 52))	('mum', 'Gene', '56925', (213, 216))	('mum', 'Gene', (213, 216))	('BB94', 'Chemical', 'MESH:C080985', (158, 162))	('migratory potential', 'CPA', (131, 150))	('improved', 'PosReg', (116, 124))
81954	27756325	Taken together, this analysis demonstrated that low levels of MT1-MMP expression (11 fold compared to parental cells) are optimal for increased migratory ability of MCF-7 breast cancer cells, whereas high MT1-MMP overexpression (>1000 fold) does not increase migration but allows for widespread ECM degradation.	('MT1-MMP', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('migratory ability', 'CPA', (144, 161))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (165, 184))	('MCF-7 breast cancer', 'Disease', (165, 184))	('increased', 'PosReg', (134, 143))
81960	27756325	Transwell migration assays demonstrated that MDA-MB 231 and HS578t were significantly more migratory than MCF-7 cells (Fig.	('MCF-7', 'CellLine', 'CVCL:0031', (106, 111))	('HS578t', 'Var', (60, 66))	('HS578t', 'CellLine', 'CVCL:0332', (60, 66))	('migratory', 'CPA', (91, 100))	('more', 'PosReg', (86, 90))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (45, 55))
81961	27756325	Importantly, HS578t cells were significantly more migratory than MDA-MB 231 cells even though they express lower levels of MT1-MMP.	('migratory', 'CPA', (50, 59))	('HS578t', 'Var', (13, 19))	('more', 'PosReg', (45, 49))	('HS578t', 'CellLine', 'CVCL:0332', (13, 19))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (65, 75))
81962	27756325	We then tested how overexpression of MT1-MMP in MDA-MB 231 cells affects the migration of cells that natively express MT1-MMP and have endogenous migratory ability.	('tested', 'Reg', (8, 14))	('MT1-MMP', 'Var', (118, 125))	('migration', 'CPA', (77, 86))	('affects', 'Reg', (65, 72))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (48, 58))
81965	27756325	Transwell migration analysis of these MDA-MB 231 MT1-MMP cell lines showed that overexpression of MT1-MMP significantly decreased their migratory potential compared to parental MDA-MB 231 cells (Fig.	('decreased', 'NegReg', (120, 129))	('migratory potential', 'CPA', (136, 155))	('MDA-MB 231 MT1', 'CellLine', 'CVCL:0062', (38, 52))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (177, 187))	('MT1-MMP', 'Var', (98, 105))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (38, 48))
81976	27756325	This quantification demonstrated that MCF-7 expressing high levels of MT1-MMP (C1 and C2) had significantly higher number of disseminations per colony than MCF-7 and C3 cells, particularly C1 cells which showed a time-dependent release of particles (Additional file 10).	('MT1-MMP', 'Var', (70, 77))	('MCF-7', 'CellLine', 'CVCL:0031', (156, 161))	('MCF-7', 'CellLine', 'CVCL:0031', (38, 43))	('higher', 'PosReg', (108, 114))
81979	27756325	9b), confirmed that while MCF-7 colonies retained circularity during 3D culture (white arrows), C1 and C2 cells had clear disorganization of colony structure with released cell fragments (disseminations) containing MT1-MMP protein (green arrows).	('MCF-7', 'CellLine', 'CVCL:0031', (26, 31))	('disorganization', 'NegReg', (122, 137))	('colony structure', 'CPA', (141, 157))	('MT1-MMP', 'Var', (215, 222))	('circularity', 'CPA', (50, 61))
81988	27756325	In contrast, all MDA-MB 231 cells expressing MT1-MMP showed a significant inhibition to form networks in 3D culture and instead retained a large proportion of circular colonies (Fig.	('MT1-MMP', 'Var', (45, 52))	('circular colonies', 'CPA', (159, 176))	('inhibition', 'NegReg', (74, 84))	('form networks in 3D culture', 'CPA', (88, 115))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (17, 27))
82009	27756325	Our data is at odds with the notion that high MT1-MMP expression is crucial for tumour progression, as numerous studies report that MT1-MMP overexpression is associated with enhanced migratory ability and tumourigenecity, although there is also evidence in agreement with our study which shows that high MT1-MMP overexpression is insufficient to increase metastasis of human cancer cells.	('tumour', 'Disease', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('enhanced', 'PosReg', (174, 182))	('MT1-MMP overexpression', 'Var', (132, 154))	('tumour', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('overexpression', 'Var', (140, 154))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (369, 374))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (375, 381))	('migratory ability', 'CPA', (183, 200))
82011	27756325	Here, using MCF-7 clonal cell lines stably expressing untagged MT1-MMP, we show that migration, as shown by a scratch closure assay and by time-lapse microscopy of cells on fluorescent substrate, is dependent on levels of MT1-MMP, with high levels decreasing migratory ability and low levels promoting it.	('promoting', 'PosReg', (292, 301))	('scratch closure', 'CPA', (110, 125))	('migration', 'CPA', (85, 94))	('decreasing', 'NegReg', (248, 258))	('MCF-7', 'CellLine', 'CVCL:0031', (12, 17))	('MT1-MMP', 'Var', (222, 229))	('migratory ability', 'CPA', (259, 276))
82013	27756325	In contrast, there are studies demonstrating that MT1-MMP overexpression does not increase migration of breast cancer cells, and also that MT1-MMP overexpression decreases ERK activation in cancer cells.	('decreases ERK', 'Phenotype', 'HP:0000654', (162, 175))	('cancer', 'Disease', (190, 196))	('ERK', 'Protein', (172, 175))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('decreases', 'NegReg', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('activation', 'MPA', (176, 186))	('MT1-MMP', 'Var', (139, 146))	('breast cancer', 'Disease', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
82014	27756325	In the latter study, the authors demonstrated that MT1-MMP overexpression in various cancer cell lines, including MCF-7 cells, downregulates ERK activation and migration in response to FGF-2, which is consistent with our findings using cells that express high levels of MT1-MMP.	('MT1-MMP', 'Var', (51, 58))	('ERK', 'Protein', (141, 144))	('migration', 'CPA', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('FGF-2', 'Gene', '2247', (185, 190))	('cancer', 'Disease', (85, 91))	('downregulates', 'NegReg', (127, 140))	('FGF-2', 'Gene', (185, 190))	('activation', 'MPA', (145, 155))	('overexpression', 'PosReg', (59, 73))	('MCF-7', 'CellLine', 'CVCL:0031', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
82015	27756325	Other studies have provided strong mechanistic evidence that MT1-MMP is involved in apoptosis protection and viability enhancement via HIF1alpha stabilization, which are in line with our observations that MT1-MMP enhances viability during serum-free incubation.	('HIF1alpha', 'Gene', '3091', (135, 144))	('HIF1alpha', 'Gene', (135, 144))	('apoptosis protection', 'CPA', (84, 104))	('MT1-MMP', 'Var', (205, 212))	('enhances', 'PosReg', (213, 221))	('enhancement', 'PosReg', (119, 130))	('MT1-MMP', 'Var', (61, 68))	('viability', 'CPA', (222, 231))	('viability', 'CPA', (109, 118))
82018	27756325	Similarly, analysis of the natural migration potential of MCF-7, MDA-MB 231, and HS578t cells is consistent with this relationship to TIMP-2, as HS578t cells were the most migratory and displayed the highest level of TIMP-2 relative to MT1-MMP.	('HS578t', 'CellLine', 'CVCL:0332', (81, 87))	('MCF-7', 'CellLine', 'CVCL:0031', (58, 63))	('HS578t', 'Var', (145, 151))	('migratory', 'CPA', (172, 181))	('HS578t', 'CellLine', 'CVCL:0332', (145, 151))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (65, 75))
82022	27756325	Instead, some have suggested that high TIMP-2 levels may promote tumourigenecity, which has been strengthened by the association of high TIMP-2 levels with poor prognosis in various human cancers, including breast.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('promote', 'PosReg', (57, 64))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', (188, 195))	('breast', 'Disease', (207, 213))	('high', 'Var', (34, 38))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))
82025	27756325	This is corroborated both with the rescued serum free viability and migration of C1 cells as a result of BB94 treatment, and with the role of TIMP-2 in mediating survivability under serum free conditions as shown by others.	('BB94', 'Gene', (105, 109))	('treatment', 'Var', (110, 119))	('BB94', 'Chemical', 'MESH:C080985', (105, 109))	('migration', 'CPA', (68, 77))
82033	27756325	We strongly believe, as suggested by others, that MCF-7 cells are MT1-MMP deficient, particularly because it has been shown that the MT1-MMP promoter in these cells is hypermethylated and thus transcriptionally repressed.	('hypermethylated', 'Var', (168, 183))	('MT1-MMP', 'Gene', (133, 140))	('MCF-7', 'CellLine', 'CVCL:0031', (50, 55))
82035	27756325	Furthermore, in the study done by Kohrmann et al., although the authors reported MT1-MMP protein in MCF-7 cells, they were not able to detect MT1-MMP protein from clinical samples via immunoblot.	('reported', 'Reg', (72, 80))	('clinical samples', 'Species', '191496', (163, 179))	('MT1-MMP', 'Var', (81, 88))	('MCF-7', 'CellLine', 'CVCL:0031', (100, 105))
82036	27756325	However, they were able to detect MT1-MMP protein in tissue sections from tumour samples and not from normal tissues.	('MT1-MMP', 'Var', (34, 41))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('detect', 'Reg', (27, 33))	('tumour', 'Disease', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
82040	27756325	Similarly, a pioneering study used MDA-MB 231 variants that produced constitutively active scr kinase, which is known to be upregulated during cancer progression.	('MDA-MB 231', 'CellLine', 'CVCL:0062', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('scr kinase', 'Enzyme', (91, 101))	('variants', 'Var', (46, 54))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('upregulated', 'PosReg', (124, 135))
82041	27756325	These MDA-MB 231 variants generated significantly more MT1-MMP containing invadopodia.	('variants', 'Var', (17, 25))	('more', 'PosReg', (50, 54))	('MT1-MMP containing invadopodia', 'MPA', (55, 85))	('MDA-MB 231', 'Gene', (6, 16))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (6, 16))
82044	27756325	Consistent with the conclusion of the importance of low levels of MT1-MMP expression are the observations seen in our physiologically relevant ex vivo and in vivo experiments, whereby MCF-7 cells expressing low levels of MT1-MMP (C3) demonstrated behavior consistent with the role of MT1-MMP during cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('MT1-MMP', 'Var', (221, 228))	('MCF-7', 'CellLine', 'CVCL:0031', (184, 189))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))
82046	27756325	Similarly, C3 cells were tumorigenic and showed metastatic potential in vivo, unlike C1 and C2 cells, which is consistent with studies that knock down MT1-MMP expression and show inhibition of these parameters.	('metastatic potential', 'CPA', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('MT1-MMP', 'Gene', (151, 158))	('knock', 'Var', (140, 145))	('expression', 'MPA', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
82051	27756325	It was surprising to us to that overexpression of MT1-MMP in invasive MDA-MB 231 cells reverted their phenotype in 3D culture towards a DCIS-like morphology where the ability to form networks in matrigel 3D culture was restricted and a higher proportion of these cells retain acini-like colonies.	('overexpression', 'PosReg', (32, 46))	('phenotype', 'MPA', (102, 111))	('MT1-MMP', 'Var', (50, 57))	('acini-like colonies', 'CPA', (276, 295))	('MDA-MB 231', 'CellLine', 'CVCL:0062', (70, 80))
82053	27756325	Additionally, although abnormally high levels of MT1-MMP overexpression may not reflect those seen in primary breast cancers, there is still mechanistic value in this approach, as utilized in this study to demonstrate the constancy of the TIMP-2 mediated activation of proMMP-2 by MT1-MMP.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MMP-2', 'Gene', (272, 277))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('primary breast cancers', 'Disease', (102, 124))	('primary breast cancers', 'Disease', 'MESH:D001943', (102, 124))	('MMP-2', 'Gene', '4313', (272, 277))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('activation', 'PosReg', (255, 265))	('MT1-MMP', 'Var', (281, 288))
82066	16154817	The risk of developing breast cancer in a gene carrier depends on a large number of factors including the penetrance of the mutation, environmental influences, the age of the individual and the age of the youngest relative when they developed breast cancer.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Disease', (243, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('mutation', 'Var', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
82067	16154817	Estimated risks have been published in a number of studies but a recent comprehensive formal meta-analysis including 22 studies and 6965 breast cancer cases has shown that 'the average cumulative risk in BRCA1-mutation carriers by age 70 years was 65% (95% confidence interval 51%-75%)'.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('carriers', 'Var', (219, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('BRCA1', 'Gene', '672', (204, 209))	('BRCA1', 'Gene', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
82069	16154817	In BRCA1 carriers, the risk is higher if the index case developed breast cancer under 40 years of age.	('BRCA1', 'Gene', '672', (3, 8))	('BRCA1', 'Gene', (3, 8))	('carriers', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('higher', 'Reg', (31, 37))
82082	16154817	Observational studies have been undertaken in the BRCA mutation carriers and those at moderate or high risk from their family history and it has been found that mammographic screening detected only 50% of cancers with the rest presenting as interval cancers.	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancers', 'Disease', (205, 212))	('cancers', 'Disease', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('interval cancers', 'Disease', (241, 257))	('BRCA', 'Gene', '672', (50, 54))	('interval cancers', 'Disease', 'MESH:D009369', (241, 257))	('mutation', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('BRCA', 'Gene', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
82099	16154817	MRI detected all six cancers in the prevalent round and three cancers in the incident round, while ultrasound and mammography only detected one-third of these cases.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('MRI', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Disease', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('detected', 'Reg', (4, 12))
82125	16154817	High grade DCIS is more likely to become high grade invasive disease and similarly low grade DCIS will become low grade cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('invasive disease', 'Disease', (52, 68))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('invasive disease', 'Disease', 'MESH:D009362', (52, 68))	('High grade', 'Var', (0, 10))
82137	16154817	If BRCA1/2 carriers opt for breast conservation with radiotherapy then intensive surveillance remains necessary as they have significantly higher rates of ipsilateral (49% vs. 21%, p=0.007) and contralateral events (42% vs. 9%, p=0.001) than women with sporadic breast cancer.	('carriers', 'Var', (11, 19))	('BRCA1/2', 'Gene', '672;675', (3, 10))	('women', 'Species', '9606', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('ipsilateral', 'CPA', (155, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('sporadic breast cancer', 'Disease', (253, 275))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (253, 275))	('contralateral events', 'CPA', (194, 214))	('BRCA1/2', 'Gene', (3, 10))	('higher', 'PosReg', (139, 145))
82143	16154817	Medullary or atypical medullary carcinoma is found more often and there is relatively less DCIS in BRCA1 carriers compared to sporadic cases.	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('BRCA1', 'Gene', (99, 104))	('DCIS', 'MPA', (91, 95))	('carcinoma', 'Disease', 'MESH:D002277', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carriers', 'Var', (105, 113))	('Medullary', 'Disease', (0, 9))	('carcinoma', 'Disease', (32, 41))	('BRCA1', 'Gene', '672', (99, 104))
82146	16154817	Although DCIS is less common in BRCA1 carriers, the carrier status is not often known in those women with a familial history.	('BRCA1', 'Gene', (32, 37))	('carriers', 'Var', (38, 46))	('women', 'Species', '9606', (95, 100))	('DCIS', 'Disease', (9, 13))	('BRCA1', 'Gene', '672', (32, 37))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))
82171	32354355	Similarly, research found that women with DCIS have comparable concerns about dying from breast cancer and experience similar psychosocial distress as women with invasive breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('psychosocial distress', 'Disease', (126, 147))	('psychosocial distress', 'Disease', 'MESH:D012128', (126, 147))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('breast cancer', 'Disease', (89, 102))	('invasive breast cancer', 'Disease', (162, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('DCIS', 'Var', (42, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (162, 184))	('women', 'Species', '9606', (31, 36))	('women', 'Species', '9606', (151, 156))
82308	30008979	The first line of radiological investigation would be mammography, which would show skin thickening, malignant calcification, masses at the level of the nipple, architectural distortion, and nipple retraction.	('malignant calcification', 'Disease', (101, 124))	('nipple retraction', 'CPA', (191, 208))	('skin thickening', 'CPA', (84, 99))	('skin thickening', 'Phenotype', 'HP:0001072', (84, 99))	('masses', 'Var', (126, 132))	('malignant calcification', 'Disease', 'MESH:D002114', (101, 124))	('architectural distortion', 'CPA', (161, 185))
82342	25905585	Patients underwent SLND at the discretion of the treating surgeon; reasons for performing SLND in patients with DCIS included planned mastectomy and the presence of features suggesting high risk for an invasive component (high grade, DCIS size >2 cm, palpable tumor, microinvasion suspected on biopsy).	('DCIS', 'Disease', (234, 238))	('tumor', 'Disease', (260, 265))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('high', 'Var', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('patients', 'Species', '9606', (98, 106))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))
82381	25905585	The majority of patients with SLN macrometastases (N=27/30, 90.0%) had a final pathologic nodal stage of pN1a.	('metastases', 'Disease', (39, 49))	('patients', 'Species', '9606', (16, 24))	('SLN', 'Var', (30, 33))	('metastases', 'Disease', 'MESH:D009362', (39, 49))	('pN1a', 'Disease', (105, 109))
82427	29980076	For example, when Matrix GLA protein or fetuin A, known mineralization inhibitors, are knocked-out in mouse models, mineral deposition is observed in multiple soft tissues due to a disruption of the normal cellular regulation of mineralization.	('observed', 'Reg', (138, 146))	('mineral deposition', 'CPA', (116, 134))	('Matrix GLA protein', 'Gene', (18, 36))	('fetuin A', 'Gene', (40, 48))	('cellular regulation', 'MPA', (206, 225))	('knocked-out', 'Var', (87, 98))	('disruption', 'Reg', (181, 191))	('fetuin A', 'Gene', '11625', (40, 48))	('mouse', 'Species', '10090', (102, 107))	('Matrix GLA protein', 'Gene', '17313', (18, 36))
82494	29980076	Both the particles and hydroxyapatite show an energy split at the white line energy (4055.4 eV - 4058.4 eV, 1s-4p transitions) and their peaks are similar in intensity.	('energy split', 'MPA', (46, 58))	('hydroxyapatite', 'Chemical', 'MESH:D006882', (23, 37))	('4055.4', 'Var', (85, 91))
82496	29980076	The high intensity of the 4062.9 eV peak relative to the hydroxyapatite standard may also be attributed to the presence of calcium sulphate.	('intensity', 'MPA', (9, 18))	('4062.9', 'Var', (26, 32))	('calcium sulphate', 'Chemical', 'MESH:D002133', (123, 139))	('hydroxyapatite', 'Chemical', 'MESH:D006882', (57, 71))
82619	31623652	Multiple clinical trials including E5194 and RTOG9804 have shown that low-risk DCIS patients tend to receive minimal benefit from adjuvant RT.	('DCIS', 'Disease', 'MESH:D002285', (79, 83))	('patients', 'Species', '9606', (84, 92))	('DCIS', 'Disease', (79, 83))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('E5194', 'Var', (35, 40))	('RTOG9804', 'Chemical', 'MESH:C439870', (45, 53))
82630	31623652	Nuclear polarity has also been implicated in the diagnosis and prognosis of urothelial and papillary thyroid cancers.	('implicated', 'Reg', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('urothelial and papillary thyroid cancers', 'Disease', 'MESH:C536915', (76, 116))	('Nuclear polarity', 'Var', (0, 16))
82671	26407954	For example, it is well-established that high body mass index (BMI) is inversely associated with breast cancer in young/premenopausal women, but positively associated with breast cancer in older/postmenopausal women.	('older/postmenopausal', 'Phenotype', 'HP:0008209', (189, 209))	('inversely', 'NegReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('high body mass index', 'Phenotype', 'HP:0031418', (41, 61))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('women', 'Species', '9606', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('high body', 'Var', (41, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('breast cancer', 'Disease', (97, 110))	('women', 'Species', '9606', (210, 215))
82702	26407954	Increased parity was not associated with overall breast cancer risk (OR=1.08, 95% CI: 0.84-1.38 for >=3 children versus no children), or risk of invasive breast cancer (OR=1.15, 95% CI: 0.88-1.50) or DCIS individually (OR=0.80, 95% CI: 0.38-1.66), though there was some evidence of an overall difference in effects by invasive status (p= 0.09).	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('invasive breast cancer', 'Disease', 'MESH:D001943', (145, 167))	('children', 'Species', '9606', (104, 112))	('parity', 'Var', (10, 16))	('DCIS individually', 'Disease', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('invasive breast cancer', 'Disease', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('DCIS', 'Phenotype', 'HP:0030075', (200, 204))	('breast cancer', 'Disease', (49, 62))	('children', 'Species', '9606', (123, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
82721	26407954	In contrast with our findings, high alcohol consumption is usually observed to be associated with increased risk of young-onset invasive breast cancer,.	('invasive breast cancer', 'Disease', 'MESH:D001943', (128, 150))	('high alcohol consumption', 'Var', (31, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('alcohol', 'Chemical', 'MESH:D000438', (36, 43))	('high alcohol consumption', 'Phenotype', 'HP:0030955', (31, 55))	('invasive breast cancer', 'Disease', (128, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
82735	26407954	estrogen receptor or triple-negative status).	('estrogen receptor', 'Gene', '2099', (0, 17))	('triple-negative status', 'Var', (21, 43))	('estrogen receptor', 'Gene', (0, 17))
82843	15642168	The frozen tumor tissue of one patient with DCIS was sliced into serial sections in the cryostat microtome chamber (Microm HM 505 N ; Microm Laborgerate GmbH, Walldorf, Germany), was mounted onto gelatin-coated slides, was dried at 37 C for 1 hour and was then incubated in a solution containing 99mTc-(V)DMSA.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('Microm', 'Var', (116, 122))	('patient', 'Species', '9606', (31, 38))	('DMSA', 'Chemical', '-', (305, 309))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
82883	15642168	Overexpression of c-erbB-2 (>= 10%) was associated with higher 99mTc-(V)DMSA uptake in DCIS/LCIS (mean +- SD T/B ratio at 60 min, 1.89 +- 0.01 versus 1.52 +- 0.09 for values >= 10% and < 10%, respectively; P = 0.004).	('DMSA', 'Chemical', '-', (72, 76))	('c-erbB-2', 'Gene', (18, 26))	('c-erbB-2', 'Gene', '2064', (18, 26))	('higher', 'PosReg', (56, 62))	('>= 10%', 'Var', (28, 34))
82890	15642168	Few reports have been published concerning the ability of 99mTc-Sestamibi not actually to detect DCIS, but rather to improve invasive breast cancer detection in the presence of DCIS, and these studies seem to be contradictory.	('invasive breast cancer', 'Disease', 'MESH:D001943', (125, 147))	('DCIS', 'Var', (177, 181))	('99mTc-Sestamibi', 'Chemical', 'MESH:D017256', (58, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('invasive breast cancer', 'Disease', (125, 147))	('DCIS', 'Disease', (97, 101))	('improve', 'PosReg', (117, 124))
82892	15642168	Several other authors, however, have suggested that diffuse 99mTc-Sestamibi uptake in benign breast disorders was associated with proliferative changes, demonstrating an increased risk of developing into breast cancer, while other workers described hormonal influence to be the cause of diffuse breast uptake on scintimammography.	('breast disorders', 'Disease', (93, 109))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('breast disorders', 'Disease', 'MESH:D001941', (93, 109))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (204, 217))	('diffuse', 'Var', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('99mTc-Sestamibi', 'Chemical', 'MESH:D017256', (60, 75))
82900	15642168	The diffuse pattern of radiotracer uptake (not patchy, but more homogeneous) was also noticed in some cases of epithelial hyperplasia, more prominently with 99mTc-(V)DMSA.	('epithelial hyperplasia', 'Disease', (111, 133))	('DMSA', 'Chemical', '-', (166, 170))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (111, 133))	('99mTc-(V)DMSA', 'Var', (157, 170))
82968	29687205	Patients were stratified based on their use of hormonal contraceptive agents, pathology (benign, atypical, in situ, invasive and pathological subtypes [luminal A, luminal B, HER2, triple negative-TN]), demography, and medical/family history.	('Patients', 'Species', '9606', (0, 8))	('HER2', 'Gene', '2064', (174, 178))	('[luminal', 'Var', (151, 159))	('HER2', 'Gene', (174, 178))
82976	29687205	A tumor was considered to be positive for 1) ER or PR when >=5% of the cells were positive; 2) HER2 + if IHC staining intensity was a 3+ or Fluorescence in situ Hybridization (FISH) indicated a ratio of >=2.2 for copies of the HER2 gene to the centromere of chromosome 17; 3) Ki-67 + when >=15% of the cells were positive.	('PR', 'Gene', '5241', (51, 53))	('ER', 'Gene', '2099', (96, 98))	('HER2', 'Gene', '2064', (227, 231))	('ER', 'Gene', '2099', (45, 47))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('HER2', 'Gene', (95, 99))	('HER2', 'Gene', '2064', (95, 99))	('ER', 'Gene', '2099', (228, 230))	('HER2', 'Gene', (227, 231))	('Ki-67 +', 'Var', (276, 283))	('A tumor', 'Disease', (0, 7))	('A tumor', 'Disease', 'MESH:D009369', (0, 7))
83045	29687205	Norgestimate did not appear to be associated with an increase in breast cancer risk (20% increase) but levonorgestrel oral contraceptives were associated with a 50% increase in risk although neither odds ratio was statistically different than using other progestin types.	('levonorgestrel', 'Var', (103, 117))	('Norgestimate', 'Chemical', 'MESH:C017576', (0, 12))	('increase in breast cancer', 'Disease', 'MESH:D001943', (53, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('increase in breast cancer', 'Disease', (53, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('levonorgestrel', 'Chemical', 'MESH:D016912', (103, 117))
83124	27522516	MIBB classification of lobular neoplasia categorizes all lesions (classical LN, ALH, LCIS, LIN1, LIN2) as B3, but LIN 3 or pleomorphic LN or those with extensive necrosis are classified as B5a.	('LIN2', 'Gene', (97, 101))	('LIN 3', 'Var', (114, 119))	('LCIS', 'Phenotype', 'HP:0030076', (85, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (31, 40))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (23, 40))	('LIN2', 'Gene', '8573', (97, 101))	('LN', 'Phenotype', 'HP:0030076', (135, 137))	('LIN1', 'Gene', (91, 95))	('MIBB', 'Chemical', '-', (0, 4))	('lobular neoplasia', 'Disease', (23, 40))	('LIN1', 'Gene', '10421', (91, 95))	('necrosis', 'Disease', (162, 170))	('lobular neoplasia', 'Disease', 'MESH:D009369', (23, 40))	('necrosis', 'Disease', 'MESH:D009336', (162, 170))	('LN', 'Phenotype', 'HP:0030076', (76, 78))
83247	20446031	These categories were based on the lifetime risk of recurrence in patients with mutated BRCA1/2 gene (>=50%), patients who were not tested for BRCA1 or BRCA2 status but in whose family a mutation was found (10-50%), and patients at average (<10%) risk of recurrence (personal communication, Dr. Robyn Andersen, Fred Hutchinson Cancer Research Center, September, 2007).	('BRCA1', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (143, 148))	('Fred Hutchinson Cancer', 'Disease', 'MESH:D013590', (311, 333))	('Fred Hutchinson Cancer', 'Disease', (311, 333))	('Cancer', 'Phenotype', 'HP:0002664', (327, 333))	('BRCA2', 'Gene', '675', (152, 157))	('BRCA1', 'Gene', (143, 148))	('person', 'Species', '9606', (267, 273))	('mutated', 'Var', (80, 87))	('Hutchinson Cancer', 'Phenotype', 'HP:0012413', (316, 333))	('BRCA1/2', 'Gene', (88, 95))	('patients', 'Species', '9606', (220, 228))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (66, 74))	('BRCA2', 'Gene', (152, 157))
83293	20446031	This finding is similar to other research reporting that more than half of African American breast cancer survivors with a 5-10% prior probability of having a BRCA1/2 mutation did not believe they were at increased risk for recurrent or new breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('BRCA1/2', 'Gene', (159, 166))	('breast cancer', 'Disease', (92, 105))	('mutation', 'Var', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('BRCA1/2', 'Gene', '672;675', (159, 166))	('breast cancer', 'Disease', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
83334	32047604	We found that the DNA methylation of the biomarker loci is gained early in carcinogenesis since most of the precancerous conditions already have biomarker loci hypermethylated.	('hypermethylated', 'Var', (160, 175))	('carcinogenesis', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
83354	32047604	We analyzed DNA methylation of the biomarker loci in normal breast tissue samples, DCIS and IBC from three GEO datasets: GSE60185 , GSE66313 , GSE53051 .	('CIS', 'Phenotype', 'HP:0030075', (84, 87))	('IBC', 'Disease', (92, 95))	('GSE66313', 'Var', (132, 140))	('GSE53051', 'Var', (143, 151))	('IBC', 'Disease', 'MESH:D001943', (92, 95))	('GSE60185', 'Var', (121, 129))	('CIS', 'Disease', 'MESH:D002278', (84, 87))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('CIS', 'Disease', (84, 87))
83355	32047604	The results ( Figure 1A) show that the biomarker loci are methylated already in DCIS at about the same level as in IBC.	('IBC', 'Disease', 'MESH:D001943', (115, 118))	('CIS', 'Phenotype', 'HP:0030075', (81, 84))	('CIS', 'Disease', 'MESH:D002278', (81, 84))	('methylated', 'Var', (58, 68))	('CIS', 'Disease', (81, 84))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('IBC', 'Disease', (115, 118))
83359	32047604	We analyzed biomarker loci in normal colorectal tissue, colorectal adenomas, colorectal carcinomas and metastatic colorectal tumors from three GEO datasets: GSE48684 , GSE77954 , GSE53051 .	('colorectal adenomas', 'Disease', 'MESH:C563924', (56, 75))	('colorectal tumors', 'Disease', 'MESH:D015179', (114, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('colorectal adenomas', 'Disease', (56, 75))	('colorectal carcinomas', 'Disease', (77, 98))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (77, 98))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal tumors', 'Disease', (114, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('GSE53051', 'Var', (179, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('GSE48684', 'Var', (157, 165))	('GSE77954', 'Var', (168, 176))
83360	32047604	Similar to DCIS, biomarker loci are already hypermethylated in colorectal adenomas with no further increase in methylation during the progression into invasive colorectal carcinomas or metastatic colorectal cancer ( Figure 1C) and again colorectal adenomas on MDS plot are scattered among colorectal carcinomas ( Figure 1D).	('colorectal adenomas', 'Disease', 'MESH:C563924', (63, 82))	('CIS', 'Phenotype', 'HP:0030075', (12, 15))	('hypermethylated', 'Var', (44, 59))	('invasive colorectal carcinomas', 'Disease', (151, 181))	('colorectal adenomas', 'Disease', (237, 256))	('colorectal adenomas', 'Disease', (63, 82))	('CIS', 'Disease', 'MESH:D002278', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('colorectal cancer', 'Disease', 'MESH:D015179', (196, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('carcinomas', 'Phenotype', 'HP:0030731', (300, 310))	('colorectal cancer', 'Disease', (196, 213))	('CIS', 'Disease', (12, 15))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('colorectal carcinomas', 'Disease', (289, 310))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (289, 310))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (160, 181))	('invasive colorectal carcinomas', 'Disease', 'MESH:D015179', (151, 181))	('colorectal adenomas', 'Disease', 'MESH:C563924', (237, 256))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))
83362	32047604	We analyzed normal esophagus together with BE and EAC samples from two GEO datasets: GSE72872 , GSE81334 .	('GSE81334', 'Var', (96, 104))	('GSE72872', 'Var', (85, 93))	('BE', 'Phenotype', 'HP:0100580', (43, 45))	('EAC', 'Disease', 'MESH:D004941', (50, 53))	('EAC', 'Disease', (50, 53))	('BE', 'Disease', 'MESH:D001471', (43, 45))	('EAC', 'Phenotype', 'HP:0011459', (50, 53))
83373	32047604	Together, these results show that the gain of DNA methylation of the biomarker loci is an early epigenetic event during human carcinogenesis.	('DNA', 'MPA', (46, 49))	('gain', 'PosReg', (38, 42))	('human', 'Species', '9606', (120, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('carcinogenesis', 'Disease', (126, 140))	('methylation', 'Var', (50, 61))
83386	32047604	The overall results indicate that aberrant methylation of the biomarker loci is an early epigenetic event of carcinogenesis, regardless of cancer type.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('carcinogenesis', 'Disease', (109, 123))	('aberrant methylation', 'Var', (34, 54))	('cancer', 'Disease', (139, 145))
83396	27398812	Of the 2,070 participant interpretations on the 72 consensus ADH cases, 48% were scored by participants as difficult and 45% as borderline between two diagnoses; the presence of both of these features was significantly associated with increased agreement (p < 0.001).	('ADH', 'Gene', '124', (61, 64))	('presence', 'Var', (166, 174))	('ADH', 'Gene', (61, 64))	('increased', 'PosReg', (235, 244))	('participant', 'Species', '9606', (91, 102))	('participant', 'Species', '9606', (13, 24))	('participants', 'Species', '9606', (91, 103))
83489	27398812	However, some studies have demonstrated increases in diagnostic agreement when cocktail stains such as ADH-5 are used on intraductal proliferative lesions (ADH-5 stains includes CK5, 14, 7 18 and p63), with more cases clearly classified as UDH.	('p63', 'Gene', (196, 199))	('UDH', 'Chemical', '-', (240, 243))	('ADH-5', 'Gene', '128', (156, 161))	('ADH-5', 'Gene', (156, 161))	('diagnostic agreement', 'MPA', (53, 73))	('p63', 'Gene', '8626', (196, 199))	('ADH-5', 'Gene', '128', (103, 108))	('ADH-5', 'Gene', (103, 108))	('increases', 'PosReg', (40, 49))	('UDH', 'Disease', (240, 243))	('CK5', 'Var', (178, 181))
83526	20956830	For women less than 50 years old, tamoxifen reduced the risk for all breast events by 29% with 77 events in 302 women on tamoxifen and 99 events in 299 women on placebo (HR = 0.71, P = .02).	('women', 'Species', '9606', (152, 157))	('women', 'Species', '9606', (112, 117))	('tamoxifen', 'Chemical', 'MESH:D013629', (34, 43))	('women', 'Species', '9606', (4, 9))	('reduced', 'NegReg', (44, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (121, 130))	('tamoxifen', 'Var', (121, 130))	('breast events', 'Disease', (69, 82))
83671	23408106	Discussions about alcohol use are of particular importance given the increased risk of breast cancer associated with alcohol use among older women, but these discussions occurred less often than discussions of weight and exercise, even among White women who reported the most alcohol consumption.	('alcohol use', 'Var', (117, 128))	('women', 'Species', '9606', (141, 146))	('alcohol', 'Chemical', 'MESH:D000438', (276, 283))	('alcohol use', 'Phenotype', 'HP:0030955', (117, 128))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('alcohol use', 'Phenotype', 'HP:0030955', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('women', 'Species', '9606', (248, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('alcohol', 'Chemical', 'MESH:D000438', (117, 124))	('alcohol', 'Chemical', 'MESH:D000438', (18, 25))
83763	15743508	CLDN1 positivity was also observed in some cell membranes in pure DCIS cases or in the DCIS component of invasive carcinomas.	('pure DCIS', 'Disease', (61, 70))	('CLDN1', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('observed', 'Reg', (26, 34))	('invasive carcinomas', 'Disease', (105, 124))	('invasive carcinomas', 'Disease', 'MESH:D009361', (105, 124))
83769	15743508	CLDN3 positivity was observed in the majority (49/56) of cases examined (12 fibrocystic breasts, 5 DCIS, 23 IDC, 4 ILC, 2 mucinous, 2 tubular and 1 papillary breast carcinomas) and in all cases analyzed by confocal microscopy.	('papillary breast carcinomas', 'Disease', (148, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('papillary breast carcinomas', 'Disease', 'MESH:D002291', (148, 175))	('IDC', 'Gene', (108, 111))	('ILC', 'Disease', (115, 118))	('fibrocystic breasts', 'Disease', 'MESH:D005348', (76, 95))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('CLDN3', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('observed', 'Reg', (21, 29))	('breast carcinomas', 'Phenotype', 'HP:0003002', (158, 175))	('IDC', 'Gene', '4000', (108, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breast carcinoma', 'Phenotype', 'HP:0003002', (158, 174))	('fibrocystic breasts', 'Disease', (76, 95))	('DCIS', 'Disease', (99, 103))
83772	15743508	CLDN4 positivity was present in all 56 tissue sections in epithelial cell membranes as well as in the frozen section and breast tumour array analyzed by confocal microscopy.	('CLDN4', 'Gene', '1364', (0, 5))	('positivity', 'Var', (6, 16))	('breast tumour', 'Phenotype', 'HP:0100013', (121, 134))	('breast tumour array', 'Disease', 'MESH:D001943', (121, 140))	('CLDN4', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('breast tumour array', 'Disease', (121, 140))
83818	15743508	Abnormalities in TJ permeability and number greatly influence the transepithelial flux of growth factors and hence the development of epithelial tumours.	('transepithelial flux of growth factors', 'MPA', (66, 104))	('Abnormalities', 'Var', (0, 13))	('epithelial tumours', 'Disease', (134, 152))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('influence', 'Reg', (52, 61))	('epithelial tumours', 'Disease', 'MESH:D000077216', (134, 152))
83832	15743508	Removal of CLDN4 disrupts fibril organization and increases junction permeability.	('disrupts', 'NegReg', (17, 25))	('CLDN4', 'Gene', '1364', (11, 16))	('Removal', 'Var', (0, 7))	('fibril organization', 'MPA', (26, 45))	('increases', 'PosReg', (50, 59))	('junction permeability', 'MPA', (60, 81))	('CLDN4', 'Gene', (11, 16))
83840	15743508	The important issue is whether loss of CLDN1 and CLDN4 plays a significant role in cell-cell adhesion and tumour differentiation.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('cell-cell adhesion', 'CPA', (83, 101))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('loss', 'Var', (31, 35))	('CLDN4', 'Gene', '1364', (49, 54))	('tumour', 'Disease', (106, 112))	('CLDN1', 'Gene', (39, 44))	('CLDN4', 'Gene', (49, 54))
83848	29932456	In contrast, among the 1089 women with screening mammograms (98 BC within 10 years), BCSC had better calibration (0.94; 95% CI 0.85 to 1.43) and discrimination (0.63; 95% CI 0.56 to 0.71) at ten vs. five years (calibration 1.31, 95% CI 0.94 to 2.25; discrimination 0.59, 95% CI 0.46 to 0.71), where discrimination was not different from chance.	('calibration', 'MPA', (101, 112))	('BCSC', 'Var', (85, 89))	('better', 'PosReg', (94, 100))	('women', 'Species', '9606', (28, 33))	('discrimination', 'MPA', (145, 159))
83929	23677482	Women who had 2 or more PCP visits during the 24-month assessment interval had lower odds of breast cancer mortality, all-cause mortality, and late-stage breast cancer diagnosis compared with women who had no PCP visits or 1 PCP visit while adjusting for other covariates, including mammography and non-PCP visits.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('lower', 'NegReg', (79, 84))	('late-stage breast cancer', 'Disease', (143, 167))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('late-stage breast cancer', 'Disease', 'MESH:D001943', (143, 167))	('women', 'Species', '9606', (192, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('all-cause', 'CPA', (118, 127))	('PCP visits', 'Var', (24, 34))
84021	23826951	Mammographic sensitivity is therefore 30-48% for ACR IV dense glandular breast tissue , and mostly breast cancer can only be inadequately displayed with this technique (occult).	('mostly breast cancer', 'Disease', 'MESH:D001943', (92, 112))	('mostly breast cancer', 'Disease', (92, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('ACR IV', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
84082	23077491	Figure 1B shows that the frequencies of immature reticulocytes (MN-RET) and mature normochromatic erythrocytes (MN-NCE) carrying micronuclei were ~36% and ~57% higher in the radiation-sensitive BALB/c strain than in the more radiation-resistant C57BL/6 strain (p<0.0001; Table S1).	('higher', 'PosReg', (160, 166))	('micronuclei', 'Var', (129, 140))	('RET', 'Gene', '5979', (67, 70))	('immature reticulocytes', 'Phenotype', 'HP:0001923', (40, 62))	('MN-NCE', 'CellLine', 'CVCL:U508', (112, 118))	('RET', 'Gene', (67, 70))
84122	23077491	Consistent with its role in the control of expression of ECM, we observed down-regulation of genes associated with ECM remodeling and epithelial differentiation (not seen in BALB/c mice) suggesting a reduced turn-over of the ECM in C57BL/6 mice (Figure S3B).	('turn-over', 'CPA', (208, 217))	('mice', 'Species', '10090', (181, 185))	('ECM', 'Gene', (57, 60))	('ECM', 'Gene', '22915', (57, 60))	('mice', 'Species', '10090', (240, 244))	('reduced', 'NegReg', (200, 207))	('down-regulation', 'NegReg', (74, 89))	('C57BL/6', 'Var', (232, 239))	('ECM', 'Gene', '22915', (115, 118))	('ECM', 'Gene', '22915', (225, 228))	('ECM', 'Gene', (225, 228))	('ECM', 'Gene', (115, 118))
84123	23077491	Figure 6 shows that expression of SOX9 protein in the MG was limited to the nuclei of luminal and myoepithelial cells and that the fraction of SOX9-positive cells was significantly reduced after LD exposure in C57BL/6 mice (p<0.0001), consistent with reduced mitotic activity in MG of C57BL/6 mice at 1 month after LD.	('mitotic activity', 'CPA', (259, 275))	('reduced', 'NegReg', (181, 188))	('C57BL/6', 'Var', (210, 217))	('LD', 'Chemical', '-', (315, 317))	('LD', 'Chemical', '-', (195, 197))	('mice', 'Species', '10090', (293, 297))	('myoepithelial', 'Disease', (98, 111))	('mice', 'Species', '10090', (218, 222))	('myoepithelial', 'Disease', 'MESH:D009208', (98, 111))	('reduced', 'NegReg', (251, 258))
84129	23077491	As shown in Figure 7A, patients with above-median expression had significantly reduced survival duration compared to patients with below-median expression (p<8.16 E-05) and had significantly worse prognosis (Figure 7B; p<0.0001).	('survival', 'MPA', (87, 95))	('reduced', 'NegReg', (79, 86))	('patients', 'Species', '9606', (23, 31))	('above-median expression', 'Var', (37, 60))	('patients', 'Species', '9606', (117, 125))
84152	23077491	This analyses (Figure 8A) identified 45 concordant genes (34 mitosis and 11 stromal genes) with opposing responses in BALB/c and C57BL/6 where the direction of the BALB/c response matched the direction of response in independent studies of human breast cancers.	('breast cancers', 'Disease', (246, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('human', 'Species', '9606', (240, 245))	('breast cancers', 'Phenotype', 'HP:0003002', (246, 260))	('C57BL/6', 'Var', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('breast cancers', 'Disease', 'MESH:D001943', (246, 260))
84158	23077491	Strain variations in baseline and LD-response expression signatures were associated with differential susceptibility to LD-induced mammary cancer in mice and with inter-individual variations in human breast cancer survival.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('LD', 'Chemical', '-', (120, 122))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('variations', 'Var', (7, 17))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('LD', 'Chemical', '-', (34, 36))	('human', 'Species', '9606', (194, 199))	('mice', 'Species', '10090', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (200, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('cancer', 'Disease', (139, 145))
84163	23077491	Surprisingly, we found no evidence for genomic instability after LD exposures in BALB/c despite its sensitivity to LD-induced mammary cancer, which led us to search for genetic variation in molecular barrier functions that may control susceptibility to LD-induced cancer.	('LD', 'Chemical', '-', (115, 117))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (134, 140))	('LD', 'Chemical', '-', (253, 255))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('variation', 'Var', (177, 186))	('LD', 'Chemical', '-', (65, 67))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('control', 'Reg', (227, 234))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
84164	23077491	The genetic differences in baseline and LD expression profiles identified several unique tissue response functions associated with mammary cancer risk (Figure 9).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('LD', 'Chemical', '-', (40, 42))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (115, 125))	('genetic', 'Var', (4, 11))	('cancer', 'Disease', (139, 145))
84174	23077491	In support of this prediction, we demonstrated that both the transcript levels of SOX9 in mammary tissue and the frequencies of SOX9-protein-positive epithelial cells were reduced in mammary tissue of C57BL/6 (but not in BALB/c) at 1 month after LD exposures.	('C57BL/6', 'Var', (201, 208))	('transcript levels', 'MPA', (61, 78))	('LD', 'Chemical', '-', (246, 248))	('reduced', 'NegReg', (172, 179))
84185	23077491	RUNX1 is a classic tumor suppressor gene in acute myeloid leukemia (AML) and loss of RUNX1 causes hyperproliferation and abnormal morphogenesis in a 3D model of breast epithelial cells.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (50, 66))	('hyperproliferation', 'Disease', (98, 116))	('causes', 'Reg', (91, 97))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (44, 66))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AML', 'Disease', 'MESH:D015470', (68, 71))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('acute myeloid leukemia', 'Disease', (44, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('RUNX1', 'Gene', (85, 90))	('AML', 'Disease', (68, 71))	('tumor', 'Disease', (19, 24))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (44, 66))	('AML', 'Phenotype', 'HP:0004808', (68, 71))	('loss', 'Var', (77, 81))
84203	23077491	Samples were kept at -80 C until shipment to Litron Laboratories where they were analyzed by flow cytometry for the frequencies of micronucleated reticulocytes (MN-RET) and micronucleated normochromatic erythrocytes (MN-NCE).	('RET', 'Gene', (164, 167))	('micronucleated reticulocytes', 'CPA', (131, 159))	('micronucleated', 'Var', (173, 187))	('RET', 'Gene', '5979', (164, 167))	('MN-NCE', 'CellLine', 'CVCL:U508', (217, 223))
84218	30927928	As far, the majority of antineoplastic treatments are small-molecules, which have had great success in saving the lives of patients with cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Disease', (137, 143))	('small-molecules', 'Var', (54, 69))
84223	30927928	Third, gene amplification in tumor cells increases the number of copies of oncogenes, which then reinforces oncogenic signaling during drug treatment.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('gene amplification', 'Var', (7, 25))	('increases', 'PosReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('oncogenes', 'Gene', (75, 84))	('tumor', 'Disease', (29, 34))
84245	30927928	Inhibition of mTOR signaling was found to blunt non-cell-autonomous resistance induced by vemurafenib, crizotinib or erlotinib (ERL).	('mTOR', 'Gene', '2475', (14, 18))	('vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('erlotinib', 'Chemical', 'MESH:D000069347', (117, 126))	('erlotinib', 'Gene', (117, 126))	('Inhibition', 'Var', (0, 10))	('crizotinib', 'Chemical', 'MESH:D000077547', (103, 113))	('blunt', 'NegReg', (42, 47))	('mTOR', 'Gene', (14, 18))	('non-cell-autonomous resistance', 'MPA', (48, 78))
84252	30927928	In an in vivo model of lymphoma, the SASP is destroyed by NF-kappaB inhibition, leading to escape from immunosurveillance by natural killer cells and p53 inactivation, thereby producing drug resistance.	('drug resistance', 'MPA', (186, 201))	('escape', 'MPA', (91, 97))	('lymphoma', 'Disease', 'MESH:D008223', (23, 31))	('drug resistance', 'Phenotype', 'HP:0020174', (186, 201))	('lymphoma', 'Phenotype', 'HP:0002665', (23, 31))	('inactivation', 'Var', (154, 166))	('NF-kappaB', 'Gene', '4790', (58, 67))	('producing', 'Reg', (176, 185))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('SASP', 'Gene', (37, 41))	('inhibition', 'NegReg', (68, 78))	('SASP', 'Gene', '7295', (37, 41))	('NF-kappaB', 'Gene', (58, 67))	('lymphoma', 'Disease', (23, 31))
84287	30927928	In addition to resistance based on the modulation of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), the hypoxic TME was recently shown to affect drug sensitivity considerably.	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (72, 110))	('O6-methylguanine-DNA methyltransferase', 'Gene', (72, 110))	('hypoxic', 'Var', (123, 130))	('MGMT', 'Gene', (112, 116))	('drug sensitivity', 'Phenotype', 'HP:0020174', (164, 180))	('MGMT', 'Gene', '4255', (112, 116))	('drug sensitivity', 'MPA', (164, 180))	('affect', 'Reg', (157, 163))
84303	30927928	AML cells cocultured with MSCs had elevated levels of Mcl-1, which is associated with multidrug resistance, and AML cell autophagy induced by MSC conferred cytarabine resistance.	('conferred', 'Reg', (146, 155))	('Mcl-1', 'Gene', (54, 59))	('MSC', 'Var', (142, 145))	('AML', 'Disease', 'MESH:D015470', (112, 115))	('cytarabine', 'MPA', (156, 166))	('levels', 'MPA', (44, 50))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('Mcl-1', 'Gene', '4170', (54, 59))	('AML', 'Phenotype', 'HP:0004808', (112, 115))	('elevated', 'PosReg', (35, 43))	('AML', 'Disease', (112, 115))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))	('cytarabine', 'Chemical', 'MESH:D003561', (156, 166))
84310	30927928	Furthermore, BMSCs could induce an increased import of cystine and its conversion into cysteine in the TME, and the resulting cysteine could be taken up by CLL B-cells for GSH synthesis.	('GSH', 'Chemical', 'MESH:D005978', (172, 175))	('increased', 'PosReg', (35, 44))	('cysteine', 'Chemical', 'MESH:D003545', (87, 95))	('cystine', 'Chemical', 'MESH:D003553', (55, 62))	('import', 'MPA', (45, 51))	('CLL', 'Phenotype', 'HP:0005550', (156, 159))	('conversion into cysteine', 'MPA', (71, 95))	('BMSCs', 'Var', (13, 18))	('cysteine', 'Chemical', 'MESH:D003545', (126, 134))
84315	30927928	The intercellular activation of survival signals by MSCs was also observed in multiple myeloma (MM), in which MSCs initiated NF-kappaB signaling through autophagy-dependent IkappaB degradation in MM cells.	('autophagy-dependent', 'CPA', (153, 172))	('NF-kappaB', 'Gene', '4790', (125, 134))	('multiple myeloma', 'Phenotype', 'HP:0006775', (78, 94))	('initiated', 'PosReg', (115, 124))	('multiple myeloma', 'Disease', 'MESH:D009101', (78, 94))	('MSCs', 'Var', (110, 114))	('multiple myeloma', 'Disease', (78, 94))	('NF-kappaB', 'Gene', (125, 134))
84352	30927928	The expression of acylglycerol-3-phosphate acyltransferase 2 (AGPAT2) under hypoxic conditions increases lipid droplet accumulation in multiple types of cancer cells, leading to etoposide resistance.	('lipid droplet accumulation', 'MPA', (105, 131))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('acylglycerol-3-phosphate acyltransferase 2', 'Gene', '10555', (18, 60))	('AGPAT2', 'Gene', (62, 68))	('cancer', 'Disease', (153, 159))	('AGPAT2', 'Gene', '10555', (62, 68))	('leading to', 'Reg', (167, 177))	('hypoxic conditions', 'Disease', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('expression', 'Var', (4, 14))	('hypoxic conditions', 'Disease', 'MESH:D009135', (76, 94))	('etoposide', 'Chemical', 'MESH:D005047', (178, 187))	('acylglycerol-3-phosphate acyltransferase 2', 'Gene', (18, 60))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))	('etoposide resistance', 'MPA', (178, 198))	('increases', 'PosReg', (95, 104))
84355	30927928	Disrupting the interaction between fibronectin and tumor cells initiated cell cycle progression into S phase, which reverted MM cells to an etoposide-sensitive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('initiated', 'Reg', (63, 72))	('fibronectin', 'Gene', (35, 46))	('tumor', 'Disease', (51, 56))	('cell cycle progression', 'CPA', (73, 95))	('Disrupting', 'Var', (0, 10))	('fibronectin', 'Gene', '2335', (35, 46))	('interaction', 'Interaction', (15, 26))	('etoposide', 'Chemical', 'MESH:D005047', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
84357	30927928	HER2 inhibitors, including monoclonal antibodies and small-molecule TKIs, have been developed for the treatment of diverse types of cancer, especially breast cancer.	('cancer', 'Disease', (132, 138))	('especially breast cancer', 'Disease', (140, 164))	('especially breast cancer', 'Disease', 'MESH:D001943', (140, 164))	('small-molecule', 'Var', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('cancer', 'Disease', (158, 164))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
84366	30927928	EGFR inhibitors are compounds and antibodies that suppress the activity of either wild-type or mutant EGFR and downstream signaling.	('activity', 'MPA', (63, 71))	('EGFR', 'Gene', (0, 4))	('suppress', 'NegReg', (50, 58))	('mutant', 'Var', (95, 101))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
84381	30927928	The B-Raf V600E mutant inhibitor sorafenib was recently developed to treat liver and renal cancers.	('V600E', 'Var', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('B-Raf', 'Gene', '673', (4, 9))	('B-Raf', 'Gene', (4, 9))	('sorafenib', 'Chemical', 'MESH:D000077157', (33, 42))	('liver and renal cancers', 'Disease', 'MESH:D006528', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('V600E', 'Mutation', 'rs113488022', (10, 15))
84392	30927928	Another hypoxia-associated mechanism involves metabolic perturbations that are relevant to the initiation of HCC resistance by hydroxyproline augmentation and accumulation.	('hypoxia', 'Disease', (8, 15))	('HCC', 'Gene', (109, 112))	('hydroxyproline', 'Var', (127, 141))	('hydroxyproline', 'Chemical', 'MESH:D006909', (127, 141))	('accumulation', 'PosReg', (159, 171))	('HCC', 'Gene', '619501', (109, 112))	('augmentation', 'PosReg', (142, 154))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('hydroxyproline augmentation', 'Phenotype', 'HP:0003260', (127, 154))	('hypoxia', 'Disease', 'MESH:D000860', (8, 15))
84393	30927928	Under hypoxic conditions, hydroxyproline is tightly related to HIF-dependent tumor phenotypes and glutamine-proline conversion in both normal and tumor cells and confers sorafenib resistance in HCC.	('sorafenib resistance', 'MPA', (170, 190))	('HIF-dependent tumor', 'Disease', (63, 82))	('glutamine-proline conversion', 'MPA', (98, 126))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('glutamine', 'Chemical', 'MESH:D005973', (98, 107))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('hypoxic conditions', 'Disease', 'MESH:D009135', (6, 24))	('tumor', 'Disease', (77, 82))	('sorafenib', 'Chemical', 'MESH:D000077157', (170, 179))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('related', 'Reg', (52, 59))	('hydroxyproline', 'Chemical', 'MESH:D006909', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('proline', 'Chemical', 'MESH:D011392', (33, 40))	('hypoxic conditions', 'Disease', (6, 24))	('HCC', 'Gene', '619501', (194, 197))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('confers', 'Reg', (162, 169))	('HIF-dependent tumor', 'Disease', 'MESH:D019966', (63, 82))	('hydroxyproline', 'Var', (26, 40))	('HCC', 'Gene', (194, 197))
84396	30927928	Vemurafenib was developed to target V600E mutant B-Raf in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('V600E', 'Var', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('B-Raf', 'Gene', '673', (49, 54))	('B-Raf', 'Gene', (49, 54))	('melanoma', 'Disease', (58, 66))
84400	30927928	As a beta-catenin inhibitor, sFRP2 suppresses the production of APE1 via MITF inactivation, losing control of ROS reactions.	('inactivation', 'Var', (78, 90))	('sFRP2', 'Gene', (29, 34))	('beta-catenin', 'Gene', '12387', (5, 17))	('control', 'MPA', (99, 106))	('losing', 'NegReg', (92, 98))	('APE1', 'Gene', (64, 68))	('sFRP2', 'Gene', '6423', (29, 34))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('ROS reactions', 'MPA', (110, 123))	('APE1', 'Gene', '328', (64, 68))	('beta-catenin', 'Gene', (5, 17))	('MITF', 'Gene', (73, 77))	('MITF', 'Gene', '4286', (73, 77))	('suppresses', 'NegReg', (35, 45))
84413	30927928	The CD11b+Gr1+ MDSC population was shown to promote resistance to anti-VEGF treatment in multiple types of refractory tumors, and inhibition of this cell population significantly promoted the outcome of anti-VEGF treatment.	('refractory tumors', 'Disease', 'MESH:D000069279', (107, 124))	('promote', 'PosReg', (44, 51))	('inhibition', 'Var', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('refractory tumors', 'Disease', (107, 124))	('VEGF', 'Gene', (208, 212))	('VEGF', 'Gene', '7422', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('VEGF', 'Gene', (71, 75))	('promoted', 'PosReg', (179, 187))	('outcome', 'MPA', (192, 199))	('CD11b', 'Gene', '3684', (4, 9))	('VEGF', 'Gene', '7422', (208, 212))	('CD11b', 'Gene', (4, 9))
84414	30927928	Comparison of the actions of sunitinib and bevacizumab suggested that sunitinib, but not bevacizumab, could quickly activate the recruitment of macrophages and MDSCs due to the rapid formation of hypoxic conditions.	('activate', 'PosReg', (116, 124))	('hypoxic conditions', 'Disease', (196, 214))	('sunitinib', 'Var', (70, 79))	('bevacizumab', 'Chemical', 'MESH:D000068258', (43, 54))	('sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (29, 38))	('hypoxic conditions', 'Disease', 'MESH:D009135', (196, 214))	('bevacizumab', 'Chemical', 'MESH:D000068258', (89, 100))	('recruitment', 'MPA', (129, 140))
84419	30927928	The inhibitor of CSF1R could significantly improve vatalanib sensitivity in GBM treatment.	('inhibitor', 'Var', (4, 13))	('improve', 'PosReg', (43, 50))	('vatalanib sensitivity', 'MPA', (51, 72))	('CSF1R', 'Gene', '1436', (17, 22))	('vatalanib', 'Chemical', 'MESH:C404768', (51, 60))	('GBM', 'Disease', (76, 79))	('CSF1R', 'Gene', (17, 22))
84422	30927928	In the K562 cell line, high HO-1 expression in BMSCs was related to imatinib resistance with considerable changes in signaling, including through the PI3K/AKT pathway, Bcl-2 and the CXCL12/CXCR4 axis.	('AKT', 'Gene', (155, 158))	('HO-1', 'Gene', (28, 32))	('high', 'Var', (23, 27))	('HO-1', 'Gene', '3162', (28, 32))	('CXCR4', 'Gene', '7852', (189, 194))	('CXCL12', 'Gene', '6387', (182, 188))	('related', 'Reg', (57, 64))	('K562', 'CellLine', 'CVCL:0004', (7, 11))	('signaling', 'MPA', (117, 126))	('imatinib resistance', 'MPA', (68, 87))	('changes', 'Reg', (106, 113))	('imatinib', 'Chemical', 'MESH:D000068877', (68, 76))	('expression', 'MPA', (33, 43))	('CXCR4', 'Gene', (189, 194))	('AKT', 'Gene', '207', (155, 158))	('Bcl-2', 'Gene', (168, 173))	('Bcl-2', 'Gene', '596', (168, 173))	('CXCL12', 'Gene', (182, 188))
84451	25191524	Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors One of the most provocative recent observations in cancer epigenetics is the discovery of large hypomethylated blocks, including single copy genes, in colorectal cancer, that correspond in location to heterochromatic LOCKs (large organized chromatin lysine-modifications) and LADs (lamin-associated domains).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('colorectal cancer', 'Phenotype', 'HP:0003003', (247, 264))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('colorectal cancer', 'Disease', (247, 264))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('lysine', 'Chemical', 'MESH:D008239', (346, 352))	('hypomethylated', 'Var', (192, 206))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (147, 153))	('heterochromatic LOCKs', 'MPA', (297, 318))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('human', 'Species', '9606', (77, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (247, 264))
84454	25191524	We find that hypomethylated blocks are a universal feature of common solid human cancer, and that they occur at the earliest stage of premalignant tumors and progress through clinical stages of thyroid and colon cancer development.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('progress', 'PosReg', (158, 166))	('colon cancer', 'Phenotype', 'HP:0003003', (206, 218))	('cancer', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('colon cancer', 'Disease', (206, 218))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('colon cancer', 'Disease', 'MESH:D015179', (206, 218))	('hypomethylated', 'Var', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))	('thyroid', 'Disease', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
84455	25191524	Thus hypomethylated blocks appear to be a universal defining epigenetic alteration in human cancer, at least for common solid tumors.	('hypomethylated blocks', 'Var', (5, 26))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('solid tumors', 'Disease', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('human', 'Species', '9606', (86, 91))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
84456	25191524	The original observation of altered DNA methylation in cancer was widespread hypomethylation affecting as many as one-third of single copy genes and arising at the earliest stages.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('hypomethylation', 'Var', (77, 92))	('cancer', 'Disease', (55, 61))
84458	25191524	Recent whole genome bisulfite sequencing studies of human colorectal cancer showed that hypomethylation affects large genomic regions corresponding to chromatin regions (LOCKs) and nuclear organization (LADs), accounting for >95% of the DNA methylation change in cancer.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('cancer', 'Disease', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('human', 'Species', '9606', (52, 57))	('bisulfite', 'Chemical', 'MESH:C042345', (20, 29))	('colorectal cancer', 'Disease', (58, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('affects', 'Reg', (104, 111))	('hypomethylation', 'Var', (88, 103))	('cancer', 'Disease', (69, 75))
84459	25191524	Other work has identified similar hypomethylated blocks in breast cancer cell lines, and found direct correlation to chromatin modifications in the same population,.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('hypomethylated', 'Var', (34, 48))	('chromatin modifications', 'MPA', (117, 140))
84461	25191524	Large-scale hypomethylated blocks have also been associated with Epstein-Barr virus-induced B-cell immortalization, neuronally expressed genes, epigenetic changes prior to morphological transformation age-related drift in the pathogenesis of MDS and AML.	('AML', 'Disease', 'MESH:D015470', (250, 253))	('MDS', 'Disease', (242, 245))	('MDS', 'Disease', 'MESH:D009190', (242, 245))	('Epstein-Barr virus', 'Species', '10376', (65, 83))	('epigenetic changes', 'Var', (144, 162))	('associated', 'Reg', (49, 59))	('AML', 'Disease', (250, 253))
84468	25191524	Furthermore, this dysregulation is occurring early in cancer - even samples taken at early stages of cancer development, and thought to be benign, have evidence of these methylation blocks.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('methylation blocks', 'Var', (170, 188))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
84482	25191524	We used the Illumina HumanMethylation450 BeadChip methylation array to probe cancer methylation 10 breast, 28 colon, nine lung, 38 thyroid, 18 pancreas cancers, and five pancreas neuroendocrine tumors as well as matched normal tissue from most of these cases and 51 premalignant lesions (Table 1).	('pancreas neuroendocrine tumors', 'Disease', 'MESH:D018358', (170, 200))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('probe', 'Reg', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (179, 199))	('cancer', 'Disease', (152, 158))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (179, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('pancreas neuroendocrine tumor', 'Phenotype', 'HP:0030405', (170, 199))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast', 'Disease', (99, 105))	('methylation', 'Var', (84, 95))	('cancer', 'Disease', (77, 83))	('Human', 'Species', '9606', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('pancreas neuroendocrine tumors', 'Disease', (170, 200))	('pancreas cancers', 'Disease', (143, 159))	('pancreas cancers', 'Disease', 'MESH:D010190', (143, 159))	('colon', 'Disease', (110, 115))
84485	25191524	We found that the majority were either hypomethylated probes located in open sea sites or hypermethylated CpG island probes (Table 2).	('open sea', 'Disease', 'MESH:D009041', (72, 80))	('hypermethylated', 'Var', (90, 105))	('open sea', 'Disease', (72, 80))	('hypomethylated', 'Var', (39, 53))
84486	25191524	For colon, lung, thyroid, and PNET there were more significantly hypomethylated probes than hypermethylated probes and for pancreas adenocarcinoma it was about the same.	('pancreas adenocarcinoma', 'Phenotype', 'HP:0006725', (123, 146))	('pancreas adenocarcinoma', 'Disease', 'MESH:D010190', (123, 146))	('pancreas adenocarcinoma', 'Disease', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('hypomethylated probes', 'Var', (65, 86))
84487	25191524	In general, the hypomethylated probes were characterized by average methylation of approximately 75% in normal samples that dropped to approximately 60% in cancer samples (Figure 1).	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('hypomethylated', 'Var', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('methylation', 'MPA', (68, 79))
84488	25191524	In contrast, the hypermethylated CpG island probes were characterized by approximately 10% methylation values for the normal samples increasing to approximately 40% in cancer (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('increasing', 'PosReg', (133, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('CpG island', 'Protein', (33, 43))	('hypermethylated', 'Var', (17, 32))	('methylation', 'MPA', (91, 102))
84495	25191524	The great majority of detected blocks were hypomethylated (83%, 99% 98%, 99%, and 78% for breast, colon, lung, PNET, and thyroid, respectively) except for pancreas adenocarcinoma for which 48% were hypermethylated.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('breast', 'Disease', (90, 96))	('hypomethylated', 'Var', (43, 57))	('pancreas adenocarcinoma', 'Phenotype', 'HP:0006725', (155, 178))	('pancreas adenocarcinoma', 'Disease', (155, 178))	('pancreas adenocarcinoma', 'Disease', 'MESH:D010190', (155, 178))
84498	25191524	In contrast, inside of blocks, the normal tissue was characterized by a unimodal distribution centered approximately 80% methylated, while cancer methylation is hypomethylated with different distributions for the different samples (Additional file 3: Figure S2).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('methylated', 'Var', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))
84501	25191524	Gene expression hyper-variability in colon cancer was reported to be enriched in long hypomethylation blocks obtained from whole genome bisulfite sequencing.	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('bisulfite', 'Chemical', 'MESH:C042345', (136, 145))	('hyper-variability', 'Var', (16, 33))	('colon cancer', 'Disease', 'MESH:D015179', (37, 49))	('colon cancer', 'Disease', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
84504	25191524	Since expression is not available for normal samples in all tissues in this platform, we defined hyper-variability by calculating the log-ratio of observed variability to expected variability (conditioned on mean expression level) across tumor samples for each gene, and then tested association between hyper-variability (observed is twice the expected variability) and the gene's TSS being inside a hypo-methylation block in each cancer type.	('cancer', 'Disease', 'MESH:D009369', (431, 437))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tested', 'Reg', (276, 282))	('cancer', 'Disease', (431, 437))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('hyper-variability', 'Var', (303, 320))
84505	25191524	We found that hyper-variability is enriched in the hypomethylation blocks in each cancer type (P <0.05) except breast cancer (P = 0.5) where the small number of hypomethylation domains results in lack of power.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hypomethylation', 'Var', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
84515	25191524	Second, the hypomethylated blocks occur early in cancer: all four groups of premalignant lesions also showed the hypomethylated blocks.	('hypomethylated', 'Var', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
84518	25191524	Note that these large domains defined by the hypomethylated blocks in cancer have been previously shown to co-localize with regions showing heterochromatin modifications such as H3K9Me2 or H3K9Me3 (LOCKs) or lamin-associated domains (LADs) in normal cells.	('hypomethylated', 'Var', (45, 59))	('lamin-associated', 'MPA', (208, 224))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('H3K9Me3', 'Var', (189, 196))	('H3K9Me2', 'Var', (178, 185))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
84520	25191524	A recent report in prostate cancer demonstrates both hypo- and hypermethylation associated with reduced chromatin acetylation.	('chromatin acetylation', 'MPA', (104, 125))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('hypermethylation', 'Var', (63, 79))	('prostate cancer', 'Disease', (19, 34))	('hypo-', 'Var', (53, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (19, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (19, 34))	('reduced', 'NegReg', (96, 103))
84525	25191524	That would explain the lack of data for specific mutations at islands or of island modifying or recognizing genes in most solid tumors.	('solid tumors', 'Disease', (122, 134))	('mutations', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('solid tumors', 'Disease', 'MESH:D009369', (122, 134))
84528	25191524	In summary, this is the first genome-scale analysis of DNA methylation in a large number of cancers and matched tissues, spanning six tumor types, and including premalignant lesions from four of the tumor types.	('tumor', 'Disease', (199, 204))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('DNA', 'Gene', (55, 58))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('methylation', 'Var', (59, 70))	('cancers', 'Disease', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (134, 139))
84537	22574838	The Delta exon 8 splice variant was detected more frequently in tumor than in RM tissues.	('Delta exon', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
84542	22574838	Knockdown of paralemmin-1 reduces filopodia and compromises dendritic spine maturation .	('compromises', 'NegReg', (48, 59))	('Knockdown', 'Var', (0, 9))	('rat', 'Species', '10116', (80, 83))	('paralemmin-1', 'Gene', (13, 25))	('dendritic spine maturation', 'CPA', (60, 86))	('reduces', 'NegReg', (26, 33))	('filopodia', 'CPA', (34, 43))
84573	22574838	Primers for detecting variants missing exons 4, 5, or 7 yielded only full length products in all cell lines, tumor and RM samples examined (data not shown).	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('variants', 'Var', (22, 30))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
84575	22574838	In contrast, primer set 8 revealed the presence of the exon 8 splice variant.	('exon 8 splice', 'Var', (55, 68))	('set 8', 'Gene', (20, 25))	('set 8', 'Gene', '387893', (20, 25))
84576	22574838	Similarly, all 24 of the tumor samples expressed both the full length and Delta exon 8 splice variant, whereas in 9 out of 10 RM samples the splice variant was clearly less abundant or undetectable (Figure 5).	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Delta exon 8 splice', 'Var', (74, 93))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
84615	22574838	Gene-specific primers were designed using Primer3 : HPRT NM_000194: ACCCCACGAAGTGTTGGATA (nucleotide 587, sense), AAGCAGATGGCCACAGAACT (nucleotide 834, antisense); Paralemmin-1 NM_002579: GAGTGAGCCACTCCTTGTCC (nucleotide 2057, sense), GTGCTCCAAGCCCAGTAGAG (nucleotide 2241, antisense).	('nucleotide', 'Var', (257, 267))	('nucleotide', 'Var', (210, 220))	('HPRT', 'Gene', '3251', (52, 56))	('HPRT', 'Gene', (52, 56))
84668	30690875	For the highest risk cohorts of the germline mutation carriers (e.g., mutations of APC, BRCA1, BRCA2, or CDH1), cancer prevention can ultimately extend to prophylactic surgery.	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', '675', (95, 100))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CDH1', 'Gene', (105, 109))	('APC', 'Gene', (83, 86))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (88, 93))	('CDH1', 'Gene', '999', (105, 109))	('APC', 'Gene', '324', (83, 86))
84728	30690875	It confirmed that long term (at least 5 years), low dose (75-325 mg per day), and regular aspirin use (2-7 times per week) can effectively reduce colorectal cancer risk (Ye et al., 2013).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('aspirin', 'Chemical', 'MESH:D001241', (90, 97))	('rectal cancer', 'Phenotype', 'HP:0100743', (150, 163))	('colorectal cancer', 'Disease', (146, 163))	('reduce', 'NegReg', (139, 145))	('75-325 mg', 'Var', (58, 67))
84744	30690875	Similar to aspirin, COX-2 inhibitors have also been reported to lower adenoma recurrence in subjects with previous adenoma history.	('adenoma', 'Disease', (115, 122))	('adenoma', 'Disease', 'MESH:D000236', (70, 77))	('lower', 'NegReg', (64, 69))	('inhibitors', 'Var', (26, 36))	('aspirin', 'Chemical', 'MESH:D001241', (11, 18))	('COX-2', 'Gene', '4513', (20, 25))	('adenoma', 'Disease', (70, 77))	('adenoma', 'Disease', 'MESH:D000236', (115, 122))	('COX-2', 'Gene', (20, 25))
84746	30690875	The results clearly confirm that at 5-year follow-up there was significantly lower adenoma recurrence in the celecoxib group (RR 0.64; 0.56-0.75 95% CI; P < 0.001) (Arber et al., 2006).	('lower', 'NegReg', (77, 82))	('celecoxib', 'Chemical', 'MESH:D000068579', (109, 118))	('celecoxib', 'Var', (109, 118))	('adenoma', 'Disease', 'MESH:D000236', (83, 90))	('adenoma', 'Disease', (83, 90))
84748	30690875	Both studies confirmed the reduction of colorectal adenoma formation due to celecoxib, but also an increased risk for cardiovascular and thrombotic events.	('celecoxib', 'Var', (76, 85))	('thrombotic', 'Disease', 'MESH:D013927', (137, 147))	('colorectal adenoma', 'Disease', 'MESH:D015179', (40, 58))	('thrombotic', 'Disease', (137, 147))	('colorectal adenoma', 'Disease', (40, 58))	('celecoxib', 'Chemical', 'MESH:D000068579', (76, 85))	('thrombotic events', 'Phenotype', 'HP:0001907', (137, 154))	('reduction', 'NegReg', (27, 36))
84753	30690875	In fact, six months of celecoxib 400 mg twice a day showed a 28% reduction in the mean number of colorectal polyps in young adults (Steinbach et al., 2000).	('colorectal polyps', 'Phenotype', 'HP:0200063', (97, 114))	('colorectal polyps', 'Disease', 'MESH:D003111', (97, 114))	('celecoxib 400 mg', 'Var', (23, 39))	('colorectal polyps', 'Disease', (97, 114))	('reduction', 'NegReg', (65, 74))	('celecoxib', 'Chemical', 'MESH:D000068579', (23, 32))
84763	30690875	Metformin is associated with reduced overall cancer incidence and mortality in observational studies.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Metformin', 'Var', (0, 9))	('reduced', 'NegReg', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('mortality', 'CPA', (66, 75))	('cancer', 'Disease', (45, 51))
84765	30690875	Evidence is similar for colorectal adenoma, with metformin use associated with a significant 24% reduction in adenoma recurrence (Jung et al., 2017).	('reduction', 'NegReg', (97, 106))	('adenoma', 'Disease', 'MESH:D000236', (35, 42))	('colorectal adenoma', 'Disease', 'MESH:D015179', (24, 42))	('adenoma', 'Disease', 'MESH:D000236', (110, 117))	('metformin', 'Chemical', 'MESH:D008687', (49, 58))	('metformin', 'Var', (49, 58))	('adenoma', 'Disease', (110, 117))	('adenoma', 'Disease', (35, 42))	('colorectal adenoma', 'Disease', (24, 42))
84767	30690875	After intervention for one year, metformin decreased adenoma recurrence by 40% compared to placebo (Higurashi et al., 2016).	('adenoma', 'Disease', (53, 60))	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('decreased', 'NegReg', (43, 52))	('adenoma', 'Disease', 'MESH:D000236', (53, 60))	('metformin', 'Var', (33, 42))
84827	28120272	Patients with node negative, small, or low grade cancers, were more likely to receive HF-WBI.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Patients', 'Species', '9606', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('low grade', 'Var', (39, 48))	('cancers', 'Disease', (49, 56))
85008	25551582	To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells.	('luminal breast cancer', 'Disease', (44, 65))	('elafin', 'Gene', (96, 102))	('M25G', 'Var', (91, 95))	('M25G', 'Mutation', 'p.M25G', (91, 95))	('protease inhibitor', 'Gene', '388007', (116, 134))	('elafin', 'Gene', '5266', (96, 102))	('luminal breast cancer', 'Disease', 'MESH:D001943', (44, 65))	('elafin', 'Gene', '5266', (34, 40))	('MCF-7', 'CellLine', 'CVCL:0031', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('T47D', 'CellLine', 'CVCL:0553', (186, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('elafin', 'Gene', (34, 40))	('protease inhibitor', 'Gene', (116, 134))
85014	25551582	Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner.	('cell proliferation', 'CPA', (134, 152))	('MCF-7', 'CellLine', 'CVCL:0031', (95, 100))	('protease inhibitor', 'Gene', (158, 176))	('protease inhibitor', 'Gene', '388007', (158, 176))	('luminal breast cancer', 'Disease', (62, 83))	('elafin', 'Gene', '5266', (33, 39))	('elafin', 'Gene', (43, 49))	('decreased', 'NegReg', (124, 133))	('elafin', 'Gene', '5266', (43, 49))	('elafin', 'Gene', (33, 39))	('luminal breast cancer', 'Disease', 'MESH:D001943', (62, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('M25G', 'Var', (50, 54))	('M25G', 'Mutation', 'p.M25G', (50, 54))	('T47D', 'CellLine', 'CVCL:0553', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
85026	25551582	We also found that ectopic expression of elafin-induced apoptosis in Rb-negative and growth arrest in Rb-positive breast cancer cell lines,.	('elafin', 'Gene', (41, 47))	('ectopic expression', 'Var', (19, 37))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('growth arrest', 'Disease', (85, 98))	('growth arrest', 'Disease', 'MESH:D006323', (85, 98))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('growth arrest', 'Phenotype', 'HP:0001510', (85, 98))	('apoptosis', 'CPA', (56, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('elafin', 'Gene', '5266', (41, 47))	('breast cancer', 'Disease', (114, 127))
85040	25551582	Invasive breast tumors were previously subclassified using the IHC markers ER, PR, human epidermal growth factor receptor 2 (HER2), and Ki67 (cutoff = 20%) into luminal A-like (ER+/PR+/Ki67low), luminal B-like (ER+/PR+/Ki67high) HER-2-positive, and triple-receptor negative breast cancer (TNBC; approximating the basal-like intrinsic subtype).	('HER2', 'Gene', (125, 129))	('breast tumors', 'Disease', 'MESH:D001943', (9, 22))	('HER-2', 'Gene', (229, 234))	('breast tumors', 'Disease', (9, 22))	('HER-2', 'Gene', '2064', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('breast tumors', 'Phenotype', 'HP:0100013', (9, 22))	('breast tumor', 'Phenotype', 'HP:0100013', (9, 21))	('ER+/PR+/Ki67low', 'Var', (177, 192))	('epidermal growth factor receptor 2', 'Gene', '2064', (89, 123))	('TNBC', 'Chemical', '-', (289, 293))	('HER2', 'Gene', '2064', (125, 129))	('epidermal growth factor receptor 2', 'Gene', (89, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('ER+/PR+/Ki67high', 'Var', (211, 227))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('breast cancer', 'Disease', (274, 287))	('human', 'Species', '9606', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
85044	25551582	Specifically, IRB LAB11-0418 entitled 'Prognostic factors in ovarian cancer' (Study Chair: JL); IRB LAB04-0796 entitled 'Biological markers of breast carcinoma' (Study Chair: CA) and IRB LAB00-222 entitled 'Cyclin E expression in breast cancer' (Study Chair: KKH).	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('breast carcinoma', 'Disease', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Disease', (230, 243))	('breast carcinoma', 'Disease', 'MESH:D001943', (143, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian cancer', 'Disease', (61, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('breast carcinoma', 'Phenotype', 'HP:0003002', (143, 159))	('IRB LAB04-0796', 'Var', (96, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
85051	25551582	1998, which consists of a final elafin IHC score (0 to 8) that is the sum of an intensity score (0 = negative, 1 = low, 2 = medium, and 3 = high) and a frequency score (0 = 0%, 1 = <1%, 2 = 1 to 10%, 3 = 10 to 33%, 4 = 33 to 66%, and 5 = 66 to 100%).	('elafin', 'Gene', '5266', (32, 38))	('elafin', 'Gene', (32, 38))	('0 = 0%', 'Var', (169, 175))
85069	25551582	Lentiviral vectors containing green fluorescent protein (GFP), elafin, or elafin M25G were generated and packaged in HEK-293 T cells using the pCMV deltaR8.2 and pMD2.G vectors produced by the Didier Trono laboratory and made available through the Addgene repository.	('deltaR8', 'Var', (148, 155))	('elafin', 'Gene', (63, 69))	('M25G', 'Var', (81, 85))	('M25G', 'Mutation', 'p.M25G', (81, 85))	('elafin', 'Gene', '5266', (63, 69))	('deltaR8', 'DELETION', 'None', (148, 155))	('elafin', 'Gene', (74, 80))	('elafin', 'Gene', '5266', (74, 80))	('HEK-293 T', 'CellLine', 'CVCL:0063', (117, 126))
85108	25551582	Overall, luminal A-like (ER+/PR+/Ki67low) subtype breast tumors were significantly less likely to have elafin-positive cells compared to luminal B (ER+/PR+/Ki67high), HER2-postive, and TNBC subtypes (Figure 4A).	('breast tumors', 'Disease', 'MESH:D001943', (50, 63))	('elafin', 'Gene', (103, 109))	('breast tumors', 'Disease', (50, 63))	('ER+/PR+/Ki67low', 'Var', (25, 40))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('HER2', 'Gene', (167, 171))	('HER2', 'Gene', '2064', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('breast tumors', 'Phenotype', 'HP:0100013', (50, 63))	('less', 'NegReg', (83, 87))	('TNBC', 'Chemical', '-', (185, 189))	('elafin', 'Gene', '5266', (103, 109))	('breast tumor', 'Phenotype', 'HP:0100013', (50, 62))
85120	25551582	Kaplan-Meier analysis revealed that tumors with residual elafin-positive cells had significantly (log rank test) reduced OS and DSS (Figure 5C).	('residual', 'Var', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('OS', 'Chemical', '-', (121, 123))	('elafin', 'Gene', (57, 63))	('elafin', 'Gene', '5266', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('DSS', 'Gene', (128, 131))	('reduced', 'NegReg', (113, 120))	('tumors', 'Disease', (36, 42))	('DSS', 'Gene', '5376', (128, 131))
85135	25551582	To interrogate the significance of elafin expression in luminal breast cancer cell lines we generated MCF-7 and T47D cells expressing either wild-type elafin or elafin M25G, bearing a mutation in the protease inhibitory rendering it incapable of protease inhibition; cells expressing GFP were used as a control (Figure 6D).	('elafin', 'Gene', (151, 157))	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('elafin', 'Gene', '5266', (35, 41))	('elafin', 'Gene', '5266', (151, 157))	('MCF-7', 'CellLine', 'CVCL:0031', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('luminal breast cancer', 'Disease', (56, 77))	('elafin', 'Gene', (35, 41))	('M25G', 'Var', (168, 172))	('elafin', 'Gene', '5266', (161, 167))	('M25G', 'Mutation', 'p.M25G', (168, 172))	('protease inhibitor', 'Gene', (200, 218))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('luminal breast cancer', 'Disease', 'MESH:D001943', (56, 77))	('protease inhibitor', 'Gene', '388007', (200, 218))	('elafin', 'Gene', (161, 167))	('mutation', 'Var', (184, 192))
85136	25551582	Cell number was quantitated at 24, 48, 72, and 96 hours revealing a decrease in cell proliferation, evidenced by an increase in cell-doubling time, in elafin and elafin M25G expressing MCF-7 and T47D cells compared to the GFP-expressing controls (Figure 6D).	('elafin', 'Gene', (151, 157))	('elafin', 'Gene', '5266', (151, 157))	('MCF-7', 'CellLine', 'CVCL:0031', (185, 190))	('T47D', 'CellLine', 'CVCL:0553', (195, 199))	('cell-doubling time', 'CPA', (128, 146))	('decrease', 'NegReg', (68, 76))	('M25G expressing', 'Var', (169, 184))	('elafin', 'Gene', (162, 168))	('elafin', 'Gene', '5266', (162, 168))	('cell proliferation', 'CPA', (80, 98))	('M25G', 'Mutation', 'p.M25G', (169, 173))	('increase', 'PosReg', (116, 124))
85151	25551582	Recently, we demonstrated that exogenous elafin expression promoted growth arrest and apoptosis in breast cancer cell lines and xenograft tumors.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('elafin', 'Gene', (41, 47))	('xenograft tumors', 'Disease', 'MESH:D009369', (128, 144))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('growth arrest', 'Disease', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('promoted', 'PosReg', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('growth arrest', 'Disease', 'MESH:D006323', (68, 81))	('xenograft tumors', 'Disease', (128, 144))	('growth arrest', 'Phenotype', 'HP:0001510', (68, 81))	('elafin', 'Gene', '5266', (41, 47))	('apoptosis', 'CPA', (86, 95))	('exogenous', 'Var', (31, 40))
85152	25551582	In melanoma cell lines and xenografts exogenous elafin expression also induced apoptotic cell death.	('elafin', 'Gene', (48, 54))	('elafin', 'Gene', '5266', (48, 54))	('induced', 'Reg', (71, 78))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('death', 'Disease', 'MESH:D003643', (94, 99))	('melanoma', 'Disease', (3, 11))	('death', 'Disease', (94, 99))	('exogenous', 'Var', (38, 47))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
85171	25551582	We stably transduced luminal breast cancer cell lines MCF-7 and T47D cells expressing either wild-type elafin or elafin M25G, bearing a mutation in the protease inhibitory rendering it incapable of protease inhibition (Figure 6D).	('luminal breast cancer', 'Disease', (21, 42))	('elafin', 'Gene', (103, 109))	('M25G', 'Mutation', 'p.M25G', (120, 124))	('protease inhibitor', 'Gene', '388007', (152, 170))	('mutation', 'Var', (136, 144))	('luminal breast cancer', 'Disease', 'MESH:D001943', (21, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('elafin', 'Gene', '5266', (113, 119))	('elafin', 'Gene', '5266', (103, 109))	('T47D', 'CellLine', 'CVCL:0553', (64, 68))	('MCF-7', 'CellLine', 'CVCL:0031', (54, 59))	('elafin', 'Gene', (113, 119))	('protease inhibitor', 'Gene', (152, 170))	('incapable', 'MPA', (185, 194))
85183	23409121	HIF-1alpha Overexpression in Ductal Carcinoma In Situ of the Breast in BRCA1 and BRCA2 Mutation Carriers Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1alpha (HIF-1alpha), the key regulator of the hypoxia response.	('HIF-1alpha', 'Gene', (261, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (228, 259))	('BRCA1', 'Gene', '672', (139, 144))	('HIF-1alpha Overexpression in Ductal Carcinoma', 'Disease', 'MESH:D044584', (0, 45))	('BRCA2', 'Gene', (81, 86))	('hypoxia inducible factor-1alpha', 'Gene', (228, 259))	('BRCA1', 'Gene', (139, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (181, 195))	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (29, 53))	('overexpression', 'PosReg', (210, 224))	('BRCA2', 'Gene', '675', (81, 86))	('hypoxia', 'Disease', (228, 235))	('BRCA2', 'Gene', (149, 154))	('Carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('HIF-1alpha', 'Gene', '3091', (261, 271))	('hypoxia', 'Disease', (299, 306))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA1', 'Gene', (71, 76))	('hypoxia', 'Disease', 'MESH:D000860', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancers', 'Disease', 'MESH:D001943', (181, 195))	('breast cancers', 'Disease', (181, 195))	('BRCA2', 'Gene', '675', (149, 154))	('Mutation', 'Var', (87, 95))	('hypoxia', 'Disease', 'MESH:D000860', (299, 306))	('HIF-1alpha Overexpression in Ductal Carcinoma', 'Disease', (0, 45))	('HIF-1alpha', 'Gene', (0, 10))
85192	23409121	Although BRCA1 and BRCA2 germline mutation-related invasive breast cancers are different in many ways, the hypoxia-related proteins HIF-1alpha, CAIX and Glut-1 are expressed in both DCIS and invasive lesions of BRCA1 and BRCA2 mutation carriers.	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('BRCA1', 'Gene', '672', (211, 216))	('BRCA2', 'Gene', '675', (19, 24))	('CAIX', 'Gene', (144, 148))	('mutation', 'Var', (227, 235))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))	('CAIX', 'Gene', '768', (144, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('breast cancers', 'Disease', (60, 74))	('BRCA1', 'Gene', (211, 216))	('BRCA2', 'Gene', (221, 226))	('BRCA1', 'Gene', '672', (9, 14))	('HIF-1alpha', 'Gene', (132, 142))	('BRCA1', 'Gene', (9, 14))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('Glut-1', 'Gene', '6513', (153, 159))	('invasive breast cancer', 'Disease', (51, 73))	('BRCA2', 'Gene', '675', (221, 226))	('invasive breast cancer', 'Disease', 'MESH:D001943', (51, 73))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('BRCA2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Glut-1', 'Gene', (153, 159))	('hypoxia', 'Disease', (107, 114))	('HIF-1alpha', 'Gene', '3091', (132, 142))
85194	23409121	Hypoxia-related proteins are therefore putative targets for therapy and molecular imaging for early detection and monitoring therapy response in BRCA mutation patients.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('mutation', 'Var', (150, 158))	('BRCA', 'Gene', '672', (145, 149))	('BRCA', 'Gene', (145, 149))	('patients', 'Species', '9606', (159, 167))
85195	23409121	Hereditary breast cancer accounts for about 5% of all breast cancers in women and is primarily caused by a germline mutation in one of the BRCA genes.	('breast cancers', 'Disease', (54, 68))	('Hereditary breast cancer', 'Disease', 'MESH:D001943', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('caused by', 'Reg', (95, 104))	('BRCA', 'Gene', '672', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('Hereditary breast cancer', 'Disease', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRCA', 'Gene', (139, 143))	('germline mutation', 'Var', (107, 124))	('women', 'Species', '9606', (72, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))
85196	23409121	Several studies have indicated that the genetic makeup of BRCA1 and BRCA2 mutation-related breast cancer is different from that of non-BRCA mutation-related breast cancer.	('mutation-related', 'Var', (74, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('BRCA', 'Gene', '672', (68, 72))	('BRCA', 'Gene', (135, 139))	('BRCA1', 'Gene', '672', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('BRCA2', 'Gene', '675', (68, 73))	('breast cancer', 'Disease', (157, 170))	('BRCA1', 'Gene', (58, 63))	('BRCA', 'Gene', (68, 72))	('BRCA', 'Gene', '672', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', '672', (135, 139))	('BRCA2', 'Gene', (68, 73))
85197	23409121	Consistent with this, the morphological and immunohistochemical phenotype of BRCA1 mutation-related breast cancer is also different from that of non-BRCA mutation-related breast.	('BRCA1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA', 'Gene', '672', (149, 153))	('BRCA1', 'Gene', '672', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('mutation-related', 'Var', (83, 99))	('BRCA', 'Gene', (149, 153))	('breast cancer', 'Disease', (100, 113))	('BRCA', 'Gene', '672', (77, 81))	('BRCA', 'Gene', (77, 81))
85198	23409121	However, the phenotype of BRCA2 mutation-related breast cancer is still difficult to distinguish from non-BRCA mutation-related breast cancers.	('mutation-related', 'Var', (32, 48))	('BRCA', 'Gene', (106, 110))	('BRCA', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BRCA2', 'Gene', (26, 31))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('breast cancer', 'Disease', (49, 62))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('BRCA', 'Gene', '672', (106, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('BRCA', 'Gene', '672', (26, 30))	('BRCA2', 'Gene', '675', (26, 31))
85207	23409121	Furthermore, functional HIF-1alpha overexpression (mostly hypoxia induced) is seen at a much higher frequency in BRCA1 mutation-related invasive breast cancer than in sporadic breast cancer.	('invasive breast cancer', 'Disease', (136, 158))	('BRCA1', 'Gene', (113, 118))	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('HIF-1alpha', 'Gene', '3091', (24, 34))	('mutation-related', 'Var', (119, 135))	('invasive breast cancer', 'Disease', 'MESH:D001943', (136, 158))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('BRCA1', 'Gene', '672', (113, 118))	('overexpression', 'PosReg', (35, 49))	('breast cancer', 'Disease', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('HIF-1alpha', 'Gene', (24, 34))
85210	23409121	There is both clinical and experimental evidence to suggest that ductal carcinoma in situ (DCIS) is a precursor lesion to most, if not all, non-BRCA mutation-related invasive breast cancers.	('mutation-related', 'Var', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancers', 'Disease', 'MESH:D001943', (175, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('breast cancers', 'Disease', (175, 189))	('BRCA', 'Gene', (144, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (65, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (175, 189))	('invasive breast cancer', 'Disease', (166, 188))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (65, 89))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('ductal carcinoma in situ', 'Disease', (65, 89))	('BRCA', 'Gene', '672', (144, 148))	('invasive breast cancer', 'Disease', 'MESH:D001943', (166, 188))
85211	23409121	DCIS and other premalignant lesions such as lobular neoplasia, fibroadenoma, and ductal hyperplasia seems to be more common in prophylactic mastectomy (PM) specimens of BRCA1 and BRCA2 mutation carriers than in control mammoplasty specimens.	('DCIS', 'Disease', (0, 4))	('common', 'Reg', (117, 123))	('BRCA2', 'Gene', '675', (179, 184))	('fibroadenoma', 'Disease', 'MESH:D018226', (63, 75))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('neoplasia', 'Phenotype', 'HP:0002664', (52, 61))	('fibroadenoma', 'Disease', (63, 75))	('lobular neoplasia', 'Disease', (44, 61))	('mutation', 'Var', (185, 193))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (81, 99))	('BRCA1', 'Gene', '672', (169, 174))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (44, 61))	('lobular neoplasia', 'Disease', 'MESH:D009369', (44, 61))	('BRCA2', 'Gene', (179, 184))	('ductal hyperplasia', 'Disease', (81, 99))	('BRCA1', 'Gene', (169, 174))
85212	23409121	Furthermore, DCIS lesions adjacent to invasive cancers in BRCA mutation carriers have been described.	('DCIS lesions', 'Disease', (13, 25))	('BRCA', 'Gene', '672', (58, 62))	('invasive cancers', 'Disease', 'MESH:D009362', (38, 54))	('BRCA', 'Gene', (58, 62))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('mutation', 'Var', (63, 71))	('invasive cancers', 'Disease', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
85213	23409121	DCIS in BRCA mutation carriers is often high grade and shows a similar morphology and immunophenotype as the accompanying invasive cancer.	('DCIS', 'Disease', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('mutation', 'Var', (13, 21))	('invasive cancer', 'Disease', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('invasive cancer', 'Disease', 'MESH:D009362', (122, 137))	('BRCA', 'Gene', '672', (8, 12))	('BRCA', 'Gene', (8, 12))
85215	23409121	Indeed, overexpression of hypoxia-related proteins HIF-1alpha, CAIX and Glut-1 DCIS of non-BRCA mutation carriers has been described.	('overexpression', 'PosReg', (8, 22))	('hypoxia', 'Disease', (26, 33))	('BRCA', 'Gene', (91, 95))	('CAIX', 'Gene', '768', (63, 67))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('HIF-1alpha', 'Gene', (51, 61))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('mutation', 'Var', (96, 104))	('Glut-1', 'Gene', (72, 78))	('Glut-1', 'Gene', '6513', (72, 78))	('HIF-1alpha', 'Gene', '3091', (51, 61))	('CAIX', 'Gene', (63, 67))	('BRCA', 'Gene', '672', (91, 95))
85216	23409121	To find clues whether changes in hypoxia related proteins also is an early event in BRCA mutation-related carcinogenesis, we evaluated HIF-1alpha expression in BRCA1 and BRCA2 mutation-related DCIS in relation with the accompanying invasive cancers.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('invasive cancers', 'Disease', (232, 248))	('BRCA2', 'Gene', '675', (170, 175))	('BRCA', 'Gene', '672', (84, 88))	('mutation-related', 'Var', (176, 192))	('hypoxia', 'Disease', (33, 40))	('BRCA', 'Gene', '672', (170, 174))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('HIF-1alpha', 'Gene', '3091', (135, 145))	('BRCA', 'Gene', (84, 88))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (170, 174))	('BRCA1', 'Gene', '672', (160, 165))	('BRCA1', 'Gene', (160, 165))	('BRCA2', 'Gene', (170, 175))	('HIF-1alpha', 'Gene', (135, 145))	('BRCA', 'Gene', (160, 164))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('invasive cancers', 'Disease', 'MESH:D009362', (232, 248))
85217	23409121	The study group comprised DCIS lesions of 32 patients with pathogenic germline BRCA1 mutations, 16 patients with pathogenic germline BRCA2 mutations and 77 patients unselected for family history (further denoted "non-BRCA mutation-related").	('patients', 'Species', '9606', (156, 164))	('pathogenic', 'Reg', (59, 69))	('BRCA1', 'Gene', '672', (79, 84))	('BRCA', 'Gene', '672', (79, 83))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('BRCA', 'Gene', '672', (217, 221))	('BRCA', 'Gene', (79, 83))	('BRCA1', 'Gene', (79, 84))	('BRCA2', 'Gene', (133, 138))	('BRCA', 'Gene', (217, 221))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (45, 53))	('BRCA', 'Gene', '672', (133, 137))	('BRCA2', 'Gene', '675', (133, 138))	('BRCA', 'Gene', (133, 137))
85230	23409121	Polyclonal primary antibodies used were: PR (1:100, Dako), Glut-1 (1:200, DAKO) and CAIX (1:1000, Abcam, Cambridge Science Park, Cambridge, UK).	('1:200', 'Var', (67, 72))	('CAIX', 'Gene', (84, 88))	('Glut-1', 'Gene', '6513', (59, 65))	('Glut-1', 'Gene', (59, 65))	('CAIX', 'Gene', '768', (84, 88))
85255	23409121	The same expression of CAIX was observed in BRCA2 mutation-related DCIS lesions and the invasive counterpart lesions, 44% (7/16) (p = 0.049).	('mutation-related', 'Var', (50, 66))	('CAIX', 'Gene', (23, 27))	('BRCA2', 'Gene', (44, 49))	('CAIX', 'Gene', '768', (23, 27))	('BRCA2', 'Gene', '675', (44, 49))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('DCIS lesions', 'Disease', (67, 79))
85256	23409121	Glut-1 was overexpressed in 75% (12/16) of DCIS cases in and in 56% (9/16) (p = 0.146) of the invasive BRCA2 mutation-related lesions (Table 3).	('BRCA2', 'Gene', '675', (103, 108))	('mutation-related lesions', 'Var', (109, 133))	('Glut-1', 'Gene', (0, 6))	('overexpressed', 'PosReg', (11, 24))	('Glut-1', 'Gene', '6513', (0, 6))	('BRCA2', 'Gene', (103, 108))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
85263	23409121	Table 4 shows the expression of HIF-1alpha, CAIX and Glut-1 in paired, DCIS and concomitant invasive cancer, for BRCA mutation and non-BRCA mutation carriers.	('invasive cancer', 'Disease', (92, 107))	('CAIX', 'Gene', (44, 48))	('HIF-1alpha', 'Gene', (32, 42))	('BRCA', 'Gene', '672', (135, 139))	('CAIX', 'Gene', '768', (44, 48))	('invasive cancer', 'Disease', 'MESH:D009362', (92, 107))	('mutation', 'Var', (118, 126))	('Glut-1', 'Gene', '6513', (53, 59))	('BRCA', 'Gene', (135, 139))	('DCIS', 'Disease', (71, 75))	('BRCA', 'Gene', '672', (113, 117))	('Glut-1', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('paired', 'Disease', (63, 69))	('BRCA', 'Gene', (113, 117))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('HIF-1alpha', 'Gene', '3091', (32, 42))
85264	23409121	HIF-1alpha expression was expressed in both lesions in 55% (16/29) of the BRCA1 mutation-related cases, whereas both lesions were negative for HIF-1alpha expression in 10% (3/29) of cases.	('HIF-1alpha', 'Gene', (143, 153))	('mutation-related', 'Var', (80, 96))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('BRCA1', 'Gene', '672', (74, 79))	('HIF-1alpha', 'Gene', '3091', (143, 153))	('BRCA1', 'Gene', (74, 79))	('HIF-1alpha', 'Gene', (0, 10))
85265	23409121	Overall, in 66% (19/29) of the BRCA1 mutation carrier cases both lesions showed similar expression levels of HIF-1alpha.	('mutation', 'Var', (37, 45))	('BRCA1', 'Gene', '672', (31, 36))	('HIF-1alpha', 'Gene', '3091', (109, 119))	('BRCA1', 'Gene', (31, 36))	('expression levels', 'MPA', (88, 105))	('HIF-1alpha', 'Gene', (109, 119))
85266	23409121	In 28% (8/29) of the BRCA1 mutation-related cases only the invasive part, and in 7% (2/29) only the DCIS lesion showed HIF-1alpha expression.	('BRCA1', 'Gene', '672', (21, 26))	('HIF-1alpha', 'Gene', '3091', (119, 129))	('BRCA1', 'Gene', (21, 26))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('mutation-related', 'Var', (27, 43))	('HIF-1alpha', 'Gene', (119, 129))
85267	23409121	CAIX and Glut1 were expressed in both lesions in 45% (13/29) and 48% (14/29) of the BRCA1 mutation carrier cases, respectively, and both lesions lacked expression of these markers in 14% (4/29) and 7%(2/29) of the cases.	('CAIX', 'Gene', '768', (0, 4))	('Glut1', 'Gene', (9, 14))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA1', 'Gene', (84, 89))	('Glut1', 'Gene', '6513', (9, 14))	('CAIX', 'Gene', (0, 4))	('lacked', 'NegReg', (145, 151))	('mutation', 'Var', (90, 98))	('expression', 'MPA', (152, 162))
85269	23409121	Only the invasive lesion of BRCA1 mutation carriers expressed both CAIX and Glut-1 in 34% (10/29) of cases.	('BRCA1', 'Gene', '672', (28, 33))	('CAIX', 'Gene', (67, 71))	('BRCA1', 'Gene', (28, 33))	('mutation', 'Var', (34, 42))	('Glut-1', 'Gene', '6513', (76, 82))	('Glut-1', 'Gene', (76, 82))	('CAIX', 'Gene', '768', (67, 71))
85272	23409121	Thus, in 75% (12/16) of the BRCA2 mutation-related cases, the DCIS and invasive lesions of the same patient showed similar expression levels of HIF-1alpha.	('BRCA2', 'Gene', '675', (28, 33))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('patient', 'Species', '9606', (100, 107))	('mutation-related', 'Var', (34, 50))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('BRCA2', 'Gene', (28, 33))	('HIF-1alpha', 'Gene', (144, 154))
85273	23409121	Expression of HIF-1alpha in only the DCIS lesion was seen in 25% (4/16) of the BRCA2 mutation-related cases.	('BRCA2', 'Gene', '675', (79, 84))	('HIF-1alpha', 'Gene', (14, 24))	('mutation-related', 'Var', (85, 101))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('BRCA2', 'Gene', (79, 84))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
85284	23409121	Expression of CAIX and Glut-1 in only the invasive lesion of non-BRCA mutation carriers occurred in 8% (4/50) and 10% (5/50) of cases, respectively, whereas these markers were expressed only in DCIS lesions in 4% (2/50) and 44% (22/50) of cases.	('CAIX', 'Gene', '768', (14, 18))	('Glut-1', 'Gene', '6513', (23, 29))	('BRCA', 'Gene', (65, 69))	('BRCA', 'Gene', '672', (65, 69))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))	('CAIX', 'Gene', (14, 18))	('mutation', 'Var', (70, 78))	('Glut-1', 'Gene', (23, 29))
85287	23409121	For Glut-1, the expression in DCIS matched the expression in the accompanying invasive cancers in 60% (27/45) of BRCA1 and BRCA2 mutation-related cases as compared to 46% (23/50) for non-BRCA mutation carrier cases.	('BRCA', 'Gene', (123, 127))	('invasive cancers', 'Disease', 'MESH:D009362', (78, 94))	('BRCA2', 'Gene', '675', (123, 128))	('invasive cancers', 'Disease', (78, 94))	('mutation-related', 'Var', (129, 145))	('BRCA1', 'Gene', (113, 118))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('Glut-1', 'Gene', (4, 10))	('BRCA', 'Gene', '672', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('Glut-1', 'Gene', '6513', (4, 10))	('BRCA', 'Gene', (187, 191))	('BRCA2', 'Gene', (123, 128))	('BRCA', 'Gene', '672', (113, 117))	('BRCA', 'Gene', '672', (123, 127))	('BRCA1', 'Gene', '672', (113, 118))	('BRCA', 'Gene', (113, 117))
85289	23409121	The aim of the present study was to examine the expression of HIF-1alpha in DCIS lesions of BRCA1 and BRCA2 mutation carriers in comparison with their invasive counterparts.	('HIF-1alpha', 'Gene', (62, 72))	('HIF-1alpha', 'Gene', '3091', (62, 72))	('BRCA2', 'Gene', (102, 107))	('BRCA1', 'Gene', '672', (92, 97))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('mutation', 'Var', (108, 116))	('DCIS lesions', 'Disease', (76, 88))	('BRCA1', 'Gene', (92, 97))	('BRCA2', 'Gene', '675', (102, 107))
85292	23409121	Overall, 63% (30/48) of BRCA mutation-related DCIS lesions were HIF-1alpha-positive, which was significantly different compared to non-BRCA mutation carriers (34%, 26/77).	('BRCA', 'Gene', '672', (24, 28))	('mutation-related', 'Var', (29, 45))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('BRCA', 'Gene', (24, 28))	('BRCA', 'Gene', '672', (135, 139))	('DCIS lesions', 'Disease', (46, 58))	('BRCA', 'Gene', (135, 139))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('HIF-1alpha', 'Gene', (64, 74))
85294	23409121	Nevertheless, the current study suggests that hypoxia and HIF-1alpha already play a similar role in the DCIS stage of BRCA mutation-related carcinogenesis as in non-BRCA mutation-related DCIS.	('BRCA', 'Gene', '672', (165, 169))	('hypoxia', 'Disease', (46, 53))	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('BRCA', 'Gene', (165, 169))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('mutation-related', 'Var', (123, 139))	('BRCA', 'Gene', '672', (118, 122))	('HIF-1alpha', 'Gene', '3091', (58, 68))	('BRCA', 'Gene', (118, 122))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('HIF-1alpha', 'Gene', (58, 68))
85296	23409121	This suggests that hypoxia plays a more important role in cancer progression in BRCA mutation carriers than in non-BRCA mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('hypoxia', 'Disease', (19, 26))	('hypoxia', 'Disease', 'MESH:D000860', (19, 26))	('BRCA', 'Gene', '672', (80, 84))	('BRCA', 'Gene', '672', (115, 119))	('mutation', 'Var', (85, 93))	('BRCA', 'Gene', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('BRCA', 'Gene', (115, 119))	('cancer', 'Disease', (58, 64))
85298	23409121	This implies that next to being involved in early BRCA mutation-related carcinogenesis, hypoxia and HIF-1alpha overexpression may also be a driver of cancer progression, especially in BRCA1 mutation carriers.	('mutation', 'Var', (190, 198))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('HIF-1alpha', 'Gene', (100, 110))	('hypoxia', 'Disease', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('BRCA1', 'Gene', '672', (184, 189))	('BRCA', 'Gene', '672', (184, 188))	('cancer', 'Disease', (150, 156))	('BRCA', 'Gene', (184, 188))	('BRCA', 'Gene', '672', (50, 54))	('HIF-1alpha', 'Gene', '3091', (100, 110))	('BRCA1', 'Gene', (184, 189))	('BRCA', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
85299	23409121	Although the number of BRCA2 mutation-related cases with DCIS and invasive lesions was small, there was a trend towards higher expression of the hypoxia-related markers in BRCA2 mutation-related DCIS as compared to the invasive lesions.	('DCIS', 'Disease', (195, 199))	('BRCA2', 'Gene', '675', (172, 177))	('expression', 'MPA', (127, 137))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('BRCA2', 'Gene', (23, 28))	('higher', 'PosReg', (120, 126))	('mutation-related', 'Var', (178, 194))	('hypoxia', 'Disease', (145, 152))	('BRCA2', 'Gene', '675', (23, 28))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('BRCA2', 'Gene', (172, 177))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
85300	23409121	We can speculate that progression to the invasive state in these BRCA2 mutation carriers might be due to the switch of the HIF-1alpha to HIF-2alpha expression under prolonged hypoxia.	('HIF-2alpha', 'Gene', '2034', (137, 147))	('BRCA2', 'Gene', '675', (65, 70))	('mutation', 'Var', (71, 79))	('HIF-1alpha', 'Gene', '3091', (123, 133))	('hypoxia', 'Disease', 'MESH:D000860', (175, 182))	('hypoxia', 'Disease', (175, 182))	('BRCA2', 'Gene', (65, 70))	('HIF-2alpha', 'Gene', (137, 147))	('HIF-1alpha', 'Gene', (123, 133))	('switch', 'Reg', (109, 115))
85302	23409121	As HIF-1alpha already plays a role in the pre-invasive lesions of BRCA mutation carriers, hypoxia proteins would therefore be putative therapeutic targets for prevention of invasive disease.	('HIF-1alpha', 'Gene', (3, 13))	('hypoxia proteins', 'Disease', (90, 106))	('mutation', 'Var', (71, 79))	('BRCA', 'Gene', (66, 70))	('BRCA', 'Gene', '672', (66, 70))	('invasive disease', 'Disease', (173, 189))	('HIF-1alpha', 'Gene', '3091', (3, 13))	('hypoxia proteins', 'Disease', 'MESH:D000860', (90, 106))	('invasive disease', 'Disease', 'MESH:D009362', (173, 189))
85517	32822113	Clinical manifestations, supersonic findings, and microcalcification upon mammography were significantly associated with the coexisting lesions of malignancy.	('associated', 'Reg', (105, 115))	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('microcalcification', 'Var', (50, 68))	('malignancy', 'Disease', (147, 157))
85518	32822113	In our results, coexisting AH associated with nipple discharge, with abnormality by ultrasound, or with microcalcification upon mammography compared with the benign lesions.	('associated', 'Reg', (30, 40))	('AH', 'Phenotype', 'HP:0025586', (27, 29))	('microcalcification', 'Var', (104, 122))	('nipple discharge', 'Disease', (46, 62))	('AH', 'Disease', 'MESH:D007039', (27, 29))
85530	32822113	36 ,  37 ,  38  Research from Korea found that the US 14G automated core needle biopsy (ACNB) has a higher false-negative rate and histological upgrading rate in the diagnosis for papillary breast lesions than US-guided VAE.	('papillary breast lesions', 'Disease', 'MESH:D001943', (180, 204))	('US 14G', 'Var', (51, 57))	('papillary breast lesions', 'Disease', (180, 204))	('upgrading', 'PosReg', (144, 153))
85627	26655422	On the other hand, it could be that detection of DCIS above two per 1000 prevents invasive cancers more than 3 years in the future, and that our study of the single interval after screen detection is too short to observe this.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('detection', 'Var', (36, 45))	('invasive cancers', 'Disease', (82, 98))	('DCIS', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prevents', 'NegReg', (73, 81))	('invasive cancers', 'Disease', 'MESH:D009362', (82, 98))
85628	26655422	We noted that the units with increased detection of DCIS overall had increased proportions of low-grade DCIS, which might be expected to progress to invasive disease over a time period longer than 3 years.	('invasive disease', 'Disease', 'MESH:D009362', (149, 165))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('DCIS', 'Disease', (52, 56))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('low-grade', 'Var', (94, 103))	('invasive disease', 'Disease', (149, 165))
85648	24558516	MCF10DCIS.com and MCF10CA1a cells were highly tumorigenic; MCF10CA1a cells showed more aggressive tumor growth than MCF10DCIS.com cells.	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (116, 129))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('aggressive tumor', 'Disease', 'MESH:D001523', (87, 103))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('MCF10CA1a', 'Var', (59, 68))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (59, 68))	('aggressive tumor', 'Disease', (87, 103))	('tumor', 'Disease', (98, 103))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
85650	24558516	Tumorigenic cell lines expressed higher levels of pErk, pAkt, Stat3 and Pak4 compared to nontumorigenic cells.	('higher', 'PosReg', (33, 39))	('pErk', 'MPA', (50, 54))	('Stat3', 'MPA', (62, 67))	('Akt', 'Gene', '207', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Pak4', 'Var', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('levels', 'MPA', (40, 46))	('tumor', 'Disease', (92, 97))	('Akt', 'Gene', (57, 60))
85652	24558516	The differences in expression of signaling proteins involved in breast cancer progression may provide new insight into the mechanisms of tumorigenesis and useful information for development of targeted therapeutics.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('expression', 'MPA', (19, 29))	('tumor', 'Disease', (137, 142))	('differences', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('breast cancer', 'Disease', (64, 77))
85653	24558516	Human breast cancer is a heterogeneous disease which evolves through a multistep process of accumulating genetic changes such as gene mutations, rearrangements and copy number amplifications, loss of heterozygosity, and epigenetic alterations.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('loss of heterozygosity', 'Var', (192, 214))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('rearrangements', 'Var', (145, 159))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('gene mutations', 'Var', (129, 143))	('copy number amplifications', 'Var', (164, 190))	('epigenetic alterations', 'Var', (220, 242))
85667	24558516	MCF10AT1 is a pre-malignant cell line produced by transfection of MCF10A with constitutively active HRAS; it forms simple ducts and lesions resembling human ADH and DCIS when transplanted into immunodeficient mice.	('MCF10A', 'CellLine', 'CVCL:0598', (66, 72))	('HRAS', 'Gene', '3265', (100, 104))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('immunodeficient', 'Disease', 'MESH:D007153', (193, 208))	('mice', 'Species', '10090', (209, 213))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('HRAS', 'Gene', (100, 104))	('human', 'Species', '9606', (151, 156))	('forms', 'Reg', (109, 114))	('MCF10A', 'Gene', (66, 72))	('ADH', 'Disease', 'MESH:D007177', (157, 160))	('ADH', 'Disease', (157, 160))	('MCF10AT1', 'CellLine', 'CVCL:5555', (0, 8))	('transfection', 'Var', (50, 62))	('immunodeficient', 'Disease', (193, 208))
85687	24558516	In contrast, the MCF10DCIS.com cells formed tumors in all injected mice (n=9).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (17, 30))	('MCF10DCIS.com', 'Var', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mice', 'Species', '10090', (67, 71))
85689	24558516	The MCF10CA1a cell also formed tumors in all mice (n=10), and the average tumor volume reached 1.79 +- 0.92 cm3 at 21 days after the injection (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('MCF10CA1a', 'Var', (4, 13))	('tumor', 'Disease', (74, 79))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
85701	24558516	A systematic review of results from clinical studies revealed an association between high concentrations of circulating IGF-I and an increased risk of breast cancer in pre-menopausal women.	('IGF-I', 'Gene', '3479', (120, 125))	('women', 'Species', '9606', (183, 188))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('high concentrations', 'Var', (85, 104))	('IGF-I', 'Gene', (120, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
85703	24558516	pErk, pAkt, signal transducer and activator of transcription 3 (Stat3), and Pak4 were highly expressed only in cell lines that form tumors quickly in immunodeficient mice-MCF10DCIS.com and MCF10CA1a.	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (171, 184))	('immunodeficient', 'Disease', 'MESH:D007153', (150, 165))	('immunodeficient', 'Disease', (150, 165))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Akt', 'Gene', '207', (7, 10))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('Akt', 'Gene', (7, 10))	('mice', 'Species', '10090', (166, 170))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('MCF10CA1a', 'Var', (189, 198))	('tumors', 'Disease', (132, 138))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (189, 198))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('signal transducer and activator of transcription 3', 'Gene', '20848', (12, 62))
85704	24558516	Importantly, their protein levels were markedly increased in the more aggressive MCF10DCIS.com and MCF10CA1a cells when compared with the MCF10AT1 cells (Fig.	('increased', 'PosReg', (48, 57))	('MCF10AT1', 'CellLine', 'CVCL:5555', (138, 146))	('protein levels', 'MPA', (19, 33))	('MCF10CA1a', 'Var', (99, 108))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (99, 108))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (81, 94))
85706	24558516	Although both the Erk pathway and the PI3-kinase activity can be stimulated by transfection of activated Ras, the high level of activated forms of Erk and Akt - pErk and pAkt - is found only in MCF10DCIS.com and MCF10CA1a cell lines indicating that overactivation of Erk and Akt might be critical for developing malignant breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('Erk', 'Gene', '5594', (147, 150))	('Erk', 'Gene', (162, 165))	('MCF10CA1a', 'Var', (212, 221))	('Erk', 'Gene', '5594', (162, 165))	('Akt', 'Gene', (155, 158))	('Akt', 'Gene', (275, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (322, 335))	('Erk', 'Gene', (18, 21))	('Erk', 'Gene', '5594', (18, 21))	('PI3-kinase', 'Enzyme', (38, 48))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (194, 207))	('Akt', 'Gene', (171, 174))	('Akt', 'Gene', '207', (275, 278))	('Akt', 'Gene', '207', (155, 158))	('malignant breast cancer', 'Disease', 'MESH:D001943', (312, 335))	('Akt', 'Gene', '207', (171, 174))	('stimulated', 'PosReg', (65, 75))	('malignant breast cancer', 'Disease', (312, 335))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (212, 221))	('Erk', 'Gene', (267, 270))	('Erk', 'Gene', '5594', (267, 270))	('Erk', 'Gene', (147, 150))
85707	24558516	Moreover, the most common activating PIK3CA mutation in human cancers (H1047R) has been detected in the MCF10CA1a cell line, but not in MCF10A and MCF10AT1 cells, suggesting the PIK3CA activating mutation as a critical genetic alteration of malignant phenotype in both human breast cancer and the MCF10 cell model.	('activating', 'PosReg', (26, 36))	('MCF10A', 'CellLine', 'CVCL:0598', (147, 153))	('mutation', 'Var', (44, 52))	('MCF10', 'CellLine', 'CVCL:5555', (136, 141))	('MCF10A', 'CellLine', 'CVCL:0598', (136, 142))	('MCF10', 'CellLine', 'CVCL:5555', (104, 109))	('PIK3CA', 'Gene', (178, 184))	('human', 'Species', '9606', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('cancers', 'Disease', (62, 69))	('MCF10AT1', 'CellLine', 'CVCL:5555', (147, 155))	('PIK3CA', 'Gene', '5290', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('human', 'Species', '9606', (269, 274))	('breast cancer', 'Disease', (275, 288))	('H1047R', 'Var', (71, 77))	('MCF10CA1a', 'CellLine', 'CVCL:6675', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('MCF10', 'CellLine', 'CVCL:5555', (297, 302))	('PIK3CA', 'Gene', '5290', (178, 184))	('MCF10', 'CellLine', 'CVCL:5555', (147, 152))	('H1047R', 'Mutation', 'rs121913279', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('PIK3CA', 'Gene', (37, 43))
85901	19800542	In addition, patients generally preferred to delay biopsy decisions until follow-up breast MR imaging 3 months later confirmed persistent nodularity or its enlargement.	('enlargement', 'PosReg', (156, 167))	('patients', 'Species', '9606', (13, 21))	('nodularity', 'Var', (138, 148))
86027	16677422	For women with germline mutations in breast cancer susceptibility genes, particularly BRCA, the cancers are likely to be of high grade, and the discovery of DCIS is infrequent.	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA', 'Gene', '672', (86, 90))	('BRCA', 'Gene', (86, 90))	('women', 'Species', '9606', (4, 9))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancers', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('germline mutations', 'Var', (15, 33))
86039	27672335	The association of PTEN hypermethylation and breast cancer: a meta-analysis Phosphatase and tensin homolog (PTEN) deleted on chromosome 10, as a tumor suppressor gene, is crucial for the development of both familial and sporadic breast cancer (BC).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('sporadic breast cancer', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PTEN', 'Gene', (108, 112))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (220, 242))	('PTEN', 'Gene', '5728', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('PTEN', 'Gene', (19, 23))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('PTEN', 'Gene', '5728', (19, 23))	('deleted', 'Var', (114, 121))	('breast cancer', 'Disease', (45, 58))	('tumor', 'Disease', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
86044	27672335	PTEN promoter hypermethylation is significantly associated with the risk of DCIS and IDC, suggesting PTEN promoter hypermethylation is a valuable biomarker for diagnosis of BC.	('IDC', 'Gene', '4000', (85, 88))	('associated', 'Reg', (48, 58))	('promoter hypermethylation', 'Var', (5, 30))	('IDC', 'Gene', (85, 88))	('DCIS', 'Disease', (76, 80))	('PTEN', 'Gene', (0, 4))
86052	27672335	Breast carcinogenesis is a stepwise accumulation of genetic changes including point mutations, deletions, oncogene activation, or tumor suppressor inactivation.	('activation', 'PosReg', (115, 125))	('deletions', 'Var', (95, 104))	('Breast carcinogenesis', 'Disease', 'MESH:D063646', (0, 21))	('point mutations', 'Var', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Breast carcinogenesis', 'Disease', (0, 21))	('tumor', 'Disease', (130, 135))
86057	27672335	Inclusion criteria were as follows: 1) studies about the relationship between PTEN methylation and the clinicopathological significance of BC and 2) studies about the association of PTEN methylation and prognosis in patients with BC.	('association', 'Interaction', (167, 178))	('PTEN', 'Gene', (78, 82))	('patients', 'Species', '9606', (216, 224))	('methylation', 'Var', (83, 94))	('PTEN', 'Gene', (182, 186))
86064	27672335	PTEN promoter hypermethylation was significantly correlated to the risk of IDC (OR =22.86, 95% CI 11.09-47.09, z=8.48, P<0.00001, I2=45%; Figure 3).	('correlated', 'Reg', (49, 59))	('IDC', 'Gene', (75, 78))	('promoter hypermethylation', 'Var', (5, 30))	('PTEN', 'Gene', (0, 4))	('IDC', 'Gene', '4000', (75, 78))
86071	27672335	Its expression is modulated by germline and somatic PTEN mutation, genomic deletion, and promoter methylation silencing in many primary and metastatic tumors.	('mutation', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PTEN', 'Gene', (52, 56))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('primary and', 'Disease', (128, 139))	('expression', 'MPA', (4, 14))	('promoter methylation silencing', 'Var', (89, 119))	('modulated', 'Reg', (18, 27))
86072	27672335	Germline mutations throughout the PTEN coding region were found in PTEN hamartoma tumor syndrome (PHTS), which is a rare disease, including the previously named Cowden syndrome and Bannayan-Rilev-Ruvalcaba syndrome.	('Germline mutations', 'Var', (0, 18))	('PTEN', 'Gene', (34, 38))	('Cowden syndrome', 'Disease', 'MESH:D006223', (161, 176))	('hamartoma', 'Phenotype', 'HP:0010566', (72, 81))	('PHTS', 'Disease', 'MESH:D006223', (98, 102))	('PTEN hamartoma tumor syndrome', 'Disease', 'MESH:D006223', (67, 96))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Cowden syndrome', 'Disease', (161, 176))	('PTEN hamartoma tumor syndrome', 'Disease', (67, 96))	('found', 'Reg', (58, 63))	('Bannayan-Rilev-Ruvalcaba syndrome', 'Disease', (181, 214))	('Bannayan-Rilev-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (181, 214))	('PHTS', 'Disease', (98, 102))
86073	27672335	PHTS patients have a high lifetime risk of developing breast, thyroid, or endometrial cancer due to PTEN silencing.	('endometrial cancer', 'Disease', 'MESH:D016889', (74, 92))	('PHTS', 'Disease', (0, 4))	('PHTS', 'Disease', 'MESH:D006223', (0, 4))	('patients', 'Species', '9606', (5, 13))	('thyroid', 'Disease', (62, 69))	('breast', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('endometrial cancer', 'Disease', (74, 92))	('silencing', 'Var', (105, 114))	('PTEN', 'Protein', (100, 104))	('endometrial cancer', 'Phenotype', 'HP:0012114', (74, 92))
86074	27672335	Lifetime risks of developing breast, ovary, colorectal, and kidney cancers and melanoma increase in patients with germline PTEN mutations.	('kidney cancers', 'Disease', 'MESH:D007680', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('kidney cancers', 'Disease', (60, 74))	('kidney cancers', 'Phenotype', 'HP:0009726', (60, 74))	('melanoma increase', 'Disease', 'MESH:D008545', (79, 96))	('mutations', 'Var', (128, 137))	('colorectal', 'Disease', 'MESH:D015179', (44, 54))	('colorectal', 'Disease', (44, 54))	('breast', 'Disease', (29, 35))	('germline', 'Var', (114, 122))	('patients', 'Species', '9606', (100, 108))	('PTEN', 'Gene', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ovary', 'Disease', (37, 42))	('melanoma increase', 'Disease', (79, 96))
86075	27672335	PTEN promoter hypermethylation was reported in cervical cancer, colorectal cancer, esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinomas, head and neck cancer, lung cancer, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (119, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (56, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('colorectal cancer', 'Disease', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('head and neck cancer', 'Phenotype', 'HP:0012288', (162, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('neck cancer', 'Disease', 'MESH:D006258', (171, 182))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (135, 160))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (127, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('neck cancer', 'Disease', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Disease', (201, 215))	('promoter hypermethylation', 'Var', (5, 30))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (135, 160))	('hepatocellular carcinomas', 'Disease', (135, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('PTEN', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('cancer', 'Disease', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', (75, 81))	('esophageal squamous cell carcinoma', 'Disease', (83, 117))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancer', 'Disease', (184, 195))
86087	27672335	In summary, PTEN promoter is more frequently hypermethylated in DCIS and IDC compared to normal breast tissue, suggesting that PTEN is a valuable biomarker for diagnosis of BC.	('PTEN', 'Gene', (12, 16))	('IDC', 'Gene', '4000', (73, 76))	('hypermethylated', 'Var', (45, 60))	('DCIS', 'Disease', (64, 68))	('IDC', 'Gene', (73, 76))
86106	24454462	Moreover, recent studies have documented an association between TC and micropapillary and cribriform ductal carcinoma in situ (DCIS) and suggested a possible precursor role of low grade DCIS in the development of tubular breast cancer.	('tubular breast cancer', 'Disease', (213, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (101, 125))	('carcinoma in situ', 'Disease', 'MESH:D002278', (108, 125))	('carcinoma in situ', 'Disease', (108, 125))	('tubular breast cancer', 'Phenotype', 'HP:0006625', (213, 234))	('low grade', 'Var', (176, 185))	('micropapillary', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('ductal carcinoma', 'Disease', 'MESH:D044584', (101, 117))	('tubular breast cancer', 'Disease', 'MESH:D001943', (213, 234))	('ductal carcinoma', 'Disease', (101, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('association', 'Interaction', (44, 55))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (101, 117))
86151	24454462	Moreover, recent studies have suggested a possible precursor role of low grade DCIS in the development of tubular breast cancer by documenting the association between TC and micropapillary and cribriform DCIS.	('association', 'Interaction', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('low grade', 'Var', (69, 78))	('tubular breast cancer', 'Disease', 'MESH:D001943', (106, 127))	('tubular breast cancer', 'Phenotype', 'HP:0006625', (106, 127))	('tubular breast cancer', 'Disease', (106, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('DCIS', 'Phenotype', 'HP:0030075', (204, 208))
86155	24454462	Specifically, high rates of hormone receptor positivity, HER2 negativity, and lower NG were also reported in several other studies.	('hormone receptor', 'Protein', (28, 44))	('HER2', 'Gene', (57, 61))	('positivity', 'Reg', (45, 55))	('HER2', 'Gene', '2064', (57, 61))	('negativity', 'Var', (62, 72))
86176	20103682	CD44+/CD24- cells were detected in 69 % of all tumors with 100% of the basal-like and 52% of HER2+ tumors having some of these cells.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('HER2', 'Gene', '2064', (93, 97))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('CD44+/CD24- cells', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('HER2', 'Gene', (93, 97))	('tumors', 'Disease', (99, 105))
86187	20103682	In breast cancer lin-/CD44+/CD24-/low cells were identified as candidate breast cancer stem cells based on xenotransplant assays in NOD/SCID mice.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SCID', 'Disease', (136, 140))	('lin-/CD44+/CD24-/low', 'Var', (17, 37))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('SCID', 'Disease', 'MESH:D053632', (136, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', (73, 86))	('mice', 'Species', '10090', (141, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
86189	20103682	In a previous study, we investigated the genome-wide gene expression profiles of lin-/CD44+/CD24-/low (CD44+) and more differentiated luminal epithelial CD44-/CD24+ (CD24+) breast cancer cells and determined that these were consistent with the presumed identity of these cells.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CD44-/CD24', 'Gene', '960;100133941', (153, 163))	('lin-/CD44+/CD24-/low', 'Var', (81, 101))	('CD44-/CD24', 'Gene', (153, 163))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
86193	20103682	In breast cancer cell lines, prior studies revealed an enrichment of CD44+/CD24- and CD44-/CD24+ phenotypes in basal-like and luminal subtypes, respectively.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('CD44-/CD24', 'Gene', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('CD44+/CD24-', 'Var', (69, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('luminal subtypes', 'CPA', (126, 142))	('CD44-/CD24', 'Gene', '960;100133941', (85, 95))	('basal-like', 'CPA', (111, 121))
86205	20103682	The following histo-pathologic variables were determined in IDCs: tumor subtype, T stage, presence of cancer in ipsilateral axillary lymph nodes, Bloom-Richardson histologic grade, ER, PR and HER2 status, Ki-67, P53, and presence of adjacent DCIS.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor subtype', 'Disease', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ipsilateral axillary lymph nodes', 'Disease', 'MESH:D000072717', (112, 144))	('ipsilateral axillary lymph nodes', 'Disease', (112, 144))	('P53', 'Gene', (212, 215))	('HER2', 'Gene', '2064', (192, 196))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('HER2', 'Gene', (192, 196))	('tumor subtype', 'Disease', 'MESH:C535673', (66, 79))	('P53', 'Gene', '7157', (212, 215))	('Ki-67', 'Var', (205, 210))	('DCIS', 'Phenotype', 'HP:0030075', (242, 246))
86212	20103682	In double immunohistochemical staining to detected CD44+/CD24- and CD44-/CD24+ cells, CD44 was visualized with Vectastain Elite avidin-biotin complex detection kit and diaminobenzidine as chromogen, whereas CD24 was detected with a polymer-linked alkaline phosphatase-conjugated secondary antibody (DAKO) and visualized with fast red.	('CD44+/CD24-', 'Var', (51, 62))	('CD44-/CD24', 'Gene', '960;100133941', (67, 77))	('avidin-biotin', 'Chemical', '-', (128, 141))	('CD44', 'Var', (86, 90))	('CD44-/CD24', 'Gene', (67, 77))	('diaminobenzidine', 'Chemical', '-', (168, 184))
86243	20103682	When analyzing by tumor subtype 69% of luminal A, 70% of luminal B, 52% of HER2, and 100% of basal-like tumors contained some CD44+/CD24- cells.	('tumor subtype', 'Disease', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HER2', 'Gene', (75, 79))	('CD44+/CD24- cells', 'Var', (126, 143))	('basal-like tumors', 'Phenotype', 'HP:0002671', (93, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('HER2', 'Gene', '2064', (75, 79))	('tumor subtype', 'Disease', 'MESH:C535673', (18, 31))	('contained', 'Reg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
86252	20103682	To further investigate inter-tumor cellular heterogeneity for the expression of stem cell-related markers in breast cancer and to correlate this with tumor subtypes, we selected additional genes that we previously identified as differentially expressed between CD44+ and CD24+ breast cancer cells and analyzed their expression by immunohistochemistry in IDCs and in DCIS (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor subtype', 'Disease', 'MESH:C535673', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor subtype', 'Disease', (150, 163))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('breast cancer', 'Disease', (277, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('breast cancer', 'Disease', (109, 122))	('CD24+', 'Var', (271, 276))	('CD44+', 'Var', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Disease', (150, 155))	('DCIS', 'Phenotype', 'HP:0030075', (366, 370))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (29, 34))
86283	20103682	We previously described the comprehensive gene expression, genetic, and DNA methylation profiles of CD44+ stem cell-like and CD24+ more differentiated luminal epithelial breast cancer cells and found cell type-specific differences for all molecular characteristics analyzed.	('CD44+', 'Var', (100, 105))	('CD24+', 'Var', (125, 130))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
86284	20103682	The relative frequency of CD44+ and CD24+ cells in breast tumors (defined based on the presence of cell type-specific gene expression signatures within tumors) was correlated with distant metastasis-free survival.	('distant metastasis-free survival', 'CPA', (180, 212))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('breast tumors', 'Disease', (51, 64))	('breast tumors', 'Disease', 'MESH:D001943', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('breast tumor', 'Phenotype', 'HP:0100013', (51, 63))	('correlated', 'Reg', (164, 174))	('CD24+', 'Var', (36, 41))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('breast tumors', 'Phenotype', 'HP:0100013', (51, 64))	('CD44+', 'Var', (26, 31))
86285	20103682	Interestingly, CD44+ cell-signature in primary invasive tumors was associated with higher risk of distant metastasis but distant metastases were enriched for more luminal epithelial CD24+ cells implying a phenotypic switch during tumor progression or clonal selection for cells with CD24+ phenotype.	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('distant metastasis', 'CPA', (98, 116))	('metastases', 'Disease', (129, 139))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CD44+', 'Var', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('invasive tumors', 'Disease', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('metastases', 'Disease', 'MESH:D009362', (129, 139))	('invasive tumors', 'Disease', 'MESH:D009369', (47, 62))
86286	20103682	Correlating with this, recent studies described that epithelial-to-mesenchymal transition (EMT) generates cells with CD44+ stem cell-like characteristics, whereas in distant metastases a reversion of this process mesenchymal-to-epithelial transition (MET) have also been reported in bladder and colon carcinomas.	('metastases', 'Disease', (174, 184))	('bladder', 'Disease', (283, 290))	('CD44+', 'Var', (117, 122))	('epithelial-to-mesenchymal transition', 'CPA', (53, 89))	('metastases', 'Disease', 'MESH:D009362', (174, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('carcinomas', 'Phenotype', 'HP:0030731', (301, 311))	('colon carcinomas', 'Disease', (295, 311))	('colon carcinomas', 'Disease', 'MESH:D015179', (295, 311))
86288	20103682	To investigate if phenotypic divergence for stem cell-like and more differentiated luminal markers might also be observed between in situ and invasive breast carcinomas in patients prior to systemic treatment, we analyzed the expression of a panel of markers previously associated with CD44+ stem cell-like and more differentiated CD24+ luminal cell characteristics in breast cancer.	('CD44+', 'Var', (286, 291))	('invasive breast carcinomas', 'Disease', (142, 168))	('breast carcinomas', 'Phenotype', 'HP:0003002', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('breast cancer', 'Disease', 'MESH:D001943', (369, 382))	('breast carcinoma', 'Phenotype', 'HP:0003002', (151, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('patients', 'Species', '9606', (172, 180))	('breast cancer', 'Disease', (369, 382))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (369, 382))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (142, 168))
86290	20103682	Confirming the results of recent reports the frequency of CD44+/CD24- cells defined based on double immunohistochemisty was the highest in basal-like tumors compared to the other three subtypes.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('CD44+/CD24- cells', 'Var', (58, 75))	('basal-like tumors', 'Phenotype', 'HP:0002671', (139, 156))	('highest', 'Reg', (128, 135))
86292	20103682	However, the expression of CD44 was lower in IDCs and microinvasive DCIS compared to pure DCIS suggesting a decrease in the number of CD44+ cells as tumors progress.	('microinvasive', 'Var', (54, 67))	('lower', 'NegReg', (36, 41))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('CD44', 'Gene', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('decrease', 'NegReg', (108, 116))	('IDCs', 'Disease', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
86295	20103682	CD44+/CD24- cells and ALDH1+ cells were more frequently found in the basal-like than in luminal subtypes and CD44+/CD24- cells but not ALDH1+ cells were less common in HER2+ than in basal-like cases.	('HER2', 'Gene', '2064', (168, 172))	('ALDH1', 'Gene', (135, 140))	('CD44+/CD24- cells', 'Var', (109, 126))	('ALDH1', 'Gene', (22, 27))	('ALDH1', 'Gene', '216', (135, 140))	('CD44+/CD24- cells', 'Var', (0, 17))	('ALDH1', 'Gene', '216', (22, 27))	('HER2', 'Gene', (168, 172))
86296	20103682	In normal breast tissue, CD44+/CD24- cells were limited to the basal layer whereas ALDH1+ cells were found in both basal and luminal compartments suggesting that ALDH might be a marker of both bipotential mammary epithelial stem cells and luminal lineage committed progenitors.	('ALDH1', 'Gene', (83, 88))	('ALDH', 'Gene', (162, 166))	('ALDH1', 'Gene', '216', (83, 88))	('CD44+/CD24-', 'Var', (25, 36))
86297	20103682	The difference in the relative frequency of CD44+/CD24- and ALDH1+ cells between basal-like and HER2+ tumor subtypes may reflect their distinct cell-of-origin or the alteration of stem cell-like gene expression programs due to tumor subtype-specific transforming events.	('tumor subtype', 'Disease', (227, 240))	('tumor subtype', 'Disease', 'MESH:C535673', (102, 115))	('alteration', 'Reg', (166, 176))	('ALDH1', 'Gene', (60, 65))	('tumor subtype', 'Disease', 'MESH:C535673', (227, 240))	('tumor subtype', 'Disease', (102, 115))	('HER2', 'Gene', (96, 100))	('CD44+/CD24-', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('HER2', 'Gene', '2064', (96, 100))	('ALDH1', 'Gene', '216', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
86302	20103682	It has also been reported that ectopic introduction of CD24 into breast carcinoma cells increases tumor cell proliferation, and stimulates cell motility and invasion.	('breast carcinoma cells increases tumor', 'Disease', 'MESH:D001943', (65, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('invasion', 'CPA', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ectopic introduction', 'Var', (31, 51))	('breast carcinoma cells increases tumor', 'Disease', (65, 103))	('CD24', 'Gene', (55, 59))	('stimulates', 'PosReg', (128, 138))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))
86314	20103682	Similar to CD44, we observed an enrichment for EPCR+ cells in basal-like tumors and the number of these cells was lower in invasive compared to in situ carcinomas within the luminal A subtype.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('situ carcinomas', 'Disease', 'MESH:D002278', (147, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('situ carcinomas', 'Disease', (147, 162))	('basal-like tumors', 'Phenotype', 'HP:0002671', (62, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('lower', 'NegReg', (114, 119))	('tumors', 'Disease', (73, 79))	('EPCR+', 'Var', (47, 52))
86316	20103682	The expression of connexin 43 was lower in microinvasive DCIS compared to IDCs and pure DCIS potentially implicating connexin 43 in the progression to invasion.	('connexin 43', 'Gene', (117, 128))	('connexin 43', 'Gene', (18, 29))	('microinvasive', 'Var', (43, 56))	('lower', 'NegReg', (34, 39))	('expression', 'MPA', (4, 14))	('connexin 43', 'Gene', '2697', (117, 128))	('connexin 43', 'Gene', '2697', (18, 29))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
86318	20103682	The decreased frequency of CD44+ cells during in situ to invasive breast carcinoma transition relates to the decreased number of these cells in distant metastases compared to primary invasive tumors.	('decreased', 'NegReg', (109, 118))	('invasive breast carcinoma', 'Disease', (57, 82))	('invasive tumors', 'Disease', (183, 198))	('decreased', 'NegReg', (4, 13))	('CD44+ cells', 'Var', (27, 38))	('invasive tumors', 'Disease', 'MESH:D009369', (183, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('metastases', 'Disease', (152, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (57, 82))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('breast carcinoma', 'Phenotype', 'HP:0003002', (66, 82))
86319	20103682	Thus, the frequency of CD44+ cells may gradually decline during breast tumor progression.	('breast tumor', 'Phenotype', 'HP:0100013', (64, 76))	('breast tumor', 'Disease', 'MESH:D001943', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CD44+', 'Var', (23, 28))	('breast tumor', 'Disease', (64, 76))	('decline', 'NegReg', (49, 56))
86327	20103682	CD44+/CD24- cells were most common in basal-like tumors, whereas the frequency of ALDH+ cells was the highest in HER2+ and basal-like tumors.	('common', 'Reg', (28, 34))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HER2', 'Gene', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('basal-like tumors', 'Phenotype', 'HP:0002671', (38, 55))	('basal-like tumors', 'Phenotype', 'HP:0002671', (123, 140))	('HER2', 'Gene', '2064', (113, 117))	('tumors', 'Disease', (49, 55))	('CD44+/CD24- cells', 'Var', (0, 17))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
86331	19920867	Correct adhesion between adjacent epithelial cells is important in determining the normal structure and function of epithelial tissues, and there is accumulating evidence that dysregulated cell-cell adhesion is associated with many cancers.	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('dysregulated', 'Var', (176, 188))	('cell-cell adhesion', 'CPA', (189, 207))	('cancers', 'Disease', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('associated', 'Reg', (211, 221))
86333	19920867	Secondly we will examine how alterations in these functions might facilitate breast cancer initiation or progression; by focussing on the regulatory influence of TJs on cell polarity, cell fate and cell migration.	('progression', 'CPA', (105, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('facilitate', 'PosReg', (66, 76))	('breast cancer initiation', 'Disease', (77, 101))	('alterations', 'Var', (29, 40))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rat', 'Species', '10116', (206, 209))	('breast cancer initiation', 'Disease', 'MESH:D001943', (77, 101))
86335	19920867	Overall we hope to illustrate that the relationship between TJ alterations and breast cancer is a complex one; but that this area offers promise in uncovering fundamental mechanisms linked to breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('rat', 'Species', '10116', (67, 70))	('alterations', 'Var', (63, 74))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('rat', 'Species', '10116', (25, 28))
86339	19920867	Specific life events associated with an enhanced breast cancer risk include reproductive factors, nulliparity, radiation exposure, hormonal status, obesity, family history, and many others.	('obesity', 'Disease', (148, 155))	('nulliparity', 'Var', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('obesity', 'Phenotype', 'HP:0001513', (148, 155))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('obesity', 'Disease', 'MESH:D009765', (148, 155))	('enhanced', 'PosReg', (40, 48))
86341	19920867	However, 10% of all breast cancer cases have a strong hereditary component in which half carry a deleterious mutation in the high penetrance genes BRCA1 or BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('BRCA1', 'Gene', '672', (147, 152))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('BRCA1', 'Gene', (147, 152))	('BRCA2', 'Gene', (156, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('BRCA2', 'Gene', '675', (156, 161))	('mutation', 'Var', (109, 117))
86355	19920867	In this review we will first outline the protein components of the TJ and discuss the biological roles of the TJ complex, review how alterations in these roles could facilitate breast cancer initiation or progression, and finally mention pharmacological approaches towards targeting TJ proteins that could have value in limiting breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('breast cancer', 'Disease', 'MESH:D001943', (329, 342))	('breast cancer', 'Phenotype', 'HP:0003002', (329, 342))	('breast cancer', 'Disease', (329, 342))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('breast cancer initiation', 'Disease', (177, 201))	('breast cancer initiation', 'Disease', 'MESH:D001943', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('rat', 'Species', '10116', (137, 140))	('facilitate', 'PosReg', (166, 176))	('alterations', 'Var', (133, 144))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('progression', 'CPA', (205, 216))
86356	19920867	It exists in unphosphorylated and serine/threonine and tyrosine phosphorylated forms, with the degree of phosphorylation affecting tight junction assembly, transepithelial resistance, and localisation of occludin to the tight junction.	('transepithelial resistance', 'MPA', (156, 182))	('serine', 'Chemical', 'MESH:D012694', (34, 40))	('tyrosine', 'Chemical', 'MESH:D014443', (55, 63))	('threonine', 'Chemical', 'MESH:D013912', (41, 50))	('phosphorylation', 'Var', (105, 120))	('affecting', 'Reg', (121, 130))	('localisation', 'MPA', (188, 200))	('tight junction assembly', 'MPA', (131, 154))
86380	19920867	Loss or mutation of cingulin does not perturb the formation of tight junctions, but results in increased claudin-2 expression and cellular proliferation, which are dependent on increased RhoA activity.	('RhoA', 'Gene', (187, 191))	('rat', 'Species', '10116', (146, 149))	('cingulin', 'Gene', '57530', (20, 28))	('cingulin', 'Gene', (20, 28))	('RhoA', 'Gene', '387', (187, 191))	('claudin-2', 'Gene', '9075', (105, 114))	('Loss', 'NegReg', (0, 4))	('expression', 'MPA', (115, 125))	('cellular proliferation', 'CPA', (130, 152))	('mutation', 'Var', (8, 16))	('claudin-2', 'Gene', (105, 114))	('increased', 'PosReg', (95, 104))
86387	19920867	Breaching of the epithelial barrier stimulates cells to extend protrusions into the wound space, which can result in TJ disruption and release of proteins such as PATJ, Par3, aPKC, Cdc42, and Par6 from their scaffolds.	('PATJ', 'Gene', (163, 167))	('PATJ', 'Gene', '10207', (163, 167))	('Par3', 'Gene', (169, 173))	('release', 'MPA', (135, 142))	('Breaching', 'Var', (0, 9))	('proteins', 'Protein', (146, 154))	('PKC', 'Gene', (176, 179))	('PKC', 'Gene', '112476', (176, 179))	('Cdc42', 'Gene', '998', (181, 186))	('Par6', 'Gene', '50855', (192, 196))	('disruption', 'NegReg', (120, 130))	('Par6', 'Gene', (192, 196))	('Cdc42', 'Gene', (181, 186))
86392	19920867	Most work to date has focused on adherens junction proteins (such as cadherins) in breast cancer progression; and in fact loss of E-cadherin is a defining feature of lobular breast carcinoma.	('lobular breast carcinoma', 'Disease', (166, 190))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('adherens junction proteins', 'Protein', (33, 59))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (166, 190))	('breast cancer', 'Disease', (83, 96))	('breast carcinoma', 'Phenotype', 'HP:0003002', (174, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('E-cadherin', 'Protein', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('loss', 'Var', (122, 126))
86395	19920867	Our review will focus on three aspects whereby functional alterations in TJs may impact breast cancer progression by altering cell polarity, cell fate, and cell migration.	('cell polarity', 'CPA', (126, 139))	('impact', 'Reg', (81, 87))	('cell fate', 'CPA', (141, 150))	('altering', 'Reg', (117, 125))	('TJs', 'Gene', (73, 76))	('rat', 'Species', '10116', (164, 167))	('cell migration', 'CPA', (156, 170))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('alterations', 'Var', (58, 69))
86396	19920867	For a broad overview of TJ alterations in cancer metastasis of other tumours, the reader is directed to a recent review.	('cancer metastasis of other tumours', 'Disease', (42, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('cancer metastasis of other tumours', 'Disease', 'MESH:D009369', (42, 76))	('rat', 'Species', '10116', (31, 34))	('alterations', 'Var', (27, 38))
86408	19920867	reported that PATJ knockdown in intestinal epithelial cells resulted in the upregulation of the mTOR pathway; and it is possible that loss of PATJ in cancers such as breast could facilitate tumour progression by allowing the prosurvival effects of mTOR activation to go unchecked.	('breast', 'Disease', (166, 172))	('PATJ', 'Gene', (142, 146))	('loss', 'Var', (134, 138))	('PATJ', 'Gene', '10207', (142, 146))	('mTOR', 'Gene', (96, 100))	('mTOR', 'Gene', (248, 252))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('knockdown', 'Var', (19, 28))	('cancers', 'Disease', (150, 157))	('PATJ', 'Gene', (14, 18))	('PATJ', 'Gene', '10207', (14, 18))	('mTOR', 'Gene', '2475', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mTOR', 'Gene', '2475', (248, 252))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('tumour', 'Disease', (190, 196))	('upregulation', 'PosReg', (76, 88))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('facilitate', 'PosReg', (179, 189))
86410	19920867	Loss of PATJ could, therefore, also promote "leaky" junctions, resulting in increased access of luminal growth factors to the basolateral epithelial surface.	('PATJ', 'Gene', (8, 12))	('promote', 'PosReg', (36, 43))	('PATJ', 'Gene', '10207', (8, 12))	('increased', 'PosReg', (76, 85))	('Loss', 'Var', (0, 4))
86416	19920867	Loss of PALS1 also resulted in defects in E-cadherin trafficking, which, taken together, suggests that analagous disruption of the CRB3 complex during breast cancer could impair barrier function and polarity, and potentially facilitate occlusion of breast duct lumens with tumour cells.	('E-cadherin trafficking', 'MPA', (42, 64))	('PALS1', 'Gene', '64398', (8, 13))	('CRB3', 'Gene', (131, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('defects', 'NegReg', (31, 38))	('impair', 'NegReg', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('tumour', 'Disease', (273, 279))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('CRB3', 'Gene', '92359', (131, 135))	('facilitate', 'Reg', (225, 235))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('barrier', 'MPA', (178, 185))	('Loss', 'Var', (0, 4))	('PALS1', 'Gene', (8, 13))	('disruption', 'Var', (113, 123))	('polarity', 'MPA', (199, 207))
86421	19920867	Activation of ErbB2 in these cells induces the formation of multiacinar structures with abnormal filled lumens, in a manner dependent on interactions of ErbB2 with the Par6-aPKC complex.	('interactions', 'Interaction', (137, 149))	('ErbB2', 'Gene', '2064', (153, 158))	('ErbB2', 'Gene', (14, 19))	('induces', 'Reg', (35, 42))	('Activation', 'Var', (0, 10))	('ErbB2', 'Gene', '2064', (14, 19))	('multiacinar structures', 'MPA', (60, 82))	('ErbB2', 'Gene', (153, 158))	('PKC', 'Gene', (174, 177))	('Par6', 'Gene', '50855', (168, 172))	('dependent', 'Reg', (124, 133))	('Par6', 'Gene', (168, 172))	('formation', 'MPA', (47, 56))	('PKC', 'Gene', '112476', (174, 177))
86422	19920867	Mutation of Par6 in cells overexpressing activated ErbB2 was observed to restore lumen formation, suggesting an inhibitory tone of Par6-ErbB2 interactions on apoptotic clearance of developing lumens.	('ErbB2', 'Gene', '2064', (51, 56))	('Par6', 'Gene', (131, 135))	('ErbB2', 'Gene', (136, 141))	('lumen formation', 'MPA', (81, 96))	('Par6', 'Gene', '50855', (131, 135))	('Par6', 'Gene', '50855', (12, 16))	('Par6', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))	('restore', 'PosReg', (73, 80))	('ErbB2', 'Gene', '2064', (136, 141))	('interactions', 'Interaction', (142, 154))	('ErbB2', 'Gene', (51, 56))
86424	19920867	Par6-aPKC interactions have also been shown to activate Rac1 in non-small cell lung cancer cells, resulting in anchorage-independent growth and invasion through activation of matrix metalloproteinase-10 (MMP-10) expression.	('Rac1', 'Gene', (56, 60))	('PKC', 'Gene', (6, 9))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('activate', 'PosReg', (47, 55))	('Par6', 'Gene', (0, 4))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('Par6', 'Gene', '50855', (0, 4))	('matrix metalloproteinase-10', 'Gene', (175, 202))	('interactions', 'Var', (10, 22))	('activation', 'PosReg', (161, 171))	('Rac1', 'Gene', '5879', (56, 60))	('matrix metalloproteinase-10', 'Gene', '4319', (175, 202))	('MMP-10', 'Gene', '4319', (204, 210))	('cancer', 'Disease', (84, 90))	('invasion', 'CPA', (144, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PKC', 'Gene', '112476', (6, 9))	('expression', 'MPA', (212, 222))	('anchorage-independent growth', 'CPA', (111, 139))	('MMP-10', 'Gene', (204, 210))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))
86425	19920867	Thus dysregulation of Par6 in cancer cells has the potential to impact tumour progression via direct effects on polarity, migration, and even apoptosis.	('dysregulation', 'Var', (5, 18))	('rat', 'Species', '10116', (125, 128))	('tumour', 'Disease', (71, 77))	('polarity', 'CPA', (112, 120))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('impact', 'Reg', (64, 70))	('Par6', 'Gene', (22, 26))	('effects', 'Reg', (101, 108))	('Par6', 'Gene', '50855', (22, 26))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('apoptosis', 'CPA', (142, 151))	('migration', 'CPA', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
86429	19920867	Since Par3 regulates Par6, loss of Par3, in turn, is likely to exert an influence over the control of proliferation, polarity, and apoptosis resistance by Par6 signalling in cancer cells.	('apoptosis resistance', 'CPA', (131, 151))	('loss', 'Var', (27, 31))	('Par6', 'Gene', '50855', (155, 159))	('Par3', 'Gene', (35, 39))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Par6', 'Gene', (21, 25))	('rat', 'Species', '10116', (109, 112))	('regulates', 'Reg', (11, 20))	('influence', 'Reg', (72, 81))	('polarity', 'CPA', (117, 125))	('Par3', 'Gene', (6, 10))	('Par6', 'Gene', '50855', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Par6', 'Gene', (155, 159))	('control', 'MPA', (91, 98))
86431	19920867	Loss of function mutations of scrib, DLG, and LGL in Drosophila have demonstrated abnormal cell polarity with increased proliferation without tumour cell overgrowth, possibly due to increased apoptosis.	('tumour', 'Disease', (142, 148))	('proliferation', 'CPA', (120, 133))	('Drosophila', 'Species', '7227', (53, 63))	('rat', 'Species', '10116', (76, 79))	('overgrowth', 'Phenotype', 'HP:0001548', (154, 164))	('LGL', 'Gene', (46, 49))	('scrib', 'Gene', (30, 35))	('increased', 'PosReg', (110, 119))	('DLG', 'Gene', (37, 40))	('LGL', 'Gene', '33156', (46, 49))	('Loss of function', 'NegReg', (0, 16))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('scrib', 'Gene', '44448', (30, 35))	('rat', 'Species', '10116', (127, 130))	('mutations', 'Var', (17, 26))	('DLG', 'Gene', '32083', (37, 40))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('cell polarity', 'CPA', (91, 104))
86436	19920867	Conversely, loss of Scrib suppressed the ability of c-myc to induce Bim expression; suggesting a mechanism for reduced apoptosis and increased resistance of breast cancer cells to cytotoxic stresses in the event of Scrib loss.	('suppressed', 'NegReg', (26, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('Scrib', 'Gene', '23513', (215, 220))	('c-myc', 'Gene', '4609', (52, 57))	('apoptosis', 'CPA', (119, 128))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancer', 'Disease', (157, 170))	('Bim', 'Gene', '10018', (68, 71))	('Scrib', 'Gene', '23513', (20, 25))	('Bim', 'Gene', (68, 71))	('resistance', 'CPA', (143, 153))	('Scrib', 'Gene', (215, 220))	('reduced', 'NegReg', (111, 118))	('c-myc', 'Gene', (52, 57))	('loss', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('loss', 'NegReg', (221, 225))	('Scrib', 'Gene', (20, 25))	('increased', 'PosReg', (133, 142))
86439	19920867	Therefore, dysregulation of LGL may play a role in EMT events associated with breast cancer progression.	('LGL', 'Gene', (28, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('play', 'Reg', (36, 40))	('LGL', 'Gene', '33156', (28, 31))	('dysregulation', 'Var', (11, 24))	('role', 'Reg', (43, 47))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
86440	19920867	Alterations in the final member of the Scrib complex, DLG, may also play a role in cancer progression.	('play', 'Reg', (68, 72))	('Alterations', 'Var', (0, 11))	('Scrib', 'Gene', '23513', (39, 44))	('DLG', 'Gene', '32083', (54, 57))	('DLG', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('role', 'Reg', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Disease', (83, 89))	('Scrib', 'Gene', (39, 44))
86445	19920867	This indicates that the integrity of cell-cell contacts regulates the Scrib polarity complex and that disruption of this complex promotes dysregulated growth and resistance to apoptosis.	('resistance to apoptosis', 'CPA', (162, 185))	('promotes', 'PosReg', (129, 137))	('dysregulated', 'MPA', (138, 150))	('disruption', 'Var', (102, 112))	('Scrib', 'Gene', (70, 75))	('Scrib', 'Gene', '23513', (70, 75))
86446	19920867	As illustrated above, alterations in CRB3, Scrib, and Par polarity complexes can promote proliferation, cell cycle progression and evasion of apoptosis as a result of disrupted apical-basolateral polarity in a variety of models.	('proliferation', 'CPA', (89, 102))	('Scrib', 'Gene', (43, 48))	('apical-basolateral', 'MPA', (177, 195))	('rat', 'Species', '10116', (9, 12))	('promote', 'PosReg', (81, 88))	('rat', 'Species', '10116', (26, 29))	('Scrib', 'Gene', '23513', (43, 48))	('cell cycle progression', 'CPA', (104, 126))	('rat', 'Species', '10116', (96, 99))	('alterations', 'Var', (22, 33))	('CRB3', 'Gene', (37, 41))	('CRB3', 'Gene', '92359', (37, 41))	('apoptosis', 'CPA', (142, 151))	('evasion', 'CPA', (131, 138))
86449	19920867	However, abnormalities in the polarity machinery are only one of several ways in which TJ dysfunction can impact upon breast cancer progression.	('abnormalities', 'Var', (9, 22))	('dysfunction', 'Var', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('impact', 'Reg', (106, 112))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
86457	19920867	Occludin overexpression was also shown to induce premature senescence in AC2M2 cells, as assessed by increased senescence-associated beta-galactosidase enzymatic activity and the upregulation of negative cell cycle regulators such as p16INK4A, p21Waf1/Cip1, and p27Kip1 but not p53.	('p21', 'Gene', (244, 247))	('increased', 'PosReg', (101, 110))	('p21', 'Gene', '644914', (244, 247))	('p16INK4A', 'Gene', (234, 242))	('overexpression', 'Var', (9, 23))	('Cip1', 'Gene', (252, 256))	('Cip1', 'Gene', '12575', (252, 256))	('p27Kip1', 'Gene', '12576', (262, 269))	('premature', 'MPA', (49, 58))	('beta-galactosidase', 'Gene', (133, 151))	('beta-galactosidase', 'Gene', '12091', (133, 151))	('p16INK4A', 'Gene', '12578', (234, 242))	('upregulation', 'PosReg', (179, 191))	('p27Kip1', 'Gene', (262, 269))
86480	19920867	Increased GEF-H1 levels can arise by mutations in p53, a frequent genetic alteration observed in breast cancer.	('GEF-H1', 'Gene', '9181', (10, 16))	('GEF-H1', 'Gene', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rat', 'Species', '10116', (78, 81))	('mutations', 'Var', (37, 46))	('Increased', 'PosReg', (0, 9))	('p53', 'Gene', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
86481	19920867	These alterations suggest a relationship between TJ alterations and the malignant potential of several carcinomas, via deficits in controlled proliferation, regulated cell cycle progression and apoptosis.	('rat', 'Species', '10116', (149, 152))	('apoptosis', 'CPA', (194, 203))	('alterations', 'Var', (52, 63))	('rat', 'Species', '10116', (56, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinomas', 'Disease', (103, 113))	('malignant potential', 'CPA', (72, 91))	('regulated cell cycle progression', 'CPA', (157, 189))	('carcinomas', 'Disease', 'MESH:D002277', (103, 113))	('controlled proliferation', 'CPA', (131, 155))	('deficits', 'NegReg', (119, 127))	('rat', 'Species', '10116', (10, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
86482	19920867	This suggests that the dysregulation of cell-cell contact machinery may be a prerequisite for cancer progression in order to turn off specific epithelial regulatory pathways.	('dysregulation', 'Var', (23, 36))	('turn off', 'NegReg', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epithelial regulatory pathways', 'Pathway', (143, 173))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
86485	19920867	There is also evidence that altered cell adhesion plays a fundamental role in breast cancer progression by freeing tumour cells from both neighbouring cells and the underlying matrix; and in parallel by conferring a motile or migratory advantage to cells during invasion and metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('altered', 'Var', (28, 35))	('rat', 'Species', '10116', (229, 232))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('motile', 'CPA', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('cell adhesion', 'CPA', (36, 49))	('tumour', 'Disease', (115, 121))	('breast cancer', 'Disease', (78, 91))
86489	19920867	Interestingly, the occludin gene can be silenced by hypermethylation, and it may be that the methylator phenotype promotes tumourigenic, invasive, and metastatic properties of cancer cells.	('occludin gene', 'Gene', (19, 32))	('hypermethylation', 'Var', (52, 68))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('invasive', 'CPA', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', (123, 129))	('promotes', 'PosReg', (114, 122))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
86497	19920867	Furthermore, MDA-MB-361 breast cancer cells deficient in claudin-1 grow as multicellular filled spheroids in three-dimensional cultures  and re-expression of claudin-1 induces central lumen formation; perhaps by nutritional deprivation of innermost cells inducing apoptosis as already discussed.	('MDA-MB-361', 'CellLine', 'CVCL:0620', (13, 23))	('re-expression', 'Var', (141, 154))	('claudin-1', 'Gene', '9076', (158, 167))	('induces', 'Reg', (168, 175))	('breast cancer cells deficient', 'Disease', 'MESH:D001943', (24, 53))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('claudin-1', 'Gene', (57, 66))	('claudin-1', 'Gene', (158, 167))	('central lumen', 'MPA', (176, 189))	('nutritional deprivation', 'Phenotype', 'HP:0004395', (212, 235))	('breast cancer cells deficient', 'Disease', (24, 53))	('claudin-1', 'Gene', '9076', (57, 66))
86499	19920867	demonstrated that decreased expression of claudin-6 in breast cancer cells (by siRNA or epigenetic silencing) increases MMP activity, likely facilitating increased cancer cell migration and invasion.	('decreased', 'NegReg', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rat', 'Species', '10116', (7, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('MMP', 'Gene', '4313;4319;4323', (120, 123))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('cancer', 'Disease', (62, 68))	('breast cancer', 'Disease', (55, 68))	('increased', 'PosReg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (164, 170))	('claudin-6', 'Gene', '9074', (42, 51))	('rat', 'Species', '10116', (179, 182))	('invasion', 'CPA', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MMP', 'Gene', (120, 123))	('expression', 'MPA', (28, 38))	('increases', 'PosReg', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('claudin-6', 'Gene', (42, 51))	('epigenetic silencing', 'Var', (88, 108))
86500	19920867	Subsequent reintroduction of claudin-6 increased cellular adhesion and abrogated enhanced invasion and migration.	('claudin-6', 'Gene', '9074', (29, 38))	('cellular adhesion', 'CPA', (49, 66))	('enhanced', 'PosReg', (81, 89))	('abrogated', 'NegReg', (71, 80))	('increased', 'PosReg', (39, 48))	('rat', 'Species', '10116', (106, 109))	('-6 increased', 'Phenotype', 'HP:0030783', (36, 48))	('claudin-6', 'Gene', (29, 38))	('reintroduction', 'Var', (11, 25))
86508	19920867	JAM proteins regulate numerous cellular adhesive processes including intercellular junction assembly, cell morphology, and leukocyte migration; while JAM-A dysregulation has recently been implicated in breast cancer.	('leukocyte migration', 'CPA', (123, 142))	('JAM', 'Gene', (0, 3))	('JAM-A', 'Gene', '50848', (150, 155))	('JAM', 'Gene', '50848', (150, 153))	('regulate', 'Reg', (13, 21))	('cell morphology', 'CPA', (102, 117))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('JAM-A', 'Gene', (150, 155))	('JAM', 'Gene', '50848', (0, 3))	('JAM', 'Gene', (150, 153))	('implicated', 'Reg', (188, 198))	('cellular adhesive processes', 'CPA', (31, 58))	('intercellular junction assembly', 'CPA', (69, 100))	('rat', 'Species', '10116', (136, 139))	('dysregulation', 'Var', (156, 169))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
86509	19920867	JAM-A has been shown to regulate epithelial cell morphology and enhance beta1-integrin expression through modulation of Rap1 GTPase activity.	('enhance', 'PosReg', (64, 71))	('modulation', 'Var', (106, 116))	('JAM-A', 'Gene', '50848', (0, 5))	('beta1-integrin', 'Gene', '3688', (72, 86))	('activity', 'MPA', (132, 140))	('Rap1', 'Gene', (120, 124))	('beta1-integrin', 'Gene', (72, 86))	('expression', 'MPA', (87, 97))	('JAM-A', 'Gene', (0, 5))	('epithelial cell morphology', 'CPA', (33, 59))	('Rap1', 'Gene', '27342', (120, 124))
86511	19920867	Indeed, disruption of JAM-A in a colonic carcinoma cell line was shown to convert cells from a stationery, polarized state to a migratory phenotype.	('disruption', 'Var', (8, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('rat', 'Species', '10116', (131, 134))	('colonic carcinoma', 'Disease', (33, 50))	('colonic carcinoma', 'Disease', 'MESH:D015179', (33, 50))	('JAM-A', 'Gene', (22, 27))	('convert', 'Reg', (74, 81))	('cells', 'CPA', (82, 87))	('JAM-A', 'Gene', '50848', (22, 27))
86512	19920867	reported that JAM-A overexpression decreased migration and invasion in breast cancer cell lines, while knockdown of JAM-A expression enhanced invasiveness.	('breast cancer', 'Disease', (71, 84))	('knockdown', 'Var', (103, 112))	('JAM-A', 'Gene', '50848', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('invasiveness', 'CPA', (142, 154))	('JAM-A', 'Gene', '50848', (14, 19))	('decreased', 'NegReg', (35, 44))	('JAM-A', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('JAM-A', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('enhanced', 'PosReg', (133, 141))	('rat', 'Species', '10116', (48, 51))
86515	19920867	Furthermore, knockdown or antagonism of JAM-A significantly decreased migration in MCF7 breast cancer cells expressing high endogenous levels of JAM-A.	('MCF7 breast cancer', 'Disease', (83, 101))	('JAM-A', 'Gene', (145, 150))	('decreased', 'NegReg', (60, 69))	('JAM-A', 'Gene', '50848', (40, 45))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (83, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('migration', 'CPA', (70, 79))	('antagonism', 'Var', (26, 36))	('JAM-A', 'Gene', (40, 45))	('JAM-A', 'Gene', '50848', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('knockdown', 'Var', (13, 22))	('rat', 'Species', '10116', (73, 76))
86516	19920867	The apparent conflict between these two studies may be resolved by the fact that underexpression of JAM-A is likely to impair cellular adhesion and polarity (favouring tumour initiation), whereas overexpression of JAM-A could promote integrin-mediated migratory events that favour tumour progression.	('impair', 'NegReg', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('JAM-A', 'Gene', '50848', (214, 219))	('tumour', 'Disease', 'MESH:D009369', (281, 287))	('tumour initiation', 'Disease', (168, 185))	('JAM-A', 'Gene', (214, 219))	('tumour', 'Disease', (281, 287))	('underexpression', 'Var', (81, 96))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('JAM-A', 'Gene', '50848', (100, 105))	('tumour', 'Disease', (168, 174))	('cellular adhesion', 'CPA', (126, 143))	('polarity', 'CPA', (148, 156))	('JAM-A', 'Gene', (100, 105))	('integrin-mediated migratory events', 'CPA', (234, 268))	('promote', 'PosReg', (226, 233))	('rat', 'Species', '10116', (255, 258))	('tumour initiation', 'Disease', 'MESH:D009369', (168, 185))
86526	19920867	Expression of mutant ZO-2 protein lacking the E4 binding site inhibits E4-mediated tumour initiation in mammary glands.	('tumour initiation', 'Disease', 'MESH:D009369', (83, 100))	('inhibits', 'NegReg', (62, 70))	('mutant', 'Var', (14, 20))	('ZO-2', 'Gene', '9414', (21, 25))	('ZO-2', 'Gene', (21, 25))	('lacking', 'NegReg', (34, 41))	('tumour initiation', 'Disease', (83, 100))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('protein', 'Protein', (26, 33))
86578	19920867	However, as before, it must be noted that disruption of TJ proteins purely for drug delivery purposes may itself promote cancer progression by upsetting homeostatic mechanisms of polarity, differentiation, cell fate, and migration which are tightly regulated by TJs in normal tissues.	('differentiation', 'CPA', (189, 204))	('migration', 'CPA', (221, 230))	('promote', 'PosReg', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cell fate', 'CPA', (206, 215))	('disruption', 'Var', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('rat', 'Species', '10116', (224, 227))	('homeostatic mechanisms of polarity', 'MPA', (153, 187))	('cancer', 'Disease', (121, 127))	('upsetting', 'Reg', (143, 152))
86583	19920867	During the initiation phase of cancer, fundamental alterations in the TJ complex may impair its functional control over important cellular processes such as polarity and cell fate determination, or cell motility characteristics.	('alterations', 'Var', (51, 62))	('impair', 'NegReg', (85, 91))	('functional control', 'MPA', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cell motility characteristics', 'CPA', (198, 227))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('rat', 'Species', '10116', (55, 58))
86584	19920867	Dysregulation of either of these aspects likely contributes to the pathologies which we recognise as ductal breast carcinoma in situ or invasive ductal carcinoma.	('invasive ductal carcinoma', 'Disease', (136, 161))	('breast carcinoma', 'Phenotype', 'HP:0003002', (108, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (145, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Dysregulation', 'Var', (0, 13))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (115, 132))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (136, 161))	('contributes', 'Reg', (48, 59))	('breast carcinoma in situ', 'Disease', (108, 132))	('breast carcinoma in situ', 'Disease', 'MESH:D000071960', (108, 132))
86589	19920867	However, any imbalance in the protein components of this complex (whether increased or decreased) will, in turn, imbalance the strict homeostatic control required to maintain breast tissue in its differentiated state, increasing the risk of inducing a pathologically dedifferentiated state such as breast cancer.	('increasing', 'PosReg', (218, 228))	('strict homeostatic control', 'MPA', (127, 153))	('breast cancer', 'Disease', 'MESH:D001943', (298, 311))	('breast cancer', 'Disease', (298, 311))	('inducing', 'Reg', (241, 249))	('imbalance', 'Reg', (113, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('imbalance', 'Var', (13, 22))	('imbalance', 'Phenotype', 'HP:0002172', (113, 122))	('protein', 'Protein', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))
86598	28508872	The multistep process of breast cancer progression results from the acquisition of genetic and epigenetic alterations in oncogenes and tumour suppressor genes, which confer growth and/or survival advantage to mammary cells.	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('growth', 'CPA', (173, 179))	('epigenetic alterations', 'Var', (95, 117))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('survival advantage', 'CPA', (187, 205))	('breast cancer', 'Disease', (25, 38))	('genetic', 'Var', (83, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('oncogenes', 'Gene', (121, 130))	('tumour', 'Disease', (135, 141))
86605	28508872	While EVL suppresses cell migration, the Mena variant Mena (INV) drives invasion, intravasation and metastasis.	('Mena', 'Gene', (54, 58))	('variant', 'Var', (46, 53))	('INV', 'Gene', (60, 63))	('EVL', 'Gene', (6, 9))	('cell migration', 'CPA', (21, 35))	('Mena', 'Gene', '55740', (41, 45))	('invasion', 'CPA', (72, 80))	('Mena', 'Gene', (41, 45))	('drives', 'PosReg', (65, 71))	('EVL', 'Gene', '51466', (6, 9))	('Mena', 'Gene', '55740', (54, 58))	('suppresses', 'NegReg', (10, 20))	('INV', 'Gene', '27130', (60, 63))	('metastasis', 'CPA', (100, 110))	('intravasation', 'CPA', (82, 95))
86629	28508872	ERK is required to potentiate Cyclin D1 expression in these cells, as co-treatment with PD184352, an inhibitor of the Mitogen-activated protein kinase kinase (MEKi), strongly reduced pERK levels in both EtOH- and TAM-treated cells at 12 h (Fig.	('reduced', 'NegReg', (175, 182))	('ERK', 'Gene', '5594', (184, 187))	('PD184352', 'Var', (88, 96))	('PD184352', 'Chemical', 'MESH:C120227', (88, 96))	('ERK', 'Gene', (184, 187))	('MEK', 'Gene', (159, 162))	('Cyclin D1', 'Gene', '595', (30, 39))	('MEK', 'Gene', '5609', (159, 162))	('TAM', 'Chemical', 'MESH:D013629', (213, 216))	('ERK', 'Gene', '5594', (0, 3))	('Cyclin D1', 'Gene', (30, 39))	('ERK', 'Gene', (0, 3))	('EtOH', 'Chemical', 'MESH:D000431', (203, 207))
86652	28508872	In contrast, knocking down ACTR3/Arp3, ARPC5L/Arpc5, DST/Shot, FHOD3/Fhos or TPM2/Tm2 enhanced the overgrowth of Nub>Src/p35-expressing wing discs (Supplementary Table 2 and Supplementary Fig.	('overgrowth', 'CPA', (99, 109))	('Fhos', 'Gene', '29109', (69, 73))	('Nub>Src/p35-expressing', 'Protein', (113, 135))	('FHOD3', 'Gene', (63, 68))	('Fhos', 'Gene', (69, 73))	('Arpc5', 'Gene', '10092', (46, 51))	('Arpc5', 'Gene', (46, 51))	('ACTR3', 'Gene', (27, 32))	('Shot', 'Gene', (57, 61))	('overgrowth', 'Phenotype', 'HP:0001548', (99, 109))	('enhanced', 'PosReg', (86, 94))	('Arp3', 'Gene', (33, 37))	('knocking down', 'Var', (13, 26))	('ARPC5L', 'Gene', (39, 45))	('ACTR3', 'Gene', '10096', (27, 32))	('Shot', 'Gene', '6474', (57, 61))	('TPM2', 'Gene', (77, 81))	('TPM2', 'Gene', '7169', (77, 81))	('Arp3', 'Gene', '10096', (33, 37))	('FHOD3', 'Gene', '80206', (63, 68))	('ARPC5L', 'Gene', '81873', (39, 45))
86657	28508872	4c) or knocking down DST/Shot or TPM2/Tm2 was sufficient to induce the overgrowth of wing discs that did not overexpress Src and p35 (Supplementary Table 2 and Supplementary Fig.	('TPM2', 'Gene', (33, 37))	('overgrowth', 'CPA', (71, 81))	('overgrowth', 'Phenotype', 'HP:0001548', (71, 81))	('knocking down', 'Var', (7, 20))	('Shot', 'Gene', (25, 29))	('TPM2', 'Gene', '7169', (33, 37))	('Shot', 'Gene', '6474', (25, 29))	('induce', 'Reg', (60, 66))
86662	28508872	Accordingly, quantification by western blot indicated that EVL/Ena levels were four times higher in wing discs extracts overexpressing Src and p35 under Scalloped-Gal4 (Sd-Gal4) control, compared to discs expressing p35 and GFP (Fig.	('Gal4', 'Gene', (163, 167))	('EVL', 'Gene', (59, 62))	('Gal4', 'Gene', '3960', (172, 176))	('EVL', 'Gene', '51466', (59, 62))	('p35', 'Var', (143, 146))	('overexpressing', 'PosReg', (120, 134))	('Gal4', 'Gene', '3960', (163, 167))	('higher', 'PosReg', (90, 96))	('Gal4', 'Gene', (172, 176))	('Src', 'Gene', (135, 138))
86668	28508872	In the absence of serum and growth factors, EVL expression was significantly increased 12 h after TAM treatment in ER-Src cells transfected with shScr (Fig.	('EVL', 'Gene', '51466', (44, 47))	('EVL', 'Gene', (44, 47))	('shScr', 'Gene', (145, 150))	('transfected', 'Var', (128, 139))	('TAM', 'Chemical', 'MESH:D013629', (98, 101))	('increased', 'PosReg', (77, 86))
86672	28508872	In these culture conditions, knocking down EVL in ER-Src cells treated with TAM for 12 h reduced the increase in pERK levels (Fig.	('ERK', 'Gene', (114, 117))	('TAM', 'Chemical', 'MESH:D013629', (76, 79))	('EVL', 'Gene', '51466', (43, 46))	('knocking down', 'Var', (29, 42))	('reduced', 'NegReg', (89, 96))	('EVL', 'Gene', (43, 46))	('ERK', 'Gene', '5594', (114, 117))
86675	28508872	Knocking down EVL also lowered the number of ER-Src cells in S-phase 12 h after TAM treatment.	('lowered', 'NegReg', (23, 30))	('Knocking down', 'Var', (0, 13))	('EVL', 'Gene', (14, 17))	('TAM', 'Chemical', 'MESH:D013629', (80, 83))	('EVL', 'Gene', '51466', (14, 17))
86678	28508872	EVL is also required for TAM-treated ER-Src cells to progress toward a fully transformed phenotype, as knocking down EVL fully suppressed the invasive spike-like phenotype of TAM-treated acini grown in the presence of serum and growth factors for 14 days (Fig.	('invasive spike-like phenotype', 'CPA', (142, 171))	('EVL', 'Gene', (0, 3))	('EVL', 'Gene', '51466', (0, 3))	('TAM', 'Chemical', 'MESH:D013629', (25, 28))	('knocking down', 'Var', (103, 116))	('EVL', 'Gene', (117, 120))	('suppressed', 'NegReg', (127, 137))	('EVL', 'Gene', '51466', (117, 120))	('TAM', 'Chemical', 'MESH:D013629', (175, 178))
86682	28508872	6), EVL knockdown reduced the size of EtOH-treated ER-Src acini (Fig.	('EVL', 'Gene', (4, 7))	('knockdown', 'Var', (8, 17))	('EVL', 'Gene', '51466', (4, 7))	('reduced', 'NegReg', (18, 25))	('ER-Src acini', 'CPA', (51, 63))	('size', 'MPA', (30, 34))	('EtOH', 'Chemical', 'MESH:D000431', (38, 42))
86683	28508872	EVL is also required for the tumorigenic potential of Src, as knocking down EVL inhibited the ability of TAM-treated ER-Src cells to produce anchorage-independent colonies in the absence of EGF (Fig.	('EGF', 'Gene', (190, 193))	('EVL', 'Gene', (0, 3))	('anchorage-independent colonies', 'CPA', (141, 171))	('knocking down', 'Var', (62, 75))	('EVL', 'Gene', '51466', (0, 3))	('EVL', 'Gene', (76, 79))	('EGF', 'Gene', '1950', (190, 193))	('TAM', 'Chemical', 'MESH:D013629', (105, 108))	('EVL', 'Gene', '51466', (76, 79))	('inhibited', 'NegReg', (80, 89))
86684	28508872	Finally, knocking down EVL in ER-Src cells treated with TAM for 12 h reduced ER-pSrc levels (Fig.	('ER-pSrc levels', 'MPA', (77, 91))	('TAM', 'Chemical', 'MESH:D013629', (56, 59))	('EVL', 'Gene', '51466', (23, 26))	('reduced', 'NegReg', (69, 76))	('knocking down', 'Var', (9, 22))	('EVL', 'Gene', (23, 26))
86690	28508872	However, knocking down EVL did not suppress the ability of TAM-treated ER-Src cells to form larger FAs at 12 h (Fig.	('EVL', 'Gene', (23, 26))	('knocking down', 'Var', (9, 22))	('EVL', 'Gene', '51466', (23, 26))	('TAM', 'Chemical', 'MESH:D013629', (59, 62))
86691	28508872	On the contrary, EVL knockdown triggered significantly higher amounts of the F-actin pool in EtOH-treated cells (Fig.	('EtOH', 'Chemical', 'MESH:D000431', (93, 97))	('EVL', 'Gene', '51466', (17, 20))	('knockdown', 'Var', (21, 30))	('higher', 'PosReg', (55, 61))	('amounts of the F-actin pool', 'MPA', (62, 89))	('EVL', 'Gene', (17, 20))
86692	28508872	Quantification of stress fibres anisotropy indicates that 12 h after TAM treatment, ER-Src cells expressing shScr, showed an anisotropic fibre arrangement, compared to those treated with EtOH (Fig.	('TAM', 'Chemical', 'MESH:D013629', (69, 72))	('EtOH', 'Chemical', 'MESH:D000431', (187, 191))	('anisotropic', 'MPA', (125, 136))	('shScr', 'Var', (108, 113))
86693	28508872	Strikingly, knocking down EVL in these cells fully suppressed the increase in fibre anisotropy (Fig.	('increase', 'PosReg', (66, 74))	('suppressed', 'NegReg', (51, 61))	('knocking down', 'Var', (12, 25))	('EVL', 'Gene', (26, 29))	('fibre anisotropy', 'MPA', (78, 94))	('EVL', 'Gene', '51466', (26, 29))
86694	28508872	Stress fibre organization by EVL impacts the stiffening of TAM-treated ER-Src cells, as knocking down EVL in these cells prevented their increased cell stiffening at 12 h (Fig.	('EVL', 'Gene', '51466', (102, 105))	('cell stiffening', 'CPA', (147, 162))	('impacts', 'Reg', (33, 40))	('TAM', 'Chemical', 'MESH:D013629', (59, 62))	('prevented', 'NegReg', (121, 130))	('EVL', 'Gene', (29, 32))	('knocking down', 'Var', (88, 101))	('Stress fibre organization', 'CPA', (0, 25))	('EVL', 'Gene', (102, 105))	('stiffening', 'MPA', (45, 55))	('EVL', 'Gene', '51466', (29, 32))
86695	28508872	In addition, knocking down EVL limited the accumulation of pMLC loaded on the Src-dependent stress fibres 12 h after TAM treatment (Fig.	('knocking down', 'Var', (13, 26))	('EVL', 'Gene', (27, 30))	('TAM', 'Chemical', 'MESH:D013629', (117, 120))	('accumulation', 'MPA', (43, 55))	('limited', 'NegReg', (31, 38))	('EVL', 'Gene', '51466', (27, 30))	('pMLC loaded', 'MPA', (59, 70))
86698	28508872	As expected, ER-Src cells co-treated with Blebbistatin and EtOH or TAM for 12 h reduced their stiffness, compared to those treated with DMSO (Fig.	('Blebbistatin', 'Chemical', 'MESH:C472645', (42, 54))	('TAM', 'Chemical', 'MESH:D013629', (67, 70))	('Blebbistatin', 'Var', (42, 54))	('reduced', 'NegReg', (80, 87))	('DMSO', 'Chemical', 'MESH:D004121', (136, 140))	('stiffness', 'MPA', (94, 103))	('EtOH', 'Chemical', 'MESH:D000431', (59, 63))
86703	28508872	Finally, Myosin II activity is also required for the stepwise increase of Src activity, as ER-Src cells co-treated with TAM and Blebbistatin for 12 h showed reduced ER-pSrc levels compared to ER-Src cells treated with TAM and DMSO for the same period of time (Fig.	('Myosin', 'Gene', (9, 15))	('DMSO', 'Chemical', 'MESH:D004121', (226, 230))	('Blebbistatin', 'Chemical', 'MESH:C472645', (128, 140))	('TAM', 'Chemical', 'MESH:D013629', (218, 221))	('Blebbistatin', 'Var', (128, 140))	('ER-pSrc levels', 'MPA', (165, 179))	('Myosin', 'Gene', '79784', (9, 15))	('TAM', 'Chemical', 'MESH:D013629', (120, 123))	('reduced', 'NegReg', (157, 164))
86716	28508872	In this manuscript, we show that early during cellular transformation, low Src activity promotes stress fibre assembly and upregulates EVL.	('promotes', 'PosReg', (88, 96))	('low', 'Var', (71, 74))	('stress fibre assembly', 'CPA', (97, 118))	('EVL', 'Gene', (135, 138))	('upregulates', 'PosReg', (123, 134))	('EVL', 'Gene', '51466', (135, 138))
86724	28508872	Thus, while low Src activity would promote stress fibre-mediated cell stiffening accompanying tumour growth, higher levels would have the opposite effect, allowing for cell migration.	('low', 'Var', (12, 15))	('Src activity', 'MPA', (16, 28))	('stress fibre-mediated cell stiffening', 'CPA', (43, 80))	('cell migration', 'CPA', (168, 182))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour growth', 'Disease', (94, 107))	('promote', 'PosReg', (35, 42))	('tumour growth', 'Disease', 'MESH:D006130', (94, 107))	('allowing', 'Reg', (155, 163))
86748	28508872	Furthermore, restoration of TPM1 and 2 expression in Ras-transformed cells suppresses the transformed phenotype.	('TPM1 and 2', 'Gene', '7168;7169', (28, 38))	('suppresses', 'NegReg', (75, 85))	('transformed phenotype', 'CPA', (90, 111))	('expression', 'MPA', (39, 49))	('restoration', 'Var', (13, 24))
86756	28508872	Mena11a, another Ena/VASP variant, is also overexpressed in a subset of benign breast lesions associated with HER2 positivity, while downregulated in invasive cells and increases the proliferation rate of MCF-7 cells.	('downregulated', 'NegReg', (133, 146))	('Mena', 'Gene', '55740', (0, 4))	('benign breast lesions', 'Disease', (72, 93))	('Mena', 'Gene', (0, 4))	('increases', 'PosReg', (169, 178))	('proliferation rate', 'CPA', (183, 201))	('positivity', 'Var', (115, 125))	('HER2', 'Gene', (110, 114))	('overexpressed', 'PosReg', (43, 56))	('HER2', 'Gene', '2064', (110, 114))	('MCF-7', 'CellLine', 'CVCL:0031', (205, 210))
86758	28508872	Surprisingly, while Src correlates with ER and HER2 expression and triple negativity, EVL is associated with the absence of HER2, the expression of ER and with the luminal A molecular subtype.	('triple negativity', 'Var', (67, 84))	('Src', 'Disease', (20, 23))	('EVL', 'Gene', (86, 89))	('HER2', 'Gene', '2064', (124, 128))	('HER2', 'Gene', (47, 51))	('EVL', 'Gene', '51466', (86, 89))	('HER2', 'Gene', '2064', (47, 51))	('HER2', 'Gene', (124, 128))
86779	28508872	To assess ERK activation and Cyclin D1 expression, cells were serum-starved for 16 h in plain DMEM/F12, before treatment with DMSO or 2.5 muM of the MEK inhibitor PD184352 (Sigma, PZ0181) or 10 muM of Blebbistatin (Sigma, B0560), or without any additive for 1 h. Culture medium was then replaced with plain DMEM/F12, containing EtOH or 4OH-TAM, and DMSO or 2.5 muM of PD184352 or 10 muM of Blebbistatin or without any additive, before analysis 12 h later.	('PD184352', 'Chemical', 'MESH:C120227', (163, 171))	('Cyclin D1', 'Gene', '595', (29, 38))	('Cyclin D1', 'Gene', (29, 38))	('DMEM', 'Chemical', '-', (307, 311))	('MEK', 'Gene', (149, 152))	('DMSO', 'Chemical', 'MESH:D004121', (349, 353))	('DMEM', 'Chemical', '-', (94, 98))	('Blebbistatin', 'Chemical', 'MESH:C472645', (201, 213))	('DMSO', 'Chemical', 'MESH:D004121', (126, 130))	('4OH-TAM', 'Chemical', '-', (336, 343))	('ERK', 'Gene', '5594', (10, 13))	('Blebbistatin', 'Chemical', 'MESH:C472645', (390, 402))	('MEK', 'Gene', '5609', (149, 152))	('PD184352', 'Chemical', 'MESH:C120227', (368, 376))	('EtOH', 'Chemical', 'MESH:D000431', (328, 332))	('ERK', 'Gene', (10, 13))	('PD184352', 'Var', (368, 376))
86836	28508872	Microarray data of 903 neoplastic breast lesions, including 12 ER+ ADH, 22 ER+ DCIS, 68 ER+ IDC1, 189 ER+ IDC2, 273 ER+ IDC3, 44 ER- IDC2 and 299 ER- IDC3, were compared to microarray data of 255 normal breast tissues.	('neoplastic breast', 'Phenotype', 'HP:0100013', (23, 40))	('ER+ IDC2', 'Var', (102, 110))	('ER+ IDC3', 'Var', (116, 124))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('neoplastic breast lesions', 'Disease', 'MESH:D001943', (23, 48))	('neoplastic breast lesions', 'Phenotype', 'HP:0100013', (23, 48))	('neoplastic breast lesions', 'Disease', (23, 48))	('ER+ IDC1', 'Var', (88, 96))
86839	28508872	Six biological replicates were used for quantification of ER-pSrc in ER-Src cells treated with EtOH or TAM for 4, 12, 24 or 36 h. Quantification of EVL protein levels in ER-Src cells knocked down for EVL was carried out from one biological replicate.	('TAM', 'Chemical', 'MESH:D013629', (103, 106))	('EVL', 'Gene', (148, 151))	('EVL', 'Gene', (200, 203))	('knocked down', 'Var', (183, 195))	('EVL', 'Gene', '51466', (148, 151))	('EtOH', 'Chemical', 'MESH:D000431', (95, 99))	('EVL', 'Gene', '51466', (200, 203))
86863	22569800	It is the comedo form that is associated with higher nuclear grade, aneuploidy, higher proliferation rate, HER2/neu gene amplification/protein over expression, and clinically more aggressive behavior.	('gene amplification/protein', 'Var', (116, 142))	('HER2/neu', 'Protein', (107, 115))	('aggressive behavior', 'CPA', (180, 199))	('rat', 'Species', '10116', (94, 97))	('rat', 'Species', '10116', (101, 104))	('aneuploidy', 'Disease', 'MESH:D000782', (68, 78))	('higher', 'PosReg', (46, 52))	('more', 'PosReg', (175, 179))	('over expression', 'PosReg', (143, 158))	('higher', 'PosReg', (80, 86))	('aggressive behavior', 'Phenotype', 'HP:0000718', (180, 199))	('comedo', 'Phenotype', 'HP:0025249', (10, 16))	('aneuploidy', 'Disease', (68, 78))
86945	22569800	Thus fluorescein was PEGylated using amide or thioether bonds, which are both relatively stable in vivo.	('amide', 'Chemical', 'MESH:D000577', (37, 42))	('thioether', 'Chemical', 'MESH:D013440', (46, 55))	('amide', 'Protein', (37, 42))	('thioether bonds', 'Var', (46, 61))	('fluorescein', 'Chemical', 'MESH:D019793', (5, 16))	('PEG', 'Chemical', 'MESH:D011092', (21, 24))
86963	22569800	As evident from the figure, fluorescein disodium (control) exhibited extremely short retention in ducts, with signals completely diminishing within 2 h. The PEGylated fluoresceins, on the other hand, exhibited higher retention in ducts.	('fluorescein disodium', 'Chemical', 'MESH:D019793', (28, 48))	('fluoresceins', 'Chemical', 'MESH:D005452', (167, 179))	('higher', 'PosReg', (210, 216))	('PEG', 'Chemical', 'MESH:D011092', (157, 160))	('retention', 'MPA', (217, 226))	('PEGylated', 'Var', (157, 166))
86964	22569800	Thus, an increase in molecular size due to PEGylation resulted in longer nanocarrier retention in ducts presumably due in part to hindered diffusion.	('diffusion', 'MPA', (139, 148))	('hindered', 'NegReg', (130, 138))	('PEGylation', 'Var', (43, 53))	('increase', 'PosReg', (9, 17))	('nanocarrier retention', 'MPA', (73, 94))	('PEG', 'Chemical', 'MESH:D011092', (43, 46))	('longer', 'PosReg', (66, 72))	('molecular size', 'MPA', (21, 35))
86971	22569800	Thus, Tmax increased in the order: fluorescein disodium < linear 12 < linear 40 < two-arm 60 kDa, similar to their order of retention in breast ducts.	('fluorescein disodium <', 'Var', (35, 57))	('fluorescein disodium', 'Chemical', 'MESH:D019793', (35, 55))	('Tmax', 'MPA', (6, 10))
86991	22569800	Several PEGylated proteins have been approved for clinical use like Adagen (PEG-adenosine deaminase), Oncaspar (PEG-L-asparaginase), Pegasys, PEG-Intron (PEG-interferon-alpha), and krystexxa or pegloticase (PEG-porcine like uricase).	('PEG', 'Chemical', 'MESH:D011092', (8, 11))	('PEG', 'Chemical', 'MESH:D011092', (142, 145))	('adenosine deaminase', 'Gene', (80, 99))	('PEG', 'Chemical', 'MESH:D011092', (76, 79))	('PEG', 'Chemical', 'MESH:D011092', (207, 210))	('adenosine deaminase', 'Gene', '24165', (80, 99))	('PEG', 'Chemical', 'MESH:D011092', (112, 115))	('PEG', 'Chemical', 'MESH:D011092', (154, 157))	('Pegasys', 'Var', (133, 140))
86992	22569800	The advantage of PEGylation is that PEGylated proteins exhibit increased solubility, greater stability, prolonged plasma half-life, reduced immunogenicity, lower renal clearance, and decreased uptake by cells of reticuloendothelial system (RES).	('increased', 'PosReg', (63, 72))	('renal clearance', 'MPA', (162, 177))	('uptake', 'MPA', (193, 199))	('immunogenicity', 'MPA', (140, 154))	('PEG', 'Chemical', 'MESH:D011092', (36, 39))	('reduced', 'NegReg', (132, 139))	('proteins', 'Protein', (46, 54))	('stability', 'MPA', (93, 102))	('decreased', 'NegReg', (183, 192))	('solubility', 'MPA', (73, 83))	('PEG', 'Chemical', 'MESH:D011092', (17, 20))	('PEGylated', 'Var', (36, 45))	('lower', 'NegReg', (156, 161))	('plasma', 'MPA', (114, 120))
86999	22569800	Thus, PEGylation delayed Tmax in a molecular-size dependent manner.	('delayed', 'NegReg', (17, 24))	('PEG', 'Chemical', 'MESH:D011092', (6, 9))	('PEGylation', 'Var', (6, 16))	('Tmax', 'MPA', (25, 29))
87027	31797077	Interestingly, the paper reveals that malignancy rates in all BI-RADS feature combinations exceed BI-RADS 3 benchmarks.	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('combinations', 'Var', (78, 90))	('BI-RADS', 'Var', (62, 69))	('malignancy', 'Disease', (38, 48))
87050	31797077	Our findings revealed that Kaiser scores <= 4 largely exclude malignancy and yielded a low number of false-negative findings, i.e., all but one non-invasive and hormonal receptor-positive tumor.	('tumor', 'Disease', (188, 193))	('exclude', 'NegReg', (54, 61))	('malignancy', 'Disease', 'MESH:D009369', (62, 72))	('malignancy', 'Disease', (62, 72))	('<= 4', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
87108	27146587	For Ki67, a minimum of 1000 tumor cells were counted from at least three high-powered (0.40) fields in areas that showed the highest labeling.	('Ki67', 'Var', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
87109	27146587	High Ki67 expression was defined as >= 10 % tumor cell staining.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (44, 49))	('Ki67', 'Var', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
87171	27146587	Limitations include the retrospective nature of collection of clinical variables increases potential for recall bias (however, none of the variables in the risk prediction are collected from women's recall); exclusion of treatments other than lumpectomy prohibits assessing association of variables with response to adjuvant therapies; imputation for missing biomarker data could lead to over-/under-estimation of risk estimates; and a restricted list of biomarkers due to limited tissue available.	('recall', 'MPA', (105, 111))	('association', 'Interaction', (274, 285))	('women', 'Species', '9606', (191, 196))	('imputation', 'Var', (336, 346))
87239	11056683	Cyclin D1 has been     shown to be important in the transition from the G1 to the S phase     of the cell cycle, and perturbations in this control point can lead to     neoplastic transformation.	('Cyclin D1', 'Gene', '58919', (0, 9))	('neoplastic transformation', 'CPA', (169, 194))	('lead to', 'Reg', (157, 164))	('Cyclin D1', 'Gene', (0, 9))	('perturbations', 'Var', (117, 130))
87298	11056683	Loss of the G1-S checkpoint control can occur     by a variety of means, including loss of p16INK4a or overexpression     of cyclin D1.	('p16INK4a', 'Gene', (91, 99))	('loss', 'Var', (83, 87))	('cyclin D1', 'Protein', (125, 134))	('Loss', 'NegReg', (0, 4))	('p16INK4a', 'Gene', '25163', (91, 99))	('overexpression', 'PosReg', (103, 117))
87307	11056683	Such changes could have profound effects over the long period of tumor     development.	('tumor', 'Disease', (65, 70))	('changes', 'Var', (5, 12))	('effects', 'Reg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
87353	33376783	Indeed, fluorescence increases of HMRef-alphaMan in cultured cells and surgical specimens were significantly inhibited in the presence of swainsonine, supporting the conclusion based on a DEG assay that MAN2C1 is a promising biomarker for breast cancer imaging (Figure 3c and Figures S4-S5).	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('breast cancer', 'Disease', (239, 252))	('swainsonine', 'Chemical', 'MESH:D017026', (138, 149))	('inhibited', 'NegReg', (109, 118))	('MAN2C1', 'Var', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('HMRef-alphaMan', 'Chemical', '-', (34, 48))	('fluorescence increases', 'MPA', (8, 30))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
87370	33376783	Interestingly, we found that HMRef-alphaMan tended to show greater fluorescence increases in FA tissues than IDC and DCIS tissues (Figures 6a, S14 and S15).	('S15', 'Gene', '6209', (151, 154))	('HMRef-alphaMan', 'Chemical', '-', (29, 43))	('fluorescence', 'MPA', (67, 79))	('S14', 'Gene', (143, 146))	('increases', 'PosReg', (80, 89))	('S14', 'Gene', '5714', (143, 146))	('S15', 'Gene', (151, 154))	('HMRef-alphaMan', 'Var', (29, 43))
87373	33376783	Considering that HMRef-alphaMan tends to show higher fluorescence increases in FA tissues than in IDC or DCIS malignant tissues (P < 0.05*), whereas gGlu-HMRG is similarly activated in both malignant and benign tissues (P = 0.145), we thought it might be possible to discriminate cancer and benign lesions by using a combination of alpha-mannosidase-reactive probe and GGT-reactive probe with different emission wavelengths (Figures 6a and S17).	('GGT', 'Gene', (369, 372))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('increases', 'PosReg', (66, 75))	('cancer', 'Disease', (280, 286))	('GGT', 'Gene', '102724197', (369, 372))	('S17', 'Gene', (440, 443))	('HMRef-alphaMan', 'Var', (17, 31))	('benign lesions', 'Disease', (291, 305))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('S17', 'Gene', '6218', (440, 443))	('benign lesions', 'Disease', 'MESH:D009369', (291, 305))	('HMRef-alphaMan', 'Chemical', '-', (17, 31))	('fluorescence', 'MPA', (53, 65))
87382	33376783	Compared to our previously reported probe gGlu-HMRG, HMRef-alphaMan shows higher sensitivity and specificity.	('HMRef-alphaMan', 'Var', (53, 67))	('sensitivity', 'MPA', (81, 92))	('HMRef-alphaMan', 'Chemical', '-', (53, 67))	('higher', 'PosReg', (74, 80))
87389	33376783	MAN2C1 itself suppresses apoptosis in cancer cells regardless of its enzymatic activity; it also attenuates PTEN function and activates PI3K/AKT signaling in PTEN-positive prostate cancer cells, thereby promoting prostate carcinogenesis (Figure S22).	('function', 'MPA', (113, 121))	('PTEN', 'Gene', (108, 112))	('AKT', 'Gene', (141, 144))	('prostate carcinogenesis', 'Disease', (213, 236))	('PTEN-positive prostate cancer', 'Disease', 'MESH:D011471', (158, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('activates', 'PosReg', (126, 135))	('PTEN', 'Gene', '5728', (158, 162))	('PTEN-positive prostate cancer', 'Disease', (158, 187))	('promoting', 'PosReg', (203, 212))	('PTEN', 'Gene', '5728', (108, 112))	('MAN2C1', 'Var', (0, 6))	('cancer', 'Disease', (38, 44))	('AKT', 'Gene', '207', (141, 144))	('prostate carcinogenesis', 'Disease', 'MESH:D011471', (213, 236))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('attenuates', 'NegReg', (97, 107))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('PTEN', 'Gene', (158, 162))
87390	33376783	We observed coexpression of MAN2C1, PTEN, and AKT-P (Ser473 phosphorylated AKT) in DCIS tissues, as in the case of PTEN-positive prostate cancer, suggesting that MAN2C1 may also attenuate PTEN function and increase AKT activation in breast cancer (Figure S23).	('MAN2C1', 'Var', (162, 168))	('AKT-P', 'Disease', (46, 51))	('PTEN', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('AKT', 'Gene', (46, 49))	('PTEN', 'Gene', '5728', (188, 192))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('S23', 'Gene', '6228', (255, 258))	('activation', 'MPA', (219, 229))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('PTEN', 'Gene', (115, 119))	('AKT', 'Gene', '207', (215, 218))	('PTEN', 'Gene', '5728', (36, 40))	('AKT', 'Gene', (75, 78))	('AKT-P', 'Disease', 'MESH:C000656865', (46, 51))	('PTEN-positive prostate cancer', 'Disease', 'MESH:D011471', (115, 144))	('attenuate', 'NegReg', (178, 187))	('AKT', 'Gene', '207', (46, 49))	('PTEN-positive prostate cancer', 'Disease', (115, 144))	('S23', 'Gene', (255, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('PTEN', 'Gene', '5728', (115, 119))	('AKT', 'Gene', '207', (75, 78))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('breast cancer', 'Disease', (233, 246))	('PTEN', 'Gene', (188, 192))	('Ser473', 'Chemical', '-', (53, 59))	('function', 'MPA', (193, 201))	('AKT', 'Gene', (215, 218))	('increase', 'PosReg', (206, 214))
87438	31783895	Furthermore, immunostaining of lysates from breast cancer cells overexpressing SIM2s showed reduction in various NFkappaB signaling proteins, as well as pAkt, whereas knockdown of SIM2 revealed increases in NFkappaB signaling proteins and pAkt.	('Akt', 'Gene', (240, 243))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('Akt', 'Gene', '207', (154, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('NFkappaB signaling proteins', 'MPA', (113, 140))	('breast cancer', 'Disease', (44, 57))	('reduction', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Akt', 'Gene', (154, 157))	('Akt', 'Gene', '207', (240, 243))	('increases', 'PosReg', (194, 203))	('NFkappaB signaling proteins', 'MPA', (207, 234))	('SIM2s', 'Var', (79, 84))
87447	31783895	Recently identified risk factors for DCIS recurrence include age < 40 at diagnosis, African American ethnicity, hormone receptor negativity, and HER2 positivity.	('hormone receptor', 'Gene', '3164', (112, 128))	('HER2', 'Gene', (145, 149))	('positivity', 'Var', (150, 160))	('HER2', 'Gene', '2064', (145, 149))	('DCIS', 'Disease', (37, 41))	('DCIS', 'Disease', 'MESH:D002285', (37, 41))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('hormone receptor', 'Gene', (112, 128))
87452	31783895	The NFkappaB signaling pathway includes five members: NFkappaB1 (p105/p50), NFkappaB2 (p100/p52), RelA (p65), RelB, and c-Rel.	('p52', 'Gene', (92, 95))	('NFkappaB signaling pathway', 'Pathway', (4, 30))	('p52', 'Gene', '4791', (92, 95))	('NFkappaB2', 'Gene', (76, 85))	('c-Rel', 'Gene', (120, 125))	('RelA', 'Gene', (98, 102))	('RelB', 'Gene', (110, 114))	('RelB', 'Gene', '5971', (110, 114))	('p65', 'Var', (104, 107))	('p50', 'Gene', '4790', (70, 73))	('p105', 'Gene', (65, 69))	('RelA', 'Gene', '5970', (98, 102))	('p105', 'Gene', '4790', (65, 69))	('NFkappaB1', 'Gene', (54, 63))	('c-Rel', 'Gene', '5966', (120, 125))	('p50', 'Gene', (70, 73))
87461	31783895	Thus, it is logical to expect that inhibition of COX-2 signaling in breast cancer patients could enhance overall prognosis.	('COX-2', 'Gene', (49, 54))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('patients', 'Species', '9606', (82, 90))	('COX-2', 'Gene', '5743', (49, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('enhance', 'PosReg', (97, 104))	('inhibition', 'Var', (35, 45))
87463	31783895	Specifically, using the MCF10-DCIS.COM progression model, we demonstrated that re-expression of SIM2s inhibits growth, invasive phenotypes, and progression to metastasis.	('DCIS', 'Disease', 'MESH:D002285', (30, 34))	('growth', 'CPA', (111, 117))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('progression', 'CPA', (144, 155))	('invasive phenotypes', 'CPA', (119, 138))	('SIM2s', 'Gene', (96, 101))	('re-expression', 'Var', (79, 92))	('MCF10', 'CellLine', 'CVCL:5555', (24, 29))	('inhibits', 'NegReg', (102, 110))	('DCIS', 'Disease', (30, 34))
87465	31783895	Consistent with the role for SIM2s in cancer progression, we have also shown that the NFkappaB signaling pathway is negatively regulated by SIM2s in normal mammary tissues during postpartum mammary involution, which has been identified as a driver of tumor progression and metastasis.	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (251, 256))	('NFkappaB signaling pathway', 'Pathway', (86, 112))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('SIM2s', 'Var', (140, 145))	('negatively', 'NegReg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
87466	31783895	In this study, we demonstrate a relationship between SIM2s, the NFkappaB signaling pathway, and COX-2 in breast cancer cells.	('COX-2', 'Gene', (96, 101))	('COX-2', 'Gene', '5743', (96, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('relationship', 'Interaction', (32, 44))	('SIM2s', 'Var', (53, 58))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('NFkappaB signaling pathway', 'Pathway', (64, 90))
87486	31783895	Similarly, we found that these same NFkappaB pathway protein levels are increased in SIM2s knockdown MCF7 cells (Fig.	('SIM2s', 'Gene', (85, 90))	('increased', 'PosReg', (72, 81))	('MCF7', 'CellLine', 'CVCL:0031', (101, 105))	('knockdown', 'Var', (91, 100))	('NFkappaB pathway', 'Pathway', (36, 52))
87489	31783895	Indeed, we observed that overexpression of SIM2s results in a modest decrease in pAkt, while SIM2s knockdown strongly restored pAkt.	('SIM2s', 'Var', (93, 98))	('Akt', 'Gene', '207', (82, 85))	('Akt', 'Gene', (128, 131))	('SIM2s', 'Var', (43, 48))	('restored', 'PosReg', (118, 126))	('decrease', 'NegReg', (69, 77))	('knockdown', 'Var', (99, 108))	('Akt', 'Gene', '207', (128, 131))	('Akt', 'Gene', (82, 85))
87500	31783895	In previous studies, we showed that overexpression of SIM2s in DCIS.COM cells blocked invasion in vivo, whereas loss of SIM2s or overexpression of the protein product of PTGS2, COX-2, resulted in increased invasion and metastasis.	('increased', 'PosReg', (196, 205))	('SIM2s', 'Gene', (120, 125))	('DCIS', 'Disease', (63, 67))	('DCIS', 'Disease', 'MESH:D002285', (63, 67))	('blocked', 'NegReg', (78, 85))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('COX-2', 'Gene', (177, 182))	('COX-2', 'Gene', '5743', (177, 182))	('loss', 'Var', (112, 116))	('invasion', 'CPA', (86, 94))
87501	31783895	To determine the relationship between SIM2s and COX-2 protein expression in vivo, we performed IHC analysis for COX-2 in tumors derived from control and SIM2s DCIS.COM xenografts to reveal that COX-2 levels were decreased with overexpression of SIM2s (Fig.	('decreased', 'NegReg', (212, 221))	('COX-2', 'Gene', '5743', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('COX-2', 'Gene', (194, 199))	('tumors', 'Disease', (121, 127))	('COX-2', 'Gene', (112, 117))	('DCIS', 'Disease', (159, 163))	('SIM2s', 'Var', (245, 250))	('DCIS', 'Disease', 'MESH:D002285', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('COX-2', 'Gene', '5743', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('COX-2', 'Gene', '5743', (112, 117))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('overexpression', 'PosReg', (227, 241))	('COX-2', 'Gene', (48, 53))
87502	31783895	Taken together, our results suggest that SIM2s may repress invasion in the DCIS.COM model by promoting downregulation of COX-2.	('COX-2', 'Gene', (121, 126))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('SIM2s', 'Var', (41, 46))	('repress', 'NegReg', (51, 58))	('COX-2', 'Gene', '5743', (121, 126))	('downregulation', 'NegReg', (103, 117))	('invasion', 'CPA', (59, 67))	('DCIS', 'Disease', (75, 79))	('DCIS', 'Disease', 'MESH:D002285', (75, 79))
87503	31783895	Since the invasive potential in DCIS.COM positively correlates with, and depends upon, expression and activity of COX-2, we tested the hypothesis that the loss of invasive phenotype observed with blocking of COX-2 expression was due, in part, to re-expression of SIM2s.	('COX-2', 'Gene', (114, 119))	('blocking', 'Var', (196, 204))	('COX-2', 'Gene', (208, 213))	('COX-2', 'Gene', '5743', (114, 119))	('DCIS', 'Disease', (32, 36))	('COX-2', 'Gene', '5743', (208, 213))	('DCIS', 'Disease', 'MESH:D002285', (32, 36))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))
87512	31783895	Consistent with this hypothesis, Oncomine analysis reveals that SIM2s is in the top 5-10% of under-expressed genes in a breast cancer metastasis concept signature and in the top 10% of copy number loss genes (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('SIM2s', 'Var', (64, 69))
87516	31783895	Specifically, genetic ablation of SIM2s in mammary epithelial cells revealed that SIM2s is required for ductal morphogenesis and differentiation of luminal cells for milk production during lactation.	('lactation', 'Disease', (189, 198))	('lactation', 'Disease', 'MESH:D007775', (189, 198))	('genetic ablation', 'Var', (14, 30))	('ablation', 'Var', (22, 30))	('SIM2s', 'Gene', (82, 87))
87521	31783895	In this study, we demonstrate a novel role for SIM2s as a negative regulator of tumorigenesis via downregulation of the NFkappaB pathway, which normally results in transcriptional activation and expression of the pro-inflammatory/pro-tumorigenic enzyme COX-2, which in turn promotes DCIS invasion.	('DCIS', 'Phenotype', 'HP:0030075', (283, 287))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (234, 239))	('downregulation', 'NegReg', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('COX-2', 'Gene', (253, 258))	('tumor', 'Disease', (80, 85))	('COX-2', 'Gene', '5743', (253, 258))	('SIM2s', 'Var', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('DCIS', 'Disease', (283, 287))	('DCIS', 'Disease', 'MESH:D002285', (283, 287))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('NFkappaB pathway', 'Pathway', (120, 136))	('activation', 'PosReg', (180, 190))	('promotes', 'PosReg', (274, 282))
87522	31783895	Interestingly, we also identify a novel link between SIM2s and preventing signaling of the pro-tumor/pro-survival kinase Akt, which has been shown to promote tumorigenesis in part through NFkappaB-mediated COX-2 expression.	('preventing signaling', 'MPA', (63, 83))	('tumor', 'Disease', (158, 163))	('COX-2', 'Gene', (206, 211))	('Akt', 'Gene', (121, 124))	('NFkappaB-mediated', 'Protein', (188, 205))	('promote', 'PosReg', (150, 157))	('COX-2', 'Gene', '5743', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('SIM2s', 'Var', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Akt', 'Gene', '207', (121, 124))	('tumor', 'Disease', (95, 100))
87524	31783895	Consistent with a role for SIM2s preventing this pro-tumorigenic cycle, loss of SIM2s also drastically increases COX-2 expression, while loss of COX-2 activity and expression results in re-expression of SIM2s and downregulation of tumor cell invasion.	('expression', 'MPA', (119, 129))	('re-expression', 'PosReg', (186, 199))	('increases', 'PosReg', (103, 112))	('COX-2', 'Gene', (145, 150))	('COX-2', 'Gene', '5743', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('downregulation', 'NegReg', (213, 227))	('loss', 'Var', (72, 76))	('tumor', 'Disease', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SIM2s', 'Gene', (80, 85))	('loss', 'NegReg', (137, 141))	('COX-2', 'Gene', (113, 118))	('tumor', 'Disease', (53, 58))	('activity', 'MPA', (151, 159))	('COX-2', 'Gene', '5743', (113, 118))
87526	31783895	Based on our previous results reporting a role for COX-2 in promotion of DCIS invasion, and results showing that SIM2 is lost in IDC compared with DCIS in patient samples, we predict that loss of SIM2s may be important for progression of in situ lesions to invasive disease via upregulation of COX-2 expression and activity.	('COX-2', 'Gene', '5743', (51, 56))	('DCIS', 'Disease', 'MESH:D002285', (73, 77))	('IDC', 'Disease', 'MESH:D044584', (129, 132))	('COX-2', 'Gene', (294, 299))	('loss', 'Var', (188, 192))	('situ lesions to invasive disease', 'Disease', (241, 273))	('upregulation', 'PosReg', (278, 290))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('DCIS', 'Disease', (73, 77))	('COX-2', 'Gene', '5743', (294, 299))	('SIM2s', 'Gene', (196, 201))	('patient', 'Species', '9606', (155, 162))	('expression', 'MPA', (300, 310))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('situ lesions to invasive disease', 'Disease', 'MESH:D002278', (241, 273))	('IDC', 'Disease', (129, 132))	('activity', 'MPA', (315, 323))	('COX-2', 'Gene', (51, 56))	('DCIS', 'Disease', 'MESH:D002285', (147, 151))	('DCIS', 'Disease', (147, 151))
87527	31783895	Consistent with this hypothesis, in the DCIS.COM model, loss of SIM2s is associated with increased invasiveness and enhanced tumor aggressiveness and progression, all of which are also observed with gain of COX-2.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (125, 145))	('enhanced', 'PosReg', (116, 124))	('progression', 'CPA', (150, 161))	('SIM2s', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('loss', 'Var', (56, 60))	('COX-2', 'Gene', (207, 212))	('DCIS', 'Disease', (40, 44))	('DCIS', 'Disease', 'MESH:D002285', (40, 44))	('tumor aggressiveness', 'Disease', (125, 145))	('COX-2', 'Gene', '5743', (207, 212))	('invasiveness', 'Disease', 'MESH:D009361', (99, 111))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('increased', 'PosReg', (89, 98))	('aggressiveness', 'Phenotype', 'HP:0000718', (131, 145))	('invasiveness', 'Disease', (99, 111))
87528	31783895	Specifically, upon loss of SIM2s in tumors, increased co-localization of keratin 5 and vimentin has been observed, which is indicative of mesenchymal and invasive phenotypes; furthermore, gain of COX-2 results in increased collagen deposition in the tumor microenvironment, which tumor cells utilize to invade the surrounding tissue and access the vasculature to form metastasis.	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', (36, 41))	('keratin 5', 'Gene', '3852', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (280, 285))	('COX-2', 'Gene', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('vimentin', 'Gene', '7431', (87, 95))	('vimentin', 'Gene', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('loss', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('gain', 'PosReg', (188, 192))	('COX-2', 'Gene', '5743', (196, 201))	('keratin 5', 'Gene', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('collagen deposition', 'MPA', (223, 242))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('increased', 'PosReg', (213, 222))	('co-localization', 'MPA', (54, 69))
87529	31783895	Matrix metalloproteinases (MMPs), which are associated with basement membrane degradation during mammary gland development and cancer, are also significantly increased with loss of SIM2s.	('MMPs', 'Gene', '81686;4314;171045;81687', (27, 31))	('Matrix metalloproteinases', 'MPA', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SIM2s', 'Gene', (181, 186))	('cancer', 'Disease', (127, 133))	('MMPs', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('basement membrane degradation', 'MPA', (60, 89))	('loss', 'Var', (173, 177))	('increased', 'PosReg', (158, 167))
87533	31783895	Here, we show that cells with low invasive potential exhibit increased expression of COX-2 upon knockdown of SIM2s and endogenously express moderate levels of SIM2s compared with the low level of SIM2s observed in the more invasive cells.	('knockdown', 'Var', (96, 105))	('expression', 'MPA', (71, 81))	('increased', 'PosReg', (61, 70))	('COX-2', 'Gene', (85, 90))	('SIM2s', 'Var', (109, 114))	('COX-2', 'Gene', '5743', (85, 90))
87534	31783895	Likewise, overexpression of SIM2s in invasive cells decreases COX-2 expression.	('COX-2', 'Gene', (62, 67))	('SIM2s', 'Var', (28, 33))	('expression', 'MPA', (68, 78))	('COX-2', 'Gene', '5743', (62, 67))	('decreases', 'NegReg', (52, 61))
87537	31783895	Furthermore, an additional implication is that SIM2s could be utilized as a marker to identify DCIS patients that are of low risk for acquisition of COX-2 expression and progression to IDC and/or metastatic disease.	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('COX-2', 'Gene', (149, 154))	('acquisition', 'PosReg', (134, 145))	('metastatic disease', 'CPA', (196, 214))	('expression', 'MPA', (155, 165))	('COX-2', 'Gene', '5743', (149, 154))	('patients', 'Species', '9606', (100, 108))	('IDC', 'Disease', 'MESH:D044584', (185, 188))	('SIM2s', 'Var', (47, 52))	('DCIS', 'Disease', (95, 99))	('DCIS', 'Disease', 'MESH:D002285', (95, 99))	('IDC', 'Disease', (185, 188))
87546	31783895	This research is supported by an NRSA F31CA236140 (LSC/TL), the University of Colorado Department of Medicine Outstanding Early Career Scholars Program (TL), and the National Cancer Institute R21CA197896 (WP), R01HD083952 (CO-PI WP, MR), R21CA185226 (TL), and R01CA211696 (TL).	('R01HD083952', 'Chemical', 'MESH:C044298', (210, 221))	('R21CA197896', 'Var', (192, 203))	('R21CA185226', 'Chemical', 'MESH:C414822', (238, 249))	('NRSA F31CA236140', 'Chemical', 'MESH:C012626', (33, 49))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('R01HD083952', 'Var', (210, 221))	('R01CA211696', 'Var', (260, 271))	('R21CA185226', 'Var', (238, 249))	('R01CA211696', 'Chemical', 'MESH:C519584', (260, 271))	('CO-PI', 'Chemical', 'MESH:C082732', (223, 228))
87553	27283985	In vivo CCL2 gene silencing inhibited primary tumor growth and metastasis, associated with a reduction in cancer stem cell renewal and recruitment of M2 macrophages.	('reduction', 'NegReg', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gene silencing', 'Var', (13, 27))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('recruitment of M2 macrophages', 'CPA', (135, 164))	('inhibited', 'NegReg', (28, 37))	('cancer', 'Disease', (106, 112))	('CCL2', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
87564	27283985	Overexpression of CCL2 in the tumor epithelium correlates with tumor grade and poor patient prognosis in various tumor types including: gliomas, prostate cancers, ovarian cancers and breast cancers.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('prostate cancers', 'Disease', 'MESH:D011471', (145, 161))	('Overexpression', 'Var', (0, 14))	('gliomas', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('prostate cancers', 'Phenotype', 'HP:0012125', (145, 161))	('ovarian cancers', 'Disease', (163, 178))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (113, 118))	('prostate cancers', 'Disease', (145, 161))	('ovarian cancers', 'Disease', 'MESH:D010051', (163, 178))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('CCL2', 'Gene', (18, 22))	('gliomas', 'Disease', 'MESH:D005910', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('breast cancers', 'Disease', 'MESH:D001943', (183, 197))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('breast cancers', 'Disease', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('patient', 'Species', '9606', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (30, 35))	('ovarian cancers', 'Phenotype', 'HP:0100615', (163, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
87566	27283985	In functional studies, CCL2 antibody neutralization in 4T1 or MDA-MB-231 breast tumor xenografts inhibited tumor growth and metastasis, while decreasing the levels of macrophages in the primary tumors, indicating that CCL2 promotes progression of TNBC through macrophage dependent mechanisms.	('decreasing', 'NegReg', (142, 152))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast tumor', 'Phenotype', 'HP:0100013', (73, 85))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('levels of macrophages', 'MPA', (157, 178))	('primary tumors', 'Disease', 'MESH:D009369', (186, 200))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('breast tumor', 'Disease', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('inhibited', 'NegReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (80, 85))	('TNBC', 'Chemical', '-', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (62, 72))	('neutralization', 'Var', (37, 51))	('primary tumors', 'Disease', (186, 200))	('breast tumor', 'Disease', 'MESH:D001943', (73, 85))	('CCL2', 'Gene', (23, 27))
87573	27283985	Gene silencing through small interfering RNAs (siRNAs) could selectively inactivate expression and activity of critical oncogenes, but would require a carrier to efficiently and specifically penetrate tumor cells and tissues.	('N', 'Chemical', 'MESH:D009584', (50, 51))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Gene', 'Var', (0, 4))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('expression', 'MPA', (84, 94))	('rat', 'Species', '10116', (196, 199))	('inactivate', 'NegReg', (73, 83))	('activity', 'MPA', (99, 107))
87579	27283985	In contrast to CCL2 antibody neutralization of breast tumor xenografts, CCL2 gene silencing did not increase tumor cell apoptosis or affect tumor angiogenesis.	('breast tumor', 'Phenotype', 'HP:0100013', (47, 59))	('gene silencing', 'Var', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('breast tumor', 'Disease', (47, 59))	('CCL2', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('breast tumor', 'Disease', 'MESH:D001943', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('affect', 'Reg', (133, 139))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', (140, 145))
87580	27283985	Instead, CCL2 gene silencing lead to increased tumor cell necrosis and autophagy, associated with a reduction in the number of cancer stem cells and recruitment of M2 macrophages.	('reduction', 'NegReg', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor cell necrosis', 'Disease', (47, 66))	('cancer', 'Disease', (127, 133))	('recruitment of M2 macrophages', 'CPA', (149, 178))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('increased', 'PosReg', (37, 46))	('gene silencing', 'Var', (14, 28))	('autophagy', 'CPA', (71, 80))	('CCL2', 'Gene', (9, 13))	('tumor cell necrosis', 'Disease', 'MESH:D009336', (47, 66))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))
87581	27283985	CCL2 gene silencing but not CCL2 antibody neutralization, significantly reduced CCL2 expression in breast cancer cells over time.	('expression', 'MPA', (85, 95))	('reduced', 'NegReg', (72, 79))	('CCL2', 'Gene', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('gene silencing', 'Var', (5, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('CCL2', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
87582	27283985	Our studies are the first to demonstrate that targeting CCL2 expression exerts therapeutic effects different from blocking CCL2 activity through antibody binding.	('targeting', 'Var', (46, 55))	('CCL2', 'Gene', (56, 60))	('rat', 'Species', '10116', (36, 39))
87583	27283985	This study demonstrates a novel approach to target CCL2 and reveals important insight into the effects of CCL2 gene silencing on necrosis, autophagy, cancer stem cell renewal and macrophage recruitment.	('rat', 'Species', '10116', (18, 21))	('CCL2', 'Gene', (106, 110))	('necrosis', 'Disease', 'MESH:D009336', (129, 137))	('autophagy', 'CPA', (139, 148))	('macrophage recruitment', 'CPA', (179, 201))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('gene silencing', 'Var', (111, 125))	('necrosis', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
87588	27283985	According to ELISA analysis of 2D cultures, Ca-TAT delivery of huCCL2si1 or huCCL2si2 to either MDA-MB-231 or DCIS.com cells resulted in over a 50% knockdown in CCL2 expression, compared to Ca-TAT peptides complexed to control siRNA (Figure 1A-1B).	('CCL2', 'Gene', (161, 165))	('knockdown', 'NegReg', (148, 157))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (96, 106))	('N', 'Chemical', 'MESH:D009584', (230, 231))	('huCCL2si2', 'Var', (76, 85))	('expression', 'MPA', (166, 176))	('DCIS.com', 'CellLine', 'CVCL:5552', (110, 118))
87590	27283985	Ca-TAT delivery of huCCL2si1 or huCCL2si2 efficiently transfected MDA-MB-231 breast cancer cells embedded in collagen and silenced CCL2 expression at 24 and 48 hours (Figure 1C).	('huCCL2si1', 'Var', (19, 28))	('huCCL2si2', 'Var', (32, 41))	('breast cancer', 'Disease', (77, 90))	('expression', 'MPA', (136, 146))	('transfected', 'Reg', (54, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('silenced', 'NegReg', (122, 130))	('CCL2', 'Gene', (131, 135))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
87596	27283985	Tumors receiving injections of Ca-TAT/huCCL2si1 or Ca-TAT/huCCL2si2 showed a significant 45% reduction in cells expressing overall human CCL2 protein compared to tumors receiving injections of control siRNA.	('Ca-TAT/huCCL2si2', 'Var', (51, 67))	('N', 'Chemical', 'MESH:D009584', (204, 205))	('reduction', 'NegReg', (93, 102))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('human', 'Species', '9606', (131, 136))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cells expressing overall', 'MPA', (106, 130))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
87597	27283985	Silencing of CCL2 in tumor tissues down-regulated CCL2 protein expression to levels found in normal mammary tissues (Figure 2B).	('CCL2', 'Gene', (13, 17))	('tumor', 'Disease', (21, 26))	('protein', 'Protein', (55, 62))	('down-regulated', 'NegReg', (35, 49))	('CCL2', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
87608	27283985	These data indicate that Ca-TAT delivery of CCL2 siRNAs inhibits breast tumor growth, invasion and metastasis.	('CCL2 siRNAs', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('breast tumor', 'Disease', (65, 77))	('breast tumor', 'Disease', 'MESH:D001943', (65, 77))	('inhibits', 'NegReg', (56, 64))	('breast tumor', 'Phenotype', 'HP:0100013', (65, 77))	('N', 'Chemical', 'MESH:D009584', (52, 53))
87609	27283985	To further understand the effects of CCL2 silencing on tumor progression, primary breast tumor xenografts were examined for changes in cell proliferation and cell death by immunohistochemistry staining.	('silencing', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('breast tumor', 'Phenotype', 'HP:0100013', (82, 94))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast tumor', 'Disease', 'MESH:D001943', (82, 94))	('rat', 'Species', '10116', (147, 150))	('cell proliferation', 'CPA', (135, 153))	('breast tumor', 'Disease', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('CCL2', 'Gene', (37, 41))
87610	27283985	We observed a significant reduction in PCNA expression from 42.9% with control siRNAs to 21.3% with huCCL2si1 and 21.2% with huCCL2si2.	('expression', 'MPA', (44, 54))	('PCNA', 'Gene', (39, 43))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('reduction', 'NegReg', (26, 35))	('huCCL2si2', 'Var', (125, 134))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('huCCL2si1', 'Var', (100, 109))
87618	27283985	Compared to Ca-TAT/control siRNA treatment, Ca-TAT delivery of huCCL2si1 or huCCL2si2 increased LC3B expression by over 45% (Figure 4D).	('increased', 'PosReg', (86, 95))	('LC3B', 'Gene', (96, 100))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('huCCL2si2', 'Var', (76, 85))	('LC3B', 'Gene', '81631', (96, 100))	('expression', 'MPA', (101, 111))
87619	27283985	Taken together, silencing of CCL2 gene expression results in decreased breast tumor cell proliferation, and increased necrosis and autophagy.	('necrosis', 'Disease', (118, 126))	('breast tumor', 'Phenotype', 'HP:0100013', (71, 83))	('increased', 'PosReg', (108, 117))	('autophagy', 'CPA', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('increased necrosis', 'Phenotype', 'HP:0010885', (108, 126))	('rat', 'Species', '10116', (96, 99))	('silencing', 'Var', (16, 25))	('breast tumor', 'Disease', 'MESH:D001943', (71, 83))	('necrosis', 'Disease', 'MESH:D009336', (118, 126))	('decreased', 'NegReg', (61, 70))	('CCL2', 'Gene', (29, 33))	('breast tumor', 'Disease', (71, 83))
87625	27283985	Therefore, we first determined the effect of CCL2 gene silencing on the numbers of CD24-/CD44+ cells, a well characterized breast cancer stem cell population.	('gene silencing', 'Var', (50, 64))	('CCL2', 'Gene', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('CD44', 'Gene', '960', (89, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('CD44', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
87626	27283985	By FACs analysis, Ca-TAT delivery of huCCL2si1 or huCCL2si2 decreased the numbers of CD24-/CD44+ cells by over 50% (Figure 5A).	('decreased', 'NegReg', (60, 69))	('huCCL2si1', 'Var', (37, 46))	('CD44', 'Gene', '960', (91, 95))	('CD44', 'Gene', (91, 95))	('huCCL2si2', 'Var', (50, 59))
87628	27283985	These data indicate that CCL2 knockdown inhibits ALDH1 expression and numbers of CD24-/CD44+ cells in breast tumor xenografts.	('ALDH1', 'Gene', (49, 54))	('breast tumor', 'Phenotype', 'HP:0100013', (102, 114))	('ALDH1', 'Gene', '216', (49, 54))	('expression', 'MPA', (55, 65))	('breast tumor', 'Disease', 'MESH:D001943', (102, 114))	('inhibits', 'NegReg', (40, 48))	('knockdown', 'Var', (30, 39))	('CD44', 'Gene', '960', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD44', 'Gene', (87, 91))	('breast tumor', 'Disease', (102, 114))
87632	27283985	Compared to the control siRNA treated group, huCCL2si1 or huCCL2si2 significantly decreased the numbers of cellular aggregates formed by MDA-MB-231 breast cancer cells (Figure 5C).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('huCCL2si2', 'Var', (58, 67))	('breast cancer', 'Disease', (148, 161))	('huCCL2si1', 'Var', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('decreased', 'NegReg', (82, 91))
87633	27283985	Consistently, Ca-TAT delivery of huCCL2si1 and huCCL2si2 resulted in fewer numbers of DCIS.com mammospheres at passage 4 (Supplementary Figure 1).	('huCCL2si1', 'Var', (33, 42))	('fewer', 'NegReg', (69, 74))	('DCIS.com mammospheres', 'CPA', (86, 107))	('huCCL2si2', 'Var', (47, 56))	('DCIS.com', 'CellLine', 'CVCL:5552', (86, 94))
87634	27283985	Taken together, these data indicate that CCL2 gene silencing inhibits self-renewal of MDA-MB-231and DCIS.com breast cancer cells.	('breast cancer', 'Disease', (109, 122))	('gene silencing', 'Var', (46, 60))	('CCL2', 'Gene', (41, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (86, 96))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('self-renewal', 'CPA', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('DCIS.com', 'CellLine', 'CVCL:5552', (100, 108))	('inhibits', 'NegReg', (61, 69))
87637	27283985	Ca-TAT delivery of huCCL2si1 or huCCL2si2 lead to over a 50% reduction in CD11b+ cells in primary tumor xenografts, as determined by flow cytometry (Figure 6A).	('huCCL2si1', 'Var', (19, 28))	('huCCL2si2', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('reduction', 'NegReg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD11b+ cells', 'MPA', (74, 86))	('tumor', 'Disease', (98, 103))
87639	27283985	CCL2 knockdown significantly reduced the number of M2 macrophages localized to necrotic tissues (Figure 6B).	('CCL2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('necrotic tissues', 'Disease', 'MESH:D009336', (79, 95))	('reduced', 'NegReg', (29, 36))	('necrotic tissues', 'Disease', (79, 95))
87641	27283985	In summary, CCL2 gene silencing decreases M2 macrophage recruitment in TNBC xenografts, and does not significantly affect tumor angiogenesis.	('TNBC', 'Chemical', '-', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('gene silencing', 'Var', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('M2 macrophage recruitment', 'MPA', (42, 67))	('CCL2', 'Gene', (12, 16))	('decreases', 'NegReg', (32, 41))	('tumor', 'Disease', (122, 127))
87649	27283985	CCL2 knockdown in MDA-MB-231 or DCIS.com cells significantly inhibited the numbers of macrophages migrating into the MMD (Figure 7D, Supplementary Figure 2).	('numbers of macrophages migrating into the MMD', 'CPA', (75, 120))	('DCIS.com', 'CellLine', 'CVCL:5552', (32, 40))	('inhibited', 'NegReg', (61, 70))	('rat', 'Species', '10116', (101, 104))	('knockdown', 'Var', (5, 14))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (18, 28))
87654	27283985	In addition, studies have shown that treatment of breast tumor xenografts with neutralizing antibodies to CCL2 lead to increased expression of IL-6 and VEGF when anti-CCL2 treatment was interrupted.	('CCL2', 'Gene', (106, 110))	('expression', 'MPA', (129, 139))	('IL-6', 'Protein', (143, 147))	('breast tumor', 'Disease', 'MESH:D001943', (50, 62))	('VEGF', 'Protein', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('breast tumor', 'Disease', (50, 62))	('neutralizing antibodies', 'Var', (79, 102))	('increased expression of IL-6', 'Phenotype', 'HP:0030783', (119, 147))	('increased', 'PosReg', (119, 128))	('breast tumor', 'Phenotype', 'HP:0100013', (50, 62))
87658	27283985	Through a novel gene silencing approach, we show that targeting CCL2 expression inhibits tumor progression associated with a reduction in cancer stem cells and M2 macrophages.	('reduction', 'NegReg', (125, 134))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibits', 'NegReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('CCL2', 'Gene', (64, 68))	('targeting', 'Var', (54, 63))
87676	27283985	Despite the lower pH in the extracellular space of tumor tissues, previous studies showed that Ca-K9 peptide/pDNA complexes significantly attenuated lung tumor growth macroscopically and microscopically when delivered by tail vein injection.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('attenuated lung tumor', 'Disease', 'MESH:C538265', (138, 159))	('tumor', 'Disease', (51, 56))	('complexes', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('lung tumor', 'Phenotype', 'HP:0100526', (149, 159))	('attenuated lung tumor', 'Disease', (138, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', (154, 159))
87678	27283985	CCL2 antibody neutralization inhibited tumor progression in mice bearing 4T1 or MDA-MB-231 breast tumor xenografts.	('inhibited', 'NegReg', (29, 38))	('CCL2', 'Gene', (0, 4))	('breast tumor', 'Disease', 'MESH:D001943', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('breast tumor', 'Disease', (91, 103))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (98, 103))	('mice', 'Species', '10090', (60, 64))	('breast tumor', 'Phenotype', 'HP:0100013', (91, 103))	('neutralization', 'Var', (14, 28))
87679	27283985	When anti-CCL2 treatment was stopped midway and 4T1 tumors were surgically removed, the anti-CCL2 treated mice showed increased metastasis associated with increased expression of IL-6 and VEGF, compared to control IgG treated mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('anti-CCL2', 'Var', (88, 97))	('mice', 'Species', '10090', (106, 110))	('metastasis', 'CPA', (128, 138))	('mice', 'Species', '10090', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('increased expression of IL-6', 'Phenotype', 'HP:0030783', (155, 183))	('increased', 'PosReg', (155, 164))	('expression', 'MPA', (165, 175))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('IL-6', 'Protein', (179, 183))	('increased', 'PosReg', (118, 127))	('VEGF', 'Protein', (188, 192))
87680	27283985	From these data, the authors suggested that cessation of CCL2 inhibition may accelerate metastasis by enhancing expression of pro-angiogenic factors.	('CCL2', 'Gene', (57, 61))	('rat', 'Species', '10116', (83, 86))	('expression of', 'MPA', (112, 125))	('enhancing', 'PosReg', (102, 111))	('metastasis', 'CPA', (88, 98))	('cessation', 'Var', (44, 53))	('inhibition', 'NegReg', (62, 72))	('accelerate', 'PosReg', (77, 87))
87687	27283985	In our studies, we found that CCL2 knockdown increased expression of LC3B, indicating cellular autophagy.	('knockdown', 'Var', (35, 44))	('CCL2', 'Gene', (30, 34))	('increased', 'PosReg', (45, 54))	('LC3B', 'Gene', (69, 73))	('cellular autophagy', 'CPA', (86, 104))	('expression', 'MPA', (55, 65))	('LC3B', 'Gene', '81631', (69, 73))
87693	27283985	Our data indicate that CCL2 gene silencing significantly remodeled the microenvironment to suppress tumor progression.	('remodeled', 'Reg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('suppress', 'NegReg', (91, 99))	('gene silencing', 'Var', (28, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CCL2', 'Gene', (23, 27))
87697	27283985	CCL2 knockdown increased necrosis in the primary tumor.	('necrosis', 'Disease', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('CCL2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('knockdown', 'Var', (5, 14))	('necrosis', 'Disease', 'MESH:D009336', (25, 33))	('tumor', 'Disease', (49, 54))	('increased', 'PosReg', (15, 24))	('increased necrosis', 'Phenotype', 'HP:0010885', (15, 33))
87700	27283985	In contrast, antibody neutralization of CCL2 in tumor xenografts enhanced tumor cell apoptosis.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('enhanced', 'PosReg', (65, 73))	('tumor', 'Disease', (74, 79))	('antibody neutralization', 'Var', (13, 36))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CCL2', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
87701	27283985	CCL2 gene silencing may provide a more selective therapeutic advantage in cases where tumors are resistant to apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CCL2', 'Gene', (0, 4))	('gene silencing', 'Var', (5, 19))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))
87705	27283985	In our studies, we demonstrated that CCL2 gene silencing in MDA-MB-231 tumor xenografts inhibited ALDH1 expression, and reduced the number of CD24-/CD44+ cells.	('inhibited', 'NegReg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('rat', 'Species', '10116', (26, 29))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))	('gene silencing', 'Var', (42, 56))	('ALDH1', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('expression', 'MPA', (104, 114))	('CD44', 'Gene', '960', (148, 152))	('ALDH1', 'Gene', '216', (98, 103))	('tumor', 'Disease', (71, 76))	('CD44', 'Gene', (148, 152))	('reduced', 'NegReg', (120, 127))	('CCL2', 'Gene', (37, 41))
87708	27283985	Thus, CCL2 gene silencing via TAT/siRNA complexes inhibit key mechanisms that promote progression of TNBC.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('CCL2', 'Gene', (6, 10))	('promote', 'PosReg', (78, 85))	('TNBC', 'Chemical', '-', (101, 105))	('TNBC', 'Disease', (101, 105))	('inhibit', 'NegReg', (50, 57))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('gene', 'Var', (11, 15))
87709	27283985	In summary, CCL2 knockdown through delivery of Ca-TAT/siRNA complexes could be an effective treatment strategy for the treatment of invasive breast cancer, particularly when combined with other anti-cancer therapies.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('invasive breast cancer', 'Disease', 'MESH:D001943', (132, 154))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('invasive breast cancer', 'Disease', (132, 154))	('cancer', 'Disease', (199, 205))	('knockdown', 'Var', (17, 26))	('CCL2', 'Gene', (12, 16))	('rat', 'Species', '10116', (104, 107))
87894	18466608	Similarly, iej can be found by: where PYRj is the number of person years in interval j and fsj,g is the probability that a clinical cancer in size group g would have been found if screened j months earlier.	('PYRj', 'Var', (38, 42))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('person', 'Species', '9606', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
88011	28046058	CS with BCS could approximately halve the reoperation rate compared with BCS alone (15.0% vs. 30.1%).	('CS', 'Chemical', '-', (9, 11))	('CS', 'Chemical', '-', (74, 76))	('BCS', 'Var', (8, 11))	('CS', 'Chemical', '-', (0, 2))	('reoperation', 'CPA', (42, 53))
88022	28046058	Consequently, surgical resection of the tumor mass in NAC-treated patients tends to leave more residual carcinoma in the cavity compared with resection in non-NAC-treated patients.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Disease', 'MESH:D002277', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('NAC', 'Chemical', '-', (159, 162))	('NAC-treated', 'Var', (54, 65))	('carcinoma', 'Disease', (104, 113))	('patients', 'Species', '9606', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('NAC', 'Chemical', '-', (54, 57))	('patients', 'Species', '9606', (66, 74))
88023	28046058	showed that the cavity margin status was significantly associated with locoregional recurrence in NAC-treated patients but not in non-NAC-treated patients.	('NAC', 'Chemical', '-', (98, 101))	('locoregional recurrence', 'CPA', (71, 94))	('associated', 'Reg', (55, 65))	('NAC-treated', 'Var', (98, 109))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (110, 118))	('NAC', 'Chemical', '-', (134, 137))
88044	20469955	While controversy exists regarding optimal treatment for DCIS, research indicates that women treated with BCS and subsequent radiation therapy have significantly reduced recurrence versus women treated with surgery alone.	('BCS', 'Var', (106, 109))	('recurrence', 'CPA', (170, 180))	('reduced', 'NegReg', (162, 169))	('women', 'Species', '9606', (188, 193))	('women', 'Species', '9606', (87, 92))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
88057	20469955	Of 3668 patients identified as potentially eligible by our cancer registries or electronic medical records, 602 were deemed ineligible for 1 or more of the following reasons based on medical record review: unavailability of medical records (n = 82), miscoding of DCIS in the cancer registry (n = 63), prior breast or other cancer (n = 216), bilateral breast cancer at diagnosis (n = 29), mastectomy for the index DCIS (n = 96), age 85 years or older at diagnosis (n = 15), or lack of follow-up in the health plan for 6 consecutive months (n = 101).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bilateral breast cancer', 'Disease', (341, 364))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (358, 364))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mastectomy', 'Disease', (388, 398))	('DCIS', 'Phenotype', 'HP:0030075', (413, 417))	('breast cancer', 'Phenotype', 'HP:0003002', (351, 364))	('cancer', 'Disease', 'MESH:D009369', (358, 364))	('cancer', 'Disease', (275, 281))	('patients', 'Species', '9606', (8, 16))	('DCIS', 'Phenotype', 'HP:0030075', (263, 267))	('cancer', 'Disease', (323, 329))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('miscoding', 'Var', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancer', 'Disease', (59, 65))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (341, 364))
88110	20469955	Patients with DCIS 70 years or older in our cohort were less likely to receive adjuvant radiation therapy.	('less', 'NegReg', (56, 60))	('Patients', 'Species', '9606', (0, 8))	('DCIS', 'Var', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))
88284	29434661	Moreover, specimen volumes at first excision were significantly lower for the USS group compared with the PGS group (p = 0.048).	('lower', 'NegReg', (64, 69))	('specimen volumes at first excision', 'CPA', (10, 44))	('PGS', 'Disease', (106, 109))	('USS', 'Var', (78, 81))	('PGS', 'Disease', 'MESH:C535773', (106, 109))
88289	29434661	Some of these can detect microscopic malignancy at the edges of the surgical specimen and therefore have potential to reduce the margin positivity and rates of re-excision to a much greater degree than conventional methods for intraoperative specimen radiography.	('detect', 'Reg', (18, 24))	('microscopic', 'Var', (25, 36))	('malignancy', 'Disease', 'MESH:D009369', (37, 47))	('malignancy', 'Disease', (37, 47))	('margin', 'MPA', (129, 135))	('reduce', 'NegReg', (118, 124))
88295	29434661	In consequence, MarginProbe can reduce rates of re-operation for the benefit of patients and the healthcare system.	('patients', 'Species', '9606', (80, 88))	('reduce', 'NegReg', (32, 38))	('MarginProbe', 'Var', (16, 27))
88338	33572420	Remarkable variations can be observed in the spectral contribution of collagen (868 cm-1), lipids (1267 cm-1, 1302 cm-1, 1440 cm-1, 2890 cm-1), protein (1608 cm-1).	('1267 cm-1', 'Var', (99, 108))	('1608 cm-1', 'Var', (153, 162))	('lipids', 'Chemical', 'MESH:D008055', (91, 97))
88352	33572420	The positive peaks in the spectral loading of PC2 were attributed to biochemical components such as protein at 868 and 1250 cm-1, phenylalanine at 1002 cm-1, lipids at 1302, 1450, 1662, and 2940 cm-1, and carotenoid at 1524 cm-1, while the negative peaks were attributed to lipids at 2854 cm-1.	('spectral loading', 'MPA', (26, 42))	('lipids', 'Chemical', 'MESH:D008055', (158, 164))	('PC2', 'Gene', '8535', (46, 49))	('PC2', 'Gene', (46, 49))	('carotenoid', 'Chemical', 'MESH:D002338', (205, 215))	('phenylalanine', 'Chemical', 'MESH:D010649', (130, 143))	('lipids', 'Chemical', 'MESH:D008055', (274, 280))	('2940 cm-1', 'Var', (190, 199))
88484	30185420	We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically-advanced lesions from 24 patients (nine ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILCs) and five invasive ductal carcinomas (IDCs)).	('LCIS', 'Phenotype', 'HP:0030076', (134, 138))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (260, 278))	('invasive ductal carcinomas', 'Disease', (295, 321))	('ductal carcinomas', 'Disease', 'MESH:D044584', (214, 231))	('IDCs', 'Disease', 'MESH:D044584', (323, 327))	('ductal carcinomas', 'Disease', (214, 231))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (251, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('ILCs', 'Disease', 'MESH:D018275', (280, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (311, 321))	('IDCs', 'Disease', (323, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('ductal carcinomas in situ', 'Phenotype', 'HP:0030075', (214, 239))	('invasive lobular carcinomas', 'Disease', (251, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('carcinomas', 'Phenotype', 'HP:0030731', (268, 278))	('invasive ductal carcinomas', 'Disease', 'MESH:D044584', (295, 321))	('ductal carcinomas', 'Disease', 'MESH:D044584', (304, 321))	('DCIS', 'Phenotype', 'HP:0030075', (241, 245))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('LCIS', 'Disease', (134, 138))	('ILCs', 'Disease', (280, 284))	('mutations', 'Var', (107, 116))	('patients', 'Species', '9606', (199, 207))
88485	30185420	WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions.	('ILCs', 'Disease', (90, 94))	('LCIS', 'Disease', (10, 14))	('LCIS', 'Phenotype', 'HP:0030076', (10, 14))	('CDH1', 'Gene', (101, 105))	('ILCs', 'Disease', 'MESH:D018275', (90, 94))	('mutations', 'Var', (106, 115))	('present', 'Reg', (116, 123))
88495	30185420	Analyses of the genomic features of ILCs by The Cancer Genome Atlas consortium (TCGA) and individual investigators have revealed the genes most commonly mutated in this subtype of breast cancer, and identified molecular differences between invasive ductal carcinomas (IDCs) of no special type and ILCs, including a higher rate of FOXA1 mutations and a lower rate of GATA3 mutations in those with lobular histology.	('IDCs', 'Disease', 'MESH:D044584', (268, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('GATA3', 'Gene', (366, 371))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('ILCs', 'Disease', 'MESH:D018275', (297, 301))	('IDCs', 'Disease', (268, 272))	('higher', 'PosReg', (315, 321))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasive ductal carcinomas', 'Disease', 'MESH:D044584', (240, 266))	('breast cancer', 'Disease', (180, 193))	('FOXA1', 'Gene', '3169', (330, 335))	('ILCs', 'Disease', (36, 40))	('FOXA1', 'Gene', (330, 335))	('Cancer', 'Disease', (48, 54))	('ILCs', 'Disease', (297, 301))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('ILCs', 'Disease', 'MESH:D018275', (36, 40))	('mutations', 'Var', (336, 345))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('invasive ductal carcinomas', 'Disease', (240, 266))	('GATA3', 'Gene', '2625', (366, 371))
88496	30185420	Additional whole-exome (WES) and targeted sequencing analyses focused on paired LCIS and ILCs demonstrated comparable rates of mutations affecting CDH1, PIK3CA and CBFB, among other genes.	('PIK3CA', 'Gene', '5290', (153, 159))	('ILCs', 'Disease', 'MESH:D018275', (89, 93))	('CBFB', 'Gene', (164, 168))	('CBFB', 'Gene', '865', (164, 168))	('LCIS', 'Phenotype', 'HP:0030076', (80, 84))	('mutations', 'Var', (127, 136))	('ILCs', 'Disease', (89, 93))	('PIK3CA', 'Gene', (153, 159))	('CDH1', 'Gene', (147, 151))
88509	30185420	To estimate the clonal architecture and composition of the lesions from each patient, mutant allelic fractions from all somatic mutations were adjusted for tumor cell content, ploidy, local copy number and sequencing errors using PyClone, as previously described (Supplementary Methods).	('mutations', 'Var', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ploidy', 'Disease', (176, 182))	('ploidy', 'Disease', 'None', (176, 182))	('tumor', 'Disease', (156, 161))	('patient', 'Species', '9606', (77, 84))
88512	30185420	Maximum parsimony trees were built using binary presence/absence matrices built from the somatic genetic alterations, including synonymous and non-synonymous SNVs, indels and CNAs, within the clonally-related lesions from each patient, essentially as described by Murugaesu et al.	('alterations', 'Var', (105, 116))	('indels', 'Var', (164, 170))	('CNAs', 'Var', (175, 179))	('patient', 'Species', '9606', (227, 234))	('SNVs', 'Var', (158, 162))
88515	30185420	TCGA luminal-A invasive breast cancers and ILCs and their mutations were retrieved from the "Final Full BRCA Sample Summary" and "Mutations - Publicly accessible MAF archives" at https://tcga-data.nci.nih.gov/docs/publications/brca_2012/ and https://tcga-data.nci.nih.gov/docs/publications/brca_2015/, including all non-silent, non-RNA mutations for 209 luminal-A primary invasive breast cancers and 127 ILCs.	('breast cancers', 'Phenotype', 'HP:0003002', (381, 395))	('invasive breast cancers', 'Disease', (372, 395))	('breast cancer', 'Phenotype', 'HP:0003002', (381, 394))	('invasive breast cancers', 'Disease', (15, 38))	('ILCs', 'Disease', 'MESH:D018275', (43, 47))	('ILCs', 'Disease', (404, 408))	('cancers', 'Phenotype', 'HP:0002664', (388, 395))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MAF', 'Gene', (162, 165))	('ILCs', 'Disease', 'MESH:D018275', (404, 408))	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('ILCs', 'Disease', (43, 47))	('invasive breast cancers', 'Disease', 'MESH:D001943', (372, 395))	('mutations', 'Var', (336, 345))	('invasive breast cancers', 'Disease', 'MESH:D001943', (15, 38))	('MAF', 'Gene', '4094', (162, 165))
88520	30185420	This study consists of a re-analysis of previously described WES data, followed by a previously unpublished targeted amplicon sequencing validation of approximately 1,800 selected mutations, from 43 LCIS and synchronous DCIS (n=9), ILCs (n=13) or IDCs (n=5) from 24 patients (Table 1).	('patients', 'Species', '9606', (266, 274))	('mutations', 'Var', (180, 189))	('DCIS', 'Phenotype', 'HP:0030075', (220, 224))	('LCIS', 'Phenotype', 'HP:0030076', (199, 203))	('ILCs', 'Disease', (232, 236))	('IDCs', 'Disease', (247, 251))	('IDCs', 'Disease', 'MESH:D044584', (247, 251))	('ILCs', 'Disease', 'MESH:D018275', (232, 236))
88525	30185420	27 somatic mutations/lesion (range 7-203) and 0.52 mutations/Mb in luminal-A and 29 somatic mutations/lesion (range 1-1,080) and 0.56 mutations/Mb in ILCs; Mann-Whitney U test, P>0.1).	('ILCs', 'Disease', 'MESH:D018275', (150, 154))	('0.56 mutations/Mb', 'Var', (129, 146))	('ILCs', 'Disease', (150, 154))	('mutations/lesion', 'Var', (92, 108))	('0.52', 'Var', (46, 50))	('mutations/Mb', 'Var', (51, 63))
88526	30185420	Consistent with the notion that CDH1 inactivation is a driver of lesions with lobular histologic features, we observed pathogenic mutations affecting the CDH1 gene in 35 of 43 (81%) LCIS, of which all but three were somatic; patient 13, who had three distinct foci of LCIS, was found to harbor a CDH1 germline mutation.	('CDH1', 'Gene', (154, 158))	('CDH1', 'Gene', (296, 300))	('LCIS', 'Phenotype', 'HP:0030076', (182, 186))	('LCIS', 'Disease', (268, 272))	('LCIS', 'Disease', (182, 186))	('LCIS', 'Phenotype', 'HP:0030076', (268, 272))	('mutations', 'Var', (130, 139))	('patient', 'Species', '9606', (225, 232))
88527	30185420	LCIS lacking CDH1 mutations did not harbor mutations or deletions affecting genes coding for additional proteins that comprise the cadherin-catenin complex, such as CTNNB1 (beta-catenin), CTNNA1 (alpha-catenin) or CTNND1 (p120-catenin), nor somatic or germline genetic alterations in RHOA (Supplementary Data File 1), a gene that has been implicated in the biology of gastric cancer, and whose alterations result in neoplastic cells displaying discohesiveness akin to that caused by CDH1 loss of function.	('discohesiveness', 'CPA', (444, 459))	('gastric cancer', 'Disease', 'MESH:D013274', (368, 382))	('loss of function', 'NegReg', (488, 504))	('CTNNB1', 'Gene', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('CDH1', 'Gene', (483, 487))	('CTNNA1', 'Gene', (188, 194))	('CDH1', 'Gene', (13, 17))	('CTNND1', 'Gene', '1500', (214, 220))	('result', 'Reg', (406, 412))	('CTNNA1', 'Gene', '1495', (188, 194))	('CTNND1', 'Gene', (214, 220))	('gastric cancer', 'Phenotype', 'HP:0012126', (368, 382))	('p120-catenin', 'Gene', '1500', (222, 234))	('p120-catenin', 'Gene', (222, 234))	('beta-catenin', 'Gene', (173, 185))	('CTNNB1', 'Gene', '1499', (165, 171))	('beta-catenin', 'Gene', '1499', (173, 185))	('gastric cancer', 'Disease', (368, 382))	('LCIS', 'Phenotype', 'HP:0030076', (0, 4))	('RHOA', 'Gene', '387', (284, 288))	('RHOA', 'Gene', (284, 288))	('alterations', 'Var', (394, 405))	('mutations', 'Var', (18, 27))
88530	30185420	Notably, TP53 mutations were significantly more frequently found in luminal A invasive breast cancers from TCGA than in the LCIS analyzed here (12% (25/209) vs 0% (0/43), Fisher's exact test, P=0.019, Fig.	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('TP53', 'Gene', '7157', (9, 13))	('LCIS', 'Phenotype', 'HP:0030076', (124, 128))	('TP53', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('found', 'Reg', (59, 64))	('luminal A invasive breast cancers', 'Disease', (68, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('mutations', 'Var', (14, 23))	('luminal A invasive breast cancers', 'Disease', 'MESH:D001943', (68, 101))
88531	30185420	Moreover, genes identified by TCGA to be significantly mutated in luminal A invasive breast cancers, including CBFB, GATA3, NCOR1 and MED23 were also found be recurrently mutated in LCIS.	('breast cancers', 'Phenotype', 'HP:0003002', (85, 99))	('NCOR1', 'Gene', (124, 129))	('CBFB', 'Gene', '865', (111, 115))	('GATA3', 'Gene', '2625', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('LCIS', 'Phenotype', 'HP:0030076', (182, 186))	('mutated', 'Var', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('luminal A invasive breast cancers', 'Disease', (66, 99))	('CBFB', 'Gene', (111, 115))	('luminal A invasive breast cancers', 'Disease', 'MESH:D001943', (66, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TCGA', 'Gene', (30, 34))	('MED23', 'Gene', (134, 139))	('NCOR1', 'Gene', '9611', (124, 129))	('MED23', 'Gene', '9439', (134, 139))	('GATA3', 'Gene', (117, 122))
88532	30185420	Interestingly, however, CBFB was found to be mutated in 19% (8/43) of LCIS, a rate significantly higher than that in 2% (2/127) of ILCs and 2% (5/209) of luminal-A breast cancers from TCGA (Fisher's exact tests, P<0.01, Fig.	('CBFB', 'Gene', (24, 28))	('ILCs', 'Disease', (131, 135))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('breast cancers', 'Disease', (164, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('LCIS', 'Disease', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('ILCs', 'Disease', 'MESH:D018275', (131, 135))	('LCIS', 'Phenotype', 'HP:0030076', (70, 74))	('CBFB', 'Gene', '865', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutated', 'Var', (45, 52))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
88548	30185420	To test this hypothesis, we resolved the clonal composition of LCIS, DCIS and/or ILC samples by applying a Bayesian clustering model (PyClone) to mutant allele fractions, incorporating tumor cellularity, ploidy and local copy number obtained from ABSOLUTE and/or FACETS (Supplementary Methods).	('tumor', 'Disease', (185, 190))	('ILC', 'Disease', (81, 84))	('ILC', 'Disease', 'MESH:D018275', (81, 84))	('LCIS', 'Phenotype', 'HP:0030076', (63, 67))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('mutant', 'Var', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
88553	30185420	Given the intra-lesion genetic heterogeneity observed in LCIS, in particular in those related to more advanced lesions, we sought to define whether the branch mutations found in these lesions would affect 'passenger' genes or genes significantly mutated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('mutations', 'Var', (159, 168))	('affect', 'Reg', (198, 204))	("'passenger", 'Gene', (205, 215))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('LCIS', 'Disease', (57, 61))	('cancer', 'Disease', (257, 263))	('LCIS', 'Phenotype', 'HP:0030076', (57, 61))
88554	30185420	Contrary to the notion that heterogeneity would primarily affect passenger genetic events, both truncal and branch non-synonymous somatic mutations detected in LCIS clonally-related to the other lesions were found to target genes significantly enriched for known cancer drivers (hypergeometric test, representation factor=2.09, P<0.01, and hypergeometric test, representation factor=1.5, P<0.01, respectively; Supplementary Figs.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('LCIS', 'Phenotype', 'HP:0030076', (160, 164))	('mutations', 'Var', (138, 147))
88555	30185420	Importantly, however, in agreement with previous multi-region analyses that suggested that most of the driver genetic alterations are early truncal events, the enrichment for cancer genes was higher in the constellation of truncal than in branch mutations.	('alterations', 'Var', (118, 129))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('truncal', 'Var', (223, 230))	('higher', 'PosReg', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
88562	30185420	MAP3K1 (2 cases), RUNX1, NCOR1, ARID1A and TBX3 (2 cases)) or LOH of the wild-type allele (Figs.	('RUNX1', 'Gene', '861', (18, 23))	('TBX3', 'Gene', '6926', (43, 47))	('LOH', 'Var', (62, 65))	('TBX3', 'Gene', (43, 47))	('MAP3K1', 'Gene', (0, 6))	('NCOR1', 'Gene', '9611', (25, 30))	('MAP3K1', 'Gene', '4214', (0, 6))	('ARID1A', 'Gene', '8289', (32, 38))	('RUNX1', 'Gene', (18, 23))	('ARID1A', 'Gene', (32, 38))	('NCOR1', 'Gene', (25, 30))
88568	30185420	Both truncal and branch mutations were found to be enriched for C>T transitions in the NpCpG context, consistent with a signature ascribed to aging, and C>G transversions and C>T transitions in the TpCpW context, suggestive of the mutational processes caused by APOBEC DNA cytosine deaminase activity; the latter being predominately found in the branch mutations of case 4 (Fig.	('C>T', 'Var', (175, 178))	('C>G transversions', 'Var', (153, 170))	('cytosine', 'Chemical', 'MESH:D003596', (273, 281))
88572	30185420	Moreover, the mRNA levels of APOBEC3B, a DNA cytosine deaminase that has been causally implicated in the development of APOBEC signature mutations in cancer, were significantly higher in samples displaying an APOBEC mutational process than in those displaying an aging signature (Fig.	('higher', 'PosReg', (177, 183))	('APOBEC3B', 'Gene', '9582', (29, 37))	('APOBEC', 'Gene', (120, 126))	('mRNA levels', 'MPA', (14, 25))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (137, 146))	('cancer', 'Disease', (150, 156))	('cytosine', 'Chemical', 'MESH:D003596', (45, 53))	('APOBEC3B', 'Gene', (29, 37))	('mutational', 'Var', (216, 226))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('APOBEC', 'Disease', (209, 215))
88575	30185420	In these patients, the APOBEC mutational process, which has been implicated in genetic instability and intra-tumor genetic heterogeneity, appears to be present later in the evolution of LCIS and may be involved in its progression to more advanced lesions.	('patients', 'Species', '9606', (9, 17))	('APOBEC', 'Gene', (23, 29))	('involved', 'Reg', (202, 210))	('intra-tumor', 'Disease', (103, 114))	('LCIS', 'Phenotype', 'HP:0030076', (186, 190))	('mutational', 'Var', (30, 40))	('LCIS', 'Disease', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('intra-tumor', 'Disease', 'MESH:D009369', (103, 114))
88576	30185420	Interestingly, the samples enriched for APOBEC mutation process displayed higher expression levels of APOBEC3B, whose activity has been shown to be mutagenic.	('higher', 'PosReg', (74, 80))	('APOBEC3B', 'Gene', '9582', (102, 110))	('APOBEC3B', 'Gene', (102, 110))	('mutation', 'Var', (47, 55))	('expression levels', 'MPA', (81, 98))
88579	30185420	Bi-directional progression between lesions of lobular (atypical lobular hyperplasia and LCIS) and ductal phenotype (atypical ductal hyperplasia and DCIS) is entirely consistent with the proposed concept of a low nuclear grade breast neoplasia family, which encompasses a group of low-grade, ER-positive neoplasms of the breast that not uncommonly affect the same segment of the breast, if not the same terminal ductal-lobular unit, and share a remarkably similar genomic landscape, having concurrent 1q gains and 16q losses, and PIK3CA mutations, as their genetic signature.	('hyperplasia', 'Disease', (72, 83))	('breast neoplasia', 'Disease', (226, 242))	('hyperplasia', 'Disease', 'MESH:D006965', (72, 83))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('PIK3CA', 'Gene', (529, 535))	('neoplasia', 'Phenotype', 'HP:0002664', (233, 242))	('breast neoplasia', 'Disease', 'MESH:D061325', (226, 242))	('neoplasms of the breast', 'Phenotype', 'HP:0100013', (303, 326))	('losses', 'NegReg', (517, 523))	('neoplasms', 'Phenotype', 'HP:0002664', (303, 312))	('ER', 'Gene', '2099', (291, 293))	('hyperplasia', 'Disease', (132, 143))	('gains', 'PosReg', (503, 508))	('hyperplasia', 'Disease', 'MESH:D006965', (132, 143))	('neoplasms of the breast', 'Disease', 'MESH:D061325', (303, 326))	('PIK3CA', 'Gene', '5290', (529, 535))	('LCIS', 'Phenotype', 'HP:0030076', (88, 92))	('mutations', 'Var', (536, 545))	('16q', 'MPA', (513, 516))	('Bi', 'Chemical', 'MESH:D001729', (0, 2))	('neoplasms of the breast', 'Disease', (303, 326))
88581	30185420	Akin to ILCs, LCIS harbors recurrent bi-allelic inactivation of CDH1 (77%), and recurrent mutations affecting genes commonly mutated in breast cancer, including PIK3CA, FOXA1 and TBX3, among other genes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (90, 99))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('LCIS', 'Phenotype', 'HP:0030076', (14, 18))	('breast cancer', 'Disease', (136, 149))	('ILCs', 'Disease', (8, 12))	('TBX3', 'Gene', '6926', (179, 183))	('PIK3CA', 'Gene', (161, 167))	('ILCs', 'Disease', 'MESH:D018275', (8, 12))	('bi-allelic inactivation', 'Var', (37, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('TBX3', 'Gene', (179, 183))	('FOXA1', 'Gene', (169, 174))	('PIK3CA', 'Gene', '5290', (161, 167))	('CDH1', 'Gene', (64, 68))	('FOXA1', 'Gene', '3169', (169, 174))
88583	30185420	These differences might be related to the fact that our cohort included only classic LCIS, but given that progression may occur via clonal selection, and that not only truncal, but also branch mutations are enriched for known cancer genes, it is plausible that acquisition of genetic alterations, including those resulting in inactivation of these two bona fide tumor suppressor genes, may play a role in the progression to ILC.	('LCIS', 'Phenotype', 'HP:0030076', (85, 89))	('ILC', 'Disease', 'MESH:D018275', (424, 427))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('ILC', 'Disease', (424, 427))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('alterations', 'Var', (284, 295))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', (362, 367))	('inactivation', 'NegReg', (326, 338))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
88584	30185420	Indeed, we and others have demonstrated previously that loss of PTEN may be associated in the progression from DCIS to IDC.	('loss', 'Var', (56, 60))	('DCIS', 'Disease', (111, 115))	('associated', 'Reg', (76, 86))	('IDC', 'Disease', (119, 122))	('PTEN', 'Gene', (64, 68))	('IDC', 'Disease', 'MESH:D044584', (119, 122))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('PTEN', 'Gene', '5728', (64, 68))
88708	29986750	However, MSH dramatically reduced the acquisition time, as it required 100-fold to 200-fold fewer Raman spectra compared with raster scanning while providing similar diagnostic accuracy for breast carcinomas, even those comprising small tumors (< 1 mm2).	('breast carcinomas', 'Phenotype', 'HP:0003002', (190, 207))	('small tumors', 'Disease', 'MESH:D058405', (231, 243))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('breast carcinomas', 'Disease', (190, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('reduced', 'NegReg', (26, 33))	('MSH', 'Var', (9, 12))	('breast carcinomas', 'Disease', 'MESH:D001943', (190, 207))	('Raman', 'Gene', (98, 103))	('acquisition time', 'MPA', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('small tumors', 'Disease', (231, 243))
88745	27303510	In all but one published case, cryoablation in breast cancer has been followed by post-procedural tumor resection.	('cryoablation', 'Var', (31, 43))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
88759	27303510	Pathology showed grade 1 invasive ductal carcinoma with low grade DCIS in the 2 o'clock lesion and grade 2 invasive ductal carcinoma in the 4 o'clock lesion.	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (107, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('invasive ductal carcinoma', 'Disease', (25, 50))	('invasive ductal carcinoma', 'Disease', (107, 132))	('low grade', 'Var', (56, 65))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (116, 132))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (34, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (25, 50))
88802	27303510	Work with a murine model demonstrates that cryoablation is superior to surgical excision in stimulating T-cell and natural killer cell activity and in significanly reducing the tumor recurrence rate after rechallenge.	('stimulating', 'PosReg', (92, 103))	('murine', 'Species', '10090', (12, 18))	('reducing', 'NegReg', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('T-cell', 'CPA', (104, 110))	('cryoablation', 'Var', (43, 55))	('tumor', 'Disease', (177, 182))
88815	21847403	High leptin expression was significantly associated with high Ki-67 expression (p=0.016).	('leptin', 'Gene', '3952', (5, 11))	('expression', 'MPA', (68, 78))	('high', 'Var', (57, 61))	('Ki-67', 'Gene', (62, 67))	('leptin', 'Gene', (5, 11))	('High leptin', 'Phenotype', 'HP:0031793', (0, 11))	('expression', 'MPA', (12, 22))
88827	21847403	Binding of leptin to ObR activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, and induction of JAK stimulates phosphoinositol-3-kinase (PI3Kinase).	('activates', 'PosReg', (25, 34))	('Janus kinase/signal transducer and', 'Pathway', (39, 73))	('phosphoinositol-3-kinase', 'MPA', (163, 187))	('leptin', 'Gene', '3952', (11, 17))	('ObR', 'Gene', '3953', (21, 24))	('leptin', 'Gene', (11, 17))	('induction', 'Var', (135, 144))	('Binding', 'Interaction', (0, 7))	('ObR', 'Gene', (21, 24))	('stimulates', 'PosReg', (152, 162))
88873	21847403	The results showed that leptin expression was significantly associated with high Ki-67 expression (p=0.016), and ObR expression was significantly associated with negative Bcl-2 expression (p=0.007).	('negative', 'NegReg', (162, 170))	('ObR', 'Gene', '3953', (113, 116))	('leptin', 'Gene', '3952', (24, 30))	('Bcl-2', 'Gene', '596', (171, 176))	('expression', 'MPA', (87, 97))	('leptin', 'Gene', (24, 30))	('expression', 'MPA', (31, 41))	('Bcl-2', 'Gene', (171, 176))	('Ki-67', 'Protein', (81, 86))	('ObR', 'Gene', (113, 116))	('high', 'Var', (76, 80))
88876	21847403	AdipoR expression was significantly associated with high Ki-67 expression (p=0.029) in invasive breast cancer (Table 4).	('AdipoR expression', 'MPA', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', (87, 109))	('high Ki-67', 'Var', (52, 62))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
88899	21847403	reported that tissue adiponectin levels in patients with breast cancer were significantly higher than healthy individuals, and that high tissue adiponectin levels were associated with a significantly increased risk for breast cancer compared with those with low tissue adiponectin levels.	('breast cancer', 'Disease', (57, 70))	('adiponectin', 'Gene', '9370', (21, 32))	('adiponectin', 'Gene', (144, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('low tissue adiponectin levels', 'Phenotype', 'HP:0030685', (258, 287))	('high', 'Var', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('high tissue adiponectin levels', 'Phenotype', 'HP:0030686', (132, 162))	('patients', 'Species', '9606', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('adiponectin', 'Gene', (269, 280))	('adiponectin', 'Gene', '9370', (144, 155))	('breast cancer', 'Disease', (219, 232))	('higher', 'PosReg', (90, 96))	('adiponectin', 'Gene', (21, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('adiponectin', 'Gene', '9370', (269, 280))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
88939	33670739	Briefly, DIN1C corresponds to low-grade DCIS, DIN2 to intermediate-grade, and DIN3 to high-grade, according to nuclear morphologic features of the neoplastic cells.	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('DIN1C', 'Var', (9, 14))	('DIN2', 'Chemical', '-', (46, 50))	('DCIS', 'Disease', (40, 44))
88955	33670739	Patients with diagnosis of low-grade DCIS showing complete removal of the lesion experienced a significantly lower upgrade rate when compared to those showing mammographically detectable residual tumor after VABB (p-value < 0.05).	('lower', 'NegReg', (109, 114))	('tumor', 'Disease', (196, 201))	('low-grade', 'Var', (27, 36))	('Patients', 'Species', '9606', (0, 8))	('upgrade', 'MPA', (115, 122))	('DCIS', 'Disease', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
88999	33332730	From January 2009 to June 2016, hospitalized patients in Oncology Department of Shengjing Hospital (Shengyang, China), who underwent surgical resection and were pathologically diagnosed with T1mic N0M0 breast cancer were included in the study.	('Oncology', 'Phenotype', 'HP:0002664', (57, 65))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('patients', 'Species', '9606', (45, 53))	('T1mic N0M0', 'Var', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
89025	33332730	The percentage of menopausal patients were higher in the DCISM group than in the DCIS group (70.00% vs 47.54%, P = 0.026).	('menopausal', 'Disease', (18, 28))	('DCISM', 'Var', (57, 62))	('patients', 'Species', '9606', (29, 37))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('higher', 'PosReg', (43, 49))	('DCISM', 'Chemical', '-', (57, 62))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
89057	32529409	Cryoablation is a minimally-invasive percutaneous procedure that is capable of reducing the psychosocial burden of surgical delay while also decreasing the morbidity of breast cancer therapy.	('reducing', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('morbidity', 'MPA', (156, 165))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('decreasing', 'NegReg', (141, 151))	('breast cancer', 'Disease', (169, 182))	('Cryoablation', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
89061	32529409	As an office-based procedure performed under local anesthesia, cryoablation eliminates the need for operating room personnel and equipment while also reducing the psychosocial impact of delayed breast cancer surgery.	('reducing', 'NegReg', (150, 158))	('psychosocial impact', 'MPA', (163, 182))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('eliminates', 'NegReg', (76, 86))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('cryoablation', 'Var', (63, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
89062	32529409	By reducing the number of patient and healthcare provider interactions, cryoablation not only decreases the risk of viral transmission but also the need for personal protective devices during resource-limited times.	('patient', 'Species', '9606', (26, 33))	('viral transmission', 'MPA', (116, 134))	('cryoablation', 'Var', (72, 84))	('decreases', 'NegReg', (94, 103))
89070	32529409	In "Recommendations for Prioritization, Treatment and Triage of Breast Cancer Patients During the COVID-19 Pandemic," the authors advocate expedited breast surgery only for breast conditions that are immediately life-threatening: abscesses and bleeding complications requiring surgical management (Surgical Priority A), prevention or management of wounds with compromised blood supply (Surgical Priority B1), and surgical management of women completing pre-operative chemotherapy for high-risk breast cancer (triple-negative or HER2/neu-positive breast cancer or breast cancers that show continued growth despite pre-operative systemic therapy) (Surgical Priority B1).	('bleeding', 'Disease', (244, 252))	('breast cancer', 'Disease', 'MESH:D001943', (494, 507))	('breast cancers', 'Phenotype', 'HP:0003002', (563, 577))	('breast cancer', 'Disease', (494, 507))	('breast cancer', 'Phenotype', 'HP:0003002', (563, 576))	('HER2', 'Gene', (528, 532))	('breast cancer', 'Phenotype', 'HP:0003002', (546, 559))	('neu', 'Gene', '2064', (533, 536))	('cancer', 'Phenotype', 'HP:0002664', (501, 507))	('breast cancer', 'Disease', 'MESH:D001943', (563, 576))	('COVID-19', 'Disease', 'MESH:C000657245', (98, 106))	('Breast Cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', 'MESH:D001943', (546, 559))	('COVID-19', 'Disease', (98, 106))	('breast cancer', 'Disease', (546, 559))	('women', 'Species', '9606', (436, 441))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Breast Cancer', 'Disease', (64, 77))	('Patients', 'Species', '9606', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (570, 577))	('Breast Cancer', 'Phenotype', 'HP:0003002', (64, 77))	('bleeding', 'Disease', 'MESH:D006470', (244, 252))	('HER2', 'Gene', '2064', (528, 532))	('cancer', 'Phenotype', 'HP:0002664', (570, 576))	('neu', 'Gene', (533, 536))	('breast cancers', 'Disease', 'MESH:D001943', (563, 577))	('breast cancers', 'Disease', (563, 577))	('abscesses', 'Phenotype', 'HP:0025615', (230, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (494, 507))	('triple-negative', 'Var', (509, 524))	('cancer', 'Phenotype', 'HP:0002664', (553, 559))
89089	32529409	As an outpatient, office-based procedure performed under local anesthesia, cryoablation also reduces burden on the healthcare system by eliminating the need for an operating theater, an anesthesiologist and surgical team and decreasing the number of requisite personal protective devices (e.g., masks, face shields, and surgical gowns):all important considerations in a pandemic where such resources are at a premium.	('decreasing', 'NegReg', (225, 235))	('burden', 'MPA', (101, 107))	('reduces', 'NegReg', (93, 100))	('eliminating', 'NegReg', (136, 147))	('outpatient', 'Species', '9606', (6, 16))	('cryoablation', 'Var', (75, 87))
89099	32529409	Unlike the average hospital outpatient surgical procedure which typically involves 15-20 patient-hospital personnel interactions, cryoablation achieves social distancing by limiting patient to 2-3 healthcare personnel interactions for the typical office-based procedure.	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (182, 189))	('outpatient', 'Species', '9606', (28, 38))	('patient', 'Species', '9606', (31, 38))	('limiting', 'NegReg', (173, 181))	('cryoablation', 'Var', (130, 142))
89103	32529409	The findings of ACOSOG Z1072 influenced the design of the FROST Trial (currently enrolling, www.clinicaltrial.gov, #NCT011992250) and the Ice3 Trial (active, non-enrolling, www.clinicaltrial.gov, #NCT02200705), two U.S. non-randomized trials examining the outcome of a similar cohort of women treated with cryoablation without subsequent surgical removal.	('women', 'Species', '9606', (287, 292))	('Z1072', 'Var', (23, 28))	('influenced', 'Reg', (29, 39))
89116	32529409	Since cryoablation intentionally eradicates tumor histology, it is critical to confirm that the diagnostic needle biopsy provided sufficient tissue samples for histological and genomic assays.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('eradicates', 'NegReg', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cryoablation', 'Var', (6, 18))	('tumor', 'Disease', (44, 49))
89122	32529409	Patients with stage I breast cancer may undergo cryoablation of the primary breast lesion, with delayed resection of the cryoablation site reserved for patients with extensive ductal carcinoma in situ and/or for those requiring surgical axillary staging, e.g., women under 70 years of age or those with hormone receptor-negative, HER2/neu-positive, or genomically high-risk disease.	('breast lesion', 'Disease', (76, 89))	('hormone receptor', 'Gene', (303, 319))	('neu', 'Gene', '2064', (335, 338))	('breast lesion', 'Disease', 'MESH:D001943', (76, 89))	('ductal carcinoma', 'Disease', 'MESH:D044584', (176, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('stage I breast cancer', 'Disease', 'MESH:D001943', (14, 35))	('Patients', 'Species', '9606', (0, 8))	('women', 'Species', '9606', (261, 266))	('HER2', 'Gene', '2064', (330, 334))	('cryoablation', 'Var', (48, 60))	('hormone receptor', 'Gene', '3164', (303, 319))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('neu', 'Gene', (335, 338))	('stage I breast cancer', 'Disease', (14, 35))	('patients', 'Species', '9606', (152, 160))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (176, 200))	('ductal carcinoma', 'Disease', (176, 192))	('HER2', 'Gene', (330, 334))
89128	32529409	However, unlike endocrine therapy which will nearly always requires subsequent surgical resection, cryoablation is capable of completely eliminating the need for breast surgery for a large proportion of women with stage I breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('stage I breast cancer', 'Disease', (214, 235))	('cryoablation', 'Var', (99, 111))	('eliminating', 'NegReg', (137, 148))	('women', 'Species', '9606', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('stage I breast cancer', 'Disease', 'MESH:D001943', (214, 235))
89132	32529409	Cryoablation might eliminate the need for surgery in patients refusing breast surgery or provide temporary control of tumor growth until the patient is able to conveniently undergo mastectomy with or without reconstruction.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patient', 'Species', '9606', (141, 148))	('tumor', 'Disease', (118, 123))	('refusing breast surgery', 'Phenotype', 'HP:0100783', (62, 85))	('Cryoablation', 'Var', (0, 12))	('patient', 'Species', '9606', (53, 60))
89148	32529409	Cryoablation can expedite definitive treatment in some patients, minimize the risk of disease progression of the primary tumor site, reduce the anxiety of prolonged surgical delay, and save healthcare resources.	('minimize', 'NegReg', (65, 73))	('anxiety', 'Disease', (144, 151))	('anxiety', 'Phenotype', 'HP:0000739', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('anxiety', 'Disease', 'MESH:D001007', (144, 151))	('definitive treatment', 'CPA', (26, 46))	('patients', 'Species', '9606', (55, 63))	('Cryoablation', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
89165	32596362	Whereas, another study showed that HER2 overexpression may not be the key factor in the progression of DCIS transforming to invasive carcinoma, and HER2 gene amplification is inversely related to the invasive progression in DCIS patients.	('HER2', 'Gene', (148, 152))	('invasive carcinoma', 'Disease', 'MESH:D009361', (124, 142))	('DCIS', 'Disease', (103, 107))	('invasive carcinoma', 'Disease', (124, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('gene amplification', 'Var', (153, 171))	('related', 'Reg', (185, 192))
89176	30725231	We identified ID2 as a critical gene for DCIS initiation and found that ID2 promoted DCIS formation by enhancing cancer stemness of premalignant cells.	('cancer stemness', 'Disease', 'MESH:D009369', (113, 128))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('DCIS formation', 'CPA', (85, 99))	('enhancing', 'PosReg', (103, 112))	('cancer stemness', 'Disease', (113, 128))	('ID2', 'Var', (72, 75))	('promoted', 'PosReg', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
89209	30725231	Lentiviral vectors expressing shRNA for ID2, GJB2, and INHBA were obtained from Dharmacon (shID2-# RHS4533-EG3398, shGJB2-# RHS4533-EG2706 and shINHBA-# RHS4533-EG3624).	('GJB2', 'Gene', '2706', (117, 121))	('INHBA', 'Gene', (55, 60))	('INHBA', 'Gene', (145, 150))	('GJB2', 'Gene', (45, 49))	('GJB2', 'Gene', (117, 121))	('shID2-', 'Var', (91, 97))	('INHBA', 'Gene', '3624', (55, 60))	('INHBA', 'Gene', '3624', (145, 150))	('GJB2', 'Gene', '2706', (45, 49))	('RHS4533-EG2706', 'CellLine', 'CVCL:1X44', (124, 138))
89219	30725231	Compounds which block the hydrogen bonding interactions between Leu49beta-Gln76alpha and Gln76alpha-Tyr 71beta act could prevent dimer formation.	('Gln76alpha', 'Chemical', '-', (74, 84))	('Tyr', 'Chemical', 'MESH:D014443', (100, 103))	('Gln76alpha', 'Chemical', '-', (89, 99))	('hydrogen bonding', 'MPA', (26, 42))	('hydrogen', 'Chemical', 'MESH:D006859', (26, 34))	('Leu49beta-Gln76alpha', 'Var', (64, 84))	('Gln76alpha-Tyr 71beta act', 'Var', (89, 114))	('block', 'NegReg', (16, 21))	('prevent', 'NegReg', (121, 128))	('dimer formation', 'MPA', (129, 144))	('Leu49beta', 'Chemical', '-', (64, 73))
89225	30725231	Of those genes, nine also showed increased expression levels in MCF10CA cells (FC>1, p<0.05,) and 24 showed decreased expression levels in MCF10CA cells compared to DCIS.com cells (FC<1, p<0.05).	('MCF10CA', 'Var', (139, 146))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('MCF10CA', 'CellLine', 'CVCL:6683', (139, 146))	('decreased', 'NegReg', (108, 117))	('increased', 'PosReg', (33, 42))	('expression levels', 'MPA', (118, 135))	('MCF10CA', 'CellLine', 'CVCL:6683', (64, 71))	('expression levels', 'MPA', (43, 60))
89235	30725231	The ectopic expression of ID2 significantly promoted cell proliferation of the pre-malignant MCF10AT cells (Fig.	('promoted', 'PosReg', (44, 52))	('ID2', 'Gene', (26, 29))	('cell proliferation of', 'CPA', (53, 74))	('MCF10A', 'CellLine', 'CVCL:0598', (93, 99))	('ectopic expression', 'Var', (4, 22))
89237	30725231	We found that the ectopic expression of ID2 significantly increased the CD24low/CD44high/ESAhigh cancer stem cell population and the number of spheres compared to control groups (Fig.	('CD44', 'Gene', (80, 84))	('ectopic expression', 'Var', (18, 36))	('increased', 'PosReg', (58, 67))	('cancer', 'Disease', (97, 103))	('ID2', 'Gene', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CD44', 'Gene', '960', (80, 84))	('number of spheres', 'CPA', (133, 150))	('CD24', 'Gene', '100133941', (72, 76))	('CD24', 'Gene', (72, 76))
89238	30725231	In addition, we knocked-down the ID2 genes in DCIS.com and Sum225 (Fig.	('Sum225', 'Chemical', '-', (59, 65))	('ID2 genes', 'Gene', (33, 42))	('Sum225', 'Gene', (59, 65))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('knocked-down', 'Var', (16, 28))
89240	30725231	As shown in Figure 2f-h knockdown of ID2 significantly decreased cell proliferation, cancer stem cell population, and mammosphere formation of DCIS.com cells.	('mammosphere formation', 'CPA', (118, 139))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('ID2', 'Gene', (37, 40))	('cancer', 'Disease', (85, 91))	('decreased', 'NegReg', (55, 64))	('cell proliferation', 'CPA', (65, 83))	('knockdown', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
89242	30725231	We found that several stem cell factors, including SOX2, SMO, and ZEB2, were upregulated in ID2 overexpressing cells (Fig.2i).	('stem cell factors', 'CPA', (22, 39))	('upregulated', 'PosReg', (77, 88))	('ID2', 'Gene', (92, 95))	('ZEB2', 'Gene', '9839', (66, 70))	('overexpressing', 'Var', (96, 110))	('ZEB2', 'Gene', (66, 70))	('SOX2', 'Gene', '6657', (51, 55))	('SMO', 'Gene', (57, 60))	('SMO', 'Gene', '6608', (57, 60))	('SOX2', 'Gene', (51, 55))
89244	30725231	Therefore, we knocked down ID2 in MCF10CA cells and found that silencing ID2 decreased plating efficiency of MCF10CA cells but not their invasive ability (Fig2, k, l).	('ID2', 'Gene', (73, 76))	('MCF10CA', 'CellLine', 'CVCL:6683', (109, 116))	('knocked down', 'Var', (14, 26))	('ID2', 'Gene', (27, 30))	('plating efficiency', 'CPA', (87, 105))	('MCF10CA', 'CellLine', 'CVCL:6683', (34, 41))	('decreased', 'NegReg', (77, 86))	('silencing', 'Var', (63, 72))
89250	30725231	In contrast, knockdown of ID2 in DCIS.com cells significantly suppressed overall tumor growth (Fig.	('ID2', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('suppressed', 'NegReg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (81, 86))
89252	30725231	To elucidate the molecular mechanisms that promote the progression of DCIS to IDC, we compared the DCIS.com and MCF10CA for mRNA expression profiles and found that 234 genes were upregulated in MCF10CA cells (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('MCF10CA', 'Var', (194, 201))	('MCF10CA', 'CellLine', 'CVCL:6683', (194, 201))	('upregulated', 'PosReg', (179, 190))	('MCF10CA', 'CellLine', 'CVCL:6683', (112, 119))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))
89253	30725231	We cross-verified expression of these genes in four clinical cohorts, GSE26304, GSE59246, GSE14548, and GSE35019 individually and found that only gap junction protein beta 2 (GJB2) and inhibin beta A subunit (INHBA) were significantly upregulated in invasive breast cancer patients compared to DCIS patients in all four cohorts (Fig.	('gap junction protein beta 2', 'Gene', '2706', (146, 173))	('upregulated', 'PosReg', (235, 246))	('patients', 'Species', '9606', (273, 281))	('GSE35019', 'Var', (104, 112))	('GJB2', 'Gene', (175, 179))	('GSE14548', 'Var', (90, 98))	('inhibin beta A subunit', 'Gene', '3624', (185, 207))	('INHBA', 'Gene', '3624', (209, 214))	('invasive breast cancer', 'Disease', 'MESH:D001943', (250, 272))	('gap junction protein beta 2', 'Gene', (146, 173))	('GJB2', 'Gene', '2706', (175, 179))	('patients', 'Species', '9606', (299, 307))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('INHBA', 'Gene', (209, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('inhibin beta A subunit', 'Gene', (185, 207))	('invasive breast cancer', 'Disease', (250, 272))	('DCIS', 'Phenotype', 'HP:0030075', (294, 298))
89260	30725231	As shown in Figure 5a-d, we found that knockdown of INHBA and GJB2 significantly suppressed 3D growth, invasion, and mammosphere formation abilities.	('suppressed', 'NegReg', (81, 91))	('knockdown', 'Var', (39, 48))	('3D growth', 'CPA', (92, 101))	('GJB2', 'Gene', (62, 66))	('mammosphere formation abilities', 'CPA', (117, 148))	('INHBA', 'Gene', '3624', (52, 57))	('GJB2', 'Gene', '2706', (62, 66))	('INHBA', 'Gene', (52, 57))	('invasion', 'CPA', (103, 111))
89261	30725231	Consistent with previously finding that GJB2 regulates self-renew ability, knockdown of GJB2 in MCF10CA cells dramatically decreased number of spheres.	('GJB2', 'Gene', (40, 44))	('decreased', 'NegReg', (123, 132))	('GJB2', 'Gene', '2706', (40, 44))	('GJB2', 'Gene', '2706', (88, 92))	('knockdown', 'Var', (75, 84))	('number of spheres', 'CPA', (133, 150))	('MCF10CA', 'CellLine', 'CVCL:6683', (96, 103))	('GJB2', 'Gene', (88, 92))
89263	30725231	5e,f) and found that knockdown of either gene significantly suppressed in vivo growth of MCF10CA cells.	('MCF10CA', 'CellLine', 'CVCL:6683', (89, 96))	('knockdown', 'Var', (21, 30))	('suppressed', 'NegReg', (60, 70))	('in vivo growth of MCF10CA cells', 'CPA', (71, 102))
89266	30725231	We found that patients with high expression of ID2 and GJB2 but not INHBA were more likely to have had recurrence after breast conserved surgery (Fig.	('GJB2', 'Gene', '2706', (55, 59))	('INHBA', 'Gene', '3624', (68, 73))	('breast conserved surgery', 'Disease', (120, 144))	('GJB2', 'Gene', (55, 59))	('ID2', 'Gene', (47, 50))	('INHBA', 'Gene', (68, 73))	('high expression', 'Var', (28, 43))	('patients', 'Species', '9606', (14, 22))
89268	30725231	As ID2 and GJB2 both regulate stemness, patients with high expression of ID2 and GJB2 are more likely to harbor a high population of cancer stem cell and may have a higher chance of recurrence and poor prognosis.	('ID2', 'Gene', (73, 76))	('GJB2', 'Gene', (81, 85))	('GJB2', 'Gene', '2706', (11, 15))	('high expression', 'Var', (54, 69))	('stemness', 'CPA', (30, 38))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('GJB2', 'Gene', (11, 15))	('cancer', 'Disease', (133, 139))	('recurrence', 'CPA', (182, 192))	('GJB2', 'Gene', '2706', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
89270	30725231	These results suggest that a patient with high expression ID2 and GJB2 has high risk of recurrence and those patients are candidates for preventive therapy after conserved surgery.	('patient', 'Species', '9606', (29, 36))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('GJB2', 'Gene', (66, 70))	('high expression', 'Var', (42, 57))	('ID2', 'Gene', (58, 61))	('GJB2', 'Gene', '2706', (66, 70))
89275	30725231	Our modeling indicated that these compounds dock in the pocket of ID2 at key residues (Leu 49, Tyr 71 of the beta-unit, and Gln 76 of the alpha-unit) that are involved in the dimerization of ID2 (Fig.	('Tyr 71', 'Var', (95, 101))	('dock', 'Reg', (44, 48))	('Gln', 'Chemical', 'MESH:D005973', (124, 127))	('Leu', 'Chemical', 'MESH:D007930', (87, 90))	('Leu 49', 'Var', (87, 93))	('Gln 76', 'Var', (124, 130))	('Tyr', 'Chemical', 'MESH:D014443', (95, 98))
89277	30725231	Because ID2 promotes cancer stemness, we also evaluated the efficacy of Helichrysetin on the self-renewal ability of cancer stem cells and found that Helichrysetin significantly suppressed mammosphere formation and decreased the population of cancer stem cells in both DCIS.com and MCF10AT-ID2 cells (Fig.	('cancer stemness', 'Disease', 'MESH:D009369', (21, 36))	('DCIS', 'Phenotype', 'HP:0030075', (269, 273))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('Helichrysetin', 'Var', (150, 163))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('mammosphere formation', 'CPA', (189, 210))	('cancer', 'Disease', (117, 123))	('decreased', 'NegReg', (215, 224))	('cancer stemness', 'Disease', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (21, 27))	('MCF10A', 'CellLine', 'CVCL:0598', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('self-renewal ability', 'CPA', (93, 113))	('suppressed', 'NegReg', (178, 188))	('Helichrysetin', 'Chemical', 'MESH:C061023', (72, 85))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('Helichrysetin', 'Chemical', 'MESH:C061023', (150, 163))
89279	30725231	We have shown that ID2 regulates initiation and progression of DCIS and that high expression of ID2 indicates poor survive in early stage breast cancer.	('high', 'Var', (77, 81))	('initiation', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('DCIS', 'MPA', (63, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ID2', 'Gene', (96, 99))	('poor', 'NegReg', (110, 114))	('progression', 'CPA', (48, 59))	('breast cancer', 'Disease', (138, 151))
89281	30725231	Several groups reported that high ID2 level in breast cancer was correlated with non-invasiveness and a favorable prognosis.	('high', 'Var', (29, 33))	('ID2 level', 'MPA', (34, 43))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('non-invasiveness', 'CPA', (81, 97))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
89306	30725231	However, the knockdown of ID2 by shRNA led to growth retardation in aggressive breast cancer cells.	('ID2', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('retardation in aggressive breast cancer', 'Disease', 'MESH:D001943', (53, 92))	('retardation in aggressive breast cancer', 'Disease', (53, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('growth retardation', 'Phenotype', 'HP:0001510', (46, 64))	('shRNA', 'Gene', (33, 38))	('knockdown', 'Var', (13, 22))
89320	22312524	Most recently, the Early Breast Cancer Trialists' Collaborative Group concluded that the avoidance of four local recurrences would avoid breast cancer-related death.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('avoid', 'NegReg', (131, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('Breast Cancer', 'Phenotype', 'HP:0003002', (25, 38))	('breast cancer', 'Disease', (137, 150))	('avoidance', 'Var', (89, 98))	('Breast Cancer', 'Disease', (25, 38))	('death', 'Disease', 'MESH:D003643', (159, 164))	('Breast Cancer', 'Disease', 'MESH:D001943', (25, 38))	('death', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
89345	16895590	There is evidence to support the notion that breast cancer arises from mutated mammary stem/progenitor cells, which have been termed 'breast cancer stem cells' because of their exclusive ability to maintain tumor formation and growth, as reviewed by Behbod and coworkers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('growth', 'CPA', (227, 233))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('mutated', 'Var', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('tumor', 'Disease', (207, 212))	('arises', 'Reg', (59, 65))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
89370	16895590	Germ-line mutations in the BRCA1 and BRCA2 genes together account for a significant portion of hereditary breast cancers.	('BRCA1', 'Gene', '672', (27, 32))	('account for', 'Reg', (58, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('BRCA2', 'Gene', (37, 42))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (95, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('BRCA1', 'Gene', (27, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (106, 120))	('BRCA2', 'Gene', '675', (37, 42))	('mutations', 'Var', (10, 19))	('hereditary breast cancers', 'Disease', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
89372	16895590	These findings suggest that the cellular origin of BRCA1 and BRCA2 mutation positive tumors may differ, or that these tumors traverse down separate pathways in their progression toward malignancy.	('malignancy', 'Disease', 'MESH:D009369', (185, 195))	('mutation', 'Var', (67, 75))	('malignancy', 'Disease', (185, 195))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('BRCA1', 'Gene', '672', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BRCA2', 'Gene', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('BRCA1', 'Gene', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', (118, 124))	('BRCA2', 'Gene', '675', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
89382	16895590	Lukas and coworkers found that the frequency of TP53 mutations in DCIS was similar to that found in invasive tumors.	('invasive tumors', 'Disease', 'MESH:D009369', (100, 115))	('TP53', 'Gene', '7157', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('DCIS', 'Disease', (66, 70))	('TP53', 'Gene', (48, 52))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('invasive tumors', 'Disease', (100, 115))
89383	16895590	Upon investigation of HER-2 in a cohort of women diagnosed with benign breast disease, Stark and colleagues concluded that women with benign breast biopsies exhibiting both HER-2 amplification and a proliferative histopathological lesion may be at substantially increased risk for developing subsequent breast cancer.	('HER-2', 'Gene', '2064', (22, 27))	('HER-2', 'Gene', (173, 178))	('HER-2', 'Gene', '2064', (173, 178))	('benign breast disease', 'Disease', 'MESH:D001941', (64, 85))	('HER-2', 'Gene', (22, 27))	('benign breast disease', 'Disease', (64, 85))	('women', 'Species', '9606', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('women', 'Species', '9606', (123, 128))	('amplification', 'Var', (179, 192))
89384	16895590	Overexpression of the HER-2/neu protein in otherwise benign biopsies may indicate a further increase in risk.	('protein', 'Protein', (32, 39))	('HER-2/neu', 'Gene', (22, 31))	('Overexpression', 'Var', (0, 14))	('HER-2/neu', 'Gene', '2064', (22, 31))
89393	16895590	Also, it has become increasingly evident that epigenetic changes must be taken into consideration in the investigation of breast cancer aetiology.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('epigenetic changes', 'Var', (46, 64))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
89396	16895590	Moreover, functional validation of causal relationships between genetic alterations and disease aetiology would increase our biological understanding of breast tumori-genesis, in addition to providing molecular targets for intervention, diagnosis and treatment.	('breast tumori-genesis', 'Disease', 'MESH:D001943', (153, 174))	('genetic', 'Var', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('breast tumori-genesis', 'Disease', (153, 174))	('breast tumor', 'Phenotype', 'HP:0100013', (153, 165))
89403	31028940	530 atypia patients were identified: 31.1% <50y (N=165), 58.1% 50-70y (N=308), and 10.8% >70y (N=57).	('patients', 'Species', '9606', (11, 19))	('50-70y', 'Var', (63, 69))	('atypia', 'Disease', (4, 10))	('<50y', 'Var', (43, 47))
89407	31028940	Of those confirmed to have atypia on surgical excision, the overall rate of a subsequent cancer diagnosis was 15.7%.	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('atypia', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
89472	31028940	The 5-year no-subsequent-carcinoma rate was similar across all age groups (<50y: 0.881, 50-70y: 0.811, >70y: 0.885; p=0.41), and the time to a subsequent breast cancer diagnosis did not vary significantly by age group (log-rank p=0.41; Figure 1, Table 6).	('age', 'Gene', (208, 211))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('age', 'Gene', '5973', (208, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('<50y', 'Var', (75, 79))	('carcinoma', 'Disease', (25, 34))	('age', 'Gene', (63, 66))	('50-70y: 0.811', 'Var', (88, 101))	('carcinoma', 'Disease', 'MESH:D009369', (25, 34))	('age', 'Gene', '5973', (63, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
89511	31028940	Similarly, we found a 10.6% overall chemoprevention uptake rate.	('a 10', 'Gene', (20, 24))	('chemoprevention', 'Var', (36, 51))	('a 10', 'Gene', '28870', (20, 24))
89535	29938367	The most frequent intraductal lesion was amputation of a duct (35.1%), followed by circular narrowing or hyperplasia (22.7%).	('amputation', 'Var', (41, 51))	('hyperplasia', 'Disease', (105, 116))	('circular narrowing', 'Disease', (83, 101))	('hyperplasia', 'Disease', 'MESH:D006965', (105, 116))
89544	29938367	Patients suspected of having breast cancer after mammography and/or ultrasonography, patients that were lactating, patients that had hypothyroidism, pituitary adenoma, ectopically produced prolactin, or hypothalamic diseases, and patients on antipsychotic, antihypertensive, antiemetic, or hormonal drugs were excluded.	('patients', 'Species', '9606', (115, 123))	('ectopically', 'Var', (168, 179))	('hypothyroidism', 'Phenotype', 'HP:0000821', (133, 147))	('pituitary adenoma', 'Disease', (149, 166))	('pituitary adenoma', 'Disease', 'MESH:D010911', (149, 166))	('hypothalamic diseases', 'Disease', (203, 224))	('hypothyroidism', 'Disease', 'MESH:D007037', (133, 147))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (85, 93))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('hypothalamic diseases', 'Disease', 'MESH:D007027', (203, 224))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (149, 166))	('breast cancer', 'Disease', (29, 42))	('hypothyroidism', 'Disease', (133, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
89554	29938367	The following types of intraductal proliferative lesions were recorded: single papilloma, multiple papilloma, amputation of a duct, circular narrowing or hyperplasia, duct ectasia, ambiguous results (i.e., reddening or red spots), and microcalcification.	('reddening', 'Disease', (206, 215))	('papilloma', 'Disease', (79, 88))	('duct ectasia', 'Disease', 'MESH:D004108', (167, 179))	('amputation', 'Var', (110, 120))	('papilloma', 'Disease', 'MESH:D010212', (79, 88))	('red spots', 'Phenotype', 'HP:0000979', (219, 228))	('microcalcification', 'Disease', (235, 253))	('papilloma', 'Phenotype', 'HP:0012740', (99, 108))	('ambiguous results', 'Disease', (181, 198))	('hyperplasia', 'Disease', (154, 165))	('papilloma', 'Disease', (99, 108))	('papilloma', 'Phenotype', 'HP:0012740', (79, 88))	('red', 'Disease', (219, 222))	('duct ectasia', 'Disease', (167, 179))	('papilloma', 'Disease', 'MESH:D010212', (99, 108))	('hyperplasia', 'Disease', 'MESH:D006965', (154, 165))	('circular narrowing', 'Disease', (132, 150))
89664	22268171	Analysis of lesion morphology showed a higher malignancy rate for masses with irregular/spiculated borders (24/90, 27%) versus for those with smooth borders (2/27, 7%) (P<0.05).	('malignancy', 'Disease', (46, 56))	('irregular/spiculated borders', 'Var', (78, 106))	('malignancy', 'Disease', 'MESH:D009369', (46, 56))
89702	22268171	The probability of malignancy was significantly higher in masses with irregular/speculated borders then in smooth masses.	('malignancy', 'Disease', (19, 29))	('higher', 'PosReg', (48, 54))	('malignancy', 'Disease', 'MESH:D009369', (19, 29))	('irregular/speculated', 'Var', (70, 90))
89708	33608619	The system was developed using the consensus DCIS grade of three expert observers on a dataset of 1186 DCIS lesions from 59 patients.	('DCIS', 'Disease', (103, 107))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('lesions', 'Var', (108, 115))	('patients', 'Species', '9606', (124, 132))
89753	33608619	This information could be used to train a deep learning system to predict which DCIS lesions have a high chance of progressing to IDC.	('lesions', 'Var', (85, 92))	('IDC', 'Gene', '4000', (130, 133))	('DCIS', 'Disease', (80, 84))	('IDC', 'Gene', (130, 133))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))
89795	32216826	As for those with missing data, immunohistochemical staining on representative tissue sections was carried out using the following antibodies: ER (clone SP1; 1:100 dilution; LabVision, Fremont, CA), PR (clone PgR 636; 1:70 dilution; Dako, Carpinteria, CA), HER2 (clone 4B5; ready to use; Ventana Medical Systems, Tuscon, AZ), p53 (clone D07; 1:600 dilution; Dako), and Ki-67 (clone MIB-1; 1:250 dilution; Dako).	('ER', 'Gene', '2099', (258, 260))	('PgR 636', 'Gene', '5241', (209, 216))	('PgR 636', 'Gene', (209, 216))	('ER', 'Gene', '2099', (143, 145))	('p53', 'Gene', (326, 329))	('HER2', 'Gene', (257, 261))	('p53', 'Gene', '7157', (326, 329))	('HER2', 'Gene', '2064', (257, 261))	('clone D07;', 'Var', (331, 341))	('PR', 'Gene', '5241', (199, 201))
89834	32216826	When comparing pure DCIS and DCIS-M in the whole group, the infiltration of CD4+ and FOXP3+ TIL was significantly higher in DCIS-M than in pure DCIS (all p < 0.001).	('FOXP3', 'Gene', (85, 90))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('FOXP3', 'Gene', '50943', (85, 90))	('CD4', 'Gene', (76, 79))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('CD4', 'Gene', '920', (76, 79))	('higher', 'PosReg', (114, 120))	('DCIS-M', 'Var', (124, 130))
89836	32216826	In HR-positive tumors, FOXP3+ TIL infiltration was significantly higher in DCIS-INV than in pure DCIS (p < 0.001) and CD4+ TIL infiltration tended to be higher in DCIS-INV than in pure DCIS (p = 0.051).	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('higher', 'PosReg', (153, 159))	('HR-positive tumors', 'Disease', 'MESH:D009369', (3, 21))	('DCIS-INV', 'Var', (75, 83))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CD4', 'Gene', (118, 121))	('FOXP3', 'Gene', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('HR-positive tumors', 'Disease', (3, 21))	('CD4', 'Gene', '920', (118, 121))	('higher', 'PosReg', (65, 71))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('FOXP3', 'Gene', '50943', (23, 28))
89852	32216826	Increased TIL density in DCIS has been associated with high-risk features including large tumor size, high nuclear grade, comedo-type necrosis, ER negativity, and HER2 positivity in previous studies.	('ER', 'Gene', '2099', (144, 146))	('ER', 'Gene', '2099', (164, 166))	('HER2', 'Gene', (163, 167))	('positivity', 'Var', (168, 178))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('HER2', 'Gene', '2064', (163, 167))	('necrosis', 'Disease', 'MESH:D009336', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('comedo', 'Phenotype', 'HP:0025249', (122, 128))	('associated', 'Reg', (39, 49))	('necrosis', 'Disease', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
89854	32216826	Similarly, the presence of PD-L1+ immune cells in DCIS has been reported to be associated with high TIL infiltration, younger patient age, ER negativity, and HER2 positivity in previous studies.	('associated', 'Reg', (79, 89))	('HER2', 'Gene', '2064', (158, 162))	('patient', 'Species', '9606', (126, 133))	('PD-L1+ immune', 'Var', (27, 40))	('ER', 'Gene', '2099', (139, 141))	('ER', 'Gene', '2099', (159, 161))	('HER2', 'Gene', (158, 162))	('positivity', 'Var', (163, 173))	('high TIL infiltration', 'CPA', (95, 116))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
89862	32216826	We showed that all TIL subset infiltration and the presence of PD-L1+ immune cells were higher in invasive carcinoma than in pure DCIS irrespective of the HR status as in previous studies which reported a gradual increase in the number of immune cells during progression of breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('higher', 'PosReg', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('breast cancer', 'Disease', (274, 287))	('invasive carcinoma', 'Disease', 'MESH:D009361', (98, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('PD-L1+', 'Var', (63, 69))	('HR', 'Gene', '3164', (155, 157))	('invasive carcinoma', 'Disease', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
89872	32216826	Growing evidence supports a role of host immune surveillance in influencing response to therapy and prognosis in HER2+ and triple-negative breast cancer, but not in HR-positive breast cancer which appears to be less immunogenic than HER2+ and triple-negative breast cancer.	('HR-positive breast cancer', 'Disease', 'MESH:D001943', (165, 190))	('HR-positive breast cancer', 'Disease', (165, 190))	('triple-negative', 'Var', (123, 138))	('HER2', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('HER2', 'Gene', '2064', (113, 117))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('HER2', 'Gene', (233, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('HER2', 'Gene', '2064', (233, 237))	('breast cancer', 'Disease', (259, 272))
89882	32216826	We showed that CD4+ and FOXP3+ TIL infiltration was significantly higher in DCIS-M and DCIS-INV compared to pure DCIS in the whole group.	('FOXP3', 'Gene', (24, 29))	('CD4', 'Gene', '920', (15, 18))	('FOXP3', 'Gene', '50943', (24, 29))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('CD4', 'Gene', (15, 18))	('DCIS-M', 'Var', (76, 82))	('higher', 'PosReg', (66, 72))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
89883	32216826	CD4+ and CD8+ TIL infiltration was significantly higher in DCIS-INV than in pure DCIS in the HR-negative group, and FOXP3+ TIL infiltration was significantly higher in DCIS-INV than in pure DCIS in the HR-positive group.	('CD8', 'Gene', '925', (9, 12))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('FOXP3', 'Gene', '50943', (116, 121))	('CD4', 'Gene', '920', (0, 3))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('CD4', 'Gene', (0, 3))	('HR', 'Gene', '3164', (202, 204))	('higher', 'PosReg', (158, 164))	('DCIS-INV', 'Var', (59, 67))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('HR', 'Gene', '3164', (93, 95))	('higher', 'PosReg', (49, 55))	('CD8', 'Gene', (9, 12))	('FOXP3', 'Gene', (116, 121))
89902	32216826	In HR-positive tumors, all immune cell infiltrations were higher in the invasive component than in the DCIS component, and FOXP3+ TIL was significantly higher in DCIS-INV than in pure DCIS.	('higher', 'PosReg', (152, 158))	('FOXP3', 'Gene', (123, 128))	('HR-positive tumors', 'Disease', 'MESH:D009369', (3, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('FOXP3', 'Gene', '50943', (123, 128))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('immune cell infiltrations', 'CPA', (27, 52))	('higher', 'PosReg', (58, 64))	('DCIS-INV', 'Var', (162, 170))	('HR-positive tumors', 'Disease', (3, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
89924	28506510	Exclusion criteria included the presence of any masses, asymmetries, or architectural distortion on a mammogram; history of breast cancer or prior surgery; and presence of microinvasion at the time of initial biopsy.	('architectural distortion', 'CPA', (72, 96))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('asymmetries', 'Var', (56, 67))
89950	28506510	Although similar in performance to our current study, the previous study included DCIS patients with microinvasion, and the overall underestimation rate of DCIS patients by preoperative biopsy was 42.6% (145/340), both of which significantly decreased the difficulty of the prediction task.	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('difficulty', 'MPA', (256, 266))	('microinvasion', 'Var', (101, 114))	('patients', 'Species', '9606', (161, 169))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('decreased', 'NegReg', (242, 251))	('patients', 'Species', '9606', (87, 95))
89985	27600076	produced by SkBr3, MDA-MB-468, T47D were used for the treatment (72 h) of NHDF (NAF) plated in 6-wells plate at a density of 750,000 cells.	('NAF', 'Gene', (80, 83))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (19, 29))	('NHDF', 'Chemical', '-', (74, 78))	('T47D', 'CellLine', 'CVCL:0553', (31, 35))	('T47D', 'Var', (31, 35))	('NAF', 'Gene', '3576', (80, 83))
89994	27600076	Following primers were obtained from Applied Biosystems (Foster City, CA, USA): TGM2, assay Hs00190278_m1; IL6 assay Hs00985639_m1; TGFB, assay Hs00998133_m1; GAPDH, Hs00266705_g1).	('TGFB', 'Gene', '7040', (132, 136))	('Hs00190278_m1', 'Var', (92, 105))	('GAPDH', 'Gene', '2597', (159, 164))	('Hs00998133_m1', 'Var', (144, 157))	('GAPDH', 'Gene', (159, 164))	('IL6', 'Gene', '3569', (107, 110))	('TGFB', 'Gene', (132, 136))	('Hs00985639_m1', 'Var', (117, 130))	('TGM2', 'Gene', (80, 84))	('TGM2', 'Gene', '7052', (80, 84))	('IL6', 'Gene', (107, 110))	('Hs00266705_g1', 'Var', (166, 179))
90014	27600076	Survival analysis for TGM2 was performed using METABRIC and a combined dataset derived from publicly available gene expression data retrieved from GEO (GSE2034, GSE2990, GSE5327, and GSE11121).	('GSE2990', 'Var', (161, 168))	('GSE2990', 'Chemical', '-', (161, 168))	('GSE5327', 'Var', (170, 177))	('TGM2', 'Gene', (22, 26))	('GSE2034', 'Chemical', '-', (152, 159))	('TGM2', 'Gene', '7052', (22, 26))	('GSE11121', 'Var', (183, 191))	('GSE2034', 'Var', (152, 159))	('GSE5327', 'Chemical', '-', (170, 177))
90022	27600076	For the others mesenchymal markers we observed: 97.2% CD105+ cells, 87.4% CD166+ cells and 100% CD73+.	('CD166', 'Gene', (74, 79))	('CD73', 'Gene', '4907', (96, 100))	('CD166', 'Gene', '214', (74, 79))	('CD73', 'Gene', (96, 100))	('CD105+', 'Var', (54, 60))
90083	27600076	In fact, this evaluation resulted in a rather unexpected result with TGM2 expression being associated with a longer DMFS in the general population, a finding which, was probably driven by the minority of basal-like tumors where the 'protective' effect of a high TGM2 expression seemed to be stronger.	('DMFS', 'Chemical', '-', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('expression', 'Var', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('TGM2', 'Gene', (69, 73))	('TGM2', 'Gene', (262, 266))	('TGM2', 'Gene', '7052', (69, 73))	('TGM2', 'Gene', '7052', (262, 266))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))	('associated', 'Reg', (91, 101))
90106	27061242	High-TIL was significantly associated with high-grade, comedo necrosis, apocrine features, healing, high CD8+ lymphocytes and HER2 and TN subtypes.	('High-TIL', 'Var', (0, 8))	('CD8', 'Gene', (105, 108))	('high-grade', 'Disease', (43, 53))	('healing', 'CPA', (91, 98))	('CD8', 'Gene', '925', (105, 108))	('comedo', 'Phenotype', 'HP:0025249', (55, 61))	('necrosis', 'Disease', (62, 70))	('associated', 'Reg', (27, 37))	('necrosis', 'Disease', 'MESH:D009336', (62, 70))	('HER2', 'Gene', (126, 130))	('apocrine features', 'Disease', (72, 89))	('HER2', 'Gene', '2064', (126, 130))
90107	27061242	Healing was significantly correlated with high CD8+ lymphocytes, high-grade, comedo necrosis, apocrine features, and HER2-positive and TN subtypes.	('apocrine', 'Disease', (94, 102))	('HER2', 'Gene', (117, 121))	('HER2', 'Gene', '2064', (117, 121))	('CD8', 'Gene', (47, 50))	('CD8', 'Gene', '925', (47, 50))	('Healing', 'CPA', (0, 7))	('comedo', 'Phenotype', 'HP:0025249', (77, 83))	('high-grade', 'CPA', (65, 75))	('necrosis', 'Disease', (84, 92))	('high', 'Var', (42, 46))	('necrosis', 'Disease', 'MESH:D009336', (84, 92))
90161	27061242	High-TIL was significantly correlated with histologic features except for patient age and DCIS structure.	('High-TIL', 'Var', (0, 8))	('patient', 'Species', '9606', (74, 81))	('DCIS structure', 'Disease', (90, 104))
90197	27061242	Although our sample size including subgrouping was limited, high-TIL, high-grade, apocrine features, comedo necrosis, TN and HER2-positive were significantly associated with healing, with a particularly strong association between CD8+ high-TIL and healing.	('HER2', 'Gene', (125, 129))	('associated with', 'Reg', (158, 173))	('necrosis', 'Disease', (108, 116))	('high-grade', 'Var', (70, 80))	('HER2', 'Gene', '2064', (125, 129))	('CD8', 'Gene', (230, 233))	('comedo', 'Phenotype', 'HP:0025249', (101, 107))	('healing', 'CPA', (174, 181))	('CD8', 'Gene', '925', (230, 233))	('necrosis', 'Disease', 'MESH:D009336', (108, 116))	('high-TIL', 'Var', (60, 68))	('healing', 'CPA', (248, 255))
90203	27023391	Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('mutations', 'Var', (10, 19))
90205	27023391	Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis.	('malignancy', 'Disease', (78, 88))	('HER-2', 'Gene', (111, 116))	('carcinogenesis', 'Disease', (211, 225))	('hormone receptor', 'Gene', '3164', (90, 106))	('hormone receptor', 'Gene', (90, 106))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))	('mutation', 'Var', (138, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))	('HER-2', 'Gene', '2064', (111, 116))
90208	27023391	Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01).	('TGFB', 'Gene', '7040', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('RUNX3', 'Gene', '864', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('RUNX3', 'Gene', (169, 174))	('E-cadherin', 'Gene', (151, 161))	('tumors', 'Disease', (131, 137))	('TGFB', 'Gene', (163, 167))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('E-cadherin', 'Gene', '999', (151, 161))	('ER', 'Gene', '2099', (127, 129))
90209	27023391	ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition.	('ER', 'Gene', '2099', (0, 2))	('c-MYC', 'Gene', '4609', (91, 96))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('BRCA1', 'Gene', '672', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('BRCA1', 'Gene', (84, 89))	('c-MYC', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (38, 47))
90211	27023391	The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('mutations', 'Var', (125, 134))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('atypia or ductal carcinoma in situ', 'Disease', (78, 112))	('atypia or ductal carcinoma in situ', 'Disease', 'MESH:D002285', (78, 112))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (88, 104))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (88, 112))	('DEABM', 'Chemical', '-', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('breast cancers', 'Phenotype', 'HP:0003002', (214, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancers', 'Disease', 'MESH:D001943', (214, 228))	('breast cancers', 'Disease', (214, 228))
90221	27023391	To what extent these lesions represent a continuum of epithelial transformation from normal to frankly malignant remains a subject of considerable debate.. An understanding of the processes by which these preneoplastic lesions arise, and how the genetic and downstream behavioral alterations cause premalignant lesions to transform and acquire the invasive, immortal phenotype that defines malignancy will be essential in answering these questions.	('behavioral alterations', 'Phenotype', 'HP:0000708', (269, 291))	('invasive', 'CPA', (348, 356))	('transform', 'CPA', (322, 331))	('alterations', 'Var', (280, 291))	('defines malignancy', 'Disease', (382, 400))	('defines malignancy', 'Disease', 'MESH:D009369', (382, 400))
90225	27023391	After implementing an algorithm to produce genetic mutations via probabilistic DNA damage and repair mechanisms, the DEABM generated simulated tumors matching age-specific incidences similar to published epidemiologic data.	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('DEABM', 'Chemical', '-', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
90226	27023391	Traditional in vivo and in vitro breast cancer research tends to either focus on one particular aspect of tumor biology, such as on how alterations in single genes or proteins affect a phenotype (e.g.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('affect', 'Reg', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('alterations', 'Var', (136, 147))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))	('proteins', 'Protein', (167, 175))
90230	27023391	The DEABM, because of its stochastic process for generating mutations and inheritance of genetic mutations passed from parent to daughter cells, is able both to demonstrate evolutionary dynamics of tumor development and generate heterogeneous populations of cells that can transform into tumors with varying genetic and functional characteristics.	('tumor', 'Disease', (288, 293))	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('transform', 'Reg', (273, 282))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('DEABM', 'Chemical', '-', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Disease', (198, 203))	('mutations', 'Var', (60, 69))	('tumors', 'Disease', (288, 294))
90234	27023391	This updated version of the DEABM is capable of generating tumors expressing any combination of ER or HER2 status, and tumors can be analyzed for mutations in any of the genes in the DEABM's functional genome, as well as the sequence in which mutations occurred.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ER', 'Gene', '2099', (103, 105))	('ER', 'Gene', '2099', (96, 98))	('mutations', 'Var', (146, 155))	('DEABM', 'Chemical', '-', (183, 188))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('HER2', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('HER2', 'Gene', '2064', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('DEABM', 'Chemical', '-', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
90235	27023391	We use this updated model to examine the progression of mutations and their functional consequences in the progression from normal mammary tissue dynamics to malignancy.	('malignancy', 'Disease', (158, 168))	('mutations', 'Var', (56, 65))	('malignancy', 'Disease', 'MESH:D009369', (158, 168))
90239	27023391	While much remains unknown about how tissues undergo the changes required for malignant transformation, recent studies have indicated that as many as half of the mutations present in malignancies may originate prior to the onset of neoplasia.	('mutations', 'Var', (162, 171))	('neoplasia', 'Disease', (232, 241))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('originate', 'Reg', (200, 209))	('neoplasia', 'Phenotype', 'HP:0002664', (232, 241))	('neoplasia', 'Disease', 'MESH:D009369', (232, 241))	('malignancies', 'Disease', (183, 195))
90240	27023391	Correspondingly, studies indicate that proliferative lesions and DCIS more frequently harbor mutations in genes known to be mutated in invasive breast cancer.	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('DCIS', 'Disease', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('invasive breast cancer', 'Disease', (135, 157))	('invasive breast cancer', 'Disease', 'MESH:D001943', (135, 157))	('harbor', 'Reg', (86, 92))	('proliferative lesions', 'CPA', (39, 60))
90243	27023391	The DEABM primarily focuses on how genetic mutations alter cellular behaviors: their effects on cell-cell signaling pathways regulating proliferation, response to estrogen, apoptosis and other features central to how malignant cell populations differ from normal populations.	('cell-cell signaling pathways', 'Pathway', (96, 124))	('alter', 'Reg', (53, 58))	('cellular', 'MPA', (59, 67))	('DEABM', 'Chemical', '-', (4, 9))	('mutations', 'Var', (43, 52))	('effects', 'Reg', (85, 92))	('response to', 'MPA', (151, 162))	('proliferation', 'CPA', (136, 149))
90256	27023391	Mutations to HER-2 can lead to a suppression of inhibition of HER-2 and augmentation of the proliferative response to mitogens.	('HER-2', 'Gene', (62, 67))	('inhibition', 'MPA', (48, 58))	('HER-2', 'Gene', '2064', (13, 18))	('Mutations', 'Var', (0, 9))	('suppression', 'NegReg', (33, 44))	('augmentation', 'PosReg', (72, 84))	('HER-2', 'Gene', (13, 18))	('HER-2', 'Gene', '2064', (62, 67))	('proliferative response to mitogens', 'MPA', (92, 126))
90257	27023391	Additionally, three variant mutations affecting the estrogen receptor, reflecting previously described mutations found in ER+ breast cancers, are now possible in the DEABM.	('breast cancers', 'Disease', 'MESH:D001943', (126, 140))	('breast cancers', 'Disease', (126, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('estrogen receptor', 'Gene', (52, 69))	('variant mutations', 'Var', (20, 37))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('breast cancers', 'Phenotype', 'HP:0003002', (126, 140))	('estrogen receptor', 'Gene', '2099', (52, 69))	('ER', 'Gene', '2099', (122, 124))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('DEABM', 'Chemical', '-', (166, 171))
90258	27023391	These mutations affecting ESR1 allow for variant behavior of ER and have various growth-promoting effects.	('growth-promoting', 'MPA', (81, 97))	('ESR1', 'Gene', '2099', (26, 30))	('ER', 'Gene', '2099', (61, 63))	('variant behavior', 'MPA', (41, 57))	('mutations', 'Var', (6, 15))	('ESR1', 'Gene', (26, 30))
90259	27023391	The effect of including these variants is to increase the diversity of behavioral profiles of nominally ER+ tumors to more closely reflect the diversity present in ER+ tumors observed clinically.	('ER', 'Gene', '2099', (164, 166))	('variants', 'Var', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ER', 'Gene', '2099', (104, 106))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('behavioral profiles', 'Phenotype', 'HP:0000708', (71, 90))	('behavioral', 'MPA', (71, 81))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('increase', 'PosReg', (45, 53))
90260	27023391	Variant 1 causes autonomous production of the growth factor amphiregulin, whose function is detailed in Fig 1 and explained in the Supplemental Methods (S1 Text), regardless of the supply of estrogen available to ER+ cells.	('autonomous production', 'MPA', (17, 38))	('ER', 'Gene', '2099', (213, 215))	('Variant 1', 'Var', (0, 9))	('amphiregulin', 'Gene', (60, 72))	('causes', 'Reg', (10, 16))	('amphiregulin', 'Gene', '374', (60, 72))
90261	27023391	Variant 2 causes a non-genomic, direct promotion of proliferation effect via increased intracellular AKT, representing a known mechanism of non-genomic, pro-proliferation activation of receptor tyrosine kinases by ER in certain breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('AKT', 'Gene', '207', (101, 104))	('proliferation', 'MPA', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('intracellular', 'MPA', (87, 100))	('Variant 2', 'Var', (0, 9))	('promotion', 'PosReg', (39, 48))	('AKT', 'Gene', (101, 104))	('breast cancers', 'Phenotype', 'HP:0003002', (228, 242))	('ER', 'Gene', '2099', (214, 216))	('increased', 'PosReg', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('breast cancers', 'Disease', 'MESH:D001943', (228, 242))	('breast cancers', 'Disease', (228, 242))
90262	27023391	These mutation effects could represent mutations to ESR1 itself, epigenetic alterations to ER function, or splice site alterations causing variant ER function.	('ESR1', 'Gene', '2099', (52, 56))	('ER', 'Gene', '2099', (147, 149))	('variant', 'Var', (139, 146))	('ESR1', 'Gene', (52, 56))	('ER', 'Gene', '2099', (91, 93))	('epigenetic alterations', 'Var', (65, 87))
90268	27023391	Mutations in the DEABM are heritable: daughter cells contain the same genome as the parent cells of which they are a product.	('DEABM', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('DEABM', 'Chemical', '-', (17, 22))
90269	27023391	As mutated cells continue to acquire functional mutations and pass them down via mitosis, it is possible for lineages of cells to exhibit increasingly altered behavior.	('pass them down', 'Phenotype', 'HP:0007185', (62, 76))	('mitosis', 'Disease', (81, 88))	('mitosis', 'Disease', 'None', (81, 88))	('mutations', 'Var', (48, 57))	('mutated', 'Var', (3, 10))
90270	27023391	No single mutation is sufficient to cause the malignant phenotype within the DEABM; combinations of multiple mutations, involving different aspects of cellular behaviors, are required to cause the uncontrolled proliferation, impaired apoptosis and invasive behavior required for the development of malignancy.	('malignancy', 'Disease', (298, 308))	('DEABM', 'Chemical', '-', (77, 82))	('impaired apoptosis', 'CPA', (225, 243))	('mutations', 'Var', (109, 118))	('invasive behavior', 'CPA', (248, 265))	('cause', 'Reg', (187, 192))	('malignancy', 'Disease', 'MESH:D009369', (298, 308))
90276	27023391	The ability of the DEABM to faithfully model both a normal and a BRCA1 mutated state allows the DEABM to explore how inherited mutations in breast cancer might lead to both increased susceptibility to cancer, as well as the tendency for BRCA1-associated cancers to develop as hormone-receptor negative subtypes.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (201, 207))	('susceptibility', 'MPA', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('BRCA1', 'Gene', '672', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('BRCA1', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('mutations', 'Var', (127, 136))	('cancers', 'Disease', (254, 261))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('breast cancer', 'Disease', (140, 153))	('DEABM', 'Chemical', '-', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('lead', 'Reg', (160, 164))	('BRCA1', 'Gene', '672', (237, 242))	('BRCA1', 'Gene', (237, 242))	('cancer', 'Disease', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('DEABM', 'Chemical', '-', (96, 101))
90288	27023391	Cancer incidence over time in the DEABM is compared to epidemiologic data of breast cancer in BRCA-1 mutated patients in Fig 6.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('BRCA-1', 'Gene', (94, 100))	('patients', 'Species', '9606', (109, 117))	('BRCA-1', 'Gene', '672', (94, 100))	('mutated', 'Var', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('DEABM', 'Chemical', '-', (34, 39))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
90290	27023391	Tumors in the BRCA-1 mutated group were 29% ER+/HER-2-, 7% ER+/HER-2+, 13% ER-/HER-2+ and 50% ER-/HER-2-.	('BRCA-1', 'Gene', (14, 20))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRCA-1', 'Gene', '672', (14, 20))	('ER', 'Gene', '2099', (49, 51))	('ER', 'Gene', '2099', (80, 82))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutated', 'Var', (21, 28))	('ER', 'Gene', '2099', (64, 66))	('ER', 'Gene', '2099', (94, 96))	('Tumors', 'Disease', (0, 6))	('HER-2', 'Gene', '2064', (98, 103))	('HER-2', 'Gene', (98, 103))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ER', 'Gene', '2099', (75, 77))	('ER', 'Gene', '2099', (99, 101))	('ER', 'Gene', '2099', (44, 46))	('ER', 'Gene', '2099', (59, 61))	('HER-2', 'Gene', '2064', (48, 53))	('HER-2', 'Gene', '2064', (79, 84))	('HER-2', 'Gene', (63, 68))	('HER-2', 'Gene', '2064', (63, 68))	('HER-2', 'Gene', (48, 53))	('HER-2', 'Gene', (79, 84))
90294	27023391	ER+ tumors were significantly more likely to accumulate early mutations in genes associated with impaired apoptosis (telomerase, p < .01) and proliferation in response to estrogen (RUNX3, TGFB-r, p < .01).	('ER', 'Gene', '2099', (0, 2))	('RUNX3', 'Gene', (181, 186))	('TGFB', 'Gene', (188, 192))	('proliferation', 'CPA', (142, 155))	('apoptosis', 'CPA', (106, 115))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TGFB', 'Gene', '7040', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (62, 71))	('RUNX3', 'Gene', '864', (181, 186))
90296	27023391	Early P53 mutations were common in all tumors.	('common', 'Reg', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('P53', 'Gene', (6, 9))	('P53', 'Gene', '7157', (6, 9))	('mutations', 'Var', (10, 19))	('tumors', 'Disease', (39, 45))
90299	27023391	Mutations present in hyperplastic populations, defined as an expansion of the cellular population to greater than 2x normal, were similar to those present in ER+ tumors but not ER- tumors.	('ER', 'Gene', '2099', (158, 160))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ER', 'Gene', '2099', (177, 179))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
90300	27023391	Hyperplastic populations were more likely to carry mutations in telomerase, E-cadherin and TGFB-r, genes directly related to increased proliferative capacity and failure of apoptosis.	('mutations', 'Var', (51, 60))	('increased', 'PosReg', (125, 134))	('TGFB', 'Gene', (91, 95))	('telomerase', 'Protein', (64, 74))	('Hyperplastic populations', 'CPA', (0, 24))	('TGFB', 'Gene', '7040', (91, 95))	('proliferative capacity', 'CPA', (135, 157))	('E-cadherin', 'Gene', (76, 86))	('E-cadherin', 'Gene', '999', (76, 86))
90302	27023391	ER- tumors were more likely to carry early mutations in BRCA1, MYC and genes associated with epithelial-mesenchymal transition (MMP-3, p < .01).	('epithelial-mesenchymal transition', 'Disease', (93, 126))	('ER', 'Gene', '2099', (0, 2))	('MYC', 'Gene', (63, 66))	('BRCA1', 'Gene', '672', (56, 61))	('MMP-3', 'Gene', '4314', (128, 133))	('MMP-3', 'Gene', (128, 133))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('BRCA1', 'Gene', (56, 61))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MYC', 'Gene', '4609', (63, 66))
90303	27023391	ER- tumors acquired significantly more mutations than ER+ tumors (p < .01).	('ER', 'Gene', '2099', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutations', 'Var', (39, 48))	('ER', 'Gene', '2099', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
90308	27023391	Conversely, ER- tumors developed early mutations that predisposed to genomic instability and a rapid rate of mutation and therefore transformation, which could be an added explanation for the paucity of clinically identifiable precursor lesions and interval cancers in ER:breast cancers and BRCA-1 mutation carriers.	('mutation', 'Var', (298, 306))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('tumors', 'Disease', (16, 22))	('ER', 'Gene', '2099', (269, 271))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancers', 'Disease', 'MESH:D001943', (272, 286))	('mutations', 'Var', (39, 48))	('breast cancers', 'Disease', (272, 286))	('interval cancers', 'Disease', (249, 265))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('interval cancers', 'Disease', 'MESH:D009369', (249, 265))	('breast cancers', 'Phenotype', 'HP:0003002', (272, 286))	('ER', 'Gene', '2099', (12, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('genomic instability', 'MPA', (69, 88))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('BRCA-1', 'Gene', (291, 297))	('BRCA-1', 'Gene', '672', (291, 297))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
90310	27023391	ER+ tumors in the DEABM were significantly more likely to carry mutations that had functional consequences related to hormone-dependent growth and failure of cell death, whereas ER- tumors were more likely to carry mutations related to genomic instability and early invasive behavior.	('ER', 'Gene', '2099', (0, 2))	('ER', 'Gene', '2099', (178, 180))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (64, 73))	('DEABM', 'Chemical', '-', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
90311	27023391	ER- tumors also accumulated a significantly greater number of mutations than ER+ tumors, a finding consistent with previously observed differences in the mutation rate between ER+ and ER- tumors.	('ER', 'Gene', '2099', (0, 2))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('ER', 'Gene', '2099', (184, 186))	('ER', 'Gene', '2099', (176, 178))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('ER', 'Gene', '2099', (77, 79))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (62, 71))
90312	27023391	An advantage of the DEABM is that it allows for the sequential tracking of the mutations acquired by malignancies, something not currently possible in cross-sectional genetic analyses of tumors.	('malignancies', 'Disease', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('DEABM', 'Chemical', '-', (20, 25))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (79, 88))
90314	27023391	One explanation is that ER- tumors must engineer a way of proliferating without any hormonal stimulus, selecting for early mutations that confer hyperactivation of proliferation-promoting transcription factors that would allow a cell population to bypass the need for external hormonal signaling.	('ER', 'Gene', '2099', (24, 26))	('hyperactivation', 'PosReg', (145, 160))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (123, 132))
90315	27023391	For example, ER- tumors in the DEABM are more likely to carry mutations in the c-MYC oncogene, which confers increased risk of hormone-independent proliferation.	('c-MYC', 'Gene', (79, 84))	('DEABM', 'Chemical', '-', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('hormone-independent proliferation', 'CPA', (127, 160))	('c-MYC', 'Gene', '4609', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (62, 71))	('ER', 'Gene', '2099', (13, 15))
90323	27023391	The three variants of ER function attainable via functional mutations in the DEABM, as well as failure to suppress c-Met in ER+ cells, allow for the generation of non-invasive proliferative overgrowths of ER+ cells that are representative of many benign hyperplastic states.	('overgrowths', 'Phenotype', 'HP:0001548', (190, 201))	('DEABM', 'Gene', (77, 82))	('ER', 'Gene', '2099', (124, 126))	('DEABM', 'Chemical', '-', (77, 82))	('c-Met', 'Gene', (115, 120))	('c-Met', 'Gene', '4233', (115, 120))	('ER', 'Gene', '2099', (205, 207))	('ER', 'Gene', '2099', (22, 24))	('mutations', 'Var', (60, 69))
90324	27023391	The inclusion of behavioral variants:representing a suite of alterations known to occur in ER function caused by epigenetic, splice site and genomic alteration:allows for a more complex representation of ER+ tumors.	('ER', 'Gene', '2099', (204, 206))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ER', 'Gene', '2099', (91, 93))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('epigenetic', 'Var', (113, 123))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
90341	27023391	However, because of the long time course of cancer development and sequential accumulation of mutations, it is plausible that many post-menopausal breast cancers have their origin in the pre-menopausal period.	('breast cancers', 'Phenotype', 'HP:0003002', (147, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('mutations', 'Var', (94, 103))	('breast cancers', 'Disease', 'MESH:D001943', (147, 161))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('breast cancers', 'Disease', (147, 161))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('pre-menopausal period', 'Phenotype', 'HP:0008209', (187, 208))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
90347	27023391	The goal of the DEABM is rather to facilitate a more global examination of the fundamental driving mechanisms behind cancer:the emergent behaviors of aberrant cellular populations that arise out of altered functional pathways, pathway alterations that are themselves the product of probabilistic insults to DNA.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DEABM', 'Chemical', '-', (16, 21))	('alterations', 'Var', (235, 246))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('altered', 'Reg', (198, 205))	('functional pathways', 'Pathway', (206, 225))	('cancer', 'Disease', (117, 123))
90350	27023391	The DEABM's simplified genome, focusing on a relatively small number mutations of with large effects on cellular behavior is consistent with observations that while cancers contain large amounts of mutation, as few as three "driver mutations" may be required for malignant transformation.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('DEABM', 'Chemical', '-', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Disease', (165, 172))
90354	27023391	As an analytic tool, the DEABM can track the exact sequence of mutations acquired by a tumor along the trajectory of its natural history from normal to malignancy.	('mutations', 'Var', (63, 72))	('DEABM', 'Chemical', '-', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('malignancy', 'Disease', (152, 162))
90389	25986869	Intergroup (Eastern Cooperative Oncology Group and North Central Cancer Treatment Group) trial E5194 enrolled patients with low- or intermediate-grade DCIS <=2.5 cm (Group 1) or high-grade DCIS <=1 cm (Group 2) with margin widths >=3 mm into a prospective trial of no adjuvant RT and found that with a median follow-up of 6.2 years, the 5-year LR rate in Group 1 was 6.1%, suggested to be low enough to consider the omission of RT for such patients .	('North Central Cancer', 'Disease', 'MESH:D009369', (51, 71))	('North Central Cancer', 'Disease', (51, 71))	('patients', 'Species', '9606', (110, 118))	('low- or', 'Var', (124, 131))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('patients', 'Species', '9606', (440, 448))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('high-grade DCIS <=1 cm', 'Var', (178, 200))	('Oncology', 'Phenotype', 'HP:0002664', (32, 40))
90413	25986869	Fifty-nine of these no-RT patients (55%) met the E5194 group 1 criteria and another 18 (17%) met the E5194 group 2 criteria.	('E5194', 'Var', (101, 106))	('patients', 'Species', '9606', (26, 34))	('E5194', 'Var', (49, 54))
90446	25986869	E5194 demonstrated a 5-year LR rate in Group 1 (low/intermediate grade stratum) of 6.1%, and a retrospective analysis of patients treated with RT who met the E5194 criteria found a LR rate of 4.4% after seven years in the low-intermediate grade cohort and 2% in the high grade patient cohort .	('E5194', 'Var', (0, 5))	('patient', 'Species', '9606', (277, 284))	('E5194', 'Var', (158, 163))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (121, 129))
90474	15700031	Of the listed features, the discohesion now appears pivotal, since there is inactivation of the E-cadherin gene, either though a truncation mutation (Berx et al, 1995, 1996) in approximately 50% (Berx et al, 1996), or methylation of its promoter (Droufakou et al, 2001).	('methylation', 'Var', (218, 229))	('inactivation', 'NegReg', (76, 88))	('E-cadherin', 'Gene', (96, 106))	('truncation mutation', 'Var', (129, 148))	('E-cadherin', 'Gene', '999', (96, 106))
90477	15700031	The number of lobular carcinomas showing E-cadherin mutations varies between studies and no doubt reflects pathologist behaviour; diagnosis historically has been made utilising the full suite of features detailed above, but awareness that E-cadherin inactivation as a major molecular alteration with consequent cellular discohesion may have influenced more recent diagnostic behaviour.	('influenced', 'Reg', (341, 351))	('lobular carcinomas', 'Disease', (14, 32))	('E-cadherin', 'Gene', (239, 249))	('E-cadherin', 'Gene', '999', (239, 249))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (14, 32))	('lobular carcinomas', 'Disease', 'MESH:D018275', (14, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('E-cadherin', 'Gene', (41, 51))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (14, 31))	('inactivation', 'Var', (250, 262))	('E-cadherin', 'Gene', '999', (41, 51))
90480	15700031	Some examples of the pleomorphic variant, which for some may also encompass some tumours with apocrine features (Eusebi et al, 1992), show attributes more in common with high-grade ductal carcinomas, such as a more diverse cytogenetic alterations (see below).	('ductal carcinomas', 'Disease', (181, 198))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('pleomorphic', 'Var', (21, 32))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (81, 88))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (181, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('ductal carcinomas', 'Disease', 'MESH:D044584', (181, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
90489	15700031	The mucin profile has other potential therapeutic ramifications; in many breast cancers, the glycosylation of the MUC-1 mucin side chains is altered and the mucin variant presents a potential target for immunotherapy (Taylor-papadimitrou et al, 2002); however, this is not an option for mucinous carcinomas which do not produce MUC-1.	('carcinomas', 'Phenotype', 'HP:0030731', (296, 306))	('MUC-1', 'Gene', (328, 333))	('MUC-1', 'Gene', '4582', (328, 333))	('altered', 'Reg', (141, 148))	('MUC-1', 'Gene', (114, 119))	('mucin', 'Gene', (287, 292))	('mucin', 'Gene', (120, 125))	('MUC-1', 'Gene', '4582', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mucin', 'Gene', '100508689', (120, 125))	('mucin', 'Gene', '100508689', (287, 292))	('mucinous carcinomas', 'Disease', (287, 306))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('mucin', 'Gene', (157, 162))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('glycosylation', 'MPA', (93, 106))	('mucin', 'Gene', '100508689', (157, 162))	('variant', 'Var', (163, 170))	('mucin', 'Gene', (4, 9))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (287, 306))	('mucin', 'Gene', '100508689', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
90494	15700031	Tubular carcinomas typically share the classic 16q/1q change seen in grade I and lobular tumours (see below) and like lobular carcinomas can be multifocal.	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (118, 136))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (118, 135))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('Tubular carcinomas', 'Disease', (0, 18))	('lobular carcinomas', 'Disease', (118, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('Tubular carcinomas', 'Disease', 'MESH:D000230', (0, 18))	('lobular carcinomas', 'Disease', 'MESH:D018275', (118, 136))	('lobular tumours', 'Disease', (81, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('16q/1q', 'Var', (47, 53))	('lobular tumours', 'Disease', 'MESH:D018275', (81, 96))
90520	15700031	In vitro studies may explain this; amplication of HER2 in breast cell lines causes them to become epidermotropic (Schelfhout et al, 2000).	('epidermotropic', 'CPA', (98, 112))	('HER2', 'Gene', (50, 54))	('HER2', 'Gene', '2064', (50, 54))	('causes', 'Reg', (76, 82))	('become', 'PosReg', (91, 97))	('amplication', 'Var', (35, 46))
90521	15700031	Another notable observation is that while 60% of pure DCIS in one study exhibited evidence of HER2 gene amplification, this dropped to 25% of with infiltrating ductal carcinoma, co-existent with the difference between in situ and invasive being even more marked when high nuclear grade lesions were matched (Barnes et al, 1992).	('ductal carcinoma', 'Phenotype', 'HP:0030075', (160, 176))	('ductal carcinoma', 'Disease', (160, 176))	('HER2', 'Gene', '2064', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('amplification', 'Var', (104, 117))	('ductal carcinoma', 'Disease', 'MESH:D044584', (160, 176))	('HER2', 'Gene', (94, 98))
90528	15700031	Correlating LOH of the BRCA-1 locus to morphology in a study of sporadic tumours also showed an association with extremely high mitotic counts - occasionally exceeding 100 per 10 high power fields.	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('sporadic tumours', 'Disease', (64, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('LOH', 'Var', (12, 15))	('BRCA-1', 'Gene', (23, 29))	('BRCA-1', 'Gene', '672', (23, 29))	('sporadic tumours', 'Disease', 'MESH:D009369', (64, 80))
90530	15700031	For tumours associated with germline mutation of BRCA-2, an association with lobular carcinomas (Armes et al, 1999) has been suggested but since then no firm morphological correlation has been proven.	('lobular carcinomas', 'Disease', 'MESH:D018275', (77, 95))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (77, 94))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (77, 95))	('BRCA-2', 'Gene', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('BRCA-2', 'Gene', '675', (49, 55))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('lobular carcinomas', 'Disease', (77, 95))	('germline mutation', 'Var', (28, 45))	('association', 'Interaction', (60, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('tumours', 'Disease', (4, 11))
90568	32053966	Breast cancer treatments are similar in dogs and humans, and dogs and humans share many of the same breast cancer risk factors including advancing age, progesterone treatment, and obesity in early life, diet, and mutations in BRCA genes.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('obesity', 'Disease', (180, 187))	('BRCA genes', 'Gene', (226, 236))	('progesterone', 'Chemical', 'MESH:D011374', (152, 164))	('humans', 'Species', '9606', (70, 76))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('humans', 'Species', '9606', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('dogs', 'Species', '9615', (40, 44))	('obesity', 'Phenotype', 'HP:0001513', (180, 187))	('breast cancer', 'Disease', (100, 113))	('mutations', 'Var', (213, 222))	('Breast cancer', 'Disease', (0, 13))	('obesity', 'Disease', 'MESH:D009765', (180, 187))	('dogs', 'Species', '9615', (61, 65))
90582	32053966	To identify molecular changes associated with DCIS progression to invasive cancer, the list of 2977 differentially expressed genes was filtered to detect 364 (DCIS log2fold-change +-3) and 28 (DCIS log2fold-change +-4) protein-coding genes (Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('invasive cancer', 'Disease', (66, 81))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('invasive cancer', 'Disease', 'MESH:D009362', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('DCIS log2fold-change +-3', 'Var', (159, 183))
90640	32053966	These findings support a model wherein alterations in myoepithelial cells promote the progression of DCIS to invasive cancer via TGFbeta signaling activation.	('promote', 'PosReg', (74, 81))	('invasive cancer', 'Disease', 'MESH:D009362', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DCIS', 'Disease', (101, 105))	('alterations', 'Var', (39, 50))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('activation', 'PosReg', (147, 157))	('invasive cancer', 'Disease', (109, 124))
90658	32053966	In this study, PAM50 assigned most of the tumors examined in this study to the HER-2 breast cancer subtype, which is the subtype most commonly associated with ER-negative and HER-2 positive subtype, corroborating the similarities between our dog model and human breast cancer.	('human', 'Species', '9606', (256, 261))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('associated', 'Reg', (143, 153))	('breast cancer', 'Disease', (85, 98))	('tumors', 'Disease', (42, 48))	('PAM50', 'Var', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('dog', 'Species', '9615', (242, 245))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('breast cancer', 'Disease', (262, 275))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HER-2', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
90681	32053966	The results of this study suggest that alteration of the Wnt signaling pathway may play a role in the progression of DCIS to invasive cancer, similar to data reported in humans.	('alteration', 'Var', (39, 49))	('Wnt signaling pathway', 'Pathway', (57, 78))	('humans', 'Species', '9606', (170, 176))	('DCIS', 'Disease', (117, 121))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('invasive cancer', 'Disease', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('invasive cancer', 'Disease', 'MESH:D009362', (125, 140))
90693	30051683	The results of our study suggest an association of the expression of COX-2 to the factors associated with poor prognosis in breast cancer, such as larger tumor size, positive lymph node status, higher T stage and N stage and lymphovascular invasion.	('COX-2', 'Gene', '5743', (69, 74))	('expression', 'Var', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lymphovascular invasion', 'CPA', (225, 248))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('association', 'Interaction', (36, 47))	('higher T stage', 'CPA', (194, 208))	('N stage', 'CPA', (213, 220))	('COX-2', 'Gene', (69, 74))	('tumor', 'Disease', (154, 159))
90725	30051683	Mean age of the patients with positive COX-2 expression was 48.41 years while in patients with negative COX-2 expression it was 54.57 years.	('COX-2', 'Gene', (104, 109))	('COX-2', 'Gene', '5743', (104, 109))	('COX-2', 'Gene', (39, 44))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (81, 89))	('COX-2', 'Gene', '5743', (39, 44))	('expression', 'Var', (45, 55))
90728	30051683	The mean tumor size in patients showing COX-2 expression was 6.93 cm while it was 2.81 cm in patients with negative COX-2 expression.	('expression', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('COX-2', 'Gene', (40, 45))	('COX-2', 'Gene', '5743', (40, 45))	('COX-2', 'Gene', (116, 121))	('COX-2', 'Gene', '5743', (116, 121))	('patients', 'Species', '9606', (93, 101))
90732	30051683	The mean number of involved lymph nodes in patients with positive COX-2 expression was 5.36 while in cases with negative COX-2 expression was 5.18.	('COX-2', 'Gene', (121, 126))	('positive', 'Var', (57, 65))	('COX-2', 'Gene', (66, 71))	('COX-2', 'Gene', '5743', (66, 71))	('patients', 'Species', '9606', (43, 51))	('COX-2', 'Gene', '5743', (121, 126))	('expression', 'Var', (72, 82))
90746	30051683	In our study, 58% of the breast carcinoma cases showed COX-2 positivity.	('COX-2', 'Gene', (55, 60))	('breast carcinoma', 'Disease', (25, 41))	('COX-2', 'Gene', '5743', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('breast carcinoma', 'Disease', 'MESH:D001943', (25, 41))	('breast carcinoma', 'Phenotype', 'HP:0003002', (25, 41))	('positivity', 'Var', (61, 71))
90756	30051683	There was a significant correlation between COX-2 positivity and lymph node involvement as indicated by a P value of 0.01.	('COX-2', 'Gene', (44, 49))	('positivity', 'Var', (50, 60))	('lymph node involvement', 'CPA', (65, 87))	('COX-2', 'Gene', '5743', (44, 49))
90766	30051683	However, they are discordant with the study done by Jana et al., (2014), who found a significantly positive correlation between COX-2 positivity and a higher tumor grade with a P value of <0.01.	('tumor', 'Disease', (158, 163))	('COX-2', 'Gene', (128, 133))	('COX-2', 'Gene', '5743', (128, 133))	('positive', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('positivity', 'Var', (134, 144))
90772	30051683	We demonstrated COX-2 positivity in 77.8% of the DCIS cases and 58% of IDC.	('COX-2', 'Gene', (16, 21))	('COX-2', 'Gene', '5743', (16, 21))	('DCIS', 'Disease', (49, 53))	('positivity', 'Var', (22, 32))
90775	30051683	The results of our study thus suggest an association of the expression of COX-2 to the factors associated with poor prognosis in breast cancer, such as larger tumor size, positive lymph node status, higher T stage and N stage and lymphovascular invasion.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('higher T stage', 'CPA', (199, 213))	('COX-2', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('association', 'Interaction', (41, 52))	('expression', 'Var', (60, 70))	('COX-2', 'Gene', '5743', (74, 79))	('tumor', 'Disease', (159, 164))	('lymphovascular invasion', 'CPA', (230, 253))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('N stage', 'CPA', (218, 225))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
90792	24833774	Each attribute is paired with a defined SNOMED CT concept value (eg, 31737007 structure of small lactiferous ductules  or 31390008 epithelial hyperplasia ), thus creating a list of attribute-value pairs.	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (131, 153))	('epithelial hyperplasia', 'Disease', (131, 153))	('31390008', 'Var', (122, 130))
90798	24833774	Invasive ductal carcinoma with associated DCIS  IS A  404684003 clinical finding : 363698007 finding site =279009002 glandular structure of breast , 116676008 associated morphology =82711006 infiltrating duct carcinoma , 47429007 associated with =404684003 clinical finding : (363698007 finding site =64633006 lactiferous duct structure , 116676008 associated morphology=86616005 intraductal carcinoma, non- infiltrating, no ICD-0 subtype ), 418775008 finding method ={104210008 hematoxylin and eosin stain method + 252416005 histopathology test +104157003 light microscopy } A defined SNOMED CT concept for the lumen of the breast duct or ductule did not exist in the July 2012 release but was pre-coordinated in July 2013 (64633006 structure of lumen of lactiferous duct (body structure) .	('ductal carcinoma', 'Phenotype', 'HP:0030075', (9, 25))	('64633006', 'Var', (725, 733))	('ductal carcinoma', 'Disease', 'MESH:D044584', (9, 25))	('carcinoma', 'Disease', 'MESH:D002277', (392, 401))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Disease', 'MESH:D002277', (209, 218))	('intraductal carcinoma', 'Disease', (380, 401))	('carcinoma', 'Disease', (16, 25))	('hematoxylin', 'Chemical', 'MESH:D006416', (479, 490))	('intraductal carcinoma', 'Disease', 'MESH:D002285', (380, 401))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (385, 401))	('IS A', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (392, 401))	('IS A', 'Gene', '312', (48, 52))	('eosin', 'Chemical', 'MESH:D004801', (495, 500))	('ductal carcinoma', 'Disease', 'MESH:D044584', (385, 401))	('carcinoma', 'Disease', (392, 401))	('carcinoma', 'Disease', 'MESH:D002277', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('ductal carcinoma', 'Disease', (9, 25))	('carcinoma', 'Disease', (209, 218))
90815	24833774	One situation states the absence of atypia suspicious for malignancy, and the other situation explicitly lists the default situational context of a clinical finding, that is, the attribute-value pairings of 410510008 temporal context value =410585006 current - unspecified  and 408732007 subject relationship context =410604004 subject of record .	('408732007', 'Var', (278, 287))	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('malignancy', 'Disease', (58, 68))	('unspecified', 'Species', '32644', (261, 272))
90824	24833774	Employing the defining attributes for 404684003 Clinical finding (clinical finding)  consistent with the SNOMED CT model definitions is demonstrated in the case of invasive carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('invasive carcinoma', 'Disease', (164, 182))	('invasive carcinoma', 'Disease', 'MESH:D009361', (164, 182))	('404684003', 'Var', (38, 47))
90829	21088888	HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('amplification', 'Var', (5, 18))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (104, 128))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('human', 'Species', '9606', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('HER2', 'Gene', (0, 4))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (104, 128))	('ductal carcinoma in situ', 'Disease', (104, 128))	('HER2', 'Gene', '2064', (0, 4))	('prevalent', 'Reg', (79, 88))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (104, 120))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
90891	21088888	Elevated Ki-67 levels, p53 mutations, and HER2 amplification are known to be associated with increased nuclear grade and necrosis which have also been associated with disease recurrence and progression [reviewed in ].	('mutations', 'Var', (27, 36))	('HER2', 'Gene', '2064', (42, 46))	('necrosis', 'Disease', (121, 129))	('associated', 'Reg', (151, 161))	('increased', 'PosReg', (93, 102))	('amplification', 'Var', (47, 60))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('HER2', 'Gene', (42, 46))	('Ki-67 levels', 'MPA', (9, 21))	('nuclear grade', 'CPA', (103, 116))
90892	21088888	p53 mutations and HER2 amplification have been seen in 25 and 30% of DCIS, respectively.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('HER2', 'Gene', '2064', (18, 22))	('DCIS', 'Disease', (69, 73))	('amplification', 'Var', (23, 36))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('mutations', 'Var', (4, 13))	('HER2', 'Gene', (18, 22))
90895	21088888	The histological features of aggressive lesions include comedo necrosis, high nuclear grade, and negative hormone receptor status while the molecular features include increased Ki-67, p53 mutation, HER2 amplification, increased COX2 expression, loss of heterozygosity at 11q13, and increased angiogenesis.	('hormone receptor', 'Gene', (106, 122))	('expression', 'MPA', (233, 243))	('necrosis', 'Disease', 'MESH:D009336', (63, 71))	('p53', 'Gene', '7157', (184, 187))	('amplification', 'Var', (203, 216))	('Ki-67', 'Gene', (177, 182))	('increased', 'PosReg', (282, 291))	('COX2', 'Gene', (228, 232))	('necrosis', 'Disease', (63, 71))	('p53', 'Gene', (184, 187))	('increased', 'PosReg', (218, 227))	('HER2', 'Gene', '2064', (198, 202))	('high nuclear grade', 'CPA', (73, 91))	('comedo', 'Phenotype', 'HP:0025249', (56, 62))	('hormone receptor', 'Gene', '3164', (106, 122))	('COX2', 'Gene', '4513', (228, 232))	('increased', 'PosReg', (167, 176))	('negative', 'NegReg', (97, 105))	('angiogenesis', 'CPA', (292, 304))	('mutation', 'Var', (188, 196))	('HER2', 'Gene', (198, 202))	('loss of heterozygosity', 'Var', (245, 267))
90896	21088888	Less aggressive DCIS has lower Ki-67, normal p53, no HER2 amplification, and deletion of chromosome 16.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('Ki-67', 'MPA', (31, 36))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('HER2', 'Gene', (53, 57))	('lower', 'NegReg', (25, 30))	('deletion', 'Var', (77, 85))	('HER2', 'Gene', '2064', (53, 57))
90915	21088888	Our study demonstrated a significant correlation between increased SIAH expression in normal breast tissue adjacent to DCIS lesions and younger patient age suggesting an overall difference in breast tissue biology in younger and older patient populations which may predispose younger patients to the development of more aggressive DCIS.	('patient', 'Species', '9606', (235, 242))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('patients', 'Species', '9606', (284, 292))	('SIAH', 'Protein', (67, 71))	('patient', 'Species', '9606', (144, 151))	('expression', 'MPA', (72, 82))	('lesions', 'Var', (124, 131))	('DCIS', 'Phenotype', 'HP:0030075', (331, 335))	('increased', 'PosReg', (57, 66))	('patient', 'Species', '9606', (284, 291))
90918	21088888	This relationship was demonstrated by increased EZH2 expression in benign breast biopsies from patients that later developed carcinoma as well as in morphologically normal mammary tissue from prophylactic mastectomy specimens of patients with BRCA1 mutations.	('patients', 'Species', '9606', (229, 237))	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (95, 103))	('mutations', 'Var', (249, 258))	('BRCA1', 'Gene', (243, 248))	('carcinoma', 'Disease', (125, 134))	('EZH2', 'Gene', '2146', (48, 52))	('EZH2', 'Gene', (48, 52))	('expression', 'MPA', (53, 63))	('BRCA1', 'Gene', '672', (243, 248))	('increased', 'PosReg', (38, 47))
90966	21113302	Mutations in p53 are the most common genetic changes found in human malignancies and the mutational status of p53 is prognostic in many malignancies.	('p53', 'Gene', (110, 113))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('malignancies', 'Disease', (68, 80))	('p53', 'Gene', '7157', (110, 113))	('malignancies', 'Disease', (136, 148))	('p53', 'Gene', '7157', (13, 16))	('human', 'Species', '9606', (62, 67))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
90967	21113302	In breast carcinoma, p53 mutations have been shown to be associated with worse overall and disease-free survival, independent of other risk factors, and have been implicated in resistance to anticancer therapies.	('disease-free survival', 'CPA', (91, 112))	('implicated', 'Reg', (163, 173))	('mutations', 'Var', (25, 34))	('breast carcinoma', 'Disease', 'MESH:D001943', (3, 19))	('breast carcinoma', 'Disease', (3, 19))	('p53', 'Gene', '7157', (21, 24))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('worse', 'NegReg', (73, 78))	('breast carcinoma', 'Phenotype', 'HP:0003002', (3, 19))	('overall', 'CPA', (79, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('p53', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
90968	21113302	Missense point mutations, which represent more than 85% of gene abnormalities, lead to a conformational change which stabilizes the p53 protein and allows it to accumulate in the nucleus to relatively high levels.	('conformational change', 'MPA', (89, 110))	('p53', 'Gene', '7157', (132, 135))	('p53', 'Gene', (132, 135))	('Missense point mutations', 'Var', (0, 24))	('protein', 'Protein', (136, 143))
90969	21113302	Accumulation of the mutant p53 in tumor cells can elicit a humoral immune response leading to the production of anti-p53 AAbs.	('production', 'MPA', (98, 108))	('elicit', 'Reg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (27, 30))	('p53', 'Gene', '7157', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mutant', 'Var', (20, 26))	('p53', 'Gene', (27, 30))
90970	21113302	Initially, it was thought that only tumors with missense p53 mutations resulting in p53 overexpression can elicit anti-p53 AAbs.	('overexpression', 'PosReg', (88, 102))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('missense', 'Var', (48, 56))	('p53', 'Gene', '7157', (119, 122))	('elicit', 'Reg', (107, 113))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('p53', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('p53', 'Gene', '7157', (57, 60))
90976	21113302	Indeed, while mutation of p53 appears a seminal event in carcinogenesis and is present in ~30% of breast carcinoma patients, it is still unclear why only a subset of p53 mutation-positive breast carcinoma patients (~50%) generates anti-p53 AAbs.	('patients', 'Species', '9606', (205, 213))	('breast carcinoma', 'Disease', (188, 204))	('breast carcinoma', 'Disease', 'MESH:D001943', (98, 114))	('p53', 'Gene', (26, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('p53', 'Gene', '7157', (166, 169))	('p53', 'Gene', '7157', (236, 239))	('breast carcinoma', 'Phenotype', 'HP:0003002', (98, 114))	('patients', 'Species', '9606', (115, 123))	('breast carcinoma', 'Disease', (98, 114))	('breast carcinoma', 'Disease', 'MESH:D001943', (188, 204))	('p53', 'Gene', (166, 169))	('p53', 'Gene', (236, 239))	('carcinogenesis', 'Disease', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('mutation-positive', 'Reg', (170, 187))	('breast carcinoma', 'Phenotype', 'HP:0003002', (188, 204))	('mutation', 'Var', (14, 22))	('p53', 'Gene', '7157', (26, 29))
90977	21113302	It has been suggested that only p53 mutations that are localized in exons 5 and 6 with an altered protein conformation and that bind to HSP-70 are associated with anti-p53 AAbs.	('bind', 'Interaction', (128, 132))	('associated', 'Reg', (147, 157))	('altered', 'Reg', (90, 97))	('p53', 'Gene', '7157', (168, 171))	('mutations', 'Var', (36, 45))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('HSP-70', 'Gene', '3308', (136, 142))	('protein conformation', 'MPA', (98, 118))	('HSP-70', 'Gene', (136, 142))	('p53', 'Gene', (168, 171))
91022	21113302	The authors concluded that measurement of serum AAbs to MUC1 protein only is of little value for screening and early diagnosis of breast carcinoma; however, AAbs to MUC1 may have promising diagnostic potential when incorporated in AAb assays against a panel of TAAs.	('MUC1', 'Gene', '4582', (56, 60))	('breast carcinoma', 'Disease', 'MESH:D001943', (130, 146))	('breast carcinoma', 'Disease', (130, 146))	('AAbs to', 'Var', (157, 164))	('breast carcinoma', 'Phenotype', 'HP:0003002', (130, 146))	('MUC1', 'Gene', (165, 169))	('MUC1', 'Gene', '4582', (165, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('MUC1', 'Gene', (56, 60))	('men', 'Species', '9606', (34, 37))
91025	21113302	Obviously, serum AAb-assay against MUC1 protein only is of little value for screening and early diagnosis of breast carcinoma; however, AAbs to MUC1 may have promising diagnostic potential when incorporated in AAb assays against a panel of TAAs.	('AAbs', 'Var', (136, 140))	('MUC1', 'Gene', (35, 39))	('breast carcinoma', 'Disease', 'MESH:D001943', (109, 125))	('MUC1', 'Gene', '4582', (35, 39))	('breast carcinoma', 'Phenotype', 'HP:0003002', (109, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('MUC1', 'Gene', (144, 148))	('MUC1', 'Gene', '4582', (144, 148))	('breast carcinoma', 'Disease', (109, 125))
91026	21113302	Moreover, there is support for the notion that preexisting AAbs to MUC1 may reduce the risk of developing breast carcinoma and presence of AAbs to MUC1 in breast carcinoma is correlated with a more favorable prognosis.	('breast carcinoma', 'Disease', 'MESH:D001943', (106, 122))	('breast carcinoma', 'Disease', (106, 122))	('MUC1', 'Gene', (67, 71))	('breast carcinoma', 'Disease', (155, 171))	('MUC1', 'Gene', '4582', (67, 71))	('breast carcinoma', 'Disease', 'MESH:D001943', (155, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('AAbs', 'Var', (139, 143))	('reduce', 'NegReg', (76, 82))	('MUC1', 'Gene', (147, 151))	('MUC1', 'Gene', '4582', (147, 151))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('presence', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('breast carcinoma', 'Phenotype', 'HP:0003002', (155, 171))
91031	21113302	Overexpression of HSP-27 in breast carcinoma has been associated with shorter disease-free survival.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('shorter', 'NegReg', (70, 77))	('HSP-27', 'Gene', '3315', (18, 24))	('breast carcinoma', 'Disease', 'MESH:D001943', (28, 44))	('breast carcinoma', 'Disease', (28, 44))	('HSP-27', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('breast carcinoma', 'Phenotype', 'HP:0003002', (28, 44))	('disease-free survival', 'CPA', (78, 99))
91033	21113302	The mortality rate was lower in women with AAbs to HSP-27 than in those who lacked such AAbs (P = .006).	('women', 'Species', '9606', (32, 37))	('mortality rate', 'MPA', (4, 18))	('HSP-27', 'Gene', '3315', (51, 57))	('HSP-27', 'Gene', (51, 57))	('lower', 'NegReg', (23, 28))	('AAbs', 'Var', (43, 47))
91034	21113302	Thus, a significant association has been found between the presence of serum AAbs to HSP-27 and improved survival in breast carcinoma patients.	('breast carcinoma', 'Phenotype', 'HP:0003002', (117, 133))	('improved', 'PosReg', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('HSP-27', 'Gene', (85, 91))	('patients', 'Species', '9606', (134, 142))	('serum', 'Var', (71, 76))	('HSP-27', 'Gene', '3315', (85, 91))	('breast carcinoma', 'Disease', 'MESH:D001943', (117, 133))	('breast carcinoma', 'Disease', (117, 133))	('survival', 'CPA', (105, 113))	('presence', 'Var', (59, 67))
91039	21113302	The frequency of AAbs to HSP-60 was significantly higher in high-grade DCIS patients (11/23, 47.8%) compared to low-grade DCIS patients (5/26, 19.2%) (P = .0188).	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('patients', 'Species', '9606', (76, 84))	('AAbs', 'Var', (17, 21))	('HSP-60', 'Gene', (25, 31))	('higher', 'PosReg', (50, 56))	('HSP-60', 'Gene', '3329', (25, 31))	('patients', 'Species', '9606', (127, 135))	('high-grade DCIS', 'Disease', (60, 75))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
91042	21113302	Notably, no significant relation was found between the frequency of AAbs to HSP-60 and estrogen receptor (ER), progesterone receptor (PR) and HER-2 status.	('ER', 'Gene', '2099', (106, 108))	('progesterone receptor', 'Gene', (111, 132))	('HSP-60', 'Gene', (76, 82))	('estrogen receptor', 'Gene', (87, 104))	('estrogen receptor', 'Gene', '2099', (87, 104))	('progesterone receptor', 'Gene', '5241', (111, 132))	('HSP-60', 'Gene', '3329', (76, 82))	('PR', 'Gene', '5241', (134, 136))	('HER-2', 'Gene', '2064', (142, 147))	('HER-2', 'Gene', (142, 147))	('ER', 'Gene', '2099', (143, 145))	('AAbs', 'Var', (68, 72))
91046	21113302	Moreover, the presence of serum AAbs to HSP-90 correlated with the development of metastases even in patients without axillary lymph node involvement.	('patients', 'Species', '9606', (101, 109))	('presence', 'Var', (14, 22))	('men', 'Species', '9606', (145, 148))	('correlated with', 'Reg', (47, 62))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('men', 'Species', '9606', (74, 77))	('metastases', 'Disease', (82, 92))	('HSP-90', 'Gene', (40, 46))	('HSP-90', 'Gene', '3320', (40, 46))
91048	21113302	Mortality rate from breast carcinoma was greater in women testing positive for AAbs to HSP-90 than those testing negative for AAbs to HSP-90.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('greater', 'PosReg', (41, 48))	('breast carcinoma', 'Disease', (20, 36))	('HSP-90', 'Gene', (87, 93))	('breast carcinoma', 'Disease', 'MESH:D001943', (20, 36))	('HSP-90', 'Gene', '3320', (87, 93))	('positive', 'Reg', (66, 74))	('women', 'Species', '9606', (52, 57))	('HSP-90', 'Gene', (134, 140))	('HSP-90', 'Gene', '3320', (134, 140))	('breast carcinoma', 'Phenotype', 'HP:0003002', (20, 36))	('AAbs to', 'Var', (79, 86))
91049	21113302	Although the difference between the two groups did not attest statistical significance, the authors have concluded that there appears to be an association between higher mortality rate from breast carcinoma and presence of serum AAbs to HSP-90.	('HSP-90', 'Gene', (237, 243))	('HSP-90', 'Gene', '3320', (237, 243))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('presence', 'Var', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('breast carcinoma', 'Disease', (190, 206))	('higher', 'PosReg', (163, 169))	('breast carcinoma', 'Disease', 'MESH:D001943', (190, 206))
91055	21113302	It has been concluded that measurement of serum AAbs to HER2 protein only is of little value for screening and early diagnosis of breast carcinoma; however, AAbs to HER2 may have promising diagnostic potential when incorporated in AAb assays against a panel of TAAs.	('HER2', 'Gene', (56, 60))	('breast carcinoma', 'Disease', 'MESH:D001943', (130, 146))	('breast carcinoma', 'Disease', (130, 146))	('HER2', 'Gene', '2064', (56, 60))	('AAbs to', 'Var', (157, 164))	('breast carcinoma', 'Phenotype', 'HP:0003002', (130, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', '2064', (165, 169))	('men', 'Species', '9606', (34, 37))
91068	21113302	GIPC-1 staining with 27.B1 and 27.F7 antibodies was positive only in invasive breast carcinomas (27.B1 displayed a higher reactivity rate than 27.F1) whereas GIPC-1 staining with 27.B1 and 27.F7 antibodies was negative in in situ and benign tumors (P < .001).	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (69, 95))	('benign tumors', 'Disease', (234, 247))	('GIPC-1', 'Gene', (158, 164))	('breast carcinomas', 'Phenotype', 'HP:0003002', (78, 95))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('GIPC-1', 'Gene', '10755', (158, 164))	('GIPC-1', 'Gene', (0, 6))	('invasive breast carcinomas', 'Disease', (69, 95))	('27.B1', 'Var', (97, 102))	('benign tumors', 'Disease', 'MESH:D009369', (234, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('GIPC-1', 'Gene', '10755', (0, 6))	('reactivity', 'MPA', (122, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
91088	21113302	It has been concluded that measurement of serum AAbs to NY-ESO-1 protein only is of little value for screening and early diagnosis of breast carcinoma; however, AAbs to NY-ESO-1 may have promising diagnostic potential when incorporated in AAb assays against a panel of TAAs.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('NY-ESO-1', 'Gene', '246100', (56, 64))	('AAbs', 'Var', (161, 165))	('breast carcinoma', 'Disease', (134, 150))	('NY-ESO-1', 'Gene', (56, 64))	('breast carcinoma', 'Disease', 'MESH:D001943', (134, 150))	('NY-ESO-1', 'Gene', '246100', (169, 177))	('NY-ESO-1', 'Gene', (169, 177))	('breast carcinoma', 'Phenotype', 'HP:0003002', (134, 150))	('men', 'Species', '9606', (34, 37))
91090	21113302	The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene have been found to be significantly more common among Ashkenazi Jews (Jews of eastern European ancestry) (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1in 300, 0.12%-0.33%).	('BRCA1', 'Gene', (43, 48))	('6174delT', 'Mutation', 'rs786204278', (62, 70))	('5382insC', 'Var', (17, 25))	('185delAG', 'Var', (4, 12))	('common', 'Reg', (139, 145))	('BRCA2', 'Gene', '675', (87, 92))	('185delAG', 'Mutation', 'c.185delAG', (4, 12))	('5382insC', 'Mutation', 'c.5382insC', (17, 25))	('BRCA1', 'Gene', '672', (43, 48))	('BRCA2', 'Gene', (87, 92))	('6174delT', 'Var', (62, 70))
91091	21113302	Carriers of these "Ashkenazi mutations" have a significantly increased lifetime risk of breast carcinoma (about 50%), ovarian carcinoma and other carcinomas as compared to noncarriers.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (118, 135))	('breast carcinoma', 'Disease', 'MESH:D001943', (88, 104))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (118, 135))	('mutations', 'Var', (29, 38))	('breast carcinoma', 'Phenotype', 'HP:0003002', (88, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('ovarian carcinoma', 'Disease', (118, 135))	('carcinomas', 'Disease', 'MESH:D002277', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('breast carcinoma', 'Disease', (88, 104))
91126	21113302	In addition, it has been suggested that AAbs to Fbln-1 may perhaps be exploited as a tool for early detection of breast carcinoma.	('Fbln-1', 'Gene', '2192', (48, 54))	('Fbln-1', 'Gene', (48, 54))	('breast carcinoma', 'Disease', 'MESH:D001943', (113, 129))	('breast carcinoma', 'Phenotype', 'HP:0003002', (113, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('AAbs', 'Var', (40, 44))	('breast carcinoma', 'Disease', (113, 129))
91132	21113302	demonstrated by specifically designed his-tagged capture ELISA (based on lysate from genetically engineered Chinese hamster ovary cells) the presence of AAbs to IGFBP-2 in the sera of 4/80 (5%) breast carcinoma patients, 32/80 (40%) colorectal carcinoma patients and 2/200 (1%) healthy controls.	('breast carcinoma', 'Disease', (194, 210))	('patients', 'Species', '9606', (211, 219))	('IGFBP-2', 'Gene', (161, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('Chinese hamster', 'Species', '10029', (108, 123))	('breast carcinoma', 'Phenotype', 'HP:0003002', (194, 210))	('colorectal carcinoma', 'Disease', (233, 253))	('AAbs', 'Var', (153, 157))	('presence', 'Reg', (141, 149))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (233, 253))	('patients', 'Species', '9606', (254, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('breast carcinoma', 'Disease', 'MESH:D001943', (194, 210))
91138	21113302	revealed by recombinant ELISA the presence of AAbs to TOPO2alpha protein in the sera of 8/115 (7%) breast carcinoma patients compared to 4/200 (2%) healthy controls.	('breast carcinoma', 'Disease', 'MESH:D001943', (99, 115))	('patients', 'Species', '9606', (116, 124))	('breast carcinoma', 'Phenotype', 'HP:0003002', (99, 115))	('TOPO2alpha protein', 'Protein', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('AAbs', 'Var', (46, 50))	('breast carcinoma', 'Disease', (99, 115))
91144	21113302	detected AAbs to cathepsin D protein in the sera of 5/100 (5%) breast carcinoma patients compared to 3/100 (3%) healthy controls.	('cathepsin D', 'Gene', '1509', (17, 28))	('patients', 'Species', '9606', (80, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('breast carcinoma', 'Disease', (63, 79))	('breast carcinoma', 'Disease', 'MESH:D001943', (63, 79))	('AAbs', 'Var', (9, 13))	('cathepsin D', 'Gene', (17, 28))	('breast carcinoma', 'Phenotype', 'HP:0003002', (63, 79))
91156	21113302	In women with probably benign findings on mammography (BI-RADS category 3), presence of serum AAbs to breast carcinoma TAAs would strengthen the decision to perform an immediate breast biopsy to obtain tissue for histological diagnosis rather than to wait six months for the next mammography.	('presence', 'Var', (76, 84))	('strengthen', 'PosReg', (130, 140))	('breast carcinoma TAAs', 'Disease', (102, 123))	('breast carcinoma TAAs', 'Disease', 'MESH:D001943', (102, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('breast carcinoma', 'Phenotype', 'HP:0003002', (102, 118))	('women', 'Species', '9606', (3, 8))
91158	21113302	In women with negative findings on mammography (BI-RADS category 1) and in women with benign finding(s) on mammography (BI-RADS category 2), presence of serum AAbs to breast carcinoma TAAs might lead to a decision to perform immediate additional imaging studies (ultrasound and/or MRI) or, in women with BI-RADS category 2, even an immediate breast biopsy to obtain tissue for histological diagnosis rather than to wait one year for the next routine annual screening mammography.	('breast carcinoma TAAs', 'Disease', (167, 188))	('breast carcinoma TAAs', 'Disease', 'MESH:D001943', (167, 188))	('AAbs', 'Protein', (159, 163))	('women', 'Species', '9606', (293, 298))	('presence', 'Var', (141, 149))	('women', 'Species', '9606', (75, 80))	('lead to', 'Reg', (195, 202))	('breast carcinoma', 'Phenotype', 'HP:0003002', (167, 183))	('women', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))
91233	32678710	Screen detection was associated with increased disease-specific survival (DSS) compared with symptom-detected breast cancer, independent of early stage and favorable prognostic clinicopathological factors.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Screen detection', 'Var', (0, 16))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('increased', 'PosReg', (37, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('breast cancer', 'Disease', (110, 123))	('DSS', 'Chemical', '-', (74, 77))	('disease-specific', 'MPA', (47, 63))
91294	32678710	Specific copy number imbalances were also noted in screen-detected breast cancers associated with more favorable, indolent tumor genotypes and might contribute to the survival advantage associated with screening.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('associated', 'Reg', (82, 92))	('tumor', 'Disease', (123, 128))	('copy number imbalances', 'Var', (9, 31))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('imbalances', 'Phenotype', 'HP:0002172', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('breast cancers', 'Phenotype', 'HP:0003002', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancers', 'Disease', 'MESH:D001943', (67, 81))	('breast cancers', 'Disease', (67, 81))
91301	32678710	A significantly higher proportion of cases expressed PgR and had a Ki67 <= 20% among screen-detected cancers compared with symptomatic tumors (78.1% v 68%, P = .04; and 57.1% v 44.1%, P = .02, respectively).	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancers', 'Disease', (101, 108))	('PgR', 'Gene', '5241', (53, 56))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PgR', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('expressed', 'Reg', (43, 52))	('Ki67', 'Var', (67, 71))
91311	32678710	In the current study, cancer in the majority of patients (82.3%) was detected at an early prognostic stage (0-I), and patients with interval cancers were more likely to have a worse prognostic stage (OR, 3.59; 95% CI, 0.9 to 14.5) with high Ki-67 scores (OR, 3.14; 95% CI, 0.9 to 11.2) compared with screen-detected cancers.	('Ki-67', 'Gene', (241, 246))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('interval cancers', 'Disease', (132, 148))	('interval cancers', 'Disease', 'MESH:D009369', (132, 148))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancer', 'Disease', (316, 322))	('cancers', 'Disease', (141, 148))	('cancers', 'Disease', (316, 323))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('high', 'Var', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (118, 126))	('cancers', 'Disease', 'MESH:D009369', (316, 323))
91391	21315410	In the invasive ductal breast cancers, we detected nuclear Snail1 frequently in ERalpha (-) but not in ERalpha (+) cancers (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('invasive ductal breast cancers', 'Disease', 'MESH:D018270', (7, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('ERalpha', 'Gene', (103, 110))	('ERalpha', 'Gene', (80, 87))	('Snail1', 'Gene', '6615', (59, 65))	('detected', 'Reg', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (30, 37))	('ERalpha', 'Gene', '2099', (103, 110))	('Snail1', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('ERalpha', 'Gene', '2099', (80, 87))	('invasive ductal breast cancers', 'Disease', (7, 37))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))	('nuclear', 'Var', (51, 58))
91450	22457730	Triple negative breast cancer (TNBC) are tumors that lack expression of estrogen receptor alpha (ERalpha), progesterone receptor (PR), and amplification/overexpression of human epidermal growth factor receptor 2 (HER2/neu).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('progesterone receptor', 'Gene', (107, 128))	('progesterone receptor', 'Gene', '5241', (107, 128))	('tumors', 'Disease', (41, 47))	('ERalpha', 'Gene', (97, 104))	('epidermal growth factor receptor 2', 'Gene', '2064', (177, 211))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Disease', (16, 29))	('PR', 'Gene', (130, 132))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('epidermal growth factor receptor 2', 'Gene', (177, 211))	('ERalpha', 'Gene', '2099', (97, 104))	('HER2', 'Gene', '2064', (213, 217))	('estrogen receptor alpha', 'Gene', '2099', (72, 95))	('amplification/overexpression', 'Var', (139, 167))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('human', 'Species', '9606', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('amplification/overexpression', 'PosReg', (139, 167))	('HER2', 'Gene', (213, 217))	('estrogen receptor alpha', 'Gene', (72, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
91463	22457730	Most importantly, inhibition of Src has recently been identified as a therapeutic target for basal breast cancers including the TNBC subtype.	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('basal breast cancers', 'Disease', (93, 113))	('breast cancers', 'Phenotype', 'HP:0003002', (99, 113))	('inhibition', 'Var', (18, 28))	('Src', 'Gene', (32, 35))	('basal breast cancers', 'Disease', 'MESH:D001943', (93, 113))	('Src', 'Gene', '6714', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
91488	22457730	The comparison of TNBC (n = 39) and ER+BC (n = 40) cases regardless of race revealed that total Src expression in the cytoplasm was significantly higher in TNBC compared to ER+BC (P = 0.0028) (Fig.	('higher', 'PosReg', (146, 152))	('Src', 'Gene', (96, 99))	('TNBC', 'Var', (156, 160))	('Src', 'Gene', '6714', (96, 99))
91560	22457730	Total Src kinase and activated phospho Src kinase expression (p-Y416Src) was assessed by IHC using antibodies against total c-Src (36D10; CAT # 2109, Cell Signaling Technology, Beverly, MA) and p-Y416Src (CAT # 2101, Cell Signaling Technology, Beverly, MA).	('Src', 'Gene', (200, 203))	('c-Src', 'Gene', (124, 129))	('Src', 'Gene', (39, 42))	('Src', 'Gene', '6714', (39, 42))	('Src', 'Gene', (68, 71))	('Src', 'Gene', '6714', (68, 71))	('c-Src', 'Gene', '6714', (124, 129))	('Src', 'Gene', '6714', (200, 203))	('Src', 'Gene', (126, 129))	('Src', 'Gene', '6714', (126, 129))	('Src', 'Gene', (6, 9))	('Src', 'Gene', '6714', (6, 9))	('CAT # 2109', 'Var', (138, 148))
91580	30290054	In IDC, the Mieap promoter was methylated in 6/46 (13%) cases, whereas p53 was mutated in 6/46 (13%) cases.	('Mieap', 'Gene', (12, 17))	('Mieap', 'Gene', '132671', (12, 17))	('methylated', 'Var', (31, 41))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('IDC', 'Disease', (3, 6))
91582	30290054	Interestingly, all tumors derived from the 12 patients with Mieap promoter methylation or p53 mutations pathologically exhibited more aggressive and malignant breast cancer phenotypes.	('more', 'PosReg', (129, 133))	('tumors', 'Disease', (19, 25))	('p53', 'Gene', (90, 93))	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (94, 103))	('p53', 'Gene', '7157', (90, 93))	('malignant breast cancer', 'Disease', 'MESH:D001943', (149, 172))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('Mieap', 'Gene', (60, 65))	('Mieap', 'Gene', '132671', (60, 65))	('malignant breast cancer', 'Disease', (149, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('exhibited', 'Reg', (119, 128))
91590	30290054	This engulfs the damaged mitochondria and results in the accumulation of lysosomes, leading to the degradation of unhealthy mitochondria.20 Further in vitro study revealed that BNIP3 and NIX co-localized with Mieap in mitochondria and reduced ROS.	('BNIP3', 'Var', (177, 182))	('ROS', 'MPA', (243, 246))	('reduced', 'NegReg', (235, 242))	('Mieap', 'Gene', (209, 214))	('Mieap', 'Gene', '132671', (209, 214))	('ROS', 'Chemical', 'MESH:D017382', (243, 246))
91606	30290054	Caspase plays a central role in apoptosis, and the cleavage of poly ADP-ribose polymerase (PARP) facilitates cellular disassembly.	('poly ADP-ribose polymerase', 'Gene', '142', (63, 89))	('PARP', 'Gene', (91, 95))	('cleavage', 'Var', (51, 59))	('PARP', 'Gene', '142', (91, 95))	('facilitates', 'PosReg', (97, 108))	('poly ADP-ribose polymerase', 'Gene', (63, 89))	('cellular disassembly', 'CPA', (109, 129))
91639	30290054	In MCF-7 cells, caspase-7, but not caspase-3, was cleaved under the same conditions because caspase-3 is deficient in MCF-7 cells.28 Cleaved PARP, which is produced through cleavage by activated caspases,29 was detected 48-72 hours after Ad-Mieap infection in both cell lines.	('Mieap', 'Gene', '132671', (241, 246))	('Cleaved', 'Var', (133, 140))	('PARP', 'Gene', '142', (141, 145))	('MCF-7', 'CellLine', 'CVCL:0031', (3, 8))	('caspases', 'Gene', (195, 203))	('PARP', 'Gene', (141, 145))	('MCF-7', 'CellLine', 'CVCL:0031', (118, 123))	('Mieap', 'Gene', (241, 246))	('caspases', 'Gene', '841;64044;842', (195, 203))
91654	30290054	Genetic alterations of p53 were found in 6 of 46 IDC (13%).	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (12, 15))	('found', 'Reg', (32, 37))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('IDC', 'Disease', (49, 52))
91656	30290054	Of 12 cases, 6 with methylated Mieap promoter were luminal B and the other 6 with mutant p53 were triple negative as follows: 4, HER2-rich; 1, luminal B; 1, whose subtypes were clinically more aggressive and malignant phenotypes in breast cancer (Table 3).30, 31  Interestingly, the group with inactivation of the p53/Mieap-regulated MQC pathway showed shorter DFS than that without these genetic alterations (P = 0.021, Figure 5).	('breast cancer', 'Disease', (232, 245))	('shorter', 'NegReg', (353, 360))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('Mieap', 'Gene', '132671', (31, 36))	('p53', 'Gene', '7157', (89, 92))	('Mieap', 'Gene', (318, 323))	('HER2', 'Gene', (129, 133))	('Mieap', 'Gene', '132671', (318, 323))	('p53', 'Gene', (314, 317))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('HER2', 'Gene', '2064', (129, 133))	('p53', 'Gene', '7157', (314, 317))	('p53', 'Gene', (89, 92))	('rat', 'Species', '10116', (401, 404))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))	('Mieap', 'Gene', (31, 36))	('DFS', 'MPA', (361, 364))	('inactivation', 'Var', (294, 306))
91657	30290054	Four of six recurrent cases showed inactivation in the p53/Mieap-regulated MQC pathway.	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('inactivation', 'Var', (35, 47))	('Mieap', 'Gene', (59, 64))	('Mieap', 'Gene', '132671', (59, 64))
91661	30290054	However, as shown in Figure S4B, there was a significant difference between those with p53 mutations (n = 6) and those without (n = 40; P = 0.00035).	('p53', 'Gene', (87, 90))	('mutations', 'Var', (91, 100))	('p53', 'Gene', '7157', (87, 90))
91663	30290054	Mieap expression was completely undetectable in 10 of 11 cases with either methylated Mieap promoter or p53 alterations.	('methylated', 'Var', (75, 85))	('p53', 'Gene', (104, 107))	('Mieap', 'Gene', '132671', (86, 91))	('alterations', 'Var', (108, 119))	('p53', 'Gene', '7157', (104, 107))	('rat', 'Species', '10116', (112, 115))	('Mieap', 'Gene', (0, 5))	('Mieap', 'Gene', '132671', (0, 5))	('Mieap', 'Gene', (86, 91))	('undetectable', 'NegReg', (32, 44))
91666	30290054	Based on the previous reports that Mieap expression is regulated by either p53 status or methylation of Mieap, BNIP3 and NIX promoters, we suggest that it is important to evaluate MQC based on these factors (i.e.	('Mieap', 'Gene', '132671', (35, 40))	('Mieap', 'Gene', (104, 109))	('regulated', 'Reg', (55, 64))	('Mieap', 'Gene', '132671', (104, 109))	('methylation', 'Var', (89, 100))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('Mieap', 'Gene', (35, 40))
91683	30290054	The p53/Mieap/BNIP3-regulated MQC pathway is inactivated in >70% of colorectal cancers, suggesting that Mieap-regulated MQC has a critical role in colorectal cancer suppression in vivo.23 In this study, we found that this pathway was inactivated in 12/46 (26.1%) invasive breast cancers via the promoter methylation of Mieap or p53 mutations, which occurred at a lower frequency compared to that observed for colorectal cancer.	('Mieap', 'Gene', '132671', (104, 109))	('colorectal cancers', 'Disease', 'MESH:D015179', (68, 86))	('inactivated', 'NegReg', (234, 245))	('Mieap', 'Gene', '132671', (8, 13))	('Mieap', 'Gene', (319, 324))	('p53', 'Gene', (4, 7))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('p53', 'Gene', (328, 331))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (409, 426))	('Mieap', 'Gene', (104, 109))	('Mieap', 'Gene', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancers', 'Disease', 'MESH:D001943', (272, 286))	('mutations', 'Var', (332, 341))	('breast cancers', 'Disease', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('breast cancers', 'Phenotype', 'HP:0003002', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancers', 'Disease', (68, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('colorectal cancer', 'Disease', 'MESH:D015179', (409, 426))	('p53', 'Gene', '7157', (4, 7))	('colorectal cancer', 'Disease', (147, 164))	('colorectal cancer', 'Disease', (409, 426))	('Mieap', 'Gene', '132671', (319, 324))	('p53', 'Gene', '7157', (328, 331))	('promoter', 'MPA', (295, 303))
91686	30290054	Interestingly, among 12 cases exhibiting inactivation of the pathway, 6 cases with methylation of the Mieap promoter were luminal B type, which comprises aggressive and fast-growing estrogen receptor-positive breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (209, 223))	('breast cancers', 'Disease', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inactivation', 'Var', (41, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('Mieap', 'Gene', (102, 107))	('Mieap', 'Gene', '132671', (102, 107))	('methylation', 'Var', (83, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (209, 223))
91687	30290054	The other 6 cases with a p53 mutation were also aggressive types (triple negative, 4; HER2-rich, 1; luminal B, 1).30, 31 Furthermore, as shown in Table 2, there were 6 cases with p53 alterations, in which 5 were subjected to IHC for Mieap.	('HER2', 'Gene', (86, 90))	('p53', 'Gene', (25, 28))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (25, 28))	('rat', 'Species', '10116', (187, 190))	('HER2', 'Gene', '2064', (86, 90))	('p53', 'Gene', '7157', (179, 182))	('alterations', 'Var', (183, 194))	('Mieap', 'Gene', (233, 238))	('Mieap', 'Gene', '132671', (233, 238))
91689	30290054	Specifically, Mieap expression completely disappeared in 10 of 11 cases with either Mieap promoter methylation or p53 alterations.	('Mieap', 'Gene', (84, 89))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('alterations', 'Var', (118, 129))	('Mieap', 'Gene', '132671', (84, 89))	('Mieap', 'Gene', (14, 19))	('rat', 'Species', '10116', (122, 125))	('disappeared', 'NegReg', (42, 53))	('Mieap', 'Gene', '132671', (14, 19))
91692	30290054	Fourth, the group with p53 mutation or Mieap promoter methylation showed shorter DFS, suggesting that inactivation of the p53/Mieap-regulated MQC pathway might lead to failed cell death induction, resulting in enhanced malignant potential and aggressiveness in vivo.	('inactivation', 'Var', (102, 114))	('aggressiveness', 'Disease', (243, 257))	('malignant potential', 'CPA', (219, 238))	('Mieap', 'Gene', '132671', (39, 44))	('aggressiveness', 'Phenotype', 'HP:0000718', (243, 257))	('mutation', 'Var', (27, 35))	('cell death induction', 'CPA', (175, 195))	('Mieap', 'Gene', '132671', (126, 131))	('p53', 'Gene', (122, 125))	('aggressiveness', 'Disease', 'MESH:D001523', (243, 257))	('Mieap', 'Gene', (39, 44))	('Mieap', 'Gene', (126, 131))	('p53', 'Gene', '7157', (23, 26))	('shorter', 'NegReg', (73, 80))	('p53', 'Gene', (23, 26))	('DFS', 'MPA', (81, 84))	('enhanced', 'PosReg', (210, 218))	('failed', 'NegReg', (168, 174))	('p53', 'Gene', '7157', (122, 125))
91705	33611664	Histopathology and tumor receptor testing were not affected by LUM015.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LUM015', 'Chemical', '-', (63, 69))	('tumor', 'Disease', (19, 24))	('LUM015', 'Var', (63, 69))
91717	33611664	The system is also being evaluated for use in surgery for peritoneal (NCT03834272), central nervous system (NCT03717142), and prostate (NCT03441464) cancers.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('NCT03717142', 'Var', (108, 119))	('central nervous system', 'Disease', (84, 106))	('peritoneal', 'Disease', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('prostate', 'Disease', (126, 134))	('NCT03834272', 'Var', (70, 81))	('NCT03441464', 'Var', (136, 147))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
91749	33611664	The system was able to distinguish tumor from normal tissue for all breast cancer histological types, with mean T:N ratios of 3.81 for IDC +- DCIS, 3.98 for ILC +- DCIS and 5.69 for specimens with only DCIS, p = 0.25 (Table 3).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('DCIS', 'Phenotype', 'HP:0030075', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('IDC +- DCIS', 'Var', (135, 146))	('breast cancer', 'Disease', (68, 81))	('tumor', 'Disease', (35, 40))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('ILC +- DCIS', 'Var', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
91769	33611664	We evaluated the impact of LUM015 on total complement, histamine, and tryptase levels prior to injection and at 15, 30 and 60 min after injection in 10 patients who received LUM015.	('LUM015', 'Chemical', '-', (174, 180))	('histamine', 'MPA', (55, 64))	('tryptase levels', 'MPA', (70, 85))	('LUM015', 'Chemical', '-', (27, 33))	('LUM015', 'Var', (174, 180))	('histamine', 'Chemical', 'MESH:D006632', (55, 64))	('total complement', 'MPA', (37, 53))	('patients', 'Species', '9606', (152, 160))
91789	33611664	LUM015 did not impact standard histopathology processing or staining, and did not affect measurement of ER, PR and HER2 by immunohistochemistry or fluorescent in situ hybridization.	('HER2', 'Gene', (115, 119))	('PR', 'Gene', '5241', (108, 110))	('HER2', 'Gene', '2064', (115, 119))	('ER', 'Gene', '2099', (104, 106))	('LUM015', 'Chemical', '-', (0, 6))	('LUM015', 'Var', (0, 6))	('ER', 'Gene', '2099', (116, 118))
91935	22745739	Here, we describe a protocol for the efficient lentiviral transduction of cell slurries derived from precancerous MIN-O lesions, in vitro culture of "MIN-O-spheres" derived from single cell clones, and the subsequent transplantation of these spheres to produce transduced sublines suitable for optical imaging applications.	('MIN-O', 'Chemical', '-', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lentiviral', 'Var', (47, 57))	('MIN-O', 'Chemical', '-', (114, 119))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
92115	26658462	Furthermore, we show that the depletion of LAMP2 is sufficient to increase acidosis-mediated toxicity.	('increase', 'PosReg', (66, 74))	('acidosis-mediated toxicity', 'Disease', 'MESH:D000138', (75, 101))	('depletion', 'Var', (30, 39))	('LAMP2', 'Gene', (43, 48))	('acidosis-mediated toxicity', 'Disease', (75, 101))	('acidosis', 'Phenotype', 'HP:0001941', (75, 83))
92136	26658462	Further, we show that cells expressing LAMP2 are more resistant to extreme acid-induced cytotoxicity, and knockdown of LAMP2 reverses this resistance.	('LAMP2', 'Var', (39, 44))	('cytotoxicity', 'Disease', (88, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('knockdown', 'Var', (106, 115))	('LAMP2', 'Gene', (119, 124))	('more', 'PosReg', (49, 53))
92137	26658462	In vivo, short hairpin RNA (shRNA) knockdown of LAMP2 in acid-adapted cells induced a lag period before commencement of tumour growth.	('knockdown', 'Var', (35, 44))	('tumour growth', 'Disease', (120, 133))	('tumour growth', 'Disease', 'MESH:D006130', (120, 133))	('lag period', 'MPA', (86, 96))	('LAMP2', 'Gene', (48, 53))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
92140	26658462	To minimize the rate of false-positive biomarker association, parallel experiments were conducted in which the acid-adapted or acid-naive cells were labelled by growing them in SILAC 'heavy' media (13C6 lysine and 13C614N4 arginine), while the comparator cells (acid-naive or acid-adapted cells, respectively) were cultured in media containing the corresponding amino acids of naturally occuring isotopic distribution.	('13C6 lysine', 'Var', (198, 209))	('13C6 lysine', 'Chemical', '-', (198, 209))	('13C614N4 arginine', 'Chemical', '-', (214, 231))	('13C614N4 arginine', 'Var', (214, 231))
92145	26658462	These data showed that the AA MCF-7 were much more sensitive to siRNA knockdown, compared with NA cells, suggesting that they require LAMP2 for their survival much more than NA MCF-7 (also see below).	('siRNA', 'Gene', (64, 69))	('MCF-7', 'CellLine', 'CVCL:0031', (30, 35))	('knockdown', 'Var', (70, 79))	('MCF-7', 'CellLine', 'CVCL:0031', (177, 182))
92157	26658462	We also stained breast tumour xenografts from Severe Combined Immune-Deficiency (SCID) mice (immunodeficient mice that have impaired ability of making T or B lymphocytes) for LAMP2 and S100A6.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('breast tumour', 'Disease', 'MESH:D001943', (16, 29))	('Immune-Deficiency', 'Disease', 'MESH:D007153', (62, 79))	('SCID', 'Disease', 'MESH:D053632', (81, 85))	('mice', 'Species', '10090', (87, 91))	('SCID', 'Disease', (81, 85))	('Immune-Deficiency', 'Phenotype', 'HP:0002721', (62, 79))	('S100A6', 'Var', (185, 191))	('immunodeficient', 'Disease', 'MESH:D007153', (93, 108))	('mice', 'Species', '10090', (109, 113))	('immunodeficient', 'Disease', (93, 108))	('breast tumour', 'Disease', (16, 29))	('Immune-Deficiency', 'Disease', (62, 79))
92183	26658462	Five female mice were injected with LAMP2 knockdown MDA-MB-231/Luc cells (clone D5) as the experiment group and five female mice injected with non-silencing shRNA transfectants as controls.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('mice', 'Species', '10090', (124, 128))	('LAMP2', 'Gene', (36, 41))	('mice', 'Species', '10090', (12, 16))	('knockdown', 'Var', (42, 51))
92185	26658462	We observed that the tumour size was smaller in the LAMP2 knockdown group in the initial phase of tumour growth (day 1-7).	('LAMP2', 'Gene', (52, 57))	('smaller', 'NegReg', (37, 44))	('knockdown', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour growth', 'Disease', 'MESH:D006130', (98, 111))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Disease', (98, 104))	('tumour', 'Disease', (21, 27))	('tumour growth', 'Disease', (98, 111))
92187	26658462	Our results showed that LAMP2 knockdown tumours were less active and smaller at the early stages, similar to the caliper data for tumour size.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('active', 'MPA', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumour', 'Disease', (40, 46))	('tumours', 'Disease', (40, 47))	('less', 'NegReg', (53, 57))	('tumour', 'Disease', (130, 136))	('smaller', 'NegReg', (69, 76))	('knockdown', 'Var', (30, 39))	('LAMP2', 'Gene', (24, 29))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
92188	26658462	It also revealed that they have significantly fewer metastases in LAMP2 knockdown groups compared with controls.	('metastases', 'Disease', (52, 62))	('LAMP2', 'Gene', (66, 71))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('fewer', 'NegReg', (46, 51))	('knockdown', 'Var', (72, 81))
92237	26658462	Cells were cultured in heavy SILAC media (Delta6-lysine and Delta10-arginine) for eight doublings.	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('arginine', 'Chemical', 'MESH:D001120', (68, 76))	('Delta6', 'Mutation', 'c.del6', (42, 48))	('Delta10-arginine', 'Var', (60, 76))	('Delta10', 'Mutation', 'c.del10', (60, 67))	('Delta6-lysine', 'Var', (42, 55))
92258	26658462	Lysates were collected using Insect Cell Lysis Buffer (554778; BD Biosciences) and RIPA buffer containing 1 x protease inhibitor cocktail (P8340; Sigma-Aldrich).	('P8340', 'Var', (139, 144))	('RIPA buffer', 'Chemical', '-', (83, 94))	('554778', 'Var', (55, 61))
92289	26658462	A 1:400 dilution of anti-LAMP2 (#ab37024, Abcam), anti-GLUT1 and anti-S100A6 antibody (Prestige Antibodies Powered by Atlas Antibodies, Sigma-Aldrich) were used as primary antibodies.	('#ab37024', 'Var', (32, 40))	('GLUT1', 'Gene', '6513', (55, 60))	('GLUT1', 'Gene', (55, 60))
92302	21908556	Inhibiting basal-type cell movement with clinically relevant drugs blocked invasion in organotypic culture and in animals, suggesting a new treatment strategy for early-stage patients.	('Inhibiting', 'Var', (0, 10))	('blocked', 'NegReg', (67, 74))	('invasion', 'CPA', (75, 83))	('patients', 'Species', '9606', (175, 183))	('basal-type cell movement', 'CPA', (11, 35))
92316	21908556	HCC1143, HCC1806, HCC1954, HCC1569 and HCC1428 cells were a gift from Michael Peyton and John Minna (UTSW) and validated by Powerplex genotyping before use.	('HCC1806', 'CellLine', 'CVCL:1258', (9, 16))	('HCC1954', 'CellLine', 'CVCL:1259', (18, 25))	('HCC1428', 'Gene', (39, 46))	('HCC1569', 'Var', (27, 34))	('HCC1143', 'Var', (0, 7))	('HCC1569', 'CellLine', 'CVCL:1255', (27, 34))	('HCC1954', 'Var', (18, 25))	('HCC1806', 'Var', (9, 16))
92340	21908556	The HCC1806 and HCC1954 spheroids displayed intraspheroid motility whereas the HCC1428 and T47D spheroids contained proliferating cells that were not motile (Fig.	('HCC1954', 'Var', (16, 23))	('intraspheroid motility', 'CPA', (44, 66))	('HCC1954', 'CellLine', 'CVCL:1259', (16, 23))	('HCC1806', 'CellLine', 'CVCL:1258', (4, 11))	('HCC1806', 'Var', (4, 11))
92342	21908556	When co-cultured with fibroblasts, the HCC1954 and HCC1806 spheroids converted to sprouting invasion and migrated towards fibroblasts, identical to results obtained in the MCFDCIS co-culture model (Fig.	('converted', 'Reg', (69, 78))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('HCC1954', 'Var', (39, 46))	('sprouting invasion', 'CPA', (82, 100))	('HCC1806', 'Var', (51, 58))	('HCC1806', 'CellLine', 'CVCL:1258', (51, 58))	('HCC1954', 'CellLine', 'CVCL:1259', (39, 46))	('migrated towards', 'CPA', (105, 121))
92369	21908556	In addition, treatment with either PD0325901 or the epidermal growth factor receptor inhibitor Erlotinib blocked fibroblast induced invasion of both MCFDCIS and HCC1806 spheroids.	('PD0325901', 'Chemical', 'MESH:C506614', (35, 44))	('fibroblast induced invasion', 'CPA', (113, 140))	('blocked', 'NegReg', (105, 112))	('epidermal growth factor receptor', 'Gene', (52, 84))	('HCC1806', 'CellLine', 'CVCL:1258', (161, 168))	('PD0325901', 'Var', (35, 44))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('Erlotinib', 'Chemical', 'MESH:D000069347', (95, 104))
92370	21908556	Treatment of mammary fibroblasts with PD0325901 or Erlotinib did not alter fibroblast morphology or block collagen reorganization (Supplementary Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (38, 47))	('Erlotinib', 'Chemical', 'MESH:D000069347', (51, 60))	('PD0325901', 'Var', (38, 47))	('block', 'NegReg', (100, 105))
92371	21908556	By comparison, treatment with the Rho kinase inhibitor Y27632 reduced fibroblast induced collagen reorganization (Supplementary Fig.	('fibroblast induced collagen reorganization', 'CPA', (70, 112))	('Y27632', 'Chemical', 'MESH:C108830', (55, 61))	('Y27632', 'Var', (55, 61))	('reduced', 'NegReg', (62, 69))
92372	21908556	To determine if ERK1/2 activity was necessary for the fibroblast induced invasion of MCFDCIS cells in vivo, mice were treated daily with either vehicle or 25 mg/ml of the MEK1/2 inhibitor PD0325901 between day 14 and day 21 of tumor growth.	('tumor', 'Disease', (227, 232))	('PD0325901', 'Var', (188, 197))	('mice', 'Species', '10090', (108, 112))	('PD0325901', 'Chemical', 'MESH:C506614', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
92374	21908556	In contrast, the tumors in mice treated with the MEK1/2 inhibitor were both noninvasive and dramatically reduced in size (Fig.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mice', 'Species', '10090', (27, 31))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('MEK1/2', 'Gene', (49, 55))	('inhibitor', 'Var', (56, 65))	('reduced', 'NegReg', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
92391	28707729	DCIS.com cells engineered to express SOX11 showed increased ALDH activity, which is a feature of cancer stem cells.	('ALDH activity', 'MPA', (60, 73))	('cancer', 'Disease', (97, 103))	('SOX11', 'Var', (37, 42))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('increased', 'PosReg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DCIS.com', 'CellLine', 'CVCL:5552', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
92411	28707729	After trypsinization, 5 x 104 MCF10A or DCIS.com cells expressing SOX11 or control LacZ vector were resuspended in 100 mul of phosphate-buffered saline (PBS) plus 10% fetal bovine serum (FBS), and incubated with combinations of antibodies, i.e.	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('DCIS.com', 'CellLine', 'CVCL:5552', (40, 48))	('PBS', 'Chemical', '-', (153, 156))	('FBS', 'Disease', (187, 190))	('MCF10A', 'CellLine', 'CVCL:0598', (30, 36))	('bovine', 'Species', '9913', (173, 179))	('FBS', 'Disease', 'MESH:D005198', (187, 190))	('SOX11', 'Var', (66, 71))
92422	28707729	All work was carried out under UK Home Office projects (70/7413 and 70/7712) and personal licenses (090/02921, I5F252069, and IFFDC436E) following receipt of local ethical approval from the Institute of Cancer Research Ethics Committee and in accordance with local and national guidelines.	('090/02921', 'Var', (100, 109))	('Cancer', 'Disease', (203, 209))	('I5F252069', 'Var', (111, 120))	('FD', 'Disease', 'MESH:D004402', (128, 130))	('70/7413', 'Var', (56, 63))	('Cancer', 'Disease', 'MESH:D009369', (203, 209))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('70/7712', 'Var', (68, 75))
92438	28707729	To study the effects of expressing SOX11 in a normal MEC line, we stably transduced SOX11 into MCF10A cells (Figure 1C), and were able to detect nuclear SOX11 expression in MCF10A-SOX11 cells (Figure 1D).	('MEC', 'Gene', '56477', (53, 56))	('MCF10A', 'CellLine', 'CVCL:0598', (173, 179))	('MEC', 'Gene', (53, 56))	('detect', 'Reg', (138, 144))	('expression', 'Species', '29278', (159, 169))	('SOX11', 'Gene', (153, 158))	('SOX11', 'Gene', (84, 89))	('transduced', 'Var', (73, 83))	('MCF10A', 'CellLine', 'CVCL:0598', (95, 101))
92442	28707729	An increase in the EpCAM-/CD49f + basal-like population was observed among MCF10A-SOX11 cells (27.44 +- 14.58%) as compared with MCF10A-control cells (11.38 +- 7.69%) (Figure 1E).	('MCF10A', 'CellLine', 'CVCL:0598', (129, 135))	('EpCAM', 'Gene', (19, 24))	('CD49f', 'Gene', (26, 31))	('MCF10A', 'CellLine', 'CVCL:0598', (75, 81))	('EpCAM', 'Gene', '4072', (19, 24))	('MCF10A-SOX11', 'Var', (75, 87))	('increase', 'PosReg', (3, 11))	('CD49f', 'Gene', '3655', (26, 31))
92443	28707729	ALDH activity was 1.76-fold greater in EpCAM-/CD49f + basal-like MCF10A-SOX11 cells than in MCF10A-control cells, suggesting an expanded population associated with stem cell properties (Figure IF; supplementary material, Figure S1).	('MCF10A', 'CellLine', 'CVCL:0598', (65, 71))	('MCF10A-SOX11', 'Var', (65, 77))	('greater', 'PosReg', (28, 35))	('CD49f', 'Gene', '3655', (46, 51))	('EpCAM', 'Gene', (39, 44))	('MCF10A', 'CellLine', 'CVCL:0598', (92, 98))	('activity', 'MPA', (5, 13))	('EpCAM', 'Gene', '4072', (39, 44))	('ALDH', 'Enzyme', (0, 4))	('CD49f', 'Gene', (46, 51))
92444	28707729	EpCAM-/CD49f+/ALDH+ cells were detected at 4.26-fold greater frequency among MCF10-SOX11 cells than among MCF10A-control cells.	('MCF10-SOX11', 'Var', (77, 88))	('EpCAM', 'Gene', '4072', (0, 5))	('CD49f', 'Gene', '3655', (7, 12))	('MCF10', 'CellLine', 'CVCL:5555', (77, 82))	('MCF10', 'CellLine', 'CVCL:5555', (106, 111))	('CD49f', 'Gene', (7, 12))	('EpCAM', 'Gene', (0, 5))	('MCF10A', 'CellLine', 'CVCL:0598', (106, 112))
92445	28707729	We observed a slight but significant reduction in cell growth in MCF10A-SOX11 cells as compared with MCF10A-LacZ cells (Figure 2A).	('MCF10A-LacZ', 'CellLine', 'CVCL:5657', (101, 112))	('MCF10A', 'CellLine', 'CVCL:0598', (65, 71))	('MCF10A-SOX11', 'Var', (65, 77))	('reduction', 'NegReg', (37, 46))	('cell growth', 'CPA', (50, 61))	('MCF10A', 'CellLine', 'CVCL:0598', (101, 107))
92446	28707729	Morphological differences were observed when MCF10A-SOX11 mammospheres were compared with MCF10A-LacZ control mammospheres grown under a variety of culture conditions; MCF10A-SOX11 mammospheres appeared more compact and solid than controls (Figure 2B; supplementary material, Figure S2A, B).	('MCF10A', 'CellLine', 'CVCL:0598', (45, 51))	('MCF10A', 'CellLine', 'CVCL:0598', (90, 96))	('MCF10A-SOX11', 'Var', (168, 180))	('more', 'PosReg', (203, 207))	('MCF10A-LacZ', 'CellLine', 'CVCL:5657', (90, 101))	('MCF10A', 'CellLine', 'CVCL:0598', (168, 174))
92447	28707729	These observations are compatible with SOX11 altering the growth features of normal MECs, as we hypothesized on the basis of clinical data.	('MEC', 'Gene', '56477', (84, 87))	('MEC', 'Gene', (84, 87))	('altering', 'Reg', (45, 53))	('SOX11', 'Var', (39, 44))	('growth', 'MPA', (58, 64))
92449	28707729	MCF10A-SOX11 cells have greater mammosphere-forming capacity and produce mammospheres with phenotypes that are distinguishable from those of MCF10A-control cells (Figure 2C, D).	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('MCF10A-SOX11', 'Var', (0, 12))	('greater', 'PosReg', (24, 31))	('mammosphere-forming capacity', 'CPA', (32, 60))	('mammospheres', 'CPA', (73, 85))	('MCF10A', 'CellLine', 'CVCL:0598', (141, 147))
92450	28707729	CC3 levels were slightly reduced in MCF10A-SOX11 mammospheres as compared with MCF10A-control mammospheres (Figure 2E).	('reduced', 'NegReg', (25, 32))	('MCF10A', 'CellLine', 'CVCL:0598', (79, 85))	('CC3', 'Chemical', '-', (0, 3))	('MCF10A', 'CellLine', 'CVCL:0598', (36, 42))	('MCF10A-SOX11', 'Var', (36, 48))	('CC3 levels', 'MPA', (0, 10))
92455	28707729	We detected lower levels of caspase-3 activity in DCIS-SOX11 spheroids than in DCIS-control spheroids (Figure 3C, D).	('activity', 'MPA', (38, 46))	('DCIS-SOX11', 'Var', (50, 60))	('caspase-3', 'Gene', '836', (28, 37))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('caspase-3', 'Gene', (28, 37))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('lower', 'NegReg', (12, 17))
92459	28707729	Cell migration through collagen was significantly enhanced in DCIS-SOX11 cells as compared with control cells in a Transwell assays (supplementary material, Figure S5A).	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('DCIS-SOX11', 'Var', (62, 72))	('enhanced', 'PosReg', (50, 58))	('S5A', 'Gene', (164, 167))	('Cell migration through collagen', 'CPA', (0, 31))	('S5A', 'Gene', '5710', (164, 167))
92461	28707729	We measured levels of melanoma inhibitory activity (MIA), encoded by a gene in the PAM50 test, which are characteristically high in basal-like breast cancer, and are decreased upon small interfering RNA-mediated knockdown of SOX11 in breast cancer cells, in a recent study 25.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('PAM50', 'Gene', (83, 88))	('breast cancer', 'Disease', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('breast cancer', 'Disease', (234, 247))	('MIA', 'Gene', '8190', (52, 55))	('melanoma inhibitory activity', 'Gene', (22, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('decreased', 'NegReg', (166, 175))	('knockdown', 'Var', (212, 221))	('SOX11', 'Gene', (225, 230))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma inhibitory activity', 'Gene', '8190', (22, 50))	('high', 'PosReg', (124, 128))	('MIA', 'Gene', (52, 55))
92463	28707729	We found that DCIS-SOX11 cells expressed over four-fold greater levels of MIA than DCIS-LacZ control cells (supplementary material, Figure S6).	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('MIA', 'Gene', (74, 77))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('greater', 'PosReg', (56, 63))	('MIA', 'Gene', '8190', (74, 77))	('DCIS-SOX11', 'Var', (14, 24))
92483	28707729	Quantitative polymerase chain reaction (qPCR) analysis revealed higher levels of SOX11, FHAD1, HORMAD1 and TFAP2B expression in DCIS-SOX11 than in DCIS-LacZ tumours (Figure 5A).	('TFAP2B', 'Gene', '7021', (107, 113))	('HORMAD1', 'Gene', '84072', (95, 102))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('FHAD1', 'Gene', (88, 93))	('higher', 'PosReg', (64, 70))	('DCIS-LacZ tumours', 'Disease', 'MESH:D002285', (147, 164))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('levels', 'MPA', (71, 77))	('FHAD1', 'Gene', '114827', (88, 93))	('expression', 'Species', '29278', (114, 124))	('expression', 'MPA', (114, 124))	('DCIS-LacZ tumours', 'Disease', (147, 164))	('SOX11', 'Gene', (81, 86))	('TFAP2B', 'Gene', (107, 113))	('HORMAD1', 'Gene', (95, 102))	('DCIS-SOX11', 'Var', (128, 138))
92487	28707729	ALDH1A1+ cells were detected in DCIS lesions from ER-/SOX11+ DCIS cases (supplementary material, Figure S8).	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('ALDH1A1', 'Gene', '216', (0, 7))	('DCIS lesions', 'Disease', (32, 44))	('ER-/SOX11+', 'Var', (50, 60))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('ALDH1A1', 'Gene', (0, 7))
92492	28707729	Our findings show that engineering SOX11 expression in MCF10A cells significantly alters progenitor cell features and confers distinct traits on mature postnatal MECs.	('expression', 'Species', '29278', (41, 51))	('MCF10A', 'CellLine', 'CVCL:0598', (55, 61))	('alters', 'Reg', (82, 88))	('SOX11', 'Gene', (35, 40))	('engineering', 'Var', (23, 34))	('MEC', 'Gene', '56477', (162, 165))	('expression', 'Var', (41, 51))	('progenitor cell features', 'CPA', (89, 113))	('MEC', 'Gene', (162, 165))
92495	28707729	These findings suggest that SOX11 expression in mature MECs increases the size of a population of cells with features of both basal and luminal lineages.	('SOX11', 'Gene', (28, 33))	('expression', 'Var', (34, 44))	('MEC', 'Gene', '56477', (55, 58))	('size of a population of cells', 'CPA', (74, 103))	('increases', 'PosReg', (60, 69))	('MEC', 'Gene', (55, 58))	('expression', 'Species', '29278', (34, 44))
92501	28707729	ALDH1A1 plays a role in the proliferation and differentiation of mammary progenitor cells in the normal breast; clonogenicity is decreased upon ALDH1A1 knockdown 34.	('clonogenicity', 'CPA', (112, 125))	('ALDH1A1', 'Gene', (144, 151))	('ALDH1A1', 'Gene', '216', (0, 7))	('knockdown 34', 'Var', (152, 164))	('ALDH1A1', 'Gene', '216', (144, 151))	('decreased', 'NegReg', (129, 138))	('ALDH1A1', 'Gene', (0, 7))
92503	28707729	Mutations in TFAP2B cause Char syndrome, a disorder characterized by defective heart, craniofacial and limb development 36.	('craniofacial', 'Disease', (86, 98))	('cause', 'Reg', (20, 25))	('craniofacial', 'Disease', 'MESH:D019465', (86, 98))	('TFAP2B', 'Gene', (13, 19))	('a disorder', 'Disease', (41, 51))	('Mutations', 'Var', (0, 9))	('Char syndrome', 'Disease', (26, 39))	('a disorder', 'Disease', 'MESH:D030342', (41, 51))	('Char syndrome', 'Disease', 'MESH:C566815', (26, 39))	('TFAP2B', 'Gene', '7021', (13, 19))	('defective heart', 'Phenotype', 'HP:0001627', (69, 84))
92522	28707729	High-level SOX11 expression is associated with poor overall survival in all breast cancer patients 9 and a poor outcome in patients with lymph node-negative disease, a group that normally has a good predicted outcome.	('expression', 'Species', '29278', (17, 27))	('SOX11', 'Gene', (11, 16))	('High-level', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('poor', 'NegReg', (47, 51))	('overall', 'MPA', (52, 59))	('patients', 'Species', '9606', (123, 131))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('patients', 'Species', '9606', (90, 98))
92530	28707729	Examples of mammospheres formed from MCF10A-LacZ and MCF10A-SOX11 cells  Figure S3.	('MCF10A-LacZ', 'Var', (37, 48))	('MCF10A-LacZ', 'CellLine', 'CVCL:5657', (37, 48))	('MCF10A', 'CellLine', 'CVCL:0598', (53, 59))	('MCF10A', 'CellLine', 'CVCL:0598', (37, 43))	('mammospheres formed', 'CPA', (12, 31))	('MCF10A-SOX11', 'Var', (53, 65))
92531	28707729	Frequency of CD44+/CD24+/ALDH+ cells in DCIS-SOX11 compared to DCIS-control populations  Figure S5.	('CD24', 'Gene', '100133941', (19, 23))	('CD24', 'Gene', (19, 23))	('DCIS-SOX11', 'Var', (40, 50))	('CD44', 'Gene', '960', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('CD44', 'Gene', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))
92544	26555555	Compared to CS + RT + TAM, a significantly higher invasive LR was observed for CS(alone), odds ratio (OR) 2.61 (P < 0.0001); CS + TAM(no RT), OR 2.52 (P = 0.001); CS + RT(no TAM), OR 1.59 (P = 0.022).	('CS', 'Chemical', '-', (12, 14))	('CS + RT', 'Chemical', '-', (12, 19))	('invasive LR', 'CPA', (50, 61))	('CS + TAM', 'Var', (125, 133))	('higher', 'PosReg', (43, 49))	('TAM', 'Chemical', 'MESH:D013629', (22, 25))	('CS + TAM', 'Chemical', '-', (125, 133))	('TAM', 'Chemical', 'MESH:D013629', (174, 177))	('TAM', 'Chemical', 'MESH:D013629', (130, 133))	('CS + RT', 'Chemical', '-', (163, 170))	('CS', 'Chemical', '-', (125, 127))	('CS', 'Chemical', '-', (79, 81))	('CS', 'Chemical', '-', (163, 165))
92550	26555555	Our earlier meta-analysis yielded summary ipsilateral local recurrence (LR)-rates of 22.5 % for breast-conserving surgery (BCS), 8.9 % for BCS and radiotherapy (RT), and 1.4 % for mastectomy (Mx), with average follow-ups of 68, 62 and 80 months, respectively.	('CS', 'Chemical', '-', (140, 142))	('mastectomy', 'Disease', (180, 190))	('breast-conserving surgery', 'Disease', (96, 121))	('BCS', 'Var', (139, 142))	('CS', 'Chemical', '-', (124, 126))
92577	26555555	Significantly higher rates of total LR occurred in patients treated with CS(alone), 25.1 %; CS + TAM(no RT) 24.7 %; and a non-significantly higher rate was seen in CS + RT(no TAM) 14.1 % (Table 3).	('TAM', 'Chemical', 'MESH:D013629', (97, 100))	('higher rates', 'PosReg', (14, 26))	('CS + RT', 'Chemical', '-', (164, 171))	('CS', 'Chemical', '-', (92, 94))	('CS', 'Chemical', '-', (164, 166))	('CS + TAM', 'Var', (92, 100))	('CS + TAM', 'Chemical', '-', (92, 100))	('TAM', 'Chemical', 'MESH:D013629', (175, 178))	('patients', 'Species', '9606', (51, 59))	('CS', 'Chemical', '-', (73, 75))
92582	26555555	Statistical significance was observed for differences in invasive LR between CS + RT + TAM and the adjuvant treatment CS + RT(no TAM) (OR = 1.59).	('TAM', 'Chemical', 'MESH:D013629', (87, 90))	('invasive LR', 'CPA', (57, 68))	('CS + RT + TAM', 'Var', (77, 90))	('TAM', 'Chemical', 'MESH:D013629', (129, 132))	('CS + RT', 'Chemical', '-', (118, 125))	('CS + RT', 'Chemical', '-', (77, 84))
92583	26555555	A trend for a higher invasive LR rate was demonstrated for the CS + TAM(no RT) group compared to CS + RT(no TAM) (OR = 1.59, CI 0.99-2.55; P = 0.055).	('TAM', 'Chemical', 'MESH:D013629', (108, 111))	('invasive LR rate', 'CPA', (21, 37))	('CS + TAM', 'Chemical', '-', (63, 71))	('TAM', 'Chemical', 'MESH:D013629', (68, 71))	('CS + RT', 'Chemical', '-', (97, 104))	('CS + TAM', 'Var', (63, 71))	('higher', 'PosReg', (14, 20))
92592	26555555	Those who have CS + RT + TAM demonstrate significantly lower invasive LR-rates (4.7 %) than those who receive CS(alone) and only one adjuvant treatment (TAM 11.0 %, RT 7.2 %).	('CS + RT + TAM', 'Var', (15, 28))	('CS + RT', 'Chemical', '-', (15, 22))	('CS', 'Chemical', '-', (15, 17))	('invasive LR-rates', 'CPA', (61, 78))	('TAM', 'Chemical', 'MESH:D013629', (153, 156))	('lower', 'NegReg', (55, 60))	('TAM', 'Chemical', 'MESH:D013629', (25, 28))	('CS', 'Chemical', '-', (110, 112))
92597	26555555	Our study highlights even longer periods of follow-up may be necessary to detect survival differences from local therapies, given the average time to ipsilateral invasive breast cancer recurrence for low-intermediate grade DCIS is 131 months and high grade, 76-months.	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (150, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('ipsilateral invasive breast cancer', 'Disease', (150, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('low-intermediate grade', 'Var', (200, 222))
92602	26555555	Our early meta-analysis recommended the addition of RT to BCS to lower ipsilateral LR risk, particularly in tumors with necrosis, high-grade cytological features, a comedo subtype, or close/positive surgical margins.	('necrosis', 'Disease', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('high-grade cytological', 'Var', (130, 152))	('ipsilateral', 'MPA', (71, 82))	('lower', 'NegReg', (65, 70))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('comedo', 'Phenotype', 'HP:0025249', (165, 171))	('CS', 'Chemical', '-', (59, 61))
92623	26555555	Factors that may influence non-use of TAM include: ER-negative DCIS, patients with a high risk of subsequent complications such as deep venous thrombosis, probability of menopausal symptoms and endometrial cancer (especially age >65 years), particularly when LR-risk is low.	('menopausal symptoms', 'Disease', (170, 189))	('TAM', 'Chemical', 'MESH:D013629', (38, 41))	('deep venous thrombosis', 'Phenotype', 'HP:0002625', (131, 153))	('DCIS', 'Disease', (63, 67))	('ER-negative', 'Var', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('endometrial cancer', 'Disease', (194, 212))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('venous thrombosis', 'Phenotype', 'HP:0004936', (136, 153))	('deep venous thrombosis', 'Disease', (131, 153))	('deep venous thrombosis', 'Disease', 'MESH:D020246', (131, 153))	('endometrial cancer', 'Phenotype', 'HP:0012114', (194, 212))	('patients', 'Species', '9606', (69, 77))	('endometrial cancer', 'Disease', 'MESH:D016889', (194, 212))
92633	26555555	In EORTC data, patients with ipsilateral invasive LR had a significantly worse breast cancer-specific survival at 60 % (HR,17.66) and overall survival (HR,5.17) ten years after LR, compared to those who had ipsilateral DCIS LR or did not experience a recurrence, with breast cancer-specific survival around 95 % (P < 0.001) highlighting that treatment strategy minimizing invasive recurrence is important for some patients.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (414, 422))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DCIS', 'Phenotype', 'HP:0030075', (219, 223))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('worse', 'NegReg', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('breast cancer', 'Disease', (268, 281))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('ipsilateral', 'Var', (29, 40))	('overall survival', 'CPA', (134, 150))
92639	31519911	Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood.	('mutation', 'Var', (53, 61))	('breast tumor', 'Disease', 'MESH:D001943', (215, 227))	('BRCA', 'Gene', (48, 52))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (78, 102))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('ductal carcinoma', 'Disease', 'MESH:D044584', (287, 303))	('breast tumor', 'Phenotype', 'HP:0100013', (215, 227))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (287, 311))	('epithelia', 'Disease', 'None', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('breast tumor', 'Disease', (215, 227))	('ductal carcinoma', 'Disease', 'MESH:D044584', (78, 94))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (78, 102))	('ductal carcinoma in situ', 'Disease', (287, 311))	('epithelia', 'Disease', 'None', (106, 115))	('epithelia', 'Disease', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('BRCA', 'Gene', '672', (48, 52))	('ductal carcinoma in situ', 'Disease', (78, 102))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (287, 311))	('epithelia', 'Disease', (106, 115))
92641	31519911	We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes.	('p63', 'Var', (142, 145))	('epithelia', 'Disease', 'None', (55, 64))	('p63', 'Gene', (98, 101))	('epithelia', 'Disease', (55, 64))	('associated', 'Reg', (188, 198))	('TCF7', 'Gene', (150, 154))	('TCF7 transcription factors', 'Gene', (106, 132))
92642	31519911	In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap.	('epithelia', 'Disease', 'None', (95, 104))	('mutation', 'Var', (47, 55))	('BRCA1', 'Gene', (41, 46))	('epithelia', 'Disease', (95, 104))	('p63+TCF7+', 'Var', (82, 91))	('decreased', 'NegReg', (129, 138))
92644	31519911	The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.	('decreased', 'NegReg', (68, 77))	('epithelia', 'Disease', 'None', (29, 38))	('epithelia', 'Disease', (29, 38))	('p63+TCF7+', 'Var', (16, 25))	('DCIS', 'Disease', (81, 85))
92646	31519911	Here, the authors show that p63 and TCF7 cooperate to regulate a transcription factor network for the maintenance of normal myoepithelial function and altered expression of these genes perturb myoepithelial function in DCIS to promote invasive progression.	('altered', 'Var', (151, 158))	('TCF7', 'Gene', (36, 40))	('regulate', 'Reg', (54, 62))	('perturb', 'NegReg', (185, 192))	('myoepithelial function', 'Disease', (124, 146))	('expression', 'Species', '29278', (159, 169))	('myoepithelial function', 'Disease', 'MESH:D009208', (124, 146))	('myoepithelial function', 'Disease', (193, 215))	('myoepithelial function', 'Disease', 'MESH:D009208', (193, 215))	('promote', 'PosReg', (227, 234))	('invasive progression', 'CPA', (235, 255))
92666	31519911	Luminal differentiation was shown to be perturbed in BRCA1 mutation carriers, but myoepithelial cells and BRCA2 mutation carriers have not been investigated.	('Luminal differentiation', 'CPA', (0, 23))	('perturbed', 'Reg', (40, 49))	('epithelia', 'Disease', 'None', (85, 94))	('mutation', 'Var', (59, 67))	('epithelia', 'Disease', (85, 94))	('BRCA2', 'Gene', (106, 111))	('BRCA2', 'Gene', '675', (106, 111))	('BRCA1', 'Gene', (53, 58))
92669	31519911	Our results suggest that a transcriptional program orchestrated by p63 and TCF7 is required for a normal differentiated myoepithelial cell phenotype and perturbations of this may contribute to the increased breast cancer risk of BRCA mutation carriers, and it may lead to the loss of myoepithelial cells in DCIS promoting progression to invasion.	('perturbations', 'Var', (153, 166))	('progression to invasion', 'CPA', (322, 345))	('epithelia', 'Disease', 'None', (287, 296))	('epithelia', 'Disease', (287, 296))	('mutation', 'Var', (234, 242))	('contribute', 'Reg', (179, 189))	('epithelia', 'Disease', 'None', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('TCF7', 'Gene', (75, 79))	('BRCA', 'Gene', (229, 233))	('BRCA', 'Gene', '672', (229, 233))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('epithelia', 'Disease', (123, 132))	('breast cancer', 'Disease', (207, 220))
92671	31519911	We analyzed normal breast tissues of nulliparous and parous women, as pregnancy and lactation may impact cellular phenotypes, from reduction mammoplasties and from prophylactic mastectomy tissues of BRCA1 and BRCA2 mutation carriers (Supplementary Data 1).	('mutation', 'Var', (215, 223))	('BRCA2', 'Gene', '675', (209, 214))	('BRCA1', 'Gene', (199, 204))	('cellular phenotypes', 'MPA', (105, 124))	('women', 'Species', '9606', (60, 65))	('impact', 'Reg', (98, 104))	('BRCA2', 'Gene', (209, 214))	('lactation', 'Disease', (84, 93))	('lactation', 'Disease', 'MESH:D007775', (84, 93))
92676	31519911	Quantification of the relative fraction of total CD10+ cells and CD10+CD44- and CD10+CD44+ subpopulations demonstrated a significant decrease in CD10+ cells in BRCA1 mutation carriers (Fig.	('BRCA1', 'Gene', (160, 165))	('CD44', 'Gene', (70, 74))	('decrease', 'NegReg', (133, 141))	('CD44', 'Gene', '960', (85, 89))	('CD44', 'Gene', (85, 89))	('CD44', 'Gene', '960', (70, 74))	('mutation', 'Var', (166, 174))	('CD10+', 'MPA', (145, 150))
92677	31519911	CyTOF analysis of non-carrier (n = 6), BRCA1 (n = 6), and BRCA2 (n = 7) samples using myoepithelial, luminal, basal, and progenitor markers also demonstrated significant differences with a decrease in SMA+CD10+ myoepithelial cells and diminished expression of SMA, CD10, CD44, and CD49f in BRCA1 mutation carriers (Fig.	('epithelia', 'Disease', 'None', (214, 223))	('BRCA1', 'Gene', (290, 295))	('diminished', 'NegReg', (235, 245))	('BRCA2', 'Gene', '675', (58, 63))	('epithelia', 'Disease', (214, 223))	('SMA', 'MPA', (260, 263))	('CD44', 'Gene', '960', (271, 275))	('epithelia', 'Disease', 'None', (89, 98))	('CD49f', 'Var', (281, 286))	('SMA+CD10+', 'MPA', (201, 210))	('decrease', 'NegReg', (189, 197))	('CD10', 'MPA', (265, 269))	('epithelia', 'Disease', (89, 98))	('expression', 'Species', '29278', (246, 256))	('BRCA2', 'Gene', (58, 63))	('CD44', 'Gene', (271, 275))	('expression', 'MPA', (246, 256))	('mutation', 'Var', (296, 304))
92679	31519911	These data suggest that the phenotype of myoepithelial cells is distinct between normal tissues of non-carrier and BRCA mutation-carrier women.	('epithelia', 'Disease', 'None', (44, 53))	('epithelia', 'Disease', (44, 53))	('BRCA', 'Gene', '672', (115, 119))	('BRCA', 'Gene', (115, 119))	('women', 'Species', '9606', (137, 142))	('mutation-carrier', 'Var', (120, 136))
92683	31519911	Next, we profiled CD10+ cells from BRCA1 and BRCA2 mutation carriers and compared them to non-carriers.	('BRCA2', 'Gene', (45, 50))	('BRCA1', 'Gene', (35, 40))	('mutation', 'Var', (51, 59))	('BRCA2', 'Gene', '675', (45, 50))
92684	31519911	Genes highly expressed in BRCA1-mutant CD10+ cells were enriched in DNA replication-related functions, whereas BRCA2-mutant CD10+ cells showed a decrease in keratins and an increase in immune-related genes (Supplementary Fig.	('BRCA2', 'Gene', (111, 116))	('keratins', 'Protein', (157, 165))	('BRCA2', 'Gene', '675', (111, 116))	('BRCA1-mutant', 'Var', (26, 38))	('increase', 'PosReg', (173, 181))	('immune-related genes', 'Gene', (185, 205))	('BRCA1-mutant', 'Gene', (26, 38))	('decrease', 'NegReg', (145, 153))
92686	31519911	Among these TFs, TP63 and TCF7 were particularly interesting, since p63 plays key roles in epithelial progenitors, whereas TCF7 regulates WNT signaling and its deletion in mice leads to mammary gland adenomas.	('adenomas', 'Disease', 'MESH:D000236', (200, 208))	('deletion', 'Var', (160, 168))	('regulates WNT signaling', 'MPA', (128, 151))	('adenomas', 'Disease', (200, 208))	('epithelia', 'Disease', 'None', (91, 100))	('epithelia', 'Disease', (91, 100))	('mice', 'Species', '10090', (172, 176))	('TCF7', 'Gene', (123, 127))	('leads to', 'Reg', (177, 185))
92687	31519911	Based on RNA-seq we detected DeltaNp63 and the long isoform of TCF7 in normal myoepithelial cells (Supplementary Fig.	('detected', 'Reg', (20, 28))	('DeltaNp63', 'Var', (29, 38))	('epithelia', 'Disease', 'None', (81, 90))	('epithelia', 'Disease', (81, 90))	('TCF7', 'Gene', (63, 67))
92690	31519911	We found that in control non-carrier women and in BRCA2 mutation carriers the majority of CD10+ myoepithelial cells were p63+TCF7+, but in BRCA1 mutation carriers the expression of p63 and TCF7 decreased, and co-localization was less frequent (Fig.	('p63+TCF7+', 'Var', (121, 130))	('women', 'Species', '9606', (37, 42))	('BRCA1', 'Gene', (139, 144))	('epithelia', 'Disease', 'None', (99, 108))	('epithelia', 'Disease', (99, 108))	('BRCA2', 'Gene', (50, 55))	('BRCA2', 'Gene', '675', (50, 55))	('decreased', 'NegReg', (194, 203))	('mutation', 'Var', (56, 64))	('expression', 'Species', '29278', (167, 177))	('expression', 'MPA', (167, 177))	('mutation', 'Var', (145, 153))
92691	31519911	These data indicate altered myoepithelial cell phenotypes in BRCA1 mutation carriers and suggest key roles for p63 and TCF7 in normal myoepithelial cell differentiation.	('BRCA1', 'Gene', (61, 66))	('mutation', 'Var', (67, 75))	('altered', 'Reg', (20, 27))	('epithelia', 'Disease', 'None', (137, 146))	('epithelia', 'Disease', (137, 146))	('epithelia', 'Disease', 'None', (31, 40))	('epithelia', 'Disease', (31, 40))
92694	31519911	We found that in DCIS the majority of CD10+ cells were also CD44+ (Fig.	('CD10+', 'Var', (38, 43))	('CD44', 'Gene', (60, 64))	('CD44', 'Gene', '960', (60, 64))
92696	31519911	We also performed immunofluorescence analysis of p63 and TCF7 expression in pure DCIS, DCIS adjacent to IDC, and IDC.	('TCF7', 'Gene', (57, 61))	('expression', 'Species', '29278', (62, 72))	('p63', 'Var', (49, 52))	('pure DCIS', 'Disease', (76, 85))
92697	31519911	Instead, a subset of DCIS tumor epithelial cells was TCF7+.	('DCIS', 'Disease', (21, 25))	('epithelia', 'Disease', 'None', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('epithelia', 'Disease', (32, 41))	('TCF7+', 'Var', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
92701	31519911	Metaplastic breast tumors are the only breast cancer subset that relatively commonly have mutations in the APC/beta-catenin pathway and the expression of TCF7 could be due to its induction by WNT/beta-catenin signaling.	('expression', 'Species', '29278', (140, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('mutations', 'Var', (90, 99))	('breast tumors', 'Disease', 'MESH:D001943', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('breast tumors', 'Disease', (12, 25))	('APC', 'Disease', 'MESH:D011125', (107, 110))	('TCF7', 'Gene', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('breast tumor', 'Phenotype', 'HP:0100013', (12, 24))	('APC', 'Disease', (107, 110))	('breast cancer', 'Disease', (39, 52))	('breast tumors', 'Phenotype', 'HP:0100013', (12, 25))
92704	31519911	We identified significant differences in both p63 and TCF7 genomic binding between control and BRCA mutation carriers (Fig.	('BRCA', 'Gene', (95, 99))	('differences', 'Reg', (26, 37))	('p63', 'Protein', (46, 49))	('TCF7', 'Gene', (54, 58))	('genomic binding', 'Interaction', (59, 74))	('mutation', 'Var', (100, 108))	('BRCA', 'Gene', '672', (95, 99))
92707	31519911	Mitosis and DNA damage checkpoint pathways were more significantly enriched in BRCA1 mutation carriers potentially due to DNA repair defects even in BRCA1+/- cells (Fig.	('Mitosis', 'Disease', 'None', (0, 7))	('Mitosis', 'Disease', (0, 7))	('enriched', 'Reg', (67, 75))	('BRCA1', 'Gene', (79, 84))	('defects', 'NegReg', (133, 140))	('mutation', 'Var', (85, 93))	('DNA damage checkpoint pathways', 'Pathway', (12, 42))
92717	31519911	Thus, while MCF10DCIS cells are tumorigenic, they have the ability to differentiate into cells with myoepithelial features making them useful for the analysis of this process.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MCF10DCIS', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('epithelia', 'Disease', 'None', (103, 112))	('tumor', 'Disease', (32, 37))	('epithelia', 'Disease', (103, 112))
92718	31519911	We previously showed that MCF10DCIS cells express DeltaNp63 and in cell culture virtually all cells are p63+, while in DCIS-like xenografts only the myoepithelial cells remain p63+.	('epithelia', 'Disease', (152, 161))	('DeltaNp63', 'Var', (50, 59))	('MCF10DCIS', 'Var', (26, 35))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (26, 35))	('p63+', 'Var', (104, 108))	('epithelia', 'Disease', 'None', (152, 161))
92727	31519911	Unexpectedly, myoepithelial cells of DCIS-like tumors were weakly p63+ in all cases except in intraductal tumors implying escape from shRNA effect (Fig.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('intraductal tumors', 'Disease', 'MESH:D002285', (94, 112))	('intraductal tumors', 'Disease', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('epithelia', 'Disease', 'None', (17, 26))	('epithelia', 'Disease', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p63+', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
92733	31519911	We found that mTOR (rapamycin), Hh (sonidegib), and WNT (XAV939) inhibitors had no effect on p63 protein levels, while treatment with TGFBR (LY2157299), MEK/ERK (PD0325901), SRC (dasatinib), FAK (Y15), and Hippo (verteporfin) inhibitors lead to a significant decrease (Fig.	('mTOR', 'Gene', '2475', (14, 18))	('FAK', 'Gene', (191, 194))	('FAK', 'Gene', '5747', (191, 194))	('p63 protein levels', 'MPA', (93, 111))	('LY2157299', 'CellLine', 'CVCL:2097', (141, 150))	('dasatinib', 'Chemical', 'MESH:D000069439', (179, 188))	('SRC', 'Gene', '6714', (174, 177))	('LY2157299', 'Var', (141, 150))	('SRC', 'Gene', (174, 177))	('verteporfin', 'Chemical', 'MESH:D000077362', (213, 224))	('MEK', 'Gene', (153, 156))	('Hippo', 'Chemical', '-', (206, 211))	('MEK', 'Gene', '5609', (153, 156))	('mTOR', 'Gene', (14, 18))	('decrease', 'NegReg', (259, 267))
92737	31519911	Normal myoepithelial-specific genes including ACTA2 and several TFs highly expressed in CD10+CD44- cells (e.g., TCF7, IRF6, TRIM29) were also direct targets of p63 in MCF10DCIS cells.	('TRIM29', 'Gene', (124, 130))	('ACTA2', 'Gene', (46, 51))	('IRF6', 'Gene', (118, 122))	('ACTA2', 'Gene', '59', (46, 51))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (167, 176))	('p63', 'Var', (160, 163))	('epithelia', 'Disease', 'None', (10, 19))	('TCF7', 'Gene', (112, 116))	('epithelia', 'Disease', (10, 19))	('CD44', 'Gene', '960', (93, 97))	('TRIM29', 'Gene', '23650', (124, 130))	('CD44', 'Gene', (93, 97))
92738	31519911	Overall, we identified 1,233 p63 targets that were common between MCF10DCIS cells and normal myoepithelium suggesting that this model reproduces at least some aspects of normal myoepithelial cell differentiation.	('MCF10DCIS', 'Var', (66, 75))	('epithelia', 'Disease', (180, 189))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (66, 75))	('epithelia', 'Disease', 'None', (180, 189))
92741	31519911	As expected, genes nearest to SEs showed higher gene expression levels, and we also observed a significant enrichment of p63 peaks in higher ranking SEs (Supplementary Fig.	('p63', 'Var', (121, 124))	('SEs', 'Chemical', 'MESH:D012643', (30, 33))	('expression', 'Species', '29278', (53, 63))	('higher', 'PosReg', (41, 47))	('gene expression levels', 'MPA', (48, 70))	('SEs', 'Chemical', 'MESH:D012643', (149, 152))
92747	31519911	3d), which is consistent with the apparent decrease in cell proliferation after shTP63 expression (Supplementary Fig.	('decrease', 'NegReg', (43, 51))	('expression', 'Var', (87, 97))	('expression', 'Species', '29278', (87, 97))	('shTP63', 'Gene', (80, 86))	('cell proliferation', 'CPA', (55, 73))
92748	31519911	These data demonstrate that p63 is required for myoepithelial cell features and is a major regulator of the enhancer landscape in the MCF10DCIS model.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (134, 143))	('epithelia', 'Disease', (51, 60))	('epithelia', 'Disease', 'None', (51, 60))	('MCF10DCIS', 'Var', (134, 143))
92749	31519911	Although TCF7 and p63 are co-expressed in normal myoepithelial cells, we were not able to detect TCF7 expression in MCF10DCIS cells neither in cell culture nor in xenografts suggesting that MCF10DCIS cells do not fully recapitulate the normal differentiated myoepithelial cell phenotype (Fig.	('epithelia', 'Disease', 'None', (52, 61))	('expression', 'Species', '29278', (102, 112))	('MCF10DCIS', 'Var', (190, 199))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (190, 199))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (116, 125))	('epithelia', 'Disease', 'None', (261, 270))	('epithelia', 'Disease', (261, 270))	('epithelia', 'Disease', (52, 61))
92756	31519911	Expression of TCF7 decreased tumor size regardless of injection site and time of induction, although again, there was a significant difference in tumors size with fat pad tumors being the largest and intraductal the smallest (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Expression', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (146, 151))	('Expression', 'Species', '29278', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumors', 'Disease', (146, 152))	('TCF7', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', (29, 34))	('decreased', 'NegReg', (19, 28))	('tumor', 'Disease', (171, 176))
92757	31519911	There were significant differences in histology as well, with mixed DCIS-IDC histology in the fat pad, invasive histology in the intraductal group, and DCIS in subcutaneous tumors (Fig.	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (160, 179))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (160, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('DCIS', 'Var', (152, 156))	('subcutaneous tumors', 'Disease', (160, 179))
92767	31519911	However, we also identified 135 SEs that were gained after TCF7 expression and many of these were associated with TCF7-binding sites.	('TCF7', 'Gene', (59, 63))	('expression', 'Var', (64, 74))	('SEs', 'Chemical', 'MESH:D012643', (32, 35))	('expression', 'Species', '29278', (64, 74))
92769	31519911	The gain of these SEs was coupled with the increased expression of the associated genes, which could contribute to the increase in cell proliferation after TCF7 expression in vitro (Supplementary Fig.	('gain', 'PosReg', (4, 8))	('expression', 'Species', '29278', (161, 171))	('TCF7', 'Gene', (156, 160))	('expression', 'Species', '29278', (53, 63))	('expression', 'Var', (161, 171))	('cell proliferation', 'CPA', (131, 149))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))	('increase', 'PosReg', (119, 127))	('SEs', 'Chemical', 'MESH:D012643', (18, 21))
92773	31519911	Pathway analysis of direct TCF7 targets that are upregulated after TCF7 expression showed enrichment in proteolysis, antigen presentation, cell cycle S phase, ESR1 pathway, mitosis, regulation of angiogenesis, and EMT (Fig.	('cell cycle S phase', 'CPA', (139, 157))	('mitosis', 'Disease', (173, 180))	('expression', 'Species', '29278', (72, 82))	('mitosis', 'Disease', 'None', (173, 180))	('TCF7', 'Gene', (67, 71))	('ESR1 pathway', 'Pathway', (159, 171))	('antigen presentation', 'MPA', (117, 137))	('angiogenesis', 'CPA', (196, 208))	('upregulated', 'PosReg', (49, 60))	('expression', 'Var', (72, 82))	('proteolysis', 'MPA', (104, 115))
92779	31519911	We found that TCF7 expression results in decreased phospho-FAKY397 and phospho-SRCY416 levels (Fig.	('SRCY416', 'Chemical', '-', (79, 86))	('decreased', 'NegReg', (41, 50))	('expression', 'Var', (19, 29))	('expression', 'Species', '29278', (19, 29))	('FAK', 'Gene', (59, 62))	('FAK', 'Gene', '5747', (59, 62))	('TCF7', 'Gene', (14, 18))	('phospho-SRCY416 levels', 'MPA', (71, 93))
92781	31519911	We found that while cell migration and invasion were not significantly different between control and shTP63 or TCF7-expressing cells, although migration and invasion is very low in MCF10DCIS cells making it difficult to see a decrease, cell adhesion to fibronectin and collagens significantly decreased (Supplementary Fig.	('invasion', 'CPA', (157, 165))	('fibronectin', 'Gene', '2335', (253, 264))	('low', 'NegReg', (174, 177))	('decreased', 'NegReg', (293, 302))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (181, 190))	('fibronectin', 'Gene', (253, 264))	('migration', 'CPA', (143, 152))	('MCF10DCIS', 'Var', (181, 190))
92784	31519911	In this study, we describe the molecular characterization of CD10+ myoepithelial cell population from normal breast tissue of healthy control nulliparous and parous women with no family history of breast cancer, and BRCA1/2 mutation carriers, as well as from DCIS.	('breast cancer', 'Disease', (197, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutation', 'Var', (224, 232))	('women', 'Species', '9606', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('BRCA1/2', 'Gene', (216, 223))	('epithelia', 'Disease', 'None', (70, 79))	('epithelia', 'Disease', (70, 79))
92785	31519911	Based on our integrated analyses of gene expression, enhancer, and p63 and TCF7 genomic target profiles, we determined that normal myoepithelial cell programs are maintained by an interactive TF network orchestrated by p63 and TCF7 in part via their regulation of ECM proteins and cell adhesion.	('expression', 'Species', '29278', (41, 51))	('TCF7', 'Gene', (227, 231))	('epithelia', 'Disease', 'None', (134, 143))	('ECM proteins', 'Protein', (264, 276))	('epithelia', 'Disease', (134, 143))	('cell adhesion', 'CPA', (281, 294))	('regulation', 'Reg', (250, 260))	('p63', 'Var', (219, 222))
92786	31519911	p63 plays key roles in the formation of epithelia during embryonic development and germline mutations in TP63 are responsible for multiple syndromes that involve malformations of various epithelial structures, limb deformations, and cleft palate.	('limb deformations', 'Phenotype', 'HP:0002813', (210, 227))	('epithelia', 'Disease', 'None', (187, 196))	('cleft palate', 'Disease', (233, 245))	('cleft palate', 'Disease', 'MESH:D002972', (233, 245))	('malformations', 'Disease', 'MESH:D000014', (162, 175))	('TP63', 'Gene', (105, 109))	('malformations', 'Disease', (162, 175))	('epithelia', 'Disease', (187, 196))	('epithelia', 'Disease', (40, 49))	('mutations', 'Var', (92, 101))	('epithelia', 'Disease', 'None', (40, 49))	('limb deformations', 'Disease', 'MESH:D017880', (210, 227))	('cleft palate', 'Phenotype', 'HP:0000175', (233, 245))	('limb deformations', 'Disease', (210, 227))	('responsible', 'Reg', (114, 125))
92790	31519911	Germline mutations in IRF6 cause van der Woude syndrome, while its deletion in mice results in skin and limb abnormalities.	('Germline mutations', 'Var', (0, 18))	('results in', 'Reg', (84, 94))	('van der Woude syndrome', 'Disease', (33, 55))	('van der Woude syndrome', 'Disease', 'MESH:C536528', (33, 55))	('IRF6', 'Gene', (22, 26))	('deletion', 'Var', (67, 75))	('mice', 'Species', '10090', (79, 83))	('limb abnormalities', 'Phenotype', 'HP:0002813', (104, 122))	('cause', 'Reg', (27, 32))	('skin and limb abnormalities', 'Disease', 'MESH:D012868', (95, 122))
92791	31519911	Germline mutations in TFAP2A and TFAP2B, TFs also co-expressed with p63 in myoepithelium, cause branchio-oculo-facial and Char syndrome, respectively.	('Germline mutations', 'Var', (0, 18))	('TFAP2B', 'Gene', (33, 39))	('branchio-oculo-facial', 'Disease', 'MESH:D019280', (96, 117))	('branchio-oculo-facial', 'Disease', (96, 117))	('TFAP2B', 'Gene', '7021', (33, 39))	('cause', 'Reg', (90, 95))	('Char syndrome', 'Disease', (122, 135))	('TFAP2A', 'Gene', (22, 28))	('Char syndrome', 'Disease', 'MESH:C566815', (122, 135))
92795	31519911	In animal models, mammary-specific deletion of Apc leads to delayed ductal development and metaplastic outgrowths, but these do not progress to neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (144, 153))	('Apc', 'Gene', (47, 50))	('deletion', 'Var', (35, 43))	('neoplasia', 'Disease', (144, 153))	('metaplastic outgrowths', 'CPA', (91, 113))	('neoplasia', 'Phenotype', 'HP:0002664', (144, 153))	('delayed', 'NegReg', (60, 67))
92796	31519911	However, combined deletion of Apc and Tcf1 (Tcf7) completely abrogates mammary gland development and leads to acanthomas.	('Tcf1', 'Gene', (38, 42))	('acanthomas', 'Disease', (110, 120))	('Tcf1', 'Gene', '21414', (38, 42))	('abrogates', 'NegReg', (61, 70))	('Tcf7', 'Gene', '21414', (44, 48))	('Apc', 'Gene', (30, 33))	('mammary gland development', 'CPA', (71, 96))	('acanthomas', 'Disease', 'MESH:D049309', (110, 120))	('Tcf7', 'Gene', (44, 48))	('leads to', 'Reg', (101, 109))	('deletion', 'Var', (18, 26))
92798	31519911	Furthermore, p63 and TCF7 also colocalize on the chromatin near genes required for normal myoepithelial cell function including ACTA2 (smooth muscle actin) and OXR1 (oxytocin receptor 1).	('epithelia', 'Disease', (93, 102))	('epithelia', 'Disease', 'None', (93, 102))	('ACTA2', 'Gene', (128, 133))	('ACTA2', 'Gene', '59', (128, 133))	('TCF7', 'Gene', (21, 25))	('p63', 'Var', (13, 16))	('colocalize', 'Reg', (31, 41))
92800	31519911	We identified an extensive cross-talk between p63 and TCF7/WNT signaling both in normal myoepithelial cells and also in the MCF10DCIS model, as well as a crosstalk of these pathways with ECM, Hh, and TGFbeta signaling (Supplementary Fig.	('crosstalk', 'Reg', (154, 163))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (124, 133))	('TGFbeta', 'Gene', '7040', (200, 207))	('MCF10DCIS', 'Var', (124, 133))	('epithelia', 'Disease', (91, 100))	('epithelia', 'Disease', 'None', (91, 100))	('cross-talk', 'Reg', (27, 37))	('TCF7/WNT', 'Gene', (54, 62))	('TGFbeta', 'Gene', (200, 207))
92802	31519911	GLI3, a transcriptional mediator of Hh signaling, is also a direct target of p63, while SMADs, transcriptional mediators of TGFbeta signaling are direct targets of TCF7.	('TGFbeta', 'Gene', '7040', (124, 131))	('GLI3', 'Gene', (0, 4))	('p63', 'Var', (77, 80))	('TGFbeta', 'Gene', (124, 131))	('GLI3', 'Gene', '2737', (0, 4))
92803	31519911	In normal myoepithelial cells p63 and TCF7 are co-expressed in non-carrier women, but the fraction of these cells is decreased in BRCA1 mutation carriers.	('BRCA1', 'Gene', (130, 135))	('carriers', 'Reg', (145, 153))	('women', 'Species', '9606', (75, 80))	('mutation', 'Var', (136, 144))	('decreased', 'NegReg', (117, 126))	('epithelia', 'Disease', 'None', (13, 22))	('epithelia', 'Disease', (13, 22))
92804	31519911	Based on the phenotype of the Tcf1-/- mice demonstrating mammary adenomas in the absence of Tcf1, it is possible that the decrease of TCF7 in basal/myoepithelial cells of BRCA1 mutation carriers may play a role in their higher risk of breast cancer, especially predisposing them to basal/triple-negative tumors.	('tumors', 'Disease', (304, 310))	('BRCA1', 'Gene', (171, 176))	('mice', 'Species', '10090', (38, 42))	('epithelia', 'Disease', 'None', (151, 160))	('Tcf1', 'Gene', (92, 96))	('Tcf1', 'Gene', (30, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('Tcf1', 'Gene', '21414', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('Tcf1', 'Gene', '21414', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('epithelia', 'Disease', (151, 160))	('breast cancer', 'Disease', (235, 248))	('mutation', 'Var', (177, 185))	('decrease', 'NegReg', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('adenomas', 'Disease', 'MESH:D000236', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('adenomas', 'Disease', (65, 73))	('TCF7', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
92805	31519911	However, functional data obtained in animal models and in the MCF10DCIS model we utilized in this study should be interpreted with caution as neither mice nor the MCF10DCIS model fully recapitulate the expression patterns of p63 and TCF7 observed in normal human breast tissues.	('mice', 'Species', '10090', (150, 154))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (163, 172))	('expression', 'Species', '29278', (202, 212))	('human', 'Species', '9606', (257, 262))	('p63', 'Var', (225, 228))	('MCF10DCIS', 'Var', (163, 172))	('TCF7', 'Gene', (233, 237))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (62, 71))
92820	31519911	Cells were stained with DAPI, and the following antibodies at 1:100 dilution in PBS + 2% BSA solution: CD10-FITC (Fisher Scientific cat#F082601F) or CD10-RPE (DAKO, clone SS2/36, cat#R084801), or CD10 (Biolegend, clone HI10A, cat#312202), CD10-FITC (BD Biosciences; clone HI10a, cat#340925), CD24-Alexa 647 (Biolegend; clone ML5, cat#311110) and CD44-PE (BD Biosciences; clone 515, cat#550989).	('FITC', 'Chemical', 'MESH:D016650', (108, 112))	('CD44', 'Gene', '960', (346, 350))	('CD44', 'Gene', (346, 350))	('F082601F', 'Mutation', 'p.F082601F', (136, 144))	('FITC', 'Chemical', 'MESH:D016650', (244, 248))	('cat#340925', 'Var', (279, 289))	('PBS', 'Chemical', 'MESH:D007854', (80, 83))
92836	31519911	For MCF10DCIS cell line raw RNA-seq datasets read alignment, quality control, and data analysis were performed using STAR.	('MCF10DCIS', 'Var', (4, 13))	('STAR', 'Gene', '6770', (117, 121))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (4, 13))	('STAR', 'Gene', (117, 121))
92843	31519911	Primary antibodies were used as follows: anti-p63 (ab735; 1:500; abcam), anti-phospho FAK-Y397 (#8556; 1:500; Cell Signaling Technology), anti-FAK (#3285; 1:1000; Cell Signaling Technology), anti-phospho Src-Y416 (#6943; 1:1000; Cell Signaling Technology), anti-Src (#2109; 1:1000; Cell Signaling Technology), TCF7 (#2203; 1:1000; Cell Signaling Technology), anti-GAPDH (#5174; 1:5000; Cell Signaling Technology), and anti-ACTB (#A2228; 1:1000, Sigma-Aldrich).	('TCF7', 'Gene', (310, 314))	('#2203', 'Var', (316, 321))	('FAK', 'Gene', '5747', (86, 89))	('Src', 'Gene', '6714', (204, 207))	('#A2228;', 'Var', (429, 436))	('FAK', 'Gene', (143, 146))	('FAK', 'Gene', '5747', (143, 146))	('Src', 'Gene', (262, 265))	('Src', 'Gene', '6714', (262, 265))	('FAK', 'Gene', (86, 89))	('ACTB', 'Gene', '60', (423, 427))	('ACTB', 'Gene', (423, 427))	('Src', 'Gene', (204, 207))
92861	31519911	Tumors were induced by mammary fat pad, intraductal and subcutaneous bi-lateral injections of MCF10DCIS-shTP63 (45 mice, 5 mice per treatment group) or MCF10DCIS-TCF7 (45 mice, 5 mice per treatment group) cells (2 x 10e5 in 50 microL, 1 x 10e5 in 20 microL, and 2 x 10e5 in 100 microL, respectively) resuspended in DMEM-F12 medium/Matrigel Growth Factor Reduced Basement Membrane Matrix, Phenol Red-Free (Fisher Scientific, cat#CB356238) in a 1:1 ratio.	('MCF10DCIS-TCF7', 'CellLine', 'CVCL:5552', (152, 166))	('mice', 'Species', '10090', (179, 183))	('mice', 'Species', '10090', (171, 175))	('Basement Membrane Matrix', 'CPA', (362, 386))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MCF10DCIS-TCF7', 'Var', (152, 166))	('mice', 'Species', '10090', (115, 119))	('mice', 'Species', '10090', (123, 127))	('MCF10DCIS-shTP63', 'CellLine', 'CVCL:5552', (94, 110))
92866	31519911	1h and 2f: p63-TCF7-, p63+TCF7+, TCF7+p63-, p63+TCF7-; Fig.	('p63+TCF7-', 'Var', (44, 53))	('p63-TCF7-', 'Var', (11, 20))	('1h', 'Chemical', '-', (0, 2))	('TCF7+p63-', 'Var', (33, 42))	('p63+TCF7+', 'Var', (22, 31))
92878	25730902	Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis.	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (206, 230))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('point mutation', 'Var', (65, 79))	('Carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('Ductal Carcinoma In Situ', 'Disease', (206, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('primary tumor', 'Disease', 'MESH:D009369', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('Ductal Carcinoma In Situ', 'Disease', 'MESH:D002285', (206, 230))	('primary tumor', 'Disease', (239, 252))	('DCIS', 'Phenotype', 'HP:0030075', (232, 236))	('one breast', 'Phenotype', 'HP:0012813', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('patient', 'Species', '9606', (162, 169))
92882	25730902	Breast cancer progression results from stochastic events leading to the acquisition of genomic alterations resulting in reduced apoptosis, replicative immortality, evasion of growth suppressors, uncontrolled proliferation, reprogrammed energy metabolism, evasion of immune destruction, angiogenesis, invasion and metastasis.	('replicative immortality', 'CPA', (139, 162))	('angiogenesis', 'CPA', (286, 298))	('invasion', 'CPA', (300, 308))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('evasion', 'CPA', (164, 171))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('reduced', 'NegReg', (120, 127))	('metastasis', 'CPA', (313, 323))	('reprogrammed', 'CPA', (223, 235))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('evasion', 'CPA', (255, 262))	('immune', 'CPA', (266, 272))	('alterations', 'Var', (95, 106))	('uncontrolled proliferation', 'CPA', (195, 221))	('Breast cancer', 'Disease', (0, 13))	('apoptosis', 'CPA', (128, 137))
92887	25730902	According to the linear progression model, the malignant cells pass through multiple successive rounds of genetic changes and selection within the primary tumor microenvironment, before tumor cell dissemination successfully results in a metastatic lesion.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('primary tumor', 'Disease', (147, 160))	('genetic changes', 'Var', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('primary tumor', 'Disease', 'MESH:D009369', (147, 160))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (186, 191))	('metastatic lesion', 'CPA', (237, 254))	('changes', 'Var', (114, 121))	('results in', 'Reg', (224, 234))
92890	25730902	Somatic copy number alterations and point mutations contribute to malignant progression, by altering the expression or functions of cancer driver genes.	('malignant progression', 'CPA', (66, 87))	('point mutations', 'Var', (36, 51))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('contribute', 'Reg', (52, 62))	('expression', 'MPA', (105, 115))	('altering', 'Reg', (92, 100))	('functions', 'MPA', (119, 128))
92909	25730902	Hence, these BAFs support copy number events by providing information about the fraction of sequenced cells in the cancer sample to be affected by a somatic copy number event, and enable detection of subclonality within the cancer cell population.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('copy number event', 'Var', (157, 174))	('BAF', 'Gene', '8815', (13, 16))	('cancer', 'Disease', (224, 230))	('BAF', 'Gene', (13, 16))
92912	25730902	Our results reveal overall striking similarities in copy number patterns between different steps of cancer evolution in the studied patient.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (132, 139))	('copy number', 'Var', (52, 63))
92914	25730902	Similarly, copy number losses on 4p, 6q, 8p, 9q, 11q, 13p-q, 14q, 16p, 16q, 17p, 17q, 19q and 21q are supported by the BAFs and are present in all samples.	('losses', 'NegReg', (23, 29))	('copy number', 'Var', (11, 22))	('BAF', 'Gene', '8815', (119, 122))	('BAF', 'Gene', (119, 122))
92919	25730902	As all aberrations are retained in later steps, 100% of the copy number events found in DCIS 1, DCIS 2 and primary tumor are found in the asynchronous metastasis.	('DCIS 1', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('primary tumor', 'Disease', (107, 120))	('DCIS 2', 'Gene', (96, 102))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('primary tumor', 'Disease', 'MESH:D009369', (107, 120))	('copy number events', 'Var', (60, 78))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
92922	25730902	Of the 65 validated point mutations detected, no mutations were private to DCIS 1 or the primary tumor while one mutation is exclusive to DCIS 2.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('primary tumor', 'Disease', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('primary tumor', 'Disease', 'MESH:D009369', (89, 102))	('point mutations', 'Var', (20, 35))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))
92923	25730902	Copy number losses on chromosome 9p and 20p are subclonal events, supported by subclonal BAFs, illustrating that only a fraction of the malignant cells are affected by the loss event.	('Copy number', 'Var', (0, 11))	('losses', 'NegReg', (12, 18))	('BAF', 'Gene', '8815', (89, 92))	('BAF', 'Gene', (89, 92))
92925	25730902	The primary tumor displays six additional copy number loss events and nine copy number gain events, solely shared between the primary tumor and the asynchronous metastasis, but not present in the pre-invasive tissue, suggesting that these events might contribute to invasiveness.	('contribute', 'Reg', (252, 262))	('primary tumor', 'Disease', 'MESH:D009369', (126, 139))	('primary tumor', 'Disease', 'MESH:D009369', (4, 17))	('copy number', 'MPA', (75, 86))	('primary tumor', 'Disease', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('invasiveness', 'Disease', 'MESH:D009362', (266, 278))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('copy number', 'Var', (42, 53))	('primary tumor', 'Disease', (126, 139))	('invasiveness', 'Disease', (266, 278))
92926	25730902	Copy number losses on chromosome 19p and 20p are subclonal events in the primary tumor but a "pure" phenomenon in the asynchronous metastasis.	('primary tumor', 'Disease', 'MESH:D009369', (73, 86))	('primary tumor', 'Disease', (73, 86))	('Copy number losses', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
92929	25730902	Copy number discordant genes between the primary tumor and the metastasis are listet in Supplementary Tables 5 and 6.	('primary tumor', 'Disease', (41, 54))	('Copy number', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('primary tumor', 'Disease', 'MESH:D009369', (41, 54))
92937	25730902	Not surprisingly, the tumor suppressor gene TP53 (17p13.1) is affected by both LOH and a point mutation, that is predicted damaging by SIFT, Polyphen2 and MutationTaster, in all stages of progression.	('point mutation', 'Var', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('MutationTaster', 'Var', (155, 169))	('SIFT', 'Disease', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('LOH', 'Var', (79, 82))	('affected', 'Reg', (62, 70))	('TP53', 'Gene', '7157', (44, 48))	('tumor', 'Disease', (22, 27))	('SIFT', 'Disease', 'None', (135, 139))	('TP53', 'Gene', (44, 48))
92938	25730902	Most noticeable are the frameshift deletion in LOXL3 which is also hit by both LOH in all samples, and the nonsynonymous mutations in ARID1B (6q25.3) and PAPPA (9q33.1), which are affected by LOH in all tumor stages but exclusively hit by point mutations in the asynchronous metastasis, suggesting that these genes might be involved in metastatic progression.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('ARID1B', 'Gene', '57492', (134, 140))	('LOXL3', 'Gene', '84695', (47, 52))	('PAPPA', 'Gene', '5069', (154, 159))	('LOXL3', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('involved', 'Reg', (324, 332))	('ARID1B', 'Gene', (134, 140))	('frameshift deletion', 'Var', (24, 43))	('PAPPA', 'Gene', (154, 159))
92939	25730902	The mutations are predicted to be deleterious by all three functional prediction scores and reduced expression of the LOXL3 gene and PAPPA gene are found to be significantly associated with shorter recurrence free survival (RFS) with p-value 3.4e-7 and p-value 1.5e-7, respectively, according to the gene expression data provided by KM Plotter (Kaplan Meier plots for the two genes are shown in Supplementary Figures 5-6).	('LOXL3', 'Gene', '84695', (118, 123))	('PAPPA', 'Gene', '5069', (133, 138))	('expression', 'MPA', (100, 110))	('recurrence free survival', 'CPA', (198, 222))	('PAPPA', 'Gene', (133, 138))	('LOXL3', 'Gene', (118, 123))	('shorter', 'NegReg', (190, 197))	('mutations', 'Var', (4, 13))	('reduced', 'NegReg', (92, 99))
92940	25730902	The CYP3A43 gene (7q22.1) is affected by a point mutation in all tumor steps and in addition LOH in the asynchronous metastasis.	('affected', 'Reg', (29, 37))	('tumor', 'Disease', (65, 70))	('asynchronous metastasis', 'CPA', (104, 127))	('CYP3A43', 'Gene', (4, 11))	('CYP3A43', 'Gene', '64816', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('point mutation', 'Var', (43, 57))	('LOH', 'NegReg', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
92951	25730902	A stepwise accumulation of aberrations in several equally competitive lineages would result in a clonally diverse tumor with branching evolution of multiple independent and prominent subclones.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('result in', 'Reg', (85, 94))	('aberrations', 'Var', (27, 38))
92961	25730902	Our study reveals evolution of copy number events and point mutations during breast cancer progression, a phenomenon influenced by several factors including time, increased genomic instability and selection pressures provided by treatment and endogenous immunological and microenvironmental factors.	('copy number events', 'Var', (31, 49))	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('point mutations', 'Var', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
92977	25730902	Epigenetic changes play key roles in cancer and recently a metastasis-specific methylation signature was reported, however, this layer in cancer biology was not included in our study.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
92979	25730902	Our study reveals common ancestry of the malignant cells and that early acquired copy number aberrations as well as point mutations are retained as imprints in the cancer genome, but also shows substantial acquisition of additional aberrations in the metastasis.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('copy number aberrations', 'Var', (81, 104))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (164, 170))	('metastasis', 'CPA', (251, 261))
92992	25730902	A single copy gain in the tumor sample (ratio 3:2) results in a Log2 ratio of 0.58, while a heterozygote loss in the tumor sample (ratio 1:2) results in a Log2 ratio of -1.	('Log2', 'MPA', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('gain', 'PosReg', (14, 18))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('loss', 'NegReg', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('single copy', 'Var', (2, 13))
92994	25730902	Cancer sample aneuploidy may introduce bias in establishing the Log2 Ratio baseline for copy number calling.	('aneuploidy', 'Disease', (14, 24))	('copy number', 'Var', (88, 99))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Log2 Ratio', 'MPA', (64, 74))	('aneuploidy', 'Disease', 'MESH:D000782', (14, 24))
93026	23664819	For example, results of recent studies have shown that rats with N-methyl N'-nitrosourea-induced breast tumors exhibited significant reduction in tumor formation upon intraductal treatment with various anticancer agents, including paclitaxel, pegylated liposomal doxorubicin (PLD), 4-hydroxytamoxifen, carboplatin, methotrexate, nanoparticle albumin-bound paclitaxel and 5-fluorouracil, with minimal toxic effects.	('breast tumors', 'Disease', 'MESH:D001943', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (146, 151))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (263, 274))	('carboplatin', 'Chemical', 'MESH:D016190', (302, 313))	('cancer', 'Disease', (206, 212))	('methotrexate', 'Chemical', 'MESH:D008727', (315, 327))	('4-hydroxytamoxifen', 'Chemical', '-', (282, 300))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	("N-methyl N'-nitrosourea-induced", 'Var', (65, 96))	('rats', 'Species', '10116', (55, 59))	('tumor', 'Disease', (104, 109))	('paclitaxel', 'Chemical', 'MESH:D017239', (231, 241))	('paclitaxel', 'Chemical', 'MESH:D017239', (356, 366))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	("N-methyl N'-nitrosourea", 'Chemical', 'MESH:D008770', (65, 88))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('reduction', 'NegReg', (133, 142))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (371, 385))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('breast tumors', 'Disease', (97, 110))
93036	23664819	Conversely, drug concentrations in the breast were considerably higher in women who received intraductal PLD compared with those administered intravenous PLD.	('drug concentrations', 'MPA', (12, 31))	('higher', 'PosReg', (64, 70))	('women', 'Species', '9606', (74, 79))	('intraductal PLD', 'Var', (93, 108))
93059	23664819	For anti-8-OHdG and anti-Ki-67, a 1:50 dilution was used, and, for anti-ANX1, a 1:750 dilution was used.	('anti-Ki-67', 'Var', (20, 30))	('8-OHdG', 'Chemical', 'MESH:C067134', (9, 15))	('anti-8-OHdG', 'Var', (4, 15))	('ANX1', 'Gene', (72, 76))	('ANX1', 'Gene', '301', (72, 76))
93067	23664819	Of the 13 women enrolled in the study (Figure 1, for a schematic of the study design), 5 were treated with 20 mg PLD, one was treated with 4 mg PLD, one was treated with saline solution, 3 had duct perforations, and 3 had ducts that were either not found or not able to be cannulated (Table 1).	('duct perforations', 'CPA', (193, 210))	('women', 'Species', '9606', (10, 15))	('PLD', 'Var', (113, 116))
93091	23664819	Finally, high Ki-67 expression levels have been associated with poorer survival outcomes in breast cancer patients, and the protein has also been found to predict response to chemotherapy.	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('Ki-67', 'Protein', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('predict', 'Reg', (155, 162))	('survival outcomes', 'CPA', (71, 88))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('poorer', 'NegReg', (64, 70))	('expression levels', 'MPA', (20, 37))	('high', 'Var', (9, 13))
93173	31609784	In their analysis, Lamb et al further identified that having a genetic mutation associated with breast cancer was significantly associated with an upgrade to carcinoma while a personal history of breast cancer was the single significant risk factor associated with an upgrade to a higher risk lesion.	('carcinoma', 'Disease', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('upgrade', 'Disease', (147, 154))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('carcinoma', 'Disease', 'MESH:D009369', (158, 167))	('associated with', 'Reg', (128, 143))	('breast cancer', 'Disease', (96, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('genetic mutation', 'Var', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
93189	31609784	On the other end, McCroskey et al found no association between presence of ALH and upgrade rate to carcinoma in cases of FEA.	('presence', 'Var', (63, 71))	('carcinoma', 'Disease', 'MESH:D009369', (99, 108))	('ALH', 'Chemical', '-', (75, 78))	('upgrade', 'CPA', (83, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('ALH', 'Gene', (75, 78))	('carcinoma', 'Disease', (99, 108))
93205	31008449	Invasive cancers diagnosed in FH02 were significantly smaller than the comparable (POSH-unscreened prospective) study group (45% (131/293) <= 2 cm in POSH vs 80% (28/35) in FH02 p < 0.0001), and were less likely to be lymph-node positive (54% (158/290, 3 unknown) in POSH vs 20% (7/35) in FH02: p = 0.0002.	('POSH', 'Gene', (83, 87))	('FH02', 'Var', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('Invasive cancers', 'Disease', (0, 16))	('POSH', 'Gene', (267, 271))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('POSH', 'Gene', '57630', (267, 271))	('POSH', 'Gene', '57630', (150, 154))	('POSH', 'Gene', (150, 154))	('smaller', 'NegReg', (54, 61))	('POSH', 'Gene', '57630', (83, 87))
93209	31008449	Although a small proportion of women in the moderate/high-risk categories (~ 5%) are eligible for MRI screening in the UK in line with NICE guidance, mainly due to carrying BRCA1/2 pathogenic variants, the vast majority of those with familial risk < 40 years of age do not currently qualify for approved health service surveillance.	('variants', 'Var', (192, 200))	('BRCA1/2', 'Gene', (173, 180))	('BRCA1', 'Gene', '672', (173, 178))	('BRCA1/2', 'Gene', '672;675', (173, 180))	('pathogenic', 'Reg', (181, 191))	('BRCA', 'Gene', '672', (173, 177))	('BRCA1', 'Gene', (173, 178))	('BRCA', 'Gene', (173, 177))
93222	31008449	Of 22 breast cancers 6 had a pathogenic BRCA1 variant, 4 in BRCA2 with 11 having no pathogenic variant identified and one remaining untested.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('variant', 'Var', (46, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (6, 20))	('pathogenic', 'Reg', (29, 39))	('breast cancers', 'Disease', (6, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('BRCA2', 'Gene', (60, 65))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('BRCA2', 'Gene', '675', (60, 65))	('BRCA1', 'Gene', (40, 45))
93236	22203527	Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs.	('metformin', 'Chemical', 'MESH:D008687', (8, 17))	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('attenuates', 'NegReg', (18, 28))	('anti-senescence effects', 'MPA', (33, 56))	('Warburg effect-', 'Disease', (105, 120))	('metformin', 'Var', (8, 17))
93278	22203527	Metformin decreases glucose absorption in the intestine and glucose production in the liver but does not stimulate insulin secretion.	('decreases glucose absorption', 'Phenotype', 'HP:0040270', (10, 38))	('decreases glucose absorption', 'Disease', (10, 38))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('insulin secretion', 'Disease', 'MESH:D007333', (115, 132))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('decreases glucose absorption', 'Disease', 'MESH:C564600', (10, 38))	('insulin secretion', 'Disease', (115, 132))	('glucose production', 'MPA', (60, 78))	('glucose', 'Chemical', 'MESH:D005947', (20, 27))
93281	22203527	Metformin also increases the affinity of the insulin receptor for insulin, reduces hyperinsulinemia and improves insulin resistance.	('insulin resistance', 'Phenotype', 'HP:0000855', (113, 131))	('affinity', 'MPA', (29, 37))	('insulin', 'Gene', (113, 120))	('insulin', 'Gene', (88, 95))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (83, 99))	('hyperinsulinemia', 'Disease', (83, 99))	('Metformin', 'Var', (0, 9))	('insulin', 'Gene', (66, 73))	('insulin', 'Gene', '3630', (113, 120))	('insulin', 'Gene', '3630', (88, 95))	('insulin', 'Gene', (45, 52))	('reduces', 'NegReg', (75, 82))	('increases', 'PosReg', (15, 24))	('improves', 'PosReg', (104, 112))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('insulin', 'Gene', '3630', (66, 73))	('insulin', 'Gene', '3630', (45, 52))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (83, 99))
93283	22203527	Metformin can also decrease fatty acid uptake and oxidation in skeletal muscle cells while lowering circulating levels of total cholesterol, Low-density lipoprotein (LDL) and triglycerides.	('lowering', 'NegReg', (91, 99))	('fatty acid uptake', 'MPA', (28, 45))	('decrease', 'NegReg', (19, 27))	('triglycerides', 'MPA', (175, 188))	('Low-density lipoprotein', 'MPA', (141, 164))	('Metformin', 'Var', (0, 9))	('oxidation', 'MPA', (50, 59))	('decrease fatty acid', 'Phenotype', 'HP:0040299', (19, 38))	('circulating levels of total cholesterol', 'MPA', (100, 139))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('triglycerides', 'Chemical', 'MESH:D014280', (175, 188))	('cholesterol', 'Chemical', 'MESH:D002784', (128, 139))	('fatty acid', 'Chemical', 'MESH:D005227', (28, 38))
93295	22203527	This group determined that metformin was associated with lower overall mortality (3.5% versus 4.9% for the sulfonylurea cohort) and mortality as a result of cancer (an HR of 1 for metformin and no insulin use versus an HR of 1.3 (CI 1.1-1.6) for the sulfonylurea group).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('insulin', 'Gene', (197, 204))	('insulin', 'Gene', '3630', (197, 204))	('metformin', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('sulfonylurea', 'Chemical', 'MESH:D013453', (107, 119))	('metformin', 'Chemical', 'MESH:D008687', (180, 189))	('metformin', 'Var', (180, 189))	('cancer', 'Disease', (157, 163))	('metformin', 'Chemical', 'MESH:D008687', (27, 36))	('sulfonylurea', 'Chemical', 'MESH:D013453', (250, 262))	('lower', 'NegReg', (57, 62))
93300	22203527	Another meta-analysis found a 31% reduction in the cancer rate in patients taking metformin and found that this relationship was also dose-dependent.	('metformin', 'Var', (82, 91))	('metformin', 'Chemical', 'MESH:D008687', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('reduction', 'NegReg', (34, 43))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('patients', 'Species', '9606', (66, 74))
93304	22203527	The treatment of type 2 diabetic patients with metformin has also been reported to lower mortality due to several solid tumor types.	('mortality', 'MPA', (89, 98))	('patients', 'Species', '9606', (33, 41))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('men', 'Species', '9606', (9, 12))	('diabetic', 'Disease', 'MESH:D003920', (24, 32))	('lower', 'NegReg', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('diabetic', 'Disease', (24, 32))	('metformin', 'Var', (47, 56))	('tumor', 'Disease', (120, 125))
93305	22203527	Although little is known about the effect of metformin on human colorectal carcinogenesis, recent epidemiological studies have shown reduced incidence of colorectal cancer in patients with type 2 diabetes taking metformin when compared with those patients who do not take metformin.	('metformin', 'Var', (212, 221))	('type 2 diabetes', 'Disease', 'MESH:D003924', (189, 204))	('colorectal cancer', 'Disease', (154, 171))	('human', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (189, 204))	('type 2 diabetes', 'Disease', (189, 204))	('colorectal carcinogenesis', 'Disease', (64, 89))	('metformin', 'Chemical', 'MESH:D008687', (212, 221))	('patients', 'Species', '9606', (247, 255))	('metformin', 'Chemical', 'MESH:D008687', (272, 281))	('patients', 'Species', '9606', (175, 183))	('rectal cancer', 'Phenotype', 'HP:0100743', (158, 171))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('reduced', 'NegReg', (133, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (64, 89))
93306	22203527	Patients with colorectal and pancreatic carcinomas who had been treated with metformin showed a 30% improvement in survival when compared with patients who had been treated with other anti-diabetic treatments.	('metformin', 'Var', (77, 86))	('improvement', 'PosReg', (100, 111))	('colorectal', 'Disease', (14, 24))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('men', 'Species', '9606', (203, 206))	('men', 'Species', '9606', (107, 110))	('diabetic', 'Disease', 'MESH:D003920', (189, 197))	('survival', 'MPA', (115, 123))	('patients', 'Species', '9606', (143, 151))	('Patients', 'Species', '9606', (0, 8))	('diabetic', 'Disease', (189, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('colorectal', 'Disease', 'MESH:D015179', (14, 24))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (29, 50))	('pancreatic carcinomas', 'Disease', (29, 50))
93313	22203527	Specifically, diabetic patients who had been treated with metformin had a pathologic complete response (pCR) rate three times higher (24%) than those who had not been treated with metformin (8%).	('patients', 'Species', '9606', (23, 31))	('higher', 'PosReg', (126, 132))	('metformin', 'Var', (58, 67))	('diabetic', 'Disease', 'MESH:D003920', (14, 22))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('diabetic', 'Disease', (14, 22))	('complete response', 'Disease', (85, 102))	('metformin', 'Chemical', 'MESH:D008687', (180, 189))
93323	22203527	For instance, several studies did not exclude individuals with prior cancers; moreover, patients who received metformin significantly differed in many key factors from those who did not receive the drug closely related to cancer risk, including age, obesity, and smoking history.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('obesity', 'Disease', 'MESH:D009765', (250, 257))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('patients', 'Species', '9606', (88, 96))	('obesity', 'Disease', (250, 257))	('cancer', 'Disease', (222, 228))	('differed', 'Reg', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('metformin', 'Var', (110, 119))	('obesity', 'Phenotype', 'HP:0001513', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('metformin', 'Chemical', 'MESH:D008687', (110, 119))	('cancers', 'Disease', (69, 76))
93333	22203527	However, a recent study in mice found that hyperinsulinemia-mediated loss and/or mutation of LKB1 is a predictor of sensitivity to metformin.	('hyperinsulinemia', 'Disease', (43, 59))	('sensitivity to metformin', 'MPA', (116, 140))	('loss', 'NegReg', (69, 73))	('mice', 'Species', '10090', (27, 31))	('mutation', 'Var', (81, 89))	('LKB1', 'Gene', (93, 97))	('is a', 'Gene', (98, 102))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (43, 59))	('is a', 'Gene', '312', (98, 102))	('metformin', 'Chemical', 'MESH:D008687', (131, 140))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (43, 59))
93334	22203527	A polymorphism in the LKB1 gene is associated with ovulatory response to treatment of Polycystic Ovarian Syndrome (PCOS) patients with metformin alone in a prospective randomized trial.	('Polycystic Ovarian Syndrome', 'Phenotype', 'HP:0000147', (86, 113))	('ovulatory response to treatment', 'MPA', (51, 82))	('Polycystic Ovarian Syndrome', 'Disease', 'MESH:D011085', (86, 113))	('is a', 'Gene', (32, 36))	('is a', 'Gene', '312', (32, 36))	('Polycystic Ovarian Syndrome', 'Disease', (86, 113))	('PCOS', 'Disease', (115, 119))	('men', 'Species', '9606', (78, 81))	('polymorphism', 'Var', (2, 14))	('LKB1', 'Gene', (22, 26))	('PCOS', 'Disease', 'MESH:D011085', (115, 119))	('metformin', 'Chemical', 'MESH:D008687', (135, 144))	('patients', 'Species', '9606', (121, 129))
93335	22203527	Additionally, genetic polymorphisms in the cell surface transporter organic cation transporter 1 (OCT1), which is required for the efficient action of metformin, have been shown to underlie metformin resistance in some patients with type 2 diabetes and PCOS.	('OCT1', 'Gene', (98, 102))	('type 2 diabetes', 'Disease', (233, 248))	('type 2 diabetes', 'Disease', 'MESH:D003924', (233, 248))	('metformin resistance', 'MPA', (190, 210))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (233, 248))	('genetic polymorphisms', 'Var', (14, 35))	('metformin', 'Chemical', 'MESH:D008687', (151, 160))	('patients', 'Species', '9606', (219, 227))	('underlie', 'Reg', (181, 189))	('metformin', 'Chemical', 'MESH:D008687', (190, 199))	('PCOS', 'Disease', (253, 257))	('PCOS', 'Disease', 'MESH:D011085', (253, 257))
93336	22203527	Although it is likely that OCT gene polymorphisms may significantly affect the efficacy and toxicity of metformin against human cancer cells, this remains to be confirmed.	('human', 'Species', '9606', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('polymorphisms', 'Var', (36, 49))	('toxicity', 'Disease', (92, 100))	('OCT gene', 'Gene', (27, 35))	('toxicity', 'Disease', 'MESH:D064420', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('efficacy', 'MPA', (79, 87))	('affect', 'Reg', (68, 74))	('metformin', 'Chemical', 'MESH:D008687', (104, 113))	('cancer', 'Disease', (128, 134))
93342	22203527	Using cultured tumor cells, we recently confirmed that metformin promotes activation of ATM and ATM targets, such as the protein kinase Chk2, suggesting a causal linkage between metformin's mechanism of action and metformin's cancer preventative effects.	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('metformin', 'Chemical', 'MESH:D008687', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metformin', 'Chemical', 'MESH:D008687', (178, 187))	('activation', 'PosReg', (74, 84))	('tumor', 'Disease', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('metformin', 'Var', (55, 64))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
93354	22203527	As such, metformin inhibits the mTOR-signaling pathway in an AMPK-dependent manner, which may provide an explanation of the observed anti-neoplastic actions in breast cancer.	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('AMPK', 'Gene', '5562', (61, 65))	('AMPK', 'Gene', (61, 65))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('inhibits', 'NegReg', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('metformin', 'Var', (9, 18))
93355	22203527	In other tumors where mTOR plays an important role, including renal cell carcinomas, a mechanism by which metformin inhibits tumorigenicity via mTOR and activation of AMPK has been demonstrated.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('renal cell carcinomas', 'Disease', (62, 83))	('AMPK', 'Gene', '5562', (167, 171))	('mTOR', 'Gene', '2475', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (62, 83))	('metformin', 'Var', (106, 115))	('metformin', 'Chemical', 'MESH:D008687', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('tumors', 'Disease', (9, 15))	('tumor', 'Disease', (9, 14))	('mTOR', 'Gene', (144, 148))	('inhibits', 'NegReg', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('AMPK', 'Gene', (167, 171))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mTOR', 'Gene', '2475', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (125, 130))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (62, 83))	('mTOR', 'Gene', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
93370	22203527	Conversely, cancer cells with a mutated p53 that have been treated with metformin are unable to reprogram metabolism, and the cell undergoes apoptosis.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('apoptosis', 'CPA', (141, 150))	('cancer', 'Disease', (12, 18))	('undergoes', 'Reg', (131, 140))	('mutated', 'Var', (32, 39))	('unable', 'NegReg', (86, 92))	('p53', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('metformin', 'Chemical', 'MESH:D008687', (72, 81))	('reprogram metabolism', 'CPA', (96, 116))
93373	22203527	Additionally, in ovarian cancer, metformin inhibits tumor growth in nude mice in a dose-dependent manner and reduces the number of lung metastases, proliferation (determined by Ki-67), vascular density and angiogenesis as measured by VEGF.	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lung metastases', 'Disease', (131, 146))	('lung metastases', 'Disease', 'MESH:D009362', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('proliferation', 'CPA', (148, 161))	('tumor', 'Disease', (52, 57))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('vascular density', 'CPA', (185, 201))	('nude mice', 'Species', '10090', (68, 77))	('is a', 'Gene', (216, 220))	('ovarian cancer', 'Disease', (17, 31))	('inhibits', 'NegReg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('is a', 'Gene', '312', (216, 220))	('metformin', 'Var', (33, 42))	('reduces', 'NegReg', (109, 116))
93376	22203527	Additionally, metformin induces both caspase-dependent and poly (ADP-ribose) polymerase-dependent cell death in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('caspase-dependent', 'CPA', (37, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('metformin', 'Var', (14, 23))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
93379	22203527	Furthermore, the metformin-induced inhibition of HER2 is independent of the molecular mechanism that contributes to the overexpression of HER2 (i.e., gene amplification or transcriptional activation).	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('transcriptional', 'MPA', (172, 187))	('gene amplification', 'Var', (150, 168))	('HER2', 'Protein', (138, 142))
93397	22203527	Metformin's ability to increase the mean lifespan of tumor-free mice while simultaneously decreasing the risk of age-related death underscores its ability to reduce cancer incidence among type 2 diabetics.	('diabetics', 'Disease', 'MESH:D003920', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('reduce', 'NegReg', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('diabetics', 'Disease', (195, 204))	('Metformin', 'Var', (0, 9))	('mice', 'Species', '10090', (64, 68))	('increase', 'PosReg', (23, 31))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('tumor', 'Disease', (53, 58))	('decreasing', 'NegReg', (90, 100))	('type 2 diabetics', 'Phenotype', 'HP:0005978', (188, 204))
93399	22203527	Furthermore, a recently conducted retrospective study reported an impressive 56% decrease in the risk of breast cancer among diabetics receiving metformin when compared with diabetics being treated with other anti-diabetic therapies.	('metformin', 'Chemical', 'MESH:D008687', (145, 154))	('diabetics', 'Disease', 'MESH:D003920', (174, 183))	('diabetic', 'Disease', (214, 222))	('decrease', 'NegReg', (81, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('breast cancer', 'Disease', (105, 118))	('diabetic', 'Disease', (174, 182))	('diabetics', 'Disease', 'MESH:D003920', (125, 134))	('diabetic', 'Disease', 'MESH:D003920', (174, 182))	('diabetics', 'Disease', (174, 183))	('diabetic', 'Disease', 'MESH:D003920', (125, 133))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('metformin', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('diabetic', 'Disease', 'MESH:D003920', (214, 222))	('diabetics', 'Disease', (125, 134))	('diabetic', 'Disease', (125, 133))
93419	22203527	Recently, we found that proliferation and size of CSC multicellular "microtumors" (i.e., mammospheres) in non-adherent and non-differentiating conditions were inhibited by metformin, indirectly reflecting metformin's ability to suppress stem cell renewal and progenitor cell proliferation, respectively.	('proliferation', 'CPA', (24, 37))	('metformin', 'Chemical', 'MESH:D008687', (205, 214))	('progenitor cell proliferation', 'CPA', (259, 288))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibited', 'NegReg', (159, 168))	('metformin', 'Var', (172, 181))	('suppress', 'NegReg', (228, 236))	('size', 'CPA', (42, 46))	('metformin', 'Chemical', 'MESH:D008687', (172, 181))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('stem cell renewal', 'CPA', (237, 254))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
93435	22203527	Senescent cells can be found abundantly in intraepithelial premalignant lesions, whereas senescent cells are scarce in invasive, life-threatening metastatic carcinomas, supporting the notion that cellular senescence suppresses cancer in vivo.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('cellular senescence', 'Var', (196, 215))	('carcinomas', 'Disease', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('suppresses', 'NegReg', (216, 226))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('carcinomas', 'Disease', 'MESH:D002277', (157, 167))
93436	22203527	Dismantling the senescence response (e.g., via inactivation of the tumor-suppressor p53) causes a significant acceleration in the development of human tumors, whereas senescence in established malignant states is associated with tumor regression.	('inactivation', 'Var', (47, 59))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('human', 'Species', '9606', (145, 150))	('tumor', 'Disease', (67, 72))	('men', 'Species', '9606', (137, 140))	('is a', 'Gene', (210, 214))	('is a', 'Gene', '312', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('acceleration', 'PosReg', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (151, 156))	('p53', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
93443	22203527	Accordingly, there is a strong selective pressure for mutation in DDR components because activation of DNA damage checkpoints acts as the innate barrier against invasion/metastasis of tumors.	('mutation', 'Var', (54, 62))	('metastasis of tumors', 'Disease', (170, 190))	('DDR', 'Chemical', '-', (66, 69))	('is a', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('is a', 'Gene', '312', (19, 23))	('metastasis of tumors', 'Disease', 'MESH:D009362', (170, 190))
93451	22203527	Because of this, it is tempting to suggest that, in the context of DDR, metformin-enhanced cellular senescence may underlie metformin's ability to increase the rate of pCR in neoadjuvant chemotherapy in diabetic patients with breast cancer and to promote tumor regression and prevent relapse when combined with suboptimal doses of chemotherapy in animal models.	('pCR', 'Disease', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('diabetic', 'Disease', 'MESH:D003920', (203, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('patients', 'Species', '9606', (212, 220))	('promote', 'PosReg', (247, 254))	('diabetic', 'Disease', (203, 211))	('metformin', 'Var', (124, 133))	('DDR', 'Chemical', '-', (67, 70))	('increase', 'PosReg', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('metformin', 'Chemical', 'MESH:D008687', (72, 81))	('metformin', 'Chemical', 'MESH:D008687', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
93454	22203527	It would also be relevant to evaluate whether metformin facilitates the "accelerated senescence" triggered in normal cells by the expression of mutated, transforming versions of oncogenes (e.g., Ras or Raf) and by some other forms of supraphysiological mitogenic signaling irrespective of senescence-inhibiting adaptations (e.g., inactivation of p53).	('orm', 'Gene', '5004', (226, 229))	('mutated', 'Var', (144, 151))	('orm', 'Gene', (226, 229))	('inactivation', 'Var', (330, 342))	('orm', 'Gene', '5004', (159, 162))	('orm', 'Gene', (159, 162))	('facilitates', 'PosReg', (56, 67))	('orm', 'Gene', '5004', (111, 114))	('orm', 'Gene', (111, 114))	('orm', 'Gene', '5004', (50, 53))	('orm', 'Gene', (50, 53))	('metformin', 'Chemical', 'MESH:D008687', (46, 55))
93456	22203527	Therefore, activating the program of senescence in tumor cells is an attractive approach to cancer treatment and may help to explain the differential impact of metformin on cancer incidence in non-prone and cancer-prone animal models and perhaps also in cancer-prone individuals.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('men', 'Species', '9606', (104, 107))	('cancer', 'Disease', (207, 213))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('metformin', 'Chemical', 'MESH:D008687', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('activating', 'Var', (11, 21))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('is a', 'Gene', (63, 67))	('is a', 'Gene', '312', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))
93487	22203527	While there was no evidence of metformin-induced activation of AMPK in lung tumors, metformin led to decreased levels of circulating insulin and IGF as well as decreased phosphorylation of IGF-IR, AKT and mTOR in tumor tissue.	('metformin', 'Chemical', 'MESH:D008687', (84, 93))	('insulin', 'Gene', (133, 140))	('tumor', 'Disease', (76, 81))	('IGF', 'MPA', (145, 148))	('AKT', 'Gene', (197, 200))	('AMPK', 'Gene', '5562', (63, 67))	('lung tumors', 'Disease', 'MESH:D008175', (71, 82))	('decreased', 'NegReg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (71, 82))	('IGF-IR', 'Protein', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('lung tumors', 'Disease', (71, 82))	('AKT', 'Gene', '207', (197, 200))	('mTOR', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('decreased', 'NegReg', (101, 110))	('insulin', 'Gene', '3630', (133, 140))	('AMPK', 'Gene', (63, 67))	('tumor', 'Disease', (213, 218))	('mTOR', 'Gene', '2475', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))	('phosphorylation', 'MPA', (170, 185))	('metformin', 'Var', (84, 93))
93509	22203527	Immunohistochemical analysis of traditional senescence effectors (e.g., upregulation of p53, INK4A, p21 and p27) can also enable the detection of metformin's ability to induce senescence as part of its therapeutic effects.	('senescence', 'CPA', (176, 186))	('upregulation', 'PosReg', (72, 84))	('INK4A', 'Gene', (93, 98))	('p53', 'Protein', (88, 91))	('p27', 'Gene', (108, 111))	('metformin', 'Chemical', 'MESH:D008687', (146, 155))	('p21', 'Var', (100, 103))
93528	29813119	Mouse models with genetic alterations closely mimic the human tumor microenvironment and allow for studying the effect of one gene or a group of genes and their role in cancer progression and metastasis.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('human', 'Species', '9606', (56, 61))	('alterations', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Mouse', 'Species', '10090', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
93531	29813119	The added advantages of GEMMs, specifically, the MMTV promoter and Cre/loxP-mediated tumor suppressor gene deletion, are that they do not result in embryonic lethality.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('embryonic lethality', 'Disease', 'MESH:D020964', (148, 167))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('embryonic lethality', 'Disease', (148, 167))	('deletion', 'Var', (107, 115))	('MMTV', 'Species', '11757', (49, 53))
93532	29813119	In GEMMs, antibiotic (e.g., doxycycline) -mediated gene deletion or activation by an inducible system allows for conducting experimental manipulation of multiple genes for functional studies of tumor suppressor genes or oncogenes.	('deletion', 'Var', (56, 64))	('doxycycline', 'Chemical', 'MESH:D004318', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('gene deletion', 'Var', (51, 64))	('tumor', 'Disease', (194, 199))
93681	21822285	In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung.	('inhibition', 'Var', (33, 43))	('rat', 'Species', '10116', (163, 166))	('collagen fibrillogenesis', 'MPA', (65, 89))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (146, 151))	('COX-2', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('reduces', 'NegReg', (53, 60))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
93701	21822285	In animal models, COX-2 overexpression induces and knockout reduces  mammary tumorigenesis and in vitro inhibition of COX-2 reduces breast cancer cell proliferation, migration, and invasion.	('rat', 'Species', '10116', (169, 172))	('migration', 'CPA', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('reduces', 'NegReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('COX-2', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('COX-2', 'Gene', (18, 23))	('rat', 'Species', '10116', (158, 161))	('invasion', 'CPA', (181, 189))	('knockout', 'Var', (51, 59))	('inhibition', 'Var', (104, 114))	('reduces', 'NegReg', (60, 67))	('breast cancer', 'Disease', (132, 145))	('tumor', 'Disease', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
93702	21822285	Finally, in xenografted breast tumor cell populations, high COX-2 expression is associated with infiltration of lung, bone, and brain.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('breast tumor', 'Disease', (24, 36))	('expression', 'MPA', (66, 76))	('breast tumor', 'Phenotype', 'HP:0100013', (24, 36))	('associated with', 'Reg', (80, 95))	('rat', 'Species', '10116', (102, 105))	('COX-2', 'Gene', (60, 65))	('high', 'Var', (55, 59))	('infiltration', 'CPA', (96, 108))	('breast tumor', 'Disease', 'MESH:D001943', (24, 36))	('bone', 'CPA', (118, 122))
93705	21822285	Within the mammary gland, MCF10DCIS cells form lesions histologically similar to human ductal carcinoma in situ (DCIS) that progress to invasive cancers,.	('invasive cancers', 'Disease', 'MESH:D009362', (136, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ductal carcinoma', 'Disease', 'MESH:D044584', (87, 103))	('progress', 'PosReg', (124, 132))	('ductal carcinoma', 'Disease', (87, 103))	('invasive cancers', 'Disease', (136, 152))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (26, 35))	('MCF10DCIS', 'Var', (26, 35))	('human', 'Species', '9606', (81, 86))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (87, 111))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
93733	21822285	Supporting these observations, both celecoxib and shRNA knockdown of COX-2 decreased tumor cell invasive morphology observed on collagen (Fig 3g&h, Supplementary Fig 3d).	('celecoxib', 'Chemical', 'MESH:D000068579', (36, 45))	('decreased tumor', 'Disease', 'MESH:D009369', (75, 90))	('decreased tumor', 'Disease', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('COX-2', 'Gene', (69, 74))	('knockdown', 'Var', (56, 65))
93739	21822285	These unexpected results suggest that COX-2 inhibitors block collagen fibrillogenesis during postpartum mammary gland involution, as well as directly target tumor cell COX-2 expression that results from interaction with collagen, as modeled in Figure 4f.	('tumor', 'Disease', (157, 162))	('inhibitors', 'Var', (44, 54))	('expression', 'MPA', (174, 184))	('interaction', 'Interaction', (203, 214))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('block', 'NegReg', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('COX-2', 'Gene', (168, 173))	('collagen fibrillogenesis', 'MPA', (61, 85))
93744	21822285	In this data set, high Col1AI1and COX-2 (gene name: prostaglandin-endoperoxide synthase 2, PTGS2) expression correlated with decreased relapse free survival with a hazard ration of 1.45, (95% CI: 1.08-1.95, multivariate Cox proportional-hazards model) that was independent of estrogen receptor (ER) status (Fig 5c, Supplementary Fig 5c&d).	('PTGS2', 'Gene', '5743', (91, 96))	('prostaglandin-endoperoxide synthase 2', 'Gene', (52, 89))	('ER', 'Gene', '2099', (295, 297))	('relapse free survival', 'CPA', (135, 156))	('Cox', 'Gene', '1351', (220, 223))	('decreased', 'NegReg', (125, 134))	('Col1AI1and', 'Gene', (23, 33))	('prostaglandin-endoperoxide synthase 2', 'Gene', '5743', (52, 89))	('Cox', 'Gene', (220, 223))	('estrogen receptor', 'Gene', '2099', (276, 293))	('rat', 'Species', '10116', (171, 174))	('estrogen receptor', 'Gene', (276, 293))	('high', 'Var', (18, 22))	('COX-2', 'Gene', (34, 39))	('PTGS2', 'Gene', (91, 96))
93746	21822285	Further, in the NKI295 dataset, high Col1 and COX-2 positively correlated with an activated wound response-gene expression signature previously shown to associate with decreased metastasis free and overall survival in breast cancer subjects (Supplementary Fig 5e).	('breast cancer', 'Disease', (218, 231))	('high', 'Var', (32, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('COX-2', 'Gene', (46, 51))	('decreased', 'NegReg', (168, 177))	('Col1', 'Gene', (37, 41))	('activated wound response-gene expression signature', 'MPA', (82, 132))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))
93864	20143325	However, financial status was positively associated with depression and anxiety at the 9-month follow-up (Table 2).	('associated', 'Reg', (41, 51))	('anxiety', 'Disease', (72, 79))	('anxiety', 'Phenotype', 'HP:0000739', (72, 79))	('financial status', 'Var', (9, 25))	('depression', 'Disease', 'MESH:D000275', (57, 67))	('depression', 'Phenotype', 'HP:0000716', (57, 67))	('anxiety', 'Disease', 'MESH:D001008', (72, 79))	('depression', 'Disease', (57, 67))
93912	33180162	False-positive screening exams are associated with temporary uncertainty and anxiety, and healthcare costs for further assessment; however, this follow-up can provide confirmation that a woman does not have breast cancer.	('anxiety', 'Disease', 'MESH:D001007', (77, 84))	('False-positive', 'Var', (0, 14))	('anxiety', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('anxiety', 'Phenotype', 'HP:0000739', (77, 84))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', (207, 220))	('woman', 'Species', '9606', (187, 192))
93958	33180162	Multiple imputation with chained equations was used to impute missing data for grade; lymph node status; ER, PR, and HER2 positivity; and Ki67 expression.	('HER2', 'Gene', (117, 121))	('positivity', 'Var', (122, 132))	('HER2', 'Gene', '2064', (117, 121))	('ER', 'Gene', '2099', (118, 120))	('PR', 'Gene', '5241', (109, 111))	('ER', 'Gene', '2099', (105, 107))
93964	33180162	Mean (SD) age at diagnosis did not differ by more than 2 years for women with true (62 (5.1)), minimal signs (62 (4.7)), or missed (63 (4.8)) screen-detected cancer, or for women with true (59 (5.8)), minimal signs (60 (5.7)), or missed (61 (5.2)) interval cancer.	('minimal signs', 'Var', (201, 214))	('women', 'Species', '9606', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('women', 'Species', '9606', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('age', 'Gene', (10, 13))	('missed', 'Var', (124, 130))	('cancer', 'Disease', (158, 164))	('minimal signs', 'Var', (95, 108))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('age', 'Gene', '5973', (10, 13))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
94028	33180162	This article focuses on the survival associated with true, missed, and minimal signs breast cancer, both screen-detected and interval breast cancer, and does not discuss the mammographic features associated with these classifications.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('minimal signs', 'Var', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('missed', 'Disease', (59, 65))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
94029	22777354	Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s) Singleminded-2s (SIM2s) is a member of the bHLH/PAS family of transcription factors and a key regulator of mammary epithelial cell differentiation.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('invasive breast cancer', 'Disease', 'MESH:D001943', (22, 44))	('Singleminded-2s', 'Var', (84, 99))	('SIM2s', 'Chemical', '-', (101, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('invasive breast cancer', 'Disease', (22, 44))	('SIM2s', 'Chemical', '-', (77, 82))
94031	22777354	Loss of Sim2s causes aberrant mouse mammary ductal development with features suggestive of malignant transformation, whereas over-expression of SIM2s promotes precocious alveolar differentiation in nulliparous mouse mammary glands, suggesting that SIM2s is required for establishing and enhancing mammary gland differentiation.	('SIM2s', 'Chemical', '-', (144, 149))	('SIM2s', 'Chemical', '-', (248, 253))	('SIM2s', 'Gene', (144, 149))	('promotes', 'PosReg', (150, 158))	('precocious alveolar differentiation', 'CPA', (159, 194))	('Sim2s', 'Gene', (8, 13))	('mouse', 'Species', '10090', (210, 215))	('mouse mammary ductal development', 'CPA', (30, 62))	('Loss', 'Var', (0, 4))	('mouse', 'Species', '10090', (30, 35))
94034	22777354	Analysis of SIM2s-MCF10DCIS.com tumors showed that SIM2s promoted a more differentiated tumor phenotype including the expression of a broad range of luminal markers (CSN2 (beta-casein), CDH1 (E-cadherin), and KER18 (keratin-18)) and suppressed genes associated with stem cell maintenance and a basal phenotype (SMO (smoothened), p63, SLUG (snail-2), KER14 (keratin-14) and VIM (vimentin)).	('beta-casein', 'Gene', (172, 183))	('SIM2s', 'Var', (51, 56))	('promoted', 'PosReg', (57, 65))	('SIM2s', 'Chemical', '-', (51, 56))	('snail-2', 'Gene', (340, 347))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('KER14', 'Gene', (350, 355))	('KER18', 'Gene', '3875', (209, 214))	('keratin-14', 'Gene', '3861', (357, 367))	('smoothened', 'Gene', (316, 326))	('keratin-18', 'Gene', '3875', (216, 226))	('CDH1', 'Gene', '999', (186, 190))	('SMO', 'Gene', '6608', (311, 314))	('keratin-14', 'Gene', (357, 367))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('genes', 'MPA', (244, 249))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (18, 31))	('CDH1', 'Gene', (186, 190))	('smoothened', 'Gene', '6608', (316, 326))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('SMO', 'Gene', (311, 314))	('CSN2', 'Gene', '1447', (166, 170))	('tumor', 'Disease', (32, 37))	('p63', 'Gene', (329, 332))	('expression', 'MPA', (118, 128))	('KER14', 'Gene', '3861', (350, 355))	('stem cell maintenance', 'CPA', (266, 287))	('p63', 'Gene', '8626', (329, 332))	('keratin-18', 'Gene', (216, 226))	('suppressed', 'NegReg', (233, 243))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('SIM2s', 'Chemical', '-', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('KER18', 'Gene', (209, 214))	('CSN2', 'Gene', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('beta-casein', 'Gene', '1447', (172, 183))	('snail-2', 'Gene', '6591', (340, 347))
94050	22777354	In the studies here, we examined the role of SIM2s in regulating the progression of DCIS to IDC and metastasis, while promoting the less aggressive, luminal-like breast cancer subtype.	('SIM2s', 'Var', (45, 50))	('SIM2s', 'Chemical', '-', (45, 50))	('promoting', 'PosReg', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('DCIS', 'Disease', (84, 88))	('less aggressive', 'CPA', (132, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))	('metastasis', 'CPA', (100, 110))
94060	22777354	To determine the effect of SIM2s loss and gain of function, we stably transduced MCF10DCIS.COM cells with SIM2s and previously validated SIM2s-shRNA (SIM2si) lentiviruses.	('SIM2s', 'Chemical', '-', (137, 142))	('SIM2s', 'Chemical', '-', (27, 32))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (81, 94))	('SIM2s loss', 'Disease', 'MESH:D015431', (27, 37))	('SIM2s', 'Var', (106, 111))	('SIM2s loss', 'Disease', (27, 37))	('SIM2s', 'Chemical', '-', (150, 155))	('SIM2s', 'Chemical', '-', (106, 111))
94062	22777354	Q-PCR analysis of SIM2s mRNA levels show an approximate 80% loss of expression in SIM2si cells compared to scrambled controls (Fig.	('SIM2s', 'Chemical', '-', (18, 23))	('expression', 'MPA', (68, 78))	('loss', 'NegReg', (60, 64))	('SIM2s', 'Chemical', '-', (82, 87))	('SIM2si', 'Var', (82, 88))
94063	22777354	In growth assays, SIM2s inhibited cell proliferation, whereas loss of SIM2s led to a significant increase in proliferation as compared to scrambled controls (Fig.	('loss', 'NegReg', (62, 66))	('increase', 'PosReg', (97, 105))	('SIM2s', 'Chemical', '-', (18, 23))	('cell proliferation', 'CPA', (34, 52))	('SIM2s', 'Chemical', '-', (70, 75))	('inhibited', 'NegReg', (24, 33))	('SIM2s', 'Gene', (70, 75))	('proliferation', 'CPA', (109, 122))	('SIM2s', 'Var', (18, 23))
94064	22777354	We observed no change in invasive potential with SIM2s over-expression in Boyden chamber assays; however, there was a significant increase in invasion in the SIM2si cells (Fig.	('SIM2s', 'Chemical', '-', (158, 163))	('SIM2s', 'Chemical', '-', (49, 54))	('increase', 'PosReg', (130, 138))	('SIM2si', 'Var', (158, 164))	('invasion', 'CPA', (142, 150))
94065	22777354	Q-PCR analysis also showed a significant increase in E-Cadherin (CDH1) expression with SIM2s expression, as well as a decrease with SIM2si (Fig.	('expression', 'MPA', (71, 81))	('E-Cadherin', 'Gene', (53, 63))	('SIM2s', 'Chemical', '-', (87, 92))	('CDH1', 'Gene', (65, 69))	('E-Cadherin', 'Gene', '999', (53, 63))	('CDH1', 'Gene', '999', (65, 69))	('SIM2si', 'Var', (132, 138))	('SIM2s', 'Chemical', '-', (132, 137))	('decrease', 'NegReg', (118, 126))	('SIM2s expression', 'Var', (87, 103))	('increase', 'PosReg', (41, 49))
94066	22777354	Similarly, p21, an important senescence and cell cycle regulator, was also significantly altered in response to SIM2s (Fig.	('p21', 'Gene', (11, 14))	('p21', 'Gene', '644914', (11, 14))	('SIM2s', 'Chemical', '-', (112, 117))	('SIM2s', 'Var', (112, 117))	('altered', 'Reg', (89, 96))
94073	22777354	Immunohistological analysis of tumors confirmed that SIM2s and SIM2si tumors continued to overexpress or knock down SIM2s protein levels in vivo (Fig.	('protein', 'Protein', (122, 129))	('SIM2si tumors', 'Disease', 'MESH:D009369', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('knock', 'Var', (105, 110))	('SIM2s', 'Chemical', '-', (63, 68))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SIM2si tumors', 'Disease', (63, 76))	('overexpress', 'PosReg', (90, 101))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('SIM2s', 'Chemical', '-', (53, 58))	('SIM2s', 'Chemical', '-', (116, 121))	('SIM2s', 'Gene', (116, 121))
94077	22777354	Immunostaining for basal markers including keratin 14 (KER14), alpha-smooth muscle actin (alphaSMA), vimentin (VIM) and p63 show a decrease in staining in SIM2s over-expressing MCF10DCIS.COM tumors, and up-regulation with loss of SIM2s (Fig.	('p63', 'Gene', (120, 123))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('keratin 14', 'Gene', '3861', (43, 53))	('SIM2s', 'Gene', (230, 235))	('KER14', 'Gene', (55, 60))	('KER14', 'Gene', '3861', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (177, 190))	('SIM2s', 'Chemical', '-', (155, 160))	('p63', 'Gene', '8626', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('keratin 14', 'Gene', (43, 53))	('tumors', 'Disease', (191, 197))	('loss', 'Var', (222, 226))	('up-regulation', 'PosReg', (203, 216))	('SIM2s', 'Chemical', '-', (230, 235))
94080	22777354	These results are consistent with SIM2s's role in mammary gland differentiation as p63, SMO and SLUG regulate cell differentiation and stem cell maintenance, which suggests that re-establishment of SIM2s is sufficient to promote a decrease in basal breast cancer markers.	('SIM2s', 'Chemical', '-', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('p63', 'Gene', (83, 86))	('SIM2s', 'Var', (198, 203))	('SMO', 'Gene', '6608', (88, 91))	('SMO', 'Gene', (88, 91))	('basal breast cancer', 'Disease', 'MESH:D001943', (243, 262))	('basal breast cancer', 'Disease', (243, 262))	('SIM2s', 'Chemical', '-', (198, 203))	('p63', 'Gene', '8626', (83, 86))	('decrease', 'NegReg', (231, 239))
94081	22777354	Analysis of p21 mRNA levels also showed a decrease in SIM2si xenografts, similar to what was seen in vitro (Fig.	('SIM2si', 'Var', (54, 60))	('decrease', 'NegReg', (42, 50))	('p21', 'Gene', (12, 15))	('SIM2s', 'Chemical', '-', (54, 59))	('p21', 'Gene', '644914', (12, 15))
94087	22777354	MUC1, an apical luminal marker that is often mis-localized in cancer, showed an increase in apical staining in SIM2s xenografts, while a loss of localization is seen in SIM2si tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('SIM2s', 'Var', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increase', 'PosReg', (80, 88))	('SIM2si tumors', 'Disease', 'MESH:D009369', (169, 182))	('SIM2s', 'Chemical', '-', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('SIM2s', 'Chemical', '-', (169, 174))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('apical staining', 'MPA', (92, 107))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))	('SIM2si tumors', 'Disease', (169, 182))
94089	22777354	Analysis of GATA3 mRNA expression showed no differences in with SIM2s expression, indicating that the differentiation phenotype associated with SIM2s expression appears to be GATA3 independent in this model (Fig.	('SIM2s', 'Var', (144, 149))	('SIM2s', 'Chemical', '-', (144, 149))	('GATA3', 'Gene', (12, 17))	('GATA3', 'Gene', '2625', (12, 17))	('GATA3', 'Gene', (175, 180))	('SIM2s', 'Chemical', '-', (64, 69))	('GATA3', 'Gene', '2625', (175, 180))
94093	22777354	Overall these data support the hypothesis that expression of SIM2s induces a luminal phenotype, including expression of milk proteins, while loss of SIM2s significantly decreases the expression of luminal markers.	('expression', 'MPA', (106, 116))	('loss', 'Var', (141, 145))	('expression', 'Var', (47, 57))	('induces', 'Reg', (67, 74))	('SIM2s', 'Chemical', '-', (149, 154))	('milk proteins', 'Protein', (120, 133))	('decreases', 'NegReg', (169, 178))	('SIM2s', 'Var', (61, 66))	('expression of luminal markers', 'MPA', (183, 212))	('SIM2s', 'Chemical', '-', (61, 66))	('SIM2s', 'Gene', (149, 154))	('luminal phenotype', 'MPA', (77, 94))
94102	22777354	In contrast, no significant change in angiogenesis was seen with loss of SIM2s, indicating that the increase in metastasis is due to other metastatic processes.	('loss', 'Var', (65, 69))	('metastasis', 'CPA', (112, 122))	('SIM2s', 'Chemical', '-', (73, 78))	('SIM2s', 'Gene', (73, 78))	('increase', 'PosReg', (100, 108))
94112	22777354	In contrast, overexpression of Sim2s in the mouse mammary gland under the MMTV promoter induces precocious lactogenic differentiation in virgin mice and delayed involution following forced weaning.	('induces', 'Reg', (88, 95))	('mouse', 'Species', '10090', (44, 49))	('mice', 'Species', '10090', (144, 148))	('precocious lactogenic differentiation', 'CPA', (96, 133))	('overexpression', 'PosReg', (13, 27))	('MMTV', 'Species', '11757', (74, 78))	('delayed involution', 'CPA', (153, 171))	('Sim2s', 'Var', (31, 36))
94113	22777354	Together, these observations led us to hypothesize that expression of SIM2s in breast cancer would inhibit tumor growth by regulating differentiation potential.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('regulating', 'Reg', (123, 133))	('differentiation potential', 'CPA', (134, 159))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('inhibit', 'NegReg', (99, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('SIM2s in breast cancer', 'Disease', 'MESH:D001943', (70, 92))	('expression', 'Var', (56, 66))	('SIM2s in breast cancer', 'Disease', (70, 92))
94129	22777354	For instance, analysis of Gata3 conditional knockout mammary glands found an increase in luminal progenitor cells during alveolar differentiation and a defect in virgin ductal morphogenesis as a result of compromised estrogen responsiveness, whereas loss of Elf5 has no effect on virgin development and exclusively regulates alveolar cell fate.	('virgin ductal morphogenesis', 'CPA', (162, 189))	('Elf5', 'Gene', '2001', (258, 262))	('Elf5', 'Gene', (258, 262))	('regulates', 'Reg', (315, 324))	('alveolar cell fate', 'CPA', (325, 343))	('estrogen responsiveness', 'MPA', (217, 240))	('Gata3', 'Gene', (26, 31))	('Gata3', 'Gene', '2625', (26, 31))	('increase', 'PosReg', (77, 85))	('defect', 'NegReg', (152, 158))	('compromised', 'NegReg', (205, 216))	('loss', 'Var', (250, 254))	('luminal progenitor cells', 'CPA', (89, 113))
94135	22777354	One of the most interesting phenotypes of this study was the dramatic increase in lung metastasis with loss of SIM2s.	('increase', 'PosReg', (70, 78))	('loss', 'Var', (103, 107))	('SIM2s', 'Chemical', '-', (111, 116))	('lung metastasis', 'CPA', (82, 97))	('SIM2s', 'Gene', (111, 116))
94138	22777354	In the study here, we observed a SIM2s-dependent regulation of MMP gene expression in SIM2s over and under-expressing DCIS xenografts.	('SIM2s', 'Var', (86, 91))	('regulation', 'Reg', (49, 59))	('SIM2s', 'Chemical', '-', (86, 91))	('MMP gene', 'Gene', (63, 71))	('expression', 'MPA', (72, 82))	('under-expressing', 'NegReg', (101, 117))	('SIM2s', 'Chemical', '-', (33, 38))
94139	22777354	We showed that MMP1 and MMP10 were significantly decreased by SIM2s expression, whereas MMP3 was significantly increased by loss of SIM2s, accompanied by increased trends in other MMPs analyzed.	('loss', 'NegReg', (124, 128))	('MMP3', 'Gene', (88, 92))	('SIM2s', 'Chemical', '-', (62, 67))	('increased', 'PosReg', (111, 120))	('MMP1', 'Gene', (15, 19))	('MMPs', 'Gene', '4312;4313;17390;81686;4314;17392;171045;4318;81687;4319', (180, 184))	('MMP1', 'Gene', '4312', (24, 28))	('MMP10', 'Gene', (24, 29))	('MMP3', 'Gene', '4314', (88, 92))	('decreased', 'NegReg', (49, 58))	('expression', 'Var', (68, 78))	('SIM2s', 'Chemical', '-', (132, 137))	('MMP1', 'Gene', (24, 28))	('SIM2s', 'Gene', (132, 137))	('MMP1', 'Gene', '4312', (15, 19))	('SIM2s expression', 'Var', (62, 78))	('MMPs', 'Gene', (180, 184))	('MMP10', 'Gene', '4319', (24, 29))
94143	22777354	Studies in gastric and ovarian cancer have also connected hedgehog signaling with invasion and MMP expression, suggesting a potential mechanism of action by which SIM2s inhibits invasion and metastasis in vivo.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('SIM2s', 'Var', (163, 168))	('hedgehog', 'Gene', (58, 66))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (11, 37))	('SIM2s', 'Chemical', '-', (163, 168))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('inhibits', 'NegReg', (169, 177))	('hedgehog', 'Gene', '3549', (58, 66))
94146	22777354	Moreover, the use of established metastatic models and the impact of SIM2s on breast cancer subtypes will help elucidate the mechanism by which SIM2s affects tumor progression as well as its possible effect on tumor initiating cells.	('SIM2s', 'Var', (144, 149))	('SIM2s', 'Chemical', '-', (144, 149))	('tumor', 'Disease', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('SIM2s', 'Chemical', '-', (69, 74))	('affects', 'Reg', (150, 157))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
94189	32691540	In set 1 (selective downgrading only for category 4a lesions), the combination of B-mode US with Emax or SMIVI resulted in significantly higher AUC values at 0.829 (95% CI, 0.769-0.890; p < 0.001) and 0.778 (95% CI, 0.713-0.843; p = 0.047) than B-mode US alone, with an AUC value of 0.719 (95% CI, 0.649-0.789).	('set 1', 'Gene', '9739', (3, 8))	('AUC values', 'MPA', (144, 154))	('0.778', 'Var', (201, 206))	('higher', 'PosReg', (137, 143))	('set 1', 'Gene', (3, 8))
94223	30108100	Low socioeconomic status (SES), as measured either at the individual or area level, has been associated with later stage of diagnosis, suboptimal treatment, and lower survival in women with invasive breast cancer.	('lower', 'NegReg', (161, 166))	('invasive breast cancer', 'Disease', 'MESH:D001943', (190, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('women', 'Species', '9606', (179, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('survival', 'MPA', (167, 175))	('invasive breast cancer', 'Disease', (190, 212))	('Low socioeconomic status', 'Var', (0, 24))
94257	30108100	Compared to urban women, rural women with DCIS were older (61.7 vs. 60.1, P < .0001), had a smaller proportion of racial minorities (1.8% vs. 12.4%, P < .0001), and were less likely to have private health insurance (47.9% vs. 61.4%, P < .0001).	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('DCIS', 'Var', (42, 46))	('women', 'Species', '9606', (18, 23))	('women', 'Species', '9606', (31, 36))	('smaller', 'NegReg', (92, 99))
94357	23873154	We hypothesized that either antibodies against serum HERV-K(HML-2) or serum HERV-K(HML-2) mRNA, or the combination of both, could indicate the presence of early stage breast cancer and examined their association with DCIS and stage I breast cancer.	('breast cancer', 'Disease', (167, 180))	('HML-2', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('HML-2', 'Gene', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('examined', 'Reg', (185, 193))	('HML-2', 'Gene', '10462', (83, 88))	('HERV-K', 'Species', '45617', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('I breast cancer', 'Disease', 'MESH:D001943', (232, 247))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('HERV-K', 'Species', '45617', (76, 82))	('HML-2', 'Gene', '10462', (60, 65))	('association', 'Interaction', (200, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('indicate', 'Reg', (130, 138))	('antibodies', 'Var', (28, 38))	('I breast cancer', 'Disease', (232, 247))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
94368	23873154	Monoclonal antibody (mAb) clones 6H5, 4D1, 4E11, 6E11, and 4E6 against HERV-K(HML-2) env surface protein were generated in our laboratory, and mAb 6H5 had the highest specificity and sensitivity toward HERV-K(HML-2).	('HML-2', 'Gene', '10462', (78, 83))	('HERV-K', 'Species', '45617', (202, 208))	('env', 'Gene', (85, 88))	('HML-2', 'Gene', '10462', (209, 214))	('HERV-K', 'Species', '45617', (71, 77))	('sensitivity', 'MPA', (183, 194))	('env', 'Gene', '100616444', (85, 88))	('HML-2', 'Gene', (78, 83))	('HML-2', 'Gene', (209, 214))	('4E6', 'Var', (59, 62))
94378	23873154	HERV-K(HML-2) MAPs containing a poly-lysine core were produced by BiomerTechnology (Pleasanton, CA).	('HML-2', 'Gene', (7, 12))	('poly-lysine', 'Chemical', 'MESH:D011107', (32, 43))	('HERV-K', 'Species', '45617', (0, 6))	('HML-2', 'Gene', '10462', (7, 12))	('poly-lysine', 'Var', (32, 43))
94385	23873154	Both primers also showed 100% identity with HERV-K HML-2_19p12b (K113), HERV-K HML-2_12q13.2, HERV-K HML-2_5q33.3 (K107/K10, K(C5), ERVK-10), HERV-K HML-2_3q27.2 (K50b, K117, ERVK-11), HERV-K HML-2_1q22 (K102, K(C1b), K50a, ERVK-7), and HERV-K HML-2_1p31.1 (K4, K116, ERVK-1).	('HERV-K', 'Species', '45617', (72, 78))	('HERV-K', 'Species', '45617', (185, 191))	('HML-2', 'Gene', '10462', (244, 249))	('HML-2', 'Gene', '10462', (101, 106))	('HML-2', 'Gene', '10462', (149, 154))	('HERV-K', 'Species', '45617', (237, 243))	('HML-2', 'Gene', (51, 56))	('HERV-K', 'Species', '45617', (94, 100))	('HERV-K', 'Species', '45617', (142, 148))	('HML-2', 'Gene', (79, 84))	('HML-2', 'Gene', (192, 197))	('K107/K10', 'Var', (115, 123))	('HML-2', 'Gene', '10462', (51, 56))	('HERV-K', 'Species', '45617', (44, 50))	('HML-2', 'Gene', (244, 249))	('HML-2', 'Gene', (101, 106))	('HML-2', 'Gene', '10462', (192, 197))	('HML-2', 'Gene', '10462', (79, 84))	('HML-2', 'Gene', (149, 154))
94400	23873154	For the breast cancer curve, the optimum cut-off value was 1.00 OD405 units at which we achieved an 86.2% sensitivity and 100% specificity.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('OD405 units', 'Var', (64, 75))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
94435	23873154	Anti-HERV-K(HML-2) antibodies may have an important diagnostic value and suggest chemotherapy success.	('HERV-K', 'Species', '45617', (5, 11))	('Anti-HERV-K', 'Var', (0, 11))	('HML-2', 'Gene', '10462', (12, 17))	('HML-2', 'Gene', (12, 17))
94451	23873154	In addition, women with genetic mutations that predispose them to increased breast cancer risk (for example, BRCA1 and BRCA2) should also benefit from HERV-K(HML-2) screening.	('HERV-K', 'Species', '45617', (151, 157))	('BRCA1', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HML-2', 'Gene', '10462', (158, 163))	('mutations', 'Var', (32, 41))	('breast cancer', 'Disease', (76, 89))	('BRCA2', 'Gene', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('women', 'Species', '9606', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('BRCA1', 'Gene', '672', (109, 114))	('BRCA2', 'Gene', '675', (119, 124))	('HML-2', 'Gene', (158, 163))
94499	23184608	CD44v6 and E-cadherin were expressed in MCF10DCIS only.	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('CD44', 'Gene', '12505', (0, 4))	('E-cadherin', 'Gene', (11, 21))	('CD44', 'Gene', (0, 4))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (40, 49))	('MCF10DCIS', 'Var', (40, 49))	('E-cadherin', 'Gene', '999', (11, 21))
94507	23184608	The NIRF dye IRDye800CW, purchased as an N-hydroxysuccinimide ester (LI-COR Biosciences, Lincoln, NE, USA), was incubated in a fourfold molar excess of dye to IgG for 2 h at room temperature.	('N-hydroxysuccinimide ester', 'Chemical', 'MESH:C008869', (41, 67))	('COR', 'Gene', (72, 75))	('rat', 'Species', '10116', (184, 187))	('COR', 'Gene', '108031', (72, 75))	('IRDye800CW', 'Var', (13, 23))
94529	23184608	For detection of IRDye800CW, tumor slides were deparaffinized, mounted with Immu-mount (Thermo Fisher Scientific), and scanned using the Odyssey Imaging System.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('IRDye800CW', 'Var', (17, 27))	('paraffin', 'Chemical', 'MESH:D010232', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))
94536	23184608	Mice bearing MCF10DCIS and MDA-MB-231 tumors (used as a CD44v6-negative control) were intravenously injected with IRDye800CW-conjugated CD44v6 Ab or control IgG.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('MCF10DCIS', 'Var', (13, 22))	('CD44', 'Gene', '12505', (56, 60))	('CD44', 'Gene', (56, 60))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('MDA-MB-231', 'Gene', (27, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (27, 37))	('CD44', 'Gene', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('CD44', 'Gene', '12505', (136, 140))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('Mice', 'Species', '10090', (0, 4))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (13, 22))
94537	23184608	Accumulation of CD44v6 Ab in the MCF10DCIS tumor became detectable 4 h postinjection, whereas control IgG was not (Fig.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (33, 42))	('CD44', 'Gene', '12505', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CD44', 'Gene', (16, 20))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('MCF10DCIS', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
94538	23184608	A clear signal of the MCF10DCIS tumor was obtained from 3 days onwards, due to accumulation of the tracer in the tumor and decreased background signal from circulating tracer.	('tumor', 'Disease', (113, 118))	('background signal from circulating tracer', 'MPA', (133, 174))	('decreased', 'NegReg', (123, 132))	('accumulation', 'PosReg', (79, 91))	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('MCF10DCIS', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (32, 37))
94539	23184608	In contrast, accumulation of free IRDye800CW was not observed (data not shown), while levels of control IgG were similar in MCF10DCIS vs. MDA-MB-231 tumors (Fig.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MCF10DCIS', 'Var', (124, 133))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (138, 148))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('DCIS', 'Phenotype', 'HP:0030075', (129, 133))
94540	23184608	The maximal fluorescence intensity in the MCF10DCIS tumor was reached after 8 h (control IgG) and 24 h (CD44v6 Ab) and decreased to background levels in 8 days (control IgG) or stabilized after 5 days (CD44v6 Ab) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('MCF10DCIS', 'Var', (42, 51))	('tumor', 'Disease', (52, 57))	('CD44', 'Gene', '12505', (202, 206))	('CD44', 'Gene', (202, 206))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (42, 51))	('CD44', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD44', 'Gene', '12505', (104, 108))	('fluorescence intensity', 'MPA', (12, 34))
94542	23184608	As a result, tumor-to-background ratio for CD44v6 Ab increased from 2.41 +- 0.39 3 days postinjection to 2.78 +- 0.31 7 days postinjection and tended to increase further in MCF10DCIS (Fig.	('tumor', 'Disease', (13, 18))	('CD44', 'Gene', (43, 47))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (173, 182))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('rat', 'Species', '10116', (33, 36))	('CD44', 'Gene', '12505', (43, 47))	('MCF10DCIS', 'Var', (173, 182))	('increase', 'PosReg', (153, 161))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
94543	23184608	In contrast, tumor-to-background ratio of control IgG declined to 1.31 +- 0.06 8 days postinjection and was significantly lower than CD44v6 Ab (p = 0.004) in the MCF10DCIS tumor.	('tumor', 'Disease', (13, 18))	('lower', 'NegReg', (122, 127))	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('MCF10DCIS', 'Var', (162, 171))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('declined', 'NegReg', (54, 62))	('CD44', 'Gene', '12505', (133, 137))	('CD44', 'Gene', (133, 137))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
94549	23184608	Specific accumulation of the CD44v6 Ab was observed in the MCF10DCIS tumor (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CD44', 'Gene', (29, 33))	('tumor', 'Disease', (69, 74))	('CD44', 'Gene', '12505', (29, 33))	('accumulation', 'PosReg', (9, 21))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('MCF10DCIS', 'Var', (59, 68))
94551	23184608	Tumor intensity of MCF10DCIS and MDA-MB-231 tumors compared to the surrounding tissue (skin and abdomen) was higher, independent of the injected IgG (Fig 2a, b), most likely due to probe retention caused by enhanced tumor vascularization.	('tumor', 'Disease', (216, 221))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (19, 28))	('higher', 'PosReg', (109, 115))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MCF10DCIS', 'Var', (19, 28))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('enhanced', 'PosReg', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Tumor intensity', 'MPA', (0, 15))	('MDA-MB-231', 'Gene', (33, 43))	('tumor', 'Disease', (44, 49))
94552	23184608	MCF10DCIS tumor signals were significantly higher in CD44v6 Ab-injected mice intraoperatively, compared to the MDA-MB-231 tumors in the same mouse and compared to the MCF10DCIS tumors in mice injected with control IgG (p = 0.014 and p = 0.006, respectively; Fig.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('CD44', 'Gene', '12505', (53, 57))	('mice', 'Species', '10090', (187, 191))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('tumor', 'Disease', (122, 127))	('MCF10DCIS', 'Var', (0, 9))	('tumor', 'Disease', (10, 15))	('rat', 'Species', '10116', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mouse', 'Species', '10090', (141, 146))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (167, 176))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('higher', 'PosReg', (43, 49))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('MCF10DCIS tumors', 'Disease', (167, 183))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (122, 128))	('CD44', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mice', 'Species', '10090', (72, 76))	('tumors', 'Disease', (177, 183))	('MCF10DCIS tumors', 'Disease', 'MESH:D009369', (167, 183))
94559	23184608	The levels of IgG in muscle was low (approximately 0.2 % ID/g tissue), while 9.9 +- 0.8 % ID/g of the CD44v6 Ab and 2.8 +- 0.2 % ID/g tissue of the control IgG were present in the MCF10DCIS tumor.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('MCF10DCIS', 'Var', (180, 189))	('CD44', 'Gene', '12505', (102, 106))	('tumor', 'Disease', (190, 195))	('CD44', 'Gene', (102, 106))
94572	23184608	In the present study, we show that optical imaging with IRDye800CW-labeled humanized antibodies directed to CD44v6 is feasible in a model of preinvasive breast cancer.	('CD44', 'Gene', (108, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('IRDye800CW-labeled', 'Var', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('human', 'Species', '9606', (75, 80))	('breast cancer', 'Disease', (153, 166))	('CD44', 'Gene', '12505', (108, 112))
94574	23184608	Tumor accumulation of IRDye800CW-labeled CD44v6 antibodies in our study (9.9 +- 0.8 % ID/g) was comparable to studies using radiolabeled CD44v6 antibodies, which reported a tumor accumulation of 12.9-15.4 % ID/g in human or 15.3 % ID/g using A431 xenografts in mice.	('IRDye800CW-labeled', 'Var', (22, 40))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD44', 'Gene', '12505', (137, 141))	('mice', 'Species', '10090', (261, 265))	('CD44', 'Gene', (137, 141))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('CD44', 'Gene', (41, 45))	('CD44', 'Gene', '12505', (41, 45))	('human', 'Species', '9606', (215, 220))
94575	23184608	This indicates that biodistribution of IRDye800CW-labeled CD44v6-specific antibodies is comparable to radiolabeled CD44v6 antibodies, which was also recently shown for epidermal growth factor receptor (EGFR)-specific antibodies.	('epidermal growth factor receptor', 'Gene', (168, 200))	('EGFR', 'Gene', (202, 206))	('EGFR', 'Gene', '13649', (202, 206))	('CD44', 'Gene', (115, 119))	('CD44', 'Gene', '12505', (115, 119))	('epidermal growth factor receptor', 'Gene', '13649', (168, 200))	('CD44', 'Gene', '12505', (58, 62))	('CD44', 'Gene', (58, 62))	('IRDye800CW-labeled', 'Var', (39, 57))
94611	19123950	Furthermore, amplification of HER2 has also been shown to correlate with poor prognosis and with resistance to conventional adjuvant chemotherapy and tamoxifen.	('poor prognosis', 'CPA', (73, 87))	('tamoxifen', 'Chemical', 'MESH:D013629', (150, 159))	('HER2', 'Gene', (30, 34))	('amplification', 'Var', (13, 26))	('HER2', 'Gene', '2064', (30, 34))
94639	19123950	Figure 2 shows that there was no association between copy number ratios before and after microdissection and tumor percentage.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('copy number', 'Var', (53, 64))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
94650	19123950	We showed in Figure 2 that there was no association between copy number ratios before and after microdissection and tumor percentage.	('copy number', 'Var', (60, 71))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
94657	19123950	Nevertheless, patients with especially a low level amplification MLPA result seem to benefit most from microdissection.	('low level amplification', 'Var', (41, 64))	('patients', 'Species', '9606', (14, 22))	('MLPA', 'Gene', (65, 69))	('benefit', 'PosReg', (85, 92))	('microdissection', 'CPA', (103, 118))	('amplification', 'Var', (51, 64))
94658	19123950	The amplification and overexpression of HER2 is seen more frequently in DCIS (50-60%) than in invasive ductal carcinoma of the breast (10-20%) and the presence of DCIS can thereby bias MLPA results.	('invasive ductal carcinoma of the breast', 'Disease', 'MESH:D018270', (94, 133))	('bias', 'Reg', (180, 184))	('HER2', 'Gene', (40, 44))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (110, 133))	('overexpression', 'PosReg', (22, 36))	('HER2', 'Gene', '2064', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('amplification', 'MPA', (4, 17))	('DCIS', 'Disease', (72, 76))	('invasive ductal carcinoma of the breast', 'Disease', (94, 133))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (103, 119))	('presence', 'Var', (151, 159))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))
94662	19123950	MLPA is a fast, accurate and cheap method to detect breast cancer HER-2/neu amplification in small quantities of DNA extracted from paraffin blocks.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('paraffin', 'Chemical', 'MESH:D010232', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('HER-2/neu', 'Gene', (66, 75))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('HER-2/neu', 'Gene', '2064', (66, 75))	('amplification', 'Var', (76, 89))
94705	31001821	The rate of upgrade to DCIS or invasive carcinoma was highest for CNB yielding atypical ductal hyperplasia (34.9%, 22/63, 18 DCIS and four invasive carcinomas), followed by "other" lesions (30.0%, 3/10, all invasive carcinomas) and papillary lesions (16.4%, 19/116, 14 DCIS and five invasive carcinomas).	('invasive carcinoma', 'Disease', 'MESH:D009361', (207, 225))	('invasive carcinoma', 'Disease', (31, 49))	('invasive carcinomas', 'Disease', 'MESH:D009361', (139, 158))	('invasive carcinomas', 'Disease', (283, 302))	('invasive carcinoma', 'Disease', 'MESH:D009361', (31, 49))	('papillary lesions', 'Phenotype', 'HP:0007482', (232, 249))	('papillary lesions', 'Disease', 'MESH:D007681', (232, 249))	('invasive carcinoma', 'Disease', 'MESH:D009361', (283, 301))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('invasive carcinomas', 'Disease', (139, 158))	('atypical ductal hyperplasia', 'Disease', (79, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('CNB', 'Var', (66, 69))	('atypical ductal hyperplasia', 'Disease', 'MESH:D006965', (79, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('invasive carcinoma', 'Disease', 'MESH:D009361', (139, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (292, 302))	('invasive carcinomas', 'Disease', 'MESH:D009361', (207, 226))	('DCIS', 'Disease', (23, 27))	('papillary lesion', 'Phenotype', 'HP:0007482', (232, 248))	('papillary lesions', 'Disease', (232, 249))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('invasive carcinomas', 'Disease', (207, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('invasive carcinomas', 'Disease', 'MESH:D009361', (283, 302))
94738	25089226	Over-expression of the human her2/neu gene, the homologue of the oncogene neu, is one of the predominant transformation-activating mechanism and achieves the same effect as the oncogenic mutations observed in the neu oncogene.	('neu', 'Gene', '2064', (74, 77))	('neu', 'Gene', '2064', (213, 216))	('neu', 'Gene', (74, 77))	('her2/neu', 'Gene', (29, 37))	('her2/neu', 'Gene', '2064', (29, 37))	('human', 'Species', '9606', (23, 28))	('Over-expression', 'Var', (0, 15))	('neu', 'Gene', (213, 216))	('neu', 'Gene', '2064', (34, 37))	('neu', 'Gene', (34, 37))
94739	25089226	Indeed, the amplification of the her2/neu gene and over-expression of the related HER2/neu receptor are observed in 20-30% of primary human breast tumors and are correlated with poor prognosis and disease progression.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('human', 'Species', '9606', (134, 139))	('breast tumors', 'Phenotype', 'HP:0100013', (140, 153))	('HER2/neu receptor', 'Gene', (82, 99))	('HER2/neu receptor', 'Gene', '2064', (82, 99))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('over-expression', 'PosReg', (51, 66))	('amplification', 'Var', (12, 25))	('breast tumors', 'Disease', 'MESH:D001943', (140, 153))	('breast tumors', 'Disease', (140, 153))	('her2/neu', 'Gene', (33, 41))	('her2/neu', 'Gene', '2064', (33, 41))	('observed', 'Reg', (104, 112))
94740	25089226	Specifically, an association between the extent of her2/neu amplification and the presence of tumor in lymph nodes was observed.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('association', 'Interaction', (17, 28))	('her2/neu', 'Gene', (51, 59))	('amplification', 'Var', (60, 73))	('her2/neu', 'Gene', '2064', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor in lymph', 'Phenotype', 'HP:0002665', (94, 108))	('tumor', 'Disease', (94, 99))
94747	25089226	Late stage breast cancer patients are more likely to have elevated HER2 ECD, while the p100 splice variant has been shown to functionally inhibit the proliferation of tumor cells.	('ECD', 'Gene', (72, 75))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('HER2', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('ECD', 'Gene', '11319', (72, 75))	('breast cancer', 'Disease', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('p100 splice variant', 'Var', (87, 106))	('patients', 'Species', '9606', (25, 33))	('HER2', 'Gene', '2064', (67, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('elevated', 'PosReg', (58, 66))	('inhibit', 'NegReg', (138, 145))	('tumor', 'Disease', (167, 172))
94775	25089226	The difference in the HER2 ECD levels between the DCIS group and the benign group was also significant (P<0.05).	('ECD', 'Gene', (27, 30))	('ECD', 'Gene', '11319', (27, 30))	('HER2', 'Gene', (22, 26))	('HER2', 'Gene', '2064', (22, 26))	('DCIS', 'Var', (50, 54))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
94780	25089226	These patients might have received treatments previously but were divided into two groups to compare their overall survival under current cares: high serum HER2 ECD (>9.48 ng/ml) and low Her2 ECD groups (<9.48 ng/ml).	('HER2', 'Gene', (156, 160))	('ECD', 'Gene', '11319', (161, 164))	('ECD', 'Gene', '11319', (192, 195))	('HER2', 'Gene', '2064', (156, 160))	('Her2', 'Gene', '2064', (187, 191))	('patients', 'Species', '9606', (6, 14))	('>9.48', 'Var', (166, 171))	('ECD', 'Gene', (161, 164))	('ECD', 'Gene', (192, 195))	('Her2', 'Gene', (187, 191))
94781	25089226	Patients with low HER2 ECD had significantly better survival (P=0.0005, logrank test).	('ECD', 'Gene', '11319', (23, 26))	('HER2', 'Gene', '2064', (18, 22))	('survival', 'MPA', (52, 60))	('better', 'PosReg', (45, 51))	('Patients', 'Species', '9606', (0, 8))	('ECD', 'Gene', (23, 26))	('low', 'Var', (14, 17))	('HER2', 'Gene', (18, 22))
94853	22952044	Overexpression of TLE1 in chicken embryo fibroblast led to significant growth stimulation and conferred anchorage-independent growth.	('chicken', 'Species', '9031', (26, 33))	('TLE1', 'Gene', (18, 22))	('expression', 'Species', '29278', (4, 14))	('anchorage-independent growth', 'CPA', (104, 132))	('growth stimulation', 'CPA', (71, 89))	('Overexpression', 'Var', (0, 14))	('conferred', 'PosReg', (94, 103))
94854	22952044	In mature neurons, exogenous expression of TLE1 prevented cell death and apoptosis.	('exogenous', 'Var', (19, 28))	('prevented', 'NegReg', (48, 57))	('cell death', 'CPA', (58, 68))	('TLE1', 'Gene', (43, 47))	('apoptosis', 'CPA', (73, 82))	('expression', 'Species', '29278', (29, 39))
94865	22952044	Normal and transformed cells in which Bit1 expression is downregulated exhibit increased Erk activation and such elevated Erk activity contributes in part to the enhanced anoikis resistance of the Bit1 knockdown cells.	('knockdown', 'Var', (202, 211))	('Bit1', 'Gene', (38, 42))	('downregulated', 'NegReg', (57, 70))	('activation', 'PosReg', (93, 103))	('increased', 'PosReg', (79, 88))	('Erk', 'Protein', (122, 125))	('Bit1', 'Gene', '51651', (197, 201))	('elevated', 'PosReg', (113, 121))	('anoikis resistance', 'CPA', (171, 189))	('Bit1', 'Gene', '51651', (38, 42))	('enhanced', 'PosReg', (162, 170))	('Bit1', 'Gene', (197, 201))	('expression', 'Species', '29278', (43, 53))	('activity', 'MPA', (126, 134))	('Erk', 'Protein', (89, 92))
94917	22952044	To examine the significance of TLE1 suppression in MCF10A following loss of attachment, we stably expressed exogenous GFP-tagged TLE1 or the GFP alone in MCF10A cells.	('TLE1', 'Gene', (129, 133))	('MCF10A', 'CellLine', 'CVCL:0598', (51, 57))	('GFP-tagged', 'Var', (118, 128))	('MCF10A', 'CellLine', 'CVCL:0598', (154, 160))
94927	22952044	Two TLE1 specific siRNAs #1(186345) and #3(117086) showed a significant 50-70% downregulation of TLE1 expression (Fig.	('expression', 'Species', '29278', (102, 112))	('TLE1', 'Gene', (97, 101))	('expression', 'MPA', (102, 112))	('117086', 'Var', (43, 49))	('186345', 'Var', (28, 34))	('downregulation', 'NegReg', (79, 93))
94931	22952044	To complement the results from the transient transfection studies, we also generated stable TLE1 knockdown clones by infecting MDA-MB-231 cells with lentiviral expression vectors for TLE1 specific shRNAs or control shRNAs.	('TLE1 specific shRNAs', 'Var', (183, 203))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (127, 137))	('TLE1', 'Gene', (92, 96))	('expression vectors', 'Species', '29278', (160, 178))
94945	22952044	Considering that TLE1 confers significant protection from anoikis in breast cancer cells and has been previously shown to inhibit Bit1 apoptosis function, we examined the notion that loss of TLE1 may contribute to Bit1-induced anoikis in breast carcinoma cells.	('Bit1', 'Gene', '51651', (214, 218))	('breast carcinoma', 'Phenotype', 'HP:0003002', (238, 254))	('loss', 'Var', (183, 187))	('Bit1', 'Gene', '51651', (130, 134))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('anoikis', 'CPA', (227, 234))	('TLE1', 'Gene', (191, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Bit1', 'Gene', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('Bit1', 'Gene', (130, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('inhibit', 'NegReg', (122, 129))	('breast carcinoma', 'Disease', 'MESH:D001943', (238, 254))	('breast carcinoma', 'Disease', (238, 254))	('contribute', 'Reg', (200, 210))
94951	22952044	Consistent with the inhibitory effect of TLE1 on Bit1 anoikis, the apoptotic activity of cytoplasmic localized Bit1 (cyto) was inhibited by TLE1 (Supplementary Fig.	('Bit1', 'Gene', (49, 53))	('apoptotic activity', 'CPA', (67, 85))	('Bit1', 'Gene', (111, 115))	('inhibited', 'NegReg', (127, 136))	('TLE1', 'Var', (140, 144))	('Bit1', 'Gene', '51651', (49, 53))	('Bit1', 'Gene', '51651', (111, 115))
94954	22952044	Knockdown of TLE1 further increased the sensitivity of MDA-MB-231 cells to Bit1 anoikis (Fig.	('Knockdown', 'Var', (0, 9))	('Bit1', 'Gene', '51651', (75, 79))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (55, 65))	('Bit1', 'Gene', (75, 79))	('increased', 'PosReg', (26, 35))	('TLE1', 'Gene', (13, 17))	('sensitivity', 'MPA', (40, 51))
94955	22952044	To address the mechanism underlying the inhibitory effect of TLE1 on Bit1 anoikis function, we examined whether TLE1 can inhibit the formation of the Bit1-AES complex, which is the pro-apoptotic component that mediates the effect of Bit1 on apoptosis.	('inhibit', 'NegReg', (121, 128))	('Bit1', 'Gene', (69, 73))	('Bit1', 'Gene', (233, 237))	('AES', 'Chemical', '-', (155, 158))	('TLE1', 'Var', (112, 116))	('Bit1', 'Gene', '51651', (150, 154))	('Bit1', 'Gene', '51651', (233, 237))	('Bit1', 'Gene', '51651', (69, 73))	('Bit1', 'Gene', (150, 154))
94959	22952044	Indeed, concomitant with the observed reduction of Bit1-AES complexes by exogenous TLE1 is the significant enrichment of AES in the nucleus (Fig.	('TLE1', 'Gene', (83, 87))	('exogenous', 'Var', (73, 82))	('AES', 'MPA', (121, 124))	('AES', 'Chemical', '-', (56, 59))	('AES', 'Chemical', '-', (121, 124))	('Bit1', 'Gene', '51651', (51, 55))	('reduction', 'NegReg', (38, 47))	('Bit1', 'Gene', (51, 55))
94966	22952044	We previously created negatively charged phosphomimetic mutation in the Ser5 amino acid within the mitochondrial localization sequence of the C-terminally GFP tagged mitochondrial Bit1 (Bit1S5D-GFP and Bit1S5E-GFP), and such Bit1 phosphomimetic mutants exhibited enhanced cytoplasmic localization as a result reduced mitochondrial import efficiency and displayed a more potent anoikis-sensitization activity.	('Bit1', 'Gene', '51651', (225, 229))	('Bit1', 'Gene', (180, 184))	('Bit1', 'Gene', (186, 190))	('Bit1', 'Gene', '51651', (186, 190))	('reduced', 'NegReg', (309, 316))	('cytoplasmic localization', 'MPA', (272, 296))	('Ser5 amino acid', 'Chemical', '-', (72, 87))	('Bit1', 'Gene', (225, 229))	('Bit1', 'Gene', '51651', (202, 206))	('mitochondrial', 'CPA', (317, 330))	('mutants', 'Var', (245, 252))	('anoikis-sensitization activity', 'CPA', (377, 407))	('Bit1', 'Gene', (202, 206))	('Bit1', 'Gene', '51651', (180, 184))	('enhanced', 'PosReg', (263, 271))
94978	22952044	6I and 6J show that treatment of Bit1-transfected cells grown in suspension with MG132 exhibited increased levels of TLE1 protein compared to untreated Bit1 transfected cells, indicating that Bit1 may channel TLE1 to proteasomal degradation.	('levels', 'MPA', (107, 113))	('Bit1', 'Gene', '51651', (33, 37))	('increased', 'PosReg', (97, 106))	('channel', 'PosReg', (201, 208))	('Bit1', 'Gene', '51651', (192, 196))	('Bit1', 'Gene', (152, 156))	('Bit1', 'Gene', (33, 37))	('TLE1 protein', 'MPA', (117, 129))	('Bit1', 'Gene', (192, 196))	('Bit1', 'Gene', '51651', (152, 156))	('MG132', 'Var', (81, 86))	('MG132', 'Chemical', 'MESH:C072553', (81, 86))	('proteasomal degradation', 'MPA', (217, 240))
94979	22952044	Based on our in vitro evidence indicating that TLE1 promotes breast cancer cell anoikis resistance, which is a primary determinant of transformation and tumor aggressiveness, we explored the possibility that TLE1 may contribute to breast tumorigenesis in humans by screening a breast tumor tissue microarray for overexpression of TLE1.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('expression', 'Species', '29278', (316, 326))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (153, 173))	('breast tumor', 'Disease', 'MESH:D001943', (231, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('breast tumor', 'Phenotype', 'HP:0100013', (231, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('contribute', 'Reg', (217, 227))	('breast tumor', 'Disease', (231, 243))	('promotes', 'PosReg', (52, 60))	('breast tumor', 'Disease', 'MESH:D001943', (277, 289))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('aggressiveness', 'Phenotype', 'HP:0000718', (159, 173))	('breast cancer', 'Disease', (61, 74))	('TLE1', 'Var', (47, 51))	('breast tumor', 'Phenotype', 'HP:0100013', (277, 289))	('overexpression', 'PosReg', (312, 326))	('tumor aggressiveness', 'Disease', (153, 173))	('breast tumor', 'Disease', (277, 289))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('humans', 'Species', '9606', (255, 261))
95015	22952044	Importantly, Grg1 (the mouse homologue of TLE1) transgenic mice developed lung tumors.	('lung tumors', 'Disease', 'MESH:D008175', (74, 85))	('Grg1', 'Gene', '21885', (13, 17))	('lung tumors', 'Phenotype', 'HP:0100526', (74, 85))	('lung tumors', 'Disease', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Grg1', 'Gene', (13, 17))	('mouse', 'Species', '10090', (23, 28))	('transgenic', 'Var', (48, 58))	('developed', 'PosReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('transgenic mice', 'Species', '10090', (48, 63))
95027	27382395	Involvement of resection margins, low tumor grade, high Ki-67 expression, and RT were independently associated with an increase in the recurrence rate (p<0.05, Pearson chi-square test).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('low tumor', 'Disease', (34, 43))	('Ki-67 expression', 'Protein', (56, 72))	('high', 'Var', (51, 55))	('low tumor', 'Disease', 'MESH:D009800', (34, 43))	('recurrence', 'CPA', (135, 145))
95050	27382395	Tumors with nonhigh nuclear grade and without necrosis were classified as low-grade, those with nonhigh nuclear grade with necrosis were classified as intermediate-grade, and those having high nuclear grade with or without necrosis were classified as high-grade disease.	('nonhigh nuclear grade', 'Var', (12, 33))	('necrosis', 'Disease', 'MESH:D009336', (123, 131))	('necrosis', 'Disease', (223, 231))	('necrosis', 'Disease', (46, 54))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('necrosis', 'Disease', 'MESH:D009336', (223, 231))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('necrosis', 'Disease', 'MESH:D009336', (46, 54))	('necrosis', 'Disease', (123, 131))
95051	27382395	The following antibodies were used for the immunohistochemistry (IHC) analysis: ER (SP1; Dako, Carpinteria, USA), PR (SP2; Dako), HER2 (A0485; Dako), Ki-67 (MIB-1; Dako), CK5/6 (D5/16; Dako), and epidermal growth factor receptor (EGFR) (E30; Dako).	('EGFR', 'Gene', '1956', (230, 234))	('epidermal growth factor receptor', 'Gene', (196, 228))	('EGFR', 'Gene', (230, 234))	('MIB-1', 'Gene', (157, 162))	('PR', 'Gene', '5241', (114, 116))	('A0485', 'Var', (136, 141))	('ER', 'Gene', '2099', (131, 133))	('MIB-1', 'Gene', '57534', (157, 162))	('ER', 'Gene', '2099', (80, 82))	('SP2', 'Gene', '6668', (118, 121))	('CK5/6', 'Gene', '3852', (171, 176))	('epidermal growth factor receptor', 'Gene', '1956', (196, 228))	('HER2', 'Gene', (130, 134))	('HER2', 'Gene', '2064', (130, 134))	('CK5/6', 'Gene', (171, 176))	('SP2', 'Gene', (118, 121))
95072	27382395	Univariate and multivariate analyses showed that recurrence rates were significantly associated with low tumor grade (p=0.001 and p=0.004, respectively), Ki-67 (p=0.010 and p=0.026, respectively), and the resection margin (p=0.000 and p=0.034, respectively).	('low tumor', 'Disease', (101, 110))	('low tumor', 'Disease', 'MESH:D009800', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Ki-67', 'Var', (154, 159))
95093	27382395	Resection margin involvement, low tumor grade, high Ki-67 expression, and RT were the key prognostic factors for tumor recurrence.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (34, 39))	('high', 'Var', (47, 51))	('Ki-67 expression', 'Protein', (52, 68))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('low tumor', 'Disease', 'MESH:D009800', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('low tumor', 'Disease', (30, 39))
95094	30652428	 BRCA1/BRCA2 mutations in Japanese women with ductal carcinoma in situ Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation.	('women', 'Species', '9606', (35, 40))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (46, 70))	('carcinoma in situ', 'Disease', 'MESH:D002278', (78, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (53, 70))	('ductal carcinoma', 'Disease', (46, 62))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('carcinoma in situ', 'Disease', 'MESH:D002278', (53, 70))	('breast cancer', 'Disease', (157, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BRCA1', 'Gene', '672', (1, 6))	('Ductal carcinoma', 'Disease', (71, 87))	('BRCA2', 'Gene', (7, 12))	('BRCA1', 'Gene', (1, 6))	('ductal carcinoma', 'Disease', 'MESH:D044584', (46, 62))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (71, 87))	('carcinoma in situ', 'Disease', (78, 95))	('BRCA1', 'Gene', '672', (190, 195))	('BRCA1/2', 'Gene', (190, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BRCA1', 'Gene', (190, 195))	('mutations', 'Var', (13, 22))	('BRCA2', 'Gene', '675', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinoma in situ', 'Disease', (53, 70))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (78, 95))	('BRCA1/2', 'Gene', '672;675', (190, 197))
95095	30652428	The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations.	('BRCA1/2', 'Gene', (86, 93))	('DCIS raised', 'Disease', (51, 62))	('mutations', 'Var', (94, 103))	('women', 'Species', '9606', (75, 80))	('BRCA1/2', 'Gene', '672;675', (86, 93))
95096	30652428	A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016.	('invasive cancer', 'Disease', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA2', 'Gene', (186, 191))	('BRCA1', 'Gene', '672', (176, 181))	('mutations', 'Var', (159, 168))	('invasive cancer', 'Disease', 'MESH:D009362', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('BRCA1', 'Gene', (176, 181))	('BRCA2', 'Gene', '675', (186, 191))	('women', 'Species', '9606', (24, 29))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
95099	30652428	(a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations.	('positive', 'Reg', (77, 85))	('invasive cancer', 'Disease', (37, 52))	('BRCA1', 'Gene', '672', (90, 95))	('BRCA2', 'Gene', '675', (96, 101))	('invasive cancer', 'Disease', 'MESH:D009362', (37, 52))	('BRCA1', 'Gene', (90, 95))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('patients', 'Species', '9606', (11, 19))	('BRCA2', 'Gene', (96, 101))
95100	30652428	And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000).	('BRCA1', 'Gene', '672', (34, 39))	('mutations', 'Var', (46, 55))	('positive', 'Reg', (21, 29))	('BRCA1', 'Gene', (34, 39))	('BRCA2', 'Gene', (40, 45))	('BRCA2', 'Gene', '675', (40, 45))
95101	30652428	Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263).	('BRCA', 'Gene', '672', (6, 10))	('mutations', 'Var', (11, 20))	('DCIS', 'Disease', (39, 43))	('BRCA', 'Gene', (6, 10))
95102	30652428	Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009).	('BRCA2', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (73, 78))	('mutations', 'Var', (43, 52))	('BRCA1', 'Gene', '672', (37, 42))	('DCIS', 'Disease', (13, 17))	('BRCA1', 'Gene', (37, 42))
95103	30652428	(b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers.	('BRCA', 'Gene', '672', (31, 35))	('BRCA', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))
95104	30652428	Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis.	('mutation', 'Var', (150, 158))	('BRCA', 'Gene', (145, 149))	('BRCA', 'Gene', '672', (145, 149))	('carriers', 'Reg', (159, 167))
95105	30652428	In a multivariate logistic model, total relatives with BC DX >= 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis <=35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation.	('BRCA', 'Gene', (332, 336))	('ER', 'Gene', '2099', (226, 228))	('HER2', 'Gene', (225, 229))	('HER2', 'Gene', '2064', (225, 229))	('ER', 'Gene', '2099', (221, 223))	('mutation', 'Var', (337, 345))	('BRCA', 'Gene', '672', (332, 336))
95106	30652428	Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651).	('BRCA', 'Gene', (58, 62))	('BRCA', 'Gene', '672', (58, 62))	('mutation', 'Var', (63, 71))
95107	30652428	(c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042).	('ER', 'Gene', '2099', (42, 44))	('carriers', 'Var', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('BRCA2', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('BRCA2', 'Gene', '675', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
95108	30652428	Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study.	('BRCA2', 'Gene', (25, 30))	('PR', 'Gene', '5241', (104, 106))	('higher', 'PosReg', (54, 60))	('ER', 'Gene', '2099', (100, 102))	('BRCA2', 'Gene', '675', (25, 30))	('lower', 'NegReg', (124, 129))	('carriers', 'Var', (31, 39))
95109	30652428	(d) BRCA mutation was not associated with an increased risk of IBTR and CBTR.	('mutation', 'Var', (9, 17))	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Gene', (4, 8))	('IBTR', 'Disease', (63, 67))	('CBTR', 'Disease', (72, 76))
95110	30652428	DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age.	('DCIS', 'Disease', (0, 4))	('patients', 'Species', '9606', (32, 40))	('women', 'Species', '9606', (98, 103))	('BRCA', 'Gene', '672', (50, 54))	('mutation', 'Var', (55, 63))	('BRCA', 'Gene', (50, 54))
95112	30652428	Total relatives with BC DX >=2, age at diagnosis <=35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.	('patients', 'Species', '9606', (156, 164))	('BRCA', 'Gene', '672', (110, 114))	('BRCA', 'Gene', (110, 114))	('HER2', 'Gene', (68, 72))	('ER', 'Gene', '2099', (64, 66))	('ER', 'Gene', '2099', (69, 71))	('women', 'Species', '9606', (136, 141))	('HER2', 'Gene', '2064', (68, 72))	('BRCA', 'Gene', '672', (243, 247))	('mutation', 'Var', (115, 123))	('BRCA', 'Gene', (243, 247))
95117	30652428	The identification of deleterious mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 has important implications for mutation carriers in general, because they are the principal cause of Hereditary Breast and/or Ovarian Cancer Syndrome (Miki et al., 1994; Wooster et al., 1995).	('Hereditary Breast and/or Ovarian Cancer', 'Disease', (203, 242))	('Cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Hereditary Breast and/or Ovarian Cancer', 'Disease', 'MESH:D061325', (203, 242))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA2', 'Gene', '675', (96, 101))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (228, 242))	('BRCA1', 'Gene', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('cause', 'Reg', (194, 199))	('breast cancer', 'Disease', (51, 64))	('mutations', 'Var', (34, 43))	('BRCA2', 'Gene', (96, 101))
95118	30652428	Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2 (Blackwood & Weber, 1998).	('BRCA2', 'Gene', '675', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('BRCA1', 'Gene', (85, 90))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('germline mutation', 'Var', (54, 71))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('BRCA2', 'Gene', (95, 100))	('women', 'Species', '9606', (7, 12))	('BRCA1', 'Gene', '672', (85, 90))
95119	30652428	The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%.	('BRCA1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('women', 'Species', '9606', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('BRCA2', 'Gene', (81, 86))	('breast cancer', 'Disease', (42, 55))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA2', 'Gene', '675', (81, 86))	('mutations', 'Var', (87, 96))
95121	30652428	Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer (Easton et al., 1999; Ford, Easton, Bishop, Narod, & Goldgar, 1994) or other primary cancers (Easton et al., 1999; Ford et al., 1994).	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('BRCA1', 'Gene', '672', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('primary cancers', 'Disease', (173, 188))	('BRCA2', 'Gene', (37, 42))	('BRCA1', 'Gene', (24, 29))	('ovarian cancer', 'Disease', (81, 95))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('BRCA2', 'Gene', '675', (37, 42))	('primary cancers', 'Disease', 'MESH:D009369', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
95122	30652428	When BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer (CBC) reached nearly 50% in the ensuing 25 years (Garber & Golshan, 2009; Graeser et al., 2009).	('BRCA2', 'Gene', '675', (11, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('mutation', 'Var', (17, 25))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (85, 112))	('BRCA1', 'Gene', '672', (5, 10))	('contralateral breast cancer', 'Disease', (85, 112))	('BRCA2', 'Gene', (11, 16))	('BRCA1', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
95123	30652428	The association of BRCA mutations with IBC is well established.	('association', 'Interaction', (4, 15))	('IBC', 'Disease', (39, 42))	('BRCA', 'Gene', '672', (19, 23))	('BRCA', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
95125	30652428	A few retrospective studies have examined the prevalence of BRCA1/BRCA2 mutations in women diagnosed with DCIS and have reported mutation rates ranging between 3.3% (Claus, Petruzella, Matloff, & Carter, 2005) and 13% (Frank et al., 2002; Hall, Reid, & Wenstrup, 2010).	('BRCA2', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('BRCA1', 'Gene', (60, 65))	('BRCA2', 'Gene', '675', (66, 71))	('women', 'Species', '9606', (85, 90))	('BRCA1', 'Gene', '672', (60, 65))	('DCIS', 'Disease', (106, 110))
95127	30652428	Notably, the knowledge of a BRCA1/BRCA2 mutation is likely to significantly change the assessment of a DCIS patient's risks for future cancers and the cancer prevention/risk reduction recommendations that would be considered.	('BRCA1', 'Gene', '672', (28, 33))	('mutation', 'Var', (40, 48))	('BRCA2', 'Gene', '675', (34, 39))	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Disease', (135, 142))	('BRCA1', 'Gene', (28, 33))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('change', 'Reg', (76, 82))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('BRCA2', 'Gene', (34, 39))	('patient', 'Species', '9606', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
95128	30652428	Subsequent studies have led to the suggestion that the preinvasive phase may be shortened or even absent in hereditary breast cancers, particularly those associated with BRCA1 mutations (Jacquemler, Eisinger, Guinebretiere, Stoppa-Lyonnet, & Sobol, 1996).	('absent', 'NegReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (176, 185))	('hereditary breast cancers', 'Disease', (108, 133))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (108, 133))	('BRCA1', 'Gene', '672', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('BRCA1', 'Gene', (170, 175))	('breast cancers', 'Phenotype', 'HP:0003002', (119, 133))
95129	30652428	But patients in studies above are almost from US and other Western countries, while only a few reports have been published concerning the prevalence of BRCA1/BRCA2 mutations with DCIS among Japanese people (Ikeda et al., 2001; Kawahara et al., 2004; Noguchi et al., 1999; Sekine et al., 2001).	('BRCA1', 'Gene', '672', (152, 157))	('BRCA1', 'Gene', (152, 157))	('patients', 'Species', '9606', (4, 12))	('BRCA2', 'Gene', (158, 163))	('mutations', 'Var', (164, 173))	('people', 'Species', '9606', (199, 205))	('BRCA2', 'Gene', '675', (158, 163))
95130	30652428	The purpose of our study is to further characterize the association between DCIS and BRCA mutations in Japanese women and to provide the genetic basis for directing the treatment and predicting prognosis for DCIS women with BRCA1/BRCA2 mutation.	('DCIS', 'Gene', (76, 80))	('BRCA', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('mutation', 'Var', (236, 244))	('BRCA', 'Gene', (230, 234))	('BRCA', 'Gene', '672', (230, 234))	('BRCA', 'Gene', '672', (224, 228))	('BRCA', 'Gene', (224, 228))	('women', 'Species', '9606', (112, 117))	('BRCA1', 'Gene', '672', (224, 229))	('BRCA2', 'Gene', (230, 235))	('BRCA1', 'Gene', (224, 229))	('association', 'Interaction', (56, 67))	('women', 'Species', '9606', (213, 218))	('BRCA', 'Gene', '672', (85, 89))	('BRCA2', 'Gene', '675', (230, 235))
95131	30652428	We also hope to find special independent predictors for BRCA mutation in DCIS and could recommend genetic counseling and testing for Japanese patients with DCIS of high risk of BRCA mutation.	('mutation', 'Var', (61, 69))	('BRCA', 'Gene', '672', (56, 60))	('BRCA', 'Gene', (56, 60))	('BRCA', 'Gene', '672', (177, 181))	('patients', 'Species', '9606', (142, 150))	('BRCA', 'Gene', (177, 181))
95132	30652428	A total of 325 Japanese women with BC (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital from December 2011 to August 2016.	('BRCA1', 'Gene', (160, 165))	('BRCA2', 'Gene', (170, 175))	('BRCA2', 'Gene', '675', (170, 175))	('invasive cancer', 'Disease', 'MESH:D009362', (55, 70))	('women', 'Species', '9606', (24, 29))	('BRCA1', 'Gene', '672', (160, 165))	('invasive cancer', 'Disease', (55, 70))	('mutations', 'Var', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
95142	30652428	HER2 negative was defined as HER2 staining 0, 1+, and FISH negative when HER2 staining was 2+.	('HER2', 'Gene', '2064', (73, 77))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', '2064', (29, 33))	('HER2', 'Gene', (0, 4))	('staining', 'Var', (34, 42))	('negative', 'NegReg', (5, 13))	('HER2', 'Gene', (73, 77))
95144	30652428	Univariate and multivariate logistic regression analyses on BRCA mutation status (carriers vs. noncarriers) were done to identify factors that were predictive of BRCA1/BRCA2 mutations in the patients with DCIS.	('BRCA2', 'Gene', '675', (168, 173))	('patients', 'Species', '9606', (191, 199))	('BRCA', 'Gene', '672', (162, 166))	('BRCA1', 'Gene', '672', (162, 167))	('BRCA', 'Gene', (168, 172))	('BRCA', 'Gene', '672', (168, 172))	('BRCA', 'Gene', (162, 166))	('BRCA1', 'Gene', (162, 167))	('BRCA', 'Gene', '672', (60, 64))	('BRCA2', 'Gene', (168, 173))	('mutations', 'Var', (174, 183))	('BRCA', 'Gene', (60, 64))
95146	30652428	Of 325 patients (with or without invasive cancer), 19.1% (62/325) had mutation of BRCA1 or/and BRCA2.	('BRCA1', 'Gene', (82, 87))	('BRCA2', 'Gene', '675', (95, 100))	('invasive cancer', 'Disease', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('invasive cancer', 'Disease', 'MESH:D009362', (33, 48))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (82, 87))	('mutation', 'Var', (70, 78))	('patients', 'Species', '9606', (7, 15))
95147	30652428	There were 49 DCIS in 325 breast cancers, and nine cases out of sixty-two BRCA mutation were DCIS, 2% (n = 1) carried a BRCA1 mutation, and 16.4% (n = 8) carried a BRCA2 mutation (Table 1).	('BRCA', 'Gene', (120, 124))	('breast cancers', 'Disease', (26, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('BRCA1', 'Gene', (120, 125))	('BRCA', 'Gene', (164, 168))	('BRCA2', 'Gene', '675', (164, 169))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (26, 40))	('mutation', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutation', 'Var', (79, 87))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', '672', (120, 124))	('BRCA1', 'Gene', '672', (120, 125))	('BRCA2', 'Gene', (164, 169))	('BRCA', 'Gene', (74, 78))	('BRCA', 'Gene', '672', (164, 168))	('breast cancers', 'Disease', 'MESH:D001943', (26, 40))
95148	30652428	The incidence of DCIS among patients with BRCA mutation (9/62 cases, 14.5%) was equal to that among patients without BRCA mutation (40/263 cases, 15.2%).	('BRCA', 'Gene', '672', (42, 46))	('mutation', 'Var', (47, 55))	('BRCA', 'Gene', '672', (117, 121))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', (42, 46))	('patients', 'Species', '9606', (100, 108))	('DCIS', 'Disease', (17, 21))	('patients', 'Species', '9606', (28, 36))
95149	30652428	Incidence of DCIS was 3.0% (1/33) of BRCA1 mutation carriers and 27.5% (8/29) of BRCA2 carriers (p = 0.009).	('mutation', 'Var', (43, 51))	('BRCA2', 'Gene', (81, 86))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA2', 'Gene', '675', (81, 86))	('DCIS', 'Disease', (13, 17))	('BRCA1', 'Gene', (37, 42))
95150	30652428	The prevalence of BRCA1/2 mutations was 17.6% (6/34) in women who had DCIS diagnosed before age 50 years, and patients had BRCA2 mutations (5/34, 14.7%) more frequently than BRCA1 mutations (1/34, 2.9%).	('BRCA2', 'Gene', '675', (123, 128))	('women', 'Species', '9606', (56, 61))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1/2', 'Gene', (18, 25))	('BRCA1', 'Gene', (174, 179))	('mutations', 'Var', (129, 138))	('BRCA1', 'Gene', (18, 23))	('BRCA1/2', 'Gene', '672;675', (18, 25))	('mutations', 'Var', (26, 35))	('BRCA2', 'Gene', (123, 128))	('BRCA1', 'Gene', '672', (174, 179))	('patients', 'Species', '9606', (110, 118))
95151	30652428	Mutations in BRCA1 was deleterious type (Q1721X).	('BRCA1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('Q1721X', 'Var', (41, 47))	('Q1721X', 'Mutation', 'rs878854957', (41, 47))	('BRCA1', 'Gene', '672', (13, 18))
95152	30652428	Mutations in BRCA2, comprised seven different deleterious type (S2835X, STOP2868, STOP959, STOP429, E1299X, R2318X, K567X) and one suspected deleterious type (I2675V) (Table 1).	('E1299X', 'Mutation', 'rs80357397', (100, 106))	('R2318X', 'Var', (108, 114))	('STOP959', 'Var', (82, 89))	('STOP429', 'Var', (91, 98))	('I2675V', 'Mutation', 'rs397507954', (159, 165))	('K567X', 'Mutation', 'p.K567X', (116, 121))	('K567X', 'Var', (116, 121))	('S2835X', 'Mutation', 'rs80359102', (64, 70))	('STOP2868', 'Var', (72, 80))	('R2318X', 'Mutation', 'rs80358920', (108, 114))	('BRCA2', 'Gene', '675', (13, 18))	('BRCA2', 'Gene', (13, 18))	('S2835X', 'Var', (64, 70))	('E1299X', 'Var', (100, 106))
95153	30652428	S2835X, 3036del4, 1506delA, R2318X and K467X was detected once, respectively, and could be searched in the BIC database; I2675V, 8817insA, E1299X was detected in one subject respectively and was far unreported in the BIC database.	('S2835X', 'Mutation', 'rs80359102', (0, 6))	('I2675V', 'Var', (121, 127))	('8817insA', 'Var', (129, 137))	('E1299X', 'Var', (139, 145))	('1506delA', 'Var', (18, 26))	('K467X', 'Mutation', 'rs80358427', (39, 44))	('E1299X', 'Mutation', 'rs80357397', (139, 145))	('S2835X', 'Var', (0, 6))	('BIC', 'Chemical', 'MESH:C100119', (107, 110))	('BIC', 'Chemical', 'MESH:C100119', (217, 220))	('R2318X', 'Mutation', 'rs80358920', (28, 34))	('I2675V', 'Mutation', 'rs397507954', (121, 127))	('8817insA', 'Mutation', 'c.8817insA', (129, 137))	('3036del4', 'Var', (8, 16))	('1506delA', 'Mutation', 'c.1506delA', (18, 26))	('R2318X', 'Var', (28, 34))	('3036del4', 'Mutation', 'c.3036del4', (8, 16))	('K467X', 'Var', (39, 44))
95159	30652428	Among BRCA mutation carriers, 44.4% (4/9) aged <=35 years and 55.6% (5/9) >35 years.	('mutation', 'Var', (11, 19))	('carriers', 'Reg', (20, 28))	('BRCA', 'Gene', '672', (6, 10))	('BRCA', 'Gene', (6, 10))
95160	30652428	For BRCA mutation noncarriers, 12.5% (12/40) aged <=35 years and 87.5% (35/40) >35 years.	('mutation', 'Var', (9, 17))	('BRCA', 'Gene', (4, 8))	('BRCA', 'Gene', '672', (4, 8))
95161	30652428	Median age of first diagnosis in BRCA mutation carriers is 39 years (32-73 years), and 46 years (22-71 years) in noncarriers.	('BRCA', 'Gene', (33, 37))	('BRCA', 'Gene', '672', (33, 37))	('mutation', 'Var', (38, 46))
95164	30652428	Patients with an FH of BC and BRCA mutation had a higher proportion compared with patients without any FH of BC (26.5% vs. 0%).	('BRCA', 'Gene', (30, 34))	('patients', 'Species', '9606', (82, 90))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (30, 34))
95165	30652428	Patients with an FH of OC and BRCA mutation had similar proportions compared with patients who had no FH of OC (20.2% vs. 18.2%).	('BRCA', 'Gene', (30, 34))	('patients', 'Species', '9606', (82, 90))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (30, 34))
95170	30652428	Patients who had an FH of BC had a higher risk of having BRCA mutations compared with patients who had no FH of BC (26.5% vs. 0%; p = 0.042), especially patients who had FH of first- or second-degree BC compared with those who had no FH of first or second degree BC (p = 0.042).	('patients', 'Species', '9606', (153, 161))	('Patients', 'Species', '9606', (0, 8))	('BRCA', 'Gene', '672', (57, 61))	('BRCA', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('patients', 'Species', '9606', (86, 94))
95175	30652428	Total relatives with BC DX >= 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis <=35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent, significant predictors for BRCA mutation.	('ER', 'Gene', '2099', (192, 194))	('HER2', 'Gene', (191, 195))	('BRCA', 'Gene', (299, 303))	('BRCA', 'Gene', '672', (299, 303))	('HER2', 'Gene', '2064', (191, 195))	('ER', 'Gene', '2099', (187, 189))	('mutation', 'Var', (304, 312))
95176	30652428	Specifically, patients who had >=2 relatives with BC were more likely to have BRCA mutations compared with patients who had no relatives with BC.	('mutations', 'Var', (83, 92))	('BRCA', 'Gene', '672', (78, 82))	('BRCA', 'Gene', (78, 82))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (107, 115))
95180	30652428	There were no significant differences in nuclear grade between BRCA2 carriers and noncarriers (p = 0.319).	('BRCA2', 'Gene', (63, 68))	('carriers', 'Var', (69, 77))	('BRCA2', 'Gene', '675', (63, 68))
95182	30652428	But it's found that BRCA2 carriers are much higher (50.0%) in Grade 2 and 3 subgroup, which is only 25.6% of BRCA2 noncarriers.	('BRCA2', 'Gene', '675', (20, 25))	('higher', 'PosReg', (44, 50))	('BRCA2', 'Gene', (109, 114))	('BRCA2', 'Gene', (20, 25))	('carriers', 'Var', (26, 34))	('BRCA2', 'Gene', '675', (109, 114))
95184	30652428	In our study, it's found that a statistically significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042).	('BRCA2', 'Gene', (97, 102))	('carriers', 'Var', (103, 111))	('ER', 'Gene', '2099', (72, 74))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA2', 'Gene', '675', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
95186	30652428	But there's no significant difference in PR-positive tumors between BRCA2 carriers and noncarriers (p = 1.000).	('BRCA2', 'Gene', '675', (68, 73))	('carriers', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA2', 'Gene', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))	('PR', 'Gene', '5241', (41, 43))
95187	30652428	The frequency of PR expression in BRCA2 mutation DCIS was similar to that in noncarriers.	('mutation', 'Var', (40, 48))	('PR', 'Gene', '5241', (17, 19))	('BRCA2', 'Gene', '675', (34, 39))	('BRCA2', 'Gene', (34, 39))
95191	30652428	But Significant difference was also noted in ER/HER2 status subgroup, DCIS with BRCA2 mutation had higher frequency of ER+/HER2+ status (p = 0.041).	('ER', 'Gene', '2099', (119, 121))	('HER2', 'Gene', '2064', (48, 52))	('BRCA2', 'Gene', (80, 85))	('ER', 'Gene', '2099', (45, 47))	('ER', 'Gene', '2099', (124, 126))	('ER', 'Gene', '2099', (49, 51))	('HER2', 'Gene', (123, 127))	('BRCA2', 'Gene', '675', (80, 85))	('HER2', 'Gene', '2064', (123, 127))	('mutation', 'Var', (86, 94))	('HER2', 'Gene', (48, 52))
95192	30652428	No significant difference was noted in Ki67 index cut off by 14% (p = 0.698) or 30% (p = 1.000) with respect to BRCA2 mutation status.	('BRCA2', 'Gene', (112, 117))	('BRCA2', 'Gene', '675', (112, 117))	('mutation', 'Var', (118, 126))
95193	30652428	But when Ki67 index cut off by 30%, 87.5% low proliferation (<30%) was found in BRCA2 carriers.	('carriers', 'Var', (86, 94))	('BRCA2', 'Gene', '675', (80, 85))	('low', 'NegReg', (42, 45))	('BRCA2', 'Gene', (80, 85))
95194	30652428	The result of multivariate logistic regression model analysis for BRCA2 mutation showed that ER+/HER2+ status (OR 5.858, 95% CI 1.263-27.167, p = 0.024) remained as independent, significant predictors for BRCA2 mutation.	('HER2', 'Gene', (97, 101))	('BRCA2', 'Gene', (66, 71))	('HER2', 'Gene', '2064', (97, 101))	('BRCA2', 'Gene', '675', (66, 71))	('BRCA2', 'Gene', (205, 210))	('ER', 'Gene', '2099', (93, 95))	('BRCA2', 'Gene', '675', (205, 210))	('ER', 'Gene', '2099', (98, 100))	('mutation', 'Var', (211, 219))
95195	30652428	It's suggested that DCIS patients with ER+/HER2+ expression of FH of BC probably have higher risk of BRCA2 mutation.	('BRCA2', 'Gene', (101, 106))	('HER2', 'Gene', (43, 47))	('ER', 'Gene', '2099', (39, 41))	('HER2', 'Gene', '2064', (43, 47))	('BRCA2', 'Gene', '675', (101, 106))	('patients', 'Species', '9606', (25, 33))	('FH of BC', 'Gene', (63, 71))	('ER', 'Gene', '2099', (44, 46))	('mutation', 'Var', (107, 115))
95196	30652428	In our study, there's only 1 patient in BRCA1 mutation.	('patient', 'Species', '9606', (29, 36))	('mutation', 'Var', (46, 54))	('BRCA1', 'Gene', '672', (40, 45))	('BRCA1', 'Gene', (40, 45))
95207	30652428	In our study, it indicated an overall 18.4% (17.6% before age 50 years) prevalence of deleterious BRCA1/BRCA2 mutations in high-risk women diagnosed with DCIS, supporting the presence of an in situ phase of carcinogenesis in the development of at least some BRCA-associated breast cancer (Arun et al., 2009).	('BRCA', 'Gene', (98, 102))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('BRCA', 'Gene', '672', (104, 108))	('BRCA2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('BRCA', 'Gene', '672', (258, 262))	('breast cancer', 'Disease', (274, 287))	('BRCA', 'Gene', (104, 108))	('carcinogenesis', 'Disease', (207, 221))	('BRCA', 'Gene', (258, 262))	('women', 'Species', '9606', (133, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('BRCA2', 'Gene', '675', (104, 109))	('BRCA1', 'Gene', '672', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('BRCA', 'Gene', '672', (98, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (207, 221))	('BRCA1', 'Gene', (98, 103))
95209	30652428	The prevalence of BRCA mutations was 13% in women who had DCIS diagnosed before age 50 years versus 24% in women who had IBC.	('BRCA', 'Gene', '672', (18, 22))	('women', 'Species', '9606', (44, 49))	('BRCA', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('women', 'Species', '9606', (107, 112))
95210	30652428	(2010) conducted a cross-sectional analysis of the Myriad Genetics BRCA1/BRCA2 database and reported an overall 5.9% prevalence of BRCA1/BRCA2 mutations in non-AJ patients with carcinoma in situ (CIS) (ductal or lobular).	('BRCA2', 'Gene', '675', (137, 142))	('BRCA2', 'Gene', (73, 78))	('patients', 'Species', '9606', (163, 171))	('carcinoma in situ', 'Disease', 'MESH:D002278', (177, 194))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA2', 'Gene', '675', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma in situ', 'Disease', (177, 194))	('BRCA1', 'Gene', '672', (67, 72))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (177, 194))	('BRCA2', 'Gene', (137, 142))	('BRCA1', 'Gene', (131, 136))	('BRCA1', 'Gene', (67, 72))	('mutations', 'Var', (143, 152))
95212	30652428	Among mutations detected in BRCA1, L63X, and Q934X were reported as founder mutation in Japanese (Ikeda et al., 2001; Lakhani, Easton, & Stratton, 1997; Sekine et al., 2001; Sugano et al., 2008).	('BRCA1', 'Gene', '672', (28, 33))	('Q934X', 'Var', (45, 50))	('L63X', 'Mutation', 'rs80357086', (35, 39))	('BRCA1', 'Gene', (28, 33))	('L63X', 'Var', (35, 39))	('Q934X', 'Mutation', 'rs80357223', (45, 50))
95217	30652428	(Lakhani et al., 1997) reported 5804del4 and R3128X was most frequent mutation.	('5804del4', 'Var', (32, 40))	('5804del4', 'Mutation', 'c.5804del4', (32, 40))	('R3128X', 'Mutation', 'rs80359212', (45, 51))	('R3128X', 'Var', (45, 51))
95218	30652428	In our study, S2835X, 3036del4, 1506delA, R2318X, I2675V, and 8817insA had been reported in Japanese (Nakamura et al., 2015).	('1506delA', 'Mutation', 'c.1506delA', (32, 40))	('S2835X', 'Mutation', 'rs80359102', (14, 20))	('8817insA', 'Mutation', 'c.8817insA', (62, 70))	('3036del4', 'Var', (22, 30))	('I2675V', 'Mutation', 'rs397507954', (50, 56))	('3036del4', 'Mutation', 'c.3036del4', (22, 30))	('R2318X', 'Mutation', 'rs80358920', (42, 48))	('I2675V', 'Var', (50, 56))	('S2835X', 'Var', (14, 20))	('1506delA', 'Var', (32, 40))	('8817insA', 'Var', (62, 70))	('R2318X', 'Var', (42, 48))
95224	30652428	In our study, cohort of women with pure DCIS who were referred for genetic risk assessment, we identified the predictive factors for BRCA1/BRCA2 mutations.	('BRCA2', 'Gene', (139, 144))	('mutations', 'Var', (145, 154))	('BRCA1', 'Gene', '672', (133, 138))	('BRCA2', 'Gene', '675', (139, 144))	('women', 'Species', '9606', (24, 29))	('BRCA1', 'Gene', (133, 138))
95227	30652428	2010 determined that women who had early onset DCIS had a significantly increased risk of BRCA1/BRCA2 mutation compared with women who had late-onset disease (aged >=50 years; OR, 1.5; 95% CI 1.1-2.1).	('late-onset disease', 'Disease', (139, 157))	('BRCA1', 'Gene', '672', (90, 95))	('mutation', 'Var', (102, 110))	('BRCA2', 'Gene', '675', (96, 101))	('late-onset disease', 'Disease', 'MESH:D020518', (139, 157))	('BRCA1', 'Gene', (90, 95))	('women', 'Species', '9606', (21, 26))	('women', 'Species', '9606', (125, 130))	('BRCA2', 'Gene', (96, 101))
95230	30652428	In our study, the BRCA mutation rate was significantly higher in patients who were younger than 35 years (p = 0.046), but it was also predictive of mutation status in multivariate analysis (OR 0.149, 95% CI 0.023-0.954, p = 0.045).	('mutation', 'Var', (23, 31))	('BRCA', 'Gene', '672', (18, 22))	('BRCA', 'Gene', (18, 22))	('patients', 'Species', '9606', (65, 73))	('higher', 'PosReg', (55, 61))
95231	30652428	ER status, PR status, HER2 status, and Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers.	('ER', 'Gene', '2099', (0, 2))	('PR', 'Gene', '5241', (11, 13))	('mutation', 'Var', (102, 110))	('BRCA', 'Gene', '672', (97, 101))	('HER2', 'Gene', (22, 26))	('BRCA', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (22, 26))	('ER', 'Gene', '2099', (23, 25))
95233	30652428	So it's suggested that DCIS patients with total relatives with BC DX >=2, age at diagnosis <=35 years and ER+/HER+ status have high risk of BRCA mutation and could be recommended to receive genetic counseling and BRCA testing.	('BRCA', 'Gene', '672', (140, 144))	('ER', 'Gene', '2099', (106, 108))	('BRCA', 'Gene', '672', (213, 217))	('BRCA', 'Gene', (140, 144))	('BRCA', 'Gene', (213, 217))	('ER', 'Gene', '2099', (111, 113))	('patients', 'Species', '9606', (28, 36))	('mutation', 'Var', (145, 153))
95236	30652428	In our study, there's only 1 BRCA1 mutation, it has Grade 3, TN subtype and higher proliferation (ki67 > 14%).	('BRCA1', 'Gene', (29, 34))	('mutation', 'Var', (35, 43))	('BRCA1', 'Gene', '672', (29, 34))
95237	30652428	It perhaps indicated that DCIS occurring in carriers of BRCA1 mutations are also more likely to be ER-negative, PR-negative, HER2 receptor-negative, and have a basal phenotype.	('HER2', 'Gene', (125, 129))	('HER2', 'Gene', '2064', (125, 129))	('BRCA1', 'Gene', '672', (56, 61))	('ER', 'Gene', '2099', (126, 128))	('PR', 'Gene', '5241', (112, 114))	('BRCA1', 'Gene', (56, 61))	('ER', 'Gene', '2099', (99, 101))	('DCIS', 'Disease', (26, 30))	('mutations', 'Var', (62, 71))
95239	30652428	In our study, no significant differences were found in grade between BRCA2 carriers and noncarriers (p = 0.319).	('BRCA2', 'Gene', (69, 74))	('BRCA2', 'Gene', '675', (69, 74))	('carriers', 'Var', (75, 83))
95243	30652428	(2004) analyzing tumors from BRCA2 positive patients <45 years, found a statistically significant difference in the percentage of ER-positive tumors among BRCA2 carriers and noncarriers.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('patients', 'Species', '9606', (44, 52))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('BRCA2', 'Gene', (29, 34))	('BRCA2', 'Gene', '675', (155, 160))	('carriers', 'Var', (161, 169))	('tumors', 'Disease', (142, 148))	('BRCA2', 'Gene', '675', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('ER', 'Gene', '2099', (130, 132))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRCA2', 'Gene', (155, 160))
95247	30652428	We found no significant difference between HER2 status and BRCA2 mutation, but subgroup analysis suggested that ER+/HER2+ could be an independent risk factor for BRCA2 mutation, and it's also one of independent predictive factors for BRCA mutation in our study.	('BRCA', 'Gene', '672', (59, 63))	('ER', 'Gene', '2099', (117, 119))	('BRCA2', 'Gene', '675', (59, 64))	('BRCA2', 'Gene', (162, 167))	('BRCA', 'Gene', (234, 238))	('BRCA', 'Gene', (59, 63))	('BRCA', 'Gene', '672', (162, 166))	('HER2', 'Gene', (43, 47))	('BRCA', 'Gene', (162, 166))	('BRCA2', 'Gene', '675', (162, 167))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', (116, 120))	('mutation', 'Var', (168, 176))	('BRCA2', 'Gene', (59, 64))	('HER2', 'Gene', '2064', (116, 120))	('ER', 'Gene', '2099', (112, 114))	('ER', 'Gene', '2099', (44, 46))	('BRCA', 'Gene', '672', (234, 238))
95249	30652428	So we also found BRCA2 carriers with DCIS were tend to be lower proliferation (<30%), whereas has no significant difference.	('DCIS', 'Var', (37, 41))	('BRCA2', 'Gene', '675', (17, 22))	('lower', 'NegReg', (58, 63))	('proliferation', 'CPA', (64, 77))	('BRCA2', 'Gene', (17, 22))
95253	30652428	BRCA1/BRCA2 mutations have been shown to indicate a higher susceptibility to develop BC.	('BRCA2', 'Gene', '675', (6, 11))	('BRCA1', 'Gene', (0, 5))	('mutations', 'Var', (12, 21))	('BRCA2', 'Gene', (6, 11))	('BRCA1', 'Gene', '672', (0, 5))
95255	30652428	It indicated that, BCS might be a treatment option for DCIS patients with BRCA mutation, for they may be more sensitive to radiation (Garcia-Etienne et al., 2009; Kirova et al., 2010).	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (79, 87))	('BRCA', 'Gene', (74, 78))	('BRCA', 'Gene', '672', (74, 78))
95257	30652428	Further study was needed to discuss whether BRCA mutation is the independent factor for CBTR in DCIS patients, and it's very important for DCIS women with BRCA mutation whether or not to choose contralateral prophylactic mastectomy.	('mutation', 'Var', (160, 168))	('patients', 'Species', '9606', (101, 109))	('BRCA', 'Gene', '672', (155, 159))	('BRCA', 'Gene', (155, 159))	('women', 'Species', '9606', (144, 149))	('BRCA', 'Gene', '672', (44, 48))	('BRCA', 'Gene', (44, 48))
95272	26391216	As a result, the US Food and Drug Administration (FDA) have advocated use of either ypT0 ypN0 or ypT0/is ypN0 as definitions of pCR in their guidance on the use of pCR as an endpoint for accelerated approval for agents in the neoadjuvant treatment of aggressive early breast cancer.	('ypT0/is ypN0', 'Var', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('breast cancer', 'Disease', (268, 281))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))
95279	26391216	In contrast, HER2-positive/ER-negative and triple-negative (ER/PR/HER2-negative) breast cancers show much higher rates of pCR, with a stronger association between not achieving a pCR and poorer outcome (Fig.	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('triple-negative', 'Var', (43, 58))	('breast cancers', 'Disease', (81, 95))	('PR', 'Gene', '5241', (63, 65))	('HER2', 'Gene', '2064', (66, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('higher', 'PosReg', (106, 112))	('HER2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HER2', 'Gene', '2064', (13, 17))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('pCR', 'Disease', (122, 125))	('HER2', 'Gene', (66, 70))
95288	26391216	To illustrate how the different definitions of pathological response can alter the headline results for a trial, we include here results from our recently published ARTemis trial, demonstrating results for ypT0/is ypN0, ypT0/is and ypT0/is plus minimal residual disease in the breast only (Table 2) for different groups of patients.	('patients', 'Species', '9606', (323, 331))	('ypT0/is plus', 'Var', (232, 244))	('ypT0/is', 'Var', (220, 227))	('ypT0/is ypN0', 'Var', (206, 218))
95363	19250546	Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer Aberrant methylation of CpG islands is a hallmark of cancer and occurs at an early stage in breast tumorigenesis.	('breast cancer', 'Disease', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('hallmark of cancer', 'Disease', 'MESH:D009369', (129, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Aberrant methylation', 'Var', (88, 108))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('homeobox genes', 'Gene', (15, 29))	('hallmark of cancer', 'Disease', (129, 147))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('methylation', 'Var', (97, 108))
95371	19250546	A substantial fraction of these hypermethylated CpG islands (32% of the annotated CpG islands) is associated with several homeobox genes, such as the TLX1, HOXB13, and HNF1B genes.	('HNF1B', 'Gene', (168, 173))	('hypermethylated', 'Var', (32, 47))	('HOXB13', 'Gene', (156, 162))	('TLX1', 'Gene', '3195', (150, 154))	('TLX1', 'Gene', (150, 154))	('HNF1B', 'Gene', '6928', (168, 173))	('associated', 'Reg', (98, 108))	('HOXB13', 'Gene', '10481', (156, 162))
95372	19250546	Fifty-three percent of the genes hypermethylated in early-stage breast cancer overlap with known Polycomb targets and include homeobox genes and other developmental transcription factors.	('Polycomb', 'Gene', (97, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('Polycomb', 'Gene', '12416', (97, 105))	('hypermethylated', 'Var', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
95374	19250546	More specifically, our results are suggestive of a critical role of homeobox gene methylation in the insurgence and/or progression of breast cancer.	('breast cancer', 'Disease', (134, 147))	('methylation', 'Var', (82, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('homeobox gene', 'Gene', (68, 81))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
95378	19250546	It is now widely recognized that aberrant epigenetic modifications play a crucial role in altering gene expression and inducing tumor formation.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('gene expression', 'MPA', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('altering', 'Reg', (90, 98))	('aberrant epigenetic modifications', 'Var', (33, 66))	('tumor', 'Disease', (128, 133))	('inducing', 'Reg', (119, 127))
95379	19250546	Methylation of CpG-rich islands encompassing gene promoter regions is especially relevant for the silencing of important tumor suppressor genes and accounts for a growing number of diseases, including breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Methylation', 'Var', (0, 11))	('silencing', 'NegReg', (98, 107))	('tumor', 'Disease', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('accounts', 'Reg', (148, 156))	('breast cancer', 'Disease', (201, 214))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
95380	19250546	Several genes involved in cell cycle regulation and apoptosis (CCND2, CDKN2A/p16, RASSF1A), DNA damage response (BRCA1), cell adhesion (CDH1) and cell signaling (ER, RARbeta 2) have been reported to undergo promoter hypermethylation in breast carcinoma as well as in other tumor types.	('promoter hypermethylation', 'Var', (207, 232))	('breast carcinoma', 'Phenotype', 'HP:0003002', (236, 252))	('tumor', 'Disease', (273, 278))	('breast carcinoma', 'Disease', (236, 252))	('RASSF1A', 'Gene', '11186', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('CCND2', 'Gene', (63, 68))	('apoptosis', 'CPA', (52, 61))	('CCND2', 'Gene', '894', (63, 68))	('BRCA1', 'Gene', '672', (113, 118))	('RASSF1A', 'Gene', (82, 89))	('BRCA1', 'Gene', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('CDKN2A', 'Gene', (70, 76))	('CDH1', 'Gene', '999', (136, 140))	('p16', 'Gene', (77, 80))	('breast carcinoma', 'Disease', 'MESH:D001943', (236, 252))	('p16', 'Gene', '1029', (77, 80))	('CDH1', 'Gene', (136, 140))	('CDKN2A', 'Gene', '1029', (70, 76))
95382	19250546	Epigenetic inactivation can also occur, at different levels depending on the gene examined, in benign diseases such as mammary epithelial hyperplasia and intraductal papillomas - but not in disease-free normal breast epithelium, proliferating lactating breast tissue or stromal cells.	('hyperplasia', 'Disease', (138, 149))	('papillomas', 'Disease', 'MESH:D010212', (166, 176))	('papillomas', 'Disease', (166, 176))	('hyperplasia', 'Disease', 'MESH:D006965', (138, 149))	('papillomas', 'Phenotype', 'HP:0012740', (166, 176))	('Epigenetic inactivation', 'Var', (0, 23))
95383	19250546	In some cases, even the normal breast tissue adjacent to the tumor site can display high levels of promoter methylation, indicating that premalignant epigenetic changes have the potential to spread gradually from the tumor epicenter to the surrounding cells or that a field defect exists that promotes tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('epigenetic changes', 'Var', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('promoter methylation', 'MPA', (99, 119))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('promotes', 'PosReg', (293, 301))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
95384	19250546	These data altogether support the evidence that methylation-driven gene silencing is a frequent as well as a relatively early event in breast tumorigenesis and can be used as a tag to detect breast cancer lesions at their very first appearance.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('breast cancer lesions', 'Disease', (191, 212))	('tumor', 'Disease', (142, 147))	('breast cancer lesions', 'Disease', 'MESH:D001943', (191, 212))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('methylation-driven gene', 'Var', (48, 71))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
95393	19250546	Homeobox-containing transcription factors control vital functional networks during tissue development and differentiation, and their aberrant expression has been often associated, in the mammary gland, with both morphological abnormalities and oncogenesis.	('associated', 'Reg', (168, 178))	('aberrant expression', 'Var', (133, 152))	('Homeobox-containing', 'Protein', (0, 19))	('morphological abnormalities', 'Disease', 'MESH:D000013', (212, 239))	('morphological abnormalities', 'Disease', (212, 239))
95402	19250546	Two micrograms each of the amplicons from MIRA-enriched tumor DNA and from MIRA-enriched normal control samples were labeled with Cy5-dCTP and Cy3-dCTP respectively (GE Healthcare Bio-Sciences Corp., Piscataway, NJ, USA), using a BioPrime Array CGH Genomic Labeling kit (Invitrogen, Carlsbad, CA, USA).	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Cy5-dCTP', 'Var', (130, 138))	('tumor', 'Disease', (56, 61))	('Cy3-dCTP', 'Chemical', '-', (143, 151))	('Cy3-dCTP', 'Var', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
95416	19250546	We next confirmed tumor-specific methylation for several of the targets identified through array analysis using the BstUI combined bisulfite restriction analysis (COBRA) assay.	('methylation', 'Var', (33, 44))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('bisulfite', 'Chemical', 'MESH:C042345', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
95421	19250546	No target region scrutinized so far exhibited robust CpG methylation across all six intraductal carcinomas (Table 1 and data not shown).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('methylation', 'Var', (57, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('intraductal carcinomas', 'Disease', (84, 106))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (89, 105))	('intraductal carcinomas', 'Disease', 'MESH:D002285', (84, 106))
95428	19250546	Likewise, the occurrence of unmethylated alleles in the cancer samples may reflect the heterogeneity of CpG methylation within the cell populations of the tumor itself, but also the presence of normal cells in the specimens.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', (155, 160))	('methylation', 'Var', (108, 119))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
95430	19250546	The TLX1 CpG island was methylated in 13 out of the 16 stage I breast tumors (81%) and in six out of the eight stage II invasive carcinomas (75%).	('TLX1', 'Gene', '3195', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('methylated', 'Var', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('invasive carcinoma', 'Disease', 'MESH:D009361', (120, 138))	('breast tumors', 'Phenotype', 'HP:0100013', (63, 76))	('carcinomas', 'Disease', (129, 139))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('carcinomas', 'Disease', 'MESH:D002277', (129, 139))	('breast tumors', 'Disease', 'MESH:D001943', (63, 76))	('TLX1', 'Gene', (4, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('invasive carcinoma', 'Disease', (120, 138))	('breast tumors', 'Disease', (63, 76))
95431	19250546	Likewise, the CpG island located on chromosome 7 (CGI 7:48) was methylated in almost every stage I tumor examined (93%) and in 15 out of the 17 more advanced tumors (stages II and III tumors, 88%).	('tumors', 'Disease', (158, 164))	('I tumor', 'Disease', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('methylated', 'Var', (64, 74))	('III tumors', 'Disease', 'MESH:D009369', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('I tumor', 'Disease', 'MESH:D009369', (182, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('III tumors', 'Disease', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('I tumor', 'Disease', 'MESH:D009369', (97, 104))
95434	19250546	Rodriguez and colleagues have reported recently that hypermethylation of the HOXB13 gene is a late event in breast tumorigenesis.	('HOXB13', 'Gene', '10481', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('HOXB13', 'Gene', (77, 83))	('hypermethylation', 'Var', (53, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
95436	19250546	Methylation of this intragenic CpG island is an early event in breast cancer development and may precede promoter methylation.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Methylation', 'Var', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))
95439	19250546	In agreement with the MIRA results, we found that the GFI1 CpG island was hypermethylated in 14 out of the 18 tumors examined (six DCIS and 12 stage I tumors, 78%) while the NR2E1 target region was methylated in 11 out of the 21 early-stage breast tumors (six DCIS and 15 stage I tumors, 52%) (Figure 4, partial data and Table 3).	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('breast tumors', 'Phenotype', 'HP:0100013', (241, 254))	('tumors', 'Disease', (248, 254))	('GFI1', 'Gene', '2672', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('I tumors', 'Disease', (149, 157))	('NR2E1', 'Gene', '7101', (174, 179))	('GFI1', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('DCIS', 'Phenotype', 'HP:0030075', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('hypermethylated', 'Var', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Disease', (280, 286))	('I tumors', 'Disease', 'MESH:D009369', (278, 286))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('NR2E1', 'Gene', (174, 179))	('I tumors', 'Disease', (278, 286))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('breast tumors', 'Disease', 'MESH:D001943', (241, 254))	('I tumors', 'Disease', 'MESH:D009369', (149, 157))	('breast tumors', 'Disease', (241, 254))
95441	19250546	As expected, there is an evident tendency towards increased methylation in tumor-derived samples; the occurrence of early-stage cancer-specific methylated CpGs is very significant (P < 0.001, Fisher's exact test) (Figure 6).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('methylated', 'Var', (144, 154))	('CpGs', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', (128, 134))
95442	19250546	DCIS is suspected to be a direct, although not obligate, precursor of invasive breast cancer, and aberrant DNA methylation is believed to play a crucial role in breast tumorigenesis.	('aberrant', 'Var', (98, 106))	('tumor', 'Disease', (168, 173))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('invasive breast cancer', 'Disease', (70, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('invasive breast cancer', 'Disease', 'MESH:D001943', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
95446	19250546	Most importantly, these gene candidates display methylation frequencies ranging from 50% to 83% in DCIS and up to 93% in stage I breast cancer, depending on the target gene, and these candidates hold great promise, alone or in combination, for future diagnostic applications.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('methylation', 'Var', (48, 59))	('DCIS', 'Disease', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
95454	19250546	Robust and frequent methylation of homeobox genes is not restricted to breast cancer, and occurs at significant frequencies (~10% to 20% of all methylated genes) in early-stage lung carcinoma - suggesting a common epigenetic pathway involving the homeobox gene network.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('homeobox genes', 'Gene', (35, 49))	('lung carcinoma', 'Disease', (177, 191))	('lung carcinoma', 'Disease', 'MESH:D008175', (177, 191))	('methylation', 'Var', (20, 31))	('occurs', 'Reg', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
95457	19250546	We cannot deduce why homeobox genes become preferential targets of aberrant CpG methylation during breast tumorigenesis and whether this extensive methylation can shift their finely tuned homeostasis, thus triggering tumorigenesis, or is merely associated with the neoplastic event.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('finely tuned homeostasis', 'MPA', (175, 199))	('neoplastic event', 'Phenotype', 'HP:0002664', (265, 281))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('triggering', 'Reg', (206, 216))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('CpG', 'Protein', (76, 79))	('methylation', 'Var', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('aberrant', 'Var', (67, 75))	('shift', 'Reg', (163, 168))	('tumor', 'Disease', (106, 111))
95473	19250546	Aberrant methylation of these master regulators may play a crucial role in the insurgence and/or progression of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('role', 'Reg', (67, 71))	('Aberrant methylation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('play', 'Reg', (52, 56))
95487	32753377	Atypia in women at high-risk may be associated with benign and malignant breast ductal abnormalities; these characteristics of high-risk ductal cells may not be reflected in gene expression profiles.	('c', 'Gene', '1356', (121, 122))	('c', 'Gene', '1356', (166, 167))	('malignant breast ductal abnormalities', 'Disease', 'MESH:D001943', (63, 100))	('c', 'Gene', '1356', (108, 109))	('c', 'Gene', '1356', (139, 140))	('malignant breast ductal abnormalities', 'Disease', (63, 100))	('c', 'Gene', '1356', (82, 83))	('Atypia', 'Var', (0, 6))	('women', 'Species', '9606', (10, 15))	('c', 'Gene', '1356', (40, 41))	('c', 'Gene', '1356', (113, 114))	('c', 'Gene', '1356', (144, 145))	('benign', 'Disease', (52, 58))
95519	32753377	Women with known deleterious mutations in BRCA1/2 or other highly-penetrant breast cancer susceptibility genes were eligible for this protocol.	('BRCA1/2', 'Gene', (42, 49))	('c', 'Gene', '1356', (93, 94))	('Women', 'Species', '9606', (0, 5))	('c', 'Gene', '1356', (86, 87))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (29, 38))	('BRCA1/2', 'Gene', '672;675', (42, 49))	('c', 'Gene', '1356', (139, 140))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('c', 'Gene', '1356', (83, 84))
95596	32753377	MRI demonstrated abnormalities in 5 subjects, two of which were in high-risk subjects - one case of invasive breast carcinoma and one case of ductal hyperplasia.	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (100, 125))	('hyperplasia', 'Disease', (149, 160))	('c', 'Gene', '1356', (56, 57))	('breast carcinoma', 'Phenotype', 'HP:0003002', (109, 125))	('c', 'Gene', '1356', (82, 83))	('invasive breast carcinoma', 'Disease', (100, 125))	('c', 'Gene', '1356', (116, 117))	('hyperplasia', 'Disease', 'MESH:D006965', (149, 160))	('c', 'Gene', '1356', (92, 93))	('c', 'Gene', '1356', (134, 135))	('c', 'Gene', '1356', (144, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('c', 'Gene', '1356', (119, 120))	('abnormalities', 'Var', (17, 30))	('c', 'Gene', '1356', (41, 42))
95737	33805352	Learning lessons from the urological community after seeing a profound shift in the management of certain low Gleason-score prostate cancer to an "observation-alone" strategy, the LORD, LORIS, COMET, and LORETTA trials are currently underway and will strive to provide an evidence-base, supporting a surveillance-alone strategy in select cases of non-high-risk DCIS.	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('DCIS', 'Phenotype', 'HP:0030075', (361, 365))	('non-high-risk DCIS', 'Disease', (347, 365))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('low Gleason-score', 'Var', (106, 123))	('prostate cancer', 'Disease', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
95830	26371145	This finding, along with molecular evidence demonstrating that gene expression can distinguish two LCIS subclasses, that approximately 70% of LCIS lesions appear to be clonally related to synchronously diagnosed invasive lesions by copy number analysis, and the frequency of common mutations in microdissected LCIS and infiltrating lobular carcinoma, suggest that LCIS is a heterogenous lesion representing both a non-obligate precursor lesion and a high-risk marker.	('LCIS', 'Phenotype', 'HP:0030076', (99, 103))	('LCIS', 'Phenotype', 'HP:0030076', (364, 368))	('LCIS', 'Disease', (364, 368))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (332, 349))	('lobular carcinoma', 'Disease', (332, 349))	('LCIS', 'Phenotype', 'HP:0030076', (142, 146))	('LCIS', 'Disease', (142, 146))	('mutations', 'Var', (282, 291))	('LCIS', 'Phenotype', 'HP:0030076', (310, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('LCIS', 'Gene', (310, 314))	('lobular carcinoma', 'Disease', 'MESH:D018275', (332, 349))
95833	26371145	Importantly, trials supporting MRI screening in women with >20% lifetime risk of breast cancer were based on elevated risk incurred by family history or suspected BRCA mutations and therefore represent a population at risk for potentially more-aggressive breast cancer subtypes and interval cancers.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('breast cancer', 'Disease', (255, 268))	('BRCA', 'Gene', '672', (163, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('breast cancer subtypes and interval cancers', 'Disease', 'MESH:D001943', (255, 298))	('BRCA', 'Gene', (163, 167))	('women', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('mutations', 'Var', (168, 177))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
95860	27073789	The range of malignancy risk of BI-RADS 4 (with subcategories of A through C) is wide with a figure showing 3%-95%, in which biopsy should be considered in this category.	('malignancy', 'Disease', 'MESH:D009369', (13, 23))	('BI-RADS 4', 'Var', (32, 41))	('malignancy', 'Disease', (13, 23))
95874	27073789	91 of 162 patients (56.2%) were diagnosed as having BI-RADS 4 lesions with findings of either microcalcification or a suspicious mass on mammography.	('calcification', 'Disease', 'MESH:D002114', (99, 112))	('calcification', 'Disease', (99, 112))	('BI-RADS', 'Var', (52, 59))	('patients', 'Species', '9606', (10, 18))
96003	25714400	It seems that different forms of invasive breast cancer that develop mostly from different types of DCIS lesions, with low-grade DCIS lesions giving rise to low-grade invasive breast carcinomas, and high-grade DCIS lesions giving rise to high-grade invasive breast carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (265, 275))	('breast carcinomas', 'Phenotype', 'HP:0003002', (258, 275))	('breast carcinoma', 'Phenotype', 'HP:0003002', (258, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('invasive breast carcinomas', 'Disease', (249, 275))	('breast carcinomas', 'Phenotype', 'HP:0003002', (176, 193))	('breast carcinoma', 'Phenotype', 'HP:0003002', (176, 192))	('lesions', 'Var', (134, 141))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (249, 275))	('giving rise to', 'Reg', (142, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('invasive breast cancer', 'Disease', (33, 55))	('low-grade', 'Var', (119, 128))	('invasive breast carcinomas', 'Disease', (167, 193))	('invasive breast cancer', 'Disease', 'MESH:D001943', (33, 55))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (167, 193))	('high-grade', 'Var', (199, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
96036	25714400	Transgenic and gene disruption techniques have shown that complete prolactin (PRL) deficiency results in the arrest of mammary organogenesis at an immature pubertal state.	('mammary organogenesis', 'CPA', (119, 140))	('prolactin', 'Gene', (67, 76))	('PRL', 'Gene', (78, 81))	('prolactin', 'Gene', '24683', (67, 76))	('PRL', 'Gene', '24683', (78, 81))	('deficiency', 'Var', (83, 93))
96126	25714400	He also found that a constant absorption for many months of excessive amounts of estrogen leads to the formation of fibroadenomas, however, fluctuations of the concentration of estrogen induced large cysts but no fibroadenomas.	('fluctuations', 'Var', (140, 152))	('induced', 'Reg', (186, 193))	('fibroadenomas', 'Disease', 'MESH:D018226', (213, 226))	('fibroadenomas', 'Disease', (116, 129))	('fibroadenomas', 'Disease', (213, 226))	('rat', 'Species', '10116', (167, 170))	('fibroadenomas', 'Disease', 'MESH:D018226', (116, 129))
96175	25714400	In Table 3 is the histological type more frequently found in a large series of 584 tumors induced by DMBA in the rat mammary gland in our laboratory at the FCCC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('DMBA', 'Var', (101, 105))	('rat', 'Species', '10116', (113, 116))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('DMBA', 'Chemical', 'MESH:D015127', (101, 105))	('rat', 'Species', '10116', (142, 145))
96423	25603785	HER2 positivity was noted in 15% and 17.7% of invasive cancers following a screening or diagnostic mammogram, respectively.	('invasive cancers', 'Disease', (46, 62))	('positivity', 'Var', (5, 15))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('invasive cancers', 'Disease', 'MESH:D009362', (46, 62))
96452	23764994	Reducing false-positive biopsies: a pilot study to reduce benign biopsy rates for BI-RADS 4A/B assessments through testing risk stratification and new thresholds for intervention The aim of this study is to evaluate Breast Imaging Reporting and Data Systems (BI-RADS) 4A/B subcategory risk estimates for ductal carcinoma in situ (DCIS) and invasive cancer (IC), determining whether changing the proposed cutoffs to a higher biopsy threshold could safely increase cancer-to-biopsy yields while minimizing false-positive biopsies.	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (304, 328))	('ductal carcinoma in situ', 'Disease', (304, 328))	('DCIS', 'Phenotype', 'HP:0030075', (330, 334))	('invasive cancer', 'Disease', (340, 355))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (463, 469))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (304, 328))	('invasive cancer', 'Disease', 'MESH:D009362', (340, 355))	('cancer', 'Disease', (463, 469))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('4A/B', 'SUBSTITUTION', 'None', (268, 272))	('4A/B', 'SUBSTITUTION', 'None', (90, 94))	('4A/B', 'Var', (268, 272))	('increase', 'PosReg', (454, 462))	('4A/B', 'Var', (90, 94))
96458	23764994	Three hypothetical thresholds for intervention were analyzed: (1) DCIS or IC >= 10 %; (2) DCIS >= 50 % or IC >= 10 %; and (3) IC >= 10 %, which translated to 22, 48, and 56 % of biopsies avoided; cancer-to-biopsy yields of 36, 47, and 46 %; and associated chance of missing an IC of 0, 1, and 2 %, respectively.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('DCIS >= 50 %', 'Var', (90, 102))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('biopsies', 'CPA', (178, 186))	('cancer', 'Disease', (196, 202))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))
96464	23764994	A Breast Imaging Reporting and Data Systems (BI-RADS) 4 assessment is given to lesions that carry a risk of malignancy between 2 and 95 % and, in the United States, most BI-RADS 4 lesions are biopsied (69-95 %).	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy', 'Disease', (108, 118))	('BI-RADS', 'Var', (170, 177))
96471	23764994	Off the remaining referred women, 7 had a BI-RADS 5 score, 30 had a BI-RADS 1-3 score on a prior mammogram, and 15 were referred for some other suspicious finding without a prior mammogram or BI-RADS score.	('women', 'Species', '9606', (27, 32))	('BI-RADS 5 score', 'Var', (42, 57))	('BI-RADS', 'Var', (68, 75))
96495	23764994	High-grade DCIS may be associated with a higher risk of developing invasive breast cancer, and this risk is usually within 5 years of diagnosis.	('invasive breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('High-grade DCIS', 'Var', (0, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('invasive breast cancer', 'Disease', (67, 89))
96499	23764994	In this pilot study, a biopsy threshold of >= 10 % DCIS or >= 10 % IC risk (scenario #1) avoids 22 % of biopsies with a cancer-to-biopsy yield of 36 % without delaying diagnosis for any malignant lesions.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('biopsies', 'CPA', (104, 112))	('avoids', 'NegReg', (89, 95))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('DCIS', 'Var', (51, 55))
96565	23372916	emphasize their genetic similarities from concordant ETV6 gene alterations in both in situ and invasive forms of SC.	('ETV6', 'Gene', (53, 57))	('alterations', 'Var', (63, 74))	('ETV6', 'Gene', '2120', (53, 57))
96657	17261174	It has been suggested that, alterations in the anatomy of the lymphatics draining the tumor could interfere with the lymphotropic agents and prevent their unobstructed transit to the sentinel node(s).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('alterations', 'Var', (28, 39))	('interfere', 'NegReg', (98, 107))	('tumor', 'Disease', (86, 91))	('unobstructed transit to the sentinel node', 'MPA', (155, 196))	('prevent', 'NegReg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('lymphotropic agents', 'MPA', (117, 136))
96724	17261174	Also, the fraction of patients with positive sentinel lymph node(s) should be 20%-30% in patients with T1a-b breast cancer and about 35% in patients with T1a-c cancer.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('patients', 'Species', '9606', (22, 30))	('T1a-b', 'Var', (103, 108))	('T1a-c cancer', 'Disease', 'MESH:D009369', (154, 166))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('T1a-c cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
96746	31147995	Current American Joint Committee on Cancer (AJCC) staging criteria were followed in defining DCISM as no invasive focus >1 mm, and in categorizing node status as negative (pN0), isolated tumor cells (pN0i+), micrometastasis (0.2-2 mm, pN1mi), and macrometastasis (>2 mm, pN1).	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Cancer', 'Disease', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('micrometastasis', 'Disease', (208, 223))	('0.2-2 mm', 'Var', (225, 233))	('pN1', 'Gene', (271, 274))	('pN1', 'Gene', '5270', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('pN1', 'Gene', '5270', (271, 274))	('pN1', 'Gene', (235, 238))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('macrometastasis', 'Disease', (247, 262))	('isolated tumor', 'Disease', (178, 192))	('isolated tumor', 'Disease', 'MESH:D009369', (178, 192))
96754	31147995	Mastectomy was more frequent for patients with the most extensive DCISM (86%, p = 0.002), but, across the other strata, the proportions of mastectomy and lumpectomy were approximately equal.	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('Mastectomy', 'Disease', (0, 10))	('patients', 'Species', '9606', (33, 41))	('DCISM', 'Var', (66, 71))
96779	31147995	In the 10 studies that specified the size of SLN metastasis, combined with the results of the six larger and more recent studies, SLNB was performed in 86% of 1443 patients; 3.4% were pN0i+, 4.9% were pN1mi, and 2.5% were pN1.	('pN0i+', 'Var', (184, 189))	('pN1', 'Gene', (201, 204))	('pN1', 'Gene', '5270', (222, 225))	('pN1', 'Gene', (222, 225))	('pN1', 'Gene', '5270', (201, 204))	('patients', 'Species', '9606', (164, 172))
96799	20551053	PIK3CA mutations in in situ and invasive breast carcinomas The PIK3 signaling pathway has been identified as one of the most important and most frequently mutated pathways in breast cancer.	('invasive breast carcinomas', 'Disease', (32, 58))	('PIK3', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('PIK3', 'Gene', (63, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (32, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('breast cancer', 'Disease', (175, 188))	('PIK3', 'Gene', '5294', (0, 4))	('breast carcinomas', 'Phenotype', 'HP:0003002', (41, 58))	('PIK3CA', 'Gene', (0, 6))	('PIK3', 'Gene', '5294', (63, 67))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
96800	20551053	Somatic mutations in the catalytic subunit of PIK3CA have been found in a significant fraction of breast carcinomas, and it has been proposed that mutant PIK3CA plays a role in tumor initiation.	('mutant', 'Var', (147, 153))	('PIK3CA', 'Gene', '5290', (46, 52))	('PIK3CA', 'Gene', (154, 160))	('breast carcinomas', 'Phenotype', 'HP:0003002', (98, 115))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PIK3CA', 'Gene', (46, 52))	('PIK3CA', 'Gene', '5290', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('plays', 'Reg', (161, 166))	('found', 'Reg', (63, 68))	('tumor', 'Disease', (177, 182))	('breast carcinomas', 'Disease', 'MESH:D001943', (98, 115))	('breast carcinomas', 'Disease', (98, 115))
96801	20551053	However, the majority of primary human tumors analyzed for genetic alterations in PIK3CA have been invasive breast carcinomas and the frequency of PIK3CA mutations in pre-invasive lesions has not been explored.	('breast carcinomas', 'Phenotype', 'HP:0003002', (108, 125))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('PIK3CA', 'Gene', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('invasive breast carcinomas', 'Disease', (99, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('PIK3CA', 'Gene', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('PIK3CA', 'Gene', '5290', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PIK3CA', 'Gene', '5290', (147, 153))	('human', 'Species', '9606', (33, 38))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (99, 125))	('tumors', 'Disease', (39, 45))	('genetic alterations', 'Var', (59, 78))
96804	20551053	We found that the frequency of PIK3CA mutations was essentially the same (~30%) in all three histologic groups.	('PIK3CA', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('PIK3CA', 'Gene', '5290', (31, 37))
96805	20551053	In some cases in situ and invasive areas of the same tumor were discordant for PIK3CA status and in two cases where multiple invasive and adjacent in situ areas within the same tumor were analyzed independently, we detected intra-tumor heterogeneity for PIK3CA mutations.	('mutations', 'Var', (261, 270))	('tumor', 'Disease', (230, 235))	('intra-tumor', 'Disease', (224, 235))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('PIK3CA', 'Gene', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PIK3CA', 'Gene', '5290', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PIK3CA', 'Gene', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('intra-tumor', 'Disease', 'MESH:D009369', (224, 235))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (177, 182))	('PIK3CA', 'Gene', '5290', (79, 85))
96806	20551053	Our results suggest that mutation of PIK3CA is an early event in breast cancer that is more likely to play a role in breast tumor initiation than in invasive progression, although a potential role for exon 9 mutations in the progression of a subset of DCIS cases cannot be excluded.	('PIK3CA', 'Gene', '5290', (37, 43))	('breast tumor initiation', 'Disease', 'MESH:D001943', (117, 140))	('breast tumor initiation', 'Disease', (117, 140))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast tumor', 'Phenotype', 'HP:0100013', (117, 129))	('PIK3CA', 'Gene', (37, 43))
96808	20551053	Highlighting the importance of PIK3 signaling in human cancer, genetic alterations have been reported in several components of the pathway in various tumor types including deletion of PTEN, amplification of AKT1 and PIK3CA, and somatic mutations of PIK3CA and AKT1.	('PIK3', 'Gene', (31, 35))	('PIK3CA', 'Gene', '5290', (249, 255))	('PIK3', 'Gene', '5294', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PIK3CA', 'Gene', '5290', (216, 222))	('AKT1', 'Gene', '207', (260, 264))	('human', 'Species', '9606', (49, 54))	('PIK3', 'Gene', (249, 253))	('PIK3', 'Gene', (216, 220))	('cancer', 'Disease', (55, 61))	('PIK3', 'Gene', '5294', (249, 253))	('PIK3CA', 'Gene', (249, 255))	('PTEN', 'Gene', (184, 188))	('PIK3', 'Gene', '5294', (216, 220))	('AKT1', 'Gene', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PIK3CA', 'Gene', (216, 222))	('AKT1', 'Gene', '207', (207, 211))	('deletion', 'Var', (172, 180))	('tumor', 'Disease', (150, 155))	('amplification', 'Var', (190, 203))	('alterations', 'Reg', (71, 82))	('PTEN', 'Gene', '5728', (184, 188))	('reported', 'Reg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('AKT1', 'Gene', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
96809	20551053	In human breast cancer, mutations in PIK3CA have been reported to occur in 8-40% of tumors making it one of the most frequently mutated genes in this tumor type.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('PIK3CA', 'Gene', '5290', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('human', 'Species', '9606', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('occur', 'Reg', (66, 71))	('breast cancer', 'Disease', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (84, 89))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (24, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('tumor', 'Disease', (150, 155))	('PIK3CA', 'Gene', (37, 43))
96810	20551053	The majority of mutations have been identified in the helical domain (exon 9) and in the kinase domain (exon 20) of PIK3CA.	('PIK3CA', 'Gene', (116, 122))	('PIK3CA', 'Gene', '5290', (116, 122))	('mutations', 'Var', (16, 25))
96811	20551053	Expression of cancer derived PIK3CA mutants in cultured cells increases kinase activity, invasion, resistance to apoptosis, and in immortalized human mammary epithelial cells it is sufficient to induce soft agar growth and tumorigenicity suggesting that mutant PIK3CA may play a role in the initiating steps of breast tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('soft agar growth', 'CPA', (202, 218))	('breast tumor', 'Disease', 'MESH:D001943', (311, 323))	('mutants', 'Var', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutant', 'Var', (254, 260))	('human', 'Species', '9606', (144, 149))	('breast tumor', 'Phenotype', 'HP:0100013', (311, 323))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (261, 267))	('tumor', 'Disease', (318, 323))	('PIK3CA', 'Gene', '5290', (29, 35))	('breast tumor', 'Disease', (311, 323))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('invasion', 'CPA', (89, 97))	('resistance to apoptosis', 'CPA', (99, 122))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('kinase activity', 'MPA', (72, 87))	('role', 'Reg', (279, 283))	('cancer', 'Disease', (14, 20))	('induce', 'PosReg', (195, 201))	('increases', 'PosReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PIK3CA', 'Gene', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('play', 'Reg', (272, 276))
96813	20551053	Analysis of pre-invasive tumors including colon adenomas and Barrett's esophagus has demonstrated a paucity of mutations in PIK3CA compared to invasive carcinomas.	('invasive carcinomas', 'Disease', (143, 162))	('mutations', 'Var', (111, 120))	("Barrett's esophagus", 'Disease', (61, 80))	('colon adenomas', 'Disease', (42, 56))	('invasive carcinomas', 'Disease', 'MESH:D009361', (143, 162))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (61, 80))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('invasive tumors', 'Disease', (16, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('invasive tumors', 'Disease', 'MESH:D009369', (16, 31))	('colon adenomas', 'Disease', 'MESH:D000236', (42, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('PIK3CA', 'Gene', (124, 130))	('PIK3CA', 'Gene', '5290', (124, 130))
96814	20551053	Similarly the frequency of PIK3CA mutations was significantly higher in advanced gastric carcinomas compared to early stage tumors and gain of PIK3CA was more frequent in high-grade dysplasias and carcinomas than in low-grade dysplasias in head and neck cancer.	('dysplasias and carcinomas', 'Disease', 'MESH:D002277', (182, 207))	('gastric carcinomas', 'Disease', 'MESH:D013274', (81, 99))	('gastric carcinomas', 'Disease', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('dysplasias in head', 'Phenotype', 'HP:0000234', (226, 244))	('PIK3CA', 'Gene', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('PIK3CA', 'Gene', '5290', (143, 149))	('head and neck cancer', 'Phenotype', 'HP:0012288', (240, 260))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('dysplasias in head and neck cancer', 'Disease', 'MESH:D006258', (226, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('tumors', 'Disease', (124, 130))	('gain', 'PosReg', (135, 139))	('higher', 'Reg', (62, 68))	('PIK3CA', 'Gene', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('PIK3CA', 'Gene', '5290', (27, 33))	('mutations', 'Var', (34, 43))
96816	20551053	In human breast cancer only a few published studies on small number of samples have analyzed PIK3CA mutations in pre-invasive tumors including DCIS.	('mutations', 'Var', (100, 109))	('PIK3CA', 'Gene', '5290', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('invasive tumors', 'Disease', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('PIK3CA', 'Gene', (93, 99))	('breast cancer', 'Disease', (9, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('DCIS', 'Disease', (143, 147))	('invasive tumors', 'Disease', 'MESH:D009369', (117, 132))
96817	20551053	performed SSCP (Single-Strand Conformational Polymorphism) analysis of PIK3CA exons 1-20 in 70 breast tumors including 3 DCIS and detected mutations in 28/67 invasive tumors and 0/3 DCIS, whereas Lee et al.	('breast tumor', 'Phenotype', 'HP:0100013', (95, 107))	('PIK3CA', 'Gene', '5290', (71, 77))	('breast tumors', 'Phenotype', 'HP:0100013', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (139, 148))	('breast tumors', 'Disease', 'MESH:D001943', (95, 108))	('breast tumors', 'Disease', (95, 108))	('invasive tumors', 'Disease', (158, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('invasive tumors', 'Disease', 'MESH:D009369', (158, 173))	('PIK3CA', 'Gene', (71, 77))
96818	20551053	analyzed exons 9 and 20 by SSCP in 93 breast tumors and identified mutations in 24/78 of invasive breast tumors and only 2/15 DCIS.	('invasive breast tumors', 'Disease', (89, 111))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('breast tumors', 'Phenotype', 'HP:0100013', (98, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (98, 110))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('breast tumors', 'Phenotype', 'HP:0100013', (38, 51))	('breast tumors', 'Disease', 'MESH:D001943', (98, 111))	('mutations', 'Var', (67, 76))	('breast tumor', 'Phenotype', 'HP:0100013', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('invasive breast tumors', 'Disease', 'MESH:D001943', (89, 111))	('breast tumors', 'Disease', 'MESH:D001943', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('breast tumors', 'Disease', (38, 51))
96820	20551053	Based on these data we hypothesized that mutational activation of the PIK3CA pathway may play a role in the progression of in situ carcinomas to invasive disease.	('situ carcinomas to invasive disease', 'Disease', (126, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('PIK3CA', 'Gene', (70, 76))	('situ carcinomas to invasive disease', 'Disease', 'MESH:D002278', (126, 161))	('PIK3CA', 'Gene', '5290', (70, 76))	('mutational', 'Var', (41, 51))
96827	20551053	We determined the frequency of PIK3CA mutations in pure DCIS, DCIS adjacent to invasive cancer, and in invasive ductal breast carcinomas (IDC).	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('invasive ductal breast carcinomas', 'Disease', 'MESH:D018270', (103, 136))	('DCIS', 'Disease', (62, 66))	('breast carcinomas', 'Phenotype', 'HP:0003002', (119, 136))	('pure DCIS', 'Disease', (51, 60))	('PIK3CA', 'Gene', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('invasive cancer', 'Disease', (79, 94))	('PIK3CA', 'Gene', '5290', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (38, 47))	('invasive cancer', 'Disease', 'MESH:D009362', (79, 94))	('invasive ductal breast carcinomas', 'Disease', (103, 136))
96829	20551053	PIK3CA mutations were found in only 5% of pure DCIS (95% CI 1-16%) but in about 16% of DCIS adjacent to IDC and 9% of IDC.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
96830	20551053	Because the frequency of PIK3CA mutations in the initial cohort was low and the 95% CIs were so large, we expanded our study to 374 Korean patients (including 48 patients with matched DCIS and IDC lesions).	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (139, 147))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (25, 31))
96831	20551053	In addition, due to the intratumor heterogeneity of PIK3CA mutations we observed in our pilot study, we analyzed the most frequent exon 9 (E542K) and exon 20 (H1047R and H1047L) mutations by mass spectrometry (Supplementary Figure S1), which is more sensitive for mutation detection than Sanger sequencing.	('H1047R', 'SUBSTITUTION', 'None', (159, 165))	('H1047R', 'Var', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('E542K', 'Var', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PIK3CA', 'Gene', (52, 58))	('H1047L', 'SUBSTITUTION', 'None', (170, 176))	('tumor', 'Disease', (29, 34))	('E542K', 'Mutation', 'rs121913273', (139, 144))	('H1047L', 'Var', (170, 176))	('PIK3CA', 'Gene', '5290', (52, 58))
96832	20551053	Using this approach, the frequency of any PIK3CA mutation was between 28% and 31% in each histologic subgroup and not significantly different (Table 1 and Supplementary Table S2).	('PIK3CA', 'Gene', (42, 48))	('PIK3CA', 'Gene', '5290', (42, 48))	('mutation', 'Var', (49, 57))
96833	20551053	The higher frequency of mutations detected by mass spectrometry is unlikely to be due to ethnic or other differences between the pilot and extended cohorts, but highlights the advantage of using this method for the testing of known mutations in cancer genes that may be present only in a subset of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('mutations', 'Var', (232, 241))	('cancer', 'Disease', (298, 304))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
96834	20551053	These results indicate that divergence for PIK3CA mutations occur in a significant fraction of breast tumors during in situ to invasive progression.	('breast tumor', 'Phenotype', 'HP:0100013', (95, 107))	('PIK3CA', 'Gene', '5290', (43, 49))	('breast tumors', 'Phenotype', 'HP:0100013', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (50, 59))	('breast tumors', 'Disease', 'MESH:D001943', (95, 108))	('breast tumors', 'Disease', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PIK3CA', 'Gene', (43, 49))
96835	20551053	Furthermore, the equal frequency of the two possible discordant patterns (i.e., mutant DCIS and wild type IDC and vice versa) implies the lack of selective advantage of cells with mutant PIK3CA during invasive progression.	('PIK3CA', 'Gene', '5290', (187, 193))	('mutant', 'Var', (80, 86))	('mutant', 'Var', (180, 186))	('PIK3CA', 'Gene', (187, 193))	('DCIS', 'Gene', (87, 91))
96836	20551053	We also explored associations between any PIK3CA mutation and age or pathologic variables (when histologic group was forced into the model), as well as interactions between histologic group and other variables (Supplementary Table S4).	('PIK3CA', 'Gene', (42, 48))	('PIK3CA', 'Gene', '5290', (42, 48))	('associations', 'Interaction', (17, 29))	('mutation', 'Var', (49, 57))
96837	20551053	Neither histologic group nor any other variable was significantly associated with frequency of any mutation (or specific H1047R, H1047L, E542K mutations).	('E542K', 'Mutation', 'rs121913273', (137, 142))	('H1047R', 'Var', (121, 127))	('E542K', 'Var', (137, 142))	('H1047L', 'SUBSTITUTION', 'None', (129, 135))	('H1047R', 'SUBSTITUTION', 'None', (121, 127))	('H1047L', 'Var', (129, 135))
96838	20551053	When matched cases were analyzed as DCIS, the only significant interaction was between mutant p53 (based on positivity by immunohistochemistry) and pure DCIS (p=0.03); mutant p53 was associated with a greater percentage of patients having a PIK3CA mutation among pure DCIS cases (Supplementary Table S5).	('p53', 'Gene', (94, 97))	('mutant', 'Var', (168, 174))	('p53', 'Gene', '7157', (94, 97))	('PIK3CA', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (241, 247))	('p53', 'Gene', (175, 178))	('patients', 'Species', '9606', (223, 231))	('p53', 'Gene', '7157', (175, 178))
96839	20551053	When matched cases were analyzed as IDC, the p53 interaction with DCIS remained significant (p=0.01), and the interaction of grade and pure DCIS was also significant (p=0.02); high grade associated with a lower percentage of patients having any PIK3CA mutation in pure DCIS (Supplementary Table S5).	('p53', 'Gene', (45, 48))	('PIK3CA', 'Gene', (245, 251))	('p53', 'Gene', '7157', (45, 48))	('patients', 'Species', '9606', (225, 233))	('PIK3CA', 'Gene', '5290', (245, 251))	('mutation', 'Var', (252, 260))	('high grade', 'Var', (176, 186))
96841	20551053	Models for H1047R mutations were similar to models of any mutation Supplementary Table S6) and there were too few H1047L mutations to analyze separately.	('H1047L', 'SUBSTITUTION', 'None', (114, 120))	('H1047L', 'Var', (114, 120))	('H1047R', 'SUBSTITUTION', 'None', (11, 17))	('H1047R', 'Var', (11, 17))	('mutations', 'Var', (18, 27))
96843	20551053	There were too few E542K mutations to estimate interactions.	('E542K', 'Var', (19, 24))	('E542K', 'Mutation', 'rs121913273', (19, 24))	('interactions', 'Interaction', (47, 59))
96844	20551053	However, this mutation was not detected among patients diagnosed with pure DCIS who were older than 46 (p=0.03) or had high-grade tumors (p=0.02) (Supplementary Table S4), implying that E542K mutation may increase the risk of DCIS progression in these subsets.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('patients', 'Species', '9606', (46, 54))	('E542K', 'Var', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('E542K', 'Mutation', 'rs121913273', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('DCIS', 'Disease', (226, 230))
96845	20551053	Correlating with our results, previous studies have found exon 9 mutations to be more frequent in IDCs of older women and that they are associated with shorter disease-free and overall survival.	('women', 'Species', '9606', (112, 117))	('exon 9', 'Gene', (58, 64))	('shorter', 'NegReg', (152, 159))	('overall survival', 'CPA', (177, 193))	('IDCs', 'Disease', (98, 102))	('mutations', 'Var', (65, 74))
96846	20551053	In summary, this is the first study to demonstrate that PIK3CA mutation is a relatively early event in breast tumorigenesis preceding invasion, since the frequency of PIK3CA mutations is the same in pure DCIS as in DCIS adjacent to IDC and in IDC.	('breast tumor', 'Disease', 'MESH:D001943', (103, 115))	('breast tumor', 'Disease', (103, 115))	('PIK3CA', 'Gene', '5290', (167, 173))	('pure DCIS', 'Disease', (199, 208))	('PIK3CA', 'Gene', '5290', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PIK3CA', 'Gene', (56, 62))	('breast tumor', 'Phenotype', 'HP:0100013', (103, 115))	('mutations', 'Var', (174, 183))	('PIK3CA', 'Gene', (167, 173))
96848	20551053	Our results support the hypothesis that mutational activation of the PIK3CA pathway may play a role in breast tumor initiation and it is not likely to be involved in promoting invasive progression.	('breast tumor initiation', 'Disease', 'MESH:D001943', (103, 126))	('breast tumor initiation', 'Disease', (103, 126))	('play', 'Reg', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast tumor', 'Phenotype', 'HP:0100013', (103, 115))	('PIK3CA', 'Gene', (69, 75))	('mutational', 'Var', (40, 50))	('PIK3CA', 'Gene', '5290', (69, 75))	('activation', 'PosReg', (51, 61))
96858	17501997	14.0% of the lesions were malignancies (5.1% of BI-RADS 3, 5.3% of BI-RADS 4A, 25% of BI-RADS 4B, and 83.3% of BI-RADS 4C lesions).	('malignancies', 'Disease', 'MESH:D009369', (26, 38))	('BI-RADS', 'Var', (86, 93))	('BI-RADS', 'Var', (48, 55))	('malignancies', 'Disease', (26, 38))	('RADS 4B', 'Phenotype', 'HP:0500055', (89, 96))	('BI-RADS', 'Var', (67, 74))
96862	17501997	BI-RADS 3 lesions are considered as probably benign with a risk for malignancy less than 2%.	('BI-RADS 3 lesions', 'Var', (0, 17))	('malignancy', 'Disease', 'MESH:D009369', (68, 78))	('malignancy', 'Disease', (68, 78))
96864	17501997	BI-RADS 5 lesions are highly suggestive of malignancy.	('malignancy', 'Disease', (43, 53))	('malignancy', 'Disease', 'MESH:D009369', (43, 53))	('BI-RADS 5', 'Var', (0, 9))
96875	17501997	Within this period, 355 women with non-palpable mammographic findings successfully underwent VABB; 107 biopsies were performed for mammographic solid tumor without microcalcifications (239 biopsies for microcalcifications and 9 for asymmetric density).	('solid tumor', 'Disease', (144, 155))	('solid tumor', 'Disease', 'MESH:D009369', (144, 155))	('women', 'Species', '9606', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('microcalcifications', 'Var', (202, 221))	('VABB', 'Chemical', '-', (93, 97))
97042	28690654	Among the 446 patients, 32 (7.2%) were reoperated to achieve the clear resection margin (total reoperation rate, 6.3%), which was comprised of 24 FN and eight DCIS-confirmed patients of the undetermined margin-group; 23 (5.2%) were with FN results and DCIS-confirmed undetermined margin-group receiving additional re-excisions using the second IOFSA and achieving BCS intraoperatively; and nine (2%) were converted to mastectomy intraoperatively following the second IOFSA re-excision.	('mastectomy', 'Disease', (418, 428))	('patients', 'Species', '9606', (174, 182))	('FN results', 'Var', (237, 247))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('patients', 'Species', '9606', (14, 22))	('DCIS', 'Phenotype', 'HP:0030075', (252, 256))
97060	22052156	Independent predictors of breast malignancy in screen-detected microcalcifications: biopsy results in 2545 cases Mammographic microcalcifications are associated with many benign lesions, ductal carcinoma in situ (DCIS) and invasive cancer.	('associated', 'Reg', (150, 160))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (187, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast malignancy', 'Disease', (26, 43))	('Mammographic', 'Gene', (113, 125))	('breast malignancy', 'Disease', 'MESH:D001943', (26, 43))	('invasive cancer', 'Disease', (223, 238))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('benign lesions', 'Disease', (171, 185))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('microcalcifications', 'Var', (126, 145))	('invasive cancer', 'Disease', 'MESH:D009362', (223, 238))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (187, 211))	('ductal carcinoma in situ', 'Disease', (187, 211))
97066	22052156	Mammographic extent of microcalcifications >15 mm, imaging grade, their pattern of distribution, presence of a palpable mass and detection after the first screening episode showed significant univariate associations with malignancy.	('malignancy', 'Disease', (221, 231))	('malignancy', 'Disease', 'MESH:D009369', (221, 231))	('microcalcifications', 'Var', (23, 42))
97160	22052156	We note that it has been established that DCIS shares the same predisposing factors as invasive breast cancer and that women with a diagnosis of DCIS are at 10 times greater risk for the future development of invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', (87, 109))	('DCIS', 'Disease', (42, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (209, 231))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('women', 'Species', '9606', (119, 124))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('DCIS', 'Var', (145, 149))	('invasive breast cancer', 'Disease', (209, 231))
97182	18726004	Aberrant c-erbB2 expression in cell clusters overlying focally disrupted breast myoepithelial cell layers: a trigger or sign for emergence of more aggressive cell clones?	('breast myoepithelial', 'Disease', 'MESH:D009208', (73, 93))	('Aberrant', 'Var', (0, 8))	('c-erbB2', 'Gene', '2064', (9, 16))	('breast myoepithelial', 'Disease', (73, 93))	('c-erbB2', 'Gene', (9, 16))
97190	18726004	Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant cerbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.	('aberrant', 'Var', (123, 131))	('biologically more aggressive cell clones', 'CPA', (190, 230))	('trigger', 'Reg', (154, 161))	('cerbB2', 'Gene', (132, 138))	('expression', 'MPA', (139, 149))	('cerbB2', 'Gene', '2064', (132, 138))
97204	18726004	Compared to adjacent counterparts within the same duct, but distant from the disruption, cell clusters overlying focal ME cell layer disruptions (FMCLD) had a significantly higher frequency of ER negativity, proliferation, genetic instabilities, expression of tumor invasion-related genes, and aberrant expression of cellular adhesion molecules.	('tumor', 'Disease', (260, 265))	('genetic instabilities', 'Disease', 'MESH:D030342', (223, 244))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('disruptions', 'Var', (133, 144))	('ER', 'Gene', '2099', (193, 195))	('proliferation', 'CPA', (208, 221))	('expression', 'MPA', (303, 313))	('cellular adhesion molecules', 'Protein', (317, 344))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('expression', 'MPA', (246, 256))	('genetic instabilities', 'Disease', (223, 244))	('higher', 'PosReg', (173, 179))	('ME', 'Chemical', '-', (119, 121))
97248	18726004	Aberrant c-erbB2 expression in cell clusters overlying FMCLD is likely to result from or to signify the emergence of biologically more aggressive cell clones for three reasons.	('result', 'Reg', (74, 80))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (17, 27))	('c-erbB2', 'Gene', '2064', (9, 16))	('c-erbB2', 'Gene', (9, 16))
97252	18726004	Second, as the epithelium is normally devoid of vascular structures and the ME cell layer is the sole source of several tumor suppressors, a FMCLD could result in several focal alterations: (1) a loss of tumor suppressors and paracrine inhibitory functions, which allow epithelial cells to escape from programmed cell death, (2) alterations in permeability for oxygen or growth factors, which selectively favor the exit of stem cells from quiescence and monoclonal proliferation of the progenitor cells, and (3) direct exposure of the epithelial cells to stromal and immunoreactive cells, which stimulates tumor angiogenesis and epithelial-mesenchymal transition.	('death', 'Disease', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('ME', 'Chemical', '-', (76, 78))	('tumor', 'Disease', (606, 611))	('loss of tumor', 'Disease', 'MESH:D009369', (196, 209))	('alterations', 'Var', (329, 340))	('tumor', 'Disease', 'MESH:D009369', (606, 611))	('alterations', 'Var', (177, 188))	('epithelial-mesenchymal transition', 'CPA', (629, 662))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('stimulates', 'PosReg', (595, 605))	('tumor', 'Disease', (120, 125))	('loss of tumor', 'Disease', (196, 209))	('death', 'Disease', 'MESH:D003643', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (606, 611))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (204, 209))	('favor', 'PosReg', (405, 410))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
97253	18726004	The above alterations may individually or collectively induce the emergence of biologically more aggressive cell clones and aberrant c-erbB2 expression.	('c-erbB2', 'Gene', (133, 140))	('alterations', 'Var', (10, 21))	('induce', 'Reg', (55, 61))	('aberrant', 'Var', (124, 132))	('expression', 'MPA', (141, 151))	('biologically more aggressive cell clones', 'CPA', (79, 119))	('c-erbB2', 'Gene', '2064', (133, 140))
97257	18726004	Aberrant c-erbB2 expression in normal appearing duct clusters is likely to result from two factors.	('expression', 'MPA', (17, 27))	('c-erbB2', 'Gene', '2064', (9, 16))	('Aberrant', 'Var', (0, 8))	('c-erbB2', 'Gene', (9, 16))
97259	18726004	Since duct branching and tumor invasion share a very similar molecular mechanism, aberrant c-erbB2 expression in these normal appearing duct clusters is likely to be associated with, or reflect these events.	('expression', 'MPA', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('c-erbB2', 'Gene', '2064', (91, 98))	('associated', 'Reg', (166, 176))	('c-erbB2', 'Gene', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('aberrant', 'Var', (82, 90))
97263	18726004	Mutations also alter the subcellular localization of coded proteins and the biological functions of the c-erbB2 protein.	('proteins', 'Protein', (59, 67))	('c-erbB2', 'Gene', '2064', (104, 111))	('c-erbB2', 'Gene', (104, 111))	('coded proteins', 'Protein', (53, 67))	('subcellular localization of', 'MPA', (25, 52))	('Mutations', 'Var', (0, 9))	('biological functions', 'MPA', (76, 96))	('protein', 'Protein', (112, 119))	('alter', 'Reg', (15, 20))
97266	18726004	In sharp contrast, a number of studies have shown that cytoplasmic expression of c-erbB2 is significantly associated with worse prognosis in breast, endometrial, and other carcinomas.	('endometrial', 'Disease', (149, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('breast', 'Disease', (141, 147))	('carcinomas', 'Disease', (172, 182))	('associated', 'Reg', (106, 116))	('carcinomas', 'Disease', 'MESH:D002277', (172, 182))	('c-erbB2', 'Gene', '2064', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('c-erbB2', 'Gene', (81, 88))	('cytoplasmic expression', 'Var', (55, 77))
97270	18726004	Coupled with a significantly higher rate of ER negativity, genetic instabilities, and expression of tumor invasion related genes, it is very likely that aberrant c-erbB2 expression in these cell clusters is associated with, or signifies the emergence of biologically more aggressive cell clones.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('c-erbB2', 'Gene', '2064', (162, 169))	('c-erbB2', 'Gene', (162, 169))	('ER', 'Gene', '2099', (44, 46))	('associated', 'Reg', (207, 217))	('biologically more aggressive cell clones', 'CPA', (254, 294))	('genetic instabilities', 'Disease', (59, 80))	('aberrant', 'Var', (153, 161))	('genetic instabilities', 'Disease', 'MESH:D030342', (59, 80))
97271	18726004	Consequently, patients with DCIS that have aberrant c-erbB2 expression in cell clusters overlying FMCLD are very likely to represent the specific individual who will develop, or at greater risk to develop, invasive breast lesions.	('invasive breast lesions', 'Disease', (206, 229))	('c-erbB2', 'Gene', '2064', (52, 59))	('develop', 'PosReg', (166, 173))	('c-erbB2', 'Gene', (52, 59))	('invasive breast lesions', 'Disease', 'MESH:D001941', (206, 229))	('patients', 'Species', '9606', (14, 22))	('aberrant', 'Var', (43, 51))
97303	32045679	Cancer originates from an altered phenotype and/or genotype due to cellular mutations that results in uncontrolled cell division.	('mutations', 'Var', (76, 85))	('results in', 'Reg', (91, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
97305	32045679	The degree of mutation is closely correlated with breast cancer progression.	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('mutation', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('correlated', 'Reg', (34, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
97306	32045679	As mutations accumulate, tumors become increasingly malignant and more difficult to treat.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutations', 'Var', (3, 12))
97313	32045679	Overall, the changes in phenotype and stiffness result in aggressive cancer cells that are able to squeeze through the ECM, enter the circulatory system and invade blood and lymph vessels, and migrate through the vessels and metastasize to secondary organs.	('aggressive cancer', 'Disease', (58, 75))	('ECM', 'Gene', (119, 122))	('squeeze', 'CPA', (99, 106))	('metastasize', 'CPA', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('changes', 'Var', (13, 20))	('migrate', 'CPA', (193, 200))	('ECM', 'Gene', '22915', (119, 122))	('aggressive cancer', 'Disease', 'MESH:D009369', (58, 75))
97321	32045679	The presence of TAFs, in conjunction with inflammation results in tissue fibrosis, which in turn increases the risk of tumorigenesis.	('results in', 'Reg', (55, 65))	('inflammation', 'Disease', (42, 54))	('tumor', 'Disease', (119, 124))	('increases', 'PosReg', (97, 106))	('fibrosis', 'Disease', 'MESH:D005355', (73, 81))	('fibrosis', 'Disease', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('TAF', 'Gene', (16, 19))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('TAF', 'Gene', '3490', (16, 19))
97332	32045679	In the early stages of tumor formation, the altered expression of cytokines and growth factors within the TME produces an environment similar to what is observed in sites of chronic inflammation.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('expression', 'MPA', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('inflammation', 'Disease', 'MESH:D007249', (182, 194))	('altered', 'Var', (44, 51))	('tumor', 'Disease', (23, 28))	('inflammation', 'Disease', (182, 194))
97351	32045679	Moreover, the loss of laminin 1 in the basement membrane enables direct contact of cells with the stromal ECM, which leads to EMT.	('loss', 'Var', (14, 18))	('ECM', 'Gene', (106, 109))	('laminin 1', 'Protein', (22, 31))	('contact', 'Interaction', (72, 79))	('leads to', 'Reg', (117, 125))	('ECM', 'Gene', '22915', (106, 109))
97356	32045679	Cleavage of perlecan, for example, promotes the invasive phenotype of tumor cells.	('Cleavage', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('promotes', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('perlecan', 'Protein', (12, 20))
97357	32045679	The peptide motifs glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) (specific for collagen I) and isoleucine-lysine-valine-alanine-valine (IKVAV) (specific for laminin), but not the arginine-glycine-aspartic acid (RGD) (found mainly in fibronectin but also in collagen), were shown to enhance the invasiveness of the aggressive cancer cells.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('arginine-glycine-aspartic acid', 'Chemical', '-', (206, 236))	('isoleucine-lysine-valine-alanine-valine', 'Var', (122, 161))	('fibronectin', 'Gene', '2335', (260, 271))	('arginine', 'Chemical', 'MESH:D001120', (206, 214))	('GFOGER', 'Chemical', '-', (84, 90))	('invasiveness of the aggressive cancer', 'Disease', 'MESH:D009362', (321, 358))	('glycine', 'Chemical', 'MESH:D005998', (56, 63))	('invasiveness of the aggressive cancer', 'Disease', (321, 358))	('enhance', 'PosReg', (309, 316))	('fibronectin', 'Gene', (260, 271))	('glycine', 'Chemical', 'MESH:D005998', (19, 26))	('RGD', 'Chemical', 'MESH:C047981', (238, 241))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('glycine', 'Chemical', 'MESH:D005998', (215, 222))
97410	32045679	Additionally, other factors such as EGF, HGF, and FGF have been shown to significantly increase cancer cell invasiveness.	('FGF', 'Var', (50, 53))	('increase', 'PosReg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGF', 'Gene', '1950', (36, 39))	('HGF', 'Gene', (41, 44))	('HGF', 'Gene', '3082', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('EGF', 'Gene', (36, 39))
97460	32045679	While small spheroids (100-200 mum) are used to study cell-cell and cell-material interactions and test anticancer drugs, larger ones (400-600 mum) have an oxygen gradient with a necrotic core and a 100-300 mum thick proliferating outer shell, and thus are used to study the effects of hypoxia as well.	('necrotic', 'Disease', (179, 187))	('oxygen gradient', 'MPA', (156, 171))	('necrotic', 'Disease', 'MESH:D009336', (179, 187))	('400-600 mum', 'Var', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('hypoxia', 'Disease', 'MESH:D000860', (286, 293))	('oxygen', 'Chemical', 'MESH:D010100', (156, 162))	('cancer', 'Disease', (108, 114))	('hypoxia', 'Disease', (286, 293))
97467	32045679	For example, in one study, the uptake and efficacy of antisense oligonucleotides (ODNs) in three formulations: free ODNs, those encapsulated in lipid, and those encapsulated in polyethyleneimine-based carriers, were tested in vitro on tumor spheroids.	('ODNs', 'Chemical', '-', (116, 120))	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('antisense', 'Var', (54, 63))	('oligonucleotides', 'Chemical', 'MESH:D009841', (64, 80))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('polyethyleneimine', 'Chemical', '-', (177, 194))	('ODNs', 'Chemical', '-', (82, 86))
97542	32045679	In one study, pre-neoplastic (MCF10AT1-EIII8) breast epithelial cells were embedded in Matrigel in the presence of HUVECs, and normal or tumor-associated fibroblasts.	('MCF10AT1-EIII8', 'Var', (30, 44))	('tumor', 'Disease', (137, 142))	('MCF10', 'CellLine', 'CVCL:5555', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
97543	32045679	The presence of TAFs increased the responsiveness of the EIII8 cells to estrogen, and introduction of HUVECs enhanced their invasiveness and induced MMP production by these pre-neoplastic cells.	('introduction', 'Var', (86, 98))	('increased', 'PosReg', (21, 30))	('MMP', 'Gene', '4312;4313;4316;4318', (149, 152))	('invasiveness', 'CPA', (124, 136))	('responsiveness', 'MPA', (35, 49))	('MMP', 'Gene', (149, 152))	('TAF', 'Gene', (16, 19))	('enhanced', 'PosReg', (109, 117))	('induced', 'Reg', (141, 148))	('TAF', 'Gene', '3490', (16, 19))
97547	32045679	Asparagine was shown to increase the invasive/metastatic potential of cells.	('Asparagine', 'Var', (0, 10))	('increase', 'PosReg', (24, 32))	('Asparagine', 'Chemical', 'MESH:D001216', (0, 10))	('invasive/metastatic potential of cells', 'CPA', (37, 75))
97548	32045679	Interestingly, blocking of asparagine synthase resulted in reduced invasion without affecting the growth of tumor, suggesting that asparagine is involved only in the metastasis process.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('asparagine', 'Protein', (27, 37))	('reduced', 'NegReg', (59, 66))	('asparagine', 'Chemical', 'MESH:D001216', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('invasion', 'CPA', (67, 75))	('tumor', 'Disease', (108, 113))	('blocking', 'Var', (15, 23))	('asparagine', 'Chemical', 'MESH:D001216', (27, 37))
97570	32045679	They showed reduced VEGF production in the presence of nanoparticles.	('VEGF', 'Gene', '7422', (20, 24))	('reduced', 'NegReg', (12, 19))	('VEGF', 'Gene', (20, 24))	('nanoparticles', 'Var', (55, 68))
97593	32045679	Four weeks after injection of the invasive breast cancer cells (MCF-10A, MDA-MB-231, and the bone-seeking sub-strain MDA-MB-231BO) into the hearts of the mice, the MDA-MB-231BO cells were shown to have metastasized to the humanized tissue engineered bone in all of the mice.	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('mice', 'Species', '10090', (154, 158))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (164, 174))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (117, 127))	('MDA-MB-231BO', 'CellLine', 'CVCL:0062', (164, 176))	('invasive breast cancer', 'Disease', 'MESH:D001943', (34, 56))	('MCF-10A', 'CellLine', 'CVCL:0598', (64, 71))	('mice', 'Species', '10090', (269, 273))	('metastasized', 'CPA', (202, 214))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MDA-MB-231BO', 'CellLine', 'CVCL:0062', (117, 129))	('human', 'Species', '9606', (222, 227))	('MDA-MB-231BO', 'Var', (164, 176))	('invasive breast cancer', 'Disease', (34, 56))
97623	32045679	They also showed that adenosine increased the permeability of vasculature but decreased the extravasation rate of breast cancer cells.	('extravasation rate', 'MPA', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('permeability of vasculature', 'MPA', (46, 73))	('adenosine', 'Var', (22, 31))	('adenosine', 'Chemical', 'MESH:D000241', (22, 31))	('increased', 'PosReg', (32, 41))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('decreased', 'NegReg', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
97678	31281083	Women who received pMRI were more likely to have additional CNBs than the no-pMRI cohort (100/332 [30%] vs. 3/41 [7%], p=0.002).	('CNBs', 'Disease', (60, 64))	('Women', 'Species', '9606', (0, 5))	('pMRI', 'Var', (19, 23))
97691	31281083	Among these women who underwent BCS first, there was a trend towards more successful BCS in the pMRI group than the no-pMRI group, though not statistically significant (194/217[89%] vs. 21/28[75%], p=0.058).	('women', 'Species', '9606', (12, 17))	('pMRI', 'Var', (96, 100))	('BCS', 'Gene', '617', (32, 35))	('BCS', 'Gene', '617', (85, 88))	('BCS', 'Gene', (32, 35))	('BCS', 'Gene', (85, 88))	('more', 'PosReg', (69, 73))
97725	23168266	Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('differentiation', 'CPA', (224, 239))	('cellular identity', 'CPA', (245, 262))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('carcinogenesis', 'Disease', (81, 95))	('pluripotency', 'MPA', (210, 222))	('breast cancer', 'Disease', (25, 38))	('influence', 'Reg', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('Epigenetic gene regulation', 'Var', (96, 122))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
97726	23168266	Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('epigenetic dysregulation', 'Var', (27, 51))	('cancer', 'Disease', (55, 61))
97742	23168266	Inhibition of HDACs has been shown to induce differentiation in cancer and shows promise as a potential epigenetic therapy for cancer treatment (reviewed briefly in).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('induce', 'PosReg', (38, 44))	('differentiation', 'CPA', (45, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (127, 133))	('HDACs', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
97748	23168266	DNMT1 methylates cytosines on the nascent DNA strand and has a preference for hemi-methylated CpG sites.	('cytosines', 'Chemical', 'MESH:D003596', (17, 26))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('methylates', 'Var', (6, 16))
97751	23168266	In summary, both histone modifications and DNA methylation have been implicated in a wide variety of biological processes such as differentiation, genomic stability, and carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('histone', 'Protein', (17, 24))	('DNA methylation', 'Var', (43, 58))	('differentiation', 'CPA', (130, 145))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('genomic stability', 'CPA', (147, 164))	('implicated', 'Reg', (69, 79))
97754	23168266	Epigenetic dysregulation has long been identified as contributing to the cancer phenotype.	('cancer', 'Disease', (73, 79))	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('contributing', 'Reg', (53, 65))
97755	23168266	Global hypomethylation of the genome is considered a hallmark of cancer and was one of the earliest epigenetic traits identified in cancer cells.	('cancer', 'Disease', (132, 138))	('Global hypomethylation', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
97756	23168266	Hypomethylation contributes to carcinogenesis in a variety of ways and, in mice, has been demonstrated to trigger the initiation of cancer.	('trigger', 'PosReg', (106, 113))	('mice', 'Species', '10090', (75, 79))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (31, 45))	('initiation of cancer', 'Disease', (118, 138))	('carcinogenesis', 'Disease', (31, 45))	('initiation of cancer', 'Disease', 'MESH:D009369', (118, 138))	('contributes', 'Reg', (16, 27))
97757	23168266	DNA methylation is crucial to the inactivation of transposable genetic elements, and during carcinogenesis genomic demethylation can lead to the reactivation of these elements.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('reactivation', 'MPA', (145, 157))	('carcinogenesis', 'Disease', (92, 106))	('lead to', 'Reg', (133, 140))	('demethylation', 'Var', (115, 128))
97758	23168266	Unwanted transposition results in genomic instability, which deals further damage to the cancer genome and contributes to phenotype.	('damage', 'MPA', (75, 81))	('Unwanted transposition', 'Var', (0, 22))	('genomic instability', 'MPA', (34, 53))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('results in', 'Reg', (23, 33))	('cancer', 'Disease', (89, 95))	('contributes', 'Reg', (107, 118))	('Unwanted transposition', 'Phenotype', 'HP:0011540', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
97759	23168266	Instead, hypomethylation at the pericentric regions results in miss-segregation of chromosomes during cell division and leads to aneuploidy.	('leads to', 'Reg', (120, 128))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('aneuploidy', 'Disease', (129, 139))	('miss-segregation of chromosomes', 'CPA', (63, 94))	('hypomethylation', 'Var', (9, 24))	('results in', 'Reg', (52, 62))
97760	23168266	Additionally, induced hypomethylation of the genome of ESCs can block the capacity for differentiation, implicating this process in the loss of differentiation and increased capacity for self-renewal witnessed in cancer.	('block', 'NegReg', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('capacity for differentiation', 'CPA', (74, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('ESCs', 'Gene', (55, 59))	('hypomethylation', 'Var', (22, 37))	('cancer', 'Disease', (213, 219))	('increased', 'PosReg', (164, 173))
97763	23168266	Several of these genes are also putative tumor suppressors, and aberrant promoter methylation is associated with gene repression and evasion of apoptosis or deregulation of the cell cycle.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('deregulation', 'CPA', (157, 169))	('evasion', 'CPA', (133, 140))	('gene repression', 'Protein', (113, 128))	('tumor', 'Disease', (41, 46))	('promoter', 'MPA', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('associated', 'Reg', (97, 107))	('aberrant', 'Var', (64, 72))
97764	23168266	A recent study by Helman and colleagues (2011) also demonstrated that hypermethylation of differentiation and developmental genes is crucial to lung carcinogenesis.	('lung carcinogenesis', 'Disease', (144, 163))	('hypermethylation', 'Var', (70, 86))	('differentiation', 'Gene', (90, 105))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (144, 163))
97765	23168266	Interestingly, several of these genes, such as PAX6, WT1, PROX1, HOXB13, HOXA1, and HOXA9, are also reported to be hypermethylated in breast cancer, suggesting that aberrant methylation and silencing of these gene sets may be as important to carcinogenesis as the aberrant silencing of tumor suppressors.	('WT1', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('WT1', 'Gene', '7490', (53, 56))	('hypermethylated', 'Var', (115, 130))	('breast cancer', 'Disease', (134, 147))	('carcinogenesis', 'Disease', (242, 256))	('HOXA1', 'Gene', (73, 78))	('PROX1', 'Gene', '5629', (58, 63))	('HOXB13', 'Gene', '10481', (65, 71))	('PROX1', 'Gene', (58, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))	('HOXA9', 'Gene', (84, 89))	('PAX6', 'Gene', (47, 51))	('PAX6', 'Gene', '5080', (47, 51))	('tumor', 'Disease', (286, 291))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('aberrant', 'Var', (165, 173))	('HOXA9', 'Gene', '3205', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('HOXB13', 'Gene', (65, 71))	('silencing', 'NegReg', (190, 199))	('HOXA1', 'Gene', '3198', (73, 78))
97772	23168266	The data also agree with earlier reports of significant CpG island hypermethylation of estrogen receptor-alpha (ESR1), E-cadherin, RASSF1A, CCND2, p16, 14-3-3-sigma, and SFRP1 in both DCIS and IDC.	('p16', 'Gene', (147, 150))	('14-3-3-sigma', 'Gene', '2810', (152, 164))	('CCND2', 'Gene', (140, 145))	('E-cadherin', 'Gene', (119, 129))	('SFRP1', 'Gene', '6422', (170, 175))	('estrogen receptor-alpha', 'Gene', (87, 110))	('hypermethylation', 'Var', (67, 83))	('RASSF1A', 'Gene', '11186', (131, 138))	('ESR1', 'Gene', '2099', (112, 116))	('E-cadherin', 'Gene', '999', (119, 129))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('RASSF1A', 'Gene', (131, 138))	('14-3-3-sigma', 'Gene', (152, 164))	('SFRP1', 'Gene', (170, 175))	('CCND2', 'Gene', '894', (140, 145))	('p16', 'Gene', '1029', (147, 150))	('ESR1', 'Gene', (112, 116))	('estrogen receptor-alpha', 'Gene', '2099', (87, 110))
97773	23168266	This suggests that DNA hypermethylation occurs early in breast carcinogenesis and is associated with higher grade.	('breast carcinogenesis', 'Disease', (56, 77))	('DNA', 'Var', (19, 22))	('hypermethylation', 'Var', (23, 39))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (56, 77))	('higher grade', 'Disease', (101, 113))	('associated', 'Reg', (85, 95))
97776	23168266	Many studies have associated promoter methylation (and subsequent gene silencing) in breast cancer with various clinic-pathological parameters.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('promoter methylation', 'Var', (29, 49))	('gene silencing', 'NegReg', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
97777	23168266	For example, hypermethylation at the promoters of putative tumor suppressors LATS1 and LATS2 was found to be associated with large tumor size, probability of metastasis, and negative estrogen/progesterone receptor status.	('associated', 'Reg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('LATS1', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('LATS1', 'Gene', '9113', (77, 82))	('tumor', 'Disease', (131, 136))	('LATS2', 'Gene', (87, 92))	('LATS2', 'Gene', '26524', (87, 92))	('metastasis', 'CPA', (158, 168))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
97778	23168266	Hypermethylation of the repressor of wnt signaling, SFRP1, was associated with reduced overall survival, and hypermethylation of APC, CDH1, or CTNNB1 can distinguish cancer from normal tissue but is not associated with clinical outcome.	('clinical', 'Species', '191496', (219, 227))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('reduced', 'NegReg', (79, 86))	('SFRP1', 'Gene', '6422', (52, 57))	('APC', 'Disease', (129, 132))	('CTNNB1', 'Gene', (143, 149))	('Hypermethylation', 'Var', (0, 16))	('APC', 'Disease', 'MESH:D011125', (129, 132))	('distinguish', 'Reg', (154, 165))	('SFRP1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('hypermethylation', 'Var', (109, 125))	('overall survival', 'MPA', (87, 103))	('CDH1', 'Gene', (134, 138))
97779	23168266	Table 1 provides a summary of all genes currently reported to have an association between promoter DNA hypermethylation or DNA hypomethylation (or both) and prognosis in breast cancer.	('association', 'Interaction', (70, 81))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('promoter DNA', 'Var', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
97781	23168266	However, hypomethylation of repetitive elements in the breast cancer genome has been associated with clinical outcome.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('clinical', 'Species', '191496', (101, 109))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('hypomethylation', 'Var', (9, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('associated', 'Reg', (85, 95))
97782	23168266	Hypomethylation of long interspersed element 1 (LINE1) in a breast cancer cohort (379 primary ductal breast tumors, assayed by MethyLight) was associated with decreased overall survival (hazard ratio (HR) = 2.19, P = 0.014), decreased disease-free survival (HR = 2.05, P = 0.016), and increased distant recurrence (HR = 2.83, P = 0.001) in a multivariate analysis.	('breast cancer', 'Disease', (60, 73))	('breast tumors', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('LINE1', 'Gene', (48, 53))	('overall survival', 'CPA', (169, 185))	('Hypomethylation', 'Var', (0, 15))	('increased', 'PosReg', (285, 294))	('breast tumors', 'Disease', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('decreased', 'NegReg', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('decreased', 'NegReg', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('breast tumors', 'Phenotype', 'HP:0100013', (101, 114))	('disease-free survival', 'CPA', (235, 256))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('distant recurrence', 'CPA', (295, 313))
97785	23168266	For example, H3K4me3 (trimethylated histone 3 lysine 4) is a transcriptionally permissive histone modification associated with gene promoters and can shed light on alternate promoter usage in carcinogenesis, whereas H3K27me3 is a repressive histone modification that marks large domains of the genome, including promoters, gene bodies, and inter-genic regions, and is important in development and differentiation.	('trimethylated', 'Chemical', '-', (22, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('H3K4me3', 'Var', (13, 20))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('H3K27me3', 'Var', (216, 224))	('carcinogenesis', 'Disease', (192, 206))
97790	23168266	Notably, genes displaying bivalent histone marks in ESCs are reported to have an increased propensity to become aberrantly hypermethylated in cancer, but the mechanism underpinning this is unknown.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ESCs', 'Disease', (52, 56))	('bivalent', 'Var', (26, 34))	('cancer', 'Disease', (142, 148))
97791	23168266	Therefore, it is important to consider both genetic and epigenetic aberrations in the investigation of carcinogenesis.	('carcinogenesis', 'Disease', (103, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('epigenetic aberrations', 'Var', (56, 78))
97797	23168266	Silencing of p16ink4a occurs in all vHMEC populations and is associated with hypermethylation of the p16ink4a transcription start site (TSS).	('p16ink4a', 'Gene', '1029', (101, 109))	('p16ink4a', 'Gene', (101, 109))	('p16ink4a', 'Gene', '1029', (13, 21))	('p16ink4a', 'Gene', (13, 21))	('Silencing', 'MPA', (0, 9))	('associated', 'Reg', (61, 71))	('hypermethylation', 'Var', (77, 93))
97801	23168266	Holst and colleagues (2003) propose that vHMECs do exist prior to selection as the authors identified p16ink4a silenced and methylated p16ink4a cells in normal breast tissue, whereas Hinshelwood and colleagues (2009) report that, in early vHMECs, p16ink4a methylation occurs only as the population of cells expand in culture and is a consequence of prior gene silencing.	('silenced', 'NegReg', (111, 119))	('methylation', 'Var', (256, 267))	('p16ink4a', 'Gene', (135, 143))	('p16ink4a', 'Gene', '1029', (102, 110))	('p16ink4a', 'Gene', '1029', (247, 255))	('p16ink4a', 'Gene', (102, 110))	('methylated', 'Var', (124, 134))	('p16ink4a', 'Gene', (247, 255))	('p16ink4a', 'Gene', '1029', (135, 143))
97804	23168266	High Cox-2 expression in vHMECs is also associated with an increased rate of growth and high motility, and silencing of Cox-2 has been shown to reduce this malignant phenotype.	('silencing', 'Var', (107, 116))	('reduce', 'NegReg', (144, 150))	('Cox-2', 'Gene', (5, 10))	('high motility', 'CPA', (88, 101))	('Cox-2', 'Gene', '5743', (5, 10))	('Cox-2', 'Gene', (120, 125))	('growth', 'CPA', (77, 83))	('Cox-2', 'Gene', '5743', (120, 125))	('increased', 'PosReg', (59, 68))
97805	23168266	In addition to changes in individual gene expression, the transforming growth factor beta (TGFbeta) pathway is consistently epigenetically silenced in vHMEC populations, and mutations in this pathway are commonly found in cancer.	('transforming growth factor beta', 'Gene', '7040', (58, 89))	('TGFbeta', 'Gene', (91, 98))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('silenced', 'NegReg', (139, 147))	('cancer', 'Disease', (222, 228))	('found', 'Reg', (213, 218))	('TGFbeta', 'Gene', '7040', (91, 98))	('transforming growth factor beta', 'Gene', (58, 89))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mutations', 'Var', (174, 183))
97808	23168266	Detailed analysis demonstrated that genes in the TGFbeta pathway are silenced without DNA hypermethylation and that gene silencing is associated with repressive chromatin remodelling and acquisition of H3K27me3 at gene promoters.	('H3K27me3', 'Var', (202, 210))	('gene silencing', 'NegReg', (116, 130))	('TGFbeta', 'Gene', '7040', (49, 56))	('TGFbeta', 'Gene', (49, 56))
97810	23168266	SUZ12 and EZH2 are components of the PRC2 complex responsible for the methylation of histone 3 lysines 9 and 27 (H3K9me3 and H3K27me3).	('H3K27me3', 'Var', (125, 133))	('SUZ12', 'Gene', (0, 5))	('EZH2', 'Gene', '2146', (10, 14))	('EZH2', 'Gene', (10, 14))	('lysines', 'Chemical', 'MESH:D008239', (95, 102))	('SUZ12', 'Gene', '23512', (0, 5))
97813	23168266	In vHMECs, upregulation of SUZ12 and EZH2 appears to be linked to the silencing of p16ink4a .	('SUZ12', 'Gene', '23512', (27, 32))	('silencing', 'Var', (70, 79))	('SUZ12', 'Gene', (27, 32))	('p16ink4a', 'Gene', '1029', (83, 91))	('EZH2', 'Gene', '2146', (37, 41))	('upregulation', 'PosReg', (11, 23))	('p16ink4a', 'Gene', (83, 91))	('EZH2', 'Gene', (37, 41))
97814	23168266	Moreover, silencing of p16ink4a in HMECs by short hairpin RNA (shRNA) induced increased expression of SUZ12 and EZH2.	('SUZ12', 'Gene', (102, 107))	('EZH2', 'Gene', (112, 116))	('p16ink4a', 'Gene', '1029', (23, 31))	('p16ink4a', 'Gene', (23, 31))	('increased', 'PosReg', (78, 87))	('SUZ12', 'Gene', '23512', (102, 107))	('expression', 'MPA', (88, 98))	('silencing', 'Var', (10, 19))	('EZH2', 'Gene', '2146', (112, 116))
97815	23168266	The deregulation of the PcG in vHMECs also results in the inappropriate hyper-methylation of specific gene promoters.	('inappropriate hyper', 'Disease', (58, 77))	('deregulation', 'Var', (4, 16))	('inappropriate hyper', 'Disease', 'MESH:D007177', (58, 77))	('results in', 'Reg', (43, 53))
97816	23168266	Silencing of p16ink4a or increased SUZ12 and EZH2 expression in HMECs leads to increased methylation at the HOXA9 promoter, mimicking its state in vHMECs.	('increased', 'PosReg', (79, 88))	('EZH2', 'Gene', '2146', (45, 49))	('increased', 'PosReg', (25, 34))	('p16ink4a', 'Gene', '1029', (13, 21))	('EZH2', 'Gene', (45, 49))	('HOXA9', 'Gene', '3205', (108, 113))	('SUZ12', 'Gene', '23512', (35, 40))	('SUZ12', 'Gene', (35, 40))	('p16ink4a', 'Gene', (13, 21))	('HOXA9', 'Gene', (108, 113))	('Silencing', 'Var', (0, 9))	('methylation', 'MPA', (89, 100))
97827	23168266	This increase in p53 stability has been linked to silencing of p16ink4a in two studies.	('stability', 'MPA', (21, 30))	('silencing', 'Var', (50, 59))	('p16ink4a', 'Gene', '1029', (63, 71))	('increase', 'PosReg', (5, 13))	('p53', 'Gene', (17, 20))	('p16ink4a', 'Gene', (63, 71))	('p53', 'Gene', '7157', (17, 20))
97828	23168266	Re-expression of p16ink4a in vHMECs results in reduced levels of p53 protein and p21 expression, whereas silencing of p16ink4a by shRNA in HMECs leads to p53/p21 activation.	('p16ink4a', 'Gene', (118, 126))	('p53', 'Gene', (65, 68))	('levels of', 'MPA', (55, 64))	('p53', 'Gene', '7157', (65, 68))	('p21', 'Gene', (158, 161))	('p16ink4a', 'Gene', '1029', (17, 25))	('p21', 'Gene', '1026', (81, 84))	('p21', 'Gene', (81, 84))	('p16ink4a', 'Gene', '1029', (118, 126))	('p16ink4a', 'Gene', (17, 25))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('silencing', 'Var', (105, 114))	('p21', 'Gene', '1026', (158, 161))	('activation', 'PosReg', (162, 172))	('reduced', 'NegReg', (47, 54))
97833	23168266	Silencing of p53 does not have an impact on the rate of growth of vHMECs.	('Silencing', 'Var', (0, 9))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', (13, 16))
97834	23168266	Interestingly, silencing of p53 in an agonescent population results in loss of cell viability and widespread cell death, indicating that aberrations other than silencing of p53 are important in breast carcinogenesis.	('p53', 'Gene', (28, 31))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (194, 215))	('cell viability', 'CPA', (79, 93))	('p53', 'Gene', (173, 176))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', '7157', (173, 176))	('silencing', 'Var', (15, 24))	('widespread cell death', 'CPA', (98, 119))	('loss', 'NegReg', (71, 75))	('breast carcinogenesis', 'Disease', (194, 215))
97835	23168266	OIS was identified in 1997 when overexpression of mutant Ras in normal rodent cells resulted in permanent growth arrest via p16ink4a and p53.	('p16ink4a', 'Gene', (124, 132))	('overexpression', 'PosReg', (32, 46))	('p53', 'Gene', '7157', (137, 140))	('Ras', 'Gene', (57, 60))	('growth arrest', 'Phenotype', 'HP:0001510', (106, 119))	('mutant', 'Var', (50, 56))	('p16ink4a', 'Gene', '1029', (124, 132))	('p53', 'Gene', (137, 140))	('growth arrest', 'CPA', (106, 119))
97837	23168266	However, further studies have demonstrated that oncogenic Ras can induce OIS in HMECs in a p16ink4a-independent manner.	('oncogenic Ras', 'Var', (48, 61))	('p16ink4a', 'Gene', '1029', (91, 99))	('p16ink4a', 'Gene', (91, 99))	('induce', 'Reg', (66, 72))	('OIS', 'Disease', (73, 76))
97838	23168266	This study found that, in p16ink4a/p53-negative HMECs, Ras-induced senescence was suppressed by the antagonism of TGFbeta signaling.	('p53', 'Gene', (35, 38))	('Ras-induced senescence', 'CPA', (55, 77))	('TGFbeta', 'Gene', '7040', (114, 121))	('p53', 'Gene', '7157', (35, 38))	('suppressed', 'NegReg', (82, 92))	('p16ink4a', 'Gene', '1029', (26, 34))	('antagonism', 'Var', (100, 110))	('p16ink4a', 'Gene', (26, 34))	('TGFbeta', 'Gene', (114, 121))
97843	23168266	DNA hypermethylation at the p16ink4a promoter is well documented in vHMECs but does not represent the only change across the genome.	('p16ink4a', 'Gene', (28, 36))	('p16ink4a', 'Gene', '1029', (28, 36))	('vHMECs', 'Disease', (68, 74))	('hypermethylation', 'Var', (4, 20))
97857	23168266	Additionally, the implantation of HMECs into mouse mammary fat pads humanized with fibroblasts transformed to abnormally express key growth factors resulted in the generation of structures similar to those seen in early breast malignancy.	('human', 'Species', '9606', (68, 73))	('abnormally', 'Var', (110, 120))	('structures', 'MPA', (178, 188))	('mouse', 'Species', '10090', (45, 50))	('breast malignancy', 'Disease', (220, 237))	('breast malignancy', 'Disease', 'MESH:D001943', (220, 237))
97860	23168266	This review has presented much evidence that demonstrates that epigenetic dysregulation is well established as a major contributor to cancer progression and phenotype.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (134, 140))	('epigenetic dysregulation', 'Var', (63, 87))
97861	23168266	It can be clearly seen that changes in DNA methylation contribute to a wide variety of cancer-associated phenomena such as genomic instability, silencing of tumor suppressors, and inappropriate regulation of differentiation-associated pathways.	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', (87, 93))	('genomic instability', 'CPA', (123, 142))	('regulation', 'MPA', (194, 204))	('differentiation-associated pathways', 'Pathway', (208, 243))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('silencing', 'NegReg', (144, 153))	('changes', 'Var', (28, 35))	('contribute', 'Reg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('DNA', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
97926	19922614	Of the 3,668 patients identified as potentially eligible by our cancer registries or electronic medical records, there were 520 patients who were determined by chart review to be ineligible for one or more of the following reasons: miscoded as having DCIS in the tumor registry or diagnosed with invasive breast cancer within six months of index DCIS (n = 97), synchronous cancer in the uninvolved or contralateral breast (n = 29), prior breast cancer (n = 91), prior invasive cancer at another site (n = 125), 85 years of age or older at diagnosis (n = 15) or had less than six months of follow-up (mastectomy within six months (n = 96), death within six months (n = 6), or not a member at diagnosis or left the health plan within six months (n = 92)).	('death', 'Disease', 'MESH:D003643', (639, 644))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Disease', (312, 318))	('cancer', 'Disease', (477, 483))	('synchronous cancer', 'Disease', (361, 379))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (477, 483))	('synchronous cancer', 'Disease', 'MESH:D009378', (361, 379))	('cancer', 'Disease', (445, 451))	('cancer', 'Disease', (64, 70))	('tumor', 'Disease', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('cancer', 'Disease', (373, 379))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (305, 318))	('miscoded', 'Var', (232, 240))	('invasive breast cancer', 'Disease', (296, 318))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('death', 'Disease', (639, 644))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('invasive cancer', 'Disease', (468, 483))	('cancer', 'Disease', 'MESH:D009369', (477, 483))	('patients', 'Species', '9606', (128, 136))	('invasive cancer', 'Disease', 'MESH:D009362', (468, 483))	('invasive breast cancer', 'Disease', 'MESH:D001943', (296, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (438, 451))	('mastectomy', 'Disease', (600, 610))	('breast cancer', 'Disease', 'MESH:D001943', (305, 318))	('cancer', 'Disease', 'MESH:D009369', (445, 451))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (438, 451))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('breast cancer', 'Disease', (438, 451))
97964	19922614	We also did not have information on the full patient cohort on other pathologic features that may be associated with an increased risk of recurrence, such as large tumor size, high nuclear grade, involved or narrowly free surgical margins, and comedo necrosis.	('necrosis', 'Disease', (251, 259))	('comedo', 'Phenotype', 'HP:0025249', (244, 250))	('tumor', 'Disease', (164, 169))	('necrosis', 'Disease', 'MESH:D009336', (251, 259))	('patient', 'Species', '9606', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('high', 'Var', (176, 180))
97983	19922614	Additional research is needed to confirm our findings, to examine whether the decline in risk of recurrence has continued for later diagnosis years, and to further examine the extent to which an increase in the proportion of patients with clear surgical margins or low or intermediate nuclear grade, or other factors, may also contribute to our observed decrease in risk of recurrence for DCIS patients treated with BCS.	('patients', 'Species', '9606', (225, 233))	('DCIS', 'Disease', (389, 393))	('decrease', 'NegReg', (354, 362))	('patients', 'Species', '9606', (394, 402))	('low', 'Var', (265, 268))
98001	30298311	The RS stratifies patients into three risk categories: low (RS <18), intermediate (RS 18-30), and high (RS >=31).	('RS 1', 'Gene', '6247', (83, 87))	('RS 1', 'Gene', (83, 87))	('patients', 'Species', '9606', (18, 26))	('RS <18', 'Var', (60, 66))
98004	30298311	In the TAILORx study, the risk categories are defined as: low, RS <11, intermediate, RS 11-25, and high, RS >25.	('RS >25', 'Var', (105, 111))	('RS 11', 'Gene', '8786', (85, 90))	('RS <11', 'Var', (63, 69))	('RS 11', 'Gene', (85, 90))
98006	30298311	The TAILORx trial concluded that there was no chemotherapy benefit for RS <25 in women over the age of 50 and no benefit for RS <=15 in women 50 years or younger.	('women', 'Species', '9606', (81, 86))	('chemotherapy', 'MPA', (46, 58))	('RS <25', 'Var', (71, 77))	('women', 'Species', '9606', (136, 141))
98007	30298311	The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend using RS to guide adjuvant systemic therapy in patients with ER+, HER2-, lymph node negative invasive BC that are >= 0.5 cm.	('ER+', 'Var', (155, 158))	('HER2', 'Gene', (160, 164))	('Oncology', 'Phenotype', 'HP:0002664', (75, 83))	('HER2', 'Gene', '2064', (160, 164))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('invasive BC', 'Disease', (187, 198))	('patients', 'Species', '9606', (141, 149))
98033	30298311	A second case with foci having RS 1 and RS 23 showed nuclear positivity in 80% and 5% of cells, respectively.	('nuclear positivity', 'MPA', (53, 71))	('RS 1', 'Gene', (31, 35))	('RS 23', 'Var', (40, 45))	('RS 1', 'Gene', '6247', (31, 35))
98039	30298311	The focus with RS 22 showed more tubule formation (MBR histologic grade 2) than the foci with RS 26 and 27 (MBR histologic grade 3).	('RS 22', 'Var', (15, 20))	('MBR', 'Gene', '706', (51, 54))	('MBR', 'Gene', (51, 54))	('more', 'PosReg', (28, 32))	('MBR', 'Gene', '706', (108, 111))	('MBR', 'Gene', (108, 111))	('tubule formation', 'CPA', (33, 49))
98043	30298311	Furthermore, Genomic Health showed microdissected BXC had an average 13.4 +- 2.1 higher RS compared with the microdissected invasive cancers.	('invasive cancers', 'Disease', 'MESH:D009362', (124, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('invasive cancers', 'Disease', (124, 140))	('microdissected', 'Var', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
98081	30989460	Alteration of miRNA expression is known to be closely associated with the pathogenesis of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('Alteration', 'Var', (0, 10))	('malignancies', 'Disease', (96, 108))	('human', 'Species', '9606', (90, 95))	('miRNA', 'Protein', (14, 19))	('associated', 'Reg', (54, 64))
98082	30989460	Diverse miRNAs are specifically expressed in breast cancer, and alterations of miRNA expression levels are assumed to be associated with the recurrence or evolution of DCIS to IDC.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('DCIS', 'Disease', (168, 172))	('associated', 'Reg', (121, 131))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('alterations', 'Var', (64, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('expressed', 'Reg', (32, 41))	('miRNA expression levels', 'MPA', (79, 102))
98122	30989460	Of these significantly dysregulated miRNAs detected between group B and group D, 17 miRNAs were included in both groups and showed similar alterations: seven miRNAs (miR-17-5p, -20a-5p, -103a-3p, -106a-5p, -107, -106b-5p, and -7641) were up-regulated and 10 miRNAs (miR-4281, -4534, -4689, -6124, -6127, -6165, -6776-5p, -6870-5p, -6879-5p, and -6891-5p) were down-regulated (Table 2), suggesting the possibility in the recurrence and/or progression of DCIS.	('DCIS', 'Disease', (453, 457))	('down-regulated', 'NegReg', (360, 374))	('up-regulated', 'PosReg', (238, 250))	('miR-4281', 'Var', (266, 274))	('DCIS', 'Phenotype', 'HP:0030075', (453, 457))	('miR-17-5p', 'Gene', '406952', (166, 175))	('miR-17-5p', 'Gene', (166, 175))
98136	30989460	Integrating the common findings in target prediction database and PanCancer pathway analyses, we selected TGFbetaRII as a main potential direct target of both miR-106b-5p and miR-17-5p, and hypothesized that aberrant expression of these miRNAs might down-regulate the TGF-beta pathway to play an important role in the recurrence and progression of DCIS.	('miR-17-5p', 'Gene', (175, 184))	('TGF-beta', 'Gene', (268, 276))	('TGF-beta', 'Gene', '7040', (268, 276))	('miR-106b', 'Gene', (159, 167))	('TGFbetaRII', 'Gene', '7048', (106, 116))	('DCIS', 'Disease', (348, 352))	('DCIS', 'Phenotype', 'HP:0030075', (348, 352))	('aberrant', 'Var', (208, 216))	('miR-106b', 'Gene', '406900', (159, 167))	('TGFbetaRII', 'Gene', (106, 116))	('miR-17-5p', 'Gene', '406952', (175, 184))	('down-regulate', 'NegReg', (250, 263))
98153	30989460	Prior miRNA clusters are both related to TGF-beta pathway and alteration of TGF- beta also influence miR-17-92 and miR-106b-25 clusters.	('TGF- beta', 'Gene', '7040', (76, 85))	('miR-106b', 'Gene', '406900', (115, 123))	('miR-17-92', 'Gene', '407975', (101, 110))	('influence', 'Reg', (91, 100))	('miR-17-92', 'Gene', (101, 110))	('alteration', 'Var', (62, 72))	('miR-106b', 'Gene', (115, 123))	('TGF-beta', 'Gene', '7040', (41, 49))	('TGF- beta', 'Gene', (76, 85))	('TGF-beta', 'Gene', (41, 49))
98160	30989460	Other than miR-106-5p and miR-17-5p, miRNAs such as miR-375, miR-592, and miR-135a also influence breast cancer proliferation by modulating ESR1, ERBB4 pathway, and miR-135a function as prognostic marker in ER-positive breast cancer.	('miR-106', 'Gene', '406899', (11, 18))	('influence', 'Reg', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ESR1', 'Gene', '2099', (140, 144))	('miR-135a', 'Var', (74, 82))	('modulating', 'Reg', (129, 139))	('ESR1', 'Gene', (140, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('miR-17-5p', 'Gene', '406952', (26, 35))	('miR-17-5p', 'Gene', (26, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('ERBB4', 'Gene', '2066', (146, 151))	('breast cancer', 'Disease', (219, 232))	('miR-592', 'Gene', '693177', (61, 68))	('ERBB4', 'Gene', (146, 151))	('miR-106', 'Gene', (11, 18))	('miR-375', 'Gene', '494324', (52, 59))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('miR-375', 'Gene', (52, 59))	('breast cancer', 'Disease', (98, 111))	('miR-592', 'Gene', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
98196	27490807	Nonetheless, after initial screening, which accounts for 12% of all screens, FFDM resulted in higher recall rate and lower PPV that requires attention.	('PPV', 'MPA', (123, 126))	('lower', 'NegReg', (117, 122))	('FFDM', 'Var', (77, 81))	('FFDM', 'Chemical', '-', (77, 81))	('recall rate', 'MPA', (101, 112))	('higher', 'PosReg', (94, 100))
98198	27490807	Studies have shown that FFDM does not result in differences in cancer detection rate or higher overall breast cancer detection compared with SFM in the clinical as well as in a population-based setting.	('FFDM', 'Var', (24, 28))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('FFDM', 'Chemical', '-', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (63, 69))
98200	27490807	Furthermore, FFDM results in a higher recall rate, in combination with higher detection rates and decreased positive predictive values (PPV) of recall.	('higher', 'PosReg', (71, 77))	('detection rates', 'MPA', (78, 93))	('recall', 'MPA', (38, 44))	('positive predictive values', 'MPA', (108, 134))	('FFDM', 'Var', (13, 17))	('FFDM', 'Chemical', '-', (13, 17))	('higher', 'PosReg', (31, 37))	('decreased', 'NegReg', (98, 107))
98237	27490807	Tumour stage was defined according to the greatest dimension of the largest tumour size (T1a: <=0.5 cm, T1b: >0.5 cm and <=1 cm, T1c: >1 cm and <=2 cm, T2+: >2 cm).	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('T1b', 'Var', (104, 107))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))
98263	27490807	No differences were found in the tumour characteristics of interval cancers diagnosed after FFDM compared with SFM after initial or after subsequent examinations (Table 4).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('interval cancers', 'Disease', (59, 75))	('tumour', 'Disease', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('FFDM', 'Var', (92, 96))	('FFDM', 'Chemical', '-', (92, 96))	('interval cancers', 'Disease', 'MESH:D009369', (59, 75))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
98360	27198513	recently reported SEER data showing that women with DCIS had a 3.3% 20-year breast cancer-specific mortality (including those who developed contralateral breast cancer), with women <35y having a higher risk of breast cancer-specific mortality than older women (HR=2.58, p<0.001).	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('DCIS', 'Var', (52, 56))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', (210, 223))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (140, 167))	('women', 'Species', '9606', (254, 259))	('women', 'Species', '9606', (175, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('women', 'Species', '9606', (41, 46))	('contralateral breast cancer', 'Disease', (140, 167))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
98404	32155777	Triple-negative and HER2-positive DCIS lesions are the subgroups of breast carcinomas that show the greatest degree of enrichment of the stroma by lymphocytes (tumor infiltrating lymphocytes, TILs).	('breast carcinomas', 'Disease', (68, 85))	('HER2', 'Gene', '2064', (20, 24))	('Triple-negative', 'Var', (0, 15))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('DCIS lesion', 'Disease', 'MESH:D002285', (34, 45))	('TIL', 'Gene', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('breast carcinomas', 'Phenotype', 'HP:0003002', (68, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('breast carcinoma', 'Phenotype', 'HP:0003002', (68, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('HER2', 'Gene', (20, 24))	('DCIS lesion', 'Disease', (34, 45))	('tumor', 'Disease', (160, 165))	('TIL', 'Gene', '7096', (192, 195))	('breast carcinomas', 'Disease', 'MESH:D001943', (68, 85))
98410	32155777	show a multifocal DCIS lesion is also associated with an increased risk of recurrence for invasive ductal carcinoma.	('DCIS lesion', 'Disease', (18, 29))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (99, 115))	('invasive ductal carcinoma', 'Disease', (90, 115))	('multifocal', 'Var', (7, 17))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (90, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('DCIS lesion', 'Disease', 'MESH:D002285', (18, 29))
98412	32155777	The following factors were found to be associated with ipsilateral recurrence within 5 years: (i) age <=50 years; (ii) comedonecrosis; and (iii) ER-negative status.	('ER-negative status', 'Var', (145, 163))	('ipsilateral recurrence', 'Disease', (55, 77))	('necrosis', 'Disease', (125, 133))	('necrosis', 'Disease', 'MESH:D009336', (125, 133))
98427	32155777	Notably the MD Anderson experience, corroborated by the Memorial Sloan Kettering Cancer Center, reported that the difference in Local recurrence rate (LRR) for patients with margins <2 mm vs. >=2 mm (10-year LRR 30.9% vs. 5.4%, respectively; p = 0.003) was abrogated in patients receiving radiotherapy (10-year LRR 4.8% vs. 3.3%, respectively; p = 0.72).	('patients', 'Species', '9606', (160, 168))	('Cancer', 'Disease', (81, 87))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (270, 278))	('margins <2 mm', 'Var', (174, 187))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('Local recurrence', 'MPA', (128, 144))
98441	32155777	The largest studies on the natural history of DCIS suggest that more than 50% of patients with high-grade DCIS have the potential to progress to an invasive carcinoma in less than 5 years if left untreated, while low-grade DCIS has a similar progression but in a small percentage of patients (35-50%) and in a more prolongated time course, up to 40 years.	('invasive carcinoma', 'Disease', 'MESH:D009361', (148, 166))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('progress', 'PosReg', (133, 141))	('patients', 'Species', '9606', (283, 291))	('patients', 'Species', '9606', (81, 89))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('invasive carcinoma', 'Disease', (148, 166))	('high-grade', 'Var', (95, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))
98445	32155777	As far as surgery is concerned, mastectomy, with immediate or subsequent breast reconstruction, is strongly recommended for those patients with large-sized tumors, multifocal tumors, small-sized breasts (cosmetic problems), family history, or documented BRCA mutations.	('BRCA', 'Gene', '672', (254, 258))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('BRCA', 'Gene', (254, 258))	('mutations', 'Var', (259, 268))	('multifocal tumors', 'Disease', 'None', (164, 181))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('small-sized breasts', 'Phenotype', 'HP:0003187', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', (156, 162))	('multifocal tumors', 'Disease', (164, 181))
98502	29095832	Specifically, patients selected for IORT in Taiwan tended to be younger (16.5% <45 y/o in T-IORTSCG, 7% 48-49 y/o in ELIOT, and 2% < 45 y/o in TARGIT-A, P<0.01), their tumors tended to be larger (T2 tumor 21.4% in T-IORTSCG compared to 13% in ELIOT, and 14% in TARGIT-A, P<0.01), the prevalence of lymph node metastasis tended to be lower (92.7% node negative in T-IORTSCG compared to 74% in ELIOT, and 82% in TARGIT-A, P<0.01).	('tumor', 'Disease', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('TARGIT-A', 'Chemical', '-', (143, 151))	('tumor', 'Disease', (168, 173))	('lower', 'NegReg', (333, 338))	('T-IORTSCG', 'Var', (363, 372))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('lymph node metastasis', 'CPA', (298, 319))	('TARGIT-A', 'Chemical', '-', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('to 7', 'Species', '1214577', (382, 386))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patients', 'Species', '9606', (14, 22))	('TARGIT-A', 'Chemical', '-', (410, 418))
98554	25028506	There were significant increases in plasma SHBG, Factor VIII and von Willebrand factor and a significant decrease in plasma IGF-1 with oral-T, but not with 4-OHT.	('IGF-1', 'Gene', (124, 129))	('4-OHT', 'Chemical', 'MESH:C032278', (156, 161))	('von Willebrand factor', 'Gene', '7450', (65, 86))	('SHBG', 'Gene', '6462', (43, 47))	('von Willebrand factor', 'Gene', (65, 86))	('SHBG', 'Gene', (43, 47))	('oral-T', 'Var', (135, 141))	('increases', 'PosReg', (23, 32))	('Factor VIII', 'MPA', (49, 60))	('decrease', 'NegReg', (105, 113))	('IGF-1', 'Gene', '3479', (124, 129))	('oral-T', 'Chemical', '-', (135, 141))
98600	25028506	Therefore, if the mean relative decrease in the 4-OHT group was at least 30%, this would be considered equivalent to a relative decrease of up to 50% in the tamoxifen group.	('tamoxifen', 'Chemical', 'MESH:D013629', (157, 166))	('4-OHT', 'Chemical', 'MESH:C032278', (48, 53))	('decrease', 'NegReg', (32, 40))	('4-OHT', 'Var', (48, 53))
98641	25028506	Our primary endpoint was Ki-67 LI, which is the best validated and most widely accepted endpoint for window-of-opportunity studies of systemic agents for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('Ki-67', 'Var', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))
98643	25028506	The drop in Ki67-LI was larger than anticipated in both groups: 61% rather than 50% in the oral group, and 52% rather than 30% in the 4-OHT group, consistent with the projected 'effect size'.	('Ki67', 'Chemical', '-', (12, 16))	('drop', 'NegReg', (4, 8))	('4-OHT', 'Chemical', 'MESH:C032278', (134, 139))	('Ki67-LI', 'Var', (12, 19))
98649	25028506	In contrast, the mean plasma level of 4-OHT was more than five-fold lower in the 4-OHT gel group than in the tamoxifen group using two independent methods in different laboratories.	('lower', 'NegReg', (68, 73))	('tamoxifen', 'Chemical', 'MESH:D013629', (109, 118))	('4-OHT gel', 'Var', (81, 90))	('4-OHT', 'Chemical', 'MESH:C032278', (81, 86))	('4-OHT', 'Chemical', 'MESH:C032278', (38, 43))	('plasma level of 4-OHT', 'MPA', (22, 43))
98658	25028506	Recently, endoxifen has attracted attention based on its greater abundance relative to 4-OHT in women on oral-T, and a report that endoxifen causes proteosomic degradation of ERalpha and may have more selective anti-estrogenic effects.	('endoxifen', 'Chemical', 'MESH:C055492', (131, 140))	('ERalpha', 'Gene', (175, 182))	('oral-T', 'Chemical', '-', (105, 111))	('endoxifen', 'Chemical', 'MESH:C055492', (10, 19))	('ERalpha', 'Gene', '2099', (175, 182))	('proteosomic degradation', 'MPA', (148, 171))	('women', 'Species', '9606', (96, 101))	('anti-estrogenic', 'MPA', (211, 226))	('4-OHT', 'Chemical', 'MESH:C032278', (87, 92))	('endoxifen', 'Var', (131, 140))
98670	25028506	Finally, population variation in the efficiency of tamoxifen metabolism, related to polymorphisms in the CYP2D6 and other genes may adversely affect efficacy of orally administered tamoxifen.	('efficacy', 'MPA', (149, 157))	('CYP2D6', 'Gene', (105, 111))	('affect', 'Reg', (142, 148))	('tamoxifen', 'Chemical', 'MESH:D013629', (181, 190))	('CYP2D6', 'Gene', '1565', (105, 111))	('tamoxifen', 'Chemical', 'MESH:D013629', (51, 60))	('polymorphisms', 'Var', (84, 97))
98715	20577822	In addition to limiting radiation exposure, APBI also shortens the duration of therapy from 6 weeks typically required for whole-breast radiation to approximately 6 days.	('shortens', 'NegReg', (54, 62))	('duration', 'MPA', (67, 75))	('APBI', 'Chemical', '-', (44, 48))	('APBI', 'Var', (44, 48))
98791	20577822	Additionally, a recent study comparing toxicity of APBI with MammoSite to whole-breast radiation found patients treated with APBI to have a higher performance status, less acute skin toxicity, and decreased fatigue.	('toxicity', 'Disease', (39, 47))	('skin toxicity', 'Disease', 'MESH:D012871', (178, 191))	('APBI', 'Chemical', '-', (51, 55))	('APBI', 'Var', (125, 129))	('higher', 'PosReg', (140, 146))	('MammoSite', 'Chemical', '-', (61, 70))	('performance status', 'MPA', (147, 165))	('APBI', 'Chemical', '-', (125, 129))	('toxicity', 'Disease', 'MESH:D064420', (183, 191))	('decreased fatigue', 'Disease', 'MESH:D005221', (197, 214))	('toxicity', 'Disease', (183, 191))	('fatigue', 'Phenotype', 'HP:0012378', (207, 214))	('patients', 'Species', '9606', (103, 111))	('skin toxicity', 'Disease', (178, 191))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('decreased fatigue', 'Disease', (197, 214))
98905	28464874	In patients with DCIS, 50% show abnormalities on MG, US, and MRI.	('abnormalities', 'Var', (32, 45))	('DCIS', 'Disease', (17, 21))	('patients', 'Species', '9606', (3, 11))	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))
98931	28464874	However, with hyperplastic change in the ductal epithelium, an intraductal lesion may progress to malignancy.	('hyperplastic change', 'Var', (14, 33))	('intraductal lesion', 'Disease', (63, 81))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('progress', 'PosReg', (86, 94))	('malignancy', 'Disease', (98, 108))
98966	25344051	Co-transplantation studies and transgenic mouse studies have demonstrated that CAFs enhance breast tumor growth and invasion.	('transgenic', 'Species', '10090', (31, 41))	('mouse', 'Species', '10090', (42, 47))	('breast tumor', 'Phenotype', 'HP:0100013', (92, 104))	('CAFs', 'Var', (79, 83))	('invasion', 'CPA', (116, 124))	('CAFs', 'Chemical', '-', (79, 83))	('breast tumor', 'Disease', 'MESH:D001943', (92, 104))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('breast tumor', 'Disease', (92, 104))	('enhance', 'PosReg', (84, 91))
99027	25344051	Endogenous peroxidases were quenched in PBS containing 3% H202 and 10% methanol for 30 minutes.	('H202', 'Chemical', '-', (58, 62))	('H202', 'Var', (58, 62))	('quenched', 'NegReg', (28, 36))	('methanol', 'Chemical', 'MESH:D000432', (71, 79))	('PBS', 'Gene', (40, 43))	('PBS', 'Gene', '1131', (40, 43))	('Endogenous peroxidases', 'Enzyme', (0, 22))
99048	25344051	Sections were then washed in PBS and incubated with the following secondary antibodies at a 1:500 dilution in blocking buffer for 1 hour: anti-goat-alexa-488 to detect CXCL1 expression, anti-mouse-alexa-568 to detect alpha-SMA, or anti-rabbit-alexa-488 to detect FSP1 expression.	('FSP1', 'Gene', (263, 267))	('CXCL1 expression', 'MPA', (168, 184))	('anti-goat-alexa-488', 'Var', (138, 157))	('alexa-568', 'Chemical', 'MESH:C000607448', (197, 206))	('goat', 'Species', '9925', (143, 147))	('SMA', 'Gene', '6606', (223, 226))	('SMA', 'Gene', (223, 226))	('expression', 'MPA', (268, 278))	('rabbit', 'Species', '9986', (236, 242))	('alexa-488', 'Chemical', '-', (243, 252))	('alexa-488', 'Chemical', '-', (148, 157))	('PBS', 'Gene', (29, 32))	('mouse', 'Species', '10090', (191, 196))	('PBS', 'Gene', '1131', (29, 32))	('anti-mouse-alexa-568', 'Var', (186, 206))	('FSP1', 'Gene', '6275', (263, 267))
99134	25344051	In previous studies, we had generated a conditional knockout mouse model (FspKO), in which exon 2 of the Tgfbr2 gene was deleted by cre, placed under the control of the Fsp1 promoter.	('Fsp1', 'Gene', (169, 173))	('rat', 'Species', '10116', (32, 35))	('Tgfbr2', 'Gene', (105, 111))	('deleted', 'Var', (121, 128))	('Fsp1', 'Gene', '73991', (169, 173))	('mouse', 'Species', '10090', (61, 66))
99170	25344051	As the binding receptors CXCR1 and CXCR2 are expressed on myeloid derived cells and carcinoma cells, CXCL1 expression in CAFs may serve to regulate paracrine signaling interactions with immune cells and cancer cells to promote chemo-resistance and tumor progression.	('CXCR1', 'Gene', (25, 30))	('carcinoma', 'Disease', 'MESH:D002277', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('CXCR1', 'Gene', '3577', (25, 30))	('tumor', 'Disease', (248, 253))	('CAFs', 'Chemical', '-', (121, 125))	('CXCR2', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('chemo-resistance', 'CPA', (227, 243))	('regulate', 'Reg', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('interactions', 'Interaction', (168, 180))	('CXCR2', 'Gene', '3579', (35, 40))	('promote', 'PosReg', (219, 226))	('cancer', 'Disease', (203, 209))	('paracrine signaling', 'MPA', (148, 167))	('carcinoma', 'Disease', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('CXCL1 expression', 'Var', (101, 117))
99182	25344051	Cre mediated deletion of exon 2 of TGF-beta type II receptor gene (Tgfbr2) in mammary fibroblasts (FspKO) inhibited TGF-beta mediated suppression of fibroblast proliferation.	('TGF-beta', 'Gene', (35, 43))	('Tgfbr2', 'Gene', (67, 73))	('inhibited', 'NegReg', (106, 115))	('deletion', 'Var', (13, 21))	('TGF-beta', 'Gene', '7040', (116, 124))	('TGF-beta', 'Gene', (116, 124))	('rat', 'Species', '10116', (167, 170))	('TGF-beta', 'Gene', '7040', (35, 43))
99183	25344051	Co-transplantation of FspKO fibroblasts with 4 T1 and PyVmT mammary carcinoma cells in the subrenal capsule of nude mice enhanced tumor progression.	('carcinoma', 'Disease', (68, 77))	('nude mice', 'Species', '10090', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('enhanced', 'PosReg', (121, 129))	('carcinoma', 'Disease', 'MESH:D002277', (68, 77))	('PyVmT', 'Var', (54, 59))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (60, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
99190	25344051	It is also possible that epigenetic mechanisms, such as methylation of TGFB and SMAD promoters would silence gene expression and down-regulate TGF-beta signaling in breast cancer stroma.	('down-regulate', 'NegReg', (129, 142))	('gene expression', 'MPA', (109, 124))	('breast cancer stroma', 'Disease', 'MESH:D001943', (165, 185))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TGF-beta', 'Gene', '7040', (143, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('TGFB', 'Gene', '7040', (71, 75))	('SMA', 'Gene', '6606', (80, 83))	('SMA', 'Gene', (80, 83))	('breast cancer stroma', 'Disease', (165, 185))	('methylation', 'Var', (56, 67))	('silence', 'NegReg', (101, 108))	('TGF-beta', 'Gene', (143, 151))	('TGFB', 'Gene', (71, 75))
99316	26356673	Persistent DDR induces a permanent proliferation arrest known as replicative senescence, which is thought to function as a tumor suppressor.	('tumor', 'Disease', (123, 128))	('DDR', 'Chemical', '-', (11, 14))	('proliferation arrest', 'CPA', (35, 55))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('DDR', 'Var', (11, 14))
99317	26356673	However, dysregulation of the DDR pathway allows cells to proliferate beyond senescence limits.	('DDR', 'Chemical', '-', (30, 33))	('DDR pathway', 'Pathway', (30, 41))	('dysregulation', 'Var', (9, 22))
99324	26356673	Moreover, our group has recently demonstrated that telomere fusions are indeed present in early-stage breast tumors including DCIS.	('breast tumors', 'Phenotype', 'HP:0100013', (102, 115))	('DCIS', 'Disease', (126, 130))	('present', 'Reg', (79, 86))	('breast tumors', 'Disease', 'MESH:D001943', (102, 115))	('breast tumor', 'Phenotype', 'HP:0100013', (102, 114))	('telomere fusions', 'Var', (51, 67))	('breast tumors', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
99327	26356673	The tumor-derived circulating cfDNA in plasma constitutes a potential source of genetic material for the identification of tumor-associated alterations, such as microsatellite instability, loss of heterozygosity (LOH), gene mutations, copy-number alternations (CNAs) and methylation.	('gene mutations', 'Var', (219, 233))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (123, 128))	('loss of heterozygosity', 'Var', (189, 211))	('methylation', 'Var', (271, 282))	('copy-number alternations', 'Var', (235, 259))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('microsatellite instability', 'MPA', (161, 187))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
99329	26356673	Most of the current cfDNA assays require information on specific genetic or epigenetic alterations present in the original tumor lesion, therefore are limited to monitoring cancer progression.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('original tumor lesion', 'Disease', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('original tumor lesion', 'Disease', 'MESH:D014012', (114, 135))	('epigenetic alterations', 'Var', (76, 98))
99333	26356673	While mammography remains the most commonly used method for the screening and early detection of breast cancer, this procedure is often limited by a high medical cost, high false-positive rate necessitating additional testing and leading to patient anxiety, as well as false-negative results which may lead to delay of diagnosis especially for younger women who has dense breast tissues.	('women', 'Species', '9606', (352, 357))	('false-negative', 'Var', (269, 283))	('anxiety', 'Disease', 'MESH:D001008', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('patient', 'Species', '9606', (241, 248))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('anxiety', 'Disease', (249, 256))	('breast cancer', 'Disease', (97, 110))	('anxiety', 'Phenotype', 'HP:0000739', (249, 256))
99403	26356673	By using qPCR, digital PCR, or sequencing technologies, recent studies reported that PIK3CA and/or TP53 mutations status could be obtained from cfDNA in advanced breast cancer patients before, during and after targeted therapy.	('TP53', 'Gene', (99, 103))	('patients', 'Species', '9606', (176, 184))	('mutations', 'Var', (104, 113))	('PIK3CA', 'Gene', '5290', (85, 91))	('R', 'Chemical', '-', (25, 26))	('obtained', 'Reg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('TP53', 'Gene', '7157', (99, 103))	('breast cancer', 'Disease', (162, 175))	('R', 'Chemical', '-', (12, 13))	('PIK3CA', 'Gene', (85, 91))
99409	26356673	Further, these findings may suggest that tumor cells with shortened telomeres might be prone to cell death and preferentially provide cfDNA.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('preferentially', 'PosReg', (111, 125))	('tumor', 'Disease', (41, 46))	('cfDNA', 'CPA', (134, 139))	('shortened telomeres', 'Var', (58, 77))	('cell death', 'CPA', (96, 106))	('shortened telomeres', 'Phenotype', 'HP:0031413', (58, 77))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('prone', 'Reg', (87, 92))
99424	26356673	For instance, several case-control studies showed that short leukocyte telomere length was associated with increased risk of breast cancer, while others indicated contradictory or insignificant associations.	('short leukocyte', 'Var', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
99450	26356673	The other primer sequences were used for the pan-centromere signal, cen96F, 5'-TTC ATC TCA CAG AGT TGA ACC TTT CCT TTG-3', and cen96R, 5'-GGC CTC AAA GTG TAC CAA ATA TCC ACT TG-3' (final concentrations 400 nM each).	('cen96F', 'Var', (68, 74))	('R', 'Chemical', '-', (132, 133))	('cen96R', 'Var', (127, 133))
99451	26356673	For the reference sequence (R), line121F, 5'-GGA TTA AGA AAA TGT GGC ACA TAT ACA CCA TGG- 3' and line121R, 5'-GAT AGT TTA CTG AGA ATG ATG GTT TCC AAT TTC AT-3' (final concentrations 250 nM each).	('line121R', 'Var', (97, 105))	('R', 'Chemical', '-', (104, 105))	('R', 'Chemical', '-', (28, 29))	('line121F', 'Var', (32, 40))
99453	26356673	Therefore, the relative quantitation is based on T/R or C/R copy ratios of each copy number from the standard curves.	('C/R', 'MPA', (56, 59))	('R', 'Chemical', '-', (58, 59))	('R', 'Chemical', '-', (51, 52))	('T/R', 'Var', (49, 52))
99458	26356673	The telomere amount (T) or centromere amount (C) were presented as T/R or C/R copy ratios where T/R = (telomere copy number) / (Line copy number), and C/R = (centromere copy number) / (Line copy number).	('R', 'Chemical', '-', (98, 99))	('T/R', 'Var', (96, 99))	('C/R', 'Var', (151, 154))	('R', 'Chemical', '-', (76, 77))	('R', 'Chemical', '-', (69, 70))	('R', 'Chemical', '-', (153, 154))
99468	26356673	Receiver operating characteristic curves (ROCs) were used to evaluate the diagnostic performance of T/R and C/R copy ratios.	('R', 'Chemical', '-', (0, 1))	('T/R', 'Var', (100, 103))	('C/R copy ratios', 'Var', (108, 123))	('R', 'Chemical', '-', (42, 43))	('R', 'Chemical', '-', (110, 111))	('R', 'Chemical', '-', (102, 103))
99574	33664822	High SQLE expression was observed in DCIS with higher nuclear grade, comedo-type necrosis and HER2 positivity.	('positivity', 'Var', (99, 109))	('SQLE', 'Gene', '6713', (5, 9))	('comedo', 'Phenotype', 'HP:0025249', (69, 75))	('HER2', 'Gene', '2064', (94, 98))	('SQLE', 'Gene', (5, 9))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('DCIS', 'Disease', (37, 41))	('necrosis', 'Disease', (81, 89))	('HER2', 'Gene', (94, 98))
99576	33664822	High SQLE expression was associated with poor disease-free and overall survival, and independently predicted poor disease-free survival in patients with BC.	('SQLE', 'Gene', '6713', (5, 9))	('SQLE', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('poor', 'NegReg', (109, 113))	('patients', 'Species', '9606', (139, 147))	('poor', 'NegReg', (41, 45))	('disease-free', 'CPA', (46, 58))
99585	33664822	Moreover, several studies have revealed that inhibition of cholesterol synthesis at different steps results in human cancer cell death in both in vitro and in vivo models.	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('human', 'Species', '9606', (111, 116))	('cholesterol', 'Chemical', 'MESH:D002784', (59, 70))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('inhibition', 'Var', (45, 55))	('cancer', 'Disease', (117, 123))	('cholesterol synthesis', 'MPA', (59, 80))
99586	33664822	Overall, dysregulation of cholesterol metabolism may be a promising new therapeutic target for cancer treatment.	('cholesterol', 'Chemical', 'MESH:D002784', (26, 37))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cholesterol metabolism', 'MPA', (26, 48))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('dysregulation', 'Var', (9, 22))	('dysregulation of cholesterol metabolism', 'Phenotype', 'HP:0003107', (9, 48))
99588	33664822	Previous studies have revealed that dysregulation of SQLE expression is involved in the molecular pathogenesis of various types of cancer, such as prostate cancer, hepatocellular carcinoma, pancreatic cancer, esophageal squamous cell carcinoma and squamous lung cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('cancer', 'Disease', (201, 207))	('esophageal squamous cell carcinoma and squamous lung cancer', 'Disease', 'MESH:D000077277', (209, 268))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('prostate cancer', 'Disease', (147, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (257, 268))	('pancreatic cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('dysregulation', 'Var', (36, 49))	('SQLE', 'Gene', '6713', (53, 57))	('SQLE', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (248, 268))	('involved', 'Reg', (72, 80))	('cancer', 'Disease', (262, 268))	('hepatocellular carcinoma', 'Disease', (164, 188))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
99595	33664822	Furthermore, high SQLE expression has been associated with increased risk of BC recurrence.	('high', 'Var', (13, 17))	('BC recurrence', 'Disease', (77, 90))	('SQLE', 'Gene', '6713', (18, 22))	('SQLE', 'Gene', (18, 22))
99597	33664822	MYC gene amplification and aberrant SQLE methylation have also been observed in aggressive BC.	('MYC', 'Gene', (0, 3))	('aberrant', 'Var', (27, 35))	('SQLE', 'Gene', (36, 40))	('aggressive BC', 'Disease', (80, 93))	('observed', 'Reg', (68, 76))	('MYC', 'Gene', '4609', (0, 3))	('amplification', 'PosReg', (9, 22))	('SQLE', 'Gene', '6713', (36, 40))
99598	33664822	Brown et al have confirmed that SQLE is a true oncogene by clinically relevant amplification in BC.	('amplification', 'Var', (79, 92))	('SQLE', 'Gene', (32, 36))	('SQLE', 'Gene', '6713', (32, 36))
99610	33664822	The following probes (Thermo Fisher Scientific, Inc.) were used: Hs01123768_m1 (SQLE) and Hs02758991_g1 (GAPDH).	('Hs01123768_m1', 'Var', (65, 78))	('Hs02758991_g1', 'Var', (90, 103))	('GAPDH', 'Gene', '2597', (105, 110))	('SQLE', 'Gene', '6713', (80, 84))	('GAPDH', 'Gene', (105, 110))	('SQLE', 'Gene', (80, 84))
99648	33664822	Patients with high SQLE expression exhibited a poor prognosis for disease-free survival and overall survival compared with those with low expression (P=0.001 and P=0.001, respectively; Fig.	('SQLE', 'Gene', '6713', (19, 23))	('SQLE', 'Gene', (19, 23))	('disease-free survival', 'CPA', (66, 87))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
99650	33664822	Following BreastMark analysis, high SQLE mRNA expression in patients with BC was significantly associated with poor prognosis in all groups [hazard ratio (HR), 1.467; P=1.57x10-10; n=2,652), lymph node negative group (HR, 1.781; P=8.53x10-8; n=1,183), lymph node positive group (HR, 1.337; P=0.011; n=744), luminal A subtype (HR, 1.427; P=0.007; n=823) and luminal B subtype (HR, 1.284; P=0.007; n=1,013) (Fig.	('luminal', 'Chemical', 'MESH:D010634', (357, 364))	('BreastMark', 'Gene', (10, 20))	('SQLE', 'Gene', (36, 40))	('patients', 'Species', '9606', (60, 68))	('luminal', 'Chemical', 'MESH:D010634', (307, 314))	('BreastMark', 'Gene', '4139', (10, 20))	('high', 'Var', (31, 35))	('SQLE', 'Gene', '6713', (36, 40))
99657	33664822	Moreover, previous studies have indicated that inhibition at different stages of cholesterol synthesis contributes to inhibition of tumor cell proliferation, cell death and resistance to therapies in cancer.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibition', 'Var', (47, 57))	('inhibition', 'NegReg', (118, 128))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('death', 'Disease', (163, 168))	('death', 'Disease', 'MESH:D003643', (163, 168))	('cancer', 'Disease', (200, 206))	('resistance to therapies', 'CPA', (173, 196))
99658	33664822	Overall, dysregulation of cholesterol metabolism may be a new therapeutic target in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cholesterol', 'Chemical', 'MESH:D002784', (26, 37))	('cholesterol metabolism', 'MPA', (26, 48))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('dysregulation', 'Var', (9, 22))	('dysregulation of cholesterol metabolism', 'Phenotype', 'HP:0003107', (9, 48))
99661	33664822	Previous studies have indicated that dysregulation of SQLE is involved in the molecular pathogenesis of various types of cancer and has also been associated with poor prognosis.	('dysregulation', 'Var', (37, 50))	('SQLE', 'Gene', '6713', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SQLE', 'Gene', (54, 58))	('involved', 'Reg', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('associated', 'Reg', (146, 156))	('cancer', 'Disease', (121, 127))
99663	33664822	Several studies have already been conducted to explore the potential role of the dysregulation of SQLE in BC.	('dysregulation', 'Var', (81, 94))	('SQLE', 'Gene', '6713', (98, 102))	('SQLE', 'Gene', (98, 102))
99681	33664822	Although the underlying mechanism of SQLE dysregulation in BC remains unclear, SQLE is frequently altered by copy number gains in BC, and SQLE expression appears to be tightly regulated by increases in the copy dosage of its gene locus.	('gains', 'PosReg', (121, 126))	('SQLE', 'Gene', '6713', (37, 41))	('increases', 'PosReg', (189, 198))	('copy number', 'Var', (109, 120))	('SQLE', 'Gene', (37, 41))	('SQLE', 'Gene', '6713', (79, 83))	('SQLE', 'Gene', (79, 83))	('SQLE', 'Gene', '6713', (138, 142))	('altered', 'Reg', (98, 105))	('SQLE', 'Gene', (138, 142))
99682	33664822	SQLE methylation has also been associated with SQLE overexpression in BC.	('methylation', 'Var', (5, 16))	('SQLE', 'Gene', '6713', (47, 51))	('SQLE', 'Gene', (47, 51))	('SQLE', 'Gene', '6713', (0, 4))	('associated', 'Reg', (31, 41))	('SQLE', 'Gene', (0, 4))
99683	33664822	Recently, it has been suggested that the dysregulation of SQLE may be associated with the prognosis in patients with BC.	('dysregulation', 'Var', (41, 54))	('associated', 'Reg', (70, 80))	('SQLE', 'Gene', '6713', (58, 62))	('patients', 'Species', '9606', (103, 111))	('SQLE', 'Gene', (58, 62))
99692	33664822	Compared with white women, black women exhibited higher expression levels of SQLE, and high SQLE expression was associated with increased risk of BC recurrence.	('SQLE', 'Gene', '6713', (92, 96))	('SQLE', 'Gene', '6713', (77, 81))	('SQLE', 'Gene', (92, 96))	('women', 'Species', '9606', (33, 38))	('BC recurrence', 'Disease', (146, 159))	('SQLE', 'Gene', (77, 81))	('expression levels', 'MPA', (56, 73))	('women', 'Species', '9606', (20, 25))	('high', 'Var', (87, 91))	('higher', 'PosReg', (49, 55))	('expression', 'MPA', (97, 107))
99693	33664822	Chin et al performed a high-resolution comparative genomic hybridization analysis in BC, revealing that 8q24 locus, where the SQLE gene resides, is one of the hotspot genomic regions exhibiting the strongest association between copy number gain and aberrant gene expression in high-grade, ER- BC.	('ER', 'Gene', '2069', (289, 291))	('gain', 'PosReg', (240, 244))	('SQLE', 'Gene', '6713', (126, 130))	('SQLE', 'Gene', (126, 130))	('copy number', 'Var', (228, 239))	('aberrant', 'Var', (249, 257))
99694	33664822	Brown et al independently confirmed that SQLE is a bona fide oncogene by amplification with clinical relevance in BC.	('SQLE', 'Gene', (41, 45))	('SQLE', 'Gene', '6713', (41, 45))	('amplification', 'Var', (73, 86))
99695	33664822	SQLE overexpression was more prevalent in high-grade, HER2+ and hormone receptor-negative invasive BC, and was an independently significant unfavorable prognostic biomarker in BC.	('high-grade', 'Var', (42, 52))	('prevalent', 'Reg', (29, 38))	('HER2', 'Gene', (54, 58))	('invasive BC', 'Disease', (90, 101))	('SQLE', 'Gene', '6713', (0, 4))	('HER2', 'Gene', '2064', (54, 58))	('SQLE', 'Gene', (0, 4))	('hormone receptor', 'Gene', (64, 80))	('hormone receptor', 'Gene', '3164', (64, 80))
99700	33664822	High SQLE expression was associated with poor disease-free survival and overall survival, and independently predicted unfavorable disease-free survival in patients with BC.	('SQLE', 'Gene', '6713', (5, 9))	('SQLE', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('poor', 'NegReg', (41, 45))	('patients', 'Species', '9606', (155, 163))	('disease-free survival', 'CPA', (46, 67))
99702	33664822	High SQLE mRNA expression was significantly associated with a poor prognosis in the 'all', lymph node negative, lymph node positive, luminal A subtype and luminal B subtype groups.	('SQLE', 'Gene', '6713', (5, 9))	('SQLE', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('luminal', 'Chemical', 'MESH:D010634', (155, 162))	("'all'", 'Disease', (84, 89))	('luminal', 'Chemical', 'MESH:D010634', (133, 140))
99703	33664822	The present results support the findings of previous studies and suggest that high SQLE expression assessed by immunohistochemistry may be associated with a more aggressive phenotype in BC and may be used as a prognostic marker in patients with BC.	('associated with', 'Reg', (139, 154))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (231, 239))	('SQLE', 'Gene', '6713', (83, 87))	('SQLE', 'Gene', (83, 87))
99707	33664822	Several studies have demonstrated that SQLE promotes cancer cell proliferation and migration, and the presence of SQLE inhibitors in both in vitro and in vivo models causes cancer cell death.	('SQLE', 'Gene', '6713', (39, 43))	('promotes', 'PosReg', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('SQLE', 'Gene', '6713', (114, 118))	('cancer', 'Disease', (53, 59))	('SQLE', 'Gene', (39, 43))	('cancer', 'Disease', (173, 179))	('SQLE', 'Gene', (114, 118))	('death', 'Disease', 'MESH:D003643', (185, 190))	('death', 'Disease', (185, 190))	('inhibitors', 'Var', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('presence', 'Var', (102, 110))	('causes', 'Reg', (166, 172))	('migration', 'CPA', (83, 92))
99816	24393444	The aim of this study was to analyze the 3D characteristics of microcalcifications detected by mammography using micro-CT. Micro-CT is a high-resolution imaging modality that complements the use of mammography.	('calcification', 'Disease', (68, 81))	('Micro-CT', 'Var', (123, 131))	('calcification', 'Disease', 'MESH:D002114', (68, 81))
99842	24393444	The survival of women with masses or linear/linear-branching calcifications (i.e., casting calcifications) is considerably worse than the survival of women with other types of lesions, suggesting that the calcifications are associated with duct-forming invasive cancer.	('worse', 'NegReg', (123, 128))	('invasive cancer', 'Disease', (253, 268))	('linear/linear-branching', 'Var', (37, 60))	('calcification', 'Disease', 'MESH:D002114', (205, 218))	('women', 'Species', '9606', (16, 21))	('invasive cancer', 'Disease', 'MESH:D009362', (253, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('calcification', 'Disease', 'MESH:D002114', (61, 74))	('women', 'Species', '9606', (150, 155))	('associated', 'Reg', (224, 234))	('calcification', 'Disease', 'MESH:D002114', (91, 104))	('calcification', 'Disease', (205, 218))	('calcification', 'Disease', (91, 104))	('calcification', 'Disease', (61, 74))
99849	24393444	The microcalcification morphologic descriptors include coarse heterogeneous, amorphous, fine pleomorphic, and fine linear; these descriptors have a progressively increasing risk of malignancy.	('malignancy', 'Disease', (181, 191))	('coarse heterogeneous', 'MPA', (55, 75))	('fine linear', 'Var', (110, 121))	('calcification', 'Disease', 'MESH:D002114', (9, 22))	('fine pleomorphic', 'Var', (88, 104))	('amorphous', 'Disease', (77, 86))	('calcification', 'Disease', (9, 22))	('malignancy', 'Disease', 'MESH:D009369', (181, 191))
99946	28440283	Furthermore, the contrast of nuclear staining in DCIS cases on p63 immunohistochemistry images was higher than in Normal cases, while their homogeneity (InverseDifferenceMoment feature) was lower.	('higher', 'PosReg', (99, 105))	('p63', 'Gene', (63, 66))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('DCIS', 'Var', (49, 53))	('p63', 'Gene', '8626', (63, 66))
99967	28440283	In turn, loss of SLIT2 reactivates the developmental program of branching, leading to invasive cancer.	('reactivates', 'Reg', (23, 34))	('SLIT2', 'Gene', (17, 22))	('SLIT2', 'Gene', '9353', (17, 22))	('leading to', 'Reg', (75, 85))	('developmental program of branching', 'CPA', (39, 73))	('loss', 'Var', (9, 13))	('invasive cancer', 'Disease', (86, 101))	('invasive cancer', 'Disease', 'MESH:D009362', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
99968	28440283	Further disruption of SLIT2 and ROBO1 has been shown to induce SDF1 and CXCR4 shifting the tumor microenvironment in an increased inflammatory state and further promoting invasion.	('disruption', 'Var', (8, 18))	('CXCR4', 'Gene', (72, 77))	('ROBO1', 'Gene', (32, 37))	('ROBO1', 'Gene', '6091', (32, 37))	('invasion', 'CPA', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('SDF1', 'Gene', '6387', (63, 67))	('induce', 'PosReg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CXCR4', 'Gene', '7852', (72, 77))	('SLIT2', 'Gene', (22, 27))	('SDF1', 'Gene', (63, 67))	('increased', 'PosReg', (120, 129))	('tumor', 'Disease', (91, 96))	('increased inflammatory state', 'Phenotype', 'HP:0012649', (120, 148))	('promoting', 'PosReg', (161, 170))	('SLIT2', 'Gene', '9353', (22, 27))
99969	28440283	Thus, the spatial disruption of myoepithelial and epithelial cells observed here leads in the case of SHH deregulation towards myoepithelial cell deficiency and tumor cell dissemination, and, in the case of SLIT2 deregulation, to a worsening of the local milieu, both having consequences for patient survival (Fig.	('tumor', 'Disease', (161, 166))	('myoepithelial cell deficiency', 'Disease', (127, 156))	('myoepithelial cell deficiency', 'Disease', 'MESH:D009208', (127, 156))	('SHH', 'Gene', '6469', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patient', 'Species', '9606', (292, 299))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('SLIT2', 'Gene', '9353', (207, 212))	('worsening', 'Reg', (232, 241))	('SHH', 'Gene', (102, 105))	('SLIT2', 'Gene', (207, 212))	('deregulation', 'Var', (106, 118))
100005	26462242	The risk appears to be higher with inherited BRCA2 rather than BRCA1 gene mutations.	('BRCA2', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA1', 'Gene', (63, 68))	('mutations', 'Var', (74, 83))	('higher', 'Reg', (23, 29))	('BRCA1', 'Gene', '672', (63, 68))
100051	26462242	In spite of its low selectivity, MRI high sensitivity enables breast cancer early diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('MRI', 'Var', (33, 36))
100071	26462242	MBI depends mainly on Tc-99m sestamibi, which is approved for breast cancer imaging.	('Tc-99m', 'Var', (22, 28))	('sestamibi', 'Chemical', '-', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Tc-99', 'Chemical', '-', (22, 27))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))
100092	26462242	Epigenetic analysis of abnormal DNA methylation has been promising in the detection of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('DNA', 'Gene', (32, 35))	('abnormal', 'Var', (23, 31))
100093	26462242	Hypermethylation of a gene is associated with the loss of expression and can inactivate tumor suppressor genes or other cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('expression', 'MPA', (58, 68))	('Hypermethylation', 'Var', (0, 16))	('inactivate', 'NegReg', (77, 87))	('loss', 'NegReg', (50, 54))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
100094	26462242	Recently, Heyn et al in a cohort study proved that hypermethylation of DOK7 (Docking Protein 7) occurs years before tumor diagnosis and thus acts as a powerful epigenetic blood-based biomarker as well as provides insights into breast cancer pathogenesis.	('hypermethylation', 'Var', (51, 67))	('insights', 'Reg', (213, 221))	('Docking Protein 7', 'Gene', '285489', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('DOK7', 'Gene', '285489', (71, 75))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('breast cancer', 'Disease', (227, 240))	('DOK7', 'Gene', (71, 75))	('tumor', 'Disease', (116, 121))	('Docking Protein 7', 'Gene', (77, 94))
100150	26462242	Inhibitors to mTOR have demonstrated antitumor activity in a variety of cancer types, including hormone receptor positive.	('mTOR', 'Gene', '2475', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Inhibitors', 'Var', (0, 10))	('hormone receptor positive', 'Disease', (96, 121))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mTOR', 'Gene', (14, 18))	('cancer', 'Disease', (72, 78))
100198	26462242	RNA interference (RNAi) of GS components showed that only Nct RNAi caused inhibition of cell proliferation and consequent cell death in breast cancer cell lines, with minimal effect on normal breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cell death', 'CPA', (122, 132))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('inhibition', 'NegReg', (74, 84))	('cell proliferation', 'CPA', (88, 106))	('Nct', 'Var', (58, 61))	('GS', 'Disease', 'MESH:D011125', (27, 29))
100205	26462242	The patent describes human genes A7322 and F3374 (SEQ ID no: 79) whose expression is markedly elevated in breast cancer.	('expression', 'MPA', (71, 81))	('breast cancer', 'Disease', (106, 119))	('elevated', 'PosReg', (94, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('human', 'Species', '9606', (21, 26))	('F3374', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('A7322', 'Var', (33, 38))
100237	26462242	NP formulation prepared with 15% PEGylated PLGA showed maximum cellular uptake due to its smallest particle size and lowest zeta potential.	('cellular uptake', 'CPA', (63, 78))	('maximum', 'PosReg', (55, 62))	('PEG', 'Chemical', 'MESH:D011092', (33, 36))	('lowest', 'NegReg', (117, 123))	('PEGylated', 'Var', (33, 42))	('zeta potential', 'MPA', (124, 138))
100313	26462242	Aravind et al described an AS1411 aptamer tagged PLGA-lecithin-PEG NPs for tumor cell targeting and drug delivery of paclitaxel.	('AS1411', 'Chemical', 'MESH:C513936', (27, 33))	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('drug delivery', 'MPA', (100, 113))	('AS1411', 'Var', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('aptamer', 'Protein', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lecithin', 'Chemical', 'MESH:D054709', (54, 62))	('PEG', 'Chemical', 'MESH:D011092', (63, 66))	('tumor', 'Disease', (75, 80))
100329	26462242	PEGylation has been shown to alter the pharmacokinetics of doxorubicin considerably; the total clearance (CL) was significantly reduced.	('reduced', 'NegReg', (128, 135))	('total clearance', 'MPA', (89, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('PEG', 'Chemical', 'MESH:D011092', (0, 3))	('pharmacokinetics', 'MPA', (39, 55))	('PEGylation', 'Var', (0, 10))	('alter', 'Reg', (29, 34))
100430	22655184	The more utilized method to detect expression of p53 is IHC, which is a surrogate assay for detecting mutations, because a gene with missense mutations codifies for inactivate protein.	('p53', 'Gene', '7157', (49, 52))	('missense mutations', 'Var', (133, 151))	('p53', 'Gene', (49, 52))
100447	22655184	Generally, IPLs with synchronous invasive cancer share more frequent genetic alterations with IDC than pure forms.	('genetic alterations', 'Var', (69, 88))	('synchronous invasive cancer', 'Disease', 'MESH:D009378', (21, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('IDC', 'Disease', (94, 97))	('synchronous invasive cancer', 'Disease', (21, 48))
100469	22655184	Also, growth characteristics and rates of expression of sex hormones, oncogenes, and tumor suppressor genes suggest that LG-DCIS is a precursor of LG-IDC and HG-DCIS is a precursor of HG-IDC.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor suppressor', 'Gene', (85, 101))	('LG-DCIS', 'Var', (121, 128))	('tumor suppressor', 'Gene', '7248', (85, 101))
100484	24634376	PI3K pathway activation in high-grade ductal carcinoma in situ:implications for progression to invasive breast carcinoma To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (221, 245))	('breast carcinoma', 'Disease', 'MESH:D001943', (104, 120))	('ductal carcinoma', 'Disease', (221, 237))	('phosphoinositide 3-kinase', 'Gene', (149, 174))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (38, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('ductal carcinoma', 'Disease', (38, 54))	('ductal carcinoma', 'Disease', 'MESH:D044584', (221, 237))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('breast carcinoma', 'Phenotype', 'HP:0003002', (104, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('ductal carcinoma', 'Disease', 'MESH:D044584', (38, 54))	('associated with', 'Reg', (262, 277))	('breast carcinoma', 'Disease', (104, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('invasive breast cancer', 'Disease', (278, 300))	('alterations', 'Var', (190, 201))	('phosphoinositide 3-kinase', 'Gene', '5290', (149, 174))	('invasive breast cancer', 'Disease', 'MESH:D001943', (278, 300))
100485	24634376	89 cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.	('HER2', 'Gene', '2064', (145, 149))	('AKT', 'Gene', '207', (328, 331))	('estrogen receptor', 'Gene', (118, 135))	('PTEN', 'Gene', (203, 207))	('mutations', 'Var', (341, 350))	('INPP4B', 'Gene', (209, 215))	('IBC', 'Disease', (82, 85))	('AKT', 'Gene', (235, 238))	('pS6', 'Gene', (243, 246))	('AKT1', 'Gene', '207', (328, 332))	('PIK3CA', 'Gene', '5290', (317, 323))	('HER2', 'Gene', (145, 149))	('PTEN', 'Gene', '5728', (203, 207))	('AKT', 'Gene', (328, 331))	('estrogen receptor', 'Gene', '2099', (118, 135))	('pS6', 'Gene', '338413', (243, 246))	('AKT1', 'Gene', (328, 332))	('AKT', 'Gene', '207', (235, 238))	('ER', 'Gene', '2099', (146, 148))	('PIK3CA', 'Gene', (317, 323))	('ER', 'Gene', '2099', (137, 139))	('INPP4B', 'Gene', '8821', (209, 215))
100486	24634376	A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (p-values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases, INPP4B loss of expression was more frequently observed in pure DCIS (p-value 0.013).	('AKT', 'Gene', '207', (111, 114))	('PIK3CA', 'Gene', (81, 87))	('INPP4B', 'Gene', (298, 304))	('pure DCIS', 'Disease', (356, 365))	('PIK3CA', 'Gene', '5290', (81, 87))	('ER', 'Gene', '2099', (176, 178))	('HER2', 'Gene', (277, 281))	('ER', 'Gene', '2099', (265, 267))	('HER2', 'Gene', '2064', (175, 179))	('ER', 'Gene', '2099', (163, 165))	('ER', 'Gene', '2099', (278, 280))	('HER2', 'Gene', '2064', (277, 281))	('prevalent', 'Reg', (150, 159))	('HER2', 'Gene', (175, 179))	('AKT', 'Gene', (111, 114))	('loss of expression', 'NegReg', (305, 323))	('mutations', 'Var', (96, 105))	('INPP4B', 'Gene', '8821', (298, 304))
100488	24634376	Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions).	('HER2', 'Gene', (166, 170))	('Molecular aberrations', 'Var', (0, 21))	('HER2', 'Gene', '2064', (166, 170))	('role', 'Reg', (60, 64))	('play', 'Reg', (53, 57))	('PI3K pathway', 'Pathway', (36, 48))	('ER', 'Gene', '2099', (167, 169))	('high-grade DCIS', 'Disease', (89, 104))	('IBC', 'Disease', (108, 111))	('ER', 'Gene', '2099', (154, 156))
100491	24634376	Although DCIS has been shown to constitute a non-obligate precursor of invasive breast cancer (IBC), with up to 40% of these lesions progressing to invasive disease if untreated, identifying which cases will either recur as in situ disease or progress to invasive breast cancer has proven challenging.	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('invasive breast cancer', 'Disease', (255, 277))	('invasive breast cancer', 'Disease', 'MESH:D001943', (71, 93))	('situ disease', 'Disease', (227, 239))	('invasive breast cancer', 'Disease', 'MESH:D001943', (255, 277))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('invasive disease', 'Disease', (148, 164))	('progressing', 'Reg', (133, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('invasive breast cancer', 'Disease', (71, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('situ disease', 'Disease', 'MESH:D002278', (227, 239))	('lesions', 'Var', (125, 132))	('invasive disease', 'Disease', 'MESH:D009362', (148, 164))
100494	24634376	In those that have focused on synchronous DCIS and IBC, amplification of MYC and FGFR1 has been reported to be more frequent in the invasive component.	('FGFR1', 'Gene', (81, 86))	('MYC', 'Gene', (73, 76))	('amplification', 'Var', (56, 69))	('frequent', 'Reg', (116, 124))	('FGFR1', 'Gene', '2260', (81, 86))	('MYC', 'Gene', '4609', (73, 76))
100499	24634376	Despite the molecular differences between ER-positive and ER-negative disease, some molecular pathways seem to be frequently targeted by genetic aberrations in both ER-positive and ER-negative breast cancers.	('ER', 'Gene', '2099', (58, 60))	('ER', 'Gene', '2099', (181, 183))	('ER', 'Gene', '2099', (42, 44))	('ER', 'Gene', '2099', (165, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('molecular pathways', 'Pathway', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('targeted', 'Reg', (125, 133))	('breast cancers', 'Phenotype', 'HP:0003002', (193, 207))	('breast cancers', 'Disease', 'MESH:D001943', (193, 207))	('breast cancers', 'Disease', (193, 207))	('genetic aberrations', 'Var', (137, 156))
100501	24634376	Activating mutations in PIK3CA, encoding the PI3K catalytic subunit p110alpha, and loss of function of the negative regulator of PI3K signaling, PTEN, have been reported in up to 35% and 13% of IBCs, respectively, and vary according to the subtype of the disease as defined by molecular subtyping, and ER and HER2 status.	('IBCs', 'Disease', (194, 198))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('ER', 'Gene', '2099', (302, 304))	('PIK3CA', 'Gene', (24, 30))	('PTEN', 'Gene', (145, 149))	('p110alpha', 'Gene', '5290', (68, 77))	('ER', 'Gene', '2099', (310, 312))	('PTEN', 'Gene', '5728', (145, 149))	('loss of function', 'NegReg', (83, 99))	('PIK3CA', 'Gene', '5290', (24, 30))	('p110alpha', 'Gene', (68, 77))	('HER2', 'Gene', (309, 313))	('HER2', 'Gene', '2064', (309, 313))
100504	24634376	PIK3CA mutations have been reported in approximately 30% of DCIS, and qualitative comparisons between DCIS and IBC have demonstrated that if a PIK3CA mutation is present in the DCIS, it would also be present in the invasive component in the vast majority of cases; however, discordances have also been recorded.	('mutation', 'Var', (150, 158))	('PIK3CA', 'Gene', (143, 149))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', '5290', (143, 149))
100505	24634376	In a pilot study using semi-quantitative methods to infer the percentage of cancer cells harboring specific mutations, we have recently documented the presence of PIK3CA mutations in the modal population of samples of DCIS, which were either present in a non-modal subset of the neoplastic cells of the invasive component or entirely absent in the invasive lesion, providing another line of evidence to support the contention that progression from DCIS to invasive breast cancers may result in the selection of genetically distinct clones.	('breast cancer', 'Phenotype', 'HP:0003002', (465, 478))	('invasive breast cancers', 'Disease', (456, 479))	('cancer', 'Disease', 'MESH:D009369', (472, 478))	('cancers', 'Phenotype', 'HP:0002664', (472, 479))	('cancer', 'Disease', (472, 478))	('mutations', 'Var', (170, 179))	('invasive breast cancers', 'Disease', 'MESH:D001943', (456, 479))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PIK3CA', 'Gene', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (472, 478))	('breast cancers', 'Phenotype', 'HP:0003002', (465, 479))	('DCIS', 'Disease', (448, 452))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('PIK3CA', 'Gene', '5290', (163, 169))
100508	24634376	Given the pivotal roles played by the PI3K pathway in both ER-positive and ER-negative breast cancers, here we sought to define the prevalence of PI3K pathway alterations in a matched cohort of high-grade DCIS that did or did not progress to IBC, and to define the differences in the frequency of molecular alterations of this pathway in samples of synchronous DCIS and IBC.	('IBC', 'Disease', (242, 245))	('ER', 'Gene', '2099', (59, 61))	('PI3K pathway', 'Pathway', (146, 158))	('alterations', 'Var', (159, 170))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('breast cancers', 'Disease', 'MESH:D001943', (87, 101))	('breast cancers', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ER', 'Gene', '2099', (75, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))
100528	24634376	DNA samples extracted from microdissected pure DCIS and from each component of the cases with adjacent DCIS and IBC were subjected to Sequenom  MassARRAY  (Sequenom, San Diego, CA, USA) analysis to detect PIK3CA hotspot (H1047R, E542K, E545K or N345K) and AKT1 (E17K) mutations, as previously described.	('PIK3CA', 'Gene', (205, 211))	('H1047R', 'Var', (221, 227))	('PIK3CA', 'Gene', '5290', (205, 211))	('E545K', 'Var', (236, 241))	('H1047R', 'SUBSTITUTION', 'None', (221, 227))	('E542K', 'Var', (229, 234))	('N345K', 'Var', (245, 250))	('N345K', 'Mutation', 'rs121913284', (245, 250))	('E542K', 'Mutation', 'rs121913273', (229, 234))	('AKT1', 'Gene', '207', (256, 260))	('E545K', 'Mutation', 'rs104886003', (236, 241))	('E17K', 'Mutation', 'rs121434592', (262, 266))	('AKT1', 'Gene', (256, 260))
100533	24634376	We posited that different subtypes of DCIS would differ in the prevalence of PTEN and INPP4B loss of expression, PIK3CA and AKT1 hotspot mutations, and pAKT and pS6 expression.	('pS6', 'Gene', (161, 164))	('loss of expression', 'NegReg', (93, 111))	('PIK3CA', 'Gene', (113, 119))	('AKT', 'Gene', '207', (153, 156))	('AKT', 'Gene', (124, 127))	('INPP4B', 'Gene', '8821', (86, 92))	('AKT1', 'Gene', '207', (124, 128))	('PIK3CA', 'Gene', '5290', (113, 119))	('pS6', 'Gene', '338413', (161, 164))	('AKT1', 'Gene', (124, 128))	('INPP4B', 'Gene', (86, 92))	('PTEN', 'Gene', (77, 81))	('AKT', 'Gene', (153, 156))	('mutations', 'Var', (137, 146))	('PTEN', 'Gene', '5728', (77, 81))	('AKT', 'Gene', '207', (124, 127))
100534	24634376	In pure DCIS, significant differences in both the prevalence of PIK3CA hotspot mutations and loss of INPP4B expression were observed according to the subtypes, with 0%, 0%, 5% and 28% of ER-positive/HER2-negative, ER-positive/HER2-positive, ER-negative/HER2-positive, and ER-negative/HER2-negative lesions harboring PIK3CA mutations, respectively (4x2 Fisher's exact test, p-value=0.0220; Table 1), and 5%, 0%, 30% and 34% of ER-positive/HER2-negative, ER-positive/HER2-positive, ER-negative/HER2-positive, and ER-negative/HER2-negative lesions, showing loss of INPP4B expression, respectively (4x2 Fisher's exact test, p-value=0.027; Table 1).	('HER2', 'Gene', (465, 469))	('INPP4B', 'Gene', (562, 568))	('loss', 'NegReg', (554, 558))	('HER2', 'Gene', (226, 230))	('HER2', 'Gene', '2064', (438, 442))	('ER', 'Gene', '2099', (214, 216))	('INPP4B', 'Gene', (101, 107))	('ER', 'Gene', '2099', (524, 526))	('HER2', 'Gene', '2064', (199, 203))	('mutations', 'Var', (79, 88))	('HER2', 'Gene', '2064', (492, 496))	('HER2', 'Gene', '2064', (523, 527))	('ER', 'Gene', '2099', (254, 256))	('ER', 'Gene', '2099', (285, 287))	('HER2', 'Gene', '2064', (284, 288))	('PIK3CA', 'Gene', '5290', (64, 70))	('HER2', 'Gene', '2064', (253, 257))	('PIK3CA', 'Gene', '5290', (316, 322))	('ER', 'Gene', '2099', (466, 468))	('ER', 'Gene', '2099', (426, 428))	('mutations', 'Var', (323, 332))	('ER', 'Gene', '2099', (227, 229))	('HER2', 'Gene', (438, 442))	('HER2', 'Gene', '2064', (465, 469))	('ER', 'Gene', '2099', (187, 189))	('HER2', 'Gene', '2064', (226, 230))	('HER2', 'Gene', (199, 203))	('ER', 'Gene', '2099', (480, 482))	('ER', 'Gene', '2099', (439, 441))	('HER2', 'Gene', (492, 496))	('HER2', 'Gene', (523, 527))	('PIK3CA', 'Gene', (64, 70))	('INPP4B', 'Gene', '8821', (562, 568))	('ER', 'Gene', '2099', (241, 243))	('expression', 'MPA', (569, 579))	('HER2', 'Gene', (284, 288))	('ER', 'Gene', '2099', (272, 274))	('HER2', 'Gene', (253, 257))	('ER', 'Gene', '2099', (200, 202))	('ER', 'Gene', '2099', (493, 495))	('PIK3CA', 'Gene', (316, 322))	('INPP4B', 'Gene', '8821', (101, 107))	('expression', 'MPA', (108, 118))	('ER', 'Gene', '2099', (511, 513))	('ER', 'Gene', '2099', (453, 455))
100536	24634376	Of note, the only PIK3CA mutation observed in pure DCIS was the oncogenic H1047R kinase domain mutation (Supplementary Table S3).	('H1047R', 'SUBSTITUTION', 'None', (74, 80))	('H1047R', 'Var', (74, 80))	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))
100537	24634376	No significant differences in the prevalence of PTEN loss of expression, AKT1 mutations or pS6 expression were observed.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('AKT1', 'Gene', '207', (73, 77))	('loss of expression', 'NegReg', (53, 71))	('AKT1', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('pS6', 'Gene', (91, 94))	('pS6', 'Gene', '338413', (91, 94))
100539	24634376	No other significant differences in the prevalence of pAKT and pS6 expression, and PIK3CA or AKT1 mutations were observed.	('AKT', 'Gene', (55, 58))	('pS6', 'Gene', (63, 66))	('AKT', 'Gene', (93, 96))	('AKT1', 'Gene', '207', (93, 97))	('mutations', 'Var', (98, 107))	('pS6', 'Gene', '338413', (63, 66))	('PIK3CA', 'Gene', (83, 89))	('AKT1', 'Gene', (93, 97))	('PIK3CA', 'Gene', '5290', (83, 89))	('AKT', 'Gene', '207', (55, 58))	('AKT', 'Gene', '207', (93, 96))
100540	24634376	In fact, AKT1 mutations, albeit previously reported in a subset of DCIS (4%) and adjacent IBC, were shown to be remarkably rare in our study (0.5% of all lesions analyzed), suggesting that mutations affecting this gene may not constitute an important driver of high-grade DCIS.	('AKT1', 'Gene', '207', (9, 13))	('DCIS', 'Disease', (67, 71))	('AKT1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
100541	24634376	Consistent with previous studies, which have demonstrated that PIK3CA mutations and PTEN loss are generally mutually exclusive in IBCs, here we demonstrate that alterations affecting these genes were largely mutually exclusive in all subtypes of both pure DCIS and DCIS adjacent to IBC.	('mutations', 'Var', (70, 79))	('IBCs', 'Disease', (130, 134))	('alterations', 'Var', (161, 172))	('DCIS', 'Disease', (265, 269))	('pure DCIS', 'Disease', (251, 260))	('PTEN', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (84, 88))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('loss', 'NegReg', (89, 93))
100542	24634376	In fact, PTEN loss of expression and PIK3CA mutations were concurrently found only in one pure DCIS of ER-negative/HER2-negative phenotype, and in two DCIS adjacent to IBC, one ER-positive/HER2-negative, and another ER-negative/HER2-negative (Figures 1 and 2).	('ER', 'Gene', '2099', (103, 105))	('ER', 'Gene', '2099', (216, 218))	('HER2', 'Gene', (228, 232))	('ER', 'Gene', '2099', (190, 192))	('HER2', 'Gene', (115, 119))	('ER', 'Gene', '2099', (229, 231))	('ER', 'Gene', '2099', (116, 118))	('HER2', 'Gene', '2064', (189, 193))	('PIK3CA', 'Gene', '5290', (37, 43))	('PTEN', 'Gene', (9, 13))	('HER2', 'Gene', '2064', (228, 232))	('expression', 'MPA', (22, 32))	('HER2', 'Gene', '2064', (115, 119))	('PTEN', 'Gene', '5728', (9, 13))	('ER', 'Gene', '2099', (177, 179))	('mutations', 'Var', (44, 53))	('HER2', 'Gene', (189, 193))	('PIK3CA', 'Gene', (37, 43))	('loss', 'NegReg', (14, 18))
100543	24634376	We also observed that INPP4B loss of expression was preferentially found in cases lacking PTEN loss of expression and/or PIK3CA hotspot mutations.	('PTEN', 'Gene', (90, 94))	('PTEN', 'Gene', '5728', (90, 94))	('PIK3CA', 'Gene', (121, 127))	('loss of', 'NegReg', (29, 36))	('loss of expression', 'NegReg', (95, 113))	('mutations', 'Var', (136, 145))	('PIK3CA', 'Gene', '5290', (121, 127))	('INPP4B', 'Gene', '8821', (22, 28))	('expression', 'MPA', (37, 47))	('INPP4B', 'Gene', (22, 28))
100545	24634376	Comparative analysis of the cases of pure DCIS and DCIS adjacent to IBC matched according to nuclear grade and subtype revealed remarkable similarities in the prevalence of PTEN and INPP4B loss of expression, presence of PIK3CA hotspot mutations, AKT1 mutations, and pAKT and pS6 expression (Table 1).	('loss of expression', 'NegReg', (189, 207))	('PIK3CA', 'Gene', '5290', (221, 227))	('AKT', 'Gene', '207', (268, 271))	('AKT1', 'Gene', (247, 251))	('INPP4B', 'Gene', '8821', (182, 188))	('INPP4B', 'Gene', (182, 188))	('PTEN', 'Gene', (173, 177))	('AKT', 'Gene', (268, 271))	('pS6', 'Gene', (276, 279))	('PTEN', 'Gene', '5728', (173, 177))	('mutations', 'Var', (252, 261))	('AKT', 'Gene', '207', (247, 250))	('mutations', 'Var', (236, 245))	('PIK3CA', 'Gene', (221, 227))	('AKT1', 'Gene', '207', (247, 251))	('pS6', 'Gene', '338413', (276, 279))	('AKT', 'Gene', (247, 250))
100546	24634376	In fact, significant differences were only observed in the group of ER-positive/HER2-negative lesions, where significantly higher frequencies of PIK3CA hotspot mutations and pAKT expression were found in DCIS adjacent to IBC than in pure DCIS (Fisher's exact test p-values: 0.005 and 0.043, respectively; Table 1), and in ER-negative/HER2-positive lesions, where a significantly higher prevalence of INPP4B loss of expression was found in pure DCIS than in DCIS adjacent to IBC (30% vs. 4%, respectively; Fisher's exact test p-value=0.013; Table 1).	('expression', 'MPA', (415, 425))	('mutations', 'Var', (160, 169))	('INPP4B', 'Gene', '8821', (400, 406))	('hotspot', 'PosReg', (152, 159))	('HER2', 'Gene', '2064', (80, 84))	('AKT', 'Gene', '207', (175, 178))	('PIK3CA', 'Gene', (145, 151))	('HER2', 'Gene', (334, 338))	('INPP4B', 'Gene', (400, 406))	('higher', 'PosReg', (123, 129))	('AKT', 'Gene', (175, 178))	('ER', 'Gene', '2099', (322, 324))	('ER', 'Gene', '2099', (68, 70))	('HER2', 'Gene', (80, 84))	('loss of', 'NegReg', (407, 414))	('PIK3CA', 'Gene', '5290', (145, 151))	('ER', 'Gene', '2099', (81, 83))	('ER', 'Gene', '2099', (335, 337))	('HER2', 'Gene', '2064', (334, 338))
100549	24634376	Although PIK3CA mutations and pAKT expression were more frequently found in DCIS adjacent to IBC than in pure ER-positive/HER2-negative DCIS, in ER-negative/HER2-positive lesions, a significantly higher frequency of loss of INPP4B expression was found in pure DCIS than in DCIS adjacent to IBC.	('AKT', 'Gene', (31, 34))	('DCIS', 'Disease', (76, 80))	('found', 'Reg', (67, 72))	('ER', 'Gene', '2099', (158, 160))	('INPP4B', 'Gene', '8821', (224, 230))	('ER', 'Gene', '2099', (110, 112))	('mutations', 'Var', (16, 25))	('HER2', 'Gene', (122, 126))	('loss', 'NegReg', (216, 220))	('HER2', 'Gene', '2064', (157, 161))	('PIK3CA', 'Gene', (9, 15))	('AKT', 'Gene', '207', (31, 34))	('expression', 'MPA', (231, 241))	('INPP4B', 'Gene', (224, 230))	('ER', 'Gene', '2099', (123, 125))	('ER', 'Gene', '2099', (145, 147))	('HER2', 'Gene', (157, 161))	('IBC', 'Disease', (93, 96))	('HER2', 'Gene', '2064', (122, 126))	('PIK3CA', 'Gene', '5290', (9, 15))
100550	24634376	Taken together, our findings suggest that alterations in the PI3K pathway may play a role in the progression from in situ to invasive disease in a subset of ER-positive/HER2-negative DCIS.	('HER2', 'Gene', (169, 173))	('alterations', 'Var', (42, 53))	('HER2', 'Gene', '2064', (169, 173))	('DCIS', 'Disease', (183, 187))	('invasive disease', 'Disease', (125, 141))	('play', 'Reg', (78, 82))	('PI3K pathway', 'Pathway', (61, 73))	('ER', 'Gene', '2099', (170, 172))	('invasive disease', 'Disease', 'MESH:D009362', (125, 141))	('ER', 'Gene', '2099', (157, 159))
100551	24634376	We sought to determine whether PTEN and INPP4B loss of expression, PIK3CA and AKT1 hotspot mutations, and pAKT and pS6 expression would differ between the in situ and invasive components of cases of synchronous DCIS and IBC.	('AKT1', 'Gene', (78, 82))	('INPP4B', 'Gene', (40, 46))	('PTEN', 'Gene', (31, 35))	('PIK3CA', 'Gene', '5290', (67, 73))	('PTEN', 'Gene', '5728', (31, 35))	('AKT', 'Gene', (107, 110))	('IBC', 'Disease', (220, 223))	('AKT', 'Gene', '207', (78, 81))	('pS6', 'Gene', '338413', (115, 118))	('pS6', 'Gene', (115, 118))	('mutations', 'Var', (91, 100))	('loss of expression', 'NegReg', (47, 65))	('AKT1', 'Gene', '207', (78, 82))	('synchronous', 'Disease', (199, 210))	('AKT', 'Gene', (78, 81))	('INPP4B', 'Gene', '8821', (40, 46))	('PIK3CA', 'Gene', (67, 73))	('AKT', 'Gene', '207', (107, 110))
100552	24634376	Although differences in PTEN loss of expression, presence of PIK3CA mutations, and pAKT and pS6 expression were observed between matched DCIS and IBC, these changes were not unidirectional (Figure 1).	('PTEN', 'Gene', '5728', (24, 28))	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('pS6', 'Gene', '338413', (92, 95))	('AKT', 'Gene', '207', (84, 87))	('presence', 'Reg', (49, 57))	('loss', 'NegReg', (29, 33))	('AKT', 'Gene', (84, 87))	('mutations', 'Var', (68, 77))	('expression', 'MPA', (37, 47))	('pS6', 'Gene', (92, 95))	('PTEN', 'Gene', (24, 28))
100555	24634376	When stratified according to ER and HER2 status, again, the DCIS and invasive components of each case were remarkably similar in regards to PTEN and INPP4B loss of expression, presence of PIK3CA and AKT1 mutations, and pAKT and pS6 expression (Table 2).	('AKT', 'Gene', (199, 202))	('PIK3CA', 'Gene', (188, 194))	('HER2', 'Gene', (36, 40))	('AKT1', 'Gene', (199, 203))	('pS6', 'Gene', (228, 231))	('presence', 'Reg', (176, 184))	('PTEN', 'Gene', (140, 144))	('AKT', 'Gene', (220, 223))	('ER', 'Gene', '2099', (29, 31))	('AKT', 'Gene', '207', (199, 202))	('ER', 'Gene', '2099', (37, 39))	('pS6', 'Gene', '338413', (228, 231))	('PTEN', 'Gene', '5728', (140, 144))	('mutations', 'Var', (204, 213))	('HER2', 'Gene', '2064', (36, 40))	('INPP4B', 'Gene', '8821', (149, 155))	('PIK3CA', 'Gene', '5290', (188, 194))	('loss of', 'NegReg', (156, 163))	('AKT', 'Gene', '207', (220, 223))	('AKT1', 'Gene', '207', (199, 203))	('expression', 'MPA', (164, 174))	('INPP4B', 'Gene', (149, 155))
100556	24634376	Although PIK3CA mutations have been reported at similar frequencies in DCIS and IBC, recent studies have described changes in the PIK3CA status in the progression from in situ to invasive disease.	('PIK3CA', 'Gene', (130, 136))	('IBC', 'Disease', (80, 83))	('invasive disease', 'Disease', (179, 195))	('PIK3CA', 'Gene', '5290', (130, 136))	('mutations', 'Var', (16, 25))	('invasive disease', 'Disease', 'MESH:D009362', (179, 195))	('DCIS', 'Disease', (71, 75))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))	('changes', 'Reg', (115, 122))
100557	24634376	Here we have observed that in 3 cases, the H1047R PIK3CA mutation was present in the invasive component but not detectable in the synchronous DCIS areas, and in 5 additional cases, the PIK3CA mutation was present in a non-modal population of the DCIS cells (PIK3CA mutant allele frequencies ranging from 25%-33.3%), but likely present in the modal population of the IBC (PIK3CA mutant allele frequencies ranging from 46.2%-52.8%; Table 3; Figures 1 and 3C).	('PIK3CA', 'Gene', '5290', (50, 56))	('H1047R', 'SUBSTITUTION', 'None', (43, 49))	('H1047R', 'Var', (43, 49))	('PIK3CA', 'Gene', (371, 377))	('PIK3CA', 'Gene', (258, 264))	('PIK3CA', 'Gene', '5290', (258, 264))	('PIK3CA', 'Gene', (185, 191))	('PIK3CA', 'Gene', '5290', (371, 377))	('PIK3CA', 'Gene', '5290', (185, 191))	('PIK3CA', 'Gene', (50, 56))
100558	24634376	In two additional cases, the H1047R PIK3CA mutation was restricted to the DCIS component but absent in the IBC (Figures 1, 3B and 3C, Table 3).	('H1047R', 'Var', (29, 35))	('H1047R', 'SUBSTITUTION', 'None', (29, 35))	('PIK3CA', 'Gene', (36, 42))	('PIK3CA', 'Gene', '5290', (36, 42))
100560	24634376	Furthermore, our data support the contention that although PIK3CA mutations may play a role from the early stages of breast tumorigenesis, their role as driver of the progression from in situ to invasive disease is less clear, given that examples of both PIK3CA wild-type DCIS adjacent to PIK3CA mutant IBC and of PIK3CA wild-type IBC adjacent to PIK3CA mutant DCIS were observed.	('invasive disease', 'Disease', (195, 211))	('mutant', 'Var', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PIK3CA', 'Gene', (347, 353))	('PIK3CA', 'Gene', (255, 261))	('tumor', 'Disease', (124, 129))	('PIK3CA', 'Gene', '5290', (314, 320))	('PIK3CA', 'Gene', (59, 65))	('PIK3CA', 'Gene', '5290', (347, 353))	('invasive disease', 'Disease', 'MESH:D009362', (195, 211))	('PIK3CA', 'Gene', '5290', (289, 295))	('PIK3CA', 'Gene', (314, 320))	('PIK3CA', 'Gene', (289, 295))	('PIK3CA', 'Gene', '5290', (255, 261))	('PIK3CA', 'Gene', '5290', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
100561	24634376	Here we demonstrate that both pure high-grade DCIS and high-grade DCIS adjacent to IBC often harbor molecular alterations that result in activation of the PI3K pathway, and that in a way akin to IBCs, different subtypes of DCIS, as defined by ER and HER2 status, display different patterns of alterations affecting genes in the PI3K canonical pathway.	('PI3K pathway', 'Pathway', (155, 167))	('ER', 'Gene', '2099', (251, 253))	('alterations', 'Var', (110, 121))	('PI3K canonical pathway', 'Pathway', (328, 350))	('HER2', 'Gene', (250, 254))	('HER2', 'Gene', '2064', (250, 254))	('activation', 'PosReg', (137, 147))	('ER', 'Gene', '2099', (243, 245))
100564	24634376	Here we not only confirmed that a subset of DCIS do harbor PIK3CA mutations, but also provided an integrative analysis combining an assessment of the most common mechanisms of activation of this pathway, and an immunohistochemical assessment of the PI3K pathway activity employing pAKT and pS6 as surrogates of activation of this pathway.	('mutations', 'Var', (66, 75))	('pS6', 'Gene', '338413', (290, 293))	('PI3K pathway', 'Pathway', (249, 261))	('AKT', 'Gene', (282, 285))	('PIK3CA', 'Gene', (59, 65))	('pS6', 'Gene', (290, 293))	('PIK3CA', 'Gene', '5290', (59, 65))	('AKT', 'Gene', '207', (282, 285))
100565	24634376	In both pure DCIS and DCIS adjacent to IBC, we have observed that the presence of PTEN and INPP4B loss of expression and/or mutations in PIK3CA or AKT1 varied significantly according to subtype (Table 1).	('AKT1', 'Gene', '207', (147, 151))	('PIK3CA', 'Gene', (137, 143))	('INPP4B', 'Gene', (91, 97))	('AKT1', 'Gene', (147, 151))	('mutations', 'Var', (124, 133))	('PIK3CA', 'Gene', '5290', (137, 143))	('loss of expression', 'NegReg', (98, 116))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('INPP4B', 'Gene', '8821', (91, 97))
100566	24634376	Importantly, the observation that PIK3CA hotspot mutations and pAKT expression were significantly more frequent in ER-positive/HER2-negative DCIS adjacent to IBC than in pure DCIS is consistent with the notion that PI3K pathway activation may impart increased risk of or association with invasive progression in this disease subtype.	('PIK3CA', 'Gene', (34, 40))	('mutations', 'Var', (49, 58))	('DCIS', 'Disease', (141, 145))	('IBC', 'Disease', (158, 161))	('AKT', 'Gene', '207', (64, 67))	('PIK3CA', 'Gene', '5290', (34, 40))	('ER', 'Gene', '2099', (128, 130))	('PI3K pathway', 'Pathway', (215, 227))	('HER2', 'Gene', (127, 131))	('ER', 'Gene', '2099', (115, 117))	('HER2', 'Gene', '2064', (127, 131))	('AKT', 'Gene', (64, 67))	('frequent', 'Reg', (103, 111))
100567	24634376	Using a subtype-matched approach, we have observed a significantly higher prevalence of PIK3CA mutations and pAKT activity in high-grade ER-positive/HER2-negative DCIS adjacent to IBC than in pure DCIS.	('HER2', 'Gene', (149, 153))	('higher', 'PosReg', (67, 73))	('PIK3CA', 'Gene', '5290', (88, 94))	('HER2', 'Gene', '2064', (149, 153))	('AKT', 'Gene', (110, 113))	('DCIS', 'Disease', (163, 167))	('mutations', 'Var', (95, 104))	('PIK3CA', 'Gene', (88, 94))	('ER', 'Gene', '2099', (150, 152))	('ER', 'Gene', '2099', (137, 139))	('AKT', 'Gene', '207', (110, 113))
100569	24634376	These observations demonstrate that loss of PTEN and INPP4B expression, and mutations affecting PIK3CA and AKT1 are present in a subset of both pure high-grade DCIS and high-grade DCIS adjacent to IBC, providing additional evidence to support the role of this pathway in the early stages of breast cancer development.	('expression', 'MPA', (60, 70))	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('mutations', 'Var', (76, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('breast cancer', 'Disease', (291, 304))	('loss', 'NegReg', (36, 40))	('AKT1', 'Gene', '207', (107, 111))	('PIK3CA', 'Gene', (96, 102))	('PTEN', 'Gene', (44, 48))	('AKT1', 'Gene', (107, 111))	('PIK3CA', 'Gene', '5290', (96, 102))	('PTEN', 'Gene', '5728', (44, 48))	('INPP4B', 'Gene', '8821', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('INPP4B', 'Gene', (53, 59))
100570	24634376	In pure high-grade DCIS, PIK3CA mutations were relatively infrequent and were not found in ER-positive lesions; on the other hand, 5% of ER-negative/HER2-positive and 28% of the ER-negative/HER2-negative high-grade DCIS harbored the H1047R PIK3CA mutation.	('ER', 'Gene', '2099', (178, 180))	('HER2', 'Gene', (190, 194))	('HER2', 'Gene', (149, 153))	('HER2', 'Gene', '2064', (190, 194))	('HER2', 'Gene', '2064', (149, 153))	('harbored', 'Reg', (220, 228))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', (240, 246))	('H1047R', 'Var', (233, 239))	('ER', 'Gene', '2099', (191, 193))	('PIK3CA', 'Gene', '5290', (25, 31))	('ER', 'Gene', '2099', (91, 93))	('PIK3CA', 'Gene', '5290', (240, 246))	('H1047R', 'SUBSTITUTION', 'None', (233, 239))	('ER', 'Gene', '2099', (150, 152))	('ER', 'Gene', '2099', (137, 139))
100571	24634376	In high-grade DCIS adjacent to IBC, however, PIK3CA mutations were present in all subtypes, ranging from 8% in ER-negative/HER2-negative lesions to 24% in ER-positive/HER2-positive disease.	('mutations', 'Var', (52, 61))	('ER', 'Gene', '2099', (168, 170))	('ER', 'Gene', '2099', (155, 157))	('ER', 'Gene', '2099', (124, 126))	('HER2', 'Gene', (167, 171))	('ER', 'Gene', '2099', (111, 113))	('HER2', 'Gene', (123, 127))	('PIK3CA', 'Gene', (45, 51))	('high-grade DCIS adjacent', 'Disease', (3, 27))	('HER2', 'Gene', '2064', (167, 171))	('HER2', 'Gene', '2064', (123, 127))	('present', 'Reg', (67, 74))	('IBC', 'Disease', (31, 34))	('PIK3CA', 'Gene', '5290', (45, 51))
100572	24634376	Out of all ER-positive DCIS analyzed in this study, only 11% harbored PIK3CA hotspot mutations.	('harbored', 'Reg', (61, 69))	('ER', 'Gene', '2099', (11, 13))	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (85, 94))	('PIK3CA', 'Gene', '5290', (70, 76))
100573	24634376	Albeit at first glance at variance with the notion that PIK3CA mutations are more frequently found in ER-positive IBCs, these seemingly unexpected findings can be reconciled by the fact that we have focused on high-grade ER-positive lesions, which have been reported to less frequently harbor PIK3CA mutations than low-grade ER-positive IBCs (24%-49%), low-grade pure DCIS (34%), and early precursors of low-grade forms of DCIS (54%).	('PIK3CA', 'Gene', '5290', (293, 299))	('mutations', 'Var', (300, 309))	('PIK3CA', 'Gene', (56, 62))	('ER', 'Gene', '2099', (221, 223))	('PIK3CA', 'Gene', (293, 299))	('ER', 'Gene', '2099', (325, 327))	('PIK3CA', 'Gene', '5290', (56, 62))	('harbor', 'Reg', (286, 292))	('ER', 'Gene', '2099', (102, 104))
100574	24634376	The high prevalence of PIK3CA mutations in non-obligate precursors of low-grade DCIS (e.g., columnar cell lesions) and low-grade DCIS, in conjunction with the low frequencies of PIK3CA mutations in high-grade ER-positive DCIS analyzed in this study are consistent with the notion that the molecular pathways involved in the development and progression of low- and high-grade DCIS are likely distinct, and that in high-grade DCIS, PIK3CA mutations may only play a role in a minority of cases.	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', (178, 184))	('PIK3CA', 'Gene', (430, 436))	('PIK3CA', 'Gene', '5290', (23, 29))	('PIK3CA', 'Gene', '5290', (178, 184))	('mutations', 'Var', (30, 39))	('PIK3CA', 'Gene', '5290', (430, 436))	('ER', 'Gene', '2099', (209, 211))
100578	24634376	The vast majority of cases (69% of pure DCIS and 75% of DCIS adjacent to IBC) harboring PTEN or INPP4B loss of expression, or PIK3CA or AKT1 mutations, displayed pAKT expression, whereas pS6 expression was found in 6% and 21% of pure DCIS and DCIS adjacent to IBC harboring these molecular aberrations.	('loss of expression', 'NegReg', (103, 121))	('PIK3CA', 'Gene', (126, 132))	('AKT1', 'Gene', (136, 140))	('mutations', 'Var', (141, 150))	('INPP4B', 'Gene', '8821', (96, 102))	('AKT', 'Gene', (163, 166))	('INPP4B', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (126, 132))	('pS6', 'Gene', (187, 190))	('PTEN', 'Gene', (88, 92))	('AKT', 'Gene', '207', (136, 139))	('PTEN', 'Gene', '5728', (88, 92))	('AKT1', 'Gene', '207', (136, 140))	('pS6', 'Gene', '338413', (187, 190))	('AKT', 'Gene', '207', (163, 166))	('AKT', 'Gene', (136, 139))
100579	24634376	The lack of pAKT and pS6 expression in cases with alterations in these genes may stem from the fact that we have i) assessed pAKT and pS6 expression in surgical specimens and that previous analyses have shown that their immunohistochemical assessment is affected by pre-analytical variables, and its expression levels are significantly lower in surgical specimens than in core biopsies; and ii) employed antibodies that recognize only a few phosphorylation sites of AKT (i.e.	('lower', 'NegReg', (336, 341))	('AKT', 'Gene', (126, 129))	('expression levels', 'MPA', (300, 317))	('pS6', 'Gene', '338413', (21, 24))	('AKT', 'Gene', '207', (466, 469))	('alterations', 'Var', (50, 61))	('pS6', 'Gene', '338413', (134, 137))	('AKT', 'Gene', '207', (13, 16))	('AKT', 'Gene', (466, 469))	('AKT', 'Gene', '207', (126, 129))	('pS6', 'Gene', (134, 137))	('AKT', 'Gene', (13, 16))	('pS6', 'Gene', (21, 24))
100582	24634376	Although our study may have underestimated the prevalence of PI3K pathway activation in DCIS, our results do demonstrate that mechanisms other than PTEN or INPP4B loss of expression, and PIK3CA or AKT1 mutations may result in activation of this pathway in DCIS, and warrant further studies investigating the causes of PI3K pathway activation in these lesions.	('PTEN', 'Gene', (148, 152))	('PIK3CA', 'Gene', '5290', (187, 193))	('PTEN', 'Gene', '5728', (148, 152))	('loss of expression', 'NegReg', (163, 181))	('mutations', 'Var', (202, 211))	('PIK3CA', 'Gene', (187, 193))	('DCIS', 'Disease', (88, 92))	('DCIS', 'Disease', (256, 260))	('AKT1', 'Gene', '207', (197, 201))	('activation', 'PosReg', (226, 236))	('INPP4B', 'Gene', '8821', (156, 162))	('AKT1', 'Gene', (197, 201))	('INPP4B', 'Gene', (156, 162))
100584	24634376	In Hernandez et al., in three of 13 cases of synchronous DCIS and IBC harboring PIK3CA mutations, these mutations were either restricted to the DCIS component (n=2) or the frequency of the PIK3CA mutant allele was decreased in the IBC when compared to the DCIS component.	('PIK3CA', 'Gene', (189, 195))	('PIK3CA', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (80, 86))	('PIK3CA', 'Gene', '5290', (189, 195))	('mutations', 'Var', (87, 96))
100585	24634376	Our results confirm and expand on previous observations, given that in two cases, PIK3CA mutations were present in the DCIS but absent in the IBC component, whereas in three cases, mutations affecting this gene were found in the invasive component but not in the DCIS.	('PIK3CA', 'Gene', '5290', (82, 88))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (89, 98))
100586	24634376	Taken together, these observations are consistent with a model where DCIS is composed of a mosaic of tumor cells that, in addition to the founder genetic aberrations, harbor private mutations, and that clonal selection is likely to take place in the progression from in situ to invasive disease.	('harbor', 'Reg', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('invasive disease', 'Disease', (278, 294))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('invasive disease', 'Disease', 'MESH:D009362', (278, 294))	('mutations', 'Var', (182, 191))
100587	24634376	These results provide another line of evidence to suggest that PIK3CA mutations may play a role in the progression from in situ to invasive disease in a small subset of cases.	('mutations', 'Var', (70, 79))	('invasive disease', 'Disease', (131, 147))	('PIK3CA', 'Gene', (63, 69))	('role', 'Reg', (91, 95))	('PIK3CA', 'Gene', '5290', (63, 69))	('invasive disease', 'Disease', 'MESH:D009362', (131, 147))
100591	24634376	Finally, we have only investigated a limited number of PIK3CA hotspot mutations; hence, we may not have captured all cases harboring activating mutations in this gene.	('PIK3CA', 'Gene', '5290', (55, 61))	('mutations', 'Var', (70, 79))	('PIK3CA', 'Gene', (55, 61))
100592	24634376	It should be noted, however, that in IBC the PIK3CA mutations included in the Sequenom MassARRAY (i.e., H1047R, E542K, E545K or N345K) assay employed here account for 87% of all mutant cases reported by The Cancer Genome Atlas.	('H1047R', 'SUBSTITUTION', 'None', (104, 110))	('IBC', 'Disease', (37, 40))	('E545K', 'Mutation', 'rs104886003', (119, 124))	('Cancer', 'Disease', 'MESH:D009369', (207, 213))	('E545K', 'Var', (119, 124))	('E542K', 'Var', (112, 117))	('N345K', 'Var', (128, 133))	('PIK3CA', 'Gene', (45, 51))	('N345K', 'Mutation', 'rs121913284', (128, 133))	('PIK3CA', 'Gene', '5290', (45, 51))	('H1047R', 'Var', (104, 110))	('E542K', 'Mutation', 'rs121913273', (112, 117))	('Cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Cancer', 'Disease', (207, 213))
100593	24634376	In conclusion, here we demonstrate that PTEN and INPP4B loss of expression, PIK3CA hotspot mutations, and AKT1 mutations are found in a subset of pure high-grade DCIS and high-grade DCIS adjacent to IBC, that the prevalence of alterations affecting these genes vary more according to the ER/HER2 subtype of DCIS than to its association with synchronous IBC.	('mutations', 'Var', (111, 120))	('AKT1', 'Gene', (106, 110))	('ER', 'Gene', '2099', (292, 294))	('PTEN', 'Gene', (40, 44))	('loss of expression', 'NegReg', (56, 74))	('INPP4B', 'Gene', '8821', (49, 55))	('PTEN', 'Gene', '5728', (40, 44))	('INPP4B', 'Gene', (49, 55))	('PIK3CA', 'Gene', (76, 82))	('HER2', 'Gene', (291, 295))	('mutations', 'Var', (91, 100))	('HER2', 'Gene', '2064', (291, 295))	('ER', 'Gene', '2099', (288, 290))	('AKT1', 'Gene', '207', (106, 110))	('PIK3CA', 'Gene', '5290', (76, 82))
100594	24634376	PTEN loss of expression was infrequent in subtypes other than high-grade ER-negative/HER2-negative DCIS, INPP4B loss of expression was preferentially found in ER-negative/HER2-positive and ER-negative/HER2-negative DCIS, PIK3CA mutations were relatively uncommon in all subtypes of high-grade in situ disease (0%-28%), and AKT1 mutations were only found in 0.5% of all lesions analyzed, yet activation of the PI3K pathway, as defined by pAKT and/or pS6 expression, was shown to be a more pervasive biological phenomenon, possibly driven by genetic (e.g., HER2 gene amplification) or epigenetic alterations other than those surveyed in our study.	('ER', 'Gene', '2099', (73, 75))	('AKT1', 'Gene', '207', (323, 327))	('HER2', 'Gene', (171, 175))	('HER2', 'Gene', (85, 89))	('ER', 'Gene', '2099', (159, 161))	('loss of expression', 'NegReg', (112, 130))	('INPP4B', 'Gene', '8821', (105, 111))	('situ disease', 'Disease', 'MESH:D002278', (296, 308))	('ER', 'Gene', '2099', (556, 558))	('HER2', 'Gene', (201, 205))	('ER', 'Gene', '2099', (86, 88))	('AKT', 'Gene', '207', (438, 441))	('AKT', 'Gene', (323, 326))	('AKT1', 'Gene', (323, 327))	('HER2', 'Gene', '2064', (555, 559))	('activation', 'PosReg', (391, 401))	('pS6', 'Gene', (449, 452))	('PI3K pathway', 'Pathway', (409, 421))	('ER', 'Gene', '2099', (172, 174))	('PIK3CA', 'Gene', '5290', (221, 227))	('INPP4B', 'Gene', (105, 111))	('ER', 'Gene', '2099', (189, 191))	('situ disease', 'Disease', (296, 308))	('gene amplification', 'Var', (560, 578))	('HER2', 'Gene', '2064', (171, 175))	('HER2', 'Gene', '2064', (85, 89))	('PTEN', 'Gene', (0, 4))	('AKT', 'Gene', '207', (323, 326))	('pS6', 'Gene', '338413', (449, 452))	('ER', 'Gene', '2099', (202, 204))	('HER2', 'Gene', '2064', (201, 205))	('HER2', 'Gene', (555, 559))	('AKT', 'Gene', (438, 441))	('PIK3CA', 'Gene', (221, 227))	('PTEN', 'Gene', '5728', (0, 4))
100596	24634376	Intra-tumor genetic heterogeneity and selection of genetically distinct clones in the progression from in situ to invasive disease, however, were documented in a subset cases, and qualitative and quantitative differences in the presence and percentage of PIK3CA mutant alleles between matched DCIS and IBC.	('mutant', 'Var', (262, 268))	('PIK3CA', 'Gene', (255, 261))	('invasive disease', 'Disease', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('PIK3CA', 'Gene', '5290', (255, 261))	('invasive disease', 'Disease', 'MESH:D009362', (114, 130))	('tumor', 'Disease', (6, 11))
100597	24634376	Our findings provide additional evidence to demonstrate the importance of the PI3K pathway in breast cancer and that PI3K pathway aberrations may be associated with a higher risk of progression in a subset of lesions; however, its role in mediating the progression from in situ to invasive disease appears to be more limited.	('invasive disease', 'Disease', (281, 297))	('PI3K pathway', 'Pathway', (117, 129))	('PI3K pathway', 'Pathway', (78, 90))	('invasive disease', 'Disease', 'MESH:D009362', (281, 297))	('associated', 'Reg', (149, 159))	('aberrations', 'Var', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
100600	24634376	Although the PI3K pathway plays a pivotal role in breast cancer, here we demonstrate that alterations in key components of this pathway may play a role in the progression from high-grade DCIS to IBC only in a subset of cases.	('alterations', 'Var', (90, 101))	('high-grade DCIS', 'Disease', (176, 191))	('IBC', 'Disease', (195, 198))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('role', 'Reg', (147, 151))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
100654	24278375	CIS, when compared with invasive cancer, often corresponds to better prognosis and is seldom life threatening.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('CIS', 'Var', (0, 3))	('invasive cancer', 'Disease', 'MESH:D009362', (24, 39))	('invasive cancer', 'Disease', (24, 39))
100738	20602252	Alteration in Protein Expression in Estrogen Receptor Alpha Negative Human Breast Cancer Tissues Indicates an Malignant and Metastatic Phenotype Ductal carcinoma in situ represents an earliest identifiable breast cancer lesion.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Estrogen Receptor Alpha', 'Gene', '2099', (36, 59))	('Alteration', 'Var', (0, 10))	('Breast Cancer', 'Disease', 'MESH:D001943', (75, 88))	('Ductal carcinoma', 'Disease', (145, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('breast cancer lesion', 'Disease', (206, 226))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (145, 161))	('carcinoma in situ', 'Disease', (152, 169))	('Estrogen Receptor Alpha', 'Gene', (36, 59))	('Breast Cancer', 'Disease', (75, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Human', 'Species', '9606', (69, 74))	('Breast Cancer', 'Phenotype', 'HP:0003002', (75, 88))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (145, 169))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (152, 169))	('breast cancer lesion', 'Disease', 'MESH:D001943', (206, 226))	('carcinoma in situ', 'Disease', 'MESH:D002278', (152, 169))
100746	20602252	The collective role of the alteration of protein expression in ER(-) cells may be promoting a more malignant phenotype than adjacent ER(+) cells, including decreased ability to undergo apoptosis and differentiation, and increased potential to damage DNA, metastasize, and resist chemotherapy.	('increased', 'PosReg', (220, 229))	('ER', 'Gene', '2099', (133, 135))	('metastasize', 'CPA', (255, 266))	('protein', 'Protein', (41, 48))	('ER', 'Gene', '2099', (63, 65))	('more malignant phenotype', 'CPA', (94, 118))	('resist chemotherapy', 'CPA', (272, 291))	('alteration', 'Var', (27, 37))	('decreased', 'NegReg', (156, 165))	('promoting', 'PosReg', (82, 91))	('damage', 'Reg', (243, 249))
100761	20602252	All of these results suggest that ERbeta exerts a protective effect against the mitogenic activity of estrogens mediated by ERalpha, and may function as a tumor suppressor, as the loss of ERbeta expression seems to correlate with the progression of breast carcinomas.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('breast carcinomas', 'Phenotype', 'HP:0003002', (249, 266))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ERbeta', 'Gene', '2100', (34, 40))	('ERbeta', 'Gene', '2100', (188, 194))	('mitogenic activity of estrogens', 'MPA', (80, 111))	('tumor', 'Disease', (155, 160))	('loss', 'Var', (180, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('ERalpha', 'Gene', (124, 131))	('ERbeta', 'Gene', (34, 40))	('ERalpha', 'Gene', '2099', (124, 131))	('ERbeta', 'Gene', (188, 194))	('breast carcinomas', 'Disease', 'MESH:D001943', (249, 266))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('breast carcinomas', 'Disease', (249, 266))
100821	20602252	Galectin-1 can induce apoptosis in breast cancer cells by blocking the cell cycle at the S/G2 transition.	('blocking', 'NegReg', (58, 66))	('Galectin-1', 'Gene', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('S/G2', 'Var', (89, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('Galectin-1', 'Gene', '3956', (0, 10))	('S/G2', 'SUBSTITUTION', 'None', (89, 93))
100837	20602252	Restoration of NDPK-A expression reduces metastasis of breast cancer.	('metastasis', 'CPA', (41, 51))	('NDPK-A', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Restoration', 'Var', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('NDPK-A', 'Gene', '4830', (15, 21))	('reduces', 'NegReg', (33, 40))	('expression', 'MPA', (22, 32))
100842	20602252	Although the specific role of alteration of each of these identified proteins remains to be further investigated, the collective role may promote a malignant phenotype for ERalpha (-) cells, including decreased ability to undergo programmed cell death and differentiate, and increased potential to damage DNA and generate genomic instability, resist chemotherapy drugs, and metastasize.	('damage', 'Reg', (298, 304))	('increased', 'PosReg', (275, 284))	('ERalpha', 'Gene', (172, 179))	('alteration', 'Var', (30, 40))	('resist', 'CPA', (343, 349))	('ERalpha', 'Gene', '2099', (172, 179))	('decreased', 'NegReg', (201, 210))	('DNA', 'Protein', (305, 308))	('metastasize', 'CPA', (374, 385))	('promote', 'PosReg', (138, 145))	('genomic instability', 'CPA', (322, 341))	('malignant phenotype', 'CPA', (148, 167))	('generate', 'Reg', (313, 321))
100901	23436342	NPV was highest for patients with HR(-) HER2(+) and TN breast cancers.	('HR(-', 'Var', (34, 38))	('HER2', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HER2', 'Gene', '2064', (40, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (55, 69))	('patients', 'Species', '9606', (20, 28))	('breast cancers', 'Disease', 'MESH:D001943', (55, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('breast cancers', 'Disease', (55, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('highest', 'Reg', (8, 15))
100908	23436342	Tumor characteristics significantly associated with both complete radiographic and pathologic response on MRI included lower radiographic baseline T classification, high grade, ER and/or PR negative status, and HR(-)HER2(+) or TN IHC phenotype (Table 1).	('ER', 'Gene', '2099', (217, 219))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('lower', 'NegReg', (119, 124))	('high grade', 'Var', (165, 175))	('HER2', 'Gene', (216, 220))	('ER', 'Gene', '2099', (177, 179))	('HER2', 'Gene', '2064', (216, 220))	('TN IHC', 'Disease', 'MESH:C562719', (227, 233))	('T classification', 'CPA', (147, 163))	('TN IHC', 'Disease', (227, 233))
100927	23436342	We confirmed that among patients with rCR, positive HR status and low tumor grade were most commonly associated with residual disease at surgery, suggesting that rCR on preoperative MRI in these patient populations should be interpreted with caution.	('residual disease', 'Disease', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('low tumor', 'Disease', (66, 75))	('positive HR status', 'Var', (43, 61))	('patient', 'Species', '9606', (195, 202))	('patient', 'Species', '9606', (24, 31))	('associated', 'Reg', (101, 111))	('patients', 'Species', '9606', (24, 32))	('low tumor', 'Disease', 'MESH:D009800', (66, 75))
100946	21255398	Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mRNA expression', 'MPA', (20, 35))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('Variations', 'Var', (0, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('clinical samples', 'Species', '191496', (43, 59))	('breast cancer', 'Disease', (111, 124))	('RAD21', 'Gene', (14, 19))
100953	21255398	Aberrant RAD21 expression has been reported in multiple cancers and cancer cell lines.	('RAD21', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('expression', 'MPA', (15, 25))	('multiple cancers', 'Disease', (47, 63))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('multiple cancers', 'Disease', 'MESH:D009369', (47, 63))
100956	21255398	Although these reports support the notion that the abnormal activity of RAD21 may be an important feature of human breast cancer, there are no data available from clinical breast cancer samples.	('RAD21', 'Gene', (72, 77))	('human', 'Species', '9606', (109, 114))	('abnormal', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('clinical', 'Species', '191496', (163, 171))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('activity', 'MPA', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
100957	21255398	We therefore, evaluated RAD21 expression in a cohort of well-characterised human in situ and invasive breast cancers to 1) assess the correlation between RAD21 expression, and conventional and molecular clinicopathological parameters and patient prognostic data; and 2) determine whether aberrant RAD21 expression might predict therapeutic outcomes.	('predict', 'Reg', (320, 327))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('human', 'Species', '9606', (75, 80))	('invasive breast cancers', 'Disease', (93, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('RAD21', 'Gene', (297, 302))	('invasive breast cancers', 'Disease', 'MESH:D001943', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('patient', 'Species', '9606', (238, 245))	('breast cancers', 'Phenotype', 'HP:0003002', (102, 116))	('aberrant', 'Var', (288, 296))
100973	21255398	Validation of the anti-RAD21 antibody was performed using small interference RNA (siRNA) knockdown of the human RAD21 gene in MCF10A cells on cell blocks (Additional file 2).	('RAD21', 'Gene', (112, 117))	('human', 'Species', '9606', (106, 111))	('MCF10A', 'CellLine', 'CVCL:0598', (126, 132))	('knockdown', 'Var', (89, 98))
101003	21255398	RAD21 amplification is present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 subtypes.	('RAD21 amplification', 'Var', (0, 19))	('HER2', 'Gene', '2064', (94, 98))	('HER2', 'Gene', (94, 98))
101006	21255398	Variations in RAD21 protein expression in clinical samples were reflected by gene expression analysis using qRT-PCR of a panel of breast cancer cell lines (Figure 3A), and by microarray profiling of 36 breast cancer cell lines derived from Hollestelle et al.	('clinical samples', 'Species', '191496', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('protein', 'Protein', (20, 27))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('Variations', 'Var', (0, 10))	('RAD21', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
101008	21255398	To test the functional significance of our cancer therapy results that RAD21 expression affects sensitivity to chemotherapeutic drug response, we used a small hairpin shRNA-mediated gene-silencing approach to knockdown the RAD21 gene in MDA-MB-231 breast cancer cell line.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('affects', 'Reg', (88, 95))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (237, 247))	('cancer', 'Disease', (43, 49))	('RAD21', 'Gene', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('sensitivity to chemotherapeutic drug response', 'MPA', (96, 141))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('breast cancer', 'Disease', (248, 261))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (255, 261))	('knockdown', 'Var', (209, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('RAD21', 'Gene', (223, 228))
101009	21255398	The RAD21 protein levels in the sh224_sc4 and sh224_sc5 clones are comparable to that in an immortalized human mammary epithelial cell line, MCF10A (Figure 4B).	('human', 'Species', '9606', (105, 110))	('RAD21', 'Protein', (4, 9))	('sh224_sc5', 'Var', (46, 55))	('sh224_sc4', 'Var', (32, 41))	('MCF10A', 'CellLine', 'CVCL:0598', (141, 147))
101011	21255398	All three RAD21 knockdown clones, sh223_sc1, sh224_sc4 and sh224_sc5, showed increased sensitivity to the drug following treatment with cyclophosphamide, in a manner that directly correlates with the level of RAD21 expression (Figure 5A).	('sensitivity to the drug', 'MPA', (87, 110))	('sh224_sc5', 'Var', (59, 68))	('sh224_sc4', 'Var', (45, 54))	('sh223_sc1', 'Var', (34, 43))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (136, 152))	('increased', 'PosReg', (77, 86))	('RAD21', 'Gene', (10, 15))
101012	21255398	Similarly, treatment of three shRAD21 clones (sh223_sc1, sh224_sc4 and sh224_sc5) with 5-FU resulted in a significant reduction in the clonogenic survival of all three clones compared to the parental line (Figure 5B).	('sh224_sc5', 'Var', (71, 80))	('reduction', 'NegReg', (118, 127))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('clonogenic survival', 'CPA', (135, 154))	('sh224_sc4', 'Var', (57, 66))
101016	21255398	This result is consistent with an early report of an enhanced etoposide-sensitivity following a siRNA-mediated transient RAD21 knockdown in MCF7 breast cancer cell line.	('etoposide-sensitivity', 'MPA', (62, 83))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (140, 158))	('etoposide', 'Chemical', 'MESH:D005047', (62, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MCF7 breast cancer', 'Disease', (140, 158))	('knockdown', 'Var', (127, 136))	('RAD21', 'Gene', (121, 126))	('enhanced', 'PosReg', (53, 61))
101019	21255398	Tumor RAD21 overexpression strongly correlated with amplification of the RAD21 gene locus in a significant subset of high grade luminal, basal and HER2 cancers.	('basal', 'Disease', (137, 142))	('RAD21', 'Gene', (73, 78))	('overexpression', 'PosReg', (12, 26))	('high grade luminal', 'Disease', (117, 135))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('correlated', 'Reg', (36, 46))	('HER2 cancers', 'Disease', (147, 159))	('HER2 cancers', 'Disease', 'MESH:D009369', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('amplification', 'Var', (52, 65))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
101020	21255398	This suggests that the observed RAD21 overexpression resulted from gene amplification, and provides a plausible explanation for the strong RAD21 prognostic effects observed in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('RAD21', 'Gene', (32, 37))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('overexpression', 'PosReg', (38, 52))	('gene amplification', 'Var', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
101023	21255398	Based on known RAD21 functions, the adverse outcome in breast cancer patients with RAD21 expression could be due to an elevated level of homologous recombination (HR) repair activity as a result of RAD21 overexpression.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('RAD21', 'Var', (198, 203))	('elevated', 'PosReg', (119, 127))	('expression', 'Var', (89, 99))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('patients', 'Species', '9606', (69, 77))	('RAD21', 'Gene', (83, 88))	('overexpression', 'PosReg', (204, 218))
101024	21255398	Overexpression of other HR proteins (for example, RAD51, BRCA1) has also been shown to be associated with increased resistance to radio- and chemo-therapy.	('BRCA1', 'Gene', (57, 62))	('associated', 'Reg', (90, 100))	('Overexpression', 'Var', (0, 14))	('RAD51', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (57, 62))	('increased', 'PosReg', (106, 115))	('RAD51', 'Gene', '5888', (50, 55))
101029	21255398	Furthermore, our survival analysis revealed that in patients receiving chemotherapy, those patients with tumors positive for RAD21 expression showed a significantly shorter overall survival than patients whose tumors were negative for RAD21, highlighting an exciting potential role for RAD21 expression in predicting cancer therapy response.	('RAD21', 'Gene', (125, 130))	('expression', 'Var', (131, 141))	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('shorter', 'NegReg', (165, 172))	('patients', 'Species', '9606', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('overall survival', 'MPA', (173, 189))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
101030	21255398	Stable knockdown of RAD21 significantly enhanced, in a graded fashion, cellular sensitivity to 5-FU, cyclophosphamide and etoposide.	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (101, 117))	('etoposide', 'Chemical', 'MESH:D005047', (122, 131))	('cellular sensitivity to 5-FU', 'MPA', (71, 99))	('RAD21', 'Gene', (20, 25))	('knockdown', 'Var', (7, 16))	('enhanced', 'PosReg', (40, 48))
101033	21255398	The decrease in cell survival that correlated with levels of RAD21 in breast cancer cells after RAD21 knockdown, is, therefore, in keeping with the dependence of breast cancer cells on the HR pathway to repair DNA damage from chemotherapy.	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('knockdown', 'Var', (102, 111))	('decrease', 'NegReg', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))	('cell survival', 'CPA', (16, 29))	('RAD21', 'Gene', (96, 101))
101040	21255398	In summary, expression of RAD21 in a significant subset of breast cancers confers poor prognosis in high grade luminal, basal and HER2 breast cancers, and resistance to chemotherapy in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RAD21', 'Gene', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('basal', 'Disease', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('expression', 'Var', (12, 22))	('high grade luminal', 'Disease', (100, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('poor', 'NegReg', (82, 86))	('breast cancers', 'Disease', 'MESH:D001943', (59, 73))	('breast cancers', 'Disease', (59, 73))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('breast cancers', 'Phenotype', 'HP:0003002', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('HER2 breast cancers', 'Disease', (130, 149))	('breast cancer', 'Disease', (185, 198))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('HER2 breast cancers', 'Disease', 'MESH:D001943', (130, 149))
101050	25331261	Methylation was seen for all the tested genes except BRCA1.	('Methylation', 'Var', (0, 11))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA1', 'Gene', (53, 58))
101051	25331261	RASSF1A was the most frequently methylated gene (90% of DCIS samples) and its methylation was associated with comedo necrosis (p = 0.018).	('RASSF1A', 'Gene', (0, 7))	('methylation', 'Var', (78, 89))	('necrosis', 'Disease', (117, 125))	('comedo', 'Phenotype', 'HP:0025249', (110, 116))	('RASSF1A', 'Gene', '11186', (0, 7))	('associated', 'Reg', (94, 104))	('necrosis', 'Disease', 'MESH:D009336', (117, 125))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))
101052	25331261	Cluster analysis based on the methylation profile revealed four groups, the highly methylated cluster being significantly associated with high nuclear grade, HER2 amplification, negative estrogen receptor (ER) alpha status, and negative progesterone receptor (PgR) status, (p = 0.038, p = 0.018, p <0.001, p = 0.001, respectively).	('associated', 'Reg', (122, 132))	('amplification', 'Var', (163, 176))	('PgR', 'Gene', '5241', (260, 263))	('estrogen receptor (ER) alpha', 'Gene', (187, 215))	('PgR', 'Gene', (260, 263))	('HER2', 'Gene', (158, 162))	('estrogen receptor (ER) alpha', 'Gene', '2099', (187, 215))	('progesterone receptor', 'Gene', '5241', (237, 258))	('HER2', 'Gene', '2064', (158, 162))	('high', 'Var', (138, 142))	('progesterone receptor', 'Gene', (237, 258))
101053	25331261	Methylation of APC (p = 0.017), CDH13 (p = 0.017), and RARbeta (p <0.001) was associated with negative ERalpha status.	('APC', 'Disease', (15, 18))	('CDH13', 'Gene', (32, 37))	('Methylation', 'Var', (0, 11))	('RARbeta', 'Gene', '5915', (55, 62))	('CDH13', 'Gene', '1012', (32, 37))	('ERalpha', 'Gene', '2099', (103, 110))	('ERalpha', 'Gene', (103, 110))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('RARbeta', 'Gene', (55, 62))
101054	25331261	Methylation of CDH13 (p <0.001), and RARbeta (p = 0.001) was associated with negative PgR status.	('PgR', 'Gene', (86, 89))	('CDH13', 'Gene', (15, 20))	('Methylation', 'Var', (0, 11))	('RARbeta', 'Gene', (37, 44))	('CDH13', 'Gene', '1012', (15, 20))	('PgR', 'Gene', '5241', (86, 89))	('RARbeta', 'Gene', '5915', (37, 44))
101055	25331261	Methylation of APC (p = 0.013) and CDH13 (p = 0.026) was associated with high nuclear grade.	('CDH13', 'Gene', (35, 40))	('APC', 'Disease', (15, 18))	('CDH13', 'Gene', '1012', (35, 40))	('Methylation', 'Var', (0, 11))	('high', 'Disease', (73, 77))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('associated', 'Reg', (57, 67))
101056	25331261	Methylation of CDH13 (p = 0.009), and RARbeta (p = 0.042) was associated with HER2-amplification.	('CDH13', 'Gene', (15, 20))	('RARbeta', 'Gene', '5915', (38, 45))	('associated', 'Reg', (62, 72))	('Methylation', 'Var', (0, 11))	('HER2', 'Gene', (78, 82))	('CDH13', 'Gene', '1012', (15, 20))	('HER2', 'Gene', '2064', (78, 82))	('RARbeta', 'Gene', (38, 45))
101057	25331261	Methylation of a panel of genes that are known to be methylated in invasive breast cancer was able to classify DCIS into distinct groups and was differentially associated with phenotypic features in DCIS.	('DCIS', 'Disease', (199, 203))	('invasive breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('DCIS', 'Disease', (111, 115))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('invasive breast cancer', 'Disease', (67, 89))	('associated', 'Reg', (160, 170))
101059	25331261	Current markers of poor prognosis to help select the use of adjuvant therapies are largely based on clinical and histopathological parameters, and include young age, large tumour size, high nuclear grade, presence of comedo necrosis, negative hormone receptor status, and HER2 amplification,.	('necrosis', 'Disease', (224, 232))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('necrosis', 'Disease', 'MESH:D009336', (224, 232))	('amplification', 'Var', (277, 290))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('high', 'Var', (185, 189))	('comedo', 'Phenotype', 'HP:0025249', (217, 223))	('HER2', 'Gene', (272, 276))	('hormone receptor', 'Gene', '3164', (243, 259))	('HER2', 'Gene', '2064', (272, 276))	('negative', 'Var', (234, 242))	('hormone receptor', 'Gene', (243, 259))
101062	25331261	DNA methylation is an epigenetic modification where a methyl group is added to the 5-carbon position of cytosine and is a mechanism of modulating gene expression.	('cytosine', 'Chemical', 'MESH:D003596', (104, 112))	('gene expression', 'MPA', (146, 161))	('methylation', 'Var', (4, 15))	('modulating', 'Reg', (135, 145))	('DNA', 'Disease', (0, 3))	('methyl group', 'MPA', (54, 66))	('carbon', 'Chemical', 'MESH:D002244', (85, 91))
101064	25331261	Promoter hypermethylation may result in gene silencing, and in cancer this can be a mechanism of tumour suppressor gene inactivation.	('tumour', 'Disease', (97, 103))	('gene', 'MPA', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Promoter hypermethylation', 'Var', (0, 25))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('silencing', 'NegReg', (45, 54))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (63, 69))
101069	25331261	These genes were chosen because methylation of the genes have previously been identified as important in invasive breast cancer by The Cancer Genome Atlas Network (TCGA) and/or associated with prognosis in DCIS (APC, CDH1, FOXC1, GSTP1, RARbeta, RASSF1A) or invasive carcinoma (BRCA1,, CDH13, MAL, TWIST1, WIF1).	('FOXC1', 'Gene', (223, 228))	('methylation', 'Var', (32, 43))	('TWIST1', 'Gene', '7291', (298, 304))	('RARbeta', 'Gene', '5915', (237, 244))	('CDH13', 'Gene', '1012', (286, 291))	('MAL', 'Gene', '4118', (293, 296))	('CDH1', 'Gene', (286, 290))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RARbeta', 'Gene', (237, 244))	('invasive carcinoma', 'Disease', (258, 276))	('APC', 'Disease', 'MESH:D011125', (212, 215))	('WIF1', 'Gene', '11197', (306, 310))	('GSTP1', 'Gene', '2950', (230, 235))	('FOXC1', 'Gene', '2296', (223, 228))	('APC', 'Disease', (212, 215))	('invasive carcinoma', 'Disease', 'MESH:D009361', (258, 276))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CDH13', 'Gene', (286, 291))	('DCIS', 'Disease', (206, 210))	('RASSF1A', 'Gene', '11186', (246, 253))	('BRCA1', 'Gene', '672', (278, 283))	('CDH1', 'Gene', '999', (217, 221))	('GSTP1', 'Gene', (230, 235))	('WIF1', 'Gene', (306, 310))	('BRCA1', 'Gene', (278, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('RASSF1A', 'Gene', (246, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('invasive breast cancer', 'Disease', (105, 127))	('MAL', 'Gene', (293, 296))	('TWIST1', 'Gene', (298, 304))	('CDH1', 'Gene', (217, 221))	('DCIS', 'Phenotype', 'HP:0030075', (206, 210))	('invasive breast cancer', 'Disease', 'MESH:D001943', (105, 127))	('CDH1', 'Gene', '999', (286, 290))	('associated', 'Reg', (177, 187))
101070	25331261	The goal of the study was to improve our understanding of methylation in in situ breast cancer, to understand its relation to important histopathological variables and conduct a proof-of-principle study to assess the potential of methylation status as a biomarker in patients with DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (281, 285))	('patients', 'Species', '9606', (267, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('situ breast cancer', 'Disease', (76, 94))	('methylation', 'Var', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('situ breast cancer', 'Disease', 'MESH:D000071960', (76, 94))
101081	25331261	Tumours exhibiting ERalpha or PgR positivity in the absence of HER2 amplification were considered of luminal subtype, human epidermal growth factor receptor-2 (HER2) subtype consisted of tumours with HER2 amplification, regardless of ERalpha and PgR status, basal-like subtype consisted of triple negative (ERalpha negative, PgR negative, HER2 non-amplified) tumours with any degree of CK5 membranous staining, and negative subtype tumours consisted of triple-negative tumours without CK5 staining.	('ERalpha', 'Gene', (19, 26))	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('HER2', 'Gene', '2064', (160, 164))	('PgR', 'Gene', (246, 249))	('HER2', 'Gene', '2064', (200, 204))	('ERalpha', 'Gene', '2099', (234, 241))	('tumours', 'Phenotype', 'HP:0002664', (432, 439))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('PgR', 'Gene', (325, 328))	('tumours', 'Disease', 'MESH:D009369', (432, 439))	('HER2', 'Gene', (339, 343))	('HER2', 'Gene', '2064', (63, 67))	('ERalpha', 'Gene', '2099', (19, 26))	('ERalpha', 'Gene', '2099', (307, 314))	('tumours', 'Disease', (359, 366))	('CK5', 'Gene', '3852', (386, 389))	('tumour', 'Phenotype', 'HP:0002664', (432, 438))	('subtype tumours', 'Disease', 'MESH:C535673', (424, 439))	('tumour', 'Phenotype', 'HP:0002664', (359, 365))	('CK5', 'Gene', (485, 488))	('tumours', 'Disease', (469, 476))	('PgR', 'Gene', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (359, 366))	('epidermal growth factor receptor-2', 'Gene', (124, 158))	('subtype tumours', 'Disease', (424, 439))	('HER2', 'Gene', (160, 164))	('tumours', 'Phenotype', 'HP:0002664', (469, 476))	('HER2', 'Gene', (200, 204))	('tumours', 'Disease', 'MESH:D009369', (359, 366))	('epidermal growth factor receptor-2', 'Gene', '2064', (124, 158))	('negative', 'NegReg', (329, 337))	('tumours', 'Disease', 'MESH:D009369', (469, 476))	('PgR', 'Gene', '5241', (246, 249))	('PgR', 'Gene', '5241', (325, 328))	('ERalpha', 'Gene', (307, 314))	('human', 'Species', '9606', (118, 123))	('HER2', 'Gene', (63, 67))	('HER2', 'Gene', '2064', (339, 343))	('CK5', 'Gene', '3852', (485, 488))	('tumour', 'Phenotype', 'HP:0002664', (469, 475))	('amplification', 'Var', (205, 218))	('tumours', 'Disease', (187, 194))	('PgR', 'Gene', '5241', (30, 33))	('ERalpha', 'Gene', (234, 241))	('tumours', 'Disease', (432, 439))	('CK5', 'Gene', (386, 389))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
101087	25331261	This method distinguishes between methylated and unmethylated templates based on melting profiles conferred by sequence alterations as a result of bisulfite modification.	('conferred', 'Reg', (98, 107))	('bisulfite', 'Chemical', 'MESH:C042345', (147, 156))	('alterations', 'Var', (120, 131))	('bisulfite', 'MPA', (147, 156))	('melting profiles', 'MPA', (81, 97))
101097	25331261	Among all DCIS, RASSF1A methylation was present in 90% (72/80) of samples, CDH13 in 53.8% (43/80), MAL in 49.4% (39/79), APC in 48.8% (39/80), WIF1 in 48.8% (39/80), GSTP1 in 47.5% (38/80), TWIST1 in 40.7% (33/81), RARbeta in 37% (30/81), and FOXC1 methylation in 11.3% (9/80) of samples.	('RARbeta', 'Gene', (215, 222))	('MAL', 'Gene', (99, 102))	('CDH13', 'Gene', (75, 80))	('FOXC1', 'Gene', '2296', (243, 248))	('methylation', 'Var', (24, 35))	('TWIST1', 'Gene', (190, 196))	('TWIST1', 'Gene', '7291', (190, 196))	('MAL', 'Gene', '4118', (99, 102))	('RASSF1A', 'Gene', '11186', (16, 23))	('GSTP1', 'Gene', '2950', (166, 171))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('RASSF1A', 'Gene', (16, 23))	('CDH13', 'Gene', '1012', (75, 80))	('GSTP1', 'Gene', (166, 171))	('FOXC1', 'Gene', (243, 248))	('WIF1', 'Gene', '11197', (143, 147))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('RARbeta', 'Gene', '5915', (215, 222))	('WIF1', 'Gene', (143, 147))	('APC', 'Disease', (121, 124))
101098	25331261	CDH1 methylation was rare (2.5%, 2/79) (Table 2, Figure 1).	('CDH1', 'Gene', '999', (0, 4))	('methylation', 'Var', (5, 16))	('CDH1', 'Gene', (0, 4))
101102	25331261	In the normal breast epithelium samples, only WIF1 methylation (27.8%, 5/18), CDH13 (5.6%, 1/18), and TWIST1 (5.9%, 1/17) methylation were identified (Table 2, Figure 1).	('TWIST1', 'Gene', (102, 108))	('TWIST1', 'Gene', '7291', (102, 108))	('CDH13', 'Gene', (78, 83))	('methylation', 'Var', (122, 133))	('WIF1', 'Gene', (46, 50))	('methylation', 'Var', (51, 62))	('CDH13', 'Gene', '1012', (78, 83))	('WIF1', 'Gene', '11197', (46, 50))
101104	25331261	Methylation of APC and CDH13 was significantly associated with high nuclear grade (P = 0.013 and P = 0.026 respectively).	('APC', 'Disease', (15, 18))	('CDH13', 'Gene', (23, 28))	('high', 'Disease', (63, 67))	('Methylation', 'Var', (0, 11))	('CDH13', 'Gene', '1012', (23, 28))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('associated', 'Reg', (47, 57))
101105	25331261	RASSF1A methylation was significantly correlated with comedo-type necrosis (P = 0.018).	('RASSF1A', 'Gene', (0, 7))	('necrosis', 'Disease', (66, 74))	('comedo', 'Phenotype', 'HP:0025249', (54, 60))	('RASSF1A', 'Gene', '11186', (0, 7))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('correlated', 'Reg', (38, 48))	('methylation', 'Var', (8, 19))
101108	25331261	HER2 amplification in DCIS tumours was associated with methylation of CDH13 (P = 0.009), and RARbeta (P = 0.042).	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('amplification', 'Var', (5, 18))	('CDH13', 'Gene', '1012', (70, 75))	('RARbeta', 'Gene', '5915', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('DCIS tumours', 'Disease', (22, 34))	('methylation', 'MPA', (55, 66))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('DCIS tumours', 'Disease', 'MESH:D002285', (22, 34))	('RARbeta', 'Gene', (93, 100))	('CDH13', 'Gene', (70, 75))
101111	25331261	Cluster 1 samples had minimal methylation, cluster 2 samples were characterized by RASSF1A methylation, cluster 3 showed APC, CDH13, and GSTP1 methylation in addition to RASSF1A, and cluster 4 samples were extensively methylated with the addition of RARbeta and WIF1 methylation.	('RARbeta', 'Gene', (250, 257))	('methylation', 'Var', (91, 102))	('WIF1', 'Gene', (262, 266))	('methylation', 'Var', (143, 154))	('WIF1', 'Gene', '11197', (262, 266))	('GSTP1', 'Gene', (137, 142))	('RASSF1A', 'Gene', (83, 90))	('CDH13', 'Gene', (126, 131))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('RARbeta', 'Gene', '5915', (250, 257))	('GSTP1', 'Gene', '2950', (137, 142))	('RASSF1A', 'Gene', (170, 177))	('RASSF1A', 'Gene', '11186', (83, 90))	('methylation', 'MPA', (30, 41))	('APC', 'Disease', (121, 124))	('CDH13', 'Gene', '1012', (126, 131))	('RASSF1A', 'Gene', '11186', (170, 177))
101112	25331261	Cluster-4 samples were significantly associated with high nuclear grade, HER2 amplification, negative ERalpha status, negative PR status, and non-luminal intrinsic subtype (P = 0.038, P = 0.018, P <0.001, P = 0.001, and P <0.001, respectively) compared with DCIS samples in the other clusters (Additional file 6).	('HER2', 'Gene', '2064', (73, 77))	('high', 'Var', (53, 57))	('ERalpha', 'Gene', (102, 109))	('negative', 'Var', (93, 101))	('amplification', 'Var', (78, 91))	('ERalpha', 'Gene', '2099', (102, 109))	('DCIS', 'Phenotype', 'HP:0030075', (258, 262))	('PR status', 'MPA', (127, 136))	('HER2', 'Gene', (73, 77))
101115	25331261	These were also methylated in the adjacent DCIS in all but one case (WIF1 in sample S25).	('WIF1', 'Gene', (69, 73))	('methylated', 'Var', (16, 26))	('WIF1', 'Gene', '11197', (69, 73))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
101117	25331261	Although the absence of a difference in methylation between pure and mixed DCIS may reflect the small number of mixed DCIS samples in this cohort, it is likely that aberrant DNA methylation is an early event in breast cancer progression, with gradual accumulation of methylation changes from epithelium of normal appearance to non-malignant epithelial lesions to DCIS, while the transition from DCIS to invasive carcinoma is less likely to rely on methylation, at least not for the genes studied here,,,,.	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('invasive carcinoma', 'Disease', 'MESH:D009361', (403, 421))	('DCIS', 'Phenotype', 'HP:0030075', (395, 399))	('DCIS', 'Phenotype', 'HP:0030075', (363, 367))	('aberrant', 'Var', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (412, 421))	('malignant epithelial lesions', 'Phenotype', 'HP:0031492', (331, 359))	('changes', 'Reg', (279, 286))	('invasive carcinoma', 'Disease', (403, 421))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('methylation', 'MPA', (267, 278))	('breast cancer', 'Disease', (211, 224))
101119	25331261	Given a frequency of approximately 20% BRCA1 methylation in invasive carcinoma, this suggests that tumours driven by BRCA1 methylation either rarely pass through a DCIS phase or have an exceedingly rapid transit through one, a notion supported by observation that DCIS is rare in carriers with BRCA1 germline mutations,.	('BRCA1', 'Gene', '672', (294, 299))	('BRCA1', 'Gene', '672', (117, 122))	('BRCA1', 'Gene', (294, 299))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('rarely', 'NegReg', (142, 148))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('methylation', 'Var', (123, 134))	('DCIS', 'Phenotype', 'HP:0030075', (264, 268))	('BRCA1', 'Gene', (117, 122))	('invasive carcinoma', 'Disease', 'MESH:D009361', (60, 78))	('methylation', 'Var', (45, 56))	('tumours', 'Disease', (99, 106))	('BRCA1', 'Gene', '672', (39, 44))	('invasive carcinoma', 'Disease', (60, 78))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('BRCA1', 'Gene', (39, 44))
101120	25331261	Cluster analysis based on methylation profile divided our DCIS cohort into four groups, which were phenotypically distinguished by nuclear grade, and in particular, the high-methylation cluster (cluster 4), being associated with additional aggressive phenotypic features including negative hormone receptor status, HER2 amplification, and non-luminal intrinsic subtype.	('non-luminal intrinsic subtype', 'Disease', (339, 368))	('associated', 'Reg', (213, 223))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('high-methylation', 'Var', (169, 185))	('HER2', 'Gene', (315, 319))	('hormone receptor', 'Gene', '3164', (290, 306))	('HER2', 'Gene', '2064', (315, 319))	('hormone receptor', 'Gene', (290, 306))
101122	25331261	Methylation of APC, CDH13, RARbeta and RASSF1A was variably significantly associated with conventional aggressive characteristics including high nuclear grade, comedo necrosis, negative ERalpha status, negative PgR status, HER2 amplification, and intrinsic subtype.	('PgR', 'Gene', '5241', (211, 214))	('necrosis', 'Disease', 'MESH:D009336', (167, 175))	('negative', 'Var', (177, 185))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('necrosis', 'Disease', (167, 175))	('ERalpha', 'Gene', '2099', (186, 193))	('HER2', 'Gene', '2064', (223, 227))	('APC', 'Disease', (15, 18))	('Methylation', 'Var', (0, 11))	('CDH13', 'Gene', '1012', (20, 25))	('RARbeta', 'Gene', '5915', (27, 34))	('PgR', 'Gene', (211, 214))	('comedo', 'Phenotype', 'HP:0025249', (160, 166))	('RARbeta', 'Gene', (27, 34))	('HER2', 'Gene', (223, 227))	('RASSF1A', 'Gene', '11186', (39, 46))	('high nuclear grade', 'CPA', (140, 158))	('CDH13', 'Gene', (20, 25))	('ERalpha', 'Gene', (186, 193))	('RASSF1A', 'Gene', (39, 46))	('associated', 'Reg', (74, 84))
101123	25331261	The association between methylation of these genes and adverse phenotypic features in DCIS is in keeping with the role of these genes as tumour suppressor genes.	('association', 'Interaction', (4, 15))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('DCIS', 'Disease', (86, 90))	('tumour', 'Disease', (137, 143))	('methylation', 'Var', (24, 35))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
101126	25331261	Indeed, in invasive breast cancer, the presence of RARbeta methylation in both tumour and serum has been associated with poor disease-free and overall survival,, while the presence of RASSF1A and APC methylation in pre-operative serum samples predicts for poorer overall survival,, and APC methylation in breast cancer tissue is associated with reduced time to recurrence.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('reduced', 'NegReg', (345, 352))	('APC', 'Disease', 'MESH:D011125', (286, 289))	('time', 'MPA', (353, 357))	('APC', 'Disease', (286, 289))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('APC', 'Disease', 'MESH:D011125', (196, 199))	('APC', 'Disease', (196, 199))	('presence', 'Var', (39, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('associated', 'Reg', (105, 115))	('poor', 'NegReg', (121, 125))	('RASSF1A', 'Gene', '11186', (184, 191))	('invasive breast cancer', 'Disease', (11, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (305, 318))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('RARbeta', 'Gene', '5915', (51, 58))	('RARbeta', 'Gene', (51, 58))	('methylation', 'Var', (59, 70))	('RASSF1A', 'Gene', (184, 191))	('invasive breast cancer', 'Disease', 'MESH:D001943', (11, 33))	('breast cancer', 'Disease', (305, 318))	('breast cancer', 'Disease', 'MESH:D001943', (305, 318))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
101127	25331261	Similarly, a recent meta-analysis demonstrated a relationship between RASSF1A methylation and higher risk of relapse and poorer survival.	('methylation', 'Var', (78, 89))	('RASSF1A', 'Gene', (70, 77))	('relapse', 'CPA', (109, 116))	('RASSF1A', 'Gene', '11186', (70, 77))	('poorer survival', 'CPA', (121, 136))
101128	25331261	While CDH13 methylation has not yet been directly associated with prognosis in breast cancer, CDH13 methylation has been associated with HER2 amplification and negative PgR status in invasive breast carcinoma, although the latter relationship was not confirmed in a subsequent study by the same group.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', (79, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('CDH13', 'Gene', '1012', (6, 11))	('PgR', 'Gene', '5241', (169, 172))	('CDH13', 'Gene', '1012', (94, 99))	('HER2', 'Gene', (137, 141))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (183, 208))	('methylation', 'Var', (100, 111))	('breast carcinoma', 'Phenotype', 'HP:0003002', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDH13', 'Gene', (6, 11))	('invasive breast carcinoma', 'Disease', (183, 208))	('negative', 'NegReg', (160, 168))	('amplification', 'Var', (142, 155))	('CDH13', 'Gene', (94, 99))	('PgR', 'Gene', (169, 172))	('associated', 'Reg', (121, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('HER2', 'Gene', '2064', (137, 141))
101133	25331261	We report for the first time an association of CDH13 methylation with nuclear grade and hormone receptor status in DCIS.	('CDH13', 'Gene', (47, 52))	('DCIS', 'Disease', (115, 119))	('hormone receptor', 'Gene', '3164', (88, 104))	('CDH13', 'Gene', '1012', (47, 52))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('hormone receptor', 'Gene', (88, 104))	('association', 'Interaction', (32, 43))	('methylation', 'Var', (53, 64))
101134	25331261	It is also likely that as with invasive carcinoma some methylated genes may be of use as predictive biomarkers of hormonal therapy, a further avenue of investigation that warrants research effort.	('invasive carcinoma', 'Disease', (31, 49))	('methylated', 'Var', (55, 65))	('invasive carcinoma', 'Disease', 'MESH:D009361', (31, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))
101235	30134951	In the xenograft tumor model, the tumor growth of MCF10DCIS.com was enhanced by the co-injection of preadipocytes, and the administration of IL-6 neutralizing antibodies resulted in potent effects on tumor inhibition.	('MCF10DCIS.com', 'Var', (50, 63))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('enhanced', 'PosReg', (68, 76))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (50, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
101280	30134951	Tumor-bearing mice were randomly assigned to one of four groups: DCIS.com (n = 4); DCIS.com+IL-6 NAb (n = 4); DCIS.com+hPreAd (n = 4); and DCIS.com+hPreAd+IL-6 NAb (n = 4).	('DCIS.com+IL-6', 'Var', (83, 96))	('DCIS.com+hPreAd', 'Var', (110, 125))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))
101304	30134951	The treatment with 3 mug/ml IL-6NAb or IL-6RNAb in the single culture resulted in a significant decrease of DCIS.com proliferation (0.92 +- 0.02, P = 0.03 and 0.92 +- 0.02, P = 0.03) but not DCIS.com migration (Fig.	('IL-6NAb', 'Var', (28, 35))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('decrease', 'NegReg', (96, 104))	('IL-6R', 'Gene', '3570', (39, 44))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('DCIS.com proliferation', 'CPA', (108, 130))	('IL-6R', 'Gene', (39, 44))
101316	30134951	5c and d, the tumor volumes were significantly increased in the mice co-injected with DCIS.com and hPreAd (942.8 +- 163.0 mm3) relative to the mice injected with DCIS.com alone (527.1 +- 77.6 mm3, P = 0.0.027).	('tumor', 'Disease', (14, 19))	('hPreAd', 'Var', (99, 105))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('increased', 'PosReg', (47, 56))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('DCIS.com', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mice', 'Species', '10090', (64, 68))	('mice', 'Species', '10090', (143, 147))
101317	30134951	The volume of tumors treated with IL-6 NAb was decreased in the mice co-injected with DCIS.com and hPreAd (207.8 +- 111.5 mm3, P = 0.012) or in the mice injected with DCIS.com alone (338.1 +- 89.4, P = 0.154) relative to the untreated mice.	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mice', 'Species', '10090', (148, 152))	('IL-6', 'Gene', (34, 38))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('DCIS.com', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mice', 'Species', '10090', (64, 68))	('mice', 'Species', '10090', (235, 239))	('decreased', 'NegReg', (47, 56))
101340	30134951	According to study reported by Bochet L et al., SUM159PT cells force mature adipocytes towards fibroblast-like cells exhibiting elongated morphology and expressing FSP1, but not alpha-SMA in adipose tissue, and acquire more aggressive and invasive capability of tumor cells.	('SUM159PT', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('force', 'CPA', (63, 68))	('FSP1', 'Gene', (164, 168))	('tumor', 'Disease', (262, 267))	('more', 'PosReg', (219, 223))	('FSP1', 'Gene', '6275', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
101413	32994341	However, frameshifts, truncated protein expression, lack of mammalian posttranslational modifications, bias towards high abundant transcripts, and labor-intensive procedures are drawbacks of this method.	('truncated', 'MPA', (22, 31))	('mammalian', 'Species', '9606', (60, 69))	('frameshifts', 'Var', (9, 20))
101438	32994341	This is an interesting study where they used pre-diagnostic plasmas from 48 women with ER+/PR+ breast cancer and 65 healthy controls and discovered significant enrichment of proteins in the glycolysis and spliceosome biological pathways.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('proteins', 'Protein', (174, 182))	('ER+/PR+', 'Var', (87, 94))	('women', 'Species', '9606', (76, 81))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
101457	32994341	When the activity of these enzymes is compromised, it results in the synthesis of aberrant glycans responsible for many diseases including cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('synthesis of', 'MPA', (69, 81))	('results in', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('activity', 'MPA', (9, 17))	('glycans', 'Chemical', 'MESH:D011134', (91, 98))	('aberrant', 'Var', (82, 90))	('cancer', 'Disease', (139, 145))
101473	32994341	The earliest report providing evidence for p53 AAbs goes back to 1979 when DeLeo et al.	('AAbs goes back', 'Disease', (47, 61))	('AAbs goes back', 'Disease', 'MESH:D001416', (47, 61))	('p53', 'Var', (43, 46))
101476	32994341	Since then numerous studies have reported the presence of p53 AAbs in various cancers including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('breast cancer', 'Disease', (96, 109))	('presence', 'Reg', (46, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p53 AAbs', 'Var', (58, 66))	('AAb', 'Chemical', '-', (62, 65))
101477	32994341	Around 10-15% of early-stage breast cancers have detected p53 AAbs.	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (29, 43))	('breast cancers', 'Disease', 'MESH:D001943', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('p53 AAbs', 'Var', (58, 66))	('breast cancers', 'Disease', (29, 43))	('AAb', 'Chemical', '-', (62, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
101478	32994341	Several studies have reported a positive correlation between the presence of p53 AAbs and p53 missense mutations and/or accumulation.	('p53', 'Gene', (90, 93))	('AAbs', 'Var', (81, 85))	('accumulation', 'MPA', (120, 132))	('AAb', 'Chemical', '-', (81, 84))	('p53', 'Gene', (77, 80))	('missense mutations', 'Var', (94, 112))
101481	32994341	In addition, only around 20-40% of patients harboring p53 mutations develop AAbs.	('mutations', 'Var', (58, 67))	('AAb', 'Chemical', '-', (76, 79))	('AAbs', 'Disease', (76, 80))	('p53', 'Gene', (54, 57))	('patients', 'Species', '9606', (35, 43))
101482	32994341	Patients with similar mutations in similar cancer types could either be positive or negative for p53 AAbs indicating the influence of other factors in antibody response.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('AAb', 'Chemical', '-', (101, 104))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('negative', 'NegReg', (84, 92))	('p53', 'Var', (97, 100))
101496	32994341	The data reported a sensitivity of 10.6% for MUC1 glycan combinations with 95% specificity.	('MUC1', 'Gene', (45, 49))	('glycan', 'Chemical', 'MESH:D011134', (50, 56))	('combinations', 'Var', (57, 69))	('MUC1', 'Gene', '4582', (45, 49))
101498	32994341	Another study conducted with a population of women with BRCA1 and BRCA2 mutations (n=127) reported lower levels of MUC1 AAbs among the mutation carriers than the healthy controls.	('BRCA2', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('lower', 'NegReg', (99, 104))	('MUC1', 'Gene', (115, 119))	('MUC1', 'Gene', '4582', (115, 119))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA2', 'Gene', '675', (66, 71))	('levels', 'MPA', (105, 111))	('BRCA1', 'Gene', (56, 61))	('AAb', 'Chemical', '-', (120, 123))	('women', 'Species', '9606', (45, 50))
101500	32994341	Around 20% of newly diagnosed breast cancers have amplification or overexpression of HER2 and show more aggressive disease with worse prognosis.	('aggressive disease', 'Disease', (104, 122))	('amplification', 'Var', (50, 63))	('breast cancers', 'Disease', (30, 44))	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('overexpression', 'PosReg', (67, 81))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('HER2', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('HER2', 'Gene', '2064', (85, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('aggressive disease', 'Disease', 'MESH:D001523', (104, 122))
101502	32994341	In a study reported with patients newly diagnosed with primary invasive breast cancer (PBC) and ductal carcinoma in situ (DCIS), AAbs for HER-2 reported a sensitivity of 18% for PBC and 13% for DCIS with 94% specificity.	('invasive breast cancer', 'Disease', (63, 85))	('ductal carcinoma', 'Disease', 'MESH:D044584', (96, 112))	('DCIS', 'Disease', (194, 198))	('PBC', 'Chemical', '-', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('invasive breast cancer', 'Disease', 'MESH:D001943', (63, 85))	('HER-2', 'Gene', '2064', (138, 143))	('AAb', 'Chemical', '-', (129, 132))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))	('PBC', 'Disease', (178, 181))	('HER-2', 'Gene', (138, 143))	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (25, 33))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (96, 120))	('PBC', 'Chemical', '-', (87, 90))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (103, 120))	('ductal carcinoma', 'Disease', (96, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('AAbs', 'Var', (129, 133))
101581	29375902	Therapeutic indications include: removal of BIRADS 3 and 4a lesions (low risk of malignancy, e.g.	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('malignancy', 'Disease', (81, 91))	('BIRADS', 'Var', (44, 50))
101594	29375902	As ALH, LCIS is not a pre-cancerous lesion and increases the risk of invasive ductal/lobular carcinoma in both breasts.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('LCIS', 'Var', (8, 12))	('lobular carcinoma', 'Disease', 'MESH:D018275', (85, 102))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (85, 102))	('lobular carcinoma', 'Disease', (85, 102))	('ALH', 'Chemical', '-', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('LCIS', 'Phenotype', 'HP:0030076', (8, 12))	('cancerous lesion', 'Disease', 'MESH:D009062', (26, 42))	('cancerous lesion', 'Phenotype', 'HP:0002664', (26, 42))	('cancerous lesion', 'Disease', (26, 42))
101661	28506312	Both direct and indirect correlations between expression of IL-6 and upregulation of proteases involved in ECM degradation (e.g., cathepsin B, MMPs, and urokinase plasminogen activator [uPA]) and invasion have been reported.	('uPA', 'Gene', (186, 189))	('expression', 'Var', (46, 56))	('upregulation', 'PosReg', (69, 81))	('proteases', 'Enzyme', (85, 94))	('MMPs', 'Gene', (143, 147))	('cathepsin B', 'Gene', '1508', (130, 141))	('uPA', 'Gene', '5328', (186, 189))	('IL-6', 'Gene', (60, 64))	('urokinase plasminogen activator', 'Gene', (153, 184))	('invasion', 'CPA', (196, 204))	('IL-6', 'Gene', '3569', (60, 64))	('MMPs', 'Gene', '4313;4318;4322;4323', (143, 147))	('cathepsin B', 'Gene', (130, 141))	('urokinase plasminogen activator', 'Gene', '5328', (153, 184))
101796	28506312	Inhibition of uPA and its interactions with uPAR reduces tumor growth and invasion.	('interactions', 'Interaction', (26, 38))	('uPAR', 'Gene', (44, 48))	('reduces', 'NegReg', (49, 56))	('uPA', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('uPA', 'Gene', '5328', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('uPAR', 'Gene', '5329', (44, 48))	('Inhibition', 'Var', (0, 10))	('uPA', 'Gene', (14, 17))	('tumor', 'Disease', (57, 62))	('uPA', 'Gene', '5328', (14, 17))
101808	28506312	In the presence of neutralizing IL-6 antibodies, degradation of DQ-collagen IV was reduced in DCIS-CAF cocultures (Fig.	('antibodies', 'Var', (37, 47))	('IL-6', 'Gene', (32, 36))	('degradation of DQ-collagen IV', 'MPA', (49, 78))	('reduced', 'NegReg', (83, 90))	('CAF', 'Gene', (99, 102))	('IL-6', 'Gene', '3569', (32, 36))	('CAF', 'Gene', '8850', (99, 102))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))
101812	28506312	Furthermore, blocking IL-6 reduced invasive outgrowths from the DCIS-CAF structures (Fig.	('reduced', 'NegReg', (27, 34))	('blocking', 'Var', (13, 21))	('IL-6', 'Gene', (22, 26))	('IL-6', 'Gene', '3569', (22, 26))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('CAF', 'Gene', (69, 72))	('CAF', 'Gene', '8850', (69, 72))	('invasive outgrowths from the', 'CPA', (35, 63))
101832	28506312	We localized uPAR to both tumor and stromal cells in DCIS tissue and demonstrated that blocking uPAR in DCIS cells decreased DQ-collagen IV degradation in vitro.	('uPAR', 'Gene', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('uPAR', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('decreased', 'NegReg', (115, 124))	('blocking', 'Var', (87, 95))	('uPAR', 'Gene', '5329', (13, 17))	('tumor', 'Disease', (26, 31))	('DQ-collagen IV degradation', 'MPA', (125, 151))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))	('DCIS', 'Gene', (104, 108))	('uPAR', 'Gene', '5329', (96, 100))
101840	28506312	Indeed, changes in DCIS-associated MEPs have been shown to result in increased expression of proangiogenic and invasive genes and ECM-degrading proteases (e.g., MMP-2; MMP-14; and cathepsins F, K, and L).	('proangiogenic', 'Gene', (93, 106))	('changes', 'Var', (8, 15))	('MMP-2', 'Gene', (161, 166))	('increased', 'PosReg', (69, 78))	('proteases', 'Enzyme', (144, 153))	('expression', 'MPA', (79, 89))	('MEP', 'Gene', '1514', (35, 38))	('MMP-14', 'Gene', (168, 174))	('cathepsins F', 'Enzyme', (180, 192))	('MMP-2', 'Gene', '4313', (161, 166))	('MEP', 'Gene', (35, 38))	('MMP-14', 'Gene', '4323', (168, 174))	('invasive genes', 'Gene', (111, 125))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))
101841	28506312	Moreover, disruption of signaling pathways that are essential to MEP differentiation and mediated by transforming growth factor beta, Hedgehog, cell adhesion, and p63 also results in loss of MEPs and accelerated progression of DCIS to invasive carcinoma.	('MEP', 'Gene', (191, 194))	('MEP', 'Gene', '1514', (65, 68))	('transforming growth factor beta', 'Gene', (101, 132))	('loss', 'NegReg', (183, 187))	('MEP', 'Gene', '1514', (191, 194))	('disruption', 'Var', (10, 20))	('invasive carcinoma', 'Disease', 'MESH:D009361', (235, 253))	('DCIS', 'Disease', (227, 231))	('signaling pathways', 'Pathway', (24, 42))	('transforming growth factor beta', 'Gene', '7040', (101, 132))	('MEP', 'Gene', (65, 68))	('p63', 'Gene', (163, 166))	('DCIS', 'Phenotype', 'HP:0030075', (227, 231))	('invasive carcinoma', 'Disease', (235, 253))	('p63', 'Gene', '8626', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('accelerated', 'PosReg', (200, 211))
101843	28506312	These changes in MEPs during tumorigenesis likely alter the paracrine interactions between MEPs and stromal cells such as CAFs to facilitate tumor invasion.	('MEP', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('paracrine interactions', 'MPA', (60, 82))	('alter', 'Reg', (50, 55))	('CAF', 'Gene', (122, 125))	('MEP', 'Gene', '1514', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (141, 146))	('MEP', 'Gene', (17, 20))	('changes', 'Var', (6, 13))	('tumor', 'Disease', (29, 34))	('MEP', 'Gene', '1514', (17, 20))	('CAF', 'Gene', '8850', (122, 125))	('facilitate', 'PosReg', (130, 140))
101845	28506312	In the present study, we show that in the presence of CAFs, orthotopic and renal capsule DCIS xenografts were larger and exhibited more collagen deposition, a stromal biomarker of breast cancer progression.	('CAF', 'Gene', (54, 57))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('CAF', 'Gene', '8850', (54, 57))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('presence', 'Var', (42, 50))	('collagen', 'MPA', (136, 144))	('more', 'PosReg', (131, 135))
101892	25593696	Patient-related risk factors include young age, a positive family history, BRCA 1/2 mutation, symptomatic detection race (slightly increased risk among African-American women) and radiation of the chest wall.	('mutation', 'Var', (84, 92))	('women', 'Species', '9606', (169, 174))	('BRCA 1/2', 'Gene', (75, 83))	('Patient', 'Species', '9606', (0, 7))	('BRCA 1/2', 'Gene', '672;675', (75, 83))
101893	25593696	Tumour-related factors include tumour-size, pattern of duct distribution (micropapillary), comedonecrosis/high grade, multifocality/multicentricity, positive surgical margins (less than 1 mm) and biological markers: ER-/PR-, Her-2/neu+, absence of Her-4, p53 mutation, High Ki-67 index, angiogenesis (Altintas et al., 2009; Wei et al., 2012; Collins et al., 2013; Kong et al., 2014).	('Her-4', 'Gene', '2066', (248, 253))	('Her-4', 'Gene', (248, 253))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('comedo', 'Phenotype', 'HP:0025249', (91, 97))	('absence', 'Var', (237, 244))	('angiogenesis', 'CPA', (287, 299))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('p53', 'Gene', '7157', (255, 258))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', (31, 37))	('p53', 'Gene', (255, 258))	('ER-/PR-, Her-2/neu', 'Gene', '2064', (216, 234))
101894	25593696	Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence (Kerlikowske et al., 2003).	('Women', 'Species', '9606', (0, 5))	('high-nuclear-grade', 'Var', (11, 29))	('invasive breast cancer', 'Disease', (142, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('invasive breast cancer', 'Disease', 'MESH:D001943', (142, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
101986	31056619	Furthermore, HER2 expression influences the motility-enhancing activity of tumor cells that are under the influence of the chemotactic factors secreted by epidermal keratinocytes.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('HER2', 'Gene', (13, 17))	('influences', 'Reg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HER2', 'Gene', '2064', (13, 17))	('expression', 'Var', (18, 28))	('tumor', 'Disease', (75, 80))
102037	31056619	Lester et al reported high nuclear grade in 93% of MPD-associated carcinomas, while Kothari et al reported high grade in all evaluated cases of IDC.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinomas', 'Disease', (66, 76))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('high', 'Var', (22, 26))	('IDC', 'Gene', '4000', (144, 147))	('IDC', 'Gene', (144, 147))	('MPD', 'Disease', (51, 54))	('MPD', 'Disease', 'None', (51, 54))
102111	25944033	HT was significantly more prescribed in case of incomplete excision (16% versus 4.5%, p = 0.041) or LIN 3 or 2 versus 1 (43%, 15% and 4% respectively, p = 0.03).	('HT', 'Disease', 'MESH:D006973', (0, 2))	('incomplete excision', 'Var', (48, 67))	('LIN', 'Var', (100, 103))
102138	25944033	This risk increases in case of associated lesions (AH) and especially when first-degree family history of BC was present, almost reaching the risk (8-10 fold) of women with BRCA 1-2 mutations.	('increases', 'PosReg', (10, 19))	('AH', 'Disease', 'MESH:D007039', (51, 53))	('BRCA 1', 'Gene', (173, 179))	('BRCA 1', 'Gene', '672', (173, 179))	('women', 'Species', '9606', (162, 167))	('mutations', 'Var', (182, 191))
102162	22270930	Ecd expression was positively associated with HER2/neu (P = 0.002) overexpression, a known marker of poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('HER2/neu', 'Gene', '2064', (46, 54))	('breast cancer', 'Disease', (119, 132))	('overexpression', 'MPA', (67, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('HER2/neu', 'Gene', (46, 54))	('Ecd expression', 'Var', (0, 14))
102169	22270930	Concurrently, ER +/PR + tumors have a more favorable prognosis while HER2/neu overexpression signifies a markedly worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('HER2/neu', 'Gene', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('ER +/PR +', 'Var', (14, 23))	('overexpression', 'PosReg', (78, 92))	('HER2/neu', 'Gene', '2064', (69, 77))
102174	22270930	Consistent with this basic paradigm, genetic alterations of cell-cycle machinery components are frequent in cancer.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('genetic alterations', 'Var', (37, 56))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
102178	22270930	Genetic deletion of Ecd in mice is embryonic lethal, while conditional deletion of Ecd in MEFs leads to retardation of the separation of Rb from E2F, delay/reduction in E2F-dependent gene expression and block in cell cycle progression.	('delay/reduction', 'NegReg', (150, 165))	('expression', 'MPA', (188, 198))	('block', 'NegReg', (203, 208))	('mice', 'Species', '10090', (27, 31))	('Rb', 'Phenotype', 'HP:0009919', (137, 139))	('Rb', 'Gene', '5925', (137, 139))	('deletion', 'Var', (71, 79))	('cell cycle progression', 'CPA', (212, 234))	('E2F-dependent gene', 'Gene', (169, 187))	('separation', 'MPA', (123, 133))	('retardation', 'Disease', (104, 115))	('Ecd', 'Gene', (83, 86))	('retardation', 'Disease', 'MESH:D008607', (104, 115))	('MEFs', 'Gene', (90, 94))
102223	22270930	Patients with high Ecd expression exhibited a statistically significant reduction term for BCSS (120 months, P = 0.008) as compared to patients with no to moderate Ecd expression (Fig.	('reduction', 'NegReg', (72, 81))	('patients', 'Species', '9606', (135, 143))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('BCSS', 'Disease', (91, 95))
102228	22270930	Furthermore, HER2/neu + patients with high levels of Ecd showed significantly reduced DFS (250 months, P = 0.003) as compared to HER2/neu + patients with no to moderate Ecd expression (Fig.	('high levels', 'Var', (38, 49))	('HER2/neu', 'Gene', '2064', (129, 137))	('HER2/neu', 'Gene', '2064', (13, 21))	('patients', 'Species', '9606', (24, 32))	('DFS', 'MPA', (86, 89))	('HER2/neu', 'Gene', (129, 137))	('patients', 'Species', '9606', (140, 148))	('reduced', 'NegReg', (78, 85))	('HER2/neu', 'Gene', (13, 21))
102235	22270930	Ecd plays an essential role in facilitating the removal of Rb-family of tumor suppressor proteins from E2F transcription factors such that lack of Ecd leads to prolonged Rb-E2F association and inhibition of cell cycle progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Rb', 'Phenotype', 'HP:0009919', (170, 172))	('Rb', 'Gene', '5925', (170, 172))	('tumor', 'Disease', (72, 77))	('inhibition', 'NegReg', (193, 203))	('Rb', 'Phenotype', 'HP:0009919', (59, 61))	('cell cycle progression', 'CPA', (207, 229))	('prolonged', 'PosReg', (160, 169))	('association', 'Interaction', (177, 188))	('Rb', 'Gene', '5925', (59, 61))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('lack', 'Var', (139, 143))
102246	22270930	Kaplan-Meier survival analysis showed that patients with high Ecd expression have a significantly reduced BCSS (120 months, P = 0.008).	('patients', 'Species', '9606', (43, 51))	('reduced', 'NegReg', (98, 105))	('high', 'Var', (57, 61))
102259	32333294	The supplemental value of mammographic screening over breast MRI alone in BRCA2 mutation carriers BRCA2 mutation carriers are offered annual breast screening with MRI and mammography.	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', (98, 103))	('BRCA2', 'Gene', '675', (74, 79))	('mutation', 'Var', (104, 112))	('BRCA2', 'Gene', '675', (98, 103))	('mutation', 'Var', (80, 88))
102260	32333294	In this multicenter study, proven BRCA2 mutation carriers, who developed breast cancer during screening using both digital mammography and state-of-art breast MRI, were identified.	('BRCA2', 'Gene', '675', (34, 39))	('mutation', 'Var', (40, 48))	('developed', 'PosReg', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('BRCA2', 'Gene', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
102262	32333294	From January 2003 till March 2019, 62 invasive breast cancers and 23 ductal carcinomas in situ were diagnosed in 83 BRCA2 mutation carriers under surveillance.	('ductal carcinomas', 'Disease', 'MESH:D044584', (69, 86))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('ductal carcinomas', 'Disease', (69, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('mutation', 'Var', (122, 130))	('BRCA2', 'Gene', (116, 121))	('breast cancers', 'Phenotype', 'HP:0003002', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('invasive breast cancers', 'Disease', (38, 61))	('ductal carcinomas in situ', 'Phenotype', 'HP:0030075', (69, 94))	('BRCA2', 'Gene', '675', (116, 121))	('invasive breast cancers', 'Disease', 'MESH:D001943', (38, 61))
102267	32333294	In BRCA2 mutation carriers younger than 40 years, the benefit of mammographic screening over MRI was very small.	('mutation', 'Var', (9, 17))	('BRCA2', 'Gene', (3, 8))	('BRCA2', 'Gene', '675', (3, 8))
102268	32333294	Hence, we propose to postpone mammographic screening in BRCA2 mutation carriers to at least age 40.	('mutation', 'Var', (62, 70))	('BRCA2', 'Gene', (56, 61))	('BRCA2', 'Gene', '675', (56, 61))
102269	32333294	Women with a BRCA1 or BRCA2 mutation have a strongly elevated risk of developing breast cancer.	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Disease', (81, 94))	('BRCA1', 'Gene', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('BRCA2', 'Gene', (22, 27))	('mutation', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA2', 'Gene', '675', (22, 27))	('BRCA1', 'Gene', '672', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
102273	32333294	Recent studies demonstrate that, especially in BRCA1 mutation carriers under the age of 40, there is little benefit of mammographic screening when MRI screening is also performed.	('BRCA1', 'Gene', '672', (47, 52))	('BRCA1', 'Gene', (47, 52))	('mutation', 'Var', (53, 61))
102274	32333294	Furthermore, the exposure to low-dose ionizing radiation as from annual mammographic screening might be more harmful in BRCA mutation carriers.	('BRCA', 'Gene', (120, 124))	('BRCA', 'Gene', '672', (120, 124))	('low-dose ionizing radiation', 'Phenotype', 'HP:0011133', (29, 56))	('mutation', 'Var', (125, 133))
102276	32333294	In BRCA gene mutation carriers, the impaired function of this pathway may lead to a higher risk of radiation-induced breast cancer.	('BRCA', 'Gene', (3, 7))	('lead to', 'Reg', (74, 81))	('BRCA', 'Gene', '672', (3, 7))	('mutation', 'Var', (13, 21))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('impaired function', 'NegReg', (36, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))
102277	32333294	As a consequence, in 2018, the Dutch screening guidelines were modified for BRCA1 mutation carriers, nowadays starting with supplemental biennial mammography only from the age of 40.	('mutation', 'Var', (82, 90))	('BRCA1', 'Gene', (76, 81))	('BRCA1', 'Gene', '672', (76, 81))
102279	32333294	However, characteristics of cancers detected in BRCA2 carriers differ significantly from those detected in BRCA1 carriers.	('cancers', 'Disease', (28, 35))	('BRCA1', 'Gene', '672', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('BRCA2', 'Gene', '675', (48, 53))	('carriers', 'Var', (54, 62))	('BRCA1', 'Gene', (107, 112))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('BRCA2', 'Gene', (48, 53))
102280	32333294	While BRCA1 carriers predominantly present with high-grade hormone receptor-negative invasive breast cancer, BRCA2 mutation carriers have more luminal breast cancers and a higher proportion of DCIS, sometimes only detected as mammographic calcifications.	('breast cancers', 'Phenotype', 'HP:0003002', (151, 165))	('DCIS', 'Disease', (193, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('mutation', 'Var', (115, 123))	('invasive breast cancer', 'Disease', (85, 107))	('hormone receptor', 'Gene', '3164', (59, 75))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('invasive breast cancer', 'Disease', 'MESH:D001943', (85, 107))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('BRCA2', 'Gene', (109, 114))	('BRCA1', 'Gene', '672', (6, 11))	('luminal', 'Chemical', 'MESH:D010634', (143, 150))	('hormone receptor', 'Gene', (59, 75))	('BRCA1', 'Gene', (6, 11))	('breast cancers', 'Disease', 'MESH:D001943', (151, 165))	('breast cancers', 'Disease', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA2', 'Gene', '675', (109, 114))
102281	32333294	Consequently, in BRCA2 carriers, supplemental annual mammography from the age of 30 is still regarded as the standard of care.	('carriers', 'Var', (23, 31))	('BRCA2', 'Gene', (17, 22))	('BRCA2', 'Gene', '675', (17, 22))
102282	32333294	The aim of this study was to assess whether this bi-modal screening protocol (i.e., with digital mammography from age 30 and state-of-art MRI) is still appropriate in BRCA2 mutation carriers.	('BRCA2', 'Gene', '675', (167, 172))	('BRCA2', 'Gene', (167, 172))	('mutation', 'Var', (173, 181))
102283	32333294	For this, we evaluated the mode of detection in BRCA2 mutation carriers who developed breast cancer while under surveillance.	('mutation', 'Var', (54, 62))	('BRCA2', 'Gene', '675', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('BRCA2', 'Gene', (48, 53))
102284	32333294	In this retrospective study, we included women with a proven BRCA2 mutation who developed breast cancer during surveillance with digital mammography and breast MRI in one of the five participating Dutch university hospitals (Erasmus University Medical Center Rotterdam, Radboud University Medical Center Nijmegen, Maastricht University Medical Center, University Medical Center Leiden, and University Medical Center Groningen) or in the Netherlands Cancer Institute in Amsterdam.	('Cancer', 'Disease', (449, 455))	('mutation', 'Var', (67, 75))	('Cancer', 'Disease', 'MESH:D009369', (449, 455))	('Cancer', 'Phenotype', 'HP:0002664', (449, 455))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('BRCA2', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('developed', 'Reg', (80, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('BRCA2', 'Gene', '675', (61, 66))	('women', 'Species', '9606', (41, 46))
102292	32333294	Firstly, previous research in women at increased risk showed a very low added value of mammography in the screening of women under 40 years of age, albeit series were too small to provide specific information for women with BRCA2 mutations.	('BRCA2', 'Gene', '675', (224, 229))	('women', 'Species', '9606', (30, 35))	('women', 'Species', '9606', (213, 218))	('mutations', 'Var', (230, 239))	('women', 'Species', '9606', (119, 124))	('BRCA2', 'Gene', (224, 229))
102294	32333294	According to the Dutch guidelines, women with a proven BRCA2 mutation were offered annual breast MRI screening from age 25 till age 60 and annual mammographic screening starting at age 30.	('BRCA2', 'Gene', (55, 60))	('women', 'Species', '9606', (35, 40))	('BRCA2', 'Gene', '675', (55, 60))	('mutation', 'Var', (61, 69))	('breast MRI', 'Disease', (90, 100))
102306	32333294	From January 2003 to March 2019, 83 BRCA2 mutation carriers were diagnosed with 85 breast cancers while under surveillance with both MRI and digital mammography.	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('BRCA2', 'Gene', (36, 41))	('mutation', 'Var', (42, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('diagnosed', 'Reg', (65, 74))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BRCA2', 'Gene', '675', (36, 41))
102324	32333294	In this multicenter study, the screening results in BRCA2 mutation carriers showed a high screening sensitivity of 95.2% as well as a high percentage of early-stage breast cancer (68.2%) and a very low fraction of interval cancers (4.7%).	('BRCA2', 'Gene', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('interval cancers', 'Disease', 'MESH:D009369', (214, 230))	('breast cancer', 'Disease', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('BRCA2', 'Gene', '675', (52, 57))	('mutation', 'Var', (58, 66))	('interval cancers', 'Disease', (214, 230))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))
102325	32333294	The most important finding of the current study is that in the 17 BRCA2 mutation carriers diagnosed with breast cancer before age 40, there was just one mammography-only lesion concerning a 6 mm DCIS grade 3 in a 38-year-old woman (5,9% (1/17)).	('BRCA2', 'Gene', (66, 71))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('BRCA2', 'Gene', '675', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('woman', 'Species', '9606', (225, 230))	('mutation', 'Var', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
102327	32333294	However, in BRCA2 mutation carriers, aged 50 and older mammographic screening did demonstrate a screening benefit in addition to MR screening.	('BRCA2', 'Gene', (12, 17))	('BRCA2', 'Gene', '675', (12, 17))	('mutation', 'Var', (18, 26))
102332	32333294	Moreover, it is known that pre-invasive lesions, such as DCIS, are common in BRCA-associated breast cancers and that in high-risk women with DCIS, the prevalence of a BRCA1/2 mutation is high.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('BRCA1/2', 'Gene', '672;675', (167, 174))	('mutation', 'Var', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('women', 'Species', '9606', (130, 135))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('breast cancers', 'Disease', 'MESH:D001943', (93, 107))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('breast cancers', 'Disease', (93, 107))	('BRCA1/2', 'Gene', (167, 174))	('DCIS', 'Disease', (57, 61))	('BRCA', 'Gene', '672', (77, 81))	('BRCA', 'Gene', '672', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('BRCA', 'Gene', (77, 81))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('BRCA', 'Gene', (167, 171))
102337	32333294	The prospective cohort study of the High Risk Ontario Breast Screening Program included, from July 2011 to December 2016, 8782 high-risk women, of which 1885 were BRCA1/2 mutation carriers.	('women', 'Species', '9606', (137, 142))	('BRCA1/2', 'Gene', (163, 170))	('BRCA1/2', 'Gene', '672;675', (163, 170))	('mutation', 'Var', (171, 179))
102339	32333294	Other studies presenting screening results in proven BRCA2 mutation carriers had small numbers, varying between 2 and 25 breast cancer cases.	('BRCA2', 'Gene', (53, 58))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutation', 'Var', (59, 67))	('breast cancer', 'Disease', (121, 134))	('BRCA2', 'Gene', '675', (53, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
102351	32333294	reported a specificity of 84.8% for first-round MRI examinations in BRCA2 carriers, which steeply increases to 97.4% in follow-up rounds, but is still somewhat lower than for mammography (94.4% and 98.8%, respectively).	('BRCA2', 'Gene', (68, 73))	('BRCA2', 'Gene', '675', (68, 73))	('carriers', 'Var', (74, 82))
102352	32333294	reported, for BRCA2 mutation carriers, a specificity of 85.1% in first-round examinations and 92.9% in follow-up examinations using multimodality screening.	('mutation', 'Var', (20, 28))	('BRCA2', 'Gene', (14, 19))	('BRCA2', 'Gene', '675', (14, 19))
102353	32333294	Further large prospective screening cohorts studies, like the High Risk Ontario Breast Screening Program, are necessary to define the optimal screening protocol for BRCA1 and BRCA2 mutation carriers.	('BRCA1', 'Gene', (165, 170))	('mutation', 'Var', (181, 189))	('BRCA2', 'Gene', (175, 180))	('BRCA1', 'Gene', '672', (165, 170))	('BRCA2', 'Gene', '675', (175, 180))
102354	32333294	Mammographic screening appears to have minimal benefit over MRI screening in BRCA2 mutation carriers younger than 40 years and may not overcome the disadvantages of increased radiation risks.	('mutation', 'Var', (83, 91))	('BRCA2', 'Gene', (77, 82))	('BRCA2', 'Gene', '675', (77, 82))
102355	32333294	In BRCA2 mutation carriers of 50 years and older, mammographic screening contributed significantly in the detection of early-stage breast cancer.	('mutation', 'Var', (9, 17))	('BRCA2', 'Gene', '675', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('BRCA2', 'Gene', (3, 8))
102356	32333294	We propose to omit mammographic screening in young BRCA2 mutation carriers and suggest to postpone mammographic screening in BRCA2 mutation carriers to at least age 40, or even to age 50.	('mutation', 'Var', (57, 65))	('BRCA2', 'Gene', (125, 130))	('BRCA2', 'Gene', (51, 56))	('BRCA2', 'Gene', '675', (125, 130))	('BRCA2', 'Gene', '675', (51, 56))
102361	20030870	Detecting DCIS should theoretically reduce the subsequent incidence of invasive cancer, and in terms of screening it should have the same effect as treating cervical intra-epithelial neoplasia of the cervix.	('invasive cancer', 'Disease', (71, 86))	('reduce', 'NegReg', (36, 42))	('invasive cancer', 'Disease', 'MESH:D009362', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('intra-epithelial neoplasia', 'Disease', (166, 192))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (172, 192))	('neoplasia', 'Phenotype', 'HP:0002664', (183, 192))	('DCIS', 'Var', (10, 14))	('Detecting', 'Var', (0, 9))	('intra-epithelial neoplasia', 'Disease', 'MESH:D009369', (166, 192))	('cervical intra-epithelial neoplasia', 'Phenotype', 'HP:0032242', (157, 192))
102364	20030870	Retrospective studies have found that, after excision (which often did not remove all of the DCIS), low-grade DCIS progresses to invasive cancer in only one-third of all women by 20 years.	('women', 'Species', '9606', (170, 175))	('invasive cancer', 'Disease', (129, 144))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('invasive cancer', 'Disease', 'MESH:D009362', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('low-grade', 'Var', (100, 109))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))
102398	31198475	Recent reviews have emphasized that epigenetic abnormalities might play an influential role in the earliest steps of cancer initiation and the progression of malignancies, especially because the methylation of a normal allele can serve as a "second hit" that leads to gene inactivation when paired with mutations in the opposite allele.	('gene', 'MPA', (268, 272))	('cancer initiation', 'Disease', (117, 134))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('methylation', 'Var', (195, 206))	('malignancies', 'Disease', (158, 170))	('epigenetic abnormalities', 'Disease', (36, 60))	('cancer initiation', 'Disease', 'MESH:D009369', (117, 134))	('epigenetic abnormalities', 'Disease', 'MESH:D000014', (36, 60))
102400	31198475	Alterations in the methylation status of DNA are among the most frequent molecular changes that are associated with human cancers.	('DNA', 'Gene', (41, 44))	('human cancers', 'Disease', 'MESH:D009369', (116, 129))	('Alterations', 'Var', (0, 11))	('methylation status', 'MPA', (19, 37))	('associated', 'Reg', (100, 110))	('human cancers', 'Disease', (116, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
102407	31198475	These genes have previously been shown to undergo cancer-specific methylation in breast tissues in the TCGA database and other reports of clinical or fundamental studies.	('methylation', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
102427	31198475	According to the results of BSP sequencing, we selected the probable promoter CpG islands that contained the methylated variant sites to design probes for each gene (Supplemental Figure 1).	('BSP', 'Gene', (28, 31))	('BSP', 'Gene', '3381', (28, 31))	('variant', 'Var', (120, 127))
102440	31198475	In conclusion, a total of nine methylated genes, including SFN, HOXA11, P16, RARbeta, PCDHGB7, hMLH1, WNT5a, HOXD13, and RASSF1a, were methylated with significantly higher frequency in BC tissues than in matched normal breast tissues from 302 BC patients.	('hMLH1', 'Gene', (95, 100))	('hMLH1', 'Gene', '4292', (95, 100))	('patients', 'Species', '9606', (246, 254))	('BC', 'Phenotype', 'HP:0003002', (243, 245))	('SFN', 'Gene', (59, 62))	('methylated', 'Var', (135, 145))	('RARbeta', 'Gene', '5915', (77, 84))	('HOXD13', 'Gene', '3239', (109, 115))	('RASSF1a', 'Gene', (121, 128))	('HOXA11', 'Gene', (64, 70))	('P16', 'Gene', '1029', (72, 75))	('RARbeta', 'Gene', (77, 84))	('PCDHGB7', 'Gene', '56099', (86, 93))	('methylated genes', 'Gene', (31, 47))	('BC', 'Phenotype', 'HP:0003002', (185, 187))	('P16', 'Gene', (72, 75))	('HOXA11', 'Gene', '3207', (64, 70))	('WNT5a', 'Gene', (102, 107))	('PCDHGB7', 'Gene', (86, 93))	('HOXD13', 'Gene', (109, 115))	('RASSF1a', 'Gene', '11186', (121, 128))	('higher frequency', 'PosReg', (165, 181))	('WNT5a', 'Gene', '7474', (102, 107))	('SFN', 'Gene', '25996', (59, 62))
102441	31198475	Among all of these markers, PCDHGB7 was most often methylated (78.81%), whereas the lowest methylation frequency was observed for WNT5a (28.48%).	('PCDHGB7', 'Gene', '56099', (28, 35))	('methylated', 'Var', (51, 61))	('WNT5a', 'Gene', '7474', (130, 135))	('WNT5a', 'Gene', (130, 135))	('PCDHGB7', 'Gene', (28, 35))
102442	31198475	The frequency of HOXD13 and hMLH1 methylation significantly increased with the progression of the disease from in situ to invasive cancer (P < 0.001 and P < 0.05, Figure 1), but there was no significant difference between IDC and IDC-L.	('HOXD13', 'Gene', (17, 23))	('methylation', 'Var', (34, 45))	('hMLH1', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('situ to invasive cancer', 'Disease', 'MESH:D002278', (114, 137))	('IDC', 'Disease', (222, 225))	('hMLH1', 'Gene', '4292', (28, 33))	('situ to invasive cancer', 'Disease', (114, 137))	('HOXD13', 'Gene', '3239', (17, 23))	('increased', 'PosReg', (60, 69))
102444	31198475	Meanwhile, the frequency of HOXA11 or WNT5a methylation was low in serum, even though the frequency of methylation of these markers in the matched BC tissues was high.	('WNT5a', 'Gene', (38, 43))	('HOXA11', 'Gene', (28, 34))	('methylation', 'Var', (44, 55))	('BC', 'Phenotype', 'HP:0003002', (147, 149))	('WNT5a', 'Gene', '7474', (38, 43))	('HOXA11', 'Gene', '3207', (28, 34))
102472	31198475	Many studies have reported that the frequency of methylation should significantly increase in parallel with the progression of cancer and that methylation could therefore potentially be used as a predictor during the determination of a prognosis in BC.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BC', 'Phenotype', 'HP:0003002', (249, 251))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('increase', 'PosReg', (82, 90))	('methylation', 'Var', (49, 60))	('cancer', 'Disease', (127, 133))
102480	31198475	Her-2 and triple-negative BC samples displayed low methylation frequencies in general, and this result may be compatible with results indicating they have unstable and aberrant genomes, which may result from reduced transposon silencing.	('methylation frequencies', 'MPA', (51, 74))	('BC', 'Phenotype', 'HP:0003002', (26, 28))	('low', 'NegReg', (47, 50))	('reduced', 'NegReg', (208, 215))	('Her-2', 'Gene', '2064', (0, 5))	('Her-2', 'Gene', (0, 5))	('transposon silencing', 'Var', (216, 236))
102485	26052481	Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer.	('Breast Cancer', 'Disease', (36, 49))	('Breast Cancer', 'Disease', 'MESH:D001943', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('miRNAs', 'Protein', (25, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('Epigenetic Regulation', 'Var', (0, 21))	('Breast Cancer', 'Phenotype', 'HP:0003002', (36, 49))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
102487	26052481	Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression.	('epigenetically activating', 'Var', (47, 72))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
102491	26052481	Breast cancer is a heterogeneous disease, which occurs via multiple genetic and epigenetic alterations in gene expression.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('epigenetic alterations', 'Var', (80, 102))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Breast cancer', 'Disease', (0, 13))
102514	26052481	Moreover, it has also been found that numerous miRNAs are subject to gain or loss of expression via dysregulation of epigenetic programs.	('expression', 'MPA', (85, 95))	('epigenetic', 'CPA', (117, 127))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('gain', 'PosReg', (69, 73))	('dysregulation', 'Var', (100, 113))	('loss', 'NegReg', (77, 81))
102522	26052481	40 miRNA were found to be differentially expressed within basal-like and normal-like/claudin low breast cancer cell lines while 39 miRNAs were associated with the ERBB2 overexpression and 24 miRNAs were associated with E-cadherin mutations within the luminal group.	('miR', 'Gene', (191, 194))	('associated', 'Reg', (143, 153))	('associated', 'Reg', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('miR', 'Gene', (3, 6))	('miR', 'Gene', '220972', (3, 6))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('E-cadherin', 'Gene', (219, 229))	('mutations', 'Var', (230, 239))	('E-cadherin', 'Gene', '999', (219, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('miR', 'Gene', '220972', (191, 194))	('miR', 'Gene', '220972', (131, 134))	('ERBB2', 'Gene', (163, 168))	('miR', 'Gene', (131, 134))	('ERBB2', 'Gene', '2064', (163, 168))	('overexpression', 'PosReg', (169, 183))
102525	26052481	Finally, 12 miRNAs were associated with DNA copy number variation of the respective locus.	('DNA copy number variation', 'Var', (40, 65))	('associated', 'Reg', (24, 34))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
102533	26052481	Epigenetic alterations in breast cancer include global DNA hypomethylation and localized hypermethylation in CpG Islands of tumor suppressor genes in addition to altered histone acetylation and methylation.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('DNA hypomethylation', 'Var', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('altered', 'Reg', (162, 169))	('histone acetylation', 'MPA', (170, 189))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('methylation', 'MPA', (194, 205))	('hypermethylation', 'Var', (89, 105))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
102538	26052481	Numerous miRNAs are dysregulated via epigenetic mechanisms in breast cancer i.e.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('epigenetic', 'Var', (37, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
102542	26052481	As cancer is akin to loss of differentiation, it is unsurprising that this involves altered epigenetic machinery and as such, dysregulated miRNA expression.	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('altered', 'Reg', (84, 91))	('epigenetic machinery', 'MPA', (92, 112))	('dysregulated', 'Var', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
102543	26052481	In addition, miRNAs have been found to directly regulate epigenetic enzymes, and dysregulation of miRNA expression may alter the epigenetic landscape.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('dysregulation', 'Var', (81, 94))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('alter', 'Reg', (119, 124))	('epigenetic enzymes', 'Enzyme', (57, 75))	('regulate', 'Reg', (48, 56))	('epigenetic landscape', 'MPA', (129, 149))
102548	26052481	As miR-200 family members are frequently downregulated in advanced breast cancer via epigenetic mechanisms, this creates a negative feedback loop promoting a stem cell-like state in cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('promoting', 'PosReg', (146, 155))	('downregulated', 'NegReg', (41, 54))	('miR', 'Gene', (3, 6))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('miR', 'Gene', '220972', (3, 6))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('negative feedback loop', 'MPA', (123, 145))	('cancer', 'Disease', (182, 188))	('epigenetic', 'Var', (85, 95))	('stem cell-like state in', 'CPA', (158, 181))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
102552	26052481	Since epigenetic mechanisms frequently underlie miRNA dysregulation in breast cancer this provides a potential therapeutic window for restoring miRNA expression.	('breast cancer', 'Disease', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('underlie', 'Reg', (39, 47))	('miR', 'Gene', '220972', (144, 147))	('miR', 'Gene', (144, 147))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('epigenetic mechanisms', 'Var', (6, 27))
102554	26052481	Furthermore, there is ongoing drug development for therapeutics to target polycomb group including EZH2 inhibitors, which would potentially target cancer stem cells.	('EZH2', 'Gene', '2146', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('EZH2', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('inhibitors', 'Var', (104, 114))
102555	26052481	Epigenetic therapy impacts global heterochromatin resulting in very nonspecific targeting, but one mechanism of anti-tumor activity is through activation of silenced tumor suppressor miRNAs.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('global heterochromatin', 'MPA', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Epigenetic therapy', 'Var', (0, 18))	('tumor', 'Disease', (117, 122))	('impacts', 'Reg', (19, 26))	('tumor', 'Disease', (166, 171))	('nonspecific targeting', 'MPA', (68, 89))	('activation', 'PosReg', (143, 153))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
102556	26052481	We have found that treatment with epigenetic therapy can reactivate multiple miRNAs in early stage breast cancer, specifically silenced miR-140, which can target DCIS stem cells and inhibit tumor growth.	('miR', 'Gene', (77, 80))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('silenced', 'Var', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('miR', 'Gene', '220972', (136, 139))	('miR-140', 'Gene', '406932', (136, 143))	('miR', 'Gene', (136, 139))	('tumor', 'Disease', (190, 195))	('inhibit', 'NegReg', (182, 189))	('epigenetic therapy', 'Var', (34, 52))	('miR-140', 'Gene', (136, 143))	('target', 'Reg', (155, 161))	('miR', 'Gene', '220972', (77, 80))
102561	26052481	For instance, lower levels of adiponectin and higher levels of leptin that are involved in insulin resistance have also been associated with abnormally regulated miRNAs in carcinogenesis such as let-7, miR-27, and miR-143, reporter tumor suppressor miRNAs.	('lower levels of adiponectin', 'Phenotype', 'HP:0030685', (14, 41))	('miR', 'Gene', (214, 217))	('miR', 'Gene', '220972', (202, 205))	('adiponectin', 'Gene', '9370', (30, 41))	('insulin', 'Disease', (91, 98))	('miR-27', 'Gene', '407018', (202, 208))	('carcinogenesis', 'Disease', (172, 186))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', '220972', (249, 252))	('higher', 'PosReg', (46, 52))	('miR', 'Gene', (202, 205))	('insulin resistance', 'Phenotype', 'HP:0000855', (91, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('tumor', 'Disease', (232, 237))	('miR', 'Gene', (162, 165))	('miR', 'Gene', (249, 252))	('insulin', 'Disease', 'MESH:D007333', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('miR-27', 'Gene', (202, 208))	('adiponectin', 'Gene', (30, 41))	('leptin', 'MPA', (63, 69))	('miR-143', 'Gene', '406935', (214, 221))	('miR', 'Gene', '220972', (214, 217))	('lower', 'NegReg', (14, 19))	('miR-143', 'Gene', (214, 221))	('let-7', 'Var', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))
102587	26052481	48 hours post-treatment with 10 microg/ml polyphenon-60 altered the expression of 23 miRNAs, including miR-21 and miR-27, both of which were downregulated.	('miR-27', 'Gene', '407018', (114, 120))	('polyphenon-60', 'Var', (42, 55))	('miR-27', 'Gene', (114, 120))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('expression', 'MPA', (68, 78))	('miR-21', 'Gene', (103, 109))	('altered', 'Reg', (56, 63))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (114, 117))	('downregulated', 'NegReg', (141, 154))	('miR', 'Gene', (103, 106))	('polyphenon', 'Chemical', '-', (42, 52))	('miR-21', 'Gene', '406991', (103, 109))
102593	26052481	MiR-221 and/or miR-222 transfection made ER-positive (luminal) MCF7 and T47D breast cancer cells resistant to tamoxifen.	('MCF7', 'CellLine', 'CVCL:0031', (63, 67))	('breast cancer', 'Disease', (77, 90))	('transfection', 'Var', (23, 35))	('ER', 'Gene', '2099', (41, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('MiR-221', 'Gene', '407006', (0, 7))	('miR-222', 'Gene', (15, 22))	('T47D', 'CellLine', 'CVCL:0553', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('miR-222', 'Gene', '407007', (15, 22))	('MiR-221', 'Gene', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('resistant to tamoxifen', 'MPA', (97, 119))
102594	26052481	On the other hand, silencing miR-221 and/or miR-222 sensitized ER-negative (basal) MDA-MB-468 cells to tamoxifen-induced cell growth arrest and apoptosis.	('miR-221', 'Gene', '407006', (29, 36))	('miR-222', 'Gene', (44, 51))	('silencing', 'Var', (19, 28))	('ER', 'Gene', '2099', (63, 65))	('sensitized', 'Reg', (52, 62))	('miR-221', 'Gene', (29, 36))	('apoptosis', 'CPA', (144, 153))	('tamoxifen', 'Chemical', 'MESH:D013629', (103, 112))	('tamoxifen-induced', 'CPA', (103, 120))	('arrest', 'Disease', 'MESH:D006323', (133, 139))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (83, 93))	('growth arrest', 'Phenotype', 'HP:0001510', (126, 139))	('miR-222', 'Gene', '407007', (44, 51))	('arrest', 'Disease', (133, 139))
102599	26052481	Another direct target of miR-200c is TUBB3, which is also associated with resistance to microtubule-binding chemotherapeutic agents.	('TUBB3', 'Gene', (37, 42))	('TUBB3', 'Gene', '10381', (37, 42))	('miR-200c', 'Var', (25, 33))	('associated', 'Reg', (58, 68))
102600	26052481	miR-200c suppresses ZEB1 and TUBB3, reduces the invasive capacity of cancer cells by restoring E-cadherin expression and increases their chemosensitivity to microtubule-targeting agents.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('increases', 'PosReg', (121, 130))	('E-cadherin', 'Gene', (95, 105))	('chemosensitivity to microtubule-targeting agents', 'MPA', (137, 185))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (106, 116))	('E-cadherin', 'Gene', '999', (95, 105))	('TUBB3', 'Gene', (29, 34))	('TUBB3', 'Gene', '10381', (29, 34))	('reduces', 'NegReg', (36, 43))	('ZEB1', 'Gene', (20, 24))	('miR-200c', 'Var', (0, 8))	('restoring', 'PosReg', (85, 94))	('ZEB1', 'Gene', '6935', (20, 24))	('cancer', 'Disease', (69, 75))	('suppresses', 'NegReg', (9, 19))
102621	26052481	Among these, three clusters including miR-200c-141, miR-200b-200a-429 and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells and embryonal carcinoma cells.	('embryonal carcinoma', 'Disease', (182, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('human', 'Species', '9606', (111, 116))	('human', 'Species', '9606', (131, 136))	('miR-183', 'Gene', '406959', (74, 81))	('miR-183', 'Gene', (74, 81))	('miR-200c-141', 'Var', (38, 50))	('miR-200b', 'Gene', '406984', (52, 60))	('murine', 'Species', '10090', (141, 147))	('downregulated', 'NegReg', (94, 107))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (182, 201))	('miR-200b', 'Gene', (52, 60))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (182, 201))
102623	26052481	Furthermore, miR-200c suppressed the clonogenicity of the BCSCs in vitro and the tumorigenicity of human BCSCs in vivo.	('suppressed', 'NegReg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('human', 'Species', '9606', (99, 104))	('miR-200c', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('clonogenicity', 'CPA', (37, 50))	('tumor', 'Disease', (81, 86))
102625	26052481	Our lab showed that epigenetic silencing of miR-200a expression was associated with the transformation of normal mammary epithelial cells through the overexpression of SIRT1.	('miR-200a', 'Gene', (44, 52))	('epigenetic silencing', 'Var', (20, 40))	('associated', 'Reg', (68, 78))	('SIRT1', 'Gene', '23411', (168, 173))	('overexpression', 'PosReg', (150, 164))	('SIRT1', 'Gene', (168, 173))	('miR-200a', 'Gene', '406983', (44, 52))
102636	26052481	Silencing H-RAS reduced the self-renewal capacity of BCSCs but had no effect on differentiation, whereas silencing the HMGA2 enhanced differentiation without having any effect on self-renewal.	('HMGA2', 'Gene', '8091', (119, 124))	('enhanced', 'PosReg', (125, 133))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (16, 23))	('HMGA2', 'Gene', (119, 124))	('differentiation', 'CPA', (134, 149))	('H-RAS', 'Gene', '3265', (10, 15))	('silencing', 'Var', (105, 114))	('self-renewal capacity of BCSCs', 'CPA', (28, 58))	('H-RAS', 'Gene', (10, 15))
102640	26052481	Similarly, silencing miR-30 in differentiated breast cancer cells increased their ability to self-renew.	('silencing', 'Var', (11, 20))	('increased', 'PosReg', (66, 75))	('ability', 'CPA', (82, 89))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
102642	26052481	Yu and colleagues also linked miR-34c dysregulation to the functions of BCSCs in luminal breast cancer models.	('miR-34c', 'Gene', '407042', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('luminal breast cancer', 'Disease', 'MESH:D001943', (81, 102))	('miR-34c', 'Gene', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('dysregulation', 'Var', (38, 51))	('luminal breast cancer', 'Disease', (81, 102))
102645	26052481	This data confirms the importance of epigenetic regulations of miRNAs in BCSC and presents miR-34c as a potential target for eliminating CSCs.	('miR', 'Gene', (91, 94))	('epigenetic regulations', 'Var', (37, 59))	('miR-34c', 'Gene', '407042', (91, 98))	('miR-34c', 'Gene', (91, 98))	('BCSC', 'Disease', (73, 77))	('CSCs', 'Disease', (137, 141))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (91, 94))
102673	26052481	Moreover, restoration of miR-140 via molecular approach or through the dietary compound sulforaphane (SFN) decreased SOX9 and ALDH1 expression in ER-negative/basal-like DCIS model as well as reducing tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('miR-140', 'Gene', (25, 32))	('restoration', 'Var', (10, 21))	('SFN', 'Chemical', 'MESH:C016766', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('SOX9', 'Gene', (117, 121))	('decreased', 'NegReg', (107, 116))	('tumor', 'Disease', (200, 205))	('ER', 'Gene', '2099', (146, 148))	('SOX9', 'Gene', '6662', (117, 121))	('miR-140', 'Gene', '406932', (25, 32))	('ALDH1', 'Gene', (126, 131))	('sulforaphane', 'Chemical', 'MESH:C016766', (88, 100))	('expression', 'MPA', (132, 142))	('ALDH1', 'Gene', '216', (126, 131))	('reducing', 'NegReg', (191, 199))
102691	27172775	296 LORIS-eligible cases were identified; 58 (20%) had invasive carcinoma on final pathology (90% invasive ductal, 78% >1 mm size, 21% high grade, 3% triple negative, 9% HER2 amplified).	('HER2', 'Gene', (170, 174))	('HER2', 'Gene', '2064', (170, 174))	('invasive carcinoma', 'Disease', (55, 73))	('invasive ductal', 'Disease', (98, 113))	('>1 mm', 'Var', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('invasive carcinoma', 'Disease', 'MESH:D009361', (55, 73))
102692	27172775	Of these, 18 (31%) were pT1b or larger and 3 (5%) were pN1.	('pN1', 'Gene', (55, 58))	('pT1b', 'Var', (24, 28))	('pN1', 'Gene', '5270', (55, 58))
102697	27172775	While the natural history of untreated DCIS is not well studied, 2 early studies reported a 40-50% rate of progression to invasive disease by 10-15 years among women with unrecognized low-grade DCIS diagnosed as benign disease in an excisional biopsy.	('invasive disease', 'Disease', (122, 138))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('women', 'Species', '9606', (160, 165))	('low-grade', 'Var', (184, 193))	('invasive disease', 'Disease', 'MESH:D009362', (122, 138))	('benign disease', 'Disease', (212, 226))	('benign disease', 'Disease', 'MESH:D009369', (212, 226))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))
102701	27172775	A meta-analysis reported an overall 21% rate of upgrade to invasive cancer at the time of surgical excision among patients with non-high-grade DCIS diagnosed on needle biopsy, but the rate of upgrade for women meeting all LORIS study eligibility criteria is currently unknown.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('women', 'Species', '9606', (204, 209))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('non-high-grade', 'Var', (128, 142))	('invasive cancer', 'Disease', (59, 74))	('patients', 'Species', '9606', (114, 122))	('invasive cancer', 'Disease', 'MESH:D009362', (59, 74))
102714	27172775	No patient had a known BRCA mutation, and 44% had one first- or second-degree family member with a history of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patient', 'Species', '9606', (3, 10))	('breast cancer', 'Disease', (110, 123))	('mutation', 'Var', (28, 36))	('BRCA', 'Gene', '672', (23, 27))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('BRCA', 'Gene', (23, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
102726	27172775	Ten of 57 (18%) patients with treatment information available were recommended to undergo chemotherapy for either high or intermediate genomic profile scores, node-positive disease, HER2 amplified or triple-negative tumors, or a combination of high-risk tumor features.	('tumor', 'Disease', (216, 221))	('HER2', 'Gene', '2064', (182, 186))	('tumor', 'Disease', (254, 259))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('amplified', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('HER2', 'Gene', (182, 186))
102729	27172775	The overall reported upgrade was 26% (range 23%-30%) among all patients; with a 21% (range 15%-28%) upgrade to invasive carcinoma seen specifically among patients selected only for the presence of non-high-grade DCIS on core needle biopsy.	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('invasive carcinoma', 'Disease', (111, 129))	('patients', 'Species', '9606', (154, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('patients', 'Species', '9606', (63, 71))	('invasive carcinoma', 'Disease', 'MESH:D009361', (111, 129))	('non-high-grade', 'Var', (197, 211))
102736	27172775	The LORIS trial is enrolling women with both low- and intermediate-grade DCIS on core needle biopsy and does not include a size limitation for mammographic calcifications.	('low-', 'Var', (45, 49))	('women', 'Species', '9606', (29, 34))	('DCIS', 'Disease', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))
102739	27172775	The LORD study is limited to women with screen-detected low-grade DCIS on core-biopsy, excluding those with intermediate-grade lesions.	('low-grade', 'Var', (56, 65))	('DCIS', 'Disease', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('women', 'Species', '9606', (29, 34))
102743	27172775	Unlike the situation in invasive carcinoma, radiation therapy after BCS for DCIS does not improve survival and the acceptance of endocrine therapy is substantially lower among women with DCIS than in those with invasive cancer.	('invasive carcinoma', 'Disease', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('lower', 'NegReg', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('invasive cancer', 'Disease', 'MESH:D009362', (211, 226))	('invasive carcinoma', 'Disease', 'MESH:D009361', (24, 42))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('women', 'Species', '9606', (176, 181))	('DCIS', 'Var', (187, 191))	('invasive cancer', 'Disease', (211, 226))
102749	27172775	It is often felt that if non-high-grade DCIS progresses to invasive carcinoma, the resulting invasive component is correspondingly indolent.	('invasive carcinoma', 'Disease', (59, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('non-high-grade', 'Var', (25, 39))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))	('invasive carcinoma', 'Disease', 'MESH:D009361', (59, 77))
102750	27172775	Interestingly, the invasive cancers identified among this population of women with non-high-grade DCIS on core needle biopsy meeting all LORIS eligibility criteria were heterogeneous in regards to tumor grade, size, and receptor status.	('invasive cancers', 'Disease', (19, 35))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('non-high-grade', 'Var', (83, 97))	('invasive cancers', 'Disease', 'MESH:D009362', (19, 35))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('women', 'Species', '9606', (72, 77))	('tumor', 'Disease', (197, 202))
102751	27172775	6% of the entire study population had poor prognostic invasive tumor features, including triple-negative, HER2 overexpressing, high-grade, T2, presence of lymphovascular invasion, or node-positive disease identified at the time of surgical excision.	('overexpressing', 'PosReg', (111, 125))	('lymphovascular invasion', 'CPA', (155, 178))	('triple-negative', 'Var', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('invasive tumor', 'Disease', 'MESH:D009369', (54, 68))	('HER2', 'Gene', (106, 110))	('HER2', 'Gene', '2064', (106, 110))	('high-grade', 'Disease', (127, 137))	('node-positive', 'Disease', (183, 196))	('invasive tumor', 'Disease', (54, 68))
102756	27172775	Interestingly, the 4 tumors identified in patients with low-grade DCIS on core biopsy in this study were all sub-centimeter, hormone receptor positive, HER2 negative cancers, while the patients with intermediate-grade DCIS on core biopsy were found to have a mix of tumor features on final pathology.	('negative', 'NegReg', (157, 165))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('tumor', 'Disease', (21, 26))	('HER2', 'Gene', '2064', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('DCIS', 'Phenotype', 'HP:0030075', (218, 222))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancers', 'Disease', (166, 173))	('HER2', 'Gene', (152, 156))	('low-grade', 'Var', (56, 65))	('tumors', 'Disease', (21, 27))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('patients', 'Species', '9606', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (21, 27))
102772	27721882	In FFDM and FFDM+CAD, the nondetecting group consisted of younger patients and patients with a denser breast composition (p<0.050).	('FFDM+CAD', 'Gene', '730249', (12, 20))	('FFDM+CAD', 'Gene', (12, 20))	('FFDM', 'Chemical', '-', (3, 7))	('FFDM', 'Chemical', '-', (12, 16))	('patients', 'Species', '9606', (79, 87))	('FFDM', 'Var', (3, 7))	('patients', 'Species', '9606', (66, 74))
102778	27721882	The Digital Mammographic Imaging Screening Trial (DMIST) has demonstrated that the diagnostic accuracy of FFDM is significantly higher than that of FSM in women younger than 50 years and in women with dense breasts on mammography.	('women', 'Species', '9606', (155, 160))	('women', 'Species', '9606', (190, 195))	('diagnostic', 'MPA', (83, 93))	('FFDM', 'Var', (106, 110))	('FFDM', 'Chemical', '-', (106, 110))	('higher', 'PosReg', (128, 134))
102889	26427334	A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways.	('ERBB2', 'Gene', (184, 189))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('TGF beta', 'Gene', (171, 179))	('cancer', 'Disease', (133, 139))	('hypomethylation', 'Var', (36, 51))	('includes', 'Reg', (62, 70))	('ERBB2', 'Gene', '2064', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TGF beta', 'Gene', '7040', (171, 179))
102897	26427334	The main focus has been on silencing of expression through hypermethylation of tumor suppressor genes and other genes that inhibit cancer progression.	('cancer', 'Disease', (131, 137))	('silencing', 'NegReg', (27, 36))	('expression', 'MPA', (40, 50))	('hypermethylation', 'Var', (59, 75))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inhibit', 'NegReg', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
102898	26427334	More recently several studies implicated activation of gene expression through hypomethylation of several pro-metastatic genes in breast, liver and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('hypomethylation', 'Var', (79, 94))	('liver and prostate cancer', 'Disease', 'MESH:D006528', (138, 163))	('gene expression', 'MPA', (55, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('activation', 'PosReg', (41, 51))	('breast', 'Disease', (130, 136))
102899	26427334	A recent analysis of cancer methylomes revealed that hypomethylation of CpG islands in breast cancer was associated with high metastatic risk and death.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('CpG islands', 'Gene', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('cancer', 'Disease', (21, 27))	('hypomethylation', 'Var', (53, 68))	('death', 'Disease', (146, 151))	('high metastatic', 'CPA', (121, 136))	('death', 'Disease', 'MESH:D003643', (146, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancer', 'Disease', (94, 100))	('associated', 'Reg', (105, 115))
102912	26427334	Heatmap and hierarchical clustering of 5368 differentially methylated CpGs between invasive cells and their non-invasive counterparts, group invasive and non-invasive cancer cell lines in separate groups (Figure 2).	('CpGs', 'Protein', (70, 74))	('invasive cancer', 'Disease', (158, 173))	('invasive cancer', 'Disease', 'MESH:D009362', (158, 173))	('differentially methylated', 'Var', (44, 69))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
102916	26427334	We validated by pyrosequencing 3 randomly selected genes (ANXA2, ELK3, PLEC1) from the list of genes that were identified to be hypomethylated in their 5' or promoter regions in our genome wide arrays in the invasive cells (Figure 3A, 3B, 3C).	('PLEC1', 'Gene', (71, 76))	('hypomethylated', 'Var', (128, 142))	('ANXA2', 'Gene', (58, 63))	('ELK3', 'Gene', '2004', (65, 69))	('PLEC1', 'Gene', '5339', (71, 76))	('ANXA2', 'Gene', '302', (58, 63))	('ELK3', 'Gene', (65, 69))
102918	26427334	Surprisingly, hypermethylated genes are organized in functional pathways that are only remotely related to cancer metastasis (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer metastasis', 'Disease', (107, 124))	('organized', 'Reg', (40, 49))	('cancer metastasis', 'Disease', 'MESH:D009362', (107, 124))	('hypermethylated genes', 'Var', (14, 35))
102926	26427334	These data support the hypothesis that common DNA methylation changes underlie the invasive phenotype across diverse cell types and that these common DNA methylation signatures capture genes that are critical for the invasive phenotype in many cancers.	('underlie', 'Reg', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('changes', 'Var', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('cancers', 'Disease', (244, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
102949	26427334	We determined the overlap between genes that were hypomethylated in 5'UTR regions and upregulated genes in invasive compared to non-invasive cancer cell lines.	('invasive cancer', 'Disease', 'MESH:D009362', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('hypomethylated', 'Var', (50, 64))	('upregulated', 'PosReg', (86, 97))	('invasive cancer', 'Disease', (132, 147))
102962	26427334	Interestingly, the expression of C11orf68 was higher in invasive ductal and lobular carcinomas compared to medullary carcinoma (n = 9) (p < 0.05), which is known to be the only carcinoma associated with BRCA1 mutation.	('lobular carcinomas', 'Disease', (76, 94))	('carcinoma', 'Disease', 'MESH:D002277', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('BRCA1', 'Gene', (203, 208))	('carcinoma', 'Disease', (177, 186))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (76, 94))	('expression', 'MPA', (19, 29))	('higher', 'PosReg', (46, 52))	('mutation', 'Var', (209, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Disease', (117, 126))	('carcinoma', 'Disease', 'MESH:D002277', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('C11orf68', 'Gene', '83638', (33, 41))	('lobular carcinomas', 'Disease', 'MESH:D018275', (76, 94))	('C11orf68', 'Gene', (33, 41))	('carcinoma', 'Disease', (84, 93))	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))	('BRCA1', 'Gene', '672', (203, 208))
102978	26427334	G0S2 and SHISA2 (Figure 6B, 6C) depletion caused significant reduction in invasiveness in all three invasive cell lines and knockdown of TMEM156 had an effect on invasiveness only in SKHep1 cells (Figure 6D).	('knockdown', 'Var', (124, 133))	('SHISA2', 'Gene', '387914', (9, 15))	('G0S2', 'Gene', '50486', (0, 4))	('depletion', 'Var', (32, 41))	('TMEM156', 'Gene', (137, 144))	('reduction', 'NegReg', (61, 70))	('TMEM156', 'Gene', '80008', (137, 144))	('invasiveness', 'CPA', (74, 86))	('G0S2', 'Gene', (0, 4))	('SHISA2', 'Gene', (9, 15))	('SKHep1', 'CellLine', 'CVCL:0525', (183, 189))
102991	26427334	First, a pathway analysis performed by IPA reveals that many of the hypomethylated genes are members of functional gene pathways with strong experimental and clinical relevance to cancer.	('hypomethylated genes', 'Var', (68, 88))	('clinical', 'Species', '191496', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
102994	26427334	Third, the hypomethylated genes in our signature are downstream to upstream regulators that have been implicated in cancer metastasis in numerous different studies (e.g., TGFB1, ERBB2).	('hypomethylated', 'Var', (11, 25))	('TGFB1', 'Gene', (171, 176))	('cancer metastasis', 'Disease', 'MESH:D009362', (116, 133))	('ERBB2', 'Gene', '2064', (178, 183))	('ERBB2', 'Gene', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TGFB1', 'Gene', '7040', (171, 176))	('cancer metastasis', 'Disease', (116, 133))
103000	26427334	By contrast, we observe significant G0S2 hypomethylation and induction in breast, liver and prostate invasive cancer cell lines (Figure 4D) that suggests the opposite role for this protein in these three cancer types.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (110, 116))	('induction', 'MPA', (61, 70))	('hypomethylation', 'Var', (41, 56))	('liver and prostate invasive cancer', 'Disease', 'MESH:D006528', (82, 116))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('G0S2', 'Gene', '50486', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('G0S2', 'Gene', (36, 40))
103003	26427334	Interestingly, CpG island within SHISA2 promoter has also been reported to be hypomethylated in recurrent tumors in comparison with non-recurrent tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('SHISA2', 'Gene', '387914', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('CpG island', 'Var', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('hypomethylated', 'Var', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (146, 152))	('SHISA2', 'Gene', (33, 39))
103006	26427334	Our findings show the relevance of hypomethylation in metastatic cancer, which can have important therapeutic implications.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('hypomethylation', 'Var', (35, 50))
103007	26427334	Most of the past literature in the field of cancer focused on identifying methylated and silenced genes.	('methylated', 'Var', (74, 84))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('silenced', 'NegReg', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
103008	26427334	However, silenced genes that suppress cancer could only be activated by epigenetic manipulations but these are not specific to the silenced genes and exert general effects such as inducing cancer-promoting genes.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('inducing', 'Reg', (180, 188))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('epigenetic manipulations', 'Var', (72, 96))	('cancer', 'Disease', (189, 195))
103009	26427334	Our strategy identifies genes that are reprogrammed by hypomethylation and activated in metastatic cancer.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activated', 'PosReg', (75, 84))	('hypomethylation', 'Var', (55, 70))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
103030	26427334	Polyclonal antibodies to C11orf68, SHISA2 and TMEM156 were purchased from Abcam (ab103656, ab107724, ab122047 consequently), for G0S2 from USBiological (G8577-80A).	('TMEM156', 'Gene', (46, 53))	('C11orf68', 'Gene', '83638', (25, 33))	('C11orf68', 'Gene', (25, 33))	('G8577-80A', 'Var', (153, 162))	('G0S2', 'Gene', (129, 133))	('TMEM156', 'Gene', '80008', (46, 53))	('SHISA2', 'Gene', (35, 41))	('G0S2', 'Gene', '50486', (129, 133))	('SHISA2', 'Gene', '387914', (35, 41))	('G8577-80A', 'SUBSTITUTION', 'None', (153, 162))
103058	25877877	High proPTPRN2 expression was associated strongly with lymph node-positive breast cancer and poor clinical outcome.	('associated', 'Reg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('High', 'Var', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('proPTPRN2', 'Gene', (5, 14))	('expression', 'MPA', (15, 25))	('clinical', 'Species', '191496', (98, 106))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
103059	25877877	Loss of proPTPRN2 in breast cancer cells promoted apoptosis and blocked tumor formation in mice, while enforced expression of proPTPRN2 in non-transformed human mammary epithelial cells exerted a converse effect.	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('tumor', 'Disease', (72, 77))	('human', 'Species', '9606', (155, 160))	('breast cancer', 'Disease', (21, 34))	('promoted', 'PosReg', (41, 49))	('blocked', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('proPTPRN2', 'Gene', (8, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('Loss', 'Var', (0, 4))	('apoptosis', 'CPA', (50, 59))
103126	25877877	In contrast, 45 out of 99 invasive breast carcinoma specimens (45%) displayed positivity for proPTPRN2 (Fig.	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (26, 51))	('positivity', 'Var', (78, 88))	('invasive breast carcinoma', 'Disease', (26, 51))	('proPTPRN2', 'Gene', (93, 102))	('breast carcinoma', 'Phenotype', 'HP:0003002', (35, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
103134	25877877	Subsequent Kaplan-Meier analysis revealed that patients with lymph node-positive breast cancer with high proPTPRN2 levels displayed significantly poorer overall survival (P = 0.009), recurrence-free survival (P = 0.018) and distant metastasis-free survival (P = 0.008) than those with low proPTPRN2 levels (Fig.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('patients', 'Species', '9606', (47, 55))	('high', 'Var', (100, 104))	('overall survival', 'CPA', (153, 169))	('distant metastasis-free survival', 'CPA', (224, 256))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))	('lymph node-positive', 'Disease', (61, 80))	('poorer', 'NegReg', (146, 152))	('recurrence-free survival', 'CPA', (183, 207))	('proPTPRN2', 'Gene', (105, 114))
103135	25877877	Therefore, high proPTPRN2 expression has a potential to be used as a clinical marker associated with aggressiveness and disease progression in breast cancer patients.	('expression', 'MPA', (26, 36))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('clinical', 'Species', '191496', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('patients', 'Species', '9606', (157, 165))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('high', 'Var', (11, 15))	('proPTPRN2', 'Gene', (16, 25))	('aggressiveness', 'Disease', (101, 115))	('associated', 'Reg', (85, 95))
103137	25877877	To study how ablation of proPTPRN2 expression may affect cell growth, we used two highly proliferative and aggressive breast cancer cell lines, MDA-MB-468 and SKBR3, as a model for this study.	('SKBR3', 'CellLine', 'CVCL:0033', (159, 164))	('cell growth', 'CPA', (57, 68))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (107, 131))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('proPTPRN2', 'Gene', (25, 34))	('ablation', 'Var', (13, 21))	('aggressive breast cancer', 'Disease', (107, 131))	('affect', 'Reg', (50, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
103142	25877877	Enhanced apoptosis in PTPRN2 knockdown cells was further confirmed by detection of cleaved caspase 3 and cleaved PARP1 (Fig.	('cleaved', 'MPA', (83, 90))	('PTPRN2', 'Gene', (22, 28))	('PARP1', 'Gene', '142', (113, 118))	('cleaved', 'Var', (105, 112))	('PARP1', 'Gene', (113, 118))	('caspase 3', 'Gene', (91, 100))	('caspase 3', 'Gene', '836', (91, 100))
103143	25877877	Most importantly, expression of shRNA-resistant proPTPRN2 fused with the C-terminal triple-epitope (SFB, S protein, Flag, and streptavidin-binding peptide) rescued cell death caused by PTPRN2 shRNA, as shown by reduction in the sub-G1 population from 32% in PTPRN2 knockdown cells to 13% in those expressing the resistant form (Fig.	('PTPRN2', 'Var', (185, 191))	('cell death', 'CPA', (164, 174))	('reduction', 'NegReg', (211, 220))	('streptavidin-binding peptide', 'Gene', (126, 154))	('streptavidin-binding peptide', 'Gene', '8991', (126, 154))	('SFB', 'Gene', (100, 103))	('SFB', 'Gene', '20388', (100, 103))	('sub-G1 population', 'CPA', (228, 245))
103153	25877877	However, expression of proPTPRN2, but not mature PTPRN2, in MCF10A cells did increase acinar size (Fig.	('expression', 'Var', (9, 19))	('MCF10A', 'CellLine', 'CVCL:0598', (60, 66))	('increase', 'PosReg', (77, 85))	('acinar size', 'CPA', (86, 97))	('proPTPRN2', 'Var', (23, 32))
103162	25877877	To map the proPTPRN2 binding site on TRAF2, we generated a set of truncated TRAF2 mutants lacking several domains essential for its activity (Fig.	('TRAF2', 'Gene', (76, 81))	('TRAF2', 'Gene', (37, 42))	('lacking', 'NegReg', (90, 97))	('several domains', 'MPA', (98, 113))	('TRAF2', 'Gene', '7186', (76, 81))	('mutants', 'Var', (82, 89))	('TRAF2', 'Gene', '7186', (37, 42))
103163	25877877	Co-expression of the corresponding mutants with proPTPRN2-SFB in HEK293T cells followed by co-immunoprecipitation revealed that deletion of the N-terminal part of TRAF2 (1-33 residues; D1 mutant) dramatically reduced its interaction with proPTPRN2 (Fig.	('TRAF2', 'Gene', (163, 168))	('interaction', 'Interaction', (221, 232))	('SFB', 'Gene', '20388', (58, 61))	('reduced', 'NegReg', (209, 216))	('SFB', 'Gene', (58, 61))	('HEK293T', 'CellLine', 'CVCL:0063', (65, 72))	('TRAF2', 'Gene', '7186', (163, 168))	('deletion', 'Var', (128, 136))
103165	25877877	Notably, deletion of the two C-terminal subdomains (coiled coil [Cc] and MATH) responsible for self-association and interactions with death receptors and other proteins did not affect TRAF2 binding to proPTPRN2 (Fig.	('TRAF2', 'Gene', (184, 189))	('interactions', 'Interaction', (116, 128))	('deletion', 'Var', (9, 17))	('TRAF2', 'Gene', '7186', (184, 189))	('binding', 'Interaction', (190, 197))
103171	25877877	Deletion of the PTP domain reduced but did not abolish their interaction (Fig.	('reduced', 'NegReg', (27, 34))	('PTP', 'Gene', (16, 19))	('PTP', 'Gene', '10076', (16, 19))	('interaction', 'Interaction', (61, 72))	('Deletion', 'Var', (0, 8))
103173	25877877	These results were also supported by mass-spectrometry data showing that in contrast to mature PTPRN2, the PTP deletion mutant was still able to bind to TRAF2, XIAP and cIAP1 (Fig.	('PTP', 'Gene', (107, 110))	('PTP', 'Gene', '10076', (107, 110))	('deletion mutant', 'Var', (111, 126))	('TRAF2', 'Gene', (153, 158))	('bind', 'Interaction', (145, 149))	('PTP', 'Gene', (95, 98))	('XIAP', 'Gene', (160, 164))	('PTP', 'Gene', '10076', (95, 98))	('cIAP1', 'Gene', (169, 174))	('XIAP', 'Gene', '331', (160, 164))	('cIAP1', 'Gene', '329', (169, 174))	('TRAF2', 'Gene', '7186', (153, 158))
103178	25877877	In a complementary experiment, depletion of proPTPRN2 sensitized MDA-MB-468 cells to contact inhibition and confluence-induced apoptosis (Supplementary Fig.	('proPTPRN2', 'Gene', (44, 53))	('confluence-induced apoptosis', 'CPA', (108, 136))	('contact inhibition', 'CPA', (85, 103))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (65, 75))	('depletion', 'Var', (31, 40))	('sensitized', 'Reg', (54, 64))
103179	25877877	Using series of proPTPRN2 mutants we found that neither restored protein tyrosine phosphatase activity of proPTPRN2 (+PTP), nor intrinsic phosphoinositide phosphatase activity (PIP), nor deletion of the whole 245 amino acid PTP domain affected the ability of proPTPRN2 to block apoptosis (as measured by caspase 3 cleavage) in overconfluent MCF10A cells (Fig.	('PTP', 'Gene', (118, 121))	('intrinsic phosphoinositide phosphatase activity', 'MPA', (128, 175))	('protein tyrosine phosphatase', 'Gene', '26191', (65, 93))	('PTP', 'Gene', (109, 112))	('PTP', 'Gene', '10076', (19, 22))	('PTP', 'Gene', '10076', (224, 227))	('MCF10A', 'CellLine', 'CVCL:0598', (341, 347))	('mutants', 'Var', (26, 33))	('deletion', 'Var', (187, 195))	('PTP', 'Gene', '10076', (262, 265))	('block', 'NegReg', (272, 277))	('PTP', 'Gene', (19, 22))	('PTP', 'Gene', '10076', (118, 121))	('PTP', 'Gene', '10076', (109, 112))	('PIP', 'Chemical', '-', (177, 180))	('PTP', 'Gene', (224, 227))	('caspase 3', 'Gene', (304, 313))	('apoptosis', 'CPA', (278, 287))	('PTP', 'Gene', (262, 265))	('caspase 3', 'Gene', '836', (304, 313))	('protein tyrosine phosphatase', 'Gene', (65, 93))
103182	25877877	Similarly to the wild type, proPTPRN2 mutant proteins (-PIP) and (+PTP) but not the PTP domain deletion mutant interacted with TRAF2 in a confluence-dependent manner (Fig.	('mutant', 'Var', (38, 44))	('PTP', 'Gene', '10076', (31, 34))	('PTP', 'Gene', (67, 70))	('proteins', 'Protein', (45, 53))	('interacted', 'Interaction', (111, 121))	('PTP', 'Gene', '10076', (67, 70))	('TRAF2', 'Gene', '7186', (127, 132))	('PTP', 'Gene', (84, 87))	('PTP', 'Gene', '10076', (84, 87))	('PIP', 'Chemical', '-', (56, 59))	('PTP', 'Gene', (31, 34))	('TRAF2', 'Gene', (127, 132))
103183	25877877	These data suggest a possibility that aberrant expression of proPTPRN2 may interfere with normal functions of TRAF2, particularly those associated with regulation of cell contact-dependent growth inhibition and apoptosis.	('TRAF2', 'Gene', (110, 115))	('aberrant expression', 'Var', (38, 57))	('functions', 'MPA', (97, 106))	('interfere', 'NegReg', (75, 84))	('TRAF2', 'Gene', '7186', (110, 115))	('proPTPRN2', 'Gene', (61, 70))
103205	25877877	Taken together with the observed reduction in phosphorylation of TRAF2 at Ser-11 and in caspase 3 cleavage in these cells, these results suggest a mechanism whereby proPTPRN2 blocks apoptosis by preventing PKC-mediated TRAF2 phosphorylation/activation and its subsequent association with FADD (Fig.	('phosphorylation/activation', 'MPA', (225, 251))	('PKC', 'Gene', (206, 209))	('Ser-11', 'Chemical', '-', (74, 80))	('proPTPRN2', 'Var', (165, 174))	('association', 'Interaction', (271, 282))	('PKC', 'Gene', '112476', (206, 209))	('TRAF2', 'Gene', (219, 224))	('TRAF2', 'Gene', '7186', (65, 70))	('TRAF2', 'Gene', '7186', (219, 224))	('caspase 3', 'Gene', (88, 97))	('apoptosis', 'CPA', (182, 191))	('caspase 3', 'Gene', '836', (88, 97))	('TRAF2', 'Gene', (65, 70))	('preventing', 'NegReg', (195, 205))	('FADD', 'Gene', '8772', (288, 292))	('FADD', 'Gene', (288, 292))
103206	25877877	This was also confirmed by knocking down endogenous proPTPRN2 in MDA-MB-468 cells, which led to enhanced TRAF2-FADD complex formation (Fig.	('TRAF2', 'Gene', '7186', (105, 110))	('enhanced', 'PosReg', (96, 104))	('knocking down', 'Var', (27, 40))	('proPTPRN2', 'Gene', (52, 61))	('TRAF2', 'Gene', (105, 110))	('FADD', 'Gene', '8772', (111, 115))	('FADD', 'Gene', (111, 115))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (65, 75))
103210	25877877	Moreover, high proPTPRN2 expression was associated with poor outcome in patients with lymph node-positive breast cancer, indicating that overexpression of proPTPRN2 is likely to have prognostic value.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('expression', 'MPA', (25, 35))	('high', 'Var', (10, 14))	('proPTPRN2', 'Gene', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('patients', 'Species', '9606', (72, 80))
103212	25877877	Therefore, targeting of PTPRN2 should have minimal side effects while significantly inhibiting tumor growth by inducing apoptosis, making it an attractive target candidate for cancer therapy.	('apoptosis', 'CPA', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inducing', 'Reg', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('targeting', 'Var', (11, 20))	('inhibiting', 'NegReg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('PTPRN2', 'Gene', (24, 30))	('tumor', 'Disease', (95, 100))
103216	25877877	One particularly interesting observation in our study is that high cell density-induced apoptosis in non-transformed MCF10A cells was significantly suppressed by proPTPRN2 but not by the mature PTPRN2 form.	('proPTPRN2', 'Var', (162, 171))	('apoptosis', 'CPA', (88, 97))	('MCF10A', 'CellLine', 'CVCL:0598', (117, 123))	('suppressed', 'NegReg', (148, 158))
103221	25877877	In this study, we found that aberrantly expressed proPTPRN2 binds to the TRAF2-cIAP complex.	('IAP', 'Gene', '84061', (80, 83))	('TRAF2', 'Gene', (73, 78))	('aberrantly expressed', 'Var', (29, 49))	('IAP', 'Gene', (80, 83))	('proPTPRN2', 'Gene', (50, 59))	('binds', 'Interaction', (60, 65))	('TRAF2', 'Gene', '7186', (73, 78))
103223	25877877	Of further importance, depletion of proPTPRN2 in breast cancer cells restored confluence-dependent apoptosis, suggesting that proPTPRN2 may be a novel therapeutic target for cancer treatment.	('confluence-dependent apoptosis', 'CPA', (78, 108))	('proPTPRN2', 'Gene', (36, 45))	('depletion', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('restored', 'PosReg', (69, 77))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
103224	25877877	In summary, proPTPRN2 overexpression dramatically suppressed apoptosis in a density-dependent manner in monolayer cultures and during acinar lumen formation, and proPTPRN2 promoted tumor growth in xenograft studies.	('suppressed', 'NegReg', (50, 60))	('apoptosis', 'CPA', (61, 70))	('tumor', 'Disease', (181, 186))	('proPTPRN2', 'Var', (162, 171))	('proPTPRN2', 'Gene', (12, 21))	('promoted', 'PosReg', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
103225	25877877	Moreover, high proPTPRN2 expression was associated with poor prognosis in patients with lymph node-positive breast cancer.	('patients', 'Species', '9606', (74, 82))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (10, 14))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('proPTPRN2', 'Gene', (15, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
103226	25877877	We thus envision that therapeutic intervention targeting proPTPRN2 may improve overall survival of breast cancer patients with high proPTPRN2 expression.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('overall survival', 'CPA', (79, 95))	('high', 'Var', (127, 131))	('breast cancer', 'Disease', (99, 112))	('expression', 'MPA', (142, 152))	('patients', 'Species', '9606', (113, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('proPTPRN2', 'Gene', (132, 141))	('proPTPRN2', 'Gene', (57, 66))	('improve', 'PosReg', (71, 78))
103269	25886531	Another advantage of our study was that the small invasive breast cancers and lesions of DCIS were associated with successful VTTQ measurement.	('VTTQ', 'Chemical', '-', (126, 130))	('lesions', 'Var', (78, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('invasive breast cancers', 'Disease', (50, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('VTTQ', 'Gene', (126, 130))	('DCIS', 'Gene', (89, 93))	('invasive breast cancers', 'Disease', 'MESH:D001943', (50, 73))
103300	21779879	Interestingly, FIP200 truncation mutants have been described in breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('described', 'Reg', (51, 60))	('FIP200', 'Gene', (15, 21))	('truncation mutants', 'Var', (22, 40))	('patients', 'Species', '9606', (78, 86))	('FIP200', 'Gene', '9821', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
103302	21779879	Under nutrient rich conditions, the ULK complex interacts with mTORC1 and remains inactivated by mTORC1-mediated phosphorylation of ULK1 and ULK2.	('mTORC1', 'Gene', (97, 103))	('ULK2', 'Gene', (141, 145))	('mTORC1', 'Gene', '382056', (63, 69))	('phosphorylation', 'Var', (113, 128))	('ULK2', 'Gene', '9706', (141, 145))	('mTORC1', 'Gene', '382056', (97, 103))	('interacts', 'Interaction', (48, 57))	('mTORC1', 'Gene', (63, 69))	('ULK1', 'Gene', (132, 136))
103305	21779879	However, the genetic deletion of ULK1 in mice has been demonstrated to have minimal effects on the initial formation or completion of the autophagosome; this lack of phenotype may arise from compensation by other ULK isoforms.	('completion of the autophagosome', 'CPA', (120, 151))	('ULK1', 'Gene', (33, 37))	('mice', 'Species', '10090', (41, 45))	('deletion', 'Var', (21, 29))
103314	21779879	PI3P produced by the class III PI3K complex subsequently recruits the next stage of effectors, including the double FYVE-containing protein 1 (DFCP1) and WD-repeat domain phosphoinositide-interacting (WIPI) family proteins, the mammalian orthologues of ATG18.	('ATG18', 'Gene', (253, 258))	('ATG18', 'Gene', '55062', (253, 258))	('double FYVE-containing protein 1', 'Gene', (109, 141))	('WD', 'Disease', 'MESH:D006527', (154, 156))	('DFCP1', 'Gene', (143, 148))	('PI3K', 'Var', (31, 35))	('mammalian', 'Species', '9606', (228, 237))	('double FYVE-containing protein 1', 'Gene', '53349', (109, 141))	('DFCP1', 'Gene', '53349', (143, 148))
103331	21779879	Since the discovery of p62/SQSTM, several additional proteins with analogous functions have been identified, including NBR1 (neighbor of Brca1 gene) and NDP52, all of which are proposed to serve as cargo receptors for the degradation of ubiquitinated substrates by autophagy.	('NDP52', 'Gene', '10241', (153, 158))	('Brca1', 'Gene', (137, 142))	('p62/SQSTM', 'Var', (23, 32))	('NBR1', 'Gene', '4077', (119, 123))	('Brca1', 'Gene', '672', (137, 142))	('NDP52', 'Gene', (153, 158))	('degradation', 'MPA', (222, 233))	('NBR1', 'Gene', (119, 123))
103341	21779879	During oxidative stress, the activity of the E3 ligase is inhibited through the modification of cysteine residues in Keap1.	('cysteine', 'Chemical', 'MESH:D003545', (96, 104))	('modification', 'Var', (80, 92))	('cysteine residues', 'MPA', (96, 113))	('E3 ligase', 'Enzyme', (45, 54))	('Keap1', 'Gene', '9817', (117, 122))	('Keap1', 'Gene', (117, 122))	('activity', 'MPA', (29, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (7, 23))	('inhibited', 'NegReg', (58, 67))
103343	21779879	Notably, the Nrf2 pathway, due to inactivating somatic mutations in Keap1, has been implicated as a survival pathway in non-small cell lung carcinomas.	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (124, 150))	('Keap1', 'Gene', '9817', (68, 73))	('Keap1', 'Gene', (68, 73))	('Nrf2', 'Gene', (13, 17))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (120, 150))	('non-small cell lung carcinomas', 'Disease', (120, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('inactivating somatic mutations', 'Var', (34, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('Nrf2', 'Gene', '4780', (13, 17))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (120, 150))
103344	21779879	Based on this result, one can speculate that the aberrant activation of Nrf2 in autophagy deficient cells promotes tumor cell survival by amplifying the oxidative stress response; at the same time, these cells are predisposed to the deleterious accumulation of damaged organelles and toxic proteins.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('oxidative stress response', 'MPA', (153, 178))	('promotes', 'PosReg', (106, 114))	('aberrant', 'Var', (49, 57))	('tumor', 'Disease', (115, 120))	('Nrf2', 'Gene', '4780', (72, 76))	('amplifying', 'PosReg', (138, 148))	('activation', 'PosReg', (58, 68))	('oxidative stress', 'Phenotype', 'HP:0025464', (153, 169))	('Nrf2', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
103359	21779879	Moreover, frameshift mutations in the polyadenine tract of the UVRAG gene are present in gastric carcinomas; gastric cancer cells harboring these mutations exhibit decreased autophagy.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('frameshift mutations in', 'Var', (10, 33))	('mutations', 'Var', (146, 155))	('polyadenine tract', 'Var', (38, 55))	('decreased', 'NegReg', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (89, 106))	('gastric cancer', 'Disease', (109, 123))	('polyadenine', 'Chemical', 'MESH:C000628261', (38, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('UVRAG', 'Gene', (63, 68))	('gastric carcinomas', 'Disease', 'MESH:D013274', (89, 107))	('gastric carcinomas', 'Disease', (89, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('autophagy', 'CPA', (174, 183))
103365	21779879	Mice with systemic mosaic deletion of atg5 and liver-specific atg7-/- mice develop liver adenomas; notably, in these models, autophagy-deficient hepatocytes exhibit p62 accumulation as well as oxidative and genotoxic stress.	('develop', 'Reg', (75, 82))	('atg5', 'Gene', '11793', (38, 42))	('autophagy-deficient', 'Disease', (125, 144))	('atg5', 'Gene', (38, 42))	('liver adenomas', 'Disease', (83, 97))	('autophagy-deficient', 'Disease', 'MESH:C564093', (125, 144))	('liver adenomas', 'Phenotype', 'HP:0012028', (83, 97))	('p62', 'Var', (165, 168))	('mice', 'Species', '10090', (70, 74))	('accumulation', 'PosReg', (169, 181))	('liver adenomas', 'Disease', 'MESH:D018248', (83, 97))	('Mice', 'Species', '10090', (0, 4))	('atg7', 'Gene', '74244', (62, 66))	('atg7', 'Gene', (62, 66))
103366	21779879	Moreover, the concomitant deletion of p62 partially suppresses tumor progression in ATG7-deficient liver, supporting a role for p62 accumulation in liver tumor progression.	('tumor', 'Disease', (63, 68))	('liver tumor', 'Disease', 'MESH:D008113', (148, 159))	('liver tumor', 'Phenotype', 'HP:0002896', (148, 159))	('liver tumor', 'Disease', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('deletion', 'Var', (26, 34))	('p62', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ATG7-deficient liver', 'Disease', (84, 104))	('ATG7-deficient liver', 'Disease', 'MESH:D017093', (84, 104))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('deficient liver', 'Phenotype', 'HP:0001410', (89, 104))	('suppresses', 'NegReg', (52, 62))	('tumor', 'Disease', (154, 159))
103371	21779879	Lastly, frameshift mutations in ATG2B, ATG5, and ATG9B have been reported in gastric and colorectal carcinomas with high microsatellite instability, further insinuating tumor suppressor functions for the core autophagic machinery in human cancers.	('human', 'Species', '9606', (233, 238))	('ATG2B', 'Gene', '55102', (32, 37))	('reported', 'Reg', (65, 73))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('gastric', 'Disease', (77, 84))	('ATG5', 'Gene', (39, 43))	('ATG9B', 'Gene', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('ATG2B', 'Gene', (32, 37))	('frameshift mutations', 'Var', (8, 28))	('colorectal carcinomas', 'Disease', (89, 110))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (89, 110))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ATG9B', 'Gene', '285973', (49, 54))
103375	21779879	In Bcl-2-overexpressing immortalized mouse mammary epithelial (iMMEC) cells and immortalized baby mouse kidney epithelial (iBMK) cells, loss of one copy of becn1 significantly sensitizes cells to metabolic stress.	('sensitizes', 'Reg', (176, 186))	('becn1', 'Gene', (156, 161))	('mouse', 'Species', '10090', (37, 42))	('cells to', 'CPA', (187, 195))	('mouse', 'Species', '10090', (98, 103))	('loss', 'Var', (136, 140))
103376	21779879	Paradoxically, in spite of increased survival, becn1+/+ cells are less tumorigenic than becn1+/- cells.	('increased', 'PosReg', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('becn1+/+', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('less', 'NegReg', (66, 70))
103377	21779879	Moreover, p62 serves as a critical link between defective autophagy and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('autophagy', 'CPA', (58, 67))	('tumor', 'Disease', (72, 77))	('p62', 'Var', (10, 13))	('defective', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
103379	21779879	Again, p62 accumulation upon metabolic stress leads to ROS generation and consequent deregulation of the NF-kappaB pathway, thereby creating a positive feedback loop.	('p62', 'Var', (7, 10))	('NF-kappaB pathway', 'Pathway', (105, 122))	('accumulation', 'PosReg', (11, 23))	('ROS', 'Chemical', '-', (55, 58))	('deregulation', 'MPA', (85, 97))	('ROS generation', 'MPA', (55, 69))
103381	21779879	Remarkably, these experiments have been conducted in cells harboring multiple genetic abnormalities, including the inactivation of the tumor suppressor p53.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('genetic abnormalities', 'Disease', (78, 99))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('tumor', 'Disease', (135, 140))	('inactivation', 'Var', (115, 127))	('genetic abnormalities', 'Disease', 'MESH:D030342', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
103382	21779879	Nonetheless, a similar DNA damage response has been observed in the spontaneous liver tumors arising in mice with mosaic atg5 or liver-specific atg7 deletion.	('liver tumors', 'Phenotype', 'HP:0002896', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('liver tumor', 'Phenotype', 'HP:0002896', (80, 91))	('mice', 'Species', '10090', (104, 108))	('atg5', 'Gene', '11793', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('atg5', 'Gene', (121, 125))	('atg7', 'Gene', '74244', (144, 148))	('liver tumors', 'Disease', 'MESH:D008113', (80, 92))	('atg7', 'Gene', (144, 148))	('mosaic', 'Var', (114, 120))	('liver tumors', 'Disease', (80, 92))
103383	21779879	Fascinatingly, in a small cohort of breast cancer patients, a significant association was found between the loss of BECN1 and amplification of HER2/NEU, both of which are located on chromosome 17q21.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('loss', 'NegReg', (108, 112))	('breast cancer', 'Disease', (36, 49))	('patients', 'Species', '9606', (50, 58))	('BECN1', 'Gene', (116, 121))	('NEU', 'Gene', (148, 151))	('NEU', 'Gene', '2064', (148, 151))	('HER2', 'Gene', (143, 147))	('amplification', 'Var', (126, 139))	('HER2', 'Gene', '2064', (143, 147))	('BECN1', 'Gene', '8678', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
103384	21779879	In this study, the authors also noted associations between BECN1 loss and mutations in other tumor suppressors, including p53 and PTEN, consistent with the idea that BECN1 loss and defective autophagy facilitates DNA damage and genomic instability in HER2+ breast cancers.	('BECN1', 'Gene', '8678', (59, 64))	('defective', 'Var', (181, 190))	('autophagy', 'CPA', (191, 200))	('genomic instability', 'CPA', (228, 247))	('BECN1', 'Gene', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('p53', 'Gene', (122, 125))	('loss', 'NegReg', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('DNA', 'MPA', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancers', 'Disease', 'MESH:D001943', (257, 271))	('breast cancers', 'Disease', (257, 271))	('facilitates', 'PosReg', (201, 212))	('PTEN', 'Gene', (130, 134))	('HER2', 'Gene', '2064', (251, 255))	('loss', 'NegReg', (65, 69))	('breast cancers', 'Phenotype', 'HP:0003002', (257, 271))	('BECN1', 'Gene', '8678', (166, 171))	('p53', 'Gene', '7157', (122, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('PTEN', 'Gene', '5728', (130, 134))	('BECN1', 'Gene', (166, 171))	('associations', 'Interaction', (38, 50))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (93, 98))	('HER2', 'Gene', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
103385	21779879	Overall, these results support the hypothesis that defective autophagy functions as a modifier, and possibly a fundamental driver, of genomic damage during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('defective', 'Var', (51, 60))	('tumor', 'Disease', (156, 161))	('autophagy', 'CPA', (61, 70))
103386	21779879	In addition, defective autophagy may contribute to the development of breast cancer in a manner independent of genotoxic stress and genomic instability through the induction of ER stress.	('contribute', 'Reg', (37, 47))	('defective', 'Var', (13, 22))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('autophagy', 'CPA', (23, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
103389	21779879	Interestingly, autophagy is induced during OIS in an inducible Ras cell culture system; accordingly, autophagy inhibition via ATG knockdown results in a significant bypass of senescence as well as inhibition of the secretion of IL6 and IL8.	('autophagy', 'CPA', (101, 110))	('secretion of', 'MPA', (215, 227))	('IL8', 'Gene', (236, 239))	('inhibition', 'NegReg', (197, 207))	('IL8', 'Gene', '3576', (236, 239))	('knockdown', 'Var', (130, 139))	('ATG', 'Gene', (126, 129))	('senescence', 'CPA', (175, 185))	('IL6', 'Gene', '3569', (228, 231))	('IL6', 'Gene', (228, 231))	('inhibition', 'NegReg', (111, 121))
103397	21779879	Based on exciting work in other inflammatory disorders, it is also tempting to speculate that perturbations in autophagy can initiate inflammation in other circumstances, thereby creating a pro-tumorigenic environment.	('perturbations', 'Var', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('creating', 'Reg', (179, 187))	('autophagy', 'CPA', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('inflammation', 'Disease', 'MESH:D007249', (134, 146))	('tumor', 'Disease', (194, 199))	('inflammation', 'Disease', (134, 146))
103400	21779879	In mouse models hypomorphic for ATG16L, or lacking ATG5 or ATG7 in the intestine, the intestinal Paneth cells severe abnormalities that strikingly resemble the changes seen in human Crohn's disease patients carrying the ATG16L1 risk allele.	('lacking', 'NegReg', (43, 50))	("Crohn's disease", 'Disease', (182, 197))	('mouse', 'Species', '10090', (3, 8))	('patients', 'Species', '9606', (198, 206))	('abnormalities', 'MPA', (117, 130))	('ATG5', 'Gene', (51, 55))	('ATG16L1', 'Gene', (220, 227))	('human', 'Species', '9606', (176, 181))	('ATG16L', 'Var', (32, 38))	('ATG16L1', 'Gene', '55054', (220, 227))	("Crohn's disease", 'Phenotype', 'HP:0100280', (182, 197))	('ATG7', 'Gene', (59, 63))	("Crohn's disease", 'Disease', 'MESH:D003424', (182, 197))
103401	21779879	In addition, ATG16L1 deficient macrophages produce drastically elevated levels of the inflammatory cytokines IL-1beta and IL-18, again intimating that defective autophagy can promote a pro-tumor inflammatory state, and in this case, independently of tumor necrosis.	('IL-1beta', 'Gene', (109, 117))	('defective', 'Var', (151, 160))	('IL-18', 'Gene', '3606', (122, 127))	('ATG16L1', 'Gene', '55054', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (250, 255))	('ATG16L1', 'Gene', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor necrosis', 'Disease', 'MESH:D009336', (250, 264))	('deficient', 'Var', (21, 30))	('promote', 'PosReg', (175, 182))	('tumor necrosis', 'Disease', (250, 264))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('levels of', 'MPA', (72, 81))	('IL-18', 'Gene', (122, 127))	('elevated', 'PosReg', (63, 71))	('autophagy', 'CPA', (161, 170))	('tumor', 'Disease', (189, 194))	('IL-1beta', 'Gene', '3553', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
103418	21779879	In fact, recent studies demonstrate autophagy deficient cells expressing activated H-Ras or K-Ras displayed decreased adhesion-independent growth.	('activated', 'Var', (73, 82))	('K-Ras', 'Gene', (92, 97))	('decreased', 'NegReg', (108, 117))	('autophagy', 'CPA', (36, 45))	('H-Ras', 'Gene', '3265', (83, 88))	('adhesion-independent growth', 'CPA', (118, 145))	('H-Ras', 'Gene', (83, 88))	('K-Ras', 'Gene', '3845', (92, 97))
103421	21779879	Recent seminal work confirms elevated basal autophagy in both primary PDAC tumors and cell lines; the genetic or pharmacologic inhibition of autophagy in PDAC cells potently suppresses proliferation in vitro and elicits robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models.	('pancreatic cancer', 'Disease', 'MESH:D010190', (270, 287))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('pancreatic cancer', 'Disease', (270, 287))	('tumor', 'Disease', (75, 80))	('PDAC', 'Gene', (154, 158))	('autophagy', 'CPA', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('prolonged survival', 'CPA', (248, 266))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('elicits', 'Reg', (212, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (270, 287))	('inhibition', 'Var', (127, 137))	('suppresses', 'NegReg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('proliferation', 'CPA', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mouse', 'Species', '10090', (311, 316))
103428	21779879	Though breast cancers do not commonly exhibit oncogenic Ras mutations, other oncogene pathways activated in breast tumors, including HER2/Neu, Myc and activated PI3K, produce metabolic alterations similar to Ras, which are required to maintain the transformed phenotype.	('breast cancers', 'Phenotype', 'HP:0003002', (7, 21))	('Myc', 'Gene', (143, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('Neu', 'Gene', (138, 141))	('oncogene', 'Pathway', (77, 85))	('Neu', 'Gene', '2064', (138, 141))	('HER2', 'Gene', '2064', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('Myc', 'Gene', '4609', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('breast tumors', 'Disease', (108, 121))	('breast tumors', 'Disease', 'MESH:D001943', (108, 121))	('HER2', 'Gene', (133, 137))	('metabolic alterations', 'MPA', (175, 196))	('breast cancers', 'Disease', 'MESH:D001943', (7, 21))	('breast cancers', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast tumors', 'Phenotype', 'HP:0100013', (108, 121))	('mutations', 'Var', (60, 69))
103436	21779879	Since the early days of autophagy research, the anti-estrogen tamoxifen has been known as a potent inducer of autophagy in a variety of breast cancer cells Originally autophagy was postulated as a nonapoptotic cell death mechanism; however, recent functional studies indicate that autophagy inhibition, which was achieved either by pharmacological means or RNAi-mediated silencing of ATGs, actually sensitizes hormone receptor positive breast cancer cells to tamoxifen, thereby promoting cytotoxicity and preventing the development of anti-estrogen resistance.	('cytotoxicity', 'Disease', 'MESH:D064420', (488, 500))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (436, 449))	('silencing', 'Var', (371, 380))	('tamoxifen', 'Chemical', 'MESH:D013629', (459, 468))	('preventing', 'NegReg', (505, 515))	('development', 'MPA', (520, 531))	('inhibition', 'NegReg', (291, 301))	('breast cancer', 'Disease', 'MESH:D001943', (436, 449))	('tamoxifen', 'Chemical', 'MESH:D013629', (62, 71))	('breast cancer', 'Disease', (436, 449))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('promoting', 'PosReg', (478, 487))	('ATGs', 'Gene', (384, 388))	('autophagy', 'CPA', (281, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cytotoxicity', 'Disease', (488, 500))
103469	21779879	Because beta1-integrin signaling blockade is a potent inducer of autophagy in ECM detached cells, one can hypothesize that disrupted integrin signaling-mediated autophagy induction in DTCs can support and maintain tumor dormancy (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('beta1-integrin', 'Gene', '3688', (8, 22))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('beta1-integrin', 'Gene', (8, 22))	('tumor', 'Disease', (214, 219))	('disrupted', 'Var', (123, 132))
103476	20712900	p53 nuclear accumulation and ERalpha expression in ductal hyperplasia of breast in a cohort of 215 Chinese women Women with ductal hyperplasia including usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) have an increased risk of developing invasive ductal carcinoma (IDC) of breast.	('Women', 'Species', '9606', (113, 118))	('ERalpha', 'Gene', '2099', (29, 36))	('ductal hyperplasia ', 'Gene', '124', (159, 178))	('ductal hyperplasia (ADH', 'Gene', (197, 220))	('IDC', 'Gene', '4000', (286, 289))	('IDC', 'Gene', (286, 289))	('p53', 'Gene', '7157', (0, 3))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (259, 284))	('hyperplasia', 'Disease', (204, 215))	('usual', 'Disease', (153, 158))	('ductal hyperplasia ', 'Gene', (124, 143))	('hyperplasia', 'Disease', (166, 177))	('ductal hyperplasia ', 'Gene', '124', (197, 216))	('hyperplasia', 'Disease', 'MESH:D006965', (204, 215))	('invasive ductal carcinoma', 'Disease', (259, 284))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (268, 284))	('hyperplasia', 'Disease', 'MESH:D006965', (166, 177))	('p53', 'Gene', (0, 3))	('ductal hyperplasia ', 'Gene', '124', (124, 143))	('ductal hyperplasia ', 'Gene', (51, 70))	('atypical', 'Var', (188, 196))	('hyperplasia', 'Disease', (58, 69))	('ERalpha', 'Gene', (29, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('ductal hyperplasia ', 'Gene', (159, 178))	('hyperplasia', 'Disease', 'MESH:D006965', (58, 69))	('UDH', 'Chemical', '-', (179, 182))	('ductal hyperplasia ', 'Gene', '124', (51, 70))	('hyperplasia', 'Disease', (131, 142))	('ductal hyperplasia (ADH)', 'Gene', '124', (197, 221))	('hyperplasia', 'Disease', 'MESH:D006965', (131, 142))	('hyperplasia of breast', 'Phenotype', 'HP:0010313', (58, 79))
103496	20712900	In its mutant form, p53 inhibits apoptosis, loses control on cell cycle progression and thus helps tumor formation.	('p53', 'Gene', (20, 23))	('tumor', 'Disease', (99, 104))	('apoptosis', 'CPA', (33, 42))	('p53', 'Gene', '7157', (20, 23))	('mutant', 'Var', (7, 13))	('inhibits', 'NegReg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('helps', 'PosReg', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('control', 'MPA', (50, 57))	('loses', 'NegReg', (44, 49))
103497	20712900	Nuclear p53 accumulation which associates with p53 mutation is one of the most common events during breast carcinogenesis.	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('mutation', 'Var', (51, 59))	('accumulation', 'PosReg', (12, 24))	('breast carcinogenesis', 'Disease', (100, 121))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (100, 121))
103513	20712900	Immunohistochemical staining for ERalpha (sc-542, Santa Cruz, 1:200) and p53 (sc-47698, Santa Cruz, 1:100) were performed using UltraSensitive  S-P kits (Maixin-Bio; P.R.	('ERalpha', 'Gene', (33, 40))	('p53', 'Gene', '7157', (73, 76))	('sc-47698', 'Var', (78, 86))	('p53', 'Gene', (73, 76))	('ERalpha', 'Gene', '2099', (33, 40))
103528	20712900	The immunohistochemical detection of nuclear p53 protein accumulation is highly associated with p53 gene mutations in breast cancer tissues, in benign breast lesions it has been associated with elevated risk of progression to breast cancer.	('p53', 'Gene', (45, 48))	('accumulation', 'PosReg', (57, 69))	('p53', 'Gene', (96, 99))	('breast lesion', 'Disease', (151, 164))	('protein', 'Protein', (49, 56))	('breast cancer', 'Disease', (226, 239))	('p53', 'Gene', '7157', (45, 48))	('p53', 'Gene', '7157', (96, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (105, 114))	('associated', 'Reg', (80, 90))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast lesion', 'Disease', 'MESH:D001941', (151, 164))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
103543	20712900	Experiments in vitro suggested that ERalpha opposes p53-mediated apoptosis in breast cancer cells by Sayeed A. Shirley SH performed animal experiments to show that p53 genotype was correlated with ER expression and response to tamoxifen in mammary tumors arising in mouse mammary tumor virus-Wnt-1 transgenic mice.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('p53', 'Gene', (52, 55))	('tumors', 'Disease', (248, 254))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('breast cancer', 'Disease', (78, 91))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('p53', 'Gene', '7157', (164, 167))	('ER expression', 'MPA', (197, 210))	('transgenic mice', 'Species', '10090', (298, 313))	('mouse mammary tumor virus', 'Species', '11757', (266, 291))	('genotype', 'Var', (168, 176))	('correlated', 'Reg', (181, 191))	('tamoxifen', 'Chemical', 'MESH:D013629', (227, 236))	('p53', 'Gene', (164, 167))	('ERalpha', 'Gene', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('response to tamoxifen', 'MPA', (215, 236))	('p53', 'Gene', '7157', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('ERalpha', 'Gene', '2099', (36, 43))
103561	32147641	DCIS lesions were distinguished from IDC lesions with a wider range of percentile values in TSE-DWI than in EPI-DWI, although diagnostic performance was not significantly different between the techniques.	('DCIS lesions', 'Disease', (0, 12))	('IDC lesions', 'Disease', (37, 48))	('IDC lesions', 'Disease', 'MESH:D001768', (37, 48))	('TSE-DWI', 'Var', (92, 99))	('DCIS lesions', 'Disease', 'MESH:D002285', (0, 12))
103569	32147641	To detect cholesteatomas in the middle ear, TSE-DWI provides excellent sensitivity and specificity compared with EPI-DWI.	('TSE-DWI', 'Var', (44, 51))	('cholesteatomas', 'Disease', 'MESH:D002781', (10, 24))	('cholesteatomas', 'Disease', (10, 24))
103592	32147641	These two sites were identified in images of the TSE-DWI (b = 850 s/mm2), EPI-DWI (b = 850 s/mm2) and DCE-MR images, respectively (Figs.	('b = 850 s/mm2', 'Var', (83, 96))	('b = 850 s/mm2', 'Var', (58, 71))	('DCE', 'Chemical', '-', (102, 105))
103596	32147641	Segmentation covering as much as possible of the tumor was performed manually on each slice of the ADC maps of TSE-DWI and EPI-DWI (Figs.	('EPI-DWI', 'Var', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (49, 54))
103601	32147641	The 10th, 25th, 50th, 75th, and 90th percentiles were derived from the cumulative frequency distributions of the voxel-based ADC data of whole tumor volume in TSE-DWI and EPI-DWI, respectively.	('tumor', 'Disease', (143, 148))	('TSE-DWI', 'Var', (159, 166))	('EPI-DWI', 'Var', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
103628	32147641	The diagnostic performance to differentiate DCIS from IDC lesions was observed with a wider range of percentile values in TSE-DWI than EPI-DWI, although the diagnostic performance as assessed using the AUCs of ROC curve analysis was not significantly different between TSE-DWI and EPI-DWI.	('IDC lesions', 'Disease', 'MESH:D001768', (54, 65))	('DCIS', 'Disease', (44, 48))	('IDC lesions', 'Disease', (54, 65))	('TSE-DWI', 'Var', (122, 129))
103634	31124276	The AUC of Ktrans, Kep, D and the combined indicator of Ktrans, Kep, and D were 0.936, 0.902, 0.860, and 0.976, respectively.	('Ktrans', 'Chemical', '-', (11, 17))	('Kep', 'Chemical', '-', (19, 22))	('Kep', 'Chemical', '-', (64, 67))	('Ktrans', 'Chemical', '-', (56, 62))	('0.902', 'Var', (87, 92))	('0.860', 'Var', (94, 99))
103662	31124276	However, some high-grade DCIS lesions could lead to life-threatening invasive breast cancers if it is left untreated.26 Because DCIS lesions are precancerous rather than malignant lesions, they lack the typical manifestations of invasive ductal carcinoma and then it is difficult to distinguish DCIS from benign lesions in morphology.	('DCIS', 'Gene', (128, 132))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (238, 254))	('DCIS', 'Phenotype', 'HP:0030075', (295, 299))	('invasive breast cancers', 'Disease', (69, 92))	('lesions', 'Var', (133, 140))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (229, 254))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('invasive breast cancers', 'Disease', 'MESH:D001943', (69, 92))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('invasive ductal carcinoma', 'Disease', (229, 254))	('cancerous', 'Disease', 'MESH:D009369', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancerous', 'Disease', (148, 157))	('breast cancers', 'Phenotype', 'HP:0003002', (78, 92))
103670	31124276	An indicator that combined Ktrans, Kep, and D had a higher diagnostic efficiency than any single parameter.	('Ktrans', 'Var', (27, 33))	('diagnostic', 'MPA', (59, 69))	('Ktrans', 'Chemical', '-', (27, 33))	('Kep', 'Chemical', '-', (35, 38))	('higher', 'PosReg', (52, 58))	('Kep', 'Var', (35, 38))
103772	32204397	In contrast to this prevailing notion, several recent studies have found a plethora of molecular changes, such as loss of heterozygosity, miRNA, and gene aberrations in normal tissues immediately adjacent to areas of breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('plethora', 'Phenotype', 'HP:0001050', (75, 83))	('miRNA', 'MPA', (138, 143))	('breast carcinoma', 'Disease', (217, 233))	('loss of heterozygosity', 'Var', (114, 136))	('gene aberrations', 'Var', (149, 165))	('breast carcinoma', 'Disease', 'MESH:D001943', (217, 233))	('breast carcinoma', 'Phenotype', 'HP:0003002', (217, 233))
103812	32204397	Indeed, rescue of let-7b-5p significantly inhibited the expression of a majority of these mature miRNAs (75%, 9 of 12 miRNAs tested; Figure 4D), further validating that let-7b-5p-mediated regulation of DICER was involved in the global miRNA alterations that we observed.	('let-7b', 'Gene', (169, 175))	('DICER', 'Gene', (202, 207))	('rescue', 'Var', (8, 14))	('expression', 'MPA', (56, 66))	('inhibited', 'NegReg', (42, 51))	('let-7b', 'Gene', '406884', (18, 24))	('let-7b', 'Gene', '406884', (169, 175))	('let-7b', 'Gene', (18, 24))	('DICER', 'Gene', '23405', (202, 207))
103819	32204397	In order to establish if let-7b-5p independently predicts patient survival, we performed a multivariate Cox regression analysis with miRNA let-7b-5p, age, and stage as variables within the model.	('patient', 'Species', '9606', (58, 65))	('let-7b', 'Gene', '406884', (25, 31))	('let-7b', 'Gene', (25, 31))	('miRNA', 'Var', (133, 138))	('let-7b', 'Gene', '406884', (139, 145))	('let-7b', 'Gene', (139, 145))
103841	32204397	Most of their upstream miRNAs (miR-181a-5p, miR-204-5p, miR-424-3p, miR-497-5p, miR-195-5p, and miR-424-5p) are known as tumor suppressor miRNAs and were found to be lost in this first transition, causing an upregulation in the gene targets.	('miR-497', 'Gene', (68, 75))	('miR-424', 'Gene', (96, 103))	('miR-204', 'Gene', (44, 51))	('miR-497', 'Gene', '574456', (68, 75))	('miR-424', 'Gene', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-181a-5p', 'Var', (31, 42))	('miR-424', 'Gene', '494336', (96, 103))	('tumor', 'Disease', (121, 126))	('upregulation', 'PosReg', (208, 220))	('miR-424', 'Gene', '494336', (56, 63))	('miR-195', 'Gene', (80, 87))	('miR-195', 'Gene', '406971', (80, 87))	('miR-204', 'Gene', '406987', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
103871	32204397	While let- 7, miRNA-103/107 and miRNA-192 have been reported to target DICER, in our analyses, miRNAs other than let-7 did not make it to the list of potential targets based on the 5% context score cut off filter applied in our study and were not tested further.	('miRNA-103/107', 'Var', (14, 27))	('let-', 'Gene', (6, 10))	('DICER', 'Gene', '23405', (71, 76))	('miRNA-192', 'Gene', '406967', (32, 41))	('DICER', 'Gene', (71, 76))	('miRNA-192', 'Gene', (32, 41))
103872	32204397	The relevance of let-7b to the biology of breast cancer is further supported by studies that show low levels of let-7b to be associated with higher grade breast tumors, and more aggressive TP53 mutated tumors - factors associated with poorer outcome.	('breast tumors', 'Phenotype', 'HP:0100013', (154, 167))	('tumors', 'Disease', (161, 167))	('TP53', 'Gene', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('let-7b', 'Gene', '406884', (112, 118))	('let-7b', 'Gene', '406884', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (125, 135))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('TP53', 'Gene', '7157', (189, 193))	('let-7b', 'Gene', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('higher', 'Disease', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('let-7b', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutated', 'Var', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (202, 208))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast tumors', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Disease', (42, 55))	('breast tumors', 'Disease', (154, 167))
103873	32204397	Similarly, we found poorer disease-specific survival and overall survival in the TCGA breast cancer dataset in patients with low let-7b.	('low', 'Var', (125, 128))	('poorer', 'NegReg', (20, 26))	('let-7b', 'Gene', '406884', (129, 135))	('let-7b', 'Gene', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('disease-specific survival', 'CPA', (27, 52))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('overall survival', 'CPA', (57, 73))	('breast cancer', 'Disease', (86, 99))	('patients', 'Species', '9606', (111, 119))
103879	32204397	Our finding that the majority of miRNA and gene alterations that defined the DCIS (MCF10.	('gene alterations', 'Var', (43, 59))	('MCF10', 'CellLine', 'CVCL:5555', (83, 88))	('miRNA', 'MPA', (33, 38))
103901	32204397	The MCF10.CA1D and MCF10.CA1H cell lines were derived from MCF10.AT1 xenografts and form malignant tumors in xenograft mouse models.	('MCF10.CA1H', 'CellLine', 'CVCL:6683', (19, 29))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (59, 68))	('mouse', 'Species', '10090', (119, 124))	('malignant tumors', 'Disease', (89, 105))	('malignant tumors', 'Disease', 'MESH:D009369', (89, 105))	('MCF10.CA1D', 'CellLine', 'CVCL:6683', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MCF10.AT1', 'Var', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
103905	32204397	To test miRNA let-7b-5p or miRNA-29c-3p's effect on DICER expression, subconfluently growing MCF10.AT1 cells (about 175,000 cells/ well) that were plated in 6-well dishes were transfected with mirVana let-7b-5p miRNA mimic (MC11050) or random scramble miRNA mimic using Lipofectamine 2000 (ThermoFisher Scientific, Waltham, MA) according to the manufacturer's instructions.	('MC11050', 'Var', (224, 231))	('DICER', 'Gene', (52, 57))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (270, 288))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (93, 102))	('DICER', 'Gene', '23405', (52, 57))	('let-7b', 'Gene', '406884', (14, 20))	('miRNA-29c', 'Gene', (27, 36))	('let-7b', 'Gene', (14, 20))	('let-7b', 'Gene', '406884', (201, 207))	('miRNA-29c', 'Gene', '407026', (27, 36))	('let-7b', 'Gene', (201, 207))
103918	32204397	Endogenous DICER and vinculin protein levels were measured in subconfluently growing MCF10A panel cells and MCF10.AT1 cells that were transfected with scramble or let-7b-5p/ miRNA-29c-3p mimic by performing Western blotting, as described previously, using DICER antibody (CST# 5362, dilution 1:1000) and vinculin (ab# 130007, 1:2000).	('DICER', 'Gene', (11, 16))	('vinculin', 'Gene', '7414', (21, 29))	('CST# 5362', 'Var', (272, 281))	('DICER', 'Gene', '23405', (256, 261))	('miRNA-29c', 'Gene', (174, 183))	('vinculin', 'Gene', (21, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (85, 91))	('miRNA-29c', 'Gene', '407026', (174, 183))	('vinculin', 'Gene', '7414', (304, 312))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (108, 117))	('let-7b', 'Gene', '406884', (163, 169))	('DICER', 'Gene', '23405', (11, 16))	('let-7b', 'Gene', (163, 169))	('DICER', 'Gene', (256, 261))	('vinculin', 'Gene', (304, 312))
103925	32204397	In conclusion, our miRNA-seq, RNA-seq, and integromics analyses suggest that a majority of miRNA-, gene-, and pathway-level deregulation occurs at the very earliest stages in the histologic progression to basal-like breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('deregulation', 'Var', (124, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('miRNA-', 'Gene', (91, 97))
103931	23216814	We previously demonstrated that DNA damage or telomere malfunction induces an activin A-dependent epithelial stress response that activates cell-intrinsic and cell-extrinsic consequences in mortal, nontumorigenic human mammary epithelial cells (HMECs and vHMECs).	('malfunction', 'Var', (55, 66))	('human', 'Species', '9606', (213, 218))	('telomere', 'Protein', (46, 54))	('cell-intrinsic', 'MPA', (140, 154))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('activin', 'Gene', (78, 85))	('induces', 'Reg', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('activates', 'PosReg', (130, 139))	('epithelial stress response', 'MPA', (98, 124))	('activin', 'Gene', '83729', (78, 85))	('tumor', 'Disease', (201, 206))	('damage', 'Var', (36, 42))
103941	23216814	Additionally, the DDR activates p53 and Rb pathway-dependent barriers to malignancy through the induction of cell-cycle arrest, apoptosis, or senescence.	('cell-cycle arrest', 'CPA', (109, 126))	('senescence', 'CPA', (142, 152))	('DDR', 'Var', (18, 21))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('p53', 'Gene', (32, 35))	('malignancy', 'Disease', (73, 83))	('p53', 'Gene', '7157', (32, 35))	('activates', 'PosReg', (22, 31))	('apoptosis', 'CPA', (128, 137))
103943	23216814	We recently showed that the consequences of DDR in mortal, nontumorigenic human mammary epithelial cells can also be cell extrinsic.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('DDR', 'Var', (44, 47))	('human', 'Species', '9606', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
103945	23216814	In the present study, we investigated whether activating DDR in primary human mammary epithelial cells (derived from disease-free tissues), could have cell-extrinsic consequences, resulting in induction of genes associated with protumorigenic phenotypes in adjacent fibroblasts in vitro.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('DDR', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('genes', 'MPA', (206, 211))	('human', 'Species', '9606', (72, 77))	('tumor', 'Disease', (231, 236))	('activating', 'Var', (46, 56))	('induction', 'PosReg', (193, 202))
103952	23216814	In vivo, we demonstrated that preinvasive lesions (ductal carcinoma in situ, DCIS) exhibiting a DDR (shorter telomeres and gammaH2AX foci) are associated with high activin A and a stromal signature consistent with protumorigenic phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('high', 'PosReg', (159, 163))	('tumor', 'Disease', (217, 222))	('activin', 'Gene', (164, 171))	('ductal carcinoma', 'Disease', 'MESH:D044584', (51, 67))	('stromal signature', 'CPA', (180, 197))	('ductal carcinoma', 'Disease', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('gammaH2AX', 'Chemical', '-', (123, 132))	('gammaH2AX', 'Var', (123, 132))	('activin', 'Gene', '83729', (164, 171))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (51, 75))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
103954	23216814	Human mammary fibroblasts (HMFs) were isolated from disease-free tissues obtained from six individuals: RM9, RM15, RM21, RM111, RM124, and RM156.	('Human', 'Species', '9606', (0, 5))	('RM111', 'Var', (121, 126))	('RM21', 'Var', (115, 119))	('RM15', 'Var', (109, 113))	('RM9', 'Var', (104, 107))	('RM124', 'Var', (128, 133))
103959	23216814	Human mammary epithelial cells with silenced p16INK4A via promoter methylation, referred to as variant human mammary epithelial cells (vHMECs), were isolated from disease-free tissues obtained from three women: RM15, RM78, and RM79.	('Human', 'Species', '9606', (0, 5))	('RM15', 'Var', (211, 215))	('women', 'Species', '9606', (204, 209))	('human', 'Species', '9606', (103, 108))	('RM79', 'Var', (227, 231))	('p16INK4A', 'Gene', (45, 53))	('RM78', 'Var', (217, 221))	('p16INK4A', 'Gene', '1029', (45, 53))
103960	23216814	TRF2 and hTERT were overexpressed in vHMECs from RM78 and RM79, as described previously.	('TRF2', 'Gene', (0, 4))	('RM79', 'Var', (58, 62))	('hTERT', 'Gene', '7015', (9, 14))	('TRF2', 'Gene', '7014', (0, 4))	('hTERT', 'Gene', (9, 14))	('RM78', 'Var', (49, 53))	('overexpressed', 'PosReg', (20, 33))
103961	23216814	In brief, 1.7 x 105 HMFs from RM15 and RM21 were plated in RPMI + 10% FBS in the bottom chamber.	('RPMI', 'Chemical', '-', (59, 63))	('RM15', 'Var', (30, 34))	('RM21', 'Var', (39, 43))
103964	23216814	HMFs from RM111 and RM124 were plated in RMPI + 5% FBS and were exposed to exogenous activin A (0.08 mug/ml) or vehicle (dH20) for 48 hours.	('dH20', 'Gene', (121, 125))	('dH20', 'Gene', '33841', (121, 125))	('activin', 'Gene', (85, 92))	('RM124', 'Var', (20, 25))	('activin', 'Gene', '83729', (85, 92))	('RM111', 'Var', (10, 15))
103975	23216814	The levels of fibronectin and alpha-smooth muscle actin (alphaSMA) protein were evaluated in HMFs obtained from RM9, RM15, and RM111.	('alpha-smooth muscle actin', 'Gene', (30, 55))	('RM9', 'Var', (112, 115))	('alphaSMA', 'Gene', (57, 65))	('alpha-smooth muscle actin', 'Gene', '11475', (30, 55))	('alphaSMA', 'Gene', '11475', (57, 65))	('RM111', 'Var', (127, 132))	('RM15', 'Var', (117, 121))
103991	23216814	Genomic DNA was denatured for 2 minutes at 84 C. Two PNA probes, one specific for telomeres (Cy3-labeled, red) and one specific for centromeres (FITC-labeled, green), were hybridized to the tissues for 2 hours at room temperature.	('PNA', 'Gene', (53, 56))	('FITC', 'Chemical', 'MESH:D016650', (145, 149))	('Cy3', 'Chemical', '-', (93, 96))	('Cy3-labeled', 'Var', (93, 104))
103996	23216814	A two-tailed Fisher Exact Test was used to evaluate the relation between staining intensity (high or low) for activin A and telomere FISH, gammaH2AX, COX-2, CD31, alphaSMA, or immune infiltrate.	('gammaH2AX', 'Chemical', '-', (139, 148))	('gammaH2AX', 'Var', (139, 148))	('activin', 'Gene', '83729', (110, 117))	('alphaSMA', 'Gene', (163, 171))	('alphaSMA', 'Gene', '11475', (163, 171))	('CD31', 'Gene', (157, 161))	('COX-2', 'Gene', (150, 155))	('COX-2', 'Gene', '5743', (150, 155))	('CD31', 'Gene', '5175', (157, 161))	('activin', 'Gene', (110, 117))
103997	23216814	Activation of a stress response in epithelial cells reprograms adjacent fibroblasts to produce proteins associated with desmoplasia We demonstrated that telomere malfunction in mortal, nontumorigenic human mammary epithelial cells, with a compromised p16/Rb pathway (vHMEC), results in sustained induction of activin A.	('tumor', 'Disease', (188, 193))	('desmoplasia', 'Disease', 'None', (120, 131))	('activin', 'Gene', '83729', (309, 316))	('malfunction', 'Var', (162, 173))	('p16', 'Gene', (251, 254))	('p16', 'Gene', '1029', (251, 254))	('telomere malfunction', 'Var', (153, 173))	('induction', 'MPA', (296, 305))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('human', 'Species', '9606', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('activin', 'Gene', (309, 316))	('desmoplasia', 'Disease', (120, 131))
103999	23216814	To appreciate fully the impact of this novel stress response, we investigated whether mammary epithelial cells (vHMECs) with telomere malfunction, resulting in the production of activin A and PGE2, could induce phenotypes associated with desmoplasia in human mammary fibroblasts (HMFs).	('PGE2', 'Chemical', 'MESH:D015232', (192, 196))	('desmoplasia', 'Disease', (238, 249))	('activin', 'Gene', (178, 185))	('PGE2', 'Gene', (192, 196))	('desmoplasia', 'Disease', 'None', (238, 249))	('induce', 'Reg', (204, 210))	('malfunction', 'Var', (134, 145))	('human', 'Species', '9606', (253, 258))	('activin', 'Gene', '83729', (178, 185))
104010	23216814	Thus, telomere malfunction in vHMECs induces many of the molecules associated with desmoplasia in neighboring fibroblasts via paracrine signaling.	('induces', 'Reg', (37, 44))	('desmoplasia', 'Disease', (83, 94))	('paracrine', 'MPA', (126, 135))	('molecules', 'MPA', (57, 66))	('desmoplasia', 'Disease', 'None', (83, 94))	('telomere malfunction', 'Var', (6, 26))
104031	23216814	Treatment of HMFs with NS398 resulted in a 25% and 30% decrease in IL-8 and IL-6 protein levels, respectively (Figure 3B), but had no effect on fibronectin, collagen 1A1, tenascin C, VEGF, HIF1alpha, or activin A (Figure 3A through 3D, respectively).	('VEGF', 'Gene', (183, 187))	('IL-6', 'Gene', (76, 80))	('fibronectin', 'MPA', (144, 155))	('activin', 'Gene', '83729', (203, 210))	('IL-8', 'Gene', '3576', (67, 71))	('IL-6', 'Gene', '3569', (76, 80))	('NS398', 'Chemical', 'MESH:C080955', (23, 28))	('IL-8', 'Gene', (67, 71))	('VEGF', 'Gene', '7422', (183, 187))	('HIF1alpha', 'Gene', (189, 198))	('collagen 1A1', 'Gene', '1277', (157, 169))	('decrease', 'NegReg', (55, 63))	('HIF1alpha', 'Gene', '3091', (189, 198))	('tenascin C', 'Gene', '3371', (171, 181))	('tenascin C', 'Gene', (171, 181))	('activin', 'Gene', (203, 210))	('NS398', 'Var', (23, 28))	('collagen 1A1', 'Gene', (157, 169))
104039	23216814	The vHMECs exposed to conditioned medium from HMFs treated with exogenous activin A were more motile than were vHMECs exposed to any of the three other media described earlier (Figure 4).	('activin', 'Gene', (74, 81))	('motile', 'CPA', (94, 100))	('more', 'PosReg', (89, 93))	('exogenous', 'Var', (64, 73))	('activin', 'Gene', '83729', (74, 81))
104045	23216814	We previously showed that double-strand DNA damage in epithelial cells results in an activin A-dependent induction of COX-2.	('induction', 'PosReg', (105, 114))	('activin', 'Gene', (85, 92))	('COX-2', 'Gene', (118, 123))	('COX-2', 'Gene', '5743', (118, 123))	('activin', 'Gene', '83729', (85, 92))	('double-strand DNA', 'Var', (26, 43))
104051	23216814	Although HMFs exhibited very different toxicities to etoposide or NU7026 (4.2-fold versus 1.8-fold cell death after 48 hours; see Additional file 3), both exposures resulted in similar expression changes for most molecules investigated.	('toxicities', 'Disease', 'MESH:D064420', (39, 49))	('NU7026', 'Chemical', 'MESH:C479235', (66, 72))	('expression', 'MPA', (185, 195))	('NU7026', 'Var', (66, 72))	('etoposide', 'Chemical', 'MESH:D005047', (53, 62))	('toxicities', 'Disease', (39, 49))
104063	23216814	Consistent with our previous study, we found that DCIS lesions with high activin A expression (Figure 7B) exhibited reduced telomere signal (P = 0.03) and higher levels of gammaH2AX (P = 0.01) and COX-2 (P = 0.01) when compared with lesions with low activin A (Figure 7A).	('activin', 'Gene', (250, 257))	('gammaH2AX', 'Chemical', '-', (172, 181))	('high', 'Var', (68, 72))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('activin', 'Gene', '83729', (73, 80))	('gammaH2AX', 'MPA', (172, 181))	('telomere signal', 'MPA', (124, 139))	('levels', 'MPA', (162, 168))	('COX-2', 'Gene', (197, 202))	('COX-2', 'Gene', '5743', (197, 202))	('higher', 'PosReg', (155, 161))	('activin', 'Gene', '83729', (250, 257))	('reduced', 'NegReg', (116, 123))	('activin', 'Gene', (73, 80))
104068	23216814	We previously showed that DNA damage and telomere malfunction in human mammary epithelial cells results in an activin A-dependent induction of COX-2, causing cell-cycle arrest in non-p16-compromised epithelial cells and increased proliferation, motility, prostaglandin synthesis, and decreased apoptosis in p16-compromised epithelial cells.	('increased', 'PosReg', (220, 229))	('human', 'Species', '9606', (65, 70))	('induction', 'PosReg', (130, 139))	('activin', 'Gene', '83729', (110, 117))	('p16', 'Gene', '1029', (307, 310))	('apoptosis', 'CPA', (294, 303))	('cell-cycle arrest', 'CPA', (158, 175))	('COX-2', 'Gene', (143, 148))	('prostaglandin synthesis', 'MPA', (255, 278))	('motility', 'CPA', (245, 253))	('p16', 'Gene', (183, 186))	('decreased', 'NegReg', (284, 293))	('COX-2', 'Gene', '5743', (143, 148))	('p16', 'Gene', '1029', (183, 186))	('prostaglandin', 'Chemical', 'MESH:D011453', (255, 268))	('malfunction', 'Var', (50, 61))	('activin', 'Gene', (110, 117))	('p16', 'Gene', (307, 310))	('proliferation', 'CPA', (230, 243))
104070	23216814	Here we extend our initial observations by documenting that epithelial cells with DNA damage (telomere malfunction) can induce activin A and COX-2 in neighboring HMFs (Figures 1, 6B, 7, and 8).	('COX-2', 'Gene', (141, 146))	('induce', 'PosReg', (120, 126))	('COX-2', 'Gene', '5743', (141, 146))	('activin', 'Gene', (127, 134))	('DNA damage', 'Var', (82, 92))	('activin', 'Gene', '83729', (127, 134))
104076	23216814	DNA double-strand breaks (DSBs) (and the induction of DDR) are a common consequence of oncogene activation, replicative stress, inflammatory reactions, chromosomal breakage, and hypoxic stress, and also result from radio- and chemotherapy.	('oncogene', 'Gene', (87, 95))	('chromosomal breakage', 'Phenotype', 'HP:0040012', (152, 172))	('hypoxic stress', 'Disease', 'MESH:D004194', (178, 192))	('hypoxic stress', 'Disease', (178, 192))	('double-strand', 'Var', (4, 17))
104077	23216814	Likewise, telomere malfunction occurs in virtually all tumor types, and, in many cases, in preinvasive lesions such as DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('telomere', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('occurs', 'Reg', (31, 37))	('tumor', 'Disease', (55, 60))	('DCIS', 'Disease', (119, 123))
104078	23216814	In situ hybridization has demonstrated that telomere malfunction typically occurs in the epithelial compartment and is associated with poor prognosis and the progression of several malignancies.	('malignancies', 'Disease', (181, 193))	('telomere malfunction', 'Var', (44, 64))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('associated', 'Reg', (119, 129))
104103	23216814	SASPs develop over several days, occurs only after DNA damage exceeds a threshold that is associated with irreversible cell-cycle arrest, and is amplified by the loss of p53.	('loss', 'Var', (162, 166))	('p53', 'Gene', (170, 173))	('amplified', 'PosReg', (145, 154))	('p53', 'Gene', '7157', (170, 173))	('SASP', 'Gene', '7295', (0, 4))	('SASP', 'Gene', (0, 4))
104115	23216814	This demonstrates that exogenous activin A can induce a wide panel of molecules associated with protumorigenic phenotypes, and implies that, in addition to its role in epithelial cells, activin A may be a potent modulator of stroma structure and function.	('tumor', 'Disease', (99, 104))	('induce', 'PosReg', (47, 53))	('activin', 'Gene', (33, 40))	('activin', 'Gene', (186, 193))	('exogenous', 'Var', (23, 32))	('activin', 'Gene', '83729', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('activin', 'Gene', '83729', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
104122	23216814	Importantly, conditioned media from HMFs exposed to exogenous activin A enhance the motility of adjacent epithelial cells.	('exogenous', 'Var', (52, 61))	('motility of adjacent epithelial cells', 'CPA', (84, 121))	('enhance', 'PosReg', (72, 79))	('activin', 'Gene', (62, 69))	('activin', 'Gene', '83729', (62, 69))
104123	23216814	This work extends our previous study, showing that activin A and COX-2, induced by DNA damage in epithelial cells, can alter the behavior of adjacent, unaffected epithelia.	('COX-2', 'Gene', '5743', (65, 70))	('activin', 'Gene', '83729', (51, 58))	('alter', 'Reg', (119, 124))	('damage', 'Var', (87, 93))	('activin', 'Gene', (51, 58))	('behavior', 'MPA', (129, 137))	('COX-2', 'Gene', (65, 70))
104132	23216814	This work was supported by NIH/NCI grants PO1 CA107584, R01 CA097214, U54 CA143803, and California Breast Cancer Research Program 14OB-0165 to TDT and R01 Research Supplement for Underrepresented Minorities to CAF.	('TDT', 'Gene', '1791', (143, 146))	('CAF', 'Gene', (210, 213))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('TDT', 'Gene', (143, 146))	('CA097214', 'Var', (60, 68))	('CAF', 'Gene', '8850', (210, 213))	('Breast Cancer', 'Phenotype', 'HP:0003002', (99, 112))
104136	28165014	Furthermore, DCISM was associated with more aggressive tumor characteristics like higher rates of oestrogen receptor (ER) and progesterone receptor (PR) negativity, HER2 positivity, and lymph node metastasis.	('estrogen receptor', 'Gene', '2099', (99, 116))	('DCISM', 'Var', (13, 18))	('aggressive tumor', 'Disease', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PR', 'Gene', '5241', (149, 151))	('ER', 'Gene', '2099', (118, 120))	('ER', 'Gene', '2099', (166, 168))	('HER2', 'Gene', '2064', (165, 169))	('negativity', 'Var', (153, 163))	('estrogen receptor', 'Gene', (99, 116))	('DCISM', 'Chemical', '-', (13, 18))	('progesterone receptor', 'Gene', '5241', (126, 147))	('progesterone receptor', 'Gene', (126, 147))	('positivity', 'Var', (170, 180))	('lymph node metastasis', 'CPA', (186, 207))	('higher', 'PosReg', (82, 88))	('HER2', 'Gene', (165, 169))	('aggressive tumor', 'Disease', 'MESH:D001523', (44, 60))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
104137	28165014	With a median follow-up of 91 months, patients with DCISM had worse cancer-specific survival (CSS) (hazard ratio [HR], 2.475; P < 0.001) and overall survival (OS) (HR, 1.263; P < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CSS', 'Gene', (94, 97))	('DCISM', 'Chemical', '-', (52, 57))	('overall survival', 'CPA', (141, 157))	('worse', 'NegReg', (62, 67))	('OS', 'Chemical', '-', (159, 161))	('patients', 'Species', '9606', (38, 46))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('DCISM', 'Var', (52, 57))	('CSS', 'Gene', '55907', (94, 97))
104138	28165014	In the multivariable analysis, microinvasion was an independent prognostic factor for worse CSS (HR, 1.919; P < 0.001) and OS (HR, 1.184; P < 0.001).	('microinvasion', 'Var', (31, 44))	('OS', 'Chemical', '-', (123, 125))	('CSS', 'Gene', (92, 95))	('CSS', 'Gene', '55907', (92, 95))
104151	28165014	In addition, DCISM was associated with more aggressive tumor characteristics like ER negative (33.1% vs. 17.5%; P < 0.001), PR negative (44.9% vs. 27.3%; P < 0.001), HER2 positive (36.5% vs. 32.4%; P = 0.009) and lymph node metastasis (7.6% vs. 0%; P < 0.001).	('aggressive tumor', 'Disease', (44, 60))	('PR', 'Gene', '5241', (124, 126))	('HER2', 'Gene', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('DCISM', 'Var', (13, 18))	('HER2', 'Gene', '2064', (166, 170))	('ER', 'Gene', '2099', (167, 169))	('aggressive tumor', 'Disease', 'MESH:D001523', (44, 60))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))	('lymph node metastasis', 'CPA', (213, 234))	('ER', 'Gene', '2099', (82, 84))	('DCISM', 'Chemical', '-', (13, 18))
104157	28165014	In univariate analysis, DCISM patients was correlated with worse CSS (hazard ratio [HR], 2.475; 95% confidence interval [CI], 2.175-2.817; P < 0.001; log-rank P < 0.001; Fig.	('CSS', 'Gene', (65, 68))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('DCISM', 'Var', (24, 29))	('patients', 'Species', '9606', (30, 38))	('CSS', 'Gene', '55907', (65, 68))	('DCISM', 'Chemical', '-', (24, 29))
104163	28165014	All of these variables were included in the multivariate analysis, and microinvasion (DCISM vs. DCIS) was an independent prognostic factor for worse CSS (HR, 1.919; 95% CI, 1.643-2.240; P < 0.001) after adjusting for other prognostic factors.	('CSS', 'Gene', (149, 152))	('DCISM', 'Chemical', '-', (86, 91))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('CSS', 'Gene', '55907', (149, 152))	('microinvasion', 'Var', (71, 84))
104167	28165014	In the multivariate analysis, microinvasion (DCISM vs. DCIS) was also an independent prognostic factor for worse OS (HR, 1.184; 95% CI, 1.085-1.291; P < 0.001) with adjusting for other prognostic factors.	('worse OS', 'Disease', (107, 115))	('DCISM', 'Chemical', '-', (45, 50))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCISM', 'Var', (45, 50))	('OS', 'Chemical', '-', (113, 115))
104182	28165014	4, HRs for OS in subgroups of age (<40 years or >=40 years), race (white or black), gradeII, grade III and UD, ER positive, PR negative, no lymph node, surgery (yes or no) and no radiotherapy were significantly different between DCISM and DCIS.	('gradeII', 'Var', (84, 91))	('DCIS', 'Phenotype', 'HP:0030075', (239, 243))	('OS', 'Chemical', '-', (11, 13))	('PR', 'Gene', '5241', (124, 126))	('ER', 'Gene', '2099', (111, 113))	('DCISM', 'Chemical', '-', (229, 234))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))	('grade III', 'Var', (93, 102))
104188	28165014	Our analysis shows that DCISM patients have worse cancer-specific survival and overall survival in the univariate analysis (CSS: HR, 2.475; 95%CI, 2.175-2.817; P < 0.001; OS: HR, 1.263; 95% CI, 1.168-1.366; P < 0.001), and in the multivariate analysis, microinvasion is an independent prognostic factor for worse CSS (HR, 1.919; 95% CI, 1.643-2.240; P < 0.001) and OS (HR, 1.184; 95% CI, 1.085-1.291; P < 0.001).	('worse', 'NegReg', (44, 49))	('CSS', 'Gene', (313, 316))	('CSS', 'Gene', (124, 127))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('OS', 'Chemical', '-', (365, 367))	('OS', 'Chemical', '-', (171, 173))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('DCISM', 'Var', (24, 29))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('microinvasion', 'Var', (253, 266))	('CSS', 'Gene', '55907', (313, 316))	('CSS', 'Gene', '55907', (124, 127))	('DCISM', 'Chemical', '-', (24, 29))
104216	28165014	It has been proven that hormonal receptors negativity and HER2 overexpression promoted breast cancer invasion and metastasis.	('metastasis', 'CPA', (114, 124))	('negativity', 'Var', (43, 53))	('overexpression promoted', 'PosReg', (63, 86))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))	('hormonal receptors', 'Protein', (24, 42))
104221	28165014	Based on the results of the above studies, we could hypothesize that hormonal receptors negativity and HER2 overexpression might play an important role in the development of microinvasion in DCIS.	('microinvasion', 'MPA', (174, 187))	('play', 'Reg', (129, 133))	('hormonal', 'Protein', (69, 77))	('DCIS', 'Disease', (191, 195))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('HER2', 'Gene', '2064', (103, 107))	('overexpression', 'PosReg', (108, 122))	('HER2', 'Gene', (103, 107))	('negativity', 'Var', (88, 98))
104228	28165014	In conclusion, the clinicopathological characteristics of breast cancer patients with microinvasion are more aggressive than those of DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('microinvasion', 'Var', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('patients', 'Species', '9606', (72, 80))
104229	28165014	Furthermore, microinvasion is an independent prognostic factor for worse CSS and OS.	('CSS', 'Gene', (73, 76))	('CSS', 'Gene', '55907', (73, 76))	('microinvasion', 'Var', (13, 26))	('OS', 'Chemical', '-', (81, 83))
104235	28165014	To identify the eligible DCIS cohort, the inclusion criteria included females aged 20 to 69 years old; the first and only cancer diagnosis with stage Tis breast cancer between 1990 and 2012; patients with the International Classification of Diseases for Oncology Version 3 (ICD-O-3) codes of 8201/2 (Cribriform carcinoma in situ), 8230/2 (Duct carcinoma in situ, solid type), 8500/2 (Intraductal carcinoma, non-infiltrating), 8501/2 (Comedocarcinoma, non-infiltrating), 8503/2 (Noninfiltrating intraductal papillary adenocarcinoma), 8201/2 (Cribriform carcinoma in situ) and 8507/2 (Intraductal micropapillary carcinoma); and without ductal carcinoma with microinvasion.	('stage Tis breast cancer', 'Disease', 'MESH:D001943', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (440, 449))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('8230/2', 'Var', (331, 337))	('Duct carcinoma', 'Disease', 'MESH:D021441', (339, 353))	('ductal carcinoma', 'Disease', 'MESH:D044584', (389, 405))	('8503/2', 'Var', (470, 476))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('stage Tis breast cancer', 'Disease', (144, 167))	('Oncology', 'Phenotype', 'HP:0002664', (254, 262))	('cancer', 'Disease', (161, 167))	('intraductal papillary adenocarcinoma', 'Disease', 'MESH:D000231', (494, 530))	('Comedocarcinoma', 'Disease', (434, 449))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (552, 569))	('ductal carcinoma', 'Disease', (634, 650))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (634, 650))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('carcinoma in situ', 'Disease', (344, 361))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (506, 530))	('intraductal papillary adenocarcinoma', 'Disease', (494, 530))	('Intraductal micropapillary carcinoma', 'Disease', (583, 619))	('carcinoma in situ', 'Disease', 'MESH:D002278', (552, 569))	('carcinoma in situ', 'Disease', (311, 328))	('ICD', 'Disease', (274, 277))	('Duct carcinoma', 'Disease', (339, 353))	('ductal carcinoma', 'Disease', 'MESH:D044584', (634, 650))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (344, 361))	('ICD', 'Disease', 'OMIM:252500', (274, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (521, 530))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (311, 328))	('carcinoma in situ', 'Disease', 'MESH:D002278', (344, 361))	('Intraductal carcinoma', 'Disease', (384, 405))	('Duct carcinoma in situ', 'Phenotype', 'HP:0030075', (339, 361))	('Intraductal micropapillary carcinoma', 'Disease', 'MESH:D002285', (583, 619))	('patients', 'Species', '9606', (191, 199))	('Comedocarcinoma', 'Disease', 'None', (434, 449))	('Intraductal carcinoma', 'Disease', 'MESH:D002285', (384, 405))	('carcinoma in situ', 'Disease', 'MESH:D002278', (311, 328))	('cancer', 'Disease', (122, 128))	('8201/2', 'Var', (533, 539))	('carcinoma in situ', 'Disease', (552, 569))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (389, 405))
104236	28165014	To identify the eligible DCISM cohort, the inclusion criteria included females aged 20 to 69 years old; the first and only cancer diagnosis with stage T1mic breast cancer between 1990 and 2012; patients with ICD-O-3 codes of 8201/3 (Cribriform carcinoma), 8230/3 (Solid carcinoma), 8500/3 (Infiltrating duct carcinoma), 8501/3 (Comedocarcinoma), 8503/3 (Intraductal papillary adenocarcinoma with invasion), and 8507/3 (Ductal carcinoma, micropapillary).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ICD', 'Disease', 'OMIM:252500', (208, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('carcinoma', 'Disease', 'MESH:D002277', (426, 435))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('carcinoma', 'Disease', (334, 343))	('Ductal carcinoma', 'Phenotype', 'HP:0030075', (419, 435))	('carcinoma', 'Disease', (308, 317))	('Comedocarcinoma', 'Disease', 'None', (328, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (381, 390))	('carcinoma', 'Disease', (270, 279))	('carcinoma', 'Disease', (244, 253))	('Ductal carcinoma', 'Disease', (419, 435))	('patients', 'Species', '9606', (194, 202))	('DCISM', 'Chemical', '-', (25, 30))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('carcinoma', 'Disease', (381, 390))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (419, 435))	('cancer', 'Disease', (164, 170))	('papillary adenocarcinoma', 'Disease', 'MESH:D000231', (366, 390))	('carcinoma', 'Disease', 'MESH:D002277', (334, 343))	('carcinoma', 'Disease', (426, 435))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Comedocarcinoma', 'Disease', (328, 343))	('papillary adenocarcinoma', 'Disease', (366, 390))	('ICD', 'Disease', (208, 211))	('carcinoma', 'Disease', 'MESH:D002277', (308, 317))	('8230/3', 'Var', (256, 262))	('carcinoma', 'Disease', 'MESH:D002277', (270, 279))	('cancer', 'Disease', (123, 129))	('carcinoma', 'Disease', 'MESH:D002277', (244, 253))	('carcinoma', 'Disease', 'MESH:D002277', (381, 390))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (366, 390))
104257	19452229	Additionally, DNA methylation is an epigenetic modification that contributes to breast cancer progression by transcriptionally silencing certain tumor suppressor genes.	('DNA methylation', 'Var', (14, 29))	('tumor suppressor', 'Gene', (145, 161))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('contributes', 'Reg', (65, 76))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('tumor suppressor', 'Gene', '7248', (145, 161))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('silencing', 'NegReg', (127, 136))
104259	19452229	Measuring elevated gene copy number and aberrant gene promoter methylation can further facilitate characterization of breast tumor molecular subtype; however, profiling of breast tumors based on epigenetic criteria has yet to be established.	('breast tumor', 'Disease', 'MESH:D001943', (172, 184))	('breast tumor', 'Disease', 'MESH:D001943', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('gene', 'MPA', (19, 23))	('breast tumors', 'Phenotype', 'HP:0100013', (172, 185))	('breast tumor', 'Disease', (118, 130))	('breast tumors', 'Disease', 'MESH:D001943', (172, 185))	('breast tumor', 'Phenotype', 'HP:0100013', (172, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('elevated', 'PosReg', (10, 18))	('gene promoter methylation', 'MPA', (49, 74))	('breast tumor', 'Phenotype', 'HP:0100013', (118, 130))	('aberrant', 'Var', (40, 48))	('breast tumors', 'Disease', (172, 185))
104277	19452229	defined an additional low/moderate-ER subtype, luminal C, which is divergent from luminal A and B tumors because of shared traits with HER2 + tumors and BLBC, including expression of a unique gene cluster, prevalence of TP53 mutations, and poorer overall survival.	('TP53', 'Gene', '7157', (220, 224))	('tumors', 'Disease', (98, 104))	('TP53', 'Gene', (220, 224))	('HER2', 'Gene', (135, 139))	('ER', 'Gene', '2099', (35, 37))	('mutations', 'Var', (225, 234))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('HER2', 'Gene', '2064', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('B tumors', 'Disease', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('prevalence', 'Reg', (206, 216))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('B tumors', 'Disease', 'MESH:D006509', (96, 104))	('ER', 'Gene', '2099', (136, 138))
104284	19452229	Breast tumors of patients carrying BRCA1 mutations are generally BLBC.	('mutations', 'Var', (41, 50))	('Breast tumor', 'Phenotype', 'HP:0100013', (0, 12))	('Breast tumors', 'Disease', (0, 13))	('Breast tumors', 'Disease', 'MESH:D001943', (0, 13))	('Breast tumors', 'Phenotype', 'HP:0100013', (0, 13))	('BRCA1', 'Gene', '672', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('BRCA1', 'Gene', (35, 40))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
104287	19452229	There is currently no standard for BLBC characterization by IHC, but the presence of one or more myoepithelial cytokeratins (CK) is highly specific.	('myoepithelial', 'Disease', 'MESH:D009208', (97, 110))	('presence', 'Var', (73, 81))	('myoepithelial', 'Disease', (97, 110))
104302	19452229	The structurally related transmembrane glycoproteins HER2 and EGFR are members of the epidermal growth factor receptor family of receptor tyrosine kinases, and both genes are targets for copy number amplification in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('EGFR', 'Gene', '1956', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('epidermal growth factor receptor', 'Gene', (86, 118))	('copy number amplification', 'Var', (187, 212))	('EGFR', 'Gene', (62, 66))	('HER2', 'Gene', (53, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('HER2', 'Gene', '2064', (53, 57))	('epidermal growth factor receptor', 'Gene', '1956', (86, 118))
104303	19452229	The HER2 + subtype essentially results from gene amplification within the ERBB2 amplicon at 17q12-q22.	('ERBB2', 'Gene', (74, 79))	('results from', 'Reg', (31, 43))	('HER2', 'Gene', (4, 8))	('HER2', 'Gene', '2064', (4, 8))	('gene amplification', 'Var', (44, 62))	('ERBB2', 'Gene', '2064', (74, 79))
104306	19452229	Conversely, EGFR upregulation in BLBC is rarely due to gene amplification but often results from either high polysomy of chromosome 7 or transcriptional induction by the transcription factor YBX1 (Y box binding protein 1).	('high polysomy', 'Var', (104, 117))	('results from', 'Reg', (84, 96))	('Y box binding protein 1', 'Gene', '4904', (197, 220))	('YBX1', 'Gene', (191, 195))	('Y box binding protein 1', 'Gene', (197, 220))	('transcriptional', 'MPA', (137, 152))	('EGFR', 'Gene', '1956', (12, 16))	('YBX1', 'Gene', '4904', (191, 195))	('upregulation', 'PosReg', (17, 29))	('EGFR', 'Gene', (12, 16))
104307	19452229	Both EGFR activating mutations and high gene copy number promote sensitivity to gefitinib (selective EGFR tyrosine kinase inhibitor), whereas altered drug uptake/efflux transporters and acquired alternative/downstream signaling are the common resistance mechanisms.	('high gene copy number', 'Var', (35, 56))	('promote', 'PosReg', (57, 64))	('EGFR', 'Gene', '1956', (101, 105))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (5, 9))	('sensitivity', 'MPA', (65, 76))	('drug uptake/efflux transporters', 'MPA', (150, 181))	('EGFR', 'Gene', (5, 9))	('mutations', 'Var', (21, 30))
104308	19452229	In this regard, even though some BLBC cell lines are sensitive to gefitinib independent of activating EGFR mutations, combining gefitinib with suppression of YBX1 is necessary for drug sensitivity of anchorage-independent BLBC cells.	('drug sensitivity', 'Phenotype', 'HP:0020174', (180, 196))	('mutations', 'Var', (107, 116))	('gefitinib', 'Chemical', 'MESH:D000077156', (66, 75))	('YBX1', 'Gene', '4904', (158, 162))	('gefitinib', 'Chemical', 'MESH:D000077156', (128, 137))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('suppression', 'NegReg', (143, 154))	('YBX1', 'Gene', (158, 162))
104309	19452229	ESR1 (estrogen receptor 1) gene amplification at the 6q25.1 amplicon has been demonstrated in 20.6% of breast cancers using FISH and a tissue microarray of more than 2,000 clinical breast samples.	('estrogen receptor', 'Gene', (6, 23))	('ESR1', 'Gene', (0, 4))	('estrogen receptor', 'Gene', '2099', (6, 23))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('breast cancers', 'Disease', (103, 117))	('amplification', 'Var', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('ESR1', 'Gene', '2099', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))
104312	19452229	More important, survival is significantly longer in women receiving tamoxifen monotherapy for luminal breast cancer with ESR1 amplification than in those without ESR1 amplification.	('ESR1', 'Gene', '2099', (162, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('longer', 'PosReg', (42, 48))	('luminal breast cancer', 'Disease', (94, 115))	('ESR1', 'Gene', (121, 125))	('tamoxifen', 'Chemical', 'MESH:D013629', (68, 77))	('ESR1', 'Gene', (162, 166))	('survival', 'MPA', (16, 24))	('amplification', 'Var', (126, 139))	('luminal breast cancer', 'Disease', 'MESH:D001943', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('women', 'Species', '9606', (52, 57))	('ESR1', 'Gene', '2099', (121, 125))
104313	19452229	Since the cancer phenotype is attributable to both genetic and epigenetic changes within the genome, several distinct aberrant epigenetic events have been observed during the process of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('epigenetic', 'Var', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
104321	19452229	Moreover, it has been amply demonstrated that hypermethylation of CpG islands associated with TSGs is closely associated with their silencing.	('CpG islands', 'Gene', (66, 77))	('associated', 'Reg', (78, 88))	('TSG', 'Gene', (94, 97))	('TSG', 'Gene', '57045', (94, 97))	('associated', 'Reg', (110, 120))	('silencing', 'MPA', (132, 141))	('hypermethylation', 'Var', (46, 62))
104323	19452229	However, how specific genes are targeted for CpG hypermethylation and consequential silencing during the process of tumorigenesis is not well understood.	('hypermethylation', 'Var', (49, 65))	('silencing', 'NegReg', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
104326	19452229	Thus, in this review, we focus on gene hypermethylation as a marker for epigenetic gene silencing in breast cancer.	('gene hypermethylation', 'Var', (34, 55))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
104327	19452229	In a manner analogous to transcriptomic profiling, epigenetic profiling has potential to provide biomarkers useful in characterizing human malignancies and monitoring cancer progression based on a tumor-specific methylation signature.	('epigenetic', 'Var', (51, 61))	('malignancies', 'Disease', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('human', 'Species', '9606', (133, 138))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('tumor', 'Disease', (197, 202))
104329	19452229	Furthermore, since the MLH1 gene is one of the targets for silencing in CIMP + tumors, this phenotype is associated with microsatellite instability.	('MLH1', 'Gene', '4292', (23, 27))	('microsatellite instability', 'Var', (121, 147))	('MLH1', 'Gene', (23, 27))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CIMP +', 'Chemical', '-', (72, 78))	('silencing', 'NegReg', (59, 68))	('associated', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
104332	19452229	Specifically in melanoma, aberrant methylation of the MINT17, MINT31, TFPI2, WIF1, RASSF1A, and SOCS1 genes was found to be associated with advanced stage cancer, and methylation of a panel of TSGs in esophageal adenocarcinoma is a predictor of poor prognosis when compared with tumors that do not display aberrant methylation of these genes.	('aberrant methylation', 'Var', (26, 46))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('methylation', 'Var', (167, 178))	('tumors', 'Disease', (279, 285))	('TSG', 'Gene', '57045', (193, 196))	('advanced', 'Disease', (140, 148))	('RASSF1A', 'Gene', '11186', (83, 90))	('SOCS1', 'Gene', '8651', (96, 101))	('WIF1', 'Gene', '11197', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('TSG', 'Gene', (193, 196))	('RASSF1A', 'Gene', (83, 90))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('melanoma', 'Disease', (16, 24))	('TFPI2', 'Gene', '7980', (70, 75))	('WIF1', 'Gene', (77, 81))	('MINT17', 'Gene', (54, 60))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (201, 226))	('MINT31', 'Gene', (62, 68))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (201, 226))	('associated', 'Reg', (124, 134))	('methylation', 'Var', (35, 46))	('cancer', 'Disease', (155, 161))	('esophageal adenocarcinoma', 'Disease', (201, 226))	('SOCS1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('TFPI2', 'Gene', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
104335	19452229	Even though a hypermethylation signature can distinguish breast cancer from other non-breast tumor types, genome methylation profiling does not correlate with histologic type due to the relatively uni-modal distribution of methylation frequency between IDC, ILC, and mucinous carcinoma.	('ILC', 'Disease', (258, 261))	('breast cancer', 'Disease', (57, 70))	('breast tumor', 'Disease', 'MESH:D001943', (86, 98))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (267, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (267, 285))	('methylation', 'Var', (223, 234))	('mucinous carcinoma', 'Disease', (267, 285))	('breast tumor', 'Disease', (86, 98))	('IDC', 'Disease', (253, 256))	('breast tumor', 'Phenotype', 'HP:0100013', (86, 98))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
104337	19452229	Nevertheless, numerous genes have been characterized as targets for silencing in breast cancer, and when considered either individually or in modest-sized gene panels, provide us with key insight into the mechanisms driving breast cancer progression and the role that aberrant epigenetic marks can play as additional prognostic/diagnostic biomarkers.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (224, 237))	('silencing', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aberrant epigenetic marks', 'Var', (268, 293))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
104338	19452229	Epigenetic silencing is one mechanism by which mammary epithelial cells repress ER expression, leading to the ER- molecular subtypes of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('ER', 'Gene', '2099', (110, 112))	('ER', 'Gene', '2099', (80, 82))	('leading to', 'Reg', (95, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('Epigenetic silencing', 'Var', (0, 20))
104340	19452229	Primary breast tumors represent a heterogeneous cell population, and while studies have shown that ESR1 methylation is more common in ER- than in ER + tumors, mapping the ESR1 promoter CpG island by methylation-specific PCR (MSP) has not revealed clear and consistent results in tumors overall.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', (279, 285))	('ESR1', 'Gene', '2099', (171, 175))	('ER', 'Gene', '2099', (134, 136))	('breast tumor', 'Phenotype', 'HP:0100013', (8, 20))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('ESR1', 'Gene', (171, 175))	('Primary breast tumors', 'Disease', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Primary breast tumors', 'Disease', 'MESH:D001943', (0, 21))	('tumors', 'Disease', (151, 157))	('common', 'Reg', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('ESR1', 'Gene', '2099', (99, 103))	('breast tumors', 'Phenotype', 'HP:0100013', (8, 21))	('tumors', 'Disease', (15, 21))	('ESR1', 'Gene', (99, 103))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('ER', 'Gene', '2099', (146, 148))	('methylation', 'Var', (104, 115))
104341	19452229	In contrast to ER + breast cancer cell lines, where the ESR1 gene is unmethylated, many ER + breast tumors have shown evidence of ESR1 methylation.	('ESR1', 'Gene', (130, 134))	('methylation', 'Var', (135, 146))	('breast tumors', 'Disease', (93, 106))	('ESR1', 'Gene', '2099', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('breast cancer', 'Disease', (20, 33))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('ESR1', 'Gene', (56, 60))	('ESR1', 'Gene', '2099', (130, 134))	('breast tumors', 'Phenotype', 'HP:0100013', (93, 106))	('breast tumor', 'Phenotype', 'HP:0100013', (93, 105))	('ER', 'Gene', '2099', (15, 17))	('ER', 'Gene', '2099', (88, 90))	('breast tumors', 'Disease', 'MESH:D001943', (93, 106))
104342	19452229	Furthermore, even though ESR1 methylation has proven to be a significantly better predictor of clinical response to adjuvant tamoxifen than hormone receptor status scored by IHC, PGR methylation was actually the best predictor of ER status (inverse association) in a panel of 35 markers that included ESR1.	('ESR1', 'Gene', (25, 29))	('methylation', 'Var', (30, 41))	('hormone receptor', 'Gene', (140, 156))	('PGR', 'Gene', '5241', (179, 182))	('hormone receptor', 'Gene', '3164', (140, 156))	('ER', 'Gene', '2099', (230, 232))	('methylation', 'Var', (183, 194))	('ESR1', 'Gene', '2099', (301, 305))	('ESR1', 'Gene', '2099', (25, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('PGR', 'Gene', (179, 182))	('ESR1', 'Gene', (301, 305))
104344	19452229	Breast tumors with BRCA1 (breast cancer 1, early onset) methylation show a disproportionately higher frequency of ESR1 promoter methylation.	('Breast tumor', 'Phenotype', 'HP:0100013', (0, 12))	('breast cancer 1', 'Gene', '672', (26, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('Breast tumors', 'Disease', (0, 13))	('Breast tumors', 'Disease', 'MESH:D001943', (0, 13))	('ESR1', 'Gene', '2099', (114, 118))	('Breast tumors', 'Phenotype', 'HP:0100013', (0, 13))	('breast cancer 1', 'Gene', (26, 41))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('BRCA1', 'Gene', '672', (19, 24))	('ESR1', 'Gene', (114, 118))	('methylation', 'Var', (56, 67))	('promoter', 'MPA', (119, 127))	('BRCA1', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
104346	19452229	Unlike many other TSGs, BRCA1 somatic mutations are extremely rare in sporadic breast cancer, but 9-13% of these tumors reveal aberrant BRCA1 gene methylation, especially when loss of heterozygosity occurs at the BRCA1 locus.	('tumors', 'Disease', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', (79, 92))	('methylation', 'MPA', (147, 158))	('aberrant', 'Var', (127, 135))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TSG', 'Gene', '57045', (18, 21))	('BRCA1', 'Gene', '672', (136, 141))	('TSG', 'Gene', (18, 21))	('BRCA1', 'Gene', (136, 141))	('BRCA1', 'Gene', '672', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BRCA1', 'Gene', (24, 29))	('loss of heterozygosity', 'Var', (176, 198))	('BRCA1', 'Gene', '672', (213, 218))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA1', 'Gene', (213, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
104347	19452229	BRCA1 methylation is associated with increased breast-cancer-specificmortality, but it was not clear in this study the relationship between BRCA1 methylation, BLBC, and mortality.	('BRCA1', 'Gene', (0, 5))	('BRCA1', 'Gene', (140, 145))	('breast-cancer', 'Disease', 'MESH:D001943', (47, 60))	('methylation', 'Var', (6, 17))	('increased', 'PosReg', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast-cancer', 'Disease', (47, 60))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1', 'Gene', '672', (140, 145))
104348	19452229	Although breast tumors of patients carrying BRCA1 mutations are generally BLBC, there is no significant difference in BRCA1 methylation between sporadic BLBC (14%) and sporadic non-BLBC controls matched for age and grade (11%).	('BRCA1', 'Gene', (44, 49))	('breast tumors', 'Disease', 'MESH:D001943', (9, 22))	('mutations', 'Var', (50, 59))	('breast tumors', 'Disease', (9, 22))	('methylation', 'MPA', (124, 135))	('breast tumors', 'Phenotype', 'HP:0100013', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('patients', 'Species', '9606', (26, 34))	('BRCA1', 'Gene', '672', (118, 123))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1', 'Gene', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('breast tumor', 'Phenotype', 'HP:0100013', (9, 21))
104350	19452229	BRCA1 promoter methylation is associated with reduced expression by IHC and qPCR, which have been positively correlated.	('expression', 'MPA', (54, 64))	('methylation', 'Var', (15, 26))	('BRCA1', 'Gene', (0, 5))	('reduced', 'NegReg', (46, 53))	('BRCA1', 'Gene', '672', (0, 5))
104352	19452229	Sporadic BLBC, however, more frequently contains unmethylated BRCA1 coupled with high BRCA1 expression, consistent with a high mitotic rate and normal regulation of BRCA1 expression.	('unmethylated', 'Var', (49, 61))	('BRCA1', 'Gene', (165, 170))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA1', 'Gene', '672', (62, 67))	('BRCA1', 'Gene', (86, 91))	('BRCA1', 'Gene', (62, 67))	('contains', 'Reg', (40, 48))	('BRCA1', 'Gene', '672', (165, 170))	('expression', 'MPA', (92, 102))
104356	19452229	Both BRCA1 and ESR1 gene methylation are also associated with medullary breast cancer, a histologic special type prevalent in BRCA1 carriers.	('BRCA1', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ESR1', 'Gene', '2099', (15, 19))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('methylation', 'Var', (25, 36))	('BRCA1', 'Gene', '672', (5, 10))	('associated', 'Reg', (46, 56))	('breast cancer', 'Disease', (72, 85))	('ESR1', 'Gene', (15, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA1', 'Gene', '672', (126, 131))	('BRCA1', 'Gene', (5, 10))
104358	19452229	Furthermore, SCGB3A1 (secretoglobin, family 3A, member 1) gene methylation is a potential surrogate marker of medullary breast tumors since it is methylated in most sporadic breast tumors and unmethylated in medullary carcinoma and BRCA1-deficient tumors.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA1-deficient tumors', 'Disease', 'MESH:D009369', (232, 254))	('breast tumors', 'Disease', 'MESH:D001943', (120, 133))	('breast tumors', 'Disease', (120, 133))	('methylation', 'Var', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('breast tumors', 'Phenotype', 'HP:0100013', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('breast tumor', 'Phenotype', 'HP:0100013', (174, 186))	('carcinoma', 'Disease', 'MESH:D002277', (218, 227))	('breast tumor', 'Phenotype', 'HP:0100013', (120, 132))	('secretoglobin, family 3A, member 1', 'Gene', '92304', (22, 56))	('breast tumors', 'Disease', 'MESH:D001943', (174, 187))	('breast tumors', 'Disease', (174, 187))	('breast tumors', 'Phenotype', 'HP:0100013', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('SCGB3A1', 'Gene', '92304', (13, 20))	('BRCA1-deficient tumors', 'Disease', (232, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('SCGB3A1', 'Gene', (13, 20))	('carcinoma', 'Disease', (218, 227))
104362	19452229	Female X-linked gene expression is quite variable, and further studies are needed to elucidate how epigenetic changes in Xi contribute to breast cancer progression and the gender specificity of certain tumors.	('epigenetic changes', 'Var', (99, 117))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('contribute', 'Reg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
104363	19452229	Epigenetic silencing is considered to be a mechanism that can act as a hit in Knudson's two-hit hypothesis of tumorigenesis.	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
104365	19452229	A subset of these genes is methylated in proliferative and in situ breast lesions, strongly suggesting a role for epigenetic silencing in the initiation and/or progression of breast cancer (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('situ breast lesions', 'Disease', (62, 81))	('situ breast lesions', 'Disease', 'MESH:D000071960', (62, 81))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('epigenetic silencing', 'Var', (114, 134))
104367	19452229	Epigenetic silencing by promoter methylation is the most common mechanism of RASSF1A inactivation and occurs early in breast cancer progression.	('inactivation', 'NegReg', (85, 97))	('RASSF1A', 'Gene', '11186', (77, 84))	('promoter', 'MPA', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', (118, 131))	('Epigenetic silencing', 'Var', (0, 20))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('RASSF1A', 'Gene', (77, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
104371	19452229	These studies characterize RASSF1A hypermethylation as a biomarker of pathologic proliferation in breast epithelium and suggest that RASSF1A methylation occurs before invasive growth develops.	('hypermethylation', 'Var', (35, 51))	('RASSF1A', 'Gene', (133, 140))	('RASSF1A', 'Gene', (27, 34))	('RASSF1A', 'Gene', '11186', (133, 140))	('RASSF1A', 'Gene', '11186', (27, 34))	('methylation', 'Var', (141, 152))
104372	19452229	SFN (stratifin), a TSG involved in cell-cycle control and regulated by TP53, is frequently epigenetically silenced in breast cancer.	('stratifin', 'Gene', '2810', (5, 14))	('SFN', 'Gene', '2810', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SFN', 'Gene', (0, 3))	('stratifin', 'Gene', (5, 14))	('epigenetically silenced', 'Var', (91, 114))	('breast cancer', 'Disease', (118, 131))	('TSG', 'Gene', (19, 22))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('TSG', 'Gene', '57045', (19, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
104373	19452229	Similar to RASSF1A, SFN methylation frequently occurs in microdissected atypical hyperplasia and DCIS.	('SFN', 'Gene', '2810', (20, 23))	('occurs', 'Reg', (47, 53))	('RASSF1A', 'Gene', (11, 18))	('DCIS', 'Disease', (97, 101))	('SFN', 'Gene', (20, 23))	('hyperplasia', 'Disease', (81, 92))	('methylation', 'Var', (24, 35))	('RASSF1A', 'Gene', '11186', (11, 18))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('hyperplasia', 'Disease', 'MESH:D006965', (81, 92))
104378	19452229	MSP has confirmed frequent RARB promoter methylation in human breast cancer at the same CpG site previously determined by BGS.	('RARB', 'Gene', '5915', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('human', 'Species', '9606', (56, 61))	('methylation', 'Var', (41, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('RARB', 'Gene', (27, 31))
104379	19452229	Furthermore, RARB methylation frequency positively correlates with increasing cytologic abnormality using the Masood cytology index, supporting a role for RARB methylation in breast cancer risk assessment.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('RARB', 'Gene', (155, 159))	('breast cancer', 'Disease', (175, 188))	('cytologic abnormality', 'MPA', (78, 99))	('RARB', 'Gene', '5915', (155, 159))	('RARB', 'Gene', (13, 17))	('methylation', 'Var', (18, 29))	('RARB', 'Gene', '5915', (13, 17))
104381	19452229	Secreted cystatin E/M inhibits the lysosomal cysteine proteases that can degrade the extracellular matrix, and this tumor suppressor (referred to as CST6) is silenced by aberrant methylation in both DCIS and IDC.	('aberrant methylation', 'Var', (170, 190))	('CST6', 'Gene', '1474', (149, 153))	('IDC', 'Gene', (208, 211))	('inhibits', 'NegReg', (22, 30))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('tumor suppressor', 'Gene', (116, 132))	('lysosomal cysteine proteases', 'Enzyme', (35, 63))	('methylation', 'Var', (179, 190))	('tumor suppressor', 'Gene', '7248', (116, 132))	('cystatin E', 'Gene', '1474', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('CST6', 'Gene', (149, 153))	('DCIS', 'Gene', (199, 203))	('cystatin E', 'Gene', (9, 19))	('degrade', 'NegReg', (73, 80))	('silenced', 'NegReg', (158, 166))
104383	19452229	WIF1 is frequently methylated in primary breast tumors, and reduced tumor expression has correlated with methylation when compared with patient-matched normal breast tissue.	('tumor', 'Disease', (68, 73))	('methylation', 'Var', (105, 116))	('WIF1', 'Gene', (0, 4))	('tumor', 'Disease', (48, 53))	('patient', 'Species', '9606', (136, 143))	('WIF1', 'Gene', '11197', (0, 4))	('breast tumors', 'Phenotype', 'HP:0100013', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('breast tumor', 'Phenotype', 'HP:0100013', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('reduced', 'NegReg', (60, 67))	('breast tumors', 'Disease', 'MESH:D001943', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('breast tumors', 'Disease', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
104384	19452229	TGM2 (transglutaminase 2) catalyzes extracellular matrix cross-links and is commonly epigenetically silenced in primary breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('epigenetically', 'Var', (85, 99))	('breast tumors', 'Phenotype', 'HP:0100013', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('extracellular', 'Protein', (36, 49))	('TGM2', 'Gene', (0, 4))	('breast tumor', 'Phenotype', 'HP:0100013', (120, 132))	('breast tumors', 'Disease', 'MESH:D001943', (120, 133))	('TGM2', 'Gene', '7052', (0, 4))	('breast tumors', 'Disease', (120, 133))	('catalyzes', 'Reg', (26, 35))	('transglutaminase 2', 'Gene', (6, 24))	('transglutaminase 2', 'Gene', '7052', (6, 24))
104386	19452229	More important, in vitro doxorubicin sensitivity is abrogated following 5-azadC treatment in breast cancer cells with TGM2 hypermethylation, making this epigenetic event a potential biomarker for chemosensitivity.	('abrogated', 'NegReg', (52, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('TGM2', 'Gene', (118, 122))	('doxorubicin sensitivity', 'MPA', (25, 48))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))	('breast cancer', 'Disease', (93, 106))	('hypermethylation', 'Var', (123, 139))	('5-azadC', 'Chemical', 'MESH:D000077209', (72, 79))	('TGM2', 'Gene', '7052', (118, 122))
104388	19452229	Both lobular carcinoma in situ (LCIS) and ILC characteristically lack E-cadherin expression by IHC, and promoter methylation is one mechanism known to silence CDH1 in this histologic special type.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (13, 30))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (5, 22))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (5, 30))	('CDH1', 'Gene', (159, 163))	('lack', 'NegReg', (65, 69))	('lobular carcinoma in situ', 'Disease', (5, 30))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (5, 30))	('CDH1', 'Gene', '999', (159, 163))	('LCIS', 'Phenotype', 'HP:0030076', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))	('expression', 'MPA', (81, 91))	('promoter methylation', 'Var', (104, 124))
104389	19452229	SCGB3A1 encodes a putative cytokine and is a candidate TSG epigenetically silenced in primary breast tumors as well as DCIS and LCIS.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('SCGB3A1', 'Gene', '92304', (0, 7))	('breast tumors', 'Phenotype', 'HP:0100013', (94, 107))	('breast tumors', 'Disease', (94, 107))	('breast tumors', 'Disease', 'MESH:D001943', (94, 107))	('TSG', 'Gene', '57045', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('LCIS', 'Phenotype', 'HP:0030076', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('DCIS', 'Disease', (119, 123))	('epigenetically silenced', 'Var', (59, 82))	('TSG', 'Gene', (55, 58))	('breast tumor', 'Phenotype', 'HP:0100013', (94, 106))	('SCGB3A1', 'Gene', (0, 7))
104390	19452229	One or more genes among a five-gene panel including SCGB3A1, RASSF1A, and RARB was methylated in 100% of IDC and ILC, 95% of DCIS, and 69% of LCIS by MSP.	('RASSF1A', 'Gene', (61, 68))	('SCGB3A1', 'Gene', (52, 59))	('RASSF1A', 'Gene', '11186', (61, 68))	('SCGB3A1', 'Gene', '92304', (52, 59))	('IDC', 'Disease', (105, 108))	('RARB', 'Gene', (74, 78))	('LCIS', 'Phenotype', 'HP:0030076', (142, 146))	('methylated', 'Var', (83, 93))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('RARB', 'Gene', '5915', (74, 78))
104394	19452229	Given the nature of aberrant epigenetic changes as early events in breast cancer progression, epigenetic analysis has the potential to improve the accuracy of cytology commonly used for breast cancer risk assessment, routine screening, diagnosis, and surveillance.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('aberrant epigenetic changes', 'Var', (20, 47))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('improve', 'PosReg', (135, 142))
104397	19452229	Furthermore, the results of this study seemed quite promising for using DNA methylation to detect cancer in NDLs taken from high-risk women with healthy mammograms, because methylation correlated to the cytology that led to a diagnosis of breast cancer in two women.	('methylation', 'Var', (173, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (239, 252))	('cancer', 'Disease', (246, 252))	('women', 'Species', '9606', (260, 265))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('women', 'Species', '9606', (134, 139))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('led to', 'Reg', (217, 223))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
104399	19452229	While aberrant DNA methylation was detected in NAF specimens from patients with DCIS or stage I cancer, Krassenstein et al.	('detected', 'Reg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NAF', 'Gene', (47, 50))	('aberrant', 'Var', (6, 14))	('DCIS', 'Disease', (80, 84))	('NAF', 'Gene', '3576', (47, 50))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('I cancer', 'Disease', 'MESH:D009369', (94, 102))	('patients', 'Species', '9606', (66, 74))	('I cancer', 'Disease', (94, 102))
104407	19452229	Furthermore, studies conducted on benign FNA samples taken ipsilateral or contralateral to a diagnosed cancer show that RASSF1A methylation correlates with increased breast cancer risk and atypical cytology.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('RASSF1A', 'Gene', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (173, 179))	('RASSF1A', 'Gene', '11186', (120, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('methylation', 'Var', (128, 139))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
104408	19452229	BRCA1 methylation, however, does not enhance risk assessment and does not predict mammary atypia in RPFNA samples from "high-risk" women.	('BRCA1', 'Gene', (0, 5))	('women', 'Species', '9606', (131, 136))	('methylation', 'Var', (6, 17))	('BRCA1', 'Gene', '672', (0, 5))	('mammary atypia', 'Disease', (82, 96))
104409	19452229	Similarly, ESR1 methylation predicts neither mammary atypia in RPFNA nor persistent atypia after 12 months of tamoxifen chemoprevention, despite its utility predicting clinical response of invasive breast cancer to adjuvant tamoxifen.	('ESR1', 'Gene', '2099', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('invasive breast cancer', 'Disease', (189, 211))	('mammary atypia', 'Disease', (45, 59))	('tamoxifen', 'Chemical', 'MESH:D013629', (224, 233))	('ESR1', 'Gene', (11, 15))	('invasive breast cancer', 'Disease', 'MESH:D001943', (189, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('predicts', 'Reg', (28, 36))	('methylation', 'Var', (16, 27))
104414	19452229	Aberrant methylation of at least one gene in a three-gene panel (RASSF1A, APC, DAPK1) was positive in the serum of 76% of preoperative patients with in situ or invasive breast cancer.	('APC', 'Disease', 'MESH:D011125', (74, 77))	('APC', 'Disease', (74, 77))	('patients', 'Species', '9606', (135, 143))	('DAPK1', 'Gene', '1612', (79, 84))	('RASSF1A', 'Gene', (65, 72))	('invasive breast cancer', 'Disease', 'MESH:D001943', (160, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Aberrant methylation', 'Var', (0, 20))	('RASSF1A', 'Gene', '11186', (65, 72))	('positive', 'Reg', (90, 98))	('DAPK1', 'Gene', (79, 84))	('invasive breast cancer', 'Disease', (160, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
104415	19452229	Furthermore, RASSF1A methylation in DNA isolated from serum is an independent indicator of poor prognosis in patients with primary or metastatic breast cancer.	('RASSF1A', 'Gene', (13, 20))	('patients', 'Species', '9606', (109, 117))	('methylation', 'Var', (21, 32))	('primary', 'Disease', (123, 130))	('RASSF1A', 'Gene', '11186', (13, 20))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
104417	19452229	Most recently, plasma from women with stage I-IV breast cancer were analyzed using a four-gene panel (APC, GSTP1, RASSF1A, and RARB), and quantitative methylation of at least one gene in this panel had moderate predictive capability for breast cancer detection.	('quantitative methylation', 'Var', (138, 162))	('APC', 'Disease', 'MESH:D011125', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('APC', 'Disease', (102, 105))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('GSTP1', 'Gene', (107, 112))	('RASSF1A', 'Gene', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (237, 250))	('RARB', 'Gene', (127, 131))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('women', 'Species', '9606', (27, 32))	('RARB', 'Gene', '5915', (127, 131))	('GSTP1', 'Gene', '2950', (107, 112))	('RASSF1A', 'Gene', '11186', (114, 121))
104420	19452229	Both gene copy number amplification and epigenetic gene silencing are prominent molecular mechanisms that can propel a malignant phenotype and the development of a specific breast tumor subtype.	('epigenetic gene silencing', 'Var', (40, 65))	('breast tumor', 'Phenotype', 'HP:0100013', (173, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('malignant phenotype', 'CPA', (119, 138))	('breast tumor', 'Disease', 'MESH:D001943', (173, 185))	('breast tumor', 'Disease', (173, 185))	('propel', 'PosReg', (110, 116))
104421	19452229	Because TSGs often undergo promoter methylation prior to observable histopathologic changes, epigenetic analysis in conjunction with minimally invasive techniques has high potential to improve risk assessment and diagnostic accuracy.	('promoter methylation', 'MPA', (27, 47))	('undergo', 'Reg', (19, 26))	('epigenetic analysis', 'Var', (93, 112))	('TSG', 'Gene', (8, 11))	('improve', 'PosReg', (185, 192))	('TSG', 'Gene', '57045', (8, 11))
104427	21559090	Clinical-pathological features analysis of breast cancer revealed that ER81 expression was significantly associated with Her2 amplification and was negatively associated with ER and PR expression.	('Her2', 'Gene', (121, 125))	('breast cancer', 'Disease', (43, 56))	('Her2', 'Gene', '2064', (121, 125))	('ER81', 'Gene', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('negatively', 'NegReg', (148, 158))	('amplification', 'Var', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('associated', 'Reg', (105, 115))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
104433	21559090	From then on, many findings suggest that dysregulation of ER81 target genes in disparate tumors like Ewing sarcomas and prostate carcinomas are causally involved in tumorigenesis.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('dysregulation', 'Var', (41, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('ER81', 'Gene', (58, 62))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (101, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('disparate tumors like Ewing sarcomas and prostate carcinomas', 'Disease', 'MESH:C563168', (79, 139))	('involved', 'Reg', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (165, 170))
104435	21559090	Moreover, ER81 mRNA levels are increased in murine cell lines and tumors overexpressing Her2/Neu and also in many human breast cancer cell lines, which suggests that ER81 may contribute to breast tumorigenesis.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('increased', 'PosReg', (31, 40))	('ER81', 'Gene', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('human', 'Species', '9606', (114, 119))	('breast tumor', 'Disease', 'MESH:D001943', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Her2/Neu', 'Protein', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('contribute', 'Reg', (175, 185))	('ER81', 'Var', (166, 170))	('murine', 'Species', '10090', (44, 50))	('mRNA levels', 'MPA', (15, 26))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('breast tumor', 'Phenotype', 'HP:0100013', (189, 201))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast tumor', 'Disease', (189, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('tumors', 'Disease', (66, 72))
104459	21559090	6 of 17 atypical hyperplasia cases were ER81 expression "++" and 1 case was ER81 expression "+++" with IRS  =  6.	('hyperplasia', 'Disease', 'MESH:D006965', (17, 28))	('ER81 expression "++', 'Var', (40, 59))	('IRS  =  6', 'Gene', (103, 112))	('IRS  =  6', 'Gene', '55816', (103, 112))	('hyperplasia', 'Disease', (17, 28))
104461	21559090	4 of 22 (18.2%) ductal carcinoma in situ tissues was ER81 expression "+++" and 8 of 22 (36.4%) cases were ER81 expression "++".	('ductal carcinoma', 'Phenotype', 'HP:0030075', (16, 32))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (16, 40))	('carcinoma in situ', 'Disease', 'MESH:D002278', (23, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('carcinoma in situ', 'Disease', (23, 40))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (23, 40))	('ductal carcinoma', 'Disease', 'MESH:D044584', (16, 32))	('ductal carcinoma', 'Disease', (16, 32))	('ER81 expression "+++', 'Var', (53, 73))
104464	21559090	The average IRS of invasive ductal carcinomas for ER81 was 3.74, and 19 of 81 cases (23.4%) showed ER81 expression "+++".	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (19, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('invasive ductal carcinomas', 'Disease', (19, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('ER81', 'Var', (50, 54))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (28, 44))	('ER81', 'Var', (99, 103))
104480	21559090	These histopathological studies data provide convincing evidence that some forms of proliferative lesions are often found in association with invasive cancer and that ADH provides a significantly increased relative risk of subsequent invasive carcinoma.	('ADH', 'Var', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('invasive carcinoma', 'Disease', 'MESH:D009361', (234, 252))	('invasive cancer', 'Disease', (142, 157))	('invasive carcinoma', 'Disease', (234, 252))	('invasive cancer', 'Disease', 'MESH:D009362', (142, 157))
104483	21559090	On the other hand, ER81 can target Her2 and upregulate Her2 expression in breast tumors, suggesting the existence of a feed-forward loop in the upregulation of HER2/Neu.	('expression', 'MPA', (60, 70))	('Her2', 'Gene', (35, 39))	('breast tumors', 'Phenotype', 'HP:0100013', (74, 87))	('HER2', 'Gene', (160, 164))	('breast tumor', 'Phenotype', 'HP:0100013', (74, 86))	('HER2', 'Gene', '2064', (160, 164))	('breast tumors', 'Disease', (74, 87))	('breast tumors', 'Disease', 'MESH:D001943', (74, 87))	('Her2', 'Gene', '2064', (35, 39))	('upregulate', 'PosReg', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('ER81', 'Var', (19, 23))	('Neu', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Neu', 'Gene', '2064', (165, 168))	('Her2', 'Gene', (55, 59))	('Her2', 'Gene', '2064', (55, 59))
104484	21559090	Moreover, ER81 mRNA levels are increased in murine cell lines and tumors overexpressing Her2/Neu and also in many human breast cancer cell lines, suggesting that ER81 may contribute to breast tumorigenesis.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('increased', 'PosReg', (31, 40))	('contribute', 'Reg', (171, 181))	('ER81', 'Var', (162, 166))	('ER81', 'Gene', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('breast tumor', 'Phenotype', 'HP:0100013', (185, 197))	('human', 'Species', '9606', (114, 119))	('breast tumor', 'Disease', (185, 197))	('Her2/Neu', 'Protein', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('murine', 'Species', '10090', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mRNA levels', 'MPA', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('tumors', 'Disease', (66, 72))	('breast tumor', 'Disease', 'MESH:D001943', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
104492	21559090	In Her2 positive amplification group, the number of ER81 positive expressed cases was more than that in Her2 negative amplification group.	('Her2', 'Gene', '2064', (3, 7))	('positive amplification', 'Var', (8, 30))	('ER81', 'Gene', (52, 56))	('Her2', 'Gene', (3, 7))	('Her2', 'Gene', (104, 108))	('Her2', 'Gene', '2064', (104, 108))
104552	31889895	MDA-MB-231 cells alone (MDA-MB-231 + Ctrl), MCF-7 + MDA-MB-231 cells (Co-culture + Ctrl), and MCF-7 + MDA-MB-231 cells + TGF-betal 10 ng/ml (Co-culture + TGF-betal).	('TGF-beta', 'Gene', (154, 162))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (102, 112))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (24, 34))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (0, 10))	('TGF-beta', 'Gene', (121, 129))	('TGF-beta', 'Gene', '7039', (154, 162))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('MCF-7', 'Var', (94, 99))	('MCF-7', 'CellLine', 'CVCL:0031', (94, 99))	('TGF-beta', 'Gene', '7039', (121, 129))	('MCF-7', 'CellLine', 'CVCL:0031', (44, 49))
104589	31889895	There were significant differences in tumor volumes between MDA-MB-231 + Ctrl and Co-culture + Ctrl or Co-culture + TGF-betal (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('MDA-MB-231 +', 'Var', (60, 72))	('TGF-beta', 'Gene', '7039', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('TGF-beta', 'Gene', (116, 124))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))
104613	31889895	Simultaneous silencing of MMP-9 in breast cancer cells decreased the adhesiveness, invasive, migratory and wound healing characteristics of cells.	('invasive', 'CPA', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('adhesiveness', 'CPA', (69, 81))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('decreased', 'NegReg', (55, 64))	('MMP-9', 'Gene', '4318', (26, 31))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('MMP-9', 'Gene', (26, 31))	('silencing', 'Var', (13, 22))
104622	31889895	These results demonstrated that the existence of TGF-beta1 in a MDA-MB-231 co-culture with MCF-7 resulted in EMT promotion, which in turn lead to increased tumor growth and metastatic capability to the lungs.	('a MDA-MB-231', 'CellLine', 'CVCL:9U30', (62, 74))	('increased', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('existence', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TGF-beta1', 'Gene', (49, 58))	('metastatic capability to the lungs', 'CPA', (173, 207))	('EMT', 'CPA', (109, 112))	('tumor', 'Disease', (156, 161))	('promotion', 'PosReg', (113, 122))	('MCF-7', 'CellLine', 'CVCL:0031', (91, 96))
104642	15217497	Overexpression of S100A7 in a breast cancer cell line is associated with increased malignancy and with several changes in gene expression that are compatible with an alteration in Jab1 activity.	('increased', 'PosReg', (73, 82))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('S100A7', 'Gene', '6278', (18, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('S100A7', 'Gene', (18, 24))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('breast cancer', 'Disease', (30, 43))	('gene expression', 'MPA', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Jab1', 'Gene', (180, 184))	('Overexpression', 'Var', (0, 14))	('malignancy', 'Disease', (83, 93))	('changes', 'Reg', (111, 118))	('Jab1', 'Gene', '10987', (180, 184))
104707	15217497	We also recently showed that expression of S100A7 can promote several features of malignancy in an already invasive ER-negative breast cell line, both in vitro and in vivo .	('promote', 'PosReg', (54, 61))	('expression', 'Var', (29, 39))	('malignancy', 'Disease', (82, 92))	('S100A7', 'Gene', (43, 49))	('S100A7', 'Gene', '6278', (43, 49))	('ER', 'Gene', '2099', (116, 118))	('malignancy', 'Disease', 'MESH:D009369', (82, 92))
104729	15217497	These findings are consistent with studies that also found that high nuclear Jab1 localization is inversely correlated with expression of p27kip1 in invasive breast carcinoma.	('Jab1', 'Gene', (77, 81))	('Jab1', 'Gene', '10987', (77, 81))	('high nuclear', 'Var', (64, 76))	('p27kip1', 'Gene', '1027', (138, 145))	('breast carcinoma', 'Phenotype', 'HP:0003002', (158, 174))	('expression', 'MPA', (124, 134))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (149, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('p27kip1', 'Gene', (138, 145))	('invasive breast carcinoma', 'Disease', (149, 174))
104766	33838670	We classified breast cancer into five subtypes: Luminal A-like, Luminal B-like/HER2 negative, Luminal B-like/HER2 positive, HER2 positive, and Triple-negative.	('Luminal', 'Chemical', 'MESH:D010634', (64, 71))	('HER2', 'Gene', '2064', (79, 83))	('HER2', 'Gene', '2064', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HER2', 'Gene', (109, 113))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('HER2', 'Gene', '2064', (109, 113))	('breast cancer', 'Disease', (14, 27))	('Luminal', 'Chemical', 'MESH:D010634', (94, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('negative', 'NegReg', (84, 92))	('Luminal', 'Chemical', 'MESH:D010634', (48, 55))	('Luminal', 'Var', (94, 101))	('HER2', 'Gene', (79, 83))	('HER2', 'Gene', (124, 128))
104897	30424539	Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations.	('mutations', 'Var', (119, 128))	('BRCA1', 'Gene', '672', (108, 113))	('women', 'Species', '9606', (84, 89))	('BRCA1', 'Gene', (108, 113))
104934	30424539	Type I tumors are associated with wild-type p53 (TP53), but often contain mutations in genes such as KRAS, BRAF, PTEN, and beta-catenin.	('BRAF', 'Gene', (107, 111))	('beta-catenin', 'Gene', '1499', (123, 135))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('KRAS', 'Gene', (101, 105))	('contain', 'Reg', (66, 73))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('KRAS', 'Gene', '3845', (101, 105))	('PTEN', 'Gene', (113, 117))	('Type I tumors', 'Disease', (0, 13))	('PTEN', 'Gene', '5728', (113, 117))	('beta-catenin', 'Gene', (123, 135))	('BRAF', 'Gene', '673', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
104935	30424539	In contrast, Type II tumors are high grade, inherently aggressive, genetically unstable, typically harboring p53 (TP53) mutations, and presenting at advanced stage.	('harboring', 'Reg', (99, 108))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (120, 129))	('TP53', 'Gene', (114, 118))	('Type II tumors', 'Disease', (13, 27))	('Type II tumors', 'Disease', 'MESH:D009369', (13, 27))
104972	30424539	The primary analysis shows no significant reduction in ovarian cancer mortality, though ovarian mortality rates are reduced in screening groups by 15% (CA125) and 11% (TVUS), compared with no screening group.	('CA125', 'Gene', (152, 157))	('reduction in ovarian cancer', 'Disease', (42, 69))	('ovarian mortality', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('screening', 'Var', (127, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('CA125', 'Gene', '94025', (152, 157))	('reduced', 'NegReg', (116, 123))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (42, 69))
105008	30424539	This metaplastic capability of OSE to Mullerian epithelium, when combined with gene mutations, could prompt the formation of ovarian carcinomas bearing a morphological similarity to the normal epithelium of the fallopian tube, uterus, and endocervix.	('prompt', 'Reg', (101, 107))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (125, 142))	('ovarian carcinomas', 'Disease', (125, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('mutations', 'Var', (84, 93))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (125, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('OSE', 'Chemical', '-', (31, 34))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (125, 143))
105014	30424539	Adenovirus-cre-mediated inactivation of Pten and Apc in the murine OSE leads to endometrioid ovarian carcinoma.	('endometrioid ovarian carcinoma', 'Disease', 'MESH:D016889', (80, 110))	('Apc', 'Gene', '11789', (49, 52))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (93, 110))	('Pten', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('murine', 'Species', '10090', (60, 66))	('inactivation', 'Var', (24, 36))	('endometrioid ovarian carcinoma', 'Disease', (80, 110))	('Apc', 'Gene', (49, 52))	('OSE', 'Chemical', '-', (67, 70))	('leads to', 'Reg', (71, 79))
105015	30424539	When Pten deletion and KrasG12D expression are induced by Amhr2 cre/+, the OSE transforms to produce low-grade serous carcinoma.	('serous carcinoma', 'Disease', (111, 127))	('KrasG12D', 'Gene', (23, 31))	('OSE', 'Chemical', '-', (75, 78))	('Pten', 'Gene', (5, 9))	('serous carcinoma', 'Disease', 'MESH:D018284', (111, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('deletion', 'Var', (10, 18))
105016	30424539	With an addition of p53 (Trp53) R172H/+ mutant expression to Pten deletion and KrasG12D expression, these mice form mucinous carcinomas from the OSE, coexisting with cells of serous features.	('p53', 'Gene', (20, 23))	('mucinous carcinomas', 'Disease', (116, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('mice', 'Species', '10090', (106, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (116, 134))	('R172H/+ mutant', 'Var', (32, 46))	('Pten', 'Gene', (61, 65))	('R172H', 'Mutation', 'rs149718671', (32, 37))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (116, 135))	('OSE', 'Chemical', '-', (145, 148))	('deletion', 'Var', (66, 74))
105018	30424539	Mutations in the p53 gene (TP53 in humans; Trp53 in mice) is the most common genetic event observed in human HGSC.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('human', 'Species', '9606', (103, 108))	('human', 'Species', '9606', (35, 40))	('mice', 'Species', '10090', (52, 56))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (17, 20))	('humans', 'Species', '9606', (35, 41))
105019	30424539	Inactivation of p53 (Trp53) and Rb1 in the OSE, via an intrabursal injection of recombinant adenovirus cre, leads to metastatic serous ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (135, 152))	('Rb1', 'Gene', (32, 35))	('OSE', 'Chemical', '-', (43, 46))	('leads to', 'Reg', (108, 116))	('serous ovarian carcinoma', 'Disease', (128, 152))	('p53 (Trp53', 'Protein', (16, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (128, 152))	('Inactivation', 'Var', (0, 12))
105024	30424539	In another mouse study, adenovirus cre was delivered inside the bursa to delete or express in the OSE the following genes: (i) inactivation of Rb1, p53, and Brca1; (ii) expression of a p53 mutant (p53R172H) with Rb1 and Brca1/2 deletion.	('inactivation', 'NegReg', (127, 139))	('Brca1', 'Gene', (157, 162))	('p53', 'Gene', (185, 188))	('mouse', 'Species', '10090', (11, 16))	('delete', 'Var', (73, 79))	('p53', 'Gene', (148, 151))	('Brca1', 'Gene', (220, 225))	('OSE', 'Chemical', '-', (98, 101))	('Brca1', 'Gene', '12189', (157, 162))	('expression', 'MPA', (169, 179))	('Rb1', 'Gene', (143, 146))	('Rb1', 'Gene', (212, 215))	('Brca1', 'Gene', '12189', (220, 225))	('Brca1/2', 'Gene', (220, 227))	('p53R172H', 'Var', (197, 205))	('Brca1/2', 'Gene', '12189;12190', (220, 227))
105029	30424539	In another model, loss of Lkb1 and Pten in the OSE leads to ovarian HGSC (100%: 12/12), but with seemingly weak metastatic potential: ascites noted in 25% (3/12) of the mice.	('ascites', 'Disease', (134, 141))	('Pten', 'Gene', (35, 39))	('ascites', 'Phenotype', 'HP:0001541', (134, 141))	('loss', 'Var', (18, 22))	('ascites', 'Disease', 'MESH:D001201', (134, 141))	('OSE', 'Chemical', '-', (47, 50))	('leads to', 'Reg', (51, 59))	('Lkb1', 'Gene', (26, 30))	('ovarian HGSC', 'Disease', 'MESH:D010051', (60, 72))	('ovarian HGSC', 'Disease', (60, 72))	('mice', 'Species', '10090', (169, 173))	('Lkb1', 'Gene', '20869', (26, 30))
105030	30424539	In addition, in a transgenic mouse model expressing SV40 large T antigen (TAg) in the OSE, ~50% of the mice produce metastatic ovarian carcinoma of serous morphology.	('SV40', 'Var', (52, 56))	('ovarian carcinoma', 'Disease', (127, 144))	('TAg', 'Gene', '404663', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('mice', 'Species', '10090', (103, 107))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (127, 144))	('mouse', 'Species', '10090', (29, 34))	('OSE', 'Chemical', '-', (86, 89))	('metastatic', 'CPA', (116, 126))	('TAg', 'Gene', (74, 77))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (127, 144))
105032	30424539	Evidently, the mouse OSE, incited by gene mutations, is capable of transforming into an ovarian carcinoma histopathologically resembling human HGSC.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('human', 'Species', '9606', (137, 142))	('transforming', 'Reg', (67, 79))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (88, 105))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (88, 105))	('OSE', 'Chemical', '-', (21, 24))	('ovarian carcinoma', 'Disease', (88, 105))	('mouse', 'Species', '10090', (15, 20))	('mutations', 'Var', (42, 51))
105035	30424539	It is possible that additional mutations could enable aggressiveness of OSE-derived murine HGSCs.	('murine', 'Species', '10090', (84, 90))	('aggressiveness', 'Disease', (54, 68))	('mutations', 'Var', (31, 40))	('aggressiveness', 'Phenotype', 'HP:0000718', (54, 68))	('enable', 'PosReg', (47, 53))	('aggressiveness', 'Disease', 'MESH:D001523', (54, 68))	('OSE', 'Chemical', '-', (72, 75))
105038	30424539	This insight came from studies of women carrying germline BRCA1 or 2 mutations, which make these women more prone to malignancies, particularly ovarian cancer as well as breast cancer.	('mutations', 'Var', (69, 78))	('women', 'Species', '9606', (97, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('prone', 'Reg', (108, 113))	('BRCA1', 'Gene', (58, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('germline', 'Var', (49, 57))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('ovarian cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (34, 39))	('breast cancer', 'Disease', (170, 183))	('malignancies', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('BRCA1', 'Gene', '672', (58, 63))
105041	30424539	When BRCA mutations were first recognized as conferring high risk for ovarian cancer, ovarian cancer was believed to arise solely from the ovary.	('ovarian cancer', 'Disease', (86, 100))	('ovarian cancer', 'Disease', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('BRCA', 'Gene', '672', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (70, 84))	('BRCA', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))
105046	30424539	In contrast, little abnormality was found in the prophylactically-removed ovaries from BRCA1 carriers.	('abnormality', 'Disease', (20, 31))	('carriers', 'Var', (93, 101))	('ovaries', 'Disease', (74, 81))	('BRCA1', 'Gene', '672', (87, 92))	('BRCA1', 'Gene', (87, 92))	('ovaries', 'Disease', 'MESH:D010051', (74, 81))	('abnormality', 'Disease', 'MESH:D000014', (20, 31))
105054	30424539	Furthermore, the evolutionary analysis of genetic changes observed in these various tumor tissues has identified alterations in BRCA1, BRCA2, TP53, and PTEN as critical early events in the initiation of STICs and subsequent development of HGSC.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('BRCA2', 'Gene', (135, 140))	('TP53', 'Gene', '7157', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TP53', 'Gene', (142, 146))	('PTEN', 'Gene', (152, 156))	('PTEN', 'Gene', '5728', (152, 156))	('BRCA2', 'Gene', '675', (135, 140))	('tumor', 'Disease', (84, 89))	('BRCA1', 'Gene', '672', (128, 133))	('STICs', 'Disease', (203, 208))	('alterations', 'Var', (113, 124))	('BRCA1', 'Gene', (128, 133))
105057	30424539	In one mouse study, expression of mutant p53 (Trp53) and inactivation of Pten and Brca1/2, together, generated STICs (83.9%: 26/31 mice) as well as HGSCs in the ovary (73.1%: 19/26) and peritoneum (73.1%: 19/26).	('Brca1/2', 'Gene', (82, 89))	('mouse', 'Species', '10090', (7, 12))	('HGSCs in the', 'CPA', (148, 160))	('STICs', 'CPA', (111, 116))	('mice', 'Species', '10090', (131, 135))	('Brca1/2', 'Gene', '12189;12190', (82, 89))	('generated', 'Reg', (101, 110))	('Pten', 'Gene', (73, 77))	('p53', 'Protein', (41, 44))	('inactivation', 'Var', (57, 69))	('mutant', 'Var', (34, 40))
105058	30424539	In another study, STIC formed in 35% (28/80) of mice harboring the inactivation of four genes (Brca1, p53, Rb1, and Nf1: 48 mice) or three genes (Brca1, p53, and Rb1: 29 mice; Brca1, p53, and Nf1: 3 mice) in the fallopian tube epithelium.	('inactivation', 'Var', (67, 79))	('Nf1', 'Gene', (116, 119))	('Nf1', 'Gene', (192, 195))	('Brca1', 'Gene', (95, 100))	('mice', 'Species', '10090', (199, 203))	('Brca1', 'Gene', '12189', (95, 100))	('mice', 'Species', '10090', (48, 52))	('mice', 'Species', '10090', (124, 128))	('Brca1', 'Gene', (146, 151))	('Nf1', 'Gene', '18015', (192, 195))	('Brca1', 'Gene', (176, 181))	('Nf1', 'Gene', '18015', (116, 119))	('Brca1', 'Gene', '12189', (176, 181))	('mice', 'Species', '10090', (170, 174))	('Brca1', 'Gene', '12189', (146, 151))
105060	30424539	In the same study, inactivation of Brca1, p53, and Pten in the fallopian tube epithelium also produced STIC or early-stage HGSC or both or HGSC in the fallopian tube in 90% of mice: STIC (40%: 4/10 mice); early-stage HGSC (60%: 6/10); and HGSC (20%: 2/10).	('p53', 'Gene', (42, 45))	('Brca1', 'Gene', '12189', (35, 40))	('Brca1', 'Gene', (35, 40))	('STIC', 'Disease', (182, 186))	('produced', 'Reg', (94, 102))	('mice', 'Species', '10090', (176, 180))	('STIC', 'Disease', (103, 107))	('mice', 'Species', '10090', (198, 202))	('Pten', 'Gene', (51, 55))	('inactivation', 'Var', (19, 31))	('early-stage HGSC', 'CPA', (111, 127))
105062	30424539	Overall, these mouse models, targeting fallopian tube epithelium with gene mutations, develop STICs and HGSCs which closely recapitulate many of clinical and molecular features of STIC and HGSC in humans.	('STICs', 'Disease', (94, 99))	('humans', 'Species', '9606', (197, 203))	('mouse', 'Species', '10090', (15, 20))	('mutations', 'Var', (75, 84))	('HGSCs', 'Disease', (104, 109))
105063	30424539	Also, notably, Brca1 or 2 inactivation appears to be necessary for STIC to advance to HGSC in mice.	('Brca1', 'Gene', '12189', (15, 20))	('inactivation', 'Var', (26, 38))	('mice', 'Species', '10090', (94, 98))	('Brca1', 'Gene', (15, 20))
105064	30424539	These mouse models therefore support a notion that STIC can be a precursor lesion for HGSC in genetically high-risk women carrying germline BRCA1/2 mutations.	('mutations', 'Var', (148, 157))	('BRCA1/2', 'Gene', '672;675', (140, 147))	('women', 'Species', '9606', (116, 121))	('STIC', 'Disease', (51, 55))	('HGSC', 'Disease', (86, 90))	('BRCA1/2', 'Gene', (140, 147))	('mouse', 'Species', '10090', (6, 11))
105065	30424539	In mouse models without Brca1 or 2 mutation, p53 mutation and Pten deletion together can produce STIC lesions in the fallopian tube epithelium (67%: 4/6 mice) (Table 2).	('p53', 'Gene', (45, 48))	('mouse', 'Species', '10090', (3, 8))	('Brca1', 'Gene', (24, 29))	('STIC lesions', 'CPA', (97, 109))	('deletion', 'Var', (67, 75))	('mutation', 'Var', (49, 57))	('produce', 'Reg', (89, 96))	('Brca1', 'Gene', '12189', (24, 29))	('mice', 'Species', '10090', (153, 157))	('Pten', 'Gene', (62, 66))
105066	30424539	In another study, expression of the SV40 large T antigen (TAg), driven by the oviductal glycoprotein 1 (Ovgp1) promoter, also results in STIC lesions in the fallopian tube epithelium along with adenocarcinoma in the ovary in some mice.	('adenocarcinoma', 'Disease', 'MESH:D000230', (194, 208))	('TAg', 'Gene', (58, 61))	('mice', 'Species', '10090', (230, 234))	('STIC', 'MPA', (137, 141))	('adenocarcinoma in the ovary', 'Phenotype', 'HP:0100615', (194, 221))	('TAg', 'Gene', '404663', (58, 61))	('oviductal glycoprotein 1', 'Gene', (78, 102))	('SV40', 'Var', (36, 40))	('results in', 'Reg', (126, 136))	('oviductal glycoprotein 1', 'Gene', '12659', (78, 102))	('carcinoma in the ovary', 'Phenotype', 'HP:0100615', (199, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('adenocarcinoma', 'Disease', (194, 208))
105079	30424539	The p53 (TP53) signatures were present in the fallopian tubes of 19% (12/64) and 33% (19/58) of women who are at average risk of ovarian cancer, compared with 11% (19/176) and 24% (10/41) of high-risk women undergoing risk-reducing salpingo-oophorectomy (RRSO).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('salpingo-oophorectomy', 'Disease', (232, 253))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('women', 'Species', '9606', (201, 206))	('fallopian tubes', 'Disease', 'MESH:D005184', (46, 61))	('ovarian cancer', 'Disease', (129, 143))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('p53', 'Var', (4, 7))	('women', 'Species', '9606', (96, 101))	('fallopian tubes', 'Disease', (46, 61))
105084	30424539	Regarding the fallopian tube as an origin of HGSC, currently available data indicate that STIC likely serves as a premalignant lesion that could develop into metastatic HGSC in high-risk women carrying germline BRCA1/2 mutations.	('women', 'Species', '9606', (187, 192))	('BRCA1/2', 'Gene', (211, 218))	('metastatic HGSC', 'Disease', (158, 173))	('develop', 'Reg', (145, 152))	('BRCA1/2', 'Gene', '672;675', (211, 218))	('mutations', 'Var', (219, 228))	('STIC', 'Disease', (90, 94))
105087	30424539	In contrast, when early-stage (I and II) HGSCs (14/131) from BRCA1/2 carriers were examined, the majority of early-stage HGSCs (78.6%: 11/14) were diagnosed as ovarian primaries, while three cases (21.4%: 3/14) as fallopian tube primaries.	('BRCA1/2', 'Gene', '672;675', (61, 68))	('BRCA1/2', 'Gene', (61, 68))	('ovarian primaries', 'Disease', (160, 177))	('HGSCs', 'Var', (121, 126))
105098	30424539	As one in eight women (12.4%) develops breast cancer during her lifetime in the U.S., this common occurrence of DCIS in the general population also bolsters the notion that many DCIS lesions do not lead to malignant breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancers', 'Phenotype', 'HP:0003002', (216, 230))	('lead to', 'Reg', (198, 205))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('women', 'Species', '9606', (16, 21))	('malignant breast cancers', 'Disease', (206, 230))	('malignant breast cancers', 'Disease', 'MESH:D001943', (206, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('lesions', 'Var', (183, 190))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('breast cancer', 'Disease', (39, 52))
105121	30424539	In this model, Amhr2-cre (Amhr2cre/+), in which the insertion of cre recombinase gene is targeted to an endogenous Amhr2 locus, would direct the deletion of Dicer1 and Pten specific to the fallopian tube stroma, not in the epithelium.	('fallopian tube stroma', 'Disease', (189, 210))	('Dicer1', 'Gene', (157, 163))	('Amhr2cre/+', 'Gene', (26, 36))	('Amhr2cre/+', 'Gene', '269', (26, 36))	('fallopian tube stroma', 'Disease', 'MESH:D005184', (189, 210))	('Pten', 'Gene', (168, 172))	('deletion', 'Var', (145, 153))
105131	30424539	Similarly, PTEN deletion is found in 38.9% of the cases for combined homozygous (6.6%) and heterozygous losses (32.3%).	('PTEN', 'Gene', (11, 15))	('deletion', 'Var', (16, 24))	('PTEN', 'Gene', '5728', (11, 15))
105133	30424539	Thus, most cases of human HGSC are unlikely to occur as a direct consequence of loss of DICER1 and PTEN.	('human', 'Species', '9606', (20, 25))	('DICER1', 'Gene', (88, 94))	('loss', 'Var', (80, 84))	('DICER1', 'Gene', '23405', (88, 94))	('human HGSC', 'Disease', (20, 30))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))
105134	30424539	Rather, this mouse model reveals critical pathways:activated by loss of Dicer1 and Pten:what are essential to the development of metastatic HGSC.	('mouse', 'Species', '10090', (13, 18))	('Pten', 'Gene', (83, 87))	('loss', 'Var', (64, 68))	('Dicer1', 'Gene', (72, 78))
105147	30424539	Salpingo-oophorectomy:surgical removal of the ovaries and fallopian tubes:is the standard preventive surgery recommended for germline BRCA1/2 carriers, who are at high risk of ovarian cancer.	('carriers', 'Var', (142, 150))	('removal of the ovaries', 'Disease', (31, 53))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('BRCA1/2', 'Gene', (134, 141))	('removal of the ovaries', 'Disease', 'MESH:D010051', (31, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('BRCA1/2', 'Gene', '672;675', (134, 141))	('ovaries and fallopian tubes', 'Disease', 'MESH:D005184', (46, 73))	('ovarian cancer', 'Disease', (176, 190))
105149	30424539	Besides ovarian cancer protection, oophorectomy also significantly decreases the risk of breast cancer (50% risk reduction) in BRCA1/2 carriers (though some studies indicate no difference in breast cancer risk, or a selective risk reduction only among BRCA2 carriers).	('ovarian cancer', 'Disease', 'MESH:D010051', (8, 22))	('BRCA1/2', 'Gene', '672;675', (127, 134))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('ovarian cancer', 'Disease', (8, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (8, 22))	('carriers', 'Var', (135, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('BRCA2', 'Gene', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('decreases', 'NegReg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('BRCA1/2', 'Gene', (127, 134))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('BRCA2', 'Gene', '675', (252, 257))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
105158	30424539	Delaying ovary removal may diminish the benefit of breast cancer protection.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Delaying', 'Var', (0, 8))	('ovary removal', 'Disease', 'MESH:D010051', (9, 22))	('ovary removal', 'Disease', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('diminish', 'NegReg', (27, 35))	('breast cancer', 'Disease', (51, 64))
105161	30424539	Presently, bilateral salpingo-oophorectomy is still the recommended prophylactic surgery for high-risk women carrying germline BRCA1 or 2 mutations.	('BRCA1', 'Gene', '672', (127, 132))	('women', 'Species', '9606', (103, 108))	('BRCA1', 'Gene', (127, 132))	('mutations', 'Var', (138, 147))
105179	30424539	In summary, in high-risk women, until further evidence is available, risk-reducing salpingo-oophorectomy (RRSO) is recommended by age 40 for BRCA1 mutation carriers and by age 45 for BRCA2 mutation carriers.	('BRCA2', 'Gene', (183, 188))	('BRCA1', 'Gene', '672', (141, 146))	('mutation', 'Var', (147, 155))	('BRCA2', 'Gene', '675', (183, 188))	('salpingo-oophorectomy', 'Disease', (83, 104))	('BRCA1', 'Gene', (141, 146))	('women', 'Species', '9606', (25, 30))
105185	30424539	In a mouse allograft study, epithelial cells in the mouse ovarian hilum that are also positive for stem-cell markers are isolated and cultured followed by inactivation of p53 (Trp53) and Rb1.	('Rb1', 'Gene', (187, 190))	('mouse', 'Species', '10090', (52, 57))	('inactivation', 'Var', (155, 167))	('mouse', 'Species', '10090', (5, 10))	('Trp53', 'Protein', (176, 181))	('p53 (Trp53', 'Protein', (171, 181))
105209	31607526	Recall% was lower for DBT (2.55%) than DM (3.21%) [RR:0.79 (0.73-0.86)].	('Recall%', 'MPA', (0, 7))	('DM', 'Disease', 'MESH:D009223', (39, 41))	('DBT', 'Var', (22, 25))	('lower', 'NegReg', (12, 17))
105220	31607526	Based on the above-described evidence that DBT screening improves BC detection, with further evidence emerging from studies undertaken in population screening programs in Norway and Italy, the Trento screening program adopted a policy decision (endorsed by national screening authorities) to transition to DBT screening.	('screening', 'Var', (47, 56))	('improves', 'PosReg', (57, 65))	('Trento', 'Chemical', '-', (193, 199))
105254	31607526	Our work shows that DBT screening (CDR 8.67/1000) has significantly increased BC detection (versus DM, CDR 5.48/1000) evidenced by the rate ratio of 1.58 (95%CI:1.34-1.87).	('DM', 'Disease', 'MESH:D009223', (99, 101))	('CDR', 'Chemical', '-', (35, 38))	('DBT screening', 'Var', (20, 33))	('CDR', 'Chemical', '-', (103, 106))	('increased', 'PosReg', (68, 77))
105260	31607526	When BC characteristics are considered in terms of detection rates per 1000 screens (Table 2), DBT effectively increased CDR for stage I-II invasive cancer, increased CDR for most tumour size categories and grade categories, and increased detection of BCs without (more so than with) node metastases, reflecting a global increase in CDR at DBT screening, with one exception - DBT did not increase CDR for DCIS.	('CDR', 'Chemical', '-', (167, 170))	('metastases', 'Disease', 'MESH:D009362', (289, 299))	('DBT', 'Var', (95, 98))	('metastases', 'Disease', (289, 299))	('I-II invasive cancer', 'Disease', (135, 155))	('detection', 'MPA', (239, 248))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('CDR', 'MPA', (121, 124))	('increased', 'PosReg', (111, 120))	('I-II invasive cancer', 'Disease', 'MESH:D009362', (135, 155))	('CDR', 'MPA', (167, 170))	('increased', 'PosReg', (229, 238))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('CDR', 'Chemical', '-', (121, 124))	('CDR', 'Chemical', '-', (397, 400))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('increased', 'PosReg', (157, 166))	('CDR', 'Chemical', '-', (333, 336))	('tumour', 'Disease', (180, 186))
105266	31607526	Our pilot study has shown that although DBT screening had a lower ICR (ICR 1.1/1000 screens) than DM screening (ICR 1.36/1000 screens), this was not a statistically significant reduction (RR 0.81 (0.55-1.19).	('DBT', 'Var', (40, 43))	('ICR 1', 'Gene', '3388', (112, 117))	('ICR 1', 'Gene', '3388', (71, 76))	('ICR', 'MPA', (66, 69))	('DM', 'Disease', 'MESH:D009223', (98, 100))	('ICR 1', 'Gene', (112, 117))	('ICR 1', 'Gene', (71, 76))	('lower', 'NegReg', (60, 65))
105268	31607526	We had hypothesized that DBT would increase CDR and hence would be expected to reduce ICR.	('CDR', 'Chemical', '-', (44, 47))	('increase', 'PosReg', (35, 43))	('CDR', 'MPA', (44, 47))	('ICR', 'Disease', (86, 89))	('DBT', 'Var', (25, 28))	('reduce', 'NegReg', (79, 85))
105273	31607526	Also, while some investigators suggest that ICR reduction is a surrogate for screening effectiveness, an effect on ICR from using new technology might not be the only indicator of screening benefit; for example, after adjusting for lead time, screen-detection of breast cancer could have benefit due to a more favourable size and node profile at diagnosis.	('breast cancer', 'Disease', (263, 276))	('screen-detection', 'Var', (243, 259))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('breast cancer', 'Disease', 'MESH:D001943', (263, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (263, 276))
105274	31607526	Overall, taking into consideration the significant increase in CDR following the transition to DBT and the lack of statistical significance for the reduction in ICR in our DBT screening pilot, it seems reasonable to suspect that some of the increased detection from DBT is contributing to over-diagnosis in population BC screening.	('increase', 'PosReg', (51, 59))	('increased', 'PosReg', (241, 250))	('DBT', 'Gene', (266, 269))	('CDR', 'Chemical', '-', (63, 66))	('CDR', 'MPA', (63, 66))	('over-diagnosis', 'PosReg', (289, 303))	('detection', 'Var', (251, 260))
105278	31607526	Although this suggests potential screening benefit, and screening sensitivity was improved with DBT screening, there was little effect in terms of a reduction in interval cancer rates.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('DBT', 'Var', (96, 99))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('improved', 'PosReg', (82, 90))
105297	29413653	ALH is associated with a 4-to-5 fold increase in the risk of subsequent breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (72, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('breast carcinoma', 'Disease', (72, 88))	('ALH', 'Var', (0, 3))	('breast carcinoma', 'Disease', 'MESH:D001943', (72, 88))
105310	29413653	Due to its solid growth pattern, marked nuclear pleomorphism, and presence of necrosis and calcifications, P-LCIS closely mimics ductal carcinoma in situ (DCIS) (Fig.	('ductal carcinoma', 'Disease', 'MESH:D044584', (129, 145))	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('ductal carcinoma', 'Disease', (129, 145))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (129, 145))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (129, 153))	('P-LCIS', 'Chemical', '-', (107, 113))	('calcifications', 'Disease', 'MESH:D002114', (91, 105))	('P-LCIS', 'Var', (107, 113))	('calcifications', 'Disease', (91, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('necrosis', 'Disease', (78, 86))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (136, 153))
105311	29413653	However, the cells of P-LCIS are dyshesive, lack true cell polarity, and do not form secondary lumina.	('P-LCIS', 'Chemical', '-', (22, 28))	('lack', 'NegReg', (44, 48))	('P-LCIS', 'Var', (22, 28))
105324	29413653	Using polymerase chain reaction (PCR)/single strand conformation polymorphism (SSCP) assay, Berx et al detected truncation mutations in the extracellular domain of Ecadherin, in combination with loss of heterozygosity (LOH) of chromosome 16q22.1 containing the CDH1 gene in over 50% of the ILC examined .	('Ecadherin', 'Gene', '999', (164, 173))	('CDH1', 'Gene', (261, 265))	('CDH1', 'Gene', '999', (261, 265))	('truncation mutations', 'Var', (112, 132))	('Ecadherin', 'Gene', (164, 173))
105326	29413653	In contrast, ILC and LCIS, including all LCIS variants, are characterized by loss or aberrant expression of the E-cadherin protein (Fig.	('aberrant', 'Var', (85, 93))	('LCIS', 'Disease', (21, 25))	('E-cadherin', 'Gene', (112, 122))	('E-cadherin', 'Gene', '999', (112, 122))	('ILC', 'Disease', (13, 16))	('loss', 'NegReg', (77, 81))	('expression', 'MPA', (94, 104))
105327	29413653	Immunohistochemical stain for E-cadherin is routinely used to distinguish lobular from ductal lesions, and is especially useful in separating LCIS variants from DCIS in cases with ambiguous morphology (Fig.	('variants', 'Var', (147, 155))	('E-cadherin', 'Gene', (30, 40))	('E-cadherin', 'Gene', '999', (30, 40))	('LCIS', 'Disease', (142, 146))	('separating LCIS', 'Phenotype', 'HP:0006304', (131, 146))	('DCIS', 'Disease', (161, 165))
105356	29413653	The management of patients with variant LCIS and no invasive carcinoma remains highly controversial, especially with respect to radiation therapy.	('variant', 'Var', (32, 39))	('invasive carcinoma', 'Disease', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('invasive carcinoma', 'Disease', 'MESH:D009361', (52, 70))	('patients', 'Species', '9606', (18, 26))	('LCIS', 'Disease', (40, 44))
105372	29413653	LCIS/ALH and ILC share some common chromosome alterations, however, the average number of copy number changes in LCIS/ALH is significantly lower than in ILC and invasive carcinoma in general .	('invasive carcinoma', 'Disease', (161, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('LCIS/ALH', 'Var', (113, 121))	('lower', 'NegReg', (139, 144))	('invasive carcinoma', 'Disease', 'MESH:D009361', (161, 179))	('copy number', 'MPA', (90, 101))
105373	29413653	Loss of 16q is also the most common genetic alteration in low grade DCIS , tubular carcinoma, well-differentiated invasive carcinoma , and premalignant lesion such as atypical ductal hyperplasia (ADH)  and columnar cell changes with atypia .	('invasive carcinoma', 'Disease', 'MESH:D009361', (114, 132))	('tubular carcinoma', 'Disease', (75, 92))	('tubular carcinoma', 'Disease', 'MESH:D000230', (75, 92))	('atypical ductal hyperplasia', 'Disease', (167, 194))	('invasive carcinoma', 'Disease', (114, 132))	('ADH', 'Gene', '128', (196, 199))	('Loss of 16q', 'Var', (0, 11))	('ADH', 'Gene', (196, 199))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (167, 194))	('columnar', 'Disease', (206, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('low grade DCIS', 'Disease', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
105375	29413653	Comparing copy number alterations of LCIS, DCIS and associated invasive carcinoma, Buerger et al proposed that LCIS and low grade DCIS are closely related neoplastic lesions evolving from a single cell clone .	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('neoplastic lesions', 'Disease', 'MESH:D051437', (155, 173))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (155, 173))	('invasive carcinoma', 'Disease', (63, 81))	('LCIS', 'Disease', (111, 115))	('copy number alterations', 'Var', (10, 33))	('invasive carcinoma', 'Disease', 'MESH:D009361', (63, 81))	('neoplastic lesions', 'Disease', (155, 173))
105376	29413653	Columnar cell changes, LCIS/ALH, low grade DCIS, tubular carcinoma, ILC and well-differentiated IDC not only frequently coexist , but also exhibit similar immunophenotypes  and clonal relationship , supporting the hypothesis that these lesions are members of a family of low grade lesions of the breast, including precursor lesions, in situ and invasive carcinoma with low grade morphology (see article by Collins in this issue of The Clinics)  (REF COLLINS).	('invasive carcinoma', 'Disease', 'MESH:D009361', (345, 363))	('tubular carcinoma', 'Disease', 'MESH:D000230', (49, 66))	('tubular carcinoma', 'Disease', (49, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (354, 363))	('invasive carcinoma', 'Disease', (345, 363))	('ILC', 'Disease', (68, 71))	('low grade', 'Var', (33, 42))	('LCIS/ALH', 'Disease', (23, 31))	('Columnar', 'Disease', (0, 8))
105378	29413653	In particular, apocrine P-LCIS displays additional recurrent changes, such as amplification of the HER2 gene at 17q11.2-17q12, gain of 16p, loss of 8p and amplification of cyclin D1 gene at 11q13.3.	('amplification', 'Var', (155, 168))	('amplification', 'MPA', (78, 91))	('HER2', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (99, 103))	('cyclin D1', 'Gene', '595', (172, 181))	('16p', 'CPA', (135, 138))	('loss', 'NegReg', (140, 144))	('gain', 'PosReg', (127, 131))	('cyclin D1', 'Gene', (172, 181))	('P-LCIS', 'Chemical', '-', (24, 30))
105384	29413653	The mutation of CDH1 gene is in keeping with the loss of Ecadherin expression, a hallmark of lobular carcinoma.	('CDH1', 'Gene', '999', (16, 20))	('loss', 'NegReg', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lobular carcinoma', 'Disease', 'MESH:D018275', (93, 110))	('mutation', 'Var', (4, 12))	('Ecadherin', 'Gene', (57, 66))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (93, 110))	('CDH1', 'Gene', (16, 20))	('expression', 'MPA', (67, 77))	('lobular carcinoma', 'Disease', (93, 110))	('Ecadherin', 'Gene', '999', (57, 66))
105385	29413653	In addition to allel loss at CDH1 locus (16q22.1) and somatic mutations of CDH1 gene, epigenetic alterations such as promoter hypermethylation can also lead to downregulation or silencing of E-cadherin .	('downregulation', 'NegReg', (160, 174))	('silencing', 'MPA', (178, 187))	('CDH1', 'Gene', '999', (75, 79))	('E-cadherin', 'Gene', (191, 201))	('CDH1', 'Gene', (29, 33))	('E-cadherin', 'Gene', '999', (191, 201))	('CDH1', 'Gene', (75, 79))	('CDH1', 'Gene', '999', (29, 33))	('mutations', 'Var', (62, 71))	('promoter hypermethylation', 'Var', (117, 142))
105386	29413653	Germline mutation of CDH1 is associated with familial early-onset, poorly differentiated, diffuse gastric cancer  and increased risk of lobular breast cancer .	('poorly differentiated', 'Disease', (67, 88))	('CDH1', 'Gene', '999', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lobular breast cancer', 'Disease', 'MESH:D013274', (136, 157))	('lobular breast cancer', 'Disease', (136, 157))	('gastric cancer', 'Disease', (98, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (136, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('familial early-onset', 'Disease', (45, 65))	('associated', 'Reg', (29, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('Germline mutation', 'Var', (0, 17))	('CDH1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
105387	29413653	In women with CDH1 germline mutation, the estimated cumulative risk by age 80 years is over 80% for gastric cancer, and 39-60% for breast cancer .	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('CDH1', 'Gene', (14, 18))	('CDH1', 'Gene', '999', (14, 18))	('germline mutation', 'Var', (19, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('women', 'Species', '9606', (3, 8))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('gastric cancer', 'Disease', (100, 114))
105432	29413653	The management of patients with variant LCIS and no invasive carcinoma upon excision is the subject of debate.	('variant', 'Var', (32, 39))	('invasive carcinoma', 'Disease', (52, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('invasive carcinoma', 'Disease', 'MESH:D009361', (52, 70))	('patients', 'Species', '9606', (18, 26))	('LCIS', 'Disease', (40, 44))
105433	29413653	LCIS is a risk factor and a non-obligate precursor lesion LCIS shows loss of E-cadherin and diffuse cytoplasmic staining for p120 catenin The most frequent chromosome alteration in LCIS is deletion of 16q; the most common somatic mutations in LCIS affect CDH1 (gene encoding for E-cadherin) Surgical excision can be safely spared in patients with classic LCIS diagnosed on needle core biopsy with concordant imaging and pathologic findings Surgical excision is recommended for LCIS with variant or pleomorphic morphology, and for classic LCIS with discordant imaging and/or pathologic findings In a resection specimen, the margin status of classic LCIS is not reported, but it should be reported for LCIS with variant and/or pleomorphic morphology	('CDH1', 'Gene', (255, 259))	('LCIS', 'Gene', (243, 247))	('CDH1', 'Gene', '999', (255, 259))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('patients', 'Species', '9606', (333, 341))	('mutations', 'Var', (230, 239))	('p120', 'Gene', '1500', (125, 129))	('E-cadherin', 'Gene', (279, 289))	('E-cadherin', 'Gene', '999', (279, 289))	('p120', 'Gene', (125, 129))
105434	23826974	DNA methylation in ductal carcinoma in situ of the breast Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of invasive carcinoma of the breast.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ductal carcinoma', 'Disease', (19, 35))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (19, 35))	('Ductal carcinoma', 'Disease', (58, 74))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (19, 43))	('methylation', 'Var', (4, 15))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (58, 82))	('invasive carcinoma of the breast', 'Disease', 'MESH:D018270', (128, 160))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (58, 74))	('breast Ductal carcinoma', 'Phenotype', 'HP:0003002', (51, 74))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (137, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('invasive carcinoma of the breast', 'Disease', (128, 160))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('ductal carcinoma', 'Disease', 'MESH:D044584', (19, 35))
105436	23826974	Epigenetic changes have been shown to be a significant driver of tumorigenesis, and DNA methylation of specific gene promoters provides predictive and prognostic markers in many types of cancer, including invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('invasive breast cancer', 'Disease', 'MESH:D001943', (205, 227))	('tumor', 'Disease', (65, 70))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('invasive breast cancer', 'Disease', (205, 227))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
105437	23826974	In general, the spectrum of genes that are methylated in DCIS strongly resembles that seen in invasive ductal carcinoma.	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (94, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('DCIS', 'Gene', (57, 61))	('invasive ductal carcinoma', 'Disease', (94, 119))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (103, 119))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('methylated', 'Var', (43, 53))
105447	23826974	Histopathological features, such as large tumor size, high nuclear grade, the presence of comedo necrosis, positive excision margin status, negative hormone receptor status, and HER-2 amplification, have also been associated with increased risk of recurrence.	('amplification', 'Var', (184, 197))	('tumor', 'Disease', (42, 47))	('necrosis', 'Disease', (97, 105))	('HER-2', 'Gene', '2064', (178, 183))	('hormone receptor', 'Gene', (149, 165))	('hormone receptor', 'Gene', '3164', (149, 165))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('HER-2', 'Gene', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('comedo', 'Phenotype', 'HP:0025249', (90, 96))
105456	23826974	In particular, inactivation of tumor suppressor genes by promoter hypermethylation can be a driver of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('promoter hypermethylation', 'Var', (57, 82))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inactivation', 'Var', (15, 27))
105457	23826974	Low-level methylation means that only a small proportion of the cells being analyzed (possibly not related to the tumor) are methylated and this may not result in detectable changes in gene transcription overall.	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('methylated', 'Var', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))
105459	23826974	From such studies, aberrant methylation has been reported in a large variety of genes, including every pathway involved in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('reported', 'Reg', (49, 57))	('methylation', 'MPA', (28, 39))	('carcinogenesis', 'Disease', (123, 137))	('aberrant', 'Var', (19, 27))
105464	23826974	Earlier studies specifically addressing DNA methylation in DCIS, or methylation changes in the progression to invasive carcinoma, examined mostly a single gene or at most a handful of genes.	('changes', 'Reg', (80, 87))	('methylation', 'Var', (44, 55))	('invasive carcinoma', 'Disease', 'MESH:D009361', (110, 128))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('invasive carcinoma', 'Disease', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))
105465	23826974	Several studies have shown an increase in the number of methylated genes from normal breast tissue to benign lesions to in situ carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('situ carcinoma', 'Disease', 'MESH:D002278', (123, 137))	('situ carcinoma', 'Disease', (123, 137))	('methylated', 'Var', (56, 66))
105468	23826974	For example, Fackler and colleagues reported TWIST1 methylation, as detected by MSP, to occur more frequently in IDC (15/27, 56%) compared with grade 3 DCIS (7/18, 39%), grade 2 DCIS (3/12, 25%), and grade 1 DCIS (2/14, 14%), and the difference in methylation frequency between IDC and combined grade 1 and 2 DCIS was statistically significant (P = 0.01).	('IDC', 'Gene', '4000', (113, 116))	('TWIST1', 'Gene', (45, 51))	('TWIST1', 'Gene', '7291', (45, 51))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('IDC', 'Gene', (113, 116))	('DCIS', 'Phenotype', 'HP:0030075', (309, 313))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('IDC', 'Gene', '4000', (278, 281))	('DCIS', 'Phenotype', 'HP:0030075', (208, 212))	('methylation', 'Var', (52, 63))	('occur', 'Reg', (88, 93))	('IDC', 'Gene', (278, 281))
105471	23826974	In mixed DCIS-IDC tumors, trends to higher frequencies of APC and CDH1 methylation were found in IDC compared with DCIS.	('methylation', 'Var', (71, 82))	('higher', 'PosReg', (36, 42))	('CDH1', 'Gene', (66, 70))	('APC', 'Disease', 'MESH:D011125', (58, 61))	('CDH1', 'Gene', '999', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('APC', 'Disease', (58, 61))	('IDC', 'Gene', '4000', (14, 17))	('DCIS-IDC tumors', 'Disease', 'MESH:D002285', (9, 24))	('IDC', 'Gene', (14, 17))	('DCIS-IDC tumors', 'Disease', (9, 24))	('IDC', 'Gene', '4000', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('IDC', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
105472	23826974	APC methylation was found in 15 (38%) of 40 DCIS samples and in 24 (53%) of 45 IDC samples, and CDH1 methylation was present in 12 (31%) of 40 of DCIS samples and 21 (47%) of 45 of invasive samples.	('CDH1', 'Gene', (96, 100))	('DCIS', 'Disease', (146, 150))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('CDH1', 'Gene', '999', (96, 100))	('IDC', 'Gene', '4000', (79, 82))	('methylation', 'Var', (4, 15))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('APC', 'Disease', (0, 3))	('found', 'Reg', (20, 25))	('IDC', 'Gene', (79, 82))	('DCIS', 'Disease', (44, 48))	('methylation', 'Var', (101, 112))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
105474	23826974	The analysis was done quantitatively by bisulfite pyrosequencing, and aberrant hypermethylation was defined as methylation levels two times above the standard deviation of the average of the normal controls.	('bisulfite', 'Chemical', 'MESH:C042345', (40, 49))	('methylation', 'MPA', (111, 122))	('aberrant', 'Var', (70, 78))
105476	23826974	Methylation of FOXC1 was observed to occur with greater frequency in invasive tumors (15/28, 53.6%) compared with pure DCIS (6/27, 22.2%).	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('FOXC1', 'Gene', '2296', (15, 20))	('invasive tumors', 'Disease', 'MESH:D009369', (69, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('FOXC1', 'Gene', (15, 20))	('occur', 'Reg', (37, 42))	('invasive tumors', 'Disease', (69, 84))
105477	23826974	An interesting finding of the above study was reduced FOXC1 gene expression (as detected by quantitative reverse transcription-polymerase chain reaction, or qRT-PCR) relative to normal breast tissue not only when the tumor tissue was methylated but also in those tumors that were unmethylated.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('FOXC1', 'Gene', '2296', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('methylated', 'Var', (234, 244))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', (263, 268))	('reduced', 'NegReg', (46, 53))	('expression', 'MPA', (65, 75))	('FOXC1', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumors', 'Disease', (263, 269))
105478	23826974	This echoes numerous other studies in which methylation of a given gene promoter is seen in a subset of tumors that are more generally silenced for that gene.	('methylation', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('seen', 'Reg', (84, 88))
105479	23826974	Mechanisms other than methylation, especially histone modifications, are known to result in gene silencing, and it has been shown that gene silencing may precede DNA methylation and thus these tumors may show varying stages along the route from histone-based silencing to histone and methylation-based silencing.	('result', 'Reg', (82, 88))	('gene', 'MPA', (135, 139))	('gene', 'MPA', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('modifications', 'Var', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))
105486	23826974	However, MGMT and CACNA1A individually were observed to be more frequently methylated in invasive cancer compared with DCIS (MGMT methylation: 8/14 invasive, 2/12 DCIS, P = 0.022; CACNA1A methylation: 6/14 invasive, 1/12 DCIS, P = 0.048).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('methylated', 'Var', (75, 85))	('CACNA1A', 'Gene', '773', (180, 187))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('MGMT', 'Gene', (125, 129))	('invasive cancer', 'Disease', (89, 104))	('MGMT', 'Gene', '4255', (125, 129))	('MGMT', 'Gene', '4255', (9, 13))	('MGMT', 'Gene', (9, 13))	('CACNA1A', 'Gene', (18, 25))	('invasive cancer', 'Disease', 'MESH:D009362', (89, 104))	('DCIS', 'Phenotype', 'HP:0030075', (221, 225))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('CACNA1A', 'Gene', (180, 187))	('CACNA1A', 'Gene', '773', (18, 25))
105496	23826974	Tommasi and colleagues identified 108 aberrantly methylated CpG islands by methylated CpG island recovery assay-assisted microarray analysis (MIRA) in early-stage breast cancer and six cases of undissected DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('aberrantly methylated', 'Var', (38, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))
105498	23826974	Another recent study used a global methylation approach to identify methylated genes on a panel of low-grade invasive breast cancer and in situ cancer and then profiled selected novel genes against a small number of additional in situ and invasive breast cancers.	('invasive breast cancers', 'Disease', 'MESH:D001943', (239, 262))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('methylated', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('situ cancer', 'Disease', (139, 150))	('invasive breast cancer', 'Disease', 'MESH:D001943', (239, 261))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('invasive breast cancer', 'Disease', 'MESH:D001943', (109, 131))	('situ cancer', 'Disease', 'MESH:D002278', (139, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (248, 262))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('low-grade', 'Disease', (99, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('invasive breast cancers', 'Disease', (239, 262))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('invasive breast cancer', 'Disease', (109, 131))
105502	23826974	In invasive breast carcinoma, the methylation status of certain genes has been reported to be associated with survival, risk of metastatic disease, risk of disease recurrence, and response to adjuvant treatment.	('breast carcinoma', 'Phenotype', 'HP:0003002', (12, 28))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (3, 28))	('metastatic disease', 'Disease', 'MESH:C538445', (128, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('invasive breast carcinoma', 'Disease', (3, 28))	('associated', 'Reg', (94, 104))	('survival', 'CPA', (110, 118))	('methylation status', 'Var', (34, 52))	('metastatic disease', 'Disease', (128, 146))
105503	23826974	However, in DCIS, no direct link between aberrant methylation and risk of recurrence, risk of progression to invasive disease, or likelihood of response to adjuvant therapy has been reported.	('invasive disease', 'Disease', 'MESH:D009362', (109, 125))	('aberrant methylation', 'Var', (41, 61))	('invasive disease', 'Disease', (109, 125))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))
105504	23826974	However, previous reports indicate associations between certain methylated genes and known predictive factors such as hormone receptor status and HER2 amplification and adverse prognostic markers such as high nuclear grade, high proliferation index, TP53 mutations, and HER2 amplification (Table 3).	('mutations', 'Var', (255, 264))	('amplification', 'Var', (275, 288))	('HER2', 'Gene', '2064', (146, 150))	('associations', 'Interaction', (35, 47))	('HER2', 'Gene', (270, 274))	('HER2', 'Gene', '2064', (270, 274))	('hormone receptor', 'Gene', '3164', (118, 134))	('high proliferation index', 'CPA', (224, 248))	('hormone receptor', 'Gene', (118, 134))	('TP53', 'Gene', '7157', (250, 254))	('TP53', 'Gene', (250, 254))	('HER2', 'Gene', (146, 150))	('amplification', 'Var', (151, 164))
105512	23826974	As DCIS is a heterogeneous disease with relatively few disease events occurring over decades, studies involving large numbers of pure DCIS cases with detailed clinical annotation and long-term follow-up are required to establish the validity of aberrant methylation as a predictive and prognostic biomarker in DCIS.	('clinical', 'Species', '191496', (159, 167))	('aberrant methylation', 'Var', (245, 265))	('DCIS', 'Disease', (3, 7))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('DCIS', 'Disease', (310, 314))	('DCIS', 'Phenotype', 'HP:0030075', (310, 314))
105515	23826974	Studies specifically designed to investigate the relationship between DNA methylation and clinical outcome in DCIS are required to establish the validity of aberrant DNA methylation as a predictive and prognostic biomarker in DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (226, 230))	('DCIS', 'Disease', (110, 114))	('aberrant', 'Var', (157, 165))	('clinical', 'Species', '191496', (90, 98))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))
105523	22809213	Epigenetic alterations leading to changes in gene regulation play a critical role in cancer development.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('gene regulation', 'MPA', (45, 60))	('cancer', 'Disease', (85, 91))	('changes', 'Reg', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
105583	29764880	For example, Skaane et al reported for DBT+s2D an overall performance level (cancer detection rates, false-positive scores) comparable with DBT plus standard 2D-DM.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DBT+s2D', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('2D-DM', 'Chemical', '-', (158, 163))
105587	29764880	They found screening with DBT+s2D in a large urban practice resulted in similar outcomes compared with 2D-DM plus DBT imaging.	('DBT+s2D', 'Var', (26, 33))	('2D-DM plus DBT', 'Disease', (103, 117))	('2D-DM plus DBT', 'Disease', 'MESH:D009223', (103, 117))
105588	29764880	Other American researchers found that screening with DBT+s2D mammography in a large community-based practice improved recall rate and positive predictive values without loss of cancer detection rate when compared with DBT plus FFDM and FFDM alone.	('DBT plus FFDM', 'Disease', 'MESH:D007625', (218, 231))	('DBT+s2D', 'Var', (53, 60))	('mammography', 'Gene', (61, 72))	('recall rate', 'MPA', (118, 129))	('improved', 'PosReg', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('positive predictive values', 'MPA', (134, 160))	('loss of cancer', 'Disease', 'MESH:D009369', (169, 183))	('DBT plus FFDM', 'Disease', (218, 231))	('loss of cancer', 'Disease', (169, 183))
105592	29764880	Consequently, a recent review concludes that new studies of DBT should preferentially use DBT with s2D instead of DBT plus 2D-DM.	('DBT plus 2D-DM', 'Disease', 'MESH:D009223', (114, 128))	('s2D', 'Var', (99, 102))	('DBT plus 2D-DM', 'Disease', (114, 128))
105593	29764880	To assess whether the findings of increased cancer detection with DBT can in fact be translated into improved screening efficacy, the incidence of interval cancers needs to be investigated.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('interval cancers', 'Disease', (147, 163))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('DBT', 'Var', (66, 69))	('interval cancers', 'Disease', 'MESH:D009369', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('increased', 'PosReg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
105619	29764880	The first primary objective of the study is to evaluate whether DBT+s2D leads to a clinically relevant increase in the detection rate of invasive breast cancers at the screening examination (predefined at >=33%) as compared with standard 2D-FFDM.	('invasive breast cancers', 'Disease', 'MESH:D001943', (137, 160))	('increase', 'PosReg', (103, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('DBT+s2D', 'Var', (64, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('invasive breast cancers', 'Disease', (137, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
105621	29764880	The second primary objective is to compare the cumulative incidence of interval cancers between the study arms in order to assess the prognostic importance of the additional cancers that will, predictably, be diagnosed by DBT+s2D and insofar to investigate the potential for overdiagnosis.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('interval cancers', 'Disease', 'MESH:D009369', (71, 87))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('DBT+s2D', 'Var', (222, 229))	('interval cancers', 'Disease', (71, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
105623	29764880	If the postulated increase in cancer detection with DBT+s2D translates into improved screening efficacy, the resulting reduction of interval cancers is expected to be up to 30%.	('screening efficacy', 'CPA', (85, 103))	('increase', 'PosReg', (18, 26))	('DBT+s2D', 'Var', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('interval cancers', 'Disease', (132, 148))	('improved', 'PosReg', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('reduction', 'NegReg', (119, 128))	('interval cancers', 'Disease', 'MESH:D009369', (132, 148))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
105660	29764880	The specific aim of the study is to show a clinically relevant difference (predefined at >=33%) between the detection rates of invasive breast cancers diagnosed by DBT+s2D and 2D-FFDM.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('2D-FFDM', 'Var', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('DBT+s2D', 'Var', (164, 171))	('invasive breast cancers', 'Disease', (127, 150))	('invasive breast cancers', 'Disease', 'MESH:D001943', (127, 150))
105677	29764880	The present evidence from non-randomised, observational studies indicates that DBT in combination with s2D image reconstruction may increase the rates of screen-detected invasive breast cancers by more than 33% compared with the conventional 2D-FFDM screening (figure 2).	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('increase', 'PosReg', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('invasive breast cancers', 'Disease', (170, 193))	('DBT', 'Var', (79, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('invasive breast cancers', 'Disease', 'MESH:D001943', (170, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (179, 193))
105678	29764880	The main objective of the TOSYMA trial is to investigate the hypothesis that DBT+s2D leads to a clinically relevant increase in the detection rate of screen-detected invasive cancers compared with standard 2D-FFDM.	('invasive cancers', 'Disease', (166, 182))	('DBT+s2D', 'Var', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('invasive cancers', 'Disease', 'MESH:D009362', (166, 182))	('increase', 'PosReg', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
105683	29764880	If the trial results confirm the view that the new screening modality DBT+s2D leads to an increased detection of invasive cancers, no rise of false-positive recalls and a concomitant decrease of interval cancers, it carries the potential of challenging the current standard screening modality.	('DBT+s2D', 'Var', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('interval cancers', 'Disease', (195, 211))	('invasive cancers', 'Disease', (113, 129))	('increased', 'PosReg', (90, 99))	('interval cancers', 'Disease', 'MESH:D009369', (195, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('recalls', 'Disease', 'MESH:D008569', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('decrease', 'NegReg', (183, 191))	('invasive cancers', 'Disease', 'MESH:D009362', (113, 129))	('recalls', 'Disease', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
105735	17058097	Although over 80% of respondents would consider foci of invasion less than 1 mm emanating from opposite poles of a duct with DCIS as microinvasion, slightly over 16% of respondents would measure DCIS with its associated microinvasion from opposite poles as one continuous invasive carcinoma, which would entail a drastically different treatment approach.	('invasive carcinoma', 'Disease', (272, 290))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('microinvasion', 'MPA', (220, 233))	('DCIS', 'Var', (195, 199))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('invasive carcinoma', 'Disease', 'MESH:D009361', (272, 290))
105748	27825140	An early biomarker and potential therapeutic target of RUNX 3 hypermethylation in breast cancer, a system review and meta-analysis Runt-related transcription factor 3 (RUNX3) methylation plays an important role in the carcinogenesis of breast cancer (BC).	('breast cancer', 'Disease', (82, 95))	('carcinogenesis of breast cancer', 'Disease', 'MESH:D063646', (218, 249))	('Runt-related transcription factor 3', 'Gene', '864', (131, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('RUNX3', 'Gene', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('Runt-related transcription factor 3', 'Gene', (131, 166))	('RUNX3', 'Gene', '864', (168, 173))	('RUNX 3', 'Gene', (55, 61))	('methylation', 'Var', (175, 186))	('carcinogenesis of breast cancer', 'Disease', (218, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('RUNX 3', 'Gene', '864', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
105749	27825140	However, the association between RUNX3 hypermethylation and significance of BC remains under investigation.	('RUNX3', 'Gene', (33, 38))	('hypermethylation', 'Var', (39, 55))	('RUNX3', 'Gene', '864', (33, 38))
105750	27825140	The purpose of this study is to perform a meta-analysis and literature review to evaluate the clinicopathological significance of RUNX3 hypermethylation in BC.	('RUNX3', 'Gene', (130, 135))	('hypermethylation', 'Var', (136, 152))	('RUNX3', 'Gene', '864', (130, 135))
105752	27825140	RUNX3 hypermethylation was significantly correlated with the risk of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), OR was 50.37, p < 0.00001 and 22.66, p < 0.00001 respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (69, 93))	('hypermethylation', 'Var', (6, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (105, 130))	('invasive ductal carcinoma', 'Disease', (105, 130))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (69, 85))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (69, 93))	('ductal carcinoma in situ', 'Disease', (69, 93))	('correlated', 'Reg', (41, 51))	('RUNX3', 'Gene', (0, 5))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (114, 130))	('RUNX3', 'Gene', '864', (0, 5))
105753	27825140	Interestingly, the frequency of RUNX3 hypermethylation increased in estrogen receptor (ER) positive BC, OR was 12.12, p = 0.005.	('hypermethylation', 'Var', (38, 54))	('estrogen receptor', 'Gene', '2099', (68, 85))	('ER', 'Gene', '2099', (87, 89))	('increased', 'PosReg', (55, 64))	('RUNX3', 'Gene', '864', (32, 37))	('RUNX3', 'Gene', (32, 37))	('estrogen receptor', 'Gene', (68, 85))	('positive', 'Reg', (91, 99))
105754	27825140	High RUNX3 mRNA expression was strongly associated with better relapse-free survival (RFS) in BC patients.	('High', 'Var', (0, 4))	('mRNA expression', 'MPA', (11, 26))	('better', 'PosReg', (56, 62))	('RUNX3', 'Gene', (5, 10))	('RUNX3', 'Gene', '864', (5, 10))	('relapse-free survival', 'CPA', (63, 84))	('patients', 'Species', '9606', (97, 105))
105755	27825140	In summary, RUNX3 methylation could be a promising early biomarker for the diagnosis of BC.	('RUNX3', 'Gene', (12, 17))	('RUNX3', 'Gene', '864', (12, 17))	('methylation', 'Var', (18, 29))
105761	27825140	The studies of molecular mechanism have demonstrated that the carcinogenesis involves the accumulation of various genetic alterations including loss of tumor suppressor genes and amplification of oncogenes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('amplification', 'Var', (179, 192))	('oncogenes', 'Gene', (196, 205))	('carcinogenesis', 'Disease', (62, 76))	('loss', 'NegReg', (144, 148))
105764	27825140	RUNX3 was first reported as a tumor suppressor in gastric cancer because of the causal link between the loss of RUNX3 and gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('loss', 'Var', (104, 108))	('RUNX3', 'Gene', (0, 5))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('RUNX3', 'Gene', (112, 117))	('RUNX3', 'Gene', '864', (112, 117))	('gastric carcinogenesis', 'Disease', (122, 144))	('tumor', 'Disease', (30, 35))	('RUNX3', 'Gene', '864', (0, 5))
105768	27825140	Previous evidences in cell lines, knockout animals, and primary human cancer tissues have indicated that RUNX3 as a suppressor is inactivated in BC by reduced copy number, protein mislocalization, hemizygous deletion and promoter hypermethylation.	('human', 'Species', '9606', (64, 69))	('RUNX3', 'Gene', '864', (105, 110))	('hemizygous deletion', 'Var', (197, 216))	('reduced', 'NegReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('promoter', 'MPA', (221, 229))	('RUNX3', 'Gene', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('copy number', 'MPA', (159, 170))	('protein mislocalization', 'MPA', (172, 195))
105770	27825140	We conducted a meta-analysis which increases the sample size and thus the power, to investigate the significance of RUNX3 hypermethylation in the progression and prognosis of BC.	('RUNX3', 'Gene', (116, 121))	('hypermethylation', 'Var', (122, 138))	('RUNX3', 'Gene', '864', (116, 121))
105771	27825140	The following variables were listed: first author, published year, country, ER status, RUNX3 methylation status and patient progressions (Table 1).	('RUNX3', 'Gene', '864', (87, 92))	('patient', 'Species', '9606', (116, 123))	('ER', 'Gene', '2099', (76, 78))	('RUNX3', 'Gene', (87, 92))	('methylation', 'Var', (93, 104))
105773	27825140	RUNX3 promoter in IDC patients was significantly methylated than in normal breast, OR was 22.66 with 95% CI 12.48-41.17, z = 10.25, p < 0.00001, I2 = 0%, p = 0.43 (Figure 3).	('IDC', 'Disease', (18, 21))	('patients', 'Species', '9606', (22, 30))	('methylated', 'Var', (49, 59))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
105776	27825140	RUNX3 methylation was strongly correlated to RUNX3 loss, OR was 0.12 with 95% CI 0.04-0.30, z = 4.41, p < 0.0001, I2 = 47% (Figure 6).	('RUNX3', 'Gene', (45, 50))	('RUNX3', 'Gene', '864', (45, 50))	('methylation', 'Var', (6, 17))	('loss', 'NegReg', (51, 55))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
105778	27825140	High RUNX3 mRNA expression was strongly correlated to better relapse-free survival (RFS) in all 3554 BC patients (Figure 8).	('High', 'Var', (0, 4))	('mRNA expression', 'MPA', (11, 26))	('relapse-free survival', 'CPA', (61, 82))	('RUNX3', 'Gene', (5, 10))	('RUNX3', 'Gene', '864', (5, 10))	('patients', 'Species', '9606', (104, 112))	('better', 'PosReg', (54, 60))
105780	27825140	The symmetry of funnel charts (Figure 9) suggested that there were no publication biases in the meta-analysis of RUNX3 methylation in BC.	('RUNX3', 'Gene', (113, 118))	('methylation', 'Var', (119, 130))	('RUNX3', 'Gene', '864', (113, 118))
105781	27825140	Several studies have reported the contribution of RUNX3 hypermethylation in BC progression by utilizing small group of patients.	('hypermethylation', 'Var', (56, 72))	('patients', 'Species', '9606', (119, 127))	('RUNX3', 'Gene', (50, 55))	('RUNX3', 'Gene', '864', (50, 55))
105782	27825140	To overcome small sizes of individual studies, we conducted the powerful meta-analysis with a total of ten studies and 747 patients, and evaluated the role of RUNX3 hypermethylation in the carcinogenic progression of BC.	('RUNX3', 'Gene', '864', (159, 164))	('patients', 'Species', '9606', (123, 131))	('RUNX3', 'Gene', (159, 164))	('carcinogenic', 'Disease', 'MESH:D063646', (189, 201))	('carcinogenic', 'Disease', (189, 201))	('hypermethylation', 'Var', (165, 181))
105791	27825140	Additionally, Omar et al reported that aberrant expression of RUNX3 was not biased toward the EGFR or KRAS mutation pathway in lung adenocarcinoma (ADC), indicating that RUNX3 methylation contributes the development of ADC in an independent of EGFR or KRAS pathway.	('methylation', 'Var', (176, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('KRAS', 'Gene', (252, 256))	('RUNX3', 'Gene', '864', (170, 175))	('EGFR', 'Gene', '1956', (244, 248))	('EGFR', 'Gene', '1956', (94, 98))	('RUNX3', 'Gene', (62, 67))	('RUNX3', 'Gene', (170, 175))	('lung adenocarcinoma', 'Disease', (127, 146))	('KRAS', 'Gene', '3845', (102, 106))	('contributes', 'Reg', (188, 199))	('RUNX3', 'Gene', '864', (62, 67))	('EGFR', 'Gene', (244, 248))	('ADC', 'Disease', (219, 222))	('EGFR', 'Gene', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('KRAS', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (252, 256))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
105792	27825140	Recent evidences indicate that RUNX3 hypermethylation attributes to the development of BC through Wnt signaling pathway.	('Wnt', 'Gene', '32838', (98, 101))	('RUNX3', 'Gene', (31, 36))	('RUNX3', 'Gene', '864', (31, 36))	('Wnt', 'Gene', (98, 101))	('attributes to', 'Reg', (54, 67))	('hypermethylation', 'Var', (37, 53))
105799	27825140	Therefore, high RUNX3 mRNA expression is associated with better relapse-free survival (RFS) in BC patients (Figure 8).	('mRNA expression', 'MPA', (22, 37))	('relapse-free survival', 'CPA', (64, 85))	('patients', 'Species', '9606', (98, 106))	('RUNX3', 'Gene', (16, 21))	('RUNX3', 'Gene', '864', (16, 21))	('high', 'Var', (11, 15))	('better', 'PosReg', (57, 63))
105802	27825140	Although more investigation needs to complete, RUNX3 could be a potential therapeutic target for the development of personalized treatment via demethylation.	('demethylation', 'Var', (143, 156))	('RUNX3', 'Gene', (47, 52))	('RUNX3', 'Gene', '864', (47, 52))
105805	27825140	RUNX3 methylation could also be detected in the sera of patient with BC.	('detected', 'Reg', (32, 40))	('methylation', 'Var', (6, 17))	('patient', 'Species', '9606', (56, 63))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
105807	27825140	We pooled four studies and evaluated the association between RUNX3 methylation and RUNX3 loss, the result showed that OR was 0.12, p < 0.0001, I2 = 47%.	('RUNX3', 'Gene', (83, 88))	('RUNX3', 'Gene', '864', (83, 88))	('loss', 'NegReg', (89, 93))	('RUNX3', 'Gene', '864', (61, 66))	('RUNX3', 'Gene', (61, 66))	('methylation', 'Var', (67, 78))
105809	27825140	Our finding indicated that RUNX3 methylation was correlated with RUNX3 loss, but more studies with a large population need to be completed.	('methylation', 'Var', (33, 44))	('RUNX3', 'Gene', (65, 70))	('RUNX3', 'Gene', '864', (65, 70))	('RUNX3', 'Gene', (27, 32))	('RUNX3', 'Gene', '864', (27, 32))	('loss', 'NegReg', (71, 75))
105814	27825140	Therefore, RUNX3 mRNA high expression was correlated to better overall survival in ER-negative patients, but not in ER-positive patients.	('RUNX3', 'Gene', '864', (11, 16))	('overall', 'MPA', (63, 70))	('patients', 'Species', '9606', (95, 103))	('ER', 'Gene', '2099', (116, 118))	('RUNX3', 'Gene', (11, 16))	('ER', 'Gene', '2099', (83, 85))	('better', 'PosReg', (56, 62))	('patients', 'Species', '9606', (128, 136))	('mRNA high expression', 'Var', (17, 37))
105815	27825140	Aberrant RUNX3 expression contribute to the development and progression of BC through modulating ER signaling pathway.	('Aberrant', 'Var', (0, 8))	('contribute', 'Reg', (26, 36))	('modulating', 'Reg', (86, 96))	('RUNX3', 'Gene', '864', (9, 14))	('RUNX3', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('ER', 'Gene', '2099', (97, 99))
105816	27825140	Overexpression of RUNX3 in BC cells decreases ERalpha expression, whereas deletion of RUNX3 by siRNA increases ER expression.	('RUNX3', 'Gene', (18, 23))	('RUNX3', 'Gene', (86, 91))	('deletion', 'Var', (74, 82))	('RUNX3', 'Gene', '864', (18, 23))	('ERalpha', 'Gene', '2099', (46, 53))	('RUNX3', 'Gene', '864', (86, 91))	('increases', 'PosReg', (101, 110))	('ER', 'Gene', '2099', (111, 113))	('ERalpha', 'Gene', (46, 53))	('ER', 'Gene', '2099', (46, 48))	('decreases', 'NegReg', (36, 45))
105818	27825140	In summary, the results of present meta-analysis suggest that the frequency of RUNX3 hypermethylation significantly increased in DCIS and IDC.	('hypermethylation', 'Var', (85, 101))	('RUNX3', 'Gene', '864', (79, 84))	('IDC', 'Disease', (138, 141))	('RUNX3', 'Gene', (79, 84))	('DCIS', 'Disease', (129, 133))	('increased', 'PosReg', (116, 125))
105819	27825140	RUNX3 methylation could be a promising biomarker for early diagnosis of BC.	('methylation', 'Var', (6, 17))	('RUNX3', 'Gene', (0, 5))	('RUNX3', 'Gene', '864', (0, 5))
105820	27825140	High RUNX3 mRNA expression is correlated to better relapse-free survival (RFS) in all BC patients.	('better', 'PosReg', (44, 50))	('High', 'Var', (0, 4))	('mRNA expression', 'MPA', (11, 26))	('patients', 'Species', '9606', (89, 97))	('RUNX3', 'Gene', (5, 10))	('RUNX3', 'Gene', '864', (5, 10))	('relapse-free survival', 'CPA', (51, 72))
105822	27825140	The following were criteria for the inclusion: 1) The studies about RUNX3 methylation and the clinicopathological significance in BC; 2) RUNX3 methylation in prognosis of patients with BC.	('RUNX3', 'Gene', '864', (68, 73))	('RUNX3', 'Gene', (137, 142))	('RUNX3', 'Gene', '864', (137, 142))	('methylation', 'Var', (143, 154))	('patients', 'Species', '9606', (171, 179))	('RUNX3', 'Gene', (68, 73))
105831	21373705	After validating the model with experimental data from a normal human breast line (MCF10A), the system was challenged to predict the growth of MCF10A where AKT-1 was overexpressed, leading to reduced apoptosis.	('human', 'Species', '9606', (64, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (83, 89))	('AKT-1', 'Gene', '207', (156, 161))	('MCF10A', 'Var', (143, 149))	('AKT-1', 'Gene', (156, 161))	('reduced', 'NegReg', (192, 199))	('apoptosis', 'CPA', (200, 209))	('MCF10A', 'CellLine', 'CVCL:0598', (143, 149))
105894	21373705	Acini grown from MCF10A-pER Akt-cells have disrupted morphogenesis that recapitulates properties of ductal carcinoma in situ (DCIS), such as delayed lumen formation, scattered apoptosis-resistant cells within the lumen, and acinar structures that fail to growth arrest.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Akt', 'Gene', (28, 31))	('MCF10A-pER', 'Var', (17, 27))	('growth arrest', 'Phenotype', 'HP:0001510', (255, 268))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('apoptosis-resistant cells', 'CPA', (176, 201))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (100, 124))	('ductal carcinoma in situ', 'Disease', (100, 124))	('Akt', 'Gene', '207', (28, 31))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (100, 124))	('MCF10A', 'CellLine', 'CVCL:0598', (17, 23))
105897	21373705	It is important to note here that the MCF10A-pER Akt cell line has been reported to be 46% larger in volume than the MCF10A line.	('MCF10A', 'CellLine', 'CVCL:0598', (38, 44))	('MCF10A', 'CellLine', 'CVCL:0598', (117, 123))	('MCF10A-pER', 'Var', (38, 48))	('larger', 'PosReg', (91, 97))	('Akt', 'Gene', '207', (49, 52))	('Akt', 'Gene', (49, 52))
105920	21373705	Furthermore, simulations highlighted that acinus growth arrest in normal acini can be achieved by controlling the fraction of proliferating cells, but also suggested that polarization has a stronger impact on enhancing growth arrest when apoptosis is fully functional.	('growth arrest', 'CPA', (219, 232))	('enhancing', 'PosReg', (209, 218))	('growth arrest', 'Phenotype', 'HP:0001510', (49, 62))	('rat', 'Species', '10116', (133, 136))	('acinus growth arrest', 'Disease', (42, 62))	('polarization', 'Var', (171, 183))	('acinus growth arrest', 'Disease', 'MESH:D006323', (42, 62))	('growth arrest', 'Phenotype', 'HP:0001510', (219, 232))
106010	23355313	Studies including DCIS are expected to yield higher estimates of overdiagnosis than those limited to IBC because including DCIS implies earlier diagnosis and greater possibility of death from other causes than breast cancer before diagnosis without screening.	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('DCIS', 'Var', (123, 127))	('death', 'Disease', 'MESH:D003643', (181, 186))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('death', 'Disease', (181, 186))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('breast cancer', 'Disease', (210, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('IBC', 'Chemical', '-', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
106012	23355313	Nevertheless, in epidemiological studies both increased risk of subsequent malignancy and mortality have been reported; even low-grade DCIS has been associated with a cancer rate of 39%, of which 45% of the women died from metastatic disease after 30 years of follow-up.	('low-grade DCIS', 'Var', (125, 139))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('women', 'Species', '9606', (207, 212))	('metastatic disease', 'CPA', (223, 241))	('cancer', 'Disease', (167, 173))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('malignancy', 'Disease', (75, 85))
106027	31040372	Reduced Basal Nitric Oxide Production Induces Precancerous Mammary Lesions via ERBB2 and TGFbeta One third of newly diagnosed breast cancers in the US are early-stage lesions.	('breast cancers', 'Disease', 'MESH:D001943', (126, 140))	('TGFbeta', 'Gene', (89, 96))	('breast cancers', 'Disease', (126, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('Precancerous Mammary Lesions', 'Disease', 'MESH:D011230', (46, 74))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Precancerous Mammary Lesions', 'Disease', (46, 74))	('Nitric Oxide', 'Chemical', 'MESH:D009569', (14, 26))	('ERBB2', 'Gene', (79, 84))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('ERBB2', 'Gene', '2064', (79, 84))	('breast cancers', 'Phenotype', 'HP:0003002', (126, 140))	('Reduced', 'Var', (0, 7))	('Basal Nitric Oxide Production', 'MPA', (8, 37))	('Induces', 'Reg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
106028	31040372	Because breast cancer risk factors are often linked to aberrant nitric oxide (NO) production, we hypothesized that abnormal NO levels might contribute to the formation of early-stage breast lesions.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('aberrant', 'Var', (55, 63))	('contribute', 'Reg', (140, 150))	('nitric oxide', 'Chemical', 'MESH:D009569', (64, 76))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
106032	31040372	Consistently, normalization of NO levels in precancerous and cancerous breast cells downmodulates TGFbeta and ERBB2 and ameliorates their proliferative phenotype.	('cancerous breast', 'Disease', (61, 77))	('cancerous breast', 'Disease', 'MESH:D001943', (61, 77))	('TGFbeta', 'Gene', (98, 105))	('ameliorates', 'PosReg', (120, 131))	('cancerous', 'Disease', (61, 70))	('cancerous', 'Disease', (47, 56))	('proliferative phenotype', 'CPA', (138, 161))	('cancerous', 'Disease', 'MESH:D009369', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('downmodulates', 'NegReg', (84, 97))	('cancerous', 'Disease', 'MESH:D009369', (61, 70))	('ERBB2', 'Gene', (110, 115))	('normalization', 'Var', (14, 27))
106039	31040372	Interestingly, these different risk factors are commonly linked to aberrant production of nitric oxide (NO), a bioactive signaling molecule produced throughout the body.	('nitric oxide', 'Chemical', 'MESH:D009569', (90, 102))	('aberrant', 'Var', (67, 75))	('linked', 'Reg', (57, 63))	('production of nitric oxide', 'MPA', (76, 102))
106054	31040372	Such alterations in the functionality of NOS might, at least in part, explain why NOS, in particular NOS2 isoform, is preferentially upregulated in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('upregulated', 'PosReg', (133, 144))	('cancers', 'Disease', (162, 169))	('NOS2', 'Gene', (101, 105))	('alterations', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NOS2', 'Gene', '4843', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
106057	31040372	In the present study, we investigate whether aberrant NO production contributes to the formation of precancerous breast lesions from normal mammary epithelia using cell lines of a breast cancer progression series as well as animal models.	('NO production', 'MPA', (54, 67))	('precancerous breast lesions', 'Disease', 'MESH:D011230', (100, 127))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant', 'Var', (45, 53))	('precancerous breast lesions', 'Disease', (100, 127))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('epithelia', 'Disease', 'None', (148, 157))	('epithelia', 'Disease', (148, 157))
106060	31040372	Importantly, pharmacological deprivation of NO in developing mouse mammary glands led to the formation of multiple (peripheral) papillomas (precancerous mammary lesions) and desmoplastic ECM in all the animals tested.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('papillomas', 'Phenotype', 'HP:0012740', (128, 138))	('cancerous', 'Disease', 'MESH:D009369', (143, 152))	('papillomas', 'Disease', 'MESH:D010212', (128, 138))	('papillomas', 'Disease', (128, 138))	('pharmacological', 'Var', (13, 28))	('desmoplastic ECM', 'Disease', (174, 190))	('mouse', 'Species', '10090', (61, 66))	('cancerous', 'Disease', (143, 152))	('desmoplastic ECM', 'Disease', 'MESH:D018220', (174, 190))
106064	31040372	Our results unravel the critical contribution of deficient basal NO production to the pathogenesis of precancerous breast lesions.	('precancerous breast lesions', 'Disease', (102, 129))	('deficient', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('basal NO production', 'MPA', (59, 78))	('precancerous breast lesions', 'Disease', 'MESH:D011230', (102, 129))
106073	31040372	AT1, showing the features of atypical hyperplasia, was generated by transfecting mutant H-Ras into MCF10A cells and serially transplanting them into nude mice.	('hyperplasia', 'Disease', 'MESH:D006965', (38, 49))	('nude mice', 'Species', '10090', (149, 158))	('H-Ras', 'Gene', (88, 93))	('H-Ras', 'Gene', '3265', (88, 93))	('MCF10A', 'CellLine', 'CVCL:0598', (99, 105))	('mutant', 'Var', (81, 87))	('hyperplasia', 'Disease', (38, 49))
106097	31040372	Single knock-down (KD) of either neuronal NOS1 or endothelial NOS3 partially reduced SNOC level, whereas KD of inducible NOS2 had no effect (Fig.	('NOS3', 'Gene', (62, 66))	('NOS2', 'Gene', (121, 125))	('NOS1', 'Gene', (42, 46))	('knock-down', 'Var', (7, 17))	('SNOC level', 'MPA', (85, 95))	('SNO', 'Chemical', '-', (85, 88))	('reduced', 'NegReg', (77, 84))	('NOS1', 'Gene', '4842', (42, 46))	('NOS2', 'Gene', '4843', (121, 125))	('NOS3', 'Gene', '4846', (62, 66))
106114	31040372	These results altogether strongly suggest that deficiency of the NOS cofactor, BH4, is a critical contributor to reduction of basal NO producion in MECs during cancer progression.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('basal NO producion', 'MPA', (126, 144))	('BH4', 'Chemical', 'MESH:C003402', (79, 82))	('BH4', 'Gene', (79, 82))	('reduction', 'NegReg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('deficiency', 'Var', (47, 57))
106122	31040372	As expected, periductal collagen level was dramatically elevated in L-NAME-treated mammary tissues, compared to control or L-arginine-treated tissues (Fig.	('elevated', 'PosReg', (56, 64))	('periductal collagen level', 'MPA', (13, 38))	('L-NAME-treated', 'Var', (68, 82))	('L-arginine', 'Chemical', 'MESH:D001120', (123, 133))	('L-NAME', 'Chemical', 'MESH:D019331', (68, 74))
106131	31040372	While a change in the ERBB2 gene locus is found in 20~30% cases of invasive breast cancers, it is even more prevalent in premalignant breast lesions (~50%), suggesting that a change in ERBB2 gene is an early event in breast carcinogenesis.	('premalignant breast lesions', 'Disease', (121, 148))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('ERBB2', 'Gene', (22, 27))	('prevalent', 'Reg', (108, 117))	('change', 'Var', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('invasive breast cancers', 'Disease', (67, 90))	('breast cancers', 'Phenotype', 'HP:0003002', (76, 90))	('ERBB2', 'Gene', (185, 190))	('breast carcinogenesis', 'Disease', (217, 238))	('premalignant breast lesions', 'Disease', 'MESH:D001941', (121, 148))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (217, 238))	('invasive breast cancers', 'Disease', 'MESH:D001943', (67, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('change', 'Var', (8, 14))
106136	31040372	All these senescence markers were highly elevated in L-NAME-treated glands, whereas they were almost undetectable in control or L-arginine-treated glands (Fig.	('L-NAME-treated', 'Var', (53, 67))	('L-NAME', 'Chemical', 'MESH:D019331', (53, 59))	('elevated', 'PosReg', (41, 49))	('senescence markers', 'MPA', (10, 28))	('L-arginine', 'Chemical', 'MESH:D001120', (128, 138))
106139	31040372	Consistent with our previous report, L-NAME impaired formation of mammary acini, but induced formation of disorganized, proliferative aggregates (Fig.	('L-NAME', 'Var', (37, 43))	('impaired', 'NegReg', (44, 52))	('L-NAME', 'Chemical', 'MESH:D019331', (37, 43))	('induced', 'Reg', (85, 92))	('formation', 'MPA', (93, 102))
106143	31040372	Surprisingly, even after a short-term (overnight) treatment, L-NAME dramatically (>3-fold) elevated the level and membrane-localization of ERBB2 over control, whereas L-arginine almost abrogated them (Supplementary Fig.	('L-NAME', 'Var', (61, 67))	('elevated', 'PosReg', (91, 99))	('membrane-localization', 'MPA', (114, 135))	('L-arginine', 'Chemical', 'MESH:D001120', (167, 177))	('L-NAME', 'Chemical', 'MESH:D019331', (61, 67))	('level', 'MPA', (104, 109))	('abrogated', 'NegReg', (185, 194))	('ERBB2', 'Gene', (139, 144))
106147	31040372	First we tested for the occurrence of bi-lineage phenotype by co-staining drug-treated mammary glands for CK8/18 (luminal) and CK14 (basal).	('CK8/18', 'Gene', '3856;3875', (106, 112))	('CK14', 'Var', (127, 131))	('CK8/18', 'Gene', (106, 112))	('tested', 'Reg', (9, 15))
106163	31040372	Both L-NAME and L-arginine-treatments increased the size, number and formation efficiency of mammospheres over control; however, L-NAME yielded the values twice as much as L-arginine (Fig.	('L-arginine', 'Chemical', 'MESH:D001120', (16, 26))	('L-NAME', 'Chemical', 'MESH:D019331', (5, 11))	('L-NAME', 'Var', (129, 135))	('size', 'CPA', (52, 56))	('L-NAME', 'Chemical', 'MESH:D019331', (129, 135))	('number', 'CPA', (58, 64))	('L-arginine', 'Chemical', 'MESH:D001120', (172, 182))	('increased', 'PosReg', (38, 47))	('formation efficiency of mammospheres', 'CPA', (69, 105))
106164	31040372	The proportions of CK18high/CK14high bi-lineage cells within mammospheres were significantly (>4-fold) higher in L-NAME and L-arginine-treated spheroids than control spheroids (Fig.	('L-arginine', 'Chemical', 'MESH:D001120', (124, 134))	('L-NAME', 'Var', (113, 119))	('L-NAME', 'Chemical', 'MESH:D019331', (113, 119))	('L-arginine-treated', 'Var', (124, 142))	('higher', 'PosReg', (103, 109))	('CK18', 'Gene', (19, 23))	('CK18', 'Gene', '3875', (19, 23))
106174	31040372	While CD24 level increased in L-arginine-treated (+6.5%) and L-NAME-treated spheroids (+24.1%), a significant fraction of cells (46~65%) showed low expression levels (Fig.	('increased', 'PosReg', (17, 26))	('expression levels', 'MPA', (148, 165))	('L-arginine', 'Chemical', 'MESH:D001120', (30, 40))	('L-NAME', 'Chemical', 'MESH:D019331', (61, 67))	('CD24', 'Gene', '100133941', (6, 10))	('CD24', 'Gene', (6, 10))	('L-arginine-treated', 'Var', (30, 48))
106184	31040372	These results confirm that deficiency of BH4 is a major contributor to reduced basal NO production and malignant phenotype of precancerous and cancerous MECs.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('BH4', 'Gene', (41, 44))	('BH4', 'Chemical', 'MESH:C003402', (41, 44))	('deficiency', 'Var', (27, 37))	('precancerous and cancerous MECs', 'Disease', 'MESH:D011230', (126, 157))	('reduced', 'NegReg', (71, 78))	('malignant phenotype', 'CPA', (103, 122))	('basal NO production', 'MPA', (79, 98))
106195	31040372	Nevertheless, it needs to be noted that sepiapterin also significantly elevated the vascular density in tumors in support of a notion that the increase of NO promotes antiogenesis (Fig.	('antiogenesis', 'MPA', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('elevated', 'PosReg', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('sepiapterin', 'Var', (40, 51))	('sepiapterin', 'Chemical', 'MESH:C016727', (40, 51))	('vascular', 'MPA', (84, 92))
106206	31040372	The findings altogether suggest that normalization of basal NO level may have a therapeutic potential for breast cancer.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('basal NO level', 'MPA', (54, 68))	('normalization', 'Var', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
106211	31040372	In the study, we hypothesized that aberrant NO production might contribute to the formation of precancerous breast lesions and tested this possibility.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('contribute', 'Reg', (64, 74))	('aberrant', 'Var', (35, 43))	('NO production', 'MPA', (44, 57))	('tested', 'Reg', (127, 133))	('precancerous breast lesions', 'Disease', 'MESH:D011230', (95, 122))	('precancerous breast lesions', 'Disease', (95, 122))
106218	31040372	Some studies report anti-cancer effects of L-NAME on already established cancer cells, while others report the opposite.	('cancer', 'Disease', (73, 79))	('L-NAME', 'Var', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('L-NAME', 'Chemical', 'MESH:D019331', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
106219	31040372	Such discrepancy may reflect the complex activities of NO and NOS in cancer as well as possible co-suppression of NOS and arginase by L-NAME at high concentrations (>5 mM).	('arginase', 'Enzyme', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('L-NAME', 'Var', (134, 140))	('L-NAME', 'Chemical', 'MESH:D019331', (134, 140))	('NOS', 'Enzyme', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
106247	31040372	Consistently, when we applied sepiapterin to ex vivo 3D cultured mouse mammary tumors, their proliferative phenotype was dramatically suppressed, whereas the vasculature was significantly enhanced (Fig.	('sepiapterin', 'Var', (30, 41))	('enhanced', 'PosReg', (188, 196))	('suppressed', 'NegReg', (134, 144))	('mouse', 'Species', '10090', (65, 70))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('proliferative phenotype', 'CPA', (93, 116))	('vasculature', 'CPA', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('sepiapterin', 'Chemical', 'MESH:C016727', (30, 41))
106260	31040372	Anti-beta-Galactosidase (Bioss, bs-4960R), anti-alkaline phosphatase (Novus Biologicals, NBP1-32948); anti-heterochromatin protein 1-gamma (HP1-gamma, phospho Ser 93, Bioss, bs-3221R); anti-p21 (Bioss, bs-10129R); anti-p27 (phospho Thr 187, Abcam, ab75908); anti-NOS-1, 2 (Thermo Fisher Scientific, PA1-033 and -036); anti-NOS-3 (Sigma-Aldrich, SAB-4300435); anti-ErbB2 (Thermo Fisher Scientific, PA5-16395); anti-pSMAD3 (Ser423/Ser425, Novous Biological, NBP1-77836); anti-CD24 (Novus Biologicals, NBP1-4639055); anti-CD44 (Bioss, bs-2507R); anti-S-Nitroso-Cysteine (Abcam, ab50185 or Alpha Diagnostics, NISC11-A); anti-Integrin alpha6 (BD Biosciences, 555734); anti-GM130 (Cell Signaling, 12480 S); anti-human CK 14 (ThermoFisher, MA511599); anti-human CK 18 (ThermoFisher, PA514263); anti-mouse CK 14 (BioLegend, 905301); anti-human CK 8/18 (DSHB, Troma-I); anti-Cleaved Caspase3 (Cell Signaling, #9664); anti-beta-Actin (Sigma, A1978); anti-DYNLL1 (Abcam, ab51603); and anti-ADMA (EMD Millipore, 09-814).	('CK 18', 'Gene', '3875', (755, 760))	('NBP1', 'Gene', (456, 460))	('Integrin alpha6', 'Gene', (621, 636))	('heterochromatin protein 1', 'Gene', (107, 132))	('SMAD3', 'Gene', '4088', (415, 420))	('DYNLL1', 'Gene', '8655', (945, 951))	('NBP1', 'Gene', '4682', (499, 503))	('CK 14', 'Gene', (798, 803))	('human', 'Species', '9606', (749, 754))	('NBP1', 'Gene', '4682', (456, 460))	('heterochromatin protein 1', 'Gene', '23468', (107, 132))	('mouse', 'Species', '10090', (792, 797))	('CD24', 'Gene', (474, 478))	('NOS-3', 'Gene', (323, 328))	('CK 14', 'Gene', '3861', (712, 717))	('SMAD3', 'Gene', (415, 420))	('NOS-1', 'Gene', (263, 268))	('beta-Galactosidase', 'Gene', '2720', (5, 23))	('Troma-I', 'Disease', 'MESH:D020754', (851, 858))	('p21', 'Gene', (190, 193))	('ErbB2', 'Gene', '2064', (364, 369))	('p21', 'Gene', '644914', (190, 193))	('human', 'Species', '9606', (706, 711))	('NBP1', 'Gene', (89, 93))	('beta-Actin', 'Gene', (913, 923))	('PA1', 'Gene', '79447', (299, 302))	('beta-Actin', 'Gene', '728378', (913, 923))	('NOS-3', 'Gene', '4846', (323, 328))	('p27', 'Gene', '3429', (219, 222))	('p27', 'Gene', (219, 222))	('Troma-I', 'Disease', (851, 858))	('CK 14', 'Gene', '3861', (798, 803))	('GM130', 'Gene', '2801', (668, 673))	('NBP1', 'Gene', '4682', (89, 93))	('CD24', 'Gene', '100133941', (474, 478))	('anti-Cleaved', 'Var', (861, 873))	('PA1', 'Gene', (299, 302))	('human', 'Species', '9606', (830, 835))	('CK 18', 'Gene', (755, 760))	('NOS-1', 'Gene', '4842', (263, 268))	('GM130', 'Gene', (668, 673))	('ErbB2', 'Gene', (364, 369))	('NBP1', 'Gene', (499, 503))	('Integrin alpha6', 'Gene', '3655', (621, 636))	('CK 8', 'Gene', (836, 840))	('CK 14', 'Gene', (712, 717))	('CK 8', 'Gene', '3856', (836, 840))	('HP1-gamma', 'Gene', '11335', (140, 149))	('beta-Galactosidase', 'Gene', (5, 23))	('HP1-gamma', 'Gene', (140, 149))	('ADMA', 'Chemical', 'MESH:C018524', (979, 983))	('DYNLL1', 'Gene', (945, 951))
106306	31040372	1 x 105 cells (100 mul in PBS) were incubated with 1 mug of anti-CD44 and anti-CD24 antibodies or isotype control, followed by the respective fluorophore-conjugated secondary antibodies at room temperature.	('PBS', 'Chemical', 'MESH:D007854', (26, 29))	('CD24', 'Gene', '100133941', (79, 83))	('CD24', 'Gene', (79, 83))	('anti-CD44', 'Var', (60, 69))
106313	28977921	Finally, complmentarity between CDK1 and three drugs, Aminophenazone, Pomalidomide and the Rosoxacin, implies novel pharmacological value of those drugs in breast cancer.	('CDK1', 'Gene', (32, 36))	('CDK1', 'Gene', '983', (32, 36))	('Aminophenazone', 'Chemical', 'MESH:D000632', (54, 68))	('Pomalidomide', 'Chemical', 'MESH:C467566', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('Rosoxacin', 'Chemical', 'MESH:C021083', (91, 100))	('complmentarity', 'Var', (9, 23))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
106336	28977921	Consequently, Aminophenazone, Pomalidomide and the Rosoxacin shared large similarity to the structures of the Zinc210393, Zinc 312408 and Zinc5316172, respectively, suggesting that these compounds can bind to the active site of the CDK1 with the similar poses of the Zinc210393, Zinc 312408 and Zinc5316172 (Figure 6).	('Zinc 312408', 'Var', (279, 290))	('Pomalidomide', 'Chemical', 'MESH:C467566', (30, 42))	('Zinc210393', 'Chemical', '-', (267, 277))	('bind', 'Interaction', (201, 205))	('Rosoxacin', 'Chemical', 'MESH:C021083', (51, 60))	('Zinc5316172', 'Chemical', '-', (138, 149))	('CDK1', 'Gene', '983', (232, 236))	('Zinc210393', 'Var', (110, 120))	('CDK1', 'Gene', (232, 236))	('Zinc210393', 'Var', (267, 277))	('Zinc5316172', 'Var', (295, 306))	('Zinc5316172', 'Chemical', '-', (295, 306))	('Aminophenazone', 'Chemical', 'MESH:D000632', (14, 28))	('Zinc210393', 'Chemical', '-', (110, 120))
106344	28977921	In this study, over-expression of CDK1 was enriched in Oocyte development and p53 signaling pathwayindicating that overexpression of CDK1 may promote DCIS progression by p53 signaling.	('Oocyte development', 'CPA', (55, 73))	('CDK1', 'Gene', (133, 137))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('overexpression', 'Var', (115, 129))	('CDK1', 'Gene', '983', (133, 137))	('p53', 'Gene', (170, 173))	('CDK1', 'Gene', (34, 38))	('p53', 'Gene', (78, 81))	('CDK1', 'Gene', '983', (34, 38))	('p53', 'Gene', '7157', (170, 173))	('DCIS progression', 'CPA', (150, 166))	('promote', 'PosReg', (142, 149))	('p53', 'Gene', '7157', (78, 81))
106367	29169230	Microcalcifications were significantly associated with high-grade DCIS (P<0.001), the presence of comedonecrosis (P<0.001), an elevated Ki-67 (P<0.001), and HER2 positivity (P=0.003).	('high-grade DCIS', 'Disease', (55, 70))	('Microcalcifications', 'Disease', (0, 19))	('Ki-67', 'CPA', (136, 141))	('necrosis', 'Disease', (104, 112))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('HER2', 'Gene', (157, 161))	('positivity', 'Var', (162, 172))	('elevated', 'PosReg', (127, 135))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('HER2', 'Gene', '2064', (157, 161))
106399	29169230	When correlations between the characteristic findings of ultrasonography and biological markers were analyzed, the ultrasonographic presence of microcalcifications showed a statistically significant association with a Ki-67 index higher than 20% (P<0.001) and HER2 positivity (P=0.003) (Table 3).	('HER2', 'Gene', (260, 264))	('positivity', 'Var', (265, 275))	('HER2', 'Gene', '2064', (260, 264))	('microcalcifications', 'Disease', (144, 163))	('Ki-67 index', 'Protein', (218, 229))
106409	29169230	In our study, microcalcifications on ultrasonography showed a significant correlation with a high nuclear grade and comedonecrosis.	('necrosis', 'Disease', 'MESH:D009336', (122, 130))	('microcalcifications', 'Var', (14, 33))	('necrosis', 'Disease', (122, 130))
106413	29169230	Microcalcifications found on ultrasonography showed a statistically significant correlation with HER2 positivity or an increased Ki-67 index.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (97, 101))	('increased', 'PosReg', (119, 128))	('positivity', 'Var', (102, 112))	('Ki-67', 'CPA', (129, 134))
106414	29169230	Previous studies have reported that frequent local recurrence of DCIS was associated with ER negativity, PR negativity, HER2 positivity, and an elevated Ki-67 index.	('ER', 'Gene', '2099', (121, 123))	('DCIS', 'Disease', (65, 69))	('ER', 'Gene', '2099', (90, 92))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('HER2', 'Gene', (120, 124))	('positivity', 'Var', (125, 135))	('PR', 'Gene', '5241', (105, 107))	('HER2', 'Gene', '2064', (120, 124))	('Ki-67', 'CPA', (153, 158))
106416	29169230	reported that a high Ki-67 index with HER2 positivity in DCIS in the presence of microinvasion was correlated with microcalcifications seen on ultrasonography.	('microcalcifications', 'Disease', (115, 134))	('HER2', 'Gene', '2064', (38, 42))	('correlated', 'Reg', (99, 109))	('HER2', 'Gene', (38, 42))	('positivity', 'Var', (43, 53))	('Ki-67', 'MPA', (21, 26))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
106419	29169230	Ultrasonographic microcalcifications and ductal changes were associated with non-mass lesions, which were correlated with poor prognostic factors such as a high nuclear grade, comedonecrosis, HER2 positivity, and an increased Ki-67 index.	('necrosis', 'Disease', (182, 190))	('Ki-67 index', 'CPA', (226, 237))	('non-mass lesions', 'Disease', (77, 93))	('necrosis', 'Disease', 'MESH:D009336', (182, 190))	('ductal changes', 'CPA', (41, 55))	('HER2', 'Gene', (192, 196))	('HER2', 'Gene', '2064', (192, 196))	('positivity', 'Var', (197, 207))	('increased', 'PosReg', (216, 225))
106427	29416627	Cancer is an evolutionary disease where the accumulation of genetic alterations leads epithelial cells to transform to premalignant lesions that ultimately may evolve to tumor cells.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (170, 175))	('genetic alterations', 'Var', (60, 79))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
106512	29416627	We downloaded in total 29 normal tissue, 16 DCIS and 59 basal-like tumor samples from five studies with the following GEO accession numbers: GSE21422, GSE26910, GSE3744, GSE3893 and GSE6519, all of them loaded onto an Affymetrix Human Genome U133 Plus 2.0 Array.	('GSE3893', 'Chemical', '-', (170, 177))	('GSE6519', 'Chemical', '-', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('GSE6519', 'Var', (182, 189))	('GSE21422', 'Var', (141, 149))	('GSE3744', 'Chemical', '-', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('GSE3893', 'Var', (170, 177))	('Human', 'Species', '9606', (229, 234))	('tumor', 'Disease', (67, 72))	('basal-like tumor', 'Phenotype', 'HP:0002671', (56, 72))	('GSE26910', 'Var', (151, 159))	('GSE3744', 'Var', (161, 168))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
106529	27926499	Moreover, the results demonstrated that patients who underwent SLNB were more likely to have a lower BCSM (P < 0.05).	('patients', 'Species', '9606', (40, 48))	('lower', 'NegReg', (95, 100))	('SLNB', 'Var', (63, 67))
106558	27926499	We also used the analysis to examine the option of radiotherapy, which showed that patients who underwent radiotherapy had a higher OS that did not affect the BCSM (Figure 2B, 2D, OS, P < 0.001, aHR = 0.303; BCSM, P = 0.32, aHR = 0.466).	('aHR', 'Gene', '196', (224, 227))	('radiotherapy', 'Var', (106, 118))	('aHR', 'Gene', (195, 198))	('patients', 'Species', '9606', (83, 91))	('aHR', 'Gene', (224, 227))	('aHR', 'Gene', '196', (195, 198))
106559	27926499	However, the results demonstrated a significant difference within the LN surgery only group in terms of BCSM, and patients who underwent SLNB were more likely to have a lower BCSM (Figure 2E, P = 0.035, aHR = 3.902).	('aHR', 'Gene', (203, 206))	('patients', 'Species', '9606', (114, 122))	('lower', 'NegReg', (169, 174))	('BCSM', 'CPA', (104, 108))	('aHR', 'Gene', '196', (203, 206))	('SLNB', 'Var', (137, 141))
106562	27926499	In our series, a dramatic difference was observed within the surgical treatment and radiotherapy subgroups with respect to OS, where patients who underwent SLNB were more likely to have a lower BCSM.	('lower BCSM', 'CPA', (188, 198))	('patients', 'Species', '9606', (133, 141))	('SLNB', 'Var', (156, 160))
106568	27926499	In contrast, another study showed that HER2 overexpression may not be the key factor in the progression of DCIS to invasive carcinoma and that HER2 gene amplification is inversely related to invasive progression in patients with DCIS.	('related', 'Reg', (180, 187))	('patients', 'Species', '9606', (215, 223))	('invasive carcinoma', 'Disease', 'MESH:D009361', (115, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('invasive', 'CPA', (191, 199))	('invasive carcinoma', 'Disease', (115, 133))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', (143, 147))	('gene amplification', 'Var', (148, 166))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('HER2', 'Gene', '2064', (39, 43))	('DCIS', 'Disease', (229, 233))	('HER2', 'Gene', '2064', (143, 147))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))
106585	27926499	Our results also demonstrated that patients who underwent BCS+R were more likely to exhibit an improved OS, and patients who underwent BCS alone tended to have a lower OS compared with those in the mastectomy subgroup.	('improved', 'PosReg', (95, 103))	('BCS+R', 'Var', (58, 63))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (35, 43))
106590	27926499	Likewise, our results reported that patients treated by SLNB had a similar OS and better BCSM in comparison with those who received ALND.	('SLNB', 'Var', (56, 60))	('BCSM', 'CPA', (89, 93))	('ALND', 'Chemical', '-', (132, 136))	('patients', 'Species', '9606', (36, 44))
106594	27926499	Simultaneously, several studies confirmed that HoR negativity, high S-phase fraction, abnormal DNA ploidy, p53 overexpression and HER2 overexpression were associated with more aggressive tumor behavior in BCIS.	('HoR', 'Gene', '3164', (47, 50))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('associated', 'Reg', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('abnormal', 'Var', (86, 94))	('BCIS', 'Disease', (205, 209))	('aggressive tumor', 'Disease', 'MESH:D001523', (176, 192))	('HER2', 'Gene', (130, 134))	('high', 'Var', (63, 67))	('aggressive tumor', 'Disease', (176, 192))	('HER2', 'Gene', '2064', (130, 134))	('HoR', 'Gene', (47, 50))	('overexpression', 'PosReg', (111, 125))	('overexpression', 'PosReg', (135, 149))
106599	27926499	As a result, HER2 targeted therapy and novel adjuvant hormone therapy remained in use for the management of BCIS to significantly improve the survival.	('improve', 'PosReg', (130, 137))	('survival', 'MPA', (142, 150))	('targeted therapy', 'Var', (18, 34))	('BCIS', 'Disease', (108, 112))	('HER2', 'Gene', (13, 17))	('HER2', 'Gene', '2064', (13, 17))
106606	27926499	Cancer characteristics were classified according to grade (well, moderately, poorly, undifferentiated, unknown), tumor size (<= 10, 10-20, 20-50, > 50 mm), laterality (right, left, others, unknown), HoR status and HER2 status (positive, negative, borderline, unknown).	('tumor', 'Disease', (113, 118))	('HER2', 'Gene', (214, 218))	('HER2', 'Gene', '2064', (214, 218))	('<= 10', 'Var', (125, 130))	('Cancer', 'Disease', (0, 6))	('HoR', 'Gene', '3164', (199, 202))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('HoR', 'Gene', (199, 202))
106607	27926499	The subtypes were characterized according to the breast subtype variable as either HoR+/HER2-, HoR+/HER2+, HoR-/HER2+ or triple-negative (TN).	('HoR', 'Gene', '3164', (95, 98))	('HoR', 'Gene', (107, 110))	('HoR', 'Gene', (83, 86))	('triple-negative', 'Var', (121, 136))	('HER2', 'Gene', (88, 92))	('HoR', 'Gene', (95, 98))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (88, 92))	('HoR', 'Gene', '3164', (83, 86))	('HER2', 'Gene', '2064', (112, 116))	('HoR', 'Gene', '3164', (107, 110))	('HER2', 'Gene', (100, 104))	('HER2', 'Gene', '2064', (100, 104))
106630	28198360	Inhibition of LOX decreases tumour angiogenesis and growth and opposes metastasis, thus exemplifying the efficacy of strategies aimed at targeting secreted factors that alter the tumour microenvironment.	('LOX', 'Gene', '4015', (14, 17))	('growth', 'CPA', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('decreases tumour', 'Disease', (18, 34))	('LOX', 'Gene', (14, 17))	('decreases tumour', 'Disease', 'MESH:D009369', (18, 34))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('rat', 'Species', '10116', (119, 122))	('metastasis', 'CPA', (71, 81))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('opposes', 'NegReg', (63, 70))	('Inhibition', 'Var', (0, 10))	('tumour', 'Disease', (28, 34))	('tumour', 'Disease', (179, 185))
106646	28198360	Atomic force microscopy (AFM) analysis indicated that iCAFs produced a matrix that was significantly stiffer than that generated by iNFs (Fig.	('iCAFs', 'Chemical', '-', (54, 59))	('rat', 'Species', '10116', (123, 126))	('iNF', 'Gene', (132, 135))	('iCAFs', 'Var', (54, 59))	('iNF', 'Gene', '2694', (132, 135))
106666	28198360	Analysis of publicly available gene expression data sets indicated higher CLIC3 levels in the stroma of ovarian (GSE40595), oral (GEOD-38517) and colon (GSE35602) carcinoma when compared with stroma of the corresponding normal tissues (Supplementary Table 3).	('higher', 'PosReg', (67, 73))	('stroma of ovarian', 'Disease', (94, 111))	('CLIC3 levels', 'MPA', (74, 86))	('stroma of ovarian', 'Disease', 'MESH:D010051', (94, 111))	('colon (GSE35602) carcinoma', 'Disease', 'MESH:D015179', (146, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('GEOD-38517', 'Var', (130, 140))	('GSE40595', 'Var', (113, 121))
106674	28198360	4a), CLIC3 knockdown (with two independent small interfering RNAs (siRNAs)) reduced the ability of iCAFs (Fig.	('CLIC3', 'Gene', (5, 10))	('iCAFs', 'Chemical', '-', (99, 104))	('reduced', 'NegReg', (76, 83))	('knockdown', 'Var', (11, 20))
106675	28198360	This was likely because of defects in EC invasiveness and not proliferation because treatment of ECs with CM from iCAFs silenced for CLIC3 had no significant impact on EC proliferation (Supplementary Fig.	('silenced', 'Var', (120, 128))	('CLIC3', 'Gene', (133, 138))	('defects in EC invasiveness', 'Disease', (27, 53))	('EC proliferation', 'CPA', (168, 184))	('rat', 'Species', '10116', (178, 181))	('iCAFs', 'Chemical', '-', (114, 119))	('rat', 'Species', '10116', (69, 72))	('defects in EC invasiveness', 'Disease', 'MESH:D009362', (27, 53))
106682	28198360	To determine whether secreted CLIC3 contributed to cancer cell invasiveness, we incubated MDA-MB-231 cells with conditioned medium from iCAFs in which CLIC3 had been knocked down (Supplementary Fig.	('iCAFs', 'Chemical', '-', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (90, 100))	('knocked down', 'Var', (166, 178))	('CLIC3', 'Gene', (151, 156))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
106683	28198360	The CM from CLIC3-knockdown iCAFs had reduced ability to drive the extension of invasive pseudopods from MDA-MB-231 cells, and this was completely restored by replacement of CLIC3 in the iCAF-CM with rCLIC3 (Fig.	('reduced', 'NegReg', (38, 45))	('replacement', 'Var', (159, 170))	('rCLIC3', 'Gene', (200, 206))	('iCAFs', 'Chemical', '-', (28, 33))	('rCLIC3', 'Gene', '296566', (200, 206))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (105, 115))	('extension of invasive pseudopods', 'CPA', (67, 99))	('CLIC3-knockdown', 'Gene', (12, 27))	('ability', 'MPA', (46, 53))
106690	28198360	We mutated the corresponding cysteine residue in CLIC3 to generate rCLIC3C22A (Fig.	('cysteine', 'Chemical', 'MESH:D003545', (29, 37))	('rCLIC3', 'Gene', (67, 73))	('rat', 'Species', '10116', (62, 65))	('rCLIC3', 'Gene', '296566', (67, 73))	('mutated', 'Var', (3, 10))
106691	28198360	As expected, this mutant had strongly reduced GSH-dependent oxidoreductase activity (Fig.	('GSH-dependent oxidoreductase activity', 'MPA', (46, 83))	('mutant', 'Var', (18, 24))	('GSH', 'Chemical', '-', (46, 49))	('reduced', 'NegReg', (38, 45))
106692	28198360	To determine whether CLIC3 oxidoreductase activity may contribute to its capacity to drive invasiveness, we tested the ability of CLIC3C22A to drive EC sprouting and extension of invasive pseudopods from tumour cells.	('tested', 'Reg', (108, 114))	('invasive pseudopods', 'CPA', (179, 198))	('tumour', 'Disease', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('CLIC3C22A', 'Var', (130, 139))	('extension', 'CPA', (166, 175))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('EC sprouting', 'CPA', (149, 161))
106716	28198360	6c) generated an ECM with significantly reduced stiffness, and this was almost completely restored simply by adding rCLIC3 to the culture medium of iCAF silenced for CLIC3 (Fig.	('rat', 'Species', '10116', (8, 11))	('stiffness', 'MPA', (48, 57))	('reduced', 'NegReg', (40, 47))	('rCLIC3', 'Gene', (116, 122))	('silenced', 'Var', (153, 161))	('rCLIC3', 'Gene', '296566', (116, 122))
106723	28198360	In fact, rCLIC3-driven EC sprouting was completely opposed by knockdown of TGM2 in ECs (Fig.	('TGM2', 'Gene', (75, 79))	('TGM2', 'Gene', '7052', (75, 79))	('rCLIC3', 'Gene', (9, 15))	('rCLIC3', 'Gene', '296566', (9, 15))	('opposed', 'NegReg', (51, 58))	('knockdown', 'Var', (62, 71))
106725	28198360	As rCLIC3-induced but not VEGF-induced EC sprouting was inhibited by Z-DON (Supplementary Fig.	('EC sprouting', 'CPA', (39, 51))	('Z-DON', 'Var', (69, 74))	('rCLIC3', 'Gene', '296566', (3, 9))	('Z-DON', 'Chemical', '-', (69, 74))	('inhibited', 'NegReg', (56, 65))	('rCLIC3', 'Gene', (3, 9))
106726	28198360	7d), we conclude that the effect of TGM2 blockade was specific for CLIC3-induced sprouting.	('TGM2', 'Gene', (36, 40))	('TGM2', 'Gene', '7052', (36, 40))	('CLIC3-induced', 'Disease', (67, 80))	('blockade', 'Var', (41, 49))
106728	28198360	The ability of rCLIC3 to drive pseudopod elongation was completely ablated when cancer cells were plated into ECM generated by TGM2 knockdown fibroblasts (Fig.	('knockdown', 'Var', (132, 141))	('pseudopod elongation', 'CPA', (31, 51))	('rat', 'Species', '10116', (118, 121))	('TGM2', 'Gene', '7052', (127, 131))	('TGM2', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rCLIC3', 'Gene', (15, 21))	('ablated', 'NegReg', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('rCLIC3', 'Gene', '296566', (15, 21))	('cancer', 'Disease', (80, 86))
106761	28198360	Corroborating our findings, in a study conducted by Gyorffy et al., patients with HGS ovarian cancer with high CLIC3 mRNA levels in the tumour had reduced overall survival compared with those with low CLIC3 (Supplementary Fig.	('CLIC3 mRNA levels', 'MPA', (111, 128))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('high', 'Var', (106, 110))	('HGS ovarian cancer', 'Disease', (82, 100))	('tumour', 'Disease', (136, 142))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('rat', 'Species', '10116', (7, 10))	('HGS ovarian cancer', 'Disease', 'MESH:D010051', (82, 100))	('overall survival', 'MPA', (155, 171))	('reduced', 'NegReg', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
106781	28198360	In combination with the fact that CLIC3 controls the GSH-dependent reduction of TGM2 at specific cysteines, and that CLIC3 influences the binding of TGM2 to its regulatory cofactors, our work supports the view that the pro-invasive capabilities of extracellular CLIC3 are imparted via its GSH-dependent oxidoreductase characteristics.	('TGM2', 'Gene', '7052', (149, 153))	('cysteines', 'Chemical', 'MESH:D003545', (97, 106))	('influences', 'Reg', (123, 133))	('GSH', 'Chemical', '-', (53, 56))	('GSH', 'Chemical', '-', (289, 292))	('reduction', 'NegReg', (67, 76))	('CLIC3', 'Var', (117, 122))	('binding', 'Interaction', (138, 145))	('TGM2', 'Gene', (80, 84))	('TGM2', 'Gene', '7052', (80, 84))	('TGM2', 'Gene', (149, 153))
106783	28198360	In the strongly reducing environment of the cytosol, high GSH concentration (0.5-10 mM) can compromise protein activity by glutathionylation, and CLICs may de-glutathionylate these cysteine residues to restore protein activity.	('compromise', 'NegReg', (92, 102))	('protein activity', 'MPA', (103, 119))	('de-glutathionylate', 'Var', (156, 174))	('restore', 'PosReg', (202, 209))	('glutathionylation', 'MPA', (123, 140))	('rat', 'Species', '10116', (69, 72))	('GSH', 'Chemical', '-', (58, 61))	('cysteine', 'Chemical', 'MESH:D003545', (181, 189))	('protein activity', 'MPA', (210, 226))
106790	28198360	Conversely, cysteine 505 was most reduced by CLIC3.	('CLIC3', 'Var', (45, 50))	('cysteine', 'Chemical', 'MESH:D003545', (12, 20))	('reduced', 'NegReg', (34, 41))	('cysteine 505', 'MPA', (12, 24))
106792	28198360	We show that iCAFs silenced for CLIC3 or TGM2 generate an ECM with significantly reduced stiffness and that this can be almost completely restored simply by adding soluble purified recombinant CLIC3 (rCLIC3) to the culture medium, but not when silenced for TGM2.	('CLIC3', 'Gene', (32, 37))	('iCAFs', 'Chemical', '-', (13, 18))	('rat', 'Species', '10116', (50, 53))	('TGM2', 'Gene', (41, 45))	('rCLIC3', 'Gene', (200, 206))	('TGM2', 'Gene', '7052', (257, 261))	('TGM2', 'Gene', (257, 261))	('TGM2', 'Gene', '7052', (41, 45))	('rCLIC3', 'Gene', '296566', (200, 206))	('silenced', 'Var', (19, 27))	('reduced', 'NegReg', (81, 88))	('stiffness', 'MPA', (89, 98))
106798	28198360	Our study discovered an unprecedented molecular mechanism used by CAFs and cancer cells to generate a pro-invasive stroma, and opens up the possibility for the development of inhibitors of CLIC3 oxidoreductase activity to alter vessel growth and oppose tumour invasiveness.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('alter', 'Reg', (222, 227))	('rat', 'Species', '10116', (95, 98))	('cancer', 'Disease', (75, 81))	('inhibitors', 'Var', (175, 185))	('oppose', 'NegReg', (246, 252))	('vessel growth', 'CPA', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumour invasiveness', 'Disease', (253, 272))	('tumour invasiveness', 'Disease', 'MESH:D009361', (253, 272))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('pro-invasive stroma', 'CPA', (102, 121))
106866	28198360	Growth factor reduced phenol red free matrigel (Corning) in liquid form at 4  C was mixed with vehicle (50 mM Tris HCl pH 7.4) or FGF2 15 U ml-1 heparin or purified human recombinant CLIC3 (wild type or C22A mutant, 500 ng) alone or in combination.	('reduced', 'NegReg', (14, 21))	('human', 'Species', '9606', (165, 170))	('HCl', 'Chemical', '-', (115, 118))	('Tris', 'Chemical', '-', (110, 114))	('C22A', 'Var', (203, 207))	('phenol red', 'Chemical', 'MESH:D010637', (22, 32))	('phenol red free', 'MPA', (22, 37))	('ml-1', 'Gene', '51761', (140, 144))	('ml-1', 'Gene', (140, 144))	('C22A', 'SUBSTITUTION', 'None', (203, 207))	('heparin', 'Chemical', 'MESH:D006493', (145, 152))
106892	28198360	This approach exploits the capability of TGM2 to bind to GDP/GTP and uses the nucleotide analogue MANT-GMPPNP (Life Technologies), where the modified ribose moiety has been shown to minimally interfere with the binding between protein and nucleotide.	('bind', 'Interaction', (49, 53))	('modified', 'Var', (141, 149))	('GDP', 'Chemical', 'MESH:D006153', (57, 60))	('MANT-GMPPNP', 'Chemical', '-', (98, 109))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('ribose', 'Chemical', 'MESH:D012266', (150, 156))	('TGM2', 'Gene', (41, 45))	('protein', 'Protein', (227, 234))	('TGM2', 'Gene', '7052', (41, 45))	('interfere', 'NegReg', (192, 201))	('binding', 'Interaction', (211, 218))
106897	28198360	The reduced monomeric CLIC1 wild type, CLIC1C24A mutant, CLIC3 wild type or CLIC3C22A mutant (10 muM final concentration) was added to 5 mM potassium phosphate buffer (pH 7) containing 1 mM EDTA, 250 muM NADPH, 50 nM GR and 1 mM HEDS.	('potassium phosphate', 'Chemical', 'MESH:C013216', (140, 159))	('rat', 'Species', '10116', (114, 117))	('CLIC1', 'Gene', (22, 27))	('CLIC1', 'Gene', (39, 44))	('muM', 'Gene', '56925', (97, 100))	('EDTA', 'Chemical', 'MESH:D004492', (190, 194))	('muM', 'Gene', '56925', (200, 203))	('NADPH', 'Chemical', 'MESH:D009249', (204, 209))	('CLIC1', 'Gene', '1192', (22, 27))	('CLIC1', 'Gene', '1192', (39, 44))	('HEDS', 'Chemical', 'MESH:C031319', (229, 233))	('CLIC3C22A mutant', 'Var', (76, 92))	('muM', 'Gene', (97, 100))	('muM', 'Gene', (200, 203))
106928	26589824	Biodistribution studies demonstrated an uptake of 14.0 +- 1.1 %I.D./g in DCIS + CAIX tumors, 4.6 +- 0.8 %I.D./g in DCIS tumors, while 2.0 +- 0.2 %I.D./g was obtained with R2-IR.	('DCIS tumors', 'Disease', 'MESH:D002285', (115, 126))	('I.D./g', 'Var', (63, 69))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('uptake', 'MPA', (40, 46))	('DCIS + CAIX', 'Disease', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('DCIS tumors', 'Disease', (115, 126))	('tumors', 'Disease', (85, 91))
106946	26589824	Firstly, the molecular weight of nanobodies is ten times lower (15 kDa vs. 150 kDa), which results in rapid tumor accumulation while having short elimination half-life in the bloodstream, which together lead to good contrast at early time points after administration.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('nanobodies', 'Var', (33, 43))	('molecular weight', 'MPA', (13, 29))	('lower', 'NegReg', (57, 62))
106965	26589824	IRDye800CW-Maleimide (further referred to as IR; LI-COR) was conjugated to nanobodies following manufacturer recommendations (see ESM for more details).	('IRDye800CW-Maleimide', 'Chemical', '-', (0, 20))	('IRDye800CW-Maleimide', 'Var', (0, 20))	('nanobodies', 'Protein', (75, 85))
106985	26589824	The mean TNR of the DCIS tumors from mice injected with B9-IR or R2-IR was 2.1 +- 0.2 and 1.3 +- 0.1, respectively (p = 0.04).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('R2-IR', 'Var', (65, 70))	('B9-IR', 'Var', (56, 61))	('DCIS tumors', 'Disease', (20, 31))	('DCIS tumors', 'Disease', 'MESH:D002285', (20, 31))	('mice', 'Species', '10090', (37, 41))
107010	26589824	An orthotopic xenograft mouse model was used to validate tumor imaging using anti-CAIX nanobodies.	('mouse', 'Species', '10090', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('anti-CAIX', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
107012	26589824	The MCF10DCIS cells express little CAIX when grown at normoxic conditions.	('MCF10DCIS', 'Var', (4, 13))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (4, 13))	('CAIX', 'Protein', (35, 39))
107019	26589824	The rapid clearance can be related to the detection of B9-IR in the kidneys, as previously described for nanobodies targeting EGFR or HER2.	('EGFR', 'Gene', (126, 130))	('B9-IR', 'Var', (55, 60))	('HER2', 'Gene', (134, 138))	('HER2', 'Gene', '2064', (134, 138))	('EGFR', 'Gene', '1956', (126, 130))
107103	23641039	The risk of an IBE was more than twofold higher for the 30% of patients with an intermediate or high DCIS Score compared with the 70% of patients with a low DCIS Score.	('DCIS', 'Gene', (101, 105))	('IBE', 'Chemical', '-', (15, 18))	('patients', 'Species', '9606', (137, 145))	('intermediate', 'Var', (80, 92))	('patients', 'Species', '9606', (63, 71))	('IBE', 'Disease', (15, 18))	('Score', 'Var', (106, 111))	('low DCIS', 'Phenotype', 'HP:0200161', (153, 161))
107136	31805996	The lowest detection rates were seen for small grade 3 cancers ( under 15 mm) and large grade 1 cancers ( over 15mm).	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	(' over 15mm', 'Var', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (96, 103))	('cancers', 'Disease', (55, 62))
107239	31805996	Images are included to illustrate typical appearances of triple negative, HER2+ and hormone sensitive carcinomas including lobular carcinoma on DWI.	('triple negative', 'Var', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lobular carcinoma', 'Disease', 'MESH:D018275', (123, 140))	('HER2', 'Gene', (74, 78))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (123, 140))	('lobular carcinoma', 'Disease', (123, 140))	('HER2', 'Gene', '2064', (74, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('carcinomas', 'Disease', 'MESH:D009369', (102, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('carcinomas', 'Disease', (102, 112))
107612	25928287	Risk of death from cardiovascular disease is increased in women treated with radiotherapy, and adjuvant treatment may be cardiotoxic (for example, taxanes, anthracyclines, or trastuzumab).	('anthracyclines', 'Var', (156, 170))	('death', 'Disease', (8, 13))	('cardiovascular disease', 'Disease', 'MESH:D002318', (19, 41))	('cardiotoxic', 'Disease', 'MESH:D066126', (121, 132))	('trastuzumab', 'Chemical', 'MESH:D000068878', (175, 186))	('anthracyclines', 'Chemical', 'MESH:D018943', (156, 170))	('cardiovascular disease', 'Disease', (19, 41))	('women', 'Species', '9606', (58, 63))	('taxanes', 'Chemical', 'MESH:D043823', (147, 154))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (19, 41))	('cardiotoxic', 'Disease', (121, 132))	('death', 'Disease', 'MESH:D003643', (8, 13))
107687	28938000	However, ectopic expression of podoplanin highly increases the migration of MSU1.1 and Hs 578Bst fibroblasts.	('ectopic expression', 'Var', (9, 27))	('increases', 'PosReg', (49, 58))	('podoplanin', 'Gene', '10630', (31, 41))	('migration', 'CPA', (63, 72))	('podoplanin', 'Gene', (31, 41))
107691	28938000	Therefore, we propose that expression of podoplanin by fibroblasts facilitates their movement into the tumor stroma, which creates a favorable microenvironment for tumor progression by increasing the number of cancer-associated fibroblasts, which produce numerous factors affecting proliferation, survival and invasion of cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('facilitates', 'PosReg', (67, 78))	('podoplanin', 'Gene', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('expression', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('cancer', 'Disease', (322, 328))	('tumor', 'Disease', (103, 108))	('increasing', 'PosReg', (185, 195))	('tumor stroma', 'Disease', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('movement', 'CPA', (85, 93))	('tumor stroma', 'Disease', 'MESH:D009369', (103, 115))	('podoplanin', 'Gene', '10630', (41, 51))	('cancer', 'Disease', (210, 216))
107703	28938000	A substantial amount of clinical data shows that the presence of PDPN-expressing CAFs correlates with poor patients' prognosis in such cancers.	('CAFs', 'Gene', (81, 85))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('presence', 'Var', (53, 61))	('PDPN-expressing', 'Protein', (65, 80))	('patients', 'Species', '9606', (107, 115))
107706	28938000	It was shown using nude mice model, that human vascular adventitial fibroblasts (hVAF) with high PDPN expression enhanced tumor progression of human lung adenocarcinoma cells more than human lung tissue-derived fibroblasts (hLF) with low expression of this glycoprotein.	('hLF', 'Gene', '3131', (224, 227))	('human', 'Species', '9606', (143, 148))	('high', 'Var', (92, 96))	('human', 'Species', '9606', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lung adenocarcinoma', 'Disease', (149, 168))	('nude mice', 'Species', '10090', (19, 28))	('PDPN', 'Gene', (97, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (149, 168))	('human', 'Species', '9606', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('hLF', 'Gene', (224, 227))	('enhanced', 'PosReg', (113, 121))	('tumor', 'Disease', (122, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (149, 168))
107709	28938000	found that CAFs with high expression of podoplanin invaded the matrix to a greater extent, and more importantly, with more cancer cells traveling within the "tracks" created by the CAFs, than with CAFs with low-expression of this glycoprotein.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('podoplanin', 'Gene', '10630', (40, 50))	('podoplanin', 'Gene', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('high expression', 'Var', (21, 36))	('cancer', 'Disease', (123, 129))
107710	28938000	When mice were injected intravenously with CAFs and tumor cells simultaneously, it was found that PDPN-high CAFs invaded in larger amounts and promoted cancer cell invasion into the lung parenchyma, more than with PDPN-low CAFs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PDPN-high CAFs', 'Var', (98, 112))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('lung parenchyma', 'Disease', 'MESH:D010195', (182, 197))	('tumor', 'Disease', (52, 57))	('promoted', 'PosReg', (143, 151))	('lung parenchyma', 'Disease', (182, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mice', 'Species', '10090', (5, 9))
107712	28938000	When pancreatic cancer cells were co-cultured with fibroblasts having high podoplanin expression, their motility and invasiveness were increased in comparison to CAFs with low expression of the PDPN.	('invasiveness', 'CPA', (117, 129))	('podoplanin', 'Gene', '10630', (75, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (5, 22))	('motility', 'CPA', (104, 112))	('podoplanin', 'Gene', (75, 85))	('expression', 'MPA', (86, 96))	('increased', 'PosReg', (135, 144))	('pancreatic cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('high', 'Var', (70, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (5, 22))
107802	28938000	In contrast to the above results, when migratory properties of fluorescently labeled MSU1.1 PDPN and MSU1.1 NC fibroblasts co-cultured with MDA-MB-231 or MCF7 cells were analyzed by in vitro migration assay a statistically significant increase in the number of migrating cells was found in the case of fibroblasts overexpressing PDPN (Fig 2A and 2B).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (140, 150))	('PDPN', 'Var', (329, 333))	('increase', 'PosReg', (235, 243))	('MCF7', 'CellLine', 'CVCL:0031', (154, 158))	('number of migrating cells', 'CPA', (251, 276))
107828	28938000	The co-cultures of endothelial cells (EC) with podoplanin expressing MSU1.1 PDPN fibroblasts presented much more disordered capillary-like network characteristic for cancer vasculature than co-cultures of EC with control MSU1.1 NC fibroblasts (Fig 6A).	('MSU1.1 PDPN', 'Var', (69, 80))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('podoplanin', 'Gene', '10630', (47, 57))	('PDPN', 'Var', (76, 80))	('podoplanin', 'Gene', (47, 57))	('disordered', 'Disease', 'MESH:D030342', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('disordered', 'Disease', (113, 123))
107832	28938000	Using real-time PCR, it was found that the expression of PDPN in MSU1.1 PDPN cells increased the level of FGF-1 and Angpt2 mRNAs (however, in case of Angpt2 the difference was not statistically significant), and decreased the level of Angpt1 and VE-cadherin gene expression, not affecting the expression of VEGF-A mRNA (Fig 7).	('decreased', 'NegReg', (212, 221))	('MSU1.1 PDPN', 'Gene', (65, 76))	('FGF-1', 'Gene', '2246', (106, 111))	('increased', 'PosReg', (83, 92))	('Angpt1', 'Gene', (235, 241))	('VE-cadherin', 'Gene', (246, 257))	('expression', 'Var', (43, 53))	('Angpt2', 'Gene', (116, 122))	('Angpt2', 'Gene', (150, 156))	('Angpt1', 'Gene', '284', (235, 241))	('Angpt2', 'Gene', '285', (116, 122))	('PDPN', 'Gene', (72, 76))	('VEGF-A', 'Gene', '7422', (307, 313))	('VE-cadherin', 'Gene', '1003', (246, 257))	('Angpt2', 'Gene', '285', (150, 156))	('VEGF-A', 'Gene', (307, 313))	('PDPN', 'Gene', (57, 61))	('FGF-1', 'Gene', (106, 111))
107846	28938000	However, an inhibitory study revealed that the absence of podoplanin on stromal fibroblasts has no effect on migratory and invasive properties of pancreatic cancer cells, indicating the lack of a functional link between podoplanin expression and their biological properties.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('pancreatic cancer', 'Disease', (146, 163))	('absence', 'Var', (47, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('podoplanin', 'Gene', '10630', (58, 68))	('podoplanin', 'Gene', '10630', (220, 230))	('podoplanin', 'Gene', (58, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('podoplanin', 'Gene', (220, 230))
107858	28938000	However, we showed that ectopic expression of podoplanin highly increases the migration of MSU1.1 fibroblasts, which are only weakly migratory and increases the migration of highly-migratory Hs578Bst fibroblasts.	('podoplanin', 'Gene', '10630', (46, 56))	('increases', 'PosReg', (147, 156))	('podoplanin', 'Gene', (46, 56))	('ectopic expression', 'Var', (24, 42))	('migration', 'CPA', (78, 87))	('highly-migratory', 'CPA', (174, 190))	('migration', 'CPA', (161, 170))	('increases', 'PosReg', (64, 73))
107859	28938000	As clinical data showed the association between the presence of podoplanin-positive CAFs and the progression of breast cancer, we propose that expression of podoplanin by fibroblasts facilitates their movement into the tumor stroma, what increases the number of CAFs and creates a favorable microenvironment for tumor progression by facilitating local invasion of cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('tumor', 'Disease', (219, 224))	('podoplanin', 'Gene', '10630', (64, 74))	('tumor stroma', 'Disease', (219, 231))	('tumor', 'Disease', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('local invasion', 'CPA', (346, 360))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('movement', 'MPA', (201, 209))	('tumor stroma', 'Disease', 'MESH:D009369', (219, 231))	('podoplanin', 'Gene', '10630', (157, 167))	('podoplanin', 'Gene', (64, 74))	('cancer', 'Disease', (119, 125))	('CAFs', 'CPA', (262, 266))	('cancer', 'Disease', (364, 370))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('increases', 'PosReg', (238, 247))	('facilitates', 'PosReg', (183, 194))	('podoplanin', 'Gene', (157, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('expression', 'Var', (143, 153))
107878	28938000	Important evidence that PDPN-positive fibroblasts can affect the formation of blood vessels comes from the clinical studies as the presence of large numbers of PDPN-positive CAFs was associated with numerous CD34-positive blood vessels in tumor stroma of IDC samples.	('PDPN-positive', 'Gene', (160, 173))	('tumor stroma', 'Disease', (239, 251))	('formation of blood vessels', 'CPA', (65, 91))	('CD34', 'Gene', (208, 212))	('CD34', 'Gene', '947', (208, 212))	('presence', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('affect', 'Reg', (54, 60))	('associated with', 'Reg', (183, 198))	('tumor stroma', 'Disease', 'MESH:D009369', (239, 251))
107880	28938000	Key role of phosphorylated ezrin in podoplanin-mediated motility of MSU1.1 and Hs578Bst fibroblasts was confirm as siRNA-directed inhibition of ezrin expression blocked the migration of these cells, and substantial amounts of phosphorylated ezrin were present only in migratory podoplanin-expressing fibroblasts.	('inhibition', 'Var', (130, 140))	('podoplanin', 'Gene', '10630', (36, 46))	('migration', 'CPA', (173, 182))	('ezrin', 'Gene', '7430', (241, 246))	('ezrin', 'Gene', '7430', (27, 32))	('ezrin', 'Gene', (241, 246))	('podoplanin', 'Gene', (36, 46))	('ezrin', 'Gene', (144, 149))	('ezrin', 'Gene', (27, 32))	('ezrin', 'Gene', '7430', (144, 149))	('podoplanin', 'Gene', '10630', (278, 288))	('podoplanin', 'Gene', (278, 288))	('blocked', 'NegReg', (161, 168))
107881	28938000	We have also shown that phophorylation of ezrin is RhoA-dependent, as inhibition of RhoA-associated kinase (ROCK) blocked the migration of these cells, what correlated with highly decreased level of phosphorylated ezrin.	('blocked', 'NegReg', (114, 121))	('ezrin', 'Gene', '7430', (214, 219))	('ezrin', 'Gene', (214, 219))	('migration of these cells', 'CPA', (126, 150))	('decreased', 'NegReg', (180, 189))	('RhoA', 'Gene', (84, 88))	('ezrin', 'Gene', '7430', (42, 47))	('RhoA', 'Gene', '387', (84, 88))	('ezrin', 'Gene', (42, 47))	('inhibition', 'Var', (70, 80))	('RhoA', 'Gene', '387', (51, 55))	('RhoA', 'Gene', (51, 55))
107900	33178912	BRCA1/2 mutations, history of ipsilateral cancer, and age over 50 years are predicting factors for malignancy in the presence of PND.	('malignancy', 'Disease', (99, 109))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('malignancy', 'Disease', 'MESH:D009369', (99, 109))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('BRCA1/2', 'Gene', (0, 7))
108018	32064280	Presence of DCIS was associated with a trend towards superior disease-free survival and overall survival, but it was not an independent predictor of improved outcome.	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))	('superior', 'PosReg', (53, 61))	('disease-free survival', 'CPA', (62, 83))	('overall survival', 'CPA', (88, 104))	('DCIS', 'Disease', (12, 16))	('DCIS', 'Disease', 'MESH:D002285', (12, 16))	('Presence', 'Var', (0, 8))
108086	32064280	FDG uptake was higher in DCIS with microinvasion than pure DCIS.	('DCIS', 'Disease', (25, 29))	('DCIS', 'Disease', (59, 63))	('DCIS', 'Disease', 'MESH:D002285', (59, 63))	('DCIS', 'Disease', 'MESH:D002285', (25, 29))	('higher', 'PosReg', (15, 21))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('microinvasion', 'Var', (35, 48))	('FDG uptake', 'CPA', (0, 10))
108094	32064280	In their study, any focally increased Tc-99m V-DMSA accumulation was regarded as associated with invasive pathology, while any other pattern of more widespread diffuse uptake was considered as corresponding to pre-invasive lesions (CIS, epithelial hyperplasia).	('increased', 'PosReg', (28, 37))	('hyperplasia', 'Disease', (248, 259))	('Tc-99m V-DMSA', 'Chemical', 'MESH:D019783', (38, 51))	('accumulation', 'PosReg', (52, 64))	('hyperplasia', 'Disease', 'MESH:D006965', (248, 259))	('Tc-99m V-DMSA', 'Var', (38, 51))	('associated', 'Reg', (81, 91))
108143	29506487	However, a recently published study showed an association between increased screen-detection of DCIS and fewer subsequent invasive interval cancer cases.	('DCIS', 'Disease', (96, 100))	('increased', 'PosReg', (66, 75))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('screen-detection', 'Var', (76, 92))	('fewer', 'NegReg', (105, 110))	('invasive interval cancer', 'Disease', (122, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('invasive interval cancer', 'Disease', 'MESH:D009362', (122, 146))
108199	29506487	There have been concerns that the increase in screen-detection of DCIS leads to overdiagnosis rather than to a significant additional reduction in breast cancer mortality.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('overdiagnosis', 'MPA', (80, 93))	('breast cancer', 'Disease', (147, 160))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('reduction', 'NegReg', (134, 143))	('screen-detection', 'Var', (46, 62))	('increase', 'PosReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
108250	28558007	In addition, overestimation of the cancer extent can cause wider excision and conversion to mastectomies.	('cause', 'Reg', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('overestimation', 'Var', (13, 27))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
108287	28558007	The enhancement pattern and HER2 status were significantly difference between breast cancer with NME and without NME.	('HER2', 'Gene', '2064', (28, 32))	('enhancement', 'PosReg', (4, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('NME', 'Chemical', '-', (113, 116))	('difference', 'Reg', (59, 69))	('NME', 'Var', (97, 100))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('HER2', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('NME', 'Chemical', '-', (97, 100))	('breast cancer', 'Disease', (78, 91))
108297	28558007	Especially, HER2 positivity was significantly associated with malignant pathologic results of NME.	('NME', 'Chemical', '-', (94, 97))	('HER2', 'Gene', (12, 16))	('positivity', 'Var', (17, 27))	('HER2', 'Gene', '2064', (12, 16))	('associated', 'Reg', (46, 56))	('malignant pathologic results', 'CPA', (62, 90))
108307	28558007	Another study also found that DCIS is the strongest independent predictor of discrepancy between MR image and pathology sizing of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('DCIS', 'Var', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
108333	27748798	Since Warburg first hypothesized that cancer cells had a significantly higher rate of glycolysis than normal cells, researchers have shown that changes in metabolism can lead to large changes in metabolites that occur downstream of genomic and proteomic alterations.	('higher', 'PosReg', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('metabolism', 'MPA', (155, 165))	('changes', 'Reg', (184, 191))	('metabolites', 'MPA', (195, 206))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('changes', 'Var', (144, 151))	('cancer', 'Disease', (38, 44))	('glycolysis', 'MPA', (86, 96))	('rate', 'MPA', (78, 82))
108358	27748798	Mass spectrometry was performed on a Quadrupole-time-of-flight mass spectrometer operating in either negative or positive electrospray ionization mode with a capillary voltage of 3.2 kV and a sampling cone voltage of 35 V. The desolvation gas flow was 800 l/h and the temperature was set to 350 C. The cone gas flow was 50 l/h, and the source temperature was 150 C. Accurate mass was maintained by infusing sulfadimethoxine (311.0814 m/z) in 50% aqueous acetonitrile (250 pg/mul) at a rate of 30 mul/min via the lockspray interface every 10 sec.	('acetonitrile', 'Chemical', 'MESH:C032159', (454, 466))	('ionization', 'Disease', (135, 145))	('ionization', 'Disease', 'MESH:D004194', (135, 145))	('311.0814 m/z', 'Var', (425, 437))
108362	27748798	In-source fragments are formed during ionization such as ion fragments of [M+H-H2O]+ or [M-H-H2O]- through neutral loss of water molecule.	('loss', 'NegReg', (115, 119))	('[M+H-H2O]+', 'Var', (74, 84))	('H2O', 'Chemical', 'MESH:D014867', (79, 82))	('ionization', 'Disease', 'MESH:D004194', (38, 48))	('water', 'Chemical', 'MESH:D014867', (123, 128))	('[M-H-H2O]-', 'Var', (88, 98))	('H2O', 'Chemical', 'MESH:D014867', (93, 96))	('ionization', 'Disease', (38, 48))
108378	27748798	Among the 21 LASSO-identified ions, we found ten metabolites that show statistically significant differences based on menopausal status (pre/post), ER (+/-), and HER2 (+/-).	('HER2', 'Gene', '2064', (162, 166))	('HER2', 'Gene', (162, 166))	('ER (+/-', 'Var', (148, 155))	('metabolites', 'MPA', (49, 60))	('differences', 'Reg', (97, 108))	('menopausal status', 'Phenotype', 'HP:0008209', (118, 135))
108380	27748798	Three metabolites (M179.1841, M121.2079 and M466.729) are higher in post-menopausal patients (P<0.05; Table IV).	('M179.1841', 'Var', (19, 28))	('patients', 'Species', '9606', (84, 92))	('M466.729', 'Var', (44, 52))	('higher', 'PosReg', (58, 64))	('M121.2079', 'Var', (30, 39))
108381	27748798	On the other hand, one metabolite (M622.627) is higher in pre-menopausal patients (P=0.040; Table IV).	('higher', 'PosReg', (48, 54))	('patients', 'Species', '9606', (73, 81))	('M622.627', 'Var', (35, 43))	('pre-menopausal', 'Disease', (58, 72))
108382	27748798	HER2 positive receptor status also shows an association with increased levels of metabolites (M724.491 and M788.4464) in patients (P<0.005; Table IV), while four metabolites (M121.2079, M178.0316, M417.1127 and M454.4747) are lower in HER2 positive patients (P<0.05; Table IV).	('metabolites', 'MPA', (81, 92))	('lower', 'NegReg', (226, 231))	('M178.0316', 'Var', (186, 195))	('M454.4747', 'Var', (211, 220))	('patients', 'Species', '9606', (249, 257))	('HER2', 'Gene', (235, 239))	('HER2', 'Gene', '2064', (235, 239))	('increased', 'PosReg', (61, 70))	('M788.4464', 'Var', (107, 116))	('HER2', 'Gene', (0, 4))	('M417.1127', 'Var', (197, 206))	('M724.491', 'Var', (94, 102))	('HER2', 'Gene', '2064', (0, 4))	('M121.2079', 'Var', (175, 184))	('patients', 'Species', '9606', (121, 129))
108400	27748798	When we stratified our patients by receptor status, we observed that the M239.1486 metabolite tends to be less expressed in ER+ patients (P=0.045; Table IV).	('expressed', 'MPA', (111, 120))	('patients', 'Species', '9606', (23, 31))	('less', 'NegReg', (106, 110))	('M239.1486', 'Var', (73, 82))	('patients', 'Species', '9606', (128, 136))	('ER+', 'Disease', (124, 127))
108403	27748798	ER- and triple-negative receptor status is indicative of more aggressive tumors and a poorer prognosis.	('triple-negative receptor', 'Protein', (8, 32))	('more', 'PosReg', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('ER- and', 'Var', (0, 7))
108439	28003873	For women who tested positive for BRCA mutations this seems logical.	('BRCA', 'Gene', '672', (34, 38))	('women', 'Species', '9606', (4, 9))	('BRCA', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
108440	28003873	But 25 % of women who tested negative for a BRCA mutation still elected for CPM.	('women', 'Species', '9606', (12, 17))	('mutation', 'Var', (49, 57))	('BRCA', 'Gene', '672', (44, 48))	('elected', 'Reg', (64, 71))	('BRCA', 'Gene', (44, 48))	('CPM', 'Disease', (76, 79))
108607	22516949	The grade distribution (49% high grade and 10% low grade) is clearly different to the EORTC randomised trial (40% poorly and 32% well-differentiated), which had higher rates of low-grade/well-differentiated DCIS (however, this trial recruited both clinically and mammographically detected DCIS treated by conservation surgery) and to the UKCCCR/ANZ (75% high and 7% low grade).	('DCIS', 'Disease', (289, 293))	('DCIS', 'Phenotype', 'HP:0030075', (289, 293))	('DCIS', 'Disease', (207, 211))	('low-grade/well-differentiated', 'Var', (177, 206))	('DCIS', 'Phenotype', 'HP:0030075', (207, 211))	('UKCCCR/ANZ', 'Chemical', '-', (338, 348))
108617	31420779	We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%).	('mutations', 'Var', (52, 61))	('IBC-related', 'Gene', (40, 51))	('PIK3CA', 'Gene', '5290', (112, 118))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('variants', 'Var', (22, 30))	('PIK3CA', 'Gene', (112, 118))
108619	31420779	PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC.	('PIK3CA', 'Gene', (0, 6))	('DCIS', 'Gene', (71, 75))	('PIK3CA', 'Gene', '5290', (0, 6))	('copy number gains', 'Var', (50, 67))	('IBC', 'Disease', (114, 117))
108626	31420779	Some events, like PIK3CA mutations, can occur quite early in the neoplastic timeline while others, like ERBB2 amplification, occur later.	('mutations', 'Var', (25, 34))	('PIK3CA', 'Gene', (18, 24))	('ERBB2', 'Gene', '2064', (104, 109))	('ERBB2', 'Gene', (104, 109))	('PIK3CA', 'Gene', '5290', (18, 24))
108645	31420779	To focus on mutations having tumor suppressive or oncogenic effects, we limited the analysis to recurrent position mutations identified in the TCGA dataset that are frequently mutated in IBC.	('mutations', 'Var', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TCGA', 'Gene', (143, 147))	('tumor', 'Disease', (29, 34))	('IBC', 'Disease', (187, 190))
108648	31420779	We identified "hotspots" of somatic mutations in the helical domain and kinase domain of PIK3CA for both DCIS-only and DCIS+IBC groups (Figure 2).	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('mutations in', 'Var', (36, 48))
108653	31420779	We performed multivariable analysis, examining the association of IBC dependent on variables including PIK3CA-KD mutational status, copy number gains, age, race, nuclear grade, tumor size, margins, and surgery type (Table 2).	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PIK3CA', 'Gene', (103, 109))	('copy number gains', 'Var', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutational', 'Var', (113, 123))	('PIK3CA', 'Gene', '5290', (103, 109))	('tumor', 'Disease', (177, 182))
108654	31420779	We identified a statistically significant association between lack of PIK3CA-KD mutation and increased risk of IBC (p<0.05).	('IBC', 'Disease', (111, 114))	('PIK3CA', 'Gene', (70, 76))	('lack', 'Var', (62, 66))	('PIK3CA', 'Gene', '5290', (70, 76))	('mutation', 'Var', (80, 88))
108655	31420779	Patients without PIK3CA-KD mutations were 4.52 times (confidence interval: 1.05-25.27) as likely to have IBC compared to subjects with the mutation.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('Patients', 'Species', '9606', (0, 8))	('IBC', 'Disease', (105, 108))
108657	31420779	In addition, the inverse association between any PIK3CA mutation and IBC risk became statistically significant (OR=4.66, p<0.05, data not shown).	('inverse', 'NegReg', (17, 24))	('PIK3CA', 'Gene', (49, 55))	('IBC', 'Disease', (69, 72))	('PIK3CA', 'Gene', '5290', (49, 55))	('mutation', 'Var', (56, 64))
108659	31420779	This trend became statistically significant (OR= 0.24, p<0.05) when modeling any PIK3CA mutations instead of PIK3CA-KD mutations in the multivariable analysis (data not shown).	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', (81, 87))	('PIK3CA', 'Gene', '5290', (109, 115))	('PIK3CA', 'Gene', '5290', (81, 87))	('mutations', 'Var', (88, 97))
108662	31420779	The association between lack of PIK3CA-KD mutations and progression to IBC was not modified by ER status (Supplementary Table S3).	('PIK3CA', 'Gene', '5290', (32, 38))	('IBC', 'Disease', (71, 74))	('lack', 'NegReg', (24, 28))	('ER', 'Gene', '2099', (95, 97))	('mutations', 'Var', (42, 51))	('PIK3CA', 'Gene', (32, 38))
108663	31420779	The association between lack of any PIK3CA mutations (including PIK3CA-KD mutations and other PIK3CA mutations) and progression to IBC was modified by ER status (p<0.05, Supplementary Table S4).	('PIK3CA', 'Gene', (64, 70))	('IBC', 'Disease', (131, 134))	('ER', 'Gene', '2099', (151, 153))	('PIK3CA', 'Gene', '5290', (36, 42))	('lack', 'NegReg', (24, 28))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (43, 52))	('PIK3CA', 'Gene', (94, 100))	('PIK3CA', 'Gene', (36, 42))	('PIK3CA', 'Gene', '5290', (94, 100))
108664	31420779	There was a statistically significant interaction between DCIS nuclear grade and the presence of PIK3CA-KD mutation for the association with IBC (data not shown).	('significant', 'Reg', (26, 37))	('association', 'Interaction', (124, 135))	('IBC', 'Disease', (141, 144))	('presence', 'Var', (85, 93))	('PIK3CA', 'Gene', (97, 103))	('PIK3CA', 'Gene', '5290', (97, 103))
108666	31420779	PIK3CA, TP53, and GATA3 are among the most commonly mutated genes in DCIS, and chromosome 1q and 8q copy number gains are frequently identified in DCIS, as seen in prior studies.	('GATA3', 'Gene', '2625', (18, 23))	('DCIS', 'Disease', (69, 73))	('copy number gains', 'Var', (100, 117))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('GATA3', 'Gene', (18, 23))
108667	31420779	We demonstrated a novel finding that the somatic mutations in the PIK3CA kinase domain provide predictive value of DCIS progression to IBC.	('mutations', 'Var', (49, 58))	('PIK3CA', 'Gene', (66, 72))	('DCIS', 'Disease', (115, 119))	('PIK3CA', 'Gene', '5290', (66, 72))	('IBC', 'Disease', (135, 138))
108668	31420779	Previous studies have investigated the role of PIK3CA mutations in in situ breast cancers.	('PIK3CA', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PIK3CA', 'Gene', '5290', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('mutations', 'Var', (54, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (75, 89))	('situ breast cancers', 'Disease', 'MESH:D001943', (70, 89))	('situ breast cancers', 'Disease', (70, 89))
108669	31420779	In a small cohort of lobular carcinoma in situ (LCIS) without invasive lobular carcinoma (ILC) versus LCIS with associated ILC, the presence of PIK3CA mutations was not correlated with progression.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (71, 88))	('lobular carcinoma', 'Disease', (71, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('PIK3CA', 'Gene', (144, 150))	('lobular carcinoma', 'Disease', 'MESH:D018275', (21, 38))	('PIK3CA', 'Gene', '5290', (144, 150))	('invasive lobular carcinoma (ILC) versus LCIS', 'Disease', 'MESH:D000071960', (62, 106))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (21, 38))	('lobular carcinoma', 'Disease', (21, 38))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (29, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('lobular carcinoma', 'Disease', 'MESH:D018275', (71, 88))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (21, 46))	('mutations', 'Var', (151, 160))
108670	31420779	One of the studies showed that in ER-positive/HER2-negative DCIS, PIK3CA "hotspot mutations" were more prevalent in DCIS associated with IBC, compared with DCIS alone.	('prevalent', 'Reg', (103, 112))	('HER2', 'Gene', (46, 50))	('IBC', 'Disease', (137, 140))	('associated', 'Reg', (121, 131))	('HER2', 'Gene', '2064', (46, 50))	('PIK3CA', 'Gene', (66, 72))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', '5290', (66, 72))	('ER', 'Gene', '2099', (47, 49))	('ER', 'Gene', '2099', (34, 36))	('DCIS', 'Disease', (116, 120))
108672	31420779	The finding that activating mutations in PIK3CA and overexpression of HER2 oncogenes are correlated with a tendency not to progress to IBC is unexpected.	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (70, 74))	('activating', 'PosReg', (17, 27))	('PIK3CA', 'Gene', (41, 47))	('PIK3CA', 'Gene', '5290', (41, 47))	('overexpression', 'PosReg', (52, 66))	('mutations', 'Var', (28, 37))	('IBC', 'Disease', (135, 138))
108674	31420779	One possible explanation for our findings is that alterations in specific pathways (such as HER2, PIK3CA) allow the cells to overcome immediate biological constraints in the process of tumorigenicity, rather than specifically promoting the DCIS to IBC transition.	('tumor', 'Disease', (185, 190))	('DCIS to IBC transition', 'CPA', (240, 262))	('PIK3CA', 'Gene', (98, 104))	('alterations', 'Var', (50, 61))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('PIK3CA', 'Gene', '5290', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('promoting', 'PosReg', (226, 235))
108676	31420779	In fact, PIK3CA mutations are extremely common in hyperplastic lesions of the breast.	('lesions of the breast', 'Phenotype', 'HP:0100013', (63, 84))	('mutations', 'Var', (16, 25))	('common', 'Reg', (40, 46))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))	('hyperplastic lesions', 'Disease', (50, 70))
108679	31420779	For PIK3CA, previous researchers have found that in a subset of paired DCIS alone and DCIS with IBC samples, the PIK3CA mutations were present in DCIS alone but not DCIS with IBC, or with lower alternative allele frequency in the IBC component.	('paired DCIS', 'Phenotype', 'HP:0006304', (64, 75))	('PIK3CA', 'Gene', (113, 119))	('PIK3CA', 'Gene', '5290', (113, 119))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))	('mutations', 'Var', (120, 129))
108680	31420779	PIK3CA KD mutations (exon 20 mutations) have also been observed in pre-neoplastic lesions (usual ductal hyperplasia, columnar cell change, or atypical ductal hyperplasia) while paired IBC lesions lack such mutations.	('hyperplasia', 'Disease', 'MESH:D006965', (158, 169))	('hyperplasia', 'Disease', 'MESH:D006965', (104, 115))	('PIK3CA', 'Gene', (0, 6))	('columnar cell change', 'Disease', (117, 137))	('hyperplasia', 'Disease', (158, 169))	('PIK3CA', 'Gene', '5290', (0, 6))	('pre-neoplastic lesions', 'Disease', (67, 89))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (71, 89))	('mutations', 'Var', (10, 19))	('observed', 'Reg', (55, 63))	('hyperplasia', 'Disease', (104, 115))
108681	31420779	These results and our current findings suggest that selection for HER2 amplification or PIK3CA mutations may address neoplastic challenges that occur well before the transition from in situ to invasive cancer.	('invasive cancer', 'Disease', 'MESH:D009362', (193, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('PIK3CA', 'Gene', '5290', (88, 94))	('HER2', 'Gene', '2064', (66, 70))	('amplification', 'Var', (71, 84))	('mutations', 'Var', (95, 104))	('PIK3CA', 'Gene', (88, 94))	('invasive cancer', 'Disease', (193, 208))	('HER2', 'Gene', (66, 70))
108682	31420779	Notably, the genomic features we found to correlate with risk of progression consisted of aneuploides or large amplicons.	('large amplicons', 'Var', (105, 120))	('aneuploides', 'Disease', (90, 101))	('aneuploides', 'Disease', 'MESH:D000782', (90, 101))
108686	31420779	However, we focused on 'hotspot' mutations with known impacts on protein functions, such as PIK3CA kinase domain mutations, that are easily recognized.	('protein functions', 'MPA', (65, 82))	('impacts', 'Reg', (54, 61))	('PIK3CA', 'Gene', '5290', (92, 98))	('mutations', 'Var', (33, 42))	('domain mutations', 'Var', (106, 122))	('PIK3CA', 'Gene', (92, 98))
108691	31420779	Previous literature has suggested that different PIK3CA variants could cause different downstream signaling pathway alteration and biological functions in in vitro systems.	('cause', 'Reg', (71, 76))	('downstream signaling pathway', 'Pathway', (87, 115))	('variants', 'Var', (56, 64))	('PIK3CA', 'Gene', (49, 55))	('alteration', 'Reg', (116, 126))	('PIK3CA', 'Gene', '5290', (49, 55))
108692	31420779	This would help us to understand the roles of PIK3CA-KD mutations and copy number gains in breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('mutations', 'Var', (56, 65))	('PIK3CA', 'Gene', '5290', (46, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('copy number gains', 'Var', (70, 87))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('PIK3CA', 'Gene', (46, 52))
108694	31420779	Our novel findings that PIK3CA-KD mutations are associated with relative lack of DCIS progression to IBC, coupled with other traditional and novel risk factors, contributes to knowledge of the sequence and mechanisms of breast cancer progression.	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('PIK3CA', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('lack', 'NegReg', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('PIK3CA', 'Gene', '5290', (24, 30))	('mutations', 'Var', (34, 43))
108723	31331982	In sharp contrast, this intact acinar structure was largely lost in tumors containing CAFs, reflecting the CAF-induced invasive propensity of these tumor cells.	('tumor', 'Disease', (68, 73))	('lost', 'NegReg', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CAFs', 'Var', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CAFs', 'Chemical', '-', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
108727	31331982	Two distinct cancer cell populations:E-cadhiZEB1lo/neg (Ehi) cells located at the center of the tumor and E-cadloZEB1hi (E/M) cells close to the stroma-tumor interface:were observed to be more numerous in CAF-containing tumors than in those admixed with control fibroblasts (Fig 1B).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (220, 225))	('CAF-containing', 'Disease', (205, 219))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('stroma-tumor', 'Disease', 'MESH:D009369', (145, 157))	('tumor', 'Disease', (152, 157))	('E-cadhiZEB1lo/neg', 'Var', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('stroma-tumor', 'Disease', (145, 157))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', (220, 226))	('cancer', 'Disease', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (220, 226))
108742	31331982	We found that CAFs raised the lung metastasis index significantly more than did no fibroblasts and control fibroblasts (Figs 1F and S1I).	('CAFs', 'Var', (14, 18))	('raised', 'PosReg', (19, 25))	('CAFs', 'Chemical', '-', (14, 18))	('lung metastasis index', 'MPA', (30, 51))
108754	31331982	DCISCAF2cy formed histologically invasive tumors with stronger E-cad, ZEB1, fibronectin, and vimentin staining (Figs 2D and S2B) and grew more rapidly than DCISalone2cy and DCIScnt2cy (Fig S2C).	('vimentin', 'Gene', '7431', (93, 101))	('fibronectin', 'Gene', (76, 87))	('vimentin', 'Gene', (93, 101))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('invasive tumors', 'Disease', (33, 48))	('grew', 'CPA', (133, 137))	('fibronectin', 'Gene', '2335', (76, 87))	('invasive tumors', 'Disease', 'MESH:D009369', (33, 48))	('E-cad', 'CPA', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('DCISCAF2cy', 'Var', (0, 10))	('stronger', 'PosReg', (54, 62))	('ZEB1', 'Protein', (70, 74))
108755	31331982	Moreover, larger Ehi and E/M cell populations were detected in tumors generated by DCISCAF2cy (Fig 2E).	('larger', 'PosReg', (10, 16))	('DCISCAF2cy', 'Var', (83, 93))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('rat', 'Species', '10116', (74, 77))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
108756	31331982	In addition, DCISCAF2cy generated lung metastatic nodules in greater number and size with a higher metastasis index than DCISalone2cy and DCIScnt2cy (Fig 2F).	('higher', 'PosReg', (92, 98))	('lung metastatic nodules', 'CPA', (34, 57))	('metastasis index', 'CPA', (99, 115))	('DCISCAF2cy', 'Var', (13, 23))	('rat', 'Species', '10116', (28, 31))
108757	31331982	These observations are consistent with earlier findings of increased invasion and metastasis associated with the Ehi and E/M states in cancer cells admixed with CAFs (Fig 1).	('Ehi', 'Var', (113, 116))	('cancer', 'Disease', (135, 141))	('CAFs', 'Chemical', '-', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('E/M', 'Var', (121, 124))	('invasion', 'CPA', (69, 77))	('increased', 'PosReg', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
108758	31331982	In addition, DCISCAF2cy, when intravenously injected into recipient mice, generated more pulmonary metastases than DCISalone1cy, DCISalone2cy, DCIScnt1cy, DCIScnt2cy, and DCISCAF1cy (Figs 2G, S2D, and E), indicating that CAFs progressively confer lung-colonizing ability upon tumor cells during tumor progression.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('pulmonary metastases', 'Disease', 'MESH:D009362', (89, 109))	('pulmonary metastases', 'Disease', (89, 109))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('rat', 'Species', '10116', (78, 81))	('tumor', 'Disease', (276, 281))	('DCISCAF2cy', 'Var', (13, 23))	('CAFs', 'Chemical', '-', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('lung-colonizing ability', 'CPA', (247, 270))	('tumor', 'Disease', (295, 300))	('more', 'PosReg', (84, 88))
108765	31331982	CIMS notably predicted poorer survival in several independent breast cancer patient cohorts (Figs 3A and S3A), indicating a clinical correlation with CAF-induced metastasis.	('clinical', 'Species', '191496', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('patient', 'Species', '9606', (76, 83))	('CIMS', 'Var', (0, 4))	('breast cancer', 'Disease', (62, 75))	('survival', 'MPA', (30, 38))	('poorer', 'NegReg', (23, 29))
108766	31331982	In addition, DCISCAF2cy markedly up-regulated expressions of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CAM5) and CEACAM6 (CAM6), tumor-promoting cell-cell adhesion molecules (Table S1).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CEACAM5', 'Gene', (120, 127))	('CEACAM6', 'Gene', (139, 146))	('CAM6', 'Gene', '4680', (142, 146))	('tumor', 'Disease', (155, 160))	('CAM6', 'Gene', '4680', (148, 152))	('carcinoembryonic antigen-related cell adhesion molecule 5', 'Gene', '1048', (61, 118))	('CEACAM5', 'Gene', '1048', (120, 127))	('up-regulated', 'PosReg', (33, 45))	('CAM6', 'Gene', (142, 146))	('CAM6', 'Gene', (148, 152))	('DCISCAF2cy', 'Var', (13, 23))	('CEACAM6', 'Gene', '4680', (139, 146))	('expressions', 'MPA', (46, 57))
108767	31331982	Levels of CAM5 and CAM6 mRNA and protein expressions were also significantly higher in DCISCAF2cy than in DCIScnt2cy and DCISCAF1cy (Fig 3D and E), indicating progressive up-regulation during tumor progression.	('CAM6', 'Gene', (19, 23))	('tumor', 'Disease', (192, 197))	('DCISCAF2cy', 'Var', (87, 97))	('CAM5', 'MPA', (10, 14))	('higher', 'PosReg', (77, 83))	('CAM6', 'Gene', '4680', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('up-regulation', 'PosReg', (171, 184))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
108768	31331982	Furthermore, CAM5 and CAM6 expressions were up-regulated in the other human breast cancer cell lines, 1dCAF1cy and MCF-7-rasCAF1cy, as compared with 1dcnt1cy and MCF-7-rascnt1cy, respectively (Fig S3C).	('CAM6', 'Gene', '4680', (22, 26))	('MCF-7-rasCAF1cy', 'Var', (115, 130))	('dCAF1', 'Gene', '41836', (103, 108))	('CAM5', 'Gene', (13, 17))	('CAM6', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MCF-7', 'CellLine', 'CVCL:0031', (162, 167))	('MCF-7', 'CellLine', 'CVCL:0031', (115, 120))	('expressions', 'MPA', (27, 38))	('dCAF1', 'Gene', (103, 108))	('human', 'Species', '9606', (70, 75))	('breast cancer', 'Disease', (76, 89))	('up-regulated', 'PosReg', (44, 56))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
108776	31331982	Inhibition of E-cad, CAM5, or CAM6 expression by shRNA attenuated the lung metastases arising from DCISCAF2cy via subcutaneous and intravenous injections into mice significantly more than did GFP-shRNA (Figs 4A-C and S4A-C).	('lung metastases', 'Disease', (70, 85))	('CAM6', 'Gene', '4680', (30, 34))	('CAM6', 'Gene', (30, 34))	('lung metastases', 'Disease', 'MESH:D009362', (70, 85))	('attenuated', 'NegReg', (55, 65))	('DCISCAF2cy', 'Var', (99, 109))	('mice', 'Species', '10090', (159, 163))
108778	31331982	Although E-cad expression was long believed to suppress tumor invasion and metastasis, its oncogenic roles promoting tumor cell cluster formation, collective cell migration, and metastatic colonization have recently been demonstrated.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('E-cad', 'Gene', (9, 14))	('expression', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('rat', 'Species', '10116', (166, 169))	('promoting', 'PosReg', (107, 116))	('rat', 'Species', '10116', (228, 231))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (56, 61))	('suppress', 'NegReg', (47, 55))	('collective cell migration', 'CPA', (147, 172))	('metastatic colonization', 'CPA', (178, 201))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
108780	31331982	As anticipated, DCISCAF2cy showed greater cell-cell adhesion (Figs 4D and S4D), cell-cell aggregation (Fig 4E), ECM-cell adhesion (Fig 4F), and antiapoptosis (Fig 4G) than did DCIScnt2cy in vitro.	('ECM', 'Gene', (112, 115))	('DCISCAF2cy', 'Var', (16, 26))	('cell-cell adhesion', 'CPA', (42, 60))	('greater', 'PosReg', (34, 41))	('cell-cell aggregation', 'CPA', (80, 101))	('antiapoptosis', 'CPA', (144, 157))	('ECM', 'Gene', '22915', (112, 115))
108791	31331982	Endogenous expression levels of phosphorylated Src (p-Src) were also markedly increased in DCISCAF2cy as compared with DCIScnt2cy (Figs 6A and S5B).	('Endogenous expression levels', 'MPA', (0, 28))	('S5B', 'Gene', '5711', (143, 146))	('S5B', 'Gene', (143, 146))	('p-Src', 'Gene', (52, 57))	('DCISCAF2cy', 'Var', (91, 101))	('increased', 'PosReg', (78, 87))	('p-Src', 'Gene', '6714', (52, 57))
108802	31331982	These findings indicate that Src activation is required for various tumor- and metastasis-promoting properties presumably mediated by the Ehi and E/M states in DCISCAF2cy.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Ehi', 'Var', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('E/M states', 'Var', (146, 156))
108803	31331982	Because Src activation is required for tumor metastasis in DCISCAF2cy, we investigated whether Src activation induces metastasis by introducing a constitutively active Src mutant into parental DCIS cells (Fig S5I).	('tumor metastasis', 'Disease', 'MESH:D009362', (39, 55))	('mutant', 'Var', (172, 178))	('metastasis', 'CPA', (118, 128))	('tumor metastasis', 'Disease', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('induces', 'Reg', (110, 117))
108806	31331982	Our previous work showed that introduction of SDF-1-shRNA into CAFs attenuates their SDF-1 and TGF-beta mRNA expressions because of disruption of the cross-communicating SDF-1 and TGF-beta autocrine signaling loop on these fibroblasts.	('attenuates', 'NegReg', (68, 78))	('cross-communicating', 'MPA', (150, 169))	('disruption', 'NegReg', (132, 142))	('CAFs', 'Chemical', '-', (63, 67))	('SDF-1 and', 'MPA', (85, 94))	('TGF-beta', 'Gene', (95, 103))	('SDF-1-shRNA', 'Var', (46, 57))
108812	31331982	DCIS cells expressing GFP-, CXCR4-, or TbetaRII-shRNA were then injected with CAFs subcutaneously into recipient mice (Fig 7E).	('TbetaRII-shRNA', 'Var', (39, 53))	('CXCR4-', 'Var', (28, 34))	('GFP-', 'Var', (22, 26))	('mice', 'Species', '10090', (113, 117))	('CAFs', 'Chemical', '-', (78, 82))
108814	31331982	CAM5, CAM6, E-cad, and ZEB1 expressions mediating the Ehi and E/M states were also significantly attenuated in DCISCAF1cy extracted from DCIS tumors expressing CXCR4- or TbetaRII-shRNA admixed with CAFs (Figs 7E, G, H, and S6B).	('CAFs', 'Chemical', '-', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CXCR4-', 'Var', (160, 166))	('CAM6', 'Gene', '4680', (6, 10))	('DCIS tumors', 'Disease', (137, 148))	('ZEB1', 'Gene', (23, 27))	('DCIS tumors', 'Disease', 'MESH:D002285', (137, 148))	('CAM6', 'Gene', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('attenuated', 'NegReg', (97, 107))
108826	31331982	Moreover, DCISCAF2cy, when injected subcutaneously into mice, frequently generated E-cad+ and Ki-67+ tumor emboli within alpha-SMA+ blood vessels in the lungs (Figs 8C and S7A), further supporting the CAF-induced tumor cell cluster formation in vivo.	('tumor', 'Disease', (213, 218))	('DCISCAF2cy', 'Var', (10, 20))	('alpha-SMA', 'Gene', '11475', (121, 130))	('rat', 'Species', '10116', (77, 80))	('E-cad+', 'CPA', (83, 89))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mice', 'Species', '10090', (56, 60))	('Ki-67+', 'Var', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('alpha-SMA', 'Gene', (121, 130))
108829	31331982	Thus, lung sections prepared from mice injected subcutaneously with DCISCAF2cy or DCIScnt2cy were stained with different antibodies.	('DCISCAF2cy', 'Var', (68, 78))	('mice', 'Species', '10090', (34, 38))	('DCIScnt2cy', 'Var', (82, 92))
108830	31331982	Of note, E-cad+, CAM5+, CAM6+, and p-Src+ lung metastatic nodules were significantly larger and more numerous with DCISCAF2cy than with DCIScnt2cy (Fig 8D), indicating maintenance of the CAF-primed Ehi state during metastatic dissemination and colonization.	('p-Src', 'Gene', '6714', (35, 40))	('CAM6', 'Gene', (24, 28))	('p-Src', 'Gene', (35, 40))	('CAM6', 'Gene', '4680', (24, 28))	('more', 'PosReg', (96, 100))	('DCISCAF2cy', 'Var', (115, 125))
108832	31331982	Given that ZEB1- pulmonary tumor emboli occur in mice in response to DCISCAF2cy (Fig 8C), we reasoned that the mesenchymal trait in E/M tumor cells is down-regulated through MET during metastatic colonization.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('DCISCAF2cy', 'Var', (69, 79))	('mesenchymal trait in', 'CPA', (111, 131))	('pulmonary tumor', 'Disease', 'MESH:D008175', (17, 32))	('M tumor', 'Disease', (134, 141))	('pulmonary tumor', 'Disease', (17, 32))	('down-regulated', 'NegReg', (151, 165))	('mice', 'Species', '10090', (49, 53))	('M tumor', 'Disease', 'MESH:C566367', (134, 141))	('pulmonary tumor', 'Phenotype', 'HP:0100526', (17, 32))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
108833	31331982	As anticipated, increased ZEB1 staining in primary tumors due to DCISCAF2cy (Fig 2D), was dramatically attenuated in the accompanying lung metastases (Fig 8D).	('attenuated', 'NegReg', (103, 113))	('primary tumors', 'Disease', 'MESH:D009369', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ZEB1', 'Protein', (26, 30))	('staining', 'MPA', (31, 39))	('increased', 'PosReg', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('lung metastases', 'Disease', (134, 149))	('lung metastases', 'Disease', 'MESH:D009362', (134, 149))	('primary tumors', 'Disease', (43, 57))	('DCISCAF2cy', 'Var', (65, 75))
108841	31331982	Positive staining for CAM6/CAM5/E-cad and E-cad/ZEB1 was detected in Her2+ER-PR- (Her2-positive, estrogen receptor-negative, and progesterone receptor-negative) breast cancers more frequently than in other tumors (Fig 9B and Tables S2, S3, S4, S5).	('CAM6', 'Gene', '4680', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('breast cancers', 'Phenotype', 'HP:0003002', (161, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('CAM6', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('breast cancers', 'Disease', (161, 175))	('breast cancers', 'Disease', 'MESH:D001943', (161, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('Her2+ER-PR-', 'Var', (69, 80))
108844	31331982	The high CAM6/CAM5/E-cad and E-cad/ZEB1 mRNA expressions were significantly associated with poorer relapse-free survival in the Her2+ER-PR-, but not in the Her2-ER+PR+ and Her2-ER-PR-, breast cancer patient cohorts (Figs 9D and S8A).	('E-cad/ZEB1', 'Gene', (29, 39))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('patient', 'Species', '9606', (199, 206))	('breast cancer', 'Disease', (185, 198))	('CAM6', 'Gene', (9, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('relapse-free survival', 'CPA', (99, 120))	('high', 'Var', (4, 8))	('CAM6', 'Gene', '4680', (9, 13))	('Her2+ER-PR-', 'Var', (128, 139))	('poorer', 'NegReg', (92, 98))
108855	31331982	Analysis of DNA methylation by pyrosequencing reveals the slightly hypomethylated promoter region present in the CAM6 gene, but not in either the CAM5 or the E-cad gene, in DCISCAF2cy as compared with DCIScnt2cy (Fig S9A), indicating minimal involvement of DNA methylation.	('slightly hypomethylated promoter region', 'MPA', (58, 97))	('DCISCAF2cy', 'Var', (173, 183))	('CAM6', 'Gene', '4680', (113, 117))	('CAM6', 'Gene', (113, 117))
108879	31331982	Previous reports have described larger numbers of SDF-1-producing myofibroblasts to comprise tumor-associated stroma in Her2-amplified human breast cancers than in luminal A and basal-like breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('breast cancers', 'Disease', 'MESH:D001943', (189, 203))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('breast cancers', 'Disease', (189, 203))	('SDF-1-producing', 'Gene', (50, 65))	('tumor', 'Disease', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancers', 'Disease', (141, 155))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('human', 'Species', '9606', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('Her2-amplified', 'Var', (120, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
108884	31331982	Thus, stromal SDF-1 and TGF-beta might play key roles in mediating the tumor-promoting interaction between the CAFs and Her2+ER-PR- breast carcinoma cells.	('TGF-beta', 'Gene', (24, 32))	('breast carcinoma', 'Phenotype', 'HP:0003002', (132, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Her2+ER-PR-', 'Var', (120, 131))	('breast carcinoma', 'Disease', (132, 148))	('CAFs', 'Chemical', '-', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('breast carcinoma', 'Disease', 'MESH:D001943', (132, 148))	('tumor', 'Disease', (71, 76))	('carcinoma cells', 'Disease', 'MESH:C538614', (139, 154))	('carcinoma cells', 'Disease', (139, 154))
108906	31331982	To measure E-cad- and ZEB1-positive DCIS cells, the single-cell suspensions dissociated from tumors were stained with anti-E-cad antibody (DECMA-1)-Alexa Fluor 488 for 40 min at 4 C and then permeabilized with IntraPrep Permeabilization Reagent (BECKMAN COULTER) before staining with anti-ZEB1-Alexa Fluor 647 (Novus Biologicals) for 30 min at 4 C. Positivity for both E-cad and ZEB1 was then determined on tdTomato+ DCIS cells to quantify E-cadhiZEB1lo/neg (Ehi), E-cadloZEB1hi (E/M), and E-cadhiZEB1hi cancer cell proportions (Fig S1G).	('cancer', 'Phenotype', 'HP:0002664', (504, 510))	('E-cadhiZEB1hi', 'Var', (490, 503))	('Alexa Fluor', 'Chemical', '-', (294, 305))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('E-cadhiZEB1lo/neg', 'Var', (440, 457))	('cancer', 'Disease', (504, 510))	('Alexa Fluor 488', 'Chemical', '-', (148, 163))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (504, 510))	('DECMA-1)', 'Chemical', '-', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Alexa Fluor', 'Chemical', '-', (148, 159))	('tumors', 'Disease', (93, 99))
108933	31331982	The gel was then mounted on a 100-mum cell strainer (BD Falcon) and fed from underneath with 9 ml of the 1:1 media with TGF-beta1 (10 ng/ml) and SDF-1 (100 ng/ml) on a six-well culture plate for 9 d before fixation with formalin.	('10 ng/ml', 'Var', (131, 139))	('100 ng/ml', 'Var', (152, 161))	('mum', 'Gene', '56925', (34, 37))	('TGF-beta1', 'Gene', '7040', (120, 129))	('formalin', 'Chemical', 'MESH:D005557', (220, 228))	('TGF-beta1', 'Gene', (120, 129))	('mum', 'Gene', (34, 37))
108939	31331982	Sections were prepared from experimental lung metastases generated by intravenous injection of DCISCAF2cy expressing GFP-, E-cad-, CAM5- or CAM6-shRNAs (n = 4).	('lung metastases', 'Disease', (41, 56))	('DCISCAF2cy', 'Gene', (95, 105))	('CAM6', 'Gene', (140, 144))	('E-cad-', 'Var', (123, 129))	('GFP-', 'Var', (117, 121))	('CAM6', 'Gene', '4680', (140, 144))	('rat', 'Species', '10116', (61, 64))	('lung metastases', 'Disease', 'MESH:D009362', (41, 56))	('CAM5-', 'Var', (131, 136))
108993	31331982	The slides were then blocked in blocking solution at 37 C for 30 min before incubation overnight at 4 C with dilution of the primary antibodies including anti-E-cad, anti-CAM5, anti-CAM6, and anti-Src antibodies, as shown in Figs 3G, 6E, and S5G.	('CAM6', 'Gene', '4680', (182, 186))	('CAM6', 'Gene', (182, 186))	('anti-E-cad', 'Var', (154, 164))	('anti-Src', 'Var', (192, 200))	('anti-CAM5', 'Var', (166, 175))
109004	31331982	On immunohistochemical analyses, we confirmed the specificity of the antibodies used by immunoblotting using DCIS cells overexpressing E-cad, CAM5, and/or CAM6 as well as DCISCAF2cy expressing shRNAs against E-cad, CAM5, CAM6, or ZEB1.	('CAM6', 'Gene', (155, 159))	('CAM6', 'Gene', '4680', (155, 159))	('CAM6', 'Gene', (221, 225))	('CAM6', 'Gene', '4680', (221, 225))	('E-cad', 'Var', (135, 140))
109013	31331982	The Pearson product-moment correlation coefficient was used to measure the strength and direction of the linear association between two variables, as shown in Figs 3F and S3D (CAM6 and CAM5; E-cad and CAM5; and E-cad and CAM6).	('E-cad', 'Var', (211, 216))	('CAM6', 'Gene', '4680', (176, 180))	('CAM6', 'Gene', (176, 180))	('CAM6', 'Gene', (221, 225))	('CAM6', 'Gene', '4680', (221, 225))	('E-cad', 'Var', (191, 196))
109016	31331982	This gene set was used to classify samples from human primary breast cancer datasets (GSE7390, GSE12276, and GSE14333) (Figs 3A and S3A).	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('GSE14333', 'Var', (109, 117))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('GSE7390', 'Chemical', '-', (86, 93))	('GSE12276', 'Var', (95, 103))	('GSE7390', 'Var', (86, 93))
109084	31363320	Presumably for the same reason, the maximum stiffness of ductal invasive carcinomas was slightly higher in our study (192.1 kPa) compared to 180 kPa in their study (Fig 4).	('higher', 'PosReg', (97, 103))	('stiffness of ductal invasive carcinomas', 'Disease', (44, 83))	('192.1', 'Var', (118, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('stiffness of ductal invasive carcinomas', 'Disease', 'MESH:D018270', (44, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
109127	32206740	Overall, we show that the use of existing RNA-seq datasets, if re-analysed with modern bioinformatic tools, can provide a valuable resource to identify lncRNAs that could have important biological roles in oncogenesis and tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('lncRNAs', 'Var', (152, 159))	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('tumour', 'Disease', (222, 228))
109180	32206740	(2015) described RNA-seq and single nucleotide polymorphism (SNP) array analysis of 675 human cancer cell lines.	('human', 'Species', '9606', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('single nucleotide polymorphism', 'Var', (29, 59))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
109223	32206740	ZNF667-AS1 is more highly expressed in MDA-MB-157 versus MDA-MB-231 (Fig.	('ZNF667-AS1', 'Gene', '100128252', (0, 10))	('highly', 'PosReg', (19, 25))	('ZNF667-AS1', 'Gene', (0, 10))	('MDA-MB-157', 'Var', (39, 49))
109251	32206740	Other studies have linked elevated CCAT1 to other cancers including acute myeloid leukaemia, gallbladder, liver and squamous cell carcinoma.	('CCAT1', 'Gene', '100507056', (35, 40))	('CCAT1', 'Gene', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('liver', 'Disease', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (74, 91))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (74, 91))	('gallbladder', 'Disease', (93, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', (116, 139))	('myeloid leukaemia', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('elevated', 'Var', (26, 34))
109353	20799509	Using multivariate analysis, it was determined that the factors associated with MRI use included multi-focality younger age, tumor size, lobular histology, body mass index, and genetic testing.	('tumor', 'Disease', (125, 130))	('genetic testing', 'Var', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (125, 130))
109366	20799509	Lifetime risk of ovarian cancer is up to 30% in individuals carrying mutations in BRCA1 and BRCA2.	('BRCA1', 'Gene', (82, 87))	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('BRCA2', 'Gene', (92, 97))	('ovarian cancer', 'Disease', (17, 31))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA2', 'Gene', '675', (92, 97))
109395	20799509	In a study involving in vivo MRI (3 T) assessment of 24 mice bearing implanted human MCF-7 breast adenocarcinomas, the USPIO-PEG-OCT CA was shown to bind specifically to MCF-7 cells, producing a significant decrease of the transverse relaxation time compared to a control group.	('human', 'Species', '9606', (79, 84))	('MCF-7', 'CellLine', 'CVCL:0031', (85, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('USPIO-PEG-OCT CA', 'Var', (119, 135))	('PEG', 'Chemical', 'MESH:D011092', (125, 128))	('bind', 'Interaction', (149, 153))	('OCT', 'Chemical', '-', (129, 132))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (91, 113))	('mice', 'Species', '10090', (56, 60))	('MCF-7', 'CellLine', 'CVCL:0031', (170, 175))	('transverse relaxation time', 'MPA', (223, 249))	('breast adenocarcinomas', 'Disease', (91, 113))	('decrease', 'NegReg', (207, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
109399	20799509	Ovarian tumors implanted in rats were imaged following injection of two FR-targeted -- P866 (Gd-chelate) and P1048 (SPIO) -- and two non-targeted -- P1001 (Gd-chelate) and P904 (SPIO) -- CAs.	('rats', 'Species', '10116', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('P904', 'Var', (172, 176))	('Gd', 'Chemical', 'MESH:D005682', (93, 95))	('P1048', 'Var', (109, 114))	('Gd', 'Chemical', 'MESH:D005682', (156, 158))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Ovarian tumors', 'Phenotype', 'HP:0100615', (0, 14))	('Ovarian tumors', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian tumors', 'Disease', (0, 14))
109401	20799509	The tumors showed uptake of P866 and P1048, which decreased with competing free folate.	('uptake', 'MPA', (18, 24))	('P866', 'Var', (28, 32))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('folate', 'Chemical', 'MESH:D005492', (80, 86))	('P1048', 'Var', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
109402	20799509	The Deltar1 values were higher at 1 h following injection of P866 than following injection of P1001, indicating a higher amount of CA retained in the tumor following injection of the targeted CA.	('P866', 'Var', (61, 65))	('higher', 'PosReg', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('Deltar1', 'MPA', (4, 11))
109403	20799509	The experiments suggested a specific accumulation of P866 in an FR-positive ovarian tumor model, demonstrating the feasibility of the method to improve diagnosis and treatment of FR-positive tumors.	('ovarian tumor', 'Phenotype', 'HP:0100615', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian tumor', 'Disease', 'MESH:D010051', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('ovarian tumor', 'Disease', (76, 89))	('tumors', 'Disease', (191, 197))	('accumulation', 'PosReg', (37, 49))	('P866', 'Var', (53, 57))
109404	20799509	assessed the ability of a FR-targeted USPIO, P1133, compared to a non-targeted USPIO, P904, to provide FR-specific enhancement of FR-positive breast cancers in T2-weighted MR images.	('P1133', 'Var', (45, 50))	('enhancement', 'PosReg', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (142, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancers', 'Disease', 'MESH:D001943', (142, 156))	('breast cancers', 'Disease', (142, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
109430	23547970	In addition, aberrant Hh signalling in adults results in carcinogenesis, metastasis and chemoresistance.	('Hh signalling', 'Protein', (22, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('results in', 'Reg', (46, 56))	('metastasis', 'CPA', (73, 83))	('carcinogenesis', 'Disease', (57, 71))	('chemoresistance', 'CPA', (88, 103))	('aberrant', 'Var', (13, 21))
109451	23547970	Ciliary ablation strongly inhibited the development of basal cell carcinoma (BCC) and medulloblastoma when these tumours were driven by an activated form of the transmembrane protein SMO.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (55, 75))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (55, 75))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('inhibited', 'NegReg', (26, 35))	('basal cell carcinoma', 'Disease', (55, 75))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('medulloblastoma', 'Disease', 'MESH:D008527', (86, 101))	('medulloblastoma', 'Phenotype', 'HP:0002885', (86, 101))	('tumours', 'Disease', (113, 120))	('ablation', 'Var', (8, 16))	('medulloblastoma', 'Disease', (86, 101))	('development', 'CPA', (40, 51))
109452	23547970	Conversely, removal of cilia accelerated tumourigenesis induced by constitutively active GLI2.	('accelerated', 'PosReg', (29, 40))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('removal', 'Var', (12, 19))	('tumour', 'Disease', (41, 47))
109472	23547970	GLI1 overexpression in mouse mammary epithelial cells leads to a defect in the complexity of the alveolar network, an inability to lactate and, importantly, the appearance of hyperplastic lesions and tumour development.	('tumour', 'Disease', (200, 206))	('GLI1', 'Gene', (0, 4))	('lactate', 'Chemical', 'MESH:D019344', (131, 138))	('inability', 'NegReg', (118, 127))	('hyperplastic lesions', 'Disease', (175, 195))	('defect', 'NegReg', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('hyperplastic lesions', 'Disease', 'MESH:D051437', (175, 195))	('mouse', 'Species', '10090', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('overexpression', 'Var', (5, 19))	('complexity of the alveolar network', 'CPA', (79, 113))	('lactate', 'CPA', (131, 138))
109474	23547970	Altogether, these data demonstrate that de-regulation of Hh signalling can perturb mammary development and promote mammary carcinogenesis.	('de-regulation', 'Var', (40, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('mammary development', 'CPA', (83, 102))	('carcinogenesis', 'Disease', (123, 137))	('perturb', 'NegReg', (75, 82))	('promote', 'PosReg', (107, 114))	('Hh signalling', 'Protein', (57, 70))
109489	23547970	Subsequently, inactivating mutations in the PTCH1 gene and activating SMO mutations were identified in BCC, medulloblastoma and rhabdomyosarcoma (Figure 2.1).	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('medulloblastoma and rhabdomyosarcoma', 'Disease', 'MESH:D008527', (108, 144))	('inactivating mutations', 'Var', (14, 36))	('PTCH1', 'Gene', (44, 49))	('activating', 'PosReg', (59, 69))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (128, 144))	('medulloblastoma', 'Phenotype', 'HP:0002885', (108, 123))	('BCC', 'Disease', (103, 106))
109497	23547970	More recently, comparative genomic hybridisation analysis identified a frequent loss of PTCH1 locus and amplification of GLI1, independently of the breast tumour subtype.	('loss', 'NegReg', (80, 84))	('GLI1', 'Gene', (121, 125))	('breast tumour', 'Phenotype', 'HP:0100013', (148, 161))	('PTCH1 locus', 'Gene', (88, 99))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('breast tumour subtype', 'Disease', (148, 169))	('breast tumour subtype', 'Disease', 'MESH:D001943', (148, 169))	('amplification', 'Var', (104, 117))
109498	23547970	Furthermore, a nonsynonymous mutation in PTCH2 has been described in the primary tumour and brain metastasis of a patient with BLBC.	('nonsynonymous mutation', 'Var', (15, 37))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', (81, 87))	('PTCH2', 'Gene', (41, 46))	('patient', 'Species', '9606', (114, 121))	('brain metastasis', 'CPA', (92, 108))	('PTCH2', 'Gene', '8643', (41, 46))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
109505	23547970	We further demonstrated that ectopic expression of Hh ligand in a mouse model of BLBC led to the development of rapidly growing, high grade invasive tumours compared to controls.	('ectopic expression', 'Var', (29, 47))	('mouse', 'Species', '10090', (66, 71))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('invasive tumours', 'Disease', (140, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('invasive tumours', 'Disease', 'MESH:D009361', (140, 156))	('rapidly growing', 'CPA', (112, 127))
109507	23547970	SHH promoter region hypomethylation is frequently observed in breast carcinomas and is significantly associated with SHH up-regulation.	('SHH', 'Gene', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('up-regulation', 'PosReg', (121, 134))	('SHH', 'Gene', (117, 120))	('hypomethylation', 'Var', (20, 35))	('breast carcinomas', 'Disease', 'MESH:D001943', (62, 79))	('breast carcinomas', 'Disease', (62, 79))	('breast carcinomas', 'Phenotype', 'HP:0003002', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
109513	23547970	Methylation of the PTCH promoter was further correlated with low PTCH1 expression in human breast neoplasms.	('expression', 'MPA', (71, 81))	('PTCH', 'Gene', (19, 23))	('PTCH', 'Gene', '5727', (19, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('low', 'NegReg', (61, 64))	('Methylation', 'Var', (0, 11))	('breast neoplasms', 'Phenotype', 'HP:0100013', (91, 107))	('PTCH', 'Gene', '5727', (65, 69))	('breast neoplasms', 'Disease', 'MESH:D001943', (91, 107))	('PTCH', 'Gene', (65, 69))	('breast neoplasms', 'Disease', (91, 107))	('human', 'Species', '9606', (85, 90))
109519	23547970	Interestingly, RNA interference-mediated knockdown of GLI1 or GLI2 in melanoma and colon cell lines or treatment with the SMO antagonist cyclopamine in vitro or as xenografts in vivo strikingly reduced tumour growth.	('GLI2', 'Gene', (62, 66))	('RNA interference-mediated', 'MPA', (15, 40))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour growth', 'Disease', (202, 215))	('cyclopamine', 'Chemical', 'MESH:C000541', (137, 148))	('melanoma and colon cell lines', 'Disease', 'MESH:D008545', (70, 99))	('tumour growth', 'Disease', 'MESH:D006130', (202, 215))	('reduced', 'NegReg', (194, 201))	('GLI1', 'Gene', (54, 58))	('knockdown', 'Var', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
109523	23547970	Using a specific small molecule SMO antagonist, a neutralising anti-Hh antibody and genetic ablation of SMO in the murine stroma, the investigators made the key observation that the secretion of Hh ligand by epithelial cells does not correlate with the expression of the Hh target genes in the tumour compartment but rather is associated with canonical activity in stromal cells.	('genetic ablation', 'Var', (84, 100))	('tumour', 'Disease', 'MESH:D009369', (294, 300))	('ablation', 'Var', (92, 100))	('tumour', 'Disease', (294, 300))	('secretion', 'MPA', (182, 191))	('tumour', 'Phenotype', 'HP:0002664', (294, 300))	('murine', 'Species', '10090', (115, 121))
109538	23547970	Harris and collaborators validated our finding that over-expression of SHH in breast cancer cells promotes aggressive behaviour of xenografts, but in addition demonstrated that SHH through GLI1 upregulates a pro-angiogenic (VEGF-independent) secreted molecule, CYR61.	('aggressive behaviour', 'Phenotype', 'HP:0000718', (107, 127))	('SHH', 'Var', (177, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('promotes', 'PosReg', (98, 106))	('GLI1', 'Gene', (189, 193))	('upregulates', 'PosReg', (194, 205))	('CYR61', 'Gene', '3491', (261, 266))	('VEGF', 'Gene', '7422', (224, 228))	('VEGF', 'Gene', (224, 228))	('over-expression', 'PosReg', (52, 67))	('SHH', 'Gene', (71, 74))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('aggressive behaviour of xenografts', 'CPA', (107, 141))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))	('CYR61', 'Gene', (261, 266))
109539	23547970	Furthermore, silencing CYR61 in their triple-negative model attenuated the malignant phenotype associated with reduced tumour vasculature and less haematogenous spread.	('malignant phenotype', 'CPA', (75, 94))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('CYR61', 'Gene', (23, 28))	('reduced', 'NegReg', (111, 118))	('tumour vasculature', 'Disease', (119, 137))	('tumour vasculature', 'Disease', 'MESH:C565633', (119, 137))	('CYR61', 'Gene', '3491', (23, 28))	('attenuated', 'NegReg', (60, 70))	('silencing', 'Var', (13, 22))	('less', 'NegReg', (142, 146))
109545	23547970	Ectopic expression of GLI1 induces the nuclear Snail expression and concomitant loss of E-cadherin expression in mouse mammary gland tissue during pregnancy.	('expression', 'MPA', (99, 109))	('mouse', 'Species', '10090', (113, 118))	('loss', 'NegReg', (80, 84))	('Ectopic expression', 'Var', (0, 18))	('E-cadherin', 'Protein', (88, 98))	('induces', 'Reg', (27, 34))	('GLI1', 'Gene', (22, 26))	('nuclear Snail expression', 'MPA', (39, 63))
109568	23547970	They include GDC-0449 (Erivedge/vismodegib), LDE225, IPI-926, BMS-833923, itraconazole, PF-0444913, LEQ506 and TAK-441 (Figure 3; Table 1).	('itraconazole', 'Chemical', 'MESH:D017964', (74, 86))	('GDC-0449', 'Chemical', 'MESH:C538724', (13, 21))	('LEQ506', 'Var', (100, 106))	('IPI-926', 'Var', (53, 60))	('BMS-833923', 'Var', (62, 72))	('IPI', 'Chemical', '-', (53, 56))	('LDE225', 'Chemical', 'MESH:C561435', (45, 51))	('PF-0444913', 'Var', (88, 98))
109574	23547970	For example, treatment of a PTCH1-mutant medulloblastoma patient with the small molecule GDC-0449 resulted in a rapid relapse due to an acquired tumour-specific mutation in SMO and the loss of interaction between the SMO mutant and the drug.	('loss of', 'NegReg', (185, 192))	('tumour', 'Disease', (145, 151))	('patient', 'Species', '9606', (57, 64))	('mutation', 'Var', (161, 169))	('medulloblastoma', 'Disease', 'MESH:D008527', (41, 56))	('SMO', 'Gene', (173, 176))	('PTCH1-mutant', 'Gene', (28, 40))	('GDC-0449', 'Chemical', 'MESH:C538724', (89, 97))	('interaction', 'Interaction', (193, 204))	('medulloblastoma', 'Phenotype', 'HP:0002885', (41, 56))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('medulloblastoma', 'Disease', (41, 56))
109576	23547970	The use of antagonists that target the Hh pathway downstream of SMO, such as GANT58 and GANT61, which blocks GLI transcriptional activity, represent an attractive therapeutic strategy in the context of resistance driven by SMO mutations.	('GLI', 'Gene', '2735', (109, 112))	('GLI', 'Gene', (109, 112))	('Hh pathway', 'Pathway', (39, 49))	('mutations', 'Var', (227, 236))
109593	23547970	Inhibiting this pathway in mouse models of triple-negative breast cancer dramatically decreases tumour growth and metastatic spread.	('Inhibiting', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('metastatic spread', 'CPA', (114, 131))	('mouse', 'Species', '10090', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('decreases tumour growth', 'Disease', (86, 109))	('breast cancer', 'Disease', (59, 72))	('decreases tumour growth', 'Disease', 'MESH:D006130', (86, 109))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))
109605	28711544	In 641 CpGs whose methylation was related with increased hazard of invasive breast cancer, lower within-subject than between-subject variability was observed in 92.3% of the study participants (P < 0.05).	('invasive breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('methylation', 'Var', (18, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('invasive breast cancer', 'Disease', (67, 89))	('participants', 'Species', '9606', (180, 192))
109610	28711544	Perturbation of DNA methylation is common in breast cancer .	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('DNA', 'Protein', (16, 19))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('methylation', 'Var', (20, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('Perturbation', 'Var', (0, 12))
109611	28711544	Previously, we characterized the landscape of DNA methylation alterations in DCIS lesions and identified DNA methylation biomarkers related with risk of developing invasive breast cancer .	('related', 'Reg', (132, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('invasive breast cancer', 'Disease', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('invasive breast cancer', 'Disease', 'MESH:D001943', (164, 186))	('alterations', 'Var', (62, 73))
109642	28711544	To further investigate the relation of protocadherin gene-body methylation with gene expression, we analyzed estrogen receptor (ER) positive early-stage breast cancers from The Cancer Genome Atlas (TCGA) , and also observed that gene-body methylation of protocadherin genes was related with increased gene expression (Supplementary Figure 5).	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (177, 196))	('methylation', 'Var', (239, 250))	('gene expression', 'MPA', (301, 316))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('estrogen receptor', 'Gene', '2099', (109, 126))	('protocadherin genes', 'Gene', (254, 273))	('breast cancers', 'Phenotype', 'HP:0003002', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('increased', 'PosReg', (291, 300))	('breast cancers', 'Disease', 'MESH:D001943', (153, 167))	('breast cancers', 'Disease', (153, 167))	('estrogen receptor', 'Gene', (109, 126))	('Cancer Genome Atlas', 'Disease', (177, 196))
109643	28711544	We recently identified CpGs with altered DNA methylation in DCIS that are related with an increased hazard of invasive breast cancer diagnosis .	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('related', 'Reg', (74, 81))	('DCIS', 'Gene', (60, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('invasive breast cancer', 'Disease', (110, 132))	('altered', 'Var', (33, 40))	('invasive breast cancer', 'Disease', 'MESH:D001943', (110, 132))
109652	28711544	This finding lends support to using pre-operative core biopsies for assessing risks of invasive cancer diagnosis through DNA methylation.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('invasive cancer', 'Disease', 'MESH:D009362', (87, 102))	('invasive cancer', 'Disease', (87, 102))	('DNA methylation', 'Var', (121, 136))
109665	26729973	These guidelines had proposed five categories to report breast lesions on FNAC, namely, inadequate (C1), benign (C2), atypia probably benign (C3), suspicious of malignancy (C4), and malignant (C5).	('atypia', 'Var', (118, 124))	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('malignancy', 'Disease', (161, 171))	('breast lesions', 'Disease', (56, 70))	('benign', 'Disease', (105, 111))	('breast lesions', 'Disease', 'MESH:D001941', (56, 70))
109696	26729973	In cytology, a cellular smear with a dispersed/discohesive population of cells with round nuclei, coarse chromatin or hyperchromatic chromatin, and prominent nucleoli raises a suspicion of malignancy.	('hyperchromatic chromatin', 'Var', (118, 142))	('malignancy', 'Disease', 'MESH:D009369', (189, 199))	('malignancy', 'Disease', (189, 199))
109906	27257388	In triple-negative breast cancer, the observed gene expression pattern (high COX-2, high MRP4, low PGT, and low 15-PGDH) would favor high levels of tumor-promoting PGE2 in the tumor microenvironment that may contribute to the overall poor prognosis of triple-negative breast cancer.	('MRP4', 'Gene', (89, 93))	('PGE2', 'Chemical', 'MESH:D015232', (164, 168))	('MRP4', 'Gene', '10257', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PGT', 'Gene', (99, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('high', 'Var', (72, 76))	('favor', 'PosReg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('low', 'NegReg', (95, 98))	('tumor', 'Disease', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('COX-2', 'Gene', (77, 82))	('breast cancer', 'Disease', (268, 281))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('15-PGDH', 'Gene', '873', (112, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('high', 'Var', (84, 88))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('COX-2', 'Gene', '5743', (77, 82))	('breast cancer', 'Disease', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('tumor', 'Disease', (148, 153))	('15-PGDH', 'Gene', (112, 119))	('PGT', 'Gene', '6578', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
109912	27257388	Inhibition of COX-2 for other indications has shown some tumor-preventative effect; however, the risk of cardiovascular toxicity limits the pursuit of COX-2 inhibition as a chemopreventative regimen.	('COX-2', 'Gene', (151, 156))	('COX-2', 'Gene', '5743', (14, 19))	('COX-2', 'Gene', (14, 19))	('COX-2', 'Gene', '5743', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Inhibition', 'Var', (0, 10))	('cardiovascular toxicity', 'Disease', 'MESH:D002318', (105, 128))	('tumor', 'Disease', (57, 62))	('cardiovascular toxicity', 'Disease', (105, 128))
109916	27257388	COX-2 expression is normally induced by inflammatory stimuli, but aberrant expression of COX-2 is often found in epithelial malignancies, including breast cancer.	('epithelial malignancies', 'Disease', (113, 136))	('found', 'Reg', (104, 109))	('epithelial malignancies', 'Disease', 'MESH:D002277', (113, 136))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (113, 136))	('COX-2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('aberrant', 'Var', (66, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (89, 94))	('expression', 'MPA', (75, 85))	('COX-2', 'Gene', '5743', (0, 5))
109955	27257388	The following gene probe IDs were used to evaluate gene expression in these datasets: ABCC4 (MRP4): 203196_at; SLCO2A1 (PGT): 204368_at; HPGD (15-PGDH): 211549_s_at; PTGS2 (COX-2): 204748_at; PTGS1 (COX-1): 205127_at; and PTGER4 (EP4): 204897_at.	('SLCO2A1', 'Gene', '6578', (111, 118))	('HPGD', 'Gene', '3248', (137, 141))	('ABCC4', 'Gene', (86, 91))	('PTGER4', 'Gene', (222, 228))	('COX-1', 'Gene', (199, 204))	('211549_s_at', 'Var', (153, 164))	('COX-2', 'Gene', (173, 178))	('EP4', 'Gene', '5734', (230, 233))	('PTGS2', 'Gene', (166, 171))	('SLCO2A1', 'Gene', (111, 118))	('MRP4', 'Gene', (93, 97))	('EP4', 'Gene', (230, 233))	('MRP4', 'Gene', '10257', (93, 97))	('HPGD', 'Gene', (137, 141))	('PTGER4', 'Gene', '5734', (222, 228))	('ABCC4', 'Gene', '10257', (86, 91))	('15-PGDH', 'Gene', '873', (143, 150))	('PGT', 'Gene', '6578', (120, 123))	('COX-2', 'Gene', '5743', (173, 178))	('PGT', 'Gene', (120, 123))	('COX-1', 'Gene', '4512', (199, 204))	('PTGS1', 'Gene', '5742', (192, 197))	('15-PGDH', 'Gene', (143, 150))	('PTGS2', 'Gene', '5743', (166, 171))	('PTGS1', 'Gene', (192, 197))
109966	27257388	Dark blue represents luminal A subtype tumors, light blue represents luminal B subtype tumors, orange represents HER2-enriched tumors, peach represents basal-like tumors, and green represents normal-like tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('subtype tumors', 'Disease', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('HER2-enriched tumors', 'Disease', 'MESH:D009369', (113, 133))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('peach', 'Species', '3760', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('subtype tumors', 'Disease', (31, 45))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', (204, 210))	('basal-like tumors', 'Phenotype', 'HP:0002671', (152, 169))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('subtype tumors', 'Disease', 'MESH:C535673', (79, 93))	('HER2-enriched tumors', 'Disease', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('light blue', 'Var', (47, 57))	('subtype tumors', 'Disease', 'MESH:C535673', (31, 45))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
109988	27257388	The relationship of high PTGS2 to basal-type breast cancers was also noted by Li et al.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('PTGS2', 'Gene', (25, 30))	('basal-type breast cancers', 'Disease', (34, 59))	('PTGS2', 'Gene', '5743', (25, 30))	('high', 'Var', (20, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('basal-type breast cancers', 'Disease', 'MESH:D001943', (34, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
110014	27257388	High HPGD (15-PGDH) expression was found to be an independent predictor of a better outcome, longer OS (hazard ratio = 0.89, P = 0.01).	('longer OS', 'Disease', (93, 102))	('15-PGDH', 'Gene', '873', (11, 18))	('High', 'Var', (0, 4))	('High HPGD', 'Phenotype', 'HP:0410246', (0, 9))	('15-PGDH', 'Gene', (11, 18))	('HPGD', 'Gene', (5, 9))	('HPGD', 'Gene', '3248', (5, 9))
110063	27257388	MRP4 expression is also regulated by alternative splicing and nonsense-mediated decay of a truncated mRNA transcript.	('MRP4', 'Gene', (0, 4))	('expression', 'MPA', (5, 15))	('MRP4', 'Gene', '10257', (0, 4))	('regulated', 'Reg', (24, 33))	('nonsense-mediated decay', 'Var', (62, 85))
110069	27257388	Expression of 15-PGDH is necessary for metabolism and inactivation of PGE2 in order to fully suppress PGE2-mediated signaling even when COX-2 is inhibited.	('suppress', 'NegReg', (93, 101))	('PGE2', 'Chemical', 'MESH:D015232', (102, 106))	('PGE2-mediated signaling', 'MPA', (102, 125))	('15-PGDH', 'Gene', '873', (14, 21))	('PGE2', 'Gene', (70, 74))	('PGE2', 'Chemical', 'MESH:D015232', (70, 74))	('COX-2', 'Gene', (136, 141))	('COX-2', 'Gene', '5743', (136, 141))	('15-PGDH', 'Gene', (14, 21))	('inactivation', 'Var', (54, 66))
110072	27257388	High HPGD expression was associated with improved OS and RFS.	('improved', 'PosReg', (41, 49))	('High', 'Var', (0, 4))	('High HPGD', 'Phenotype', 'HP:0410246', (0, 9))	('RFS', 'CPA', (57, 60))	('HPGD', 'Gene', '3248', (5, 9))	('HPGD', 'Gene', (5, 9))
110172	21827679	Other studies confirmed the indolent nature of LCIS; clinically, LCIS was considered a risk marker for invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('LCIS', 'Phenotype', 'HP:0030076', (65, 69))	('invasive breast cancer', 'Disease', (103, 125))	('LCIS', 'Var', (65, 69))	('invasive breast cancer', 'Disease', 'MESH:D001943', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('LCIS', 'Phenotype', 'HP:0030076', (47, 51))
110190	21827679	Cases that harbored more than one subtype of LN were classified by the lesion with the greatest risk of developing carcinoma: pleomorphic LCIS > Classic LCIS > DIALH > ALH.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('pleomorphic LCIS > Classic LCIS > DIALH', 'Var', (126, 165))	('carcinoma', 'Disease', (115, 124))	('LCIS', 'Phenotype', 'HP:0030076', (138, 142))	('ALH', 'Chemical', '-', (168, 171))	('LCIS', 'Phenotype', 'HP:0030076', (153, 157))	('DIALH', 'Chemical', '-', (160, 165))	('LN', 'Phenotype', 'HP:0030076', (45, 47))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))	('ALH', 'Chemical', '-', (162, 165))
69821	21827679	In the patients with LIN 3 (equivalent to LCIS), the frequency of association with IDC and ILC was 23% and 86%, respectively.	('LIN', 'Var', (21, 24))	('IDC', 'Disease', (83, 86))	('association', 'Interaction', (66, 77))	('ILC', 'Disease', (91, 94))	('LCIS', 'Phenotype', 'HP:0030076', (42, 46))	('patients', 'Species', '9606', (7, 15))
110238	21827679	Invasive and in situ lobular carcinomas confer similar genetic gains and losses, often bearing the same mutations in the gene that encodes E-cadherin (CDH1).	('CDH1', 'Gene', (151, 155))	('E-cadherin', 'Gene', (139, 149))	('gains', 'Disease', (63, 68))	('losses', 'NegReg', (73, 79))	('mutations', 'Var', (104, 113))	('situ lobular carcinomas', 'Disease', 'MESH:D000071960', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('E-cadherin', 'Gene', '999', (139, 149))	('gains', 'Disease', 'MESH:D015430', (63, 68))	('situ lobular carcinomas', 'Disease', (16, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (21, 38))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (21, 39))
110240	21827679	demonstrated that somatic alterations in CDH1 are a hallmark of LCIS but not ALH.	('CDH1', 'Gene', (41, 45))	('ALH', 'Chemical', '-', (77, 80))	('alterations', 'Var', (26, 37))	('LCIS', 'Phenotype', 'HP:0030076', (64, 68))	('LCIS', 'Disease', (64, 68))
110241	21827679	This disparity suggests that mutations that inactivate CDH1 can distinguish LNs that are able to progress to invasive disease, explaining our morphological data.	('inactivate', 'Var', (44, 54))	('CDH1', 'Gene', (55, 59))	('invasive disease', 'Disease', 'MESH:D009362', (109, 125))	('mutations', 'Var', (29, 38))	('invasive disease', 'Disease', (109, 125))	('LN', 'Phenotype', 'HP:0030076', (76, 78))
110279	12927034	The detection of high-grade DCIS by screening is likely to prevent the development of high-grade invasive cancer within a few years and could be important in producing part of the mortality reduction seen in randomized trials of mammographic screening.	('high-grade', 'Var', (17, 27))	('invasive cancer', 'Disease', 'MESH:D009362', (97, 112))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('prevent', 'NegReg', (59, 66))	('invasive cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
110283	12927034	High-grade DCIS on core and more than 40 calcifications on mammography indicates a 48% chance of occult invasion, whereas high-grade DCIS on core and fewer than 40 calcifications indicates a 15% risk for invasion.	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('calcification', 'Disease', (41, 54))	('calcification', 'Disease', (164, 177))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('calcification', 'Disease', 'MESH:D002114', (41, 54))	('high-grade DCIS', 'Var', (122, 137))	('calcification', 'Disease', 'MESH:D002114', (164, 177))
110419	21557226	HER2 positivity in DCIS was the dominant factor associated with IBC.	('positivity', 'Var', (5, 15))	('IBC', 'Chemical', '-', (64, 67))	('IBC', 'Disease', (64, 67))	('associated', 'Reg', (48, 58))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('HER2', 'Protein', (0, 4))
110469	21557226	HER2 positivity was significantly associated with a higher rate of invasive disease (35.8% in HER2 positive vs. 12.2% vs. HER2 negative patients, p=0.001).	('positivity', 'Var', (5, 15))	('invasive disease', 'Disease', 'MESH:D009362', (67, 83))	('HER2', 'Protein', (94, 98))	('positive', 'Var', (99, 107))	('patients', 'Species', '9606', (136, 144))	('invasive disease', 'Disease', (67, 83))	('HER2', 'Protein', (0, 4))
110470	21557226	These results suggest that HER2 positivity in DCIS is the strongest single marker associated with an occult invasive disease.	('occult invasive disease', 'Disease', (101, 124))	('occult invasive disease', 'Disease', 'MESH:D005596', (101, 124))	('associated', 'Reg', (82, 92))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('positivity', 'Var', (32, 42))	('HER2', 'Protein', (27, 31))
110498	21557226	HER2 positivity in DCIS was the dominant factor associated with early invasive disease in this expanded study series (35.8% in HER2 positive vs. 12.2% vs. HER2 negative DCIS, p=0.001), confirming our previous results.	('positivity', 'Var', (5, 15))	('associated', 'Reg', (48, 58))	('invasive disease', 'Disease', (70, 86))	('positive', 'Var', (132, 140))	('DCIS', 'Phenotype', 'HP:0030075', (169, 173))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('HER2', 'Protein', (0, 4))	('invasive disease', 'Disease', 'MESH:D009362', (70, 86))
110510	21557226	using FISH method showed a significantly higher incidence of HER2 gene amplification in DCIS (50% of pure DCIS cases) than invasive ductal carcinoma (29%) in their series corroborating that the higher incidence of HER2 overexpression in DCIS likely represents a naturally occurring phenomenon.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('amplification', 'Var', (71, 84))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (123, 148))	('HER2', 'Protein', (214, 218))	('DCIS', 'Phenotype', 'HP:0030075', (237, 241))	('overexpression', 'PosReg', (219, 233))	('HER2', 'Protein', (61, 65))	('DCIS', 'Disease', (88, 92))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (132, 148))	('invasive ductal carcinoma', 'Disease', (123, 148))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
110527	21557226	Other novel therapies targeting HER2 are also recently under investigation for breast cancer prevention in patients with HER2 positive DCIS.	('HER2', 'Protein', (121, 125))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('positive DCIS', 'Var', (126, 139))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('patients', 'Species', '9606', (107, 115))
110529	21557226	In addition, our data showed that a lower incidence of invasive disease in anti-HER2 vaccine treated patients than untreated patients, which seems to suggest a potential cancer preventive effect of this anti-HER2 vaccine treatment.	('vaccine', 'Var', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('lower', 'NegReg', (36, 41))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Disease', (170, 176))	('invasive disease', 'Disease', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('anti-HER2', 'Gene', (75, 84))	('invasive disease', 'Disease', 'MESH:D009362', (55, 71))	('patients', 'Species', '9606', (125, 133))
110542	21486440	Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFalpha & IL-1beta may be important for disease course, and that TNFalpha & IL-1beta may promote disease relapse.	('IL-1beta', 'Gene', '3553', (149, 157))	('CCL5', 'Gene', (63, 67))	('and that', 'Var', (129, 137))	('CCL2', 'Gene', '6347', (56, 60))	('TNFalpha', 'Gene', (138, 146))	('TNFalpha', 'Gene', (72, 80))	('IL-1beta', 'Gene', '3553', (83, 91))	('CCL2', 'Gene', (56, 60))	('TNFalpha', 'Gene', '7124', (138, 146))	('CCL5', 'Gene', '6352', (63, 67))	('TNFalpha', 'Gene', '7124', (72, 80))	('IL-1beta', 'Gene', (83, 91))	('IL-1beta', 'Gene', (149, 157))
110566	21486440	Moreover, our results suggest an important role for TNFalpha in breast malignancy, because the cytokine has substantial ability to promote progression-related processes by inducing EMT processes in the tumor cells.	('inducing', 'PosReg', (172, 180))	('tumor', 'Disease', (202, 207))	('breast malignancy', 'Disease', (64, 81))	('breast malignancy', 'Disease', 'MESH:D001943', (64, 81))	('TNFalpha', 'Gene', (52, 60))	('progression-related processes', 'CPA', (139, 168))	('cytokine', 'Var', (95, 103))	('TNFalpha', 'Gene', '7124', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('promote', 'PosReg', (131, 138))
110696	21486440	These results suggest that events dictated by genetic/epigenetic alterations in the tumor cells, or by the microenvironment, lead to a synchronized up-regulation in the expression of several inflammatory mediators together, by transformed breast epithelial cells.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('up-regulation', 'PosReg', (148, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('expression', 'MPA', (169, 179))	('genetic/epigenetic alterations', 'Var', (46, 76))
110721	21486440	Supporting this possibility is the finding that in a specific setting of Her2-neu, ER and PR expression in the tumors, IL-1beta was identified as a risk factor for disease recurrence, suggesting that it can act jointly with other pro-malignancy factors to promote disease progression in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('Her2-neu', 'Gene', '2064', (73, 81))	('expression', 'Var', (93, 103))	('malignancy', 'Disease', 'MESH:D009369', (234, 244))	('promote', 'PosReg', (256, 263))	('PR', 'Gene', '5241', (90, 92))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('malignancy', 'Disease', (234, 244))	('IL-1beta', 'Gene', (119, 127))	('IL-1beta', 'Gene', '3553', (119, 127))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('breast cancer', 'Disease', (287, 300))	('Her2-neu', 'Gene', (73, 81))
110819	30333016	When comparing dietary intake recorded around surgery, the median intake in the FFQ compared to the PFD was significantly higher for most nutrients, including total PUFA, total n-6 and n-3 PUFAs, EPA and DHA.	('PUFA', 'Gene', '9933', (165, 169))	('EPA', 'Chemical', 'MESH:D015118', (196, 199))	('PUFA', 'Gene', '9933', (189, 193))	('higher', 'PosReg', (122, 128))	('PUFA', 'Gene', (165, 169))	('FFQ', 'Chemical', '-', (80, 83))	('PUFA', 'Gene', (189, 193))	('PFD', 'Chemical', '-', (100, 103))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (185, 194))	('n-3', 'Var', (185, 188))	('DHA', 'Chemical', 'MESH:D004281', (204, 207))
110935	32484822	Our IHC findings in tissue microarrays showed that TRPM4 protein was overexpressed in breast cancers (n = 83/99 TRPM4+; 83.8%) compared with normal breast ducts (n = 5/10 TRPM4+; 50%) (p = 0.022).	('overexpressed', 'PosReg', (69, 82))	('breast cancers', 'Phenotype', 'HP:0003002', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Disease', 'MESH:D001943', (86, 100))	('TRPM4', 'Gene', (51, 56))	('breast cancers', 'Disease', (86, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('TRPM4+', 'Var', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('protein', 'Protein', (57, 64))
110940	32484822	Transient receptor potential (TRP) ion channels were identified in Drosophila in which mutated trp and trpl genes led to transient depolarization as well as receptor potential.	('Drosophila', 'Species', '7227', (67, 77))	('mutated', 'Var', (87, 94))	('trpl genes', 'Gene', (103, 113))	('trp', 'Gene', (95, 98))	('receptor potential', 'MPA', (157, 175))	('transient depolarization', 'MPA', (121, 145))
110974	32484822	Microarray GEP datasets of normal breast epithelium from reduction mammoplasty individuals were obtained from GSE10797 (n = 5), GSE9574 (n = 15) and GSE20437 (n = 18), while microarray GEP datasets of breast cancer patients were obtained from GSE54002 (n = 417), GSE20685 (n = 327) and GSE23720 (n = 197) available on the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/).	('GSE23720', 'Var', (286, 294))	('patients', 'Species', '9606', (215, 223))	('GSE9574', 'Var', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (201, 214))	('GSE10797', 'Var', (110, 118))	('GSE20437', 'Var', (149, 157))
110977	32484822	50%) was used as the cut-off, and the group of patients with >=50% TRPM4 frequency was compared with patients harboring <50% TRPM4 frequency.	('frequency', 'Var', (73, 82))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (47, 55))	('>=50%', 'Var', (61, 66))	('TRPM4', 'Gene', (67, 72))
110986	32484822	Half of the NBT cases (n = 5/10; 50%) were negative for TRPM4 (Fig 4B and 4C), and TRPM4 protein was significantly overexpressed in breast cancers (n = 83/99 TRPM4+; 83.8%) compared with normal breast ducts (n = 5/10 TRPM4+; 50%) (p = 0.022).	('TRPM4+', 'Var', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('overexpressed', 'PosReg', (115, 128))	('TRPM4', 'Gene', (83, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (132, 146))	('protein', 'Protein', (89, 96))	('breast cancers', 'Disease', 'MESH:D001943', (132, 146))	('breast cancers', 'Disease', (132, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('negative', 'NegReg', (43, 51))
111004	32484822	GSE10797 n = 5, and GSE20437 n = 18) consisting of Oxidative Phosphorylation (Hallmark ID: M5936), Adipogenesis (M5905), Fatty Acid Metabolism (M5935) and DNA Repair (M5898) gene sets (Fig 5).	('Fatty Acid', 'Chemical', 'MESH:D005227', (121, 131))	('Fatty', 'MPA', (121, 126))	('Oxidative Phosphorylation', 'MPA', (51, 76))	('M5905', 'Var', (113, 118))	('GSE20437', 'Var', (20, 28))	('M5935', 'Var', (144, 149))	('Adipogenesis', 'MPA', (99, 111))	('M5936', 'Var', (91, 96))
111007	32484822	One consensus gene set positively associated with TRPM4 transcript expression was shared in GSE20685 (n = 327) and GSE23720 (n = 197) series of breast cancer cases as demonstrated in the Venn diagram of Fig 6.	('TRPM4', 'Gene', (50, 55))	('associated', 'Reg', (34, 44))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('GSE23720', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('positively', 'PosReg', (23, 33))	('transcript expression', 'MPA', (56, 77))	('rat', 'Species', '10116', (174, 177))
111014	32484822	Both the anti-TRPM4 (HPA041169) and anti-AR (CAB065764) antibodies used for IHC received the "Enhanced" validation score by HPA whereby IHC staining with the antibodies corresponded with mRNA expression levels across 37 normal tissues by HPA.	('mRNA expression levels', 'MPA', (187, 209))	('CAB065764', 'Var', (45, 54))	('HPA', 'Disease', 'MESH:D010661', (21, 24))	('HPA', 'Disease', (21, 24))	('HPA', 'Disease', 'MESH:D010661', (124, 127))	('AR', 'Gene', '367', (41, 43))	('HPA', 'Disease', 'MESH:D010661', (238, 241))	('HPA', 'Disease', (238, 241))	('HPA', 'Disease', (124, 127))
111032	32484822	Moreover, colorectal cancer cell clones with TRPM4 knockout showed decreased migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('invasion', 'CPA', (91, 99))	('rat', 'Species', '10116', (80, 83))	('colorectal cancer', 'Disease', (10, 27))	('TRPM4', 'Gene', (45, 50))	('knockout', 'Var', (51, 59))	('decreased', 'NegReg', (67, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
111035	32484822	This observation is in line with those observed in other cancers pertaining to TRPM4 and EMT as follows: (1) Independent studies have shown that TRPM4 knockdown could suppress migration and invasion of prostate cancer cells through reduction of EMT.	('invasion of prostate cancer', 'Disease', 'MESH:D011471', (190, 217))	('prostate cancer', 'Phenotype', 'HP:0012125', (202, 217))	('migration', 'CPA', (176, 185))	('invasion of prostate cancer', 'Disease', (190, 217))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('reduction', 'NegReg', (232, 241))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('EMT', 'CPA', (245, 248))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TRPM4', 'Gene', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('rat', 'Species', '10116', (179, 182))	('suppress', 'NegReg', (167, 175))	('knockdown', 'Var', (151, 160))
111059	32484822	Small molecule inhibitors of TRPM4 include the most commonly investigated TRPM4 inhibitor 9-phenanthrol (a phenanthrene derivative) but the compound lacks specificity as it also targets the Ca2+-activated Cl- channel TMEM16A in arterial myocytes, or the recently identified specific and potent TRPM4 inhibitor aryloxyacyl-anthranilic 5 (termed as compound 5) with approximately 20 times stronger TRPM4 inhibition than 9-phenanthrol.	('TMEM16A', 'Gene', '55107', (217, 224))	('TRPM4', 'Gene', (294, 299))	('9-phenanthrol', 'Chemical', 'MESH:C091375', (90, 103))	('aryloxyacyl-anthranilic 5', 'Chemical', '-', (310, 335))	('TRPM4', 'Gene', (396, 401))	('aryloxyacyl-anthranilic', 'Var', (310, 333))	('Ca2+', 'Chemical', 'MESH:D000069285', (190, 194))	('TMEM16A', 'Gene', (217, 224))	('phenanthrene', 'Chemical', 'MESH:C031181', (107, 119))	('inhibition', 'NegReg', (402, 412))	('9-phenanthrol', 'Chemical', 'MESH:C091375', (418, 431))
111065	32484822	These findings support future experimental investigations on TRPM4 inhibitors in the destruction of breast cancer cells, and their potential inhibitory effects on ER signaling cascade and EMT phenotypes.	('inhibitors', 'Var', (67, 77))	('TRPM4', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ER', 'Gene', '2099', (163, 165))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))
111075	31065110	The frequency of HER2 positivity in DCIS is comparable to IBC- and HER2-positive DCIS is associated with features of poor prognosis.	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', (17, 21))	('HER2', 'Gene', '2064', (67, 71))	('HER2', 'Gene', '2064', (17, 21))	('positivity', 'Var', (22, 32))
111089	31065110	Some studies report an even higher proportion of HER2 positivity in microinvasive cancer and, in preoperative tumour biopsies displaying DCIS, HER2 over-expression has been related to increased incidence of invasive carcinoma in the surgical specimen.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('invasive carcinoma', 'Disease', 'MESH:D009361', (207, 225))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('over-expression', 'PosReg', (148, 163))	('HER2', 'Gene', (143, 147))	('invasive carcinoma', 'Disease', (207, 225))	('microinvasive cancer', 'Disease', 'MESH:D009369', (68, 88))	('HER2', 'Gene', '2064', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('HER2', 'Gene', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('microinvasive cancer', 'Disease', (68, 88))	('HER2', 'Gene', '2064', (49, 53))	('tumour', 'Disease', (110, 116))	('positivity', 'Var', (54, 64))
111090	31065110	Furthermore, HER2 positivity is associated with high-histopathological grade both in invasive cancer and in DCIS.	('invasive cancer', 'Disease', (85, 100))	('DCIS', 'Disease', (108, 112))	('invasive cancer', 'Disease', 'MESH:D009362', (85, 100))	('HER2', 'Gene', '2064', (13, 17))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (32, 42))
111110	31065110	Nuclear staining was scored for ER, PR and Ki67 and membrane staining for HER2.	('HER2', 'Gene', '2064', (74, 78))	('Ki67', 'Var', (43, 47))	('HER2', 'Gene', (74, 78))
111117	31065110	Chromosome 17 (represented by the red signals) was used as an internal control particularly in the low HER2 gene copy number cases as per the recommended protocol.	('HER2', 'Gene', (103, 107))	('low', 'Var', (99, 102))	('HER2', 'Gene', '2064', (103, 107))
111126	31065110	All 3+ cases showed HER2 amplification with CISH.	('CISH', 'Disease', (44, 48))	('CISH', 'Chemical', '-', (44, 48))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))
111128	31065110	CISH confirmed high-copy number of HER2 gene in all IHC 3+ cases.	('HER2', 'Gene', '2064', (35, 39))	('CISH', 'Chemical', '-', (0, 4))	('HER2', 'Gene', (35, 39))	('high-copy number', 'Var', (15, 31))
111134	31065110	In pure DCIS, HER2 positivity was associated with larger tumour size, high-nuclear grade, comedo type DCIS, negative hormone receptor status, high-Ki67 proliferation index and abnormal expression of p53 (all p < 0.0001).	('HER2', 'Gene', '2064', (14, 18))	('positivity', 'Var', (19, 29))	('high-Ki67 proliferation index', 'CPA', (142, 171))	('p53', 'Gene', (199, 202))	('tumour', 'Disease', (57, 63))	('comedo type DCIS', 'Disease', (90, 106))	('expression', 'MPA', (185, 195))	('p53', 'Gene', '7157', (199, 202))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('pure DCIS', 'Disease', (3, 12))	('larger', 'PosReg', (50, 56))	('abnormal', 'Var', (176, 184))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('comedo', 'Phenotype', 'HP:0025249', (90, 96))	('HER2', 'Gene', (14, 18))	('high-nuclear grade', 'CPA', (70, 88))
111152	31065110	The 26.5% (26/98) IHC-equivocal/HER2 non-amplified tumours in this study, all of which had 2+ IHC scores, is higher than the result obtained by other studies on invasive tumours.	('non-amplified', 'Var', (37, 50))	('HER2', 'Gene', (32, 36))	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Disease', (170, 177))	('invasive tumours', 'Disease', (161, 177))	('HER2', 'Gene', '2064', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('invasive tumours', 'Disease', 'MESH:D009361', (161, 177))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))	('tumours', 'Disease', (51, 58))
111166	31065110	HER2-positive DCIS was associated with predictors of local recurrence like larger tumour size, high-nuclear grade, comedo type DCIS, negative-hormone receptor status and high-Ki67 proliferation index, which was consistent with other studies.	('local recurrence', 'CPA', (53, 69))	('negative-hormone receptor', 'CPA', (133, 158))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('DCIS', 'Disease', (14, 18))	('comedo', 'Disease', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('high-Ki67', 'Var', (170, 179))	('high-nuclear grade', 'CPA', (95, 113))	('tumour', 'Disease', (82, 88))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('comedo', 'Phenotype', 'HP:0025249', (115, 121))
111167	31065110	Local recurrence (invasive or DCIS) was associated with higher-grade, comedo necrosis and margin status.	('necrosis', 'Disease', 'MESH:D009336', (77, 85))	('Local recurrence', 'CPA', (0, 16))	('invasive', 'Disease', (18, 26))	('margin status', 'Var', (90, 103))	('comedo', 'Phenotype', 'HP:0025249', (70, 76))	('necrosis', 'Disease', (77, 85))
111168	31065110	DCIS local recurrence was associated with HER2 positivity and invasive local recurrence was associated with tumour size.	('tumour', 'Disease', (108, 114))	('DCIS', 'Disease', (0, 4))	('invasive local recurrence', 'CPA', (62, 87))	('HER2', 'Gene', '2064', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('HER2', 'Gene', (42, 46))	('positivity', 'Var', (47, 57))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
111170	31065110	DCIS patients with HER2 amplification had higher nuclear grade lesions and therefore are probably at risk of relapse more frequently than the HER2 unamplified group, but the prognostic role of HER2 over-expression in DCIS is still not fully clarified.	('DCIS', 'Disease', (0, 4))	('nuclear grade lesions', 'MPA', (49, 70))	('HER2', 'Gene', (142, 146))	('HER2', 'Gene', (193, 197))	('patients', 'Species', '9606', (5, 13))	('HER2', 'Gene', (19, 23))	('HER2', 'Gene', '2064', (142, 146))	('HER2', 'Gene', '2064', (193, 197))	('HER2', 'Gene', '2064', (19, 23))	('higher', 'PosReg', (42, 48))	('amplification', 'Var', (24, 37))
111171	31065110	Some studies suggest that patients with HER2 amplified DCIS are more frequently high-nuclear grade and this aspect is related to an increased risk of relapse.	('high-nuclear', 'Var', (80, 92))	('HER2', 'Gene', (40, 44))	('amplified', 'Var', (45, 54))	('HER2', 'Gene', '2064', (40, 44))	('patients', 'Species', '9606', (26, 34))
111173	31065110	In the current study, HER2 amplification was more frequent in the pure DCIS cohort (20%) than in the mixed DCIS (15%) despite the more prevalent higher-grade DCIS in the mixed cases.	('HER2', 'Gene', (22, 26))	('higher-grade DCIS', 'Disease', (145, 162))	('HER2', 'Gene', '2064', (22, 26))	('pure DCIS', 'Disease', (66, 75))	('amplification', 'Var', (27, 40))
111174	31065110	HER2 positivity alone was not predictive of recurrence as a whole or as invasive disease but showed a trend to DCIS recurrence.	('positivity', 'Var', (5, 15))	('invasive disease', 'Disease', 'MESH:D009361', (72, 88))	('invasive disease', 'Disease', (72, 88))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
111175	31065110	This result is consistent with our observation that HER2 positive DCIS tend to extend within the ductal system and even in the epidermis (Paget's disease) than associated with invasive disease.	('positive', 'Var', (57, 65))	("Paget's disease", 'Disease', (138, 153))	('HER2', 'Gene', '2064', (52, 56))	("Paget's disease", 'Disease', 'MESH:C538098', (138, 153))	('invasive disease', 'Disease', (176, 192))	('invasive disease', 'Disease', 'MESH:D009361', (176, 192))	('HER2', 'Gene', (52, 56))
111179	31065110	HER2/Ki67 positivity was a predictor of recurrence, independent of other studied clinicopathological parameters such as nuclear grade and presence of comedo necrosis.	('necrosis', 'Disease', 'MESH:D009336', (157, 165))	('positivity', 'Var', (10, 20))	('comedo', 'Phenotype', 'HP:0025249', (150, 156))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('recurrence', 'Disease', (40, 50))	('necrosis', 'Disease', (157, 165))
111185	31065110	Similarly, other studies have observed that HER2 positivity is often in patients with pure DCIS compared to those with microinvasive or invasive carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('invasive carcinoma', 'Disease', 'MESH:D009361', (136, 154))	('positivity', 'Var', (49, 59))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (44, 48))	('pure DCIS', 'Disease', (86, 95))	('invasive carcinoma', 'Disease', (136, 154))	('patients', 'Species', '9606', (72, 80))
111194	31065110	As HER2 status is not currently routinely measured in clinical practice, we aimed to show statistically significant correlations between the development of local recurrence as well as poor prognostic pathologic factors and HER2 positive DCIS which could alert clinicians.	('HER2', 'Gene', '2064', (3, 7))	('HER2', 'Gene', '2064', (223, 227))	('positive DCIS', 'Var', (228, 241))	('HER2', 'Gene', (223, 227))	('HER2', 'Gene', (3, 7))
111197	31065110	To conclude, the frequency of HER2 positivity, driven by gene amplification, in DCIS is comparable to IBC and in combination with Ki67, is an independent predictor of recurrence.	('HER2', 'Gene', '2064', (30, 34))	('HER2', 'Gene', (30, 34))	('positivity', 'Var', (35, 45))
111205	30306389	Although only a small subset of DCIS lesions are predicted to progress into a breast cancer, distinguishing innocuous from minacious DCIS lesions remains a clinical challenge.	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('lesions', 'Var', (37, 44))	('DCIS', 'Disease', (32, 36))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
111218	30306389	Herein we will review how epigenetic modifications may be critical to driving early stage breast lesions to invasive carcinomas.	('epigenetic modifications', 'Var', (26, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('breast lesions', 'Disease', (90, 104))	('invasive carcinomas', 'Disease', 'MESH:D009361', (108, 127))	('invasive carcinomas', 'Disease', (108, 127))
111221	30306389	Dense methylation of CpG islands functionally silences the associated promoter and represses transcription by blocking transcription factor binding and recruiting chromatin remodeling complexes such as histone deacetylases (HDACs) or polycomb repressive complexes (PRC).	('HDAC', 'Gene', '9734', (224, 228))	('polycomb', 'Gene', (234, 242))	('binding', 'Interaction', (140, 147))	('transcription', 'MPA', (119, 132))	('promoter', 'MPA', (70, 78))	('represses', 'NegReg', (83, 92))	('blocking', 'NegReg', (110, 118))	('transcription', 'MPA', (93, 106))	('Dense methylation', 'Var', (0, 17))	('polycomb', 'Gene', '12416', (234, 242))	('silences', 'NegReg', (46, 54))	('HDAC', 'Gene', (224, 228))	('recruiting', 'PosReg', (152, 162))
111224	30306389	While hypomethylation is a general characteristic of many cancers, including breast, a number of individual genes become hypermethylated.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('hypomethylation', 'Var', (6, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('breast', 'Disease', (77, 83))
111231	30306389	identified 15 loci differentially methylated between matched IDC and normal tissue.	('methylated', 'Var', (34, 44))	('IDC', 'Gene', '4000', (61, 64))	('IDC', 'Gene', (61, 64))
111238	30306389	evaluated methylation status in nine putative tumor supressor genes in synchronous preinvasive (either ADH or DCIS) and IDC lesions as well as pure IDC and normal tissue samples.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('IDC', 'Gene', '4000', (120, 123))	('tumor', 'Disease', (46, 51))	('IDC', 'Gene', (120, 123))	('IDC', 'Gene', '4000', (148, 151))	('IDC', 'Gene', (148, 151))	('methylation status', 'Var', (10, 28))
111240	30306389	From these studies and more a model is emerging wherein epigenetic DNA methylation changes are an early event in breast cancer occuring prior to development of invasive growth.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('epigenetic DNA methylation changes', 'Var', (56, 90))
111249	30306389	HOTAIR (HOX transcript antisense RNA) epigenetically silences genes through redirecting the polycomb repressive complex 2 (PRC2) to many loci including the HOXD cluster thus suggesting one potential mechanism by which both homeobox genes and PRC2 targets may be effected.	('polycomb', 'Gene', (92, 100))	('HOTAIR', 'Gene', '100124700', (0, 6))	('epigenetically', 'Var', (38, 52))	('polycomb', 'Gene', '12416', (92, 100))	('redirecting', 'Reg', (76, 87))	('genes', 'Gene', (62, 67))	('HOX transcript antisense RNA', 'Gene', (8, 36))	('HOTAIR', 'Gene', (0, 6))	('HOX transcript antisense RNA', 'Gene', '100124700', (8, 36))	('silences', 'NegReg', (53, 61))
111262	30306389	DNA methylation clearly plays a role in early breast cancer progression, with the majority of changes occuring between normal and even the earliest atypical lesions.	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
111272	30306389	interrogated the relationship between EZH2 expression and clinical outcomes and found elevated EZH2 to be associated with a more aggressive breast cancer and shorter metastasis, disease free, and overall survival.	('shorter', 'NegReg', (158, 165))	('disease free', 'CPA', (178, 190))	('EZH2', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (106, 116))	('EZH2', 'Gene', '2146', (38, 42))	('elevated', 'Var', (86, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('EZH2', 'Gene', (38, 42))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (129, 153))	('overall survival', 'CPA', (196, 212))	('aggressive breast cancer', 'Disease', (129, 153))	('EZH2', 'Gene', '2146', (95, 99))
111273	30306389	Furthermore, exogenous expression of EZH2 in normal immortalized H16N2 cells increased anchorage independent growth and invasion.	('invasion', 'CPA', (120, 128))	('anchorage independent growth', 'CPA', (87, 115))	('increased', 'PosReg', (77, 86))	('EZH2', 'Gene', '2146', (37, 41))	('H16N2', 'CellLine', 'CVCL:J086', (65, 70))	('exogenous', 'Var', (13, 22))	('EZH2', 'Gene', (37, 41))
111284	30306389	Following the discovery of HDACs in 1996, the HDAC inhibitors that followed were found to attenuate cell proliferation, induce differentiation of both normal and breast cancer cell lines, and regulate expression of cell cycle genes.	('HDAC', 'Gene', '9734', (27, 31))	('induce', 'PosReg', (120, 126))	('HDAC', 'Gene', (46, 50))	('regulate', 'Reg', (192, 200))	('HDAC', 'Gene', '9734', (46, 50))	('cell cycle genes', 'Gene', (215, 231))	('attenuate', 'NegReg', (90, 99))	('cell proliferation', 'CPA', (100, 118))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('expression', 'MPA', (201, 211))	('breast cancer', 'Disease', (162, 175))	('inhibitors', 'Var', (51, 61))	('HDAC', 'Gene', (27, 31))	('differentiation', 'CPA', (127, 142))
111294	30306389	The majority of histone modification studies have been performed on invasive disease where many groups have found specific modifications, and associated proteins, differ based on breast cancer subtype and can correlate with tumor phenotypes and clinical outcomes.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('correlate', 'Reg', (209, 218))	('differ', 'Reg', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (224, 229))	('breast cancer', 'Disease', (179, 192))	('invasive disease', 'Disease', 'MESH:D009362', (68, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('modifications', 'Var', (123, 136))	('invasive disease', 'Disease', (68, 84))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
111295	30306389	used 880 well-characterized breast carcinomas to perform tissue microarrays for a number of epigenetic marks.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('breast carcinomas', 'Disease', 'MESH:D001943', (28, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('breast carcinomas', 'Disease', (28, 45))	('epigenetic', 'Var', (92, 102))	('breast carcinomas', 'Phenotype', 'HP:0003002', (28, 45))
111298	30306389	found no correlation between HDAC1 and overall survival using univariate analysis, however high HDAC1 expression was positively correlated with overall survival in ER+ patients.	('HDAC1', 'Gene', (29, 34))	('HDAC1', 'Gene', '3065', (96, 101))	('correlated', 'Reg', (128, 138))	('expression', 'MPA', (102, 112))	('high', 'Var', (91, 95))	('HDAC1', 'Gene', '3065', (29, 34))	('ER+', 'Disease', (164, 167))	('HDAC1', 'Gene', (96, 101))	('patients', 'Species', '9606', (168, 176))	('overall survival', 'MPA', (144, 160))
111299	30306389	also found patients with high HDAC1 expression had better patient outcomes, expression was not an independent prognostic indicator for overall or disease free survival.	('HDAC1', 'Gene', (30, 35))	('patient', 'Species', '9606', (58, 65))	('expression', 'Var', (36, 46))	('high', 'Var', (25, 29))	('better', 'PosReg', (51, 57))	('patient outcomes', 'CPA', (58, 74))	('patient', 'Species', '9606', (11, 18))	('HDAC1', 'Gene', '3065', (30, 35))	('patients', 'Species', '9606', (11, 19))
111303	30306389	These elements are identified by regions of DNase1 hypersensitivity, demonstrating open chromatin confirmation, associated protein binding (CTCF, Med1, CBP300), and histone modification (H3K4me1, H3K27ac).	('CTCF', 'Gene', (140, 144))	('DNase1', 'Gene', '1773', (44, 50))	('H3K27ac', 'Var', (196, 203))	('DNase1', 'Gene', (44, 50))	('Med1', 'Gene', (146, 150))	('H3K4me1', 'Var', (187, 194))	('CTCF', 'Gene', '10664', (140, 144))	('Med1', 'Gene', '5469', (146, 150))	('hypersensitivity,', 'Disease', 'MESH:D004342', (51, 68))	('histone', 'Reg', (165, 172))
111306	30306389	To ask this question the authors examined normal mammary epithelia compared to the ER+ MCF7 cell line through ChIP-seq for H3K27ac and found an active super-enhancer at the estrogen receptor (ESR1) locus only in the MCF7 cells.	('H3K27ac', 'Var', (123, 130))	('ESR1', 'Gene', (192, 196))	('MCF7', 'CellLine', 'CVCL:0031', (87, 91))	('ESR1', 'Gene', '2099', (192, 196))	('MCF7', 'CellLine', 'CVCL:0031', (216, 220))
111321	30306389	Loss of RACK7, or KDM5C, results in loss of H3K4me1, gain of H3K4me3, and increased transcription of associated enhancer targeted genes, including the S100A oncogenes.	('H3K4me1', 'Protein', (44, 51))	('loss', 'NegReg', (36, 40))	('S100A', 'SUBSTITUTION', 'None', (151, 156))	('increased', 'PosReg', (74, 83))	('RACK7', 'Gene', '23613', (8, 13))	('S100A', 'Var', (151, 156))	('KDM5C', 'Gene', (18, 23))	('RACK7', 'Gene', (8, 13))	('transcription', 'MPA', (84, 97))	('gain', 'PosReg', (53, 57))	('enhancer', 'PosReg', (112, 120))	('KDM5C', 'Gene', '8242', (18, 23))	('Loss', 'Var', (0, 4))	('H3K4me3', 'Protein', (61, 68))
111322	30306389	RACK7 knockout drives tumorigenic phenotypes including increased soft agar growth, invasion, migration, and tumor volume in mammary fat pad xenograft models, suggesting RACK7 functions as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RACK7', 'Gene', '23613', (169, 174))	('migration', 'CPA', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('increased', 'PosReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('soft agar growth', 'CPA', (65, 81))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (190, 195))	('invasion', 'CPA', (83, 91))	('RACK7', 'Gene', (169, 174))	('tumor', 'Disease', (22, 27))	('knockout', 'Var', (6, 14))	('RACK7', 'Gene', '23613', (0, 5))	('RACK7', 'Gene', (0, 5))
111324	30306389	While these observations need to be further validated on a larger patient cohort, together these data suggest that epigenetic chromatin remodeling and enhancer activation as a critical step in the transition to invasive disease.	('epigenetic', 'Var', (115, 125))	('invasive disease', 'Disease', 'MESH:D009362', (211, 227))	('invasive disease', 'Disease', (211, 227))	('patient', 'Species', '9606', (66, 73))
111329	30306389	Dysregulation of miRNAs have been found to influence several aspects of tumorigenesis including differentiation, tumor initiation, and metastasis.	('tumor', 'Disease', (113, 118))	('metastasis', 'CPA', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('differentiation', 'CPA', (96, 111))	('influence', 'Reg', (43, 52))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (72, 77))	('miRNAs', 'Protein', (17, 23))	('tumor initiation', 'Disease', 'MESH:D009369', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor initiation', 'Disease', (113, 129))
111332	30306389	Despite the global trend, specific miRNAs have been found to function as tumor suppressors or oncogenes which can be enriched in tumor over normal.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (129, 134))	('miRNAs', 'Var', (35, 41))
111337	30306389	profiled miRNA expression from 80 IDC, 8 DCIS and 6 normal mammary epithelial samples and found 66 miRNAs differentially expressed between normal and DCIS and only 9 altered in the DCIS to IDC transition (increased let-7d, miR-181a, miR-210, miR-221 decreased miR-10b, miR-126, miR-143, miR-218, miR-335-5p).	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('miR-10b', 'Gene', (260, 267))	('let-7d', 'Gene', '406886', (215, 221))	('miR-126', 'Gene', '406913', (269, 276))	('miR-210', 'Gene', '406992', (233, 240))	('miR-21', 'Gene', '406991', (233, 239))	('miR-10b', 'Gene', '406903', (260, 267))	('miR-335', 'Gene', (296, 303))	('miR-21', 'Gene', '406991', (287, 293))	('let-7d', 'Gene', (215, 221))	('IDC', 'Gene', '4000', (189, 192))	('miR-210', 'Gene', (233, 240))	('IDC', 'Gene', (189, 192))	('miR-21', 'Gene', (233, 239))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('miR-221', 'Gene', (242, 249))	('miR-126', 'Gene', (269, 276))	('miR-21', 'Gene', (287, 293))	('miR-143', 'Gene', '406935', (278, 285))	('miR-143', 'Gene', (278, 285))	('miR-221', 'Gene', '407006', (242, 249))	('miR-181a', 'Var', (223, 231))	('IDC', 'Gene', '4000', (34, 37))	('miR-335', 'Gene', '442904', (296, 303))	('IDC', 'Gene', (34, 37))	('decreased', 'NegReg', (250, 259))
111342	30306389	HOTAIR expression is known to be elevated in primary breast tumors and depletion can inhibit tumor invasiveness.	('HOTAIR', 'Gene', '100124700', (0, 6))	('tumor invasiveness', 'Disease', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('elevated', 'PosReg', (33, 41))	('depletion', 'Var', (71, 80))	('breast tumors', 'Disease', 'MESH:D001943', (53, 66))	('breast tumors', 'Disease', (53, 66))	('expression', 'MPA', (7, 17))	('inhibit', 'NegReg', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor invasiveness', 'Disease', 'MESH:D009369', (93, 111))	('HOTAIR', 'Gene', (0, 6))	('breast tumors', 'Phenotype', 'HP:0100013', (53, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
111354	30306389	Attenuation of NKILA in invasive disease enhances Nf-kB signaling and correlates with poor patient prognosis.	('Nf-kB signaling', 'MPA', (50, 65))	('invasive disease', 'Disease', (24, 40))	('Attenuation', 'Var', (0, 11))	('invasive disease', 'Disease', 'MESH:D009362', (24, 40))	('enhances', 'PosReg', (41, 49))	('patient', 'Species', '9606', (91, 98))	('NKILA', 'Gene', (15, 20))
111362	30306389	As with proteomic and transcriptomic studies, the majority of epigenetic changes are found as early events, existing even in the earliest pre-cursor lesions, with far fewer alterations between DCIS and IDC.	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('IDC', 'Gene', (202, 205))	('epigenetic changes', 'Var', (62, 80))	('IDC', 'Gene', '4000', (202, 205))
111369	30306389	To that end, epigenetic targeted therapeutics, such as BET inhibitors may find a place in early treatment of more aggressive DCIS.	('BET', 'Gene', (55, 58))	('epigenetic targeted', 'Var', (13, 32))	('more aggressive DCIS', 'Disease', (109, 129))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('BET', 'Gene', '92737', (55, 58))
111424	31472981	The pattern of mutations in DCIS appears to be identical to that in invasive carcinomas with high frequency mutations in PI3K and p53.	('invasive carcinomas', 'Disease', (68, 87))	('invasive carcinomas', 'Disease', 'MESH:D009361', (68, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('mutations', 'Var', (108, 117))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('p53', 'Gene', (130, 133))	('PI3K', 'Gene', (121, 125))	('DCIS', 'Gene', (28, 32))	('p53', 'Gene', '7157', (130, 133))
111428	31472981	Epigenetic events in tumour cells might be critical drivers for the progression.	('tumour', 'Disease', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('Epigenetic events', 'Var', (0, 17))
111480	14580250	The genomes of breast tumors are characterized by numerous chromosomal gains and losses (aneuploidy), as well as more localized regions of gene amplification and deletion.	('deletion', 'Var', (162, 170))	('breast tumor', 'Phenotype', 'HP:0100013', (15, 27))	('breast tumors', 'Disease', 'MESH:D001943', (15, 28))	('breast tumors', 'Phenotype', 'HP:0100013', (15, 28))	('breast tumors', 'Disease', (15, 28))	('aneuploidy', 'Disease', 'MESH:D000782', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('losses', 'NegReg', (81, 87))	('aneuploidy', 'Disease', (89, 99))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('numerous chromosomal gains', 'Disease', 'MESH:D015430', (50, 76))	('numerous chromosomal gains', 'Disease', (50, 76))
111486	14580250	The ratio of fluorescence along each chromosome provides a cytogenetic representation of DNA copy number changes in the tumor compared to normal sample.	('DNA', 'Gene', (89, 92))	('changes', 'Var', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
111492	14580250	Well-differentiated DCIS is characterized most frequently by loss of 16q and gain of 1q, while poorly differentiated DCIS displays localized amplifications, frequently involving 11q13 (CCND1) and 17q12 (ERBB2).	('CCND1', 'Gene', '595', (185, 190))	('Well-differentiated DCIS', 'Disease', (0, 24))	('16q', 'MPA', (69, 72))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('11q13', 'Var', (178, 183))	('ERBB2', 'Gene', '2064', (203, 208))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('ERBB2', 'Gene', (203, 208))	('CCND1', 'Gene', (185, 190))	('loss', 'NegReg', (61, 65))	('gain', 'PosReg', (77, 81))
111526	14580250	The basal-like group (ER-negative and without ERBB2 overexpression) contained high-grade tumors that were associated with high proliferation rates and 82% harbored mutations in the TP53 gene.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('TP53', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('harbored', 'Reg', (155, 163))	('ER', 'Gene', '2099', (22, 24))	('ERBB2', 'Gene', '2064', (46, 51))	('ER', 'Gene', '2099', (46, 48))	('mutations', 'Var', (164, 173))	('ERBB2', 'Gene', (46, 51))	('TP53', 'Gene', '7157', (181, 185))
111528	14580250	Olopade and Grushko suggest that tumors with BRCA1 mutations may be consistent with a basal-like pattern of gene expression because six out of seven tumors from patients with BRCA1 mutations stained positive for basal keratins and none showed ERBB2 overexpression.	('mutations', 'Var', (51, 60))	('BRCA1', 'Gene', '672', (45, 50))	('ERBB2', 'Gene', '2064', (243, 248))	('BRCA1', 'Gene', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('basal keratins', 'Protein', (212, 226))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('mutations', 'Var', (181, 190))	('BRCA1', 'Gene', '672', (175, 180))	('positive', 'Reg', (199, 207))	('BRCA1', 'Gene', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('patients', 'Species', '9606', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('ERBB2', 'Gene', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (33, 39))
111530	14580250	This is in contrast to tumors from patients with BRCA2 mutations that, in a limited number, appeared to have a luminal, ER-positive pattern.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('mutations', 'Var', (55, 64))	('BRCA2', 'Gene', '675', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ER', 'Gene', '2099', (120, 122))	('patients', 'Species', '9606', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('BRCA2', 'Gene', (49, 54))
111531	14580250	The findings of estrogen and progesterone receptor negativity, lack of ERBB2 overexpression, and overall higher grade in tumors from patients with BRCA1 mutations, compatible with a basal-like molecular phenotype, was confirmed by Lakhani and colleagues in a larger series of 217 patients with BRCA1 or BRCA2 mutations, comparing them to 103 patients with sporadic breast cancer.	('mutations', 'Var', (153, 162))	('patients', 'Species', '9606', (133, 141))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('estrogen', 'Protein', (16, 24))	('mutations', 'Var', (309, 318))	('BRCA1', 'Gene', '672', (147, 152))	('BRCA2', 'Gene', (303, 308))	('ERBB2', 'Gene', (71, 76))	('BRCA1', 'Gene', (147, 152))	('patients', 'Species', '9606', (280, 288))	('ERBB2', 'Gene', '2064', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('BRCA2', 'Gene', '675', (303, 308))	('BRCA1', 'Gene', '672', (294, 299))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (356, 378))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BRCA1', 'Gene', (294, 299))	('higher', 'PosReg', (105, 111))	('tumors', 'Disease', (121, 127))	('patients', 'Species', '9606', (342, 350))	('progesterone receptor', 'Gene', (29, 50))	('progesterone receptor', 'Gene', '5241', (29, 50))	('sporadic breast cancer', 'Disease', (356, 378))	('breast cancer', 'Phenotype', 'HP:0003002', (365, 378))
111532	14580250	They also found that breast cancers caused by BRCA2 mutations had immunohistochemical profiles similar to sporadic breast cancers, although they were more likely to be ERBB2 negative.	('sporadic breast cancers', 'Disease', (106, 129))	('breast cancers', 'Disease', 'MESH:D001943', (21, 35))	('breast cancers', 'Disease', (21, 35))	('ERBB2', 'Gene', (168, 173))	('breast cancers', 'Disease', 'MESH:D001943', (115, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('breast cancers', 'Phenotype', 'HP:0003002', (21, 35))	('BRCA2', 'Gene', (46, 51))	('breast cancers', 'Phenotype', 'HP:0003002', (115, 129))	('ERBB2', 'Gene', '2064', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (106, 129))	('BRCA2', 'Gene', '675', (46, 51))	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('caused', 'Reg', (36, 42))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
111576	14580250	Because basal-like invasive breast cancers overexpress epidermal growth factor receptor (EGFR) by immunostain and expression profiling [Jeffrey lab, unpublished data], EGFR antagonists may prove to be a useful chemo-prophylactic therapy for precursor lesions with a basal-like molecular profile or for women with BRCA1 mutations.	('BRCA1', 'Gene', '672', (313, 318))	('overexpress', 'PosReg', (43, 54))	('basal-like', 'Disease', (8, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('epidermal growth factor receptor', 'Gene', (55, 87))	('BRCA1', 'Gene', (313, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('invasive breast cancers', 'Disease', (19, 42))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('mutations', 'Var', (319, 328))	('invasive breast cancers', 'Disease', 'MESH:D001943', (19, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('women', 'Species', '9606', (302, 307))
111577	14580250	A lack of response to tamoxifen chemo-prophylaxis has been demonstrated in a small number of women with BRCA1 mutations, suggesting that agents useful in luminal precursor lesions do not impact basal-like lesions.	('basal-like lesions', 'CPA', (194, 212))	('tamoxifen', 'Chemical', 'MESH:D013629', (22, 31))	('mutations', 'Var', (110, 119))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA1', 'Gene', (104, 109))	('women', 'Species', '9606', (93, 98))
111580	14580250	Other questions remain: whether lesions of a particular molecular subtype always herald invasive and ultimately metastatic disease; and whether developing invasive disease would be unifocal or multifocal/multicentric, thereby influencing the type of prophylactic surgery (lumpectomy versus mastectomy for excision of diseased ducts before development of invasive cancer) and decisions regarding chemo-prophylaxis.	('influencing', 'Reg', (226, 237))	('invasive cancer', 'Disease', 'MESH:D009362', (354, 369))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('invasive disease', 'Disease', (155, 171))	('metastatic disease', 'CPA', (112, 130))	('invasive and', 'CPA', (88, 100))	('herald', 'Reg', (81, 87))	('invasive disease', 'Disease', 'MESH:D009362', (155, 171))	('lesions', 'Var', (32, 39))	('invasive cancer', 'Disease', (354, 369))
111676	30206177	Finally, a recent study in a KRasG12D model of lung cancer has shown that deregulated oncogenes in cancer cells like Myc trigger the transition of indolent lung adenomas to aggressive adenocarcinomas.	('trigger', 'Reg', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('lung adenomas to aggressive adenocarcinomas', 'Disease', 'MESH:D000236', (156, 199))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('deregulated', 'Var', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Myc', 'Gene', '4609', (117, 120))	('cancer', 'Disease', (99, 105))	('lung adenomas to aggressive adenocarcinomas', 'Disease', (156, 199))	('Myc', 'Gene', (117, 120))	('cancer', 'Disease', (52, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('oncogenes', 'Gene', (86, 95))
111677	30206177	This is because changes in Myc stimulated an increase in CCL9 and IL-23 expression by lung epithelial cells.	('CCL9', 'Chemical', '-', (57, 61))	('changes', 'Var', (16, 23))	('Myc', 'Gene', '4609', (27, 30))	('Myc', 'Gene', (27, 30))	('CCL9', 'Gene', (57, 61))	('expression', 'MPA', (72, 82))	('IL-23', 'Gene', '51561', (66, 71))	('IL-23', 'Gene', (66, 71))	('increase', 'PosReg', (45, 53))
111678	30206177	CCL9 then stimulated the accumulation of VEGFA+ macrophages (and thus tumor angiogenesis), and their PD-L1-dependent expulsion of T and B cells.	('CCL9', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PD-L1', 'Gene', '29126', (101, 106))	('CCL9', 'Var', (0, 4))	('tumor', 'Disease', (70, 75))	('VEGFA+', 'Protein', (41, 47))	('accumulation', 'PosReg', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('PD-L1', 'Gene', (101, 106))
111704	30206177	However, high nest TAMs also correlate with reduced overall and RFS in malignant melanomas, as well as breast and esophageal tumors (Table).	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('malignant melanomas', 'Phenotype', 'HP:0002861', (71, 90))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('malignant melanomas', 'Disease', 'MESH:D008545', (71, 90))	('nest TAMs', 'Protein', (14, 23))	('RFS', 'MPA', (64, 67))	('reduced', 'NegReg', (44, 51))	('malignant melanomas', 'Disease', (71, 90))	('breast and esophageal tumors', 'Disease', 'MESH:D001943', (103, 131))	('TAMs', 'Chemical', '-', (19, 23))	('esophageal tumors', 'Phenotype', 'HP:0100751', (114, 131))	('high', 'Var', (9, 13))
111708	30206177	Various studies have shown that blocking CD47 interrupts this 'don't-eat-me' signal and triggers cancer destruction by TAMs in mouse tumors, and high CD47 expression is associated with poor prognosis of bladder cancer, acute myeloid leukemia, non-Hodgkin's lymphoma, and breast cancer.	('TAMs', 'Chemical', '-', (119, 123))	("non-Hodgkin's lymphoma", 'Disease', (243, 265))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', (278, 284))	("'don't-eat-me' signal", 'MPA', (62, 83))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mouse', 'Species', '10090', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', (97, 103))	('CD47', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('acute myeloid leukemia', 'Disease', (219, 241))	('CD47', 'Protein', (41, 45))	('tumors', 'Disease', (133, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('bladder cancer', 'Disease', 'MESH:D001749', (203, 217))	('bladder cancer', 'Disease', (203, 217))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (247, 265))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (243, 265))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (219, 241))	('interrupts', 'NegReg', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (225, 241))	('breast cancer', 'Disease', 'MESH:D001943', (271, 284))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('leukemia', 'Phenotype', 'HP:0001909', (233, 241))	('cancer', 'Disease', (211, 217))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (243, 265))	('breast cancer', 'Disease', (271, 284))	('expression', 'MPA', (155, 165))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (219, 241))	('bladder cancer', 'Phenotype', 'HP:0009725', (203, 217))	('associated', 'Reg', (169, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (257, 265))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('high', 'Var', (145, 149))
111729	30206177	Interestingly, the frequency of TEMs has also been shown to positively correlate with MVD in some human tumor types (Table).	('TEMs', 'Var', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('MVD', 'Gene', (86, 89))	('human', 'Species', '9606', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('MVD', 'Gene', '4597', (86, 89))
111735	30206177	Their role in promoting metastasis is supported by the finding that high TMEM frequency correlates with increased risk of distant metastasis in ER+HER2- breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('high', 'Var', (68, 72))	('TMEM', 'Gene', (73, 77))	('distant metastasis', 'CPA', (122, 140))	('patients', 'Species', '9606', (167, 175))	('ER+HER2-', 'Var', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
111736	30206177	Interestingly, a recent study has shown that TMEMs containing TIE2+VEGFA+ PV TAMs are also present in pre-malignant lesions in a mouse model of HER2+ breast cancer and promote the early dissemination of cancer cells (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('HER2+', 'Var', (144, 149))	('TAMs', 'Chemical', '-', (77, 81))	('promote', 'PosReg', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', (157, 163))	('mouse', 'Species', '10090', (129, 134))	('TIE2+VEGFA+', 'Var', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
111737	30206177	PV TIE2+ TAMs have also been implicated in the relapse of primary mouse tumors after various forms of treatment.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PV TIE2+ TAMs', 'Var', (0, 13))	('implicated', 'Reg', (29, 39))	('mouse', 'Species', '10090', (66, 71))	('tumors', 'Disease', (72, 78))	('relapse', 'CPA', (47, 54))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('TAMs', 'Chemical', '-', (9, 13))
111777	30206177	As mentioned earlier, genetic changes taking place during early neoplasia can be 'sensed' by neighboring macrophages and trigger their tumor-promoting functions.	('trigger', 'Reg', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('neoplasia', 'Disease', (64, 73))	('genetic changes', 'Var', (22, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('neoplasia', 'Disease', 'MESH:D009369', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
111778	30206177	Activation of the oncogene, c-Myc, and mutations in the tumor suppressor gene, p53, in breast epithelial cells are prominent in high-grade DCIS, and regulate the function of macrophages in such in such preinvasive lesions.	('regulate', 'Reg', (149, 157))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('c-Myc', 'Gene', (28, 33))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (39, 48))	('function', 'MPA', (162, 170))	('Activation', 'PosReg', (0, 10))	('c-Myc', 'Gene', '4609', (28, 33))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('high-grade', 'Disease', (128, 138))
111827	28535496	High-grade DCIS was under-interpreted relative to the reference diagnosis for 14% (95% CI 12-16) of interpretations; only 3% (95% CI 2-4) of interpretations were over-interpreted as invasive carcinoma.	('invasive carcinoma', 'Disease', (182, 200))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('High-grade', 'Var', (0, 10))	('invasive carcinoma', 'Disease', 'MESH:D009361', (182, 200))
111830	28535496	Overall, reference low-grade DCIS cases exhibited extensive categorical diagnostic variation by pathologists within individual cases supporting the hypothesis that the inherent histopathological and morphological challenges in the diagnosis of low-grade DCIS are similar to the known challenges in diagnosing atypical ductal hyperplasia.	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (309, 336))	('DCIS', 'Phenotype', 'HP:0030075', (254, 258))	('atypical ductal hyperplasia', 'Disease', (309, 336))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('low-grade', 'Var', (244, 253))
111833	28535496	Our goal was to objectively evaluate from where on the spectrum of DCIS the majority of discordance stems and not necessarily endorse new classifications; however, we acknowledge that combining atypical hyperplasia and low grade DCIS improved categorical diagnostic agreement to 62%.	('improved', 'PosReg', (234, 242))	('hyperplasia', 'Disease', (203, 214))	('low grade', 'Var', (219, 228))	('hyperplasia', 'Disease', 'MESH:D006965', (203, 214))	('categorical diagnostic agreement', 'MPA', (243, 275))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
111840	28535496	In a natural history study, even low-grade DCIS was associated with subsequent invasive breast cancer in 39% of cases when the follow-up was extended to over four decades.	('invasive breast cancer', 'Disease', (79, 101))	('low-grade', 'Var', (33, 42))	('invasive breast cancer', 'Disease', 'MESH:D001943', (79, 101))	('DCIS', 'Disease', (43, 47))	('associated with', 'Reg', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
111853	26062614	HER2 positivity was related to large tumor size (P = 0.002), high grade (P < 0.001) and ER- and PR negativity (P < 0.001 for both).	('positivity', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('high grade', 'CPA', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('PR', 'Gene', '5241', (96, 98))
111856	26062614	The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P = 0.03, (HR) 0.60 (95 % CI 0.38-0.94)).	('positive DCIS', 'Var', (76, 89))	('IBCR', 'Chemical', '-', (12, 16))	('HER2', 'Gene', (71, 75))	('HER2', 'Gene', '2064', (71, 75))	('lower', 'NegReg', (49, 54))	('IBCR', 'Disease', (12, 16))	('HER2', 'Gene', (104, 108))	('HER2', 'Gene', '2064', (104, 108))
111857	26062614	In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P = 0.003), but not for women with ER positive DCIS.	('women', 'Species', '9606', (153, 158))	('lower', 'NegReg', (66, 71))	('women', 'Species', '9606', (91, 96))	('ER negative DCIS', 'Var', (102, 118))	('IBCR', 'Disease', (80, 84))	('positive DCIS', 'Var', (32, 45))	('HER2', 'Gene', (27, 31))	('IBCR', 'Chemical', '-', (80, 84))	('HER2', 'Gene', '2064', (27, 31))
111866	26062614	Some studies report an even higher proportion of HER2 positivity in micro-invasive cancer and, in pre-operative tumour biopsies displaying DCIS, HER2 over-expression has been related to a co-existing invasive component in the surgical specimen.	('HER2', 'Gene', (145, 149))	('invasive cancer', 'Disease', (74, 89))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('invasive component', 'Disease', (200, 218))	('HER2', 'Gene', '2064', (145, 149))	('tumour', 'Disease', (112, 118))	('invasive cancer', 'Disease', 'MESH:D009362', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HER2', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('over-expression', 'PosReg', (150, 165))	('HER2', 'Gene', '2064', (49, 53))	('positivity', 'Var', (54, 64))
111882	26062614	Gene amplification was assessed using the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria for single HER2 probe testing (diploid, 1 to 2.5 copies/nucleus; polysemy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/ nucleus; and high-level amplification >10 copies/nucleus) and for dual HER2/CHR17 probe testing (non-amplified ratio <1.8; equivocal ratio, 1.8 to 2.2; gene amplification, >2.2).	('HER2', 'Gene', '2064', (415, 419))	('HER2', 'Gene', '2064', (138, 142))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('HER2', 'Gene', (178, 182))	('HER2', 'Gene', (415, 419))	('polysemy', 'Var', (232, 240))	('HER2', 'Gene', (138, 142))	('HER2', 'Gene', '2064', (178, 182))
111911	26062614	In analyses assessing risk of recurrences according to established patient-and tumor characteristics, clinically detected DCIS were more prone to recur locally (HR 1.78 (1.04-3.07), larger DCIS lesions were correlated to a borderline significant increased risk of in situ IBEs but not invasive IBEs (HR 1.88 (0.97-3.62) and 0.64 (0.30-1.34)), respectively.	('lesions', 'Var', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('IBE', 'Chemical', '-', (294, 297))	('in situ IBEs', 'Disease', (264, 276))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('DCIS', 'Gene', (189, 193))	('IBE', 'Chemical', '-', (272, 275))	('patient', 'Species', '9606', (67, 74))
111913	26062614	HER2 positivity in the primary DCIS was not a risk factor for IBE in women undergoing BCS (Log-Rank P = 0.40, HR 1.20 (95 % CI, 0.78-1.85)), (Fig.	('positivity', 'Var', (5, 15))	('IBE', 'Disease', (62, 65))	('HER2', 'Gene', (0, 4))	('IBE', 'Chemical', '-', (62, 65))	('HER2', 'Gene', '2064', (0, 4))	('women', 'Species', '9606', (69, 74))
111914	26062614	Interestingly, divided by type of IBE, HER2 positivity showed a borderline statistically significant increased risk of in situ IBEs (Log-Rank P = 0.09, HR 1.63 (95 % CI, 0.92-2.89), and no association with risk of invasive IBEs (Log-Rank p = 0.48, HR 0.78 (95 % CI, 0.40-1.55)), (Fig.	('invasive IBEs', 'Disease', (214, 227))	('in situ IBEs', 'Disease', (119, 131))	('HER2', 'Gene', (39, 43))	('IBE', 'Chemical', '-', (127, 130))	('HER2', 'Gene', '2064', (39, 43))	('IBE', 'Chemical', '-', (34, 37))	('IBE', 'Chemical', '-', (223, 226))	('positivity', 'Var', (44, 54))
111916	26062614	The survival analyses were stratified for ER-status, and for patients with an ER negative DCIS, HER2 positivity predicted a significantly lower risk of IBCR (Log-Rank, P = 0.003), (Fig.	('IBCR', 'Chemical', '-', (152, 156))	('lower', 'NegReg', (138, 143))	('patients', 'Species', '9606', (61, 69))	('IBCR', 'Disease', (152, 156))	('HER2', 'Gene', (96, 100))	('positivity', 'Var', (101, 111))	('HER2', 'Gene', '2064', (96, 100))
111921	26062614	In contrast, for women who were older than 50 years of age at diagnosis, HER2 positivity was associated with a markedly improved recurrence-free survival for invasive disease (Log-Rank, P = 0.002), (Fig.	('improved', 'PosReg', (120, 128))	('HER2', 'Gene', '2064', (73, 77))	('positivity', 'Var', (78, 88))	('recurrence-free survival', 'CPA', (129, 153))	('invasive disease', 'Disease', (158, 174))	('invasive disease', 'Disease', 'MESH:D009362', (158, 174))	('women', 'Species', '9606', (17, 22))	('HER2', 'Gene', (73, 77))
111923	26062614	In this long-term follow-up DCIS cohort, positive HER2 status in the primary lesion predicted lower risk of late invasive breast cancer recurrence compared to negative HER2 status in the primary DCIS.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HER2', 'Gene', '2064', (168, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('HER2', 'Gene', (50, 54))	('positive', 'Var', (41, 49))	('HER2', 'Gene', '2064', (50, 54))	('late invasive breast cancer', 'Disease', 'MESH:D001943', (108, 135))	('late invasive breast cancer', 'Disease', (108, 135))	('lower', 'NegReg', (94, 99))	('HER2', 'Gene', (168, 172))	('status', 'Var', (55, 61))
111924	26062614	HER2 positivity did on the other hand indicate a non-significant higher risk of local in situ IBEs.	('positivity', 'Var', (5, 15))	('local in situ IBEs', 'Disease', (80, 98))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('IBE', 'Chemical', '-', (94, 97))
111940	26062614	The significantly reduced risk estimates for patients with HER2 positive DCIS might help identifying a low-risk group for whom adjuvant treatment after surgical excision could safely be omitted.	('reduced', 'NegReg', (18, 25))	('patients', 'Species', '9606', (45, 53))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', '2064', (59, 63))	('positive', 'Var', (64, 72))
112000	33194733	The summary receiver operating characteristic (SROC) curves and Fagan's nomograms were also plotted to determine the diagnostic values and predict the post-test probabilities of the ADC, D, D* and f values in obtaining a differential diagnosis of breast tumors.	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('ADC', 'Var', (182, 185))	('breast tumors', 'Phenotype', 'HP:0100013', (247, 260))	('ADC', 'Chemical', '-', (182, 185))	('breast tumors', 'Disease', 'MESH:D001943', (247, 260))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('breast tumors', 'Disease', (247, 260))
112030	33194733	Tumors with high Ki-67 expression had a lower D value than those with low Ki-67 expression (SMD = 0.26, P = 0.002).	('D value', 'MPA', (46, 53))	('high', 'Var', (12, 16))	('Ki-67', 'Gene', (17, 22))	('expression', 'Var', (23, 33))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('lower', 'NegReg', (40, 45))
112052	33194733	The pooled results also suggested that the D value improved the diagnostic performance with a slightly higher sensitivity, specificity, AUC, DOR and post-test probability than conventional ADC.	('ADC', 'Chemical', '-', (189, 192))	('improved', 'PosReg', (51, 59))	('AUC', 'MPA', (136, 139))	('D value', 'Var', (43, 50))	('higher', 'PosReg', (103, 109))	('diagnostic performance', 'MPA', (64, 86))
112062	33194733	It can promote tumor angiogenesis and lymphangiogenesis via regulation of vascular endothelial growth factor (VEGF) in breast cancer and therefore improve tumor perfusion.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('vascular endothelial growth factor', 'Gene', '7422', (74, 108))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('improve', 'PosReg', (147, 154))	('regulation', 'Var', (60, 70))	('breast cancer', 'Disease', (119, 132))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('VEGF', 'Gene', '7422', (110, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumor', 'Disease', (155, 160))	('promote', 'PosReg', (7, 14))	('tumor', 'Disease', (15, 20))	('vascular endothelial growth factor', 'Gene', (74, 108))	('VEGF', 'Gene', (110, 114))	('lymphangiogenesis', 'CPA', (38, 55))
112063	33194733	Our study also suggested that breast cancer with high Ki-67 expression has a significantly lower D value (P = 0.002) instead of ADC value (P = 0.27), which was mainly due to active proliferation and a higher cell density.	('lower', 'NegReg', (91, 96))	('ADC', 'Chemical', '-', (128, 131))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('active proliferation', 'CPA', (174, 194))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('high', 'Var', (49, 53))	('cell density', 'CPA', (208, 220))	('D value', 'MPA', (97, 104))	('Ki-67', 'Gene', (54, 59))	('higher', 'PosReg', (201, 207))
112085	30739992	As much as 50-60% of FA has been shown to harbor point mutations in codon 44 of exon 2 of mediator complex subunit 12 (MED12), , .	('MED12', 'Gene', '679693', (119, 124))	('point mutations in', 'Var', (49, 67))	('mediator complex subunit 12', 'Gene', (90, 117))	('MED12', 'Gene', (119, 124))	('mediator complex subunit 12', 'Gene', '679693', (90, 117))
112123	23217148	Furthermore, patients with high expression of Rab27B had inferior survival outcomes.	('inferior', 'NegReg', (57, 65))	('patients', 'Species', '9606', (13, 21))	('Rab27B', 'Gene', '5874', (46, 52))	('high expression', 'Var', (27, 42))	('Rab27B', 'Gene', (46, 52))	('survival outcomes', 'CPA', (66, 83))
112138	23217148	Also, the presence of Rab27B protein was observed to be associated with a low degree of differentiation and the presence of lymph node metastasis in ER-positive BC.	('ER', 'Gene', '2099', (149, 151))	('BC', 'Phenotype', 'HP:0003002', (161, 163))	('Rab27B', 'Gene', '5874', (22, 28))	('protein', 'Protein', (29, 36))	('presence', 'Var', (10, 18))	('Rab27B', 'Gene', (22, 28))
112193	23217148	Subset analysis showed that high Rab27B expression had a decreased survival time regardless of clinical stage, tumor size stage, and lymph node metastasis (P < 0.05, Figure 2B -2G).	('expression', 'MPA', (40, 50))	('survival time', 'CPA', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Rab27B', 'Gene', '5874', (33, 39))	('tumor', 'Disease', (111, 116))	('Rab27B', 'Gene', (33, 39))	('high', 'Var', (28, 32))	('decreased', 'NegReg', (57, 66))
112194	23217148	Cox regression proportional hazard analyses indicated that high expression of Rab27B was a significant risk factor for adverse DSS (hazard ratio, 8.661; 95% confidence interval [CI], 3.897-19.251, P < 0.001).	('Cox', 'Gene', '9377', (0, 3))	('DSS', 'Chemical', '-', (127, 130))	('Rab27B', 'Gene', (78, 84))	('Cox', 'Gene', (0, 3))	('adverse DSS', 'Disease', (119, 130))	('high expression', 'Var', (59, 74))	('Rab27B', 'Gene', '5874', (78, 84))
112240	31386197	Patients undergoing MRI were more likely to have a mastectomy, either as first surgical treatment or following breast-conserving surgery (BCS) in the event of positive margins (odds ratio (OR) 2 11, 95 per cent c.i.	('MRI', 'Var', (20, 23))	('Patients', 'Species', '9606', (0, 8))	('mastectomy', 'Disease', (51, 61))	('odds ratio (OR) 2 11', 'Gene', '81079', (177, 197))	('odds ratio (OR) 2 11', 'Gene', (177, 197))
112245	31386197	MRI was also associated with a significantly increased risk of final mastectomy (OR 2 11, 1 91 to 2 33).	('OR 2 11', 'Gene', '81079', (81, 88))	('final mastectomy', 'Disease', (63, 79))	('MRI', 'Var', (0, 3))	('OR 2 11', 'Gene', (81, 88))
112255	25858806	Depending on age at diagnosis, women diagnosed with DCIS are 3-13 times more likely to die from non-breast cancer related causes, such as cardiovascular disease, than from breast cancer.	('cardiovascular disease', 'Disease', (138, 160))	('non-breast cancer', 'Disease', 'MESH:D001943', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (138, 160))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('breast cancer', 'Disease', (172, 185))	('DCIS', 'Var', (52, 56))	('cardiovascular disease', 'Disease', 'MESH:D002318', (138, 160))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('non-breast cancer', 'Disease', (96, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('women', 'Species', '9606', (31, 36))
112278	25858806	Despite having an excellent prognosis, women with DCIS experience substantial reductions in health-related quality of life, comparable to women with localized invasive breast cancer.	('localized invasive breast cancer', 'Disease', (149, 181))	('localized invasive breast cancer', 'Disease', 'MESH:D001943', (149, 181))	('women', 'Species', '9606', (39, 44))	('DCIS', 'Var', (50, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('reductions', 'NegReg', (78, 88))	('women', 'Species', '9606', (138, 143))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('health-related quality of life', 'MPA', (92, 122))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
112279	25858806	In a separate cohort of women with DCIS, notable declines were observed in general health, vitality, and mental health at 9 and 18 months after diagnosis, compared to pre-diagnosis scores.	('declines', 'NegReg', (49, 57))	('vitality', 'CPA', (91, 99))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('mental health', 'CPA', (105, 118))	('general', 'MPA', (75, 82))	('women', 'Species', '9606', (24, 29))	('DCIS', 'Var', (35, 39))
112301	25858806	In the HEAL study, women with DCIS decreased their total physical activity levels by about 4% per week and their vigorous physical activity by 33% per week in the year following diagnosis.	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('women', 'Species', '9606', (19, 24))	('DCIS', 'Var', (30, 34))	('decreased', 'NegReg', (35, 44))	('vigorous physical activity', 'MPA', (113, 139))
112310	25858806	In the WISC cohort, weight gain was highest among women who received tamoxifen, yet substantial weight gain was also observed in women who had not.	('weight gain', 'Phenotype', 'HP:0004324', (20, 31))	('women', 'Species', '9606', (129, 134))	('women', 'Species', '9606', (50, 55))	('weight gain', 'Disease', 'MESH:D015430', (20, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (69, 78))	('weight gain', 'Disease', 'MESH:D015430', (96, 107))	('tamoxifen', 'Var', (69, 78))	('weight gain', 'Phenotype', 'HP:0004324', (96, 107))	('weight gain', 'Disease', (20, 31))	('weight gain', 'Disease', (96, 107))
112335	25858806	There are long established associations between physical inactivity and weight gain, smoking, and other health-related behaviors with a variety of health outcomes in the general population.	('weight gain', 'Disease', (72, 83))	('associations', 'Interaction', (27, 39))	('physical inactivity', 'Var', (48, 67))	('weight gain', 'Disease', 'MESH:D015430', (72, 83))	('weight gain', 'Phenotype', 'HP:0004324', (72, 83))
112337	25858806	Sedentary behavior and decreased physical activity have also been found to contribute to elevated risks of all-cause, CVD, and cancer mortality.	('physical activity', 'CPA', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CVD', 'Phenotype', 'HP:0001626', (118, 121))	('CVD', 'Disease', (118, 121))	('Sedentary behavior', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('decreased', 'NegReg', (23, 32))	('all-cause', 'Disease', (107, 116))
112338	25858806	Importantly, physical inactivity and sedentary behavior can lead to weight gain.	('physical inactivity', 'Var', (13, 32))	('weight gain', 'Disease', 'MESH:D015430', (68, 79))	('lead', 'Reg', (60, 64))	('weight gain', 'Phenotype', 'HP:0004324', (68, 79))	('weight gain', 'Disease', (68, 79))	('sedentary', 'Disease', (37, 46))
112339	25858806	Excess weight is associated with increased risk of multiple chronic diseases, including diabetes, hypertension, osteoarthritis, coronary heart disease, and cancer.	('coronary heart disease', 'Disease', (128, 150))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('hypertension', 'Disease', (98, 110))	('coronary heart disease', 'Disease', 'MESH:D003324', (128, 150))	('coronary heart disease', 'Phenotype', 'HP:0001677', (128, 150))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('osteoarthritis', 'Phenotype', 'HP:0002758', (112, 126))	('osteoarthritis', 'Disease', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('diabetes', 'Disease', (88, 96))	('osteoarthritis', 'Disease', 'MESH:D010003', (112, 126))	('diabetes', 'Disease', 'MESH:D003920', (88, 96))	('Excess weight', 'Var', (0, 13))
112390	30903856	In both women and men, the most common cause of a heritable increase in breast cancer susceptibility is due to pathogenic mutations in the BRCA genes associated with DNA repair.	('men', 'Species', '9606', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('women', 'Species', '9606', (8, 13))	('men', 'Species', '9606', (18, 21))	('increase', 'PosReg', (60, 68))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('BRCA', 'Gene', '672', (139, 143))	('mutations', 'Var', (122, 131))	('breast cancer', 'Disease', (72, 85))	('BRCA', 'Gene', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
112438	30903856	While there is no clear proof of causation, the conversion of male hormones to estrogens in the peripheral tissues can lead to a hyperestrogenic environment favorable to the development of estrogen dependent and sensitive tumors.	('estrogen dependent', 'MPA', (189, 207))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('lead to', 'Reg', (119, 126))	('conversion', 'Var', (48, 58))	('men', 'Species', '9606', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('hyperestrogenic environment', 'MPA', (129, 156))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('men', 'Species', '9606', (181, 184))
112443	11305954	Allelic loss on chromosome band 18p11.3 occurs early and reveals heterogeneity in breast cancer progression We examined the stage specificity and heterogeneity of 18p11 alterations in a series of tumors representing 96 microdissected samples.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('Allelic loss', 'Var', (0, 12))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
112446	11305954	These analyses suggest chromosome 18p11 alteration is a common and early event in breast disease.	('chromosome 18p11 alteration', 'Var', (23, 50))	('breast disease', 'Disease', (82, 96))	('breast disease', 'Disease', 'MESH:D001941', (82, 96))
112450	11305954	These results are analyzed in conjunction with other LOH data available for markers on 3p, 11p, 13q, 16p, 17p, and 17q in an effort to place chromosome 18p alterations on the breast cancer progression pathway.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('alterations', 'Var', (156, 167))
112454	11305954	Matching normal and tumor DNA were subjected to polymerase chain reaction (PCR)-based LOH analysis using two 18p11.3 markers (D18S59 and D18S481) and one 18p11.2 marker (D18S452).	('D18S452', 'Chemical', '-', (170, 177))	('D18S481', 'Var', (137, 144))	('D18S59', 'Var', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
112455	11305954	Forward primers were synthesized with either a fluorescent FAM tag (D18S481 and D18S452) or a fluorescent TET tag (D18S59) on the 5' end.	('D18S452', 'Chemical', '-', (80, 87))	('D18S452', 'Var', (80, 87))	('TET', 'Chemical', 'MESH:C010349', (106, 109))	('D18S481', 'Var', (68, 75))
112461	11305954	Four tumors (27%) were, however, interestingly identified with genetic heterogeneity for chromosome 18p events where DCIS-identified events were not found in associated invasive foci.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('chromosome 18p', 'Gene', (89, 103))	('events', 'Var', (104, 110))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
112465	11305954	It was discovered, by analyzing multiple foci occurring simultaneously within individual tumors, that chromosome 18p events occur at a significant frequency (56%) early in the tumorigenic process, making LOH at chromosome 18p one of the most common known events in DCIS tumors.	('tumors', 'Disease', (89, 95))	('LOH at chromosome', 'Var', (204, 221))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('DCIS tumors', 'Disease', (265, 276))	('DCIS tumors', 'Disease', 'MESH:D002285', (265, 276))	('tumors', 'Disease', (270, 276))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('DCIS', 'Phenotype', 'HP:0030075', (265, 269))	('tumor', 'Disease', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
112471	11305954	However, 37% of ductal hyperplasias and 42% of atypical ductal hyperplasias exhibit LOH, suggesting that these foci are benign lesions resulting from the alteration of tumor suppressor genes.	('LOH', 'Disease', (84, 87))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('alteration', 'Var', (154, 164))	('ductal hyperplasias', 'Disease', 'MESH:D002285', (56, 75))	('ductal hyperplasias', 'Disease', (56, 75))	('ductal hyperplasias', 'Disease', 'MESH:D002285', (16, 35))	('ductal hyperplasias', 'Disease', (16, 35))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
112475	11305954	An extensive analysis of markers on chromosome 11p15 showed LOH early in breast disease (DCIS), although examples of late stage LOH without concomittant DCIS involvement were also found.	('breast disease', 'Disease', 'MESH:D001941', (73, 87))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('LOH', 'Var', (60, 63))	('breast disease', 'Disease', (73, 87))
112477	11305954	The heterogeneous nature of breast cancer alterations could have important implications for the development of targeted therapies.	('alterations', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('implications', 'Reg', (75, 87))
112484	11305954	These results were analyzed in conjunction with other LOH data available for markers on 3p, 11p, 13q, 16p, 17p, and 17q in an effort to place chromosome 18p alterations on the breast cancer progression pathway.	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('alterations', 'Var', (157, 168))
112487	11305954	Matching normal and tumor DNA were subjected to PCR-based LOH analysis using two 18p11.3 markers (D18S59 and D18S481) and one 18p11.2 marker (D18S452).	('D18S59', 'Var', (98, 104))	('D18S481', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('D18S452', 'Chemical', '-', (142, 149))
112495	11305954	A total of 96 foci were individually microdissected from 30 breast tumor cases and analyzed for LOH at the polymorphic markers D18S59 and D18S481 spanning 18p11.3.	('breast tumor', 'Phenotype', 'HP:0100013', (60, 72))	('breast tumor', 'Disease', 'MESH:D001943', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('D18S59', 'Var', (127, 133))	('D18S481', 'Var', (138, 145))	('breast tumor', 'Disease', (60, 72))
112502	11305954	Of the 15 tumor foci with LOH at 18p11.3 and for which D18S452 was informative, 73% (11/15) retained heterozygosity at this 18p11.2 marker.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('LOH', 'Var', (26, 29))	('tumor', 'Disease', (10, 15))	('D18S452', 'Var', (55, 62))	('heterozygosity', 'MPA', (101, 115))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('D18S452', 'Chemical', '-', (55, 62))
112504	11305954	We could examine, by studying multistage individually microdissected tumor components from the same specimen, the extent of heterogeneity associated with chromosome 18p LOH (Fig.	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('chromosome 18p LOH', 'Var', (154, 172))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
112511	11305954	The LOH results specifically for those tumors also showing detectable chromosome 18p LOH are presented in Figure 3.	('chromosome', 'Var', (70, 80))	('tumors', 'Disease', (39, 45))	('LOH', 'NegReg', (85, 88))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
112513	11305954	Chromosome 16q LOH (region D16S496-D16S513), in contrast, was only found in 81%, chromosome 13q (D13S260-D13S263) in 55%, and chromosome 11p (region D11S922-D11S988 including TH) in 48% of tumors also having 18p LOH.	('D13S260-D13S263', 'Var', (97, 112))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (189, 195))	('S988', 'CellLine', 'CVCL:V789', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('D16S496-D16S513', 'CellLine', 'CVCL:B072', (27, 42))
112514	11305954	These frequencies suggest that alterations on chromosome 18p occur more often in the presence of alterations affecting regions containing such tumor suppressors as p16 (9p) and p53 (17p), while events on chromosomes 13q, 16q and 11p occur more independently.	('alterations', 'Var', (31, 42))	('tumor', 'Disease', (143, 148))	('p53', 'Gene', (177, 180))	('p16', 'Gene', (164, 167))	('alterations', 'Var', (97, 108))	('p53', 'Gene', '7157', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('p16', 'Gene', '1029', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
112527	11305954	Studying 15 loci in 264 women, Emi et al found that LOH at markers 1p34, 13q12, 17p13.3 and 17q21.1, as well as two pairs of markers (1p34/17p13.3 and 13q12/17p13.3), had significant prognostic value and carried significant relative risk of death.	('death', 'Disease', 'MESH:D003643', (241, 246))	('LOH', 'Var', (52, 55))	('women', 'Species', '9606', (24, 29))	('death', 'Disease', (241, 246))	('1p34/17p13.3', 'Var', (134, 146))
112531	11305954	Allelic deletion on chromosomes 16q, 13q and 11p occurred less consistently (81, 55 and 46%, respectively), suggesting these regional events are more varied depending on the stage and/or type of tumor foci analyzed.	('Allelic', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))
112534	11305954	Future studies will determine whether this or another tumor suppressor gene is the target of the high frequency of allelic deletion measured in this study for breast cancer.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('allelic deletion', 'Var', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('tumor', 'Disease', (54, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
112537	14735188	Epidemiological studies have reported a significant reduction in the incidence of human gastro-intestinal cancers with COX inhibition by NSAIDS (Shaheen et al, 2002).	('gastro-intestinal cancers', 'Disease', (88, 113))	('gastro-intestinal cancers', 'Disease', 'MESH:D007414', (88, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('NSAIDS', 'Var', (137, 143))	('COX', 'MPA', (119, 122))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('inhibition', 'NegReg', (123, 133))	('human', 'Species', '9606', (82, 87))	('reduction', 'NegReg', (52, 61))
112539	14735188	Pharmacological studies with selective COX-2 inhibitors in animal models of breast cancer (and other cancers) have consistently demonstrated a dose-dependent arrest of tumour growth, invasion and metastasis (Alshafie et al, 2000; Harris et al, 2000; Rozic et al, 2001; Kundu and Fulton, 2002).	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('COX-2', 'Gene', (39, 44))	('breast cancer', 'Disease', (76, 89))	('inhibitors', 'Var', (45, 55))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('COX-2', 'Gene', '5743', (39, 44))	('arrest of tumour growth', 'Disease', 'MESH:D006323', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('arrest of tumour growth', 'Disease', (158, 181))
112558	14735188	For Ki67 (MIB-1), a primary mouse monoclonal antibody to MIB-1 was used (DAKO Ltd, UK, M7240) at 1 : 50 for 1 h, followed by a biotinylated goat anti-mouse secondary antibody (DAKO Ltd, UK, E432) diluted 1 : 200 for 40 min.	('mouse', 'Species', '10090', (28, 33))	('Ki67', 'Var', (4, 8))	('biotin', 'Chemical', 'MESH:D001710', (127, 133))	('MIB-1', 'Gene', '57534', (57, 62))	('MIB-1', 'Gene', (10, 15))	('goat', 'Species', '9925', (140, 144))	('MIB-1', 'Gene', '57534', (10, 15))	('mouse', 'Species', '10090', (150, 155))	('MIB-1', 'Gene', (57, 62))
112569	14735188	The percentage of COX-2 positivity (a staining score >=2+) for DCIS, invasive cancer and normal breast from reduction and around DCIS was 67, 63, 23 and 22, respectively.	('COX-2', 'Gene', '5743', (18, 23))	('DCIS', 'Disease', (63, 67))	('positivity', 'Var', (24, 34))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('invasive cancer', 'Disease', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('COX-2', 'Gene', (18, 23))	('DCIS', 'Phenotype', 'HP:0030075', (129, 133))	('invasive cancer', 'Disease', 'MESH:D009362', (69, 84))
112573	14735188	The group of DCIS tumours with a ki67 cell proliferation of >=10% (n=90) was associated with 79% COX-2 positivity compared to 55% in the group with <10% (n=93) of cell expressing the Ki67 antigen (P<0.0001, chi2 test, Table 2).	('positivity', 'MPA', (103, 113))	('COX-2', 'Gene', (97, 102))	('DCIS tumours', 'Disease', (13, 25))	('COX-2', 'Gene', '5743', (97, 102))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('ki67', 'Var', (33, 37))	('DCIS tumours', 'Disease', 'MESH:D002285', (13, 25))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
112574	14735188	There was a significant association between ER negativity (40% of DCIS) and COX-2 positivity, with 80% of ER-negative DCIS showing COX-2 positivity compared to 58% of ER-positive DCIS tumours (P=0.003, chi2 test, Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('COX-2', 'Gene', (131, 136))	('positivity', 'Var', (82, 92))	('COX-2', 'Gene', (76, 81))	('COX-2', 'Gene', '5743', (76, 81))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('COX-2', 'Gene', '5743', (131, 136))	('DCIS tumours', 'Disease', (179, 191))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('DCIS tumours', 'Disease', 'MESH:D002285', (179, 191))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('ER-negative', 'Var', (106, 117))
112578	14735188	Similar to DCIS, there was an association between COX-2 expression in IBC with a higher cell proliferation (Ki67, P=0.04, chi2 test), HER-2 positivity (P=0.014) and with ER negativity (P=0.005).	('higher', 'PosReg', (81, 87))	('HER-2', 'Gene', '2064', (134, 139))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('COX-2', 'Gene', (50, 55))	('HER-2', 'Gene', (134, 139))	('COX-2', 'Gene', '5743', (50, 55))	('IBC', 'Disease', (70, 73))	('positivity', 'Var', (140, 150))
112583	14735188	Since most IBC is believed to originate from DCIS (the two coexist in about 50% of cases), the inhibition of COX-2 represents a potential target for preventing breast cancer oncogenesis and as an adjuvant treatment following surgery to reduce local recurrence.	('inhibition', 'Var', (95, 105))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('IBC', 'Disease', (11, 14))	('COX-2', 'Gene', (109, 114))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('COX-2', 'Gene', '5743', (109, 114))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
112645	32375854	Despite the association between breast stromal collagen density and invasive breast cancer, which is second only to deleterious germline BRCA1 and BRCA2 mutations, stromal biology remains poorly delineated compared with other cancer cell compartments and immune cell populations.	('invasive breast cancer', 'Disease', (68, 90))	('BRCA1', 'Gene', '672', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('BRCA2', 'Gene', '675', (147, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (153, 162))	('BRCA1', 'Gene', (137, 142))	('invasive breast cancer', 'Disease', 'MESH:D001943', (68, 90))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BRCA2', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
112655	32375854	CAFs also affect tumor progression by reprogramming the tumor microenvironment at both the metabolic and immune levels and by promoting adaptive resistance to chemotherapy.	('promoting', 'PosReg', (126, 135))	('affect', 'Reg', (10, 16))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CAFs', 'Var', (0, 4))	('tumor', 'Disease', (56, 61))	('adaptive resistance to chemotherapy', 'CPA', (136, 171))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reprogramming', 'Reg', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
112665	32375854	Several imaging features were strongly correlated with clinicopathological characteristics, and ATC collagen fiber density (CFD) and DTC collagen fiber length (CFL) were revealed to be of prognostic value based on our patient cohort and their clinical outcomes.	('patient', 'Species', '9606', (218, 225))	('DTC', 'Var', (133, 136))	('DTC', 'Chemical', '-', (133, 136))	('CFD', 'Disease', 'MESH:C563256', (124, 127))	('CFD', 'Disease', (124, 127))
112754	32375854	Differences in DTC may cause different degrees of cell migration, including both immune cells and malignant cells, in the tissue, as well as subsequent invasion, with longer collagen fibers facilitating cancer cell migration to remote areas.	('invasion', 'CPA', (152, 160))	('Differences', 'Var', (0, 11))	('DTC', 'Chemical', '-', (15, 18))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cell migration', 'CPA', (50, 64))	('DTC', 'Gene', (15, 18))	('cause', 'Reg', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
112800	32375854	Tumor progression is an outcome of mutations in multiple different genes, and the relationships between collagen characteristics and other critical tumor compartments, such as the immune response, EMT, adipose, and angiogenesis, should be investigated in a more systematic study.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations', 'Var', (35, 44))
112829	30998679	Abnormalities of the gene may give rise to a cancer after accumulation of many mutations in the same cells.	('give rise to', 'Reg', (30, 42))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (79, 88))
112884	30998679	We found overexpression of DCR2 protein was associated with unfavourable prognostic factors such as poor tumour differentiation, ER and PR negativity and HER2 positivity (Table 2).	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('overexpression', 'PosReg', (9, 23))	('ER', 'Gene', '2099', (155, 157))	('DCR2', 'Gene', '8793', (27, 31))	('tumour', 'Disease', (105, 111))	('positivity', 'Var', (159, 169))	('protein', 'Protein', (32, 39))	('PR', 'Gene', '5241', (136, 138))	('HER2', 'Gene', (154, 158))	('ER', 'Gene', '2099', (129, 131))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('HER2', 'Gene', '2064', (154, 158))	('DCR2', 'Gene', (27, 31))
112894	30998679	While the DCR2 positive group showed a pattern of worse survival compared to negative group, it was not statistically significant (log rank test, p = 0.765).	('DCR2', 'Gene', (10, 14))	('positive', 'Var', (15, 23))	('DCR2', 'Gene', '8793', (10, 14))
112916	30998679	However, invasive cancer may be formed after the cells surpass the cell cycle regulatory mechanisms when mutations occur in the tumour suppressor gene itself.	('invasive cancer', 'Disease', (9, 24))	('tumour', 'Disease', (128, 134))	('invasive cancer', 'Disease', 'MESH:D009362', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('mutations occur', 'Var', (105, 120))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
112917	30998679	It is reported that mutations of P53 are one of the most common known genetic alterations in human cancer.	('P53', 'Gene', (33, 36))	('P53', 'Gene', '7157', (33, 36))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (20, 29))
112918	30998679	More than 75% of the mutations do not affect the translation of P53 protein, but mutant P53 protein loses its wild-type functions.	('wild-type functions', 'MPA', (110, 129))	('P53', 'Gene', (88, 91))	('P53', 'Gene', (64, 67))	('P53', 'Gene', '7157', (88, 91))	('loses', 'NegReg', (100, 105))	('P53', 'Gene', '7157', (64, 67))	('mutant', 'Var', (81, 87))	('protein', 'Protein', (92, 99))	('mutations', 'Var', (21, 30))
112919	30998679	Mutant P53 is more stable compared to the short-lived wild-type P53.	('P53', 'Gene', (64, 67))	('P53', 'Gene', (7, 10))	('P53', 'Gene', '7157', (64, 67))	('P53', 'Gene', '7157', (7, 10))	('Mutant', 'Var', (0, 6))
112920	30998679	The long presence of mutant P53 itself may have an oncogenic effect on the cells.	('P53', 'Gene', '7157', (28, 31))	('P53', 'Gene', (28, 31))	('oncogenic effect', 'CPA', (51, 67))	('mutant', 'Var', (21, 27))
112921	30998679	However, it remains unknown whether the upregulation of P53 in this study is representative of the wild-type or mutant P53 protein.	('P53', 'Gene', '7157', (56, 59))	('P53', 'Gene', (119, 122))	('upregulation', 'PosReg', (40, 52))	('P53', 'Gene', '7157', (119, 122))	('mutant', 'Var', (112, 118))	('P53', 'Gene', (56, 59))
112928	30998679	It was reported that senescent cells expressing high DCR2 protein show a less aggressive proliferation index, whereas loss of DCR2 expression in tumour cells is associated with high proliferation rate.	('protein', 'Protein', (58, 65))	('tumour', 'Disease', (145, 151))	('DCR2', 'Gene', '8793', (126, 130))	('DCR2', 'Gene', (126, 130))	('DCR2', 'Gene', (53, 57))	('aggressive proliferation index', 'CPA', (78, 108))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('high', 'Var', (48, 52))	('less', 'NegReg', (73, 77))	('DCR2', 'Gene', '8793', (53, 57))
112929	30998679	Overexpressed DCR2 is also seen in other human malignancies such as colon cancer and lung cancer.	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('Overexpressed', 'Var', (0, 13))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('DCR2', 'Gene', '8793', (14, 18))	('malignancies', 'Disease', (47, 59))	('human', 'Species', '9606', (41, 46))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('colon cancer', 'Disease', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('seen', 'Reg', (27, 31))	('DCR2', 'Gene', (14, 18))
112931	30998679	Physiologically, DCR2 is frequently expressed in normal tissues, but often silenced by hypermethylation in a wide range tumour cells including breast cancer, cervical cancer, malignant mesothelioma, neuroblastoma and prostate cancer.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (217, 232))	('cervical cancer', 'Disease', (158, 173))	('cervical cancer', 'Disease', 'MESH:D002583', (158, 173))	('malignant mesothelioma', 'Disease', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DCR2', 'Gene', (17, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (199, 212))	('hypermethylation', 'Var', (87, 103))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('silenced', 'NegReg', (75, 83))	('neuroblastoma and prostate cancer', 'Disease', 'MESH:D011471', (199, 232))	('DCR2', 'Gene', '8793', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
112934	30998679	Our study showed absence of P53 was significantly associated with favourable prognostic factors such as moderate differentiation, early stage tumour, absence of lymphovascular invasion, positive ER and PR status as well as negative HER2.	('tumour', 'Disease', (142, 148))	('moderate differentiation', 'CPA', (104, 128))	('absence', 'Var', (17, 24))	('HER2', 'Gene', (232, 236))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('P53', 'Gene', (28, 31))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('HER2', 'Gene', '2064', (232, 236))	('positive', 'Var', (186, 194))	('ER', 'Gene', '2099', (195, 197))	('early', 'Disease', (130, 135))	('P53', 'Gene', '7157', (28, 31))	('PR', 'Gene', '5241', (202, 204))	('ER', 'Gene', '2099', (233, 235))
112939	30998679	On the other hand, mutant P53 is more stable and accumulates in the nucleus due to elongated half-life or by binding with other oncogene proteins.	('P53', 'Gene', (26, 29))	('accumulates', 'PosReg', (49, 60))	('P53', 'Gene', '7157', (26, 29))	('mutant', 'Var', (19, 25))	('binding', 'Interaction', (109, 116))
112940	30998679	An elevated level of mutated P53 does not give protection to the cellular integrity, and thus is directly linked to unfavourable prognostic factors.	('P53', 'Gene', (29, 32))	('mutated', 'Var', (21, 28))	('P53', 'Gene', '7157', (29, 32))	('linked', 'Reg', (106, 112))
112941	30998679	This finding may suggest that the upregulation of P53 is associated with mutant P53 protein.	('P53', 'Gene', (50, 53))	('P53', 'Gene', '7157', (80, 83))	('P53', 'Gene', '7157', (50, 53))	('mutant', 'Var', (73, 79))	('protein', 'Protein', (84, 91))	('P53', 'Gene', (80, 83))	('upregulation', 'PosReg', (34, 46))
112942	30998679	Nevertheless, there is no conclusive evidence that positivity in IHC staining is a result of P53 mutations, thus further analysis is required.	('mutations', 'Var', (97, 106))	('P53', 'Gene', (93, 96))	('P53', 'Gene', '7157', (93, 96))
112943	30998679	Interestingly, we found overexpressed DCR2 protein is associated with unfavourable prognostic factors such as poor tumour differentiation, ER and PR negativity and HER2 positivity.	('overexpressed', 'PosReg', (24, 37))	('ER', 'Gene', '2099', (165, 167))	('DCR2', 'Gene', '8793', (38, 42))	('PR', 'Gene', '5241', (146, 148))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('ER', 'Gene', '2099', (139, 141))	('HER2', 'Gene', (164, 168))	('positivity', 'Var', (169, 179))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('DCR2', 'Gene', (38, 42))	('tumour', 'Disease', (115, 121))	('protein', 'Protein', (43, 50))	('HER2', 'Gene', '2064', (164, 168))
112957	30998679	Furthermore, the association of P53 gene mutation with P53 protein overexpression may contribute to the abrogation of the suppressor pathway thus leading to aggressive tumour behaviour.	('leading to', 'Reg', (146, 156))	('association', 'Interaction', (17, 28))	('P53', 'Gene', '7157', (32, 35))	('overexpression', 'PosReg', (67, 81))	('protein', 'Protein', (59, 66))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('abrogation', 'NegReg', (104, 114))	('aggressive tumour', 'Disease', 'MESH:D001523', (157, 174))	('mutation', 'Var', (41, 49))	('P53', 'Gene', '7157', (55, 58))	('P53', 'Gene', (55, 58))	('P53', 'Gene', (32, 35))	('aggressive tumour', 'Disease', (157, 174))	('suppressor pathway', 'Pathway', (122, 140))
112967	25332145	MTA1:a stress response protein: a master regulator of gene expression and cancer cell behavior Gene mutation's role in initiating carcinogenesis has been controversial, but it is consensually accepted that both carcinogenesis and cancer metastasis are gene-regulated processes.	('MTA1', 'Gene', '9112', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('carcinogenesis', 'Disease', (211, 225))	('cancer metastasis', 'Disease', 'MESH:D009362', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinogenesis', 'Disease', (130, 144))	('cancer', 'Disease', (74, 80))	('mutation', 'Var', (100, 108))	('cancer', 'Disease', (230, 236))	('MTA1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer metastasis', 'Disease', (230, 247))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))
112981	25332145	Third, increasing evidence shows that most high occurrence gene mutations in cancer cells are associated with better clinical outcomes, which means gene mutations lower cancer malignancy.	('cancer malignancy', 'Disease', (169, 186))	('cancer', 'Disease', (169, 175))	('mutations', 'Var', (153, 162))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lower', 'NegReg', (163, 168))	('cancer malignancy', 'Disease', 'MESH:D009369', (169, 186))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
112982	25332145	For example, IDH1 and IDH2 mutations are associated with better glioma patient prognosis, and Braf mutations are associated with better prognosis in acral lentiginous melanoma.	('mutations', 'Var', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('Braf', 'Gene', (94, 98))	('acral lentiginous melanoma', 'Phenotype', 'HP:0012060', (149, 175))	('Braf', 'Gene', '673', (94, 98))	('acral lentiginous melanoma', 'Disease', 'MESH:D007911', (149, 175))	('IDH2', 'Gene', (22, 26))	('acral lentiginous melanoma', 'Disease', (149, 175))	('IDH1', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('mutations', 'Var', (99, 108))	('glioma', 'Disease', (64, 70))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('patient', 'Species', '9606', (71, 78))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
112986	25332145	This model asserts that an epithelial cell is malignantly transformed due to gene mutation, further proliferates to form atypical hyperplasia, progresses to in situ carcinoma, and with gene mutation accumulation, it breaks down the basement membrane separating the epithelium from the connective stroma.	('situ carcinoma', 'Disease', (160, 174))	('breaks down', 'Phenotype', 'HP:0001061', (216, 227))	('gene mutation', 'Var', (77, 90))	('accumulation', 'PosReg', (199, 211))	('hyperplasia', 'Disease', (130, 141))	('hyperplasia', 'Disease', 'MESH:D006965', (130, 141))	('gene mutation', 'Var', (185, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breaks down', 'NegReg', (216, 227))	('situ carcinoma', 'Disease', 'MESH:D002278', (160, 174))
113051	25332145	For example, heat shock proteins, hypoxia inducible factors, and MAPK kinases such as p38MAPK, MAPK13, p53, and MTA1 are all stress-related proteins and proposed therapeutic cancer targets.	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('MAPK13', 'Gene', '5603', (95, 101))	('p38MAPK', 'Var', (86, 93))	('MAPK', 'Gene', (65, 69))	('MTA1', 'Gene', (112, 116))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('heat shock proteins', 'Disease', 'MESH:D012769', (13, 32))	('hypoxia', 'Disease', (34, 41))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('MAPK13', 'Gene', (95, 101))	('heat shock proteins', 'Disease', (13, 32))	('shock', 'Phenotype', 'HP:0031273', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
113063	25332145	Although it is widely believed that cancer is the result of accumulated gene mutations, many of these mutations are associated with better clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (36, 42))
113064	25332145	For example, IDH1 and IDH2 mutations are associated with much better glioma patient prognosis, and the BRAF mutation was associated with more favorable acral lentiginous melanoma prognosis.	('glioma', 'Disease', (69, 75))	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('acral lentiginous melanoma', 'Phenotype', 'HP:0012060', (152, 178))	('BRAF', 'Gene', '673', (103, 107))	('better', 'PosReg', (62, 68))	('acral lentiginous melanoma', 'Disease', (152, 178))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('acral lentiginous melanoma', 'Disease', 'MESH:D007911', (152, 178))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('patient', 'Species', '9606', (76, 83))	('BRAF', 'Gene', (103, 107))
113075	25332145	Similarly, in cells cultured under hypoxic conditions, MTA1 and HIF1alpha expression were both upregulated, and MTA1 bonded to and stabilized HIF1alpha.	('expression', 'MPA', (74, 84))	('upregulated', 'PosReg', (95, 106))	('MTA1', 'Var', (112, 116))	('HIF1alpha', 'Gene', (64, 73))	('HIF1alpha', 'Gene', '3091', (64, 73))	('HIF1alpha', 'Gene', (142, 151))	('hypoxic conditions', 'Disease', (35, 53))	('hypoxic conditions', 'Disease', 'MESH:D009135', (35, 53))	('HIF1alpha', 'Gene', '3091', (142, 151))	('MTA1', 'Gene', (55, 59))
113082	25332145	A reduced rate of breast cancer metastasis to lung was observed in the MTA1 null genetic background.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer metastasis to lung', 'Disease', 'MESH:D009362', (18, 50))	('breast cancer metastasis to lung', 'Disease', (18, 50))	('MTA1', 'Gene', (71, 75))	('null genetic', 'Var', (76, 88))	('reduced', 'NegReg', (2, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))
113087	25332145	MTA1 overexpression stabilizes both HIF1alpha and p53, which both play important roles in carcinogenesis.	('HIF1alpha', 'Gene', (36, 45))	('HIF1alpha', 'Gene', '3091', (36, 45))	('stabilizes', 'PosReg', (20, 30))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('MTA1', 'Gene', (0, 4))	('overexpression', 'Var', (5, 19))	('carcinogenesis', 'Disease', (90, 104))
113129	19277037	Tumour size was evaluable in 1062 (82.4%) tumours: 431 (40.6%) <=10 mm, 291 (27.4%) 11-20 mm and 340 (32%) >20 mm.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('<=10 mm', 'Var', (63, 70))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('11-20 mm', 'Var', (84, 92))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))
113134	19277037	The margin was <1 mm in 10.6% (CS) and 12.1% (CS+RT) of patients, 1-3 mm in 21% of patients (whether CS or CS+RT), 4-10 mm in 51.5% (CS) and 57.1% (CS+RT) of patients, and >1 cm in 16.7% (CS) and 10.3% (CS+RT) of patients.	('CS', 'Chemical', '-', (148, 150))	('patients', 'Species', '9606', (56, 64))	('CS', 'Chemical', '-', (101, 103))	('CS', 'Chemical', '-', (46, 48))	('1-3 mm', 'Var', (66, 72))	('CS', 'Chemical', '-', (188, 190))	('CS', 'Chemical', '-', (133, 135))	('CS', 'Chemical', '-', (203, 205))	('CS+RT', 'Chemical', '-', (203, 208))	('CS', 'Chemical', '-', (107, 109))	('patients', 'Species', '9606', (213, 221))	('CS+RT', 'Chemical', '-', (107, 112))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (158, 166))	('CS', 'Chemical', '-', (31, 33))	('CS+RT', 'Chemical', '-', (148, 153))	('4-10 mm', 'Var', (115, 122))	('CS+RT', 'Chemical', '-', (46, 51))
113157	19277037	The multiple logistic regression analysis showed that sentinel biopsy procedure rates were higher in case of mastectomy, comedocarcinoma subtypes, large tumour size and high-grade lesions (Table 6).	('comedo', 'Phenotype', 'HP:0025249', (121, 127))	('tumour', 'Disease', (153, 159))	('high-grade lesions', 'Var', (169, 187))	('higher', 'PosReg', (91, 97))	('comedocarcinoma subtypes', 'Disease', (121, 145))	('comedocarcinoma subtypes', 'Disease', 'MESH:C535673', (121, 145))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('mastectomy', 'Disease', (109, 119))	('large', 'Var', (147, 152))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('sentinel biopsy procedure', 'CPA', (54, 79))
113230	27411549	This identified that a positive margin (ink on tumor) was associated with at least a 2-fold increase in IBTR, thus requiring re-excision.	('IBTR', 'MPA', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increase', 'PosReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('positive margin', 'Var', (23, 38))
113336	27611215	Therefore, our study only included confirmed BI-RADS 4 pleomorphic or amorphous microcalcifications without an associated mass, which were essentially recommended for biopsy after assessment.	('calcification', 'Disease', (85, 98))	('BI-RADS', 'Var', (45, 52))	('calcification', 'Disease', 'MESH:D002114', (85, 98))
113344	27611215	Morphology of microcalcifications alone is a predictive factor for cancer risk, with a reported malignancy rate of 7% for coarse heterogeneous, 11% for punctate, 20-26% for amorphous, 25-41% for fine pleomorphic and >80% for linear/branching/casting calcifications.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('linear/branching/casting', 'CPA', (225, 249))	('cancer', 'Disease', (67, 73))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('malignancy', 'Disease', (96, 106))	('calcification', 'Disease', 'MESH:D002114', (250, 263))	('calcification', 'Disease', 'MESH:D002114', (19, 32))	('fine pleomorphic', 'Var', (195, 211))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('calcification', 'Disease', (19, 32))	('calcification', 'Disease', (250, 263))
113355	27611215	One study reported that the detection rate of known cancers using DE-CESM was similar to that of enhanced MRI, with significantly improved specificity and fewer false positives.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('DE-CESM', 'Var', (66, 73))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('specificity', 'MPA', (139, 150))	('improved', 'PosReg', (130, 138))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
113359	27611215	A previous report regarding DE-CESM on women referred from a screening program because of a suspicious mass, abnormal density, parenchymal distortion or microcalcification showed an overall sensitivity of 100%, specificity of 87.7%, PPV of 76.2% and NPV of 100%, based on either biopsy or standard reference procedures.	('women', 'Species', '9606', (39, 44))	('calcification', 'Disease', (158, 171))	('calcification', 'Disease', 'MESH:D002114', (158, 171))	('abnormal density', 'Var', (109, 125))
113386	19452544	In addition, AA women are more frequently diagnosed with higher-stage carcinomas, and the carcinomas are significantly more likely to be high grade, hormone receptor negative, aneuploid, and lymph node positive.	('higher-stage', 'CPA', (57, 69))	('aneuploid', 'Var', (176, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('women', 'Species', '9606', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Disease', (70, 80))	('carcinomas', 'Disease', 'MESH:D002277', (70, 80))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('high grade', 'CPA', (137, 147))	('carcinomas', 'Disease', (90, 100))	('diagnosed', 'Reg', (42, 51))	('hormone receptor', 'Gene', (149, 165))	('negative', 'NegReg', (166, 174))	('hormone receptor', 'Gene', '3164', (149, 165))
113508	19258476	CpG Island Tumor Suppressor Promoter Methylation in Non-BRCA-Associated Early Mammary Carcinogenesis Only 5% of all breast cancers are the result of BRCA1/2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancers', 'Disease', 'MESH:D001943', (116, 130))	('breast cancers', 'Disease', (116, 130))	('BRCA1/2', 'Gene', (149, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('Tumor', 'Phenotype', 'HP:0002664', (11, 16))	('BRCA', 'Gene', '672', (56, 60))	('BRCA1/2', 'Gene', '672;675', (149, 156))	('BRCA', 'Gene', '672', (149, 153))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (157, 166))	('BRCA', 'Gene', (56, 60))	('BRCA', 'Gene', (149, 153))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))	('result', 'Reg', (139, 145))
113509	19258476	Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known.	('familial breast cancer', 'Disease', 'MESH:D001943', (114, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('Methylation silencing', 'Var', (0, 21))	('tumor', 'Disease', (25, 30))	('familial breast cancer', 'Disease', (114, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('breast cancer', 'Disease', (78, 91))
113512	19258476	In contrast, CpG island methylation of RARB M4 (P = 0.051), INK4a/ARF (P = 0.042), HIN-1 (P = 0.044), and PRA (P = 0.032), as well as the overall frequency of methylation events (P = 0.004), was associated with abnormal Masood cytology.	('associated', 'Reg', (195, 205))	('HIN-1', 'Gene', '92304', (83, 88))	('INK4a/ARF', 'Gene', '1029', (60, 69))	('PRA', 'Gene', (106, 109))	('HIN-1', 'Gene', (83, 88))	('INK4a/ARF', 'Gene', (60, 69))	('methylation', 'Var', (24, 35))	('RARB', 'Gene', (39, 43))	('PRA', 'Gene', '6277', (106, 109))	('RARB', 'Gene', '5915', (39, 43))
113513	19258476	The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing.	('women', 'Species', '9606', (114, 119))	('familial breast cancer', 'Disease', (49, 71))	('BRCA1/2', 'Gene', (148, 155))	('familial breast cancer', 'Disease', 'MESH:D001943', (49, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA1/2', 'Gene', '672;675', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('tested', 'Reg', (76, 82))	('mutation', 'Var', (156, 164))
113514	19258476	Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had <=4 methylation events), whereas women without a mutation showed a high frequency of promoter methylation events (24 of 25 women had 5-8 methylation events; P < 0.0001).	('women', 'Species', '9606', (94, 99))	('Women', 'Species', '9606', (0, 5))	('BRCA1/2', 'Gene', '672;675', (11, 18))	('CpG island promoter methylation', 'MPA', (52, 83))	('mutations', 'Var', (19, 28))	('women', 'Species', '9606', (137, 142))	('women', 'Species', '9606', (227, 232))	('BRCA1/2', 'Gene', (11, 18))
113515	19258476	Of women with a BRCA1/2 mutation, none showed methylation of HIN-1 and only 1 of 15 women showed CpG island methylation of RARB M4, INK4a/ARF, or PRB promoters.	('women', 'Species', '9606', (84, 89))	('PRB', 'Gene', (146, 149))	('BRCA1/2', 'Gene', (16, 23))	('PRB', 'Gene', '5925', (146, 149))	('HIN-1', 'Gene', '92304', (61, 66))	('INK4a/ARF', 'Gene', '1029', (132, 141))	('RARB', 'Gene', (123, 127))	('mutation', 'Var', (24, 32))	('women', 'Species', '9606', (3, 8))	('BRCA1/2', 'Gene', '672;675', (16, 23))	('RARB', 'Gene', '5915', (123, 127))	('HIN-1', 'Gene', (61, 66))	('INK4a/ARF', 'Gene', (132, 141))
113516	19258476	This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('familial breast cancer', 'Disease', (103, 125))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BRCA1/2', 'Gene', (95, 102))	('methylation', 'Var', (41, 52))	('familial breast cancer', 'Disease', 'MESH:D001943', (103, 125))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('BRCA1/2', 'Gene', '672;675', (95, 102))
113517	19258476	Transcriptional silencing of tumor suppressor genes (TSG) through methylation of CpG islands in promoter regions is thought to be an important early mechanism of human carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('silencing', 'NegReg', (16, 25))	('human', 'Species', '9606', (162, 167))	('methylation', 'Var', (66, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('TSG', 'Gene', (53, 56))	('tumor', 'Disease', (29, 34))	('carcinogenesis', 'Disease', (168, 182))
113518	19258476	Growing evidence suggests that epigenetic inactivation via cytosine methylation plays a role in the transformation of normal cells to cancerous cells, underscoring the need to investigate global CpG island methylation patterns.	('cytosine methylation', 'Var', (59, 79))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('epigenetic inactivation', 'Var', (31, 54))	('cytosine', 'Chemical', 'MESH:D003596', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
113519	19258476	proposed that cancer may develop through the simultaneous inactivation of multiple TSGs and induction of mismatch repair deficiency.	('cancer', 'Disease', (14, 20))	('inactivation', 'NegReg', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('deficiency', 'Var', (121, 131))	('induction', 'Reg', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mismatch repair', 'Protein', (105, 120))
113522	19258476	Two types of methylation patterns have been reported in colorectal cancer: type A for aging-specific methylation and type C for cancer-specific methylation.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('cancer', 'Disease', (67, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('methylation', 'Var', (101, 112))	('cancer', 'Disease', (128, 134))
113523	19258476	Type A methylation is characterized by a high incidence of CpG island methylation in tumors accompanied by a slight incidence in the detection of methylation in normal colon mucosa as well.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('colon mucosa', 'Disease', 'MESH:D015179', (168, 180))	('CpG island', 'Protein', (59, 69))	('methylation', 'Var', (7, 18))	('methylation', 'Var', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('colon mucosa', 'Disease', (168, 180))	('tumors', 'Disease', (85, 91))
113525	19258476	Type C methylation in colorectal cancer is observed for INK4a/ARF, thrombospondin-1 (THBS1), a p53-inducible angiogenesis inhibitor, and the mismatch repair gene hMLH1.	('THBS1', 'Gene', (85, 90))	('colorectal cancer', 'Disease', (22, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('THBS1', 'Gene', '7057', (85, 90))	('methylation', 'Var', (7, 18))	('hMLH1', 'Gene', (162, 167))	('thrombospondin-1', 'Gene', (67, 83))	('INK4a/ARF', 'Gene', '1029', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('INK4a/ARF', 'Gene', (56, 65))	('hMLH1', 'Gene', '4292', (162, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('thrombospondin-1', 'Gene', '7057', (67, 83))
113526	19258476	While identification of BRCA1/2 mutations represents a major milestone in understanding inherited breast cancer, only 5% of all breast cancers are the result of such mutations.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('breast cancer', 'Disease', (98, 111))	('BRCA1/2', 'Gene', '672;675', (24, 31))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('result', 'Reg', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (32, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancers', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('BRCA1/2', 'Gene', (24, 31))
113527	19258476	Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, the role for methylation silencing of tumor suppressor genes in familial breast cancer is not known.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('Methylation silencing', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (25, 30))	('familial breast cancer', 'Disease', (166, 188))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('familial breast cancer', 'Disease', 'MESH:D001943', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('breast cancer', 'Disease', (78, 91))	('tumor', 'Disease', (140, 145))
113528	19258476	Here, we provide the first evidence of CpG island methylation of tumor suppressor gene promoters during breast cancer initiation, as well as in non-BRCA1/2 familial breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('breast cancer initiation', 'Disease', 'MESH:D001943', (104, 128))	('familial breast cancer', 'Disease', 'MESH:D001943', (156, 178))	('BRCA1/2', 'Gene', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1/2', 'Gene', '672;675', (148, 155))	('familial breast cancer', 'Disease', (156, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CpG island methylation', 'Var', (39, 61))	('methylation', 'Var', (50, 61))	('breast cancer initiation', 'Disease', (104, 128))
113531	19258476	We also tested for the association between individual promoter methylation events and the presence or absence of a BRCA1/2 mutation in unaffected women with a high pretest probability of carrying a mutation.	('tested', 'Reg', (8, 14))	('mutation', 'Var', (123, 131))	('BRCA1/2', 'Gene', (115, 122))	('absence', 'NegReg', (102, 109))	('BRCA1/2', 'Gene', '672;675', (115, 122))	('women', 'Species', '9606', (146, 151))
113532	19258476	There was a significant association between the number of CpG island methylation events and absence of a BRCA1 or BRCA2 mutation.	('BRCA1', 'Gene', (105, 110))	('absence', 'NegReg', (92, 99))	('BRCA2', 'Gene', (114, 119))	('mutation', 'Var', (120, 128))	('BRCA2', 'Gene', '675', (114, 119))	('BRCA1', 'Gene', '672', (105, 110))
113535	19258476	performed a genome-wide screening of 276 CpG island loci in a group of breast cancer cell lines using differential methylation hybridization, a novel array-based method, and found that preexisting methylation within CpG island loci may stimulate subsequent de novo methylation in cancer cells.	('breast cancer', 'Disease', (71, 84))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('stimulate', 'PosReg', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('de novo methylation', 'MPA', (257, 276))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('CpG', 'Gene', (216, 219))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('methylation', 'Var', (197, 208))
113539	19258476	found that if estrogen receptor-a (ESR1) promoter was methylated, then E-cadherin (CDH1), glutathione S-transferase (GSTP1), cyclin D2 (CCND2), and thyroid hormone receptor-beta1 (TRB1) promoters were also likely to be methylated independent of the overall methylation frequency.	('estrogen receptor-a', 'Gene', '2099', (14, 33))	('estrogen receptor-a', 'Gene', (14, 33))	('glutathione S-transferase', 'Gene', '373156', (90, 115))	('thyroid hormone receptor-beta1', 'Gene', (148, 178))	('TRB1', 'Gene', '50840', (180, 184))	('thyroid hormone receptor-beta1', 'Gene', '50840', (148, 178))	('CDH1', 'Gene', '999', (83, 87))	('CCND2', 'Gene', (136, 141))	('glutathione S-transferase', 'Gene', (90, 115))	('CCND2', 'Gene', '894', (136, 141))	('cyclin D2', 'Gene', '894', (125, 134))	('methylated', 'Var', (54, 64))	('TRB1', 'Gene', (180, 184))	('CDH1', 'Gene', (83, 87))	('ESR1', 'Gene', '2099', (35, 39))	('ESR1', 'Gene', (35, 39))	('GSTP1', 'Gene', '2950', (117, 122))	('cyclin D2', 'Gene', (125, 134))	('E-cadherin', 'Gene', (71, 81))	('GSTP1', 'Gene', (117, 122))	('E-cadherin', 'Gene', '999', (71, 81))
113551	19258476	We also tested these samples for the association between CpG island promoter methylation and the presence or absence of a BRCA1/2 mutation in women with a high pretest probability of carrying a mutation.	('tested', 'Reg', (8, 14))	('BRCA1/2', 'Gene', '672;675', (122, 129))	('absence', 'NegReg', (109, 116))	('mutation', 'Var', (130, 138))	('BRCA1/2', 'Gene', (122, 129))	('women', 'Species', '9606', (142, 147))
113554	19258476	Entry to the Duke High-Risk Clinic is defined as individuals with one of the following: (a) a 5-year Gail model risk score >=1.7%, (b) a prior biopsy exhibiting atypia, LCIS, or DCIS, and (c) known or suspected BRCA1/2 mutation carrier.	('BRCA1/2', 'Gene', (211, 218))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('atypia', 'Var', (161, 167))	('LCIS', 'Disease', (169, 173))	('BRCA1/2', 'Gene', '672;675', (211, 218))	('LCIS', 'Phenotype', 'HP:0030076', (169, 173))
113561	19258476	To be eligible for the high-risk BRCA1/2 analysis, subjects were required to be (a) unaffected and (b) have a 5% probability of having a BRCA1/2 mutation by either the BRCA1PRO or the BRCA2PRO model (see below).	('BRCA1', 'Gene', '672', (137, 142))	('BRCA2', 'Gene', (184, 189))	('BRCA1', 'Gene', '672', (168, 173))	('BRCA1', 'Gene', (137, 142))	('BRCA1', 'Gene', (168, 173))	('BRCA1/2', 'Gene', (33, 40))	('BRCA2', 'Gene', '675', (184, 189))	('BRCA1', 'Gene', '672', (33, 38))	('BRCA1/2', 'Gene', '672;675', (137, 144))	('BRCA1/2', 'Gene', (137, 144))	('BRCA1', 'Gene', (33, 38))	('BRCA1/2', 'Gene', '672;675', (33, 40))	('mutation', 'Var', (145, 153))
113565	19258476	The BRCAPRO model calculates the probability of an individual carrying a mutation in the BRCA1 or BRCA2 genes using Bayesian methods to incorporate relevant family history of breast and/or ovarian cancers, including second-degree relatives.	('BRCA', 'Gene', (98, 102))	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Gene', (89, 93))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('BRCA', 'Gene', (4, 8))	('BRCA1', 'Gene', (89, 94))	('breast and/or ovarian cancers', 'Disease', (175, 204))	('BRCA2', 'Gene', (98, 103))	('breast and/or ovarian cancers', 'Disease', 'MESH:D010051', (175, 204))	('ovarian cancers', 'Phenotype', 'HP:0100615', (189, 204))	('BRCA', 'Gene', '672', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('BRCA1', 'Gene', '672', (89, 94))	('mutation', 'Var', (73, 81))	('BRCA2', 'Gene', '675', (98, 103))	('BRCA', 'Gene', '672', (89, 93))
113567	19258476	The presence of atypia in RPFNA cytology obtained from pooled aspirates is prospectively validated to predict a 5.6-fold increase in breast cancer risk in high-risk women.	('atypia', 'Var', (16, 22))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('RPFNA', 'Gene', (26, 31))	('women', 'Species', '9606', (165, 170))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
113570	19258476	The number of epithelial cells was quantified and classified as <10 (insufficient quantity for cytologic analysis), 10-100, 100-500, 500-1,000, 1,000-5,000, and >5,000 cells.	('10-100', 'Var', (116, 122))	('insufficient', 'Disease', (69, 81))	('insufficient', 'Disease', 'MESH:D000309', (69, 81))	('100-500', 'Var', (124, 131))
113586	19258476	Ten MSP promoter methylation targets were tested: RARB at M3 (nucleotides -51 to +162), RARB at M4 (nucleotides +104 to +251; ref.	('RARB', 'Gene', (50, 54))	('RARB', 'Gene', (88, 92))	('RARB', 'Gene', '5915', (50, 54))	('nucleotides', 'Var', (100, 111))	('RARB', 'Gene', '5915', (88, 92))
113588	19258476	), ESR1 (nucleotides +357 to +474; ref.	('ESR1', 'Gene', (3, 7))	('ESR1', 'Gene', '2099', (3, 7))	('nucleotides +357 to +474;', 'Var', (9, 34))
113599	19258476	The Wilcoxon rank-sum test was used to compare the mean ranks of each covariate (median age, body mass index, Gail model score, probability of BRCA1/2 mutation, and Masood score) according to positive or negative marker methylation status.	('BRCA1/2', 'Gene', '672;675', (143, 150))	('mutation', 'Var', (151, 159))	('BRCA1/2', 'Gene', (143, 150))
113602	19258476	The correlation between the number of CpG island promoter methylation events and body mass index, age, Gail model score, and probability of an individual having a BRCA1/2 mutation (BRCAPRO score) was tested using the Spearman rank correlation coefficients.	('BRCA1/2', 'Gene', (163, 170))	('BRCA', 'Gene', (181, 185))	('mutation', 'Var', (171, 179))	('BRCA1/2', 'Gene', '672;675', (163, 170))	('BRCA', 'Gene', '672', (163, 167))	('BRCA', 'Gene', (163, 167))	('BRCA', 'Gene', '672', (181, 185))
113607	19258476	Twenty-nine unaffected premenopausal women with a familial pattern of breast cancer underwent BRCA1/2 mutation testing; 34% (10 of 29) of women tested positive for either BRCA1 (8 of 10) or BRCA2 (2 of 10) mutation.	('BRCA1/2', 'Gene', (94, 101))	('BRCA2', 'Gene', (190, 195))	('women', 'Species', '9606', (37, 42))	('BRCA1', 'Gene', (171, 176))	('positive', 'Reg', (151, 159))	('mutation', 'Var', (102, 110))	('BRCA1', 'Gene', '672', (94, 99))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('BRCA2', 'Gene', '675', (190, 195))	('BRCA1/2', 'Gene', '672;675', (94, 101))	('breast cancer', 'Disease', (70, 83))	('BRCA1', 'Gene', (94, 99))	('BRCA1', 'Gene', '672', (171, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('women', 'Species', '9606', (138, 143))
113610	19258476	Among the 10 genes tested, the most frequently methylated CpG island markers in RPFNA cytology from high-risk women were PRA (125 of 190; 65.8%) and RARB M3 (112 of 193; 58.0%).	('methylated', 'Var', (47, 57))	('RARB', 'Gene', (149, 153))	('RARB', 'Gene', '5915', (149, 153))	('PRA', 'Gene', (121, 124))	('PRA', 'Gene', '6277', (121, 124))	('women', 'Species', '9606', (110, 115))
113611	19258476	The least frequently methylated CpG island markers were HIN-1 (29 of 190; 15.3%) and PRB (30 of 190; 15.8%).	('PRB', 'Gene', (85, 88))	('HIN-1', 'Gene', '92304', (56, 61))	('methylated', 'Var', (21, 31))	('HIN-1', 'Gene', (56, 61))	('PRB', 'Gene', '5925', (85, 88))
113614	19258476	Two types of methylation patterns are described previously in colorectal cancer: aging-specific methylation and cancer-specific methylation.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colorectal cancer', 'Disease', (62, 79))	('methylation', 'Var', (96, 107))	('methylation', 'Var', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
113615	19258476	In contrast, methylation of RARB M4 (P = 0.051), INK4a/ARF (P = 0.042), HIN-1 (P = 0.044), and PRA (P = 0.032), as well as the overall number of methylation events (P = 0.004), was associated with increased Masood cytology index score.	('RARB', 'Gene', (28, 32))	('methylation', 'Var', (13, 24))	('PRA', 'Gene', '6277', (95, 98))	('HIN-1', 'Gene', '92304', (72, 77))	('RARB', 'Gene', '5915', (28, 32))	('HIN-1', 'Gene', (72, 77))	('increased', 'PosReg', (197, 206))	('INK4a/ARF', 'Gene', '1029', (49, 58))	('INK4a/ARF', 'Gene', (49, 58))	('Masood', 'MPA', (207, 213))	('PRA', 'Gene', (95, 98))
113625	19258476	We tested women with a familial pattern of breast cancer to observe whether there was an association between CpG island promoter methylation frequency and the presence or absence of a BRCA1/2 mutation.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('BRCA1/2', 'Gene', (184, 191))	('mutation', 'Var', (192, 200))	('women', 'Species', '9606', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BRCA1/2', 'Gene', '672;675', (184, 191))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
113626	19258476	Forty unaffected women in the cohort underwent BRCA1/2 mutation testing.	('mutation testing', 'Var', (55, 71))	('BRCA1/2', 'Gene', (47, 54))	('BRCA1/2', 'Gene', '672;675', (47, 54))	('women', 'Species', '9606', (17, 22))
113627	19258476	To be eligible for BRCA1/2 mutation testing, women were required to have a pretest probability of >=0.05 by either the BRCA1PRO or the BRCA2PRO model.	('BRCA2', 'Gene', (135, 140))	('BRCA1', 'Gene', (119, 124))	('BRCA1/2', 'Gene', (19, 26))	('mutation', 'Var', (27, 35))	('BRCA2', 'Gene', '675', (135, 140))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA1/2', 'Gene', '672;675', (19, 26))	('BRCA1', 'Gene', (19, 24))	('women', 'Species', '9606', (45, 50))	('BRCA1', 'Gene', '672', (119, 124))
113629	19258476	Twenty-five of 40 women tested negative for both BRCA1 and BRCA2 mutations; 15 of 40 women tested positive for either a BRCA1 or a BRCA2 mutation.	('BRCA2', 'Gene', '675', (59, 64))	('BRCA2', 'Gene', (131, 136))	('BRCA1', 'Gene', (120, 125))	('BRCA1', 'Gene', '672', (49, 54))	('BRCA2', 'Gene', '675', (131, 136))	('women', 'Species', '9606', (85, 90))	('BRCA1', 'Gene', (49, 54))	('BRCA2', 'Gene', (59, 64))	('women', 'Species', '9606', (18, 23))	('BRCA1', 'Gene', '672', (120, 125))	('mutations', 'Var', (65, 74))
113630	19258476	The distribution of CpG island methylation events for women with or without BRCA1/2 mutation is shown in Fig.	('BRCA1/2', 'Gene', (76, 83))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('women', 'Species', '9606', (54, 59))	('mutation', 'Var', (84, 92))
113631	19258476	3, and the number and percentage of CpG island methylation events for 15 women testing positive for BRCA1/2 mutations is shown in Table 5.	('BRCA1/2', 'Gene', (100, 107))	('BRCA1/2', 'Gene', '672;675', (100, 107))	('women', 'Species', '9606', (73, 78))	('mutations', 'Var', (108, 117))
113633	19258476	Of women with a BRCA1/2 mutation, none showed methylation of HIN-1 promoter and 1 of 15 women showed methylation of each of the following promoters: RARB M4, INK4a/ARF, or PRB.	('PRB', 'Gene', '5925', (172, 175))	('women', 'Species', '9606', (88, 93))	('INK4a/ARF', 'Gene', '1029', (158, 167))	('HIN-1 promoter and 1', 'Gene', '92304;11169', (61, 81))	('RARB', 'Gene', (149, 153))	('INK4a/ARF', 'Gene', (158, 167))	('BRCA1/2', 'Gene', (16, 23))	('PRB', 'Gene', (172, 175))	('RARB', 'Gene', '5915', (149, 153))	('mutation', 'Var', (24, 32))	('women', 'Species', '9606', (3, 8))	('BRCA1/2', 'Gene', '672;675', (16, 23))
113634	19258476	In contrast, 8 women with a BRCA1/2 mutation exhibited methylation of PRA and 6 women with a BRCA1/2 mutation exhibited methylation of RARB M3.	('women', 'Species', '9606', (80, 85))	('BRCA1/2', 'Gene', (28, 35))	('PRA', 'Gene', '6277', (70, 73))	('BRCA1/2', 'Gene', (93, 100))	('women', 'Species', '9606', (15, 20))	('BRCA1/2', 'Gene', '672;675', (28, 35))	('RARB', 'Gene', (135, 139))	('methylation', 'MPA', (55, 66))	('BRCA1/2', 'Gene', '672;675', (93, 100))	('RARB', 'Gene', '5915', (135, 139))	('PRA', 'Gene', (70, 73))	('methylation', 'MPA', (120, 131))	('mutation', 'Var', (36, 44))
113639	19258476	These observations provide preliminary evidence that, in unaffected high-risk women with a familial pattern of inherited breast cancer, there is an inverse association between frequency of promoter methylation events and presence of a BRCA1/2 mutation.	('promoter methylation', 'MPA', (189, 209))	('mutation', 'Var', (243, 251))	('women', 'Species', '9606', (78, 83))	('presence', 'Var', (221, 229))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('BRCA1/2', 'Gene', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('BRCA1/2', 'Gene', '672;675', (235, 242))	('inverse', 'NegReg', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
113644	19258476	Our exploratory analysis of women at high-risk for breast cancer provides preliminary evidence for CpG island promoter methylation in non-BRCA-mediated carcinogenesis.	('carcinogenesis', 'Disease', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA', 'Gene', '672', (138, 142))	('methylation', 'Var', (119, 130))	('BRCA', 'Gene', (138, 142))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('women', 'Species', '9606', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
113645	19258476	Importantly, we also observe (a) a bimodal distribution of promoter methylation events in mammary epithelial cells from high-risk women, which is expected because not all risk is hypothesized to result from a high frequency of promoter methylation events, and (b) an association between abnormal Masood cytology and methylation of RARB M4 (P = 0.051), INK4a/ARF (P = 0.042), HIN-1 (P = 0.044), and PRA (P = 0.032) promoters.	('PRA', 'Gene', (398, 401))	('abnormal Masood cytology', 'Disease', (287, 311))	('RARB', 'Gene', (331, 335))	('HIN-1', 'Gene', '92304', (375, 380))	('women', 'Species', '9606', (130, 135))	('HIN-1', 'Gene', (375, 380))	('PRA', 'Gene', '6277', (398, 401))	('RARB', 'Gene', '5915', (331, 335))	('INK4a/ARF', 'Gene', '1029', (352, 361))	('methylation', 'Var', (316, 327))	('association', 'Interaction', (267, 278))	('INK4a/ARF', 'Gene', (352, 361))
113646	19258476	Because the presence of atypia in RPFNA is associated with a 5.6-fold independent short-term breast cancer risk, these data provide evidence that specific CpG island promoter methylation events are associated with early mammary carcinogenesis.	('associated with', 'Reg', (198, 213))	('carcinogenesis', 'Disease', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('presence', 'Var', (12, 20))	('atypia', 'Var', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('methylation', 'Var', (175, 186))	('RPFNA', 'Gene', (34, 39))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('carcinogenesis', 'Disease', 'MESH:D063646', (228, 242))
113650	19258476	In premenopausal women with a familial pattern of breast cancer, we observe an association between total number of promoter methylation events and the presence or absence of a BRCA1/2 mutation.	('BRCA1/2', 'Gene', (176, 183))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('BRCA1/2', 'Gene', '672;675', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('women', 'Species', '9606', (17, 22))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('absence', 'NegReg', (163, 170))	('mutation', 'Var', (184, 192))
113651	19258476	The 40 high-risk women we tested for BRCA1/2 mutations (a) were premenopausal, (b) had a strong family history of breast cancer, and (c) were unaffected.	('BRCA1/2', 'Gene', '672;675', (37, 44))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('women', 'Species', '9606', (17, 22))	('BRCA1/2', 'Gene', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
113652	19258476	Of the 15 women testing positive for BRCA1/2 mutations, 100% had <=4 methylated promoter events, whereas only 1 of the 25 women testing negative for BRCA1/2 mutations had <=4 CpG island promoter methylation events (P < 0.0001).	('BRCA1/2', 'Gene', '672;675', (37, 44))	('mutations', 'Var', (45, 54))	('BRCA1/2', 'Gene', (149, 156))	('methylated promoter events', 'MPA', (69, 95))	('BRCA1/2', 'Gene', '672;675', (149, 156))	('women', 'Species', '9606', (122, 127))	('women', 'Species', '9606', (10, 15))	('BRCA1/2', 'Gene', (37, 44))
113653	19258476	Consistent with prior observations by Krop et al., no woman with a BRCA1/2 mutation showed methylation of HIN-1.	('HIN-1', 'Gene', '92304', (106, 111))	('woman', 'Species', '9606', (54, 59))	('mutation', 'Var', (75, 83))	('BRCA1/2', 'Gene', (67, 74))	('BRCA1/2', 'Gene', '672;675', (67, 74))	('methylation', 'MPA', (91, 102))	('HIN-1', 'Gene', (106, 111))
113654	19258476	We observed previously that the frequency of INK4a/ARF promoter methylation was inversely associated with the likelihood of an individual carrying a BRCA1 or BRCA2 mutation as measured by BRCAPRO.	('BRCA', 'Gene', (158, 162))	('methylation', 'Var', (64, 75))	('INK4a/ARF', 'Gene', (45, 54))	('BRCA', 'Gene', '672', (149, 153))	('INK4a/ARF', 'Gene', '1029', (45, 54))	('mutation', 'Var', (164, 172))	('BRCA1', 'Gene', '672', (149, 154))	('BRCA', 'Gene', '672', (188, 192))	('BRCA', 'Gene', (149, 153))	('BRCA1', 'Gene', (149, 154))	('BRCA', 'Gene', (188, 192))	('BRCA2', 'Gene', (158, 163))	('inversely', 'NegReg', (80, 89))	('BRCA', 'Gene', '672', (158, 162))	('BRCA2', 'Gene', '675', (158, 163))
113655	19258476	Consistent with this observation, only one woman with a BRCA1/2 mutation showed CpG island promoter methylation of INK4a/ARF, RARB M4, or PRB.	('RARB', 'Gene', '5915', (126, 130))	('mutation', 'Var', (64, 72))	('INK4a/ARF', 'Gene', (115, 124))	('woman', 'Species', '9606', (43, 48))	('methylation', 'MPA', (100, 111))	('BRCA1/2', 'Gene', (56, 63))	('PRB', 'Gene', '5925', (138, 141))	('INK4a/ARF', 'Gene', '1029', (115, 124))	('BRCA1/2', 'Gene', '672;675', (56, 63))	('PRB', 'Gene', (138, 141))	('RARB', 'Gene', (126, 130))
113656	19258476	These observations provide evidence that unaffected women with a BRCA1/2 mutation have an overall low frequency of CpG island promoter methylation events (<=4 of the 10 markers tested) relative to high-risk unaffected women who test negative for a BRCA1/2 mutation and that they do not frequently exhibit methylation of HIN-1, INK4a/ARF, RARB M4, or PRB promoters.	('BRCA1/2', 'Gene', (248, 255))	('PRB', 'Gene', (350, 353))	('women', 'Species', '9606', (218, 223))	('BRCA1/2', 'Gene', '672;675', (65, 72))	('RARB', 'Gene', '5915', (338, 342))	('HIN-1', 'Gene', '92304', (320, 325))	('HIN-1', 'Gene', (320, 325))	('CpG island promoter methylation', 'MPA', (115, 146))	('BRCA1/2', 'Gene', '672;675', (248, 255))	('INK4a/ARF', 'Gene', '1029', (327, 336))	('women', 'Species', '9606', (52, 57))	('INK4a/ARF', 'Gene', (327, 336))	('mutation', 'Var', (73, 81))	('PRB', 'Gene', '5925', (350, 353))	('BRCA1/2', 'Gene', (65, 72))	('RARB', 'Gene', (338, 342))
113658	19258476	Dysregulation and loss of expression of RARB, p16 (INK4a/ARF), and HIN-1 are known to play key roles in mammary carcinogenesis.	('expression', 'MPA', (26, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('Dysregulation', 'Var', (0, 13))	('loss of', 'NegReg', (18, 25))	('carcinogenesis', 'Disease', (112, 126))	('p16', 'Gene', '1029', (46, 49))	('RARB', 'Gene', (40, 44))	('INK4a/ARF', 'Gene', '1029', (51, 60))	('HIN-1', 'Gene', '92304', (67, 72))	('RARB', 'Gene', '5915', (40, 44))	('INK4a/ARF', 'Gene', (51, 60))	('p16', 'Gene', (46, 49))	('HIN-1', 'Gene', (67, 72))
113660	19258476	The RARB promoter has been shown to be hypermethylated in early mammary carcinogenesis and predicts an aggressive phenotype in salivary gland cancer.	('salivary gland cancer', 'Disease', (127, 148))	('RARB', 'Gene', '5915', (4, 8))	('predicts', 'Reg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hypermethylated', 'Var', (39, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('carcinogenesis', 'Disease', (72, 86))	('salivary gland cancer', 'Disease', 'MESH:D012468', (127, 148))	('RARB', 'Gene', (4, 8))
113674	19258476	Thirty-six of 40 (90%) subjects with CpG island promoter methylation of CRBP1 also displayed methylation of the RARB promoter (M3 and/or M4 site).	('RARB', 'Gene', '5915', (112, 116))	('CRBP1', 'Gene', '5947', (72, 77))	('methylation', 'Var', (57, 68))	('CRBP1', 'Gene', (72, 77))	('RARB', 'Gene', (112, 116))	('methylation', 'MPA', (93, 104))
113675	19258476	However, of 81 subjects with RARB methylation, only 36 (44%) displayed CRBP1 methylation.	('methylation', 'Var', (34, 45))	('RARB', 'Gene', (29, 33))	('CRBP1', 'Gene', '5947', (71, 76))	('RARB', 'Gene', '5915', (29, 33))	('CRBP1', 'Gene', (71, 76))
113676	19258476	that RARB promoter methylation precedes CRBP1 promoter methylation.	('methylation', 'Var', (19, 30))	('RARB', 'Gene', (5, 9))	('CRBP1', 'Gene', '5947', (40, 45))	('RARB', 'Gene', '5915', (5, 9))	('CRBP1', 'Gene', (40, 45))
113683	19258476	In contrast, our study shows a bimodal distribution of methylation frequency in women at high risk for developing breast cancer.	('women', 'Species', '9606', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('methylation', 'Var', (55, 66))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
113688	19258476	Our studies provide evidence that the combination of RARB M4, INK4a/ARF, PRB, and HIN-1 CpG island promoter methylation may predict non-BRCA1/2-associated mammary carcinogenesis and tumor progression.	('carcinogenesis', 'Disease', (163, 177))	('predict', 'Reg', (124, 131))	('tumor', 'Disease', (182, 187))	('RARB', 'Gene', '5915', (53, 57))	('PRB', 'Gene', '5925', (73, 76))	('RARB', 'Gene', (53, 57))	('INK4a/ARF', 'Gene', '1029', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('BRCA1/2', 'Gene', (136, 143))	('HIN-1', 'Gene', '92304', (82, 87))	('methylation', 'Var', (108, 119))	('INK4a/ARF', 'Gene', (62, 71))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('HIN-1', 'Gene', (82, 87))	('PRB', 'Gene', (73, 76))	('BRCA1/2', 'Gene', '672;675', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
113689	19258476	While there are limitations to our studies, i.e we are testing for promoter methylation in a small sample set (approximately 100 women and 40 women tested for BRCA1/2 mutations), our studies demonstrate a statistically significant association between promoter methylation events and BRCA1/2 mutation status.	('BRCA1/2', 'Gene', (159, 166))	('women', 'Species', '9606', (129, 134))	('BRCA1/2', 'Gene', (283, 290))	('mutations', 'Var', (167, 176))	('significant association', 'Reg', (219, 242))	('BRCA1/2', 'Gene', '672;675', (159, 166))	('BRCA1/2', 'Gene', '672;675', (283, 290))	('women', 'Species', '9606', (142, 147))	('promoter', 'MPA', (251, 259))
113705	32194672	In MDA-MB-231 breast carcinoma cells, Smad2 and Smad3 have diametrically opposite effects, with Smad3 knockdown resulting in a delayed bone metastasis of carcinoma cells, and Smad2 knockdown resulting in an enhanced invasive ability of MDA-MB-231 cells.	('bone metastasis of carcinoma cells', 'Disease', 'MESH:D009362', (135, 169))	('Smad3', 'Gene', '4088', (48, 53))	('bone metastasis of carcinoma cells', 'Disease', (135, 169))	('invasive ability', 'CPA', (216, 232))	('knockdown', 'Var', (102, 111))	('breast carcinoma', 'Disease', (14, 30))	('Smad2', 'Gene', (175, 180))	('Smad3', 'Gene', '4088', (96, 101))	('breast carcinoma', 'Disease', 'MESH:D001943', (14, 30))	('enhanced', 'PosReg', (207, 215))	('Smad3', 'Gene', (48, 53))	('knockdown', 'Var', (181, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('breast carcinoma', 'Phenotype', 'HP:0003002', (14, 30))	('Smad3', 'Gene', (96, 101))
113706	32194672	Smad4 has been identified as a tumor suppressor gene, and its mutation inactivation or decreased expression is often observed in tumor tissues, including colorectal and pancreatic carcinomas.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('decreased', 'NegReg', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('colorectal and pancreatic carcinomas', 'Disease', 'MESH:D010190', (154, 190))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('Smad4', 'Gene', (0, 5))	('mutation inactivation', 'Var', (62, 83))	('expression', 'MPA', (97, 107))
113745	32194672	Univariate analysis revealed that distant metastasis significantly predicted an increased risk of breast carcinoma progression (P=0.017; Table III) and poor OS time (P=0.010; Table III).	('breast carcinoma', 'Disease', (98, 114))	('breast carcinoma', 'Disease', 'MESH:D001943', (98, 114))	('distant', 'Var', (34, 41))	('poor OS time', 'CPA', (152, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('breast carcinoma', 'Phenotype', 'HP:0003002', (98, 114))
113755	32194672	Subsequently, the inactivation of Smad4 may further interfere with TGF-beta-induced growth inhibition.	('TGF-beta', 'Gene', '7039', (67, 75))	('Smad4', 'Gene', (34, 39))	('growth inhibition', 'CPA', (84, 101))	('inactivation', 'Var', (18, 30))	('TGF-beta', 'Gene', (67, 75))	('interfere', 'NegReg', (52, 61))
113756	32194672	Similarly, in human pancreatic ductal adenocarcinoma, the activation of HER2 and inactivation of Smad4 were also the most frequent gene alterations, which enabled human pancreatic ductal epithelial cells to acquire sustaining proliferative signaling, evade growth suppressors and finally result in tumorigenic transformation.	('evade', 'NegReg', (251, 256))	('pancreatic', 'Disease', (20, 30))	('activation', 'PosReg', (58, 68))	('pancreatic ductal adenocarcinoma', 'Disease', (20, 52))	('pancreatic', 'Disease', 'MESH:D010195', (169, 179))	('acquire', 'PosReg', (207, 214))	('tumor', 'Disease', (298, 303))	('HER2', 'Gene', '2064', (72, 76))	('alterations', 'Var', (136, 147))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (20, 52))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('inactivation', 'NegReg', (81, 93))	('pancreatic', 'Disease', (169, 179))	('human', 'Species', '9606', (14, 19))	('sustaining proliferative', 'MPA', (215, 239))	('Smad4', 'Gene', (97, 102))	('result in', 'Reg', (288, 297))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('HER2', 'Gene', (72, 76))	('growth suppressors', 'CPA', (257, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('pancreatic', 'Disease', 'MESH:D010195', (20, 30))	('human', 'Species', '9606', (163, 168))
113761	32194672	Although Smad2 is not so much regarded as a tumor-suppressor gene, certain studies have demonstrated that the functional inactivation of Smad2 is sufficient to inhibit the physiological function of TGF-beta.	('TGF-beta', 'Gene', '7039', (198, 206))	('physiological function', 'MPA', (172, 194))	('inhibit', 'NegReg', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('inactivation', 'Var', (121, 133))	('TGF-beta', 'Gene', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Smad2', 'Gene', (137, 142))	('tumor', 'Disease', (44, 49))
113762	32194672	Furthermore, one previous study tested Smad2-targeted knockout mouse keratinocytes and revealed that Smad2-/- mice did not naturally develop into skin tumor types, but that Smad2 may accelerate tumor formation and malignant transformation in chemical carcinogenesis experiments, and that Smad2-/- skin cancer was poorly differentiated and exhibited an increase in EMT, indicating that an Smad2-deficient epithelium was more likely to form a tumor and malignant transformation.	('mouse', 'Species', '10090', (63, 68))	('skin tumor', 'Disease', (146, 156))	('Smad2-/-', 'Var', (288, 296))	('tumor', 'Disease', (194, 199))	('skin cancer', 'Phenotype', 'HP:0008069', (297, 308))	('accelerate', 'PosReg', (183, 193))	('tumor', 'Disease', (441, 446))	('cancer', 'Disease', (302, 308))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('EMT', 'CPA', (364, 367))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', 'MESH:D009369', (441, 446))	('skin tumor', 'Phenotype', 'HP:0008069', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('Smad2', 'Gene', (173, 178))	('skin tumor', 'Disease', 'MESH:D012878', (146, 156))	('tumor', 'Disease', (151, 156))	('malignant transformation', 'CPA', (451, 475))	('increase', 'PosReg', (352, 360))	('mice', 'Species', '10090', (110, 114))	('malignant transformation', 'CPA', (214, 238))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
113765	32194672	Previous studies have revealed that the frequency of Smad4 gene mutant inactivation was high in solid tumor types, including breast carcinoma, which may partially explain the loss of Smad4 expression in the present study.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('breast carcinoma', 'Phenotype', 'HP:0003002', (125, 141))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('breast carcinoma', 'Disease', (125, 141))	('Smad4', 'Gene', (53, 58))	('breast carcinoma', 'Disease', 'MESH:D001943', (125, 141))	('tumor', 'Disease', (102, 107))	('mutant', 'Var', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
113772	32194672	In turn, the co-activation of p-Smad2 and Smad4 may serve a synergistic function in tumor suppression by transmitting TGF-beta signaling in the 100 p-Smad2/Smad4 co-positive expression breast carcinoma cases, resulting in a longer survival time and better prognosis.	('co-positive', 'Var', (162, 173))	('Smad4', 'Gene', (42, 47))	('co-activation', 'Var', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TGF-beta', 'Gene', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('breast carcinoma', 'Disease', 'MESH:D001943', (185, 201))	('breast carcinoma', 'Disease', (185, 201))	('tumor', 'Disease', (84, 89))	('longer', 'PosReg', (224, 230))	('TGF-beta', 'Gene', '7039', (118, 126))	('breast carcinoma', 'Phenotype', 'HP:0003002', (185, 201))	('p-Smad2/Smad4', 'Gene', (148, 161))	('survival time', 'CPA', (231, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('better', 'PosReg', (249, 255))
113773	32194672	In a similar study, although the effect of p-Smad2 and Smad4 co-expression or co-inactivation on prognosis was not observed, the OS time of patients with breast carcinoma which was p-Smad2-positive was significantly longer compared with that of p-Smad2-negative patients, which may have been due to the distinct specimen groups, the cut-offs used for the assessment or the antibodies used.	('patients', 'Species', '9606', (262, 270))	('breast carcinoma', 'Disease', (154, 170))	('longer', 'PosReg', (216, 222))	('breast carcinoma', 'Disease', 'MESH:D001943', (154, 170))	('patients', 'Species', '9606', (140, 148))	('breast carcinoma', 'Phenotype', 'HP:0003002', (154, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('p-Smad2-positive', 'Var', (181, 197))
113774	32194672	Furthermore, the close correlation between p-Smad2 and Smad4 expression was also discovered in other types of cancer, including osteosarcoma; Smad4 expression was significantly associated with p-Smad2 expression, and they each co-regulated the expression of the cell cycle inhibitor p21/waf1 to inhibit tumor cell growth.	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('p-Smad2', 'Var', (193, 200))	('cancer', 'Disease', (110, 116))	('waf1', 'Gene', (287, 291))	('Smad4', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('osteosarcoma', 'Disease', (128, 140))	('tumor', 'Disease', (303, 308))	('waf1', 'Gene', '1026', (287, 291))	('p21', 'Gene', '1026', (283, 286))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('associated', 'Reg', (177, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('inhibit', 'NegReg', (295, 302))	('expression', 'MPA', (201, 211))	('p21', 'Gene', (283, 286))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
113777	32194672	In addition, according to the results of the present study, p-Smad2 and Smad4 co-expression or co-inactivation may be seen as an independent predictor of prognosis in patients with invasive breast ductal carcinoma.	('co-expression', 'Var', (78, 91))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (197, 213))	('invasive breast ductal carcinoma', 'Disease', 'MESH:D018270', (181, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('Smad4', 'Gene', (72, 77))	('co-inactivation', 'Interaction', (95, 110))	('invasive breast ductal carcinoma', 'Disease', (181, 213))	('patients', 'Species', '9606', (167, 175))	('p-Smad2', 'Gene', (60, 67))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (190, 213))
113779	32194672	Of course, it is also limited to detecting the expression of proteins in paraffin samples only by immunohistochemistry, and future research will attempt to confirm the results of the present study by analyzing Smad2, p-Smad2 and Smad4 mRNA and protein levels in fresh breast ductal carcinoma samples.	('breast ductal carcinoma', 'Disease', (268, 291))	('paraffin', 'Chemical', 'MESH:D010232', (73, 81))	('p-Smad2', 'Var', (217, 224))	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (268, 291))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (275, 291))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (268, 291))	('Smad2', 'MPA', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))
113794	23598968	The differential diagnosis of monotonous, low-nuclear grade intraductal epithelial proliferations of the breast includes atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (LGDCIS).	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (169, 193))	('proliferations of the breast', 'Phenotype', 'HP:0100013', (83, 111))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (130, 148))	('ductal hyperplasia', 'Disease', (130, 148))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (169, 193))	('ductal carcinoma in situ', 'Disease', (169, 193))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (169, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('low-nuclear grade', 'Var', (42, 59))
113807	23598968	One was a cohort of patients with low-nuclear grade or intermediate-nuclear grade DCIS [LGDCIS (38%) or IGDCIS (62%); nuclear grade 1 or 2], whereas the second was a cohort of patients diagnosed with conventional ADH.	('patients', 'Species', '9606', (176, 184))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('patients', 'Species', '9606', (20, 28))	('intermediate-nuclear grade', 'Var', (55, 81))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('low-nuclear grade', 'Var', (34, 51))	('DCIS', 'Disease', (82, 86))
113853	23598968	Abundant residual lesion was significantly associated with DCIS/IDC on EB (P < 0.05 vs. all other amounts of residual lesion; Fisher exact test); conversely, the absence of any residual lesion was significantly associated with the absence of DCIS/IDC on EB (P < 0.001 vs. any amount of residual lesion; Fisher exact test).	('IDC', 'Gene', '4000', (64, 67))	('IDC', 'Gene', '4000', (247, 250))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('EB', 'Chemical', '-', (254, 256))	('EB', 'Chemical', '-', (71, 73))	('IDC', 'Gene', (64, 67))	('IDC', 'Gene', (247, 250))	('absence of DCIS', 'Phenotype', 'HP:0006485', (231, 246))	('DCIS', 'Phenotype', 'HP:0030075', (242, 246))	('absence', 'Var', (162, 169))
113939	32621785	The majority of the invasive cancers were of the ductal type (76.7%, 23 cancers), <=20 mm (86.7%, 26 cancers), lymph node negative (73.3%, 22 cancers) and Bloom and Richardson grade I (43.3%, 13 cancers) or II (46.7%, 14 cancers).	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('<=20 mm', 'Var', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Disease', (142, 149))	('cancers', 'Disease', (221, 228))	('invasive cancers', 'Disease', 'MESH:D009362', (20, 36))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('invasive cancers', 'Disease', (20, 36))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancers', 'Disease', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (195, 202))
113998	31027259	Whole genome expression studies using microarrays have led to classification of BC into five different subtypes of breast carcinomas based solely on clustered gene expression: luminal A (ER+ and/or PR+, HER2-, low Ki-67), luminal B (ER+ and/or PR+, HER2-/+, high Ki-67), HER2-overexpressing (ER-, PR- and HER2+), basal-like (express markers of basal/myoepithelial cells), and normal breast-like (enriched in markers of adipose cells/normal mammary cells).	('HER2', 'Gene', (203, 207))	('breast carcinomas', 'Phenotype', 'HP:0003002', (115, 132))	('high Ki-67', 'Var', (258, 268))	('BC', 'Disease', 'MESH:D001943', (80, 82))	('ER', 'Gene', '2099', (292, 294))	('ER', 'Gene', '2099', (204, 206))	('HER2', 'Gene', (249, 253))	('HER2', 'Gene', (305, 309))	('HER2', 'Gene', (271, 275))	('ER', 'Gene', '2099', (306, 308))	('ER', 'Gene', '2099', (187, 189))	('ER', 'Gene', '2099', (250, 252))	('ER', 'Gene', '2099', (233, 235))	('HER2', 'Gene', '2064', (203, 207))	('basal-like', 'CPA', (313, 323))	('ER', 'Gene', '2099', (272, 274))	('HER2', 'Gene', '2064', (249, 253))	('breast carcinomas', 'Disease', 'MESH:D001943', (115, 132))	('breast carcinomas', 'Disease', (115, 132))	('HER2', 'Gene', '2064', (305, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('HER2', 'Gene', '2064', (271, 275))
114004	31027259	These observations suggest that different types of BC originate from dysregulation of different oncogenes, paving the way for the search for highly specific therapeutic targets.	('originate from', 'Reg', (54, 68))	('dysregulation', 'Var', (69, 82))	('BC', 'Disease', 'MESH:D001943', (51, 53))
114015	31027259	It is noteworthy to mention that the term TNBC refers to the immunohistochemical description of the tumor (ER-, PR-, HER2-); while basal-like BC is defined from its gene expression signature and refers to a subset of TNBCs that express other markers of basal/myoepithelial cells such as basal cytokeratins (CK5/6, CK14 and CK17), vimentin, and epidermal growth factor receptor (EGFR).	('HER2', 'Gene', (117, 121))	('tumor', 'Disease', (100, 105))	('EGFR', 'Gene', (378, 382))	('CK5/6', 'Var', (307, 312))	('CK17', 'Gene', '3872', (323, 327))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('TNBCs', 'Chemical', '-', (217, 222))	('ER', 'Gene', '2099', (118, 120))	('EGFR', 'Gene', '1956', (378, 382))	('BC', 'Disease', 'MESH:D001943', (142, 144))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HER2', 'Gene', '2064', (117, 121))	('ER', 'Gene', '2099', (107, 109))	('epidermal growth factor receptor', 'Gene', (344, 376))	('BC', 'Disease', 'MESH:D001943', (219, 221))	('CK17', 'Gene', (323, 327))	('vimentin', 'Gene', '7431', (330, 338))	('epidermal growth factor receptor', 'Gene', '1956', (344, 376))	('vimentin', 'Gene', (330, 338))	('CK14', 'Gene', (314, 318))	('BC', 'Disease', 'MESH:D001943', (44, 46))	('CK14', 'Gene', '3861', (314, 318))
114027	31027259	Derepression of SMO subsequently activates the glioma-associated oncogene (GLI) transcription factors (GLI1, GLI2 and GLI3), which in turn stimulate expression of downstream target genes.	('stimulate', 'PosReg', (139, 148))	('GLI', 'Gene', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('GLI', 'Gene', (75, 78))	('GLI', 'Gene', '2735', (103, 106))	('GLI', 'Gene', (109, 112))	('activates', 'PosReg', (33, 42))	('glioma', 'Disease', (47, 53))	('GLI', 'Gene', '2735', (118, 121))	('SMO', 'Gene', (16, 19))	('GLI', 'Gene', '2735', (75, 78))	('Derepression', 'Var', (0, 12))	('expression', 'MPA', (149, 159))	('GLI', 'Gene', '2735', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('GLI', 'Gene', (103, 106))
114033	31027259	Ligand-independent constitutive activation of GLIs (as a consequence of loss-of-function mutations of PTCH1 or gain-of-function mutations of SMO) drives basal cell carcinoma (BCC) and Shh-type medulloblastoma development.	('SMO', 'Gene', (141, 144))	('mutations', 'Var', (89, 98))	('basal cell carcinoma', 'Disease', (153, 173))	('BCC', 'Disease', 'MESH:D002280', (175, 178))	('Shh-type medulloblastoma', 'Disease', 'MESH:D008527', (184, 208))	('PTCH1', 'Gene', (102, 107))	('mutations', 'Var', (128, 137))	('BCC', 'Disease', (175, 178))	('GLI', 'Gene', (46, 49))	('activation', 'PosReg', (32, 42))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (153, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('loss-of-function', 'NegReg', (72, 88))	('medulloblastoma', 'Phenotype', 'HP:0002885', (193, 208))	('GLI', 'Gene', '2735', (46, 49))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (153, 173))	('drives', 'PosReg', (146, 152))	('gain-of-function', 'PosReg', (111, 127))	('Shh-type medulloblastoma', 'Disease', (184, 208))
114034	31027259	Even though epithelial cancers do not present mutations in the components of the Hh pathway, they are characterized by upregulation of SHH and/or IHH, which can modulate tumorigenesis in an autocrine, paracrine, or reserve-paracrine fashion.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('mutations', 'Var', (46, 55))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('IHH', 'Gene', (146, 149))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancers', 'Disease', (23, 30))	('upregulation', 'PosReg', (119, 131))	('tumor', 'Disease', (170, 175))	('modulate', 'Reg', (161, 169))	('SHH', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('IHH', 'Gene', '3549', (146, 149))
114041	31027259	Ductal morphogenesis is impaired in mice carrying a mutation in the C-terminal domain of PTCH1 (ptc1mes) that affects type I non-canonical Hh signaling but not GLI activation.	('type I non-canonical Hh signaling', 'MPA', (118, 151))	('ptc1', 'Gene', (96, 100))	('PTCH1', 'Gene', (89, 94))	('GLI', 'Gene', (160, 163))	('ptc1', 'Gene', '19206', (96, 100))	('Ductal morphogenesis', 'CPA', (0, 20))	('GLI', 'Gene', '2735', (160, 163))	('mice', 'Species', '10090', (36, 40))	('affects', 'Reg', (110, 117))	('impaired', 'NegReg', (24, 32))	('mutation in', 'Var', (52, 63))
114044	31027259	Mutations in SHH, PTCH1, and GLI1 are very rare in BC, arguing against mutational activation of the Hh pathway in BC.	('BC', 'Disease', 'MESH:D001943', (114, 116))	('Hh pathway', 'Pathway', (100, 110))	('PTCH1', 'Gene', (18, 23))	('Mutations', 'Var', (0, 9))	('GLI1', 'Gene', (29, 33))	('SHH', 'Gene', (13, 16))	('BC', 'Disease', 'MESH:D001943', (51, 53))
114050	31027259	In one study, hyperactivation of the pathway by overexpression of GLI1 under the MMTV promoter in the mammary epithelium was sufficient to induce hyperplastic lesions and tumor development in mice.	('hyperactivation', 'Var', (14, 29))	('mice', 'Species', '10090', (192, 196))	('GLI1', 'Gene', (66, 70))	('hyperplastic lesions', 'Disease', 'MESH:D054514', (146, 166))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('MMTV', 'Species', '11757', (81, 85))	('overexpression', 'PosReg', (48, 62))	('induce', 'PosReg', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('hyperplastic lesions', 'Disease', (146, 166))
114058	31027259	Reduced CpG methylation of the SHH promoter has been linked to increased SHH expression in several cancers.	('SHH promoter', 'Gene', (31, 43))	('expression', 'MPA', (77, 87))	('increased', 'PosReg', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('SHH', 'Gene', (73, 76))	('Reduced', 'NegReg', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('CpG methylation', 'Var', (8, 23))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
114060	31027259	Moreover, 5-azacytidine potentiated SHH upregulation following TNFalpha stimulation of BC cells (which activates NF-kappaB) but not when the NF-kappaB inhibitor PDTC was present.	('NF-kappaB', 'Gene', '4790', (113, 122))	('TNFalpha', 'Gene', (63, 71))	('BC', 'Disease', 'MESH:D001943', (87, 89))	('5-azacytidine', 'Chemical', 'MESH:D001374', (10, 23))	('SHH', 'MPA', (36, 39))	('upregulation', 'PosReg', (40, 52))	('NF-kappaB', 'Gene', (113, 122))	('TNFalpha', 'Gene', '7124', (63, 71))	('5-azacytidine', 'Var', (10, 23))	('NF-kappaB', 'Gene', '4790', (141, 150))	('potentiated', 'PosReg', (24, 35))	('NF-kappaB', 'Gene', (141, 150))
114067	31027259	To be able to elucidate PTCH involvement in BC and its therapeutic potential, further studies should address the discrepancies among authors and clearly determine if BC features can be associated or not to a dysregulation of PTCH1 expression.	('PTCH', 'Gene', (225, 229))	('associated', 'Reg', (185, 195))	('BC', 'Disease', 'MESH:D001943', (166, 168))	('BC', 'Disease', 'MESH:D001943', (44, 46))	('PTCH', 'Gene', '5727', (24, 28))	('PTCH', 'Gene', (24, 28))	('PTCH', 'Gene', '5727', (225, 229))	('dysregulation', 'Var', (208, 221))
114071	31027259	Silencing of GLI1 expression with siRNA or inhibition of SMO with the plant-derived alkaloid cyclopamine in two ER-negative, one TNBC and one basal-like BC cell line reduced proliferation and invasion.	('cyclopamine', 'Chemical', 'MESH:C000541', (93, 104))	('BC', 'Disease', 'MESH:D001943', (153, 155))	('alkaloid', 'Chemical', 'MESH:D000470', (84, 92))	('inhibition', 'NegReg', (43, 53))	('reduced', 'NegReg', (166, 173))	('invasion', 'CPA', (192, 200))	('ER', 'Gene', '2099', (112, 114))	('GLI1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('BC', 'Disease', 'MESH:D001943', (131, 133))	('proliferation', 'CPA', (174, 187))
114072	31027259	Similar experiments in SUM145 TNBC cells showed increased apoptosis and reduced migration after GLI1 silencing.	('reduced', 'NegReg', (72, 79))	('GLI1', 'Gene', (96, 100))	('silencing', 'Var', (101, 110))	('migration', 'CPA', (80, 89))	('BC', 'Disease', 'MESH:D001943', (32, 34))	('SUM145', 'CellLine', 'CVCL:B570', (23, 29))
114074	31027259	A GLI1 mRNA splice variant that eliminates 41 codons spanning exon 3 and part of exon 4 results in expression of a truncated form of GLI1 (tGLI1).	('expression', 'MPA', (99, 109))	('results in', 'Reg', (88, 98))	('variant', 'Var', (19, 26))	('tGLI1', 'Chemical', '-', (139, 144))	('41 codons', 'MPA', (43, 52))	('eliminates', 'NegReg', (32, 42))
114078	31027259	In agreement, BC cells expressing tGLI1 migrate faster, are more invasive and more pro-angiogenic than cells expressing the longer GLI1 variant.	('tGLI1', 'Var', (34, 39))	('more', 'PosReg', (60, 64))	('faster', 'PosReg', (48, 54))	('more', 'PosReg', (78, 82))	('tGLI1', 'Chemical', '-', (34, 39))	('BC', 'Disease', 'MESH:D001943', (14, 16))	('pro-angiogenic', 'CPA', (83, 97))	('invasive', 'CPA', (65, 73))
114080	31027259	These results suggest that expression of tGLI1 might increase the metastatic potential of BC cells.	('increase', 'PosReg', (53, 61))	('tGLI1', 'Chemical', '-', (41, 46))	('tGLI1', 'Gene', (41, 46))	('expression', 'Var', (27, 37))	('BC', 'Disease', 'MESH:D001943', (90, 92))
114082	31027259	LKB1 has been shown to inhibit Hh signaling and impair xenograft growth of MDA-MB-231 BC cells, while knockdown of LKB1 increased both Hh signaling and the rate of xenograft growth.	('BC', 'Disease', 'MESH:D001943', (86, 88))	('Hh signaling', 'MPA', (135, 147))	('xenograft growth', 'CPA', (55, 71))	('LKB1', 'Gene', (0, 4))	('inhibit', 'NegReg', (23, 30))	('impair', 'NegReg', (48, 54))	('knockdown', 'Var', (102, 111))	('LKB1', 'Gene', '6794', (0, 4))	('LKB1', 'Gene', (115, 119))	('LKB1 increased', 'Phenotype', 'HP:0030269', (115, 129))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))	('increased', 'PosReg', (120, 129))	('LKB1', 'Gene', '6794', (115, 119))	('Hh signaling', 'MPA', (31, 43))
114086	31027259	Estrogen increases cell proliferation and particularly boosts the proportion of cancer stem cells (CSC) within a cancer cell population.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (113, 119))	('Estrogen', 'Var', (0, 8))	('increases', 'PosReg', (9, 18))	('boosts', 'PosReg', (55, 61))	('cell proliferation', 'CPA', (19, 37))	('Estrogen increases', 'Phenotype', 'HP:0025134', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (80, 86))
114088	31027259	A recent study showed that estrogen increases the levels of GLI1 and GLI2 in several ER-positive BC cell lines, whereas inhibition of GLI1 and GLI2 activity with GANT61 reduced the number of mammosphere-forming CSC in the cultures.	('BC', 'Disease', 'MESH:D001943', (97, 99))	('inhibition', 'Var', (120, 130))	('activity', 'MPA', (148, 156))	('reduced', 'NegReg', (169, 176))	('levels', 'MPA', (50, 56))	('increases', 'PosReg', (36, 45))	('ER', 'Gene', '2099', (85, 87))	('estrogen increases', 'Phenotype', 'HP:0025134', (27, 45))
114101	31027259	The central role of canonical Hh signaling in TNBC angiogenesis is also highlighted by the reduction of xenograft proliferation and vascularization caused by administration of NVP-LDE225, an FDA-approved SMO inhibitor.	('xenograft proliferation', 'CPA', (104, 127))	('NVP-LDE225', 'Var', (176, 186))	('vascularization', 'CPA', (132, 147))	('reduction', 'NegReg', (91, 100))	('BC', 'Disease', 'MESH:D001943', (48, 50))
114114	31027259	In support, inhibition of NF-kappaB reduces GLI1 expression in several BC cell lines (BT549, HS578T, MDA-MB-231, MDA-MB-157, MDA-MB-436 and MCF10A).	('NF-kappaB', 'Gene', '4790', (26, 35))	('inhibition', 'Var', (12, 22))	('BT549', 'CellLine', 'CVCL:1092', (86, 91))	('NF-kappaB', 'Gene', (26, 35))	('BC', 'Disease', 'MESH:D001943', (71, 73))	('expression', 'MPA', (49, 59))	('GLI1', 'Gene', (44, 48))	('reduces', 'NegReg', (36, 43))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (101, 111))	('MCF10A', 'CellLine', 'CVCL:0598', (140, 146))	('HS578T', 'CellLine', 'CVCL:0332', (93, 99))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (125, 135))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (113, 123))
114124	31027259	Silencing of GLI1 in TNBC cells abrogates hypoxia-induced upregulation of Vimentin and loss of E-Cadherin.	('loss', 'NegReg', (87, 91))	('Vimentin', 'Gene', '7431', (74, 82))	('Vimentin', 'Gene', (74, 82))	('BC', 'Disease', 'MESH:D001943', (23, 25))	('abrogates', 'NegReg', (32, 41))	('E-Cadherin', 'Protein', (95, 105))	('hypoxia', 'Disease', (42, 49))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('GLI1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('upregulation', 'PosReg', (58, 70))
114125	31027259	Another report showed that GLI1 represses E-Cadherin expression in basal type B SUM145 cells but not through reduction of Snail, a classical E-Cadherin repressor.	('Snail', 'Gene', (122, 127))	('Snail', 'Gene', '6615', (122, 127))	('SUM145', 'CellLine', 'CVCL:B570', (80, 86))	('E-Cadherin', 'Protein', (42, 52))	('represses', 'NegReg', (32, 41))	('GLI1', 'Var', (27, 31))	('expression', 'MPA', (53, 63))
114127	31027259	Mammary ductal hyperplasia in transgenic mice expressing a constitutively active SMO mutant (SMO-M2) exhibits signs of loss of basolateral polarity reminiscent of EMT.	('hyperplasia', 'Disease', (15, 26))	('transgenic mice', 'Species', '10090', (30, 45))	('basolateral polarity', 'MPA', (127, 147))	('loss', 'NegReg', (119, 123))	('hyperplasia', 'Disease', 'MESH:D006965', (15, 26))	('mutant', 'Var', (85, 91))
114128	31027259	Mice expressing a conditional GLI1 transgene develop basal-like ER-negative tumors characterized by loss of E-Cadherin.	('GLI1', 'Gene', (30, 34))	('E-Cadherin', 'Protein', (108, 118))	('basal-like', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('transgene', 'Var', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Mice', 'Species', '10090', (0, 4))	('ER', 'Gene', '2099', (64, 66))	('loss', 'NegReg', (100, 104))
114134	31027259	Indeed, pharmacological inhibition of GLI1 with GANT61, but not of SMO with IPI926, in non-EMT cells prevents the phenotypic changes caused by EMT-cells, suggesting that the paracrine effect is not mediated by Hh ligands.	('prevents', 'NegReg', (101, 109))	('phenotypic changes', 'CPA', (114, 132))	('GANT61', 'Var', (48, 54))	('IPI926', 'Chemical', 'MESH:C541444', (76, 82))	('GLI1', 'Gene', (38, 42))
114136	31027259	Inhibition of GLI1, although pharmacologically more challenging, could be preferable for the treatment of TNBC and to prevent metastasis and recurrence.	('BC', 'Disease', 'MESH:D001943', (108, 110))	('GLI1', 'Gene', (14, 18))	('metastasis', 'CPA', (126, 136))	('Inhibition', 'Var', (0, 10))
114145	31027259	Interestingly, GLI1 also induces LCP1/L-PLASTIN, a signaling mediator of CXCL12/CXCR4 signaling in BC cells, resulting in enhanced ERK phosphorylation and cell migration.	('CXCR4', 'Gene', (80, 85))	('LCP1', 'Gene', (33, 37))	('enhanced', 'PosReg', (122, 130))	('ERK', 'Gene', '5594', (131, 134))	('CXCL12', 'Gene', (73, 79))	('GLI1', 'Var', (15, 19))	('induces', 'Reg', (25, 32))	('ERK', 'Gene', (131, 134))	('cell migration', 'CPA', (155, 169))	('L-PLASTIN', 'Gene', (38, 47))	('BC', 'Disease', 'MESH:D001943', (99, 101))	('CXCL12', 'Gene', '6387', (73, 79))	('CXCR4', 'Gene', '7852', (80, 85))	('L-PLASTIN', 'Gene', '3936', (38, 47))	('LCP1', 'Gene', '3936', (33, 37))
114146	31027259	These results point to the therapeutic inhibition of GLI1 as a rational approach to reduce the metastatic burden in BC.	('inhibition', 'Var', (39, 49))	('reduce', 'NegReg', (84, 90))	('BC', 'Disease', 'MESH:D001943', (116, 118))	('metastatic burden', 'CPA', (95, 112))	('GLI1', 'Gene', (53, 57))
114154	31027259	Moreover, the study of the dysregulation of the Hh signaling pathway in samples from affected patients would strongly validate its role in the onset and/or progression of BC.	('BC', 'Disease', 'MESH:D001943', (171, 173))	('dysregulation', 'Var', (27, 40))	('Hh signaling pathway', 'Pathway', (48, 68))	('patients', 'Species', '9606', (94, 102))
114170	31027259	Moreover, high expression levels of members of the Hh pathway was associated with shorter survival related to occurrence of metastasis in patients with luminal-B tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('survival', 'MPA', (90, 98))	('Hh pathway', 'Pathway', (51, 61))	('high', 'Var', (10, 14))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('patients', 'Species', '9606', (138, 146))	('shorter', 'NegReg', (82, 89))
114186	31027259	Hypomethylation of SHH promoter region was also observed in BC tumors with higher levels of SHH and NF-kappaB nuclear staining.	('Hypomethylation', 'Var', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('NF-kappaB', 'Gene', '4790', (100, 109))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('BC', 'Disease', 'MESH:D001943', (60, 62))	('SHH', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('NF-kappaB', 'Gene', (100, 109))	('observed', 'Reg', (48, 56))
114191	31027259	Missense PTCH1 mutations were found in some BC patients, and a specific PTCH1 polymorphism was linked to the association between the risk of BC and the use of oral contraceptives.	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (47, 55))	('BC', 'Disease', 'MESH:D001943', (44, 46))	('PTCH1', 'Gene', (72, 77))	('PTCH1', 'Gene', (9, 14))	('linked to', 'Reg', (95, 104))	('association', 'Interaction', (109, 120))	('Missense', 'Var', (0, 8))	('BC', 'Disease', 'MESH:D001943', (141, 143))
114192	31027259	No SMO mutations have been reported to date in BC.	('SMO', 'Gene', (3, 6))	('BC', 'Disease', 'MESH:D001943', (47, 49))	('mutations', 'Var', (7, 16))
114226	31027259	In one study, 5E1 mAb was shown to sequester Hh proteins secreted by BC cells and, as a consequence, reduce osteoclast differentiation.	('BC', 'Disease', 'MESH:D001943', (69, 71))	('reduce', 'NegReg', (101, 107))	('5E1 mAb', 'Var', (14, 21))	('osteoclast differentiation', 'CPA', (108, 134))	('sequester', 'NegReg', (35, 44))	('Hh proteins', 'Protein', (45, 56))
114231	31027259	Interestingly, the tumors tend to develop resistance to the inhibitors by novel mutations in SMO or by hijacking other pathways that activate GLI1 downstream of SMO, such as those described here in BC.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('develop', 'PosReg', (34, 41))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SMO', 'Gene', (93, 96))	('BC', 'Disease', 'MESH:D001943', (198, 200))	('GLI1', 'Protein', (142, 146))	('resistance', 'MPA', (42, 52))	('hijacking', 'Reg', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('activate', 'PosReg', (133, 141))
114240	31027259	In TNBC MDA-MB-231 cells, cyclopamine was shown to reduced cyclin D1 and BCL2, two classical GLI-target genes and, as consequence, to decrease proliferation and stimulate apoptosis.	('GLI', 'Gene', (93, 96))	('BC', 'Disease', 'MESH:D001943', (73, 75))	('reduced', 'NegReg', (51, 58))	('cyclopamine', 'Chemical', 'MESH:C000541', (26, 37))	('GLI', 'Gene', '2735', (93, 96))	('BCL2', 'Gene', '596', (73, 77))	('stimulate', 'PosReg', (161, 170))	('apoptosis', 'CPA', (171, 180))	('BCL2', 'Gene', (73, 77))	('decrease', 'NegReg', (134, 142))	('BC', 'Disease', 'MESH:D001943', (5, 7))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (8, 18))	('cyclin D1', 'Gene', '595', (59, 68))	('cyclopamine', 'Var', (26, 37))	('cyclin D1', 'Gene', (59, 68))	('proliferation', 'CPA', (143, 156))
114249	31027259	Since NOTCH and Hh are involved in self-renewal of stem cells, the rationale was that inhibiting both pathways would eliminate CSCs and prevent recurrence in advanced cases of TNBC.	('prevent', 'NegReg', (136, 143))	('eliminate', 'NegReg', (117, 126))	('inhibiting', 'Var', (86, 96))	('CSCs', 'Disease', (127, 131))	('BC', 'Disease', 'MESH:D001943', (178, 180))
114264	31027259	When administered systemically in mice, itraconazole suppressed the growth of medulloblastoma and reduced Hh activation markers at similar concentrations than required for its antifungal activity.	('mice', 'Species', '10090', (34, 38))	('medulloblastoma', 'Disease', 'MESH:D008527', (78, 93))	('medulloblastoma', 'Phenotype', 'HP:0002885', (78, 93))	('reduced Hh activation markers', 'Phenotype', 'HP:0031270', (98, 127))	('growth', 'MPA', (68, 74))	('Hh activation markers', 'MPA', (106, 127))	('medulloblastoma', 'Disease', (78, 93))	('itraconazole', 'Var', (40, 52))	('reduced', 'NegReg', (98, 105))	('itraconazole', 'Chemical', 'MESH:D017964', (40, 52))	('suppressed', 'NegReg', (53, 63))
114268	31027259	In effect, a pilot trial in 13 metastatic BC patients showed that itraconazole decreased the plasma levels of betaFGF and PIGF, two proangiogenic factors, and increased the level of thrombospondin-1, an inhibitor of angiogenesis (trial ID NCT00798135,) (Table 3).	('thrombospondin-1', 'Gene', (182, 198))	('PIGF', 'Gene', '5281', (122, 126))	('plasma levels', 'MPA', (93, 106))	('itraconazole', 'Var', (66, 78))	('decreased', 'NegReg', (79, 88))	('thrombospondin-1', 'Gene', '7057', (182, 198))	('increased', 'PosReg', (159, 168))	('betaFGF', 'Protein', (110, 117))	('itraconazole', 'Chemical', 'MESH:D017964', (66, 78))	('patients', 'Species', '9606', (45, 53))	('BC', 'Disease', 'MESH:D001943', (42, 44))	('NC', 'Chemical', 'MESH:C013615', (239, 241))	('level', 'MPA', (173, 178))	('PIGF', 'Gene', (122, 126))
114288	31027259	GANT61 not only inhibited proliferation of ER-positive cells, but also reduced the CSC compartment in combination with antiestrogens.	('inhibited', 'NegReg', (16, 25))	('GANT61', 'Var', (0, 6))	('CSC compartment', 'CPA', (83, 98))	('reduced', 'NegReg', (71, 78))	('ER', 'Gene', '2099', (43, 45))	('proliferation', 'CPA', (26, 39))
114293	31027259	The drugs in this category inhibit GLI transcriptional activity indirectly by interfering with primary cilium formation, trafficking of GLI proteins into the cilium, regulation of post-translational modifications of GLIs and by epigenetic silencing.	('trafficking', 'MPA', (121, 132))	('GLI', 'Gene', '2735', (216, 219))	('GLI', 'Gene', '2735', (35, 38))	('primary cilium formation', 'CPA', (95, 119))	('GLI', 'Gene', (136, 139))	('post-translational modifications', 'MPA', (180, 212))	('regulation', 'Reg', (166, 176))	('GLI', 'Gene', (216, 219))	('interfering', 'NegReg', (78, 89))	('epigenetic silencing', 'Var', (228, 248))	('GLI', 'Gene', (35, 38))	('GLI', 'Gene', '2735', (136, 139))	('inhibit', 'NegReg', (27, 34))
114325	31027259	Improved delivery of curcumin in nano-micelles or as conjugate of a self-assembling variant of human apoferritin improved its solubility and stability and displayed cytotoxic effects on MDA-MB-468 and MDA-MB-231 cells by inducing G0/G1 cell cycle arrest and reduction of PI3K/Akt signaling, enhanced the cytotoxic effect of doxorubicin by interfering with multidrug resistance transporters, and reduced TNBC tumor growth in mice without systemic toxicity.	('mice', 'Species', '10090', (38, 42))	('Akt', 'Gene', (276, 279))	('toxicity', 'Disease', (446, 454))	('drug resistance', 'Phenotype', 'HP:0020174', (361, 376))	('interfering', 'NegReg', (339, 350))	('Akt', 'Gene', '207', (276, 279))	('reduction', 'NegReg', (258, 267))	('tumor', 'Disease', (408, 413))	('tumor', 'Disease', 'MESH:D009369', (408, 413))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (201, 211))	('BC', 'Disease', 'MESH:D001943', (405, 407))	('mice', 'Species', '10090', (424, 428))	('doxorubicin', 'Chemical', 'MESH:D004317', (324, 335))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (186, 196))	('human', 'Species', '9606', (95, 100))	('solubility', 'MPA', (126, 136))	('inducing', 'PosReg', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('enhanced', 'PosReg', (291, 299))	('reduced', 'NegReg', (395, 402))	('multidrug resistance transporters', 'MPA', (356, 389))	('variant', 'Var', (84, 91))	('toxicity', 'Disease', 'MESH:D064420', (446, 454))	('stability', 'MPA', (141, 150))	('curcumin', 'Chemical', 'MESH:D003474', (21, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (236, 253))	('apoferritin', 'Gene', (101, 112))	('G0/G1 cell cycle arrest', 'CPA', (230, 253))	('improved', 'PosReg', (113, 121))	('apoferritin', 'Gene', '2495', (101, 112))	('cytotoxic effect', 'CPA', (304, 320))
114368	31027259	BC patients with high expression of the vitamin D receptor (VDR) have reduced incidence of metastasis and better survival than those with low VDR.	('survival', 'CPA', (113, 121))	('vitamin D receptor', 'Gene', '7421', (40, 58))	('reduced', 'NegReg', (70, 77))	('better', 'PosReg', (106, 112))	('vitamin D receptor', 'Gene', (40, 58))	('VDR', 'Gene', (60, 63))	('high expression', 'Var', (17, 32))	('metastasis', 'CPA', (91, 101))	('patients', 'Species', '9606', (3, 11))	('BC', 'Disease', 'MESH:D001943', (0, 2))
114369	31027259	In addition, some VDR polymorphisms were associated with higher risk of BC.	('VDR', 'Gene', (18, 21))	('BC', 'Disease', 'MESH:D001943', (72, 74))	('polymorphisms', 'Var', (22, 35))
114383	31027259	Key factors involved in tamoxifen resistance are loss of ERalpha function, ERalpha mutations, and the activation of ER signaling through the dysregulation of tyrosine kinase receptors (EGFR, HER2, IGF1R, FGFR), and a number of signaling pathways, including PI3K-PTEN/AKT/mTOR and NF-kappaB, among others.	('ER', 'Gene', '2099', (192, 194))	('PTEN', 'Gene', '5728', (262, 266))	('HER2', 'Gene', '2064', (191, 195))	('tamoxifen', 'Chemical', 'MESH:D013629', (24, 33))	('mTOR', 'Gene', (271, 275))	('ERalpha', 'Gene', (57, 64))	('EGFR', 'Gene', (185, 189))	('AKT', 'Gene', (267, 270))	('ER', 'Gene', '2099', (116, 118))	('mTOR', 'Gene', '2475', (271, 275))	('ERalpha', 'Gene', '2099', (57, 64))	('loss', 'NegReg', (49, 53))	('HER2', 'Gene', (191, 195))	('signaling pathways', 'Pathway', (227, 245))	('IGF1R', 'Gene', '3480', (197, 202))	('ER', 'Gene', '2099', (75, 77))	('ERalpha', 'Gene', (75, 82))	('EGFR', 'Gene', '1956', (185, 189))	('PTEN', 'Gene', (262, 266))	('NF-kappaB', 'Gene', (280, 289))	('dysregulation', 'MPA', (141, 154))	('mutations', 'Var', (83, 92))	('IGF1R', 'Gene', (197, 202))	('AKT', 'Gene', '207', (267, 270))	('activation', 'PosReg', (102, 112))	('ER', 'Gene', '2099', (57, 59))	('NF-kappaB', 'Gene', '4790', (280, 289))	('ERalpha', 'Gene', '2099', (75, 82))
114391	31027259	GLI1 silencing was shown to attenuate cell proliferation and to enhance tamoxifen cytotoxicity in both tamoxifen-resistant and -sensitive BC cells.	('GLI1', 'Gene', (0, 4))	('enhance', 'PosReg', (64, 71))	('cell proliferation', 'CPA', (38, 56))	('BC', 'Disease', 'MESH:D001943', (138, 140))	('cytotoxicity', 'Disease', (82, 94))	('attenuate', 'NegReg', (28, 37))	('silencing', 'Var', (5, 14))	('tamoxifen', 'Chemical', 'MESH:D013629', (103, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('tamoxifen', 'Chemical', 'MESH:D013629', (72, 81))
114392	31027259	GLI1 depletion also decreases ERalpha protein levels and ERalpha transcriptional activity.	('ERalpha', 'Gene', (30, 37))	('GLI1', 'Gene', (0, 4))	('depletion', 'Var', (5, 14))	('decreases', 'NegReg', (20, 29))	('ERalpha', 'Gene', (57, 64))	('ERalpha', 'Gene', '2099', (57, 64))	('ERalpha', 'Gene', '2099', (30, 37))
114408	31027259	Upregulation of Hh ligands might contribute to BC progression by modulation of non-canonical Hh signaling in epithelial cells and/or promoting a pro-oncogenic stroma.	('Upregulation', 'PosReg', (0, 12))	('pro-oncogenic stroma', 'CPA', (145, 165))	('modulation', 'Var', (65, 75))	('contribute', 'Reg', (33, 43))	('non-canonical Hh signaling', 'MPA', (79, 105))	('Hh ligands', 'Protein', (16, 26))	('BC', 'Disease', 'MESH:D001943', (47, 49))	('promoting', 'PosReg', (133, 142))
114423	22025283	Furthermore, PIK3CA mutations were found in 43% and 29% of papillary carcinomas and grade- and ER-matched IDC-NSTs respectively.	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('PIK3CA', 'Gene', (13, 19))	('papillary carcinomas', 'Disease', 'MESH:D002291', (59, 79))	('papillary carcinomas', 'Disease', (59, 79))	('PIK3CA', 'Gene', '5290', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('mutations', 'Var', (20, 29))	('found', 'Reg', (35, 40))
114427	22025283	Furthermore, the good prognosis of papillary carcinomas may stem from the low rates of lymph node metastasis and p53 expression, low number of gene copy number aberrations, and high prevalence of PIK3CA mutations.	('p53', 'Gene', (113, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('PIK3CA', 'Gene', (196, 202))	('PIK3CA', 'Gene', '5290', (196, 202))	('papillary carcinomas', 'Disease', 'MESH:D002291', (35, 55))	('papillary carcinomas', 'Disease', (35, 55))	('low rates of lymph node', 'Phenotype', 'HP:0002732', (74, 97))	('p53', 'Gene', '7157', (113, 116))	('mutations', 'Var', (203, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
114457	22025283	The rationale for matching case and control samples according to grade- and ER status stems from the several lines of evidence suggesting that grade- and ER are strongly associated with the pattern of genomic changes in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('grade-', 'Var', (143, 149))	('associated', 'Reg', (170, 180))
114459	22025283	>50% of neoplastic cells expressing chromogranin and/ or synaptophysin, which would be consistent with a diagnosis of neuroendocrine carcinoma according to the WHO classification).	('synaptophysin', 'Gene', (57, 70))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (118, 142))	('neuroendocrine carcinoma', 'Disease', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('chromogranin', 'Var', (36, 48))	('synaptophysin', 'Gene', '6855', (57, 70))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (118, 142))
114471	22025283	Forty-nine papillary breast cancers were subjected to mutation screening using the OncoCarta Panel v1.0 (Sequenom Inc., San Diego, CA) detecting 238 mutations in 19 oncogenes as previously described.	('breast cancers', 'Phenotype', 'HP:0003002', (21, 35))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('papillary breast cancers', 'Disease', 'MESH:D001943', (11, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('papillary breast cancers', 'Disease', (11, 35))
114475	22025283	aCGH analysis of papillary carcinomas revealed a relative paucity of copy number aberrations, with a median of 12.1% (range 3.23%-34.1%) of BACs showing either gains, losses or amplifications.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('papillary carcinomas', 'Disease', 'MESH:D002291', (17, 37))	('papillary carcinomas', 'Disease', (17, 37))	('gains', 'PosReg', (160, 165))	('losses', 'NegReg', (167, 173))	('amplifications', 'Var', (177, 191))	('BACs', 'Gene', (140, 144))
114490	22025283	The patterns of copy number gains and losses found in papillary carcinomas were similar to those found in grade- and ER-matched IDC-NSTs, however the prevalence of specific changes was lower in papillary cancers.	('papillary carcinomas', 'Disease', 'MESH:D002291', (54, 74))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('copy number', 'Var', (16, 27))	('papillary carcinomas', 'Disease', (54, 74))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('papillary cancers', 'Disease', 'MESH:D000077273', (194, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('losses', 'NegReg', (38, 44))	('papillary cancers', 'Disease', (194, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
114491	22025283	Significant differences observed included a lower prevalence of 1q whole arm gains and whole arm losses of 6q, 17p, 19p and 22q, and a higher frequency of 19p gains in papillary carcinomas than in grade- and ER-matched IDC-NSTs (multi-Fisher's exact test p < 0.05; Figure 3A, Supplementary Table 6).	('gains', 'PosReg', (159, 164))	('19p', 'Var', (155, 158))	('losses', 'NegReg', (97, 103))	('papillary carcinomas', 'Disease', 'MESH:D002291', (168, 188))	('gains', 'PosReg', (77, 82))	('papillary carcinomas', 'Disease', (168, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
114501	22025283	Although all PIK3CA mutations were validated, the two AKT1 mutations and the five MET mutations were shown to be either germline single nucleotide variants or false positive results, respectively.	('PIK3CA', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (13, 19))	('mutations', 'Var', (59, 68))	('AKT1', 'Gene', '207', (54, 58))	('AKT1', 'Gene', (54, 58))
114502	22025283	We next sequenced the exons of PIK3CA found to be mutated in papillary carcinomas in the cohort of grade- and ER-matched IDC-NSTs.	('papillary carcinomas', 'Disease', 'MESH:D002291', (61, 81))	('papillary carcinomas', 'Disease', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('PIK3CA', 'Gene', (31, 37))	('mutated', 'Var', (50, 57))	('PIK3CA', 'Gene', '5290', (31, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))
114503	22025283	This analysis revealed a similar prevalence of PIK3CA mutations in both groups: 43% (21/49) of papillary carcinomas and 29% (14/49) of IDC-NSTs (Fisher's exact test, p = 0.142) (Table 2, Supplementary Table 7).	('PIK3CA', 'Gene', (47, 53))	('PIK3CA', 'Gene', '5290', (47, 53))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('papillary carcinomas', 'Disease', (95, 115))	('papillary carcinomas', 'Disease', 'MESH:D002291', (95, 115))
114508	22025283	The only significant differences observed were the higher prevalence of high Cyclin D1 expression, lower prevalence of p53 expression and a more overt luminal phenotype than IDC-NSTs of similar histological grade.	('expression', 'MPA', (123, 133))	('lower', 'NegReg', (99, 104))	('Cyclin D1', 'Gene', '595', (77, 86))	('p53', 'Gene', '7157', (119, 122))	('Cyclin D1', 'Gene', (77, 86))	('expression', 'MPA', (87, 97))	('p53', 'Gene', (119, 122))	('high', 'Var', (72, 76))
114511	22025283	Finally, papillary carcinomas were found to harbour PIK3CA mutations in approximately 40% of cases, a feature of ER-positive IDC-NSTs of good prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('harbour', 'Reg', (44, 51))	('PIK3CA', 'Gene', (52, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', '5290', (52, 58))	('papillary carcinomas', 'Disease', 'MESH:D002291', (9, 29))	('papillary carcinomas', 'Disease', (9, 29))
114512	22025283	The observations that papillary carcinomas significantly less frequently displayed lymphovascular invasion or lymph node metastasis at diagnosis, and more frequently harboured a lower prevalence of p53 expression, low number of genomic aberrations and high prevalence of PIK3CA mutations potentially provide a rationale for the relatively good prognosis of papillary carcinomas.	('lymphovascular invasion', 'CPA', (83, 106))	('mutations', 'Var', (278, 287))	('lymph node metastasis', 'CPA', (110, 131))	('papillary carcinomas', 'Disease', 'MESH:D002291', (357, 377))	('lower', 'NegReg', (178, 183))	('papillary carcinomas', 'Disease', (357, 377))	('PIK3CA', 'Gene', (271, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('expression', 'MPA', (202, 212))	('less', 'NegReg', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('p53', 'Gene', (198, 201))	('PIK3CA', 'Gene', '5290', (271, 277))	('p53', 'Gene', '7157', (198, 201))	('papillary carcinomas', 'Disease', (22, 42))	('papillary carcinomas', 'Disease', 'MESH:D002291', (22, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (367, 377))
114513	22025283	In fact, previous studies have demonstrated that absence of lymphovascular invasion and lymph node metastasis, lack of p53 expression, low number of genomic aberrations, and presence of PIK3CA mutations are associated with good clinical outcome in patients with ER-positive breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('expression', 'MPA', (123, 133))	('breast cancers', 'Disease', 'MESH:D001943', (274, 288))	('breast cancers', 'Disease', (274, 288))	('lymph node metastasis', 'CPA', (88, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('p53', 'Gene', '7157', (119, 122))	('lack', 'NegReg', (111, 115))	('mutations', 'Var', (193, 202))	('presence', 'Var', (174, 182))	('PIK3CA', 'Gene', (186, 192))	('absence', 'NegReg', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('p53', 'Gene', (119, 122))	('patients', 'Species', '9606', (248, 256))	('breast cancers', 'Phenotype', 'HP:0003002', (274, 288))	('PIK3CA', 'Gene', '5290', (186, 192))
114519	22025283	copy number silent loss of heterozygosity events, somatic mutations or fusion genes), epigenetic changes or distinctive tumour-microenvironment interactions.	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('copy number silent', 'Var', (0, 18))	('loss of', 'NegReg', (19, 26))	('epigenetic changes', 'Var', (86, 104))	('fusion genes', 'Var', (71, 83))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
114524	22025283	With the advent of massively parallel sequencing, further studies investigating the repertoire of somatic mutations, fusion genes, and epigenetic changes in papillary carcinomas are warranted.	('papillary carcinomas', 'Disease', 'MESH:D002291', (157, 177))	('papillary carcinomas', 'Disease', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('epigenetic changes', 'Var', (135, 153))
114527	22025283	In fact, histological analysis of conditional mouse models of mammary gland cancers revealed that genetic alterations of various pathways, including the ERBB, RAS, WNT, CDK2 and LKB1 pathways, result in tumours with papillary morphology.	('tumours', 'Disease', (203, 210))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (76, 83))	('mouse', 'Species', '10090', (46, 51))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('ERBB', 'Gene', '13649', (153, 157))	('genetic alterations', 'Var', (98, 117))	('tumours', 'Disease', 'MESH:D009369', (203, 210))	('LKB1', 'Gene', '20869', (178, 182))	('CDK2', 'Gene', (169, 173))	('RAS', 'Pathway', (159, 162))	('papillary morphology', 'Phenotype', 'HP:0007482', (216, 236))	('ERBB', 'Gene', (153, 157))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('LKB1', 'Gene', (178, 182))	('result in', 'Reg', (193, 202))	('WNT', 'Pathway', (164, 167))	('CDK2', 'Gene', '12566', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
114535	22025283	In a way akin to good prognosis ER-positive IDC-NSTs, papillary carcinomas are characterised by consistent ER expression, high prevalence of PIK3CA mutations and relatively low rates of p53 expression and gene copy number aberrations.	('papillary carcinomas', 'Disease', 'MESH:D002291', (54, 74))	('mutations', 'Var', (148, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('p53', 'Gene', (186, 189))	('PIK3CA', 'Gene', (141, 147))	('p53', 'Gene', '7157', (186, 189))	('PIK3CA', 'Gene', '5290', (141, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('papillary carcinomas', 'Disease', (54, 74))
114543	26511489	GFN supplementation was associated with a significant decrease in PBMC HDAC activity (p = 0.04).	('decrease', 'NegReg', (54, 62))	('GFN', 'Chemical', '-', (0, 3))	('HDAC', 'Gene', (71, 75))	('supplementation', 'Var', (4, 19))	('HDAC', 'Gene', '9734', (71, 75))
114559	26511489	SFN has been shown to be an effective chemopreventive agent in both in vitro and in vivo models for breast cancer where SFN is able to selectively induce apoptosis and slow tumor growth.	('SFN', 'Var', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('induce', 'PosReg', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('apoptosis', 'CPA', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('slow', 'NegReg', (168, 172))	('breast cancer', 'Disease', (100, 113))	('SFN', 'Chemical', 'MESH:C016766', (0, 3))	('SFN', 'Chemical', 'MESH:C016766', (120, 123))
114561	26511489	SFN has also been shown to decrease levels of Ki-67, a marker of cell proliferation, in prostate tumor tissue and breast cancer cell xenografts.	('Ki-67', 'Gene', '17345', (46, 51))	('prostate tumor', 'Disease', (88, 102))	('rat', 'Species', '10116', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate tumor', 'Phenotype', 'HP:0100787', (88, 102))	('decrease', 'NegReg', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Ki-67', 'Gene', (46, 51))	('levels', 'MPA', (36, 42))	('prostate tumor', 'Disease', 'MESH:D011471', (88, 102))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('SFN', 'Chemical', 'MESH:C016766', (0, 3))	('breast cancer', 'Disease', (114, 127))	('SFN', 'Var', (0, 3))
114565	26511489	Inhibiting HDACs can lead to increased histone acetylation and re-expression of tumor suppressor genes (e.g., p21) that are often silenced in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Inhibiting', 'Var', (0, 10))	('HDAC', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HDAC', 'Gene', '9734', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('p21', 'Gene', (110, 113))	('histone acetylation', 'MPA', (39, 58))	('tumor', 'Disease', (80, 85))	('re-expression', 'MPA', (63, 76))	('increased', 'PosReg', (29, 38))	('cancer', 'Disease', (142, 148))
114604	26511489	Matched pre and post samples were analyzed for SFN, SFN-Cys (299 > 114), SFN-GSH (485 > 179), SFN-CG (356 > 114), and SFN-NAC (341.1 > 114) in duplicate following a 10-mul injection.	('SFN-Cys', 'Chemical', '-', (52, 59))	('SFN', 'Chemical', 'MESH:C016766', (52, 55))	('NAC', 'Gene', (122, 125))	('SFN', 'Chemical', 'MESH:C016766', (94, 97))	('356 > 114', 'Var', (102, 111))	('NAC', 'Gene', '6622', (122, 125))	('SFN', 'Chemical', 'MESH:C016766', (118, 121))	('SFN', 'Chemical', 'MESH:C016766', (73, 76))	('485 > 179', 'Var', (82, 91))	('SFN-CG', 'Chemical', '-', (94, 100))	('299 > 114', 'Var', (61, 70))	('SFN-GSH', 'Chemical', '-', (73, 80))	('SFN', 'Chemical', 'MESH:C016766', (47, 50))
114627	26511489	Pre- to post-intervention changes in total urinary SFN isothiocyanates and in individual SFN metabolites (SFN-NAC, SFN-Cys, SFN-GSH, and SFN) were statistically higher in the SFN group compared to the placebo group.	('SFN', 'Chemical', 'MESH:C016766', (51, 54))	('SFN-Cys', 'MPA', (115, 122))	('SFN', 'Chemical', 'MESH:C016766', (124, 127))	('SFN isothiocyanates', 'Chemical', '-', (51, 70))	('SFN', 'Chemical', 'MESH:C016766', (137, 140))	('SFN', 'Chemical', 'MESH:C016766', (115, 118))	('SFN-Cys', 'Chemical', '-', (115, 122))	('NAC', 'Gene', '6622', (110, 113))	('NAC', 'Gene', (110, 113))	('SFN-GSH', 'Chemical', '-', (124, 131))	('higher', 'PosReg', (161, 167))	('SFN', 'Chemical', 'MESH:C016766', (89, 92))	('urinary SFN isothiocyanates', 'MPA', (43, 70))	('SFN', 'Chemical', 'MESH:C016766', (175, 178))	('SFN', 'Chemical', 'MESH:C016766', (106, 109))	('SFN', 'Var', (175, 178))
114636	26511489	Levels of H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67 and p21 were evaluated by IHC from pre-treatment biopsies followed by post-treatment biopsies lumpectomy or mastectomy specimens (when available).	('Ki-67', 'Gene', (41, 46))	('H3K18ac', 'Var', (10, 17))	('H3K9ac', 'Var', (19, 25))	('Ki-67', 'Gene', '17345', (41, 46))
114637	26511489	Through multiple comparison adjusted p-value using the Benjamini-Hochberg False Discovery rate, there was no statistical significance between treatment groups for pre-to-post changes of all the examined tissue biomarkers including H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67 and p21 levels in all the three tissue types.	('p21 levels', 'MPA', (272, 282))	('Ki-67', 'Gene', (262, 267))	('H3K9ac', 'Var', (240, 246))	('HDAC6', 'MPA', (255, 260))	('H3K18ac', 'Var', (231, 238))	('HDAC3', 'MPA', (248, 253))	('Ki-67', 'Gene', '17345', (262, 267))	('rat', 'Species', '10116', (90, 93))
114639	26511489	Comparing pre- and post-treatment levels within each treatment group, there was a significant decrease in Ki-67 and HDAC3 in benign tissues in the SFN group and a significant decrease in H3K9ac in DCIS tissue in the placebo group.	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('H3K9ac', 'Protein', (187, 193))	('HDAC3', 'Protein', (116, 121))	('decrease', 'NegReg', (94, 102))	('decrease', 'NegReg', (175, 183))	('Ki-67', 'Gene', '17345', (106, 111))	('SFN', 'Chemical', 'MESH:C016766', (147, 150))	('Ki-67', 'Gene', (106, 111))	('SFN', 'Var', (147, 150))
114640	26511489	In this analysis of 54 women who participated in this randomized, placebo-controlled trial, we found that SFN supplementation was associated with reduced PBMC HDAC activity.	('reduced PBMC', 'Phenotype', 'HP:0025547', (146, 158))	('women', 'Species', '9606', (23, 28))	('SFN', 'Gene', (106, 109))	('reduced', 'NegReg', (146, 153))	('HDAC', 'Gene', (159, 163))	('HDAC', 'Gene', '9734', (159, 163))	('PBMC', 'Disease', (154, 158))	('SFN', 'Chemical', 'MESH:C016766', (106, 109))	('supplementation', 'Var', (110, 125))
114642	26511489	However, we did not observe significant differences between SFN and placebo groups for any of the tissue biomarkers examined including H3K9ac, H3K18ac, HDAC3, HDAC6, Ki-67 and p21.	('Ki-67', 'Gene', '17345', (166, 171))	('H3K18ac', 'Var', (143, 150))	('Ki-67', 'Gene', (166, 171))	('SFN', 'Chemical', 'MESH:C016766', (60, 63))	('H3K9ac', 'Var', (135, 141))
114644	26511489	We observed significant decreases in Ki-67 levels via IHC following SFN supplementation in benign tissue.	('decreases', 'NegReg', (24, 33))	('Ki-67', 'Gene', '17345', (37, 42))	('Ki-67', 'Gene', (37, 42))	('SFN', 'Chemical', 'MESH:C016766', (68, 71))	('supplementation', 'Var', (72, 87))
114645	26511489	The difference between treatment groups was not significant after adjusting for multiple comparisons; however, the change in the SFN group was significant and quite different than that of the placebo group, which had a non-significant increase in Ki-67 levels.	('Ki-67', 'Gene', (247, 252))	('Ki-67', 'Gene', '17345', (247, 252))	('increase', 'PosReg', (235, 243))	('SFN', 'Var', (129, 132))	('SFN', 'Chemical', 'MESH:C016766', (129, 132))
114646	26511489	There is evidence that Ki-67 gene expression is regulated in part through epigenetic mechanisms involving HDACs.	('regulated', 'Reg', (48, 57))	('expression', 'MPA', (34, 44))	('Ki-67', 'Gene', '17345', (23, 28))	('epigenetic', 'Var', (74, 84))	('Ki-67', 'Gene', (23, 28))	('HDAC', 'Gene', (106, 110))	('HDAC', 'Gene', '9734', (106, 110))
114648	26511489	Similar to this report, we also did not observe changes in Ki-67 protein levels following SFN supplementation in cancer tissue.	('supplementation', 'Var', (94, 109))	('Ki-67', 'Gene', (59, 64))	('SFN', 'Chemical', 'MESH:C016766', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('SFN', 'Gene', (90, 93))	('cancer', 'Disease', (113, 119))	('Ki-67', 'Gene', '17345', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
114667	26511489	HDAC3 was significantly decreased in the supplement group, which may have contributed to the decreases in total HDAC activity we observed.	('HDAC', 'Gene', (0, 4))	('decreased', 'NegReg', (24, 33))	('HDAC', 'Gene', '9734', (0, 4))	('decreases', 'NegReg', (93, 102))	('HDAC', 'Gene', (112, 116))	('HDAC', 'Gene', '9734', (112, 116))	('supplement', 'Var', (41, 51))
114672	26511489	In this study, we did not observe increased H3K18ac or H3K9ac, despite decreases in HDAC3 expression and total HDAC activity.	('H3K18ac', 'Var', (44, 51))	('HDAC', 'Gene', (111, 115))	('HDAC', 'Gene', '9734', (111, 115))	('HDAC', 'Gene', (84, 88))	('H3K9ac', 'Var', (55, 61))	('HDAC', 'Gene', '9734', (84, 88))	('decreases', 'NegReg', (71, 80))
114674	26511489	Though it cannot be determined from the present data, GFN supplementation may have mitigated decreases in histone acetylation.	('GFN', 'Chemical', '-', (54, 57))	('supplementation', 'Var', (58, 73))	('mitigated decreases', 'NegReg', (83, 102))	('histone acetylation', 'MPA', (106, 125))
114724	24197133	Cell lines were authenticated using short tandem repeat profiling by MD Anderson Cancer Center (MDACC; Houston, TX) Cell Line Characterization Core Facility.	('short tandem repeat', 'Var', (36, 55))	('MD Anderson Cancer', 'Disease', (69, 87))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (69, 87))
114742	24197133	MMTV-HA-14-3-3zeta mice exhibited significantly decreased tumor free survival compared to wild-type mice (Figure 1F).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mice', 'Species', '10090', (100, 104))	('MMTV-HA-14-3-3zeta', 'Var', (0, 18))	('decreased', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mice', 'Species', '10090', (19, 23))
114767	24197133	Virgin MMTV-zeta.neu mice had a significantly (P< 0.05) increased incidence of lung metastases (66.7%) with high HA-14-3-3zeta expression compared to MMTV-neu mice (27.7%), 3-4 weeks after palpable mammary tumor detection (Figures 2E, S2A).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('lung metastases', 'Disease', (79, 94))	('increased', 'PosReg', (56, 65))	('mice', 'Species', '10090', (21, 25))	('lung metastases', 'Disease', 'MESH:D009362', (79, 94))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('neu', 'Gene', '13866', (17, 20))	('high', 'Var', (108, 112))	('mice', 'Species', '10090', (159, 163))	('MMTV', 'Species', '11757', (150, 154))	('neu', 'Gene', (17, 20))	('neu', 'Gene', '13866', (155, 158))	('MMTV', 'Species', '11757', (7, 11))	('neu', 'Gene', (155, 158))
114773	24197133	Furthermore, the EMT phenotype acquisition is critical for 14-3-3zeta overexpressing MECs to gain invasive ability for subsequent metastases.	('MECs', 'Gene', (85, 89))	('gain', 'PosReg', (93, 97))	('metastases', 'Disease', (130, 140))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('overexpressing', 'Var', (70, 84))
114783	24197133	Moreover, mammary tumor cells of MMTV-HA-14-3-3zeta mice showed increased proliferation compared to mammary epithelial cells from age-matched wild type mice (Figure S4A).	('tumor', 'Disease', (18, 23))	('rat', 'Species', '10116', (81, 84))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mice', 'Species', '10090', (152, 156))	('proliferation', 'CPA', (74, 87))	('increased', 'PosReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('MMTV-HA-14-3-3zeta', 'Var', (33, 51))
114792	24197133	Conversely, 14-3-3zeta knockdown by two independent shRNAs in MCF7 cells increased p27 protein expression with no impact on p27 mRNA expression (Figures 4C, S5C).	('S5C', 'Mutation', 'p.S5C', (157, 160))	('increased', 'PosReg', (73, 82))	('MCF7', 'CellLine', 'CVCL:0031', (62, 66))	('knockdown', 'Var', (23, 32))	('p27 protein', 'Protein', (83, 94))
114796	24197133	Conversely, 14-3-3zeta knockdown in MCF7 cells resulted in a significant miR-221 expression decrease (Figure 4E) affirming that miR-221 expression is regulated by 14-3-3zeta.	('decrease', 'NegReg', (92, 100))	('miR-221', 'Gene', (73, 80))	('knockdown', 'Var', (23, 32))	('MCF7', 'CellLine', 'CVCL:0031', (36, 40))	('expression', 'MPA', (81, 91))
114804	24197133	MCF7-zeta cells had significantly increased pri-miR-221 expression, consistent with increased mature-miR-221 expression (Figure 5A), suggesting that 14-3-3zeta transcriptionally upregulates miR-221.	('expression', 'MPA', (109, 119))	('MCF7', 'CellLine', 'CVCL:0031', (0, 4))	('pri-miR-221', 'Gene', (44, 55))	('upregulates', 'PosReg', (178, 189))	('expression', 'MPA', (56, 66))	('increased', 'PosReg', (84, 93))	('increased', 'PosReg', (34, 43))	('MCF7-zeta', 'Var', (0, 9))
114809	24197133	c-Jun knockdown in MCF7-zeta cells resulted in pri-miR-221 expression decrease (Figure 5E), indicating that the JNK/c-Jun pathway is esssential in 14-3-3zeta-induced miR-221 transcriptional upregulation.	('JNK', 'Gene', '26419', (112, 115))	('c-Jun', 'Gene', '16476', (116, 121))	('c-Jun', 'Gene', '16476', (0, 5))	('MCF7', 'CellLine', 'CVCL:0031', (19, 23))	('pri-miR-221', 'Gene', (47, 58))	('expression', 'MPA', (59, 69))	('JNK', 'Gene', (112, 115))	('c-Jun', 'Gene', (116, 121))	('knockdown', 'Var', (6, 15))	('c-Jun', 'Gene', (0, 5))	('decrease', 'NegReg', (70, 78))
114810	24197133	We performed a chromatin immunoprecipitation (ChIP) assay using c-Jun antibody and found a robust enhancement of c-Jun binding to miR-221 promoter in the MCF7-zeta cells compared to MCF7-Vec cells (Figure 5F).	('MCF7', 'CellLine', 'CVCL:0031', (182, 186))	('c-Jun', 'Gene', '16476', (113, 118))	('c-Jun', 'Gene', '16476', (64, 69))	('enhancement', 'PosReg', (98, 109))	('miR-221', 'Gene', (130, 137))	('c-Jun', 'Gene', (113, 118))	('c-Jun', 'Gene', (64, 69))	('MCF7-zeta', 'Var', (154, 163))	('MCF7', 'CellLine', 'CVCL:0031', (154, 158))	('binding', 'Interaction', (119, 126))
114812	24197133	14-3-3zeta overexpression in MMTV-zeta.neu mammary tumors correlated with increased phospho-JNK, phospho-c-Jun, total c-Jun, miR-221 expression, Ki-67 positivity and reduced p27 expression compared to MMTV-neu tumors (Figure 5G).	('MMTV', 'Species', '11757', (29, 33))	('MMTV-neu tumors', 'Disease', (201, 216))	('Ki-67', 'Gene', (145, 150))	('c-Jun', 'Gene', (105, 110))	('neu', 'Gene', (39, 42))	('MMTV', 'Species', '11757', (201, 205))	('mammary tumors', 'Disease', 'MESH:D001943', (43, 57))	('mammary tumors', 'Disease', (43, 57))	('increased', 'PosReg', (74, 83))	('neu', 'Gene', '13866', (206, 209))	('miR-221', 'Var', (125, 132))	('c-Jun', 'Gene', '16476', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('neu', 'Gene', '13866', (39, 42))	('reduced', 'NegReg', (166, 173))	('c-Jun', 'Gene', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('JNK', 'Gene', (92, 95))	('Ki-67', 'Gene', '17345', (145, 150))	('p27', 'Protein', (174, 177))	('JNK', 'Gene', '26419', (92, 95))	('expression', 'MPA', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('MMTV-neu tumors', 'Disease', 'MESH:C537366', (201, 216))	('neu', 'Gene', (206, 209))	('c-Jun', 'Gene', '16476', (118, 123))
114816	24197133	Inhibition of Erk1/2 in MCF7-zeta cells by chemical inhibitor (AZD6244) or knockdown of Erk1/2 or c-Fos by siRNAs led to a decrease in pri-miR-221 expression (Figures S6B, S6C, S6D).	('AZD6244', 'Chemical', 'MESH:C517975', (63, 70))	('c-Fos', 'Gene', (98, 103))	('decrease', 'NegReg', (123, 131))	('expression', 'MPA', (147, 157))	('S6D', 'Mutation', 'p.S6D', (177, 180))	('pri-miR-221', 'Gene', (135, 146))	('Erk1/2', 'Gene', '26417;26413', (14, 20))	('Erk1/2', 'Gene', '26417;26413', (88, 94))	('knockdown', 'Var', (75, 84))	('Erk1/2', 'Gene', (14, 20))	('c-Fos', 'Gene', '14281', (98, 103))	('Erk1/2', 'Gene', (88, 94))	('MCF7', 'CellLine', 'CVCL:0031', (24, 28))
114819	24197133	Using tissue microarrays (TMA) containing 180 breast cancer tissue cores and 27 normal breast tissues cores, we detected 14-3-3zeta, p27, ErbB2, miR-221 and Ki-67 expression (Figure 6A, Supplementary Tables 3A, 3B, 3C).	('p27', 'Var', (133, 136))	('Ki-67', 'Gene', '17345', (157, 162))	('ErbB2', 'Gene', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('miR-221', 'Var', (145, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('Ki-67', 'Gene', (157, 162))
114825	24197133	Specifically, we tested whether the deviance in tumor grades were associated with 14-3-3zeta, miR-221, p27 expression and percentage of Ki-67 positivity in the TMA cases.	('Ki-67', 'Gene', (136, 141))	('miR-221', 'Gene', (94, 101))	('tumor', 'Disease', (48, 53))	('p27 expression', 'Var', (103, 117))	('tested', 'Reg', (17, 23))	('Ki-67', 'Gene', '17345', (136, 141))	('14-3-3zeta', 'Protein', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
114834	24197133	Mammary tumors developed in MMTV-HA-14-3-3zeta transgenic mice but not in wild-type mice, implicating 14-3-3zeta as an onco-protein.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mice', 'Species', '10090', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('MMTV-HA-14-3-3zeta', 'Var', (28, 46))	('tumors', 'Disease', (8, 14))	('transgenic mice', 'Species', '10090', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('mice', 'Species', '10090', (84, 88))
114840	24197133	In cooperation with a tumor inducing carcinogen (DMBA), 14-3-3zeta accelerated mammary tumorigenesis.	('rat', 'Species', '10116', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('accelerated', 'PosReg', (67, 78))	('14-3-3zeta', 'Var', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('DMBA', 'Chemical', 'MESH:D015127', (49, 53))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('rat', 'Species', '10116', (73, 76))
114866	18279539	Over the past several years, detailed high-throughput molecular genetic, gene expression and epigenetic analyses have enhanced our understanding of these early neoplastic lesions and have re-shaped our view of human breast cancer progression to include multiple distinct pathways of evolution.	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('epigenetic', 'Var', (93, 103))	('breast cancer', 'Disease', (216, 229))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (160, 177))	('neoplastic lesions', 'Disease', (160, 178))	('neoplastic lesions', 'Disease', 'MESH:D051437', (160, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('enhanced', 'PosReg', (118, 126))	('human', 'Species', '9606', (210, 215))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (160, 178))
114870	18279539	The classic model of breast cancer progression (Figure 1) is seen as a linear multi-step process manifesting itself as a sequence of pathologically defined stages in which molecular alterations within normal breast epithelium give rise to ADH, the first premalignant stage of breast cancer progression, upon which progressive molecular alterations give rise to DCIS, the second premalignant stage of breast cancer.	('ADH', 'Gene', '124', (239, 242))	('give rise', 'Reg', (348, 357))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('ADH', 'Gene', (239, 242))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Disease', 'MESH:D001943', (400, 413))	('DCIS', 'Disease', (361, 365))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('breast cancer', 'Disease', (400, 413))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (400, 413))	('breast cancer', 'Disease', (276, 289))	('DCIS', 'Phenotype', 'HP:0030075', (361, 365))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('alterations', 'Var', (182, 193))
114871	18279539	Additional molecular alterations in DCIS are thought to give rise to the malignant stages of invasive and metastatic carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('DCIS', 'Gene', (36, 40))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('carcinoma', 'Disease', (117, 126))	('give rise to', 'Reg', (56, 68))	('molecular alterations', 'Var', (11, 32))	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))
114894	18279539	One pathway is characterized by 16q loss and is observed predominantly in low grade tumors.	('16q', 'Var', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('loss', 'NegReg', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
114905	26657114	Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively.	('CEIN', 'Disease', (74, 78))	('CEIN', 'Chemical', '-', (19, 23))	('CEIN', 'Chemical', '-', (74, 78))	('Ki67', 'Var', (52, 56))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('Ki67', 'Chemical', '-', (52, 56))
114970	26657114	In terms of biomarker relation to sample type, only p53 expression showed a significant relation (p = 0.0091) with sample type, tending to be positive when DCIS was associated with a co-existent invasive carcinoma (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('associated', 'Reg', (165, 175))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('invasive carcinoma', 'Disease', 'MESH:D009361', (195, 213))	('positive', 'Reg', (142, 150))	('DCIS', 'Var', (156, 160))	('invasive carcinoma', 'Disease', (195, 213))
114992	26657114	In the 170 patients with progression, a combination of Ki67 positivity with positivity for p16 and COX2 in the initial in situ lesion was significantly associated with subsequent invasion.	('positivity', 'Var', (60, 70))	('p16', 'Gene', (91, 94))	('associated with', 'Reg', (152, 167))	('Ki67', 'Gene', (55, 59))	('Ki67', 'Chemical', '-', (55, 59))	('COX2', 'Gene', (99, 103))	('invasion', 'CPA', (179, 187))	('p16', 'Gene', '1029', (91, 94))	('COX2', 'Gene', '4513', (99, 103))	('situ lesion', 'Disease', 'MESH:D002278', (122, 133))	('situ lesion', 'Disease', (122, 133))	('patients', 'Species', '9606', (11, 19))
114994	26657114	Ki67 positivity in our study was associated but not significantly (p = 0.06) with greater likelihood of presence of invasion.	('positivity', 'Var', (5, 15))	('Ki67', 'Protein', (0, 4))	('Ki67', 'Chemical', '-', (0, 4))
115039	31992771	And abnormal GPER expression is associated with depression, hypertension, diabetes, and osteoporosis.	('hypertension', 'Disease', (60, 72))	('abnormal', 'Var', (4, 12))	('hypertension', 'Phenotype', 'HP:0000822', (60, 72))	('depression', 'Disease', (48, 58))	('osteoporosis', 'Disease', 'MESH:D010024', (88, 100))	('associated', 'Reg', (32, 42))	('osteoporosis', 'Phenotype', 'HP:0000939', (88, 100))	('GPER', 'Protein', (13, 17))	('depression', 'Disease', 'MESH:D003866', (48, 58))	('diabetes', 'Disease', (74, 82))	('osteoporosis', 'Disease', (88, 100))	('hypertension', 'Disease', 'MESH:D006973', (60, 72))	('diabetes', 'Disease', 'MESH:D003920', (74, 82))	('depression', 'Phenotype', 'HP:0000716', (48, 58))
115040	31992771	Also, high GPER expression in breast cancer is associated with increased recurrence.	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('high', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('GPER', 'Protein', (11, 15))	('expression', 'MPA', (16, 26))
115055	31992771	In this study, we verified that cAMP was activated in E2- (32 nM) and E2-Glow (32 nM)-treated MCF-10A cells (Fig.	('cAMP', 'Chemical', 'MESH:D000242', (32, 36))	('MCF-10A', 'CellLine', 'CVCL:0598', (94, 101))	('cAMP', 'MPA', (32, 36))	('activated', 'PosReg', (41, 50))	('E2-', 'Var', (54, 57))
115066	31992771	To validate the role of GPER in E2 stimulation, we next used siRNAs to knock down GPER (Supplementary Fig.	('knock down', 'Var', (71, 81))	('GPER', 'Gene', (82, 86))	('N', 'Chemical', 'MESH:D009584', (64, 65))
115118	31992771	Actually, when GPER was knocked down using siRNA, E2-Glow was localized in mitochondria (Fig.	('knocked', 'Var', (24, 31))	('E2-Glow', 'MPA', (50, 57))	('N', 'Chemical', 'MESH:D009584', (46, 47))
115158	31992771	The following antibodies were used in this study: pan-dadherin rabbit polyclonal antibody (ab16505, Abcam, 1:500 for WB); laminin-5 (gamma2 chain) mouse mAb (MAB19562, Merck, 1:500 for IF); GPER rabbit polyclonal antibody (PA5-28647, Thermo Fisher, 1:1000 for WB and 1:100 for IF and IHC); p38 MAPK (D13E1) rabbit mAb (#8690, Cell Signaling Technology, 1:1000 for WB); phospho-p38 MAPK (Thr180/Tyr182) (D3F9) rabbit mAb (#4511, Cell Signaling Technology, 1:1000 for WB); SAPK/JNK rabbit polyclonal antibody (#9252, Cell Signaling Technology, 1:1000 for WB); phospho-SAPK/JNK (Thr183/Tyr185) rabbit mAb (#81E11, Cell Signaling Technology, 1:1000 for WB); cleaved caspase-3 (Asp175) rabbit polyclonal antibody (#9661, Cell Signaling Technology, 1:1000 for WB and 1:400 for IF); cytochrome C (7H8.2C12) mouse monoclonal antibody (ab13575, Abcam, 0.1-1 mug for 106 cells for FCM); FLAG mAb (F3165, Sigma-Aldrich, 1:5000 for WB); beta-actin mAb (AC-74, Sigma-Aldrich, 1:2000 for WB); p63 rabbit monoclonal (ab124762, Abcam, 1:200 for IHC); IRAK1 rabbit polyclonal antibody (PA5-19855, Thermo Fisher, 1:1000 for WB); phospho-IRAK1 (Thr100); rabbit polyclonal antibody (PA5-38631, Thermo Fisher, 1:1000 for WB); GSDMD (126-138) antibody produced in rabbit (G7422, Sigma, 1:500 for WB, 1:200 for IF); caspase-1 (p20) mouse mAb (AG-20B-0042, Adipogen, 1:500 for IHC); IkappaB-alpha (L35A5) mouse mAb (#4814, Cell Signaling Technology, 1:1000 for WB); phospho-IkB alpha (Ser32 and Ser36) monoclonal antibody (MA5-15224, Thermo Fisher, 1:1000 for WB); c-Jun mouse monoclonal antibody (MA5-15881, Thermo Fisher, 1:1000 for WB); phospho-c-Jun (Ser63) rabbit polyclonal antibody (PA5-17890, Thermo Fisher, 1:1000 for WB); FITC-Annexin V (cat.	('rabbit', 'Species', '9986', (591, 597))	('FITC', 'Chemical', 'MESH:D016650', (1708, 1712))	('JNK', 'Gene', (476, 479))	('p63', 'Gene', '22061', (979, 982))	('IkB alpha', 'Gene', '18035', (1450, 1459))	('rabbit', 'Species', '9986', (307, 313))	('phospho', 'Chemical', 'MESH:C033601', (1111, 1118))	('AG-20B-0042', 'Chemical', 'MESH:C578954', (1320, 1331))	('mouse', 'Species', '10090', (1381, 1386))	('cytochrome C', 'Gene', '100341175', (776, 788))	('cytochrome C', 'Gene', (776, 788))	('p38', 'Gene', (290, 293))	('rabbit', 'Species', '9986', (480, 486))	('JNK', 'Gene', '5599', (476, 479))	('MA5-15224', 'Chemical', 'MESH:D008694', (1499, 1508))	('Ser', 'Chemical', 'MESH:C530429', (1461, 1464))	('rabbit', 'Species', '9986', (1638, 1644))	('mouse', 'Species', '10090', (1547, 1552))	('rabbit', 'Species', '9986', (1242, 1248))	('MA5-15881', 'Chemical', 'MESH:D008694', (1574, 1583))	('p38', 'Gene', (377, 380))	('rabbit', 'Species', '9986', (409, 415))	('IkB alpha', 'Gene', (1450, 1459))	('mouse', 'Species', '10090', (800, 805))	('JNK', 'Gene', (571, 574))	('phospho', 'Chemical', 'MESH:C033601', (1616, 1623))	('mouse', 'Species', '10090', (1309, 1314))	('JNK', 'Gene', '5599', (571, 574))	('phospho', 'Chemical', 'MESH:C033601', (1442, 1449))	('GSDMD', 'Gene', '79792', (1205, 1210))	('IkappaB-alpha', 'Gene', (1359, 1372))	('p38', 'Gene', '1432', (290, 293))	('p38', 'Gene', '1432', (377, 380))	('rabbit', 'Species', '9986', (1041, 1047))	('ab124762', 'Var', (1002, 1010))	('rabbit', 'Species', '9986', (1135, 1141))	('GSDMD', 'Gene', (1205, 1210))	('Asp175', 'Chemical', 'MESH:C061052', (673, 679))	('phospho', 'Chemical', 'MESH:C033601', (558, 565))	('mouse', 'Species', '10090', (147, 152))	('rabbit', 'Species', '9986', (63, 69))	('H8.2C12', 'CellLine', 'CVCL:0188', (791, 798))	('rabbit', 'Species', '9986', (983, 989))	('Ser', 'Chemical', 'MESH:C530429', (1631, 1634))	('Annexin V', 'Gene', '308', (1713, 1722))	('rabbit', 'Species', '9986', (681, 687))	('Annexin V', 'Gene', (1713, 1722))	('phospho', 'Chemical', 'MESH:C033601', (369, 376))	('MAB19562', 'Chemical', 'MESH:C034071', (158, 166))	('p63', 'Gene', (979, 982))	('rabbit', 'Species', '9986', (195, 201))	('Tyr182', 'Chemical', 'MESH:C096583', (394, 400))	('Ser', 'Chemical', 'MESH:C530429', (1471, 1474))	('IkappaB-alpha', 'Gene', '18035', (1359, 1372))	('Thr183', 'Chemical', 'MESH:C083647', (576, 582))
115212	29137369	In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('NR5A2', 'Gene', '2494', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('NR5A2', 'Gene', (48, 53))	('Cancer Genome Atlas breast cancer', 'Disease', (7, 40))	('methylation', 'Var', (118, 129))	('associated', 'Interaction', (80, 90))	('Cancer Genome Atlas breast cancer', 'Disease', 'MESH:D001943', (7, 40))
115214	29137369	Densely punctate/coarsely granular nuclear reactivity was significantly associated with high tumour grade (p<0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively).	('invasive carcinomas', 'Disease', (127, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (368, 378))	('invasive carcinomas', 'Disease', 'MESH:D009361', (513, 532))	('estrogen receptor', 'Gene', (180, 197))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('invasive carcinomas', 'Disease', (245, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (254, 264))	('invasive carcinomas', 'Disease', 'MESH:D009361', (359, 378))	('invasive carcinomas', 'Disease', (513, 532))	('HER2', 'Gene', '2064', (395, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (522, 531))	('carcinomas', 'Phenotype', 'HP:0030731', (522, 532))	('invasive carcinomas', 'Disease', (359, 378))	('high tumour', 'Disease', (88, 99))	('high tumour', 'Disease', 'MESH:D009369', (88, 99))	('estrogen receptor', 'Gene', '2099', (180, 197))	('negative', 'Var', (171, 179))	('non-luminal intrinsic subtype', 'Disease', (443, 472))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('invasive carcinomas', 'Disease', 'MESH:D009361', (127, 146))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('HER2', 'Gene', (395, 399))	('progesterone receptor', 'Gene', (290, 311))	('progesterone receptor', 'Gene', '5241', (290, 311))	('invasive carcinomas', 'Disease', 'MESH:D009361', (245, 264))
115221	29137369	Reduction of cell proliferation upon LRH-1 knockdown occurs in a p53-independent manner and results in an increased proportion of cells in the G0/G1 phase of the cell cycle and reduction of cells in the S and G2/M phases.	('LRH-1', 'Gene', (37, 42))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('cell proliferation', 'CPA', (13, 31))	('reduction', 'NegReg', (177, 186))	('knockdown', 'Var', (43, 52))	('G0/G1 phase of the cell cycle', 'CPA', (143, 172))	('Reduction', 'NegReg', (0, 9))	('LRH-1', 'Gene', '2494', (37, 42))	('increased', 'PosReg', (106, 115))	('cells', 'CPA', (130, 135))
115222	29137369	Compared with ER-positive breast cancer cells, the anti-proliferative effect of LRH-1 knockdown on the cell cycle is more pronounced in MCF-7 in the absence of E2, in MCF7- derived anti-estrogen-resistant cell lines (MCF7/LCC2 and MCF7/LCC9) and in the ER-negative cell line BT-549.	('breast cancer', 'Disease', (26, 39))	('MCF7', 'CellLine', 'CVCL:0031', (217, 221))	('knockdown', 'Var', (86, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('ER', 'Gene', '2099', (14, 16))	('cell cycle', 'CPA', (103, 113))	('MCF7', 'CellLine', 'CVCL:0031', (231, 235))	('MCF7/LCC9', 'CellLine', 'CVCL:0031', (231, 240))	('BT-549', 'CellLine', 'CVCL:1092', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('MCF7', 'CellLine', 'CVCL:0031', (167, 171))	('LRH-1', 'Gene', '2494', (80, 85))	('LRH-1', 'Gene', (80, 85))	('anti-proliferative effect', 'MPA', (51, 76))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('ER', 'Gene', '2099', (253, 255))	('MCF-7', 'CellLine', 'CVCL:0031', (136, 141))	('more', 'PosReg', (117, 121))
115230	29137369	in 2011, is reported to be the predominant mRNA variant in breast cancer cell lines and to be highly estrogen regulated compared with other variants.	('estrogen regulated', 'MPA', (101, 119))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('variant', 'Var', (48, 55))
115236	29137369	Similar to published breast cancer cell line data, variant 4 was the predominantly expressed transcript in invasive breast cancers in the TCGA cohort (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('invasive breast cancers', 'Disease', (107, 130))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('variant 4', 'Var', (51, 60))	('invasive breast cancers', 'Disease', 'MESH:D001943', (107, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
115238	29137369	This is not a consequence of the frequent copy number gain of NR5A2 in ER-positive tumours, as copy number and mRNA expression are not positively correlated in TCGA data (Pearson r=-0.093).	('tumours', 'Disease', (83, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('ER', 'Gene', '2099', (71, 73))	('NR5A2', 'Gene', '2494', (62, 67))	('gain', 'PosReg', (54, 58))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('NR5A2', 'Gene', (62, 67))	('copy number', 'Var', (42, 53))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
115244	29137369	In the overall cohort (Table 2), the IHC-granular group was significantly associated with high grade (p<0.0005), ER negativity (p=0.008), PR negativity (p=0.003), HER2 amplification (p=0.034) and non-luminal intrinsic subtypes (p=0.018) compared with cases not showing this pattern.	('ER', 'Gene', '2099', (164, 166))	('HER2', 'Gene', (163, 167))	('HER2', 'Gene', '2064', (163, 167))	('PR negativity', 'Var', (138, 151))	('high', 'Disease', (90, 94))	('ER', 'Gene', '2099', (113, 115))
115252	29137369	In keeping with this theory, analysis of TCGA Infinium HumanMethylation450 array data revealed that methylation of CpG2 was associated with lower levels of NR5A2 variant 4 expression, whereas methylation of CpG3 was associated with higher NR5A2 variant 4 expression.	('variant', 'Var', (162, 169))	('lower', 'NegReg', (140, 145))	('NR5A2', 'Gene', '2494', (156, 161))	('NR5A2', 'Gene', '2494', (239, 244))	('NR5A2', 'Gene', (239, 244))	('CpG2', 'Gene', (115, 119))	('NR5A2', 'Gene', (156, 161))	('expression', 'MPA', (255, 265))	('expression', 'MPA', (172, 182))	('methylation', 'Var', (100, 111))	('Human', 'Species', '9606', (55, 60))
115253	29137369	The expression of NR5A2 variant 4 has been reported in both ER-positive and ER-negative breast cancer cell lines and our analysis of mRNA sequencing data of TCGA invasive breast cancer cohort found that variant 4 was also the predominantly expressed NR5A2 transcript in primary breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('invasive breast cancer', 'Disease', (162, 184))	('variant', 'Var', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('invasive breast cancer', 'Disease', 'MESH:D001943', (162, 184))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('NR5A2', 'Gene', '2494', (250, 255))	('ER', 'Gene', '2099', (76, 78))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('NR5A2', 'Gene', (250, 255))	('variant 4', 'Var', (203, 212))	('breast cancers', 'Disease', (278, 292))	('breast cancers', 'Disease', 'MESH:D001943', (278, 292))	('NR5A2', 'Gene', '2494', (18, 23))	('ER', 'Gene', '2099', (60, 62))	('NR5A2', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('breast cancers', 'Phenotype', 'HP:0003002', (278, 292))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
115254	29137369	Expression of this variant was higher in ER-positive breast tumours compared with ER-negative tumours, supporting the findings of Muscat et al., who in their study of 66 invasive breast cancers and 50 normal breast samples observed that NR5A2 mRNA expression was greater in ER-positive tumours compared with ER-negative tumours and was negatively correlated with tumour grade.	('tumour', 'Disease', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (363, 369))	('tumours', 'Disease', (320, 327))	('ER', 'Gene', '2099', (41, 43))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('breast tumours', 'Disease', 'MESH:D001943', (53, 67))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (363, 369))	('mRNA expression', 'MPA', (243, 258))	('variant', 'Var', (19, 26))	('tumour', 'Disease', (363, 369))	('NR5A2', 'Gene', '2494', (237, 242))	('tumours', 'Phenotype', 'HP:0002664', (320, 327))	('NR5A2', 'Gene', (237, 242))	('higher', 'PosReg', (31, 37))	('tumours', 'Disease', 'MESH:D009369', (320, 327))	('breast cancers', 'Phenotype', 'HP:0003002', (179, 193))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (320, 326))	('tumour', 'Disease', (60, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('tumour', 'Disease', 'MESH:D009369', (320, 326))	('invasive breast cancers', 'Disease', 'MESH:D001943', (170, 193))	('ER', 'Gene', '2099', (308, 310))	('tumour', 'Disease', (320, 326))	('tumours', 'Disease', (94, 101))	('breast tumours', 'Disease', (53, 67))	('tumours', 'Disease', (286, 293))	('Expression', 'MPA', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('invasive breast cancers', 'Disease', (170, 193))	('tumour', 'Disease', 'MESH:D009369', (286, 292))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('ER', 'Gene', '2099', (274, 276))	('tumour', 'Disease', (286, 292))	('tumours', 'Phenotype', 'HP:0002664', (286, 293))	('tumours', 'Disease', 'MESH:D009369', (286, 293))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumours', 'Disease', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('greater', 'PosReg', (263, 270))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('ER', 'Gene', '2099', (82, 84))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
115256	29137369	Variant 4 is subject to E2-mediated degradation, resulting in a significantly shorter half-life in ER-positive cells compared with ER-negative cells.	('ER', 'Gene', '2099', (131, 133))	('half-life', 'MPA', (86, 95))	('ER', 'Gene', '2099', (99, 101))	('shorter', 'NegReg', (78, 85))	('Variant', 'Var', (0, 7))
115264	29137369	used an anti-LRH-1 IHC antibody directed only towards the 541 amino acid protein resulting from the mRNA transcript NM_205860 (uc001gvb.2).	('NM_205860', 'Var', (116, 125))	('LRH-1', 'Gene', (13, 18))	('LRH-1', 'Gene', '2494', (13, 18))
115270	29137369	SUMOylation of LRH-1 leads to sequestration of LRH-1 in promyelocytic leukaemia (PML) protein nuclear bodies, localising as discrete nuclear dots, in contrast to unSUMOylated LRH-1, which is distributed diffusely in the nucleus.	('sequestration', 'MPA', (30, 43))	('SUMOylation', 'Var', (0, 11))	('PML', 'Gene', '5371', (81, 84))	('LRH-1', 'Gene', '2494', (175, 180))	('PML', 'Phenotype', 'HP:0004836', (81, 84))	('LRH-1', 'Gene', (47, 52))	('PML', 'Gene', (81, 84))	('promyelocytic leukaemia', 'Phenotype', 'HP:0004836', (56, 79))	('LRH-1', 'Gene', (175, 180))	('promyelocytic leukaemia', 'Disease', (56, 79))	('LRH-1', 'Gene', '2494', (15, 20))	('LRH-1', 'Gene', (15, 20))	('LRH-1', 'Gene', '2494', (47, 52))	('promyelocytic leukaemia', 'Disease', 'MESH:D015473', (56, 79))
115274	29137369	If coarsely granular nuclear LRH-1 IHC staining is indeed indicative of tumours with higher intra-nuclear levels of LRH-1, the association of this staining pattern with aggressive phenotypic features in breast cancer is consistent with previously reported associations of LRH-1 with tumorigenic functions in breast cancer cells, the association of LRH-1 knockdown with down-regulation of genes that are overexpressed in high-grade tumours and associated with poor outcome, and with the observation that high NR5A2 mRNA expression in conjunction with low CDKN1A expression conferred poor disease-free survival in breast cancer patients in TCGA dataset.	('LRH-1', 'Gene', (348, 353))	('LRH-1', 'Gene', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (308, 321))	('LRH-1', 'Gene', '2494', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumours', 'Disease', (431, 438))	('tumours', 'Disease', (72, 79))	('breast cancer', 'Disease', 'MESH:D001943', (308, 321))	('tumours', 'Phenotype', 'HP:0002664', (431, 438))	('breast cancer', 'Disease', (308, 321))	('disease-free survival', 'CPA', (587, 608))	('tumours', 'Disease', 'MESH:D009369', (431, 438))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('LRH-1', 'Gene', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (619, 625))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (431, 437))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('breast cancer', 'Disease', (203, 216))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('poor', 'NegReg', (582, 586))	('LRH-1', 'Gene', '2494', (348, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (612, 625))	('LRH-1', 'Gene', '2494', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CDKN1A', 'Gene', '1026', (554, 560))	('CDKN1A', 'Gene', (554, 560))	('LRH-1', 'Gene', '2494', (116, 121))	('mRNA expression', 'MPA', (514, 529))	('high', 'Var', (503, 507))	('down-regulation', 'NegReg', (369, 384))	('breast cancer', 'Disease', 'MESH:D001943', (612, 625))	('NR5A2', 'Gene', '2494', (508, 513))	('tumorigenic functions', 'CPA', (283, 304))	('breast cancer', 'Disease', (612, 625))	('NR5A2', 'Gene', (508, 513))	('LRH-1', 'Gene', (29, 34))	('patients', 'Species', '9606', (626, 634))
115276	29137369	Analysis of TCGA cohort of invasive breast carcinomas revealed that, similar to breast cancer cell lines, variant 4 was the predominantly expressed transcript and expression of variant 4 was associated with DNA methylation status.	('variant 4', 'Var', (106, 115))	('variant', 'Var', (177, 184))	('breast carcinomas', 'Phenotype', 'HP:0003002', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('invasive breast carcinomas', 'Disease', (27, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('breast cancer', 'Disease', (80, 93))	('associated', 'Reg', (191, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (27, 53))
115282	29137369	The RNA sequencing data was examined for expression of isoforms uc009wzg.1, uc001gvb.2, uc001gvc.2, uc009wzh.2, and uc010pph.1, corresponding to the five NR5A2 transcripts, variant 4 being uc009wzh.2.	('NR5A2', 'Gene', '2494', (154, 159))	('NR5A2', 'Gene', (154, 159))	('uc010pph.1', 'Var', (116, 126))	('uc001gvc.2', 'Var', (88, 98))	('uc009wzh.2', 'Var', (100, 110))
115283	29137369	The HM450 methylation array data was examined for methylation of the CpG island associated with the presumed promoter region of variant 4 (CpG2) and of the four intragenic CpG islands (CpG3, CpG4, CpG5, CpG6), specifically methylation of two CpG2 probes (cg24352938, cg21540765), two CpG3 probes (cg04097639, cg17804356), three CpG4 probes (cg18203366, cg17520027, cg04025964), eight CpG5 probes (cg06244002, cg14025556, cg05391318, cg17486263, cg00001583, cg02773945, cg 05470502, cg22515278) and six CpG6 probes (cg00026457, cg11800251, cg01333884, cg02901753, cg17873998, cg23455785).	('cg14025556', 'Var', (409, 419))	('cg24352938', 'Var', (255, 265))	('cg11800251', 'Var', (527, 537))	('cg04097639', 'Var', (297, 307))	('cg23455785', 'Var', (575, 585))	('cg17873998', 'Var', (563, 573))	('cg17486263', 'Var', (433, 443))	('cg06244002', 'Var', (397, 407))	('cg02773945', 'Var', (457, 467))	('cg 05470502', 'Var', (469, 480))	('cg05391318', 'Var', (421, 431))	('cg02901753', 'Var', (551, 561))	('HM450', 'Chemical', '-', (4, 9))	('cg00026457', 'Var', (515, 525))	('cg00001583', 'Var', (445, 455))	('cg22515278', 'Var', (482, 492))	('cg01333884', 'Var', (539, 549))	('cg21540765', 'Var', (267, 277))
115455	26525720	Although it has recently been stated that removal of the term cancer may reduce anxiety and desire for more invasive treatments, we could find only one research letter directly addressing this issue.	('anxiety', 'Disease', 'MESH:D001008', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('removal', 'Var', (42, 49))	('anxiety', 'Disease', (80, 87))	('anxiety', 'Phenotype', 'HP:0000739', (80, 87))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('reduce', 'NegReg', (73, 79))	('men', 'Species', '9606', (122, 125))
115487	22009639	Predictive Factors for BRCA1/BRCA2 Mutations in Women With Ductal Carcinoma In Situ It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high-risk variables.	('Women', 'Species', '9606', (48, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (124, 141))	('Ductal Carcinoma', 'Disease', (59, 75))	('Mutations', 'Var', (35, 44))	('invasive breast cancer', 'Disease', (179, 201))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (117, 141))	('invasive breast cancer', 'Disease', 'MESH:D001943', (179, 201))	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (59, 83))	('BRCA2', 'Gene', (29, 34))	('Carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (117, 141))	('BRCA1', 'Gene', '672', (23, 28))	('CIS', 'Phenotype', 'HP:0030075', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('BRCA1', 'Gene', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Ductal Carcinoma', 'Disease', 'MESH:D044584', (59, 75))	('women', 'Species', '9606', (106, 111))	('BRCA2', 'Gene', '675', (29, 34))	('ductal carcinoma in situ', 'Disease', (117, 141))
115488	22009639	The authors of this report identified predictive factors for mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS.	('BRCA2', 'Gene', '675', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('CIS', 'Phenotype', 'HP:0030075', (163, 166))	('women', 'Species', '9606', (132, 137))	('BRCA1', 'Gene', (113, 118))	('mutations', 'Var', (61, 70))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('BRCA2', 'Gene', (123, 128))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA1', 'Gene', '672', (113, 118))	('breast cancer', 'Disease', (78, 91))
115489	22009639	One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study.	('mutations', 'Var', (124, 133))	('CIS', 'Phenotype', 'HP:0030075', (33, 36))	('BRCA2', 'Gene', (118, 123))	('DCIS', 'Disease', (32, 36))	('BRCA1', 'Gene', '672', (112, 117))	('BRCA2', 'Gene', '675', (118, 123))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('women', 'Species', '9606', (21, 26))	('BRCA1', 'Gene', (112, 117))
115490	22009639	Of 118 high-risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations.	('BRCA2', 'Gene', (73, 78))	('CIS', 'Phenotype', 'HP:0030075', (29, 32))	('tested positive', 'Reg', (47, 62))	('BRCA2', 'Gene', '675', (73, 78))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('BRCA1', 'Gene', '672', (67, 72))	('women', 'Species', '9606', (17, 22))	('BRCA1', 'Gene', (67, 72))	('mutations', 'Var', (79, 88))
115491	22009639	Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively.	('BRCA1', 'Gene', (44, 49))	('BRCA2', 'Gene', (54, 59))	('BRCA1', 'Gene', '672', (44, 49))	('mutations', 'Var', (60, 69))	('BRCA2', 'Gene', '675', (54, 59))
115493	22009639	In a multivariate logistic model, >=2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38-56.29; P = .034), and a score >=10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23-18.22; P = .0005) remained as independent significant predictors for a BRCA mutation.	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('BRCA', 'Gene', '672', (185, 189))	('OC', 'Phenotype', 'HP:0100615', (69, 71))	('ovarian cancer', 'Disease', (53, 67))	('BRCA', 'Gene', (185, 189))	('BRCAPRO', 'Chemical', '-', (185, 192))	('mutation', 'Var', (409, 417))	('BRCA', 'Gene', '672', (404, 408))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRCA', 'Gene', '672', (295, 299))	('BRCA', 'Gene', (404, 408))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('BRCA', 'Gene', (295, 299))
115496	22009639	These findings suggest that high-risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('CIS', 'Phenotype', 'HP:0030075', (53, 56))	('BRCA', 'Gene', (108, 112))	('BRCA', 'Gene', '672', (108, 112))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('invasive breast cancer', 'Disease', (186, 208))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (38, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (186, 208))
115499	22009639	The identification of deleterious mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 has important implications for carriers in general, because they are the principal cause of hereditary breast and ovarian cancer syndrome (HBOC).	('HBOC', 'Disease', (241, 245))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA1', 'Gene', '672', (86, 91))	('HBOC', 'Disease', 'MESH:D061325', (241, 245))	('BRCA2', 'Gene', '675', (96, 101))	('cause', 'Reg', (185, 190))	('OC', 'Phenotype', 'HP:0100615', (243, 245))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ovarian cancer', 'Phenotype', 'HP:0100615', (216, 230))	('BRCA1', 'Gene', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (194, 239))	('breast cancer', 'Disease', (51, 64))	('mutations', 'Var', (34, 43))	('BRCA2', 'Gene', (96, 101))
115500	22009639	Women who carry a germ line mutation in BRCA1 or BRCA2 have a 43% to 84% risk of developing breast cancer (BC) and a 22% to 39% risk of developing ovarian cancer (OC) by age 70 years.	('BRCA2', 'Gene', (49, 54))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('Women', 'Species', '9606', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('breast cancer', 'Disease', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('BRCA2', 'Gene', '675', (49, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('mutation', 'Var', (28, 36))	('BC', 'Phenotype', 'HP:0003002', (107, 109))	('BRCA1', 'Gene', '672', (40, 45))	('OC', 'Phenotype', 'HP:0100615', (163, 165))	('ovarian cancer', 'Disease', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BRCA1', 'Gene', (40, 45))
115502	22009639	Although early studies revealed a lower prevalence of DCIS associated with IBC in BRCA1/BRCA2 mutation carriers, the subsequent identification of DCIS in prophylactic mastectomy specimens from carriers led investigators to reconsider DCIS as a component of HBOC.	('BRCA1', 'Gene', (82, 87))	('IBC', 'Disease', (75, 78))	('HBOC', 'Disease', 'MESH:D061325', (257, 261))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('BRCA2', 'Gene', (88, 93))	('CIS', 'Phenotype', 'HP:0030075', (235, 238))	('CIS', 'Phenotype', 'HP:0030075', (147, 150))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('DCIS', 'Disease', (54, 58))	('BRCA2', 'Gene', '675', (88, 93))	('BRCA1', 'Gene', '672', (82, 87))	('HBOC', 'Disease', (257, 261))	('OC', 'Phenotype', 'HP:0100615', (259, 261))	('CIS', 'Phenotype', 'HP:0030075', (55, 58))	('mutation', 'Var', (94, 102))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))
115504	22009639	A few retrospective studies have examined the prevalence of BRCA1/BRCA2 mutations in women diagnosed with DCIS and have reported mutation rates ranging between 3.3% and 13%.	('BRCA2', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('BRCA1', 'Gene', (60, 65))	('CIS', 'Phenotype', 'HP:0030075', (107, 110))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('BRCA2', 'Gene', '675', (66, 71))	('women', 'Species', '9606', (85, 90))	('BRCA1', 'Gene', '672', (60, 65))	('DCIS', 'Disease', (106, 110))
95127	22009639	Notably, the knowledge of a BRCA1/BRCA2 mutation is likely to significantly change the assessment of a DCIS patient's risks for future cancers and the cancer prevention/risk reduction recommendations that would be considered.	('BRCA1', 'Gene', '672', (28, 33))	('mutation', 'Var', (40, 48))	('BRCA2', 'Gene', '675', (34, 39))	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancers', 'Disease', (135, 142))	('BRCA1', 'Gene', (28, 33))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('change', 'Reg', (76, 82))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('BRCA2', 'Gene', (34, 39))	('patient', 'Species', '9606', (108, 115))	('CIS', 'Phenotype', 'HP:0030075', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
115505	22009639	Therefore, it is important to define the disease and clinical predisposing conditions for mutations in the BRCA1/BRCA2 genes as accurately as possible to facilitate genetic counseling and risk estimation in women with DCIS.	('BRCA1', 'Gene', '672', (107, 112))	('mutations', 'Var', (90, 99))	('women', 'Species', '9606', (207, 212))	('BRCA2', 'Gene', (113, 118))	('BRCA1', 'Gene', (107, 112))	('CIS', 'Phenotype', 'HP:0030075', (219, 222))	('DCIS', 'Disease', (218, 222))	('DCIS', 'Phenotype', 'HP:0030075', (218, 222))	('BRCA2', 'Gene', '675', (113, 118))
115506	22009639	Herein, we report the prevalence of deleterious BRCA1/BRCA2 mutations and further identify the predictive factors for BRCA1/BRCA2 mutations in a selected population of women with pure DCIS who had no previous history of BC.	('BRCA1', 'Gene', '672', (48, 53))	('BRCA2', 'Gene', (124, 129))	('BRCA1', 'Gene', (48, 53))	('BRCA1', 'Gene', '672', (118, 123))	('BRCA2', 'Gene', '675', (124, 129))	('BRCA2', 'Gene', (54, 59))	('mutations', 'Var', (130, 139))	('BRCA1', 'Gene', (118, 123))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('BC', 'Phenotype', 'HP:0003002', (220, 222))	('women', 'Species', '9606', (168, 173))	('mutations', 'Var', (60, 69))	('CIS', 'Phenotype', 'HP:0030075', (185, 188))	('BRCA2', 'Gene', '675', (54, 59))	('pure', 'Disease', (179, 183))
115507	22009639	The prospectively maintained Breast Cancer Management System database at the University of Texas M. D. Anderson Cancer Center (MDACC) identified 118 women with DCIS who were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes between 2003 and 2010.	('BRCA1', 'Gene', '672', (257, 262))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('women', 'Species', '9606', (149, 154))	('BRCA2', 'Gene', (267, 272))	('BRCA1', 'Gene', (257, 262))	('Breast Cancer', 'Phenotype', 'HP:0003002', (29, 42))	('CIS', 'Phenotype', 'HP:0030075', (161, 164))	('BRCA2', 'Gene', '675', (267, 272))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))	('mutations', 'Var', (240, 249))
115510	22009639	Also excluded were women who had a previous history of BC or whose BRCA mutations indicated a variant of uncertain significance.	('mutations', 'Var', (72, 81))	('women', 'Species', '9606', (19, 24))	('indicated', 'Reg', (82, 91))	('BRCA', 'Gene', (67, 71))	('BC', 'Phenotype', 'HP:0003002', (55, 57))	('BRCA', 'Gene', '672', (67, 71))
115511	22009639	Demographic and clinical information was collected from the prospectively maintained breast cancer research database under institutional review board-approved protocols and included age at the time of diagnosis, race, ethnicity (Ashkenazi Jewish [AJ] ancestry or non-AJ ancestry), FH of BC and/or OC in at least 1 first-degree and/or second-degree relative, number of relatives affected with BC and/or OC (first-degree and/or second-degree relatives only), status according to BRCAPRO (a mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation), histopathologic features of tumors, type of surgery, and recurrence information.	('tumors', 'Disease', (634, 640))	('tumors', 'Disease', 'MESH:D009369', (634, 640))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('BC', 'Phenotype', 'HP:0003002', (287, 289))	('BRCA', 'Gene', (590, 594))	('BRCA', 'Gene', '672', (477, 481))	('breast cancer', 'Disease', (85, 98))	('BRCAPRO', 'Chemical', '-', (477, 484))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (634, 639))	('BRCA', 'Gene', (477, 481))	('OC', 'Phenotype', 'HP:0100615', (402, 404))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (634, 640))	('BC', 'Phenotype', 'HP:0003002', (392, 394))	('mutation', 'Var', (595, 603))	('BRCA', 'Gene', '672', (590, 594))	('OC', 'Phenotype', 'HP:0100615', (297, 299))
115521	22009639	Univariate and multivariate logistic regression analyses on BRCA mutation status (carrier vs noncarrier) were done to identify factors that were predictive of BRCA1/BRCA2 mutations in the patients with DCIS.	('BRCA', 'Gene', '672', (165, 169))	('BRCA2', 'Gene', '675', (165, 170))	('DCIS', 'Phenotype', 'HP:0030075', (202, 206))	('BRCA', 'Gene', (165, 169))	('BRCA', 'Gene', '672', (159, 163))	('BRCA1', 'Gene', '672', (159, 164))	('patients', 'Species', '9606', (188, 196))	('BRCA1', 'Gene', (159, 164))	('BRCA', 'Gene', (159, 163))	('BRCA', 'Gene', '672', (60, 64))	('BRCA2', 'Gene', (165, 170))	('mutations', 'Var', (171, 180))	('CIS', 'Phenotype', 'HP:0030075', (203, 206))	('BRCA', 'Gene', (60, 64))
115522	22009639	Of 118 women who were included in our analysis, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations, 10% (n = 12) carried a BRCA1 mutation, and 17% (n = 20) carried a BRCA2 mutation.	('BRCA2', 'Gene', (170, 175))	('mutation', 'Var', (133, 141))	('positive', 'Reg', (68, 76))	('mutations', 'Var', (93, 102))	('BRCA1', 'Gene', (81, 86))	('BRCA1', 'Gene', '672', (127, 132))	('BRCA2', 'Gene', '675', (87, 92))	('BRCA2', 'Gene', '675', (170, 175))	('BRCA1', 'Gene', (127, 132))	('women', 'Species', '9606', (7, 12))	('BRCA1', 'Gene', '672', (81, 86))	('BRCA2', 'Gene', (87, 92))
115524	22009639	The prevalence of BRCA1 and BRCA2 mutations with regard to patient demographics and clinical characteristics is displayed in Table 2.	('BRCA1', 'Gene', '672', (18, 23))	('BRCA2', 'Gene', '675', (28, 33))	('patient', 'Species', '9606', (59, 66))	('BRCA1', 'Gene', (18, 23))	('BRCA2', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
115525	22009639	Seven patients had a previous history of OC, including 4 patients with BRCA1 mutations and 3 patients with BRCA2 mutations.	('BRCA1', 'Gene', (71, 76))	('BRCA2', 'Gene', '675', (107, 112))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (6, 14))	('OC', 'Phenotype', 'HP:0100615', (41, 43))	('BRCA1', 'Gene', '672', (71, 76))	('patients', 'Species', '9606', (93, 101))	('BRCA2', 'Gene', (107, 112))
115527	22009639	Among 51% of patients who did not report any FH of BC or OC, the BRCA1 and BRCA2 mutation prevalence was 10% (6 of 60 patients) and 8% (5 of 60 patients), respectively.	('BRCA1', 'Gene', '672', (65, 70))	('OC', 'Phenotype', 'HP:0100615', (57, 59))	('patients', 'Species', '9606', (13, 21))	('BRCA1', 'Gene', (65, 70))	('mutation', 'Var', (81, 89))	('BRCA2', 'Gene', (75, 80))	('patients', 'Species', '9606', (144, 152))	('BC', 'Phenotype', 'HP:0003002', (51, 53))	('BRCA2', 'Gene', '675', (75, 80))	('patients', 'Species', '9606', (118, 126))
115528	22009639	Patients with an FH of BC had a higher proportion of BRCA2 mutations compared with patients without any FH of BC (26% vs 9%).	('BRCA2', 'Gene', (53, 58))	('BC', 'Phenotype', 'HP:0003002', (23, 25))	('Patients', 'Species', '9606', (0, 8))	('BRCA2', 'Gene', '675', (53, 58))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (83, 91))	('BC', 'Phenotype', 'HP:0003002', (110, 112))
115529	22009639	Similarly, compared with patients who had no FH of OC, patients with an FH of OC had higher proportions of BRCA1 and BRCA2 mutations (8% vs 38% and 16% vs 25%, respectively).	('BRCA1', 'Gene', '672', (107, 112))	('BRCA2', 'Gene', '675', (117, 122))	('OC', 'Phenotype', 'HP:0100615', (78, 80))	('BRCA1', 'Gene', (107, 112))	('patients', 'Species', '9606', (25, 33))	('OC', 'Phenotype', 'HP:0100615', (51, 53))	('patients', 'Species', '9606', (55, 63))	('BRCA2', 'Gene', (117, 122))	('mutations', 'Var', (123, 132))
115530	22009639	BRCA2 mutations were identified in 25 of 74 patients (24%) who had >=2 family members diagnosed with BC compared with 1 of 27 patients (4%) who had a single relative affected by BC.	('BRCA2', 'Gene', '675', (0, 5))	('identified', 'Reg', (21, 31))	('patients', 'Species', '9606', (44, 52))	('BC', 'Phenotype', 'HP:0003002', (178, 180))	('BRCA2', 'Gene', (0, 5))	('patients', 'Species', '9606', (126, 134))	('mutations', 'Var', (6, 15))	('BC', 'Phenotype', 'HP:0003002', (101, 103))
115532	22009639	Of 98 patients with known BRCAPRO status, 25 had an FH of BC and/or OC that exceeded a 10% prior probability of carrying a BRCA mutation using the BRCAPRO model.	('BRCA', 'Gene', (123, 127))	('BRCA', 'Gene', (26, 30))	('BRCA', 'Gene', (147, 151))	('BRCAPRO', 'Chemical', '-', (147, 154))	('OC', 'Phenotype', 'HP:0100615', (68, 70))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('patients', 'Species', '9606', (6, 14))	('mutation', 'Var', (128, 136))	('BRCA', 'Gene', '672', (123, 127))	('BRCA', 'Gene', '672', (26, 30))	('BRCA', 'Gene', '672', (147, 151))	('BRCAPRO', 'Chemical', '-', (26, 33))
115533	22009639	Among patients who had a BRCAPRO probability of <10%, BRCA1 and BRCA2 mutations were detected in 7% and 11%, respectively.	('BRCA2', 'Gene', '675', (64, 69))	('mutations', 'Var', (70, 79))	('BRCAPRO', 'Chemical', '-', (25, 32))	('patients', 'Species', '9606', (6, 14))	('BRCA2', 'Gene', (64, 69))	('BRCA1', 'Gene', '672', (54, 59))	('detected', 'Reg', (85, 93))	('BRCA1', 'Gene', (54, 59))
115534	22009639	Among patients who had a BRCAPRO mutation probability >=10%, 50% of the patients aged <=40 years at first diagnosis tested positive for BRCA mutations compared with 65% of patients aged >40 years at first diagnosis (data not shown).	('positive', 'Reg', (123, 131))	('BRCA', 'Gene', (25, 29))	('mutations', 'Var', (141, 150))	('BRCAPRO', 'Chemical', '-', (25, 32))	('patients', 'Species', '9606', (6, 14))	('BRCA', 'Gene', '672', (136, 140))	('patients', 'Species', '9606', (172, 180))	('BRCA', 'Gene', '672', (25, 29))	('BRCA', 'Gene', (136, 140))	('patients', 'Species', '9606', (72, 80))
115536	22009639	The BRCA1/BRCA2 mutation rate was significantly higher in patients who had bilateral synchronous DCIS compared with patients who had unilateral DCIS (80% vs 25%; P = .018).	('mutation', 'Var', (16, 24))	('BRCA2', 'Gene', '675', (10, 15))	('BRCA1', 'Gene', (4, 9))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('patients', 'Species', '9606', (116, 124))	('CIS', 'Phenotype', 'HP:0030075', (98, 101))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('bilateral synchronous DCIS', 'Disease', (75, 101))	('CIS', 'Phenotype', 'HP:0030075', (145, 148))	('patients', 'Species', '9606', (58, 66))	('BRCA2', 'Gene', (10, 15))	('BRCA1', 'Gene', '672', (4, 9))	('higher', 'Reg', (48, 54))
115537	22009639	Patients who had an FH of OC had a higher risk of having BRCA mutations compared with patients who had no FH of OC (63% vs 25%; P = .033).	('OC', 'Phenotype', 'HP:0100615', (112, 114))	('OC', 'Phenotype', 'HP:0100615', (26, 28))	('Patients', 'Species', '9606', (0, 8))	('BRCA', 'Gene', '672', (57, 61))	('BRCA', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('patients', 'Species', '9606', (86, 94))
115539	22009639	Conversely, BRCA mutation status was not associated significantly with an FH of BC, early onset BC, or the number of relatives affected by BC (P > .06).	('mutation', 'Var', (17, 25))	('BC', 'Phenotype', 'HP:0003002', (96, 98))	('BRCA', 'Gene', '672', (12, 16))	('BC', 'Phenotype', 'HP:0003002', (80, 82))	('early onset BC', 'Disease', (84, 98))	('BRCA', 'Gene', (12, 16))	('BC', 'Phenotype', 'HP:0003002', (139, 141))
115540	22009639	BRCA1/BRCA2 mutations were detected more frequently among patients who had a BRCAPRO calculated probability >= 10% compared with patients who had a BRCAPRO mutation probability <10% (60% vs 18%; P= .0001).	('BRCA2', 'Gene', '675', (6, 11))	('BRCA1', 'Gene', (0, 5))	('patients', 'Species', '9606', (129, 137))	('mutations', 'Var', (12, 21))	('BRCA2', 'Gene', (6, 11))	('BRCAPRO', 'Chemical', '-', (148, 155))	('patients', 'Species', '9606', (58, 66))	('BRCA1', 'Gene', '672', (0, 5))	('BRCAPRO', 'Chemical', '-', (77, 84))
115541	22009639	The presence of >=2 family members diagnosed with OC and a BRCAPRO mutation probability >=10% remained as independent, significant predictors for a BRCA mutation.	('BRCA', 'Gene', '672', (59, 63))	('OC', 'Phenotype', 'HP:0100615', (50, 52))	('BRCA', 'Gene', '672', (148, 152))	('BRCA', 'Gene', (59, 63))	('BRCAPRO', 'Chemical', '-', (59, 66))	('BRCA', 'Gene', (148, 152))	('mutation', 'Var', (153, 161))
115543	22009639	Specifically, patients who had >=2 relatives with OC were more likely to have BRCA mutations compared with patients who had no relatives with OC (odds ratios [OR], 8.81; 95% confidence interval [CI], 1.38-56.29; P = .0214).	('mutations', 'Var', (83, 92))	('OC', 'Phenotype', 'HP:0100615', (50, 52))	('BRCA', 'Gene', '672', (78, 82))	('BRCA', 'Gene', (78, 82))	('patients', 'Species', '9606', (14, 22))	('OC', 'Phenotype', 'HP:0100615', (142, 144))	('patients', 'Species', '9606', (107, 115))
115545	22009639	A BRCAPRO mutation probability >=10% was associated with a 6-fold increase in the likelihood of identifying a mutation (OR, 6.37; 95% CI, 2.23-18.22; P= .0005).	('BRCAPRO', 'Gene', (2, 9))	('BRCAPRO', 'Chemical', '-', (2, 9))	('mutation', 'Var', (110, 118))
115557	22009639	Our data indicate an overall 27% prevalence of deleterious BRCA1/BRCA2 mutations in high-risk women diagnosed with DCIS, supporting the presence of an in situ phase of carcinogenesis in the development of at least some BRCA-associated breast cancers.	('BRCA1', 'Gene', '672', (59, 64))	('BRCA1', 'Gene', (59, 64))	('CIS', 'Phenotype', 'HP:0030075', (116, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('breast cancers', 'Disease', 'MESH:D001943', (235, 249))	('BRCA', 'Gene', '672', (59, 63))	('breast cancers', 'Disease', (235, 249))	('BRCA2', 'Gene', '675', (65, 70))	('BRCA', 'Gene', '672', (219, 223))	('mutations', 'Var', (71, 80))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (235, 249))	('women', 'Species', '9606', (94, 99))	('BRCA', 'Gene', (59, 63))	('BRCA', 'Gene', '672', (65, 69))	('BRCA', 'Gene', (219, 223))	('carcinogenesis', 'Disease', (168, 182))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('BRCA', 'Gene', (65, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (168, 182))	('BRCA2', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
115559	22009639	Previous studies have assessed the prevalence rates of BRCA1/BRCA2 mutations in patients with in situ carcinomas, with reported rates of up to 13%.	('patients', 'Species', '9606', (80, 88))	('BRCA1', 'Gene', '672', (55, 60))	('BRCA2', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))	('situ carcinomas', 'Disease', 'MESH:D002278', (97, 112))	('BRCA1', 'Gene', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('situ carcinomas', 'Disease', (97, 112))	('BRCA2', 'Gene', '675', (61, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))
95209	22009639	The prevalence of BRCA mutations was 13% in women who had DCIS diagnosed before age 50 years versus 24% in women who had IBC.	('CIS', 'Phenotype', 'HP:0030075', (59, 62))	('BRCA', 'Gene', '672', (18, 22))	('BC', 'Phenotype', 'HP:0003002', (122, 124))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('women', 'Species', '9606', (44, 49))	('BRCA', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('women', 'Species', '9606', (107, 112))
115561	22009639	Subsequently, Claus et al reported a BRCA1/BRCA2 mutation prevalence of 3.3% (12 of 369 patients) in a population-based sample of women with DCIS from the Connecticut Tumor Registry.	('DCIS', 'Disease', (141, 145))	('patients', 'Species', '9606', (88, 96))	('women', 'Species', '9606', (130, 135))	('mutation', 'Var', (49, 57))	('BRCA2', 'Gene', (43, 48))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA2', 'Gene', '675', (43, 48))	('Tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CIS', 'Phenotype', 'HP:0030075', (142, 145))	('BRCA1', 'Gene', (37, 42))
115562	22009639	In another study, deleterious mutations were identified in 10 of 79 women (12.7%) with DCIS who were referred for hereditary cancer risk assessment, similar to the frequency (14%) in IBC probands and slightly less than the 17% prevalence observed among women with IBC diagnosed before age 50 years.	('CIS', 'Phenotype', 'HP:0030075', (88, 91))	('DCIS', 'Disease', (87, 91))	('women', 'Species', '9606', (253, 258))	('hereditary cancer', 'Disease', 'MESH:D009369', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hereditary cancer', 'Disease', (114, 131))	('BC', 'Phenotype', 'HP:0003002', (265, 267))	('women', 'Species', '9606', (68, 73))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('mutations', 'Var', (30, 39))	('BC', 'Phenotype', 'HP:0003002', (184, 186))	('IBC', 'Disease', (183, 186))
115563	22009639	Recently, Hall et al conducted a cross-sectional analysis of the Myriad Genetics BRCA1/BRCA2 database and reported an overall 5.9% prevalence of BRCA1/BRCA2 mutations in non-AJ patients with carcinoma in situ (CIS) (ductal or lobular).	('carcinoma in situ', 'Disease', 'MESH:D002278', (191, 208))	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (87, 92))	('BRCA2', 'Gene', '675', (151, 156))	('patients', 'Species', '9606', (177, 185))	('BRCA1', 'Gene', '672', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('mutations', 'Var', (157, 166))	('carcinoma in situ', 'Disease', (191, 208))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (191, 208))	('CIS', 'Phenotype', 'HP:0030075', (210, 213))	('BRCA1', 'Gene', (145, 150))	('BRCA1', 'Gene', '672', (81, 86))	('BRCA2', 'Gene', (151, 156))	('BRCA2', 'Gene', (87, 92))
115565	22009639	Similar to our findings, patients with CIS had BRCA2 mutations (72.2%) more frequently than BRCA1 mutations (27.8%).	('CIS', 'Phenotype', 'HP:0030075', (39, 42))	('BRCA2', 'Gene', (47, 52))	('mutations', 'Var', (53, 62))	('CIS', 'Disease', (39, 42))	('BRCA1', 'Gene', '672', (92, 97))	('patients', 'Species', '9606', (25, 33))	('BRCA2', 'Gene', '675', (47, 52))	('BRCA1', 'Gene', (92, 97))
115566	22009639	It is of considerable interest that we observed the highest incidence of BRCA mutations reported to date in a population of women with pure DCIS, most of whom (62%) had a BRCAPRO mutation probability <10%.	('BRCA', 'Gene', (171, 175))	('BRCAPRO', 'Chemical', '-', (171, 178))	('BRCA', 'Gene', '672', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('BRCA', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('CIS', 'Phenotype', 'HP:0030075', (141, 144))	('BRCA', 'Gene', '672', (171, 175))	('women', 'Species', '9606', (124, 129))
115567	22009639	These rates are comparable to the 28% prevalence observed in male BC and with the 24% associated with the BRCA2 999del5 mutation in Icelandic women diagnosed with IBC before age 40 years.	('BC', 'Phenotype', 'HP:0003002', (164, 166))	('999del5', 'Mutation', 'c.999del5', (112, 119))	('999del5', 'Var', (112, 119))	('BC', 'Phenotype', 'HP:0003002', (66, 68))	('BRCA2', 'Gene', (106, 111))	('IBC', 'Disease', (163, 166))	('BRCA2', 'Gene', '675', (106, 111))	('women', 'Species', '9606', (142, 147))
115569	22009639	BRCA mutations may have been more prevalent in the clinic-based ascertainment because of increased BC screening in women.	('BRCA', 'Gene', (0, 4))	('BC screening', 'Gene', (99, 111))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('mutations', 'Var', (5, 14))	('increased', 'PosReg', (89, 98))	('women', 'Species', '9606', (115, 120))	('BRCA', 'Gene', '672', (0, 4))
115571	22009639	In our study cohort of women with pure DCIS who were referred for genetic risk assessment, we identified the predictive factors for BRCA1/BRCA2 mutations.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('BRCA2', 'Gene', '675', (138, 143))	('women', 'Species', '9606', (23, 28))	('CIS', 'Phenotype', 'HP:0030075', (40, 43))	('BRCA1', 'Gene', '672', (132, 137))	('BRCA2', 'Gene', (138, 143))	('BRCA1', 'Gene', (132, 137))	('mutations', 'Var', (144, 153))
115572	22009639	Multivariate analysis revealed that >=2 family members with OC (OR, 8.81) and a BRCAPRO mutation probability >=10% (OR, 6.37) were strongly predictive of mutation status.	('predictive', 'Reg', (140, 150))	('BRCAPRO', 'Gene', (80, 87))	('OC', 'Phenotype', 'HP:0100615', (60, 62))	('mutation status', 'Var', (154, 169))	('BRCAPRO', 'Chemical', '-', (80, 87))
115573	22009639	Several studies have identified an FH of OC and early onset BC as risk factors for BRCA mutations among DCIS probands.	('BRCA', 'Gene', '672', (83, 87))	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('CIS', 'Phenotype', 'HP:0030075', (105, 108))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('BRCA', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('OC', 'Phenotype', 'HP:0100615', (41, 43))
115576	22009639	Hall et al determined that women who had early onset DCIS had a significantly increased risk of a BRCA1/BRCA2 mutation compared with women who had late-onset disease (aged >=50 years; OR, 1.5; 95% CI, 1.1-2.1).	('BRCA2', 'Gene', (104, 109))	('late-onset disease', 'Disease', 'MESH:D020518', (147, 165))	('CIS', 'Phenotype', 'HP:0030075', (54, 57))	('women', 'Species', '9606', (133, 138))	('BRCA2', 'Gene', '675', (104, 109))	('BRCA1', 'Gene', '672', (98, 103))	('mutation', 'Var', (110, 118))	('late-onset disease', 'Disease', (147, 165))	('women', 'Species', '9606', (27, 32))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))	('BRCA1', 'Gene', (98, 103))
115580	22009639	The likelihood of identifying a BRCA mutation often is calculated using the BRCAPRO model.	('mutation', 'Var', (37, 45))	('BRCA', 'Gene', '672', (76, 80))	('BRCA', 'Gene', '672', (32, 36))	('BRCA', 'Gene', (76, 80))	('BRCA', 'Gene', (32, 36))	('BRCAPRO', 'Chemical', '-', (76, 83))
115581	22009639	Yet the current BRCAPRO program does not account for DCIS as a risk factor in the likelihood of detecting a BRCA1/BRCA2 mutation.	('CIS', 'Phenotype', 'HP:0030075', (54, 57))	('BRCA2', 'Gene', (114, 119))	('BRCA1', 'Gene', '672', (108, 113))	('mutation', 'Var', (120, 128))	('BRCA2', 'Gene', '675', (114, 119))	('BRCAPRO', 'Chemical', '-', (16, 23))	('BRCA1', 'Gene', (108, 113))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
115583	22009639	Conversely, our findings also suggest that the BRCAPRO model may underestimate the relative contribution DCIS had on the likelihood of detecting a BRCA1/BRCA2 mutation, because the model predicted only 54% of the mutations that were actually identified in the study cohort.	('BRCAPRO', 'Chemical', '-', (47, 54))	('BRCA1', 'Gene', '672', (147, 152))	('BRCA2', 'Gene', (153, 158))	('BRCA1', 'Gene', (147, 152))	('CIS', 'Phenotype', 'HP:0030075', (106, 109))	('mutation', 'Var', (159, 167))	('BRCA2', 'Gene', '675', (153, 158))	('underestimate', 'NegReg', (65, 78))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))
115586	22009639	Second, confidence in the conclusions is weakened by the possibility of selection bias, because BRCA genetic testing among patients with BRCAPRO mutation probability <10% can only be made through self-referral, and women who self-referred are likely to do so based on FH.	('BRCA', 'Gene', (137, 141))	('BRCA', 'Gene', '672', (96, 100))	('BRCAPRO', 'Chemical', '-', (137, 144))	('BRCA', 'Gene', (96, 100))	('women', 'Species', '9606', (215, 220))	('patients', 'Species', '9606', (123, 131))	('BRCA', 'Gene', '672', (137, 141))	('mutation', 'Var', (145, 153))
115604	25648490	In the short term FPs can increase cancer worry, anxiety and perceived susceptibly to breast cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('anxiety', 'Disease', (49, 56))	('anxiety', 'Phenotype', 'HP:0000739', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('anxiety', 'Disease', 'MESH:D001008', (49, 56))	('breast cancer', 'Disease', (86, 99))	('increase', 'PosReg', (26, 34))	('FPs', 'Var', (18, 21))	('cancer', 'Disease', (35, 41))
115786	25285161	+- 5.3 a.u), and invasive carcinoma (280.0 a.u.	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('invasive carcinoma', 'Disease', (17, 35))	('280.0', 'Var', (37, 42))	('invasive carcinoma', 'Disease', 'MESH:D009361', (17, 35))
115791	25285161	), hyperplasia (297.6 a.u.	('297.6 a.u', 'Var', (16, 25))	('hyperplasia', 'Disease', (3, 14))	('hyperplasia', 'Disease', 'MESH:D006965', (3, 14))
115870	29416938	In the EMBRACE trial the overall survival (OS) was significantly improved in eribulin arm (median 13.1 months, 95% CI 11.8-14.3) when compared with treatment of physician's choice (10.6 months, 9.3-12.5; HR 0.81, 95% CI 0.66-0.99; p = 0.041) but neutropenia occurred in 52% of subjects in eribulin group.	('neutropenia', 'Phenotype', 'HP:0001875', (246, 257))	('eribulin', 'Var', (77, 85))	('improved', 'PosReg', (65, 73))	('neutropenia', 'Disease', (246, 257))	('OS', 'Chemical', '-', (43, 45))	('HR', 'Gene', '3164', (204, 206))	('neutropenia', 'Disease', 'MESH:D009503', (246, 257))	('overall survival', 'MPA', (25, 41))
115912	27421187	The European Society of Breast Cancer Specialists (EUSOMA) recommendations state that acceptable indications for preoperative MRI include a diagnosis of invasive lobular carcinoma, a discrepancy greater than 1 cm between mammography and ultrasound size with expected impact on treatment, and consideration for partial breast irradiation.	('Breast Cancer', 'Phenotype', 'HP:0003002', (24, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('invasive lobular carcinoma', 'Disease', (153, 179))	('Breast Cancer', 'Disease', (24, 37))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (153, 179))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (162, 179))	('Breast Cancer', 'Disease', 'MESH:D001943', (24, 37))	('discrepancy', 'Var', (183, 194))
115916	27421187	Prior studies have shown conflicting results on the ability of MRI to decrease reoperation rates, diminish ipsilateral breast tumor recurrence, or improve survival.	('breast tumor', 'Phenotype', 'HP:0100013', (119, 131))	('improve', 'PosReg', (147, 154))	('MRI', 'Var', (63, 66))	('survival', 'CPA', (155, 163))	('breast tumor', 'Disease', 'MESH:D001943', (119, 131))	('diminish', 'NegReg', (98, 106))	('diminish ipsilateral breast', 'Phenotype', 'HP:0012813', (98, 125))	('reoperation rates', 'CPA', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast tumor', 'Disease', (119, 131))	('decrease', 'NegReg', (70, 78))
115938	27421187	Mastectomy was most strongly associated with older age, rural residence, lower income, Medicaid enrollment, comorbidities, high grade, stage II or III, nodal and ER status, large tumors, invasive lobular histology (compared to invasive ductal), non-teaching hospitals, and cancer or other hospitals (compared to general hospital), as shown in Figure 2.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('high grade', 'Var', (123, 133))	('tumors', 'Disease', (179, 185))	('large', 'Var', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('comorbidities', 'Var', (108, 121))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('invasive lobular', 'Var', (187, 203))	('lower', 'NegReg', (73, 78))	('nodal', 'Var', (152, 157))	('associated', 'Reg', (29, 39))	('Mastectomy', 'Disease', (0, 10))
115943	27421187	A median of 28 days (IQR 19-42 days) for a reoperation of a mastectomy for women undergoing preoperative MRI vs. 28 days (IQR 15-44 days) without MRI was calculated.	('women', 'Species', '9606', (75, 80))	('mastectomy', 'Disease', (60, 70))	('MRI', 'Var', (105, 108))
115952	27421187	In this group of women, they reported that in their adjusted model, MRI was associated with a significantly higher rate of mastectomy in women with MRI (compared to BCS (adjusted OR =1.21 (95% CI (1.14-1.28)), but did not look at association between MRI and receipt of RT in women with BCS.	('mastectomy', 'Disease', (123, 133))	('MRI', 'Var', (148, 151))	('women', 'Species', '9606', (17, 22))	('women', 'Species', '9606', (137, 142))	('women', 'Species', '9606', (275, 280))	('higher', 'PosReg', (108, 114))
115996	27815748	Several risk factors for CBC have been identified in the literature such as BRCA1/2 mutations, young age at diagnosis of the first primary, family history of BC, lobular histology, negative estrogen receptor/progesterone receptor (ER/PR) status, positive lymph node status, and larger tumor size.	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('BRCA1/2', 'Gene', (76, 83))	('tumor', 'Disease', (285, 290))	('progesterone receptor', 'Gene', (208, 229))	('mutations', 'Var', (84, 93))	('progesterone receptor', 'Gene', '5241', (208, 229))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('estrogen receptor', 'Gene', (190, 207))	('estrogen receptor', 'Gene', '2099', (190, 207))	('CBC', 'Disease', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
115998	27815748	For example, only a small percentage of BC patients are BRCA1/2 mutation carriers, and women without family history of BC are more prevalent than those with family history.	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (43, 51))	('BRCA1/2', 'Gene', (56, 63))	('BRCA1/2', 'Gene', '672;675', (56, 63))	('women', 'Species', '9606', (87, 92))
116002	27815748	Another factor to consider is that there is little to no convincing evidence that CPM prolongs either overall or BC-specific survival or reduces BC mortality in women with sporadic BC.	('BC-specific survival', 'CPA', (113, 133))	('prolongs', 'PosReg', (86, 94))	('CPM', 'Var', (82, 85))	('BC mortality', 'CPA', (145, 157))	('women', 'Species', '9606', (161, 166))	('overall', 'CPA', (102, 109))	('reduces', 'NegReg', (137, 144))
116050	27815748	For patients with a strong family history of breast or ovarian cancer and/or who are carrying BRCA1/2 mutations, the Mendelian genetic risk prediction model BRCAPRO is preferable as it uses extensive family history information including ovarian cancer.	('BRCA1/2', 'Gene', (94, 101))	('BRCAPRO', 'Chemical', '-', (157, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast or ovarian cancer', 'Disease', (45, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (237, 251))	('BRCA1/2', 'Gene', '672;675', (94, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('mutations', 'Var', (102, 111))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('ovarian cancer', 'Disease', (237, 251))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (45, 69))
116056	26823093	We use statistical algorithms for dissecting intra- and inter-sample cellular heterogeneity and demonstrate that normal tissue adjacent to breast cancer is characterized by tens to thousands of epigenetic alterations.	('epigenetic alterations', 'Var', (194, 216))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))
116057	26823093	We validate the field defects in an independent cohort and demonstrate that over 30% of the alterations exhibit increased enrichment within matched cancer samples.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('alterations', 'Var', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
116058	26823093	Breast cancers highly enriched for epigenetic field defects, exhibit adverse clinical outcome.	('epigenetic', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('Breast cancers', 'Disease', (0, 14))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))
116059	26823093	Our data support a model where clonal epigenetic reprogramming towards reduced differentiation in normal tissue is an important step in breast carcinogenesis.	('breast carcinogenesis', 'Disease', (136, 157))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (136, 157))	('epigenetic', 'Var', (38, 48))
116063	26823093	Detecting molecular alterations, which happen early in carcinogenesis, is not only important for our understanding of carcinogenesis but also for implementing potential cancer prevention and early detection strategies.	('alterations', 'Var', (20, 31))	('carcinogenesis', 'Disease', (118, 132))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('carcinogenesis', 'Disease', (55, 69))
116065	26823093	Such alterations, commonly known as field defects/effects, have been predicted to exist mathematically and are thought to constitute the earliest clones in the carcinogenic process.	('alterations', 'Var', (5, 16))	('carcinogenic process', 'Disease', 'MESH:D009385', (160, 180))	('carcinogenic process', 'Disease', (160, 180))
116067	26823093	More recently, a sequencing study identified genetic field defects in normal prostate tissue, with the specific mutations, also seen in the adjacent prostate cancers.	('prostate cancers', 'Phenotype', 'HP:0012125', (149, 165))	('prostate cancers', 'Disease', (149, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('mutations', 'Var', (112, 121))	('prostate cancers', 'Disease', 'MESH:D011471', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
116068	26823093	Although epigenetic field defects, notably DNA methylation alterations, have also been described, it is still unknown how widespread epigenetic field effects are and how they contribute to carcinogenesis.	('DNA', 'MPA', (43, 46))	('contribute', 'Reg', (175, 185))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('carcinogenesis', 'Disease', (189, 203))	('methylation alterations', 'Var', (47, 70))
116070	26823093	These data are consistent with a model in which epigenetic alterations predate the emergence of cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('epigenetic alterations', 'Var', (48, 70))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
116077	26823093	We were able to confirm this for the great majority of hypervariable DVMCs, with the outlier samples exhibiting hyper or hypomethylation, depending on the average beta-value in the normal samples from cancer-free women (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('women', 'Species', '9606', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('DVMCs', 'Chemical', '-', (69, 74))	('hypervariable', 'Var', (55, 68))
116085	26823093	Although from the perspective of any one of the hypervariable DVMCs, the field defects appear largely stochastic across different women, it could be that normal-adjacent samples carrying a higher fraction of field defects are associated with specific tumour characteristics.	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('associated', 'Reg', (226, 236))	('women', 'Species', '9606', (130, 135))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('tumour', 'Disease', (251, 257))	('DVMCs', 'Chemical', '-', (62, 67))	('field defects', 'Var', (208, 221))
116087	26823093	A strong association was only observed for stage, with stage-2 tumours exhibiting a significantly higher load of epigenetic changes at the hypervariable DVMC loci compared with stage-1 cancers (Supplementary Fig.	('tumours', 'Disease', (63, 70))	('DVMC', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('epigenetic changes', 'Var', (113, 131))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Disease', (185, 192))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
116091	26823093	The normal-adjacent samples exhibited fractions of alteration at the hypervariable DVMC loci, similar to the fractions in the discovery set, and significantly higher than those of the normal samples (Fig.	('higher', 'PosReg', (159, 165))	('DVMC', 'Chemical', '-', (83, 87))	('alteration', 'Var', (51, 61))
116092	26823093	If the DNAm defects identified in the normal adjacent tissue mark cells that are important for the development of breast cancer, we would expect to see that these loci exhibit larger differences in DNAm when comparing breast cancers (presumably enriched for these cells) to the normal samples of healthy subjects.	('breast cancers', 'Disease', 'MESH:D001943', (218, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('defects', 'Var', (12, 19))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancers', 'Disease', (218, 232))	('DNAm', 'Gene', (7, 11))	('breast cancer', 'Disease', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
116100	26823093	DVMCs hypermethylated in normal adjacent tissue also exhibited statistically significant increases in DNA methylation in the matched breast cancers (Wilcoxon rank sum Paired test: P<1e-8, Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('DNA methylation', 'MPA', (102, 117))	('DVMCs', 'Chemical', '-', (0, 5))	('breast cancers', 'Disease', 'MESH:D001943', (133, 147))	('breast cancers', 'Disease', (133, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('hypermethylated', 'Var', (6, 21))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))	('increases', 'PosReg', (89, 98))
116101	26823093	Confirming the generality of this, we observed that up to 32% of the hypervariable and hypermethylated DVMCs underwent further significant increases in DNA methylation in breast cancer, in contrast to only 2% exhibiting a reversal in DNAm change (that is, hypomethylation; Fisher's exact test, P<1e-100, Fig.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('increases', 'PosReg', (139, 148))	('DVMCs', 'Chemical', '-', (103, 108))	('hypervariable', 'Var', (69, 82))	('DNA methylation', 'MPA', (152, 167))	('hypermethylated', 'Var', (87, 102))
116102	26823093	Thus, a substantial proportion of the DVMCs hypermethylated in normal-adjacent tissue relative to the normal samples of cancer-free women, continue to exhibit further DNAm increases in the matched breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('increases', 'PosReg', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('women', 'Species', '9606', (132, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('hypermethylated', 'Var', (44, 59))	('DVMCs', 'Chemical', '-', (38, 43))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('breast cancers', 'Phenotype', 'HP:0003002', (197, 211))	('breast cancers', 'Disease', 'MESH:D001943', (197, 211))	('breast cancers', 'Disease', (197, 211))
116103	26823093	In contrast, the 2% of DVMCs exhibiting hypomethylation likely represent either subclones whose relative representation in the breast cancer is reduced or sites undergoing active DNA demethylation in cancer.	('reduced', 'NegReg', (144, 151))	('DVMCs', 'Chemical', '-', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('hypomethylation', 'Var', (40, 55))	('cancer', 'Disease', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
116104	26823093	We note that none of the other three categories of DVMCs exhibited as consistent patterns of progression in the breast cancers as those of hypervariable and hypermethylated DVMCs (Supplementary Fig.	('breast cancers', 'Disease', (112, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('hypermethylated', 'Var', (157, 172))	('breast cancers', 'Phenotype', 'HP:0003002', (112, 126))	('DVMCs', 'Chemical', '-', (51, 56))	('DVMCs', 'Chemical', '-', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancers', 'Disease', 'MESH:D001943', (112, 126))
116124	26823093	We only found enrichment among the hypervariable and hypermethylated DVMCs (Supplementary Data 2), with the top five transcription factors including two Polycomb Repressive Complex 2 (PRC2) members (EZH2 and SUZ12) as well as RBBP5, CTCF and RAD21.	('hypermethylated', 'Var', (53, 68))	('RAD21', 'Gene', (242, 247))	('EZH2', 'Gene', '2146', (199, 203))	('PR', 'Gene', '5241', (184, 186))	('CTCF', 'Gene', (233, 237))	('DVMCs', 'Gene', (69, 74))	('RBBP5', 'Gene', '5929', (226, 231))	('EZH2', 'Gene', (199, 203))	('RAD21', 'Gene', '5885', (242, 247))	('CTCF', 'Gene', '10664', (233, 237))	('SUZ12', 'Gene', '23512', (208, 213))	('DVMCs', 'Chemical', '-', (69, 74))	('hypervariable', 'Var', (35, 48))	('RBBP5', 'Gene', (226, 231))	('SUZ12', 'Gene', (208, 213))
116129	26823093	Gene set enrichment analysis (GSEA) of DVMCs mapping to either the TSS1500, TSS200 or the first exon regions (regions containing 450k probes which are most informative of gene expression), confirmed that the strongest enrichment of any biological term was for hypervariable and hypermethylated DVMCs, which were strongly enriched for bivalently or PRC2 marked genes (Hypergeometric test: P<1e-40, Supplementary Data 3 and Supplementary Fig.	('DVMCs', 'Gene', (294, 299))	('DVMCs', 'Chemical', '-', (39, 44))	('P<1e-4', 'Gene', '1423;5394', (388, 394))	('PR', 'Gene', '5241', (348, 350))	('DVMCs', 'Chemical', '-', (294, 299))	('P<1e-4', 'Gene', (388, 394))	('hypervariable', 'Var', (260, 273))	('hypermethylated', 'Var', (278, 293))	('GSEA', 'Chemical', '-', (30, 34))
116131	26823093	This revealed a number of significant hotspots of epigenetic deregulation, centred around important breast cancer genes, including FOXA2, PAX6 and L1CAM (Supplementary Data 4), with the two largest modules mapping to the WNT and FGF signalling pathways, respectively (Fig.	('L1CAM', 'Gene', '3897', (147, 152))	('FOXA2', 'Gene', '3170', (131, 136))	('epigenetic deregulation', 'Var', (50, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('FOXA2', 'Gene', (131, 136))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('PAX6', 'Gene', (138, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('L1CAM', 'Gene', (147, 152))	('breast cancer', 'Disease', (100, 113))	('PAX6', 'Gene', '5080', (138, 142))
116133	26823093	We reasoned that breast tumours highly enriched for cells marked by epigenetic field defects would correspond to tumours with a higher clonogenic potential, exhibit increased proliferation rates and adverse outcome.	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('breast tumour', 'Phenotype', 'HP:0100013', (17, 30))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('proliferation rates', 'CPA', (175, 194))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('breast tumours', 'Disease', (17, 31))	('epigenetic field defects', 'Var', (68, 92))	('tumours', 'Disease', (113, 120))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('breast tumours', 'Disease', 'MESH:D001943', (17, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('increased', 'PosReg', (165, 174))	('higher', 'PosReg', (128, 134))
116139	26823093	16B and Supplementary Table 5), which was strongest for the hypervariable and hypermethylated DVMCs.	('hypervariable', 'Var', (60, 73))	('DVMCs', 'Chemical', '-', (94, 99))	('hypermethylated', 'Var', (78, 93))
116147	26823093	Previous to this work, the frequency of epigenetic field defects in breast cancer was largely unknown.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('epigenetic field defects', 'Var', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
116150	26823093	We further posited that these DNAm changes would mark cells in the normal-adjacent tissue, which drive carcinogenesis.	('changes', 'Var', (35, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('carcinogenesis', 'Disease', (103, 117))
116160	26823093	In summary, epigenetic field defects in breast cancer are widespread.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('epigenetic field defects', 'Var', (12, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
116161	26823093	As with genetic mutations, alterations in DNA methylation also appear to mark pre-neoplastic normal cells that later transform and become enriched in cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('methylation', 'Var', (46, 57))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('DNA', 'Gene', (42, 45))	('cancer', 'Disease', (150, 156))	('alterations', 'Var', (27, 38))
116192	26823093	For each category of DVMCs (hypervariable+hypermethylated, hypervariable+hypomethylated, hypovariable+hypermethylated, hypovariable+hypomethylated) and for each sample, we constructed a progression Z-score, as the average Z-statistic over all CpGs in that category.	('hypovariable+hypermethylated', 'Var', (89, 117))	('hypervariable+hypermethylated', 'Var', (28, 57))	('hypovariable+hypomethylated', 'Var', (119, 146))	('DVMCs', 'Chemical', '-', (21, 26))	('hypervariable+hypomethylated', 'Var', (59, 87))
116206	21264346	In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03).	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('women', 'Species', '9606', (16, 21))	('HER2-positive', 'Gene', (47, 60))	('women', 'Species', '9606', (157, 162))	('HER2-positive', 'Protein', (97, 110))	('DCIS/LCIS', 'Var', (27, 36))	('women', 'Species', '9606', (119, 124))	('BC', 'Phenotype', 'HP:0003002', (145, 147))	('M0 BC', 'Var', (40, 45))	('CTCs', 'Disease', (61, 65))
116216	21264346	The same investigators reported the detection of CK+ tumor cells in the bone marrow of 13% of 39 women with DCIS.	('CK+', 'Var', (49, 52))	('women', 'Species', '9606', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('DCIS', 'Disease', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
116246	21264346	Among women with DCIS/LCIS or M0 BC and detectable CTCs, 5 of 5 women with HER2-positive tumors versus 5 out of 12 women with HER2-negative primary tumors had >=1 HER2-positive CTC (p = 0.03).	('HER2-positive tumors', 'Disease', (75, 95))	('primary tumors', 'Disease', (140, 154))	('HER2-positive tumors', 'Disease', 'MESH:D009369', (75, 95))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('primary tumors', 'Disease', 'MESH:D009369', (140, 154))	('women', 'Species', '9606', (64, 69))	('DCIS/LCIS', 'Var', (17, 26))	('women', 'Species', '9606', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('BC', 'Phenotype', 'HP:0003002', (33, 35))	('M0 BC', 'Var', (30, 35))	('women', 'Species', '9606', (115, 120))
116258	21264346	In our series of non metastatic BC, HER2-positive CTCs were more commonly detected in HER2-positive as opposed to HER2-negative primary tumors but these results should be interpreted with caution due to the low number of cases with HER2-positive CTCs.	('BC', 'Phenotype', 'HP:0003002', (32, 34))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('detected', 'Reg', (74, 82))	('primary tumors', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HER2-positive', 'Var', (86, 99))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))
116298	15841074	Further studies have suggested that activation of ETAR by ET-1 induces the production of VEGF, which in turn stimulates tumour growth and angiogenesis by increasing the levels of hypoxia-inducible factor-1 (HIF-1alpha), in a time- and dose-dependent manner (Spinella et al, 2002).	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour growth', 'Disease', (120, 133))	('ETAR', 'Gene', '1909', (50, 54))	('HIF-1alpha', 'Gene', '3091', (207, 217))	('increasing', 'PosReg', (154, 164))	('ET-1', 'Gene', '1906', (58, 62))	('stimulates', 'PosReg', (109, 119))	('levels', 'MPA', (169, 175))	('VEGF', 'Gene', '7422', (89, 93))	('tumour growth', 'Disease', 'MESH:D006130', (120, 133))	('HIF-1alpha', 'Gene', (207, 217))	('hypoxia', 'Disease', (179, 186))	('hypoxia', 'Disease', 'MESH:D000860', (179, 186))	('ETAR', 'Gene', (50, 54))	('angiogenesis', 'CPA', (138, 150))	('activation', 'Var', (36, 46))	('VEGF', 'Gene', (89, 93))	('ET-1', 'Gene', (58, 62))
116383	15841074	This is also in good agreement with survival data in patients with invasive breast carcinomas in which bFGF expression was found to correlate with a longer disease-free interval (Colomer et al, 1997).	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('patients', 'Species', '9606', (53, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('bFGF', 'Gene', '2247', (103, 107))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (67, 93))	('bFGF', 'Gene', (103, 107))	('disease-free interval', 'CPA', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('invasive breast carcinomas', 'Disease', (67, 93))	('breast carcinomas', 'Phenotype', 'HP:0003002', (76, 93))	('expression', 'Var', (108, 118))
116384	15841074	Thus, although it has been shown that bFGF expression is related to higher angiogenic activity (De Jong et al, 1998b), bFGF may represent an indicator for invasive breast carcinomas with favourable prognosis as well as for DCIS lesions less likely to progress to invasive breast cancer.	('bFGF', 'Gene', (119, 123))	('invasive breast cancer', 'Disease', 'MESH:D001943', (263, 285))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (155, 181))	('bFGF', 'Gene', '2247', (38, 42))	('angiogenic activity', 'CPA', (75, 94))	('expression', 'Var', (43, 53))	('higher', 'PosReg', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('bFGF', 'Gene', (38, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('invasive breast cancer', 'Disease', (263, 285))	('invasive breast carcinomas', 'Disease', (155, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('breast carcinomas', 'Phenotype', 'HP:0003002', (164, 181))	('breast carcinoma', 'Phenotype', 'HP:0003002', (164, 180))	('bFGF', 'Gene', '2247', (119, 123))
116387	15841074	We have previously shown that expression of the ET-axis is increased in invasive breast cancer and that, in particular, ETAR expression correlates with more aggressive tumour types and poor survival (Wulfing et al, 2003a).	('expression', 'Var', (125, 135))	('expression', 'MPA', (30, 40))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('invasive breast cancer', 'Disease', (72, 94))	('aggressive tumour', 'Disease', 'MESH:D001523', (157, 174))	('ETAR', 'Gene', '1909', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ET-axis', 'Gene', (48, 55))	('invasive breast cancer', 'Disease', 'MESH:D001943', (72, 94))	('increased', 'PosReg', (59, 68))	('ETAR', 'Gene', (120, 124))	('aggressive tumour', 'Disease', (157, 174))
116419	26070788	However, ALDH1 positive invasive breast cancers were significantly more likely to be with large tumor size (P = 0.001), high grade (P < 0.001), and high Ki67 expression (P = 0.009).	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('invasive breast cancer', 'Disease', (24, 46))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'MPA', (158, 168))	('ALDH1', 'Gene', (9, 14))	('tumor', 'Disease', (96, 101))	('high grade', 'CPA', (120, 130))	('invasive breast cancer', 'Disease', 'MESH:D001943', (24, 46))	('breast cancers', 'Phenotype', 'HP:0003002', (33, 47))	('breast cancers', 'Disease', 'MESH:D001943', (33, 47))	('breast cancers', 'Disease', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('positive', 'Reg', (15, 23))	('high Ki67', 'Var', (148, 157))
116423	26070788	BT-ICs bear the phenotype of CD44+/CD24-, and aldehyde dehydrogenase 1 (ALDH1) is also an important marker of BT-ICs.	('ALDH1', 'Gene', (72, 77))	('aldehyde dehydrogenase 1', 'Gene', '216', (46, 70))	('aldehyde dehydrogenase 1', 'Gene', (46, 70))	('CD44+/CD24-', 'Var', (29, 40))	('BT-ICs', 'Disease', (0, 6))
116429	26070788	Isfoss and colleagues have found a positive association between the frequency of ductular ALDH1 positive cells and several breast cancer risk factors in histologically normal breast tissue, which supports previous evidence that ALDH1 may play a role in the development of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('play', 'Reg', (238, 242))	('role', 'Reg', (245, 249))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancer', 'Disease', (272, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ductular', 'Var', (81, 89))
116439	26070788	Immunohistochemical (IHC) analyses on paraffin-embedded material were used to determine the status of estrogen receptor (ER), progesterone receptor (PR), Her2, and Ki67.	('paraffin', 'Chemical', 'MESH:D010232', (38, 46))	('progesterone receptor', 'Gene', (126, 147))	('Ki67', 'Var', (164, 168))	('PR', 'Gene', '5241', (149, 151))	('Her2', 'Gene', (154, 158))	('progesterone receptor', 'Gene', '5241', (126, 147))	('Her2', 'Gene', '2064', (154, 158))
116448	26070788	The variables in this study included: age at diagnose, pathology, tumor size, axillary node status, tumor grade, ER, Her2, Ki67, and molecular subtype.	('Ki67', 'Var', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Her2', 'Gene', '2064', (117, 121))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Her2', 'Gene', (117, 121))
116461	26070788	In these 47 DCIS cases, no significant association was observed between ALDH1 positivity and age (P = 0.528), tumor size (P = 0.951), grade (P = 0.812), ER status (P = 0.428), Her2 status (P = 0.536), or Ki67 (P = 0.667).	('ALDH1', 'Gene', (72, 77))	('positivity', 'Var', (78, 88))	('Her2', 'Gene', '2064', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))	('Her2', 'Gene', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
116467	26070788	No significant association was observed between intratumoral ALDH1 positivity and ER status (P = 0.604), or Her2 status (P = 0.801).	('ER status', 'Disease', (82, 91))	('Her2', 'Gene', '2064', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('positivity', 'Var', (67, 77))	('tumor', 'Disease', (53, 58))	('ALDH1', 'Protein', (61, 66))	('Her2', 'Gene', (108, 112))
116468	26070788	Similarly, the frequencies of intratumoral ALDH1 positivity between triple negative and non-triple negative breast cancers were not significantly different (P = 0.992).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('positivity', 'Var', (49, 59))	('tumor', 'Disease', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ALDH1', 'Gene', (43, 48))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
116469	26070788	The frequency of intratumoral ALDH1 positive tumors with high Ki67 expression was significantly higher than that with low Ki67 expression (P = 0.009).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('high Ki67 expression', 'Var', (57, 77))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('ALDH1', 'Gene', (30, 35))	('tumor', 'Disease', (22, 27))	('higher', 'PosReg', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
116491	26070788	In the present study, the high frequencies of stromal ALDH1 positivity among different stages of breast cancer were significantly different.	('positivity', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('stromal ALDH1', 'Protein', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
116510	20625812	Despite high levels of telomerase activity in tumor cells, telomeres are generally maintained at a relatively short length and telomere length abnormalities are seen as early events in the initiation of epithelial carcinogenesis, including ductal carcinoma in situ (DCIS) of the breast.	('DCIS', 'Phenotype', 'HP:0030075', (266, 270))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('initiation of epithelial carcinogenesis', 'Disease', (189, 228))	('tumor', 'Disease', (46, 51))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (240, 264))	('ductal carcinoma in situ', 'Disease', (240, 264))	('abnormalities', 'Var', (143, 156))	('short length and telomere length abnormalities', 'Phenotype', 'HP:0031413', (110, 156))	('initiation of epithelial carcinogenesis', 'Disease', 'MESH:D063646', (189, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (240, 264))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
116513	20625812	TRF2 has emerged as a major protective factor at chromosome ends, and functional inactivation of TRF2 results in a high frequency of end-to-end fusions, which arise from the cells' inability to distinguish natural telomeric ends from broken DNA.	('inactivation', 'Var', (81, 93))	('TRF2', 'Gene', (0, 4))	('TRF2', 'Gene', '7014', (97, 101))	('TRF2', 'Gene', (97, 101))	('end-to-end', 'MPA', (133, 143))	('TRF2', 'Gene', '7014', (0, 4))
116515	20625812	A cell, in response to loss or inactivation of TRF2, typically undergoes rapid senescence or death.	('inactivation', 'Var', (31, 43))	('TRF2', 'Gene', (47, 51))	('loss', 'NegReg', (23, 27))	('TRF2', 'Gene', '7014', (47, 51))
116520	20625812	If TRF2 is overexpressed in breast cancers and this telomere binding protein is mechanistically linked to malignant transformation, then targeting TRF2 in breast cancer cells, most of which have short telomeres, could prove to be a highly efficacious therapy.	('short telomeres', 'Phenotype', 'HP:0031413', (195, 210))	('TRF2', 'Gene', (147, 151))	('targeting', 'Var', (137, 146))	('short telomere', 'Phenotype', 'HP:0031413', (195, 209))	('TRF2', 'Gene', (3, 7))	('breast cancers', 'Disease', 'MESH:D001943', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancers', 'Disease', (28, 42))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('TRF2', 'Gene', '7014', (147, 151))	('TRF2', 'Gene', '7014', (3, 7))
116560	20625812	Intuitively, one would predict that cancers with short telomeres would be genomically more unstable, in part due to fewer telomeric repeats for telomere binding proteins to associate.	('associate', 'Interaction', (173, 182))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('telomere binding proteins', 'Protein', (144, 169))	('short', 'Var', (49, 54))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('telomeric', 'Protein', (122, 131))	('short telomere', 'Phenotype', 'HP:0031413', (49, 63))	('fewer', 'NegReg', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('short telomeres', 'Phenotype', 'HP:0031413', (49, 64))
116581	20625812	We found that there is a significant inverse relationship between high expression of TRF2 and short telomeres within invasive breast carcinomas.	('short telomeres within invasive breast carcinomas', 'Disease', (94, 143))	('short telomeres', 'Phenotype', 'HP:0031413', (94, 109))	('inverse', 'NegReg', (37, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('short telomeres within invasive breast carcinomas', 'Disease', 'MESH:D001929', (94, 143))	('breast carcinomas', 'Phenotype', 'HP:0003002', (126, 143))	('high', 'Var', (66, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('short telomere', 'Phenotype', 'HP:0031413', (94, 108))	('TRF2', 'Gene', '7014', (85, 89))	('TRF2', 'Gene', (85, 89))
116681	30275852	The questionnaire-based survey comprised 39 questions on six domains: (1) hypofractionated whole breast RT (WBRT), (2) accelerated partial breast RT, (3) PMRT, (4) RNI, (5) RT for DCIS, and (6) RT toxicity.	('partial breast RT', 'CPA', (131, 148))	('accelerated', 'PosReg', (119, 130))	('PMRT', 'Var', (154, 158))	('RNI', 'Chemical', '-', (164, 167))	('DCIS', 'Phenotype', 'HP:0030075', (180, 184))	('toxicity', 'Disease', 'MESH:D064420', (197, 205))	('toxicity', 'Disease', (197, 205))
116719	30275852	Two-thirds (62.5%) of the surveyed radiation oncologists considered RNI in pN1 and pathologic risk factors.	('pN1', 'Gene', (75, 78))	('RNI', 'Var', (68, 71))	('pN1', 'Gene', '5270', (75, 78))	('RNI', 'Chemical', '-', (68, 71))
116724	30275852	The EBCTCG meta-analysis analyzed 8,135 patients from 22 trials that randomly assigned patients to treatment groups of either no PMRT or PMRT (including SCN, IMN, and axilla), and showed PMRT reduced both recurrence and breast cancer mortality in pN1 as well as pN2.	('recurrence', 'CPA', (205, 215))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('pN2', 'Gene', (262, 265))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('pN1', 'Gene', '5270', (247, 250))	('pN2', 'Gene', '351', (262, 265))	('pN1', 'Gene', (247, 250))	('patients', 'Species', '9606', (87, 95))	('reduced', 'NegReg', (192, 199))	('PMRT', 'Var', (187, 191))
116945	29474446	Here,  That is, necrotic death begins when pO2 < pO2,threshold, and the death rate ramps linearly until saturating at a maximum rate rN,max for pO2 < pO2,crit.	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('necrotic death', 'Disease', 'MESH:D003643', (16, 30))	('necrotic death', 'Disease', (16, 30))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('pO2', 'Chemical', 'MESH:C093415', (43, 46))	('pO2 <', 'Var', (43, 48))	('pO2', 'Chemical', 'MESH:C093415', (150, 153))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('ramps', 'Species', '138334', (83, 88))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('pO2', 'Chemical', 'MESH:C093415', (49, 52))	('pO2', 'Chemical', 'MESH:C093415', (144, 147))
116985	29474446	BioFVM was previously tested as first-order accurate in Deltat, second-order accurate in Deltax, and sufficiently accurate at Deltax = 20 mum and Deltatdiff = 0.01 to 0.05 min for tumor growth problems.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Deltat', 'MPA', (56, 62))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('growth problems', 'Phenotype', 'HP:0001510', (186, 201))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('tumor', 'Disease', (180, 185))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('Deltatdiff', 'Var', (146, 156))	('Deltax', 'MPA', (89, 95))
117048	29474446	The rate of cycle entry increases linearly with pO2 (see Cell cycling).	('pO2', 'Chemical', 'MESH:C093415', (48, 51))	('pO2', 'Var', (48, 51))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('increases', 'PosReg', (24, 33))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('cycle entry', 'MPA', (12, 23))	('n', 'Chemical', 'MESH:D009584', (25, 26))
117091	29474446	Adhered "cargo" cells detach themselves from "worker" cells when pO2 < pO2,drop and secrete a therapeutic compound [drug] that diffuses with the typical form given in Biochemical microenvironment.	('pO2', 'Chemical', 'MESH:C093415', (65, 68))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (165, 166))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('secrete', 'MPA', (84, 91))	('pO2', 'Chemical', 'MESH:C093415', (71, 74))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('pO2 <', 'Var', (65, 70))	('n', 'Chemical', 'MESH:D009584', (193, 194))
117103	29474446	Such a system could potentially activate and deactivate to keep a tumor cell population in control, and to reduce hypoxia (which is known to drive cancer cell adaptation to more aggressive phenotypes).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('tumor', 'Disease', (66, 71))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('reduce', 'NegReg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('deactivate', 'Var', (45, 55))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('cancer', 'Disease', (147, 153))	('hypoxia', 'Disease', (114, 121))
117105	29474446	We seeded an initial tumor, and assigned each cell a random expression of a mutant "oncoprotein" 0 <= p <= 2.	('n', 'Chemical', 'MESH:D009584', (29, 30))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('tumor', 'Disease', (21, 26))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('mutant', 'Var', (76, 82))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
117115	29474446	As a simple model of immunogenicity, the mutant oncoprotein is assumed to increase immunogenicity proportionally to p, similarly to mutant tumor-associated epitopes being presented on MHCs (major histocompatibility complexes).	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('tumor', 'Disease', (139, 144))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (176, 177))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutant', 'Var', (41, 47))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('increase', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('immunogenicity', 'MPA', (83, 97))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('oncoprotein', 'Protein', (48, 59))
117210	28611039	Younger women were less likely to take chemoprevention (RR: 0.61; 95% CI: 0.42-0.87) and there was a trend towards increased uptake in Hispanic compared to non-Hispanic white women.	('increased', 'PosReg', (115, 124))	('Hispanic', 'Var', (135, 143))	('women', 'Species', '9606', (8, 13))	('less', 'NegReg', (19, 23))	('women', 'Species', '9606', (175, 180))
117219	28611039	LCIS is estimated to increase the risk of breast cancer by approximately 7-10 times the general population with an estimated 10-year breast cancer risk of 23.7%.	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('LCIS', 'Var', (0, 4))	('breast cancer', 'Disease', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
117220	28611039	DCIS also significantly increases the risk of invasive breast cancer with an estimated 11.2% of women developing a subsequent invasive breast cancer within 10 years.	('invasive breast cancer', 'Disease', (126, 148))	('invasive breast cancer', 'Disease', 'MESH:D001943', (46, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('DCIS', 'Var', (0, 4))	('invasive breast cancer', 'Disease', 'MESH:D001943', (126, 148))	('invasive breast cancer', 'Disease', (46, 68))	('women', 'Species', '9606', (96, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
117243	28611039	All subjects with a diagnosis of AH or LCIS/DCIS were initially identified by their corresponding ICD-9/10 codes in these databases, 610.9/N60.99 and 233.0/D05.90, respectively.	('LCIS/DCIS', 'Disease', (39, 48))	('610.9/N60.99', 'Var', (133, 145))	('AH', 'Disease', 'MESH:D007039', (33, 35))
117268	28611039	In univariate analysis (Table 2), type of breast disease, age, menopausal status, race/ethnicity, BMI, family history of breast cancer, HRT use, and medical oncology referral were associated with chemoprevention uptake.	('chemoprevention', 'Var', (196, 211))	('oncology', 'Phenotype', 'HP:0002664', (157, 165))	('associated', 'Reg', (180, 190))	('menopausal status', 'Phenotype', 'HP:0008209', (63, 80))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast disease', 'Disease', (42, 56))	('breast disease', 'Disease', 'MESH:D001941', (42, 56))
117300	28611039	Given that women with AH and LCIS may have a higher baseline risk of breast cancer [10-year risk ranging from 20-23% ], they will likely derive a greater absolute risk reduction from chemoprevention use compared to other high-risk women.	('women', 'Species', '9606', (231, 236))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('AH', 'Disease', 'MESH:D007039', (22, 24))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('women', 'Species', '9606', (11, 16))	('reduction', 'NegReg', (168, 177))	('LCIS', 'Var', (29, 33))
117329	28611039	Our study provides evidence that women with AH, LCIS, or DCIS may take chemoprevention at a higher rate than other high-risk populations and that consultation with a medical oncologist also increases chemoprevention uptake.	('DCIS', 'Var', (57, 61))	('take chemoprevention', 'MPA', (66, 86))	('women', 'Species', '9606', (33, 38))	('higher rate', 'PosReg', (92, 103))	('increases', 'PosReg', (190, 199))	('AH', 'Disease', 'MESH:D007039', (44, 46))
117341	30090744	Risk factors for developing breast cancer occurrence or recurrence are multiple and complex, including family history, genetic mutations, lifestyle, radiation exposure, parity, previous history, etc., The clinical features and the type of primary cancer treatment can affect the risk of the recurrence as well.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('affect', 'Reg', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('breast cancer', 'Disease', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (127, 136))	('cancer', 'Disease', (35, 41))
117347	30090744	Mutations affecting known genes, compelling family history, having benign breast diseases with specific histologic features, previous history of breast cancer or radiation therapy to the breast all increase the risk of developing breast cancer.	('benign breast diseases', 'Disease', (67, 89))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Disease', (230, 243))	('increase', 'PosReg', (198, 206))	('benign breast diseases', 'Disease', 'MESH:D001941', (67, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
117349	30090744	Mutations in breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes explain ~20% of the familial clustering of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA1', 'Gene', (30, 35))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('BRCA2', 'Gene', '675', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancer', 'Disease', (13, 26))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('Mutations', 'Var', (0, 9))	('BRCA1', 'Gene', '672', (30, 35))	('BRCA2', 'Gene', (58, 63))	('breast cancer', 'Disease', (114, 127))
117351	30090744	Its protein product is part of a complex compound responsible for repairing double-strand breaks in deoxyribonucleic acid (DNA) that contribute to genomic instability and drive cancer development.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('drive', 'PosReg', (171, 176))	('contribute', 'Reg', (133, 143))	('double-strand breaks', 'Var', (76, 96))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('genomic instability', 'CPA', (147, 166))
117355	30090744	Thus, women carrying BRCA1 or 2 gene mutations are thought to have a significantly higher risk of developing breast cancer, usually diagnosed at a younger age compared to general population.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('BRCA1 or 2', 'Gene', (21, 31))	('BRCA1 or 2', 'Gene', '672;675', (21, 31))	('women', 'Species', '9606', (6, 11))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
117356	30090744	It is estimated that the average cumulative risk of breast cancer by age 70 years is 57%-65% for BRCA1 gene mutation carriers and 45%-49% for BRCA2 gene mutation carriers with 20-times increase in the risk of breast cancer compared to general population.	('increase', 'PosReg', (185, 193))	('BRCA2', 'Gene', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (209, 222))	('BRCA1', 'Gene', '672', (97, 102))	('BRCA2', 'Gene', '675', (142, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('breast cancer', 'Disease', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('BRCA1', 'Gene', (97, 102))	('mutation', 'Var', (108, 116))
117358	30090744	Mutations in this gene are found in 50% of all cancer types.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('found', 'Reg', (27, 32))
117362	30090744	Mutations in this gene underlie a number of tumor syndromes: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus and Proteus-like syndromes.	('Cowden syndrome', 'Disease', (61, 76))	('underlie', 'Reg', (23, 31))	('Cowden syndrome', 'Disease', 'MESH:D006223', (61, 76))	('Mutations', 'Var', (0, 9))	('tumor syndromes', 'Disease', 'MESH:D009369', (44, 59))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', (78, 111))	('Bannayan-Riley-Ruvalcaba syndrome', 'Disease', 'MESH:D006223', (78, 111))	('tumor syndromes', 'Disease', (44, 59))
117364	30090744	It is estimated that the absolute lifetime risk of breast cancer for PTEN mutation carriers is 25%.	('PTEN', 'Gene', '5728', (69, 73))	('mutation', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('PTEN', 'Gene', (69, 73))
117365	30090744	In general, genetic mutations are considered high risk for developing breast cancer when they show a 4-fold increased risk of breast cancer in carriers compared to general population.	('genetic mutations', 'Var', (12, 29))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (126, 139))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
117377	30090744	One study found that low-grade DCIS has 9 times increased risk of developing cancer at the same site within 30 years after diagnosis (95% confidence interval, 4.7-17).	('low-grade', 'Var', (21, 30))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
117387	30090744	In BRCA gene mutation carriers, several studies showed a significant reduction in the incidence of breast cancer occurring in women who underwent bilateral prophylactic mastectomies.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('breast cancer', 'Disease', (99, 112))	('mutation', 'Var', (13, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('women', 'Species', '9606', (126, 131))	('reduction', 'NegReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
117396	30090744	assessed the relationship between prophylactic mastectomy and breast cancer outcomes in BRCA1 and 2 gene mutation carriers.	('mutation', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('BRCA1 and 2', 'Gene', '672;675', (88, 99))	('breast cancer', 'Disease', (62, 75))
117398	30090744	Moreover, in a study conducted in 2015, 63 women carrying BRCA1 or 1 gene mutation who underwent nipple-sparing prophylactic mastectomy reported no newly diagnosed breast cancers at a median follow-up of 26 months supporting the same conclusion.	('mutation', 'Var', (74, 82))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('breast cancers', 'Disease', (164, 178))	('women', 'Species', '9606', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('BRCA1 or 1', 'Gene', (58, 68))	('BRCA1 or 1', 'Gene', '672', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
117417	30090744	This study reported that in BRCA1 gene mutation carriers, bilateral prophylactic mastectomy at age 25 years yields a 13% gain relative to no intervention, whereas delaying prophylactic mastectomy to age 40 years yields a small (2%) decrement in gain compared with prophylactic mastectomy at age 25 years.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (28, 33))	('mutation', 'Var', (39, 47))	('gain', 'PosReg', (121, 125))
117418	30090744	In BRCA2 gene mutation carriers, the reduction in mortality decreases to 8% (from 79% to 71%) only at age 25 years compared with no intervention; postponing prophylactic mastectomy to age 40 years reduces gain by 1%.	('decreases', 'NegReg', (60, 69))	('BRCA2', 'Gene', '675', (3, 8))	('mortality', 'MPA', (50, 59))	('mutation', 'Var', (14, 22))	('to 7', 'Species', '1214577', (86, 90))	('BRCA2', 'Gene', (3, 8))
117419	30090744	This study considers prophylactic mastectomy the most effective single intervention in overall survival in BRCA2 gene mutation carriers.	('BRCA2', 'Gene', '675', (107, 112))	('mutation', 'Var', (118, 126))	('carriers', 'Reg', (127, 135))	('BRCA2', 'Gene', (107, 112))
117420	30090744	Delaying prophylactic mastectomy by 5-10 years could decrease the gain in life expectancy by a range from 1 to 9.9 years in BRCA1 gene mutation carriers and from 0.5 to 4.2 years in BRCA2 gene mutation carriers.	('decrease', 'NegReg', (53, 61))	('gain', 'PosReg', (66, 70))	('BRCA2', 'Gene', '675', (182, 187))	('BRCA1', 'Gene', '672', (124, 129))	('BRCA1', 'Gene', (124, 129))	('to 9', 'Species', '1214577', (108, 112))	('life expectancy', 'CPA', (74, 89))	('mutation', 'Var', (135, 143))	('BRCA2', 'Gene', (182, 187))
117459	30090744	In a recent prospective study conducted by Manning et al., 26 BRCA gene mutation carriers of median age 41 years had contralateral prophylactic nipple-sparing mastectomy.	('prophylactic nipple', 'Phenotype', 'HP:0002558', (131, 150))	('BRCA', 'Gene', '672', (62, 66))	('BRCA', 'Gene', (62, 66))	('mutation', 'Var', (72, 80))
117484	29388015	Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size <= 1 versus  > 1-2.5 cm (1.45, 1.47), age >= 50 versus < 50 year (0.61, 0.84) and year >= 2000 (0.67, 0.49).	('DS', 'Chemical', '-', (62, 64))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('E5194', 'Var', (19, 24))
117511	29388015	In E5194 cohort, tumor size was <= 1 cm in 260 (79.5%) patients, the median DS was 25 and the median follow-up interval was 11.5 years (range: 0.2-15.9).	('tumor', 'Disease', (17, 22))	('E5194', 'Var', (3, 8))	('DS', 'Chemical', '-', (76, 78))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
117514	29388015	Among 327 patients in the E5194 cohort, there were 53 LRs (27 invasive LRs).	('LRs', 'Disease', (54, 57))	('E5194', 'Var', (26, 31))	('patients', 'Species', '9606', (10, 18))
117517	29388015	In the E5194 cohort, an increase of 50 units in the DS (DS/50) was associated with a 2.5-fold increased hazard of LR (HR 2.48; 95% CI 1.29, 4.75).	('E5194', 'Var', (7, 12))	('increase', 'PosReg', (24, 32))	('DS', 'Chemical', '-', (52, 54))	('DS', 'Chemical', '-', (56, 58))
117519	29388015	In the Ontario cohort, an increase in DS/50 was associated with a twofold increased hazard for LR (HR 1.95; 95% CI 1.14, 3.32).	('increase', 'PosReg', (26, 34))	('DS/50', 'Var', (38, 43))	('DS', 'Chemical', '-', (38, 40))
117520	29388015	The hazard ratio for LR associated with tumor size > 1-2.5 cm was 1.47 (95% CI 0.82, 2.64) and 2.99 (95% CI 1.32, 6.76) for tumor size >= 2.5 cm compared to <= 1 cm.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('>= 2.5 cm', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
117523	29388015	In the E5194 cohort, an increase of DS/50 was associated with a 3.02-fold (95% CI 1.28, 7.14) increased hazard of invasive LR and diagnosis in year 2000 or later was associated with a decreased hazard of invasive LR (HR 0.92, 95% CI: 0.42,2.00).	('increase', 'PosReg', (24, 32))	('DS/50', 'Var', (36, 41))	('E5194', 'Var', (7, 12))	('invasive LR', 'Disease', (114, 125))	('invasive LR', 'Disease', (204, 215))	('DS', 'Chemical', '-', (36, 38))
117694	27635065	From the user perspective, this tissue resource can be used for molecular characterizations of the tumors such as genetic mutations, epigenetic changes and abnormally expressed gene products.	('genetic mutations', 'Var', (114, 131))	('epigenetic changes', 'Var', (133, 151))	('abnormally', 'Var', (156, 166))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
117719	26400100	Knocking down of Slit2 expression in gastric cancer cells promoted cells motility.	('cells motility', 'CPA', (67, 81))	('gastric cancer', 'Disease', (37, 51))	('Knocking down', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('Slit2', 'Gene', '9353', (17, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('promoted', 'PosReg', (58, 66))	('Slit2', 'Gene', (17, 22))
117744	26400100	The median PFS was 60.3 (range, 6-110) months and 71.5 (range, 1-124) months in low or high Slit2 expression patients, respectively.	('Slit2', 'Gene', (92, 97))	('Slit2', 'Gene', '9353', (92, 97))	('low', 'Var', (80, 83))	('patients', 'Species', '9606', (109, 117))
117747	26400100	The mean PFS of patients with low or high Robo1 expression was 58.4 and 74.3 month, respectively (Fig.	('high', 'Var', (37, 41))	('Robo1', 'Gene', '6091', (42, 47))	('low', 'NegReg', (30, 33))	('patients', 'Species', '9606', (16, 24))	('expression', 'MPA', (48, 58))	('Robo1', 'Gene', (42, 47))
117767	26400100	Brain metastasis occurred earlier in patients with low Slit2 expression than high Slit2 expression group (P = 0.004, Fig.	('Slit2', 'Gene', (55, 60))	('patients', 'Species', '9606', (37, 45))	('Slit2', 'Gene', (82, 87))	('Slit2', 'Gene', '9353', (55, 60))	('Brain metastasis', 'CPA', (0, 16))	('Slit2', 'Gene', '9353', (82, 87))	('low', 'Var', (51, 54))
117774	26400100	The survival after diagnosis of brain metastasis was worse in low Robo1 expression patients than that of high Robo1 expression group (P = 0.038, Fig.	('patients', 'Species', '9606', (83, 91))	('Robo1', 'Gene', '6091', (66, 71))	('brain metastasis', 'Disease', (32, 48))	('worse', 'NegReg', (53, 58))	('low', 'Var', (62, 65))	('Robo1', 'Gene', '6091', (110, 115))	('Robo1', 'Gene', (66, 71))	('Robo1', 'Gene', (110, 115))	('brain metastasis', 'Disease', 'MESH:D009362', (32, 48))
117781	26400100	In the following, we applied recombinant human Slit2-N peptide (corresponding to the N-terminal portion of the full length Slit2 precursor) as a chemoattractant, and we found more MDA-MB-231 cells migrated into the lower chamber in the Slit2-N group (50 ng/ml or 100 ng/ml) than the control (One-way ANOVA, P < 0.001, Fig.	('Slit2', 'Gene', '9353', (123, 128))	('more', 'PosReg', (175, 179))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (180, 190))	('human', 'Species', '9606', (41, 46))	('Slit2', 'Gene', (236, 241))	('Slit2', 'Gene', (47, 52))	('50 ng/ml', 'Var', (251, 259))	('Slit2', 'Gene', (123, 128))	('Slit2', 'Gene', '9353', (236, 241))	('Slit2', 'Gene', '9353', (47, 52))
117782	26400100	Furthermore, co-culture of siRobo1/MDA-MB-231 cells (upper chamber) with brain derived cells (glioblastoma cell line LN229, lower chamber) were performed in the transwell system, we found LN229 cells with 100 ng/ml of Slit2-N in the lower chamber promoted the migration of siRobo1 cells compared with the Slit2-N absent group (Student's t test, P = 0.013, Fig.	('Robo1', 'Gene', (29, 34))	('LN229', 'CellLine', 'CVCL:0393', (188, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('LN229', 'CellLine', 'CVCL:0393', (117, 122))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (35, 45))	('promoted', 'PosReg', (247, 255))	('Robo1', 'Gene', '6091', (275, 280))	('Slit2-N', 'Var', (218, 225))	('Robo1', 'Gene', '6091', (29, 34))	('Robo1', 'Gene', (275, 280))	('glioblastoma', 'Disease', (94, 106))	('migration', 'CPA', (260, 269))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
117783	26400100	It is well established that Slit2/Robo1 axis plays an important role in breast development and morphology, loss of Slit2 or Robo1 resulted in a precocious branching phenotype characterized by an excess of disorganized basal myoepithelial cells.	('resulted in', 'Reg', (130, 141))	('Slit2', 'Gene', (115, 120))	('disorganized basal myoepithelial cells', 'CPA', (205, 243))	('Robo1', 'Gene', '6091', (34, 39))	('excess', 'PosReg', (195, 201))	('loss', 'Var', (107, 111))	('Slit2', 'Gene', '9353', (28, 33))	('Robo1', 'Gene', (34, 39))	('Slit2', 'Gene', '9353', (115, 120))	('precocious branching phenotype', 'CPA', (144, 174))	('Robo1', 'Gene', '6091', (124, 129))	('Robo1', 'Gene', (124, 129))	('Slit2', 'Gene', (28, 33))
117784	26400100	Slit2 promoter hypermethylation in tissue and serum samples from breast cancer patients was a possible marker for early detection.	('Slit2', 'Gene', '9353', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('patients', 'Species', '9606', (79, 87))	('Slit2', 'Gene', (0, 5))	('promoter hypermethylation', 'Var', (6, 31))
117793	26400100	Slit2 secreted by midline glia could prevent axons with high level of Robo1 to cross the midline, while growth cones expressing low level of Robo1 were allowed to cross.	('high level', 'Var', (56, 66))	('Slit2', 'Gene', '9353', (0, 5))	('midline glia', 'Disease', 'MESH:D009436', (18, 30))	('Robo1', 'Gene', '6091', (70, 75))	('midline glia', 'Disease', (18, 30))	('Robo1', 'Gene', '6091', (141, 146))	('Robo1', 'Gene', (70, 75))	('Robo1', 'Gene', (141, 146))	('Slit2', 'Gene', (0, 5))
117797	26400100	It was reported that inhibition of Slit2/Robo1 signaling could promote progression of breast cancer via activating PI3K/Akt/beta-catenin pathway and accelerated translocation of beta-catenin into nucleus in vitro and in vivo.	('Akt', 'Gene', '207', (120, 123))	('Robo1', 'Gene', '6091', (41, 46))	('activating', 'PosReg', (104, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('accelerated', 'PosReg', (149, 160))	('progression', 'CPA', (71, 82))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('promote', 'PosReg', (63, 70))	('breast cancer', 'Disease', (86, 99))	('Robo1', 'Gene', (41, 46))	('beta-catenin', 'Gene', (124, 136))	('beta-catenin', 'Gene', '1499', (124, 136))	('Slit2', 'Gene', '9353', (35, 40))	('beta-catenin', 'Gene', (178, 190))	('Slit2', 'Gene', (35, 40))	('beta-catenin', 'Gene', '1499', (178, 190))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibition', 'Var', (21, 31))	('Akt', 'Gene', (120, 123))
117822	26400100	Patients were categorized into groups according to IHC score of Slit2 or Robo1: low Slit2 expression (0-2), high Slit2 expression (3-6), low Robo1 expression (0-2), and high Robo1 expression (3-6).	('Slit2', 'Gene', '9353', (64, 69))	('expression', 'MPA', (147, 157))	('low', 'NegReg', (137, 140))	('expression', 'MPA', (90, 100))	('Robo1', 'Gene', '6091', (73, 78))	('Slit2', 'Gene', (64, 69))	('Slit2', 'Gene', '9353', (84, 89))	('Robo1', 'Gene', '6091', (174, 179))	('Slit2', 'Gene', (84, 89))	('Robo1', 'Gene', '6091', (141, 146))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (108, 112))	('Robo1', 'Gene', (73, 78))	('expression', 'MPA', (119, 129))	('low', 'NegReg', (80, 83))	('expression', 'MPA', (180, 190))	('Robo1', 'Gene', (174, 179))	('Robo1', 'Gene', (141, 146))	('Slit2', 'Gene', '9353', (113, 118))	('Slit2', 'Gene', (113, 118))
117824	26400100	Antibodies used in Western Blot for beta-actin (sc-47778) and Robo1 (sc-25672) were acquired from Santa Cruz Biotechnology (Santa Cruz, CA).	('beta-actin', 'Gene', '728378', (36, 46))	('sc-25672', 'Var', (69, 77))	('beta-actin', 'Gene', (36, 46))	('Robo1', 'Gene', '6091', (62, 67))	('Robo1', 'Gene', (62, 67))
117825	26400100	Fluorescent secondary antibody used for Western Blots include anti-rabbit antibody (926-32211, Odyssey LiCor, IR800) and anti-mouse antibody (926-32210, Odyssey LiCor, IR700).	('mouse', 'Species', '10090', (126, 131))	('926-32211', 'Var', (84, 93))	('926-32210', 'Var', (142, 151))	('rabbit', 'Species', '9986', (67, 73))
117917	18779878	Patients were grouped by heterogeneity of their nuclear grade: Group A: nuclear grade 1 only, nuclear grades 1 and 2, or nuclear grade 2 only (32 patients), Group B: nuclear grades 1, 2 and 3, or nuclear grades 2 and 3 (31 patients), Group 3: nuclear grade 3 only (17 patients).	('nuclear grades', 'Var', (166, 180))	('patients', 'Species', '9606', (146, 154))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (223, 231))	('patients', 'Species', '9606', (268, 276))	('nuclear grade 2', 'Var', (121, 136))
118015	16287501	Alterations in the gene CDH1 on chromosome 16q22 are associated with changes in E-cadherin protein expression and function.	('E-cadherin', 'Gene', (80, 90))	('expression', 'MPA', (99, 109))	('CDH1', 'Gene', (24, 28))	('E-cadherin', 'Gene', '999', (80, 90))	('CDH1', 'Gene', '999', (24, 28))	('Alterations', 'Var', (0, 11))	('function', 'MPA', (114, 122))	('changes', 'Reg', (69, 76))
118016	16287501	Inactivation of E-cadherin in lobular carcinomas and certain diffuse gastric carcinomas may play a role in the dispersed, discohesive "single cell" growth patterns seen in these tumors.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (30, 47))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (30, 48))	('dispersed', 'CPA', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('Inactivation', 'Var', (0, 12))	('lobular carcinomas', 'Disease', 'MESH:D018275', (30, 48))	('play', 'Reg', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gastric carcinomas', 'Disease', 'MESH:D013274', (69, 87))	('gastric carcinomas', 'Disease', (69, 87))	('E-cadherin', 'Gene', (16, 26))	('E-cadherin', 'Gene', '999', (16, 26))	('tumors', 'Disease', (178, 184))	('lobular carcinomas', 'Disease', (30, 48))
118043	16287501	In this case, aberrant E-cadherin protein expression was represented by absence of cell membrane immunoreactivity in gland-forming regions of invasive as well as metastatic carcinoma which appeared to be phenotypically "ductal".	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('expression', 'MPA', (42, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('aberrant', 'Var', (14, 22))	('absence', 'NegReg', (72, 79))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('cell membrane immunoreactivity', 'MPA', (83, 113))	('carcinoma', 'Disease', (173, 182))
118055	16287501	In this case, aberrant E-cadherin protein expression consisted of weak immunoreactivity in the "ductal" areas of invasive carcinoma, whereas strong positivity was appreciated in areas of invasive and metastatic carcinoma with a lobular histologic phenotype.	('invasive carcinoma', 'Disease', (113, 131))	('weak', 'NegReg', (66, 70))	('expression', 'MPA', (42, 52))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('aberrant', 'Var', (14, 22))	('E-cadherin', 'Gene', (23, 33))	('immunoreactivity', 'MPA', (71, 87))	('invasive carcinoma', 'Disease', 'MESH:D009361', (113, 131))	('E-cadherin', 'Gene', '999', (23, 33))	('carcinoma', 'Disease', 'MESH:D002277', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', (211, 220))	('carcinoma', 'Disease', (122, 131))
118092	16287501	Mutations in the E-cadherin gene (CDHI) located on chromosome 16q22.1 have been demonstrated in gastric, ovarian, endometrial and thyroid carcinomas in addition to lobular breast carcinomas.	('endometrial', 'Disease', (114, 125))	('CDHI', 'Gene', (34, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('demonstrated', 'Reg', (80, 92))	('breast carcinomas', 'Phenotype', 'HP:0003002', (172, 189))	('breast carcinoma', 'Phenotype', 'HP:0003002', (172, 188))	('gastric', 'Disease', (96, 103))	('Mutations', 'Var', (0, 9))	('ovarian', 'Disease', (105, 112))	('lobular breast carcinomas', 'Disease', (164, 189))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (130, 148))	('thyroid carcinomas', 'Disease', (130, 148))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (130, 148))	('lobular breast carcinomas', 'Disease', 'MESH:D018275', (164, 189))
118093	16287501	More recently molecular alteration in the E-cadherin gene resulting in loss of expression of E-cadherin in in situ and invasive lobular carcinomas has been demonstrated by molecular studies.	('lobular carcinomas', 'Phenotype', 'HP:0030076', (128, 146))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('expression', 'MPA', (79, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('alteration', 'Var', (24, 34))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (119, 146))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (128, 145))	('E-cadherin', 'Gene', (42, 52))	('loss of', 'NegReg', (71, 78))	('invasive lobular carcinomas', 'Disease', (119, 146))	('E-cadherin', 'Gene', '999', (42, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
118095	16287501	Molecular alteration with loss of heterozygosity at 16q21.1 is the most frequent chromosome alteration in lobular carcinoma and correlates with the loss of E-cadherin expression.	('loss', 'NegReg', (148, 152))	('E-cadherin', 'Gene', (156, 166))	('lobular carcinoma', 'Disease', (106, 123))	('E-cadherin', 'Gene', '999', (156, 166))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (106, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('loss', 'NegReg', (26, 30))	('Molecular alteration', 'Var', (0, 20))	('expression', 'MPA', (167, 177))	('lobular carcinoma', 'Disease', 'MESH:D018275', (106, 123))
118137	16287501	Such aberrant staining may be due to mutant E-cadherin, which is incorrectly processed within the Golgi apparatus, or from accelerated protein turnover.	('protein', 'MPA', (135, 142))	('accelerated', 'PosReg', (123, 134))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('mutant', 'Var', (37, 43))
118139	16287501	This observation was taken to be evidence that alteration in E-cadherin occurs early in the development of gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (107, 129))	('alteration', 'Var', (47, 57))	('E-cadherin', 'Gene', (61, 71))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (107, 129))	('E-cadherin', 'Gene', '999', (61, 71))
118145	16287501	Disruption of E-cadherin signaling with inactivation of E-cadherin protein by phosphorylation by activation of SRC family kinases and several growth factor receptors has been previously reported.. Normal E-cadherin expression can be seen despite compromised functional ability via defects in catenin (alpha, beta and gamma) Loss of E-cadherin expression can occur by gene deletion, as well as defects in transcription and methylation.	('E-cadherin', 'Gene', (204, 214))	('E-cadherin', 'Gene', '999', (204, 214))	('expression', 'MPA', (343, 353))	('E-cadherin', 'Gene', '999', (14, 24))	('E-cadherin', 'Gene', '999', (332, 342))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', (332, 342))	('defects', 'NegReg', (281, 288))	('transcription', 'MPA', (404, 417))	('Loss', 'NegReg', (324, 328))	('E-cadherin', 'Gene', (14, 24))	('gene deletion', 'Var', (367, 380))	('E-cadherin', 'Gene', '999', (56, 66))	('defects', 'NegReg', (393, 400))	('methylation', 'MPA', (422, 433))
118153	33363702	Abnormalities in cell nuclear morphology are a hallmark of cancer.	('cell nuclear morphology', 'CPA', (17, 40))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
118199	28366759	Ductal enhancement regions detected in images acquired between 12 and 21 minutes after contrast injection was five times smaller in SV40 mouse mammary ducts (p < 0.001) than in non-cancerous FVB/N mouse mammary ducts, perhaps due to rapid washout of contrast agent from the SV40 ducts.	('non-cancerous FVB/N', 'Disease', (177, 196))	('Ductal', 'MPA', (0, 6))	('SV40', 'Var', (132, 136))	('mouse', 'Species', '10090', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('smaller', 'NegReg', (121, 128))	('mouse', 'Species', '10090', (197, 202))	('non-cancerous FVB/N', 'Disease', 'MESH:D009369', (177, 196))	('enhancement', 'PosReg', (7, 18))
118244	28366759	The FVB/N mouse and SV40 mouse have different ductal tree structures, and the FVB/N mouse has a much larger enhanced ductal volume at 12 - 21 minutes after injection than the SV40 mouse.	('mouse', 'Species', '10090', (10, 15))	('mouse', 'Species', '10090', (25, 30))	('mouse', 'Species', '10090', (180, 185))	('ductal volume', 'CPA', (117, 130))	('enhanced', 'PosReg', (108, 116))	('mouse', 'Species', '10090', (84, 89))	('FVB/N', 'Var', (78, 83))
118245	28366759	3(a)) in the first post-injection scan was about five times higher in FVB/N mice relative to SV40 mice (p < 0.005).	('mice', 'Species', '10090', (76, 80))	('FVB/N', 'Var', (70, 75))	('mice', 'Species', '10090', (98, 102))	('higher', 'PosReg', (60, 66))
118247	28366759	Figure 3(b) shows on average that the specific volume of enhancement was about four times higher (p < 0.007) in FVB/N mice relative to SV40 mice.	('mice', 'Species', '10090', (140, 144))	('FVB/N', 'Var', (112, 117))	('enhancement', 'PosReg', (57, 68))	('higher', 'PosReg', (90, 96))	('mice', 'Species', '10090', (118, 122))	('specific volume', 'MPA', (38, 53))
118249	28366759	The average washout rate in the mammary gland was about 20% faster in SV40 mice (p < 0.05) relative to the FVB/N mice.	('SV40', 'Var', (70, 74))	('mice', 'Species', '10090', (75, 79))	('faster', 'PosReg', (60, 66))	('mice', 'Species', '10090', (113, 117))	('washout rate', 'MPA', (12, 24))
118250	28366759	The average rate of washout from the aorta was slower in the SV40 mice than in the FVB/N mice, but the difference was not statistically significant (p = 0.16).	('slower', 'NegReg', (47, 53))	('washout from the aorta', 'MPA', (20, 42))	('mice', 'Species', '10090', (89, 93))	('mice', 'Species', '10090', (66, 70))	('SV40', 'Var', (61, 65))	('rate', 'MPA', (12, 16))
118256	28366759	In addition, the washout of the contrast agent from mammary ducts during the imaging period (from 12 minutes to 90 minutes post injection) is significantly more rapid in SV40 mice than in FVB/N mice, consistent with increased permeability of the walls of the ductal lumens.	('mice', 'Species', '10090', (175, 179))	('SV40', 'Var', (170, 174))	('permeability', 'MPA', (226, 238))	('washout', 'MPA', (17, 24))	('mice', 'Species', '10090', (194, 198))	('increased', 'PosReg', (216, 225))	('more', 'PosReg', (156, 160))
118258	28366759	Contrast agent washout rate measured from the aorta was somewhat slower in SV40 mice than in FVB/N mice (although this difference was not statistically significant).	('mice', 'Species', '10090', (99, 103))	('Contrast agent washout rate', 'MPA', (0, 27))	('slower', 'NegReg', (65, 71))	('SV40', 'Var', (75, 79))	('mice', 'Species', '10090', (80, 84))
118262	28366759	The XFM data provide further support for the hypothesis that increased permeability of mammary ducts of SV40 mice is due to the presence of small in situ cancers, and may be an MRI detectable marker for early cancer.	('permeability', 'MPA', (71, 83))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (154, 160))	('situ cancers', 'Disease', 'MESH:D002278', (149, 161))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('increased', 'PosReg', (61, 70))	('cancer', 'Disease', (209, 215))	('fur', 'Chemical', '-', (21, 24))	('mice', 'Species', '10090', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('situ cancers', 'Disease', (149, 161))	('SV40', 'Var', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
118269	28366759	In addition, serial MRI studies of increasing ductal permeability in mouse models during cancer development, and changes in ductal permeability during therapy could guide the development of new therapies for human breast cancer and could enhance understanding of the biology of in situ breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('cancer', 'Disease', (89, 95))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('human', 'Species', '9606', (208, 213))	('breast cancer', 'Disease', (214, 227))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('mouse', 'Species', '10090', (69, 74))	('cancers', 'Phenotype', 'HP:0002664', (293, 300))	('cancer', 'Disease', (293, 299))	('changes', 'Var', (113, 120))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('ductal permeability', 'MPA', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('situ breast cancers', 'Disease', 'MESH:D000071960', (281, 300))	('increasing', 'PosReg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancers', 'Phenotype', 'HP:0003002', (286, 300))	('enhance', 'PosReg', (238, 245))	('situ breast cancers', 'Disease', (281, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))
118332	26955499	If the nuclear pleomorphism exists to some extent, but not prominent like HG-DCIS, the lesion is diagnosed as IM-DCIS.	('IM-DCIS', 'Disease', (110, 117))	('IM-DCIS', 'Chemical', '-', (110, 117))	('nuclear pleomorphism', 'Var', (7, 27))	('HG-DCIS', 'Disease', (74, 81))
118338	19789364	CHANGES IN CpG ISLANDS METHYLATION PATTERNS DURING DUCTAL BREAST CARCINOMA PROGRESSION CpG island hypermethylation is emerging as one of the main mechanisms for inactivation of cancer related genes in breast tumorigenesis.	('CARCINOMA', 'Phenotype', 'HP:0030731', (65, 74))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('DUCTAL BREAST CARCINOMA', 'Disease', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('BREAST CARCINOMA', 'Phenotype', 'HP:0003002', (58, 74))	('tumor', 'Disease', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('inactivation', 'NegReg', (161, 173))	('CHANGES', 'Reg', (0, 7))	('hypermethylation', 'Var', (98, 114))
118345	19789364	Our data point to direct involvement of APC, CDH1, and CTNNB1 CpG island promoter methylation in the early stages of breast cancer progression, and suggest that these molecular alterations might be involved in the transition to an invasive phenotype.	('APC', 'Disease', 'MESH:D011125', (40, 43))	('CTNNB1', 'Gene', '1499', (55, 61))	('methylation', 'Var', (82, 93))	('APC', 'Disease', (40, 43))	('CDH1', 'Gene', '999', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('CTNNB1', 'Gene', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('involvement', 'Reg', (25, 36))	('involved', 'Reg', (198, 206))	('CDH1', 'Gene', (45, 49))
118355	19789364	There is now a compelling body of evidence supporting the importance of epigenetic mechanisms in the development and progression of cancer.	('epigenetic mechanisms', 'Var', (72, 93))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
118372	19789364	Median age for the normal breast tissue group was 56 years (IQR 50-63), 19 of the 20 patients were affected by breast cancer (9 pT1cN0, 7 pT1cN1b, 1 pT1cN1a, 1 pT2N0 and 1 pT2N1b) and one patient was diagnosed with fibroadenoma.	('patient', 'Species', '9606', (85, 92))	('cN1b', 'Gene', (141, 145))	('cN1a', 'Gene', '84618', (152, 156))	('patient', 'Species', '9606', (188, 195))	('cN1a', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('affected', 'Reg', (99, 107))	('patients', 'Species', '9606', (85, 93))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('fibroadenoma', 'Disease', 'MESH:D018226', (215, 227))	('cN1b', 'Gene', '93034', (141, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('pT1cN0', 'Var', (128, 134))	('fibroadenoma', 'Disease', (215, 227))
118387	19789364	An example of APC, CDH1 and CTNNB1 methylation in multiple lesions from patient BP18 is shown in Figure 2.	('BP18', 'Gene', (80, 84))	('CTNNB1', 'Gene', '1499', (28, 34))	('CTNNB1', 'Gene', (28, 34))	('CDH1', 'Gene', (19, 23))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('patient', 'Species', '9606', (72, 79))	('methylation', 'Var', (35, 46))	('APC', 'Disease', (14, 17))	('CDH1', 'Gene', '999', (19, 23))	('BP18', 'Gene', '474213', (80, 84))
118391	19789364	Methylation at two or three gene loci was found in 5 ADH (25%), 9 DCIS (28%) and 16 IDC (37%) (P=0.03).	('IDC', 'Gene', (84, 87))	('Methylation', 'Var', (0, 11))	('DCIS', 'Disease', (66, 70))	('ADH', 'Disease', (53, 56))	('found', 'Reg', (42, 47))	('IDC', 'Gene', '4000', (84, 87))
118399	19789364	Loss of heterozigosity at the E-cadherin gene locus (CDH1) is a frequent event in both ductal and lobular carcinomas, but inactivation of the second allele by mutation was demonstrated only in the lobular subtype.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (98, 116))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (98, 115))	('heterozigosity', 'Var', (8, 22))	('E-cadherin', 'Gene', (30, 40))	('E-cadherin', 'Gene', '999', (30, 40))	('Loss', 'NegReg', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('ductal', 'Disease', (87, 93))	('lobular carcinomas', 'Disease', (98, 116))	('CDH1', 'Gene', (53, 57))	('CDH1', 'Gene', '999', (53, 57))	('lobular carcinomas', 'Disease', 'MESH:D018275', (98, 116))
118400	19789364	Approximately 40% of breast cancers (both lobular and ductal type) harbored methylation at the CDH1 promoter CpG island.	('breast cancers', 'Phenotype', 'HP:0003002', (21, 35))	('CDH1', 'Gene', '999', (95, 99))	('breast cancers', 'Disease', 'MESH:D001943', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancers', 'Disease', (21, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('methylation', 'Var', (76, 87))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('CDH1', 'Gene', (95, 99))
118401	19789364	APC mutation or epigenetic inactivation play a key role in colorectal carcinogenesis and in particular in the early stages of disease progression.	('APC', 'Disease', 'MESH:D011125', (0, 3))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('mutation', 'Var', (4, 12))	('APC', 'Disease', (0, 3))	('colorectal carcinogenesis', 'Disease', (59, 84))	('epigenetic inactivation', 'Var', (16, 39))
118404	19789364	In colorectal cancer, beta-catenin is activated by oncogenic mutation affecting the phosphorylation site resulting in a constitutively stable protein, or by loss of functional APC.	('beta-catenin', 'Gene', '1499', (22, 34))	('loss of functional APC', 'Disease', (157, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('constitutively stable protein', 'MPA', (120, 149))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('phosphorylation site', 'MPA', (84, 104))	('colorectal cancer', 'Disease', (3, 20))	('beta-catenin', 'Gene', (22, 34))	('activated', 'PosReg', (38, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('loss of functional APC', 'Disease', 'MESH:D011125', (157, 179))
118405	19789364	However, CTNNB1 methylation (and presumably inactivation) was recently reported in gastric and endometrial cancers.	('endometrial cancers', 'Disease', 'MESH:D016889', (95, 114))	('endometrial cancers', 'Disease', (95, 114))	('CTNNB1', 'Gene', '1499', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric', 'Disease', (83, 90))	('CTNNB1', 'Gene', (9, 15))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('reported', 'Reg', (71, 79))	('methylation', 'Var', (16, 27))
118408	19789364	Moreover, Whitcomb et al reported methylation at the CTNNB1 promoter region in 17% of primary endometrial tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('methylation', 'Var', (34, 45))	('endometrial tumors', 'Disease', (94, 112))	('CTNNB1', 'Gene', '1499', (53, 59))	('endometrial tumors', 'Disease', 'MESH:D016889', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CTNNB1', 'Gene', (53, 59))
118409	19789364	To the best of our knowledge, our present study is the first to report CTNNB1 methylation in breast cancer.	('methylation', 'Var', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('CTNNB1', 'Gene', '1499', (71, 77))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('CTNNB1', 'Gene', (71, 77))
118430	19789364	However, these similar epigenetic patterns do not exclude that promoter methylation may play a role in carcinogenesis.	('promoter methylation', 'Var', (63, 83))	('carcinogenesis', 'Disease', (103, 117))	('play', 'Reg', (88, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))
118431	19789364	Alterations in stromal and myoepithelial cells may establish an abnormal tumor microenviroment and contribute to cancer progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('contribute', 'Reg', (99, 109))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('abnormal tumor', 'Phenotype', 'HP:0002664', (64, 78))	('cancer', 'Disease', (113, 119))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
118432	19789364	We propose a model for the timing of epigenetic modifications in breast cancer development APC methylation would be an early event, correlated with abnormal proliferation of the breast epithelia.	('APC', 'Disease', (91, 94))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast epithelia', 'Disease', 'MESH:D001943', (178, 194))	('APC', 'Disease', 'MESH:D011125', (91, 94))	('breast epithelia', 'Disease', (178, 194))	('epigenetic modifications', 'Var', (37, 61))
118433	19789364	CDH1 and CTNNB1 methylation occur later and are likely to play a more direct role in the loss of cell-to-cell adhesion and the acquisition of invasive properties by the cancer cells.	('cancer', 'Disease', (169, 175))	('cell-to-cell adhesion', 'CPA', (97, 118))	('CTNNB1', 'Gene', '1499', (9, 15))	('CDH1', 'Gene', '999', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CTNNB1', 'Gene', (9, 15))	('invasive properties', 'CPA', (142, 161))	('methylation', 'Var', (16, 27))	('CDH1', 'Gene', (0, 4))	('loss', 'NegReg', (89, 93))
118435	19789364	Our results indicate that methylation not only occurs early during tumor progression, but also that the analysis of specific genes may allow to distinguish between normal and transformed cells and even between pre-invasive and invasive carcinomas, thus representing a promising tool for the identification of tumor cells in clinical specimens.	('methylation', 'Var', (26, 37))	('invasive carcinomas', 'Disease', 'MESH:D009361', (227, 246))	('tumor', 'Disease', (309, 314))	('invasive carcinomas', 'Disease', (227, 246))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (236, 246))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
118439	19789364	Thus, it is likely that the combined detection of methylation of APC, CDH1 and CTNNB1 could be more informative than other methylation markers in identifying cancer cells in cytological specimens.	('CTNNB1', 'Gene', '1499', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('CDH1', 'Gene', (70, 74))	('APC', 'Disease', 'MESH:D011125', (65, 68))	('CDH1', 'Gene', '999', (70, 74))	('cancer', 'Disease', (158, 164))	('APC', 'Disease', (65, 68))	('CTNNB1', 'Gene', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('methylation', 'Var', (50, 61))
118460	30384839	All participants had FFDM and DBT on Siemens Mammomat Inspiration units.	('DBT', 'Var', (30, 33))	('participants', 'Species', '9606', (4, 16))	('FFDM', 'Disease', (21, 25))	('men', 'Species', '9606', (40, 43))	('FFDM', 'Chemical', '-', (21, 25))
118501	30384839	At prevalent (first) screens (women aged 45-52), FFDM increased the overall detection rate by 19% from 6.33 to 7.59 per 1000 (p<0.001) and for incident (subsequent) screens (women aged 53-70) by 13% from 7.11 to 8.02 per 1000.	('FFDM', 'Var', (49, 53))	('FFDM', 'Chemical', '-', (49, 53))	('women', 'Species', '9606', (30, 35))	('increased', 'PosReg', (54, 63))	('to 7', 'Species', '1214577', (108, 112))	('women', 'Species', '9606', (174, 179))	('detection', 'MPA', (76, 85))
118609	30384839	3-way agreement between the radiographers was substantial to almost perfect for inadequate IMF, cut off, and inadequate pec (k=0.79, 0.74, and 0.64, respectively); moderate for concave or thin pectoralis, other body parts, CC exaggeration, and under exposure (k=0.59, 0.49, 0.43, and 0.43, respectively); and poor to fair for the remaining parameters.	('exaggeration', 'PosReg', (226, 238))	('thin pectoralis', 'Phenotype', 'HP:0008998', (188, 203))	('inadequate pec', 'Phenotype', 'HP:0008998', (109, 123))	('concave', 'Var', (177, 184))	('men', 'Species', '9606', (11, 14))
118970	29628987	Surgical excision rather than vacuum-assisted excision was significantly associated with upgrading to high-risk lesions or malignancy.	('malignancy', 'Disease', 'MESH:D009369', (123, 133))	('malignancy', 'Disease', (123, 133))	('Surgical excision', 'Var', (0, 17))	('upgrading', 'PosReg', (89, 98))
119110	18953612	We demonstrated that a large proportion of the patients in our sample were inactive both at the time of enrollment and 18 months later, and although most women in our study did not change exercise frequency between the baseline and the 18-month follow-up survey, women who underwent mastectomy for DCIS, as well as those who were anxious, were far more likely to decrease physical activity over this time period.	('mastectomy', 'Var', (283, 293))	('DCIS', 'Phenotype', 'HP:0030075', (298, 302))	('women', 'Species', '9606', (263, 268))	('decrease', 'NegReg', (363, 371))	('patients', 'Species', '9606', (47, 55))	('decrease physical activity', 'Phenotype', 'HP:0003546', (363, 389))	('women', 'Species', '9606', (154, 159))	('physical activity', 'MPA', (372, 389))
119112	18953612	Although it is possible that the decrease in activity seen in women who underwent mastectomy for DCIS could reflect inherent differences in the patients who chose this procedure compared with those who chose lumpectomy, mastectomy itself may make exercise more difficult for patients for a variety of reasons.	('activity', 'MPA', (45, 53))	('decrease', 'NegReg', (33, 41))	('mastectomy', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('patients', 'Species', '9606', (275, 283))	('women', 'Species', '9606', (62, 67))
119113	18953612	Ganz and colleagues demonstrated that women who underwent mastectomy had decreased physical functioning both shortly after surgery and at the completion of adjuvant therapy compared with women who underwent breast-conserving surgery, but physical activity was not assessed.	('women', 'Species', '9606', (187, 192))	('decreased', 'NegReg', (73, 82))	('women', 'Species', '9606', (38, 43))	('mastectomy', 'Var', (58, 68))	('physical functioning', 'MPA', (83, 103))
119114	18953612	These investigators also found that women who underwent mastectomy were more likely to complain of pain around their incision site and a number of other physical problems, including lymphedema, compared with women who underwent breast-conserving surgery.	('lymphedema', 'Disease', 'MESH:D008209', (182, 192))	('lymphedema', 'Phenotype', 'HP:0001004', (182, 192))	('women', 'Species', '9606', (208, 213))	('women', 'Species', '9606', (36, 41))	('complain', 'Reg', (87, 95))	('lymphedema', 'Disease', (182, 192))	('pain', 'Phenotype', 'HP:0012531', (99, 103))	('mastectomy', 'Var', (56, 66))	('pain', 'Disease', 'MESH:D010146', (99, 103))	('pain', 'Disease', (99, 103))
119124	18953612	In summary, a large proportion of women with newly diagnosed DCIS reported infrequent exercise, and although most of these women did not substantially change physical activity patterns over time, women who underwent mastectomy and those who were anxious were far more likely to experience further decreases in activity in the months after diagnosis.	('DCIS', 'Disease', (61, 65))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('women', 'Species', '9606', (123, 128))	('activity', 'MPA', (310, 318))	('mastectomy', 'Var', (216, 226))	('women', 'Species', '9606', (34, 39))	('women', 'Species', '9606', (196, 201))	('decreases', 'NegReg', (297, 306))
119313	21553295	Other unmeasured variables, such as known BRCA 1 and 2 mutations, also might be associated with FCR and require further study.	('FCR', 'Disease', (96, 99))	('associated', 'Reg', (80, 90))	('BRCA 1 and 2', 'Gene', '672;675', (42, 54))	('mutations', 'Var', (55, 64))
119348	19105706	As with tamoxifen, raloxifene increased the risk of thromboembolic disease but did not appear to increase the risk of endometrial cancer.	('thromboembolic disease', 'Phenotype', 'HP:0001907', (52, 74))	('endometrial cancer', 'Disease', (118, 136))	('thromboembolic disease', 'Disease', (52, 74))	('endometrial cancer', 'Phenotype', 'HP:0012114', (118, 136))	('raloxifene', 'Var', (19, 29))	('raloxifene', 'Chemical', 'MESH:D020849', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('endometrial cancer', 'Disease', 'MESH:D016889', (118, 136))	('thromboembolic disease', 'Disease', 'MESH:D013923', (52, 74))	('tamoxifen', 'Chemical', 'MESH:D013629', (8, 17))
119354	19105706	By contrast, the incidence of invasive ER-negative breast cancer in women who received raloxifene was not statistically significantly different from that in women who received placebo.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('raloxifene', 'Var', (87, 97))	('women', 'Species', '9606', (157, 162))	('raloxifene', 'Chemical', 'MESH:D020849', (87, 97))	('ER', 'Gene', '2099', (39, 41))	('women', 'Species', '9606', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
119357	19105706	During these 8 years, 40 invasive breast cancers were reported in the raloxifene group and 58 invasive breast cancers were reported in the placebo group.	('breast cancers', 'Phenotype', 'HP:0003002', (34, 48))	('invasive breast cancers', 'Disease', (94, 117))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('raloxifene', 'Chemical', 'MESH:D020849', (70, 80))	('invasive breast cancers', 'Disease', 'MESH:D001943', (25, 48))	('invasive breast cancers', 'Disease', 'MESH:D001943', (94, 117))	('raloxifene', 'Var', (70, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('invasive breast cancers', 'Disease', (25, 48))
119358	19105706	Thus, the raloxifene group had a 66% reduction in the incidence of invasive breast cancer compared with the placebo group.	('raloxifene', 'Var', (10, 20))	('invasive breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('reduction', 'NegReg', (37, 46))	('raloxifene', 'Chemical', 'MESH:D020849', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('invasive breast cancer', 'Disease', (67, 89))
119359	19105706	During these 8 years, the raloxifene group had a 76% reduction in the incidence of invasive ER-positive breast cancer compared with the placebo group.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('reduction', 'NegReg', (53, 62))	('raloxifene', 'Chemical', 'MESH:D020849', (26, 36))	('breast cancer', 'Disease', (104, 117))	('raloxifene', 'Var', (26, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('ER', 'Gene', '2099', (92, 94))
119405	19105706	The difference in total number of strokes was small, with the number of events occurring in women assigned to tamoxifen being only two more than in those assigned to raloxifene (53 vs 51).	('stroke', 'Phenotype', 'HP:0001297', (34, 40))	('women', 'Species', '9606', (92, 97))	('strokes', 'Disease', 'MESH:D020521', (34, 41))	('raloxifene', 'Chemical', 'MESH:D020849', (166, 176))	('strokes', 'Disease', (34, 41))	('strokes', 'Phenotype', 'HP:0001297', (34, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('tamoxifen', 'Var', (110, 119))
119413	19105706	Of the women in the symptom assessment analyses, the raloxifene group reported greater mean symptom severity over 60 months of assessments than the tamoxifen group for musculoskeletal problems, dyspareunia and weight gain.	('dyspareunia', 'Disease', (194, 205))	('raloxifene', 'Var', (53, 63))	('greater', 'PosReg', (79, 86))	('dyspareunia', 'Disease', 'MESH:D004414', (194, 205))	('dyspareunia', 'Phenotype', 'HP:0030016', (194, 205))	('musculoskeletal problems', 'Disease', (168, 192))	('weight gain', 'Phenotype', 'HP:0004324', (210, 221))	('weight gain', 'Disease', 'MESH:D015430', (210, 221))	('raloxifene', 'Chemical', 'MESH:D020849', (53, 63))	('women', 'Species', '9606', (7, 12))	('tamoxifen', 'Chemical', 'MESH:D013629', (148, 157))	('weight gain', 'Disease', (210, 221))
119427	19105706	In the several osteoporosis trials and the Raloxifene Use for the Heart Trial of older postmenopausal women, raloxifene decreased the risk of ER-positive breast cancer by 44-90%.	('decreased', 'NegReg', (120, 129))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('osteoporosis', 'Phenotype', 'HP:0000939', (15, 27))	('breast cancer', 'Disease', (154, 167))	('raloxifene', 'Chemical', 'MESH:D020849', (109, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('women', 'Species', '9606', (102, 107))	('ER', 'Gene', '2099', (142, 144))	('raloxifene', 'Var', (109, 119))	('osteoporosis', 'Disease', 'MESH:D010024', (15, 27))	('Raloxifene', 'Chemical', 'MESH:D020849', (43, 53))	('osteoporosis', 'Disease', (15, 27))
119434	19105706	Approximately 25% fewer cases of uterine cancer were diagnosed in the raloxifene than the tamoxifen group.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('raloxifene', 'Chemical', 'MESH:D020849', (70, 80))	('uterine cancer', 'Phenotype', 'HP:0010784', (33, 47))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tamoxifen', 'Chemical', 'MESH:D013629', (90, 99))	('raloxifene', 'Var', (70, 80))
119437	19105706	The number of participants undergoing a hysterectomy for noncancer-related reasons was significantly reduced in the raloxifene group (RR: 0.39; 95% CI: 0.30-0.50).	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('reduced', 'NegReg', (101, 108))	('participants', 'Species', '9606', (14, 26))	('raloxifene', 'Var', (116, 126))	('raloxifene', 'Chemical', 'MESH:D020849', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
119440	19105706	Across all placebo-controlled trials with raloxifene, however, in situ cancers occurred more often with raloxifene than with placebo or tamoxifen.	('situ cancers', 'Disease', 'MESH:D002278', (66, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('raloxifene', 'Var', (104, 114))	('tamoxifen', 'Chemical', 'MESH:D013629', (136, 145))	('raloxifene', 'Chemical', 'MESH:D020849', (104, 114))	('situ cancers', 'Disease', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('occurred', 'Reg', (79, 87))	('raloxifene', 'Chemical', 'MESH:D020849', (42, 52))
119496	30044853	The presence of an intact myoepithelial cell layer is characteristic of DCIS, however disruption of the myoepithelial boundary can lead to invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (139, 157))	('myoepithelial', 'Disease', (104, 117))	('invasive carcinoma', 'Disease', (139, 157))	('myoepithelial', 'Disease', 'MESH:D009208', (104, 117))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('myoepithelial', 'Disease', (26, 39))	('disruption', 'Var', (86, 96))	('myoepithelial', 'Disease', 'MESH:D009208', (26, 39))	('lead to', 'Reg', (131, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
119526	30044853	Fresh sections (formalin-fixed, paraffin embedded) were dewaxed following standard protocols and antigen retrieval with pH6 citrate retrieval buffer was undertaken for SMMHC, CK14, p63 and Ki67 staining.	('Ki67', 'Gene', '17345', (189, 193))	('p63', 'Gene', (181, 184))	('formalin', 'Chemical', 'MESH:D005557', (16, 24))	('CK14', 'Var', (175, 179))	('pH6 citrate', 'Chemical', '-', (120, 131))	('paraffin', 'Chemical', 'MESH:D010232', (32, 40))	('p63', 'Gene', '8626', (181, 184))	('Ki67', 'Gene', (189, 193))
119529	30044853	To confirm the timing of spontaneous development of mammary gland tumours in the C57BL/6J MMTV-PyMT model, mammary glands of C57BL/6J MMTV-PyMT mice at different stages were taken and morphologically evaluated by H&E (Fig 1) by an expert human breast and murine mammary gland pathologist (O'Toole).	('H&E', 'Chemical', '-', (213, 216))	('murine', 'Species', '10090', (255, 261))	('mice', 'Species', '10090', (144, 148))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('MMTV', 'Species', '11757', (90, 94))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('C57BL/6J', 'Var', (125, 133))	('human', 'Species', '9606', (238, 243))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('MMTV', 'Species', '11757', (134, 138))
119531	30044853	In C57BL/6J MMTV-PyMT positive mice, hyperplasia was observed at approximately day 30, which correlates with previous findings of hyperplasia development at approximately 28 days in this strain of mice.	('C57BL/6J', 'Var', (3, 11))	('hyperplasia', 'Disease', (130, 141))	('hyperplasia', 'Disease', (37, 48))	('MMTV', 'Species', '11757', (12, 16))	('mice', 'Species', '10090', (31, 35))	('hyperplasia', 'Disease', 'MESH:D006965', (130, 141))	('mice', 'Species', '10090', (197, 201))	('hyperplasia', 'Disease', 'MESH:D006965', (37, 48))
119547	30044853	For normal, hyperplastic and MIN tissue from C57BL/6J MMTV-PyMT mice, antibodies against SMMHC and CK14 were superior for myoepithelial staining (Fig 3 and Table 1), with expression observed in 100% of mammary glands analysed from our laboratory.	('C57BL/6J', 'Var', (45, 53))	('SMMHC', 'Gene', (89, 94))	('MMTV', 'Species', '11757', (54, 58))	('CK14', 'Gene', (99, 103))	('myoepithelial', 'Disease', (122, 135))	('mice', 'Species', '10090', (64, 68))	('myoepithelial', 'Disease', 'MESH:D009208', (122, 135))
119549	30044853	As expected, expression of myoepithelial markers was not detected in invasive areas of C57BL/6J MMTV-PyMT tumours.	('myoepithelial', 'Disease', (27, 40))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('MMTV-PyMT tumours', 'Disease', 'MESH:D009369', (96, 113))	('myoepithelial', 'Disease', 'MESH:D009208', (27, 40))	('C57BL/6J', 'Var', (87, 95))	('MMTV-PyMT tumours', 'Disease', (96, 113))
119550	30044853	In contrast to myoepithelial staining, Ki67 expression, which indicates an increase in proliferation, was expressed most abundantly in the invasive regions of tissues derived from the C57BL/6J MMTV-PyMT mice (Fig 3 and Table 1), as expected due to the high rate of growth of invasive tumour upon palpation in this model.	('mice', 'Species', '10090', (203, 207))	('MMTV', 'Species', '11757', (193, 197))	('Ki67', 'Gene', (39, 43))	('myoepithelial', 'Disease', (15, 28))	('myoepithelial', 'Disease', 'MESH:D009208', (15, 28))	('C57BL/6J', 'Var', (184, 192))	('Ki67', 'Gene', '17345', (39, 43))	('invasive tumour', 'Disease', 'MESH:D009361', (275, 290))	('invasive tumour', 'Disease', (275, 290))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
119555	30044853	The scoring matrix (Table 2) suggests the use of at least two myoepithelial markers, especially to distinguish MIN from invasive lesions in the C57BL/6J MMTV-PyMT model.	('C57BL/6J', 'Var', (144, 152))	('myoepithelial', 'Disease', (62, 75))	('MMTV', 'Species', '11757', (153, 157))	('myoepithelial', 'Disease', 'MESH:D009208', (62, 75))
119562	30044853	Further, in our previous study, we also identified SMA to be a suitable myoepithelial marker for both normal and MIN lesions in the C57BL/6J MMTV-PyMT model.	('MMTV', 'Species', '11757', (141, 145))	('myoepithelial', 'Disease', (72, 85))	('MIN lesions', 'Disease', 'MESH:D051437', (113, 124))	('myoepithelial', 'Disease', 'MESH:D009208', (72, 85))	('C57BL/6J', 'Var', (132, 140))	('MIN lesions', 'Disease', (113, 124))
119583	30044853	Our study revealed that Ki67 epithelial cell positivity is clearly enhanced in hyperplastic regions of C57BL/6J MMTV-PyMT mouse tissue compared to normal tissue.	('Ki67', 'Gene', '17345', (24, 28))	('C57BL/6J', 'Var', (103, 111))	('MMTV', 'Species', '11757', (112, 116))	('Ki67', 'Gene', (24, 28))	('mouse', 'Species', '10090', (122, 127))	('enhanced', 'PosReg', (67, 75))
119666	33389397	Increased risk of iIBC <= 5 years post-DCIS was demonstrated for ages 40-49 (Hazard ratio (HR) 1.86, 95% Confidence Interval (CI) 1.34-2.57 compared to age 50-69), grade 3 lesions (HR 1.42, 95%CI 1.05-1.91) compared to grade 2, lesion size >= 2 cm (HR 1.66, 95%CI 1.23-2.25), and Black race (HR 2.52, 95%CI 1.83-3.48 compared to White).	('iIBC', 'Disease', (18, 22))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('grade 3 lesions', 'Var', (164, 179))	('iIBC', 'Chemical', '-', (18, 22))
119687	33389397	Exclusion was warranted under any of the following criteria: iIBC <= 2 months following DCIS as this might signify upstaging of the DCIS lesion to invasive carcinoma; death of any cause <=6 months following DCIS diagnosis; synchronous diagnosis of contralateral invasive carcinoma (cIBC); Paget's disease; patients treated with postmastectomy radiation therapy; and patients not receiving treatment due to comorbidities or refusal (as coded in SEER).	('ER', 'Gene', '2099', (446, 448))	('death', 'Disease', (167, 172))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('iIBC', 'Chemical', '-', (61, 65))	('upstaging of the DCIS lesion', 'Phenotype', 'HP:0011095', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	("Paget's disease", 'Disease', (289, 304))	('<=6', 'Var', (186, 189))	('patients', 'Species', '9606', (306, 314))	('DCIS lesion to invasive carcinoma', 'Disease', (132, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('death', 'Disease', 'MESH:D003643', (167, 172))	('contralateral invasive carcinoma', 'Disease', 'MESH:D009361', (248, 280))	("Paget's disease", 'Disease', 'MESH:C538098', (289, 304))	('DCIS', 'Phenotype', 'HP:0030075', (207, 211))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))	('contralateral invasive carcinoma', 'Disease', (248, 280))	('patients', 'Species', '9606', (366, 374))	('cIBC', 'Chemical', '-', (282, 286))	('DCIS lesion to invasive carcinoma', 'Disease', 'MESH:D002285', (132, 165))
119728	33389397	When analyzing their low-risk subgroup (non-high grade, ER/PR+, > 40 years at diagnosis) in a competing risk analysis, the 7.5-year cumulative incidence of iIBC was 5.9% (95% CI 2.3-9.5%).	('PR', 'Gene', '140738', (59, 61))	('iIBC', 'Disease', (156, 160))	('iIBC', 'Chemical', '-', (156, 160))	('ER', 'Gene', '2099', (56, 58))	('non-high grade', 'Var', (40, 54))
119793	29862084	Overall, there is a worse prognosis for the triple negative and Her2+ groups, as well as a clear distinction between two ER+ groups.	('ER', 'Gene', '2099', (121, 123))	('Her2', 'Gene', (64, 68))	('triple negative', 'Var', (44, 59))	('Her2', 'Gene', '2064', (64, 68))
119807	29862084	The latest American Society of Clinical Oncology (ASCO) guideline finds that the strongest level of evidence currently supports the use of either Oncotype DX Recurrence Score or PAM50 ROR.	('Oncology', 'Phenotype', 'HP:0002664', (40, 48))	('ROR', 'Gene', (184, 187))	('Oncotype', 'Var', (146, 154))	('PAM50', 'Var', (178, 183))	('ROR', 'Gene', '100885779', (184, 187))
119823	29862084	Studies using this technology have identified the most commonly mutated genes in breast cancer, which include PIK3CA, p53, and Her2 amplification mutations in 15% to 30% of breast cancers, although many other candidate genes are present in frequencies <5%.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('breast cancer', 'Disease', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('p53', 'Gene', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast cancers', 'Disease', (173, 187))	('PIK3CA', 'Gene', '5290', (110, 116))	('Her2', 'Gene', (127, 131))	('breast cancers', 'Disease', 'MESH:D001943', (173, 187))	('p53', 'Gene', '7157', (118, 121))	('breast cancers', 'Phenotype', 'HP:0003002', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))	('Her2', 'Gene', '2064', (127, 131))	('amplification mutations', 'Var', (132, 155))	('PIK3CA', 'Gene', (110, 116))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))
119825	29862084	Using mutational status to test for response to specific agents has great promise to personalize systemic therapy based on the genomic pathways driving each cancer and to enhance survivorship surveillance.	('mutational', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('enhance', 'PosReg', (171, 178))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('person', 'Species', '9606', (85, 91))	('survivorship surveillance', 'CPA', (179, 204))
119879	21352579	Alterations of nine of these genes, and particularly NDC80, were also detected in benign breast tumors, indicating that they may be involved in pre-neoplastic processes.	('benign breast tumors', 'Disease', 'MESH:D001943', (82, 102))	('neoplastic processes', 'Phenotype', 'HP:0002664', (148, 168))	('detected', 'Reg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Alterations', 'Var', (0, 11))	('breast tumors', 'Phenotype', 'HP:0100013', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('breast tumor', 'Phenotype', 'HP:0100013', (89, 101))	('NDC80', 'Gene', (53, 58))	('benign breast tumors', 'Disease', (82, 102))	('involved', 'Reg', (132, 140))	('NDC80', 'Gene', '10403', (53, 58))
119880	21352579	We also identified a two-gene expression signature (PLK1 + AURKA) which discriminated between DNA aneuploid and DNA diploid breast tumor samples.	('AURKA', 'Gene', (59, 64))	('PLK1', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('diploid breast tumor', 'Disease', (116, 136))	('PLK1', 'Gene', '5347', (52, 56))	('aneuploid', 'Var', (98, 107))	('breast tumor', 'Phenotype', 'HP:0100013', (124, 136))	('AURKA', 'Gene', '6790', (59, 64))	('diploid breast tumor', 'Disease', 'MESH:D001943', (116, 136))	('diploid breast tumor', 'Phenotype', 'HP:0006625', (116, 136))
119884	21352579	A very large proportion of cancers consist of cells with an abnormal chromosome content, a feature known as aneuploidy.	('abnormal chromosome content', 'Phenotype', 'HP:0031411', (60, 87))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('aneuploidy', 'Disease', (108, 118))	('abnormal chromosome', 'Var', (60, 79))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('aneuploidy', 'Disease', 'MESH:D000782', (108, 118))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancers', 'Disease', (27, 34))
119888	21352579	Like other phenotypes characteristic of cancer, it was first thought that nucleotide mutations in genes that control chromosome stability were responsible for CIN.	('CIN', 'Phenotype', 'HP:0040012', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('CIN', 'Disease', (159, 162))	('cancer', 'Disease', (40, 46))	('responsible', 'Reg', (143, 154))	('nucleotide mutations', 'Var', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CIN', 'Disease', 'MESH:D007674', (159, 162))
119896	21352579	We identified nine genes involved in early breast tumorigenesis, and also a two-gene expression signature (PLK1 + AURKA) associated with aneuploid status.	('PLK1', 'Gene', (107, 111))	('PLK1', 'Gene', '5347', (107, 111))	('AURKA', 'Gene', '6790', (114, 119))	('associated', 'Reg', (121, 131))	('breast tumor', 'Phenotype', 'HP:0100013', (43, 55))	('AURKA', 'Gene', (114, 119))	('breast tumor', 'Disease', 'MESH:D001943', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('aneuploid', 'Var', (137, 146))	('breast tumor', 'Disease', (43, 55))
119924	21352579	Interesting, 3 of these 5 genes (BIRC5, TPX2 and AURKA) showed significantly higher mRNA levels in amplified tumors than in unamplified tumors.	('AURKA', 'Gene', '6790', (49, 54))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BIRC5', 'Gene', (33, 38))	('TPX2', 'Gene', (40, 44))	('higher', 'PosReg', (77, 83))	('BIRC5', 'Gene', '332', (33, 38))	('AURKA', 'Gene', (49, 54))	('TPX2', 'Gene', '22974', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mRNA levels', 'MPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('amplified', 'Var', (99, 108))	('tumors', 'Disease', (109, 115))
119925	21352579	It is noteworthy that the other two genes (NEK2 and PLK), that showed similar mRNA levels in amplified and unamplified breast tumors, are located on chromosome arms (1q and 16p, respectively) showing polysomy and no DNA amplification in breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('breast tumors', 'Disease', (237, 250))	('NEK2', 'Gene', (43, 47))	('NEK2', 'Gene', '4751', (43, 47))	('PLK', 'Gene', '5347', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('breast tumor', 'Phenotype', 'HP:0100013', (119, 131))	('breast tumors', 'Phenotype', 'HP:0100013', (119, 132))	('polysomy', 'Var', (200, 208))	('breast tumors', 'Phenotype', 'HP:0100013', (237, 250))	('breast tumors', 'Disease', 'MESH:D001943', (119, 132))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('breast tumor', 'Phenotype', 'HP:0100013', (237, 249))	('PLK', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast tumors', 'Disease', (119, 132))	('breast tumors', 'Disease', 'MESH:D001943', (237, 250))
119931	21352579	Prediction Analysis for Microarrays (PAM) and Class Prediction results obtained with the BRB Array Tools software packages were then used to identify a gene expression signature capable of discriminating between DNA aneuploid and DNA diploid breast tumors.	('diploid breast tumors', 'Phenotype', 'HP:0006625', (234, 255))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('diploid breast tumors', 'Disease', (234, 255))	('diploid breast tumor', 'Phenotype', 'HP:0006625', (234, 254))	('diploid breast tumors', 'Disease', 'MESH:D001943', (234, 255))	('breast tumor', 'Phenotype', 'HP:0100013', (242, 254))	('DNA aneuploid', 'Var', (212, 225))	('breast tumors', 'Phenotype', 'HP:0100013', (242, 255))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))
119937	21352579	It is noteworthy that the DNA aneuploid tumor (5448-T) included in the intermediate group had a low SPF value.	('aneuploid tumor', 'Disease', 'MESH:D000782', (30, 45))	('SPF', 'Gene', '23541', (100, 103))	('SPF', 'Gene', (100, 103))	('5448-T', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('aneuploid tumor', 'Disease', (30, 45))
119938	21352579	Recent studies suggest that abnormal division of tetraploid cells might facilitate genetic changes that give rise to aneuploid cancers and therefore that tetraploidy could be a transitional step between diploid status and classical aneuploid status.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rise to aneuploid cancers', 'Disease', 'MESH:D000782', (109, 134))	('facilitate', 'PosReg', (72, 82))	('abnormal', 'Var', (28, 36))	('genetic changes', 'CPA', (83, 98))	('rise to aneuploid cancers', 'Disease', (109, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))
119942	21352579	As the validation set includes a limited number of breast tumor samples, this two-gene expression signature capable of discriminating between DNA aneuploid and diploid breast tumors needs to be further validated in a large prospective randomized study.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('breast tumor', 'Disease', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('aneuploid', 'Var', (146, 155))	('diploid breast tumors', 'Disease', 'MESH:D001943', (160, 181))	('breast tumors', 'Phenotype', 'HP:0100013', (168, 181))	('breast tumor', 'Phenotype', 'HP:0100013', (168, 180))	('breast tumor', 'Phenotype', 'HP:0100013', (51, 63))	('breast tumor', 'Disease', 'MESH:D001943', (168, 180))	('diploid breast tumors', 'Disease', (160, 181))	('diploid breast tumor', 'Phenotype', 'HP:0006625', (160, 180))	('breast tumor', 'Disease', 'MESH:D001943', (51, 63))	('diploid breast tumors', 'Phenotype', 'HP:0006625', (160, 181))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
119979	21352579	AURKA amplification induces resistance to taxol and several aurora kinase inhibitors and polo-like kinase 1 inhibitors are in the preclinical development phase.	('AURKA', 'Gene', (0, 5))	('resistance to taxol', 'MPA', (28, 47))	('induces', 'Reg', (20, 27))	('polo-like kinase 1', 'Gene', '5347', (89, 107))	('polo-like kinase 1', 'Gene', (89, 107))	('AURKA', 'Gene', '6790', (0, 5))	('amplification', 'Var', (6, 19))	('taxol', 'Chemical', 'MESH:D017239', (42, 47))
120012	21352579	The parameter Ct (threshold cycle) is defined as the fractional cycle number at which the fluorescence generated by cleavage of a TaqMan probe (or by SYBR green dye-amplicon complex formation) passes a fixed threshold above baseline.	('cleavage', 'Var', (116, 124))	('fluorescence generated', 'MPA', (90, 112))	('SYBR green', 'Chemical', '-', (150, 160))
120019	21352579	Briefly, 1 mug each of breast tumor DNA and commercial pooled human normal genomic DNAs (Promega, Madison, WI) was digested with 5 mug of AluI (50 units) and 5 ml of RsaI (50 units) (Promega, Madison, WI) and labeled by random priming with CY3- and CY5-dUTP, respectively (Agilent Technologies, Massy, France).	('CY5-dUTP', 'Chemical', 'MESH:C088942', (249, 257))	('breast tumor', 'Phenotype', 'HP:0100013', (23, 35))	('CY5-dUTP', 'Var', (249, 257))	('human', 'Species', '9606', (62, 67))	('breast tumor', 'Disease', 'MESH:D001943', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('breast tumor', 'Disease', (23, 35))	('CY3', 'Chemical', '-', (240, 243))	('CY3-', 'Var', (240, 244))
120055	20697529	There are a combined total of 66 human tissue types represented on the microarrays, with a spot size of 0.6 mm (CHTN2002N1) or 2 mm (CHTN2002X) at 4 muM thickness.	('CHTN2002X', 'Var', (133, 142))	('human', 'Species', '9606', (33, 38))	('CHTN2002N1', 'Var', (112, 122))
120151	32854385	The presence of omega-3 and omega-9 fatty acids are not only beneficial for reducing hypertension, stroke risk, decreasing risk of arthritis, but most of all, it aids in the prevention of cancer and plays a role in inhibiting breast cancer and promoting healthy inflammation responses.	('promoting', 'PosReg', (244, 253))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('omega-9 fatty acids', 'Chemical', '-', (28, 47))	('prevention', 'CPA', (174, 184))	('inflammation', 'Disease', (262, 274))	('hypertension', 'Disease', 'MESH:D006973', (85, 97))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('hypertension', 'Disease', (85, 97))	('stroke', 'Disease', 'MESH:D020521', (99, 105))	('stroke', 'Disease', (99, 105))	('aids', 'PosReg', (162, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('arthritis', 'Phenotype', 'HP:0001369', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('hypertension', 'Phenotype', 'HP:0000822', (85, 97))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('breast cancer', 'Disease', (226, 239))	('omega-3', 'Chemical', 'MESH:D015525', (16, 23))	('decreasing', 'NegReg', (112, 122))	('cancer', 'Disease', (188, 194))	('inhibiting', 'NegReg', (215, 225))	('inflammation', 'Disease', 'MESH:D007249', (262, 274))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('arthritis', 'Disease', 'MESH:D001168', (131, 140))	('cancer', 'Disease', (233, 239))	('omega-9', 'Var', (28, 35))	('reducing', 'NegReg', (76, 84))	('arthritis', 'Disease', (131, 140))	('stroke', 'Phenotype', 'HP:0001297', (99, 105))
120227	32854385	A possible explanation could be that the presence of 4-OHT might mask the anti-tumor activity of emu oil, or DLT by itself served as an effective penetration enhancer.	('enhancer', 'PosReg', (158, 166))	('penetration', 'CPA', (146, 157))	('4-OHT', 'Chemical', 'MESH:C032278', (53, 58))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('emu oil', 'Chemical', 'MESH:C575034', (97, 104))	('4-OHT', 'Var', (53, 58))	('mask', 'NegReg', (65, 69))	('presence', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('DLT', 'Chemical', '-', (109, 112))
120263	32854385	An extensive systematic review and meta-analysis of these studies reported that plasma levels of 4-OHT was a significantly lower in patients who were treated with topical 4-OHT hydro-alcoholic gel, compared to oral TAMX.	('4-OHT', 'Var', (171, 176))	('plasma levels', 'MPA', (80, 93))	('lower', 'NegReg', (123, 128))	('4-OHT', 'Chemical', 'MESH:C032278', (171, 176))	('4-OHT hydro-alcoholic gel', 'Chemical', '-', (171, 196))	('patients', 'Species', '9606', (132, 140))	('4-OHT', 'Chemical', 'MESH:C032278', (97, 102))	('TAMX', 'Chemical', 'MESH:D013629', (215, 219))
120264	32854385	Circulation of TAMX or 4-OHT was reported to be detrimental to humans, as this could result in various side-effects like uterine and endometrial cancers.	('TAMX', 'Chemical', 'MESH:D013629', (15, 19))	('endometrial cancers', 'Disease', 'MESH:D016889', (133, 152))	('uterine', 'Disease', (121, 128))	('4-OHT', 'Chemical', 'MESH:C032278', (23, 28))	('endometrial cancers', 'Disease', (133, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('result in', 'Reg', (85, 94))	('4-OHT', 'Var', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('humans', 'Species', '9606', (63, 69))
120286	32854385	A higher degree of necrosis was observed in the tumor sections of animals that received topically administered 4-OHT, which further strengthens the finding that these formulations might be more effective than orally administered TAMX.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('necrosis', 'Disease', 'MESH:D009336', (19, 27))	('tumor', 'Disease', (48, 53))	('4-OHT', 'Var', (111, 116))	('necrosis', 'Disease', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('4-OHT', 'Chemical', 'MESH:C032278', (111, 116))	('TAMX', 'Chemical', 'MESH:D013629', (229, 233))
120342	31803615	The posttest probability of lambda1 reached 74% with a PLR of 11.3 and would reduce the posttest probability as low as 2% when negative with an NLR of 0.16, indicating that it has the best predictive ability to diagnose breast cancer or benign lesions depending on its value.	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('diagnose', 'Reg', (211, 219))	('benign lesions', 'Disease', (237, 251))	('lambda1', 'Var', (28, 35))
120367	31803615	Their compositions, hormone status, invasiveness, tumor subtypes, lesion sizes, and type of genetic mutations may form a completely different biologic behavior and structural characteristic that confounded the results.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
120402	29947001	Thus MDD reduced the number of positive or close margins compared to surgeon assessment by 6.1% (11.1% versus 4.9%, p=0.25) in cases with a mass, but only reduced the number by 2.5% (12.5% versus 10%, p=1.0) in cases with calcifications.	('calcifications', 'Disease', (222, 236))	('reduced', 'NegReg', (9, 16))	('MDD', 'Var', (5, 8))	('calcifications', 'Disease', 'MESH:D002114', (222, 236))
120405	29947001	Re-operation increases the costs and risks of complications associated with breast cancer surgery.	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('Re-operation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
120430	32989258	Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo.	('Tpl2', 'Gene', (142, 146))	('Akt', 'Gene', '207', (19, 22))	('lesion breast cancer', 'Disease', 'MESH:D001943', (100, 120))	('enhances', 'PosReg', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('early dissemination in vivo', 'CPA', (156, 183))	('Akt', 'Gene', (19, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('inhibition', 'Var', (128, 138))	('lesion breast cancer', 'Disease', (100, 120))
120442	32989258	Tpl2 (tumor progression loci 2) was identified as MAPK3K initially for ERK, and later for p38and JNK.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('ERK', 'Disease', (71, 74))	('p38and', 'Var', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
120445	32989258	Also, Tpl2 is sequestered in a complex with NF-kappaB1-p105 and ABIN2; upon NF-kappaB1-p105 phosphorylation by IKKbeta, Tpl2 is released from the complex resulting in activation of MKK3/6.	('ABIN2', 'Gene', (64, 69))	('Tpl2', 'MPA', (120, 124))	('p105', 'Gene', (87, 91))	('p105', 'Gene', '4790', (55, 59))	('activation', 'PosReg', (167, 177))	('p105', 'Gene', '4790', (87, 91))	('p105', 'Gene', (55, 59))	('IKKbeta', 'Gene', '1147', (111, 118))	('IKKbeta', 'Gene', (111, 118))	('phosphorylation', 'Var', (92, 107))	('MKK3/6', 'Pathway', (181, 187))	('ABIN2', 'Gene', '79155', (64, 69))
120448	32989258	In established cancer cell lines, p38 promotes cancer cell migration/metastasis, but in cell and mouse models for early lesion breast cancer, p38 suppresses Her2-mediated early dissemination.	('suppresses', 'NegReg', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('lesion breast cancer', 'Disease', 'MESH:D001943', (120, 140))	('cancer', 'Disease', (15, 21))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mouse', 'Species', '10090', (97, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Her2-mediated', 'Protein', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('p38', 'Var', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lesion breast cancer', 'Disease', (120, 140))
120465	32989258	In a survey of p38 upstream regulators, ectopically expressed Her2 decreased phosphorylation but not expression of MKK3/6, reduced the protein but not mRNA levels of Tpl2, both protein and mRNA levels of MLK2, MLK3 and MEKK4, and the mRNA but not the protein levels of MEKK3, TAK1, TAO2 and TAB1beta in MCF-10A cells (Fig.	('protein', 'MPA', (177, 184))	('TAK1', 'Gene', '6885', (276, 280))	('MEKK4', 'Gene', (219, 224))	('MLK2', 'Gene', '4294', (204, 208))	('TAK1', 'Gene', (276, 280))	('Tpl2', 'MPA', (166, 170))	('TAO2', 'Gene', '9344', (282, 286))	('mRNA', 'MPA', (151, 155))	('Her2', 'Gene', (62, 66))	('MEKK3', 'Gene', '4215', (269, 274))	('MEKK3', 'Gene', (269, 274))	('ectopically expressed', 'Var', (40, 61))	('phosphorylation', 'MPA', (77, 92))	('MEKK4', 'Gene', '4216', (219, 224))	('protein', 'MPA', (135, 142))	('TAO2', 'Gene', (282, 286))	('MLK3', 'Gene', (210, 214))	('mRNA levels', 'MPA', (189, 200))	('MLK2', 'Gene', (204, 208))	('MCF-10A', 'CellLine', 'CVCL:0598', (303, 310))	('mRNA', 'MPA', (234, 238))	('decreased', 'NegReg', (67, 76))	('MLK3', 'Gene', '4296', (210, 214))	('reduced', 'NegReg', (123, 130))
120477	32989258	Ectopic expression of Tpl2 increased phosphorylation of MKK3/6, p38 and Hsp27 and E-cadherin expression and junctions, and reduced migration and percentage of organoids with outward invading cells (Fig.	('increased', 'PosReg', (27, 36))	('phosphorylation', 'MPA', (37, 52))	('migration', 'CPA', (131, 140))	('MKK3/6', 'Protein', (56, 62))	('Ectopic expression', 'Var', (0, 18))	('Tpl2', 'Gene', (22, 26))	('Hsp27', 'Gene', '3315', (72, 77))	('expression', 'MPA', (93, 103))	('Hsp27', 'Gene', (72, 77))	('rat', 'Species', '10116', (134, 137))	('E-cadherin', 'Protein', (82, 92))	('p38', 'Protein', (64, 67))	('reduced', 'NegReg', (123, 130))
120481	32989258	Consistent with reports that p38 suppresses breast cancer cell early dissemination by inhibiting beta-catenin activation, Tpl2 overexpression reduced the levels of activated beta-catenin (Fig.	('beta-catenin', 'Protein', (97, 109))	('suppresses', 'NegReg', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('reduced', 'NegReg', (142, 149))	('p38', 'Var', (29, 32))	('breast cancer', 'Disease', (44, 57))	('levels of activated beta-catenin', 'MPA', (154, 186))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('inhibiting', 'NegReg', (86, 96))	('activation', 'MPA', (110, 120))	('Tpl2', 'Gene', (122, 126))
120486	32989258	In SK-BR-3, a Her2+ metastatic breast adenocarcinoma cell line, Tpl2 overexpression activated MKK3/6 and p38, but downregulated E-cadherin and upregulated Vimentin and cell migration (Fig S2J-K), consistent with the reported metastasis-promoting function of p38 in late stage breast cancer cells, suggesting that Tpl2 and p38 have opposite roles in metastatic dissemination in early and late lesions of breast cancer.	('late lesions of breast cancer', 'Disease', (387, 416))	('breast adenocarcinoma', 'Disease', (31, 52))	('rat', 'Species', '10116', (176, 179))	('late lesions of breast cancer', 'Disease', 'MESH:D001943', (387, 416))	('activated', 'PosReg', (84, 93))	('Vimentin', 'Protein', (155, 163))	('overexpression', 'Var', (69, 83))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (31, 52))	('downregulated', 'NegReg', (114, 127))	('breast cancer', 'Disease', (276, 289))	('lesions of breast', 'Phenotype', 'HP:0100013', (392, 409))	('breast cancer', 'Phenotype', 'HP:0003002', (403, 416))	('E-cadherin', 'Protein', (128, 138))	('Tpl2', 'Gene', (64, 68))	('breast cancer', 'Disease', 'MESH:D001943', (403, 416))	('cell migration', 'CPA', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('MKK3/6', 'Enzyme', (94, 100))	('breast adenocarcinoma', 'Disease', 'MESH:D001943', (31, 52))	('upregulated', 'PosReg', (143, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('p38', 'Protein', (105, 108))	('SK-BR-3', 'CellLine', 'CVCL:0033', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))
120492	32989258	Supporting the notion that Her2-mediated Tpl2 downregulation contributes to breast cancer early dissemination in vivo, most Her2+Tpl2low cells in the mammary ducts of MMTV-Her2 mice were also low or negative for E-cadherin, indicative of their disseminating nature (Fig.	('downregulation', 'NegReg', (46, 60))	('Her2+Tpl2low', 'Var', (124, 136))	('low', 'NegReg', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('negative', 'NegReg', (199, 207))	('breast cancer', 'Disease', (76, 89))	('MMTV', 'Species', '11757', (167, 171))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('early dissemination', 'CPA', (90, 109))	('mice', 'Species', '10090', (177, 181))	('E-cadherin', 'Protein', (212, 222))
120509	32989258	shRNA-mediated Skp2 knockdown increased Tpl2, p-p38 and p-Hsp27 levels in MMTV-Her2 cells (Fig.	('Hsp27', 'Gene', '3315', (58, 63))	('Hsp27', 'Gene', (58, 63))	('p-p38', 'MPA', (46, 51))	('knockdown', 'Var', (20, 29))	('MMTV', 'Species', '11757', (74, 78))	('increased', 'PosReg', (30, 39))	('Skp2', 'Gene', (15, 19))	('Tpl2', 'MPA', (40, 44))
120511	32989258	Overexpression of wild type, but not the catalytically inactive mutants (Skp2-NES and -LRR) of, Skp2 alone was sufficient to reduce Tpl2, p-p38 and p-Hsp27 in MCF-10A cells and further enhanced the Her2 effects on these proteins in MMTV-Her2 and MCF-10A-Her2 cells (Fig.	('Hsp27', 'Gene', '3315', (150, 155))	('Hsp27', 'Gene', (150, 155))	('Skp2', 'Var', (96, 100))	('enhanced', 'PosReg', (185, 193))	('p-p38', 'MPA', (138, 143))	('MCF-10A', 'CellLine', 'CVCL:0598', (159, 166))	('MMTV', 'Species', '11757', (232, 236))	('reduce', 'NegReg', (125, 131))	('Tpl2', 'MPA', (132, 136))	('MCF-10A', 'CellLine', 'CVCL:0598', (246, 253))	('NES', 'Gene', '10763', (78, 81))	('Her2 effects on', 'MPA', (198, 213))	('NES', 'Gene', (78, 81))
120512	32989258	Skp2 shRNAs also increased Tpl2, p-p38 and p-Hsp27 in MCF-10A cells (Fig.	('increased', 'PosReg', (17, 26))	('Skp2', 'Var', (0, 4))	('Tpl2', 'MPA', (27, 31))	('Hsp27', 'Gene', '3315', (45, 50))	('Hsp27', 'Gene', (45, 50))	('MCF-10A', 'CellLine', 'CVCL:0598', (54, 61))	('p-p38', 'MPA', (33, 38))
120513	32989258	In MCF-10A cells, Skp2 shRNAs abrogated Her2-induced Tpl2 protein ubiquitination, while the wild type, but not the catalytically inactive mutants of, Skp2 increased Tpl2 ubiquitination (Fig.	('MCF-10A', 'CellLine', 'CVCL:0598', (3, 10))	('Tpl2 protein ubiquitination', 'MPA', (53, 80))	('Skp2 shRNAs', 'Var', (18, 29))	('abrogated', 'NegReg', (30, 39))	('Her2-induced', 'Protein', (40, 52))
120518	32989258	Skp2 knockdown increased E-cadherin expression and junctions and reduced Vimentin expression, migration and percentage of invasive organoids in MMTV-Her2 cells (Fig.	('rat', 'Species', '10116', (97, 100))	('Skp2', 'Gene', (0, 4))	('reduced', 'NegReg', (65, 72))	('expression', 'MPA', (82, 92))	('knockdown', 'Var', (5, 14))	('junctions', 'MPA', (51, 60))	('migration', 'CPA', (94, 103))	('increased', 'PosReg', (15, 24))	('Vimentin', 'Protein', (73, 81))	('percentage of invasive organoids', 'CPA', (108, 140))	('E-cadherin', 'Protein', (25, 35))	('MMTV', 'Species', '11757', (144, 148))	('expression', 'MPA', (36, 46))
120522	32989258	Skp2 knockdown reversed Her2-mediated increase in SOX2, OCT4 and ALDHA1 expression in MCF-10A-Her2 cells (Fig.	('OCT4', 'Gene', '5460', (56, 60))	('increase', 'PosReg', (38, 46))	('ALDHA1', 'Gene', (65, 71))	('knockdown', 'Var', (5, 14))	('OCT4', 'Gene', (56, 60))	('SOX2', 'Gene', '6657', (50, 54))	('expression', 'MPA', (72, 82))	('SOX2', 'Gene', (50, 54))
120525	32989258	Skp2 shRNAs also moderately altered some, but not all, of these disseminating phenotypes (e.g., E-cadherin junctions and migration, Fig.	('rat', 'Species', '10116', (124, 127))	('migration', 'CPA', (121, 130))	('Skp2', 'Var', (0, 4))	('altered', 'Reg', (28, 35))	('E-cadherin junctions', 'Protein', (96, 116))	('rat', 'Species', '10116', (21, 24))
120528	32989258	Tpl2 knockdown abrogated Skp2 shRNA-induced increases in Tpl2, p-MKK3/6, p-p38, p-Hsp27 and E-cadherin levels and E-cadherin junctions and decreases in invasive organoids in MMTV-Her2 and MCF-10A-Her2 cells (Fig.	('Tpl2', 'MPA', (57, 61))	('Hsp27', 'Gene', (82, 87))	('p-MKK3/6', 'MPA', (63, 71))	('E-cadherin junctions', 'MPA', (114, 134))	('Skp2', 'Var', (25, 29))	('Hsp27', 'Gene', '3315', (82, 87))	('knockdown', 'Var', (5, 14))	('abrogated', 'NegReg', (15, 24))	('E-cadherin levels', 'MPA', (92, 109))	('decreases', 'NegReg', (139, 148))	('p-p38', 'MPA', (73, 78))	('increases', 'PosReg', (44, 53))	('invasive organoids', 'CPA', (152, 170))	('MMTV', 'Species', '11757', (174, 178))
120530	32989258	These rescue studies established an epistatic order of Her2-Skp2-Tpl2 in Her2-mediated migration/invasion in early lesion breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Her2-mediated', 'Protein', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('lesion breast cancer', 'Disease', (115, 135))	('Her2-Skp2-Tpl2', 'Var', (55, 69))	('lesion breast cancer', 'Disease', 'MESH:D001943', (115, 135))	('rat', 'Species', '10116', (90, 93))
120537	32989258	Her2-induced Skp2 phosphorylation was reduced by Akt inhibitor MK2206 in MCF-10A cells (Fig.	('Skp2', 'Gene', (13, 17))	('reduced', 'NegReg', (38, 45))	('Her2-induced', 'Protein', (0, 12))	('MCF-10A', 'CellLine', 'CVCL:0598', (73, 80))	('MK2206', 'Chemical', 'MESH:C548887', (63, 69))	('phosphorylation', 'MPA', (18, 33))	('Akt', 'Gene', '207', (49, 52))	('MK2206', 'Var', (63, 69))	('Akt', 'Gene', (49, 52))
120539	32989258	PI3K inhibitor GDC-0941 and MK2206 abrogated Her2-induced increase in Skp2 proteins and decreases in Tpl2 and p-p38 levels (Fold Change by Her2, Fig.	('increase', 'PosReg', (58, 66))	('abrogated', 'NegReg', (35, 44))	('MK2206', 'Chemical', 'MESH:C548887', (28, 34))	('Skp2 proteins', 'Protein', (70, 83))	('GDC-0941', 'Chemical', 'MESH:C532162', (15, 23))	('PI3', 'Gene', '5266', (0, 3))	('decreases', 'NegReg', (88, 97))	('MK2206', 'Var', (28, 34))	('Her2-induced', 'Gene', (45, 57))	('p-p38 levels', 'MPA', (110, 122))	('PI3', 'Gene', (0, 3))
120542	32989258	Overexpression of wild type Skp2, but not that carrying a non-phosphorylatable mutation at Ser72 (S72A), reduced Tpl2, p-p38 and p-Hsp27 levels and E-cadherin expression and junctions, and increased Vimentin, cell migration, invasive organoids and beta-catenin activation in MCF-10A-Her2 cells (Fig.	('Tpl2', 'MPA', (113, 117))	('invasive organoids', 'CPA', (225, 243))	('beta-catenin', 'CPA', (248, 260))	('E-cadherin expression', 'MPA', (148, 169))	('S72A', 'Mutation', 'p.S72A', (98, 102))	('reduced', 'NegReg', (105, 112))	('Vimentin', 'MPA', (199, 207))	('mutation', 'Var', (79, 87))	('increased', 'PosReg', (189, 198))	('Hsp27', 'Gene', '3315', (131, 136))	('Ser72', 'Chemical', '-', (91, 96))	('Hsp27', 'Gene', (131, 136))	('rat', 'Species', '10116', (217, 220))	('cell migration', 'CPA', (209, 223))	('junctions', 'MPA', (174, 183))	('activation', 'PosReg', (261, 271))
120544	32989258	6D-I), likely because Ser72-phosphorylation is necessary, but not sufficient, to fully activate Skp2 in this pathway.	('activate', 'PosReg', (87, 95))	('Ser72', 'Chemical', '-', (22, 27))	('Ser72-phosphorylation', 'Var', (22, 43))	('Skp2', 'Gene', (96, 100))
120559	32989258	Decreased Tpl2 expression also associated with the Her2+ status in breast cancer in a previous study using a small sample size.	('Her2+ status', 'Var', (51, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Decreased', 'NegReg', (0, 9))	('associated', 'Reg', (31, 41))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('expression', 'MPA', (15, 25))	('Tpl2', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
120570	32989258	Possibly, manipulations of Tpl2 and MKK6/p38 may not have same effects on the p38 signaling strength or the negative feedback involving p38 and ERK.	('MKK6', 'Gene', (36, 40))	('negative feedback', 'MPA', (108, 125))	('p38 signaling strength', 'MPA', (78, 100))	('manipulations', 'Var', (10, 23))	('MKK6', 'Gene', '5608', (36, 40))
120574	32989258	It is thus highly likely that the cellular machinery mediating the activating phosphorylation of Tpl2 is not rate-limiting and is not suppressed by Her2 in mammary epithelial cells, suggesting that Her2 suppresses Tpl2 mainly by downregulating its protein expression, but not phosphorylation.	('Her2', 'Var', (198, 202))	('Tpl2', 'Gene', (214, 218))	('rat', 'Species', '10116', (109, 112))	('protein expression', 'MPA', (248, 266))	('downregulating', 'NegReg', (229, 243))	('suppresses', 'NegReg', (203, 213))
120580	32989258	S4E-F) and Akt-dependent phosphorylation of Skp2 (Fig.	('Akt', 'Gene', '207', (11, 14))	('S4E-F', 'Var', (0, 5))	('Akt', 'Gene', (11, 14))	('Skp2', 'Gene', (44, 48))
120582	32989258	Importantly, PI3K/Akt-mediated phosphorylation of Skp2-Ser72 was essential for the ability of Skp2 to suppress Tpl2-p38 and to promote the disseminating phenotypes (Fig.	('PI3', 'Gene', '5266', (13, 16))	('Akt', 'Gene', (18, 21))	('promote', 'PosReg', (127, 134))	('Tpl2-p38', 'MPA', (111, 119))	('Ser72', 'Chemical', '-', (55, 60))	('Skp2', 'Var', (94, 98))	('PI3', 'Gene', (13, 16))	('Akt', 'Gene', '207', (18, 21))	('suppress', 'NegReg', (102, 110))	('disseminating phenotypes', 'MPA', (139, 163))
120624	31823173	Genetic testing was performed in 270 (60.1%) patients; 28 (10.4%) were positive for a deleterious BRCA1 mutation and 18 (6.7%) were positive for the BRCA2 mutation.	('positive', 'Reg', (71, 79))	('BRCA2', 'Gene', (149, 154))	('BRCA2', 'Gene', '675', (149, 154))	('BRCA1', 'Gene', '672', (98, 103))	('mutation', 'Var', (104, 112))	('patients', 'Species', '9606', (45, 53))	('BRCA1', 'Gene', (98, 103))
120649	31823173	BRCA1/BRCA2 testing, increased use of preoperative MRI, and increased anxiety have all been implicated in the increasing rates of mastectomy (in patients who are candidates for BCS) and CPM.	('patients', 'Species', '9606', (145, 153))	('anxiety', 'Disease', (70, 77))	('BRCA2', 'Gene', '675', (6, 11))	('BRCA1', 'Gene', (0, 5))	('mastectomy', 'Disease', (130, 140))	('anxiety', 'Phenotype', 'HP:0000739', (70, 77))	('testing', 'Var', (12, 19))	('CPM', 'Disease', (186, 189))	('anxiety', 'Disease', 'MESH:D001007', (70, 77))	('BRCA2', 'Gene', (6, 11))	('BRCA1', 'Gene', '672', (0, 5))
120650	31823173	60.1% of women in our cohort had genetic testing, 17.1% tested positive for BRCA1/BRCA2, and 65.5% had a preoperative MRI.	('genetic testing', 'Var', (33, 48))	('women', 'Species', '9606', (9, 14))	('BRCA2', 'Gene', (82, 87))	('BRCA1', 'Gene', '672', (76, 81))	('BRCA2', 'Gene', '675', (82, 87))	('BRCA1', 'Gene', (76, 81))	('tested positive', 'Reg', (56, 71))
120683	23538389	It seems probable, therefore, that nodal metastasis in postoperatively diagnosed DCIS actually involves both true metastases (pT1mi/1a-pN1mi-M0 tumours) and iatrogenic dissemination (pTis-pN0-M0 tumours).	('DCIS', 'Disease', (81, 85))	('metastases', 'Disease', (114, 124))	('iatrogenic dissemination', 'Disease', 'MESH:D007049', (157, 181))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('iatrogenic dissemination', 'Disease', (157, 181))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('pTis-pN0-M0 tumours', 'Disease', (183, 202))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('pT1mi/1a-pN1mi-M0', 'Var', (126, 143))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('tumours', 'Disease', (144, 151))	('tumours', 'Disease', (195, 202))	('pTis-pN0-M0 tumours', 'Disease', 'MESH:D009369', (183, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
120710	22920283	Also there was an inverse correlation between high LSD1 expression levels and low progesterone receptor status.	('high', 'Var', (46, 50))	('LSD1', 'Gene', '23028', (51, 55))	('expression levels', 'MPA', (56, 73))	('low progesterone', 'Phenotype', 'HP:0008233', (78, 94))	('progesterone receptor', 'Gene', (82, 103))	('progesterone receptor', 'Gene', '5241', (82, 103))	('LSD1', 'Gene', (51, 55))
120741	22920283	Differences were also statistically significant between low/intermediate DCIS and high grade DCIS (p <0.032), but also between low/intermediate DCIS and invasive ductal breast carcinoma (p <0.001).	('invasive ductal breast carcinoma', 'Disease', (153, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('significant', 'Reg', (36, 47))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (153, 185))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('low/intermediate DCIS', 'Var', (127, 148))	('low/intermediate DCIS', 'Var', (56, 77))	('breast carcinoma', 'Phenotype', 'HP:0003002', (169, 185))
120742	22920283	Consistently, statistical significance of LSD1 expression was also reached between low grade DCIS and invasive ductal carcinoma (p <0.0001) and low grade DCIS versus high grade DCIS/invasive ductal carcinoma (p <0.0001) (Bonferroni-Holm-procedure).	('ductal carcinoma', 'Phenotype', 'HP:0030075', (191, 207))	('LSD1', 'Gene', (42, 46))	('invasive ductal carcinoma', 'Disease', (182, 207))	('low grade', 'Var', (144, 153))	('LSD1', 'Gene', '23028', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (102, 127))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('invasive ductal carcinoma', 'Disease', (102, 127))	('low grade DCIS', 'Disease', (83, 97))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (182, 207))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (111, 127))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
120760	22920283	Even though the concrete mechanism in which LSD1 is linked to cancer development has not been fully examined, it has been shown that high LSD1 expression is a characteristic feature of cancer cells.	('LSD1', 'Gene', (138, 142))	('expression', 'MPA', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('high', 'Var', (133, 137))	('LSD1', 'Gene', '23028', (138, 142))	('cancer', 'Disease', (62, 68))	('LSD1', 'Gene', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('LSD1', 'Gene', '23028', (44, 48))	('cancer', 'Disease', (185, 191))
120763	22920283	In conclusion our data imply a positive association between LSD1 overexpression and progression, proliferation as well as increasing invasiveness of breast cancer cells.	('progression', 'CPA', (84, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('overexpression', 'Var', (65, 79))	('increasing', 'PosReg', (122, 132))	('proliferation', 'CPA', (97, 110))	('LSD1', 'Gene', (60, 64))	('invasiveness', 'CPA', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('LSD1', 'Gene', '23028', (60, 64))	('breast cancer', 'Disease', (149, 162))
120773	22920283	With regard to offering other suitable options of breast cancer therapy in connection with other eligible targets, LSD1 may be such a target mark as LSD1 inhibitors were discussed as novel breast cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('inhibitors', 'Var', (154, 164))	('LSD1', 'Gene', (115, 119))	('LSD1', 'Gene', (149, 153))	('mark', 'Gene', (141, 145))	('mark', 'Gene', '4139', (141, 145))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('LSD1', 'Gene', '23028', (115, 119))	('LSD1', 'Gene', '23028', (149, 153))	('breast cancer', 'Disease', (189, 202))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
120775	22920283	tranylcypromine was found to inhibit embryonal carcinoma cells.	('inhibit', 'NegReg', (29, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (37, 56))	('tranylcypromine', 'Chemical', 'MESH:D014191', (0, 15))	('tranylcypromine', 'Var', (0, 15))	('embryonal carcinoma', 'Disease', (37, 56))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (37, 56))
120787	32451329	In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44+/CD24-, ALDH activity, or by tumor sphere formation.	('ALDH', 'Gene', (184, 188))	('CD44+/CD24-', 'Var', (171, 182))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('proportion of stem-like cells', 'CPA', (92, 121))	('EMP2', 'Gene', (63, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('knockdown', 'Var', (68, 77))	('tumor', 'Disease', (205, 210))	('expression', 'MPA', (141, 151))	('ALDH', 'Gene', '11670', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('decreased', 'NegReg', (78, 87))	('EMP2', 'Gene', (29, 33))
120788	32451329	In vivo, upregulation of EMP2 promoted tumor growth while knockdown reduced the ALDHhigh CSC population as well as retarded tumor growth.	('ALDH', 'Gene', (80, 84))	('upregulation', 'PosReg', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('retarded tumor', 'Disease', 'MESH:D009369', (115, 129))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('EMP2', 'Gene', (25, 29))	('tumor', 'Disease', (124, 129))	('retarded tumor', 'Disease', (115, 129))	('promoted', 'PosReg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ALDH', 'Gene', '11670', (80, 84))	('tumor', 'Disease', (39, 44))	('reduced', 'NegReg', (68, 75))	('knockdown', 'Var', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
120791	32451329	Collectively, our results show that EMP2 increases the proportion of tumor initiating cells providing a rationale for the continued development of EMP2 targeting agents.	('EMP2', 'Var', (36, 40))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
120795	32451329	A number of cell surface markers including CD44+/CD24- and enzymatic activities including aldehyde dehydrogenase (ALDH) are associated with cells that display increased tumor initiating capacity in mouse xenograft models.	('ALDH', 'Gene', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('aldehyde dehydrogenase', 'Gene', (90, 112))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('aldehyde dehydrogenase', 'Gene', '11670', (90, 112))	('tumor', 'Disease', (169, 174))	('mouse', 'Species', '10090', (198, 203))	('ALDH', 'Gene', '11670', (114, 118))	('CD44+/CD24-', 'Var', (43, 54))
120810	32451329	SUM149PT cells was maintained in Ham's F12K media supplemented with 5% FBS, 5mug/ml insulin, 1mug/ml hydrocortisone and 4 mug/ml gentamicin in addition to the supplements listed above.	('F12K', 'SUBSTITUTION', 'None', (39, 43))	('F12K', 'Var', (39, 43))	('insulin', 'Gene', (84, 91))	('hydrocortisone', 'Chemical', 'MESH:D006854', (101, 115))	('insulin', 'Gene', '3630', (84, 91))	('SUM149', 'Chemical', '-', (0, 6))	('gentamicin', 'Chemical', 'MESH:D005839', (129, 139))
120830	32451329	To investigate its functional role within these cells, we overexpressed or knocked down EMP2 utilizing specific shRNAs in cell lines representing major breast cancer subtypes.	('knocked', 'Var', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('EMP2', 'Gene', (88, 92))
120831	32451329	Overexpression of EMP2 accelerated and knockdown significantly inhibited the growth of both hormone receptor positive and TNBC cells lines represented by BT474 and MDA-MB-231 (Fig 1B-C).	('hormone receptor', 'Gene', '3164', (92, 108))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (164, 174))	('knockdown', 'Var', (39, 48))	('EMP2', 'Gene', (18, 22))	('inhibited', 'NegReg', (63, 72))	('growth', 'CPA', (77, 83))	('hormone receptor', 'Gene', (92, 108))
120832	32451329	In the case of SUM149, whereas knockdown of EMP2 significantly inhibited tumor growth compared to the vector control, less pronounced changes were observed upon overexpression (Fig 1D).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SUM149', 'Chemical', '-', (15, 21))	('tumor', 'Disease', (73, 78))	('inhibited', 'NegReg', (63, 72))	('EMP2', 'Gene', (44, 48))	('knockdown', 'Var', (31, 40))
120834	32451329	In order to elucidate pathways regulated by EMP2, we determined the effect of EMP2 knockdown on gene expression in SUM149 cells via RNA sequencing (RNAseq).	('SUM149', 'Chemical', '-', (115, 121))	('knockdown', 'Var', (83, 92))	('EMP2', 'Gene', (78, 82))
120837	32451329	Several markers including CD44+/CD24- and ALDH activity have been shown to enrich for tumor cells displaying "stemlike" properties.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('ALDH', 'Gene', '11670', (42, 46))	('CD44+/CD24-', 'Var', (26, 37))	('ALDH', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
120838	32451329	As hypoxia is a known regulator of CSC, we interrogated the RNAseq data to elucidate the effect of EMP2 knockdown on CSC marker expression.	('EMP2', 'Gene', (99, 103))	('hypoxia', 'Disease', 'MESH:D000860', (3, 10))	('hypoxia', 'Disease', (3, 10))	('knockdown', 'Var', (104, 113))
120839	32451329	As shown in Fig 1E, EMP2 knockdown increased CD24 expression while decreasing expression of CD44 as well as a number of ALDH isoforms.	('decreasing', 'NegReg', (67, 77))	('ALDH', 'Gene', '11670', (120, 124))	('increased', 'PosReg', (35, 44))	('expression', 'MPA', (78, 88))	('CD44', 'Gene', (92, 96))	('EMP2', 'Gene', (20, 24))	('ALDH', 'Gene', (120, 124))	('CD24', 'Gene', (45, 49))	('knockdown', 'Var', (25, 34))	('expression', 'MPA', (50, 60))
120842	32451329	In both MDA-MB-231 and BT474, overexpression of EMP2 correlated with higher sphere forming efficiency than the vector control, and conversely, reduction in EMP2 levels significantly prevented tumorsphere formation (Fig 2A).	('sphere forming efficiency', 'CPA', (76, 101))	('tumors', 'Disease', (192, 198))	('BT474', 'Var', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('overexpression', 'PosReg', (30, 44))	('prevented', 'NegReg', (182, 191))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (8, 18))	('EMP2', 'Gene', (48, 52))	('reduction', 'NegReg', (143, 152))	('MDA-MB-231', 'Gene', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('higher', 'PosReg', (69, 75))
120846	32451329	A number of previous studies have characterized CSC using markers such as CD44, CD24, as well as ALDHhigh activity.	('CD24', 'Gene', (80, 84))	('CSC', 'Disease', (48, 51))	('ALDH', 'Gene', '11670', (97, 101))	('ALDH', 'Gene', (97, 101))	('CD44', 'Var', (74, 78))
120850	32451329	Consistent with previous reports, the expression of CD44+/CD24- and ALDHhigh activity varied significantly among these different cells (Fig 2B).	('expression', 'MPA', (38, 48))	('CD44+/CD24-', 'Var', (52, 63))	('ALDH', 'Gene', (68, 72))	('ALDH', 'Gene', '11670', (68, 72))
120857	32451329	To further our understanding of the relationship between EMP2 and ALDH1, the effects of EMP2 knockdown on ALDH activity were analyzed using DEAB as a negative control.	('knockdown', 'Var', (93, 102))	('ALDH1', 'Gene', (66, 71))	('ALDH', 'Gene', '11670', (106, 110))	('ALDH', 'Gene', '11670', (66, 70))	('ALDH1', 'Gene', '216', (66, 71))	('ALDH', 'Gene', (106, 110))	('ALDH', 'Gene', (66, 70))	('EMP2', 'Gene', (88, 92))	('DEAB', 'Chemical', 'MESH:C007368', (140, 144))
120858	32451329	In these cells, knockdown of EMP2 significantly reduced ALDH activity as assessed by the ALDEFLUOR assay (Fig 3A).	('ALDEFLUOR', 'Chemical', '-', (89, 98))	('reduced', 'NegReg', (48, 55))	('knockdown', 'Var', (16, 25))	('ALDH', 'Gene', '11670', (56, 60))	('EMP2', 'Gene', (29, 33))	('ALDH', 'Gene', (56, 60))
120860	32451329	Similar to effects observed with the shRNA knockdown, transient knockdown of EMP2 using a pooled set of four siRNA significantly reduced ALDH1 expression (Fig 3B).	('EMP2', 'Gene', (77, 81))	('ALDH1', 'Gene', '216', (137, 142))	('expression', 'MPA', (143, 153))	('knockdown', 'Var', (64, 73))	('reduced', 'NegReg', (129, 136))	('ALDH1', 'Gene', (137, 142))
120887	32451329	Together these results suggest that EMP2, ALDH1 co-expressing cells may represent a subset of the EMP2+ primary tumor with increased metastatic capacity.	('ALDH1', 'Gene', '216', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('EMP2', 'Var', (36, 40))	('tumor', 'Disease', (112, 117))	('ALDH1', 'Gene', (42, 47))
120890	32451329	In contrast, low to moderate levels of ALDH1 were observed in the vector control samples, while knockdown of EMP2 produced a statistically significant reduction in its levels (Fig 4C).	('knockdown', 'Var', (96, 105))	('ALDH1', 'Gene', (39, 44))	('ALDH1', 'Gene', '216', (39, 44))	('levels', 'MPA', (168, 174))	('reduction', 'NegReg', (151, 160))	('EMP2', 'Gene', (109, 113))
120895	32451329	In all three cell lines, anti-EMP2 mAbs significantly reduced ALDH activity by 50-80% compared to those treated with control mAbs (Fig 5B).	('ALDH', 'Gene', '11670', (62, 66))	('reduced', 'NegReg', (54, 61))	('anti-EMP2 mAbs', 'Var', (25, 39))	('ALDH', 'Gene', (62, 66))
120896	32451329	We next tested the ability of the anti-EMP2 mAbs to reduce the self-renewal capability of CSC using a tumorsphere assay.	('tested', 'Reg', (8, 14))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('anti-EMP2', 'Var', (34, 43))	('reduce', 'NegReg', (52, 58))	('self-renewal capability of CSC', 'CPA', (63, 93))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
120899	32451329	To extend upon these observations, we tested the ability of the anti-EMP2 mAbs to reduce the self-renewal capability of CSC using a single cell tumorsphere assay.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('anti-EMP2', 'Var', (64, 73))	('reduce', 'NegReg', (82, 88))	('tested', 'Reg', (38, 44))	('self-renewal capability of CSC', 'CPA', (93, 123))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
120900	32451329	1, 5, or 10 live cells were incubated with 10mug/ml of control or anti-EMP2 mAb, and viable tumorspheres enumerated after two weeks (Table 2).	('tumorspheres', 'Disease', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('anti-EMP2', 'Var', (66, 75))	('tumorspheres', 'Disease', 'None', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
120904	32451329	In both cases, anti-EMP2 mAbs significantly inhibited tumorsphere formation compared to control mAbs (Fig 5D).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('inhibited', 'NegReg', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('anti-EMP2', 'Var', (15, 24))
120910	32451329	In two independent experiments, treatment with anti-EMP2 mAb significantly reduced tumor load compared to treatment with control human mAbs (Fig 5F; Fig S3D-E).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('anti-EMP2 mAb', 'Var', (47, 60))	('tumor', 'Disease', (83, 88))	('reduced', 'NegReg', (75, 82))	('human', 'Species', '9606', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
120913	32451329	Treatment with anti-EMP2 mAb produced a marked reduction in ALDH activity as measured by the ALDEFLUOR assay compared to those treated with human control mAbs (Fig 5F, right).	('human', 'Species', '9606', (140, 145))	('ALDH', 'Gene', (60, 64))	('ALDEFLUOR assay', 'MPA', (93, 108))	('reduction', 'NegReg', (47, 56))	('ALDEFLUOR', 'Chemical', '-', (93, 102))	('anti-EMP2', 'Var', (15, 24))	('ALDH', 'Gene', '11670', (60, 64))
120915	32451329	Fig 5G follows tumor re-initiation from cells injected with 50,000 cells, and results indicate that anti-EMP2 mAbs dampen the efficiency of tumor re-initiation.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('dampen', 'NegReg', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('anti-EMP2', 'Var', (100, 109))	('tumor', 'Disease', (140, 145))
120923	32451329	Treatment with anti-EMP2 mAbs significantly reduced primary tumor load compared to those treated with control mAbs (Fig 6B; Two way ANOVA, p=0.002), and a reduction in tumor weight was also computed following anti-EMP2 mAb treatment (right panel; p=0.002).	('tumor', 'Disease', (168, 173))	('anti-EMP2', 'Var', (209, 218))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (60, 65))	('reduction', 'NegReg', (155, 164))
120927	32451329	Anti-EMP2 mAbs produced a significant reduction in ALDH activity, supporting previous studies that ALDH activity serves as a surrogate for metastatic potential (p=0.003; Fig 6D bottom).	('ALDH', 'Gene', '11670', (99, 103))	('ALDH', 'Gene', '11670', (51, 55))	('ALDH', 'Gene', (99, 103))	('ALDH', 'Gene', (51, 55))	('reduction', 'NegReg', (38, 47))	('mAbs', 'Var', (10, 14))	('Anti-EMP2', 'Gene', (0, 9))
120928	32451329	Collectively, our results identify EMP2 as an attractive therapeutic target and demonstrate that anti-EMP2 mAbs effectively inhibit the BCSC population reducing tumor initiation, growth and metastasis across a spectrum of breast cancer models.	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('BCSC', 'Protein', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('reducing', 'NegReg', (152, 160))	('inhibit', 'NegReg', (124, 131))	('anti-EMP2', 'Var', (97, 106))	('tumor', 'Disease', (161, 166))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
120932	32451329	In these studies, we identify EMP2 as an important regulator of BCSC and demonstrate that EMP2 genetic knockdown or inhibition with a mAb reduces the proportion of CSC in vitro and in vivo using mouse xenograft models.	('genetic knockdown', 'Var', (95, 112))	('reduces', 'NegReg', (138, 145))	('inhibition', 'NegReg', (116, 126))	('EMP2', 'Gene', (90, 94))	('knockdown', 'Var', (103, 112))	('mouse', 'Species', '10090', (195, 200))
120943	32451329	First, we have reported that while ALDH1 is a marker of epithelial proliferative BCSC, more mesenchymal BCSC are characterized by CD44+/CD24- expression.	('ALDH1', 'Gene', '216', (35, 40))	('CD44+/CD24- expression', 'Var', (130, 152))	('ALDH1', 'Gene', (35, 40))
120957	32451329	Similar to the results observed in immunocompromised models, anti-EMP2 mAbs inhibited tumor growth and specifically suppressed markers associated with stem-ness including ALDH1.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('suppressed', 'NegReg', (116, 126))	('anti-EMP2', 'Var', (61, 70))	('tumor', 'Disease', (86, 91))	('markers', 'MPA', (127, 134))	('ALDH1', 'Gene', (171, 176))	('inhibited', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('ALDH1', 'Gene', '216', (171, 176))
120961	28465875	This study examined long-term outcomes in a population-based cohort of patients with pure DCIS treated with breast-conserving surgery (BCS) alone, BCS + radiotherapy (RT), and mastectomy.	('patients', 'Species', '9606', (71, 79))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('pure DCIS', 'Disease', (85, 94))	('BCS', 'Var', (147, 150))
121026	28465875	In the current multivariable analysis, factors associated with reduced risk of invasive local recurrence were older age at diagnosis, low comorbidity score, absence of comedonecrosis, mastectomy, and post-BCS RT.	('necrosis', 'Disease', 'MESH:D009336', (174, 182))	('reduced', 'NegReg', (63, 70))	('post-BCS RT', 'Var', (200, 211))	('invasive local recurrence', 'Disease', (79, 104))	('mastectomy', 'Disease', (184, 194))	('comedo', 'Phenotype', 'HP:0025249', (168, 174))	('necrosis', 'Disease', (174, 182))
121038	28330493	Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (17, 41))	('MMP-8', 'Gene', '4317', (8, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (287, 311))	('DCIS', 'Phenotype', 'HP:0030075', (313, 317))	('ductal carcinoma in situ', 'Disease', (17, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('tumour', 'Disease', 'MESH:D009369', (328, 334))	('ductal carcinoma in situ', 'Disease', (287, 311))	('gaining', 'PosReg', (320, 327))	('tumour', 'Disease', (328, 334))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (17, 41))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('Loss', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (214, 220))	('MMP-8', 'Gene', (8, 13))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (287, 311))	('tumour', 'Disease', (95, 101))
121044	28330493	Over-expression of MMP-8 WT but not MMP-8 EA in beta6-1089 cells increased adhesion to ECM proteins and reduced migration.	('increased', 'PosReg', (65, 74))	('reduced', 'NegReg', (104, 111))	('rat', 'Species', '10116', (115, 118))	('MMP-8 WT', 'Var', (19, 27))	('migration', 'CPA', (112, 121))	('adhesion', 'MPA', (75, 83))
121045	28330493	Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration.	('migration', 'CPA', (73, 82))	('reduced', 'NegReg', (42, 49))	('increased', 'PosReg', (63, 72))	('rat', 'Species', '10116', (76, 79))	('MMP-8', 'Gene', (26, 31))	('N-1089', 'CellLine', 'CVCL:9D84', (35, 41))	('adhesion', 'CPA', (50, 58))	('knock-down', 'Var', (12, 22))
121046	28330493	Expression of MMP-8 WT in beta6-1089 led to greater localisation of alpha6beta4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089.	('reduced', 'NegReg', (90, 97))	('localisation', 'MPA', (52, 64))	('retraction fibre formation', 'CPA', (98, 124))	('HD', 'Disease', 'MESH:D006816', (83, 85))	('alpha6beta4', 'Protein', (68, 79))	('N-1089', 'CellLine', 'CVCL:9D84', (169, 175))	('greater', 'PosReg', (44, 51))	('reduced retraction', 'Phenotype', 'HP:0001265', (90, 108))	('beta6-1089', 'Var', (26, 36))
121048	28330493	MMP-8 knock-down enhanced TGF-beta signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor.	('enhanced', 'PosReg', (17, 25))	('knock-down', 'Var', (6, 16))	('MMP-8', 'Gene', (0, 5))	('TGF-beta', 'Gene', '7040', (26, 34))	('gelatinolytic activity', 'MPA', (50, 72))	('MMP-9', 'Gene', '4318', (105, 110))	('TGF-beta', 'Gene', (26, 34))	('MMP-9', 'Gene', (105, 110))
121049	28330493	MMP-8 WT but not MMP-8 EA over-expression in beta6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (71, 77))	('reduced', 'NegReg', (56, 63))	('enhanced', 'PosReg', (155, 163))	('beta6-1089', 'Var', (45, 55))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('N-1089', 'CellLine', 'CVCL:9D84', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
121063	28330493	Since it was first reported that MMP-8-/- mice exhibit increased incidence of skin tumours when challenged with chemical carcinogenesis, MMP-8 has been demonstrated to exert a clear tumour-suppressor function.	('tumour', 'Disease', (83, 89))	('skin tumours', 'Disease', 'MESH:D012878', (78, 90))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('mice', 'Species', '10090', (42, 46))	('MMP-8', 'Var', (137, 142))	('increased', 'PosReg', (55, 64))	('skin tumours', 'Disease', (78, 90))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('tumour', 'Disease', (182, 188))	('rat', 'Species', '10116', (159, 162))
121066	28330493	The biological significance of loss of MEC-derived MMP-8 on MEC phenotype and MEC-breast cancer cell crosstalk remains elusive, especially whether MMP-8 may contribute to the tumour-suppressor function of MECs.	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MEC-breast cancer', 'Disease', (78, 95))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('MEC-breast cancer', 'Disease', 'MESH:D001943', (78, 95))	('loss', 'Var', (31, 35))	('tumour', 'Disease', (175, 181))	('contribute', 'Reg', (157, 167))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
121067	28330493	In this study we employed 2D and 3D in vitro models to recapitulate the DCIS tumour microenvironment in order to investigate how MMP-8 is involved in MEC-breast cancer cell communication, and whether loss of MMP-8 contributes to loss of tumour-suppressor activity and promotes progression to invasive disease.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('MMP-8', 'Gene', (208, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('progression', 'CPA', (277, 288))	('MEC-breast cancer', 'Disease', (150, 167))	('tumour', 'Disease', (77, 83))	('invasive disease', 'Disease', (292, 308))	('loss', 'Var', (200, 204))	('loss', 'NegReg', (229, 233))	('MEC-breast cancer', 'Disease', 'MESH:D001943', (150, 167))	('promotes', 'PosReg', (268, 276))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('tumour', 'Disease', (237, 243))	('invasive disease', 'Disease', 'MESH:D009362', (292, 308))
121143	28330493	(Invitrogen, anti-mouse 546, A11030, anti-rabbit 546, A11035, anti-mouse 488, A11029, anti-rabbit 488, A11008, phalloidin 546, A22283).	('phalloidin', 'Chemical', 'MESH:D010590', (111, 121))	('anti-mouse', 'Var', (62, 72))	('mouse', 'Species', '10090', (18, 23))	('A11035', 'Var', (54, 60))	('A11008', 'Var', (103, 109))	('rabbit', 'Species', '9986', (91, 97))	('rabbit', 'Species', '9986', (42, 48))	('mouse', 'Species', '10090', (67, 72))	('A11030', 'Var', (29, 35))	('anti-rabbit 488', 'Var', (86, 101))	('A11029', 'Var', (78, 84))
121152	28330493	The Ki67 index is calculated as the percentage of Ki67-positive invading breast cancer cells out of the total cell number.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('Ki67-positive', 'Var', (50, 63))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
121164	28330493	MMP-8 expression was downregulated in beta6-1089 cells as compared to N-1089 cells at both the mRNA (Fig.	('beta6-1089', 'Var', (38, 48))	('expression', 'MPA', (6, 16))	('downregulated', 'NegReg', (21, 34))	('MMP-8', 'Gene', (0, 5))	('N-1089', 'CellLine', 'CVCL:9D84', (70, 76))
121170	28330493	LAP is an established ligand for alphavbeta6 integrin whereby LAP cleavage by alphavbeta6 integrin leads to TGF-beta activation.	('TGF-beta', 'Gene', '7040', (108, 116))	('LAP', 'Gene', '7040', (0, 3))	('TGF-beta', 'Gene', (108, 116))	('LAP', 'Gene', '7040', (62, 65))	('cleavage', 'Var', (66, 74))	('LAP', 'Gene', (62, 65))	('LAP', 'Gene', (0, 3))	('activation', 'PosReg', (117, 127))
121173	28330493	Migration towards Fib, Col-I, Lam-I, Ten-C and LAP was significantly reduced in MMP-8 WT but not in MMP-8 EA cells compared to control empty vector transfected cells.	('Fib', 'Gene', (18, 21))	('MMP-8 WT', 'Var', (80, 88))	('LAP', 'Gene', '7040', (47, 50))	('reduced', 'NegReg', (69, 76))	('Ten-C', 'Gene', '3371', (37, 42))	('LAP', 'Gene', (47, 50))	('Fib', 'Gene', '2335', (18, 21))	('Migration', 'CPA', (0, 9))	('rat', 'Species', '10116', (3, 6))	('Ten-C', 'Gene', (37, 42))
121179	28330493	MMP-8 knock-down in N-1089 cells led to increased migration towards Col-IV, Lam-I and Ten-C while there was no significant alteration in migration towards other ECM molecules (Fig.	('Ten-C', 'Gene', '3371', (86, 91))	('migration towards', 'CPA', (50, 67))	('N-1089', 'CellLine', 'CVCL:9D84', (20, 26))	('Ten-C', 'Gene', (86, 91))	('knock-down', 'Var', (6, 16))	('MMP-8', 'Gene', (0, 5))	('rat', 'Species', '10116', (53, 56))	('rat', 'Species', '10116', (127, 130))	('increased', 'PosReg', (40, 49))	('rat', 'Species', '10116', (140, 143))
121183	28330493	Confocal analysis of dual-labelling for alpha6beta4 and the HD component plectin revealed that alpha6beta4 localises more to HD structures in MMP-8 WT compared to MMP-8 EA or control cells (Fig.	('HD', 'Disease', 'MESH:D006816', (125, 127))	('alpha6beta4', 'Var', (95, 106))	('plectin', 'Gene', (73, 80))	('plectin', 'Gene', '5339', (73, 80))	('localises', 'MPA', (107, 116))	('HD', 'Disease', 'MESH:D006816', (60, 62))	('more', 'PosReg', (117, 121))	('MMP-8 WT', 'Var', (142, 150))
121184	28330493	Dual staining of alpha6beta4 with phalloidin showed that alpha6beta4 also localises to actin-rich protrusion sites (Fig.	('alpha6beta4', 'Var', (57, 68))	('phalloidin', 'Chemical', 'MESH:D010590', (34, 44))	('localises', 'MPA', (74, 83))
121186	28330493	Immunofluorescence analysis of N-1089 cells following MMP-8 knock-down revealed an increase in the length and number of retraction fibres compared to control knock-down cells, suggesting that MMP-8 inhibits the formation of these fibres (Fig.	('increase', 'PosReg', (83, 91))	('knock-down', 'Var', (60, 70))	('length', 'CPA', (99, 105))	('MMP-8', 'Gene', (54, 59))	('N-1089', 'CellLine', 'CVCL:9D84', (31, 37))	('inhibits', 'NegReg', (198, 206))	('formation', 'CPA', (211, 220))
121189	28330493	A significant reduction in the number of breast cancer cells invading through Matrigel in the presence of beta6-1089 cells expressing MMP-8 WT was observed compared to cells transfected with EA or empty vector (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('MMP-8', 'Var', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('reduction', 'NegReg', (14, 23))
121196	28330493	To dissect whether loss of normal MEC-derived MMP-8 has an influence on breast cancer cell invasion, MCF-7, MDA-MB-231 and SUM159 cells were co-cultured with N-1089 control cells following knock-down of MMP-8 in a transwell setup.	('N-1089', 'CellLine', 'CVCL:9D84', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('influence', 'Reg', (59, 68))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (108, 118))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('loss', 'Var', (19, 23))	('MCF-7', 'CellLine', 'CVCL:0031', (101, 106))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
121197	28330493	This demonstrated that breast cancer cell invasion was significantly enhanced in the absence of MMP-8 (Fig.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('rat', 'Species', '10116', (12, 15))	('enhanced', 'PosReg', (69, 77))	('absence', 'Var', (85, 92))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
121198	28330493	These data support the earlier contention that reduction in MCF-7 invasion was too small to measure, as co-culturing with MECs knocked down for MMP-8 enhanced MCF-7 invasion significantly.	('MCF-7', 'CellLine', 'CVCL:0031', (60, 65))	('enhanced', 'PosReg', (150, 158))	('knocked down', 'Var', (127, 139))	('invasion', 'CPA', (165, 173))	('MCF-7', 'CellLine', 'CVCL:0031', (159, 164))	('MMP-8', 'Gene', (144, 149))	('MCF-7', 'Gene', (159, 164))
121199	28330493	No significant difference in breast cancer cell number was demonstrated in the presence of N-1089 control or MMP-8 knock-down CM (Fig.	('N-1089', 'CellLine', 'CVCL:9D84', (91, 97))	('knock-down CM', 'Var', (115, 128))	('MMP-8', 'Gene', (109, 114))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('N-1089', 'Var', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('rat', 'Species', '10116', (66, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
121207	28330493	We previously have identified increased MMP-9 activity in beta6-1089 cells compared to N-1089, downstream of enhanced TGF-beta signalling.	('beta6-1089', 'Var', (58, 68))	('TGF-beta', 'Gene', (118, 126))	('activity', 'MPA', (46, 54))	('MMP-9', 'Gene', '4318', (40, 45))	('N-1089', 'CellLine', 'CVCL:9D84', (87, 93))	('increased', 'PosReg', (30, 39))	('enhanced', 'PosReg', (109, 117))	('MMP-9', 'Gene', (40, 45))	('TGF-beta', 'Gene', '7040', (118, 126))
121214	28330493	Gelatin degradation was significantly downregulated upon MMP-9 knock-down in siMMP-8-treated N-1089 cells.	('downregulated', 'NegReg', (38, 51))	('knock-down', 'Var', (63, 73))	('MMP-9', 'Gene', '4318', (57, 62))	('N-1089', 'CellLine', 'CVCL:9D84', (93, 99))	('MMP-9', 'Gene', (57, 62))	('Gelatin degradation', 'MPA', (0, 19))	('siMMP-8', 'Chemical', '-', (77, 84))
121220	28330493	The phosphorylation levels of SMAD-2 were decreased in beta6-1089 cells over-expressing MMP-8 WT as compared to empty vector control and EA mutant cells at 5 minutes.	('SMAD-2', 'Gene', '4087', (30, 36))	('decreased', 'NegReg', (42, 51))	('MMP-8 WT', 'Var', (88, 96))	('phosphorylation levels', 'MPA', (4, 26))	('SMAD-2', 'Gene', (30, 36))	('over-expressing', 'PosReg', (72, 87))
121221	28330493	There also was a reduction in phospho-SMAD-2 in beta6-1089 cells over-expressing MMP-8 EA as compared to empty vector at 15 minutes.	('MMP-8 EA', 'Var', (81, 89))	('SMAD-2', 'Gene', '4087', (38, 44))	('over-expressing', 'PosReg', (65, 80))	('reduction', 'NegReg', (17, 26))	('SMAD-2', 'Gene', (38, 44))
121222	28330493	The phosphorylation levels of SMAD-2 in MMP-8 EA were higher than phospho-SMAD-2 levels in MMP-8 WT at 5 minutes (Fig.	('SMAD-2', 'Gene', '4087', (74, 80))	('SMAD-2', 'Gene', '4087', (30, 36))	('higher', 'PosReg', (54, 60))	('SMAD-2', 'Gene', (74, 80))	('phosphorylation levels', 'MPA', (4, 26))	('SMAD-2', 'Gene', (30, 36))	('MMP-8', 'Var', (40, 45))
121224	28330493	This revealed an increase in phosphorylated SMAD-2 in MMP-8 knocked-down N-1089 cells compared to control siRNA transfected cells at 5, 10 and 15 minutes (Fig.	('knocked-down', 'Var', (60, 72))	('SMAD-2', 'Gene', '4087', (44, 50))	('MMP-8', 'Gene', (54, 59))	('phosphorylated', 'MPA', (29, 43))	('SMAD-2', 'Gene', (44, 50))	('N-1089', 'CellLine', 'CVCL:9D84', (73, 79))	('increase', 'PosReg', (17, 25))
121225	28330493	6d ii and Additional file 5: Figure S3ii), suggesting that MMP-8 reduces TGF-beta signalling, and this may not be dependent on enzymatic activity.	('MMP-8', 'Var', (59, 64))	('reduces', 'NegReg', (65, 72))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', (73, 81))
121234	28330493	Particularly in melanoma; MMP-8 is frequently mutated by loss of heterozygosity (LOH), which is a hallmark for tumour-suppressor proteins.	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('MMP-8', 'Gene', (26, 31))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('loss of heterozygosity', 'Var', (57, 79))
121239	28330493	These models were used to investigate gain-of-function effects, through over-expression of MMP-8 or an inactive mutant (EA, which carries a point mutation in catalytic site) in beta6-1089, and loss-of-function effects, through MMP-8 knock-down in N-1089 cells.	('over-expression', 'PosReg', (72, 87))	('N-1089', 'CellLine', 'CVCL:9D84', (247, 253))	('MMP-8', 'Gene', (91, 96))	('gain-of-function', 'PosReg', (38, 54))	('loss-of-function', 'NegReg', (193, 209))	('point mutation in', 'Var', (140, 157))
121243	28330493	Similarly, knock-down of MMP-8 in N-1089 cells resulted in decreased adhesion and enhanced migration to ECM proteins, confirming a role for MMP-8 in matrix adhesion.	('enhanced', 'PosReg', (82, 90))	('rat', 'Species', '10116', (94, 97))	('decreased', 'NegReg', (59, 68))	('adhesion', 'MPA', (69, 77))	('N-1089', 'CellLine', 'CVCL:9D84', (34, 40))	('knock-down', 'Var', (11, 21))	('MMP-8', 'Gene', (25, 30))	('migration to', 'CPA', (91, 103))
121246	28330493	Disassociation of HDs and localisation of alpha6beta4 to actin-rich protrusions are characteristics of the acquisition of a migratory phenotype in basal cells, and has been well studied in migrating keratinocytes during wound healing.	('HDs', 'Disease', (18, 21))	('rat', 'Species', '10116', (201, 204))	('HDs', 'Disease', 'None', (18, 21))	('rat', 'Species', '10116', (192, 195))	('rat', 'Species', '10116', (127, 130))	('alpha6beta4', 'Var', (42, 53))
121250	28330493	In keeping with this, knock-down of MMP-8 in N-1089 cells resulted in significantly longer and increased number of retraction fibres compared to control cells, which we speculate indicates the acquisition of a more migratory phenotype.	('knock-down', 'Var', (22, 32))	('MMP-8', 'Gene', (36, 41))	('retraction fibres', 'CPA', (115, 132))	('N-1089', 'CellLine', 'CVCL:9D84', (45, 51))	('rat', 'Species', '10116', (218, 221))	('increased', 'PosReg', (95, 104))
121254	28330493	A significant decrease in tumour invasion was observed for MDA MD 231 and SUM159 cells co-cultured with MMP-8 WT over-expressing beta6-1089 compared to empty vector and MMP-8 EA, suggesting that MMP-8 contributes to MEC invasion-suppressor effect.	('beta6-1089', 'Var', (129, 139))	('tumour invasion', 'Disease', 'MESH:D009361', (26, 41))	('over-expressing', 'PosReg', (113, 128))	('tumour invasion', 'Disease', (26, 41))	('decrease', 'NegReg', (14, 22))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('MDA MD', 'CellLine', 'CVCL:6420', (59, 65))
121255	28330493	This was further supported by enhanced transwell invasion for all tumour cells in the presence of N-1089 MMP-8 knock-down cells.	('N-1089', 'Var', (98, 104))	('enhanced', 'PosReg', (30, 38))	('transwell invasion', 'CPA', (39, 57))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('N-1089', 'CellLine', 'CVCL:9D84', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))
121261	28330493	This showed that phosphorylation of SMAD-2 was downregulated in beta6-1089 cells expressing MMP-8 WT and enhanced in N-1089 cells following MMP-8 knock-down, supporting a role for MMP-8 in dampening TGF-beta signalling.	('TGF-beta', 'Gene', (199, 207))	('downregulated', 'NegReg', (47, 60))	('phosphorylation', 'MPA', (17, 32))	('SMAD-2', 'Gene', (36, 42))	('N-1089', 'CellLine', 'CVCL:9D84', (117, 123))	('TGF-beta', 'Gene', '7040', (199, 207))	('MMP-8', 'Var', (92, 97))	('enhanced', 'PosReg', (105, 113))	('SMAD-2', 'Gene', '4087', (36, 42))
121263	28330493	In contrast, gelatin degradation was significantly enhanced by knock-down in N-1089 cells, and importantly this effect could be rescued by MMP-9 inhibition or by MMP-9 knock-down.	('N-1089', 'CellLine', 'CVCL:9D84', (77, 83))	('MMP-9', 'Gene', '4318', (162, 167))	('gelatin degradation', 'MPA', (13, 32))	('MMP-9', 'Gene', '4318', (139, 144))	('MMP-9', 'Gene', (162, 167))	('enhanced', 'PosReg', (51, 59))	('knock-down', 'Var', (63, 73))	('MMP-9', 'Gene', (139, 144))
121264	28330493	This suggests some form of inhibitory interaction between MMP-8 and MMP-9: it previously has been shown that MMP-8 can establish a complex with MMP-9 but the function of this complex remains elusive.	('MMP-9', 'Gene', (68, 73))	('MMP-9', 'Gene', (144, 149))	('MMP-8', 'Var', (109, 114))	('MMP-9', 'Gene', '4318', (144, 149))	('MMP-9', 'Gene', '4318', (68, 73))	('complex', 'Interaction', (131, 138))
121268	28330493	CM Conditioned media Col-I Collagen-I Col-IV Collagen-IV DCIS Ductal carcinoma in situ EA Inactive mutant ECM Extracellular matrix Fib Fibronectin HD Hemidesmosomes IBC Invasive breast cancer Lam-I Laminin-I LAP Latency-associated peptide LEC Luminal epithelial cell MEC Myoepithelial cell MMP-8 Matrix metalloproteinase-8 SFM Serum-free media Ten-C Tenascin-C TGF-beta Transforming growth factor beta WT Wild-type	('TGF-beta', 'Gene', '7040', (361, 369))	('LAP', 'Gene', (208, 211))	('Fib', 'Gene', (131, 134))	('Ten-C', 'Gene', (344, 349))	('HD', 'Disease', 'MESH:D006816', (147, 149))	('Fib', 'Gene', '2335', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('TGF-beta', 'Gene', (361, 369))	('Matrix metalloproteinase-8', 'Gene', '4317', (296, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Fib', 'Gene', (135, 138))	('Ductal carcinoma', 'Disease', (62, 78))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (62, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('Fib', 'Gene', '2335', (135, 138))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('Ten-C', 'Gene', '3371', (344, 349))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))	('LAP', 'Gene', '7040', (208, 211))	('mutant', 'Var', (99, 105))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (62, 86))	('Matrix metalloproteinase-8', 'Gene', (296, 322))
121277	30804999	DCIS was defined as in situ breast cancer with ICD-O-3 code 8201, 8230, 8500-8507, or 8523.	('DCIS', 'Disease', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('ICD', 'Disease', 'OMIM:252500', (47, 50))	('ICD', 'Disease', (47, 50))	('8500-8507', 'Var', (72, 81))	('situ breast cancer', 'Disease', (23, 41))	('situ breast cancer', 'Disease', 'MESH:D000071960', (23, 41))
121299	27066096	Based on molecular subtypes, high EZH2 expression was significantly associated with HER2-negative luminal B, HER2-positive luminal B, and HER2 type and triple-negative basal cancers (p<0.001).	('high', 'Var', (29, 33))	('HER2', 'Gene', '2064', (138, 142))	('EZH2', 'Gene', '2146', (34, 38))	('basal cancers', 'Disease', (168, 181))	('HER2', 'Gene', (109, 113))	('HER2', 'Gene', (84, 88))	('basal cancers', 'Disease', 'MESH:D002280', (168, 181))	('EZH2', 'Gene', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('HER2', 'Gene', '2064', (84, 88))	('HER2', 'Gene', '2064', (109, 113))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('HER2', 'Gene', (138, 142))
121300	27066096	In patients with luminal A, there was a significant trend toward shorter overall survival for those with tumors having high EZH2 expression compared to those with tumors having low EZH2 expression (p=0.045).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('EZH2', 'Gene', '2146', (181, 185))	('expression', 'MPA', (129, 139))	('high', 'Var', (119, 123))	('EZH2', 'Gene', (181, 185))	('shorter', 'NegReg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EZH2', 'Gene', '2146', (124, 128))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('EZH2', 'Gene', (124, 128))	('patients', 'Species', '9606', (3, 11))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('overall survival', 'MPA', (73, 89))
121304	27066096	EZH2, which has a SET domain, epigenetically regulates chromatin structure and represses target gene transcription by trimethylating histone 3 lysine 27 (H3K27me3).	('EZH2', 'Gene', '2146', (0, 4))	('represses', 'NegReg', (79, 88))	('epigenetically', 'Var', (30, 44))	('EZH2', 'Gene', (0, 4))	('trimethylating', 'MPA', (118, 132))	('chromatin structure', 'MPA', (55, 74))	('regulates', 'Reg', (45, 54))	('lysine', 'Chemical', 'MESH:D008239', (143, 149))
121308	27066096	Two EZH2 inhibitors are currently being tested in phase I and II clinical trials in patients with and without EZH2 mutations in their lymphoma.	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (84, 92))	('lymphoma', 'Disease', (134, 142))	('lymphoma', 'Disease', 'MESH:D008223', (134, 142))	('EZH2', 'Gene', '2146', (4, 8))	('EZH2', 'Gene', (4, 8))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))
121363	27066096	High EZH2 expression significantly correlated with high histologic grade (p<0.001), large tumor size (p=0.014), advanced pathologic stage (p-stage, p=0.006), negative ER expression (p<0.001), positive HER2 expression (p<0.001), high Ki-67 staining index (p<0.001), positive CK5/6 expression (p=0.003), positive EGFR expression (p<0.001), positive p53 expression (p<0.001), endocrine therapy status (p=0.001), and chemotherapy (p=0.032) (Table 2).	('HER2', 'Gene', (201, 205))	('EGFR', 'Gene', (311, 315))	('p53', 'Gene', (347, 350))	('ER', 'Gene', '2099', (202, 204))	('HER2', 'Gene', '2064', (201, 205))	('p53', 'Gene', '7157', (347, 350))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CK5/6', 'Gene', '3852', (274, 279))	('expression', 'MPA', (351, 361))	('high histologic grade', 'CPA', (51, 72))	('positive', 'Var', (338, 346))	('CK5/6', 'Gene', (274, 279))	('ER', 'Gene', '2099', (167, 169))	('EZH2', 'Gene', '2146', (5, 9))	('EGFR', 'Gene', '1956', (311, 315))	('EZH2', 'Gene', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
121371	27066096	Patients with high EZH2 expression had a significantly worse DFS (p=0.041) and OS (p=0.009) than did patients with low EZH2 expression (Figure 3A, B).	('EZH2', 'Gene', '2146', (119, 123))	('EZH2', 'Gene', (119, 123))	('patients', 'Species', '9606', (101, 109))	('DFS', 'MPA', (61, 64))	('worse', 'NegReg', (55, 60))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('EZH2', 'Gene', '2146', (19, 23))	('EZH2', 'Gene', (19, 23))
121375	27066096	To evaluate EZH2 positivity in IDC as an independent predictor of DFS and OS, multivariate analysis using the Cox proportional hazard model was performed and included age, tumor size, lymph node metastasis, and EZH2 expression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('positivity', 'Var', (17, 27))	('DFS', 'Disease', (66, 69))	('IDC', 'Gene', '4000', (31, 34))	('IDC', 'Gene', (31, 34))	('EZH2', 'Gene', '2146', (211, 215))	('EZH2', 'Gene', '2146', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('EZH2', 'Gene', (211, 215))	('EZH2', 'Gene', (12, 16))
121391	27066096	High EZH2 expression was associated with features of aggressive tumors, such as high histologic grade, large tumor size, advanced p-stage, ER negativity, HER2 positivity, high Ki-67 proliferative index, CK5/6 and EGFR positivity, and positive p53 expression.	('CK5/6', 'Gene', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('associated', 'Reg', (25, 35))	('aggressive tumors', 'Disease', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('EGFR', 'Gene', '1956', (213, 217))	('aggressive tumors', 'Disease', 'MESH:D001523', (53, 70))	('High', 'Var', (0, 4))	('expression', 'MPA', (247, 257))	('expression', 'MPA', (10, 20))	('HER2', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ER', 'Gene', '2099', (155, 157))	('ER', 'Gene', '2099', (139, 141))	('p53', 'Gene', '7157', (243, 246))	('EZH2', 'Gene', '2146', (5, 9))	('CK5/6', 'Gene', '3852', (203, 208))	('EZH2', 'Gene', (5, 9))	('tumor', 'Disease', (64, 69))	('EGFR', 'Gene', (213, 217))	('positivity', 'Var', (159, 169))	('p53', 'Gene', (243, 246))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('HER2', 'Gene', '2064', (154, 158))	('tumor', 'Disease', (109, 114))
121392	27066096	For molecular subtypes, high EZH2 expression was significantly associated with HER2-negative luminal B, HER2-positive luminal B, and HER2-positive cancers as well as basal TNBC.	('HER2', 'Gene', '2064', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (34, 44))	('HER2-positive cancers', 'Disease', 'MESH:D009369', (133, 154))	('associated', 'Reg', (63, 73))	('HER2', 'Gene', (133, 137))	('HER2', 'Gene', '2064', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('high', 'Var', (24, 28))	('basal TNBC', 'Disease', (166, 176))	('HER2', 'Gene', (104, 108))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('HER2', 'Gene', '2064', (104, 108))	('HER2-positive cancers', 'Disease', (133, 154))	('HER2', 'Gene', (79, 83))
121396	27066096	Our findings regarding the association of high EZH2 expression with aggressive breast cancer features are consistent with previous reports.	('aggressive breast cancer', 'Disease', (68, 92))	('EZH2', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('high', 'Var', (42, 46))	('EZH2', 'Gene', '2146', (47, 51))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (68, 92))
121400	27066096	While previous reports showed no association between high EZH2 expression and HER2 positivity, our study reveals the specific association between high EZH2 expression and HER2 positivity in a cohort of patients with IDC from a single institution.	('EZH2', 'Gene', '2146', (151, 155))	('EZH2', 'Gene', '2146', (58, 62))	('EZH2', 'Gene', (151, 155))	('HER2', 'Gene', (78, 82))	('EZH2', 'Gene', (58, 62))	('HER2', 'Gene', (171, 175))	('positivity', 'Var', (176, 186))	('IDC', 'Gene', (216, 219))	('IDC', 'Gene', '4000', (216, 219))	('patients', 'Species', '9606', (202, 210))	('HER2', 'Gene', '2064', (171, 175))	('HER2', 'Gene', '2064', (78, 82))	('expression', 'MPA', (156, 166))	('high', 'Var', (146, 150))
121404	27066096	We also found a significant correlation between high EZH2 expression and both p53 overexpression and high Ki-67 proliferative index.	('expression', 'MPA', (58, 68))	('overexpression', 'PosReg', (82, 96))	('p53', 'Gene', (78, 81))	('high', 'Var', (48, 52))	('p53', 'Gene', '7157', (78, 81))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
121406	27066096	reported high EZH2 expression as a prognostic factor for shorter OS for patients with breast cancer, including the ER+ breast cancer subtype.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('expression', 'MPA', (19, 29))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('EZH2', 'Gene', (14, 18))	('patients', 'Species', '9606', (72, 80))	('EZH2', 'Gene', '2146', (14, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ER', 'Gene', '2099', (115, 117))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('high', 'Var', (9, 13))
121495	23663560	Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity Co-Activator Arginine Methyltransferase 1(CARM1) is an Estrogen Receptor (ER) cofactor that remodels chromatin for gene regulation via methylation of Histone3.	('associated', 'Reg', (123, 133))	('CARM1', 'Gene', '10498', (227, 232))	('Estrogen Receptor', 'Gene', '2099', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('CARM1', 'Gene', (112, 117))	('ER', 'Gene', '2099', (259, 261))	('methylation', 'Var', (320, 331))	('breast cancer', 'Disease', (148, 161))	('Histone3', 'Protein', (335, 343))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('Estrogen Receptor', 'Gene', (240, 257))	('CARM1', 'Gene', '10498', (112, 117))	('CARM1', 'Gene', (227, 232))
121511	23663560	Aside from DNA changes, epigenetic modifications, which regulate the expression potential of a gene, have been increasingly implicated in breast tumorgenesis.	('implicated', 'Reg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('epigenetic modifications', 'Var', (24, 48))	('expression potential', 'MPA', (69, 89))	('breast tumor', 'Phenotype', 'HP:0100013', (138, 150))	('regulate', 'Reg', (56, 64))	('breast tumorgenesis', 'Disease', (138, 157))	('breast tumorgenesis', 'Disease', 'MESH:D001943', (138, 157))
121521	23663560	Specifically, histone modifications have been repeatedly implicated in the differential regulation of genes which impact tumorgenesis including the regulation of steroid and growth signal target genes.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('implicated', 'Reg', (57, 67))	('tumor', 'Disease', (121, 126))	('histone', 'Var', (14, 21))	('steroid', 'Chemical', 'MESH:D013256', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
121522	23663560	Recently, studies show that epigenetic haplotypes are associated with ER-negative breast cancer subtypes.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('epigenetic haplotypes', 'Var', (28, 49))	('ER', 'Gene', '2099', (70, 72))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('associated', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
121524	23663560	It is a chromatin remodeling regulator of steroid hormone signaling pathways, acting through methylation of several proteins, including Histone 3, and has been associated with breast and prostate cancer etiology.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('steroid hormone', 'Chemical', 'MESH:D013256', (42, 57))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (176, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('methylation', 'Var', (93, 104))	('associated with', 'Reg', (160, 175))	('Histone', 'Protein', (136, 143))
121576	23663560	These data indicate that tumors with an amplified HER2 gene also have high levels of CARM1 expression overall.	('expression', 'MPA', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HER2', 'Gene', (50, 54))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('HER2', 'Gene', '2064', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('CARM1', 'Gene', (85, 90))	('amplified', 'Var', (40, 49))
121587	23663560	In fact, a recent study shows evidence that EGFR, a receptor which is exclusively expressed in basal-like subtypes, is methylated by PRMT5, a member of the CARM1 protein family.	('methylated', 'Var', (119, 129))	('PRMT5', 'Gene', (133, 138))	('PRMT5', 'Gene', '10419', (133, 138))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
121588	23663560	Their model speculates that this EGFR arginine methylation might enhance the protein's autophosphorylation and attenuation of EGFR-mediated ERK activation.	('EGFR', 'Gene', (126, 130))	('enhance', 'PosReg', (65, 72))	('arginine', 'Chemical', 'MESH:D001120', (38, 46))	('EGFR', 'Gene', '1956', (33, 37))	('arginine methylation', 'Var', (38, 58))	('ERK', 'Gene', '2048', (140, 143))	('EGFR', 'Gene', (33, 37))	('ERK', 'Gene', (140, 143))	('autophosphorylation', 'MPA', (87, 106))	('EGFR', 'Gene', '1956', (126, 130))	('attenuation', 'NegReg', (111, 122))
121600	23663560	Many of our CARM1 associations correlate with tumor categories that are reported to be more prevalent in specific ethnic groups.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('associations', 'Var', (18, 30))	('tumor', 'Disease', (46, 51))	('CARM1', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
121616	23663560	There are over 500 known polymorphisms in the CARM-1 gene, of which approximately 10% show unique minor allele frequencies restricted to African ancestral groups in HapMap analyses.	('polymorphisms', 'Var', (25, 38))	('CARM-1', 'Gene', '10498', (46, 52))	('CARM-1', 'Gene', (46, 52))
121749	22622473	Among women who underwent BCS and who did not receive radiotherapy, the 5 year rate of LRR was significantly higher among younger patients.	('LRR', 'Disease', (87, 90))	('higher', 'PosReg', (109, 115))	('women', 'Species', '9606', (6, 11))	('patients', 'Species', '9606', (130, 138))	('BCS', 'Var', (26, 29))
121757	22622473	showed that multifocality in DCIS is associated with higher LRR in women treated with BCS.	('multifocality', 'Var', (12, 25))	('higher', 'PosReg', (53, 59))	('women', 'Species', '9606', (67, 72))	('DCIS', 'Gene', (29, 33))	('LRR', 'Disease', (60, 63))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))
121794	24116006	Overexpression of some ion channels has been linked to poor prognosis while other channels are now recognised as potential biomarkers for particular cancer types.	('particular cancer', 'Disease', (138, 155))	('particular cancer', 'Disease', 'MESH:D009369', (138, 155))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))
121798	24116006	In a similar manner, K+ channel control of membrane potential has been shown to impact cell migration through regulation of cell volume, pH and intracellular Ca2+ concentration.	('Ca2+', 'Chemical', 'MESH:D000069285', (158, 162))	('cell migration', 'CPA', (87, 101))	('cell volume', 'CPA', (124, 135))	('impact', 'Reg', (80, 86))	('K+ channel control', 'Var', (21, 39))
121813	24116006	While experimental knockdown of K2P5.1 moderately reduced basal proliferation of T47D cells, a significantly greater reduction in estrogen-induced proliferation was observed.	('reduction', 'NegReg', (117, 126))	('K2P5.1', 'Gene', (32, 38))	('basal proliferation', 'CPA', (58, 77))	('estrogen-induced proliferation', 'CPA', (130, 160))	('K2P5.1', 'Gene', '8645', (32, 38))	('knockdown', 'Var', (19, 28))	('reduced', 'NegReg', (50, 57))	('T47D', 'CellLine', 'CVCL:0553', (81, 85))
121814	24116006	Evidence from these studies supports the hypothesis that alterations to the expression or function of K2P channels in cancer cells may play a role in cancer development and progression.	('cancer', 'Disease', (118, 124))	('role', 'Reg', (142, 146))	('play', 'Reg', (135, 139))	('K2P', 'Gene', '51350', (102, 105))	('K2P', 'Gene', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('alterations', 'Var', (57, 68))	('cancer', 'Disease', (150, 156))	('function', 'MPA', (90, 98))	('progression', 'CPA', (173, 184))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
121916	24116006	This, together with their acute sensitivity to the internal and external environment of the cell which is known to change in the cancer microenvironment means that altered expression of these channels may provide cancer cells with a survival advantage.	('survival advantage', 'CPA', (233, 251))	('provide', 'Reg', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('expression', 'MPA', (172, 182))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('altered', 'Var', (164, 171))
121922	24247619	Amplification of PHB was detected in 13 of 235 cases (5.5%) but was not associated with PHB expression.	('PHB', 'Gene', (88, 91))	('Amplification', 'Var', (0, 13))	('PHB', 'Gene', '5245', (88, 91))	('PHB', 'Gene', (17, 20))	('PHB', 'Gene', '5245', (17, 20))
121923	24247619	PHB amplification was most common in the ERBB2+ breast cancer subtype, although high expression was most prevalent in basal-like and luminal B cancers.	('luminal B cancers', 'Disease', 'MESH:D009369', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('luminal B cancers', 'Disease', (133, 150))	('PHB', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('PHB', 'Gene', '5245', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('ERBB2', 'Gene', '2064', (41, 46))	('breast cancer', 'Disease', (48, 61))	('amplification', 'Var', (4, 17))	('ERBB2', 'Gene', (41, 46))	('common', 'Reg', (27, 33))
121924	24247619	Amplification at 17q21.33 is a recurrent feature of breast cancer that forms part of a 'firestorm' pattern of genomic aberration.	('Amplification at 17q21.33', 'Var', (0, 25))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
121928	24247619	More certain is the impact of key genetic lesions on breast cancer biology with over-expression of the ERBB2 (HER2) oncoprotein as a consequence of amplification at 17q12.21, the definitive example of a genomic lesion that has a critical influence on cancer cell growth.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('over-expression', 'PosReg', (80, 95))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('ERBB2', 'Gene', (103, 108))	('ERBB2', 'Gene', '2064', (103, 108))	('amplification at 17q12.21', 'Var', (148, 173))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('HER2', 'Gene', (110, 114))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Disease', (251, 257))	('HER2', 'Gene', '2064', (110, 114))	('breast cancer', 'Disease', (53, 66))
121935	24247619	This is consistent with other genomic profiling studies of breast cancer that have described a region of recurrent amplification at 17q21.33.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('amplification', 'Var', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))
121937	24247619	A further repeated observation has been that 17q21.33 and ERBB2 amplification commonly co-exist in breast cancer, forming part of an 'amplifier' or 'firestorm' pattern of genomic aberration.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('amplification', 'Var', (64, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('ERBB2', 'Gene', '2064', (58, 63))	('ERBB2', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
121952	24247619	To the cooled DNA was added: 5 muL of nucleotide mix (1.2mM each of dATP, dGTP, dCTP, and 0.6mM dTTP), 3 nmol of appropriate labelled nucleotide (test DNA and reference DNA labelled with Cy5-dUTP and Cy3-dUTP, respectively), and 1 muL Exo-Klenow.	('dGTP', 'Chemical', 'MESH:C029603', (74, 78))	('dATP', 'Chemical', 'MESH:C026600', (68, 72))	('Cy5-dUTP', 'Var', (187, 195))	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (187, 195))	('dCTP', 'Chemical', 'MESH:C024107', (80, 84))	('dTTP', 'Chemical', 'MESH:C024157', (96, 100))	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (200, 208))	('Cy3-dUTP', 'Var', (200, 208))
121958	24247619	FISH of stored TMA sections was performed to assess PHB copy number.	('PHB', 'Gene', '5245', (52, 55))	('PHB', 'Gene', (52, 55))	('copy number', 'Var', (56, 67))
121968	24247619	Chi squared or Fisher's exact test, as appropriate, were used to test for associations between PHB expression and copy number and clinicopathological features.	('expression', 'MPA', (99, 109))	('PHB', 'Gene', '5245', (95, 98))	('test', 'Reg', (65, 69))	('associations', 'Interaction', (74, 86))	('PHB', 'Gene', (95, 98))	('copy number', 'Var', (114, 125))
121970	24247619	In a previous genomic profiling study, complex alterations of 17q were identified in a number of samples of microdissected in situ breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('17q', 'Gene', (62, 65))	('situ breast carcinoma', 'Disease', 'MESH:D001943', (126, 147))	('breast carcinoma', 'Phenotype', 'HP:0003002', (131, 147))	('situ breast carcinoma', 'Disease', (126, 147))	('identified', 'Reg', (71, 81))	('alterations', 'Var', (47, 58))
121972	24247619	Of the remaining 15 samples, nine showed amplification at the ERBB2 (HER2) locus and four showed a distinct region of amplification at 17q21.33.	('ERBB2', 'Gene', (62, 67))	('amplification', 'Var', (41, 54))	('ERBB2', 'Gene', '2064', (62, 67))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', '2064', (69, 73))
121973	24247619	In three samples, including two microdissected from the same invasive breast cancer, there was amplification at both ERBB2 and 17q21.33.	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('17q21.33', 'Gene', (127, 135))	('amplification', 'Var', (95, 108))	('ERBB2', 'Gene', (117, 122))	('ERBB2', 'Gene', '2064', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasive breast cancer', 'Disease', (61, 83))
121979	24247619	None of the four genes were differentially expressed between samples from ERBB2 positive and ERBB2 negative breast cancer (Table 1).	('ERBB2', 'Gene', (74, 79))	('positive', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ERBB2', 'Gene', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('ERBB2', 'Gene', '2064', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))	('ERBB2', 'Gene', '2064', (74, 79))
121980	24247619	These data showing an association between PHB copy number and expression, in combination with relatively high level expression in high grade cancer compared with low grade cancer and normal cells, respectively, identified PHB as a potential driver of amplification at 17q21.33.	('PHB', 'Gene', (222, 225))	('copy number', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (172, 178))	('expression', 'MPA', (62, 72))	('PHB', 'Gene', '5245', (222, 225))	('PHB', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('association', 'Interaction', (22, 33))	('cancer', 'Disease', (141, 147))	('PHB', 'Gene', '5245', (42, 45))
121989	24247619	There was a significant association between PHB and ERBB2 amplification (p = 0.002) with six of 11 (54.5%) PHB amplified cases also ERBB2 amplified, and six of 34 ERBB2 amplified cases showing amplification at PHB (17.6%) (Table 2C).	('PHB', 'Gene', '5245', (107, 110))	('ERBB2', 'Gene', (132, 137))	('PHB', 'Gene', (44, 47))	('amplified', 'Var', (138, 147))	('PHB', 'Gene', '5245', (44, 47))	('PHB', 'Gene', (210, 213))	('PHB', 'Gene', (107, 110))	('ERBB2', 'Gene', '2064', (52, 57))	('ERBB2', 'Gene', (52, 57))	('PHB', 'Gene', '5245', (210, 213))	('ERBB2', 'Gene', (163, 168))	('ERBB2', 'Gene', '2064', (132, 137))	('ERBB2', 'Gene', '2064', (163, 168))
121990	24247619	PHB amplification was not associated with age at diagnosis (p = 0.445), tumour size (p = 0.242), lymph node status (p = 0.583), grade (p = 0.126), ER (p = 0.528) or PR (p = 0.211) (Table 2C).	('PHB', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('amplification', 'Var', (4, 17))	('ER', 'Gene', '2069', (147, 149))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('PHB', 'Gene', '5245', (0, 3))	('tumour', 'Disease', (72, 78))	('PR', 'Gene', '5241', (165, 167))
121993	24247619	Comparison of these subtype allocations with PHB amplification showed a significant association (p = 0.001), with the majority of PHB amplified cases belonging to the ERBB2+ subtype and the remainder belonging to the luminal subgroups (Table 2C).	('ERBB2', 'Gene', (167, 172))	('PHB', 'Gene', (130, 133))	('ERBB2', 'Gene', '2064', (167, 172))	('PHB', 'Gene', (45, 48))	('PHB', 'Gene', '5245', (130, 133))	('amplified', 'Var', (134, 143))	('PHB', 'Gene', '5245', (45, 48))	('luminal', 'Chemical', 'MESH:D010634', (217, 224))
121997	24247619	These data suggested that amplification at 17q21.33 could provide a selective advantage to breast cancer by supporting high level expression of one or more genes that actively contributed to an aggressive tumour phenotype.	('supporting', 'PosReg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('aggressive tumour', 'Disease', 'MESH:D009369', (194, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('high level expression', 'MPA', (119, 140))	('amplification', 'Var', (26, 39))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('aggressive tumour', 'Disease', (194, 211))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
122000	24247619	In breast cancer, the main interest in PHB has been in the tumour suppressor function of the 3' untranslated region (UTR) of the PHB transcript which is abolished by a rare single nucleotide polymorphism (SNP).	('PHB', 'Gene', (39, 42))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PHB', 'Gene', '5245', (39, 42))	('breast cancer', 'Disease', (3, 16))	('PHB', 'Gene', '5245', (129, 132))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('single nucleotide polymorphism', 'Var', (173, 203))	('PHB', 'Gene', (129, 132))
122001	24247619	This SNP has been inconsistently associated with breast cancer risk, although there is evidence that it may act as a modifier of breast and ovarian cancer risk in BRCA1/2 mutation carriers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (140, 154))	('BRCA1/2', 'Gene', (163, 170))	('mutation', 'Var', (171, 179))	('carriers', 'Reg', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRCA1/2', 'Gene', '672;675', (163, 170))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (129, 154))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
122003	24247619	In addition to a key supportive role mitochondrial PHB plays in cellular respiration, in cancer cells PHB expression has been shown to generally promote an aggressive malignant phenotype.	('aggressive malignant phenotype', 'CPA', (156, 186))	('PHB', 'Gene', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PHB', 'Gene', '5245', (102, 105))	('PHB', 'Gene', (51, 54))	('cancer', 'Disease', (89, 95))	('expression', 'Var', (106, 116))	('promote', 'PosReg', (145, 152))	('PHB', 'Gene', '5245', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
122010	24247619	Moreover, breast cancer specific survival in individuals with cancers expressing intermediate and high levels of PHB was reduced compared with negative/low expressing cases.	('PHB', 'Gene', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('high', 'Var', (98, 102))	('reduced', 'NegReg', (121, 128))	('PHB', 'Gene', '5245', (113, 116))	('breast cancer', 'Disease', (10, 23))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
122012	24247619	In a series of 23 cancers showing a 17q firestorm pattern, these investigators identified at least five distinct amplification peaks including ERBB2 and 17q21.33.	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('ERBB2', 'Gene', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ERBB2', 'Gene', '2064', (143, 148))	('17q21.33', 'Var', (153, 161))
122016	24247619	This failure of association between copy number and expression of PHB was counter-intuitive in view of the link between high PHB expression and poor prognosis, high grade breast cancer and also between PHB and ERBB2 amplification.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('PHB', 'Gene', '5245', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('expression', 'MPA', (129, 139))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('high', 'Var', (120, 124))	('PHB', 'Gene', (202, 205))	('PHB', 'Gene', (66, 69))	('amplification', 'Var', (216, 229))	('PHB', 'Gene', (125, 128))	('PHB', 'Gene', '5245', (202, 205))	('PHB', 'Gene', '5245', (66, 69))	('ERBB2', 'Gene', '2064', (210, 215))	('ERBB2', 'Gene', (210, 215))
122018	24247619	We have previously reported sub-classification of this cohort of invasive breast cancers into four subgroups by hierarchical cluster analysis based on components of histopathological grade, ER, ERBB2 (HER2) amplification and CK5/6 expression.	('HER2', 'Gene', (201, 205))	('CK5/6', 'Gene', '3852', (225, 230))	('invasive breast cancers', 'Disease', (65, 88))	('HER2', 'Gene', '2064', (201, 205))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('invasive breast cancers', 'Disease', 'MESH:D001943', (65, 88))	('CK5/6', 'Gene', (225, 230))	('ER', 'Gene', '2069', (194, 196))	('ERBB2', 'Gene', '2064', (194, 199))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('ER', 'Gene', '2069', (202, 204))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ER', 'Gene', '2069', (190, 192))	('ERBB2', 'Gene', (194, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('amplification', 'Var', (207, 220))
122023	24247619	that specifically documented genomic changes in breast cancers subtypes, 17q21.33 amplification was also identified as a feature of ERBB2+ and luminal, but not basal-like breast cancers.	('17q21.33 amplification', 'Var', (73, 95))	('ERBB2', 'Gene', (132, 137))	('breast cancers', 'Disease', (171, 185))	('luminal', 'Chemical', 'MESH:D010634', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('amplification', 'Var', (82, 95))	('breast cancers', 'Disease', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('luminal', 'Disease', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('ERBB2', 'Gene', '2064', (132, 137))	('breast cancers', 'Disease', 'MESH:D001943', (171, 185))
122024	24247619	Interestingly, studies investigating PPM1D (protein phosphatase magnesium-dependent delta) as a potential driver of another discrete 17q amplicon at 17q23.2 showed some similar results, with a 6% overall rate of amplification, association with ERBB2 amplification, and amplification seen only in luminal or ERBB2 breast cancer types.	('PPM1D', 'Gene', (37, 42))	('ERBB2', 'Gene', (307, 312))	('luminal', 'Chemical', 'MESH:D010634', (296, 303))	('amplification', 'MPA', (212, 225))	('association', 'Interaction', (227, 238))	('breast cancer', 'Disease', 'MESH:D001943', (313, 326))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('breast cancer', 'Disease', (313, 326))	('amplification', 'Var', (250, 263))	('ERBB2', 'Gene', (244, 249))	('PPM1D', 'Gene', '8493', (37, 42))	('ERBB2', 'Gene', '2064', (244, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (313, 326))	('magnesium', 'Chemical', 'MESH:D008274', (64, 73))	('ERBB2', 'Gene', '2064', (307, 312))
122025	24247619	However, in contrast to PHB, amplification of PPM1D was associated with high level expression at the transcript level in a validation cohort, although there was no apparent relationship between PPM1D expression and clinicopathological features of breast cancer or survival.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('PPM1D', 'Gene', '8493', (46, 51))	('amplification', 'Var', (29, 42))	('PHB', 'Gene', '5245', (24, 27))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('PPM1D', 'Gene', '8493', (194, 199))	('PHB', 'Gene', (24, 27))	('breast cancer', 'Disease', (247, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('PPM1D', 'Gene', (46, 51))	('PPM1D', 'Gene', (194, 199))	('high level expression', 'MPA', (72, 93))
122033	24247619	In this study we have delineated a region of recurrent amplification on chromosome 17q21.33 that included a number of genes highly expressed in high molecular grade breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('amplification', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))
122034	24247619	This genomic feature was significantly associated with amplification at ERBB2, consistent with a 'firestorm' pattern of localised high level amplification which is itself associated with high grade forms of breast cancer.	('amplification', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('ERBB2', 'Gene', '2064', (72, 77))	('associated', 'Reg', (39, 49))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('ERBB2', 'Gene', (72, 77))	('breast cancer', 'Disease', (207, 220))	('associated', 'Reg', (171, 181))
122036	24247619	However, high level expression of PHB was associated with high grade breast cancer and poor survival, suggesting that PHB may contribute to the growth of an aggressive tumour type.	('PHB', 'Gene', '5245', (118, 121))	('high level', 'Var', (9, 19))	('associated', 'Reg', (42, 52))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('PHB', 'Gene', (34, 37))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('contribute', 'Reg', (126, 136))	('aggressive tumour', 'Disease', 'MESH:D009369', (157, 174))	('breast cancer', 'Disease', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('PHB', 'Gene', '5245', (34, 37))	('PHB', 'Gene', (118, 121))	('aggressive tumour', 'Disease', (157, 174))
122076	24936506	Although a US-14G-CNB is a highly accurate and widely used method for the diagnosis of breast lesions, sampling errors can result in the histologic underestimation of lesions containing atypical ductal hyperplasia (ADH) or DCIS, as well as invasive carcinomas.	('CNB', 'Gene', (18, 21))	('breast lesions', 'Disease', (87, 101))	('DCIS', 'Disease', (223, 227))	('invasive carcinomas', 'Disease', (240, 259))	('invasive carcinomas', 'Disease', 'MESH:D009361', (240, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('errors', 'Var', (112, 118))	('breast lesions', 'Disease', 'MESH:D001941', (87, 101))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (195, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (249, 259))	('ductal hyperplasia', 'Disease', (195, 213))	('underestimation', 'NegReg', (148, 163))	('CNB', 'Gene', '5534', (18, 21))
122135	22514560	To analyze gene expression patterns, qRT-PCR was performed using specific TaqMan probes (Applied Biosystems) for ASPN (Hs00214385_m1), TMSB10 (Hs00363670_m1), KRT5 (Hs00361185_m1), GJB2 (Hs00955889_m1), ENPP2 (Hs00196470_m1), and ST6GAL2 (Hs00383541_m1).	('Hs00363670_m1', 'Var', (143, 156))	('ST6GAL2', 'Gene', (230, 237))	('KRT5', 'Gene', '3852', (159, 163))	('Hs00214385_m1', 'Var', (119, 132))	('ENPP2', 'Gene', '5168', (203, 208))	('ASPN', 'Gene', '54829', (113, 117))	('TMSB10', 'Gene', '9168', (135, 141))	('Hs00196470_m1', 'Var', (210, 223))	('KRT5', 'Gene', (159, 163))	('Hs00383541_m1', 'Var', (239, 252))	('ASPN', 'Gene', (113, 117))	('ENPP2', 'Gene', (203, 208))	('ST6GAL2', 'Gene', '84620', (230, 237))	('TMSB10', 'Gene', (135, 141))	('Hs00955889_m1', 'Var', (187, 200))	('Hs00361185_m1', 'Var', (165, 178))
122187	22514560	Later, it was suggested that low-grade DCIS tends to progress to low grade IDC and, in parallel, high-grade DCIS tends to progress to high-grade IDC.	('IDC', 'Gene', (75, 78))	('low-grade', 'Var', (29, 38))	('IDC', 'Gene', '4000', (145, 148))	('IDC', 'Gene', (145, 148))	('IDC', 'Gene', '4000', (75, 78))
122222	21992187	A recent study of 994 women diagnosed with ductal carcinoma in situ (DCIS) showed that both treatment strategy (BCS alone, BCS with radiation therapy, or mastectomy) and margin status strongly correlated with long-term ipsilateral disease-free survival, but that positive or close margins following the last surgical treatment significantly reduced 5-year and 10-year ipsilateral event-free survival independent of treatment strategy.	('positive', 'Var', (263, 271))	('rat', 'Species', '10116', (427, 430))	('women', 'Species', '9606', (22, 27))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (43, 67))	('ductal carcinoma in situ', 'Disease', (43, 67))	('correlated', 'Reg', (193, 203))	('reduced', 'NegReg', (341, 348))	('ipsilateral event-free survival', 'MPA', (368, 399))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (43, 59))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (50, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (43, 67))	('rat', 'Species', '10116', (104, 107))
122280	21992187	Figure 7 reveals that the slopes for the modified cepstra displayed significant differences for seven of the benign pathology types as compared to the normal breast tissue and carcinoma pathologies.	('modified', 'Var', (41, 49))	('carcinoma pathologies', 'Disease', (176, 197))	('benign', 'Disease', (109, 115))	('carcinoma pathologies', 'Disease', 'MESH:D005598', (176, 197))	('differences', 'Reg', (80, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
122539	26292362	Through a combination of expression analysis and functional testing across multiple BLBC cell populations, we determined that DeltaNp63alpha induces migration by elevating the expression of the EMT program components Slug and Axl.	('elevating', 'PosReg', (162, 171))	('Axl', 'Gene', '558', (226, 229))	('migration', 'CPA', (149, 158))	('Slug', 'Gene', '6591', (217, 221))	('induces', 'PosReg', (141, 148))	('Slug', 'Gene', (217, 221))	('DeltaNp63alpha', 'Chemical', '-', (126, 140))	('DeltaNp63alpha', 'Var', (126, 140))	('expression', 'MPA', (176, 186))	('Axl', 'Gene', (226, 229))
122540	26292362	Interestingly, DeltaNp63alpha also increased the expression of miR205, which can silence ZEB1/2 to prevent the loss of epithelial character caused by EMT induction.	('miR205', 'Gene', (63, 69))	('increased', 'PosReg', (35, 44))	('DeltaNp63alpha', 'Var', (15, 29))	('ZEB1/2', 'Gene', '6935;9839', (89, 95))	('DeltaNp63alpha', 'Chemical', '-', (15, 29))	('expression', 'MPA', (49, 59))	('ZEB1/2', 'Gene', (89, 95))	('miR205', 'Gene', '406988', (63, 69))
122543	26292362	Notably, in an orthotopic tumor model, Slug expression was sufficient to induce collective invasion of E-cadherin expressing BLBC cells.	('Slug', 'Gene', (39, 43))	('collective invasion', 'CPA', (80, 99))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('expression', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('induce', 'PosReg', (73, 79))	('tumor', 'Disease', (26, 31))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', '999', (103, 113))	('Slug', 'Gene', '6591', (39, 43))
122544	26292362	Together, our results illustrate how DeltaNp63alpha can drive breast cancer cell invasion by selectively engaging pro-migratory components of the EMT program while, in parallel, still promoting the retention of epithelial character.	('DeltaNp63alpha', 'Chemical', '-', (37, 51))	('DeltaNp63alpha', 'Var', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('promoting', 'PosReg', (184, 193))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('pro-migratory', 'CPA', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('drive', 'PosReg', (56, 61))	('engaging', 'PosReg', (105, 113))
122558	26292362	Interestingly, DeltaNp63alpha enhances the expression of miR205, which increases BLBC migration rate and can block cells from converting to a mesenchymal state by silencing ZEB1 and ZEB2.	('DeltaNp63alpha', 'Var', (15, 29))	('BLBC migration rate', 'CPA', (81, 100))	('miR205', 'Gene', '406988', (57, 63))	('silencing', 'NegReg', (163, 172))	('DeltaNp63alpha', 'Chemical', '-', (15, 29))	('ZEB1', 'Gene', (173, 177))	('ZEB1', 'Gene', '6935', (173, 177))	('miR205', 'Gene', (57, 63))	('enhances', 'PosReg', (30, 38))	('cells', 'CPA', (115, 120))	('ZEB2', 'Gene', '9839', (182, 186))	('increases', 'PosReg', (71, 80))	('ZEB2', 'Gene', (182, 186))	('expression', 'MPA', (43, 53))	('block', 'NegReg', (109, 114))
122559	26292362	Further investigation revealed that DeltaNp63alpha promoted motility by inducing the transcription factor Slug (SNAI2) and the tyrosine kinase Axl, both of which can contribute to the EMT programs.	('Axl', 'Gene', '558', (143, 146))	('Slug', 'Gene', (106, 110))	('inducing', 'PosReg', (72, 80))	('DeltaNp63alpha', 'Chemical', '-', (36, 50))	('DeltaNp63alpha', 'Var', (36, 50))	('Axl', 'Gene', (143, 146))	('promoted', 'PosReg', (51, 59))	('motility', 'CPA', (60, 68))	('SNAI2', 'Gene', '6591', (112, 117))	('SNAI2', 'Gene', (112, 117))	('Slug', 'Gene', '6591', (106, 110))
122560	26292362	Thus, DeltaNp63alpha confers BLBC cells with a migratory phenotype through inducing a hybrid state in which components of EMT programs promote migration while the parallel activation of a miRNA maintains key features of epithelial character.	('promote', 'PosReg', (135, 142))	('DeltaNp63alpha', 'Var', (6, 20))	('migration', 'CPA', (143, 152))	('DeltaNp63alpha', 'Chemical', '-', (6, 20))	('hybrid', 'MPA', (86, 92))	('inducing', 'Reg', (75, 83))
122563	26292362	HCC1428, HCC1806 and HCC1954 cells were a gift from John Minna (UTSW).	('HCC1806', 'CellLine', 'CVCL:1258', (9, 16))	('HCC1954', 'Gene', (21, 28))	('HCC1954', 'CellLine', 'CVCL:1259', (21, 28))	('HCC1806', 'Var', (9, 16))
122588	26292362	The requirement of DeltaNp63alpha for miR205 expression suggested that DeltaNp63alpha may promote BLBC motility.	('DeltaNp63alpha', 'Chemical', '-', (19, 33))	('DeltaNp63alpha', 'Chemical', '-', (71, 85))	('DeltaNp63alpha', 'Var', (71, 85))	('BLBC motility', 'CPA', (98, 111))	('miR205', 'Gene', '406988', (38, 44))	('promote', 'PosReg', (90, 97))	('miR205', 'Gene', (38, 44))
122593	26292362	Together, these results suggest that DeltaNp63alpha promotes the motile phenotype of BLBC cells through the induction of miR205 (Fig.	('miR205', 'Gene', (121, 127))	('DeltaNp63alpha', 'Chemical', '-', (37, 51))	('DeltaNp63alpha', 'Var', (37, 51))	('promotes', 'PosReg', (52, 60))	('motile phenotype of', 'CPA', (65, 84))	('miR205', 'Gene', '406988', (121, 127))
122601	26292362	Therefore, to determine if factors that contribute to EMT could promote the motile phenotype of hybrid mesenchymal/epithelial BLBC cells, we further investigated the regulation of Slug by DeltaNp63alpha.	('DeltaNp63alpha', 'Var', (188, 202))	('investigated', 'Reg', (149, 161))	('Slug', 'Gene', '6591', (180, 184))	('DeltaNp63alpha', 'Chemical', '-', (188, 202))	('Slug', 'Gene', (180, 184))
122605	26292362	However, MCFDCIS-Slug cells remained dependent on DeltaNp63alpha for migration (Fig.	('DeltaNp63alpha', 'Chemical', '-', (50, 64))	('DeltaNp63alpha', 'Var', (50, 64))	('migration', 'CPA', (69, 78))	('MCFDCIS-Slug', 'CellLine', 'None', (9, 21))
122607	26292362	Our discovery that DeltaNp63alpha could regulate Slug expression suggested that DeltaNp63alpha may promote motility through the regulation of additional genes that can contribute to EMTs.	('DeltaNp63alpha', 'Chemical', '-', (19, 33))	('Slug', 'Gene', '6591', (49, 53))	('motility', 'CPA', (107, 115))	('promote', 'PosReg', (99, 106))	('Slug', 'Gene', (49, 53))	('DeltaNp63alpha', 'Chemical', '-', (80, 94))	('DeltaNp63alpha', 'Var', (80, 94))
122610	26292362	Indeed, DeltaNp63alpha could bind to the Axl promoter in MCFDCIS cells (Fig.	('Axl', 'Gene', '558', (41, 44))	('DeltaNp63alpha', 'Chemical', '-', (8, 22))	('DeltaNp63alpha', 'Var', (8, 22))	('MCFDCIS', 'CellLine', 'None', (57, 64))	('bind', 'Interaction', (29, 33))	('Axl', 'Gene', (41, 44))
122611	26292362	4A) and DeltaNp63alpha was necessary for Axl protein expression in MCFDCIS, HCC1806 and HCC1954 BLBC cells (Fig.	('MCFDCIS', 'CellLine', 'None', (67, 74))	('Axl', 'Gene', '558', (41, 44))	('DeltaNp63alpha', 'Chemical', '-', (8, 22))	('HCC1954', 'Var', (88, 95))	('Axl', 'Gene', (41, 44))	('HCC1954 BLBC', 'CellLine', 'CVCL:1259', (88, 100))	('HCC1806', 'CellLine', 'CVCL:1258', (76, 83))
122616	26292362	Axl siRNAs and a pharmacological inhibitor of Axl, R428, reduced MCFDCIS wound closure, demonstrating that DeltaNp63alpha induced Axl expression contributed to BLBC motility (Fig.	('Axl', 'Gene', (46, 49))	('Axl', 'Gene', '558', (130, 133))	('Axl', 'Gene', '558', (0, 3))	('Axl', 'Gene', (130, 133))	('Axl', 'Gene', (0, 3))	('MCFDCIS', 'CellLine', 'None', (65, 72))	('Axl', 'Gene', '558', (46, 49))	('reduced', 'NegReg', (57, 64))	('DeltaNp63alpha', 'Chemical', '-', (107, 121))	('DeltaNp63alpha', 'Var', (107, 121))
122620	26292362	DeltaNp63alpha can promote the retention of epithelial character through inducing miR205, which can silence ZEB1 and ZEB2 to prevent a conversion to a mesenchymal-state.	('ZEB1', 'Gene', (108, 112))	('promote', 'PosReg', (19, 26))	('inducing', 'Reg', (73, 81))	('miR205', 'Gene', '406988', (82, 88))	('silence', 'NegReg', (100, 107))	('ZEB2', 'Gene', (117, 121))	('ZEB2', 'Gene', '9839', (117, 121))	('miR205', 'Gene', (82, 88))	('DeltaNp63alpha', 'Var', (0, 14))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('prevent', 'NegReg', (125, 132))	('ZEB1', 'Gene', '6935', (108, 112))	('conversion', 'CPA', (135, 145))
122622	26292362	Similar to observations in prostate and bladder cancer, DeltaNp63alpha and miR205 were also expressed at a low level in mesenchymal-like breast cancer cells (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR205', 'Gene', '406988', (75, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('miR205', 'Gene', (75, 81))	('DeltaNp63alpha', 'Chemical', '-', (56, 70))	('DeltaNp63alpha', 'Var', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
122623	26292362	These results suggest that high levels DeltaNp63alpha and miR205 contribute to the retention of epithelial character in BLBC cells and that low levels of DeltaNp63alpha and miR205 are necessary for breast cancer cells to adopt a mesenchymal state.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('miR205', 'Gene', '406988', (173, 179))	('DeltaNp63alpha', 'Chemical', '-', (39, 53))	('DeltaNp63alpha', 'Var', (39, 53))	('miR205', 'Gene', (173, 179))	('DeltaNp63alpha', 'Chemical', '-', (154, 168))	('miR205', 'Gene', '406988', (58, 64))	('DeltaNp63alpha', 'Var', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('miR205', 'Gene', (58, 64))	('breast cancer', 'Disease', (198, 211))
122626	26292362	Together these results suggest that DeltaNp63alpha can increase Slug and Axl expression to promote motility, while simultaneously inducing miR205, which can silence signaling pathways that suppress epithelial traits (Fig.	('Slug', 'Gene', (64, 68))	('inducing', 'Reg', (130, 138))	('expression', 'MPA', (77, 87))	('increase', 'PosReg', (55, 63))	('miR205', 'Gene', (139, 145))	('promote', 'PosReg', (91, 98))	('Slug', 'Gene', '6591', (64, 68))	('silence', 'NegReg', (157, 164))	('DeltaNp63alpha', 'Chemical', '-', (36, 50))	('DeltaNp63alpha', 'Var', (36, 50))	('Axl', 'Gene', '558', (73, 76))	('signaling pathways', 'Pathway', (165, 183))	('epithelial traits', 'CPA', (198, 215))	('miR205', 'Gene', '406988', (139, 145))	('Axl', 'Gene', (73, 76))	('motility', 'CPA', (99, 107))	('suppress', 'NegReg', (189, 197))
122627	26292362	We next determined if DeltaNp63alpha was sufficient to confer intrinsically nonmotile HCC1428 LBC cells with a migratory phenotype.	('HCC1428 LBC', 'CellLine', 'CVCL:1252', (86, 97))	('confer', 'Reg', (55, 61))	('DeltaNp63alpha', 'Chemical', '-', (22, 36))	('DeltaNp63alpha', 'Var', (22, 36))	('HCC1428', 'Gene', (86, 93))
122628	26292362	Exogenous DeltaNp63alpha increased miR205 expression (Fig.	('miR205', 'Gene', (35, 41))	('increased', 'PosReg', (25, 34))	('miR205', 'Gene', '406988', (35, 41))	('DeltaNp63alpha', 'Chemical', '-', (10, 24))	('DeltaNp63alpha', 'Var', (10, 24))
122629	26292362	5A), indicating that DeltaNp63alpha was capable of interacting with DNA and promoting transcription in LBC cells.	('interacting', 'Interaction', (51, 62))	('promoting', 'PosReg', (76, 85))	('transcription', 'MPA', (86, 99))	('DeltaNp63alpha', 'Chemical', '-', (21, 35))	('DeltaNp63alpha', 'Var', (21, 35))
122630	26292362	However, DeltaNp63alpha overexpression did not increase Slug and Axl protein levels (Fig.	('DeltaNp63alpha', 'Var', (9, 23))	('DeltaNp63alpha', 'Chemical', '-', (9, 23))	('Axl', 'Gene', '558', (65, 68))	('Slug', 'Gene', '6591', (56, 60))	('Axl', 'Gene', (65, 68))	('Slug', 'Gene', (56, 60))
122632	26292362	This suggested that the high level of endogenous miR203a in HCC1428 cells may prevent DeltaNp63alpha from inducing Slug and Axl expression, thereby impinging on the ability of DeltaNp63alpha to induce a motile state.	('DeltaNp63alpha', 'Var', (86, 100))	('prevent', 'NegReg', (78, 85))	('inducing', 'Reg', (106, 114))	('Axl', 'Gene', '558', (124, 127))	('miR203a', 'Gene', (49, 56))	('impinging', 'NegReg', (148, 157))	('Slug', 'Gene', '6591', (115, 119))	('DeltaNp63alpha', 'Chemical', '-', (176, 190))	('DeltaNp63alpha', 'Chemical', '-', (86, 100))	('Slug', 'Gene', (115, 119))	('miR203a', 'Gene', '406986', (49, 56))	('Axl', 'Gene', (124, 127))
122633	26292362	To test this possibility, we measured the expression of Slug and Axl in MCFDCIS cells expressing exogenous DeltaNp63alpha (Fig.	('Axl', 'Gene', '558', (65, 68))	('expression', 'MPA', (42, 52))	('Slug', 'Gene', '6591', (56, 60))	('MCFDCIS', 'CellLine', 'None', (72, 79))	('DeltaNp63alpha', 'Chemical', '-', (107, 121))	('Axl', 'Gene', (65, 68))	('Slug', 'Gene', (56, 60))	('DeltaNp63alpha', 'Var', (107, 121))
122637	26292362	Together, these results indicate that the low expression of miR203a in BLBC cells permits DeltaNp63alpha to induce Slug and Axl expression.	('DeltaNp63alpha', 'Chemical', '-', (90, 104))	('DeltaNp63alpha', 'Var', (90, 104))	('Axl', 'Gene', '558', (124, 127))	('miR203a', 'Gene', '406986', (60, 67))	('Slug', 'Gene', '6591', (115, 119))	('induce', 'PosReg', (108, 114))	('Slug', 'Gene', (115, 119))	('miR203a', 'Gene', (60, 67))	('Axl', 'Gene', (124, 127))
122638	26292362	Thus, the miRNA content of a cell may influence the expression of DeltaNp63alpha target genes and the nature of DeltaNp63alpha induced cell phenotypes (Fig.	('DeltaNp63alpha', 'Chemical', '-', (112, 126))	('DeltaNp63alpha', 'Var', (112, 126))	('influence', 'Reg', (38, 47))	('expression', 'MPA', (52, 62))	('DeltaNp63alpha', 'Chemical', '-', (66, 80))
122639	26292362	We next investigated how DeltaNp63alpha expression correlated with breast cancer patient survival time.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('patient', 'Species', '9606', (81, 88))	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('DeltaNp63alpha', 'Var', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))	('correlated', 'Reg', (51, 61))
122640	26292362	Interestingly, high DeltaNp63alpha expression correlated with shorter overall survival time in ER-/HER2- patients (Fig.	('high', 'Var', (15, 19))	('shorter', 'NegReg', (62, 69))	('patients', 'Species', '9606', (105, 113))	('ER', 'Gene', '2099', (100, 102))	('DeltaNp63alpha', 'Protein', (20, 34))	('overall survival time', 'MPA', (70, 91))	('expression', 'MPA', (35, 45))	('HER2', 'Gene', (99, 103))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('HER2', 'Gene', '2064', (99, 103))	('ER', 'Gene', '2099', (95, 97))
122641	26292362	6A); however, no correlation between DeltaNp63alpha expression and ER+/HER2- patient survival was observed (Fig.	('DeltaNp63alpha', 'Chemical', '-', (37, 51))	('ER', 'Gene', '2099', (72, 74))	('DeltaNp63alpha', 'Var', (37, 51))	('HER2', 'Gene', (71, 75))	('HER2', 'Gene', '2064', (71, 75))	('ER', 'Gene', '2099', (67, 69))	('patient', 'Species', '9606', (77, 84))
122642	26292362	These clinical observations are consistent with our results showing that DeltaNp63alpha can contribute to the motile state of ER-/HER2- breast cancer cells, which frequently are classified as BLBC tumors.	('DeltaNp63alpha', 'Chemical', '-', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('DeltaNp63alpha', 'Var', (73, 87))	('contribute', 'Reg', (92, 102))	('BLBC tumors', 'Disease', 'MESH:D009369', (192, 203))	('ER', 'Gene', '2099', (131, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('ER', 'Gene', '2099', (126, 128))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('HER2- breast cancer', 'Disease', 'MESH:D001943', (130, 149))	('HER2- breast cancer', 'Disease', (130, 149))	('motile state', 'CPA', (110, 122))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('BLBC tumors', 'Disease', (192, 203))
122649	26292362	Consistent with this possibility, myoepithelial cells, basal mammary epithelial cells and mammary stem cells, all interact with ECM components and express DeltaNp63alpha, Slug and miR205.	('miR205', 'Gene', (180, 186))	('express', 'Reg', (147, 154))	('myoepithelial', 'Disease', 'MESH:D009208', (34, 47))	('Slug', 'Gene', (171, 175))	('ECM', 'Gene', '22915', (128, 131))	('ECM', 'Gene', (128, 131))	('miR205', 'Gene', '406988', (180, 186))	('myoepithelial', 'Disease', (34, 47))	('DeltaNp63alpha', 'Chemical', '-', (155, 169))	('DeltaNp63alpha', 'Var', (155, 169))	('Slug', 'Gene', '6591', (171, 175))
122651	26292362	6B), suggesting that the induction of DeltaNp63alpha and Slug was contributing to the transition from DCIS to invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Slug', 'Gene', (57, 61))	('contributing', 'Reg', (66, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('invasive breast cancer', 'Disease', (110, 132))	('DeltaNp63alpha', 'Chemical', '-', (38, 52))	('DeltaNp63alpha', 'Var', (38, 52))	('Slug', 'Gene', '6591', (57, 61))	('invasive breast cancer', 'Disease', 'MESH:D001943', (110, 132))	('DCIS', 'Disease', (102, 106))
122653	26292362	This may be because DeltaNp63alpha and Slug were both necessary for long-term cell growth (Supplementary Fig.	('Slug', 'Gene', (39, 43))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('Slug', 'Gene', '6591', (39, 43))	('DeltaNp63alpha', 'Var', (20, 34))
122655	26292362	We next determined if the DeltaNp63alpha pathway was sufficient to induce invasion.	('DeltaNp63alpha', 'Var', (26, 40))	('DeltaNp63alpha', 'Chemical', '-', (26, 40))	('induce', 'PosReg', (67, 73))	('invasion', 'CPA', (74, 82))
122659	26292362	Because DeltaNp63alpha was potentially promoting invasion by increasing Slug expression, we determined if Slug could induce invasion.	('DeltaNp63alpha', 'Chemical', '-', (8, 22))	('increasing', 'PosReg', (61, 71))	('DeltaNp63alpha', 'Var', (8, 22))	('Slug', 'Gene', (106, 110))	('Slug', 'Gene', '6591', (72, 76))	('invasion', 'CPA', (49, 57))	('promoting', 'PosReg', (39, 48))	('Slug', 'Gene', (72, 76))	('Slug', 'Gene', '6591', (106, 110))
122664	26292362	6C), consistent with DeltaNp63alpha being essential for Slug induced motility and invasion.	('invasion', 'CPA', (82, 90))	('Slug', 'Gene', '6591', (56, 60))	('DeltaNp63alpha', 'Chemical', '-', (21, 35))	('DeltaNp63alpha', 'Var', (21, 35))	('Slug', 'Gene', (56, 60))
122665	26292362	It is possible that DeltaNp63alpha expression is increased when the MCFDCIS cells come in contact with the ECM, or that Slug contributes to the induction of DeltaNp63alpha expression in vivo.	('DeltaNp63alpha', 'Gene', (20, 34))	('Slug', 'Gene', (120, 124))	('increased', 'PosReg', (49, 58))	('MCFDCIS', 'CellLine', 'None', (68, 75))	('ECM', 'Gene', '22915', (107, 110))	('expression', 'MPA', (35, 45))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('DeltaNp63alpha', 'Chemical', '-', (157, 171))	('DeltaNp63alpha', 'Var', (157, 171))	('ECM', 'Gene', (107, 110))	('Slug', 'Gene', '6591', (120, 124))
122668	26292362	DeltaNp63alpha promoted migration by inducing the expression of Slug and Axl, two genes that can facilitate EMT.	('Slug', 'Gene', (64, 68))	('migration', 'CPA', (24, 33))	('promoted', 'PosReg', (15, 23))	('Slug', 'Gene', '6591', (64, 68))	('Axl', 'Gene', '558', (73, 76))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('inducing', 'PosReg', (37, 45))	('DeltaNp63alpha', 'Var', (0, 14))	('Axl', 'Gene', (73, 76))	('expression', 'MPA', (50, 60))
122669	26292362	Interestingly, DeltaNp63alpha also directly increased the expression miR205, which can enhance the rate of BLBC motility and defend against the loss of epithelial traits.	('miR205', 'Gene', (69, 75))	('DeltaNp63alpha', 'Var', (15, 29))	('DeltaNp63alpha', 'Chemical', '-', (15, 29))	('enhance', 'PosReg', (87, 94))	('increased', 'PosReg', (44, 53))	('miR205', 'Gene', '406988', (69, 75))	('BLBC motility', 'CPA', (107, 120))
122670	26292362	Thus, DeltaNp63alpha promoted motility through the induction of a hybrid mesenchymal/epithelial state.	('DeltaNp63alpha', 'Chemical', '-', (6, 20))	('DeltaNp63alpha', 'Var', (6, 20))	('promoted', 'PosReg', (21, 29))	('motility', 'CPA', (30, 38))
122676	26292362	Interestingly, because a mesenchymal phenotype can be incompatible with growth in distant tissues, the ability of DeltaNp63alpha to confer migratory ability through the induction of a hybrid mesenchymal/epithelial state may promote the development of metastasis more potently than signaling mechanisms that induce a complete and sustained EMT.	('development', 'CPA', (236, 247))	('DeltaNp63alpha', 'Chemical', '-', (114, 128))	('DeltaNp63alpha', 'Var', (114, 128))	('promote', 'PosReg', (224, 231))	('metastasis', 'CPA', (251, 261))	('migratory ability', 'CPA', (139, 156))
122681	22032724	Mutations in BRCA1 are associated with an increased risk for breast cancer (up to 80% lifetime risk) and ovarian cancer (up to 50%).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA1', 'Gene', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('ovarian cancer', 'Disease', (105, 119))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (23, 33))	('BRCA1', 'Gene', '672', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
122685	22032724	In this study, we used both single-end and paired-end sequencing strategies to discover gene fusions in breast cancer transcriptomes with BRCA1 mutations.	('BRCA1', 'Gene', '672', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1', 'Gene', (138, 143))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('mutations', 'Var', (144, 153))
122686	22032724	Our findings suggest that while gene fusions are present in some BRCA1-mutated breast cancers, they are infrequent and not recurrent.	('breast cancers', 'Phenotype', 'HP:0003002', (79, 93))	('BRCA1', 'Gene', '672', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancers', 'Disease', 'MESH:D001943', (79, 93))	('BRCA1', 'Gene', (65, 70))	('breast cancers', 'Disease', (79, 93))	('gene fusions', 'Var', (32, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))
122690	22032724	Mutations in BRCA1 (and BRCA2) confer a high risk for breast cancer, with a lifetime risk of up to 80%.	('breast cancer', 'Disease', (54, 67))	('BRCA2', 'Gene', '675', (24, 29))	('BRCA1', 'Gene', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRCA2', 'Gene', (24, 29))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('BRCA1', 'Gene', '672', (13, 18))
122691	22032724	BRCA1 mutations also confer a medium to high risk of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('BRCA1', 'Gene', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('ovarian cancer', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BRCA1', 'Gene', '672', (0, 5))	('mutations', 'Var', (6, 15))
122697	22032724	Recurrent gene fusions have been implicated in some forms of breast cancer, such as ETV6-NTRK3 in secretory breast ductal carcinoma.	('NTRK3', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gene fusions', 'Var', (10, 22))	('breast cancer', 'Disease', (61, 74))	('implicated', 'Reg', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('breast ductal carcinoma', 'Disease', (108, 131))	('NTRK3', 'Gene', '4916', (89, 94))	('ETV6', 'Gene', (84, 88))	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (108, 131))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (108, 131))	('ETV6', 'Gene', '2120', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (115, 131))
122701	22032724	When BRCA1 is deficient in HR, evidence supporting increased activity of a second repair pathway, non-homologous end joining (NHEJ), has been shown.	('non-homologous', 'MPA', (98, 112))	('increased', 'PosReg', (51, 60))	('BRCA1', 'Gene', '672', (5, 10))	('deficient', 'Var', (14, 23))	('activity', 'MPA', (61, 69))	('BRCA1', 'Gene', (5, 10))
122702	22032724	While the role of BRCA1 in NHEJ is not well known, NHEJ is more vulnerable to errors as it involves repairing DSBs by incorporating or deleting nucleotides at the site of breakage to make the two broken ends compatible for ligation.	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (18, 23))	('incorporating', 'Reg', (118, 131))	('deleting', 'Var', (135, 143))	('nucleotides', 'MPA', (144, 155))
122703	22032724	Errors resulting from NHEJ can lead to increased chromosomal aberrations, translocations, and unchecked DNA damage.	('increased chromosomal aberrations', 'Phenotype', 'HP:0040012', (39, 72))	('translocations', 'CPA', (74, 88))	('Errors', 'Var', (0, 6))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (49, 72))	('NHEJ', 'Gene', (22, 26))	('increased', 'PosReg', (39, 48))	('chromosomal aberrations', 'Disease', (49, 72))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (49, 72))
122704	22032724	investigated genomic rearrangements in 24 breast cancer genomes with and without BRCA1 mutations and found genomic rearrangements to be significantly widespread.	('BRCA1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('BRCA1', 'Gene', '672', (81, 86))	('mutations', 'Var', (87, 96))
122705	22032724	Hence, we hypothesized that deficiencies in BRCA1 would cause increased chromosomal instability in a tumor cell due to impaired DNA repair pathways and NHEJ dysfunction.	('increased', 'PosReg', (62, 71))	('BRCA1', 'Gene', (44, 49))	('NHEJ dysfunction', 'Disease', 'MESH:D006331', (152, 168))	('deficiencies', 'Var', (28, 40))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (62, 95))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('DNA repair pathways', 'Pathway', (128, 147))	('NHEJ dysfunction', 'Disease', (152, 168))	('impaired', 'NegReg', (119, 127))	('BRCA1', 'Gene', '672', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('chromosomal instability', 'CPA', (72, 95))
122711	22032724	SUM149PT, SEC1 and SEC2 were sequenced at the Institute of Cancer Research (36 bp, 54 bp and 54 bp PE, respectively).	('SUM149PT', 'Var', (0, 8))	('SEC1', 'Gene', (10, 14))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Cancer', 'Disease', (59, 65))	('SEC2', 'Gene', (19, 23))	('SEC1', 'Gene', '653677', (10, 14))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('SEC2', 'Gene', '2524', (19, 23))
122712	22032724	SUM1315O2, HCC3153, HCC2337, T92, T50, T160 and MCF10A were sequenced at the McGill University and Genome Quebec Innovation Centre (76 bp PE per sample).	('HCC3153', 'CellLine', 'CVCL:3377', (11, 18))	('MCF10A', 'CellLine', 'CVCL:0598', (48, 54))	('T160', 'Gene', '6749', (39, 43))	('MCF10A', 'Gene', (48, 54))	('HCC2337', 'Gene', (20, 27))	('T160', 'Gene', (39, 43))	('HCC3153', 'Gene', (11, 18))	('SUM1315O2', 'Var', (0, 9))	('T92', 'Var', (29, 32))
122714	22032724	Due to poor base quality at the 3' end of SUM1315O2 and HCC3153, reads in these samples were trimmed by 40 bp from the 3' end to produce 36 bp high quality PE reads.	('base quality', 'MPA', (12, 24))	('HCC3153', 'Gene', (56, 63))	('SUM1315O2', 'Var', (42, 51))	('HCC3153', 'CellLine', 'CVCL:3377', (56, 63))
122718	22032724	Sequence data of the breast cancer cell lines (HCC1937, SUM149PT, SUM1315O2, HCC3153, HCC2337 and MCF10A) from this study has been deposited to the NCBI Sequence Read Archive (http://trace.ncbi.nlm.nih.gov/Traces/sra/sra.cgi) under accession no.	('sra', 'Gene', '10011', (213, 216))	('sra', 'Gene', (213, 216))	('HCC2337', 'Var', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('SUM149PT', 'Var', (56, 64))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('HCC1937', 'CellLine', 'CVCL:0290', (47, 54))	('sra', 'Gene', '10011', (217, 220))	('sra', 'Gene', (217, 220))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('HCC3153', 'CellLine', 'CVCL:3377', (77, 84))	('MCF10A', 'CellLine', 'CVCL:0598', (98, 104))
122721	22032724	This cell line has been previously found to have a translocation involving exon 2 of NFIA on chromosome 1 joining with exon 5 of EHF on chromosome 11 using massively parallel DNA sequencing.	('NFIA', 'Gene', '4774', (85, 89))	('NFIA', 'Gene', (85, 89))	('translocation', 'Var', (51, 64))
122726	22032724	This fusion is caused by a balanced translocation, t(12;15)(p13;q25), joining exon 5 of ETV6 and exon 14 of NTRK3 and is recurrent in this cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ETV6', 'Gene', '2120', (88, 92))	('NTRK3', 'Gene', '4916', (108, 113))	('t(12;15)(p13;q25', 'Var', (51, 67))	('caused by', 'Reg', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('t(12;15)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (51, 68))	('NTRK3', 'Gene', (108, 113))	('ETV6', 'Gene', (88, 92))	('cancer', 'Disease', (139, 145))
122735	22032724	A summary of the number of fusions found in each sample is shown in Table 2 In total, we found four candidates in samples with BRCA1 mutations that were supported by both misaligning PE reads and individual fusion junction-spanning reads.	('BRCA1', 'Gene', '672', (127, 132))	('mutations', 'Var', (133, 142))	('BRCA1', 'Gene', (127, 132))
122737	22032724	We identified a novel in-frame interchromosomal fusion transcript in SUM149PT involving exon 6 of MTAP on chromosome 9 joining with exon 3 of PCDH7 on chromosome 4.	('SUM149PT', 'Var', (69, 77))	('MTAP', 'Gene', (98, 102))	('PCDH7', 'Gene', (142, 147))	('MTAP', 'Gene', '4507', (98, 102))	('PCDH7', 'Gene', '5099', (142, 147))
122739	22032724	Interestingly, a deletion resulting in a fusion protein between MTAP and tumor suppressor gene encoding p15INK5B was reported in a glioma xenograft as well as other malignant cell lines.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('glioma xenograft', 'Disease', (131, 147))	('MTAP', 'Gene', (64, 68))	('glioma xenograft', 'Disease', 'MESH:D005910', (131, 147))	('tumor', 'Disease', (73, 78))	('deletion', 'Var', (17, 25))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('fusion protein', 'MPA', (41, 55))	('MTAP', 'Gene', '4507', (64, 68))	('p15INK5B', 'Gene', (104, 112))
122757	22032724	: 1) a 5266dupC germline mutation in BRCA1; 2) a somatic deletion of PTEN; and 3) a somatic C->T substitution in TP53 (data not shown).	('5266dupC', 'Var', (7, 15))	('PTEN', 'Gene', '5728', (69, 73))	('PTEN', 'Gene', (69, 73))	('deletion', 'Var', (57, 65))	('TP53', 'Gene', '7157', (113, 117))	('BRCA1', 'Gene', '672', (37, 42))	('C->T', 'Var', (92, 96))	('TP53', 'Gene', (113, 117))	('5266dupC', 'Mutation', 'rs80357906', (7, 15))	('BRCA1', 'Gene', (37, 42))
122758	22032724	Our analysis of MTAP-PCHD7 showed that both genes were not highly expressed in SUM149PT compared to the other samples.	('SUM149PT', 'Var', (79, 87))	('MTAP', 'Gene', (16, 20))	('MTAP', 'Gene', '4507', (16, 20))
122768	22032724	For both MTAP and PCDH7 in SUM149PT, copy number losses were reported in BAC clones nearest these genes.	('MTAP', 'Gene', (9, 13))	('PCDH7', 'Gene', (18, 23))	('MTAP', 'Gene', '4507', (9, 13))	('PCDH7', 'Gene', '5099', (18, 23))	('SUM149PT', 'Var', (27, 35))	('losses', 'NegReg', (49, 55))
122773	22032724	In addition to identifying previously described gene fusions, we identified three novel in-frame fusions, MTAP-PCDH7 in SUM149PT, WWC1-ADRBK2 in HCC3153 and ADNP-C20orf132 in one primary tumor.	('ADNP', 'Gene', '23394', (157, 161))	('C20orf132', 'Gene', '140699', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ADRBK2', 'Gene', (135, 141))	('ADNP', 'Gene', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('MTAP', 'Gene', '4507', (106, 110))	('C20orf132', 'Gene', (162, 171))	('HCC3153', 'CellLine', 'CVCL:3377', (145, 152))	('tumor', 'Disease', (187, 192))	('PCDH7', 'Gene', (111, 116))	('MTAP', 'Gene', (106, 110))	('WWC1', 'Gene', '23286', (130, 134))	('ADRBK2', 'Gene', '157', (135, 141))	('WWC1', 'Gene', (130, 134))	('SUM149PT', 'Var', (120, 128))	('PCDH7', 'Gene', '5099', (111, 116))
122776	22032724	It is well understood that driver gene fusions are typically found to be recurrent, such as BCR-ABL, ETV6-NTRK3, and TMPRSS2-ERG in prostate cancer, and consequently they are ideal targets for therapeutic intervention.	('prostate cancer', 'Disease', (132, 147))	('NTRK3', 'Gene', (106, 111))	('TMPRSS2', 'Gene', '7113', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BCR-ABL', 'Gene', (92, 99))	('BCR-ABL', 'Gene', '25', (92, 99))	('ETV6', 'Gene', (101, 105))	('fusions', 'Var', (39, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('ERG', 'Gene', '2078', (125, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('ERG', 'Gene', (125, 128))	('TMPRSS2', 'Gene', (117, 124))	('NTRK3', 'Gene', '4916', (106, 111))	('ETV6', 'Gene', '2120', (101, 105))
122783	22032724	For this study, we focused our analysis on a collection of breast cancer samples with BRCA1 mutations.	('BRCA1', 'Gene', '672', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('BRCA1', 'Gene', (86, 91))	('mutations', 'Var', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))
122790	22032724	In a study by Stephens et al., gene fusions were identified in breast cancer genomes, but none of them were recurrent.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gene fusions', 'Var', (31, 43))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))
122791	22032724	We hypothesized that mutations in BRCA1 may increase the frequency of chromosomal aberrations due to defects in the DNA repair and NHEJ pathways.	('BRCA1', 'Gene', '672', (34, 39))	('DNA repair', 'Pathway', (116, 126))	('defects', 'NegReg', (101, 108))	('BRCA1', 'Gene', (34, 39))	('increase', 'PosReg', (44, 52))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (70, 93))	('chromosomal aberrations', 'Disease', (70, 93))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (70, 93))	('NHEJ pathways', 'Pathway', (131, 144))	('mutations', 'Var', (21, 30))
122793	22032724	However, this does not discount other genomic instabilities and lesions that arise from BRCA1 mutations and are not detected by RNA-Seq.	('BRCA1', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (88, 93))	('mutations', 'Var', (94, 103))
122801	22032724	Thus, the discovery and cataloguing of gene fusions will play an important role in the clinical treatment of solid tumours.	('solid tumours', 'Disease', (109, 122))	('gene fusions', 'Var', (39, 51))	('solid tumours', 'Disease', 'MESH:D009369', (109, 122))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))
122873	21542915	When the tumor suppressor gene Pten was deleted in Nkx3-1 positive luminal epithelial cells, the populations rapidly formed high-grade intraepithelial neoplasm and carcinoma after androgen mediated regeneration of the prostate.	('Nkx3-1', 'Gene', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('carcinoma', 'Disease', (164, 173))	('intraepithelial neoplasm', 'Disease', 'MESH:D002278', (135, 159))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('intraepithelial neoplasm', 'Phenotype', 'HP:0032187', (135, 159))	('Nkx3-1', 'Gene', '4824', (51, 57))	('intraepithelial neoplasm', 'Disease', (135, 159))	('tumor', 'Disease', (9, 14))	('carcinoma', 'Disease', 'MESH:D002277', (164, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('deleted', 'Var', (40, 47))	('Pten', 'Gene', '5728', (31, 35))	('Pten', 'Gene', (31, 35))	('neoplasm', 'Phenotype', 'HP:0002664', (151, 159))
122874	21542915	Therefore, Nkx3-1 positive luminal epithelial cells were a type of prostate stem cells and mutation of tumor suppressor genes would lead to prostate carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (91, 99))	('tumor', 'Disease', (103, 108))	('prostate carcinogenesis', 'Disease', (140, 163))	('Nkx3-1', 'Gene', '4824', (11, 17))	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (140, 163))	('Nkx3-1', 'Gene', (11, 17))	('lead to', 'Reg', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
122877	21542915	Deletion of Apc or activation of endogenous Wnt signaling in such intestinal stem cells led to their transformation to abnormal stem cells, resulting in intestinal neoplasm.	('transformation', 'MPA', (101, 115))	('resulting in', 'Reg', (140, 152))	('Apc', 'Gene', (12, 15))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('intestinal neoplasm', 'Disease', (153, 172))	('Apc', 'Gene', '324', (12, 15))	('intestinal neoplasm', 'Disease', 'MESH:D007414', (153, 172))	('Deletion', 'Var', (0, 8))
122878	21542915	However, when the same mutations occurred in transit-amplifying cells without unlimited self-renewal capacity, the induced adenomas grew slowly and disappeared after long observation.	('mutations', 'Var', (23, 32))	('slowly', 'NegReg', (137, 143))	('adenomas', 'Disease', (123, 131))	('adenomas', 'Disease', 'MESH:D000236', (123, 131))
122882	21542915	These variants expressed higher levels of pluripotency markers Oct4 and SSEA3, less depended on exogenous growth factors, had decreased differentiation capacity in either hematopoietic or neural conditions, and had increased frequency of teratoma initiating cells, however, their teratoma cells did not metastasize to other organs upon in vivo transplantation.	('decreased', 'NegReg', (126, 135))	('variants', 'Var', (6, 14))	('pluripotency', 'Disease', 'None', (42, 54))	('teratoma', 'Phenotype', 'HP:0009792', (238, 246))	('Oct4', 'Gene', (63, 67))	('teratoma', 'Disease', 'MESH:D013724', (238, 246))	('SSEA3', 'Gene', (72, 77))	('teratoma', 'Phenotype', 'HP:0009792', (280, 288))	('teratoma', 'Disease', 'MESH:D013724', (280, 288))	('increased', 'PosReg', (215, 224))	('Oct4', 'Gene', '5460', (63, 67))	('higher', 'PosReg', (25, 31))	('teratoma', 'Disease', (238, 246))	('differentiation capacity', 'CPA', (136, 160))	('pluripotency', 'Disease', (42, 54))	('teratoma', 'Disease', (280, 288))
122883	21542915	Therefore, variant hES cells undergo neoplastic progression and may be the origin of malignant teratoma stem cells.	('neoplastic progression', 'CPA', (37, 59))	('teratoma', 'Phenotype', 'HP:0009792', (95, 103))	('malignant teratoma', 'Disease', (85, 103))	('malignant teratoma', 'Disease', 'MESH:D013724', (85, 103))	('variant', 'Var', (11, 18))	('undergo', 'Reg', (29, 36))
122886	21542915	Guibal et al showed that in a murine model of acute promyelocytic leukemia (APL), a population of committed myeloid cells (CD34+, c-kit+, FcgammaRIII/II+, Gr1int) demonstrated enhanced self-renewal capacity through the down-regulation of the transcription factor CCAAT/enhancer binding protein-alpha(C/EBP-alpha) and were capable of efficiently generating leukemia in recipient mice.	('C/EBP-alpha', 'Gene', (300, 311))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (46, 74))	('leukemia', 'Disease', (66, 74))	('enhanced', 'PosReg', (176, 184))	('leukemia', 'Disease', 'MESH:D007938', (66, 74))	('C/EBP-alpha', 'Gene', '12606', (300, 311))	('leukemia', 'Phenotype', 'HP:0001909', (356, 364))	('APL', 'Phenotype', 'HP:0004836', (76, 79))	('mice', 'Species', '10090', (378, 382))	('murine', 'Species', '10090', (30, 36))	('APL', 'Disease', 'MESH:D015473', (76, 79))	('down-regulation', 'NegReg', (219, 234))	('CCAAT/enhancer binding protein-alpha', 'Gene', (263, 299))	('leukemia', 'Disease', (356, 364))	('leukemia', 'Disease', 'MESH:D007938', (356, 364))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (46, 74))	('CD34+', 'Var', (123, 128))	('self-renewal capacity', 'CPA', (185, 206))	('CCAAT/enhancer binding protein-alpha', 'Gene', '12606', (263, 299))	('acute promyelocytic leukemia', 'Disease', (46, 74))	('APL', 'Disease', (76, 79))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))
122905	21542915	Hermann et al reported that CD133+CXCR4+ subsets determined the migrating phenotype of pancreatic cancer, although both CD133+CXCR4+ and CD133+CXCR4- pancreatic cancer stem cells could form pancreatic cancer when transplanted into athymic mice.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('CD133+CXCR4-', 'Var', (137, 149))	('pancreatic cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('CD133+CXCR4+', 'Var', (120, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('pancreatic cancer', 'Disease', (150, 167))	('mice', 'Species', '10090', (239, 243))
122907	21542915	Furthermore, removal of CD133+CXCR4+ subset from CD133+ cancer stem cells could disrupt the metastasis of pancreatic cancer, but did not affect tumorigenesis in primary organ.	('CD133+CXCR4+', 'Var', (24, 36))	('tumor', 'Disease', (144, 149))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (92, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('metastasis of pancreatic cancer', 'Disease', (92, 123))	('CD133+', 'Gene', (49, 55))	('disrupt', 'NegReg', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
122908	21542915	Collectively, these data suggest that CD133+CXCR4+ cancer stem cells determine the metastasis and represent the migrating cancer stem cells of pancreatic cancer.	('CD133+CXCR4+', 'Var', (38, 50))	('metastasis', 'CPA', (83, 93))	('cancer', 'Disease', (122, 128))	('determine', 'Reg', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))
122951	33255756	DKC1 Overexpression Induces a More Aggressive Cellular Behavior and Increases Intrinsic Ribosomal Activity in Immortalized Mammary Gland Cells Dyskerin is a nucleolar protein involved in the modification and processing of ribosomal RNA and in the stabilization of the telomerase RNA component.	('Aggressive Cellular', 'CPA', (35, 54))	('More', 'PosReg', (30, 34))	('DKC1', 'Gene', (0, 4))	('Overexpression', 'Var', (5, 19))	('Increases', 'PosReg', (68, 77))	('Intrinsic Ribosomal Activity', 'MPA', (78, 106))	('DKC1', 'Gene', '1736', (0, 4))
122953	33255756	We firstly confirmed the correlation between high dyskerin expression with patients' shorter survival.	('shorter', 'NegReg', (85, 92))	('patients', 'Species', '9606', (75, 83))	('expression', 'MPA', (59, 69))	('high', 'Var', (45, 49))	('dyskerin', 'Chemical', '-', (50, 58))
122958	33255756	Loss of function mutations in DKC1 causes X-linked dyskeratosis congenita, which is characterized by a failure of proliferating tissues and increased susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('X-linked dyskeratosis congenita', 'Disease', 'MESH:D019871', (42, 73))	('X-linked dyskeratosis congenita', 'Disease', (42, 73))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('DKC1', 'Gene', (30, 34))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Disease', (168, 174))	('DKC1', 'Gene', '1736', (30, 34))	('mutations', 'Var', (17, 26))
122960	33255756	We observed that patients with primary breast cancers with high dyskerin levels are more frequently characterized by shorter survival rates and positive lymph node status than those with tumors with a lower dyskerin expression.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('survival rates', 'CPA', (125, 139))	('primary breast cancers', 'Disease', (31, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('primary breast cancers', 'Disease', 'MESH:D001943', (31, 53))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('shorter', 'NegReg', (117, 124))	('dyskerin', 'Chemical', '-', (207, 215))	('high', 'Var', (59, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('dyskerin', 'Chemical', '-', (64, 72))	('patients', 'Species', '9606', (17, 25))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
122962	33255756	Contextually, DKC1 overexpression led to an upregulation of some snoRNAs, including SNORA67 and a significantly increased U1445 modification on 18S rRNA, the known target of SNORA67.	('overexpression', 'PosReg', (19, 33))	('SNORA67', 'Gene', '26781', (174, 181))	('snoRNAs', 'Enzyme', (65, 72))	('DKC1', 'Gene', '1736', (14, 18))	('U1445', 'Chemical', '-', (122, 127))	('U1445', 'Var', (122, 127))	('SNORA67', 'Gene', (84, 91))	('SNORA67', 'Gene', '26781', (84, 91))	('upregulation', 'PosReg', (44, 56))	('increased', 'PosReg', (112, 121))	('SNORA67', 'Gene', (174, 181))	('DKC1', 'Gene', (14, 18))
122970	33255756	Germline DKC1 mutations cause X-linked dyskeratosis congenita (X-DC), an inherited syndrome characterized by a failure of proliferating tissues, such as bone marrow and skin, and increased susceptibility to cancer.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('inherited syndrome', 'Disease', 'MESH:D061325', (73, 91))	('DKC1', 'Gene', (9, 13))	('cancer', 'Disease', (207, 213))	('cause', 'Reg', (24, 29))	('bone marrow', 'Disease', 'MESH:D001855', (153, 164))	('DKC1', 'Gene', '1736', (9, 13))	('inherited syndrome', 'Disease', (73, 91))	('X-linked dyskeratosis congenita', 'Disease', 'MESH:D019871', (30, 61))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('bone marrow', 'Disease', (153, 164))	('mutations', 'Var', (14, 23))	('X-linked dyskeratosis congenita', 'Disease', (30, 61))
122978	33255756	In a previous study, we presented follow-up data from 62 patients with primary breast carcinoma in which patients with tumors expressing high DKC1 mRNA levels were characterized by a worse prognosis than patients with intermediate or low levels.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (204, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Disease', (119, 125))	('DKC1', 'Gene', '1736', (142, 146))	('patients', 'Species', '9606', (57, 65))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('high', 'Var', (137, 141))	('primary breast carcinoma', 'Disease', 'MESH:D001943', (71, 95))	('primary breast carcinoma', 'Disease', (71, 95))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('breast carcinoma', 'Phenotype', 'HP:0003002', (79, 95))	('DKC1', 'Gene', (142, 146))
122998	33255756	We previously demonstrated that breast tumors with high dyskerin expression are also characterized by increased hTR levels.	('breast tumors', 'Phenotype', 'HP:0100013', (32, 45))	('breast tumors', 'Disease', 'MESH:D001943', (32, 45))	('hTR', 'Gene', (112, 115))	('dyskerin', 'Chemical', '-', (56, 64))	('breast tumors', 'Disease', (32, 45))	('dyskerin', 'Protein', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('expression', 'MPA', (65, 75))	('high', 'Var', (51, 55))	('hTR', 'Gene', '2149', (112, 115))	('increased', 'PosReg', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
123013	33255756	Three of these snoRNAs have known target uridines on rRNAs: SNORA64 targets U1692 on 18S rRNA, SNORA70 targets U4975 on 28S rRNA, and SNORA67 targets U1445 on 18S rRNA.	('uridines', 'Chemical', 'MESH:D014529', (41, 49))	('U1445', 'Var', (150, 155))	('U1445', 'Chemical', '-', (150, 155))	('U4975', 'Var', (111, 116))	('U1692', 'Var', (76, 81))	('SNORA70', 'Gene', (95, 102))	('SNORA67', 'Gene', (134, 141))	('SNORA64', 'Gene', '26784', (60, 67))	('SNORA67', 'Gene', '26781', (134, 141))	('SNORA64', 'Gene', (60, 67))	('SNORA70', 'Gene', '26778', (95, 102))
123029	33255756	In addition, our study showed that tumors characterized by high dyskerin expression metastasize more frequently to lymph nodes than other tumors.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('high', 'Var', (59, 63))	('metastasize', 'CPA', (84, 95))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', (35, 41))	('dyskerin', 'Gene', (64, 72))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('dyskerin', 'Chemical', '-', (64, 72))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
123033	33255756	On the other side, in MCF10A cells, DKC1 overexpression led to a significant increase in the levels of selected H/ACA box snoRNAs including SNORA67.	('DKC1', 'Gene', (36, 40))	('overexpression', 'Var', (41, 55))	('MCF10A', 'CellLine', 'CVCL:0598', (22, 28))	('DKC1', 'Gene', '1736', (36, 40))	('levels of', 'MPA', (93, 102))	('increase', 'PosReg', (77, 85))	('SNORA67', 'Gene', (140, 147))	('SNORA67', 'Gene', '26781', (140, 147))
123034	33255756	This was associated with an increase in U1445 site-specific pseudouridylation in 18S rRNA of mature cytoplasmic ribosomes.	('U1445', 'Chemical', '-', (40, 45))	('U1445', 'Var', (40, 45))	('increase', 'PosReg', (28, 36))
123036	33255756	Thus, U1445 is involved in the ribosome structural changes during the translation elongation phase, and so its site-specific pseudouridylation may possibly affect elongation efficiency.	('U1445', 'Chemical', '-', (6, 11))	('U1445', 'Var', (6, 11))	('affect', 'Reg', (156, 162))	('elongation efficiency', 'CPA', (163, 184))	('pseudouridylation', 'MPA', (125, 142))	('involved', 'Reg', (15, 23))
123038	33255756	Altogether, our findings and the above-reported considerations suggest that dyskerin may play a direct role in supporting the neoplastic transformation of mammary epithelium being consistent with a model in which variable levels of DKC1-mediated pseudouridylation of rRNA nucleotides, such as U1445 on 18S rRNA, play an important role in regulating mRNA translation.	('neoplastic transformation of mammary', 'CPA', (126, 162))	('mRNA translation', 'MPA', (349, 365))	('DKC1', 'Gene', (232, 236))	('dyskerin', 'Chemical', '-', (76, 84))	('U1445 on', 'Var', (293, 301))	('DKC1', 'Gene', '1736', (232, 236))	('U1445', 'Chemical', '-', (293, 298))
123041	33255756	On the other hand, there is increasing evidence in literature that snoRNAs may themselves contribute to malignancy in specific human cancer types, such as breast cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('human', 'Species', '9606', (127, 132))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('snoRNAs', 'Var', (67, 74))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Disease', (133, 139))	('malignancy', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('contribute', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
123055	33255756	A semi-quantitative Taqman approach (SsoAdvanced Universal Probes Supermix, Bio-Rad Laboratories) was used to evaluate the expression of DKC1 and beta-glucuronidase as endogenous control (Applied Biosystems, Bedford, MA, USA; Hs 00154737_mL and 4326320E, respectively).	('DKC1', 'Gene', '1736', (137, 141))	('DKC1', 'Gene', (137, 141))	('4326320E', 'Var', (245, 253))
123062	33255756	In particular, for the colonies formation assays 100 cells for MCF10A CTRL/DKC1 OE and MDA-MB-231 CTRL/DKC1 OE, or 250 cells for MCF7 CTRL/DKC1 OE, respectively, were seeded in a single 6-well plate and analyses were conducted as described in Galbiati et al..	('DKC1', 'Gene', '1736', (103, 107))	('CTRL', 'Gene', (98, 102))	('CTRL', 'Gene', '1506', (134, 138))	('DKC1', 'Gene', (139, 143))	('MCF10A', 'CellLine', 'CVCL:0598', (63, 69))	('colonies formation assays', 'CPA', (23, 48))	('CTRL', 'Gene', (134, 138))	('DKC1', 'Gene', (75, 79))	('DKC1', 'Gene', '1736', (139, 143))	('MCF7', 'CellLine', 'CVCL:0031', (129, 133))	('CTRL', 'Gene', '1506', (70, 74))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (87, 97))	('MCF10A', 'Var', (63, 69))	('CTRL', 'Gene', (70, 74))	('DKC1', 'Gene', (103, 107))	('DKC1', 'Gene', '1736', (75, 79))	('CTRL', 'Gene', '1506', (98, 102))
123065	33255756	Human ribosomes from MCF10A CTRL/DKC1 OE were purified as described elsewhere.	('Human', 'Species', '9606', (0, 5))	('DKC1', 'Gene', (33, 37))	('CTRL', 'Gene', '1506', (28, 32))	('DKC1', 'Gene', '1736', (33, 37))	('CTRL', 'Gene', (28, 32))	('MCF10A', 'Var', (21, 27))	('MCF10A', 'CellLine', 'CVCL:0598', (21, 27))
123078	33255756	Results are shown as Psi/U ratio, Figure S6: LC-MS analyses on Psi1692 18S rRNA (A) and Psi4975 28S rRNA (B) performed on MCF10A total cellular RNA, Figure S7: SNORA67, SNORA70 and SNORA64 expression evaluated by RT-qPCR in (A) MCF7 and (B) MDA-MB-231 stable dyskerin overexpression models, Figure S8: LC/MS analyses of Psi1445 on 18S rRNA in parental MCF7 cell lines, Figure S9: Evaluation of the transient DKC1 knockdown (KD) effects in MDA-MB-231 cells.	('Psi', 'Disease', (88, 91))	('SNORA64', 'Gene', '26784', (181, 188))	('KD', 'Disease', 'MESH:C537017', (424, 426))	('DKC1', 'Gene', '1736', (408, 412))	('SNORA64', 'Gene', (181, 188))	('MCF7', 'CellLine', 'CVCL:0031', (228, 232))	('Psi', 'Disease', (63, 66))	('Psi', 'Disease', 'None', (88, 91))	('Psi', 'Disease', 'None', (63, 66))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (439, 449))	('SNORA70', 'Gene', (169, 176))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (241, 251))	('Psi', 'Disease', (21, 24))	('SNORA67', 'Gene', '26781', (160, 167))	('Psi', 'Disease', 'None', (21, 24))	('MCF7', 'CellLine', 'CVCL:0031', (352, 356))	('dyskerin', 'Chemical', '-', (259, 267))	('SNORA70', 'Gene', '26778', (169, 176))	('Psi', 'Disease', (320, 323))	('Psi', 'Disease', 'None', (320, 323))	('knockdown', 'Var', (413, 422))	('SNORA67', 'Gene', (160, 167))	('DKC1', 'Gene', (408, 412))	('MCF10A', 'CellLine', 'CVCL:0598', (122, 128))
123126	33173485	In addition, human epidermal growth factor receptor type 2 positivity and a high Ki-67 labeling index (>10%) have been reported to be pathological prognostic markers associated with recurrence and distant metastasis.	('human', 'Species', '9606', (13, 18))	('human epidermal growth factor receptor type 2', 'Protein', (13, 58))	('positivity', 'Var', (59, 69))	('distant metastasis', 'CPA', (197, 215))	('recurrence', 'CPA', (182, 192))	('associated', 'Reg', (166, 176))
123182	29622131	Uptake of FDG in normal breast tissue increases with visual mammographic BI-RADS breast density and decreases with patient age/postmenopausal status.	('increases', 'PosReg', (38, 47))	('postmenopausal status', 'Phenotype', 'HP:0008209', (127, 148))	('Uptake', 'MPA', (0, 6))	('BI-RADS', 'Var', (73, 80))	('decreases', 'NegReg', (100, 109))	('menopausal status', 'Phenotype', 'HP:0008209', (131, 148))	('patient', 'Species', '9606', (115, 122))	('FDG', 'Chemical', '-', (10, 13))
123241	25326349	We defined CVD death as any of the following causes of death as coded in the SEER database (International Classification of Diseases, Tenth Revision [ICD-10] codes): diseases of heart (I00-I09, I11, I13, I20-I51), cerebrovascular diseases (I60-I69), atherosclerosis (I70), and other diseases of arteries, arterioles, capillaries (I72-I78).	('atherosclerosis', 'Phenotype', 'HP:0002621', (250, 265))	('atherosclerosis', 'Disease', 'MESH:D050197', (250, 265))	('cerebrovascular diseases', 'Disease', (214, 238))	('death', 'Disease', 'MESH:D003643', (55, 60))	('I11', 'Var', (194, 197))	('diseases of heart', 'Disease', (166, 183))	('cerebrovascular diseases', 'Disease', 'MESH:D002561', (214, 238))	('atherosclerosis', 'Disease', (250, 265))	('CVD death', 'Disease', (11, 20))	('I60-I69', 'Var', (240, 247))	('I20-I51', 'Var', (204, 211))	('CVD death', 'Disease', 'MESH:D003643', (11, 20))	('I13', 'Var', (199, 202))	('I00-I09', 'Var', (185, 192))	('CVD', 'Phenotype', 'HP:0001626', (11, 14))	('death', 'Disease', (55, 60))	('death', 'Disease', 'MESH:D003643', (15, 20))	('death', 'Disease', (15, 20))
123266	25326349	Among women with DCIS, there was a greater incidence of CVD death than breast cancer death and this was most pronounced in women diagnosed with DCIS at age 70 years or greater.	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('DCIS', 'Var', (17, 21))	('CVD', 'Phenotype', 'HP:0001626', (56, 59))	('women', 'Species', '9606', (6, 11))	('women', 'Species', '9606', (123, 128))	('CVD death than breast cancer death', 'Disease', 'MESH:D003643', (56, 90))	('CVD death than breast cancer death', 'Disease', (56, 90))
123381	22863309	FGFR1 is amplified during the progression of in situ to invasive breast carcinoma Gene amplification is an important mechanism for activating oncogenes in malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (155, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('activating', 'PosReg', (131, 141))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (56, 81))	('malignant tumors', 'Disease', (155, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('invasive breast carcinoma', 'Disease', (56, 81))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))	('amplification', 'Var', (87, 100))
123382	22863309	Although amplification of HER2, C-MYC, CCND1 and FGFR1 has been reported in breast cancers, their role in the progression of in situ to invasive breast carcinoma is unclear.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancers', 'Disease', 'MESH:D001943', (76, 90))	('breast cancers', 'Disease', (76, 90))	('HER2', 'Gene', '2064', (26, 30))	('FGFR1', 'Gene', (49, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (76, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('reported', 'Reg', (64, 72))	('CCND1', 'Gene', '595', (39, 44))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (136, 161))	('amplification', 'Var', (9, 22))	('CCND1', 'Gene', (39, 44))	('breast carcinoma', 'Phenotype', 'HP:0003002', (145, 161))	('C-MYC', 'Gene', '4609', (32, 37))	('HER2', 'Gene', (26, 30))	('C-MYC', 'Gene', (32, 37))	('invasive breast carcinoma', 'Disease', (136, 161))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
123389	22863309	In survival analyses, FGFR1 amplification was found to be an independent prognostic factor for poor disease-free survival for all patients with invasive carcinoma and for the hormone receptor-positive subgroup.	('invasive carcinoma', 'Disease', (144, 162))	('hormone receptor', 'Gene', (175, 191))	('hormone receptor', 'Gene', '3164', (175, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('poor', 'NegReg', (95, 99))	('patients', 'Species', '9606', (130, 138))	('invasive carcinoma', 'Disease', 'MESH:D009361', (144, 162))	('disease-free survival', 'CPA', (100, 121))	('amplification', 'Var', (28, 41))	('FGFR1', 'Gene', (22, 27))
123390	22863309	Amplification of HER2, C-MYC and CCND1 seems to play a role in the early development of breast cancer, but not in its progression.	('C-MYC', 'Gene', (23, 28))	('role', 'Reg', (55, 59))	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', (33, 38))	('C-MYC', 'Gene', '4609', (23, 28))	('HER2', 'Gene', (17, 21))	('HER2', 'Gene', '2064', (17, 21))	('CCND1', 'Gene', '595', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('early development of breast', 'Phenotype', 'HP:0010314', (67, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
123391	22863309	However, the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure DCIS and in the invasive components of individual tumors, and its association with decreased disease-free survival, suggests a role for FGFR1 amplification in the progression of breast cancer including in situ-to-invasive transition, as well as initiation.	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('breast cancer', 'Disease', (276, 289))	('disease-free survival', 'CPA', (191, 212))	('increased frequency of FGFR1', 'Phenotype', 'HP:0030269', (13, 41))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('invasive carcinomas', 'Disease', 'MESH:D009361', (59, 78))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('amplification', 'Var', (42, 55))	('amplification', 'Var', (240, 253))	('decreased', 'NegReg', (181, 190))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('invasive carcinomas', 'Disease', (59, 78))	('FGFR1', 'Gene', (234, 239))	('tumors', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('FGFR1', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
123392	22863309	Development of breast cancer depends on the accumulation of a variety of genetic alterations, including activation or amplification of oncogenes.	('amplification', 'Var', (118, 131))	('oncogenes', 'Protein', (135, 144))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
123393	22863309	In breast cancer, the most prominent and frequent amplicons have been located at chromosomal positions 1q, 8p12, 8q24, 11q13, 12p13, 16p13, 7q12-21 and 20q13, and several target oncogenes have been identified.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('p13', 'Gene', (128, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('p13', 'Gene', (135, 138))	('amplicons', 'Var', (50, 59))	('p13', 'Gene', '440926', (128, 131))	('p13', 'Gene', '440926', (135, 138))
123397	22863309	The frequency of C-MYC amplification in breast cancer varies, with an average frequency of 16%.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('C-MYC', 'Gene', (17, 22))	('amplification', 'Var', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('C-MYC', 'Gene', '4609', (17, 22))
123398	22863309	Although C-MYC amplification is associated with a risk of relapse and death, its prognostic role is still unclear.	('C-MYC', 'Gene', (9, 14))	('C-MYC', 'Gene', '4609', (9, 14))	('relapse', 'CPA', (58, 65))	('amplification', 'Var', (15, 28))
123400	22863309	FGFR1 amplification is associated with a poor prognosis in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('FGFR1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('amplification', 'Var', (6, 19))
123411	22863309	Furthermore, there have been few studies comparing amplification of FGFR1 in pure DCIS, DCIS associated with invasive cancer, and invasive breast cancer, although it has been found to be associated with breast cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pure DCIS', 'Disease', (77, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('invasive breast cancer', 'Disease', (130, 152))	('amplification', 'Var', (51, 64))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('breast cancer', 'Disease', (203, 216))	('invasive breast cancer', 'Disease', 'MESH:D001943', (130, 152))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('associated', 'Reg', (93, 103))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('associated', 'Reg', (187, 197))	('invasive cancer', 'Disease', (109, 124))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))	('FGFR1', 'Gene', (68, 73))	('invasive cancer', 'Disease', 'MESH:D009362', (109, 124))
123424	22863309	To characterize C-MYC and CCND1 amplification, we performed fluorescence in situ hybridization (FISH) analyses on TMA samples with commercially available locus-specific probes and chromosome enumeration probes (CEPs): LSI C-MYC SpectrumOrange probe (8q24.12-q24.13) and CEP 8 SpectrumGreen probe (8p11.1-q11.1); and LSI CCND1 SpectrumOrange probe (11q13) and CEP 11 SpectrumGreen probe (11p11.11-q11)] (Abbott Molecular, Downers Grove, IL, USA).	('CCND1', 'Gene', (320, 325))	('C-MYC', 'Gene', (222, 227))	('C-MYC', 'Gene', '4609', (16, 21))	('C-MYC', 'Gene', '4609', (222, 227))	('CCND1', 'Gene', (26, 31))	('CCND1', 'Gene', '595', (320, 325))	('11q13', 'Var', (348, 353))	('TMA', 'Chemical', '-', (114, 117))	('CCND1', 'Gene', '595', (26, 31))	('C-MYC', 'Gene', (16, 21))	('11p11.11-q11)]', 'Var', (387, 401))
123434	22863309	Immunohistochemical staining was carried out in a BenchMark XT autostainer (Ventana Medical Systems, Tucson, AZ, USA) using an i-View detection kit (Ventana Medical Systems) for ER (1:100, clone SP1; Labvision, Fremont, CA, USA), PR (1:70, PgR 636; Dako, Capinteria, CA, USA), HER2 (1:700, polyclonal; Dako), p53 (1:600, D07; Dako), Ki-67 (1:250, MIB-1; Dako), cytokeratin 5/6 (1:50, clone D5/16 B4; Dako) and EGFR (EGFR pharmDx ; Dako).	('ER', 'Gene', '2099', (178, 180))	('PgR', 'Gene', (240, 243))	('EGFR', 'Gene', '1956', (416, 420))	('p53', 'Gene', '7157', (309, 312))	('EGFR', 'Gene', (416, 420))	('ER', 'Gene', '2099', (278, 280))	('HER2', 'Gene', (277, 281))	('MIB-1', 'Gene', (347, 352))	('1:700', 'Var', (283, 288))	('HER2', 'Gene', '2064', (277, 281))	('EGFR', 'Gene', '1956', (410, 414))	('MIB-1', 'Gene', '57534', (347, 352))	('EGFR', 'Gene', (410, 414))	('cytokeratin 5/6', 'Gene', '3852', (361, 376))	('PgR', 'Gene', '5241', (240, 243))	('cytokeratin 5/6', 'Gene', (361, 376))	('PR', 'Gene', '5241', (230, 232))	('p53', 'Gene', (309, 312))
123449	22863309	The frequency of FGFR1 amplification was higher in invasive carcinomas than in pure DCIS (12.5% vs. 6.0%, P = 0.020) (Table 2 and Figure 2).	('invasive carcinomas', 'Disease', 'MESH:D009361', (51, 70))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))	('invasive carcinomas', 'Disease', (51, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('higher', 'Reg', (41, 47))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))
123450	22863309	On the contrary, HER2 gene amplification was more frequent in pure DCIS than in invasive carcinomas (30.9% vs. 19.9%, P = 0.004).	('frequent', 'Reg', (50, 58))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('HER2', 'Gene', (17, 21))	('pure DCIS', 'Disease', (62, 71))	('invasive carcinomas', 'Disease', (80, 99))	('invasive carcinomas', 'Disease', 'MESH:D009361', (80, 99))	('HER2', 'Gene', '2064', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('amplification', 'Var', (27, 40))
123457	22863309	HER2 amplification was more frequent in high-grade pure DCIS than in DCIS associated with invasive carcinoma (59.7% vs. 38.2%, P = 0.004).	('amplification', 'Var', (5, 18))	('invasive carcinoma', 'Disease', (90, 108))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('HER2', 'Gene', (0, 4))	('high-grade pure DCIS', 'Disease', (40, 60))	('frequent', 'Reg', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('HER2', 'Gene', '2064', (0, 4))	('invasive carcinoma', 'Disease', 'MESH:D009361', (90, 108))
123460	22863309	CCND1 amplification was correlated with HER2 and FGFR1 amplification in invasive carcinoma, but not in the pure DCIS.	('invasive carcinoma', 'Disease', 'MESH:D009361', (72, 90))	('HER2', 'Gene', (40, 44))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('invasive carcinoma', 'Disease', (72, 90))	('HER2', 'Gene', '2064', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CCND1', 'Gene', (0, 5))	('FGFR1', 'Gene', (49, 54))	('amplification', 'Var', (6, 19))	('amplification', 'MPA', (55, 68))	('CCND1', 'Gene', '595', (0, 5))
123464	22863309	The combined data for initial TMA and the whole-section examination revealed the concordance rate of 99.0% for HER2, 96.0% for C-MYC, 98.0% for CCCND1 and 96.9% for FGFR1 amplification (Figure 3).	('HER2', 'Gene', (111, 115))	('CCND1', 'Gene', (145, 150))	('TMA', 'Chemical', '-', (30, 33))	('HER2', 'Gene', '2064', (111, 115))	('CCND1', 'Gene', '595', (145, 150))	('C-MYC', 'Gene', (127, 132))	('FGFR1', 'Gene', (165, 170))	('amplification', 'Var', (171, 184))	('C-MYC', 'Gene', '4609', (127, 132))
123472	22863309	In the invasive carcinomas, HER2 and C-MYC amplification were associated with the aggressive features of tumor, such as high histologic grade, ER/PR negativity, p53 overexpression and high Ki-67 proliferation index.	('C-MYC', 'Gene', (37, 42))	('invasive carcinomas', 'Disease', (7, 26))	('overexpression', 'PosReg', (165, 179))	('p53', 'Gene', (161, 164))	('HER2', 'Gene', (28, 32))	('ER', 'Gene', '2099', (143, 145))	('associated', 'Reg', (62, 72))	('amplification', 'Var', (43, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('ER', 'Gene', '2099', (29, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('HER2', 'Gene', '2064', (28, 32))	('invasive carcinomas', 'Disease', 'MESH:D009361', (7, 26))	('C-MYC', 'Gene', '4609', (37, 42))	('PR', 'Gene', '5241', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('p53', 'Gene', '7157', (161, 164))
123473	22863309	CCND1 amplification was only correlated with ER positivity, and FGFR1 amplification was not associated with any clinicopatholgic features of the tumors.	('ER', 'Gene', '2099', (45, 47))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('FGFR1', 'Gene', (64, 69))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('CCND1', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('amplification', 'Var', (6, 19))	('CCND1', 'Gene', '595', (0, 5))
123475	22863309	Gene amplification frequencies were also associated with the tumor subtype (Table 3).	('Gene amplification frequencies', 'Var', (0, 30))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
123478	22863309	CCND1 and FGFR1 amplification was most common in the luminal B subtype, being significantly higher than in the luminal A, HER2-positive and triple-negative, nonbasal subtypes.	('higher', 'PosReg', (92, 98))	('luminal B subtype', 'Disease', (53, 70))	('common', 'Reg', (39, 45))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', (10, 15))	('HER2', 'Gene', (122, 126))	('CCND1', 'Gene', (0, 5))	('HER2', 'Gene', '2064', (122, 126))	('CCND1', 'Gene', '595', (0, 5))
123479	22863309	In pure DCIS, CCND1 and FGFR1 amplification was also most common in the luminal B subtype and tended to be more frequent in the luminal B subtype than in the luminal A subtype (P = 0.099 and P = 0.071, respectively).	('common', 'Reg', (58, 64))	('CCND1', 'Gene', '595', (14, 19))	('luminal B subtype', 'Disease', (72, 89))	('frequent', 'Reg', (112, 120))	('amplification', 'Var', (30, 43))	('FGFR1', 'Gene', (24, 29))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))	('CCND1', 'Gene', (14, 19))
123487	22863309	On the contrary, there were no survival differences associated with HER-2, C-MYC or CCND1 amplification (P = 0.160, P = 0.268, and P = 0.670, respectively).	('C-MYC', 'Gene', (75, 80))	('CCND1', 'Gene', (84, 89))	('HER-2', 'Gene', '2064', (68, 73))	('C-MYC', 'Gene', '4609', (75, 80))	('CCND1', 'Gene', '595', (84, 89))	('HER-2', 'Gene', (68, 73))	('amplification', 'Var', (90, 103))
123489	22863309	Similarly, there was no survival differences with regard to FGFR1 amplification in the HER2-positive subtype (P = 0.514) and the basal-like subtype (P = 0.505).	('amplification', 'Var', (66, 79))	('FGFR1', 'Gene', (60, 65))	('HER2', 'Gene', (87, 91))	('HER2', 'Gene', '2064', (87, 91))
123490	22863309	In addition to FGFR1 amplification, high T stage (T1 to T2 vs. T3 to T4, P < 0.001), nodal metastasis (N0 vs. N1 to N3, P = 0.002), hormone receptor negativity (P = 0.004), p53 overexpression (P = 0.005) and high Ki-67 proliferation index (P = 0.006) were significantly associated with poor disease-free survival in all patients with invasive carcinoma.	('disease-free survival', 'CPA', (291, 312))	('overexpression', 'PosReg', (177, 191))	('p53', 'Gene', (173, 176))	('invasive carcinoma', 'Disease', (334, 352))	('hormone receptor', 'Gene', (132, 148))	('hormone receptor', 'Gene', '3164', (132, 148))	('p53', 'Gene', '7157', (173, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('invasive carcinoma', 'Disease', 'MESH:D009361', (334, 352))	('nodal metastasis', 'CPA', (85, 101))	('FGFR1', 'Gene', (15, 20))	('high', 'Var', (36, 40))	('poor', 'NegReg', (286, 290))	('patients', 'Species', '9606', (320, 328))
123491	22863309	In multivariate analysis, only the T stage (pT1 to pT2 vs. pT3 to pT4, HR = 2.916, 95% CI = 1.254 to 6.781, P = 0.013), N stage (N0 vs. N1 to N3, HR = 2.585, 95% CI = 1.324 to 5.049, P = 0.005) and FGFR1 amplification (HR = 2.794, 95% CI = 1.375 to 5.678, P = 0.001) remained independent prognostic factors for disease-free survival.	('HR', 'Gene', '3164', (71, 73))	('FGFR1', 'Gene', (198, 203))	('amplification', 'Var', (204, 217))	('pT3', 'Gene', '7694', (59, 62))	('HR', 'Gene', '3164', (219, 221))	('pT1', 'Gene', '58492', (44, 47))	('pT3', 'Gene', (59, 62))	('HR', 'Gene', '3164', (146, 148))	('pT1', 'Gene', (44, 47))
123492	22863309	In the hormone receptor-positive group, the N stage (N0 vs. N1 to N3, HR = 4.514, 95% CI = 1.506 to 13.531, P = 0.007), p53 overexpression (HR = 2.757, 95% CI = 1.029 to 7.388, P = 0.044) and FGFR1 amplification (HR = 2.659, 95% CI = 1.042 to 6.785, P = 0.041) were identified as independent prognostic factors.	('hormone receptor', 'Gene', (7, 23))	('to 7', 'Species', '1214577', (167, 171))	('hormone receptor', 'Gene', '3164', (7, 23))	('HR', 'Gene', '3164', (140, 142))	('HR', 'Gene', '3164', (213, 215))	('p53', 'Gene', '7157', (120, 123))	('amplification', 'Var', (198, 211))	('FGFR1', 'Gene', (192, 197))	('HR', 'Gene', '3164', (70, 72))	('p53', 'Gene', (120, 123))	('overexpression', 'PosReg', (124, 138))
123493	22863309	In this study we have shown that FGFR1 amplification is more frequent in invasive carcinoma than in pure DCIS, and in the invasive components of tumors with invasive and DICS components.	('invasive carcinoma', 'Disease', 'MESH:D009361', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('amplification', 'Var', (39, 52))	('invasive carcinoma', 'Disease', (73, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('frequent', 'Reg', (61, 69))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('FGFR1', 'Gene', (33, 38))
123494	22863309	In addition, FGFR1 amplification was found to be associated with decreased disease-free survival, suggesting a role for FGFR1 amplification in the progression of breast cancer including the in situ to invasive transition.	('disease-free survival', 'CPA', (75, 96))	('FGFR1', 'Gene', (120, 125))	('decreased', 'NegReg', (65, 74))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('amplification', 'Var', (126, 139))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))
123496	22863309	Although FGFR1 is not widely accepted as the driver breast cancer oncogene affected in the 8p11-12 amplification, its amplification has been reported to be associated with poor prognosis, especially in patients with ER-positive tumors.	('ER', 'Gene', '2099', (216, 218))	('amplification', 'Var', (118, 131))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('breast cancer', 'Disease', (52, 65))	('patients', 'Species', '9606', (202, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('tumors', 'Disease', (228, 234))	('associated', 'Reg', (156, 166))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('FGFR1', 'Gene', (9, 14))
123497	22863309	In this study, we confirmed the prognostic impact of FGFR1 amplification, especially in the hormone receptor-positive group.	('amplification', 'Var', (59, 72))	('hormone receptor', 'Gene', '3164', (92, 108))	('hormone receptor', 'Gene', (92, 108))	('FGFR1', 'Gene', (53, 58))
123498	22863309	Furthermore, we showed that FGFR1 amplification is most frequently found in the luminal B subtype among the various breast cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('luminal B subtype', 'Disease', (80, 97))	('FGFR1', 'Gene', (28, 33))	('found', 'Reg', (67, 72))	('amplification', 'Var', (34, 47))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
123500	22863309	In the hormone receptor-positive group, however, FGFR1 amplification was associated with high histologic grade (P = 0.018), PR negativity (P = 0.017) and high Ki-67 proliferation index (P = 0.020) (data not shown).	('hormone receptor', 'Gene', (7, 23))	('amplification', 'Var', (55, 68))	('hormone receptor', 'Gene', '3164', (7, 23))	('PR', 'Gene', '5241', (124, 126))	('high histologic grade', 'CPA', (89, 110))	('associated', 'Reg', (73, 83))	('FGFR1', 'Gene', (49, 54))
123502	22863309	Taken together, these findings suggest that FGFR1 amplification makes an important contribution to the aggressive phenotype of hormone receptor-positive breast cancer.	('hormone receptor', 'Gene', (127, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('amplification', 'Var', (50, 63))	('hormone receptor', 'Gene', '3164', (127, 143))	('FGFR1', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('contribution', 'Reg', (83, 95))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
123503	22863309	Although FGFR1 amplification has been shown to be associated with breast cancer progression, there have been no studies of its association with the in situ to invasive transition.	('amplification', 'Var', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('associated', 'Reg', (50, 60))	('FGFR1', 'Gene', (9, 14))
123504	22863309	In our study, FGFR1 amplification was more frequent in invasive carcinoma than in pure DCIS, and tended to be higher in invasive carcinomas than in pure DCIS in the high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('higher', 'Reg', (110, 116))	('invasive carcinomas', 'Disease', (120, 139))	('invasive carcinomas', 'Disease', 'MESH:D009361', (120, 139))	('frequent', 'Reg', (43, 51))	('FGFR1', 'Gene', (14, 19))	('invasive carcinoma', 'Disease', (55, 73))	('invasive carcinoma', 'Disease', 'MESH:D009361', (120, 138))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('amplification', 'Var', (20, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('invasive carcinoma', 'Disease', 'MESH:D009361', (55, 73))
123505	22863309	More importantly, FGFR1 amplification was more frequent in the invasive components of tumors than in the corresponding DCIS components.	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('frequent', 'Reg', (47, 55))	('FGFR1', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('amplification', 'Var', (24, 37))	('invasive components', 'CPA', (63, 82))
123507	22863309	The same authors have developed an in vitro three-dimensional HC11 mouse mammary epithelial cell culture model expressing a drug-inducible FGFR1 and have demonstrated that inducible FGFR1 activation results in a gain of invasive properties and promotes the epithelial-mesenchymal transition, which is caused by induction of matrix metalloproteinase-3.	('FGFR1', 'Gene', (139, 144))	('epithelial-mesenchymal transition', 'CPA', (257, 290))	('inducible', 'Var', (172, 181))	('invasive properties', 'CPA', (220, 239))	('FGFR1', 'Gene', (182, 187))	('activation', 'PosReg', (188, 198))	('promotes', 'PosReg', (244, 252))	('matrix metalloproteinase-3', 'Gene', '17392', (324, 350))	('matrix metalloproteinase-3', 'Gene', (324, 350))	('mouse', 'Species', '10090', (67, 72))	('gain', 'PosReg', (212, 216))
123508	22863309	FGFR1 amplification, and hence increased FGFR1 signaling, therefore seems to contribute to early breast cancer invasion; that is, the in situ to invasive transition.	('signaling', 'MPA', (47, 56))	('increased FGFR1 signaling', 'Phenotype', 'HP:0030269', (31, 56))	('increased', 'PosReg', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (77, 87))	('FGFR1', 'Gene', (0, 5))	('amplification', 'Var', (6, 19))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('FGFR1', 'Gene', (41, 46))
123509	22863309	This result may have clinical implications, because DCIS with FGFR1 amplification is more likely to progress to invasive carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('invasive carcinoma', 'Disease', 'MESH:D009361', (112, 130))	('progress', 'PosReg', (100, 108))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('FGFR1', 'Gene', (62, 67))	('invasive carcinoma', 'Disease', (112, 130))	('amplification', 'Var', (68, 81))
123510	22863309	In this study, we focused on the role of genetic alterations in the progression of DCIS to invasive carcinoma.	('genetic alterations', 'Var', (41, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('DCIS', 'Disease', (83, 87))	('invasive carcinoma', 'Disease', 'MESH:D009361', (91, 109))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('invasive carcinoma', 'Disease', (91, 109))
123517	22863309	Amplification of HER2, C-MYC and CCND1 therefore seems to play a role in the early development of breast cancer, but not in the progression of DCIS to invasive carcinomas.	('invasive carcinomas', 'Disease', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CCND1', 'Gene', '595', (33, 38))	('early development of breast', 'Phenotype', 'HP:0010314', (77, 104))	('CCND1', 'Gene', (33, 38))	('HER2', 'Gene', (17, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('C-MYC', 'Gene', '4609', (23, 28))	('role', 'Reg', (65, 69))	('C-MYC', 'Gene', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('Amplification', 'Var', (0, 13))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('breast cancer', 'Disease', (98, 111))	('invasive carcinomas', 'Disease', 'MESH:D009361', (151, 170))	('HER2', 'Gene', '2064', (17, 21))	('play', 'Reg', (58, 62))
123519	22863309	However, we detected amplification in the DCIS components but not in the invasive carcinoma components in a few cases for HER2 (n = 2), C-MYC (n = 2) and CCND1 (n = 3).	('CCND1', 'Gene', '595', (154, 159))	('invasive carcinoma', 'Disease', 'MESH:D009361', (73, 91))	('C-MYC', 'Gene', (136, 141))	('invasive carcinoma', 'Disease', (73, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('CCND1', 'Gene', (154, 159))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('HER2', 'Gene', (122, 126))	('C-MYC', 'Gene', '4609', (136, 141))	('HER2', 'Gene', '2064', (122, 126))	('amplification', 'Var', (21, 34))
123520	22863309	Interestingly, the two cases with C-MYC amplification and the three cases with CCND1 amplification in only the DCIS component showed heterogeneous amplification.	('CCND1', 'Gene', '595', (79, 84))	('C-MYC', 'Gene', (34, 39))	('amplification', 'Var', (40, 53))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('CCND1', 'Gene', (79, 84))	('C-MYC', 'Gene', '4609', (34, 39))
123521	22863309	Four of the 32 cases with CCND1 amplification in both components and three of the 20 cases that had FGFR1 amplification in both components also had heterogeneous amplification in the DCIS component.	('DCIS component', 'MPA', (183, 197))	('amplification', 'Var', (32, 45))	('CCND1', 'Gene', (26, 31))	('DCIS', 'Phenotype', 'HP:0030075', (183, 187))	('CCND1', 'Gene', '595', (26, 31))
123526	22863309	The different breast cancer subtypes have been suggested to have distinct patterns of copy number alterations.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('copy number alterations', 'Var', (86, 109))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))
123528	22863309	Moreover, CCND1 amplification on 11q13 has been reported to be associated with luminal subtypes, and in agreement with this we found that CCND1 and FGFR1 amplification was most frequent in the luminal B subtype whereas CCND1 amplification was absent from all of the basal-like breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (277, 291))	('breast cancers', 'Disease', (277, 291))	('CCND1', 'Gene', '595', (10, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('frequent', 'Reg', (177, 185))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('CCND1', 'Gene', '595', (138, 143))	('CCND1', 'Gene', '595', (219, 224))	('luminal B subtype', 'Disease', (193, 210))	('basal-like', 'Disease', (266, 276))	('amplification', 'Var', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('FGFR1', 'Gene', (148, 153))	('breast cancers', 'Phenotype', 'HP:0003002', (277, 291))	('CCND1', 'Gene', (138, 143))	('CCND1', 'Gene', (219, 224))	('CCND1', 'Gene', (10, 15))
123530	22863309	The amplification frequencies of C-MYC and CCND1 did not differ between pure DCIS and invasive carcinomas, and HER2 amplification was more frequent in pure DCIS.	('HER2', 'Gene', (111, 115))	('HER2', 'Gene', '2064', (111, 115))	('frequent', 'Reg', (139, 147))	('invasive carcinomas', 'Disease', (86, 105))	('invasive carcinomas', 'Disease', 'MESH:D009361', (86, 105))	('amplification', 'Var', (116, 129))	('C-MYC', 'Gene', '4609', (33, 38))	('pure DCIS', 'Disease', (151, 160))	('CCND1', 'Gene', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('pure DCIS', 'Disease', (72, 81))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('CCND1', 'Gene', '595', (43, 48))	('C-MYC', 'Gene', (33, 38))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
123532	22863309	However, FGFR1 amplification was more frequent in invasive carcinomas than in pure DCIS, and in the invasive components of the same tumors.	('amplification', 'Var', (15, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('invasive carcinomas', 'Disease', 'MESH:D009361', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('invasive carcinomas', 'Disease', (50, 69))	('tumors', 'Disease', (132, 138))	('frequent', 'Reg', (38, 46))	('FGFR1', 'Gene', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
123533	22863309	Our results therefore suggest that FGFR1 amplification play an important role in the progression of breast cancer, including the in situ to invasive transition, as well as initiation.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('amplification', 'Var', (41, 54))	('FGFR1', 'Gene', (35, 40))
123537	23110523	Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inhibition', 'Var', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (156, 161))	('PADI2', 'Gene', (54, 59))
123545	23110523	We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold.	('Cl-amidine', 'Chemical', 'MESH:C558727', (76, 86))	('suppressed', 'NegReg', (92, 102))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('MCF10DCIS tumors', 'Disease', (129, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mice', 'Species', '10090', (56, 60))	('growth', 'MPA', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('Cl-amidine', 'Var', (76, 86))	('MCF10DCIS tumors', 'Disease', 'MESH:D009369', (129, 145))
123546	23110523	Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67.	('inhibitor', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('GADD45alpha', 'Gene', '1647', (240, 251))	('p21', 'Gene', '1026', (235, 238))	('p21', 'Gene', (235, 238))	('PADI', 'Gene', (117, 121))	('Cl-amidine', 'Chemical', 'MESH:C558727', (50, 60))	('GADD45alpha', 'Gene', (240, 251))	('affects', 'Reg', (141, 148))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('expression', 'MPA', (153, 163))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (81, 90))	('cell cycle genes', 'Gene', (175, 191))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
123547	23110523	Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.	('HER2/ERBB2+', 'Protein', (90, 101))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Cl-amidine', 'Chemical', 'MESH:C558727', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('PADI2', 'Gene', (37, 42))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('Cl-amidine', 'Var', (118, 128))
123550	23110523	Increasingly, the dysregulation of PADI activity is associated with a range of diseases, including rheumatoid arthritis (RA), multiple sclerosis, ulcerative colitis, neural degeneration, COPD, and cancer.	('RA', 'Disease', 'MESH:D001172', (121, 123))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (146, 164))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('neural degeneration', 'Disease', (166, 185))	('multiple sclerosis', 'Disease', (126, 144))	('colitis', 'Phenotype', 'HP:0002583', (157, 164))	('arthritis', 'Phenotype', 'HP:0001369', (110, 119))	('COPD', 'Disease', 'MESH:D029424', (187, 191))	('rheumatoid arthritis', 'Disease', (99, 119))	('COPD', 'Disease', (187, 191))	('neural degeneration', 'Phenotype', 'HP:0002180', (166, 185))	('ulcerative colitis', 'Disease', (146, 164))	('dysregulation', 'Var', (18, 31))	('RA', 'Phenotype', 'HP:0001370', (121, 123))	('multiple sclerosis', 'Disease', 'MESH:D009103', (126, 144))	('PADI', 'Gene', (35, 39))	('neural degeneration', 'Disease', 'MESH:C565640', (166, 185))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (99, 119))	('cancer', 'Disease', (197, 203))	('associated', 'Reg', (52, 62))	('ulcerative colitis', 'Disease', 'MESH:D003093', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (99, 119))
123555	23110523	Additionally, others have shown that citrullination of the p53 tumor suppressor protein affects the expression of p53 target genes p21, OKL38, CIP1 and WAF1.	('tumor', 'Disease', (63, 68))	('p53', 'Gene', (59, 62))	('citrullination', 'Var', (37, 51))	('p53', 'Gene', '7157', (59, 62))	('CIP1', 'Gene', '1026', (143, 147))	('p53', 'Gene', (114, 117))	('affects', 'Reg', (88, 95))	('p53', 'Gene', '7157', (114, 117))	('p21', 'Gene', '1026', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('expression', 'MPA', (100, 110))	('p21', 'Gene', (131, 134))	('WAF1', 'Gene', '1026', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('OKL38', 'Gene', '29948', (136, 141))	('OKL38', 'Gene', (136, 141))	('CIP1', 'Gene', (143, 147))	('WAF1', 'Gene', (152, 156))
123568	23110523	MCF10DCIS xenograft tumors were generated by injecting 1 x 106 cells in 0.1 mL Matrigel (1:1) (BD Biosciences, San Jose, CA, USA) subcutaneously near the nipple of gland #3 in 6-week old female nude (nu/nu) mice (Taconic, Germantown, NY, USA).	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mice', 'Species', '10090', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS', 'Var', (0, 9))
123580	23110523	Primary antibodies are as follows: anti-PADI2 1:100 (ProteinTech, Chicago, IL, USA), anti-ERBB2 (A0485) 1:100 (Dako, Carpentaria, CA, USA), anti-Cytokeratin 1:100 (Dako), and anti-p63 1:100 (Abcam, Cambridge, MA, USA).	('p63', 'Gene', '8626', (180, 183))	('p63', 'Gene', (180, 183))	('anti-PADI2', 'Var', (35, 45))	('anti-Cytokeratin', 'Var', (140, 156))	('anti-ERBB2', 'Var', (85, 95))
123585	23110523	Basement membrane integrity was determined using periodic acid-Schiff (PAS) stained slides, and was scored by SM on a scale of 0-3: 0- continuous with no breaching, 1- a few small interruptions, 2- several interruptions with breaching by tumor cells, 3- extensive loss of basement membrane with invasion of tumor cells over the breached area; observations were performed under 10X magnification.	('basement', 'Protein', (272, 280))	('loss', 'NegReg', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('PAS', 'Chemical', '-', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('breaching', 'Var', (225, 234))	('tumor', 'Disease', (307, 312))	('tumor', 'Disease', (238, 243))	('periodic acid-Schiff', 'Chemical', '-', (49, 69))
123586	23110523	Primary antibodies were incubated overnight at 4 C using the following concentrations: anti-PADI2 1:1000 (ProteinTech) and anti-ErbB2 1:5000 (Dako).	('anti-PADI2', 'Var', (87, 97))	('ErbB2', 'Gene', '2064', (128, 133))	('ErbB2', 'Gene', (128, 133))
123587	23110523	TaqMan Gene Expression Assays (ABI) for human PADI2 (Hs00247108_m1) and GAPDH (4352934E) were used for qRT-PCR.	('4352934E', 'Var', (79, 87))	('GAPDH', 'Gene', '2597', (72, 77))	('GAPDH', 'Gene', (72, 77))	('human', 'Species', '9606', (40, 45))
123601	23110523	While these cell lines have been previously classified as basal-like, both MCF10A and MCF10DCIS have been shown to possess bipotential progenitor properties.	('MCF10A', 'Var', (75, 81))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (86, 95))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('MCF10DCIS', 'Var', (86, 95))	('MCF10A', 'CellLine', 'CVCL:0598', (75, 81))	('bipotential progenitor properties', 'CPA', (123, 156))
123607	23110523	Analysis of PADI2 transcript levels in these cell lines finds that, as expected, PADI2 mRNA is sharply elevated in the BT-474 line (Figure 2b), and is ~2 fold higher that that seen in the MCF10DCIS cells (Additional file 1, Figure S1b) when compared to MCF10A cells.	('MCF10DCIS', 'Var', (188, 197))	('mRNA', 'MPA', (87, 91))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (188, 197))	('MCF10A', 'CellLine', 'CVCL:0598', (253, 259))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('PADI2', 'Gene', (81, 86))	('elevated', 'PosReg', (103, 111))	('higher', 'PosReg', (159, 165))
123631	23110523	Using a threshold value of 2-fold expression change and a statistical significance of p < 0.05, we found that Cl-amidine affected the expression of a subset of genes (for the full unsorted list see Additional file 3, Table S1), with the top 10-upregulated and -downregulated genes presented in Table 2.	('Cl-amidine', 'Var', (110, 120))	('Cl-amidine', 'Chemical', 'MESH:C558727', (110, 120))	('expression', 'MPA', (134, 144))
123632	23110523	Importantly, previous studies have shown that increased expression of GADD45alpha, the second most highly upregulated gene in our study, leads to cell cycle arrest and apoptosis in a range of cell types, including breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('increased', 'PosReg', (46, 55))	('cell cycle arrest', 'CPA', (146, 163))	('apoptosis', 'CPA', (168, 177))	('GADD45alpha', 'Gene', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('GADD45alpha', 'Gene', '1647', (70, 81))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('expression', 'Var', (56, 66))	('leads to', 'Reg', (137, 145))	('breast cancer', 'Disease', (214, 227))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (146, 163))
123633	23110523	p21), Cl-amidine might also alter MCF10DCIS cell growth by inducing apoptosis.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('p21', 'Gene', (0, 3))	('inducing', 'Reg', (59, 67))	('MCF10DCIS', 'Gene', (34, 43))	('apoptosis', 'CPA', (68, 77))	('Cl-amidine', 'Var', (6, 16))	('alter', 'Reg', (28, 33))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (34, 43))	('p21', 'Gene', '1026', (0, 3))	('Cl-amidine', 'Chemical', 'MESH:C558727', (6, 16))
123638	23110523	Furthermore, we also show that treatment of MCF10DCIS cells with Cl-amidine appears to induce cell cycle arrest in S-phase (Figure 4f).	('Cl-amidine', 'Chemical', 'MESH:C558727', (65, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (94, 111))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (44, 53))	('cell cycle arrest in S-phase', 'CPA', (94, 122))	('MCF10DCIS', 'Var', (44, 53))
123642	23110523	Again, we see a reduction in cell growth (Figure 5a) and an increase in apoptosis (Figure 5b) that is coupled to S-phase cell cycle arrest (Figure 5c) for both BT-474 and SK-BR-3.	('cell growth', 'CPA', (29, 40))	('reduction', 'NegReg', (16, 25))	('SK-BR-3', 'Var', (171, 178))	('SK-BR-3', 'CellLine', 'CVCL:0033', (171, 178))	('apoptosis', 'CPA', (72, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))
123643	23110523	These results show that Cl-amidine is effective in inhibiting the growth of luminal-HER2/ERBB2+ cell lines, BT-474 and SK-BR-3, and agree with previously reported data on Cl-amidine inhibition of growth in MCF7 cells.	('Cl-amidine', 'Var', (24, 34))	('Cl-amidine', 'Chemical', 'MESH:C558727', (171, 181))	('SK-BR-3', 'CellLine', 'CVCL:0033', (119, 126))	('inhibiting', 'NegReg', (51, 61))	('Cl-amidine', 'Chemical', 'MESH:C558727', (24, 34))	('growth', 'MPA', (66, 72))	('MCF7', 'CellLine', 'CVCL:0031', (206, 210))
123647	23110523	Taken together, these results suggest that Cl-amidine blocks the growth of MCF10DCIS cells by inducing cell cycle arrest and apoptosis.	('blocks', 'NegReg', (54, 60))	('MCF10DCIS', 'Gene', (75, 84))	('Cl-amidine', 'Chemical', 'MESH:C558727', (43, 53))	('growth', 'CPA', (65, 71))	('cell cycle arrest', 'CPA', (103, 120))	('inducing', 'PosReg', (94, 102))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('apoptosis', 'CPA', (125, 134))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (75, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))	('Cl-amidine', 'Var', (43, 53))
123648	23110523	This prediction is supported by our previous finding that Cl-amidine can also drive apoptosis in lymphocytic cell lines in vitro.	('drive', 'PosReg', (78, 83))	('Cl-amidine', 'Var', (58, 68))	('Cl-amidine', 'Chemical', 'MESH:C558727', (58, 68))	('apoptosis', 'CPA', (84, 93))
123652	23110523	Previous studies have shown that when MCF10DCIS cells are injected into the mammary fat-pad of immunodeficient nude (nu/nu) mice, tumors develop within 2-3 weeks.	('tumors', 'Disease', (130, 136))	('MCF10DCIS', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('immunodeficient', 'Disease', (95, 110))	('immunodeficient', 'Disease', 'MESH:D007153', (95, 110))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('pad', 'Gene', '23569', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (38, 47))	('pad', 'Gene', (88, 91))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
123655	23110523	In our study, we found that PADI2 protein expression was restricted to the luminal epithelium of the duct-like structures in the MCF10DCIS xenografts, and was not observed in the stromal tissue or the necrotic core (Figure 6a, panel I and II).	('PADI2', 'Gene', (28, 33))	('necrotic', 'Disease', (201, 209))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (129, 138))	('MCF10DCIS', 'Var', (129, 138))	('necrotic', 'Disease', 'MESH:D009336', (201, 209))
123662	23110523	For this study, mouse fat-pads were injected with MCF10DCIS cells (1 x 106) and the tumors were allowed to establish and grow for ~2 weeks as described previously.	('pad', 'Gene', '23569', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (50, 59))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('MCF10DCIS', 'Var', (50, 59))	('tumors', 'Disease', (84, 90))	('mouse', 'Species', '10090', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('pad', 'Gene', (26, 29))
123668	23110523	Furthermore, the basement membrane of Cl-amidine treated tumors remained largely intact (Figure 7c) and had considerably less membrane breaching and leukocyte infiltration compared to the control group.	('less', 'NegReg', (121, 125))	('Cl-amidine', 'Var', (38, 48))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Cl-amidine', 'Chemical', 'MESH:C558727', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('membrane breaching', 'CPA', (126, 144))
123669	23110523	These findings suggest that PADI2 plays an important role in comedo-DCIS progression and that the inhibition of PADI activity can suppress tumor progression in vivo.	('inhibition', 'Var', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('comedo', 'Phenotype', 'HP:0025249', (61, 67))	('comedo-DCIS progression', 'CPA', (61, 84))	('suppress', 'NegReg', (130, 138))	('PADI activity', 'Gene', (112, 125))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
123671	23110523	In addition, we demonstrate here for the first time that Cl-amidine is successful in suppressing tumor growth in a xenograft mouse model of comedo-DCIS.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Cl-amidine', 'Var', (57, 67))	('suppressing', 'NegReg', (85, 96))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mouse', 'Species', '10090', (125, 130))	('Cl-amidine', 'Chemical', 'MESH:C558727', (57, 67))	('tumor', 'Disease', (97, 102))	('comedo', 'Phenotype', 'HP:0025249', (140, 146))
123674	23110523	To accomplish this, we utilized the well-established MCF10AT model and found that PADI2 expression was highly upregulated in MCF10DCIS cells, a cell line that forms comedo-DCIS lesions that spontaneously progress to invasive tumors.	('invasive tumors', 'Disease', 'MESH:D009369', (216, 231))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('MCF10DCIS', 'Var', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('expression', 'MPA', (88, 98))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('MCF10A', 'CellLine', 'CVCL:0598', (53, 59))	('upregulated', 'PosReg', (110, 121))	('progress', 'PosReg', (204, 212))	('comedo', 'Phenotype', 'HP:0025249', (165, 171))	('invasive tumors', 'Disease', (216, 231))	('PADI2', 'Gene', (82, 87))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
123678	23110523	While we did find that HER2/ERBB2 and PADI2 protein expression correlated well across the MCF10AT cell lines, PADI2 protein levels are particularly high in the MCF10DCIS line, relative to HER2/ERBB2.	('PADI2', 'Gene', (38, 43))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('MCF10A', 'CellLine', 'CVCL:0598', (90, 96))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (160, 169))	('MCF10DCIS', 'Var', (160, 169))	('PADI2', 'Gene', (110, 115))	('protein levels', 'MPA', (116, 130))	('high', 'PosReg', (148, 152))
123694	23110523	Our studies expand on these previous results by showing that Cl-amidine suppresses the growth of the transformed lines of the MCF10AT model, especially the MCF10DCIS cell line, in both 2D and 3D cultures.	('growth', 'MPA', (87, 93))	('Cl-amidine', 'Var', (61, 71))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (156, 165))	('MCF10AT', 'Gene', (126, 133))	('Cl-amidine', 'Chemical', 'MESH:C558727', (61, 71))	('MCF10A', 'CellLine', 'CVCL:0598', (126, 132))	('suppresses', 'NegReg', (72, 82))
123696	23110523	Given that the loss of basement membrane integrity is an important event during the progression of DCIS to invasive disease, it is significant that Cl-amidine treated xenografts maintain their basement membrane integrity and show reduced leukocytic infiltration across the basement membrane compared to the control group.	('reduced', 'NegReg', (230, 237))	('invasive disease', 'Disease', 'MESH:D009362', (107, 123))	('leukocytic infiltration', 'Disease', (238, 261))	('Cl-amidine', 'Chemical', 'MESH:C558727', (148, 158))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('leukocytic infiltration', 'Disease', 'MESH:D017254', (238, 261))	('invasive disease', 'Disease', (107, 123))	('basement membrane integrity', 'CPA', (193, 220))	('Cl-amidine', 'Var', (148, 158))
123704	23110523	Previous reports have shown that Cl-amidine effectively upregulates a number of p53-regulated genes, including p21, PUMA, and GADD45.	('upregulates', 'PosReg', (56, 67))	('p21', 'Gene', '1026', (111, 114))	('Cl-amidine', 'Chemical', 'MESH:C558727', (33, 43))	('p53', 'Gene', (80, 83))	('GADD45', 'Gene', (126, 132))	('p21', 'Gene', (111, 114))	('p53', 'Gene', '7157', (80, 83))	('Cl-amidine', 'Var', (33, 43))	('GADD45', 'Gene', '1647', (126, 132))	('PUMA', 'Disease', (116, 120))
123705	23110523	Our qRT-PCR cell cycle array results confirm that two of these genes, p21 and GADD45alpha, are upregulated after treatment of MCF10DCIS cells with Cl-amidine by 17.68- and 13.53-fold, respectively.	('upregulated', 'PosReg', (95, 106))	('GADD45alpha', 'Gene', (78, 89))	('p21', 'Gene', '1026', (70, 73))	('GADD45alpha', 'Gene', '1647', (78, 89))	('p21', 'Gene', (70, 73))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('Cl-amidine', 'Chemical', 'MESH:C558727', (147, 157))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (126, 135))	('MCF10DCIS', 'Var', (126, 135))
123711	23110523	Using the MCF10AT model, we show that PADI2 is highly upregulated following transformation at both the mRNA and protein level, with highest levels in the cell line that recapitulates human comedo-DCIS.	('PADI2', 'Gene', (38, 43))	('transformation', 'Var', (76, 90))	('DCIS', 'Phenotype', 'HP:0030075', (196, 200))	('upregulated', 'PosReg', (54, 65))	('human', 'Species', '9606', (183, 188))	('comedo', 'Phenotype', 'HP:0025249', (189, 195))	('MCF10A', 'CellLine', 'CVCL:0598', (10, 16))
123728	29928319	Similarly, the molecular characteristics of steroid receptor, epidermal growth factor, proliferation marker, metalloproteinase and cyclooxygenase expression, and the mutation of the p53 tumor suppressor gene in CMT, mimic HBC.	('epidermal growth factor', 'Gene', (62, 85))	('steroid', 'Chemical', 'MESH:D013256', (44, 51))	('rat', 'Species', '10116', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('oxygen', 'Chemical', 'MESH:D010100', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('epidermal growth factor', 'Gene', '1950', (62, 85))	('tumor', 'Disease', (186, 191))	('p53', 'Gene', (182, 185))	('mutation', 'Var', (166, 174))	('steroid', 'MPA', (44, 51))
123784	29928319	Several rodent studies have demonstrated that exposure to cancer-causing agents, including radiation or chemicals produces specific tumors, have effects of these agents resulting in uncontrolled cell growth due to mutations and alterations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('rat', 'Species', '10116', (232, 235))	('radiation', 'Disease', 'MESH:D004194', (91, 100))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('alterations', 'Var', (228, 239))	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (214, 223))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('radiation', 'Disease', (91, 100))	('tumors', 'Disease', (132, 138))	('uncontrolled cell growth', 'MPA', (182, 206))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
123801	29928319	The incidence of breast cancer in rat models is either spontaneous, or generated by the transgenesis of activated oncogenes or the induction of mutations in tumor suppressor genes.	('tumor', 'Disease', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('oncogenes', 'Gene', (114, 123))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('rat', 'Species', '10116', (75, 78))	('breast cancer', 'Disease', (17, 30))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('transgenesis', 'Var', (88, 100))	('mutations', 'Var', (144, 153))
123802	29928319	Chemical carcinogens have been used to induce breast cancer in the rat mammary gland for >50 years, most commonly N-nitroso-N-methylurea or 7,12-dimethylbenz(a)anthracene.	('anthracene', 'Chemical', 'MESH:C034020', (160, 170))	('rat', 'Species', '10116', (67, 70))	('7,12-dimethylbenz', 'Chemical', '-', (140, 157))	('N-nitroso-N-methylurea', 'Var', (114, 136))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('N-nitroso-N-methylurea', 'Chemical', 'MESH:D008770', (114, 136))
123838	29928319	A mutagenesis strategy for effectively generating breast cancer-associated (BRCA) 1 and BRCA2 gene mutants was developed; however, this method still requires more efficient technologies for the complete gene knockouts used in breast cancer investigation.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('rat', 'Species', '10116', (16, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('BRCA2', 'Gene', (88, 93))	('breast cancer-associated (BRCA) 1', 'Gene', '672', (50, 83))	('rat', 'Species', '10116', (43, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('mutants', 'Var', (99, 106))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
123851	29928319	The molecular characteristics, including steroid receptor, epidermal growth factor (EGF), proliferation markers, metalloproteinase and cyclooxygenase overexpression, and p53 mutation, also mimic HBC.	('oxygen', 'Chemical', 'MESH:D010100', (140, 146))	('rat', 'Species', '10116', (97, 100))	('EGF', 'Gene', (84, 87))	('HBC', 'Disease', (195, 198))	('mutation', 'Var', (174, 182))	('epidermal growth factor', 'Gene', (59, 82))	('epidermal growth factor', 'Gene', '1950', (59, 82))	('EGF', 'Gene', '1950', (84, 87))	('overexpression', 'PosReg', (150, 164))	('p53', 'Gene', (170, 173))	('steroid', 'Chemical', 'MESH:D013256', (41, 48))	('mimic', 'Reg', (189, 194))
123868	29928319	Previously, it was identified that the inhibition of GH/IGF-1 may prevent pre-neoplastic breast disease and cancer.	('inhibition', 'Var', (39, 49))	('GH', 'Gene', '2688', (53, 55))	('neoplastic breast', 'Phenotype', 'HP:0100013', (78, 95))	('neoplastic breast disease', 'Disease', (78, 103))	('prevent', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('neoplastic breast disease', 'Disease', 'MESH:D001943', (78, 103))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
123880	29928319	It has been observed in breast cancer that prolactin supplementation promotes the survival of mammary tissue, and that the clinical condition of patients may improve following hypophysectomy, indicating a hormonal dependency on prolactin.	('patients', 'Species', '9606', (145, 153))	('supplementation', 'Var', (53, 68))	('prolactin', 'Gene', '5617', (43, 52))	('prolactin', 'Gene', (228, 237))	('survival of mammary tissue', 'CPA', (82, 108))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('prolactin', 'Gene', (43, 52))	('improve', 'PosReg', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('promotes', 'PosReg', (69, 77))	('breast cancer', 'Disease', (24, 37))	('prolactin', 'Gene', '5617', (228, 237))	('men', 'Species', '9606', (59, 62))
123888	29928319	These markers include BRCA gene mutations, EGF receptor (EGFR), Ki-67, human epidermal growth factor receptor (HER2)/neu, p53, p63, matrix metalloproteinases, phosphatase and tensin homolog, heat-shock proteins, mucins, maspin, Sialyl Lewis X antigen and cyclooxygenase-2.	('heat-shock proteins', 'Disease', (191, 210))	('EGF receptor', 'Gene', '1956', (43, 55))	('BRCA', 'Gene', '672', (22, 26))	('epidermal growth factor receptor', 'Gene', (77, 109))	('oxygen', 'Chemical', 'MESH:D010100', (260, 266))	('epidermal growth factor receptor', 'Gene', '1956', (77, 109))	('p63', 'Gene', (127, 130))	('HER2', 'Gene', '2064', (111, 115))	('neu', 'Gene', (117, 120))	('p63', 'Gene', '8626', (127, 130))	('EGF receptor', 'Gene', (43, 55))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', (57, 61))	('human', 'Species', '9606', (71, 76))	('BRCA', 'Gene', (22, 26))	('heat-shock proteins', 'Disease', 'MESH:D012769', (191, 210))	('cyclooxygenase-2', 'Enzyme', (255, 271))	('Sialyl Lewis X antigen', 'MPA', (228, 250))	('HER2', 'Gene', (111, 115))	('neu', 'Gene', '2064', (117, 120))	('shock', 'Phenotype', 'HP:0031273', (196, 201))	('EGFR', 'Gene', '1956', (57, 61))
123890	29928319	Germline mutations in BRCA genes have been associated with a relatively high risk (4-fold) of mammary tumor development in certain breeds of dogs.	('Germline mutations', 'Var', (0, 18))	('men', 'Species', '9606', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('dogs', 'Species', '9615', (141, 145))	('associated', 'Reg', (43, 53))	('BRCA', 'Gene', '672', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('BRCA', 'Gene', (22, 26))
123891	29928319	An association between the expression of mutated BRCA1 or BRCA2, and RAD51 recombinase (RAD51), a DNA-repairing protein that is, when upregulated, associated with the development of mammary tumors, was also reported in dogs.	('mutated', 'Var', (41, 48))	('associated with', 'Reg', (147, 162))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('dogs', 'Species', '9615', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('BRCA1', 'Gene', (49, 54))	('tumors', 'Disease', (190, 196))	('BRCA2', 'Gene', (58, 63))	('men', 'Species', '9606', (174, 177))
123903	29928319	Kerns et al detected the co-expression of HER2/neu and p53 mutation, which induced malignant cell behavior.	('induced', 'Reg', (75, 82))	('p53', 'Gene', (55, 58))	('malignant cell behavior', 'CPA', (83, 106))	('co-expression', 'Interaction', (25, 38))	('mutation', 'Var', (59, 67))	('HER2/neu', 'Gene', '2064', (42, 50))	('HER2/neu', 'Gene', (42, 50))
123911	29928319	The immunohistochemical expression of Ki-67 and PCNA has also been studied in CMT; the expression of Ki-67 has been associated with a poor prognosis.	('expression', 'Var', (87, 97))	('CMT', 'Disease', (78, 81))	('Ki-67', 'Var', (101, 106))	('PCNA', 'Gene', (48, 52))	('PCNA', 'Gene', '5111', (48, 52))	('associated', 'Reg', (116, 126))
123915	29928319	Deregulated cell proliferation occurs following mutations of this gene, which causes tumor formation and progression.	('Deregulated cell proliferation', 'CPA', (0, 30))	('tumor', 'Disease', (85, 90))	('progression', 'CPA', (105, 116))	('causes', 'Reg', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rat', 'Species', '10116', (24, 27))	('mutations', 'Var', (48, 57))
123916	29928319	In humans and dogs, mutations in the conserved domains of p53 appear to have an essential role in the carcinogenesis of mammary glands.	('mammary glands', 'Disease', (120, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('role', 'Reg', (90, 94))	('dogs', 'Species', '9615', (14, 18))	('carcinogenesis', 'Disease', (102, 116))	('humans', 'Species', '9606', (3, 9))	('p53', 'Gene', (58, 61))	('mutations', 'Var', (20, 29))
123917	29928319	It was identified that p53 mutations in CMT occur within the second, fourth and fifth exons, and Ala125Val point mutations are common between human and canine p53 genes.	('mutations', 'Var', (27, 36))	('p53', 'Gene', (159, 162))	('canine', 'Species', '9615', (152, 158))	('human', 'Species', '9606', (142, 147))	('p53', 'Gene', (23, 26))	('Ala125Val', 'Mutation', 'p.A125V', (97, 106))	('Ala125Val', 'Var', (97, 106))
123918	29928319	A study of aggressive CMT carcinomas indicated an association between p53 mutations and the aggressive type, which has also been concluded in HBC studies.	('aggressive type', 'Disease', (92, 107))	('p53', 'Gene', (70, 73))	('aggressive CMT carcinomas', 'Disease', (11, 36))	('mutations', 'Var', (74, 83))	('aggressive CMT carcinomas', 'Disease', 'MESH:C537989', (11, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('association', 'Interaction', (50, 61))
123954	29928319	Dogs are an excellent resource for testing these modalities in a preclinical setting, as remarkable similarities exist between humans and dogs with regard to tumor infiltrating lymphocytes (TIL), including the association between TIL numbers and mammary tumor aggressiveness, the association between the CD4+/CD8+ T-cell ratio and survival rate, the promotion of tumor progression by Th2 cells, and the association between Treg cell numbers and poor prognostic factors.	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('promotion', 'PosReg', (350, 359))	('survival rate', 'CPA', (331, 344))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (254, 274))	('humans', 'Species', '9606', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Dogs', 'Species', '9615', (0, 4))	('rat', 'Species', '10116', (340, 343))	('tumor', 'Disease', (254, 259))	('association', 'Interaction', (210, 221))	('rat', 'Species', '10116', (321, 324))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (363, 368))	('association', 'Interaction', (280, 291))	('tumor', 'Disease', (158, 163))	('CD4+/CD8+', 'Var', (304, 313))	('tumor aggressiveness', 'Disease', (254, 274))	('aggressiveness', 'Phenotype', 'HP:0000718', (260, 274))	('rat', 'Species', '10116', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('dogs', 'Species', '9615', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
123959	29928319	Given the high homology between the canine genome sequence and its human counterpart, the dog model offers an excellent resource to explore prevention strategies for triple-negative breast cancer in females, particularly high-risk BRCA1/2 mutation carriers.	('mutation', 'Var', (239, 247))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('rat', 'Species', '10116', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('canine', 'Species', '9615', (36, 42))	('breast cancer', 'Disease', (182, 195))	('BRCA1/2', 'Gene', (231, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('human', 'Species', '9606', (67, 72))	('dog', 'Species', '9615', (90, 93))
123976	25385439	Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention.	('breast cancer', 'Disease', (134, 147))	('hyperglycemia', 'Disease', (9, 22))	('IGF-I pathway', 'Pathway', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inhibiting', 'Var', (66, 76))	('hyperglycemia', 'Phenotype', 'HP:0003074', (9, 22))	('hyperglycemia', 'Disease', 'MESH:D006943', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
123987	25385439	Indeed, published and as yet unpublished data from our laboratory have shown that blockade of IGF-I action in the mammary gland prevents the development of premalignant mammary lesions in different mouse models -.	('IGF-I', 'Gene', (94, 99))	('blockade', 'Var', (82, 90))	('development of premalignant mammary lesions', 'CPA', (141, 184))	('prevents', 'NegReg', (128, 136))	('rat', 'Species', '10116', (59, 62))	('mouse', 'Species', '10090', (198, 203))
124020	25385439	After completing the immunostaining for Ki67, ER, and PR and the TUNEL, there was good-quality tissue left for further staining in five cases only for phosphorylated AKT and ERK 1/2 and four cases for phosphorylated IGF-1R in both core and excision biopsies.	('AKT', 'Gene', '207', (166, 169))	('ERK 1/2', 'Gene', '5595;5594', (174, 181))	('PR', 'Gene', '5241', (54, 56))	('AKT', 'Gene', (166, 169))	('ERK 1/2', 'Gene', (174, 181))	('ER', 'Gene', '2099', (46, 48))	('IGF-1R', 'Gene', '3480', (216, 222))	('Ki67', 'Var', (40, 44))	('Ki67', 'Chemical', '-', (40, 44))	('ER', 'Gene', '2099', (174, 176))	('IGF-1R', 'Gene', (216, 222))
124021	25385439	Sections were stained for phosphorylated AKT (Ser473) and phosphorylated ERK 1/2 (Thr202/Tyr204) by using rabbit monoclonal primary antibodies (Cell Signaling Technologies, Danvers, MA, USA) and biotinylated anti-rabbit secondary antibodies, streptavidin-HRP, and DAB for detection.	('ERK 1/2', 'Gene', (73, 80))	('Thr202', 'Chemical', '-', (82, 88))	('Tyr204', 'Chemical', '-', (89, 95))	('Ser473', 'Var', (46, 52))	('Ser473', 'Chemical', '-', (46, 52))	('AKT', 'Gene', '207', (41, 44))	('rabbit', 'Species', '9986', (213, 219))	('DAB', 'Chemical', 'MESH:D015100', (264, 267))	('rabbit', 'Species', '9986', (106, 112))	('ERK 1/2', 'Gene', '5595;5594', (73, 80))	('AKT', 'Gene', (41, 44))
124025	25385439	To quantify the phosphorylated IGF-1R (Y1161) ten images per case, which included glandular tissue, were randomly imaged using 40x objective with 0.95 numerical aperture Zeiss Plan-Apochromat objective on a Zeiss Axionvert equipped with epifluorescence.	('IGF-1R', 'Gene', (31, 37))	('IGF-1R', 'Gene', '3480', (31, 37))	('Y1161', 'Var', (39, 44))
124029	25385439	Two pathologists blinded to patient status read the slides for Ki67 and apoptosis.	('Ki67', 'Var', (63, 67))	('patient', 'Species', '9606', (28, 35))	('Ki67', 'Chemical', '-', (63, 67))	('apoptosis', 'CPA', (72, 81))
124040	25385439	Compared with pre-treatment core biopsies, pasireotide caused a reduction in cell proliferation in all proliferative and AH lesions in the excision biopsies (WSR, P = 0.001 and P = 0.031 respectively) (Figure 2A).	('rat', 'Species', '10116', (110, 113))	('AH lesions', 'Disease', 'MESH:D007039', (121, 131))	('AH lesions', 'Disease', (121, 131))	('rat', 'Species', '10116', (89, 92))	('reduction', 'NegReg', (64, 73))	('cell proliferation', 'CPA', (77, 95))	('pasireotide', 'Var', (43, 54))	('proliferative', 'CPA', (103, 116))
124046	25385439	An increase in apoptosis was found in all proliferative and AH lesions upon treatment with pasireotide (WSR, P = 0.001 and WSR, P = 0.031, respectively; Figure 4A-C), as well as in the DCIS (from 0.1% to 0.4%; Figure 4D).	('proliferative', 'CPA', (42, 55))	('apoptosis', 'CPA', (15, 24))	('AH lesions', 'Disease', 'MESH:D007039', (60, 70))	('AH lesions', 'Disease', (60, 70))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('pasireotide', 'Var', (91, 102))	('rat', 'Species', '10116', (49, 52))	('increase', 'PosReg', (3, 11))
124065	25385439	In recent years a number of IGF-I inhibitors have been tested in the treatment of various carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('inhibitors', 'Var', (34, 44))	('carcinomas', 'Disease', (90, 100))	('IGF-I', 'Gene', (28, 33))	('tested', 'Reg', (55, 61))
124068	25385439	Studies from our laboratory show that growth hormone-induced IGF-I is essential for mammary development in mice and rats,, and that growth hormone (GH), or IGF-I absence or inhibition, block development,.	('rats', 'Species', '10116', (116, 120))	('inhibition', 'NegReg', (173, 183))	('IGF-I', 'Gene', (156, 161))	('mice', 'Species', '10090', (107, 111))	('rat', 'Species', '10116', (116, 119))	('rat', 'Species', '10116', (21, 24))	('development', 'CPA', (191, 202))	('absence', 'Var', (162, 169))	('block', 'NegReg', (185, 190))
124071	25385439	Although a side-by-side comparison of pasireotide with tamoxifen was not done, the experiments provided evidence that pasireotide was at least as, or possibly more, effective than tamoxifen in preventing hormone-induced hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (220, 231))	('pasireotide', 'Var', (118, 129))	('hyperplasia', 'Disease', (220, 231))	('tamoxifen', 'Chemical', 'MESH:D013629', (180, 189))	('tamoxifen', 'Chemical', 'MESH:D013629', (55, 64))
124079	25385439	Importantly, pasireotide also reduced the percentage of proliferating cells in one case of DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('rat', 'Species', '10116', (63, 66))	('reduced', 'NegReg', (30, 37))	('pasireotide', 'Var', (13, 24))
124083	25385439	Deregulated proliferation underlies the entire spectrum of precancerous breast lesions and it is also a main feature of established cancer.	('cancer', 'Disease', (132, 138))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('precancerous breast lesions', 'Disease', 'MESH:D011230', (59, 86))	('precancerous breast lesions', 'Disease', (59, 86))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rat', 'Species', '10116', (19, 22))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
124088	25385439	The inter-rater agreement was excellent, Pasireotide was also found to significantly increase apoptosis in proliferative lesions, AH, and in one case of DCIS.	('rat', 'Species', '10116', (114, 117))	('Pasireotide', 'Var', (41, 52))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('AH', 'Disease', 'MESH:D007039', (130, 132))	('rat', 'Species', '10116', (10, 13))	('increase', 'PosReg', (85, 93))	('apoptosis', 'CPA', (94, 103))
124110	25385439	Further trials might support the concept that IGF-I inhibition might serve as a chemoprevention tool for breast cancer, especially in patients unable to tolerate direct estrogen inhibition.	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('patients', 'Species', '9606', (134, 142))	('rat', 'Species', '10116', (157, 160))	('inhibition', 'Var', (52, 62))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('IGF-I', 'Gene', (46, 51))
124127	21812955	In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('expression', 'Var', (22, 32))	('breast carcinomas', 'Disease', 'MESH:D001943', (3, 20))	('breast carcinomas', 'Disease', (3, 20))	('estrogen receptor', 'Gene', (125, 142))	('breast carcinoma', 'Phenotype', 'HP:0003002', (3, 19))	('estradiol', 'Chemical', 'MESH:D004958', (77, 86))	('GREB1', 'Gene', (36, 41))	('AREG', 'Gene', '374', (46, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('associated', 'Reg', (55, 65))	('serum estradiol', 'MPA', (71, 86))	('breast carcinomas', 'Phenotype', 'HP:0003002', (3, 20))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))	('estrogen receptor', 'Gene', '2099', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('AREG', 'Gene', (46, 50))	('GREB1', 'Gene', '9687', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
124129	21812955	SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers.	('SCGB3A1', 'Gene', '92304', (0, 7))	('down-regulated', 'NegReg', (106, 120))	('epithelial cancers', 'Disease', 'MESH:D000077216', (129, 147))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('epithelial cancers', 'Disease', (129, 147))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('inhibits', 'NegReg', (50, 58))	('SCGB3A1', 'Gene', (0, 7))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('methylated', 'Var', (91, 101))
124132	21812955	The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('basal-like cancer', 'Phenotype', 'HP:0002671', (94, 111))	('basal-like cancers', 'Phenotype', 'HP:0002671', (94, 112))	('cancers', 'Disease', (105, 112))	('carcinogenic', 'Disease', 'MESH:D063646', (21, 33))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('silencing', 'Var', (50, 59))	('luminal', 'Disease', (77, 84))	('carcinogenic', 'Disease', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
124137	21812955	For postmenopausal women, high serum estradiol levels are associated with increased risk of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('high', 'Var', (26, 30))	('high serum estradiol', 'Phenotype', 'HP:0025134', (26, 46))	('women', 'Species', '9606', (19, 24))	('estradiol', 'Chemical', 'MESH:D004958', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
124188	21812955	There were no significant gene ontology terms enriched in the down-regulated genes with FDR < 50 (n = 8), although response to steroid hormone stimulus was the most enriched term with three observed genes (prostaglandin-endoperoxide synthase 1 (PTGS1), ESR1 and GATA3)(Additional file 2).	('prostaglandin-endoperoxide synthase 1', 'Gene', '5742', (206, 243))	('PTGS1', 'Gene', (245, 250))	('GATA3', 'Gene', '2625', (262, 267))	('steroid hormone', 'Chemical', 'MESH:D013256', (127, 142))	('down-regulated', 'NegReg', (62, 76))	('ESR1', 'Gene', '2099', (253, 257))	('prostaglandin-endoperoxide synthase 1', 'Gene', (206, 243))	('FDR < 50', 'Var', (88, 96))	('ESR1', 'Gene', (253, 257))	('GATA3', 'Gene', (262, 267))	('PTGS1', 'Gene', '5742', (245, 250))
124224	21812955	Methylation of the gene is suggested to be an early event in non-BRCA-associated breast cancer.	('breast cancer', 'Disease', (81, 94))	('BRCA', 'Gene', (65, 69))	('Methylation', 'Var', (0, 11))	('BRCA', 'Gene', '672', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
124229	21812955	This could also be linked to the lack of methylation in BRCA-associated breast cancers, which are often basal-like.	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA', 'Gene', '672', (56, 60))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('methylation', 'Var', (41, 52))	('breast cancers', 'Disease', (72, 86))	('BRCA', 'Gene', (56, 60))	('lack', 'NegReg', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
124232	21812955	Women with methylation of the SCGB3A1-promoter may be at risk of developing luminal, but not basal-like, breast cancer and a reduction in serum estradiol levels may be protective for these women.	('reduction', 'NegReg', (125, 134))	('estradiol', 'Chemical', 'MESH:D004958', (144, 153))	('serum estradiol levels', 'MPA', (138, 160))	('Women', 'Species', '9606', (0, 5))	('luminal', 'Disease', (76, 83))	('reduction in serum estradiol levels', 'Phenotype', 'HP:0008214', (125, 160))	('SCGB3A1', 'Gene', (30, 37))	('methylation', 'Var', (11, 22))	('SCGB3A1', 'Gene', '92304', (30, 37))	('women', 'Species', '9606', (189, 194))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
124238	21812955	Hence, the expression of PTGS1 may increase the local production of estradiol (Figure 2).	('increase', 'PosReg', (35, 43))	('local production of estradiol', 'MPA', (48, 77))	('PTGS1', 'Gene', '5742', (25, 30))	('increase the local production of estradiol', 'Phenotype', 'HP:0025134', (35, 77))	('estradiol', 'Chemical', 'MESH:D004958', (68, 77))	('expression', 'Var', (11, 21))	('PTGS1', 'Gene', (25, 30))
124262	21812955	Our study is the first study to identify the expression of SCGB3A1, TLN2 and PTGS1 in normal breast tissue to be significantly associated with serum estradiol levels.	('SCGB3A1', 'Gene', (59, 66))	('SCGB3A1', 'Gene', '92304', (59, 66))	('serum estradiol levels', 'MPA', (143, 165))	('PTGS1', 'Gene', '5742', (77, 82))	('associated', 'Reg', (127, 137))	('TLN2', 'Gene', '83660', (68, 72))	('PTGS1', 'Gene', (77, 82))	('estradiol', 'Chemical', 'MESH:D004958', (149, 158))	('expression', 'Var', (45, 55))	('TLN2', 'Gene', (68, 72))
124264	21812955	The high beta-value in the regression equation implies a large magnitude of impact which supports the hypothesis that high serum estradiol levels increases mammographic density with both statistical and biological significance.	('high', 'Var', (118, 122))	('high serum estradiol', 'Phenotype', 'HP:0025134', (118, 138))	('increases', 'PosReg', (146, 155))	('mammographic density', 'CPA', (156, 176))	('estradiol', 'Chemical', 'MESH:D004958', (129, 138))
124272	21812955	This supports the hypothesis that high serum estradiol increases the proliferative pressure in normal breasts, which leads to an activation of mechanisms counter-acting this proliferative pressure.	('estradiol', 'Chemical', 'MESH:D004958', (45, 54))	('proliferative pressure', 'MPA', (69, 91))	('activation', 'PosReg', (129, 139))	('increases', 'PosReg', (55, 64))	('high', 'Var', (34, 38))	('high serum estradiol', 'Phenotype', 'HP:0025134', (34, 54))
124425	21054873	Furthermore, [THb] was also significantly increased in malignant sites (42.70 muM +- 29.31MAD) compared to normal (32.09 muM +- 16.73MAD) sites (P = 0.031, Figure 2C).	('increased', 'PosReg', (42, 51))	('42.70', 'Var', (72, 77))	('muM', 'Gene', (78, 81))	('muM', 'Gene', '56925', (121, 124))	('malignant', 'Var', (55, 64))	('THb', 'Chemical', '-', (14, 17))	('muM', 'Gene', (121, 124))	('muM', 'Gene', '56925', (78, 81))	('[THb]', 'MPA', (13, 18))
124437	21054873	For example, scattering was observed to be higher in FG than in IDC with an unadjusted P-value of P = 0.044; DCIS exhibited increased [beta-carotene] compared to FG with an un-adjusted P-value of P = 0.028.	('increased', 'PosReg', (124, 133))	('DCIS', 'Var', (109, 113))	('[beta-carotene]', 'MPA', (134, 149))	('beta-carotene', 'Chemical', 'MESH:D019207', (135, 148))
124442	21054873	In contrast, [beta-carotene] followed an increasing trend with increased distance of malignancy; it was highest in close sites (1+ to 2 mm) (19.00 muM +- 7.81MAD), followed by close sites (0+ to 1 mm) (15.59 muM +- 9.53MAD), then positive sites (0 mm) (13.89 muM +- 6.23MAD).	('malignancy', 'Disease', (85, 95))	('muM', 'Gene', (147, 150))	('beta-carotene', 'Chemical', 'MESH:D019207', (14, 27))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))	('1+ to 2', 'Var', (128, 135))	('muM', 'Gene', '56925', (208, 211))	('muM', 'Gene', '56925', (259, 262))	('muM', 'Gene', (208, 211))	('muM', 'Gene', (259, 262))	('muM', 'Gene', '56925', (147, 150))
124483	21054873	In contrast, [beta-carotene] was higher while scattering was lower in close sites (1+ to 2 mm) compared to close sites (0+ to 1 mm), indicative of fatty tissue.	('[beta-carotene]', 'MPA', (13, 28))	('lower', 'NegReg', (61, 66))	('higher', 'PosReg', (33, 39))	('1+ to 2 mm', 'Var', (83, 93))	('fat', 'Gene', (147, 150))	('fat', 'Gene', '2195', (147, 150))	('scattering', 'MPA', (46, 56))	('beta-carotene', 'Chemical', 'MESH:D019207', (14, 27))
124558	24729388	When the effect of tamoxifen was examined according to the location of the first event, the cumulative incidence of ipsilateral breast cancers was reduced by 31% (11.1% with tamoxifen vs. 7.7% with placebo, P = 0.02) and the cumulative incidence of contralateral breast cancers was reduced by 47% (4.9% vs. 2.3%, P = 0.010).	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (249, 277))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('ipsilateral breast cancers', 'Disease', 'MESH:D001943', (116, 142))	('breast cancers', 'Phenotype', 'HP:0003002', (263, 277))	('tamoxifen', 'Var', (174, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('contralateral breast cancers', 'Disease', (249, 277))	('tamoxifen', 'Chemical', 'MESH:D013629', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('reduced', 'NegReg', (147, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (263, 276))	('ipsilateral breast cancers', 'Disease', (116, 142))
124587	24729388	In addition to the effects of adjuvant M-F in reducing distant recurrence and death, the B-13 trial also demonstrated that M-F significantly reduced the rates of IBTR following lumpectomy plus breast irradiation.	('reduced', 'NegReg', (141, 148))	('B-13', 'Gene', '4698', (89, 93))	('M-F', 'Var', (123, 126))	('IBTR', 'Chemical', '-', (162, 166))	('B-13', 'Gene', (89, 93))	('IBTR', 'Disease', (162, 166))
124589	24729388	These effects on reduction of IBTR have persisted with 8 years of follow-up, with IBTR rates of 2.6% for patients who received M-F versus 13.4% in those who were treated with surgery alone and no chemotherapy (P =0.001).	('patients', 'Species', '9606', (105, 113))	('M-F', 'Var', (127, 130))	('IBTR', 'Disease', (30, 34))	('IBTR', 'Chemical', '-', (82, 86))	('IBTR', 'Chemical', '-', (30, 34))	('reduction', 'NegReg', (17, 26))
124595	24729388	In addition to the effects of adjuvant CMF versus methotrexate and 5-FU in reducing distant recurrence and death, the B-19 trial also demonstrated that compared to M-F, treatment with CMF significantly reduced the rates of IBTR following lumpectomy plus breast irradiation.	('reduced', 'NegReg', (202, 209))	('IBTR', 'Chemical', '-', (223, 227))	('B-19', 'Gene', (118, 122))	('B-19', 'Gene', '30811', (118, 122))	('CMF', 'Chemical', 'MESH:C034456', (184, 187))	('methotrexate', 'Chemical', 'MESH:D008727', (50, 62))	('CMF', 'Chemical', 'MESH:C034456', (39, 42))	('CMF', 'Var', (184, 187))	('distant recurrence', 'CPA', (84, 102))	('IBTR', 'Disease', (223, 227))	('5-FU', 'Chemical', 'MESH:D005472', (67, 71))
124602	24729388	Similarly to what has been shown in the previous node-negative, ER-negative NSABP trials evaluating adjuvant chemotherapy, the rate of IBTR following lumpectomy plus breast irradiation was significantly reduced with the addition of chemotherapy to tamoxifen and more so with CMFT than with M-FT.	('M-FT', 'Chemical', 'MESH:C000430', (290, 294))	('IBTR', 'Disease', (135, 139))	('reduced', 'NegReg', (203, 210))	('IBTR', 'Chemical', '-', (135, 139))	('CMFT', 'Chemical', '-', (275, 279))	('CMFT', 'Var', (275, 279))	('lumpectomy', 'Disease', (150, 160))	('tamoxifen', 'Chemical', 'MESH:D013629', (248, 257))	('ER', 'Gene', '2099', (64, 66))
124625	24729388	In the first report of the joint analysis of B-31 and N9831, a significant benefit from adding trastuzumab to adjuvant chemotherapy was evident at both local-regional and distant sites.	('trastuzumab', 'Chemical', 'MESH:D000068878', (95, 106))	('N9831', 'Var', (54, 59))	('B-31', 'Gene', (45, 49))	('B-31', 'Gene', '9595', (45, 49))	('benefit', 'PosReg', (75, 82))	('N9831', 'CellLine', 'CVCL:D425', (54, 59))
124666	28114948	Furthermore, some researchers suggest a change in the attitude towards low grade DCIS arguing that it should be regarded as a risk factor for a subsequent breast cancer rather than a malignant disease by itself.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('change', 'Reg', (40, 46))	('malignant disease', 'Disease', (183, 200))	('low grade DCIS', 'Var', (71, 85))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('malignant disease', 'Disease', 'MESH:D009369', (183, 200))
124673	28114948	Multicatheter brachytherapy is the technique with the longest experience for APBI and the only technique for which 10 year-data from a randomized controlled trial are available.	('APBI', 'Chemical', '-', (77, 81))	('APBI', 'Disease', (77, 81))	('Multicatheter', 'Var', (0, 13))
124694	28114948	The 5-year ipsilateral breast tumor recurrence rate, although within the prespecified equivalence margin, was significantly higher in the IOERT-arm with 4.4% compared to 0.4% in the WBI-arm (p < 0.001).	('breast tumor', 'Phenotype', 'HP:0100013', (23, 35))	('IOERT-arm', 'Var', (138, 147))	('ipsilateral breast tumor', 'Disease', (11, 35))	('ipsilateral breast tumor', 'Disease', 'MESH:D001943', (11, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('WBI', 'Chemical', '-', (182, 185))	('higher', 'PosReg', (124, 130))
124705	28114948	The 5 year-local recurrence rate was 1.5% in patients receiving APBI and 1.4% in patients receiving standard treatment (p = 0.86).	('year-local recurrence', 'CPA', (6, 27))	('patients', 'Species', '9606', (81, 89))	('APBI', 'Var', (64, 68))	('patients', 'Species', '9606', (45, 53))	('APBI', 'Chemical', '-', (64, 68))
124723	28114948	Axillary morbidity was significantly higher in the ALND-arm with lymphedema rates being almost twice as high as in patients treated without ALND.	('patients', 'Species', '9606', (115, 123))	('higher', 'PosReg', (37, 43))	('ALND-arm', 'Var', (51, 59))	('lymphedema', 'Disease', 'MESH:D008209', (65, 75))	('Axillary', 'Disease', (0, 8))	('lymphedema', 'Phenotype', 'HP:0001004', (65, 75))	('lymphedema', 'Disease', (65, 75))
124737	28114948	It was designed to detect a 10% benefit in overall survival in the patients treated with RNI including IMN and was thus underpowered to show a difference between the two treatment arms.	('RNI', 'Var', (89, 92))	('benefit', 'PosReg', (32, 39))	('overall survival', 'MPA', (43, 59))	('patients', 'Species', '9606', (67, 75))
124842	26185737	Furthermore, the 10 year rate of chest wall recurrence was 1.4% among women with margins <=1 mm, and 1% for those with positive resection margins (p = 0.33).	('<=1 mm', 'Var', (89, 95))	('chest wall', 'Disease', (33, 43))	('women', 'Species', '9606', (70, 75))
124844	26185737	The 10-year actuarial rate of chest wall recurrence was 3.5% (13/426) among women with high grade DCIS, <=5% (<=5/286) for those with intermediate grade DCIS, 2.5% (18/713) for those with unreported grade and <=5% (<=5/99) for those with low grade disease (p = 0.44).	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('chest wall', 'Disease', (30, 40))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('high grade', 'Var', (87, 97))	('women', 'Species', '9606', (76, 81))
124846	26185737	Among 83 women younger than 45 years with high grade DCIS, the 10 year actuarial rate of chest wall recurrence was <5%.	('chest wall', 'Disease', (89, 99))	('women', 'Species', '9606', (9, 14))	('high grade', 'Var', (42, 52))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
124848	26185737	It is well documented that factors such as young age at diagnosis, presence of high grade DCIS and close or positive resection margins are associated with an increased risk of local (in-breast) recurrence following breast-conserving therapy for DCIS, but it remains unclear if women with these features experience an increased risk of chest wall recurrence after mastectomy (Bijker et al.	('DCIS', 'Gene', (90, 94))	('high grade', 'Var', (79, 89))	('women', 'Species', '9606', (277, 282))	('chest wall', 'Disease', (335, 345))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('DCIS', 'Phenotype', 'HP:0030075', (245, 249))
124850	26185737	reported the outcomes of 214 women with DCIS treated by mastectomy with median follow-up of 4.6 years; 2 of 24 (8%) cases with margins <=1 mm developed chest wall recurrence compared to none of 187 women with wider resection margins (p = 0.013).	('women', 'Species', '9606', (29, 34))	('chest wall recurrence', 'Disease', (152, 173))	('women', 'Species', '9606', (198, 203))	('<=1 mm', 'Var', (135, 141))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))
124851	26185737	Another study including 80 women with DCIS treated by mastectomy with resection margins <10 mm with median follow-up period of 82.3 months, reported that 5 of 31 women (16%) with margins <=2 mm developed chest wall recurrence compared to 1 of 49 (2%) with wider margins (p = 0.04).	('chest', 'Disease', (204, 209))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('margins <=2 mm', 'Var', (179, 193))	('women', 'Species', '9606', (27, 32))	('women', 'Species', '9606', (162, 167))
124853	26185737	A larger single institutional study of 803 patients with median follow-up of 6.3 years found an increased risk of chest wall recurrence (5.0%) among 59 women with margins <=1 mm compared to a rate of 3.6% among 35 women with margins 1.1-2.9 mm and 1% among 744 women with wider negative resection margins (>=3 mm) (p = 0.005) (Fitzsullivan et al.).	('Fitzsullivan', 'Disease', (327, 339))	('women', 'Species', '9606', (152, 157))	('women', 'Species', '9606', (214, 219))	('patients', 'Species', '9606', (43, 51))	('Fitzsullivan', 'Disease', 'None', (327, 339))	('chest wall recurrence', 'Disease', (114, 135))	('margins <=1 mm', 'Var', (163, 177))	('women', 'Species', '9606', (261, 266))
124856	26185737	In our population, the 10 year rates of chest wall recurrence were 2.7% among 668 women with close margins <=2 mm, 1.4% among women with negative margins <=1 mm, 1% among women with positive resection margins and 2% for 436 women with margins >2 mm (p = 0.33).	('women', 'Species', '9606', (171, 176))	('women', 'Species', '9606', (82, 87))	('chest wall', 'Disease', (40, 50))	('women', 'Species', '9606', (126, 131))	('<=2 mm', 'Var', (107, 113))	('women', 'Species', '9606', (224, 229))
124857	26185737	reported a higher rate of chest wall recurrence among 16 patients with high grade DCIS and margins <=2 mm (25%) compared to 3% for 64 patients without either risk factor (p = 0.0055) after median follow-up of 61 months.	('high grade', 'Var', (71, 81))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('<=2 mm', 'Var', (99, 105))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (134, 142))	('chest wall', 'Disease', (26, 36))	('DCIS', 'Disease', (82, 86))
124865	26185737	For 83 women <45 years with high grade DCIS, the 10 year rate of chest wall recurrence was <5%.	('women', 'Species', '9606', (7, 12))	('chest wall', 'Disease', (65, 75))	('high grade', 'Var', (28, 38))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))
124874	25029110	Lysine methylation/demethylation on Histone H3 and H4 is known to affect transcription and is mediated by histone methyl transferases and histone demethylases.	('Lysine methylation/demethylation', 'Var', (0, 32))	('affect', 'Reg', (66, 72))	('transcription', 'MPA', (73, 86))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
124879	25029110	Silencing KDM2A with small interfering RNAs demonstrated increased invasion and migration of breast cancer cells by suppressing a subset of matrix metalloproteinases (MMP-2, -9, -14 and -15), as seen by real-time PCR.	('matrix metalloproteinases', 'MPA', (140, 165))	('invasion', 'CPA', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('suppressing', 'NegReg', (116, 127))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('KDM2A', 'Gene', (10, 15))	('breast cancer', 'Disease', (93, 106))	('small interfering RNAs', 'Var', (21, 43))	('increased', 'PosReg', (57, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('Silencing', 'Var', (0, 9))	('MMP-2, -9, -14 and -15', 'Gene', '4313;4318;4323;4324', (167, 189))
124880	25029110	HUVEC cells showed increased angiogenic tubule formation ability in the absence of KDM2A, with a concomitant increase in the expression of VEGF receptors, FLT-1 and KDR.	('HUVEC', 'CellLine', 'CVCL:2959', (0, 5))	('KDR', 'Gene', (165, 168))	('VEGF', 'Gene', (139, 143))	('increase', 'PosReg', (109, 117))	('FLT-1', 'Gene', '2321', (155, 160))	('expression', 'MPA', (125, 135))	('KDM2A', 'Gene', (83, 88))	('increased', 'PosReg', (19, 28))	('absence', 'Var', (72, 79))	('KDR', 'Gene', '3791', (165, 168))	('VEGF', 'Gene', '7422', (139, 143))	('FLT-1', 'Gene', (155, 160))	('angiogenic tubule formation ability', 'CPA', (29, 64))
124886	25029110	Non-methylated CpG islands constitute up to 70% of higher eukaryotic genes and KDM2A has been reported to functionally delineate the genomic architecture to differentiate the CpG islands from bulk chromatin by demethylating lysine 36.	('lysine', 'Chemical', 'MESH:D008239', (224, 230))	('lysine', 'Protein', (224, 230))	('demethylating', 'Var', (210, 223))	('KDM2A', 'Gene', (79, 84))
124888	25029110	Study on human prostate cancers showed low levels of KDM2A in prostate cancers while a recent study states that high levels of KDM2A correlates with poor prognosis in NSCLC patients.	('prostate cancers', 'Phenotype', 'HP:0012125', (15, 31))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('prostate cancers', 'Disease', (15, 31))	('patients', 'Species', '9606', (173, 181))	('prostate cancers', 'Disease', 'MESH:D011471', (62, 78))	('human', 'Species', '9606', (9, 14))	('KDM2A', 'Var', (127, 132))	('prostate cancers', 'Disease', 'MESH:D011471', (15, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('prostate cancers', 'Phenotype', 'HP:0012125', (62, 78))	('NSCLC', 'Disease', (167, 172))	('prostate cancers', 'Disease', (62, 78))
124892	25029110	It is well established that Rb mediated repression of the E2F transcription factors, especially E2Fs 1- 3, prevents cell cycle progression and the inactivation of Rb by phosphorylation mediated by cyclin dependent kinases facilitates S-phase entry.	('inactivation', 'NegReg', (147, 159))	('facilitates', 'PosReg', (222, 233))	('phosphorylation', 'Var', (169, 184))	('repression', 'NegReg', (40, 50))	('S-phase entry', 'CPA', (234, 247))	('E2Fs 1- 3', 'Gene', '1869;1870;1871', (96, 105))	('E2Fs 1- 3', 'Gene', (96, 105))	('Rb', 'Phenotype', 'HP:0009919', (28, 30))	('cell cycle progression', 'CPA', (116, 138))	('Rb', 'Phenotype', 'HP:0009919', (163, 165))	('prevents', 'NegReg', (107, 115))	('Rb', 'Gene', '5925', (163, 165))	('Rb', 'Gene', '5925', (28, 30))
124894	25029110	Our results indicate that KDM2A represses migration and invasion of breast cancer cells, and inhibits angiogenic tubule formation by endothelial cells.	('migration', 'CPA', (42, 51))	('angiogenic tubule formation by endothelial cells', 'CPA', (102, 150))	('KDM2A', 'Var', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('inhibits', 'NegReg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('represses', 'NegReg', (32, 41))	('invasion', 'CPA', (56, 64))
124895	25029110	KDM2A could bind to Rb and E2F1 and repress the transcriptional activity of E2F1.	('E2F1', 'Gene', (76, 80))	('transcriptional activity', 'MPA', (48, 72))	('Rb', 'Phenotype', 'HP:0009919', (20, 22))	('KDM2A', 'Var', (0, 5))	('Rb', 'Gene', '5925', (20, 22))	('bind', 'Interaction', (12, 16))	('repress', 'NegReg', (36, 43))	('E2F1', 'Gene', (27, 31))
124955	25029110	As shown in Figure 2A, transfection of two independent KDM2A siRNAs, KDM2A siRNA 1 and KDM2A siRNA 2, at 100 pmol concentration reduced the protein levels significantly compared to control siRNA transfected cells, as observed by Western blot analysis.	('KDM2A siRNA 1', 'Gene', '22992', (69, 82))	('transfection', 'Var', (23, 35))	('reduced', 'NegReg', (128, 135))	('KDM2A siRNA 2', 'Gene', '22992', (87, 100))	('protein levels', 'MPA', (140, 154))	('KDM2A siRNA 1', 'Gene', (69, 82))	('KDM2A siRNA 2', 'Gene', (87, 100))
124959	25029110	MCF7 cells showed a significant increase in invasion by about 145+-23% with KDM2A siRNA 1 and 118+-21% with KDM2A siRNA 2 while T47D cells showed a 48+-28% increase in invasion with KDM2A siRNA 1 and a 64+-16% increase in invasion with KDM2A siRNA 2, demonstrating that KDM2A inhibits the invasion of breast cancer cells (Figure 2B and 2C).	('breast cancer', 'Phenotype', 'HP:0003002', (301, 314))	('KDM2A siRNA 2', 'Gene', '22992', (108, 121))	('inhibits', 'NegReg', (276, 284))	('invasion', 'CPA', (289, 297))	('breast cancer', 'Disease', 'MESH:D001943', (301, 314))	('KDM2A siRNA 1', 'Gene', (76, 89))	('KDM2A', 'Var', (270, 275))	('breast cancer', 'Disease', (301, 314))	('KDM2A siRNA 1', 'Gene', '22992', (182, 195))	('KDM2A siRNA 2', 'Gene', (236, 249))	('invasion', 'MPA', (44, 52))	('MCF7', 'CellLine', 'CVCL:0031', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('KDM2A siRNA 2', 'Gene', (108, 121))	('KDM2A siRNA 1', 'Gene', '22992', (76, 89))	('increase', 'PosReg', (32, 40))	('T47D', 'CellLine', 'CVCL:0553', (128, 132))	('KDM2A siRNA 2', 'Gene', '22992', (236, 249))	('KDM2A siRNA 1', 'Gene', (182, 195))
124961	25029110	Taken together, these results show that KDM2A represses invasion and migration of breast cancer cells, and depletion of KDM2A enhances these processes.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('KDM2A', 'Gene', (120, 125))	('KDM2A', 'Var', (40, 45))	('represses', 'NegReg', (46, 55))	('enhances', 'PosReg', (126, 134))	('depletion', 'Var', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
124965	25029110	Silencing KDM2A led to a significant increase (upto 2 fold) in the number of tubules and sprouting points (Figures 3A and 3B) compared to control siRNA transfected cells, both in the presence or absence of VEGF.	('VEGF', 'Gene', '7422', (206, 210))	('KDM2A', 'Gene', (10, 15))	('increase', 'PosReg', (37, 45))	('Silencing', 'Var', (0, 9))	('VEGF', 'Gene', (206, 210))
124967	25029110	RT-PCR results show that both FLT-1 and KDR mRNA expression increased in HUVECs depleted of KDM2A by 2.2+-0.11-fold and 1.7+-0.9-fold respectively (Figure 3C).	('FLT-1', 'Gene', '2321', (30, 35))	('KDR', 'Gene', '3791', (40, 43))	('FLT-1', 'Gene', (30, 35))	('expression', 'MPA', (49, 59))	('HUVEC', 'CellLine', 'CVCL:2959', (73, 78))	('depleted', 'Var', (80, 88))	('KDR', 'Gene', (40, 43))	('increased', 'PosReg', (60, 69))	('KDM2A', 'Gene', (92, 97))
124970	25029110	Current data suggests that KDM2A works in conjunction with E2F1 to affect FLT-1 and KDR expression in endothelial cells and MMP expression in breast cancer cells.	('FLT-1', 'Gene', (74, 79))	('KDR', 'Gene', '3791', (84, 87))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('affect', 'Reg', (67, 73))	('MMP expression', 'MPA', (124, 138))	('KDM2A', 'Var', (27, 32))	('breast cancer', 'Disease', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('KDR', 'Gene', (84, 87))	('FLT-1', 'Gene', '2321', (74, 79))
124971	25029110	The finding that KDM2A could modulate many processes known to be regulated by E2F1 raises the possibility that KDM2A could be executing these functions through the modulation of the Rb-E2F1 transcriptional regulatory pathway.	('modulate', 'Reg', (29, 37))	('KDM2A', 'Var', (17, 22))	('Rb', 'Phenotype', 'HP:0009919', (182, 184))	('modulation', 'Reg', (164, 174))	('E2F1', 'Gene', (78, 82))	('Rb', 'Gene', '5925', (182, 184))	('KDM2A', 'Var', (111, 116))
124978	25029110	It was found that KDM2A bound to GST-Rb and GST-E2F1 beads, but there was no binding to glutathione sepharose beads carrying uncoupled GST (Figure 5A).	('bound', 'Interaction', (24, 29))	('GST-E2F1', 'Gene', (44, 52))	('Rb', 'Gene', '5925', (37, 39))	('KDM2A', 'Var', (18, 23))	('sepharose', 'Chemical', 'MESH:D012685', (100, 109))	('glutathione', 'Chemical', 'MESH:D005978', (88, 99))	('Rb', 'Phenotype', 'HP:0009919', (37, 39))
124979	25029110	This suggests that KDM2A can bind to both Rb and E2F1 and this binding is probably direct.	('bind', 'Interaction', (29, 33))	('Rb', 'Phenotype', 'HP:0009919', (42, 44))	('Rb', 'Gene', '5925', (42, 44))	('E2F1', 'Gene', (49, 53))	('KDM2A', 'Var', (19, 24))
124992	25029110	Since KDM2A could bind to E2F1, transient transfection experiments were conducted in MCF7 breast cancer cells to assess whether KDM2A had an effect on the transcriptional activity of E2F1.	('effect', 'Reg', (141, 147))	('E2F1', 'Gene', (183, 187))	('bind', 'Interaction', (18, 22))	('transcriptional activity', 'MPA', (155, 179))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('E2F1', 'Gene', (26, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('MCF7 breast cancer', 'Disease', (85, 103))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (85, 103))	('KDM2A', 'Var', (128, 133))
124994	25029110	The above data lends support to the findings that KDM2A represses angiogenic and invasive properties in endothelial and breast cancer cells, probably through repressing E2F1-mediated transcription.	('invasive properties', 'CPA', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('KDM2A', 'Var', (50, 55))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('represses', 'NegReg', (56, 65))	('E2F1-mediated', 'Gene', (169, 182))	('repressing', 'NegReg', (158, 168))	('angiogenic', 'CPA', (66, 76))
125002	25029110	Taken together, these results indicate that the E2F1-mediated expression of MMP2, MMP9, MMP14, and MMP15 might be repressed by KDM2A, eventually hindering the migration and invasion of breast cancer cells.	('MMP14', 'Gene', '4323', (88, 93))	('MMP15', 'Gene', '4324', (99, 104))	('invasion', 'CPA', (173, 181))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('MMP15', 'Gene', (99, 104))	('MMP14', 'Gene', (88, 93))	('hindering', 'NegReg', (145, 154))	('breast cancer', 'Disease', (185, 198))	('E2F1-mediated', 'Var', (48, 61))	('migration', 'CPA', (159, 168))	('MMP2', 'Gene', (76, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('MMP9', 'Gene', (82, 86))	('MMP2', 'Gene', '4313', (76, 80))	('MMP9', 'Gene', '4318', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
125005	25029110	ChIP assays revealed that similar to E2F1, KDM2A also occupied the promoters of KDR and FLT-1 (Figure 6A).	('KDM2A', 'Var', (43, 48))	('KDR', 'Gene', '3791', (80, 83))	('FLT-1', 'Gene', (88, 93))	('KDR', 'Gene', (80, 83))	('FLT-1', 'Gene', '2321', (88, 93))
125008	25029110	It was found that co-transfection of E2F1 alone led to a significant induction of both KDR and FLT-1 promoters (Figures 6F and G); co-transfection of KDM2A along with E2F1 considerably repressed the E2F1-mediated induction of KDR and FLT-1.	('KDR', 'Gene', (226, 229))	('KDM2A', 'Var', (150, 155))	('FLT-1', 'Gene', '2321', (234, 239))	('FLT-1', 'Gene', '2321', (95, 100))	('KDR', 'Gene', (87, 90))	('FLT-1', 'Gene', (95, 100))	('FLT-1', 'Gene', (234, 239))	('KDR', 'Gene', '3791', (226, 229))	('KDR', 'Gene', '3791', (87, 90))
125009	25029110	These results indicate that E2F1-mediated transcriptional activation of KDR and FLT-1 is significantly repressed by KDM2A, thereby inhibiting the angiogenic tubule formation.	('KDM2A', 'Var', (116, 121))	('angiogenic tubule formation', 'CPA', (146, 173))	('KDR', 'Gene', (72, 75))	('E2F1-mediated', 'Var', (28, 41))	('FLT-1', 'Gene', '2321', (80, 85))	('inhibiting', 'NegReg', (131, 141))	('activation', 'PosReg', (58, 68))	('FLT-1', 'Gene', (80, 85))	('KDR', 'Gene', '3791', (72, 75))
125020	25029110	Overexpression of KDM2A in lung cancer was associated with poor prognosis and is believed to promote lung tumorigenesis by repressing DUSP3 (dual-specificity phosphatase 3) and activating ERK1/2.	('dual-specificity phosphatase 3', 'Gene', (141, 171))	('ERK1/2', 'Gene', '5595;5594', (188, 194))	('dual-specificity phosphatase 3', 'Gene', '1845', (141, 171))	('DUSP3', 'Gene', '1845', (134, 139))	('promote', 'PosReg', (93, 100))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('KDM2A', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('repressing', 'NegReg', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('DUSP3', 'Gene', (134, 139))	('activating', 'PosReg', (177, 187))	('ERK1/2', 'Gene', (188, 194))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('tumor', 'Disease', (106, 111))
125024	25029110	The expression of KDM2A in the MEPCs also suggested a tumor suppressor function for KDM2A, consistent with the myoepithelial cell function in the breast; supporting this contention, KDM2A repressed migration and invasion of breast cancer cells.	('myoepithelial', 'Disease', (111, 124))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('myoepithelial', 'Disease', 'MESH:D009208', (111, 124))	('tumor', 'Disease', (54, 59))	('KDM2A', 'Var', (182, 187))	('breast cancer', 'Disease', (224, 237))	('invasion', 'CPA', (212, 220))	('migration', 'CPA', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('repressed', 'NegReg', (188, 197))
125035	25029110	Not surprisingly, KDM2A depletion resulted in increased VEGF receptors, FLT1 and KDR activity.	('VEGF', 'Gene', (56, 60))	('FLT1', 'Gene', (72, 76))	('KDR', 'Gene', '3791', (81, 84))	('increased', 'PosReg', (46, 55))	('depletion', 'Var', (24, 33))	('FLT1', 'Gene', '2321', (72, 76))	('KDM2A depletion', 'Var', (18, 33))	('KDR', 'Gene', (81, 84))	('VEGF', 'Gene', '7422', (56, 60))
125036	25029110	We have previously shown that E2F1 occupies the promoters of FLT1 and KDR and enhances the expression of these receptors.	('expression', 'MPA', (91, 101))	('FLT1', 'Gene', '2321', (61, 65))	('KDR', 'Gene', (70, 73))	('enhances', 'PosReg', (78, 86))	('E2F1', 'Var', (30, 34))	('KDR', 'Gene', '3791', (70, 73))	('FLT1', 'Gene', (61, 65))
125037	25029110	Simultaneously, KDM2A suppressed different MMPs in the presence of E2F1.	('suppressed', 'NegReg', (22, 32))	('MMPs', 'Gene', '4313;4318;4323;4324', (43, 47))	('E2F1', 'Var', (67, 71))	('MMPs', 'Gene', (43, 47))	('KDM2A', 'Var', (16, 21))
125038	25029110	MMPs not only facilitate invasion of cancer cells by degrading extracellular matrices but also facilitate angiogenesis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('MMPs', 'Var', (0, 4))	('extracellular', 'MPA', (63, 76))	('cancer', 'Disease', (37, 43))	('facilitate', 'PosReg', (14, 24))	('degrading', 'NegReg', (53, 62))	('invasion', 'CPA', (25, 33))	('angiogenesis', 'CPA', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('facilitate', 'PosReg', (95, 105))
125044	22458887	Selection criteria included patients with pTis-T2N0 disease, <= 3 cm unifocal tumors, and negative margins who underwent breast conservation surgery.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('unifocal tumors', 'Disease', 'MESH:D009369', (69, 84))	('unifocal tumors', 'Disease', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('pTis-T2N0', 'Var', (42, 51))	('patients', 'Species', '9606', (28, 36))
125090	22458887	that suggested dose-volume predictors for fat necrosis, our dosimetric goals expanded to limit the volume receiving more than 150% (V150) of the prescription dose to <= 50 mL, V200 <= 20 mL, and 1-V150/V100 >= 0.70.	('V200 <', 'Var', (176, 182))	('necrosis', 'Disease', (46, 54))	('necrosis', 'Disease', 'MESH:D009336', (46, 54))	('fat', 'Disease', (42, 45))	('fat necrosis', 'Phenotype', 'HP:0010885', (42, 54))
125205	21118480	Gene amplification was assessed using the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria for single HER2 probe testing (diploid, 1 to 2.5 copies/nucleus; polysomy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/nucleus; and high-level amplification >10 copies/nucleus) and for dual HER2/CHR17 probe testing (nonamplified ratio <1.8; equivocal ratio, 1.8 to 2.2; gene amplification, >2.2).	('HER2', 'Gene', '2064', (138, 142))	('HER2', 'Gene', (414, 418))	('HER2', 'Gene', '2064', (414, 418))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('polysomy', 'Var', (232, 240))	('HER2', 'Gene', (178, 182))	('HER2', 'Gene', (138, 142))	('HER2', 'Gene', '2064', (178, 182))
125245	21118480	We also assessed the prognostic implications of triple-negative (ER-, PR- and HER2-negative) vs. non triple-negative DCIS.	('PR', 'Gene', '5241', (70, 72))	('ER', 'Gene', '2099', (79, 81))	('ER', 'Gene', '2099', (65, 67))	('HER2', 'Gene', (78, 82))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('triple-negative', 'Var', (48, 63))	('HER2', 'Gene', '2064', (78, 82))
125247	21118480	Triple-negative tumors had a HR of 1.1 (95% CI, 0.4-2.7) and 1.1 (0.4-2.9) for local recurrence compared with the non triple-negative in the univariate and multivariate analyses, respectively.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('Triple-negative', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('local recurrence', 'CPA', (79, 95))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))
125289	29495885	However, when it comes to low-grade DCIS, this standard of care has been questioned by several groups, as recent studies have suggested that it does not seem to increase the breast cancer-specific survival for patients with low-grade DCIS at the time of diagnosis, and the rise in DCIS diagnoses (and treatment) has not been accompanied by a corresponding reduction in invasive cancer incidence (Narod et al.,; Sagara et al.,).	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('invasive cancer', 'Disease', (369, 384))	('DCIS', 'Phenotype', 'HP:0030075', (281, 285))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('invasive cancer', 'Disease', 'MESH:D009362', (369, 384))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('patients', 'Species', '9606', (210, 218))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('low-grade', 'Var', (224, 233))
125296	29495885	Our ultimate goal is to develop a new alternative that can be employed for local treatment of low grade DCIS as well as other pre-cancer lesions and benign diseases that increase the risk for development of breast cancer.	('benign diseases', 'Disease', (149, 164))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('cancer lesions', 'Disease', 'MESH:D009369', (130, 144))	('benign diseases', 'Disease', 'MESH:D009369', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('low grade', 'Var', (94, 103))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('cancer lesions', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', (207, 220))
125350	29495885	Our goals in this experiment were to assess the effect of nanoencapsulation on C6 ceramide cytotoxicity, and whether the presence of tributyrin in the formulation potentiates drug cytotoxicity.	('cytotoxicity', 'Disease', (180, 192))	('C6 ceramide', 'Chemical', 'MESH:C101954', (79, 90))	('potentiates', 'PosReg', (163, 174))	('presence', 'Var', (121, 129))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('tributyrin', 'Chemical', 'MESH:C005830', (133, 143))	('drug cytotoxicity', 'Disease', 'MESH:D064420', (175, 192))	('drug cytotoxicity', 'Disease', (175, 192))	('cytotoxicity', 'Disease', (91, 103))
125383	29495885	Ideally, nanocarriers should improve the cytotoxicity of anti-tumor drugs mainly against cancer cells.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('nanocarriers', 'Var', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cytotoxicity', 'Disease', (41, 53))	('cancer', 'Disease', (89, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))	('improve', 'PosReg', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
125399	29495885	In accordance with previous observations, NAOH (positive control) caused lysis, coagulation and severe hemorrhage during the studied time period, resulting in a score of 17.1 +- 0.4, which classifies this solution as severe irritant (McKenzie et al.,; Fangueiro et al.,).	('hemorrhage', 'Disease', (103, 113))	('coagulation', 'CPA', (80, 91))	('hemorrhage', 'Disease', 'MESH:D006470', (103, 113))	('lysis', 'CPA', (73, 78))	('NAOH', 'Var', (42, 46))	('NAOH', 'Chemical', '-', (42, 46))
125417	29495885	These results demonstrate that incorporation in the nanoemulsion increases C6 Ceramide cytotoxicity, and that presence of tributyrin potentiates this effect.	('presence', 'Var', (110, 118))	('nanoemulsion increases C6 Ceramide cytotoxicity', 'Disease', 'MESH:C567307', (52, 99))	('nanoemulsion increases C6 Ceramide cytotoxicity', 'Disease', (52, 99))	('potentiates', 'PosReg', (133, 144))	('rat', 'Species', '10116', (21, 24))	('tributyrin', 'Chemical', 'MESH:C005830', (122, 132))	('rat', 'Species', '10116', (38, 41))
125426	29495885	Similarly to what we observed for transformed cells, nanoencapsulation of C6 ceramide in the selected nanocarrier promoted a shift to the left of the viability curve, demonstrating increased cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('nanoencapsulation', 'Var', (53, 70))	('shift', 'MPA', (125, 130))	('C6 ceramide', 'Chemical', 'MESH:C101954', (74, 85))	('rat', 'Species', '10116', (174, 177))	('increased', 'PosReg', (181, 190))	('cytotoxicity', 'Disease', (191, 203))
125437	29495885	Intraductal administration of drugs for treatment of low grade DCIS and other pre-cancer lesions and diseases that increase the risk for breast cancer represents a new strategy to combine efficacy and reduction of systemic adverse effects frequently observed in cancer treatment.	('cancer', 'Disease', (262, 268))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer lesions', 'Disease', 'MESH:D009369', (82, 96))	('rat', 'Species', '10116', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (144, 150))	('rat', 'Species', '10116', (20, 23))	('low grade', 'Var', (53, 62))	('cancer lesions', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
125445	29495885	Even when targeting is possible, healthy areas in the administration site should be safeguarded, especially in the case of small lesions that do not largely compromise the tissue architecture such as atypical and pre-tumor breast lesions and low grade DCIS (Benson et al.,; Akram et al.,).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor breast lesions', 'Disease', (217, 237))	('tumor breast lesions', 'Disease', 'MESH:D061325', (217, 237))	('atypical', 'Disease', (200, 208))	('rat', 'Species', '10116', (62, 65))	('low grade', 'Var', (242, 251))	('DCIS', 'Phenotype', 'HP:0030075', (252, 256))
125482	27589390	The high expression of lipogenic genes, such as sterol regulatory element-binding proteins (SREBPs), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1), appears early in oncogenesis, and lipid accumulation confers cell survival in epithelial stem-like cells in DCIS and promotes the transition of DCIS to invasive cancer.	('lipid accumulation', 'Var', (199, 217))	('FAS', 'Gene', '2194', (122, 125))	('fatty acid synthase', 'Gene', '2194', (101, 120))	('DCIS', 'Disease', (309, 313))	('acetyl-CoA carboxylase 1', 'Gene', (131, 155))	('lipid', 'Chemical', 'MESH:D008055', (199, 204))	('FAS', 'Gene', (122, 125))	('ACC-1', 'Gene', (157, 162))	('fatty acid synthase', 'Gene', (101, 120))	('ACC-1', 'Gene', '31', (157, 162))	('acetyl-CoA carboxylase 1', 'Gene', '31', (131, 155))	('invasive cancer', 'Disease', (317, 332))	('promotes', 'PosReg', (282, 290))	('confers', 'PosReg', (218, 225))	('cell survival', 'CPA', (226, 239))	('lipogenic genes', 'Gene', (23, 38))	('invasive cancer', 'Disease', 'MESH:D009362', (317, 332))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
125499	27589390	The lower chambers were filled with medium supplemented with 2% FBS and 0.1 mM OA or 0.25 mM PA in the presence or absence of 10 muM LY294002, 10 muM PD98059 or 10 muM FAK PF573228.	('muM', 'Gene', (129, 132))	('LY294002', 'Chemical', 'MESH:C085911', (133, 141))	('FBS', 'Disease', 'MESH:D005198', (64, 67))	('PD98059', 'Chemical', 'MESH:C093973', (150, 157))	('muM', 'Gene', (164, 167))	('OA', 'Chemical', 'MESH:D019301', (79, 81))	('FAK', 'Gene', (168, 171))	('FAK', 'Gene', '5747', (168, 171))	('muM', 'Gene', '56925', (146, 149))	('PA', 'Chemical', 'MESH:D019308', (93, 95))	('PF573228', 'Chemical', 'MESH:C521108', (172, 180))	('FBS', 'Disease', (64, 67))	('LY294002', 'Var', (133, 141))	('muM', 'Gene', (146, 149))	('muM', 'Gene', '56925', (129, 132))	('PD98059', 'Var', (150, 157))	('muM', 'Gene', '56925', (164, 167))
125527	27589390	The migrating MCF10DCIS.COM cells increased more than 2-fold by treatment with 0.1 mM OA but not 0.25 mM PA (**p<0.01, Fig 1C).	('migrating', 'CPA', (4, 13))	('PA', 'Chemical', 'MESH:D019308', (105, 107))	('0.1 mM', 'Var', (79, 85))	('OA', 'Chemical', 'MESH:D019301', (86, 88))	('increased', 'PosReg', (34, 43))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (14, 27))
125529	27589390	Wound healing to monitor lateral migration was assayed in MCF10DCIS.COM cells; 0.1 mM OA significantly enhanced the lateral migration ability of MCF10DCIS.COM cells (Fig 1D).	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (145, 158))	('lateral migration ability', 'CPA', (116, 141))	('OA', 'Chemical', 'MESH:D019301', (86, 88))	('enhanced', 'PosReg', (103, 111))	('MCF10DCIS.COM', 'Var', (145, 158))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (58, 71))
125532	27589390	The treatment of 0.1 mM OA in MCF10DCIS.COM cells resulted in a 3-fold increase by quantitative analysis of Oil Red O staining (**p<0.01, Fig 2B).	('Oil Red O', 'Chemical', 'MESH:C011049', (108, 117))	('MCF10DCIS.COM', 'Var', (30, 43))	('Oil Red O staining', 'MPA', (108, 126))	('OA', 'Chemical', 'MESH:D019301', (24, 26))	('increase', 'PosReg', (71, 79))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (30, 43))
125534	27589390	When compared to SREBP-1, FAS and ACC-1 levels between MCF10DCIS.COM and SUM225 cells, the SREBP-1 level was higher in MCF10DCIS.COM cells than SUM225 cells (1.91 +- 0.17 vs 0.57 +- 0.17, *p<0.05, Fig 2D top).	('SREBP-1', 'Gene', (91, 98))	('MCF10DCIS.COM', 'Var', (119, 132))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (55, 68))	('higher', 'PosReg', (109, 115))	('SREBP-1', 'Gene', '6720', (91, 98))	('FAS', 'Gene', '2194', (26, 29))	('FAS', 'Gene', (26, 29))	('ACC-1', 'Gene', (34, 39))	('SREBP-1', 'Gene', '6720', (17, 24))	('ACC-1', 'Gene', '31', (34, 39))	('SREBP-1', 'Gene', (17, 24))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (119, 132))
125535	27589390	The FAS level was higher in SUM225 cells than MCF10DCIS.COM cells (1.56 +- 0.17 vs 0.88 +- 0.17, *p<0.05, Fig 2D top).	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (46, 59))	('higher', 'PosReg', (18, 24))	('SUM225', 'Var', (28, 34))	('FAS', 'Gene', '2194', (4, 7))	('FAS', 'Gene', (4, 7))
125536	27589390	The expression level of ACC-1 was similar between MCF10DCIS.COM cells and SUM225 cells (Fig 2D top).	('MCF10DCIS.COM', 'Var', (50, 63))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (50, 63))	('ACC-1', 'Gene', '31', (24, 29))	('ACC-1', 'Gene', (24, 29))
125541	27589390	Pretreatment with potent chemical inhibitors of PI3K (LY294002, 20muM), MEK (PD98059, 20muM), or FAK (PF573228, 5muM) caused cell death and significantly suppressed OA-induced cell proliferation ability (*p<0.05, **p<0.01, Fig 3C).	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('muM', 'Gene', '56925', (66, 69))	('muM', 'Gene', (66, 69))	('MEK', 'Gene', (72, 75))	('muM', 'Gene', '56925', (113, 116))	('muM', 'Gene', (113, 116))	('PF573228', 'Var', (102, 110))	('PF573228', 'Chemical', 'MESH:C521108', (102, 110))	('OA-induced cell proliferation ability', 'CPA', (165, 202))	('muM', 'Gene', '56925', (88, 91))	('FAK', 'Gene', (97, 100))	('muM', 'Gene', (88, 91))	('OA', 'Chemical', 'MESH:D019301', (165, 167))	('PI3K', 'Var', (48, 52))	('LY294002', 'Var', (54, 62))	('cell death', 'CPA', (125, 135))	('FAK', 'Gene', '5747', (97, 100))	('suppressed', 'NegReg', (154, 164))	('PD98059', 'Chemical', 'MESH:C093973', (77, 84))	('MEK', 'Gene', '5609', (72, 75))	('PD98059', 'Var', (77, 84))
125542	27589390	OA-enhanced migration ability was also inhibited by pretreatment with PI3K, MEK and FAK inhibitors, and the result was statistically significant (*p<0.05, Fig 3D).	('inhibited', 'NegReg', (39, 48))	('FAK', 'Gene', (84, 87))	('FAK', 'Gene', '5747', (84, 87))	('OA', 'Chemical', 'MESH:D019301', (0, 2))	('MEK', 'Gene', (76, 79))	('PI3K', 'Var', (70, 74))	('MEK', 'Gene', '5609', (76, 79))	('migration ability', 'CPA', (12, 29))
125544	27589390	Our data indicate the presence of a large, clearly distinguishable subpopulation of ALDH-positive cells in MCF10DCIS.COM cells compared to SUM225 cells.	('ALDH-positive', 'Gene', (84, 97))	('MCF10DCIS.COM', 'Var', (107, 120))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (107, 120))
125566	27589390	The cell viabilities in untreated ALDHhigh and ALDHlow cells were significantly decreased by treatment with PI3K and FAK inhibitors, and the OA-induced proliferative activity in ALDHhigh and ALDHlow cells was significantly suppressed by PI3K, MEK and FAK inhibitors (*p<0.05, **p<0.01, Fig 6C).	('OA-induced', 'Disease', (141, 151))	('proliferative activity', 'CPA', (152, 174))	('cell viabilities', 'CPA', (4, 20))	('PI3K', 'Var', (237, 241))	('OA', 'Chemical', 'MESH:D019301', (141, 143))	('PI3K', 'Var', (108, 112))	('suppressed', 'NegReg', (223, 233))	('decreased', 'NegReg', (80, 89))	('FAK', 'Gene', (251, 254))	('FAK', 'Gene', '5747', (251, 254))	('FAK', 'Gene', '5747', (117, 120))	('MEK', 'Gene', (243, 246))	('FAK', 'Gene', (117, 120))	('MEK', 'Gene', '5609', (243, 246))
125568	27589390	Adding the PI3K, MEK and FAK inhibitors significantly decreased migration in untreated ALDHlow cells and strongly reduced OA-augmented migration of ALDHlow cells under the basal levels obtained in the absence of OA (*p<0.05, **p<0.01, Fig 6F right).	('MEK', 'Gene', (17, 20))	('OA', 'Chemical', 'MESH:D019301', (212, 214))	('migration', 'CPA', (135, 144))	('reduced', 'NegReg', (114, 121))	('MEK', 'Gene', '5609', (17, 20))	('PI3K', 'Var', (11, 15))	('FAK', 'Gene', (25, 28))	('FAK', 'Gene', '5747', (25, 28))	('decreased', 'NegReg', (54, 63))	('migration', 'CPA', (64, 73))	('OA', 'Chemical', 'MESH:D019301', (122, 124))
125585	27589390	In our study, OA treatment resulted in lipid accumulation in MCF10DCIS.COM cells but not SUM225 cells.	('MCF10DCIS.COM', 'Var', (61, 74))	('OA', 'Chemical', 'MESH:D019301', (14, 16))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (61, 74))	('lipid accumulation', 'MPA', (39, 57))	('lipid', 'Chemical', 'MESH:D008055', (39, 44))
125624	22323911	In a univariate analysis, ANXA1 positivity tended to be related with poor breast cancer-related survival (p=0.062); however, the same results was not realized in multivariate results (p=0.406).	('poor breast cancer', 'Disease', 'MESH:D001943', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('poor breast cancer', 'Disease', (69, 87))	('ANXA1', 'Gene', (26, 31))	('positivity', 'Var', (32, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
125658	22323911	ANXA1 positivity was 87.7% in normal tissues, 53.2% in benign diseases, 14.3% in DCIS, and 30.9% in invasive carcinoma.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('invasive carcinoma', 'Disease', (100, 118))	('benign diseases', 'Disease', (55, 70))	('positivity', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ANXA1', 'Gene', (0, 5))	('invasive carcinoma', 'Disease', 'MESH:D009361', (100, 118))	('DCIS', 'Disease', (81, 85))
125667	22323911	HER2 positivity and advanced stage were associated with poor RFS in multivariate analysis (p=0.037 and p=0.048, respectively).	('poor', 'NegReg', (56, 60))	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('RFS', 'MPA', (61, 64))
125687	22323911	In the current study, ANXA1 expression was significantly correlated with unfavorable prognostic features of breast cancer, such as hormone receptor negativity (p<0.001), positive HER2 status and TNBC type (p<0.001), high nuclear grade (p=0.004).	('expression', 'MPA', (28, 38))	('correlated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ANXA1', 'Gene', (22, 27))	('HER2', 'Gene', (179, 183))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('positive', 'Var', (170, 178))	('HER2', 'Gene', '2064', (179, 183))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
125688	22323911	The ANXA1 positivity was also correlated with poor RFS in some groups of invasive breast cancer such as node positive, HER2 positive and non-TNBC.	('invasive breast cancer', 'Disease', 'MESH:D001943', (73, 95))	('RFS', 'MPA', (51, 54))	('poor', 'NegReg', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('HER2', 'Gene', (119, 123))	('positivity', 'Var', (10, 20))	('HER2', 'Gene', '2064', (119, 123))	('invasive breast cancer', 'Disease', (73, 95))	('ANXA1', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
125692	22323911	However, in cases of invasive breast cancer, ANXA1 positivity was significantly correlated with unfavorable prognostic factors.	('correlated', 'Reg', (80, 90))	('ANXA1', 'Gene', (45, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('invasive breast cancer', 'Disease', (21, 43))	('positivity', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('invasive breast cancer', 'Disease', 'MESH:D001943', (21, 43))
125708	21453513	The tumor antigen loss was due to hypermethylation of the neu promoter and loss of neu both at mRNA and protein levels, resulting in escape of the tumor from further neu-specific immune responses.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('escape', 'MPA', (133, 139))	('hypermethylation', 'Var', (34, 50))	('loss', 'NegReg', (18, 22))	('neu', 'Gene', '2064', (166, 169))	('neu', 'Gene', (83, 86))	('neu', 'Gene', (166, 169))	('neu', 'Gene', '2064', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('loss', 'NegReg', (75, 79))	('neu', 'Gene', (58, 61))	('neu', 'Gene', '2064', (83, 86))
125723	21453513	After Ficoll density gradient separation, PBMCs were cultured at 37 C for 2 hr, adherent cells were used for the generation of monocyte-derived DCs in the presence of GM-CSF (100 ng/ml) and IL-4 (50 ng/ml), as previously described by our group.	('GM-CSF', 'Gene', (167, 173))	('100 ng/ml', 'Var', (175, 184))	('GM-CSF', 'Gene', '1437', (167, 173))	('rat', 'Species', '10116', (117, 120))	('IL-4', 'Gene', '3565', (190, 194))	('rat', 'Species', '10116', (34, 37))	('IL-4', 'Gene', (190, 194))
125725	21453513	The IL-2 maintained lymphocytes were then cultured with autologous DCs (4:1) in the presence or absence of recombinant HER-2/neu (100 mug/ml) or LPS (10 mug/ml).	('100 mug/ml', 'Var', (130, 140))	('IL-2', 'Gene', '3558', (4, 8))	('LPS', 'Disease', (145, 148))	('IL-2', 'Gene', (4, 8))	('HER-2/neu', 'Gene', (119, 128))	('LPS', 'Disease', 'MESH:C536528', (145, 148))	('HER-2/neu', 'Gene', '2064', (119, 128))
125751	21453513	We have already shown that T cell-mediated tumor antigen loss was due to hypermethylation of the neu promoter and loss of neu both at mRNA and protein levels.	('hypermethylation', 'Var', (73, 89))	('neu', 'Gene', (97, 100))	('loss', 'NegReg', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('neu', 'Gene', '2064', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('loss', 'NegReg', (57, 61))	('tumor', 'Disease', (43, 48))	('neu', 'Gene', (122, 125))	('neu', 'Gene', '2064', (97, 100))
125794	16251872	Virgin females that carry the transgene develop poorly differentiated, multi-focal, invasive ductal carcinoma by 10-12 weeks of age, with a high incidence of lung metastases stemming from the primary mammary tumour (Lin et al, 2003).	('ductal carcinoma', 'Phenotype', 'HP:0030075', (93, 109))	('poorly differentiated', 'CPA', (48, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumour', 'Disease', (208, 214))	('transgene', 'Var', (30, 39))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (84, 109))	('invasive ductal carcinoma', 'Disease', (84, 109))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('lung metastases', 'Disease', (158, 173))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('lung metastases', 'Disease', 'MESH:D009362', (158, 173))
125843	16251872	Most significantly, our observations of PpIX accumulation in early DCIS of the WapTag1 transgenic mammary glands also suggested this phenotypic switch is an early event in the tumorigenic process.	('transgenic', 'Species', '10090', (87, 97))	('transgenic', 'Var', (87, 97))	('tumor', 'Disease', (176, 181))	('accumulation', 'PosReg', (45, 57))	('PpIX', 'Chemical', 'MESH:C028025', (40, 44))	('Wap', 'Gene', (79, 82))	('Wap', 'Gene', '114596', (79, 82))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('PpIX', 'Gene', (40, 44))
125901	29085162	Of the IC-NSTs for which false-negative results were obtained in DWI, the majority were large tumors with high histological and nuclear grades, as well as high Ki-67 expression, which can be associated with necrosis and edema, factors that are related to an increase in the ADC value.	('edema', 'Disease', 'MESH:D004487', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('edema', 'Phenotype', 'HP:0000969', (220, 225))	('expression', 'MPA', (166, 176))	('necrosis', 'Disease', (207, 215))	('edema', 'Disease', (220, 225))	('Ki-67', 'Protein', (160, 165))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('necrosis', 'Disease', 'MESH:D009336', (207, 215))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (191, 201))	('high', 'Var', (155, 159))	('DWI', 'Disease', (65, 68))
125922	22761798	Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines.	('expression', 'MPA', (19, 29))	('HtrA1 gene', 'Gene', (8, 18))	('Loss', 'NegReg', (0, 4))	('epigenetic silencing', 'Var', (60, 80))	('expression', 'Species', '29278', (19, 29))
125937	22761798	Modulation of HtrA protein levels may have relevance for cancer therapy, as supported by a number of findings in animal models and human cancers.	('Modulation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('human', 'Species', '9606', (131, 136))	('HtrA', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('cancer', 'Disease', (137, 143))	('HtrA', 'Gene', '5654', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
125951	22761798	Deregulation of the response to reactive oxygen species (ROS) also has been related to the EMT.	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('Deregulation', 'Var', (0, 12))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (32, 55))	('EMT', 'CPA', (91, 94))	('response to reactive oxygen species', 'MPA', (20, 55))	('related', 'Reg', (76, 83))
125969	22761798	Loss of gene expression could arise from several mechanisms, including genetic and epigenetic changes.	('Loss', 'NegReg', (0, 4))	('epigenetic changes', 'Var', (83, 101))	('gene expression', 'MPA', (8, 23))	('expression', 'Species', '29278', (13, 23))
125974	22761798	These results suggest that the decreased expression of HtrA1 in these cell lines may be caused by promoter hypermethylation.	('expression', 'Species', '29278', (41, 51))	('expression', 'MPA', (41, 51))	('decreased', 'NegReg', (31, 40))	('promoter hypermethylation', 'Var', (98, 123))	('HtrA1', 'Gene', (55, 60))
125982	22761798	Two of the cell lines showing complete promoter methylation (MCF7 and M4A4) showed little response to either inhibitor (with M4A4 cells, the small response was attributable to DEC alone).	('MCF7', 'CellLine', 'CVCL:0031', (61, 65))	('DEC', 'Gene', '5728', (176, 179))	('DEC', 'Gene', (176, 179))	('M4A4', 'Var', (125, 129))
125994	22761798	Over-expression of HtrA1 induced a slightly slower growth rate, but this was not statistically significant.	('HtrA1', 'Gene', (19, 24))	('slower', 'NegReg', (44, 50))	('Over-expression', 'Var', (0, 15))	('growth', 'MPA', (51, 57))	('expression', 'Species', '29278', (5, 15))
125996	22761798	Both the MCF10A/siRNA1 and/siRNA4 cell lines showed significantly increased invasion ability compared to the control cell line (p-value <0.01; see Figure 7B), while the vector control and over-expressing MCF10A/HtrA1 cell lines showed no change in invasion capability.	('increased', 'PosReg', (66, 75))	('MCF10A', 'CellLine', 'CVCL:0598', (204, 210))	('MCF10A', 'CellLine', 'CVCL:0598', (9, 15))	('invasion ability', 'CPA', (76, 92))	('MCF10A/siRNA1', 'Var', (9, 22))
126010	22761798	We confirmed changes in transcript levels for many of the pertinent genes using QPCR, including VIM, CDH1, CLDN1, and ATM (not shown).	('ATM', 'Gene', (118, 121))	('CLDN1', 'Gene', '9076', (107, 112))	('CDH1', 'Gene', (101, 105))	('changes', 'Reg', (13, 20))	('VIM', 'Gene', (96, 99))	('ATM', 'Gene', '472', (118, 121))	('CDH1', 'Gene', '999', (101, 105))	('CLDN1', 'Gene', (107, 112))	('QPCR', 'Var', (80, 84))	('transcript levels', 'MPA', (24, 41))
126033	22761798	In turn, activated ATM can phosphorylate Ser139 of H2AX (forming gammaH2AX) at the site of a double strand DNA break (DSB).	('H2AX', 'Gene', '3014', (70, 74))	('Ser139', 'Var', (41, 47))	('H2AX', 'Gene', (70, 74))	('ATM', 'Gene', (19, 22))	('ATM', 'Gene', '472', (19, 22))	('gammaH2AX', 'Chemical', '-', (65, 74))	('H2AX', 'Gene', '3014', (51, 55))	('Ser139', 'Chemical', '-', (41, 47))	('double strand DNA', 'Var', (93, 110))	('H2AX', 'Gene', (51, 55))
126036	22761798	Stained gammaH2AX foci were observed in the H2O2-treated MCF10A groups, but not in the untreated MCF10A cells (Figure 10, lower panels).	('gammaH2AX foci', 'CPA', (8, 22))	('gammaH2AX', 'Chemical', '-', (8, 17))	('MCF10A', 'CellLine', 'CVCL:0598', (97, 103))	('H2O2-treated', 'Var', (44, 56))	('MCF10A', 'CellLine', 'CVCL:0598', (57, 63))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))
126040	22761798	By focusing on changes in expression of at least 40%, with a p-value <0.05, the number of differentially expressed miRs was reduced to 140 (MCF10A/siRNA1,/siRNA2,/siRNA3, and/siRNA4 cell lines had 53, 16, 32, and 39 significantly changed miRs, respectively), vs. the control MCF10A/HPVsh cell line.	('MCF10A/siRNA1', 'Var', (140, 153))	('reduced', 'NegReg', (124, 131))	('MCF10A', 'CellLine', 'CVCL:0598', (275, 281))	('expression', 'Species', '29278', (26, 36))	('MCF10A/HPVsh', 'CellLine', 'CVCL:0598', (275, 287))	('MCF10A', 'CellLine', 'CVCL:0598', (140, 146))	('changed', 'Reg', (230, 237))	('miRs', 'MPA', (238, 242))
126043	22761798	Cluster 1 contained miR-200a, 429, 200b, and 200a*, while Cluster 6 contained 200c*.	('miR-200', 'Chemical', '-', (20, 27))	('miR-200a', 'Var', (20, 28))	('429', 'Var', (30, 33))
126045	22761798	Considering all analyses, the miR-200 family members (miR-429, 200a(a*), 200b(b*), 200c(c*), and miR-141) were consistently identified as differentially regulated in response to altered HtrA1 expression (Table 2).	('miR-429', 'Gene', (54, 61))	('expression', 'Species', '29278', (192, 202))	('miR-141', 'Var', (97, 104))	('miR-200', 'Gene', (30, 37))	('miR-200', 'Chemical', '-', (30, 37))	('HtrA1', 'Protein', (186, 191))	('miR-429', 'Gene', '554210', (54, 61))	('altered', 'Var', (178, 185))
126062	22761798	In addition to the EMT changes, we observed alterations in the expression profiles of many CSC-associated genes and ATM DDR pathway components in response to changes in HtrA1 levels, potentially providing a link to HtrA1's puzzling role in response to chemotherapeutics.	('expression profiles', 'MPA', (63, 82))	('HtrA1 levels', 'MPA', (169, 181))	('expression', 'Species', '29278', (63, 73))	('CSC-associated genes', 'Gene', (91, 111))	('changes', 'Var', (158, 165))	('ATM', 'Gene', (116, 119))	('alterations', 'Reg', (44, 55))	('ATM', 'Gene', '472', (116, 119))
126081	22761798	Importantly, the miR-200 transcriptional cluster has recently been found to be epigenetically controlled by methylation of the miR-200 promoter, so this may represent a mechanism underlying our results.	('miR-200', 'Chemical', '-', (17, 24))	('miR-200', 'Gene', (127, 134))	('miR-200', 'Chemical', '-', (127, 134))	('miR-200', 'Gene', (17, 24))	('methylation', 'Var', (108, 119))
126082	22761798	This family of miRs may directly regulate EMT transcription factors, such as ZEB1, ZEB2, or may act on their target genes.	('act', 'Reg', (96, 99))	('EMT transcription factors', 'Gene', (42, 67))	('regulate', 'Reg', (33, 41))	('ZEB2', 'Gene', '9839', (83, 87))	('ZEB1', 'Gene', (77, 81))	('ZEB1', 'Gene', '6935', (77, 81))	('miRs', 'Var', (15, 19))	('ZEB2', 'Gene', (83, 87))
126087	22761798	On the other hand, in several cancer types high levels of TGFbeta in patient serum are associated with poor prognosis.	('high levels', 'Var', (43, 54))	('cancer', 'Disease', (30, 36))	('TGFbeta', 'Gene', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('associated', 'Reg', (87, 97))	('patient', 'Species', '9606', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
126095	22761798	Therefore, our observed ATM activation in untreated MCF10A/siRNA cells may indicate that loss of HtrA1 results in increased endogenous intracellular ROS levels.	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('ATM', 'Gene', '472', (24, 27))	('loss', 'Var', (89, 93))	('increased', 'PosReg', (114, 123))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('ATM', 'Gene', (24, 27))	('endogenous intracellular ROS levels', 'MPA', (124, 159))	('HtrA1', 'Gene', (97, 102))
126096	22761798	After acute oxidative stress, we observed that MCF10A/siRNA cells displayed an increased number of gammaH2AX foci, relative to control cells, further suggesting that loss of HtrA1 correlates with higher levels of DNA damage.	('increased', 'PosReg', (79, 88))	('loss', 'Var', (166, 170))	('HtrA1', 'Protein', (174, 179))	('MCF10A/siRNA', 'Var', (47, 59))	('gammaH2AX', 'Chemical', '-', (99, 108))	('higher', 'PosReg', (196, 202))	('DNA damage', 'MPA', (213, 223))	('MCF10A', 'CellLine', 'CVCL:0598', (47, 53))	('oxidative stress', 'Phenotype', 'HP:0025464', (12, 28))	('levels', 'MPA', (203, 209))	('gammaH2AX foci', 'MPA', (99, 113))
126099	22761798	However, we did see up-regulation of PARP1, so single-strand break levels may also be increased following down-regulation of HtrA1.	('down-regulation', 'Var', (106, 121))	('increased', 'PosReg', (86, 95))	('single-strand break levels', 'MPA', (47, 73))	('PARP1', 'Gene', '142', (37, 42))	('PARP1', 'Gene', (37, 42))	('HtrA1', 'Gene', (125, 130))	('up-regulation', 'PosReg', (20, 33))
126233	32727823	We additionally conducted stratified analyses by menopausal status since alterations in endogenous sex hormone levels with menopause are thought to be related to periodontal disease as well as breast cancer.	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('endogenous sex hormone levels', 'MPA', (88, 117))	('alterations', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('menopausal status', 'Phenotype', 'HP:0008209', (49, 66))	('related', 'Reg', (151, 158))	('periodontal disease', 'Disease', 'MESH:D010510', (162, 181))	('periodontal disease', 'Disease', (162, 181))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('periodontal disease', 'Phenotype', 'HP:0000704', (162, 181))
126362	33505957	Briefly, miRNAs were modified by extending the 3' end of the transcript through a poly(A) addition, then lengthening the 5' end by adaptor ligation.	('poly(A) addition', 'Var', (82, 98))	('poly(A)', 'Chemical', 'MESH:D011061', (82, 89))	('extending', 'PosReg', (33, 42))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
126390	33505957	Cells from women of normal weight and obese women, whether hASCs or MAs, appeared to decrease the viability of the MECs in the same proportions (-12% with hASC20; -8% with hASC30; -14% with MA20, p < 0.01; -8% with MA30, ns) (Figure 2A).	('obese', 'Disease', 'MESH:D009765', (38, 43))	('women', 'Species', '9606', (44, 49))	('decrease', 'NegReg', (85, 93))	('MA30', 'Chemical', '-', (215, 219))	('MA30', 'Var', (215, 219))	('hASC20; -8', 'Var', (155, 165))	('women', 'Species', '9606', (11, 16))	('hASCs', 'Chemical', '-', (59, 64))	('hASC30; -14', 'Var', (172, 183))	('MA20', 'Var', (190, 194))	('obese', 'Disease', (38, 43))
126396	33505957	A second cluster presented the inverse observation, with a group of genes over-expressed in the MECs co-cultured with MAs (Cluster 2: Leptin, leptin receptor, CYP191A1, PTGS2).	('over-expressed', 'PosReg', (74, 88))	('Leptin', 'Gene', (134, 140))	('Leptin', 'Gene', '3952', (134, 140))	('leptin receptor', 'Gene', (142, 157))	('leptin receptor', 'Gene', '3953', (142, 157))	('CYP191A1', 'Var', (159, 167))	('PTGS2', 'Gene', (169, 174))	('PTGS2', 'Gene', '5743', (169, 174))
126429	33505957	So a modification to the functionality of MECs could promote carcinogenesis instead of suppressing it.	('modification', 'Var', (5, 17))	('carcinogenesis', 'Disease', (61, 75))	('MECs', 'Gene', (42, 46))	('promote', 'PosReg', (53, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
126432	33505957	Using a co-culture model with myoepithelial cells and human adipose cells (hASCs and MAs) from women of normal weight and from obese women, we have shown that hASCs can reduce the viability of MECs, regardless of initial BMI.	('human', 'Species', '9606', (54, 59))	('hASCs', 'Chemical', '-', (159, 164))	('women', 'Species', '9606', (133, 138))	('obese', 'Disease', 'MESH:D009765', (127, 132))	('hASCs', 'Var', (159, 164))	('women', 'Species', '9606', (95, 100))	('hASCs', 'Chemical', '-', (75, 80))	('viability', 'CPA', (180, 189))	('obese', 'Disease', (127, 132))	('MECs', 'CPA', (193, 197))	('reduce', 'NegReg', (169, 175))
126493	23292359	Our results shed light on the interactions between growth factors, mechanical properties of the ECM, and feedback signaling loops between stromal and tumor cells, and suggest how epigenetic changes in transformed cells affect tumor progression.	('interactions', 'Interaction', (30, 42))	('epigenetic changes', 'Var', (179, 197))	('growth factor', 'Gene', '79215', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('growth factor', 'Gene', (51, 64))	('tumor', 'Disease', (150, 155))	('affect', 'Reg', (219, 225))	('tumor', 'Disease', (226, 231))
126497	23292359	Two important growth factors involved in maintaining homeostasis in a duct are EGF and TGF-beta, and here we incorporate these into a model of epithelial cells in order to understand how perturbations in the associated signal transduction pathways influence tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('EGF', 'Gene', '1950', (79, 82))	('perturbations', 'Var', (187, 200))	('growth factor', 'Gene', '79215', (14, 27))	('TGF-beta', 'Gene', (87, 95))	('tumor', 'Disease', (258, 263))	('growth factor', 'Gene', (14, 27))	('EGF', 'Gene', (79, 82))	('influence', 'Reg', (248, 257))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
126544	23292359	This low level of pSmad would correspond to partial accumulation of Smad2/Smad3 in the nucleus of mutant (EpRas cells) with up-regulated EGF levels.	('Smad2/Smad3', 'Gene', (68, 79))	('up-regulated', 'PosReg', (124, 136))	('EGF', 'Gene', (137, 140))	('accumulation', 'PosReg', (52, 64))	('EGF', 'Gene', '1950', (137, 140))	('mutant', 'Var', (98, 104))
126546	23292359	These authors also examined the pattern of Smad2/Smad3 nuclear accumulation in five human colon carcinoma cell lines and found that nuclear accumulation of Smad2/Smad3 in response to an intermediate (10 pM) TGF-beta concentration was poor or absent in these tumorogenic cell lines (with oncogenic K-Ras mutations), but extensive in wild-type cells.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('mutations', 'Var', (303, 312))	('colon carcinoma cell lines', 'Disease', 'MESH:D003110', (90, 116))	('K-Ras', 'Gene', '3845', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('K-Ras', 'Gene', (297, 302))	('tumor', 'Disease', (258, 263))	('nuclear accumulation', 'MPA', (132, 152))	('colon carcinoma cell lines', 'Disease', (90, 116))	('response', 'MPA', (171, 179))	('absent', 'NegReg', (242, 248))	('human', 'Species', '9606', (84, 89))	('Smad2/Smad3', 'Gene', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
126679	23292359	If a tumor has been located by some imaging method, microinjection of a large bolus of chemoattractant could serve to recruit migrating cells to the primary tumor site, thereby localizing them and increasing the efficacy of surgical removal or other treatments.	('tumor', 'Disease', (157, 162))	('migrating cells', 'CPA', (126, 141))	('increasing', 'PosReg', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('recruit', 'PosReg', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('surgical removal', 'CPA', (224, 240))	('tumor', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('microinjection', 'Var', (52, 66))
126814	30607168	In our study, CEDM resulted in a higher PPV for secondary (72.2% vs. 65.0%) cancers in the ipsilateral breast than CEMRI, with fewer FP findings (10/15 [66.7%] vs. 14/15 [93.3%]) in the ipsilateral breast.	('PPV', 'MPA', (40, 43))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('CEMRI', 'Chemical', '-', (115, 120))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CEDM', 'Var', (14, 18))	('CEDM', 'Chemical', '-', (14, 18))
126825	30607168	There is debate, however, as to whether BPE negatively affects the sensitivity and specificity of CEMRI interpretation by obscuring enhancing malignancies.	('BPE', 'Var', (40, 43))	('BPE', 'Chemical', '-', (40, 43))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('CEMRI', 'Chemical', '-', (98, 103))	('malignancies', 'Disease', (142, 154))
126850	33795819	We determined that age <45 years, HER2 amplification, and GATA3 mutation are possible indicators of relapse.	('mutation', 'Var', (64, 72))	('GATA3', 'Gene', '2625', (58, 63))	('amplification', 'Var', (39, 52))	('HER2', 'Gene', (34, 38))	('HER2', 'Gene', '2064', (34, 38))	('GATA3', 'Gene', (58, 63))
126851	33795819	PIK3CA mutation negativity and PgR negativity were also suggested to be risk factors.	('PgR', 'Gene', (31, 34))	('negativity', 'Var', (16, 26))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('negativity', 'Var', (35, 45))	('mutation negativity', 'Var', (7, 26))	('PgR', 'Gene', '5241', (31, 34))
126852	33795819	Spatial transcriptome analysis further revealed that GATA3 dysfunction upregulates epithelial-to-mesenchymal transition and angiogenesis, followed by PgR downregulation.	('epithelial-to-mesenchymal transition', 'CPA', (83, 119))	('GATA3', 'Gene', (53, 58))	('upregulates', 'PosReg', (71, 82))	('dysfunction', 'Var', (59, 70))	('downregulation', 'NegReg', (154, 168))	('PgR', 'Gene', '5241', (150, 153))	('GATA3', 'Gene', '2625', (53, 58))	('PgR', 'Gene', (150, 153))	('angiogenesis', 'CPA', (124, 136))
126854	33795819	They find that for patients under 45 years of age, HER2 amplification and GATA3 mutation are associated with higher risk of relapse, suggesting they could be used as predictive markers when deciding on a treatment course.	('patients', 'Species', '9606', (19, 27))	('relapse', 'Disease', (124, 131))	('GATA3', 'Gene', (74, 79))	('GATA3', 'Gene', '2625', (74, 79))	('HER2', 'Gene', (51, 55))	('HER2', 'Gene', '2064', (51, 55))	('mutation', 'Var', (80, 88))	('amplification', 'Var', (56, 69))
126869	33795819	S1) and HER2 amplification status appeared to be significantly and independently associated with relapse in multivariate analysis, with hazard ratios (HRs) of 3.57 (95% confidence interval [CI] = 1.46-8.73, P = 0.0054) and 3.14 (95% CI = 1.28-7.7, P = 0.0123), respectively.	('HER2', 'Gene', (8, 12))	('amplification status', 'Var', (13, 33))	('HER2', 'Gene', '2064', (8, 12))	('relapse', 'Disease', (97, 104))	('associated', 'Reg', (81, 91))
126874	33795819	GATA3 and PIK3CA mutations were the most commonly detected mutations in the cohort and were present in four (19%) and five patients (24%), respectively.	('GATA3', 'Gene', '2625', (0, 5))	('PIK3CA', 'Gene', (10, 16))	('patients', 'Species', '9606', (123, 131))	('GATA3', 'Gene', (0, 5))	('PIK3CA', 'Gene', '5290', (10, 16))	('mutations', 'Var', (17, 26))
126875	33795819	Of the four patients with GATA3 mutations, three experienced IDC relapse.	('experienced', 'Reg', (49, 60))	('patients', 'Species', '9606', (12, 20))	('GATA3', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('IDC', 'Disease', (61, 64))	('GATA3', 'Gene', '2625', (26, 31))
126876	33795819	The odds ratio (OR) for relapse for GATA3 mutation positivity versus GATA3 mutation negativity was 5.5 (95% CI = 0.63-76.7).	('mutation positivity', 'Var', (42, 61))	('GATA3', 'Gene', '2625', (69, 74))	('positivity', 'Var', (51, 61))	('GATA3', 'Gene', (36, 41))	('GATA3', 'Gene', '2625', (36, 41))	('GATA3', 'Gene', (69, 74))
126877	33795819	To further investigate the significance of GATA3 mutation in relapse, samples from patients with relapsed tumors were additionally analyzed to determine the mutation status in comparison with their paired primary DCIS.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('mutation', 'Var', (49, 57))	('GATA3', 'Gene', (43, 48))	('GATA3', 'Gene', '2625', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (83, 91))
126878	33795819	Importantly, two of the four patients harbored the same GATA3 mutation in their primary and relapsed tumors (Fig.	('patients', 'Species', '9606', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('GATA3', 'Gene', '2625', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('harbored', 'Reg', (38, 46))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('GATA3', 'Gene', (56, 61))	('tumors', 'Disease', (101, 107))
126881	33795819	Although the HR was not significant, based on these results, we considered GATA3 mutation to be a candidate genomic high-risk factor in the discovery cohort.	('GATA3', 'Gene', '2625', (75, 80))	('mutation', 'Var', (81, 89))	('GATA3', 'Gene', (75, 80))
126882	33795819	It was recently reported that GATA3 variants with altered DNA-binding capacity led to reduced expression of a gene set containing the progesterone receptor (PgR) gene and increased expression of genes involved in epithelial-to-mesenchymal transition (EMT), such as cell movement and cell invasion pathways.	('reduced', 'NegReg', (86, 93))	('expression', 'MPA', (181, 191))	('progesterone receptor', 'Gene', (134, 155))	('cell invasion pathways', 'CPA', (283, 305))	('cell movement', 'CPA', (265, 278))	('PgR', 'Gene', '5241', (157, 160))	('progesterone receptor', 'Gene', '5241', (134, 155))	('GATA3', 'Gene', (30, 35))	('variants', 'Var', (36, 44))	('expression', 'MPA', (94, 104))	('GATA3', 'Gene', '2625', (30, 35))	('epithelial-to-mesenchymal transition', 'CPA', (213, 249))	('increased', 'PosReg', (171, 180))	('PgR', 'Gene', (157, 160))
126885	33795819	We determined that GATA3 mutation was associated with reduced PgR expression (Supplementary Table S2, P = 0.0192 by Fisher's exact test).	('GATA3', 'Gene', (19, 24))	('mutation', 'Var', (25, 33))	('expression', 'MPA', (66, 76))	('reduced', 'NegReg', (54, 61))	('GATA3', 'Gene', '2625', (19, 24))	('PgR', 'Gene', '5241', (62, 65))	('PgR', 'Gene', (62, 65))
126888	33795819	ER-positive patients with low PgR expression (<=60%) had a significantly higher incidence of relapse than those with high PgR expression (Fig.	('ER', 'Gene', '2099', (0, 2))	('patients', 'Species', '9606', (12, 20))	('low', 'Var', (26, 29))	('PgR', 'Gene', '5241', (30, 33))	('PgR', 'Gene', (30, 33))	('PgR', 'Gene', '5241', (122, 125))	('PgR', 'Gene', (122, 125))	('relapse', 'CPA', (93, 100))
126890	33795819	Contrary to the findings for GATA3 mutation, no patient with PIK3CA mutation experienced relapse, whereas 9 of 16 patients without PIK3CA mutation (56.2%) experienced relapses.	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('mutation', 'Var', (68, 76))	('GATA3', 'Gene', (29, 34))	('GATA3', 'Gene', '2625', (29, 34))	('patient', 'Species', '9606', (48, 55))	('PIK3CA', 'Gene', (131, 137))	('patient', 'Species', '9606', (114, 121))	('patients', 'Species', '9606', (114, 122))	('PIK3CA', 'Gene', '5290', (131, 137))
126891	33795819	Although PIK3CA mutations are known cancer drivers in many cancer types, interestingly, they have been associated with better patient prognosis in invasive breast cancer than wild-type PIK3CA.	('invasive breast cancer', 'Disease', (147, 169))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('PIK3CA', 'Gene', '5290', (9, 15))	('cancer', 'Disease', (36, 42))	('mutations', 'Var', (16, 25))	('patient', 'Species', '9606', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PIK3CA', 'Gene', (185, 191))	('invasive breast cancer', 'Disease', 'MESH:D001943', (147, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('PIK3CA', 'Gene', '5290', (185, 191))	('PIK3CA', 'Gene', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
126892	33795819	Thus, we identified PIK3CA mutation as a candidate genomic low-risk factor for DCIS in the discovery cohort.	('DCIS', 'Disease', (79, 83))	('PIK3CA', 'Gene', (20, 26))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('PIK3CA', 'Gene', '5290', (20, 26))	('mutation', 'Var', (27, 35))
126896	33795819	In total, 40 (56%) and 36 patients (50%) harbored GATA3 and PIK3CA mutations, respectively.	('PIK3CA', 'Gene', (60, 66))	('harbored', 'Reg', (41, 49))	('PIK3CA', 'Gene', '5290', (60, 66))	('GATA3', 'Gene', (50, 55))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (26, 34))	('GATA3', 'Gene', '2625', (50, 55))
126897	33795819	In accordance with the results for cohort 2, GATA3 mutations were positively associated with relapse (OR = 7.8; 95% CI = 1.17-88.4), whereas PIK3CA mutations tended to be negatively associated with relapse (OR = 0.45; 95% CI = 0.12-1.7).	('GATA3', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('GATA3', 'Gene', '2625', (45, 50))	('PIK3CA', 'Gene', (141, 147))	('PIK3CA', 'Gene', '5290', (141, 147))	('relapse', 'Disease', (198, 205))	('associated with', 'Reg', (77, 92))	('relapse', 'CPA', (93, 100))
126899	33795819	In conjunction with cohort 2, we identified GATA3 mutations in 8 out of 11 cases for which PgR was low despite ER positivity.	('mutations', 'Var', (50, 59))	('PgR', 'Gene', '5241', (91, 94))	('ER', 'Gene', '2099', (111, 113))	('PgR', 'Gene', (91, 94))	('GATA3', 'Gene', (44, 49))	('GATA3', 'Gene', '2625', (44, 49))
126901	33795819	Patient A had DCIS with a GATA3 mutation (Fig.	('DCIS', 'Disease', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('GATA3', 'Gene', (26, 31))	('mutation', 'Var', (32, 40))	('GATA3', 'Gene', '2625', (26, 31))	('Patient', 'Species', '9606', (0, 7))
126903	33795819	Patient C had DCIS with a PIK3CA mutation (Fig.	('mutation', 'Var', (33, 41))	('DCIS', 'Disease', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('PIK3CA', 'Gene', '5290', (26, 32))	('Patient', 'Species', '9606', (0, 7))	('PIK3CA', 'Gene', (26, 32))
126907	33795819	The panel sequencing analysis at an average depth of x2391.4 revealed that this sample harbored a GATA3 mutation (exon 4: c.865dupG: p. C288fs, variant allele frequency [VAF] = 7%; the full mutation list is provided in Supplementary Data 3).	('C288fs', 'Var', (136, 142))	('c.865dupG', 'Mutation', 'c.865dupG', (122, 131))	('GATA3', 'Gene', (98, 103))	('GATA3', 'Gene', '2625', (98, 103))	('C288fs', 'FRAMESHIFT', 'None', (136, 142))
126908	33795819	Interestingly, a PIK3CA mutation was also detected at a higher VAF (exon 5:c.T1035A:p. N345K, VAF = 26.1%), suggesting that the emerging GATA3 mutation was overwriting the basal features of DCIS with the PIK3CA mutation.	('GATA3', 'Gene', '2625', (137, 142))	('PIK3CA', 'Gene', '5290', (204, 210))	('N345K', 'Var', (87, 92))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('mutation', 'Var', (143, 151))	('GATA3', 'Gene', (137, 142))	('N345K', 'SUBSTITUTION', 'None', (87, 92))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('PIK3CA', 'Gene', (204, 210))	('c.T1035A', 'Mutation', 'rs121913284', (75, 83))	('overwriting', 'PosReg', (156, 167))
126912	33795819	Fortunately, in this patient, the GATA3 mutation was located at the 3'-end of the transcript and could thus be represented by the Visium reads.	('mutation', 'Var', (40, 48))	('patient', 'Species', '9606', (21, 28))	('GATA3', 'Gene', '2625', (34, 39))	('GATA3', 'Gene', (34, 39))
126913	33795819	To investigate whether cells harboring the GATA3 mutation (spots) are clonal, we examined the GATA3 mutation sites on Visium reads of 46 spots carrying GATA3 mutations.	('GATA3', 'Gene', (152, 157))	('GATA3', 'Gene', (94, 99))	('GATA3', 'Gene', '2625', (152, 157))	('GATA3', 'Gene', '2625', (94, 99))	('GATA3', 'Gene', (43, 48))	('GATA3', 'Gene', '2625', (43, 48))	('mutations', 'Var', (158, 167))
126915	33795819	Using the TCC R package, we detected differentially expressed genes (DEGs) between the spots with and without GATA3 mutations.	('differentially', 'Reg', (37, 51))	('TCC', 'Gene', '94081', (10, 13))	('GATA3', 'Gene', (110, 115))	('GATA3', 'Gene', '2625', (110, 115))	('TCC', 'Gene', (10, 13))	('mutations', 'Var', (116, 125))
126916	33795819	1d, downregulated PgR expression was noted in the spots with GATA3 mutations (P = 0.02901; t-test; Fig.	('PgR', 'Gene', (18, 21))	('downregulated', 'NegReg', (4, 17))	('GATA3', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))	('GATA3', 'Gene', '2625', (61, 66))	('expression', 'MPA', (22, 32))	('PgR', 'Gene', '5241', (18, 21))
126917	33795819	Nine key pathways, which were associated with 11 cancer hallmarks, were affected in the cancer spots with GATA3 mutations compared with the findings in the mutation-negative spots (Fig.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('key pathways', 'Pathway', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer hallmarks', 'Disease', (49, 65))	('cancer hallmarks', 'Disease', 'MESH:D009369', (49, 65))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('GATA3', 'Gene', (106, 111))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('affected', 'Reg', (72, 80))	('GATA3', 'Gene', '2625', (106, 111))	('cancer', 'Disease', (49, 55))
126918	33795819	Importantly, the key genes with expression changes were those identified to occur in response to aberrant GATA3 function, such as VIM and FN1 (Fig.	('GATA3', 'Gene', '2625', (106, 111))	('VIM', 'Gene', '7431', (130, 133))	('FN1', 'Gene', '2335', (138, 141))	('aberrant', 'Var', (97, 105))	('GATA3', 'Gene', (106, 111))	('VIM', 'Gene', (130, 133))	('FN1', 'Gene', (138, 141))
126919	33795819	These results indicate that GATA3 mutations arise during DCIS progression accompanied by malignant features.	('GATA3', 'Gene', '2625', (28, 33))	('arise', 'Reg', (44, 49))	('DCIS', 'Disease', (57, 61))	('mutations', 'Var', (34, 43))	('GATA3', 'Gene', (28, 33))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
126920	33795819	It has been reported that increased VIM expression occurs downstream of GATA3 mutations in luminal cancer cells; thus, the observed GATA3 mutations in the spots could represent prior genetic alterations during malignant development.	('expression', 'MPA', (40, 50))	('GATA3', 'Gene', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('GATA3', 'Gene', (132, 137))	('VIM', 'Gene', (36, 39))	('GATA3', 'Gene', '2625', (72, 77))	('mutations', 'Var', (78, 87))	('cancer', 'Disease', (99, 105))	('GATA3', 'Gene', '2625', (132, 137))	('increased', 'PosReg', (26, 35))	('luminal', 'Chemical', 'MESH:D010634', (91, 98))	('VIM', 'Gene', '7431', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (138, 147))
126921	33795819	Conversely, in the spots without GATA3 mutations, the DEGs were mainly enriched in estrogen response, tight junction, and mTORC1 signaling pathways, suggesting that the cells in those spots acquired the minimum changes permitting cell transformation.	('tight junction', 'Pathway', (102, 116))	('GATA3', 'Gene', (33, 38))	('mTORC1', 'Gene', (122, 128))	('mutations', 'Var', (39, 48))	('GATA3', 'Gene', '2625', (33, 38))	('estrogen', 'Pathway', (83, 91))	('mTORC1', 'Gene', '382056', (122, 128))
126922	33795819	We next investigated Patient B as an exceptional patient with low PgR expression despite the absence of GATA3 mutation (Fig.	('PgR', 'Gene', (66, 69))	('GATA3', 'Gene', (104, 109))	('patient', 'Species', '9606', (49, 56))	('GATA3', 'Gene', '2625', (104, 109))	('Patient', 'Species', '9606', (21, 28))	('mutation', 'Var', (110, 118))	('PgR', 'Gene', '5241', (66, 69))	('absence', 'NegReg', (93, 100))
126923	33795819	From targeted sequencing at an average depth of x3030.6, a PIK3CA mutation was detected (exon 21:c.A3140T:p. H1047L, VAF = 40%, Supplementary Data 3), whereas no GATA3 mutation was detected even at this sufficient sequencing depth.	('detected', 'Reg', (79, 87))	('GATA3', 'Gene', (162, 167))	('GATA3', 'Gene', '2625', (162, 167))	('PIK3CA', 'Gene', (59, 65))	('H1047L', 'SUBSTITUTION', 'None', (109, 115))	('c.A3140T', 'Mutation', 'rs121913279', (97, 105))	('PIK3CA', 'Gene', '5290', (59, 65))	('H1047L', 'Var', (109, 115))
126934	33795819	Even without genomic mutations, aberrant GATA3 expression may result in an equivalent consequence in some patients.	('GATA3', 'Gene', (41, 46))	('GATA3', 'Gene', '2625', (41, 46))	('patients', 'Species', '9606', (106, 114))	('aberrant', 'Var', (32, 40))	('expression', 'MPA', (47, 57))	('result in', 'Reg', (62, 71))
126937	33795819	2 in cohort 3, which was characterized by PIK3CA mutations, an absence of GATA3 mutations or downregulation, no microinvasion, and no relapse after surgery.	('mutations', 'Var', (49, 58))	('PIK3CA', 'Gene', (42, 48))	('GATA3', 'Gene', (74, 79))	('GATA3', 'Gene', '2625', (74, 79))	('PIK3CA', 'Gene', '5290', (42, 48))	('absence', 'NegReg', (63, 70))	('downregulation', 'NegReg', (93, 107))
126938	33795819	The DCIS lesion in this patient harbored two PIK3CA mutations (exon 10:c.G1633A:p. E545K, exon10:c.A1634G:p. E545G, VAF = 25% for both mutations), as determined via whole-exome sequencing with an average depth of x134.8.	('E545G', 'SUBSTITUTION', 'None', (109, 114))	('c.A1634G', 'Mutation', 'rs121913274', (97, 105))	('DCIS', 'Phenotype', 'HP:0030075', (4, 8))	('patient', 'Species', '9606', (24, 31))	('PIK3CA', 'Gene', (45, 51))	('E545G', 'Var', (109, 114))	('E545K', 'Var', (83, 88))	('PIK3CA', 'Gene', '5290', (45, 51))	('c.G1633A', 'Mutation', 'rs104886003', (71, 79))	('E545K', 'SUBSTITUTION', 'None', (83, 88))
126953	33795819	Overall, the DCIS lesion in Patient C did not harbor any genomic or transcriptomic alterations leading to malignant transition, such as EMT and angiogenesis, which were observed in patients with GATA3 mutation or downregulation, supporting the presumption that the lesion was possibly false DCIS.	('GATA3', 'Gene', '2625', (195, 200))	('DCIS', 'Phenotype', 'HP:0030075', (291, 295))	('false DCIS', 'Phenotype', 'HP:0003771', (285, 295))	('downregulation', 'NegReg', (213, 227))	('patients', 'Species', '9606', (181, 189))	('GATA3', 'Gene', (195, 200))	('mutation', 'Var', (201, 209))	('Patient', 'Species', '9606', (28, 35))	('DCIS', 'Disease', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
126954	33795819	From the aforementioned clinical and molecular analyses, we propose the following five critical markers for a new DCIS classification approach: age <45 years, HER2 amplification, GATA3 mutation or downregulation, PgR protein negativity (for high-risk and true DCIS), and PIK3CA mutation positivity (for false DCIS).	('HER2', 'Gene', (159, 163))	('GATA3', 'Gene', '2625', (179, 184))	('downregulation', 'NegReg', (197, 211))	('DCIS', 'Phenotype', 'HP:0030075', (260, 264))	('HER2', 'Gene', '2064', (159, 163))	('negativity', 'NegReg', (225, 235))	('PIK3CA', 'Gene', (271, 277))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('false DCIS', 'Phenotype', 'HP:0003771', (303, 313))	('mutation', 'Var', (185, 193))	('DCIS', 'Phenotype', 'HP:0030075', (309, 313))	('PgR', 'Gene', '5241', (213, 216))	('mutation positivity', 'Reg', (278, 297))	('amplification', 'Var', (164, 177))	('PIK3CA', 'Gene', '5290', (271, 277))	('PgR', 'Gene', (213, 216))	('GATA3', 'Gene', (179, 184))
126955	33795819	In this study, we identified GATA3 mutation as a potential marker for classifying DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('GATA3', 'Gene', (29, 34))	('GATA3', 'Gene', '2625', (29, 34))	('mutation', 'Var', (35, 43))	('DCIS', 'Disease', (82, 86))
126956	33795819	PIK3CA mutation negativity and PgR protein negativity in patients with ER-positive DCIS were also suggested to be risk factors.	('PgR', 'Gene', (31, 34))	('negativity', 'Var', (16, 26))	('negativity', 'NegReg', (43, 53))	('patients', 'Species', '9606', (57, 65))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('PIK3CA', 'Gene', (0, 6))	('ER', 'Gene', '2099', (71, 73))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation negativity', 'Var', (7, 26))	('PgR', 'Gene', '5241', (31, 34))
126958	33795819	HER2 amplification is a well-known poor prognostic factor in IDC in the absence of HER2-targeted therapy.	('amplification', 'Var', (5, 18))	('IDC', 'Disease', (61, 64))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', '2064', (83, 87))
126960	33795819	The HR for HER2 positivity/age >=45 years versus HER2 negativity/age >=45 years was 1.54 (95% CI = 0.31-7.65, P = 0.595).	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', (11, 15))	('positivity/age >', 'Var', (16, 32))	('HER2', 'Gene', '2064', (49, 53))	('HER2', 'Gene', '2064', (11, 15))
126962	33795819	In contrast, the HR for HER2 positivity/age <45 years versus HER2 negativity/age >=45 was 11.03 (95% CI = 3.54-34.4, P < 0.0001).	('positivity/age <45 years', 'Var', (29, 53))	('HER2', 'Gene', (61, 65))	('HER2', 'Gene', (24, 28))	('HER2', 'Gene', '2064', (61, 65))	('HER2', 'Gene', '2064', (24, 28))
126965	33795819	A limited number of studies have investigated GATA3 mutations in DCIS, and the prognostic consequences of mutations remain to be clarified.	('mutations', 'Var', (52, 61))	('GATA3', 'Gene', (46, 51))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('GATA3', 'Gene', '2625', (46, 51))	('DCIS', 'Gene', (65, 69))
126967	33795819	GATA3 mutation, which occurs at a high incidence rate in IDC, is believed to abolish this critical function and promote the progression of cells to a more advanced stage.	('GATA3', 'Gene', '2625', (0, 5))	('promote', 'PosReg', (112, 119))	('mutation', 'Var', (6, 14))	('abolish', 'NegReg', (77, 84))	('GATA3', 'Gene', (0, 5))	('progression', 'CPA', (124, 135))	('IDC', 'Disease', (57, 60))
126968	33795819	Therefore, GATA3 mutations may play critical roles in migration and invasion of cancer cells but not in initial carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('play', 'Reg', (31, 35))	('GATA3', 'Gene', '2625', (11, 16))	('carcinogenesis', 'Disease', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('invasion', 'CPA', (68, 76))	('migration', 'CPA', (54, 63))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('roles', 'Reg', (45, 50))	('GATA3', 'Gene', (11, 16))	('cancer', 'Disease', (80, 86))
126969	33795819	In clinical practice, examination of GATA3 mutations is not always possible.	('mutations', 'Var', (43, 52))	('GATA3', 'Gene', (37, 42))	('GATA3', 'Gene', '2625', (37, 42))
126970	33795819	In such patients, our results suggest that PgR protein expression is associated with GATA3 mutation.	('mutation', 'Var', (91, 99))	('associated', 'Reg', (69, 79))	('expression', 'MPA', (55, 65))	('PgR', 'Gene', '5241', (43, 46))	('GATA3', 'Gene', (85, 90))	('PgR', 'Gene', (43, 46))	('GATA3', 'Gene', '2625', (85, 90))	('patients', 'Species', '9606', (8, 16))
126972	33795819	A future extensive analysis is needed to elucidate how PgR negativity is caused by GATA3 mutation.	('PgR', 'Gene', (55, 58))	('PgR', 'Gene', '5241', (55, 58))	('GATA3', 'Gene', '2625', (83, 88))	('mutation', 'Var', (89, 97))	('caused', 'Reg', (73, 79))	('GATA3', 'Gene', (83, 88))
126973	33795819	PIK3CA mutations are reported to be crucial for breast carcinogenesis.	('breast carcinogenesis', 'Disease', 'MESH:D001943', (48, 69))	('PIK3CA', 'Gene', (0, 6))	('breast carcinogenesis', 'Disease', (48, 69))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
126974	33795819	However, PIK3CA mutation is correlated with a favorable prognosis in IDC.	('IDC', 'Disease', (69, 72))	('mutation', 'Var', (16, 24))	('PIK3CA', 'Gene', '5290', (9, 15))	('PIK3CA', 'Gene', (9, 15))
126975	33795819	It was also recently reported that mutations in the PIK3CA kinase domain and the absence of copy number gains in DCIS protect against progression to invasive cancer.	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('absence', 'NegReg', (81, 88))	('DCIS', 'Gene', (113, 117))	('PIK3CA', 'Gene', (52, 58))	('invasive cancer', 'Disease', (149, 164))	('PIK3CA', 'Gene', '5290', (52, 58))	('invasive cancer', 'Disease', 'MESH:D009362', (149, 164))	('copy number gains', 'Var', (92, 109))	('mutations', 'Var', (35, 44))
126976	33795819	Our results indicating that DCIS cells with PIK3CA mutations possess a monoclonal structure in which expression modules are required specifically for proliferation pathways support previous findings and suggest that PIK3CA mutations alone should be included as a marker for predicting a lower risk of progression to IDC and for reassessment of treatment options.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', (216, 222))	('PIK3CA', 'Gene', '5290', (44, 50))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('PIK3CA', 'Gene', '5290', (216, 222))	('mutations', 'Var', (223, 232))	('IDC', 'Disease', (316, 319))
126977	33795819	A logical interpretation is that sequential mutation of GATA3 facilitates acquisition of invasive characteristics following PIK3CA mutations to promote tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (131, 140))	('mutation', 'Var', (44, 52))	('facilitates', 'PosReg', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('GATA3', 'Gene', '2625', (56, 61))	('PIK3CA', 'Gene', '5290', (124, 130))	('tumor', 'Disease', (152, 157))	('promote', 'PosReg', (144, 151))	('PIK3CA', 'Gene', (124, 130))	('invasive characteristics', 'CPA', (89, 113))	('acquisition', 'MPA', (74, 85))	('GATA3', 'Gene', (56, 61))
126983	33795819	To complement this, by performing spatial transcriptome analysis of DCIS using STseq for three representative cases, we directly demonstrated that GATA3 mutation-harboring DCIS cells become more aggressive.	('more', 'PosReg', (190, 194))	('GATA3', 'Gene', '2625', (147, 152))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('mutation-harboring', 'Var', (153, 171))	('GATA3', 'Gene', (147, 152))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))	('aggressive', 'CPA', (195, 205))
127003	33795819	Libraries were sequenced on a NovaSeq 6000 System (Illumina) using a NovaSeq S4 Reagent Kit (200 cycles, 20027466, Illumina) at a sufficient sequencing depth (approximately 700 million to 1.2 billion reads per sample).	('Kit', 'Gene', (88, 91))	('20027466', 'Var', (105, 113))	('Kit', 'Gene', '3815', (88, 91))
127005	33795819	We extracted reads with confirmed GATA3 mutations in whole-exome sequencing from the Visium alignment results and identified spots with GATA3 mutations (Fig.	('GATA3', 'Gene', '2625', (34, 39))	('mutations', 'Var', (142, 151))	('mutations', 'Var', (40, 49))	('GATA3', 'Gene', (136, 141))	('GATA3', 'Gene', (34, 39))	('GATA3', 'Gene', '2625', (136, 141))
127006	33795819	In Patient A, we compared 46 spots with GATA3 mutations (red in Fig.	('GATA3', 'Gene', (40, 45))	('GATA3', 'Gene', '2625', (40, 45))	('mutations', 'Var', (46, 55))	('Patient', 'Species', '9606', (3, 10))
127010	33795819	To assess whether there were differences in mRNA expression between the spots with and without GATA3 mutations using an unpaired t-test (Fig.	('mRNA expression', 'MPA', (44, 59))	('GATA3', 'Gene', '2625', (95, 100))	('mutations', 'Var', (101, 110))	('GATA3', 'Gene', (95, 100))
127040	24796968	Although DCIS is not immediately life threatening, patients with DCIS in 1 breast are at increased risk for developing contralateral breast cancer (CBC).	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('contralateral breast cancer', 'Disease', (119, 146))	('DCIS', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (119, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('CBC', 'Chemical', '-', (148, 151))
127044	24796968	The BRCA1 and BRCA2 gene mutations have been shown to indicate a higher susceptibility to develop BC.	('mutations', 'Var', (25, 34))	('BRCA1', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (14, 19))	('BRCA2', 'Gene', (14, 19))	('BRCA1', 'Gene', '672', (4, 9))
127045	24796968	Individuals who carry 1 of these mutations have a 43% to 84% risk of developing BC, and up to a 65% risk for CBC.	('CBC', 'Chemical', '-', (109, 112))	('CBC', 'Disease', (109, 112))	('mutations', 'Var', (33, 42))
127046	24796968	Prospective studies of BRCA mutation carriers have shown that bilateral prophylactic mastectomy (BPM) reduces BC risk by more than 90%.	('reduces', 'NegReg', (102, 109))	('mutation', 'Var', (28, 36))	('BRCA', 'Gene', (23, 27))	('BRCA', 'Gene', '672', (23, 27))
127047	24796968	It has been reported that among BRCA mutation carriers, up to 65% of women with BC and 15% to 60% of unaffected women undergo risk-reduction breast surgeries.	('mutation', 'Var', (37, 45))	('women', 'Species', '9606', (112, 117))	('BRCA', 'Gene', '672', (32, 36))	('BRCA', 'Gene', (32, 36))	('women', 'Species', '9606', (69, 74))
127049	24796968	The prevalence of BRCA mutations in patients with DCIS has been reported.	('BRCA', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('BRCA', 'Gene', '672', (18, 22))	('patients', 'Species', '9606', (36, 44))
127050	24796968	Our previous study indicated a 27% prevalence of deleterious BRCA mutations among 118 patients with DCIS who were referred for genetic counseling.	('mutations', 'Var', (66, 75))	('BRCA', 'Gene', '672', (61, 65))	('patients', 'Species', '9606', (86, 94))	('BRCA', 'Gene', (61, 65))
127053	24796968	Several previous studies assessed the prevalence of BRCA1 and BRCA2 mutations among women with DCIS and reported rates between 3.3% and 13%.	('women', 'Species', '9606', (84, 89))	('BRCA1', 'Gene', '672', (52, 57))	('BRCA2', 'Gene', '675', (62, 67))	('BRCA1', 'Gene', (52, 57))	('mutations', 'Var', (68, 77))	('DCIS', 'Disease', (95, 99))	('BRCA2', 'Gene', (62, 67))
127054	24796968	The frequency and patterns regarding CPM choice among patients with DCIS and BRCA mutations have not been well reported.	('patients', 'Species', '9606', (54, 62))	('CPM', 'Disease', (37, 40))	('mutations', 'Var', (82, 91))	('BRCA', 'Gene', '672', (77, 81))	('BRCA', 'Gene', (77, 81))
127059	24796968	We excluded patients who had micro-invasion, bilateral DCIS, OC, or a genetic test result indicating a BRCA1 or BRCA2 variant of uncertain significance.	('patients', 'Species', '9606', (12, 20))	('variant', 'Var', (118, 125))	('BRCA1', 'Gene', '672', (103, 108))	('BRCA2', 'Gene', (112, 117))	('BRCA1', 'Gene', (103, 108))	('BRCA2', 'Gene', '675', (112, 117))
127068	24796968	Seventeen (10.3%) of 165 patients were found to have a deleterious BRCA mutation, 91 (55%) did not have a BRCA mutation, and 57 (35%) did not undergo genetic testing.	('BRCA', 'Gene', (106, 110))	('patients', 'Species', '9606', (25, 33))	('BRCA', 'Gene', '672', (106, 110))	('BRCA', 'Gene', (67, 71))	('mutation', 'Var', (72, 80))	('BRCA', 'Gene', '672', (67, 71))
127069	24796968	CPM was elected in 12 (71%) of the 17 patients who tested positive for a BRCA mutation, 23 (25%) of patients who tested negative, and 9 (16%) of the 57 patients who did not undergo genetic testing.	('mutation', 'Var', (78, 86))	('BRCA', 'Gene', '672', (73, 77))	('positive', 'Reg', (58, 66))	('BRCA', 'Gene', (73, 77))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (152, 160))
127076	24796968	Age at diagnosis and having 1 or more family members with OC and positive BRCA mutation status remained independent significant predictors of having elected CPM.	('mutation', 'Var', (79, 87))	('BRCA', 'Gene', (74, 78))	('BRCA', 'Gene', '672', (74, 78))
127079	24796968	Results of BRCA genetic testing were significantly associated with the probability of having chosen to have CPM (P = 0.0041).	('associated', 'Reg', (51, 61))	('genetic testing', 'Var', (16, 31))	('BRCA', 'Gene', (11, 15))	('BRCA', 'Gene', '672', (11, 15))
127083	24796968	Age at diagnosis and having 1 or more family members with OC remained independent significant predictors of having elected CPM among patients who tested negative for a BRCA mutation.	('BRCA', 'Gene', '672', (168, 172))	('BRCA', 'Gene', (168, 172))	('patients', 'Species', '9606', (133, 141))	('CPM', 'Disease', (123, 126))	('mutation', 'Var', (173, 181))
127100	24796968	It has been well established that BPM in BRCA mutation carriers reduces BC risk by 90%.	('BPM', 'MPA', (34, 37))	('BRCA', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('reduces', 'NegReg', (64, 71))	('BRCA', 'Gene', '672', (41, 45))
127101	24796968	In a prospective study, Meijers-Heijbor et al evaluated the incidence of BC among 139 BRCA1 and BRCA2 mutation carriers who elected to undergo either BPM or close surveillance only.	('BRCA1', 'Gene', '672', (86, 91))	('mutation', 'Var', (102, 110))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', (86, 91))	('BRCA2', 'Gene', (96, 101))
127104	24796968	evaluated 483 women with deleterious BRCA1 and BRCA2 mutations from the time of their ascertainment to time of surgery.	('BRCA2', 'Gene', (47, 52))	('mutations', 'Var', (53, 62))	('BRCA1', 'Gene', '672', (37, 42))	('women', 'Species', '9606', (14, 19))	('BRCA2', 'Gene', '675', (47, 52))	('BRCA1', 'Gene', (37, 42))
127106	24796968	Hartmann and associates identified 26 women with an alteration in the BRCA1 or BRCA2 genes (18 had deleterious changes, and 8 had variants of uncertain clinical significance) who underwent prophylactic mastectomy.	('BRCA2', 'Gene', '675', (79, 84))	('BRCA1', 'Gene', '672', (70, 75))	('BRCA1', 'Gene', (70, 75))	('alteration', 'Var', (52, 62))	('women', 'Species', '9606', (38, 43))	('BRCA2', 'Gene', (79, 84))
127108	24796968	These studies provide a plethora of evidence for the effectiveness of BPM in BC risk reduction among BRCA mutation carriers.	('plethora', 'Phenotype', 'HP:0001050', (24, 32))	('mutation', 'Var', (106, 114))	('BRCA', 'Gene', (101, 105))	('BRCA', 'Gene', '672', (101, 105))
127109	24796968	Our data show a substantial proportion (25%) of patients who tested negative for a BRCA mutation still elected CPM.	('CPM', 'Disease', (111, 114))	('mutation', 'Var', (88, 96))	('BRCA', 'Gene', '672', (83, 87))	('BRCA', 'Gene', (83, 87))	('patients', 'Species', '9606', (48, 56))
127111	24796968	Few studies examined CPM among patients who tested negative for BRCA mutations; therefore we are currently analyzing a prospective cohort.	('mutations', 'Var', (69, 78))	('CPM', 'Disease', (21, 24))	('patients', 'Species', '9606', (31, 39))	('BRCA', 'Gene', (64, 68))	('BRCA', 'Gene', '672', (64, 68))
127112	24796968	Howard-McNatt et al  examined CPM among patients with invasive BC who tested negative for a BRCA mutation.	('patients', 'Species', '9606', (40, 48))	('BRCA', 'Gene', '672', (92, 96))	('mutation', 'Var', (97, 105))	('BRCA', 'Gene', (92, 96))	('CPM', 'MPA', (30, 33))	('invasive BC', 'Disease', (54, 65))
127115	24796968	It has been shown that family history of OC is more suggestive of a BRCA mutation than a family history of BC.	('mutation', 'Var', (73, 81))	('BRCA', 'Gene', (68, 72))	('BRCA', 'Gene', '672', (68, 72))
127116	24796968	In turn, BRCA positivity is associated with increased risk for primary BC and CBC, which explains why patients are concerned about risk for CBC and elect CPM.	('primary BC', 'Disease', (63, 73))	('patients', 'Species', '9606', (102, 110))	('CBC', 'Chemical', '-', (78, 81))	('BRCA', 'Gene', '672', (9, 13))	('positivity', 'Var', (14, 24))	('CBC', 'Disease', (78, 81))	('BRCA', 'Gene', (9, 13))	('CBC', 'Chemical', '-', (140, 143))
127137	24989024	High histological grade was defined by the presence of either of two features: (1) high nuclear grade, defined as nuclear size >2.5 times lymphocyte or benign ductal epithelial cell nuclei, marked pleomorphism, irregular chromatin with single or multiple nucleoli and conspicuous mitoses, or (2) necrosis, defined by the presence of ghost cells with karyorrhectic debris, in a third or greater of the neoplastic ducts.	('necrosis', 'Disease', (296, 304))	('mitoses', 'CPA', (280, 287))	('necrosis', 'Disease', 'MESH:D009336', (296, 304))	('marked pleomorphism', 'Var', (190, 209))
127148	24989024	While nuclear grade and comedonecrosis have been strongly associated with increased risk of ipsilateral breast recurrence after lumpectomy alone in many studies,   heterogeneity of populations and methods make consensus regarding true risk elusive.	('associated', 'Reg', (58, 68))	('necrosis', 'Disease', 'MESH:D009336', (30, 38))	('nuclear', 'Var', (6, 13))	('ipsilateral breast recurrence', 'Disease', (92, 121))	('necrosis', 'Disease', (30, 38))
127152	24989024	Among 1617 women treated with lumpectomy alone evaluated by nuclear grade, the 10-year ipsilateral breast cancer recurrence was 28.4%, 29.8% and 33.1% for DCIS nuclear grade low, intermediate and high, respectively.	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (87, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('high', 'Var', (196, 200))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('women', 'Species', '9606', (11, 16))	('ipsilateral breast cancer', 'Disease', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
127179	32178425	A low MD is usually reported to be associated with a better BC outcome, with a lower risk of local recurrence, although it does not seem to affect neither the risk of metastasis nor the mortality specifically associated to BC.	('mortality', 'Disease', 'MESH:D003643', (186, 195))	('mortality', 'Disease', (186, 195))	('low', 'Var', (2, 5))
127180	32178425	However, so far the biological mechanisms underlying the phenomenon of how breast density increases the risk of breast cancer have proven elusive and it is upon this point that recent studies of the interactions between cancer cells and stroma can shed some new light.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast', 'Var', (75, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', (112, 125))	('interactions', 'Interaction', (199, 211))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('increases', 'PosReg', (90, 99))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
127182	32178425	New players such as mutagens, inflammatory molecules, cytokines and growth factors and other promoting forces, acting alone or in combination, can break the myoepithelial and basement membrane barrier prompting tumour formation (Figure 2).	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('mutagens', 'Var', (20, 28))	('tumour', 'Disease', (211, 217))	('break', 'NegReg', (147, 152))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
127207	32178425	The possible role of MD in the relationship between HRT and BC has been studied and a partial role of MD has been found since the association between HRT and BC risk is stronger in women with high MD.	('stronger', 'PosReg', (169, 177))	('HRT', 'Gene', (150, 153))	('high MD', 'Var', (192, 199))	('women', 'Species', '9606', (181, 186))	('association', 'Interaction', (130, 141))
127212	32178425	In fact, DCIS is usually regarded as a non-obligate previous step in the development of IDC, since the loss of myoepithelial cells and the breach of BM leads to an IDC, in which tumour epithelial cells invade the mammary stroma and eventually evolve to metastatic BC (Figure 1B1).	('loss of myoepithelial', 'Disease', (103, 124))	('metastatic', 'CPA', (253, 263))	('IDC', 'Gene', '4000', (88, 91))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('IDC', 'Gene', (88, 91))	('IDC', 'Gene', '4000', (164, 167))	('IDC', 'Gene', (164, 167))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('evolve', 'PosReg', (243, 249))	('leads to', 'Reg', (152, 160))	('loss of myoepithelial', 'Disease', 'MESH:D009208', (103, 124))	('tumour', 'Disease', (178, 184))	('breach', 'Var', (139, 145))
127215	32178425	It has been reported that patients diagnosed with DCIS and presenting high MD (over 75%) have a higher probability to develop a second breast cancer, particularly in the contralateral breast when compared with low MD (under 25%) patients.	('patients', 'Species', '9606', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (26, 34))	('develop', 'PosReg', (118, 125))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('DCIS', 'Var', (50, 54))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
127229	32178425	In a different study using samples from women undergoing prophylactic mastectomy because of their high BC risk profile, high MD tissues with no alterations in hormone receptor or Ki-67 marker status (and thus reputed as cancer-free) were described to have increased collagen deposition and changes in its organization, compared to low MD tissues.	('increased', 'PosReg', (256, 265))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('changes', 'Reg', (290, 297))	('women', 'Species', '9606', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('organization', 'MPA', (305, 317))	('high MD', 'Var', (120, 127))	('collagen deposition', 'CPA', (266, 285))
127235	32178425	Furthermore, CAFs can also secrete plasminogen activators and different MMPs, that can be used by the tumour in two different ways: to degrade ECM components and thus allow tumour expansion and promote angiogenesis; or to cleave soluble factors and cell adhesion molecules, which will result in an increased motility and EMT capacity (Figure 3B).	('degrade', 'NegReg', (135, 142))	('tumour', 'Disease', (173, 179))	('promote', 'PosReg', (194, 201))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('ECM components', 'MPA', (143, 157))	('cell', 'Protein', (249, 253))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('angiogenesis', 'CPA', (202, 214))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('EMT capacity', 'CPA', (321, 333))	('soluble factors', 'Protein', (229, 244))	('increased', 'PosReg', (298, 307))	('cleave', 'Var', (222, 228))	('motility', 'CPA', (308, 316))
127245	32178425	CAFs have also been shown to induce trastuzumab resistance in HER2-positive BC cells by expanding the cancer stem cell population and activating several signalling pathways such as NFkB.	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CAFs', 'Var', (0, 4))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('signalling pathways', 'Pathway', (153, 172))	('trastuzumab', 'Chemical', 'MESH:D000068878', (36, 47))	('induce', 'PosReg', (29, 35))	('trastuzumab resistance', 'MPA', (36, 58))	('HER2', 'Gene', (62, 66))	('activating', 'PosReg', (134, 144))	('expanding', 'PosReg', (88, 97))
127267	32178425	In the context of breast cancer, a phase 1 study evaluates the safety, pharmacokinetics and therapeutic activity of RO6874281 as monotherapy, RO6874281 combined with Trastuzumab, or RO6874281 combined with Cetuximab, for patients with breast and head and neck cancers (NCT02627274).	('RO6874281', 'Var', (142, 151))	('patients', 'Species', '9606', (221, 229))	('Cetuximab', 'Chemical', 'MESH:D000068818', (206, 215))	('head and neck cancers', 'Disease', 'MESH:D006258', (246, 267))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('head and neck cancers', 'Phenotype', 'HP:0012288', (246, 267))	('RO6874281', 'Chemical', '-', (116, 125))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('RO6874281', 'Var', (116, 125))	('RO6874281', 'Chemical', '-', (182, 191))	('RO6874281', 'Chemical', '-', (142, 151))	('breast', 'Disease', (235, 241))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('RO6874281', 'Var', (182, 191))
127269	32178425	Finally, it has been postulated that changes in MD could be used as a biomarker for evaluating breast cancer prevention strategies and as a surrogate biomarker for preventive and adjuvant endocrine therapies.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('changes', 'Var', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
127294	29187227	Recent studies using transgenic mouse models and human tissue xenografts have suggested that the most common types of breast cancer arise from mutations in progenitor cells in the luminal lineage.	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('mouse', 'Species', '10090', (32, 37))	('arise from', 'Reg', (132, 142))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('mutations', 'Var', (143, 152))
127323	29187227	Cells were resuspended in organoid medium with 0.1 mg/ml DNAse (Roche 10104159001) and 5 mg/ml Dispase II (Roche, 04942078001) for 5 min.	('Roche 10104159001', 'Var', (64, 81))	('for 5', 'Gene', '109647', (127, 132))	('organoid medium', 'Chemical', '-', (26, 41))	('Roche', 'Var', (107, 112))	('for 5', 'Gene', (127, 132))
127370	29187227	After 17 weeks, mice fed HFD weighed significantly more (33.5 g +- 9.0; n = 7) than control mice (24.5 g +- 3.2; n = 7; p = 0.004, Mann-Whitney test).	('HFD', 'Var', (25, 28))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (16, 20))	('more', 'PosReg', (51, 55))
127378	29187227	When compared to control mice, the ratio of luminal to basal epithelial cells was significantly increased in mice fed HFD (Fig.	('increased', 'PosReg', (96, 105))	('mice', 'Species', '10090', (25, 29))	('HFD', 'Var', (118, 121))	('ratio', 'MPA', (35, 40))	('mice', 'Species', '10090', (109, 113))	('rat', 'Species', '10116', (35, 38))
127382	29187227	Similar to our observations in the mouse mammary glands, the ratio of luminal to basal/myoepithelial cells was significantly enhanced with increasing BMI (Fig.	('myoepithelial', 'Disease', (87, 100))	('rat', 'Species', '10116', (61, 64))	('mouse', 'Species', '10090', (35, 40))	('myoepithelial', 'Disease', 'MESH:D009208', (87, 100))	('increasing BMI', 'Phenotype', 'HP:0031418', (139, 153))	('enhanced', 'PosReg', (125, 133))	('BMI', 'Var', (150, 153))
127395	29187227	We and others have observed variability in the cell populations expressing CK14, so we also examined expression of the basal/myoepithelial cell marker p63, a member of the p53 family of transcription factors.	('myoepithelial', 'Disease', (125, 138))	('p53', 'Gene', '22060', (172, 175))	('CK14', 'Var', (75, 79))	('myoepithelial', 'Disease', 'MESH:D009208', (125, 138))	('p53', 'Gene', (172, 175))
127422	29187227	In both FVB/N and C57Bl/6 strains of mice, inguinal mammary glands from the HFD-fed B6 3-week-old and FVB 3-week-old mice weighed significantly more than those from control mice after 17 weeks on the diets (Fig.	('weighed', 'CPA', (122, 129))	('FVB', 'Var', (102, 105))	('more', 'PosReg', (144, 148))	('mice', 'Species', '10090', (117, 121))	('mice', 'Species', '10090', (173, 177))	('mice', 'Species', '10090', (37, 41))
127454	29187227	However, floating colony formation was significantly enhanced in patient samples with increasing BMI (Fig.	('floating colony formation', 'CPA', (9, 34))	('increasing BMI', 'Phenotype', 'HP:0031418', (86, 100))	('patient', 'Species', '9606', (65, 72))	('BMI', 'Var', (97, 100))	('enhanced', 'PosReg', (53, 61))
127455	29187227	4h), suggesting that luminal progenitor cells were significantly enhanced in human samples with increasing BMI.	('luminal progenitor cells', 'CPA', (21, 45))	('increasing BMI', 'Phenotype', 'HP:0031418', (96, 110))	('enhanced', 'PosReg', (65, 73))	('BMI', 'Var', (107, 110))	('human', 'Species', '9606', (77, 82))
127469	29187227	However, these ERalpha+Ki67+ cells were observed in breast samples from women in both the overweight (BMI 25-29.9) and obese (BMI >30) ranges.	('obese', 'Gene', (119, 124))	('Ki67', 'Gene', (23, 27))	('BMI 25-29.9', 'Var', (102, 113))	('overweight', 'Phenotype', 'HP:0025502', (90, 100))	('obese', 'Gene', '16846', (119, 124))	('Ki67', 'Gene', '17345', (23, 27))	('women', 'Species', '9606', (72, 77))
127507	29187227	Given their central role in suppression of tumor progression and invasion (for review see), discontinuity of the basal/myoepithelial layer under conditions of obesity may weaken local defenses, which could facilitate tumor invasion into the surrounding tissue once cancer arises.	('obesity', 'Disease', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('facilitate', 'PosReg', (206, 216))	('tumor', 'Disease', (217, 222))	('myoepithelial', 'Disease', 'MESH:D009208', (119, 132))	('discontinuity', 'Var', (92, 105))	('weaken', 'NegReg', (171, 177))	('local defenses', 'MPA', (178, 192))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('obesity', 'Phenotype', 'HP:0001513', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', (43, 48))	('obesity', 'Disease', 'MESH:D009765', (159, 166))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('myoepithelial', 'Disease', (119, 132))
127523	29187227	TGFbeta signaling inhibits the proliferation of ERalpha+ epithelial cells in mouse mammary glands and cultured human breast epithelial cells, and loss of TGFbeta signaling may play a role in the observed increases in ERalpha+ proliferating cells in mammary tissue in obesity.	('proliferation', 'CPA', (31, 44))	('TGFbeta', 'Gene', (154, 161))	('inhibits', 'NegReg', (18, 26))	('increases', 'PosReg', (204, 213))	('loss', 'Var', (146, 150))	('ERalpha+', 'CPA', (217, 225))	('TGFbeta', 'Gene', (0, 7))	('obesity', 'Disease', 'MESH:D009765', (267, 274))	('human', 'Species', '9606', (111, 116))	('obesity', 'Disease', (267, 274))	('rat', 'Species', '10116', (233, 236))	('rat', 'Species', '10116', (38, 41))	('mouse', 'Species', '10090', (77, 82))	('obesity', 'Phenotype', 'HP:0001513', (267, 274))
127537	29187227	These changes may contribute to lifetime risk of the development of ERalpha+ tumors in postmenopausal women.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('women', 'Species', '9606', (102, 107))	('changes', 'Var', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('contribute', 'Reg', (18, 28))
127587	23774990	Patients with ER-negative DCIS were somewhat more likely to present with a clinical abnormality, but this difference did not reach statistical significance (18% vs 13%, p=0.083).	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('clinical abnormality', 'MPA', (75, 95))	('ER', 'Gene', '2099', (14, 16))	('DCIS', 'Var', (26, 30))	('Patients', 'Species', '9606', (0, 8))
127601	23774990	In the subset of 126 patients with noncalcified DCIS, 85 patients (67%) had a corresponding mammographic abnormality: 52 (61%) had a mass, 20 (24%) focal asymmetry, and 13 (15%) architectural distortion.	('focal asymmetry', 'Var', (148, 163))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (21, 29))	('DCIS', 'Phenotype', 'HP:0030075', (48, 52))	('mass', 'Disease', (133, 137))	('architectural distortion', 'CPA', (178, 202))
127625	23774990	Both high nuclear grade and comedonecrosis are associated with higher likelihood of local recurrence and development of invasive cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('local recurrence', 'CPA', (84, 100))	('comedonecrosis', 'Disease', (28, 42))	('invasive cancer', 'Disease', (120, 135))	('high nuclear grade', 'Var', (5, 23))	('invasive cancer', 'Disease', 'MESH:D009362', (120, 135))
127650	15018618	High grade was associated with presence of linear calcifications (p < 0.001).	('calcification', 'Disease', 'MESH:D002114', (50, 63))	('calcification', 'Disease', (50, 63))	('High grade', 'Var', (0, 10))
127651	15018618	Association between mammograhic- and pathological size was better for DCIS presented as microcalcifications (r = 0.89, p < 0.001) than for DCIS presented as a density (r = 0.77, p < 0.001).	('calcification', 'Disease', (93, 106))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('Association', 'Interaction', (0, 11))	('DCIS', 'Var', (70, 74))	('calcification', 'Disease', 'MESH:D002114', (93, 106))
127772	26152557	The results reported here, based on precise correlation of a large number of lesions on MR and histopathology, demonstrate quantitatively for the first time that MRI reliably identifies early mammary cancers in SV40Tag mice, and differentiates in situ from invasive cancers with high sensitivity and specificity.	('invasive cancers', 'Disease', 'MESH:D009362', (257, 273))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('mice', 'Species', '10090', (219, 223))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('invasive cancers', 'Disease', (257, 273))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('SV40Tag', 'Var', (211, 218))
127822	26152557	The diameter of the invasive cancer was 0.710+-0.020 mm, 0.707+-0.018 mm, and 0.713+-0.011 mm from in vivo, ex vivo MR, and histology images, respectively.	('0.713+-0.011', 'Var', (78, 90))	('invasive cancer', 'Disease', 'MESH:D009362', (20, 35))	('invasive cancer', 'Disease', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
127996	23843846	MUC6 expression was correlated with higher histologic grade, lymphatic invasion, lymph node metastasis, and HER2 positivity.	('HER2', 'Gene', (108, 112))	('positivity', 'Var', (113, 123))	('expression', 'MPA', (5, 15))	('higher', 'PosReg', (36, 42))	('HER2', 'Gene', '2064', (108, 112))	('lymphatic invasion', 'CPA', (61, 79))	('lymph node metastasis', 'CPA', (81, 102))	('MUC6', 'Gene', (0, 4))
128004	23843846	MUC5AC is located mainly in the gastric mucosa of the cardia, fundus, and antrum, where as MUC6 is located in pyloric glands.	('MUC5AC', 'Var', (0, 6))	('gastric mucosa of the cardia', 'Disease', (32, 60))	('gastric mucosa of the cardia', 'Disease', 'MESH:D004938', (32, 60))
128017	22588560	Long-term results of screening with magnetic resonance imaging in women with BRCA mutations The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes.	('increases', 'PosReg', (217, 226))	('women', 'Species', '9606', (177, 182))	('sensitivity', 'MPA', (227, 238))	('mutations', 'Var', (193, 202))	('mutations', 'Var', (82, 91))	('women', 'Species', '9606', (66, 71))	('BRCA', 'Gene', (188, 192))
128019	22588560	From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography.	('women', 'Species', '9606', (23, 28))	('BRCA1', 'Gene', '672', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('BRCA1', 'Gene', (62, 67))	('mutation', 'Var', (70, 78))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
128022	22588560	Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%).	('mutation', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA1', 'Gene', (68, 73))	('invasive cancer', 'Disease', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('women', 'Species', '9606', (28, 33))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('BRCA1', 'Gene', '672', (68, 73))	('invasive cancer', 'Disease', 'MESH:D009362', (49, 64))
128024	22588560	Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('women', 'Species', '9606', (43, 48))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('breast cancers', 'Disease', (100, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('BRCA1', 'Gene', '672', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('mutations', 'Var', (62, 71))	('BRCA1', 'Gene', (54, 59))
128026	22588560	In women with a BRCA1 or BRCA2 gene mutation, the risk of breast cancer is low until the age of 25, but by age 70, the cumulative risk reaches 57-65% for BRCA1 and 45-49% for BRCA2 mutations.	('BRCA2', 'Gene', (25, 30))	('BRCA1', 'Gene', (154, 159))	('BRCA1', 'Gene', '672', (154, 159))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('BRCA2', 'Gene', '675', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('BRCA1', 'Gene', '672', (16, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRCA2', 'Gene', (175, 180))	('women', 'Species', '9606', (3, 8))	('BRCA1', 'Gene', (16, 21))	('mutation', 'Var', (36, 44))	('BRCA2', 'Gene', '675', (175, 180))
128031	22588560	It has been suggested that MRI may not be necessary in women over age 50 or that annual screening may not be frequent enough in young women with BRCA1 mutations.	('women', 'Species', '9606', (55, 60))	('BRCA1', 'Gene', '672', (145, 150))	('women', 'Species', '9606', (134, 139))	('BRCA1', 'Gene', (145, 150))	('mutations', 'Var', (151, 160))
128032	22588560	Between 1997 and 2009, we screened 496 women with BRCA1 or BRCA2 mutations using annual MRI and mammography.	('BRCA2', 'Gene', '675', (59, 64))	('BRCA1', 'Gene', (50, 55))	('women', 'Species', '9606', (39, 44))	('en 1', 'Gene', (5, 9))	('en 1', 'Gene', '2019', (5, 9))	('BRCA2', 'Gene', (59, 64))	('BRCA1', 'Gene', '672', (50, 55))	('mutations', 'Var', (65, 74))
128034	22588560	Between 1 November 1997 and 30 June 2009, women aged 25 to 65 with a known BRCA1 or BRCA2 mutation, and at least one breast in which cancer had never been diagnosed, were enrolled consecutively in a prospective breast cancer screening trial at a single tertiary centre.	('one breast', 'Phenotype', 'HP:0012813', (113, 123))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('BRCA1', 'Gene', (75, 80))	('cancer', 'Disease', (218, 224))	('BRCA2', 'Gene', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('en 1', 'Gene', (5, 9))	('cancer', 'Disease', (133, 139))	('en 1', 'Gene', '2019', (5, 9))	('BRCA2', 'Gene', '675', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('women', 'Species', '9606', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('BRCA1', 'Gene', '672', (75, 80))	('mutation', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (211, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))
128059	22588560	A total of 496 women (267 BRCA1 and 229 BRCA2 mutation carriers) completed from 1 to 9 rounds of screening (median 3), for a total of 1847 rounds (Table 1).	('women', 'Species', '9606', (15, 20))	('BRCA1', 'Gene', (26, 31))	('to 9', 'Species', '1214577', (82, 86))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (26, 31))	('mutation', 'Var', (46, 54))	('BRCA2', 'Gene', '675', (40, 45))
128065	22588560	A single interval cancer was detected in a 40-year-old BRCA1 mutation carrier 8 months after her last negative screen, yielding an interval cancer rate of 2% overall and 3% for the BRCA1 cohort.	('BRCA1', 'Gene', '672', (181, 186))	('BRCA1', 'Gene', (181, 186))	('mutation', 'Var', (61, 69))	('interval cancer', 'Disease', (131, 146))	('BRCA1', 'Gene', '672', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('interval cancer', 'Disease', 'MESH:D009369', (131, 146))	('interval cancer', 'Disease', (9, 24))	('BRCA1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('interval cancer', 'Disease', 'MESH:D009369', (9, 24))
128070	22588560	The third case was a 0.6-cm invasive, node-negative ductal cancer diagnosed in a 36-year-old BRCA1 mutation carrier 6 months after her last screen.	('BRCA1', 'Gene', '672', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutation', 'Var', (99, 107))	('invasive', 'Disease', (28, 36))	('BRCA1', 'Gene', (93, 98))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
128077	22588560	Of the 37 invasive cancers, 89% were detected by MRI and 22% were detected by mammography (P<0.0001).	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('invasive cancers', 'Disease', 'MESH:D009362', (10, 26))	('MRI', 'Var', (49, 52))	('invasive cancers', 'Disease', (10, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
128080	22588560	The sensitivity of mammography was low for both BRCA1 (21%) and BRCA2 (20%) mutation carriers, whereas the sensitivity of MRI was high for both subgroups.	('BRCA2', 'Gene', '675', (64, 69))	('BRCA1', 'Gene', '672', (48, 53))	('mammography', 'Disease', (19, 30))	('BRCA1', 'Gene', (48, 53))	('low', 'NegReg', (35, 38))	('BRCA2', 'Gene', (64, 69))	('mutation', 'Var', (76, 84))
128082	22588560	Of 57 cancers diagnosed, 31 occurred in BRCA1 mutation carriers and 26 in BRCA2 carriers.	('occurred', 'Reg', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('BRCA1', 'Gene', '672', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('mutation', 'Var', (46, 54))	('BRCA1', 'Gene', (40, 45))
128083	22588560	Of these, 8 (26%) were DCIS in BRCA1 mutation carriers (3 with micro-invasion) compared with 12 (46%) in BRCA2 mutation carriers (1 with micro-invasion).	('mutation', 'Var', (37, 45))	('BRCA1', 'Gene', '672', (31, 36))	('BRCA2', 'Gene', (105, 110))	('DCIS', 'Chemical', '-', (23, 27))	('BRCA1', 'Gene', (31, 36))	('BRCA2', 'Gene', '675', (105, 110))
128086	22588560	Cancers in BRCA1 mutation carriers were significantly more likely to be hormone-receptor negative and to have been treated with chemotherapy.	('BRCA1', 'Gene', '672', (11, 16))	('Cancers', 'Disease', (0, 7))	('negative', 'NegReg', (89, 97))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('mutation', 'Var', (17, 25))	('BRCA1', 'Gene', (11, 16))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('hormone-receptor', 'Protein', (72, 88))
128087	22588560	A greater proportion of DCIS cases in BRCA1 mutation carriers had a micro-invasive component compared with BRCA2 mutation carriers (38% vs 8%, P=0.26).	('mutation', 'Var', (44, 52))	('DCIS', 'Disease', (24, 28))	('BRCA2', 'Gene', '675', (107, 112))	('BRCA1', 'Gene', (38, 43))	('micro-invasive component', 'CPA', (68, 92))	('DCIS', 'Chemical', '-', (24, 28))	('BRCA1', 'Gene', '672', (38, 43))	('BRCA2', 'Gene', (107, 112))
128099	22588560	One of these women, a BRCA1 mutation carrier, died of breast cancer 5 years after her initial diagnosis.	('breast cancer', 'Disease', (54, 67))	('mutation', 'Var', (28, 36))	('BRCA1', 'Gene', '672', (22, 27))	('women', 'Species', '9606', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('BRCA1', 'Gene', (22, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
128104	22588560	In this study of 496 women with BRCA1 or BRCA2 mutations screened with annual MRI plus mammography, 54 developed breast cancer.	('BRCA2', 'Gene', (41, 46))	('BRCA1', 'Gene', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', (113, 126))	('BRCA2', 'Gene', '675', (41, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('mutations', 'Var', (47, 56))	('developed', 'Reg', (103, 112))	('BRCA1', 'Gene', '672', (32, 37))	('women', 'Species', '9606', (21, 26))
128106	22588560	On the basis of these results, we recommend annual screening with MRI for women with a BRCA1 or BRCA2 mutation who have not undergone prophylactic mastectomy.	('women', 'Species', '9606', (74, 79))	('BRCA1', 'Gene', '672', (87, 92))	('mutation', 'Var', (102, 110))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', (87, 92))	('BRCA2', 'Gene', (96, 101))
128107	22588560	In a Dutch trial of MRI screening for high-risk women, conducted from 1999 to 2006, 47 cancers were found among 594 previously unaffected BRCA mutation carriers.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutation', 'Var', (143, 151))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('BRCA', 'Gene', (138, 142))	('women', 'Species', '9606', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
128111	22588560	Despite a median age at cancer diagnosis of 45 years (range 27 to 68 years) in the Dutch study that was similar to our cohort of unaffected carriers (median 46 years, range 32 to 68 years), 3 BRCA1 mutation carriers under the age of 30 were diagnosed with cancer in the Dutch trial, whereas no cancers were diagnosed in this age group in our study.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('BRCA1', 'Gene', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Disease', (256, 262))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('diagnosed with', 'Reg', (241, 255))	('cancers', 'Disease', (294, 301))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('BRCA1', 'Gene', '672', (192, 197))	('mutation', 'Var', (198, 206))
128112	22588560	As tumour growth is more rapid in younger BRCA1 mutation carriers, this may have contributed to their higher interval cancer rate.	('BRCA1', 'Gene', '672', (42, 47))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('BRCA1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rapid', 'PosReg', (25, 30))	('mutation', 'Var', (48, 56))	('tumour', 'Disease', (3, 9))	('interval cancer', 'Disease', (109, 124))	('interval cancer', 'Disease', 'MESH:D009369', (109, 124))
128113	22588560	The UK MARIBS study was another large multicentre MRI screening study of 649 high-risk women, including 120 BRCA mutation carriers.	('mutation', 'Var', (113, 121))	('BRCA', 'Gene', (108, 112))	('women', 'Species', '9606', (87, 92))
128117	22588560	We found MRI to be equally effective in the screening of women with BRCA1 and BRCA2 mutations.	('BRCA1', 'Gene', (68, 73))	('women', 'Species', '9606', (57, 62))	('BRCA2', 'Gene', (78, 83))	('mutations', 'Var', (84, 93))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1', 'Gene', '672', (68, 73))
128118	22588560	In the Dutch study, MRI was more sensitive than mammography for detecting tumours in BRCA1 mutation carriers, but not in BRCA2 carriers.	('mutation', 'Var', (91, 99))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('BRCA1', 'Gene', (85, 90))	('BRCA2', 'Gene', '675', (121, 126))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('tumours', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('BRCA1', 'Gene', '672', (85, 90))	('BRCA2', 'Gene', (121, 126))
128120	22588560	In our study, 26% of all cancers in BRCA1 carriers and 46% of cancers in BRCA2 carriers were DCIS.	('DCIS', 'Chemical', '-', (93, 97))	('BRCA1', 'Gene', (36, 41))	('BRCA2', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('DCIS', 'Disease', (93, 97))	('BRCA2', 'Gene', '675', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', (62, 69))	('carriers', 'Var', (42, 50))	('BRCA1', 'Gene', '672', (36, 41))
128122	22588560	Some studies suggest that BRCA1-associated cancers grow faster than BRCA2-related breast cancers, and the authors have suggested that the screening interval may need to be shorter for BRCA1 carriers than for BRCA2 carriers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('faster', 'PosReg', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('BRCA2', 'Gene', (208, 213))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('BRCA2', 'Gene', '675', (68, 73))	('carriers', 'Var', (190, 198))	('BRCA1', 'Gene', '672', (184, 189))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA1', 'Gene', (184, 189))	('BRCA2', 'Gene', '675', (208, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BRCA1', 'Gene', (26, 31))	('breast cancers', 'Disease', 'MESH:D001943', (82, 96))	('breast cancers', 'Disease', (82, 96))	('grow', 'CPA', (51, 55))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA2', 'Gene', (68, 73))
128129	22588560	A prior detailed analysis of mammographic sensitivity based on breast density in BRCA mutation carriers revealed that, although there was a trend towards greater mammographic sensitivity for invasive cancers (not DCIS) in women with less dense breasts compared to women with greater breast density (37-43% vs 8-12% P=0.1), the sensitivity of mammography was still inadequate in the former group.	('BRCA', 'Gene', (81, 85))	('invasive cancers', 'Disease', (191, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('women', 'Species', '9606', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('invasive cancers', 'Disease', 'MESH:D009362', (191, 207))	('DCIS', 'Chemical', '-', (213, 217))	('mutation', 'Var', (86, 94))	('women', 'Species', '9606', (264, 269))	('mammographic', 'MPA', (162, 174))	('greater', 'PosReg', (154, 161))
128130	22588560	This study is unable to address the issue of whether the MRI screening interval can be increased in older women (with recommended age-based intervals possibly varying between BRCA1 and BRCA2 mutation carriers).	('BRCA2', 'Gene', '675', (185, 190))	('BRCA1', 'Gene', (175, 180))	('women', 'Species', '9606', (106, 111))	('BRCA2', 'Gene', (185, 190))	('mutation', 'Var', (191, 199))	('BRCA1', 'Gene', '672', (175, 180))
128137	22588560	Longer follow-up of larger numbers of BRCA mutation carriers undergoing MRI screening matched to an appropriate control group would be needed to determine the degree to which the increased detection of DCIS lowers the subsequent incidence of invasive disease.	('mutation', 'Var', (43, 51))	('BRCA', 'Gene', (38, 42))	('invasive disease', 'CPA', (242, 258))	('lowers', 'NegReg', (207, 213))	('DCIS lowers', 'Phenotype', 'HP:0200161', (202, 213))	('DCIS', 'Chemical', '-', (202, 206))	('DCIS', 'Gene', (202, 206))
128145	22588560	In conclusion, our study suggests that MRI surveillance of women with BRCA mutations performed at an experienced centre, beginning at age 30, detects the majority of breast cancers at an early stage, yielding a low rate of distant relapse at 8.4 years follow-up.	('breast cancers', 'Phenotype', 'HP:0003002', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('BRCA', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('breast cancers', 'Disease', (166, 180))	('women', 'Species', '9606', (59, 64))	('breast cancers', 'Disease', 'MESH:D001943', (166, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
128146	22588560	These results are encouraging and suggest that MRI surveillance may be a safe alternative to prophylactic mastectomy for women with BRCA mutations who can tolerate the high risk of a future breast cancer diagnosis, but longer-term follow-up data is needed.	('BRCA', 'Gene', (132, 136))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('women', 'Species', '9606', (121, 126))
128152	19457236	We have recently demonstrated that the activation of ERK1/2 induces a non-invasive form of motility, where cells can track along the basement membrane and adjacent epithelial cells, but do not become invasive over time, using real-time imaging of a mammary epithelial organotypic culture model.	('induces', 'Reg', (60, 67))	('non-invasive form of motility', 'CPA', (70, 99))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('ERK1/2', 'Gene', (53, 59))	('activation', 'Var', (39, 49))
128162	19457236	Since such a wide range of molecular perturbations can induce and enhance tumor growth, there are probably shared molecular signaling modules that integrate biochemical signals from the suite of genetic contexts found in epithelial tumors.	('perturbations', 'Var', (37, 50))	('enhance', 'PosReg', (66, 73))	('epithelial tumors', 'Disease', 'MESH:D002277', (221, 238))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (74, 79))	('induce', 'PosReg', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (232, 237))	('epithelial tumor', 'Phenotype', 'HP:0031492', (221, 237))	('epithelial tumors', 'Disease', (221, 238))
128170	19457236	In addition, the sequencing of breast cancer patient genomes suggests that infrequent mutations may drive tumor progression through known signaling pathways, such as the Raf-MEK1/2-ERK1/2 cascade.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Raf', 'Gene', (170, 173))	('ERK1/2', 'Gene', '5595;5594', (181, 187))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('drive', 'Reg', (100, 105))	('Raf', 'Gene', '22882', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('breast cancer', 'Disease', (31, 44))	('patient', 'Species', '9606', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('signaling pathways', 'Pathway', (138, 156))	('tumor', 'Disease', (106, 111))	('ERK1/2', 'Gene', (181, 187))
128178	19457236	For example, the chemically induced homodimerization of the epidermal growth factor receptor (EGFR) is sufficient to induce focus formation in Rat 1 cells and the proliferation of MCF-10A mammary epithelial cells in monolayer cultures.	('focus formation', 'CPA', (124, 139))	('Rat 1', 'CellLine', 'CVCL:0492', (143, 148))	('induce', 'Reg', (117, 123))	('proliferation', 'CPA', (163, 176))	('EGFR', 'Gene', (94, 98))	('MCF-10A', 'CellLine', 'CVCL:0598', (180, 187))	('homodimerization', 'Var', (36, 52))
128189	19457236	4-Hydroxytamoxifen (4-HT), LY294002, U0126 and AG1478 were from Calbiochem.	('U0126', 'Var', (37, 42))	('4-HT', 'Chemical', '-', (20, 24))	('AG1478', 'Chemical', 'MESH:C101044', (47, 53))	('U0126', 'Chemical', 'MESH:C113580', (37, 42))	('LY294002', 'Chemical', 'MESH:C085911', (27, 35))	('AG1478', 'Var', (47, 53))	('4-Hydroxytamoxifen', 'Chemical', '-', (0, 18))	('LY294002', 'Var', (27, 35))
128217	19457236	Only 17% of the control acini contained three or more cells expressing Ki-67, whereas 65% of the acini treated with 4-HT had three or more cells expressing Ki-67, indicating that the activation of ERK1/2 is sufficient to stimulate an increased rate of proliferation in cultured acini (Figure 1c,d).	('increased', 'PosReg', (234, 243))	('ERK1/2', 'Gene', (197, 203))	('Ki-67', 'Var', (71, 76))	('ERK1/2', 'Gene', '5595;5594', (197, 203))	('4-HT', 'Chemical', '-', (116, 120))
128226	19457236	We found that inhibiting EGFR activity with 300 nM AG1478 had no effect on the Raf:ER-induced disruption of epithelial architecture or stimulation of proliferation as judged by Ki-67 staining (Figure 2a).	('stimulation', 'PosReg', (135, 146))	('AG1478', 'Var', (51, 57))	('Raf', 'Gene', '22882', (79, 82))	('EGFR', 'Protein', (25, 29))	('Raf', 'Gene', (79, 82))	('AG1478', 'Chemical', 'MESH:C101044', (51, 57))	('inhibiting', 'NegReg', (14, 24))	('proliferation', 'CPA', (150, 163))
128228	19457236	Blockade of EGFR kinase activity with AG1478 did not cause caspase-dependent apoptosis in lumens of Raf:ER-induced acini as judged by immunostaining for cleaved caspase 3 (Figure 2a).	('Raf', 'Gene', '22882', (100, 103))	('AG1478', 'Chemical', 'MESH:C101044', (38, 44))	('Raf', 'Gene', (100, 103))	('AG1478', 'Var', (38, 44))	('caspase 3', 'Gene', (161, 170))	('caspase 3', 'Gene', '836', (161, 170))
128247	19457236	We examined c-Fos expression in day 10 acini or later acini after treatment with 100 nM 4-HT for 48 hours by immunostaining, and found that c-Fos protein levels were increased in acini treated with 100 nM 4-HT (Figure 3a).	('c-Fos', 'Gene', (12, 17))	('increased', 'PosReg', (166, 175))	('c-Fos', 'Gene', (140, 145))	('c-Fos', 'Gene', '2353', (12, 17))	('4-HT', 'Chemical', '-', (205, 209))	('c-Fos', 'Gene', '2353', (140, 145))	('100 nM 4-HT', 'Var', (198, 209))	('4-HT', 'Chemical', '-', (88, 92))
128273	19457236	As expected, inhibition of MEK1/2 with 10 muM U0126 prevented any gross change in acinar morphology (Figure 5a).	('muM', 'Gene', '56925', (42, 45))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('MEK1/2', 'Enzyme', (27, 33))	('muM', 'Gene', (42, 45))	('prevented', 'NegReg', (52, 61))	('inhibition', 'NegReg', (13, 23))	('acinar morphology', 'CPA', (82, 99))	('U0126', 'Var', (46, 51))
128274	19457236	Blockade of PI-3K with 50 muM LY294002 also prevented Raf:ER-induced morphological changes (Figure 5a, upper panels).	('muM', 'Gene', (26, 29))	('prevented', 'NegReg', (44, 53))	('Raf', 'Gene', (54, 57))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('muM', 'Gene', '56925', (26, 29))	('Raf', 'Gene', '22882', (54, 57))	('LY294002', 'Var', (30, 38))
128280	19457236	Raf:ER acini were grown for 10 or days more in organotypic culture and the acini were stimulated with 100 nM 4-HT in the presence or absence of the PI-3K inhibitor LY294002.	('Raf', 'Gene', '22882', (0, 3))	('LY294002', 'Var', (164, 172))	('Raf', 'Gene', (0, 3))	('LY294002', 'Chemical', 'MESH:C085911', (164, 172))	('4-HT', 'Chemical', '-', (109, 113))
128281	19457236	We found that the treatment of acini with LY294002 was sufficient to block the induction of noninvasive motility in all of the acini that were stimulated by Raf:ER activation (Figure 5b and see Additional files 1 to 3).	('LY294002', 'Var', (42, 50))	('block', 'NegReg', (69, 74))	('noninvasive motility', 'CPA', (92, 112))	('Raf', 'Gene', (157, 160))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('Raf', 'Gene', '22882', (157, 160))
128286	19457236	We examined whether PI-3K activity was necessary for the loss of E-cadherin induced by Raf:ER, and found that treatment of acini with LY294002 had no effect on the loss of E-cadherin at cell-cell contacts (Figure 6a, upper panels).	('LY294002', 'Var', (134, 142))	('Raf', 'Gene', '22882', (87, 90))	('LY294002', 'Chemical', 'MESH:C085911', (134, 142))	('E-cadherin', 'Gene', '999', (65, 75))	('Raf', 'Gene', (87, 90))	('E-cadherin', 'Gene', (172, 182))	('E-cadherin', 'Gene', '999', (172, 182))	('E-cadherin', 'Gene', (65, 75))	('loss', 'NegReg', (164, 168))
128288	19457236	The pharmacological blockade of PI-3K activity prevents RhoA and Rho kinase activation in neutrophil-like HL-60 cells, which suggested to us that the inhibition of PI-3K could be reducing the level of MLC2 phosphorylation and contraction in the Raf:ER-induced acini.	('Rho', 'Enzyme', (65, 68))	('MLC2', 'Gene', '4633', (201, 205))	('Raf', 'Gene', (245, 248))	('RhoA', 'Gene', (56, 60))	('inhibition', 'Var', (150, 160))	('reducing', 'NegReg', (179, 187))	('prevents', 'NegReg', (47, 55))	('MLC2', 'Gene', (201, 205))	('RhoA', 'Gene', '387', (56, 60))	('HL-60', 'CellLine', 'CVCL:0002', (106, 111))	('Raf', 'Gene', '22882', (245, 248))	('contraction', 'CPA', (226, 237))
128289	19457236	We treated day 10 acini with diluent or LY294002 at the time of Raf:ER activation and examined the MLC2 phosphorylation at Ser19 using a phoshospecific antibody.	('MLC2', 'Gene', (99, 103))	('LY294002', 'Chemical', 'MESH:C085911', (40, 48))	('Raf', 'Gene', (64, 67))	('MLC2', 'Gene', '4633', (99, 103))	('LY294002', 'Var', (40, 48))	('Ser19', 'Chemical', '-', (123, 128))	('Raf', 'Gene', '22882', (64, 67))
128290	19457236	The treatment of acini with LY294002 did not reduce MLC2 phosphorylation at Ser19 in response to Raf:ER activation or GFP-Raf:ER activation under conditions where AKT phosphorylation is reduced (Figure 6a, lower panels, and 6b).	('AKT', 'Gene', '207', (163, 166))	('Raf', 'Gene', '22882', (122, 125))	('Ser19', 'Chemical', '-', (76, 81))	('LY294002', 'Var', (28, 36))	('MLC2', 'Gene', (52, 56))	('AKT', 'Gene', (163, 166))	('reduced', 'NegReg', (186, 193))	('Raf', 'Gene', (122, 125))	('Raf', 'Gene', '22882', (97, 100))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('Raf', 'Gene', (97, 100))	('MLC2', 'Gene', '4633', (52, 56))
128294	19457236	Real-time imaging showed that cells in Raf:ER-induced acini did not divide when they were treated with LY294002.	('Raf', 'Gene', (39, 42))	('LY294002', 'Chemical', 'MESH:C085911', (103, 111))	('LY294002', 'Var', (103, 111))	('Raf', 'Gene', '22882', (39, 42))
128303	19457236	Inhibiting MEK1/2 or PI-3K was sufficient to prevent AKT activation, the suppression of p27 expression, and cyclin B1 induction (Figure 7b).	('induction', 'MPA', (118, 127))	('Inhibiting', 'Var', (0, 10))	('suppression', 'NegReg', (73, 84))	('cyclin B1', 'Gene', '891', (108, 117))	('cyclin B1', 'Gene', (108, 117))	('activation', 'PosReg', (57, 67))	('AKT', 'Gene', '207', (53, 56))	('PI-3K', 'Var', (21, 26))	('prevent', 'NegReg', (45, 52))	('AKT', 'Gene', (53, 56))	('p27', 'Gene', '3429', (88, 91))	('p27', 'Gene', (88, 91))
128306	19457236	Since the concentration of AG1478 used blocked the growth of co-cultured MCF-10A cells (Figure 2b), the failure of AG1478 to block AKT phosphorylation, p27 degradation or Ki-67 expression was probably not due to a failure to inhibit EGFR.	('AKT', 'Gene', '207', (131, 134))	('AG1478', 'Var', (115, 121))	('AG1478', 'Chemical', 'MESH:C101044', (27, 33))	('degradation', 'MPA', (156, 167))	('AKT', 'Gene', (131, 134))	('MCF-10A', 'CellLine', 'CVCL:0598', (73, 80))	('AG1478', 'Chemical', 'MESH:C101044', (115, 121))	('p27', 'Gene', '3429', (152, 155))	('p27', 'Gene', (152, 155))	('expression', 'MPA', (177, 187))	('Ki-67', 'Gene', (171, 176))
128313	19457236	Furthermore, by uncoupling the activation of the Raf-MEK1/2-ERK1/2 module from a specific oncogenic lesion, our results suggest that the inappropriate expression of growth factor receptor ligands could promote tumorigenesis through the sustained stimulation of ERK1/2.	('ERK1/2', 'Gene', (261, 267))	('ERK1/2', 'Gene', '5595;5594', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('Raf', 'Gene', '22882', (49, 52))	('oncogenic lesion', 'Disease', 'MESH:D000074723', (90, 106))	('tumor', 'Disease', (210, 215))	('promote', 'PosReg', (202, 209))	('oncogenic lesion', 'Disease', (90, 106))	('Raf', 'Gene', (49, 52))	('ERK1/2', 'Gene', (60, 66))	('inappropriate', 'Var', (137, 150))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('ERK1/2', 'Gene', '5595;5594', (60, 66))	('stimulation', 'PosReg', (246, 257))
128321	19457236	In the event that a positive connection between ERK1/2 activation and recurrent growth is revealed, there are a number of inhibitors of MEK1/2, the direct upstream activators of ERK1/2, that have undergone various stages of in clinical testing and could be tested as adjuvant therapy in the clinic.	('ERK1/2', 'Gene', (48, 54))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('inhibitors', 'Var', (122, 132))	('ERK1/2', 'Gene', (178, 184))	('MEK1/2', 'Gene', (136, 142))	('ERK1/2', 'Gene', '5595;5594', (178, 184))
128325	19457236	For instance, p90 RSK1/2 are activated by direct ERK phosphorylation on serine 363, in the linker between the N-terminal and C-terminal catalytic domains, and threonine 573, in the activation loop of the C-terminal catalytic domain, resulting in autophosphorylation at serine 380 and creation of a docking site for PDK1, which then phosphorylates serine 239.	('activated', 'PosReg', (29, 38))	('PDK1', 'Gene', '5163', (315, 319))	('docking', 'Interaction', (298, 305))	('threonine', 'Chemical', 'MESH:D013912', (159, 168))	('serine', 'Chemical', 'MESH:D012694', (347, 353))	('PDK1', 'Gene', (315, 319))	('threonine 573', 'Var', (159, 172))	('serine', 'Chemical', 'MESH:D012694', (269, 275))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('autophosphorylation at serine 380', 'MPA', (246, 279))	('p90 RSK1/2', 'Gene', '6195;6197', (14, 24))	('p90 RSK1/2', 'Gene', (14, 24))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'Gene', (49, 52))
128345	19457236	Although PI-3K and the phospholipid products of PI-3K activity can be elevated through mutation of the catalytic domain of PI-3K or deletion of the phosphatase and tensin homolog lipid phosphatase or amplification and activation of transmembrane receptor proteins, the activation of PI-3K in breast cancer does not require these mutagenic events.	('elevated', 'PosReg', (70, 78))	('deletion', 'Var', (132, 140))	('phospholipid', 'Chemical', 'MESH:D010743', (23, 35))	('activation', 'PosReg', (218, 228))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Disease', (292, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('activity', 'MPA', (54, 62))	('mutation', 'Var', (87, 95))	('PI-3K', 'Gene', (123, 128))	('phospholipid products', 'MPA', (23, 44))
128350	19457236	The requirement of PI-3K activity for Raf:ER-stimulated cell motility is independent of MLC2 phosphorylation or E-cadherin expression, which suggests that PI-3K regulates at least one additional process that is necessary for cells to become motile in mammary epithelial acini.	('Raf', 'Gene', '22882', (38, 41))	('E-cadherin', 'Gene', (112, 122))	('E-cadherin', 'Gene', '999', (112, 122))	('MLC2', 'Gene', '4633', (88, 92))	('regulates', 'Reg', (161, 170))	('Raf', 'Gene', (38, 41))	('MLC2', 'Gene', (88, 92))	('PI-3K', 'Var', (155, 160))
128351	19457236	In these model systems, PI-3K contributes the production of phosphatidylinositol (3,4,5)-triphosphate at the leasing edge of the cell, which is necessary for the polarization of the cell and the directional migration towards a chemoattractant.	('PI-3K', 'Var', (24, 29))	('directional migration', 'CPA', (195, 216))	('phosphatidylinositol (3,4,5)-triphosphate', 'Chemical', 'MESH:C060974', (60, 101))
128353	19457236	In the future, determining how PI-3K regulates movement in mammary epithelial acini will serve to further explain how cells become motile during breast cancer progression.	('regulates', 'Reg', (37, 46))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('PI-3K', 'Var', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
128426	31552614	On multivariable analysis, patients with synchronous DCIS and LCIS had double the risk of CBC as compared to patients with DCIS alone (HR 2.06, p=0.001).	('synchronous', 'Var', (41, 52))	('DCIS', 'Var', (53, 57))	('CBC', 'Disease', (90, 93))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('patients', 'Species', '9606', (109, 117))	('LCIS', 'Disease', (62, 66))	('LCIS', 'Phenotype', 'HP:0030076', (62, 66))	('patients', 'Species', '9606', (27, 35))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
128456	26365872	However, it has been estimated that nearly half of DCIS lesions would never lead to life threatening invasive breast cancers if left untreated.	('DCIS', 'Disease', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('invasive breast cancers', 'Disease', (101, 124))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('lesions', 'Var', (56, 63))	('invasive breast cancers', 'Disease', 'MESH:D001943', (101, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('lead to', 'Reg', (76, 83))
128464	26365872	Of the 36 patients with 40 unique DCIS lesions who met these initial inclusion criteria, one patient with one DCIS lesion was excluded due to excessive DWI motion artifact precluding accurate region of interest (ROI) placement and three patients with a total of three biopsy-proven DCIS lesions were excluded due to lack of any residual suspicious enhancement on DCE images.	('lesions', 'Var', (39, 46))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('patient', 'Species', '9606', (237, 244))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('patient', 'Species', '9606', (10, 17))	('DCE', 'Gene', '1718', (363, 366))	('DCIS', 'Phenotype', 'HP:0030075', (282, 286))	('patient', 'Species', '9606', (93, 100))	('patients', 'Species', '9606', (10, 18))	('DCE', 'Gene', (363, 366))	('patients', 'Species', '9606', (237, 245))
128473	26365872	The DWI contrast-to-noise ratio (CNR) between each lesion and normal tissue was calculated for both the diffusion weighted (b = 800 s/mm2) and unweighted (b = 0 s/mm2) images as described previously  using the following equation: where mulesion and mutissue are the mean DWI signal intensities for DCIS and normal tissue ROIs, respectively, and sigmalesion and sigmatissue are the corresponding ROI standard deviations.	('DCIS', 'Phenotype', 'HP:0030075', (298, 302))	('mutissue', 'Var', (249, 257))	('mm2', 'Gene', (134, 137))	('mm2', 'Gene', '10687', (163, 166))	('mm2', 'Gene', (163, 166))	('mulesion', 'Var', (236, 244))	('mm2', 'Gene', '10687', (134, 137))
128484	26365872	Examples of a low risk (VNPC 1) and two higher risk (VNPC 2 and 3) DCIS lesions on DCE MRI and DWI features are provided in Figures 1-3, respectively.	('DCE', 'Gene', (83, 86))	('lesions', 'Var', (72, 79))	('DCIS', 'Disease', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('DCE', 'Gene', '1718', (83, 86))
128491	26365872	In our own preliminary work, however, we did not identify a difference in ADC values between DCIS nuclear grades  but did identify that high nuclear grade DCIS lesions exhibit lower DWI signal (assessed as lesion to normal tissue CNR at b=600 s/mm2), higher peak initial enhancement at 90 seconds, and greater maximum lesion size on breast MRI than lower nuclear grade lesions .	('DWI signal', 'MPA', (182, 192))	('DCIS', 'Gene', (155, 159))	('lower', 'NegReg', (176, 181))	('higher', 'PosReg', (251, 257))	('high nuclear grade', 'Var', (136, 154))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('mm2', 'Gene', '10687', (245, 248))	('mm2', 'Gene', (245, 248))
128553	24396518	To generate an orthotopic breast cancer model with both early stage ductal carcinoma in situ (DCIS) and invasive cancer characteristics, 5x106 of MCF-10DCIS cells were mixed with Matrigel (BD Biosciences, San Jose, CA) and then injected into the mammary fat pad of nude mice.	('breast cancer', 'Disease', (26, 39))	('MCF-10DCIS', 'Var', (146, 156))	('invasive cancer', 'Disease', 'MESH:D009362', (104, 119))	('stage ductal carcinoma in situ', 'Disease', 'MESH:D002285', (62, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('MCF-10DCIS', 'CellLine', 'CVCL:5552', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('stage ductal carcinoma in situ', 'Disease', (62, 92))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (7, 10))	('invasive cancer', 'Disease', (104, 119))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (68, 92))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('nude mice', 'Species', '10090', (265, 274))
128589	24396518	For optical imaging of the mice that received Cy5.5 or IRDye 800 dye labeled imaging probes, the mice were placed on an alfalfa-free rodent diet (Harlan Teklad, Madison, WI) 3 to 5 days before the experiment to reduce body background.	('mice', 'Species', '10090', (27, 31))	('mice', 'Species', '10090', (97, 101))	('Cy5.5', 'Chemical', 'MESH:C098793', (46, 51))	('alfalfa-free', 'Disease', (120, 132))	('Cy5.5', 'Var', (46, 51))	('alfalfa-free', 'Disease', 'MESH:D000072662', (120, 132))
128607	24396518	After simultaneous delivery of a mixture of Cy5.5-human ATF and IRDye 800-ScFvEGFR into a nude mouse bearing an orthotopic MDA-MB-231 human breast cancer xenograft for 24 hours, whole body optical imaging showed that both optical imaging probes were selectively accumulated in the tumor that enabled tumor imaging (Figure 3).	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (123, 133))	('Cy5.5', 'Chemical', 'MESH:C098793', (44, 49))	('human', 'Species', '9606', (134, 139))	('ATF', 'Gene', '2668', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('ATF', 'Gene', (56, 59))	('tumor', 'Disease', (300, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('human', 'Species', '9606', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('Cy5.5-human', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Disease', (281, 286))	('mouse', 'Species', '10090', (95, 100))
128651	24396518	On the other hand, the tumor bearing mice that received non-targeted NIR-830 MSA-IONP lacked the optical signal in the tumor and Prussian blue positive cells were not found in the frozen tumor sections (Figure 6B).	('NIR-830', 'Var', (69, 76))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('optical signal', 'MPA', (97, 111))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lacked', 'NegReg', (86, 92))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Prussian blue', 'Chemical', 'MESH:C000170', (129, 142))	('mice', 'Species', '10090', (37, 41))
128678	24396518	Systemic delivery of 64Cu-labeled AE105-DOTA showed target specificity in uPAR expressing U87MG human glioblastoma xenografts and the ability of PET imaging of the tumor.	('64Cu', 'Chemical', 'MESH:C000615411', (21, 25))	('AE105-DOTA', 'Chemical', '-', (34, 44))	('AE105-DOTA', 'Var', (34, 44))	('tumor', 'Disease', (164, 169))	('glioblastoma', 'Disease', (102, 114))	('U87MG', 'Var', (90, 95))	('human', 'Species', '9606', (96, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('uPAR expressing', 'PosReg', (74, 89))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('U87MG', 'CellLine', 'CVCL:0022', (90, 95))
128785	26806348	The following were used: Merlin (sc-332) and NEDD4 (sc-25508) from Santa Cruz, CA; phospho-histone H3 ser10 (H0412), AMOTL1 (HPA001196), and actin (A2228) from Sigma-Aldrich; YAP (#4912), p27 (#2552), AIP4 (#12117), and cleaved caspase 3 (#9661) from Cell Signaling Technology (Ozyme, France); E-cadherin (610182) from BD Biosciences; phospho-Src Y418 (44-660G) and phospho-FAK Y397 (44-624G) from Invitrogen; AMOTL1 p-S262 Covalab (pab0956-P, Lyon, France); and Tead2 Covalab (pab0961-P, Lyon, France).	('YAP', 'Gene', (175, 178))	('Src', 'Gene', (343, 346))	('p27', 'Gene', (188, 191))	('Src', 'Gene', '6714', (343, 346))	('p27', 'Gene', '3429', (188, 191))	('Tead2', 'Gene', (463, 468))	('610182', 'Var', (306, 312))	('NEDD4', 'Gene', (45, 50))	('NEDD4', 'Gene', '4734', (45, 50))	('E-cadherin', 'Gene', (294, 304))	('E-cadherin', 'Gene', '999', (294, 304))	('Tead2', 'Gene', '8463', (463, 468))	('YAP', 'Gene', '10413', (175, 178))	('Merlin', 'Gene', '4771', (25, 31))	('AIP4', 'Gene', (201, 205))	('phospho-histone', 'Chemical', '-', (83, 98))	('Merlin', 'Gene', (25, 31))	('AIP4', 'Gene', '83737', (201, 205))
128786	26806348	The following were used: Merlin (sc-332, Santa Cruz), AMOTL1 (HPA001196), and anti Flag M2 (F3165) from Sigma-Aldrich.	('Merlin', 'Gene', (25, 31))	('F3165', 'Var', (92, 97))	('Merlin', 'Gene', '4771', (25, 31))
128789	26806348	The following were used: AMOTL1 (HPA001196, Sigma Aldrich) at 1/100, YAP (sc-15407, Santa cruz) at 1/100, E-cadherin (#610182, BD Biosciences) at 1/100, and cleaved caspase 3 (#9661, Cell Signaling Technology) at 1/50.	('#610182', 'Var', (118, 125))	('YAP', 'Gene', (69, 72))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('YAP', 'Gene', '10413', (69, 72))	('HPA001196, Sigma Aldrich', 'Disease', 'MESH:D014923', (33, 57))
128790	26806348	The following were used: human AMOTL1 on-target plus smartpool siRNA (#L-017595-01-0005) and nontargeting control siRNAs (D-001810-03), Dharmacon (Thermo Scientific, France); pLKO-shRNA lentiviral constructs targeting human Merlin (TRCN0000018338, called sh #1 and TRCN0000039974, called sh #2), AMOTL1 (TRCN0000130193), and nontargeting control shRNA (SHC002V), Sigma, France.	('TRCN0000018338', 'Var', (232, 246))	('human', 'Species', '9606', (25, 30))	('human', 'Species', '9606', (218, 223))	('Merlin', 'Gene', '4771', (224, 230))	('Merlin', 'Gene', (224, 230))
128836	26806348	By immunofluorescence, we also observed that the expression of GFP-Merlin was leading to a decrease of overexpressed AMOTL1 signal in inducible BC52 tet on AMOTL1, whereas a mutant of Merlin (1-532) unable to bind to AMOTL1 as well as the GFP alone had no effect (Figure 4C).	('Merlin', 'Gene', '4771', (67, 73))	('Merlin', 'Gene', (67, 73))	('inducible BC52 tet on AMOTL1', 'MPA', (134, 162))	('tet', 'Chemical', 'MESH:C010349', (149, 152))	('Merlin', 'Gene', '4771', (184, 190))	('decrease', 'NegReg', (91, 99))	('expression', 'Var', (49, 59))	('Merlin', 'Gene', (184, 190))
128839	26806348	In BC52, we observed that AIP4 and NEDD4 expression resulted in a loss of AMOTL1 expression compared with the control, and a mutant AIP4 devoid of ubiquitin ligase activity (AIP4 CS) had no impact on AMOTL1 (Figure 4, D, upper and lower panels).	('AIP4', 'Gene', '83737', (132, 136))	('AMOTL1', 'Gene', (74, 80))	('loss', 'NegReg', (66, 70))	('AIP4', 'Gene', (26, 30))	('NEDD4', 'Gene', (35, 40))	('mutant', 'Var', (125, 131))	('AIP4', 'Gene', '83737', (26, 30))	('AIP4', 'Gene', (174, 178))	('AIP4', 'Gene', '83737', (174, 178))	('AIP4', 'Gene', (132, 136))	('NEDD4', 'Gene', '4734', (35, 40))	('expression', 'Var', (41, 51))	('expression', 'MPA', (81, 91))
128843	26806348	Finally, using the same strategy as in Figure 4A, we also observed that Merlin expression did not modify the half-life of the S262A mutant of AMOTL1 that cannot be phosphorylated (Figure 4H).	('S262A', 'Var', (126, 131))	('S262A', 'Mutation', 'p.S262A', (126, 131))	('Merlin', 'Gene', (72, 78))	('AMOTL1', 'Gene', (142, 148))	('Merlin', 'Gene', '4771', (72, 78))
128858	26806348	Finally, when a constitutively active Yap5SA mutant was stably expressed in MCF10A, it led to elevated levels of AMOTL1 protein (Figure 5H).	('mutant', 'Var', (45, 51))	('MCF10A', 'CellLine', 'CVCL:0598', (76, 82))	('levels of AMOTL1 protein', 'MPA', (103, 127))	('elevated', 'PosReg', (94, 102))	('Yap', 'Gene', (38, 41))	('Yap', 'Gene', '10413', (38, 41))
128868	26806348	A mutant of Merlin defective for AMOTL1 binding had no such effect, indicating that the interaction with Merlin is necessary for AMOTL1 delocalization (Figure 6, C, right).	('Merlin', 'Gene', '4771', (12, 18))	('Merlin', 'Gene', (12, 18))	('Merlin', 'Gene', (105, 111))	('Merlin', 'Gene', '4771', (105, 111))	('mutant', 'Var', (2, 8))	('interaction', 'Interaction', (88, 99))
128871	26806348	When expressed in BC52, the S262D phospho-mimicking AMOTL1 mutant did not localize to the lamellipodia but presented a vesicular distribution (Figure 6D).	('S262D', 'Mutation', 'p.S262D', (28, 33))	('AMOTL1', 'Gene', (52, 58))	('S262D', 'Var', (28, 33))	('vesicular distribution', 'MPA', (119, 141))
128872	26806348	The S262A mutant was strongly associated to actin filaments but could localize to the lamellipodia although not as clearly as the WT AMOTL1 (Figure 6D).	('S262A', 'Mutation', 'p.S262A', (4, 9))	('associated', 'Interaction', (30, 40))	('actin filaments', 'MPA', (44, 59))	('S262A', 'Var', (4, 9))
128874	26806348	Hence, based on our results, we propose that Merlin induction of S262 phosphorylation releases AMOTL1 from actin, leading to its removal from the lamellipodia.	('S262', 'Var', (65, 69))	('phosphorylation', 'MPA', (70, 85))	('Merlin', 'Gene', (45, 51))	('Merlin', 'Gene', '4771', (45, 51))	('removal from the', 'MPA', (129, 145))
128880	26806348	We next investigated which mitogenic signaling might be activated by AMOTL1 overexpression in mouse tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('overexpression', 'Var', (76, 90))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('mouse', 'Species', '10090', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('AMOTL1', 'Gene', (69, 75))	('activated', 'PosReg', (56, 65))	('mitogenic signaling', 'MPA', (27, 46))
128900	26806348	This is consistent with a previous study and in contrast with the induction of EMT by AMOTL2 knock down in this cell type.	('EMT', 'Gene', (79, 82))	('knock down', 'Var', (93, 103))	('EMT', 'Gene', '3702', (79, 82))	('AMOTL2', 'Gene', '51421', (86, 92))	('AMOTL2', 'Gene', (86, 92))
128916	26806348	This observation is corroborated by a previous study showing that AMOTL1 expression does not modify the mRNA level of CTGF and Cyr61, bona fide targets of YAP.	('Cyr61', 'Gene', '3491', (127, 132))	('expression', 'Var', (73, 83))	('YAP', 'Gene', (155, 158))	('mRNA level', 'MPA', (104, 114))	('CTGF', 'Gene', '1490', (118, 122))	('AMOTL1', 'Gene', (66, 72))	('CTGF', 'Gene', (118, 122))	('Cyr61', 'Gene', (127, 132))	('YAP', 'Gene', '10413', (155, 158))
128928	26806348	Our results suggest that Merlin delocalization of AMOTL1 from the lamellipodia and subsequent degradation could result in the localized inactivation of Rac and participate in this process.	('Rac', 'Gene', '207', (152, 155))	('inactivation', 'NegReg', (136, 148))	('delocalization', 'Var', (32, 46))	('participate', 'Reg', (160, 171))	('Rac', 'Gene', (152, 155))	('result in', 'Reg', (112, 121))	('Merlin', 'Gene', '4771', (25, 31))	('Merlin', 'Gene', (25, 31))	('AMOTL1', 'Gene', (50, 56))
128929	26806348	An alternate possibility is that degradation of AMOTL1 prevents local activation of Src, thus impairing its role in cell migration.	('Src', 'Gene', (84, 87))	('Src', 'Gene', '6714', (84, 87))	('degradation', 'Var', (33, 44))	('impairing', 'NegReg', (94, 103))	('AMOTL1', 'Gene', (48, 54))	('activation', 'MPA', (70, 80))	('prevents', 'NegReg', (55, 63))	('cell migration', 'CPA', (116, 130))
128930	26806348	Delocalization and degradation of AMOTL1 are a consequence of AMOTL1 S262 phosphorylation induced by Merlin.	('Merlin', 'Gene', '4771', (101, 107))	('Merlin', 'Gene', (101, 107))	('AMOTL1', 'Gene', (62, 68))	('phosphorylation', 'Var', (74, 89))	('degradation', 'MPA', (19, 30))	('induced', 'Reg', (90, 97))	('S262 phosphorylation', 'Var', (69, 89))
128939	26806348	This happens following Merlin phosphorylation, a consequence of AKT activation, which is frequently observed in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('phosphorylation', 'Var', (30, 45))	('Merlin', 'Gene', (23, 29))	('AKT', 'Gene', '207', (64, 67))	('activation', 'PosReg', (68, 78))	('Merlin', 'Gene', '4771', (23, 29))	('AKT', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
128986	32217457	Pathological germline variants in the BRCA1/2 genes can greatly increase risk; other gene variants can also add variable risk.	('BRCA1/2', 'Gene', '672;675', (38, 45))	('increase', 'PosReg', (64, 72))	('risk', 'MPA', (73, 77))	('variants', 'Var', (22, 30))	('BRCA1/2', 'Gene', (38, 45))
128992	32217457	Risk factors for breast cancer in men include older age, family history, BRCA1/2 variants (especially in BRCA2), gynecomastia, heavy alcohol intake, liver disease, obesity and radiation exposure.	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('liver disease', 'Phenotype', 'HP:0001392', (149, 162))	('breast cancer', 'Disease', (17, 30))	('BRCA2', 'Gene', (105, 110))	('obesity', 'Disease', 'MESH:D009765', (164, 171))	('liver disease', 'Disease', 'MESH:D008107', (149, 162))	('heavy alcohol intake', 'Phenotype', 'HP:0030955', (127, 147))	('gynecomastia', 'Disease', (113, 125))	('gynecomastia', 'Phenotype', 'HP:0000771', (113, 125))	('men', 'Species', '9606', (34, 37))	('BRCA1/2', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('liver disease', 'Disease', (149, 162))	('alcohol', 'Chemical', 'MESH:D000438', (133, 140))	('BRCA2', 'Gene', '675', (105, 110))	('gynecomastia', 'Disease', 'MESH:D006177', (113, 125))	('obesity', 'Phenotype', 'HP:0001513', (164, 171))	('variants', 'Var', (81, 89))	('BRCA1/2', 'Gene', '672;675', (73, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('obesity', 'Disease', (164, 171))
129001	32217457	Genetic testing for the BRCA 1/2 mutations is recommended in certain cases as it has implications for clinical management.	('men', 'Species', '9606', (51, 54))	('BRCA 1/2', 'Gene', '672;675', (24, 32))	('men', 'Species', '9606', (117, 120))	('mutations', 'Var', (33, 42))	('BRCA 1/2', 'Gene', (24, 32))
129004	32217457	Systemic therapy options include chemotherapy, endocrine therapy, HER2 targeted therapy and bisphosphonates, according to risk of relapse and receptor status, and can be offered before (primary systemic therapy, also known as neoadjuvant or preoperative) and/or after surgery (adjuvant therapy).	('bisphosphonates', 'Chemical', 'MESH:D004164', (92, 107))	('HER2', 'Gene', '2064', (66, 70))	('targeted therapy', 'Var', (71, 87))	('HER2', 'Gene', (66, 70))
129044	32217457	There are well-established protocols for testing women at high risk of breast cancer, such as Ashkenazi Jews or those with many affected family members for variants of the BRCA1/2 genes, but there is rapidly developing research on lesser risk genes and also in the most common genetic variants, SNPs.	('women', 'Species', '9606', (49, 54))	('breast cancer', 'Disease', (71, 84))	('BRCA1/2', 'Gene', '672;675', (172, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('variants', 'Var', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('BRCA1/2', 'Gene', (172, 179))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
129254	32217457	There is evidence from well conducted observational studies and meta-analyses that physical activity reduces overall and cause specific mortality in breast cancer patients.	('patients', 'Species', '9606', (163, 171))	('mortality', 'Disease', 'MESH:D003643', (136, 145))	('mortality', 'Disease', (136, 145))	('reduces', 'NegReg', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))	('physical', 'Var', (83, 91))
129263	32217457	Looking at multidisciplinary aspects, an observational cohort study evaluated the effects on breast cancer survival on nearly 14,000 women in Scotland, and found MDT working was associated with a 18% lower breast cancer mortality at 5 years.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('women', 'Species', '9606', (133, 138))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('mortality', 'Disease', 'MESH:D003643', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (206, 219))	('lower', 'NegReg', (200, 205))	('breast cancer', 'Disease', (93, 106))	('MDT working', 'Var', (162, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('mortality', 'Disease', (220, 229))
129272	32217457	It reports that low-volume hospitals with <=30 cases/year had a statistically significant 3-fold increased risk of death after breast conserving treatment and a significantly increased the likelihood of postoperative complications after both breast conserving treatment and breast ablative therapy.	('men', 'Species', '9606', (150, 153))	('men', 'Species', '9606', (265, 268))	('postoperative complications', 'CPA', (203, 230))	('<=30', 'Var', (42, 46))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('increased', 'PosReg', (175, 184))
129334	31921184	Although the aggressive 4T1 cells rapidly formed solid tumors, Py230 tumors eventually grew to a similar size through enhanced proliferation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('proliferation', 'CPA', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('solid tumors', 'Disease', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('enhanced', 'PosReg', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', (55, 61))	('Py230', 'Var', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('solid tumors', 'Disease', 'MESH:D009369', (49, 61))
129335	31921184	Yet, ductal tumor cell breakthrough and metastasis occurred earlier in the 4T1- compared to the Py230-based intraductal model and was associated with high expression of matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) as well as an increased influx of immune cells (mainly macrophages, neutrophils and T-cells).	('chitinase 3-like 1', 'Gene', '12654', (246, 264))	('chitinase 3-like 1', 'Gene', (246, 264))	('lipocalin 2', 'Gene', (278, 289))	('VEGF', 'Gene', '22339', (239, 243))	('increased', 'PosReg', (311, 320))	('vascular endothelial growth factor', 'Gene', '22339', (203, 237))	('vascular endothelial growth factor', 'Gene', (203, 237))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('expression', 'MPA', (155, 165))	('VEGF', 'Gene', (239, 243))	('4T1-', 'Var', (75, 79))	('matrix metalloproteinase (MMP)-9', 'Gene', '17395', (169, 201))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('metastasis', 'CPA', (40, 50))	('lipocalin 2', 'Gene', '16819', (278, 289))	('influx of immune cells', 'MPA', (321, 343))	('tumor', 'Disease', (12, 17))
129337	31921184	Py230-based tumors showed a more immunosuppressed anti-inflammatory profile with a high amount of regulatory T-cells, which may account for the decreased T-cell activation but increased proliferation compared to the 4T1-based tumors.	('Py230-based', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('decreased', 'NegReg', (144, 153))	('decreased T-cell', 'Phenotype', 'HP:0005403', (144, 160))	('increased', 'PosReg', (176, 185))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('proliferation', 'CPA', (186, 199))	('immunosuppressed anti-inflammatory profile', 'MPA', (33, 75))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('T-cell activation', 'CPA', (154, 171))	('more', 'PosReg', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Disease', (12, 18))	('decreased T-cell activation', 'Phenotype', 'HP:0005419', (144, 171))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
129350	31921184	The different tumor outgrowth was also associated with a differential tumor immunology as 4T1 primary tumors were more pro-inflammatory showing high amounts of activated cytotoxic T-cells and immune-stimulating cytokines, and Py230 primary tumors were more anti-inflammatory containing a high number of regulatory T-cells, weak cytotoxic T-cell activation, and increased immunosuppressive cytokines.	('primary tumors', 'Disease', (232, 246))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('primary tumors', 'Disease', 'MESH:D001932', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor outgrowth', 'Disease', (14, 29))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('anti-inflammatory', 'CPA', (257, 274))	('tumor', 'Disease', (240, 245))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('increased', 'PosReg', (361, 370))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('primary tumors', 'Disease', (94, 108))	('Py230', 'Var', (226, 231))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('primary tumors', 'Disease', 'MESH:D001932', (232, 246))	('tumor', 'Disease', (14, 19))	('tumor outgrowth', 'Disease', 'MESH:D009369', (14, 29))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
129353	31921184	All animal research was conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Committee on the Ethics of Animal Experiments of The Faculty of Veterinary Medicine at Ghent University (approval numbers: EC2015/127, EC2016/56, and EC2017/80).	('EC2015/127', 'Var', (309, 319))	('EC2017', 'CellLine', 'CVCL:K779', (336, 342))	('EC2016/56', 'Var', (321, 330))	('EC2016/56', 'CellLine', 'CVCL:K778', (321, 330))	('EC2017/80', 'Var', (336, 345))	('EC2015', 'CellLine', 'CVCL:K777', (309, 315))
129394	31921184	RNA was isolated from 4T1 and Py230 tumors at 3 different time points (i.e., 1, 3, and 6 w p.i.)	('Py230', 'Var', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
129400	31921184	the Py230 and 4T1 primary tumor volumes no longer differed (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Py230', 'Var', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (26, 31))
129403	31921184	was verified based on decreased cytokeratin 5 positivity in 4T1 compared to Py230 primary tumors (Figure 2).	('cytokeratin 5', 'Gene', (32, 45))	('primary tumors', 'Disease', (82, 96))	('cytokeratin 5', 'Gene', '110308', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('primary tumors', 'Disease', 'MESH:D001932', (82, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('4T1', 'Var', (60, 63))	('decreased', 'NegReg', (22, 31))
129404	31921184	Ki67 staining confirmed the increased tumor cell proliferation in 4T1 compared to Py230 primary tumors at 1 w p.i., but not at 3 and 6 w p.i.	('increased', 'PosReg', (28, 37))	('tumor', 'Disease', (38, 43))	('4T1', 'Var', (66, 69))	('primary tumors', 'Disease', 'MESH:D001932', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Ki67', 'Gene', '17345', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('Ki67', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('primary tumors', 'Disease', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
129405	31921184	Moreover, calculation of the Ki67 proliferation index (i.e., the percentage of Ki67 stained nuclei relative to all nuclei in the primary tumor) showed that, in marked contrast to the index at 1 w p.i., Py230 primary tumors were more proliferative than 4T1 primary tumors by 3 w p.i.	('primary tumors', 'Disease', (208, 222))	('primary tumors', 'Disease', (256, 270))	('Ki67', 'Gene', (79, 83))	('proliferative', 'CPA', (233, 246))	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (137, 142))	('Ki67', 'Gene', '17345', (79, 83))	('Ki67', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('primary tumors', 'Disease', 'MESH:D001932', (208, 222))	('primary tumors', 'Disease', 'MESH:D001932', (256, 270))	('more', 'PosReg', (228, 232))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('Ki67', 'Gene', '17345', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('Py230', 'Var', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
129406	31921184	(Figure 2), supporting the earlier finding that Py230 tumors are able to catch up with 4T1 tumor growth.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Py230', 'Var', (48, 53))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', (54, 60))
129408	31921184	H&E histology showed metastases in axillary lymph nodes, lungs and liver from 4T1, but not from Py230 tumor-bearing mice (Supplementary Figure 1B).	('mice', 'Species', '10090', (116, 120))	('Supplementary Figure 1B', 'Disease', (122, 145))	('from', 'Var', (73, 77))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (122, 145))	('showed', 'CPA', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('metastases', 'Disease', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
129413	31921184	The fold induction of the mean MMP-9 and VEGF levels in the 4T1- compared to the Py230-based model showed remarkable differences in primary tumors (Supplementary Figures 2A,B).	('primary tumors', 'Disease', 'MESH:D001932', (132, 146))	('MMP-9', 'Gene', '17395', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('VEGF', 'Gene', '22339', (41, 45))	('4T1-', 'Var', (60, 64))	('MMP-9', 'Gene', (31, 36))	('differences', 'Reg', (117, 128))	('primary tumors', 'Disease', (132, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('VEGF', 'Gene', (41, 45))
129425	31921184	(Figure 4C), when 4T1 and Py230 primary tumors reached similar volumes.	('primary tumors', 'Disease', 'MESH:D001932', (32, 46))	('Py230', 'Var', (26, 31))	('primary tumors', 'Disease', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
129432	31921184	Based on the pan-immune cell marker CD45, the number of leukocytes increased over time in the 4T1 as well as the Py230 primary tumors (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('primary tumors', 'Disease', 'MESH:D001932', (119, 133))	('CD45', 'Gene', (36, 40))	('CD45', 'Gene', '19264', (36, 40))	('Py230', 'Var', (113, 118))	('number of leukocytes increased', 'Phenotype', 'HP:0001974', (46, 76))	('primary tumors', 'Disease', (119, 133))
129433	31921184	a significantly higher number of CD45+ immune cells was detected in 4T1 compared to Py230 primary tumors, indicative for a substantially more enriched tumor immune microenvironment in the 4T1-based intraductal model at these early time points (Figure 5B).	('higher', 'PosReg', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CD45', 'Gene', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (151, 156))	('CD45', 'Gene', '19264', (33, 37))	('primary tumors', 'Disease', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('primary tumors', 'Disease', 'MESH:D001932', (90, 104))	('4T1', 'Var', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
129436	31921184	When the CD3epsilon+ T-cell population was subdivided into CD4+ T-helper cells and CD8a+ cytotoxic T-cells, an increase in the CD8a/CD4 T-cell ratio was found in 4T1 as well as Py230 primary tumors between 1 and 6 w p.i.	('CD3epsilon+', 'Gene', '12501', (9, 20))	('increase', 'PosReg', (111, 119))	('4T1', 'Disease', (162, 165))	('CD4', 'Gene', (59, 62))	('Py230', 'Var', (177, 182))	('CD8a', 'Gene', (127, 131))	('CD8a', 'Gene', '12525', (83, 87))	('CD4', 'Gene', '12504', (59, 62))	('CD8a', 'Gene', (83, 87))	('CD4', 'Gene', (132, 135))	('primary tumors', 'Disease', (183, 197))	('CD4', 'Gene', '12504', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('CD8a', 'Gene', '12525', (127, 131))	('CD3epsilon+', 'Gene', (9, 20))	('primary tumors', 'Disease', 'MESH:D001932', (183, 197))
129453	31921184	FoxP3 stainings for immunosuppressive regulatory T-cells significantly increased in the Py230 compared to 4T1 primary tumors at 6 w p.i.	('FoxP3', 'Gene', (0, 5))	('Py230', 'Var', (88, 93))	('FoxP3', 'Gene', '20371', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('primary tumors', 'Disease', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('increased', 'PosReg', (71, 80))	('primary tumors', 'Disease', 'MESH:D001932', (110, 124))
129464	31921184	In contrast, IL-4 and IL-10 levels were significantly higher in Py230 compared to 4T1 primary tumors at all 3 time points (Figures 8A-C).	('higher', 'PosReg', (54, 60))	('IL-10', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IL-4', 'Gene', (13, 17))	('primary tumors', 'Disease', (86, 100))	('IL-4', 'Gene', '16189', (13, 17))	('Py230', 'Var', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('primary tumors', 'Disease', 'MESH:D001932', (86, 100))	('IL-10', 'Gene', '16153', (22, 27))
129470	31921184	Immunohistochemical stainings for granzyme B and PD-1, both markers for activated cytotoxic T-cells, showed increased positivity in 4T1 compared to Py230 primary tumors at 1, 3, and 6 w p.i.	('primary tumors', 'Disease', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PD-1', 'Gene', (49, 53))	('increased', 'PosReg', (108, 117))	('4T1', 'Var', (132, 135))	('PD-1', 'Gene', '18566', (49, 53))	('primary tumors', 'Disease', 'MESH:D001932', (154, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('positivity', 'Var', (118, 128))
129476	31921184	More specifically, all 9 tumor immunology-related gene sets remained upregulated in 4T1 compared to Py230 primary tumors across the 3 time points, but only significantly at 1 and/or 3 w p.i.	('primary tumors', 'Disease', (106, 120))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (25, 30))	('primary tumors', 'Disease', 'MESH:D001932', (106, 120))	('tumor', 'Disease', (114, 119))	('upregulated', 'PosReg', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('4T1', 'Var', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
129478	31921184	in 4T1 compared to Py230 primary tumors, indicative for decreased tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('decreased tumor', 'Disease', 'None', (56, 71))	('primary tumors', 'Disease', (25, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('decreased tumor', 'Disease', (56, 71))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('primary tumors', 'Disease', 'MESH:D001932', (25, 39))	('4T1', 'Var', (3, 6))
129479	31921184	At 6 w p.i., the gene sets went back to baseline, highlighting the similar tumor size in 4T1 and Py230 primary tumors.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('primary tumors', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (111, 116))	('primary tumors', 'Disease', 'MESH:D001932', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Py230', 'Var', (97, 102))	('tumor', 'Disease', (75, 80))
129480	31921184	in 4T1 compared to Py230 primary tumors (Figure 9), indicative for metastatic progression.	('primary tumors', 'Disease', (25, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('primary tumors', 'Disease', 'MESH:D001932', (25, 39))	('4T1', 'Var', (3, 6))
129482	31921184	in 4T1 compared to Py230 primary tumors (Figure 9), indicating that at the time 4T1 tumor cells were less proliferative compared to Py230 tumor cells, the surrounding stroma and fat tissue were more active in the 4T1- compared to the Py230-based intraductal model.	('less', 'NegReg', (101, 105))	('more', 'PosReg', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('primary tumors', 'Disease', (25, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('4T1', 'Var', (80, 83))	('tumor', 'Disease', (84, 89))	('proliferative', 'CPA', (106, 119))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (33, 38))	('primary tumors', 'Disease', 'MESH:D001932', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
129483	31921184	The hallmark androgen response also showed a significantly upregulated expression in Py230 tumors at 3 and 6 w p.i.	('tumors', 'Disease', (91, 97))	('expression', 'MPA', (71, 81))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Py230', 'Var', (85, 90))	('upregulated', 'PosReg', (59, 70))	('androgen', 'Chemical', 'MESH:D000728', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
129486	31921184	and in Py230 primary tumors at 3 and 6 w p.i.	('primary tumors', 'Disease', (13, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('primary tumors', 'Disease', 'MESH:D001932', (13, 27))	('Py230', 'Var', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
129490	31921184	in 4T1 and Py230 primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('primary tumors', 'Disease', (17, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('primary tumors', 'Disease', 'MESH:D001932', (17, 31))	('Py230', 'Var', (11, 16))
129492	31921184	Yet, the difference in T-cell receptor gene expression between the 4T1 and Py230 primary tumors decreased over time (Figure 10D).	('primary tumors', 'Disease', (81, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('expression', 'MPA', (44, 54))	('decreased', 'NegReg', (96, 105))	('T-cell receptor', 'Protein', (23, 38))	('Py230', 'Var', (75, 80))	('primary tumors', 'Disease', 'MESH:D001932', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
129493	31921184	in 4T1 compared to Py230 primary tumors (Figure 11A).	('primary tumors', 'Disease', (25, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('primary tumors', 'Disease', 'MESH:D001932', (25, 39))	('4T1', 'Var', (3, 6))
129496	31921184	in 4T1 compared to Py230 primary tumors (Figure 11C).	('primary tumors', 'Disease', (25, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('primary tumors', 'Disease', 'MESH:D001932', (25, 39))	('4T1', 'Var', (3, 6))
129500	31921184	With the current comparative study, we aimed to gain deeper insight in the immunological changes underlying aggressive 4T1 vs. non-aggressive Py230 intraductal tumor progression, providing further characterization of the intraductal model prior to its envisaged use for evaluation of novel breast cancer therapeutics.	('immunological changes', 'Phenotype', 'HP:0002715', (75, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('intraductal tumor', 'Disease', (148, 165))	('breast cancer', 'Disease', (290, 303))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('4T1', 'Var', (119, 122))	('intraductal tumor', 'Disease', 'MESH:D002285', (148, 165))
129502	31921184	Although it was not checked how long it takes for the Py230-based intraductal model to induce detectable metastases, previous studies reported that it may take up to 20 weeks for the development of Py230 lung metastases.	('metastases', 'Disease', 'MESH:D009362', (209, 219))	('Py230', 'Var', (198, 203))	('lung metastases', 'Disease', (204, 219))	('metastases', 'Disease', (105, 115))	('lung metastases', 'Disease', 'MESH:D009362', (204, 219))	('metastases', 'Disease', (209, 219))	('metastases', 'Disease', 'MESH:D009362', (105, 115))
129504	31921184	At 6 w p.i., 4T1 and Py230 primary tumors had a similar size, which could be explained by their marked difference in Ki67 positivity and Ki67 proliferation index, reflecting a decreased proliferation of 4T1 in time compared to Py230 primary tumors.	('primary tumors', 'Disease', (233, 247))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('primary tumors', 'Disease', (27, 41))	('Ki67', 'Gene', '17345', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('decreased', 'NegReg', (176, 185))	('proliferation', 'MPA', (186, 199))	('Ki67', 'Gene', (137, 141))	('primary tumors', 'Disease', 'MESH:D001932', (233, 247))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('Py230', 'Var', (21, 26))	('primary tumors', 'Disease', 'MESH:D001932', (27, 41))	('Ki67', 'Gene', '17345', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Ki67', 'Gene', (117, 121))
129506	31921184	Our data further demonstrated that Py230 tumors were able to catch up with 4T1 tumor growth by proliferating both at the tumor core and the edges.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('proliferating', 'PosReg', (95, 108))	('tumors', 'Disease', (41, 47))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Py230', 'Var', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
129508	31921184	At that time point, a significant upregulation of genes involved in EMT and adipogenic/stromal processes indicated that 4T1 cells focus on both EMT and stromal development for metastasis rather than on primary tumor growth compared to Py230 cells.	('genes', 'Gene', (50, 55))	('EMT', 'CPA', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('4T1', 'Var', (120, 123))	('upregulation', 'PosReg', (34, 46))
129512	31921184	Indeed, at 1 w p.i., when 4T1 primary tumors were significantly more proliferative than Py230 primary tumors and cellular mitosis hallmarks were significantly increased in 4T1 compared to Py230 primary tumors, the MMP-9 levels were also more induced, allowing the fast expansion and ductal breakthrough of 4T1 tumor cells.	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('mitosis hallmarks', 'Disease', 'OMIM:604588', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('primary tumors', 'Disease', 'MESH:D001932', (94, 108))	('mitosis hallmarks', 'Disease', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('4T1', 'Var', (172, 175))	('more', 'PosReg', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (202, 207))	('primary tumors', 'Disease', 'MESH:D001932', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('primary tumors', 'Disease', 'MESH:D001932', (194, 208))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('primary tumors', 'Disease', (94, 108))	('tumor', 'Disease', (310, 315))	('induced', 'PosReg', (242, 249))	('tumor', 'Disease', (102, 107))	('fast expansion', 'CPA', (264, 278))	('primary tumors', 'Disease', (30, 44))	('proliferative', 'CPA', (69, 82))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('ductal breakthrough', 'CPA', (283, 302))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('increased', 'PosReg', (159, 168))	('MMP-9', 'Gene', '17395', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('primary tumors', 'Disease', (194, 208))	('MMP-9', 'Gene', (214, 219))
129521	31921184	Similar to VEGF levels, CD31 positivity identified enhanced vascularity in the 4T1-based intraductal model.	('vascularity', 'CPA', (60, 71))	('VEGF', 'Gene', (11, 15))	('enhanced', 'PosReg', (51, 59))	('VEGF', 'Gene', '22339', (11, 15))	('CD31', 'Gene', '18613', (24, 28))	('CD31', 'Gene', (24, 28))	('positivity', 'Var', (29, 39))
129529	31921184	Our results also showed how spleen sizes significantly increased over time in the 4T1-based intraductal model, whereas in the Py230-based intraductal model spleens remained almost at a normal size, suggesting differential leukemoid reactions in both models.	('leukemoid reactions', 'Disease', (222, 241))	('leukemoid reactions', 'Disease', 'MESH:D007955', (222, 241))	('4T1-based', 'Var', (82, 91))	('increased', 'PosReg', (55, 64))	('spleen sizes', 'CPA', (28, 40))
129539	31921184	Moreover, as both 4T1 and Py230 tumors were infiltrated with TILs, and more specifically immunoreactive CD8a+ cytotoxic T-cells and CD4+ T-helper cells, they can be classified as so called "hot" tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('CD8a', 'Gene', '12525', (104, 108))	('CD8a', 'Gene', (104, 108))	('Py230', 'Var', (26, 31))	('CD4', 'Gene', (132, 135))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('CD4', 'Gene', '12504', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
129540	31921184	Yet, FoxP3+ regulatory T-cells were upregulated in Py230 compared to 4T1 primary tumors, highlighting a strongly immunosuppressed and proliferative microenvironment in the Py230-based model.	('FoxP3', 'Gene', '20371', (5, 10))	('upregulated', 'PosReg', (36, 47))	('primary tumors', 'Disease', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('primary tumors', 'Disease', 'MESH:D001932', (73, 87))	('FoxP3', 'Gene', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Py230', 'Var', (51, 56))
129541	31921184	The progressive NF-kappaB activation in Py230 primary tumors and draining axillary lymph nodes corroborated the increases in tumor immune cell populations over time.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('primary tumors', 'Disease', 'MESH:D001932', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('NF-kappaB', 'Gene', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Py230', 'Var', (40, 45))	('tumor', 'Disease', (125, 130))	('activation', 'PosReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('NF-kappaB', 'Gene', '18033', (16, 25))	('tumor', 'Disease', (54, 59))	('primary tumors', 'Disease', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
129542	31921184	Cytokine profiles further corroborated the enhanced local and systemic leukemoid responses in the 4T1- compared to Py230-based intraductal model.	('4T1-', 'Var', (98, 102))	('enhanced', 'PosReg', (43, 51))	('systemic leukemoid', 'Disease', (62, 80))	('systemic leukemoid', 'Disease', 'MESH:D007955', (62, 80))
129545	31921184	In marked contrast, Py230 primary tumors showed a stimulated anti-inflammatory cytokine profile including increased IL-10 and IL-4 levels at all time points, corroborating the enhanced regulatory T-cell positivity and immunosuppressive properties of Py230 primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('IL-10', 'Gene', '16153', (116, 121))	('primary tumors', 'Disease', 'MESH:D001932', (256, 270))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('regulatory T-cell positivity', 'Phenotype', 'HP:0031399', (185, 213))	('primary tumors', 'Disease', 'MESH:D001932', (26, 40))	('IL-10', 'Gene', (116, 121))	('anti-inflammatory cytokine profile', 'MPA', (61, 95))	('stimulated', 'PosReg', (50, 60))	('IL-4', 'Gene', (126, 130))	('Py230', 'Var', (20, 25))	('IL-4', 'Gene', '16189', (126, 130))	('enhanced', 'PosReg', (176, 184))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('primary tumors', 'Disease', (256, 270))	('increased', 'PosReg', (106, 115))	('primary tumors', 'Disease', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
129546	31921184	Moreover, based on granzyme B and PD-1 positivity, 4T1 tumors showed significantly stronger activation of cytotoxic T-cells compared to Py230 tumors, in line with the differential cytokine profiles.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('PD-1', 'Gene', '18566', (34, 38))	('cytotoxic T-cells', 'CPA', (106, 123))	('4T1', 'Var', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PD-1', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('stronger activation', 'PosReg', (83, 102))
129550	31921184	Yet, the current study shows that C57BL/6-derived Py230 primary tumors are more immunosuppressive compared to BALB/c-derived 4T1 primary tumors, demonstrating that tumor cell intrinsic or other extrinsic factors overruled the strain-specific immunity in regulating the mammary tumor immune responses and phenotype.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (164, 169))	('immunosuppressive', 'MPA', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('primary tumors', 'Disease', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('primary tumors', 'Disease', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (64, 69))	('C57BL/6-derived', 'Var', (34, 49))	('primary tumors', 'Disease', 'MESH:D001932', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('Py230', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('primary tumors', 'Disease', 'MESH:D001932', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
129557	31921184	Further corroborating the cytokine profiles and the reports that T-cell activation may decrease tumor proliferation, RNA-seq also identified increased tumor-associated immune responses in 4T1 compared to Py230 primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('primary tumors', 'Disease', 'MESH:D001932', (210, 224))	('increased', 'PosReg', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (96, 101))	('primary tumors', 'Disease', (210, 224))	('cytokine profiles', 'MPA', (26, 43))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('decrease', 'NegReg', (87, 95))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (218, 223))	('4T1', 'Var', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
129559	31921184	This finding was also highlighted by gene sets for T-cell receptors and antigen presentation, showing a decrease over time in differential gene expression between 4T1 and Py230 primary tumors.	('primary tumors', 'Disease', 'MESH:D001932', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('Py230', 'Var', (171, 176))	('decrease', 'NegReg', (104, 112))	('primary tumors', 'Disease', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('differential gene expression', 'MPA', (126, 154))
129565	31921184	The decreased expression of anti-inflammatory and increased expression of pro-inflammatory cytokines and macrophage markers over time in 4T1 compared to Py230 primary tumors again confirmed that Py230 tumors are highly immunosuppressed and likely will be even more refractory to checkpoint inhibitors.	('expression', 'MPA', (60, 70))	('decreased', 'NegReg', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('increased', 'PosReg', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('Py230', 'Var', (195, 200))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('primary tumors', 'Disease', (159, 173))	('anti-inflammatory', 'MPA', (28, 45))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('primary tumors', 'Disease', 'MESH:D001932', (159, 173))
129566	31921184	recently reported that TNBC can be eradicated by targeting glycosylated PD-L1, inducing both immune re-activation as well as 4T1 tumor cell killing.	('inducing', 'PosReg', (79, 87))	('glycosylated', 'Var', (59, 71))	('PD-L1', 'Gene', '60533', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('immune', 'CPA', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TNBC', 'Disease', (23, 27))	('tumor', 'Disease', (129, 134))	('PD-L1', 'Gene', (72, 77))
129569	31921184	Taken together, the 4T1- and Py230-based intraductal model are characterized by a different tumor outgrowth and associated tumor microenvironment.	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Py230-based', 'Var', (29, 40))	('tumor outgrowth', 'Disease', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor outgrowth', 'Disease', 'MESH:D009369', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
129570	31921184	More specifically, whereas 4T1 tumors are aggressively metastatic and show high levels of EMT, hypoxia and inflammation, Py230 tumors remain locally invasive and show high proliferation and immunosuppression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('inflammation', 'Disease', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('hypoxia', 'Disease', (95, 102))	('tumors', 'Disease', (31, 37))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Py230', 'Var', (121, 126))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))
129572	31921184	The animal study was reviewed and approved by the Committee on the Ethics of Animal Experiments of The Faculty of Veterinary Medicine at Ghent University (approval numbers: EC2015/127, EC2016/56 and EC2017/80).	('EC2015', 'CellLine', 'CVCL:K777', (173, 179))	('EC2017', 'CellLine', 'CVCL:K779', (199, 205))	('EC2015/127', 'Var', (173, 183))	('EC2016/56', 'Var', (185, 194))	('EC2016/56', 'CellLine', 'CVCL:K778', (185, 194))	('EC2017/80', 'Var', (199, 208))
129710	31300453	Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is recognized as one of the earliest, most frequent, and robust alterations in cancer development.	('cancer', 'Disease', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('alterations', 'Reg', (154, 165))	('tumor', 'Disease', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
129739	31300453	We evaluated differences in DNA methylation among four IHC subtypes of breast cancer, using clinical data for expression of estrogen receptor/progesterone receptors (ER/PR) and HER2: ER/PR+, HER2-; ER/PR+, HER2+; ER/PR-,HER2+; ER/PR-,HER2- (triple-negative breast cancer, TNBC) in samples from training and test sets (total N = 108).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('HER2', 'Gene', '2064', (191, 195))	('HER2', 'Gene', '2064', (177, 181))	('HER2', 'Gene', (234, 238))	('HER2', 'Gene', '2064', (206, 210))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('breast cancer', 'Disease', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('HER2', 'Gene', '2064', (220, 224))	('HER2', 'Gene', (191, 195))	('HER2', 'Gene', (177, 181))	('ER/PR-', 'Var', (213, 219))	('ER/PR+', 'Var', (198, 204))	('HER2', 'Gene', (206, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('HER2', 'Gene', '2064', (234, 238))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('breast cancer', 'Disease', (257, 270))	('HER2', 'Gene', (220, 224))	('ER/PR-', 'Var', (227, 233))
129757	31300453	Candidate gene markers were among those previously identified by us as having frequent measurable gene hypermethylation in ER/PR+, HER2-; ER/PR+, HER2+; ER/PR-, HER2+ and ER/PR-, HER2- breast cancer.	('ER/PR+', 'Var', (123, 129))	('HER2', 'Gene', '2064', (146, 150))	('HER2', 'Gene', (131, 135))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('ER/PR-', 'Var', (171, 177))	('HER2', 'Gene', '2064', (131, 135))	('breast cancer', 'Disease', (185, 198))	('ER/PR+', 'Var', (138, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('HER2', 'Gene', (161, 165))	('HER2', 'Gene', (179, 183))	('HER2', 'Gene', '2064', (161, 165))	('HER2', 'Gene', '2064', (179, 183))	('ER/PR-', 'Var', (153, 159))	('HER2', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
129768	31300453	Age-related DNA hypermethylation in normal tissues has been observed to be associated with the subsequent development of cancer.	('associated with', 'Reg', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('DNA hypermethylation', 'Var', (12, 32))	('cancer', 'Disease', (121, 127))
129769	31300453	This raises a concern for cancer detection tests since the presence of hypermethylation in normal tissue can be a source of false positives.	('cancer', 'Disease', (26, 32))	('hypermethylation', 'Var', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))
129792	31300453	Some genes in the panel, such as APC, CCND2, RASGRF2 and TMEFF2 were frequently methylated in ER+/PR+ tumors, APC, AKR1B1 and RASSF1 were frequently methylated in HER2 over-expressed tumors, while ZNF671 was more frequently hypermethylated in TNBC, also consistent with reports in the literature.	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('ZNF671', 'Gene', '79891', (197, 203))	('RASSF1', 'Gene', '11186', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('TMEFF2', 'Gene', '23671', (57, 63))	('RASSF1', 'Gene', (126, 132))	('RASGRF2', 'Gene', (45, 52))	('methylated', 'Var', (80, 90))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('AKR1B1', 'Gene', '231', (115, 121))	('tumors', 'Disease', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('APC', 'Disease', (110, 113))	('HER2', 'Gene', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('methylated', 'Var', (149, 159))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('TMEFF2', 'Gene', (57, 63))	('over-expressed', 'PosReg', (168, 182))	('tumors', 'Disease', (102, 108))	('CCND2', 'Gene', (38, 43))	('CCND2', 'Gene', '894', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('HER2', 'Gene', '2064', (163, 167))	('AKR1B1', 'Gene', (115, 121))	('ZNF671', 'Gene', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('RASGRF2', 'Gene', '5924', (45, 52))
129793	31300453	We chose to develop a DNA methylation-based assay because aberrant DNA methylation is detectable very early in nearly all breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('aberrant', 'Var', (58, 66))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))
129794	31300453	As has been well established, gene promoter-associated CpG island methylation can silence tumor suppressor genes, much like gene deletions or mutations.	('silence', 'NegReg', (82, 89))	('mutations', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('methylation', 'Var', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
129795	31300453	Moreover, methylation alterations, in contrast to mutations, are extremely common in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('common', 'Reg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('methylation alterations', 'Var', (10, 33))
129835	29266172	The first theory implicates cellular progression in the development of breast cancer, whereby changes that lead to high risk benign lesions, such as atypical ductal hyperplasia (ADH), are indicators of genomic and cellular instability that when left untreated may lead to the development of invasive breast cancer .	('breast cancer', 'Disease', (71, 84))	('invasive breast cancer', 'Disease', (291, 313))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (149, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('invasive breast cancer', 'Disease', 'MESH:D001943', (291, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('breast cancer', 'Disease', 'MESH:D001943', (300, 313))	('ADH', 'Disease', 'MESH:D007177', (178, 181))	('atypical ductal hyperplasia', 'Disease', (149, 176))	('ADH', 'Disease', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (300, 313))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('changes', 'Var', (94, 101))	('lead to', 'Reg', (264, 271))
129863	29266172	Among the 586 women with a history of BBD, PBDA was associated with ipsilateral cancer risk (71.7% v 54.3%; p < 0.0001) and a shorter latency period (61.0% v 46.6% of cancer diagnosis occurring within 57 months of the first report of benign breast disease; p <0.0001).	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('ipsilateral cancer', 'Disease', (68, 86))	('ipsilateral cancer', 'Disease', 'MESH:D009369', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PBDA', 'Chemical', '-', (43, 47))	('PBDA', 'Var', (43, 47))	('benign breast disease', 'Disease', 'MESH:D001941', (234, 255))	('women', 'Species', '9606', (14, 19))	('benign breast disease', 'Disease', (234, 255))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (80, 86))
129883	29266172	Our results are not counter to this theory, as 71.7% of women with PBDA had ipsilateral breast cancer, and 11.5% had breast cancer on both sides versus 54.3% of women with a BBD without atypia having ipsilateral breast cancer and 5.5% having breast cancer on both sides.	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (200, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('PBDA', 'Chemical', '-', (67, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('women', 'Species', '9606', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('ipsilateral breast cancer', 'Disease', (76, 101))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('atypia having ipsilateral breast cancer', 'Disease', (186, 225))	('breast cancer', 'Disease', (117, 130))	('PBDA', 'Var', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('breast cancer', 'Disease', (242, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (76, 101))	('atypia having ipsilateral breast cancer', 'Disease', 'MESH:D001943', (186, 225))	('women', 'Species', '9606', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
129885	29266172	In contrast, a high grade neoplastic pathway is associated with an increased number of genetic alterations, including P53 mutations, is often negative for hormone receptors, and is frequently positive for either Her-2 or basal markers .	('positive', 'Reg', (192, 200))	('P53', 'Gene', '7157', (118, 121))	('negative', 'NegReg', (142, 150))	('mutations', 'Var', (122, 131))	('Her-2', 'Gene', '2064', (212, 217))	('P53', 'Gene', (118, 121))	('Her-2', 'Gene', (212, 217))
129886	29266172	Suggestive evidence is found in the slightly higher incidence of breast cancer in the breast contralateral to the initial PBDA (7.1% with MFBC vs. 5.8% without MFBC.	('MFBC', 'Var', (138, 142))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('PBDA', 'Chemical', '-', (122, 126))	('breast cancer in the breast', 'Phenotype', 'HP:0100013', (65, 92))	('MFBC', 'Chemical', '-', (138, 142))	('MFBC', 'Chemical', '-', (160, 164))
129969	24273096	The monoexponential fitting of the DW signal intensity in FGTN at b = [0,...,600] s/mm2 yielded ADC600 = (2.18 +- 0.19) x 10-3 mm2/s with R2 = 1.000 in 14/16 subjects and R2 > 0.998 in two remaining subjects (Fig.	('mm2', 'Gene', '10687', (127, 130))	('FGTN', 'Gene', (58, 62))	('mm2', 'Gene', (127, 130))	('ADC600', 'Var', (96, 102))	('mm2', 'Gene', '10687', (84, 87))	('mm2', 'Gene', (84, 87))
129970	24273096	The IVIM analysis performed with bmono = [120,...,600] s/mm2 produced fp = 1.1 +- 1.1% and Dd = (2.16 +- 0.20) x 10-3 mm2/s.	('mm2', 'Gene', (57, 60))	('mm2', 'Gene', '10687', (118, 121))	('Dd', 'Chemical', '-', (91, 93))	('bmono = [120', 'Var', (33, 45))	('mm2', 'Gene', (118, 121))	('mm2', 'Gene', '10687', (57, 60))
129973	24273096	The IVIM analysis with bmono = [400,...,800] s/mm2 yielded a slightly lower Dd ((2.06 +- 0.24) x 10-3 mm2/s, P = 0.24) and a significantly higher fp = 5.6 +- 3.2% (P < 0.001).	('Dd', 'Chemical', '-', (76, 78))	('mm2', 'Gene', (102, 105))	('mm2', 'Gene', (47, 50))	('lower', 'NegReg', (70, 75))	('mm2', 'Gene', '10687', (102, 105))	('bmono = [400', 'Var', (23, 35))	('mm2', 'Gene', '10687', (47, 50))	('higher', 'PosReg', (139, 145))
129980	24273096	The mean fp values in malignant lesions were significantly higher than in FGTM (P < 0.001) and both ADC600 and Dd were significantly lower than in FGTM (P < 0.001).	('fp values', 'MPA', (9, 18))	('Dd', 'Chemical', '-', (111, 113))	('ADC600', 'Var', (100, 106))	('malignant lesion', 'Disease', 'MESH:D009369', (22, 38))	('higher', 'PosReg', (59, 65))	('lower', 'NegReg', (133, 138))	('malignant lesion', 'Disease', (22, 38))
129991	24273096	Benign lesions were significantly smaller than malignant lesions (P = 0.003) and, as a result, their DW signal was more strongly affected by the motion and partial volume artifacts.	('malignant lesion', 'Disease', (47, 63))	('affected', 'Reg', (129, 137))	('smaller', 'NegReg', (34, 41))	('partial volume', 'Var', (156, 170))	('DW signal', 'MPA', (101, 110))	('malignant lesion', 'Disease', 'MESH:D009369', (47, 63))
129996	24273096	Both ADC600 and Dd in the FGT of the high-risk normal patients were significantly higher than in the FGT of the patients with lesions (ADC600, P = 0.032; Dd, P = 0.019), owing to the larger amount of glandular tissue found in this set of normal subjects.	('patients', 'Species', '9606', (54, 62))	('higher', 'PosReg', (82, 88))	('patients', 'Species', '9606', (112, 120))	('Dd', 'Chemical', '-', (16, 18))	('Dd', 'Chemical', '-', (154, 156))	('ADC600', 'Var', (5, 11))
129998	24273096	The diffusion coefficients ADC600 and Dd were strongly correlated (rho = 0.99, P < 0.001 for all ROIs) and ADC600 was significantly higher than Dd in all tissue groups (malignant lesions, P < 0.001; benign lesions, P = 0.028; FGTL, P < 0.001; FGTN, P = 0.005).	('higher', 'PosReg', (132, 138))	('benign lesion', 'Disease', 'MESH:D051437', (199, 212))	('ADC600', 'Var', (107, 113))	('malignant lesion', 'Disease', 'MESH:D009369', (169, 185))	('diffusion', 'MPA', (4, 13))	('malignant lesion', 'Disease', (169, 185))	('Dd', 'Chemical', '-', (38, 40))	('Dd', 'Chemical', '-', (144, 146))	('benign lesion', 'Disease', (199, 212))
130005	24273096	Lesions misclassified based on fp at the optimal point of ROC included two false positives (both LCIS, fp >8.0%) and seven false negatives, including three malignant lesions with fp <= 2.2% (IDC, ILC and DCIS) and four malignant lesions with 4.0% <= fp <= 4.8% (all IDC).	('IDC', 'Gene', '4000', (266, 269))	('IDC', 'Gene', (266, 269))	('malignant lesion', 'Disease', 'MESH:D009369', (219, 235))	('malignant lesion', 'Disease', (219, 235))	('malignant lesion', 'Disease', 'MESH:D009369', (156, 172))	('fp <= 2.2%', 'Var', (179, 189))	('malignant lesion', 'Disease', (156, 172))	('ILC', 'Disease', (196, 199))	('IDC', 'Gene', '4000', (191, 194))	('IDC', 'Gene', (191, 194))
130047	29432428	Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors.	('HER2- tumors', 'Disease', (210, 222))	('HER2', 'Gene', (186, 190))	('HER2', 'Gene', '2064', (186, 190))	('DCIS', 'Var', (180, 184))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('DCIS', 'Phenotype', 'HP:0030075', (180, 184))	('TNBC', 'Gene', (193, 197))	('HER2', 'Gene', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('HER2', 'Gene', '2064', (210, 214))	('HER2- tumors', 'Disease', 'MESH:D009369', (210, 222))
130081	29432428	In 50% of the cases where tissue blocks from the same serum donor were available to determine PLAC1 expression by IHC, 92% of DCIS, 97% of ER+/PR+/HER2- and 100% of HER2+ and TNBC cancers expressed PLAC1 (Table 2, Fig 2A).	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('TNBC cancers', 'Disease', (175, 187))	('TNBC cancers', 'Disease', 'MESH:D009369', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('PLAC1', 'Var', (198, 203))	('HER2', 'Gene', (147, 151))	('donor', 'Species', '9606', (60, 65))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', '2064', (165, 169))
130090	29432428	In conclusion, the serum level of PLAC1 in breast cancer subjects with DCIS, HER2+, triple-negative and ER+/PR+ subtypes was a sensitive indicator of disease in 40-60 percent of subjects based on the mean+2 SD of levels in control subjects.	('breast cancer', 'Disease', (43, 56))	('serum level', 'MPA', (19, 30))	('DCIS', 'Var', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('PLAC1', 'Gene', (34, 39))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('ER+/PR+', 'Var', (104, 111))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
130095	29161296	The present study aimed to assess the role of periostin alteration in breast tumorigenesis and evaluate the putative prognostic value of periostin as a function of its compartmentalization.	('breast tumor', 'Disease', 'MESH:D001943', (70, 82))	('breast tumor', 'Disease', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('alteration', 'Var', (56, 66))	('breast tumor', 'Phenotype', 'HP:0100013', (70, 82))
130110	29161296	Alterations in the ECM components within the tumor microenvironment have a significant impact on the process of cancer progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('impact', 'Reg', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
130120	29161296	Furthermore, there have been few studies examining the role of periostin alteration in DCIS, a precursor, albeit non-obligatory, to IBC.	('DCIS', 'Disease', (87, 91))	('IBC', 'Chemical', '-', (132, 135))	('alteration', 'Var', (73, 83))
130128	29161296	The following probes of TaqMan  Gene Expression Assays (Thermo Fisher Scientific) were used: Hs001566734_m1 (periostin) and Hs02758991_g1 (glyceraldehyde 3-phosphate dehydrogenase, GAPDH).	('Hs001566734_m1', 'Var', (93, 107))	('GAPDH', 'Gene', (181, 186))	('Hs02758991_g1', 'Var', (124, 137))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (139, 179))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (139, 179))	('GAPDH', 'Gene', '2597', (181, 186))
130173	29161296	Patients with high epithelial periostin expression had a significantly poorer prognosis for disease-free and overall survival than those with low periostin expression (P = 0.000 and P = 0.000, respectively).	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (109, 125))	('high epithelial', 'Var', (14, 29))	('poorer', 'NegReg', (71, 77))	('disease-free', 'CPA', (92, 104))
130224	29161296	The patients with high epithelial periostin expression had a significantly poorer prognosis for disease-free and overall survival than those with low epithelial expression.	('high epithelial', 'Var', (18, 33))	('poorer', 'NegReg', (75, 81))	('patients', 'Species', '9606', (4, 12))
130226	29161296	and suggest that epithelial expression of periostin may be associated with a more aggressive tumor phenotype in IBC and may be considered an essential biomarker of breast carcinoma for predicting the prognosis and identifying patients who may benefit the most from adjuvant treatment.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IBC', 'Chemical', '-', (112, 115))	('IBC', 'Disease', (112, 115))	('aggressive tumor', 'Disease', (82, 98))	('breast carcinoma', 'Disease', 'MESH:D001943', (164, 180))	('breast carcinoma', 'Disease', (164, 180))	('associated with', 'Reg', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patients', 'Species', '9606', (226, 234))	('breast carcinoma', 'Phenotype', 'HP:0003002', (164, 180))	('epithelial', 'Var', (17, 27))	('aggressive tumor', 'Disease', 'MESH:D001523', (82, 98))
130246	27382391	Low uPA and PAI-1 levels are associated with a low risk of recurrence.	('PAI-1', 'Gene', (12, 17))	('PAI-1', 'Gene', '5054', (12, 17))	('uPA', 'Gene', (4, 7))	('uPA', 'Gene', '5328', (4, 7))	('Low', 'Var', (0, 3))
130254	27382391	The patients were also characterized based on their pathological characteristics such as skin or chest wall invasion, Paget disease, lymphovascular invasion (LVI), ER positivity, PR positivity, HER2 overexpression, triple negativity in immunohistochemical staining, TNM stage, lymph node metastasis, and AJCC stage.	('lymphovascular invasion', 'Disease', (133, 156))	('ER', 'Gene', '2099', (164, 166))	('TNM', 'Gene', (266, 269))	('PR', 'Gene', '5241', (179, 181))	('HER2', 'Gene', '2064', (194, 198))	('HER2', 'Gene', (194, 198))	('ER', 'Gene', '2099', (195, 197))	('lymph', 'Disease', (277, 282))	('overexpression', 'PosReg', (199, 213))	('AJCC', 'Disease', (304, 308))	('skin', 'Disease', (89, 93))	('patients', 'Species', '9606', (4, 12))	('TNM', 'Gene', '10178', (266, 269))	('Paget disease', 'Disease', (118, 131))	('triple negativity', 'Var', (215, 232))
130287	27382391	Univariate analyses showed that HRT, skin and chest wall invasion, LVI, ER positivity, triple-negative subtype, and N stage were significantly associated with OS (p<0.050) (Supplementary Table 1, available online).	('associated', 'Reg', (143, 153))	('LVI', 'Disease', (67, 70))	('ER', 'Gene', '2099', (72, 74))	('triple-negative subtype', 'Var', (87, 110))	('HRT', 'Disease', (32, 35))
130302	27382391	Although results of a previous study indicated an association between high PAI-1 expression in primary breast cancer tissue and poor prognosis, the results of our study did not show a significant association between high PAI-1 expression and prognosis of patients with IDC.	('primary breast cancer', 'Disease', 'MESH:D001943', (95, 116))	('expression', 'MPA', (81, 91))	('PAI-1', 'Gene', '5054', (221, 226))	('primary breast cancer', 'Disease', (95, 116))	('PAI-1', 'Gene', '5054', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (255, 263))	('PAI-1', 'Gene', (221, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('high', 'Var', (70, 74))	('PAI-1', 'Gene', (75, 80))	('IDC', 'Disease', (269, 272))
130306	27382391	However, high uPA expression was detected in higher percentage of patients with lymph node metastasis (56.3%) than in patients without lymph node metastasis (33.6%) (p=0.001) (Table 3).	('lymph node', 'Disease', (80, 90))	('uPA', 'Gene', (14, 17))	('uPA', 'Gene', '5328', (14, 17))	('patients', 'Species', '9606', (118, 126))	('patients', 'Species', '9606', (66, 74))	('high', 'Var', (9, 13))
130336	25729421	Dr Karin Ribi from the International Breast Cancer Study Group on behalf of colleagues then presented an assessment of patient recorded outcome measures of the SOFT trial and identified that overall patients receiving T+OFS experienced worse endocrine symptoms and sexual functioning than those receiving T alone during the first two years of treatment, but most differences between treatments were no longer apparent thereafter.	('Breast Cancer', 'Disease', (37, 50))	('patient', 'Species', '9606', (119, 126))	('T+OFS', 'Chemical', '-', (218, 223))	('SOFT', 'Gene', (160, 164))	('Breast Cancer', 'Disease', 'MESH:D001943', (37, 50))	('SOFT', 'Gene', '25886', (160, 164))	('Cancer', 'Phenotype', 'HP:0002664', (44, 50))	('sexual functioning', 'CPA', (265, 283))	('patient', 'Species', '9606', (199, 206))	('T+OFS', 'Var', (218, 223))	('Breast Cancer', 'Phenotype', 'HP:0003002', (37, 50))	('endocrine', 'MPA', (242, 251))	('patients', 'Species', '9606', (199, 207))	('worse', 'NegReg', (236, 241))
130346	25729421	They demonstrated by subgroup analysis of the fulvestrant 500mg versus 250mg in endocrine patients of the CONFIRM trial that high progesterone receptor (PR) level was associated with improved progression free survival (PFS), whilst positive HER-2 was associated with decreased PFS and also a trend existed for high Ki67 and decreased PFS.	('PFS', 'MPA', (277, 280))	('Ki67', 'Var', (315, 319))	('progression free survival', 'CPA', (192, 217))	('PR', 'Gene', '5241', (153, 155))	('improved', 'PosReg', (183, 191))	('decreased', 'NegReg', (324, 333))	('fulvestrant', 'Chemical', 'MESH:D000077267', (46, 57))	('HER-2', 'Gene', '2064', (241, 246))	('progesterone receptor', 'Gene', (130, 151))	('progesterone receptor', 'Gene', '5241', (130, 151))	('decreased', 'NegReg', (267, 276))	('high progesterone', 'Phenotype', 'HP:0031216', (125, 142))	('patients', 'Species', '9606', (90, 98))	('HER-2', 'Gene', (241, 246))	('high', 'Var', (125, 129))
130366	25729421	Dr Soonmyung Paik on behalf of the NSABP presented their assessment of intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP-31.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('trastuzumab', 'Chemical', 'MESH:D000068878', (148, 159))	('mutation', 'Var', (98, 106))
130369	25729421	The PD-1 receptor-ligand pathway once activated can be used by tumours to evade immune surveillance, allowing neoplastic growth, therefore anti-PD-1 antibodies can potentially block such activation and reactivate the immune system to eradicate tumours.	('tumours', 'Disease', (63, 70))	('anti-PD-1 antibodies', 'Var', (139, 159))	('tumours', 'Disease', (244, 251))	('block', 'NegReg', (176, 181))	('allowing', 'PosReg', (101, 109))	('antibodies', 'Var', (149, 159))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('neoplastic growth', 'MPA', (110, 127))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (244, 251))	('PD-1', 'Pathway', (4, 8))	('immune', 'CPA', (217, 223))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
130384	25729421	Dr Obi Griffith from Washington University Medical School, St Louis, MO presented on behalf of his colleagues the prognostic effects of gene mutations in ER positive breast cancer from a cohort of 636 patients treated with tamoxifen monotherapy for five years and 10.4 years mean follow-up.	('patients', 'Species', '9606', (201, 209))	('ER positive', 'Gene', (154, 165))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('tamoxifen', 'Chemical', 'MESH:D013629', (223, 232))	('gene mutations', 'Var', (136, 150))	('breast cancer', 'Disease', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))
130385	25729421	They demonstrated significant associations between mutation status and improved survival for PIK3CA, ARID1B, ERBB3, MAP3K1, and GATA3 or worse survival for PTEN, DDR1, TP53, and JAK2.	('DDR1', 'Gene', (162, 166))	('PTEN', 'Gene', (156, 160))	('GATA3', 'Gene', '2625', (128, 133))	('mutation', 'Var', (51, 59))	('PIK3CA', 'Gene', (93, 99))	('JAK2', 'Gene', (178, 182))	('ERBB3', 'Gene', '2065', (109, 114))	('DDR1', 'Gene', '780', (162, 166))	('TP53', 'Gene', '7157', (168, 172))	('GATA3', 'Gene', (128, 133))	('PTEN', 'Gene', '5728', (156, 160))	('improved', 'PosReg', (71, 79))	('MAP3K1', 'Gene', (116, 122))	('MAP3K1', 'Gene', '4214', (116, 122))	('survival', 'MPA', (80, 88))	('ARID1B', 'Gene', (101, 107))	('ARID1B', 'Gene', '57492', (101, 107))	('worse', 'NegReg', (137, 142))	('ERBB3', 'Gene', (109, 114))	('PIK3CA', 'Gene', '5290', (93, 99))	('TP53', 'Gene', (168, 172))	('JAK2', 'Gene', '3717', (178, 182))
130389	25729421	They identified a novel fusion gene between ESR1 (oestrogen receptor-alpha, ERalpha) and DAB2 (disabled-2) only in recurrent disease -confirmed on RT-PCR and western blot analysis- which they hypothesised conferred ligand independent cell growth and signaling.	('disabled-2', 'Gene', (95, 105))	('DAB2', 'Gene', '1601', (89, 93))	('ESR1', 'Gene', '2099', (44, 48))	('disabled-2', 'Gene', '1601', (95, 105))	('DAB2', 'Gene', (89, 93))	('ESR1', 'Gene', (44, 48))	('fusion gene', 'Var', (24, 35))
130393	25729421	Dr Christine Desmedt from the University of Brussels, Belgium and colleagues in their characterisation of lobular breast cancers discovered that CDH1, PIK3CA, TBX3, FOXA1, and the chromatin-related genes MLL2, MLL3, ARID1A, and ARID1B were more frequently mutated in ER positive/HER-2 negative invasive lobular cancer (n = 451) compared to the ER positive/HER-2 negative invasive ductal cancer (n = 266) from The Cancer Genome Atlas, whereas GATA3, TP53, and MAP3K1 were less frequently mutated.	('HER-2', 'Gene', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (294, 317))	('lobular cancer', 'Phenotype', 'HP:0030076', (303, 317))	('FOXA1', 'Gene', '3169', (165, 170))	('HER-2', 'Gene', (356, 361))	('HER-2', 'Gene', '2064', (356, 361))	('TP53', 'Gene', (449, 453))	('invasive ductal cancer', 'Disease', 'MESH:D018270', (371, 393))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('invasive ductal cancer', 'Disease', (371, 393))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('MLL3', 'Gene', '58508', (210, 214))	('MLL2', 'Gene', '9757', (204, 208))	('FOXA1', 'Gene', (165, 170))	('ARID1A', 'Gene', (216, 222))	('ARID1B', 'Gene', (228, 234))	('GATA3', 'Gene', '2625', (442, 447))	('lobular breast cancers', 'Disease', 'MESH:D013274', (106, 128))	('PIK3CA', 'Gene', '5290', (151, 157))	('TBX3', 'Gene', '6926', (159, 163))	('ARID1B', 'Gene', '57492', (228, 234))	('invasive lobular cancer', 'Disease', (294, 317))	('Cancer', 'Phenotype', 'HP:0002664', (413, 419))	('MAP3K1', 'Gene', (459, 465))	('MLL2', 'Gene', (204, 208))	('MAP3K1', 'Gene', '4214', (459, 465))	('ARID1A', 'Gene', '8289', (216, 222))	('GATA3', 'Gene', (442, 447))	('mutated', 'Var', (256, 263))	('TP53', 'Gene', '7157', (449, 453))	('MLL3', 'Gene', (210, 214))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('CDH1', 'Gene', '999', (145, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('lobular breast cancers', 'Disease', (106, 128))	('TBX3', 'Gene', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('PIK3CA', 'Gene', (151, 157))	('negative', 'NegReg', (285, 293))	('CDH1', 'Gene', (145, 149))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (106, 127))	('HER-2', 'Gene', '2064', (279, 284))
130399	25729421	They carried out a study on fibroblasts and mammary epithelial cells of BRCA1 mutation carriers and confirmed that a stalled fork repair defect was evident in the BRCA1 mutation carrier cells, meaning that in vitro, the inability to repair a stall fork in the BRCA1 carriers generates a kind of replication stress and genomic instability that eventually push the cells towards tumourigenesis.	('mutation', 'Var', (169, 177))	('nab', 'Chemical', '-', (221, 224))	('mutation', 'Var', (78, 86))	('push', 'PosReg', (354, 358))	('BRCA1', 'Gene', (260, 265))	('BRCA1', 'Gene', '672', (72, 77))	('tumour', 'Phenotype', 'HP:0002664', (377, 383))	('tumour', 'Disease', 'MESH:D009369', (377, 383))	('BRCA1', 'Gene', (72, 77))	('BRCA1', 'Gene', '672', (163, 168))	('tumour', 'Disease', (377, 383))	('BRCA1', 'Gene', (163, 168))	('BRCA1', 'Gene', '672', (260, 265))	('replication stress', 'CPA', (295, 313))	('inability', 'Var', (220, 229))
130411	25729421	The team identified that whilst the side-effect profile of nab paclitaxel was significantly higher than solvent based, the primary endpoint of complete pCR was 38% versus 29% (P = 0.001) respectively.	('nab paclitaxel', 'Chemical', '-', (59, 73))	('nab', 'Var', (59, 62))	('side-effect', 'MPA', (36, 47))	('higher', 'PosReg', (92, 98))
130424	25729421	Dr Katherine Hoardley from the University of North Carolina and colleagues presented the mutational analysis of CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER-2-positive breast cancer, in which they identified the presence of a TP53 mutation was significantly associated with achieving pCR (59% compared to 28% in wild type; OR = 3.7, P < 0.0001) which did not vary by treatment arm.	('achieving pCR', 'Disease', (366, 379))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('trastuzumab', 'Chemical', 'MESH:D000068878', (195, 206))	('HER-2', 'Gene', '2064', (245, 250))	('breast cancer', 'Disease', (260, 273))	('paclitaxel', 'Chemical', 'MESH:D017239', (176, 186))	('lapatinib', 'Chemical', 'MESH:D000077341', (227, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('HER-2', 'Gene', (245, 250))	('presence', 'Var', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('TP53', 'Gene', '7157', (318, 322))	('TP53', 'Gene', (318, 322))	('mutation', 'Var', (323, 331))	('associated', 'Reg', (350, 360))
130425	25729421	Therefore, concluding that TP53 mutation is a frequent, clinically important event in HER-2-positive disease, and it predicts pCR to chemotherapy plus HER-2-targeting.	('TP53', 'Gene', '7157', (27, 31))	('HER-2', 'Gene', (151, 156))	('TP53', 'Gene', (27, 31))	('HER-2', 'Gene', '2064', (86, 91))	('HER-2', 'Gene', '2064', (151, 156))	('mutation', 'Var', (32, 40))	('HER-2', 'Gene', (86, 91))
130432	25729421	High proliferation, high p53 mutation and low oestrogen signaling signatures were prognostic for higher pCR rates and predictive of the benefits from Bev (interaction P = 0.031, 0.0017, 0.0002, respectively).	('p53', 'Gene', (25, 28))	('mutation', 'Var', (29, 37))	('p53', 'Gene', '7157', (25, 28))	('higher', 'PosReg', (97, 103))	('pCR rates', 'CPA', (104, 113))	('benefits', 'PosReg', (136, 144))	('high', 'Var', (20, 24))	('low', 'NegReg', (42, 45))	('Bev', 'Chemical', 'MESH:D000068258', (150, 153))	('High proliferation', 'CPA', (0, 18))
130447	25729421	The investigators aimed to evaluate if the Oncotype DX DCIS score is associated with the risk of local recurrence (LR) in patients treated with BCS alone with negative margins in ER positive tumours and in all tumours regardless of ER status.	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('tumours', 'Disease', (191, 198))	('local recurrence', 'Disease', (97, 113))	('BC', 'Phenotype', 'HP:0003002', (144, 146))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('tumours regardless', 'Disease', (210, 228))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('patients', 'Species', '9606', (122, 130))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('Oncotype DX DCIS score', 'Var', (43, 65))	('tumours', 'Disease', 'MESH:D009369', (210, 217))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('tumours regardless', 'Disease', 'MESH:D009369', (210, 228))	('tumours', 'Disease', (210, 217))
130461	25729421	On the gene analysis of 59 patients diagnosed with male breast cancer, they found that the ER positive subgroup is characterised by somatic mutations in PI3K, GATA3, TP53 and MAP3K1, and that luminal B like tumours more frequently display GATA3 somatic mutations, mutations affecting DNA related-genes and 11q losses compared to luminal A cancers.	('mutations', 'Var', (264, 273))	('MAP3K1', 'Gene', (175, 181))	('GATA3', 'Gene', '2625', (159, 164))	('GATA3', 'Gene', (239, 244))	('A cancers', 'Disease', 'MESH:D009369', (337, 346))	('MAP3K1', 'Gene', '4214', (175, 181))	('GATA3', 'Gene', (159, 164))	('PI3K', 'Gene', (153, 157))	('A cancers', 'Disease', (337, 346))	('tumours', 'Disease', (207, 214))	('display', 'Reg', (231, 238))	('TP53', 'Gene', '7157', (166, 170))	('11q', 'Gene', (306, 309))	('patients', 'Species', '9606', (27, 35))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('losses', 'NegReg', (310, 316))	('male breast cancer', 'Disease', 'MESH:D018567', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('DNA related-genes', 'Gene', (284, 301))	('GATA3', 'Gene', '2625', (239, 244))	('male breast cancer', 'Disease', (51, 69))	('TP53', 'Gene', (166, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))
130462	25729421	From a comparative analysis of male breast cancer and luminal female breast cancer, it has emerged that PI3K and TP53 mutations are less frequent, but have similar patterns of gene copy alterations.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('male breast cancer', 'Disease', (64, 82))	('male breast cancer', 'Disease', 'MESH:D018567', (31, 49))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PI3K', 'Gene', (104, 108))	('male breast cancer', 'Disease', (31, 49))	('TP53', 'Gene', '7157', (113, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('male breast cancer', 'Disease', 'MESH:D018567', (64, 82))	('TP53', 'Gene', (113, 117))
130465	25729421	Professor Mary-Claire King from the University of Washington, Seattle, WA gave a thought-provoking lecture on the genomic analysis of inherited breast and ovarian cancer calling for a population-based screening approach to BRCA1 and BRCA2 mutations in women over 30 years of age as part of a routine medical care.	('BRCA1', 'Gene', '672', (223, 228))	('BRCA2', 'Gene', '675', (233, 238))	('BRCA1', 'Gene', (223, 228))	('women', 'Species', '9606', (252, 257))	('mutations', 'Var', (239, 248))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('BRCA2', 'Gene', (233, 238))	('inherited breast and ovarian cancer', 'Disease', 'MESH:D061325', (134, 169))
130466	25729421	The rationale was based on the evidence that 50% of patients who carry BRCA1 and BRCA2 mutations have no close family history of breast or ovarian cancer.	('BRCA1', 'Gene', (71, 76))	('breast or ovarian cancer', 'Disease', (129, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (129, 153))	('BRCA2', 'Gene', (81, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA2', 'Gene', '675', (81, 86))	('mutations', 'Var', (87, 96))	('patients', 'Species', '9606', (52, 60))
130467	25729421	Concluding that every breast and ovarian patient with a BRCA1 and BRCA2 mutation detected after diagnosis is a missed opportunity to prevent a cancer, Professor King declared that based on a UK cost-effectiveness analysis of population-based screening, costs would be absolutely acceptable, considering that market forces are driving down test expenses.	('BRCA2', 'Gene', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast and ovarian', 'Disease', 'MESH:D010051', (22, 40))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA2', 'Gene', '675', (66, 71))	('patient', 'Species', '9606', (41, 48))	('BRCA1', 'Gene', (56, 61))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutation', 'Var', (72, 80))
130567	32120324	However, more recently recognized subtypes of LCIS often create diagnostic problems because of the presence of histologic features that overlap with those of ductal carcinoma in situ (DCIS), including nuclear pleomorphism, necrosis, and marked distension of involved spaces.	('necrosis', 'Disease', (223, 231))	('ductal carcinoma', 'Disease', 'MESH:D044584', (158, 174))	('ductal carcinoma', 'Disease', (158, 174))	('necrosis', 'Disease', 'MESH:D009336', (223, 231))	('LCIS', 'Disease', (46, 50))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (165, 182))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (158, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('nuclear', 'Var', (201, 208))
130584	32120324	Conversely, DCIS with necrosis/degeneration or suboptimal fixation may appear dyscohesive.	('necrosis/degeneration', 'Disease', (22, 43))	('dyscohesive', 'Disease', (78, 89))	('suboptimal', 'Var', (47, 57))	('necrosis/degeneration', 'Disease', 'MESH:D009336', (22, 43))	('DCIS', 'Disease', (12, 16))
130590	32120324	Most pleomorphic LCIS are also ER positive and HER2 negative, but the apocrine variant is often ER negative (and androgen receptor positive) and may show HER2 overexpression or gene amplification.	('gene', 'CPA', (177, 181))	('overexpression', 'PosReg', (159, 173))	('ER', 'Gene', '2099', (48, 50))	('ER', 'Gene', '2099', (96, 98))	('ER', 'Gene', '2099', (155, 157))	('negative', 'NegReg', (99, 107))	('ER', 'Gene', '2099', (31, 33))	('HER2', 'Gene', (47, 51))	('androgen receptor', 'Gene', (113, 130))	('apocrine', 'Gene', (70, 78))	('HER2', 'Gene', '2064', (47, 51))	('HER2', 'Gene', (154, 158))	('androgen receptor', 'Gene', '367', (113, 130))	('HER2', 'Gene', '2064', (154, 158))	('variant', 'Var', (79, 86))
130602	32120324	Functional inactivation or downregulation of E-cadherin can occur through genetic or epigenetic mechanisms.	('E-cadherin', 'Gene', '999', (45, 55))	('E-cadherin', 'Gene', (45, 55))	('epigenetic', 'Var', (85, 95))	('downregulation', 'NegReg', (27, 41))
130603	32120324	The loss of E-cadherin expression is most commonly caused by loss of heterozygosity at 16q with subsequent bi-allelic inactivation of CDH1 due to inactivating somatic mutations, promoter hypermethylation or other forms of transcriptional repression.	('loss of heterozygosity', 'Var', (61, 83))	('CDH1', 'Gene', (134, 138))	('E-cadherin', 'Gene', (12, 22))	('inactivating', 'Var', (146, 158))	('CDH1', 'Gene', '999', (134, 138))	('E-cadherin', 'Gene', '999', (12, 22))	('loss', 'NegReg', (4, 8))	('promoter hypermethylation', 'Var', (178, 203))	('expression', 'MPA', (23, 33))
130604	32120324	Somatic mutations of CDH1 are frequently truncating, however, in-frame deletions and missense mutations have also been identified, which result in nonfunctional protein expression.	('nonfunctional', 'MPA', (147, 160))	('protein', 'Protein', (161, 168))	('missense mutations', 'Var', (85, 103))	('result', 'Reg', (137, 143))	('CDH1', 'Gene', '999', (21, 25))	('mutations', 'Var', (8, 17))	('truncating', 'MPA', (41, 51))	('CDH1', 'Gene', (21, 25))
130605	32120324	Rarely, germline mutations in the CDH1 gene can be associated with the development of lobular neoplasms.	('germline mutations', 'Var', (8, 26))	('CDH1', 'Gene', '999', (34, 38))	('associated', 'Reg', (51, 61))	('lobular neoplasms', 'Disease', (86, 103))	('neoplasms', 'Phenotype', 'HP:0002664', (94, 103))	('lobular neoplasms', 'Disease', 'MESH:D018275', (86, 103))	('CDH1', 'Gene', (34, 38))
130616	32120324	In particular, demonstrating the loss of membranous beta-catenin and/or aberrant cytoplasmic p120 staining is supportive of a lobular phenotype.	('p120', 'Gene', (93, 97))	('beta-catenin', 'Gene', (52, 64))	('loss', 'NegReg', (33, 37))	('beta-catenin', 'Gene', '1499', (52, 64))	('aberrant', 'Var', (72, 80))	('p120', 'Gene', '1500', (93, 97))
130621	32120324	Long-term follow-up studies have indicated that classic LCIS is associated with a 7- to 10-fold increase in breast cancer risk compared to that in women in the reference population.	('classic LCIS', 'Var', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('women', 'Species', '9606', (147, 152))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
130625	32120324	A family history of breast cancer in women <40 years of age, maximal distension of involved spaces, a mixture of type A and B cells, >10 involved spaces, a higher proportion of slides involved, and focal E-cadherin staining have all been reported to be associated with a greater risk of cancer development.	('E-cadherin', 'Gene', (204, 214))	('women', 'Species', '9606', (37, 42))	('E-cadherin', 'Gene', '999', (204, 214))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('maximal distension', 'Var', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
130637	32120324	Retrospective data with relatively few events suggest that there may be a higher rate of local recurrence in patients with positive margins than in those with negative margins, but these data are insufficient to draw firm conclusions about the clinical significance of positive margins.	('patients', 'Species', '9606', (109, 117))	('positive margins', 'Var', (123, 139))	('local recurrence', 'CPA', (89, 105))
130677	12927035	Pure DCIS accounts for 15 to 20% of breast cancers compared with only 5% of cases before the advent of breast cancer screening.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('Pure DCIS', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancers', 'Phenotype', 'HP:0003002', (36, 50))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('breast cancers', 'Disease', 'MESH:D001943', (36, 50))	('breast cancers', 'Disease', (36, 50))
130724	15987446	Cleavage of laminin-5 by matrix metalloproteinases (MMPs) produces a fragment (DIII) that binds to epidermal growth factor receptor and stimulates downstream signaling through mitogen-activated protein kinase, MMP-2 expression, and cell migration.	('Cleavage', 'Var', (0, 8))	('stimulates', 'PosReg', (136, 146))	('MMPs', 'Gene', '4313;4323', (52, 56))	('binds', 'Interaction', (90, 95))	('epidermal growth factor receptor', 'Gene', '1956', (99, 131))	('mitogen-activated protein kinase', 'MPA', (176, 208))	('expression', 'MPA', (216, 226))	('cell migration', 'CPA', (232, 246))	('MMP-2', 'Gene', (210, 215))	('MMPs', 'Gene', (52, 56))	('rat', 'Species', '10116', (240, 243))	('epidermal growth factor receptor', 'Gene', (99, 131))	('MMP-2', 'Gene', '4313', (210, 215))
130800	15987446	It has been shown that cleavage of laminin-5 gamma2 chain by MMP-2 facilitates cell migration.	('cell migration', 'CPA', (79, 93))	('laminin-5 gamma2 chain', 'Protein', (35, 57))	('MMP-2', 'Gene', '4313', (61, 66))	('facilitates', 'PosReg', (67, 78))	('cleavage', 'Var', (23, 31))	('MMP-2', 'Gene', (61, 66))	('rat', 'Species', '10116', (87, 90))
130808	15987446	It may be suggested that the sequential downregulation of laminin beta2 chain after the inactivation of PTEN and its downstream transcription factor Egr-2 in invasive breast cancer may bring about a compensatory increase in beta1 chain expression, with the appearance of new laminin isoforms laminin-2, laminin-8, and laminin-10.	('laminin beta2', 'Gene', (58, 71))	('breast cancer', 'Disease', (167, 180))	('beta1', 'Gene', '10678', (224, 229))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('downregulation', 'NegReg', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('inactivation', 'Var', (88, 100))	('Egr-2', 'Gene', '1959', (149, 154))	('Egr-2', 'Gene', (149, 154))	('increase', 'PosReg', (212, 220))	('laminin beta2', 'Gene', '16779', (58, 71))	('PTEN', 'Gene', '5728', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('expression', 'MPA', (236, 246))	('PTEN', 'Gene', (104, 108))	('beta1', 'Gene', (224, 229))
130811	15987446	Antisense inhibition of laminin-8 expression reduced glioma cell invasion through a BM matrix in vitro .	('reduced', 'NegReg', (45, 52))	('glioma', 'Disease', (53, 59))	('laminin-8', 'Protein', (24, 33))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('Antisense inhibition', 'Var', (0, 20))
130814	15987446	Antisense oligonucleotides to beta1 chain were more effective than those to laminin alpha4 chain in inhibiting glioma invasion in vitro .	('glioma', 'Disease', (111, 117))	('laminin alpha4 chain', 'Gene', (76, 96))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('beta1', 'Gene', (30, 35))	('inhibiting', 'NegReg', (100, 110))	('laminin alpha4 chain', 'Gene', '3910', (76, 96))	('beta1', 'Gene', '10678', (30, 35))	('Antisense oligonucleotides', 'Var', (0, 26))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))
130818	15987446	Antibodies, antisense oligonucleotides, or siRNA to laminin beta1 chain might be useful for future treatment of solid tumors of various sites.	('laminin beta1', 'Gene', '3912', (52, 65))	('solid tumors', 'Disease', (112, 124))	('oligonucleotides', 'Chemical', 'MESH:D009841', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('laminin beta1', 'Gene', (52, 65))	('solid tumors', 'Disease', 'MESH:D009369', (112, 124))	('antisense oligonucleotides', 'Var', (12, 38))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))
130820	15987446	It may be concluded that laminin-2, laminin-8, and laminin-10 are important components of breast cancer microvessels, and that lack of laminin-9 and laminin-11 may play a role in remodeling of new vessels in breast cancer.	('lack', 'Var', (127, 131))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('remodeling', 'CPA', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('play', 'Reg', (164, 168))	('laminin-11', 'Chemical', '-', (149, 159))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('laminin-9', 'Protein', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
130833	33620141	This showed that non-high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non-high grade cases, respectively).	('negativity', 'Var', (109, 119))	('ER', 'Gene', '2069', (105, 107))	('non-high', 'Var', (17, 25))	('HER2', 'Gene', (104, 108))	('ER', 'Gene', '2069', (86, 88))	('HER2', 'Gene', '2064', (104, 108))
130871	33620141	Positive ER/PR and negative HER2 status is used in the COMET trial as inclusion criteria for the active surveillance regimen [7] in keeping with the data presented here; when DCIS shows ER negativity and/or HER2 positivity, classification as high-grade DCIS should be considered.	('HER2', 'Gene', '2064', (28, 32))	('ER', 'Gene', '2069', (186, 188))	('DCIS', 'Phenotype', 'HP:0030075', (253, 257))	('HER2', 'Gene', (207, 211))	('ER', 'Gene', '2069', (29, 31))	('ER', 'Gene', '2069', (208, 210))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('HER2', 'Gene', '2064', (207, 211))	('ER', 'Gene', '2069', (9, 11))	('positivity', 'Var', (212, 222))	('PR', 'Gene', '5241', (12, 14))	('HER2', 'Gene', (28, 32))
130874	33620141	As a first step in improving reproducibility, we suggest that ER negativity and/or HER2 positivity of an individual DCIS lesion is indicative of a high-grade lesion, which may be of value in distinguishing this from low- and intermediate-grade DCIS, although validation is required.	('ER', 'Gene', '2069', (84, 86))	('DCIS', 'Phenotype', 'HP:0030075', (244, 248))	('positivity', 'Var', (88, 98))	('ER', 'Gene', '2069', (62, 64))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (83, 87))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
130885	32734520	Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05-6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35-5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34-10.23) were independently associated with a higher iIBC risk.	('BCS', 'Gene', '617', (30, 33))	('iIBC', 'Chemical', '-', (89, 93))	('high', 'Var', (38, 42))	('cribriform/solid', 'CPA', (248, 264))	('iIBC', 'Disease', (409, 413))	('iIBC', 'Disease', (89, 93))	('BCS', 'Gene', (30, 33))	('papillary growth pattern', 'Phenotype', 'HP:0007482', (311, 335))	('iIBC', 'Chemical', '-', (409, 413))	('grade 3', 'Var', (193, 200))	('patients', 'Species', '9606', (8, 16))
130890	32734520	reported a 10-year net risk of ipsilateral IBC (iIBC) of 12.2% (95% Confidence Interval (95% CI) 8.6-17.1%) for women with DCIS grade 1/2 and 17.6% (95% CI 12.1-25.2%) for grade 3.	('IBC', 'Chemical', '-', (43, 46))	('iIBC', 'Chemical', '-', (48, 52))	('DCIS', 'Var', (123, 127))	('women', 'Species', '9606', (112, 117))	('IBC', 'Chemical', '-', (49, 52))	('ipsilateral IBC', 'Disease', (31, 46))
130931	32734520	In patients treated with BCS alone, grade 3 (versus grade 1 + 2 combined), a cribriform/solid growth pattern (versus FEA, clinging, and (micro)papillary growth pattern), and mitotically active DCIS (versus DCIS with low mitotic activity) were also associated with a higher iIBC risk, whereas in patients treated with BCS + RT these associations were not found.	('BCS', 'Gene', '617', (317, 320))	('cribriform/solid growth pattern', 'CPA', (77, 108))	('papillary growth pattern', 'Phenotype', 'HP:0007482', (143, 167))	('BCS', 'Gene', (317, 320))	('patients', 'Species', '9606', (295, 303))	('iIBC', 'Chemical', '-', (273, 277))	('iIBC', 'Disease', (273, 277))	('mitotically', 'Var', (174, 185))	('patients', 'Species', '9606', (3, 11))	('BCS', 'Gene', '617', (25, 28))	('BCS', 'Gene', (25, 28))
130943	32734520	Our study supports the rationale to distinguish between grade 1 + 2 versus grade 3 as DCIS grade 3 is independently associated with an increased risk of iIBC in patients treated with BCS alone.	('BCS', 'Gene', '617', (183, 186))	('iIBC', 'Chemical', '-', (153, 157))	('iIBC', 'Disease', (153, 157))	('BCS', 'Gene', (183, 186))	('patients', 'Species', '9606', (161, 169))	('grade 3', 'Var', (91, 98))
130957	32734520	A semi-quantitative grading system incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, analogue to IBC grading, may improve the reliability and prognostic value of these histopathological features.	('improve', 'PosReg', (164, 171))	('IBC', 'Chemical', '-', (147, 150))	('growth pattern', 'CPA', (97, 111))	('mitotic activity', 'CPA', (117, 133))	('nuclear pleomorphism', 'Var', (75, 95))
130975	22764768	It has been reported that amplification of the HER2 oncogene in 25% of breast cancers is associated with a shorter disease-free and overall survival.	('breast cancers', 'Disease', 'MESH:D001943', (71, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('amplification', 'Var', (26, 39))	('HER2', 'Gene', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('HER2', 'Gene', '2064', (47, 51))	('shorter', 'NegReg', (107, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancers', 'Disease', (71, 85))
130992	22764768	For instance, patients with triple-negative (ER-negative [ER-]/PR-negative/HER2-) breast cancer are at greater risk of relapse with a one- to three-times greater risk following initial treatment compared with patients who had other subtypes of breast cancer, including patients with HER2+ tumors.	('HER2', 'Gene', (283, 287))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Disease', 'MESH:D001943', (244, 257))	('HER2', 'Gene', (75, 79))	('breast cancer', 'Disease', (244, 257))	('ER', 'Gene', '2099', (284, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('ER', 'Gene', '2099', (45, 47))	('ER', 'Gene', '2099', (76, 78))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('triple-negative', 'Var', (28, 43))	('HER2', 'Gene', '2064', (283, 287))	('patients', 'Species', '9606', (209, 217))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('ER', 'Gene', '2099', (58, 60))	('breast cancer', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('HER2', 'Gene', '2064', (75, 79))	('tumors', 'Disease', (289, 295))
130999	22764768	A comparative analysis of Oncotype DX  and PAM50 showed that high-risk specimens identified by Oncotype DX corresponded to luminal B or basal-like tumors identified by PAM50.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('luminal B', 'Disease', (123, 132))	('basal-like tumors', 'Phenotype', 'HP:0002671', (136, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('Oncotype DX', 'Var', (95, 106))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))
131036	22764768	Genetic instability and plasticity of tumor cells facilitates constant changes in the tumor cells in response to the host defense system, making it difficult to develop a gold-standard prognostic biomarker that can accurately determine whether a patient would relapse following initial treatment.	('patient', 'Species', '9606', (246, 253))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('Genetic instability', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
131049	22764768	It was also reported that gene signatures of CD10+ stromal cells are associated with poor prognosis, particularly in HER2+ tumors of patients who were not treated.	('HER2', 'Gene', (117, 121))	('gene signatures', 'Var', (26, 41))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('CD10', 'Gene', '4311', (45, 49))	('HER2', 'Gene', '2064', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (133, 141))	('CD10', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
131087	22764768	Presence of such immune function genes would suggest the possibility for the expression of highly immunogenic tumor antigens in the tumors of patients who remained relapse free.	('expression', 'MPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (132, 138))	('patients', 'Species', '9606', (142, 150))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('Presence', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
131090	22764768	Interestingly, expression of MAGE-4 antigen was reported to be associated with a reduced risk of breast cancer recurrence.	('MAGE-4 antigen', 'Gene', (29, 43))	('expression', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('reduced', 'NegReg', (81, 88))	('MAGE-4 antigen', 'Gene', '4103', (29, 43))	('breast cancer', 'Disease', (97, 110))
131102	22764768	Papers of special note have been highlighted as:   of interest   of considerable interest   The prognostic impact of HER2 positivity is lower in node-negative compared with node-positive patients.	('lower', 'NegReg', (136, 141))	('HER2', 'Gene', (117, 121))	('positivity', 'Var', (122, 132))	('patients', 'Species', '9606', (187, 195))	('HER2', 'Gene', '2064', (117, 121))
131122	32677379	In patients with ILC, multifocality and the presence of NME on preoperative breast MRI were associated with positive resection margins.	('presence', 'Var', (44, 52))	('patients', 'Species', '9606', (3, 11))	('ILC', 'Disease', (17, 20))	('NME', 'Gene', (56, 59))	('associated', 'Reg', (92, 102))
131125	32677379	Positive resection margins are associated with a two-fold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.	('ipsilateral breast tumor', 'Disease', 'MESH:D001943', (82, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Positive', 'Var', (0, 8))	('ipsilateral breast tumor', 'Disease', (82, 106))	('breast tumor', 'Phenotype', 'HP:0100013', (94, 106))
131131	32677379	Although the association between preoperative MRI and surgical outcomes in patients with breast cancer is still under debate, multiple studies have shown that preoperative MRI can significantly reduce re-excision rates after initial surgery in patients with ILC.	('ILC', 'Disease', (258, 261))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MRI', 'Var', (172, 175))	('breast cancer', 'Disease', (89, 102))	('patients', 'Species', '9606', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('patients', 'Species', '9606', (244, 252))	('re-excision rates', 'CPA', (201, 218))	('reduce', 'NegReg', (194, 200))
131146	32677379	HER2 positivity was defined as a HER2/chromosome 17 ratio greater than 2.0.	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (33, 37))	('HER2', 'Gene', '2064', (33, 37))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
131164	32677379	The mean pathologic tumor size was significantly larger in the positive resection margin group (22.3 +- 10.5 mm vs. 13.4 +- 7.5 mm, p < 0.001), and patients with positive resection margins had a higher rate of pathologic lymph node metastasis (38.1% vs. 8.8%, p = 0.003) (Table 1).	('larger', 'PosReg', (49, 55))	('patients', 'Species', '9606', (148, 156))	('pathologic lymph node metastasis', 'CPA', (210, 242))	('positive', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
131167	32677379	In our study, we found that multifocality on preoperative breast MRI was independently associated with positive resection margins in patients with ILC, whereas NME showed borderline significance.	('multifocality', 'Var', (28, 41))	('patients', 'Species', '9606', (133, 141))	('ILC', 'Disease', (147, 150))	('associated with', 'Reg', (87, 102))	('breast MRI', 'Gene', (58, 68))	('positive resection margins', 'CPA', (103, 129))
131175	32677379	In addition, as DCIS commonly presents as microcalcifications on mammography, previous studies have reported that the presence of microcalcifications on mammography and presence of DCIS were both associated with resection margin status in patient populations composed mostly of patients with IDC.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('IDC', 'Disease', (292, 295))	('patient', 'Species', '9606', (239, 246))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('associated with', 'Reg', (196, 211))	('presence', 'Var', (169, 177))	('resection margin status', 'CPA', (212, 235))	('DCIS', 'Gene', (181, 185))	('patient', 'Species', '9606', (278, 285))	('patients', 'Species', '9606', (278, 286))
131178	32677379	However, our study results showed that multifocality and NME on preoperative MRI were associated with positive resection margins in ILC patients, although NME showed borderline significance.	('NME', 'Var', (57, 60))	('associated', 'Reg', (86, 96))	('positive resection margins', 'CPA', (102, 128))	('patients', 'Species', '9606', (136, 144))	('multifocality', 'Var', (39, 52))
131184	32677379	In a previous study that focused on the associations between clinicopathologic variables and positive resection margins, tumor size exceeding 2 cm and lymph node involvement were associated with positive resection margins in ILC.	('associated', 'Reg', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ILC', 'Disease', (225, 228))	('positive', 'Var', (195, 203))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
131189	32677379	In conclusion, in patients with ILC, multifocality and NME on preoperative breast MRI were associated with positive resection margins.	('positive resection margins', 'CPA', (107, 133))	('multifocality', 'Var', (37, 50))	('ILC', 'Disease', (32, 35))	('NME', 'Var', (55, 58))	('patients', 'Species', '9606', (18, 26))	('associated', 'Reg', (91, 101))
131201	32244556	Most somatic genetic alterations are perceived to provide little or no advantage to the neoplastic cells in which they arise (passenger mutations), however some enhance or inhibit the activity of cancer genes, and hence are termed driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('enhance', 'PosReg', (161, 168))	('activity', 'MPA', (184, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('inhibit', 'NegReg', (172, 179))	('alterations', 'Var', (21, 32))
131208	32244556	From an architectural point view, some breast cancers have 'simple' genomes (e.g., tumours with the 1q gain and 16q deletion pattern of alterations), whilst other tumours exhibit complex arrays of structural variants involving interchromosomal rearrangements and high level amplification of major oncogenic driver genes (e.g., including ERBB2/HER2, CCND1, ZNF703/FGFR1, MYC); and tumours associated with defective HR repair exhibit extremely high levels of chromosomal instability.	('MYC', 'Gene', (370, 373))	('tumours', 'Disease', (83, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('chromosomal instability', 'MPA', (457, 480))	('tumours', 'Disease', 'MESH:D009369', (83, 90))	('FGFR1', 'Gene', (363, 368))	('MYC', 'Gene', '4609', (370, 373))	('HER2', 'Gene', (343, 347))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Disease', (380, 387))	('alterations', 'Var', (136, 147))	('variants', 'Var', (208, 216))	('CCND1', 'Gene', '595', (349, 354))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('tumours', 'Phenotype', 'HP:0002664', (380, 387))	('tumours', 'Disease', 'MESH:D009369', (380, 387))	('gain', 'PosReg', (103, 107))	('chromosomal instability', 'Phenotype', 'HP:0040012', (457, 480))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CCND1', 'Gene', (349, 354))	('ZNF703', 'Gene', '80139', (356, 362))	('breast cancers', 'Disease', (39, 53))	('ERBB2', 'Gene', (337, 342))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('tumour', 'Phenotype', 'HP:0002664', (380, 386))	('tumours', 'Disease', (163, 170))	('FGFR1', 'Gene', '2260', (363, 368))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('ERBB2', 'Gene', '2064', (337, 342))	('HER2', 'Gene', '2064', (343, 347))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('ZNF703', 'Gene', (356, 362))	('tumours', 'Disease', 'MESH:D009369', (163, 170))
131210	32244556	Approximately three driver gene mutations are found per tumour and there are a multitude of combinations possible.	('mutations', 'Var', (32, 41))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (56, 62))
131212	32244556	For instance, the distribution of driver mutations differs between ER positive and ER negative tumours, including the most common driver genes, PIK3CA and TP53, respectively.	('mutations', 'Var', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('TP53', 'Gene', '7157', (155, 159))	('PIK3CA', 'Gene', (144, 150))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('PIK3CA', 'Gene', '5290', (144, 150))	('TP53', 'Gene', (155, 159))	('tumours', 'Disease', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
131213	32244556	This is also evident in familial breast cancer, where the inheritance of a pathogenic germline driver mutation is also strongly related to the resulting tumour phenotype: ER-negative in BRCA1-associated tumours (with high frequency of TP53 mutations); ER-positive in BRCA2, ATM and CHEK2-associated tumours; HER2-positive in TP53-carriers; and E-cadherin negative and lobular growth pattern in CDH1-carriers.	('TP53', 'Gene', (325, 329))	('tumours', 'Disease', (203, 210))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('BRCA1', 'Gene', '672', (186, 191))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('CHEK2', 'Gene', (282, 287))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour', 'Disease', (203, 209))	('BRCA1', 'Gene', (186, 191))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumours', 'Disease', 'MESH:D009369', (203, 210))	('TP53', 'Gene', (235, 239))	('tumour', 'Disease', (299, 305))	('CHEK2', 'Gene', '11200', (282, 287))	('CDH1', 'Gene', '999', (394, 398))	('ER-positive', 'Var', (252, 263))	('HER2', 'Gene', '2064', (308, 312))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('ATM', 'Gene', '472', (274, 277))	('TP53', 'Gene', '7157', (325, 329))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('E-cadherin', 'Gene', (344, 354))	('E-cadherin', 'Gene', '999', (344, 354))	('CDH1', 'Gene', (394, 398))	('tumour', 'Disease', (153, 159))	('BRCA2', 'Gene', (267, 272))	('TP53', 'Gene', '7157', (235, 239))	('familial breast cancer', 'Disease', 'MESH:D001943', (24, 46))	('related', 'Reg', (128, 135))	('tumours', 'Disease', (299, 306))	('familial breast cancer', 'Disease', (24, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('ATM', 'Gene', (274, 277))	('mutation', 'Var', (102, 110))	('HER2', 'Gene', (308, 312))	('tumours', 'Phenotype', 'HP:0002664', (299, 306))	('BRCA2', 'Gene', '675', (267, 272))	('tumours', 'Disease', 'MESH:D009369', (299, 306))
131214	32244556	Some driver mutations manifest more frequently in morphologically distinct tumours and some are pathognomonic for special histological types of the disease (Figure 1B-D).	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('mutations', 'Var', (12, 21))	('pathognomonic', 'Reg', (96, 109))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
131218	32244556	The archetypal alteration in ILC involves dysfunction of the epithelial cell adhesion complex involving E-cadherin and its binding partners beta-catenin and P120-catenin.	('beta-catenin', 'Gene', '1499', (140, 152))	('P120-catenin', 'Gene', '1500', (157, 169))	('P120-catenin', 'Gene', (157, 169))	('ILC', 'Disease', (29, 32))	('E-cadherin', 'Gene', '999', (104, 114))	('dysfunction', 'Var', (42, 53))	('E-cadherin', 'Gene', (104, 114))	('beta-catenin', 'Gene', (140, 152))
131219	32244556	E-cadherin is encoded by the gene CDH1, which is inactivated in ~65% of ILC by gene mutation and loss of heterozygosity.	('ILC', 'Disease', (72, 75))	('CDH1', 'Gene', '999', (34, 38))	('loss of', 'NegReg', (97, 104))	('gene mutation', 'Var', (79, 92))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))	('CDH1', 'Gene', (34, 38))
131221	32244556	In addition to CDH1 mutations, the only other highly recurrent oncogenic driver was PI3KCA (43-48%), with a plethora of low frequency (<15% of cases) driver mutations affecting FOXA1, TBX3, ERBB2, ERBB3 and PTEN that were enriched in ILC relative to IC NST, while GATA3 and TP53 mutations were enriched in IC NST relative to ILC.	('CDH1', 'Gene', (15, 19))	('TBX3', 'Gene', '6926', (184, 188))	('TP53', 'Gene', (274, 278))	('ERBB3', 'Gene', '2065', (197, 202))	('ERBB2', 'Gene', (190, 195))	('IC NST', 'Disease', (306, 312))	('FOXA1', 'Gene', (177, 182))	('mutations', 'Var', (157, 166))	('IC NST', 'Disease', (250, 256))	('ERBB2', 'Gene', '2064', (190, 195))	('TBX3', 'Gene', (184, 188))	('PTEN', 'Gene', (207, 211))	('TP53', 'Gene', '7157', (274, 278))	('ILC', 'Disease', (234, 237))	('ERBB3', 'Gene', (197, 202))	('FOXA1', 'Gene', '3169', (177, 182))	('GATA3', 'Gene', '2625', (264, 269))	('PTEN', 'Gene', '5728', (207, 211))	('plethora', 'Phenotype', 'HP:0001050', (108, 116))	('CDH1', 'Gene', '999', (15, 19))	('GATA3', 'Gene', (264, 269))
131222	32244556	TP53 mutations occur at significantly different frequencies between ER+ and ER- tumours, and so the TP53 mutation finding is likely driven by the presence of ER negative tumours in the IC NST cohort.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', '7157', (0, 4))	('mutation', 'Var', (105, 113))	('TP53', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Disease', (170, 177))	('TP53', 'Gene', (100, 104))	('mutations', 'Var', (5, 14))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))
131224	32244556	Although generally triple-negative, they have a high frequency of PIK3CA mutations, and indeed have the unusual co-occurrence of PIK3CA and TP53 driver mutations in some instances.	('PIK3CA', 'Gene', (129, 135))	('TP53', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (140, 144))	('PIK3CA', 'Gene', (66, 72))	('PIK3CA', 'Gene', '5290', (129, 135))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))
131235	32244556	In individual cases, all lesions shared precise genetic alterations as likely early events in tumour development; all cases also exhibited private mutations unique to a morphological lineage (e.g., TBX3), suggesting they may be important in the separate evolution from a common antecedent.	('tumour', 'Disease', (94, 100))	('mutations', 'Var', (147, 156))	('TBX3', 'Gene', (198, 202))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('exhibited', 'Reg', (129, 138))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('TBX3', 'Gene', '6926', (198, 202))
131242	32244556	Each of these lesions harbour genetic alterations and are considered clonal neoplastic proliferations; CCL harbour both DNA copy number alterations and gene mutations, including an usually high rate of PIK3CA mutations (54%).	('CCL', 'Disease', (103, 106))	('PIK3CA', 'Gene', (202, 208))	('CCL', 'Chemical', '-', (103, 106))	('PIK3CA', 'Gene', '5290', (202, 208))	('mutations', 'Var', (209, 218))
131246	32244556	Topographically mapped single cell sequencing has elegantly demonstrated that most copy number alterations identified in invasive cancer arise in DCIS; and that clonal diversity observed in invasive cancer is driven in large part by existing clonal diversity present within DCIS, whereby distinct subclones may escape from the ductal tree to seed polyclonal invasive disease (neoplastic cells escaping from different regions of the ductal tree could seed apparently multifocal invasive cancer) (Figure 2C).	('invasive cancer', 'Disease', (190, 205))	('invasive disease', 'Disease', 'MESH:D009361', (358, 374))	('multifocal invasive cancer', 'Disease', 'MESH:D009362', (466, 492))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('multifocal invasive cancer', 'Phenotype', 'HP:0006625', (466, 492))	('invasive cancer', 'Disease', 'MESH:D009362', (190, 205))	('invasive disease', 'Disease', (358, 374))	('cancer', 'Phenotype', 'HP:0002664', (486, 492))	('invasive cancer', 'Disease', (121, 136))	('alterations', 'Var', (95, 106))	('copy', 'Var', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('seed', 'Reg', (450, 454))	('invasive cancer', 'Disease', 'MESH:D009362', (121, 136))	('invasive cancer', 'Disease', 'MESH:D009362', (477, 492))	('multifocal invasive cancer', 'Disease', (466, 492))
131249	32244556	Interestingly, PIK3CA mutations arise frequently but quite heterogeneously within this early stage of disease, including in normal epithelium.	('PIK3CA', 'Gene', '5290', (15, 21))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', (15, 21))
131251	32244556	Recent sequencing has revealed an amazing level of genetic instability in 'normal' cells of various tissues, caused by environmental exposure or local pathological processes related to tissue injury.	('genetic', 'Var', (51, 58))	('tissue injury', 'Disease', (185, 198))	('tissue injury', 'Disease', 'MESH:D017695', (185, 198))	('caused', 'Reg', (109, 115))
131253	32244556	Indeed, morphologically normal epithelium adjacent to tumour harbours a higher level of genetic instability relative to reduction mammoplasty tissue, particularly when normal is within 1 cm of tumour; furthermore normal epithelium from cancer-free patients who carry a pathogenic germline mutation in BRCA1 or BRCA2 also acquire an elevated level of chromosomal instability compared to controls.	('pathogenic', 'Reg', (269, 279))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumour', 'Disease', (54, 60))	('BRCA2', 'Gene', (310, 315))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('tumour', 'Disease', (193, 199))	('cancer', 'Disease', (236, 242))	('chromosomal instability', 'MPA', (350, 373))	('BRCA2', 'Gene', '675', (310, 315))	('BRCA1', 'Gene', '672', (301, 306))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('elevated level of chromosomal instability', 'Phenotype', 'HP:0040012', (332, 373))	('patients', 'Species', '9606', (248, 256))	('BRCA1', 'Gene', (301, 306))	('germline mutation', 'Var', (280, 297))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (350, 373))
131254	32244556	In the case of germline mutation carriers, haploinsufficiency for genes with clear roles in DNA damage response (such as BRCA1 and BRCA2) is likely to underpin the predilection to acquire genomic alterations in cells prior to morphological abnormalities being observed; in non-carriers the genetic instability may be arising as part of a field cancerisation or 'sick lobe' effect, in which a duct/lobe or a proportion of a lobe is clonally affected by genetic instability and hence the entire lobe is 'at risk' of further genetic instability and oncogenic activation.	('BRCA2', 'Gene', (131, 136))	('cancer', 'Disease', (344, 350))	('haploinsufficiency', 'Disease', 'MESH:D058495', (43, 61))	('genetic instability', 'Var', (452, 471))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA2', 'Gene', '675', (131, 136))	('haploinsufficiency', 'Disease', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('BRCA1', 'Gene', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
131259	32244556	Genomic data reveal a high concordance in the mutations and in particular copy number alterations between matched primary and metastatic tumours.	('copy number alterations', 'Var', (74, 97))	('mutations', 'Var', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('tumours', 'Disease', (137, 144))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
131260	32244556	Thus, there is a clear clonal ancestry during progression, and the early molecular drivers of behaviour and phenotype (e.g., mutations in TP53, PIK3CA, CDH1, GATA3, amplification of MYC, CCND1, ERRB2/HER2) remain prevalent drivers in metastatic deposits.	('GATA3', 'Gene', (158, 163))	('mutations', 'Var', (125, 134))	('TP53', 'Gene', '7157', (138, 142))	('HER2', 'Gene', (200, 204))	('PIK3CA', 'Gene', (144, 150))	('CCND1', 'Gene', (187, 192))	('prevalent', 'Reg', (213, 222))	('PIK3CA', 'Gene', '5290', (144, 150))	('HER2', 'Gene', '2064', (200, 204))	('TP53', 'Gene', (138, 142))	('CDH1', 'Gene', (152, 156))	('amplification', 'Var', (165, 178))	('CCND1', 'Gene', '595', (187, 192))	('MYC', 'Gene', '4609', (182, 185))	('CDH1', 'Gene', '999', (152, 156))	('metastatic deposits', 'CPA', (234, 253))	('MYC', 'Gene', (182, 185))	('GATA3', 'Gene', '2625', (158, 163))
131265	32244556	Most notably, activating mutations in ESR1 and amplification of the ESR1 gene region (6q25.1) are rarely observed in primary disease, but are prominent and critical drivers of resistance observed in around 20% of metastases arising following endocrine therapy.	('ESR1', 'Gene', (38, 42))	('ESR1', 'Gene', '2099', (68, 72))	('amplification', 'Var', (47, 60))	('activating', 'PosReg', (14, 24))	('ESR1', 'Gene', '2099', (38, 42))	('metastases', 'Disease', (213, 223))	('ESR1', 'Gene', (68, 72))	('metastases', 'Disease', 'MESH:D009362', (213, 223))
131266	32244556	Enrichment of mutations in TP53, GATA3, KMT2C, AKT1, NF1, PTEN, ERBB2, FGFR4, or amplification of 7p11.2 (EGFR), 8q24 (MYC), 11q13.3 (CCND1) and 20q13.2 (AURKA) may also underpin endocrine therapy resistance as they are more frequently identified in ER+/HER2- breast cancer metastases compared to ER+/HER2- primary tumours; many of these gene mutations are mutually exclusive to ESR1 mutations, emphasising their potential equivalence in driving resistance.	('GATA3', 'Gene', (33, 38))	('ESR1', 'Gene', '2099', (379, 383))	('AURKA', 'Gene', '6790', (154, 159))	('mutations', 'Var', (343, 352))	('ESR1', 'Gene', (379, 383))	('HER2', 'Gene', '2064', (254, 258))	('AURKA', 'Gene', (154, 159))	('EGFR', 'Gene', (106, 110))	('AKT1', 'Gene', (47, 51))	('TP53', 'Gene', (27, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('ERBB2', 'Gene', (64, 69))	('NF1', 'Gene', '4763', (53, 56))	('primary tumour', 'Disease', 'MESH:D009369', (307, 321))	('HER2', 'Gene', '2064', (301, 305))	('cancer metastases', 'Disease', 'MESH:D009362', (267, 284))	('FGFR4', 'Gene', '2264', (71, 76))	('MYC', 'Gene', (119, 122))	('mutations', 'Var', (14, 23))	('PTEN', 'Gene', (58, 62))	('CCND1', 'Gene', '595', (134, 139))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('primary tumour', 'Disease', (307, 321))	('breast cancer', 'Disease', (260, 273))	('NF1', 'Gene', (53, 56))	('KMT2C', 'Gene', '58508', (40, 45))	('KMT2C', 'Gene', (40, 45))	('CCND1', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (64, 69))	('tumours', 'Disease', (315, 322))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('HER2', 'Gene', (254, 258))	('FGFR4', 'Gene', (71, 76))	('EGFR', 'Gene', '1956', (106, 110))	('TP53', 'Gene', '7157', (27, 31))	('cancer metastases', 'Disease', (267, 284))	('PTEN', 'Gene', '5728', (58, 62))	('tumours', 'Phenotype', 'HP:0002664', (315, 322))	('underpin', 'Reg', (170, 178))	('HER2', 'Gene', (301, 305))	('MYC', 'Gene', '4609', (119, 122))	('tumours', 'Disease', 'MESH:D009369', (315, 322))	('GATA3', 'Gene', '2625', (33, 38))	('mutations', 'Var', (384, 393))	('AKT1', 'Gene', '207', (47, 51))	('tumour', 'Phenotype', 'HP:0002664', (315, 321))
131267	32244556	Mutational signatures found in the primary tumour are also found in metastases; but as with individual gene mutations, the frequencies of individual mutation signatures may also change, with an enrichment in signatures associated with APOBEC enzymatic activity and homologous recombination deficiency being higher in metastases than in primary tumours.	('APOBEC', 'Gene', (235, 241))	('primary tumour', 'Disease', 'MESH:D009369', (35, 49))	('tumours', 'Disease', (344, 351))	('metastases', 'Disease', (317, 327))	('metastases', 'Disease', 'MESH:D009362', (317, 327))	('homologous recombination deficiency', 'Var', (265, 300))	('primary tumour', 'Disease', (336, 350))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('tumour', 'Phenotype', 'HP:0002664', (344, 350))	('primary tumour', 'Disease', 'MESH:D009369', (336, 350))	('metastases', 'Disease', (68, 78))	('tumours', 'Phenotype', 'HP:0002664', (344, 351))	('primary tumour', 'Disease', (35, 49))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumours', 'Disease', 'MESH:D009369', (344, 351))	('higher', 'PosReg', (307, 313))
131269	32244556	Such efforts reveal, for example, that driver mutations that are enriched in metastasis are indeed rarely found in the matched primary tumour, indicating they arose either in a small subclone not sampled when the primary tumour was sequenced, or they occurred during the metastatic process after cells had disseminated from the breast (i.e., treatment induced mutations).	('mutations', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('primary tumour', 'Disease', (213, 227))	('primary tumour', 'Disease', (127, 141))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('occurred', 'Reg', (251, 259))	('primary tumour', 'Disease', 'MESH:D009369', (213, 227))	('primary tumour', 'Disease', 'MESH:D009369', (127, 141))
131270	32244556	Indeed, mutations in ESR1, ERBB2 and NF1 were significantly enriched in ER+/HER2- tumours post hormone treatment compared to tumours from ER+/HER2- untreated patients.	('ESR1', 'Gene', (21, 25))	('tumours', 'Disease', (82, 89))	('ERBB2', 'Gene', '2064', (27, 32))	('patients', 'Species', '9606', (158, 166))	('HER2', 'Gene', (76, 80))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('HER2', 'Gene', '2064', (142, 146))	('mutations', 'Var', (8, 17))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('NF1', 'Gene', '4763', (37, 40))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('enriched', 'Reg', (60, 68))	('NF1', 'Gene', (37, 40))	('HER2', 'Gene', (142, 146))	('tumours', 'Disease', (125, 132))	('HER2', 'Gene', '2064', (76, 80))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('ERBB2', 'Gene', (27, 32))	('ESR1', 'Gene', '2099', (21, 25))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
131272	32244556	However, subclonal divergence of metastases is invariably observed within patients: driver and non-driver gene mutations are heterogeneously accumulated in different metastases, subsets of metastases may therefore be more closely related to each other than they are to other metastases, and heterogenous tumour phenotypes (ER positive and ER negative) often coincide with this divergent history.	('metastases', 'Disease', (275, 285))	('mutations', 'Var', (111, 120))	('metastases', 'Disease', (189, 199))	('tumour', 'Disease', 'MESH:D009369', (304, 310))	('metastases', 'Disease', (166, 176))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('metastases', 'Disease', (33, 43))	('metastases', 'Disease', 'MESH:D009362', (275, 285))	('patients', 'Species', '9606', (74, 82))	('tumour', 'Disease', (304, 310))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('tumour', 'Phenotype', 'HP:0002664', (304, 310))
131288	32244556	They are, therefore, of great potential benefit in capturing phenotypic heterogeneity or driver mutations acquired or enriched for during treatment; and they are not biased by tumour sampling.	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('phenotypic heterogeneity', 'MPA', (61, 85))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (176, 182))	('mutations', 'Var', (96, 105))
131292	32244556	Genomic analysis of single CTCs reveals important heterogeneity in the mutation of various driver genes (e.g., PIK3CA, ESR1, KRAS, PTCH1, NOTCH1) reflecting the presence of discrete subclonal mutations within the tumour of origin and/or the presence of genomic alterations driving resistance/metastasis.	('NOTCH1', 'Gene', (138, 144))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('PTCH1', 'Gene', '5727', (131, 136))	('KRAS', 'Gene', (125, 129))	('mutation', 'Var', (71, 79))	('KRAS', 'Gene', '3845', (125, 129))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('ESR1', 'Gene', '2099', (119, 123))	('PIK3CA', 'Gene', (111, 117))	('tumour', 'Disease', (213, 219))	('PTCH1', 'Gene', (131, 136))	('NOTCH1', 'Gene', '4851', (138, 144))	('PIK3CA', 'Gene', '5290', (111, 117))	('ESR1', 'Gene', (119, 123))
131294	32244556	They demonstrated the presence of four alterations (CDH1 and TP53 frameshift mutations; PIK3CA and SOX2 amplifications) in CTC samples at baseline and progression.	('PIK3CA', 'Gene', '5290', (88, 94))	('CDH1', 'Gene', (52, 56))	('frameshift mutations', 'Var', (66, 86))	('CDH1', 'Gene', '999', (52, 56))	('SOX2', 'Gene', '6657', (99, 103))	('PIK3CA', 'Gene', (88, 94))	('SOX2', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
131295	32244556	However, high-level MYCN amplifications were only identified in CTCs sampled at progression, likely conferring treatment resistance.	('amplifications', 'Var', (25, 39))	('MYCN', 'Gene', (20, 24))	('MYCN', 'Gene', '4613', (20, 24))	('conferring', 'Reg', (100, 110))
131296	32244556	Similarly, the development of mutations and splice variants within ESR1 identified in single CTCs of metastatic patients on endocrine therapy also correlated with the onset of endocrine resistance.	('correlated', 'Reg', (147, 157))	('patients', 'Species', '9606', (112, 120))	('ESR1', 'Gene', '2099', (67, 71))	('mutations', 'Var', (30, 39))	('splice variants', 'Var', (44, 59))	('ESR1', 'Gene', (67, 71))
131297	32244556	ESR1 mutations are also readily detected in ctDNA, and in fact, ctDNA represents a more sensitive method of detection compared to CTCs.	('ESR1', 'Gene', (0, 4))	('ESR1', 'Gene', '2099', (0, 4))	('mutations', 'Var', (5, 14))
131301	32244556	The detection of minimal residual disease was also demonstrated in patients who continued to have detectable ctDNA PIK3CA mutations after surgery.	('PIK3CA', 'Gene', (115, 121))	('PIK3CA', 'Gene', '5290', (115, 121))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (67, 75))
131304	32244556	This has been demonstrated in the setting of endocrine therapy (various types of ESR1 alterations, including mutations, rearrangements and amplifications), CDK4/6 inhibition with endocrine therapy (ESR1, RB1 and PIK3CA mutations) and anti-HER2 therapy (copy number variations in the ERBB2 gene as well as increase in TP53 or PI3K/AKT/mTOR pathway mutations).	('PIK3CA', 'Gene', (212, 218))	('HER2', 'Gene', '2064', (239, 243))	('mTOR', 'Gene', (334, 338))	('AKT', 'Gene', (330, 333))	('TP53', 'Gene', '7157', (317, 321))	('RB1', 'Gene', (204, 207))	('mTOR', 'Gene', '2475', (334, 338))	('inhibition', 'NegReg', (163, 173))	('ERBB2', 'Gene', (283, 288))	('CDK4/6', 'Gene', (156, 162))	('HER2', 'Gene', (239, 243))	('increase', 'PosReg', (305, 313))	('PIK3CA', 'Gene', '5290', (212, 218))	('ESR1', 'Gene', '2099', (81, 85))	('AKT', 'Gene', '207', (330, 333))	('RB1', 'Gene', '5925', (204, 207))	('ERBB2', 'Gene', '2064', (283, 288))	('alterations', 'Var', (86, 97))	('mutations', 'Reg', (347, 356))	('ESR1', 'Gene', (81, 85))	('ESR1', 'Gene', '2099', (198, 202))	('TP53', 'Gene', (317, 321))	('ESR1', 'Gene', (198, 202))	('CDK4/6', 'Gene', '1019;1021', (156, 162))
131305	32244556	Importantly, and reflecting the inter-metastasis molecular heterogeneity described above, ESR1 mutations identified from either CTC or ctDNA from an individual patient are often heterogenous, suggesting that distinct subclones develop in parallel and utilise overlapping mechanisms of resistance.	('ESR1', 'Gene', (90, 94))	('ESR1', 'Gene', '2099', (90, 94))	('mutations', 'Var', (95, 104))	('patient', 'Species', '9606', (160, 167))
131312	32244556	In breast cancer, ERBB2 amplifications (targeted with anti-HER2 therapies) and PIK3CA mutations (targeted with Alpelisib + Fulvestrant) are the only Level 1 biomarkers as noted by OncoKB, while inactivating mutations of BRCA1 and BRCA2 are classed as Level 2 biomarkers for intervention with talazoparib and olaparib.	('talazoparib', 'Chemical', 'MESH:C586365', (292, 303))	('BRCA1', 'Gene', '672', (220, 225))	('amplifications', 'Var', (24, 38))	('inactivating mutations', 'Var', (194, 216))	('BRCA1', 'Gene', (220, 225))	('ERBB2', 'Gene', '2064', (18, 23))	('BRCA2', 'Gene', (230, 235))	('HER2', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PIK3CA', 'Gene', '5290', (79, 85))	('BRCA2', 'Gene', '675', (230, 235))	('olaparib', 'Chemical', 'MESH:C531550', (308, 316))	('mutations', 'Var', (86, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('HER2', 'Gene', '2064', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('PIK3CA', 'Gene', (79, 85))	('ERBB2', 'Gene', (18, 23))
131323	32244556	The pan-AKT inhibitor, AZD5363, is potent and sensitivity is predicted by PIK3CA mutations.	('AKT', 'Gene', '207', (8, 11))	('PIK3CA', 'Gene', '5290', (74, 80))	('AZD5363', 'Chemical', 'MESH:C575618', (23, 30))	('AKT', 'Gene', (8, 11))	('mutations', 'Var', (81, 90))	('sensitivity', 'MPA', (46, 57))	('PIK3CA', 'Gene', (74, 80))
131330	25049275	RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('distant dissemination', 'CPA', (64, 85))	('promote', 'PosReg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('RAB5A', 'Var', (0, 5))	('local invasion', 'CPA', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('rat', 'Species', '10116', (202, 205))	('tumor', 'Disease', (120, 125))
131354	25049275	This analysis revealed that overexpression of RAB5A, but not RAB5B or RAB5C (not depicted), correlates with poor prognosis (P = 0.031; Fig.	('RAB5B', 'Gene', (61, 66))	('RAB5C', 'Gene', '5878', (70, 75))	('RAB5C', 'Gene', (70, 75))	('overexpression', 'PosReg', (28, 42))	('RAB5B', 'Gene', '5869', (61, 66))	('RAB5A', 'Var', (46, 51))
131355	25049275	The prognostic power of RAB5A became progressively more significant in the following subgroups of patients: lymph node negative (N0; P = 0.01); N0 and ER+ (P = 0.003); and grade 2 (G2), N0, ER+ (P = 0.0004) breast tumor patients (Fig.	('ER+', 'Var', (151, 154))	('breast tumor', 'Disease', 'MESH:D001943', (207, 219))	('patients', 'Species', '9606', (98, 106))	('breast tumor', 'Disease', (207, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('patients', 'Species', '9606', (220, 228))	('ER+', 'Var', (190, 193))	('breast tumor', 'Phenotype', 'HP:0100013', (207, 219))
131371	25049275	Conversely, there was a significant decrease in both the number and size of local and distant metastatic outgrowths in mice injected with RAB5AS34N-MDA-MB-231 cells compared with mice injected with control cells (Fig.	('AS34N-MDA-MB-231', 'CellLine', 'CVCL:0062', (142, 158))	('mice', 'Species', '10090', (119, 123))	('mice', 'Species', '10090', (179, 183))	('RAB5AS34N-MDA-MB-231', 'Var', (138, 158))	('decrease', 'NegReg', (36, 44))
131376	25049275	RAB5 knockdown did not significantly alter the cell cycle profile or survival of MDA-MB-231 cells (unpublished data); thus, it presumably affected the ability of these cells to extravasate, spread within, or adhere to lung tissue.	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (0, 3))	('RAB', 'Gene', (0, 3))	('knockdown', 'Var', (5, 14))	('spread', 'CPA', (190, 196))	('affected', 'Reg', (138, 146))	('adhere', 'CPA', (208, 214))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (81, 91))	('extravasate', 'MPA', (177, 188))
131382	25049275	However, although MCF10.DCIS.com control lesions lost the myoepithelial layer and progressed to become invasive tumors after 3 wk, RAB5AS34N-expressing cells maintained the typical DCIS histology and their invasiveness was significantly impaired (Fig.	('invasive tumors', 'Disease', (103, 118))	('MCF10.DCIS.com', 'CellLine', 'CVCL:5552', (18, 32))	('RAB5AS34N-expressing', 'Var', (131, 151))	('invasive tumors', 'Disease', 'MESH:D009369', (103, 118))	('DCIS', 'MPA', (181, 185))	('lost', 'NegReg', (49, 53))	('myoepithelial', 'Disease', 'MESH:D009208', (58, 71))	('impaired', 'NegReg', (237, 245))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('invasiveness', 'CPA', (206, 218))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('myoepithelial', 'Disease', (58, 71))
131385	25049275	However, after 96 h the number of RAB5A-MCF10.DCIS.com cells was significantly higher than that of control cells (Fig.	('MCF10.DCIS.com', 'CellLine', 'CVCL:5552', (40, 54))	('higher', 'PosReg', (79, 85))	('RAB5A-MCF10.DCIS.com', 'Var', (34, 54))
131403	25049275	Thus, ectopic RAB5A expression is sufficient to transform a poorly invasive HeLa-originated tumor into a collagen remodeling, invasive tumor.	('HeLa', 'CellLine', 'CVCL:0030', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RAB5A', 'Gene', (14, 19))	('ectopic', 'Var', (6, 13))	('transform', 'Reg', (48, 57))	('tumor', 'Disease', (92, 97))	('invasive tumor', 'Disease', (126, 140))	('invasive tumor', 'Disease', 'MESH:D009369', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
131413	25049275	The invasive outgrowths were abrogated by the expression of RAB5AS34N, which was induced by the addition of doxycycline at the same time as HGF (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (108, 119))	('HGF', 'Gene', (140, 143))	('abrogated', 'NegReg', (29, 38))	('invasive outgrowths', 'CPA', (4, 23))	('HGF', 'Gene', '3082', (140, 143))	('RAB5AS34N', 'Var', (60, 69))
131414	25049275	Thus, RAB5A is necessary and sufficient to promote a proteolytic mesenchymal program of cell invasion in vitro and tumor dissemination in vivo.	('proteolytic', 'MPA', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('promote', 'PosReg', (43, 50))	('tumor', 'Disease', (115, 120))	('RAB5A', 'Var', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
131423	25049275	Additionally, genetic or functional interference with RAB5 severely inhibited HGF-stimulated matrix proteolysis (Fig.	('HGF', 'Gene', (78, 81))	('HGF', 'Gene', '3082', (78, 81))	('matrix proteolysis', 'MPA', (93, 111))	('genetic', 'Var', (14, 21))	('inhibited', 'NegReg', (68, 77))	('RAB', 'Gene', (54, 57))	('functional interference', 'Var', (25, 48))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (54, 57))
131432	25049275	Silencing of the two RAB4 isoforms (A and B), or expression of a dominant-negative RAB4A mutant reduced (>80%) the number of invadosomes and matrix degradation (Fig.	('RAB', 'Gene', (21, 24))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (21, 24))	('RAB', 'Gene', (83, 86))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (83, 86))	('Silencing', 'Var', (0, 9))	('mutant', 'Var', (89, 95))	('reduced', 'NegReg', (96, 103))
131434	25049275	Similar effects were obtained by silencing RABENOSYN-5, whereas suppression of RAB11 activity had no effect (Fig.	('RAB11', 'Gene', '8766', (79, 84))	('silencing', 'Var', (33, 42))	('RABENOSYN-5', 'Gene', (43, 54))	('RABENOSYN-5', 'Gene', '64145', (43, 54))	('RAB11', 'Gene', (79, 84))
131436	25049275	Like in HeLa cells, silencing of RAB4 (or expression of RAB4AS22N) or of RABENOSYN-5, but not of RABAPTIN-5, impaired matrix proteolysis of MCF10.DCIS.com (Fig.	('RABAPTIN-5', 'Gene', '9135', (97, 107))	('RABAPTIN-5', 'Gene', (97, 107))	('RABENOSYN-5', 'Gene', '64145', (73, 84))	('HeLa', 'CellLine', 'CVCL:0030', (8, 12))	('impaired', 'NegReg', (109, 117))	('RAB', 'Gene', (56, 59))	('RAB', 'Gene', (73, 76))	('matrix proteolysis', 'MPA', (118, 136))	('MCF10.DCIS.com', 'CellLine', 'CVCL:5552', (140, 154))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (97, 100))	('RAB', 'Gene', (97, 100))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (56, 59))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (73, 76))	('RAB', 'Gene', (33, 36))	('silencing', 'Var', (20, 29))	('RABENOSYN-5', 'Gene', (73, 84))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (33, 36))
131441	25049275	6, C and D), siRNA-resistant RABENOSYN-5 mutants impaired either in the binding to RAB5 or to RAB4 failed to do so (Fig.	('mutants', 'Var', (41, 48))	('RABENOSYN-5', 'Gene', (29, 40))	('RAB', 'Gene', (83, 86))	('binding', 'Interaction', (72, 79))	('RAB', 'Gene', (94, 97))	('RABENOSYN-5', 'Gene', '64145', (29, 40))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (83, 86))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (94, 97))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (29, 32))	('impaired', 'NegReg', (49, 57))	('RAB', 'Gene', (29, 32))
131443	25049275	Consistently, silencing of MT1-MMP abrogated HGF- and RAB5A-induced matrix degradation and reduced the number of invadosomes (Fig.	('silencing', 'Var', (14, 23))	('abrogated', 'NegReg', (35, 44))	('matrix', 'CPA', (68, 74))	('MT1-MMP', 'Gene', (27, 34))	('number of invadosomes', 'MPA', (103, 124))	('HGF', 'Gene', (45, 48))	('reduced', 'NegReg', (91, 98))	('RAB5A-induced', 'Gene', (54, 67))	('HGF', 'Gene', '3082', (45, 48))
131448	25049275	Notably, in these cells, only a fraction of MT1-MMP localizes in LAMP-1-positive late endosomes (Fig.	('MT1-MMP', 'Var', (44, 51))	('LAMP-1', 'Gene', '3916', (65, 71))	('LAMP-1', 'Gene', (65, 71))
131449	25049275	Additionally, after treatment with HGF, or ectopic RAB5A expression, MT1-MMP relocalized to ventrally restricted, F-actin-rich structures (Video 6), which were also transiently targeted by RAB5A- and RAB4A-positive early endosomes (Fig.	('ectopic', 'Var', (43, 50))	('HGF', 'Gene', (35, 38))	('MT1-MMP', 'Gene', (69, 76))	('HGF', 'Gene', '3082', (35, 38))	('RAB5A', 'Gene', (51, 56))
131452	25049275	HGF-induced recycling of MT1-MMP was reduced by silencing of RAB5, RAB4, and RABENOSYN-5, but not of integrin beta3 expression (see the following paragraph; Fig.	('RAB', 'Gene', (61, 64))	('silencing', 'Var', (48, 57))	('recycling', 'MPA', (12, 21))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (61, 64))	('HGF', 'Gene', (0, 3))	('RABENOSYN-5', 'Gene', (77, 88))	('HGF', 'Gene', '3082', (0, 3))	('RABENOSYN-5', 'Gene', '64145', (77, 88))	('integrin beta3', 'Gene', '3690', (101, 115))	('integrin beta3', 'Gene', (101, 115))	('RAB', 'Gene', (67, 70))	('reduced', 'NegReg', (37, 44))	('RAB', 'Gene', (77, 80))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (67, 70))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (77, 80))
131471	25049275	RAB5A-dependent invasion was impaired by silencing of MT1-MMP, RAB4A/B, and beta3 integrin, but only marginally affected by silencing of beta1 integrin (Fig.	('RAB5A-dependent invasion', 'CPA', (0, 24))	('RAB4A/B', 'Gene', (63, 70))	('integrin', 'Gene', (82, 90))	('beta1 integrin', 'Gene', (137, 151))	('RAB4A/B', 'Gene', '5867', (63, 70))	('silencing', 'Var', (41, 50))	('integrin', 'Gene', (143, 151))	('impaired', 'NegReg', (29, 37))	('beta3', 'Gene', '1934', (76, 81))	('silencing', 'Var', (124, 133))	('beta3', 'Gene', (76, 81))	('integrin', 'Gene', '3688', (143, 151))	('integrin', 'Gene', '3688', (82, 90))	('beta1 integrin', 'Gene', '3688', (137, 151))	('MT1-MMP', 'Gene', (54, 61))
131472	25049275	Silencing of RAB4A/B and beta3 integrin also impaired MDA-MB-231 invasion (Fig.	('integrin', 'Gene', (31, 39))	('beta3', 'Gene', (25, 30))	('integrin', 'Gene', '3688', (31, 39))	('RAB4A/B', 'Gene', (13, 20))	('MDA-MB-231 invasion', 'CPA', (54, 73))	('impaired', 'NegReg', (45, 53))	('Silencing', 'Var', (0, 9))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (54, 64))	('beta3', 'Gene', '1934', (25, 30))	('RAB4A/B', 'Gene', '5867', (13, 20))
131476	25049275	However, while MCF10.DCIS.com control lesions lost the myoepithelial layer and progressed to become invasive tumors after 3 wk, RAB4AS22N-expressing cells maintained the typical DCIS histology and their invasiveness was impaired (Fig.	('invasiveness', 'CPA', (203, 215))	('MCF10.DCIS.com', 'CellLine', 'CVCL:5552', (15, 29))	('invasive tumors', 'Disease', 'MESH:D009369', (100, 115))	('RAB4AS22N-expressing', 'Var', (128, 148))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('myoepithelial', 'Disease', (55, 68))	('DCIS', 'MPA', (178, 182))	('myoepithelial', 'Disease', 'MESH:D009208', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('impaired', 'NegReg', (220, 228))	('lost', 'NegReg', (46, 50))	('invasive tumors', 'Disease', (100, 115))
131492	25049275	Similarly, we found that interference with late endosomal routes by silencing RAB7 reduced, but did not abrogate, RAB5-dependent invasion into dense collagen matrix (unpublished data).	('RAB', 'Gene', (78, 81))	('RAB7', 'Gene', '338382', (78, 82))	('reduced', 'NegReg', (83, 90))	('RAB7', 'Gene', (78, 82))	('RAB', 'Gene', (114, 117))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (114, 117))	('silencing', 'Var', (68, 77))	('invasion into dense collagen matrix', 'CPA', (129, 164))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (78, 81))
131504	25049275	Genetic or pharmaceutical inhibition impairment of MMPs, and specifically of MT1-MMPs, reduces breast metastasis.	('MMPs', 'Gene', '4314;4318;4323;17387', (51, 55))	('breast metastasis', 'CPA', (95, 112))	('reduces', 'NegReg', (87, 94))	('MMPs', 'Gene', (81, 85))	('MT1-MMPs', 'Gene', (77, 85))	('MMPs', 'Gene', (51, 55))	('MT1-MMPs', 'Gene', '4323', (77, 85))	('impairment', 'Var', (37, 47))	('inhibition impairment', 'Var', (26, 47))	('MMPs', 'Gene', '4314;4318;4323;17387', (81, 85))
131509	25049275	It is thus not surprising that elevation of RAB5A and/or amplification of RAB4A may be selected events in a subset of breast cancers to increase their metastatic potential.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('metastatic potential', 'CPA', (151, 171))	('RAB5A', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('amplification', 'Var', (57, 70))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('increase', 'PosReg', (136, 144))	('RAB4A', 'Gene', (74, 79))	('elevation', 'PosReg', (31, 40))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('breast cancers', 'Disease', (118, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
131515	25049275	pEGFP vector was from Takara Bio Inc. For lentiviral infection, RAB5AWT, RAB5AS34N, and GFP-RAB4AS22N were cloned in the TET ON pSLIK vector.	('RAB5AS34N', 'Var', (73, 82))	('lentiviral infection', 'Disease', (42, 62))	('TET', 'Chemical', 'MESH:C010349', (121, 124))	('lentiviral infection', 'Disease', 'MESH:D007239', (42, 62))
131516	25049275	pEGFP-res WT-RABENOSYN5 containing silent mismatches in the target sequence of RABENOSYN5 oligo 2 (GGTCTATaATGTGCAAaAAGTGTAT), pEGFP-res RAB4-Delta-RABENOSYN5 (W443A), pEGFP-res RAB5-Delta-RABENOSYN5 (I734E), and pEGFP-res RAB4/5-Delta-RABENOSYN5 (W443A and I734E) were provided by Mutagenex Inc. Antibodies used were: rabbit anti-RAC 1/2/3 and anti-Caspase3 (Cell Signaling Technology); mouse anti-HA1 (BabCo); rabbit anti-RAB5A (S-19), anti-Integrin beta3 (H96), anti-GFP (FL), mouse monoclonal anti-ARP3 (4), and goat anti-EEA1 (N-19; all from Santa Cruz Biotechnology, Inc.); mouse monoclonal anti-clathrin (X22; Thermo Fisher Scientific); mouse monoclonal anti-FAK and anti-VASP (BD); anti-Actin (AC-40); anti-LAMP1; anti-SMA (alpha smooth muscle actin); mouse monoclonal anti-alpha Tubulin and anti-RAB4 (1C10; both from Sigma-Aldrich); rabbit anti-GFP (Takara Bio Inc.); anti-Cortactin (4F11; EMD Millipore); mouse monoclonal anti-MT1-MMP (LEM-2/15.8; EMD Millipore); mouse monoclonal anti-alphav/beta3 (LM609) and anti-alpha5/beta1 (P1D6; Immunological Sciences); mouse monoclonal anti-beta1 (4B4; Beckman Coulter); rabbit anti-Rabenosyn5 (No.	('RABENOSYN5', 'Gene', '64145', (79, 89))	('W443A', 'Var', (248, 253))	('ARP3', 'Gene', (502, 506))	('beta3', 'Gene', (1004, 1009))	('RAC 1/2/3', 'Gene', (331, 340))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (137, 140))	('beta3', 'Gene', '1934', (1004, 1009))	('mouse', 'Species', '10090', (760, 765))	('Rabenosyn5', 'Gene', (1136, 1146))	('RABENOSYN5', 'Gene', (236, 246))	('RAB', 'Gene', (79, 82))	('RABENOSYN5', 'Gene', (148, 158))	('Integrin beta3', 'Gene', (443, 457))	('beta3', 'Gene', '1934', (452, 457))	('W443A', 'SUBSTITUTION', 'None', (160, 165))	('LAMP1', 'Gene', (715, 720))	('beta1', 'Gene', (1094, 1099))	('HA1', 'Gene', '3881', (399, 402))	('mouse', 'Species', '10090', (1072, 1077))	('HA1', 'Gene', (399, 402))	('LM609', 'CellLine', 'CVCL:V308', (1011, 1016))	('EEA1', 'Gene', (526, 530))	('alpha5/beta1', 'Gene', '10678', (1027, 1039))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (805, 808))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (424, 427))	('RABENOSYN5', 'Gene', (79, 89))	('RAB', 'Gene', (178, 181))	('EEA1', 'Gene', '8411', (526, 530))	('ARP3', 'Gene', '10096', (502, 506))	('RABENOSYN5', 'Gene', '64145', (13, 23))	('goat', 'Species', '9925', (516, 520))	('Rabenosyn5', 'Gene', '64145', (1136, 1146))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (223, 226))	('beta1', 'Gene', (1034, 1039))	('rabbit', 'Species', '9986', (412, 418))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (13, 16))	('RABENOSYN5', 'Gene', (189, 199))	('FAK', 'Gene', '5747', (666, 669))	('RAB', 'Gene', (236, 239))	('mouse', 'Species', '10090', (580, 585))	('Cortactin', 'Gene', (883, 892))	('RAB', 'Gene', (189, 192))	('I734E', 'Mutation', 'p.I734E', (258, 263))	('RAB', 'Gene', (148, 151))	('LEM-2', 'Gene', '221496', (947, 952))	('mouse', 'Species', '10090', (975, 980))	('mouse', 'Species', '10090', (388, 393))	('beta1', 'Gene', '10678', (1094, 1099))	('W443A', 'Var', (160, 165))	('I734E', 'Mutation', 'p.I734E', (201, 206))	('Caspase3', 'Gene', '836', (350, 358))	('RAB', 'Gene', (137, 140))	('W443A', 'SUBSTITUTION', 'None', (248, 253))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (79, 82))	('Integrin beta3', 'Gene', '3690', (443, 457))	('LAMP1', 'Gene', '3916', (715, 720))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (236, 239))	('RABENOSYN5', 'Gene', (13, 23))	('Caspase3', 'Gene', (350, 358))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (148, 151))	('VASP', 'Gene', (679, 683))	('beta1', 'Gene', '10678', (1034, 1039))	('rabbit', 'Species', '9986', (1124, 1130))	('alpha5/beta1', 'Gene', (1027, 1039))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (178, 181))	('RAC 1/2/3', 'Gene', '5879;5880;5881', (331, 340))	('rabbit', 'Species', '9986', (843, 849))	('LEM-2', 'Gene', (947, 952))	('RAB', 'Gene', (805, 808))	('RAB', 'Gene', (424, 427))	('RABENOSYN5', 'Gene', '64145', (236, 246))	('rabbit', 'Species', '9986', (319, 325))	('VASP', 'Gene', '7408', (679, 683))	('RABENOSYN5', 'Gene', '64145', (189, 199))	('FAK', 'Gene', (666, 669))	('RABENOSYN5', 'Gene', '64145', (148, 158))	('beta3', 'Gene', (452, 457))	('mouse', 'Species', '10090', (480, 485))	('mouse', 'Species', '10090', (916, 921))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (189, 192))	('RAB', 'Gene', (223, 226))	('mouse', 'Species', '10090', (644, 649))	('Cortactin', 'Gene', '2017', (883, 892))	('RAB', 'Gene', (13, 16))
131556	25049275	Primer assay IDs were: MT1-MMP, Hs00237119_m1; beta1 Integrin, Hs00559595_m1; beta3 Integrin, Hs01001469_m1; RAB5A, Hs00991290_m1; RAB5B, Hs00161184_m1; RAB5C, Hs00428044_m1; RAB4A, Hs00190157_m1; RAB4B, Hs00535053_m1; RAB7A, Hs01115139_m1; RAB7B, Hs00332830_m1; RAB8A, Hs00180479_m1; RAB8B, Hs00213008_m1; RABENOSIN-5 (ZFYVE20), Hs00223482_m1; and RABAPTIN-5, Hs01091595_m1.	('Integrin', 'Gene', '3688', (53, 61))	('Hs00332830_m1', 'Var', (248, 261))	('Integrin', 'Gene', '3688', (84, 92))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (241, 244))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (219, 222))	('RAB7A', 'Gene', '7879', (219, 224))	('RAB', 'Gene', (307, 310))	('RAB5B', 'Gene', '5869', (131, 136))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (131, 134))	('Hs00223482_m1', 'Var', (330, 343))	('ZFYVE20', 'Gene', '64145', (320, 327))	('RAB8A', 'Gene', '4218', (263, 268))	('RAB', 'Gene', (197, 200))	('RAB4B', 'Gene', '53916', (197, 202))	('RAB', 'Gene', (241, 244))	('RABAPTIN-5', 'Gene', (349, 359))	('RAB', 'Gene', (219, 222))	('RAB8B', 'Gene', '51762', (285, 290))	('beta1 Integrin', 'Gene', '3688', (47, 61))	('RAB', 'Gene', (131, 134))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (263, 266))	('RAB7B', 'Gene', (241, 246))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (153, 156))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (349, 352))	('RAB7B', 'Gene', '338382', (241, 246))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (175, 178))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (285, 288))	('RAB5C', 'Gene', '5878', (153, 158))	('beta3', 'Gene', (78, 83))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (197, 200))	('RAB', 'Gene', (153, 156))	('ZFYVE20', 'Gene', (320, 327))	('RAB', 'Gene', (349, 352))	('RAB', 'Gene', (263, 266))	('RAB8A', 'Gene', (263, 268))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (109, 112))	('RAB', 'Gene', (175, 178))	('RAB', 'Gene', (285, 288))	('RAB8B', 'Gene', (285, 290))	('Integrin', 'Gene', (84, 92))	('Hs01115139_m1', 'Var', (226, 239))	('Integrin', 'Gene', (53, 61))	('RABAPTIN-5', 'Gene', '9135', (349, 359))	('RAB7A', 'Gene', (219, 224))	('RAB5B', 'Gene', (131, 136))	('RAB4B', 'Gene', (197, 202))	('RAB', 'Gene', '8766;11021;11021;9545;5867;19341;53916;5868;271457;5869;5878;7879;338382;4218;51762', (307, 310))	('beta3', 'Gene', '1934', (78, 83))	('RAB5C', 'Gene', (153, 158))	('RAB', 'Gene', (109, 112))	('beta1 Integrin', 'Gene', (47, 61))
131602	25049275	Formalin-fixed, paraffin-embedded (FFPE) human or mouse tumor tissue sections were stained with anti-RAB5A or ant-RAB4A antibody by IHC.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('anti-RAB5A', 'Var', (96, 106))	('tumor', 'Disease', (56, 61))	('human', 'Species', '9606', (41, 46))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('mouse', 'Species', '10090', (50, 55))	('ant-RAB4A', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
131611	25049275	: GSE4922, GSE6532, GSE2034, GSE7390, and GSE1456.	('GSE2034', 'Var', (20, 27))	('GSE1456', 'Var', (42, 49))	('GSE7390', 'Chemical', '-', (29, 36))	('GSE1456', 'Chemical', '-', (42, 49))	('GSE7390', 'Var', (29, 36))	('GSE4922', 'Var', (2, 9))	('GSE6532', 'Var', (11, 18))	('GSE4922', 'Chemical', '-', (2, 9))	('GSE2034', 'Chemical', '-', (20, 27))	('GSE6532', 'Chemical', '-', (11, 18))
131624	25049275	Video 5 shows time-lapse microscopy of invading breast tumor cells upon deregulation of RAB5A.	('RAB5A', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('breast tumor', 'Disease', (48, 60))	('deregulation', 'Var', (72, 84))	('breast tumor', 'Phenotype', 'HP:0100013', (48, 60))	('breast tumor', 'Disease', 'MESH:D001943', (48, 60))
131626	25049275	Video 7 shows time-lapse microscopy of RFP-LifeAct and either GFP-RAB5A or GFP-RAB4A in HGF-stimulated HeLa.	('GFP-RAB4A', 'Var', (75, 84))	('RFP', 'Gene', '2358', (39, 42))	('HGF', 'Gene', '3082', (88, 91))	('HeLa', 'CellLine', 'CVCL:0030', (103, 107))	('GFP-RAB5A', 'Var', (62, 71))	('RFP', 'Gene', (39, 42))	('HGF', 'Gene', (88, 91))
131666	22894137	The other antibodies are from Novocastra, Newcastle upon Tyne, UK: p53 (1:50, clone DO-7), ER (1:100, clone 6 F11), PR (1:100, clone 16), HER-2 (1:100, clone CB11) and Ki67 (1:100, clone MM1).	('p53', 'Gene', (67, 70))	('ER', 'Gene', '2099', (139, 141))	('p53', 'Gene', '7157', (67, 70))	('1:100', 'Var', (145, 150))	('PR', 'Gene', '5241', (116, 118))	('ER', 'Gene', '2099', (91, 93))	('HER-2', 'Gene', '2064', (138, 143))	('MM1', 'Gene', (187, 190))	('MM1', 'Gene', '23654', (187, 190))	('HER-2', 'Gene', (138, 143))
131690	22894137	Our results indicate that the expression of beta1 integrin has an impact in disease-specific survival (number of months from diagnosis to the time of death due to breast cancer) with p = 0.002 (Figure  1).	('beta1 integrin', 'Gene', (44, 58))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('expression', 'Var', (30, 40))	('beta1 integrin', 'Gene', '3688', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('disease-specific survival', 'CPA', (76, 101))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('impact', 'Reg', (66, 72))	('breast cancer', 'Disease', (163, 176))
131715	22894137	For example, Hayashida and colleagues  founded that beta1 integrin are dependently linked with TGF-beta1, and that knocking beta1 integrin down enhances the cell collagen production trough TGF-beta1.	('TGF-beta1', 'Gene', (95, 104))	('beta1 integrin', 'Gene', '3688', (52, 66))	('beta1 integrin', 'Gene', '3688', (124, 138))	('TGF-beta1', 'Gene', '7040', (189, 198))	('TGF-beta1', 'Gene', (189, 198))	('cell', 'CPA', (157, 161))	('beta1 integrin', 'Gene', (52, 66))	('knocking', 'Var', (115, 123))	('beta1 integrin', 'Gene', (124, 138))	('down', 'NegReg', (139, 143))	('TGF-beta1', 'Gene', '7040', (95, 104))
131719	22894137	In this study the authors founded that the knockout of beta1 integrin in embryonic stem cells, neither the proliferation of the endothelial cells nor sprouting of blood vessels occurred, suggesting that VEGF had no effect in beta1-null embryoid bodies .	('beta1', 'Gene', (225, 230))	('beta1', 'Gene', (55, 60))	('beta1 integrin', 'Gene', '3688', (55, 69))	('beta1', 'Gene', '10678', (225, 230))	('beta1', 'Gene', '10678', (55, 60))	('VEGF', 'Gene', '7422', (203, 207))	('knockout', 'Var', (43, 51))	('beta1 integrin', 'Gene', (55, 69))	('VEGF', 'Gene', (203, 207))
131720	22894137	More interestingly Lee and colleagues  with in vitro studies, with human brain microvascular endothelial cells, showed that blocking beta1 integrin, all processes of angiogenesis was inhibited (adhesion, migration, and capillary morphogenesis) and they also suggested that the alpha6beta1 integrin is closely related to the metastasis of breast cancer cells to the brain.	('beta1 integrin', 'Gene', '3688', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('breast cancer', 'Phenotype', 'HP:0003002', (338, 351))	('blocking', 'Var', (124, 132))	('breast cancer', 'Disease', 'MESH:D001943', (338, 351))	('beta1 integrin', 'Gene', '3688', (133, 147))	('beta1 integrin', 'Gene', (283, 297))	('processes of angiogenesis', 'CPA', (153, 178))	('breast cancer', 'Disease', (338, 351))	('human', 'Species', '9606', (67, 72))	('inhibited', 'NegReg', (183, 192))	('related', 'Reg', (309, 316))	('beta1 integrin', 'Gene', (133, 147))
131727	22894137	In the present study, we found a relationship between low expression of beta1 integrin and negativity for HER-2 demonstrating some evidence that this subgroup of patients might have a less aggressive phenotype.	('patients', 'Species', '9606', (162, 170))	('negativity', 'Var', (91, 101))	('low', 'NegReg', (54, 57))	('expression', 'MPA', (58, 68))	('HER-2', 'Gene', '2064', (106, 111))	('beta1 integrin', 'Gene', (72, 86))	('HER-2', 'Gene', (106, 111))	('beta1 integrin', 'Gene', '3688', (72, 86))
131730	22894137	The amplification of the proto-oncogene HER-2 is observed in approximately 15-30% of all breast cancer samples and has been correlated with a shorter survival .	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('correlated', 'Reg', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('HER-2', 'Gene', (40, 45))	('shorter', 'NegReg', (142, 149))	('HER-2', 'Gene', '2064', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('amplification', 'Var', (4, 17))	('observed', 'Reg', (49, 57))
131738	22894137	Subgroups of patients with negativity for beta1 integrin and HER-2 might have a less aggressive phenotype.	('beta1 integrin', 'Gene', (42, 56))	('patients', 'Species', '9606', (13, 21))	('HER-2', 'Gene', '2064', (61, 66))	('HER-2', 'Gene', (61, 66))	('negativity', 'Var', (27, 37))	('beta1 integrin', 'Gene', '3688', (42, 56))
131789	30278958	Of the 14 patients (9.2%) found to have atypia on CNB, 2 of these patients (14.2%) were found to have DCIS and 6 patients (42.9%) were found to have atypical ductal hyperplasia (ADH) on final excisional pathology.	('ductal hyperplasia', 'Disease', 'MESH:D006965', (158, 176))	('atypia', 'Var', (40, 46))	('patients', 'Species', '9606', (113, 121))	('CNB', 'Gene', (50, 53))	('DCIS', 'Disease', (102, 106))	('patients', 'Species', '9606', (10, 18))	('DCIS', 'Disease', 'MESH:D002285', (102, 106))	('ductal hyperplasia', 'Disease', (158, 176))	('patients', 'Species', '9606', (66, 74))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
131810	30278958	Our results are also consistent with previous studies that showed higher upgrade rates in IDPs with atypia than that of IDPs without atypia on CNB.	('IDPs', 'Disease', (120, 124))	('IDPs', 'Disease', 'MESH:D018300', (120, 124))	('upgrade', 'CPA', (73, 80))	('higher', 'PosReg', (66, 72))	('atypia', 'Var', (100, 106))	('IDPs', 'Disease', (90, 94))	('IDPs', 'Disease', 'MESH:D018300', (90, 94))
131827	30278958	described that age, menopausal status, lesions peripheral to the nipple and atypia on core needle biopsy were predictors of malignancy.	('atypia', 'Var', (76, 82))	('menopausal status', 'Phenotype', 'HP:0008209', (20, 37))	('malignancy', 'Disease', (124, 134))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))
131861	28096732	In invasive cancers, T2* relaxation time is significantly longer in higher histologic grades and high signal intensity on T2WI.	('invasive cancers', 'Disease', 'MESH:D009362', (3, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('invasive cancers', 'Disease', (3, 19))	('longer', 'PosReg', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('T2* relaxation time', 'MPA', (21, 40))	('high', 'Var', (97, 101))
131881	28096732	T2 signal intensity of cancer was compared with that of breast parenchyma on T2-weighted image (T2WI) and classified into three groups: iso-signal intensity, high and very high signal intensity.	('iso-signal', 'Var', (136, 146))	('breast parenchyma', 'Disease', (56, 73))	('breast parenchyma', 'Disease', 'MESH:D010195', (56, 73))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
131900	28096732	Multiple linear regression analysis was performed to find independent predictive factors of cancer associated with T2* values.	('T2* values', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
131910	28096732	The following variables with p values < 0.2 at univariate analysis were entered into the multiple linear regression model: calcification at mammography, lesion location and T2 signal intensity of cancer at MRI, histologic grade, ER, PR, HER2, p53, and Ki-67.	('HER2', 'Gene', '2064', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('calcification', 'Disease', (123, 136))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('p53', 'Gene', (243, 246))	('cancer', 'Disease', (196, 202))	('calcification', 'Disease', 'MESH:D002114', (123, 136))	('PR', 'Gene', '5241', (233, 235))	('p53', 'Gene', '7157', (243, 246))	('HER2', 'Gene', (237, 241))	('Ki-67', 'Var', (252, 257))
131968	18607345	This evidence suggests that abnormal estrogen signaling may have an important role in the development and promotion of certain types of proliferative breast lesions.	('abnormal', 'Var', (28, 36))	('breast lesions', 'Disease', 'MESH:D001941', (150, 164))	('abnormal estrogen signaling', 'Phenotype', 'HP:0025132', (28, 55))	('breast lesions', 'Disease', (150, 164))	('estrogen signaling', 'MPA', (37, 55))
132032	18607345	Expression of ESR1 was detected in ~50 - 55% of cells within CCLs, which was higher than normal ductal epithelium within each treatment group (P < 0.01 for all) (Figure 4a).	('CCLs', 'Var', (61, 65))	('CCLs', 'Chemical', '-', (61, 65))	('higher', 'PosReg', (77, 83))	('Expression', 'MPA', (0, 10))	('ESR1', 'Gene', (14, 18))	('ESR1', 'Gene', '2099', (14, 18))
132049	18607345	In contrast, a large clinical trial reported a substantial reduction in BBD incidence and subsequent cancer risk associated with BBD in women taking tamoxifen, which is antiestrogenic in the breast.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('women', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('reduction', 'NegReg', (59, 68))	('BBD', 'Disease', (72, 75))	('tamoxifen', 'Chemical', 'MESH:D013629', (149, 158))	('BBD', 'Var', (129, 132))
132052	18607345	A recent follow-up study from this trial reported a significant increase in benign proliferative breast lesions (primarily those without atypia) in women receiving CEE, supporting the idea that estrogen therapy may promote at least a subset of benign breast lesions.	('benign breast lesions', 'Disease', 'MESH:D001941', (244, 265))	('CEE', 'Var', (164, 167))	('benign breast lesions', 'Disease', (244, 265))	('increase', 'PosReg', (64, 72))	('benign proliferative breast lesions', 'Disease', (76, 111))	('benign proliferative breast lesions', 'Disease', 'MESH:D001941', (76, 111))	('women', 'Species', '9606', (148, 153))
132086	33406793	It has been demonstrated that inhibition of the activity of certain enzymes, such as that of phospholipase A2 in BC cell lines sensitizes these cells and decreases the IC50 values for forthcoming therapy with traditional drugs, such as doxorubicin and tamoxifen.	('doxorubicin', 'Chemical', 'MESH:D004317', (236, 247))	('inhibition', 'Var', (30, 40))	('activity', 'MPA', (48, 56))	('BC', 'Phenotype', 'HP:0003002', (113, 115))	('IC50 values', 'MPA', (168, 179))	('tamoxifen', 'Chemical', 'MESH:D013629', (252, 261))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('C', 'Chemical', 'MESH:D002244', (169, 170))	('phospholipase A2', 'Gene', (93, 109))	('phospholipase A2', 'Gene', '5319', (93, 109))	('sensitizes', 'Reg', (127, 137))	('decreases', 'NegReg', (154, 163))
132131	33406793	Phospholipases are key enzymes in the PL metabolism, and their aberrant expression and altered activity correlate with the development and progression of numerous diseases, including cancer.	('cancer', 'Disease', (183, 189))	('numerous diseases', 'Disease', 'MESH:D003141', (154, 171))	('aberrant', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('Phospholipases', 'Enzyme', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('activity', 'MPA', (95, 103))	('numerous diseases', 'Disease', (154, 171))	('PL', 'Chemical', 'MESH:D010743', (38, 40))
132143	33406793	The signaling role of PLA2 and the products of its activity is demonstrated in cancer cell lines, in which the inhibition of the PLA2 activity increases the sensitivity towards chemotherapy of breast and cervical epithelial cell line Ect/E6E7.	('increases', 'PosReg', (143, 152))	('PLA2', 'Gene', '8398', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PLA2', 'Gene', '8398', (22, 26))	('PLA2', 'Gene', (129, 133))	('PLA2', 'Gene', (22, 26))	('activity', 'MPA', (134, 142))	('inhibition', 'Var', (111, 121))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('sensitivity towards chemotherapy', 'MPA', (157, 189))
132153	33406793	DAGs with Ca2+ activates protein kinase C (PKC), which is one of the central enzymes in the regulation of the cell cycle.	('Ca2+', 'Var', (10, 14))	('Ca2+', 'Chemical', 'MESH:D000069285', (10, 14))	('activates', 'PosReg', (15, 24))	('protein kinase C', 'Gene', (25, 41))	('PKC', 'Gene', (43, 46))	('PKC', 'Gene', '112476', (43, 46))	('protein kinase C', 'Gene', '112476', (25, 41))	('DAGs', 'Chemical', 'MESH:C011439', (0, 4))
132159	33406793	Therefore, an aberrant PLC activity can contribute to tumorigenesis.	('contribute', 'Reg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('aberrant', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('PLC', 'Gene', (23, 26))	('PLC', 'Gene', '3339', (23, 26))
132164	33406793	Inhibitors of PLD are also shown to suppress the growth of the patient-derived prostate cancer cell line and PLD activity and production of PA are associated with the mechanism of invasion of BC cells in a xenograft model.	('PA', 'Chemical', 'MESH:D010712', (140, 142))	('associated', 'Reg', (147, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('PLD', 'Gene', '2822', (14, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('growth', 'CPA', (49, 55))	('suppress', 'NegReg', (36, 44))	('Inhibitors', 'Var', (0, 10))	('C', 'Chemical', 'MESH:D002244', (193, 194))	('BC', 'Phenotype', 'HP:0003002', (192, 194))	('PLD', 'Gene', (14, 17))	('patient', 'Species', '9606', (63, 70))	('activity', 'MPA', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('prostate cancer', 'Disease', (79, 94))	('PLD', 'Gene', '2822', (109, 112))	('PLD', 'Gene', (109, 112))
132166	33406793	The aberrant activity of phospholipases is associated with tumor initiation, development, progression, and metastatic potential.	('development', 'CPA', (77, 88))	('metastatic potential', 'CPA', (107, 127))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('aberrant activity', 'Var', (4, 21))	('phospholipases', 'Enzyme', (25, 39))	('progression', 'CPA', (90, 101))	('associated', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
132194	33406793	The results showed that the phosphatidylinositol (PI) provides the greatest difference between concentrations of normal and tumor tissues (more than four times) for the analyzed patients, whereas PE species (P-36:4, P-38:5/O-38:6, and P-38:4/O-38:5) were more abundant in normal tissues.	('P-38:5/O-38:6', 'Var', (216, 229))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('phosphatidylinositol', 'MPA', (28, 48))	('P-38:4/O-38:5', 'Var', (235, 248))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (28, 48))	('patients', 'Species', '9606', (178, 186))	('tumor', 'Disease', (124, 129))	('P-36:4', 'Var', (208, 214))
132199	33406793	The ratios of C=C isomers may be used for the discovery of lipid biomarkers, as the position of the double bond (e.g., C18:1, the ratio between isomer Delta9 and Delta11 in PEs and PCs) within the individual PLs in BC tissue, is more related to the morphological changes of breast cancer, and demonstrates less interpersonal variability, thus being a reliable biomarker for disease progression.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('PLs', 'Chemical', 'MESH:D010743', (208, 211))	('C', 'Chemical', 'MESH:D002244', (216, 217))	('BC', 'Phenotype', 'HP:0003002', (215, 217))	('C18:1', 'Var', (119, 124))	('breast cancer', 'Disease', (274, 287))	('lipid', 'Chemical', 'MESH:D008055', (59, 64))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('PC', 'Gene', '5091', (181, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('Delta11', 'Mutation', 'c.del11', (162, 169))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('related', 'Reg', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('Delta11', 'Var', (162, 169))	('C', 'Chemical', 'MESH:D002244', (182, 183))
132204	33406793	Thus, PLs may have diagnostic potential as well as, modulation of their metabolism may provide therapeutic opportunities in BC.	('C', 'Chemical', 'MESH:D002244', (125, 126))	('modulation', 'Var', (52, 62))	('PLs', 'Chemical', 'MESH:D010743', (6, 9))	('BC', 'Phenotype', 'HP:0003002', (124, 126))	('metabolism', 'MPA', (72, 82))
132210	33406793	The easiest approach is the acquisition of the same spectra mixture in the negative ion mode, or the addition of ions, such as Cs+ or NH4+ to the mixture to facilitate ionization and shift the masses towards a higher region and discover overlapping signals.	('Cs+', 'Chemical', 'MESH:D002586', (127, 130))	('Cs+', 'Var', (127, 130))	('masses', 'MPA', (193, 199))	('ionization', 'MPA', (168, 178))	('NH4+', 'Chemical', '-', (134, 138))	('shift', 'PosReg', (183, 188))	('NH4+', 'Var', (134, 138))	('facilitate', 'PosReg', (157, 167))
132278	33406793	The most common CV test is the K-fold, which is based on a random partition of the original dataset into equal-sized subsamples (k); more specifically, the K-CV leave-one-out cross-validation (LOOCV) and the Monte Carlo cross-validation (MCCV), the former being used in small datasets.	('leave-one-out', 'Var', (161, 174))	('C', 'Chemical', 'MESH:D002244', (214, 215))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('K-CV', 'Var', (156, 160))	('C', 'Chemical', 'MESH:D002244', (239, 240))	('C', 'Chemical', 'MESH:D002244', (240, 241))	('C', 'Chemical', 'MESH:D002244', (196, 197))	('C', 'Chemical', 'MESH:D002244', (158, 159))
132306	33406793	Additionally, LPA is a mitogenic factor, that is overproduced in ovarian cancer cells, in an iPLA2-dependent manner, and inhibition of this enzyme suppresses the proliferation of ovarian cancer.	('iPLA2', 'Gene', '8398', (93, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (179, 193))	('LPA', 'Chemical', 'MESH:C032881', (14, 17))	('proliferation of ovarian cancer', 'Disease', 'MESH:C565054', (162, 193))	('LPA', 'Protein', (14, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('inhibition', 'Var', (121, 131))	('proliferation of ovarian cancer', 'Disease', (162, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('suppresses', 'NegReg', (147, 157))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('ovarian cancer', 'Disease', (65, 79))	('iPLA2', 'Gene', (93, 98))
132307	33406793	sPLA2 has an important role in the progression of various cancers, including BC, and its aberrant expression was associated with BC malignancy.	('BC', 'Phenotype', 'HP:0003002', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('sPLA2', 'Gene', '8399', (0, 5))	('aberrant', 'Var', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('BC malignancy', 'Disease', 'MESH:D009369', (129, 142))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('sPLA2', 'Gene', (0, 5))	('BC malignancy', 'Disease', (129, 142))	('associated', 'Reg', (113, 123))
132311	33406793	This statement is supported by the findings in which the inhibition of PLA2 sensitizes cancer cells towards further chemotherapy.	('cancer', 'Disease', (87, 93))	('sensitizes', 'Reg', (76, 86))	('inhibition', 'Var', (57, 67))	('PLA2', 'Gene', '8398', (71, 75))	('PLA2', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
132460	33752671	Ninety (29.3%) patients had high nuclear grade, and half (49.8%) had comedo necrosis.	('patients', 'Species', '9606', (15, 23))	('comedo', 'Phenotype', 'HP:0025249', (69, 75))	('necrosis', 'Disease', (76, 84))	('necrosis', 'Disease', 'MESH:D009336', (76, 84))	('high', 'Var', (28, 32))
132467	33752671	Furthermore, upstaged patients experienced comedo necrosis, ER and PR negativity, and high nuclear grade and Ki-67 labelling index more frequently.	('ER', 'Gene', '2069', (60, 62))	('patients', 'Species', '9606', (22, 30))	('comedo', 'Phenotype', 'HP:0025249', (43, 49))	('PR', 'Gene', '5241', (67, 69))	('necrosis', 'Disease', (50, 58))	('Ki-67', 'Protein', (109, 114))	('necrosis', 'Disease', 'MESH:D009336', (50, 58))	('high', 'Var', (86, 90))
132469	33752671	When grouped by diagnostic method, 53 (30.5%) of 174 patients diagnosed with core-needle biopsy were upstaged, while only five (4.0%) of 125 patients diagnosed with excisional biopsy were upstaged to invasive cancer (p < 0.001).	('core-needle biopsy', 'Var', (77, 95))	('patients', 'Species', '9606', (53, 61))	('invasive cancer', 'Disease', (200, 215))	('patients', 'Species', '9606', (141, 149))	('invasive cancer', 'Disease', 'MESH:D009362', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
132476	33752671	Preoperative tumour size, high-grade DCIS, and histological type of DCIS were not associated with increased risk of upstaging in our multivariate analysis.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('Preoperative tumour', 'Disease', (0, 19))	('Preoperative tumour', 'Disease', 'MESH:D009369', (0, 19))	('high-grade', 'Var', (26, 36))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
132509	33752671	According to the results of a nationwide study from the Danish Breast Cancer group, palpable DCIS, larger areas of DCIS, and younger age were associated with SLN metastasis.	('Breast Cancer', 'Phenotype', 'HP:0003002', (63, 76))	('SLN', 'Gene', (158, 161))	('DCIS', 'Disease', (93, 97))	('SLN', 'Gene', '6588', (158, 161))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Breast Cancer', 'Disease', (63, 76))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('associated', 'Reg', (142, 152))	('Breast Cancer', 'Disease', 'MESH:D001943', (63, 76))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('palpable', 'Var', (84, 92))
132582	28980458	Based on the optimal cut-off point, patients were stratified into two groups: low-ILI group with ILI <=5 scores and high-ILI group with ILI > 5 scores.	('ILI', 'Var', (97, 100))	('low-ILI', 'Disease', (78, 85))	('patients', 'Species', '9606', (36, 44))
132586	28980458	According to the Kaplan-Meier analysis, patients in the high-ILI group had significantly shorter DFS and OS compared with patients in the low-ILI groups (P < 0.001, Fig.	('high-ILI', 'Var', (56, 64))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (122, 130))	('shorter', 'NegReg', (89, 96))
132587	28980458	In the subgroup of patients without LNM, those in high-ILI group still had significant shorter DFS (shown in Fig.	('DFS', 'MPA', (95, 98))	('shorter', 'NegReg', (87, 94))	('patients', 'Species', '9606', (19, 27))	('high-ILI', 'Var', (50, 58))
132596	28980458	In a study of 301 consecutive cases of 1-14 mm invasive breast carcinomas, Tibor and his colleagues found that mutifocality of the invasive component was associated with a substantially elevated risk of vascular invasion and LNM 18.	('LNM 18', 'CPA', (225, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('breast carcinomas', 'Disease', 'MESH:D001943', (56, 73))	('breast carcinomas', 'Disease', (56, 73))	('mutifocality', 'Var', (111, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('breast carcinomas', 'Phenotype', 'HP:0003002', (56, 73))	('vascular invasion', 'CPA', (203, 220))
132602	28980458	As shown in our results, patients in the high-ILI group had a significantly higher incidence of LNM and shorter DFS and OS than those in the low-ILI group.	('LNM', 'Disease', (96, 99))	('shorter', 'NegReg', (104, 111))	('high-ILI', 'Var', (41, 49))	('patients', 'Species', '9606', (25, 33))	('DFS', 'CPA', (112, 115))
132710	22988516	This study shows that the presence of DCIS significantly affects the accuracy of measuring the sizes of malignant breast tumors when using either B-mode ultrasonography or real time elastography.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('malignant breast tumors', 'Disease', 'MESH:D001943', (104, 127))	('breast tumors', 'Disease', 'MESH:D001943', (114, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('malignant breast tumors', 'Disease', (104, 127))	('affects', 'Reg', (57, 64))	('breast tumor', 'Phenotype', 'HP:0100013', (114, 126))	('DCIS', 'Gene', (38, 42))	('presence', 'Var', (26, 34))	('breast tumors', 'Phenotype', 'HP:0100013', (114, 127))
132747	22295227	Little data is available, but ADH associated with DCIS has been reported to increase the risk of contralateral breast cancer above that of DCIS alone, and clear surgical margins at duct excision for ADH did not affect the risk of developing breast cancer.	('contralateral breast cancer', 'Disease', 'MESH:D001943', (97, 124))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('contralateral breast cancer', 'Disease', (97, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('ADH', 'Var', (30, 33))
132754	31073859	Some women have genetic mutations, making them more susceptible to develop breast cancer in their life.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('women', 'Species', '9606', (5, 10))	('genetic mutations', 'Var', (16, 33))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
132755	31073859	These include, for example, BRCA-1, BRCA-2, TP53, PALB2, CDH1, STK11, and PTEN gene mutations.	('STK11', 'Gene', (63, 68))	('PALB2', 'Gene', (50, 55))	('PALB2', 'Gene', '79728', (50, 55))	('BRCA-2', 'Gene', '675', (36, 42))	('mutations', 'Var', (84, 93))	('PTEN', 'Gene', (74, 78))	('STK11', 'Gene', '6794', (63, 68))	('CDH1', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (44, 48))	('PTEN', 'Gene', '5728', (74, 78))	('BRCA-2', 'Gene', (36, 42))	('BRCA-1', 'Gene', (28, 34))	('TP53', 'Gene', (44, 48))	('BRCA-1', 'Gene', '672', (28, 34))	('CDH1', 'Gene', '999', (57, 61))
132784	31073859	In our national guidelines, annual breast MRI screening is recommended for most women with a known genetic predisposition for developing breast cancer, such as BRCA-1, BRCA-2, TP53, PALB2, CDH1, STK11, and PTEN gene mutations.	('STK11', 'Gene', (195, 200))	('CDH1', 'Gene', '999', (189, 193))	('TP53', 'Gene', '7157', (176, 180))	('PALB2', 'Gene', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('women', 'Species', '9606', (80, 85))	('CDH1', 'Gene', (189, 193))	('BRCA-2', 'Gene', '675', (168, 174))	('STK11', 'Gene', '6794', (195, 200))	('PALB2', 'Gene', '79728', (182, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('BRCA-1', 'Gene', (160, 166))	('BRCA-2', 'Gene', (168, 174))	('BRCA-1', 'Gene', '672', (160, 166))	('TP53', 'Gene', (176, 180))	('PTEN', 'Gene', (206, 210))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('mutations', 'Var', (216, 225))	('PTEN', 'Gene', '5728', (206, 210))
132824	30682163	In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-to-hip-ratio (WHR), and >=10 years of oral contraceptive use between DCIS and invasive disease.	('obese', 'Disease', (110, 115))	('invasive disease', 'Disease', (210, 226))	('invasive disease', 'Disease', 'MESH:D009362', (210, 226))	('CIS', 'Phenotype', 'HP:0030075', (202, 205))	('obese', 'Disease', 'MESH:D009765', (110, 115))	('DCIS', 'Phenotype', 'HP:0030075', (201, 205))	('high', 'Var', (121, 125))	('high waist-to-hip-ratio', 'Phenotype', 'HP:0031819', (121, 144))
132875	30682163	Physical activity was inversely associated with invasive disease and was not associated with DCIS.	('associated', 'Interaction', (32, 42))	('Physical', 'Var', (0, 8))	('inversely', 'NegReg', (22, 31))	('invasive disease', 'Disease', (48, 64))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('invasive disease', 'Disease', 'MESH:D009362', (48, 64))	('CIS', 'Phenotype', 'HP:0030075', (94, 97))
132889	30682163	The literature on BMI and risk of DCIS are consistent with our results in that high BMI has been associated with decreased DCIS risk and increased risk of invasive disease, particularly among postmenopausal women.	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('invasive disease', 'Disease', (155, 171))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('women', 'Species', '9606', (207, 212))	('high', 'Var', (79, 83))	('invasive disease', 'Disease', 'MESH:D009362', (155, 171))	('BMI', 'Gene', (84, 87))	('CIS', 'Phenotype', 'HP:0030075', (35, 38))	('CIS', 'Phenotype', 'HP:0030075', (124, 127))	('DCIS', 'Disease', (123, 127))	('decreased', 'NegReg', (113, 122))
132961	27071351	A difficult challenge, therefore, is to avoid preferential detection of indolent (slowgrowing) cancers that might not otherwise come to clinical attention; detection of these cancers might increase the incidence of early stage cancers, but is unlikely to substantially reduce the incidence of advancedstage cancers because they would probably never progress to such a stage during the patient's lifetime.	('advancedstage cancers', 'Disease', 'MESH:D009369', (293, 314))	('reduce', 'NegReg', (269, 275))	('increase', 'PosReg', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('detection', 'Var', (156, 165))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('stage cancers', 'Disease', 'MESH:D009369', (221, 234))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('stage cancers', 'Disease', 'MESH:D009369', (301, 314))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('stage cancers', 'Disease', (221, 234))	('cancers', 'Disease', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('advancedstage cancers', 'Disease', (293, 314))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('cancers', 'Disease', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('patient', 'Species', '9606', (385, 392))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))
132962	27071351	Herein lies a potential harm of screening: in addition to the intrinsic risk of falsenegative and falsepositive results owing to the imperfect sensitivity and specificity of the screening tests, screening incurs 'overdiagnosis', defined as the detection of cancerous lesions that would not have caused morbidity or mortality.	('cancerous lesions', 'Disease', 'MESH:D009062', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('screening', 'Var', (195, 204))	('cancerous lesions', 'Disease', (257, 274))	("'overdiagnosis'", 'Disease', (212, 227))	('incurs', 'Reg', (205, 211))
133000	27071351	Polypectomy to remove colonic polyps can rarely be complicated by bleeding or colonic perforation, and colonoscopy can commonly lead to abdominal pain and bloating.	('bleeding', 'Disease', (66, 74))	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('abdominal pain', 'Phenotype', 'HP:0002027', (136, 150))	('abdominal pain', 'Disease', 'MESH:D015746', (136, 150))	('colonoscopy', 'Var', (103, 114))	('bloating', 'Disease', (155, 163))	('colonic polyps', 'Disease', (22, 36))	('colonic perforation', 'Phenotype', 'HP:0031369', (78, 97))	('colonic polyps', 'Disease', 'MESH:D003111', (22, 36))	('bloating', 'Phenotype', 'HP:0003270', (155, 163))	('bleeding', 'Disease', 'MESH:D006470', (66, 74))	('lead to', 'Reg', (128, 135))	('abdominal pain', 'Disease', (136, 150))
133013	27071351	Lowgrade DCIS, even if untreated, is unlikely to cause breastcancerspecific mortality: a recent study reported 10year survival of 98.8% for women with untreated lowgrade DCIS, and 98.6% for those in whom lowgrade DCIS was surgically excised.	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('lowgrade', 'Var', (161, 169))	('cancers', 'Disease', (61, 68))	('women', 'Species', '9606', (140, 145))	('DCIS', 'Phenotype', 'HP:0030075', (170, 174))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
133020	27071351	In metaanalyses of screening trials, investigators have reported a decrease in diseasespecific mortality associated with screening for breast cancer of approximately 20%, although the mortality reduction varies by age: the absolute mortality reduction at 10 years is greatest in women aged 60-69 years (21 deaths per 10,000 women), and lowest in those aged 40-49 years (3 deaths per 10,000 women).	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('decrease', 'NegReg', (67, 75))	('reduction', 'NegReg', (242, 251))	('women', 'Species', '9606', (390, 395))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('diseasespecific mortality', 'MPA', (79, 104))	('screening', 'Var', (121, 130))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('women', 'Species', '9606', (279, 284))	('women', 'Species', '9606', (324, 329))
133044	27071351	Additionally, a normal serum PSA level (typically below 4 ng/ml) does not exclude the possibility of prostate cancer: in the Prostate Cancer Prevention Trial, 42.4% of all cancers with Gleason score >=7 occurred in men with PSA values of <=3 ng/ml.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Gleason', 'Var', (185, 192))	('prostate cancer', 'Disease', (101, 116))	('PSA', 'Gene', '354', (224, 227))	('PSA', 'Gene', (224, 227))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (125, 140))	('men', 'Species', '9606', (215, 218))	('PSA', 'Gene', '354', (29, 32))	('PSA', 'Gene', (29, 32))	('Prostate Cancer', 'Disease', 'MESH:D011471', (125, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('cancers', 'Disease', (172, 179))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('Prostate Cancer', 'Disease', (125, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))
133113	27071351	A polygenic risk score based on 76 single nucleotide polymorphisms (SNPs) has been shown to independently predict breast-cancer risk, and improved riskprediction when incorporated into the existing BCSC model.	('breast-cancer', 'Disease', 'MESH:D001943', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('single nucleotide polymorphisms', 'Var', (35, 66))	('improved', 'PosReg', (138, 146))	('breast-cancer', 'Disease', (114, 127))	('predict', 'Reg', (106, 113))
133142	27071351	Lowhistologicalgrade DCIS, as defined by pathologists, is probably a risk factor for the development of such indolent cancers, and this disease entity closely matches the definition of indolent lesions of epithelial origin, or 'IDLE' conditions, that was proposed by the working group convened by the NCI.	('men', 'Species', '9606', (96, 99))	('cancers', 'Disease', (118, 125))	('Lowhistologicalgrade', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
133154	27071351	For instance, lowgrade DCIS is more likely to be an indicator for an increased risk of future invasive cancer, similarly to its closely related pathological entity atypical ductal hyperplasia, rather than an indication for immediate surgery and radiation therapy; a potentially better alternative is to consider these lesions as an opportunity for prevention, using selective oestrogenreceptor modulators or aromatase inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (173, 191))	('ductal hyperplasia', 'Disease', (173, 191))	('invasive cancer', 'Disease', (94, 109))	('lowgrade', 'Var', (14, 22))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('invasive cancer', 'Disease', 'MESH:D009362', (94, 109))
133187	29532604	The Role of Non-coding RNAs and Isothiocyanates in Cancer Cancer is the second leading cause of mortalities in the United States, only exceeded by heart disease.	('Isothiocyanates', 'Chemical', 'MESH:D017879', (32, 47))	('heart disease', 'Disease', (147, 160))	('Isothiocyanates', 'Var', (32, 47))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (51, 57))	('Non-coding', 'Var', (12, 22))	('heart disease', 'Disease', 'MESH:D006331', (147, 160))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))
133202	29532604	While some epigenetic modifications have a role in cellular differentiation and numerous other biological processes, major epigenetic modifications can result in an increase in chronic diseases such as cancer.	('result in', 'Reg', (152, 161))	('increase', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('epigenetic modifications', 'Var', (123, 147))	('cellular differentiation', 'CPA', (51, 75))	('epigenetic modifications', 'Var', (11, 35))	('chronic diseases', 'Disease', (177, 193))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('chronic diseases', 'Disease', 'MESH:D002908', (177, 193))	('cancer', 'Disease', (202, 208))
133204	29532604	ncRNAs include microRNAs (miRs), small interfering RNAs (siRNAs), piwi interacting RNAs (piRNAs) and long non-coding RNAs (lncRNAs).	('piwi', 'Gene', '9271', (66, 70))	('small interfering', 'Var', (33, 50))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('piwi', 'Gene', (66, 70))
133220	29532604	lncRNAs are the largest of the non-coding RNAs with approximate base pair lengths greater than 200. lncRNAs have gained widespread attention and have been attributed to playing a key role in biological regulation and are numerous amounting to several thousand in comparison to the 5000 discovered miRNAs.	('miR', 'Gene', '220972', (297, 300))	('miR', 'Gene', (297, 300))	('lncRNAs', 'Var', (100, 107))
133227	29532604	Studies have reported that overcooking and/or boiling cruciferous vegetables could result in glucosinolate content.	('glucosinolate content', 'MPA', (93, 114))	('overcooking', 'Var', (27, 38))	('boiling', 'Phenotype', 'HP:0020083', (46, 53))	('glucosinolate', 'Chemical', 'MESH:D005961', (93, 106))	('result in', 'Reg', (83, 92))
133254	29532604	SFN has also been documented to significantly alter miR expression profiles in nontransformed human epithelial cells.	('miR', 'Gene', '220972', (52, 55))	('human', 'Species', '9606', (94, 99))	('alter', 'Reg', (46, 51))	('miR', 'Gene', (52, 55))	('SFN', 'Chemical', 'MESH:C016766', (0, 3))	('SFN', 'Var', (0, 3))
133273	29532604	BITC has been documented to inhibit cancer in many animal models and BITC has also demonstrated strong anti-cancer effects via HDAC inhibition in pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('inhibit', 'NegReg', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('inhibition', 'NegReg', (132, 142))	('cancer', 'Disease', (36, 42))	('pancreatic cancer', 'Disease', (146, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('HDAC', 'MPA', (127, 131))	('BITC', 'Var', (69, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('BITC', 'Chemical', 'MESH:C031403', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (157, 163))	('BITC', 'Chemical', 'MESH:C031403', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
133275	29532604	For example, miR-375, known to function as a tumor suppressor in pancreatic cancer cells, was significantly upregulated by BITC treatments.	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('BITC treatments', 'Var', (123, 138))	('BITC', 'Chemical', 'MESH:C031403', (123, 127))	('pancreatic cancer', 'Disease', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-375', 'Gene', '494324', (13, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('miR-375', 'Gene', (13, 20))	('upregulated', 'PosReg', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
133281	29532604	For example, Lai and colleagues found AITC to be capable of inhibiting migratory ability of colorectal cancer cells (CRCs).	('inhibiting', 'NegReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('migratory ability', 'CPA', (71, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('AITC', 'Var', (38, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('AITC', 'Chemical', 'MESH:C004471', (38, 42))	('colorectal cancer', 'Disease', (92, 109))
133283	29532604	Other investigators have reported AITC to induce reactive oxygen species while decreasing mitochondrial membrane potential in breast cancer cells.	('mitochondrial membrane potential', 'MPA', (90, 122))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('induce', 'PosReg', (42, 48))	('breast cancer', 'Disease', (126, 139))	('reactive oxygen species', 'MPA', (49, 72))	('decreasing', 'NegReg', (79, 89))	('AITC', 'Var', (34, 38))	('AITC', 'Chemical', 'MESH:C004471', (34, 38))	('decreasing mitochondrial membrane', 'Phenotype', 'HP:0040013', (79, 112))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
133287	29532604	Further, AITC caused Bcl-2 phosphorylation thereby nullifying Bcl-2's protective properties by allowing lipid peroxidation.	('Bcl-2', 'Gene', (62, 67))	('Bcl-2', 'Gene', (21, 26))	('Bcl-2', 'Gene', '596', (62, 67))	('AITC', 'Var', (9, 13))	('protective properties', 'MPA', (70, 91))	('caused', 'Reg', (14, 20))	('allowing', 'Reg', (95, 103))	('AITC', 'Chemical', 'MESH:C004471', (9, 13))	('phosphorylation', 'MPA', (27, 42))	('nullifying', 'NegReg', (51, 61))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('lipid peroxidation', 'MPA', (104, 122))	('Bcl-2', 'Gene', '596', (21, 26))
133291	29532604	In 2012, Wagner and colleagues reported AITC to be capable of decreasing TNFalpha and pro-inflammatory markers.	('AITC', 'Var', (40, 44))	('AITC', 'Chemical', 'MESH:C004471', (40, 44))	('TNFalpha', 'Gene', (73, 81))	('decreasing', 'NegReg', (62, 72))	('pro-inflammatory markers', 'MPA', (86, 110))	('TNFalpha', 'Gene', '7124', (73, 81))
133301	29532604	It was shown that PEITC is involved in the inhibition of androgen receptor transcriptional activity, which when mutated causes prostate cancer cell progression.	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('androgen receptor', 'Gene', '367', (57, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('causes', 'Reg', (120, 126))	('inhibition', 'NegReg', (43, 53))	('prostate cancer', 'Disease', (127, 142))	('androgen receptor', 'Gene', (57, 74))	('mutated', 'Var', (112, 119))	('PEITC', 'Chemical', 'MESH:C058305', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
133352	23477322	(Figure 1) A treatment that kills pre-invasive breast lesions follows the same rationale used for the prevention of a) colorectal cancer by colon polypectomy, and b) cervical cancer by ablating cervical dysplasia.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cervical dysplasia', 'Disease', (194, 212))	('colorectal cancer', 'Disease', (119, 136))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (130, 136))	('ablating', 'Var', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cervical dysplasia', 'Disease', 'MESH:D002575', (194, 212))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (194, 212))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
133357	23477322	Necrosis can be a prominent feature of low and high grade DCIS, and the degree of necrosis correlates with the probability of invasive cancer.	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('Necrosis', 'Disease', 'MESH:D009336', (0, 8))	('Necrosis', 'Disease', (0, 8))	('invasive cancer', 'Disease', (126, 141))	('low', 'Var', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('invasive cancer', 'Disease', 'MESH:D009362', (126, 141))	('necrosis', 'Disease', (82, 90))
133377	23477322	Hydroxylated HIFalpha is recognized by the von Hippel Lindau tumor suppressor (VHL) and thereby targeted for proteasomal degradation.	('Hydroxylated', 'Var', (0, 12))	('HIFalpha', 'Gene', (13, 21))	('VHL', 'Disease', 'MESH:D006623', (79, 82))	('VHL', 'Disease', (79, 82))	('von Hippel Lindau tumor suppressor', 'Gene', '7428', (43, 77))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('von Hippel Lindau tumor suppressor', 'Gene', (43, 77))
133381	23477322	Consequently pre-invasive cells that adapt to living in a state of hypoxia can proliferate in the presence of genetic mutations that drive tumor progression and induce or de-repress invasion.	('de-repress', 'NegReg', (171, 181))	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('induce', 'Reg', (161, 167))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('invasion', 'CPA', (182, 190))
133396	23477322	For this reason, high grade DCIS is associated with central necrosis, and the accumulation of lipofuschin and calcium.	('necrosis', 'Disease', 'MESH:D009336', (60, 68))	('calcium', 'CPA', (110, 117))	('high grade', 'Var', (17, 27))	('lipofuschin', 'Protein', (94, 105))	('lipofuschin', 'Chemical', '-', (94, 105))	('necrosis', 'Disease', (60, 68))	('associated', 'Reg', (36, 46))	('calcium', 'Chemical', 'MESH:D002118', (110, 117))	('accumulation', 'PosReg', (78, 90))
133410	23477322	Beyond breast cancer treatment, CQ therapy has also been shown to reduce lymphoma progression, suppress melanoma invasion and arrest pancreatic cancer in animal models, and has been employed in clinical trials of glioblastoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('CQ therapy', 'Var', (32, 42))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('glioblastoma', 'Disease', (213, 225))	('suppress', 'NegReg', (95, 103))	('lymphoma', 'Disease', (73, 81))	('breast cancer', 'Disease', (7, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (213, 225))	('melanoma invasion and arrest pancreatic cancer', 'Disease', 'MESH:C563985', (104, 150))	('CQ', 'Chemical', 'MESH:D002738', (32, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))	('lymphoma', 'Disease', 'MESH:D008223', (73, 81))	('reduce', 'NegReg', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
133421	23477322	Outcome measures, post versus pre therapy, are a) reduction in DCIS lesion volume by MRI b) pathologic regression, c) the reduction or elimination of genetically abnormal tumorigenic DCIS stem like cells, d) and the suppression of cellular proliferation, induction of apoptosis, or disruption of autophagy, as measured by changes in proteomic markers in the post treatment versus the pre-treatment specimen.	('genetically abnormal', 'Var', (150, 170))	('DCIS', 'Disease', (63, 67))	('reduction', 'NegReg', (50, 59))	('autophagy', 'CPA', (296, 305))	('changes', 'Reg', (322, 329))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cellular proliferation', 'CPA', (231, 253))	('apoptosis', 'CPA', (268, 277))	('elimination', 'NegReg', (135, 146))	('reduction', 'NegReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('suppression', 'NegReg', (216, 227))	('DCIS', 'Gene', (183, 187))
133435	23477322	In contrast, microcalcifications restricted to the lobules, and not the ductal tree, are almost always associated with benign disease such as microcystic adenosis.	('microcystic adenosis', 'Disease', 'MESH:D005348', (142, 162))	('microcalcifications', 'Var', (13, 32))	('microcystic adenosis', 'Disease', (142, 162))	('associated', 'Reg', (103, 113))
133445	23477322	Alterations in intracellular calcium (Ca+2) serve as important signals that modulate many cellular processes.	('modulate', 'Reg', (76, 84))	('cellular', 'CPA', (90, 98))	('calcium', 'Chemical', 'MESH:D002118', (29, 36))	('Alterations', 'Var', (0, 11))	('Ca+2', 'Chemical', 'MESH:D000069285', (38, 42))
133450	23477322	A specific splice variant of the PMCA2 gene, PMCA2wb, which traffics to the apical membrane, is greatly upregulated in the breast at the onset of lactation, and the loss of PMCA2 reduces milk Ca2+ by 60-70%.	('reduces', 'NegReg', (179, 186))	('PMCA2', 'Gene', (45, 50))	('lactation', 'Disease', (146, 155))	('PMCA2', 'Gene', '491', (45, 50))	('upregulated', 'PosReg', (104, 115))	('Ca2', 'Gene', '760', (192, 195))	('PMCA2', 'Gene', '491', (173, 178))	('PMCA2', 'Gene', (33, 38))	('lactation', 'Disease', 'MESH:D007775', (146, 155))	('PMCA2', 'Gene', (173, 178))	('PMCA2', 'Gene', '491', (33, 38))	('loss', 'Var', (165, 169))	('Ca2', 'Gene', (192, 195))
133469	23477322	However, a significant distinction is that in normal cells, vitamin D induces a transient rise in intracellular calcium levels, while in breast cancer cell lines, it induces a sustained increase in intracellular calcium and induces cell-cycle arrest in malignant breast cells, but not normal mammary epithelium in culture.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('intracellular calcium levels', 'MPA', (98, 126))	('cell-cycle arrest', 'CPA', (232, 249))	('breast cancer', 'Disease', (137, 150))	('rise', 'PosReg', (90, 94))	('increase', 'PosReg', (186, 194))	('induces', 'Reg', (224, 231))	('calcium', 'Chemical', 'MESH:D002118', (112, 119))	('calcium', 'Chemical', 'MESH:D002118', (212, 219))	('vitamin D', 'Var', (60, 69))	('intracellular calcium', 'MPA', (198, 219))	('vitamin D', 'Chemical', 'MESH:D014807', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
133492	23477322	A treatment that kills pre-invasive breast lesions follows the same rationale used for the prevention of a) colorectal cancer by colon polypectomy, and b) cervical cancer by ablating cervical dysplasia.	('ablating', 'Var', (174, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cervical dysplasia', 'Disease', (183, 201))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cervical dysplasia', 'Disease', 'MESH:D002575', (183, 201))	('colorectal cancer', 'Disease', (108, 125))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (183, 201))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
133546	29374150	Whereas, alpha-SMA and FSP1 expressions were increased in NFs which knock down of miR-200b/c (Fig.	('FSP1', 'Gene', (23, 27))	('alpha-SMA', 'Protein', (9, 18))	('FSP1', 'Gene', '6275', (23, 27))	('increased', 'PosReg', (45, 54))	('miR-200b/c', 'Gene', '406985;406984', (82, 92))	('miR-200b/c', 'Gene', (82, 92))	('expressions', 'MPA', (28, 39))	('knock down', 'Var', (68, 78))
133556	29374150	Using luciferase assay, the 3'-UTR of IKKbeta was consolidated to be suppressed by miR-200b/c and mutation of the binding sites in the 3'-UTR of IKKbeta impaired the responsiveness of IKKbeta to miR-200b/c (Fig.	("3'-UTR", 'MPA', (28, 34))	('mutation', 'Var', (98, 106))	('IKKbeta', 'Gene', (38, 45))	('impaired', 'NegReg', (153, 161))	('IKKbeta', 'Gene', (145, 152))	('responsiveness', 'MPA', (166, 180))	('IKKbeta', 'Gene', '3551', (38, 45))	('IKKbeta', 'Gene', (184, 191))	('binding', 'Interaction', (114, 121))	('miR-200b/c', 'Gene', (195, 205))	('miR-200b/c', 'Gene', '406985;406984', (195, 205))	('IKKbeta', 'Gene', '3551', (145, 152))	('IKKbeta', 'Gene', '3551', (184, 191))	('miR-200b/c', 'Gene', '406985;406984', (83, 93))	('miR-200b/c', 'Gene', (83, 93))
133559	29374150	The IKKbeta is critical to NF-kappaB activity via phosphorylating IkappaBalpha in translocation of P65 into the nucleus, indicating that loss of miR-200b/c in fibroblasts during the process of breast tumor initiation may be accompanied with activation of NF-kappaB.	('miR-200b/c', 'Gene', '406985;406984', (145, 155))	('miR-200b/c', 'Gene', (145, 155))	('translocation', 'MPA', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('IKKbeta', 'Gene', (4, 11))	('breast tumor initiation', 'Disease', 'MESH:D001943', (193, 216))	('IkappaBalpha', 'Gene', (66, 78))	('breast tumor initiation', 'Disease', (193, 216))	('IKKbeta', 'Gene', '3551', (4, 11))	('NF-kappaB', 'Gene', '4790', (255, 264))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (255, 264))	('NF-kappaB', 'Gene', (27, 36))	('loss', 'Var', (137, 141))	('breast tumor', 'Phenotype', 'HP:0100013', (193, 205))	('P65', 'Gene', '5970', (99, 102))	('IkappaBalpha', 'Gene', '4792', (66, 78))	('P65', 'Gene', (99, 102))
133562	29374150	Further, IKKbeta, p-IkappaBalpha, and nuclear P65 protein levels in AHFs were upregulated by knockdown of miR-200b/c (Supplementary Fig.	('knockdown', 'Var', (93, 102))	('IkappaBalpha', 'Gene', (20, 32))	('upregulated', 'PosReg', (78, 89))	('IKKbeta', 'Gene', (9, 16))	('miR-200b/c', 'Gene', '406985;406984', (106, 116))	('IkappaBalpha', 'Gene', '4792', (20, 32))	('P65', 'Gene', '5970', (46, 49))	('AH', 'Disease', 'MESH:D007039', (68, 70))	('P65', 'Gene', (46, 49))	('IKKbeta', 'Gene', '3551', (9, 16))	('miR-200b/c', 'Gene', (106, 116))
133579	29374150	These data support that NF-kappaB activity induces the activated fibroblasts in the process of breast tumor initiation.	('breast tumor', 'Phenotype', 'HP:0100013', (95, 107))	('activity', 'Var', (34, 42))	('NF-kappaB', 'Gene', '4790', (24, 33))	('breast tumor initiation', 'Disease', 'MESH:D001943', (95, 118))	('breast tumor initiation', 'Disease', (95, 118))	('NF-kappaB', 'Gene', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('induces', 'PosReg', (43, 50))
133587	29374150	Our above findings disclosed that activated fibroblasts could endow MCF-7 with strong cell proliferation potential and induce cell polarity change under co-culture system (Fig.	('MCF-7', 'CellLine', 'CVCL:0031', (68, 73))	('MCF-7', 'Gene', (68, 73))	('cell polarity change', 'CPA', (126, 146))	('endow', 'Var', (62, 67))	('cell proliferation potential', 'CPA', (86, 114))	('induce', 'Reg', (119, 125))
133589	29374150	6d, compared with the MCF-7 alone, addition of the recombinant PAI-1 into the supernatant of MCF-7 (MCF-7/PAI-1) could notably increase cell proliferation of MCF-7; similarly, application of the recombinant PAI-1 into the supernatant of NFs, or PAI-1 inhibitor tiplaxtinin (Tipla) into the supernatant of CAFs, or knockdown of PAI-1 expression by the specific shRNA in CAFs (Supplementary Fig.	('PAI-1', 'Gene', '5054', (245, 250))	('PAI-1', 'Gene', (63, 68))	('PAI-1', 'Gene', '5054', (207, 212))	('MCF-7/PAI-1', 'Gene', '5054', (100, 111))	('cell proliferation', 'CPA', (136, 154))	('PAI-1', 'Gene', (245, 250))	('PAI-1', 'Gene', (207, 212))	('MCF-7', 'CellLine', 'CVCL:0031', (158, 163))	('knockdown', 'Var', (314, 323))	('MCF-7', 'CellLine', 'CVCL:0031', (93, 98))	('MCF-7', 'CellLine', 'CVCL:0031', (22, 27))	('expression', 'MPA', (333, 343))	('MCF-7', 'CellLine', 'CVCL:0031', (100, 105))	('PAI-1', 'Gene', '5054', (106, 111))	('CAFs', 'Gene', (369, 373))	('tiplaxtinin', 'Chemical', 'MESH:C488103', (261, 272))	('MCF-7/PAI-1', 'Gene', (100, 111))	('CAFs', 'Gene', '6899', (369, 373))	('CAFs', 'Gene', (305, 309))	('PAI-1', 'Gene', '5054', (327, 332))	('PAI-1', 'Gene', (106, 111))	('CAFs', 'Gene', '6899', (305, 309))	('increase', 'PosReg', (127, 135))	('PAI-1', 'Gene', (327, 332))	('PAI-1', 'Gene', '5054', (63, 68))
133591	29374150	Furthermore, adding recombinant PAI-1 into the supernatant of AHFs stimulated cell proliferation MCF-7; silencing PAI-1 expression or inhibition of PAI-1 activation using shRNA or tiplaxtinin obviously declined proliferation of MCF-7 in the co-culture system (Supplementary Fig.	('PAI-1', 'Gene', '5054', (148, 153))	('tiplaxtinin', 'Chemical', 'MESH:C488103', (180, 191))	('silencing', 'Var', (104, 113))	('PAI-1', 'Gene', '5054', (114, 119))	('PAI-1', 'Gene', '5054', (32, 37))	('proliferation', 'CPA', (211, 224))	('inhibition', 'NegReg', (134, 144))	('PAI-1', 'Gene', (148, 153))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))	('AH', 'Disease', 'MESH:D007039', (62, 64))	('PAI-1', 'Gene', (114, 119))	('declined', 'NegReg', (202, 210))	('PAI-1', 'Gene', (32, 37))	('MCF-7', 'CellLine', 'CVCL:0031', (228, 233))	('cell', 'CPA', (78, 82))
133597	29374150	Similarly, addition of PAI-1 to the supernatant from AHFs destroyed the cell polarity of MCF-7 and promoted invasion of MFC-7; and loss of PAI-1 or inhibition of PAI-1 activity in supernatant from AHFs had a benefit to maintain the cell polarity of MCF-7 and reduced its cell invasion (Supplementary Fig.	('MCF-7', 'CellLine', 'CVCL:0031', (89, 94))	('PAI-1', 'Gene', '5054', (23, 28))	('AH', 'Disease', 'MESH:D007039', (197, 199))	('AH', 'Disease', 'MESH:D007039', (53, 55))	('PAI-1', 'Gene', (23, 28))	('cell polarity', 'CPA', (232, 245))	('cell invasion', 'CPA', (271, 284))	('activity', 'MPA', (168, 176))	('cell polarity', 'CPA', (72, 85))	('maintain', 'PosReg', (219, 227))	('PAI-1', 'Gene', '5054', (162, 167))	('inhibition', 'NegReg', (148, 158))	('PAI-1', 'Gene', '5054', (139, 144))	('loss', 'Var', (131, 135))	('PAI-1', 'Gene', (162, 167))	('MCF-7', 'CellLine', 'CVCL:0031', (249, 254))	('destroyed', 'NegReg', (58, 67))	('PAI-1', 'Gene', (139, 144))	('promoted', 'PosReg', (99, 107))	('reduced', 'NegReg', (259, 266))	('invasion', 'CPA', (108, 116))
133614	29374150	The miR-200 family consisting of five members (miR-200a, -200b, -200c, -141, and -429) is an emerging miRNA family that has been shown to play crucial roles in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('miR-200', 'Gene', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('miR-200a', 'Var', (47, 55))
133615	29374150	Recent research done in our laboratory reveal that miR-200 families (miR-200a, -141, -200b, and -200c) are generally downregulated in activated CAFs, and act as direct mediators for NFs reprogramming into CAFs and ECM remodeling.	('CAFs', 'Gene', '6899', (205, 209))	('CAFs', 'Gene', (144, 148))	('miR-200', 'Gene', (51, 58))	('and -200c', 'Var', (92, 101))	('reprogramming', 'CPA', (186, 199))	('CAFs', 'Gene', '6899', (144, 148))	('CAFs', 'Gene', (205, 209))	('downregulated', 'NegReg', (117, 130))
133617	29374150	Importantly, NFs knocked down with miR-200b/c could be primed and differentiated into CAF-like fibroblasts, which have the characteristics of enhanced alpha-SMA and FSP1, and strong growth and invasion abilities.	('growth', 'CPA', (182, 188))	('knocked down', 'Var', (17, 29))	('FSP1', 'Gene', (165, 169))	('FSP1', 'Gene', '6275', (165, 169))	('CAF', 'Gene', (86, 89))	('enhanced', 'PosReg', (142, 150))	('invasion abilities', 'CPA', (193, 211))	('alpha-SMA', 'Protein', (151, 160))	('CAF', 'Gene', '8850', (86, 89))	('miR-200b/c', 'Gene', '406985;406984', (35, 45))	('miR-200b/c', 'Gene', (35, 45))
133669	29374150	Antibodies against alpha-SMA (1:1000; Abcam), FSP1 (1:800; Abcam), E-cadherin (1:800; Bioworld), Vimentin (1:4000; Abcam), IKKbeta (1:1000; Abcam), IkappaBalpha (1:1000; Abcam), P65 (1:5000; Abcam), p-IkappaBalpha (1:2000; RabMAb), H3 (1:2000; RabMAb), and GAPDH (1:5000; Abcam).	('IKKbeta', 'Gene', (123, 130))	('IkappaBalpha', 'Gene', '4792', (201, 213))	('IkappaBalpha', 'Gene', '4792', (148, 160))	('Vimentin', 'Gene', (97, 105))	('H3', 'Gene', '126961', (232, 234))	('GAPDH', 'Gene', '2597', (257, 262))	('GAPDH', 'Gene', (257, 262))	('E-cadherin', 'Gene', (67, 77))	('P65', 'Gene', (178, 181))	('E-cadherin', 'Gene', '999', (67, 77))	('IKKbeta', 'Gene', '3551', (123, 130))	('1:4000', 'Var', (107, 113))	('P65', 'Gene', '5970', (178, 181))	('IkappaBalpha', 'Gene', (201, 213))	('IkappaBalpha', 'Gene', (148, 160))	('Vimentin', 'Gene', '7431', (97, 105))	('FSP1', 'Gene', '6275', (46, 50))	('FSP1', 'Gene', (46, 50))
133719	27837296	In general, high-grade and ER-negative tumors were more likely to recur, however there were insufficient events to confirm this.	('insufficient', 'Disease', 'MESH:D000309', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('ER', 'Gene', '2099', (27, 29))	('insufficient', 'Disease', (92, 104))	('high-grade', 'Var', (12, 22))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))
133752	10408407	Expression of Ki-67, c-erbB2 and p53 was generally low, and that of ER, PR and Bcl-2 high.	('PR', 'Gene', '5241', (72, 74))	('c-erbB2', 'Gene', (21, 28))	('Expression', 'MPA', (0, 10))	('Ki-67', 'Var', (14, 19))	('low', 'NegReg', (51, 54))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('Bcl-2', 'Gene', (79, 84))	('c-erbB2', 'Gene', '2064', (21, 28))	('Bcl-2', 'Gene', '596', (79, 84))
133765	27713176	HER2 is normally expressed on all breast epithelial cells, but HER2 gene (ERBB2) amplification and/or HER2 protein overexpression is detected in approximately 15%-20% of breast cancers and associated with more aggressive disease progression, metastasis, and a poorer prognosis.	('more', 'PosReg', (205, 209))	('ERBB2', 'Gene', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('metastasis', 'CPA', (242, 252))	('associated with', 'Reg', (189, 204))	('HER2 protein', 'Protein', (102, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (170, 184))	('protein', 'Protein', (107, 114))	('amplification', 'Var', (81, 94))	('aggressive disease', 'Disease', 'MESH:D001523', (210, 228))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancers', 'Disease', 'MESH:D001943', (170, 184))	('breast cancers', 'Disease', (170, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('aggressive disease', 'Disease', (210, 228))	('overexpression', 'PosReg', (115, 129))	('ERBB2', 'Gene', '2064', (74, 79))
133772	27713176	The authors concluded that there was no significant correlation between ERBB2 copy number and trastuzumab benefit.	('ERBB2', 'Gene', (72, 77))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('copy number', 'Var', (78, 89))	('ERBB2', 'Gene', '2064', (72, 77))
133775	27713176	One emerging hypothesis is that aberrant HER2 signaling, rather than increased HER2 expression, may account for the clinical benefit of HER2 targeted therapy in some HER2- breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (172, 186))	('HER2- breast cancers', 'Disease', (166, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('HER2- breast cancers', 'Disease', 'MESH:D001943', (166, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('aberrant', 'Var', (32, 40))	('HER2', 'Protein', (41, 45))
133777	27713176	Recent data also suggests that expression of NRG1b, a cognate ligand for HER3 and HER4, is associated with HER2 activation in HER2- tumors.	('HER2- tumors', 'Disease', (126, 138))	('HER3', 'Gene', (73, 77))	('HER4', 'Gene', (82, 86))	('NRG1b', 'Gene', (45, 50))	('HER2', 'Protein', (107, 111))	('activation', 'PosReg', (112, 122))	('HER4', 'Gene', '2066', (82, 86))	('HER3', 'Gene', '2065', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'Var', (31, 41))	('HER2- tumors', 'Disease', 'MESH:D009369', (126, 138))	('associated', 'Reg', (91, 101))
133817	27713176	CELx HSP curves representing primary tumor samples that have high (R39) and low (R58) HER2 signaling activities are shown in Figure 3A.	('CELx', 'Chemical', '-', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('HER2', 'Protein', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('R39', 'Var', (67, 70))
133851	27713176	While not definitive evidence of the lack of DCIS cells or the lack of potential bias from the presence of DCIS cells in our test samples, the equal proportion of HSP+ patients in the patients with DCIS and without DCIS is suggestive that no bias exists in our sample set due to potential presence of DCIS cells.	('DCIS', 'Var', (198, 202))	('patients', 'Species', '9606', (184, 192))	('HSP+', 'Gene', (163, 167))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('patients', 'Species', '9606', (168, 176))	('DCIS', 'Phenotype', 'HP:0030075', (301, 305))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('DCIS', 'Phenotype', 'HP:0030075', (215, 219))
133852	27713176	In the event that DCIS cells were included in the test sample, it has been suggested that abnormal HER2 in DCIS is indicative of patients more likely to progress to invasive carcinoma.	('invasive carcinoma', 'Disease', (165, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('patients', 'Species', '9606', (129, 137))	('abnormal', 'Var', (90, 98))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('invasive carcinoma', 'Disease', 'MESH:D009361', (165, 183))	('HER2', 'Protein', (99, 103))	('progress', 'PosReg', (153, 161))
133865	27713176	Studies have suggested that upregulation of HER2 signaling in HER2- patients is caused by activating mutations in the extracellular or kinase domains of HER2 receptor.	('mutations in', 'Var', (101, 113))	('HER2', 'Protein', (44, 48))	('HER2', 'Protein', (153, 157))	('patients', 'Species', '9606', (68, 76))	('upregulation', 'PosReg', (28, 40))
133866	27713176	report that in 5,605 cases 10.6% had ERBB2 amplification, 2.4% had ERBB2 mutation where 0.7% had co-occurring ERBB2 amplification and mutation with only about 11% of all mutations found affecting the extracellular (ligand binding and dimerization) domain of the receptor.	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (67, 72))	('ERBB2', 'Gene', '2064', (37, 42))	('ERBB2', 'Gene', (67, 72))	('ERBB2', 'Gene', '2064', (110, 115))	('mutation', 'Var', (73, 81))	('ERBB2', 'Gene', (110, 115))
133868	27713176	While HER2 mutation may explain some HER2- patients' dysfunctional HER2 signaling, it could likely explain, at most, one of our results.	('mutation', 'Var', (11, 19))	('HER2 signaling', 'MPA', (67, 81))	('patients', 'Species', '9606', (43, 51))	('HER2', 'Protein', (6, 10))
133871	27713176	recently review biomarker studies in breast cancer and conclude: "It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer.	('breast cancer', 'Disease', (37, 50))	('drives', 'Reg', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('variations', 'Var', (125, 135))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('clinical', 'MPA', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
133896	27713176	In addition, specimens from patients with known BRCA1 or BRCA2 gene mutations were excluded to prevent inadvertent inclusion of patients who may have undiagnosed cancer.	('BRCA1', 'Gene', '672', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('BRCA1', 'Gene', (48, 53))	('BRCA2', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BRCA2', 'Gene', '675', (57, 62))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (28, 36))
133973	19423528	Parity and younger age at first full-term pregnancy, and younger age at menopause (<40) were inversely associated with both DCIS and IBC, while older age at menopause was positively associated with IBC only, and older age at menarche was inversely associated with IBC only.	('IBC', 'Chemical', '-', (133, 136))	('CIS', 'Phenotype', 'HP:0030075', (125, 128))	('IBC', 'Disease', (133, 136))	('IBC', 'Chemical', '-', (198, 201))	('IBC', 'Disease', (198, 201))	('DCIS', 'Disease', (124, 128))	('age at menopause', 'Phenotype', 'HP:0008209', (150, 166))	('Parity', 'Var', (0, 6))	('IBC', 'Chemical', '-', (264, 267))	('associated', 'Interaction', (103, 113))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('age at menopause', 'Phenotype', 'HP:0008209', (65, 81))
134115	18389278	All eight presented with abnormalities detected by mammographic screening: calcification in five, calcification and distortion in one, mass in one and distortion in one.	('calcification', 'Disease', (98, 111))	('mass', 'Disease', (135, 139))	('calcification', 'Disease', 'MESH:D002114', (75, 88))	('presented', 'Reg', (10, 19))	('calcification', 'Disease', 'MESH:D002114', (98, 111))	('distortion', 'Var', (116, 126))	('distortion', 'Disease', (151, 161))	('calcification', 'Disease', (75, 88))
134167	18389278	In the present study, both cores with pleomorphic LCIS had associated calcification.	('LCIS', 'Phenotype', 'HP:0030076', (50, 54))	('calcification', 'Disease', 'MESH:D002114', (70, 83))	('calcification', 'Disease', (70, 83))	('pleomorphic LCIS', 'Var', (38, 54))
134183	28295791	Multivariate analysis revealed that the presence of suspicious enhancement on MRI was the most significant predictor of upgrade to malignancy (P = 0.0006) Our study revealed a high NPV of DCE-MRI for patients with ADH in terms of malignant upgrade at subsequent surgery.	('DCE', 'Chemical', '-', (188, 191))	('patients', 'Species', '9606', (200, 208))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('ADH', 'Disease', (214, 217))	('malignancy', 'Disease', (131, 141))	('DCE-MRI', 'Var', (188, 195))
134236	28295791	Sanders et al reported that low-grade DCIS had a capability to evolve into invasive carcinoma in 35-50% of cases, but the time course might span >40 years.	('low-grade', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('invasive carcinoma', 'Disease', 'MESH:D009361', (75, 93))	('invasive carcinoma', 'Disease', (75, 93))
134239	28295791	Since we know that the DCE-MRI is the most sensitive imaging modality for detecting breast cancers, especially high-grade DCIS and invasive car-cinoma, patients with low-grade DCIS might undergo a watchful waiting strategy, and be followed up with DCE-MRI.	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('high-grade DCIS', 'Disease', (111, 126))	('low-grade', 'Var', (166, 175))	('DCE', 'Chemical', '-', (248, 251))	('breast cancers', 'Phenotype', 'HP:0003002', (84, 98))	('car-cinoma', 'Disease', 'MESH:C566176', (140, 150))	('car-cinoma', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancers', 'Disease', 'MESH:D001943', (84, 98))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('breast cancers', 'Disease', (84, 98))	('DCE', 'Chemical', '-', (23, 26))	('patients', 'Species', '9606', (152, 160))
134258	27065336	In both in vitro and in vivo models, shRNA mediated silencing of SEMA7A reveals roles for semaphorin 7a in the promotion of DCIS growth, motility, and invasion as well as lymphangiogenesis in the tumor microenvironment.	('silencing', 'Var', (52, 61))	('tumor', 'Disease', (196, 201))	('SEMA7A', 'Gene', (65, 71))	('promotion', 'PosReg', (111, 120))	('invasion', 'CPA', (151, 159))	('DCIS growth', 'CPA', (124, 135))	('SEMA7A', 'Gene', '8482', (65, 71))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('lymphangiogenesis', 'CPA', (171, 188))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('motility', 'CPA', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
134259	27065336	Our studies also uncover a relationship between COX-2 and semaphorin 7a expression and suggest that semaphorin 7a promotes tumor cell invasion on collagen and lymphangiogenesis via activation of beta1-integrin receptor.	('beta1-integrin', 'Gene', (195, 209))	('tumor', 'Disease', (123, 128))	('beta1-integrin', 'Gene', '3688', (195, 209))	('activation', 'PosReg', (181, 191))	('promotes', 'PosReg', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('COX-2', 'Gene', '4513', (48, 53))	('COX-2', 'Gene', (48, 53))	('semaphorin 7a', 'Var', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
134262	27065336	Unlike other semaphorins, which act to stunt axon outgrowth and inhibit angiogenesis, semaphorin 7a enhances axon migration and development and angiogenesis.	('rat', 'Species', '10116', (117, 120))	('angiogenesis', 'CPA', (72, 84))	('axon migration', 'CPA', (109, 123))	('inhibit', 'NegReg', (64, 71))	('axon outgrowth', 'CPA', (45, 59))	('angiogenesis', 'CPA', (144, 156))	('enhances', 'PosReg', (100, 108))	('semaphorin 7a', 'Var', (86, 99))
134269	27065336	To investigate whether Sem7a is a mediator of human breast tumor aggressiveness we silenced SEMA7A in MCF10DCIS cells.	('breast tumor aggressiveness', 'Disease', 'MESH:D001943', (52, 79))	('silenced', 'Var', (83, 91))	('breast tumor aggressiveness', 'Disease', (52, 79))	('SEMA7A', 'Gene', (92, 98))	('human', 'Species', '9606', (46, 51))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (102, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (52, 64))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('SEMA7A', 'Gene', '8482', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
134279	27065336	We examined the effects of Sem7a silencing on tumor cell growth, motility, and invasion in vitro and in vivo; we show that reducing Sem7a expression decreases human breast tumor cell growth, motility, invasion, and adhesion.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('breast tumor', 'Disease', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('reducing', 'Var', (123, 131))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (46, 51))	('human', 'Species', '9606', (159, 164))	('breast tumor', 'Phenotype', 'HP:0100013', (165, 177))	('adhesion', 'CPA', (215, 223))	('motility', 'CPA', (191, 199))	('decreases', 'NegReg', (149, 158))	('expression', 'MPA', (138, 148))	('Sem7a', 'Gene', (132, 137))	('breast tumor', 'Disease', 'MESH:D001943', (165, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('invasion', 'CPA', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
134280	27065336	We also show that Sem7a is regulated by COX-2 expression and that loss of Sem7a from tumor cells reduces tumor cell invasion and activation of beta1-integrin receptor.	('tumor', 'Disease', (85, 90))	('beta1-integrin', 'Gene', (143, 157))	('loss', 'Var', (66, 70))	('COX-2', 'Gene', '4513', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('activation', 'PosReg', (129, 139))	('Sem7a', 'Gene', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('COX-2', 'Gene', (40, 45))	('reduces', 'NegReg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (105, 110))	('beta1-integrin', 'Gene', '3688', (143, 157))
134288	27065336	We utilized Kaplan-Meier analysis to determine whether expression of SEMA7A is associated with poor prognosis in breast cancer patients in the METABRIC (Curtis) breast tumor dataset, which is a large breast cancer dataset that is annotated for clinical characteristics and outcomes such as overall survival (OS) and ER status.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('overall', 'Disease', (290, 297))	('breast tumor', 'Phenotype', 'HP:0100013', (161, 173))	('SEMA7A', 'Gene', '8482', (69, 75))	('large breast', 'Phenotype', 'HP:0010313', (194, 206))	('breast tumor', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('SEMA7A', 'Gene', (69, 75))	('ER', 'Gene', '2099', (316, 318))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Curtis', 'Disease', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('patients', 'Species', '9606', (127, 135))	('breast tumor', 'Disease', 'MESH:D001943', (161, 173))	('breast cancer', 'Disease', (200, 213))	('Curtis', 'Disease', 'MESH:C537936', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('expression', 'Var', (55, 65))
134291	27065336	To further validate that Sem7a is associated with decreased overall survival, we utilized the gene expression-based outcome for breast cancer online (GOBO) tool to analyze SEMA7A expression and outcomes in additional breast tumor data sets.	('Sem7a', 'Var', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('breast tumor', 'Disease', (217, 229))	('SEMA7A', 'Gene', '8482', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decreased', 'NegReg', (50, 59))	('breast tumor', 'Phenotype', 'HP:0100013', (217, 229))	('overall survival', 'MPA', (60, 76))	('breast tumor', 'Disease', 'MESH:D001943', (217, 229))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('SEMA7A', 'Gene', (172, 178))
134302	27065336	We observed decreased growth with both KD1 and KD2 (SFigure 3A).	('KD2', 'Var', (47, 50))	('growth', 'MPA', (22, 28))	('KD1', 'Var', (39, 42))	('decreased growth', 'Phenotype', 'HP:0001510', (12, 28))	('KD1', 'Species', '752783', (39, 42))	('KD2', 'Species', '752784', (47, 50))	('decreased', 'NegReg', (12, 21))
134306	27065336	Nevertheless, we observed decreased Ki67+ nuclei in the shSEM7a tumors suggestive of decreased tumor cell proliferation (Figure 3C;SFigure 3C).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Ki67+', 'Var', (36, 41))	('rat', 'Species', '10116', (113, 116))	('decreased tumor', 'Disease', 'MESH:D009369', (85, 100))	('shSEM7a', 'Gene', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('decreased tumor', 'Disease', (85, 100))	('decreased', 'NegReg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
134310	27065336	Furthermore, when all knockdown tumors were compared to wild-type, there was an overall significant decrease in the invasion score (SFigure 3E).	('invasion score', 'CPA', (116, 130))	('knockdown', 'Var', (22, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('decrease', 'NegReg', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
134321	27065336	Furthermore, the localization of beta1integrin was restricted to the structure periphery in the shSem7a cells, but was observed throughout the structures in the controls (Figure 4F) suggesting that Sem7a mediates invasion on collagen through activation of beta1-integrin receptors.	('beta1integrin', 'Gene', '3688', (33, 46))	('activation', 'PosReg', (242, 252))	('beta1integrin', 'Gene', (33, 46))	('invasion on', 'CPA', (213, 224))	('Sem7a', 'Var', (198, 203))	('beta1-integrin', 'Gene', '3688', (256, 270))	('beta1-integrin', 'Gene', (256, 270))
134327	27065336	Compared to controls, we observed a significant increase in the size of in vitro lymphatic structures with addition of Sem7a to levels that were comparable to those observed with PGE2 (SFigure 3C).	('size of in vitro lymphatic structures', 'CPA', (64, 101))	('Sem7a', 'Var', (119, 124))	('PGE2', 'Chemical', 'MESH:D015232', (179, 183))	('increase', 'PosReg', (48, 56))
134328	27065336	Having also shown that MCF10DCIS tumor cell conditioned media promotes lymphangiogenesis in vitro, we examined the effects of conditioned media from shSEMA7A cells on in vitro lymphangiogenesis.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('SEMA7A', 'Gene', '8482', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('lymphangiogenesis', 'CPA', (71, 88))	('promotes', 'PosReg', (62, 70))	('MCF10DCIS', 'Var', (23, 32))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (23, 32))	('tumor', 'Disease', (33, 38))	('SEMA7A', 'Gene', (151, 157))
134330	27065336	In addition, when we added a function blocking antibody for beta1-integrin receptor, Sem7a was unable to rescue suggesting that Sem7a also mediates lymphangiogenesis via beta1-integrin receptor activation (Figure 5C).	('activation', 'PosReg', (194, 204))	('Sem7a', 'Var', (128, 133))	('beta1-integrin', 'Gene', '3688', (170, 184))	('lymphangiogenesis', 'CPA', (148, 165))	('beta1-integrin', 'Gene', (170, 184))	('mediates', 'Reg', (139, 147))	('beta1-integrin', 'Gene', '3688', (60, 74))	('beta1-integrin', 'Gene', (60, 74))
134331	27065336	Furthermore, in vivo tumor associated lymphangiogenesis was deceased with shSem7a tumor cells as evidenced by a significant decrease in lymphatic vessel density in the peritumor region of shSem7a tumors (Figure D&E; SFigure 3D).	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (172, 177))	('shSem7a', 'Gene', (74, 81))	('decrease', 'NegReg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('decrease in lymphatic vessel density', 'Phenotype', 'HP:0003759', (124, 160))	('shSem7a', 'Var', (188, 195))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('deceased', 'NegReg', (60, 68))
134332	27065336	Finally, in the METABRIC dataset high Sem7a was associated with increased risk for lymphatic invasion (OR: 2.93, 95% CI: 1.021-8.397, p 0.0387), which we have previously shown to also be COX-2 dependent (Figure 5F).	('high Sem7a', 'Var', (33, 43))	('COX-2', 'Gene', (187, 192))	('COX-2', 'Gene', '4513', (187, 192))	('lymphatic invasion', 'CPA', (83, 101))
134342	27065336	Importantly, our analyses of multiple tumor datasets suggests that high Sem7a is associated with decreased survival and increased metastasis in breast cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('high', 'Var', (67, 71))	('multiple tumor', 'Disease', (29, 43))	('multiple tumor', 'Disease', 'MESH:D009369', (29, 43))	('breast cancer', 'Disease', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('Sem7a', 'Gene', (72, 77))	('metastasis', 'CPA', (130, 140))	('survival', 'CPA', (107, 115))	('decreased', 'NegReg', (97, 106))	('patients', 'Species', '9606', (158, 166))	('increased', 'PosReg', (120, 129))
134349	27065336	Thus, in the absence of targeted drugs for Sem7a, combination therapies that target downstream effectors and COX-2 could be tested in clinical trials to determine whether tumor progression can be blocked in breast cancer patients with high Sem7a expression.	('high', 'Var', (235, 239))	('Sem7a', 'Gene', (240, 245))	('patients', 'Species', '9606', (221, 229))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('COX-2', 'Gene', '4513', (109, 114))	('COX-2', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('breast cancer', 'Disease', (207, 220))
134378	27065336	Experimental medias were made with either 5 mug/mL recombinant Sem7a (Origene), 0.082nM PGE2 (Sigma), or 9EG7.	('0.082nM', 'Var', (80, 87))	('PGE2', 'Chemical', 'MESH:D015232', (88, 92))	('Sem7a', 'Gene', (63, 68))	('PGE2', 'Gene', (88, 92))
134388	27065336	For Ki67 and p63+ the denominator is total nuclei, for vimentin and E-cadherin the denominator is total tumor area.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('vimentin', 'Gene', (55, 63))	('Ki67', 'Var', (4, 8))	('tumor', 'Disease', (104, 109))	('p63', 'Gene', '8626', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('p63', 'Gene', (13, 16))	('vimentin', 'Gene', '7431', (55, 63))
134398	28388580	Importantly, TIPE3 knockdown in breast cancer cells inhibited cell proliferation, migration, and invasion in vitro, whereas TIPE3 overexpression had the opposite effect.	('breast cancer', 'Disease', (32, 45))	('TIPE3', 'Gene', '388121', (124, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('knockdown', 'Var', (19, 28))	('cell proliferation', 'CPA', (62, 80))	('migration', 'CPA', (82, 91))	('TIPE3', 'Gene', (124, 129))	('invasion in vitro', 'CPA', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibited', 'NegReg', (52, 61))	('TIPE3', 'Gene', '388121', (13, 18))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('TIPE3', 'Gene', (13, 18))
134400	28388580	TIPE3 expression also increased the level of MMP2 and uPA, and the activation of the AKT and NF-kappaB signaling pathways.	('TIPE3', 'Gene', (0, 5))	('MMP2', 'Gene', (45, 49))	('uPA', 'Gene', (54, 57))	('activation', 'PosReg', (67, 77))	('AKT', 'Gene', '207', (85, 88))	('NF-kappaB', 'Gene', '4790', (93, 102))	('increased', 'PosReg', (22, 31))	('MMP2', 'Gene', '4313', (45, 49))	('TIPE3', 'Gene', '388121', (0, 5))	('AKT', 'Gene', (85, 88))	('uPA', 'Gene', '118471', (54, 57))	('expression', 'Var', (6, 16))	('NF-kappaB', 'Gene', (93, 102))
134429	28388580	Therefore, TIPE3 expression vector was used to transfect MCF-7 and MDA-MB-231 cells (denoted as MCF-7-TIPE3 and MDA-MB-231-TIPE3, respectively, Figure 2C, Supplementary Figure 2A) to upregulate TIPE3 expression, whereas MDA-MB-231 cells were infected with Lenti-shRNA-hTIPE3 to knock down TIPE3 expression (denoted as MDA-MB-231-shTIPE3, Figure 2D).	('upregulate', 'PosReg', (183, 193))	('TIPE3', 'Gene', (102, 107))	('TIPE3', 'Gene', '388121', (331, 336))	('TIPE3', 'Gene', '388121', (269, 274))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (220, 230))	('TIPE3', 'Gene', (331, 336))	('MCF-7', 'CellLine', 'CVCL:0031', (96, 101))	('MDA-MB-231-TIPE3', 'CellLine', 'CVCL:0062', (112, 128))	('TIPE3', 'Gene', (269, 274))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (67, 77))	('expression', 'MPA', (200, 210))	('MDA-MB-231-shTIPE3', 'CellLine', 'CVCL:0062', (318, 336))	('TIPE3', 'Gene', '388121', (194, 199))	('hTIPE3', 'Gene', '388121', (330, 336))	('hTIPE3', 'Gene', '388121', (268, 274))	('TIPE3', 'Gene', (194, 199))	('TIPE3', 'Gene', '388121', (123, 128))	('MCF-7-TIPE3', 'CellLine', 'CVCL:0031', (96, 107))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('knock', 'Var', (278, 283))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (318, 328))	('hTIPE3', 'Gene', (330, 336))	('TIPE3', 'Gene', '388121', (11, 16))	('hTIPE3', 'Gene', (268, 274))	('TIPE3', 'Gene', (123, 128))	('TIPE3', 'Gene', '388121', (289, 294))	('TIPE3', 'Gene', (11, 16))	('TIPE3', 'Gene', (289, 294))	('TIPE3', 'Gene', '388121', (102, 107))	('MCF-7', 'CellLine', 'CVCL:0031', (57, 62))
134432	28388580	Conversely, knocking down TIPE3 in MDA-MB-231 cells significantly reduced cell proliferation (Figure 2H) and clonogenicity (Figure 2F).	('clonogenicity', 'CPA', (109, 122))	('reduced', 'NegReg', (66, 73))	('cell proliferation', 'CPA', (74, 92))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (35, 45))	('TIPE3', 'Gene', '388121', (26, 31))	('knocking down', 'Var', (12, 25))	('TIPE3', 'Gene', (26, 31))
134433	28388580	As shown in Figure 3, overexpression of TIPE3 in MCF-7 cells significantly reduced the population of G0/G1 cells and increased S/G2/M cells (Figure 3A and 3B), whereas knockdown of TIPE3 in MDA-MB-231 cells significantly increased the population of G0/G1 cells and reduced S/G2/M cells (Figure 3C and 3D).	('TIPE3', 'Gene', (181, 186))	('reduced', 'NegReg', (265, 272))	('increased', 'PosReg', (117, 126))	('increased', 'PosReg', (221, 230))	('reduced', 'NegReg', (75, 82))	('S/G2', 'Var', (273, 277))	('MCF-7', 'CellLine', 'CVCL:0031', (49, 54))	('G0/G1 cells', 'CPA', (249, 260))	('TIPE3', 'Gene', '388121', (40, 45))	('S/G2', 'Var', (127, 131))	('S/G2', 'SUBSTITUTION', 'None', (273, 277))	('S/G2', 'SUBSTITUTION', 'None', (127, 131))	('TIPE3', 'Gene', '388121', (181, 186))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (190, 200))	('knockdown', 'Var', (168, 177))	('TIPE3', 'Gene', (40, 45))
134437	28388580	Conversely, knocking down TIPE3 in MDA-MB-231 cells dramatically inhibited the migration and invasion (Figure 4B and 4D).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (35, 45))	('TIPE3', 'Gene', '388121', (26, 31))	('knocking down', 'Var', (12, 25))	('inhibited', 'NegReg', (65, 74))	('TIPE3', 'Gene', (26, 31))
134440	28388580	As expected, overexpressed TIPE3 in MCF-7 or MDA-MB-231 cells promoted p65 nuclear localization (Figure 5F).	('p65', 'Gene', (71, 74))	('TIPE3', 'Gene', (27, 32))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (45, 55))	('TIPE3', 'Gene', '388121', (27, 32))	('p65', 'Gene', '5970', (71, 74))	('promoted', 'PosReg', (62, 70))	('overexpressed', 'Var', (13, 26))	('MCF-7', 'CellLine', 'CVCL:0031', (36, 41))
134443	28388580	Conversely, TIPE3 knockdown in MDA-MB-231 cells inhibited the expression of MMP-2 and uPA molecules (Figure 5D).	('knockdown', 'Var', (18, 27))	('MMP-2', 'Gene', '4313', (76, 81))	('uPA', 'Gene', '118471', (86, 89))	('TIPE3', 'Gene', '388121', (12, 17))	('expression', 'MPA', (62, 72))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (31, 41))	('inhibited', 'NegReg', (48, 57))	('MMP-2', 'Gene', (76, 81))	('uPA', 'Gene', (86, 89))	('TIPE3', 'Gene', (12, 17))
134444	28388580	To confirm the effect of TIPE3 on AKT and NF-kappaB pathways in breast cancer, inhibitors CAPE (inhibitor of NF-kappaB) and LY294002 (inhibitor of PI3K inhibitor) were used in this study.	('NF-kappaB', 'Gene', '4790', (109, 118))	('AKT', 'Gene', (34, 37))	('TIPE3', 'Gene', '388121', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('CAPE', 'Gene', '10592', (90, 94))	('TIPE3', 'Gene', (25, 30))	('LY294002', 'Var', (124, 132))	('NF-kappaB', 'Gene', (109, 118))	('NF-kappaB', 'Gene', '4790', (42, 51))	('LY294002', 'Chemical', 'MESH:C085911', (124, 132))	('AKT', 'Gene', '207', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CAPE', 'Gene', (90, 94))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('NF-kappaB', 'Gene', (42, 51))	('breast cancer', 'Disease', (64, 77))
134446	28388580	Similarly, the activation of p-AKT induced by overexpressed TIPE3 was inhibited through blocking the AKT activity by LY294002 (Figure 7C and 7D).	('activation', 'PosReg', (15, 25))	('AKT', 'Gene', '207', (101, 104))	('LY294002', 'Var', (117, 125))	('AKT', 'Gene', (31, 34))	('overexpressed', 'Var', (46, 59))	('AKT', 'Gene', (101, 104))	('TIPE3', 'Gene', '388121', (60, 65))	('blocking', 'NegReg', (88, 96))	('inhibited', 'NegReg', (70, 79))	('LY294002', 'Chemical', 'MESH:C085911', (117, 125))	('AKT', 'Gene', '207', (31, 34))	('TIPE3', 'Gene', (60, 65))
134447	28388580	As a result, the enhanced proliferation (Figure 8A and 8B), colony formation (Figure 8C and 8D, Supplementary Figure 5A and 5B) and migration (Figure 8E and 8F, Supplementary Figure 5C and 5D) in MCF-7 and MDA-MB-231 cells induced by overexpressed TIPE3 were largely blocked by CAPE or LY294002.	('enhanced', 'PosReg', (17, 25))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (206, 216))	('MCF-7', 'CellLine', 'CVCL:0031', (196, 201))	('TIPE3', 'Gene', (248, 253))	('LY294002', 'Var', (286, 294))	('colony formation', 'CPA', (60, 76))	('migration', 'CPA', (132, 141))	('CAPE', 'Gene', (278, 282))	('CAPE', 'Gene', '10592', (278, 282))	('LY294002', 'Chemical', 'MESH:C085911', (286, 294))	('TIPE3', 'Gene', '388121', (248, 253))
134448	28388580	Interestingly, the elevation of p-IkBalpha and p-P65 induced by overexpressed TIPE3 was also largely blocked by LY294002 (Figure 7C and 7D), suggesting that TIPE3 might activate NF-kappaB pathway through AKT pathway in breast cancer cells.	('NF-kappaB', 'Gene', '4790', (178, 187))	('elevation', 'PosReg', (19, 28))	('P65', 'Gene', '5970', (49, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('P65', 'Gene', (49, 52))	('p-IkBalpha', 'Protein', (32, 42))	('AKT', 'Gene', (204, 207))	('LY294002', 'Var', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Disease', (219, 232))	('activate', 'PosReg', (169, 177))	('LY294002', 'Chemical', 'MESH:C085911', (112, 120))	('AKT', 'Gene', '207', (204, 207))	('TIPE3', 'Gene', '388121', (78, 83))	('TIPE3', 'Gene', '388121', (157, 162))	('NF-kappaB', 'Gene', (178, 187))	('TIPE3', 'Gene', (78, 83))	('TIPE3', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
134457	28388580	The HE staining results showed more and bigger metastatic foci in the lungs of nude mice injected with MDA-MB-231-shCtrl cells than in the lungs of nude mice injected with MDA-MB-231-shTIPE3 cells (Figure 6F).	('HE', 'Chemical', 'MESH:D006371', (4, 6))	('metastatic foci', 'CPA', (47, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (103, 113))	('MDA-MB-231-shCtrl cells', 'Var', (103, 126))	('bigger', 'PosReg', (40, 46))	('MDA-MB-231-shTIPE3', 'CellLine', 'CVCL:0062', (172, 190))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (172, 182))	('nude mice', 'Species', '10090', (79, 88))	('more', 'PosReg', (31, 35))	('nude mice', 'Species', '10090', (148, 157))
134469	28388580	Overexpression of HER2, Ki67 and p53 are found in 20~30% of breast cancer patients and is associated with poor prognosis and relapse.	('breast cancer', 'Disease', (60, 73))	('HER2', 'Gene', '2064', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('Ki67', 'Var', (24, 28))	('patients', 'Species', '9606', (74, 82))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('HER2', 'Gene', (18, 22))
134473	28388580	Furthermore, overexpressed TIPE3 could reduce the population of G0/G1 cells and increase S/G2/M cells.	('reduce', 'NegReg', (39, 45))	('S/G2', 'SUBSTITUTION', 'None', (89, 93))	('TIPE3', 'Gene', (27, 32))	('increase', 'PosReg', (80, 88))	('G0/G1 cells', 'CPA', (64, 75))	('S/G2', 'Var', (89, 93))	('overexpressed', 'Var', (13, 26))	('TIPE3', 'Gene', '388121', (27, 32))
134475	28388580	Wherefore, knocking down the expression of TIPE3 in MDA-MB-231 cells inhibited cell growth, decreased the size of colony formation, and arrested cell cycle progression.	('knocking down', 'Var', (11, 24))	('size of colony formation', 'CPA', (106, 130))	('arrested', 'NegReg', (136, 144))	('cell cycle progression', 'CPA', (145, 167))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('TIPE3', 'Gene', '388121', (43, 48))	('inhibited', 'NegReg', (69, 78))	('TIPE3', 'Gene', (43, 48))	('decreased', 'NegReg', (92, 101))	('expression', 'MPA', (29, 39))	('cell growth', 'CPA', (79, 90))
134476	28388580	Subcutaneous xenograft tumor experiment demonstrated that overexpressed TIPE3 could promote tumor formation in vivo.	('TIPE3', 'Gene', '388121', (72, 77))	('overexpressed', 'Var', (58, 71))	('promote', 'PosReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('TIPE3', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (23, 28))
134483	28388580	Overexpressed TIPE3 in MCF-7 cells could promote cell migration and invasion, while knocking down of TIPE3 in MDA-MB-231 cells reduced cell migration and invasion.	('TIPE3', 'Gene', '388121', (101, 106))	('cell migration', 'CPA', (49, 63))	('MCF-7', 'CellLine', 'CVCL:0031', (23, 28))	('TIPE3', 'Gene', (14, 19))	('invasion', 'CPA', (68, 76))	('promote', 'PosReg', (41, 48))	('TIPE3', 'Gene', (101, 106))	('invasion', 'CPA', (154, 162))	('knocking down', 'Var', (84, 97))	('cell migration', 'CPA', (135, 149))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (110, 120))	('reduced', 'NegReg', (127, 134))	('TIPE3', 'Gene', '388121', (14, 19))
134491	28388580	The PI3K/AKT signaling pathway is frequently activated in more than 50% of human breast cancers and most commonly through mutational activation of the PIK3CA gene.	('AKT', 'Gene', '207', (9, 12))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('breast cancers', 'Disease', (81, 95))	('human', 'Species', '9606', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('PIK3CA', 'Gene', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('activation', 'PosReg', (133, 143))	('AKT', 'Gene', (9, 12))	('PIK3CA', 'Gene', '5290', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutational', 'Var', (122, 132))	('activated', 'PosReg', (45, 54))
134492	28388580	Coordinately, PIK3CA mutations and AKT activation by phosphorylation (pAKT) are often identified at high frequencies in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('AKT', 'Gene', (35, 38))	('breast cancer', 'Disease', (120, 133))	('AKT', 'Gene', '207', (71, 74))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('PIK3CA', 'Gene', (14, 20))	('AKT', 'Gene', (71, 74))	('AKT', 'Gene', '207', (35, 38))	('PIK3CA', 'Gene', '5290', (14, 20))	('activation by phosphorylation', 'PosReg', (39, 68))	('mutations', 'Var', (21, 30))
134494	28388580	Similarly, TIPE3 knockdown in MDA-MB-231 cells impaired AKT and IkBalpha activation.	('activation', 'PosReg', (73, 83))	('AKT', 'Gene', '207', (56, 59))	('TIPE3', 'Gene', (11, 16))	('AKT', 'Gene', (56, 59))	('IkBalpha', 'Pathway', (64, 72))	('impaired', 'NegReg', (47, 55))	('knockdown', 'Var', (17, 26))	('TIPE3', 'Gene', '388121', (11, 16))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (30, 40))
134495	28388580	The inhibitors of AKT and NF-kappaB pathways, such as CAPE and LY294002, could block the enhanced proliferation, colony formation and migration of breast cancer cells induced by overexpressed TIPE3.	('TIPE3', 'Gene', (192, 197))	('NF-kappaB', 'Gene', '4790', (26, 35))	('block', 'NegReg', (79, 84))	('enhanced', 'PosReg', (89, 97))	('LY294002', 'Var', (63, 71))	('NF-kappaB', 'Gene', (26, 35))	('colony formation', 'CPA', (113, 129))	('CAPE', 'Gene', (54, 58))	('AKT', 'Gene', (18, 21))	('breast cancer', 'Disease', (147, 160))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('CAPE', 'Gene', '10592', (54, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('LY294002', 'Chemical', 'MESH:C085911', (63, 71))	('migration', 'CPA', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('TIPE3', 'Gene', '388121', (192, 197))	('AKT', 'Gene', '207', (18, 21))
134496	28388580	Interestingly, blocking PI3K-AKT pathway by LY294002 largely abolished the activation of NF-kappaB induced by TIPE3 overexpression, suggesting that TIPE3 might activate NF-kappaB through AKT pathway during breast cancer development.	('TIPE3', 'Gene', '388121', (148, 153))	('NF-kappaB', 'Gene', (169, 178))	('TIPE3', 'Gene', '388121', (110, 115))	('NF-kappaB', 'Gene', (89, 98))	('overexpression', 'PosReg', (116, 130))	('TIPE3', 'Gene', (148, 153))	('TIPE3', 'Gene', (110, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('NF-kappaB', 'Gene', '4790', (169, 178))	('NF-kappaB', 'Gene', '4790', (89, 98))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('AKT', 'Gene', (187, 190))	('breast cancer', 'Disease', (206, 219))	('AKT', 'Gene', (29, 32))	('activation', 'MPA', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('blocking', 'NegReg', (15, 23))	('abolished', 'NegReg', (61, 70))	('activate', 'PosReg', (160, 168))	('AKT', 'Gene', '207', (187, 190))	('AKT', 'Gene', '207', (29, 32))	('LY294002', 'Var', (44, 52))
134501	28388580	In this paper we found that the expression of MMP-2 and uPA was increased in TIPE3 overexpressed MCF-7 and MDA-MB-231 cells, while decreased in TIPE3 knocked down MDA-MB-231 cells.	('TIPE3', 'Gene', (144, 149))	('overexpressed', 'Var', (83, 96))	('MMP-2', 'Gene', '4313', (46, 51))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (107, 117))	('uPA', 'Gene', '118471', (56, 59))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (163, 173))	('TIPE3', 'Gene', (77, 82))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))	('MMP-2', 'Gene', (46, 51))	('TIPE3', 'Gene', '388121', (77, 82))	('TIPE3', 'Gene', '388121', (144, 149))	('increased', 'PosReg', (64, 73))	('expression', 'MPA', (32, 42))	('uPA', 'Gene', (56, 59))
134514	28388580	Cells were then treated with the PI3K inhibitor LY294002 (10 mM, Apexbiotochnology, USA) or the NF-kappaB inhibitor CAPE (70 mM, Apexbiotochnology, USA).	('CAPE', 'Gene', (116, 120))	('CAPE', 'Gene', '10592', (116, 120))	('LY294002', 'Var', (48, 56))	('NF-kappaB', 'Gene', '4790', (96, 105))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('NF-kappaB', 'Gene', (96, 105))
134518	28388580	The sequences of primers were as follows: hTIPE3: Forward 5'-TTCAGAGGGGAAAGGGACT-3', reverse 5'-AACATCAGGACCTGCGGC-3'; h-beta-actin: Forward 5'-AGTTGCGTTACACCCTTTC-3', reverse 5'-CCTTCACCGTTCCAGTTT-3'; h-uPA: Forward 5'-CACGCTTGCTCACCACAACGACA-3', reverse 5'-CTGACACTCCCGGTGGGAAATCA-3'; h- MMP2: Forward 5'-GATACCCCTTTGACGGTAA GGA-3', reverse5'-CCTTCTCCCAAGGTCCATAGC-3'.	('hTIPE3', 'Gene', '388121', (42, 48))	('uPA', 'Gene', (204, 207))	('MMP2', 'Gene', '4313', (290, 294))	("reverse5'-CCTTCTCCCAAGGTCCATAGC-3", 'Var', (335, 368))	('MMP2', 'Gene', (290, 294))	('uPA', 'Gene', '118471', (204, 207))	('beta-actin', 'Gene', '728378', (121, 131))	('beta-actin', 'Gene', (121, 131))	('hTIPE3', 'Gene', (42, 48))
134522	28388580	Specific primary antibodies include anti-hTIPE3 (1:1000, Sigma, USA) and anti-flag (1:1000, Sigma, USA), anti-pAKT and anti-AKT, anti-IkBalpha and anti-pIkBalpha, anti-p-P65 and anti-P65 antibodies (1:1000, Cell Signaling Technology, Beverly, USA), anti-beta-actin (1:1000, ZSGB-BIO), anti-beta-tubulin antibody and anti-LaminA antibody (Sino Biological Inc, China).	('AKT', 'Gene', '207', (111, 114))	('anti-beta-tubulin', 'Var', (285, 302))	('hTIPE3', 'Gene', '388121', (41, 47))	('AKT', 'Gene', (124, 127))	('P65', 'Gene', '5970', (183, 186))	('AKT', 'Gene', (111, 114))	('P65', 'Gene', (183, 186))	('beta-actin', 'Gene', '728378', (254, 264))	('beta-actin', 'Gene', (254, 264))	('P65', 'Gene', '5970', (170, 173))	('P65', 'Gene', (170, 173))	('AKT', 'Gene', '207', (124, 127))	('hTIPE3', 'Gene', (41, 47))
134529	28388580	For the cell proliferation assay, 1 x 104 TIPE3-overexpressing MCF-7-TIPE3 or MDA-MB-231-TIPE3 cells, and MDA-MB-231-shTIPE3 cells and their controls were treated with or without CAPE or LY294002, seeded and cultured in 96-well plates.	('TIPE3', 'Gene', (119, 124))	('TIPE3', 'Gene', '388121', (69, 74))	('TIPE3', 'Gene', (89, 94))	('TIPE3', 'Gene', (42, 47))	('TIPE3', 'Gene', (69, 74))	('CAPE', 'Gene', (179, 183))	('CAPE', 'Gene', '10592', (179, 183))	('LY294002', 'Var', (187, 195))	('MDA-MB-231-TIPE3', 'CellLine', 'CVCL:0062', (78, 94))	('TIPE3', 'Gene', '388121', (42, 47))	('TIPE3', 'Gene', '388121', (119, 124))	('TIPE3', 'Gene', '388121', (89, 94))	('cell proliferation', 'CPA', (8, 26))	('MCF-7-TIPE3', 'CellLine', 'CVCL:0031', (63, 74))	('LY294002', 'Chemical', 'MESH:C085911', (187, 195))	('MDA-MB-231-shTIPE3', 'CellLine', 'CVCL:0062', (106, 124))
134531	28388580	For the colony formation assay, 1 x 103 TIPE3-overexpressing MCF-7-TIPE3 or 3 x 103 MDA-MB-231-TIPE3 cells treated with or without CAPE or LY294002 were seeded and cultured in six-well plates for 1-2 weeks until visible colonies were formed.	('TIPE3', 'Gene', (67, 72))	('LY294002', 'Chemical', 'MESH:C085911', (139, 147))	('MDA-MB-231-TIPE3', 'CellLine', 'CVCL:0062', (84, 100))	('MCF-7-TIPE3', 'CellLine', 'CVCL:0031', (61, 72))	('TIPE3', 'Gene', (40, 45))	('TIPE3', 'Gene', '388121', (67, 72))	('TIPE3', 'Gene', '388121', (40, 45))	('LY294002', 'Var', (139, 147))	('TIPE3', 'Gene', '388121', (95, 100))	('TIPE3', 'Gene', (95, 100))	('CAPE', 'Gene', '10592', (131, 135))	('CAPE', 'Gene', (131, 135))
134599	27690173	Three large scale studies of women with locally advanced breast cancer undergoing neoadjuvant chemotherapy (n=519 women total) each showed low pretreatment tumor ADC values to be predictive of pathological complete response for triple-negative tumors, with more variable findings in luminal and HER2+ subtypes.	('breast cancer', 'Disease', (57, 70))	('women', 'Species', '9606', (114, 119))	('low', 'NegReg', (139, 142))	('tumor', 'Disease', (156, 161))	('HER2', 'Gene', '2064', (295, 299))	('triple-negative', 'Var', (228, 243))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('women', 'Species', '9606', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (244, 250))	('HER2', 'Gene', (295, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumor', 'Disease', (244, 249))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
134661	27797363	Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer The gene encoding phosphatidylinositol 3-kinase catalytic subunit alpha-isoform (PIK3CA, p110alpha) is frequently activated by mutation in human cancers.	('tumor initiation', 'Disease', 'MESH:D009369', (42, 58))	('human', 'Species', '9606', (243, 248))	('accelerates', 'PosReg', (30, 41))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('tumor initiation', 'Disease', (42, 58))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancers', 'Disease', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PIK3CA', 'Gene', (185, 191))	('p110alpha', 'Var', (193, 202))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
134662	27797363	Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('tumor initiation', 'Disease', 'MESH:D009369', (107, 123))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('tumor initiation', 'Disease', (107, 123))	('mutations', 'Var', (60, 69))	('PIK3CA', 'Gene', (53, 59))
134664	27797363	After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110alpha accelerated breast tumor initiation in a copy number-dependent manner.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('myr-p110alpha', 'Var', (94, 107))	('breast tumor', 'Phenotype', 'HP:0100013', (120, 132))	('breast tumor initiation', 'Disease', 'MESH:D001943', (120, 143))	('breast tumor initiation', 'Disease', (120, 143))	('accelerated', 'PosReg', (108, 119))
134665	27797363	Breast tumors induced by p53fl/fl;KrasG12D with no or one copy of myr-p110alpha had predominantly sarcomatoid features, whereas two copies of myr-p110alpha resulted in tumors with a carcinoma phenotype.	('Breast tumors', 'Disease', (0, 13))	('sarcomatoid', 'Disease', 'MESH:C538614', (98, 109))	('tumors', 'Disease', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Kras', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('resulted in', 'Reg', (156, 167))	('myr-p110alpha', 'Var', (66, 79))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (7, 13))	('Kras', 'Gene', '16653', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('Breast tumors', 'Disease', 'MESH:D001943', (0, 13))	('carcinoma', 'Disease', (182, 191))	('Breast tumors', 'Phenotype', 'HP:0100013', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('sarcomatoid', 'Disease', (98, 109))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
134666	27797363	This novel model provides experimental support for importance of active p110alpha in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.	('p110alpha', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('tumor initiation', 'Disease', 'MESH:D009369', (176, 192))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('modify', 'Reg', (197, 203))	('rate', 'MPA', (168, 172))	('breast cancer', 'Disease', (234, 247))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor initiation', 'Disease', (176, 192))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('breast tumor initiation', 'Disease', (85, 108))	('breast tumor initiation', 'Disease', 'MESH:D001943', (85, 108))	('affect', 'Reg', (157, 163))
134667	27797363	Receptor tyrosine kinase-phosphatidylinositol 3-kinase (PI3K) signaling is a central integrator of metabolism, cell growth and cell survival, and deregulated PI3K signaling increases tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('PI3K', 'Protein', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('increases', 'PosReg', (173, 182))	('tumor', 'Disease', (183, 188))	('deregulated', 'Var', (146, 157))
134668	27797363	Cancer-associated mutations occur in several components of the pathway including activating mutations of both the PI3K catalytic subunit alpha-isoform gene (PIK3CA, p110alpha) and the downstream signaling molecule AKT1, as well as deletion of the negative pathway regulator, PTEN.	('mutations', 'Var', (18, 27))	('deletion', 'Var', (231, 239))	('PIK3CA', 'Gene', (157, 163))	('mutations', 'Var', (92, 101))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('AKT1', 'Gene', '11651', (214, 218))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('PTEN', 'Gene', '19211', (275, 279))	('PTEN', 'Gene', (275, 279))	('AKT1', 'Gene', (214, 218))
134669	27797363	The significance of p110alpha in cancer is demonstrated by the high frequency of activating mutations in many common human cancers that increase the catalytic activity of PI3K.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('human', 'Species', '9606', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancers', 'Disease', (123, 130))	('cancer', 'Disease', (123, 129))	('increase', 'PosReg', (136, 144))	('catalytic activity', 'MPA', (149, 167))	('p110alpha', 'Var', (20, 29))
134670	27797363	High-throughput RNA sequencing and tumor resequencing have revealed that hyperactivating mutations in the PI3K signaling pathway occur in a substantial percentage of breast cancers.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (166, 180))	('tumor', 'Disease', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancers', 'Disease', 'MESH:D001943', (166, 180))	('breast cancers', 'Disease', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('hyperactivating mutations', 'Var', (73, 98))	('PI3K signaling pathway', 'Pathway', (106, 128))
134671	27797363	The PIK3CA gene itself, encoding the p110alpha catalytic subunit, is the most frequently mutated gene in breast cancer, with mutations in 25-40% of all breast cancers.	('mutations', 'Var', (125, 134))	('PIK3CA', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (152, 166))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancers', 'Disease', 'MESH:D001943', (152, 166))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('breast cancers', 'Disease', (152, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
134672	27797363	Whole-exome analysis of finely dissected and matched mammary tumors has shown that alterations in the p110alpha gene are detected at the same frequencies in ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma and invasive carcinoma.	('invasive carcinoma', 'Disease', 'MESH:D009361', (207, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (157, 181))	('p110alpha', 'Gene', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('alterations', 'Var', (83, 94))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (61, 67))	('detected', 'Reg', (121, 129))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (157, 181))	('DCIS', 'Disease', (190, 194))	('DCIS', 'Phenotype', 'HP:0030075', (183, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('invasive carcinoma', 'Disease', (230, 248))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ductal carcinoma in situ', 'Disease', (157, 181))	('invasive carcinoma', 'Disease', (207, 225))	('invasive carcinoma', 'Disease', 'MESH:D009361', (230, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))
134673	27797363	In addition, the p110alpha sequences are often found to be identical in invasive and in situ areas of the same breast tumor.	('breast tumor', 'Disease', 'MESH:D001943', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('breast tumor', 'Disease', (111, 123))	('breast tumor', 'Phenotype', 'HP:0100013', (111, 123))	('p110alpha', 'Var', (17, 26))
134674	27797363	This pattern of mutation suggests that p110alpha mutations are a relatively early event in breast cancer development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('p110alpha mutations', 'Var', (39, 58))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
134675	27797363	In light of these findings, mutational activation of the PI3K signaling pathway has been proposed to have a role in breast tumor initiation.	('breast tumor', 'Phenotype', 'HP:0100013', (116, 128))	('breast tumor initiation', 'Disease', 'MESH:D001943', (116, 139))	('breast tumor initiation', 'Disease', (116, 139))	('mutational', 'Var', (28, 38))	('PI3K signaling pathway', 'Pathway', (57, 79))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
134676	27797363	Multiple mouse models of the PI3K pathway-driven cancer have recently been developed to investigate the impact of PI3K mutation or combination of other related mutations on breast cancer development under the control of MMTV LTR or WAP promoter.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('PI3K', 'Gene', (114, 118))	('cancer', 'Disease', (180, 186))	('mutation', 'Var', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mouse', 'Species', '10090', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('MMTV', 'Species', '11757', (220, 224))	('cancer', 'Disease', (49, 55))	('breast cancer', 'Disease', (173, 186))
134678	27797363	To ascertain the impact of p110alpha activating mutations in tumor initiation and progression, we combined myr-p110alpha with frequently co-occurring mutations of two genes, p53 and Kras, to generate novel models of breast, lung and potentially other cancers whose induction is controlled by the researcher.	('lung', 'Disease', (224, 228))	('breast', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('mutations', 'Var', (48, 57))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('tumor initiation', 'Disease', 'MESH:D009369', (61, 77))	('cancers', 'Disease', (251, 258))	('Kras', 'Gene', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('p53', 'Gene', (174, 177))	('Kras', 'Gene', '16653', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor initiation', 'Disease', (61, 77))
134679	27797363	To elucidate the role of activating mutations of p110alpha in tumorigenesis, we engineered a mouse with conditional myristoylated-p110alpha (myr-p110alpha) ubiquitously expressed from the Rosa26 locus (Supplementary Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mouse', 'Species', '10090', (93, 98))	('tumor', 'Disease', (62, 67))	('Rosa26', 'Gene', '14910', (188, 194))	('mutations', 'Var', (36, 45))	('Rosa26', 'Gene', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
134682	27797363	In line with its tumorigenic potential in mouse embryonic fibroblasts (MEFs; Supplementary Figure 2) and previous studies showing the cooperation between Pik3caH1047R activating mutation and p53 knockout in vivo, mice expressing one copy of myr-p110alpha and homozygous for p53 deletion (p53fl/fl;myr-p110alphawt/fl) developed mammary tumors with 100% penetrance but with a long latency (mean tumor onset 259.6+-10.6 days; Figure 1a).	('MEFs', 'CellLine', 'CVCL:9115', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('tumor', 'Disease', (17, 22))	('developed', 'PosReg', (317, 326))	('tumors', 'Disease', (335, 341))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('mice', 'Species', '10090', (213, 217))	('mouse', 'Species', '10090', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('p53', 'Gene', (274, 277))	('tumor', 'Disease', (393, 398))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('p53fl/fl', 'Var', (288, 296))	('tumor', 'Disease', (335, 340))
134685	27797363	In contrast, mice harboring either myr-p110alphawt/fl or homozygous p53 deletion only, failed to form mammary tumors during 12 months of observation.	('mice', 'Species', '10090', (13, 17))	('myr-p110alphawt/fl', 'Var', (35, 53))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('p53', 'Gene', (68, 71))
134687	27797363	To test for PI3K signaling activation, mammary tumors were analyzed for levels of total p110alpha, total AKT, the active phosphorylated form of AKT (p-AKT), PI3K regulatory subunit p85alpha, PI3K negative regulator PTEN and the less active phosphorylated form of PTEN with reduced lipid phosphatase activity (p-PTEN).	('AKT', 'Gene', (151, 154))	('AKT', 'Gene', (144, 147))	('PTEN', 'Gene', '19211', (215, 219))	('p85alpha', 'Gene', '18708', (181, 189))	('PTEN', 'Gene', '19211', (263, 267))	('AKT', 'Gene', '11651', (105, 108))	('PTEN', 'Gene', '19211', (311, 315))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (273, 280))	('tumors', 'Disease', (47, 53))	('AKT', 'Gene', '11651', (151, 154))	('AKT', 'Gene', '11651', (144, 147))	('p-AKT', 'Gene', '11651', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('PTEN', 'Gene', (215, 219))	('PTEN', 'Gene', (263, 267))	('lipid phosphatase activity', 'MPA', (281, 307))	('AKT', 'Gene', (105, 108))	('PTEN', 'Gene', (311, 315))	('p-AKT', 'Gene', (149, 154))	('PI3K', 'Var', (157, 161))	('p85alpha', 'Gene', (181, 189))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
134688	27797363	As compared with normal mammary tissue, mammary tumors from p53fl/fl;myr-p110alphawt/fl females had elevated levels of total p110alpha (32-fold), p-AKT (37-fold) and p-AKT/AKT ratio (34-fold; Figures 1c and d).	('p110alpha', 'Var', (125, 134))	('AKT', 'Gene', '11651', (148, 151))	('AKT', 'Gene', (172, 175))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('AKT', 'Gene', (148, 151))	('elevated', 'PosReg', (100, 108))	('AKT', 'Gene', '11651', (168, 171))	('p-AKT', 'Gene', '11651', (166, 171))	('AKT', 'Gene', '11651', (172, 175))	('p-AKT', 'Gene', '11651', (146, 151))	('p-AKT', 'Gene', (146, 151))	('p-AKT', 'Gene', (166, 171))	('AKT', 'Gene', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('p53fl/fl', 'Var', (60, 68))
134689	27797363	Expression of myr-p110alpha was confirmed by the detection of GFP in mammary tumors (Figure 1c).	('myr-p110alpha', 'Var', (14, 27))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
134690	27797363	The p53fl/fl;myr-p110alphawt/fl mammary tumors also displayed significantly increased total protein levels of p85alpha (1.9-fold), PTEN (1.3-fold) and p-PTEN (1.7-fold; Figures 1e and f), suggesting naturally occurring negative feedback mechanisms to inhibit abnormal PI3K activity driven by myr-p110alpha.	('PTEN', 'Gene', '19211', (153, 157))	('PTEN', 'Gene', '19211', (131, 135))	('PTEN', 'Gene', (131, 135))	('increased', 'PosReg', (76, 85))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('p85alpha', 'Gene', '18708', (110, 118))	('PTEN', 'Gene', (153, 157))	('inhibit', 'NegReg', (251, 258))	('p85alpha', 'Gene', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('p53fl/fl;myr-p110alphawt/fl', 'Var', (4, 31))	('myr-p110alpha', 'Var', (292, 305))
134692	27797363	It has been proposed that PIK3CA has a role in tumor initiation, as its mutations are detected in precursors of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('mutations', 'Var', (72, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('detected', 'Reg', (86, 94))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor initiation', 'Disease', (47, 63))	('PIK3CA', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
134693	27797363	To investigate the role of myr-p110alpha in tumor initiation and progression, we exploited the Cre-inducible oncogenic mouse model p53fl/fl;KrasG12D, which harbors a homozygous p53 deletion and a KrasG12D activating missense allele that rapidly grows tumors.	('mouse', 'Species', '10090', (119, 124))	('tumors', 'Disease', (251, 257))	('p53', 'Gene', (177, 180))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('Kras', 'Gene', (140, 144))	('Kras', 'Gene', (196, 200))	('Kras', 'Gene', '16653', (196, 200))	('Kras', 'Gene', '16653', (140, 144))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletion', 'Var', (181, 189))	('activating', 'PosReg', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor initiation', 'Disease', (44, 60))
134694	27797363	Based on the published breast cancer genomics data, KrasG12D mutation tends to co-occur with p53 mutations (Supplementary Figures 3A and 3B).	('breast cancer', 'Disease', (23, 36))	('mutations', 'Var', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('p53', 'Gene', (93, 96))	('Kras', 'Gene', '16653', (52, 56))	('Kras', 'Gene', (52, 56))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
134698	27797363	Notably, although p53fl/fl;KrasG12D mice began to form palpable mammary tumors (tumor size ranges 12-15 mm2) with a mean tumor onset of 54.8+-0.7 days, p53fl/fl;KrasG12D;myr-p110alphawt/fl mice started to form palpable mammary tumors with a mean tumor onset of 28.7+-0.4 days (Figure 2a), indicating roughly two-fold acceleration of tumor initiation due to expression of myr-p110alpha.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (189, 193))	('Kras', 'Gene', (161, 165))	('tumors', 'Disease', (72, 78))	('Kras', 'Gene', '16653', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('acceleration', 'PosReg', (317, 329))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('Kras', 'Gene', '16653', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', (227, 233))	('tumor', 'Disease', (80, 85))	('myr-p110alpha', 'Var', (371, 384))	('tumor initiation', 'Disease', 'MESH:D009369', (333, 349))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (333, 338))	('tumor initiation', 'Disease', (333, 349))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Kras', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (333, 338))
134702	27797363	To biochemically characterize mammary tumors from p53fl/fl;KrasG12D and p53fl/fl;KrasG12D;myr-p110alphawt/fl, we tested the PI3K pathway activation status of the mammary tumors by analyzing the levels of p110alpha, AKT, p-AKT, p85alpha, PTEN and p-PTEN.	('PTEN', 'Gene', '19211', (248, 252))	('PTEN', 'Gene', (237, 241))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Kras', 'Gene', '16653', (59, 63))	('p85alpha', 'Gene', (227, 235))	('AKT', 'Gene', (222, 225))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('PI3K pathway', 'Pathway', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('AKT', 'Gene', '11651', (215, 218))	('tumors', 'Disease', (38, 44))	('p110alpha', 'Var', (204, 213))	('Kras', 'Gene', (81, 85))	('p85alpha', 'Gene', '18708', (227, 235))	('PTEN', 'Gene', '19211', (237, 241))	('PTEN', 'Gene', (248, 252))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Kras', 'Gene', '16653', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('AKT', 'Gene', '11651', (222, 225))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('p-AKT', 'Gene', '11651', (220, 225))	('tested', 'Reg', (113, 119))	('Kras', 'Gene', (59, 63))	('AKT', 'Gene', (215, 218))	('p-AKT', 'Gene', (220, 225))	('tumors', 'Disease', (170, 176))
134704	27797363	p53fl/fl;KrasG12D;myr-p110alphawt/fl mammary tumors with one copy of myr-p110alpha had further elevated expression levels of total p110alpha (39-fold), and this resulted in increased p-AKT levels by 48-fold and increased p-AKT/AKT ratio (52-fold; Figures 2c and d).	('AKT', 'Gene', '11651', (227, 230))	('AKT', 'Gene', (223, 226))	('increased', 'PosReg', (173, 182))	('AKT', 'Gene', '11651', (185, 188))	('Kras', 'Gene', (9, 13))	('p-AKT', 'Gene', '11651', (221, 226))	('p-AKT', 'Gene', '11651', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('increased', 'PosReg', (211, 220))	('expression', 'MPA', (104, 114))	('AKT', 'Gene', '11651', (223, 226))	('p-AKT', 'Gene', (221, 226))	('Kras', 'Gene', '16653', (9, 13))	('p-AKT', 'Gene', (183, 188))	('p110alpha', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('elevated', 'PosReg', (95, 103))	('tumors', 'Disease', (45, 51))	('AKT', 'Gene', (227, 230))	('AKT', 'Gene', (185, 188))	('tumors', 'Disease', 'MESH:D009369', (45, 51))
134706	27797363	Mammary tumors from p53fl/fl;KrasG12D;myr-p110alphawt/fl mice had elevated accumulation of regulatory subunit p85alpha by two-fold as compared with normal mammary tissue, whereas p53fl/fl;KrasG12D mammary tumors displayed significantly decreased p85alpha level (0.6-fold) as shown in Figures 2e and f. The PTEN levels had a modest but statistically significant 0.6-fold decrease in p53fl/fl;KrasG12D mammary tumors compared with normal mammary tissue (Figures 2e and f).	('Kras', 'Gene', '16653', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (408, 414))	('Kras', 'Gene', (391, 395))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('elevated accumulation', 'PosReg', (66, 87))	('PTEN', 'Gene', (306, 310))	('decrease', 'NegReg', (370, 378))	('Kras', 'Gene', '16653', (391, 395))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (408, 414))	('Kras', 'Gene', (188, 192))	('p53fl/fl', 'Var', (20, 28))	('p85alpha', 'Gene', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('Kras', 'Gene', (29, 33))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Disease', (408, 414))	('PTEN', 'Gene', '19211', (306, 310))	('p85alpha', 'Gene', (246, 254))	('Kras', 'Gene', '16653', (188, 192))	('p85alpha', 'Gene', '18708', (110, 118))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('p85alpha', 'Gene', '18708', (246, 254))
134712	27797363	In accordance with this result, addition of two copies of myr-p110alpha into homozygous p53 deletion (p53fl/fl;myr-p110alphafl/fl) also facilitated mammary tumor initiation compared with p53fl/fl;myr-p110alphawt/fl (135.1+-6.2 days vs 259.6+-10.6 days; Figure 3b).	('deletion', 'Var', (92, 100))	('facilitated', 'PosReg', (136, 147))	('tumor initiation', 'Disease', 'MESH:D009369', (156, 172))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('p53', 'Gene', (88, 91))	('tumor initiation', 'Disease', (156, 172))
134713	27797363	To check whether there would be a correlation between the extent of PI3K signaling activation and the rate of tumor initiation, we evaluated the PI3K signaling activation status by comparing the levels of p-AKT between p53fl/fl;myr-p110alphawt/fl, p53fl/fl;myr-p110alphafl/fl, p53fl/fl;KrasG12D;myr-p110alphawt/fl and p53fl/fl;KrasG12D;myr-p110alphafl/fl mammary tumors.	('Kras', 'Gene', '16653', (327, 331))	('tumor initiation', 'Disease', 'MESH:D009369', (110, 126))	('p53fl/fl', 'Var', (277, 285))	('tumors', 'Disease', (363, 369))	('tumors', 'Disease', 'MESH:D009369', (363, 369))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('p-AKT', 'Gene', (205, 210))	('p-AKT', 'Gene', '11651', (205, 210))	('p53fl/fl', 'Var', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('p53fl/fl', 'Var', (248, 256))	('tumor initiation', 'Disease', (110, 126))	('Kras', 'Gene', '16653', (286, 290))	('mammary', 'Disease', (355, 362))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('Kras', 'Gene', (327, 331))	('Kras', 'Gene', (286, 290))
134714	27797363	Two copies of myr-p110alpha significantly elevated levels of total p110alpha (1.9-fold) and p-AKT (2.1-fold), as compared with one copy of myr-p110alpha (Figures 3c and d).	('myr-p110alpha', 'Var', (14, 27))	('p110alpha', 'MPA', (67, 76))	('p-AKT', 'Gene', (92, 97))	('p-AKT', 'Gene', '11651', (92, 97))	('elevated', 'PosReg', (42, 50))
134715	27797363	We also tested the extent of PI3K signaling activation in mammary tumors harboring zero, one or two copies of myr-p110alpha transgene combined with either p53fl/fl or p53fl/fl;KrasG12D mutants.	('tested', 'Reg', (8, 14))	('Kras', 'Gene', '16653', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('myr-p110alpha', 'Gene', (110, 123))	('p53fl/fl', 'Var', (155, 163))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Kras', 'Gene', (176, 180))
134716	27797363	These data demonstrate that a single copy of myr-p110alpha does not saturate the PI3K signaling pathway with regard to p-AKT levels and two copies of myr-p110alpha further activate PI3K signaling to a greater degree than that induced by a single copy of myr-p110alpha in mammary tumors, resulting in the increased rate of tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('PI3K signaling', 'Pathway', (181, 195))	('activate', 'PosReg', (172, 180))	('p-AKT', 'Gene', (119, 124))	('tumors', 'Disease', (279, 285))	('tumor initiation', 'Disease', (322, 338))	('p-AKT', 'Gene', '11651', (119, 124))	('tumor initiation', 'Disease', 'MESH:D009369', (322, 338))	('increased', 'PosReg', (304, 313))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('myr-p110alpha', 'Var', (150, 163))	('rate', 'MPA', (314, 318))
134717	27797363	As the rate of tumor initiation was further influenced by the addition of KrasG12D mutation into p53fl/fl;myr-p110alpha, which has been shown to signal primarily through the PI3K/AKT pathway, we assessed the levels of PI3K signaling activation in p53fl/fl;myr-p110alpha mammary tumors with or without KrasG12D mutation.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('Kras', 'Gene', (74, 78))	('AKT', 'Gene', (179, 182))	('Kras', 'Gene', '16653', (74, 78))	('Kras', 'Gene', (301, 305))	('Kras', 'Gene', '16653', (301, 305))	('tumors', 'Disease', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('influenced', 'Reg', (44, 54))	('tumor initiation', 'Disease', 'MESH:D009369', (15, 31))	('p53fl/fl;myr-p110alpha', 'Var', (247, 269))	('activation', 'PosReg', (233, 243))	('AKT', 'Gene', '11651', (179, 182))	('tumor initiation', 'Disease', (15, 31))
134719	27797363	Interestingly, the addition of two copies of myr-p110alpha also modestly but significantly accelerated tumor progression, as revealed by the survival curve (Figure 3e).	('myr-p110alpha', 'Var', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('accelerated', 'PosReg', (91, 102))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
134724	27797363	Histological analysis of mammary tumors from p53fl/fl;KrasG12D;myr-p110alphafl/fl mice demonstrated an increase in tumors with a carcinoma phenotype including both DCIS and invasive ductal carcinoma (Figure 4a).	('increase', 'PosReg', (103, 111))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (182, 198))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (173, 198))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('carcinoma', 'Disease', 'MESH:D002277', (129, 138))	('p53fl/fl', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('invasive ductal carcinoma', 'Disease', (173, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('mice', 'Species', '10090', (82, 86))	('Kras', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('carcinoma', 'Disease', (189, 198))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('Kras', 'Gene', '16653', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('carcinoma', 'Disease', (129, 138))	('tumors', 'Disease', (33, 39))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))	('DCIS', 'Disease', (164, 168))
134727	27797363	As the copy number of myr-p110alpha doubled, the majority of p53fl/fl;myr-p110alphafl/flmammary tumors also developed a carcinoma phenotype, whereas p53fl/fl;myr-p110alphawt/fl mammary tumors developed dedifferentiated mixed tumors with sarcomatoid features and only focal areas of carcinoma (Supplementary Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', (185, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('carcinoma', 'Disease', 'MESH:D002277', (282, 291))	('carcinoma', 'Disease', (120, 129))	('myr-p110alpha doubled', 'Var', (22, 43))	('sarcomatoid', 'Disease', 'MESH:C538614', (237, 248))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('developed', 'Reg', (108, 117))	('flmammary tumors', 'Disease', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('carcinoma', 'Disease', (282, 291))	('tumors', 'Disease', (225, 231))	('flmammary tumors', 'Disease', 'MESH:D009369', (86, 102))	('sarcomatoid', 'Disease', (237, 248))
134728	27797363	These findings show that increased PI3K activity mediated by two copies of myr-p110alpha, when combined with either p53fl/fl or p53fl/fl;KrasG12D, have the potential to skew mammary tumors from a sarcomatoid phenotype to a carcinoma phenotype more common in humans.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Kras', 'Gene', (137, 141))	('PI3K', 'Enzyme', (35, 39))	('myr-p110alpha', 'Var', (75, 88))	('activity', 'MPA', (40, 48))	('sarcomatoid', 'Disease', (196, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('carcinoma', 'Disease', (223, 232))	('Kras', 'Gene', '16653', (137, 141))	('tumors', 'Disease', (182, 188))	('humans', 'Species', '9606', (258, 264))	('increased PI3K activity', 'Phenotype', 'HP:0003240', (25, 48))	('p53fl/fl', 'Var', (116, 124))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('sarcomatoid', 'Disease', 'MESH:C538614', (196, 207))	('carcinoma', 'Disease', 'MESH:D002277', (223, 232))	('increased', 'PosReg', (25, 34))	('skew', 'Reg', (169, 173))
134729	27797363	As part of the pathological characterization, tumors were stained for the following markers: CK5, CK14, CK8, ERalpha, PR, Her2/neu and vimentin.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Her2/neu', 'Protein', (122, 130))	('CK14', 'Var', (98, 102))	('vimentin', 'Protein', (135, 143))	('CK5', 'Var', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('CK8', 'Gene', (104, 107))	('tumors', 'Disease', (46, 52))	('ERalpha', 'Gene', (109, 116))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
134735	27797363	17 days after injection, mice injected with the p53fl/fl;KrasG12D;myr-p110alphafl/fl breast tumor cells produced significantly more identifiable tumors in the lungs (mean 318.6+-7.4) compared with mice injected either with p53fl/fl;KrasG12D breast tumor cells (mean 6.3+-2.6) or p53fl/fl;KrasG12D;myr-p110alphawt/fl breast tumor cells (mean 206.1+-10.0; Figure 5).	('breast tumor', 'Disease', 'MESH:D001943', (241, 253))	('Kras', 'Gene', (288, 292))	('p53fl/fl', 'Var', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('breast tumor', 'Phenotype', 'HP:0100013', (241, 253))	('mice', 'Species', '10090', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('Kras', 'Gene', (232, 236))	('Kras', 'Gene', (57, 61))	('more', 'PosReg', (127, 131))	('breast tumor', 'Disease', (241, 253))	('Kras', 'Gene', '16653', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast tumor', 'Disease', 'MESH:D001943', (316, 328))	('mice', 'Species', '10090', (25, 29))	('Kras', 'Gene', '16653', (232, 236))	('Kras', 'Gene', '16653', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('breast tumor', 'Disease', 'MESH:D001943', (85, 97))	('breast tumor', 'Phenotype', 'HP:0100013', (316, 328))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('breast tumor', 'Disease', (316, 328))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('breast tumor', 'Disease', (85, 97))
134736	27797363	This suggests that the myr-p110alpha promotes growth of metastatic tumors in a copy number-dependent manner.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('myr-p110alpha', 'Var', (23, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('growth', 'CPA', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('promotes', 'PosReg', (37, 45))
134737	27797363	One intentional aspect of the generation of this Cre-inducible mouse model and the utilization of Ad-cre virus is the ability to genetically modify different anatomic locations and potentially cause different tumor types.	('mouse', 'Species', '10090', (63, 68))	('cause', 'Reg', (193, 198))	('tumor', 'Disease', (209, 214))	('genetically', 'Var', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('modify', 'Reg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
134742	27797363	These findings indicate that the addition of myr-p110alpha promotes lung tumor development.	('myr-p110alpha', 'Var', (45, 58))	('lung tumor', 'Phenotype', 'HP:0100526', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('lung tumor', 'Disease', 'MESH:D008175', (68, 78))	('promotes', 'PosReg', (59, 67))	('lung tumor', 'Disease', (68, 78))
134743	27797363	In contrast with breast cancer, the addition of one copy of myr-p110alpha into p53fl/fl;KrasG12D did not change histology of the lung tumors.	('lung tumors', 'Disease', 'MESH:D008175', (129, 140))	('Kras', 'Gene', (88, 92))	('Kras', 'Gene', '16653', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung tumors', 'Disease', (129, 140))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('myr-p110alpha', 'Var', (60, 73))	('lung tumors', 'Phenotype', 'HP:0100526', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lung tumor', 'Phenotype', 'HP:0100526', (129, 139))
134746	27797363	This finding was similar to the breast tumor experiments, in which survival time was cut in half by addition of one copy of myr-p110alpha.	('cut', 'NegReg', (85, 88))	('survival time', 'CPA', (67, 80))	('myr-p110alpha', 'Var', (124, 137))	('breast tumor', 'Disease', 'MESH:D001943', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('breast tumor', 'Disease', (32, 44))	('breast tumor', 'Phenotype', 'HP:0100013', (32, 44))
134747	27797363	Overall, our observations demonstrate that the addition of constitutively active myr-p110alpha allele causes early tumor initiation in the lung, leading to early death related to lung tumors.	('lung tumor', 'Phenotype', 'HP:0100526', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lung tumors', 'Disease', 'MESH:D008175', (179, 190))	('tumor initiation', 'Disease', 'MESH:D009369', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('lung tumors', 'Disease', (179, 190))	('myr-p110alpha', 'Gene', (81, 94))	('tumor initiation', 'Disease', (115, 131))	('death', 'Disease', 'MESH:D003643', (162, 167))	('death', 'Disease', (162, 167))	('addition', 'Var', (47, 55))	('lung tumors', 'Phenotype', 'HP:0100526', (179, 190))
134749	27797363	Notably, by evaluating differences in the p-AKT levels between mammary tumors harboring zero, one or two copies of myr-p110alpha allele combined with either p53fl/fl or p53fl/fl;KrasG12D mutants, our results proved that the levels of PI3K signaling activation are significantly increased and strongly correlated with the increased rate of tumor initiation in a myr-p110alpha copy number-dependent manner.	('p53fl/fl', 'Var', (157, 165))	('tumor initiation', 'Disease', (339, 355))	('increased', 'PosReg', (278, 287))	('tumor initiation', 'Disease', 'MESH:D009369', (339, 355))	('PI3K signaling', 'Pathway', (234, 248))	('activation', 'PosReg', (249, 259))	('tumors', 'Disease', (71, 77))	('Kras', 'Gene', (178, 182))	('Kras', 'Gene', '16653', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('p-AKT', 'Gene', (42, 47))	('p-AKT', 'Gene', '11651', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
134750	27797363	These data demonstrated that higher levels of PI3K activity induced by myr-p110alpha addition have profound effects on tumor initiation.	('higher', 'PosReg', (29, 35))	('tumor initiation', 'Disease', (119, 135))	('effects', 'Reg', (108, 115))	('PI3K', 'CPA', (46, 50))	('myr-p110alpha', 'Var', (71, 84))	('tumor initiation', 'Disease', 'MESH:D009369', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
134751	27797363	In addition, our results showed that the biological activity of PI3K signaling can be further activated by cooperation of myr-p110alpha with KrasG12D mutation.	('biological activity', 'MPA', (41, 60))	('Kras', 'Gene', '16653', (141, 145))	('myr-p110alpha', 'Var', (122, 135))	('cooperation', 'Interaction', (107, 118))	('Kras', 'Gene', (141, 145))	('activated', 'PosReg', (94, 103))
134752	27797363	Our data from the use of breast tumor cells also determined that the addition of myr-p110alpha allele into p53fl/fl;KrasG12D mutants facilitates engraftment in the lungs, as an assay of metastatic potential, in a copy number-dependent manner.	('breast tumor', 'Disease', (25, 37))	('facilitates', 'PosReg', (133, 144))	('Kras', 'Gene', (116, 120))	('Kras', 'Gene', '16653', (116, 120))	('breast tumor', 'Phenotype', 'HP:0100013', (25, 37))	('mutants', 'Var', (125, 132))	('p53fl/fl', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('breast tumor', 'Disease', 'MESH:D001943', (25, 37))	('engraftment in the lungs', 'CPA', (145, 169))
134754	27797363	Although p53fl/fl;KrasG12D;myr-p110alphawt/fl mice did not have increased growth rates of breast tumors as compared with p53fl/fl;KrasG12D mice once tumors had developed, there was a modest but significant increase in the growth rate of tumors following initiation in p53fl/fl;KrasG12D mice with two copies of myr-p110alpha as compared with p53fl/fl;KrasG12D mice and p53fl/fl;KrasG12Dmice with one copy of myr-p110alpha.	('breast tumors', 'Disease', (90, 103))	('Kras', 'Gene', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('Kras', 'Gene', '16653', (377, 381))	('breast tumors', 'Phenotype', 'HP:0100013', (90, 103))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumors', 'Disease', (97, 103))	('Kras', 'Gene', (18, 22))	('breast tumor', 'Phenotype', 'HP:0100013', (90, 102))	('breast tumors', 'Disease', 'MESH:D001943', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumors', 'Disease', (237, 243))	('Kras', 'Gene', '16653', (130, 134))	('mice', 'Species', '10090', (385, 389))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53fl/fl', 'Var', (268, 276))	('Kras', 'Gene', (350, 354))	('tumors', 'Disease', (149, 155))	('Kras', 'Gene', '16653', (18, 22))	('mice', 'Species', '10090', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('Kras', 'Gene', (277, 281))	('myr-p110alpha', 'Var', (310, 323))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('Kras', 'Gene', '16653', (350, 354))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('mice', 'Species', '10090', (359, 363))	('growth', 'MPA', (222, 228))	('Kras', 'Gene', '16653', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Kras', 'Gene', (377, 381))	('mice', 'Species', '10090', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mice', 'Species', '10090', (286, 290))	('p53fl/fl', 'Var', (9, 17))	('increase', 'PosReg', (206, 214))
134756	27797363	In our study, the addition of myr-p110alpha allele into p53fl/fl;KrasG12D or p53fl/fl that resulted in significantly increased PI3K/AKT signaling activation generated a carcinoma histologic phenotype in a myr-p110alpha copy number-dependent manner.	('activation', 'PosReg', (146, 156))	('p53fl/fl', 'Var', (77, 85))	('increased', 'PosReg', (117, 126))	('AKT', 'Gene', '11651', (132, 135))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('AKT', 'Gene', (132, 135))	('carcinoma', 'Disease', (169, 178))	('Kras', 'Gene', (65, 69))	('p53fl/fl', 'Var', (56, 64))	('Kras', 'Gene', '16653', (65, 69))
134757	27797363	The resulting tumors induced by the addition of myr-p110alpha allele resembled those that are commonly seen in the majority of human breast cancer.	('myr-p110alpha', 'Var', (48, 61))	('breast cancer', 'Disease', (133, 146))	('human', 'Species', '9606', (127, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
134759	27797363	Thus, these findings suggest that levels of PI3K signaling might have a distinct impact on developing carcinoma phenotypes in humans.	('impact', 'Reg', (81, 87))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))	('humans', 'Species', '9606', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('PI3K', 'Var', (44, 48))	('carcinoma', 'Disease', (102, 111))
134760	27797363	As the histological phenotype of tumors with two copies of myr-p110alpha was quite different than tumors with one copy, the increased growth rate induced by two copies could be attributed to the difference in tumor type generated by one versus two copies.	('tumors', 'Disease', (98, 104))	('tumor', 'Disease', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('increased', 'PosReg', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('growth rate', 'MPA', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (98, 103))	('myr-p110alpha', 'Var', (59, 72))	('tumors', 'Disease', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
134761	27797363	One limitation of our study is that we did not define the relation between the spatial expression levels of myr-p110alpha or resulting p-AKT levels and histological features within the specific tumor areas.	('p-AKT', 'Gene', (135, 140))	('p-AKT', 'Gene', '11651', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('myr-p110alpha', 'Var', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))
134766	27797363	Current mouse breast tumors driven by PI3KCA activating mutations mimic histopathologic phenotypes observed in human breast cancers; however, these single genetic mutation mouse models can take a year to develop breast tumors.	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('mouse', 'Species', '10090', (8, 13))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (111, 116))	('breast tumors', 'Disease', 'MESH:D001943', (212, 225))	('breast tumors', 'Disease', (212, 225))	('breast tumors', 'Disease', (14, 27))	('breast tumors', 'Disease', 'MESH:D001943', (14, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('breast tumors', 'Phenotype', 'HP:0100013', (212, 225))	('mouse', 'Species', '10090', (172, 177))	('breast tumor', 'Phenotype', 'HP:0100013', (212, 224))	('breast tumors', 'Phenotype', 'HP:0100013', (14, 27))	('breast tumor', 'Phenotype', 'HP:0100013', (14, 26))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('PI3KCA', 'Gene', (38, 44))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
134767	27797363	Our mouse model that combines one or two copies of myr-p110alpha with p53fl/fl;KrasG12D can resemble human breast cancer subtypes, as well as develop tumors early and grow quickly, leading to a shortened experimental timeline from tumor initiation to end stage.	('grow', 'CPA', (167, 171))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Disease', (150, 156))	('myr-p110alpha', 'Var', (51, 64))	('develop', 'PosReg', (142, 149))	('Kras', 'Gene', (79, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('mouse', 'Species', '10090', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumor initiation', 'Disease', 'MESH:D009369', (231, 247))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('human', 'Species', '9606', (101, 106))	('experimental timeline', 'MPA', (204, 225))	('breast cancer', 'Disease', (107, 120))	('Kras', 'Gene', '16653', (79, 83))	('tumor initiation', 'Disease', (231, 247))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))
134768	27797363	Spontaneous additional mutations have been demonstrated to accumulate along with epigenetic events resulting in an increased level of genetic complexity in human cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('human', 'Species', '9606', (156, 161))
134770	27797363	These mutations are repeatedly altered in human cancers, so they represent relevant genetic alterations that can be used in developing models to closely mimic the pathological and biochemical features of cancers.	('cancers', 'Disease', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('human', 'Species', '9606', (42, 47))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('mutations', 'Var', (6, 15))
134773	27797363	In summary, this novel triple mutation model system (1) is an autochthonous genetic model of human cancer, (2) provides controlled inducible expression of genetic changes spatially and temporally, (3) induces tumor subtypes matched histologically to human breast tumors, and (4) develops tumors very rapidly.	('mutation', 'Var', (30, 38))	('breast tumors', 'Disease', 'MESH:D001943', (256, 269))	('breast tumors', 'Disease', (256, 269))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('changes', 'Var', (163, 170))	('breast tumors', 'Phenotype', 'HP:0100013', (256, 269))	('tumor', 'Disease', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('breast tumor', 'Phenotype', 'HP:0100013', (256, 268))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('human', 'Species', '9606', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('induces', 'PosReg', (201, 208))	('cancer', 'Disease', (99, 105))	('tumors', 'Disease', (263, 269))	('human', 'Species', '9606', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (288, 294))
134775	27797363	The transgenic Cre-inducible myristoylated-p110alpha mice on C57BL/6 backgrounds were generated and intercrossed with Cre-inducible mice carrying either only p53 deletion homozygote (p53fl/fl, which deletes exon 2 to exon 10 leading to null alleles of p53 upon Cre-mediated excision) or p53fl/fl and KrasG12D mutations (p53fl/fl;KrasG12D, intercrossed) on C57BL/6 backgrounds.	('deletes', 'Var', (199, 206))	('mice', 'Species', '10090', (53, 57))	('Kras', 'Gene', (329, 333))	('Kras', 'Gene', '16653', (329, 333))	('Kras', 'Gene', '16653', (300, 304))	('mice', 'Species', '10090', (132, 136))	('transgenic', 'Species', '10090', (4, 14))	('Kras', 'Gene', (300, 304))
134784	27797363	Sections were immunostained using standard manufacturer's protocols at the Dartmouth-Hitchcock Medical Center Laboratory for Clinical Genomics and Advanced Technology with the following antibodies: anti-CK5 (ab52635, Abcam, Cambridge, MA, USA), anti-CK14 (RB-9020, Thermo Scientific, Fremont, CA, USA), anti-CK8 (ab53280, Abcam), anti-estrogen receptor alpha (SC-542, Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-PR (RM-9102, Thermo Scientific), anti-HER2/neu (MA5-15050, Thermo Scientific) and anti-vimentin (ab92547, Abcam).	('anti-vimentin', 'Protein', (503, 516))	('HER2/neu', 'Gene', '13866', (459, 467))	('anti-CK5', 'Var', (198, 206))	('HER2/neu', 'Gene', (459, 467))	('anti-CK8', 'Var', (303, 311))	('anti-CK14', 'Var', (245, 254))	('MA5-15050', 'Var', (469, 478))
134786	27797363	Mammary tumors were lysed in ice-cold lysis buffer containing 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 1 mM NaVO4, protease inhibitor (11836170001, Roche, Indianapolis, IN, USA) and phosphatase inhibitor cocktail (P5726, Sigma-Aldrich, St Louis, MO, USA).	('P5726', 'Var', (238, 243))	('11836170001', 'Var', (159, 170))	('NaVO4', 'Chemical', '-', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Triton X-100', 'Chemical', 'MESH:D017830', (103, 115))	('P5726', 'Chemical', '-', (238, 243))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('Tris-HCl', 'Chemical', '-', (68, 76))	('SDS', 'Chemical', 'MESH:D012967', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('NaCl', 'Chemical', 'MESH:D012965', (94, 98))
134837	21035945	Here we report the cancer inhibitory activity of potential non-ALDH binding PDTC analogues in human breast cancer cells through the inhibition of proteasomal chymotrypsin-like activity.	('proteasomal chymotrypsin-like activity', 'MPA', (146, 184))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('non-ALDH binding', 'Protein', (59, 75))	('inhibition', 'NegReg', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PDTC', 'Gene', (76, 80))	('cancer', 'Disease', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('PDTC', 'Chemical', 'MESH:C020972', (76, 80))	('analogues', 'Var', (81, 90))	('human', 'Species', '9606', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancer', 'Disease', (107, 113))
134893	21035945	After treatment, cell condensation and rounding were detected in the cells treated with 1-Cu and 9-Cu, but not in cells treated with 5-Cu mixture even at concentration of 2.0 muM (Fig.	('rounding', 'CPA', (39, 47))	('1-Cu', 'Var', (88, 92))	('9-Cu', 'Chemical', '-', (97, 101))	('muM', 'Gene', (175, 178))	('cell condensation', 'CPA', (17, 34))	('1-Cu', 'Chemical', '-', (88, 92))	('detected', 'Reg', (53, 61))	('9-Cu', 'Var', (97, 101))	('5-Cu', 'Chemical', '-', (133, 137))	('muM', 'Gene', '56925', (175, 178))
134902	21035945	In the presence of 20 muM caspase inhibitor Z-VAD-FMK, the percentages of apoptotic cells (both early stage and late stage) were 13.7 +- 0.8% and 16.4 +- 0.7% respectively upon treatment with DSF-Cu mixture or 9-Cu mixture (Fig.	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (44, 53))	('9-Cu', 'Chemical', '-', (210, 214))	('muM', 'Gene', '56925', (22, 25))	('DSF-Cu', 'Chemical', '-', (192, 198))	('muM', 'Gene', (22, 25))	('Z-VAD-FMK', 'Var', (44, 53))
134906	21035945	The caspase 3/7 activity of MDA-MB-231 treated with DSF-Cu and 9-Cu mixtures are 61.6% and 60.6% respectively, corresponding to at least 6-fold increase of caspase 3/7 activity compared with that of cells treated with vehicle (Fig.	('9-Cu', 'Chemical', '-', (63, 67))	('activity', 'MPA', (168, 176))	('caspase 3', 'Gene', '836', (4, 13))	('DSF-Cu', 'Chemical', '-', (52, 58))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (28, 38))	('caspase 3', 'Gene', (156, 165))	('DSF-Cu', 'Var', (52, 58))	('caspase 3', 'Gene', '836', (156, 165))	('activity', 'MPA', (16, 24))	('increase', 'PosReg', (144, 152))	('caspase 3', 'Gene', (4, 13))
134913	21035945	However, the accumulation of ubiquitinated proteins was detected by Western blot analysis in the cells treated with 9-Cu and 1-Cu but not in cells treated with 5-Cu (Fig.	('ubiquitinated proteins', 'MPA', (29, 51))	('accumulation', 'PosReg', (13, 25))	('9-Cu', 'Var', (116, 120))	('1-Cu', 'Chemical', '-', (125, 129))	('5-Cu', 'Chemical', '-', (160, 164))	('9-Cu', 'Chemical', '-', (116, 120))	('1-Cu', 'Var', (125, 129))
134934	21035945	To develop potent anti-cancer compounds that are not ALDH inhibitors, we synthesized a series of PDTC analogues and studied their ALDH-independent anti-cancer activities.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('PDTC', 'Gene', (97, 101))	('cancer', 'Disease', (23, 29))	('analogues', 'Var', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('PDTC', 'Chemical', 'MESH:C020972', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
134936	21035945	In docking studies using structures of ALDH1 and ALDH2 as templates, we found that it is less likely that compound 9 can form covalent bond with Cys302 in both ALDH1 and ALDH2 (Fig.	('ALDH2', 'Gene', (170, 175))	('Cys302', 'Chemical', '-', (145, 151))	('ALDH1', 'Gene', (39, 44))	('ALDH1', 'Gene', (160, 165))	('ALDH1', 'Gene', '216', (39, 44))	('Cys302', 'Var', (145, 151))	('ALDH1', 'Gene', '216', (160, 165))
134967	32889303	Considering all the FNs, 91.1% (317/348) of index lesions were enhanced with CEDM, 94.57% for invasive cancer (296/313), and 60.00% for DCIS (21/35).	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CEDM', 'Var', (77, 81))	('enhanced', 'PosReg', (63, 71))	('invasive cancer', 'Disease', (94, 109))	('invasive cancer', 'Disease', 'MESH:D009362', (94, 109))
134983	31637884	By definition, pure DCIS has no potential to spread tumor cells to the axillary lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('pure DCIS', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
135263	30627022	Forty breast cancers (13.3%) were detectable only with DBT; 191 (63.7%) breast cancers were detected with both FFDM and DBT, and 69 (23%) were not detected with either.	('FFDM', 'Chemical', '-', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancers', 'Disease', 'MESH:D001943', (6, 20))	('DBT', 'Var', (120, 123))	('breast cancers', 'Disease', (6, 20))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('breast cancers', 'Disease', (72, 86))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
135264	30627022	Cancer detectability scores were significantly higher for DBT than for conventional FFDM (median score, 6; range, 0-6; p < 0.001).	('DBT', 'Var', (58, 61))	('higher', 'PosReg', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('FFDM', 'Chemical', '-', (84, 88))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
135270	30627022	Invasive lobular, low-grade, or HER-2-negative cancer is more detectable with DBT than with conventional FFDM in patients with dense breasts, but cancers surrounded by mostly glandular tissue might be missed with both techniques.	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', (146, 153))	('DBT', 'Var', (78, 81))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('HER-2', 'Gene', '2064', (32, 37))	('patients', 'Species', '9606', (113, 121))	('low-grade', 'CPA', (18, 27))	('cancer', 'Disease', (47, 53))	('FFDM', 'Chemical', '-', (105, 109))	('HER-2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Invasive lobular', 'Disease', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
135275	30627022	One study reported that DBT increases the sensitivity and specificity of breast cancer detection, while another demonstrated that DBT increases the diagnostic accuracy of lesion detection and margin characterization.	('increases', 'PosReg', (28, 37))	('diagnostic accuracy', 'CPA', (148, 167))	('DBT', 'Var', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('DBT', 'Var', (24, 27))	('margin characterization', 'CPA', (192, 215))	('lesion detection', 'CPA', (171, 187))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('increases', 'PosReg', (134, 143))
135311	30627022	Detectability scores for DBT images were significantly higher than those for conventional FFDM images (median score, 6; range 0-6; p < 0.001).	('DBT', 'Var', (25, 28))	('FFDM', 'Chemical', '-', (90, 94))	('higher', 'PosReg', (55, 61))	('Detectability scores', 'MPA', (0, 20))
135325	30627022	Forty breast cancers (13.3%) were more detectable on DBT and the detectability score was higher on DBT than on conventional FFDM.	('FFDM', 'Chemical', '-', (124, 128))	('DBT', 'Var', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancers', 'Phenotype', 'HP:0003002', (6, 20))	('breast cancers', 'Disease', 'MESH:D001943', (6, 20))	('breast cancers', 'Disease', (6, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('higher', 'PosReg', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))
135326	30627022	Our result of 13.3% increase in cancer detection on DBT is comparable to those of single- or multi-center studies, which reported a 10-51% increase in cancer detection.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', (151, 157))	('DBT', 'Var', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('increase', 'PosReg', (20, 28))
135327	30627022	In our study, 271 of 300 lesions (90.3%) showed a higher detectability score on DBT than on FFDM, which was similar to the results of several previous studies that reported the superiority of DBT over conventional FFDM images.	('detectability', 'MPA', (57, 70))	('higher', 'PosReg', (50, 56))	('FFDM', 'Chemical', '-', (214, 218))	('FFDM', 'Chemical', '-', (92, 96))	('DBT', 'Var', (80, 83))
135328	30627022	compared breast cancer detectability between one-view breast tomosynthesis and one- or two-view conventional FFDM, and observed that breast cancer visibility was ranked higher on DBT than on conventional FFDM in 55%.	('higher', 'PosReg', (169, 175))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('FFDM', 'Chemical', '-', (109, 113))	('FFDM', 'Chemical', '-', (204, 208))	('DBT', 'Var', (179, 182))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
135333	30627022	reported that 96% (28/29) of breast cancers detected with DBT were invasive, while only 75% (46/61) of breast cancers detected with conventional FFDM mammography were invasive.	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('DBT', 'Var', (58, 61))	('FFDM', 'Chemical', '-', (145, 149))	('breast cancers', 'Disease', (103, 117))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('breast cancers', 'Phenotype', 'HP:0003002', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancers', 'Disease', 'MESH:D001943', (29, 43))	('breast cancers', 'Disease', (29, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
135337	30627022	In a study analyzing discrepancies in breast cancer detection on DBT and FFDM, it was found that invasive lobular cancer was more often visible on DBT as spiculated masses, where there was any radiologic findings on FFDM.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('DBT', 'Var', (147, 150))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('invasive lobular cancer', 'Disease', (97, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (97, 120))	('FFDM', 'Chemical', '-', (216, 220))	('lobular cancer', 'Phenotype', 'HP:0030076', (106, 120))	('FFDM', 'Chemical', '-', (73, 77))
135427	27515302	Blockade of IL-6 reduced TAF-stimulated DCIS growth and proliferation and reduced the formation of TAF-cancer cell interconnections.	('formation of', 'CPA', (86, 98))	('TAF', 'Gene', '3490', (99, 102))	('TAF', 'Gene', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TAF-cancer', 'Disease', (99, 109))	('IL-6', 'Gene', (12, 16))	('Blockade', 'Var', (0, 8))	('IL-6', 'Gene', '3569', (12, 16))	('TAF', 'Gene', '3490', (25, 28))	('reduced', 'NegReg', (74, 81))	('TAF', 'Gene', (99, 102))	('TAF-cancer', 'Disease', 'MESH:D009369', (99, 109))	('reduced', 'NegReg', (17, 24))	('DCIS growth', 'CPA', (40, 51))
135451	27515302	Dysregulation of miR expression has been implicated in tumor cell promotion, migration, and invasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR', 'Protein', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Dysregulation', 'Var', (0, 13))	('invasion', 'CPA', (92, 100))	('tumor', 'Disease', (55, 60))	('migration', 'CPA', (77, 86))	('implicated', 'Reg', (41, 51))
135455	27515302	Among these, high miR-21 expression was found to be correlated with decreased overall patient survival as well as patient lymph node invasion and metastasis.	('decreased', 'NegReg', (68, 77))	('miR-21', 'Gene', '406991', (18, 24))	('patient survival', 'CPA', (86, 102))	('metastasis', 'CPA', (146, 156))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('miR-21', 'Gene', (18, 24))	('patient', 'Species', '9606', (86, 93))	('patient lymph node invasion', 'CPA', (114, 141))	('patient', 'Species', '9606', (114, 121))
135460	27515302	Dysregulation of miRs has also been found to impact common signaling cascades in TAFs, such as the mitogen-activated protein kinase (MAPK)/ERK pathway.	('Dysregulation', 'Var', (0, 13))	('ERK', 'Gene', '5594', (139, 142))	('signaling', 'MPA', (59, 68))	('ERK', 'Gene', (139, 142))	('impact', 'Reg', (45, 51))	('TAF', 'Gene', (81, 84))	('miRs', 'Gene', (17, 21))	('TAF', 'Gene', '3490', (81, 84))
135466	27515302	Recent evidence suggests that epigenetic gene silencing due to CpG island methylation may be responsible for miR dysregulation in TAFs.	('miR dysregulation', 'Disease', (109, 126))	('TAF', 'Gene', (130, 133))	('epigenetic gene silencing', 'Var', (30, 55))	('TAF', 'Gene', '3490', (130, 133))	('CpG', 'Protein', (63, 66))
135468	27515302	The authors identified a GC-rich region upstream of the miR-149 start site which was hypermethylated in TAFs compared with normal fibroblasts.	('hypermethylated', 'Var', (85, 100))	('TAF', 'Gene', (104, 107))	('TAF', 'Gene', '3490', (104, 107))	('miR-149', 'Gene', (56, 63))	('miR-149', 'Gene', '406941', (56, 63))
135469	27515302	Furthermore, the authors found that prostaglandin E2, an inflammatory mediator in cancer, triggered DNA methylation of the miR-149 gene, leading to a reduction in miR-149 expression.	('DNA', 'Var', (100, 103))	('expression', 'MPA', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR-149', 'Gene', (123, 130))	('miR-149', 'Gene', '406941', (123, 130))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('reduction', 'NegReg', (150, 159))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (36, 52))	('miR-149', 'Gene', (163, 170))	('miR-149', 'Gene', '406941', (163, 170))
135470	27515302	Interestingly, while hypomethylation of miRs is frequent in cancer, no examples of hypomethylation as a possible mechanism of miR dysregulation in TAFs were found.	('TAF', 'Gene', (147, 150))	('hypomethylation', 'Var', (21, 36))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('TAF', 'Gene', '3490', (147, 150))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
135472	27515302	found that, upon delivery of microvesicles expressing miR-155, normal pancreatic murine fibroblasts converted into a TAF-like cell.	('pancreatic', 'Disease', (70, 80))	('TAF', 'Gene', (117, 120))	('murine', 'Species', '10090', (81, 87))	('miR-155', 'Var', (54, 61))	('TAF', 'Gene', '3490', (117, 120))	('pancreatic', 'Disease', 'MESH:D010195', (70, 80))
135473	27515302	In addition, the authors determined that microvesicles derived from pancreatic cancer cells overexpressed miR-155, indicating that pancreatic cancer cells may co-opt normal fibroblasts, transitioning them into TAFs via production of microvesicles containing miR-155.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('TAF', 'Gene', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('miR-155', 'Var', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('TAF', 'Gene', '3490', (210, 213))	('pancreatic cancer', 'Disease', (131, 148))	('transitioning', 'Reg', (186, 199))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
135474	27515302	In a similar study, normal human omental fibroblasts were triple transfected with anti-miR-31, anti-miR-214, and pre-miR-155.	('miR-214', 'Gene', (100, 107))	('miR-214', 'Gene', '406996', (100, 107))	('human', 'Species', '9606', (27, 32))	('miR-31', 'Gene', (87, 93))	('pre-miR-155', 'Var', (113, 124))	('miR-31', 'Gene', '407035', (87, 93))
135476	27515302	On the other hand, when ovarian cancer cell-associated fibroblasts were triple transfected with pre-miR-31, pre-miR-214, and anti-miR-155, the fibroblasts exhibited reduced migration, reduced invasion, as well as reduced colony formation.	('reduced', 'NegReg', (213, 220))	('ovarian cancer', 'Phenotype', 'HP:0100615', (24, 38))	('anti-miR-155', 'Var', (125, 137))	('miR-31', 'Gene', '407035', (100, 106))	('colony formation', 'CPA', (221, 237))	('miR-31', 'Gene', (100, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (24, 38))	('migration', 'CPA', (173, 182))	('miR-214', 'Gene', (112, 119))	('invasion', 'CPA', (192, 200))	('reduced', 'NegReg', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('ovarian cancer', 'Disease', (24, 38))	('miR-214', 'Gene', '406996', (112, 119))	('reduced', 'NegReg', (165, 172))
135477	27515302	Dysregulation of miR-210 has also been shown to convert fibroblasts into TAF-like cells.	('Dysregulation', 'Var', (0, 13))	('TAF', 'Gene', (73, 76))	('TAF', 'Gene', '3490', (73, 76))	('miR-210', 'Gene', (17, 24))	('miR-210', 'Gene', '406992', (17, 24))	('fibroblasts', 'CPA', (56, 67))	('convert', 'Reg', (48, 55))
135480	27515302	In one study, the miR pair miR-126/miR-126* was found to suppress MSC recruitment into the tumor stroma of breast cancer cells.	('tumor stroma of breast cancer', 'Disease', 'MESH:D001943', (91, 120))	('suppress', 'NegReg', (57, 65))	('miR-126/miR-126*', 'Var', (27, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor stroma of breast cancer', 'Disease', (91, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
135481	27515302	This phenomenon also led to inhibition of lung metastases in a mouse xenograft model via miR-126/miR-126* inhibition of stromal-derived factor-1 alpha and CCL2.	('mouse', 'Species', '10090', (63, 68))	('miR-126/miR-126*', 'Var', (89, 105))	('stromal-derived', 'Protein', (120, 135))	('inhibition', 'NegReg', (106, 116))	('inhibition', 'NegReg', (28, 38))	('lung metastases', 'Disease', (42, 57))	('lung metastases', 'Disease', 'MESH:D009362', (42, 57))
135483	27515302	Hypermethylation of the miR-149 promotor via cyclooxygenase-2/prostaglandin E2 and IL-6-mediated signaling led to repression of miR-149 expression in both human and murine fibroblasts in vitro and in vivo.	('repression', 'NegReg', (114, 124))	('expression', 'MPA', (136, 146))	('IL-6', 'Gene', '3569', (83, 87))	('Hypermethylation', 'Var', (0, 16))	('human', 'Species', '9606', (155, 160))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (62, 78))	('miR-149', 'Gene', (24, 31))	('miR-149', 'Gene', (128, 135))	('miR-149', 'Gene', '406941', (24, 31))	('murine', 'Species', '10090', (165, 171))	('IL-6', 'Gene', (83, 87))	('cyclooxygenase-2', 'Gene', (45, 61))	('miR-149', 'Gene', '406941', (128, 135))	('cyclooxygenase-2', 'Gene', '5743', (45, 61))
135509	27515302	Blockade of exosome biogenesis with GW4869 markedly decreased colorectal cancer-derived stem cell therapeutic resistance to both 5-fluorouracil and oxaliplatin, suggesting that fibroblast-derived exosomes act on colorectal cancer-derived stem cells via the Wnt3a signaling pathway to increase drug resistance.	('drug resistance', 'MPA', (293, 308))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('Wnt3a', 'Gene', '89780', (257, 262))	('colorectal cancer', 'Disease', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('decreased', 'NegReg', (52, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Wnt3a', 'Gene', (257, 262))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (129, 143))	('increase', 'PosReg', (284, 292))	('GW4869', 'Chemical', 'MESH:C468773', (36, 42))	('colorectal cancer', 'Disease', (62, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (212, 229))	('drug resistance', 'Phenotype', 'HP:0020174', (293, 308))	('colorectal cancer', 'Phenotype', 'HP:0003003', (212, 229))	('GW4869', 'Var', (36, 42))
135552	21468687	Aberrant expression patterns of BMP, which have been correlated to outcomes and prognosis in breast cancer, as well as stages of tumor progression, might be correlated to changes in TGF-ss signaling.	('BMP', 'Gene', '649', (32, 35))	('TGF', 'Gene', (182, 185))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (182, 185))	('Aberrant', 'Var', (0, 8))	('correlated', 'Reg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('changes', 'Reg', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('expression', 'MPA', (9, 19))	('BMP', 'Gene', (32, 35))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('tumor', 'Disease', (129, 134))
135558	21468687	Dysregulated expression of LTBP isoforms seem to be related to the onset of epithelial neoplasms.	('LTBP', 'Gene', (27, 31))	('expression', 'MPA', (13, 23))	('epithelial neoplasms', 'Disease', (76, 96))	('epithelial neoplasms', 'Phenotype', 'HP:0031492', (76, 96))	('Dysregulated', 'Var', (0, 12))	('neoplasms', 'Phenotype', 'HP:0002664', (87, 96))	('epithelial neoplasms', 'Disease', 'MESH:D002277', (76, 96))	('related', 'Reg', (52, 59))
135559	21468687	Here we investigated the possibility that changes in LTBP4 expression might be linked to the carcinogenesis of human mammary carcinomas, DCIS as well as mouse mammary tumors and DCIS.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('LTBP4', 'Gene', (53, 58))	('linked', 'Reg', (79, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('carcinomas', 'Disease', 'MESH:D002277', (125, 135))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (117, 134))	('human', 'Species', '9606', (111, 116))	('carcinomas', 'Disease', (125, 135))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('mouse', 'Species', '10090', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('changes', 'Var', (42, 49))	('DCIS', 'Disease', (137, 141))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
135584	21468687	It has been shown in the literature that the chosen cell lines MCF-7, Hs578T and Hs578BsT are sensitive to TGF-ss signaling and are therefore widely used to investigate the TGF-ss/BMP pathway.	('BMP', 'Gene', '649', (180, 183))	('Hs578BsT', 'Var', (81, 89))	('MCF-7', 'CellLine', 'CVCL:0031', (63, 68))	('BMP', 'Gene', (180, 183))	('sensitive', 'Reg', (94, 103))	('TGF', 'Gene', (107, 110))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (107, 110))	('TGF', 'Gene', (173, 176))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (173, 176))	('investigate', 'Reg', (157, 168))	('Hs578T', 'CellLine', 'CVCL:0332', (70, 76))
135623	21468687	Changes in their expression levels might change patterns of TGF-ss secretion, and that might influence the signaling pathways that it normally activates in cells that receive the signal.	('secretion', 'MPA', (67, 76))	('expression levels', 'MPA', (17, 34))	('change', 'Reg', (41, 47))	('signaling pathways', 'Pathway', (107, 125))	('Changes', 'Var', (0, 7))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (60, 63))	('influence', 'Reg', (93, 102))	('TGF', 'Gene', (60, 63))
135637	21468687	We found that a striking reduction in p-SMAD staining in Hs578T and Hs578BsT cells (Fig.	('reduction', 'NegReg', (25, 34))	('Hs578BsT', 'Var', (68, 76))	('Hs578T', 'CellLine', 'CVCL:0332', (57, 63))	('p-SMAD', 'Protein', (38, 44))	('Hs578T', 'Var', (57, 63))
135639	21468687	This indicates that the lack of LTBP4 leads to a reduction in active TGF-ss1, and therefore reduced bioavailability and p-SMAD formation.	('reduction', 'NegReg', (49, 58))	('active', 'MPA', (62, 68))	('LTBP4', 'Gene', (32, 37))	('TGF', 'Gene', (69, 72))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (69, 72))	('lack', 'Var', (24, 28))	('bioavailability', 'MPA', (100, 115))	('ss1', 'Gene', (73, 76))	('reduced', 'NegReg', (92, 99))	('p-SMAD formation', 'MPA', (120, 136))	('ss1', 'Gene', '3123', (73, 76))
135640	21468687	In accordance with this findings, the addition of rTGF-ss1 to Hs578BsT and Hs578T results in the increased formation of p-SMAD (Fig.	('addition', 'Var', (38, 46))	('increased', 'PosReg', (97, 106))	('formation of p-SMAD', 'MPA', (107, 126))	('TGF', 'Gene', (51, 54))	('ss1', 'Gene', (55, 58))	('Hs578T', 'CellLine', 'CVCL:0332', (75, 81))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (51, 54))	('ss1', 'Gene', '3123', (55, 58))	('Hs578T', 'Var', (75, 81))
135648	21468687	c-Myc levels were enhanced in Hs578T cells and in mammary tumors compared to non-malignant mammary tissues (data not shown), another indication that TGF-ss1 signaling is reduced in Hs578T.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Hs578T', 'Var', (181, 187))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('ss1', 'Gene', '3123', (153, 156))	('TGF', 'Gene', (149, 152))	('Hs578T', 'CellLine', 'CVCL:0332', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('enhanced', 'PosReg', (18, 26))	('reduced', 'NegReg', (170, 177))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (149, 152))	('Hs578T', 'CellLine', 'CVCL:0332', (181, 187))	('c-Myc', 'Gene', '4609', (0, 5))	('ss1', 'Gene', (153, 156))	('Hs578T', 'Var', (30, 36))	('c-Myc', 'Gene', (0, 5))
135701	21468687	In addition human colon carcinomas are often associated with mutations of components of the TGF-ss signaling pathway.	('TGF', 'Gene', (92, 95))	('colon carcinomas', 'Disease', (18, 34))	('TGF', 'Gene', '7040;21803;7042;21808;21809', (92, 95))	('colon carcinomas', 'Disease', 'MESH:D015179', (18, 34))	('mutations', 'Var', (61, 70))	('associated', 'Reg', (45, 55))	('human', 'Species', '9606', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
135709	21468687	Aberrant expression of BMPs and changes in BMP4 signaling have been implicated in breast cancer.	('changes', 'Reg', (32, 39))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BMP4', 'Gene', (43, 47))	('Aberrant', 'Var', (0, 8))	('BMP', 'Gene', '649', (23, 26))	('BMP', 'Gene', '649', (43, 46))	('expression', 'MPA', (9, 19))	('BMP4', 'Gene', '652', (43, 47))	('implicated', 'Reg', (68, 78))	('BMP', 'Gene', (23, 26))	('BMP', 'Gene', (43, 46))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
135716	21468687	Although changes in the expression of specific BMPs such as BMP4 in breast cancer are still the subject of controversy, the aberrant expression of BMP4 has been indicated in the development and progression of breast cancer.	('BMP4', 'Gene', (147, 151))	('BMP', 'Gene', '649', (60, 63))	('BMP', 'Gene', '649', (147, 150))	('BMP', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('BMP4', 'Gene', '652', (60, 64))	('BMP4', 'Gene', '652', (147, 151))	('BMP', 'Gene', (60, 63))	('BMP', 'Gene', (147, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('indicated', 'Reg', (161, 170))	('aberrant', 'Var', (124, 132))	('expression', 'MPA', (133, 143))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Disease', (209, 222))	('breast cancer', 'Disease', (68, 81))	('BMP', 'Gene', '649', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('changes', 'Reg', (9, 16))	('BMP4', 'Gene', (60, 64))
135838	32512721	We found that single gene alterations (SGAs) and copy-number alterations (CNAs) work together in forward and backward evolution manners to fine-tune the signaling pathways operating in tumors.	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('fine-tune', 'Reg', (139, 148))	('copy-number alterations', 'Var', (49, 72))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('signaling pathways', 'Pathway', (153, 171))
135841	32512721	Indeed, further genetic alterations in later stages do not establish de novo malignancy routes; however, they serve to fine-tune antecedent signaling pathways.	('malignancy', 'Disease', (77, 87))	('genetic alterations', 'Var', (16, 35))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))	('antecedent', 'Pathway', (129, 139))	('fine-tune', 'Reg', (119, 128))
135861	32512721	We discovered that further genetic alterations in advanced tumors do not generate new functional pathways in the tumor, but rather serve as fine-tuning effectors for antecedent changes from earlier stages.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (59, 64))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('genetic alterations', 'Var', (27, 46))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
135875	32512721	Altogether, these results suggest that the increase in genetic alterations in IDC as compared to DCIS does not necessarily increase the malignant properties of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('genetic alterations', 'Var', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
135881	32512721	Surprisingly, further genetic alterations specific to the later stages did not generate further signaling pathways in the tumor, contradicting a forward evolution model for extra genetic alterations in the later stages.	('genetic alterations', 'Var', (22, 41))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
135882	32512721	The first scenario was to consider a neutral evolution model whereby further genetic alterations randomly accumulate in tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('accumulate', 'PosReg', (106, 116))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('genetic alterations', 'Var', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
135884	32512721	Since in the late stage of tumors, genetic alterations are the accumulative results of the early (common SGAs) and late stages (disparate SGAs), we studied the function of disparate SGAs as a part of the whole running program (common + disparate) in the late stage.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('genetic', 'Var', (35, 42))
135885	32512721	Surprisingly, we found that the higher connectivity of the network suggested more intricate biological functions for the protein network of all DEG3 compared to the common SGAs (Figure S5a).	('higher', 'PosReg', (32, 38))	('DEG3', 'Var', (144, 148))	('connectivity', 'MPA', (39, 51))	('protein', 'Protein', (121, 128))	('S5a', 'Gene', '5710', (185, 188))	('S5a', 'Gene', (185, 188))
135890	32512721	These results indicated that further genetic alterations in later stages do not establish new paths for the operating pathways of tumor cells, but rather fine-tune and increase the function of descendant pathways, which can be explained by the forward evolution model.	('increase', 'PosReg', (168, 176))	('function', 'MPA', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('genetic alterations', 'Var', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('fine-tune', 'Reg', (154, 163))
135901	32512721	We further found that the increase in genomic alterations in later stages of tumor progression had no distinctive prognostic value.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('genomic', 'Var', (38, 45))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
135916	32512721	In addition, recent evidence has indicated the uniformity of driver gene alterations, even at the single nucleotide level, in primary tumor samples, and in metastases of breast as well as pancreatic cancers, suggesting an early divergence of metastases from the primary tumor.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (188, 206))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('metastases of breast', 'Disease', 'MESH:D001943', (156, 176))	('metastases', 'Disease', (242, 252))	('metastases', 'Disease', (156, 166))	('alterations', 'Var', (73, 84))	('pancreatic cancers', 'Disease', 'MESH:D010190', (188, 206))	('pancreatic cancers', 'Disease', (188, 206))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('metastases of breast', 'Disease', (156, 176))	('metastases', 'Disease', 'MESH:D009362', (242, 252))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', (134, 139))
135925	32512721	In order to study the evolutionary relationships between different stages of tumor progression, we used a mutation map of driver genes of DCIS, IDC, and Met, and a binary (0,1) dataset was created in which 1 represented genes with a point mutation in the driver gene lists and 0 represented nonmutated genes (Figure 6k).	('point mutation', 'Var', (233, 247))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
135927	32512721	Indeed, the fundamental genetic alterations of SGAs occurring in the earlier stages of tumor development and further SGAs in later stages serve, in a forward evolution model, as a fine-tuning mechanism of those primary changes.	('SGAs', 'Gene', (47, 51))	('genetic alterations', 'Var', (24, 43))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
135960	30272328	Intron-pairing introns can trigger exon circularization.	('circ', 'Chemical', '-', (40, 44))	('trigger', 'Reg', (27, 34))	('exon circularization', 'MPA', (35, 55))	('Intron-pairing introns', 'Var', (0, 22))
135994	30272328	Zhang et al and Memczak et al demonstrated that circRNAs could regulate parental gene expression, and that circRNAs are widely detected in the nuclei with a small concentration on miRNA targets; most notably, inhibition of ciRNAs may have led to the reduced expression of their parental genes.	('expression', 'MPA', (258, 268))	('inhibition', 'Var', (209, 219))	('circ', 'Chemical', '-', (48, 52))	('regulate', 'Reg', (63, 71))	('reduced', 'NegReg', (250, 257))	('ciRNAs', 'Gene', (223, 229))	('miR', 'Gene', '220972', (180, 183))	('circ', 'Chemical', '-', (107, 111))	('miR', 'Gene', (180, 183))
135997	30272328	Thus, knockout of ci-ankrd52 may reduce parental gene expression.	('parental gene expression', 'MPA', (40, 64))	('ankrd52', 'Gene', (21, 28))	('ankrd52', 'Gene', '283373', (21, 28))	('knockout', 'Var', (6, 14))	('reduce', 'NegReg', (33, 39))
136000	30272328	Previous studies have demonstrated that circRNAs can act as sponges for RBPs by stably binding with trinucleotide repeat containing 6A, RNA quaking homolog KH domain containing RNA binding, mannose binding lectin, AGO proteins, Pol II, and eukaryotic initiation factor 4A-III, to form RNA-protein complexes (RPCs).	('mannose', 'Chemical', 'MESH:D008358', (190, 197))	('trinucleotide repeat', 'Var', (100, 120))	('RBP', 'Gene', '27303', (72, 75))	('binding', 'Interaction', (87, 94))	('eukaryotic initiation factor 4A-III', 'Gene', (240, 275))	('RBP', 'Gene', (72, 75))	('trinucleotide', 'Chemical', '-', (100, 113))	('eukaryotic initiation factor 4A-III', 'Gene', '9775', (240, 275))	('circ', 'Chemical', '-', (40, 44))
136012	30272328	For the first time, Yang et al recently reported that N6-methyladenosine (m6A) is the most common and abundant base modification of RNA and promotes the protein translation of circRNAs in the human body.	('m6A', 'Chemical', 'MESH:C010223', (74, 77))	('human', 'Species', '9606', (192, 197))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (54, 72))	('N6-methyladenosine', 'Var', (54, 72))	('promotes', 'PosReg', (140, 148))	('circ', 'Chemical', '-', (176, 180))	('protein translation', 'MPA', (153, 172))
136013	30272328	The group demonstrated that m6A motifs contained many circRNAs and only one m6A was required to drive translation initiation.	('m6A', 'Var', (28, 31))	('m6A', 'Chemical', 'MESH:C010223', (76, 79))	('m6A', 'Chemical', 'MESH:C010223', (28, 31))	('circRNAs', 'MPA', (54, 62))	('circ', 'Chemical', '-', (54, 58))
136040	30272328	The expression of an miRNA is dysregulated via different mechanisms in humans, such as miRNA gene amplification or deletion, the abnormal transcriptional regulation of miRNAs, and epigenetic changes in miRNA generation.	('deletion', 'Var', (115, 123))	('abnormal', 'Reg', (129, 137))	('humans', 'Species', '9606', (71, 77))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (168, 171))	('miR', 'Gene', (202, 205))	('gene amplification', 'Var', (93, 111))	('miR', 'Gene', (21, 24))	('miR', 'Gene', '220972', (202, 205))	('transcriptional regulation', 'MPA', (138, 164))	('miR', 'Gene', '220972', (87, 90))	('epigenetic changes', 'Var', (180, 198))	('miR', 'Gene', (87, 90))
136042	30272328	Compared to normal tissues, circRNAs were usually downregulated in tumor tissues and circRNA levels were significantly associated with clinical features including staging, age, gender and distant metastasis, due to errors in the back-splicing machinery of malignant tumors, the dysregulation of miRNAs due to the degradation of circRNAs in cancerous tissues, or the reduction in circRNAs as a result of increasing cell proliferation.	('cell proliferation', 'CPA', (414, 432))	('cancer', 'Disease', 'MESH:D009369', (340, 346))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (266, 271))	('increasing', 'PosReg', (403, 413))	('associated', 'Reg', (119, 129))	('malignant tumors', 'Disease', 'MESH:D018198', (256, 272))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('errors', 'Var', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('circ', 'Chemical', '-', (379, 383))	('malignant tumors', 'Disease', (256, 272))	('miR', 'Gene', '220972', (295, 298))	('circ', 'Chemical', '-', (85, 89))	('distant metastasis', 'CPA', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('dysregulation', 'Var', (278, 291))	('circ', 'Chemical', '-', (28, 32))	('cancer', 'Disease', (340, 346))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('circ', 'Chemical', '-', (328, 332))	('miR', 'Gene', (295, 298))	('downregulated', 'NegReg', (50, 63))
136046	30272328	Hsa_circ_002059, a representative circRNA, was observed to be downregulated in 101 gastric cancer tissues.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('circ', 'Chemical', '-', (4, 8))	('downregulated', 'NegReg', (62, 75))	('circ', 'Chemical', '-', (34, 38))	('gastric cancer', 'Disease', (83, 97))	('Hsa_circ_002059', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
136048	30272328	In conclusion, these results suggest that circRNAs, particularly hsa_circ_002059, may be potentially stable biomarkers for gastric carcinoma diagnosis and staging.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('gastric carcinoma', 'Disease', 'MESH:D013274', (123, 140))	('hsa_circ_002059', 'Var', (65, 80))	('circ', 'Chemical', '-', (42, 46))	('circ', 'Chemical', '-', (69, 73))	('gastric carcinoma', 'Disease', (123, 140))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (123, 140))
136052	30272328	Therefore, the abnormal expression of circPVT1 may reduce the anticancer effect of E2F2 and miR-125b.	('cancer', 'Disease', (66, 72))	('E2F2', 'Gene', '1870', (83, 87))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('circPVT1', 'Gene', (38, 46))	('reduce', 'NegReg', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('E2F2', 'Gene', (83, 87))	('abnormal expression', 'Var', (15, 34))
136053	30272328	Furthermore, circPVT1 was shown to facilitate the colony formation of gastric cancer by inhibiting miR-125.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('colony formation', 'CPA', (50, 66))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('facilitate', 'PosReg', (35, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('circPVT1', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibiting', 'NegReg', (88, 98))	('gastric cancer', 'Disease', (70, 84))
136055	30272328	Furthermore, the knockdown of hsa_circ_0000096 by siRNA has been observed to significantly inhibit cell proliferation and migration both in vitro and in vivo, and it also was found to suppress the progression of the cell cycle, arresting the S phase of cell transition from G0/G1 in gastric cancer cells.	('gastric cancer', 'Disease', (283, 297))	('inhibit', 'NegReg', (91, 98))	('hsa_circ_0000096', 'Var', (30, 46))	('arresting', 'PosReg', (228, 237))	('S phase of cell transition', 'CPA', (242, 268))	('gastric cancer', 'Disease', 'MESH:D013274', (283, 297))	('suppress', 'NegReg', (184, 192))	('circ', 'Chemical', '-', (34, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (283, 297))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('progression', 'CPA', (197, 208))
136056	30272328	In addition, knockdown of hsa_circ_0000096 has been observed to suppress tumor growth in xenograft nude mouse models.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('hsa_circ_0000096', 'Gene', (26, 42))	('circ', 'Chemical', '-', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (64, 72))	('mouse', 'Species', '10090', (104, 109))	('tumor', 'Disease', (73, 78))	('knockdown', 'Var', (13, 22))
136060	30272328	The circRNA databases have revealed that hsa_circ_0000096 can bind with 17 different miRNAs.	('bind', 'Interaction', (62, 66))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('hsa_circ_0000096', 'Var', (41, 57))	('circ', 'Chemical', '-', (4, 8))	('circ', 'Chemical', '-', (45, 49))
136062	30272328	These previous studies have presented the clinical implications of hsa_circ_002059 and hsa_circ_0000096 as biomarkers, as determing their expression level is able to distinguish between normal gastric mucosa and gastric cancer tissue.	('distinguish', 'Reg', (166, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('circ', 'Chemical', '-', (71, 75))	('expression level', 'MPA', (138, 154))	('circ', 'Chemical', '-', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('hsa_circ_002059', 'Var', (67, 82))	('hsa_circ_0000096', 'Var', (87, 103))	('gastric cancer', 'Disease', (212, 226))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))
136073	30272328	Yao et al confirmed that in tissues from 101 patients with non-small cell lung cancer (NSCLC), circRNA_100876 was significantly upregulated when compared with the corresponding adjacent normal lung tissues.	('NSCLC', 'Disease', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('circ', 'Chemical', '-', (95, 99))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('patients', 'Species', '9606', (45, 53))	('non-small cell lung cancer', 'Disease', (59, 85))	('upregulated', 'PosReg', (128, 139))	('circRNA_100876', 'Var', (95, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
136074	30272328	Among the estimated clinicopathological results, the overexpression of circRNA_100876 was significantly associated with regional lymph node metastasis and advanced stages of the tumor.	('tumor', 'Disease', (178, 183))	('circ', 'Chemical', '-', (71, 75))	('overexpression', 'PosReg', (53, 67))	('regional lymph node metastasis', 'CPA', (120, 150))	('associated', 'Reg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('circRNA_100876', 'Var', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
136075	30272328	Patients with NSCLC and elevated circRNA_100876 expression exhibited notably shorter overall survival than those with low expression.	('shorter', 'NegReg', (77, 84))	('NSCLC', 'Disease', (14, 19))	('circ', 'Chemical', '-', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (85, 101))	('circRNA_100876 expression', 'Var', (33, 58))
136076	30272328	This therefore suggested that circ_100876 may be a potential biomarker for tumor cell proliferation, progression and metastasis in NSCLC.	('NSCLC', 'Disease', (131, 136))	('circ_100876', 'Chemical', '-', (30, 41))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('circ_100876', 'Var', (30, 41))	('tumor', 'Disease', (75, 80))
136080	30272328	It has also been suggested that the aberrant expression of circ-ITCH may inhibit the expression of the target genes c-Myc and cyclin D1 of the Wnt/beta-catenin signaling pathway.	('aberrant expression', 'Var', (36, 55))	('ITCH', 'Gene', (64, 68))	('expression', 'MPA', (85, 95))	('beta-catenin', 'Gene', '1499', (147, 159))	('-ITCH', 'Phenotype', 'HP:0000989', (63, 68))	('circ', 'Chemical', '-', (59, 63))	('cyclin D1', 'Gene', '595', (126, 135))	('c-Myc', 'Gene', '4609', (116, 121))	('ITCH', 'Phenotype', 'HP:0000989', (64, 68))	('cyclin D1', 'Gene', (126, 135))	('beta-catenin', 'Gene', (147, 159))	('ITCH', 'Gene', '83737', (64, 68))	('c-Myc', 'Gene', (116, 121))	('inhibit', 'NegReg', (73, 80))
136087	30272328	hsa_circ_001569 has been demonstrated to promote CRC cell proliferation and invasion by blocking the downregulation of E2F5/BAG4/FMNL2 by miR-145.	('E2F5', 'Gene', '1875', (119, 123))	('E2F5', 'Gene', (119, 123))	('miR-145', 'Gene', '406937', (138, 145))	('hsa_circ_001569', 'Var', (0, 15))	('CRC cell proliferation', 'CPA', (49, 71))	('circ', 'Chemical', '-', (4, 8))	('downregulation', 'MPA', (101, 115))	('promote', 'PosReg', (41, 48))	('blocking', 'NegReg', (88, 96))	('miR-145', 'Gene', (138, 145))	('invasion', 'CPA', (76, 84))
136088	30272328	Subsequently, the group revealed that hsa_circ_001569 promotes cell proliferation by increasing the number of S and G2/M phase cells in the cell cycle.	('hsa_circ_001569', 'Var', (38, 53))	('increasing', 'PosReg', (85, 95))	('cell proliferation', 'CPA', (63, 81))	('circ', 'Chemical', '-', (42, 46))	('promotes', 'PosReg', (54, 62))
136093	30272328	Furthermore, the expression of phosphorylated (p)-protein kinase B (Akt) was downregulated via this knockout, indicating that it may be involved in the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, which is known to have roles in controlling cancer cell survival and the cell cycle.	('downregulated', 'NegReg', (77, 90))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('involved', 'Reg', (136, 144))	('Akt', 'Gene', '207', (68, 71))	('cancer', 'Disease', (252, 258))	('expression', 'MPA', (17, 27))	('knockout', 'Var', (100, 108))	('Akt', 'Gene', '207', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Akt', 'Gene', (68, 71))	('Akt', 'Gene', (185, 188))
136094	30272328	Guo et al demonstrated that hsa_circ_0000069 was also overexpressed in CRC, as determined by unsupervised hierarchical cluster analysis.	('CRC', 'Disease', (71, 74))	('circ', 'Chemical', '-', (32, 36))	('overexpressed', 'PosReg', (54, 67))	('hsa_circ_0000069', 'Var', (28, 44))
136096	30272328	Hsa_circ_001988 was also found to be downregulated in CRC cell lines when compared with normal samples in 31 matched CRC tissues and non-cancerous colon mucosa.	('Hsa_circ_001988', 'Var', (0, 15))	('downregulated', 'NegReg', (37, 50))	('non-cancerous colon mucosa', 'Disease', 'MESH:D015179', (133, 159))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('non-cancerous colon mucosa', 'Disease', (133, 159))	('Hsa_circ_001988', 'Chemical', '-', (0, 15))	('CRC cell lines', 'CPA', (54, 68))
136099	30272328	These results indicate that hsa_circ_001988 may be a potential new biomarker of CRC prognosis.	('circ', 'Chemical', '-', (32, 36))	('CRC', 'Disease', (80, 83))	('hsa_circ_001988', 'Var', (28, 43))
136106	30272328	Previous studies have reported that several circRNAs, including hsa_circ_001059, hsa_circ_000167, hsa_circ_0067934, and circ-ITCH, may be involved in cancer-associated mortality in esophageal squamous cell carcinoma (ESCC).	('hsa_circ_000167', 'Var', (81, 96))	('circ', 'Chemical', '-', (120, 124))	('ITCH', 'Phenotype', 'HP:0000989', (125, 129))	('-ITCH', 'Phenotype', 'HP:0000989', (124, 129))	('hsa_circ_001059', 'Var', (64, 79))	('circ', 'Chemical', '-', (102, 106))	('hsa_circ_0067934', 'Var', (98, 114))	('cancer', 'Disease', (150, 156))	('ITCH', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('circ', 'Chemical', '-', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('circ', 'Chemical', '-', (68, 72))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('circ', 'Chemical', '-', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('ITCH', 'Gene', '83737', (125, 129))	('involved', 'Reg', (138, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
136112	30272328	When considering other clinical factors, lymph node metastasis or tumor size was not associated with the expression of hsa_circ_0067934.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('circ', 'Chemical', '-', (123, 127))	('tumor', 'Disease', (66, 71))	('hsa_circ_0067934', 'Var', (119, 135))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
136113	30272328	Notably, TNM staging was applied to assess patient prognosis, and it is possible that hsa_circ_0067934 may also have the potential to become a biomarker for diagnosing ESCC.	('circ', 'Chemical', '-', (90, 94))	('hsa_circ_0067934', 'Var', (86, 102))	('ESCC', 'Disease', (168, 172))	('patient', 'Species', '9606', (43, 50))
136118	30272328	Generally, DCIS is deemed to be highly curable; however, some women with DCIS unfortunately suffer from the life-threatening type of invasive breast cancer, invasive ductal cancer (IDC); even though the invasive factors of progression remain unclear.	('suffer from', 'Reg', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('invasive breast cancer', 'Disease', 'MESH:D001943', (133, 155))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('DCIS', 'Var', (73, 77))	('invasive ductal cancer', 'Disease', 'MESH:D018270', (157, 179))	('invasive ductal cancer', 'Disease', (157, 179))	('invasive breast cancer', 'Disease', (133, 155))	('women', 'Species', '9606', (62, 67))
136121	30272328	hsa-circ-0001358 was found to be associated with five miRNAs, miR-200c-3p, miR-200b-3p, miR-376a-3p, miR-376b-3p and miR-429, as determined by the Starbase human Pan Cancer tool.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (54, 57))	('miR', 'Gene', (117, 120))	('miR', 'Gene', (101, 104))	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('miR', 'Gene', (75, 78))	('miR-200b', 'Gene', '406984', (75, 83))	('miR-429', 'Gene', '554210', (117, 124))	('miR', 'Gene', '220972', (88, 91))	('miR', 'Gene', '220972', (62, 65))	('circ', 'Chemical', '-', (4, 8))	('hsa-circ-0001358', 'Var', (0, 16))	('miR', 'Gene', (88, 91))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('miR', 'Gene', '220972', (54, 57))	('miR-200b', 'Gene', (75, 83))	('miR', 'Gene', (62, 65))	('miR', 'Gene', '220972', (117, 120))	('miR-429', 'Gene', (117, 124))	('Cancer', 'Disease', (166, 172))	('human', 'Species', '9606', (156, 161))	('miR', 'Gene', '220972', (101, 104))
136127	30272328	Overexpression of circ-Foxo3 was found to significantly reduce proliferation and cell survival in the breast cancer cell line, MDA-MB-231.	('breast cancer', 'Disease', (102, 115))	('proliferation', 'CPA', (63, 76))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (127, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('circ', 'Chemical', '-', (18, 22))	('reduce', 'NegReg', (56, 62))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('circ-Foxo3', 'Var', (18, 28))	('cell survival', 'CPA', (81, 94))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
136128	30272328	Du et al injected MDA-MB-231 cells transfected with circ-Foxo3 subcutaneously in nude mice, demonstrating that circ-Foxo3 suppressed tumor growth.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('suppressed', 'NegReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('nude mice', 'Species', '10090', (81, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (18, 28))	('circ', 'Chemical', '-', (52, 56))	('tumor', 'Disease', (133, 138))	('circ', 'Chemical', '-', (111, 115))	('circ-Foxo3', 'Var', (111, 121))
136136	30272328	Of the three mentioned above that were further verified through RT-qPCR, hsa_circ_0005075 was significantly associated with a number of clinicopathological factors of HCC patients.	('HCC', 'Gene', (167, 170))	('circ', 'Chemical', '-', (77, 81))	('hsa_circ_0005075', 'Var', (73, 89))	('patients', 'Species', '9606', (171, 179))	('HCC', 'Gene', '619501', (167, 170))	('associated', 'Reg', (108, 118))	('men', 'Species', '9606', (13, 16))
136138	30272328	Furthermore, larger liver cancer tumors were found to exhibit a higher expression level of hsa_circ_0005075 than smaller tumors, demonstrating that hsa_circ_0005075 may regulate tumor growth.	('higher', 'PosReg', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('liver cancer', 'Phenotype', 'HP:0002896', (20, 32))	('tumor', 'Disease', (178, 183))	('liver cancer tumors', 'Disease', 'MESH:D006528', (20, 39))	('circ', 'Chemical', '-', (95, 99))	('tumor', 'Disease', (121, 126))	('larger liver', 'Phenotype', 'HP:0002240', (13, 25))	('expression level', 'MPA', (71, 87))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (33, 38))	('hsa_circ_0005075', 'Var', (91, 107))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('regulate', 'Reg', (169, 177))	('liver cancer tumors', 'Disease', (20, 39))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('circ', 'Chemical', '-', (152, 156))	('tumors', 'Disease', (33, 39))
136139	30272328	Therefore, hsa_circ_0005075 is likely to be a promising biomarker for HCC.	('hsa_circ_0005075', 'Var', (11, 27))	('HCC', 'Gene', '619501', (70, 73))	('HCC', 'Gene', (70, 73))	('circ', 'Chemical', '-', (15, 19))
136143	30272328	It has been hypothesized that hsa_circ_0005075 may act as a miRNA sponge to suppress the expression of miR-23b-5p in cancer.	('hsa_circ_0005075', 'Var', (30, 46))	('expression', 'MPA', (89, 99))	('miR', 'Gene', '220972', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR', 'Gene', (60, 63))	('suppress', 'NegReg', (76, 84))	('miR-23b', 'Gene', '407011', (103, 110))	('circ', 'Chemical', '-', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('cancer', 'Disease', (117, 123))	('miR-23b', 'Gene', (103, 110))
136145	30272328	However, further study is required to elucidate the molecular mechanisms underlying the development of HCC and how hsa_circ_0005075 functions as a miRNA sponge.	('circ', 'Chemical', '-', (119, 123))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('men', 'Species', '9606', (95, 98))	('hsa_circ_0005075', 'Var', (115, 131))	('HCC', 'Gene', (103, 106))	('HCC', 'Gene', '619501', (103, 106))
136146	30272328	Hsa_circ_0001649 has also been indicated to have decreased expression in HCC tissues, when compared with that observed in adjacent liver tissues.	('HCC', 'Gene', '619501', (73, 76))	('circ', 'Chemical', '-', (4, 8))	('decreased', 'NegReg', (49, 58))	('expression', 'MPA', (59, 69))	('Hsa_circ_0001649', 'Var', (0, 16))	('HCC', 'Gene', (73, 76))
136148	30272328	These results demonstrated that the expression of hsa_circ_0001649 is negatively correlated with the metastasis of HCC and thus, could represent a potential marker of HCC prognosis.	('HCC', 'Gene', '619501', (115, 118))	('negatively', 'NegReg', (70, 80))	('HCC', 'Gene', (167, 170))	('hsa_circ_0001649', 'Var', (50, 66))	('metastasis', 'CPA', (101, 111))	('HCC', 'Gene', '619501', (167, 170))	('HCC', 'Gene', (115, 118))	('expression', 'MPA', (36, 46))	('circ', 'Chemical', '-', (54, 58))
136154	30272328	Using this method, the authors revealed that circ-transcription factor 25 (TCF25), circ-protein tyrosine kinase 2, circ-zinc finger RNA binding protein, and circBC048201 were significantly upregulated, and the two circRNA circ-family with sequence similarity 169 member A and circ-tripartite motif-containing 24 were both downregulated in bladder cancer tissues when compared with paired non-cancerous tissues.	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('non-cancer', 'Disease', (388, 398))	('upregulated', 'PosReg', (189, 200))	('TCF25', 'Gene', (75, 80))	('circ', 'Chemical', '-', (276, 280))	('circ', 'Chemical', '-', (214, 218))	('circ', 'Chemical', '-', (222, 226))	('circ', 'Chemical', '-', (157, 161))	('circ', 'Chemical', '-', (45, 49))	('circ-transcription factor 25', 'Gene', (45, 73))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('bladder cancer', 'Disease', 'MESH:D001749', (339, 353))	('bladder cancer', 'Disease', (339, 353))	('circ', 'Chemical', '-', (83, 87))	('circ', 'Chemical', '-', (115, 119))	('downregulated', 'NegReg', (322, 335))	('TCF25', 'Gene', '22980', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (339, 353))	('non-cancer', 'Disease', 'MESH:D009369', (388, 398))	('circ-transcription factor 25', 'Gene', '22980', (45, 73))	('circBC048201', 'Var', (157, 169))
136159	30272328	Guarnerio et al demonstrated that cancer-associated chromosomal translocations result in the fusion of circRNAs (f-circRNAs), which are produced by the transcriptional exons of different genes that are affected post-translation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('chromosomal translocations', 'Var', (52, 78))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('circ', 'Chemical', '-', (103, 107))	('result in', 'Reg', (79, 88))	('circ', 'Chemical', '-', (115, 119))
136182	30272328	Analysis of laryngeal squamous cell cancers (LSCCs) revealed that hsa_circ_100855 and hsa_circ_104912, among the 698 identified aberrant circRNAs, were markedly upregulated and downregulated, respectively.	('circ', 'Chemical', '-', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('hsa_circ_100855', 'Var', (66, 81))	('upregulated', 'PosReg', (161, 172))	('hsa_circ_104912', 'Var', (86, 101))	('laryngeal squamous cell cancers', 'Disease', 'MESH:D002294', (12, 43))	('laryngeal squamous cell cancers', 'Disease', (12, 43))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (22, 42))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (22, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('circ', 'Chemical', '-', (70, 74))	('circ', 'Chemical', '-', (90, 94))	('downregulated', 'NegReg', (177, 190))
136184	30272328	The results of this previous study indicated that hsa_circ_100855 and hsa_circ_104912 may be potential neoteric biomarkers for the diagnosis and progression of LSCC.	('circ', 'Chemical', '-', (74, 78))	('hsa_circ_104912', 'Var', (70, 85))	('LSCC', 'Disease', (160, 164))	('hsa_circ_100855', 'Var', (50, 65))	('circ', 'Chemical', '-', (54, 58))
136229	28027219	As such, the ASPS clinical trials committee sought to establish whether adjunctive fat transfer is associated with a higher risk of recurrence in patients who have undergone mastectomy with reconstruction for invasive breast cancer.	('adjunctive', 'Var', (72, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('invasive breast cancer', 'Disease', 'MESH:D001943', (209, 231))	('fat', 'Gene', '948', (83, 86))	('fat', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('patients', 'Species', '9606', (146, 154))	('invasive breast cancer', 'Disease', (209, 231))
136287	28027219	Patients younger than fifty, high grade neoplasia, and a Ki-67 >= 14, were also associated with an increased rate of recurrence after fat transfer in this study.	('neoplasia', 'Phenotype', 'HP:0002664', (40, 49))	('fat', 'Gene', '948', (134, 137))	('fat', 'Gene', (134, 137))	('>= 14', 'Var', (63, 68))	('neoplasia', 'Disease', (40, 49))	('Patients', 'Species', '9606', (0, 8))	('high', 'Disease', (29, 33))	('Ki-67', 'Gene', (57, 62))	('neoplasia', 'Disease', 'MESH:D009369', (40, 49))
136337	27974799	Moreover, expression of PGR-B, the main isoform for mammary gland development, correlated with low-moderate HER2 in EL and wild-type mammary tissue (Extended Data Fig 1f).	('HER2', 'Protein', (108, 112))	('PGR-B', 'Gene', (24, 29))	('expression', 'MPA', (10, 20))	('EL', 'Chemical', '-', (116, 118))	('low-moderate', 'Var', (95, 107))
136342	27974799	Furthermore, HER2-negative cells (67NR and MM3MG) did not express the EL signature (Extended Data Fig 1g), but progesterone treatment or transduction of Pgr-B up-regulated HER2 in 4T1 and MM3MG cells, respectively (Extended Data Fig 1h-i).	('HER2', 'Protein', (172, 176))	('up-regulated', 'PosReg', (159, 171))	('transduction', 'Var', (137, 149))	('Pgr-B', 'Gene', (153, 158))	('progesterone', 'Chemical', 'MESH:D011374', (111, 123))	('EL', 'Chemical', '-', (70, 72))	('MM3MG', 'CellLine', 'CVCL:5818', (43, 48))	('MM3MG', 'CellLine', 'CVCL:5818', (188, 193))
136355	27974799	Estrogen also induced migration and sphere formation, however the progesterone inhibitor, RU486 inhibited this pro-migratory and pro-sphere forming effect (Extended Data Fig 2h), possibly because estrogen acts via transcriptional induction of Pgr.	('sphere formation', 'CPA', (36, 52))	('progesterone', 'Chemical', 'MESH:D011374', (66, 78))	('RU486', 'Var', (90, 95))	('migration', 'CPA', (22, 31))	('RU486', 'Chemical', 'MESH:D015735', (90, 95))	('inhibited', 'NegReg', (96, 105))	('induced', 'Reg', (14, 21))
136356	27974799	Together, these results suggested that moderate HER2 expression with progesterone or PIPS availability promote sphere-formation and migratory responses upon mammary epithelial cells.	('progesterone', 'Chemical', 'MESH:D011374', (69, 81))	('HER2', 'Protein', (48, 52))	('moderate', 'Var', (39, 47))	('sphere-formation', 'CPA', (111, 127))	('migratory responses upon mammary', 'CPA', (132, 164))	('expression', 'MPA', (53, 63))	('promote', 'PosReg', (103, 110))	('PIPS', 'Chemical', '-', (85, 89))
136358	27974799	MM3MG cells transduced with Pgr-B or Her2 were subjected to sphere formation and migration assays (Extended Data Fig 3 and described in the supplementary legend) confirmed that PIPS-responsive cells (migration and sphere formation) were HER2low/PGR-, whereas HER2high cells mimicked non-migrating primary tumour cells (enhanced proliferation).	('tumour', 'Disease', 'MESH:D009369', (305, 311))	('sphere formation', 'CPA', (214, 230))	('tumour', 'Disease', (305, 311))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('PIPS', 'Chemical', '-', (177, 181))	('MM3MG', 'CellLine', 'CVCL:5818', (0, 5))	('HER2low/PGR-', 'Var', (237, 249))
136386	27974799	Together, the in vivo results are in line with in vitro findings that PIPS induces migration and sphere-formation of EL cells and proliferation of advanced PT cells.	('PIPS', 'Chemical', '-', (70, 74))	('EL', 'Chemical', '-', (117, 119))	('induces', 'PosReg', (75, 82))	('sphere-formation of EL cells', 'CPA', (97, 125))	('proliferation', 'CPA', (130, 143))	('PIPS', 'Var', (70, 74))	('migration', 'CPA', (83, 92))
136399	27974799	Strikingly, in breast cancers with high PGR score, genetic activation of HER2 increased the dissemination rate (p<=0.05; Figure 5b), akin to EL lesions in the Balb-NeuT model.	('HER2', 'Protein', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('Neu', 'Gene', (164, 167))	('Neu', 'Gene', '13866', (164, 167))	('EL', 'Chemical', '-', (141, 143))	('dissemination rate', 'CPA', (92, 110))	('breast cancers', 'Phenotype', 'HP:0003002', (15, 29))	('increased', 'PosReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancers', 'Disease', 'MESH:D001943', (15, 29))	('breast cancers', 'Disease', (15, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('genetic activation', 'Var', (51, 69))
136416	27974799	The genomic profiles of human DCCs isolated intraoperatively months to years before metastasis represented early cancer cells, not the predominant PT clones, indicating that early DCCs have yet to acquire critical alterations such as 8q gains to form metastases.	('metastases', 'Disease', 'MESH:D009362', (251, 261))	('human', 'Species', '9606', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('8q gains', 'Var', (234, 242))	('cancer', 'Disease', (113, 119))	('metastases', 'Disease', (251, 261))
136426	27974799	Strongly oncogenic mutations characterize benign tumours that do not metastasize; indeed, strong activation of oncogenic pathways represses metastasis while increasing proliferation.	('proliferation', 'CPA', (168, 181))	('activation', 'PosReg', (97, 107))	('increasing', 'PosReg', (157, 167))	('mutations', 'Var', (19, 28))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('oncogenic pathways', 'Pathway', (111, 129))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('metastasis', 'CPA', (140, 150))	('benign tumours', 'Disease', (42, 56))	('represses', 'NegReg', (130, 139))	('benign tumours', 'Disease', 'MESH:D009369', (42, 56))
136491	27974799	cDNA was generated using reverse transcriptase kit (Qiagen: 205311 for total RNA and 218161 for miRNA).	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('218161', 'Var', (85, 91))
136545	23476791	Risk factors for the development of DCIS are similar to those for invasive breast cancer suggesting that both diseases are etiologically related and include increasing age (mean age at diagnosis for DCIS is 50-59 years), family history of a first degree relative with breast cancer, nulliparity or late age of first birth, late age of menopause, long-term use of postmenopausal hormonal therapy, elevated body mass index (BMI) in postmenopausal women, BRCA mutational status, and high mammographic breast density.	('late age of first birth', 'Phenotype', 'HP:0012569', (298, 321))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('BRCA', 'Gene', (452, 456))	('nulliparity', 'Var', (283, 294))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('women', 'Species', '9606', (445, 450))	('elevated body mass index', 'Phenotype', 'HP:0031418', (396, 420))	('breast cancer', 'Disease', (268, 281))	('mutational status', 'Var', (457, 474))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('invasive breast cancer', 'Disease', (66, 88))	('invasive breast cancer', 'Disease', 'MESH:D001943', (66, 88))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('elevated', 'PosReg', (396, 404))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('body mass index', 'MPA', (405, 420))	('BRCA', 'Gene', '672', (452, 456))
136561	23476791	Intermediate-grade apocrine DCIS describes those lesions that have nuclei in the size range of low-grade ADCIS that is, 3-4X a benign apocrine cell but have comedo-type necrosis or those lesions with apocrine cells typical of high-grade disease (>=5 times the size of a normal apocrine cell) but comedo-type necrosis is not evident.	('necrosis', 'Disease', 'MESH:D009336', (169, 177))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('necrosis', 'Disease', 'MESH:D009336', (308, 316))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('necrosis', 'Disease', (169, 177))	('necrosis', 'Disease', (308, 316))	('comedo', 'Phenotype', 'HP:0025249', (157, 163))	('low-grade', 'Var', (95, 104))	('comedo', 'Phenotype', 'HP:0025249', (296, 302))
136567	23476791	Microinvasion particularly in association with high-grade DCIS will often prompt a sentinel lymph node biopsy and in ~10% (and in some series up to 20%) of cases lymph node metastases have been indentified, predominantly micrometastases or isolated tumor cells.	('metastases', 'Disease', 'MESH:D009362', (226, 236))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('metastases', 'Disease', (173, 183))	('prompt', 'Reg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('Microinvasion', 'MPA', (0, 13))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('high-grade', 'Var', (47, 57))	('tumor', 'Disease', (249, 254))	('metastases', 'Disease', (226, 236))	('sentinel lymph node biopsy', 'CPA', (83, 109))
136568	23476791	DCIS is a recognised precursor (albeit nonobligate one) of invasive carcinoma and if left untreated small retrospective studies have shown that approximately 30% of DCIS lesions will progress to invasive cancer over a 30-year time period.	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('progress', 'Reg', (183, 191))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('invasive carcinoma', 'Disease', (59, 77))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('invasive cancer', 'Disease', (195, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('DCIS', 'Gene', (165, 169))	('invasive cancer', 'Disease', 'MESH:D009362', (195, 210))	('invasive carcinoma', 'Disease', 'MESH:D009361', (59, 77))	('lesions', 'Var', (170, 177))
136577	23476791	HER2 Positivity.	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('Positivity', 'Var', (5, 15))
136578	23476791	HER2 positive DCIS is associated with a higher risk of recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('positive DCIS', 'Var', (5, 18))
136588	23476791	Subsequent analysis of the ER status of the DCIS demonstrated that the reduction in subsequent cancer development was restricted to those patients with ER+ DCIS.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('reduction', 'NegReg', (71, 80))	('cancer', 'Disease', (95, 101))	('ER+', 'Var', (152, 155))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('patients', 'Species', '9606', (138, 146))
136601	23476791	A small percentage of high-grade DCIS exhibits CK5/6 positivity and ER negativity (so-called basal-like DCIS) and this should not cause confusion with UDH.	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('UDH', 'Chemical', '-', (151, 154))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('confusion', 'Phenotype', 'HP:0001289', (136, 145))	('CK5/6', 'Gene', '3852', (47, 52))	('positivity', 'Var', (53, 63))	('CK5/6', 'Gene', (47, 52))
136609	23476791	To support this view low-grade in situ and invasive lesions (and many of their presumed precursor lesions FEA, ADH, ALH, and LCIS) are predominantly ER positive, HER2 negative lesions, have diploid or near diploid karyotypes, and are characterized oftentimes by the shared deletion of the long arm of chromosome 16 (16q) and 1q gain.	('HER2', 'Gene', '2064', (162, 166))	('HER2', 'Gene', (162, 166))	('deletion', 'Var', (273, 281))	('LCIS', 'Phenotype', 'HP:0030076', (125, 129))	('gain', 'PosReg', (328, 332))
136729	29566728	The %MD is well-established as a risk factor for a first primary breast cancer diagnosis.	('%MD', 'Var', (4, 7))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('or', 'Gene', '31118', (46, 48))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('or', 'Gene', '31118', (42, 44))
136806	25960662	We and others have shown that inhibition of the epidermal growth factor receptor with the clinical drug gefitinib leads to an increase in TP levels in BC cells.	('TP', 'Gene', '1890', (138, 140))	('inhibition', 'Var', (30, 40))	('gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))	('epidermal growth factor receptor', 'Gene', (48, 80))	('BC', 'Phenotype', 'HP:0003002', (151, 153))	('increase', 'PosReg', (126, 134))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))
136854	25960662	There was no correlation between TP positivity and Ki67 expression, but all HER2-positive patients had high Ki67.	('HER2', 'Gene', (76, 80))	('TP', 'Gene', '1890', (33, 35))	('HER2', 'Gene', '2064', (76, 80))	('Ki67', 'Chemical', '-', (51, 55))	('Ki67', 'Var', (108, 112))	('Ki67', 'Chemical', '-', (108, 112))	('patients', 'Species', '9606', (90, 98))
136886	25960662	Apart from tumor size, axillary lymph node status, tumor grade Ki67, and ER, PR, and HER2 status, there are no other biomarkers predictive of the response to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ER', 'Gene', '2099', (86, 88))	('ER', 'Gene', '2099', (73, 75))	('tumor', 'Disease', (11, 16))	('Ki67', 'Chemical', '-', (63, 67))	('tumor', 'Disease', (51, 56))	('Ki67', 'Var', (63, 67))	('HER2', 'Gene', (85, 89))	('PR', 'Gene', '5241', (77, 79))	('axillary lymph node status', 'Phenotype', 'HP:0025289', (23, 49))	('HER2', 'Gene', '2064', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
136912	25960662	According to the literature, high intratumoral DPD levels confer resistance to treatment, whereas its cytotoxic efficacy is improved in tumor cells expressing a high TP/DPD ratio.	('tumoral', 'Disease', (39, 46))	('tumoral', 'Disease', 'MESH:D009369', (39, 46))	('cytotoxic efficacy', 'CPA', (102, 120))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('improved', 'PosReg', (124, 132))	('TP', 'Gene', '1890', (166, 168))	('DPD', 'Gene', (47, 50))	('resistance', 'CPA', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('high', 'Var', (161, 165))	('DPD', 'Gene', '1806', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (136, 141))	('DPD', 'Gene', (169, 172))	('DPD', 'Gene', '1806', (47, 50))
136915	25960662	Our ER-negative patients had a higher associated positivity for TP staining and for Ki67, but their TP status did not correlate with a predictive TTP.	('Ki67', 'Var', (84, 88))	('TP', 'Gene', '1890', (100, 102))	('positivity', 'MPA', (49, 59))	('ER', 'Gene', '2099', (4, 6))	('patients', 'Species', '9606', (16, 24))	('TTP', 'Gene', (146, 149))	('TTP', 'Gene', '7538', (146, 149))	('TP', 'Gene', '1890', (64, 66))	('TP', 'Gene', '1890', (147, 149))	('Ki67', 'Chemical', '-', (84, 88))
136922	25153721	Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation.	('PTK6', 'Gene', (47, 51))	('tyrosine residue 342', 'Var', (19, 39))	('Phosphorylation', 'MPA', (0, 15))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('activation', 'PosReg', (89, 99))
136933	25153721	Targeting PTK6 to the plasma membrane by addition of a palmitoylation/myristoylation signal promoted the epithelial mesenchymal transition and enhanced growth and metastasis of prostate cancer xenograft tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('metastasis of prostate cancer xenograft tumors', 'Disease', (163, 209))	('enhanced', 'PosReg', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('promoted', 'PosReg', (92, 100))	('epithelia', 'Disease', 'None', (105, 114))	('epithelia', 'Disease', (105, 114))	('metastasis of prostate cancer xenograft tumors', 'Disease', 'MESH:D009362', (163, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('PTK6', 'Gene', (10, 14))	('palmitoylation/myristoylation', 'Var', (55, 84))
136936	25153721	In addition, PTK6 confers cancer cell resistance to anoikis and knockdown of PTK6 increases sensitivity of cancer cells to different therapeutic agents.	('sensitivity', 'MPA', (92, 103))	('cancer', 'Disease', (26, 32))	('PTK6', 'Gene', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('increases', 'PosReg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('knockdown', 'Var', (64, 73))	('cancer', 'Disease', (107, 113))
136939	25153721	Disruption of the Ptk6 gene led to impaired differentiation and increased growth in the mouse small intestine.	('Ptk6', 'Gene', '20459', (18, 22))	('growth in the mouse small intestine', 'CPA', (74, 109))	('Ptk6', 'Gene', (18, 22))	('mouse', 'Species', '10090', (88, 93))	('increased', 'PosReg', (64, 73))	('differentiation', 'CPA', (44, 59))	('impaired', 'NegReg', (35, 43))	('Disruption', 'Var', (0, 10))
136961	25153721	Phosphorylation of tyrosine residue 342 (P-Y342) in the PTK6 activation loop promotes its activation, and may serve as a marker for increased PTK6 activity.	('PTK6', 'Gene', (56, 60))	('promotes', 'PosReg', (77, 85))	('tyrosine residue 342 (P-Y342', 'Var', (19, 47))	('P-Y342', 'Var', (41, 47))	('activation', 'MPA', (90, 100))	('Phosphorylation', 'MPA', (0, 15))	('increased', 'PosReg', (132, 141))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('increased PTK6 activity', 'Phenotype', 'HP:0003240', (132, 155))
136963	25153721	In addition, we have found that the PTK6 P-Y342 antibody recognizes only active PTK6 but not kinase-defective PTK6 in expression studies, and we can detect PTK6 P-Y342 immunoreactivity in mammary gland tumors that formed in wild type but not Ptk6-/- mice, further indicating antibody specificity (data not shown).	('gland tumors', 'Disease', (196, 208))	('gland tumors', 'Disease', 'MESH:D010871', (196, 208))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('Ptk6', 'Gene', '20459', (242, 246))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mice', 'Species', '10090', (250, 254))	('Ptk6', 'Gene', (242, 246))	('PTK6 P-Y342', 'Var', (156, 167))
136972	25153721	125 cores from 44 patients contained enough tissue for total and P-Y342 PTK6 staining and corresponding cores for ER/PR/HER2 readings.	('P-Y342', 'Var', (65, 71))	('patients', 'Species', '9606', (18, 26))	('PTK6', 'Gene', (72, 76))
136979	25153721	While more than 90% of patients overexpressed PTK6, only half of the patients were positive for active P-Y342 PTK6.	('PTK6', 'Gene', (46, 50))	('patients', 'Species', '9606', (23, 31))	('P-Y342', 'Var', (103, 109))	('patients', 'Species', '9606', (69, 77))	('overexpressed', 'PosReg', (32, 45))
136982	25153721	Active PTK6 appeared to correlate with grade of tumor; in low-grade ductal carcinomas, the P-Y342 signal was low to undetectable, but in the high-grade invasive ductal carcinomas, a strong P-Y342 PTK6 signal was detected at the membrane of tumors cells that had breached the basement membrane (Fig 3).	('tumors', 'Disease', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('invasive ductal carcinomas', 'Disease', (152, 178))	('tumor', 'Disease', (240, 245))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('ductal carcinomas', 'Disease', 'MESH:D044584', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('ductal carcinomas', 'Disease', (68, 85))	('tumor', 'Disease', (48, 53))	('P-Y342', 'Var', (189, 195))	('PTK6', 'Gene', (196, 200))	('ductal carcinomas', 'Disease', 'MESH:D044584', (161, 178))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (152, 178))
136984	25153721	Unlike in the ductal carcinomas, PTK6 was nuclear in the LCIS that we examined.	('ductal carcinomas', 'Disease', (14, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('PTK6', 'Var', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('ductal carcinomas', 'Disease', 'MESH:D044584', (14, 31))
136987	25153721	When analyzing PTK6 expression in normal and tumor tissue from the same patient, we found that active P-Y342 PTK6 is only detectable in the tumor tissue but not in normal glands, although total PTK6 levels may not change much from normal to tumor tissue (Figure 5).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('P-Y342', 'Var', (102, 108))	('PTK6', 'Gene', (109, 113))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (45, 50))	('patient', 'Species', '9606', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (140, 145))
137004	25153721	While no PTK6 P-Y342 was detected in the normal mammary gland samples, we detected membrane associated active P-Y342 PTK6 in all tumor subtypes, with the highest percentages of strong positives in the triple negative (25%) and HER2 overexpressing (25%) subtypes (Table 3).	('HER2', 'Protein', (227, 231))	('overexpressing', 'PosReg', (232, 246))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('P-Y342', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PTK6', 'Gene', (117, 121))	('tumor', 'Disease', (129, 134))
137005	25153721	Striking localization of PTK6 P-Y342 at the plasma membrane was detected in IDC, the most common type of breast cancer, as well as in DCIS, the most common non-invasive breast cancer (Fig.	('DCIS', 'Disease', (134, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('IDC', 'Disease', (76, 79))	('invasive breast cancer', 'Disease', 'MESH:D001943', (160, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('PTK6 P-Y342', 'Var', (25, 36))	('detected', 'Reg', (64, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('invasive breast cancer', 'Disease', (160, 182))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
137006	25153721	In contrast, total PTK6 and PTK6 P-Y342 were localized in nuclei in high-grade LCIS, a premalignant condition that indicates risk for developing invasive breast cancer (Fig.	('invasive breast cancer', 'Disease', 'MESH:D001943', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('invasive breast cancer', 'Disease', (145, 167))	('PTK6 P-Y342', 'Var', (28, 39))	('high-grade LCIS', 'Disease', (68, 83))
137009	25153721	Interestingly, in breast tumors expressing high levels of PTK6 P-Y342, luminal A, B and HER2 subtypes contain both IDC and DCIS or LCIS.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('breast tumors', 'Phenotype', 'HP:0100013', (18, 31))	('PTK6 P-Y342', 'Var', (58, 69))	('HER2', 'Protein', (88, 92))	('breast tumor', 'Phenotype', 'HP:0100013', (18, 30))	('breast tumors', 'Disease', 'MESH:D001943', (18, 31))	('breast tumors', 'Disease', (18, 31))
137011	25153721	Although the sample size was limited, these data suggest that PTK6 activation at the membrane as measured by P-Y342 may be most apparent in invasive breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('activation', 'PosReg', (67, 77))	('breast cancers', 'Phenotype', 'HP:0003002', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('PTK6', 'Gene', (62, 66))	('P-Y342', 'Var', (109, 115))	('invasive breast cancers', 'Disease', 'MESH:D001943', (140, 163))	('invasive breast cancers', 'Disease', (140, 163))
137024	25153721	Antibodies against beta-actin (A-5441) and alpha-tubulin (T-9026) were from Sigma-Aldrich(St. Louis, MO).	('T-9026', 'Var', (58, 64))	('A-5441', 'Var', (31, 37))	('beta-actin', 'Gene', '728378', (19, 29))	('alpha-tubulin', 'Protein', (43, 56))	('beta-actin', 'Gene', (19, 29))
137132	25073898	Although our case presented with a component of poor differentiated carcinoma without any component of breast ductal carcinoma, other evidence supports the diagnosis of BCCF: an immunohistochemical profile of GCDFP-15 (+), CK7 (+), CK20 (-), CK (+), CK5(-), EMA (+), 32-year-old female with regular menstruation and no history of reproductive system tumors,and no pregnancy during disease occurrence.	('carcinoma', 'Disease', (68, 77))	('CK (+', 'Var', (242, 247))	('CK5', 'Gene', (250, 253))	('BCCF', 'Chemical', '-', (169, 173))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (103, 126))	('CK20', 'Gene', (232, 236))	('GCDFP-15', 'Gene', '5304', (209, 217))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (110, 126))	('GCDFP-15', 'Gene', (209, 217))	('system tumors', 'Disease', 'MESH:D009369', (343, 356))	('component of breast ductal carcinoma', 'Disease', (90, 126))	('CK5', 'Gene', '3852', (250, 253))	('carcinoma', 'Disease', 'MESH:D002277', (68, 77))	('CK20', 'Gene', '54474', (232, 236))	('CK7', 'Gene', (223, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Disease', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (350, 356))	('CK7', 'Gene', '3855', (223, 226))	('component of breast ductal carcinoma', 'Disease', 'MESH:D018270', (90, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('system tumors', 'Disease', (343, 356))	('carcinoma', 'Disease', 'MESH:D002277', (117, 126))
137137	25073898	Further, animmunohistochemical profile of CK7 (+), CK20 (-), CK (+), and PLAP (-) in kidney cancer was found, supporting a diagnosis of the BCCF metastatic to the kidney.	('kidney cancer', 'Phenotype', 'HP:0009726', (85, 98))	('CK20', 'Gene', (51, 55))	('CK7', 'Gene', '3855', (42, 45))	('CK20', 'Gene', '54474', (51, 55))	('kidney cancer', 'Disease', (85, 98))	('CK (+', 'Var', (61, 66))	('PLAP', 'Gene', '250', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BCCF', 'Chemical', '-', (140, 144))	('PLAP', 'Gene', (73, 77))	('kidney cancer', 'Disease', 'MESH:D007680', (85, 98))	('CK7', 'Gene', (42, 45))
137180	32838814	Our results were consistent with the previous publications regarding SPAG5 gene expression and amplification in breast cancer with an emphasis on the prominent role of this protein in tumor pathogenesis.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('breast cancer', 'Disease', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('amplification', 'Var', (95, 108))	('tumor', 'Disease', (184, 189))	('SPAG5', 'Gene', (69, 74))	('SPAG5', 'Gene', '10615', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
137196	32838814	This interaction is reciprocal in a way that the lack of SPAG5 interferes with the appropriate NuMA spindle distribution and function.	('NuMA', 'Gene', '4926', (95, 99))	('SPAG5', 'Gene', (57, 62))	('interferes', 'NegReg', (63, 73))	('NuMA', 'Gene', (95, 99))	('SPAG5', 'Gene', '10615', (57, 62))	('lack', 'Var', (49, 53))
137202	32838814	Since SPAG5 gene amplification was also involved in the pathogenesis of the breast cancer, we also intended to identify any association between the amplified genome and SPAG5 / NuMA mRNA levels.	('SPAG5', 'Gene', (169, 174))	('NuMA', 'Gene', (177, 181))	('SPAG5', 'Gene', (6, 11))	('SPAG5', 'Gene', '10615', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('NuMA', 'Gene', '4926', (177, 181))	('amplification', 'Var', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('SPAG5', 'Gene', '10615', (6, 11))	('involved', 'Reg', (40, 48))
137303	32838814	They suggested A794G variant as a susceptibility allele for breast cancer.	('breast cancer', 'Disease', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('A794G', 'SUBSTITUTION', 'None', (15, 20))	('A794G', 'Var', (15, 20))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
137304	32838814	However, additional investigations did not support the role of NuMA variants as breast cancer susceptibility alleles.	('variants', 'Var', (68, 76))	('NuMA', 'Gene', '4926', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('NuMA', 'Gene', (63, 67))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
137305	32838814	The other phenomenon of interest in our study was the SPAG5 gene amplification.	('amplification', 'Var', (65, 78))	('SPAG5', 'Gene', (54, 59))	('SPAG5', 'Gene', '10615', (54, 59))
137307	32838814	that reported 10-19% SPAG5 gene amplification in breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('breast tumors', 'Disease', (49, 62))	('amplification', 'Var', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SPAG5', 'Gene', (21, 26))	('breast tumors', 'Phenotype', 'HP:0100013', (49, 62))	('SPAG5', 'Gene', '10615', (21, 26))	('breast tumors', 'Disease', 'MESH:D001943', (49, 62))
137308	32838814	Defects in DNA replication or telomere dysfunction promote gene amplification which can lead to tumor progression in any stage of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DNA', 'Protein', (11, 14))	('breast cancer', 'Disease', (130, 143))	('gene amplification', 'MPA', (59, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lead to', 'Reg', (88, 95))	('Defects', 'Var', (0, 7))	('tumor', 'Disease', (96, 101))	('promote', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
137309	32838814	Gene amplification confers a selective advantage during early-stage of cancer by increasing oncogenes expression in amplified regions.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('increasing', 'PosReg', (81, 91))	('expression', 'MPA', (102, 112))	('cancer', 'Disease', (71, 77))	('oncogenes', 'Gene', (92, 101))	('Gene amplification', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
137310	32838814	It has been shown that gene amplification is associated with more aggressive tumors as well as resistance to chemotherapy which can predict disease prognosis.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('aggressive tumors', 'Disease', (66, 83))	('resistance to chemotherapy', 'CPA', (95, 121))	('associated', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gene amplification', 'Var', (23, 41))	('aggressive tumors', 'Disease', 'MESH:D001523', (66, 83))
137312	32838814	Our study highlights the role of increased SPAG5 gene expression and gene amplification in breast cancer.	('expression', 'MPA', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('SPAG5', 'Gene', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('SPAG5', 'Gene', '10615', (43, 48))	('gene amplification', 'Var', (69, 87))	('increased', 'PosReg', (33, 42))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
137334	29141852	Multiple facets of the tumor microenvironment govern disease progression including the presence of specific cell types such as macrophages, fibroblasts, or neutrophils that transition into cancer-associated variants.	('neu', 'Gene', '2064', (156, 159))	('neu', 'Gene', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('variants', 'Var', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', (23, 28))	('cancer', 'Disease', (189, 195))
137341	29141852	This finding was validated in 207 invasive breast cancer patient samples, where stromal syndecan-1 expression was associated with increased vessel density and higher average vessel area as well as the TACS signature.	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('patient', 'Species', '9606', (57, 64))	('syndecan-1', 'Gene', '6382', (88, 98))	('invasive breast cancer', 'Disease', 'MESH:D001943', (34, 56))	('expression', 'Var', (99, 109))	('vessel density', 'CPA', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('increased', 'PosReg', (130, 139))	('syndecan-1', 'Gene', (88, 98))	('increased vessel density', 'Phenotype', 'HP:0002634', (130, 154))	('higher', 'PosReg', (159, 165))	('invasive breast cancer', 'Disease', (34, 56))
137342	29141852	These results support the hypothesis that expression of syndecan-1 in carcinoma-associated fibroblasts stimulates changes in collagen architecture associated with tumor progression.	('syndecan-1', 'Gene', '6382', (56, 66))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('collagen architecture', 'MPA', (125, 146))	('carcinoma', 'Disease', (70, 79))	('syndecan-1', 'Gene', (56, 66))	('tumor', 'Disease', (163, 168))	('expression', 'Var', (42, 52))	('changes', 'Reg', (114, 121))
137343	29141852	Furthermore, forced syndecan-1 expression in mammary fibroblasts leads to the production of an extracellular matrix with aligned fibers in vitro, so that the extracellular matrix is permissive to the directional migration and invasion of breast carcinoma cells.	('breast carcinoma', 'Disease', 'MESH:D001943', (238, 254))	('breast carcinoma', 'Phenotype', 'HP:0003002', (238, 254))	('syndecan-1', 'Gene', (20, 30))	('leads to', 'Reg', (65, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('invasion', 'CPA', (226, 234))	('forced', 'Var', (13, 19))	('directional migration', 'CPA', (200, 221))	('syndecan-1', 'Gene', '6382', (20, 30))	('breast carcinoma', 'Disease', (238, 254))
137345	29141852	We also evaluated whether the presence of syndecan-1 expression in stromal fibroblasts was associated with collagen alignment and recurrence.	('recurrence', 'CPA', (130, 140))	('collagen alignment', 'CPA', (107, 125))	('syndecan-1', 'Gene', (42, 52))	('presence', 'Var', (30, 38))	('syndecan-1', 'Gene', '6382', (42, 52))	('associated', 'Reg', (91, 101))
137387	29141852	Comedo type architecture, high grade, and larger tumor size are associated with small (~2-fold) increases in the likelihood of recurrence after DCIS.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('high grade', 'Var', (26, 36))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('Comedo', 'Phenotype', 'HP:0025249', (0, 6))
137389	29141852	We did not have available data for the Oncotype DX DCIS Score to compare to the collagen alignment score, although our study did suggest that TACS is correlated with comedo necrosis, ER and PR negativity, and HER2 positivity.	('comedo', 'Phenotype', 'HP:0025249', (166, 172))	('TACS', 'Gene', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('HER2', 'Gene', (209, 213))	('necrosis', 'Disease', (173, 181))	('correlated', 'Reg', (150, 160))	('HER2', 'Gene', '2064', (209, 213))	('positivity', 'Var', (214, 224))	('necrosis', 'Disease', 'MESH:D009336', (173, 181))
137503	30862637	There is recognition that high-grade DCIS is more likely to progress to an invasive breast cancer and these patients are excluded from the study.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('high-grade DCIS', 'Var', (26, 41))	('invasive breast cancer', 'Disease', 'MESH:D001943', (75, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('invasive breast cancer', 'Disease', (75, 97))	('patients', 'Species', '9606', (108, 116))	('progress', 'PosReg', (60, 68))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
137531	31605250	We expanded on those observations, using a series of isogenic 10A variants developed by Fred Miller, to establish 3D mono-culture models for various stages of breast cancer progression (Fig.	('variants', 'Var', (66, 74))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
137533	31605250	Growing 10A variants in 3D cultures results in histopathologies and morphologies comparable to those observed in vivo in xenograft models and in genomic and transcriptomic profiles observed in primary breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('variants', 'Var', (12, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (201, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancers', 'Disease', 'MESH:D001943', (201, 215))	('breast cancers', 'Disease', (201, 215))
137539	31605250	To 3D rBM overlay cultures of human MCF-10 breast variants, we have added human breast myoepithelial cells and human breast carcinoma-associated fibroblasts (CAFs).	('human', 'Species', '9606', (30, 35))	('breast carcinoma', 'Phenotype', 'HP:0003002', (117, 133))	('MCF-10', 'Gene', (36, 42))	('breast myoepithelial', 'Disease', 'MESH:D001943', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('CAFs', 'Chemical', '-', (158, 162))	('human', 'Species', '9606', (111, 116))	('breast carcinoma', 'Disease', 'MESH:D001943', (117, 133))	('breast myoepithelial', 'Disease', (80, 100))	('breast carcinoma', 'Disease', (117, 133))	('variants', 'Var', (50, 58))	('human', 'Species', '9606', (74, 79))	('MCF-10', 'CellLine', 'CVCL:5555', (36, 42))
137562	31605250	In tripartite cultures, proteolysis by MCF10 variant structures in the upper layers of the cultures is reduced in the presence of myoepithelial cells whereas proteolysis by CAFs in the lower collagen I layer is not affected (Fig.	('CAFs', 'Chemical', '-', (173, 177))	('MCF10', 'Gene', (39, 44))	('reduced', 'NegReg', (103, 110))	('MCF10 variant', 'CellLine', 'CVCL:7204', (39, 52))	('variant', 'Var', (45, 52))	('tripartite', 'Chemical', '-', (3, 13))	('proteolysis', 'MPA', (24, 35))
137563	31605250	3 and 5), MCF10 variant structures (Fig.	('MCF10 variant', 'CellLine', 'CVCL:7204', (10, 23))	('MCF10', 'Gene', (10, 15))	('variant structures', 'Var', (16, 34))
137637	29720211	Breast cancer is well known to be a genetic disease, with very frequent somatic copy number changes, a number of driver mutations such as in PIK3CA and TP53, and widespread transcriptional deregulation.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('TP53', 'Gene', '7157', (152, 156))	('PIK3CA', 'Gene', (141, 147))	('TP53', 'Gene', (152, 156))	('mutations', 'Var', (120, 129))	('PIK3CA', 'Gene', '5290', (141, 147))	('genetic disease', 'Disease', 'MESH:D030342', (36, 51))	('Breast cancer', 'Disease', (0, 13))	('genetic disease', 'Disease', (36, 51))	('copy number changes', 'Var', (80, 99))
137640	29720211	An LOH study of 41 ADH samples at 15 genetic loci selected based on the locations of frequently inactivated tumor suppressor genes in IDC, such as TP53, RB1, and BRCA1, reported that 42% of "pure" ADH (without synchronous DCIS/IDC) showed LOH in at least one locus, suggesting that inactivation of these tumor suppressor genes might be an early neoplastic event and related to the subsequent development of IDC.	('DCIS', 'Phenotype', 'HP:0030075', (222, 226))	('BRCA1', 'Gene', '672', (162, 167))	('tumor', 'Disease', (108, 113))	('BRCA1', 'Gene', (162, 167))	('tumor', 'Disease', (304, 309))	('RB1', 'Gene', '5925', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TP53', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('IDC', 'Gene', '4000', (134, 137))	('inactivation', 'Var', (282, 294))	('IDC', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('neoplastic event', 'Phenotype', 'HP:0002664', (345, 361))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('IDC', 'Gene', '4000', (227, 230))	('IDC', 'Gene', (227, 230))	('IDC', 'Gene', '4000', (407, 410))	('TP53', 'Gene', '7157', (147, 151))	('IDC', 'Gene', (407, 410))	('RB1', 'Gene', (153, 156))
137641	29720211	This study identified loss of 16q as an LOH "hot spot" in ADH and also in low-grade DCIS and IDC.	('loss of 16q', 'Var', (22, 33))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('low-grade DCIS', 'Disease', (74, 88))	('IDC', 'Gene', '4000', (93, 96))	('ADH', 'Disease', (58, 61))	('IDC', 'Gene', (93, 96))
137642	29720211	Loss of 16q was also confirmed as a common event in breast cancer by other studies (Table 1), signifying that this event might be particularly important in the early development of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Disease', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('Loss of 16q', 'Var', (0, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))
137645	29720211	detected copy number aberrations in 15 pure ADH samples by array CGH and found that although there were similar genetic alterations among ADH, DCIS, and IDC, there were also alterations unique to each lesion.	('IDC', 'Gene', (153, 156))	('copy number aberrations', 'Var', (9, 32))	('DCIS', 'Phenotype', 'HP:0030075', (143, 147))	('IDC', 'Gene', '4000', (153, 156))
137656	29720211	Given that genetic heterogeneity may be a bad prognostic feature in several tumor types, its detection in benign lesions could be relevant for patient management.	('patient', 'Species', '9606', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('genetic heterogeneity', 'Var', (11, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
137677	29720211	demonstrated that clonality between ADH and synchronous carcinoma was more likely when the carcinoma was low grade and that ADH lacking any AI was most commonly associated with high grade cancer, although these trends were non-significant.	('clonality', 'Var', (18, 27))	('synchronous carcinoma', 'Disease', 'MESH:D009378', (44, 65))	('carcinoma', 'Disease', 'MESH:D002277', (56, 65))	('associated with', 'Reg', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('synchronous carcinoma', 'Disease', (44, 65))	('carcinoma', 'Disease', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cancer', 'Disease', (188, 194))	('likely', 'Reg', (75, 81))	('carcinoma', 'Disease', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
137688	29720211	Fifty-four percent of ADH synchronous with HER2+ IDC showed low or moderate ERBB2 amplification, suggesting ERBB2 amplification can be involved early in breast oncogenesis but higher amplification may be required for progression.	('amplification', 'Var', (114, 127))	('amplification', 'MPA', (82, 95))	('HER2', 'Gene', (43, 47))	('breast oncogenesis', 'Disease', (153, 171))	('involved', 'Reg', (135, 143))	('HER2', 'Gene', '2064', (43, 47))	('IDC', 'Gene', '4000', (49, 52))	('ADH synchronous', 'Disease', 'MESH:D009378', (22, 37))	('ERBB2', 'Gene', '2064', (108, 113))	('ADH synchronous', 'Disease', (22, 37))	('IDC', 'Gene', (49, 52))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))	('ERBB2', 'Gene', (108, 113))
137693	29720211	In addition, a sequencing study found that while few driver point mutations were found, patients with atypical hyperplasia shared aneuploidy events with the carcinomas, suggesting that copy number change, particularly the 1q gain commonly observed in IDC, might be an early driver of the neoplastic phenotype.	('aneuploidy', 'Disease', 'MESH:D000782', (130, 140))	('copy number change', 'Var', (185, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('carcinomas', 'Disease', (157, 167))	('hyperplasia', 'Disease', (111, 122))	('patients', 'Species', '9606', (88, 96))	('IDC', 'Gene', '4000', (251, 254))	('IDC', 'Gene', (251, 254))	('gain', 'PosReg', (225, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('hyperplasia', 'Disease', 'MESH:D006965', (111, 122))	('aneuploidy', 'Disease', (130, 140))	('carcinomas', 'Disease', 'MESH:D002277', (157, 167))
137694	29720211	Their findings also suggested that early neoplasias can harbor sufficient driver aneuploidy events to progress into carcinoma, possibly with a combination of mutational load and accumulated aneuploidy, as well as epigenetic and stromal changes over time.	('mutational load', 'Var', (158, 173))	('progress', 'PosReg', (102, 110))	('aneuploidy', 'Disease', 'MESH:D000782', (81, 91))	('neoplasias', 'Phenotype', 'HP:0002664', (41, 51))	('aneuploidy', 'Disease', (190, 200))	('neoplasia', 'Phenotype', 'HP:0002664', (41, 50))	('neoplasias', 'Disease', 'MESH:D009369', (41, 51))	('carcinoma', 'Disease', 'MESH:D002277', (116, 125))	('neoplasias', 'Disease', (41, 51))	('aneuploidy', 'Disease', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('aneuploidy', 'Disease', 'MESH:D000782', (190, 200))	('carcinoma', 'Disease', (116, 125))
137695	29720211	A similar aneuploidy hypothesis was proposed by Forsberg et al., who observed copy number changes in histologically normal epithelial cells at uninvolved margins of IDC.	('aneuploidy', 'Disease', (10, 20))	('IDC', 'Gene', '4000', (165, 168))	('copy number changes', 'Var', (78, 97))	('aneuploidy', 'Disease', 'MESH:D000782', (10, 20))	('IDC', 'Gene', (165, 168))
137705	29720211	The prognostic and predictive factors of ERBB2 amplification and/or overexpression should be studied extensively in a larger cohort.	('amplification', 'Var', (47, 60))	('ERBB2', 'Gene', '2064', (41, 46))	('ERBB2', 'Gene', (41, 46))
137727	29720211	ADH Atypical ductal hyperplasia AI Allelic imbalance CGH Comparative genomic hybridization CNB Core needle biopsy DCIS Ductal carcinoma in situ ER Estrogen receptor FISH Fluorescence in situ hybridisation IDC Invasive ductal carcinoma LG DCIS Low-grade DCIS LOH Loss of heterozygosity PR Progesterone receptor VAB Vacuum assisted biopsy WGS Whole genome sequencing TK performed the literature search, wrote and edited the manuscript, and generated the figures.	('ER', 'Gene', '2099', (144, 146))	('DCIS', 'Phenotype', 'HP:0030075', (253, 257))	('ductal carcinoma', 'Disease', 'MESH:D044584', (218, 234))	('VAB', 'Chemical', '-', (310, 313))	('carcinoma in situ', 'Disease', 'MESH:D002278', (126, 143))	('DCIS Low', 'Phenotype', 'HP:0200161', (238, 246))	('Ductal carcinoma', 'Disease', (119, 135))	('IDC', 'Gene', '4000', (205, 208))	('IDC', 'Gene', (205, 208))	('PR', 'Gene', '5241', (285, 287))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (119, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (4, 31))	('carcinoma in situ', 'Disease', (126, 143))	('Loss', 'Var', (262, 266))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('ductal carcinoma', 'Disease', (218, 234))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (218, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (119, 143))	('imbalance', 'Phenotype', 'HP:0002172', (43, 52))	('Atypical ductal hyperplasia', 'Disease', (4, 31))	('DCIS', 'Phenotype', 'HP:0030075', (238, 242))
137740	26697227	Approximately 29% of surgeons in Scotland believed that high-grade DCIS had >50% risk of invasive cancer at 10 years compared to 80% of surgeons in South of England and 59% in North of England.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('invasive cancer', 'Disease', (89, 104))	('high-grade', 'Var', (56, 66))	('invasive cancer', 'Disease', 'MESH:D009362', (89, 104))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
137752	15026788	Unlike standard methodologies that rely on a few pathological features and immunohistochemical markers, molecular profiling allows tumours to be defined by the expression pattern or genomic alteration of thousands of genes simultaneously.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('alteration', 'Var', (190, 200))
137838	31632134	In fact, some authors have assessed cryoablation in patients with metastatic disease, whereas others have used it in those who were unsuitable for surgery, or refused surgical treatment.	('cryoablation', 'Var', (36, 48))	('metastatic disease', 'Disease', (66, 84))	('patients', 'Species', '9606', (52, 60))
137843	31632134	Cryoablation also damages tumor cells by causing endothelial cell dysfunction, microthrombus formation, ischemia, and platelet aggregation.	('causing', 'Reg', (41, 48))	('platelet aggregation', 'Disease', (118, 138))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('platelet aggregation', 'Disease', 'MESH:D001791', (118, 138))	('platelet aggregation', 'Phenotype', 'HP:0003540', (118, 138))	('ischemia', 'Disease', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('endothelial cell', 'CPA', (49, 65))	('microthrombus formation', 'CPA', (79, 102))	('Cryoablation', 'Var', (0, 12))	('ischemia', 'Disease', 'MESH:D007511', (104, 112))
137847	31632134	In general, cryoablation of invasive breast cancer is supposed to create an ice ball extended at least 1 cm beyond the tumor margins.	('tumor', 'Disease', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancer', 'Disease', (28, 50))	('cryoablation', 'Var', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('invasive breast cancer', 'Disease', 'MESH:D001943', (28, 50))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
137859	31632134	Cryoablation for breast cancer represents an extension of its use in benign breast diseases.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast diseases', 'Disease', 'MESH:D061325', (76, 91))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('breast diseases', 'Disease', (76, 91))	('Cryoablation', 'Var', (0, 12))
137862	31632134	Cryoablation destroyed successfully 100% of cancers <=1.0 cm, whereas in patients with invasive ductal carcinomas between 1.0 and 1.5 cm, 100% success rate was obtained only for tumors without a significant ductal carcinoma in situ (DCIS) component.	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('ductal carcinoma', 'Disease', 'MESH:D044584', (96, 112))	('invasive ductal carcinomas', 'Disease', (87, 113))	('ductal carcinoma', 'Disease', 'MESH:D044584', (207, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('invasive ductal carcinomas', 'Disease', 'MESH:D044584', (87, 113))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (207, 231))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('tumors', 'Disease', (178, 184))	('cancers', 'Disease', (44, 51))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (96, 112))	('ductal carcinoma', 'Disease', (207, 223))	('Cryoablation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (207, 223))
137869	31632134	Central pathologic review showed successful cryoablation in 75.9% of cancer lesions and residual invasive carcinoma and/or DCIS in 24.1%.	('invasive carcinoma', 'Disease', 'MESH:D009361', (97, 115))	('cancer lesions', 'Disease', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cryoablation', 'Var', (44, 56))	('invasive carcinoma', 'Disease', (97, 115))	('DCIS', 'Disease', (123, 127))	('cancer lesions', 'Disease', 'MESH:D009369', (69, 83))
137913	31632134	However, technique efficacy was significantly better in patients submitted to radiofrequency and cryoablation compared to laser, microwaves, and high intensity focused ultrasound.	('better', 'PosReg', (46, 52))	('patients', 'Species', '9606', (56, 64))	('cryoablation', 'Var', (97, 109))
137922	31632134	Cryoablation of tumor lesions causes the coagulative necrosis of neoplastic cells.	('tumor lesions', 'Disease', 'MESH:D001932', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('coagulative necrosis', 'Disease', 'MESH:D025861', (41, 61))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (41, 61))	('tumor lesions', 'Disease', (16, 29))	('Cryoablation', 'Var', (0, 12))	('coagulative necrosis', 'Disease', (41, 61))
137928	31632134	Experimental and clinical studies demonstrated the complementary roles for cytotoxic T-lymphocyte-associated protein (CTLA-4) and PD-1 antagonists in influencing adaptive immunity.	('PD-1', 'Gene', (130, 134))	('adaptive immunity', 'CPA', (162, 179))	('CTLA-4', 'Gene', (118, 124))	('antagonists', 'Var', (135, 146))	('CTLA-4', 'Gene', '1493', (118, 124))	('influencing', 'Reg', (150, 161))
137941	31632134	Cryoablation as an alternative to surgery in patients with early breast cancer is the most interesting aspect, because it may represent a conceptual shift toward a minimally invasive treatment.	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('patients', 'Species', '9606', (45, 53))	('Cryoablation', 'Var', (0, 12))
137962	29207971	Some studies reported similar associations with risk factors such as family history of breast cancer, previous breast biopsy, or parity between DCIS and IDC, whereas other studies reported differential association.	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('associations', 'Interaction', (30, 42))	('parity', 'Var', (129, 135))
138045	28412963	To better understand the role of modified PRs in breast cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('PRs', 'Chemical', '-', (42, 45))	('human', 'Species', '9606', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('phospho-Ser294', 'Var', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('human', 'Species', '9606', (246, 251))	('breast tumor', 'Phenotype', 'HP:0100013', (118, 130))	('breast tumors', 'Disease', 'MESH:D001943', (118, 131))	('breast tumors', 'Disease', (118, 131))	('breast tumors', 'Phenotype', 'HP:0100013', (118, 131))	('Ser294', 'Chemical', '-', (94, 100))	('PRs', 'Chemical', '-', (101, 104))	('tumor', 'Disease', (125, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumor', 'Disease', (252, 257))
138046	28412963	To complement this analysis, we assayed PR target gene regulation in T47D luminal breast cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation).	('T47D luminal breast cancer', 'Disease', (69, 95))	('aglepristone', 'Chemical', 'MESH:C419063', (210, 222))	('T47D luminal breast cancer', 'Disease', 'MESH:D001943', (69, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('onapristone', 'Chemical', 'MESH:C053238', (194, 205))	('Lys388', 'Chemical', '-', (279, 285))	('Ser294', 'Chemical', '-', (373, 379))	('mifepristone', 'Chemical', 'MESH:D015735', (180, 192))	('PR', 'Gene', '5241', (40, 42))	('K388', 'Chemical', '-', (299, 303))	('K388', 'Chemical', '-', (338, 342))	('Ser294', 'MPA', (373, 379))	('promegestone', 'Chemical', 'MESH:D011397', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Lys388', 'Var', (279, 285))	('K388R', 'Mutation', 'p.K388R', (338, 343))	('K388R mutation', 'Var', (338, 352))	('R5020', 'Chemical', 'MESH:D011397', (153, 158))
138048	28412963	Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast cancer stem cell biology.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('PRs', 'Chemical', '-', (84, 87))	('breast cancer', 'Disease', (137, 150))	('Ser294', 'Chemical', '-', (77, 83))	('phospho-Ser294', 'Var', (69, 83))	('implicate', 'Reg', (59, 68))	('RUNX2', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
138053	28412963	In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast cancer stem cell fate.	('EGF', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('phospho-Ser294-PRs', 'Var', (57, 75))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('EGF', 'Gene', '1950', (95, 98))	('RUNX2', 'Gene', (121, 126))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('Ser294', 'Chemical', '-', (65, 71))	('PRs', 'Chemical', '-', (72, 75))
138059	28412963	Most notably, the four major breast cancer subtypes (luminal A, luminal B, HER2-enriched, and basal-like) were identified and comprehensively analyzed across datasets that included mRNA expression, protein expression/activation, microRNA expression, DNA copy number variation, DNA methylation, and exome sequencing.	('protein', 'MPA', (198, 205))	('copy number variation', 'Var', (254, 275))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', '2064', (75, 79))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('expression/activation', 'MPA', (206, 227))	('mRNA expression', 'MPA', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
138060	28412963	These results revealed that breast cancers display a wide range of tumor heterogeneity caused by alterations in multiple factors, including somatically mutated driver genes (e.g., TP53, PIK3CA, AKT1, CBFB, GATA3, and MAP3K1), gene amplifications (ERBB2), and hormonally regulated gene programs (driven primarily by estrogen, progesterone, and androgen steroids).	('CBFB', 'Gene', '865', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancers', 'Disease', 'MESH:D001943', (28, 42))	('breast cancers', 'Disease', (28, 42))	('TP53', 'Gene', (180, 184))	('ERBB2', 'Gene', (247, 252))	('PIK3CA', 'Gene', (186, 192))	('tumor', 'Disease', (67, 72))	('steroids', 'Chemical', 'MESH:D013256', (352, 360))	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))	('GATA3', 'Gene', '2625', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('ERBB2', 'Gene', '2064', (247, 252))	('AKT1', 'Gene', '207', (194, 198))	('progesterone', 'Chemical', 'MESH:D011374', (325, 337))	('GATA3', 'Gene', (206, 211))	('alterations', 'Var', (97, 108))	('TP53', 'Gene', '7157', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('caused', 'Reg', (87, 93))	('CBFB', 'Gene', (200, 204))	('AKT1', 'Gene', (194, 198))	('PIK3CA', 'Gene', '5290', (186, 192))	('MAP3K1', 'Gene', (217, 223))	('MAP3K1', 'Gene', '4214', (217, 223))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
138062	28412963	For example, recent TCGA analysis compared ductal and lobular histological subtypes, revealing new molecular factors strongly associated with lobular subtypes, including mutations that lead to activation of AKT and increased FOXA1 expression and activity (i.e., key inputs to amplified estrogen receptor (ER) signaling).	('AKT', 'Gene', '207', (207, 210))	('mutations', 'Var', (170, 179))	('estrogen receptor', 'Gene', (286, 303))	('activation', 'PosReg', (193, 203))	('estrogen receptor', 'Gene', '2099', (286, 303))	('AKT', 'Gene', (207, 210))	('FOXA1', 'Gene', (225, 230))	('activity', 'MPA', (246, 254))	('increased', 'PosReg', (215, 224))	('ER', 'Gene', '2099', (305, 307))	('expression', 'MPA', (231, 241))	('FOXA1', 'Gene', '3169', (225, 230))
138077	28412963	Phosphorylation of PR Ser294 is associated with transcriptional hyperactivity at select phosphorylation-responsive PR target genes required for increased cell proliferation and survival in vitro.	('Ser294', 'Chemical', '-', (22, 28))	('hyperactivity', 'Disease', 'MESH:D006948', (64, 77))	('transcriptional', 'MPA', (48, 63))	('hyperactivity', 'Disease', (64, 77))	('Phosphorylation', 'Var', (0, 15))	('PR', 'Gene', '5241', (115, 117))	('hyperactivity', 'Phenotype', 'HP:0000752', (64, 77))	('PR', 'Gene', '5241', (19, 21))
138080	28412963	Herein, we detected Ser294-phosphorylated PRs in 54% of luminal breast cancers (n = 209).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('luminal breast cancers', 'Disease', (56, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('detected', 'Reg', (11, 19))	('Ser294', 'Chemical', '-', (20, 26))	('Ser294-phosphorylated', 'Var', (20, 41))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PRs', 'Protein', (42, 45))	('PRs', 'Chemical', '-', (42, 45))	('luminal breast cancers', 'Disease', 'MESH:D001943', (56, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))
138082	28412963	Additionally, consistent with our finding of rapid PR protein loss (i.e., by turnover) of activated (deSUMOylated and phosphorylated) receptors, we detected phospho-PR gene signatures in breast tumors clinically designated as PR-low to PR-null (luminal B) and identified novel gene sets (HER2, PAX2, AHR, AR, and RUNX) uniquely regulated by modified PRs that are associated with cancer stem cell biology.	('loss', 'NegReg', (62, 66))	('AHR', 'Gene', (300, 303))	('regulated', 'Reg', (328, 337))	('AR', 'Gene', '367', (305, 307))	('HER2', 'Gene', (288, 292))	('PRs', 'Chemical', '-', (350, 353))	('PR', 'Gene', '5241', (236, 238))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('PR', 'Gene', '5241', (165, 167))	('AHR', 'Gene', '196', (300, 303))	('cancer', 'Disease', (379, 385))	('modified', 'Var', (341, 349))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('breast tumor', 'Phenotype', 'HP:0100013', (187, 199))	('PR', 'Gene', '5241', (226, 228))	('PR', 'Gene', '5241', (51, 53))	('breast tumors', 'Disease', (187, 200))	('breast tumors', 'Disease', 'MESH:D001943', (187, 200))	('HER2', 'Gene', '2064', (288, 292))	('PR', 'Gene', '5241', (350, 352))	('RUNX', 'Gene', (313, 317))	('PAX2', 'Gene', (294, 298))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('breast tumors', 'Phenotype', 'HP:0100013', (187, 200))
138084	28412963	In sum, our data demonstrate that phospho-Ser294 PRs represent regulatory "gatekeepers" for subsequent expression of key transcription factors implicated in tumor heterogeneity and stem cell biology.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Ser294', 'Chemical', '-', (42, 48))	('PRs', 'Chemical', '-', (49, 52))	('gatekeepers', 'Species', '111938', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('phospho-Ser294 PRs', 'Var', (34, 52))
138086	28412963	T47D human breast cancer cell lines engineered to stably express PR variants (null, WT, K388R, or S294A) were previously described.	('S294A', 'Var', (98, 103))	('PR', 'Gene', '5241', (65, 67))	('K388R', 'Mutation', 'p.K388R', (88, 93))	('T47D', 'CellLine', 'CVCL:0553', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('K388R', 'Var', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('S294A', 'Mutation', 'rs1309400161', (98, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('human', 'Species', '9606', (5, 10))
138089	28412963	In various experiments, cells or explants were treated with E2, R5020, mifepristone, aglepristone, or onapristone (kindly provided by Arno Therapeutics, Inc.).	('Arno', 'Gene', '9266', (134, 138))	('R5020', 'Chemical', 'MESH:D011397', (64, 69))	('Arno', 'Gene', (134, 138))	('onapristone', 'Chemical', 'MESH:C053238', (102, 113))	('R5020', 'Var', (64, 69))	('aglepristone', 'Chemical', 'MESH:C419063', (85, 97))	('mifepristone', 'Chemical', 'MESH:D015735', (71, 83))
138107	28412963	For genome-wide microarray expression analysis, T47D cells expressing pIRES-neo3 empty vector, WT PR, or K388R PR were serum starved in modified IMEM (Gibco) for 1 day before treatment.	('K388R', 'Mutation', 'p.K388R', (105, 110))	('K388R', 'Var', (105, 110))	('T47D', 'CellLine', 'CVCL:0553', (48, 52))	('PR', 'Gene', '5241', (111, 113))	('pIRES-neo3', 'Gene', (70, 80))	('PR', 'Gene', '5241', (98, 100))
138122	28412963	Gene set enrichment analysis (GSEA) software was used to identify gene sets from the Molecular Signatures Database (MSigDB) collections 1-7 that were significantly regulated in cells stably expressing SUMO-deficient PR (K388R) compared to WT PR.	('PR', 'Gene', '5241', (242, 244))	('regulated', 'Reg', (164, 173))	('K388R', 'Mutation', 'p.K388R', (220, 225))	('SUMO-deficient', 'Var', (201, 215))	('GSEA', 'Chemical', '-', (30, 34))	('PR', 'Gene', '5241', (216, 218))
138132	28412963	To demonstrate the prevalence of PR Ser294 phosphorylation in human luminal breast tumors in vivo, we completed IHC staining of a tissue microarray (TMA) containing 209 patient breast tumors (split into 2754 tissue spots) for both total PR and phospho-Ser294 PR (Table 1).	('Ser294', 'Chemical', '-', (36, 42))	('breast tumors', 'Disease', (177, 190))	('breast tumors', 'Disease', 'MESH:D001943', (177, 190))	('luminal breast tumors', 'Disease', 'MESH:D001943', (68, 89))	('PR', 'Gene', '5241', (237, 239))	('breast tumors', 'Phenotype', 'HP:0100013', (177, 190))	('breast tumor', 'Phenotype', 'HP:0100013', (177, 189))	('PR', 'Gene', '5241', (259, 261))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('human', 'Species', '9606', (62, 67))	('phospho-Ser294', 'Var', (244, 258))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('TMA', 'Chemical', '-', (149, 152))	('breast tumors', 'Disease', 'MESH:D001943', (76, 89))	('Ser294', 'Chemical', '-', (252, 258))	('luminal breast tumors', 'Disease', (68, 89))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PR', 'Gene', '5241', (33, 35))	('breast tumors', 'Phenotype', 'HP:0100013', (76, 89))	('patient', 'Species', '9606', (169, 176))	('breast tumor', 'Phenotype', 'HP:0100013', (76, 88))
138146	28412963	Thirty-nine percent of tumors were negative for both total PR and phospho-Ser294 PR (quadrant 3) while 17% of tumors were positive for both total and Ser294-phosphorylated receptors (quadrant 1).	('Ser294-phosphorylated', 'Var', (150, 171))	('PR', 'Gene', '5241', (59, 61))	('tumors', 'Disease', (23, 29))	('positive', 'Reg', (122, 130))	('Ser294', 'Chemical', '-', (74, 80))	('Ser294', 'Chemical', '-', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('PR', 'Gene', '5241', (81, 83))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
138147	28412963	Positive staining for phospho-Ser294 PR was greatest in tissue spots pathologically classified as "Normal" (54%; normal-like tissue within tumor-containing tissue), followed by "DCIS" (47%), "Inflammatory" (43%), and "Invasive" (38%) sections, having the lowest H-score levels for expression of phospho-Ser294 PR.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('PR', 'Gene', '5241', (310, 312))	('Ser294', 'Chemical', '-', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PR', 'Gene', '5241', (37, 39))	('Ser294', 'Chemical', '-', (303, 309))	('phospho-Ser294', 'Var', (22, 36))
138158	28412963	These tumors also expressed heterogeneous levels of total and phospho-Ser294 PRs.	('phospho-Ser294 PRs', 'Var', (62, 80))	('PRs', 'Chemical', '-', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('Ser294', 'Chemical', '-', (70, 76))	('heterogeneous levels', 'MPA', (28, 48))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
138164	28412963	These findings suggest that PR Ser294 phosphorylation is a relatively common but early event in breast cancer development.	('PR', 'Gene', '5241', (28, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('Ser294', 'Chemical', '-', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('phosphorylation', 'Var', (38, 53))
138170	28412963	ER+ tumor explants treated with progesterone (10 nM) but not estrogen (1 and 10 nM) had a significantly higher percentage of Ki67-positive cells (a marker of cell proliferation), compared to vehicle treatment (P = 0.006, ANOVA with TukeyHSD posttest; n = 6) (Fig.	('tumor', 'Disease', (4, 9))	('ER', 'Gene', '2099', (0, 2))	('progesterone', 'Chemical', 'MESH:D011374', (32, 44))	('Ki67-positive', 'Var', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('higher', 'PosReg', (104, 110))
138173	28412963	We previously demonstrated a proliferative and pro-survival role for MAPK-dependent phosphorylation of PR on Ser294 in breast cancer cells.	('Ser294', 'Chemical', '-', (109, 115))	('PR', 'Gene', '5241', (103, 105))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('proliferative', 'CPA', (29, 42))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('phosphorylation', 'Var', (84, 99))	('pro-survival', 'CPA', (47, 59))
138179	28412963	Phospho-ERK1/2 staining confirmed that progesterone (but not estrogen) activated ERKs 1/2 and that U0126 also blocked the majority of hormone-induced ERK 1/2 activity in breast tumor tissues (Fig.	('breast tumor', 'Phenotype', 'HP:0100013', (170, 182))	('activity', 'MPA', (158, 166))	('ERKs 1/2', 'Gene', (81, 89))	('ERK 1/2', 'Gene', '5595;5594', (150, 157))	('ERK 1/2', 'Gene', (150, 157))	('U0126', 'Var', (99, 104))	('breast tumor', 'Disease', 'MESH:D001943', (170, 182))	('progesterone', 'Chemical', 'MESH:D011374', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('breast tumor', 'Disease', (170, 182))	('blocked', 'NegReg', (110, 117))	('ERKs 1/2', 'Gene', '5595;5594', (81, 89))	('U0126', 'Chemical', 'MESH:C113580', (99, 104))
138185	28412963	To probe changes in PR target gene expression in the presence or absence of commonly used PR ligands (R5020, RU486), including diverse antiprogestins (aglepristone, onapristone) currently in development for clinical use, we utilized the well-characterized model system of T47D breast cancer cells, stably expressing either unmodified wild-type (WT) PR-B or a transcriptionally hyperactive form of deSUMOylated K388R PR-B (KR; this receptor faithfully mimics phosphorylated PR-B with regard to target gene selection).	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('K388R', 'Var', (410, 415))	('K388R', 'Mutation', 'p.K388R', (410, 415))	('PR', 'Gene', '5241', (90, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Disease', (277, 290))	('T47D', 'CellLine', 'CVCL:0553', (272, 276))	('R5020', 'Chemical', 'MESH:D011397', (102, 107))	('RU486', 'Chemical', 'MESH:D015735', (109, 114))	('PR', 'Gene', '5241', (349, 351))	('onapristone', 'Chemical', 'MESH:C053238', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('PR', 'Gene', '5241', (473, 475))	('PR', 'Gene', '5241', (20, 22))	('PR', 'Gene', '5241', (416, 418))	('aglepristone', 'Chemical', 'MESH:C419063', (151, 163))
138194	28412963	These data show that PR Ser294 phosphorylation is stimulated by multiple ligands including the common PR antagonists mifepristone and aglepristone.	('Ser294', 'Chemical', '-', (24, 30))	('mifepristone', 'Chemical', 'MESH:D015735', (117, 129))	('stimulated', 'PosReg', (50, 60))	('phosphorylation', 'MPA', (31, 46))	('aglepristone', 'Chemical', 'MESH:C419063', (134, 146))	('PR', 'Gene', '5241', (102, 104))	('Ser294', 'Var', (24, 30))	('PR', 'Gene', '5241', (21, 23))
138199	28412963	1a), we conducted global gene expression analyses in T47D breast cancer cells expressing either WT or K388R PR-B receptors treated as above (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('K388R', 'Mutation', 'p.K388R', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('K388R', 'Var', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('PR-B', 'Gene', (108, 112))	('T47D', 'CellLine', 'CVCL:0553', (53, 57))
138201	28412963	The cells were then treated with vehicle control (ethanol), progesterone (P), mifepristone (M), aglepristone (A), onapristone (O), or combined (progesterone agonist plus each antagonist) treatments of P + M, P + A, or P + O.	('aglepristone', 'Chemical', 'MESH:C419063', (96, 108))	('progesterone', 'Chemical', 'MESH:D011374', (144, 156))	('onapristone', 'Chemical', 'MESH:C053238', (114, 125))	('ethanol', 'Chemical', 'MESH:D000431', (50, 57))	('progesterone', 'Chemical', 'MESH:D011374', (60, 72))	('P + O', 'Var', (218, 223))	('mifepristone', 'Chemical', 'MESH:D015735', (78, 90))	('P + A', 'Var', (208, 213))	('P + M', 'Var', (201, 206))
138212	28412963	However, based on this clustering analysis, all samples (expressing WT or KR PR) treated with onapristone were closely related (and members of the second branch), suggesting that onapristone effectively inhibited PR (either WT or KR) transcriptional activity comparable to the level found in PR-null (control) cells (Fig.	('PR', 'Gene', '5241', (292, 294))	('onapristone', 'Var', (179, 190))	('transcriptional activity', 'MPA', (234, 258))	('inhibited', 'NegReg', (203, 212))	('PR', 'Gene', '5241', (77, 79))	('onapristone', 'Chemical', 'MESH:C053238', (179, 190))	('onapristone', 'Chemical', 'MESH:C053238', (94, 105))	('PR', 'Gene', '5241', (213, 215))
138214	28412963	We demonstrated that PR transcriptional activity is directly linked to rapid proteasome-mediated turnover of ligand-bound receptors and that ligand-dependent PR downregulation is greatly augmented by phosphorylation of PR Ser294 in response to activated MAPK or CDK2 signaling pathways.	('phosphorylation', 'Var', (200, 215))	('CDK2', 'Gene', (262, 266))	('PR', 'Gene', '5241', (158, 160))	('CDK2', 'Gene', '1017', (262, 266))	('downregulation', 'NegReg', (161, 175))	('augmented', 'PosReg', (187, 196))	('MAPK', 'Pathway', (254, 258))	('PR', 'Gene', '5241', (219, 221))	('PR', 'Gene', '5241', (21, 23))	('Ser294', 'Chemical', '-', (222, 228))
138215	28412963	To address this context-dependent complexity, we identified activated PR target genes that were specifically regulated in cells expressing SUMO-deficient PRs (as markers of phosphorylated or hyperactivated PR transcriptional activity) and examined their average expression levels in the TCGA breast cancer patient cohort.	('PR', 'Gene', '5241', (206, 208))	('PR', 'Gene', '5241', (70, 72))	('PRs', 'Chemical', '-', (154, 157))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('breast cancer', 'Disease', (292, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('PR', 'Gene', '5241', (154, 156))	('regulated', 'PosReg', (109, 118))	('SUMO-deficient', 'Var', (139, 153))	('patient', 'Species', '9606', (306, 313))
138217	28412963	Next, in these tumors, we compared the expression of genes known to be primarily upregulated by deSUMOylated (i.e., phosphorylated) activated PRs relative to genes known to be regulated by SUMOylated PRs (Fig.	('PRs', 'Chemical', '-', (142, 145))	('PRs', 'Gene', (142, 145))	('upregulated', 'PosReg', (81, 92))	('PRs', 'Chemical', '-', (200, 203))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('deSUMOylated', 'Var', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('expression', 'MPA', (39, 49))	('tumors', 'Disease', (15, 21))
138233	28412963	In addition, PAX2 and aryl hydrocarbon receptor (AHR) as well as androgen receptor (AR) and glucocorticoid receptor (GR) gene sets (which share similar consensus sequences to that of PR) were significantly upregulated in cells expressing KR-PR (+SPRMs) but not in similarly treated cells expressing WT-PR (Additional file 3C-E), suggesting that genes regulated by active SUMO-deficient or phospho-Ser294 PRs are more likely to contain classical steroid receptor binding motifs near the transcriptional start site and may thus have DNA binding priority relative to unmodified WT PRs (i.e., primarily de-phosphorylated but capable of undergoing ligand-induced SUMOylation).	('aryl hydrocarbon receptor', 'Gene', (22, 47))	('PR', 'Gene', '5241', (183, 185))	('phospho-Ser294', 'Var', (389, 403))	('PAX2', 'Gene', (13, 17))	('aryl hydrocarbon receptor', 'Gene', '196', (22, 47))	('glucocorticoid receptor', 'Gene', '2908', (92, 115))	('PR', 'Gene', '5241', (578, 580))	('GR', 'Gene', '2908', (117, 119))	('PR', 'Gene', '5241', (404, 406))	('Ser294', 'Chemical', '-', (397, 403))	('AHR', 'Gene', (49, 52))	('PRs', 'Chemical', '-', (578, 581))	('PRs', 'Chemical', '-', (404, 407))	('PR', 'Gene', '5241', (241, 243))	('androgen receptor', 'Gene', (65, 82))	('androgen receptor', 'Gene', '367', (65, 82))	('AR', 'Gene', '367', (84, 86))	('upregulated', 'PosReg', (206, 217))	('glucocorticoid receptor', 'Gene', (92, 115))	('AHR', 'Gene', '196', (49, 52))	('PR', 'Gene', '5241', (247, 249))	('PR', 'Gene', '5241', (302, 304))
138236	28412963	The above GSEA results suggest that SUMO-deficient phospho-Ser294 PRs regulate a set of genes also regulated by RUNX factors.	('GSEA', 'Chemical', '-', (10, 14))	('phospho-Ser294', 'Var', (51, 65))	('Ser294', 'Chemical', '-', (59, 65))	('PRs', 'Chemical', '-', (66, 69))	('regulate', 'Reg', (70, 78))
138245	28412963	Similarly, in MCF-7 cell line models overexpressing SUMO-deficient K388R PR, SLC37A2 expression was upregulated by progestin exposure but blocked by mifepristone (Fig.	('SLC37A2', 'Gene', (77, 84))	('expression', 'MPA', (85, 95))	('MCF-7', 'CellLine', 'CVCL:0031', (14, 19))	('K388R', 'Mutation', 'p.K388R', (67, 72))	('PR', 'Gene', '5241', (73, 75))	('K388R', 'Var', (67, 72))	('upregulated', 'PosReg', (100, 111))	('mifepristone', 'Chemical', 'MESH:D015735', (149, 161))	('SLC37A2', 'Gene', '219855', (77, 84))
138250	28412963	We then tested the requirement for RUNX2 expression in transcriptional responses to progestin by knocking down RUNX2 in T47D cells using shRNAs.	('tested', 'Reg', (8, 14))	('knocking down', 'Var', (97, 110))	('RUNX2', 'Gene', (111, 116))	('T47D', 'CellLine', 'CVCL:0553', (120, 124))
138251	28412963	Although T47D cells remained relatively resistant to RUNX2 loss in our hands, RUNX2 expression was reproducibly reduced by approximately 50% upon expression of specific shRNAs relative to shRNA controls (Fig.	('RUNX2', 'Gene', (78, 83))	('specific shRNAs', 'Var', (160, 175))	('T47D', 'CellLine', 'CVCL:0553', (9, 13))	('reduced', 'NegReg', (112, 119))	('expression', 'MPA', (84, 94))
138257	28412963	To demonstrate a role for phosphorylated PRs in breast cancer stem cell biology, we performed mammosphere assays using our well-defined T47D cell model systems expressing either empty vector (EV PR-null), unmodified WT PR-B, point mutant KR PR-B (K388R), or point mutant S294A PR-B missing the consensus MAPK phosphorylation site Ser residue (Fig.	('Ser', 'Chemical', 'MESH:D012694', (330, 333))	('S294A', 'Mutation', 'rs1309400161', (271, 276))	('missing', 'NegReg', (282, 289))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('PRs', 'Chemical', '-', (41, 44))	('breast cancer', 'Disease', (48, 61))	('point mutant', 'Var', (225, 237))	('EV', 'Disease', 'MESH:D004819', (192, 194))	('S294A', 'Var', (271, 276))	('PR', 'Gene', '5241', (195, 197))	('PR', 'Gene', '5241', (277, 279))	('PR', 'Gene', '5241', (219, 221))	('point mutant S294A', 'Var', (258, 276))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('K388R', 'Mutation', 'p.K388R', (247, 252))	('PR', 'Gene', '5241', (241, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('T47D', 'CellLine', 'CVCL:0553', (136, 140))	('PR', 'Gene', '5241', (41, 43))
138265	28412963	These data suggest that formation of secondary mammospheres, a definitive assay of stem cell outgrowth, is largely dependent on the presence of signaling inputs (EGF) to phospho-Ser294 PRs in T47D breast cancer cells but does not require exogenously added progesterone.	('breast cancer', 'Disease', (197, 210))	('EGF', 'Gene', '1950', (162, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('phospho-Ser294 PRs', 'Var', (170, 188))	('Ser294', 'Chemical', '-', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('PRs', 'Chemical', '-', (185, 188))	('progesterone', 'Chemical', 'MESH:D011374', (256, 268))	('EGF', 'Gene', (162, 165))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('T47D', 'CellLine', 'CVCL:0553', (192, 196))
138266	28412963	Further, the finding that expression of S294A PR attenuated mammosphere formation to levels below that of either PR-null or WT PR-containing cells in EGF-containing media suggests a dominant negative effect of this mutant receptor, perhaps via interaction with other steroid receptors such as ER or AR (see "Discussion").	('S294A', 'Var', (40, 45))	('EGF', 'Gene', (150, 153))	('mammosphere formation', 'CPA', (60, 81))	('AR', 'Gene', '367', (299, 301))	('attenuated', 'NegReg', (49, 59))	('ER', 'Gene', '2099', (293, 295))	('PR', 'Gene', '5241', (113, 115))	('EGF', 'Gene', '1950', (150, 153))	('PR', 'Gene', '5241', (46, 48))	('PR', 'Gene', '5241', (127, 129))	('negative', 'NegReg', (191, 199))	('S294A', 'Mutation', 'rs1309400161', (40, 45))
138267	28412963	We next tested the ability of PR-B+ T47D cells stably expressing either control shRNA (shGFP) or RUNX2 shRNA to form mammospheres (Fig.	('tested', 'Reg', (8, 14))	('T47D', 'CellLine', 'CVCL:0553', (36, 40))	('RUNX2', 'Var', (97, 102))
138268	28412963	Again, cells expressing K388R PR-B formed larger and significantly greater numbers of primary mammospheres relative to cells expressing unmodified (WT) PR-B.	('K388R PR-B', 'Var', (24, 34))	('K388R', 'Mutation', 'p.K388R', (24, 29))	('larger', 'PosReg', (42, 48))	('greater', 'PosReg', (67, 74))
138269	28412963	Knockdown of RUNX2 greatly attenuated the formation of primary mammospheres in T47D cells expressing either WT PR-B or K388R PR-B, rendering the assay of secondary mammospheres infeasible.	('attenuated', 'NegReg', (27, 37))	('T47D', 'CellLine', 'CVCL:0553', (79, 83))	('formation of primary mammospheres', 'CPA', (42, 75))	('RUNX2', 'Gene', (13, 18))	('K388R', 'Mutation', 'p.K388R', (119, 124))	('K388R', 'Var', (119, 124))
138280	28412963	Additionally, our findings support a growing body of evidence implicating PR as a master regulator of cell fate of both normal mammary epithelial and cancer stem/progenitor cell populations and reveal a key role for Ser294-phosphorylated PRs in this aspect of PR-driven cell biology.	('cell', 'CPA', (102, 106))	('Ser294-phosphorylated', 'Var', (216, 237))	('PR', 'Gene', '5241', (238, 240))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('Ser294', 'Chemical', '-', (216, 222))	('cancer', 'Disease', (150, 156))	('PR', 'Gene', '5241', (260, 262))	('PR', 'Gene', '5241', (74, 76))	('PRs', 'Chemical', '-', (238, 241))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
138296	28412963	The finding that PR Ser294 phosphorylation is widely observed in breast tumors and is primarily found in premalignant regions suggests that this modification of PR is a relatively early event in tumor progression that is likely most relevant to luminal A to luminal B transition, wherein PR expression appears diminished as PR target gene expression peaks.	('PR', 'Gene', '5241', (161, 163))	('Ser294', 'Var', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('PR', 'Gene', '5241', (17, 19))	('tumor', 'Disease', (195, 200))	('PR', 'Gene', '5241', (324, 326))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Ser294', 'Chemical', '-', (20, 26))	('tumor', 'Disease', (72, 77))	('breast tumors', 'Phenotype', 'HP:0100013', (65, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('breast tumor', 'Phenotype', 'HP:0100013', (65, 77))	('breast tumors', 'Disease', 'MESH:D001943', (65, 78))	('PR', 'Gene', '5241', (288, 290))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('breast tumors', 'Disease', (65, 78))
138302	28412963	In breast cancer cells expressing KR PR, mifepristone and aglepristone stimulated considerable Ser294 phosphorylation and gene regulation, suggesting these antagonists may be less effective in cells that contain the highly transcriptionally active deSUMOylated PR.	('Ser294', 'Chemical', '-', (95, 101))	('aglepristone', 'Chemical', 'MESH:C419063', (58, 70))	('mifepristone', 'Chemical', 'MESH:D015735', (41, 53))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('gene regulation', 'MPA', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('stimulated', 'PosReg', (71, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('PR', 'Gene', '5241', (37, 39))	('Ser294', 'Protein', (95, 101))	('mifepristone', 'Var', (41, 53))	('aglepristone', 'Gene', (58, 70))	('PR', 'Gene', '5241', (261, 263))
138308	28412963	Our data may explain why mifepristone (RU486) has not been successful in clinical trials for breast cancer, considering that our TMA revealed that PRs in a majority of breast tumors are phosphorylated on Ser294, a posttranslational event predicted to confer partial agonist activity to ligands of this class.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('mifepristone', 'Chemical', 'MESH:D015735', (25, 37))	('TMA', 'Chemical', '-', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast tumors', 'Phenotype', 'HP:0100013', (168, 181))	('Ser294', 'Var', (204, 210))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('PRs', 'Chemical', '-', (147, 150))	('breast tumor', 'Phenotype', 'HP:0100013', (168, 180))	('breast cancer', 'Disease', (93, 106))	('Ser294', 'Chemical', '-', (204, 210))	('breast tumors', 'Disease', 'MESH:D001943', (168, 181))	('RU486', 'Chemical', 'MESH:D015735', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('breast tumors', 'Disease', (168, 181))
138310	28412963	We previously defined phospho-Ser294 PRs as major transcriptional drivers of gene programs significantly associated with HER2/ERBB2 signaling in breast cancers.	('HER2', 'Gene', '2064', (121, 125))	('Ser294', 'Chemical', '-', (30, 36))	('PRs', 'Chemical', '-', (37, 40))	('ERBB2', 'Gene', '2064', (126, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (145, 159))	('ERBB2', 'Gene', (126, 131))	('breast cancers', 'Disease', 'MESH:D001943', (145, 159))	('breast cancers', 'Disease', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('phospho-Ser294 PRs', 'Var', (22, 40))	('associated', 'Reg', (105, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('HER2', 'Gene', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
138315	28412963	Pax2 knockout in murine mammary glands phenotypically resembled PR or Wnt4-knockout mice.	('Pax2', 'Gene', '18504', (0, 4))	('Wnt4', 'Gene', '22417', (70, 74))	('knockout', 'Var', (5, 13))	('Wnt4', 'Gene', (70, 74))	('murine', 'Species', '10090', (17, 23))	('PR', 'Gene', '5241', (64, 66))	('Pax2', 'Gene', (0, 4))	('mice', 'Species', '10090', (84, 88))
138328	28412963	AML is primarily caused by gene translocations between strong promoters and the EVI1 and runt-related transcription factor 1 (RUNX1) genes.	('EV', 'Disease', 'MESH:D004819', (80, 82))	('runt-related transcription factor 1', 'Gene', '861', (89, 124))	('RUNX1', 'Gene', (126, 131))	('gene translocations', 'Var', (27, 46))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('caused by', 'Reg', (17, 26))	('RUNX1', 'Gene', '861', (126, 131))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('runt-related transcription factor 1', 'Gene', (89, 124))	('AML', 'Disease', (0, 3))
138336	28412963	Runx2 gene deletion resulted in disrupted alveolar progenitor cell populations, differentiated cell type histology, reduced levels of cell proliferation, reduced tumor burden, and longer overall survival in a mouse model of breast cancer.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('reduced', 'NegReg', (154, 161))	('disrupted', 'NegReg', (32, 41))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('tumor', 'Disease', (162, 167))	('levels of cell proliferation', 'MPA', (124, 152))	('breast cancer', 'Disease', (224, 237))	('Runx2', 'Gene', '12393', (0, 5))	('alveolar progenitor cell populations', 'CPA', (42, 78))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('longer', 'PosReg', (180, 186))	('deletion', 'Var', (11, 19))	('reduced', 'NegReg', (116, 123))	('Runx2', 'Gene', (0, 5))	('mouse', 'Species', '10090', (209, 214))
138337	28412963	In addition, deletion of RUNX2 in human breast cancer cells resulted in reduced tumorigenic properties, such as invasion and migration.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('reduced', 'NegReg', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('human', 'Species', '9606', (34, 39))	('migration', 'CPA', (125, 134))	('breast cancer', 'Disease', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('invasion', 'CPA', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('tumor', 'Disease', (80, 85))	('deletion', 'Var', (13, 21))	('RUNX2', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
138339	28412963	Interestingly, while mammosphere formation was insensitive to added hormones, EGF was required for spheroid formation in breast cancer cells expressing K388R (phospho-mimic) PRs (Fig.	('EGF', 'Gene', (78, 81))	('PRs', 'Chemical', '-', (174, 177))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('EGF', 'Gene', '1950', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('K388R', 'Mutation', 'p.K388R', (152, 157))	('K388R', 'Var', (152, 157))
138343	28412963	In sum, PR is emerging as a major mechanistic player that mediates early breast tumor progression in part via "feeding" the stem cell compartment (i.e., via paracrine signals); our data support a requirement for phosphorylation of PR Ser294 in this activity as an important gatekeeper of breast cancer cell fate and expanded tumor heterogeneity.	('breast cancer', 'Disease', (288, 301))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Ser294', 'Var', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast tumor', 'Disease', (73, 85))	('gatekeeper', 'Species', '111938', (274, 284))	('Ser294', 'Chemical', '-', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Disease', (80, 85))	('PR', 'Gene', '5241', (8, 10))	('PR', 'Gene', '5241', (231, 233))	('breast tumor', 'Phenotype', 'HP:0100013', (73, 85))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('breast tumor', 'Disease', 'MESH:D001943', (73, 85))
138485	24084766	Diagnosed tumours are categorised by size: ductal carcinomas in situ (DCIS), <=10 mm, 11-20 mm, 21-50 mm, and >=51 mm.	('tumours', 'Disease', (10, 17))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('11-20 mm', 'Var', (86, 94))	('ductal carcinomas in situ', 'Phenotype', 'HP:0030075', (43, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('carcinomas', 'Disease', 'MESH:D002277', (50, 60))	('<=10 mm', 'Var', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('21-50 mm', 'Var', (96, 104))	('carcinomas', 'Disease', (50, 60))
138511	24084766	In the absence of screening, with all breast cancers detected by other means, the proportion detected with a DCIS was 9% (95% CI: 4-15%), <=10 mm was 10% (95% CI: 8-14%), 11-20 mm was 41% (95% CI: 35-48%), 21-50 mm was 34% (95% CI: 28-41%), and >=51 mm was 5% (95% CI: 2-9%).	('breast cancers', 'Phenotype', 'HP:0003002', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancers', 'Disease', 'MESH:D001943', (38, 52))	('<=10 mm', 'Var', (138, 145))	('breast cancers', 'Disease', (38, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('21-50 mm', 'Var', (206, 214))	('11-20 mm', 'Var', (171, 179))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))
138512	24084766	At any instant of time, of those with asymptomatic cancer, 30% (95% CI: 12-53%) will have indolent DCIS, 2% (95% CI: 0-4%) aggressive DCIS, 24% (95% CI: 15-33%) <=10 mm, 33% (95% CI: 21-47%) 11-20 mm, 10% (95% CI: 5-18%) 21-50 mm, and 1% (95% CI: 0-2%) >=51 mm.	('indolent', 'MPA', (90, 98))	('<=10 mm', 'Var', (161, 168))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('aggressive DCIS', 'CPA', (123, 138))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
138514	24084766	Under different screening frequencies, the more significant impacts are observed in the proportions of <=10 mm and 21-50 mm tumours.	('21-50 mm', 'Var', (115, 123))	('impacts', 'Reg', (60, 67))	('<=10 mm', 'Var', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
138517	24084766	By introducing annual screening, there is a much higher proportion of women diagnosed with <=10 mm tumour (from 0.3 to 1.0%) and a substantially lower proportion of women diagnosed with 21-50 mm tumour (from 0.8 to 0.3%), as compared with no screening.	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (99, 105))	('tumour', 'Disease', (195, 201))	('<=10 mm', 'Var', (91, 98))	('women', 'Species', '9606', (165, 170))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('women', 'Species', '9606', (70, 75))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
138624	20069109	Its uptake "is due to an increase in blood flow, number of mitochondria and cancer cell membrane hyperpolarization in the tumor and as a function of the expression of the multidrug resistance gene".	('blood flow', 'CPA', (37, 47))	('expression', 'Var', (153, 163))	('multidrug resistance gene', 'Gene', (171, 196))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('number of mitochondria', 'MPA', (49, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('increase', 'PosReg', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('uptake', 'MPA', (4, 10))	('cancer', 'Disease', (76, 82))	('tumor', 'Disease', (122, 127))
138659	20069109	found that THI increased gray-scale contrast between fatty tissue and breast lesions in 90.6% of 254 lesions.	('THI', 'Var', (11, 14))	('THI', 'Chemical', '-', (11, 14))	('gray-scale contrast', 'MPA', (25, 44))	('increased', 'PosReg', (15, 24))
138721	20069109	The bend induces a voltage across the sensing PZT layer, which is then measured, indicating the displacement.	('induces', 'Reg', (9, 16))	('voltage across the sensing PZT', 'MPA', (19, 49))	('bend', 'Var', (4, 8))	('men', 'Species', '9606', (104, 107))
138726	20069109	The system works better with a lubricating gel (similar to manual palpation methods) and can detect inclusions farther from the breast surface than a human finger can.	('human', 'Species', '9606', (150, 155))	('inclusions', 'Var', (100, 110))	('detect', 'Reg', (93, 99))
138836	28766199	Oversensitivity of MRI and/or inclusion of areas of borderline enhancement in the segmented tumor volume could also lead to distances >2 cm.	('Oversensitivity', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('lead to', 'Reg', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
138932	19650921	Alongside the predicted increase in tumor number and decrease in tumor latency with increasing NMU dose, we observed a number of microscopic lesions and other epithelial abnormalities in the mammary glands for all NMU doses.	('increase', 'PosReg', (24, 32))	('NMU', 'Chemical', 'MESH:D008770', (95, 98))	('decrease', 'NegReg', (53, 61))	('tumor', 'Disease', (65, 70))	('NMU', 'Chemical', 'MESH:D008770', (214, 217))	('epithelial abnormalities', 'Disease', 'MESH:D002277', (159, 183))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('NMU', 'Var', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('epithelial abnormalities', 'Disease', (159, 183))
138933	19650921	Two types of non-neoplastic histological changes were observed in rats exposed to 10 or 20 mg NMU/kg BW: namely, (i) an increase in the number of acinar structures often accompanied by secretion into the lumen which is normally associated with pregnancy and lactation, and (ii) an increase in the number of epithelial cells sloughed into the lumen of the epithelial ducts.	('secretion into the lumen', 'MPA', (185, 209))	('lactation', 'Disease', (258, 267))	('acinar structures', 'CPA', (146, 163))	('lactation', 'Disease', 'MESH:D007775', (258, 267))	('rats', 'Species', '10116', (66, 70))	('neoplastic histological changes', 'Phenotype', 'HP:0002664', (17, 48))	('increase', 'PosReg', (281, 289))	('increase', 'PosReg', (120, 128))	('NMU/kg', 'Var', (94, 100))	('NMU', 'Chemical', 'MESH:D008770', (94, 97))
138939	19650921	In addition, NMU exposure results in point mutations in codon 12 of the Ha-ras-1 gene.	('results in', 'Reg', (26, 36))	('point mutations', 'Var', (37, 52))	('NMU', 'Chemical', 'MESH:D008770', (13, 16))	('Ha-ras-1', 'Gene', (72, 80))
138940	19650921	A single NMU injection will produce 100% incidence of mammary tumors in susceptible rats and its specificity for the mammary and salivary glands is unexplained.	('NMU', 'Chemical', 'MESH:D008770', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('NMU', 'Var', (9, 12))	('mammary', 'Disease', (54, 61))	('rats', 'Species', '10116', (84, 88))
138941	19650921	Accordingly, numerous studies have been conducted using NMU to generate mammary gland tumors in several rat strains including Wistar-Furth.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('rat', 'Species', '10116', (67, 70))	('NMU', 'Var', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('gland tumors', 'Disease', 'MESH:D010871', (80, 92))	('gland tumors', 'Disease', (80, 92))	('NMU', 'Chemical', 'MESH:D008770', (56, 59))	('rat', 'Species', '10116', (104, 107))
138965	19650921	The animals treated with 50 mg NMU/kg BW were sacrificed earlier than the other groups as palpable tumor incidence in this group reached 100% by 17 weeks p.i.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('NMU/kg', 'Var', (31, 37))	('NMU', 'Chemical', 'MESH:D008770', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
138982	19650921	In addition, we calculated the average tumor latency for each group and found a decrease in tumor latency with increasing NMU dose.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (92, 97))	('NMU', 'Chemical', 'MESH:D008770', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('NMU', 'Var', (122, 125))	('decrease', 'NegReg', (80, 88))
138985	19650921	A log rank analysis showed a significantly shorter latency in the group treated with 50 mg NMU/kg BW compared to all other groups (p < 0.0000).	('NMU', 'Chemical', 'MESH:D008770', (91, 94))	('latency', 'MPA', (51, 58))	('NMU/kg', 'Var', (91, 97))	('shorter', 'NegReg', (43, 50))
138990	19650921	Tumors from animals exposed to 30 mg NMU/kg BW were predominately DCIS with some showing invasive tendencies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NMU/kg', 'Var', (37, 43))	('NMU', 'Chemical', 'MESH:D008770', (37, 40))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
138994	19650921	This paired data set showed that the aberrant structure incidence increased with NMU dose.	('increased', 'PosReg', (66, 75))	('NMU dose', 'Var', (81, 89))	('aberrant structure incidence', 'CPA', (37, 65))	('NMU', 'Chemical', 'MESH:D008770', (81, 84))
138998	19650921	for all other groups) analysis of left and right side abdominal-inguinal mammary glands for each animal showed a similar NMU dose-dependant incidence increase (Table 1).	('NMU', 'Chemical', 'MESH:D008770', (121, 124))	('NMU', 'Var', (121, 124))	('increase', 'PosReg', (150, 158))
139015	19650921	Neoplastic and non-neoplastic features were observed in the mammary glands of rats treated with 30 mg or 50 mg NMU/kg BW as early as 12 weeks p.i.	('rats', 'Species', '10116', (78, 82))	('NMU', 'Chemical', 'MESH:D008770', (111, 114))	('Neoplastic', 'Disease', 'MESH:D009369', (0, 10))	('NMU/kg', 'Var', (111, 117))	('Neoplastic', 'Disease', (0, 10))
139027	19650921	Palpable tumor incidence reached 100% in the 50 mg NMU/kg BW animals, thus all aberrant structures found in this group were coincident with tumor formation.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('NMU', 'Chemical', 'MESH:D008770', (51, 54))	('50 mg NMU/kg', 'Var', (45, 57))
139032	19650921	Furthermore, the latency to the first palpable tumor for the low dose animals was substantially longer than in those receiving higher doses of NMU (14-24 weeks vs 6-8 weeks, respectively).	('NMU', 'Chemical', 'MESH:D008770', (143, 146))	('low dose', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('longer', 'PosReg', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('latency', 'MPA', (17, 24))
139034	19650921	In the animals exposed to 10 mg or 20 mg NMU/kg BW, two distinct types of histological changes were observed, namely, (i) an increase in the number of acinar structures often accompanied by secretion into the lumen which is normally associated with pregnancy and lactation, and (ii) an increase in the number of epithelial cells sloughing into the lumen of the epithelial ducts.	('increase', 'PosReg', (286, 294))	('increase', 'PosReg', (125, 133))	('NMU', 'Chemical', 'MESH:D008770', (41, 44))	('secretion into the lumen', 'MPA', (190, 214))	('lactation', 'Disease', (263, 272))	('NMU/kg', 'Var', (41, 47))	('lactation', 'Disease', 'MESH:D007775', (263, 272))
139043	19650921	For instance, out of 40 animals in the lowest dose of NMU only 2 exhibited palpable tumors, however 2 other animals in this group developed non-neoplastic lesions.	('NMU', 'Chemical', 'MESH:D008770', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('neoplastic lesions', 'Disease', 'MESH:D051437', (144, 162))	('neoplastic lesions', 'Disease', (144, 162))	('NMU', 'Var', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (144, 162))
139048	19650921	Similarly, an additional dose-response study highlights the importance of the route of NMU exposure as the Sprague-Dawley rats receiving an intravenous infusion of NMU at 50 days of age seemed to develop tumors faster than those Wistar-Furth rats in this study that were injected intraperitoneally; nevertheless, the overall tumor burden appeared similar.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('develop', 'PosReg', (196, 203))	('rats', 'Species', '10116', (122, 126))	('Sprague-Dawley rats', 'Species', '10116', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('NMU', 'Chemical', 'MESH:D008770', (164, 167))	('tumor', 'Disease', (204, 209))	('NMU', 'Chemical', 'MESH:D008770', (87, 90))	('tumors', 'Disease', (204, 210))	('rats', 'Species', '10116', (242, 246))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('NMU', 'Var', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
139209	25541438	Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor.	('BXL0124', 'Chemical', 'MESH:C552206', (43, 50))	('decreased', 'NegReg', (51, 60))	('Notch1 receptor', 'Protein', (84, 99))	('BXL0124', 'Var', (43, 50))	('level of activated', 'MPA', (65, 83))	('vitamin D', 'Chemical', 'MESH:D014807', (26, 35))
139210	25541438	In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling.	('c-Myc', 'Gene', (178, 183))	('BXL0124', 'Chemical', 'MESH:C552206', (133, 140))	('reduced', 'NegReg', (107, 114))	('Jagged-1', 'Gene', (59, 67))	('BXL0124', 'Var', (133, 140))	('Jagged-1', 'Gene', '182', (59, 67))	('DLL1', 'Gene', '28514', (82, 86))	('c-Myc', 'Gene', '4609', (178, 183))	('Jagged-2', 'Gene', (69, 77))	('DLL1', 'Gene', (82, 86))	('Jagged-2', 'Gene', '3714', (69, 77))
139211	25541438	Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124.	('BXL0124', 'Chemical', 'MESH:C552206', (105, 112))	('HES1', 'Gene', (15, 19))	('HES1', 'Gene', '3280', (15, 19))	('BXL0124', 'Var', (105, 112))	('induced', 'Reg', (79, 86))
139212	25541438	The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1.	('Notch signaling', 'MPA', (36, 51))	('HES1', 'Gene', (81, 85))	('BXL0124', 'Chemical', 'MESH:C552206', (25, 32))	('knockdown', 'Var', (68, 77))	('BXL0124', 'Gene', (25, 32))	('HES1', 'Gene', '3280', (81, 85))
139214	25541438	In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling.	('Notch1 signaling', 'Pathway', (129, 145))	('inhibition', 'NegReg', (115, 125))	('BXL0124', 'Chemical', 'MESH:C552206', (44, 51))	('HES1', 'Gene', '3280', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BXL0124', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('represses', 'NegReg', (53, 62))	('tumor', 'Disease', (67, 72))	('vitamin D', 'Chemical', 'MESH:D014807', (26, 35))	('HES1', 'Gene', (101, 105))
139215	25541438	The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('breast cancer', 'Disease', (127, 140))	('BXL0124', 'Chemical', 'MESH:C552206', (31, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BXL0124', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
139229	25541438	In addition to its roles in stem cells, aberrant Notch signaling has been reported in different types of human cancers, such as T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, glioblastoma and breast cancer.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (128, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('glioblastoma', 'Disease', 'MESH:D005909', (195, 207))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (135, 163))	('human', 'Species', '9606', (105, 110))	('reported', 'Reg', (74, 82))	('aberrant', 'Var', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('Notch signaling', 'MPA', (49, 64))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (141, 163))	('breast cancer', 'Disease', (212, 225))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (128, 163))	('T-cell acute lymphoblastic leukemia', 'Disease', (128, 163))	('glioblastoma', 'Disease', (195, 207))	('leukemia', 'Phenotype', 'HP:0001909', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (195, 207))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (165, 193))	('cancers', 'Disease', (111, 118))	('chronic lymphocytic leukemia', 'Disease', (165, 193))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (165, 193))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))
139237	25541438	Recently, we have shown that a Gemini vitamin D analog, BXL0124, repressed the expression of a tumor-initiating cell marker CD44 and reduced the CD44+/CD24-/low subpopulation in MCF10DCIS cells, a basal-like human breast cancer cell line derived from the MCF10A cell line with the ability to form ductal carcinoma in situ (DCIS)-like lesions in animals.	('BXL0124', 'Var', (56, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('DCIS', 'Phenotype', 'HP:0030075', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('human', 'Species', '9606', (208, 213))	('CD44', 'Gene', '960', (145, 149))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (178, 187))	('breast cancer', 'Disease', (214, 227))	('MCF10A', 'CellLine', 'CVCL:0598', (255, 261))	('CD44', 'Gene', (145, 149))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (297, 321))	('CD24', 'Gene', '100133941', (151, 155))	('ductal carcinoma', 'Disease', (297, 313))	('DCIS', 'Phenotype', 'HP:0030075', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('CD44', 'Gene', '960', (124, 128))	('ductal carcinoma', 'Disease', 'MESH:D044584', (297, 313))	('reduced', 'NegReg', (133, 140))	('tumor', 'Disease', (95, 100))	('CD44', 'Gene', (124, 128))	('vitamin D', 'Chemical', 'MESH:D014807', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CD24', 'Gene', (151, 155))	('BXL0124', 'Chemical', 'MESH:C552206', (56, 63))
139238	25541438	The mechanism by which BXL0124 reduces the CD44+/CD24-/low subpopulation, however, is not understood.	('CD44', 'Gene', '960', (43, 47))	('BXL0124', 'Chemical', 'MESH:C552206', (23, 30))	('reduces', 'NegReg', (31, 38))	('CD44', 'Gene', (43, 47))	('BXL0124', 'Var', (23, 30))	('CD24', 'Gene', '100133941', (49, 53))	('CD24', 'Gene', (49, 53))
139240	25541438	In the present study, we report that BXL0124 inhibits Notch signaling via the transcriptional repressor HES1, leading to the reduction of the CD44+/CD24-/low subpopulation in basal-like breast cancer.	('reduction', 'NegReg', (125, 134))	('CD24', 'Gene', (148, 152))	('HES1', 'Gene', '3280', (104, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('BXL0124', 'Chemical', 'MESH:C552206', (37, 44))	('inhibits', 'NegReg', (45, 53))	('Notch signaling', 'MPA', (54, 69))	('BXL0124', 'Var', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('CD44', 'Gene', '960', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('HES1', 'Gene', (104, 108))	('CD24', 'Gene', '100133941', (148, 152))	('CD44', 'Gene', (142, 146))
139246	25541438	The transduced cells were sorted by FACS using MoFlo XDP Cell Sorter (Beckman Coulter, Brea, CA) to obtain GFP-labeled HES1 overexpressing MCF10DCIS cells (DCIS-HES1) and GFP-unlabeled control MCF10DCIS cells (DCIS).	('HES1', 'Gene', '3280', (119, 123))	('DCIS-HES1', 'CellLine', 'CVCL:5552', (156, 165))	('overexpressing', 'PosReg', (124, 138))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('HES1', 'Gene', (119, 123))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (139, 148))	('DCIS', 'Phenotype', 'HP:0030075', (210, 214))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (193, 202))	('HES1', 'Gene', (161, 165))	('MCF10DCIS', 'Var', (139, 148))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('HES1', 'Gene', '3280', (161, 165))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))
139258	25541438	Primary antibodies recognizing c-Notch1 (4147), Notch1 (4380), Notch2 (5732), Notch3 (5276), Jagged-1 (2155), Jagged-2 (2210), DLL1 (2588), c-Myc (5605) and HES1 (11988) were from Cell Signaling Technology (Beverly, MA); vitamin D receptor (VDR) (GR37) was from Millipore (Billerica, MA); beta-actin (A1978) was from Sigma-Aldrich (St. Louis, MO).	('A1978', 'Var', (301, 306))	('c-Notch1 (4147', 'Var', (31, 45))	('Jagged-1', 'Gene', (93, 101))	('Jagged-2', 'Gene', '3714', (110, 118))	('Notch3', 'Gene', '4854', (78, 84))	('Notch3', 'Gene', (78, 84))	('VDR', 'Gene', '7421', (241, 244))	('vitamin D receptor', 'Gene', (221, 239))	('HES1', 'Gene', (157, 161))	('Notch2', 'Gene', (63, 69))	('Notch1 (4380', 'Var', (48, 60))	('DLL1', 'Gene', '28514', (127, 131))	('vitamin D receptor', 'Gene', '7421', (221, 239))	('beta-actin', 'Gene', (289, 299))	('Jagged-2', 'Gene', (110, 118))	('Jagged-1', 'Gene', '182', (93, 101))	('HES1', 'Gene', '3280', (157, 161))	('c-Myc', 'Gene', (140, 145))	('Notch2', 'Gene', '4853', (63, 69))	('c-Myc', 'Gene', '4609', (140, 145))	('VDR', 'Gene', (241, 244))	('DLL1', 'Gene', (127, 131))	('beta-actin', 'Gene', '728378', (289, 299))
139259	25541438	MCF10DCIS cells were incubated with 1 muM of VDR siRNA (A-003448-13-0010, Thermo Fisher Scientific Inc., Waltham, MA) or 1 muM of HES1 siRNA (A-007770-20-0010, Thermo Fisher Scientific Inc.) in Accell siRNA delivery medium (Thermo Fisher Scientific Inc.) for 72 h to knockdown VDR or HES1, respectively.	('VDR', 'Gene', '7421', (277, 280))	('HES1', 'Gene', (284, 288))	('muM', 'Gene', '56925', (38, 41))	('muM', 'Gene', (123, 126))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('knockdown', 'Var', (267, 276))	('VDR', 'Gene', '7421', (45, 48))	('HES1', 'Gene', (130, 134))	('muM', 'Gene', (38, 41))	('VDR', 'Gene', (277, 280))	('HES1', 'Gene', '3280', (284, 288))	('HES1', 'Gene', '3280', (130, 134))	('muM', 'Gene', '56925', (123, 126))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('VDR', 'Gene', (45, 48))
139264	25541438	The procedure was described previously; the labeled primers for Notch1, Notch2, Notch3, Notch4, Jagged-1, Jagged-2, DLL1, DLL2, c-Myc, HES1, VDR and glyceraldehyde 3-phosphate dehydrogenase were obtained from Life Technologies (Carlsbad, CA).	('Notch4', 'Gene', (88, 94))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (149, 189))	('Jagged-1', 'Gene', '182', (96, 104))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (149, 189))	('Notch2', 'Gene', (72, 78))	('HES1', 'Gene', (135, 139))	('c-Myc', 'Gene', (128, 133))	('VDR', 'Gene', (141, 144))	('DLL1', 'Gene', (116, 120))	('Notch4', 'Gene', '4855', (88, 94))	('Notch2', 'Gene', '4853', (72, 78))	('Jagged-1', 'Gene', (96, 104))	('c-Myc', 'Gene', '4609', (128, 133))	('Notch1', 'Var', (64, 70))	('HES1', 'Gene', '3280', (135, 139))	('Jagged-2', 'Gene', (106, 114))	('VDR', 'Gene', '7421', (141, 144))	('Jagged-2', 'Gene', '3714', (106, 114))	('Notch3', 'Gene', '4854', (80, 86))	('Notch3', 'Gene', (80, 86))	('DLL1', 'Gene', '28514', (116, 120))
139274	25541438	Treatment with BXL0124 lowered the levels of c-Notch1, Jagged-2 and c-Myc (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (15, 22))	('c-Myc', 'Gene', (68, 73))	('lowered', 'NegReg', (23, 30))	('c-Notch1', 'MPA', (45, 53))	('BXL0124', 'Var', (15, 22))	('c-Myc', 'Gene', '4609', (68, 73))	('Jagged-2', 'Gene', (55, 63))	('Jagged-2', 'Gene', '3714', (55, 63))
139277	25541438	In the previous study, the synthetic analog BXL0124 demonstrated much more potent activity than naturally occurring 1alpha,25(OH)2D3 to inhibit proliferation of MCF10DCIS cells.	('BXL0124', 'Chemical', 'MESH:C552206', (44, 51))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (116, 132))	('inhibit', 'NegReg', (136, 143))	('BXL0124', 'Var', (44, 51))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('activity', 'MPA', (82, 90))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (161, 170))
139279	25541438	Both 1alpha,25(OH)2D3 and BXL0124 decreased protein levels of c-Notch1, total Notch3, Jagged-1, Jagged-2, DLL1 and c-Myc in a dose-dependent manner with the greatest effects on c-Notch1 and Jagged-2.	('decreased', 'NegReg', (34, 43))	('c-Myc', 'Gene', '4609', (115, 120))	('Jagged-2', 'Gene', (190, 198))	('Jagged-1', 'Gene', (86, 94))	('DLL1', 'Gene', '28514', (106, 110))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (5, 21))	('Notch3', 'Gene', '4854', (78, 84))	('Notch3', 'Gene', (78, 84))	('Jagged-2', 'Gene', '3714', (190, 198))	('BXL0124', 'Chemical', 'MESH:C552206', (26, 33))	('c-Notch1', 'Var', (177, 185))	('c-Notch1', 'MPA', (62, 70))	('BXL0124', 'Var', (26, 33))	('protein levels', 'MPA', (44, 58))	('Jagged-1', 'Gene', '182', (86, 94))	('Jagged-2', 'Gene', (96, 104))	('DLL1', 'Gene', (106, 110))	('c-Myc', 'Gene', (115, 120))	('Jagged-2', 'Gene', '3714', (96, 104))
139281	25541438	Total Notch1 and total Notch2 were not affected by either 1alpha,25(OH)2D3 or BXL0124 (Fig.	('Notch1', 'MPA', (6, 12))	('BXL0124', 'Chemical', 'MESH:C552206', (78, 85))	('Notch2', 'Gene', (23, 29))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (58, 74))	('Notch2', 'Gene', '4853', (23, 29))	('BXL0124', 'Var', (78, 85))
139284	25541438	In a time course study, the protein level of c-Notch1 was markedly reduced by BXL0124 at 12 and 24 h, while the protein level of total Notch1 was not affected (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (78, 85))	('protein level', 'MPA', (28, 41))	('reduced', 'NegReg', (67, 74))	('c-Notch1', 'Gene', (45, 53))	('BXL0124', 'Var', (78, 85))
139285	25541438	BXL0124 treatment decreased Jagged-1 at 4, 12 and 24 h, and Jagged-2 at 12 and 24 h, respectively (Fig.	('Jagged-2', 'Gene', '3714', (60, 68))	('decreased', 'NegReg', (18, 27))	('BXL0124', 'Chemical', 'MESH:C552206', (0, 7))	('Jagged-2', 'Gene', (60, 68))	('Jagged-1', 'Gene', (28, 36))	('Jagged-1', 'Gene', '182', (28, 36))	('BXL0124', 'Var', (0, 7))
139290	25541438	VDR level in the nucleus was markedly increased by BXL0124 (Fig.	('VDR', 'Gene', '7421', (0, 3))	('BXL0124', 'Chemical', 'MESH:C552206', (51, 58))	('VDR', 'Gene', (0, 3))	('BXL0124', 'Var', (51, 58))	('increased', 'PosReg', (38, 47))
139292	25541438	The repression of c-Notch1 and Jagged-2 by BXL0124 was reduced by knockdown of VDR, indicating that the inhibition of Notch1 activation by BXL0124 is a VDR-dependent event (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (139, 146))	('VDR', 'Gene', (152, 155))	('BXL0124', 'Chemical', 'MESH:C552206', (43, 50))	('BXL0124', 'Var', (139, 146))	('VDR', 'Gene', '7421', (79, 82))	('Notch1', 'Gene', (118, 124))	('Jagged-2', 'Gene', '3714', (31, 39))	('c-Notch1', 'Gene', (18, 26))	('VDR', 'Gene', '7421', (152, 155))	('Jagged-2', 'Gene', (31, 39))	('VDR', 'Gene', (79, 82))
139297	25541438	The mRNA levels of Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly decreased by BXL0124 at 8, 16 and 24 h (Fig.	('mRNA levels', 'MPA', (4, 15))	('BXL0124', 'Chemical', 'MESH:C552206', (95, 102))	('Jagged-1', 'Gene', (34, 42))	('Jagged-2', 'Gene', '3714', (44, 52))	('Jagged-1', 'Gene', '182', (34, 42))	('DLL1', 'Gene', (57, 61))	('BXL0124', 'Var', (95, 102))	('Jagged-2', 'Gene', (44, 52))	('DLL1', 'Gene', '28514', (57, 61))	('decreased', 'NegReg', (82, 91))
139298	25541438	The mRNA level of c-Myc, a key downstream target of Notch signaling, was significantly decreased by BXL0124 at 16 and 24 h (Fig.	('decreased', 'NegReg', (87, 96))	('c-Myc', 'Gene', (18, 23))	('BXL0124', 'Chemical', 'MESH:C552206', (100, 107))	('c-Myc', 'Gene', '4609', (18, 23))	('BXL0124', 'Var', (100, 107))
139299	25541438	Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by BXL0124 at 1, 4, 8, 16 and 24 h (Fig.	('BXL0124', 'Var', (90, 97))	('HES1', 'Gene', (15, 19))	('induced', 'PosReg', (79, 86))	('HES1', 'Gene', '3280', (15, 19))	('BXL0124', 'Chemical', 'MESH:C552206', (90, 97))
139300	25541438	The rapid induction of HES1 mRNA by BXL0124 was confirmed with additional earlier time point studies (10 min, 30 min and 2 h) (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (36, 43))	('HES1', 'Gene', (23, 27))	('BXL0124', 'Var', (36, 43))	('HES1', 'Gene', '3280', (23, 27))
139301	25541438	The expression of HES1 mRNA was significantly increased by BXL0124 as early as 30 min, and the induction of HES1 was maintained up to 24 h (Fig.	('HES1', 'Gene', '3280', (18, 22))	('HES1', 'Gene', '3280', (108, 112))	('increased', 'PosReg', (46, 55))	('expression', 'MPA', (4, 14))	('BXL0124', 'Chemical', 'MESH:C552206', (59, 66))	('HES1', 'Gene', (18, 22))	('BXL0124', 'Var', (59, 66))	('HES1', 'Gene', (108, 112))
139302	25541438	The protein level of HES1 was also markedly increased by BXL0124 at 1 and 4 h (Fig.	('protein level', 'MPA', (4, 17))	('BXL0124', 'Chemical', 'MESH:C552206', (57, 64))	('BXL0124', 'Var', (57, 64))	('HES1', 'Gene', (21, 25))	('increased', 'PosReg', (44, 53))	('HES1', 'Gene', '3280', (21, 25))
139306	25541438	Because of the partial depletion of HES1, BXL0124 still increased HES1 and caused down-regulation of c-Notch1 and Jagged 2 (Fig.	('BXL0124', 'Var', (42, 49))	('c-Notch1', 'Protein', (101, 109))	('HES1', 'Gene', (36, 40))	('Jagged 2', 'Gene', (114, 122))	('HES1', 'Gene', '3280', (66, 70))	('Jagged 2', 'Gene', '3714', (114, 122))	('increased', 'PosReg', (56, 65))	('HES1', 'Gene', '3280', (36, 40))	('down-regulation', 'NegReg', (82, 97))	('BXL0124', 'Chemical', 'MESH:C552206', (42, 49))	('HES1', 'Gene', (66, 70))
139307	25541438	However, the extent of c-Notch1 and Jagged-2 reduction by BXL0124 was decreased by the knockdown of HES1, indicating that the inhibition of Notch1 signaling by BXL0124 is a HES1-dependent event (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (160, 167))	('HES1', 'Gene', (173, 177))	('Jagged-2', 'Gene', '3714', (36, 44))	('Jagged-2', 'Gene', (36, 44))	('BXL0124', 'Var', (160, 167))	('BXL0124', 'Chemical', 'MESH:C552206', (58, 65))	('inhibition', 'NegReg', (126, 136))	('HES1', 'Gene', (100, 104))	('HES1', 'Gene', '3280', (173, 177))	('reduction', 'NegReg', (45, 54))	('c-Notch1', 'MPA', (23, 31))	('HES1', 'Gene', '3280', (100, 104))
139308	25541438	The induction of VDR by BXL0124 was not affected by HES1 knockdown (Fig.	('HES1', 'Gene', '3280', (52, 56))	('VDR', 'Gene', '7421', (17, 20))	('knockdown', 'Var', (57, 66))	('BXL0124', 'Chemical', 'MESH:C552206', (24, 31))	('VDR', 'Gene', (17, 20))	('HES1', 'Gene', (52, 56))	('BXL0124', 'Var', (24, 31))
139309	25541438	5C), suggesting that VDR is an upstream effector of HES1 for the regulation of Notch1 signaling by BXL0124.	('VDR', 'Gene', '7421', (21, 24))	('regulation', 'MPA', (65, 75))	('HES1', 'Gene', '3280', (52, 56))	('BXL0124', 'Chemical', 'MESH:C552206', (99, 106))	('Notch1 signaling', 'MPA', (79, 95))	('BXL0124', 'Var', (99, 106))	('VDR', 'Gene', (21, 24))	('HES1', 'Gene', (52, 56))
139316	25541438	The mRNA levels of Jagged-2, DLL1 and c-Myc were also significantly decreased by HES1 overexpression, but the mRNA levels of Notch1 and Jagged-1 were not affected (Fig.	('mRNA levels', 'MPA', (4, 15))	('c-Myc', 'Gene', (38, 43))	('decreased', 'NegReg', (68, 77))	('Jagged-1', 'Gene', (136, 144))	('DLL1', 'Gene', '28514', (29, 33))	('Jagged-1', 'Gene', '182', (136, 144))	('Jagged-2', 'Gene', '3714', (19, 27))	('Jagged-2', 'Gene', (19, 27))	('overexpression', 'Var', (86, 100))	('HES1', 'Gene', (81, 85))	('DLL1', 'Gene', (29, 33))	('HES1', 'Gene', '3280', (81, 85))	('c-Myc', 'Gene', '4609', (38, 43))
139322	25541438	Aberrant activation of Notch signaling has been reported in DCIS as well as in invasive breast cancer.	('invasive breast cancer', 'Disease', (79, 101))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('Notch signaling', 'Pathway', (23, 38))	('invasive breast cancer', 'Disease', 'MESH:D001943', (79, 101))	('DCIS', 'Disease', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
139324	25541438	Recent studies have demonstrated that inhibition of Notch1 signaling by knockdown of Notch1 receptor or Notch1 receptor-targeting antibody reduced the number of tumor-initiating cells, indicating the important role of Notch1 signaling in the maintenance of these cells.	('knockdown', 'Var', (72, 81))	('Notch1', 'Gene', (52, 58))	('Notch1', 'Gene', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('reduced', 'NegReg', (139, 146))	('inhibition', 'NegReg', (38, 48))	('Notch1', 'Gene', (85, 91))	('tumor', 'Disease', (161, 166))
139330	25541438	In addition, gamma-secretase inhibitors were shown to inhibit the proteasome which might have adverse effects in humans.	('inhibitors', 'Var', (29, 39))	('inhibit', 'NegReg', (54, 61))	('proteasome', 'Enzyme', (66, 76))	('humans', 'Species', '9606', (113, 119))	('gamma-secretase', 'Protein', (13, 28))
139331	25541438	In the present study, BXL0124 markedly reduced Notch ligands but not Notch receptors, and the decrease of Notch ligands was positively correlated with the reduced activation of Notch receptor (determined by protein level of c-Notch1) (Fig.	('activation', 'PosReg', (163, 173))	('Notch ligands', 'MPA', (47, 60))	('BXL0124', 'Chemical', 'MESH:C552206', (22, 29))	('reduced', 'NegReg', (155, 162))	('BXL0124', 'Var', (22, 29))	('reduced', 'NegReg', (39, 46))	('decrease', 'NegReg', (94, 102))
139337	25541438	Furthermore, constitutively high expression of HES1 inhibited Notch signaling by directly repressing the expression of Notch ligands, such as Jagged-1 and DLL1, in embryonic stem cells.	('DLL1', 'Gene', '28514', (155, 159))	('repressing', 'NegReg', (90, 100))	('expression', 'Var', (33, 43))	('HES1', 'Gene', (47, 51))	('DLL1', 'Gene', (155, 159))	('HES1', 'Gene', '3280', (47, 51))	('Jagged-1', 'Gene', (142, 150))	('inhibited', 'NegReg', (52, 61))	('Jagged-1', 'Gene', '182', (142, 150))	('Notch signaling', 'MPA', (62, 77))	('expression', 'MPA', (105, 115))
139342	25541438	Moreover, the mRNA level of HES1 was rapidly induced by BXL0124 as early as 30 min (Fig.	('BXL0124', 'Var', (56, 63))	('HES1', 'Gene', '3280', (28, 32))	('mRNA level', 'MPA', (14, 24))	('HES1', 'Gene', (28, 32))	('induced', 'Reg', (45, 52))	('BXL0124', 'Chemical', 'MESH:C552206', (56, 63))
139343	25541438	4), suggesting that HES1 might be a key effector of BXL0124 to inhibit Notch signaling in breast cancer.	('HES1', 'Gene', '3280', (20, 24))	('BXL0124', 'Var', (52, 59))	('Notch signaling', 'Pathway', (71, 86))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('HES1', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('BXL0124', 'Chemical', 'MESH:C552206', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('inhibit', 'NegReg', (63, 70))
139346	25541438	The direct up-regulation of c-Myc by activated Notch1 was shown to induce growth of T-cell acute lymphoblastic leukemia and lymphoma cells.	('up-regulation', 'PosReg', (11, 24))	('c-Myc', 'Gene', (28, 33))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (84, 119))	('growth', 'MPA', (74, 80))	('T-cell acute lymphoblastic leukemia', 'Disease', (84, 119))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (84, 119))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (97, 119))	('lymphoma', 'Disease', (124, 132))	('leukemia', 'Phenotype', 'HP:0001909', (111, 119))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (91, 119))	('c-Myc', 'Gene', '4609', (28, 33))	('lymphoma', 'Disease', 'MESH:D008223', (124, 132))	('Notch1', 'Gene', (47, 53))	('activated', 'Var', (37, 46))	('induce', 'PosReg', (67, 73))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))
139347	25541438	In a transgenic mouse model overexpressing activated Notch1, c-Myc was a direct transcriptional target of Notch1 and was required for Notch1-induced mammary tumorigenesis.	('tumor', 'Disease', (157, 162))	('Notch1', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('c-Myc', 'Gene', '4609', (61, 66))	('Notch1', 'Gene', (53, 59))	('mouse', 'Species', '10090', (16, 21))	('c-Myc', 'Gene', (61, 66))	('Notch1-induced', 'Var', (134, 148))
139349	25541438	2B and 2C), and BXL0124 repressed cell proliferation as well as the levels of c-Myc and c-Notch1 (Fig.	('c-Myc', 'Gene', (78, 83))	('BXL0124', 'Var', (16, 23))	('cell proliferation', 'CPA', (34, 52))	('c-Myc', 'Gene', '4609', (78, 83))	('c-Notch1', 'MPA', (88, 96))	('BXL0124', 'Chemical', 'MESH:C552206', (16, 23))
139351	25541438	The present study demonstrates that BXL0124 inhibits Notch signaling by rapid induction of HES1, resulting in the reduction of the CD44+/CD24-/low subpopulation and proliferation of MCF10DCIS cells.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (182, 191))	('CD44', 'Gene', (131, 135))	('BXL0124', 'Chemical', 'MESH:C552206', (36, 43))	('reduction', 'NegReg', (114, 123))	('Notch signaling', 'MPA', (53, 68))	('BXL0124', 'Var', (36, 43))	('HES1', 'Gene', (91, 95))	('CD24', 'Gene', (137, 141))	('CD24', 'Gene', '100133941', (137, 141))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('HES1', 'Gene', '3280', (91, 95))	('inhibits', 'NegReg', (44, 52))	('CD44', 'Gene', '960', (131, 135))	('proliferation', 'CPA', (165, 178))
139353	25541438	Our study suggests the Gemini vitamin D analog, BXL0124, may be useful as an inhibitor of Notch signaling to target tumor-initiating cells in breast cancer.	('BXL0124', 'Var', (48, 55))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('BXL0124', 'Chemical', 'MESH:C552206', (48, 55))	('tumor', 'Disease', (116, 121))	('vitamin D', 'Chemical', 'MESH:D014807', (30, 39))
139357	25541438	The inhibition of Notch1 signaling by BXL0124 is mediated by induction of HES1.	('HES1', 'Gene', (74, 78))	('Notch1 signaling', 'MPA', (18, 34))	('HES1', 'Gene', '3280', (74, 78))	('BXL0124', 'Chemical', 'MESH:C552206', (38, 45))	('inhibition', 'NegReg', (4, 14))	('BXL0124', 'Var', (38, 45))
139365	24490077	And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer.	('related to', 'Reg', (58, 68))	('cancer', 'Disease', (97, 103))	('ER+', 'Var', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('HER2-', 'Protein', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('EGFR-', 'Gene', (47, 52))
139385	24490077	Among the HER2+ tumors 1.5% were of NG1, 19.7% of NG2, and 78.8% of NG3 compared to 13.6%, 50.5%, and 35.9%, respectively, for the HER2- tumors (P < 0.0001).	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('HER2- tumors', 'Disease', 'MESH:D009369', (131, 143))	('HER2- tumors', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('HER2+', 'Protein', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('NG3', 'Var', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
139390	24490077	In conclusion, given that a woman experienced a recurrence after a primary DCIS, tumor markers related to a recurrence being invasive compared to a new in situ were ER+, HER2-, and EGFR-.	('ER+', 'Var', (165, 168))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('EGFR-', 'Gene', (181, 186))	('HER2-', 'Protein', (170, 175))	('woman', 'Species', '9606', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
139432	20105298	Although the clinical significance of micrometastases and ICT in DCIS has been unclear, the latest report has shown that micrometastases or ICT may decrease the probability of survival in invasive breast cancers.	('invasive breast cancer', 'Disease', (188, 210))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('metastases', 'Disease', 'MESH:D009362', (43, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('metastases', 'Disease', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('metastases', 'Disease', (126, 136))	('invasive breast cancer', 'Disease', 'MESH:D001943', (188, 210))	('survival', 'CPA', (176, 184))	('breast cancers', 'Phenotype', 'HP:0003002', (197, 211))	('ICT', 'Var', (140, 143))	('decrease', 'NegReg', (148, 156))	('breast cancers', 'Disease', 'MESH:D001943', (197, 211))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('breast cancers', 'Disease', (197, 211))
139441	19291276	The finding of Castro and colleagues that pure DCIS and DCIS associated with invasive cancer showed a substantial number of differentially expressed genes is of interest and appears to be at odds with this concept.	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('invasive cancer', 'Disease', (77, 92))	('pure DCIS', 'Var', (42, 51))	('invasive cancer', 'Disease', 'MESH:D009362', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('differentially expressed genes', 'MPA', (124, 154))	('associated', 'Reg', (61, 71))
139452	19291276	While MECs are retained around ductal-lobular spaces containing DCIS, recent molecular studies have indicated that MECs that surround spaces involved by DCIS differ substantially from normal MECs in several respects.	('MEC', 'Gene', (115, 118))	('MEC', 'Gene', '56477', (191, 194))	('MEC', 'Gene', (191, 194))	('MEC', 'Gene', (6, 9))	('MEC', 'Gene', '56477', (6, 9))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('DCIS', 'Var', (153, 157))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('MEC', 'Gene', '56477', (115, 118))
139516	17286208	In contrast, human breast cancers arise from combinations of multiple mutations in women with heterogenous genetic backgrounds.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('mutations', 'Var', (70, 79))	('arise from', 'Reg', (34, 44))	('human', 'Species', '9606', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('breast cancers', 'Phenotype', 'HP:0003002', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancers', 'Disease', 'MESH:D001943', (19, 33))	('breast cancers', 'Disease', (19, 33))	('women', 'Species', '9606', (83, 88))
139518	17286208	There are, however, also significant drawbacks to the use of transgenic models, such as the fact that they express oncogenes in the entire mammary epithelium (or at least a large part of it) often giving rise to multiple tumors and in some models a general hyperplasia of the entire gland.	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('hyperplasia', 'Disease', 'MESH:D006965', (257, 268))	('transgenic', 'Species', '10090', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('giving rise to', 'Reg', (197, 211))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('oncogenes', 'Var', (115, 124))	('tumors', 'Disease', (221, 227))	('hyperplasia', 'Disease', (257, 268))
139581	17286208	In fact, disruption of the ECM and cellular microenvironment caused by overexpression of MMPs-3, -7 or -14 in the mammary gland is sufficient to initiate mammary epithelial hyperplasia.	('overexpression', 'PosReg', (71, 85))	('MMPs', 'Gene', '17386;4313;17390;4314;17392;17393;17394;4318;17395;17384;4320;17385;17381;4322;17386;4323;17387;17388;17389;58223', (89, 93))	('MMPs', 'Gene', (89, 93))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (162, 184))	('epithelial hyperplasia', 'Disease', (162, 184))	('disruption', 'Var', (9, 19))
139583	17286208	Similar transgenic overexpression of Plg activators has not been reported for the mammary gland, but a K14-uPA/uPAR double transgene elicits extensive skin hyperplasia.	('transgenic', 'Species', '10090', (8, 18))	('skin hyperplasia', 'Disease', 'MESH:D006965', (151, 167))	('K14-uPA/uPAR double transgene', 'Var', (103, 132))	('Plg', 'Gene', '18815', (37, 40))	('skin hyperplasia', 'Disease', (151, 167))	('Plg', 'Gene', (37, 40))	('elicits', 'Reg', (133, 140))
139587	17286208	Nevertheless, ectopically expressed proteases act as independent tumor promoters, presumably by compromising the growth-inhibitory role of the stroma, and eventually lead to genetic instability as if they were conventional oncogenes.	('tumor', 'Disease', (65, 70))	('growth-inhibitory role of the stroma', 'MPA', (113, 149))	('genetic instability', 'MPA', (174, 193))	('ectopically expressed', 'Var', (14, 35))	('compromising', 'NegReg', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('lead to', 'Reg', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
139589	17286208	Tumor onset is thus promoted by MMP-7 overexpression in the MMTV-neu model and delayed by MMP-11 deficiency in the MMTV-ras model or by TIMP-2 overexpression in the MMTV-Wnt1 model.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('neu', 'Gene', (65, 68))	('Tumor onset', 'CPA', (0, 11))	('TIMP-2', 'Gene', '21858', (136, 142))	('MMP-11', 'Gene', (90, 96))	('TIMP-2', 'Gene', (136, 142))	('MMTV', 'Species', '11757', (115, 119))	('MMP-7', 'Gene', (32, 37))	('MMP-11', 'Gene', '17385', (90, 96))	('promoted', 'PosReg', (20, 28))	('overexpression', 'PosReg', (38, 52))	('MMTV', 'Species', '11757', (60, 64))	('MMP-7', 'Gene', '17393', (32, 37))	('neu', 'Gene', '13866', (65, 68))	('MMTV', 'Species', '11757', (165, 169))	('deficiency', 'Var', (97, 107))
139591	17286208	The results of two studies were inconsistent with the general finding: MMP-3 overexpression resulted in reduced rather than increased tumor incidence in the DMBA model, and MMP-9 deficiency led to increased tumorigenesis in the MMTV-neu model.	('neu', 'Gene', (233, 236))	('MMP-3', 'Gene', '17392', (71, 76))	('deficiency', 'Var', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('DMBA', 'Chemical', 'MESH:D015127', (157, 161))	('MMP-3', 'Gene', (71, 76))	('MMTV', 'Species', '11757', (228, 232))	('neu', 'Gene', '13866', (233, 236))	('increased', 'PosReg', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('MMP-9', 'Gene', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (134, 139))
139600	17286208	In the MMTV-PymT model, tumors grow equally fast in the genetic absence or presence of Plg, uPA, PAI-1 or uPAR (unpublished data), indicating that vascularization is not rate limiting for tumor growth in these cases.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('genetic absence', 'Disease', (56, 71))	('tumors', 'Disease', (24, 30))	('Plg', 'Gene', '18815', (87, 90))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('Plg', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('genetic absence', 'Disease', 'MESH:D030342', (56, 71))	('presence', 'Var', (75, 83))	('PAI-1', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MMTV', 'Species', '11757', (7, 11))
139604	17286208	Deficiency of MMP-9 reduces tumor growth in transgenic models of skin or beta-cell islet tumors, most likely due to a requirement for MMP-9 to release vascular endothelial growth factor (VEGF) from ECM deposits in order to activate the angiogenic response.	('tumors', 'Disease', (89, 95))	('VEGF', 'Gene', (187, 191))	('tumor', 'Disease', (28, 33))	('MMP-9', 'Gene', (14, 19))	('reduces', 'NegReg', (20, 27))	('transgenic', 'Species', '10090', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('VEGF', 'Gene', '22339', (187, 191))	('Deficiency', 'Var', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('vascular endothelial growth factor', 'Gene', (151, 185))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (89, 94))	('vascular endothelial growth factor', 'Gene', '22339', (151, 185))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('angiogenic response', 'CPA', (236, 255))	('activate', 'PosReg', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('skin', 'Disease', (65, 69))
139607	17286208	Final tumor size in MMTV-PymT-transgenic mice is not significantly affected by single gene deficiencies of MMPs-2, -7, -9 (Fingleton and Matrisian, personal communication), or MMP-13 (unpublished data).	('MMP-13', 'Gene', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('MMPs-2', 'Gene', (107, 113))	('transgenic mice', 'Species', '10090', (30, 45))	('deficiencies', 'Var', (91, 103))	('MMTV', 'Species', '11757', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
139609	17286208	In contrast, simultaneous inhibition of a number of MMPs through a liver-specific TIMP-1 transgene significantly reduced final tumor size (by 42%) in MMTV-PymT mice.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('transgene', 'Var', (89, 98))	('tumor', 'Disease', (127, 132))	('MMPs', 'Gene', '17386;4313;17390;4314;17392;17393;17394;4318;17395;17384;4320;17385;17381;4322;17386;4323;17387;17388;17389;58223', (52, 56))	('TIMP-1', 'Gene', '21857', (82, 88))	('inhibition', 'NegReg', (26, 36))	('MMTV', 'Species', '11757', (150, 154))	('mice', 'Species', '10090', (160, 164))	('MMPs', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('TIMP-1', 'Gene', (82, 88))	('reduced', 'NegReg', (113, 120))
139635	17286208	MMP-9 deficiency results in reduced metastasis in the MMTV-PymT model, although this phenotype was mouse strain dependent (Fingleton and Matrisian, personal communication).	('mouse', 'Species', '10090', (99, 104))	('reduced', 'NegReg', (28, 35))	('deficiency', 'Var', (6, 16))	('MMTV', 'Species', '11757', (54, 58))	('metastasis', 'CPA', (36, 46))	('MMP-9', 'Gene', (0, 5))
139636	17286208	Deficiency of MMP-2, which is abundantly expressed in the stroma of MMTV-PymT tumors, also results in reduced metastasis in the same model (Fingleton and Matrisian, personal communication).	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('metastasis', 'CPA', (110, 120))	('MMP-2', 'Gene', (14, 19))	('MMP-2', 'Gene', '17390', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('stroma of MMTV-PymT tumors', 'Disease', (58, 84))	('stroma of MMTV-PymT tumors', 'Disease', 'MESH:D009369', (58, 84))	('reduced', 'NegReg', (102, 109))	('Deficiency', 'Var', (0, 10))
139641	17286208	In the MMTV-ras model, MMP-11 deficiency results in a higher number of metastases despite a lower number and volume of primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MMP-11', 'Gene', '17385', (23, 29))	('deficiency', 'Var', (30, 40))	('primary tumors', 'Disease', 'MESH:D009369', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('metastases', 'Disease', (71, 81))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('MMP-11', 'Gene', (23, 29))	('lower', 'NegReg', (92, 97))	('primary tumors', 'Disease', (119, 133))	('MMTV', 'Species', '11757', (7, 11))
139688	30327564	We also analysed the association of predicted risk with minimal-volume DCIS and with the occurrence of unfavourable features of the underestimated invasive breast cancer.	('minimal-volume', 'Var', (56, 70))	('invasive breast cancer', 'Disease', (147, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('invasive breast cancer', 'Disease', 'MESH:D001943', (147, 169))	('DCIS', 'Disease', (71, 75))	('DCIS', 'Disease', 'MESH:D002285', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
139713	30327564	Of these, 379 (13%) had missing data for one or more potential risk factor: 148 for palpability, 223 for BI-RADS score, 84 for DCIS grade and 81 for detection mode.	('BI-RADS score', 'Var', (105, 118))	('palpability', 'Disease', (84, 95))	('DCIS', 'Disease', 'MESH:D002285', (127, 131))	('DCIS', 'Disease', (127, 131))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))
139719	30327564	The underestimation rate was 21% on average for all cases, 26% for non-screen-detected lesions, 36% for palpable lesions, 41% for BI-RADS score 5 and 23% for high-grade DCIS (p values between different categories were <0.001 for all variables).	('DCIS', 'Phenotype', 'HP:0030075', (169, 173))	('DCIS', 'Disease', (169, 173))	('DCIS', 'Disease', 'MESH:D002285', (169, 173))	('high-grade', 'Var', (158, 168))
139723	30327564	For each of the 2892 DCIS, the risk of an underestimated invasive breast cancer was calculated based on the prediction model with the following formula:with score = -2.1131 + 0.1555 x detection_mode_otherwise + 0.7985 x palpable - 0.1464 x BI-RADS_score_3 + 0.8589 x BI-RADS_score_5 + 0.3111 x intermediate_DCIS_grade + 0.3571 x high_DCIS_grade + 1.3445 x suspected_invasive_component, where for all risk factors: 1 = if condition applies, 0 = otherwise.	('DCIS', 'Disease', 'MESH:D002285', (334, 338))	('DCIS', 'Disease', (21, 25))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('DCIS', 'Disease', (334, 338))	('DCIS', 'Disease', 'MESH:D002285', (307, 311))	('invasive breast cancer', 'Disease', 'MESH:D001943', (57, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BI-RADS_score_5 + 0.3111 x', 'Var', (267, 293))	('DCIS', 'Disease', (307, 311))	('DCIS', 'Phenotype', 'HP:0030075', (307, 311))	('DCIS', 'Phenotype', 'HP:0030075', (334, 338))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('invasive breast cancer', 'Disease', (57, 79))	('DCIS', 'Disease', 'MESH:D002285', (21, 25))
139738	30327564	Preoperatively known risk factors for an underestimated diagnosis of invasive breast cancer were a high DCIS grade, a palpable tumour, a BI-RADS score 5 and a histologically suspected invasive component.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('DCIS', 'Disease', (104, 108))	('DCIS', 'Disease', 'MESH:D002285', (104, 108))	('invasive breast cancer', 'Disease', (69, 91))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('high', 'Var', (99, 103))	('tumour', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('invasive breast cancer', 'Disease', 'MESH:D001943', (69, 91))
139744	30327564	In our study the DCIS grade was less discriminative than the other risk factors in the model, but on the other hand the underestimation rate of 15% for low DCIS grade was the lowest rate for a subgroup in the model and high grade was the largest subgroup with an increased risk.	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('low', 'Var', (152, 155))	('DCIS', 'Disease', (156, 160))	('DCIS', 'Disease', 'MESH:D002285', (156, 160))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('low DCIS', 'Phenotype', 'HP:0200161', (152, 160))	('DCIS', 'Disease', (17, 21))	('DCIS', 'Disease', 'MESH:D002285', (17, 21))
139748	30327564	In this study, minimal-volume DCIS was associated with the predicted underestimation risk.	('DCIS', 'Disease', 'MESH:D002285', (30, 34))	('minimal-volume', 'Var', (15, 29))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('DCIS', 'Disease', (30, 34))
139762	30327564	The model in this study is based on a large dataset that is based on nationwide Dutch data, and it demonstrated the association of risk for underestimation with minimal-volume DCIS and unfavourable features of invasive cancer, which makes the results valuable.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('DCIS', 'Disease', (176, 180))	('DCIS', 'Disease', 'MESH:D002285', (176, 180))	('invasive cancer', 'Disease', (210, 225))	('underestimation', 'MPA', (140, 155))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('invasive cancer', 'Disease', 'MESH:D009362', (210, 225))	('minimal-volume', 'Var', (161, 175))
139772	29974357	According to the Guidelines, double reading enhances the sensitivity of the screening test with 5-15%, and sensitivity is certainly important to a screening program as it measures the ability of the screening test to find the cancers.	('ability', 'MPA', (184, 191))	('enhances', 'PosReg', (44, 52))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('double reading', 'Var', (29, 43))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('sensitivity', 'MPA', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
139795	29974357	Our data, which included the screen-detected and the interval cancer cases, showed a doubling of the odds from BI-RADS density code 1 to BI-RADS density code 4; from 7 to 14 cases per 1000 screened women.	('BI-RADS density', 'Var', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('women', 'Species', '9606', (198, 203))	('BI-RADS density code 1', 'Var', (111, 133))	('interval cancer', 'Disease', (53, 68))	('interval cancer', 'Disease', 'MESH:D009369', (53, 68))
139901	20565942	Immunohistochemical staining was positive for CK903 (Figure 4), CK5/6, p63 (Figure 5), and calponin and negative for estrogen and progesterone receptors as well as Her-2/neu, supporting a diagnosis of SCC.	('p63', 'Gene', '8626', (71, 74))	('SCC', 'Gene', (201, 204))	('CK903', 'Var', (46, 51))	('negative', 'NegReg', (104, 112))	('CK5/6', 'Gene', '3852', (64, 69))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('Her-2/neu', 'Gene', (164, 173))	('SCC', 'Gene', '6317', (201, 204))	('p63', 'Gene', (71, 74))	('Her-2/neu', 'Gene', '2064', (164, 173))	('CK5/6', 'Gene', (64, 69))	('positive', 'Reg', (33, 41))
139965	20146248	In this report, we furthered our investigation to reveal the minimal, noncytotoxic concentration of GSPE required for suppressing chronic, precancerous cellular carcino-genesis induced by combined NNK and B[a]P. We also investigated molecular target endpoints and potential mechanism for GSPE in suppression of cellular carcinogenesis.	('carcinogenesis', 'Disease', (320, 334))	('NNK', 'Chemical', 'MESH:C016583', (197, 200))	('B[a]P.', 'Var', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancerous', 'Disease', 'MESH:D009369', (142, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (320, 334))	('B[a]P', 'Chemical', 'MESH:D001564', (205, 210))	('suppressing', 'NegReg', (118, 129))	('cancerous', 'Disease', (142, 151))	('rat', 'Species', '10116', (90, 93))
139986	20146248	For each sample, 15 mug of RNA was reverse transcribed to cDNA and labeled with either Cy3 or Cy5 using the CyScribe First-Strand cDNA Labeling Kit (Amersham, Piscataway, NJ).	('Cy5', 'Var', (94, 97))	('Cy3', 'Var', (87, 90))	('Cy5', 'Chemical', 'MESH:C085321', (94, 97))	('Cy3', 'Chemical', '-', (87, 90))
140007	20146248	We have shown that repeated exposures of noncancerous breast epithelial MCF10A cells to a low dose of individual NNK and B[a]P at 100 pM resulted in progressive acquisition of the cancer-related ability of reduced dependence on growth factors.	('MCF10A', 'CellLine', 'CVCL:0598', (72, 78))	('cancerous', 'Disease', 'MESH:D009369', (44, 53))	('reduced', 'NegReg', (206, 213))	('NNK', 'Chemical', 'MESH:C016583', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('B[a]P', 'Chemical', 'MESH:D001564', (121, 126))	('B[a]P at 100 pM', 'Var', (121, 136))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('acquisition', 'PosReg', (161, 172))	('cancerous', 'Disease', (44, 53))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
140017	20146248	Accordingly, repeated exposures of cells to NNK and B[a]P resulted in acquisition of the cancer-related ability of reduced dependence on growth factors for cell survival and growth.	('NNK', 'Chemical', 'MESH:C016583', (44, 47))	('B[a]P', 'Var', (52, 57))	('dependence on growth factors for cell survival', 'MPA', (123, 169))	('B[a]P', 'Chemical', 'MESH:D001564', (52, 57))	('reduced', 'NegReg', (115, 122))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('acquisition', 'PosReg', (70, 81))	('NNK', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
140022	20146248	Investigating whether GSPE is able to suppress combined NNK- and B[a]P-induced acquisition of reduced dependence on growth factors, we detected that exposure of MCF10A cells to combined NNK and B[a]P in the presence of GSPE, at the maximal noncytotoxic concentration of 40 mug/mL, for 10, 15, and 20 cycles, but not 5 cycles, showed significant reduction of colonies acquiring the ability of reduced dependence on growth factors by 40-50% (Figure 1C), indicating that GSPE was able to suppress the ability of combined NNK and B[a]P in inducing precancerous cellular carcinogenesis with acquisition of reduced dependence on growth factors.	('NNK', 'Chemical', 'MESH:C016583', (56, 59))	('MCF10A', 'CellLine', 'CVCL:0598', (161, 167))	('NNK', 'Chemical', 'MESH:C016583', (186, 189))	('NNK', 'Chemical', 'MESH:C016583', (518, 521))	('B[a]P', 'Var', (526, 531))	('B[a]P', 'Chemical', 'MESH:D001564', (65, 70))	('B[a]P', 'Chemical', 'MESH:D001564', (526, 531))	('rat', 'Species', '10116', (260, 263))	('B[a]P', 'Chemical', 'MESH:D001564', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (547, 553))	('precancerous cellular carcinogenesis', 'Disease', 'MESH:D063646', (544, 580))	('precancerous cellular carcinogenesis', 'Disease', (544, 580))	('suppress', 'NegReg', (485, 493))	('inducing', 'Reg', (535, 543))
140047	20146248	These results indicated that increased HSD11B2 expression was likely to be a molecular target endpoint for GSPE in suppression of precancerous cellular carcinogenesis induced by repeated exposure of cells to NNK and B[a]P. To determine whether increased HSD11B2 expression played an important role in NNK- and B[a]P-induced precancerous cellular carcinogenesis, we used validated siRNAs to knock down the increased HSD11B2 gene expression in NB-P20 cells and studied the effect of the reduced HSD11B2 gene expression on the acquired ability of reduced dependence on growth factors.	('precancerous cellular carcinogenesis', 'Disease', 'MESH:D063646', (130, 166))	('B[a]P', 'Chemical', 'MESH:D001564', (310, 315))	('HSD11B2', 'Gene', '3291', (39, 46))	('NNK', 'Chemical', 'MESH:C016583', (208, 211))	('NNK', 'Chemical', 'MESH:C016583', (301, 304))	('NB-P20', 'Gene', '51673', (442, 448))	('HSD11B2', 'Gene', (415, 422))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('precancerous cellular carcinogenesis', 'Disease', (324, 360))	('HSD11B2', 'Gene', (493, 500))	('knock', 'Var', (390, 395))	('HSD11B2', 'Gene', (254, 261))	('precancerous cellular carcinogenesis', 'Disease', 'MESH:D063646', (324, 360))	('HSD11B2', 'Gene', '3291', (415, 422))	('NB-P20', 'Gene', (442, 448))	('increased', 'PosReg', (405, 414))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HSD11B2', 'Gene', (39, 46))	('precancerous cellular carcinogenesis', 'Disease', (130, 166))	('B[a]P', 'Chemical', 'MESH:D001564', (216, 221))	('HSD11B2', 'Gene', '3291', (493, 500))	('HSD11B2', 'Gene', '3291', (254, 261))
140075	20146248	In our previous reports, upregulated gene expression of HSD11B2 was detected in MCF10A cells exposed to either B[a]P or NNK.	('HSD11B2', 'Gene', '3291', (56, 63))	('gene expression', 'MPA', (37, 52))	('MCF10A', 'CellLine', 'CVCL:0598', (80, 86))	('NNK', 'Chemical', 'MESH:C016583', (120, 123))	('B[a]P', 'Var', (111, 116))	('upregulated', 'PosReg', (25, 36))	('B[a]P', 'Chemical', 'MESH:D001564', (111, 116))	('HSD11B2', 'Gene', (56, 63))
140079	20146248	In addition, we furthered our investigation to show that knocking down the upregulated expression in NB-P20 cells with validated HSD11B2-specific siRNAs not only reduced the elevated HSD11B2 protein level but also suppressed the acquired cancer-related ability of reduced dependence on growth factors.	('suppressed', 'NegReg', (214, 224))	('cancer', 'Disease', (238, 244))	('HSD11B2', 'Gene', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('HSD11B2', 'Gene', '3291', (183, 190))	('reduced', 'NegReg', (162, 169))	('NB-P20', 'Gene', '51673', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('HSD11B2', 'Gene', '3291', (129, 136))	('HSD11B2', 'Gene', (183, 190))	('knocking', 'Var', (57, 65))	('NB-P20', 'Gene', (101, 107))
140081	20146248	The human HSD11B2 gene encodes a 45 kDa protein exhibiting dehydrogenase activity, which is able to deactivate glucocorticoids; expression of HSD11B2 results in inhibition of antiproliferative activity of glucocorticoids.	('expression', 'Var', (128, 138))	('human', 'Species', '9606', (4, 9))	('deactivate glucocorticoids', 'MPA', (100, 126))	('rat', 'Species', '10116', (186, 189))	('HSD11B2', 'Gene', '3291', (142, 149))	('HSD11B2', 'Gene', (10, 17))	('HSD11B2', 'Gene', (142, 149))	('inhibition', 'NegReg', (161, 171))	('antiproliferative activity', 'CPA', (175, 201))	('HSD11B2', 'Gene', '3291', (10, 17))
140082	20146248	Upregulation of HSD11B2 is detected in breast cancer cell lines and breast tumors, and inhibition of HSD11B2 by glycyrrhetinic acid reduces cell proliferation of breast cancer PMC42 cells.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('rat', 'Species', '10116', (152, 155))	('breast tumors', 'Phenotype', 'HP:0100013', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('breast cancer', 'Disease', (39, 52))	('HSD11B2', 'Gene', '3291', (101, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('HSD11B2', 'Gene', (16, 23))	('PMC42', 'CellLine', 'CVCL:5215', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', (162, 175))	('inhibition', 'Var', (87, 97))	('cell proliferation', 'CPA', (140, 158))	('HSD11B2', 'Gene', '3291', (16, 23))	('glycyrrhetinic acid', 'Chemical', 'MESH:D006034', (112, 131))	('reduces', 'NegReg', (132, 139))	('HSD11B2', 'Gene', (101, 108))	('breast tumors', 'Disease', 'MESH:D001943', (68, 81))	('breast tumors', 'Disease', (68, 81))
140113	29398498	Exclusion criteria included the presence of any masses, asymmetries, or architectural distortion; history of breast cancer or prior surgery; and presence of microinvasion at the time of initial biopsy.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('architectural distortion', 'CPA', (72, 96))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('asymmetries', 'Var', (56, 67))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
140129	28058695	Studies of invasive breast cancer survivors have found that obesity, physical inactivity, excessive alcohol consumption, and smoking are associated with elevated all-cause and breast cancer specific mortality.	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))	('invasive breast cancer', 'Disease', (11, 33))	('obesity', 'Disease', 'MESH:D009765', (60, 67))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('elevated', 'PosReg', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('obesity', 'Disease', (60, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('physical inactivity', 'Var', (69, 88))	('all-cause', 'CPA', (162, 171))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('smoking', 'Disease', (125, 132))	('breast cancer', 'Disease', (176, 189))	('invasive breast cancer', 'Disease', 'MESH:D001943', (11, 33))	('obesity', 'Phenotype', 'HP:0001513', (60, 67))	('excessive alcohol', 'Phenotype', 'HP:0030955', (90, 107))
140152	28058695	Deaths caused by cardiovascular disease (CVD) included the following: diseases of the heart (I00-I09, I11, I13, I20-I51), cerebrovascular diseases (I60-I69), atherosclerosis (I70), and other diseases of arteries, arterioles, capillaries (I72-I78).	('Deaths', 'Disease', (0, 6))	('I13', 'Var', (107, 110))	('I00-I09', 'Var', (93, 100))	('Deaths', 'Disease', 'MESH:D003643', (0, 6))	('CVD', 'Phenotype', 'HP:0001626', (41, 44))	('atherosclerosis', 'Disease', 'MESH:D050197', (158, 173))	('cardiovascular disease', 'Disease', 'MESH:D002318', (17, 39))	('cerebrovascular diseases', 'Disease', (122, 146))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (17, 39))	('atherosclerosis', 'Phenotype', 'HP:0002621', (158, 173))	('I11', 'Var', (102, 105))	('cerebrovascular diseases', 'Disease', 'MESH:D002561', (122, 146))	('atherosclerosis', 'Disease', (158, 173))	('I60-I69', 'Var', (148, 155))	('I20-I51', 'Var', (112, 119))	('diseases', 'Disease', (70, 78))	('cardiovascular disease', 'Disease', (17, 39))
140172	28058695	Post-diagnosis smoking was associated with elevated cancer-specific mortality (HR=2.59; 95% CI: 1.43, 4.70); the hazard ratio remained elevated after adjusting for pre-diagnosis smoking but was no longer statistically significant (HR=2.88; 95% CI: 0.88, 9.44).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('elevated', 'PosReg', (43, 51))	('smoking', 'Var', (15, 22))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
140189	28058695	Two large studies of invasive breast cancer survivors found that moderate alcohol intake was associated with 15-30% reductions in the all-cause mortality rate.	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('invasive breast cancer', 'Disease', (21, 43))	('alcohol', 'Chemical', 'MESH:D000438', (74, 81))	('reductions', 'NegReg', (116, 126))	('moderate alcohol intake', 'Var', (65, 88))	('all-cause mortality rate', 'MPA', (134, 158))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('invasive breast cancer', 'Disease', 'MESH:D001943', (21, 43))
140199	26496879	A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992-2011) and had pathology available for review were included for study.	('BRCA2', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('mutation', 'Var', (28, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('BRCA1', 'Gene', '672', (12, 17))	('breast cancer', 'Disease', (86, 99))	('BRCA2', 'Gene', '675', (22, 27))	('BRCA1', 'Gene', (12, 17))
140202	26496879	DCIS and IBC expression of tumor markers were examined by BRCA mutation.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('BRCA', 'Gene', '672', (58, 62))	('tumor', 'Disease', (27, 32))	('BRCA', 'Gene', (58, 62))	('mutation', 'Var', (63, 71))	('IBC', 'Chemical', '-', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
140206	26496879	In BRCA1 and BRCA2 mutation carriers with IBC + DCIS, there was a significant correlation in ER, PR, and HER3 expression between the DCIS and IBC components.	('BRCA1', 'Gene', '672', (3, 8))	('ER', 'Gene', '2099', (106, 108))	('mutation', 'Var', (19, 27))	('BRCA1', 'Gene', (3, 8))	('PR', 'Gene', '5241', (97, 99))	('HER3', 'Gene', (105, 109))	('IBC', 'Chemical', '-', (42, 45))	('IBC', 'Chemical', '-', (142, 145))	('expression', 'MPA', (110, 120))	('ER', 'Gene', '2099', (93, 95))	('HER3', 'Gene', '2065', (105, 109))	('BRCA2', 'Gene', (13, 18))	('BRCA2', 'Gene', '675', (13, 18))
140211	26496879	Oncodrivers HER3 and C-MET were expressed in the DCIS of mutation carriers, suggesting an opportunity for prevention strategies.	('mutation', 'Var', (57, 65))	('C-MET', 'Gene', (21, 26))	('HER3', 'Gene', (12, 16))	('C-MET', 'Gene', '4233', (21, 26))	('HER3', 'Gene', '2065', (12, 16))
140212	26496879	For individuals who carry a germline mutation in either the BRCA1 or BRCA2 gene, risk of developing breast and/or ovarian cancer is much greater than among the general population.	('BRCA1', 'Gene', (60, 65))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('BRCA2', 'Gene', '675', (69, 74))	('ovarian cancer', 'Disease', (114, 128))	('breast', 'Disease', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('BRCA1', 'Gene', '672', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('germline mutation', 'Var', (28, 45))	('BRCA2', 'Gene', (69, 74))
140213	26496879	However, mutation carriers only account for 7-10 % of breast cancers cases and 10-15 % of ovarian cancers cases.	('mutation', 'Var', (9, 17))	('breast cancers', 'Disease', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('ovarian cancers', 'Phenotype', 'HP:0100615', (90, 105))	('ovarian cancers', 'Disease', (90, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('ovarian cancers', 'Disease', 'MESH:D010051', (90, 105))
140221	26496879	However, more recent studies have found that high-risk pre-invasive lesions such as DCIS are more frequently found in prophylactic mastectomy specimens of BRCA mutation carriers than in control mammoplasty specimens.	('BRCA', 'Gene', (155, 159))	('BRCA', 'Gene', '672', (155, 159))	('mutation', 'Var', (160, 168))	('DCIS', 'Disease', (84, 88))
140226	26496879	Today, the prevention of breast cancer among BRCA1 and BRCA2 mutation carriers has focused on surgical options such as risk-reducing bilateral mastectomy and bilateral salpingo-oophorectomy.	('BRCA2', 'Gene', (55, 60))	('BRCA1', 'Gene', '672', (45, 50))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('mutation', 'Var', (61, 69))	('BRCA2', 'Gene', '675', (55, 60))	('breast cancer', 'Disease', (25, 38))	('BRCA1', 'Gene', (45, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
140229	26496879	Importantly, there is evidence that tamoxifen decreases risk of primary breast cancer as well as contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.	('mutation', 'Var', (145, 153))	('tamoxifen', 'Chemical', 'MESH:D013629', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA2', 'Gene', (139, 144))	('primary breast cancer', 'Disease', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('decreases', 'NegReg', (46, 55))	('BRCA2', 'Gene', '675', (139, 144))	('BRCA1', 'Gene', '672', (129, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('primary breast cancer', 'Disease', 'MESH:D001943', (64, 85))	('BRCA1', 'Gene', (129, 134))
140231	26496879	Due to the substantial risk of breast cancer conferred by the BRCA1 and BRCA2 mutations, development of prevention strategies for mutation carriers is imperative.	('BRCA2', 'Gene', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BRCA1', 'Gene', '672', (62, 67))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('BRCA2', 'Gene', '675', (72, 77))	('mutations', 'Var', (78, 87))	('BRCA1', 'Gene', (62, 67))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))
140235	26496879	In this study we first aimed to identify the prevalence of pure DCIS and DCIS associated with invasive tumors among BRCA mutation carriers.	('associated', 'Reg', (78, 88))	('invasive tumors', 'Disease', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('DCIS', 'Disease', (73, 77))	('pure DCIS', 'Disease', (59, 68))	('invasive tumors', 'Disease', 'MESH:D009369', (94, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('mutation', 'Var', (121, 129))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))
140238	26496879	After receiving approval from the Institutional Review Board at the University of Pennsylvania (protocol #814211), we obtained a list of patients seen in the High Risk Screening Clinic who were found to have a BRCA1 or BRCA2 mutation and were enlisted in the database for research purposes.	('BRCA2', 'Gene', '675', (219, 224))	('BRCA1', 'Gene', '672', (210, 215))	('patients', 'Species', '9606', (137, 145))	('BRCA1', 'Gene', (210, 215))	('BRCA2', 'Gene', (219, 224))	('mutation', 'Var', (225, 233))
140259	26496879	In BRCA1 mutation carriers with IBC + DCIS, the correlation between the DCIS and IBC (Tables 2, 3) was highly significant for ER, PR, HER1, HER3 (Fig.	('mutation', 'Var', (9, 17))	('BRCA1', 'Gene', '672', (3, 8))	('HER3', 'Gene', '2065', (140, 144))	('HER1', 'Gene', '1956', (134, 138))	('ER', 'Gene', '2099', (141, 143))	('BRCA1', 'Gene', (3, 8))	('ER', 'Gene', '2099', (135, 137))	('HER1', 'Gene', (134, 138))	('PR', 'Gene', '5241', (130, 132))	('IBC', 'Chemical', '-', (32, 35))	('significant', 'Reg', (110, 121))	('HER3', 'Gene', (140, 144))	('ER', 'Gene', '2099', (126, 128))	('IBC', 'Chemical', '-', (81, 84))
140261	26496879	In BRCA2 mutation carriers with IBC + DCIS, the correlation between the DCIS and IBC was highly significant for ER, PR, HER2, and HER3.	('mutation', 'Var', (9, 17))	('ER', 'Gene', '2099', (121, 123))	('BRCA2', 'Gene', '675', (3, 8))	('ER', 'Gene', '2099', (131, 133))	('HER3', 'Gene', '2065', (130, 134))	('HER2', 'Gene', (120, 124))	('PR', 'Gene', '5241', (116, 118))	('HER2', 'Gene', '2064', (120, 124))	('ER', 'Gene', '2099', (112, 114))	('HER3', 'Gene', (130, 134))	('significant', 'Reg', (96, 107))	('IBC', 'Chemical', '-', (32, 35))	('BRCA2', 'Gene', (3, 8))	('IBC', 'Chemical', '-', (81, 84))
140277	26496879	Our study suggests that DCIS occurs within hereditary invasive tumors at a rate similar to that of sporadic tumors, further supporting the hypothesis that DCIS is a precursor to invasive carcinoma in BRCA mutation carriers.	('invasive carcinoma', 'Disease', (178, 196))	('sporadic tumors', 'Disease', 'MESH:D009369', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRCA', 'Gene', '672', (200, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('invasive tumors', 'Disease', (54, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('BRCA', 'Gene', (200, 204))	('sporadic tumors', 'Disease', (99, 114))	('invasive tumors', 'Disease', 'MESH:D009369', (54, 69))	('invasive carcinoma', 'Disease', 'MESH:D009361', (178, 196))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutation', 'Var', (205, 213))
140281	26496879	These findings further support the existence of a DCIS-associated premalignant pathway among patients with BRCA mutations.	('mutations', 'Var', (112, 121))	('patients', 'Species', '9606', (93, 101))	('BRCA', 'Gene', '672', (107, 111))	('BRCA', 'Gene', (107, 111))
140285	26496879	Our finding that ER, PR, and HER2 expression in mutation carriers mimics what has been demonstrated in many other studies, serves to validate and strengthen the other results of this current study.	('ER', 'Gene', '2099', (17, 19))	('expression', 'MPA', (34, 44))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (29, 33))	('mutation', 'Var', (48, 56))	('ER', 'Gene', '2099', (30, 32))	('PR', 'Gene', '5241', (21, 23))
140288	26496879	We found that DCIS expressed HER3 and C-MET for both BRCA1 and BRCA2 mutation carriers.	('BRCA2', 'Gene', '675', (63, 68))	('C-MET', 'Gene', (38, 43))	('HER3', 'Gene', (29, 33))	('mutation', 'Var', (69, 77))	('C-MET', 'Gene', '4233', (38, 43))	('BRCA1', 'Gene', '672', (53, 58))	('HER3', 'Gene', '2065', (29, 33))	('BRCA2', 'Gene', (63, 68))	('BRCA1', 'Gene', (53, 58))
140289	26496879	This finding begs the consideration of how to implement strategies to target these oncodriver signaling pathways in BRCA mutation carriers so to prevent DCIS and invasive tumors.	('invasive tumors', 'Disease', (162, 177))	('invasive tumors', 'Disease', 'MESH:D009369', (162, 177))	('prevent', 'PosReg', (145, 152))	('DCIS', 'Disease', (153, 157))	('mutation', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
140292	26496879	Nonetheless, it is clear that BRCA mutation carriers are a unique patient population deserving further investigation, particularly in regards to prevention strategies that might one day be utilized to prevent the development of pre-invasive or invasive tumors.	('invasive tumors', 'Disease', (244, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('BRCA', 'Gene', (30, 34))	('invasive tumors', 'Disease', 'MESH:D009369', (244, 259))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('patient', 'Species', '9606', (66, 73))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (30, 34))
140293	26496879	First, while our study was able to directly assess the prevalence and immunophenotypes of DCIS in patients with known BRCA mutations, our dataset did not include patients with sporadic breast tumors for comparison.	('patients', 'Species', '9606', (162, 170))	('DCIS', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('breast tumors', 'Phenotype', 'HP:0100013', (185, 198))	('BRCA', 'Gene', '672', (118, 122))	('patients', 'Species', '9606', (98, 106))	('BRCA', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mutations', 'Var', (123, 132))	('sporadic breast tumors', 'Disease', (176, 198))	('sporadic breast tumors', 'Disease', 'MESH:D001943', (176, 198))
140295	26496879	Secondly, women with BRCA mutations are a small patient population and thus the number of subjects available for study inclusion was quite limited.	('BRCA', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('patient', 'Species', '9606', (48, 55))	('women', 'Species', '9606', (10, 15))	('BRCA', 'Gene', '672', (21, 25))
140311	26244162	TP53, PIK3CA and AKT1), copy number alterations and chromothripsis, but had significantly fewer driver genes and co-occurrence of mutation/copy number alterations compared with synchronous DCIS with IBC.	('mutation/copy', 'Var', (130, 143))	('driver', 'MPA', (96, 102))	('AKT1', 'Gene', (17, 21))	('fewer', 'NegReg', (90, 95))	('IBC', 'Chemical', '-', (199, 202))	('copy number alterations', 'Var', (24, 47))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('chromothripsis', 'CPA', (52, 66))
140323	23122537	A key finding in this study was that underglycosylated MUC1 overexpression and sialation were observed in tissues adjacent to tumor but identified as "normal" on pathology reports.	('sialation', 'MPA', (79, 88))	('MUC1', 'Protein', (55, 59))	('overexpression', 'PosReg', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('underglycosylated', 'Var', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
140340	23122537	Among sialated antigens, sialyl-Tn (STn) is a mucin-type O-glycan, which is associated with 30% of all breast carcinoma and is correlated with a decrease of overall survival of patients.	('sialyl-Tn', 'Var', (25, 34))	('breast carcinoma', 'Phenotype', 'HP:0003002', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patients', 'Species', '9606', (177, 185))	('O-glycan', 'Chemical', '-', (57, 65))	('breast carcinoma', 'Disease', (103, 119))	('associated with', 'Reg', (76, 91))	('mucin', 'Gene', '100508689', (46, 51))	('breast carcinoma', 'Disease', 'MESH:D001943', (103, 119))	('mucin', 'Gene', (46, 51))	('decrease', 'NegReg', (145, 153))	('overall', 'MPA', (157, 164))
140375	23122537	Samples from patients with no history of breast cancer (NB-NC) showed normal glandular architecture with very weak staining with VU4H5 antibody as well as with MH1 antibody (Fig.	('VU4H5', 'Var', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('patients', 'Species', '9606', (13, 21))	('glandular architecture', 'CPA', (77, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('VU4H5', 'Chemical', '-', (129, 134))	('staining', 'MPA', (115, 123))
140377	23122537	Off note, the VU4H5 antibody reflects the posttranslational modification of the antigen, because it binds to the tandemly repeated protein backbone (this backbone is differentially exposed for antibody binding by the differential glycosylation of the tandem repeat).	('VU4H5', 'Chemical', '-', (14, 19))	('binding', 'Interaction', (202, 209))	('VU4H5', 'Var', (14, 19))	('binds', 'Interaction', (100, 105))
140380	23122537	MUC1 staining with both VU4H5 and MH1 antibodies showed intermediate intensity with the distribution restricted to the apical surface of the glandular epithelium.	('VU4H5', 'Var', (24, 29))	('MH1', 'Gene', (34, 37))	('VU4H5', 'Chemical', '-', (24, 29))
140405	23122537	Next we confirmed that the presence of sialated uMUC1 in breast cancer tissue samples concomitant with the disease initiation was due to ST enzyme activity.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('sialated', 'Var', (39, 47))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
140413	23122537	Altered glycosylation/sialation among cell surface proteins is common and important in cancer- related transformation and metastasis.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Altered', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('glycosylation/sialation', 'MPA', (8, 31))
140414	23122537	Aberrant glycosylation frequently observed in breast cancer results in the synthesis of multiple cancer-associated glycan including STn, an O-linked antigen carried by mucins and other glycoproteins.	('mucin', 'Gene', '100508689', (168, 173))	('cancer', 'Disease', (97, 103))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('results in', 'Reg', (60, 70))	('mucin', 'Gene', (168, 173))	('STn', 'Gene', (132, 135))	('glycan', 'Chemical', 'MESH:D011134', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('synthesis of', 'MPA', (75, 87))	('breast cancer', 'Disease', (46, 59))	('glycosylation', 'MPA', (9, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
140416	23122537	In this study, we analyzed expression of underglycosylated MUC1 and its transformation in various stages of breast cancer using both tissues in TMA and freshly frozen tissue from patients.	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (179, 187))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('MUC1', 'Gene', (59, 63))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('underglycosylated', 'Var', (41, 58))
140421	23122537	Considering that sialation and the associated underglycosylation of MUC1 enhances tumor cell binding to selectins and dissemination of these cells into the bloodstream, our hypothesis would be consistent with the transition to post-translational modification of MUC1 in more invasive stages.	('dissemination of', 'CPA', (118, 134))	('selectins', 'Protein', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('MUC1', 'Gene', (68, 72))	('sialation', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('underglycosylation', 'MPA', (46, 64))	('tumor', 'Disease', (82, 87))	('enhances', 'PosReg', (73, 81))
140430	23122537	In terms of treatment, more radical surgical intervention might be necessary to clear the tissue with aberrant uMUC1 expression, which could cause breast cancer recurrence in the future.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('uMUC1', 'Gene', (111, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('cause', 'Reg', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('aberrant', 'Var', (102, 110))
140439	23122537	The availability of clinical cancer imaging modalities would be instrumental in detecting patients with aberrant uMUC1 expression in normal tissues and deciding on the individualized course of therapy.	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('aberrant', 'Var', (104, 112))	('uMUC1', 'Gene', (113, 118))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
140524	25918554	Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote.	('breast neoplasia', 'Phenotype', 'HP:0100013', (74, 90))	('breast neoplasia', 'Disease', 'MESH:D009369', (74, 90))	('mutation', 'Var', (38, 46))	('neoplasia', 'Phenotype', 'HP:0002664', (81, 90))	('breast neoplasia', 'Disease', (74, 90))
140525	25918554	When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression.	('mutation', 'Var', (83, 91))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (173, 178))
140527	25918554	We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma.	('invasive carcinoma', 'Disease', (219, 237))	('neoplasia', 'Disease', 'MESH:D009369', (185, 194))	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('carcinoma', 'Disease', (196, 205))	('carcinoma', 'Disease', 'MESH:D002277', (228, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('variants', 'Var', (73, 81))	('patients', 'Species', '9606', (133, 141))	('invasive carcinoma', 'Disease', 'MESH:D009361', (219, 237))	('carcinoma', 'Disease', 'MESH:D002277', (196, 205))	('neoplasia', 'Disease', (185, 194))	('carcinoma', 'Disease', (228, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (196, 213))
140529	25918554	On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Disease', 'MESH:D002277', (201, 210))	('mutations', 'Var', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Disease', (201, 210))	('PIK3CA', 'Gene', (94, 100))	('PIK3CA', 'Gene', '5290', (94, 100))
140530	25918554	Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mutations', 'Var', (108, 117))	('neoplasias', 'Disease', 'MESH:D009369', (216, 226))	('neoplasias', 'Phenotype', 'HP:0002664', (216, 226))	('neoplasias', 'Disease', (216, 226))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('primary tumors', 'Disease', (236, 250))	('neoplasia', 'Phenotype', 'HP:0002664', (216, 225))	('primary tumors', 'Disease', 'MESH:D009369', (236, 250))
140531	25918554	PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (14, 23))	('cellular proliferation', 'CPA', (64, 86))	('PIK3CA', 'Gene', (0, 6))
140532	25918554	Cancer evolution is driven by the accumulation of somatic mutations that confer fitness advantages to the tumor cells, enabling them to evade homeostatic mechanisms and to proliferate.	('proliferate', 'CPA', (172, 183))	('mutations', 'Var', (58, 67))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('homeostatic mechanisms', 'MPA', (142, 164))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('evade', 'NegReg', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
140537	25918554	Phylogenetic reconstruction of tumor progression, with the goal of deriving an evolutionary tree of the tumor and related tissue samples, can then be performed on the basis of the presence of the somatic mutations across the diversity of samples from that patient.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (204, 213))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (104, 109))	('patient', 'Species', '9606', (256, 263))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
140541	25918554	In a prior study we established that a subset of these neoplasms were closely related to the concurrent invasive carcinoma; those neoplasms carried a significant mutational burden and contained characteristic genomic alterations such as chromosome amplifications.	('neoplasms', 'Phenotype', 'HP:0002664', (130, 139))	('mutational', 'MPA', (162, 172))	('invasive carcinoma', 'Disease', (104, 122))	('neoplasms', 'Disease', 'MESH:D009369', (55, 64))	('neoplasms', 'Disease', (55, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('neoplasms', 'Disease', 'MESH:D009369', (130, 139))	('chromosome amplifications', 'Var', (237, 262))	('invasive carcinoma', 'Disease', 'MESH:D009361', (104, 122))	('carried', 'Reg', (140, 147))	('neoplasms', 'Disease', (130, 139))
140544	25918554	Building on a prior study in which we deeply sequenced 31 somatic genomes of tumors, neoplasias, and controls in six patients, we here obtain much more accurate estimates of variant allele frequencies (VAFs) of phylogenetically informative single nucleotide variants (SNVs) in a much greater number of samples, with emphasis on pre-invasive neoplasias.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('neoplasias', 'Disease', 'MESH:D009369', (85, 95))	('neoplasia', 'Phenotype', 'HP:0002664', (341, 350))	('neoplasias', 'Disease', (85, 95))	('VAF', 'Chemical', '-', (202, 205))	('neoplasias', 'Disease', 'MESH:D009369', (341, 351))	('neoplasias', 'Phenotype', 'HP:0002664', (341, 351))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('neoplasias', 'Disease', (341, 351))	('patients', 'Species', '9606', (117, 125))	('neoplasia', 'Phenotype', 'HP:0002664', (85, 94))	('single nucleotide variants', 'Var', (240, 266))	('neoplasias', 'Phenotype', 'HP:0002664', (85, 95))
140546	25918554	From more than a thousand phylogenetically informative SNVs (on average 181 per patient), we reconstructed highly resolved trees that illuminate the history of clonal expansion and cell-lineage heterogeneity of these cases, as well as the occurrence of independent PIK3CA mutations within the same patient.	('mutations', 'Var', (272, 281))	('patient', 'Species', '9606', (298, 305))	('PIK3CA', 'Gene', (265, 271))	('PIK3CA', 'Gene', '5290', (265, 271))	('patient', 'Species', '9606', (80, 87))
140576	25918554	Only one of these assayed neoplasias (in patient 2) has an aberrant genome and a genetic relationship with the concurrent carcinomas (Figure 2b).	('carcinomas', 'Disease', (122, 132))	('neoplasias', 'Disease', (26, 36))	('patient', 'Species', '9606', (41, 48))	('aberrant genome', 'Var', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('neoplasia', 'Phenotype', 'HP:0002664', (26, 35))	('carcinomas', 'Disease', 'MESH:D002277', (122, 132))	('neoplasias', 'Disease', 'MESH:D009369', (26, 36))	('neoplasias', 'Phenotype', 'HP:0002664', (26, 36))
140586	25918554	The only previously identified gene-specific driver changes in our patients were the HER2 amplifications in patient 6 and two missense mutations in PIK3CA in patients 1, 3, 4, and 5.	('PIK3CA', 'Gene', '5290', (148, 154))	('missense mutations', 'Var', (126, 144))	('patients', 'Species', '9606', (67, 75))	('patient', 'Species', '9606', (158, 165))	('HER2', 'Gene', (85, 89))	('amplifications', 'Var', (90, 104))	('PIK3CA', 'Gene', (148, 154))	('HER2', 'Gene', '2064', (85, 89))	('patients', 'Species', '9606', (158, 166))	('patient', 'Species', '9606', (108, 115))	('patient', 'Species', '9606', (67, 74))
140588	25918554	On that same branch, the majority of the aneuploidies in this patient arose, followed by some additional aneuploidies and point mutations in the ancestral lineage of the IDC.	('aneuploidies', 'Disease', 'MESH:D000782', (105, 117))	('IDC', 'Gene', (170, 173))	('aneuploidies', 'Disease', (105, 117))	('patient', 'Species', '9606', (62, 69))	('point mutations', 'Var', (122, 137))	('aneuploidies', 'Disease', (41, 53))	('aneuploidies', 'Disease', 'MESH:D000782', (41, 53))	('IDC', 'Gene', '4000', (170, 173))
140596	25918554	In addition to H1047R, H1047L occurred once in patient 1 and once in patient 3, in both instances in a neoplasia that also carries H1047R (Figure 3).	('H1047R', 'SUBSTITUTION', 'None', (131, 137))	('H1047R', 'Var', (131, 137))	('patient', 'Species', '9606', (47, 54))	('neoplasia', 'Phenotype', 'HP:0002664', (103, 112))	('H1047R', 'Var', (15, 21))	('neoplasia', 'Disease', 'MESH:D009369', (103, 112))	('H1047R', 'SUBSTITUTION', 'None', (15, 21))	('patient', 'Species', '9606', (69, 76))	('neoplasia', 'Disease', (103, 112))	('H1047L', 'Mutation', 'rs121913279', (23, 29))	('H1047L', 'Var', (23, 29))
140600	25918554	The trees reveal insights into three aspects of cancer evolution that are of future clinical relevance: phylogenetic relationships among the pre-invasive lesions and with the IDCs, lineage heterogeneity of pre-invasive lesions, and recurrence of mutations in PIK3CA.	('PIK3CA', 'Gene', '5290', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('IDC', 'Gene', '4000', (175, 178))	('IDC', 'Gene', (175, 178))	('mutations', 'Var', (246, 255))	('cancer', 'Disease', (48, 54))	('PIK3CA', 'Gene', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
140608	25918554	As yet unexplored mechanisms such as copy number alterations determine the variance in VAFs and so we do not yet know whether the sensitivity of our study limited the detected number of mixed-lineage clones, or whether our results are an accurate estimate of the typical number of mixed-lineage clones in pathologically well-defined samples.	('copy number alterations', 'Var', (37, 60))	('VAF', 'Chemical', '-', (87, 90))	('alterations', 'Var', (49, 60))	('determine', 'Reg', (61, 70))
140611	25918554	On the basis of the trees we were able to show repeated within-patient recurrence of two mutations, H1047R and H1047L, in PIK3CA.	('PIK3CA', 'Gene', (122, 128))	('H1047L', 'Mutation', 'rs121913279', (111, 117))	('PIK3CA', 'Gene', '5290', (122, 128))	('H1047L', 'Var', (111, 117))	('patient', 'Species', '9606', (63, 70))	('H1047R', 'Var', (100, 106))	('H1047R', 'SUBSTITUTION', 'None', (100, 106))
140612	25918554	The mutations frequently occurred in pre-invasive neoplasias and were absent from all invasive carcinoma samples in two out of four patients.	('invasive carcinoma', 'Disease', 'MESH:D009361', (86, 104))	('neoplasias', 'Disease', 'MESH:D009369', (50, 60))	('neoplasias', 'Disease', (50, 60))	('invasive carcinoma', 'Disease', (86, 104))	('neoplasias', 'Phenotype', 'HP:0002664', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('neoplasia', 'Phenotype', 'HP:0002664', (50, 59))	('mutations', 'Var', (4, 13))	('occurred', 'Reg', (25, 33))	('patients', 'Species', '9606', (132, 140))
140614	25918554	Across all negative samples, including all samples in patients 2 and 6 which do not have H1047R or H10147L at all, the absence of the mutations is well-supported and not due to low read coverage or another technical artifact.	('H10147L', 'Mutation', 'p.H10147L', (99, 106))	('patients', 'Species', '9606', (54, 62))	('H10147L', 'Var', (99, 106))	('H1047R', 'SUBSTITUTION', 'None', (89, 95))	('H1047R', 'Var', (89, 95))
140616	25918554	However, it is difficult to envision how a mutation that has been functionally linked to causing proliferation (for example,) and that recurs so frequently in tumors (for example,) would be selected against so as to be completely lost in a large number of samples (and billions of cells) from each patient.	('patient', 'Species', '9606', (298, 305))	('mutation', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('causing proliferation', 'CPA', (89, 110))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
140620	25918554	This is consistent with previous studies that have shown PIK3CA H1047R to be highly prevalent in CCL.	('PIK3CA', 'Gene', '5290', (57, 63))	('CCL', 'Disease', (97, 100))	('H1047R', 'Var', (64, 70))	('prevalent', 'Reg', (84, 93))	('CCL', 'Chemical', '-', (97, 100))	('H1047R', 'SUBSTITUTION', 'None', (64, 70))	('PIK3CA', 'Gene', (57, 63))
140621	25918554	In our prior study, we observed a poor correlation of CCL mutational status with the status of the accompanying carcinoma.	('mutational status', 'Var', (58, 75))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('CCL', 'Chemical', '-', (54, 57))	('CCL', 'Gene', (54, 57))	('carcinoma', 'Disease', (112, 121))
140623	25918554	A CCL bearing a PIK3CA mutation was typically accompanied by wild-type carcinoma, or carcinoma with a different PIK3CA mutation (in 9 of 14 cases).	('carcinoma', 'Disease', (85, 94))	('PIK3CA', 'Gene', '5290', (16, 22))	('mutation', 'Var', (23, 31))	('PIK3CA', 'Gene', '5290', (112, 118))	('carcinoma', 'Disease', 'MESH:D002277', (71, 80))	('accompanied', 'Reg', (46, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('CCL', 'Chemical', '-', (2, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('PIK3CA', 'Gene', (16, 22))	('carcinoma', 'Disease', (71, 80))	('PIK3CA', 'Gene', (112, 118))
140624	25918554	Given the prevalence of PIK3CA mutations in benign proliferative lesions, its absence from some IDCs even in patients that have it in other sites, and the only very slightly increased risk of cancer associated with neoplastic lesions in general and CCL in particular, it is worth considering whether PIK3CA H1047R is really a driver of neoplasia at this stage of cancer development or a comparatively benign inducer of proliferation alone.	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('PIK3CA', 'Gene', '5290', (24, 30))	('cancer', 'Disease', (192, 198))	('CCL', 'Chemical', '-', (249, 252))	('neoplasia', 'Phenotype', 'HP:0002664', (336, 345))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('H1047R', 'Var', (307, 313))	('PIK3CA', 'Gene', '5290', (300, 306))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('H1047R', 'SUBSTITUTION', 'None', (307, 313))	('cancer', 'Disease', (363, 369))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (215, 233))	('neoplasia', 'Disease', 'MESH:D009369', (336, 345))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('PIK3CA', 'Gene', (300, 306))	('IDC', 'Gene', '4000', (96, 99))	('IDC', 'Gene', (96, 99))	('neoplasia', 'Disease', (336, 345))
140629	25918554	We used multi-sample phylogenetic inference to provide insights into the origin of driver mutations, the nature of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with primary tumors.	('mutations', 'Var', (90, 99))	('primary tumors', 'Disease', (203, 217))	('primary tumors', 'Disease', 'MESH:D009369', (203, 217))	('neoplasia', 'Phenotype', 'HP:0002664', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('neoplasias', 'Disease', 'MESH:D009369', (187, 197))	('neoplasias', 'Phenotype', 'HP:0002664', (187, 197))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('neoplasias', 'Disease', (187, 197))
140631	25918554	We show that PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', '5290', (13, 19))	('cellular proliferation', 'CPA', (77, 99))	('PIK3CA', 'Gene', (13, 19))
140632	25918554	AH hyperplasia with atypia bp base pair CCL columnar cell lesion FEA flat epithelial atypia DCIS ductal carcinoma in situ IDC invasive ductal carcinoma PCR polymerase chain reaction SNV single nucleotide variant VAF variant allele frequency	('FEA', 'Gene', (65, 68))	('FEA', 'Gene', '7959', (65, 68))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (126, 151))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (97, 113))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (97, 121))	('variant', 'Var', (216, 223))	('single nucleotide variant', 'Var', (186, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (135, 151))	('invasive ductal carcinoma', 'Disease', (126, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('VAF', 'Chemical', '-', (212, 215))	('CCL', 'Chemical', '-', (40, 43))	('ductal carcinoma in situ', 'Disease', (97, 121))	('flat epithelial atypia', 'Disease', (69, 91))	('columnar cell lesion', 'Disease', 'MESH:D056784', (44, 64))	('hyperplasia', 'Disease', (3, 14))	('hyperplasia', 'Disease', 'MESH:D006965', (3, 14))	('columnar cell lesion', 'Disease', (44, 64))	('VAF', 'Gene', (212, 215))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (97, 121))	('IDC', 'Gene', '4000', (122, 125))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (104, 121))	('IDC', 'Gene', (122, 125))	('flat epithelial atypia', 'Disease', 'MESH:D005413', (69, 91))
140652	24884941	In a recently published report, the rate of axillary lymph node metastases is low in patients with DCISM, it mainly concerns micrometastases or isolated tumour cells.	('tumour', 'Disease', (153, 159))	('metastases', 'Disease', 'MESH:D009362', (64, 74))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('DCISM', 'Var', (99, 104))	('low', 'NegReg', (78, 81))	('patients', 'Species', '9606', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('metastases', 'Disease', (130, 140))	('metastases', 'Disease', (64, 74))	('axillary lymph node metastases', 'Disease', 'MESH:D009362', (44, 74))	('axillary lymph node metastases', 'Disease', (44, 74))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('DCISM', 'Chemical', '-', (99, 104))
140688	24884941	Among prognostic factors for the outcome in DCISM, the number of microinvasive foci, metastases to the sentinel lymph node, high Ki-67, negative oestrogen receptor status, and HER2 overexpression were found.	('HER2', 'Gene', (176, 180))	('HER2', 'Gene', '2064', (176, 180))	('overexpression', 'PosReg', (181, 195))	('Ki-67', 'Protein', (129, 134))	('metastases', 'Disease', (85, 95))	('metastases', 'Disease', 'MESH:D009362', (85, 95))	('oestrogen receptor', 'Protein', (145, 163))	('DCISM', 'Chemical', '-', (44, 49))	('high', 'Var', (124, 128))	('DCISM', 'Disease', (44, 49))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
140709	24884941	The co-expression of HER2 and 14.3.3 zeta could be important since HER2 overexpression plays a role in the process of first invasion and 14.3.3. zeta in the reduction of cell adhesion.	('14.3.3. zeta', 'Var', (137, 149))	('HER2', 'Gene', (67, 71))	('cell adhesion', 'CPA', (170, 183))	('reduction', 'NegReg', (157, 166))	('14.3.3 zeta', 'Gene', '7534', (30, 41))	('14.3.3 zeta', 'Gene', (30, 41))	('HER2', 'Gene', '2064', (67, 71))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('overexpression', 'PosReg', (72, 86))
140737	22139081	Ectopic expression of chimeric HER2 molecules that can be homodimerized by synthetic ligands revealed that HER2 homodimers, unlike EGFR homodimers, can induce the generation of multiacinar structures with filled lumen.	('HER2', 'Protein', (107, 111))	('homodimers', 'Var', (112, 122))	('EGFR', 'Gene', '1956', (131, 135))	('multiacinar structures', 'MPA', (177, 199))	('EGFR', 'Gene', (131, 135))	('induce', 'Reg', (152, 158))
140748	22139081	As expected, the overexpressed HER2 enhanced both basal and EGF-induced cellular invasion in a monolayer (two-dimensional) configuration (Figure 1a).	('overexpressed', 'Var', (17, 30))	('EGF', 'Gene', (60, 63))	('HER2', 'Protein', (31, 35))	('EGF', 'Gene', '1950', (60, 63))	('enhanced', 'PosReg', (36, 44))
140757	22139081	Moreover, acini expressing a catalytically inactive HER2 mutant (D845N; Supplementary Figure S1F) exhibited cleared lumina and failed to protrude invasive arms (Supplementary Figure S1G), suggesting that HER2/EGFR heterodimers, as well as kinase activity, are required for the EGF-induced outgrowths.	('EGFR', 'Gene', (209, 213))	('EGF', 'Gene', (277, 280))	('EGF', 'Gene', (209, 212))	('D845N;', 'Var', (65, 71))	('D845N', 'Mutation', 'p.D845N', (65, 70))	('EGF', 'Gene', '1950', (209, 212))	('cleared lumina', 'MPA', (108, 122))	('EGF', 'Gene', '1950', (277, 280))	('EGFR', 'Gene', '1956', (209, 213))	('HER2', 'Gene', (52, 56))
140761	22139081	Consistent with previous reports that attributed to HER2 an ability to inhibit apoptosis while stimulating proliferation of MCF10A cells, enriched GO terms in a group of 490 genes, which are higher in MCF10A/HER2 cells, included primarily cell proliferation modules (Supplementary Figure S2B and Supplementary File 2; sheet 2), along with prosurvival genes, whereas a few pro-apoptosis genes were downregulated (Supplementary Figure S2C).	('stimulating', 'PosReg', (95, 106))	('higher', 'PosReg', (191, 197))	('MCF10A/HER2', 'Var', (201, 212))	('MCF10A', 'CellLine', 'CVCL:0598', (124, 130))	('inhibit', 'NegReg', (71, 78))	('proliferation', 'CPA', (107, 120))	('MCF10A', 'CellLine', 'CVCL:0598', (201, 207))	('MCF10A/HER2', 'CellLine', 'CVCL:0U80', (201, 212))	('cell proliferation modules', 'CPA', (239, 265))	('apoptosis', 'CPA', (79, 88))	('downregulated', 'NegReg', (397, 410))
140762	22139081	Conceivably, the effect of HER2 on MCF10A proliferation reflects the association of this oncogene with enhanced luminal proliferation in patients with HER2+ DCIS.	('luminal', 'MPA', (112, 119))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('MCF10A', 'CellLine', 'CVCL:0598', (35, 41))	('patients', 'Species', '9606', (137, 145))	('enhanced', 'PosReg', (103, 111))	('HER2+ DCIS', 'Var', (151, 161))	('MCF10A', 'Gene', (35, 41))
140764	22139081	Moreover, a group of shared genes, exhibiting concordant changes in both MCF10A vs MCF10A/HER2 spheroids and in the comparison of normal breast epithelia vs HER2-positive DCIS, were significantly enriched for functions related to cell proliferation/survival (Supplementary Figures S3B and C, Supplementary File 2; sheet 3).	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('MCF10A/HER2', 'CellLine', 'CVCL:0U80', (83, 94))	('MCF10A', 'CellLine', 'CVCL:0598', (83, 89))	('MCF10A', 'CellLine', 'CVCL:0598', (73, 79))	('changes', 'Reg', (57, 64))	('breast epithelia', 'Disease', 'MESH:D001943', (137, 153))	('MCF10A', 'Var', (73, 79))	('breast epithelia', 'Disease', (137, 153))
140781	22139081	In line with SMAD-controlled invasive growth, knockdown of SMAD4 (Figure 4e) inhibited invasiveness (Figures 4f and g).	('invasiveness', 'CPA', (87, 99))	('SMAD4', 'Gene', '4089', (59, 64))	('knockdown', 'Var', (46, 55))	('inhibited', 'NegReg', (77, 86))	('SMAD', 'Gene', (13, 17))	('SMAD', 'Gene', '4089;4086;4089', (13, 17))	('SMAD', 'Gene', '4089;4086;4089', (59, 63))	('SMAD4', 'Gene', (59, 64))	('SMAD', 'Gene', (59, 63))
140797	22139081	In line with this report, we found that exogenous MFGE8 activates ERK phosphorylation (Figure 7a) and enhances invasiveness of HER2-overexpressing cells (Figures 7b and c).	('activates', 'PosReg', (56, 65))	('invasiveness', 'CPA', (111, 123))	('enhances', 'PosReg', (102, 110))	('MFGE8', 'Gene', '4240', (50, 55))	('exogenous', 'Var', (40, 49))	('ERK', 'Gene', '2048', (66, 69))	('ERK', 'Gene', (66, 69))	('MFGE8', 'Gene', (50, 55))
140799	22139081	As expected, inhibition of MFGE8 action by using an integrin alphaV blocking antibody attenuated invasive growth (Figure 7d), and stable knockdown of MFGE8 (Figure 7e) inhibited the EGF-induced formation of invasive structures (Figures 7f and g).	('MFGE8', 'Gene', '4240', (27, 32))	('MFGE8', 'Gene', (27, 32))	('attenuated', 'NegReg', (86, 96))	('EGF', 'Gene', (182, 185))	('formation of invasive structures', 'CPA', (194, 226))	('invasive growth', 'CPA', (97, 112))	('knockdown', 'Var', (137, 146))	('inhibited', 'NegReg', (168, 177))	('EGF', 'Gene', '1950', (182, 185))	('inhibition', 'NegReg', (13, 23))	('MFGE8', 'Gene', '4240', (150, 155))	('MFGE8', 'Gene', (150, 155))
140864	24862985	GATA factors can function in undifferentiated progenitor cells and can direct the coordinated maturation and cell cycle withdrawal in terminally differentiating cells; alteration of GATA factor expression is suggested to contribute to the development of various human cancers.	('cancers', 'Disease', (268, 275))	('contribute', 'Reg', (221, 231))	('cancers', 'Disease', 'MESH:D009369', (268, 275))	('human', 'Species', '9606', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('alteration', 'Var', (168, 178))	('GATA', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('GATA', 'Gene', (182, 186))	('GATA', 'Gene', '55278', (0, 4))	('GATA', 'Gene', '55278', (182, 186))
140885	24862985	Rabbit polyclonal antibody for HER2 (A0485) was obtained from DAKO.	('HER2', 'Gene', '2064', (31, 35))	('HER2', 'Gene', (31, 35))	('A0485', 'Var', (37, 42))	('Rabbit', 'Species', '9986', (0, 6))
140909	24862985	As demonstrated in Figure3(a), GATA4 status was significantly associated with an increased incidence of recurrence in stage I-III patients (n = 140) (P = 0.0069 using the log-rank test).	('patients', 'Species', '9606', (130, 138))	('GATA4 status', 'Var', (31, 43))	('recurrence', 'Disease', (104, 114))
140930	24862985	GATA4 promoter demethylation was induced by several factors including the mitogen-activated protein kinase pathway and MYC, and GATA4 promoted initiation of adrenocortical neoplasms in mice.	('promoter', 'MPA', (6, 14))	('induced', 'Reg', (33, 40))	('promoted', 'PosReg', (134, 142))	('mice', 'Species', '10090', (185, 189))	('GATA4', 'Var', (128, 133))	('initiation of adrenocortical neoplasms', 'Disease', 'MESH:D018268', (143, 181))	('neoplasms', 'Phenotype', 'HP:0002664', (172, 181))	('GATA4', 'Gene', (0, 5))	('initiation of adrenocortical neoplasms', 'Disease', (143, 181))	('mitogen-activated', 'Pathway', (74, 91))
141044	18954444	Inactivation of the E-cadherin protein, a key component of the adherens junction that interacts with the actin cytoskeleton via binding of alpha, beta and delta catenins, is a hallmark of LCIS.	('E-cadherin', 'Gene', (20, 30))	('alpha', 'Protein', (139, 144))	('E-cadherin', 'Gene', '999', (20, 30))	('binding', 'Interaction', (128, 135))	('LCIS', 'Phenotype', 'HP:0030076', (188, 192))	('Inactivation', 'Var', (0, 12))
141066	18954444	It is certainly conceivable that the expression of activated MMP9 helps effect the characteristic, permeative, 'Indian file' growth pattern of invasive lobular carcinoma.	('MMP9', 'Gene', '4318', (61, 65))	('expression', 'Var', (37, 47))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (143, 169))	('effect', 'Reg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (152, 169))	("'Indian file' growth pattern", 'MPA', (111, 139))	('MMP9', 'Gene', (61, 65))	('invasive lobular carcinoma', 'Disease', (143, 169))
141158	23959857	In ovariectomized mice, subcutanteous fat depots demonstrated elevated macrophage recruitment as well as increased expression of CCL2 compared to control mice, suggesting that CCL2 may enhance inflammation in postmenopausal breast tissue.	('macrophage recruitment', 'CPA', (71, 93))	('mice', 'Species', '10090', (154, 158))	('inflammation', 'Disease', 'MESH:D007249', (193, 205))	('inflammation', 'Disease', (193, 205))	('enhance', 'PosReg', (185, 192))	('mice', 'Species', '10090', (18, 22))	('CCL2', 'Var', (176, 180))	('expression', 'MPA', (115, 125))	('increased', 'PosReg', (105, 114))	('CCL2', 'Gene', (129, 133))	('elevated', 'PosReg', (62, 70))
141191	23959857	For inhibitor studies, mice were treated following humanization with daily subcutaneous injections of 10mg/kg Kineret (Amgen) or 2mg/kg RS504393 (Tocris), and tissues were collected 2 weeks following tumor cell transplant or when tumors reached 1 cm in diameter.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', (200, 205))	('human', 'Species', '9606', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('RS504393', 'Var', (136, 144))	('mice', 'Species', '10090', (23, 27))
141196	23959857	For inhibitor studies, HL-60 macrophages were treated with SVF/CCL2 CM and vehicle (DMSO), 330nM RS504393 (Tocris), 40ng/mL IL-1ra (R&D Systems) or 330nM RS504393+40ng/mL IL-1ra.	('SVF', 'Disease', (59, 62))	('DMSO', 'Chemical', 'MESH:D004121', (84, 88))	('HL-60', 'CellLine', 'CVCL:0002', (23, 28))	('RS504393', 'Var', (97, 105))	('SVF', 'Disease', 'None', (59, 62))	('330nM', 'Var', (148, 153))
141206	23959857	Consistent with the formation of CLS, total numbers of macrophages were significantly increased in glands of HFD mice (4.4x105 +- 0.5x105; macrophages/gland+-sd) compared with ND mice (2.5x105+-0.5x105; p=0.05).	('increased', 'PosReg', (86, 95))	('mice', 'Species', '10090', (179, 183))	('CLS', 'Gene', (33, 36))	('CLS', 'Gene', '66586', (33, 36))	('ND', 'Disease', 'MESH:C537849', (176, 178))	('HFD', 'Var', (109, 112))	('mice', 'Species', '10090', (113, 117))
141208	23959857	Macrophages that express M1-type cytokines have been proposed to have tumoricidal functions, while those that produce M2-type cytokines may be tumor promoting.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (70, 75))	('M1-type cytokines', 'Var', (25, 42))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
141216	23959857	CD31+ vessels surrounding adipocytes were significantly increased in glands of HFD females compared with those fed the ND (p=0.0001; Figure 1D).	('HFD', 'Var', (79, 82))	('CD31+ vessels surrounding', 'CPA', (0, 25))	('ND', 'Disease', 'MESH:C537849', (119, 121))	('increased', 'PosReg', (56, 65))
141217	23959857	Transcripts from whole glands for CD31 and pericyte marker PDGFRbeta were significantly increased in HFD glands compared to ND glands (Figure 1E), suggesting that both endothelial cells and pericytes were increased in the obese glands.	('obese', 'Disease', 'MESH:D009765', (222, 227))	('Transcripts', 'MPA', (0, 11))	('PDGFRbeta', 'Gene', '18596', (59, 68))	('HFD', 'Var', (101, 104))	('increased', 'PosReg', (205, 214))	('increased', 'PosReg', (88, 97))	('CD31', 'Gene', (34, 38))	('obese', 'Disease', (222, 227))	('ND', 'Disease', 'MESH:C537849', (124, 126))	('PDGFRbeta', 'Gene', (59, 68))
141251	23959857	Plugs containing SVF/CCL2 cells significantly enhanced F4/80+ (p=0.002) and CD31+ (p=0.0004) cell recruitment compared to SVF/EV cells containing plugs, indicating that CCL2 expression augments macrophage recruitment and angiogenesis (Figure 3C).	('SVF', 'Disease', (122, 125))	('angiogenesis', 'CPA', (221, 233))	('CD31+', 'MPA', (76, 81))	('F4/80', 'Gene', (55, 60))	('SVF', 'Disease', 'None', (122, 125))	('SVF', 'Disease', 'None', (17, 20))	('F4/80', 'Gene', '13733', (55, 60))	('expression', 'Var', (174, 184))	('augments', 'PosReg', (185, 193))	('CCL2', 'Gene', (169, 173))	('enhanced', 'PosReg', (46, 54))	('SVF', 'Disease', (17, 20))	('macrophage recruitment', 'CPA', (194, 216))
141266	23959857	Additionally, HL-60 macrophages treated with rhIL-1beta exhibited a significant increase in CXCL12 expression (p=0.003; Figure 4B), and the induction of CXCL12 by SVF/CCL2 CM was abolished in the presence of an IL-1beta blocking antibody (p=0.0001; Figure 4D).	('rhIL-1beta', 'Var', (45, 55))	('SVF', 'Disease', 'None', (163, 166))	('increase', 'PosReg', (80, 88))	('SVF', 'Disease', (163, 166))	('CXCL12 expression', 'MPA', (92, 109))	('HL-60', 'CellLine', 'CVCL:0002', (14, 19))
141267	23959857	HL-60 macrophages treated with specific inhibitors against the CCL2 receptor, CCR2 (RS504393), or IL-1beta activity (IL-1ra), significantly attenuated induction of CXCL12 following stimulation with SVF/CCL2 CM (p=0.001; Figure S3F).	('SVF', 'Disease', 'None', (198, 201))	('CCR2', 'Gene', (78, 82))	('inhibitors', 'Var', (40, 50))	('RS504393', 'Var', (84, 92))	('HL-60', 'CellLine', 'CVCL:0002', (0, 5))	('SVF', 'Disease', (198, 201))	('induction of CXCL12', 'MPA', (151, 170))	('attenuated', 'NegReg', (140, 150))	('CCR2', 'Gene', '12772', (78, 82))
141294	23959857	After 2 weeks, humanized SVF/CCL2 fat pads from vehicle-treated mice demonstrated significantly larger outgrowths compared to DT-treated mice, indicating that ablation of macrophages significantly reduced tumorigenesis (Figure 6A).	('SVF', 'Disease', (25, 28))	('outgrowths', 'CPA', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('SVF', 'Disease', 'None', (25, 28))	('reduced', 'NegReg', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('human', 'Species', '9606', (15, 20))	('mice', 'Species', '10090', (137, 141))	('mice', 'Species', '10090', (64, 68))	('ablation', 'Var', (159, 167))
141295	23959857	Vehicle-treated mice exhibited significantly increased number of CD31+ blood vessels, suggesting that ablation of macrophages attenuates angiogenesis (p=0.0081; Figure 6A).	('attenuates', 'NegReg', (126, 136))	('angiogenesis', 'CPA', (137, 149))	('mice', 'Species', '10090', (16, 20))	('ablation', 'Var', (102, 110))
141302	23959857	To determine whether inhibition of CCL2 and IL-1beta might be a viable prophylactic strategy in treating breast cancers associated with obesity, mice humanized with SVF/CCL2 cells and implanted with SV40/Kras transduced human breast epithelial cells were treated daily with small molecule inhibitors for CCL2 (RS504393) and of IL-1beta (Kineret; IL-1ra).	('human', 'Species', '9606', (150, 155))	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('breast cancers', 'Disease', (105, 119))	('SVF', 'Disease', (165, 168))	('obesity', 'Disease', 'MESH:D009765', (136, 143))	('human', 'Species', '9606', (220, 225))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('obesity', 'Disease', (136, 143))	('RS504393', 'Var', (310, 318))	('mice', 'Species', '10090', (145, 149))	('SVF', 'Disease', 'None', (165, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('CCL2', 'Gene', (304, 308))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('IL-1beta', 'Gene', (327, 335))	('obesity', 'Phenotype', 'HP:0001513', (136, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
141303	23959857	After 2 weeks of treatment, mice receiving inhibitors exhibited a significant reduction in recruited F4/80+ macrophages compared to fat pads of vehicle-treated mice (p=0.02; Figure 6C).	('inhibitors', 'Var', (43, 53))	('F4/80', 'Gene', (101, 106))	('mice', 'Species', '10090', (28, 32))	('F4/80', 'Gene', '13733', (101, 106))	('reduction', 'NegReg', (78, 87))	('mice', 'Species', '10090', (160, 164))
141310	23959857	Although the DT experiments demonstrated that ablation of macrophages may limit tumor development, the method of drug delivery may need to target macrophages specifically to limit the response of other cell types within the tumor parenchyma.	('ablation', 'Var', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (80, 85))	('tumor parenchyma', 'Disease', 'MESH:D010195', (224, 240))	('tumor parenchyma', 'Disease', (224, 240))	('limit', 'NegReg', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
141328	23959857	Our findings here suggest that inhibition of inflammation can limit macrophage infiltration and angiogenesis during early tumor development.	('inflammation', 'Disease', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('angiogenesis', 'CPA', (96, 108))	('limit', 'NegReg', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inhibition', 'Var', (31, 41))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('tumor', 'Disease', (122, 127))	('macrophage infiltration', 'CPA', (68, 91))
141353	31754513	The following risk factors are absolute indications screening breast MRI: breast cancer susceptibility gene (BRCA) mutations (including being a first-degree relative of a person with known BRCA mutation) other genetic disorders chest radiation for lymphoma >20% lifetime risk.	('person', 'Species', '9606', (171, 177))	('breast cancer', 'Disease', (74, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (248, 256))	('mutations', 'Var', (115, 124))	('genetic disorders', 'Disease', (210, 227))	('BRCA', 'Gene', '672', (189, 193))	('BRCA', 'Gene', (189, 193))	('lymphoma', 'Disease', (248, 256))	('genetic disorders', 'Disease', 'MESH:D030342', (210, 227))	('BRCA', 'Gene', '672', (109, 113))	('lymphoma', 'Disease', 'MESH:D008223', (248, 256))	('BRCA)', 'Gene', '672', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRCA', 'Gene', (109, 113))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
141355	31754513	Family:  previous biopsy where a high-risk lesion was found, for example, atypical ductal hyperplasia (ADH) and lobular carcinoma in situ (LCIS) nulliparity dense breast tissue early menarche or late menopause hormone replacement therapy obesity personal history of breast cancer.	('lobular carcinoma', 'Disease', (112, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('obesity', 'Phenotype', 'HP:0001513', (238, 245))	('ductal hyperplasia', 'Disease', 'MESH:D006965', (83, 101))	('person', 'Species', '9606', (246, 252))	('LCIS', 'Phenotype', 'HP:0030076', (139, 143))	('obesity', 'Disease', (238, 245))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (112, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('nulliparity', 'Var', (145, 156))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (112, 137))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('obesity', 'Disease', 'MESH:D009765', (238, 245))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (120, 137))	('breast cancer', 'Disease', (266, 279))	('menopause hormone replacement therapy obesity', 'Phenotype', 'HP:0008209', (200, 245))	('ductal hyperplasia', 'Disease', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lobular carcinoma', 'Disease', 'MESH:D018275', (112, 129))
141442	29622044	discovered anisotropy in SWE as an indicator of malignancy.	('malignancy', 'Disease', (48, 58))	('anisotropy', 'Var', (11, 21))	('malignancy', 'Disease', 'MESH:D009369', (48, 58))
141467	29622044	ADs showed no significant difference between two groups (P > 0.05), while AFs were significantly higher in high-suspicious group than in low-suspicious group (P < 0.001) Fig.	('higher', 'PosReg', (97, 103))	('AD', 'Disease', 'MESH:D000544', (0, 2))	('AD', 'Disease', (0, 2))	('high-suspicious', 'Var', (107, 122))	('AF', 'Disease', 'MESH:D001281', (74, 76))
141499	29622044	In our study, AUC of AFmax was 0.760, higher than 0.67 reported by Skerl et al., with lower threshold of AFmax (159 kPa2 vs 200 kPa2), indicating higher sensitivity.	('AF', 'Disease', 'MESH:D001281', (21, 23))	('AF', 'Disease', 'MESH:D001281', (105, 107))	('159', 'Var', (112, 115))	('lower', 'NegReg', (86, 91))
141502	29622044	Previous studies demonstrated that ER (-), PR (-), p53 (+), Ki-67 (-) and high nuclear grade were associated with a significantly higher Eratio (P < 0.05).	('p53', 'Gene', (51, 54))	('high nuclear', 'Var', (74, 86))	('p53', 'Gene', '7157', (51, 54))	('ER', 'Gene', '2099', (35, 37))	('higher', 'PosReg', (130, 136))	('PR (-', 'Var', (43, 48))	('Eratio', 'CPA', (137, 143))	('Ki-67', 'Var', (60, 65))
141503	29622044	Nevertheless in our study, AF was higher in ER (+) and PR (+) lesions, while no significant correlation with HER2, Ki-67 and lymphatic metastasis.	('HER2', 'Gene', (109, 113))	('AF', 'Disease', 'MESH:D001281', (27, 29))	('higher', 'PosReg', (34, 40))	('ER', 'Gene', '2099', (110, 112))	('HER2', 'Gene', '2064', (109, 113))	('PR (+', 'Var', (55, 60))	('ER', 'Gene', '2099', (44, 46))
141527	17480238	Immunostaining showed positivity for CAM 5.2, CEA and EMA, consistent with.	('CEA', 'Gene', (46, 49))	('CEA', 'Gene', '5670', (46, 49))	('positivity', 'Var', (22, 32))	('CAM 5.2', 'Gene', (37, 44))
141554	28714966	In proExM, the succinimidyl ester of 6-((Acryloyl)amino)hexanoic acid (Acryloyl-X, SE; here abbreviated AcX) is used to chemically modify amines on biomolecules with an acrylamide functional group, which enables proteins to be linked to the polymer network; then, polymerization followed by proteinase K digestion (to an extent that spares the proteins of interest, e.g.	('polymerization', 'Var', (264, 278))	('acrylamide', 'Chemical', 'MESH:D020106', (169, 179))	('6-((Acryloyl)amino)hexanoic acid', 'Chemical', '-', (37, 69))	('polymer', 'Chemical', 'MESH:D011108', (241, 248))	('succinimidyl ester', 'Chemical', '-', (15, 33))	('Acryloyl-X', 'Chemical', '-', (71, 81))	('proteinase', 'Enzyme', (291, 301))	('polymer', 'Chemical', 'MESH:D011108', (264, 271))	('amines', 'Chemical', 'MESH:D000588', (138, 144))
141602	28714966	Because ExPath substantially increases image resolution, we anticipated that the extra information enabled by ExPath could lead to a higher quality of extracted features, and thus improve the classification of pre-invasive breast lesions.	('breast lesions', 'Disease', (223, 237))	('increases', 'PosReg', (29, 38))	('image resolution', 'MPA', (39, 55))	('breast lesions', 'Disease', 'MESH:D001941', (223, 237))	('improve', 'PosReg', (180, 187))	('quality', 'MPA', (140, 147))	('ExPath', 'Var', (8, 14))
141652	28714966	The following filter cubes (Semrock, Rochester, NY) were used: DAPI, DAPI-11LP-A-000; Alexa Fluor 488, GFP-1828A-NTE-ZERO; Alexa Fluor 546, FITC/TXRED-2X-B-NTE; Atto 647N or CF 633, Cy5-4040C-000.	('Alexa Fluor 488', 'Chemical', '-', (86, 101))	('-2X-B-NTE', 'Chemical', '-', (150, 159))	('DAPI-11LP-A', 'Chemical', '-', (69, 80))	('DAPI', 'Chemical', 'MESH:C007293', (63, 67))	('Alexa Fluor 546', 'Chemical', 'MESH:C481052', (123, 138))	('DAPI', 'Chemical', 'MESH:C007293', (69, 73))	('CF 633', 'Var', (174, 180))	('Cy5-4040C-000', 'Var', (182, 195))	('Cy5', 'Chemical', 'MESH:C085321', (182, 185))	('FITC', 'Chemical', 'MESH:D016650', (140, 144))	('Atto 647N', 'Chemical', '-', (161, 170))
141733	26806567	Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative epithelial cells.	('HER2', 'Gene', (386, 390))	('myoepithelial', 'Disease', 'MESH:D009208', (264, 277))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (75, 92))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Disease', (56, 69))	('Microglandular adenosis', 'Disease', (156, 179))	('S100', 'Gene', (297, 301))	('Microglandular adenosis', 'Disease', 'MESH:D005348', (0, 23))	('adenosis', 'Disease', 'MESH:D005348', (15, 23))	('S100', 'Gene', '6271', (297, 301))	('TP53', 'Gene', '7157', (133, 137))	('adenosis', 'Disease', (15, 23))	('myoepithelial', 'Disease', (264, 277))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HER2', 'Gene', '2064', (386, 390))	('PR', 'Gene', '5241', (369, 371))	('adenosis', 'Disease', 'MESH:D005348', (171, 179))	('Microglandular adenosis', 'Disease', 'MESH:D005348', (156, 179))	('lesion of the breast', 'Phenotype', 'HP:0100013', (210, 230))	('adenosis', 'Disease', (171, 179))	('mutations', 'Var', (146, 155))	('Microglandular adenosis', 'Disease', (0, 23))	('progesterone receptor', 'Gene', (346, 367))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('progesterone receptor', 'Gene', '5241', (346, 367))	('TP53', 'Gene', (133, 137))
141737	26806567	In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC.	('found', 'Reg', (104, 109))	('mutations', 'Var', (55, 64))	('TNBC', 'Disease', (155, 159))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))	('TNBCs', 'Chemical', '-', (19, 24))
141738	26806567	In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (e.g.	('mutations', 'Var', (69, 78))	('PI3K pathway-related', 'Pathway', (89, 109))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('TNBC', 'Gene', (32, 36))	('TP53', 'Gene', '7157', (45, 49))	('lacking', 'NegReg', (37, 44))
141741	26806567	Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal and neoplastic lesions, harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.	('neoplastic lesion', 'Phenotype', 'HP:0002664', (155, 172))	('TP53', 'Gene', (209, 213))	('neoplastic lesions', 'Disease', 'MESH:D051437', (155, 173))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (155, 173))	('TNBCs', 'Chemical', '-', (337, 342))	('associated', 'Reg', (65, 75))	('neoplastic lesions', 'Disease', (155, 173))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('TNBC', 'Disease', (81, 85))	('TP53', 'Gene', '7157', (209, 213))	('mutations', 'Var', (196, 205))
141750	26806567	The repertoires of somatic mutations in ER-positive and TNBCs have been shown to differ, with the latter being characterized by recurrent somatic mutations affecting TP53 and PIK3CA in 80% and 10% of cases, respectively.	('PIK3CA', 'Gene', (175, 181))	('mutations', 'Var', (146, 155))	('PIK3CA', 'Gene', '5290', (175, 181))	('TP53', 'Gene', '7157', (166, 170))	('TNBCs', 'Chemical', '-', (56, 61))	('TP53', 'Gene', (166, 170))
141758	26806567	Genomic DNA samples obtained from available morphologic components and paired normal breast tissue of each case were subjected to targeted capture MPS using customized sequencing assays targeting all exons of 273 or 297 genes recurrently mutated in breast cancer, genes related to DNA repair and potentially actionable cancer genes, with 236 genes present on both assays (Supplementary Table S1) as previously described.	('MPS', 'Disease', (147, 150))	('breast cancer', 'Disease', (249, 262))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', (256, 262))	('mutated', 'Var', (238, 245))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('MPS', 'Disease', 'MESH:D009084', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
141760	26806567	Genes affected by non-passenger mutations were assessed for their presence in three cancer gene datasets, Kandoth et al., the cancer gene census and Lawrence et al.. Allele-specific CNAs were identified using FACETS(Supplementary Methods).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
141769	26806567	In the TP53 wild-type samples, somatic mutations in other genes recurrently mutated in breast cancers were identified, including somatic mutations affecting PI3K pathway-related genes (e.g.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('breast cancers', 'Disease', 'MESH:D001943', (87, 101))	('breast cancers', 'Disease', (87, 101))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('PI3K pathway-related', 'Pathway', (157, 177))
141771	26806567	Additional somatic mutations in other bona fide tumour suppressor genes were also detected, comprising a BRCA1 frame-shift mutation and an APC nonsense mutation, both of which were coupled with loss of heterozygosity of the wild-type allele (Figure 2).	('frame-shift mutation', 'Var', (111, 131))	('BRCA1', 'Gene', (105, 110))	('APC', 'Disease', (139, 142))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('BRCA1', 'Gene', '672', (105, 110))	('APC', 'Disease', 'MESH:D011125', (139, 142))
141774	26806567	A subset of mutations identified in MGA and AMGA associated with TNBC were found to be subclonal and present in 10-86% of tumour cells (Supplementary Table S2, Supplementary Figure S3), suggesting that MGA and AMGA associated with TNBC may be composed of multiple clones at diagnosis.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (49, 59))	('tumour', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
141777	26806567	FGFR2 S252W in 13-MGA and PIK3CA E542Q in 13-AMGA) were found to be subclonal in specific MGA and AMGA samples.	('S252W', 'Mutation', 'rs79184941', (6, 11))	('PIK3CA', 'Gene', '5290', (26, 32))	('E542Q', 'Var', (33, 38))	('S252W', 'Var', (6, 11))	('E542Q', 'Mutation', 'rs121913273', (33, 38))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))	('PIK3CA', 'Gene', (26, 32))
141778	26806567	Interestingly, in case 13 (Figure 4), the FGFR2 S252W somatic hotspot mutation was subclonal in the MGA component but clonal in the AMGA component, potentially suggesting a clonal shift in the progression from MGA to AMGA.	('FGFR2', 'Gene', (42, 47))	('S252W', 'Mutation', 'rs79184941', (48, 53))	('S252W', 'Var', (48, 53))	('FGFR2', 'Gene', '2263', (42, 47))
141779	26806567	Moreover, the MGA and AMGA components harboured two distinct somatic mutations in PTEN, R308H and H93R, respectively, suggestive of a potential convergent phenotype (Figure 4).	('R308H', 'Var', (88, 93))	('R308H', 'Mutation', 'rs786201507', (88, 93))	('H93R', 'Mutation', 'rs121909238', (98, 102))	('H93R', 'Var', (98, 102))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))
141782	26806567	Whilst pure MGAs appear not to harbour clonal non-synonymous mutations or CNAs affecting genes reported to be involved in the pathogenesis of TNBCs, MGAs and AMGAs associated with DCIS or invasive breast cancer are genetically advanced lesions that harbour a genomic landscape that resembles that of TNBCs, including recurrent TP53 mutations and high levels of genomic instability.	('invasive breast cancer', 'Disease', (188, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('associated', 'Reg', (164, 174))	('TP53', 'Gene', '7157', (327, 331))	('TP53', 'Gene', (327, 331))	('MGAs', 'Disease', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (332, 341))	('DCIS', 'Disease', (180, 184))	('invasive breast cancer', 'Disease', 'MESH:D001943', (188, 210))	('TNBCs', 'Chemical', '-', (142, 147))	('TNBCs', 'Chemical', '-', (300, 305))
141785	26806567	In a way akin to unselected TNBCs, all invasive tumours harboured TP53 mutations; in addition, nonsense or frameshift somatic mutations coupled with loss of heterozygosity of the wild-type allele of APC, BRCA1 and CDKN2A, and missense somatic mutations in BRCA2 and RAD51B coupled with loss of heterozygosity of the wild-type allele were documented (Supplementary Figure S5).	('TP53', 'Gene', '7157', (66, 70))	('loss', 'NegReg', (149, 153))	('APC', 'Disease', 'MESH:D011125', (199, 202))	('BRCA2', 'Gene', (256, 261))	('TNBCs', 'Chemical', '-', (28, 33))	('invasive tumours', 'Disease', 'MESH:D009361', (39, 55))	('APC', 'Disease', (199, 202))	('invasive tumours', 'Disease', (39, 55))	('RAD51B', 'Gene', '5890', (266, 272))	('mutations', 'Var', (71, 80))	('BRCA2', 'Gene', '675', (256, 261))	('CDKN2A', 'Gene', (214, 220))	('nonsense', 'Var', (95, 103))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('TP53', 'Gene', (66, 70))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('CDKN2A', 'Gene', '1029', (214, 220))	('BRCA1', 'Gene', '672', (204, 209))	('RAD51B', 'Gene', (266, 272))	('BRCA1', 'Gene', (204, 209))	('missense somatic mutations', 'Var', (226, 252))
141790	26806567	For example, in case 7, three non-synonymous clonal somatic mutations, including mutations affecting TP53, PTEN and APC, were shared among MGA, AMGA and the associated metaplastic breast cancer (Figure 5).	('PTEN', 'Gene', (107, 111))	('PTEN', 'Gene', '5728', (107, 111))	('APC', 'Disease', 'MESH:D011125', (116, 119))	('TP53', 'Gene', '7157', (101, 105))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('APC', 'Disease', (116, 119))	('TP53', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('mutations', 'Var', (81, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))
141791	26806567	The MGA and IDC-NST components of case 8 shared two somatic non-synonymous mutations, including clonal somatic non-synonymous mutations in TP53 and BRCA1, likely representing founder genetic events (Figure 5).	('BRCA1', 'Gene', '672', (148, 153))	('TP53', 'Gene', '7157', (139, 143))	('non-synonymous mutations', 'Var', (111, 135))	('BRCA1', 'Gene', (148, 153))	('TP53', 'Gene', (139, 143))
141792	26806567	In case 14, the MGA and TNBC showed a highly heterogeneous clonal composition with six shared somatic non-synonymous mutations, including a clonal TP53 G266R mutation and a somatic non-synonymous mutation of BRCA2 coupled with loss-of-heterozygosity of the wild-type allele restricted to the invasive component (Figure 5 and Supplementary Figure S5).	('TP53', 'Gene', (147, 151))	('loss-of-heterozygosity', 'NegReg', (227, 249))	('G266R', 'Var', (152, 157))	('G266R', 'Mutation', 'rs1057519990', (152, 157))	('BRCA2', 'Gene', (208, 213))	('BRCA2', 'Gene', '675', (208, 213))	('TP53', 'Gene', '7157', (147, 151))
141793	26806567	In case 27, both the MGA and the associated metaplastic breast carcinoma displayed heterogeneous clonal architecture and shared a clonal TP53 C176F mutation (Figure 5).	('breast carcinoma', 'Phenotype', 'HP:0003002', (56, 72))	('C176F', 'Var', (142, 147))	('TP53', 'Gene', '7157', (137, 141))	('breast carcinoma', 'Disease', (56, 72))	('C176F', 'Mutation', 'rs786202962', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('breast carcinoma', 'Disease', 'MESH:D001943', (56, 72))	('TP53', 'Gene', (137, 141))
141795	26806567	In case 5, for which MGA, DCIS and TNBC samples were available, targeted capture MPS analysis revealed that the MGA and TNBC components were clonally related, displaying similar patterns of CNAs and sharing five somatic mutations, including a somatic TP53 frameshift mutation (L265fs) (Figure 6).	('TP53', 'Gene', (251, 255))	('L265fs', 'Mutation', 'p.L265fsX', (277, 283))	('MPS', 'Disease', 'MESH:D009084', (81, 84))	('L265fs', 'Var', (277, 283))	('MPS', 'Disease', (81, 84))	('TP53', 'Gene', '7157', (251, 255))
141797	26806567	Most importantly, somatic mutations affecting TSC2 (A289V), LAMA5 (D79G) and MXRA5 (E58K), which were subclonal in the MGA became clonal in the TNBC, providing evidence supportive of the notion that a minor subclone from MGA might have progressed and become the dominant clone of the TNBC.	('E58K', 'Mutation', 'p.E58K', (84, 88))	('MXRA5', 'Gene', (77, 82))	('LAMA5', 'Gene', (60, 65))	('D79G', 'Mutation', 'p.D79G', (67, 71))	('TSC2', 'Gene', '7249', (46, 50))	('mutations', 'Var', (26, 35))	('TSC2', 'Gene', (46, 50))	('MXRA5', 'Gene', '25878', (77, 82))	('A289V', 'Mutation', 'rs755631210', (52, 57))	('LAMA5', 'Gene', '3911', (60, 65))	('A289V', 'Var', (52, 57))
141798	26806567	On the other hand, the DCIS present in this case was found not to be clonally-related to the MGA and TNBC, and displayed a completely different repertoire of genomic alterations, including a TP53 V173L somatic missense mutation, distinct from the TP53 mutation found in the MGA and TNBC (Figure 6, Supplementary Figure S6).	('TP53', 'Gene', (247, 251))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('Supplementary Figure S6', 'Disease', 'MESH:D017034', (298, 321))	('Supplementary Figure S6', 'Disease', (298, 321))	('V173L', 'Var', (196, 201))	('TP53', 'Gene', '7157', (247, 251))	('V173L', 'Mutation', 'rs876660754', (196, 201))
141801	26806567	MGA and AMGA associated with DCIS and/or TNBCs were found to be genetically advanced neoplastic lesions, harbouring recurrent somatic mutations in TP53, somatic mutations in other bona fide cancer-related genes and complex patterns of CNAs.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('TP53', 'Gene', (147, 151))	('neoplastic lesions', 'Disease', (85, 103))	('neoplastic lesions', 'Disease', 'MESH:D051437', (85, 103))	('TNBCs', 'Chemical', '-', (41, 46))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (134, 143))	('TNBCs', 'Gene', (41, 46))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (85, 102))	('TP53', 'Gene', '7157', (147, 151))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (85, 103))
141805	26806567	Furthermore, the lack of TP53 mutations in the two pure MGAs analyzed here may not be surprising, given that Khalifeh et al.	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (25, 29))
141807	26806567	It is possible that TP53 inactivation in MGA cells may abrogate cell cycle checkpoints and play a role in the acquisition of genetic instability, creating a permissive context for the acquisition of mutations and CNAs and phenotypic progression to AMGA and TNBC.	('mutations', 'Var', (199, 208))	('TP53', 'Gene', (20, 24))	('inactivation', 'Var', (25, 37))	('TNBC', 'Gene', (257, 261))	('cell cycle checkpoints', 'CPA', (64, 86))	('genetic instability', 'MPA', (125, 144))	('AMGA', 'Disease', (248, 252))	('abrogate', 'NegReg', (55, 63))	('TP53', 'Gene', '7157', (20, 24))
141808	26806567	In fact, TP53 mutations were present in all but one case (6/7) of MGA with clonally related invasive TNBC, whereas the three cases without invasive carcinoma were TP53 wild-type.	('invasive carcinoma', 'Disease', 'MESH:D009361', (139, 157))	('TP53', 'Gene', '7157', (163, 167))	('invasive carcinoma', 'Disease', (139, 157))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('TP53', 'Gene', (163, 167))	('present', 'Reg', (29, 36))	('mutations', 'Var', (14, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('MGA', 'Disease', (66, 69))
141809	26806567	Consistent with these findings, the MGA and AMGA of case 13 harboured 36% of somatic non-synonymous mutations in common, including two truncal mutations; the AMGA component, however, displayed a higher number of somatic non-synonymous mutations (10 vs 5, respectively), including a PIK3CA E542Q hotspot mutation, which was restricted to the AMGA component.	('E542Q', 'Var', (289, 294))	('PIK3CA', 'Gene', (282, 288))	('PIK3CA', 'Gene', '5290', (282, 288))	('E542Q', 'Mutation', 'rs121913273', (289, 294))
141810	26806567	This case is particularly interesting, given that in the progression from MGA to AMGA, we observed evidence of i) clonal shifts, supported by the presence of a subclonal FGFR2 S252W hotspot mutation in the MGA component that became clonal in the AMGA component, and ii) of a convergent phenotype, where the MGA and AMGA components harboured distinct PTEN somatic mutations.	('S252W', 'Var', (176, 181))	('hotspot', 'PosReg', (182, 189))	('FGFR2', 'Gene', (170, 175))	('S252W', 'Mutation', 'rs79184941', (176, 181))	('FGFR2', 'Gene', '2263', (170, 175))	('PTEN', 'Gene', (350, 354))	('PTEN', 'Gene', '5728', (350, 354))
141812	26806567	Akin to TNBCs, MGAs and AMGAs associated with cancer not only harboured pathogenic TP53 somatic mutations coupled with loss of heterozygosity of the wild-type allele, but also PTEN somatic mutations, a PIK3CA hotspot somatic mutation, and a frameshift BRCA1 somatic mutation associated with loss of heterozygosity of the wild-type allele.	('BRCA1', 'Gene', (252, 257))	('frameshift', 'Var', (241, 251))	('TP53', 'Gene', '7157', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('PTEN', 'Gene', (176, 180))	('TP53', 'Gene', (83, 87))	('cancer', 'Disease', (46, 52))	('PTEN', 'Gene', '5728', (176, 180))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('BRCA1', 'Gene', '672', (252, 257))	('mutations', 'Var', (96, 105))	('TNBCs', 'Chemical', '-', (8, 13))
141814	26806567	Given the clonal and neoplastic nature of MGAs and AMGAs associated with TNBC, and the fact that these lesions display TP53, PTEN, PIK3CA and BRCA1 mutations, which are also found in their associated TNBCs, it could be argued that MGAs and AMGAs may constitute an indolent form of triple-negative disease, with minimal local aggressiveness and lacking metastatic behaviour, but with the potential to progress to high-grade lesions.	('mutations', 'Var', (148, 157))	('aggressiveness', 'Disease', (325, 339))	('MGAs', 'Disease', (42, 46))	('PTEN', 'Gene', (125, 129))	('BRCA1', 'Gene', '672', (142, 147))	('TNBC', 'Disease', (73, 77))	('PTEN', 'Gene', '5728', (125, 129))	('PIK3CA', 'Gene', '5290', (131, 137))	('aggressiveness', 'Phenotype', 'HP:0000718', (325, 339))	('BRCA1', 'Gene', (142, 147))	('MGAs', 'Disease', (231, 235))	('aggressiveness', 'Disease', 'MESH:D001523', (325, 339))	('PIK3CA', 'Gene', (131, 137))	('TNBCs', 'Chemical', '-', (200, 205))	('AMGAs', 'Disease', (240, 245))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('associated', 'Reg', (57, 67))
141816	26806567	In all cases analyzed identical likely driver genetic events were identified in both MGA and associated invasive tumours, including identical somatic mutations in TP53 and BRCA1.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA1', 'Gene', '672', (172, 177))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('TP53', 'Gene', '7157', (163, 167))	('BRCA1', 'Gene', (172, 177))	('TP53', 'Gene', (163, 167))	('invasive tumours', 'Disease', (104, 120))	('mutations', 'Var', (150, 159))	('MGA', 'Disease', (85, 88))	('invasive tumours', 'Disease', 'MESH:D009361', (104, 120))
141817	26806567	Although mutations restricted to, or enriched for in, the TNBCs as compared to their respective MGAs/AMGAs were documented, including somatic mutations coupled with loss of heterozygosity of the wild-type allele of TP53, APC, RAD51B, CDKN2A and BRCA2, which could be interpreted as a possible evolutionary mechanism, additional drivers of progression such as epigenetic and/or other genetic events not tested in our sequencing panel may have also played a role.	('APC', 'Disease', (221, 224))	('mutations', 'Var', (142, 151))	('BRCA2', 'Gene', (245, 250))	('mutations', 'Var', (9, 18))	('TNBCs', 'Chemical', '-', (58, 63))	('TP53', 'Gene', '7157', (215, 219))	('TNBCs', 'Gene', (58, 63))	('APC', 'Disease', 'MESH:D011125', (221, 224))	('BRCA2', 'Gene', '675', (245, 250))	('RAD51B', 'Gene', '5890', (226, 232))	('CDKN2A', 'Gene', (234, 240))	('TP53', 'Gene', (215, 219))	('RAD51B', 'Gene', (226, 232))	('CDKN2A', 'Gene', '1029', (234, 240))
141826	26806567	In conjunction with the results by Khalifeh et al., the presence of recurrent TP53 somatic mutations in MGAs and/or AMGAs associated with TNBCs and the lack of these alterations in the pure MGAs analyzed here might be interpreted as evidence to that the acquisition of TP53 mutations may result in increased genetic instability and a greater likelihood of an MGA and/or AMGA to progress to TNBC.	('associated', 'Reg', (122, 132))	('genetic instability', 'MPA', (308, 327))	('TP53', 'Gene', '7157', (269, 273))	('TNBC', 'Disease', (390, 394))	('MGA', 'Disease', (359, 362))	('TNBCs', 'Chemical', '-', (138, 143))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', (269, 273))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('mutations', 'Var', (274, 283))	('increased', 'PosReg', (298, 307))
141827	26806567	Larger clinical studies coupled with comprehensive molecular analyses will be required to i) determine whether TP53 mutations may constitute a biomarker to define the risk of an MGA to progress to invasive disease, ii) identify potential founder genetic/epigenetic events of pure MGAs, and iii) to define whether MGA and AMGA would constitute low-malignant invasive neoplasms associated with minimal local aggressiveness and lacking metastatic behaviour, but with the potential to progress to high-grade TNBC.	('invasive disease', 'Disease', 'MESH:D009362', (197, 213))	('MGA', 'Disease', (313, 316))	('low-malignant invasive neoplasms', 'Disease', 'MESH:D009369', (343, 375))	('TP53', 'Gene', '7157', (111, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (406, 420))	('neoplasms', 'Phenotype', 'HP:0002664', (366, 375))	('TP53', 'Gene', (111, 115))	('low-malignant invasive neoplasms', 'Disease', (343, 375))	('mutations', 'Var', (116, 125))	('invasive disease', 'Disease', (197, 213))	('aggressiveness', 'Disease', 'MESH:D001523', (406, 420))	('aggressiveness', 'Disease', (406, 420))
141831	27094307	ADC, FA, and eigenvalues of E1, E2, E3, and E1-E3 in breast cancers were all significantly lower than in normal tissue (P<0.001 for all) with mean reduction of (32+-17)%, (24+-13)%, (33+-19)%, (32+-17)%, (31+-18)%, and (37+-20)% for ADC, FA, E1, E2, E3, and E1-E3, respectively.	('E1-E3', 'Var', (44, 49))	('lower', 'NegReg', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('ADC', 'Disease', (233, 236))	('breast cancers', 'Phenotype', 'HP:0003002', (53, 67))	('reduction', 'NegReg', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancers', 'Disease', 'MESH:D001943', (53, 67))	('breast cancers', 'Disease', (53, 67))
141834	27094307	ADC, E1, E2, E3, and E1-E3 are much lower in breast cancers than in normal tissue and benign lesions.	('lower', 'NegReg', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('E1-E3', 'Var', (21, 26))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('breast cancers', 'Disease', (45, 59))	('ADC', 'MPA', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
141835	27094307	The reduction of ADC, E1, E2, E3, and E1-E3 of a mass in the breast is highly associated with the risk of breast cancer, but the FA has no utility in breast cancer risk prediction.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('E1-E3', 'Var', (38, 43))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('breast cancer', 'Disease', (150, 163))	('ADC', 'Var', (17, 20))	('reduction', 'NegReg', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
141862	27094307	ADC, FA, E1, E2, E3, and E1-E3 were all significantly lower in breast cancers than those in normal breast tissue (Figure 2 and Table 2).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('E1-E3', 'Var', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('breast cancers', 'Disease', (63, 77))	('lower', 'NegReg', (54, 59))
141867	27094307	DTI-derived parameters of ADC, E1, E2, E3, and E1-E3 were all significantly lower in breast cancers than those in benign lesions (P<0.01; Figure 3 and Table 3).	('breast cancers', 'Disease', 'MESH:D001943', (85, 99))	('breast cancers', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('lower', 'NegReg', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('E1-E3', 'Var', (47, 52))	('breast cancers', 'Phenotype', 'HP:0003002', (85, 99))
141868	27094307	The ADC, E1, E2, E3, and E1-E3 were all significantly lower in invasive cancer (P<0.01) and DCIS (P<0.01) than in benign lesions, except for FA (P>0.05).	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('E1-E3', 'Var', (25, 30))	('invasive cancer', 'Disease', (63, 78))	('DCIS', 'Disease', (92, 96))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('invasive cancer', 'Disease', 'MESH:D009362', (63, 78))	('lower', 'NegReg', (54, 59))
141871	27094307	To confirm the value of every parameter in predicting the risk of breast cancer, the values of ADC, FA, E1, E2, E3, and E1-E3 of breast cancer and benign lesions were divided into equal quartiles, as shown in Table 4.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('E1-E3', 'Var', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
141872	27094307	ADC, E1, E2, E3, and E1-E3 were strongly associated with breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('breast cancers', 'Disease', (57, 71))	('E1-E3', 'Var', (21, 26))	('associated', 'Reg', (41, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('ADC', 'Var', (0, 3))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
141873	27094307	A mass with ADC, E1, E2, E3, or E1-E3 in the lowest quartiles was over 50-90 times more likely to be a malignancy, and the odds ratios were 95.0, 95.0, 67.67, 67.67, and 47.7, respectively.	('ADC', 'Disease', (12, 15))	('malignancy', 'Disease', (103, 113))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('E1-E3', 'Var', (32, 37))
141879	27094307	Our results showed that ADC, E1, E2, E3, and E1-E3 were significantly lower in cancer lesions compared to normal breast tissue.	('cancer lesions', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('E1-E3', 'Var', (45, 50))	('lower', 'NegReg', (70, 75))	('ADC', 'MPA', (24, 27))	('cancer lesions', 'Disease', 'MESH:D009062', (79, 93))
141881	27094307	In breast cancer differentiation, ADC, E1, E2, and E3, as malignancy predictors, were highly associated with breast cancers risk, which had much more high-differentiation efficacy than other DTI parameters used in our study.	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('breast cancers', 'Disease', 'MESH:D001943', (109, 123))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancers', 'Disease', (109, 123))	('malignancy', 'Disease', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('associated', 'Reg', (93, 103))	('ADC', 'Var', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancers', 'Phenotype', 'HP:0003002', (109, 123))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
141884	27094307	Besides the influence of hormonal level, the heterogeneous fibroglandular (especially the collagen) fibers may also result in the reduction of signal and mimic breast carcinomas, which may in turn produce the variations in the breast.	('breast', 'Disease', (227, 233))	('produce', 'Reg', (197, 204))	('breast carcinoma', 'Phenotype', 'HP:0003002', (160, 176))	('heterogeneous', 'Var', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('reduction', 'NegReg', (130, 139))	('signal', 'MPA', (143, 149))	('variations', 'Reg', (209, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('breast carcinomas', 'Disease', 'MESH:D001943', (160, 177))	('breast carcinomas', 'Disease', (160, 177))	('breast carcinomas', 'Phenotype', 'HP:0003002', (160, 177))
141889	27094307	Our study found that the DTI parameters ADC, E1, E2, E3, and E1-E3 were reduced much more than FA in breast cancer compared to normal tissue.	('reduced', 'NegReg', (72, 79))	('ADC', 'MPA', (40, 43))	('DTI', 'MPA', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('E1-E3', 'Var', (61, 66))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
141898	27094307	Comparisons between benign and malignant tumors showed no significant difference in FA values between the 2 different type of lesions, while ADC, E1, E2, E3, and E1-E3, as predictors for breast cancer, were significantly lower in breast cancer than in benign lesions, which is consistent with the findings of Partridge and Cakir, but opposite to the results of Tsougos.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', (230, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('E1-E3', 'Var', (162, 167))	('malignant tumors', 'Disease', (31, 47))	('lower', 'NegReg', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('malignant tumors', 'Disease', 'MESH:D018198', (31, 47))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('ADC', 'Var', (141, 144))	('breast cancer', 'Disease', (187, 200))
141899	27094307	Our results suggest that ADC, E1, E2, E3, and E1-E3 all help to distinguish breast cancers from benign lesions.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (76, 90))	('E1-E3', 'Var', (46, 51))	('breast cancers', 'Disease', 'MESH:D001943', (76, 90))	('breast cancers', 'Disease', (76, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
141901	27094307	In our study, the reduction of ADC, as well as E1, E2, E3, and E1-E3, was found to be very closely related to breast cancer risk.	('E1-E3', 'Var', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('ADC', 'Disease', (31, 34))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('breast cancer', 'Disease', (110, 123))	('reduction', 'NegReg', (18, 27))
141902	27094307	In fact, we did not observe a single malignant lesion when ADC <0.56 mm2/s or E1 <0.97 mm2/s or E2 <0.8 mm2/s or E3 <0.6 mm2/s, and only 1 lesion with E1-E3 less than 0.29 mm2/s.	('mm2', 'Gene', '10687', (172, 175))	('mm2', 'Gene', '10687', (69, 72))	('mm2', 'Gene', (172, 175))	('E1 <0.97', 'Var', (78, 86))	('mm2', 'Gene', '10687', (104, 107))	('mm2', 'Gene', '10687', (121, 124))	('E2 <0.8', 'Var', (96, 103))	('mm2', 'Gene', '10687', (87, 90))	('E3 <0.6', 'Var', (113, 120))	('mm2', 'Gene', (69, 72))	('mm2', 'Gene', (87, 90))	('mm2', 'Gene', (121, 124))	('mm2', 'Gene', (104, 107))
141903	27094307	With the reduction of ADC, E1, E2, E3, and E1-E3 from the values that most benign lesions are in, the risk of breast cancer increases rapidly.	('ADC', 'Var', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('reduction', 'NegReg', (9, 18))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('breast cancer', 'Disease', (110, 123))	('E1-E3', 'Var', (43, 48))
141905	27094307	Due to the impact of cyclical changes in hormone levels, the DTI indices of tissues may be affected, especially in the 2nd week, which means the detection and differentiation of breast cancers by using ADC, E1, E2, E3, and E1-E3 may be influenced.	('E1-E3', 'Var', (223, 228))	('breast cancers', 'Disease', 'MESH:D001943', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancers', 'Disease', (178, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('ADC', 'Var', (202, 205))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('breast cancers', 'Phenotype', 'HP:0003002', (178, 192))
141909	27094307	We investigated the diffusion tensor indices of breast cancers, and found that ADC, E1, E2, E3, and E1-E3 were significantly lower in cancer lesions compared to normal breast tissue and benign lesions.	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('breast cancers', 'Disease', (48, 62))	('cancer lesions', 'Disease', 'MESH:D009062', (134, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('lower', 'NegReg', (125, 130))	('ADC', 'Var', (79, 82))	('cancer lesions', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
141910	27094307	ADC, E1, E2, E3, and E1-E3 of a breast mass were highly associated with the risk of breast cancer in a reverse relationship, while the FA is useless in breast cancer risk prediction.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('E1-E3', 'Var', (21, 26))	('breast mass', 'Phenotype', 'HP:0032408', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ADC', 'Var', (0, 3))	('associated', 'Reg', (56, 66))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))
141976	26843057	For HR-negative index DCIS cases, a relatively larger proportion of recurrences occurred within 4 years and many were attributable to non-invasive or HR-negative invasive disease.	('HR-negative', 'Var', (4, 15))	('invasive disease', 'Disease', 'MESH:D009362', (162, 178))	('invasive disease', 'Disease', (162, 178))
142019	21547576	Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown.	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('develop', 'PosReg', (69, 76))	('DCIS', 'Var', (59, 63))	('invasive breast cancer', 'Disease', (94, 116))	('ductal cancer', 'Disease', 'MESH:D009369', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('ductal cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (48, 53))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('invasive breast cancer', 'Disease', 'MESH:D001943', (94, 116))
142023	21547576	Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS.	('PRDM14', 'Gene', '63978', (97, 103))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('AURKA', 'Gene', (28, 33))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('high-grade DCIS', 'Disease', (148, 163))	('found', 'Reg', (61, 66))	('frequent', 'Reg', (136, 144))	('CCNE1', 'Gene', '898', (38, 43))	('CCNE1', 'Gene', (38, 43))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (91, 95))	('EMSY', 'Gene', '56946', (108, 112))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('alterations', 'Var', (13, 24))	('EMSY', 'Gene', (108, 112))	('AURKA', 'Gene', '6790', (28, 33))	('PRDM14', 'Gene', (97, 103))	('high-grade DCIS', 'Disease', (70, 85))
142024	21547576	In contrast, the average number of alterations in low/intermediate and high grade IDC was similar, and although EGFR alterations were exclusively found in high grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.	('alterations', 'Var', (117, 128))	('EGFR', 'Gene', (112, 116))	('IDC', 'Gene', '4000', (295, 298))	('DCIS', 'Phenotype', 'HP:0030075', (350, 354))	('IDC', 'Gene', (205, 208))	('IDC', 'Gene', '4000', (166, 169))	('IDC', 'Gene', '4000', (82, 85))	('IDC', 'Gene', (82, 85))	('fewer', 'NegReg', (231, 236))	('IDC', 'Gene', (295, 298))	('EGFR', 'Gene', '1956', (112, 116))	('IDC', 'Gene', '4000', (205, 208))	('IDC', 'Gene', (166, 169))
142026	21547576	However, high grade DCIS showed more copy number changes than low/intermediate grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes.	('IDC', 'Gene', (252, 255))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('copy number changes', 'Var', (37, 56))	('progress', 'PosReg', (240, 248))	('IDC', 'Gene', '4000', (252, 255))
142034	21547576	In the most popular model to explain the development of IDC, low-grade DCIS tends to progress to low-grade IDC, and high-grade DCIS tends to progress to high-grade IDC by accumulation of fairly specific chromosomal and gene alterations.	('progress', 'PosReg', (85, 93))	('IDC', 'Gene', '4000', (164, 167))	('IDC', 'Gene', (164, 167))	('IDC', 'Gene', '4000', (107, 110))	('progress', 'PosReg', (141, 149))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('IDC', 'Gene', '4000', (56, 59))	('chromosomal', 'Var', (203, 214))	('IDC', 'Gene', (56, 59))	('IDC', 'Gene', (107, 110))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))
142039	21547576	In previous studies we used MLPA to detect HER2 and TOP2A amplification and used its multiplex aspect to determine the frequency of polysomy 17 in breast tumors.	('TOP2A', 'Gene', '7153', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('breast tumors', 'Phenotype', 'HP:0100013', (147, 160))	('HER2', 'Gene', (43, 47))	('polysomy', 'Var', (132, 140))	('amplification', 'MPA', (58, 71))	('TOP2A', 'Gene', (52, 57))	('HER2', 'Gene', '2064', (43, 47))	('breast tumors', 'Disease', (147, 160))	('breast tumors', 'Disease', 'MESH:D001943', (147, 160))
142040	21547576	In the current study, we applied MLPA to compare copy number changes in 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('IDC', 'Gene', '4000', (150, 153))	('IDC', 'Gene', (150, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('patients', 'Species', '9606', (168, 176))	('copy number changes', 'Var', (49, 68))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
142056	21547576	Then, we again dichotomized data and compared the mean number of gains/amplifications between low/intermediate and high grade DCIS, as well as between low/intermediate grade and high grade IDC by T-test.	('gains/amplifications', 'PosReg', (65, 85))	('low/intermediate', 'Var', (94, 110))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('IDC', 'Gene', '4000', (189, 192))	('IDC', 'Gene', (189, 192))
142063	21547576	Also, as shown in Table 2, the pattern of alterations differed between low/intermediate-grade and high-grade DCIS, and in a much lesser extent between low/intermediate and high-grade IDC.	('IDC', 'Gene', (183, 186))	('low/intermediate-grade', 'Var', (71, 93))	('DCIS', 'Disease', (109, 113))	('IDC', 'Gene', '4000', (183, 186))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))
142064	21547576	Alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and alterations of EGFR were exclusively found in high-grade IDC.	('found', 'Reg', (115, 120))	('IDC', 'Gene', (135, 138))	('EGFR', 'Gene', '1956', (93, 97))	('Alterations', 'Var', (0, 11))	('AURKA', 'Gene', '6790', (15, 20))	('high-grade DCIS', 'Disease', (57, 72))	('EGFR', 'Gene', (93, 97))	('CCNE1', 'Gene', '898', (25, 30))	('CCNE1', 'Gene', (25, 30))	('found', 'Reg', (48, 53))	('AURKA', 'Gene', (15, 20))	('IDC', 'Gene', '4000', (135, 138))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
142065	21547576	Figure 2 shows that gene copy numbers of HER2 (p = 0.013), MYC (p = 0.009) and MTDH (not significant) were higher in high-grade DCIS compared to low-intermediate grade DCIS.	('MYC', 'Gene', '4609', (59, 62))	('MYC', 'Gene', (59, 62))	('MTDH', 'Gene', (79, 83))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('HER2', 'Gene', (41, 45))	('MTDH', 'Gene', '92140', (79, 83))	('HER2', 'Gene', '2064', (41, 45))	('higher', 'PosReg', (107, 113))	('gene', 'MPA', (20, 24))	('high-grade', 'Var', (117, 127))
142069	21547576	Although not consistently, most of the low/intermediate grade DCIS/IDC seemed to belong to a different cluster than high-grade DCIS/IDC.	('low/intermediate grade', 'Var', (39, 61))	('IDC', 'Gene', (67, 70))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('IDC', 'Gene', '4000', (67, 70))	('IDC', 'Gene', '4000', (132, 135))	('IDC', 'Gene', (132, 135))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))
142073	21547576	Although copy number changes of some genes such as BIRC5 seemed to be more prevalent in DCIS than IDC, overall, no significant differences in gene copy number between DCIS and adjacent IDC were found.	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('BIRC5', 'Gene', (51, 56))	('copy number changes', 'Var', (9, 28))	('IDC', 'Gene', '4000', (98, 101))	('IDC', 'Gene', (98, 101))	('IDC', 'Gene', '4000', (185, 188))	('prevalent', 'Reg', (75, 84))	('DCIS', 'Disease', (88, 92))	('IDC', 'Gene', (185, 188))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))	('BIRC5', 'Gene', '332', (51, 56))
142084	21547576	Furthermore, MYC amplifications seem to be more prevalent in high-grade DCIS lesions (65%) than in low/intermediate-grade lesions (42%), which is consistent with previous studies.	('high-grade DCIS lesions', 'Disease', (61, 84))	('prevalent', 'Reg', (48, 57))	('amplifications', 'Var', (17, 31))	('MYC', 'Gene', '4609', (13, 16))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('MYC', 'Gene', (13, 16))
142086	21547576	Table 2 and statistical analysis show that, overall, the differences between low/intermediate and high grade DCIS seemed to be bigger than between low/intermediate and high-grade IDC.	('IDC', 'Gene', '4000', (179, 182))	('low/intermediate', 'Var', (77, 93))	('DCIS', 'Disease', (109, 113))	('IDC', 'Gene', (179, 182))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))
142095	21547576	In conclusion, this study showed that MLPA is suited to simultaneously detect amplification or loss of many potential prognostic or predictive genes in breast cancer.	('amplification', 'Var', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('loss', 'NegReg', (95, 99))
142097	21547576	Overall, the differences between low/intermediate and high-grade DCIS seemed to be bigger than between low/intermediate and high-grade IDC.	('low/intermediate', 'Var', (33, 49))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('IDC', 'Gene', '4000', (135, 138))	('IDC', 'Gene', (135, 138))
142107	33725814	A 61-year-old non-symptomatic Japanese housewife presented to our hospital because of an abnormality on chest radiography undergone during a lung cancer screening program in her city of residence.	('abnormality', 'Var', (89, 100))	('abnormality on chest radiography', 'Phenotype', 'HP:0031983', (89, 121))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('abnormality on chest', 'Phenotype', 'HP:0000765', (89, 109))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
142137	33725814	Complex FA also increases the risk of breast cancer in women, with the relative risk reported to increase to 3.10.	('women', 'Species', '9606', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('increases', 'PosReg', (16, 25))	('Complex FA', 'Var', (0, 10))
142361	28748520	3, where the number of papers in PubMed which have used MCF-7 far exceeds those using the second most common breast cancer cell line, MDA-MB-231, often used to model the more aggressive triple negative breast cancer, while aggregate publications of other less commonly used breast cancer cell lines, e.g.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (134, 144))	('MCF-7', 'Var', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Disease', (274, 287))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('MCF-7', 'CellLine', 'CVCL:0031', (56, 61))	('breast cancer', 'Disease', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
142440	26684357	The first of its kind, we reported that patients with high expression of BMPRIB exhibited favorable prognosis by a retrospective analysis consisting of 168 patients treated with TE (taxane and anthracycline) regimens.	('patients', 'Species', '9606', (156, 164))	('BMPRIB', 'Gene', '658', (73, 79))	('high expression', 'Var', (54, 69))	('BMPRIB', 'Gene', (73, 79))	('patients', 'Species', '9606', (40, 48))	('anthracycline', 'Chemical', 'MESH:D018943', (193, 206))	('TE (taxane', 'Chemical', '-', (178, 188))
142454	26684357	Patients with high expression of BMPRIB were more sensitive to TE regimens which was validated by detecting 32 paired pre-neoadjuvant and post-neoadjuvant specimens.	('sensitive', 'MPA', (50, 59))	('BMPRIB', 'Gene', '658', (33, 39))	('TE', 'Chemical', 'MESH:D013691', (63, 65))	('BMPRIB', 'Gene', (33, 39))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))
142487	26684357	IDC patients with low BMPRIB expression exhibited a trend for shorter time (median 30.0 months) to develop bone metastasis than those (median 60.0 months) with high expression (P = 0.011, Figure 4F).	('BMPRIB', 'Gene', '658', (22, 28))	('IDC', 'Gene', '4000', (0, 3))	('BMPRIB', 'Gene', (22, 28))	('IDC', 'Gene', (0, 3))	('patients', 'Species', '9606', (4, 12))	('develop', 'PosReg', (99, 106))	('bone metastasis', 'CPA', (107, 122))	('low', 'Var', (18, 21))
142488	26684357	Low BMPRIB expression has the potential for a reduced survival compared with those with high expression, and the median interval time were 13.0 months and 25.0 months, respectively (P = 0.016, Figure 4G).	('survival', 'MPA', (54, 62))	('reduced', 'NegReg', (46, 53))	('BMPRIB', 'Gene', '658', (4, 10))	('BMPRIB', 'Gene', (4, 10))	('Low', 'Var', (0, 3))
142497	26684357	We found no correlation between the expression of BMPRIB and OS (P = 0.072, Figure 5F) in patients (189 cases) who received other chemotherapy, although low expression of BMPRIB indicated a shorter PFS (P=0.030, Figure 5E).	('PFS', 'MPA', (198, 201))	('BMPRIB', 'Gene', '658', (50, 56))	('low', 'Var', (153, 156))	('BMPRIB', 'Gene', (50, 56))	('BMPRIB', 'Gene', '658', (171, 177))	('BMPRIB', 'Gene', (171, 177))	('OS', 'Chemical', '-', (61, 63))	('shorter', 'NegReg', (190, 197))	('patients', 'Species', '9606', (90, 98))
142510	26684357	showed that high expression of BMP 7 (a member of BMP family) inhibited the formation of bone metastases in breast cancer patients.	('breast cancer', 'Disease', (108, 121))	('bone metastases', 'Disease', (89, 104))	('BMP', 'Gene', (31, 34))	('BMP 7', 'Gene', '655', (31, 36))	('bone metastases', 'Disease', 'MESH:D009362', (89, 104))	('BMP', 'Gene', '649', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('inhibited', 'NegReg', (62, 71))	('BMP', 'Gene', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('BMP 7', 'Gene', (31, 36))	('BMP', 'Gene', '649', (31, 34))	('high expression', 'Var', (12, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
142511	26684357	found loss of BMPRIB induced increased expression of cytokeratin17, which is a promoting factor of invasion.	('BMPRIB', 'Gene', '658', (14, 20))	('BMPRIB', 'Gene', (14, 20))	('cytokeratin17', 'Gene', '3872', (53, 66))	('loss', 'Var', (6, 10))	('cytokeratin17', 'Gene', (53, 66))	('increased', 'PosReg', (29, 38))	('expression', 'MPA', (39, 49))
142551	26684357	Patients were categorized into groups according to H score of BMPRIB: low BMPRIB expression (0-140), high BMPRIB expression (141-200).	('BMPRIB', 'Gene', '658', (74, 80))	('BMPRIB', 'Gene', (74, 80))	('Patients', 'Species', '9606', (0, 8))	('0-140', 'Var', (93, 98))	('BMPRIB', 'Gene', (106, 112))	('BMPRIB', 'Gene', '658', (106, 112))	('BMPRIB', 'Gene', '658', (62, 68))	('141-200', 'Var', (125, 132))	('BMPRIB', 'Gene', (62, 68))	('low', 'NegReg', (70, 73))
142570	19194754	Lymphedema developed in 7% of the 319 patients who underwent SLNB and 21% of the 759 patients who underwent ALND.	('SLNB', 'Var', (61, 65))	('patients', 'Species', '9606', (85, 93))	('Lymphedema', 'Disease', 'MESH:D008209', (0, 10))	('edema', 'Phenotype', 'HP:0000969', (5, 10))	('patients', 'Species', '9606', (38, 46))	('Lymphedema', 'Phenotype', 'HP:0001004', (0, 10))	('Lymphedema', 'Disease', (0, 10))
142656	19194754	However, adjusting for the number of lymph nodes removed as part of their surgical treatment and lymph node status, women with DCIS had the same risk of developing lymphedema as invasive cancer patients (Table 2).	('DCIS', 'Var', (127, 131))	('patients', 'Species', '9606', (194, 202))	('lymphedema', 'Phenotype', 'HP:0001004', (164, 174))	('edema', 'Phenotype', 'HP:0000969', (169, 174))	('invasive cancer', 'Disease', (178, 193))	('women', 'Species', '9606', (116, 121))	('invasive cancer', 'Disease', 'MESH:D009362', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('lymphedema', 'Disease', (164, 174))	('lymphedema', 'Disease', 'MESH:D008209', (164, 174))
142664	19194754	Of note, though, is our finding that the removal of only 6-10 lymph nodes is associated with a substantial risk of lymphedema (OR 4.68, 95% CI 1.36-16.08).	('removal', 'Var', (41, 48))	('lymphedema', 'Disease', 'MESH:D008209', (115, 125))	('lymphedema', 'Phenotype', 'HP:0001004', (115, 125))	('edema', 'Phenotype', 'HP:0000969', (120, 125))	('lymphedema', 'Disease', (115, 125))
142693	19194754	However, after accounting for the number of lymph nodes removed as part of their surgical treatment and lymph node status, women with DCIS had the same risk of developing lymphedema as invasive cancer patients.	('patients', 'Species', '9606', (201, 209))	('edema', 'Phenotype', 'HP:0000969', (176, 181))	('DCIS', 'Var', (134, 138))	('lymphedema', 'Disease', (171, 181))	('invasive cancer', 'Disease', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lymphedema', 'Disease', 'MESH:D008209', (171, 181))	('women', 'Species', '9606', (123, 128))	('invasive cancer', 'Disease', 'MESH:D009362', (185, 200))	('lymphedema', 'Phenotype', 'HP:0001004', (171, 181))
142757	32333293	BRCA mutation carriers under the age of 40 may be considered for screening if delays of more than 6 months are expected.	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Gene', '672', (0, 4))
142783	32333293	Patients with ER + , HER2- tumors can defer surgery and receive neoadjuvant endocrine therapy for 6 to 12 months without clinical compromise (Priority B1).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Patients', 'Species', '9606', (0, 8))	('ER +', 'Var', (14, 18))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))
142788	32333293	Patients with Stage 1 or 2, HER2 + BCs may consider ado-trastuzumab emtansine (+- pertuzumab) with comparable efficacy to chemotherapy/trastuzumab-based regimens in either neoadjuvant or adjuvant settings (Priority B2) to minimize neutropenia, visits, and steroid-use.	('steroid', 'Chemical', 'MESH:D013256', (256, 263))	('HER2', 'Gene', '2064', (28, 32))	('ado-trastuzumab', 'Var', (52, 67))	('visits', 'Disease', (244, 250))	('neutropenia', 'Disease', (231, 242))	('Patients', 'Species', '9606', (0, 8))	('trastuzumab', 'Chemical', 'MESH:D000068878', (56, 67))	('BC', 'Phenotype', 'HP:0003002', (35, 37))	('pertuzumab', 'Chemical', 'MESH:C485206', (82, 92))	('ado-trastuzumab', 'Chemical', 'MESH:C550911', (52, 67))	('emtansine', 'Chemical', 'MESH:D008453', (68, 77))	('HER2', 'Gene', (28, 32))	('trastuzumab', 'Chemical', 'MESH:D000068878', (135, 146))	('neutropenia', 'Phenotype', 'HP:0001875', (231, 242))	('neutropenia', 'Disease', 'MESH:D009503', (231, 242))
142880	27562113	Moreover, survival analyses showed that DFS and 10-year OS rates were significantly lower in breast cancer patients with high Tiam1 expression than those with low Tiam1 expression.	('expression', 'Var', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('DFS', 'CPA', (40, 43))	('breast cancer', 'Disease', (93, 106))	('lower', 'NegReg', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('Tiam1', 'Gene', (126, 131))	('high', 'Var', (121, 125))	('patients', 'Species', '9606', (107, 115))
142895	27562113	Overexpression of Tiam1 protein participates in many processes underpinning tumor progression, including apoptosis, lymphangiogenesis, invasion and migration.	('Tiam1', 'Gene', (18, 23))	('protein', 'Protein', (24, 31))	('migration', 'CPA', (148, 157))	('apoptosis', 'CPA', (105, 114))	('participates', 'Reg', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Overexpression', 'Var', (0, 14))	('lymphangiogenesis', 'CPA', (116, 133))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('invasion', 'CPA', (135, 143))
142922	27562113	The proportion of samples with high Tiam1 expression was 76.5 % (117/153) in breast cancer; it was significantly higher than in DCIS (51.1 %, 35/67) or adjacent non-tumor tissues (28.6 %, 18/63).	('breast cancer', 'Disease', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('expression', 'MPA', (42, 52))	('higher', 'PosReg', (113, 119))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Tiam1', 'Gene', (36, 41))	('high', 'Var', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('tumor', 'Disease', (165, 170))
142929	27562113	In addition, Tiam1 was significantly higher in breast cancers with high Ki-67 expression (50.0 %, 51/102) than in cases with low Ki-67 expression (27.5 %, 14/51) (P = 0.008).	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('high', 'Var', (67, 71))	('higher', 'PosReg', (37, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('Ki-67', 'Gene', (72, 77))	('expression', 'Var', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancers', 'Phenotype', 'HP:0003002', (47, 61))	('Tiam1', 'Gene', (13, 18))	('breast cancers', 'Disease', 'MESH:D001943', (47, 61))	('breast cancers', 'Disease', (47, 61))
142932	27562113	We found that breast cancer patients with high Tiam1 expression had lower DFS and 10-year OS (P = 0.003, respectively) rates than those with low Tiam1 expression (Fig.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('DFS', 'MPA', (74, 77))	('lower', 'NegReg', (68, 73))	('expression', 'Var', (53, 63))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('Tiam1', 'Gene', (47, 52))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))
142934	27562113	In early-stage breast cancers, patients with low-level Tiam1 expression had higher DFS and OS rates compared with those with high-level Tiam1 expression (P = 0.021 and P = 0.043, respectively).	('low-level', 'Var', (45, 54))	('DFS', 'CPA', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('Tiam1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('expression', 'Var', (61, 71))	('breast cancers', 'Phenotype', 'HP:0003002', (15, 29))	('patients', 'Species', '9606', (31, 39))	('breast cancers', 'Disease', 'MESH:D001943', (15, 29))	('higher', 'PosReg', (76, 82))	('breast cancers', 'Disease', (15, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
142936	27562113	Univariate analysis demonstrated that breast cancer patients with high Tiam1 expression had significantly lower DFS and 10-year OS rates than those with low Tiam1 expression tumors.	('lower', 'NegReg', (106, 111))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('Tiam1', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('DFS', 'CPA', (112, 115))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('10-year OS rates', 'CPA', (120, 136))
142941	27562113	Importantly, high Tiam1 expression also emerged as a significant independent prognostic factor for DFS (HR: 1.470, 95 % CI: 1.056-2.047, P = 0.022) and 10-year OS (HR: 1.549, 95 % CI: 1.112-2.157, P = 0.010) in patients with breast cancer (Table 3).	('Tiam1', 'Gene', (18, 23))	('DFS', 'Disease', (99, 102))	('patients', 'Species', '9606', (211, 219))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))
142975	27562113	In regards to survival, we found that high expression of Tiam1 protein was strongly associated with molecular subtype and tumor stage, which were important features associated with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('protein', 'Protein', (63, 70))	('high', 'Var', (38, 42))	('breast cancer', 'Disease', (199, 212))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('Tiam1', 'Gene', (57, 62))	('associated', 'Reg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
142985	27562113	In part, this may be due to Tiam1's ability to regulate E-cadherin expression, since loss of E-cadherin expression is considered to be a signature event in Epithelial-Mesenchymal transition (EMT), which is the reverse process of MET and has a pivotal role in cancer invasion and metastasis.	('loss', 'Var', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Epithelial-Mesenchymal transition', 'CPA', (156, 189))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))	('cancer', 'Disease', (259, 265))
142987	27562113	Therefore, these data suggest that altered Tiam1 expression patterns might regulate a certain signaling pathway to play a key role in cancer invasion and metastasis.	('altered', 'Var', (35, 42))	('signaling pathway', 'Pathway', (94, 111))	('regulate', 'Reg', (75, 83))	('cancer', 'Disease', (134, 140))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Tiam1', 'Gene', (43, 48))
142997	21421520	On univariate analysis, patients undergoing MRI were younger (50 years vs. 59 years; P < .001) and had larger DCIS size on final pathology (1.6 cm vs. 1.0 cm; P = .007) than those without MRI.	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('DCIS', 'MPA', (110, 114))	('patients', 'Species', '9606', (24, 32))	('larger', 'PosReg', (103, 109))	('MRI', 'Var', (44, 47))
143020	21421520	Women who underwent preoperative MRI were significantly younger (50 years vs. 59 years; P < .001) and had larger DCIS size (1.6 cm vs. 1.0 cm; P = .007) compared with those without preoperative MRI.	('larger', 'PosReg', (106, 112))	('Women', 'Species', '9606', (0, 5))	('MRI', 'Var', (33, 36))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
143031	21421520	On multivariable analysis including MRI, age at diagnosis, multifocality, family history, and DCIS size, use of MRI was found to be an independent predictor for mastectomy; women who had preoperative MRI were more likely to choose mastectomy than women without MRI (OR, 3.2; 95% CI, 1.22-8.18).	('women', 'Species', '9606', (173, 178))	('mastectomy', 'Disease', (161, 171))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))	('MRI', 'Var', (200, 203))	('women', 'Species', '9606', (247, 252))	('mastectomy', 'Disease', (231, 241))
143039	21421520	These results indicate that the rates of mastectomy and SLNB were significantly higher among women who underwent preoperative MRI than those without preoperative MRI.	('preoperative MRI', 'Var', (113, 129))	('MRI', 'Var', (126, 129))	('mastectomy', 'Disease', (41, 51))	('higher', 'PosReg', (80, 86))	('women', 'Species', '9606', (93, 98))	('SLNB', 'Disease', (56, 60))
143040	21421520	In a multivariable analysis of factors associated with mastectomy, we found that women who received preoperative MRI were more likely to undergo mastectomy than their counterparts who did not receive preoperative MRI.	('women', 'Species', '9606', (81, 86))	('mastectomy', 'Disease', (145, 155))	('MRI', 'Var', (113, 116))
143082	25884667	In addition to the degree of immune cell infiltration, the presence of TLS was associated with organized immune cell aggregates, hormone receptor status and tumor grade.	('tumor', 'Disease', (157, 162))	('associated', 'Reg', (79, 89))	('TLS', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('rat', 'Species', '10116', (47, 50))	('hormone receptor', 'Gene', (129, 145))	('organized immune cell aggregates', 'CPA', (95, 127))	('hormone receptor', 'Gene', '3164', (129, 145))	('presence', 'Var', (59, 67))
143084	25884667	The model also predicted that the odds for having intratumoral TLS formation were ten times higher for patients with high grade of inflammation than low grade.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('higher', 'PosReg', (92, 98))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('rat', 'Species', '10116', (53, 56))	('high grade', 'Var', (117, 127))	('patients', 'Species', '9606', (103, 111))
143085	25884667	Human breast carcinomas frequently contain TLS and the presence of these structures is associated with aggressive forms of tumors.	('Human', 'Species', '9606', (0, 5))	('presence', 'Var', (55, 63))	('breast carcinomas', 'Disease', 'MESH:D001943', (6, 23))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinomas', 'Disease', (6, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('TLS', 'MPA', (43, 46))	('aggressive forms of tumors', 'Disease', 'MESH:D001523', (103, 129))	('associated', 'Reg', (87, 97))	('breast carcinomas', 'Phenotype', 'HP:0003002', (6, 23))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('aggressive forms of tumors', 'Disease', (103, 129))	('breast carcinoma', 'Phenotype', 'HP:0003002', (6, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))
143121	25884667	Tumors demonstrating HER2 protein overexpression or amplified HER2 gene (IHC 3+ or FISH HER2 gene ratio >=2) were considered to be positive.	('amplified', 'Var', (52, 61))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HER2 protein', 'Protein', (21, 33))	('HER2 gene', 'Gene', (62, 71))	('overexpression', 'PosReg', (34, 48))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('rat', 'Species', '10116', (98, 101))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rat', 'Species', '10116', (14, 17))
143237	21125683	The cells with advantageous genetic and epigenetic alterations are selected over time to contribute to tumor progression.	('epigenetic alterations', 'Var', (40, 62))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
143245	21125683	It has been further proposed that such molecular alterations result in deregulation of normal self-renewal leading to the development of a cancer stem cell (cSC).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('alterations', 'Var', (49, 60))	('normal self-renewal', 'CPA', (87, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('deregulation', 'MPA', (71, 83))	('cancer', 'Disease', (139, 145))
143249	21125683	in a series of elegant experiments provide functional and molecular evidence that progenitor cells within the luminal compartment of the human breast represent a cancer initiating population in BRCA1 mutation carriers and possibly other basal subtype breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('human', 'Species', '9606', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', (162, 168))	('BRCA1', 'Gene', '672', (194, 199))	('breast tumors', 'Phenotype', 'HP:0100013', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BRCA1', 'Gene', (194, 199))	('breast tumors', 'Disease', (251, 264))	('breast tumors', 'Disease', 'MESH:D001943', (251, 264))	('mutation', 'Var', (200, 208))
143287	21125683	Similar to that observed for IDC, several comparative genomic-based studies have revealed that DCIS is a genetically advanced process and that distinct patterns of genomic alterations in DCIS are associated with tumor grade.	('DCIS', 'Gene', (187, 191))	('associated', 'Reg', (196, 206))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('DCIS', 'Disease', (95, 99))	('tumor', 'Disease', (212, 217))	('alterations', 'Var', (172, 183))
143307	21125683	Significant alterations in gene expression patterns in the non-epithelial compartment of the tumor microenvironment in conjunction with lack of clonally restricted genetic changes in the same cells suggest that epigenetic modifications may be responsible for such gene expression patterns.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alterations', 'Reg', (12, 23))	('tumor', 'Disease', (93, 98))	('gene expression patterns', 'MPA', (27, 51))	('epigenetic modifications', 'Var', (211, 235))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
143309	21125683	Independently, Fiegl and colleagues have confirmed the observation that tumor-associated stroma cells display epigenetic alterations and that the frequency of such epigenetic modifications is greater in HER2 positive than in HER2 negative tumors.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('epigenetic alterations', 'MPA', (110, 132))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('HER2', 'Gene', (225, 229))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', (72, 77))	('HER2', 'Gene', '2064', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (239, 244))	('HER2', 'Gene', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('positive', 'Var', (208, 216))	('HER2', 'Gene', '2064', (203, 207))
143312	21125683	These two pathways are defined at the genetic level by either the presence or absence of chromosome 1q, 16q, 13q, gain of chromosomal region 11q13 and amplification of the 17q12, and these pathways also strongly correlate with the transcriptomic equivalent of tumor grade/proliferation.	('tumor', 'Disease', (260, 265))	('absence', 'NegReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('gain', 'PosReg', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('amplification', 'Var', (151, 164))
143321	21125683	The results of this array-CGH-based study demonstrate that some breast cancers are composed of different "non-modal" clones that possess distinct genetic alterations and that these alterations may underpin morphological heterogeneity within a tumor.	('alterations', 'Var', (181, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancers', 'Disease', 'MESH:D001943', (64, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('breast cancers', 'Disease', (64, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))	('underpin', 'Reg', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
143324	21125683	Although most of the original mutations present in the primary tumor are carried forward during progression, additional somatic coding changes were identified in patient-matched metastatic breast cancer samples in both studies.	('tumor', 'Disease', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (30, 39))	('patient', 'Species', '9606', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
143325	21125683	Altogether these studies support the clonal evolution model in which the acquisition of genetic alterations under selective pressure is associated with progression from invasive to metastatic breast cancer.	('invasive', 'Disease', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('genetic alterations', 'Var', (88, 107))	('acquisition', 'Var', (73, 84))	('associated with', 'Reg', (136, 151))
143334	29805754	Levels of miR-126 and miR-218 are elevated in ductal carcinoma in situ (DCIS) and inhibit malignant potential of DCIS derived cells A substantial number of ductal carcinoma in situ (DCIS) detected by mammography never progress to invasive ductal carcinoma (IDC) and current approaches fail to identify low-risk patients not at need of adjuvant therapies.	('ductal carcinoma in situ', 'Disease', (156, 180))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (46, 70))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (239, 255))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (53, 70))	('miR-218', 'Var', (22, 29))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (46, 62))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (156, 180))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (163, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('miR-126', 'Gene', (10, 17))	('elevated', 'PosReg', (34, 42))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (46, 70))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (156, 172))	('IDC', 'Gene', '4000', (257, 260))	('IDC', 'Gene', (257, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('malignant potential of DCIS', 'CPA', (90, 117))	('ductal carcinoma in situ', 'Disease', (46, 70))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (156, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('inhibit', 'NegReg', (82, 89))	('miR-126', 'Gene', '406913', (10, 17))	('patients', 'Species', '9606', (311, 319))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (230, 255))	('invasive ductal carcinoma', 'Disease', (230, 255))
143339	29805754	We propose that miR-126 and miR-218 have a protective role in DCIS and represent novel biomarkers for the risk assessment in women with early detection of breast cancer.	('DCIS', 'Disease', (62, 66))	('miR-218', 'Var', (28, 35))	('protective', 'NegReg', (43, 53))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('miR-126', 'Gene', '406913', (16, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('miR-126', 'Gene', (16, 23))	('women', 'Species', '9606', (125, 130))
143346	29805754	An intra-tumor genetic heterogeneity was also observed in adjacent DCIS and IDC, indicating that tumor cells with specific genetic and/or epigenetic variants may be selected during progression.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('intra-tumor', 'Disease', (3, 14))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (9, 14))	('intra-tumor', 'Disease', 'MESH:D009369', (3, 14))	('adjacent DCIS', 'Disease', (58, 71))	('IDC', 'Gene', '4000', (76, 79))	('epigenetic variants', 'Var', (138, 157))	('IDC', 'Gene', (76, 79))
143350	29805754	MiRNAs control many cancer hallmarks such as proliferation, growth suppression, cell death, angiogenesis, invasion and metastasis, but also genome instability and inflammation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('growth suppression', 'CPA', (60, 78))	('MiRNAs', 'Var', (0, 6))	('inflammation', 'Disease', (163, 175))	('angiogenesis', 'CPA', (92, 104))	('genome instability', 'CPA', (140, 158))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('metastasis', 'CPA', (119, 129))	('invasion', 'CPA', (106, 114))	('cancer', 'Disease', (20, 26))	('control', 'Reg', (7, 14))	('cell death', 'CPA', (80, 90))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))
143356	29805754	miR-125b, miR-126, miR-218 and miR-195 were over-expressed in DCIS vs. IDC (P < 0.001) and their over-expression was confirmed in the small Farazi DCIS cohort (P < 0.001) (Figure 1A).	('over-expressed', 'PosReg', (44, 58))	('miR-195', 'Gene', (31, 38))	('IDC', 'Gene', (71, 74))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('miR-125b', 'Gene', (0, 8))	('miR-195', 'Gene', '406971', (31, 38))	('miR-126', 'Gene', '406913', (10, 17))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('miR-126', 'Gene', (10, 17))	('IDC', 'Gene', '4000', (71, 74))	('miR-218', 'Var', (19, 26))
143357	29805754	Among these miRNAs we successfully cross-validated miR-126 and miR-218 when using the samples from the Norway study by Sorlie and coworkers (Supplementary Figure 1).	('miR-218', 'Var', (63, 70))	('miR-126', 'Gene', (51, 58))	('miR-126', 'Gene', '406913', (51, 58))
143359	29805754	We then studied the levels of validated miR-126 and miR-218 in patients with DCIS adjacent to invasive carcinoma (Figure 1B).	('miR-218', 'Var', (52, 59))	('invasive carcinoma', 'Disease', (94, 112))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))	('patients', 'Species', '9606', (63, 71))	('miR-126', 'Gene', '406913', (40, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('miR-126', 'Gene', (40, 47))	('invasive carcinoma', 'Disease', 'MESH:D009361', (94, 112))
143362	29805754	Two miRNAs often lost in breast cancer, miR-125b and miR-195, were also included in the assay.	('miR-125b', 'Var', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR-195', 'Gene', (53, 60))	('miR-195', 'Gene', '406971', (53, 60))
143363	29805754	The levels of the epithelial marker E-cadherin were significantly reduced (P = 0.008) by miR-126 inhibitor and were increased by the over-expression of either miR-126 (P = 0.003) or miR-218 (P = 0.02).	('over-expression', 'PosReg', (133, 148))	('reduced', 'NegReg', (66, 73))	('miR-218', 'Var', (182, 189))	('miR-126', 'Gene', (89, 96))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('miR-126', 'Gene', '406913', (159, 166))	('miR-126', 'Gene', (159, 166))	('increased', 'PosReg', (116, 125))	('miR-126', 'Gene', '406913', (89, 96))
143365	29805754	As visualized by plotting the E-cadherin/Vimentin ratio, high levels of miR-126 and miR-218 led to the prevalent expression of the epithelial marker while their inhibition promoted the predominance of the mesenchymal marker (Figure 2C).	('miR-218', 'Var', (84, 91))	('expression', 'MPA', (113, 123))	('Vimentin', 'Gene', '7431', (41, 49))	('miR-126', 'Gene', '406913', (72, 79))	('E-cadherin', 'Gene', (30, 40))	('miR-126', 'Gene', (72, 79))	('E-cadherin', 'Gene', '999', (30, 40))	('mesenchymal marker', 'CPA', (205, 223))	('promoted', 'PosReg', (172, 180))	('inhibition', 'NegReg', (161, 171))	('epithelial marker', 'Protein', (131, 148))	('Vimentin', 'Gene', (41, 49))
143367	29805754	xCELLigence real-time analysis on MCF10DCIS cells in which each miRNA was modulated showed that the inhibitors of miR-126 or miR-218 increased the invasion rate through Matrigel (P = 0.03, P = 0.04, respectively) while their mimics had the opposite effect (P = 0.04, P = 0.03, respectively) (Figure 3A, Supplementary Figure 2B).	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('increased', 'PosReg', (133, 142))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (34, 43))	('invasion rate through Matrigel', 'CPA', (147, 177))	('miR-126', 'Gene', '406913', (114, 121))	('miR-218', 'Var', (125, 132))	('miR-126', 'Gene', (114, 121))
143369	29805754	Finally, invasiveness was not influenced by co-treatment with inhibitors of other down-regulated miRNAs in IDC such as miR-125b or miR-195 (Figure 3B).	('miR-125b', 'Var', (119, 127))	('down-regulated', 'NegReg', (82, 96))	('miR-195', 'Gene', (131, 138))	('miR-195', 'Gene', '406971', (131, 138))	('IDC', 'Gene', '4000', (107, 110))	('IDC', 'Gene', (107, 110))
143370	29805754	The effects of miR-126 and miR-218 on cell invasion were evaluated in the low invasive BT-474 and in the highly invasive MDA-MB-231 cells, demonstrating that inhibition of each of the two miRNAs increased the ability of both cell lines to pass through Matrigel, while the use of mimics significantly reduced the invasiveness of the MDA-MB-231 cells (Figure 3C).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (332, 342))	('miR-126', 'Gene', (15, 22))	('reduced', 'NegReg', (300, 307))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (121, 131))	('inhibition', 'Var', (158, 168))	('invasiveness', 'CPA', (312, 324))	('increased', 'PosReg', (195, 204))	('miR-126', 'Gene', '406913', (15, 22))	('pass through Matrigel', 'CPA', (239, 260))
143375	29805754	Again, the levels of miR-126 and miR-218 were significantly higher (P = 0.002, P = 0.0012, respectively) in indolent DCIS (Figure 4A).	('higher', 'PosReg', (60, 66))	('miR-126', 'Gene', '406913', (21, 28))	('miR-126', 'Gene', (21, 28))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('miR-218', 'Var', (33, 40))
143378	29805754	To further investigate the clinical relevance of miR-126 and miR-218 in BC, we measured their association with prognosis in three well-characterized IDC cohorts: TCGA (n = 918), METABRIC (n = 796), and UK cohort from Oxford (n = 210).	('miR-218', 'Var', (61, 68))	('miR-126', 'Gene', '406913', (49, 56))	('association', 'Interaction', (94, 105))	('miR-126', 'Gene', (49, 56))	('IDC', 'Gene', '4000', (149, 152))	('BC', 'Phenotype', 'HP:0003002', (72, 74))	('IDC', 'Gene', (149, 152))
143382	29805754	The protein coding genes correlated with miR-126 and miR-218 in BC were identified using Spearman correlation, and cross-validation in METABRIC, TCGA, and UK breast cancer cohorts.	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('miR-126', 'Gene', '406913', (41, 48))	('BC', 'Phenotype', 'HP:0003002', (64, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('miR-126', 'Gene', (41, 48))	('miR-218', 'Var', (53, 60))
143383	29805754	High miR-126 and miR-218 were associated with cell adhesion, with miR-218 impacting on the Wnt, Notch, cadherin and integrin signaling pathways.	('associated', 'Reg', (30, 40))	('miR-126', 'Gene', (5, 12))	('integrin signaling pathways', 'Pathway', (116, 143))	('impacting', 'Reg', (74, 83))	('miR-218', 'Var', (17, 24))	('miR-218', 'Var', (66, 73))	('cell adhesion', 'CPA', (46, 59))	('Wnt', 'Pathway', (91, 94))	('miR-126', 'Gene', '406913', (5, 12))	('Notch', 'Pathway', (96, 101))
143384	29805754	Lack of miR-126 or miR-218, on the other hand was associated with cell proliferation and mitosis.	('Lack', 'NegReg', (0, 4))	('cell proliferation', 'CPA', (66, 84))	('mitosis', 'Disease', (89, 96))	('mitosis', 'Disease', 'None', (89, 96))	('miR-126', 'Gene', '406913', (8, 15))	('associated', 'Reg', (50, 60))	('miR-126', 'Gene', (8, 15))	('miR-218', 'Var', (19, 26))
143392	29805754	Most importantly, we detected high miR-126 and miR-218 in pure DCIS with no concomitant invasive lesions, but not in DCIS with adjacent IDC.	('miR-218', 'Var', (47, 54))	('miR-126', 'Gene', '406913', (35, 42))	('IDC', 'Gene', '4000', (136, 139))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('pure DCIS', 'Disease', (58, 67))	('IDC', 'Gene', (136, 139))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('miR-126', 'Gene', (35, 42))
143394	29805754	Thus, our findings, although obtained from relatively small DCIS cohorts, strongly indicate that high levels of miR-126 and miR-218 at diagnosis characterize low-risk DCIS.	('miR-126', 'Gene', '406913', (112, 119))	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('miR-126', 'Gene', (112, 119))	('low-risk', 'Disease', (158, 166))	('miR-218', 'Var', (124, 131))	('DCIS', 'Disease', (167, 171))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
143395	29805754	The presence of miR-126 and miR-218 was also associated with better prognosis in three large cohorts of patients with invasive breast cancer, reiterating that these miRNAs down-modulate malignant properties, as shown in vitro for breast and other solid cancers.	('better', 'PosReg', (61, 67))	('invasive breast cancer', 'Disease', 'MESH:D001943', (118, 140))	('malignant properties', 'CPA', (186, 206))	('breast', 'Disease', (230, 236))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('miR-218', 'Var', (28, 35))	('down-modulate', 'NegReg', (172, 185))	('patients', 'Species', '9606', (104, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('invasive breast cancer', 'Disease', (118, 140))	('solid cancers', 'Disease', (247, 260))	('miR-126', 'Gene', '406913', (16, 23))	('presence', 'Var', (4, 12))	('miR-126', 'Gene', (16, 23))	('solid cancers', 'Disease', 'MESH:D009369', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
143402	29805754	Using these models we revealed that miR-126 and miR-218 individually affect the invasion potential of these different cell lines.	('miR-126', 'Gene', (36, 43))	('affect', 'Reg', (69, 75))	('invasion potential of these', 'CPA', (80, 107))	('miR-218', 'Var', (48, 55))	('miR-126', 'Gene', '406913', (36, 43))
143406	29805754	Thus we investigated miR-126 or miR-218 for their ability to affect this process in non-invasive BC cells.	('miR-126', 'Gene', '406913', (21, 28))	('miR-126', 'Gene', (21, 28))	('BC', 'Phenotype', 'HP:0003002', (97, 99))	('affect', 'Reg', (61, 67))	('miR-218', 'Var', (32, 39))
143408	29805754	Both in vitro assays and Gene Ontology analysis of patient samples highlighted the role of miR-126 and miR-218 in invasion.	('miR-126', 'Gene', (91, 98))	('miR-218', 'Var', (103, 110))	('patient', 'Species', '9606', (51, 58))	('invasion', 'CPA', (114, 122))	('miR-126', 'Gene', '406913', (91, 98))
143429	29805754	RNA was reverse-transcribed for miR-126 and miR-218 using the TaqMan MicroRNA RT kit (Applied Biosystems).	('miR-126', 'Gene', '406913', (32, 39))	('miR-218', 'Var', (44, 51))	('miR-126', 'Gene', (32, 39))
143442	29805754	To pinpoint the cellular roles of miR-126 and miR-218 in breast cancer, we performed a Gene Ontology analysis of the correlated gene sets using the Panther Classification System (as described in Supplementary Materials).	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('miR-126', 'Gene', '406913', (34, 41))	('miR-126', 'Gene', (34, 41))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('miR-218', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
143523	26146825	The antibodies used were anti-pSTAT5 (9359, 1:500, Cell Signaling), anti-pSTAT3 (9145, 1:500, Cell Signaling), and anti-Ki67 (2011-11, 1:500, Novocastra), and were incubated at 4 C overnight.	('Ki67', 'Chemical', '-', (120, 124))	('9359', 'Var', (38, 42))	('9145', 'Var', (81, 85))
143546	26146825	We have previously reported preclinical evidence that blockade of STAT5 activity can prevent breast cancer.	('blockade', 'Var', (54, 62))	('STAT5 activity', 'Protein', (66, 80))	('prevent', 'NegReg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
143547	26146825	Therefore, the observations in this study suggest that prophylactic therapy targeting STAT5 and STAT3 in high-risk women may also lower their breast cancer risk.	('lower', 'NegReg', (130, 135))	('STAT3', 'Gene', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('women', 'Species', '9606', (115, 120))	('STAT5', 'Var', (86, 91))
143585	28004220	Using SEER data, women were classified as having DCIS (stage 0) (with almost no risk of distant recurrence) or low risk invasive breast cancer (with <10% actual risk of distant recurrence); stage 1A, ER+, HER2-, tumor grade 1-2, and either having a 21-gene assay test result of 0-10, or the result was not indicated.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('DCIS', 'Disease', (49, 53))	('HER2', 'Gene', (205, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('HER2', 'Gene', '2064', (205, 209))	('invasive breast cancer', 'Disease', 'MESH:D001943', (120, 142))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('ER+', 'Var', (200, 203))	('women', 'Species', '9606', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))	('invasive breast cancer', 'Disease', (120, 142))
143621	28004220	Our study revealed associations between overestimation and reduced physical and mental health, using validated PROMIS QoL measures, and more frequent patient self-reported worry about recurrence.	('reduced', 'NegReg', (59, 66))	('patient', 'Species', '9606', (150, 157))	('overestimation', 'Var', (40, 54))
143647	25204426	WNT5A overexpression also increased RHOA expression of both cell lines and subsequent RHOA knockdown blocked WNT5A-induced migration, but only partially blocked WNT5A-induced invasion of 21NT cells.	('RHOA', 'Gene', '387', (36, 40))	('blocked', 'NegReg', (101, 108))	('RHOA', 'Gene', (36, 40))	('knockdown', 'Var', (91, 100))	('RHOA', 'Gene', (86, 90))	('increased', 'PosReg', (26, 35))	('rat', 'Species', '10116', (126, 129))	('migration', 'CPA', (123, 132))	('RHOA', 'Gene', '387', (86, 90))
143650	25204426	VANGL1 knockdown inhibited WNT5A-induced invasion of 21NT cells, but had no effect on WNT5A-induced migration of either 21PT or 21NT cells.	('rat', 'Species', '10116', (103, 106))	('VANGL1', 'Gene', (0, 6))	('invasion', 'CPA', (41, 49))	('inhibited', 'NegReg', (17, 26))	('knockdown', 'Var', (7, 16))
143663	25204426	Activation of Fzd7 in particular has been shown to promote invasion of colon carcinoma and migration of hepatocellular carcinoma cells.	('Fzd7', 'Gene', (14, 18))	('rat', 'Species', '10116', (94, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (104, 128))	('hepatocellular carcinoma', 'Disease', (104, 128))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (104, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('promote', 'PosReg', (51, 58))	('Activation', 'Var', (0, 10))	('Fzd7', 'Gene', '8324', (14, 18))	('migration', 'CPA', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('colon carcinoma', 'Disease', 'MESH:D015179', (71, 86))	('colon carcinoma', 'Disease', (71, 86))	('invasion', 'CPA', (59, 67))
143670	25204426	VANGL1 overexpression also increases invasion and migration of squamous carcinoma cells in vitro and promotes metastasis in a mouse squamous tumor model in vivo.	('mouse', 'Species', '10090', (126, 131))	('promotes', 'PosReg', (101, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('invasion', 'CPA', (37, 45))	('overexpression', 'Var', (7, 21))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('increases', 'PosReg', (27, 36))	('metastasis', 'CPA', (110, 120))	('squamous tumor', 'Phenotype', 'HP:0002860', (132, 146))	('VANGL1', 'Gene', (0, 6))	('rat', 'Species', '10116', (53, 56))	('squamous tumor', 'Disease', 'MESH:D002294', (132, 146))	('squamous carcinoma', 'Disease', 'MESH:D002294', (63, 81))	('squamous carcinoma', 'Disease', (63, 81))	('squamous tumor', 'Disease', (132, 146))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (63, 81))
143675	25204426	For example, disruption of WNT5A expression with a WNT5A antisense expression vector has been found to mimic transformation caused by Wnt1 in the mouse mammary epithelial cell line C57MG, suggesting that WNT5A is an important regulator of cell growth and differentiation of these cells.	('WNT5A', 'Gene', (27, 32))	('Wnt1', 'Gene', '22408', (134, 138))	('disruption', 'Var', (13, 23))	('mouse', 'Species', '10090', (146, 151))	('Wnt1', 'Gene', (134, 138))
143711	25204426	RHOA expression was increased by 1.75-fold in WNT5A transfected 21PT cells (P < 0.01) (Figure 4A left panel), and by 1.77-fold in WNT5A transfected 21NT cells (P < 0.01) (Figure 4B left panel).	('RHOA', 'Gene', (0, 4))	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (5, 15))	('transfected', 'Var', (52, 63))	('RHOA', 'Gene', '387', (0, 4))
143713	25204426	In RHOA knockdowns of both WNT5A transfected 21PT and 21NT cells, RHOA expression was decreased to a level significantly less that of the off target (luciferase) knockdown control, to a level similar to, or lower than that of non-WNT5A transfected (empty vector control) cells (Figure 4A and B left panels).	('RHOA', 'Gene', (3, 7))	('less', 'NegReg', (121, 125))	('expression', 'MPA', (71, 81))	('RHOA', 'Gene', (66, 70))	('decreased', 'NegReg', (86, 95))	('transfected', 'Var', (33, 44))	('RHOA', 'Gene', '387', (3, 7))	('RHOA', 'Gene', '387', (66, 70))
143714	25204426	To assess the change in migration due to RHOA knockdown in 21PT + WNT5A and 21NT + WNT5A cells, transwell migration assays were used.	('RHOA', 'Gene', (41, 45))	('knockdown', 'Var', (46, 55))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (27, 30))	('RHOA', 'Gene', '387', (41, 45))	('migration', 'MPA', (24, 33))
143716	25204426	RHOA knockdown decreased migration of 21PT + WNT5A cells from 59.3 (SE 9.53) cells per field of view to 15.0 (SE 0.580) cells per field of view (P < 0.01), a level comparable to that of 21PT + EV (Figure 4A middle panel and Supplementary Figure S3).	('RHOA', 'Gene', (0, 4))	('migration', 'CPA', (25, 34))	('EV', 'Chemical', '-', (193, 195))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (15, 24))	('RHOA', 'Gene', '387', (0, 4))	('rat', 'Species', '10116', (28, 31))
143717	25204426	Similarly, RHOA knockdown decreased the migration of 21NT + WNT5A cells from 240 (SE 41.6) cells per field of view to 107 (SE 6.88) cells per field of view (P < 0.05), a level comparable to that of 21NT + EV (Figure 4B middle panel and Supplementary Figure S3).	('RHOA', 'Gene', (11, 15))	('EV', 'Chemical', '-', (205, 207))	('rat', 'Species', '10116', (43, 46))	('knockdown', 'Var', (16, 25))	('migration', 'CPA', (40, 49))	('decreased', 'NegReg', (26, 35))	('RHOA', 'Gene', '387', (11, 15))
143718	25204426	To assess the change in invasion due to RHOA knockdown in 21PT + WNT5A and 21NT + WNT5A cells, transwell invasion assays were again used.	('RHOA', 'Gene', (40, 44))	('knockdown', 'Var', (45, 54))	('RHOA', 'Gene', '387', (40, 44))
143721	25204426	In 21PT cells, VANGL1 mRNA levels remained unchanged after WNT5A overexpression (21PT + WNT5A + shScr vs. 21PT + EV + shScr), but were significantly reduced by 5.50-fold and 4.81-fold (P < 0.001) after VANGL1 knockdown (21PT + WNT5A + shVANGL1 vs. 21PT + EV + shScr and 21PT + WNT5A + shScr cells respectively (Figure 5A left panel)).	('VANGL1', 'Gene', (15, 21))	('VANGL1', 'Gene', (202, 208))	('reduced', 'NegReg', (149, 156))	('EV', 'Chemical', '-', (113, 115))	('mRNA levels', 'MPA', (22, 33))	('knockdown', 'Var', (209, 218))	('EV', 'Chemical', '-', (255, 257))
143722	25204426	In 21NT cells, VANGL1 mRNA levels were increased by 1.37-fold (P < 0.05) after WNT5A overexpression (21NT + WNT5A + shScr vs. 21NT + EV + shScr), and were significantly reduced by 3.26-fold and 4.47-fold (P < 0.01) after VANGL1 knockdown (21NT + WNT5A + shVANGL1 vs. 21NT + EV + shScr and 21NT + WNT5A + shScr cells respectively (Figure 5B left panel)).	('VANGL1', 'Gene', (15, 21))	('knockdown', 'Var', (228, 237))	('reduced', 'NegReg', (169, 176))	('EV', 'Chemical', '-', (274, 276))	('mRNA levels', 'MPA', (22, 33))	('increased', 'PosReg', (39, 48))	('EV', 'Chemical', '-', (133, 135))	('VANGL1', 'Gene', (221, 227))
143723	25204426	Transwell assays, performed as described above, were used to assess the change in migration and invasion due to VANGL1 knockdown in 21PT + WNT5A and 21NT + WNT5A cells.	('VANGL1', 'Gene', (112, 118))	('rat', 'Species', '10116', (85, 88))	('migration', 'CPA', (82, 91))	('invasion', 'CPA', (96, 104))	('knockdown', 'Var', (119, 128))
143724	25204426	VANGL1 knockdown did not significantly alter the migratory ability of either 21PT + WNT5A or 21NT + WNT5A cells (Figure 5A and B middle panels and Supplementary Figure S4), but did result in decreased cell invasion of both cell lines (Figure 5A and B right panels and Supplementary Figure S4).	('rat', 'Species', '10116', (52, 55))	('cell invasion', 'CPA', (201, 214))	('VANGL1', 'Gene', (0, 6))	('decreased', 'NegReg', (191, 200))	('knockdown', 'Var', (7, 16))
143728	25204426	Using real-time PCR and primers specific to COX-2, and MMP3, we found that WNT5A overexpression resulted in a 9.40-fold and 5.38-fold increase in COX-2 expression in 21PT and 21NT cells respectively (21PT + WNT5A + shScr vs. 21PT + EV + shScr and 21NT + WNT5A + shScr vs. 21NT + EV + shScr) (Figure 6A); however, VANGL1 knockdown did not alter the elevated levels of COX-2 present in either cell line overexpressing WNT5A (21PT + WNT5A + shVANGL1 vs. 21PT + WNT5A + shScr and 21NT + WNT5A + shVANGL1 vs. 21NT + WNT5A + shScr) (Figure 6A).	('EV', 'Chemical', '-', (279, 281))	('COX-2', 'Gene', (146, 151))	('MMP3', 'Gene', '4314', (55, 59))	('21PT + WNT5A + shVANGL1', 'Var', (423, 446))	('EV', 'Chemical', '-', (232, 234))	('COX-2', 'Gene', '4513', (44, 49))	('COX-2', 'Gene', (44, 49))	('COX-2', 'Gene', '4513', (367, 372))	('MMP3', 'Gene', (55, 59))	('COX-2', 'Gene', '4513', (146, 151))	('COX-2', 'Gene', (367, 372))
143731	25204426	In work not shown here, we found no change in MMP1 expression in either the 21PT or 21NT cells in response to WNT5A overexpression or with knockdown of VANGL1.	('MMP1', 'Gene', (46, 50))	('knockdown', 'Var', (139, 148))	('MMP1', 'Gene', '4312', (46, 50))	('VANGL1', 'Gene', (152, 158))
143740	25204426	Although VANGL1 knockdown in WNT5A overexpressing 21PT or 21NT did not significantly affect cell migration, cell invasiveness was markedly inhibited, suggesting a role for VANGL1 in the signaling involved in cell invasiveness.	('knockdown', 'Var', (16, 25))	('VANGL1', 'Gene', (9, 15))	('cell invasiveness', 'CPA', (108, 125))	('rat', 'Species', '10116', (100, 103))	('inhibited', 'NegReg', (139, 148))
143756	25204426	Interestingly, knockdown of Ryk but not Ror2 reduced WNT5A-induced invasion and MMP2 activity of the glioma cells.	('reduced', 'NegReg', (45, 52))	('knockdown', 'Var', (15, 24))	('invasion', 'CPA', (67, 75))	('glioma', 'Disease', (101, 107))	('Ryk', 'Gene', '6259', (28, 31))	('Ryk', 'Gene', (28, 31))	('MMP2', 'Gene', (80, 84))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('MMP2', 'Gene', '4313', (80, 84))
143786	25204426	To knockdown expression of RHOA and VANGL1 and to express ZsGreen for extravasation assay, cells were seeded into 6-well plates at a density of 5 x 104 cells per well into 2 mL of alphaHE10F.	('RHOA', 'Gene', (27, 31))	('alphaHE10F', 'Chemical', '-', (180, 190))	('RHOA', 'Gene', '387', (27, 31))	('knockdown', 'Var', (3, 12))	('VANGL1', 'Gene', (36, 42))
143845	23509716	Paired Ductal Carcinoma In Situ and Invasive Breast Cancer Lesions in the D-Loop of the Mitochondrial Genome Indicate a Cancerization Field Effect Alterations in the mitochondrial genome have been chronicled in most solid tumors, including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('Breast Cancer', 'Phenotype', 'HP:0003002', (45, 58))	('Alterations', 'Var', (147, 158))	('solid tumors', 'Disease', (216, 228))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', (240, 253))	('Carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('Ductal Carcinoma In Situ', 'Disease', (7, 31))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Ductal Carcinoma In Situ', 'Disease', 'MESH:D002285', (7, 31))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('Invasive Breast Cancer Lesions', 'Disease', 'MESH:D001943', (36, 66))	('solid tumors', 'Disease', 'MESH:D009369', (216, 228))	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (7, 31))	('Invasive Breast Cancer Lesions', 'Disease', (36, 66))
143846	23509716	The intent of this paper is to compare and document somatic mitochondrial D-loop mutations in paired samples of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) indicating a potential breast ductal epithelial cancerization field effect.	('invasive breast cancer', 'Disease', 'MESH:D001943', (148, 170))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (112, 136))	('ductal carcinoma in situ', 'Disease', (112, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (112, 136))	('invasive breast cancer', 'Disease', (148, 170))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('mitochondrial D-loop', 'Gene', (60, 80))	('mutations', 'Var', (81, 90))
143858	23509716	Alterations in the mitochondrial genome have been chronicled in most solid tumors, including breast cancer.	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('solid tumors', 'Disease', (69, 81))	('breast cancer', 'Disease', (93, 106))	('mitochondrial genome', 'Gene', (19, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
143861	23509716	There are other characteristics suggesting that the mtGenome may be an ideal "biosensor" as follows: (1) each copy of the mtGenome is clonal; (2) the mtGenome has a maternal inheritance pattern which precludes generational recombination; (3) somatic mutations appearing in a subset of mtGenomes, known as heteroplasmy, afford early disease detection; (4) the modest size of the mtGenome (16,568 bp) allows inexpensive, targeted, and concentrated genetic analyses; (5) the mtGenome has a 10-100-fold copy advantage over the nuclear genome; (6) the mitochondrial organelle is the center of ATP synthesis and is the mediator of cell apoptosis, and for successful tumorigenesis to occur, energy production must be replaced by an alternative process and apoptosis must be by-passed; (7) mitochondrial DNA (mtDNA) has an accelerated somatic mutation rate in which mutations occur within years, and perhaps months, from when molecular pathways are altered by early molecular changes associated with malignant transformation; (8) mutations in the mtGenome have been attested in a wide variety of solid tumors.	('tumor', 'Disease', 'MESH:D009369', (1094, 1099))	('solid tumors', 'Disease', 'MESH:D009369', (1088, 1100))	('tumor', 'Phenotype', 'HP:0002664', (660, 665))	('altered', 'Reg', (941, 948))	('tumor', 'Phenotype', 'HP:0002664', (1094, 1099))	('tumor', 'Disease', (660, 665))	('tumor', 'Disease', (1094, 1099))	('solid tumors', 'Disease', (1088, 1100))	('mutations', 'Var', (1022, 1031))	('mitochondrial DNA', 'Disease', (782, 799))	('molecular pathways', 'Pathway', (918, 936))	('tumors', 'Phenotype', 'HP:0002664', (1094, 1100))	('tumor', 'Disease', 'MESH:D009369', (660, 665))
143883	23509716	Primer set MT2/MT19 (15424-102) was used to generate template for nested amplification with D1 primers (15898-16525).	('MT2', 'Gene', '4502', (11, 14))	('MT1', 'Gene', (15, 18))	('MT2', 'Gene', (11, 14))	('MT1', 'Gene', '644314', (15, 18))	('15898-16525', 'Var', (104, 115))
143885	23509716	Analyses were performed on HV1 mutation patterns and all applicable parameters listed in the pathology report: age, receptor status, tumor grade, nuclear grade, tubule formation, mitotic score, modified Bloom-Richardson grade, and presence or absence of extensive intraductal component.	('nuclear grade', 'CPA', (146, 159))	('tubule formation', 'CPA', (161, 177))	('mitotic score', 'CPA', (179, 192))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('HV1', 'Gene', (27, 30))	('mutation', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))
143895	23509716	37.5% of the patients had this mutation in DCIS only, and 37.5% had this mutation in IBC exclusively.	('DCIS', 'Gene', (43, 47))	('patients', 'Species', '9606', (13, 21))	('mutation', 'Var', (31, 39))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
143896	23509716	Three other sites, 16223, 16270, and 16291, occur in 8 patients, 2 sites (16311, 16362) in 7 patients, 1 site (16390) in 6 patients, 1 site (16304) in 4 patients, 1 site (16126) in 3 patients, and 2 sites (16093 and 16298) in 2 patients.	('16093', 'Var', (206, 211))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (228, 236))	('16311', 'Var', (74, 79))	('16291', 'Var', (37, 42))	('16126', 'Var', (171, 176))	('16223', 'Var', (19, 24))	('patients', 'Species', '9606', (123, 131))	('16390', 'Var', (111, 116))	('patients', 'Species', '9606', (55, 63))	('16304', 'Var', (141, 146))	('16270', 'Var', (26, 31))	('patients', 'Species', '9606', (183, 191))
143897	23509716	Finally, 6 sites (16188, 16192, 16203, 16249, 16319, and 16357) are exclusive to 6 individual patients.	('16192', 'Var', (25, 30))	('16188', 'Var', (18, 23))	('patients', 'Species', '9606', (94, 102))	('16249', 'Var', (39, 44))	('16357', 'Var', (57, 62))
143900	23509716	Since sites such as 16189 and 16224 are present in almost every patient, they demonstrate near confluence in this small cohort.	('16224', 'Var', (30, 35))	('patient', 'Species', '9606', (64, 71))	('16189', 'Var', (20, 25))
143903	23509716	This idea is demonstrated in multiple matching heteroplasmic and homoplasmic changes in HV1 in corresponding patient-matched DCIS and IBC samples from 10 patients in the study.	('homoplasmic changes', 'Var', (65, 84))	('HV1', 'Gene', (88, 91))	('patient', 'Species', '9606', (109, 116))	('patient', 'Species', '9606', (154, 161))	('DCIS', 'Disease', (125, 129))	('patients', 'Species', '9606', (154, 162))	('IBC', 'Disease', (134, 137))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('heteroplasmic', 'Var', (47, 60))
143916	23509716	It has been reported that D-loop mutations are associated with tumors which are both estrogen and progesterone receptor negative in women 50 years of age or older.	('women', 'Species', '9606', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (63, 69))	('progesterone receptor', 'Gene', (98, 119))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('progesterone receptor', 'Gene', '5241', (98, 119))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))	('D-loop', 'Protein', (26, 32))
143918	23509716	Moreover, women with alterations in the D-loop experience poorer outcomes than those free of mutations.	('poorer', 'NegReg', (58, 64))	('women', 'Species', '9606', (10, 15))	('alterations', 'Var', (21, 32))
143919	23509716	This suggests that HV1 mutations found in both DCIS and IBC, when found in patients with DICS only, may be indicators of DCIS with potential aggressive behavior.	('HV1', 'Gene', (19, 22))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('DCIS', 'Disease', (121, 125))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (23, 32))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('DCIS', 'Disease', (47, 51))	('IBC', 'Disease', (56, 59))	('aggressive behavior', 'Phenotype', 'HP:0000718', (141, 160))
143927	23509716	This study was able to identify mtGenome alterations that occur in both DCIS and IBC within individual patients that are suggestive of a cancerization field effect, and DCIS that may be aggressive in nature.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('IBC', 'Disease', (81, 84))	('DCIS', 'Disease', (72, 76))	('mtGenome', 'Gene', (32, 40))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('DCIS', 'Phenotype', 'HP:0030075', (169, 173))	('patients', 'Species', '9606', (103, 111))	('alterations', 'Var', (41, 52))
143952	31655940	Details of the findings were as follows: hypoechoic areas in the mammary gland were found to be the most frequent lesion (48.6%) of DCIS lesions, followed by solid masses (28%) and abnormalities of the ducts (10.2%) or mixed masses (8.1%).	('DCIS', 'Disease', (132, 136))	('DCIS', 'Disease', 'MESH:D002285', (132, 136))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('hypoechoic areas', 'Var', (41, 57))
143958	31655940	Of the 78 cases with abnormalities of the ducts, there were 48 cases with duct abnormalities alone (Fig.	('duct abnormalities', 'Disease', (74, 92))	('abnormalities', 'Var', (21, 34))	('duct abnormalities', 'Disease', 'MESH:D002869', (74, 92))
143978	30207088	ColXalpha1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression.	('neoplastic progression', 'CPA', (215, 237))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('breast tumor', 'Phenotype', 'HP:0100013', (71, 83))	('tissue development', 'CPA', (142, 160))	('elastin', 'Gene', '2006', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('contributes', 'Reg', (200, 211))	('breast tumor', 'Disease', 'MESH:D001943', (71, 83))	('homeostasis', 'MPA', (165, 176))	('elastin', 'Gene', (56, 63))	('tumor', 'Disease', (78, 83))	('regulates', 'Reg', (132, 141))	('dysregulation', 'Var', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('breast tumor', 'Disease', (71, 83))	('tumor', 'Disease', (109, 114))
143989	30207088	These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('collagen complex', 'Protein', (69, 85))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('aberrant collagen', 'Phenotype', 'HP:0008271', (60, 77))	('aberrant', 'Var', (60, 68))
143992	30207088	When such control mechanisms are disrupted, the resultant deregulation contributes to the initiation and progression of cancer 2.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('disrupted', 'Var', (33, 42))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('deregulation', 'MPA', (58, 70))	('contributes', 'Reg', (71, 82))
144002	30207088	Mutations in COL10A1 are associated with Schmid-type metaphyseal chondrodysplasia and Japanese-type spondylometaphyseal dysplasia 16.	('metaphyseal chondrodysplasia', 'Phenotype', 'HP:0005871', (53, 81))	('COL10A1', 'Gene', '1300', (13, 20))	('associated', 'Reg', (25, 35))	('Schmid-type metaphyseal chondrodysplasia', 'Disease', 'MESH:C537352', (41, 81))	('spondylometaphyseal dysplasia', 'Phenotype', 'HP:0002657', (100, 129))	('Mutations', 'Var', (0, 9))	('COL10A1', 'Gene', (13, 20))	('Schmid-type metaphyseal chondrodysplasia', 'Disease', (41, 81))	('spondylometaphyseal dysplasia', 'Disease', 'MESH:C537501', (100, 129))	('spondylometaphyseal dysplasia', 'Disease', (100, 129))
144142	30207088	These findings establish a foundation for investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression that may be leveraged in future therapeutic and theranostic applications.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('collagen complex', 'Protein', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aberrant collagen', 'Phenotype', 'HP:0008271', (73, 90))	('aberrant', 'Var', (73, 81))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
144155	17233903	Genetic and epigenetic changes that occur early in the process of carcinogenesis may enable the survival and growth of cells that subsequently acquire oncogenic mutations.	('survival', 'CPA', (96, 104))	('Genetic', 'Var', (0, 7))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('growth', 'CPA', (109, 115))	('enable', 'PosReg', (85, 91))	('carcinogenesis', 'Disease', (66, 80))	('epigenetic changes', 'Var', (12, 30))
144160	17233903	Multiple types of single changes that prevent Rb-mediated growth inhibition will overcome stasis.	('stasis', 'MPA', (90, 96))	('Rb', 'Chemical', 'MESH:D012413', (46, 48))	('changes', 'Var', (25, 32))
144161	17233903	Loss of CDKN2A (encoding p16ink4a) expression, from methylation-induced CDKN2A promoter silencing, or mutations, is one alteration frequently observed in human breast cancers and cultured HMEC.	('breast cancers', 'Disease', 'MESH:D001943', (160, 174))	('breast cancers', 'Disease', (160, 174))	('CDKN2A', 'Gene', (8, 14))	('human', 'Species', '9606', (154, 159))	('CDKN2A', 'Gene', '1029', (72, 78))	('CDKN2A', 'Gene', '1029', (8, 14))	('p16ink4a', 'Gene', '1029', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('expression', 'MPA', (35, 45))	('Loss', 'NegReg', (0, 4))	('mutations', 'Var', (102, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('p16ink4a', 'Gene', (25, 33))	('CDKN2A', 'Gene', (72, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
144164	17233903	Rare HMEC with silenced p16 are also observed in vivo and have been called variant HMEC (vHMEC).	('p16', 'Gene', '1029', (24, 27))	('variant HMEC', 'CellLine', 'CVCL:0307', (75, 87))	('variant HMEC', 'Disease', (75, 87))	('p16', 'Gene', (24, 27))	('Rare HMEC', 'Disease', (0, 9))	('silenced', 'Var', (15, 23))
144183	17233903	These groups consist of 1) all finite lifespan cells, 2) p53+/+ immortalized 184A1 and 184B5, 3) p53-/- immortalized 184AA2 and 184AA3, and 4) immortalized non-184 derived cells (including MCF10A, MCF10A-2, and MCF12A).	('MCF10A', 'CellLine', 'CVCL:0598', (189, 195))	('MCF10A-2', 'CellLine', 'CVCL:3743', (197, 205))	('p53+/+', 'Var', (57, 63))	('MCF10A', 'CellLine', 'CVCL:0598', (197, 203))	('MCF12A', 'CellLine', 'CVCL:3744', (211, 217))	('p53-/-', 'Var', (97, 103))
144199	17233903	Genes expressed exclusively in post-selection 195L HMEC (Group A) fall into two categories: genes previously identified as cancer-associated (including several antigens proposed as cancer biomarkers), and genes induced by interferons.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('post-selection', 'Var', (31, 45))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (123, 129))	('fall', 'Phenotype', 'HP:0002527', (66, 70))	('cancer', 'Disease', (181, 187))
144215	17233903	SIAH2, Lipocalin 2, Asparagine synthase and Keratin 15 are all upregulated in both 184AA2 and 184AA3, relative to both 184A1 and184B5.	('Asparagine synthase', 'Enzyme', (20, 39))	('SIAH2', 'Gene', (0, 5))	('Lipocalin 2', 'Gene', (7, 18))	('Keratin 15', 'Gene', '3866', (44, 54))	('Lipocalin 2', 'Gene', '3934', (7, 18))	('184AA2', 'Var', (83, 89))	('Keratin 15', 'Gene', (44, 54))	('184AA3', 'Var', (94, 100))	('upregulated', 'PosReg', (63, 74))	('SIAH2', 'Gene', '6478', (0, 5))
144217	17233903	Examples include DUSP1 and BIRC3, expressed at significantly higher levels 184AA3 than in 184AA2, and FABP4, IFI27, HRASLS3, and Fibulin 1, expressed much more robustly in 184A1 than in 184B5.	('FABP4', 'Gene', (102, 107))	('184AA3', 'Var', (75, 81))	('DUSP1', 'Gene', (17, 22))	('BIRC3', 'Gene', '330', (27, 32))	('HRASLS3', 'Gene', (116, 123))	('DUSP1', 'Gene', '1843', (17, 22))	('IFI27', 'Gene', (109, 114))	('Fibulin 1', 'Gene', '2192', (129, 138))	('higher', 'PosReg', (61, 67))	('184A1', 'Var', (172, 177))	('HRASLS3', 'Gene', '11145', (116, 123))	('FABP4', 'Gene', '2167', (102, 107))	('IFI27', 'Gene', '3429', (109, 114))	('BIRC3', 'Gene', (27, 32))	('Fibulin 1', 'Gene', (129, 138))
144221	17233903	Over-expression of ERBB2/Her2 in 184B5 results in anchorage independent growth, a malignancy-associated property, while over-expression of oncogenic ERBB2/Her2 in 184B5 can confer tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Her2', 'Gene', (155, 159))	('ERBB2', 'Gene', '2064', (19, 24))	('Her2', 'Gene', '2064', (25, 29))	('Her2', 'Gene', '2064', (155, 159))	('ERBB2', 'Gene', (19, 24))	('malignancy', 'Disease', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('results in', 'Reg', (39, 49))	('tumor', 'Disease', (180, 185))	('Her2', 'Gene', (25, 29))	('Over-expression', 'Var', (0, 15))	('malignancy', 'Disease', 'MESH:D009369', (82, 92))	('ERBB2', 'Gene', (149, 154))	('ERBB2', 'Gene', '2064', (149, 154))	('anchorage independent growth', 'CPA', (50, 78))
144241	17233903	Levels of IGFBP4 were significantly reduced in 184B5ME relative to 184B5.	('Levels', 'MPA', (0, 6))	('IGFBP4', 'Gene', '3487', (10, 16))	('IGFBP4', 'Gene', (10, 16))	('184B5ME', 'Var', (47, 54))	('reduced', 'NegReg', (36, 43))
144256	17233903	Increased expression of S100P is seen in DCIS, and was also observed in several of the immortalized lines, particularly 184B5ME, the ERBB2/Her2 transduced line.	('Her2', 'Gene', (139, 143))	('ERBB2', 'Gene', (133, 138))	('S100P', 'Var', (24, 29))	('Her2', 'Gene', '2064', (139, 143))	('expression', 'MPA', (10, 20))	('S100P', 'SUBSTITUTION', 'None', (24, 29))	('ERBB2', 'Gene', '2064', (133, 138))
144268	17233903	Specifically, short telomeres and moderate chromosomal instability, as well as telomerase re-activation, are common to many early-stage tumors, including the breast.	('short telomeres', 'Phenotype', 'HP:0031413', (14, 29))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('chromosomal instability', 'Phenotype', 'HP:0040012', (43, 66))	('chromosomal instability', 'CPA', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('telomerase', 'CPA', (79, 89))	('breast', 'Disease', (158, 164))	('re-activation', 'PosReg', (90, 103))	('short', 'Var', (14, 19))
144277	17233903	While established breast cancer cell lines are usually derived from advanced, metastatic tumors (particularly pleural effusions), and therefore are quite different from immortalized cell lines, immortalized lines themselves have undergone extensive genetic and epigenetic changes, especially in frequently studied aspects of oncogenesis, such as G1 checkpoint function and the DNA damage response.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('pleural effusions', 'Phenotype', 'HP:0002202', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('DNA', 'CPA', (377, 380))	('breast cancer', 'Disease', (18, 31))	('metastatic tumors', 'Disease', 'MESH:C538445', (78, 95))	('epigenetic changes', 'Var', (261, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('pleural effusions', 'Disease', (110, 127))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('metastatic tumors', 'Disease', (78, 95))	('pleural effusions', 'Disease', 'MESH:D010996', (110, 127))
144290	32134153	5 ,  6 ,  7 ,  8 ,  9 ,  10   To date, DCIS biomarker discovery has focused predominantly on tumor intrinsic attributes, with one study of 1492 DCIS cases identifying lesions positive for p16, COX2, and ERBB2, and negative for estrogen receptor (ER) at high risk for progression.	('COX2', 'Gene', (193, 197))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('positive', 'Reg', (175, 183))	('ER', 'Gene', '100737874', (203, 205))	('COX2', 'Gene', '808504', (193, 197))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('estrogen receptor', 'Gene', (227, 244))	('ERBB2', 'Gene', '100516641', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('estrogen receptor', 'Gene', '100737874', (227, 244))	('ERBB2', 'Gene', (203, 208))	('ER', 'Gene', '100737874', (246, 248))	('p16', 'Var', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
144333	32134153	Figure 2C shows a representative pseudocolored mIHC image of a DCIS lesion with a microinvasive foci, as evidenced by a loss of the myoepithelial cell layer and invasion of CK18+ tumor cells (albeit with reduced staining compared with the noninvasive tumor cells) into the adjacent stroma (Figure 2C, top panel).	('tumor', 'Disease', (251, 256))	('DCIS', 'Disease', (63, 67))	('mIHC', 'Gene', (47, 51))	('loss of the myoepithelial', 'Disease', 'MESH:D009208', (120, 145))	('CK18+', 'Var', (173, 178))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('invasion', 'CPA', (161, 169))	('mIHC', 'Gene', '11796', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('loss of the myoepithelial', 'Disease', (120, 145))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Disease', (179, 184))
144341	32134153	We found that mixed and pure DCIS were differentiated by the total number of CD45+ immune cells, but contrary to our initial expectations, mixed DCIS lesions had significantly fewer immune cells compared with pure DCIS lesions (Figure 3A).	('lesions', 'Var', (150, 157))	('immune cells', 'CPA', (182, 194))	('fewer', 'NegReg', (176, 181))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('CD4', 'Gene', (77, 80))	('DCIS', 'Phenotype', 'HP:0030075', (214, 218))	('CD4', 'Gene', '404704', (77, 80))	('mixed DCIS lesions', 'Var', (139, 157))
144352	32134153	Further evidence that calponin-1 expressing myoepithelial cells may serve as a barrier between DCIS tumor cells and cytotoxic T cells is suggested by nearest neighbor visualization, which showed that CD8+ T cells were adjacent to calponin-1 positive myoepithelium, but absent within the tumor mass (Figure 4C, top right and 4D).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('DCIS tumor', 'Disease', 'MESH:D002285', (95, 105))	('CD8+', 'Var', (200, 204))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('DCIS tumor', 'Disease', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
144355	32134153	Cluster 1 is characterized by low calponin-1 and SMA expression and enrichment for CD3+, CD8+, and PD-1+CD8+ T cells, consistent with a myoepithelial immune barrier function.	('SMA expression', 'MPA', (49, 63))	('PD-1', 'Gene', (99, 103))	('CD3', 'Gene', '397455', (83, 86))	('PD-1', 'Gene', '100513601', (99, 103))	('low', 'NegReg', (30, 33))	('CD3', 'Gene', (83, 86))	('calponin-1', 'MPA', (34, 44))	('CD8+', 'Var', (89, 93))
144359	32134153	Thus, distinct immune milieus with infiltrates enriched for either CD8+, CD4+, or a CD3- immune cells were found in the three clusters with compromised myoepithelium, as defined by low calponin-1 expression.	('CD4', 'Gene', (73, 76))	('CD8+', 'Var', (67, 71))	('CD3', 'Gene', '397455', (84, 87))	('CD4', 'Gene', '404704', (73, 76))	('CD3', 'Gene', (84, 87))
144372	32134153	These changes in calponin-1 expression may impact immune surveillance of the DCIS tumor cells, either through immune cells permeating the myoepithelial layer or increased cross-talk across the myoepithelial layer.	('calponin-1', 'Gene', (17, 27))	('impact', 'Reg', (43, 49))	('cross-talk', 'Interaction', (171, 181))	('DCIS tumor', 'Disease', 'MESH:D002285', (77, 87))	('expression', 'MPA', (28, 38))	('changes', 'Var', (6, 13))	('DCIS tumor', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('immune surveillance', 'CPA', (50, 69))	('increased', 'PosReg', (161, 170))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
144373	32134153	Specifically, we found that microinvasive regions with focal loss of the myoepithelial layer had an increase in total immune infiltration with a lymphoid signature similar to mixed DCIS, including enrichment for CD8+ T cells and PD-1+CD8+ T cells (Figures 2 and 3).	('PD-1', 'Gene', '100513601', (229, 233))	('mixed DCIS', 'Disease', (175, 185))	('immune infiltration', 'CPA', (118, 137))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('CD8+', 'Var', (212, 216))	('PD-1', 'Gene', (229, 233))	('increase', 'PosReg', (100, 108))	('focal loss of the myoepithelial', 'Disease', 'MESH:D009208', (55, 86))	('focal loss of the myoepithelial', 'Disease', (55, 86))
144374	32134153	33 ,  34 ,  35 ,  36 ,  37 ,  63  Further, one study demonstrated that microinvasive DCIS had increased infiltration of CD8+ T cells and a concomitant increase in PD-L1 expression and PD-1+CD8+ T cells compared with DCIS without microinvasion, which is consistent with our findings.	('PD-L1', 'Gene', (163, 168))	('microinvasive', 'Var', (71, 84))	('DCIS', 'Phenotype', 'HP:0030075', (216, 220))	('PD-L1', 'Gene', '574058', (163, 168))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('increased', 'PosReg', (94, 103))	('PD-1', 'Gene', (184, 188))	('expression', 'MPA', (169, 179))	('infiltration', 'CPA', (104, 116))	('PD-1', 'Gene', '100513601', (184, 188))	('increase', 'PosReg', (151, 159))	('CD8+ T cells', 'CPA', (120, 132))	('DCIS', 'Disease', (85, 89))
144384	32134153	Our data showing increased PD-1+CD8+ T cell activation in low calponin-1 DCIS lesions expand this model by suggesting that reduced myoepithelial barrier function, rather than a physical breach, may be sufficient to expose tumor cells to immune surveillance and lead to eventual immune cell exhaustion.	('increased', 'PosReg', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('calponin-1', 'Gene', (62, 72))	('expose', 'Reg', (215, 221))	('PD-1', 'Gene', (27, 31))	('increased PD', 'Phenotype', 'HP:0008151', (17, 29))	('PD-1', 'Gene', '100513601', (27, 31))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('low', 'Var', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('myoepithelial', 'MPA', (131, 144))	('reduced', 'NegReg', (123, 130))
144396	27698816	The average tumor diameter was 2.5+-0.8 cm using ABVS and 2.0+-0.9 cm using conventional ultrasound (the former being significantly higher than the latter; t=6.325, P=0.034).	('higher', 'PosReg', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('ABVS', 'Var', (49, 53))
144418	27698816	The tumor diameter using ABVS was significantly larger than that measured using conventional ultrasound, (t=6.325, P=0.034) (Table I).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ABVS', 'Var', (25, 29))	('larger', 'PosReg', (48, 54))
144433	20477526	Considering all samples, 16 protein masses were associated with the presence of cancer, the most discriminating being 3592, 6570/6580 and 15870 Da.	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('6570/6580', 'Var', (124, 133))	('3592', 'Var', (118, 122))	('15870 Da', 'Var', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
144435	20477526	The best cancer detection models included Breast Imaging Reporting and Data System, age, and either the 4262 (best sensitivity: >87%) or 3592 (best specificity: >94%) peak.	('3592', 'Var', (137, 141))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
144436	20477526	MALDI-TOF mass spectrometry demonstrated the 3592 peak, which was most discriminating in many of our cancer prediction models, to be a beta-casein-like peptide.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('TOF', 'Gene', '55079', (6, 9))	('cancer', 'Disease', (101, 107))	('TOF', 'Gene', (6, 9))	('a beta', 'Gene', '351', (133, 139))	('beta-casein', 'Gene', '1447', (135, 146))	('beta-casein', 'Gene', (135, 146))	('a beta', 'Gene', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('3592', 'Var', (45, 49))
144446	20477526	In two pilot studies we performed SELDI-TOF MS on noninvasively collected NAF samples and identified five protein ion masses in the first (6500, 8000, 15,940, 28,100 and 31,770 Da) and four in the second (5200, 11,880 13,880 and 33,400 Da) that were associated with breast cancer.	('breast cancer', 'Disease', (266, 279))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('TOF', 'Gene', '55079', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('5200', 'Var', (205, 209))	('associated', 'Reg', (250, 260))	('TOF', 'Gene', (40, 43))	('6500', 'Var', (139, 143))
144461	20477526	External standards were added to all NAF samples: bovine ubiquitin (8564 Da); bovine insulin (5733 Da); human b-endorphin (3465 Da); human ACTH (2933 Da); porcine dynorphin A (2147 Da); fibrinopeptide (1570 Da); human angiotensin (1296 Da), bovine cytochrome C (12,230 Da); bovine superoxide dismutase (15,591 da); equine myobglobin (16,950); bovine lactoglobulin (18363 Da); and horseradish peroxidase (43,240 Da).	('insulin', 'Gene', (85, 92))	('18363 Da', 'Var', (365, 373))	('bovine', 'Species', '9913', (241, 247))	('2933 Da', 'Var', (145, 152))	('2147 Da', 'Var', (176, 183))	('1570 Da', 'Var', (202, 209))	('bovine', 'Species', '9913', (50, 56))	('bovine', 'Species', '9913', (343, 349))	('1296 Da', 'Var', (231, 238))	('5733 Da', 'Var', (94, 101))	('human', 'Species', '9606', (104, 109))	('3465 Da', 'Var', (123, 130))	('human', 'Species', '9606', (133, 138))	('43,240 Da', 'Var', (404, 413))	('human', 'Species', '9606', (212, 217))	('horseradish', 'Species', '3704', (380, 391))	('cytochrome C', 'Gene', (248, 260))	('bovine', 'Species', '9913', (78, 84))	('insulin', 'Gene', '280829', (85, 92))	('equine', 'Species', '9796', (315, 321))	('cytochrome C', 'Gene', '104968582', (248, 260))	('bovine', 'Species', '9913', (274, 280))
144485	20477526	Spectral data were collected from 163 unique breasts using IMAC chips, 157 using Q10 chips and 141 using CM10 chips.	('IMAC', 'Gene', '10344', (59, 63))	('CM10', 'Var', (105, 109))	('IMAC', 'Gene', (59, 63))	('Q10 chips', 'Var', (81, 90))
144487	20477526	When we divided samples by whether or not they had cancer (defined as DCIS or IBC), five proteins (3592, 15334, 15135, 15157 and 15870 Da) were associated with the presence of breast cancer and 11 (6570, 6580, 6710, 11747, 13005, 13207, 14698, 15427, 15447, 22434 and 22512 Da) with the absence of cancer in univariate analysis obtained from one or more chips (Table 3).	('associated', 'Reg', (144, 154))	('15157', 'Var', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('15427', 'Var', (244, 249))	('15447', 'Var', (251, 256))	('6570', 'Var', (198, 202))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('3592', 'Var', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('15870 Da', 'Var', (129, 137))	('11747', 'Var', (216, 221))	('cancer', 'Disease', (298, 304))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Disease', (176, 189))	('cancer', 'Disease', (51, 57))	('6710', 'Var', (210, 214))
144488	20477526	Considering protein masses within 1% of each other to be possibly related, the 6570/6580, 6710 and 15870 Da peaks were possibly related to proteins we previously identified as associated with breast cancer, whereas peaks not found in our earlier studies at 11747, 13005, 13207, 14698, 15135/15157, 15334, 15427/15447, 22434 and 22512 Da were also identified.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('13207', 'Var', (271, 276))	('6570/6580', 'Var', (79, 88))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('15870 Da', 'Var', (99, 107))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('associated', 'Reg', (176, 186))	('11747', 'Var', (257, 262))	('22512 Da', 'Var', (328, 336))	('15427/15447', 'Var', (305, 316))	('related', 'Reg', (128, 135))
144489	20477526	The best sensitivity (~67%) mass (15870) was approximately threefold more likely (odds ratio: 3.33) to be present in cancerous than non-cancerous breasts.	('cancerous', 'Disease', 'MESH:D009369', (136, 145))	('mass (15870', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('non-cancerous breasts', 'Disease', (132, 153))	('cancerous', 'Disease', 'MESH:D009369', (117, 126))	('cancerous', 'Disease', (136, 145))	('cancerous', 'Disease', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('non-cancerous breasts', 'Disease', 'MESH:D001943', (132, 153))
144490	20477526	Mass 6570 was fivefold more likely (odds ratio: 0.19) to be present in noncancerous than cancerous breasts.	('cancerous', 'Disease', 'MESH:D009369', (89, 98))	('Mass 6570', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancerous', 'Disease', (74, 83))	('cancerous breasts', 'Disease', 'MESH:D001943', (89, 106))	('cancerous', 'Disease', (89, 98))	('cancerous', 'Disease', 'MESH:D009369', (74, 83))	('cancerous breasts', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
144491	20477526	After excluding women with PND, seven additional peaks (6383, 6441, 6621, 11719/11739 and 11916) discriminating cancerous from non-cancerous breasts were detected (Table 4 & Figure 1) and four peaks (11747, 15334, 15447 and 22434) that differentiated cancer from noncancer when all samples were considered were absent when PND samples are excluded.	('non-cancerous breasts', 'Disease', (127, 148))	('6621', 'Var', (68, 72))	('cancer', 'Disease', (112, 118))	('that', 'Reg', (231, 235))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancerous', 'Disease', 'MESH:D009369', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancerous', 'Disease', (131, 140))	('6383', 'Var', (56, 60))	('women', 'Species', '9606', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('differentiated', 'Disease', (236, 250))	('cancerous', 'Disease', (112, 121))	('non-cancerous breasts', 'Disease', 'MESH:D001943', (127, 148))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancerous', 'Disease', 'MESH:D009369', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('11719/11739', 'Var', (74, 85))
144492	20477526	The SELDI software averaged 3592 Da cancer-specific peak (Figure 2A) was corroborated by MALDI TOF-TOF MS analysis to be two peaks (3585.5 and 3603.6 Da; Figure 2B).	('TOF', 'Gene', (95, 98))	('TOF', 'Gene', (99, 102))	('3603.6 Da', 'Var', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('3585.5', 'Var', (132, 138))	('TOF', 'Gene', '55079', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TOF', 'Gene', '55079', (99, 102))
144494	20477526	Electrospray ionization-based QTOF analysis (Applied Biosystems QSTAR Pulsar I) yielded two major ions (Figure 3A), one of which yielded by de novo sequencing (Figure 3B) a putative sequence of KKVEKVKHEDQQQGEXEHQDKIYXXXXPQP, with the best match upon searching NCBInr database limited to humans yielded beta-casein (GI number 288098) with an excellent E value (4e-18).	('TOF', 'Gene', '55079', (31, 34))	('beta-casein', 'Gene', '1447', (303, 314))	('KKVEKVKHEDQQQGEXEHQDKIYXXXXPQP', 'Var', (194, 224))	('TOF', 'Gene', (31, 34))	('beta-casein', 'Gene', (303, 314))	('humans', 'Species', '9606', (288, 294))	('ionization', 'Disease', 'MESH:D004194', (13, 23))	('ionization', 'Disease', (13, 23))	('yielded', 'Reg', (295, 302))
144495	20477526	At position 33-62 within the beta-casein sequence, the following peptide KKVEKVKHEDQQQGEDEHQDKIYPSFQPQP matches the molecular mass of the 3603 Da ion perfectly (with loss of ammonia from the true sequence molecular weight).	('beta-casein', 'Gene', (29, 40))	('KKVEKVKHEDQQQGEDEHQDKIYPSFQPQP', 'Var', (73, 103))	('ammonia', 'Chemical', 'MESH:D000641', (174, 181))	('beta-casein', 'Gene', '1447', (29, 40))
144503	20477526	Based on an earlier study, it is likely that the 15870 peak represents hemoglobin-beta.	('15870 peak', 'Var', (49, 59))	('hemoglobin-beta', 'Gene', (71, 86))	('hemoglobin-beta', 'Gene', '3043', (71, 86))
144504	20477526	As can been seen for the 15870 peak in Table 3 & Table 4, the association of this peak with breast cancer decreased when PND samples were eliminated.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('15870', 'Var', (25, 30))	('the', 'Interaction', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
144505	20477526	Of the eight models for which SELDI proteins were considered (Table 5), 3592 was independently associated with cancer in five models.	('3592', 'Var', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('associated', 'Reg', (95, 105))
144509	20477526	All of these differences likely influenced the proteins that were determined to be associated with cancer or no cancer.	('differences', 'Var', (13, 24))	('influenced', 'Reg', (32, 42))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('proteins', 'Protein', (47, 55))
144513	20477526	If the term entered a model, it would imply that the impact of a certain peak (e.g., 3592) on the odds of cancer differs depending on age.	('3592', 'Var', (85, 89))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
144515	20477526	Peaks of similar size include 6570/6580 Da (compared with 6500 Da) and 15870 Da (compared with 15940 Da); 6710 Da is close in size to 6650 Da, which we previously identified, but 6650 Da was not significantly associated with breast cancer in the earlier study.	('15870 Da', 'Var', (71, 79))	('6650 Da', 'Var', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('6570/6580 Da', 'Var', (30, 42))	('breast cancer', 'Disease', (225, 238))
144530	20477526	The proteins that best discriminated if a breast contained cancer were 3592, 6383, 6570/6580 and 15870 Da.	('proteins', 'Protein', (4, 12))	('breast', 'Disease', (42, 48))	('6570/6580', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('6383', 'Var', (77, 81))	('3592', 'Var', (71, 75))	('15870 Da', 'Var', (97, 105))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
144542	20477526	The protein with the highest specificity (3592 Da) was identified as a beta-casein-like peptide.	('3592 Da', 'Var', (42, 49))	('beta-casein', 'Gene', '1447', (71, 82))	('beta-casein', 'Gene', (71, 82))	('a beta', 'Gene', '351', (69, 75))	('a beta', 'Gene', (69, 75))
144752	15217486	Conversely, reintroduction of S100A2 expression in already invasive carcinoma cell lines was found to decrease their aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (117, 131))	('reintroduction', 'Var', (12, 26))	('decrease', 'NegReg', (102, 110))	('invasive carcinoma', 'Disease', (59, 77))	('aggressiveness', 'Disease', (117, 131))	('S100A2', 'Gene', (30, 36))	('S100A2', 'Gene', '6273', (30, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('aggressiveness', 'Phenotype', 'HP:0000718', (117, 131))	('invasive carcinoma', 'Disease', 'MESH:D009361', (59, 77))
144754	15217486	As a result of this knowledge, it is clear that the alteration of S100 gene expression can foster specific aspects of the progression of breast cancer and is associated with a more aggressive phenotype.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('foster', 'PosReg', (91, 97))	('associated with', 'Reg', (158, 173))	('breast cancer', 'Disease', (137, 150))	('progression', 'CPA', (122, 133))	('alteration', 'Var', (52, 62))	('S100', 'Gene', (66, 70))	('S100', 'Gene', '6271', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
144767	15217486	S100A7 alterations may be due to genomic or gene regulation changes within individual cells or cell selection.	('S100A7', 'Gene', '6278', (0, 6))	('alterations', 'Var', (7, 18))	('S100A7', 'Gene', (0, 6))
144773	15217486	Examination of S100A7 and prognostic parameters in both preinvasive DCIS (n = 136) and four invasive carcinoma cohorts (n = 57, n = 79, n = 122, n = 246) has highlighted consistent associations with ER-negative status in all series, and with higher nuclear grade, node-positive status, necrosis and increased inflammation in some series.	('associations', 'Interaction', (181, 193))	('increased', 'PosReg', (299, 308))	('higher', 'PosReg', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('invasive carcinoma', 'Disease', 'MESH:D009361', (92, 110))	('necrosis', 'Disease', (286, 294))	('inflammation', 'CPA', (309, 321))	('S100A7', 'Gene', '6278', (15, 21))	('S100A7', 'Gene', (15, 21))	('necrosis', 'Disease', 'MESH:D009336', (286, 294))	('invasive carcinoma', 'Disease', (92, 110))	('ER-negative status', 'Var', (199, 217))	('node-positive', 'CPA', (264, 277))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
144782	15217486	The ER-positive status is both the hallmark of a distinct differentiation pathway and phenotypic subgroup, and also an indicator of a tumor that can respond to estrogen with the accompanying induction or repression of a subset of specific estrogen responsive genes.	('ER-positive', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('respond to estrogen', 'MPA', (149, 168))	('repression', 'NegReg', (204, 214))	('tumor', 'Disease', (134, 139))
144813	15217486	To determine whether these effects are mediated through the interaction with Jab1 we generated MDA-MB-231 cells expressing S100A7 mutated in the region of the putative Jab1 binding domain.	('Jab1', 'Gene', (77, 81))	('Jab1', 'Gene', '10987', (77, 81))	('Jab1', 'Gene', (168, 172))	('Jab1', 'Gene', '10987', (168, 172))	('mutated', 'Var', (130, 137))	('S100A7', 'Gene', '6278', (123, 129))	('S100A7', 'Gene', (123, 129))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (95, 105))
144814	15217486	The mutated S100A7 protein did not interact with Jab1 in a yeast two-hybrid assay or exert any significant Jab1 downstream effects when expressed within MDA-MB-231 cells.	('mutated', 'Var', (4, 11))	('interact', 'Interaction', (35, 43))	('S100A7', 'Gene', (12, 18))	('Jab1', 'Gene', (49, 53))	('S100A7', 'Gene', '6278', (12, 18))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (153, 163))	('Jab1', 'Gene', (107, 111))	('Jab1', 'Gene', '10987', (49, 53))	('Jab1', 'Gene', '10987', (107, 111))	('protein', 'Protein', (19, 26))
144815	15217486	Functional analysis of MDA-MB-231 cells expressing mutated S100A7 confirmed that the Jab1 binding site is necessary for the effect of S100A7 on NF-kappaB, phospho-Akt, and promotion of tumorigenesis in vivo .	('tumor', 'Disease', (185, 190))	('promotion', 'PosReg', (172, 181))	('S100A7', 'Gene', '6278', (59, 65))	('Akt', 'Gene', (163, 166))	('S100A7', 'Gene', (59, 65))	('Jab1', 'Gene', (85, 89))	('Jab1', 'Gene', '10987', (85, 89))	('S100A7', 'Gene', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Akt', 'Gene', '207', (163, 166))	('S100A7', 'Gene', '6278', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('NF-kappaB', 'Protein', (144, 153))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (23, 33))	('mutated', 'Var', (51, 58))
144824	15217486	One of these amino acids lies within the conserved Jab1-binding domain, and we would predict that this difference abolishes any significant capacity to form an interaction with Jab1 or a similar mechanism of action.	('Jab1', 'Gene', (177, 181))	('abolishes', 'NegReg', (114, 123))	('difference', 'Var', (103, 113))	('Jab1', 'Gene', '10987', (177, 181))	('Jab1', 'Gene', (51, 55))	('Jab1', 'Gene', '10987', (51, 55))	('interaction', 'Interaction', (160, 171))
144845	26384318	The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('alterations', 'Var', (77, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BCL9', 'Gene', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
144847	26384318	Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2).	('Estrogen receptor', 'Gene', '2099', (150, 167))	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('human', 'Species', '9606', (243, 248))	('Estrogen receptor', 'Gene', (150, 167))	('negative', 'NegReg', (204, 212))	('high nuclear', 'Var', (214, 226))	('DCIS', 'Phenotype', 'HP:0030075', (20, 24))	('ER', 'Gene', '2099', (285, 287))	('HER2', 'Gene', '2064', (284, 288))	('progesterone receptor', 'Gene', (177, 198))	('progesterone receptor', 'Gene', '5241', (177, 198))	('high human', 'Var', (238, 248))	('epidermal growth factor receptor2', 'Gene', '2064', (249, 282))	('DCIS', 'Disease', (133, 137))	('patient', 'Species', '9606', (12, 19))	('epidermal growth factor receptor2', 'Gene', (249, 282))	('HER2', 'Gene', (284, 288))	('PR', 'Gene', '5241', (200, 202))	('ER', 'Gene', '2099', (169, 171))
144862	26384318	Collectively, these latter studies suggest that unique genomic aberrations in some cancer cells or distinct population of cancer cells may drive DCIS to IDC.	('IDC', 'Gene', '4000', (153, 156))	('IDC', 'Gene', (153, 156))	('genomic aberrations', 'Var', (55, 74))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('DCIS', 'Disease', (145, 149))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('drive', 'Reg', (139, 144))	('cancer', 'Disease', (83, 89))
144950	26384318	Western blot on cell lysates obtained from DCIS cell lines also showed no change in BCL9L expression with BCL9 KD.	('BCL9 KD', 'Var', (106, 113))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('BCL9L', 'Gene', '283149', (84, 89))	('BCL9L', 'Gene', (84, 89))
144953	26384318	However, aberrant activation of canonical Wnt signaling has been implicated in the development and progression of many cancers including breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('men', 'Species', '9606', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('Wnt', 'Gene', '32838', (42, 45))	('aberrant', 'Var', (9, 17))	('Wnt', 'Gene', (42, 45))	('implicated', 'Reg', (65, 75))	('activation', 'PosReg', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
144961	26384318	5c, BCL9 KD DCIS.COM and SUM225 MIND lesions showed a significant reduction in the maximum distance of invasion (DCIS.COM = 78.0 +- 22.3 mum in KD compared to 302.7 +- 12.4 mum in control and for SUM225 = 75.5 +- 18.9 mum in KD compared to 338.3 +- 18.8 mum in control; p <0.05) and in the number of invasive lesions per field compared to the control (DCIS.COM = 1.4 +- 0.5 in KD compared to 4.3 +- 0.9 in control and for SUM225 = 3.0 +- 3.0 invasive lesions in KD compared to 11.7 +- 1.2 invasive lesions in control; p <0.05).	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))	('MIND lesions', 'Disease', (32, 44))	('SUM225 =', 'Var', (422, 430))	('MIND lesions', 'Disease', 'MESH:D051437', (32, 44))	('invasive lesions', 'CPA', (300, 316))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))	('DCIS', 'Phenotype', 'HP:0030075', (352, 356))	('reduction', 'NegReg', (66, 75))
144962	26384318	Previous studies in colon carcinoma and multiple myeloma models showed that tumors with BCL9 KD exhibited altered expression and distribution of mesenchymal and epithelial markers, vimentin, beta-catenin and E-cadherin, indicative of reduced EMT.	('altered', 'Reg', (106, 113))	('reduced', 'NegReg', (234, 241))	('colon carcinoma', 'Disease', 'MESH:D015179', (20, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('multiple myeloma', 'Disease', (40, 56))	('expression', 'MPA', (114, 124))	('distribution', 'MPA', (129, 141))	('BCL9 KD', 'Var', (88, 95))	('EMT', 'CPA', (242, 245))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('vimentin', 'Protein', (181, 189))	('E-cadherin', 'Gene', (208, 218))	('E-cadherin', 'Gene', '999', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('multiple myeloma', 'Phenotype', 'HP:0006775', (40, 56))	('reduced EMT', 'Phenotype', 'HP:0032198', (234, 245))	('beta-catenin', 'Protein', (191, 203))	('colon carcinoma', 'Disease', (20, 35))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('multiple myeloma', 'Disease', 'MESH:D009101', (40, 56))
144963	26384318	Likewise, Deka, J and Colleagues showed that mice with the conditionally deleted Bcl9/Bcl9l in intestinal cells exposed to a carcinogen (dimethylhydrazine followed by DSS) showed higher expression of both Wnt target genes that regulate EMT (vimentin, fibronectin and beta-catenin) and stem-cell-related genes such as Sox6 compared to wild type.	('Sox6', 'Gene', (317, 321))	('Wnt', 'Gene', (205, 208))	('Bcl9', 'Gene', '77578', (81, 85))	('mice', 'Species', '10090', (45, 49))	('Sox6', 'Gene', '20679', (317, 321))	('deleted', 'Var', (73, 80))	('Bcl9', 'Gene', (81, 85))	('dimethylhydrazine', 'Chemical', 'MESH:D004127', (137, 154))	('Bcl9', 'Gene', (86, 90))	('Bcl9', 'Gene', '77578', (86, 90))	('expression', 'MPA', (186, 196))	('Bcl9l', 'Gene', '80288', (86, 91))	('higher', 'PosReg', (179, 185))	('Wnt', 'Gene', '32838', (205, 208))	('Bcl9l', 'Gene', (86, 91))
144965	26384318	BCL9 KD in DCIS.COM cells resulted in a reduction in vimentin and an increase in epithelial marker E-cadherin (Fig.	('increase', 'PosReg', (69, 77))	('BCL9 KD', 'Var', (0, 7))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('reduction', 'NegReg', (40, 49))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('vimentin', 'MPA', (53, 61))
144966	26384318	SUM225 also showed an increase in E-cadherin, but control cells did not express vimentin, so as expected, BCL9 KD did not change vimentin expression.	('E-cadherin', 'Gene', '999', (34, 44))	('SUM225', 'Var', (0, 6))	('E-cadherin', 'Gene', (34, 44))
144981	26384318	Furthermore, cells that overexpressed both BCL9 and constitutively active beta-catenin showed significantly higher beta-catenin/TCF-mediated transcription compared to beta-catenin overexpression alone and in response to Wnt3A stimulation (approximately 1.7-fold increase; p <0.05).	('Wnt3A', 'Gene', '89780', (220, 225))	('TCF', 'Gene', (128, 131))	('TCF', 'Gene', '3172', (128, 131))	('Wnt3A', 'Gene', (220, 225))	('BCL9', 'Var', (43, 47))	('higher', 'PosReg', (108, 114))
144995	26384318	Interestingly, analysis of TCGA data (provisional TCGA; 959 cases) showed that 26 % of invasive breast cancers contain BCL9 gene alterations.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancers', 'Disease', (87, 110))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('invasive breast cancers', 'Disease', 'MESH:D001943', (87, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('BCL9', 'Gene', (119, 123))	('gene alterations', 'Var', (124, 140))
144997	26384318	Furthermore, BCL9 amplification is observed in a significantly higher proportion of invasive basal breast cancer (BLBC) subtypes compared to the other subtypes (Additional file 9: Figure S6B-C).	('invasive basal breast cancer', 'Disease', 'MESH:D001943', (84, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('BCL9', 'Var', (13, 17))	('invasive basal breast cancer', 'Disease', (84, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
145001	26384318	Canonical Wnt signaling can be constitutively activated in cancer by a variety of mechanisms including mutations in adenomatous polyposis coli (APC), Axin, and beta-catenin.	('mutations', 'Var', (103, 112))	('activated', 'PosReg', (46, 55))	('adenomatous polyposis coli', 'Disease', (116, 142))	('beta-catenin', 'Protein', (160, 172))	('Axin', 'Gene', (150, 154))	('APC', 'Phenotype', 'HP:0005227', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('APC', 'Disease', 'MESH:D011125', (144, 147))	('Wnt', 'Gene', '32838', (10, 13))	('APC', 'Disease', (144, 147))	('Wnt', 'Gene', (10, 13))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (116, 142))	('Axin', 'Gene', '8312', (150, 154))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (116, 142))
145002	26384318	These mutations enable beta-catenin to escape destruction and drive oncogenic Wnt signaling.	('Wnt', 'Gene', '32838', (78, 81))	('Wnt', 'Gene', (78, 81))	('beta-catenin', 'Protein', (23, 35))	('drive', 'PosReg', (62, 67))	('oncogenic', 'CPA', (68, 77))	('mutations', 'Var', (6, 15))
145004	26384318	The mechanism by which BCL9 is overexpressed in some cancers is not entirely understood, but cancer genome analysis via GISTIC reveals copy number alterations in 13 % of all breast cancer cases examined.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (53, 59))	('cancers', 'Disease', (53, 60))	('breast cancer', 'Disease', (174, 187))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('copy number alterations', 'Var', (135, 158))	('cancer', 'Disease', (181, 187))
145005	26384318	Chromosome 1q amplification is a common finding in several cancers including breast.	('breast', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Chromosome 1q amplification', 'Var', (0, 27))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Disease', (59, 66))
145008	26384318	Indeed, BCL9 is recognized as an adaptor that helps PYGO in recognizing modified histone H3 tails by their plant homeodomain (PHD) fingers.	('PYGO', 'Gene', (52, 56))	('PHD', 'Disease', 'MESH:D011547', (126, 129))	('PYGO', 'Gene', '43718', (52, 56))	('PHD', 'Disease', (126, 129))	('histone H3 tails', 'Protein', (81, 97))	('modified', 'Var', (72, 80))
145020	26384318	Immunocompromised mice injected with colo320 KD of BCL9 showed significant increase in survival and reduced lung metastasis.	('colo320 KD', 'Var', (37, 47))	('lung metastasis', 'Disease', (108, 123))	('BCL9', 'Gene', (51, 55))	('reduced', 'NegReg', (100, 107))	('mice', 'Species', '10090', (18, 22))	('survival', 'CPA', (87, 95))	('increase', 'PosReg', (75, 83))	('lung metastasis', 'Disease', 'MESH:D009362', (108, 123))
145023	26384318	We demonstrated that BCL9 KD resulted in suppression of Wnt signaling as assessed by TOP-FLASH Wnt reporter assays in our basal DCIS cell line (DCIS.COM), while BCL9 KD in SUM225 (luminal HER2 overexpressing) did not affect the canonical Wnt signaling.	('Wnt', 'Gene', (95, 98))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('HER2', 'Gene', (188, 192))	('BCL9 KD', 'Var', (21, 28))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('BCL9 KD', 'Var', (161, 168))	('HER2', 'Gene', '2064', (188, 192))	('Wnt', 'Gene', '32838', (95, 98))	('Wnt', 'Gene', '32838', (56, 59))	('Wnt', 'Gene', (238, 241))	('Wnt', 'Gene', '32838', (238, 241))	('suppression', 'NegReg', (41, 52))	('Wnt', 'Gene', (56, 59))
145040	26078790	Another significant predictor of CPM among patients with DCIS is having a germline BRCA mutation.	('mutation', 'Var', (88, 96))	('BRCA', 'Gene', '672', (83, 87))	('CPM', 'Disease', (33, 36))	('patients', 'Species', '9606', (43, 51))	('BRCA', 'Gene', (83, 87))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
145041	26078790	Defining BRCA1 and BRCA2 mutation carrier status is crucial, because mutation carriers have a 43% to 84% risk of developing breast cancer (BC) and up to a 65% risk for CBC.	('BRCA2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRCA1', 'Gene', '672', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('mutation', 'Var', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('BRCA2', 'Gene', '675', (19, 24))	('breast cancer', 'Disease', (124, 137))	('CBC', 'Disease', (168, 171))	('BRCA1', 'Gene', (9, 14))	('BC', 'Phenotype', 'HP:0003002', (169, 171))	('BC', 'Phenotype', 'HP:0003002', (139, 141))
127049	26078790	The prevalence of BRCA mutations in patients with DCIS has been reported.	('patients', 'Species', '9606', (36, 44))	('BRCA', 'Gene', '672', (18, 22))	('BRCA', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
127050	26078790	Our previous study indicated a 27% prevalence of deleterious BRCA mutations among 118 patients with DCIS who were referred for genetic counseling.	('mutations', 'Var', (66, 75))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('BRCA', 'Gene', '672', (61, 65))	('BRCA', 'Gene', (61, 65))	('patients', 'Species', '9606', (86, 94))
145043	26078790	Predictors of CPM among that group were age 45 years or younger, BRCA positivity, and having one or more relatives with ovarian cancer (OC).	('OC', 'Phenotype', 'HP:0100615', (136, 138))	('BRCA', 'Gene', (65, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('positivity', 'Var', (70, 80))	('BRCA', 'Gene', '672', (65, 69))	('ovarian cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CPM', 'Disease', (14, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
145046	26078790	It has been reported that women testing negative for a BRCA mutation and with a family history of BC (>= 2 BC under age 50, or >= 3 BC at any age) have almost a four-fold increased risk of BC.	('mutation', 'Var', (60, 68))	('BRCA', 'Gene', '672', (55, 59))	('women', 'Species', '9606', (26, 31))	('BRCA', 'Gene', (55, 59))	('BC', 'Phenotype', 'HP:0003002', (98, 100))	('BC', 'Phenotype', 'HP:0003002', (107, 109))	('BC', 'Phenotype', 'HP:0003002', (189, 191))	('BC', 'Phenotype', 'HP:0003002', (132, 134))
145050	26078790	In the current study, we further evaluated factors associated with CPM in patients with DCIS who tested negative for BRCA mutation.	('CPM', 'Disease', (67, 70))	('patients', 'Species', '9606', (74, 82))	('mutation', 'Var', (122, 130))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', '672', (117, 121))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
145074	26078790	Our study found a 31% CPM election rate among 100 DCIS patients who tested negative for a BRCA mutation.	('CPM election', 'MPA', (22, 34))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', (90, 94))	('patients', 'Species', '9606', (55, 63))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('mutation', 'Var', (95, 103))
145084	26078790	BRCA positivity is known to be associated with significantly increased risks for BC and CBC, which may contribute to CPM election among BRCA-positive patients.	('positivity', 'Var', (5, 15))	('BC', 'Phenotype', 'HP:0003002', (81, 83))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Gene', (136, 140))	('BC', 'Phenotype', 'HP:0003002', (89, 91))	('CBC', 'Disease', (88, 91))	('patients', 'Species', '9606', (150, 158))	('BRCA', 'Gene', '672', (136, 140))	('BRCA', 'Gene', '672', (0, 4))
145106	26078790	In this cohort, patients who had mastectomy were significantly more likely to elect CPM than those who had only breast-conserving surgery.	('elect CPM', 'Disease', (78, 87))	('patients', 'Species', '9606', (16, 24))	('mastectomy', 'Var', (33, 43))	('CPM', 'Disease', (84, 87))
145150	22082486	Recent characterization of their molecular features, such as the dysfunction of the BRCA1 pathway or the frequent expression of EGFR, provides opportunities for optimizing the systemic treatment.	('EGFR', 'Gene', '1956', (128, 132))	('dysfunction', 'Var', (65, 76))	('EGFR', 'Gene', (128, 132))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA1', 'Gene', (84, 89))
145190	22082486	Loss of PTEN and activation of the PI3K/AKT pathway, and TP53 mutations are frequent in basal breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('TP53', 'Gene', '7157', (57, 61))	('AKT', 'Gene', '207', (40, 43))	('basal breast cancers', 'Disease', 'MESH:D001943', (88, 108))	('PTEN', 'Gene', (8, 12))	('breast cancers', 'Phenotype', 'HP:0003002', (94, 108))	('PTEN', 'Gene', '5728', (8, 12))	('Loss', 'NegReg', (0, 4))	('activation', 'PosReg', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AKT', 'Gene', (40, 43))	('basal breast cancers', 'Disease', (88, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
145191	22082486	Regions altered in basal samples such as 6p21-p25, 12p13 (gained) or 5q11 (lost) likely harbor candidate oncogenes and tumor suppressor genes respectively, which remain to be identified.	('12p13', 'Var', (51, 56))	('tumor', 'Disease', (119, 124))	('gained', 'PosReg', (58, 64))	('p25', 'Gene', '8851', (46, 49))	('p25', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
145192	22082486	Inactivation of the RB pathway is also frequent and constitutes another reason of genome instability.	('RB', 'Chemical', 'MESH:D012413', (20, 22))	('RB pathway', 'Pathway', (20, 30))	('Inactivation', 'Var', (0, 12))
145199	22082486	Whether BRCA1 inactivation is a cause or a consequence of the basal phenotype is not clear.	('BRCA1', 'Gene', '672', (8, 13))	('BRCA1', 'Gene', (8, 13))	('inactivation', 'Var', (14, 26))
145201	22082486	The inactivation of BRCA1, involved in repair of double-strand DNA breaks, partially explains the genomic instability of basal breast cancers, and theorically confers sensitivity to chemotherapy agents causing inter-strand and double-strand breaks and to PARP inhibitors (see below).	('sensitivity', 'MPA', (167, 178))	('inactivation', 'Var', (4, 16))	('BRCA1', 'Gene', (20, 25))	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('PARP', 'Gene', (255, 259))	('inter-strand', 'MPA', (210, 222))	('basal breast cancers', 'Disease', (121, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('PARP', 'Gene', '142', (255, 259))	('BRCA1', 'Gene', '672', (20, 25))	('basal breast cancers', 'Disease', 'MESH:D001943', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
145218	22082486	In contrast, luminal cancers may derive from an ER-positive luminal progenitor; due to specific alterations, in luminal B breast cancers this progenitor may have lost ER expression.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('alterations', 'Var', (96, 107))	('luminal cancers', 'Disease', (13, 28))	('breast cancers', 'Disease', (122, 136))	('ER', 'Gene', '2099', (48, 50))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lost', 'NegReg', (162, 166))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('ER', 'Gene', '2099', (167, 169))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('luminal cancers', 'Disease', 'MESH:D009369', (13, 28))
145231	22082486	At the molecular level, the presence of a BRCA1 mutation strongly increases the risk to develop a basal breast cancer.	('BRCA1', 'Gene', '672', (42, 47))	('presence', 'Var', (28, 36))	('increases', 'PosReg', (66, 75))	('BRCA1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutation', 'Var', (48, 56))	('basal breast cancer', 'Disease', 'MESH:D001943', (98, 117))	('basal breast cancer', 'Disease', (98, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
145233	22082486	A significant association between the G/G genotype (combination of G and G alleles at the locus) of a non-synonymous MYBL2 germline variant and an increased risk of basal breast cancer was recently reported.	('MYBL2', 'Gene', '4605', (117, 122))	('MYBL2', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('G/G', 'Var', (38, 41))	('non-synonymous', 'Var', (102, 116))	('basal breast cancer', 'Disease', 'MESH:D001943', (165, 184))	('basal breast cancer', 'Disease', (165, 184))
145275	22082486	In a series of 3000 breast cancer patients with brain metastasis, the TN status was the strongest risk factor for brain relapse.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('brain metastasis', 'Disease', (48, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('patients', 'Species', '9606', (34, 42))	('brain metastasis', 'Disease', 'MESH:D009362', (48, 64))	('brain relapse', 'Disease', (114, 127))	('TN status', 'Var', (70, 79))
145303	22082486	Resistance to PARP inhibitors has been observed in vitro due to the restoration of a functional BRCA2 isoform resulting from a gene deletion.	('gene deletion', 'Var', (127, 140))	('BRCA2', 'Gene', '675', (96, 101))	('PARP', 'Gene', (14, 18))	('restoration', 'PosReg', (68, 79))	('PARP', 'Gene', '142', (14, 18))	('BRCA2', 'Gene', (96, 101))
145316	22082486	Another completed phase II trial compared irinotecan plus carboplatin with versus without cetuximab: the response rate was higher with the antibody (49 vs. 30%), but the PFS was similar.	('response', 'MPA', (105, 113))	('cetuximab', 'Chemical', 'MESH:D000068818', (90, 99))	('carboplatin', 'Chemical', 'MESH:D016190', (58, 69))	('antibody', 'Var', (139, 147))	('higher', 'PosReg', (123, 129))	('irinotecan', 'Chemical', 'MESH:D000077146', (42, 52))
145340	28744752	Radiotherapy was associated with an increased risk of all second non-breast cancers combined (RR=1.17, 95% Confidence Interval [CI]1.08-1.28) and all in-field, radiation-related second cancers combined (RR=1.37, 95%CI:1.15-1.63), driven by second lung cancers (RR=1.33, 95CI:1.10-1.60) and non-CLL leukemia (RR=1.71, 95%CI:1.02-2.86).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('lung cancers', 'Disease', 'MESH:D008175', (247, 259))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('non-CLL leukemia', 'Disease', (290, 306))	('cancers', 'Disease', (185, 192))	('non-breast cancers', 'Disease', 'MESH:D001943', (65, 83))	('lung cancers', 'Disease', (247, 259))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('non-breast cancers', 'Disease', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('non-CLL leukemia', 'Disease', 'MESH:D015451', (290, 306))	('lung cancers', 'Phenotype', 'HP:0100526', (247, 259))	('leukemia', 'Phenotype', 'HP:0001909', (298, 306))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', (252, 259))	('Radiotherapy', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('CLL', 'Phenotype', 'HP:0005550', (294, 297))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
145342	28744752	Radiotherapy was associated with an increased risk of second non-breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (65, 79))	('Radiotherapy', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('non-breast cancers', 'Disease', 'MESH:D001943', (61, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('non-breast cancers', 'Disease', (61, 79))
145347	28744752	In the context of invasive breast cancer, radiotherapy has been associated with significantly increased risk of cancers within the radiation field, but the absolute risks are small compared to the absolute benefits in terms of reduction in breast cancer mortality.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('invasive breast cancer', 'Disease', (18, 40))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (240, 253))	('mortality', 'Disease', 'MESH:D003643', (254, 263))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('cancers', 'Disease', (112, 119))	('invasive breast cancer', 'Disease', 'MESH:D001943', (18, 40))	('radiotherapy', 'Var', (42, 54))	('mortality', 'Disease', (254, 263))
145353	28744752	DCIS was defined as female breast cancer with in situ behavior and one of the following International Classification of Disease for Oncology (ICD-O-3) histology codes: 8201, 8500, 8501, 8503, 8507, and 8523.	('DCIS', 'Disease', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('8523', 'Var', (202, 206))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('8201', 'Var', (168, 172))	('Oncology', 'Phenotype', 'HP:0002664', (132, 140))
145387	28744752	After adjustment for covariates, radiotherapy was associated with a significantly increased relative risk of all non-breast second cancers combined (RR: 1.17, 95%CI: 1.08-1.28), lung cancer (RR:1.33, 95%CI:1.10-1.60), melanoma (RR:1.52, 95%CI: 1.04-2.22), non-CLL leukemias (RR: 1.71, 95% CI: 1.02-2.86) and in-field/radiation-related cancers combined (RR:1.37, 95%CI: 1.15-1.63).	('leukemias', 'Disease', (264, 273))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('cancers', 'Phenotype', 'HP:0002664', (335, 342))	('non-breast second cancers', 'Disease', (113, 138))	('cancers', 'Disease', (335, 342))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('radiotherapy', 'Var', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('non-CLL leukemia', 'Disease', (256, 272))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('lung cancer', 'Disease', (178, 189))	('non-breast second cancers', 'Disease', 'MESH:D001943', (113, 138))	('non-CLL leukemia', 'Disease', 'MESH:D015451', (256, 272))	('leukemias', 'Disease', 'MESH:D007938', (264, 273))	('cancers', 'Disease', 'MESH:D009369', (335, 342))	('leukemias', 'Phenotype', 'HP:0001909', (264, 273))	('leukemia', 'Phenotype', 'HP:0001909', (264, 272))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('melanoma', 'Disease', (218, 226))	('CLL', 'Phenotype', 'HP:0005550', (260, 263))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))
145397	28744752	Among DCIS survivors, radiotherapy was associated with an increased risk of all non-breast second cancers, and in particular a significantly increased risk of lung cancer, melanoma, and in aggregate, second cancers within the radiation field.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('DCIS', 'Phenotype', 'HP:0030075', (6, 10))	('cancers', 'Disease', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('cancers', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('non-breast second cancers', 'Disease', (80, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('radiotherapy', 'Var', (22, 34))	('lung cancer', 'Disease', (159, 170))	('non-breast second cancers', 'Disease', 'MESH:D001943', (80, 105))
145433	28744752	Overall, we found that 5-year survivors of DCIS are at lower risk of non-breast second cancers than women in the general population, likely attributable in large part to a healthy screener effect.	('DCIS', 'Var', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lower', 'NegReg', (55, 60))	('non-breast second cancers', 'Disease', 'MESH:D001943', (69, 94))	('non-breast second cancers', 'Disease', (69, 94))	('women', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
145434	28744752	However, radiotherapy was associated with an increased risk of some second cancers.	('radiotherapy', 'Var', (9, 21))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
145437	28744752	Clinical trials of radiotherapy for DCIS have not found a reduction in breast cancer mortality but have shown that radiotherapy reduces the risk of any ipsilateral breast event (i.e., either recurrent or invasive cancer) by a factor of 2.	('breast cancer', 'Disease', (71, 84))	('radiotherapy', 'Var', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('mortality', 'Disease', 'MESH:D003643', (85, 94))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('reduces', 'NegReg', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('mortality', 'Disease', (85, 94))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('recurrent', 'Disease', (191, 200))
145462	32025985	In addition, breast specialists should take into account that women diagnosed with high-risk/B3 lesions have a long-term moderately increased risk of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('high-risk/B3 lesions', 'Var', (83, 103))	('women', 'Species', '9606', (62, 67))
145683	32058674	Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('breast cancers', 'Disease', (48, 62))	('copy number variations', 'Var', (22, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('HER2', 'Gene', (82, 86))	('carcinogenesis', 'Disease', (133, 147))	('tumour', 'Disease', (106, 112))	('HER2', 'Gene', '2064', (82, 86))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))
145684	32058674	HER2 gene amplification is associated with poor outcome in invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('invasive breast cancer', 'Disease', (59, 81))	('HER2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HER2', 'Gene', '2064', (0, 4))	('invasive breast cancer', 'Disease', 'MESH:D001943', (59, 81))	('gene amplification', 'Var', (5, 23))
145685	32058674	Heterogeneous HER2 amplification has been described in 5-41% of breast cancers.	('HER2', 'Gene', '2064', (14, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancers', 'Disease', 'MESH:D001943', (64, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('breast cancers', 'Disease', (64, 78))	('amplification', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HER2', 'Gene', (14, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))
145689	32058674	Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('missense variants', 'Var', (91, 108))	('insertions', 'Var', (76, 86))	('deletions', 'Var', (63, 72))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))
145690	32058674	One patient had an EGFR copy number gain restricted to a HER2-negative in situ component, resulting in EGFR protein overexpression.	('EGFR', 'Gene', '1956', (103, 107))	('HER2', 'Gene', (57, 61))	('EGFR', 'Gene', (103, 107))	('overexpression', 'PosReg', (116, 130))	('patient', 'Species', '9606', (4, 11))	('EGFR', 'Gene', '1956', (19, 23))	('HER2', 'Gene', '2064', (57, 61))	('copy number', 'Var', (24, 35))	('EGFR', 'Gene', (19, 23))
145691	32058674	Two patients had FGFR1 copy number gains in at least one tumour component.	('tumour component', 'Disease', (57, 73))	('FGFR1', 'Gene', (17, 22))	('tumour component', 'Disease', 'MESH:D009369', (57, 73))	('FGFR1', 'Gene', '2260', (17, 22))	('patients', 'Species', '9606', (4, 12))	('copy number gains', 'Var', (23, 40))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
145692	32058674	Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1.	('gain', 'PosReg', (25, 29))	('tumour component', 'Disease', 'MESH:D009369', (46, 62))	('MYC', 'Gene', (103, 106))	('increase', 'PosReg', (91, 99))	('8q24', 'Var', (20, 24))	('PVT1', 'Gene', (111, 115))	('patients', 'Species', '9606', (4, 12))	('copy number', 'MPA', (79, 90))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('MYC', 'Gene', '4609', (103, 106))	('PVT1', 'Gene', '5820', (111, 115))	('tumour component', 'Disease', (46, 62))
145693	32058674	One patient had a CCND1 copy number gain restricted to a HER2-negative tumour component.	('CCND1', 'Gene', '595', (18, 23))	('patient', 'Species', '9606', (4, 11))	('HER2-negative tumour component', 'Disease', (57, 87))	('gain', 'PosReg', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('copy number', 'Var', (24, 35))	('CCND1', 'Gene', (18, 23))	('HER2-negative tumour component', 'Disease', 'MESH:D064726', (57, 87))
145696	32058674	This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere 'passenger' molecular anomalies.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('breast carcinogenesis', 'Disease', 'MESH:D001943', (29, 50))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('breast carcinogenesis', 'Disease', (29, 50))	('genetic', 'Var', (156, 163))
145699	32058674	ASCO/CAP American Society of Clinical Oncology/College of American Pathologists CNV copy number variation DCIS ductal carcinoma in situ  ER oestrogen receptor FEDERA Federation of Dutch Medical Scientific Societies FFPE formalin-fixed, paraffin-embedded ILC invasive lobular carcinoma LCIS lobular carcinoma in situ  lncRNA long noncoding RNA NGS next-generation sequencing NST no special type PR progesterone receptor SNP single nucleotide polymorphism Cancer is a genetic disease, resulting from an accumulation of successive somatic gene mutations that drive cancer cell proliferation (Tomasetti et al., 2017).	('lobular carcinoma', 'Phenotype', 'HP:0030076', (267, 284))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (111, 135))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (290, 307))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (258, 284))	('single nucleotide polymorphism', 'Var', (423, 453))	('cancer', 'Disease', 'MESH:D009369', (562, 568))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (118, 135))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (290, 315))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (298, 315))	('mutations', 'Var', (541, 550))	('invasive lobular carcinoma', 'Disease', (258, 284))	('paraffin', 'Chemical', 'MESH:D010232', (236, 244))	('ductal carcinoma', 'Disease', (111, 127))	('drive', 'PosReg', (556, 561))	('Oncology', 'Phenotype', 'HP:0002664', (38, 46))	('lobular carcinoma', 'Disease', 'MESH:D018275', (267, 284))	('PR', 'Gene', '5241', (394, 396))	('lobular carcinoma', 'Disease', 'MESH:D018275', (290, 307))	('ductal carcinoma', 'Disease', 'MESH:D044584', (111, 127))	('Cancer', 'Phenotype', 'HP:0002664', (454, 460))	('genetic disease', 'Disease', 'MESH:D030342', (466, 481))	('lobular carcinoma', 'Disease', (290, 307))	('genetic disease', 'Disease', (466, 481))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('progesterone receptor', 'Gene', (397, 418))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('progesterone receptor', 'Gene', '5241', (397, 418))	('Cancer', 'Disease', (454, 460))	('cancer', 'Disease', (562, 568))	('formalin', 'Chemical', 'MESH:D005557', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (562, 568))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('LCIS', 'Phenotype', 'HP:0030076', (285, 289))	('Cancer', 'Disease', 'MESH:D009369', (454, 460))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))
145704	32058674	HER2 amplification is associated with shorter disease-free and overall survival in patients with node-negative and node-positive invasive breast cancer treated with adjuvant chemotherapy and/or local radiation (Slamon et al., 1987, 1989).	('invasive breast cancer', 'Disease', (129, 151))	('amplification', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('shorter', 'NegReg', (38, 45))	('invasive breast cancer', 'Disease', 'MESH:D001943', (129, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('HER2', 'Gene', (0, 4))	('patients', 'Species', '9606', (83, 91))	('HER2', 'Gene', '2064', (0, 4))
145707	32058674	Most HER2-positive carcinomas, both in situ and invasive, present with homogeneous HER2 overexpression and amplification, implying that it is a key molecular event that propels cancer cell proliferation.	('amplification', 'Var', (107, 120))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('overexpression', 'PosReg', (88, 102))	('HER2', 'Gene', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('HER2', 'Gene', '2064', (5, 9))	('carcinomas', 'Disease', 'MESH:D009369', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('HER2', 'Gene', (83, 87))	('carcinomas', 'Disease', (19, 29))	('HER2', 'Gene', '2064', (83, 87))
145712	32058674	Genetic HER2 heterogeneity is defined as > 5% and < 50% of infiltrating tumour cells presenting with a HER2 copy number >= 6 (Pekar et al., 2019; Vance et al., 2009).	('HER2', 'Gene', (8, 12))	('copy number >= 6', 'Var', (108, 124))	('HER2', 'Gene', '2064', (8, 12))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('HER2', 'Gene', (103, 107))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('HER2', 'Gene', '2064', (103, 107))
145715	32058674	Other genomic aberrations might act as potent alternative drivers of cancer cell proliferation and invasion in HER2-negative subclones, such as the previously identified BRF2 and DSN1 gene amplification and the HER2 p.I767M somatic mutation (Ng et al., 2015).	('HER2', 'Gene', (111, 115))	('BRF2', 'Gene', (170, 174))	('HER2', 'Gene', (211, 215))	('HER2', 'Gene', '2064', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HER2', 'Gene', '2064', (211, 215))	('DSN1', 'Gene', (179, 183))	('p.I767M', 'Mutation', 'p.I767M', (216, 223))	('p.I767M', 'Var', (216, 223))	('invasion', 'CPA', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('BRF2', 'Gene', '55290', (170, 174))	('DSN1', 'Gene', '79980', (179, 183))	('cancer', 'Disease', (69, 75))
145716	32058674	In the current study, we aimed to further explore the landscape of somatic mutations and copy number variations (CNVs) in HER2-heterogeneous breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('HER2', 'Gene', (122, 126))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('copy number variations', 'Var', (89, 111))	('HER2', 'Gene', '2064', (122, 126))
145731	32058674	Tissue sections were treated with ISH-Protease-3 at 36  C for 12 min, followed by HER2 probe denaturation at 96  C for 8 min and hybridization at 80  C for 6 min.	('HER2', 'Gene', (82, 86))	('HER2', 'Gene', '2064', (82, 86))	('hybridization', 'Var', (129, 142))
145739	32058674	Variants were kept in the dataset if they had a minimum read depth of 100 reads and if they were present within a tumour component with a frequency higher than 10%.	('tumour component', 'Disease', 'MESH:D009369', (114, 130))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('Variants', 'Var', (0, 8))	('tumour component', 'Disease', (114, 130))
145750	32058674	In some patients, heterogeneous HER2 amplification was associated with heterogeneous hormone receptor status as well (Fig.	('hormone receptor', 'Gene', (85, 101))	('hormone receptor', 'Gene', '3164', (85, 101))	('HER2', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (32, 36))	('associated', 'Reg', (55, 65))	('amplification', 'Var', (37, 50))	('patients', 'Species', '9606', (8, 16))
145756	32058674	No pathogenic or likely pathogenic somatic variants were detected in ARID1B, BRCA2, CCND3, CHECK2, ERBB2, ERBB3, MAP2K4 , MLL, NCOR1, NOTCH1, PBRM1 and PDGFRA.	('ERBB3', 'Gene', (106, 111))	('MLL', 'Gene', (122, 125))	('MLL', 'Gene', '4297', (122, 125))	('NOTCH1', 'Gene', (134, 140))	('ERBB2', 'Gene', '2064', (99, 104))	('variants', 'Var', (43, 51))	('PBRM1', 'Gene', '55193', (142, 147))	('CCND3', 'Gene', '896', (84, 89))	('NOTCH1', 'Gene', '4851', (134, 140))	('PBRM1', 'Gene', (142, 147))	('ERBB3', 'Gene', '2065', (106, 111))	('ARID1B', 'Gene', (69, 75))	('BRCA2', 'Gene', (77, 82))	('ARID1B', 'Gene', '57492', (69, 75))	('NCOR1', 'Gene', (127, 132))	('CHECK2', 'Gene', (91, 97))	('pathogenic', 'CPA', (24, 34))	('CCND3', 'Gene', (84, 89))	('ERBB2', 'Gene', (99, 104))	('NCOR1', 'Gene', '9611', (127, 132))	('PDGFRA', 'Gene', '5156', (152, 158))	('MAP2K4', 'Gene', '6416', (113, 119))	('PDGFRA', 'Gene', (152, 158))	('BRCA2', 'Gene', '675', (77, 82))	('MAP2K4', 'Gene', (113, 119))
145758	32058674	The tumour suppressor gene TP53 was mutated in at least one component in 7 out of 10 breast cancers (70%).	('TP53', 'Gene', '7157', (27, 31))	('breast cancers', 'Disease', 'MESH:D001943', (85, 99))	('TP53', 'Gene', (27, 31))	('breast cancers', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('mutated', 'Var', (36, 43))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancers', 'Phenotype', 'HP:0003002', (85, 99))
145759	32058674	The TP53 aberrations included five missense variants, two deletions and one splice site change.	('deletions', 'Var', (58, 67))	('missense variants', 'Var', (35, 52))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
145760	32058674	The presence of a TP53 mutation was homogeneously present in all components of the breast cancers of patients #4, #5 and #8.	('patients', 'Species', '9606', (101, 109))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', (83, 97))	('TP53', 'Gene', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
145761	32058674	Patients #1, #2, #7 and #10 each presented with a tumour with heterogeneous presence of a TP53 mutation (Table 2).	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('TP53', 'Gene', '7157', (90, 94))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('presented', 'Reg', (33, 42))	('mutation', 'Var', (95, 103))
145762	32058674	Patient #1 presented a p.R248W TP53 mutation in the HER2-negative DCIS component and the HER2-positive invasive component, which was absent in the HER2-positive DCIS component.	('p.R248W', 'Var', (23, 30))	('HER2', 'Gene', '2064', (52, 56))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('p.R248W', 'Mutation', 'rs121912651', (23, 30))	('HER2', 'Gene', (147, 151))	('HER2', 'Gene', (89, 93))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', '2064', (89, 93))	('Patient', 'Species', '9606', (0, 7))	('HER2', 'Gene', (52, 56))
145763	32058674	However, the latter presented with a p.Y234H TP53 mutation.	('TP53', 'Gene', (45, 49))	('p.Y234H', 'Mutation', 'rs864622237', (37, 44))	('presented', 'Reg', (20, 29))	('p.Y234H', 'Var', (37, 44))	('TP53', 'Gene', '7157', (45, 49))
145764	32058674	Patient #2 presented with a p.S241fs deletion in both the HER2-positive DCIS and the HER2-positive invasive component, whereas the HER2-negative DCIS component harboured a p.R273C missense variant.	('HER2', 'Gene', (131, 135))	('p.S241fs deletion', 'Var', (28, 45))	('p.R273C missense', 'Var', (172, 188))	('p.S241fs', 'Mutation', 'p.S241fsX', (28, 36))	('HER2', 'Gene', '2064', (131, 135))	('HER2', 'Gene', (85, 89))	('p.R273C', 'Mutation', 'rs121913343', (172, 179))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('HER2', 'Gene', '2064', (85, 89))	('HER2', 'Gene', (58, 62))	('Patient', 'Species', '9606', (0, 7))	('HER2', 'Gene', '2064', (58, 62))
145766	32058674	Patient #10 showed a p.D259V missense variant in the HER2-negative invasive component, which was not detected in the HER2-positive DCIS, nor in the HER2-negative axillary metastasis.	('HER2', 'Gene', (117, 121))	('invasive component', 'CPA', (67, 85))	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', '2064', (117, 121))	('HER2', 'Gene', '2064', (148, 152))	('p.D259V missense', 'Var', (21, 37))	('HER2', 'Gene', (53, 57))	('p.D259V', 'Mutation', 'rs745425759', (21, 28))	('HER2', 'Gene', '2064', (53, 57))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('Patient', 'Species', '9606', (0, 7))
145767	32058674	Seven out of ten (70%) breast cancers harboured a PIK3CA mutation in at least one tumour component.	('mutation', 'Var', (57, 65))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('PIK3CA', 'Gene', '5290', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('harboured', 'Reg', (38, 47))	('tumour component', 'Disease', (82, 98))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))	('tumour component', 'Disease', 'MESH:D009369', (82, 98))	('breast cancers', 'Disease', (23, 37))	('PIK3CA', 'Gene', (50, 56))	('breast cancers', 'Disease', 'MESH:D001943', (23, 37))
145768	32058674	Patients #1, #4, #5, #7 and #9 presented with a breast cancer with homogeneous presence of a PIK3CA mutation in each individual tumour component, whereas PIK3CA mutations were heterogeneously distributed in the tumours of patients #3 and #6 (Table 2).	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('patients', 'Species', '9606', (222, 230))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Disease', (48, 61))	('PIK3CA', 'Gene', (93, 99))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('PIK3CA', 'Gene', (154, 160))	('Patients', 'Species', '9606', (0, 8))	('tumour component', 'Disease', (128, 144))	('presented with', 'Reg', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('PIK3CA', 'Gene', '5290', (93, 99))	('tumours', 'Disease', (211, 218))	('tumour component', 'Disease', 'MESH:D009369', (128, 144))	('PIK3CA', 'Gene', '5290', (154, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('mutation', 'Var', (100, 108))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))
145769	32058674	Patient #3 showed a p.G1049R missense mutation in the HER2-negative invasive component, which was not detected in the DCIS components, irrespective of their HER2 status.	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('HER2', 'Gene', (54, 58))	('invasive component', 'CPA', (68, 86))	('p.G1049R', 'Mutation', 'rs121913277', (20, 28))	('HER2', 'Gene', '2064', (54, 58))	('HER2', 'Gene', (157, 161))	('HER2', 'Gene', '2064', (157, 161))	('p.G1049R missense', 'Var', (20, 37))	('Patient', 'Species', '9606', (0, 7))
145770	32058674	Patient #6 showed a p.Q546E PIK3CA mutation which was present in the HER2-negative invasive component and absent in the admixed HER2-positive invasive component.	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', '2064', (128, 132))	('p.Q546E', 'Mutation', 'rs121913286', (20, 27))	('PIK3CA', 'Gene', (28, 34))	('p.Q546E', 'Var', (20, 27))	('PIK3CA', 'Gene', '5290', (28, 34))	('HER2', 'Gene', (69, 73))	('Patient', 'Species', '9606', (0, 7))	('HER2', 'Gene', '2064', (69, 73))
145771	32058674	Patient #4 had a p.H1047R PIK3CA mutation in each tumour component, but the HER2-negative invasive component harboured an additional p.W1057X mutation, which was not detected in the other tumour components.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumour component', 'Disease', (50, 66))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (76, 80))	('PIK3CA', 'Gene', '5290', (26, 32))	('tumour component', 'Disease', (188, 204))	('p.H1047R', 'Mutation', 'rs121913279', (17, 25))	('tumour component', 'Disease', 'MESH:D009369', (50, 66))	('p.W1057X', 'Var', (133, 141))	('tumour component', 'Disease', 'MESH:D009369', (188, 204))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('PIK3CA', 'Gene', (26, 32))	('p.W1057X', 'Mutation', 'rs267599698', (133, 141))	('Patient', 'Species', '9606', (0, 7))	('p.H1047R', 'Var', (17, 25))
145772	32058674	Somatic ARID1A, MLL3 and NF1 mutations were found in at least one component in three, six and four breast tumours, respectively, and the presence of these mutations was unrelated to the HER2 status (Fig.	('breast tumours', 'Disease', (99, 113))	('HER2', 'Gene', (186, 190))	('MLL3', 'Gene', (16, 20))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('mutations', 'Var', (29, 38))	('HER2', 'Gene', '2064', (186, 190))	('found', 'Reg', (44, 49))	('breast tumours', 'Disease', 'MESH:D001943', (99, 113))	('ARID1A', 'Gene', '8289', (8, 14))	('MLL3', 'Gene', '58508', (16, 20))	('NF1', 'Gene', (25, 28))	('ARID1A', 'Gene', (8, 14))	('NF1', 'Gene', '4763', (25, 28))
145773	32058674	For instance, patient #1 showed a p.C327F MLL3 mutation in the HER2-positive carcinoma component, which was absent in both DCIS components.	('HER2-positive carcinoma component', 'Disease', (63, 96))	('p.C327F', 'Mutation', 'p.C327F', (34, 41))	('p.C327F', 'Var', (34, 41))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('MLL3', 'Gene', '58508', (42, 46))	('HER2-positive carcinoma component', 'Disease', 'MESH:C565165', (63, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('patient', 'Species', '9606', (14, 21))	('MLL3', 'Gene', (42, 46))
145774	32058674	Patient #3 had a nonsense mutation in the HER2-negative invasive component, which was lacking in both DCIS components.	('HER2', 'Gene', '2064', (42, 46))	('invasive component', 'Protein', (56, 74))	('nonsense mutation', 'Var', (17, 34))	('HER2', 'Gene', (42, 46))	('Patient', 'Species', '9606', (0, 7))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
145775	32058674	Patient #8 had a missense MLL3 mutation in the HER2-positive DCIS and HER2-negative invasive component, whereas the HER2-negative DCIS component presented with a different nonsense MLL3 mutation.	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('HER2', 'Gene', (70, 74))	('MLL3', 'Gene', '58508', (181, 185))	('HER2', 'Gene', '2064', (70, 74))	('MLL3', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('HER2', 'Gene', (47, 51))	('MLL3', 'Gene', (181, 185))	('HER2', 'Gene', (116, 120))	('HER2', 'Gene', '2064', (47, 51))	('HER2', 'Gene', '2064', (116, 120))	('MLL3', 'Gene', '58508', (26, 30))	('Patient', 'Species', '9606', (0, 7))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
145776	32058674	Less common somatic variants were observed in AKAP9, ATM, BRCA1, CBFB, CDH1, EGFR, ESR1, FBXW7, GATA3, MAP3K1 , MED12, MLL2, MLLT4, NFATC2, PTEN, RB1, RNF213, RUNX1, SF3B1, SPEN and TBX3 (Table S5).	('variants', 'Var', (20, 28))	('GATA3', 'Gene', '2625', (96, 101))	('FBXW7', 'Gene', (89, 94))	('MLL2', 'Gene', (119, 123))	('MED12', 'Gene', '9968', (112, 117))	('CDH1', 'Gene', (71, 75))	('MLLT4', 'Gene', (125, 130))	('MAP3K1', 'Gene', (103, 109))	('MAP3K1', 'Gene', '4214', (103, 109))	('NFATC2', 'Gene', '4773', (132, 138))	('ESR1', 'Gene', '2099', (83, 87))	('PTEN', 'Gene', (140, 144))	('BRCA1', 'Gene', '672', (58, 63))	('GATA3', 'Gene', (96, 101))	('SPEN', 'Gene', '23013', (173, 177))	('MLL2', 'Gene', '8085', (119, 123))	('CBFB', 'Gene', '865', (65, 69))	('ESR1', 'Gene', (83, 87))	('BRCA1', 'Gene', (58, 63))	('EGFR', 'Gene', '1956', (77, 81))	('SF3B1', 'Gene', (166, 171))	('MLLT4', 'Gene', '4301', (125, 130))	('ATM', 'Gene', '472', (53, 56))	('PTEN', 'Gene', '5728', (140, 144))	('FBXW7', 'Gene', '55294', (89, 94))	('MED12', 'Gene', (112, 117))	('RB1', 'Gene', (146, 149))	('CBFB', 'Gene', (65, 69))	('SPEN', 'Gene', (173, 177))	('AKAP9', 'Gene', '10142', (46, 51))	('AKAP9', 'Gene', (46, 51))	('TBX3', 'Gene', '6926', (182, 186))	('RNF213', 'Gene', '57674', (151, 157))	('SF3B1', 'Gene', '23451', (166, 171))	('RUNX1', 'Gene', (159, 164))	('NFATC2', 'Gene', (132, 138))	('ATM', 'Gene', (53, 56))	('RUNX1', 'Gene', '861', (159, 164))	('RNF213', 'Gene', (151, 157))	('RB1', 'Gene', '5925', (146, 149))	('TBX3', 'Gene', (182, 186))	('EGFR', 'Gene', (77, 81))	('CDH1', 'Gene', '999', (71, 75))
145778	32058674	Somatic GATA3 mutations occurred in HER2-positive tumour components.	('tumour component', 'Disease', (50, 66))	('HER2', 'Gene', (36, 40))	('GATA3', 'Gene', (8, 13))	('HER2', 'Gene', '2064', (36, 40))	('tumour component', 'Disease', 'MESH:D009369', (50, 66))	('GATA3', 'Gene', '2625', (8, 13))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (14, 23))	('occurred', 'Reg', (24, 32))
145782	32058674	Additionally, we observed an EGFR copy number gain in the HER2-negative DCIS component of patient #1 (Fig.	('copy number', 'Var', (34, 45))	('EGFR', 'Gene', '1956', (29, 33))	('patient', 'Species', '9606', (90, 97))	('EGFR', 'Gene', (29, 33))	('gain', 'PosReg', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))
145783	32058674	Patients #3 and #5 had an FGFR1 copy number gain in at least one tumour component.	('copy number', 'Var', (32, 43))	('tumour component', 'Disease', 'MESH:D009369', (65, 81))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('Patients', 'Species', '9606', (0, 8))	('gain', 'PosReg', (44, 48))	('tumour component', 'Disease', (65, 81))
145786	32058674	In patient #5, all tumour components displayed the FGFR1 copy number gain.	('copy number', 'Var', (57, 68))	('tumour component', 'Disease', (19, 35))	('gain', 'PosReg', (69, 73))	('patient', 'Species', '9606', (3, 10))	('tumour component', 'Disease', 'MESH:D009369', (19, 35))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('FGFR1', 'Gene', (51, 56))	('FGFR1', 'Gene', '2260', (51, 56))
145788	32058674	Patient #9 also had a CCND1 copy number gain in the HER2-negative tumour component.	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('HER2-negative tumour component', 'Disease', 'MESH:D064726', (52, 82))	('CCND1', 'Gene', (22, 27))	('gain', 'PosReg', (40, 44))	('CCND1', 'Gene', '595', (22, 27))	('copy number', 'Var', (28, 39))	('HER2-negative tumour component', 'Disease', (52, 82))	('Patient', 'Species', '9606', (0, 7))
145790	32058674	In patient #1, the identified EGFR amplification in the HER2-negative DCIS component was associated with EGFR protein overexpression (Fig.	('amplification', 'Var', (35, 48))	('HER2', 'Gene', (56, 60))	('associated', 'Reg', (89, 99))	('EGFR', 'Gene', (30, 34))	('overexpression', 'PosReg', (118, 132))	('HER2', 'Gene', '2064', (56, 60))	('patient', 'Species', '9606', (3, 10))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (105, 109))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('EGFR', 'Gene', '1956', (30, 34))
145794	32058674	Acquisition of additional oncogenic drivers and passenger mutations will result in subpopulations of cancer cells with different genotypes and phenotypes, and these subclonal aberrations contribute to intratumour heterogeneity (McDonald et al., 2019).	('contribute', 'Reg', (187, 197))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', (206, 212))	('result in', 'Reg', (73, 82))
145801	32058674	In this study, we subjected ten breast cancers with spatially heterogeneous HER2 amplification and corresponding HER2 overexpression to targeted NGS.	('HER2', 'Gene', (76, 80))	('overexpression', 'PosReg', (118, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('HER2', 'Gene', '2064', (76, 80))	('HER2', 'Gene', (113, 117))	('HER2', 'Gene', '2064', (113, 117))	('amplification', 'Var', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancers', 'Phenotype', 'HP:0003002', (32, 46))	('breast cancers', 'Disease', 'MESH:D001943', (32, 46))	('breast cancers', 'Disease', (32, 46))
145803	32058674	For instance, four of seven tumours with a PIK3CA mutation presented this mutation in each component.	('PIK3CA', 'Gene', '5290', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
145804	32058674	Somatic TP53 mutations seemed more often heterogeneously distributed, and their presence seemed generally unrelated to the HER2 amplification status.	('HER2', 'Gene', (123, 127))	('HER2', 'Gene', '2064', (123, 127))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
145808	32058674	High PVT1 expression was associated with clinicopathological markers of poor prognosis, such as larger tumour size, higher TNM stage and the presence of both lymph node and distant metastases (Zou et al., 2019).	('PVT1', 'Gene', (5, 9))	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('High', 'Var', (0, 4))	('PVT1', 'Gene', '5820', (5, 9))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (10, 20))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('metastases', 'Disease', (181, 191))	('tumour', 'Disease', (103, 109))
145809	32058674	In vitro studies demonstrated that PVT1 expression drives cancer cell proliferation through promotion of the KLF5/BAP1/beta-catenin signalling pathway (Tang et al., 2018).	('beta-catenin', 'Gene', '1499', (119, 131))	('PVT1', 'Gene', '5820', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'Var', (40, 50))	('BAP1', 'Gene', '8314', (114, 118))	('drives', 'PosReg', (51, 57))	('promotion', 'PosReg', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('beta-catenin', 'Gene', (119, 131))	('KLF5', 'Gene', '688', (109, 113))	('KLF5', 'Gene', (109, 113))	('cancer', 'Disease', (58, 64))	('PVT1', 'Gene', (35, 39))	('BAP1', 'Gene', (114, 118))
145810	32058674	One patient had a CCND1 copy number gain in a HER2-negative invasive tumour component.	('tumour component', 'Disease', 'MESH:D009369', (69, 85))	('HER2', 'Gene', (46, 50))	('CCND1', 'Gene', '595', (18, 23))	('HER2', 'Gene', '2064', (46, 50))	('invasive tumour', 'Disease', 'MESH:D009361', (60, 75))	('patient', 'Species', '9606', (4, 11))	('invasive tumour', 'Disease', (60, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('gain', 'PosReg', (36, 40))	('tumour component', 'Disease', (69, 85))	('copy number', 'Var', (24, 35))	('CCND1', 'Gene', (18, 23))
145811	32058674	CCND1 amplification is associated with a particular gene expression profile and decreased survival in ER-positive, HER2-negative node-negative breast cancer patients (Lundberg et al., 2019), indicating that CCND1 amplification might act as an alternative driver of carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('HER2', 'Gene', (115, 119))	('breast cancer', 'Disease', (143, 156))	('HER2', 'Gene', '2064', (115, 119))	('CCND1', 'Gene', (207, 212))	('survival', 'MPA', (90, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('carcinogenesis', 'Disease', (265, 279))	('patients', 'Species', '9606', (157, 165))	('decreased', 'NegReg', (80, 89))	('CCND1', 'Gene', (0, 5))	('carcinogenesis', 'Disease', 'MESH:D063646', (265, 279))	('amplification', 'Var', (6, 19))	('CCND1', 'Gene', '595', (207, 212))	('gene expression', 'MPA', (52, 67))	('CCND1', 'Gene', '595', (0, 5))
145812	32058674	Similar observations have been reported for FGFR1 amplification within breast cancer and other types of carcinoma (Helsten et al., 2016).	('breast cancer', 'Disease', (71, 84))	('amplification', 'Var', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('FGFR1', 'Gene', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('FGFR1', 'Gene', '2260', (44, 49))	('carcinoma', 'Disease', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carcinoma', 'Disease', 'MESH:D009369', (104, 113))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
145813	32058674	By using targeted NGS with a 53-gene panel, we identified a plethora of somatic mutations and CNVs within the HER2-negative components in this series of ten HER2 heterogeneous breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (176, 190))	('mutations', 'Var', (80, 89))	('plethora', 'Phenotype', 'HP:0001050', (60, 68))	('HER2', 'Gene', (157, 161))	('breast cancers', 'Disease', 'MESH:D001943', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancers', 'Disease', (176, 190))	('HER2', 'Gene', '2064', (157, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', '2064', (110, 114))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
145819	32058674	Nevertheless, our findings are in accordance with the observations of the TCGA network, who described a high frequency of TP53 (55%) and PIK3CA (31%) mutations, and an low frequency of mutations in RUNX1 (1%), PTEN (0%), NCOR (0%) and CDH1 (3%) in 75 clinically HER2-positive breast cancers (Koboldt et al., 2012).	('NCOR', 'Gene', (221, 225))	('PIK3CA', 'Gene', '5290', (137, 143))	('CDH1', 'Gene', '999', (235, 239))	('breast cancers', 'Phenotype', 'HP:0003002', (276, 290))	('PTEN', 'Gene', (210, 214))	('HER2', 'Gene', '2064', (262, 266))	('NCOR', 'Gene', '9611', (221, 225))	('mutations', 'Var', (150, 159))	('CDH1', 'Gene', (235, 239))	('PTEN', 'Gene', '5728', (210, 214))	('TP53', 'Gene', (122, 126))	('PIK3CA', 'Gene', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('HER2', 'Gene', (262, 266))	('RUNX1', 'Gene', (198, 203))	('RUNX1', 'Gene', '861', (198, 203))	('TP53', 'Gene', '7157', (122, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('breast cancers', 'Disease', 'MESH:D001943', (276, 290))	('breast cancers', 'Disease', (276, 290))
145820	32058674	The TCGA network identified a high frequency of TP53 mutations in ER-negative, HER2-positive breast cancers, whereas ER-positive, HER2-positive breast cancers displayed more often a GATA3 mutation (Koboldt et al., 2012).	('breast cancers', 'Disease', 'MESH:D001943', (93, 107))	('breast cancers', 'Disease', (93, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('HER2', 'Gene', '2064', (79, 83))	('TP53', 'Gene', '7157', (48, 52))	('GATA3', 'Gene', '2625', (182, 187))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('HER2', 'Gene', (130, 134))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('GATA3', 'Gene', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancers', 'Disease', 'MESH:D001943', (144, 158))	('breast cancers', 'Disease', (144, 158))	('mutations', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('HER2', 'Gene', (79, 83))	('breast cancers', 'Phenotype', 'HP:0003002', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('TP53', 'Gene', (48, 52))	('ER-negative', 'Disease', (66, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('HER2', 'Gene', '2064', (130, 134))
145827	32058674	Although regional HER2 heterogeneity is uncommon, this series illustrates that not all cells within one tumour depend exclusively on HER2 amplification and overexpression.	('HER2', 'Gene', '2064', (18, 22))	('overexpression', 'PosReg', (156, 170))	('HER2', 'Gene', (133, 137))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('HER2', 'Gene', '2064', (133, 137))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('amplification', 'Var', (138, 151))	('tumour', 'Disease', (104, 110))	('HER2', 'Gene', (18, 22))
145832	32058674	One in three women with a HER2-positive pure DCIS lesion develops a subsequent HER2-negative invasive breast cancer (Visser et al., 2019), although the clonal relationship between primary and recurrent lesions was not investigated in that study.	('HER2', 'Gene', '2064', (79, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('invasive breast cancer', 'Disease', (93, 115))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('invasive breast cancer', 'Disease', 'MESH:D001943', (93, 115))	('HER2', 'Gene', (26, 30))	('women', 'Species', '9606', (13, 18))	('HER2', 'Gene', '2064', (26, 30))	('lesion', 'Var', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HER2', 'Gene', (79, 83))
145834	32058674	The series of pathogenic and likely pathogenic somatic variants that we describe here yields a wide range of potential alternative drivers of cancer cell proliferation and invasion.	('pathogenic', 'Reg', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('variants', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('invasion', 'CPA', (172, 180))	('cancer', 'Disease', (142, 148))
145835	32058674	Moreover, some genetic anomalies (such as PIK3CA and GATA3 mutations, or FGFR1 copy number gain) might drive resistance to treatment (Pernas et al., 2018; Turner et al., 2010).	('FGFR1', 'Gene', '2260', (73, 78))	('GATA3', 'Gene', (53, 58))	('PIK3CA', 'Gene', (42, 48))	('genetic anomalies', 'Disease', 'MESH:D030342', (15, 32))	('drive', 'Reg', (103, 108))	('GATA3', 'Gene', '2625', (53, 58))	('genetic anomalies', 'Disease', (15, 32))	('PIK3CA', 'Gene', '5290', (42, 48))	('mutations', 'Var', (59, 68))	('copy number', 'Var', (79, 90))	('resistance to treatment', 'MPA', (109, 132))	('FGFR1', 'Gene', (73, 78))	('gain', 'PosReg', (91, 95))
145845	30582225	Ectopic expression of PLC-beta2 in non-invasive breast tumor cells plays a protective role against malignant progression and is correlated with the deregulation of miR-146a Cells in non-invasive breast lesions are widely believed to possess molecular alterations that render them either susceptible or refractory to the acquisition of invasive capability.	('deregulation', 'MPA', (148, 160))	('miR', 'Gene', '220972', (164, 167))	('breast tumor', 'Disease', (48, 60))	('miR', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Ectopic expression', 'Var', (0, 18))	('malignant progression', 'CPA', (99, 120))	('PLC-beta2', 'Gene', '5330', (22, 31))	('breast tumor', 'Phenotype', 'HP:0100013', (48, 60))	('PLC-beta2', 'Gene', (22, 31))	('breast tumor', 'Disease', 'MESH:D001943', (48, 60))
145851	30582225	This suggests that alterations of the PLC-beta2/miR-146a relationship in DCIS may constitute a molecular risk factor for the appearance of new breast lesions.	('miR-146a', 'Gene', '406938', (48, 56))	('breast lesions', 'Disease', (143, 157))	('miR-146a', 'Gene', (48, 56))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('alterations', 'Var', (19, 30))	('risk factor', 'Reg', (105, 116))
145886	30582225	High-quality total RNA from MCF10A and MCF10DCIS cells was extracted with mirVana  miRNA Isolation Kit (Life Technologies) according to the manufacturer's instruction.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (39, 48))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('MCF10DCIS', 'Var', (39, 48))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('MCF10A', 'CellLine', 'CVCL:0598', (28, 34))
145888	30582225	MicroRNAs from MCF10A and MCF10DCIS cells were extracted with miRNeasy Micro kit (QIAGEN), following the manufacturer's instructions.	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('MCF10A', 'CellLine', 'CVCL:0598', (15, 21))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (26, 35))	('MCF10DCIS', 'Var', (26, 35))
145903	30582225	As reported in Figures 2A and 2B, in MCF10DCIS but not in MCF10A the epithelial marker E-cadherin increased and the mesenchymal marker Vimentin decreased when PLC-beta2 was over-expressed.	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('E-cadherin', 'Gene', (87, 97))	('decreased', 'NegReg', (144, 153))	('E-cadherin', 'Gene', '999', (87, 97))	('PLC-beta2', 'Gene', (159, 168))	('Vimentin', 'Gene', (135, 143))	('over-expressed', 'PosReg', (173, 187))	('MCF10DCIS', 'Var', (37, 46))	('Vimentin', 'Gene', '7431', (135, 143))	('increased', 'PosReg', (98, 107))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (37, 46))	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('mesenchymal', 'CPA', (116, 127))
145905	30582225	The analysis of invasion capability performed with the xCELLigence real-time system indicated that down-modulation of PLC-beta2 is sufficient to increase the ability of MCF10DCIS to pass through Matrigel, while it was completely ineffective on motility of untransformed MCF10A (Figures 2C and 2D).	('DCIS', 'Phenotype', 'HP:0030075', (174, 178))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (169, 178))	('increase', 'PosReg', (145, 153))	('pass through Matrigel', 'CPA', (182, 203))	('MCF10DCIS', 'Var', (169, 178))	('PLC-beta2', 'Protein', (118, 127))	('MCF10A', 'CellLine', 'CVCL:0598', (270, 276))	('down-modulation', 'NegReg', (99, 114))
145907	30582225	As revealed by flow cytometry (Figure 2E), only in MCF10DCIS the number of cells expressing CD133 at surface level significantly increased as a consequence of the silencing of PLC-beta2.	('PLC-beta2', 'Protein', (176, 185))	('MCF10DCIS', 'Var', (51, 60))	('silencing', 'NegReg', (163, 172))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (51, 60))	('increased', 'PosReg', (129, 138))	('CD133', 'Gene', (92, 97))	('CD133', 'Gene', '8842', (92, 97))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))
145916	30582225	In particular, PLC-beta2 was almost undetectable in MCF10A cells, coherently with their non-transformed status, while a higher expression was found in MCF10DCIS, in terms of both mRNA (Figure 4A) and protein (Figures 2A and 4C).	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('MCF10DCIS', 'Var', (151, 160))	('expression', 'MPA', (127, 137))	('higher', 'PosReg', (120, 126))	('mRNA', 'MPA', (179, 183))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('PLC-beta2', 'Gene', (15, 24))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (151, 160))
145918	30582225	The use of synthetic mimic and inhibitors showed that silencing of miR-146a induces the expression of PLC-beta2 in both cell lines and that its up-regulation partially down-modulates PLC-beta2 expression only in MCF10DCIS (Figures 4B and 4C).	('PLC-beta2', 'Gene', (102, 111))	('miR-146a', 'Gene', (67, 75))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('up-regulation', 'PosReg', (144, 157))	('silencing', 'Var', (54, 63))	('miR-146a', 'Gene', '406938', (67, 75))	('down-modulates', 'NegReg', (168, 182))	('PLC-beta2', 'Gene', (183, 192))	('MCF10DCIS', 'Var', (212, 221))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (212, 221))	('expression', 'MPA', (193, 203))	('induces', 'Reg', (76, 83))	('expression', 'MPA', (88, 98))
145928	30582225	The luciferase activity, first evaluated in HeLa cells, significantly decreased as a consequence of transfection with miR-146a mimic (Supplementary Figure S4B).	('miR-146a', 'Gene', '406938', (118, 126))	('HeLa', 'CellLine', 'CVCL:0030', (44, 48))	('decreased', 'NegReg', (70, 79))	('activity', 'MPA', (15, 23))	('transfection', 'Var', (100, 112))	('miR-146a', 'Gene', (118, 126))	('luciferase', 'Enzyme', (4, 14))
145935	30582225	When the expression of miR-146a was allocated in two levels on the basis of an arbitrarily selected cut-off, allowing to identify "high" or "low" samples (Figures 6B and 6C), we found that all patients bearing primary DCIS with weak PLC-beta2 and high miR-146a or strong PLC-beta2 and low miR-146a did not recur.	('patients', 'Species', '9606', (193, 201))	('miR-146a', 'Gene', (23, 31))	('miR-146a', 'Gene', (252, 260))	('PLC-beta2', 'Gene', (233, 242))	('miR-146a', 'Gene', '406938', (289, 297))	('high', 'Var', (247, 251))	('miR-146a', 'Gene', '406938', (23, 31))	('miR-146a', 'Gene', '406938', (252, 260))	('miR-146a', 'Gene', (289, 297))	('weak', 'NegReg', (228, 232))	('primary DCIS', 'Disease', (210, 222))	('DCIS', 'Phenotype', 'HP:0030075', (218, 222))
145941	30582225	Using the non-transformed MCF10A and the MCF10DCIS cells, a well-established model of DCIS-derived cells that spontaneously progress into IDC in immune-deficient mice,17 we demonstrate that the forced modulation of PLC-beta2 is unable to modify the phenotype of MCF10A.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (41, 50))	('MCF10A', 'CellLine', 'CVCL:0598', (262, 268))	('modulation', 'Var', (201, 211))	('mice', 'Species', '10090', (162, 166))	('MCF10A', 'CellLine', 'CVCL:0598', (26, 32))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('IDC', 'Gene', '4000', (138, 141))	('IDC', 'Gene', (138, 141))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('PLC-beta2', 'Gene', (215, 224))
145942	30582225	On the other hand, up-modulation of PLC-beta2 promotes an epithelial-like phenotype in non-invasive DCIS, as we previously demonstrated in pre-EMT BT-474 cells.10 Accordingly, its silencing in MCF10DCIS cells is sufficient to up-regulate the mesenchymal marker Vimentin.	('EMT', 'Gene', (143, 146))	('EMT', 'Gene', '3702', (143, 146))	('up-regulate', 'PosReg', (226, 237))	('Vimentin', 'Gene', '7431', (261, 269))	('silencing', 'Var', (180, 189))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (193, 202))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('mesenchymal marker', 'CPA', (242, 260))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('Vimentin', 'Gene', (261, 269))	('MCF10DCIS', 'Gene', (193, 202))
145948	30582225	This was addressed in MCF10-derived cells that, despite their high content of miR-146a, typical of triple-negative breast tumors,31 are suitable for studying the PLC-beta2/miR-146a relationship since a lower miR-146a level and higher PLC-beta2 level characterizes MCF10DCIS when compared with non-transformed MCF10A.	('miR-146a', 'Gene', (208, 216))	('MCF10DCIS', 'Var', (264, 273))	('PLC-beta2', 'MPA', (234, 243))	('miR-146a', 'Gene', '406938', (208, 216))	('DCIS', 'Phenotype', 'HP:0030075', (269, 273))	('MCF10', 'CellLine', 'CVCL:5555', (309, 314))	('miR-146a', 'Gene', (78, 86))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (264, 273))	('lower', 'NegReg', (202, 207))	('higher', 'PosReg', (227, 233))	('miR-146a', 'Gene', '406938', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('MCF10A', 'CellLine', 'CVCL:0598', (309, 315))	('MCF10', 'CellLine', 'CVCL:5555', (22, 27))	('miR-146a', 'Gene', (172, 180))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('miR-146a', 'Gene', '406938', (172, 180))	('breast tumors', 'Disease', 'MESH:D001943', (115, 128))	('breast tumors', 'Disease', (115, 128))	('MCF10', 'CellLine', 'CVCL:5555', (264, 269))	('breast tumors', 'Phenotype', 'HP:0100013', (115, 128))	('breast tumor', 'Phenotype', 'HP:0100013', (115, 127))
145949	30582225	In this breast cancer progression model32 we demonstrate that inhibition of miR-146a significantly increases the PLC-beta2 level in both non-transformed and DCIS-derived cells, suggesting that the down-modulation of this miRNA may underlie the ectopic appearance of PLC-beta2 in mammary tumor cells.	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('miR', 'Gene', '220972', (221, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('PLC-beta2 level', 'MPA', (113, 128))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('miR-146a', 'Gene', '406938', (76, 84))	('inhibition', 'Var', (62, 72))	('tumor', 'Disease', (287, 292))	('miR', 'Gene', (76, 79))	('miR-146a', 'Gene', (76, 84))	('miR', 'Gene', '220972', (76, 79))	('increases', 'PosReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('breast cancer', 'Disease', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('miR', 'Gene', (221, 224))
146044	33498737	Results: 3586 female patients were treated for breast cancer over the 9-year study period (1469 patients from 2009 to 2013 and 2117 from 2014 to 2018), of which 270 (7.53%) had pure DCIS in the final pathology.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('patients', 'Species', '9606', (21, 29))	('pure DCIS', 'Var', (177, 186))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
146180	32980776	Available data on HER2 importance in DCIS are scarce and contradicting, but it has been suggested that the status of HER2 might affect the type of disease recurrence.	('HER2', 'Gene', (117, 121))	('HER2', 'Gene', '2064', (18, 22))	('affect', 'Reg', (128, 134))	('HER2', 'Gene', '2064', (117, 121))	('status', 'Var', (107, 113))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('HER2', 'Gene', (18, 22))
146182	32980776	In addition, HER2 positivity was found more often in patients with pure DCIS compared to those with microinvasive DCIS and DCIS with IDC.	('pure DCIS', 'Disease', (67, 76))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('patients', 'Species', '9606', (53, 61))	('found', 'Reg', (33, 38))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('HER2', 'Gene', '2064', (13, 17))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))
146200	32980776	Cells were grown: (i) HB2 in DMEM supplemented with 10% FBS, 5 mug/ml insulin, 5 mug/ml hydrocortisone and penicillin/streptomycin solution (Pen-Strep); (ii) MCF10A in DMEM F12 supplemented with 5% horse serum, 20 ng/ml EGF, 0.5 mg/ml hydrocortisone, 100 ng/ml cholera toxin, 10 mug/ml insulin and Pen-Strep; and (iii) THP-1 in RPMI-1640 with 10% FBS.	('Pen', 'Gene', '340348', (298, 301))	('Pen', 'Gene', (141, 144))	('insulin', 'Gene', '3630', (286, 293))	('MCF10A', 'Var', (158, 164))	('Pen', 'Gene', '340348', (141, 144))	('HB2', 'Gene', (22, 25))	('Pen', 'Gene', (298, 301))	('THP-1', 'CellLine', 'CVCL:0006', (319, 324))	('insulin', 'Gene', (70, 77))	('insulin', 'Gene', '3630', (70, 77))	('MCF10A', 'CellLine', 'CVCL:0598', (158, 164))	('insulin', 'Gene', (286, 293))	('HB2', 'Gene', '3888', (22, 25))
146275	32980776	Moreover, M1-CM induced stronger phosphorylation of NF-kappaB p65-Ser536 and upregulation of both COX2 and HIF1-alpha in HER2-negative than in HER2-positive HB2 cells (Fig.	('HB2', 'Gene', (157, 160))	('HIF1-alpha', 'Gene', (107, 117))	('phosphorylation', 'MPA', (33, 48))	('HER2', 'Gene', '2064', (121, 125))	('NF-kappaB p65', 'Gene', (52, 65))	('HB2', 'Gene', '3888', (157, 160))	('NF-kappaB p65', 'Gene', '5970', (52, 65))	('M1-CM', 'Var', (10, 15))	('COX2', 'Gene', (98, 102))	('HIF1-alpha', 'Gene', '3091', (107, 117))	('HER2', 'Gene', (143, 147))	('COX2', 'Gene', '4513', (98, 102))	('Ser536', 'Chemical', '-', (66, 72))	('stronger', 'PosReg', (24, 32))	('upregulation', 'PosReg', (77, 89))	('HER2', 'Gene', '2064', (143, 147))	('HER2', 'Gene', (121, 125))
146311	27286830	They genotyped 5067 cases of DCIS, 24,584 cases of IDC, and 37,467 non-cancer controls for 76 different single nucleotide polymorphisms (SNPs), each of which has been shown to be associated with breast cancer susceptibility in previous studies.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('associated', 'Reg', (179, 189))	('non-cancer', 'Disease', (67, 77))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('non-cancer', 'Disease', 'MESH:D009369', (67, 77))	('breast cancer', 'Disease', (195, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('single nucleotide polymorphisms', 'Var', (104, 135))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))
146334	20868895	Over the 3-year study, cysts were seen in 48 (66%) of 73 women using estrogen compared with 489 (37.9%) of 1290 who were not (P<.0001) (see Table 2).	('cysts', 'Disease', (23, 28))	('estrogen', 'Var', (69, 77))	('women', 'Species', '9606', (57, 62))
146385	20868895	Hemorrhagic and proteinaceous cysts appear hyperintense on T1 and hypointense on T2 or STIR.	('proteinaceous cysts', 'Phenotype', 'HP:0200040', (16, 35))	('hypointense', 'Var', (66, 77))	('Hemorrhagic', 'Disease', 'MESH:D006470', (0, 11))	('Hemorrhagic', 'Disease', (0, 11))
146478	20868895	Lactational change can also produce cystic areas within fibroadenomata (also known as lactating adenoma).	('adenoma', 'Disease', 'MESH:D000236', (61, 68))	('cystic areas within fibroadenomata', 'Disease', (36, 70))	('Lactational change', 'Var', (0, 18))	('adenoma', 'Disease', 'MESH:D000236', (96, 103))	('adenoma', 'Disease', (61, 68))	('adenoma', 'Disease', (96, 103))	('cystic areas within fibroadenomata', 'Disease', 'MESH:D001929', (36, 70))	('produce', 'Reg', (28, 35))
146499	31599393	In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively.	('aggressiveness', 'Disease', 'MESH:D001523', (83, 97))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('tumour', 'Disease', 'MESH:D009369', (220, 226))	('HER2', 'Gene', (243, 247))	('protein', 'Protein', (32, 39))	('tumour', 'Disease', (220, 226))	('associated', 'Reg', (55, 65))	('IBC', 'Disease', (17, 20))	('LVI', 'Disease', (194, 197))	('IDH2', 'Gene', (27, 31))	('DCIS', 'Disease', 'MESH:D002285', (8, 12))	('high', 'Var', (108, 112))	('necrosis', 'Disease', 'MESH:D009336', (148, 156))	('BC', 'Phenotype', 'HP:0003002', (18, 20))	('higher grade', 'CPA', (199, 211))	('IDH2', 'Gene', '3418', (27, 31))	('high', 'Var', (22, 26))	('necrosis', 'Disease', (148, 156))	('DCIS', 'Disease', (8, 12))	('HER2', 'Gene', '2064', (243, 247))	('comedo', 'Phenotype', 'HP:0025249', (141, 147))	('aggressiveness', 'Disease', (83, 97))	('IBC', 'Disease', 'MESH:D001943', (17, 20))	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))
146500	31599393	High expression of IDH2 either in mRNA or in protein levels was associated with poor patient's outcome in both DCIS and IBC.	('associated', 'Reg', (64, 74))	('patient', 'Species', '9606', (85, 92))	('IDH2', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('DCIS', 'Disease', (111, 115))	('DCIS', 'Disease', 'MESH:D002285', (111, 115))	('IBC', 'Disease', (120, 123))	('IDH2', 'Gene', '3418', (19, 23))	('BC', 'Phenotype', 'HP:0003002', (121, 123))	('IBC', 'Disease', 'MESH:D001943', (120, 123))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))
146517	31599393	Previous studies have reported upregulation of wild-type IDH2 in lung cancer, ovarian cancer, endometrioid carcinoma, and advanced colorectal cancer.	('wild-type', 'Var', (47, 56))	('ovarian cancer', 'Disease', (78, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('upregulation', 'PosReg', (31, 43))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (94, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (94, 116))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('IDH2', 'Gene', (57, 61))	('lung cancer', 'Disease', (65, 76))	('IDH2', 'Gene', '3418', (57, 61))	('endometrioid carcinoma', 'Disease', (94, 116))	('colorectal cancer', 'Disease', (131, 148))
146518	31599393	Gain of function mutations in IDH2 result in an increase in the oncometabolite 2-hydroxyglutarate (2-HG) which is believed to link aberrant metabolism and aberrant epigenetics and gene regulation in cancer.	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('oncometabolite 2-hydroxyglutarate', 'MPA', (64, 97))	('2-HG', 'Chemical', 'MESH:C019417', (99, 103))	('IDH2', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('IDH2', 'Gene', '3418', (30, 34))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))	('increase', 'PosReg', (48, 56))
146519	31599393	A well-known function of mutant IDH2 has been demonstrated in cancers such as glioma, cholangiocarcinoma, and breast solid papillary carcinoma with reverse polarity (SPCRP).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('mutant', 'Var', (25, 31))	('breast solid papillary carcinoma', 'Disease', (110, 142))	('IDH2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cholangiocarcinoma', 'Disease', (86, 104))	('demonstrated', 'Reg', (46, 58))	('IDH2', 'Gene', '3418', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('glioma', 'Disease', (78, 84))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 104))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('cancers', 'Disease', (62, 69))	('breast solid papillary carcinoma', 'Disease', 'MESH:D001943', (110, 142))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
146563	31599393	In pure DCIS, numerous clinicopathological parameters indicating poor DCIS prognosis were associated with high IDH2 expression (Table 1) including younger age at diagnosis, (p = 0.035), larger tumour size, higher nuclear grade (both p < 0.0001), presence of comedo type necrosis (p = 0.001), hormonal receptor negativity and HER2 positivity (all p < 0.0001).	('IDH2', 'Gene', '3418', (111, 115))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('DCIS', 'Disease', 'MESH:D002285', (8, 12))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('HER2', 'Gene', '2064', (325, 329))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('tumour', 'Disease', (193, 199))	('DCIS', 'Disease', 'MESH:D002285', (70, 74))	('DCIS', 'Disease', (8, 12))	('type necrosis', 'Disease', 'MESH:D009336', (265, 278))	('higher nuclear grade', 'CPA', (206, 226))	('expression', 'MPA', (116, 126))	('high', 'Var', (106, 110))	('type necrosis', 'Disease', (265, 278))	('DCIS', 'Disease', (70, 74))	('HER2', 'Gene', (325, 329))	('IDH2', 'Gene', (111, 115))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))	('comedo', 'Phenotype', 'HP:0025249', (258, 264))
146564	31599393	In IBC, high IDH2 protein expression was associated with positive LVI status (p = 0.002), high histological grade, high Nottingham Prognostic Index (NPI), hormonal receptor negativity, HER2 positivity (all p < 0.0001), large tumour size (p = 0.005), basal phenotype (p = 0.007) and high proliferation index (Ki67) (p = 0.008) (Table 2).	('expression', 'MPA', (26, 36))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('high', 'Var', (8, 12))	('HER2', 'Gene', '2064', (185, 189))	('tumour', 'Disease', (225, 231))	('high proliferation index', 'CPA', (282, 306))	('IDH2', 'Gene', (13, 17))	('IBC', 'Disease', (3, 6))	('BC', 'Phenotype', 'HP:0003002', (4, 6))	('basal phenotype', 'CPA', (250, 265))	('IDH2', 'Gene', '3418', (13, 17))	('IBC', 'Disease', 'MESH:D001943', (3, 6))	('HER2', 'Gene', (185, 189))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('positive LVI status', 'CPA', (57, 76))
146570	31599393	Multivariate survival analysis revealed that a high expression of IDH2 was an independent poor prognostic factor for DCIS recurrence (HR 2.0; 95% CI 1.1-3.9; p = 0.034) regardless of the other variables including patient age at diagnosis, DCIS size, nuclear grade, presence of comedo necrosis and surgical margin width (Table 3).	('DCIS', 'Phenotype', 'HP:0030075', (239, 243))	('IDH2', 'Gene', '3418', (66, 70))	('patient', 'Species', '9606', (213, 220))	('DCIS', 'Disease', 'MESH:D002285', (117, 121))	('DCIS', 'Disease', (117, 121))	('high expression', 'Var', (47, 62))	('comedo', 'Phenotype', 'HP:0025249', (277, 283))	('DCIS', 'Phenotype', 'HP:0030075', (117, 121))	('necrosis', 'Disease', (284, 292))	('DCIS', 'Disease', 'MESH:D002285', (239, 243))	('IDH2', 'Gene', (66, 70))	('DCIS', 'Disease', (239, 243))	('necrosis', 'Disease', 'MESH:D009336', (284, 292))
146571	31599393	Comparable results were obtained in IBC where high IDH2 protein expression was associated with shorter BCSS (HR 1.6; 95% CI 1.2-2.2; p = 0.003; Fig.	('IDH2', 'Gene', '3418', (51, 55))	('IBC', 'Disease', (36, 39))	('high', 'Var', (46, 50))	('expression', 'MPA', (64, 74))	('IBC', 'Disease', 'MESH:D001943', (36, 39))	('BC', 'Disease', 'MESH:D001943', (37, 39))	('protein', 'Protein', (56, 63))	('BC', 'Phenotype', 'HP:0003002', (103, 105))	('IDH2', 'Gene', (51, 55))	('BC', 'Disease', 'MESH:D001943', (103, 105))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
146573	31599393	When the cohort was split into the intrinsic molecular subtypes, high expression of IDH2 protein in luminal B-like was associated with poor outcome in LVI positive tumours (HR 2.1; 95% CI 1.0-4.5; p = 0.044; Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('IDH2', 'Gene', (84, 88))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('IDH2', 'Gene', '3418', (84, 88))	('high', 'Var', (65, 69))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('protein', 'Protein', (89, 96))
146574	31599393	HER2 positivity was in borderline association with overexpression of IDH2 in LVI positive status (p = 0.062; Supplementary Fig.	('positivity', 'Var', (5, 15))	('IDH2', 'Gene', '3418', (69, 73))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('IDH2', 'Gene', (69, 73))	('overexpression', 'PosReg', (51, 65))
146576	31599393	In multivariate Cox regression analysis, high IDH2 protein expression was an independent predictor of shorter BCSS (HR 1.4; 95% CI 1.1-1.9; p = 0.042) regardless of the tumour grade, lymph node stage and nodal status (Table 4).	('IDH2', 'Gene', (46, 50))	('tumour', 'Disease', (169, 175))	('protein', 'Protein', (51, 58))	('IDH2', 'Gene', '3418', (46, 50))	('high', 'Var', (41, 45))	('BC', 'Phenotype', 'HP:0003002', (110, 112))	('Cox', 'Gene', '1351', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('Cox', 'Gene', (16, 19))	('BC', 'Disease', 'MESH:D001943', (110, 112))
146581	31599393	Moreover, in the METABRIC cohort, high IDH2 mRNA levels were associated with large tumour size (p = 0.038), axillary lymph node positivity and HER2 positivity (all; p < 0.0001); (Table 5).	('tumour', 'Disease', (83, 89))	('IDH2', 'Gene', (39, 43))	('HER2', 'Gene', (143, 147))	('mRNA levels', 'MPA', (44, 55))	('high', 'Var', (34, 38))	('IDH2', 'Gene', '3418', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('HER2', 'Gene', '2064', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('positivity', 'Var', (148, 158))	('axillary lymph node positivity', 'CPA', (108, 138))
146582	31599393	In the METABRIC cohort, BCSS of patients with high IDH2 mRNA expression was significantly shorter than those with low expression (HR 1.38; 95% CI 1.2-1.6; p < 0.0001) (Fig.	('IDH2', 'Gene', '3418', (51, 55))	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('shorter', 'NegReg', (90, 97))	('BC', 'Phenotype', 'HP:0003002', (24, 26))	('IDH2', 'Gene', (51, 55))	('mRNA expression', 'MPA', (56, 71))	('BC', 'Disease', 'MESH:D001943', (24, 26))
146583	31599393	External validation using the Gene Miner datasets (n = 4039) of IDH2 further supported that high expression of IDH2 mRNA was positively associated with shorter patient outcome (HR 1.26; 95% CI 1.1-1.4; p = 0.0002), Supplementary Fig.	('IDH2', 'Gene', (64, 68))	('high expression', 'Var', (92, 107))	('IDH2', 'Gene', '3418', (111, 115))	('IDH2', 'Gene', '3418', (64, 68))	('shorter', 'NegReg', (152, 159))	('IDH2', 'Gene', (111, 115))	('patient', 'Species', '9606', (160, 167))
146587	31599393	Wild-type IDH2 was previously described as a key factor in DCIS progression into invasive disease, and controlling LVI.	('DCIS', 'Disease', (59, 63))	('invasive disease', 'Disease', (81, 97))	('DCIS', 'Disease', 'MESH:D002285', (59, 63))	('LVI', 'Disease', (115, 118))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('Wild-type', 'Var', (0, 9))	('IDH2', 'Gene', (10, 14))	('invasive disease', 'Disease', 'MESH:D009361', (81, 97))	('IDH2', 'Gene', '3418', (10, 14))
146593	31599393	Similarly, results in IBC showed that a high IDH2 expression was associated with criteria of aggressive behaviour including LVI, larger tumour size, higher grade and poor NPI.	('high', 'Var', (40, 44))	('IBC', 'Disease', (22, 25))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (93, 113))	('LVI', 'Disease', (124, 127))	('IBC', 'Disease', 'MESH:D001943', (22, 25))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('BC', 'Phenotype', 'HP:0003002', (23, 25))	('tumour', 'Disease', (136, 142))	('associated', 'Reg', (65, 75))	('IDH2', 'Gene', '3418', (45, 49))	('IDH2', 'Gene', (45, 49))	('expression', 'MPA', (50, 60))	('aggressive behaviour', 'Disease', (93, 113))
146595	31599393	High IDH2 expression was also an independent predictor of shorter BCSS either in proteomic or transcriptomic datasets.	('IDH2', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('IDH2', 'Gene', '3418', (5, 9))	('BC', 'Phenotype', 'HP:0003002', (66, 68))	('BC', 'Disease', 'MESH:D001943', (66, 68))
146596	31599393	In METABRIC and bc-Exminer, datasets support the poor prognostic significance of high IDH2 expression.	('IDH2', 'Gene', (86, 90))	('expression', 'MPA', (91, 101))	('high', 'Var', (81, 85))	('IDH2', 'Gene', '3418', (86, 90))
146603	31599393	It has been shown that blocking of alphaKG inhibits cellular transformation and cancerous cell invasion through transamination or reverse TCA cycle.	('blocking', 'Var', (23, 31))	('cancerous', 'Disease', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('alphaKG', 'Protein', (35, 42))	('transamination', 'CPA', (112, 126))	('TCA cycle', 'CPA', (138, 147))	('alphaKG', 'Chemical', 'MESH:C029743', (35, 42))	('TCA', 'Chemical', 'MESH:D014233', (138, 141))	('cancerous', 'Disease', 'MESH:D009369', (80, 89))	('cellular transformation', 'CPA', (52, 75))	('inhibits', 'NegReg', (43, 51))
146605	31599393	This study showed that high IDH2 protein was significantly associated with EGFR which can regulate epithelial mesenchymal transition (EMT), migration and invasion.	('IDH2', 'Gene', '3418', (28, 32))	('high', 'Var', (23, 27))	('invasion', 'CPA', (154, 162))	('IDH2', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (75, 79))	('regulate', 'Reg', (90, 98))	('protein', 'Protein', (33, 40))	('migration', 'CPA', (140, 149))	('EGFR', 'Gene', (75, 79))
146606	31599393	Moreover, this study also demonstrates that high N-cadherin is associated with high IDH2 protein.	('IDH2', 'Gene', (84, 88))	('N-cadherin', 'Gene', (49, 59))	('IDH2', 'Gene', '3418', (84, 88))	('high', 'Var', (79, 83))	('N-cadherin', 'Gene', '1000', (49, 59))
146618	31599393	Many studies provide evidence that oncogenes can alter cancer cell metabolism including glutamine transporters which were associated with high IDH2 in this study.	('glutamine', 'Chemical', 'MESH:C578860', (88, 97))	('IDH2', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('glutamine transporters', 'MPA', (88, 110))	('IDH2', 'Gene', '3418', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('alter', 'Reg', (49, 54))	('high', 'Var', (138, 142))	('cancer', 'Disease', (55, 61))
146620	31599393	Our observations showed that high IDH2 was associated with high grade DCIS and IBC with a highly proliferative index.	('high', 'Var', (29, 33))	('DCIS', 'Disease', 'MESH:D002285', (70, 74))	('DCIS', 'Disease', (70, 74))	('IDH2', 'Gene', (34, 38))	('associated', 'Reg', (43, 53))	('IBC', 'Disease', (79, 82))	('BC', 'Phenotype', 'HP:0003002', (80, 82))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('IBC', 'Disease', 'MESH:D001943', (79, 82))	('IDH2', 'Gene', '3418', (34, 38))
146622	31599393	In this study, IDH2 was also associated with high Ki67 expression reflecting increased cellular proliferation.	('IDH2', 'Gene', (15, 19))	('Ki67', 'Gene', (50, 54))	('IDH2', 'Gene', '3418', (15, 19))	('expression', 'MPA', (55, 65))	('high', 'Var', (45, 49))	('increased', 'PosReg', (77, 86))	('cellular proliferation', 'CPA', (87, 109))
146628	31599393	HER2+ tumours were more likely to have IDH2 protein which is perhaps unsurprising as high grade progressing DCIS and LVI are significantly associated with HER2 positivity.	('HER2', 'Gene', '2064', (155, 159))	('LVI', 'Disease', (117, 120))	('IDH2', 'Gene', (39, 43))	('DCIS', 'Disease', 'MESH:D002285', (108, 112))	('DCIS', 'Disease', (108, 112))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('HER2', 'Gene', '2064', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('IDH2', 'Gene', '3418', (39, 43))	('associated', 'Reg', (139, 149))	('HER2', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('positivity', 'Var', (160, 170))	('tumours', 'Disease', (6, 13))	('HER2', 'Gene', (155, 159))
146630	31599393	IDH2 high expression might enhance HER2 signalling pathways that can have effect on the tumour microenvironment to support the growth of the tumour cell, stimulating invasion, LVI and metastasis in BC.	('invasion', 'CPA', (166, 174))	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('BC', 'Phenotype', 'HP:0003002', (198, 200))	('HER2', 'Gene', (35, 39))	('metastasis', 'CPA', (184, 194))	('high expression', 'Var', (5, 20))	('tumour', 'Disease', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('HER2', 'Gene', '2064', (35, 39))	('stimulating', 'Reg', (154, 165))	('enhance', 'PosReg', (27, 34))	('BC', 'Disease', 'MESH:D001943', (198, 200))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('IDH2', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', (141, 147))	('LVI', 'CPA', (176, 179))	('IDH2', 'Gene', '3418', (0, 4))
146636	31599393	In conclusion high expression of IDH2 is an independent poor prognostic factor in BC.	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('IDH2', 'Gene', (33, 37))	('IDH2', 'Gene', '3418', (33, 37))	('high', 'Var', (14, 18))	('BC', 'Disease', 'MESH:D001943', (82, 84))
146637	31599393	High expression of IDH2 may have a key role in BC progression from DCIS to IBC and in the development of LVI and metastasis.	('IBC', 'Disease', (75, 78))	('High expression', 'Var', (0, 15))	('IDH2', 'Gene', (19, 23))	('IBC', 'Disease', 'MESH:D001943', (75, 78))	('BC', 'Phenotype', 'HP:0003002', (47, 49))	('IDH2', 'Gene', '3418', (19, 23))	('role', 'Reg', (39, 43))	('LVI', 'Disease', (105, 108))	('BC', 'Disease', 'MESH:D001943', (47, 49))	('DCIS', 'Disease', 'MESH:D002285', (67, 71))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('DCIS', 'Disease', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('BC', 'Disease', 'MESH:D001943', (76, 78))
146671	31285590	Some studies showed a slight tendency for high-grade DCIS to progress to invasive breast cancer, but others demonstrated that grade is not significantly associated with the risk of local invasive recurrence.	('high-grade', 'Var', (42, 52))	('invasive breast cancer', 'Disease', 'MESH:D001943', (73, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('progress', 'Reg', (61, 69))	('invasive breast cancer', 'Disease', (73, 95))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
146689	31285590	A retrospective Surveillance, Epidemiology, and End Results (SEER) study demonstrated for the first time that patients with low-grade DCIS had the same overall survival and breast-cancer-specific survival rates with or without surgery.	('breast-cancer', 'Disease', 'MESH:D001943', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('low-grade', 'Var', (124, 133))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('breast-cancer', 'Disease', (173, 186))	('patients', 'Species', '9606', (110, 118))
146718	31285590	Many studies have focussed on identifying molecular markers of the invasive process and recent studies have linked mutations in PIK3CA, TP53 and GATA3 genes with aggressive DCIS; TP53 mutations were reported to be exclusively associated with high-grade DCIS.	('PIK3CA', 'Gene', '5290', (128, 134))	('DCIS', 'Phenotype', 'HP:0030075', (253, 257))	('GATA3', 'Gene', (145, 150))	('mutations', 'Var', (115, 124))	('associated', 'Reg', (226, 236))	('mutations', 'Var', (184, 193))	('high-grade DCIS', 'Disease', (242, 257))	('GATA3', 'Gene', '2625', (145, 150))	('DCIS', 'Phenotype', 'HP:0030075', (173, 177))	('PIK3CA', 'Gene', (128, 134))	('aggressive DCIS', 'Disease', (162, 177))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
146724	31285590	In patients with invasive breast cancer - particularly those with triple-negative and HER2-positive subtypes - the presence of tumour-infiltrating lymphocytes (TILs), especially higher numbers of CD8+ cells, together with fewer FOXP3+ regulatory T cells, is associated with a better outcome.	('HER2', 'Gene', (86, 90))	('FOXP3', 'Gene', '50943', (228, 233))	('CD8+ cells', 'Var', (196, 206))	('invasive breast cancer', 'Disease', (17, 39))	('HER2', 'Gene', '2064', (86, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('TILs', 'Chemical', '-', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (3, 11))	('invasive breast cancer', 'Disease', 'MESH:D001943', (17, 39))	('FOXP3', 'Gene', (228, 233))	('tumour', 'Disease', (127, 133))
146725	31285590	One of the key molecular differences between DCIS and invasive breast cancer is the prevalence of HER2 amplification: 34% for DCIS versus 13% for invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (146, 162))	('DCIS', 'Disease', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('invasive breast cancer', 'Disease', 'MESH:D001943', (54, 76))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('HER2', 'Gene', (98, 102))	('invasive disease', 'Disease', (146, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('HER2', 'Gene', '2064', (98, 102))	('invasive breast cancer', 'Disease', (54, 76))	('amplification', 'Var', (103, 116))
146726	31285590	HER2 amplification might be a prognostic factor in predicting an in situ recurrence after DCIS, but it seems not to be predictive for an invasive recurrence.	('in situ recurrence', 'CPA', (65, 83))	('amplification', 'Var', (5, 18))	('HER2', 'Gene', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('HER2', 'Gene', '2064', (0, 4))
146727	31285590	That said, one study with a long follow-up (mean follow-up >15 years) counterintuitively demonstrated that HER2 positivity in primary DCIS was associated with a lower risk of late invasive breast cancer compared with HER2 negativity.	('lower', 'NegReg', (161, 166))	('late invasive breast cancer', 'Disease', 'MESH:D001943', (175, 202))	('HER2', 'Gene', '2064', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('late invasive breast cancer', 'Disease', (175, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('primary DCIS', 'Disease', (126, 138))	('HER2', 'Gene', (217, 221))	('HER2', 'Gene', (107, 111))	('positivity', 'Var', (112, 122))	('HER2', 'Gene', '2064', (217, 221))
146782	27724884	Figure 5 presents 3 ROC curves for 3 feature size categories - above 0.8 mm (the size of the sensor), 0.5-0.8 mm and below 0.5 mm (including any detectable cancer by pathology, even below 0.1 mm).	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('0.5-0.8 mm', 'Var', (102, 112))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
146797	27724884	Using these differences a good differentiating was achieved between breast tissue states, specifically between cancerous and normal tissue.	('cancerous', 'Disease', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancerous', 'Disease', 'MESH:D009369', (111, 120))	('differences', 'Var', (12, 23))	('breast', 'Disease', (68, 74))
146981	27923387	Other studies have shown that differences in texture and density features are related to predisposing mutations and tumor type including BRCA1/BRCA2 mutation carriers and estrogen receptor (ER) status.	('estrogen receptor', 'Gene', (171, 188))	('BRCA1', 'Gene', '672', (137, 142))	('BRCA2', 'Gene', '675', (143, 148))	('tumor', 'Disease', (116, 121))	('ER', 'Gene', '2099', (190, 192))	('related', 'Reg', (78, 85))	('BRCA1', 'Gene', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BRCA2', 'Gene', (143, 148))	('mutation', 'Var', (149, 157))	('estrogen receptor', 'Gene', '2099', (171, 188))
147056	27923387	Other studies provided an important role for mammographic textures such as fractal dimensions, GLCM matrix parameters, and power Fourier spectrum in distinguishing between BRCA1/BRCA2 gene mutations and cancer risks.	('BRCA1', 'Gene', '672', (172, 177))	('BRCA1', 'Gene', (172, 177))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('BRCA2', 'Gene', (178, 183))	('mutations', 'Var', (189, 198))	('GLCM', 'Chemical', '-', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('BRCA2', 'Gene', '675', (178, 183))
147075	27433280	By univariate analysis, variables associated with an increased LRR were for BCS: HER2 positive, grade III, ductal carcinoma in situ (DCIS), No-pCR (ypTis, ypN0), and age < 40 years; and for mastectomy, HER2-positive, DCIS, No-pCR, and LVI.	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('BCS', 'Gene', '617', (76, 79))	('DCIS', 'Disease', (217, 221))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('HER2', 'Gene', (81, 85))	('BCS', 'Gene', (76, 79))	('HER2', 'Gene', (202, 206))	('grade III', 'Var', (96, 105))	('HER2', 'Gene', '2064', (81, 85))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (107, 131))	('ductal carcinoma in situ', 'Disease', (107, 131))	('HER2', 'Gene', '2064', (202, 206))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (107, 131))
147140	27433280	The role of regional radiotherapy has not been determined; it is indicated for patients with involved lymph nodes undergoing breast cancer or chest wall radiotherapy and should be considered for patients with pN0 and less than 10 nodes removed by axillary lymph node dissection, especially when other risk factors are also present.	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (79, 87))	('breast cancer', 'Disease', (125, 138))	('pN0', 'Var', (209, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
147170	22001071	Two members of this family in particular, MMP-2 and MMP-9, degrade, among other substrates, typeIV collagen, fibronectin and laminin, major components of the basement membrane and are commonly used as markers of the malignant phenotype.	('MMP-9', 'Var', (52, 57))	('fibronectin', 'Gene', '2335', (109, 120))	('MMP-2', 'Gene', (42, 47))	('typeIV collagen', 'MPA', (92, 107))	('degrade', 'NegReg', (59, 66))	('fibronectin', 'Gene', (109, 120))	('laminin', 'Protein', (125, 132))	('MMP-2', 'Gene', '4313', (42, 47))
147175	22001071	Based on their metalloprotease function and substrate specificity, MMPs and ADAMs have been shown to be involved in normal developmental processes such as cardiac and neuronal development, mammary involution and bone turnover and when dysregulated, their activity can lead to diseases including cancer, inflammation, obesity and cardiac hypertrophy.	('MMPs', 'Gene', (67, 71))	('inflammation', 'Disease', 'MESH:D007249', (303, 315))	('inflammation', 'Disease', (303, 315))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('MMPs', 'Gene', '4312;4313;4314;4317;4318;81687', (67, 71))	('cardiac hypertrophy', 'Disease', (329, 348))	('cancer', 'Disease', (295, 301))	('obesity', 'Disease', 'MESH:D009765', (317, 324))	('obesity', 'Phenotype', 'HP:0001513', (317, 324))	('dysregulated', 'Var', (235, 247))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (329, 348))	('lead to', 'Reg', (268, 275))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (329, 348))	('activity', 'MPA', (255, 263))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('obesity', 'Disease', (317, 324))
147200	22001071	Since the presence of MMP-9 and not MMP-2 in urine was shown to correlate with breast cancer, we reasoned that these two substrates could potentially be used successfully to predict disease status.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('correlate', 'Reg', (64, 73))	('MMP-9', 'Var', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('MMP-2', 'Gene', '4313', (36, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('MMP-2', 'Gene', (36, 41))
147201	22001071	Flsub63 is a substrate selective for MMP-2 over MMP-9 and therefore served as a negative control.	('MMP-2', 'Gene', (37, 42))	('MMP-2', 'Gene', '4313', (37, 42))	('Flsub63', 'Var', (0, 7))
147212	22001071	Purified recombinant human ADAM12 has been previously reported to cleave Flsub21 efficiently but not Flsub13 whereas ADAM8 could selectively cleave Flsub13.	('ADAM12', 'Gene', '8038', (27, 33))	('ADAM12', 'Gene', (27, 33))	('Flsub21', 'Gene', (73, 80))	('human', 'Species', '9606', (21, 26))	('cleave', 'Var', (66, 72))	('ADAM8', 'Gene', '101', (117, 122))	('ADAM8', 'Gene', (117, 122))
147242	22001071	This substitution was shown previously to be helpful in increasing TACE activity although it is cleaved by a number of MMP and ADAM family members.	('TACE', 'Gene', (67, 71))	('substitution', 'Var', (5, 17))	('MMP', 'Gene', '4312;4313;4314;4317;4318;81687', (119, 122))	('TACE', 'Gene', '6868', (67, 71))	('increasing', 'PosReg', (56, 66))	('MMP', 'Gene', (119, 122))
147247	22001071	More importantly, however, is the finding that a combination of Flsub21 and Flsub13 activity determined, with 90% certainty, that the individual has either invasive breast cancer or metastatic disease.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('invasive breast cancer', 'Disease', 'MESH:D001943', (156, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('combination', 'Var', (49, 60))	('Flsub21', 'Gene', (64, 71))	('Flsub13', 'Gene', (76, 83))	('metastatic disease', 'Disease', (182, 200))	('invasive breast cancer', 'Disease', (156, 178))
147286	31500225	Additionally, in situ hybridization (e.g., fluorescence in situ hybridization and chromogenic in situ hybridization) is performed to quantify HER2 gene amplification which often results in HER2 overexpression.	('amplification', 'Var', (152, 165))	('HER2', 'Gene', (142, 146))	('overexpression', 'PosReg', (194, 208))	('HER2', 'Gene', '2064', (142, 146))	('results in', 'Reg', (178, 188))	('HER2', 'Gene', (189, 193))	('HER2', 'Gene', '2064', (189, 193))
147309	31500225	Comprehensive BRCA testing is offered by multiple companies to identify BC patients with germline BRCA mutations.	('BRCA', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('BRCA', 'Gene', (14, 18))	('BRCA', 'Gene', '672', (14, 18))	('BC', 'Disease', 'MESH:D001943', (72, 74))	('patients', 'Species', '9606', (75, 83))	('BRCA', 'Gene', '672', (98, 102))
147337	31500225	The ease of sampling combined with the ability to monitor tumor burden or mutation changes temporally with ctDNA, allows for disease monitoring, the evaluation of therapeutic response, and molecular profiling in the advanced disease setting to determine therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutation', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ctDNA', 'Disease', (107, 112))
147338	31500225	For example, the BELLE-2 trial and the SoFEA trial have demonstrated the clinical applicability of ctDNA to detect PI3K and ESR1 mutations, respectively, and the benefit of targeting these mutations with PI3K inhibitors and fulvestrant, respectively.	('clinical', 'Species', '191496', (73, 81))	('mutations', 'Var', (129, 138))	('ESR1', 'Gene', (124, 128))	('PI3K', 'Gene', (115, 119))	('fulvestrant', 'Chemical', 'MESH:C070081', (224, 235))	('ESR1', 'Gene', '2099', (124, 128))
147340	31500225	Another study in a series of patients with advanced breast cancer, showed that mutation levels in plasma samples (liquid biopsies) can provide similar information about clonal hierarchy as that determined by sequencing tissue biopsies.	('patients', 'Species', '9606', (29, 37))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('mutation', 'Var', (79, 87))
147398	31500225	CA20 is an independent predictor of poor survival and a high score is indicative of high chromosomal instability (CIN) and tumor aggressiveness.	('tumor aggressiveness', 'Disease', (123, 143))	('chromosomal instability', 'Phenotype', 'HP:0040012', (89, 112))	('high chromosomal instability', 'MPA', (84, 112))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (123, 143))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('CA20', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
147400	31500225	In their study, CA20 correlated with poor prognosis in eight different cancers (including BC) and can aid stratification of patients with BC.	('CA20', 'Var', (16, 20))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('BC', 'Disease', 'MESH:D001943', (138, 140))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('aid', 'Gene', (102, 105))	('cancers', 'Disease', (71, 78))	('BC', 'Disease', 'MESH:D001943', (90, 92))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aid', 'Gene', '57379', (102, 105))	('patients', 'Species', '9606', (124, 132))
147416	31500225	DNA, RNA, proteomic, copy number variant, and other information can now be seamlessly woven together using sophisticated big data analytics to generate probabilistic causal networks, improving the chances of identifying the perturbations that drive a tumor's biology, or enabling a deeper segmentation of heterogeneous patient cohorts for precision medicine.	('patient', 'Species', '9606', (319, 326))	('tumor', 'Disease', (251, 256))	('drive', 'Reg', (243, 248))	('copy number', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
147418	31500225	Projects like the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) are working toward a shared goal of cataloging oncogenic mutations in order to further our understanding of the genetic basis of cancer, which can have a direct bearing on the diagnosis and management of the disease.	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
147437	23975313	Independent risk factors for close margins included multicentricity, pathologic lesion size >=1.5 cm, and necrosis, but not age, use of skin-sparing mastectomy, or immediate reconstruction (p >0.05).	('necrosis', 'Disease', (106, 114))	('necrosis', 'Disease', 'MESH:D009336', (106, 114))	('skin-sparing', 'Phenotype', 'HP:0000973', (136, 148))	('multicentricity', 'Var', (52, 67))
147451	23975313	Margin status was assigned to one of three groups according to the proximity of carcinoma to the inked surface of the specimen: positive, <=1, 1.1-2.9, and >=3 mm.	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('1.1-2.9', 'Var', (143, 150))	('carcinoma', 'Disease', (80, 89))	('<=1', 'Var', (138, 141))
147469	23975313	On multivariate analysis, the only independent predictors of margins <3 mm were multicentricity, presence of necrosis, and largest recorded pathologic lesion size >=1.5 cm (Table 3).	('multicentricity', 'Var', (80, 95))	('margins', 'Var', (61, 68))	('necrosis', 'Disease', (109, 117))	('necrosis', 'Disease', 'MESH:D009336', (109, 117))
147480	23975313	We found that margin status was the only independent predictor of LRR and on multivariate analysis, the only independent predictors of close margins were pathologic size >=1.5 cm, multicentricity, and necrosis.	('necrosis', 'Disease', (201, 209))	('multicentricity', 'Var', (180, 195))	('necrosis', 'Disease', 'MESH:D009336', (201, 209))
147485	23975313	found a 10.5 % LRR rate among patient with margins <1 mm and suggested reexcision or PMRT for such patients.	('patient', 'Species', '9606', (99, 106))	('patient', 'Species', '9606', (30, 37))	('<1 mm', 'Var', (51, 56))	('LRR', 'Disease', (15, 18))	('patients', 'Species', '9606', (99, 107))
147487	23975313	After excluding four of these patients who were treated with PMRT, they found a 7.5 % LRR rate overall, a 16 % LRR rate for patients with margins <=2 mm, and a 2 % LRR rate for patients with margins 2.1-10 mm.	('LRR', 'Disease', (86, 89))	('<=2 mm', 'Var', (146, 152))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (124, 132))
147610	11092983	RAR alpha LI was significantly correlated with Ki67 LI in DCIS (P=0.0040), especially in estrogen receptor (ER)-positive DCIS.	('estrogen receptor', 'Gene', '2099', (89, 106))	('RAR alpha', 'Gene', '5914', (0, 9))	('DCIS', 'Disease', (58, 62))	('DCIS', 'Disease', (121, 125))	('ER', 'Gene', '2099', (108, 110))	('RAR alpha', 'Gene', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('Ki67 LI', 'Var', (47, 54))	('correlated', 'Reg', (31, 41))	('estrogen receptor', 'Gene', (89, 106))
147620	26812884	Clinical evidence suggested that up-regulation of AQP1 was observed in a variety of malignancies such as brain tumors, cervical carcinoma, and colon tumors and high expression of AQP1 promoted tumor progression.	('brain tumors', 'Disease', 'MESH:D001932', (105, 117))	('brain tumors', 'Phenotype', 'HP:0030692', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cervical carcinoma', 'Disease', 'MESH:D002575', (119, 137))	('up-regulation', 'PosReg', (33, 46))	('AQP1', 'Gene', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('colon tumors', 'Disease', 'MESH:D015179', (143, 155))	('AQP1', 'Gene', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('brain tumors', 'Disease', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('colon tumors', 'Phenotype', 'HP:0100273', (143, 155))	('tumor', 'Disease', (193, 198))	('colon tumors', 'Disease', (143, 155))	('high expression', 'Var', (160, 175))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (111, 116))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('malignancies', 'Disease', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cervical carcinoma', 'Disease', (119, 137))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (149, 154))	('promoted', 'PosReg', (184, 192))
147627	26812884	Furthermore, we demonstrated firstly that high expression of AQP1 indicated a poor prognosis and cytoplasmic expression of AQP1 was an independent prognostic factor of IDC patients.	('IDC', 'Gene', '4000', (168, 171))	('AQP1', 'Gene', (123, 127))	('rat', 'Species', '10116', (23, 26))	('AQP1', 'Gene', (61, 65))	('IDC', 'Gene', (168, 171))	('patients', 'Species', '9606', (172, 180))	('high', 'Var', (42, 46))
147650	26812884	Moreover, patients with high level of AQP1 showed shorter overall survival (OS) (P = 0.001, Figure 4A) and progression-free survival (PFS) (P = 0.002, Figure 4B).	('overall', 'MPA', (58, 65))	('progression-free survival', 'CPA', (107, 132))	('AQP1', 'Gene', (38, 42))	('shorter', 'NegReg', (50, 57))	('patients', 'Species', '9606', (10, 18))	('high level', 'Var', (24, 34))
147653	26812884	In multivariate Cox regression analysis, high cytoplasmic expression of AQP1 was proved to be an independent prognostic factor (Table 3).	('high cytoplasmic expression', 'Var', (41, 68))	('AQP1', 'Gene', (72, 76))	('Cox', 'Gene', (16, 19))	('Cox', 'Gene', '9377', (16, 19))
147655	26812884	The results indicated that high cytoplasmic expression of AQP1 led to a worse prognosis in 275 cases of luminal breast cancer (including 60 luminal A cases and 215 luminal B cases) (Figure 4C-4H).	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('luminal breast cancer', 'Disease', (104, 125))	('high cytoplasmic', 'Var', (27, 43))	('luminal breast cancer', 'Disease', 'MESH:D001943', (104, 125))	('AQP1', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
147661	26812884	Furthermore, the abilities of both proliferation and colony formation increased in both AQP1/MDA-MB-231 and AQP1/MCF7 cells compared with control cells (Figure 5D and 5E).	('increased', 'PosReg', (70, 79))	('proliferation', 'CPA', (35, 48))	('colony formation', 'CPA', (53, 69))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('MCF7', 'CellLine', 'CVCL:0031', (113, 117))	('AQP1/MDA-MB-231', 'Var', (88, 103))	('rat', 'Species', '10116', (42, 45))
147672	26812884	FAK is crucial for migrating and the depletion of AQP1 led to the degradation of FAK which abolished the promotion effects of AQP1 on migration.	('AQP1', 'Gene', (50, 54))	('FAK', 'Gene', (81, 84))	('depletion', 'Var', (37, 46))	('FAK', 'Gene', '5747', (81, 84))	('rat', 'Species', '10116', (22, 25))	('FAK', 'Gene', (0, 3))	('degradation', 'NegReg', (66, 77))	('rat', 'Species', '10116', (137, 140))	('FAK', 'Gene', '5747', (0, 3))
147673	26812884	Moreover, AQP1 also co-localized with ezrin (a cytoskeletal protein that crosslink the actin cytoskeleton and plasma membrane) and knockdown of AQP1 could significantly inhibit cell migration and invasion.	('rat', 'Species', '10116', (185, 188))	('inhibit', 'NegReg', (169, 176))	('AQP1', 'Gene', (144, 148))	('knockdown', 'Var', (131, 140))
147719	25962646	According to the model proposed for breast cancer progression, normal epithelial cells progressively accumulate molecular alterations that result in a series of histologically identifiable, even if non-obligate, cancer precursors.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('result in', 'Reg', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('breast cancer', 'Disease', (36, 49))	('cancer', 'Disease', (43, 49))	('molecular alterations', 'Var', (112, 133))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
147733	25962646	As shown in Figure 1, the subset included genes encoding proteins typically involved in cell fate decision (ABCG2, JAG2, MYC, NOTCH3, PROM1, SOX9, and SOX10), embryonic development (HOXB2, HOXC10, and HOXC11), cell differentiation (ELF5, FOXA1, and PGR), epigenetic control of gene transcription (EZH1, MLL4, and SMARCA4), and cell adhesion (CDC42, CLDN10, EPCAM, ITGA6, ITGB, and ITGB4).	('FOXA1', 'Gene', '3169', (238, 243))	('NOTCH3', 'Gene', (126, 132))	('ABCG2', 'Gene', (108, 113))	('EPCAM', 'Gene', (357, 362))	('cell fate decision', 'CPA', (88, 106))	('SOX9', 'Gene', (141, 145))	('ITGA6', 'Gene', (364, 369))	('HOXC10', 'Gene', '3226', (189, 195))	('ABCG2', 'Gene', '9429', (108, 113))	('HOXC11', 'Gene', '3227', (201, 207))	('FOXA1', 'Gene', (238, 243))	('ELF5', 'Gene', (232, 236))	('HOXC11', 'Gene', (201, 207))	('CDC42', 'Gene', (342, 347))	('JAG2', 'Gene', (115, 119))	('ITGB4', 'Gene', '3691', (381, 386))	('MYC', 'Gene', (121, 124))	('PROM1', 'Gene', (134, 139))	('MLL4', 'Gene', '9757', (303, 307))	('ELF5', 'Gene', '2001', (232, 236))	('SMARCA4', 'Gene', '6597', (313, 320))	('CLDN10', 'Gene', (349, 355))	('HOXB2', 'Gene', '3212', (182, 187))	('CDC42', 'Gene', '998', (342, 347))	('PGR', 'Gene', '5241', (249, 252))	('SOX9', 'Gene', '6662', (141, 145))	('epigenetic', 'Var', (255, 265))	('PROM1', 'Gene', '8842', (134, 139))	('ITGB4', 'Gene', (381, 386))	('CLDN10', 'Gene', '9071', (349, 355))	('ITGA6', 'Gene', '3655', (364, 369))	('JAG2', 'Gene', '3714', (115, 119))	('MLL4', 'Gene', (303, 307))	('HOXC10', 'Gene', (189, 195))	('SOX10', 'Gene', '6663', (151, 156))	('embryonic', 'CPA', (159, 168))	('EPCAM', 'Gene', '4072', (357, 362))	('cell differentiation', 'CPA', (210, 230))	('EZH1', 'Gene', (297, 301))	('MYC', 'Gene', '4609', (121, 124))	('EZH1', 'Gene', '2145', (297, 301))	('SMARCA4', 'Gene', (313, 320))	('cell adhesion', 'CPA', (327, 340))	('NOTCH3', 'Gene', '4854', (126, 132))	('PGR', 'Gene', (249, 252))	('HOXB2', 'Gene', (182, 187))	('involved', 'Reg', (76, 84))	('SOX10', 'Gene', (151, 156))
147735	25962646	Most of the genes in common between ADHs and DCISs encoded proteins involved in cell fate decision (JAG2 and SOX10), embryonic development (HOXA4, HOXA5, HOXA7, HOXA9, and HOXB6), cell differentiation (ELF5 and GATA3) and organization (ACTA2, CD24, CLDN7, JAM2, JAM3, KRT17, MME, and TPJ3), and epigenetic control of gene transcription (CBX8 and EZH2).	('HOXA9', 'Gene', '3205', (161, 166))	('HOXA5', 'Gene', '3202', (147, 152))	('HOXB6', 'Gene', '3216', (172, 177))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('MME', 'Gene', (275, 278))	('HOXB6', 'Gene', (172, 177))	('SOX10', 'Gene', (109, 114))	('HOXA4', 'Gene', '3201', (140, 145))	('JAG2', 'Gene', '3714', (100, 104))	('HOXA5', 'Gene', (147, 152))	('CBX8', 'Gene', (337, 341))	('encoded', 'Reg', (51, 58))	('KRT17', 'Gene', (268, 273))	('cell fate decision', 'CPA', (80, 98))	('CD24', 'Gene', (243, 247))	('HOXA7', 'Gene', '3204', (154, 159))	('HOXA4', 'Gene', (140, 145))	('embryonic development', 'CPA', (117, 138))	('epigenetic control', 'Var', (295, 313))	('JAM3', 'Gene', (262, 266))	('JAM2', 'Gene', (256, 260))	('JAM3', 'Gene', '83700', (262, 266))	('JAM2', 'Gene', '58494', (256, 260))	('cell differentiation', 'CPA', (180, 200))	('ACTA2', 'Gene', (236, 241))	('MME', 'Gene', '4311', (275, 278))	('CLDN7', 'Gene', (249, 254))	('ACTA2', 'Gene', '59', (236, 241))	('GATA3', 'Gene', '2625', (211, 216))	('CLDN7', 'Gene', '1366', (249, 254))	('HOXA9', 'Gene', (161, 166))	('involved', 'Reg', (68, 76))	('CD24', 'Gene', '100133941', (243, 247))	('ELF5', 'Gene', (202, 206))	('GATA3', 'Gene', (211, 216))	('SOX10', 'Gene', '6663', (109, 114))	('HOXA7', 'Gene', (154, 159))	('JAG2', 'Gene', (100, 104))	('CBX8', 'Gene', '57332', (337, 341))	('ELF5', 'Gene', '2001', (202, 206))	('KRT17', 'Gene', '3872', (268, 273))
147755	25962646	Hence, the unexpected underexpression of ELF5 that we observed in HELUs suggests that silencing this gene, possibly via promoter methylation, may be an early event in pathologic transformation.	('ELF5', 'Gene', (41, 45))	('ELF5', 'Gene', '2001', (41, 45))	('silencing', 'Var', (86, 95))
147789	26313374	Nipple-sparing mastectomy in patients with BRCA 1/2 mutations and variants of uncertain significance Nipple-sparing mastectomy (NSM) is associated with improved cosmesis and is increasingly performed.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (29, 37))	('Nipple-sparing mastectomy', 'Disease', (0, 25))	('improved', 'PosReg', (152, 160))	('BRCA 1', 'Gene', (43, 49))	('cosmesis', 'CPA', (161, 169))	('Nipple-sparing mastectomy', 'Disease', (101, 126))	('BRCA 1', 'Gene', '672', (43, 49))
147790	26313374	Its role in BRCA mutation carriers has not been well described.	('BRCA', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('BRCA', 'Gene', '672', (12, 16))
147803	26313374	Nipple-sparing mastectomy is an acceptable choice for patients with BRCA mutations, with no evidence of compromise to oncological safety at short-term follow-up.	('patients', 'Species', '9606', (54, 62))	('BRCA', 'Gene', '672', (68, 72))	('BRCA', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
147805	26313374	It is estimated that 55-65% of women with a BRCA1 mutation and 45% of women with BRCA2 mutation will develop breast cancer by age 70 years.	('BRCA1', 'Gene', (44, 49))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('BRCA2', 'Gene', (81, 86))	('develop', 'PosReg', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA2', 'Gene', '675', (81, 86))	('women', 'Species', '9606', (31, 36))	('women', 'Species', '9606', (70, 75))	('mutation', 'Var', (50, 58))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
147806	26313374	Women diagnosed with breast cancer who are known to have or subsequently found to have a BRCA mutation usually undergo mastectomy, even for early-stage breast cancer amenable to breast-conserving therapy, due to the high risk of developing a second cancer in the ipsilateral breast, and a contralateral prophylactic mastectomy (CPM) is common.	('Women', 'Species', '9606', (0, 5))	('BRCA', 'Gene', (89, 93))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('undergo', 'Reg', (111, 118))	('mastectomy', 'Disease', (119, 129))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (28, 34))	('BRCA', 'Gene', '672', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('mutation', 'Var', (94, 102))
147807	26313374	In addition, many asymptomatic women known to be BRCA mutation carriers choose to undergo risk-reducing bilateral mastectomies with immediate breast reconstruction.	('mutation', 'Var', (54, 62))	('BRCA', 'Gene', (49, 53))	('BRCA', 'Gene', '672', (49, 53))	('women', 'Species', '9606', (31, 36))
147811	26313374	It is also an option for many patients undergoing prophylactic mastectomy who are not limited by such tumor factors, such as asymptomatic BRCA mutation carriers; however, its role in this high-risk population has seldom been reported.	('BRCA', 'Gene', '672', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutation', 'Var', (143, 151))	('BRCA', 'Gene', (138, 142))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
147812	26313374	Because NSM necessitates leaving behind a small amount of breast tissue behind the nipple areolar complex to provide a blood supply, its oncologic safety in BRCA mutation carriers is of particular concern.	('BRCA', 'Gene', (157, 161))	('areolar complex', 'Phenotype', 'HP:0010856', (90, 105))	('carriers', 'Reg', (171, 179))	('mutation', 'Var', (162, 170))	('BRCA', 'Gene', '672', (157, 161))
147813	26313374	In the present study, the indications and outcomes of a large series of BRCA mutation carriers and some patients with Variants of Uncertain Significance (VUS) undergoing NSM at Memorial Sloan Kettering Cancer Center (MSKCC) are presented.	('mutation', 'Var', (77, 85))	('BRCA', 'Gene', '672', (72, 76))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Cancer', 'Disease', (202, 208))	('BRCA', 'Gene', (72, 76))	('Cancer', 'Disease', 'MESH:D009369', (202, 208))	('patients', 'Species', '9606', (104, 112))
147814	26313374	Patients with a documented BRCA mutation undergoing mastectomy for treatment of breast cancer (therapeutic) or risk reduction (prophylactic) were given the option of nipple-sparing versus conventional skin-sparing mastectomy following consideration of several patient and, where relevant, tumor characteristics.	('patient', 'Species', '9606', (260, 267))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('skin-sparing', 'Phenotype', 'HP:0000973', (201, 213))	('BRCA', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (289, 294))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('mutation', 'Var', (32, 40))	('BRCA', 'Gene', '672', (27, 31))
147823	26313374	Although 11 different breast surgeons performed NSMs on BRCA mutation carriers at the institution during this time period, most cases (72%) were performed by only three surgeons.	('mutation', 'Var', (61, 69))	('BRCA', 'Gene', (56, 60))	('BRCA', 'Gene', '672', (56, 60))
147827	26313374	Following approval by the MSKCC institutional review board, a prospectively maintained breast surgery database was used to identify all female patients with BRCA mutations who underwent NSM.	('BRCA', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('BRCA', 'Gene', '672', (157, 161))	('patients', 'Species', '9606', (143, 151))
147829	26313374	These included indications for surgery, type of BRCA mutation, family history of breast and ovarian cancer, and type of reconstruction.	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('mutation', 'Var', (53, 61))	('BRCA', 'Gene', '672', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA', 'Gene', (48, 52))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (81, 106))
147835	26313374	A total of 177 NSMs were performed in 89 patients with a documented BRCA mutation or VUS between September 2005 and December 2013, in total representing 25.5% of the NSMs performed during that period.	('patients', 'Species', '9606', (41, 49))	('mutation', 'Var', (73, 81))	('BRCA', 'Gene', (68, 72))	('BRCA', 'Gene', '672', (68, 72))
147863	26313374	BRCA mutation carriers often undergo bilateral mastectomy for breast cancer treatment or as risk-reducing surgery, but the high breast cancer risk associated with these mutations understandably leads to concern among patients and physicians regarding the oncological safety of NSM.	('BRCA', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (62, 75))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('patients', 'Species', '9606', (217, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
147870	26313374	Although this occurred in only three cases (two in the nipple margin and one in the retroareolar ducts of the breast specimen), it highlights the importance of focused retroareolar tissue assessment and designation of a separate nipple margin even in BRCA mutation carriers undergoing prophylactic NSM.	('BRCA', 'Gene', '672', (251, 255))	('mutation', 'Var', (256, 264))	('BRCA', 'Gene', (251, 255))
147871	26313374	This procedure was performed in 96 of 151 prophylactic NSMs in this study, and the incidental diagnosis of DCIS in 2 of 96 nipple margins (2.1%) justifies sending a separate nipple margin for permanent section in all BRCA mutation carriers undergoing prophylactic NSM.	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('mutation', 'Var', (222, 230))	('BRCA', 'Gene', (217, 221))	('BRCA', 'Gene', '672', (217, 221))
147886	26313374	In a similar study by Yao et al, three of 51 BRCA1/2 mutation carriers undergoing NSM for breast cancer had developed local or regional recurrence at mean follow-up of 32.6 months.	('mutation', 'Var', (53, 61))	('BRCA1/2', 'Gene', '672;675', (45, 52))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('local or regional recurrence', 'CPA', (118, 146))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('BRCA1/2', 'Gene', (45, 52))
147889	26313374	In addition to the risk of true local recurrence following mastectomy, the risk of a new primary breast cancer developing in residual breast tissue is of particular concern in the high-risk group of BRCA mutation carriers undergoing prophylactic or therapeutic mastectomy, and is regarded by some as a reason enough to avoid NSM in these patients.	('mutation', 'Var', (204, 212))	('BRCA', 'Gene', '672', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BRCA', 'Gene', (199, 203))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('patients', 'Species', '9606', (338, 346))
147890	26313374	Only few studies have reported on the incidence of new primary breast cancer post mastectomy in BRCA mutation carriers, and these have not shown an increased risk in such patients.	('carriers', 'Reg', (110, 118))	('BRCA', 'Gene', '672', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BRCA', 'Gene', (96, 100))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('patients', 'Species', '9606', (171, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('mutation', 'Var', (101, 109))
147891	26313374	Domchek et al reported that none of 247 BRCA mutation carriers undergoing prophylactic skin-sparing mastectomy developed breast cancer during a three year follow-up.	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('BRCA', 'Gene', '672', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutation', 'Var', (45, 53))	('breast cancer', 'Disease', (121, 134))	('BRCA', 'Gene', (40, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('skin-sparing', 'Phenotype', 'HP:0000973', (87, 99))
147892	26313374	In a smaller series of 26 BRCA mutation carriers undergoing skin-sparing mastectomy, Hartmann et al similarly reported that none developed breast cancer at 13 years follow-up.	('BRCA', 'Gene', (26, 30))	('skin-sparing', 'Phenotype', 'HP:0000973', (60, 72))	('mutation', 'Var', (31, 39))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('BRCA', 'Gene', '672', (26, 30))
147893	26313374	More recently, Peled et al report that none of 26 patients undergoing prophylactic NSM developed a new primary breast cancer at 51 months follow-up, and Yao et al report development of a new breast cancer in merely one of 150 BRCA1/2 mutation carriers undergoing NSM for risk reduction.	('BRCA1/2', 'Gene', '672;675', (226, 233))	('patients', 'Species', '9606', (50, 58))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('mutation', 'Var', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast cancer', 'Disease', (111, 124))	('breast cancer', 'Disease', (191, 204))	('BRCA1/2', 'Gene', (226, 233))	('Peled', 'Species', '107322', (15, 20))
147895	26313374	Within this large study of BRCA mutation carriers undergoing NSM, only five out of 89 (5.6%) patients and eight out of 177 (4.5%) of breasts subsequently required excision of the NAC for the finding of unexpected carcinoma or due to surgical complications.	('carcinoma', 'Disease', (213, 222))	('BRCA', 'Gene', (27, 31))	('NAC', 'Chemical', '-', (179, 182))	('carcinoma', 'Disease', 'MESH:D002277', (213, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('mutation', 'Var', (32, 40))	('patients', 'Species', '9606', (93, 101))	('BRCA', 'Gene', '672', (27, 31))
147896	26313374	At follow-up of 26 months, there were no cases of local or regional recurrence, or new cancers, supporting the view that this procedure can be safely performed in patients with BRCA mutations or VUS, although a larger cohort and longer follow-up are needed to determine the risk of subsequent cancers in the retained breast tissue.	('cancers', 'Disease', (293, 300))	('cancers', 'Disease', (87, 94))	('patients', 'Species', '9606', (163, 171))	('cancers', 'Phenotype', 'HP:0002664', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('BRCA', 'Gene', '672', (177, 181))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (293, 300))	('BRCA', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))
147897	19491271	Loss of Retinal Cadherin Facilitates Mammary Tumor Progression and Metastasis The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad).	('E-cad', 'Gene', (170, 175))	('E-cadherin', 'Gene', (170, 180))	('Metastasis', 'CPA', (67, 77))	('E-cadherin', 'Gene', '999', (170, 180))	('Tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Facilitates', 'PosReg', (25, 36))	('Retinal Cadherin', 'Gene', (8, 24))	('E-cad', 'Gene', '999', (170, 175))	('E-cad', 'Gene', '999', (182, 187))	('Retinal Cadherin', 'Gene', '1002', (8, 24))	('E-cad', 'Gene', (182, 187))	('Mammary Tumor Progression', 'CPA', (37, 62))	('Loss', 'Var', (0, 4))
147902	19491271	Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression.	('formation of acini', 'CPA', (115, 133))	('disrupted', 'NegReg', (105, 114))	('stimulated', 'PosReg', (77, 87))	('invasiveness', 'CPA', (88, 100))	('E-cad', 'Gene', '999', (152, 157))	('knockdown', 'Var', (38, 47))	('E-cad', 'Gene', (152, 157))
147911	19491271	Ectopic expression of R-cad in BT-20 breast tumor cells induced lamellipodia and motility via Rho GTPase activation.	('breast tumor', 'Phenotype', 'HP:0100013', (37, 49))	('activation', 'PosReg', (105, 115))	('breast tumor', 'Disease', 'MESH:D001943', (37, 49))	('Ectopic expression', 'Var', (0, 18))	('induced', 'PosReg', (56, 63))	('lamellipodia', 'CPA', (64, 76))	('motility', 'CPA', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('breast tumor', 'Disease', (37, 49))	('Rho GTPase', 'Protein', (94, 104))	('R-cad', 'Gene', (22, 27))
147914	19491271	Conversely, another study implicated R-cad in suppression of malignancy:expression was found to be down-regulated in gastrointestinal tumors due to DNA methylation.	('down-regulated', 'NegReg', (99, 113))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('DNA methylation', 'Var', (148, 163))	('expression', 'MPA', (72, 82))	('gastrointestinal tumors', 'Disease', (117, 140))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (117, 140))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (117, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))	('malignancy', 'Disease', (61, 71))
147921	19491271	Furthermore, R-cad suppressed tumor formation and lung colonization in vivo and was associated with repression of the matrix metalloproteinase 1 (MMP1), MMP2, cyclooxygenase 2 (Cox2) gene signature characteristic of pulmonary metastasis.	('MMP1', 'Gene', (146, 150))	('R-cad', 'Var', (13, 18))	('suppressed', 'NegReg', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cyclooxygenase 2', 'Gene', '5743', (159, 175))	('repression', 'NegReg', (100, 110))	('lung colonization', 'CPA', (50, 67))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (216, 236))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MMP2', 'Gene', (153, 157))	('matrix metalloproteinase 1', 'Gene', '4312', (118, 144))	('cyclooxygenase 2', 'Gene', (159, 175))	('MMP2', 'Gene', '4313', (153, 157))	('pulmonary metastasis', 'Disease', (216, 236))	('matrix metalloproteinase 1', 'Gene', (118, 144))	('Cox2', 'Gene', (177, 181))	('Cox2', 'Gene', '5743', (177, 181))	('MMP1', 'Gene', '4312', (146, 150))	('tumor', 'Disease', (30, 35))
147974	19491271	We sought to determine if R-cad is critical for maintenance of the epithelial phenotype using siRNA-mediated knockdown in normal breast cells and overexpression in invasive cells.	('knockdown', 'Var', (109, 118))	('epithelia', 'Disease', (67, 76))	('epithelia', 'Disease', 'None', (67, 76))
147977	19491271	R-cad loss was confirmed by immunostaining of MCF10A knockdowns with anti-R-cad (Fig.	('loss', 'NegReg', (6, 10))	('knockdowns', 'Var', (53, 63))	('R-cad', 'CPA', (0, 5))	('MCF10A', 'CellLine', 'CVCL:0598', (46, 52))	('MCF10A', 'Gene', (46, 52))
147981	19491271	However, transduction of the cells with a green fluorescent protein (GFP)-tagged R-cad (R-cad-GFP) retroviral construct resulted in membrane localization of R-cad (Fig.	('R-cad-GFP', 'Gene', '1002', (88, 97))	('R-cad', 'Var', (157, 162))	('R-cad-GFP', 'Gene', (88, 97))	('membrane localization', 'MPA', (132, 153))	('resulted in', 'Reg', (120, 131))
147989	19491271	Thus, R-cad induces differentiation and morphogenesis of carcinoma cells into structures resembling mammary acini.	('morphogenesis', 'CPA', (40, 53))	('differentiation', 'CPA', (20, 35))	('R-cad', 'Var', (6, 11))	('carcinoma', 'Disease', 'MESH:D002277', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('induces', 'Reg', (12, 19))	('carcinoma', 'Disease', (57, 66))
147993	19491271	We, therefore, tested whether R-cad expression in MDA-MB-231 cells alters endogenous expression of the proinvasive cad-11, because loss of this cadherin might attenuate invasion.	('alters', 'Reg', (67, 73))	('invasion', 'CPA', (169, 177))	('tested', 'Reg', (15, 21))	('cad-11', 'Gene', (115, 121))	('endogenous expression', 'MPA', (74, 95))	('loss', 'Var', (131, 135))	('attenuate', 'NegReg', (159, 168))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (50, 60))	('cad-11', 'Gene', '1009', (115, 121))
147995	19491271	As expected, increases in cell-cell adhesion caused by R-cad led to increases in alpha-cat, beta-cat, and p120 levels (Supplementary Fig.	('increases', 'PosReg', (68, 77))	('increases', 'PosReg', (13, 22))	('p120', 'Gene', '1500', (106, 110))	('beta-cat', 'MPA', (92, 100))	('alpha-cat', 'MPA', (81, 90))	('p120', 'Gene', (106, 110))	('R-cad', 'Var', (55, 60))	('cell-cell adhesion', 'CPA', (26, 44))
147996	19491271	Indeed, R-cad expressing cells had reduced cad-11 expression relative to controls, and the effect was apparent at low and high cell densities (Supplementary Fig.	('cad-11', 'Gene', '1009', (43, 49))	('reduced', 'NegReg', (35, 42))	('R-cad expressing', 'Var', (8, 24))	('cad-11', 'Gene', (43, 49))	('expression', 'MPA', (50, 60))
147997	19491271	However, R-cad expression into an MDA-MB-231 variant cell line devoid of cad-11 and R-cad (231v) suppressed invasion and induced acini (Supplementary Fig.	('invasion', 'CPA', (108, 116))	('cad-11', 'Gene', '1009', (73, 79))	('cad-11', 'Gene', (73, 79))	('induced', 'PosReg', (121, 128))	('acini', 'CPA', (129, 134))	('R-cad', 'Var', (9, 14))	('MDA-MB-231 variant', 'CellLine', 'CVCL:0062', (34, 52))	('suppressed', 'NegReg', (97, 107))
148019	19491271	Aberrations in any of these features can lead to disruption of tissue integrity and onset of metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('lead to', 'Reg', (41, 48))	('Aberrations', 'Var', (0, 11))
148023	19491271	Recently, the gene for R-cad or CDH4 was also found to be methylated in 78% and 95% of colorectal and gastrointestinal tumors, suggesting that it fulfills a previously unsuspected tumor-suppressive function.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (102, 125))	('colorectal and gastrointestinal tumors', 'Disease', 'MESH:D015179', (87, 125))	('methylated', 'Var', (58, 68))	('tumor', 'Disease', (180, 185))	('CDH4', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CDH4', 'Gene', '1002', (32, 36))
148028	19491271	Moreover, knockdown of R-cad in MCF10A mammary cells stimulated invasiveness and disrupted acini formation despite E-cad expression.	('acini formation', 'CPA', (91, 106))	('stimulated', 'PosReg', (53, 63))	('E-cad', 'Gene', (115, 120))	('disrupted', 'NegReg', (81, 90))	('MCF10A', 'CellLine', 'CVCL:0598', (32, 38))	('E-cad', 'Gene', '999', (115, 120))	('invasiveness', 'CPA', (64, 76))	('knockdown', 'Var', (10, 19))	('R-cad', 'Gene', (23, 28))	('MCF10A', 'Gene', (32, 38))
148031	19491271	Other studies found that R-cad knockout in vivo suppressed mesenchymal-to-epithelial transition in the kidney, whereas E-cad ablation did not.	('epithelia', 'Disease', 'None', (74, 83))	('epithelia', 'Disease', (74, 83))	('E-cad', 'Gene', '999', (119, 124))	('suppressed', 'NegReg', (48, 58))	('E-cad', 'Gene', (119, 124))	('knockout', 'Var', (31, 39))	('R-cad', 'Protein', (25, 30))
148032	19491271	Moreover, R-cad expression in E-cad null embryonic stem cell could rescue formation of epithelia, muscle, and gastrointestinal tract.	('E-cad', 'Gene', '999', (30, 35))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (110, 132))	('expression', 'Var', (16, 26))	('E-cad', 'Gene', (30, 35))	('rescue', 'PosReg', (67, 73))	('epithelia', 'Disease', 'None', (87, 96))	('epithelia', 'Disease', (87, 96))	('gastrointestinal tract', 'Disease', (110, 132))
148034	19491271	In contrast to our data, however, a study reported that R-cad transfection into BT-20 breast tumor cells increased motility due to Rac1 and Cdc42 activation.	('Rac1', 'Gene', (131, 135))	('breast tumor', 'Disease', 'MESH:D001943', (86, 98))	('activation', 'PosReg', (146, 156))	('breast tumor', 'Phenotype', 'HP:0100013', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Cdc42', 'Gene', (140, 145))	('Cdc42', 'Gene', '998', (140, 145))	('breast tumor', 'Disease', (86, 98))	('motility', 'CPA', (115, 123))	('increased', 'PosReg', (105, 114))	('transfection', 'Var', (62, 74))	('Rac1', 'Gene', '5879', (131, 135))
148062	22649753	Another biologically distinct subset of breast cancer was discovered by novel work investigating the amplification of the human epidermal growth factor receptor 2 (HER2/neu) oncogene in breast cancer (Slamon et al.,).	('human', 'Species', '9606', (122, 127))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('neu', 'Gene', '2064', (169, 172))	('neu', 'Gene', (169, 172))	('breast cancer', 'Disease', (40, 53))	('amplification', 'Var', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('epidermal growth factor receptor 2', 'Gene', (128, 162))	('HER2', 'Gene', (164, 168))	('epidermal growth factor receptor 2', 'Gene', '2064', (128, 162))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('HER2', 'Gene', '2064', (164, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))
148063	22649753	The analysis of 189 primary breast tumors showed that the amplification of the HER2/neu oncogene occurred in 25-30% of the specimens and that this genomic alteration predicted poor clinical outcome, even after adjustment for other prognostic variables.	('HER2', 'Gene', '2064', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('neu', 'Gene', '2064', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('neu', 'Gene', (84, 87))	('breast tumors', 'Phenotype', 'HP:0100013', (28, 41))	('breast tumor', 'Phenotype', 'HP:0100013', (28, 40))	('breast tumors', 'Disease', (28, 41))	('breast tumors', 'Disease', 'MESH:D001943', (28, 41))	('amplification', 'Var', (58, 71))	('HER2', 'Gene', (79, 83))
148113	22649753	TN tumors with high Ki-67 were also found to have an increased rate of LRR.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('Ki-67', 'Var', (20, 25))	('TN tumors', 'Disease', 'MESH:C562719', (0, 9))	('high Ki-67', 'Var', (15, 25))	('TN tumors', 'Disease', (0, 9))	('LRR', 'Disease', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
148158	22649753	Currently, the National Comprehensive Cancer Network (NCCN) recommends tumor bed boost for women at higher risk for recurrence including women <50 years old, positive axillary lymph nodes, close surgical margins, or LVI1.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('women', 'Species', '9606', (91, 96))	('Cancer', 'Disease', (38, 44))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('LVI1', 'Var', (216, 220))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('women', 'Species', '9606', (137, 142))	('tumor', 'Disease', (71, 76))
148178	22649753	One example is a 21-gene recurrence score assay (Oncotype DX, Genomic Health, Redwood City, CA, USA) that was developed through the prospective selection of genes that were thought to correlate with distant recurrence risk in node-negative, ER(+) breast cancer (Paik et al.,).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('node-negative', 'Disease', (226, 239))	('ER', 'Gene', '2099', (241, 243))	('genes', 'Var', (157, 162))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (247, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('Redwood', 'Species', '28980', (78, 85))
148250	28877935	Targeting Aberrant p70S6K Activation for Estrogen Receptor Negative Breast Cancer Prevention The prevention of estrogen receptor negative (ER-) breast cancer remains a major challenge in the cancer prevention field although anti-estrogen and aromatase inhibitors (AIs) have shown adequate efficacy in preventing estrogen receptor positive (ER+) breast cancer.	('p70S6K', 'Gene', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (352, 358))	('Aberrant', 'Var', (10, 18))	('breast cancer', 'Disease', (144, 157))	('Breast Cancer', 'Disease', 'MESH:D001943', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Disease', (191, 197))	('Activation', 'PosReg', (26, 36))	('Breast Cancer', 'Disease', (68, 81))	('cancer', 'Disease', (151, 157))	('estrogen receptor', 'Gene', '2099', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('estrogen receptor', 'Gene', (312, 329))	('breast cancer', 'Phenotype', 'HP:0003002', (345, 358))	('Estrogen Receptor', 'Gene', '2099', (41, 58))	('Breast Cancer', 'Phenotype', 'HP:0003002', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('p70S6K', 'Gene', '6198', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (345, 358))	('Estrogen Receptor', 'Gene', (41, 58))	('breast cancer', 'Disease', (345, 358))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('estrogen receptor', 'Gene', (111, 128))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('estrogen receptor', 'Gene', '2099', (312, 329))
148253	28877935	Additionally, p70S6K activation induced transformation of ER- human mammary epithelial cells (hMECs).	('ER- human mammary epithelial cells', 'CPA', (58, 92))	('human', 'Species', '9606', (62, 67))	('p70S6K', 'Var', (14, 20))	('transformation', 'CPA', (40, 54))	('activation', 'PosReg', (21, 31))
148254	28877935	Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER- hMECs models and mouse mammary tumor models for the prevention of ER- breast cancer.	('p70S6K', 'Var', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Disease', (121, 126))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
148255	28877935	We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell cycle blockade at G0-G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs.	('Cyclin B1', 'Gene', '891', (162, 171))	('ErbB2', 'Gene', (126, 131))	('rat', 'Species', '10116', (105, 108))	('Cyclin B1', 'Gene', (162, 171))	('p70S6K', 'Var', (140, 146))	('LY2780301', 'Var', (65, 74))	('cell cycle', 'CPA', (187, 197))	('ErbB2', 'Gene', '2064', (126, 131))	('decreased', 'NegReg', (88, 97))	('LY2780301', 'Chemical', '-', (65, 74))	('activation', 'PosReg', (147, 157))	('proliferation of hMECs', 'CPA', (98, 120))
148256	28877935	In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (115, 140))	('hyperplasic MECs', 'Disease', (258, 274))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (76, 96))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('mice', 'Species', '10090', (56, 60))	('LY2780301', 'Var', (34, 43))	('MMTV', 'Species', '11757', (47, 51))	('hyperplasic MECs', 'Disease', 'None', (258, 274))	('decrease', 'NegReg', (227, 235))	('p70S6K', 'Var', (170, 176))	('LY2780301', 'Chemical', '-', (34, 43))	('suppress', 'NegReg', (195, 203))	('intraepithelial neoplasia (MIN) lesions', 'Disease', 'MESH:D019048', (115, 154))	('atypical hyperplasia', 'Disease', (76, 96))	('rat', 'Species', '10116', (248, 251))
148257	28877935	In summary, targeting the aberrant Akt/p70S6K activation in ER- hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER- breast cancer.	('aberrant', 'Var', (26, 34))	('breast cancer', 'Disease', (312, 325))	('Akt/p70S6K', 'Gene', (35, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (312, 325))	('activation', 'PosReg', (46, 56))	('transgenic', 'Species', '10090', (105, 115))	('reduced', 'NegReg', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('rat', 'Species', '10116', (195, 198))	('Akt/S6K signaling', 'Pathway', (158, 175))	('inhibited', 'NegReg', (148, 157))	('p70S6K', 'Var', (291, 297))	('mouse', 'Species', '10090', (116, 121))	('proliferation', 'CPA', (188, 201))	('MMTV', 'Species', '11757', (96, 100))	('breast cancer', 'Disease', 'MESH:D001943', (312, 325))
148260	28877935	Over the last two decades, extensive clinical trials testing the efficacy of selective estrogen receptor modulators (SERMs, such as Tamoxifen) or aromatase inhibitors (AIs) on breast cancer prevention in high risk populations have demonstrated that anti-estrogen could reduce the development of ER+ breast tumor by approximately 50% in various age groups.	('estrogen receptor', 'Gene', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('breast tumor', 'Disease', (299, 311))	('Tamoxifen', 'Chemical', 'MESH:D013629', (132, 141))	('estrogen receptor', 'Gene', '2099', (87, 104))	('anti-estrogen', 'Var', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('rat', 'Species', '10116', (238, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast tumor', 'Phenotype', 'HP:0100013', (299, 311))	('reduce', 'NegReg', (269, 275))	('breast cancer', 'Disease', (176, 189))	('breast tumor', 'Disease', 'MESH:D001943', (299, 311))
148265	28877935	Aberrantly activated kinase pathways are ideal targets that can be specifically targeted with kinase inhibitors for the treatment of cancer and other diseases.	('Aberrantly', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('kinase pathways', 'Pathway', (21, 36))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
148270	28877935	Aberrations at multiple levels may lead to the 70kDa ribosomal protein S6 kinase (p70S6K) pathway activation, contributing to the development of breast cancer.	('activation', 'PosReg', (98, 108))	('70kDa', 'Pathway', (47, 52))	('ribosomal protein S6', 'Gene', (53, 73))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('lead to', 'Reg', (35, 42))	('ribosomal protein S6', 'Gene', '6194', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('contributing to', 'Reg', (110, 125))
148273	28877935	We investigated the effect of targeting this pathway with an Akt/p70S6K dual inhibitor LY2780301 in p70S6K-activated, ER- human mammary epithelial cell (hMEC) model and the MMTV-neu mouse model of ER- mammary tumors having p70S6K activation to develop targeted prevention strategies for ER- breast cancer.	('human', 'Species', '9606', (122, 127))	('tumors', 'Disease', (209, 215))	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('p70S6K', 'Var', (223, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('mouse', 'Species', '10090', (182, 187))	('breast cancer', 'Disease', (291, 304))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('rat', 'Species', '10116', (274, 277))	('MMTV', 'Species', '11757', (173, 177))	('LY2780301', 'Var', (87, 96))	('LY2780301', 'Chemical', '-', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
148274	28877935	We found that LY2780301 blocked the phosphorylation of ribosomal protein S6 and PRAS40, downstream of p70S6K and Akt, respectively, in hMECs and resulted in a drastic decrease in cell proliferation, although LY2780301 did not apparently reverse the acinar morphology of p70S6K-activated hMECs.	('ribosomal protein S6', 'Gene', (55, 75))	('cell proliferation', 'CPA', (179, 197))	('LY2780301', 'Var', (208, 217))	('p70S6K', 'Var', (102, 108))	('LY2780301', 'Chemical', '-', (208, 217))	('rat', 'Species', '10116', (191, 194))	('ribosomal protein S6', 'Gene', '6194', (55, 75))	('decrease', 'NegReg', (167, 175))	('LY2780301', 'Var', (14, 23))	('Akt', 'Gene', (113, 116))	('LY2780301', 'Chemical', '-', (14, 23))	('PRAS40', 'Gene', '84335', (80, 86))	('PRAS40', 'Gene', (80, 86))	('blocked', 'NegReg', (24, 31))	('phosphorylation', 'MPA', (36, 51))
148275	28877935	Nevertheless, a brief treatment of LY2780301 in MMTV-neu mice with atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions was sufficient to suppress S6 phosphorylation in these lesions and led to a decreased cell proliferation in early stage mammary lesions in vivo, suggesting that targeting p70S6K could deter abnormal proliferation of ER- early mammary lesions.	('deter', 'NegReg', (330, 335))	('mice', 'Species', '10090', (57, 61))	('MMTV', 'Species', '11757', (48, 52))	('rat', 'Species', '10116', (352, 355))	('atypical hyperplasia', 'Disease', (67, 87))	('ER- early mammary lesions', 'CPA', (362, 387))	('p70S6K', 'Var', (317, 323))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (106, 131))	('LY2780301', 'Var', (35, 44))	('intraepithelial neoplasia (MIN) lesions', 'Disease', 'MESH:D019048', (106, 145))	('phosphorylation', 'MPA', (176, 191))	('LY2780301', 'Chemical', '-', (35, 44))	('cell proliferation in early stage mammary lesions', 'CPA', (232, 281))	('rat', 'Species', '10116', (244, 247))	('atypical hyperplasia', 'Disease', 'MESH:D004714', (67, 87))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))	('decreased', 'NegReg', (222, 231))	('suppress', 'NegReg', (164, 172))
148282	28877935	Cultures were fixed with 4% paraformaldehyde, permeabilized with 0.5% Triton X-100, washed 3 times with PBS/Glycine buffer (130 mM, 7 mM, Na2HPO4, 3.5 mM NaH2PO4, and 100 mM glycine) and incubated with IF buffer (130 mM, 7 mM Na2HPO4, 3.5 mM NaH2PO4, 7.7 mM NaN3, 0.1% bovine serum albumin, 0.2% Triton X-100, and 0.05% Tween 20) for 1 hour.	('Na2HPO4', 'Var', (226, 233))	('bovine', 'Species', '9913', (269, 275))	('PBS', 'Chemical', 'MESH:D007854', (104, 107))	('NaH2PO4', 'Var', (242, 249))
148316	28877935	To examine the function of Akt/p70S6K pathway in early transformation of ER- hMECs, we stably overexpressed p70S6K in the non-tumorigenic ER- hMEC line MCF-10A (10A.S6K) along with vector control cells (10A.Vec) (Fig.	('p70S6K', 'Var', (108, 114))	('MCF-10A', 'CellLine', 'CVCL:0598', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
148319	28877935	Furthermore, we treated the 10A.S6K cells and the 10A.Vec cells under 3D culture with LY2780301, a small molecule dual inhibitor that acts as a selective and reversible ATP-competitor for p70S6 kinase and Akt [Eli Lilly and Company].	('ATP', 'Chemical', 'MESH:D000255', (169, 172))	('LY2780301', 'Chemical', '-', (86, 95))	('LY2780301', 'Var', (86, 95))	('Akt', 'Pathway', (205, 208))
148320	28877935	Remarkably, the abnormal acinar growth of 10A.S6K cells was effectively blocked by the inhibitor LY2780301 in 3D culture (Fig.	('LY2780301', 'Chemical', '-', (97, 106))	('LY2780301', 'Var', (97, 106))	('blocked', 'NegReg', (72, 79))
148322	28877935	ErbB2 overexpression was found in >60% early stage breast cancer in patients and could lead to p70S6K activation via PI3K/Akt pathway.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ErbB2', 'Gene', (0, 5))	('patients', 'Species', '9606', (68, 76))	('activation', 'PosReg', (102, 112))	('ErbB2', 'Gene', '2064', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('overexpression', 'PosReg', (6, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('p70S6K', 'Var', (95, 101))	('early', 'Disease', (39, 44))	('breast cancer', 'Disease', (51, 64))	('PI3K/Akt pathway', 'Pathway', (117, 133))
148323	28877935	To test the general effect of targeting aberrant p70S6K activation in p70S6K-activated mammary epithelial cells of early transformation frequently seen in patients, we employed ErbB2-expressing vector transfected MCF-10A hMECs (10A.B2) that have constitutive p70S6K activation due to the overexpression of ErbB2.	('ErbB2', 'Gene', (177, 182))	('MCF-10A', 'CellLine', 'CVCL:0598', (213, 220))	('ErbB2', 'Gene', '2064', (306, 311))	('overexpression', 'PosReg', (288, 302))	('activation', 'PosReg', (266, 276))	('ErbB2', 'Gene', '2064', (177, 182))	('p70S6K', 'Var', (259, 265))	('patients', 'Species', '9606', (155, 163))	('ErbB2', 'Gene', (306, 311))
148325	28877935	LY2780301 treatment efficiently reduced the levels of p-S6 in 10A.B2 cells in a concentration-dependent manner under 3D culture, however, it only mildly inhibited p-PRAS40 (downstream target of Akt) at higher concentrations (1~2 microM) (Fig.	('LY2780301', 'Var', (0, 9))	('p-S6', 'MPA', (54, 58))	('reduced', 'NegReg', (32, 39))	('PRAS40', 'Gene', '84335', (165, 171))	('LY2780301', 'Chemical', '-', (0, 9))	('PRAS40', 'Gene', (165, 171))	('levels', 'MPA', (44, 50))	('rat', 'Species', '10116', (216, 219))	('rat', 'Species', '10116', (87, 90))	('inhibited', 'NegReg', (153, 162))
148328	28877935	LY2780301 (1 microM) treatment significantly inhibited the growth of 10A.B2 disorganized acini and 10A.Vec acini, although the "DCIS-like" morphology in treated 10A.B2 cells was not completely reversed (Fig.	('growth', 'CPA', (59, 65))	('LY2780301', 'Var', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('LY2780301', 'Chemical', '-', (0, 9))	('inhibited', 'NegReg', (45, 54))
148329	28877935	Consistently, a proliferation marker, PCNA level was more dramatically reduced in 10A.B2 cells with LY2780301 treatment compared with 10A.Vec cells under the same conditions (Fig.	('rat', 'Species', '10116', (23, 26))	('PCNA level', 'MPA', (38, 48))	('reduced', 'NegReg', (71, 78))	('LY2780301 treatment', 'Var', (100, 119))	('LY2780301', 'Chemical', '-', (100, 109))
148330	28877935	Furthermore, 10A.B2 cells undergoing LY2780301 treatment had reduced Ki-67 staining indicating a consistent decrease in cell proliferation; whereas they showed no significant change in cleaved Caspase-3 staining indicating no induction of apoptosis (Fig.	('cell proliferation', 'CPA', (120, 138))	('LY2780301', 'Var', (37, 46))	('Ki-67', 'Gene', (69, 74))	('rat', 'Species', '10116', (132, 135))	('LY2780301', 'Chemical', '-', (37, 46))	('Ki-67', 'Gene', '17345', (69, 74))	('Caspase-3', 'Gene', (193, 202))	('decrease', 'NegReg', (108, 116))	('Caspase-3', 'Gene', '836', (193, 202))	('reduced', 'NegReg', (61, 68))
148332	28877935	Again, LY2780301 significantly inhibited proliferation of the 10A.B2 cells (p<0.001) but had a less degree of inhibition on 10A.Vec cells when compared to vehicle-treated cells (Fig.	('proliferation', 'CPA', (41, 54))	('LY2780301', 'Var', (7, 16))	('LY2780301', 'Chemical', '-', (7, 16))	('inhibited', 'NegReg', (31, 40))	('rat', 'Species', '10116', (48, 51))
148334	28877935	Moreover, flow cytometry detection of BrdU incorporation (DNA synthesis marker) and propidium iodide (PI, marks DNA content) staining revealed a major dose-dependent cell cycle stall in G0-G1 phase in 10A.B2 cells treated with LY2780301, resulting in dramatic decreases in actively proliferating cells (S phase and G2-M phase) (Fig.	('rat', 'Species', '10116', (289, 292))	('BrdU', 'Chemical', 'MESH:D001973', (38, 42))	('rat', 'Species', '10116', (50, 53))	('propidium iodide', 'Chemical', 'MESH:D011419', (84, 100))	('LY2780301', 'Var', (227, 236))	('cell cycle', 'CPA', (166, 176))	('LY2780301', 'Chemical', '-', (227, 236))	('decreases', 'NegReg', (260, 269))
148336	28877935	RPPA data showed that LY2780301 indeed inhibited p70S6K effectively, leading to reduced phosphorylation on S6 at multiple sites (Fig.	('phosphorylation', 'MPA', (88, 103))	('LY2780301', 'Var', (22, 31))	('inhibited', 'NegReg', (39, 48))	('reduced', 'NegReg', (80, 87))	('p70S6K', 'Var', (49, 55))	('LY2780301', 'Chemical', '-', (22, 31))
148337	28877935	Notably, the level of Cyclin B1 was significantly decreased in 10A.B2 cells treated with LY2780301 under both 2D and 3D conditions, while Cyclin B1 level was not significantly reduced in 10A.Vec cells treated by LY2780301 (Fig.	('level', 'MPA', (13, 18))	('LY2780301', 'Var', (89, 98))	('Cyclin B1', 'Gene', (138, 147))	('LY2780301', 'Chemical', '-', (89, 98))	('LY2780301', 'Chemical', '-', (212, 221))	('decreased', 'NegReg', (50, 59))	('Cyclin B1', 'Gene', '891', (22, 31))	('Cyclin B1', 'Gene', (22, 31))	('Cyclin B1', 'Gene', '891', (138, 147))
148338	28877935	The decrease in Cyclin B1 is likely resulted from lowered protein synthesis due to p70S6K inhibition.	('lowered', 'NegReg', (50, 57))	('inhibition', 'NegReg', (90, 100))	('p70S6K', 'Var', (83, 89))	('decrease', 'NegReg', (4, 12))	('Cyclin B1', 'Gene', '891', (16, 25))	('protein synthesis', 'MPA', (58, 75))	('Cyclin B1', 'Gene', (16, 25))
148341	28877935	RPPA data also showed that Akt phosphorylation at both Ser473 and Thr308 sites were dramatically increased by LY2780301 treatment compared to vehicle control, in both culture conditions (Fig.	('Ser473', 'Chemical', '-', (55, 61))	('Akt', 'Pathway', (27, 30))	('increased', 'PosReg', (97, 106))	('Thr308', 'Chemical', '-', (66, 72))	('LY2780301', 'Var', (110, 119))	('Thr308', 'Var', (66, 72))	('LY2780301', 'Chemical', '-', (110, 119))	('Ser473', 'Var', (55, 61))
148343	28877935	The increased Akt phosphorylation could account for no induction of apoptosis by LY2780301 treatment.	('Akt phosphorylation', 'CPA', (14, 33))	('LY2780301', 'Var', (81, 90))	('increased', 'PosReg', (4, 13))	('LY2780301', 'Chemical', '-', (81, 90))
148344	28877935	Additionally, phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) was another consistently elevated phospho-protein by LY2780301 treatment (Fig.	('phospho-protein', 'MPA', (93, 108))	('LY2780301', 'Var', (112, 121))	('Erk1/2', 'Gene', '5595;5594', (35, 41))	('elevated', 'PosReg', (84, 92))	('LY2780301', 'Chemical', '-', (112, 121))	('phospho-p44/42', 'Var', (14, 28))	('Thr202/Tyr204', 'Var', (44, 57))	('Erk1/2', 'Gene', (35, 41))	('Tyr204', 'Chemical', '-', (51, 57))	('Thr202', 'Chemical', '-', (44, 50))
148345	28877935	To suppress LY2780301 induced Akt phosphorylation, we used the PI3Kalpha/delta inhibitor GDC-0941.	('LY2780301', 'Chemical', '-', (12, 21))	('PI3Kalpha', 'Gene', '5290', (63, 72))	('PI3Kalpha', 'Gene', (63, 72))	('Akt', 'Pathway', (30, 33))	('suppress', 'NegReg', (3, 11))	('GDC-0941', 'Chemical', 'MESH:C532162', (89, 97))	('LY2780301', 'Var', (12, 21))
148346	28877935	Combination of GDC-0941 with LY2780301 effectively blocked S6 phosphorylation and hampered Akt activation (Fig.	('LY2780301', 'Var', (29, 38))	('LY2780301', 'Chemical', '-', (29, 38))	('GDC-0941', 'Chemical', 'MESH:C532162', (15, 23))	('Akt', 'Pathway', (91, 94))	('blocked', 'NegReg', (51, 58))	('hampered', 'NegReg', (82, 90))
148348	28877935	These data indicate that LY2780301-induced Akt phosphorylation is PI3K-dependent.	('LY2780301-induced', 'Var', (25, 42))	('phosphorylation', 'MPA', (47, 62))	('Akt', 'Pathway', (43, 46))	('LY2780301', 'Chemical', '-', (25, 34))
148349	28877935	Since LY2780301 effectively inhibited the abnormal proliferation of the partially transformed 10A.B2 MECs in both 2D and 3D culture conditions, we reasoned that LY2780301 may also reduce the proliferation of hyperplasia mammary lesions in vivo.	('abnormal proliferation', 'CPA', (42, 64))	('LY2780301', 'Var', (161, 170))	('hyperplasia', 'Disease', (208, 219))	('LY2780301', 'Chemical', '-', (161, 170))	('hyperplasia mammary lesions', 'Phenotype', 'HP:0010313', (208, 235))	('rat', 'Species', '10116', (198, 201))	('inhibited', 'NegReg', (28, 37))	('LY2780301', 'Var', (6, 15))	('rat', 'Species', '10116', (58, 61))	('LY2780301', 'Chemical', '-', (6, 15))	('proliferation', 'CPA', (191, 204))	('reduce', 'NegReg', (180, 186))	('hyperplasia', 'Disease', 'MESH:D006965', (208, 219))
148351	28877935	Therefore, we treated 28 week old mice (before development of palpable mammary tumors) with LY2780301 briefly for 2 weeks, and examined whether LY2780301 treatment could inhibit S6K activity in the mammary gland, and whether the brief treatment could impact on mammary cell proliferation, atypia/DCIS progression, and tissue microenvironment.	('activity', 'MPA', (182, 190))	('inhibit', 'NegReg', (170, 177))	('LY2780301', 'Var', (92, 101))	('mice', 'Species', '10090', (34, 38))	('LY2780301', 'Chemical', '-', (92, 101))	('mammary cell proliferation', 'CPA', (261, 287))	('LY2780301', 'Var', (144, 153))	('DCIS', 'Phenotype', 'HP:0030075', (296, 300))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('LY2780301', 'Chemical', '-', (144, 153))	('impact', 'Reg', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (281, 284))	('S6K', 'Protein', (178, 181))	('atypia/DCIS progression', 'CPA', (289, 312))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
148352	28877935	Specifically, 5 MMTV-neu mice at 28 weeks of age were treated with 40 mg/kg LY2780301 per day (comparable to 200 mg daily dose in human, and it is ~40% of recommended dose for cancer treatment clinical trials) for 2 weeks, and control age-matched MMTV-neu mice were treated with vehicle only.	('mice', 'Species', '10090', (256, 260))	('mice', 'Species', '10090', (25, 29))	('LY2780301 per', 'Var', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('MMTV', 'Species', '11757', (16, 20))	('MMTV', 'Species', '11757', (247, 251))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('LY2780301', 'Chemical', '-', (76, 85))	('human', 'Species', '9606', (130, 135))
148355	28877935	Western blotting showed that LY2780301 decreased the p185 neu protein level in the treated MFPs, similar to what we observed in 3D 10A.B2 cell culture (Fig.	('LY2780301', 'Var', (29, 38))	('decreased', 'NegReg', (39, 48))	('p185 neu protein level', 'MPA', (53, 75))	('LY2780301', 'Chemical', '-', (29, 38))
148356	28877935	Importantly, LY2780301 effectively inhibited the phosphorylation of ribosomal protein S6.	('LY2780301', 'Var', (13, 22))	('ribosomal protein S6', 'Gene', (68, 88))	('LY2780301', 'Chemical', '-', (13, 22))	('phosphorylation', 'MPA', (49, 64))	('inhibited', 'NegReg', (35, 44))	('ribosomal protein S6', 'Gene', '6194', (68, 88))
148358	28877935	Consistent with our findings in 2D and 3D culture (Figures 2C, 3B), we detected a decrease in PCNA, which suggested that LY2780301 could suppress cell proliferation in the MFP of MMTV-neu mice in vivo (Fig.	('mice', 'Species', '10090', (188, 192))	('suppress', 'NegReg', (137, 145))	('rat', 'Species', '10116', (158, 161))	('LY2780301', 'Var', (121, 130))	('cell proliferation', 'CPA', (146, 164))	('MMTV', 'Species', '11757', (179, 183))	('LY2780301', 'Chemical', '-', (121, 130))
148360	28877935	5B, top), suggesting that LY2780301 could effectively inhibit its target in vivo, even at relatively low dose with short time treatment.	('LY2780301', 'Chemical', '-', (26, 35))	('LY2780301', 'Var', (26, 35))	('inhibit', 'NegReg', (54, 61))
148361	28877935	Moreover, staining of the proliferation marker Ki-67 in the vehicle-treated group showed an average ~40% Ki-67+ cells (index), while the LY2780301-treated mice all had Ki-67 indices below 5% (Fig.	('LY2780301-treated', 'Var', (137, 154))	('Ki-67', 'Gene', (168, 173))	('LY2780301', 'Chemical', '-', (137, 146))	('Ki-67', 'Gene', '17345', (47, 52))	('Ki-67', 'Gene', '17345', (105, 110))	('rat', 'Species', '10116', (33, 36))	('Ki-67', 'Gene', '17345', (168, 173))	('mice', 'Species', '10090', (155, 159))	('Ki-67', 'Gene', (105, 110))	('Ki-67', 'Gene', (47, 52))
148362	28877935	5A) and confirmed that a brief LY2780301 treatment could inhibit abnormal cell proliferation of MMTV-neu mice in vivo.	('rat', 'Species', '10116', (86, 89))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (65, 92))	('inhibit', 'NegReg', (57, 64))	('LY2780301', 'Var', (31, 40))	('mice', 'Species', '10090', (105, 109))	('LY2780301', 'Chemical', '-', (31, 40))	('MMTV', 'Species', '11757', (96, 100))
148366	28877935	Dysregulation of kinases in many cancer types has placed them at the central nodes of cancer cell signaling networks, especially in the early stages of malignant transformation.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
148372	28877935	Dysregulation of the PI3K/Akt/mTOR/p70S6K pathway is one of the most common signaling events found in multiple types of cancer including breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (144, 150))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))
148380	28877935	LY2780301 is a small molecule dual inhibitor that conveniently targets both p70S6 kinase and Akt activation.	('LY2780301', 'Var', (0, 9))	('LY2780301', 'Chemical', '-', (0, 9))	('Akt', 'Pathway', (93, 96))
148381	28877935	This agent has been already tested in Phase I clinical trial which showed favorable profile of tolerance, and Phase Ib/II trial is ongoing to evaluate the tolerance and efficacy of LY2780301 in combination with paclitaxel in locally advanced or metastatic breast cancer (ClinicalTrials.gov NCT01980277).	('breast cancer', 'Disease', (256, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('LY2780301', 'Var', (181, 190))	('LY2780301', 'Chemical', '-', (181, 190))	('paclitaxel', 'Chemical', 'MESH:D017239', (211, 221))	('locally advanced', 'Disease', (225, 241))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
148382	28877935	Using the clinically applicable dual kinase inhibitor LY2780301, we were able to inhibit p70S6K activity as indicated by the significantly reduced phosphorylation of downstream ribosomal protein S6 in ER- MECs, which resulted in decreased level of Cyclin B1 (Figs.	('LY2780301', 'Var', (54, 63))	('Cyclin B1', 'Gene', '891', (248, 257))	('activity', 'MPA', (96, 104))	('p70S6K', 'Protein', (89, 95))	('ribosomal protein S6', 'Gene', (177, 197))	('LY2780301', 'Chemical', '-', (54, 63))	('Cyclin B1', 'Gene', (248, 257))	('inhibit', 'NegReg', (81, 88))	('ribosomal protein S6', 'Gene', '6194', (177, 197))	('decreased', 'NegReg', (229, 238))	('reduced', 'NegReg', (139, 146))
148385	28877935	LY2780301 did not have significant effect on reversing disorganized acinar growth of p70S6K-activated hMECs in 3D culture, which may be due to activation of Akt and Erk1/2 signaling in treated cells (Fig.	('Akt', 'Pathway', (157, 160))	('Erk1/2', 'Gene', '5595;5594', (165, 171))	('LY2780301', 'Var', (0, 9))	('Erk1/2', 'Gene', (165, 171))	('LY2780301', 'Chemical', '-', (0, 9))	('activation', 'PosReg', (143, 153))
148386	28877935	Nevertheless, a brief treatment of LY2780301 in the ER- mammary tumor model of MMTV-neu mice before development of palpable tumors was sufficient to suppress S6 phosphorylation and to decrease cell proliferation in the MFP in vivo.	('decrease', 'NegReg', (184, 192))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cell proliferation in the MFP', 'CPA', (193, 222))	('rat', 'Species', '10116', (205, 208))	('suppress', 'NegReg', (149, 157))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('LY2780301', 'Var', (35, 44))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('LY2780301', 'Chemical', '-', (35, 44))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('MMTV', 'Species', '11757', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
148388	28877935	In addition, it is notable that ErbB2 activates multiple downstream signaling events including the p70S6K pathway, therefore targeting more upstream signal, e.g., PI3K, may be more effective in prevention of ER- breast cancer.	('ErbB2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', (212, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('ErbB2', 'Gene', '2064', (32, 37))	('PI3K', 'Var', (163, 167))	('activates', 'PosReg', (38, 47))	('p70S6K pathway', 'Pathway', (99, 113))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
148391	28877935	Our data warrants further testing of the efficacy of targeting p70S6K upstream signal, e.g., PI3K and/or EGFR/HER2, on breast cancer prevention.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('EGFR', 'Gene', '1956', (105, 109))	('p70S6K', 'Var', (63, 69))	('EGFR', 'Gene', (105, 109))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', '2064', (110, 114))
148416	27334052	Research out of Kitamura's laboratory established the link between GI stromal tumors and mutations in the KIT protooncogene, resulting in activation of tyrosine kinase receptors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('GI stromal tumors', 'Phenotype', 'HP:0100723', (67, 84))	('GI stromal tumors', 'Disease', 'MESH:D046152', (67, 84))	('GI stromal tumors', 'Disease', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (89, 98))	('tyrosine kinase receptors', 'MPA', (152, 177))	('KIT', 'Gene', (106, 109))	('activation', 'PosReg', (138, 148))
148484	27334052	Of the four types of thyroid cancer: papillary, follicular, medullary and anaplastic; papillary has the highest survival rate, at greater than 95% at 10 years and it is the largest contributor to the rising incidence rate.	('thyroid cancer', 'Disease', 'MESH:D013964', (21, 35))	('papillary', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('thyroid cancer', 'Phenotype', 'HP:0002890', (21, 35))	('thyroid cancer', 'Disease', (21, 35))
148530	27334989	Evidence suggesting that LCIS is a precursor lesion includes comparative genomic hybridization studies demonstrating losses on chromosomes 16q and 17p in both LCIS and ILC; truncating mutations in the E-cadherin gene and loss of heterozygosity of the wild-type E-cadherin allele in LCIS and adjacent ILCs; and recent studies, including one by our group, demonstrating a clonal relationship in a small number of coexisting LCIS and ILC on the basis of similarities in genome-wide copy number profiles.	('E-cadherin', 'Gene', '999', (261, 271))	('E-cadherin', 'Gene', (201, 211))	('E-cadherin', 'Gene', '999', (201, 211))	('LCIS', 'Phenotype', 'HP:0030076', (422, 426))	('losses', 'NegReg', (117, 123))	('LCIS', 'Phenotype', 'HP:0030076', (25, 29))	('loss', 'Var', (221, 225))	('LCIS', 'Phenotype', 'HP:0030076', (282, 286))	('LCIS', 'Phenotype', 'HP:0030076', (159, 163))	('E-cadherin', 'Gene', (261, 271))	('truncating mutations', 'Var', (173, 193))
148535	27334989	Sample pairs were selected on the basis of availability of an LCIS lesion and at least one additional LCIS, ILC, DCIS, or IDC lesion.	('IDC lesion', 'Disease', 'MESH:D051437', (122, 132))	('LCIS', 'Phenotype', 'HP:0030076', (102, 106))	('IDC lesion', 'Disease', (122, 132))	('LCIS', 'Disease', (62, 66))	('LCIS', 'Phenotype', 'HP:0030076', (62, 66))	('lesion', 'Var', (67, 73))
148546	27334989	The copy number log ratio data represent the logarithm of the tumor to normal coverage depth at these loci.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('copy', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
148557	27334989	This table was constructed after excluding the 5 tumors that were hypermutated with >200 mutations (see Additional file 3) as well as an outlier gene (FSIP2) that exhibited 13 nonfunctional mutations in 2 cases.	('FSIP2', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('FSIP2', 'Gene', '401024', (151, 156))	('mutations', 'Var', (89, 98))
148558	27334989	The table shows clearly that the most common driver mutations, CDH1 (E-cadherin) and PIK3CA, have high percentages of clonal mutations, but that the relative frequency rapidly drops to the overall average of <20 %.	('mutations', 'Var', (52, 61))	('E-cadherin', 'Gene', '999', (69, 79))	('CDH1', 'Gene', (63, 67))	('PIK3CA', 'Gene', '5290', (85, 91))	('CDH1', 'Gene', '999', (63, 67))	('clonal', 'MPA', (118, 124))	('drops', 'NegReg', (176, 181))	('E-cadherin', 'Gene', (69, 79))	('PIK3CA', 'Gene', (85, 91))
148561	27334989	Indeed, for all 16 patients with mutations in CDH1, the mutations occurred in lobular lesions.	('mutations', 'Var', (56, 65))	('occurred', 'Reg', (66, 74))	('patients', 'Species', '9606', (19, 27))	('lobular lesions', 'Disease', (78, 93))	('CDH1', 'Gene', (46, 50))	('mutations', 'Var', (33, 42))	('CDH1', 'Gene', '999', (46, 50))
148562	27334989	All of the 37 mutations observed in either of the two most frequently mutated genes, CDH1 and PIK3CA, were functional (nonsynonymous, truncating, or nonsense as opposed to synonymous).	('nonsense', 'Var', (149, 157))	('CDH1', 'Gene', '999', (85, 89))	('truncating', 'MPA', (134, 144))	('PIK3CA', 'Gene', (94, 100))	('CDH1', 'Gene', (85, 89))	('PIK3CA', 'Gene', '5290', (94, 100))
148564	27334989	The median numbers of mutations per lesion were 33 for LCIS, 38 for ILC, 29 for IDC, and 33 for DCIS, numbers that are not significantly different.	('IDC', 'Gene', (80, 83))	('LCIS', 'Disease', (55, 59))	('LCIS', 'Phenotype', 'HP:0030076', (55, 59))	('ILC', 'Disease', (68, 71))	('mutations', 'Var', (22, 31))	('IDC', 'Gene', '4000', (80, 83))
148568	27334989	Furthermore, the mutational data exhibit large numbers of mutations in both the LCIS and DCIS samples, with absolute numbers similar to the mutational burdens of invasive cancers.	('DCIS', 'Disease', (89, 93))	('mutations', 'Var', (58, 67))	('invasive cancers', 'Disease', 'MESH:D009362', (162, 178))	('LCIS', 'Phenotype', 'HP:0030076', (80, 84))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('LCIS', 'Disease', (80, 84))	('invasive cancers', 'Disease', (162, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
148569	27334989	The dominant influence of mutations in CDH1 and PIK3CA reflects the recent results from TCGA showing that these two genes harbor by far the most frequently recurring mutations in lobular breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('mutations', 'Var', (166, 175))	('PIK3CA', 'Gene', (48, 54))	('lobular breast cancer', 'Disease', 'MESH:D013274', (179, 200))	('lobular breast cancer', 'Disease', (179, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (26, 35))	('PIK3CA', 'Gene', '5290', (48, 54))	('CDH1', 'Gene', (39, 43))	('CDH1', 'Gene', '999', (39, 43))
148582	27334989	It is also possible that the early events in breast tumorigenesis are more typically mutational events and that the copy number gains and losses tend to occur later.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('losses', 'NegReg', (138, 144))	('tumor', 'Disease', (52, 57))	('copy number', 'Var', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
148583	27334989	The most frequently mutated gene is the E-cadherin gene (CDH1), known to be silenced in most LCIS tumors, through either allelic losses of chromosome 16q or the presence of a mutation.	('LCIS tumors', 'Disease', (93, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('LCIS tumors', 'Disease', 'MESH:D000071960', (93, 104))	('presence', 'Reg', (161, 169))	('E-cadherin', 'Gene', (40, 50))	('mutation', 'Var', (175, 183))	('E-cadherin', 'Gene', '999', (40, 50))	('LCIS', 'Phenotype', 'HP:0030076', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CDH1', 'Gene', (57, 61))	('CDH1', 'Gene', '999', (57, 61))
148584	27334989	Our results showed no ductal lesions harboring a mutation in CDH1, confirming the diagnostic contrast of this gene in ductal versus lobular in situ lesions.	('CDH1', 'Gene', '999', (61, 65))	('CDH1', 'Gene', (61, 65))	('mutation', 'Var', (49, 57))
148590	27334989	In particular, the presence of concordant gene copy number changes and identical mutations in matched LCIS and ILC from the same patients, as demonstrated here, supports the premise that the majority of LCIS lesions found in association with ILC are in fact true precursor lesions.	('lesions', 'Var', (208, 215))	('LCIS', 'Phenotype', 'HP:0030076', (102, 106))	('gene copy number changes', 'Var', (42, 66))	('ILC', 'Disease', (242, 245))	('patients', 'Species', '9606', (129, 137))	('LCIS', 'Phenotype', 'HP:0030076', (203, 207))	('LCIS', 'Gene', (203, 207))
148602	32090518	The number of biopsies classified based on the tumor size, BI-RADS category, and pathologic findings all increased over time, except for BI-RADS categories 1 or 2 and category 3 (odds ratio [OR] = 0.951 per year, 95% confidence interval [CI]: 0.902, 1.002 and odds ratio = 0.979, 95% CI: 0.970, 0.988, respectively).	('tumor', 'Disease', (47, 52))	('BI-RADS', 'Var', (137, 144))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
148680	22674478	Seventy-one percent of patients with high grade index DCIS had high grade SBC, 50% of patients with intermediate grade index DCIS had intermediate grade SBC, and no patients with low grade index DCIS had high grade SBC.	('patients', 'Species', '9606', (23, 31))	('high grade index DCIS', 'Var', (37, 58))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('high grade SBC', 'Disease', (63, 77))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('patients', 'Species', '9606', (165, 173))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))	('patients', 'Species', '9606', (86, 94))
148722	17705880	The present review focuses on the paradoxical roles of innate and adaptive leukocytes as regulators of breast carcinogenesis, and highlights recent experimental data indicating that therapeutically targeting these diverse immune cell types by either neutralizing and/or bolstering their specific bioactivities may provide a therapeutic advantage to patients with breast cancer.	('breast cancer', 'Disease', (363, 376))	('neutralizing', 'Var', (250, 262))	('breast cancer', 'Phenotype', 'HP:0003002', (363, 376))	('patients', 'Species', '9606', (349, 357))	('breast carcinogenesis', 'Disease', (103, 124))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (103, 124))	('breast cancer', 'Disease', 'MESH:D001943', (363, 376))	('specific bioactivities', 'MPA', (287, 309))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))
148731	17705880	While sporadic or inherited genetic mutations in critical genes regulating cell cycle, programmed cell death, differentiation and adhesion may represent initiating events in tumorigenesis ('initiation'), chronic inflammation favors selection of additional features in initiated cells that may promote their full malignant transition ('promotion').	('tumor', 'Disease', (174, 179))	('full malignant transition', 'CPA', (307, 332))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('inflammation', 'Disease', 'MESH:D007249', (212, 224))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('genetic mutations', 'Var', (28, 45))	('promote', 'PosReg', (293, 300))	('inflammation', 'Disease', (212, 224))
148771	17705880	While it is unclear whether the presence of CD8+ CTLs alone provides any prognostic information, the presence of high percentages of CD4+ T-helper cells at primary tumor sites positively correlates with disease progression, including metastatic spread to sentinel lymph nodes and increased primary tumor size.	('correlates with', 'Reg', (187, 202))	('CD8', 'Gene', (44, 47))	('CD4', 'Gene', '920', (133, 136))	('tumor', 'Disease', (164, 169))	('disease progression', 'CPA', (203, 222))	('tumor', 'Disease', (298, 303))	('CD8', 'Gene', '925', (44, 47))	('increased', 'PosReg', (280, 289))	('presence', 'Var', (101, 109))	('metastatic spread to sentinel lymph nodes', 'CPA', (234, 275))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('CD4', 'Gene', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
148792	17705880	This regulation is exemplified by positive correlations between numbers of innate immune cells (macrophages, mast cells and neutrophils) infiltrating human tumors with the number of blood vessels, and by experimental findings in mouse models where attenuating innate immune cell infiltration of premalignant tissue reduces angiogenesis and limits tumor development.	('human', 'Species', '9606', (150, 155))	('tumor', 'Disease', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('angiogenesis', 'CPA', (323, 335))	('mouse', 'Species', '10090', (229, 234))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('attenuating', 'Var', (248, 259))	('limits', 'NegReg', (340, 346))	('tumors', 'Disease', (156, 162))	('reduces', 'NegReg', (315, 322))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
148796	17705880	For example, active immunization of mice harboring a mutant ras oncogene resulted in activation of humoral immune responses and enhanced papilloma formation upon chemical promotion.	('papilloma', 'Phenotype', 'HP:0012740', (137, 146))	('papilloma', 'Disease', 'MESH:D010212', (137, 146))	('activation', 'PosReg', (85, 95))	('enhanced', 'PosReg', (128, 136))	('ras', 'Gene', (60, 63))	('papilloma', 'Disease', (137, 146))	('mutant', 'Var', (53, 59))	('mice', 'Species', '10090', (36, 40))	('humoral immune responses', 'CPA', (99, 123))
148866	29426355	While tumour side was balanced between the two cohorts, there were a number of significant differences between patients undergoing BCS and patients receiving additional postoperative radiotherapy.	('differences', 'Reg', (91, 102))	('patients', 'Species', '9606', (139, 147))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('BCS', 'Var', (131, 134))	('tumour', 'Disease', (6, 12))	('patients', 'Species', '9606', (111, 119))
148869	29426355	Similarly, negative hormone receptor status was more frequent in the radiotherapy group, as compared to patients not receiving radiotherapy (17.3% vs 10.4%, p = 0.012).	('hormone receptor', 'Gene', (20, 36))	('patients', 'Species', '9606', (104, 112))	('hormone receptor', 'Gene', '3164', (20, 36))	('radiotherapy', 'Var', (69, 81))
148875	29426355	The standard radiotherapy regimen at the Department of Radiation Oncology of LMU University was whole-breast irradiation (50.4 Gy in 28 fractions or 50 Gy in 25 fractions) followed by a boost of 10-16 Gy to the tumour bed in high-risk cases with close resection margins.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', (211, 217))	('50.4', 'Var', (122, 126))	('Oncology', 'Phenotype', 'HP:0002664', (65, 73))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
148975	25640082	Ve was not significantly different among the three groups; for instance, the averaged Ktrans value was 0.713+-0.169/min DCIS and 0.803+-0.224 for IDC, whereas it was 0.313+-0.238 for MDD.	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('0.713+-0.169/min', 'Var', (103, 119))	('MDD', 'Disease', (183, 186))	('0.803+-0.224', 'Var', (129, 141))	('MDD', 'Disease', 'MESH:D003865', (183, 186))
148980	25640082	The mean ADC value showed a significant inverse correlation with Ki67 (p=0.025, r=-0.566).	('Ki67', 'Chemical', '-', (65, 69))	('inverse', 'NegReg', (40, 47))	('ADC value', 'MPA', (9, 18))	('Ki67', 'Var', (65, 69))
148997	25640082	CD105 was found to be inversely proportional to the survival of cancer patients.	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('CD105', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
149010	15558069	Characterisation of breast fine-needle aspiration biopsies by centrosome aberrations and genomic instability Recent studies have suggested that aneuploidy in malignant tumours could be a consequence of centrosome aberrations.	('centrosome aberrations', 'Var', (202, 224))	('aneuploidy in malignant tumours', 'Disease', 'MESH:D000782', (144, 175))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('aspiration', 'Phenotype', 'HP:0002835', (39, 49))	('aneuploidy in malignant tumours', 'Disease', (144, 175))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))
149065	15558069	These results confirm our data received from a former study, where we investigated three gs aneuploid and diploid breast carcinomas each, and four gu aneuploid ones (Kronenwett et al, 2004).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('breast carcinomas', 'Phenotype', 'HP:0003002', (114, 131))	('diploid breast carcinomas', 'Disease', (106, 131))	('diploid breast carcinomas', 'Disease', 'MESH:C548012', (106, 131))	('aneuploid', 'Var', (92, 101))
149070	15558069	Comparative genomic hybridisation analysis of DNA diploid breast carcinomas revealed few copy number changes that involve mainly the gain or loss of entire chromosomes or chromosomal arms (Ried et al, 1995), an observation that may indicate a segregation error as a primary event in carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('loss', 'NegReg', (141, 145))	('copy number', 'Var', (89, 100))	('carcinogenesis', 'Disease', (283, 297))	('diploid breast carcinomas', 'Disease', 'MESH:C548012', (50, 75))	('breast carcinomas', 'Phenotype', 'HP:0003002', (58, 75))	('diploid breast carcinomas', 'Disease', (50, 75))	('entire', 'Protein', (149, 155))	('gain', 'PosReg', (133, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (283, 297))	('changes', 'Reg', (101, 108))
149073	15558069	Consequently, centrosome aberrations might play an important role in carcinogenesis and in malignant tumours promote further karyotypic heterogeneity.	('karyotypic heterogeneity', 'MPA', (125, 149))	('promote', 'PosReg', (109, 116))	('play', 'Reg', (43, 47))	('malignant tumours', 'Disease', 'MESH:D009369', (91, 108))	('malignant tumours', 'Disease', (91, 108))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('centrosome aberrations', 'Var', (14, 36))	('carcinogenesis', 'Disease', (69, 83))
149191	26621543	However, among postmenopausal women, risk for pure IDC was lower in women with body mass index (BMI) 25 to <30 kg/m2 (Odds Ratio (OR)=0.66; 95% confidence interval (CI), 0.35-1.23) and BMI>=30 kg/m2 (OR=0.33; 95% CI, 0.18-0.67) compared to women with BMI<25 kg/m2, with no associations with mixed IDC/DCIS.	('IDC', 'Gene', (51, 54))	('lower', 'NegReg', (59, 64))	('BMI>=30 kg/m2', 'Var', (185, 198))	('women', 'Species', '9606', (30, 35))	('women', 'Species', '9606', (68, 73))	('IDC', 'Gene', '4000', (51, 54))	('women', 'Species', '9606', (240, 245))	('IDC', 'Gene', '4000', (297, 300))	('IDC', 'Gene', (297, 300))
149201	26621543	Castro and colleagues found a substantial number of differentially expressed genes in pure DCIS compared with those expressed in mixed IDC/DCIS and some studies suggest that the presence of a DCIS component is associated with cell-mediated immune changes in the microenvironment and neoplastic epithelial cells surrounding the DCIS leading to differences in tumor progression and improved prognosis.	('prognosis', 'CPA', (389, 398))	('improved', 'PosReg', (380, 388))	('IDC', 'Gene', (135, 138))	('differences', 'Reg', (343, 354))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('DCIS', 'Gene', (192, 196))	('tumor', 'Disease', (358, 363))	('presence', 'Var', (178, 186))	('IDC', 'Gene', '4000', (135, 138))
149205	26621543	Common risk factors for breast cancer, such as older age at menarche, nulliparity, older age at first birth, breast cancer in a first degree relative, and higher postmenopausal body mass index (BMI) are consistently associated with increased overall risk of invasive breast cancer, however, the impact of these factors on the presence or absence of concomitant DCIS remain largely unknown.	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('invasive breast cancer', 'Disease', (258, 280))	('breast cancer', 'Disease', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('higher postmenopausal body', 'Phenotype', 'HP:0008209', (155, 181))	('associated', 'Reg', (216, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))	('nulliparity', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('invasive breast cancer', 'Disease', 'MESH:D001943', (258, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
149265	26621543	There was some indication that increasing parity was protective for pure IDC (OR=0.46; 95% CI, 0.21-1.01; p-interaction =0.24) and mixed IDC/DCIS (OR=0.61; 95% CI, 0.40-0.93; p-interaction=0.82) among EA women, but not among AA women, and older age at last birth was protective for pure IDC, but only among AA women (> 33 vs <= 28 years, OR=0.48; 95% CI, 0.28-0.85; p-interaction = 0.24).	('parity', 'Var', (42, 48))	('women', 'Species', '9606', (204, 209))	('IDC', 'Gene', '4000', (287, 290))	('IDC', 'Gene', '4000', (137, 140))	('women', 'Species', '9606', (228, 233))	('IDC', 'Gene', (287, 290))	('IDC', 'Gene', (137, 140))	('IDC', 'Gene', '4000', (73, 76))	('IDC', 'Gene', (73, 76))	('women', 'Species', '9606', (310, 315))
149271	26621543	Among AAs, postmenopausal women with BMI >30 kg/m2 showed significantly reduced odds of pure IDC (OR=0.33; 95% CI, 0.13-0.86) compared to those with BMI <=25 kg/m2; no differences were observed among EA women.	('reduced', 'NegReg', (72, 79))	('BMI >30 kg/m2', 'Var', (37, 50))	('women', 'Species', '9606', (26, 31))	('IDC', 'Gene', '4000', (93, 96))	('women', 'Species', '9606', (203, 208))	('IDC', 'Gene', (93, 96))
149276	26621543	Triple negative tumors were over 3 times more likely to be pure IDC than mixed IDC/DCIS (OR=3.26; 95% CI, 2.08-5.12).	('tumors', 'Disease', (16, 22))	('IDC', 'Gene', '4000', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('IDC', 'Gene', '4000', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('IDC', 'Gene', (64, 67))	('Triple negative', 'Var', (0, 15))	('IDC', 'Gene', (79, 82))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
149291	26621543	found that breast cancer patients with p53 mutations were more likely to have lower incomes, and suggested that a lifetime of exposures associated with socioeconomic status might result in different breast cancer etiologies.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('breast cancer', 'Disease', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('mutations', 'Var', (43, 52))	('p53', 'Gene', (39, 42))	('result in', 'Reg', (179, 188))	('p53', 'Gene', '7157', (39, 42))	('incomes', 'MPA', (84, 91))	('patients', 'Species', '9606', (25, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('lower', 'NegReg', (78, 83))
149302	26621543	A decreased risk of overall invasive breast cancer was observed among postmenopausal AA women with BMI>=25 in the Black Women's Health Study, similar to the decreased risk for pure IDC observed among postmenopausal AA women in our study.	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancer', 'Disease', (28, 50))	('women', 'Species', '9606', (88, 93))	('IDC', 'Gene', '4000', (181, 184))	('women', 'Species', '9606', (218, 223))	('BMI>=25', 'Var', (99, 106))	('IDC', 'Gene', (181, 184))	('invasive breast cancer', 'Disease', 'MESH:D001943', (28, 50))	('decreased', 'NegReg', (2, 11))	('Women', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
149335	26621543	Although a portion of pure IDC cancers may have progressed from mixed IDC/DCIS cancers, the absence of a DCIS component may also represent a tumor type with a distinctive developmental pathway, associated with lower BMI in postmenopausal women and shorter breastfeeding duration.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('lower BMI', 'Phenotype', 'HP:0045082', (210, 219))	('DCIS cancers', 'Disease', (74, 86))	('women', 'Species', '9606', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('lower', 'NegReg', (210, 215))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('IDC cancers', 'Disease', 'MESH:D009369', (27, 38))	('IDC', 'Gene', '4000', (70, 73))	('IDC', 'Gene', (70, 73))	('BMI', 'MPA', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('IDC', 'Gene', '4000', (27, 30))	('IDC', 'Gene', (27, 30))	('absence', 'Var', (92, 99))	('tumor', 'Disease', (141, 146))	('DCIS cancers', 'Disease', 'MESH:D002285', (74, 86))	('IDC cancers', 'Disease', (27, 38))
149349	24480577	Atypia represents a high risk premalignant lesion of the breast, conveying a relative risk of approximately 4 for a later breast cancer (BC) with a cumulative incidence of 29% at 25 years.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('lesion of the breast', 'Phenotype', 'HP:0100013', (43, 63))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('Atypia', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
149414	24480577	Genomic analyses of women with atypia have revealed that these lesions are generally clonal, with similar genomic alterations to those found in low grade BC, including frequent deletions of 16q.	('women', 'Species', '9606', (20, 25))	('deletions', 'Var', (177, 186))	('BC', 'Phenotype', 'HP:0003002', (154, 156))	('16q', 'Gene', (190, 193))
149445	21647677	Deregulation of signaling pathways that control cell proliferation, differentiation, survival, and death is thought to play an important role in the breast cancer initiation and progression.	('Deregulation', 'Var', (0, 12))	('breast cancer initiation', 'Disease', (149, 173))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer initiation', 'Disease', 'MESH:D001943', (149, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('signaling pathways', 'Pathway', (16, 34))
149458	21647677	The presence of cytological atypia in breast RPFNAs of high-risk women confers a 5.6-fold increase of short-term risk for the subsequent development of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('cytological atypia', 'Var', (16, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Disease', (152, 165))	('women', 'Species', '9606', (65, 70))	('presence', 'Var', (4, 12))
149466	21647677	Women recruited to this study were required to have at least one of the following risk factors for breast cancer: (a) 5-year Gail risk calculation >=1.7%, (b) a prior excisional biopsy exhibiting atypical hyperplasia, DCIS, or LCIS, (c) a known BRCA1/2 mutation, or (d) a history of invasive breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('Women', 'Species', '9606', (0, 5))	('mutation', 'Var', (253, 261))	('invasive breast cancer', 'Disease', 'MESH:D001943', (283, 305))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('hyperplasia', 'Disease', (205, 216))	('LCIS', 'Disease', (227, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('BRCA1/2', 'Gene', (245, 252))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('hyperplasia', 'Disease', 'MESH:D006965', (205, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('DCIS', 'Disease', (218, 222))	('invasive breast cancer', 'Disease', (283, 305))	('BRCA1/2', 'Gene', '672;675', (245, 252))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
149488	21647677	RPFNA samples from 65% (17/26) of these women were obtained from the operating room due to (a) removal of suspicious lesion or (b) prophylactic mastectomy given the strong family history of breast cancer or the presence of BRCA1 mutation.	('mutation', 'Var', (229, 237))	('BRCA1', 'Gene', '672', (223, 228))	('BRCA1', 'Gene', (223, 228))	('women', 'Species', '9606', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
149501	21647677	Regardless of the technique employed to sample mammary cells, the presence of atypia increases the risk of women to short-term breast cancer.	('presence', 'Var', (66, 74))	('women', 'Disease', (107, 112))	('atypia', 'Var', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('women', 'Species', '9606', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
149506	21647677	Three of the women in the high Masood group were BRCA1 mutation carriers; two of which elected to have bilateral mastectomies.	('BRCA1', 'Gene', '672', (49, 54))	('women', 'Species', '9606', (13, 18))	('BRCA1', 'Gene', (49, 54))	('mutation', 'Var', (55, 63))
149515	21647677	Unadjusted Wilcoxon rank sum test indicated differential expression or activation of the following proteins between the samples with low Masood scores and high Masood scores: Bcl-xL (P = 0.003), Bad (P = 0.011), phosphorylated Akt S473 (P = 0.025), phosphorylated EGFR Y992 (P = 0.036), and phosphorylated EGFR Y1068 (P = 0.043).	('expression', 'MPA', (57, 67))	('proteins', 'Protein', (99, 107))	('Akt', 'Gene', (227, 230))	('Bcl-xL', 'Gene', (175, 181))	('EGFR', 'Gene', '1956', (264, 268))	('EGFR', 'Gene', '1956', (306, 310))	('EGFR', 'Gene', (264, 268))	('activation', 'PosReg', (71, 81))	('EGFR', 'Gene', (306, 310))	('phosphorylated', 'Var', (249, 263))	('Akt', 'Gene', '207', (227, 230))	('Bcl-xL', 'Gene', '598', (175, 181))
149521	21647677	When similar correlation analysis was performed by the group classification system, the positive correlation between the Bcl-xL and Bad levels was more statistically significant in the high Masood group (P = 0.009) than in the low Masood group (P = 0.036).	('high Masood', 'Var', (185, 196))	('Bad levels', 'MPA', (132, 142))	('Bcl-xL', 'Gene', '598', (121, 127))	('Bcl-xL', 'Gene', (121, 127))
149529	21647677	The presence of atypia in cytological specimens has been utilized as a surrogate marker of breast cancer risk in high-risk populations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('atypia', 'Var', (16, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
149538	21647677	1) indicated that six of the proteins contribute to cell survival (i.e., Bcl-xL, Bad S136, p-EGFR Y1148, p-Stat3 S727, p-PTEN S380, and VEG-FR2), while four of the proteins promote cell death (cleaved caspase7 D198, Bad, Bax, and PTEN).	('PTEN', 'Gene', '5728', (230, 234))	('cell survival', 'CPA', (52, 65))	('caspase7', 'Gene', (201, 209))	('EGFR', 'Gene', '1956', (93, 97))	('S136', 'Chemical', '-', (85, 89))	('promote', 'PosReg', (173, 180))	('Bcl-xL', 'Gene', (73, 79))	('Bax', 'Gene', (221, 224))	('PTEN', 'Gene', (121, 125))	('cell death', 'CPA', (181, 191))	('Bad S136', 'Var', (81, 89))	('Bcl-xL', 'Gene', '598', (73, 79))	('Bax', 'Gene', '581', (221, 224))	('PTEN', 'Gene', (230, 234))	('caspase7', 'Gene', '840', (201, 209))	('PTEN', 'Gene', '5728', (121, 125))	('EGFR', 'Gene', (93, 97))	('contribute', 'Reg', (38, 48))	('p-Stat3 S727', 'Var', (105, 117))
149543	21647677	5), which in turn phos-phorylates Bad at S136.	('phos-phorylates', 'MPA', (18, 33))	('S136', 'Chemical', '-', (41, 45))	('S136', 'Var', (41, 45))
149544	21647677	Subsequent interaction of p-Bad S136 with 14-3-3 prevents translocation of Bad to the mitochondria.	('p-Bad S136', 'Var', (26, 36))	('interaction', 'Interaction', (11, 22))	('S136', 'Chemical', '-', (32, 36))	('translocation', 'MPA', (58, 71))	('prevents', 'NegReg', (49, 57))
149548	21647677	Although our study did not examine casein kinase II (CK2) expression levels, PTEN phosphorylation at S380 has been shown to be mediated by CK2, resulting in decreased PTEN stability and subsequent proteosome-mediated degradation.	('CK2', 'Var', (139, 142))	('phosphorylation', 'MPA', (82, 97))	('stability', 'MPA', (172, 181))	('mediated', 'Reg', (127, 135))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', (167, 171))	('PTEN', 'Gene', '5728', (77, 81))	('PTEN', 'Gene', '5728', (167, 171))	('proteosome-mediated degradation', 'MPA', (197, 228))	('decreased', 'NegReg', (157, 166))
149549	21647677	Phosphorylation of PTEN at S380 prevents PTEN from binding to its PDZ domain-containing partners, such as the p85 subunit of PI3K, and localizing to the plasma membrane.	('prevents', 'NegReg', (32, 40))	('S380', 'Var', (27, 31))	('binding', 'Interaction', (51, 58))	('PI3', 'Gene', (125, 128))	('localizing', 'MPA', (135, 145))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('PI3', 'Gene', '5266', (125, 128))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))
149556	21647677	Examination of the mean relative expression levels indicated an increase in p-Bad S136 expression by as much as 2.8-fold compared with positive regulators of cytochrome C release, such as non-phosphorylated Bad and Bax.	('cytochrome C', 'Gene', '54205', (158, 170))	('Bax', 'Gene', (215, 218))	('increase', 'PosReg', (64, 72))	('expression', 'MPA', (87, 97))	('S136', 'Chemical', '-', (82, 86))	('cytochrome C', 'Gene', (158, 170))	('p-Bad S136', 'Var', (76, 86))	('Bax', 'Gene', '581', (215, 218))
149572	15642160	Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS.	('increased', 'PosReg', (72, 81))	('HER-2', 'Gene', (159, 164))	('negativity', 'NegReg', (133, 143))	('IGFBP-3', 'Gene', '3486', (9, 16))	('DCIS', 'Phenotype', 'HP:0030075', (271, 275))	('invasive tumours', 'Disease', (195, 211))	('invasive tumours', 'Disease', 'MESH:D009361', (195, 211))	('IGFBP-3', 'Gene', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('oestrogen', 'MPA', (109, 118))	('proliferation', 'CPA', (82, 95))	('overexpression', 'PosReg', (165, 179))	('Positive', 'Var', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('HER-2', 'Gene', '2064', (159, 164))
149594	15642160	In keeping with these findings, high levels of fibronectin expression are associated with poor prognostic breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (106, 120))	('breast cancers', 'Disease', (106, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('fibronectin', 'Gene', '2335', (47, 58))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('high levels', 'Var', (32, 43))	('fibronectin', 'Gene', (47, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
149613	15642160	ER immunostaining was performed with a standard three-layered streptavidin-avidin-biotin horseradish peroxidase method with a mouse anti-human ER primary antibody (M0747, 1:100 dilution; DAKO, Ely, Cambridgeshire, UK) and a biotinylated rabbit anti-mouse secondary antibody (E354, 1:350 dilution; DAKO).	('mouse', 'Species', '10090', (126, 131))	('human', 'Species', '9606', (137, 142))	('biotin', 'Chemical', 'MESH:D001710', (82, 88))	('biotin', 'Chemical', 'MESH:D001710', (224, 230))	('M0747', 'Var', (164, 169))	('mouse', 'Species', '10090', (249, 254))	('horseradish', 'Species', '3704', (89, 100))	('rabbit', 'Species', '9986', (237, 243))	('E354', 'Var', (275, 279))
149656	15642160	Generally poor prognostic factors such as large tumour size, high tumour grade, lymphovascular invasion, lymph node metastases, ER negativity, HER-2 overexpression and NPI were significantly associated with decreased OS and DFS.	('lymphovascular invasion', 'CPA', (80, 103))	('NPI', 'Disease', (168, 171))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('high', 'Var', (61, 65))	('ER negativity', 'Var', (128, 141))	('HER-2', 'Gene', (143, 148))	('DFS', 'Disease', (224, 227))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('metastases', 'Disease', (116, 126))	('HER-2', 'Gene', '2064', (143, 148))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (48, 54))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('tumour', 'Disease', (66, 72))	('decreased', 'NegReg', (207, 216))	('OS', 'Chemical', '-', (217, 219))	('overexpression', 'PosReg', (149, 163))
149660	15642160	Where IGFBP-3 was categorised as positive (1+/2+) or negative (0), the Kaplan-Meier survival curves (Fig.	('IGFBP-3', 'Gene', (6, 13))	('IGFBP-3', 'Gene', '3486', (6, 13))	('positive', 'Var', (33, 41))
149671	15642160	This study suggests that most breast cancers express epithelial IGFBP-3 (1+/2+), mostly with a weak/moderate immunoreactivity (1+).	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancers', 'Disease', (30, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('epithelial', 'Var', (53, 63))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('immunoreactivity', 'MPA', (109, 125))	('IGFBP-3', 'Gene', '3486', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('IGFBP-3', 'Gene', (64, 71))
149706	15642160	Although high levels of IGFBP-3 in breast cancers are associated with poor prognostic features of the tumour, few studies have substantiated any significant implications on patient outcome.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('IGFBP-3', 'Gene', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (35, 49))	('patient', 'Species', '9606', (173, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancers', 'Disease', 'MESH:D001943', (35, 49))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('breast cancers', 'Disease', (35, 49))	('tumour', 'Disease', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('high levels', 'Var', (9, 20))	('IGFBP-3', 'Gene', '3486', (24, 31))
149707	15642160	Tissue IGFBP-3 concentrations have been reported to predict a reduced OS, but this was not associated with breast cancer recurrence.	('concentrations', 'Var', (15, 29))	('OS', 'Chemical', '-', (70, 72))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('reduced', 'NegReg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('IGFBP-3', 'Gene', '3486', (7, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('IGFBP-3', 'Gene', (7, 14))
149708	15642160	This study suggests that IGFBP-3 expression in breast cancers might be associated with a shorter OS and DFS, although few patients were negative for IGFBP-3 expression.	('IGFBP-3', 'Gene', (25, 32))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('IGFBP-3', 'Gene', '3486', (149, 156))	('expression', 'Var', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('IGFBP-3', 'Gene', (149, 156))	('OS', 'Chemical', '-', (97, 99))	('shorter OS', 'Disease', (89, 99))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('DFS', 'Disease', (104, 107))	('breast cancers', 'Phenotype', 'HP:0003002', (47, 61))	('IGFBP-3', 'Gene', '3486', (25, 32))	('associated', 'Reg', (71, 81))	('breast cancers', 'Disease', 'MESH:D001943', (47, 61))	('breast cancers', 'Disease', (47, 61))
149752	33033500	In architecture S2a, where MDA-MB-231 cells surrounded the MCF-10A cells, a significant population of MDA-MB-231 cells were observed to detach from the spheroid (Fig.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (102, 112))	('MCF-10A', 'CellLine', 'CVCL:0598', (59, 66))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (27, 37))	('detach', 'NegReg', (136, 142))	('MDA-MB-231', 'Var', (102, 112))
149754	33033500	In architectures S2b and S4b, where part of the MDA-MB-231 cells was at the periphery and in direct contact with collagen matrix initially, majority of the tumor cells invaded out from the side of the spheroid away from the MCF-10A aggregate ((Fig.	('S4b', 'Var', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('MCF-10A', 'CellLine', 'CVCL:0598', (224, 231))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))
149766	33033500	However, the persistence of the tumor cells in S4a is greater than those in S2a, with an average persistence of 0.574 +- 0.022 for S4a in contrast to 0.491 +- 0.021 for S2a, or a 16.9% increase.	('S4a', 'Var', (47, 50))	('persistence', 'MPA', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('persistence', 'MPA', (97, 108))	('S4a', 'Var', (131, 134))	('greater', 'PosReg', (54, 61))	('tumor', 'Disease', (32, 37))
149767	33033500	Accordingly, there is a slight increase at later time points in the MSDs measured for S4a spheroids than S2a spheroids.	('S4a', 'Var', (86, 89))	('MSDs', 'Disease', 'None', (68, 72))	('MSDs', 'Disease', (68, 72))	('increase', 'PosReg', (31, 39))
149775	33033500	Among the four tumor architectures we created, we found that S4b, the case where tumor cells were surrounded by the non-tumorigenic cells with a small opening to the ECM facilitated a persistent and fast movement of the malignant cells.	('S4b', 'Var', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('facilitated', 'PosReg', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fast movement of the malignant cells', 'CPA', (199, 235))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (120, 125))
149809	32082460	Discordance was associated with larger tumour size.	('tumour', 'Disease', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('Discordance', 'Var', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))
149819	32082460	Also, accuracy in estimating preoperative tumour size with the use of clinical breast examination (CBE), US, MG, and DCE-MRI, has been studied in the literature, and CBE, MG, and DCE-MRI are more likely to overestimate the size, whereas US mostly underestimates it.	('CBE', 'Var', (166, 169))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('overestimate', 'PosReg', (206, 218))	('DCE', 'Chemical', 'MESH:C024565', (179, 182))	('tumour', 'Disease', (42, 48))	('DCE', 'Chemical', 'MESH:C024565', (117, 120))
149823	32082460	Although the presence of ductal carcinoma in situ (DCIS), non-mass enhancement in DCE-MRI, and oestrogen receptor positivity have been found to be related with overestimation, the BI-RADS descriptives have not found the right place, in our opinion.	('oestrogen', 'Protein', (95, 104))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('ductal carcinoma', 'Disease', 'MESH:D044584', (25, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('ductal carcinoma', 'Disease', (25, 41))	('DCE', 'Chemical', 'MESH:C024565', (82, 85))	('positivity', 'Var', (114, 124))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (25, 41))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (25, 49))
149891	32082460	However, it was shown that high BPE causes overestimation or underestimation of tumour size by obscuring the margin of tumour.	('tumour', 'Disease', (80, 86))	('overestimation', 'PosReg', (43, 57))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('high BPE', 'Var', (27, 35))	('margin', 'MPA', (109, 115))	('obscuring', 'NegReg', (95, 104))
149903	29743735	The histopathological classification of VABB core samples was as follows: pB2 (benign); pB3 (uncertain malignant potential); pB4 (suspicion of malignancy); and pB5 (malignant).	('pB4', 'Var', (125, 128))	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('malignancy', 'Disease', (143, 153))	('pB3', 'Gene', (88, 91))	('pB5', 'Var', (160, 163))	('pB2', 'Gene', (74, 77))
149948	29743735	Studies of screening programs have shown that cancer detection rates are higher for digital mammography than for conventional screen-film mammography, especially among patients with microcalcifications.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('calcification', 'Disease', 'MESH:D002114', (187, 200))	('digital', 'Var', (84, 91))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('calcification', 'Disease', (187, 200))	('higher', 'PosReg', (73, 79))
150040	25716949	Consistent with our earlier analyses, we found significant positive associations between percent MD and breast cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('percent MD', 'Var', (89, 99))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
150084	25716949	On the other hand, some studies have suggested breast fat as a risk factor for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('breast fat', 'Var', (47, 57))
150143	24744802	found that the sensitivity and specificity of 18F-FDG PET/CT in detecting distant metastasis were 100% and 96.4%, respectively, whereas those of conventional imaging were 61.5% and 99.2%, respectively.	('distant metastasis', 'CPA', (74, 92))	('18F-FDG', 'Var', (46, 53))	('18F-FDG', 'Chemical', 'MESH:D019788', (46, 53))
150155	24744802	Three percent of patients with the polyostotic form have endocrine disease and are cases of McCune-Albright syndrome.	('McCune-Albright syndrome', 'Disease', (92, 116))	('endocrine disease', 'Phenotype', 'HP:0000818', (57, 74))	('polyostotic', 'Var', (35, 46))	('patients', 'Species', '9606', (17, 25))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (92, 116))	('endocrine disease', 'Disease', 'MESH:D004700', (57, 74))	('endocrine disease', 'Disease', (57, 74))
150373	30697064	Amplification of the HER2/neu oncogene located on chromosome 17q12 is the primary pathway of HER2 receptor overexpression, which is the hallmark of HER2-positive or enriched breast tumors.	('HER2', 'Gene', (148, 152))	('Amplification', 'Var', (0, 13))	('HER2', 'Gene', '2064', (93, 97))	('breast tumors', 'Phenotype', 'HP:0100013', (174, 187))	('HER2', 'Gene', '2064', (148, 152))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('neu', 'Gene', '2064', (26, 29))	('breast tumor', 'Phenotype', 'HP:0100013', (174, 186))	('breast tumors', 'Disease', 'MESH:D001943', (174, 187))	('neu', 'Gene', (26, 29))	('breast tumors', 'Disease', (174, 187))	('overexpression', 'PosReg', (107, 121))	('HER2', 'Gene', (21, 25))	('HER2', 'Gene', '2064', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('HER2', 'Gene', (93, 97))
150375	30697064	Overexpression of HER2 is an adverse prognostic factor that is associated with breast tumors of aggressive phenotype, poor survival, and increased risk of disease recurrence.	('breast tumors of aggressive', 'Disease', 'MESH:D001943', (79, 106))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HER2', 'Gene', '2064', (18, 22))	('associated', 'Reg', (63, 73))	('breast tumors', 'Phenotype', 'HP:0100013', (79, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('breast tumor', 'Phenotype', 'HP:0100013', (79, 91))	('Overexpression', 'Var', (0, 14))	('breast tumors of aggressive', 'Disease', (79, 106))	('HER2', 'Gene', (18, 22))
150394	30697064	These findings were further confirmed by the Neo-ALTTO trial in which the presence of TILs at diagnosis was associated with higher rates of pCR and event-free survival (EFS) in early-stage HER2-positive patients treated with lapatinib and trastuzumab.	('pCR', 'Disease', (140, 143))	('TIL', 'Gene', '7096', (86, 89))	('HER2', 'Gene', (189, 193))	('Neo-ALTTO', 'Chemical', '-', (45, 54))	('presence', 'Var', (74, 82))	('lapatinib', 'Chemical', 'MESH:D000077341', (225, 234))	('TIL', 'Gene', (86, 89))	('patients', 'Species', '9606', (203, 211))	('event-free survival', 'CPA', (148, 167))	('higher', 'PosReg', (124, 130))	('trastuzumab', 'Chemical', 'MESH:D000068878', (239, 250))	('HER2', 'Gene', '2064', (189, 193))
150434	30697064	Multiple ongoing clinical trials are assessing the therapeutic effect of CTLA-4 inhibitors in different breast cancer subtypes and settings.	('CTLA-4', 'Gene', '1493', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CTLA-4', 'Gene', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('inhibitors', 'Var', (80, 90))
150451	30697064	The overall objective response rate (ORR) was 3%; however, avelumab produces better clinical activity among patients with positive expression of PD-L1 and among patients with TNBC.	('better', 'PosReg', (77, 83))	('avelumab', 'Chemical', 'MESH:C000609138', (59, 67))	('positive', 'Var', (122, 130))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (108, 116))	('PD-L1', 'Gene', (145, 150))	('clinical activity', 'MPA', (84, 101))
150463	30697064	In addition, E75 vaccination has been shown to decrease circulating levels of Tregs in the majority of vaccinated breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('decrease', 'NegReg', (47, 55))	('E75 vaccination', 'Var', (13, 28))	('vaccination', 'Var', (17, 28))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('patients', 'Species', '9606', (128, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('circulating levels of', 'MPA', (56, 77))	('Tregs', 'Protein', (78, 83))	('breast cancer', 'Disease', (114, 127))
150464	30697064	Earlier clinical trials showed that nelipepimut-S was immunogenic and of reasonable safety profile and reduced recurrence rate among high-risk breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('reduced', 'NegReg', (103, 110))	('nelipepimut-S', 'Var', (36, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('nelipepimut-S', 'Chemical', '-', (36, 49))	('patients', 'Species', '9606', (157, 165))	('recurrence rate', 'CPA', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
150465	30697064	Mild pain and erythema at the site of injection were most frequent treatment-related AEs to E75 and GM-CSF vaccine.	('erythema', 'Disease', (14, 22))	('pain', 'Phenotype', 'HP:0012531', (5, 9))	('AEs', 'Chemical', '-', (85, 88))	('pain', 'Disease', 'MESH:D010146', (5, 9))	('GM-CSF', 'Gene', (100, 106))	('GM-CSF', 'Gene', '1437', (100, 106))	('erythema', 'Phenotype', 'HP:0010783', (14, 22))	('pain', 'Disease', (5, 9))	('erythema', 'Disease', 'MESH:D004890', (14, 22))	('E75', 'Var', (92, 95))
150483	30697064	AE37 is a 15 amino acid MHC class II epitope capable of stimulating CD4+ Th lymphocytes.	('stimulating', 'PosReg', (56, 67))	('CD4', 'Gene', (68, 71))	('CD4', 'Gene', '920', (68, 71))	('AE37', 'Var', (0, 4))
150485	30697064	AE37 vaccine has been found to reduce the number of Tregs in peripheral blood from breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AE37 vaccine', 'Var', (0, 12))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('reduce', 'NegReg', (31, 37))	('patients', 'Species', '9606', (97, 105))
150486	30697064	A Phase I clinical trial showed that AE37 vaccine is safe and well tolerated with minimal toxicity in breast cancer patients.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('patients', 'Species', '9606', (116, 124))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('toxicity', 'Disease', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('AE37 vaccine', 'Var', (37, 49))
150487	30697064	AE37 was shown to induce HER2-specific immune response without the use of an immunoadjuvant.	('induce', 'Reg', (18, 24))	('HER2', 'Gene', '2064', (25, 29))	('HER2', 'Gene', (25, 29))	('AE37', 'Var', (0, 4))
150490	30697064	Patients receiving AE37 and GM-CSF had mild local toxicities which were grade I/II.	('GM-CSF', 'Gene', (28, 34))	('GM-CSF', 'Gene', '1437', (28, 34))	('toxicities', 'Disease', (50, 60))	('Patients', 'Species', '9606', (0, 8))	('AE37', 'Var', (19, 23))	('toxicities', 'Disease', 'MESH:D064420', (50, 60))
150496	30697064	In a pilot Phase III randomized, double-blind study, patients with stage II breast cancer received subcutaneous injections of either placebo or oxidized mannan-MUC1.	('patients', 'Species', '9606', (53, 61))	('stage II breast cancer', 'Disease', 'MESH:D001943', (67, 89))	('MUC1', 'Gene', (160, 164))	('MUC1', 'Gene', '4582', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mannan', 'Chemical', 'MESH:D008351', (153, 159))	('oxidized', 'Var', (144, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('stage II breast cancer', 'Disease', (67, 89))
150498	30697064	Most patients receiving oxidized mannan-MUC1 had measurable antibodies to MUC1 and some reported T cell responses.	('patients', 'Species', '9606', (5, 13))	('MUC1', 'Gene', (40, 44))	('MUC1', 'Gene', (74, 78))	('MUC1', 'Gene', '4582', (40, 44))	('mannan', 'Chemical', 'MESH:D008351', (33, 39))	('antibodies', 'Interaction', (60, 70))	('MUC1', 'Gene', '4582', (74, 78))	('T cell responses', 'CPA', (97, 113))	('oxidized', 'Var', (24, 32))
150547	30697064	Meaningful combinations may enhance immunogenicity by increasing antigen and MHC class I expression on tumor cells, promoting TIL infiltration and vascular permeability, positively modulating CTL anti-tumor activity, or by relieving immunosuppressive signals within tumors.	('CTL', 'MPA', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('MHC class I', 'Gene', (77, 88))	('TIL', 'Gene', (126, 129))	('promoting', 'PosReg', (116, 125))	('immunosuppressive signals', 'MPA', (233, 258))	('tumor', 'Disease', (266, 271))	('expression', 'MPA', (89, 99))	('increasing', 'PosReg', (54, 64))	('antigen', 'Protein', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('modulating', 'Reg', (181, 191))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('combinations', 'Var', (11, 23))	('enhance', 'PosReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumors', 'Disease', (266, 272))	('TIL', 'Gene', '7096', (126, 129))	('immunogenicity', 'MPA', (36, 50))	('relieving', 'NegReg', (223, 232))	('vascular', 'CPA', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
150557	30697064	In addition, the presence of TILs was associated with improved outcomes in patients receiving trastuzumab treatment.	('TIL', 'Gene', (29, 32))	('patients', 'Species', '9606', (75, 83))	('outcomes', 'MPA', (63, 71))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('improved', 'PosReg', (54, 62))	('presence', 'Var', (17, 25))	('TIL', 'Gene', '7096', (29, 32))
150566	30697064	Durvalumab and nivolumab are also being evaluated among advanced HER2-postive breast cancer patients in combination with trastuzumab (NCT02649686 and NCT03523572, respectively).	('HER2-postive breast cancer', 'Disease', 'MESH:D001943', (65, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('nivolumab', 'Chemical', 'MESH:D000077594', (15, 24))	('NCT02649686', 'Var', (134, 145))	('trastuzumab', 'Chemical', 'MESH:D000068878', (121, 132))	('HER2-postive breast cancer', 'Disease', (65, 91))	('patients', 'Species', '9606', (92, 100))	('Durvalumab', 'Chemical', 'MESH:C000613593', (0, 10))	('NCT03523572', 'Var', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
150608	29662532	Moreover, recent results of a randomized study evaluating acute and 6 months toxicity, and quality of life in patients treated with CFRT compared with HF have been published.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('CFRT', 'Var', (132, 136))	('toxicity', 'Disease', (77, 85))	('patients', 'Species', '9606', (110, 118))
150660	29662532	Dose inhomogeneity has been described as a predictor of pain after breast RT.	('pain', 'Disease', 'MESH:D010146', (56, 60))	('pain', 'Phenotype', 'HP:0012531', (56, 60))	('pain', 'Disease', (56, 60))	('Dose inhomogeneity', 'Var', (0, 18))
150665	29662532	The effect that axillary surgery had was not evaluated directly, but it may be that those with DCIS who do not have a sentinel node study, and therefore, have less surgical manipulation, have a better evaluation of breast cosmesis and toxicity.	('toxicity', 'Disease', (235, 243))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('DCIS', 'Var', (95, 99))	('breast cosmesis', 'Disease', (215, 230))	('breast cosmesis', 'Disease', 'MESH:D001943', (215, 230))	('better', 'PosReg', (194, 200))	('toxicity', 'Disease', 'MESH:D064420', (235, 243))
150720	33461287	The histological features of DCIS associated with increased risk of recurrence are large lesion size, high nuclear grade, certain architectural patterns, central necrosis, and positive surgical margin.	('high', 'Var', (102, 106))	('necrosis', 'Disease', (162, 170))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('DCIS', 'Disease', (29, 33))	('necrosis', 'Disease', 'MESH:D009336', (162, 170))	('architectural', 'CPA', (130, 143))
150844	27119227	The efficacy of 225Ac, the parent of 213Bi, was significantly superior to the other treatments using common beta-emitter particles.	('225Ac', 'Var', (16, 21))	('213Bi', 'Chemical', '-', (37, 42))	('superior', 'PosReg', (62, 70))	('225Ac', 'Chemical', 'MESH:C000615155', (16, 21))
150866	27119227	SUM225-Luc+ breast cancer cells were injected i.duc into 4 inguinal mammary glands, and 10 mul of vehicle (Matrigel and complete media mixture) without cells was injected into the right and left 3rd mammary glands as controls.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('SUM225-Luc+', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
150878	27119227	At 28 days after treatment, all i.duc 225Ac-T treated groups showed inhibition of tumor growth compared to i.v.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('i.duc 225Ac-T', 'Var', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'NegReg', (68, 78))	('225Ac-T', 'Chemical', '-', (38, 45))	('tumor', 'Disease', (82, 87))
150884	27119227	225Ac-T, no appreciable weight loss was observed in the other treatment groups (Figure S2).	('weight loss', 'Disease', 'MESH:D015431', (24, 35))	('225Ac-T', 'Var', (0, 7))	('weight loss', 'Disease', (24, 35))	('225Ac-T', 'Chemical', '-', (0, 7))	('weight loss', 'Phenotype', 'HP:0001824', (24, 35))
150893	27119227	The therapeutic study using alpha-particle emitter conjugated trastuzumab showed that a total of 120 nCi of i.duc 225Ac-Trastuzumab, distributed over three mammary glands inhibited tumor growth significantly more effectively than the same dose administered intravenously (Figure 4).	('tumor', 'Disease', (181, 186))	('trastuzumab', 'Chemical', 'MESH:D000068878', (62, 73))	('inhibited', 'NegReg', (171, 180))	('225Ac-Trastuzumab', 'Chemical', '-', (114, 131))	('i.duc 225Ac-Trastuzumab', 'Var', (108, 131))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
150894	27119227	Body weight loss during radioimmunotherapy was lower in the mice treated by the i.duc route compared to the i.v route.	('i.duc', 'Var', (80, 85))	('lower', 'NegReg', (47, 52))	('weight loss', 'Phenotype', 'HP:0001824', (5, 16))	('weight loss', 'Disease', 'MESH:D015431', (5, 16))	('mice', 'Species', '10090', (60, 64))	('weight loss', 'Disease', (5, 16))
150898	27119227	Although highly effective in achieving long term cures in Her2-transgenic mouse tumors, i.duc Doxil induced mammary tumors in nearly 70% of naive FVB/N mice, precluding its use through the intraductal route.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('i.duc', 'Var', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Her2', 'Gene', '13866', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mice', 'Species', '10090', (152, 156))	('tumors', 'Disease', (80, 86))	('mouse', 'Species', '10090', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('Doxil', 'Chemical', 'MESH:C506643', (94, 99))	('Her2', 'Gene', (58, 62))
150899	27119227	225Ac was significantly less carcinogenic in the mammary gland (1/39 mammary glands injected; 1/13 mice), but induced lung tumors in 4/13 mice (Supplementary Table S2).	('mice', 'Species', '10090', (99, 103))	('carcinogenic', 'Disease', (29, 41))	('lung tumors', 'Phenotype', 'HP:0100526', (118, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('225Ac', 'Chemical', 'MESH:C000615155', (0, 5))	('lung tumors', 'Disease', 'MESH:D008175', (118, 129))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('225Ac', 'Var', (0, 5))	('induced', 'Reg', (110, 117))	('carcinogenic', 'Disease', 'MESH:D063646', (29, 41))	('lung tumors', 'Disease', (118, 129))
150904	27119227	IVIS spectrum imaging at one week after inoculation showed visible signals of luciferase activity in the inoculated mammary gland, and immunohistochemical staining showed that SUM225-Luc+ cells grew as a 1-2 layers on the mouse luminal epithelial cell layer, leaving ductal lumens open (Figure 3A, 3B).	('luciferase', 'Enzyme', (78, 88))	('leaving', 'Reg', (259, 266))	('mouse', 'Species', '10090', (222, 227))	('SUM225-Luc+', 'Var', (176, 187))	('activity', 'MPA', (89, 97))
150905	27119227	In addition, we observed that therapeutic efficacy of the i.duc 225Ac-trastuzumab was significantly higher than i.v administration (Figure 4), without attendant toxicity.	('rat', 'Species', '10116', (124, 127))	('toxicity', 'Disease', 'MESH:D064420', (161, 169))	('toxicity', 'Disease', (161, 169))	('i.duc 225Ac-trastuzumab', 'Var', (58, 81))	('higher', 'PosReg', (100, 106))	('225Ac-trastuzumab', 'Chemical', '-', (64, 81))	('therapeutic', 'MPA', (30, 41))
150937	27119227	We chose a one-tailed test because we expect that the AUC following i.duc administration will be lower than after IV administration.	('rat', 'Species', '10116', (125, 128))	('AUC', 'MPA', (54, 57))	('rat', 'Species', '10116', (82, 85))	('lower', 'NegReg', (97, 102))	('i.duc administration', 'Var', (68, 88))
150941	27362268	Tumors often harbor aneuploid or polyploid cell populations.	('Tumors often harbor aneuploid', 'Disease', (0, 29))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('polyploid', 'Var', (33, 42))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors often harbor aneuploid', 'Disease', 'MESH:D000782', (0, 29))
150948	27362268	Nonetheless, it is generally agreed that mutations in single genes, changes of copy numbers of genes, genomic rearrangements, and missegregation of chromosomes or their arms drive tumor progression.	('mutations', 'Var', (41, 50))	('missegregation', 'Var', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('drive', 'Reg', (174, 179))	('changes', 'Var', (68, 75))	('tumor', 'Disease', (180, 185))
150950	27362268	At early stages of cancer, when treatment is most effective, there may be low-proportion subclones that carry mutations that are especially deleterious per se or could later lead to resistance to some types of treatment.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (19, 25))	('lead to', 'Reg', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('resistance', 'MPA', (182, 192))
150962	27362268	Such sequence data are typically presented as lists of variants present in part of the tumor, sometimes along with copy number estimates for different chromosomes or chromosomal intervals.	('variants', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
150965	27362268	While the infinite sites assumption is plausible for point mutations and insertions/deletions for most tumor types, it is not plausible for copy number changes of single genes or small regions.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('point mutations', 'Var', (53, 68))	('tumor', 'Disease', (103, 108))	('insertions/deletions', 'Var', (73, 93))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
150966	27362268	The algorithmic problem of identifying subclones would be greatly simplified if one could easily sequence many single cells of the same tumor, thus phasing completely any sequence mutations, or copy number changes.	('copy number changes', 'Var', (194, 213))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))
150982	27362268	In the present paper, we present a new version (3.0) of the software package FISHtrees for single-cell tumor phylogenetics via copy number variation.	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('copy number variation', 'Var', (127, 148))
150987	27362268	These comparisons show a clear improvement in accuracy of ploidy-based over ploidyless inference when reconstructing tumor phylogenies in the presence of copy number variation at both local and genomic scales.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('copy number variation', 'Var', (154, 175))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvement', 'PosReg', (31, 42))
151032	27362268	For the merged tree, the first number in each oval is the copy number of the ploidy probe, the second the copy number of MYC and the third the copy number of CCND1.	('CCND1', 'Gene', '595', (158, 163))	('MYC', 'Gene', (121, 124))	('copy number', 'Var', (106, 117))	('CCND1', 'Gene', (158, 163))	('MYC', 'Gene', '4609', (121, 124))
151065	27362268	The lower average depth of the metastatic samples suggests that a) the subclones that have the capability to metastasize are not necessarily those with the most copy number changes, and b) after metastasis takes place new copy number changes arise in cells that did not necessarily accumulate many changes in the primary tumor phase.	('tumor', 'Disease', (321, 326))	('copy number changes', 'Var', (222, 241))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))
151097	27362268	These results provide indirect support for the prior suggestion that taking into account variation in cell ploidy is also likely to improve tumor phylogenetics methods focused on point mutations.	('variation', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('improve', 'PosReg', (132, 139))	('tumor', 'Disease', (140, 145))
151108	27362268	Much of the recent work in tumor phylogenetics has been focused on modeling point mutations, since that has been greatly facilitated by next generation sequencing.	('tumor', 'Disease', (27, 32))	('point mutations', 'Var', (76, 91))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
151280	24377727	Another systematic selection bias between the two groups could be due to the Norway action plan for surveillance of breast cancer in carriers of certain BRCA mutations or evidence of risk of hereditary breast cancer without documented mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (191, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('BRCA', 'Gene', '672', (153, 157))	('hereditary breast cancer', 'Disease', (191, 215))	('BRCA', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
151341	16611371	Effect of a farnesyl transferase inhibitor (R115777) on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo The ras pathway is essential for cell growth and proliferation.	('ovarian cancer', 'Phenotype', 'HP:0100615', (140, 154))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (56, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (100, 105))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (129, 154))	('ductal carcinoma', 'Disease', 'MESH:D044584', (56, 72))	('ductal carcinoma', 'Disease', (56, 72))	('R115777', 'Var', (44, 51))
151342	16611371	The effects of R115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status.	('R115777', 'Var', (15, 22))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
151354	16611371	R115777 is a promising treatment for breast cancer but the relation between effect and growth factor receptor and ras status has to be established.	('breast cancer', 'Disease', (37, 50))	('R115777', 'Var', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
151358	16611371	The incidence of ras mutations in human tumours overall is about 30%, whereas the incidence of activating ras mutations in breast cancers is low, at only a few percent.	('breast cancers', 'Phenotype', 'HP:0003002', (123, 137))	('human', 'Species', '9606', (34, 39))	('breast cancers', 'Disease', 'MESH:D001943', (123, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('breast cancers', 'Disease', (123, 137))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('ras', 'Gene', (17, 20))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('mutations', 'Var', (21, 30))
151359	16611371	The ras pathway is activated by a variety of extracellullar factors and aberrant function of the ras signal transduction pathway is thought to be common in breast cancer.	('aberrant function', 'Var', (72, 89))	('ras pathway', 'Pathway', (4, 15))	('ras signal transduction pathway', 'Pathway', (97, 128))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
151363	16611371	In the present study we tested the effects of the FTI R115777 on growth of breast and ovarian cancer cell lines expressing varying levels of HER2 and epidermal growth factor receptor and with differing ras status, and on ductal carcinoma in situ (DCIS) of the breast in a human xenograft model.	('epidermal growth factor receptor', 'Gene', (150, 182))	('HER2', 'Gene', '2064', (141, 145))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (221, 245))	('human', 'Species', '9606', (272, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('FTI', 'Var', (50, 53))	('DCIS', 'Phenotype', 'HP:0030075', (247, 251))	('epidermal growth factor receptor', 'Gene', '1956', (150, 182))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tested', 'Reg', (24, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ductal carcinoma', 'Disease', 'MESH:D044584', (221, 237))	('ductal carcinoma', 'Disease', (221, 237))	('HER2', 'Gene', (141, 145))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (75, 100))
151365	16611371	In this study we have shown that treatment with the FTI R115777 reduced cell growth in vitro and cell tumour growth in vivo.	('cell growth', 'CPA', (72, 83))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour growth', 'Disease', 'MESH:D006130', (102, 115))	('FTI R115777', 'Var', (52, 63))	('reduced', 'NegReg', (64, 71))	('tumour growth', 'Disease', (102, 115))
151385	16611371	Treatment with R115777 50 mg/kg or 100 mg/kg or control vehicle (20% beta-cyclodextrin) was begun when measurable tumours were formed in about 75% of injection sites.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (114, 121))	('beta-cyclodextrin', 'Chemical', 'MESH:C031215', (69, 86))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('R115777', 'Var', (15, 22))
151390	16611371	The growth inhibitory effect of R115777 was calculated using the following formula: 1 - ([D - C]/[Bmedian - Amedian]) x 100%, where D is the final tumour volume after R115777 treatment, C is the tumour volume before R115777 treatment, B is the median final tumour volume among control tumours after treatment, and A is the median tumour volume among control tumours before treatment.	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('tumour', 'Disease', 'MESH:D009369', (330, 336))	('tumour', 'Disease', (330, 336))	('tumours', 'Disease', (358, 365))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Disease', (257, 263))	('tumours', 'Phenotype', 'HP:0002664', (358, 365))	('tumour', 'Disease', (147, 153))	('tumours', 'Disease', 'MESH:D009369', (358, 365))	('R115777', 'Var', (167, 174))	('tumours', 'Disease', (285, 292))	('tumours', 'Phenotype', 'HP:0002664', (285, 292))	('tumour', 'Disease', 'MESH:D009369', (358, 364))	('tumours', 'Disease', 'MESH:D009369', (285, 292))	('tumour', 'Disease', (358, 364))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('tumour', 'Disease', 'MESH:D009369', (285, 291))	('tumour', 'Disease', (285, 291))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
151397	16611371	Western blots were performed on MCF-7 and MCF-7/HER2-18 cells treated with different doses of R115777 and on MCF-7/HER2-18 tumours from the in vivo experiments.	('MCF-7', 'CellLine', 'CVCL:0031', (109, 114))	('MCF-7', 'CellLine', 'CVCL:0031', (42, 47))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('MCF-7/HER2-18', 'CellLine', 'CVCL:0U80', (109, 122))	('R115777', 'Var', (94, 101))	('HER2-18 tumours', 'Disease', (115, 130))	('MCF-7/HER2-18', 'CellLine', 'CVCL:0U80', (42, 55))	('HER2-18 tumours', 'Disease', 'MESH:D015179', (115, 130))	('MCF-7', 'CellLine', 'CVCL:0031', (32, 37))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
151407	16611371	Comparisons between the R115777 treated and control samples in the DCIS xenograft experiments were made 'within-patient' using a repeated analysis of variance model with patient and group (R155777 versus control) as factors.	('patient', 'Species', '9606', (112, 119))	('R155777', 'Var', (189, 196))	('R115777 treated', 'Var', (24, 39))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('patient', 'Species', '9606', (170, 177))
151412	16611371	The cell line with the mutated k-ras, namely MDA-MB231, had the highest IC50, whereas in the cell lines with wild-type ras the drug was effective at lower doses.	('k-ras', 'Gene', '3845', (31, 36))	('IC50', 'MPA', (72, 76))	('k-ras', 'Gene', (31, 36))	('mutated', 'Var', (23, 30))	('MDA-MB231', 'CellLine', 'CVCL:0062', (45, 54))
151413	16611371	In mice, growth of MCF-7/HER2-18 tumours was inhibited by R115777 50 mg/kg (n = 19) and 100 mg/kg (n = 11) by 80.8% (interquartile range 56.4-99.0%; P = 0.001) and 95.9% (68.2-110.1%; P = 0.02), respectively, compared with control tumours (n = 22; Figure 1a and Table 1).	('R115777', 'Var', (58, 65))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('HER2-18 tumours', 'Disease', (25, 40))	('tumours', 'Disease', 'MESH:D009369', (231, 238))	('MCF-7/HER2-18', 'CellLine', 'CVCL:0U80', (19, 32))	('mice', 'Species', '10090', (3, 7))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('HER2-18 tumours', 'Disease', 'MESH:D015179', (25, 40))	('tumours', 'Disease', (33, 40))	('growth', 'CPA', (9, 15))	('tumours', 'Disease', (231, 238))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('inhibited', 'NegReg', (45, 54))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
151414	16611371	The proliferation index was lower in the treated tumours; for R115777 50 mg/kg it was 69.6% (63.4-74.8%; P = 0.003) and for R115777 100 mg/kg it was 65.5% (62.0-70.1%; P < 0.0001) as compared with 77.7% for the control tumours (74.4-81.1%; Table 2).	('tumours', 'Disease', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('R115777', 'Var', (62, 69))	('lower', 'NegReg', (28, 33))	('R115777 100 mg/kg', 'Var', (124, 141))	('tumours', 'Phenotype', 'HP:0002664', (219, 226))	('proliferation index', 'CPA', (4, 23))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Disease', 'MESH:D009369', (219, 226))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('tumours', 'Disease', (219, 226))
151415	16611371	The apoptotic index was higher in the treated tumours; for R115777 50 mg/kg it was 1.5% (1.2-1.6%; P = 0.04) and for R115777 100 mg/kg it was 1.6% (1.4-1.9%; P = 0.003) as compared with 1.2% in the control tumours (0.9-1.5%).	('R115777', 'Var', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumours', 'Disease', (46, 53))	('apoptotic index', 'CPA', (4, 19))	('R115777 100 mg/kg', 'Var', (117, 134))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Disease', (206, 213))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
151416	16611371	The CTIs for tumours treated with R115777 50 mg/kg and 100 mg/kg were 48.7 (41.6-57.4; P = 0.0009) and 38.0 (30.1-43.3; P < 0.0001), respectively, and these values were statistically significantly reduced as compared with the CTI of 61.6 in controls (55.5-79.5; Table 2).	('CTIs', 'Chemical', 'MESH:C096521', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('CTI', 'Chemical', '-', (226, 229))	('CTI', 'Chemical', '-', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('R115777', 'Var', (34, 41))	('reduced', 'NegReg', (197, 204))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('CTIs', 'MPA', (4, 8))
151417	16611371	Growth of SKOV3 tumours was inhibited by R115777 50 mg/kg (n = 30) and 100 mg/kg (n = 14) by 60.1% (32.3-83.9%; P = 0.04) and 20.4% (-65.7 to +38.3%; P = 0.4), respectively, as compared with that in control tumours (n = 14; Figure 1b and Table 1).	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('R115777', 'Var', (41, 48))	('tumours', 'Disease', (16, 23))	('SKOV3 tumours', 'Disease', (10, 23))	('SKOV3 tumours', 'Disease', 'MESH:D009369', (10, 23))	('tumours', 'Disease', (207, 214))	('inhibited', 'NegReg', (28, 37))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('Growth', 'CPA', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))
151418	16611371	The proliferation index was lower in treated tumours; for R115777 50 mg/kg it was 34.1% (26.5-44.4%; P = 0.009) and for R115777 100 mg/kg it was 40.1% (33.1-44.0%; P = 0.08) as compared with 46.6% in the control tumours (37.6-55.0%).	('R115777', 'Var', (58, 65))	('R115777 100 mg/kg', 'Var', (120, 137))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('lower', 'NegReg', (28, 33))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('proliferation index', 'CPA', (4, 23))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('tumours', 'Disease', (212, 219))	('tumours', 'Disease', (45, 52))
151419	16611371	The apoptotic index did not differ between treated tumours; for R115777 50 mg/kg it was 0.49% (0.4-0.7%; P = 0.11), for R115777 100 mg/kg it was 0.48% (0.4-0.8%; P = 0.18) and it was 0.35% in the control tumours (0.3-0.5%).	('R115777 100 mg/kg', 'Var', (120, 137))	('tumours', 'Disease', 'MESH:D009369', (204, 211))	('tumours', 'Disease', (204, 211))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('R115777', 'Var', (64, 71))	('tumours', 'Phenotype', 'HP:0002664', (204, 211))	('tumours', 'Disease', (51, 58))
151420	16611371	The CTIs for tumours treated with R115777 50 mg/kg and 100 mg/kg were 67.5 (45.6-96.1; P = 0.004) and 81.0 (38.6-110.2; P = 0.05), respectively; these values were statistically significantly reduced as compared with the CTI of 125.4 in controls (87.1-188.9; Table 2).	('CTIs', 'Chemical', 'MESH:C096521', (4, 8))	('CTI', 'Chemical', '-', (220, 223))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('CTI', 'Chemical', '-', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('R115777', 'Var', (34, 41))	('reduced', 'NegReg', (191, 198))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('CTIs', 'MPA', (4, 8))
151421	16611371	Growth of k-ras mutated MDA-MB231 tumours was not inhibited by R115777 50 mg/kg (n = 25) and 100 mg/kg (n = 15).	('k-ras', 'Gene', '3845', (10, 15))	('MDA-MB231 tumours', 'Disease', 'MESH:D009369', (24, 41))	('k-ras', 'Gene', (10, 15))	('MDA-MB231 tumours', 'Disease', (24, 41))	('R115777', 'Var', (63, 70))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
151423	16611371	The proliferation index was higher, although not statistically significantly higher, in the treated tumours; for R115777 50 mg/kg it was 68.2% (63.3-71.5%; P = 0.24) and for R115777 100 mg/kg it was 72.4% (66.4-78.4%; P = 0.06) as compared with 57.9% in the control tumours (54.1-71.4%).	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('tumours', 'Disease', (100, 107))	('R115777 100 mg/kg', 'Var', (174, 191))	('tumours', 'Disease', 'MESH:D009369', (266, 273))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumours', 'Disease', (266, 273))	('proliferation index', 'CPA', (4, 23))	('higher', 'PosReg', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('R115777', 'Var', (113, 120))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('tumours', 'Phenotype', 'HP:0002664', (266, 273))
151424	16611371	The apoptotic index was similar in treated and control tumours; for R115777 50 mg/kg it was 0.4% (0.3-0.6%; P = 0.98), for R115777 100 mg/kg it was 0.4% (0.3-0.7%; P = 0.75) and for controls it was 0.4% (0.3-0.6%).	('tumours', 'Disease', (55, 62))	('R115777 100 mg/kg', 'Var', (123, 140))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('R115777', 'Var', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
151425	16611371	The CTIs for tumours treated with R115777 50 mg/kg and 100 mg/kg were 180.1 (115.9-205.4; P = 0.32) and 180.8 (90.5-227.7; P = 0.37), respectively, and the CTI for controls was 106.0 (85.8-191.0; Table 2).	('CTIs', 'Chemical', 'MESH:C096521', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('CTI', 'Chemical', '-', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('R115777', 'Var', (34, 41))	('CTI', 'Chemical', '-', (156, 159))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))
151426	16611371	In the xenograft experiments no difference in body weight was seen between R115777 and controls; neither was there any difference in the number of deaths seen between treated and control animals.	('deaths', 'Disease', (147, 153))	('R115777', 'Var', (75, 82))	('deaths', 'Disease', 'MESH:D003643', (147, 153))
151446	16611371	Furthermore, by showing an unfarnesylated protein in treated cell pellets and cell line tumours, we demonstrated the effect on farnesylation by the FTI R115777.	('effect', 'Reg', (117, 123))	('farnesylation', 'MPA', (127, 140))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('FTI R115777', 'Var', (148, 159))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
151456	16611371	The MCF-7/HER2-18 is a MCF-7 cell line with 45-fold over-expression of the HER2 receptor caused by transfection with full-length HER2 cDNA.	('transfection', 'Var', (99, 111))	('MCF-7', 'CellLine', 'CVCL:0031', (4, 9))	('HER2', 'Gene', (129, 133))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', '2064', (129, 133))	('HER2', 'Gene', '2064', (75, 79))	('over-expression', 'PosReg', (52, 67))	('MCF-7/HER2-18', 'CellLine', 'CVCL:0U80', (4, 17))	('HER2', 'Gene', (10, 14))	('MCF-7', 'CellLine', 'CVCL:0031', (23, 28))	('HER2', 'Gene', '2064', (10, 14))
151460	16611371	The effect on the HER2 transfected MCF-7 cell line tumours was also considerably more pronounced than the effect on the SKOV3 cell tumours, and this was also reflected in a 10-fold lower IC50.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('HER2', 'Gene', '2064', (18, 22))	('lower', 'NegReg', (181, 186))	('tumours', 'Disease', (131, 138))	('IC50', 'MPA', (187, 191))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('MCF-7', 'CellLine', 'CVCL:0031', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('SKOV3 cell tumours', 'Disease', (120, 138))	('SKOV3 cell tumours', 'Disease', 'MESH:C538614', (120, 138))	('transfected', 'Var', (23, 34))	('tumours', 'Disease', (51, 58))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('HER2', 'Gene', (18, 22))
151462	16611371	Clinical studies of R115777 in phase I trials have shown that a reversible myelosuppression is the dose-limiting toxicity of the drug.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('myelosuppression', 'Disease', 'MESH:D001855', (75, 91))	('R115777', 'Var', (20, 27))	('myelosuppression', 'Disease', (75, 91))
151463	16611371	In a phase II study of continuous and intermittent dosing of R15777 in women with advanced breast cancer, partial response or stable disease was demonstrated in about 20% of treated women.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('women', 'Species', '9606', (71, 76))	('women', 'Species', '9606', (182, 187))	('R15777', 'Var', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
151464	16611371	Forty-one of the primary tumours in the study conducted by Johnston and coworkers were analyzed for ras mutations and only one tumour had an h-ras mutation.	('ras', 'Gene', (100, 103))	('mutations', 'Var', (104, 113))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('h-ras', 'Gene', '3265', (141, 146))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('h-ras', 'Gene', (141, 146))	('tumour', 'Disease', (127, 133))	('tumour', 'Disease', (25, 31))	('tumours', 'Disease', (25, 32))
151481	16611371	The FTI R115777 is a promising new treatment for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('FTI R115777', 'Var', (4, 15))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
151490	32051475	We report hypo- and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration.	('hypermethylation', 'Var', (20, 36))	('cell migration', 'CPA', (165, 179))	('hypo-', 'Var', (10, 15))	('apoptosis', 'CPA', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
151491	32051475	DNA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', (87, 109))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (40, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
151492	32051475	Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DCIS.	('invasive cancer', 'Disease', (144, 159))	('alterations', 'Var', (73, 84))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('methylation alterations', 'Var', (61, 84))	('determine', 'Reg', (108, 117))	('invasive cancer', 'Disease', 'MESH:D009362', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('progress', 'PosReg', (132, 140))	('DNA', 'Gene', (57, 60))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
151499	32051475	It has been shown that patients with TNBC have poor prognosis and shorter median time to relapse compared to patients with other subtypes of breast cancer.	('TNBC', 'Var', (37, 41))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
151506	32051475	However, Kojima and collegues reported that abnormal breast calcifications were only detected in 22% of TN-DCIS compared to 59-72% of other types of DCIS cases, emphazising the challenge associated with detecting this specific breast cancer subtype during its non-invasive term.	('abnormal breast', 'Phenotype', 'HP:0000769', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('abnormal breast calcifications', 'Disease', (44, 74))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('abnormal breast calcifications', 'Disease', 'MESH:D061325', (44, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('breast cancer', 'Disease', (227, 240))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('TN-DCIS', 'Var', (104, 111))
151507	32051475	It has been suggested that TN-DCIS-derived tumors proliferate twice as fast as luminal A and three times faster than HER2-positive tumors, increasing its metastatic potential to other tissues.	('HER2', 'Gene', (117, 121))	('metastatic potential to other tissues', 'CPA', (154, 191))	('HER2', 'Gene', '2064', (117, 121))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('TN-DCIS-derived', 'Var', (27, 42))	('increasing', 'PosReg', (139, 149))
151513	32051475	Dogs and humans share many of the same breast cancer risk factors including aging, progesterone exposure, obesity in early life, poor diet, and mutations in BRCA genes.	('poor diet', 'Phenotype', 'HP:0011968', (129, 138))	('humans', 'Species', '9606', (9, 15))	('BRCA', 'Gene', (157, 161))	('progesterone', 'Chemical', 'MESH:D011374', (83, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('obesity', 'Phenotype', 'HP:0001513', (106, 113))	('obesity', 'Disease', 'MESH:D009765', (106, 113))	('obesity', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('mutations', 'Var', (144, 153))	('BRCA', 'Gene', '672', (157, 161))	('Dogs', 'Species', '9615', (0, 4))	('breast cancer', 'Disease', (39, 52))
151519	32051475	Epigenetic alterations within all three components of the epigenome such as DNA methylation, histone covalent modifications, and noncoding RNA mechanisms (including microRNAs) have been reported in canine cancers.	('Epigenetic alterations', 'Var', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('canine', 'Species', '9615', (198, 204))	('cancers', 'Disease', (205, 212))	('reported', 'Reg', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('methylation', 'Var', (80, 91))	('DNA', 'MPA', (76, 79))	('histone', 'Protein', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
151520	32051475	Promoter hypermethylation can result in gene silencing, and it is an early event in neoplastic progression through transcriptional silencing of tumor suppressor genes.	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('gene silencing', 'MPA', (40, 54))	('Promoter hypermethylation', 'Var', (0, 25))
151522	32051475	Global hypomethylation also contributes to multi-step carcinogenesis by activating transcription of repetitive sequences and transposable elements, which consequently contributes to genome rearrangements and chromosomal instability in cancer, including breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', (235, 241))	('transcription', 'MPA', (83, 96))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('Global hypomethylation', 'Var', (0, 22))	('cancer', 'Disease', (260, 266))	('activating', 'PosReg', (72, 82))	('contributes', 'Reg', (28, 39))	('contributes to', 'Reg', (167, 181))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('genome', 'MPA', (182, 188))	('chromosomal instability', 'Phenotype', 'HP:0040012', (208, 231))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('breast cancer', 'Disease', (253, 266))	('chromosomal', 'MPA', (208, 219))
151528	32051475	Hypomethylation of these elements robustly differentiated canine breast tumors from normal breast tissue.	('breast tumors', 'Disease', 'MESH:D061325', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('differentiated', 'Reg', (43, 57))	('Hypomethylation', 'Var', (0, 15))	('breast tumors', 'Phenotype', 'HP:0100013', (65, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('canine', 'Species', '9615', (58, 64))	('breast tumors', 'Disease', (65, 78))
151535	32051475	This confirms that dysregulation of the DNA methylating machinery plays a role in malignant transformation of lymphoid cells in humans and dogs as well.	('dysregulation', 'Var', (19, 32))	('dogs', 'Species', '9615', (139, 143))	('malignant transformation of lymphoid cells', 'CPA', (82, 124))	('humans', 'Species', '9606', (128, 134))
151543	32051475	Epigenetic alterations, particularly changes in DNA methylation that occur throughout these stages, could distinguish stages and be potentially used to predict progression from ADH to DCIS and subsequently to IDC.	('Epigenetic alterations', 'Var', (0, 22))	('ADH', 'Disease', (177, 180))	('DCIS', 'Disease', (184, 188))	('IDC', 'Disease', (209, 212))	('IDC', 'Disease', 'MESH:D044584', (209, 212))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('DNA methylation', 'MPA', (48, 63))	('ADH', 'Disease', 'MESH:D006965', (177, 180))
151546	32051475	1B), 38 of which were hypomethylated and the remaining 30 hypermethylated in ADH.	('ADH', 'Disease', 'MESH:D006965', (77, 80))	('hypermethylated', 'Var', (58, 73))	('hypomethylated', 'Var', (22, 36))	('ADH', 'Disease', (77, 80))
151548	32051475	S1), PLAU is categorized into "transcriptional misregulation," the most prominent pathway of genes with hypomethylated promoters in ADH versus healthy tissue.	('ADH', 'Disease', 'MESH:D006965', (132, 135))	('ADH', 'Disease', (132, 135))	('hypomethylated promoters', 'Var', (104, 128))	('PLAU', 'Gene', (5, 9))	('PLAU', 'Gene', '5328', (5, 9))
151551	32051475	Along the same line, hypermethylation of IL-13, an anti-inflammatory cytokine, could also contribute to the observed targeting of inflammation and immune regulation during the DCIS stage.	('hypermethylation', 'Var', (21, 37))	('IL-13', 'Gene', (41, 46))	('targeting', 'MPA', (117, 126))	('IL-13', 'Gene', '3596', (41, 46))	('inflammation', 'Disease', 'MESH:D007249', (130, 142))	('DCIS', 'Phenotype', 'HP:0030075', (176, 180))	('inflammation', 'Disease', (130, 142))	('contribute', 'Reg', (90, 100))
151552	32051475	In contrast to earlier stages, hypermethylation dominates in the invasive breast cancer stage as opposed to hypomethylation, with 40 promoters hypomethylated and 110 promoters hypermethylated (P < 0.05, Fisher's exact test) (Fig.	('invasive breast cancer', 'Disease', (65, 87))	('hypomethylated', 'Var', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasive breast cancer', 'Disease', 'MESH:D001943', (65, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
151553	32051475	Function and pathway analyses suggest that this widespread differential methylation leads to the disruption of many processes such as cell proliferation and migration, phosphorylation, focal adhesion, and TNF signaling pathway (Fig.	('cell proliferation', 'CPA', (134, 152))	('focal adhesion', 'CPA', (185, 199))	('phosphorylation', 'CPA', (168, 183))	('disruption', 'NegReg', (97, 107))	('TNF', 'Gene', (205, 208))	('methylation', 'Var', (72, 83))	('TNF', 'Gene', '7124', (205, 208))	('leads to', 'Reg', (84, 92))	('differential methylation', 'Var', (59, 83))
151558	32051475	96 gene promoters are significantly hypo- or hypermethylated exclusively in invasive cancer stage, while 35 other promoters are hypo- or hypermethylated in both DCIS and invasive stages (Fig.	('invasive cancer', 'Disease', 'MESH:D009362', (76, 91))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('invasive cancer', 'Disease', (76, 91))	('hypermethylated', 'Var', (45, 60))	('hypo-', 'Var', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
151565	32051475	Hypermethylation of pro-apoptotic genes DNAJC25 and FASTK in addition to hypomethylation of anti-apoptotic genes BDNF and MADCAM1 could be responsible for the survival capability of cells at later stages of TN-DCIS progression.	('DNAJC25', 'Gene', (40, 47))	('responsible', 'Reg', (139, 150))	('DNAJC25', 'Gene', '548645', (40, 47))	('BDNF', 'Gene', (113, 117))	('MADCAM1', 'Gene', (122, 129))	('Hypermethylation', 'Var', (0, 16))	('FASTK', 'Gene', '10922', (52, 57))	('DCIS', 'Phenotype', 'HP:0030075', (210, 214))	('FASTK', 'Gene', (52, 57))	('BDNF', 'Gene', '627', (113, 117))
151566	32051475	Hypermethylation of DNA damage-induced cellular response gene MCPH1 could also provide cancer cells with a safeguard against cell death mechanisms.	('cancer', 'Disease', (87, 93))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MCPH1', 'Gene', (62, 67))	('provide', 'Reg', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
151567	32051475	Several genes important in cellular signal transduction such as PDE6G, CALCB, BDNF, SFRP2, and transport such as ATOX1, FXYD2, SLC7A9, were hypomethylated in later stages of TN-DCIS progression, with the exception of CTXN1, a mediator of intracellular and extracellular signaling.	('SLC7A9', 'Gene', '11136', (127, 133))	('BDNF', 'Gene', '627', (78, 82))	('SLC7A9', 'Gene', (127, 133))	('SFRP2', 'Gene', (84, 89))	('SFRP2', 'Gene', '6423', (84, 89))	('PDE6G', 'Gene', '5148', (64, 69))	('BDNF', 'Gene', (78, 82))	('hypomethylated', 'Var', (140, 154))	('CALCB', 'Gene', (71, 76))	('FXYD2', 'Gene', '486', (120, 125))	('FXYD2', 'Gene', (120, 125))	('PDE6G', 'Gene', (64, 69))	('CALCB', 'Gene', '797', (71, 76))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
151569	32051475	Genes involved in transport such as ATOX1, a copper chaperone protein that functions as an antioxidant and is involved in breast cancer cell migration and FXYD2, a sodium/potassium-transporting ATPase subunit whose increased expression in tumors may contribute to angiogenesis, were hypomethylated in TN-DCIS and invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('FXYD2', 'Gene', '486', (155, 160))	('ATOX1', 'Gene', (36, 41))	('angiogenesis', 'CPA', (264, 276))	('TN-DCIS', 'Disease', (301, 308))	('tumors', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (322, 335))	('invasive breast cancer', 'Disease', (313, 335))	('contribute', 'Reg', (250, 260))	('hypomethylated', 'Var', (283, 297))	('invasive breast cancer', 'Disease', 'MESH:D001943', (313, 335))	('breast cancer', 'Disease', 'MESH:D001943', (322, 335))	('DCIS', 'Phenotype', 'HP:0030075', (304, 308))	('copper', 'Chemical', 'MESH:D003300', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('breast cancer', 'Disease', (122, 135))	('FXYD2', 'Gene', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))
151570	32051475	Hypomethylation of signal transduction-related genes BDNF and CALCB have the potential to lead to a myriad of cellular responses associated with cancer such as cell growth and proliferation, angiogenesis, and inflammation.	('cancer', 'Disease', (145, 151))	('angiogenesis', 'CPA', (191, 203))	('BDNF', 'Gene', '627', (53, 57))	('CALCB', 'Gene', '797', (62, 67))	('CALCB', 'Gene', (62, 67))	('Hypomethylation', 'Var', (0, 15))	('cell growth', 'CPA', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('BDNF', 'Gene', (53, 57))	('cellular', 'MPA', (110, 118))	('inflammation', 'Disease', 'MESH:D007249', (209, 221))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('lead to', 'Reg', (90, 97))	('inflammation', 'Disease', (209, 221))
151571	32051475	Genes involved in pathways related to increased cell motility, PFDN1 and MADCAM1, were hypomethylated while a gene associated with increased cell adhesion, COL7A1, was hypermethylated in TN-DCIS and invasive stages of TNBC.	('PFDN1', 'Gene', (63, 68))	('hypermethylated', 'Var', (168, 183))	('MADCAM1', 'Gene', (73, 80))	('TN-DCIS', 'Disease', (187, 194))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('PFDN1', 'Gene', '5201', (63, 68))	('hypomethylated', 'Var', (87, 101))	('COL7A1', 'Gene', (156, 162))
151577	32051475	The inability to initiate transcription of essential tumor suppressor genes, due to hypermethylation and potential silencing of TAF13, could contribute to the aggressive phenotype characteristic of TNBC.	('initiate transcription', 'MPA', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TAF13', 'Gene', '6884', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TAF13', 'Gene', (128, 133))	('tumor', 'Disease', (53, 58))	('TNBC', 'Disease', (198, 202))	('inability', 'NegReg', (4, 13))	('hypermethylation', 'Var', (84, 100))	('contribute', 'Reg', (141, 151))	('silencing', 'NegReg', (115, 124))
151581	32051475	Silencing of genes integral to pro-apoptotic mechanisms provides invasive cancer cells with the capacity to live and thrive in environments that typically promote programmed cell death.	('genes', 'Gene', (13, 18))	('invasive cancer', 'Disease', (65, 80))	('Silencing', 'Var', (0, 9))	('invasive cancer', 'Disease', 'MESH:D009362', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
151582	32051475	Negative regulator of Wnt oncogenic signaling, Frizzled receptor 6 (FZD6) is also hypermethylated in invasive breast cancer.	('Frizzled receptor 6', 'Gene', '8323', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive breast cancer', 'Disease', (101, 123))	('Frizzled receptor 6', 'Gene', (47, 66))	('hypermethylated', 'Var', (82, 97))	('FZD6', 'Gene', '8323', (68, 72))	('FZD6', 'Gene', (68, 72))	('invasive breast cancer', 'Disease', 'MESH:D001943', (101, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
151586	32051475	In previous studies, regulation of RECK by DNA methylation has been described and proposed as a potential marker for predicting breast cancer prognosis.	('RECK', 'Gene', '8434', (35, 39))	('methylation', 'Var', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('RECK', 'Gene', (35, 39))
151588	32051475	We also found that there are gene promoters specifically hypomethylated at the invasive breast cancer stage.	('invasive breast cancer', 'Disease', (79, 101))	('hypomethylated', 'Var', (57, 71))	('invasive breast cancer', 'Disease', 'MESH:D001943', (79, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
151589	32051475	Genes associated with signal transduction, such as CXCR3 and DHRS4, and transport, such as BEST1, UCP2, and FXYD1, as well as increased cell migration and metastasis, namely TRAF5, FUT5, and DHRS4, were hypomethylated (Fig.	('DHRS4', 'Gene', (61, 66))	('DHRS4', 'Gene', '10901', (61, 66))	('FXYD1', 'Gene', '5348', (108, 113))	('TRAF5', 'Gene', (174, 179))	('FUT5', 'Gene', '2527', (181, 185))	('BEST1', 'Gene', '7439', (91, 96))	('UCP2', 'Gene', '7351', (98, 102))	('CXCR3', 'Gene', (51, 56))	('hypomethylated', 'Var', (203, 217))	('TRAF5', 'Gene', '7188', (174, 179))	('cell migration', 'CPA', (136, 150))	('metastasis', 'CPA', (155, 165))	('CXCR3', 'Gene', '2833', (51, 56))	('BEST1', 'Gene', (91, 96))	('DHRS4', 'Gene', (191, 196))	('DHRS4', 'Gene', '10901', (191, 196))	('FUT5', 'Gene', (181, 185))	('FXYD1', 'Gene', (108, 113))	('UCP2', 'Gene', (98, 102))	('increased', 'PosReg', (126, 135))
151597	32051475	As for genes involved in signaling pathways whose alterations have the potential to disrupt a wide variety of cell processes, TRAF5 and FUT5 are two candidates that could have a robust impact.	('FUT5', 'Gene', (136, 140))	('cell processes', 'CPA', (110, 124))	('TRAF5', 'Gene', (126, 131))	('disrupt', 'Reg', (84, 91))	('alterations', 'Var', (50, 61))	('FUT5', 'Gene', '2527', (136, 140))	('TRAF5', 'Gene', '7188', (126, 131))
151600	32051475	Inhibition of fucosylation has been shown to reduce oncogenic properties of breast cancer; therefore, hypomethylation and subsequent activation of FUT5 to increase fucosylation could exacerbate oncogenic properties.	('hypomethylation', 'Var', (102, 117))	('increase', 'PosReg', (155, 163))	('FUT5', 'Gene', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('oncogenic properties', 'CPA', (52, 72))	('FUT5', 'Gene', '2527', (147, 151))	('fucosylation', 'Protein', (14, 26))	('exacerbate', 'PosReg', (183, 193))	('activation', 'PosReg', (133, 143))	('breast cancer', 'Disease', (76, 89))	('reduce', 'NegReg', (45, 51))	('Inhibition', 'Var', (0, 10))	('fucosylation', 'MPA', (164, 176))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('oncogenic properties', 'CPA', (194, 214))
151602	32051475	Specifically, UCP2 and TXNRD1, key players in oxidative stress and redox homeostasis, were hypomethylated.	('hypomethylated', 'Var', (91, 105))	('TXNRD1', 'Gene', (23, 29))	('UCP2', 'Gene', '7351', (14, 18))	('UCP2', 'Gene', (14, 18))	('TXNRD1', 'Gene', '7296', (23, 29))	('oxidative stress', 'Phenotype', 'HP:0025464', (46, 62))
151603	32051475	Hypomethylation and upregulation of these antioxidant-related genes could suggest that cancer cells can deal with oxidative stress and even take advantage of antioxidant-related mechanisms to ensure their survival.	('cancer', 'Disease', (87, 93))	('oxidative stress', 'MPA', (114, 130))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('oxidative stress', 'Phenotype', 'HP:0025464', (114, 130))	('upregulation', 'PosReg', (20, 32))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
151605	32051475	For instance, hypermethylation and potentially reduced expression of IDS, a sulphatase whose silencing may lead to accumulation and export of estrogen sulfates contributing to multidrug resistance, could play a role in the problematic nature of treating TNBC.	('TNBC', 'Disease', (254, 258))	('hypermethylation', 'Var', (14, 30))	('play', 'Reg', (204, 208))	('IDS', 'Gene', (69, 72))	('drug resistance', 'Phenotype', 'HP:0020174', (181, 196))	('expression', 'MPA', (55, 65))	('accumulation', 'MPA', (115, 127))	('IDS', 'Gene', '3423', (69, 72))	('estrogen sulfates', 'Chemical', '-', (142, 159))	('reduced', 'NegReg', (47, 54))	('export of estrogen sulfates', 'MPA', (132, 159))	('lead', 'Reg', (107, 111))
151609	32051475	Hypermethylation and potential silencing of this anti-apoptotic stress sensor would disallow breast cancer cell adaptation and shift the balance toward promoting programmed cell death in response to the changing cellular microenvironment.	('stress sensor would disallow breast cancer cell adaptation', 'Disease', 'MESH:D001943', (64, 122))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('shift', 'Reg', (127, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('silencing', 'NegReg', (31, 40))
151611	32051475	Cell death pathways may be further strengthened by hypomethylation-activated PMAIP1, a gene that promotes activation of caspases involved in apoptosis.	('strengthened', 'PosReg', (35, 47))	('PMAIP1', 'Gene', (77, 83))	('Cell death', 'CPA', (0, 10))	('caspases', 'Gene', (120, 128))	('hypomethylation-activated', 'Var', (51, 76))	('caspases', 'Gene', '842', (120, 128))	('PMAIP1', 'Gene', '5366', (77, 83))	('activation', 'PosReg', (106, 116))
151615	32051475	Hypomethylation and potential activation of PPBP, TLR9, MS4A2, CCL1, and BDKRB1 may allow innate immune cells to target sites of inflammation and appropriately counteract inflammation-inducing processes.	('TLR9', 'Gene', (50, 54))	('CCL1', 'Gene', '6346', (63, 67))	('Hypomethylation', 'Var', (0, 15))	('BDKRB1', 'Gene', (73, 79))	('activation', 'PosReg', (30, 40))	('BDKRB1', 'Gene', '623', (73, 79))	('PPBP', 'Gene', (44, 48))	('inflammation', 'Disease', (129, 141))	('MS4A2', 'Gene', '2206', (56, 61))	('inflammation', 'Disease', 'MESH:D007249', (171, 183))	('PPBP', 'Gene', '5473', (44, 48))	('TLR9', 'Gene', '54106', (50, 54))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('inflammation', 'Disease', (171, 183))	('CCL1', 'Gene', (63, 67))	('MS4A2', 'Gene', (56, 61))
151620	32051475	For example, hypomethylated GSTA4 encodes for an enzyme involved in defense against toxic and carcinogenic compounds.	('GSTA4', 'Gene', (28, 33))	('GSTA4', 'Gene', '2941', (28, 33))	('hypomethylated', 'Var', (13, 27))	('carcinogenic', 'Disease', 'MESH:D063646', (94, 106))	('carcinogenic', 'Disease', (94, 106))
151621	32051475	Hypermethylated RAB9A is involved in GTPase-mediated signal transduction and protein transport between endosomes and the Golgi network.	('involved', 'Reg', (25, 33))	('Hypermethylated', 'Var', (0, 15))	('RAB9A', 'Gene', (16, 21))	('RAB9A', 'Gene', '9367', (16, 21))	('protein transport', 'MPA', (77, 94))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
151623	32051475	Therefore, RAB9A hypermethylation and potential downregulation could be a contributing factor to maintaining the DCIS stage without progression to invasive breast cancer.	('invasive breast cancer', 'Disease', (147, 169))	('RAB9A', 'Gene', '9367', (11, 16))	('RAB9A', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('invasive breast cancer', 'Disease', 'MESH:D001943', (147, 169))	('downregulation', 'NegReg', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('hypermethylation', 'Var', (17, 33))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
151627	32051475	Hypermethylated PRR5, an established tumor suppressor gene in breast cancer, is a component of mTOR complex 2 which acts as a central regulator of cell growth and survival in response to hormonal signals.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Hypermethylated', 'Var', (0, 15))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('breast cancer', 'Disease', (62, 75))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('PRR5', 'Gene', (16, 20))	('PRR5', 'Gene', '55615', (16, 20))
151635	32051475	Taking into account the functions of these genes, their hypomethylation and potential activation may aid to promote cell death by apoptosis (DNASE1), induce degradation and turnover of mitochondria to facilitate necessary cell turnover (FUNDC2), and convert estrogen sulfates into free estrogens to protect from breast cancer resistance protein (BCRP)-mediated drug resistance (IDS) during ADH and DCIS stages.	('convert', 'Reg', (250, 257))	('IDS', 'Gene', (378, 381))	('ADH', 'Disease', (390, 393))	('FUNDC2', 'Gene', '65991', (237, 243))	('drug resistance', 'Phenotype', 'HP:0020174', (361, 376))	('DNASE1', 'Gene', (141, 147))	('IDS', 'Gene', '3423', (378, 381))	('degradation', 'MPA', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('breast cancer resistance protein', 'Gene', '9429', (312, 344))	('DNASE1', 'Gene', '1773', (141, 147))	('mitochondria', 'MPA', (185, 197))	('facilitate', 'PosReg', (201, 211))	('turnover', 'MPA', (173, 181))	('induce', 'Reg', (150, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (312, 325))	('BCRP', 'Gene', (346, 350))	('breast cancer resistance protein', 'Gene', (312, 344))	('BCRP', 'Gene', '9429', (346, 350))	('promote', 'PosReg', (108, 115))	('FUNDC2', 'Gene', (237, 243))	('cell death', 'CPA', (116, 126))	('ADH', 'Disease', 'MESH:D006965', (390, 393))	('DCIS', 'Phenotype', 'HP:0030075', (398, 402))	('hypomethylation', 'Var', (56, 71))	('estrogen sulfates', 'Chemical', '-', (258, 275))
151636	32051475	On the other hand, hypermethylation of DNASE1, FUNDC2, and IDS during the invasive stage may result in cells' capablility to relieve themselves of safeguards from programmed cell death and cell turnover.	('IDS', 'Gene', '3423', (59, 62))	('DNASE1', 'Gene', (39, 45))	('IDS', 'Gene', (59, 62))	('hypermethylation', 'Var', (19, 35))	('FUNDC2', 'Gene', (47, 53))	('cell turnover', 'CPA', (189, 202))	('FUNDC2', 'Gene', '65991', (47, 53))	('DNASE1', 'Gene', '1773', (39, 45))	('result in', 'Reg', (93, 102))
151648	32051475	Higher concordance between DNA methylation in our canine model and gene expression in human TNBC cell lines, especially MDA-MB-231 cells, was detected for genes hypermethylated in invasive cancer compared to normal tissue (54% alignment).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (120, 130))	('invasive cancer', 'Disease', 'MESH:D009362', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('canine', 'Species', '9615', (50, 56))	('human', 'Species', '9606', (86, 91))	('hypermethylated', 'Var', (161, 176))	('invasive cancer', 'Disease', (180, 195))
151652	32051475	Compared to vehicle-treated cells (PBS), significant upregulation of 9 of the 10 canine candidate genes was detected in 5-aza-treated cells, with the remaining gene demonstrating a trend for upregulation (P = 0.08) (Fig.	('upregulation', 'PosReg', (191, 203))	('5-aza-treated', 'Var', (120, 133))	('canine', 'Species', '9615', (81, 87))	('PBS', 'Chemical', 'MESH:D007854', (35, 38))	('upregulation', 'PosReg', (53, 65))	('5-aza', 'Chemical', 'MESH:D001374', (120, 125))
151660	32051475	Gene candidates hypomethylated (MADCAM1 and ATOX1) and hypermethylated (MATR3 and MCPH1) in DCIS and invasive stages of canine TNBC progression show corresponding changes in gene expression in human breast tissues (Fig.	('hypomethylated', 'Var', (16, 30))	('gene expression', 'MPA', (174, 189))	('canine', 'Species', '9615', (120, 126))	('changes', 'Reg', (163, 170))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('hypermethylated', 'Var', (55, 70))	('human', 'Species', '9606', (193, 198))
151667	32051475	Such testing to date has not yet been extensively developed despite the fact that TNBC makes up about 15%-20% of breast cancer cases and results in a disproportionate number of breast cancer deaths.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (177, 190))	('TNBC', 'Var', (82, 86))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('results in', 'Reg', (137, 147))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
151677	32051475	For the first time, we use a canine model of triple-negative invasive breast cancer to follow all stages of progression of TN-DCIS to invasive breast cancer and identify DNA methylation alterations to distinguish changes that may predict progression.	('canine', 'Species', '9615', (29, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('alterations', 'Var', (186, 197))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('invasive breast cancer', 'Disease', 'MESH:D001943', (134, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasive breast cancer', 'Disease', (61, 83))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('invasive breast cancer', 'Disease', (134, 156))
151687	32051475	Several groups have sought to establish DNA methylation alterations as markers of breast cancer diagnosis and progression.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('alterations', 'Var', (56, 67))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
151747	26656378	Given that SA has a tendency for bilaterality, sections from breast cancer patients with non-Bc-SA in the contralateral breast were also reviewed by the pathologist to determine whether it was accompanied by previously undiscovered SA.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('SA', 'Chemical', '-', (232, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('patients', 'Species', '9606', (75, 83))	('Bc-SA', 'Chemical', '-', (93, 98))	('non-Bc-SA', 'Var', (89, 98))	('SA', 'Chemical', '-', (96, 98))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('SA', 'Chemical', '-', (11, 13))
151751	26656378	In the subgroup analysis, patients were categorized into 3 groups according to BI-RADS classification to investigate the diagnosis of SA using imaging methods: BI-RADS 0, BI-RADS 1-3 and BI-RADS 4-5.	('patients', 'Species', '9606', (26, 34))	('BI-RADS', 'Var', (187, 194))	('SA', 'Chemical', '-', (134, 136))	('BI-RADS 0', 'Var', (160, 169))	('BI-RADS', 'Var', (171, 178))
151783	26656378	In a retrospective study analyzing 117 synchronous bilateral breast cancer and 7400 unilateral breast cancer patients, the author indicated that the presence of SA was a risk factor for developing synchronous bilateral breast cancer (hazard ratio: 11.8; 95% confidence interval: 5.3-26.3; P < 0.001).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('unilateral breast cancer', 'Disease', (84, 108))	('unilateral breast', 'Phenotype', 'HP:0012813', (84, 101))	('patients', 'Species', '9606', (109, 117))	('synchronous bilateral breast cancer', 'Disease', (197, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('synchronous bilateral breast cancer', 'Disease', (39, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('synchronous bilateral breast cancer', 'Disease', 'MESH:D009378', (197, 232))	('presence', 'Var', (149, 157))	('synchronous bilateral breast cancer', 'Disease', 'MESH:D009378', (39, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('unilateral breast cancer', 'Disease', 'MESH:D000069584', (84, 108))	('SA', 'Chemical', '-', (161, 163))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
151844	27026436	Patient residence in a rural location, poorly differentiated or NOS tumor grade, and tumor size >=2 cm were significantly associated with undergoing subsequent surgery after the initial partial mastectomy.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (85, 90))	('associated', 'Reg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('poorly', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Patient', 'Species', '9606', (0, 7))
151873	17640394	Complementary experimental studies have established that both conventional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors suppress mammary tumor formation in rodent breast cancer models.	('inhibitors', 'Var', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('mammary', 'Disease', (152, 159))	('COX-2', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('suppress', 'NegReg', (143, 151))	('breast cancer', 'Disease', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('tumor', 'Disease', (160, 165))
151874	17640394	Furthermore, knocking out Cox-2 reduces mammary tumorigenesis and angiogenesis, and, conversely, transgenic COX-2 over-expression induces tumor formation.	('COX-2', 'Gene', (108, 113))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (138, 143))	('transgenic', 'Species', '10090', (97, 107))	('over-expression', 'PosReg', (114, 129))	('reduces', 'NegReg', (32, 39))	('knocking out', 'Var', (13, 25))	('Cox-2', 'Gene', '5743', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Cox-2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('angiogenesis', 'CPA', (66, 78))	('induces', 'Reg', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
151883	17640394	Transgenic COX-2 over-expression drives mammary tumor formation, and, conversely, knocking out Cox-2 reduces tumor formation in rodent models of intestinal, breast, and skin cancer.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('skin cancer', 'Disease', (169, 180))	('breast', 'Disease', (157, 163))	('Transgenic', 'Species', '10090', (0, 10))	('skin cancer', 'Phenotype', 'HP:0008069', (169, 180))	('Cox-2', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('over-expression', 'PosReg', (17, 32))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('COX-2', 'Gene', (11, 16))	('skin cancer', 'Disease', 'MESH:D012878', (169, 180))	('reduces', 'NegReg', (101, 108))	('knocking out', 'Var', (82, 94))	('Cox-2', 'Gene', '5743', (95, 100))	('intestinal', 'Disease', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (109, 114))
151888	17640394	Therefore, it behooves us to identify alternative components of the COX/PG signaling pathway, antagonism of which will achieve protection comparable to that afforded by COXibs but with minimal collateral toxicity.	('COX/PG signaling pathway', 'Pathway', (68, 92))	('PG', 'Chemical', 'MESH:D011453', (72, 74))	('antagonism', 'Var', (94, 104))	('protection', 'MPA', (127, 137))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('toxicity', 'Disease', (204, 212))
151895	17640394	Inhibitors that are selective for COX-2 have also been developed as anti-inflammatory agents, with the goal of minimizing the gastrointestinal complications associated with traditional NSAIDs.	('gastrointestinal complications', 'Phenotype', 'HP:0004798', (126, 156))	('gastrointestinal complications', 'Disease', (126, 156))	('Inhibitors', 'Var', (0, 10))	('gastrointestinal complications', 'Disease', 'MESH:D005767', (126, 156))
151896	17640394	Aberrant activation of COX/PG signaling is widespread in human neoplasia.	('activation', 'PosReg', (9, 19))	('neoplasia', 'Phenotype', 'HP:0002664', (63, 72))	('Aberrant', 'Var', (0, 8))	('neoplasia', 'Disease', 'MESH:D009369', (63, 72))	('PG', 'Chemical', 'MESH:D011453', (27, 29))	('neoplasia', 'Disease', (63, 72))	('COX/PG', 'MPA', (23, 29))	('human', 'Species', '9606', (57, 62))
151918	17640394	Intriguingly, COX-2 expression has also been detected in focal regions of normal breast in association with silencing of CDKN2A (p16INK4a), suggesting that COX-2 upregulation may be a very early event in breast neoplasia.	('CDKN2A', 'Gene', '1029', (121, 127))	('breast neoplasia', 'Phenotype', 'HP:0100013', (204, 220))	('silencing', 'Var', (108, 117))	('p16INK4a', 'Gene', (129, 137))	('p16INK4a', 'Gene', '1029', (129, 137))	('breast neoplasia', 'Disease', 'MESH:D009369', (204, 220))	('neoplasia', 'Phenotype', 'HP:0002664', (211, 220))	('CDKN2A', 'Gene', (121, 127))	('breast neoplasia', 'Disease', (204, 220))
151921	17640394	Furthermore, genetic ablation of Cox-2 decreases mammary tumor formation.	('genetic ablation', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Cox-2', 'Gene', (33, 38))	('Cox-2', 'Gene', '5743', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('decreases', 'NegReg', (39, 48))	('tumor', 'Disease', (57, 62))
151938	17640394	MMTV/NDL mice express a mutationally activated HER2/neu transgene that drives formation of multiple DCIS-like tumors in each mammary gland.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('tumors', 'Disease', (110, 116))	('HER2/neu', 'Protein', (47, 55))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mice', 'Species', '10090', (9, 13))	('MMTV', 'Species', '11757', (0, 4))	('mutationally', 'Var', (24, 36))
151940	17640394	Hence, we employed the MMTV/NDL strain as a breast cancer model system in which to examine the consequences of knocking out Cox-2.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('knocking out', 'Var', (111, 123))	('Cox-2', 'Gene', '5743', (124, 129))	('breast cancer', 'Disease', (44, 57))	('Cox-2', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('MMTV', 'Species', '11757', (23, 27))
151943	17640394	Complete ablation of Cox-2 reduced the mean tumor multiplicity by approximately 50%.	('reduced', 'NegReg', (27, 34))	('Cox-2', 'Gene', '5743', (21, 26))	('ablation', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('Cox-2', 'Gene', (21, 26))
151945	17640394	PGE2 levels in MMTV/NDL mammary glands correlated with Cox-2 gene dosage.	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('Cox-2', 'Gene', (55, 60))	('correlated', 'Reg', (39, 49))	('Cox-2', 'Gene', '5743', (55, 60))	('MMTV', 'Species', '11757', (15, 19))	('PGE2', 'Gene', (0, 4))	('gene dosage', 'Var', (61, 72))
151949	17640394	Specifically, we observed a striking reduction in mammary vasculature in Cox-2 null animals relative to wild-type controls.	('null', 'Var', (79, 83))	('reduction', 'NegReg', (37, 46))	('Cox-2', 'Gene', (73, 78))	('mammary vasculature', 'MPA', (50, 69))	('Cox-2', 'Gene', '5743', (73, 78))
151951	17640394	Consistent with the marked reduction in mammary vasculature in Cox-2 null mammary tissues, the expression of several angiogenesis-associated genes was decreased (Figure 5b), including VEGF (which encodes vascular endothelial growth factor), Ang1 and Ang2 (which encode Tie-2 ligands), and Flk-1 and Flt-1 (which encode vascular endothelial growth factor receptors).	('Flt-1', 'Gene', (299, 304))	('vascular endothelial growth factor', 'Gene', (319, 353))	('null', 'Var', (69, 73))	('Flk-1', 'Gene', (289, 294))	('Ang2', 'Gene', (250, 254))	('Cox-2', 'Gene', (63, 68))	('vascular endothelial growth factor', 'Gene', '7422', (204, 238))	('Flk-1', 'Gene', '3791', (289, 294))	('Ang1', 'Gene', (241, 245))	('VEGF', 'Gene', '7422', (184, 188))	('angiogenesis-associated genes', 'Gene', (117, 146))	('vascular endothelial growth factor', 'Gene', (204, 238))	('expression', 'MPA', (95, 105))	('reduction', 'NegReg', (27, 36))	('Tie-2', 'Gene', '7010', (269, 274))	('Tie-2', 'Gene', (269, 274))	('VEGF', 'Gene', (184, 188))	('mammary vasculature', 'MPA', (40, 59))	('decreased', 'NegReg', (151, 160))	('Flt-1', 'Gene', '2321', (299, 304))	('Ang2', 'Gene', '285', (250, 254))	('Cox-2', 'Gene', '5743', (63, 68))	('Ang1', 'Gene', '284', (241, 245))	('vascular endothelial growth factor', 'Gene', '7422', (319, 353))
151954	17640394	As described above, mammary tumorigenesis can be suppressed by both genetic and pharmacologic ablation of Cox-2, thus clearly identifying a role for COX-2 in breast neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (165, 174))	('ablation', 'Var', (94, 102))	('tumor', 'Disease', (28, 33))	('breast neoplasia', 'Disease', (158, 174))	('suppressed', 'NegReg', (49, 59))	('breast neoplasia', 'Phenotype', 'HP:0100013', (158, 174))	('Cox-2', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Cox-2', 'Gene', '5743', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('breast neoplasia', 'Disease', 'MESH:D009369', (158, 174))
151958	17640394	Furthermore, mammary gland involution after weaning was delayed in transgenic animals relative to wild-type littermates, with an accompanying decrease in apoptosis.	('transgenic', 'Species', '10090', (67, 77))	('transgenic', 'Var', (67, 77))	('apoptosis', 'CPA', (154, 163))	('decrease', 'NegReg', (142, 150))	('delayed', 'NegReg', (56, 63))	('mammary gland involution after', 'CPA', (13, 43))
151961	17640394	Furthermore, these studies offer mechanistic insights into the role of COX-2 in mammary neoplasia, indicating that COX-2 is important for angiogenesis and may also play a critical role in suppressing apoptosis.	('suppressing', 'NegReg', (188, 199))	('neoplasia', 'Disease', (88, 97))	('neoplasia', 'Disease', 'MESH:D009369', (88, 97))	('neoplasia', 'Phenotype', 'HP:0002664', (88, 97))	('COX-2', 'Var', (115, 120))	('apoptosis', 'CPA', (200, 209))
151965	17640394	Of particular relevance to breast cancer, PGs can increase estrogen biosynthesis via upregulation of aromatase transcription (discussed below).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PGs', 'Var', (42, 45))	('estrogen biosynthesis', 'MPA', (59, 80))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('increase', 'PosReg', (50, 58))	('PGs', 'Chemical', 'MESH:D010715', (42, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('aromatase', 'Protein', (101, 110))	('upregulation', 'PosReg', (85, 97))
151982	17640394	These data support the concept that COX inhibition reduces mammary neoplasia at least in part through suppression of estrogen biosynthesis.	('COX', 'Enzyme', (36, 39))	('inhibition', 'Var', (40, 50))	('reduces', 'NegReg', (51, 58))	('neoplasia', 'Disease', (67, 76))	('neoplasia', 'Disease', 'MESH:D009369', (67, 76))	('neoplasia', 'Phenotype', 'HP:0002664', (67, 76))	('suppression', 'NegReg', (102, 113))	('estrogen biosynthesis', 'MPA', (117, 138))
151997	17640394	mPGES-1 ablation does not increase thrombogenesis or blood pressure, consistent with the hypothesis that prostacyclin suppression is a key component of COXib-induced cardiotoxicity.	('increase thrombogenesis', 'Disease', 'MESH:D019586', (26, 49))	('mPGES-1', 'Gene', (0, 7))	('prostacyclin', 'Chemical', 'MESH:D011464', (105, 117))	('cardiotoxicity', 'Disease', 'MESH:D066126', (166, 180))	('cardiotoxicity', 'Disease', (166, 180))	('increase thrombogenesis', 'Disease', (26, 49))	('ablation', 'Var', (8, 16))	('mPGES-1', 'Gene', '64292', (0, 7))
152004	17640394	Enhancing PGE2 inactivation may provide an alternative mechanism for ameliorating COX-associated neoplasia.	('PGE2', 'Chemical', 'MESH:D015232', (10, 14))	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('neoplasia', 'Disease', 'MESH:D009369', (97, 106))	('PGE2', 'Gene', (10, 14))	('inactivation', 'Var', (15, 27))	('neoplasia', 'Disease', (97, 106))
152007	17640394	These observations suggest the intriguing possibility that PGE2 signaling could be terminated by reversing epigenetic inactivation of the 15-PGDH locus, and that this could offer a novel approach to targeting PGE2-driven neoplasia.	('neoplasia', 'Disease', (221, 230))	('PGE2', 'Chemical', 'MESH:D015232', (209, 213))	('PGE2', 'Chemical', 'MESH:D015232', (59, 63))	('neoplasia', 'Disease', 'MESH:D009369', (221, 230))	('neoplasia', 'Phenotype', 'HP:0002664', (221, 230))	('15-PGDH', 'Gene', '873', (138, 145))	('epigenetic inactivation', 'Var', (107, 130))	('15-PGDH', 'Gene', (138, 145))
152010	17640394	Both pharmacologic and genetic ablation of Cox-2 suppress experimental breast cancer, and transgenic COX-2 over-expression drives tumor formation.	('breast cancer', 'Disease', (71, 84))	('transgenic', 'Species', '10090', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('COX-2', 'Gene', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('over-expression', 'PosReg', (107, 122))	('Cox-2', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Cox-2', 'Gene', '5743', (43, 48))	('ablation', 'Var', (31, 39))	('tumor', 'Disease', (130, 135))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('suppress', 'NegReg', (49, 57))
152122	31898104	One patient in a separate trial had an allergic reaction after LUM015 injection but recovered completely (personal communication).	('allergic reaction', 'Disease', 'MESH:D004342', (39, 56))	('patient', 'Species', '9606', (4, 11))	('LUM015', 'Chemical', '-', (63, 69))	('allergic reaction', 'Disease', (39, 56))	('allergic reaction', 'Phenotype', 'HP:0012393', (39, 56))	('LUM015', 'Var', (63, 69))
152124	31898104	The LUM Imaging System is also being evaluated in clinical trials for peritoneal (NCT03834272), central nervous system (NCT03717142), and prostate (NCT03441464) cancers, and is being assessed for use in ovarian, esophagus, pancreas, and colorectal cancers.	('colorectal cancers', 'Disease', (237, 255))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('LUM', 'Gene', (4, 7))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers', 'Disease', (248, 255))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ovarian', 'Disease', (203, 210))	('NCT03441464', 'Var', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('peritoneal', 'Disease', (70, 80))	('esophagus', 'Disease', (212, 221))	('LUM', 'Gene', '4060', (4, 7))	('colorectal cancers', 'Disease', 'MESH:D015179', (237, 255))	('NCT03834272', 'Var', (82, 93))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('prostate', 'Disease', (138, 146))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('pancreas', 'Disease', (223, 231))	('NCT03717142', 'Var', (120, 131))
152259	28053633	Abnormal findings on FFDM in 68 patients included: dense breast tissue in three, mass in 20, calcification in 20, asymmetry in 17, distortion in one, mass with calcification in one, mass with distortion in one, asymmetry with calcification in three, calcification and distortion in one, and left breast mass and right breast calcification in one.	('right breast calcification', 'Disease', (312, 338))	('calcification', 'Disease', 'MESH:D002114', (226, 239))	('calcification', 'Disease', (325, 338))	('distortion', 'Var', (268, 278))	('calcification', 'Disease', 'MESH:D002114', (250, 263))	('calcification', 'Disease', (93, 106))	('calcification', 'Disease', (226, 239))	('distortion', 'Var', (131, 141))	('asymmetry', 'Var', (211, 220))	('left breast mass', 'CPA', (291, 307))	('calcification', 'Disease', 'MESH:D002114', (160, 173))	('right breast calcification', 'Disease', 'MESH:D002114', (312, 338))	('calcification', 'Disease', (250, 263))	('patients', 'Species', '9606', (32, 40))	('breast mass', 'Phenotype', 'HP:0032408', (296, 307))	('calcification', 'Disease', 'MESH:D002114', (325, 338))	('calcification', 'Disease', (160, 173))	('FFDM', 'Chemical', '-', (21, 25))	('calcification', 'Disease', 'MESH:D002114', (93, 106))
152293	28053633	The overall FOM of DBT alone was also higher than that of FFDM alone (0.807 vs. 0.775, p=0.027).	('DBT', 'Var', (19, 22))	('FFDM', 'Chemical', '-', (58, 62))	('FOM', 'MPA', (12, 15))	('higher', 'PosReg', (38, 44))
152307	28053633	All five cancers that were occult on combined DBT and FFDM were obscured by dense parenchymal tissue, and BI-RADS breast density was interpreted as heterogeneously dense or extremely dense in each case (Figure 2).	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('BI-RADS', 'Var', (106, 113))	('cancers', 'Disease', (9, 16))	('FFDM', 'Chemical', '-', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
152312	28053633	Prior investigators have reported on the interpretive advantages of adding DBT to conventional FFDM in the diagnostic and screening setting and demonstrated a reduction in recall rate and gain in diagnostic accuracy.	('reduction', 'NegReg', (159, 168))	('recall rate', 'MPA', (172, 183))	('FFDM', 'Chemical', '-', (95, 99))	('gain', 'PosReg', (188, 192))	('DBT', 'Var', (75, 78))	('diagnostic', 'MPA', (196, 206))
152351	22007214	The imbalance between tumor cell growth and vascular formation may often cause a collapse of tumor cells and the new vasculature.	('collapse', 'CPA', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('vascular formation', 'CPA', (44, 62))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('imbalance', 'Var', (4, 13))	('tumor', 'Disease', (22, 27))	('cause', 'Reg', (73, 78))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
152373	22007214	In another study of 564 tissue microarrays from primary tumors from premenopausal breast cancer patients who had been randomized to adjuvant tamoxifen or no adjuvant treatment, TNBCs show increased protein expression of epithelial growth factor receptor (EGFR) and VEGFR2, whereas the expression of VEGF-A is not a specific biomarker of TNBCs.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('VEGFR2', 'Gene', (265, 271))	('increased', 'PosReg', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('EGFR', 'Gene', (255, 259))	('VEGFR2', 'Gene', '3791', (265, 271))	('primary tumors', 'Disease', (48, 62))	('VEGF-A', 'Gene', '7422', (299, 305))	('EGFR', 'Gene', '1956', (266, 270))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (68, 95))	('TNBC', 'Chemical', '-', (337, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('primary tumors', 'Disease', 'MESH:D009369', (48, 62))	('protein expression', 'MPA', (198, 216))	('patients', 'Species', '9606', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('epithelial growth factor receptor', 'Gene', (220, 253))	('EGFR', 'Gene', '1956', (255, 259))	('breast cancer', 'Disease', (82, 95))	('TNBC', 'Chemical', '-', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('VEGF-A', 'Gene', (299, 305))	('EGFR', 'Gene', (266, 270))	('TNBCs', 'Var', (177, 182))	('epithelial growth factor receptor', 'Gene', '1956', (220, 253))
152374	22007214	A pathological examination using CD34 of one thousand early-stage primary breast cancer specimens has shown that basal-like breast cancer and TNBCs had significantly higher microvessel densities (MVDs) than the nonbasal and non-TNBC groups.	('higher', 'PosReg', (166, 172))	('breast cancer', 'Disease', (74, 87))	('CD34', 'Gene', '947', (33, 37))	('TNBC', 'Chemical', '-', (142, 146))	('TNBC', 'Chemical', '-', (228, 232))	('CD34', 'Gene', (33, 37))	('TNBCs', 'Var', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('microvessel densities', 'CPA', (173, 194))	('breast cancer', 'Disease', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
152392	22007214	BRCA-associated breast cancers are different from spontaneous breast cancers in many aspects, such as morphology, triple negativity, basal cytokeratin expression, and p53 mutations.	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('BRCA', 'Gene', (0, 4))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('p53', 'Gene', '7157', (167, 170))	('triple negativity', 'Disease', (114, 131))	('mutations', 'Var', (171, 180))	('p53', 'Gene', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('breast cancers', 'Disease', (16, 30))	('BRCA', 'Gene', '672', (0, 4))
152404	22007214	These drugs change the balance of pro- and antiangiogenic factors in the tumor tissue and fix the delivery system to ensure that oxygen and therapeutic drugs are effectively distributed to a larger number of tumor cells.	('oxygen', 'Chemical', 'MESH:D010100', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('drugs', 'Var', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (208, 213))	('change', 'Reg', (12, 18))
152416	22007214	DLL4 expression on ECs activates the Notch signaling pathway, which results in the regulation of tumor angiogenesis in a VEGF-independent manner.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'Var', (5, 15))	('DLL4', 'Gene', (0, 4))	('tumor', 'Disease', (97, 102))	('activates', 'PosReg', (23, 32))	('results in', 'Reg', (68, 78))	('Notch signaling pathway', 'Pathway', (37, 60))	('DLL4', 'Gene', '54567', (0, 4))
152418	22007214	Disruption of DLL4 signaling in combination with anti-VEGF treatment has shown additive effects on tumor growth.	('tumor', 'Disease', (99, 104))	('DLL4', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('DLL4', 'Gene', '54567', (14, 18))	('Disruption', 'Var', (0, 10))
152430	22007214	The combination of anti-VEGF-R and anti-PDGF-R antibodies enforces tumor vessel regression by interfering with PC-mediated EC survival mechanisms.	('anti-PDGF-R', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('interfering', 'NegReg', (94, 105))	('VEGF-R', 'Gene', '3791', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('VEGF-R', 'Gene', (24, 30))	('tumor', 'Disease', (67, 72))	('enforces', 'PosReg', (58, 66))
152431	22007214	Other studies have revealed that inhibiting PDGF-R improves tumor drug uptake in experimental tumor models.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('PDGF-R', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (94, 99))	('inhibiting', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('improves', 'PosReg', (51, 59))	('tumor', 'Disease', (60, 65))
152434	22007214	XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small molecule inhibitors that potently block multiple RTKs including VEGFR and the receptor of hepatocyte growth factor, c-Met.	('foretinib', 'Chemical', 'MESH:C544831', (7, 16))	('c-Met', 'Gene', '4233', (181, 186))	('VEGFR', 'Gene', (129, 134))	('cabozantinib', 'Chemical', 'MESH:C558660', (41, 53))	('XL184', 'Var', (34, 39))	('RTKs', 'Enzyme', (114, 118))	('hepatocyte growth factor', 'Gene', (155, 179))	('XL184', 'Chemical', 'MESH:C558660', (34, 39))	('GSK1363089', 'Chemical', 'MESH:C544831', (18, 28))	('hepatocyte growth factor', 'Gene', '3082', (155, 179))	('VEGFR', 'Gene', '3791', (129, 134))	('c-Met', 'Gene', (181, 186))	('block', 'NegReg', (99, 104))
152435	22007214	In a mouse model of pancreatic islet tumors, treatment with XL880 or XL184 led to rapid, widespread, and progressive regression of the tumor vasculature and reduced pericyte numbers.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('XL880', 'Var', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('pancreatic islet tumors', 'Disease', 'MESH:C535838', (20, 43))	('pericyte numbers', 'CPA', (165, 181))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('XL184', 'Var', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('XL184', 'Chemical', 'MESH:C558660', (69, 74))	('mouse', 'Species', '10090', (5, 10))	('pancreatic islet tumors', 'Disease', (20, 43))	('regression', 'NegReg', (117, 127))	('reduced', 'NegReg', (157, 164))
152447	22007214	In another study of a small number of breast cancer samples (n = 50), blood vessel maturity was assessed by the positivity of LH39 at the lamina lucida of mature microvessels.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('blood vessel maturity', 'CPA', (70, 91))	('LH39', 'Gene', (126, 130))	('positivity', 'Var', (112, 122))
152558	27785654	HG-DCIS had significantly higher percentages of FoxP3+ cells, CD68+ and CD68+PCNA+ macrophages, HLA-DR+ cells, CD4+ T cells, CD20+ B cells, and total tumor infiltrating lymphocytes (TILs) compared to nHG-DCIS.	('CD68', 'Gene', '968', (72, 76))	('CD20', 'Gene', '54474', (125, 129))	('CD4', 'Gene', (111, 114))	('PCNA', 'Gene', '5111', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('DCIS', 'Phenotype', 'HP:0030075', (204, 208))	('CD68', 'Gene', '968', (62, 66))	('CD68', 'Gene', (72, 76))	('FoxP3', 'Gene', (48, 53))	('FoxP3', 'Gene', '50943', (48, 53))	('CD68', 'Gene', (62, 66))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('tumor', 'Disease', (150, 155))	('HG-DCIS', 'Var', (0, 7))	('higher', 'PosReg', (26, 32))	('PCNA', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CD20', 'Gene', (125, 129))	('CD4', 'Gene', '920', (111, 114))
152573	27785654	Increased inflammation in DCIS is associated with high nuclear grade, HER2 positivity, and extent of lesions.	('HER2', 'Gene', (70, 74))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('inflammation', 'Disease', (10, 22))	('HER2', 'Gene', '2064', (70, 74))	('inflammation', 'Disease', 'MESH:D007249', (10, 22))	('positivity', 'Var', (75, 85))	('high', 'Var', (50, 54))	('DCIS', 'Disease', (26, 30))
152599	27785654	The HG-DCIS lesions demonstrated more comedonecrosis and were skewed towards hormone receptor negativity, HER2 positivity, higher proliferation (Ki67), and higher VNPI scores compared to the nHG-DCIS lesions.	('hormone receptor', 'Gene', (77, 93))	('necrosis', 'Disease', 'MESH:D009336', (44, 52))	('higher', 'PosReg', (156, 162))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('higher', 'PosReg', (123, 129))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('HER2', 'Gene', (106, 110))	('VNPI', 'MPA', (163, 167))	('positivity', 'Var', (111, 121))	('necrosis', 'Disease', (44, 52))	('HER2', 'Gene', '2064', (106, 110))	('proliferation', 'CPA', (130, 143))	('HG-DCIS', 'Disease', (4, 11))	('comedo', 'Phenotype', 'HP:0025249', (38, 44))	('hormone receptor', 'Gene', '3164', (77, 93))
152610	27785654	CD115+ macrophages correlated with high Ki67 and HER2 positivity, while CD115 expression on the DCIS lesions correlated with high Ki67, HER2 positivity, high grade, and HR negativity.	('CD115', 'Gene', (72, 77))	('high Ki67', 'Var', (35, 44))	('high grade', 'CPA', (153, 163))	('high Ki67', 'Var', (125, 134))	('CD115', 'Gene', '1436', (0, 5))	('CD115', 'Gene', '1436', (72, 77))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('HER2', 'Gene', '2064', (136, 140))	('HER2', 'Gene', (136, 140))	('CD115', 'Gene', (0, 5))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))	('positivity', 'Var', (54, 64))
152612	27785654	CD8+ cells were correlated with high grade, HER2 positivity, and HR negativity, but not with other high risk features such as VNPI, size, or comedonecrosis.	('necrosis', 'Disease', 'MESH:D009336', (147, 155))	('positivity', 'Var', (49, 59))	('HER2', 'Gene', (44, 48))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('HER2', 'Gene', '2064', (44, 48))	('HR negativity', 'Disease', (65, 78))	('high', 'Disease', (32, 36))	('comedo', 'Phenotype', 'HP:0025249', (141, 147))	('necrosis', 'Disease', (147, 155))
152623	27785654	This is consistent with previous studies that found increased inflammation associated with high nuclear grade in DCIS.	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('increased', 'PosReg', (52, 61))	('high nuclear grade', 'Var', (91, 109))	('DCIS', 'Disease', (113, 117))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
152624	27785654	We also observed higher levels of CD68+ macrophages in HG-DCIS, consistent with our earlier study, as well as increased numbers of CD68+PCNA+ macrophages, which we have previously reported as being associated with poor outcomes in invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('invasive breast cancer', 'Disease', 'MESH:D001943', (231, 253))	('PCNA', 'Gene', (136, 140))	('CD68', 'Gene', (131, 135))	('HG-DCIS', 'Var', (55, 62))	('increased', 'PosReg', (110, 119))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('higher', 'PosReg', (17, 23))	('CD68', 'Gene', '968', (131, 135))	('PCNA', 'Gene', '5111', (136, 140))	('invasive breast cancer', 'Disease', (231, 253))	('CD68', 'Gene', (34, 38))	('CD68', 'Gene', '968', (34, 38))
152640	27389414	However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability.	('Ki-67', 'Var', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
152660	27389414	While the average discrepancy rate in defined clinical settings for ER, PR and HER2 is frequently under debate, it is beyond any doubt that among all four breast cancer biomarkers, Ki-67 carries the highest degree of inter- and even intra-observer variability which makes scoring particularly hard to reproduce even between experienced pathologists.	('PR', 'Gene', '5241', (72, 74))	('Ki-67', 'Var', (181, 186))	('HER2', 'Gene', '2064', (79, 83))	('ER', 'Gene', '2099', (80, 82))	('clinical', 'Species', '191496', (46, 54))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('HER2', 'Gene', (79, 83))	('ER', 'Gene', '2099', (68, 70))
152922	24225267	Preliminarily, we have found support for the hypothesis that peri-lesional mammographic density is increased around some DCIS lesions relative to that of the entire breast, suggesting that analysis of regional density may represent a fruitful avenue for improving detection (Figure 4).	('DCIS', 'Disease', (121, 125))	('lesions', 'Var', (126, 133))	('peri', 'Gene', (61, 65))	('mammographic density', 'CPA', (75, 95))	('increased', 'PosReg', (99, 108))	('peri', 'Gene', '5346', (61, 65))
152939	24225267	These observations raise questions about whether the metastatic niche is primed prior to or coincidentally with the onset of invasion and support the view that both DCIS biology and systemic factors may be determinants of whether a DCIS lesion will give rise to an invasive metastatic carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (285, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('lesion', 'Var', (237, 243))	('carcinoma', 'Disease', (285, 294))	('invasive', 'Disease', (265, 273))	('give rise to', 'Reg', (249, 261))
152967	23086766	Reoperation results in increased healthcare costs, inconvenience and increased risks to the patient, and delays to subsequent radiation and other adjuvant therapy.	('patient', 'Species', '9606', (92, 99))	('increased', 'PosReg', (23, 32))	('Reoperation', 'Var', (0, 11))
153008	23086766	The 3 FN cases consisted of 2 with micrometastases (>0.2 mm but <2 mm) of ductal carcinoma, both present only in the routinely processed PS slides and not identified on re-review of the FS slides and one patient with macrometastatic (>2 mm) lobular carcinoma that was confirmed to have tumor present in FS slides upon re-review.	('patient', 'Species', '9606', (204, 211))	('ductal carcinoma', 'Disease', 'MESH:D044584', (74, 90))	('lobular carcinoma', 'Disease', 'MESH:D018275', (241, 258))	('tumor', 'Disease', (286, 291))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lobular carcinoma', 'Disease', (241, 258))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (241, 258))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('>0.2 mm', 'Var', (52, 59))	('ductal carcinoma', 'Disease', (74, 90))
153047	23086766	Many of these patients, however, had risk factors known to be associated with an increased likelihood of margin positivity including tumor multifocality, lobular subtype, and larger tumor size.	('tumor multifocality', 'Disease', (133, 152))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('margin positivity', 'Var', (105, 122))	('tumor multifocality', 'Disease', 'None', (133, 152))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
153097	23915805	The primary antibodies were incubated for 15 minutes: CK5D3 at 1:100 (Biogenix, Fremont, CA, USA), CD31 at 1:50 (Dako, Carpinteria, CA, USA), and CD105 at 1:60 (Vector, Burlingame, CA, USA).	('CK5D3', 'Var', (54, 59))	('CD31', 'Gene', '5175', (99, 103))	('CD31', 'Gene', (99, 103))	('CD105', 'Var', (146, 151))
153100	23915805	Mean vessel density (MVD) was quantified according to the areas of CD31-positive (preexisting vasculature) or CD105-positive (tumor-induced) vessels, and segmented in pseudo-color, as a percentage of the total slide area.	('CD31', 'Gene', (67, 71))	('CD31', 'Gene', '5175', (67, 71))	('CD105-positive', 'Var', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
153152	21276239	However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018).	('SOX2', 'Gene', '6657', (14, 18))	('expression', 'MPA', (19, 29))	('SOX2', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('positive lymph node status', 'CPA', (94, 120))	('tumor', 'Disease', (67, 72))	('high', 'Var', (9, 13))
153155	21276239	Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential.	('metastatic potential', 'CPA', (104, 124))	('promote', 'PosReg', (96, 103))	('SOX2', 'Gene', '6657', (22, 26))	('SOX2', 'Gene', (22, 26))	('high expression', 'Var', (76, 91))	('breast carcinogenesis', 'Disease', (50, 71))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (50, 71))
153160	21276239	For example, overexpression of Sox2 in mouse neural stem cells blocks their differentiation, and conversely, depletion of Sox2 in neural stem cells causes their premature exit from the cell cycle and respectively differentiation into neurons.	('differentiation', 'CPA', (76, 91))	('depletion', 'Var', (109, 118))	('overexpression', 'PosReg', (13, 27))	('blocks', 'NegReg', (63, 69))	('mouse', 'Species', '10090', (39, 44))	('Sox2', 'Gene', (122, 126))	('causes', 'Reg', (148, 154))	('differentiation', 'CPA', (213, 228))
153187	21276239	Briefly, a probe spanning the locus 3q26.33 (BAC clone CTD-2348H10) was applied to detect SOX2 copy number status and was compared to a reference probe hybridizing to 3p22.3-3p22.2 (BAC clone RP11-286G5) (both clones were purchased from Invitrogen, Carlsbad, CA, USA).	('RP11', 'Gene', '26121', (192, 196))	('copy number', 'Var', (95, 106))	('detect', 'Reg', (83, 89))	('SOX2', 'Gene', '6657', (90, 94))	('SOX2', 'Gene', (90, 94))	('RP11', 'Gene', (192, 196))
153204	21276239	Interestingly, if high SOX2 expressors (score 3) were analyzed separately and compared to the rest of the group (score 0 to 2), they displayed significantly more often lymph-node metastases (p = 0.018) and larger primary tumors (p = 0.047; Figure 2; Table 3).	('primary tumors', 'Disease', (213, 227))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('primary tumors', 'Disease', 'MESH:D009369', (213, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('more', 'PosReg', (157, 161))	('SOX2', 'Gene', (23, 27))	('high', 'Var', (18, 22))	('SOX2', 'Gene', '6657', (23, 27))	('metastases', 'Disease', (179, 189))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
153221	21276239	by chromosomal gain, as described in some tumors), can promote tumorigenesis by processes resembling partial reprogramming.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', (42, 48))	('chromosomal gain', 'Var', (3, 19))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('promote', 'PosReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
153228	21276239	Among sporadic cancers, basal-like tumors are showing most genetic and phenotypic similarities to the aggressive tumors arising in BRCA1 germ line mutation carriers.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('aggressive tumors', 'Disease', 'MESH:D001523', (102, 119))	('mutation', 'Var', (147, 155))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('BRCA1', 'Gene', '672', (131, 136))	('basal-like tumors', 'Phenotype', 'HP:0002671', (24, 41))	('sporadic cancers', 'Disease', 'MESH:D009369', (6, 22))	('tumors', 'Disease', (35, 41))	('aggressive tumors', 'Disease', (102, 119))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('sporadic cancers', 'Disease', (6, 22))	('BRCA1', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
153229	21276239	Consistently, 3q gains are most frequently observed in tumors arising in BRCA1 mutation carriers and, among sporadic cancers, seen with highest incidence in basal-like tumors (20% of cases, in comparison to 10% of luminal tumors).	('tumors', 'Disease', (168, 174))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('luminal tumors', 'Disease', 'MESH:D009369', (214, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('sporadic cancers', 'Disease', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (55, 61))	('luminal tumors', 'Disease', (214, 228))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRCA1', 'Gene', '672', (73, 78))	('mutation', 'Var', (79, 87))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('BRCA1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('basal-like tumors', 'Phenotype', 'HP:0002671', (157, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('observed', 'Reg', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('sporadic cancers', 'Disease', 'MESH:D009369', (108, 124))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('gains', 'PosReg', (17, 22))
153230	21276239	In squamous lung and esophageal cancers, aberrant SOX2 expression was linked to the genomic amplification of its chromosomal location on chromosome 3q26.33.	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('linked', 'Reg', (70, 76))	('aberrant', 'Var', (41, 49))	('esophageal cancers', 'Disease', (21, 39))	('SOX2', 'Gene', '6657', (50, 54))	('expression', 'MPA', (55, 65))	('SOX2', 'Gene', (50, 54))	('esophageal cancers', 'Disease', 'MESH:D004938', (21, 39))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('squamous lung', 'Disease', (3, 16))	('squamous lung', 'Disease', 'MESH:D002294', (3, 16))
153231	21276239	3q copy number gains are a common event in breast cancers and have been implicated as an independent predictor of poor prognosis in node-negative breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (43, 57))	('breast cancers', 'Disease', (43, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('3q copy number gains', 'Var', (0, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (43, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('breast cancers', 'Disease', (146, 160))
153233	21276239	In our study on a cohort of postmenopausal patients displaying both negative and positive lymphonodal status we could confirm the aberrant expression of SOX2 in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('aberrant', 'Var', (130, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('patients', 'Species', '9606', (43, 51))	('breast cancer', 'Disease', (161, 174))	('SOX2', 'Gene', '6657', (153, 157))	('SOX2', 'Gene', (153, 157))	('expression', 'MPA', (139, 149))
153238	21276239	Taken together, these results suggest that aberrant SOX2 expression plays a broader role in breast cancer pathogenesis, exerting effects also outside of the subgroup of triple negative tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('SOX2', 'Gene', '6657', (52, 56))	('breast cancer', 'Disease', (92, 105))	('SOX2', 'Gene', (52, 56))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('aberrant', 'Var', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
153257	24093668	Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome.	('breast tumors', 'Disease', 'MESH:D001943', (128, 141))	('breast cancers', 'Disease', 'MESH:D001943', (222, 236))	('breast cancers', 'Disease', (222, 236))	('human', 'Species', '9606', (216, 221))	('breast tumors', 'Disease', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('found', 'Reg', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Aberrant', 'Var', (142, 150))	('breast tumors', 'Phenotype', 'HP:0100013', (128, 141))	('breast cancers', 'Phenotype', 'HP:0003002', (222, 236))	('breast tumor', 'Phenotype', 'HP:0100013', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
153263	24093668	Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53.	('PPP2R2B', 'Gene', '5521', (28, 35))	('PPP2R2B', 'Gene', (28, 35))	('ABCB1', 'Gene', (44, 49))	('ABCB1', 'Gene', '5243', (44, 49))	('Methylation levels', 'MPA', (0, 18))	('PTEN', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('TP53', 'Gene', '7157', (136, 140))	('mutations', 'Var', (96, 105))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('lower', 'NegReg', (65, 70))	('FOXC1', 'Gene', (37, 42))	('tumors', 'Disease', (74, 80))	('PTEN', 'Gene', '5728', (22, 26))	('TP53', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TP53', 'Gene', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('FOXC1', 'Gene', '2296', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('BRCA1', 'Gene', '672', (54, 59))	('TP53', 'Gene', '7157', (91, 95))	('BRCA1', 'Gene', (54, 59))
153264	24093668	Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53.	('methylation levels', 'MPA', (81, 99))	('TP53', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', '7157', (134, 138))	('TP53', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('lower', 'NegReg', (67, 72))	('tumors', 'Disease', (112, 118))	('mutated', 'Var', (34, 41))
153266	24093668	Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors.	('z-scores', 'MPA', (80, 88))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('HER2', 'Gene', (120, 124))	('higher', 'PosReg', (73, 79))	('HER2', 'Gene', '2064', (120, 124))	('HER2', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('HER2', 'Gene', '2064', (34, 38))	('methylation', 'MPA', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('positive', 'Var', (39, 47))
153267	24093668	Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival.	('PPP2R2B', 'Gene', '5521', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('PPP2R2B', 'Gene', (62, 69))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('predictor', 'Reg', (85, 94))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('methylation status', 'Var', (40, 58))	('overall survival', 'CPA', (98, 114))
153268	24093668	In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('breast cancers', 'Disease', (136, 150))	('aberrant', 'Var', (49, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))
153272	24093668	Epigenetic changes are considered to be an early event in tumor development and one of the hallmarks of cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
153274	24093668	Identification of early epigenetic changes in breast cancer might give valuable markers for early detection and contribute to the understanding of how these changes affect the progression of the disease and prognosis for the patient.	('affect', 'Reg', (165, 171))	('epigenetic changes', 'Var', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('patient', 'Species', '9606', (225, 232))
153288	24093668	Further, multivariate, the Cox proportional hazard model was used to identify independent prognostic markers for all genes and from all clinical parameters: age, stage, tumor size and grade, lymph node status, TP53 mutation status, ER, PR status, T status.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('TP53', 'Gene', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutation status', 'Var', (215, 230))	('tumor', 'Disease', (169, 174))	('TP53', 'Gene', '7157', (210, 214))
153290	24093668	Our analysis showed that five genes ABCB1, FOXC1, GSTP1, PPP2R2B and RASSF1A were the most frequently hypermethylated genes in all invasive samples as well as in the DCIS samples.	('FOXC1', 'Gene', '2296', (43, 48))	('ABCB1', 'Gene', (36, 41))	('ABCB1', 'Gene', '5243', (36, 41))	('GSTP1', 'Gene', '2950', (50, 55))	('RASSF1A', 'Gene', (69, 76))	('hypermethylated', 'Var', (102, 117))	('RASSF1A', 'Gene', '11186', (69, 76))	('FOXC1', 'Gene', (43, 48))	('PPP2R2B', 'Gene', '5521', (57, 64))	('PPP2R2B', 'Gene', (57, 64))	('GSTP1', 'Gene', (50, 55))
153291	24093668	PTEN was hypermethylated in invasive cancer of stage II, III and IV and MGMT was hypomethylated in invasive tumors of stage II, III and IV.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', (37, 43))	('MGMT', 'Gene', '4255', (72, 76))	('MGMT', 'Gene', (72, 76))	('invasive tumors', 'Disease', (99, 114))	('invasive tumors', 'Disease', 'MESH:D009369', (99, 114))	('hypomethylated', 'Var', (81, 95))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
153309	24093668	We compared the DNA methylation profiles with the TP53 mutations status and found that tumors with TP53 mutations had significantly lower DNA methylation levels then tumors with TP53 wild type in RASSF1A, PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 (p = 0.028, p = 0.031, p = 0.002, p = 0.017, p = 0.010, p = 0.001 respectively).	('TP53', 'Gene', '7157', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RASSF1A', 'Gene', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PTEN', 'Gene', '5728', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('lower', 'NegReg', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (87, 93))	('TP53', 'Gene', (50, 54))	('tumors', 'Disease', (166, 172))	('FOXC1', 'Gene', (220, 225))	('TP53', 'Gene', (99, 103))	('DNA methylation levels', 'MPA', (138, 160))	('TP53', 'Gene', (178, 182))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('BRCA1', 'Gene', '672', (237, 242))	('PTEN', 'Gene', (205, 209))	('BRCA1', 'Gene', (237, 242))	('RASSF1A', 'Gene', '11186', (196, 203))	('TP53', 'Gene', '7157', (50, 54))	('PPP2R2B', 'Gene', '5521', (211, 218))	('FOXC1', 'Gene', '2296', (220, 225))	('PPP2R2B', 'Gene', (211, 218))	('ABCB1', 'Gene', (227, 232))	('ABCB1', 'Gene', '5243', (227, 232))	('TP53', 'Gene', '7157', (99, 103))
153310	24093668	After Bonferroni correction DNA methylation levels in PPP2R2B and BRCA1 were still significantly lower in tumors with TP53 mutations.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('BRCA1', 'Gene', '672', (66, 71))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('BRCA1', 'Gene', (66, 71))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('PPP2R2B', 'Gene', '5521', (54, 61))	('lower', 'NegReg', (97, 102))	('PPP2R2B', 'Gene', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutations', 'Var', (123, 132))
153315	24093668	Also HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors (Figure 3).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('methylation', 'MPA', (63, 74))	('HER2', 'Gene', (5, 9))	('higher', 'PosReg', (44, 50))	('positive', 'Var', (10, 18))	('HER2', 'Gene', '2064', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('z-scores', 'MPA', (51, 59))	('HER2', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', '2064', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
153316	24093668	Univariate survival analysis identified methylation status of PPP2R2B as significant predictor of overall survival.	('methylation status', 'Var', (40, 58))	('PPP2R2B', 'Gene', (62, 69))	('PPP2R2B', 'Gene', '5521', (62, 69))	('overall', 'MPA', (98, 105))
153318	24093668	The Kaplan-Meier plot (Figure 4) showed a significant difference in survival between hypermethylated and normal-like samples for PPP2R2B (p = 0.012) indicating that patients with hypermethylated genes had better survival.	('difference', 'Reg', (54, 64))	('hypermethylated', 'Var', (85, 100))	('PPP2R2B', 'Gene', '5521', (129, 136))	('survival', 'MPA', (212, 220))	('patients', 'Species', '9606', (165, 173))	('hypermethylated', 'Var', (179, 194))	('better', 'PosReg', (205, 211))	('PPP2R2B', 'Gene', (129, 136))
153319	24093668	Breast cancer specific survival was significantly improved in patients with hyper-methylated promoters for PPP2R2B (p = 0.012).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('hyper-methylated promoters', 'Var', (76, 102))	('PPP2R2B', 'Gene', '5521', (107, 114))	('PPP2R2B', 'Gene', (107, 114))	('improved', 'PosReg', (50, 58))	('Breast cancer', 'Disease', (0, 13))	('patients', 'Species', '9606', (62, 70))
153321	24093668	For categorical methylation data AIC identified a model explaining survival, which included the methylation status of IGF2, GSTP1, estrogen receptor status, TP53, N status and stage.	('TP53', 'Gene', (157, 161))	('IGF2', 'Gene', '3481', (118, 122))	('GSTP1', 'Gene', '2950', (124, 129))	('IGF2', 'Gene', (118, 122))	('estrogen receptor', 'Gene', (131, 148))	('methylation', 'Var', (96, 107))	('GSTP1', 'Gene', (124, 129))	('estrogen receptor', 'Gene', '2099', (131, 148))	('TP53', 'Gene', '7157', (157, 161))
153322	24093668	For continuous methylation data the best model explaining survival included TP53, T status, N status, estrogen receptor status and methylation status of IGF2 and GSTP1.	('estrogen receptor', 'Gene', '2099', (102, 119))	('GSTP1', 'Gene', '2950', (162, 167))	('IGF2', 'Gene', '3481', (153, 157))	('TP53', 'Gene', '7157', (76, 80))	('IGF2', 'Gene', (153, 157))	('GSTP1', 'Gene', (162, 167))	('TP53', 'Gene', (76, 80))	('estrogen receptor', 'Gene', (102, 119))	('methylation', 'Var', (131, 142))
153326	24093668	In the present study, five genes, ABCB1, FOXC1, GSTP1, PPP2R2B and RASSF1A were hypermethylated already in early stage breast cancer (stage I and II).	('hypermethylated', 'Var', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('FOXC1', 'Gene', (41, 46))	('breast cancer', 'Disease', (119, 132))	('ABCB1', 'Gene', (34, 39))	('PPP2R2B', 'Gene', '5521', (55, 62))	('PPP2R2B', 'Gene', (55, 62))	('GSTP1', 'Gene', (48, 53))	('ABCB1', 'Gene', '5243', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('RASSF1A', 'Gene', (67, 74))	('FOXC1', 'Gene', '2296', (41, 46))	('GSTP1', 'Gene', '2950', (48, 53))	('RASSF1A', 'Gene', '11186', (67, 74))
153328	24093668	We found that RASSF1A was hypermethylated in approximately 85% of all invasive tumors and DCIS, and our results are in agreement with such a high incidence of RASSF1A methylation.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('invasive tumors', 'Disease', 'MESH:D009369', (70, 85))	('RASSF1A', 'Gene', (14, 21))	('hypermethylated', 'Var', (26, 41))	('DCIS', 'Disease', (90, 94))	('RASSF1A', 'Gene', (159, 166))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('RASSF1A', 'Gene', '11186', (14, 21))	('RASSF1A', 'Gene', '11186', (159, 166))	('invasive tumors', 'Disease', (70, 85))
153330	24093668	It belongs to an increasing list of tumor suppressor genes that are frequently inactivated by promoter methylation rather than by somatic mutations.	('promoter methylation', 'Var', (94, 114))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
153331	24093668	Since we detected a constant hypermethylation of RASSF1A in all of the different stages of the breast carcinomas we can suggest that hypermethylation of RASSF1A is an early event during breast cancer pathogenesis and also the main mechanism of inactivation.	('breast carcinomas', 'Disease', (95, 112))	('RASSF1A', 'Gene', (49, 56))	('hypermethylation', 'MPA', (29, 45))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('RASSF1A', 'Gene', (153, 160))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('RASSF1A', 'Gene', '11186', (49, 56))	('breast cancer', 'Disease', (186, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('hypermethylation', 'Var', (133, 149))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('RASSF1A', 'Gene', '11186', (153, 160))
153332	24093668	In our study, GSTP1 was found to be hypermethylated in different stages of breast carcinomas, for early stages (I and II) our results are in agreement with previous reports.	('breast carcinomas', 'Disease', (75, 92))	('hypermethylated', 'Var', (36, 51))	('breast carcinomas', 'Phenotype', 'HP:0003002', (75, 92))	('GSTP1', 'Gene', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('breast carcinomas', 'Disease', 'MESH:D001943', (75, 92))	('breast carcinoma', 'Phenotype', 'HP:0003002', (75, 91))	('GSTP1', 'Gene', '2950', (14, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
153333	24093668	The frequency of GSTP1 promoter hypermethylation in stage III and IV (around 70%) was found to be higher than reported previously.	('promoter', 'MPA', (23, 31))	('hypermethylation', 'Var', (32, 48))	('GSTP1', 'Gene', (17, 22))	('GSTP1', 'Gene', '2950', (17, 22))
153334	24093668	It is known that GSTP1 plays a role in detoxification of potential carcinogens and that loss of the expression of GSTP1 will lead to DNA damage of breast cells and they will be more easily exposed to carcinogens.	('GSTP1', 'Gene', '2950', (114, 119))	('GSTP1', 'Gene', (17, 22))	('loss', 'Var', (88, 92))	('detoxification', 'MPA', (39, 53))	('DNA damage', 'MPA', (133, 143))	('GSTP1', 'Gene', (114, 119))	('GSTP1', 'Gene', '2950', (17, 22))	('lead to', 'Reg', (125, 132))
153336	24093668	It appears that promoter hypermethylation is associated with loss of GSTP1 expression.	('promoter hypermethylation', 'Var', (16, 41))	('GSTP1', 'Gene', (69, 74))	('loss', 'NegReg', (61, 65))	('GSTP1', 'Gene', '2950', (69, 74))	('expression', 'MPA', (75, 85))
153338	24093668	We found that already in DCIS there is a high proportion of hypermethylated GSTP1 (58%), which indicates that GSTP1 promoter hypermethylation is an early event in breast carcinogenesis.	('breast carcinogenesis', 'Disease', 'MESH:D063646', (163, 184))	('GSTP1', 'Gene', '2950', (110, 115))	('GSTP1', 'Gene', '2950', (76, 81))	('hypermethylated', 'Var', (60, 75))	('GSTP1', 'Gene', (76, 81))	('GSTP1', 'Gene', (110, 115))	('breast carcinogenesis', 'Disease', (163, 184))
153339	24093668	From our analysis we observed that hypermethylation of ABCB1, PPP2R2B and FOXC1 is also an early event in breast carcinogenesis since our results indicate high level of hypermethylation of these genes already in DCIS which was reported before.	('hypermethylation', 'Var', (35, 51))	('PPP2R2B', 'Gene', '5521', (62, 69))	('PPP2R2B', 'Gene', (62, 69))	('breast carcinogenesis', 'Disease', (106, 127))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (106, 127))	('FOXC1', 'Gene', (74, 79))	('ABCB1', 'Gene', (55, 60))	('ABCB1', 'Gene', '5243', (55, 60))	('FOXC1', 'Gene', '2296', (74, 79))	('hypermethylation', 'MPA', (169, 185))
153341	24093668	According to our results, we could suggest that hypermethylation of CDKN2A is possible event leading to its inactivation in late stage breast cancers.	('late stage breast cancers', 'Disease', 'MESH:D001943', (124, 149))	('inactivation', 'MPA', (108, 120))	('late stage breast cancers', 'Disease', (124, 149))	('hypermethylation', 'Var', (48, 64))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CDKN2A', 'Gene', (68, 74))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('CDKN2A', 'Gene', '1029', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
153344	24093668	We suggest here that epigenetic silencing of PTEN might be an early event in initiation of cancer and also the mechanism of its inactivation.	('epigenetic silencing', 'Var', (21, 41))	('initiation of cancer', 'Disease', (77, 97))	('initiation of cancer', 'Disease', 'MESH:D009369', (77, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))
153351	24093668	They identified 33 cancer specific genes that were either highly methylated in early stage breast cancer or showed stage dependent methylation pattern, lower methylation frequency in early stage breast cancers and a higher methylation frequency in late stage breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancers', 'Disease', 'MESH:D001943', (195, 209))	('breast cancers', 'Disease', (195, 209))	('late stage breast cancers', 'Disease', (248, 273))	('cancer', 'Disease', (19, 25))	('breast cancers', 'Phenotype', 'HP:0003002', (259, 273))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('breast cancers', 'Phenotype', 'HP:0003002', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('lower', 'NegReg', (152, 157))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('methylation', 'MPA', (223, 234))	('late stage breast cancers', 'Disease', 'MESH:D001943', (248, 273))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('highly', 'PosReg', (58, 64))	('methylation', 'MPA', (158, 169))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('methylation', 'Var', (131, 142))	('breast cancer', 'Disease', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancer', 'Disease', (266, 272))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('higher', 'PosReg', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (202, 208))	('breast cancers', 'Disease', 'MESH:D001943', (259, 273))
153353	24093668	In the present study we showed the associations between DNA methylation levels of candidate genes and the TP53 mutation status, estrogen receptor status, and HER2 status.	('associations', 'Interaction', (35, 47))	('mutation status', 'Var', (111, 126))	('estrogen receptor', 'Gene', (128, 145))	('estrogen receptor', 'Gene', '2099', (128, 145))	('HER2', 'Gene', (158, 162))	('HER2', 'Gene', '2064', (158, 162))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
153354	24093668	The TP53 tumor suppressor gene has a central role in cell cycle regulation, DNA repair and apoptosis, and a large number of reports have discussed the important role of TP53 alterations in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TP53', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('TP53', 'Gene', '7157', (169, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('tumor', 'Disease', (9, 14))	('TP53', 'Gene', (169, 173))	('alterations', 'Var', (174, 185))	('TP53', 'Gene', '7157', (4, 8))
153355	24093668	Also, a number of studies have shown that breast tumors with TP53 mutations are strongly associated with poor prognosis and lacking methylation in a number of regulatory genes.	('mutations', 'Var', (66, 75))	('TP53', 'Gene', '7157', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('breast tumors', 'Phenotype', 'HP:0100013', (42, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (42, 54))	('breast tumors', 'Disease', (42, 55))	('breast tumors', 'Disease', 'MESH:D001943', (42, 55))	('TP53', 'Gene', (61, 65))
153356	24093668	Additionally, studies on different expression subtypes in breast cancer showed that different subtypes have a different underlying biology reflected in methylation and is strongly influenced by TP53 mutation status.	('influenced', 'Reg', (180, 190))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('mutation', 'Var', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('methylation', 'MPA', (152, 163))	('TP53', 'Gene', '7157', (194, 198))	('TP53', 'Gene', (194, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))
153358	24093668	In present study we have identified 26,6% of breast tumors with TP53 mutations and significantly lower levels of DNA methylation in RASSF1A, PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 compared to tumors with wild type TP53.	('PTEN', 'Gene', (141, 145))	('FOXC1', 'Gene', '2296', (156, 161))	('DNA methylation', 'MPA', (113, 128))	('TP53', 'Gene', (213, 217))	('RASSF1A', 'Gene', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('TP53', 'Gene', '7157', (64, 68))	('tumors', 'Disease', (191, 197))	('levels', 'MPA', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('PTEN', 'Gene', '5728', (141, 145))	('lower', 'NegReg', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('TP53', 'Gene', '7157', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', (52, 58))	('breast tumor', 'Phenotype', 'HP:0100013', (45, 57))	('FOXC1', 'Gene', (156, 161))	('TP53', 'Gene', (64, 68))	('breast tumors', 'Disease', 'MESH:D001943', (45, 58))	('breast tumors', 'Disease', (45, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BRCA1', 'Gene', '672', (173, 178))	('breast tumors', 'Phenotype', 'HP:0100013', (45, 58))	('BRCA1', 'Gene', (173, 178))	('ABCB1', 'Gene', (163, 168))	('RASSF1A', 'Gene', '11186', (132, 139))	('ABCB1', 'Gene', '5243', (163, 168))	('PPP2R2B', 'Gene', '5521', (147, 154))	('PPP2R2B', 'Gene', (147, 154))
153365	24093668	Furthermore, in a study on methylation in breast cancer and breast cancer molecular subtypes it was shown that RASSF1A is hypermethylated in HER2 positive breast tumors (ERBB2 and luminal B).	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hypermethylated', 'Var', (122, 137))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Disease', (60, 73))	('HER2', 'Gene', '2064', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (155, 167))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('RASSF1A', 'Gene', '11186', (111, 118))	('breast tumors', 'Disease', 'MESH:D001943', (155, 168))	('ERBB2', 'Gene', (170, 175))	('breast tumors', 'Disease', (155, 168))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Disease', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast tumors', 'Phenotype', 'HP:0100013', (155, 168))	('RASSF1A', 'Gene', (111, 118))	('ERBB2', 'Gene', '2064', (170, 175))	('HER2', 'Gene', (141, 145))
153366	24093668	In our study RASSF1A was hypermethylated in ERBB2 and luminal B tumors (data not shown).	('RASSF1A', 'Gene', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('ERBB2', 'Gene', '2064', (44, 49))	('luminal B tumors', 'Disease', (54, 70))	('luminal B tumors', 'Disease', 'MESH:D006509', (54, 70))	('ERBB2', 'Gene', (44, 49))	('RASSF1A', 'Gene', '11186', (13, 20))	('hypermethylated', 'Var', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
153367	24093668	Taken all together, these results, suggest that methylation plays a significant role in the different breast tumor phenotypes.	('role', 'Reg', (80, 84))	('breast tumor', 'Phenotype', 'HP:0100013', (102, 114))	('breast tumor', 'Disease', 'MESH:D001943', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('methylation', 'Var', (48, 59))	('breast tumor', 'Disease', (102, 114))
153368	24093668	We report here for the first time the PPP2R2B methylation status as significant predictor for breast cancer survival as well as for overall survival.	('PPP2R2B', 'Gene', '5521', (38, 45))	('methylation', 'Var', (46, 57))	('PPP2R2B', 'Gene', (38, 45))	('predictor', 'Reg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
153372	24093668	Hypermethylation of GSTP1 is a well established biomarker for hormone dependent cancers.	('GSTP1', 'Gene', (20, 25))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('Hypermethylation', 'Var', (0, 16))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GSTP1', 'Gene', '2950', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
153373	24093668	Our previous analyses suggest that methylation of GSTP1 in locally advanced breast cancer patients treated with doxorubicin was associated to survival.	('associated to', 'Reg', (128, 141))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('GSTP1', 'Gene', '2950', (50, 55))	('breast cancer', 'Disease', (76, 89))	('survival', 'Disease', (142, 150))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('methylation', 'Var', (35, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('patients', 'Species', '9606', (90, 98))	('GSTP1', 'Gene', (50, 55))
153375	24093668	Here we report aberrant methylation levels of ABCB1, FOXC1, GSTP1, PPP2R2B and RASSF1A in DCIS and stage I-IV providing evidence that suggests that changes in methylation level is an early event and may also be important in progression to later stages of breast cancer.	('GSTP1', 'Gene', (60, 65))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('RASSF1A', 'Gene', (79, 86))	('methylation level', 'MPA', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('methylation levels', 'MPA', (24, 42))	('breast cancer', 'Disease', (255, 268))	('GSTP1', 'Gene', '2950', (60, 65))	('PPP2R2B', 'Gene', '5521', (67, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('PPP2R2B', 'Gene', (67, 74))	('FOXC1', 'Gene', (53, 58))	('ABCB1', 'Gene', (46, 51))	('RASSF1A', 'Gene', '11186', (79, 86))	('ABCB1', 'Gene', '5243', (46, 51))	('changes', 'Var', (148, 155))	('FOXC1', 'Gene', '2296', (53, 58))
153376	24093668	We also report that methylation levels of important breast cancer genes are associated to hormone receptor status and TP53 mutation status suggesting mechanisms of deactivation of tumor suppressor genes in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutation', 'Var', (123, 131))	('hormone receptor', 'Gene', '3164', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('methylation levels', 'MPA', (20, 38))	('hormone receptor', 'Gene', (90, 106))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('tumor', 'Disease', (180, 185))	('breast cancer', 'Disease', (52, 65))	('associated', 'Reg', (76, 86))	('breast cancer', 'Disease', (206, 219))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
153405	23372687	Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-beta pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells.	('SMAD7', 'Gene', (40, 45))	('expression', 'MPA', (17, 27))	('knockdown', 'Var', (129, 138))	('miR-21', 'Gene', '406991', (122, 128))	('MCF-7', 'CellLine', 'CVCL:0031', (147, 152))	('restored', 'PosReg', (103, 111))	('SMAD7', 'Gene', '4092', (40, 45))	('breast cancer', 'Disease', (164, 177))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('MSH2', 'Gene', (31, 35))	('Hs578T', 'CellLine', 'CVCL:0332', (157, 163))	('MSH2', 'Gene', '4436', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('miR-21', 'Gene', (122, 128))
153406	23372687	In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition.	('tumor', 'Disease', (168, 173))	('deregulation', 'Var', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miRNA expression', 'MPA', (137, 153))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
153434	23372687	As a proof of principle, we used anti-miR-21 oligo to transfect MCF-7 and Hs578T cells, and as predicted, we observed restoration of MSH2 and SMAD7 expression levels following miR-21 knock-down.	('MSH2', 'Gene', (133, 137))	('miR-21', 'Gene', (38, 44))	('MCF-7', 'CellLine', 'CVCL:0031', (64, 69))	('MSH2', 'Gene', '4436', (133, 137))	('expression levels', 'MPA', (148, 165))	('Hs578T', 'CellLine', 'CVCL:0332', (74, 80))	('miR-21', 'Gene', (176, 182))	('miR-21', 'Gene', '406991', (38, 44))	('restoration', 'PosReg', (118, 129))	('SMAD7', 'Gene', (142, 147))	('knock-down', 'Var', (183, 193))	('miR-21', 'Gene', '406991', (176, 182))	('SMAD7', 'Gene', '4092', (142, 147))
153435	23372687	MSH2 is a component of the post-replicative DNA mismatch repair system (MMR), frequently mutated in hereditary nonpolyposis colon cancer (HNPCC).	('HNPCC', 'Disease', (138, 143))	('hereditary nonpolyposis colon cancer', 'Disease', (100, 136))	('HNPCC', 'Disease', 'None', (138, 143))	('MSH2', 'Gene', (0, 4))	('MSH2', 'Gene', '4436', (0, 4))	('HNPCC', 'Phenotype', 'HP:0006716', (138, 143))	('colon cancer', 'Phenotype', 'HP:0003003', (124, 136))	('mutated', 'Var', (89, 96))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (100, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (100, 136))
153442	23372687	Four miRNAs (miR-21, miR-183, miR-200c and miR-200b) were significantly up-regulated when comparing ADH vs. normal.	('miR-21', 'Gene', (13, 19))	('up-regulated', 'PosReg', (72, 84))	('miR-200b', 'Gene', (43, 51))	('ADH', 'Var', (100, 103))	('miR-21', 'Gene', '406991', (13, 19))	('miR-200c', 'Gene', (30, 38))	('miR-183', 'Gene', '406959', (21, 28))	('miR-183', 'Gene', (21, 28))	('miR-200c', 'Gene', '406985', (30, 38))	('miR-200b', 'Gene', '406984', (43, 51))
153459	23372687	We selected a short list of miRNAs (miR-644, miR-556-3p, miR-557, miR-141, miR-183, miR-200b and miR-21) based on both their representation of different clusters for classification on discrete stages, as well as their higher expression levels and relevance to breast cancer.	('miR-141', 'Gene', '406933', (66, 73))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('miR-200b', 'Gene', (84, 92))	('breast cancer', 'Disease', (260, 273))	('miR-21', 'Gene', '406991', (97, 103))	('miR-644', 'Gene', (36, 43))	('miR-557', 'Gene', (57, 64))	('miR-183', 'Gene', (75, 82))	('miR-183', 'Gene', '406959', (75, 82))	('miR-644', 'Gene', '693229', (36, 43))	('expression levels', 'MPA', (225, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('miR-21', 'Gene', (97, 103))	('miR-556-3p', 'Var', (45, 55))	('miR-557', 'Gene', '693142', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('miR-141', 'Gene', (66, 73))	('miR-200b', 'Gene', '406984', (84, 92))
153466	23372687	However, miR-644 and miR-556-3p were hardly detectable by qRT-PCR, as raw Ct values were underneath the detectable baseline (data not shown).	('miR-644', 'Gene', (9, 16))	('miR-556-3p', 'Var', (21, 31))	('miR-644', 'Gene', '693229', (9, 16))
153481	23372687	After 48 hours, with 60%-80% miR-21 knock-down, we observed a significant restoration of MSH2 and SMAD7 mRNA expression (Fig.	('knock-down', 'Var', (36, 46))	('SMAD7', 'Gene', (98, 103))	('miR-21', 'Gene', '406991', (29, 35))	('MSH2', 'Gene', (89, 93))	('SMAD7', 'Gene', '4092', (98, 103))	('MSH2', 'Gene', '4436', (89, 93))	('miR-21', 'Gene', (29, 35))	('restoration', 'PosReg', (74, 85))	('mRNA expression', 'MPA', (104, 119))
153482	23372687	The protein level was increased by ~35% in MCF-7 and ~43% in Hs578T for MSH2; and by ~80% in MCF-7 and ~133% in Hs578T for SMAD7 by Western blot analysis (Fig.	('protein level', 'MPA', (4, 17))	('SMAD7', 'Gene', (123, 128))	('SMAD7', 'Gene', '4092', (123, 128))	('Hs578T', 'CellLine', 'CVCL:0332', (112, 118))	('Hs578T', 'CellLine', 'CVCL:0332', (61, 67))	('MCF-7', 'CellLine', 'CVCL:0031', (93, 98))	('increased', 'PosReg', (22, 31))	('MSH2', 'Gene', (72, 76))	('MSH2', 'Gene', '4436', (72, 76))	('MCF-7', 'Var', (43, 48))	('MCF-7', 'CellLine', 'CVCL:0031', (43, 48))	('Hs578T', 'Var', (61, 67))
153484	23372687	Silencing TGF-beta signaling may in turn induce the expression of tumor suppressor genes, such as MSH2.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MSH2', 'Gene', (98, 102))	('MSH2', 'Gene', '4436', (98, 102))	('tumor', 'Disease', (66, 71))	('TGF-beta', 'Protein', (10, 18))	('induce', 'PosReg', (41, 47))	('expression', 'MPA', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Silencing', 'Var', (0, 9))
153513	23372687	In conclusion, deregulation of miRNA expression during tumorigenesis might be an early event as it occurs significantly during normal to ADH transition.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miRNA', 'Protein', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('deregulation', 'Var', (15, 27))
153532	23372687	The membrane was incubated overnight with either MSH2 rabbit polyclonal antibody (Cat# AP11570c, Cell Signaling) at a dilution of 1:500 in TBS buffer with 0.05% Tween and 5% milk, SMAD7 rabbit polyclonal antibody (Cat# AP6753c, Cell Signaling), at a dilution of 1:200 in TBS buffer with 0.05% Tween and 5% milk, or GAPDH mouse monoclonal antibody (Cat# MA5-15738, Sigma) at a dilution of 1:1,000 in TBS buffer with 0.05% Tween.	('GAPDH', 'Gene', (315, 320))	('SMAD7', 'Gene', '4092', (180, 185))	('Tween', 'Chemical', 'MESH:D011136', (161, 166))	('TBS', 'Chemical', '-', (271, 274))	('rabbit', 'Species', '9986', (186, 192))	('TBS', 'Chemical', '-', (399, 402))	('TBS', 'Chemical', '-', (139, 142))	('Cat# MA5-15738', 'Var', (348, 362))	('MSH2', 'Gene', (49, 53))	('SMAD7', 'Gene', (180, 185))	('rabbit', 'Species', '9986', (54, 60))	('Tween', 'Chemical', 'MESH:D011136', (293, 298))	('MSH2', 'Gene', '4436', (49, 53))	('Tween', 'Chemical', 'MESH:D011136', (421, 426))	('mouse', 'Species', '10090', (321, 326))	('GAPDH', 'Gene', '2597', (315, 320))
153537	29534682	Conversely, Smurf2 knockdown resulted in a marked decrease in the protein level expression of CNKSR2 by facilitating enhanced polyubiquitination and proteasomal degradation and reduced the proliferation and clonogenic survival of MDA-MB-231 breast cancer cell lines.	('proliferation', 'CPA', (189, 202))	('CNKSR2', 'Gene', (94, 100))	('protein level expression', 'MPA', (66, 90))	('knockdown', 'Var', (19, 28))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (230, 240))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('reduced', 'NegReg', (177, 184))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('polyubiquitination', 'MPA', (126, 144))	('proteasomal degradation', 'MPA', (149, 172))	('enhanced', 'PosReg', (117, 125))	('clonogenic survival', 'CPA', (207, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('breast cancer', 'Disease', (241, 254))	('Smurf2', 'Gene', (12, 18))	('decrease', 'NegReg', (50, 58))
153553	29534682	Indeed, we observed that knockdown of Smurf2 downregulated the expression of CNKSR2 and reduced the proliferative potential of human breast cancer cells.	('breast cancer', 'Disease', (133, 146))	('human', 'Species', '9606', (127, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('Smurf2', 'Gene', (38, 44))	('expression', 'MPA', (63, 73))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('CNKSR2', 'Gene', (77, 83))	('downregulated', 'NegReg', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('reduced', 'NegReg', (88, 95))	('knockdown', 'Var', (25, 34))
153569	29534682	For cultured cells, in a 10-cm dish format, HEK293 cells transfected with empty vector, pCMV5B-Flag-Smurf2 WT, or pCMV5B-Flag-Smurf2 C716A were washed in 1 x PBS and resuspended in 1 ml of lysis buffer (70 mM NaCl, 50 mM Tris, pH 8 and 0.5% NP-40), supplemented with phosphatase inhibitor and protease inhibitor cocktails (Sigma; St. Louis, MO, USA).	('HEK293 cells', 'CellLine', 'CVCL:0045', (44, 56))	('C716A', 'Mutation', 'c.716C>A', (133, 138))	('pCMV5B-Flag-Smurf2 C716A', 'Var', (114, 138))	('NP-40', 'Chemical', 'MESH:C010615', (241, 246))	('pCMV5B-Flag-Smurf2', 'Var', (88, 106))	('PBS', 'Chemical', 'MESH:D007854', (158, 161))	('NaCl', 'Chemical', 'MESH:D012965', (209, 213))	('Tris', 'Chemical', '-', (221, 225))
153597	29534682	Breast cancer tissue arrays with progressive changes- BRC961 and BRC962, non-overlapping with each other and each containing 48 cases from normal, premalignant and cancer tissues with progressive grades and stages in duplicates were purchased from Pantomics.	('BRC962', 'CellLine', 'CVCL:A588', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('BRC962', 'Var', (65, 71))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('changes- BRC961', 'Var', (45, 60))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))
153616	29534682	Anchorage-independent growth was determined by soft agar analysis as follows: Smurf2 knockdown MDA-MB-231 cells were trypsinized and 1 x 104 cells per 35-mm dish were seeded in 0.35% agar on top of a base layer containing 0.8% agar.	('agar', 'Chemical', 'MESH:D000362', (227, 231))	('agar', 'Chemical', 'MESH:D000362', (183, 187))	('agar', 'Chemical', 'MESH:D000362', (52, 56))	('knockdown', 'Var', (85, 94))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (95, 105))	('Smurf2', 'Gene', (78, 84))
153626	29534682	Interestingly, expression of a catalytically inactive Smurf2 mutant (C716A, targeting the HECT domain) also upregulated the levels of CNKSR2 (Fig.	('CNKSR2', 'MPA', (134, 140))	('Smurf2', 'Gene', (54, 60))	('levels', 'MPA', (124, 130))	('C716A', 'Var', (69, 74))	('HEC', 'CellLine', 'CVCL:N814', (90, 93))	('C716A', 'Mutation', 'c.716C>A', (69, 74))	('upregulated', 'PosReg', (108, 119))
153627	29534682	Even though CNKSR2 was found to interact with both wild type and ligase deficient mutant Smurf2, the expression level of CNKSR2 was significantly high in Smurf2 WT transfected cells compared with Smurf2 C716A transfected cells, which prompted us to investigate the ubiquitination status of CNKSR2 following interaction with Smurf2.	('high', 'PosReg', (146, 150))	('Smurf2', 'Gene', (89, 95))	('expression level', 'MPA', (101, 117))	('investigate', 'Reg', (249, 260))	('C716A', 'Mutation', 'c.716C>A', (203, 208))	('CNKSR2', 'Gene', (121, 127))	('mutant', 'Var', (82, 88))
153628	29534682	Hence we immunoprecipitated CNKSR2 from HEK293 cells transfected with either catalytically active wild-type (WT) or a catalytically dead C716A mutant of Smurf2 and immunoblot analysis was performed using mouse ubiquitin antibody.	('HEK293 cells', 'CellLine', 'CVCL:0045', (40, 52))	('C716A', 'Var', (137, 142))	('C716A', 'Mutation', 'c.716C>A', (137, 142))	('mouse', 'Species', '10090', (204, 209))	('Smurf2', 'Gene', (153, 159))	('CNKSR2', 'Gene', (28, 34))
153640	29534682	We reported previously that Smurf2 knockdown significantly downregulated the CNKSR2 protein levels in MDA-MB-231, MCF-7, SW480, and SCC131 cancer cell lines without any effect on CNKSR2 mRNA, suggesting that Smurf2 controls the CNKSR2 protein level possibly through proteolytic regulation.	('CNKSR2 protein levels', 'MPA', (77, 98))	('knockdown', 'Var', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('downregulated', 'NegReg', (59, 72))	('Smurf2', 'Gene', (28, 34))	('SCC131', 'CellLine', 'CVCL:6726', (132, 138))	('MCF-7', 'CellLine', 'CVCL:0031', (114, 119))	('SW480', 'CellLine', 'CVCL:0546', (121, 126))	('cancer', 'Disease', (139, 145))
153643	29534682	Our experiments showed increase in CNKSR2 expression following MG132 treatment.	('MG132', 'Var', (63, 68))	('CNKSR2', 'Gene', (35, 41))	('MG132', 'Chemical', 'MESH:C072553', (63, 68))	('expression', 'MPA', (42, 52))	('increase', 'PosReg', (23, 31))
153644	29534682	Concomitantly, the expression of Smurf2 was also found to be upregulated following MG132 treatment (Fig.	('upregulated', 'PosReg', (61, 72))	('expression', 'MPA', (19, 29))	('MG132', 'Chemical', 'MESH:C072553', (83, 88))	('MG132', 'Var', (83, 88))	('Smurf2', 'Gene', (33, 39))
153645	29534682	Further we examined whether Smurf2 depletion accelerates the proteasome mediated degradation of CNKSR2.	('amine', 'Chemical', 'MESH:D000588', (13, 18))	('accelerates', 'PosReg', (45, 56))	('depletion', 'Var', (35, 44))	('proteasome mediated degradation', 'MPA', (61, 92))	('CNKSR2', 'Gene', (96, 102))
153648	29534682	Polyubiquitination of CNKSR2 was significantly enhanced in cells treated with Smurf2 siRNA and MG132, compared with cells treated with non-specific siRNAs and MG132.	('MG132', 'Var', (95, 100))	('enhanced', 'PosReg', (47, 55))	('Polyubiquitination', 'MPA', (0, 18))	('CNKSR2', 'Gene', (22, 28))	('MG132', 'Chemical', 'MESH:C072553', (159, 164))	('MG132', 'Chemical', 'MESH:C072553', (95, 100))	('Smurf2', 'Gene', (78, 84))
153700	29534682	Furthermore we observed that Smurf2 knockdown significantly decreases the tumorigenic potential of breast cancer cells.	('decreases', 'NegReg', (60, 69))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', (74, 79))	('Smurf2', 'Gene', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
153708	29534682	Unlike the interaction of Smurf2 with Mad2 and EGFR, we observed that CNKSR2 can interact with both wild type and ligase inactive mutant of Smurf2.	('Smurf2', 'Gene', (140, 146))	('CNKSR2', 'Gene', (70, 76))	('Mad2', 'Gene', '4087', (38, 42))	('Mad2', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (47, 51))	('mutant', 'Var', (130, 136))	('interact', 'Interaction', (81, 89))	('EGFR', 'Gene', (47, 51))
153722	29534682	In order to assess the physiological significance of Smurf2-CNKSR2 interaction, we stably knocked down Smurf2 using Smurf2 shRNA in MDA-MB-231 cells, and observed that Smurf2 knockdown induced CNKSR2 degradation (Fig.	('degradation', 'MPA', (200, 211))	('CNKSR2', 'Gene', (193, 199))	('Smurf2', 'Gene', (103, 109))	('knockdown', 'Var', (175, 184))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))	('knocked', 'Var', (90, 97))
153727	29534682	Altogether, these findings motivate the investigation of the therapeutic efficacy of Smurf2 knockdown in treating CNKSR2-addicted cancers more effectively either as an individual therapy or in combination with already existing chemotherapy and/or radiotherapy.	('Smurf2', 'Gene', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('knockdown', 'Var', (92, 101))	('CNKSR2-addicted cancers', 'Disease', 'MESH:D009369', (114, 137))	('CNKSR2-addicted cancers', 'Disease', (114, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
153762	28382226	This study was supported by the National Cancer Institute (R01CA140560, R01CA172343, K05CA104699, U01CA86082, U01CA70013) and the NCI-funded Breast Cancer Surveillance Consortium (HHSN261201100031C).	('Breast Cancer', 'Disease', 'MESH:D001943', (141, 154))	('U01', 'CellLine', 'CVCL:2220', (98, 101))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Cancer', 'Disease', (41, 47))	('K05CA104699', 'Var', (85, 96))	('Breast Cancer', 'Phenotype', 'HP:0003002', (141, 154))	('R01CA172343', 'Var', (72, 83))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('U01', 'CellLine', 'CVCL:2220', (110, 113))	('Breast Cancer', 'Disease', (141, 154))	('Cancer', 'Disease', (148, 154))	('U01CA86082', 'Var', (98, 108))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('U01CA70013', 'Var', (110, 120))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))	('R01CA140560', 'Var', (59, 70))
153791	19861962	We also noted an increase in the number of tumours with a diameter <=10 mm or 11-20 mm in the more recent period, whereas cases with a diameter greater than 20 mm declined, both at all ages (P=0.0441, Table 1) and in the age group 50-69 years (P=0.1821, data not shown).	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('number of tumours', 'Disease', (33, 50))	('number of tumours', 'Disease', 'MESH:D009369', (33, 50))	('11-20 mm', 'Var', (78, 86))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
153816	19861962	Although data are limited, poorly differentiated DCIS lesions (high grade) are probably associated with a significantly higher risk for invasive carcinoma (Vainio, 2002).	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('invasive carcinoma', 'Disease', 'MESH:D009361', (136, 154))	('invasive carcinoma', 'Disease', (136, 154))	('poorly differentiated', 'Var', (27, 48))
153821	19861962	In southern Switzerland, we observed, among all tumours analysed (DCIS and invasive cases), a proportion of DCIS equal to 6.4% in the period 2002-2007, similar to that reported in two studies in the Netherlands (10% in 2000-2004 and 7.4% in 1984-2006), but our estimates are lower than in some US studies (13 and 15% in 1987-2001 and 1999-2005, respectively) (Table 2).	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (108, 112))	('DCIS', 'Var', (108, 112))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
153864	28893303	CESM and MRI were performed thrice: time (t)0, before the beginning of NAC (pre-NAC); t3m, after about 3 months (during-NAC) and t6m, after the end of treatment (post-NAC), just before surgery.	('t3m', 'Var', (86, 89))	('NAC', 'Chemical', '-', (120, 123))	('t6m', 'Var', (129, 132))	('NAC', 'Chemical', '-', (71, 74))	('NAC', 'Chemical', '-', (80, 83))	('NAC', 'Chemical', '-', (167, 170))
153868	28893303	Additional copper (Cu) filters were installed to allow the combinations of Mo/Cu or Rh/Cu and shape the X-ray spectra for CESM dual-energy exposures.	('Cu', 'Chemical', 'MESH:D003300', (87, 89))	('copper', 'Chemical', 'MESH:D003300', (11, 17))	('Cu', 'Chemical', 'MESH:D003300', (19, 21))	('Cu', 'Chemical', 'MESH:D003300', (78, 80))	('Rh/Cu', 'Gene', (84, 89))	('Mo/Cu', 'Var', (75, 80))
153995	24124550	Further, over-expression of HGF has been detected in various invasive carcinomas, including breast carcinomas, and high expression of HGF has been identified as a predictor of recurrence and shortened survival in breast cancer patients.	('breast carcinomas', 'Phenotype', 'HP:0003002', (92, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('HGF', 'Gene', (28, 31))	('invasive carcinomas', 'Disease', (61, 80))	('high expression', 'Var', (115, 130))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('patients', 'Species', '9606', (227, 235))	('detected', 'Reg', (41, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('HGF', 'Gene', '3082', (134, 137))	('over-expression', 'PosReg', (9, 24))	('breast carcinomas', 'Disease', 'MESH:D001943', (92, 109))	('breast carcinomas', 'Disease', (92, 109))	('recurrence', 'Disease', (176, 186))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('HGF', 'Gene', (134, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('HGF', 'Gene', '3082', (28, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('invasive carcinomas', 'Disease', 'MESH:D009361', (61, 80))	('shortened', 'NegReg', (191, 200))
154013	24124550	These results indicate that HGF is a main paracrine factor secreted from HMFs modulating the invasion of MCF-DCIS cells and is up-regulated in 3D conditions, and that removal of this factor rescues the non-invasive phenotype.	('non-invasive phenotype', 'CPA', (202, 224))	('HGF', 'Gene', (28, 31))	('HGF', 'Gene', '3082', (28, 31))	('invasion', 'CPA', (93, 101))	('up-regulated', 'PosReg', (127, 139))	('removal', 'Var', (167, 174))	('rescues', 'PosReg', (190, 197))	('MCF-DCIS', 'CellLine', 'CVCL:5552', (105, 113))
154025	24124550	Based on the AR data shown in Figure 3C and Figure 5A, we observed that MCF-DCIS cells in co-culture with 3D fibroblasts presented a higher AR value than MCF-DCIS cells cultured in the conditioned medium collected from 3D fibroblasts (approximate AR values of 2.5 vs 1.5, p<0.05).	('MCF-DCIS', 'Var', (72, 80))	('MCF-DCIS', 'CellLine', 'CVCL:5552', (154, 162))	('higher', 'PosReg', (133, 139))	('AR value', 'MPA', (140, 148))	('MCF-DCIS', 'CellLine', 'CVCL:5552', (72, 80))
154029	24124550	This result is consistent with the previous findings that HMFs in 2D produce significantly lower amounts of HGF and correspondingly induce less activation of the c-Met pathway.	('lower', 'NegReg', (91, 96))	('c-Met', 'Gene', (162, 167))	('c-Met', 'Gene', '4233', (162, 167))	('HGF', 'Gene', (108, 111))	('HMFs in', 'Var', (58, 65))	('HGF', 'Gene', '3082', (108, 111))
154081	24124550	Real-time PCR was performed on StepOne Real-Time PCR System (Applied Biosystem) using TaqMan qPCR master mix (Applied Biosystems) along primer/probe sets from Applied Biosystems for the HGF (Hs00300159_m1), MMP14 (Hs01037009_g1), COX2 (Hs01573471_m1), CXCL12 (Hs00171022_m1), and GAPDH (Hs99999905_m1) used as a housekeeping gene to normalize the total number of molecules in each sample.	('HGF', 'Gene', '3082', (186, 189))	('Hs00300159_m1', 'Var', (191, 204))	('Hs99999905_m1', 'Var', (287, 300))	('MMP14', 'Gene', (207, 212))	('Hs01573471_m1', 'Var', (236, 249))	('COX2', 'Gene', (230, 234))	('Hs01037009_g1', 'Var', (214, 227))	('CXCL12', 'Gene', (252, 258))	('COX2', 'Gene', '4513', (230, 234))	('CXCL12', 'Gene', '6387', (252, 258))	('GAPDH', 'Gene', '2597', (280, 285))	('HGF', 'Gene', (186, 189))	('GAPDH', 'Gene', (280, 285))	('MMP14', 'Gene', '4323', (207, 212))	('Hs00171022_m1', 'Var', (260, 273))
154105	32397505	Moreover, according to the most recent publications of consensus an important role emerges in the second-line VABB procedure using a 7-8G needle instead of excisional biopsy surgery: this would allow the complete removal of small B3 lesions and the exclusion of invasive carcinomas in several lesions that have already undergone core biopsy.	('carcinomas', 'Phenotype', 'HP:0030731', (271, 281))	('invasive carcinomas', 'Disease', 'MESH:D009361', (262, 281))	('invasive carcinomas', 'Disease', (262, 281))	('small B3', 'Var', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
154118	32397505	At the end of the procedure, in order to relocate the site, a small non-magnetic clip may be inserted, which is visible in mammography and ultrasound for up to a maximum of 6 months, in cases of lesions that could mutate over time, such as complex cysts or tumors needing neoadjuvant therapy (Figure 5).	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('mutate', 'Var', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('complex cysts', 'Disease', (240, 253))
154130	32397505	The diagnostic underestimation for the CB procedure was equal to 25.26% and concerned 153 cases in class B5 (DCIS in CB resulting IDC and invasive lobular carcinoma (ILC) at conclusive histology), 16 cases in class B4 (6 IDC and 10 DCIS at conclusive histology) and 24 cases in class B3 (18 DCIS and 6 IDC).	('invasive lobular carcinoma', 'Disease', (138, 164))	('DCIS', 'Var', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('DCIS', 'Phenotype', 'HP:0030075', (291, 295))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (138, 164))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (147, 164))	('IDC', 'Disease', (130, 133))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('DCIS', 'Phenotype', 'HP:0030075', (232, 236))
154176	28534000	Conversely, a small proportion of women with DCIS will develop a subsequent invasive breast cancer, which is associated with an increased risk of breast cancer death.	('breast cancer death', 'Disease', 'MESH:D001943', (146, 165))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('invasive breast cancer', 'Disease', (76, 98))	('DCIS', 'Var', (45, 49))	('develop', 'PosReg', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('women', 'Species', '9606', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer death', 'Disease', (146, 165))	('invasive breast cancer', 'Disease', 'MESH:D001943', (76, 98))
154237	26511204	Among women with DCIS, those with low grade, larger tumors and those whose surgery was performed at a hospital that participated in an NCI cooperative group trial were more likely to receive preoperative breast MRI.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('low grade', 'Var', (34, 43))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('women', 'Species', '9606', (6, 11))	('breast', 'Disease', (204, 210))	('DCIS', 'Disease', (17, 21))
154283	25659579	Breast cancer develops through a multistep process driven by genetic and epigenetic changes that gradually transform normal breast epithelium into pre-invasive (pre-cancerous) lesions such as ductal carcinoma in situ (DCIS) and finally culminate in invasive breast cancer.	('ductal carcinoma', 'Disease', 'MESH:D044584', (192, 208))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('epigenetic changes', 'Var', (73, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('invasive breast cancer', 'Disease', (249, 271))	('DCIS', 'Phenotype', 'HP:0030075', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('invasive breast cancer', 'Disease', 'MESH:D001943', (249, 271))	('cancerous', 'Disease', 'MESH:D009369', (165, 174))	('culminate in', 'Reg', (236, 248))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (192, 216))	('transform', 'Reg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ductal carcinoma', 'Disease', (192, 208))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancerous', 'Disease', (165, 174))	('Breast cancer', 'Disease', (0, 13))
154290	25659579	VBIM was used to identify genes capable of cooperating with HER2/neu enabling malignant transformation.	('cooperating', 'Var', (43, 54))	('malignant transformation', 'CPA', (78, 102))	('HER2/neu', 'Gene', '2064', (60, 68))	('HER2/neu', 'Gene', (60, 68))
154291	25659579	We now provide evidence that the loss of HECT and Ankyrin domain containing E3 ubiquitin ligase 1 (HACE1), an E3 ligase that tags activated Rac1 for proteosomal degradation, leads to breast cancer transformation.	('HACE1', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('loss', 'Var', (33, 37))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('Rac1', 'Protein', (140, 144))	('breast cancer', 'Disease', (183, 196))	('leads to', 'Reg', (174, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
154292	25659579	Molecular characterization of HACE1 in breast cancer shows that HACE1 attenuates Rac signaling in mammary epithelial cells, and that loss of HACE1 results in enhanced Rac signaling resulting in tumorigenicity.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('HACE1', 'Var', (64, 69))	('Rac signaling in mammary epithelial', 'MPA', (81, 116))	('Rac signaling', 'MPA', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('enhanced', 'PosReg', (158, 166))	('attenuates', 'NegReg', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('loss', 'Var', (133, 137))	('HACE1', 'Gene', (141, 146))	('breast cancer', 'Disease', (39, 52))
154301	25659579	Previous studies have provided evidence that HACE1 is lost in multiple cancer types due to allelic loss or promoter methylation.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('promoter', 'MPA', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HACE1', 'Gene', (45, 50))	('allelic loss', 'Var', (91, 103))	('lost', 'NegReg', (54, 58))
154302	25659579	In addition, HACE1 knockout mice have been shown to develop spontaneous tumors at multiple locations, including the breast, after a prolonged latency period.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('knockout', 'Var', (19, 27))	('mice', 'Species', '10090', (28, 32))	('develop', 'PosReg', (52, 59))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('HACE1', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
154304	25659579	HACE1 was found to be highly significantly underexpressed in HER2+ invasive ductal breast carcinoma compared with normal breast epithelium (Figure 2a).	('breast carcinoma', 'Phenotype', 'HP:0003002', (83, 99))	('invasive ductal breast carcinoma', 'Disease', (67, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('HER2+', 'Var', (61, 66))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (67, 99))	('HACE1', 'Gene', (0, 5))	('underexpressed', 'NegReg', (43, 57))
154306	25659579	Moreover, allelic loss of HACE1 in invasive ductal breast carcinoma was also observed in the TCGA breast data set (Figure 2b).	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (35, 67))	('HACE1', 'Gene', (26, 31))	('allelic loss', 'Var', (10, 22))	('invasive ductal breast carcinoma', 'Disease', (35, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('breast carcinoma', 'Phenotype', 'HP:0003002', (51, 67))
154309	25659579	Notably, HACE1 was underexpressed or underwent allelic loss in cancer compared with respective normal tissues in glioblastoma, melanoma, lymphoma, lung and pancreatic cancers (Supplementary Figure 1).	('cancer', 'Disease', (167, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('lung and pancreatic cancers', 'Disease', 'MESH:D010190', (147, 174))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (156, 174))	('HACE1', 'Gene', (9, 14))	('cancer', 'Disease', (63, 69))	('glioblastoma', 'Disease', (113, 125))	('lymphoma', 'Disease', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('allelic', 'Var', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
154311	25659579	To further validate HACE1 as a human tumor suppressor gene, we determined whether HACE1 ablation in the normal human mammary epithelial cell line MCF12A increased malignant potential.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ablation', 'Var', (88, 96))	('HACE1', 'Gene', (82, 87))	('increased', 'PosReg', (153, 162))	('human', 'Species', '9606', (111, 116))	('human', 'Species', '9606', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('malignant potential', 'CPA', (163, 182))	('MCF12A', 'CellLine', 'CVCL:3744', (146, 152))
154315	25659579	Analysis of HACE1 ablation in another human mammary epithelial cell line, HME3, recapitulated the results found using the MCF12A cells (Supplementary Figures 2A and B).	('MCF12A', 'CellLine', 'CVCL:3744', (122, 128))	('HACE1', 'Gene', (12, 17))	('human', 'Species', '9606', (38, 43))	('ablation', 'Var', (18, 26))	('HME3', 'CellLine', 'CVCL:3383', (74, 78))
154318	25659579	Consequently, the loss of HACE1 resulted in the accumulation of GTP-bound Rac1 resulting in hyperactive Rac signaling.	('GTP', 'Chemical', 'MESH:D006160', (64, 67))	('loss', 'Var', (18, 22))	('HACE1', 'Gene', (26, 31))	('Rac1', 'Gene', (74, 78))	('accumulation', 'PosReg', (48, 60))	('Rac signaling', 'MPA', (104, 117))	('GTP-bound', 'MPA', (64, 73))	('hyperactive', 'PosReg', (92, 103))
154326	25659579	The overexpression of HACE1 enhanced Rac1 polyubiquitination compared with control cells, whereas the overexpression of catalytically inactive HACE1 (C876S) showed no change in levels of Rac1 polyubiquitination (Figure 3d) Moreover, to verify that HACE1 ubiquitylation of Rac1 occurs at lysine 147 (citation), we ectopically expressed HA-tagged wild-type Rac1 as well as a K147R mutant.	('C876S', 'Mutation', 'p.C876S', (150, 155))	('Rac1 polyubiquitination', 'MPA', (37, 60))	('polyubiquitination', 'Chemical', '-', (192, 210))	('polyubiquitination', 'Chemical', '-', (42, 60))	('K147R', 'Mutation', 'p.K147R', (373, 378))	('enhanced', 'PosReg', (28, 36))	('lysine', 'Chemical', 'MESH:D008239', (287, 293))	('K147R', 'Var', (373, 378))	('Rac1', 'Gene', (355, 359))
154327	25659579	Consistent with previous groups, we observed that HACE1 overexpression enhances polyubiquitination of wild-type Rac1 but not the K147R mutant (Figure 3d).	('HACE1', 'Gene', (50, 55))	('overexpression enhances', 'PosReg', (56, 79))	('K147R', 'Var', (129, 134))	('polyubiquitination', 'Chemical', '-', (80, 98))	('polyubiquitination', 'MPA', (80, 98))	('K147R', 'Mutation', 'p.K147R', (129, 134))
154328	25659579	Thus, the decrease in levels of activated Rac1 in HACE1 overexpressing MCF7 cells is due to the proteosomal degradation of polyubiquitination of Rac1 at lysine 147 by HACE1.	('polyubiquitination', 'Chemical', '-', (123, 141))	('Rac1', 'Protein', (145, 149))	('lysine', 'Chemical', 'MESH:D008239', (153, 159))	('HACE1', 'Gene', (167, 172))	('polyubiquitination', 'MPA', (123, 141))	('decrease', 'NegReg', (10, 18))	('MCF7', 'CellLine', 'CVCL:0031', (71, 75))	('levels', 'MPA', (22, 28))	('proteosomal degradation', 'MPA', (96, 119))	('lysine', 'Var', (153, 159))
154335	25659579	To determine whether HACE1 loss leads to enhanced Rac1 activity in mammary epithelial cells, MCF12A cells that have HACE1 knocked down were tested for Rac1 activation.	('enhanced', 'PosReg', (41, 49))	('HACE1', 'Gene', (116, 121))	('knocked down', 'Var', (122, 134))	('Rac1', 'Enzyme', (50, 54))	('HACE1', 'Gene', (21, 26))	('MCF12A', 'CellLine', 'CVCL:3744', (93, 99))	('loss', 'NegReg', (27, 31))
154338	25659579	Rac1-GTP levels in HACE1 knockdown cells were enhanced >2-fold over control cells as determined by Rac1-GTP enzyme-linked immunosorbent assay corroborating the results of the Rac1-GTP pull-down assays (Figure 3f).	('HACE1', 'Gene', (19, 24))	('GTP', 'Chemical', 'MESH:D006160', (104, 107))	('GTP', 'Chemical', 'MESH:D006160', (180, 183))	('enhanced', 'PosReg', (46, 54))	('Rac1-GTP levels', 'MPA', (0, 15))	('GTP', 'Chemical', 'MESH:D006160', (5, 8))	('knockdown', 'Var', (25, 34))
154341	25659579	Loss of HACE1 stimulated the ability of the noninvasive MCF12A cells to invade through Matrigel (Figure 3h).	('HACE1', 'Gene', (8, 13))	('invade through Matrigel', 'CPA', (72, 95))	('MCF12A', 'CellLine', 'CVCL:3744', (56, 62))	('Loss', 'Var', (0, 4))	('stimulated', 'PosReg', (14, 24))
154343	25659579	However, Rac1 knockdown in MCF12A cells that had HACE1 knocked down was capable of reverting their migratory, invasive and clonogenic potential, indicating that the phenotypic effects of HACE1 loss is driven by the accumulation of activated Rac1 signaling (Supplementary Figure 5).	('HACE1', 'Gene', (187, 192))	('Rac1', 'Gene', (9, 13))	('loss', 'NegReg', (193, 197))	('MCF12A', 'CellLine', 'CVCL:3744', (27, 33))	('knocked down', 'Var', (55, 67))	('migratory', 'CPA', (99, 108))	('HACE1', 'Gene', (49, 54))	('knockdown', 'Var', (14, 23))	('accumulation', 'PosReg', (215, 227))	('reverting', 'NegReg', (83, 92))
154344	25659579	After establishing Rac1 as the major signaling component resulting from HACE1 loss, we used a small molecule inhibitor EHT1864 known to inhibit Rac by promoting the loss of the nucleotide-bound Rac1 in an inert and inactive state, thus inhibiting downstream signal transduction.	('EHT1864', 'Chemical', 'MESH:C506907', (119, 126))	('Rac', 'Gene', (144, 147))	('promoting', 'PosReg', (151, 160))	('inhibit', 'NegReg', (136, 143))	('EHT1864', 'Var', (119, 126))	('Rac1', 'Protein', (194, 198))	('loss', 'NegReg', (78, 82))	('downstream signal transduction', 'MPA', (247, 277))	('nucleotide-bound', 'MPA', (177, 193))	('HACE1', 'Gene', (72, 77))	('loss', 'NegReg', (165, 169))	('inhibiting', 'NegReg', (236, 246))
154345	25659579	MCF12A cells were treated with EHT1864 and then stimulated with EGF and HRG to induce Rac1 activation.	('MCF12A', 'CellLine', 'CVCL:3744', (0, 6))	('activation', 'PosReg', (91, 101))	('EGF', 'Gene', (64, 67))	('EHT1864', 'Chemical', 'MESH:C506907', (31, 38))	('EGF', 'Gene', '1950', (64, 67))	('EHT1864', 'Var', (31, 38))	('Rac1', 'MPA', (86, 90))
154346	25659579	Pretreatment with the Rac inhibitor EHT1864 at a concentration of 25 muM inhibited Rac signaling in the control MCF12A cells as well as MCF12A cells with HACE1 knocked down, while the vehicle control had no suppression of Rac1 activation (Figure 4a).	('MCF12A', 'CellLine', 'CVCL:3744', (136, 142))	('EHT1864', 'Var', (36, 43))	('HACE1', 'Gene', (154, 159))	('Rac signaling', 'MPA', (83, 96))	('inhibited', 'NegReg', (73, 82))	('knocked down', 'Var', (160, 172))	('EHT1864', 'Chemical', 'MESH:C506907', (36, 43))	('MCF12A', 'CellLine', 'CVCL:3744', (112, 118))
154347	25659579	These results support previous studies that EHT1864 is a potent RAC inhibitor and indicate that EHT1864 can be used to inhibit Rac1 signaling of human mammary epithelial cells.	('EHT1864', 'Chemical', 'MESH:C506907', (44, 51))	('EHT1864', 'Var', (44, 51))	('EHT1864', 'Chemical', 'MESH:C506907', (96, 103))	('RAC', 'Gene', (64, 67))	('inhibit', 'NegReg', (119, 126))	('human', 'Species', '9606', (145, 150))	('Rac1 signaling', 'MPA', (127, 141))	('EHT1864', 'Var', (96, 103))	('RAC', 'Gene', '207', (64, 67))
154353	25659579	These results suggest that the inhibition of Rac signaling has the ability to reduce migratory gains caused by HACE1 loss similar to that of the molecular knockdown of Rac1, and support the mechanism of action of EHT1864 as an inhibitor of Rac signaling.	('migratory gains', 'Disease', (85, 100))	('loss', 'NegReg', (117, 121))	('reduce', 'NegReg', (78, 84))	('EHT1864', 'Chemical', 'MESH:C506907', (213, 220))	('migratory gains', 'Disease', 'MESH:D015430', (85, 100))	('inhibition', 'Var', (31, 41))	('HACE1', 'Gene', (111, 116))
154361	25659579	The knockdown of Rac1 using shRNA (Supplementary Figure 7) or pharmaceutical inhibition using the Rac inhibitor EHT1864 reversed the cooperative effects observed by HER2 overexpression and HACE1 loss.	('EHT1864', 'Chemical', 'MESH:C506907', (112, 119))	('HACE1', 'Gene', (189, 194))	('HER2', 'Protein', (165, 169))	('knockdown', 'Var', (4, 13))	('overexpression', 'PosReg', (170, 184))	('loss', 'NegReg', (195, 199))
154362	25659579	HACE1 knockdown in a primary HER2+ breast cancer cell line, DT13, also resulted in enhanced anchorage-independent growth in soft agar owing to enhanced levels of activated Rac1 (Supplementary Figure 8).	('Rac1', 'Protein', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('enhanced', 'PosReg', (143, 151))	('enhanced', 'PosReg', (83, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('HACE1', 'Gene', (0, 5))	('activated', 'MPA', (162, 171))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('levels', 'MPA', (152, 158))	('anchorage-independent growth in', 'CPA', (92, 123))	('DT13', 'CellLine', 'CVCL:1081', (60, 64))	('breast cancer', 'Disease', (35, 48))	('knockdown', 'Var', (6, 15))	('agar', 'Chemical', 'MESH:D000362', (129, 133))
154363	25659579	EHT1864 suppressed the ability of the DT13 cells to grow in soft agar as well as MCF7 cells (Supplementary Figure 9), suggesting that breast cancers including those that overexpress HER2 may be susceptible to Rac-targeted therapies.	('DT13', 'CellLine', 'CVCL:1081', (38, 42))	('breast cancers', 'Disease', (134, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('EHT1864', 'Chemical', 'MESH:C506907', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('agar', 'Chemical', 'MESH:D000362', (65, 69))	('EHT1864', 'Var', (0, 7))	('MCF7', 'CellLine', 'CVCL:0031', (81, 85))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (134, 148))	('overexpress', 'PosReg', (170, 181))	('breast cancers', 'Disease', 'MESH:D001943', (134, 148))	('HER2', 'Protein', (182, 186))
154364	25659579	To test whether colony formation translates to tumor formation in vivo, MCF12A and MCF12A-HER2 cell lines with HACE1 knockdown were implanted orthotopically into mammary fat pads of NOD-SCID mice.	('NOD', 'Gene', (182, 185))	('SCID', 'Disease', 'MESH:D053632', (186, 190))	('tumor', 'Disease', (47, 52))	('MCF12A', 'CellLine', 'CVCL:3744', (83, 89))	('MCF12A', 'CellLine', 'CVCL:3744', (72, 78))	('NOD', 'Gene', '1822', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (191, 195))	('knockdown', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('HACE1', 'Gene', (111, 116))	('SCID', 'Disease', (186, 190))
154366	25659579	The MCF12A cells that had enhanced Rac1 activation due to HACE1 knockdown were also unable to form tumors.	('enhanced', 'PosReg', (26, 34))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('MCF12A', 'CellLine', 'CVCL:3744', (4, 10))	('activation', 'PosReg', (40, 50))	('HACE1', 'Gene', (58, 63))	('Rac1', 'MPA', (35, 39))	('knockdown', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
154378	25659579	We showed that HACE1 deficiency results in the accumulation of activated Rac1 resulting in enhanced clonogenicty, migration/invasion and tumorigenesis in mice.	('HACE1', 'Gene', (15, 20))	('tumor', 'Disease', (137, 142))	('migration/invasion', 'CPA', (114, 132))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('deficiency', 'Var', (21, 31))	('clonogenicty', 'CPA', (100, 112))	('Rac1', 'Protein', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('enhanced', 'PosReg', (91, 99))	('accumulation', 'PosReg', (47, 59))
154380	25659579	HACE1 was found to undergo allelic loss in breast cancer as well as many other cancers while hypermethylation of the HACE1 promoter has also been observed.	('breast cancer', 'Disease', (43, 56))	('cancers', 'Disease', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('loss', 'NegReg', (35, 39))	('HACE1', 'Gene', (0, 5))	('allelic', 'Var', (27, 34))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
154381	25659579	Gene inactivation of Hace1 in mice results in spontaneous cancers after long latency in multiple sites including the breast, further supporting the notion of HACE1 being a breast tumor suppressor gene.	('results in', 'Reg', (35, 45))	('mice', 'Species', '10090', (30, 34))	('breast tumor', 'Disease', 'MESH:D001943', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast tumor', 'Disease', (172, 184))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Hace1', 'Gene', '209462', (21, 26))	('Hace1', 'Gene', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('Gene inactivation', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancers', 'Disease', (58, 65))	('breast tumor', 'Phenotype', 'HP:0100013', (172, 184))
154386	25659579	Constitutively, active Rac1 variants have also been identified in breast cancers such as the splice variant Rac1b and activating mutational variants, suggesting that Rac1 signaling is a major component in breast cancer.	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('Rac1', 'Gene', (23, 27))	('variants', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancers', 'Disease', 'MESH:D001943', (66, 80))	('breast cancers', 'Disease', (66, 80))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Rac1b', 'Gene', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Disease', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
154387	25659579	Although knockdown of HACE1 alone was not sufficient for normal mammary epithelial cells to become tumorigenic in mice, HER2 overexpression coupled with knockdown of HACE1 allowed robust tumor formation.	('tumor', 'Disease', (99, 104))	('knockdown', 'Var', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mice', 'Species', '10090', (114, 118))	('HER2', 'Protein', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('overexpression', 'PosReg', (125, 139))	('HACE1', 'Gene', (166, 171))
154391	25659579	The Rac inhibitor EHT1864 was able to inhibit Rac1 activation nullifying the phenotypic effects of enhanced Rac signaling in vitro.	('Rac signaling', 'MPA', (108, 121))	('EHT1864', 'Chemical', 'MESH:C506907', (18, 25))	('Rac1 activation', 'Protein', (46, 61))	('inhibit', 'NegReg', (38, 45))	('EHT1864', 'Var', (18, 25))
154398	25659579	Because aberrant Rac signaling drives these tumors, treatment with the Rac inhibitor diminishes the oncogenic addiction, thus hauling the Rac-driven phenotypes both in vitro and in vivo.	('tumors', 'Disease', (44, 50))	('diminishes', 'NegReg', (85, 95))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('Rac signaling', 'MPA', (17, 30))	('oncogenic addiction', 'CPA', (100, 119))	('aberrant', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
154405	25659579	Viral vectors for HACE1 (E2838-Lv105), HACE1 C876S (E2838-C876S-Lv105), HA-Rac1 (EX-A0247-Lv157), control vector (EX-EGFP-Lv105) and HER2 (EX-Z2866-Lv151) were obtained from Genecopoeia (Rockville, MD, USA).	('EGF', 'Gene', '1950', (117, 120))	('C876S', 'Mutation', 'p.C876S', (58, 63))	('C876S', 'Mutation', 'p.C876S', (45, 50))	('EX-Z2866-Lv151', 'Var', (139, 153))	('E2838-Lv105', 'Var', (25, 36))	('EGF', 'Gene', (117, 120))	('E2838-C876S-Lv105', 'Var', (52, 69))
154434	23741658	and, as far as quality outcomes are concerned, re-excisions increase the risk of postoperative infections, negatively impact cosmesis and increase medical costs due to a longer hospital stay (Thill et al.	('increase', 'PosReg', (138, 146))	('postoperative infections', 'Disease', 'MESH:D010149', (81, 105))	('impact cosmesis', 'Disease', (118, 133))	('negatively', 'NegReg', (107, 117))	('impact cosmesis', 'Disease', 'MESH:D004834', (118, 133))	('postoperative infections', 'Disease', (81, 105))	('medical', 'MPA', (147, 154))	('re-excisions', 'Var', (47, 59))
154476	23741658	As reported in the series by Rudloff, in the most favorable subgroup (margin width >=10 mm, older age, absent palpable mass, absent lobular neoplasia), the 10-year cumulative IBTR rate was 13% without RT.	('neoplasia', 'Phenotype', 'HP:0002664', (140, 149))	('absent lobular neoplasia', 'Disease', (125, 149))	('absent lobular neoplasia', 'Disease', 'MESH:D009369', (125, 149))	('>=10', 'Var', (83, 87))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (132, 149))
154513	16168104	There is much evidence from studies in rodents of a complex interaction between breast stroma and epithelial tissue, and increased epithelial cell proliferation secondary to increased density could explain why mammographic density is associated with an increased risk for epithelial malignancy.	('epithelial malignancy', 'Phenotype', 'HP:0031492', (272, 293))	('increased', 'PosReg', (121, 130))	('epithelial malignancy', 'Disease', 'MESH:D002277', (272, 293))	('epithelial malignancy', 'Disease', (272, 293))	('breast stroma', 'Disease', 'MESH:D001943', (80, 93))	('mammographic density', 'Var', (210, 230))	('epithelial cell proliferation', 'CPA', (131, 160))	('breast stroma', 'Disease', (80, 93))
154528	29094250	On univariate analysis, increasing tumor size, high grade, positive margins, lymphovascular invasion, node involvement, lack of axillary surgery, chemotherapy, radiation therapy, and IBTR type (TR vs. NP) were significantly associated with worse DFS.	('high grade', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('node involvement', 'CPA', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('lymphovascular invasion', 'CPA', (77, 100))	('tumor', 'Disease', (35, 40))	('increasing', 'PosReg', (24, 34))	('DFS', 'Disease', (246, 249))
154615	28165479	Molecular analysis of FFPE specimens, however, is challenging, given that formalin fixation introduces several types of artifacts, mainly caused by protein and nucleic acid cross-links.	('caused', 'Reg', (138, 144))	('nucleic acid cross-links', 'Var', (160, 184))	('formalin', 'Chemical', 'MESH:D005557', (74, 82))	('protein', 'Protein', (148, 155))
154631	28165479	The CNAs detected in FFPE repaired and frozen nuclei revealed high, significant correlations with the corresponding tumor bulk profiles (Spearman's correlation r2=0.9058983 for FFPE repaired and 0.9116344 for frozen unrepaired, p-values <2.2e-16).	('0.9116344', 'Var', (195, 204))	('correlations', 'Interaction', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
154652	28165479	6a and 6b), whereas the introduction of the single nucleus DNA repair step resulted in the detection of CNAs largely concordant with those detected in frozen nuclei and matching tumor bulk profiles (Figs.	('tumor', 'Disease', (178, 183))	('single nucleus', 'Phenotype', 'HP:0003687', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('CNAs', 'Var', (104, 108))
154655	28165479	Subclonal events such as losses of 1p and 8p and alterations on chromosomes 5 and 8 were found in the profiles from DCIS and from the invasive tumor samples from both FFPE and frozen tissue (Figs.	('alterations', 'Var', (49, 60))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('losses', 'NegReg', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
154660	28165479	Clonal alterations identified in analysis of the matched frozen bulk tumor tissue such as loss of 13q (RB1) and 17p (TP53) as well as focal amplifications on 8p11.2-p12 (FGFR1) and 11q13.3-q13.4 (CCND1), were detected in all single FFPE and frozen nuclei (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FGFR1', 'Gene', '2260', (170, 175))	('RB1', 'Gene', (103, 106))	('CCND1', 'Gene', '595', (196, 201))	('tumor', 'Disease', (69, 74))	('TP53', 'Gene', (117, 121))	('loss', 'Var', (90, 94))	('TP53', 'Gene', '7157', (117, 121))	('RB1', 'Gene', '5925', (103, 106))	('FGFR1', 'Gene', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCND1', 'Gene', (196, 201))
154664	28165479	Interestingly, this putative evolutionary bottleneck was associated with a homozygous deletion at the PTEN locus (Fig.	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))	('deletion', 'Var', (86, 94))
154671	28165479	Hence, the detection of nucleotide substitutions, small insertions and deletions or rearrangements in FFPE single cells, alone or in combination with CN profiling, will require further development.	('nucleotide substitutions', 'Var', (24, 48))	('ran', 'Gene', (88, 91))	('deletions', 'Var', (71, 80))	('ran', 'Gene', '5901', (88, 91))
154702	28165479	Probe panel-3 consisted of BAC clones spanning CCND1/11q13 (as above), PTEN/10q23 (as above) and the chromosome 10 centromeric region (CEN) (p10RP8; labeled with Orange dUTP).	('p10RP8;', 'Var', (141, 148))	('dUTP', 'Chemical', 'MESH:C027078', (169, 173))	('CCND1', 'Gene', (47, 52))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('ran', 'Gene', (163, 166))	('CCND1', 'Gene', '595', (47, 52))	('ran', 'Gene', '5901', (163, 166))
154705	28165479	The probe mix consisted of BAC clones containing the ERBB2 gene (RP11-94L15, RP11-62N23 and CTD-3211L18; labeled with Red dUTP) and a centromeric repeat plasmid for Chromosome 17 (clone p17H8p; labeled with Green dUTP).	('ERBB2', 'Gene', '2064', (53, 58))	('RP11', 'Gene', '26121', (65, 69))	('CTD-3211L18', 'Var', (92, 103))	('RP11', 'Gene', (77, 81))	('dUTP', 'Chemical', 'MESH:C027078', (122, 126))	('mix', 'Gene', '83881', (10, 13))	('dUTP', 'Chemical', 'MESH:C027078', (213, 217))	('RP11', 'Gene', '26121', (77, 81))	('mix', 'Gene', (10, 13))	('RP11', 'Gene', (65, 69))	('ERBB2', 'Gene', (53, 58))
154714	28165479	The number of total events per second and the percentage of single-cell events for FFPE MCF-7, FFPE CAMA-1, frozen MCF-7 and frozen CAMA-1 were determined and used to compute the fraction of single-cell events per second in each nuclei preparation, which were employed to prepare the mixes for sorting.	('mix', 'Gene', '83881', (284, 287))	('mix', 'Gene', (284, 287))	('MCF-7', 'CellLine', 'CVCL:0031', (115, 120))	('FFPE', 'Var', (95, 99))	('MCF-7', 'CellLine', 'CVCL:0031', (88, 93))
154792	28470685	First, we assumed a theoretical 10% increase in the cumulative risk of breast cancer due to DCIS (instead of the observed 2.8%).	('DCIS', 'Var', (92, 96))	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
154801	28470685	The sensitivity analyses, assuming a theoretical increase of breast cancer incidence of 10% due to DCIS, resulted in an expected cumulative risk of breast cancer in absence of screening of 95.6 per 1,000 women aged 50-79.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('women', 'Species', '9606', (204, 209))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('DCIS', 'Var', (99, 103))	('theoretical increase of breast cancer', 'Disease', 'MESH:D001943', (37, 74))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('theoretical increase of breast cancer', 'Disease', (37, 74))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
154887	28025748	Within the last 5 years, detailed genomic analysis of breast cancers by several groups including the ICGC, TCGA and METABRIC consortia, have shown that additional molecular subytypes associated with distinct survival trends can be distinguished, such as the 4% of breast cancers that are ER+ with complex amplifications around 11q and those showing differential survival associated with PIK3CA mutation.	('breast cancers', 'Disease', (54, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('PIK3CA', 'Gene', (387, 393))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('breast cancers', 'Disease', 'MESH:D001943', (264, 278))	('breast cancers', 'Disease', (264, 278))	('PIK3CA', 'Gene', '5290', (387, 393))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('mutation', 'Var', (394, 402))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))
154937	28025748	As expected, the metastatic lesion retained mutations found in the primary tumor, but also possessed de novo mutations and deletions not observed in the primary tumor.	('deletions', 'Var', (123, 132))	('mutations', 'Var', (44, 53))	('primary tumor', 'Disease', (67, 80))	('mutations', 'Var', (109, 118))	('primary tumor', 'Disease', (153, 166))	('primary tumor', 'Disease', 'MESH:D009369', (153, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('primary tumor', 'Disease', 'MESH:D009369', (67, 80))
154943	28025748	At the histological level, several studies have demonstrated that PDX are virtually indistinguishable from the tumor of origin, including H&E stained sections, as well as by immunostaining for biomarkers such as ER, PR, HER2, and Ki67 positivity etc.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('and Ki67', 'Var', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('HER2', 'Gene', (220, 224))	('PDX', 'Disease', (66, 69))	('HER2', 'Gene', '2064', (220, 224))
154965	28025748	Until approximately a decade ago, the most commonly used immunocompromised mouse model used for generation of breast cancer xenografts was the athymic "nude" mouse, which is homozygous for loss-of-function mutation of the Foxn1 gene (encoding the Forkhead box N1 transcription factor) (a.k.a.	('mouse', 'Species', '10090', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('loss-of-function', 'NegReg', (189, 205))	('Foxn1', 'Gene', (222, 227))	('mutation', 'Var', (206, 214))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('mouse', 'Species', '10090', (75, 80))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
154975	28025748	Rag knockout mice may be a useful alternative for some treatment response studies using anthracycline-based or other DNA damaging therapies because the consequences of Rag mutations are relatively specific to the hematopoietic system.	('mutations', 'Var', (172, 181))	('mice', 'Species', '10090', (13, 17))	('Rag', 'Gene', (168, 171))	('anthracycline', 'Chemical', 'MESH:D018943', (88, 101))
154978	28025748	These include SCID (severe combined immunodeficiency disorder) mice which carry a mutation of the Prkdc gene (protein kinase, DNA activated, catalytic polypeptide) encoding a protein kinase required for somatic VDJ (variable, diversity, joining) region recombination of antibody chains and T-cell receptors, as well as for DNA repair.	('immunodeficiency disorder', 'Disease', 'MESH:D007153', (36, 61))	('protein kinase', 'Gene', '53859', (110, 124))	('immunodeficiency disorder', 'Disease', (36, 61))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (20, 52))	('mutation', 'Var', (82, 90))	('protein kinase', 'Gene', (175, 189))	('immunodeficiency', 'Phenotype', 'HP:0002721', (36, 52))	('mice', 'Species', '10090', (63, 67))	('protein kinase', 'Gene', '53859', (175, 189))	('Prkdc gene (protein kinase, DNA activated, catalytic polypeptide', 'Gene', '53859', (98, 162))	('SCID', 'Gene', '19090', (14, 18))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (27, 52))	('protein kinase', 'Gene', (110, 124))	('SCID', 'Gene', (14, 18))
154983	28025748	Combination of the Beige (Bg) mutation with the SCID mutation has been shown to enhance the take rate of human leukemias and other cell types, including breast cancers.	('leukemias', 'Disease', (111, 120))	('human', 'Species', '9606', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('Beige (Bg', 'Gene', (19, 28))	('mutation', 'Var', (53, 61))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('mutation', 'Var', (30, 38))	('take rate', 'CPA', (92, 101))	('leukemias', 'Disease', 'MESH:D007938', (111, 120))	('SCID', 'Gene', '19090', (48, 52))	('breast cancers', 'Phenotype', 'HP:0003002', (153, 167))	('enhance', 'PosReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancers', 'Disease', 'MESH:D001943', (153, 167))	('breast cancers', 'Disease', (153, 167))	('leukemias', 'Phenotype', 'HP:0001909', (111, 120))	('SCID', 'Gene', (48, 52))
154984	28025748	In addition to B- and T-cell deficiencies, disruption of Bg results in a lysosomal trafficking defect and eliminates NK cell function, but leads to a ~3-fold increase in the number of macrophages relative to the parental wild type Balb/C mice.	('T-cell deficiencies', 'Disease', 'MESH:D016399', (22, 41))	('NK cell function', 'MPA', (117, 133))	('disruption', 'Var', (43, 53))	('T-cell deficiencies', 'Disease', (22, 41))	('eliminates NK cell', 'Phenotype', 'HP:0040219', (106, 124))	('eliminates', 'NegReg', (106, 116))	('T-cell deficiencies', 'Phenotype', 'HP:0005435', (22, 41))	('mice', 'Species', '10090', (238, 242))	('defect', 'NegReg', (95, 101))	('increase', 'PosReg', (158, 166))	('lysosomal trafficking', 'MPA', (73, 94))
154986	28025748	Use of this genetic background allows stable take rates in excess of 20% under various conditions, but successful transplantation in this background is enhanced significantly by estradiol supplementation (Table 3), likely by an ER-alpha-mediated stimulation of bone marrow-derived monocytes.	('estradiol', 'Chemical', 'MESH:D004958', (178, 187))	('ER-alpha', 'Gene', (228, 236))	('supplementation', 'Var', (188, 203))	('enhanced', 'PosReg', (152, 160))	('ER-alpha', 'Gene', '2099', (228, 236))	('estradiol', 'Protein', (178, 187))
154987	28025748	A major advance for the generation of PDX models came after genetic introgression of the NOD (non-obese diabetic) mutation in to the SCID background, which compromises cellular immunity, via impaired function of NK, APC and macrophage cells.	('non-obese diabetic', 'Disease', (94, 112))	('non-obese diabetic', 'Disease', 'MESH:D009765', (94, 112))	('compromises', 'NegReg', (156, 167))	('impaired', 'NegReg', (191, 199))	('APC', 'Disease', 'MESH:D011125', (216, 219))	('SCID', 'Gene', (133, 137))	('APC', 'Disease', (216, 219))	('SCID', 'Gene', '19090', (133, 137))	('function', 'MPA', (200, 208))	('mutation', 'Var', (114, 122))	('cellular immunity', 'CPA', (168, 185))	('NOD', 'Gene', (89, 92))
154989	28025748	Development of the NOD/SCID background has continued with the addition of IL2-receptor gamma truncation/disruption mutations ("NOG" or "NSG" mice, respectively) which compromises the mouse immune system further by impairing cytokine signaling involved in innate cellular immunity.	('NOG', 'Gene', '9241', (127, 130))	('truncation/disruption mutations', 'Var', (93, 124))	('cytokine signaling', 'MPA', (224, 242))	('SCID', 'Gene', '19090', (23, 27))	('impairing', 'NegReg', (214, 223))	('IL2-receptor', 'Gene', (74, 86))	('mouse', 'Species', '10090', (183, 188))	('SCID', 'Gene', (23, 27))	('compromises', 'NegReg', (167, 178))	('mice', 'Species', '10090', (141, 145))	('NOG', 'Gene', (127, 130))
154991	28025748	In NOG, the Il2rg mutation still produces a protein product that can bind to cytokines, but there is no signaling activation.	('bind', 'Interaction', (69, 73))	('NOG', 'Gene', '9241', (3, 6))	('Il2rg', 'Gene', (12, 17))	('mutation', 'Var', (18, 26))	('NOG', 'Gene', (3, 6))	('Il2rg', 'Gene', '3561', (12, 17))
154992	28025748	NSG mice are less susceptible to thymic lymphomas than NOD/SCID mice, and have a longer lifespan, making them well-suited for engrafting slower growing human tumors.	('tumors', 'Disease', (158, 164))	('NSG', 'Var', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('mice', 'Species', '10090', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('lymphomas', 'Disease', (40, 49))	('human', 'Species', '9606', (152, 157))	('SCID', 'Gene', '19090', (59, 63))	('SCID', 'Gene', (59, 63))	('lymphomas', 'Disease', 'MESH:D008223', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mice', 'Species', '10090', (64, 68))	('lymphomas', 'Phenotype', 'HP:0002665', (40, 49))
154993	28025748	An interesting modification of the NSG is the NRG strain, which replaces the SCID mutation with a Rag1 mutation.	('Rag1', 'Gene', (98, 102))	('SCID', 'Gene', (77, 81))	('SCID', 'Gene', '19090', (77, 81))	('mutation', 'Var', (103, 111))
155013	28025748	These stem cells could be activated to self-renew upon transplantation of small duct fragments (~1000-2000 cells) into the epithelium-free mammary fat pad of recipient mice, and were capable of regenerating a morphologically normal and functional, ductal tree.	('mice', 'Species', '10090', (168, 172))	('regenerating', 'CPA', (194, 206))	('~1000-2000 cells', 'Var', (96, 112))
155026	28025748	However, comparison of stable take rates of primary cancers from statistically similar cohorts in the SCID/Bg host strain, with and without supplementation with slow-release estradiol pellets, demonstrated that supplementation increased the stable take rate almost 10-fold, from 2.6% without supplementation (only a single TNBC PDX generated from 38 patients attempted) to 21% with supplementation (15 PDX representing multiple IHC subtypes from 70 patients attempted) in this host background.	('increased', 'PosReg', (227, 236))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('supplementation', 'Var', (211, 226))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('patients', 'Species', '9606', (449, 457))	('SCID', 'Gene', '19090', (102, 106))	('patients', 'Species', '9606', (350, 358))	('SCID', 'Gene', (102, 106))	('stable take', 'MPA', (241, 252))	('estradiol', 'Chemical', 'MESH:D004958', (174, 183))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
155027	28025748	These data indicating a requirement for estradiol supplementation were consistent with previous studies showing that estradiol supplementation stimulates growth of breast cancer xenografts, including ER-negative xenografts.	('estradiol', 'Chemical', 'MESH:D004958', (117, 126))	('estradiol', 'Gene', (117, 126))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('growth', 'MPA', (154, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast cancer', 'Disease', (164, 177))	('supplementation', 'Var', (127, 142))	('stimulates', 'PosReg', (143, 153))	('estradiol', 'Chemical', 'MESH:D004958', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
155084	28025748	The immune system is also instrumental in sustaining tumor regression upon oncogene inactivation, which is highly relevant when considering therapeutic effects.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('oncogene', 'Protein', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('inactivation', 'Var', (84, 96))
155137	28025748	One of the best examples has been seen in the case of colorectal cancer, where PDX studies showed that tumors with a mutated KRAS gene were not responsive to cetuximab, closely mimicking that seen in large clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutated', 'Var', (117, 124))	('KRAS', 'Gene', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Disease', (103, 109))	('cetuximab', 'Chemical', 'MESH:D000068818', (158, 167))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('clinical', 'Species', '191496', (206, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('colorectal cancer', 'Disease', (54, 71))	('not', 'NegReg', (140, 143))
155151	19174581	High Prevalence of Pre-invasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers Mutations in BRCA1 and BRCA2 increase a woman's lifetime risk of developing breast cancer to 43%-84%.	('BRCA1', 'Gene', '672', (52, 57))	('woman', 'Species', '9606', (126, 131))	('BRCA1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA1', 'Gene', '672', (99, 104))	('Breast Cancers', 'Phenotype', 'HP:0003002', (71, 85))	('Cancers', 'Phenotype', 'HP:0002664', (78, 85))	('Breast Cancers', 'Disease', (71, 85))	('BRCA1', 'Gene', (99, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('increase', 'PosReg', (115, 123))	('BRCA2', 'Gene', (109, 114))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Disease', (162, 175))	('Mutations', 'Var', (86, 95))	('Breast Cancers', 'Disease', 'MESH:D001943', (71, 85))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Breast Cancer', 'Phenotype', 'HP:0003002', (71, 84))	('BRCA2', 'Gene', '675', (109, 114))
155159	19174581	Pre-invasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% vs. 52%, respectively).	('prevalent', 'Reg', (31, 40))	('Pre-invasive lesions', 'Disease', (0, 20))	('BRCA1', 'Gene', '672', (76, 81))	('BRCA2', 'Gene', (44, 49))	('BRCA2', 'Gene', '675', (44, 49))	('BRCA1', 'Gene', (76, 81))	('mutation', 'Var', (50, 58))
155164	19174581	The majority of these cancers result from germline mutations in the BRCA1 and BRCA2 genes.	('result from', 'Reg', (30, 41))	('BRCA1', 'Gene', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('BRCA2', 'Gene', (78, 83))	('germline mutations', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1', 'Gene', '672', (68, 73))
155165	19174581	Risk factors to carry a mutation in BRCA1 or BRCA2 include diagnosis of breast cancer at an early age (<50 years), diagnosis of ovarian cancer at any age, diagnosis of bilateral breast cancer, diagnosis of breast and ovarian cancer, diagnosis of male breast cancer, family history positive for breast and/or ovarian cancer, and Ashkenazi Jewish ancestry.	('BRCA2', 'Gene', '675', (45, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (217, 231))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('BRCA1', 'Gene', '672', (36, 41))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (206, 231))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('male breast cancer', 'Disease', (246, 264))	('ovarian cancer', 'Phenotype', 'HP:0100615', (308, 322))	('BRCA1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (294, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('ovarian cancer', 'Disease', (217, 231))	('ovarian cancer', 'Phenotype', 'HP:0100615', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (168, 191))	('breast and/or ovarian cancer', 'Disease', (294, 322))	('mutation', 'Var', (24, 32))	('bilateral breast cancer', 'Disease', (168, 191))	('BRCA2', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('ovarian cancer', 'Disease', (128, 142))	('ovarian cancer', 'Disease', 'MESH:D010051', (308, 322))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('male breast cancer', 'Disease', 'MESH:D018567', (246, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
155166	19174581	Women who carry a germline mutation in BRCA1 or BRCA2 have a 43%-84% risk of developing breast cancer and a 22%-39% risk of developing ovarian cancer by age 70 years,,.	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Women', 'Species', '9606', (0, 5))	('ovarian cancer', 'Disease', (135, 149))	('BRCA2', 'Gene', (48, 53))	('BRCA2', 'Gene', '675', (48, 53))	('germline mutation', 'Var', (18, 35))	('BRCA1', 'Gene', '672', (39, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('BRCA1', 'Gene', (39, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (135, 149))
155175	19174581	The Breast Cancer Linkage Consortium study for example, showed a lower prevalence of DCIS, among BRCA mutation carriers, whereas another study did not.	('Breast Cancer', 'Phenotype', 'HP:0003002', (4, 17))	('mutation', 'Var', (102, 110))	('Breast Cancer', 'Disease', (4, 17))	('lower', 'NegReg', (65, 70))	('BRCA', 'Gene', '672', (97, 101))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA', 'Gene', (97, 101))	('Breast Cancer', 'Disease', 'MESH:D001943', (4, 17))	('DCIS', 'Disease', (85, 89))
155176	19174581	Currently, most of the BRCA risk assessment models do not take the presence of pre-invasive lesions, including DCIS, into consideration when calculating the risk of carrying a BRCA mutation.	('DCIS', 'Disease', (111, 115))	('BRCA', 'Gene', '672', (176, 180))	('mutation', 'Var', (181, 189))	('BRCA', 'Gene', (176, 180))	('BRCA', 'Gene', '672', (23, 27))	('BRCA', 'Gene', (23, 27))
155177	19174581	None of the studies evaluated the presence of these lesions within the context of a breast cancer progression model in patients who are BRCA mutation carriers.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('BRCA', 'Gene', (136, 140))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('mutation', 'Var', (141, 149))	('BRCA', 'Gene', '672', (136, 140))	('breast cancer', 'Disease', (84, 97))
155178	19174581	To further advance the understanding of the role that high-risk pre-invasive lesions play in BRCA-associated breast carcinogenesis, we retrospectively evaluated the presence and prevalence of pre-invasive high-risk lesions adjacent to invasive breast cancers from BRCA1/2 mutation carriers, as compared to BRCA1/2-negative sporadic breast cancers.	('BRCA-', 'Gene', (93, 98))	('BRCA-', 'Gene', '672', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (332, 345))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('BRCA1/2', 'Gene', (264, 271))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (109, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (244, 258))	('sporadic breast cancers', 'Disease', (323, 346))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (323, 346))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('invasive breast cancers', 'Disease', (235, 258))	('mutation', 'Var', (272, 280))	('invasive breast cancers', 'Disease', 'MESH:D001943', (235, 258))	('breast cancers', 'Phenotype', 'HP:0003002', (332, 346))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('breast carcinogenesis', 'Disease', (109, 130))
155179	19174581	Between 1997 and 2006, approximately 900 individuals received genetic counseling and testing for BRCA1/2 at the University of Texas M. D. Anderson Cancer Center and 209 were found to be carriers for a deleterious mutation either in the BRCA 1 or BRCA 2 gene.	('mutation', 'Var', (213, 221))	('Cancer', 'Disease', (147, 153))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('BRCA 1', 'Gene', '672', (236, 242))	('BRCA 2', 'Gene', '675', (246, 252))	('BRCA 1', 'Gene', (236, 242))	('Cancer', 'Disease', 'MESH:D009369', (147, 153))	('BRCA 2', 'Gene', (246, 252))
155183	19174581	146 patients with invasive breast cancer who had tested negative for mutations in BRCA1 and BRCA2 were selected as controls and matched to mutation carriers by age +- 2 years at a ratio of 2:1.	('BRCA1', 'Gene', (82, 87))	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('invasive breast cancer', 'Disease', (18, 40))	('BRCA2', 'Gene', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('patients', 'Species', '9606', (4, 12))	('BRCA1', 'Gene', '672', (82, 87))	('invasive breast cancer', 'Disease', 'MESH:D001943', (18, 40))	('BRCA2', 'Gene', '675', (92, 97))
155184	19174581	Breast tumor pathology from 146 sporadic cases and 73 BRCA1/2 mutation carriers were evaluated for histologic tumor type, modified Black's nuclear grade, estrogen receptor (ER) status and progesterone receptor (PR) status by immunohistochemistry (IHC), HER-2/neu by IHC, HER-2/neu gene amplification by fluorescent in situ hybridization (FISH), and the presence of adjacent pre-invasive lesions.	('estrogen receptor', 'Gene', '2099', (154, 171))	('HER-2/neu', 'Gene', (271, 280))	('HER-2/neu', 'Gene', (253, 262))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('ER', 'Gene', '2099', (254, 256))	('Breast tumor', 'Disease', 'MESH:D001943', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ER', 'Gene', '2099', (173, 175))	('Breast tumor', 'Phenotype', 'HP:0100013', (0, 12))	('estrogen receptor', 'Gene', (154, 171))	('PR', 'Gene', '5241', (211, 213))	('BRCA1/2', 'Gene', (54, 61))	('progesterone receptor', 'Gene', (188, 209))	('progesterone receptor', 'Gene', '5241', (188, 209))	('HER-2/neu', 'Gene', '2064', (271, 280))	('HER-2/neu', 'Gene', '2064', (253, 262))	('tumor', 'Disease', (7, 12))	('ER', 'Gene', '2099', (272, 274))	('Breast tumor', 'Disease', (0, 12))	('tumor', 'Disease', (110, 115))	('mutation', 'Var', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
155190	19174581	The control group consisted of 146 patients with sporadic breast cancer who were negative for the BRCA1/2 mutation.	('sporadic breast cancer', 'Disease', (49, 71))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (49, 71))	('mutation', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRCA1/2', 'Gene', (98, 105))	('patients', 'Species', '9606', (35, 43))
155191	19174581	The median age at diagnosis was 42 years of age (21y-71y) for patients with BRCA mutations, and 42 years of age (22y-70y) for sporadic controls.	('patients', 'Species', '9606', (62, 70))	('BRCA', 'Gene', '672', (76, 80))	('BRCA', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))
155192	19174581	Twenty-five % of the BRCA mutation carriers 36 % of the controls underwent segmental mastectomy, respectively.	('BRCA', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (21, 25))	('mutation', 'Var', (26, 34))
155194	19174581	The histologic types of the invasive cancers were not statistically significantly different in BRCA1 versus BRCA2 mutation carriers.	('BRCA2', 'Gene', (108, 113))	('BRCA1', 'Gene', (95, 100))	('invasive cancers', 'Disease', 'MESH:D009362', (28, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('BRCA2', 'Gene', '675', (108, 113))	('invasive cancers', 'Disease', (28, 44))	('carriers', 'Reg', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutation', 'Var', (114, 122))	('BRCA1', 'Gene', '672', (95, 100))
155202	19174581	A wide spectrum of pre-invasive lesions, including atypical lesions and in situ carcinoma, was found in tissue adjacent to invasive breast carcinomas, both in BRCA1/2 mutation carriers and in BRCA1/2-negative controls.	('BRCA1/2', 'Gene', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('situ carcinoma', 'Disease', (75, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('mutation', 'Var', (167, 175))	('invasive breast carcinomas', 'Disease', (123, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (123, 149))	('situ carcinoma', 'Disease', 'MESH:D002278', (75, 89))	('breast carcinomas', 'Phenotype', 'HP:0003002', (132, 149))
155216	19174581	Sun et al reviewed a database of BRCA1 mutation carriers and their families and found 200 cases of invasive breast cancer but only 4 cases of DCIS.	('invasive breast cancer', 'Disease', (99, 121))	('mutation', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('invasive breast cancer', 'Disease', 'MESH:D001943', (99, 121))	('BRCA1', 'Gene', '672', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('BRCA1', 'Gene', (33, 38))
155218	19174581	Similarly, Frank et al evaluated BRCA mutations from 10,000 individuals tested at Myriad Genetic Laboratories.	('BRCA', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('BRCA', 'Gene', '672', (33, 37))
155219	19174581	The prevalence of BRCA mutations was significantly lower in patients ages 50 years and less with DCIS, than in patients with invasive breast cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (125, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('BRCA', 'Gene', '672', (18, 22))	('invasive breast cancer', 'Disease', (125, 147))	('patients', 'Species', '9606', (60, 68))	('DCIS', 'Disease', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BRCA', 'Gene', (18, 22))	('lower', 'NegReg', (51, 56))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (111, 119))
155220	19174581	Comparison of prophylactic specimens from BRCA1/2 mutation carriers and BRCA negative individuals showed no significant difference in the prevalence of DCIS, atypical ductal hyperplasia or lobular neoplasias with no BRCA1/2 mutation but who had a strong family history of breast cancer, and individuals with no family history of breast cancer.	('BRCA', 'Gene', (72, 76))	('ductal hyperplasia', 'Disease', (167, 185))	('mutation', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('lobular neoplasias', 'Disease', 'MESH:D009369', (189, 207))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('mutation', 'Var', (224, 232))	('DCIS', 'Disease', (152, 156))	('BRCA', 'Gene', '672', (216, 220))	('BRCA', 'Gene', '672', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (329, 342))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (167, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('lobular neoplasias', 'Disease', (189, 207))	('BRCA', 'Gene', (216, 220))	('breast cancer', 'Disease', 'MESH:D001943', (329, 342))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('BRCA', 'Gene', '672', (72, 76))	('breast cancer', 'Disease', (329, 342))	('BRCA', 'Gene', (42, 46))	('breast cancer', 'Disease', (272, 285))	('neoplasias', 'Phenotype', 'HP:0002664', (197, 207))
155221	19174581	Claus et al examined the prevalence of BRCA mutations in women with DCIS and reported mutation rates similar to those found for invasive breast cancer.	('BRCA', 'Gene', (39, 43))	('invasive breast cancer', 'Disease', 'MESH:D001943', (128, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('women', 'Species', '9606', (57, 62))	('invasive breast cancer', 'Disease', (128, 150))	('mutations', 'Var', (44, 53))	('BRCA', 'Gene', '672', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
155223	19174581	A very recent study by Hwang et al evaluated breast cancer outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women and reported that DCIS was equally prevalent in patients who have BRCA mutations as in BRCA non-carriers, suggesting that DCIS may be on the casual pathway to invasive disease.	('BRCA', 'Gene', (230, 234))	('BRCA-', 'Gene', (101, 106))	('BRCA-', 'Gene', '672', (101, 106))	('BRCA', 'Gene', '672', (101, 105))	('women', 'Species', '9606', (137, 142))	('BRCA', 'Gene', '672', (123, 127))	('DCIS', 'Disease', (161, 165))	('mutations', 'Var', (214, 223))	('BRCA', 'Gene', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('BRCA-', 'Gene', (123, 128))	('BRCA', 'Gene', '672', (209, 213))	('BRCA', 'Gene', (123, 127))	('BRCA-', 'Gene', '672', (123, 128))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('invasive disease', 'Disease', 'MESH:D009362', (302, 318))	('BRCA', 'Gene', '672', (230, 234))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRCA', 'Gene', (209, 213))	('invasive disease', 'Disease', (302, 318))
155225	19174581	The investigators went on to perform a larger study in which they compared the pathology of prophylactic mastectomy tissue specimens from BRCA1/2 mutation carriers with the pathology of prophylactic specimens from individuals at high risk for breast cancer who did not carry the mutation.	('breast cancer', 'Disease', (243, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('BRCA1/2', 'Gene', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('mutation', 'Var', (146, 154))
155226	19174581	They found that high-risk pre-invasive lesions were more common in women who did not carry a BRCA1/2 mutation than in women who did carry the mutation (71% vs. 43%, respectively).	('BRCA1/2', 'Gene', (93, 100))	('women', 'Species', '9606', (118, 123))	('women', 'Species', '9606', (67, 72))	('pre-invasive', 'Disease', (26, 38))	('mutation', 'Var', (101, 109))
155227	19174581	These investigators also found no significant difference between BRCA1 carriers and BRCA2 carriers in the prevalence of high-risk pre-invasive lesions.	('BRCA1', 'Gene', '672', (65, 70))	('BRCA2', 'Gene', (84, 89))	('BRCA1', 'Gene', (65, 70))	('carriers', 'Var', (71, 79))	('BRCA2', 'Gene', '675', (84, 89))
155229	19174581	reported that pre-invasive lesions were actually more common in prophylactic mastectomy tissue specimens from carriers of the BRCA1/2 mutation than in breast tissue obtained at autopsy in from unaffected women with no known hereditary predisposition to breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('BRCA1/2', 'Gene', (126, 133))	('women', 'Species', '9606', (204, 209))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('pre-invasive lesions', 'Disease', (14, 34))	('mutation', 'Var', (134, 142))	('common', 'Reg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('breast cancer', 'Disease', (253, 266))
155230	19174581	In our study we have observed a similar incidence of DCIS in patients with BRCA 1/2 positive tumors compared to BRCA negative tumors.	('positive', 'Var', (84, 92))	('BRCA', 'Gene', (112, 116))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (61, 69))	('BRCA', 'Gene', '672', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BRCA 1', 'Gene', (75, 81))	('BRCA', 'Gene', '672', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (93, 99))	('DCIS', 'Disease', (53, 57))	('BRCA 1', 'Gene', '672', (75, 81))	('BRCA', 'Gene', (75, 79))
155236	19174581	However, the finding of DCIS with considerable frequency in prophylactic mastectomy tissue samples from carriers of the BRCA1/2 mutation supported the theory that BRCA1/2-associated breast cancers and sporadic breast cancers undergo similar tumor development, although no definitive conclusions could be reached.	('breast cancers', 'Phenotype', 'HP:0003002', (182, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('tumor', 'Disease', (241, 246))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (201, 224))	('breast cancers', 'Disease', 'MESH:D001943', (210, 224))	('mutation', 'Var', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('BRCA1/2', 'Gene', (120, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (210, 224))	('BRCA1/2-associated', 'Gene', (163, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancers', 'Disease', 'MESH:D001943', (182, 196))	('sporadic breast cancers', 'Disease', (201, 224))	('breast cancers', 'Disease', (182, 196))	('BRCA1/2-associated', 'Reg', (163, 181))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
155284	26394558	The EBCTCG has reinforced the importance of local control in improving overall long-term survival, suggesting that avoidance of four local recurrences would subsequently avoid one breast cancer death over 15 years and thus reduce long-term mortality.	('avoid', 'NegReg', (170, 175))	('breast cancer death', 'Disease', (180, 199))	('one breast', 'Phenotype', 'HP:0012813', (176, 186))	('breast cancer death', 'Disease', 'MESH:D001943', (180, 199))	('mortality', 'Disease', 'MESH:D003643', (240, 249))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('reduce', 'NegReg', (223, 229))	('avoidance', 'Var', (115, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('mortality', 'Disease', (240, 249))	('EBCTCG', 'Chemical', '-', (4, 10))
155331	30111373	The CRISPR/Cas9 system was employed to knockout ERK1, ERK2 or TNFAIP3 in DCIS-iFGFR1 cells.	('TNFAIP3', 'Gene', (62, 69))	('ERK2', 'Gene', (54, 58))	('knockout', 'Var', (39, 47))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('ERK1', 'Gene', '5595', (48, 52))	('ERK2', 'Gene', '5594', (54, 58))	('ERK1', 'Gene', (48, 52))
155332	30111373	Established cell lines were treated with/without AP20187 and with/without FGFR1, MEK, or ERK1/2 inhibitor.	('ERK1/2', 'Gene', '5595;5594', (89, 95))	('MEK', 'Gene', '5609', (81, 84))	('AP20187', 'Var', (49, 56))	('ERK1/2', 'Gene', (89, 95))	('MEK', 'Gene', (81, 84))	('FGFR1', 'Gene', (74, 79))	('AP20187', 'Chemical', 'MESH:C463061', (49, 56))
155338	30111373	Importantly, TNFAIP3 knockout not only inhibited the AP20187-induced proliferation and tumor growth of DCIS-iFGFR1 cells, but also further reduced baseline proliferation and tumor growth of DCIS-iFGFR1 cells without AP20187 treatment.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibited', 'NegReg', (39, 48))	('proliferation', 'CPA', (69, 82))	('AP20187', 'Chemical', 'MESH:C463061', (53, 60))	('tumor', 'Disease', (87, 92))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('knockout', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('reduced', 'NegReg', (139, 146))	('AP20187', 'Chemical', 'MESH:C463061', (216, 223))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('AP20187-induced', 'Gene', (53, 68))	('baseline proliferation', 'CPA', (147, 169))	('TNFAIP3', 'Gene', (13, 20))
155354	30111373	Whole genome sequencing data of multiple types of human cancers showed that amplifications, mutations and rearrangements of FGFR1/2/3/4 were detected in 3.5%, 1.5%, 2.0%, and 0.5%, respectively.	('rearrangements', 'Var', (106, 120))	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('FGFR1/2/3/4', 'Gene', (124, 135))	('detected', 'Reg', (141, 149))	('amplifications', 'MPA', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (92, 101))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
155355	30111373	Importantly, the frequency of these genetic aberrations of FGFR1 was found to be particularly high in breast cancers, which reached 18% of the breast tumor samples examined.	('breast cancers', 'Disease', 'MESH:D001943', (102, 116))	('breast cancers', 'Disease', (102, 116))	('high', 'Reg', (94, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('breast tumor', 'Phenotype', 'HP:0100013', (143, 155))	('FGFR1', 'Gene', (59, 64))	('breast tumor', 'Disease', 'MESH:D001943', (143, 155))	('genetic aberrations', 'Var', (36, 55))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast tumor', 'Disease', (143, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (102, 116))
155363	30111373	For example, although activation of the FGF signaling in the estrogen receptor-positive (ER+) MCF7 breast cancer cells is unable to enhance cell proliferation, activation of FGFR1 in the ER-negative (ER-) human mammary epithelial cells increases cell proliferation, and knockdown of FGFR1 in the ER- mouse breast cancer cells also inhibits cell proliferation.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('MCF7', 'CellLine', 'CVCL:0031', (94, 98))	('cell proliferation', 'CPA', (340, 358))	('breast cancer', 'Disease', (99, 112))	('mouse', 'Species', '10090', (300, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('knockdown', 'Var', (270, 279))	('FGFR1', 'Gene', (174, 179))	('inhibits', 'NegReg', (331, 339))	('breast cancer', 'Disease', 'MESH:D001943', (306, 319))	('increases', 'PosReg', (236, 245))	('breast cancer', 'Disease', (306, 319))	('human', 'Species', '9606', (205, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (306, 319))	('cell proliferation', 'CPA', (246, 264))	('FGFR1', 'Gene', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
155364	30111373	Deregulated FGFR1 signaling also causes epithelial hyperplasia or adenocarcinoma and synergizes with the Wnt1-signaling pathway or PTEN loss-activated PI3K-AKT signaling to drive carcinogenesis and metastasis in mouse models of breast or prostate cancers.	('breast or prostate cancers', 'Disease', 'MESH:D011471', (228, 254))	('breast or prostate cancers', 'Disease', (228, 254))	('epithelial hyperplasia or adenocarcinoma', 'Disease', (40, 80))	('metastasis', 'CPA', (198, 208))	('carcinogenesis', 'Disease', (179, 193))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('mouse', 'Species', '10090', (212, 217))	('Wnt1', 'Gene', '22408', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Deregulated', 'Var', (0, 11))	('PTEN', 'Gene', (131, 135))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('AKT', 'Gene', (156, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('prostate cancers', 'Phenotype', 'HP:0012125', (238, 254))	('epithelial hyperplasia or adenocarcinoma', 'Disease', 'MESH:D017573', (40, 80))	('Wnt1', 'Gene', (105, 109))	('drive', 'PosReg', (173, 178))	('AKT', 'Gene', '207', (156, 159))	('FGFR1', 'Gene', (12, 17))	('PTEN', 'Gene', '19211', (131, 135))	('loss-activated', 'NegReg', (136, 150))	('causes', 'Reg', (33, 39))
155365	30111373	FGFR1 amplification and overexpression in certain breast cancer cells increases MAPK and PI3K-AKT activities.	('AKT', 'Gene', '207', (94, 97))	('AKT', 'Gene', (94, 97))	('increases', 'PosReg', (70, 79))	('FGFR1', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('overexpression', 'PosReg', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('amplification', 'Var', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('MAPK', 'CPA', (80, 84))
155366	30111373	In ER+/human epidermal growth factor receptor 2-negative (HER2-) breast cancers, FGFR gene amplification is more frequent in endocrine therapy-resistant cases versus endocrine therapy-sensitive cases.	('breast cancers', 'Phenotype', 'HP:0003002', (65, 79))	('FGFR', 'Gene', (81, 85))	('gene amplification', 'Var', (86, 104))	('human', 'Species', '9606', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('frequent', 'Reg', (113, 121))	('endocrine therapy-resistant', 'Disease', (125, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancers', 'Disease', 'MESH:D001943', (65, 79))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('breast cancers', 'Disease', (65, 79))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))
155370	30111373	Finally, although clinical trials with FGFR inhibitors are currently underway, it is possible that FGFR mutation, gene fusion, alternative kinase activation or MAPK/Akt reactivation may make the cancer cells resistant to these inhibitors.	('activation', 'PosReg', (146, 156))	('FGFR', 'Gene', (99, 103))	('alternative kinase', 'MPA', (127, 145))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('resistant', 'CPA', (208, 217))	('gene fusion', 'Var', (114, 125))	('Akt', 'Gene', '207', (165, 168))	('mutation', 'Var', (104, 112))	('Akt', 'Gene', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
155373	30111373	AP20187-induced dimerization of this iFGFR1 fusion protein faithfully activates the FGFR1 signaling pathway.	('activates', 'PosReg', (70, 79))	('dimerization', 'MPA', (16, 28))	('FGFR1 signaling pathway', 'Pathway', (84, 107))	('AP20187-induced', 'Var', (0, 15))	('iFGFR1', 'Gene', (37, 43))	('AP20187', 'Chemical', 'MESH:C463061', (0, 7))
155375	30111373	We show that the AP20187-activated iFGFR1 enhances extracellular-signal regulated kinases 1/2 (ERK1/2) MAPK activities, increases DCIS.COM cell proliferation in culture and promotes DCIS progression to invasive cancer in mice.	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('activities', 'MPA', (108, 118))	('invasive cancer', 'Disease', (202, 217))	('invasive cancer', 'Disease', 'MESH:D009362', (202, 217))	('enhances', 'PosReg', (42, 50))	('promotes', 'PosReg', (173, 181))	('DCIS progression', 'CPA', (182, 198))	('DCIS.COM', 'CellLine', 'CVCL:5552', (130, 138))	('ERK1/2', 'Gene', (95, 101))	('DCIS.COM', 'MPA', (130, 138))	('increases', 'PosReg', (120, 129))	('ERK1/2', 'Gene', '5595;5594', (95, 101))	('extracellular-signal regulated kinases 1/2', 'Gene', '5594', (51, 93))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))	('iFGFR1', 'Gene', (35, 41))	('AP20187-activated', 'Var', (17, 34))	('extracellular-signal regulated kinases 1/2', 'Gene', (51, 93))	('mice', 'Species', '10090', (221, 225))	('AP20187', 'Chemical', 'MESH:C463061', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
155378	30111373	However, other studies have reported the cancer-promoting roles for TNFAIP3 in conferring tamoxifen resistance in ER+ breast cancers, promoting EMT and metastasis of basal-like breast cancers by mono-ubiquitination of SNAIL1, and preventing adult T-cell leukemia cells from apoptosis.	('cancer', 'Disease', (184, 190))	('promoting', 'PosReg', (134, 143))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('SNAIL1', 'Gene', (218, 224))	('SNAIL1', 'Gene', '6615', (218, 224))	('EMT', 'CPA', (144, 147))	('metastasis', 'CPA', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('leukemia', 'Phenotype', 'HP:0001909', (254, 262))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('cancer', 'Disease', (41, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('tamoxifen', 'Chemical', 'MESH:D013629', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('leukemia', 'Disease', 'MESH:D007938', (254, 262))	('leukemia', 'Disease', (254, 262))	('cancer', 'Disease', (125, 131))	('breast cancers', 'Disease', 'MESH:D001943', (177, 191))	('tamoxifen resistance', 'MPA', (90, 110))	('breast cancers', 'Disease', (177, 191))	('mono-ubiquitination', 'Var', (195, 214))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('conferring', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('apoptosis', 'CPA', (274, 283))	('breast cancers', 'Phenotype', 'HP:0003002', (177, 191))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('TNFAIP3', 'Gene', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('breast cancers', 'Disease', (118, 132))	('preventing', 'NegReg', (230, 240))
155420	30111373	It has been shown that AP20187-induced dimerization of iFGFR1 resulted in the activation of the FGFR1 signaling.	('AP20187-induced', 'Var', (23, 38))	('dimerization', 'MPA', (39, 51))	('iFGFR1', 'Gene', (55, 61))	('AP20187', 'Chemical', 'MESH:C463061', (23, 30))	('FGFR1 signaling', 'MPA', (96, 111))	('activation', 'PosReg', (78, 88))
155421	30111373	After treatment with AP20187, both total ERK1/2 and p-ERK1/2 showed no changes in DCIS-Ctrl cells, while the levels of pERK1/2 were significantly increased in DCIS-iFGFR1 cell lines although total ERK1/2 levels remained the same (Fig.	('AP20187', 'Var', (21, 28))	('ERK1/2', 'Gene', '5595;5594', (120, 126))	('ERK1/2', 'Gene', (41, 47))	('ERK1/2', 'Gene', '5595;5594', (41, 47))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('increased', 'PosReg', (146, 155))	('ERK1/2', 'Gene', (197, 203))	('levels', 'MPA', (109, 115))	('ERK1/2', 'Gene', (54, 60))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('AP20187', 'Chemical', 'MESH:C463061', (21, 28))	('ERK1/2', 'Gene', '5595;5594', (197, 203))	('ERK1/2', 'Gene', (120, 126))	('ERK1/2', 'Gene', '5595;5594', (54, 60))
155422	30111373	The high levels of p-ERK1/2 in DCIS-iFGFR1 cells were significantly induced by AP20187 within 1 min and could be maintained for hours (Fig.	('AP20187', 'Chemical', 'MESH:C463061', (79, 86))	('ERK1/2', 'Gene', (21, 27))	('ERK1/2', 'Gene', '5595;5594', (21, 27))	('induced', 'Reg', (68, 75))	('AP20187', 'Var', (79, 86))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))
155424	30111373	In the AP20187-treated cells, the epithelial markers E-cadherin, cytokeratin 8 (K8), and beta-catenin were significantly reduced and the mesenchymal markers including vimentin, fibronectin, and N-cadherin were increased (Fig.	('fibronectin', 'Gene', '2335', (177, 188))	('cytokeratin 8', 'Gene', '3856', (65, 78))	('E-cadherin', 'Gene', (53, 63))	('increased', 'PosReg', (210, 219))	('E-cadherin', 'Gene', '999', (53, 63))	('beta-catenin', 'Gene', '1499', (89, 101))	('reduced', 'NegReg', (121, 128))	('fibronectin', 'Gene', (177, 188))	('N-cadherin', 'Gene', '1000', (194, 204))	('vimentin', 'Gene', '7431', (167, 175))	('AP20187', 'Chemical', 'MESH:C463061', (7, 14))	('N-cadherin', 'Gene', (194, 204))	('cytokeratin 8', 'Gene', (65, 78))	('vimentin', 'Gene', (167, 175))	('AP20187-treated', 'Var', (7, 22))	('beta-catenin', 'Gene', (89, 101))	('mesenchymal markers', 'CPA', (137, 156))	('epithelial', 'CPA', (34, 44))
155425	30111373	Moreover, AP20187 treatment had no effect on DCIS-Ctrl cells but significantly increased the proliferation rates of DCIS-iFGFR1 cells (Fig.	('increased', 'PosReg', (79, 88))	('DCIS-iFGFR1', 'Gene', (116, 127))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('AP20187 treatment', 'Var', (10, 27))	('proliferation rates', 'CPA', (93, 112))	('AP20187', 'Chemical', 'MESH:C463061', (10, 17))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
155426	30111373	These results demonstrate that the AP20187-activated iFGFR1 is fully functional in terms of ERK1/2 activation, EMT induction, and cell proliferation.	('AP20187-activated', 'Var', (35, 52))	('activation', 'PosReg', (99, 109))	('ERK1/2', 'Gene', (92, 98))	('EMT induction', 'CPA', (111, 124))	('iFGFR1', 'Gene', (53, 59))	('ERK1/2', 'Gene', '5595;5594', (92, 98))	('cell proliferation', 'CPA', (130, 148))	('AP20187', 'Chemical', 'MESH:C463061', (35, 42))
155427	30111373	To identify the genes regulated by the iFGFR1-signaling, we performed RNA-Seq analyses with nine RNA samples prepared from DCIS-iFGFR1 cells treated with vehicle (n = 3), AP20187 for 3 h (n = 3) or AP20187 for 16 h (n = 3).	('AP20187', 'Var', (198, 205))	('AP20187', 'Var', (171, 178))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('DCIS-iFGFR1', 'Gene', (123, 134))	('AP20187', 'Chemical', 'MESH:C463061', (198, 205))	('AP20187', 'Chemical', 'MESH:C463061', (171, 178))
155428	30111373	In general, more than 15,000 mRNA transcripts were detected in all three groups, and the expression levels of 6-7% of these transcripts were changed by AP20187 treatment (Fig.	('changed', 'Reg', (141, 148))	('AP20187', 'Chemical', 'MESH:C463061', (152, 159))	('mRNA transcripts', 'MPA', (29, 45))	('AP20187', 'Var', (152, 159))	('expression levels', 'MPA', (89, 106))
155429	30111373	Specifically, when compared with vehicle treatment, AP20187 treatment for 3 h upregulated and downregulated mRNA expression of 259 and 314 genes, respectively (Fig.	('AP20187', 'Chemical', 'MESH:C463061', (52, 59))	('upregulated', 'PosReg', (78, 89))	('AP20187 treatment', 'Var', (52, 69))	('downregulated', 'NegReg', (94, 107))	('mRNA expression', 'MPA', (108, 123))
155430	30111373	2b and Additional file 1), and AP20187 treatment for 16 h upregulated and downregulated mRNA expression of 201 and 195 genes, respectively (Fig.	('mRNA expression', 'MPA', (88, 103))	('AP20187', 'Var', (31, 38))	('upregulated', 'PosReg', (58, 69))	('AP20187', 'Chemical', 'MESH:C463061', (31, 38))	('downregulated', 'NegReg', (74, 87))
155433	30111373	RT-qPCR analysis validated all of the six selected mRNAs upregulated by AP20187 and two of the three selected mRNAs downregulated by AP20187 in DCIS-iFGFR1 cells.	('downregulated', 'NegReg', (116, 129))	('AP20187', 'Var', (133, 140))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('AP20187', 'Var', (72, 79))	('AP20187', 'Chemical', 'MESH:C463061', (133, 140))	('AP20187', 'Chemical', 'MESH:C463061', (72, 79))	('upregulated', 'PosReg', (57, 68))
155434	30111373	GO analysis of the differentially expressed 946 mRNAs upon AP20187 treatment revealed their enrichment in multiple biological processes such as inflammatory responses, angiogenesis, cell proliferation/migration/adhesion and gene regulation, and in multiple molecular functions including DNA binding, gene transcription, signaling protein-protein interaction, and Ras signaling (Fig.	('signaling', 'Protein', (320, 329))	('AP20187', 'Var', (59, 66))	('gene', 'CPA', (224, 228))	('gene transcription', 'CPA', (300, 318))	('DNA binding', 'Interaction', (287, 298))	('inflammatory responses', 'CPA', (144, 166))	('cell proliferation/migration/adhesion', 'CPA', (182, 219))	('angiogenesis', 'CPA', (168, 180))	('AP20187', 'Chemical', 'MESH:C463061', (59, 66))	('Ras signaling', 'MPA', (363, 376))
155437	30111373	Among the genes consecutively upregulated by AP20187-activated iFGFR1, we were particularly interested in understanding how FGFR1 signaling regulates TNFAIP3 expression, since it plays an important role in NF-kappaB regulation but its role in breast cancer is unknown.	('breast cancer', 'Disease', (243, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('AP20187-activated', 'Var', (45, 62))	('regulates', 'Reg', (140, 149))	('expression', 'MPA', (158, 168))	('upregulated', 'PosReg', (30, 41))	('iFGFR1', 'Gene', (63, 69))	('TNFAIP3', 'Gene', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('AP20187', 'Chemical', 'MESH:C463061', (45, 52))
155438	30111373	AP20187-activated iFGFR1 robustly increased the expression of TNFAIP3 mRNA in DCIS-iFGFR1 cells, while this increase could be completely blocked by treating cells with FGFR inhibitors LY2874455 and AZD4547 (Fig.	('AP20187-activated', 'Var', (0, 17))	('LY2874455', 'Var', (184, 193))	('TNFAIP3', 'Gene', (62, 69))	('LY2874455', 'Chemical', 'MESH:C570663', (184, 193))	('expression', 'MPA', (48, 58))	('iFGFR1', 'Gene', (18, 24))	('AP20187', 'Chemical', 'MESH:C463061', (0, 7))	('AZD4547', 'Chemical', 'MESH:C572463', (198, 205))	('increased', 'PosReg', (34, 43))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))
155439	30111373	Accordingly, the TNFAIP3 and p-ERK1/2 protein levels were similar in DCIS-Ctrl cells treated with AP20187 or FGFR inhibitors, while the TNFAIP3 and p-ERK1/2 protein levels in DCIS-iFGFR1 cells were increased by AP20187 treatment and these increases were abolished by LY2874455 or AZD4547 treatment (Fig.	('ERK1/2', 'Gene', (31, 37))	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('AP20187', 'Chemical', 'MESH:C463061', (211, 218))	('increased', 'PosReg', (198, 207))	('LY2874455', 'Chemical', 'MESH:C570663', (267, 276))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('TNFAIP3', 'MPA', (17, 24))	('AZD4547', 'Chemical', 'MESH:C572463', (280, 287))	('AP20187', 'Chemical', 'MESH:C463061', (98, 105))	('AP20187', 'Var', (211, 218))	('ERK1/2', 'Gene', (150, 156))	('ERK1/2', 'Gene', '5595;5594', (150, 156))
155440	30111373	Furthermore, the AP20187-induced TNFAIP3 mRNA and protein were positively associated with the increases in the phosphorylated active forms of ERK1/2 and/or p90-RSK.	('p90-RSK', 'Gene', (156, 163))	('protein', 'MPA', (50, 57))	('ERK1/2', 'Gene', (142, 148))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('AP20187-induced', 'Var', (17, 32))	('increases', 'PosReg', (94, 103))	('TNFAIP3', 'Gene', (33, 40))	('AP20187', 'Chemical', 'MESH:C463061', (17, 24))	('p90-RSK', 'Gene', '6195;83987', (156, 163))	('phosphorylated active', 'MPA', (111, 132))
155447	30111373	Again, AP20187 treatment induced TNFAIP3 protein expression in DCIS-iFGFR1 cells.	('protein', 'Protein', (41, 48))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('AP20187 treatment', 'Var', (7, 24))	('expression', 'MPA', (49, 59))	('TNFAIP3', 'Gene', (33, 40))	('induced', 'Reg', (25, 32))	('AP20187', 'Chemical', 'MESH:C463061', (7, 14))
155448	30111373	Interestingly, AP20187 treatment also upregulated TNFAIP3 protein in two DCIS-iFGFR1 cell lines with ERK1 KO as it did in DCIS-iFGFR1 control cells with wild-type ERK1/2.	('protein', 'Protein', (58, 65))	('ERK1', 'Gene', (163, 167))	('ERK1', 'Gene', (101, 105))	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('ERK1/2', 'Gene', (163, 169))	('ERK1', 'Gene', '5595', (163, 167))	('upregulated', 'PosReg', (38, 49))	('AP20187', 'Chemical', 'MESH:C463061', (15, 22))	('ERK1/2', 'Gene', '5595;5594', (163, 169))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('TNFAIP3', 'Gene', (50, 57))	('ERK1', 'Gene', '5595', (101, 105))	('AP20187 treatment', 'Var', (15, 32))
155449	30111373	However, AP20187 treatment failed to induce TNFAIP3 protein in two DCIS-iFGFR1 cell lines with ERK2 KO.	('ERK2', 'Gene', (95, 99))	('AP20187', 'Chemical', 'MESH:C463061', (9, 16))	('TNFAIP3', 'Gene', (44, 51))	('ERK2', 'Gene', '5594', (95, 99))	('AP20187', 'Var', (9, 16))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
155450	30111373	Accordingly, AP20187 induced a more dramatic increase in ERK2 phosphorylation in ERK1 KO cells than ERK1 phosphorylation in ERK2 KO cells (Fig.	('AP20187', 'Var', (13, 20))	('ERK2', 'Gene', (57, 61))	('ERK2', 'Gene', '5594', (124, 128))	('ERK1', 'Gene', '5595', (81, 85))	('ERK1', 'Gene', (81, 85))	('phosphorylation', 'MPA', (62, 77))	('AP20187', 'Chemical', 'MESH:C463061', (13, 20))	('ERK1', 'Gene', '5595', (100, 104))	('ERK2', 'Gene', '5594', (57, 61))	('ERK1', 'Gene', (100, 104))	('ERK2', 'Gene', (124, 128))	('increase', 'PosReg', (45, 53))
155453	30111373	As expected, AP20187 treatment significantly increased the proliferation rate of the DCIS-iFGFR1 #2 parent control cells.	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('increased', 'PosReg', (45, 54))	('AP20187 treatment', 'Var', (13, 30))	('proliferation rate', 'CPA', (59, 77))	('AP20187', 'Chemical', 'MESH:C463061', (13, 20))
155457	30111373	The DCIS-iFGFR1 #2 parent control cells formed medium-sized spheres in the absence of AP20187, while AP20187 treatment significantly increased the sphere sizes formed from these cells.	('AP20187', 'Chemical', 'MESH:C463061', (101, 108))	('DCIS', 'Phenotype', 'HP:0030075', (4, 8))	('sphere sizes formed', 'CPA', (147, 166))	('AP20187', 'Var', (101, 108))	('medium-sized spheres', 'CPA', (47, 67))	('increased', 'PosReg', (133, 142))	('AP20187', 'Chemical', 'MESH:C463061', (86, 93))
155459	30111373	To investigate the role of TNFAIP3 in FGFR1-promoted breast tumor growth in vivo, we injected DCIS-iFGFR1 #2 parent control cells and TNFAIP3 KO DCIS-iFGFR1 cells into the fat pads of nude mouse mammary glands.	('mouse', 'Species', '10090', (189, 194))	('TNFAIP3', 'Var', (134, 141))	('breast tumor', 'Disease', 'MESH:D001943', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast tumor', 'Disease', (53, 65))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))	('DCIS', 'Phenotype', 'HP:0030075', (145, 149))	('DCIS-iFGFR1', 'Gene', (94, 105))	('breast tumor', 'Phenotype', 'HP:0100013', (53, 65))
155461	30111373	AP20187 treatment of mice markedly accelerated tumor growth, which increased the average tumor weight to about 0.5 g in 14 days.	('AP20187', 'Var', (0, 7))	('mice', 'Species', '10090', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('increased', 'PosReg', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AP20187', 'Chemical', 'MESH:C463061', (0, 7))	('accelerated', 'PosReg', (35, 46))	('tumor', 'Disease', (47, 52))
155467	30111373	However, in AP20187-treated DCIS-iFGFR1 tumors, the tumor cell morphology exhibited much higher degrees of heterogeneity and invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('invasiveness', 'CPA', (125, 137))	('tumor', 'Disease', (52, 57))	('AP20187', 'Chemical', 'MESH:C463061', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('AP20187-treated', 'Var', (12, 27))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('heterogeneity', 'MPA', (107, 120))	('higher', 'PosReg', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumors', 'Disease', (40, 46))	('DCIS-iFGFR1', 'Gene', (28, 39))
155469	30111373	In the AP20187-treated TNFAIP3 KO tumors, most tumor areas displayed similar morphologies observed in the vehicle-treated TNFAIP3 KO tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('KO tumors', 'Disease', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('KO tumors', 'Disease', 'MESH:D009369', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('KO tumors', 'Disease', (130, 139))	('AP20187', 'Chemical', 'MESH:C463061', (7, 14))	('tumor', 'Disease', (133, 138))	('TNFAIP3', 'Gene', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AP20187-treated', 'Var', (7, 22))	('KO tumors', 'Disease', 'MESH:D009369', (31, 40))	('tumor', 'Disease', (47, 52))
155474	30111373	In this study, we established DCIS-iFGFR1 cell lines in which iFGFR1 activation is induced by AP20187 treatment.	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('iFGFR1', 'Gene', (62, 68))	('AP20187', 'Var', (94, 101))	('activation', 'PosReg', (69, 79))	('AP20187', 'Chemical', 'MESH:C463061', (94, 101))
155475	30111373	We demonstrated that activated iFGFR1 activates ERK1/2, induces partial EMT, and increases cell proliferation, which is consistent with the results reported previously.	('ERK1/2', 'Gene', (48, 54))	('partial EMT', 'CPA', (64, 75))	('activated', 'Var', (21, 30))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('iFGFR1', 'Gene', (31, 37))	('induces', 'Reg', (56, 63))	('activates', 'PosReg', (38, 47))	('cell proliferation', 'CPA', (91, 109))	('increases', 'PosReg', (81, 90))
155483	30111373	Consistent results were also observed in the xenograft tumor growth assay in mice, where activation of the iFGFR1 signaling markedly enhanced tumor growth and KO of TNFAIP3 inhibited tumor growth derived from DCIS-iFGFR1 cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mice', 'Species', '10090', (77, 81))	('TNFAIP3', 'Gene', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inhibited', 'NegReg', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('DCIS', 'Phenotype', 'HP:0030075', (209, 213))	('xenograft tumor growth', 'Disease', 'MESH:D006130', (45, 67))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('iFGFR1', 'Gene', (107, 113))	('KO of', 'Var', (159, 164))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('xenograft tumor growth', 'Disease', (45, 67))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('enhanced', 'PosReg', (133, 141))
155484	30111373	Interestingly, KO of TNFAIP3 not only abolished cell, mammosphere, and tumor growth induced by AP29187-activated iFGFR1, but also reduced cell, mammoshpere, and tumor growth in the absence of AP29187 treatment when compared with the tumors derived from DCIS-iFGFR1 cells with wild-type TNFAIP3.	('DCIS', 'Phenotype', 'HP:0030075', (253, 257))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('AP29187-activated', 'PosReg', (95, 112))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cell', 'CPA', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('abolished', 'NegReg', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (71, 76))	('TNFAIP3', 'Gene', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('iFGFR1', 'Gene', (113, 119))	('tumors', 'Disease', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('AP29187-activated', 'Var', (95, 112))	('cell', 'CPA', (48, 52))	('reduced', 'NegReg', (130, 137))
155487	30111373	Interestingly, TNFAIP3 KO DCIS.COM xenograft tumors were insensitive to iFGFR1 activation induced by AP20187.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('AP20187', 'Chemical', 'MESH:C463061', (101, 108))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('DCIS.COM', 'CellLine', 'CVCL:5552', (26, 34))	('iFGFR1', 'Gene', (72, 78))	('xenograft tumors', 'Disease', (35, 51))	('AP20187', 'Var', (101, 108))	('xenograft tumors', 'Disease', 'MESH:D009369', (35, 51))
155490	30111373	The active mutants of HRAS, KRAS, and NRAS were found in a subset of breast cancers.	('NRAS', 'Gene', '4893', (38, 42))	('KRAS', 'Gene', (28, 32))	('mutants', 'Var', (11, 18))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('KRAS', 'Gene', '3845', (28, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('HRAS', 'Gene', '3265', (22, 26))	('breast cancers', 'Disease', 'MESH:D001943', (69, 83))	('found', 'Reg', (48, 53))	('breast cancers', 'Disease', (69, 83))	('NRAS', 'Gene', (38, 42))	('HRAS', 'Gene', (22, 26))
155491	30111373	Although active Ras mutations and FGFR1 amplification and overexpression barely occur in the same breast cancer cells, FGFs are always present in the tumor microenvironment and FGFRs are expressed in breast epithelial and cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('FGFR1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', (150, 155))	('mutations', 'Var', (20, 29))
155492	30111373	It is unknown whether FGFR1 activation can further activate downstream signaling in breast epithelial and tumor cells with an active Ras mutation to promote these cell growth and progression to a more aggressive cancer cell phenotype.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cell growth', 'CPA', (163, 174))	('mutation', 'Var', (137, 145))	('aggressive cancer', 'Disease', 'MESH:D009369', (201, 218))	('activate', 'PosReg', (51, 59))	('aggressive cancer', 'Disease', (201, 218))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('active Ras', 'Gene', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('downstream signaling', 'MPA', (60, 80))	('promote', 'PosReg', (149, 156))	('tumor', 'Disease', (106, 111))	('FGFR1', 'Gene', (22, 27))
155493	30111373	MCF10AT cells are derived from mutant H-Ras transfected MCF10A normal cells and the initial transplantation of MCF10AT cells only develop differentiated ducts in mice.	('MCF10A', 'CellLine', 'CVCL:0598', (111, 117))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('mutant', 'Var', (31, 37))	('MCF10A', 'CellLine', 'CVCL:0598', (56, 62))	('differentiated ducts', 'CPA', (138, 158))	('mice', 'Species', '10090', (162, 166))	('MCF10A', 'Gene', (56, 62))	('H-Ras', 'Gene', (38, 43))	('H-Ras', 'Gene', '3265', (38, 43))
155495	30111373	These findings suggest that expression of mutant H-Ras in these cells is insufficient to promote invasive cancer cells.	('H-Ras', 'Gene', '3265', (49, 54))	('H-Ras', 'Gene', (49, 54))	('mutant', 'Var', (42, 48))	('promote', 'PosReg', (89, 96))	('invasive cancer', 'Disease', 'MESH:D009362', (97, 112))	('invasive cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
155497	30111373	Our results indicate that FGFR1 activation has an additive role to mutant H-Ras in promoting DCIS cell growth and progression.	('promoting', 'PosReg', (83, 92))	('H-Ras', 'Gene', '3265', (74, 79))	('FGFR1', 'Gene', (26, 31))	('activation', 'PosReg', (32, 42))	('DCIS cell growth', 'CPA', (93, 109))	('H-Ras', 'Gene', (74, 79))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('mutant', 'Var', (67, 73))
155498	30111373	It has been reported that wild-type H- and N-Ras promote mutant K-ras-driven tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutant', 'Var', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('K-ras', 'Gene', (64, 69))	('K-ras', 'Gene', '3845', (64, 69))	('tumor', 'Disease', (77, 82))	('wild-type H- and N-Ras', 'Gene', '4893', (26, 48))
155499	30111373	It is possible that activation of FGFR1 activates the endogenous Ras proteins in DCIS.COM cells, which cooperate with mutant H-Ras to promote breast cancer cell proliferation, and progression.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('H-Ras', 'Gene', '3265', (125, 130))	('H-Ras', 'Gene', (125, 130))	('promote', 'PosReg', (134, 141))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('DCIS.COM', 'CellLine', 'CVCL:5552', (81, 89))	('FGFR1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('activates', 'PosReg', (40, 49))	('breast cancer', 'Disease', (142, 155))	('mutant', 'Var', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('progression', 'CPA', (180, 191))
155500	30111373	Alternatively, FGFR1 activation may also work with mutant Ras to promote breast cancer cell proliferation and progression via its other signaling pathways that do not use Ras and ERK1/2.	('ERK1/2', 'Gene', (179, 185))	('ERK1/2', 'Gene', '5595;5594', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutant', 'Var', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('promote', 'PosReg', (65, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('progression', 'CPA', (110, 121))	('activation', 'PosReg', (21, 31))	('FGFR1', 'Gene', (15, 20))	('Ras', 'Gene', (58, 61))
155501	30111373	Importantly, KO of TNFAIP3 inhibited tumor growth promoted by both mutant H-Ras and FGFR1 activation, suggesting that TNFAIP3 may serve as a potential target for inhibiting ER- breast cancer with active mutant Ras and/or active FGFR1 signaling.	('FGFR1', 'Gene', (84, 89))	('breast cancer', 'Disease', (177, 190))	('activation', 'PosReg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('H-Ras', 'Gene', '3265', (74, 79))	('H-Ras', 'Gene', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibiting', 'NegReg', (162, 172))	('tumor', 'Disease', (37, 42))	('TNFAIP3', 'Gene', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('inhibited', 'NegReg', (27, 36))	('mutant', 'Var', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
155704	24746949	Our data suggest that the relationship between residual disease and margin index is less strong when the residual disease is DCIS than when the residual disease is invasive cancer.	('invasive cancer', 'Disease', (164, 179))	('invasive cancer', 'Disease', 'MESH:D009362', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('DCIS', 'Var', (125, 129))
155777	21605383	We did not analyze the strategy for ages 50-64, but our biennial 50-69 strategy, compared with the background, resulted in around 28,500 $ per avoided death and 3,500 $ per year of life saved.	('biennial', 'Var', (56, 64))	('death', 'Disease', 'MESH:D003643', (151, 156))	('death', 'Disease', (151, 156))
155794	21297224	Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels.	('myoepithelial', 'Disease', 'MESH:D009208', (61, 74))	('murine', 'Species', '10090', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('rise to tumors', 'Disease', 'MESH:D009369', (125, 139))	('rise to tumors', 'Disease', (125, 139))	('GFP/RFP', 'Protein', (156, 163))	('human', 'Species', '9606', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('myoepithelial', 'Disease', (61, 74))	('RFP-human', 'Var', (51, 60))
155855	21297224	There was not much heterogeneity in the intensities of immunoreactivity exhibited by the cells positive for p63, CD31, D2-40, Prox-1 and VEGFR-3.	('Prox-1', 'Gene', (126, 132))	('VEGFR-3', 'Gene', (137, 144))	('p63', 'Gene', (108, 111))	('D2-40', 'Chemical', '-', (119, 124))	('D2-40', 'Var', (119, 124))	('VEGFR-3', 'Gene', '2324', (137, 144))	('Prox-1', 'Gene', '5629', (126, 132))	('CD31', 'Var', (113, 117))	('p63', 'Gene', '8626', (108, 111))
155924	21297224	But our study observed CD31, D2-40, VEGFR-3 and Prox-1 differences in the embolic channels.	('CD31', 'Var', (23, 27))	('Prox-1', 'Gene', '5629', (48, 54))	('D2-40', 'Chemical', '-', (29, 34))	('embolic channels', 'Phenotype', 'HP:0001907', (74, 90))	('embolic', 'Disease', (74, 81))	('Prox-1', 'Gene', (48, 54))	('embolic', 'Disease', 'MESH:D004617', (74, 81))	('VEGFR-3', 'Gene', '2324', (36, 43))	('VEGFR-3', 'Gene', (36, 43))
155930	21297224	In our human studies we studied the endothelial immunoreactivites for four markers, CD31, D2-40, VEGFR-3 and Prox-1.	('Prox-1', 'Gene', (109, 115))	('human', 'Species', '9606', (7, 12))	('VEGFR-3', 'Gene', '2324', (97, 104))	('VEGFR-3', 'Gene', (97, 104))	('Prox-1', 'Gene', '5629', (109, 115))	('D2-40', 'Chemical', '-', (90, 95))	('CD31', 'Var', (84, 88))
155937	21297224	In these studies the findings suggested that myoepithelial cells can become less differentiated and manifest aberrant gene expression including expression of endothelial-related genes.	('myoepithelial', 'Disease', (45, 58))	('expression', 'MPA', (144, 154))	('endothelial-related genes', 'Gene', (158, 183))	('myoepithelial', 'Disease', 'MESH:D009208', (45, 58))	('gene expression', 'MPA', (118, 133))	('aberrant', 'Var', (109, 117))
155981	21297224	We chose two tags and two cell lines because we wanted to see both a single pattern of fluorescence in nude mice (using GFP-labeled HMS-1 or MEFs or RFP-labeled HMS-1 or MEFs) or a double pattern of fluorescence in GFP-transgenic nudes (using RFP-labeled HMS-1 or MEFs).	('HMS-1 or MEFs', 'Disease', (132, 145))	('HMS-1 or MEFs', 'Disease', 'MESH:C537627', (132, 145))	('fluorescence', 'MPA', (87, 99))	('GFP-labeled', 'Var', (120, 131))	('HMS-1 or MEFs', 'Disease', (161, 174))	('transgenic', 'Species', '10090', (219, 229))	('HMS-1 or MEFs', 'Disease', 'MESH:C537627', (161, 174))	('nude mice', 'Species', '10090', (103, 112))	('HMS-1 or MEFs', 'Disease', 'MESH:C537627', (255, 268))	('HMS-1 or MEFs', 'Disease', (255, 268))
156017	21297224	For Ki-67, E-cadherin and D2-40, the detection system used was a labeled Streptavidin-Biotin Complex.	('Biotin', 'Chemical', 'MESH:D001710', (86, 92))	('D2-40', 'Chemical', '-', (26, 31))	('E-cadherin', 'Gene', (11, 21))	('E-cadherin', 'Gene', '999', (11, 21))	('Ki-67', 'Var', (4, 9))
156021	21297224	These included p63/CD31, p63/D2-40, p63/VEGFR-3, D2-40/CD31.	('VEGFR-3', 'Gene', (40, 47))	('p63', 'Gene', '8626', (36, 39))	('D2-40', 'Chemical', '-', (29, 34))	('p63', 'Gene', '8626', (15, 18))	('p63', 'Gene', (25, 28))	('p63', 'Gene', '8626', (25, 28))	('p63', 'Gene', (36, 39))	('p63/D2-40', 'Gene', (25, 34))	('p63/D2-40', 'Gene', '8626', (25, 34))	('p63', 'Gene', (15, 18))	('VEGFR-3', 'Gene', '2324', (40, 47))	('D2-40/CD31', 'Var', (49, 59))	('D2-40', 'Chemical', '-', (49, 54))
156034	21297224	Similarly the presence of single p63, CD31, D2-40, VEGFR-3 or Prox-1 or dual p63/D2-40, p63/CD31, p63/VEGFR-3 and D2-40/CD31 immunoreactivities within the lining myoepithelium or endothelium was quantitated.	('Prox-1', 'Gene', '5629', (62, 68))	('p63', 'Gene', (98, 101))	('p63', 'Gene', '8626', (98, 101))	('D2-40', 'Chemical', '-', (44, 49))	('p63', 'Gene', (88, 91))	('p63', 'Gene', (33, 36))	('VEGFR-3', 'Gene', '2324', (102, 109))	('D2-40', 'Var', (44, 49))	('D2-40', 'Chemical', '-', (114, 119))	('p63/D2-40', 'Gene', '8626', (77, 86))	('D2-40', 'Chemical', '-', (81, 86))	('p63', 'Gene', '8626', (88, 91))	('Prox-1', 'Gene', (62, 68))	('p63', 'Gene', '8626', (33, 36))	('p63', 'Gene', (77, 80))	('VEGFR-3', 'Gene', '2324', (51, 58))	('p63', 'Gene', '8626', (77, 80))	('VEGFR-3', 'Gene', (102, 109))	('p63/D2-40', 'Gene', (77, 86))	('CD31', 'Var', (38, 42))	('VEGFR-3', 'Gene', (51, 58))
156046	28108623	Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progression in vivo.	('delayed', 'NegReg', (95, 102))	('periductal reactive', 'MPA', (62, 81))	('breast cancer', 'Disease', (109, 122))	('fibrosis', 'Disease', (82, 90))	('fibrosis', 'Disease', 'MESH:D005355', (82, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('delayed early breast', 'Phenotype', 'HP:0010314', (95, 115))	('depletion', 'Var', (13, 22))	('reduced', 'NegReg', (54, 61))	('CAFs', 'Chemical', '-', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('STAT1', 'Gene', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
156049	28108623	Stepwise accumulation of mutations in key oncogenes and tumor suppressors in somatic cells typifies the classic tumor progression model.	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('oncogenes', 'Gene', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
156058	28108623	Deregulated STAT1 expression has been implicated in breast cancer development with both tumor suppressing and promoting roles of STAT1.	('Deregulated', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('promoting', 'PosReg', (110, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('STAT1', 'Gene', (12, 17))	('expression', 'MPA', (18, 28))	('implicated', 'Reg', (38, 48))	('tumor', 'Disease', (88, 93))
156063	28108623	Ablation of STAT1 in CAFs decreases cancer cell proliferation through STAT1-dependent secretion of pentraxin 3 (PTX3).	('pentraxin 3', 'Gene', '5806', (99, 110))	('pentraxin 3', 'Gene', (99, 110))	('CAFs decreases cancer', 'Disease', 'MESH:D009369', (21, 42))	('Ablation', 'Var', (0, 8))	('STAT1-dependent', 'MPA', (70, 85))	('STAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('CAFs decreases cancer', 'Disease', (21, 42))
156097	28108623	After blocking endogenous peroxidase with 3% H2O2 for 15 minutes, slides were washed 3 times in 1x PBS prior to blocking for 60 minutes at room temperature (Protein Block, Serum-Free; Dako), followed with primary antibody (STAT1, 1:1000, #14994S, Cell Signaling Technologies; alpha-SMA, 1:500, #ab124964, Abcam; 1:500.	('#ab124964', 'Var', (294, 303))	('PBS', 'Chemical', 'MESH:D007854', (99, 102))	('alpha-SMA', 'Gene', (276, 285))	('alpha-SMA', 'Gene', '11475', (276, 285))	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))
156134	28108623	Interestingly, coculture with siSTAT1 CAFs resulted in decreased proliferation as evidenced by significantly less EdU incorporation in the tdTomato-red-positive MDA-MB-231 cancer cells (Fig.	('proliferation', 'CPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (161, 171))	('less', 'NegReg', (109, 113))	('EdU', 'Chemical', '-', (114, 117))	('CAFs', 'Chemical', '-', (38, 42))	('tdTomato-red', 'Chemical', '-', (139, 151))	('siSTAT1 CAFs', 'Var', (30, 42))	('decreased', 'NegReg', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('EdU incorporation', 'CPA', (114, 131))
156137	28108623	To exclude the possible contact-dependent role of CAFs, we treated MDA-MB-231 tumor cells with conditioned media collected from either siSTAT1 CAFs or non-silencing control CAFs for 48 hours.	('CAFs', 'Chemical', '-', (173, 177))	('CAFs', 'Chemical', '-', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('siSTAT1', 'Var', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (67, 77))	('tumor', 'Disease', (78, 83))	('CAFs', 'Chemical', '-', (50, 54))
156145	28108623	Moreover, coculture MDA-MB-231 breast tumor cells with PTX3-depleted CAFs led to a significant decrease of EdU incorporation in tumor cells (23.25% in siPTX3 group vs. 50.3% in siNS group) (Fig.	('decrease', 'NegReg', (95, 103))	('breast tumor', 'Disease', (31, 43))	('tumor', 'Disease', (38, 43))	('EdU incorporation', 'MPA', (107, 124))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('EdU', 'Chemical', '-', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('siPTX3', 'Var', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CAFs', 'Chemical', '-', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('breast tumor', 'Phenotype', 'HP:0100013', (31, 43))	('tumor', 'Disease', (128, 133))	('breast tumor', 'Disease', 'MESH:D001943', (31, 43))
156153	28108623	5C), suggesting a less aggressive mammary tumor development conferred by deprivation of STAT1 in CAFs.	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('deprivation', 'Var', (73, 84))	('CAFs', 'Chemical', '-', (97, 101))	('STAT1', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('less', 'NegReg', (18, 22))
156175	28108623	Mechanistically, analysis of tumor-associated stroma using a systems biology approach revealed upregulation of STAT1 specific to CAFs (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('STAT1', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('upregulation', 'PosReg', (95, 107))	('tumor', 'Disease', (29, 34))	('CAFs', 'Chemical', '-', (129, 133))	('CAFs', 'Var', (129, 133))
156187	28108623	published evidence suggesting the opposite, showing increased susceptibility for epithelial and mesenchymal tumorigenesis and Trp53 mutations in PTX3-/- mice.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Trp53', 'Gene', '22059', (126, 131))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', (108, 113))	('mice', 'Species', '10090', (153, 157))	('Trp53', 'Gene', (126, 131))
156188	28108623	Despite compelling analyses suggesting PTX3 promoter methylation in certain subtypes of cancer, we strongly believe that the role of PTX3 in regulating the tumor niche is complex and entirely context dependent.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('PTX3', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (156, 161))	('methylation', 'Var', (53, 64))
156208	21727289	Biennial mammography cost less than $100 000 per QALY gained for women aged 40 to 79 years with BI-RADS category 3 or 4 breast density or aged 50 to 69 years with category 2 density; women aged 60 to 79 years with category 1 density and either a family history of breast cancer or a previous breast biopsy; and all women aged 40 to 79 years with both a family history of breast cancer and a previous breast biopsy, regardless of breast density.	('breast cancer', 'Disease', 'MESH:D001943', (371, 384))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('BI-RADS', 'Var', (96, 103))	('breast cancer', 'Disease', (371, 384))	('women', 'Species', '9606', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (371, 384))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('breast cancer', 'Disease', (264, 277))	('women', 'Species', '9606', (315, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('women', 'Species', '9606', (65, 70))
156211	21727289	Results are not applicable to carriers of BRCA1 or BRCA2 mutations.	('BRCA1', 'Gene', '672', (42, 47))	('BRCA2', 'Gene', (51, 56))	('BRCA1', 'Gene', (42, 47))	('BRCA2', 'Gene', '675', (51, 56))	('mutations', 'Var', (57, 66))
156226	21727289	Those with DCIS could transition to an invasive breast cancer state or die of causes other than breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', 'MESH:D001943', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('DCIS', 'Var', (11, 15))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('invasive breast cancer', 'Disease', (39, 61))	('transition', 'Reg', (22, 32))
156233	21727289	We also assumed that women with DCIS who had no mammography would have a 3.4-fold greater risk for subsequent invasive breast cancer than healthy women, and those with DCIS who had mammography would have a 1.9-fold greater risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('invasive breast cancer', 'Disease', (110, 132))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('women', 'Species', '9606', (21, 26))	('DCIS', 'Var', (32, 36))	('invasive breast cancer', 'Disease', 'MESH:D001943', (110, 132))	('women', 'Species', '9606', (146, 151))
156255	21727289	In addition, our model-predicted cumulative incidence ratios for invasive breast cancer in women with BI-RADS category 1, 3, or 4 breast density, compared with those with category 2 breast density, were all within 2% of the estimates published by Tice and colleagues (Supplement).	('BI-RADS', 'Var', (102, 109))	('women', 'Species', '9606', (91, 96))	('invasive breast cancer', 'Disease', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasive breast cancer', 'Disease', 'MESH:D001943', (65, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
156259	21727289	A systematic review by the USPSTF estimated that biennial mammography reduced breast cancer mortality by 16% and 25%, respectively, for women in the same age ranges.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('reduced', 'NegReg', (70, 77))	('women', 'Species', '9606', (136, 141))	('biennial', 'Var', (49, 57))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
156276	21727289	Among women aged 40 to 49 years with no additional risk factors for breast cancer, probabilistic sensitivity analyses showed that the probability of mammography every 3 to 4 years being cost-effective compared with no mammography was less than 1% and 5.4%, respectively, for those with BI-RADS category 1 or 2 breast density.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('BI-RADS category', 'Var', (286, 302))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('women', 'Species', '9606', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
156280	21727289	In contrast, our analysis found that mammography every 3 to 4 years is cost-effective for women aged 50 to 79 years who have BI-RADS category 1 breast density, no previous breast biopsy, and no family history of breast cancer, but that biennial mammography may not be.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', (212, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('BI-RADS', 'Var', (125, 132))	('women', 'Species', '9606', (90, 95))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
156288	21727289	First, our results are sensitive to the rates of DCIS detection and overdetection of invasive breast cancer with mammography, and they do not apply to women who carry the BRCA1 or BRCA2 mutation, for whom more frequent mammography and screening with magnetic resonance imaging may be indicated.	('invasive breast cancer', 'Disease', (85, 107))	('BRCA1', 'Gene', (171, 176))	('BRCA2', 'Gene', '675', (180, 185))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('invasive breast cancer', 'Disease', 'MESH:D001943', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA1', 'Gene', '672', (171, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('mutation', 'Var', (186, 194))	('women', 'Species', '9606', (151, 156))	('BRCA2', 'Gene', (180, 185))
156290	21727289	Stratifying the stage distributions by both age and breast density resulted in a lower estimated cost per QALY gained for women with BI-RADS category 3 or 4 breast density and a higher cost for women with category 1 or 2 breast density, compared with age alone, for mammography every 2 versus every 3 to 4 years.	('BI-RADS', 'Var', (133, 140))	('lower', 'NegReg', (81, 86))	('women', 'Species', '9606', (194, 199))	('cost', 'MPA', (97, 101))	('women', 'Species', '9606', (122, 127))
156323	33606809	Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants.	('BRCA', 'Gene', '672', (69, 73))	('BRCA', 'Gene', (69, 73))	('patients', 'Species', '9606', (20, 28))	('variants', 'Var', (53, 61))
156324	33606809	Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.	('PVs', 'Var', (39, 42))	('BRCA1/2', 'Gene', '672;675', (70, 77))	('BRCA1/2', 'Gene', (70, 77))
156325	33606809	Inherited germline pathogenic variants (PVs) in high or moderate penetrance breast cancer (BC) susceptibility genes are the underlying cause of approximately 15% of all BC cases.	('variants', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('cause', 'Reg', (135, 140))
156330	33606809	Studies in populations with known founder mutations may detect mutations in 1.1-4.5% of individuals not selected based on a personal or family history of cancer.	('mutations', 'Var', (63, 72))	('detect', 'Reg', (56, 62))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
156361	33606809	A total of 219 patients (97.7%) underwent multigene panel testing, 3 patients (1.3%) had family variant testing, and 2 patients (0.8%) underwent only BRCA1/2 sequencing.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (119, 127))	('BRCA1/2', 'Gene', (150, 157))	('patients', 'Species', '9606', (69, 77))	('multigene panel testing', 'Var', (42, 65))	('BRCA1/2', 'Gene', '672;675', (150, 157))
156369	33606809	Sixty-one percent of patients (28/46) had PVs in a high-penetrance gene for BC: 19 (8.5%) in BRCA1/2, 8 (3.5%) in TP53, and 1 (0.5%) in PALB2.	('BRCA1/2', 'Gene', (93, 100))	('PALB2', 'Gene', '79728', (136, 141))	('BRCA1/2', 'Gene', '672;675', (93, 100))	('TP53', 'Gene', '7157', (114, 118))	('PALB2', 'Gene', (136, 141))	('BC', 'Gene', (76, 78))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', (114, 118))	('PVs', 'Var', (42, 45))
156373	33606809	Twenty out of 39 (51.2%) actionable variants were found in non-BRCA genes.	('BRCA', 'Gene', (63, 67))	('BRCA', 'Gene', '672', (63, 67))	('variants', 'Var', (36, 44))
156375	33606809	Considering all the cases of bilateral BC (13/224), 31% (4/13) harbored PVs in non-BRCA genes.	('PVs', 'Var', (72, 75))	('BRCA', 'Gene', (83, 87))	('BRCA', 'Gene', '672', (83, 87))	('harbored', 'Reg', (63, 71))
156377	33606809	The remaining four variants (4/48, 8.4%) were pathogenic copy number variations (CNVs), including the diagnosis of one Alu insertion in BRCA2 (c.156_157insAlu, a Portuguese founder mutation), one case of BRCA1 exons 8-19 deletion, one PALB2 exon 2-3 deletion, and one TP53 partial deletion of exon 5 (possibly mosaic).	('PALB2', 'Gene', '79728', (235, 240))	('TP53', 'Gene', '7157', (268, 272))	('copy number variations', 'Disease', (57, 79))	('c.156_157insA', 'INSERTION', 'None', (143, 156))	('PALB2', 'Gene', (235, 240))	('c.156_157insA', 'Var', (143, 156))	('pathogenic', 'Reg', (46, 56))	('BRCA2', 'Gene', '675', (136, 141))	('TP53', 'Gene', (268, 272))	('BRCA1', 'Gene', '672', (204, 209))	('Alu', 'Chemical', '-', (119, 122))	('BRCA2', 'Gene', (136, 141))	('BRCA1', 'Gene', (204, 209))	('Alu', 'Chemical', '-', (155, 158))
156378	33606809	The partial deletion in TP53, possibly in mosaic, was not confirmed using fibroblast genetic testing due to patient death.	('death', 'Disease', 'MESH:D003643', (116, 121))	('death', 'Disease', (116, 121))	('TP53', 'Gene', (24, 28))	('partial deletion', 'Var', (4, 20))	('patient', 'Species', '9606', (108, 115))	('TP53', 'Gene', '7157', (24, 28))
156381	33606809	High grade tumors were associated with a higher probability of PV detection (p = 0.002).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('PV detection', 'Disease', (63, 75))	('tumors', 'Disease', (11, 17))	('High grade', 'Var', (0, 10))
156383	33606809	Multiple primary tumors were more common among patients with a positive test compared to patients with a negative/VUS test result (26.1% vs. 15.2%, p = 0.042).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('patients', 'Species', '9606', (47, 55))	('positive', 'Var', (63, 71))	('patients', 'Species', '9606', (89, 97))	('common', 'Reg', (34, 40))
156385	33606809	There was a statistical association between PVs and a family history of ovarian cancer only for PVs in the BRCA1 gene (p < 0.001).	('PVs', 'Var', (96, 99))	('BRCA1', 'Gene', '672', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('BRCA1', 'Gene', (107, 112))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('ovarian cancer', 'Disease', (72, 86))
156390	33606809	There is cumulative evidence that variants in BARD1, BRIP1, MSH2, MLH1, MSH6, PMS2, RAD51C, and RAD51D may also be implicated in hereditary BC.	('implicated', 'Reg', (115, 125))	('MSH6', 'Gene', (72, 76))	('MSH6', 'Gene', '2956', (72, 76))	('BARD1', 'Gene', '580', (46, 51))	('BARD1', 'Gene', (46, 51))	('variants', 'Var', (34, 42))	('RAD51C', 'Gene', '5889', (84, 90))	('RAD51D', 'Gene', '5892', (96, 102))	('BRIP1', 'Gene', '83990', (53, 58))	('MSH2', 'Gene', (60, 64))	('PMS2', 'Gene', '5395', (78, 82))	('RAD51C', 'Gene', (84, 90))	('hereditary BC', 'Disease', (129, 142))	('MLH1', 'Gene', (66, 70))	('MSH2', 'Gene', '4436', (60, 64))	('RAD51D', 'Gene', (96, 102))	('BRIP1', 'Gene', (53, 58))	('MLH1', 'Gene', '4292', (66, 70))	('PMS2', 'Gene', (78, 82))
156400	33606809	Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, representing 43.5% of the positive results and 51.2% of the actionable variants.	('BRCA', 'Gene', '672', (69, 73))	('BRCA', 'Gene', (69, 73))	('patients', 'Species', '9606', (20, 28))	('variants', 'Var', (53, 61))
156402	33606809	Although there is a higher frequency of CHEK2 founder mutations (c.1100delC, c.470T>C) in European ancestry populations, these mutations were not observed in our cohort.	('c.1100delC', 'Mutation', 'rs555607708', (65, 75))	('c.1100delC', 'Var', (65, 75))	('c.470T>C', 'Var', (77, 85))	('CHEK2', 'Gene', '11200', (40, 45))	('c.470T>C', 'Mutation', 'rs17879961', (77, 85))	('CHEK2', 'Gene', (40, 45))
156411	33606809	In the present study, 8.7% of the patients with PV (4/46) had pathogenic CNVs detected using multigene panel testing: one Alu insertion in BRCA2 (c.156_157insAlu), one BRCA1 exon 8-19 deletion, one PALB2 exon 2-3 deletion, and one TP53 partial deletion of exon 5.	('BRCA1', 'Gene', '672', (168, 173))	('PALB2', 'Gene', (198, 203))	('PALB2', 'Gene', '79728', (198, 203))	('BRCA2', 'Gene', (139, 144))	('Alu', 'Chemical', '-', (122, 125))	('BRCA1', 'Gene', (168, 173))	('TP53', 'Gene', '7157', (231, 235))	('c.156_157insA', 'INSERTION', 'None', (146, 159))	('BRCA2', 'Gene', '675', (139, 144))	('patients', 'Species', '9606', (34, 42))	('TP53', 'Gene', (231, 235))	('Alu', 'Chemical', '-', (158, 161))	('c.156_157insA', 'Var', (146, 159))
156412	33606809	(2016) observed a 3.4% prevalence of BRCA1/2 CNVs among 145 unrelated Brazilian individuals at risk of HBOC syndrome, which included three cases of Alu insertion in BRCA2 (c.156_157insAlu).	('BRCA1/2', 'Gene', '672;675', (37, 44))	('BRCA2', 'Gene', '675', (165, 170))	('BRCA2', 'Gene', (165, 170))	('Alu', 'Chemical', '-', (148, 151))	('HBOC syndrome', 'Disease', 'MESH:D061325', (103, 116))	('c.156_157insA', 'INSERTION', 'None', (172, 185))	('Alu', 'Chemical', '-', (184, 187))	('c.156_157insA', 'Var', (172, 185))	('HBOC syndrome', 'Disease', (103, 116))	('BRCA1/2', 'Gene', (37, 44))
156416	33606809	Six out of eight patients diagnosed with LFS in this study carried the Brazilian TP53 p.R337H variant, which corresponds to a prevalence of 2.7% (6/224).	('p.R337H', 'Var', (86, 93))	('p.R337H', 'Mutation', 'rs121912664', (86, 93))	('patients', 'Species', '9606', (17, 25))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
156418	33606809	It is well known that LFS has a higher prevalence in Brazil due to the TP53 founder mutation c.1010G>A (p.Arg337His), also known as p.R337H.	('c.1010G>A', 'Mutation', 'rs121912664', (93, 102))	('Brazil', 'Disease', (53, 59))	('c.1010G>A', 'Var', (93, 102))	('p.R337H', 'Var', (132, 139))	('p.R337H', 'Mutation', 'rs121912664', (132, 139))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('p.Arg337His', 'Mutation', 'rs121912664', (104, 115))
156420	33606809	In the Ashkenazi Jewish population, in which BRCA1/2 founder mutations are present in 2.5% of the individuals, cost-effectiveness studies have implied that population testing is justified.	('BRCA1/2', 'Gene', (45, 52))	('BRCA1/2', 'Gene', '672;675', (45, 52))	('mutations', 'Var', (61, 70))
156421	33606809	Patients with cancer predisposition syndromes have a higher risk of developing a second primary BC, especially for BRCA 1/2 mutation carriers.	('cancer', 'Disease', (14, 20))	('BRCA 1/2', 'Gene', (115, 123))	('second primary BC', 'Disease', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('BRCA 1/2', 'Gene', '672;675', (115, 123))	('mutation', 'Var', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
156422	33606809	Nevertheless, 8-36% of patients with bilateral BC harbor PVs in other genes beyond BRCA.	('patients', 'Species', '9606', (23, 31))	('PVs', 'Var', (57, 60))	('BRCA', 'Gene', (83, 87))	('BRCA', 'Gene', '672', (83, 87))
156424	33606809	Genes classified as BC potential increased risk or unknown risk are not expected to change BC screening or management; nevertheless, they may provide information for high-risk assessment or risk reduction surgeries for other cancer sites.	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('Genes', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
156433	33606809	Nine percent of the patients had actionable variants in non-BRCA genes, representing 43.5% of the positive results and 51.2% of the actionable variants.	('patients', 'Species', '9606', (20, 28))	('variants', 'Var', (44, 52))	('BRCA', 'Gene', (60, 64))	('BRCA', 'Gene', '672', (60, 64))
156437	33606809	It is unusual that missense variants make up the majority of pathogenic variants (unless we are considering TP53).	('TP53', 'Gene', (108, 112))	('missense variants', 'Var', (19, 36))	('TP53', 'Gene', '7157', (108, 112))
156449	33606809	The partial deletion in TP53, possibly in mosaic, was not confirmed using fibroblast genetic testing due to patient death."	('death', 'Disease', 'MESH:D003643', (116, 121))	('death', 'Disease', (116, 121))	('TP53', 'Gene', (24, 28))	('partial deletion', 'Var', (4, 20))	('patient', 'Species', '9606', (108, 115))	('TP53', 'Gene', '7157', (24, 28))
156456	33606809	Ductal carcinoma in situ in BRCA mutation carriers.	('mutation', 'Var', (33, 41))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (0, 16))	('BRCA', 'Gene', '672', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('BRCA', 'Gene', (28, 32))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 24))	('Ductal carcinoma', 'Disease', (0, 16))	('carriers', 'Reg', (42, 50))
156457	33606809	Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('BRCA2', 'Gene', (29, 34))	('ductal carcinoma', 'Disease', 'MESH:D044584', (59, 75))	('ductal carcinoma', 'Disease', (59, 75))	('mutations', 'Var', (35, 44))	('BRCA1', 'Gene', '672', (23, 28))	('BRCA2', 'Gene', '675', (29, 34))	('women', 'Species', '9606', (48, 53))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (59, 83))	('BRCA1', 'Gene', (23, 28))
156460	33606809	BRCA1/BRCA2 mutations in Japanese women with ductal carcinoma in situ.	('BRCA2', 'Gene', '675', (6, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('BRCA1', 'Gene', (0, 5))	('mutations', 'Var', (12, 21))	('ductal carcinoma', 'Disease', 'MESH:D044584', (45, 61))	('ductal carcinoma', 'Disease', (45, 61))	('BRCA2', 'Gene', (6, 11))	('women', 'Species', '9606', (34, 39))	('BRCA1', 'Gene', '672', (0, 5))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (45, 69))
156463	33606809	Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy.	('Breast Cancer', 'Disease', 'MESH:D001943', (56, 69))	('Germline Mutations', 'Var', (13, 31))	('DNA Repair Genes', 'Gene', (35, 51))	('PARP', 'Gene', (106, 110))	('Breast Cancer', 'Phenotype', 'HP:0003002', (56, 69))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Breast Cancer', 'Disease', (56, 69))	('PARP', 'Gene', '1302', (106, 110))
156465	33606809	The main reported barriers are related to the lack of structured genetic counseling and genetic testing networks, insufficient number of trained professionals in high risk cancer assessment, absence of genetic testing access in the public health system, limited health insurance coverage, costs of genetic testing and lack of national policies (27,28)" Changes in the text of the revised manuscript: page 13-14 line 209-240, "The detection rate of actionable PVs varies widely depending on the selected studied population and the genetic testing approach (founder mutations, single gene analysis, copy number variation evaluation, multigene panel testing).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('copy number variation evaluation', 'Var', (597, 629))	('single gene analysis', 'Var', (575, 595))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))
156485	33606809	Furthermore, four of these patients (25%, 4/16) harbored pathogenic variants.	('pathogenic', 'Reg', (57, 67))	('patients', 'Species', '9606', (27, 35))	('harbored', 'Reg', (48, 56))	('variants', 'Var', (68, 76))
156486	33606809	Multiple primary cancers was a criteria statistically significantly correlated with pathogenic variant detection.	('variant', 'Var', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('correlated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
156500	33606809	(2020) described a cohort (n=496) with 15% of bilateral BC, 31,6% harbored PVs in non-BRCA genes (CHEK2, TP53, NBN, CDH1, MRE11A).	('CDH1', 'Gene', '999', (116, 120))	('BRCA', 'Gene', '672', (86, 90))	('NBN', 'Gene', '4683', (111, 114))	('NBN', 'Gene', (111, 114))	('PVs', 'Var', (75, 78))	('BRCA', 'Gene', (86, 90))	('MRE11A', 'Gene', (122, 128))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('CHEK2', 'Gene', '11200', (98, 103))	('CHEK2', 'Gene', (98, 103))	('CDH1', 'Gene', (116, 120))	('MRE11A', 'Gene', '4361', (122, 128))
156502	33606809	They analysed a cohort of 139 cases of bilateral BC, 35.8% (19/53) harbored PVs in non-BRCA genes (PTEN, PALB2, CHEK2, ATM, RAD51C).	('PVs', 'Var', (76, 79))	('RAD51C', 'Gene', (124, 130))	('PALB2', 'Gene', (105, 110))	('ATM', 'Gene', (119, 122))	('RAD51C', 'Gene', '5889', (124, 130))	('BRCA', 'Gene', '672', (87, 91))	('PALB2', 'Gene', '79728', (105, 110))	('BRCA', 'Gene', (87, 91))	('CHEK2', 'Gene', '11200', (112, 117))	('ATM', 'Gene', '472', (119, 122))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('CHEK2', 'Gene', (112, 117))	('harbored', 'Reg', (67, 75))
156503	33606809	Changes in the text of the revised manuscript: page 15 line 262-266, "Patients with cancer predisposition syndromes have a higher risk of developing a second primary BC, especially for BRCA 1/2 mutation carriers [45].	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('mutation', 'Var', (194, 202))	('cancer', 'Disease', (84, 90))	('BRCA 1/2', 'Gene', '672;675', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BRCA 1/2', 'Gene', (185, 193))	('Patients', 'Species', '9606', (70, 78))
156504	33606809	Nevertheless, 8 - 36% of patients with bilateral BC harbor PVs in other genes beyond BRCA [32,47,48].	('patients', 'Species', '9606', (25, 33))	('BRCA', 'Gene', (85, 89))	('BRCA', 'Gene', '672', (85, 89))	('PVs', 'Var', (59, 62))
156509	20234365	We have updated and extended our population-based analysis of breast cancer diagnosed at the age <=30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested.	('BRCA2', 'Gene', (194, 199))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1', 'Gene', '672', (187, 192))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('mutation testing', 'Var', (167, 183))	('TP53', 'Gene', '7157', (204, 208))	('BRCA2', 'Gene', '675', (194, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRCA1', 'Gene', (187, 192))	('TP53', 'Gene', (204, 208))
156513	20234365	Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed.	('mutations', 'Var', (41, 50))	('BRCA2', 'Gene', '675', (24, 29))	('TP53', 'Gene', (36, 40))	('BRCA1', 'Gene', (15, 20))	('TP53', 'Gene', '7157', (36, 40))	('BRCA1', 'Gene', '672', (15, 20))	('found', 'Reg', (65, 70))	('BRCA2', 'Gene', (24, 29))
156517	20234365	Mutations in BRCA1, BRCA2 and TP53 account for a proportion of early-onset and familial breast cancer.	('BRCA2', 'Gene', '675', (20, 25))	('BRCA1', 'Gene', '672', (13, 18))	('TP53', 'Gene', (30, 34))	('BRCA1', 'Gene', (13, 18))	('early-onset', 'Disease', (63, 74))	('Mutations', 'Var', (0, 9))	('BRCA2', 'Gene', (20, 25))	('familial breast cancer', 'Disease', 'MESH:D001943', (79, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TP53', 'Gene', '7157', (30, 34))	('familial breast cancer', 'Disease', (79, 101))	('account', 'Reg', (35, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
156518	20234365	These mutations confer a lifetime breast cancer risk of 43-85% (Varley et al, 1997; Ford et al, 1998).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('mutations', 'Var', (6, 15))
156519	20234365	Several studies have investigated the frequency of BRCA1/2 and TP53 mutations in families with breast and/or ovarian cancer or Li-Fraumeni (LFS) or LFS-like (LFL) syndrome (Sidransky et al, 1992; Varley et al, 1997; Gayther et al, 1998; Peto et al, 1999; Loman et al, 2001).	('Li-Fraumeni', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('BRCA1/2', 'Gene', '672;675', (51, 58))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (95, 123))	('LFS-like (LFL) syndrome', 'Disease', 'MESH:D016864', (148, 171))	('breast and/or ovarian cancer', 'Disease', (95, 123))	('mutations', 'Var', (68, 77))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (127, 138))	('BRCA1/2', 'Gene', (51, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
156520	20234365	Among breast cancer cases unselected for family history (FH), the prevalence of BRCA1/2 mutations is dependent on the population studied and on the age at diagnosis of malignancy (Fitzgerald et al, 1996; Krainer et al, 1997; Peto et al, 1999; Loman et al, 2001).	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('malignancy', 'Disease', (168, 178))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('mutations', 'Var', (88, 97))	('BRCA1/2', 'Gene', (80, 87))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('BRCA1/2', 'Gene', '672;675', (80, 87))
156522	20234365	Lalloo et al (2003, 2006) reported on the frequency and penetrance of BRCA1/2 and TP53 mutations in early-onset breast cancer in earlier papers.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('TP53', 'Gene', (82, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('BRCA1/2', 'Gene', '672;675', (70, 77))	('TP53', 'Gene', '7157', (82, 86))	('BRCA1/2', 'Gene', (70, 77))	('mutations', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
156523	20234365	These papers showed a predominance of BRCA1/2 mutations in familial aggregations of breast cancer, with penetrance estimates of breast cancer as high as 80-90% by 70 years of age.	('familial aggregations of breast cancer', 'Disease', 'MESH:D001943', (59, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('mutations', 'Var', (46, 55))	('BRCA1/2', 'Gene', '672;675', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('familial aggregations of breast cancer', 'Disease', (59, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('BRCA1/2', 'Gene', (38, 45))
156524	20234365	This paper presents a detailed analysis of survival, contralateral breast cancer and other tumour incidence in index cases aged <=30 years, both with and without BRCA1/2 or TP53 mutations.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('BRCA1/2', 'Gene', (162, 169))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (53, 80))	('tumour', 'Disease', (91, 97))	('BRCA1/2', 'Gene', '672;675', (162, 169))	('contralateral breast cancer', 'Disease', (53, 80))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
156532	20234365	A further series of 84 patients diagnosed with breast cancer at or under 30 years of age who had tested positive for mutations in BRCA1/2 or TP53 were included for some analyses of contralateral and other tumour risks to enrich the inherited subtypes.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('mutations', 'Var', (117, 126))	('breast cancer', 'Disease', (47, 60))	('tumour', 'Disease', (205, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', '7157', (141, 145))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('TP53', 'Gene', (141, 145))	('BRCA1/2', 'Gene', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA1/2', 'Gene', '672;675', (130, 137))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
156537	20234365	All samples were screened for mutations in BRCA1, BRCA2 and TP53 as described previously (Lalloo et al, 2003).	('BRCA1', 'Gene', (43, 48))	('BRCA2', 'Gene', (50, 55))	('TP53', 'Gene', '7157', (60, 64))	('mutations', 'Var', (30, 39))	('BRCA1', 'Gene', '672', (43, 48))	('BRCA2', 'Gene', '675', (50, 55))	('TP53', 'Gene', (60, 64))
156538	20234365	Since then, further mutation screening of BRCA1 and BRCA2 has been undertaken using direct sequencing and multiple ligation-dependent probe amplification, which is a dosage test to detect large single or multiple exon deletions or duplications.	('BRCA2', 'Gene', (52, 57))	('duplications', 'Var', (231, 243))	('BRCA1', 'Gene', '672', (42, 47))	('BRCA1', 'Gene', (42, 47))	('BRCA2', 'Gene', '675', (52, 57))
156542	20234365	Her-2 was regarded as positive if the tumour showed gene amplification by fluorescent in situ hybridisation (FISH) or, in the absence of FISH, if the immunohistochemical score was 3+ (scale of 0-3).	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('gene', 'Var', (52, 56))	('Her-2', 'Gene', '2064', (0, 5))	('tumour', 'Disease', (38, 44))	('Her-2', 'Gene', (0, 5))
156560	20234365	Overall, pathogenic mutations in BRCA1, BRCA2 and TP53 were identified in 31 women: 26 of 53 (49%) familial and 5 of 62 (8%) non-familial cases (Tables 2, 3 and 4).	('pathogenic', 'Reg', (9, 19))	('women', 'Species', '9606', (77, 82))	('TP53', 'Gene', '7157', (50, 54))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (33, 38))	('TP53', 'Gene', (50, 54))	('BRCA1', 'Gene', (33, 38))	('mutations', 'Var', (20, 29))	('BRCA2', 'Gene', '675', (40, 45))
156561	20234365	Three patients with BRCA1/2 mutations were sporadic at the time of diagnosis and one patient had only a paternal grandmother with breast cancer aged 65 years.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('patient', 'Species', '9606', (85, 92))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('patient', 'Species', '9606', (6, 13))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('patients', 'Species', '9606', (6, 14))	('BRCA1/2', 'Gene', (20, 27))	('mutations', 'Var', (28, 37))
156563	20234365	Pathogenic BRCA1 mutations were identified in 16 women (14%) diagnosed with breast cancer at <=30 years of age.	('women', 'Species', '9606', (49, 54))	('BRCA1', 'Gene', '672', (11, 16))	('Pathogenic', 'Reg', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA1', 'Gene', (11, 16))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('mutations', 'Var', (17, 26))
156564	20234365	BRCA2 mutations were detected in nine women (8%).	('BRCA2', 'Gene', '675', (0, 5))	('women', 'Species', '9606', (38, 43))	('BRCA2', 'Gene', (0, 5))	('detected', 'Reg', (21, 29))	('mutations', 'Var', (6, 15))
156565	20234365	Pathogenic TP53 mutations were found in 5 patients (5%) including 3 of 6 (50%) of the LFS/LFL subgroup.	('TP53', 'Gene', '7157', (11, 15))	('Pathogenic', 'Reg', (0, 10))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('patients', 'Species', '9606', (42, 50))	('found', 'Reg', (31, 36))	('LFS/LFL', 'Disease', (86, 93))
156566	20234365	The updated analysis demonstrated an additional TP53 mutation: 659A>G in a family fulfilling LFS criteria, four further BRCA1 mutations (2682C>T, del exons 1-17, del exons 5-17, 1953DupG) in four familial breast cancers and 1 BRCA2 mutation (1058C>A) out of the 15 additional samples obtained since our last report (Lalloo et al, 2006).	('1058C>A', 'Mutation', 'rs769368098', (242, 249))	('2682C>T', 'Var', (137, 144))	('BRCA2', 'Gene', '675', (226, 231))	('TP53', 'Gene', '7157', (48, 52))	('BRCA1', 'Gene', (120, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('659A>G', 'Mutation', 'rs121912666', (63, 69))	('2682C>T', 'Mutation', 'c.2682C>T', (137, 144))	('TP53', 'Gene', (48, 52))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('familial breast cancers', 'Disease', 'MESH:D001943', (196, 219))	('1058C>A', 'Var', (242, 249))	('BRCA2', 'Gene', (226, 231))	('del exons 5-17', 'Var', (162, 176))	('familial breast cancers', 'Disease', (196, 219))	('BRCA1', 'Gene', '672', (120, 125))	('breast cancers', 'Phenotype', 'HP:0003002', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
156568	20234365	Only in grade 3 triple-negative breast cancer does the rate of BRCA1 mutation among sporadic cases increase above 10% (2 of 16).	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('BRCA1', 'Gene', (63, 68))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('BRCA1', 'Gene', '672', (63, 68))
156569	20234365	An additional 30 patients with BRCA1 mutations diagnosed at <=30 years of age after 31 December 1979 and 19 with BRCA2 mutations with the same criteria were identified from our clinic mutation database.	('BRCA1', 'Gene', '672', (31, 36))	('mutations', 'Var', (37, 46))	('BRCA2', 'Gene', (113, 118))	('BRCA1', 'Gene', (31, 36))	('patients', 'Species', '9606', (17, 25))	('BRCA2', 'Gene', '675', (113, 118))
156571	20234365	In all, 13 of the total 84 mutation carriers (46 BRCA1, 27 BRCA2, 11 TP53) have had risk-reducing contralateral mastectomy (RRM) representing 20% of the total.	('BRCA2', 'Gene', '675', (59, 64))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('BRCA1', 'Gene', '672', (49, 54))	('mutation', 'Var', (27, 35))	('BRCA1', 'Gene', (49, 54))	('BRCA2', 'Gene', (59, 64))	('contralateral mastectomy', 'Disease', (98, 122))
156574	20234365	Of these cases, two had comedo DCIS and were shown to have a TP53 mutation.	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('comedo', 'Phenotype', 'HP:0025249', (24, 30))	('mutation', 'Var', (66, 74))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('comedo DCIS', 'Disease', (24, 35))
156583	20234365	Surprisingly, no ovarian cancer has so far occurred even among BRCA1/2 carriers, given the fact that the age of these women now without oophorectomy is 38-55 years.	('women', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('BRCA1/2', 'Gene', '672;675', (63, 70))	('carriers', 'Var', (71, 79))	('ovarian cancer', 'Disease', (17, 31))	('BRCA1/2', 'Gene', (63, 70))
156584	20234365	Indeed, in 620.5 years of follow-up in the enhanced data set of 72 women with BRCA1/2 mutations (censored at date of oophorectomy in 13 women), no ovarian cancers have occurred.	('mutations', 'Var', (86, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('women', 'Species', '9606', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancers', 'Phenotype', 'HP:0100615', (147, 162))	('ovarian cancers', 'Disease', (147, 162))	('women', 'Species', '9606', (136, 141))	('BRCA1/2', 'Gene', (78, 85))	('ovarian cancers', 'Disease', 'MESH:D010051', (147, 162))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('BRCA1/2', 'Gene', '672;675', (78, 85))
156589	20234365	In 11 families with a predicted BRCA1/2 mutation status >90% (10.47 predicted), only 6 BRCA1/2 mutations were found (1 in BRCA2).	('mutation', 'Var', (40, 48))	('BRCA1/2', 'Gene', (87, 94))	('BRCA1/2', 'Gene', (32, 39))	('BRCA1/2', 'Gene', '672;675', (87, 94))	('BRCA2', 'Gene', (122, 127))	('BRCA1/2', 'Gene', '672;675', (32, 39))	('BRCA2', 'Gene', '675', (122, 127))
156596	20234365	We have previously published the prevalence of both BRCA1/2 and TP53 mutations in this cohort (Lalloo et al, 2003), demonstrating a higher prevalence of TP53 mutations than previously expected.	('mutations', 'Var', (69, 78))	('BRCA1/2', 'Gene', (52, 59))	('TP53', 'Gene', (153, 157))	('TP53', 'Gene', '7157', (153, 157))	('BRCA1/2', 'Gene', '672;675', (52, 59))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('mutations', 'Var', (158, 167))
156597	20234365	The mutation detection rate in familial breast cancer in these three genes is ~50% (26 of 53), demonstrating the importance of accurately documenting a FH when estimating the likelihood of a mutation carrier.	('familial breast cancer', 'Disease', 'MESH:D001943', (31, 53))	('familial breast cancer', 'Disease', (31, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
156601	20234365	Lakhani et al (2005) reported data on the likelihood of breast cancer being caused by a BRCA1 mutation by pathological grade and ER status at various ages in women not selected by FH.	('BRCA1', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('women', 'Species', '9606', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('BRCA1', 'Gene', '672', (88, 93))	('breast cancer', 'Disease', (56, 69))	('mutation', 'Var', (94, 102))	('caused by', 'Reg', (76, 85))
156602	20234365	Women aged between 20 and 29 years with grade 3 ER-negative breast cancers had a 35% chance of a BRCA1 mutation, with a similarly high risk for women aged 30-34 years at 26.5%.	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('breast cancers', 'Disease', (60, 74))	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', '672', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('women', 'Species', '9606', (144, 149))	('BRCA1', 'Gene', (97, 102))	('mutation', 'Var', (103, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
156608	20234365	For instance, a recent North American study demonstrated mutations in 9% of triple-negative breast cancer patients aged <40 years without, or with minimal, FH of breast or ovarian cancer (Young et al, 2009).	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ovarian cancer', 'Phenotype', 'HP:0100615', (172, 186))	('FH of breast or ovarian cancer', 'Disease', (156, 186))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (106, 114))	('FH of breast or ovarian cancer', 'Disease', 'MESH:D010051', (156, 186))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
156613	20234365	The diagnosis of a second primary tumour should prompt the clinician to consider a TP53 mutation.	('TP53', 'Gene', '7157', (83, 87))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', (83, 87))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
156614	20234365	One patient with a renal carcinoma and a de novo TP53 mutation went on to develop a sarcoma behind the remaining kidney that was subjected to regular screening radiation from intravenous urograms.	('mutation', 'Var', (54, 62))	('renal carcinoma', 'Disease', 'MESH:C538614', (19, 34))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('renal carcinoma', 'Disease', (19, 34))	('sarcoma', 'Disease', 'MESH:D012509', (84, 91))	('patient', 'Species', '9606', (4, 11))	('sarcoma', 'Disease', (84, 91))	('renal carcinoma', 'Phenotype', 'HP:0005584', (19, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('develop', 'PosReg', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
156616	20234365	However, surprisingly, no ovarian cancers occurred in BRCA1/2 carriers, even though 21 women have lived beyond 40 years of age without an oophorectomy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ovarian cancers', 'Phenotype', 'HP:0100615', (26, 41))	('ovarian cancers', 'Disease', (26, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('ovarian cancers', 'Disease', 'MESH:D010051', (26, 41))	('BRCA1/2', 'Gene', (54, 61))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('women', 'Species', '9606', (87, 92))	('BRCA1/2', 'Gene', '672;675', (54, 61))	('carriers', 'Var', (62, 70))
156618	20234365	This is most likely to suggest a high probability of a BRCA1/2 mutation rather than another mechanism increasing ovarian cancer risk.	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('BRCA1/2', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutation', 'Var', (63, 71))	('BRCA1/2', 'Gene', '672;675', (55, 62))	('ovarian cancer', 'Disease', (113, 127))
156619	20234365	The data from our study do not suggest a higher ovarian cancer risk in women with known mutations with early-onset breast cancer, compared with mutation carriers with later-onset disease.	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('mutations', 'Var', (88, 97))	('women', 'Species', '9606', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('ovarian cancer', 'Disease', (48, 62))
156622	20234365	As no non-Jewish sporadic case (even the adopted individuals) reached the 10% combined threshold even at the time of diagnosis, this supports the hypothesis that, in Western populations, the rates of BRCA1/2 mutations even in early-onset breast cancer cases without a FH are low.	('mutations', 'Var', (208, 217))	('BRCA1/2', 'Gene', (200, 207))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('BRCA1/2', 'Gene', '672;675', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', (238, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
156627	20234365	Ductal carcinoma in situ at the age of <=30 years is clearly an important diagnosis, as 45% of the 11 cases had a pathogenic mutation, with DCIS being a particular marker for a TP53 mutation.	('Ductal carcinoma', 'Disease', 'MESH:D044584', (0, 16))	('pathogenic', 'Reg', (114, 124))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (7, 24))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('TP53', 'Gene', '7157', (177, 181))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (0, 24))	('Ductal carcinoma', 'Disease', (0, 16))	('TP53', 'Gene', (177, 181))	('mutation', 'Var', (125, 133))
156631	20234365	We have estimated that a combined score of 40+ using the Manchester score suggests a very high probability of a BRCA1/2 mutation (Evans et al, 2009).	('mutation', 'Var', (120, 128))	('BRCA1/2', 'Gene', (112, 119))	('BRCA1/2', 'Gene', '672;675', (112, 119))
156636	20234365	There are high rates of BRCA1, BRCA2 and TP53 mutations in women aged <=30 years with a FH.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('BRCA2', 'Gene', (31, 36))	('BRCA1', 'Gene', '672', (24, 29))	('mutations', 'Var', (46, 55))	('BRCA1', 'Gene', (24, 29))	('BRCA2', 'Gene', '675', (31, 36))	('women', 'Species', '9606', (59, 64))
156637	20234365	Among sporadic patients, mutations are generally in those with grade 3 triple-negative tumours.	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (25, 34))	('tumours', 'Disease', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))
156646	27590331	By univariate analysis, the following features were significantly associated with involved margins: age < 60 years, multifocality, lobular subtype, tumor size >2 cm, intermediate- and high-grade, positive ER status, positive Her2 status, angio-invasion, and the presence/extent of a ductal carcinoma in situ (DCIS) component.	('multifocality', 'Var', (116, 129))	('Her2', 'Gene', (225, 229))	('positive ER status', 'Var', (196, 214))	('ductal carcinoma in situ', 'Disease', (283, 307))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (283, 307))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('associated', 'Reg', (66, 76))	('intermediate-', 'Var', (166, 179))	('Her2', 'Gene', '2064', (225, 229))	('DCIS', 'Phenotype', 'HP:0030075', (309, 313))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (283, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('angio-invasion', 'CPA', (238, 252))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
156680	27590331	Briefly, the following variables were associated with increased risk of more than focally positive resection margins in univariate analysis: age <60 years, multifocality, lobular subtype, large tumor size (>2 cm), intermediate- and high-grade, positive ER status, positive Her2 status, angio-invasion, and the presence/extent of a DCIS component.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Her2', 'Gene', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('angio-invasion', 'CPA', (286, 300))	('positive', 'Var', (244, 252))	('Her2', 'Gene', '2064', (273, 277))	('tumor', 'Disease', (194, 199))	('high-grade', 'CPA', (232, 242))	('DCIS', 'Phenotype', 'HP:0030075', (331, 335))	('ER status', 'CPA', (253, 262))
156682	27590331	In multivariate analyses, the following variables were significantly associated with focally or more than focally involved margins: age <50 years, multifocality, lobular subtype, size >2 cm, grade 2, positive ER status, positive Her2 status, angio-invasion, and the presence of a DCIS component.	('Her2', 'Gene', (229, 233))	('grade 2', 'Var', (191, 198))	('Her2', 'Gene', '2064', (229, 233))	('DCIS', 'Phenotype', 'HP:0030075', (280, 284))	('angio-invasion', 'CPA', (242, 256))	('positive', 'Var', (200, 208))
156750	26496323	Previous literatures revealed a 4- to 5-fold increased risk of cancer development with ADH,  and a reported cancer rate of approximately 3% in FEA.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ADH', 'Var', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
156774	20356418	Tumor development is usually associated to alterations in cellsurface carbohydrates.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor development', 'CPA', (0, 17))	('alterations', 'Var', (43, 54))	('associated', 'Reg', (29, 39))	('cellsurface carbohydrates', 'Protein', (58, 83))	('carbohydrates', 'Chemical', 'MESH:D002241', (70, 83))
156779	20356418	Alterations in the glycosylation of carcinoma-associated mucins may modulate the biological behavior of carcinoma cells and allow the cells to disseminate, invade and survive at distant organ sites.	('mucin', 'Gene', (57, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('glycosylation', 'MPA', (19, 32))	('Alterations', 'Var', (0, 11))	('carcinoma', 'Disease', (104, 113))	('carcinoma', 'Disease', 'MESH:D002277', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('modulate', 'Reg', (68, 76))	('mucin', 'Gene', '100508689', (57, 62))	('biological behavior', 'CPA', (81, 100))	('allow', 'Reg', (124, 129))	('invade', 'CPA', (156, 162))	('carcinoma', 'Disease', 'MESH:D002277', (104, 113))	('carcinoma', 'Disease', (36, 45))
156852	20356418	Alterations in mucin-type O-glycans has been associated with malignant transformation, resulting in the formation of less complex structures and leading to an increase of the simple short determinants.	('O-glycans', 'Chemical', '-', (26, 35))	('simple short determinants', 'MPA', (175, 200))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (45, 55))	('formation', 'MPA', (104, 113))	('mucin', 'Gene', '100508689', (15, 20))	('less complex structures', 'MPA', (117, 140))	('malignant transformation', 'CPA', (61, 85))	('mucin', 'Gene', (15, 20))	('increase', 'PosReg', (159, 167))
156882	20356418	Therefore, O-glycosylation may competitively inhibit the Ser/Thr phosphorylation.	('Ser/Thr phosphorylation', 'MPA', (57, 80))	('Thr', 'Chemical', 'MESH:D013912', (61, 64))	('O-glycosylation', 'Var', (11, 26))	('inhibit', 'NegReg', (45, 52))	('Ser', 'Chemical', 'MESH:D012694', (57, 60))
156883	20356418	Abnormal expression of GalNAc-T14 may result in initiation of O-linked glycosylation at normally unoccupied potential phosphorylation sites leading to altered proteins with changed biological activity which may contribute to the pathogenesis of cancer.	('altered', 'Reg', (151, 158))	('proteins', 'MPA', (159, 167))	('contribute', 'Reg', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('changed', 'Reg', (173, 180))	('cancer', 'Disease', (245, 251))	('GalNAc-T14', 'Gene', (23, 33))	('O-linked glycosylation at', 'MPA', (62, 87))	('result in', 'Reg', (38, 47))	('Abnormal', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('GalNAc-T14', 'Gene', '79623', (23, 33))
156888	20356418	Considering that abnormal O-glycosylation greatly contributes to the phenotype and biology of breast cancer cells, our results contribute to understanding the molecular mechanisms that underlie aberrant glycosylation in breast carcinogenesis and in breast carcinoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (249, 265))	('breast carcinogenesis', 'Disease', (220, 241))	('breast carcinoma', 'Phenotype', 'HP:0003002', (249, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (220, 241))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (194, 216))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('aberrant', 'Var', (194, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('breast carcinoma', 'Disease', (249, 265))
156898	27087654	Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors.	('Women', 'Species', '9606', (0, 5))	('better', 'PosReg', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('overall', 'CPA', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('lumpectomy', 'Var', (20, 30))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('tumors', 'Disease', (225, 231))
156900	27087654	Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumor-growth.	('expression', 'MPA', (91, 101))	('amplification', 'Var', (50, 63))	('ESR1', 'Gene', '2099', (40, 44))	('tumor', 'Disease', (221, 226))	('ER-alpha', 'Gene', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('ESR1', 'Gene', (40, 44))	('ER-alpha', 'Gene', '2099', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
156944	27087654	Low estrogen level mean a high risk for breast cancer development, while a counteractive overexpression of ERs may strengthen estrogen signaling and reduce the risk of malignancies.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('estrogen signaling', 'MPA', (126, 144))	('malignancies', 'Disease', (168, 180))	('strengthen', 'PosReg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('reduce', 'NegReg', (149, 155))	('Low', 'Var', (0, 3))
156947	27087654	In cases with serious mutations in human gene (CYP19) encoding aromatase P450, deficient conversion of androgens to estrogen leads to estrogen deficiency.	('estrogen deficiency', 'MPA', (134, 153))	('CYP19', 'Gene', '1588', (47, 52))	('aromatase', 'Gene', '1588', (63, 72))	('conversion of androgens to estrogen', 'MPA', (89, 124))	('CYP19', 'Gene', (47, 52))	('deficient', 'NegReg', (79, 88))	('human', 'Species', '9606', (35, 40))	('deficient conversion of androgens to estrogen', 'Phenotype', 'HP:0008226', (79, 124))	('leads to', 'Reg', (125, 133))	('mutations', 'Var', (22, 31))	('estrogen deficiency', 'Phenotype', 'HP:0008226', (134, 153))	('aromatase', 'Gene', (63, 72))
156949	27087654	Estrogen deficiency hampers all phases of glucose metabolism from insulin synthesis to intracellular glucose uptake leading to insulin resistance.	('Estrogen', 'Protein', (0, 8))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('phases of glucose metabolism', 'MPA', (32, 60))	('insulin', 'Gene', (127, 134))	('leading to', 'Reg', (116, 126))	('insulin', 'Gene', (66, 73))	('deficiency', 'Var', (9, 19))	('insulin', 'Gene', '3630', (127, 134))	('insulin resistance', 'Phenotype', 'HP:0000855', (127, 145))	('insulin', 'Gene', '3630', (66, 73))	('hampers', 'NegReg', (20, 27))	('Estrogen deficiency', 'Phenotype', 'HP:0008226', (0, 19))	('intracellular glucose uptake', 'MPA', (87, 115))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))
156950	27087654	Moreover, a defective estrogen signaling inadequately interacts with the DNA-stabilizer systems and the defect of DNA-surveillance increases the risk of malignancies developing at different sites.	('defect', 'Var', (104, 110))	('estrogen signaling', 'MPA', (22, 40))	('malignancies', 'Disease', (153, 165))	('increases', 'PosReg', (131, 140))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('defective', 'Var', (12, 21))
156956	27087654	Diverse naturally occurring mutagenic variants of both ER-alpha and ER-beta have been identified, however, only a few point mutations proved to be pathogenic in human tissue samples, including breast cancers.	('human', 'Species', '9606', (161, 166))	('ER-alpha', 'Gene', '2099', (55, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('variants', 'Var', (38, 46))	('ER-beta', 'Gene', '2100', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('ER-beta', 'Gene', (68, 75))	('breast cancers', 'Phenotype', 'HP:0003002', (193, 207))	('ER-alpha', 'Gene', (55, 63))	('breast cancers', 'Disease', 'MESH:D001943', (193, 207))	('breast cancers', 'Disease', (193, 207))
156957	27087654	In postmenopausal women, the dramatically decreasing serum estrogen levels may manifest the earlier hidden point mutations of ER-regulator genes and the defective estrogen signaling increase the risk of breast cancer development.	('increase', 'PosReg', (182, 190))	('ER-regulator genes', 'Gene', (126, 144))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('women', 'Species', '9606', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('mutations', 'Var', (113, 122))	('decreasing serum estrogen levels', 'Phenotype', 'HP:0008214', (42, 74))	('decreasing', 'NegReg', (42, 52))	('serum estrogen levels', 'MPA', (53, 74))	('estrogen signaling', 'MPA', (163, 181))	('defective', 'NegReg', (153, 162))
156958	27087654	Loss or mutation of BRCA1/2 genes results in a defect, inhibiting the expression and liganded transcriptional activity of ERs, while upregulating aromatase mediated estrogen synthesis.	('liganded transcriptional activity', 'MPA', (85, 118))	('aromatase', 'Gene', (146, 155))	('ERs', 'MPA', (122, 125))	('aromatase', 'Gene', '1588', (146, 155))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('Loss', 'NegReg', (0, 4))	('expression', 'MPA', (70, 80))	('inhibiting', 'NegReg', (55, 65))	('mutation', 'Var', (8, 16))	('BRCA1/2', 'Gene', (20, 27))	('upregulating', 'PosReg', (133, 145))
156959	27087654	BRCA mutation carriers frequently exhibit clinical symptoms of defective estrogen signaling, while the serum estrogen levels in such cases are compensatory increased.	('serum estrogen levels', 'MPA', (103, 124))	('BRCA', 'Gene', (0, 4))	('increased', 'PosReg', (156, 165))	('defective', 'NegReg', (63, 72))	('estrogen signaling', 'MPA', (73, 91))	('mutation', 'Var', (5, 13))	('BRCA', 'Gene', '672', (0, 4))
156960	27087654	Stronger estrogen synthesis is usually effective in stimulating refractory ERs and may decrease breast cancer risk in cases with BRCA mutations.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('decrease', 'NegReg', (87, 95))	('mutations', 'Var', (134, 143))	('stimulating', 'PosReg', (52, 63))	('BRCA', 'Gene', '672', (129, 133))	('BRCA', 'Gene', (129, 133))
156961	27087654	Severe resistance of ER-alpha, attributed to the crude mutation of ESR1 gene, provokes sky-high compensatory estrogen levels, while clinical symptoms suggest estrogen deficiency.	('provokes', 'Reg', (78, 86))	('compensatory estrogen levels', 'MPA', (96, 124))	('ER-alpha', 'Gene', (21, 29))	('ESR1', 'Gene', '2099', (67, 71))	('estrogen', 'MPA', (158, 166))	('mutation', 'Var', (55, 63))	('ER-alpha', 'Gene', '2099', (21, 29))	('ESR1', 'Gene', (67, 71))	('estrogen deficiency', 'Phenotype', 'HP:0008226', (158, 177))
156962	27087654	In a young male patient with serious ESR1 gene mutation, ER-alpha resistance was associated with insulin resistance, obesity and premature cardiovascular lesions despite the extremely high serum estrogen levels.	('insulin resistance', 'Phenotype', 'HP:0000855', (97, 115))	('insulin', 'Gene', '3630', (97, 104))	('ER-alpha', 'Gene', (57, 65))	('ESR1', 'Gene', '2099', (37, 41))	('mutation', 'Var', (47, 55))	('obesity', 'Phenotype', 'HP:0001513', (117, 124))	('premature cardiovascular lesions', 'Disease', 'MESH:D002318', (129, 161))	('ER-alpha', 'Gene', '2099', (57, 65))	('insulin', 'Gene', (97, 104))	('obesity', 'Disease', (117, 124))	('ESR1', 'Gene', (37, 41))	('obesity', 'Disease', 'MESH:D009765', (117, 124))	('premature cardiovascular lesions', 'Phenotype', 'HP:0001626', (129, 161))	('associated', 'Reg', (81, 91))	('patient', 'Species', '9606', (16, 23))	('high serum estrogen levels', 'Phenotype', 'HP:0025134', (184, 210))	('premature cardiovascular lesions', 'Disease', (129, 161))
156963	27087654	In an ESR1 gene mutation carrier young girl, delayed puberty was observed with the misleading symptoms of estrogen deficiency, whilst exhibiting extremely high compensatory estrogen levels.	('delayed puberty', 'Phenotype', 'HP:0000823', (45, 60))	('estrogen deficiency', 'Phenotype', 'HP:0008226', (106, 125))	('mutation', 'Var', (16, 24))	('ESR1', 'Gene', (6, 10))	('estrogen deficiency', 'Disease', (106, 125))	('girl', 'Species', '9606', (39, 43))	('ESR1', 'Gene', '2099', (6, 10))
156967	27087654	In breast cancer cases, of all tumor markers, ER-negativity is the strongest predictor of poor prognosis and fatal outcome of the disease.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', (31, 36))	('breast cancer', 'Disease', (3, 16))	('ER-negativity', 'Var', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
156968	27087654	In women, the stronger the defect of estrogen signaling, the higher is the risk of poorly differentiated, ER-negative breast cancer development, irrespective of serum estrogen concentrations.	('poorly', 'Disease', (83, 89))	('estrogen signaling', 'MPA', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('higher', 'Reg', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('women', 'Species', '9606', (3, 8))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('defect', 'Var', (27, 33))
156969	27087654	In women, anovulatory infertility and nulliparity are associated with increased risk for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('nulliparity', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('infertility', 'Disease', 'MESH:D007247', (22, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('infertility', 'Phenotype', 'HP:0000789', (22, 33))	('women', 'Species', '9606', (3, 8))	('infertility', 'Disease', (22, 33))
156972	27087654	It can be concluded that benign breast lesions with high ER-alpha expressions are indicators of defective estrogen-signaling and breast cancer risk.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('ER-alpha', 'Gene', (57, 65))	('defective', 'NegReg', (96, 105))	('high', 'Var', (52, 56))	('ER-alpha', 'Gene', '2099', (57, 65))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('estrogen-signaling', 'Pathway', (106, 124))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
156985	27087654	In young premenopausal cases with breast cancer, clinical control and the examination of removed tumor samples revealed that the absence of CYP19-aromatase activity carried a significantly high risk for local tumor recurrence and poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (209, 214))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('CYP19-aromatase', 'Disease', 'MESH:C537436', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('absence', 'Var', (129, 136))	('CYP19-aromatase', 'Disease', (140, 155))	('activity', 'MPA', (156, 164))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('local tumor', 'Disease', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('local tumor', 'Disease', 'MESH:D009364', (203, 214))
156993	27087654	The crucial significance of estrogen signaling underlines the fact that any attack against the transcriptional activity of ERs results in an emergency situation, since it endangers the life of patients and requires intense counteractions.	('patients', 'Species', '9606', (193, 201))	('life', 'CPA', (185, 189))	('endangers', 'NegReg', (171, 180))	('ERs', 'Gene', (123, 126))	('attack against', 'Var', (76, 90))	('transcriptional activity', 'MPA', (95, 119))
157014	27087654	Although, antiestrogen therapy targets the inhibition of ER transcriptional activity, endocrine therapy resistance seems to be in close correlation with defective ER function and/or mutagenic ESR1-gene alterations.	('ER transcriptional activity', 'MPA', (57, 84))	('ESR1', 'Gene', (192, 196))	('mutagenic', 'Var', (182, 191))	('ESR1', 'Gene', '2099', (192, 196))	('defective', 'Var', (153, 162))	('ER function', 'MPA', (163, 174))	('alterations', 'Var', (202, 213))
157024	27087654	Preserved phosphorylation capacity at S167, S118, and S282 sites is beneficial for tamoxifen-induced tumor regression according to reported experimental and clinical data.	('S167', 'Var', (38, 42))	('phosphorylation capacity', 'MPA', (10, 34))	('S282', 'Var', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tamoxifen', 'Chemical', 'MESH:D013629', (83, 92))	('S118', 'Var', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
157025	27087654	By contrast, tamoxifen resistance associated tumor growth is likely to occur when S104/S106 or S305 is preferentially phosphorylated.	('preferentially', 'PosReg', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (13, 22))	('S305', 'Var', (95, 99))	('S104/S106', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
157027	27087654	Since Ser167 phosphorylation is the most important element of the physiologic transcriptional activity of ERs, this result justified that compensatory maintenance of appropriate ER signaling defines longer disease-free and overall survival even among antiestrogen-treated breast cancer patients.	('overall survival', 'CPA', (223, 239))	('longer disease-free', 'Disease', (199, 218))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('longer disease-free', 'Disease', 'MESH:D015673', (199, 218))	('Ser167', 'Chemical', '-', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancer', 'Disease', (272, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('Ser167', 'Var', (6, 12))	('patients', 'Species', '9606', (286, 294))
157028	27087654	ESR1-gene mutations affecting the ligand-binding domain of ER alpha were presumed as crucial mechanisms in the acquired antiestrogen resistance of metastatic breast cancers.	('ESR1', 'Gene', (0, 4))	('mechanisms', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancers', 'Disease', 'MESH:D001943', (158, 172))	('breast cancers', 'Disease', (158, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('ER alpha', 'Gene', '2099', (59, 67))	('ER alpha', 'Gene', (59, 67))	('ESR1', 'Gene', '2099', (0, 4))	('metastatic', 'Disease', (147, 157))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('mutations', 'Var', (10, 19))	('breast cancers', 'Phenotype', 'HP:0003002', (158, 172))
157029	27087654	Point mutations of ESR1 gene are relatively frequent and result in slightly variant forms of ERs.	('ESR1', 'Gene', '2099', (19, 23))	('result in', 'Reg', (57, 66))	('ESR1', 'Gene', (19, 23))	('ERs', 'Disease', (93, 96))	('Point mutations', 'Var', (0, 15))
157031	27087654	There may be a strong parallelism between postmenopausal estrogen loss and the antiestrogenic inhibition of estrogen signaling, resulting in manifested defects of estrogen surveillance in ESR1-gene mutation carriers.	('ESR1', 'Gene', (188, 192))	('defects', 'NegReg', (152, 159))	('ESR1', 'Gene', '2099', (188, 192))	('estrogen surveillance', 'MPA', (163, 184))	('estrogen loss', 'Phenotype', 'HP:0008226', (57, 70))	('mutation', 'Var', (198, 206))
157033	27087654	ESR1 amplification was frequently found in proliferative breast diseases and seems to be a characteristic finding in highly ER-positive breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('ESR1', 'Gene', (0, 4))	('breast cancers', 'Disease', (136, 150))	('amplification', 'Var', (5, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('ESR1', 'Gene', '2099', (0, 4))	('found', 'Reg', (34, 39))	('breast diseases', 'Disease', 'MESH:D001941', (57, 72))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('breast diseases', 'Disease', (57, 72))
157034	27087654	In breast cancer cases who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancers exhibiting ESR1 amplification than for women with cancers without ESR1 amplification.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ESR1', 'Gene', '2099', (195, 199))	('ESR1', 'Gene', '2099', (140, 144))	('women', 'Species', '9606', (168, 173))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tamoxifen', 'Chemical', 'MESH:D013629', (49, 58))	('longer', 'PosReg', (99, 105))	('cancers', 'Disease', (121, 128))	('ESR1', 'Gene', (195, 199))	('ESR1', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('women', 'Species', '9606', (110, 115))	('amplification', 'Var', (145, 158))	('survival', 'MPA', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
157043	27087654	Special MUC1 peptides have been shown to inhibit growth and promote death of MUC1-expressing tumor cells.	('promote', 'PosReg', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('peptides', 'Var', (13, 21))	('MUC1', 'Gene', (8, 12))	('death', 'Disease', (68, 73))	('growth', 'CPA', (49, 55))	('tumor', 'Disease', (93, 98))	('death', 'Disease', 'MESH:D003643', (68, 73))	('MUC1', 'Gene', (77, 81))	('MUC1', 'Gene', '4582', (77, 81))	('MUC1', 'Gene', '4582', (8, 12))	('inhibit', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
157047	27087654	A recent disclosure provides methods for assaying the mutations of ESR1 gene at different domains and for the analysis of mutation associated ER protein variants influencing the effectiveness of treatment course.	('ER protein', 'Protein', (142, 152))	('ESR1', 'Gene', (67, 71))	('variants', 'Var', (153, 161))	('ESR1', 'Gene', '2099', (67, 71))
157048	27087654	Breast cancers with acquired ESR1 gene mutations maintained sensitivity to antiestrogen therapy, particularly in tumors developing resistance to aromatase inhibitors associated with ESR1 amplification reactions.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('aromatase', 'Gene', (145, 154))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('aromatase', 'Gene', '1588', (145, 154))	('ESR1', 'Gene', (182, 186))	('ESR1', 'Gene', '2099', (29, 33))	('mutations', 'Var', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('sensitivity to antiestrogen therapy', 'MPA', (60, 95))	('Breast cancers', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('ESR1', 'Gene', (29, 33))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('ESR1', 'Gene', '2099', (182, 186))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
157049	27087654	This finding justifies that acquired ESR1 gene mutations may further enhance ER expression and maintain its apoptotic activity when ESR1 amplification is no longer enough for the restoration of ER signaling.	('ER expression', 'MPA', (77, 90))	('apoptotic activity', 'CPA', (108, 126))	('ESR1', 'Gene', '2099', (37, 41))	('ESR1', 'Gene', (132, 136))	('enhance', 'PosReg', (69, 76))	('mutations', 'Var', (47, 56))	('ESR1', 'Gene', (37, 41))	('ESR1', 'Gene', '2099', (132, 136))
157050	27087654	A proposed in vitro method for detection of ESR1 gene amplification in breast cancers is capable of identifying candidate patients with a proliferative benign or malignant breast disease as suitable for antiestrogen treatment.	('breast cancers', 'Disease', 'MESH:D001943', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('amplification', 'Var', (54, 67))	('ESR1', 'Gene', '2099', (44, 48))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('patients', 'Species', '9606', (122, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('malignant breast disease', 'Disease', (162, 186))	('malignant breast disease', 'Disease', 'MESH:D001943', (162, 186))	('breast cancers', 'Disease', (71, 85))	('ESR1', 'Gene', (44, 48))
157076	27087654	Breast cancer recurrences were registered separately in low- or intermediate-grade DCIS cases (group 1); and in high-grade DCIS cases (group 2).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('low-', 'Var', (56, 60))	('Breast cancer', 'Disease', (0, 13))
157080	27087654	These results strongly suggest that ageing related increase in the defect of estrogen signaling may be directly associated with recurrent breast cancer development, in spite of the surgical removal of tumors.	('increase', 'PosReg', (51, 59))	('estrogen signaling', 'MPA', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('defect', 'Var', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('associated', 'Reg', (112, 122))
157088	27087654	In young patients, the incidence of high risk, ER-negative DCIS indicates the strong disturbances of the hormonal balance requiring increased exogenous estrogen substitution so as to strengthen the DNA-stabilizer mechanisms.	('DCIS', 'Disease', (59, 63))	('patients', 'Species', '9606', (9, 17))	('disturbances', 'MPA', (85, 97))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('strengthen', 'PosReg', (183, 193))	('DNA-stabilizer mechanisms', 'MPA', (198, 223))	('hormonal balance', 'MPA', (105, 121))	('ER-negative', 'Var', (47, 58))
157093	27087654	Natural light deficiency is associated with melatonin excess and further deleterious metabolic and hormonal alterations; such as deficiencies of estrogen, thyroxin and vitamin-D and deepening insulin resistance.	('thyroxin', 'MPA', (155, 163))	('vitamin-D', 'Gene', (168, 177))	('insulin resistance', 'Phenotype', 'HP:0000855', (192, 210))	('vitamin-D', 'Chemical', 'MESH:D014807', (168, 177))	('estrogen', 'Protein', (145, 153))	('insulin', 'Gene', (192, 199))	('melatonin', 'MPA', (44, 53))	('excess', 'PosReg', (54, 60))	('melatonin', 'Chemical', 'MESH:D008550', (44, 53))	('insulin', 'Gene', '3630', (192, 199))	('thyroxin', 'Chemical', 'MESH:D013974', (155, 163))	('deficiencies', 'Var', (129, 141))	('deficiency', 'NegReg', (14, 24))	('deepening', 'PosReg', (182, 191))
157107	27087654	These results reveal that among cases with early stage ductal carcinoma, patients who underwent lumpectomy had a higher breast cancer-specific survival rate than those treated with either mastectomy alone (HR: 1.31) or mastectomy with radiation (HR: 1.47).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('higher', 'PosReg', (113, 119))	('patients', 'Species', '9606', (73, 81))	('ductal carcinoma', 'Disease', 'MESH:D044584', (55, 71))	('ductal carcinoma', 'Disease', (55, 71))	('lumpectomy', 'Var', (96, 106))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (55, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
157128	27087654	Consistent findings have shown that women who have undergone mastectomy have a higher risk of breast cancer related death as those who had only a lumpectomy.	('death', 'Disease', 'MESH:D003643', (116, 121))	('death', 'Disease', (116, 121))	('mastectomy', 'Var', (61, 71))	('women', 'Species', '9606', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
157204	25905948	When present, cryoablation-related swelling, ecchymosis, and pain were most common on the 1st day after ablation and improved over the 2-week period of clinical evaluation.	('swelling', 'Disease', (35, 43))	('ecchymosis', 'Phenotype', 'HP:0031364', (45, 55))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('ecchymosis', 'Disease', 'MESH:D004438', (45, 55))	('ecchymosis', 'Disease', (45, 55))	('pain', 'Disease', 'MESH:D010146', (61, 65))	('cryoablation-related', 'Var', (14, 34))	('pain', 'Disease', (61, 65))
157307	27681693	When a CNB yields a high risk breast lesion, the decision to recommend surgical excision depends on several factors including the radiologic-pathologic concordance and the rsik of an upgraded lesion in the excision specimen.	('breast lesion', 'Disease', (30, 43))	('breast lesion', 'Disease', 'MESH:D001941', (30, 43))	('CNB', 'Var', (7, 10))
157309	27681693	Excision of ADH can yield DCIS or, less often, invasive carcinoma.	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('invasive carcinoma', 'Disease', 'MESH:D009361', (47, 65))	('yield', 'Reg', (20, 25))	('ADH', 'Disease', (12, 15))	('invasive carcinoma', 'Disease', (47, 65))	('Excision', 'Var', (0, 8))	('DCIS', 'Disease', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
157326	27681693	For CNB yielding LCIS with atypical features such as pleomorphic nuclei, necrosis, or massive acinar distension surgical excision is warranted.	('LCIS', 'Phenotype', 'HP:0030076', (17, 21))	('necrosis', 'Disease', (73, 81))	('CNB', 'Var', (4, 7))	('necrosis', 'Disease', 'MESH:D009336', (73, 81))	('LCIS', 'Disease', (17, 21))
157362	27681693	For CNB yielding ADH, IDP with atypia, or RS with atypia, the risk of upgrade to malignancy in the surgical excision is high and these patients should be referred for surgical consultation.	('patients', 'Species', '9606', (135, 143))	('RS', 'Chemical', '-', (42, 44))	('IDP', 'Gene', '3417', (22, 25))	('IDP', 'Gene', (22, 25))	('CNB', 'Var', (4, 7))	('ADH', 'Disease', (17, 20))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('malignancy', 'Disease', (81, 91))
157435	30443411	The order of mammary retention was 40 kDa PEG-(DOX)4 > 5 kDa PEG-DOX >> DOX, in normal and tumour-bearing rats.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('rats', 'Species', '10116', (106, 110))	('mammary', 'MPA', (13, 20))	('DOX', 'Chemical', 'MESH:D004317', (65, 68))	('PEG-DOX', 'Chemical', '-', (61, 68))	('tumour', 'Disease', (91, 97))	('DOX', 'Chemical', 'MESH:D004317', (72, 75))	('PEG-', 'Var', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('DOX', 'Chemical', 'MESH:D004317', (47, 50))	('PEG-(DOX)4', 'Chemical', '-', (42, 52))
157506	30443411	Among the linear structures of nanocarriers, the 20 and 40 kDa PEG-DOX were significantly less potent than free DOX and 5 or 10 kDa PEG-DOX.	('less', 'NegReg', (90, 94))	('DOX', 'Chemical', 'MESH:D004317', (136, 139))	('PEG-DOX', 'Var', (63, 70))	('DOX', 'Chemical', 'MESH:D004317', (67, 70))	('PEG-DOX', 'Chemical', '-', (63, 70))	('PEG-DOX', 'Chemical', '-', (132, 139))	('DOX', 'Chemical', 'MESH:D004317', (112, 115))	('potent', 'MPA', (95, 101))
157523	30443411	Fluorescence intensities of free DOX, 5 kDa PEG-DOX, and 40 kDa PEG-(DOX)4 nanocarriers in the mammary gland exhibited a rapid increase and subsequent reduction with time, which was consistent in both normal and tumour-bearing rats (Figs 3, 4).	('PEG-', 'Var', (64, 68))	('PEG-DOX', 'Chemical', '-', (44, 51))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('DOX', 'Chemical', 'MESH:D004317', (69, 72))	('DOX', 'Chemical', 'MESH:D004317', (48, 51))	('rats', 'Species', '10116', (227, 231))	('Fluorescence intensities', 'MPA', (0, 24))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('increase', 'PosReg', (127, 135))	('tumour', 'Disease', (212, 218))	('DOX', 'Chemical', 'MESH:D004317', (33, 36))	('reduction', 'NegReg', (151, 160))	('PEG-(DOX)4', 'Chemical', '-', (64, 74))
157527	30443411	Under both normal and tumour conditions, 40 kDa PEG-(DOX)4 manifested the longest retention time.	('tumour conditions', 'Disease', 'MESH:D009369', (22, 39))	('tumour conditions', 'Disease', (22, 39))	('retention', 'MPA', (82, 91))	('PEG-', 'Var', (48, 52))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('PEG-(DOX)4', 'Chemical', '-', (48, 58))
157571	30443411	Because of the larger molecular size and inherent viscosity and/or aggregate formation of their aqueous solution (4 and 8% w/v), PEG-DOX nanocarriers exhibited prolonged ductal retention half-lives with respect to free DOX, which was consistent with the results we obtained previously in SD rats (Veronese et al., 2005).	('viscosity', 'MPA', (50, 59))	('rats', 'Species', '10116', (291, 295))	('PEG-DOX', 'Chemical', '-', (129, 136))	('DOX', 'Chemical', 'MESH:D004317', (219, 222))	('molecular', 'MPA', (22, 31))	('larger', 'PosReg', (15, 21))	('ductal retention half-lives', 'MPA', (170, 197))	('prolonged', 'PosReg', (160, 169))	('aggregate formation', 'CPA', (67, 86))	('PEG-DOX', 'Var', (129, 136))	('DOX', 'Chemical', 'MESH:D004317', (133, 136))
157601	25239595	1,25D inhibits the proliferation of non-tumorigenic mammary epithelial cells and VDR ablation enhances the risk of carcinogenesis.	('enhances', 'PosReg', (94, 102))	('inhibits', 'NegReg', (6, 14))	('VDR', 'Gene', (81, 84))	('ablation', 'Var', (85, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('carcinogenesis', 'Disease', (115, 129))
157652	25239595	Similar heterogeneity in 1,25D regulation of gene expression was observed in the tumorigenic breast cancer cell lines examined despite comparable CYP24A1 induction.	('tumorigenic breast cancer', 'Disease', (81, 106))	('tumorigenic breast cancer', 'Disease', 'MESH:D001943', (81, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('CYP24A1', 'Var', (146, 153))
157654	25239595	This is surprising since the DCIS.com cells were derived from a variant of the MCF10A cells which did not respond similarly to the hTERT and HME cells.	('hTERT', 'Gene', '7015', (131, 136))	('MCF10A', 'CellLine', 'CVCL:0598', (79, 85))	('variant', 'Var', (64, 71))	('hTERT', 'Gene', (131, 136))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('MCF10A', 'Gene', (79, 85))
157670	25239595	It should also be noted that CYP24A1 was identified as a gene highly enriched in the luminal progenitor population of both human and mouse breast epithelium suggesting the possibility that CYP24A1 may have an as yet unidentified role in breast biology which may or may not be VDR dependent.	('CYP24A1', 'Var', (189, 196))	('human', 'Species', '9606', (123, 128))	('breast biology', 'Disease', (237, 251))	('mouse', 'Species', '10090', (133, 138))
157679	25785189	The levels of the IGF-IR and Rap1 protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 -) DCIS relative to normal epithelium (P <0.0001).	('elevated', 'PosReg', (72, 80))	('Rap1', 'Gene', (29, 33))	('levels', 'MPA', (4, 10))	('HER2', 'Gene', '2064', (107, 111))	('PR', 'Gene', '5241', (101, 103))	('Rap1', 'Gene', '5906', (29, 33))	('ER-positive', 'Var', (84, 95))	('IGF-IR', 'Gene', (18, 24))	('HER2', 'Gene', (107, 111))	('IGF-IR', 'Gene', '3480', (18, 24))
157695	25785189	In the human BC model, hyperactivation of Rap1 was related to loss of mammary epithelial cell polarity, cell invasion in vitro and tumorigenicity in nude mice.	('loss', 'NegReg', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('nude mice', 'Species', '10090', (149, 158))	('Rap1', 'Gene', '5906', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (7, 12))	('cell invasion', 'CPA', (104, 117))	('tumor', 'Disease', (131, 136))	('Rap1', 'Gene', (42, 46))	('hyperactivation', 'Var', (23, 38))	('mammary epithelial cell polarity', 'CPA', (70, 102))
157741	25785189	There was no association between HER2 positivity and higher IGF-IR, Rap1, and Vav2 protein levels.	('higher', 'PosReg', (53, 59))	('Vav2', 'Gene', (78, 82))	('IGF-IR', 'Gene', (60, 66))	('positivity', 'Var', (38, 48))	('Rap1', 'Gene', (68, 72))	('HER2', 'Gene', (33, 37))	('Vav2', 'Gene', '7410', (78, 82))	('IGF-IR', 'Gene', '3480', (60, 66))	('HER2', 'Gene', '2064', (33, 37))	('Rap1', 'Gene', '5906', (68, 72))
157751	25785189	Because Vav2 was increased in IBC, but not in DCIS lesions, we hypothesized that change in Vav2 protein expression might be associated specifically with the onset of invasive potential in tumor cells, i.e.	('tumor', 'Disease', (188, 193))	('change', 'Var', (81, 87))	('increased', 'PosReg', (17, 26))	('protein', 'Protein', (96, 103))	('Vav2', 'Gene', '7410', (8, 12))	('IBC', 'Chemical', '-', (30, 33))	('IBC', 'Disease', (30, 33))	('Vav2', 'Gene', (91, 95))	('Vav2', 'Gene', '7410', (91, 95))	('invasive potential in', 'CPA', (166, 187))	('associated', 'Reg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Vav2', 'Gene', (8, 12))
157759	25785189	Remarkably, Vav2 levels in the DCIS group were similar to the normal group (P = 0.99), but were increased in DCIS /T1mic and further significantly increased in DCIS/IDC + LCIS/ILC (P = 0.03).	('Vav2', 'Gene', (12, 16))	('DCIS /T1mic', 'Var', (109, 120))	('increased', 'PosReg', (96, 105))	('Vav2', 'Gene', '7410', (12, 16))	('increased', 'PosReg', (147, 156))	('DCIS/IDC', 'Disease', (160, 168))
157763	25785189	Moreover, patients that had high levels of Vav2 protein expression in DCIS were more than twice as likely to have concurrent invasion than those with low levels of Vav2 (OR, 2.42; 95% CI 1.26-4-65; P = 0.008).	('Vav2', 'Gene', (43, 47))	('Vav2', 'Gene', '7410', (43, 47))	('Vav2', 'Gene', (164, 168))	('Vav2', 'Gene', '7410', (164, 168))	('patients', 'Species', '9606', (10, 18))	('high', 'Var', (28, 32))
157773	25785189	Depletion or inhibition of the IGF-IR has been shown to delay repair of radiation-induced DNA double-strand breaks, enhance tumor radiation sensitivity and amplify RT-induced apoptosis.	('tumor radiation', 'Disease', 'MESH:D004194', (124, 139))	('RT-induced apoptosis', 'CPA', (164, 184))	('enhance', 'PosReg', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor radiation', 'Disease', (124, 139))	('delay', 'NegReg', (56, 61))	('Depletion', 'Var', (0, 9))	('IGF-IR', 'Gene', (31, 37))	('IGF-IR', 'Gene', '3480', (31, 37))	('inhibition', 'NegReg', (13, 23))	('amplify', 'PosReg', (156, 163))	('repair', 'MPA', (62, 68))
157792	23752191	MicroRNA (miRNA) profiling of paired DCIS tumors revealed that loss of miR-140 is a hallmark of DCIS lesions.	('DCIS', 'Disease', (96, 100))	('DCIS tumors', 'Disease', (37, 48))	('paired DCIS', 'Phenotype', 'HP:0006304', (30, 41))	('loss', 'Var', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('DCIS tumors', 'Disease', 'MESH:D002285', (37, 48))	('miR-140', 'Gene', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
157795	23752191	Furthermore, we found that SOX9 and ALDH1, the most significantly activated stem-cell factors in DCIS stem-like cells, are direct targets of miR-140.	('miR-140', 'Var', (141, 148))	('SOX9', 'Gene', (27, 31))	('SOX9', 'Gene', '6662', (27, 31))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('ALDH1', 'Gene', (36, 41))	('activated', 'PosReg', (66, 75))	('ALDH1', 'Gene', '216', (36, 41))
157797	23752191	We examined a model of ERalpha-negative/basal-like DCIS and found that restoration of miR-140 via a genetic approach or with the dietary compound sulforaphane decreased SOX9 and ALDH1, and reduced tumor growth in vivo.	('tumor', 'Disease', (197, 202))	('ALDH1', 'Gene', '216', (178, 183))	('ERalpha', 'Gene', '2099', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ALDH1', 'Gene', (178, 183))	('miR-140', 'Gene', (86, 93))	('reduced', 'NegReg', (189, 196))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('sulforaphane', 'Chemical', 'MESH:C016766', (146, 158))	('decreased', 'NegReg', (159, 168))	('restoration', 'Var', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SOX9', 'Gene', (169, 173))	('SOX9', 'Gene', '6662', (169, 173))	('ERalpha', 'Gene', (23, 30))
157809	23752191	Not surprisingly, epigenetic mechanisms are frequently implicated in miRNA dysregulation in breast tumors.	('epigenetic mechanisms', 'Var', (18, 39))	('breast tumors', 'Phenotype', 'HP:0100013', (92, 105))	('breast tumor', 'Phenotype', 'HP:0100013', (92, 104))	('breast tumors', 'Disease', (92, 105))	('breast tumors', 'Disease', 'MESH:D001943', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('implicated', 'Reg', (55, 65))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
157815	23752191	Our criteria for follow-up analysis included miRNAs that were (1) among the most consistent markers of DCIS from independent studies, (2) were known to target stem cell self-renewal regulators or (3) those miRNAs previously implicated in invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('invasive breast cancer', 'Disease', 'MESH:D001943', (238, 260))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('invasive breast cancer', 'Disease', (238, 260))	('miRNAs', 'Var', (45, 51))
157829	23752191	When injected into the mammary glands of nude mice, MCF10DCIS forms well recognizable DCIS lesions.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (52, 61))	('DCIS lesions', 'CPA', (86, 98))	('MCF10DCIS', 'Var', (52, 61))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('nude mice', 'Species', '10090', (41, 50))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
157833	23752191	Fifty percent of the CpGs were methylated in CpG Island 2 in nontumorigenic MCF-10A cells.	('tumor', 'Disease', (64, 69))	('methylated', 'Var', (31, 41))	('CpG Island 2', 'Gene', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('MCF-10A', 'CellLine', 'CVCL:0598', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
157835	23752191	However, in MCF10DCIS cells, 69.8% of the CpGs were methylated, roughly a 20% increase.	('CpGs', 'Protein', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (12, 21))	('increase', 'PosReg', (78, 86))	('MCF10DCIS', 'Var', (12, 21))	('methylated', 'MPA', (52, 62))
157838	23752191	We found that epigenetic therapy was able to restore normal methylation levels in MCF10DCIS cells and activate miR-140 expression (Figures 3b and c).	('activate', 'PosReg', (102, 110))	('expression', 'MPA', (119, 129))	('methylation levels', 'MPA', (60, 78))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (82, 91))	('restore', 'PosReg', (45, 52))	('miR-140', 'Gene', (111, 118))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('epigenetic therapy', 'Var', (14, 32))
157858	23752191	As we were particularly interested in which pathways contribute to the malignant properties of CSCs compared with tightly regulated normal stem cells, we compared expression of several of these genes in MCF10DCIS stem-like cancer cells to stem cells isolated from parental MCF-10A cells.	('MCF10DCIS', 'Var', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('DCIS', 'Phenotype', 'HP:0030075', (208, 212))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('MCF-10A', 'CellLine', 'CVCL:0598', (273, 280))	('compared', 'Reg', (154, 162))	('cancer', 'Disease', (223, 229))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (203, 212))
157859	23752191	Among these miR-140 targets, we found that SOX9, a transcription factor previously associated with miR-140 expression and recently shown to be a master regulator of mammary stem cell state, and ALDH1, an enzyme that oxidizes aldehydes and is a marker of breast CSCs and poor prognosis, were both dramatically upregulated in MCF10DCIS stem-like cells compared with MCF-10A normal mammary stem cells (Figure 6b upper panel; Supplementary Figure S2).	('aldehydes', 'Chemical', 'MESH:D000447', (225, 234))	('DCIS', 'Phenotype', 'HP:0030075', (329, 333))	('MCF-10A', 'CellLine', 'CVCL:0598', (364, 371))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (324, 333))	('ALDH1', 'Gene', (194, 199))	('SOX9', 'Gene', '6662', (43, 47))	('MCF10DCIS', 'Var', (324, 333))	('ALDH1', 'Gene', '216', (194, 199))	('upregulated', 'PosReg', (309, 320))	('miR-140', 'Gene', (99, 106))	('SOX9', 'Gene', (43, 47))
157863	23752191	Mutation of the miR-140 miRNA response elements in the SOX9 3'-UTR and ALDH1 3'-UTR effectively blocked miR-140 targeting, resulting in restored luciferase activity and demonstrating specificity of miR-140 interactions with the predicted targeting sites in the SOX9 and ALDH1 3'-UTRs.	('interactions', 'Interaction', (206, 218))	('restored', 'PosReg', (136, 144))	('SOX9', 'Gene', (261, 265))	('Mutation', 'Var', (0, 8))	('miR-140', 'Gene', (104, 111))	('activity', 'MPA', (156, 164))	('SOX9', 'Gene', (55, 59))	('ALDH1', 'Gene', (71, 76))	('blocked', 'NegReg', (96, 103))	('SOX9', 'Gene', '6662', (55, 59))	('ALDH1', 'Gene', (270, 275))	('ALDH1', 'Gene', '216', (71, 76))	('SOX9', 'Gene', '6662', (261, 265))	('ALDH1', 'Gene', '216', (270, 275))	('targeting', 'MPA', (112, 121))	('luciferase', 'Enzyme', (145, 155))
157868	23752191	Using western blotting we found that SOX9 was overexpressed in MCF10DCIS cells compared with nontumorigenic MCF-10A mammary epithelial cells (Figure 7a).	('MCF10DCIS', 'Var', (63, 72))	('SOX9', 'Gene', '6662', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MCF-10A', 'CellLine', 'CVCL:0598', (108, 115))	('tumor', 'Disease', (96, 101))	('overexpressed', 'PosReg', (46, 59))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (63, 72))	('SOX9', 'Gene', (37, 41))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
157873	23752191	MiR-140 overexpression resulted in smaller and fewer mammospheres (Figures 7d and e), whereas miR-140 knockdown resulted in increased mammosphere formation (Supplementary Figure S4).	('overexpression', 'PosReg', (8, 22))	('MiR-140', 'Gene', (0, 7))	('increased', 'PosReg', (124, 133))	('mammosphere formation', 'CPA', (134, 155))	('knockdown', 'Var', (102, 111))	('MiR-140', 'Gene', '406932', (0, 7))	('miR-140', 'Gene', (94, 101))	('fewer', 'NegReg', (47, 52))	('mammospheres', 'CPA', (53, 65))
157874	23752191	In MCF10DCIS cells, which express low levels of miR-140, re-expression of miR-140 resulted in a significant decrease in mammosphere formation (Figures 7f and g).	('mammosphere formation', 'CPA', (120, 141))	('miR-140', 'Var', (74, 81))	('decrease', 'NegReg', (108, 116))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (3, 12))
157880	23752191	SOX9 knockdown resulted in decreased mammosphere formation in MCF10DCIS cells, whereas SOX9 overexpression resulted in a significant increase in sphere formation in MCF-10A cells (Figures 7d-g).	('MCF-10A', 'CellLine', 'CVCL:0598', (165, 172))	('sphere formation', 'CPA', (145, 161))	('MCF10DCIS', 'Var', (62, 71))	('SOX9', 'Gene', (0, 4))	('SOX9', 'Gene', (87, 91))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (27, 36))	('mammosphere formation', 'CPA', (37, 58))	('SOX9', 'Gene', '6662', (0, 4))	('SOX9', 'Gene', '6662', (87, 91))	('increase', 'PosReg', (133, 141))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (62, 71))
157892	23752191	However, many epigenetic drugs show high levels of toxicity in vivo.	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('toxicity', 'Disease', (51, 59))	('epigenetic drugs', 'Var', (14, 30))
157894	23752191	We found that sulforaphane treatment of MCF10DCIS stem-like cells significantly inhibited tumor growth (Figure 8c).	('sulforaphane', 'Chemical', 'MESH:C016766', (14, 26))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (40, 49))	('MCF10DCIS', 'Var', (40, 49))	('inhibited', 'NegReg', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
157909	23752191	Finally, we were able to show in vivo that miR-140 activation through genetic approaches or epigenetic drugs reduced the tumorigenic potential of DCIS stem-like cells.	('miR-140', 'Gene', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('epigenetic drugs', 'Var', (92, 108))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('reduced', 'NegReg', (109, 116))	('activation', 'PosReg', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
157913	23752191	MCF10DCIS, SUM225CWN, SUM102PT were grown in Dulbecco's modified Eagle medium/F-12 +5% horse serum (Invitrogen, Carlsbad, CA, USA) and 1% L-Glut.	('F-12', 'Chemical', 'MESH:C007782', (78, 82))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (45, 77))	('horse', 'Species', '9796', (87, 92))	('SUM102PT', 'Var', (22, 30))	('SUM225CWN', 'Var', (11, 20))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))
157923	23752191	The resulting ALDH1A3 mutant contains three point mutations CCCC(T-to-A)G (T-to-A)G(G-to-C)TGT GGTTT, and the SOX9 mutant contains two point mutations GATCAGC(C-to-G)C(A-to-T)CTGACA, as confirmed by sequencing.	('CCCC', 'Gene', (60, 64))	('SOX9', 'Gene', (110, 114))	('SOX9', 'Gene', '6662', (110, 114))	('ALDH1A3', 'Gene', (14, 21))	('mutant', 'Var', (22, 28))	('ALDH1A3', 'Gene', '220', (14, 21))
157943	33531640	Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit.	('BRCA1/2', 'Gene', (88, 95))	('pathogenic', 'Reg', (62, 72))	('variant', 'Var', (73, 80))	('BRCA1/2', 'Gene', '672;675', (88, 95))
157944	33531640	On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status.	('variant', 'Var', (137, 144))	('BRCA1', 'Gene', '672', (120, 125))	('BRCA1', 'Gene', (120, 125))
157958	33531640	BRCA1/2), a survival benefit from CRRM has been shown, particularly in those with a pathogenic variant in BRCA1 and BRCA2 .	('BRCA1', 'Gene', (0, 5))	('BRCA1', 'Gene', (106, 111))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('variant', 'Var', (95, 102))	('BRCA2', 'Gene', (116, 121))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1', 'Gene', '672', (106, 111))	('BRCA1/2', 'Gene', (0, 7))	('BRCA2', 'Gene', '675', (116, 121))
157960	33531640	Amongst high-risk patients who test negative for the BRCA1 or BRCA2 mutation, the risk of CBC appears to remain elevated, although some studies have suggested otherwise.	('CBC', 'Disease', (90, 93))	('mutation', 'Var', (68, 76))	('BRCA2', 'Gene', '675', (62, 67))	('BRCA1', 'Gene', '672', (53, 58))	('patients', 'Species', '9606', (18, 26))	('BRCA2', 'Gene', (62, 67))	('BRCA1', 'Gene', (53, 58))
157961	33531640	On May 14th 2013, Angelina Jolie (AJ) shared with the world her experience of bilateral risk reducing mastectomies (BRRMs) based on her inheriting a maternally derived pathogenic variant mutation in the BRCA1 gene.	('BRCA1', 'Gene', (203, 208))	('variant mutation', 'Var', (179, 195))	('mastectomies', 'Disease', (102, 114))	('BRCA1', 'Gene', '672', (203, 208))
157974	33531640	In the NBCPC, testing for BRCA1 and BRCA2 mutations has been available within our services since 1996.	('BRCA1', 'Gene', (26, 31))	('BRCA2', 'Gene', (36, 41))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA2', 'Gene', '675', (36, 41))	('mutations', 'Var', (42, 51))
157996	33531640	For the subgroup of BRCA1/2 carriers (N = 105), a similar increase in CRRM rates from 47.6% (40/84) to 90.5% (19/21) was observed between the periods (p < 0.001).	('increase', 'PosReg', (58, 66))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('CRRM rates', 'CPA', (70, 80))	('BRCA1/2', 'Gene', (20, 27))	('carriers', 'Var', (28, 36))
158002	33531640	A recent study from Denmark confirmed that uptake of CRRM amongst women before the age of 45 years was significantly higher in those harbouring a pathogenic variant of the BRCA1/2 gene and those from high-risk families, compared to those with a lower genetic risk.	('age', 'Gene', '5973', (83, 86))	('BRCA1/2', 'Gene', '672;675', (172, 179))	('uptake', 'MPA', (43, 49))	('pathogenic', 'Reg', (146, 156))	('variant', 'Var', (157, 164))	('women', 'Species', '9606', (66, 71))	('age', 'Gene', (83, 86))	('higher', 'PosReg', (117, 123))	('BRCA1/2', 'Gene', (172, 179))
158006	33531640	In our study, CRRM was most commonly performed in younger breast cancer patients (p < 0.001) who, amongst BRCA1 and BRCA2 carriers, derive the greatest survival benefit.	('BRCA1', 'Gene', (106, 111))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('BRCA2', 'Gene', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRCA1', 'Gene', '672', (106, 111))	('carriers', 'Var', (122, 130))	('BRCA2', 'Gene', '675', (116, 121))	('patients', 'Species', '9606', (72, 80))
158010	33531640	There are wide variations in uptake of CRRM worldwide with the highest for BRCA1/2 carriers in North America (49.3%), compared to 0% in Norway.	('uptake', 'MPA', (29, 35))	('carriers', 'Var', (83, 91))	('BRCA1/2', 'Gene', (75, 82))	('highest', 'Reg', (63, 70))	('BRCA1/2', 'Gene', '672;675', (75, 82))
158018	33531640	Amongst women who tested positive for a pathogenic variant in either BRCA genes, uptake of CRRM in the post-AJ period was extremely high, at 90%.	('BRCA', 'Gene', '672', (69, 73))	('women', 'Species', '9606', (8, 13))	('uptake', 'MPA', (81, 87))	('BRCA', 'Gene', (69, 73))	('pathogenic', 'Reg', (40, 50))	('variant', 'Var', (51, 58))
158019	33531640	Data from a recent prospective study assessing the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer found that this group (tested positive for BRCA1 or BRCA2) had similar survival compared to non-carriers.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('BRCA1', 'Gene', (208, 213))	('BRCA2', 'Gene', '675', (217, 222))	('BRCA1', 'Gene', '672', (72, 77))	('breast cancer', 'Disease', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('BRCA2', 'Gene', (81, 86))	('BRCA1', 'Gene', (72, 77))	('BRCA2', 'Gene', '675', (81, 86))	('BRCA1', 'Gene', '672', (208, 213))	('breast cancer', 'Disease', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('mutation', 'Var', (87, 95))	('BRCA2', 'Gene', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('patients', 'Species', '9606', (125, 133))
158029	33531640	When considering the trends over time of CRRM, it may be important to assess those with a significant family history and/or those harbouring a pathogenic variant in one of the breast cancer susceptibility genes as a separate group to those with sporadic breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('sporadic breast cancer', 'Disease', (245, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (245, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('variant', 'Var', (154, 161))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))
158035	30296938	However, the mutagenesis and genetic evolution in the tumor mass, resulting in intra-tumor heterogeneity, impede precise deciphering of a causation underlying carcinogenesis.	('carcinogenesis', 'Disease', (159, 173))	('tumor', 'Disease', (85, 90))	('heterogeneity', 'MPA', (91, 104))	('intra-tumor', 'Disease', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('intra-tumor', 'Disease', 'MESH:D009369', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('impede', 'NegReg', (106, 112))	('tumor', 'Disease', (54, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutagenesis', 'Var', (13, 24))
158047	30296938	Here, we describe phenotype-based high-throughput laser-aided isolation and sequencing (PHLI-seq), which can efficiently detect tumor subclonality and variants with low-level allele fractions with high sensitivity and accuracy while preserving information of the 3D spatial organization and histopathological phenotypes of cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('variants', 'Var', (151, 159))	('tumor', 'Disease', (128, 133))
158051	30296938	By establishing this novel approach, we identified distinct subclones and their somatic variants in breast cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('variants', 'Var', (88, 96))
158061	30296938	To confirm the sequencing performance, we isolated the HL60 cells using the PHLI-seq method, sequenced their genomes, and tested the coverage breadth, allele dropout (ADO), and false-positive rate (FPR) (see Additional file 1: Note S2, Figure S2, and Figure S3).	('HL60', 'CellLine', 'CVCL:0002', (55, 59))	('tested', 'Reg', (122, 128))	('allele', 'Var', (151, 157))
158080	30296938	In contrast, the CNA plots from LPC and LMD presented large deletion or severe amplification bias.	('LMD', 'Disease', (40, 43))	('deletion', 'Var', (60, 68))	('amplification bias', 'MPA', (79, 97))	('LMD', 'Disease', 'MESH:C537267', (40, 43))
158084	30296938	The shared alterations include 1q gain, 8q gain, 8p loss, and HER2 amplifications, all of which had been previously reported as frequent CNAs in human breast cancer and other types of cancer.	('cancer', 'Disease', (184, 190))	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gain', 'PosReg', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('human', 'Species', '9606', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('cancer', 'Disease', (158, 164))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('gain', 'PosReg', (43, 47))	('HER2', 'Gene', (62, 66))	('amplifications', 'Var', (67, 81))
158088	30296938	In our targeted sequencing analysis of 53 cell cluster samples, we found that mutations in PIK3CA, EPHA3, KIT, ERBB4, and KMT2C occurred in subclone 1; mutations in KMT2C, ATR, and KDM5B in subclone 2; and mutations in TOP2A, NF1, ESR1, JAK1, and MST1R in subclone 3.	('TOP2A', 'Gene', '7153', (219, 224))	('mutations', 'Var', (152, 161))	('ERBB4', 'Gene', '2066', (111, 116))	('KMT2C', 'Gene', (122, 127))	('MST1R', 'Gene', '4486', (247, 252))	('KMT2C', 'Gene', '58508', (122, 127))	('ERBB4', 'Gene', (111, 116))	('PIK3CA', 'Gene', (91, 97))	('MST1R', 'Gene', (247, 252))	('KDM5B', 'Gene', '10765', (181, 186))	('mutations', 'Var', (78, 87))	('ATR', 'Gene', (172, 175))	('NF1', 'Gene', '4763', (226, 229))	('JAK1', 'Gene', (237, 241))	('KIT', 'Gene', (106, 109))	('mutations', 'Var', (206, 215))	('EPHA3', 'Gene', (99, 104))	('ESR1', 'Gene', '2099', (231, 235))	('KMT2C', 'Gene', '58508', (165, 170))	('KMT2C', 'Gene', (165, 170))	('ESR1', 'Gene', (231, 235))	('NF1', 'Gene', (226, 229))	('EPHA3', 'Gene', '2042', (99, 104))	('TOP2A', 'Gene', (219, 224))	('PIK3CA', 'Gene', '5290', (91, 97))	('ATR', 'Gene', '545', (172, 175))	('KDM5B', 'Gene', (181, 186))	('JAK1', 'Gene', '3716', (237, 241))
158089	30296938	We found that 75 mutations were shared in the three subclones and that 99, 75, and 382 mutations in VHL, KDSR, PIK3CA, EPHA3, FCRL4, KDM5A, MET, POT1, KMT2A, GPHN, COL1A1, SRSF3, ATR, NCOR1, MSH2, RPN1, and XPO1 occurred exclusively in subclones 1, 2, and 3, respectively.	('POT1', 'Gene', (145, 149))	('SRSF3', 'Gene', '6428', (172, 177))	('EPHA3', 'Gene', (119, 124))	('ATR', 'Gene', '545', (179, 182))	('RPN1', 'Gene', '6184', (197, 201))	('PIK3CA', 'Gene', '5290', (111, 117))	('MSH2', 'Gene', '4436', (191, 195))	('mutations', 'Var', (87, 96))	('COL1A1', 'Gene', '1277', (164, 170))	('KMT2A', 'Gene', '4297', (151, 156))	('KDSR', 'Gene', (105, 109))	('EPHA3', 'Gene', '2042', (119, 124))	('NCOR1', 'Gene', (184, 189))	('KDSR', 'Gene', '2531', (105, 109))	('VHL', 'Disease', 'MESH:D006623', (100, 103))	('RPN1', 'Gene', (197, 201))	('KDM5A', 'Gene', '5927', (133, 138))	('COL1A1', 'Gene', (164, 170))	('NCOR1', 'Gene', '9611', (184, 189))	('XPO1', 'Gene', '7514', (207, 211))	('KDM5A', 'Gene', (133, 138))	('PIK3CA', 'Gene', (111, 117))	('ATR', 'Gene', (179, 182))	('GPHN', 'Gene', '10243', (158, 162))	('SRSF3', 'Gene', (172, 177))	('KMT2A', 'Gene', (151, 156))	('POT1', 'Gene', '25913', (145, 149))	('GPHN', 'Gene', (158, 162))	('MET', 'Gene', (140, 143))	('VHL', 'Disease', (100, 103))	('FCRL4', 'Gene', (126, 131))	('MSH2', 'Gene', (191, 195))	('FCRL4', 'Gene', '83417', (126, 131))	('XPO1', 'Gene', (207, 211))
158093	30296938	Also, we mapped the detailed information for the CNAs, driver mutations, and passenger mutations to the topological information and spatial positions of the tumor tissue (Fig.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mutations', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
158103	30296938	The result shows that the tumor cells in the invasive clone had mutations which do not exist in in situ clones.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutations', 'Var', (64, 73))
158109	30296938	This could result from wavelength (355 nm) and applied energy (~ 10 muJ) of the laser used in LPC and LMD.	('LMD', 'Disease', (102, 105))	('result', 'Reg', (11, 17))	('355 nm', 'Var', (35, 41))	('LMD', 'Disease', 'MESH:C537267', (102, 105))
158185	30296938	Based on these study results, we chose the genes that showed a high frequency and recurrent mutations, genomic copy number amplifications and deletions, and expression changes in breast cancer samples, which could be oncogenes, tumor suppressor genes, or breast cancer-associated genes.	('expression', 'MPA', (157, 167))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Disease', (255, 268))	('mutations', 'Var', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('deletions', 'Var', (142, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('changes', 'Reg', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy number amplifications', 'Var', (111, 137))
158321	19632594	Although the use of MRI in younger women with breast cancer might be justified by the higher incidence of BRCA1 and 2 mutations in this group, a family history of breast or ovarian cancer was not associated with MRI use in this study.	('women', 'Species', '9606', (35, 40))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (163, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (118, 127))	('breast or ovarian cancer', 'Disease', (163, 187))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('BRCA1 and 2', 'Gene', '672;675', (106, 117))	('breast cancer', 'Disease', (46, 59))
158339	19632594	Although additional follow-up studies are needed to address this important issue, the incidence of additional carcinoma detected by MRI is 2-3 times higher than rates of local failure observed in women selected for BCT without MRI, suggesting that much of this disease is controlled with radiotherapy.	('additional carcinoma', 'Disease', 'MESH:D002277', (99, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('local failure', 'Disease', 'MESH:D012594', (170, 183))	('additional carcinoma', 'Disease', (99, 119))	('MRI', 'Var', (132, 135))	('women', 'Species', '9606', (196, 201))	('local failure', 'Disease', (170, 183))
158345	19632594	In summary, we observed that despite its greater sensitivity for cancer detection, MRI is not associated with a decrease in either the need for re-excision for positive margins or initial unsuccessful lumpectomy attempts in patients who ultimately require mastectomy.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MRI', 'Var', (83, 86))	('patients', 'Species', '9606', (224, 232))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
158365	19450579	They also showed that the proto-oncogene found in normal tissues differed from the oncogenic form by a single base mutation that lead to substitution of a valine residue to a glutamic acid residue which introduces a negative charge into the transmembrane region of the receptor.	('lead to', 'Reg', (129, 136))	('substitution', 'Var', (137, 149))	('glutamic acid', 'Chemical', 'MESH:D018698', (175, 188))	('negative charge', 'MPA', (216, 231))	('mutation', 'Var', (115, 123))	('valine', 'Chemical', 'MESH:D014633', (155, 161))
158377	19450579	Mammary tumorigenesis is influenced by the over-expression and/or amplification of wild-type HER2, somatic activation of wild-type HER2, and the temporal expression pattern of activated HER2 (Table 2).	('amplification', 'Var', (66, 79))	('HER2', 'Protein', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('influenced', 'Reg', (25, 35))	('over-expression', 'PosReg', (43, 58))
158381	19450579	Similarly, women with benign breast biopsies demonstrating both HER2 amplification and a proliferative histopathologic diagnosis may have a substantially increased risk for subsequent IBC.	('rat', 'Species', '10116', (52, 55))	('IBC', 'Disease', (184, 187))	('HER2', 'Protein', (64, 68))	('women', 'Species', '9606', (11, 16))	('rat', 'Species', '10116', (96, 99))	('amplification', 'Var', (69, 82))
158386	19450579	There is a correlation between HER2 amplification/over-expression and aneuploidy in clinical breast cancer samples.	('aneuploidy', 'Disease', (70, 80))	('HER2', 'Protein', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('aneuploidy', 'Disease', 'MESH:D000782', (70, 80))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('amplification/over-expression', 'PosReg', (36, 65))	('amplification/over-expression', 'Var', (36, 65))
158387	19450579	HER2 amplification/over-expression and aneuploidy are considered downstream effects of p53 dysfunction.	('amplification/over-expression', 'PosReg', (5, 34))	('amplification/over-expression', 'Var', (5, 34))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('aneuploidy', 'Disease', (39, 49))	('dysfunction', 'Var', (91, 102))	('aneuploidy', 'Disease', 'MESH:D000782', (39, 49))	('HER2', 'Protein', (0, 4))
158388	19450579	In addition, over-expression of ras is often restricted to aneuploid cells that already over-express HER2; and the presence of both HER2 and ras abnormalities defines a subset of aggressive high-grade tumors.	('over-express', 'PosReg', (88, 100))	('ras abnormalities defines', 'Disease', 'MESH:D000014', (141, 166))	('HER2', 'Protein', (132, 136))	('HER2', 'Protein', (101, 105))	('presence', 'Var', (115, 123))	('ras abnormalities defines', 'Disease', (141, 166))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('over-expression', 'PosReg', (13, 28))
158391	19450579	Thus, in addition to aneuploidy and gene amplification, transcriptional deregulation involving cis-acting enhancer elements near the HER2 promoter and increased expression of transcription factors that bind to these sequences may cause HER2 over-expression.	('increased', 'PosReg', (151, 160))	('over-expression', 'MPA', (241, 256))	('deregulation', 'Var', (72, 84))	('expression', 'MPA', (161, 171))	('cause', 'Reg', (230, 235))	('aneuploidy', 'Disease', 'MESH:D000782', (21, 31))	('HER2', 'Protein', (236, 240))	('aneuploidy', 'Disease', (21, 31))
158404	19450579	For instance, loss of integrin beta4 signaling delayed the onset of HER2 induced mammary tumors, reduced tumor burden, and suppressed tumor progression and metastasis.	('integrin beta4', 'Gene', '3691', (22, 36))	('tumors', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('loss', 'Var', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('reduced', 'NegReg', (97, 104))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('HER2', 'Protein', (68, 72))	('integrin beta4', 'Gene', (22, 36))	('tumor', 'Disease', (134, 139))	('delayed', 'NegReg', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('suppressed', 'NegReg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
158422	19450579	Therefore, it is not surprising that in addition to HER2 over-expression, loss of E-cadherin contributes to mammary tumor initiation, progression, dissemination, and metastasis.	('HER2', 'Protein', (52, 56))	('progression', 'CPA', (134, 145))	('metastasis', 'CPA', (166, 176))	('dissemination', 'CPA', (147, 160))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('over-expression', 'PosReg', (57, 72))	('E-cadherin', 'Gene', (82, 92))	('loss', 'Var', (74, 78))	('E-cadherin', 'Gene', '999', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
158424	19450579	For instance, the patterns of genetic alterations in metastases are often discordant with those of the primary tumor, and differ almost completely in approximately one-third of the cases.	('primary tumor', 'Disease', (103, 116))	('metastases', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('genetic alterations', 'Var', (30, 49))	('primary tumor', 'Disease', 'MESH:D009369', (103, 116))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('rat', 'Species', '10116', (42, 45))
158426	19450579	Cytogenetic analyses of breast cancer patients have demonstrated extreme genetic heterogeneity, for instance up to 70% of polyclonality.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('polyclonality', 'Var', (122, 135))	('breast cancer', 'Disease', (24, 37))	('rat', 'Species', '10116', (59, 62))	('patients', 'Species', '9606', (38, 46))
158472	19450579	Although CK itself is not a marker of malignancy, many studies demonstrate that the presence of CK-positive cells in bone marrow has a strong prognostic impact on relapse-free as well as overall survival in breast cancer and many other types of cancer.	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('malignancy', 'Disease', (38, 48))	('cancer', 'Disease', (245, 251))	('overall survival', 'CPA', (187, 203))	('relapse-free', 'CPA', (163, 175))	('presence', 'Var', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('CK-positive', 'Gene', (96, 107))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', (207, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
158478	19450579	Similarly, genomic analysis of single CK-positive cells from bone marrow reveals early mutational events, including very early HER2 amplification, in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('amplification', 'Var', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('HER2', 'Protein', (127, 131))
158482	19450579	In contrast to the traditional "stochastic" model of oncogenesis where transformation results from random mutations and subsequent clonal selection, the CSC model postulates that cancer originates in tissue stem cells (or more likely their recent progenitors cells) through dysregulation of self-renewal pathways.	('self-renewal pathways', 'Pathway', (291, 312))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('dysregulation', 'Var', (274, 287))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
158484	19450579	This leads to expansion of this cell population that may undergo subsequent genetic and epigenetic changes, and the only cells within an organism that live long enough to accumulate the necessary mutations that lead to cancer are stem cells.	('lead to', 'Reg', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('mutations', 'Var', (196, 205))
158485	19450579	discovered that genomic mutations and rearrangements of stem cells that give rise to all the cells of the blood can lead to some forms of leukemia.	('rearrangements', 'Var', (38, 52))	('genomic mutations', 'Var', (16, 33))	('lead to', 'Reg', (116, 123))	('leukemia', 'Disease', (138, 146))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('leukemia', 'Disease', 'MESH:D007938', (138, 146))
158489	19450579	The Wicha laboratory and others have found a sub-population of cells in human breast tumors, with the phenotype CD44+/CD24-/lin-, that display CSC characteristics.	('breast tumors', 'Phenotype', 'HP:0100013', (78, 91))	('breast tumor', 'Phenotype', 'HP:0100013', (78, 90))	('breast tumors', 'Disease', 'MESH:D001943', (78, 91))	('CD44+/CD24-/lin-', 'Var', (112, 128))	('human', 'Species', '9606', (72, 77))	('breast tumors', 'Disease', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rat', 'Species', '10116', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
158493	19450579	CSCs promote blood vessel formation, support cell motility as well as resistance to a variety of therapies, and are implicated in breast metastasis.	('CSCs', 'Var', (0, 4))	('promote', 'PosReg', (5, 12))	('breast metastasis', 'Disease', (130, 147))	('resistance', 'CPA', (70, 80))	('support cell motility', 'CPA', (37, 58))	('breast metastasis', 'Disease', 'MESH:D009362', (130, 147))	('implicated', 'Reg', (116, 126))	('blood vessel formation', 'CPA', (13, 35))
158509	19450579	We were the first to show that disabling a protein complex needed for transformation would reverse the malignant properties of tumor cells in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('disabling', 'Var', (31, 40))	('reverse', 'NegReg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('protein', 'Protein', (43, 50))
158521	19450579	We have shown that HER2 targeted antibodies not only inhibit growth of already established tumors, but also can prevent tumor development in transgenic mice over-expressing the activated neu oncogene in mammary epithelial cells.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('transgenic mice', 'Species', '10090', (141, 156))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('prevent', 'NegReg', (112, 119))	('inhibit', 'NegReg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('neu oncogene', 'Gene', '13866', (187, 199))	('HER2', 'Protein', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('neu oncogene', 'Gene', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('growth', 'CPA', (61, 67))	('tumor', 'Disease', (91, 96))	('antibodies', 'Var', (33, 43))	('tumor', 'Disease', (120, 125))
158522	19450579	In this study, treatment of transgenic animals after 20 weeks of age but before tumor emergence led to a dose-dependent reduction in tumor incidence, and the tumor-free mice seemed to be protected for life.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('reduction', 'NegReg', (120, 129))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (169, 173))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('transgenic', 'Var', (28, 38))	('transgenic', 'Species', '10090', (28, 38))
158531	19450579	In addition, tumors treated with HER2 TKIs may acquire secondary mutations within the HER2 kinase domain, which leads to TKI resistance.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('leads to', 'Reg', (112, 120))	('TKI resistance', 'MPA', (121, 135))	('mutations', 'Var', (65, 74))
158532	19450579	In the case of EGFR, a point mutation in the kinase domain, namely T790M, has been shown to cause resistance to the TKIs by producing steric hindrance for the binding of the small molecules.	('cause', 'Reg', (92, 97))	('steric hindrance', 'MPA', (134, 150))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('resistance', 'MPA', (98, 108))	('T790M', 'Var', (67, 72))	('binding', 'Interaction', (159, 166))	('TKIs', 'MPA', (116, 120))
158533	19450579	Many of these mutations are in-frame insertions located in the kinase domain in the analogous structural region of the in-frame EGFR deletions that are associated with some lung cancers.	('deletions', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancers', 'Phenotype', 'HP:0100526', (173, 185))	('EGFR', 'Gene', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('lung cancers', 'Disease', (173, 185))	('associated', 'Reg', (152, 162))	('mutations', 'Var', (14, 23))	('lung cancers', 'Disease', 'MESH:D008175', (173, 185))
158535	19450579	Although cancer cells expressing this mutation appear to be sensitive to HER2-targeted therapies, they become more resistant to EGFR TKIs.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('HER2-targeted', 'Protein', (73, 86))	('mutation', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
158543	19450579	These findings suggest that amplification of ligand-induced activation of erbB receptors is a plausible mechanism of acquired resistance to trastuzumab in breast cancers.	('trastuzumab', 'Chemical', 'MESH:D000068878', (140, 151))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('erbB', 'Gene', (74, 78))	('activation', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('erbB', 'Gene', '1956', (74, 78))	('amplification', 'Var', (28, 41))
158551	19450579	Conversely, inhibition of Alk5, PI3-kinase, TACE, or erbB3 restored sensitivity to trastuzumab.	('Alk5', 'Gene', '7046', (26, 30))	('inhibition', 'Var', (12, 22))	('sensitivity to trastuzumab', 'MPA', (68, 94))	('Alk5', 'Gene', (26, 30))	('restored', 'PosReg', (59, 67))	('PI3-kinase', 'Enzyme', (32, 42))	('erbB3', 'Gene', '2065', (53, 58))	('trastuzumab', 'Chemical', 'MESH:D000068878', (83, 94))	('TACE', 'Gene', '6868', (44, 48))	('erbB3', 'Gene', (53, 58))	('TACE', 'Gene', (44, 48))
158558	19450579	In particular, activation of Notch-1 or Notch-4 cause mammary tumors in animal models.	('Notch-1', 'Gene', (29, 36))	('Notch-4', 'Gene', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cause', 'Reg', (48, 53))	('activation', 'Var', (15, 25))	('Notch-4', 'Gene', '4855', (40, 47))	('Notch-1', 'Gene', '4851', (29, 36))
158562	19450579	Inhibition of the Notch signaling pathway increases the inhibitory effect of HER2-targeted therapeutics.	('inhibitory effect', 'MPA', (56, 73))	('HER2-targeted', 'Protein', (77, 90))	('increases', 'PosReg', (42, 51))	('Notch', 'Gene', '4851;18128;4855', (18, 23))	('Notch', 'Gene', (18, 23))	('Inhibition', 'Var', (0, 10))
158563	19450579	Processes of cancer metastasis appear to provide selection pressure for the early incompletely transformed tumor cells to accumulate genetic and epigenetic changes in order to survive at the secondary sites.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('genetic', 'Var', (133, 140))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('epigenetic changes', 'Var', (145, 163))
158570	19450579	Current understanding of how untransformed, stem/progenitor cell-like, HER2-expressing cells metastasize and how they could be therapeutically targeted to prevent HER2+ breast cancer progression should lead to new treatment schedules of targeted antibodies which are directed at incompletely transformed cells.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))	('HER2+', 'Var', (163, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
158609	30591993	The multivariate logistic regression analysis of disease underestimation also identified the absence of calcification (p = 0.0252) and the presence of multifocality (unifocal vs multifocal ADH, p = 0.0147) in VAB specimens as significant risk factors.	('presence', 'Var', (139, 147))	('absence of calcification', 'Disease', 'MESH:D004832', (93, 117))	('absence of calcification', 'Disease', (93, 117))	('VAB', 'Chemical', '-', (209, 212))
158619	30591993	Patients with necrosis and multifocality (at least three ducts or more than one biopsy core involved) reportedly have a significantly higher diagnostic upgrade rate than patients lacking these factors, suggesting that these patients should undergo open surgery.	('patients', 'Species', '9606', (170, 178))	('necrosis', 'Disease', (14, 22))	('higher', 'PosReg', (134, 140))	('multifocality', 'Var', (27, 40))	('necrosis', 'Disease', 'MESH:D009336', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (224, 232))	('diagnostic upgrade', 'MPA', (141, 159))
158630	30591993	We have shown that if only one terminal ductal lobular unit is involved, the upgrade rate is significantly lower after VAB, but not after CNB.	('VAB', 'Var', (119, 122))	('VAB', 'Chemical', '-', (119, 122))	('lower', 'NegReg', (107, 112))	('upgrade', 'CPA', (77, 84))
158635	30591993	Especially in cases of ADH diagnosed by VAB, the presence of calcification in a unifocal lesion is associated with a significantly lower disease upgrade rate than is the absence of calcification and/or the presence of multifocality.	('presence', 'Var', (49, 57))	('calcification', 'Disease', (181, 194))	('disease', 'MPA', (137, 144))	('absence of calcification', 'Disease', (170, 194))	('calcification', 'Disease', 'MESH:D002114', (61, 74))	('VAB', 'Chemical', '-', (40, 43))	('ADH', 'Disease', (23, 26))	('absence of calcification', 'Disease', 'MESH:D004832', (170, 194))	('calcification', 'Disease', 'MESH:D002114', (181, 194))	('lower', 'NegReg', (131, 136))	('calcification', 'Disease', (61, 74))
158637	26070784	Genetic risk variants associated with in situ breast cancer Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs.	('breast cancers', 'Phenotype', 'HP:0003002', (174, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('BC', 'Phenotype', 'HP:0003002', (83, 85))	('Breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('situ breast cancer', 'Disease', 'MESH:D000071960', (41, 59))	('Breast cancer', 'Disease', (60, 73))	('Breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('BC', 'Phenotype', 'HP:0003002', (190, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('invasive breast cancer', 'Disease', (123, 145))	('situ breast cancer', 'Disease', (41, 59))	('invasive breast cancer', 'Disease', 'MESH:D001943', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('variants', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancers', 'Disease', 'MESH:D001943', (174, 188))	('breast cancers', 'Disease', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
158638	26070784	To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3).	('single nucleotide polymorphisms', 'Var', (86, 117))	('Cancer', 'Phenotype', 'HP:0002664', (253, 259))	('BC', 'Phenotype', 'HP:0003002', (171, 173))	('BC', 'Phenotype', 'HP:0003002', (199, 201))	("Cancer Institute's Breast and Prostate Cancer Cohort", 'Disease', 'MESH:D011471', (253, 305))	('Cancer', 'Phenotype', 'HP:0002664', (292, 298))	('BC', 'Phenotype', 'HP:0003002', (59, 61))	('BC', 'Phenotype', 'HP:0003002', (31, 33))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (283, 298))	('BC', 'Phenotype', 'HP:0003002', (159, 161))	('invasive BC', 'Disease', (150, 161))
158639	26070784	We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016).	('FGFR2', 'Gene', (62, 67))	('5p12-rs10941679', 'Var', (96, 111))	('rs10941679', 'Mutation', 'rs10941679', (101, 111))	('BC', 'Phenotype', 'HP:0003002', (148, 150))	('FGFR2', 'Gene', (45, 50))	('FGFR2', 'Gene', '2263', (45, 50))	('rs3803662', 'Mutation', 'rs3803662', (85, 94))	('FGFR2', 'Gene', '2263', (62, 67))	('rs2981582', 'Mutation', 'rs2981582', (68, 77))	('BCIS risk', 'Disease', (148, 157))	('CDKN2BAS', 'Gene', (25, 33))	('rs3750817', 'Mutation', 'rs3750817', (51, 60))	('TNRC9', 'Gene', (79, 84))	('rs1011970', 'Mutation', 'rs1011970', (34, 43))	('associated', 'Reg', (132, 142))	('CDKN2BAS', 'Gene', '100048912', (25, 33))	('TNRC9', 'Gene', '27324', (79, 84))
158643	26070784	Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.	('invasive BC', 'Disease', (116, 127))	('rs1011970', 'Var', (160, 169))	('BC', 'Phenotype', 'HP:0003002', (252, 254))	('rs1011970', 'Mutation', 'rs1011970', (160, 169))	('CDKN2BAS', 'Gene', '100048912', (215, 223))	('BCIS', 'Disease', (107, 111))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('risk factors', 'Reg', (85, 97))	('BC', 'Phenotype', 'HP:0003002', (107, 109))	('BC', 'Phenotype', 'HP:0003002', (125, 127))	('CDKN2BAS', 'Gene', (215, 223))
158648	26070784	DCIS is generally considered a precursor lesion of invasive BC; however, a direct causality has not been firmly established because it is not possible to verify that the removal of DCIS decreases the risk of developing the invasive disease.	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('invasive disease', 'Disease', (223, 239))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('decreases', 'NegReg', (186, 195))	('DCIS', 'Gene', (181, 185))	('removal', 'Var', (170, 177))	('invasive disease', 'Disease', 'MESH:D009362', (223, 239))
158649	26070784	Findings from the Million Women Study indicated that 2p-rs4666451 may be differentially associated with invasive BC and BCIS, while Milne and colleagues identified the association of 5p12-rs10941679 with lower-grade BC as well as with DCIS, but not with high-grade BC.	('BCIS', 'Disease', (120, 124))	('lower-grade BC', 'Disease', (204, 218))	('BC', 'Phenotype', 'HP:0003002', (120, 122))	('BC', 'Phenotype', 'HP:0003002', (113, 115))	('association', 'Interaction', (168, 179))	('5p12-rs10941679', 'Var', (183, 198))	('rs4666451', 'Mutation', 'rs4666451', (56, 65))	('invasive BC', 'Disease', (104, 115))	('2p-rs4666451', 'Var', (53, 65))	('BC', 'Phenotype', 'HP:0003002', (216, 218))	('rs10941679', 'Mutation', 'rs10941679', (188, 198))	('BC', 'Phenotype', 'HP:0003002', (265, 267))	('DCIS', 'Disease', (235, 239))	('DCIS', 'Phenotype', 'HP:0030075', (235, 239))	('associated', 'Reg', (88, 98))	('Women', 'Species', '9606', (26, 31))
158650	26070784	With the aim of verifying whether susceptibility SNPs identified through GWAS on invasive BC are also relevant for BCIS, we selected 39 single nucleotide polymorphisms (SNPs) previously shown to be associated with invasive BC, and performed an association study on 1317 BCIS cases and 14,006 controls in the context of the US National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3).	('BC', 'Phenotype', 'HP:0003002', (270, 272))	('Cancer', 'Phenotype', 'HP:0002664', (374, 380))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	("Cancer Institute's Breast and Prostate Cancer Cohort", 'Disease', 'MESH:D011471', (335, 387))	('BC', 'Phenotype', 'HP:0003002', (223, 225))	('associated', 'Reg', (198, 208))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (365, 380))	('single nucleotide polymorphisms', 'Var', (136, 167))	('BC', 'Phenotype', 'HP:0003002', (90, 92))	('invasive BC', 'Disease', (214, 225))	('BC', 'Phenotype', 'HP:0003002', (115, 117))
158655	26070784	In particular, for the following SNPs we have genotyped either the original SNP or the surrogate: rs4415084 (surrogate rs920329), rs9344191 (surrogate rs9449341), rs1250003 (surrogate rs704010), rs999737 (surrogate rs10483813), rs2284378 (surrogates rs8119937 and rs6059651), rs2180341 (surrogate rs9398840), rs311499 (surrogate rs311498,) and rs1917063 (surrogate rs9344208).	('rs4415084', 'Mutation', 'rs4415084', (98, 107))	('rs2284378', 'Mutation', 'rs2284378', (228, 237))	('rs9398840', 'Mutation', 'rs9398840', (297, 306))	('rs311499', 'Var', (309, 317))	('rs9344191', 'Mutation', 'rs9344191', (130, 139))	('rs6059651', 'Var', (264, 273))	('rs2180341', 'Mutation', 'rs2180341', (276, 285))	('rs999737', 'Mutation', 'rs999737', (195, 203))	('rs2284378', 'Var', (228, 237))	('rs8119937', 'Mutation', 'rs8119937', (250, 259))	('rs6059651', 'Mutation', 'rs6059651', (264, 273))	('rs999737', 'Var', (195, 203))	('rs2180341', 'Var', (276, 285))	('rs9449341', 'Mutation', 'rs9449341', (151, 160))	('rs4415084', 'Var', (98, 107))	('rs1917063', 'Var', (344, 353))	('rs10483813', 'Mutation', 'rs10483813', (215, 225))	('rs311498', 'Mutation', 'rs311498', (329, 337))	('rs311499', 'Mutation', 'rs311499', (309, 317))	('rs920329', 'Mutation', 'rs920329', (119, 127))	('rs1250003', 'Mutation', 'rs1250003', (163, 172))	('rs1917063', 'Mutation', 'rs1917063', (344, 353))	('rs704010', 'Mutation', 'rs704010', (184, 192))	('rs1250003', 'Var', (163, 172))	('rs9344208', 'Mutation', 'rs9344208', (365, 374))	('rs9344191', 'Var', (130, 139))
158660	26070784	We removed subjects from the NHS cohort for the analysis of ZMIZ1-rs1045485 and 11q13-rs614367 since the genotype distribution showed departure from the Hardy-Weinberg equilibrium among the controls (P = 8.4 x 10-4 and P = 6 x 10-4, respectively) in this cohort.	('ZMIZ1', 'Gene', '57178', (60, 65))	('NHS', 'Gene', (29, 32))	('ZMIZ1', 'Gene', (60, 65))	('11q13-rs614367', 'Var', (80, 94))	('rs614367', 'Mutation', 'rs614367', (86, 94))	('rs1045485', 'Mutation', 'rs1045485', (66, 75))	('NHS', 'Gene', '4810', (29, 32))
158661	26070784	We found significant associations (at the conventional 0.05 level) between 14 SNPs and risk of BCIS, with P values ranging from 0.041 (GMBE2-rs311499) to 3.0 x 10-6 (FGFR2-rs2981582) (Table 2).	('BCIS', 'Disease', (95, 99))	('BC', 'Phenotype', 'HP:0003002', (95, 97))	('GMBE2-rs311499', 'Var', (135, 149))	('FGFR2', 'Gene', '2263', (166, 171))	('FGFR2', 'Gene', (166, 171))	('rs2981582', 'Mutation', 'rs2981582', (172, 181))	('rs311499', 'Mutation', 'rs311499', (141, 149))
158662	26070784	When accounting for multiple testing (P <0.0016), five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) showed a statistically significant association with BCIS.	('TNRC9', 'Gene', (115, 120))	('rs1011970', 'Mutation', 'rs1011970', (70, 79))	('TNRC9', 'Gene', '27324', (115, 120))	('CDKN2BAS', 'Gene', (61, 69))	('5p12-rs10941679', 'Var', (132, 147))	('BCIS', 'Disease', (201, 205))	('rs10941679', 'Mutation', 'rs10941679', (137, 147))	('rs3750817', 'Mutation', 'rs3750817', (87, 96))	('significant association', 'Reg', (172, 195))	('FGFR2', 'Gene', (81, 86))	('FGFR2', 'Gene', (98, 103))	('CDKN2BAS', 'Gene', '100048912', (61, 69))	('rs2981582', 'Mutation', 'rs2981582', (104, 113))	('rs3803662', 'Mutation', 'rs3803662', (121, 130))	('FGFR2', 'Gene', '2263', (98, 103))	('FGFR2', 'Gene', '2263', (81, 86))	('BC', 'Phenotype', 'HP:0003002', (201, 203))
158664	26070784	None of the SNPs associated exclusively with estrogen receptor negative (ER-) BC (C19Orf62-rs8170, RALY-rs2284378, USHBP1-rs12982178 and TERT-rs10069690) or with both ER- and estrogen receptor positive (ER+) (6q14-rs13437553, 6q14-rs9344191, 6q14-rs17530068 and 20q11-rs4911414) in the literature showed an association with BCIS in this study, even at the 0.05 level.	('RALY', 'Gene', (99, 103))	('C19Orf62', 'Gene', (82, 90))	('C19Orf62', 'Gene', '29086', (82, 90))	('rs8170', 'Mutation', 'rs8170', (91, 97))	('rs4911414', 'Mutation', 'rs4911414', (268, 277))	('rs9344191', 'Mutation', 'rs9344191', (231, 240))	('6q14-rs17530068', 'Var', (242, 257))	('USHBP1', 'Gene', '83878', (115, 121))	('rs10069690', 'Mutation', 'rs10069690', (142, 152))	('rs17530068', 'Mutation', 'rs17530068', (247, 257))	('TERT', 'Gene', (137, 141))	('6q14-rs9344191', 'Var', (226, 240))	('20q11-rs4911414', 'Var', (262, 277))	('rs12982178', 'Mutation', 'rs12982178', (122, 132))	('TERT', 'Gene', '7015', (137, 141))	('rs13437553', 'Mutation', 'rs13437553', (214, 224))	('6q14-rs13437553', 'Var', (209, 224))	('BC', 'Phenotype', 'HP:0003002', (324, 326))	('rs2284378', 'Mutation', 'rs2284378', (104, 113))	('BC', 'Phenotype', 'HP:0003002', (78, 80))	('BCIS', 'Disease', (324, 328))	('USHBP1', 'Gene', (115, 121))	('RALY', 'Gene', '22913', (99, 103))
158671	26070784	For CDKN2BAS-rs1011970, HaploReg showed that the G to T nucleotide change of the SNP may alter the binding site for three transcription factors: FOXO4, TFC12 and p300.	('binding site', 'Interaction', (99, 111))	('G to', 'Var', (49, 53))	('CDKN2BAS', 'Gene', (4, 12))	('FOXO4', 'Gene', '4303', (145, 150))	('p300', 'Gene', (162, 166))	('alter', 'Reg', (89, 94))	('CDKN2BAS', 'Gene', '100048912', (4, 12))	('TFC12', 'Gene', (152, 157))	('rs1011970', 'Mutation', 'rs1011970', (13, 22))	('FOXO4', 'Gene', (145, 150))	('p300', 'Gene', '2033', (162, 166))
158672	26070784	The Regulome DB had no data for this SNP and Genevar showed that the T allele is associated with decreased CDKN2BA gene expression (P = 0.002).	('CDKN2B', 'Gene', '1030', (107, 113))	('expression', 'MPA', (120, 130))	('T allele', 'Var', (69, 77))	('decreased', 'NegReg', (97, 106))	('CDKN2B', 'Gene', (107, 113))
158677	26070784	The association between rs1011970 and BC risk (OR = 1.20) was reported by Turnbull using a large GWAS conducted in European studies and was replicated in the Breast Cancer Association Consortium (BCAC; OR = 1.09).	('Breast Cancer', 'Disease', (158, 171))	('BC', 'Phenotype', 'HP:0003002', (196, 198))	('rs1011970', 'Var', (24, 33))	('BC', 'Phenotype', 'HP:0003002', (38, 40))	('Breast Cancer', 'Disease', 'MESH:D001943', (158, 171))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('BCAC', 'Chemical', '-', (196, 200))	('rs1011970', 'Mutation', 'rs1011970', (24, 33))	('Breast Cancer', 'Phenotype', 'HP:0003002', (158, 171))
158678	26070784	From a biological point of view the association between rs1011970 and BCIS is intriguing since the SNP lies on 9p21, in an intron of the CDKN2B antisense (CDKN2B-AS1) gene, whose sequence overlaps with that of CDKN2B and flanks CDKN2A.	('CDKN2B', 'Gene', '1030', (210, 216))	('CDKN2B', 'Gene', '1030', (155, 161))	('CDKN2A', 'Gene', (228, 234))	('CDKN2B-AS1', 'Gene', (155, 165))	('rs1011970', 'Mutation', 'rs1011970', (56, 65))	('BC', 'Phenotype', 'HP:0003002', (70, 72))	('CDKN2A', 'Gene', '1029', (228, 234))	('BCIS', 'Disease', (70, 74))	('CDKN2B', 'Gene', (137, 143))	('CDKN2B-AS1', 'Gene', '100048912', (155, 165))	('rs1011970', 'Var', (56, 65))	('CDKN2B', 'Gene', '1030', (137, 143))	('CDKN2B', 'Gene', (210, 216))	('CDKN2B', 'Gene', (155, 161))
158680	26070784	HaploReg showed that the G to T nucleotide change of rs1011970 altered the binding ability of three important cell cycle regulators (FOXO4, TFC12 and p300), possibly altering CDKN2B regulation.	('rs1011970', 'Var', (53, 62))	('FOXO4', 'Gene', (133, 138))	('p300', 'Gene', (150, 154))	('altered', 'Reg', (63, 70))	('CDKN2B', 'Gene', (175, 181))	('p300', 'Gene', '2033', (150, 154))	('rs1011970', 'Mutation', 'rs1011970', (53, 62))	('altering', 'Reg', (166, 174))	('regulation', 'MPA', (182, 192))	('CDKN2B', 'Gene', '1030', (175, 181))	('FOXO4', 'Gene', '4303', (133, 138))	('binding', 'Interaction', (75, 82))
158682	26070784	The malfunctioning of this checkpoint might be particularly important in the initiation of the tumor.	('malfunctioning', 'Var', (4, 18))	('initiation of the tumor', 'Disease', 'MESH:D009369', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('initiation of the tumor', 'Disease', (77, 100))
158683	26070784	CDKN2B has been repeatedly found to be hypermethylated - a sign that the gene has been shut down, in benign lesions of the breast and in BCIS, indicating its involvement in the early phases of carcinogenesis.	('carcinogenesis', 'Disease', (193, 207))	('lesions of the breast', 'Phenotype', 'HP:0100013', (108, 129))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('shut down', 'NegReg', (87, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('hypermethylated', 'Var', (39, 54))	('involvement', 'Reg', (158, 169))	('CDKN2B', 'Gene', (0, 6))	('CDKN2B', 'Gene', '1030', (0, 6))
158686	26070784	In conclusion, our findings further support that the genetic variants associated with risk of BCIS and invasive BC largely overlap, with the possible exception of rs1011970, a putatively functionally relevant SNP situated in the CDKN2BAS gene that may be a specific BCIS locus.	('BC', 'Phenotype', 'HP:0003002', (266, 268))	('rs1011970', 'Var', (163, 172))	('rs1011970', 'Mutation', 'rs1011970', (163, 172))	('BC', 'Phenotype', 'HP:0003002', (112, 114))	('CDKN2BAS', 'Gene', '100048912', (229, 237))	('invasive BC', 'Disease', (103, 114))	('BCIS', 'Disease', (94, 98))	('BC', 'Phenotype', 'HP:0003002', (94, 96))	('CDKN2BAS', 'Gene', (229, 237))
158784	22833199	We categorize histopathological tumor size into four groups: <=20 mm, >20 and <=50 mm, >50 mm, and missing/not available, according to current International Union Against Cancer guidelines.	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('<=50 mm', 'Var', (78, 85))
158863	19735549	MCF10DCIS.COM represented a basal-like DCIS model, whereas SUM-225 and FSK-H7 cells were models for HER-2+ DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS.COM', 'Var', (0, 13))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('MCF10DCIS.COM', 'CellLine', 'CVCL:5552', (0, 13))	('HER-2', 'Gene', '2064', (100, 105))	('H7', 'Chemical', 'MESH:D019307', (75, 77))	('FSK', 'Chemical', '-', (71, 74))	('SUM-225', 'Chemical', '-', (59, 66))	('HER-2', 'Gene', (100, 105))
158977	19735549	Moreover, genetic manipulations of the microenvironment could potentially be used to study the roles of various factors involved in cancer cell invasion.	('genetic', 'Var', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
159006	19735549	This work was supported by NCI (1K99CA127462) and 5 P50 CA058183-13 DEV PJ19 to FB, NIH (CA116235) awarded to KP, Susan G Komen Breast Cancer Foundation (PDF042234) to MH, and the Breast Cancer Research Foundation (BCRF) to DCA.	('Breast Cancer', 'Disease', 'MESH:D001943', (180, 193))	('Breast Cancer', 'Disease', 'MESH:D001943', (128, 141))	('CA116235', 'Var', (89, 97))	('Breast Cancer', 'Phenotype', 'HP:0003002', (180, 193))	('Breast Cancer', 'Phenotype', 'HP:0003002', (128, 141))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Breast Cancer', 'Disease', (180, 193))	('Breast Cancer', 'Disease', (128, 141))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))
159071	32493410	Therefore, in patients diagnosed with DCIS by VAB, the rate of postoperative invasion detection was 27.1%, in contrast with that found in patients diagnosed by CNB, which was 52.2%.	('VAB', 'Var', (46, 49))	('VAB', 'Chemical', '-', (46, 49))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('DCIS', 'Var', (38, 42))	('invasion detection', 'CPA', (77, 95))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (138, 146))
159087	32493410	LDH and tumor markers showed no significant difference based on pre- and postoperative concordance, but invasion was significantly more likely to be found in the high PLR group than in the low PLR group.	('high PLR', 'Var', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('invasion', 'CPA', (104, 112))	('more', 'PosReg', (131, 135))
159089	32493410	High proliferative potential and malignancy, such as HER2-positive and high nuclear grade, cause comedonecrosis and intraductal calcification.	('cause', 'Reg', (91, 96))	('high', 'Var', (71, 75))	('calcification', 'Disease', 'MESH:D002114', (128, 141))	('HER2', 'Gene', (53, 57))	('malignancy', 'Disease', 'MESH:D009369', (33, 43))	('HER2', 'Gene', '2064', (53, 57))	('malignancy', 'Disease', (33, 43))	('calcification', 'Disease', (128, 141))	('comedonecrosis', 'Disease', (97, 111))
159108	31605508	High stromal integrin alpha11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple-negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels.	('increased', 'PosReg', (141, 150))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (76, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('positivity', 'Var', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('breast cancer', 'Disease', (268, 281))	('HER2', 'Gene', (192, 196))	('aggressive breast cancer', 'Disease', (76, 100))	('high histologic', 'Var', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('tumor', 'Disease', (151, 156))	('High', 'Protein', (0, 4))	('ER', 'Gene', '2099', (193, 195))	('ER', 'Gene', '2099', (177, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HER2', 'Gene', '2064', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
159177	31605508	Of note, cells positive for integrin alpha11 were mainly spindle-shaped, fibroblast-like cells, and the staining was often markedly accentuated in direct proximity to the cancer cells, indicating a 'border' between the epithelial component and the ECM (Figure 2B,D,E,G-I and see supplementary material, Figure S2A,B and D-F).	('accentuated', 'PosReg', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('integrin', 'Var', (28, 36))	('cancer', 'Disease', (171, 177))	('alpha11', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
159188	31605508	Using the lower tertile as cut-off value (SI 0-3 = 34% versus SI 4-9 = 66%), high integrin alpha11 protein expression was significantly associated with high histologic grade (OR 5.0), estrogen receptor (ER) negativity (OR 2.9), HER2 positivity (OR 2.7), triple-negative phenotype (OR 2.5) and high tumor cell proliferation by Ki-67 (OR 2.9) and mitotic count (OR 4.5) (Table 2).	('associated', 'Reg', (136, 146))	('ER', 'Gene', '2099', (203, 205))	('tumor', 'Disease', (298, 303))	('triple-negative', 'CPA', (254, 269))	('HER2', 'Gene', (228, 232))	('positivity', 'Var', (233, 243))	('high', 'Var', (77, 81))	('mitotic count', 'CPA', (345, 358))	('HER2', 'Gene', '2064', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('estrogen receptor', 'Gene', (184, 201))	('ER', 'Gene', '2099', (229, 231))	('estrogen receptor', 'Gene', '2099', (184, 201))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('high histologic grade', 'CPA', (152, 173))
159189	31605508	Furthermore, high integrin alpha11 protein expression was associated with the basal cell marker CK5/6 (OR 3.3), but not with tumor diameter or lymph node metastasis (Table 2).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CK5/6', 'Gene', (96, 101))	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('integrin alpha11 protein', 'Protein', (18, 42))	('expression', 'MPA', (43, 53))	('CK5/6', 'Gene', '3852', (96, 101))
159191	31605508	No significant associations between integrin alpha11 expression and breast cancer specific survival were found across different molecular breast cancer subgroups (see supplementary material, Figures [Link], [Link], [Link]), except that high integrin alpha11 mRNA expression was found to be associated with reduced survival in the Luminal B subgroup in the METABRIC discovery cohort (see supplementary material, Figure S5B), but this was not validated at the protein level or in the METABRIC validation cohort (see supplementary material, Figures S4B,C and S6B).	('S5B', 'Gene', '5711', (418, 421))	('S4B', 'Chemical', 'MESH:D013455', (546, 549))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('high', 'Var', (236, 240))	('S5B', 'Gene', (418, 421))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('survival', 'MPA', (314, 322))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (68, 81))	('reduced', 'NegReg', (306, 313))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('S6B', 'Chemical', 'MESH:C012008', (556, 559))
159193	31605508	Here, we present two new monoclonal mouse anti-human integrin alpha11 antibodies, 210F4B6A4 and D120.4, which bind to extracellular and intracellular epitopes of the integrin alpha11 subunit, respectively.	('human', 'Species', '9606', (47, 52))	('bind', 'Reg', (110, 114))	('mouse', 'Species', '10090', (36, 41))	('D120.4', 'Var', (96, 102))
159196	31605508	In agreement with a tumor-supportive effect of integrin alpha11beta1, high integrin alpha11 expression was associated with more aggressive breast cancer phenotypes, even though integrin alpha11 expression was not significantly correlated to breast cancer specific survival.	('aggressive breast cancer', 'Disease', 'MESH:D001943', (128, 152))	('aggressive breast cancer', 'Disease', (128, 152))	('expression', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('integrin alpha11', 'Gene', (75, 91))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('breast cancer', 'Disease', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('high', 'Var', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tumor', 'Disease', (20, 25))
159199	31605508	In the present study, investigating a breast cancer cohort of 392 patients, high integrin alpha11 expression in stromal spindle-shaped cells was significantly associated with high histologic grade, HER2 positivity, ER negativity, triple-negative phenotype and expression of the basal cell marker CK5/6, as well as high tumor cell proliferation by Ki-67 expression and mitotic count - all markers of aggressive breast cancer phenotypes.	('high histologic grade', 'CPA', (175, 196))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (399, 423))	('associated', 'Reg', (159, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('ER', 'Gene', '2099', (215, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (410, 423))	('triple-negative', 'CPA', (230, 245))	('CK5/6', 'Gene', (296, 301))	('positivity', 'Var', (203, 213))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('HER2', 'Gene', '2064', (198, 202))	('aggressive breast cancer', 'Disease', (399, 423))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Disease', 'MESH:D001943', (410, 423))	('tumor', 'Disease', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('HER2', 'Gene', (198, 202))	('integrin alpha11', 'Gene', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('CK5/6', 'Gene', '3852', (296, 301))	('mitotic', 'CPA', (368, 375))	('ER', 'Gene', '2099', (199, 201))	('expression', 'MPA', (98, 108))
159226	29973218	RU486 is able to partially block the effects of cortisol in vitro and in vivo.	('RU486', 'Chemical', 'MESH:D015735', (0, 5))	('effects', 'MPA', (37, 44))	('block', 'NegReg', (27, 32))	('cortisol', 'Chemical', 'MESH:D006854', (48, 56))	('RU486', 'Var', (0, 5))
159242	29973218	During the transition from DCIS to IDC, epigenetic changes have been observed in stromal cells, including fibroblasts and myoepithelial cells, suggesting that the microenvironment plays a relevant role.	('epigenetic changes', 'Var', (40, 58))	('IDC', 'Gene', '4000', (35, 38))	('IDC', 'Gene', (35, 38))	('myoepithelial', 'Disease', (122, 135))	('myoepithelial', 'Disease', 'MESH:D009208', (122, 135))
159258	29973218	Moreover, the GR antagonist, RU486 or mifepristone, has been suggested to be a normal breast epithelium protector, and in this context, there is an ongoing clinical trial based on the activity of RU486 in patients with breast cancer genes 1/2 (BRCA1/2) (clinical trial identifier NCT01898312).	('mifepristone', 'Chemical', 'MESH:D015735', (38, 50))	('GR', 'Gene', '2908', (14, 16))	('RU486', 'Var', (196, 201))	('patients', 'Species', '9606', (205, 213))	('RU486', 'Chemical', 'MESH:D015735', (196, 201))	('BRCA1/2', 'Gene', '672;675', (244, 251))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('activity', 'MPA', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('breast cancer', 'Disease', (219, 232))	('RU486', 'Chemical', 'MESH:D015735', (29, 34))	('BRCA1/2', 'Gene', (244, 251))
159264	29973218	MCF10DCIS (Asterand, MI, USA) and MCF10A (American Type Culture Collection (ATCC), VA, USA) human mammary cell lines were cultured at 37  in a humidified atmosphere with 5% CO2 in Dulbecco's modified Eagle's medium nutrient mixture-F12 (DMEM-F12) (Gibco, Life Technologies, CA, USA), supplemented with 1% of L-GlutaMAX  200 mM (Gibco, Life Technologies CA, USA), 100 U/mL penicillin, 100 mug/mL streptomycin and 5 mug/mL Fungizone (PSF) (Gibco, Life Technologies CA, USA), 5% of horse serum (Gibco, Life Technologies CA, USA) and, specifically, for MCF10A, 20 ng/mL epithelial growth factor (EGF) (Peprotech, NJ, USA), 0.5 mug/mL hydrocortisone (Sigma, MO, USA), 10 mug/mL insulin (Sigma, MO, USA) and 100 ng/mL cholera toxin (Sigma, MO, USA) were also added.	('PSF', 'Gene', (432, 435))	('GF', 'Chemical', 'MESH:C029660', (593, 595))	('CO2', 'Gene', (173, 176))	('MCF10A', 'Var', (549, 555))	('VA', 'Chemical', '-', (83, 85))	('horse', 'Species', '9796', (479, 484))	('PSF', 'Gene', '3490', (432, 435))	('MCF10A', 'CellLine', 'CVCL:0598', (549, 555))	('CO2', 'Gene', '717', (173, 176))	('MCF10A', 'CellLine', 'CVCL:0598', (34, 40))	('human', 'Species', '9606', (92, 97))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))
159269	29973218	After 24 h, cells were treated for 48 h with increasing concentrations of cortisol (0.1, 0.25, 0.5, 1, 2.5, 5 and 10 muM), corticosterone (0.125, 0.25, 0.375, 0.5, 0.75, 1, 1.25 and 1.5 muM) or with the corresponding vehicle concentration (methanol).	('0.125', 'Var', (139, 144))	('cortisol', 'Chemical', 'MESH:D006854', (74, 82))	('muM', 'Gene', '56925', (117, 120))	('muM', 'Gene', '56925', (186, 189))	('corticosterone', 'Chemical', 'MESH:D003345', (123, 137))	('muM', 'Gene', (117, 120))	('methanol', 'Chemical', 'MESH:D000432', (240, 248))	('muM', 'Gene', (186, 189))
159282	29973218	Cortisol 0.7 muM, corticosterone 1 muM and RU486 0.5 muM (Sigma, MO, USA) was used as treatment.	('Cortisol', 'Chemical', 'MESH:D006854', (0, 8))	('muM', 'Gene', '56925', (35, 38))	('muM', 'Gene', (53, 56))	('corticosterone', 'Chemical', 'MESH:D003345', (18, 32))	('muM', 'Gene', (13, 16))	('RU486', 'Chemical', 'MESH:D015735', (43, 48))	('muM', 'Gene', (35, 38))	('muM', 'Gene', '56925', (13, 16))	('RU486', 'Var', (43, 48))	('muM', 'Gene', '56925', (53, 56))
159287	29973218	Tumour growth and animal weight were monitored twice a week for 29 days after MCF10DCIS inoculation.	('Tumour growth', 'Disease', 'MESH:D006130', (0, 13))	('MCF10DCIS', 'Var', (78, 87))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (78, 87))	('Tumour growth', 'Disease', (0, 13))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))
159298	29973218	The day after inoculation, the tumours were treated with cortisol 0.7 muM or/and RU486 0.5 muM for 5 days.	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('RU486', 'Var', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('muM', 'Gene', '56925', (70, 73))	('RU486', 'Chemical', 'MESH:D015735', (81, 86))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('muM', 'Gene', '56925', (91, 94))	('muM', 'Gene', (70, 73))	('muM', 'Gene', (91, 94))	('tumours', 'Disease', (31, 38))
159303	29973218	Three-dimensional immunofluorescence was carried out in 3D cell cultures for 14 days after 8 days treatment with cortisol 0.7 muM, corticosterone 1 muM and RU486 0.5 muM as previously described.	('corticosterone', 'Chemical', 'MESH:D003345', (131, 145))	('muM', 'Gene', '56925', (126, 129))	('cortisol', 'Chemical', 'MESH:D006854', (113, 121))	('muM', 'Gene', (126, 129))	('muM', 'Gene', '56925', (148, 151))	('muM', 'Gene', '56925', (166, 169))	('RU486', 'Var', (156, 161))	('muM', 'Gene', (148, 151))	('muM', 'Gene', (166, 169))	('RU486', 'Chemical', 'MESH:D015735', (156, 161))
159305	29973218	Muc1-FITC (#559774, Becton Dickinson, NJ, USA) was used as primary antibody to counterstain epithelial cells.	('Muc1', 'Gene', '4582', (0, 4))	('Muc1', 'Gene', (0, 4))	('#559774', 'Var', (11, 18))	('FITC', 'Chemical', 'MESH:D016650', (5, 9))
159312	29973218	Depending on the technique performed and the manufacturer's specifications, different antibodies were used to detect myoepithelial cells: CD10 (1/100, #M7308, Dako, CA, USA), p63 (1/100, #sc-8431, Santa Cruz Biotechnologies, TE, USA) and alphaSMA (1/100) were used as primary antibodies.	('CD10', 'Gene', '4311', (138, 142))	('CD10', 'Gene', (138, 142))	('myoepithelial', 'Disease', (117, 130))	('myoepithelial', 'Disease', 'MESH:D009208', (117, 130))	('#M7308', 'Var', (151, 157))
159318	29973218	The primary antibodies, p63 (1/100) and cleaved caspase 3 (1/100) or laminin (1/100) were diluted in 5% normal goat serum in PBS and the mix was incubated for 2 h at RT in a humid box.	('laminin', 'Gene', '373980', (69, 76))	('caspase 3', 'Gene', (48, 57))	('caspase 3', 'Gene', '12367', (48, 57))	('PBS', 'Gene', (125, 128))	('laminin', 'Gene', (69, 76))	('PBS', 'Gene', '1131', (125, 128))	('goat', 'Species', '9925', (111, 115))	('p63', 'Var', (24, 27))
159357	29973218	However, RU486 treatment only partially prevented cortisol inhibition of laminin levels (Fig.	('prevented', 'NegReg', (40, 49))	('laminin', 'Gene', '373980', (73, 80))	('laminin', 'Gene', (73, 80))	('RU486', 'Var', (9, 14))	('RU486', 'Chemical', 'MESH:D015735', (9, 14))	('cortisol inhibition', 'MPA', (50, 69))	('cortisol', 'Chemical', 'MESH:D006854', (50, 58))
159363	29973218	The results showed that the first duct-like structures, surrounded by a layer of cells positive for alphaSMA and p63 (Additional file 5: Figure S2A), were formed at day 7 after inoculation of MCF10DCIS cells.	('alphaSMA', 'Protein', (100, 108))	('p63', 'Var', (113, 116))	('MCF10DCIS', 'Var', (192, 201))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (192, 201))
159389	29973218	Our results have shown that cortisol treatment slightly increases tumour volume, while treatment with cortisol and RU486 partially reverts this effect.	('increases', 'PosReg', (56, 65))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('cortisol', 'Chemical', 'MESH:D006854', (102, 110))	('RU486', 'Var', (115, 120))	('RU486', 'Chemical', 'MESH:D015735', (115, 120))	('cortisol', 'Chemical', 'MESH:D006854', (28, 36))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))
159392	29973218	However, combination of cortisol and RU486, not only reverted cortisol inhibition of alphaSMA and disruption of the myoepithelial cell layer, but also prevented cortisol induction of acinar fusion and reduced acini size (Fig.	('cortisol', 'MPA', (161, 169))	('alphaSMA', 'MPA', (85, 93))	('cortisol', 'Chemical', 'MESH:D006854', (161, 169))	('prevented', 'NegReg', (151, 160))	('acinar fusion', 'CPA', (183, 196))	('cortisol', 'Chemical', 'MESH:D006854', (24, 32))	('RU486', 'Var', (37, 42))	('reduced', 'NegReg', (201, 208))	('acini size', 'CPA', (209, 219))	('cortisol', 'Chemical', 'MESH:D006854', (62, 70))	('myoepithelial', 'Disease', (116, 129))	('myoepithelial', 'Disease', 'MESH:D009208', (116, 129))	('RU486', 'Chemical', 'MESH:D015735', (37, 42))
159395	29973218	Interestingly, RU486 treatment partially reverted the effects of cortisol on myoepithelial cell apoptosis (Fig.	('RU486', 'Var', (15, 20))	('RU486', 'Chemical', 'MESH:D015735', (15, 20))	('cortisol', 'Chemical', 'MESH:D006854', (65, 73))	('myoepithelial', 'Disease', (77, 90))	('myoepithelial', 'Disease', 'MESH:D009208', (77, 90))
159396	29973218	Thus, treatment with RU486 in vivo hampers cortisol induction of acinar fusion, degradation of the BM and myoepithelial cells apoptosis, preventing cortisol promotion of DCIS invasiveness.	('myoepithelial', 'Disease', 'MESH:D009208', (106, 119))	('cortisol', 'Chemical', 'MESH:D006854', (43, 51))	('RU486', 'Var', (21, 26))	('RU486', 'Chemical', 'MESH:D015735', (21, 26))	('cortisol', 'MPA', (148, 156))	('cortisol', 'Chemical', 'MESH:D006854', (148, 156))	('myoepithelial', 'Disease', (106, 119))	('DCIS invasiveness', 'CPA', (170, 187))	('preventing', 'NegReg', (137, 147))	('hampers', 'NegReg', (35, 42))	('acinar fusion', 'CPA', (65, 78))
159452	25445919	We have previously reported that a vitamin D compound, BXL0124, inhibits the progression of DCIS to IDC.	('progression', 'CPA', (77, 88))	('vitamin D', 'Chemical', 'MESH:D014807', (35, 44))	('IDC', 'Gene', '4000', (100, 103))	('DCIS', 'Disease', (92, 96))	('IDC', 'Gene', (100, 103))	('BXL0124', 'Chemical', 'MESH:C552206', (55, 62))	('inhibits', 'NegReg', (64, 72))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('BXL0124', 'Var', (55, 62))
159453	25445919	In MCF10DCIS cells treated with vitamin D compounds (1alpha25(OH)2D3 or BXL0124), the breast cancer stem cell-like population, identified by the CD44+/CD24-/low and CD49f+/CD24-/low subpopulations, was reduced.	('reduced', 'NegReg', (202, 209))	('MCF10DCIS', 'Var', (3, 12))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (53, 68))	('CD49f', 'Gene', (165, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('CD44', 'Gene', '960', (145, 149))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (3, 12))	('CD44', 'Gene', (145, 149))	('CD24', 'Gene', '100133941', (151, 155))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Disease', (86, 99))	('CD24', 'Gene', (172, 176))	('BXL0124', 'Chemical', 'MESH:C552206', (72, 79))	('vitamin D', 'Chemical', 'MESH:D014807', (32, 41))	('CD49f', 'Gene', '3655', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CD24', 'Gene', (151, 155))	('CD24', 'Gene', '100133941', (172, 176))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))
159456	25445919	When MCF10DCIS cells were treated with 1alpha25(OH)2D3 or BXL0124, the mammospheres that formed exhibited a more organized, symmetrical and circular shape, similar to the appearance of spheres formed by the non-malignant, normal mammary epithelial cell line, MCF10A.	('1alpha25', 'Var', (39, 47))	('exhibited', 'Reg', (96, 105))	('MCF10A', 'CellLine', 'CVCL:0598', (259, 265))	('BXL0124', 'Chemical', 'MESH:C552206', (58, 65))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (39, 54))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (5, 14))	('more', 'PosReg', (108, 112))	('BXL0124', 'Var', (58, 65))
159457	25445919	The mammosphere forming efficiency (MFE) was significantly decreased upon treatment with 1alpha25(OH)2D3 or BXL0124, indicating that these compounds have an inhibitory effect on mammosphere development.	('mammosphere forming efficiency', 'CPA', (4, 34))	('decreased', 'NegReg', (59, 68))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (89, 104))	('MFE', 'Chemical', '-', (36, 39))	('BXL0124', 'Chemical', 'MESH:C552206', (108, 115))	('BXL0124', 'Var', (108, 115))
159458	25445919	Treatment with 1alpha25(OH)2D3 or BXL0124 repressed markers associated with the stem cell-like phenotype, such as CD44, CD49f, c-Notch1, and pNFkappaB.	('Notch1', 'Gene', '4851', (129, 135))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (15, 30))	('CD44', 'Gene', (114, 118))	('CD49f', 'Gene', (120, 125))	('NFkappaB', 'Gene', (142, 150))	('BXL0124', 'Chemical', 'MESH:C552206', (34, 41))	('CD44', 'Gene', '960', (114, 118))	('NFkappaB', 'Gene', '4790', (142, 150))	('BXL0124', 'Var', (34, 41))	('Notch1', 'Gene', (129, 135))	('CD49f', 'Gene', '3655', (120, 125))
159459	25445919	Furthermore, 1alpha25(OH)2D3 and BXL0124 reduced the expression of pluripotency markers, OCT4 and KLF-4 in mammospheres.	('reduced', 'NegReg', (41, 48))	('BXL0124', 'Chemical', 'MESH:C552206', (33, 40))	('pluripotency markers', 'MPA', (67, 87))	('BXL0124', 'Var', (33, 40))	('KLF-4', 'Gene', '9314', (98, 103))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (13, 28))	('expression', 'MPA', (53, 63))	('OCT4', 'Gene', '5460', (89, 93))	('KLF-4', 'Gene', (98, 103))	('OCT4', 'Gene', (89, 93))
159473	25445919	Previous studies have shown that 1alpha25(OH)2D3 promoted the differentiation of colon cancer cells through increased E-cadherin expression and the inhibition of beta-catenin.	('differentiation', 'CPA', (62, 77))	('E-cadherin', 'Gene', (118, 128))	('E-cadherin', 'Gene', '999', (118, 128))	('expression', 'MPA', (129, 139))	('inhibition', 'NegReg', (148, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (33, 48))	('beta-catenin', 'Gene', (162, 174))	('increased', 'PosReg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colon cancer', 'Disease', 'MESH:D015179', (81, 93))	('beta-catenin', 'Gene', '1499', (162, 174))	('colon cancer', 'Disease', (81, 93))	('promoted', 'PosReg', (49, 57))	('1alpha25(OH)2D3', 'Var', (33, 48))
159478	25445919	Previously, we have shown that a Gemini vitamin D analog, BXL0124, can inhibit the transition from DCIS to IDC in vivo.	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('inhibit', 'NegReg', (71, 78))	('BXL0124', 'Chemical', 'MESH:C552206', (58, 65))	('transition', 'MPA', (83, 93))	('IDC', 'Gene', '4000', (107, 110))	('BXL0124', 'Var', (58, 65))	('vitamin D', 'Chemical', 'MESH:D014807', (40, 49))	('IDC', 'Gene', (107, 110))
159479	25445919	We have also demonstrated that BXL0124 was capable of reducing the CD44+/CD24-/low subpopulation of MCF10DCIS cells.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (100, 109))	('CD44', 'Gene', '960', (67, 71))	('CD44', 'Gene', (67, 71))	('CD24', 'Gene', '100133941', (73, 77))	('BXL0124', 'Chemical', 'MESH:C552206', (31, 38))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('BXL0124', 'Var', (31, 38))	('CD24', 'Gene', (73, 77))
159501	25445919	Primary antibodies against CD44 (sc-7297, 1:200), which recognizes both CD44s (standard form) and CD44v (variant form), NFkappaB (sc-372, 1:200) and cyclin D1 (sc-718, 1:200) were from Santa Cruz Biotechnology (Santa Cruz, CA); CD49f (3750, 1:1000), Notch1 (4380, 1:1000), c-Notch1 (4147, 1:1000), and pNFkappaB (3031, 1:1000) were from Cell Signaling Technology (Beverly, MA); CD24 (555426, 1:200) was from BD Biosciences (San Jose, CA), proliferating cell nuclear antigen (PCNA) (M0879, 1:400) was from Dako (Carpinteria, CA), and beta-actin (A1978, 1:2000) was from Sigma-Aldrich (St. Louis, MO).	('proliferating cell nuclear antigen', 'Gene', (439, 473))	('CD44', 'Gene', '960', (98, 102))	('CD44', 'Gene', (98, 102))	('A1978', 'Var', (545, 550))	('CD49f', 'Gene', (228, 233))	('CD44', 'Gene', '960', (72, 76))	('CD24', 'Gene', (378, 382))	('NFkappaB', 'Gene', '4790', (303, 311))	('CD44', 'Gene', (72, 76))	('cyclin D1', 'Gene', (149, 158))	('proliferating cell nuclear antigen', 'Gene', '5111', (439, 473))	('NFkappaB', 'Gene', '4790', (120, 128))	('PCNA', 'Gene', (475, 479))	('NFkappaB', 'Gene', (303, 311))	('cyclin D1', 'Gene', '595', (149, 158))	('CD44', 'Gene', '960', (27, 31))	('NFkappaB', 'Gene', (120, 128))	('Notch1', 'Gene', (275, 281))	('Notch1', 'Gene', '4851', (275, 281))	('Notch1', 'Gene', (250, 256))	('CD44', 'Gene', (27, 31))	('CD49f', 'Gene', '3655', (228, 233))	('CD24', 'Gene', '100133941', (378, 382))	('Notch1', 'Gene', '4851', (250, 256))	('PCNA', 'Gene', '5111', (475, 479))
159502	25445919	MCF10DCIS cells represent a basal-like or claudin-low breast tumor subtype, which typically carries a poor prognosis.	('breast tumor', 'Phenotype', 'HP:0100013', (54, 66))	('breast tumor', 'Disease', 'MESH:D001943', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('breast tumor', 'Disease', (54, 66))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS', 'Var', (0, 9))
159506	25445919	These populations were decreased with 1alpha25(OH)2D3 (100 nM) and BXL0124 (10 nM) treatment (Fig.	('1alpha25(OH)2D3', 'Var', (38, 53))	('decreased', 'NegReg', (23, 32))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (38, 53))	('BXL0124', 'Chemical', 'MESH:C552206', (67, 74))
159507	25445919	The CD44+/CD24-/low subpopulation was decreased from 68.7% in the control to 42.9% with 1alpha25(OH)2D3 (p < 0.01) and to 40.3% with BXL0124 treatment (p < 0.01).	('1alpha25', 'Var', (88, 96))	('BXL0124', 'Chemical', 'MESH:C552206', (133, 140))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (88, 103))	('CD44', 'Gene', '960', (4, 8))	('CD24', 'Gene', '100133941', (10, 14))	('CD24', 'Gene', (10, 14))	('CD44', 'Gene', (4, 8))
159508	25445919	Similarly, the CD49f+/CD24-/low population was decreased from 69.0% to 37.6% with 1alpha25(OH)2D3 (p < 0.01) and to 39.7% with BXL0124 treatment (p < 0.05).	('CD49f', 'Gene', (15, 20))	('1alpha25', 'Var', (82, 90))	('BXL0124', 'Chemical', 'MESH:C552206', (127, 134))	('CD24', 'Gene', '100133941', (22, 26))	('CD24', 'Gene', (22, 26))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (82, 97))	('CD49f', 'Gene', '3655', (15, 20))	('decreased', 'NegReg', (47, 56))
159509	25445919	Concomitantly, the CD44+/CD24high cell fraction was increased from 31.3% to 59.7% and 57.1% with 1alpha25(OH)2D3 and BXL0124 treatments, respectively, and the CD49f+/CD24high population was increased from 31.0% to 62.4% with 1alpha25(OH)2D3 and to 60.3% with BXL0124 treatment (Fig.	('CD49f', 'Gene', (159, 164))	('increased', 'PosReg', (52, 61))	('CD24', 'Gene', (166, 170))	('BXL0124', 'Chemical', 'MESH:C552206', (259, 266))	('CD44', 'Gene', (19, 23))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (97, 112))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (225, 240))	('CD49f', 'Gene', '3655', (159, 164))	('CD24', 'Gene', '100133941', (25, 29))	('CD24', 'Gene', (25, 29))	('BXL0124', 'Chemical', 'MESH:C552206', (117, 124))	('1alpha25', 'Var', (97, 105))	('1alpha25(OH)2D3', 'Var', (225, 240))	('CD24', 'Gene', '100133941', (166, 170))	('CD44', 'Gene', '960', (19, 23))	('BXL0124', 'Var', (117, 124))
159512	25445919	Spheres that formed from MCF10DCIS cells were irregularly shaped and formless (Fig.	('MCF10DCIS', 'Var', (25, 34))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (25, 34))	('formless', 'CPA', (69, 77))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))
159513	25445919	When these spheres were grown in the presence of 1alpha25(OH)2D3 or BXL0124, they showed a more round and uniform shape (Fig.	('more', 'PosReg', (91, 95))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (49, 64))	('BXL0124', 'Chemical', 'MESH:C552206', (68, 75))	('BXL0124', 'Var', (68, 75))
159514	25445919	Spheres from the normal mammary epithelial cell line, MCF10A, appeared relatively round and uniform, and there was no significant change in the MCF10A mammosphere shape in the presence of 1alpha25(OH)2D3 or BXL0124 (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (207, 214))	('1alpha25(OH)2D3', 'Var', (188, 203))	('mammosphere shape', 'CPA', (151, 168))	('MCF10A', 'Gene', (144, 150))	('BXL0124', 'Var', (207, 214))	('MCF10A', 'CellLine', 'CVCL:0598', (54, 60))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (188, 203))	('MCF10A', 'CellLine', 'CVCL:0598', (144, 150))
159518	25445919	The mammosphere forming efficiency (MFE) of MCF10DCIS was 0.12% and 0.12% at days 4 and 5 respectively, and by day 7 the MFE was reduced to 0.06% in the control.	('mammosphere forming efficiency', 'CPA', (4, 34))	('MFE', 'Chemical', '-', (121, 124))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('MFE', 'Chemical', '-', (36, 39))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (44, 53))	('MCF10DCIS', 'Var', (44, 53))
159520	25445919	The treatment with BXL0124 also inhibited the MFE of MCF10DCIS mammospheres at day 4 (40.8% inhibition, p < 0.01), day 5 (53.8% inhibition, p < 0.01), and day 7 (48.6% inhibition, p < 0.01) (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (19, 26))	('inhibited', 'NegReg', (32, 41))	('BXL0124', 'Var', (19, 26))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('MFE', 'Chemical', '-', (46, 49))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (53, 62))	('MFE', 'CPA', (46, 49))	('MCF10DCIS', 'Gene', (53, 62))
159521	25445919	Although 1alpha25(OH)2D3 and BXL0124 modestly affected the MFE in MCF10A cells, the changes were not statistically significant (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (29, 36))	('MCF10A', 'CellLine', 'CVCL:0598', (66, 72))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (9, 24))	('MFE', 'Chemical', '-', (59, 62))	('BXL0124', 'Var', (29, 36))	('MFE', 'MPA', (59, 62))	('affected', 'Reg', (46, 54))
159529	25445919	Cell surface receptor CD44 expression was decreased by 65% and 73% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('CD44', 'Gene', '960', (22, 26))	('decreased', 'NegReg', (42, 51))	('1alpha25(OH)2D3', 'Var', (72, 87))	('Cell surface', 'MPA', (0, 12))	('CD44', 'Gene', (22, 26))	('expression', 'MPA', (27, 37))	('BXL0124', 'Chemical', 'MESH:C552206', (103, 110))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (72, 87))	('BXL0124', 'Var', (103, 110))
159530	25445919	Integrin ITGA6 expression was decreased by 63% and 72% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('BXL0124', 'Chemical', 'MESH:C552206', (91, 98))	('BXL0124', 'Var', (91, 98))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (60, 75))	('expression', 'MPA', (15, 25))	('ITGA6', 'Gene', '3655', (9, 14))	('ITGA6', 'Gene', (9, 14))	('1alpha25(OH)2D3', 'Var', (60, 75))	('decreased', 'NegReg', (30, 39))
159531	25445919	Expression of another integrin, ITGB6, was decreased by 48% and 56% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('BXL0124', 'Var', (104, 111))	('Expression', 'MPA', (0, 10))	('ITGB6', 'Gene', '3694', (32, 37))	('ITGB6', 'Gene', (32, 37))	('1alpha25(OH)2D3', 'Var', (73, 88))	('BXL0124', 'Chemical', 'MESH:C552206', (104, 111))	('decreased', 'NegReg', (43, 52))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (73, 88))
159532	25445919	LAMA5 expression was decreased by 66% and 70% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('LAMA5', 'Gene', '3911', (0, 5))	('BXL0124', 'Chemical', 'MESH:C552206', (82, 89))	('decreased', 'NegReg', (21, 30))	('1alpha25(OH)2D3', 'Var', (51, 66))	('BXL0124', 'Var', (82, 89))	('LAMA5', 'Gene', (0, 5))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (51, 66))
159533	25445919	CD24 expression was modestly decreased by 26% and 40% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('BXL0124', 'Var', (90, 97))	('expression', 'MPA', (5, 15))	('CD24', 'Gene', '100133941', (0, 4))	('CD24', 'Gene', (0, 4))	('BXL0124', 'Chemical', 'MESH:C552206', (90, 97))	('decreased', 'NegReg', (29, 38))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (59, 74))
159535	25445919	Receptor NOTCH1 expression was decreased by 72% and 84% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('BXL0124', 'Chemical', 'MESH:C552206', (92, 99))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (61, 76))	('decreased', 'NegReg', (31, 40))	('BXL0124', 'Var', (92, 99))	('1alpha25(OH)2D3', 'Var', (61, 76))	('expression', 'MPA', (16, 26))	('NOTCH1', 'Gene', '4851', (9, 15))	('NOTCH1', 'Gene', (9, 15))
159536	25445919	Ligand JAG1 expression was decreased by 54% and 65% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('JAG1', 'Gene', '182', (7, 11))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (57, 72))	('BXL0124', 'Chemical', 'MESH:C552206', (88, 95))	('decreased', 'NegReg', (27, 36))	('Ligand', 'MPA', (0, 6))	('JAG1', 'Gene', (7, 11))	('BXL0124', 'Var', (88, 95))	('1alpha25(OH)2D3', 'Var', (57, 72))	('expression', 'MPA', (12, 22))
159537	25445919	Another ligand, JAG2 expression was decreased by 69% and 75% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('BXL0124', 'Var', (97, 104))	('1alpha25(OH)2D3', 'Var', (66, 81))	('expression', 'MPA', (21, 31))	('JAG2', 'Gene', (16, 20))	('JAG2', 'Gene', '3714', (16, 20))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (66, 81))	('BXL0124', 'Chemical', 'MESH:C552206', (97, 104))	('decreased', 'NegReg', (36, 45))
159538	25445919	NFKB1 expression was decreased by 62% and 66% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('NFKB1', 'Gene', (0, 5))	('BXL0124', 'Chemical', 'MESH:C552206', (82, 89))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('BXL0124', 'Var', (82, 89))	('NFKB1', 'Gene', '4790', (0, 5))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (51, 66))
159539	25445919	Genes involved in pluripotency and maintenance of the stem cell population were also suppressed, including OCT4 by 74% and 79% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively (Fig.	('BXL0124', 'Var', (163, 170))	('OCT4', 'Gene', '5460', (107, 111))	('suppressed', 'NegReg', (85, 95))	('OCT4', 'Gene', (107, 111))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (132, 147))	('1alpha25(OH)2D3', 'Var', (132, 147))	('pluripotency', 'MPA', (18, 30))	('BXL0124', 'Chemical', 'MESH:C552206', (163, 170))
159540	25445919	Expression of GATA3, a transcription factor regulating luminal-epithelial differentiation, was decreased by 76% and 78% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('decreased', 'NegReg', (95, 104))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (125, 140))	('GATA3', 'Gene', '2625', (14, 19))	('Expression', 'MPA', (0, 10))	('1alpha25(OH)2D3', 'Var', (125, 140))	('BXL0124', 'Var', (156, 163))	('GATA3', 'Gene', (14, 19))	('BXL0124', 'Chemical', 'MESH:C552206', (156, 163))
159541	25445919	Transcription factor KLF4 (Kruppel-like factor 4) expression was decreased by 53% and 53% with 1alpha25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.01), respectively.	('Kruppel-like factor 4', 'Gene', '9314', (27, 48))	('KLF4', 'Gene', '9314', (21, 25))	('decreased', 'NegReg', (65, 74))	('KLF4', 'Gene', (21, 25))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (95, 110))	('BXL0124', 'Chemical', 'MESH:C552206', (126, 133))	('BXL0124', 'Var', (126, 133))	('1alpha25(OH)2D3', 'Var', (95, 110))	('expression', 'MPA', (50, 60))	('Kruppel-like factor 4', 'Gene', (27, 48))
159542	25445919	The expression of transcription factors SOX2 and MYC were slightly decreased by with 1alpha25(OH)2D3 and BXL0124.	('1alpha25(OH)2D3', 'Var', (85, 100))	('BXL0124', 'Chemical', 'MESH:C552206', (105, 112))	('MYC', 'Gene', (49, 52))	('SOX2', 'Gene', (40, 44))	('expression', 'MPA', (4, 14))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (85, 100))	('SOX2', 'Gene', '6657', (40, 44))	('BXL0124', 'Var', (105, 112))	('decreased', 'NegReg', (67, 76))	('MYC', 'Gene', '4609', (49, 52))
159544	25445919	When MCF10DCIS spheres were grown in the presence of 1alpha25(OH)2D3 (100 nM) or BXL0124 (10 nM), they showed a more round and uniform shape (Fig.	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (53, 68))	('BXL0124', 'Chemical', 'MESH:C552206', (81, 88))	('more', 'PosReg', (112, 116))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('BXL0124', 'Var', (81, 88))	('MCF10DCIS', 'Var', (5, 14))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (5, 14))
159545	25445919	The mammosphere forming efficiency (MFE) of MCF10DCIS primary mammospheres was significantly reduced upon treatment with 1alpha25(OH)2D3 (37.2% inhibition, p < 0.01) or BXL0124 (48.0% inhibition, p < 0.01) (Fig.	('mammosphere forming efficiency', 'CPA', (4, 34))	('BXL0124', 'Var', (169, 176))	('BXL0124', 'Chemical', 'MESH:C552206', (169, 176))	('reduced', 'NegReg', (93, 100))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('MFE', 'Chemical', '-', (36, 39))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (44, 53))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (121, 136))	('MCF10DCIS', 'Var', (44, 53))
159547	25445919	Similar to the results with primary mammospheres, the MFE of secondary mammospheres was significantly repressed with 1alpha25(OH)2D3 (52.6% inhibition, p < 0.01) or BXL0124 (50.6% inhibition, p < 0.01).	('BXL0124', 'Chemical', 'MESH:C552206', (165, 172))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (117, 132))	('1alpha25', 'Var', (117, 125))	('MFE', 'Chemical', '-', (54, 57))	('BXL0124', 'Var', (165, 172))
159548	25445919	Tertiary mammospheres had a MFE of 0.56% in the control, and MFE was inhibited by 1alpha25(OH)2D3 (46.5% inhibition, p < 0.01) or BXL0124 (41.7% inhibition, p < 0.01) (Fig.	('MFE', 'CPA', (61, 64))	('MFE', 'Chemical', '-', (61, 64))	('BXL0124', 'Chemical', 'MESH:C552206', (130, 137))	('MFE', 'Chemical', '-', (28, 31))	('BXL0124', 'Var', (130, 137))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (82, 97))	('inhibited', 'NegReg', (69, 78))	('MFE', 'MPA', (28, 31))
159556	25445919	MCF10DCIS falls under the basal-like or claudin-low breast tumor subtype, which consist primarily of a CD44+ population.	('breast tumor', 'Disease', 'MESH:D001943', (52, 64))	('breast tumor', 'Disease', (52, 64))	('falls', 'Phenotype', 'HP:0002527', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast tumor', 'Phenotype', 'HP:0100013', (52, 64))	('basal-like', 'Disease', (26, 36))	('CD44', 'Gene', '960', (103, 107))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('CD44', 'Gene', (103, 107))	('MCF10DCIS', 'Var', (0, 9))
159564	25445919	The irregular shape formed from MCF10DCIS cells grown in mammospheres was altered to a more round appearance by 1alpha25(OH)2D3 and BXL0124 treatment.	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (112, 127))	('MCF10DCIS', 'Var', (32, 41))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (32, 41))	('altered', 'Reg', (74, 81))	('BXL0124', 'Chemical', 'MESH:C552206', (132, 139))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
159571	25445919	Knockdown of CD44 induces differentiation and drives the BCSC-like population toward a non-BCSC-like phenotype.	('BCSC-like population', 'CPA', (57, 77))	('Knockdown', 'Var', (0, 9))	('CD44', 'Gene', '960', (13, 17))	('CD44', 'Gene', (13, 17))	('induces', 'Reg', (18, 25))	('differentiation', 'CPA', (26, 41))	('drives', 'PosReg', (46, 52))
159580	25445919	Oct4 is a transcription factor that forms a heterodimer with Sox2 and regulates stem cell self-renewal capacity, and the knockdown of Oct4 promotes differentiation.	('knockdown', 'Var', (121, 130))	('stem cell self-renewal capacity', 'CPA', (80, 111))	('Oct4', 'Gene', (0, 4))	('Oct4', 'Gene', (134, 138))	('differentiation', 'CPA', (148, 163))	('Oct4', 'Gene', '5460', (0, 4))	('Oct4', 'Gene', '5460', (134, 138))	('heterodimer', 'Interaction', (44, 55))	('Sox2', 'Gene', '6657', (61, 65))	('regulates', 'Reg', (70, 79))	('Sox2', 'Gene', (61, 65))	('promotes', 'PosReg', (139, 147))
159582	25445919	The repression of pluripotency markers, such as OCT4, KLF-4, and GATA3, indicate that MCF10DCIS mammospheres treated with vitamin D compounds could potentially induce the differentiation of putative BCSCs.	('putative BCSCs', 'CPA', (190, 204))	('GATA3', 'Gene', '2625', (65, 70))	('OCT4', 'Gene', '5460', (48, 52))	('OCT4', 'Gene', (48, 52))	('vitamin D', 'Chemical', 'MESH:D014807', (122, 131))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (86, 95))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('MCF10DCIS', 'Var', (86, 95))	('KLF-4', 'Gene', '9314', (54, 59))	('GATA3', 'Gene', (65, 70))	('induce', 'PosReg', (160, 166))	('KLF-4', 'Gene', (54, 59))	('differentiation', 'CPA', (171, 186))
159618	24868232	The diagnostic criteria of DCIS within fibroadenoma requires showing at least one of the following findings: 1) intraductal carcinoma focus is also seen in the adjacent breast tissue and 2) intraductal proliferative lesions within fibroadenoma show cancer-characteristic findings, e.g., epithelial necrosis.	('fibroadenoma', 'Disease', (39, 51))	('intraductal carcinoma', 'Disease', 'MESH:D002285', (112, 133))	('proliferative lesions within fibroadenoma', 'Disease', (202, 243))	('proliferative lesions within fibroadenoma', 'Disease', 'MESH:D001929', (202, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('intraductal', 'Var', (190, 201))	('cancer', 'Disease', (249, 255))	('fibroadenoma', 'Disease', 'MESH:D018226', (231, 243))	('epithelial necrosis', 'Disease', 'MESH:D009336', (287, 306))	('fibroadenoma', 'Disease', 'MESH:D018226', (39, 51))	('fibroadenoma', 'Disease', (231, 243))	('intraductal carcinoma', 'Disease', (112, 133))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('epithelial necrosis', 'Disease', (287, 306))
159721	23693000	It can be seen that curves corresponding to ROI(a) and ROI(b) show a Type III curve, characterized by a rapid enhancement greater than 100% at the first time point and a subsequent washout, which is typical of a malignant tumor.	('enhancement', 'PosReg', (110, 121))	('malignant tumor', 'Disease', 'MESH:D018198', (212, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('ROI', 'Var', (55, 58))	('malignant tumor', 'Disease', (212, 227))
159723	23693000	However, enhancement curves corresponding to ROIs (d) and (e), which are within the tumor maps generated by the position and composite tuples but outside the velocity tumor map, correspond to a Type I persistent curve.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('enhancement', 'PosReg', (9, 20))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ROIs', 'Var', (45, 49))	('tumor', 'Disease', (167, 172))
159726	23693000	Considering the radiologist's segmentation as the gold standard, the DSC for the tumor map generated by the SLATS corresponding to the velocity tuple is higher than the DSC of the tumor maps generated from other observation tuples.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('higher', 'PosReg', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DSC', 'MPA', (69, 72))	('velocity tuple', 'Var', (135, 149))	('tumor', 'Disease', (81, 86))
159772	32823855	Mechanistic studies on human mammary cells and mammary glands of mice showed that ANXA8 upregulation is caused by genetic mutations affecting RARA functions.	('genetic mutations', 'Var', (114, 131))	('mice', 'Species', '10090', (65, 69))	('upregulation', 'PosReg', (88, 100))	('RARA', 'Gene', (142, 146))	('human', 'Species', '9606', (23, 28))	('ANXA8', 'Gene', (82, 87))
159790	32823855	Similar studies performed by the National Cancer Institute Breast and Prostate Cancer Cohort Consortium and the European Prospective Investigation of Cancer (EPIC) on subjects with different cancer predisposing conditions (e.g., obesity, diabetes, defective immunity, and aging) did not lead to firm conclusions.	('obesity', 'Disease', 'MESH:D009765', (229, 236))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('diabetes', 'Disease', (238, 246))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', (191, 197))	('Cancer', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('obesity', 'Phenotype', 'HP:0001513', (229, 236))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (70, 85))	('defective', 'Var', (248, 257))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('diabetes', 'Disease', 'MESH:D003920', (238, 246))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Breast and Prostate Cancer', 'Disease', 'MESH:D001943', (59, 85))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('obesity', 'Disease', (229, 236))	('Cancer', 'Disease', (150, 156))	('Cancer', 'Disease', (79, 85))
159793	32823855	It is noteworthy that APL was the first cancer showing the dysregulation of ANXA8, which is a member of the Annexin family of calcium (Ca2+) and phospholipid binding proteins involved in several cellular functions.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('APL', 'Phenotype', 'HP:0004836', (22, 25))	('Annexin', 'Gene', '191716', (108, 115))	('dysregulation', 'Var', (59, 72))	('cancer', 'Disease', (40, 46))	('APL', 'Disease', (22, 25))	('ANXA8', 'Gene', (76, 81))	('Annexin', 'Gene', (108, 115))	('APL', 'Disease', 'MESH:D015473', (22, 25))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('lipid', 'Chemical', 'MESH:D008055', (152, 157))	('Ca2+', 'Chemical', 'MESH:D000069285', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
159797	32823855	More than forty years ago, the laboratory of Dr. Janet Rowley detected chromosome translocation in acute promyelocytic leukemia (APL) cells.	('detected', 'Reg', (62, 70))	('APL', 'Disease', 'MESH:D015473', (129, 132))	('acute promyelocytic leukemia', 'Disease', (99, 127))	('rat', 'Species', '10116', (35, 38))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (99, 127))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (99, 127))	('APL', 'Phenotype', 'HP:0004836', (129, 132))	('APL', 'Disease', (129, 132))	('chromosome translocation', 'Var', (71, 95))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))
159803	32823855	Specifically, a small percentage of APL patients were characterized by other RARA fusion proteins generated by different translocations.	('translocations', 'Var', (121, 135))	('patients', 'Species', '9606', (40, 48))	('APL', 'Phenotype', 'HP:0004836', (36, 39))	('APL', 'Disease', 'MESH:D015473', (36, 39))	('APL', 'Disease', (36, 39))	('rat', 'Species', '10116', (102, 105))
159816	32823855	Human APL displayed a specific signature of miRNAs involved in regulatory loops of myeloid differentiation.	('Human', 'Species', '9606', (0, 5))	('involved', 'Reg', (51, 59))	('miRNAs', 'Var', (44, 50))	('APL', 'Phenotype', 'HP:0004836', (6, 9))	('APL', 'Disease', (6, 9))	('APL', 'Disease', 'MESH:D015473', (6, 9))
159833	32823855	Consistently, in vivo mouse studies showed that T47D cells expressing wild type RARA and T47D cells with a dominant negative RARA mutant (DN-RARA403), when grown in nude mice fed a control diet providing physiological RA, developed dorsal xenograft tumors of similar sizes.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('developed', 'Reg', (222, 231))	('RA', 'Chemical', 'MESH:D014212', (143, 145))	('T47D', 'CellLine', 'CVCL:0553', (89, 93))	('RA', 'Chemical', 'MESH:D014212', (127, 129))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('RA', 'Chemical', 'MESH:D014212', (141, 143))	('RA', 'Chemical', 'MESH:D014212', (80, 82))	('T47D', 'CellLine', 'CVCL:0553', (48, 52))	('RA', 'Chemical', 'MESH:D014212', (125, 127))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('nude mice', 'Species', '10090', (165, 174))	('RA', 'Chemical', 'MESH:D014212', (218, 220))	('mouse', 'Species', '10090', (22, 27))	('mutant', 'Var', (130, 136))	('RA', 'Chemical', 'MESH:D014212', (82, 84))	('tumors', 'Disease', (249, 255))
159846	32823855	In contrast, HME1 cells with mutations (e.g., the dominant negative RARA403 or the mutant PI3KCAH1047R p110 subunit) that affect the physiological RA transcriptional signaling developed 3D morphologically aberrant structures with a lumen filled with ANXA8-positive cells (Figure 3A, middle and right columns).	('RA', 'Chemical', 'MESH:D014212', (147, 149))	('mutant', 'Var', (83, 89))	('PI3KCAH1047R', 'Gene', (90, 102))	('HME1', 'CellLine', 'CVCL:3383', (13, 17))	('negative', 'NegReg', (59, 67))	('mutations', 'Var', (29, 38))	('RA', 'Chemical', 'MESH:D014212', (70, 72))	('affect', 'Reg', (122, 128))	('physiological RA transcriptional signaling', 'MPA', (133, 175))	('RARA403', 'Gene', (68, 75))	('RA', 'Chemical', 'MESH:D014212', (68, 70))
159848	32823855	In contrast, transgenic FVB female mice of the same age, expressing either MMTV-RARA403 or MMTV-PI3KCAH1047R mutations, showed mammary glands with ductal hyperplasia (DH) characterized by an enlarged lumen filled with ANXA8-positive cells (Figure 3B, middle and right columns) similar to human breast DH.	('ductal hyperplasia', 'Disease', 'MESH:D002285', (147, 165))	('ductal hyperplasia', 'Disease', (147, 165))	('human', 'Species', '9606', (288, 293))	('MMTV-PI3KCAH1047R mutations', 'Var', (91, 118))	('MMTV', 'Species', '11757', (75, 79))	('mice', 'Species', '10090', (35, 39))	('MMTV-RARA403', 'Gene', 'None', (75, 87))	('MMTV', 'Species', '11757', (91, 95))	('MMTV-RARA403', 'Gene', (75, 87))
159855	32823855	Apparently, ectopic ANXA8, by repressing the transcription of RARA-target genes, generates a downward spiral mechanism of aberrant morphogenesis (Figure 4B).	('ectopic', 'Var', (12, 19))	('transcription', 'MPA', (45, 58))	('rat', 'Species', '10116', (85, 88))
159858	32823855	RA via RARA can induce baseline ANXA8 protein expression by regulating the transcription of specific miRNAs targeting the ANXA8 mRNA 3'untranslated region (3'UTR), including miR-218 associated with breast DCIS and miR-342 associated with triple negative breast cancer (TNBC) (Figure 5A).	('miR-218', 'Var', (174, 181))	('associated', 'Reg', (182, 192))	('regulating', 'Reg', (60, 70))	('TNBC', 'Disease', 'None', (269, 273))	('RA', 'Chemical', 'MESH:D014212', (7, 9))	('RA', 'Chemical', 'MESH:D014212', (0, 2))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('TNBC', 'Disease', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('breast cancer', 'Disease', (254, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('miR-342', 'Gene', '442909', (214, 221))	('breast DCIS', 'Disease', (198, 209))	('associated', 'Reg', (222, 232))	('RA', 'Chemical', 'MESH:D014212', (9, 11))	('transcription', 'MPA', (75, 88))	('miR-342', 'Gene', (214, 221))
159859	32823855	Factors (e.g., genetic mutations) that inhibit the RA-RARA transcriptional regulation of these miRNAs upregulate the ANXA8 protein (Figure 5B).	('RA-RARA transcriptional regulation', 'MPA', (51, 85))	('ANXA8 protein', 'Protein', (117, 130))	('RA', 'Chemical', 'MESH:D014212', (56, 58))	('RA', 'Chemical', 'MESH:D014212', (51, 53))	('inhibit', 'NegReg', (39, 46))	('mutations', 'Var', (23, 32))	('upregulate', 'PosReg', (102, 112))	('RA', 'Chemical', 'MESH:D014212', (54, 56))
159862	32823855	Several years ago, epigenetic markers such as hypermethylated RARB2 enabled the detection of early stage breast cancer in ductal lavage fluid and random periareolar fine needle aspirates.	('hypermethylated', 'Var', (46, 61))	('RARB', 'Gene', '5915', (62, 66))	('rat', 'Species', '10116', (181, 184))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('RARB', 'Gene', (62, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
159863	32823855	Even if hypermethylated RARB2 has been proven useful for detecting RA-resistant breast cancer at pre-symptomatic stages, it has also shown some limitations (e.g., heterozygous RARB2 methylation may lead to false positives).	('hypermethylated', 'Var', (8, 23))	('RARB', 'Gene', '5915', (24, 28))	('RARB', 'Gene', (176, 180))	('RARB', 'Gene', '5915', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('methylation', 'Var', (182, 193))	('RA-resistant breast cancer', 'Disease', 'MESH:D001943', (67, 93))	('heterozygous', 'Var', (163, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('RARB', 'Gene', (24, 28))	('RA-resistant breast cancer', 'Disease', (67, 93))
159875	32823855	Several published studies have suggested that the dysregulation of annexins plays a role in prostate cancer (PCa) progression through distinct mechanisms.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('PCa', 'Phenotype', 'HP:0012125', (109, 112))	('prostate cancer', 'Disease', (92, 107))	('annexin', 'Gene', '191716', (67, 74))	('annexin', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('dysregulation', 'Var', (50, 63))
159882	32823855	The most significant risk factors for ovarian cancer are inherited genetic mutations of BRCA1 or BRCA2 genes that are responsible for about 10 to 15 percent of all ovarian cancers.	('responsible', 'Reg', (118, 129))	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', (97, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('genetic mutations', 'Var', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (164, 178))	('ovarian cancer', 'Disease', 'MESH:D010051', (38, 52))	('BRCA2', 'Gene', '675', (97, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (164, 178))	('ovarian cancers', 'Phenotype', 'HP:0100615', (164, 179))	('ovarian cancers', 'Disease', (164, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ovarian cancers', 'Disease', 'MESH:D010051', (164, 179))	('BRCA1', 'Gene', '672', (88, 93))	('ovarian cancer', 'Disease', (38, 52))
159891	32823855	A pancreatic cancer study speculated that ANXA8 expression was low in a normal pancreas due to CpG hypermethylation of the ANXA8 promoter-exon 1 region, while demethylation of the ANXA8 promoter-exon 1 region induced ANXA8 upregulation in pancreatic cancer that invaded the surrounding tissue and metastasized.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (239, 256))	('ANXA8', 'Gene', (217, 222))	('ANXA8', 'Gene', (42, 47))	('ANXA8', 'Gene', (123, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (2, 19))	('expression', 'MPA', (48, 58))	('metastasized', 'CPA', (297, 309))	('hypermethylation', 'Var', (99, 115))	('low', 'NegReg', (63, 66))	('pancreatic cancer', 'Disease', (2, 19))	('pancreatic cancer', 'Disease', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (2, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (239, 256))	('demethylation', 'Var', (159, 172))	('upregulation', 'PosReg', (223, 235))
159895	32823855	A high expression of ANXA8 represents a poor prognosis of overall survival and disease-free survival, and significantly correlates with the TNM (T for the size of the tumor and any spread of cancer into nearby tissue, N for the spread of cancer to nearby lymph nodes, and M for metastasis) staging system that was created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).	('ANXA8', 'Gene', (21, 26))	('Cancer', 'Disease', 'MESH:D009369', (357, 363))	('Cancer', 'Phenotype', 'HP:0002664', (407, 413))	('high expression', 'Var', (2, 17))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', (191, 197))	('TNM', 'Gene', '10178', (140, 143))	('CC', 'Phenotype', 'HP:0030153', (417, 419))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('TNM', 'Gene', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (167, 172))	('Cancer', 'Disease', (407, 413))	('correlates', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Cancer', 'Phenotype', 'HP:0002664', (357, 363))	('CC', 'Phenotype', 'HP:0030153', (367, 369))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('Cancer', 'Disease', 'MESH:D009369', (407, 413))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Disease', (357, 363))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
159899	32823855	Two studies showed that ANXA8; S100P, which is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs; and Glutathione Peroxidase 1 (GPX1) expression were decreased in CC dedifferentiation.	('GPX1', 'Gene', '2876', (164, 168))	('GPX1', 'Gene', (164, 168))	('ANXA8', 'Gene', (24, 29))	('Glutathione Peroxidase 1', 'Gene', '2876', (138, 162))	('S100P', 'Var', (31, 36))	('decreased', 'NegReg', (186, 195))	('CC', 'Phenotype', 'HP:0030153', (199, 201))	('Glutathione Peroxidase 1', 'Gene', (138, 162))	('S100P', 'SUBSTITUTION', 'None', (31, 36))	('calcium', 'Chemical', 'MESH:D002118', (110, 117))	('expression', 'MPA', (170, 180))
159998	29221896	Additional trace elements are detected for all the calcifications in varying proportions: sodium and aluminum are particularly prominent for particles in DCIS 1 and DCIS 2 while fluorine was unique to particles from DCIS 3.	('aluminum', 'Chemical', 'MESH:D000535', (101, 109))	('calcification', 'Disease', 'MESH:D002114', (51, 64))	('DCIS', 'Var', (154, 158))	('fluorine', 'Chemical', 'MESH:D005461', (178, 186))	('calcification', 'Disease', (51, 64))	('sodium', 'Chemical', 'MESH:D012964', (90, 96))
160084	21602195	For example, if the pathology showed extensive high nuclear-grade DCIS with comedo histology and close margins, the woman would be more likely to undergo mastectomy and, all else equal, would be more likely to have a recurrence than women without these characteristics.	('mastectomy', 'Disease', (154, 164))	('woman', 'Species', '9606', (116, 121))	('high nuclear-grade DCIS', 'Var', (47, 70))	('recurrence', 'CPA', (217, 227))	('women', 'Species', '9606', (233, 238))	('comedo', 'Phenotype', 'HP:0025249', (76, 82))
160098	21602195	Estimates of the correlation coefficients in the 3-equation model (rho12, rho13, and rho23) were modest in magnitude but jointly significantly different from 0 (p=0.035).	('rho23', 'Var', (85, 90))	('rho12', 'Gene', (67, 72))	('rho13', 'Var', (74, 79))	('rho12', 'Gene', '387', (67, 72))
160115	30911675	DCIS reflects the genomic changes (e.g., copy number changes, point mutations) and protein expression profile (e.g., estrogen receptor (ER), HER2 receptor) of subsequent invasive disease.	('HER2', 'Gene', '2064', (141, 145))	('invasive disease', 'Disease', 'MESH:D009362', (170, 186))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('point mutations', 'Var', (62, 77))	('estrogen receptor', 'Gene', (117, 134))	('ER', 'Gene', '2099', (142, 144))	('estrogen receptor', 'Gene', '2099', (117, 134))	('invasive disease', 'Disease', (170, 186))	('ER', 'Gene', '2099', (136, 138))	('copy number changes', 'Var', (41, 60))	('HER2', 'Gene', (141, 145))
160175	28412736	As for the subtype/immunophenotype, the chance of developing luminal A cancer was much lower for T1c compared to T1a, b disease (32.8% vs 40.7-43.7%, p = 0.021) whereas chance of developing triple-negative breast cancer (TNBC) much higher (13.0% vs 7.0-7.8%, p = 0.039).	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lower', 'NegReg', (87, 92))	('T1a', 'Gene', (113, 116))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('T1a', 'Gene', '10630', (113, 116))	('breast cancer', 'Disease', (206, 219))	('A cancer', 'Disease', 'MESH:D009369', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('T1c', 'Var', (97, 100))	('A cancer', 'Disease', (69, 77))
160177	28412736	The breast conserving rate was higher for T1b NPBC compared with T1a or T1c diseases (29.6% vs 13.6 and 19.8%, p = 0.008) (Supplementary Table 1).	('breast conserving rate', 'CPA', (4, 26))	('T1b', 'Var', (42, 45))	('higher', 'PosReg', (31, 37))	('T1a', 'Gene', '10630', (65, 68))	('T1a', 'Gene', (65, 68))
160178	28412736	The 5-year Kaplan-Meier estimated disease free survival (DFS) of T1a, T1b and T1c NPBC patients were 99.0%, 96.9% and 92.9%, whereas the 5-year overall survival (OS) were 100.0%, 100.0% and 97.9% respectively.	('T1c NPBC', 'Gene', '9173', (78, 86))	('T1c NPBC', 'Gene', (78, 86))	('T1b', 'Var', (70, 73))	('T1a', 'Gene', '10630', (65, 68))	('patients', 'Species', '9606', (87, 95))	('T1a', 'Gene', (65, 68))	('disease', 'Disease', (34, 41))
160198	28412736	Compared to T1a and b small breast cancer (<= 1.0 cm), T1c tumor (1.1-2.0 cm) had less chance of being luminal A and more chance of TNBC.	('small breast', 'Phenotype', 'HP:0003187', (22, 34))	('T1a', 'Gene', (12, 15))	('tumor', 'Disease', (59, 64))	('T1a', 'Gene', '10630', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('less', 'NegReg', (82, 86))	('T1c', 'Var', (55, 58))	('breast cancer', 'Disease', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
160216	28412736	In conclusion, the percentage of lymph node metastasis, pN, TNM stage, high Ki-67, receiving chemotherapy and targeted therapy increased in parallel with T1a, b, c unilateral invasive screen-detected NPBC.	('high', 'Var', (71, 75))	('TNM', 'Gene', (60, 63))	('lymph node metastasis', 'CPA', (33, 54))	('T1a', 'Gene', '10630', (154, 157))	('T1a', 'Gene', (154, 157))	('Ki-67', 'Gene', (76, 81))	('TNM', 'Gene', '10178', (60, 63))
160237	23704896	Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (77, 101))	('DEPDC1', 'Gene', (281, 287))	('CCNB1', 'Gene', '891', (296, 301))	('alterations', 'Var', (187, 198))	('invasive ductal carcinoma', 'Gene', (112, 137))	('BIRC5', 'Gene', '332', (234, 239))	('CEP55', 'Gene', (221, 226))	('BIRC5', 'Gene', (234, 239))	('NUSAP1', 'Gene', (273, 279))	('UBE2T', 'Gene', (259, 264))	('PTTG1', 'Gene', (266, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('HELLS', 'Gene', (289, 294))	('tumor', 'Disease', (344, 349))	('invasive ductal carcinoma', 'Gene', '4000', (112, 137))	('TOP2A', 'Gene', (214, 219))	('HELLS', 'Gene', '3070', (289, 294))	('KIF4A', 'Gene', '24137', (303, 308))	('DEPDC1', 'Gene', '55635', (281, 287))	('UBE2T', 'Gene', '29089', (259, 264))	('CCNB1', 'Gene', (296, 301))	('SHCBP1', 'Gene', '79801', (251, 257))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (77, 101))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('involved', 'Reg', (332, 340))	('CCNB2', 'Gene', '9133', (200, 205))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (77, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('KIAA0101', 'Gene', (241, 249))	('TOP2A', 'Gene', '7153', (214, 219))	('invasive ductal carcinoma', 'Gene', (68, 93))	('RRM2', 'Gene', '6241', (314, 318))	('NUSAP1', 'Gene', '51203', (273, 279))	('CEP55', 'Gene', '55165', (221, 226))	('IDC', 'Gene', '4000', (139, 142))	('ductal carcinoma in situ', 'Disease', (77, 101))	('UBE2C', 'Gene', (207, 212))	('IDC', 'Gene', (139, 142))	('TPX2', 'Gene', (228, 232))	('PTTG1', 'Gene', '9232', (266, 271))	('KIF4A', 'Gene', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('TPX2', 'Gene', '22974', (228, 232))	('RRM2', 'Gene', (314, 318))	('invasive ductal carcinoma', 'Gene', '4000', (68, 93))	('CCNB2', 'Gene', (200, 205))	('KIAA0101', 'Gene', '9768', (241, 249))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (121, 137))	('UBE2C', 'Gene', '11065', (207, 212))	('SHCBP1', 'Gene', (251, 257))
160253	23704896	The rationale is that genomic aberrations and altered pathways involved in oncogenesis are conserved by evolution across different species, and a number of important driver mutations in various cancers have been identified using comparative genomic approaches.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('mutations', 'Var', (173, 182))	('cancers', 'Disease', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))
160256	23704896	There are areas of genomic instability reported in many cancers, including breast cancer, and some regions commonly exhibit either deletion or increased gene dosage, leading to changes in DNA copy number (CN).	('cancers', 'Disease', (56, 63))	('changes', 'Reg', (177, 184))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('DNA copy number', 'MPA', (188, 203))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('deletion', 'Var', (131, 139))
160279	23704896	Global expression profiling of samples from tumor, IDC (n = 64) and DCIS (n = 7), and adjacent disease free tissues (n = 33) were probed using Affymetrix's GeneChip  Human Genome U133 Plus 2.0 Arrays representing over 47,000 transcripts and variants using more than 54,000 probe sets.	('variants', 'Var', (241, 249))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Human', 'Species', '9606', (166, 171))	('IDC', 'Gene', '4000', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('IDC', 'Gene', (51, 54))	('tumor', 'Disease', (44, 49))
160334	23704896	The presence of altered DNA CN may contribute to cancer formation and progression and could include transcriptional control mechanisms that locally impact gene expression levels.	('impact', 'Reg', (148, 154))	('cancer', 'Disease', (49, 55))	('DNA CN', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('include', 'Reg', (92, 99))	('altered', 'Var', (16, 23))	('progression', 'CPA', (70, 81))	('gene expression levels', 'MPA', (155, 177))	('presence', 'Var', (4, 12))	('contribute', 'Reg', (35, 45))
160356	23704896	Unsupervised clustering was performed and we found that our gene signature was sufficient to separate patients into two clusters which differed significantly by p53 mutation status (Figure S4).	('p53', 'Gene', (161, 164))	('patients', 'Species', '9606', (102, 110))	('mutation', 'Var', (165, 173))	('p53', 'Gene', '7157', (161, 164))
160357	23704896	The cluster which had high expression of these genes comprised nearly of all the p53 mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutant', 'Var', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
160358	23704896	Intriguingly, TP53 mutations in breast cancer are associated with poor survival independent of other risk factors.	('breast cancer', 'Disease', (32, 45))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('poor', 'NegReg', (66, 70))
160365	23704896	The TGFA positivity was significantly associated with young age (Fisher's exact test, p value = 0.02).	('positivity', 'Var', (9, 19))	('TGFA', 'Gene', '7039', (4, 8))	('associated', 'Reg', (38, 48))	('TGFA', 'Gene', (4, 8))
160382	23704896	Previous reports have shown in experimental models that Interleukin 1 (IL-1) promotes angiogenesis, tumor growth, and metastasis, and its presence in some human cancers is associated with aggressive tumor biology.	('aggressive tumor', 'Disease', (188, 204))	('tumor', 'Disease', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('IL-1', 'Gene', (71, 75))	('cancers', 'Disease', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('promotes', 'PosReg', (77, 85))	('metastasis', 'CPA', (118, 128))	('tumor', 'Disease', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('Interleukin 1', 'Gene', (56, 69))	('angiogenesis', 'CPA', (86, 98))	('aggressive tumor', 'Disease', 'MESH:D001523', (188, 204))	('presence', 'Var', (138, 146))	('human', 'Species', '9606', (155, 160))	('associated with', 'Reg', (172, 187))	('IL-1', 'Gene', '3552', (71, 75))	('Interleukin 1', 'Gene', '3552', (56, 69))
160385	23704896	Interestingly, mutant alleles of IL1RN were associated with shortened disease-free and overall survival among Caucasian women with breast cancer.	('shortened', 'NegReg', (60, 69))	('overall survival', 'CPA', (87, 103))	('breast cancer', 'Disease', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('women', 'Species', '9606', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('mutant', 'Var', (15, 21))	('IL1RN', 'Gene', '3557', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('IL1RN', 'Gene', (33, 38))
160390	23704896	The expression of TIAM1 has been shown to be associated with increased invasiveness and progression of breast carcinomas.	('breast carcinoma', 'Phenotype', 'HP:0003002', (103, 119))	('progression', 'CPA', (88, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('associated', 'Reg', (45, 55))	('breast carcinomas', 'Disease', 'MESH:D001943', (103, 120))	('breast carcinomas', 'Disease', (103, 120))	('increased', 'PosReg', (61, 70))	('invasiveness', 'CPA', (71, 83))	('TIAM1', 'Gene', '7074', (18, 23))	('TIAM1', 'Gene', (18, 23))	('expression', 'Var', (4, 14))	('breast carcinomas', 'Phenotype', 'HP:0003002', (103, 120))
160392	23704896	Previous studies have shown that important driver mutations in various cancers can be identified using comparative genomic approaches.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('mutations', 'Var', (50, 59))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
160402	23704896	Previous studies have reported that TP53 mutations in breast cancer are associated with poor survival independent of other risk factors and have a strong association with hormone receptor negative, HER2+ and basal-like subgroups.	('mutations', 'Var', (41, 50))	('breast cancer', 'Disease', (54, 67))	('association', 'Interaction', (154, 165))	('HER2', 'Gene', (198, 202))	('poor', 'NegReg', (88, 92))	('HER2', 'Gene', '2064', (198, 202))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
160408	23704896	This gene has been found to be functionally inactivated in the majority of human cancers, and aberrant in nearly half of breast cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('human', 'Species', '9606', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (121, 135))	('inactivated', 'NegReg', (44, 55))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancers', 'Disease', 'MESH:D001943', (121, 135))	('breast cancers', 'Disease', (121, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('aberrant', 'Var', (94, 102))
160416	23704896	The implication from these findings is that these genes may be contributing to the aggressive tumor behavior often present in these patients.	('contributing', 'Reg', (63, 75))	('genes', 'Var', (50, 55))	('aggressive tumor', 'Disease', 'MESH:D001523', (83, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('aggressive tumor', 'Disease', (83, 99))	('patients', 'Species', '9606', (132, 140))
160417	23704896	Our results confirm previous studies as well as provide additional insights into young age (<=45 years) and very young age (<=35 years) specific oncogenic alterations that may be promoting tumorigenesis.	('tumor', 'Disease', (189, 194))	('alterations', 'Var', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('promoting', 'PosReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('<=35', 'Var', (124, 128))
160418	23704896	Our cross species data analyses coupled with genomic copy number alterations may provide robust biomarkers for the detection of disease progression in young women and may lead to improved diagnosis and therapeutic options.	('copy number alterations', 'Var', (53, 76))	('women', 'Species', '9606', (157, 162))	('lead to', 'Reg', (171, 178))
160419	31528167	Comparing the Diagnostic Outcomes of Staining Various Breast Lesions with Either Anti-CK 5/6 or Anti-CK 5 Anti-CK5/6 monoclonal antibodies have an established role in breast disease diagnosis.	('CK 5/6', 'Gene', '3852', (86, 92))	('CK5/6', 'Gene', '3852', (111, 116))	('breast disease', 'Disease', (167, 181))	('CK5/6', 'Gene', (111, 116))	('breast disease', 'Disease', 'MESH:D001941', (167, 181))	('CK 5/6', 'Gene', (86, 92))	('Anti-CK 5', 'Var', (96, 105))
160436	31528167	These anti-CK 5/6 antibodies, recognize both CK5 and CK6 (and also CK4) in breast lesions.	('CK4', 'Gene', '3851', (67, 70))	('breast lesions', 'Disease', 'MESH:D001941', (75, 89))	('CK5', 'Gene', (45, 48))	('CK 5/6', 'Gene', '3852', (11, 17))	('breast lesions', 'Disease', (75, 89))	('CK4', 'Gene', (67, 70))	('CK5', 'Gene', '3852', (45, 48))	('CK6', 'Var', (53, 56))	('CK 5/6', 'Gene', (11, 17))
160438	31528167	It is unknown whether the staining seen with anti-CK5/6 monoclonal antibody is due mainly or in part to the anti-CK5 or the anti-CK6 activity (or whether both have equal importance in its use).	('CK5', 'Gene', (50, 53))	('anti-CK6', 'Var', (124, 132))	('CK5', 'Gene', (113, 116))	('CK5/6', 'Gene', '3852', (50, 55))	('CK5', 'Gene', '3852', (50, 53))	('CK5', 'Gene', '3852', (113, 116))	('CK5/6', 'Gene', (50, 55))
160440	31528167	There is some suggestion that with the anti-CK5/6 monoclonal antibody, the contribution of the anti-CK6 activity in breast cancer diagnosis is possibly less important than the anti-CK5 activity.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('CK5', 'Gene', (44, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('anti-CK6', 'Var', (95, 103))	('CK5', 'Gene', (181, 184))	('CK5/6', 'Gene', '3852', (44, 49))	('CK5', 'Gene', '3852', (44, 47))	('CK5/6', 'Gene', (44, 49))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('CK5', 'Gene', '3852', (181, 184))
160454	31528167	The H&E slide corresponding to a particular pair of anti-CK5/6 and anti-CK5 slides, was first examined, before viewing the test slides, to replicate as far as possible the real clinical diagnostic sequence in this study.	('CK5', 'Gene', (57, 60))	('CK5', 'Gene', '3852', (72, 75))	('H&E', 'Chemical', '-', (4, 7))	('CK5/6', 'Gene', '3852', (57, 62))	('CK5', 'Gene', '3852', (57, 60))	('and', 'Var', (63, 66))	('CK5', 'Gene', (72, 75))	('CK5/6', 'Gene', (57, 62))
160560	28427436	We observed a significant increase in cell/total volume ratio when this strategy was applied to cultures treated with doxycycline compared with untreated controls (Fig.	('cell/total volume ratio', 'MPA', (38, 61))	('rat', 'Species', '10116', (56, 59))	('doxycycline', 'Chemical', 'MESH:D004318', (118, 129))	('rat', 'Species', '10116', (74, 77))	('doxycycline', 'Var', (118, 129))	('increase', 'PosReg', (26, 34))
160570	28427436	Overexpression of HER2 in the luminal component of our bilayer model resulted in the destabilisation of the bilayer and filling of the luminal centre.	('destabilisation', 'NegReg', (85, 100))	('HER2', 'Gene', '2064', (18, 22))	('filling of the', 'CPA', (120, 134))	('Overexpression', 'Var', (0, 14))	('HER2', 'Gene', (18, 22))
160608	28427436	Lentiviral particles were generated by co-transfecting HEK293T cells with the packaging plasmids pMD2.G (12259; Addgene) and pCMVR8.2 (12263; Addgene) and either pLV-GFP (36083; Addgene), pLV-Azurite (36086; Addgene) or pINDUCER21-ERBB2 using FuGENE HD transfection reagent (Promega, Madison, WI, USA) following the manufacturer's guidelines.	('HD', 'Disease', 'MESH:D006816', (250, 252))	('rat', 'Species', '10116', (30, 33))	('36086', 'Var', (201, 206))	('HEK293T', 'CellLine', 'CVCL:0063', (55, 62))	('ERBB2', 'Gene', '2064', (231, 236))	('12263', 'Var', (135, 140))	('ERBB2', 'Gene', (231, 236))
160616	26424146	Aberrant activation of NF-kappaB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS).	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (94, 118))	('situ disease', 'Disease', 'MESH:D002278', (201, 213))	('carcinoma in situ', 'Disease', 'MESH:D002278', (101, 118))	('carcinoma in situ', 'Disease', (240, 257))	('DCIS', 'Phenotype', 'HP:0030075', (259, 263))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('NF-kappaB', 'Gene', (23, 32))	('situ disease', 'Disease', (201, 213))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (233, 257))	('ductal carcinoma', 'Disease', (94, 110))	('ductal carcinoma', 'Disease', (233, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('abnormal growth', 'Phenotype', 'HP:0001507', (74, 89))	('NF-kappaB', 'Gene', '18033', (23, 32))	('women', 'Species', '9606', (140, 145))	('carcinoma in situ', 'Disease', 'MESH:D002278', (240, 257))	('ductal carcinoma', 'Disease', 'MESH:D044584', (94, 110))	('ductal carcinoma', 'Disease', 'MESH:D044584', (233, 249))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('carcinoma in situ', 'Disease', (101, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
160624	26424146	These results indicate that aberrant NF-kappaB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('lead to', 'Reg', (88, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('activation', 'PosReg', (47, 57))	('aberrant', 'Var', (28, 36))	('NF-kappaB', 'Protein', (37, 46))
160701	26424146	In these transgenics, deletion of the inhibitor is systemic and activity through the canonical pathway is increased within every tissue, causing mortality by day 9 post birth.	('transgenic', 'Species', '10090', (9, 19))	('deletion', 'Var', (22, 30))	('canonical pathway', 'Pathway', (85, 102))	('activity', 'MPA', (64, 72))	('increased', 'PosReg', (106, 115))	('causing', 'Reg', (137, 144))
160717	26424146	In addition, we found that the terminal end-buds of the IKMV glands were larger than the controls.	('terminal end-buds', 'CPA', (31, 48))	('IKMV', 'Chemical', '-', (56, 60))	('larger', 'PosReg', (73, 79))	('IKMV', 'Var', (56, 60))
160720	26424146	Surprisingly, we found that after this short pulse of transgene induction, striking changes had occurred throughout the IKMV ductal structure.	('IKMV', 'Chemical', '-', (120, 124))	('changes', 'Reg', (84, 91))	('transgene', 'Var', (54, 63))
160732	26424146	Upon collection, we saw that the IKMV ducts were significantly larger than the control ducts in cross sectional area and had indeed become filled with cells (Fig.	('larger', 'PosReg', (63, 69))	('IKMV', 'Var', (33, 37))	('IKMV', 'Chemical', '-', (33, 37))
160736	26424146	To quantify apoptotic cells, we stained the tissue with caspase-3, but found no significant change in the number of caspase-3 positive cells in IKMV vs. control tissue (data not shown).	('caspase-3', 'Gene', '12367', (116, 125))	('caspase-3', 'Gene', (116, 125))	('IKMV', 'Chemical', '-', (144, 148))	('caspase-3', 'Gene', '12367', (56, 65))	('IKMV', 'Var', (144, 148))	('caspase-3', 'Gene', (56, 65))
160743	26424146	Furthermore, expression of the mitotic inhibitor p18INK4c (CDKN2C) was significantly decreased in IKMV tissue (Fig.	('decreased', 'NegReg', (85, 94))	('p18INK4c', 'Var', (49, 57))	('expression', 'MPA', (13, 23))	('mitotic inhibitor', 'MPA', (31, 48))	('IKMV', 'Chemical', '-', (98, 102))	('CDKN2C', 'Gene', '12580', (59, 65))	('CDKN2C', 'Gene', (59, 65))
160744	26424146	This change is consistent with the observed phenotype, as p18INK4c normally functions to restrain luminal progenitor cell expansion and inhibit luminal tumorigenesis in the mammary gland.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p18INK4c', 'Var', (58, 66))	('inhibit', 'NegReg', (136, 143))	('ser', 'Chemical', 'MESH:D012694', (37, 40))	('tumor', 'Disease', (152, 157))	('luminal progenitor cell expansion', 'CPA', (98, 131))	('restrain', 'NegReg', (89, 97))
160750	26424146	Our analysis revealed that downstream read-outs of inflammatory signaling, such as CXCL1, IL-1beta, TNF-alpha, and Cox-2, were significantly increased in the IKMV tissue.	('TNF-alpha', 'Gene', '21926', (100, 109))	('CXCL1', 'Gene', '14825', (83, 88))	('increased', 'PosReg', (141, 150))	('Cox-2', 'Gene', (115, 120))	('TNF-alpha', 'Gene', (100, 109))	('IL-1beta', 'Gene', '16176', (90, 98))	('IKMV', 'Chemical', '-', (158, 162))	('Cox-2', 'Gene', '17709', (115, 120))	('CXCL1', 'Gene', (83, 88))	('IL-1beta', 'Gene', (90, 98))	('IKMV', 'Var', (158, 162))	('inflammatory signaling', 'MPA', (51, 73))
160757	26424146	Converse to the up-regulation of these inflammatory components, we observed decreased hormone receptor expression in the IKMV mammary, including lower levels of estrogen receptor alpha (ERalpha), progesterone receptor, and prolactin receptor.	('levels', 'MPA', (151, 157))	('progesterone receptor', 'Gene', (196, 217))	('estrogen receptor alpha', 'Gene', '13982', (161, 184))	('hormone', 'Protein', (86, 93))	('IKMV', 'Var', (121, 125))	('decreased', 'NegReg', (76, 85))	('progesterone receptor', 'Gene', '18667', (196, 217))	('lower', 'NegReg', (145, 150))	('estrogen receptor alpha', 'Gene', (161, 184))	('prolactin receptor', 'Gene', '19116', (223, 241))	('ser', 'Chemical', 'MESH:D012694', (69, 72))	('prolactin receptor', 'Gene', (223, 241))	('IKMV', 'Chemical', '-', (121, 125))
160761	26424146	In addition, expression of Elf-5, a key regulator of mammary epithelial differentiation, was also decreased in IKMV epithelium.	('expression', 'MPA', (13, 23))	('IKMV', 'Chemical', '-', (111, 115))	('IKMV', 'Var', (111, 115))	('Elf-5', 'Gene', (27, 32))	('decreased', 'NegReg', (98, 107))	('Elf-5', 'Gene', '13711', (27, 32))
160762	26424146	Deletion of Elf-5 can lead to disorganized mammary structures and collapsed lumens, suggesting that this decrease in expression could be playing a role in the observed phenotype.	('lead to', 'Reg', (22, 29))	('Elf-5', 'Gene', '13711', (12, 17))	('expression', 'MPA', (117, 127))	('collapsed lumens', 'CPA', (66, 82))	('Deletion', 'Var', (0, 8))	('ser', 'Chemical', 'MESH:D012694', (161, 164))	('Elf-5', 'Gene', (12, 17))	('disorganized mammary structures', 'CPA', (30, 61))
160764	26424146	Dr. Striker observed that the ducts in the IKMV mice were expanded, containing mildly atypical cells with increased nuclear-cytoplasmic ratio, chromatin condensation, nuclear membrane abnormalities, and nucleoli.	('nuclear membrane abnormalities', 'CPA', (167, 197))	('nuclear-cytoplasmic', 'CPA', (116, 135))	('mice', 'Species', '10090', (48, 52))	('IKMV', 'Chemical', '-', (43, 47))	('chromatin condensation', 'CPA', (143, 165))	('IKMV', 'Var', (43, 47))	('rat', 'Species', '10116', (136, 139))	('increased', 'PosReg', (106, 115))	('ser', 'Chemical', 'MESH:D012694', (14, 17))
160771	26424146	Transplant studies using IKMV transgenic tissue revealed that aberrant activation of NF-kappaB during ductal outgrowth leads to hyper-branched, hyperplastic ductal structures.	('leads to', 'Reg', (119, 127))	('hyper-branched', 'Disease', (128, 142))	('activation', 'PosReg', (71, 81))	('hyper-branched', 'Disease', 'MESH:D002037', (128, 142))	('NF-kappaB', 'Gene', (85, 94))	('aberrant', 'Var', (62, 70))	('IKMV', 'Chemical', '-', (25, 29))	('transgenic', 'Species', '10090', (30, 40))
160774	26424146	Because the IKMV transgene is epithelial specific, we definitively show that aberrant NF-kappaB signaling originating within the epithelium can drive these morphological changes.	('NF-kappaB signaling', 'MPA', (86, 105))	('IKMV', 'Chemical', '-', (12, 16))	('aberrant', 'Var', (77, 85))
160779	26424146	We found that we could establish a network of normal ducts in 6 week old virgin females, and then induce hyperplasia through 3 days of aberrant NF-kappaB signaling.	('induce', 'Reg', (98, 104))	('hyperplasia', 'Disease', (105, 116))	('NF-kappaB signaling', 'MPA', (144, 163))	('aberrant', 'Var', (135, 143))	('hyperplasia', 'Disease', 'MESH:D006965', (105, 116))
160780	26424146	Though aberrant signaling through other cell-signaling pathways is certainly able to induce mammary ductal hyperplasia, it is often over a period of weeks or months, not days.	('ductal hyperplasia', 'Disease', 'MESH:D002285', (100, 118))	('aberrant', 'Var', (7, 15))	('induce', 'Reg', (85, 91))	('ductal hyperplasia', 'Disease', (100, 118))
160788	26424146	However, we did not find a significant increase in cyclin d1 mRNA expression in IKMV vs. control glands after the three day dox treatment (data not shown).	('IKMV', 'Chemical', '-', (80, 84))	('mRNA expression', 'MPA', (61, 76))	('dox', 'Chemical', 'MESH:D004318', (124, 127))	('IKMV', 'Var', (80, 84))	('cyclin d1', 'Gene', '12443', (51, 60))	('cyclin d1', 'Gene', (51, 60))
160789	26424146	We did observe changes in two other cell cycle mediators: cyclin b1 and p18INK4c.	('ser', 'Chemical', 'MESH:D012694', (9, 12))	('cyclin b1', 'Gene', '268697', (58, 67))	('changes', 'Reg', (15, 22))	('p18INK4c', 'Var', (72, 80))	('cyclin b1', 'Gene', (58, 67))
160791	26424146	Via CHIP analysis, it was shown that NF-kappaB bound the p18INK4c promoter, which contains these Alu-repeats, following viral infection of Hela cells.	('viral infection', 'Disease', 'MESH:D001102', (120, 135))	('viral infection', 'Disease', (120, 135))	('CHIP', 'Disease', (4, 8))	('Hela cells', 'CellLine', 'CVCL:0030', (139, 149))	('CHIP', 'Disease', 'None', (4, 8))	('p18INK4c', 'Var', (57, 65))
160796	26424146	We determined that aberrant NF-kappaB activation leads to decreased expression of hormone receptors and other markers of mammary epithelial differentiation such as Elf5 and CSN2.	('CSN2', 'Gene', '12991', (173, 177))	('Elf5', 'Gene', '13711', (164, 168))	('hormone receptors', 'Protein', (82, 99))	('expression of', 'MPA', (68, 81))	('decreased', 'NegReg', (58, 67))	('CSN2', 'Gene', (173, 177))	('activation', 'PosReg', (38, 48))	('aberrant', 'Var', (19, 27))	('NF-kappaB', 'Protein', (28, 37))	('Elf5', 'Gene', (164, 168))
160838	20602789	Triple-negative IDCs exhibited significantly lower Hsp90 expression.	('expression', 'MPA', (57, 67))	('Triple-negative', 'Var', (0, 15))	('Hsp90', 'Gene', (51, 56))	('lower', 'NegReg', (45, 50))	('Hsp90', 'Gene', '3320', (51, 56))
160839	20602789	The multivariable logistic regression model revealed that between the three markers, solely ER Allred score and c-erbB-2 positivity were independently associated with higher Hsp90 expression in IDC.	('Hsp90', 'Gene', (174, 179))	('higher', 'PosReg', (167, 173))	('c-erbB-2', 'Gene', (112, 120))	('c-erbB-2', 'Gene', '2064', (112, 120))	('Hsp90', 'Gene', '3320', (174, 179))	('ER Allred score', 'Gene', (92, 107))	('positivity', 'Var', (121, 131))	('expression', 'MPA', (180, 190))
160882	20602789	Table 3 presents the associations of Hsp90 Allred score with the immunohistochemical markers (figure 6, 7, 8).	('Hsp90', 'Gene', '3320', (37, 42))	('Hsp90', 'Gene', (37, 42))	('Allred', 'Var', (43, 49))	('associations', 'Interaction', (21, 33))
160885	20602789	The multivariable logistic regression model revealed that between the three markers, solely ER Allred score (OR = 1.29, 95%CI: 0.99-1.66) and c-erbB-2 positivity were independently associated with higher Hsp90 expression (OR = 1.85, 95%CI: 1.14-3.02).	('higher', 'PosReg', (197, 203))	('positivity', 'Var', (151, 161))	('expression', 'MPA', (210, 220))	('c-erbB-2', 'Gene', (142, 150))	('c-erbB-2', 'Gene', '2064', (142, 150))	('Hsp90', 'Gene', (204, 209))	('Hsp90', 'Gene', '3320', (204, 209))
160935	19691836	Therefore, in one contemporary model of the evolution of invasive ductal breast carcinomas, well-differentiated ductal carcinomas evolve from low-grade DCIS whereas poorly differentiated invasive ductal carcinomas evolve from high-grade DCIS, with minimal, if any, overlap.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('breast carcinomas', 'Phenotype', 'HP:0003002', (73, 90))	('low-grade', 'Var', (142, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('invasive ductal breast carcinomas', 'Disease', (57, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('ductal carcinomas', 'Disease', 'MESH:D044584', (112, 129))	('ductal carcinomas', 'Disease', (112, 129))	('invasive ductal breast carcinomas', 'Disease', 'MESH:D018270', (57, 90))	('ductal carcinomas', 'Disease', 'MESH:D044584', (196, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ductal carcinomas', 'Disease', (196, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))
161106	23935627	Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin.	('Breast Cancer', 'Disease', 'MESH:D001943', (50, 63))	('epidermal growth factor receptor', 'Gene', (120, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumour', 'Disease', (253, 259))	('human', 'Species', '9606', (114, 119))	('epidermal growth factor receptor', 'Gene', '1956', (120, 152))	('Breast Cancer', 'Disease', (50, 63))	('Herceptin', 'Chemical', 'MESH:D000068878', (322, 331))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (181, 195))	('rat', 'Species', '10116', (228, 231))	('Overexpression', 'PosReg', (96, 110))	('Breast Cancer', 'Phenotype', 'HP:0003002', (50, 63))	('Drug Resistance', 'Phenotype', 'HP:0020174', (80, 95))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('HER-2', 'Gene', (273, 278))	('HER-2', 'Gene', '2064', (154, 159))	('HER-2', 'Gene', '2064', (273, 278))	('proliferative advantages', 'CPA', (221, 245))	('HER-2', 'Gene', (154, 159))	('Splice Variants', 'Var', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancers', 'Disease', 'MESH:D001943', (181, 195))	('breast cancers', 'Disease', (181, 195))	('HER-2', 'Gene', '2064', (25, 30))	('survival', 'CPA', (208, 216))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('HER-2', 'Gene', (25, 30))
161107	23935627	Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology.	('HER-2', 'Gene', '2064', (74, 79))	('HER-2', 'Gene', (74, 79))	('delineation of tumour', 'Disease', 'MESH:D009369', (10, 31))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('delineation of tumour', 'Disease', (10, 31))	('splice variants', 'Var', (55, 70))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (25, 31))	('tumour', 'Disease', (107, 113))
161109	23935627	This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance.	('splice variants', 'Var', (102, 117))	('HER-2', 'Gene', (96, 101))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('HER-2', 'Gene', '2064', (96, 101))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Disease', (121, 127))
161136	23935627	HER-2 is routinely measured in clinical practice, and patients whose tumours score 3+ on HercepTest immunocytochemical staining (Figure 1(d)) and test positive for amplification of the HER-2 gene using fluorescence in situ hybridization (FISH) will be offered treatment with Herceptin in combination with chemotherapy.	('tumours', 'Disease', (69, 76))	('Herceptin', 'Chemical', 'MESH:D000068878', (275, 284))	('patients', 'Species', '9606', (54, 62))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('HER-2', 'Gene', (185, 190))	('amplification', 'Var', (164, 177))	('HER-2', 'Gene', '2064', (185, 190))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
161138	23935627	Moreover, amplification of the HER-2 gene occurs in a number of different cancers and is particularly prevalent in invasive carcinoma of the breast (Figure 3).	('HER-2', 'Gene', (31, 36))	('invasive carcinoma of the breast', 'Disease', (115, 147))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('occurs', 'Reg', (42, 48))	('cancers', 'Disease', (74, 81))	('prevalent', 'Reg', (102, 111))	('amplification', 'Var', (10, 23))	('HER-2', 'Gene', '2064', (31, 36))	('invasive carcinoma of the breast', 'Disease', 'MESH:D018270', (115, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
161151	23935627	To date, three naturally occurring HER-2 spliced variants in breast cancer have been reported (Table 1), namely, Delta16HER-2, Herstatin, and p100.	('Herstatin', 'Gene', '2064', (127, 136))	('HER-2', 'Gene', (35, 40))	('breast cancer', 'Disease', (61, 74))	('Herstatin', 'Gene', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('HER-2', 'Gene', '2064', (120, 125))	('p100', 'Var', (142, 146))	('HER-2', 'Gene', (120, 125))	('HER-2', 'Gene', '2064', (35, 40))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
161159	23935627	reported that 89% of patients with HER-2-positive breast tumours, in whom disease progresses to local lymph nodes, expressed Delta16HER2.	('breast tumours', 'Disease', (50, 64))	('HER-2', 'Gene', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('breast tumours', 'Disease', 'MESH:D001943', (50, 64))	('patients', 'Species', '9606', (21, 29))	('Delta16HER2', 'Var', (125, 136))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('HER-2', 'Gene', '2064', (35, 40))
161161	23935627	first described an HER-2 mRNA variant encoding a protein constituting only the extracellular domain of the full-length protein.	('HER-2', 'Gene', (19, 24))	('HER-2', 'Gene', '2064', (19, 24))	('variant', 'Var', (30, 37))
161162	23935627	Termed p100, this splice variant interferes with the oncogenic activity of wild-type HER-2 and arises via an in-frame stop codon as a result of intron 15 retention.	('interferes', 'NegReg', (33, 43))	('oncogenic activity', 'CPA', (53, 71))	('HER-2', 'Gene', '2064', (85, 90))	('HER-2', 'Gene', (85, 90))	('intron 15 retention', 'Var', (144, 163))
161163	23935627	Studied in cell lines and tumours derived from breast cancer and gastric cancer, p100 has the capacity to inhibit tumour cell proliferation.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumours', 'Disease', (26, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('breast cancer', 'Disease', (47, 60))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rat', 'Species', '10116', (133, 136))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('tumour', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('inhibit', 'NegReg', (106, 113))	('gastric cancer', 'Disease', (65, 79))	('p100', 'Var', (81, 85))
161170	23935627	This secreted HER-2 variant, like p100, contains only the extracellular domain of the full-length protein and has a novel C-terminus of 79 amino acids.	('HER-2', 'Gene', (14, 19))	('HER-2', 'Gene', '2064', (14, 19))	('C-terminus', 'MPA', (122, 132))	('variant', 'Var', (20, 27))
161191	23935627	reported that HER-2 positivity in DCIS patients was associated with increased risk of developing invasive carcinoma.	('positivity', 'Var', (20, 30))	('patients', 'Species', '9606', (39, 47))	('invasive carcinoma', 'Disease', 'MESH:D009361', (97, 115))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('HER-2', 'Gene', '2064', (14, 19))	('invasive carcinoma', 'Disease', (97, 115))	('HER-2', 'Gene', (14, 19))
161202	23935627	For example, induced exon skipping in Duchenne muscular dystrophy produces a "Becker muscular dystrophy-like dystrophin isoform," successfully reducing disease severity.	('reducing', 'NegReg', (143, 151))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (38, 65))	('Becker muscular dystrophy', 'Disease', 'MESH:D020388', (78, 103))	('dystrophin', 'Gene', (109, 119))	('Becker muscular dystrophy', 'Disease', (78, 103))	('induced exon skipping', 'Var', (13, 34))	('dystrophin', 'Gene', '1756', (109, 119))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (47, 65))	('Duchenne muscular dystrophy', 'Disease', (38, 65))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (85, 103))
161204	23935627	reported that SSO-induced skipping of exon 15 produced a novel protein, Delta15HER2, which acted to downregulate wild-type HER-2 and induce apoptosis of HER-2 overexpressing tumour cells.	('skipping', 'Var', (26, 34))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('HER-2', 'Gene', (153, 158))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('HER-2', 'Gene', '2064', (153, 158))	('induce', 'PosReg', (133, 139))	('apoptosis', 'CPA', (140, 149))	('downregulate', 'NegReg', (100, 112))	('exon', 'Gene', (38, 42))	('tumour', 'Disease', (174, 180))	('HER-2', 'Gene', '2064', (123, 128))	('Delta15HER2', 'Var', (72, 83))	('HER-2', 'Gene', (123, 128))
161206	23935627	Whilst research is ongoing to improve delivery methods of splicing-targeted therapies, they do appear as a promising strategy for future anticancer therapeutic intervention.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rat', 'Species', '10116', (119, 122))	('splicing-targeted', 'Var', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
161208	23935627	These spliced variants could consequently impact treatment routes in HER-2-positive tumours and also HER-2-negative tumours and DCIS.	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('HER-2', 'Gene', (101, 106))	('HER-2', 'Gene', '2064', (101, 106))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('variants', 'Var', (14, 22))	('treatment routes', 'CPA', (49, 65))	('DCIS', 'Phenotype', 'HP:0030075', (128, 132))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Disease', (116, 123))	('impact', 'Reg', (42, 48))	('HER-2', 'Gene', '2064', (69, 74))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('HER-2', 'Gene', (69, 74))
161209	23935627	For example, tumours previously deemed HER-2 negative which express that these variants above a specified threshold may in fact benefit from therapies targeting the HER-2 spliced variant thereby improving stratification of patients to "individualized" treatments.	('stratification', 'MPA', (205, 219))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (207, 210))	('HER-2', 'Gene', '2064', (39, 44))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('HER-2', 'Gene', (39, 44))	('variants', 'Var', (79, 87))	('benefit', 'PosReg', (128, 135))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('improving', 'PosReg', (195, 204))	('tumours', 'Disease', (13, 20))	('HER-2', 'Gene', (165, 170))	('HER-2', 'Gene', '2064', (165, 170))	('patients', 'Species', '9606', (223, 231))
161210	23935627	Additionally, proportions of splice variants in patients who do not respond to, or regress on, anti-HER-2 drugs may indicate treatment with alternative drugs as a superior alternative.	('splice variants', 'Var', (29, 44))	('patients', 'Species', '9606', (48, 56))	('HER-2', 'Gene', (100, 105))	('HER-2', 'Gene', '2064', (100, 105))
161229	30537987	This model system includes the parental normal-like cell line [MCF10A (P)]; MCF10.AT1, which recapitulates atypia; MCF10.DCIS, which is similar to ductal carcinoma in situ and MCF10.Ca1d, an invasive cancer line.	('MCF10.Ca1', 'CellLine', 'CVCL:5555', (176, 185))	('MCF10A', 'CellLine', 'CVCL:0598', (63, 69))	('invasive cancer', 'Disease', 'MESH:D009362', (191, 206))	('MCF10.DCIS', 'Var', (115, 125))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (147, 171))	('ductal carcinoma in situ', 'Disease', (147, 171))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (76, 85))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (147, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('invasive cancer', 'Disease', (191, 206))
161232	30537987	Lately, numerous RNA sequencing studies have consistently reported the presence of variants of canonical miRNAs called isomiRNAs.	('miR', 'Gene', (105, 108))	('variants', 'Var', (83, 91))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('miR', 'Gene', '220972', (105, 108))
161233	30537987	These isomiRNAs are generated by deletion, substitution, insertion, or a 1 nt shift in the 5'/3' cleavage site of DICER.	("5'/3' cleavage site", 'MPA', (91, 110))	('insertion', 'Var', (57, 66))	('DICER', 'Gene', '23405', (114, 119))	('shift', 'Reg', (78, 83))	('deletion', 'Var', (33, 41))	('substitution', 'Var', (43, 55))	('DICER', 'Gene', (114, 119))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
161236	30537987	A couple of studies have suggested that isomiR-140-3p has functional significance, based on its expression levels in breast cancer cell lines and the fact that targeting this isomiRNA inhibited cell proliferation in breast cancer cell lines.	('targeting', 'Var', (160, 169))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('expression levels', 'MPA', (96, 113))	('breast cancer', 'Disease', (216, 229))	('miR', 'Gene', (178, 181))	('miR', 'Gene', '220972', (178, 181))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cell proliferation', 'CPA', (194, 212))	('inhibited', 'NegReg', (184, 193))
161238	30537987	We also report on the functional significance of this variant in TNBC tumorigenesis, mediated by regulation of the cholesterol biosynthesis/mevalonic acid (MVA) pathway, which creates a metabolic vulnerability that can be targeted for breast cancer prevention.	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cholesterol', 'Chemical', 'MESH:D002784', (115, 126))	('mevalonic acid', 'Chemical', 'MESH:D008798', (140, 154))	('tumor', 'Disease', (70, 75))	('variant', 'Var', (54, 61))	('TNBC', 'Gene', (65, 69))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('regulation', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('MVA', 'Chemical', 'MESH:D008798', (156, 159))	('breast cancer', 'Disease', (235, 248))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
161244	30537987	Premalignant MCF10.AT1 cells were obtained by transfection of MCF10A(P) cells with constitutively active oncogene H-ras, which form simple ducts in mice xenografts .	('MCF10.AT1', 'CellLine', 'CVCL:5555', (13, 22))	('MCF10A', 'Gene', (62, 68))	('H-ras', 'Gene', '3265', (114, 119))	('mice', 'Species', '10090', (148, 152))	('transfection', 'Var', (46, 58))	('H-ras', 'Gene', (114, 119))	('MCF10A', 'CellLine', 'CVCL:0598', (62, 68))
161269	30537987	Mutant versions of the HMGCR and HMGCS1 3'UTR reporter plasmids were generated by site-specific mutagenesis, as described previously.	('Mutant', 'Var', (0, 6))	('HMGCS1', 'Gene', '3157', (33, 39))	('HMGCR', 'Gene', (23, 28))	('HMGCS1', 'Gene', (33, 39))
161298	30537987	We found ectopic expression of miR-140-3p-1 to preferentially inhibit the colonization ability of preneoplastic MCF10.AT1 cells (62% reduction, p < 0.05 compared to control) but did not have functional effect further down the disease progression spectrum in MCF10.DCIS cells (Fig.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (258, 268))	('ectopic expression', 'Var', (9, 27))	('colonization ability', 'CPA', (74, 94))	('reduction', 'NegReg', (133, 142))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('inhibit', 'NegReg', (62, 69))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (112, 121))
161299	30537987	Similarly, ki-67 staining indicated that miR-140-3p-1 restoration modestly inhibited the cell proliferation (by 9.8%, p = 0.08) of preneoplastic MCF10.AT1 cells but not in MCF10.DCIS cells (Additional file 2: Figure S1).	('MCF10.AT1', 'Var', (145, 154))	('cell proliferation', 'CPA', (89, 107))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (172, 182))	('inhibited', 'NegReg', (75, 84))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (145, 154))
161314	30537987	As a control, we also studied the effect of miR-140-3p-1 mimic on luciferase activity of constructs that harbor a mutated miR-140-3p-1 binding site from the 3' UTR of HMGCR and HMGCS1.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('mutated', 'Var', (114, 121))	('HMGCS1', 'Gene', '3157', (177, 183))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('HMGCS1', 'Gene', (177, 183))	('binding', 'Interaction', (135, 142))
161315	30537987	As expected, the miR-140-3p-1 mimic failed to repress the luciferase activity of the mutant constructs (Fig.	('activity', 'MPA', (69, 77))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('luciferase', 'Enzyme', (58, 68))	('mutant', 'Var', (85, 91))
161325	30537987	Although we found fluvastatin-treated lesions to be 25% smaller than vehicle treated lesions, as indicated by their average weight (16.05 vs 12.48 mg, p = 0.03) (Fig.	('smaller', 'NegReg', (56, 63))	('fluvastatin', 'Chemical', 'MESH:D000077340', (18, 29))	('fluvastatin-treated', 'Var', (18, 37))
161361	30537987	Replacement of miR-140-3p-1 through strand-specific miRNA mimic preferentially inhibited the growth of preneoplastic cells, but not DCIS cells, suggesting its biologic relevance lies primarily in the normal-to-preneoplastic transition and less so in the later stages of disease evolution.	('growth of preneoplastic cells', 'CPA', (93, 122))	('inhibited', 'NegReg', (79, 88))	('Replacement', 'Var', (0, 11))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
161363	30537987	We found that miR-140-3p-1 controls the mevalonate (MVA) pathway, through direct regulation of HMGCR and HMGCS1, with the loss of miR-140-3p-1 promoting upregulation of HMGCR and HMGCS1 during the multi-step tumorigenic process.	('HMGCS1', 'Gene', (179, 185))	('mevalonate', 'Chemical', 'MESH:D008798', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('upregulation', 'PosReg', (153, 165))	('HMGCS1', 'Gene', '3157', (105, 111))	('miR', 'Gene', '220972', (130, 133))	('MVA', 'Chemical', 'MESH:D008798', (52, 55))	('miR', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('HMGCS1', 'Gene', (105, 111))	('loss', 'Var', (122, 126))	('HMGCS1', 'Gene', '3157', (179, 185))
161364	30537987	Of interest, and in line with our observations, high expression of MVA pathway genes e.g., HMGCR, has been reported to be associated with resistance to therapeutic targeting of the MVA pathway and with poor patient prognosis in breast cancer.	('associated', 'Reg', (122, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('MVA', 'Chemical', 'MESH:D008798', (181, 184))	('MVA pathway', 'Gene', (67, 78))	('MVA', 'Chemical', 'MESH:D008798', (67, 70))	('patient', 'Species', '9606', (207, 214))	('HMGCR', 'Gene', (91, 96))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('high', 'Var', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('MVA pathway', 'Pathway', (181, 192))	('breast cancer', 'Disease', (228, 241))
161366	30537987	Specifically, within the context of preneoplastic disease, this upregulation of the MVA pathway through loss of miR-140-3p-1 creates metabolic vulnerability that may be targeted by repurposing Food and Drug Administration (FDA)-approved low-toxicity drugs such as statins.	('preneoplastic disease', 'Disease', 'MESH:D011230', (36, 57))	('MVA', 'Chemical', 'MESH:D008798', (84, 87))	('loss', 'Var', (104, 108))	('metabolic vulnerability', 'MPA', (133, 156))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('toxicity', 'Disease', 'MESH:D064420', (241, 249))	('upregulation', 'PosReg', (64, 76))	('preneoplastic disease', 'Disease', (36, 57))	('toxicity', 'Disease', (241, 249))	('MVA pathway', 'Pathway', (84, 95))
161369	30537987	Statins have been previously shown to inhibit the tumor volume in MCF10NeuA-, MDA-MB-435- and HepG2-driven xenografts, which is in agreement with the reduced growth of MCF10.AT1-driven lesions in the current study.	('HepG2', 'CellLine', 'CVCL:0027', (94, 99))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('MCF10', 'CellLine', 'CVCL:5555', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (78, 88))	('MCF10NeuA-', 'Var', (66, 76))	('inhibit', 'NegReg', (38, 45))	('MCF10', 'CellLine', 'CVCL:5555', (66, 71))	('tumor', 'Disease', (50, 55))
161382	30537987	Recently, statin treatments have been suggested to show anticancer effects on tumors that were derived from cells possessing mutated p53.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutated', 'Var', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (60, 66))	('p53', 'Gene', (133, 136))	('p53', 'Gene', '7157', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
161383	30537987	P53 mutants have been shown to aberrantly activate the MVA pathway, and conversely statin inhibition of the MVA pathway is also shown to destabilize and degrade mutated p53, indicating that statins are most likely to work in patients in whom the MVA pathway is activated through p53 mutations.	('p53', 'Gene', (279, 282))	('p53', 'Gene', '7157', (279, 282))	('patients', 'Species', '9606', (225, 233))	('mutants', 'Var', (4, 11))	('MVA pathway', 'Pathway', (55, 66))	('destabilize', 'NegReg', (137, 148))	('activate', 'PosReg', (42, 50))	('mutations', 'Var', (283, 292))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('MVA', 'Chemical', 'MESH:D008798', (108, 111))	('P53', 'Gene', (0, 3))	('MVA', 'Chemical', 'MESH:D008798', (55, 58))	('mutated', 'MPA', (161, 168))	('P53', 'Gene', '7157', (0, 3))	('degrade', 'NegReg', (153, 160))	('MVA', 'Chemical', 'MESH:D008798', (246, 249))
161385	30537987	We believe that inability of fluvastatin to inhibit the histological progression was due to insufficient suppression of the cholesterol pathway and that activating AMPK will sensitize cells to statins irrespective of p53 status (wild-type or mutant).	('p53', 'Gene', (217, 220))	('statins', 'MPA', (193, 200))	('p53', 'Gene', '7157', (217, 220))	('cholesterol pathway', 'Pathway', (124, 143))	('fluvastatin', 'Chemical', 'MESH:D000077340', (29, 40))	('activating', 'Var', (153, 163))	('AMPK', 'Gene', '5564', (164, 168))	('mutant', 'Var', (242, 248))	('AMPK', 'Gene', (164, 168))	('cholesterol', 'Chemical', 'MESH:D002784', (124, 135))	('sensitize', 'Reg', (174, 183))
161389	30537987	Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer cell metastasis and invasion.	('breast cancer cell metastasis', 'Disease', 'MESH:D009362', (67, 96))	('LKB1', 'Gene', '6794', (8, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('disrupts', 'NegReg', (13, 21))	('breast cancer cell metastasis', 'Disease', (67, 96))	('breast epithelial cell polarity', 'CPA', (22, 53))	('promotes', 'PosReg', (58, 66))	('Loss', 'Var', (0, 4))	('LKB1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('invasion', 'CPA', (101, 109))
161432	23054103	Similarly, when stratified by DCIS size, a greater proportion of women with DCIS>5 cm (71 %) received a SLNB than women with DCIS between 2 and 5 cm (58 %) and women with DCIS that was<2 cm (45 %; Fig.	('women', 'Species', '9606', (114, 119))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('women', 'Species', '9606', (160, 165))	('DCIS>5 cm', 'Var', (76, 85))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('SLNB', 'MPA', (104, 108))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('women', 'Species', '9606', (65, 70))
161450	23054103	Both high grade and large DCIS size have been associated with increased risk of harboring invasive cancer, which may explain why patients with these characteristics were more likely to undergo SLNB at time of mastectomy in our study.	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('high grade', 'Var', (5, 15))	('patients', 'Species', '9606', (129, 137))	('large DCIS', 'Var', (20, 30))	('invasive cancer', 'Disease', (90, 105))	('invasive cancer', 'Disease', 'MESH:D009362', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
161451	23054103	Risk of invasive cancer also is increased with DCIS recurrence, which may explain why women without a prior primary tumor were less likely to undergo SLNB than women with a history of prior cancers.	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('tumor', 'Disease', (116, 121))	('invasive cancer', 'Disease', 'MESH:D009362', (8, 23))	('DCIS', 'Var', (47, 51))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('women', 'Species', '9606', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('invasive cancer', 'Disease', (8, 23))	('women', 'Species', '9606', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
161477	25566499	This review presents current perspectives on research of HER-Notch crosstalk in breast cancer and culminates recent publications to give an up-to-date view of the intricate mechanisms that describe how communication between these two pathways is affecting the development of malignancies, drug resistance, recurrence, and metastatic progression.	('ER', 'Gene', '2099', (58, 60))	('malignancies', 'Disease', 'MESH:D009369', (275, 287))	('development', 'CPA', (260, 271))	('Notch', 'Gene', '31293', (61, 66))	('recurrence', 'CPA', (306, 316))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('drug resistance', 'CPA', (289, 304))	('malignancies', 'Disease', (275, 287))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (289, 304))	('metastatic progression', 'CPA', (322, 344))	('breast cancer', 'Disease', (80, 93))	('communication', 'Var', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('Notch', 'Gene', (61, 66))	('affecting', 'Reg', (246, 255))
161488	25566499	HER2 amplification results in overexpression of the HER2 receptor on the surface of breast cancer cell.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('HER2', 'Gene', '2064', (52, 56))	('amplification', 'Var', (5, 18))	('HER2', 'Gene', (52, 56))	('overexpression', 'PosReg', (30, 44))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))
161499	25566499	There are many different mutations that can cause breast cancer and this heterogeneity makes it a difficult disease to treat and at times, diagnose.	('mutations', 'Var', (25, 34))	('cause', 'Reg', (44, 49))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
161510	25566499	HER/HER receptor(s) dimerization stimulates auto-phosphorylation, followed by trans-phosphorylation of the receptor partner.	('stimulates', 'PosReg', (33, 43))	('auto-phosphorylation', 'MPA', (44, 64))	('dimerization', 'Var', (20, 32))	('trans-phosphorylation', 'MPA', (78, 99))	('ER', 'Gene', '2099', (1, 3))	('ER', 'Gene', '2099', (5, 7))
161513	25566499	These phosphorylated tyrosine residues recruit adaptor proteins such as Grb2 and the p85 subunit of the PI3K complex, which elicit the activation of several downstream pathways such as Protein Kinase B (AKT/PKB) and the mitogen activated protein kinase (MAPK) pathways (Figure 1E).	('p85', 'Gene', (85, 88))	('activation', 'PosReg', (135, 145))	('AKT/PKB', 'Gene', (203, 210))	('Protein Kinase B', 'Gene', (185, 201))	('Protein Kinase B', 'Gene', '2185', (185, 201))	('Grb2', 'Gene', (72, 76))	('tyrosine', 'Chemical', 'MESH:D014443', (21, 29))	('Grb2', 'Gene', '2885', (72, 76))	('p85', 'Gene', '5296', (85, 88))	('elicit', 'Reg', (124, 130))	('AKT/PKB', 'Gene', '207', (203, 210))	('tyrosine residues', 'Var', (21, 38))
161523	25566499	For example, only one EGF ligand is needed for downstream pathway activation when bound to EGFR and hetero-dimerized with HER2.	('EGF', 'Gene', (91, 94))	('hetero-dimerized', 'Var', (100, 116))	('EGF', 'Gene', '1950', (22, 25))	('EGF', 'Gene', '1950', (91, 94))	('HER2', 'Gene', (122, 126))	('HER2', 'Gene', '2064', (122, 126))	('bound', 'Interaction', (82, 87))	('EGF', 'Gene', (22, 25))
161529	25566499	HER2 gene amplification and subsequent HER2 protein overexpression occurs in 15-25% of DCIS and invasive forms of HER2+ breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('HER2', 'Gene', (114, 118))	('DCIS', 'Disease', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('HER2', 'Gene', '2064', (114, 118))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('HER2', 'Gene', '2064', (39, 43))	('HER2', 'Gene', (0, 4))	('amplification', 'Var', (10, 23))	('overexpression', 'PosReg', (52, 66))
161537	25566499	HER-mediated activation of PI3K causes the phosphorylation of the serine/threonine-specific protein kinase, AKT, which in turn activates mammalian Target of Rapamycin (mTOR).	('mTOR', 'Gene', (168, 172))	('AKT', 'Gene', '207', (108, 111))	('mTOR', 'Gene', '2475', (168, 172))	('threonine', 'Chemical', 'MESH:D013912', (73, 82))	('mammalian Target of Rapamycin', 'Gene', (137, 166))	('phosphorylation', 'MPA', (43, 58))	('PI3K', 'Var', (27, 31))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('AKT', 'Gene', (108, 111))	('mammalian Target of Rapamycin', 'Gene', '2475', (137, 166))	('ER', 'Gene', '2099', (1, 3))	('activates', 'PosReg', (127, 136))
161539	25566499	Many components of the AKT pathway have been implicated in tumorigenesis events such as the oncogenic activity of PI3K and the loss of the tumor suppressive activity of protein "Phosphatase and tensin homolog deleted on chromosome TEN (PTEN)".	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (59, 64))	('AKT', 'Gene', '207', (23, 26))	('loss of the tumor', 'Disease', 'MESH:D009369', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PTEN', 'Gene', (236, 240))	('loss of the tumor', 'Disease', (127, 144))	('AKT', 'Gene', (23, 26))	('PI3K', 'Var', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('PTEN', 'Gene', '5728', (236, 240))	('implicated', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
161540	25566499	These mutations have been suggested to drive cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (6, 15))	('drive', 'PosReg', (39, 44))
161541	25566499	Due to AKT's role in a variety of human solid tumors and hematological malignancies, several therapies have been developed to target components of the AKT pathway to reduce tumor survival such as: Wortmannin and LY294002, which are reversible and non-reversible inhibitors of PI3K, respectively.	('AKT', 'Gene', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('AKT', 'Gene', (7, 10))	('human', 'Species', '9606', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('solid tumors', 'Disease', 'MESH:D009369', (40, 52))	('LY294002', 'Chemical', 'MESH:C085911', (212, 220))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('Wortmannin', 'Chemical', 'MESH:D000077191', (197, 207))	('reduce', 'NegReg', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('AKT', 'Gene', '207', (7, 10))	('AKT', 'Gene', '207', (151, 154))	('hematological malignancies', 'Disease', 'MESH:D019337', (57, 83))	('tumor', 'Disease', (46, 51))	('hematological malignancies', 'Phenotype', 'HP:0004377', (57, 83))	('LY294002', 'Var', (212, 220))	('solid tumors', 'Disease', (40, 52))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', (173, 178))	('hematological malignancies', 'Disease', (57, 83))
161542	25566499	HER activation of the MAPK pathway via docking of the Grb2 adaptor protein to HER phosphorylated tyrosine residue induces a Ras-mediated phosphorylation cascade resulting in the transcription of a number of genes that promote cell proliferation, survival, and cell migration (reviewed in Hynes).	('cell proliferation', 'CPA', (226, 244))	('tyrosine', 'Chemical', 'MESH:D014443', (97, 105))	('cell migration', 'CPA', (260, 274))	('Ras-mediated', 'Pathway', (124, 136))	('promote', 'PosReg', (218, 225))	('docking', 'Var', (39, 46))	('survival', 'CPA', (246, 254))	('transcription', 'MPA', (178, 191))	('ER', 'Gene', '2099', (79, 81))	('Grb2', 'Gene', '2885', (54, 58))	('ER', 'Gene', '2099', (1, 3))	('induces', 'Reg', (114, 121))	('MAPK pathway', 'Pathway', (22, 34))	('Grb2', 'Gene', (54, 58))	('activation', 'PosReg', (4, 14))
161543	25566499	Similar to the AKT pathway, several components of the MAPK pathway are involved in promoting tumorigenesis making these two pathways central nodes where activating mutations are known to trigger tumorigenesis and metastasis.	('AKT', 'Gene', '207', (15, 18))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('metastasis', 'CPA', (213, 223))	('AKT', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('mutations', 'Var', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('trigger', 'Reg', (187, 194))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
161548	25566499	Cancer cells can adapt to treatments using a variety of mutations that enable the cancer cell to overcome targeted therapies and enable them to propagate under such conditions.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (56, 65))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))
161569	25566499	Cleavage by the gamma-secretase complex releases the NICD portion of the Notch receptor (Figure 2A).	('Cleavage', 'Var', (0, 8))	('NICD portion', 'MPA', (53, 65))	('Notch', 'Gene', (73, 78))	('releases', 'PosReg', (40, 48))	('Notch', 'Gene', '31293', (73, 78))
161576	25566499	Activation of the Notch receptor inhibits Delta production in the same cell.	('Delta production', 'MPA', (42, 58))	('Notch', 'Gene', (18, 23))	('Notch', 'Gene', '31293', (18, 23))	('Activation', 'Var', (0, 10))	('inhibits', 'NegReg', (33, 41))
161593	25566499	There is a growing body of evidence that Notch up-regulation or mutation results in several events that enable breast cancer cells to: become resistant to targeted treatments, undergo EMT, metastasize, and promote BCSC survival, and self-renewal.	('BCSC survival', 'CPA', (214, 227))	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Notch', 'Gene', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('promote', 'PosReg', (206, 213))	('self-renewal', 'CPA', (233, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('up-regulation', 'PosReg', (47, 60))	('breast cancer', 'Disease', (111, 124))	('undergo EMT', 'CPA', (176, 187))	('Notch', 'Gene', '31293', (41, 46))	('metastasize', 'CPA', (189, 200))
161594	25566499	Increased co-expression of Notch-1 and Jagged-1 has been associated with poor prognosis for women diagnosed with breast cancer.	('Jagged-1', 'Gene', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('Jagged-1', 'Gene', '182', (39, 47))	('breast cancer', 'Disease', (113, 126))	('women', 'Species', '9606', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('co-expression', 'Var', (10, 23))	('Notch-1', 'Gene', '4851', (27, 34))	('Increased', 'PosReg', (0, 9))	('Notch-1', 'Gene', (27, 34))
161607	25566499	Notch-EGFR crosstalk has been shown to increase MUC5AC expression causing increased goblet cell secretion of mucin, a feature attributed to chronic airway inflammatory disease as well as a potential activator of inflammatory induced lung cancer.	('crosstalk', 'Var', (11, 20))	('MUC5AC', 'Gene', (48, 54))	('Notch', 'Gene', (0, 5))	('mucin', 'Gene', (109, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('airway inflammatory disease', 'Phenotype', 'HP:0002099', (148, 175))	('lung cancer', 'Disease', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('expression', 'MPA', (55, 65))	('increased', 'PosReg', (74, 83))	('increase', 'PosReg', (39, 47))	('Notch', 'Gene', '31293', (0, 5))	('MUC5AC', 'Gene', '4586', (48, 54))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('mucin', 'Gene', '100508689', (109, 114))
161609	25566499	These are just a few examples of Notch-EGFR crosstalk promoting drug resistance, EMT, and disease progression in various carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('Notch', 'Gene', '31293', (33, 38))	('carcinomas', 'Disease', 'MESH:D002277', (121, 131))	('disease progression', 'CPA', (90, 109))	('carcinomas', 'Disease', (121, 131))	('promoting', 'PosReg', (54, 63))	('EMT', 'CPA', (81, 84))	('Notch', 'Gene', (33, 38))	('drug', 'CPA', (64, 68))	('crosstalk', 'Var', (44, 53))	('drug resistance', 'Phenotype', 'HP:0020174', (64, 79))
161610	25566499	Activation of the PI3K pathway by deletion or inactivation of PTEN or oncogenic mutation of PIK3CA has been observed in many types of cancer as well as being implicated in drug resistance.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('PIK3CA', 'Gene', '5290', (92, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (172, 187))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('implicated', 'Reg', (158, 168))	('deletion', 'Var', (34, 42))	('Activation', 'PosReg', (0, 10))	('inactivation', 'NegReg', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('observed', 'Reg', (108, 116))	('PIK3CA', 'Gene', (92, 98))	('PI3K pathway', 'Pathway', (18, 30))
161617	25566499	showed that the use of a dual PI3K and mTOR inhibitor, NVP-BEZ235, can reverse anti-EGFR/HER2 resistance in HER2+ breast cancers that express low PTEN or contain PIK3CA activating mutations.	('HER2', 'Gene', (108, 112))	('PIK3CA', 'Gene', '5290', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('HER2', 'Gene', '2064', (89, 93))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('PTEN', 'Gene', (146, 150))	('breast cancers', 'Disease', 'MESH:D001943', (114, 128))	('breast cancers', 'Disease', (114, 128))	('PIK3CA', 'Gene', (162, 168))	('HER2', 'Gene', '2064', (108, 112))	('PTEN', 'Gene', '5728', (146, 150))	('mTOR', 'Gene', (39, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('HER2', 'Gene', (89, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('low', 'Var', (142, 145))	('BEZ235', 'Chemical', 'MESH:C531198', (59, 65))	('mTOR', 'Gene', '2475', (39, 43))	('activating', 'PosReg', (169, 179))
161631	25566499	Preclinical studies have combined EGFR and HER2 inhibitors with MAPK/MEK or AKT/PI3K/mTOR inhibitors to reduce resistance to EGFR/HER2 TKIs.	('resistance', 'MPA', (111, 121))	('AKT', 'Gene', '207', (76, 79))	('EGFR', 'Gene', (34, 38))	('HER2', 'Gene', (43, 47))	('MEK', 'Gene', (69, 72))	('AKT', 'Gene', (76, 79))	('HER2', 'Gene', '2064', (43, 47))	('MEK', 'Gene', '5609', (69, 72))	('HER2', 'Gene', (130, 134))	('reduce', 'NegReg', (104, 110))	('inhibitors', 'Var', (48, 58))	('HER2', 'Gene', '2064', (130, 134))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))
161638	25566499	This important research described siRNA knockdown or GSI-mediated inhibition of Notch-1 enhanced trastuzumab sensitivity and reversed resistance to trastuzumab treatment in vitro.	('resistance to trastuzumab treatment', 'MPA', (134, 169))	('knockdown', 'Var', (40, 49))	('GS', 'Disease', 'MESH:D011125', (53, 55))	('trastuzumab sensitivity', 'MPA', (97, 120))	('inhibition', 'Var', (66, 76))	('trastuzumab', 'Chemical', 'MESH:D000068878', (148, 159))	('trastuzumab', 'Chemical', 'MESH:D000068878', (97, 108))	('Notch-1', 'Gene', (80, 87))	('reversed', 'NegReg', (125, 133))	('Notch-1', 'Gene', '4851', (80, 87))	('enhanced', 'PosReg', (88, 96))
161639	25566499	These findings led to the conclusion that HER2 inhibition increased Notch-1 activity in a compensatory manner to promote survival and resistance of HER2+ breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('HER2', 'Gene', '2064', (42, 46))	('HER2', 'Gene', (148, 152))	('Notch-1', 'Gene', (68, 75))	('increased', 'PosReg', (58, 67))	('breast cancer', 'Disease', (154, 167))	('inhibition', 'Var', (47, 57))	('activity', 'MPA', (76, 84))	('promote', 'PosReg', (113, 120))	('HER2', 'Gene', '2064', (148, 152))	('Notch-1', 'Gene', '4851', (68, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('survival', 'CPA', (121, 129))	('HER2', 'Gene', (42, 46))	('resistance', 'CPA', (134, 144))
161647	25566499	Conversely, crosstalk between HER2 and Notch could be stimulatory rather than inhibitory.	('Notch', 'Gene', '31293', (39, 44))	('crosstalk', 'Var', (12, 21))	('HER2', 'Gene', (30, 34))	('Notch', 'Gene', (39, 44))	('HER2', 'Gene', '2064', (30, 34))
161654	25566499	Knock down of Notch-3 reduced HER2 + DCIS cell proliferation, spheroid formation, and luminal spheroid filling indicating that HER2-mediated up-regulation of Notch-3 promoted HER2+ DCIS cell proliferation and survival.	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('Notch-3', 'Gene', (14, 21))	('HER2', 'Gene', (30, 34))	('luminal spheroid filling', 'CPA', (86, 110))	('HER2', 'Gene', '2064', (127, 131))	('HER2', 'Gene', '2064', (175, 179))	('promoted', 'PosReg', (166, 174))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('Notch-3', 'Gene', '4854', (158, 165))	('Knock down', 'Var', (0, 10))	('up-regulation', 'PosReg', (141, 154))	('HER2', 'Gene', (127, 131))	('HER2', 'Gene', (175, 179))	('reduced', 'NegReg', (22, 29))	('HER2', 'Gene', '2064', (30, 34))	('spheroid formation', 'CPA', (62, 80))	('Notch-3', 'Gene', (158, 165))	('survival', 'CPA', (209, 217))	('Notch-3', 'Gene', '4854', (14, 21))
161662	25566499	Interestingly, combined inhibition of the Notch and EGFR/HER2 receptors reduced both acini size and mammosphere formation regardless of HER2 expression indicating that the crosstalk between Notch and EGFR/HER2 receptors maintains BCSC survival and self-renewal (Figure 5).	('crosstalk', 'Var', (172, 181))	('reduced', 'NegReg', (72, 79))	('HER2', 'Gene', (205, 209))	('Notch', 'Gene', '31293', (42, 47))	('HER2', 'Gene', (57, 61))	('Notch', 'Gene', (42, 47))	('HER2', 'Gene', '2064', (205, 209))	('BCSC survival', 'CPA', (230, 243))	('acini size', 'CPA', (85, 95))	('self-renewal', 'CPA', (248, 260))	('HER2', 'Gene', '2064', (57, 61))	('HER2', 'Gene', '2064', (136, 140))	('HER2', 'Gene', (136, 140))	('inhibition', 'NegReg', (24, 34))	('mammosphere formation', 'CPA', (100, 121))	('Notch', 'Gene', (190, 195))	('maintains', 'PosReg', (220, 229))	('Notch', 'Gene', '31293', (190, 195))
161667	25566499	Notch-EGFR crosstalk has been implicated as a paracrine mediator of estrogen to promote ER-/ER low BCSC survival and proliferation within ER+ breast cancer cell lines and patient samples.	('crosstalk', 'Var', (11, 20))	('Notch', 'Gene', (0, 5))	('proliferation', 'CPA', (117, 130))	('patient', 'Species', '9606', (171, 178))	('low BCSC', 'Phenotype', 'HP:0025066', (95, 103))	('ER', 'Gene', '2099', (138, 140))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('Notch', 'Gene', '31293', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('ER', 'Gene', '2099', (88, 90))	('ER', 'Gene', '2099', (92, 94))	('promote', 'PosReg', (80, 87))
161670	25566499	Crosstalk between EGFR, FGFR, and Notch pathways are responsible for estrogen induced changes in the ER-/ER low BCSC population and may play a role in endocrine resistance as well as offer suitable targets for the treatment of ER+ breast tumors.	('responsible', 'Reg', (53, 64))	('Notch', 'Gene', (34, 39))	('breast tumors', 'Disease', (231, 244))	('ER', 'Gene', '2099', (227, 229))	('breast tumors', 'Disease', 'MESH:D001943', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('FGFR', 'Gene', (24, 28))	('EGFR', 'Gene', (18, 22))	('ER', 'Gene', '2099', (101, 103))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('estrogen', 'MPA', (69, 77))	('play', 'Reg', (136, 140))	('role', 'Reg', (143, 147))	('Crosstalk', 'Var', (0, 9))	('Notch', 'Gene', '31293', (34, 39))	('ER', 'Gene', '2099', (105, 107))	('breast tumors', 'Phenotype', 'HP:0100013', (231, 244))	('low BCSC', 'Phenotype', 'HP:0025066', (108, 116))
161673	25566499	Synergistic effects of camptothecin with gefitinib or NSC 23766 [ras-related C3 botulinum toxin substrate 1 inhibitor (RAC1)], as well as imatinib with DAPT or NSC 23766 and additive effects of temozolomide with gefitinib or PF-573228 (focal kinase inhibitor) to sensitize glioblastoma cells to cytotoxic chemotherapy causing cancer cell death and growth arrest.	('growth arrest', 'Disease', (348, 361))	('gefitinib', 'Chemical', 'MESH:D000077156', (41, 50))	('ras-related C3 botulinum toxin substrate 1', 'Gene', '5879', (65, 107))	('camptothecin', 'Chemical', 'MESH:D002166', (23, 35))	('gefitinib', 'Chemical', 'MESH:D000077156', (212, 221))	('NSC', 'Disease', 'OMIM:617394', (54, 57))	('NSC', 'Disease', (160, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (273, 285))	('RAC1', 'Gene', (119, 123))	('DAPT', 'Chemical', '-', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('cancer cell death', 'Disease', 'MESH:D003643', (326, 343))	('glioblastoma', 'Disease', (273, 285))	('imatinib', 'Chemical', 'MESH:D000068877', (138, 146))	('PF-573228', 'Var', (225, 234))	('NSC', 'Disease', (54, 57))	('growth arrest', 'Phenotype', 'HP:0001510', (348, 361))	('glioblastoma', 'Phenotype', 'HP:0012174', (273, 285))	('RAC1', 'Gene', '5879', (119, 123))	('growth arrest', 'Disease', 'MESH:D006323', (348, 361))	('ras-related C3 botulinum toxin substrate 1', 'Gene', (65, 107))	('cancer cell death', 'Disease', (326, 343))	('NSC', 'Disease', 'OMIM:617394', (160, 163))	('temozolomide', 'Chemical', 'MESH:D000077204', (194, 206))	('PF-573228', 'Chemical', 'MESH:C521108', (225, 234))
161677	25566499	A variety of cancer cell lines, including ER+ MCF7 and triple negative MDA-MB-486 expresses elevated mTOR signaling and Notch activity.	('ER', 'Gene', '2099', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Notch', 'Gene', (120, 125))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('MCF7', 'CellLine', 'CVCL:0031', (46, 50))	('Notch', 'Gene', '31293', (120, 125))	('MDA-MB-486', 'Gene', (71, 81))	('elevated', 'PosReg', (92, 100))	('MDA-MB-486', 'CellLine', 'CVCL:0062', (71, 81))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('triple negative', 'Var', (55, 70))
161678	25566499	examined this correlation to find that RTK activation of the PI3K/mTORC1 pathway caused up-regulation of several new mTORC1 effectors: Signal Transducer and Activator of Transcription 3 (STAT3), p63 (a member of the p53 family), Jagged-1, Notch, and HES-1.	('Notch', 'Gene', '31293', (239, 244))	('up-regulation', 'PosReg', (88, 101))	('Signal Transducer and Activator of Transcription 3', 'Gene', '6774', (135, 185))	('p53', 'Gene', (216, 219))	('mTORC1', 'Gene', (66, 72))	('mTORC1', 'Gene', '382056', (66, 72))	('HES-1', 'Gene', (250, 255))	('Notch', 'Gene', (239, 244))	('Jagged-1', 'Gene', '182', (229, 237))	('STAT3', 'Gene', (187, 192))	('RTK', 'Var', (39, 42))	('mTORC1', 'Gene', (117, 123))	('HES-1', 'Gene', '3280', (250, 255))	('STAT3', 'Gene', '6774', (187, 192))	('p63', 'Gene', (195, 198))	('mTORC1', 'Gene', '382056', (117, 123))	('p63', 'Gene', '8626', (195, 198))	('Jagged-1', 'Gene', (229, 237))	('p53', 'Gene', '7157', (216, 219))
161679	25566499	Aberrant RTK/PI3K/AKT/mTORC1 signaling caused an increase in STAT3, which in turn increased p63 transcription.	('p63', 'Gene', (92, 95))	('increase', 'PosReg', (49, 57))	('Aberrant', 'Var', (0, 8))	('p63', 'Gene', '8626', (92, 95))	('AKT', 'Gene', (18, 21))	('STAT3', 'Gene', '6774', (61, 66))	('mTORC1', 'Gene', (22, 28))	('STAT3', 'Gene', (61, 66))	('increased', 'PosReg', (82, 91))	('mTORC1', 'Gene', '382056', (22, 28))	('AKT', 'Gene', '207', (18, 21))
161685	25566499	Activated Notch-1 signaling was found to inhibit p53 activation by blocking nuclear localization as well as phosphorylation at Ser15, Ser20, and Ser392 residues.	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('activation', 'PosReg', (53, 63))	('Ser15', 'Chemical', '-', (127, 132))	('Ser392 residues', 'Var', (145, 160))	('nuclear localization', 'MPA', (76, 96))	('Ser15', 'Var', (127, 132))	('Ser20', 'Chemical', '-', (134, 139))	('blocking', 'NegReg', (67, 75))	('Notch-1', 'Gene', (10, 17))	('Ser20', 'Var', (134, 139))	('Notch-1', 'Gene', '4851', (10, 17))	('inhibit', 'NegReg', (41, 48))	('phosphorylation', 'MPA', (108, 123))	('Ser392', 'Chemical', '-', (145, 151))
161694	25566499	Similar studies were done in vivo in which the MDA-MB-231 cells with TRB3 knock down had significantly smaller tumors than mice with without TRB3 knock down.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TRB3', 'Gene', (69, 73))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('smaller', 'NegReg', (103, 110))	('knock down', 'Var', (74, 84))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (47, 57))	('mice', 'Species', '10090', (123, 127))
161702	25566499	More studies are needed to uncover novel interactions, downstream pathway mutations, microRNA dysregulation, or epigenetic changes that may be critical to understanding how cancer cells move between pathways to create their own signaling circuit for survival.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (173, 179))
161740	23260325	The Sox10 gene was first discovered in mouse embryos in 1993 and subsequently described in the human genome in 1998.Of all the Sox family proteins, the function of the Sox10 protein has been one of the most studied, largely because of the association of mutated Sox10 with clinical neurocristopathies such as Waardenburg-Shah syndrome.	('Sox10', 'Gene', (262, 267))	('human', 'Species', '9606', (95, 100))	('Waardenburg-Shah syndrome', 'Disease', (309, 334))	('mutated', 'Var', (254, 261))	('association', 'Reg', (239, 250))	('mouse', 'Species', '10090', (39, 44))	('Waardenburg-Shah syndrome', 'Disease', 'MESH:C536467', (309, 334))
161829	31813636	Significantly more evaluable patients in the APBI group had recurrence-free interval events than patients in the whole-breast irradiation group (figure 3).	('patients', 'Species', '9606', (29, 37))	('APBI', 'Chemical', '-', (45, 49))	('recurrence-free interval events', 'MPA', (60, 91))	('APBI', 'Var', (45, 49))	('patients', 'Species', '9606', (97, 105))
161906	28705168	MRI is usually recommended in cases of discrepancy between clinical, mammography and ultrasound before certain specific therapeutic approaches are used (oncoplastic surgery, NAC) in young women or with a high family risk of breast cancer; in the event of MFT, it can also be provided for evaluation of the contralateral breast.	('NAC', 'Chemical', '-', (174, 177))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (224, 237))	('women', 'Species', '9606', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('MFT', 'Var', (255, 258))
161931	28705168	Two patients (1.9%) were operated in the context of BRCA2 gene mutations.	('BRCA2', 'Gene', (52, 57))	('mutations', 'Var', (63, 72))	('BRCA2', 'Gene', '675', (52, 57))	('patients', 'Species', '9606', (4, 12))
161950	28705168	In the second case, the patient was treated in the context of a BRCA2 mutation and histology demonstrated a high-grade IDC 11 mm focus.	('BRCA2', 'Gene', '675', (64, 69))	('IDC', 'Gene', '4000', (119, 122))	('IDC', 'Gene', (119, 122))	('patient', 'Species', '9606', (24, 31))	('BRCA2', 'Gene', (64, 69))	('mutation', 'Var', (70, 78))
161971	28705168	However, in three cases, tentative explanations exist for the absence of tumour in MRI images: for the patient with a BRCA2 mutation, the extended 5 months period between imaging and surgery may explain the lack of detection.	('tumour', 'Disease', (73, 79))	('BRCA2', 'Gene', (118, 123))	('patient', 'Species', '9606', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('mutation', 'Var', (124, 132))	('BRCA2', 'Gene', '675', (118, 123))	('tumour', 'Disease', 'MESH:D009369', (73, 79))
162051	28641365	Our data likewise showed a much higher malignant rate of 14.4% in discordant benign CNBs, which is within the 6.8%-24.4% range reported in previous studies, compared with a malignancy rate of 0.5% in concordant benign CNBs.	('discordant', 'Var', (66, 76))	('higher', 'PosReg', (32, 38))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('benign CNBs', 'Disease', (77, 88))	('malignancy', 'Disease', (173, 183))	('malignant rate', 'CPA', (39, 53))
162069	23562473	We report that high IRS1 sensitized MCF7 cells to specific chemotherapeutic agents.	('high', 'Var', (15, 19))	('sensitized', 'Reg', (25, 35))	('MCF7', 'CellLine', 'CVCL:0031', (36, 40))	('IRS1', 'Gene', (20, 24))
162082	23562473	IRS2 has been proposed to regulate mammary tumor metastasis in a mouse model of breast cancer and in breast cancer cell lines since the lack of IRS2 rendered tumor cells less invasive.	('less', 'NegReg', (170, 174))	('lack', 'Var', (136, 140))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('tumor metastasis', 'Disease', 'MESH:D009362', (43, 59))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('IRS2', 'Gene', (144, 148))	('tumor metastasis', 'Disease', (43, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (158, 163))	('mouse', 'Species', '10090', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
162083	23562473	IRS1 was not required for metastasis and was actually suggested to be a suppressor of metastasis in breast cancer; instead IRS1 enhanced breast cancer cell proliferation.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('IRS1', 'Var', (123, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('enhanced', 'PosReg', (128, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
162084	23562473	Knocking out IRS2 rendered mammary tumor cells more apoptotic in basal conditions and also after serum deprivation; conversely, knocking out IRS1 rendered the cells resistant to apoptotic stimuli under similar conditions.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('knocking out', 'Var', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('IRS1', 'Gene', (141, 145))	('IRS2', 'Gene', (13, 17))	('Knocking', 'Var', (0, 8))
162085	23562473	Furthermore, IRS2 suppressed the function of IRS1 by strongly activating the Akt/ mTOR signaling pathway and inducing the serine phosphorylation of IRS1.	('Akt', 'Gene', '207', (77, 80))	('IRS1', 'Protein', (148, 152))	('serine phosphorylation', 'MPA', (122, 144))	('IRS1', 'Gene', (45, 49))	('activating', 'PosReg', (62, 72))	('Akt', 'Gene', (77, 80))	('IRS2', 'Var', (13, 17))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('inducing', 'Reg', (109, 117))	('suppressed', 'NegReg', (18, 28))	('function', 'MPA', (33, 41))	('serine', 'Chemical', 'MESH:D012694', (122, 128))
162124	23562473	On the other hand, membrane localization of IRS2 was associated with decreased overall survival in progesterone receptor (PR) negative breast tumors.	('breast tumor', 'Phenotype', 'HP:0100013', (135, 147))	('breast tumors', 'Disease', (135, 148))	('breast tumors', 'Disease', 'MESH:D001943', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('membrane localization', 'Var', (19, 40))	('decreased', 'NegReg', (69, 78))	('PR', 'Gene', '5241', (122, 124))	('progesterone receptor', 'Gene', (99, 120))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('IRS2', 'Gene', (44, 48))	('breast tumors', 'Phenotype', 'HP:0100013', (135, 148))	('progesterone receptor', 'Gene', '5241', (99, 120))
162127	23562473	Normal breast undergoing lactational changes was also positive for IRS1, STAT6, and pSTAT6, but did not express IRS2.	('STAT6', 'Gene', '6778', (85, 90))	('STAT6', 'Gene', (73, 78))	('STAT6', 'Gene', '6778', (73, 78))	('IRS1', 'Var', (67, 71))	('STAT6', 'Gene', (85, 90))
162160	23562473	In a previously published study, we showed that IRS1, but not IRS2, expression sensitized 32D cells to chemotherapy-induced death.	('sensitized', 'Reg', (79, 89))	('IRS1', 'Var', (48, 52))	('expression', 'Var', (68, 78))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))
162196	23562473	Several studies reported that IRS1 expression correlated with poorly differentiated breast cancer and lymph node involvement and that high levels of IRS1 predicted worse disease-free survival for breast cancer patients.	('expression', 'MPA', (35, 45))	('IRS1', 'Gene', (149, 153))	('poorly', 'Disease', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('IRS1', 'Gene', (30, 34))	('worse', 'NegReg', (164, 169))	('high', 'Var', (134, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('lymph node involvement', 'Disease', 'MESH:D000072717', (102, 124))	('patients', 'Species', '9606', (210, 218))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('disease-free survival', 'CPA', (170, 191))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('correlated', 'Reg', (46, 56))	('lymph node involvement', 'Disease', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
162227	23562473	Our studies suggest that localized breast tumors that express high ERalpha and low IRS2 would be much more sensitive to death induced by specific chemotherapeutic agents due to their higher IRS1 levels.	('higher', 'PosReg', (183, 189))	('IRS2', 'Gene', (83, 87))	('breast tumors', 'Disease', (35, 48))	('death', 'Disease', 'MESH:D003643', (120, 125))	('death', 'Disease', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IRS1 levels', 'MPA', (190, 201))	('breast tumor', 'Phenotype', 'HP:0100013', (35, 47))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('low', 'Var', (79, 82))	('ERalpha', 'Gene', '2099', (67, 74))	('ERalpha', 'Gene', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('breast tumors', 'Disease', 'MESH:D001943', (35, 48))
162230	23562473	Our finding that IRS1 plays an important role in sensitizing MCF7 cells to taxol, etoposide, and vincristine suggests that localized ERalpha positive breast tumors that express high cytoplasmic IRS1 may be highly sensitive to specific chemotherapeutic agents in combination with hormone therapies like tamoxifen and aromatase inhibitors.	('vincristine', 'Chemical', 'MESH:D014750', (97, 108))	('aromatase', 'Gene', (316, 325))	('ERalpha', 'Gene', '2099', (133, 140))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('ERalpha', 'Gene', (133, 140))	('aromatase', 'Gene', '1588', (316, 325))	('breast tumors', 'Phenotype', 'HP:0100013', (150, 163))	('breast tumor', 'Phenotype', 'HP:0100013', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('etoposide', 'Chemical', 'MESH:D005047', (82, 91))	('breast tumors', 'Disease', (150, 163))	('breast tumors', 'Disease', 'MESH:D001943', (150, 163))	('IRS1', 'Gene', (194, 198))	('taxol', 'Chemical', 'MESH:D017239', (75, 80))	('MCF7', 'CellLine', 'CVCL:0031', (61, 65))	('tamoxifen', 'Chemical', 'MESH:D013629', (302, 311))	('high cytoplasmic', 'Var', (177, 193))
162238	23562473	Studies in cancer cell lines reflect the findings in tumor samples and suggest that high IRS1 could be a good indicator of the effectiveness of specific types of chemotherapy in breast cancer.	('high', 'Var', (84, 88))	('IRS1', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('breast cancer', 'Disease', (178, 191))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (185, 191))
162240	23562473	We predict that more differentiated, ERalpha positive breast tumors that express high IRS1 would respond favorably to chemotherapy.	('breast tumors', 'Phenotype', 'HP:0100013', (54, 67))	('ERalpha', 'Gene', '2099', (37, 44))	('breast tumor', 'Phenotype', 'HP:0100013', (54, 66))	('ERalpha', 'Gene', (37, 44))	('breast tumors', 'Disease', (54, 67))	('breast tumors', 'Disease', 'MESH:D001943', (54, 67))	('high', 'Var', (81, 85))	('IRS1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
162279	31391072	Cells were plated (2 x 105 cells/well) in 24-well plates and co-transfected with 100 ng of DNA with pEZX-FOXM1-3'UTR (wild type or mutant) expression clones inserted downstream of a secreted Gaussia luciferase (GLuc) reporter and 100 ng of DNA with pEZX-miR-671-5p or the pEZX-MT scrambled control (mock), using the FuGENE Transfection Reagent (Promega).	('mutant', 'Var', (131, 137))	('FOXM1', 'Gene', (105, 110))	('miR-671', 'Gene', '768213', (254, 261))	('FOXM1', 'Gene', '2305', (105, 110))	('secreted Gaussia luciferase', 'Disease', 'MESH:D002640', (182, 209))	('Luc', 'Chemical', '-', (212, 215))	('miR-671', 'Gene', (254, 261))	('secreted Gaussia luciferase', 'Disease', (182, 209))
162286	31391072	The following antibodies and dilution factors were used: FOXM1 rabbit polyclonal antibody (13147-1-AP, 1:800, Proteintech), anti-rabbit vimentin (5741, 1:200 Cell Signaling), anti-rabbit E-cadherin (3195, 1:400, Cell Signaling), anti-rabbit beta-actin (4970 s, 1:2000, Cell Signaling), anti-rabbit IgG conjugated to horseradish peroxidase (7074S, 1:2000, Cell Signaling), and anti-mouse IgG (7076S, 1:2,000, Cell Signaling).	('4970 s', 'Var', (253, 259))	('rabbit', 'Species', '9986', (234, 240))	('E-cadherin', 'Gene', (187, 197))	('E-cadherin', 'Gene', '999', (187, 197))	('rabbit', 'Species', '9986', (63, 69))	('rabbit', 'Species', '9986', (180, 186))	('mouse', 'Species', '10090', (381, 386))	('FOXM1', 'Gene', (57, 62))	('horseradish', 'Species', '3704', (316, 327))	('rabbit', 'Species', '9986', (291, 297))	('FOXM1', 'Gene', '2305', (57, 62))	('rabbit', 'Species', '9986', (129, 135))	('vimentin', 'Gene', '7431', (136, 144))	('vimentin', 'Gene', (136, 144))
162320	31391072	This data suggests that aberrantly expressed miR-671-5p might be used to distinguish ADHs from ADHs.	('miR-671', 'Gene', (45, 52))	('ADHs', 'Disease', (85, 89))	('miR-671', 'Gene', '768213', (45, 52))	('aberrantly', 'Var', (24, 34))
162343	31391072	miR-671-5p ectopic expression resulted in a significant inhibition of invasive capability in 21PT (46%), 21NT (30%), and 21MT (59%), but not in H16N2 cells when compared to the mock control.	('inhibition', 'NegReg', (56, 66))	('miR-671', 'Gene', '768213', (0, 7))	('miR-671', 'Gene', (0, 7))	('H16N2', 'CellLine', 'CVCL:J086', (144, 149))	('invasive capability', 'CPA', (70, 89))	('ectopic expression', 'Var', (11, 29))
162355	31391072	Rescue experiments by transfections of FOXM1 abrogated the effect of miR-671-5p on EMT alleviation.	('abrogated', 'NegReg', (45, 54))	('EMT', 'CPA', (83, 86))	('FOXM1', 'Gene', (39, 44))	('FOXM1', 'Gene', '2305', (39, 44))	('miR-671', 'Gene', '768213', (69, 76))	('miR-671', 'Gene', (69, 76))	('transfections', 'Var', (22, 35))
162370	31391072	The slightly reduced post-UV HCR activity was still observed in H16N2, 21PT, and 21NT, despite the difference did not reach statistical significance.	('H16N2', 'CellLine', 'CVCL:J086', (64, 69))	('reduced', 'NegReg', (13, 20))	('post-UV', 'CPA', (21, 28))	('H16N2', 'Var', (64, 69))
162381	31391072	These data showed that re-expression of FOXM1 abrogated the alleviating effect of miR-671-5p on DNA repair compared to the pcDNA3.1 empty plasmid one (Fig.	('miR-671', 'Gene', '768213', (82, 89))	('re-expression', 'Var', (23, 36))	('abrogated', 'NegReg', (46, 55))	('miR-671', 'Gene', (82, 89))	('FOXM1', 'Gene', '2305', (40, 45))	('alleviating effect', 'MPA', (60, 78))	('FOXM1', 'Gene', (40, 45))	('DNA repair', 'MPA', (96, 106))
162416	31391072	Loss of miR-671-5p leads to the activation of FOXM1-mediated EMT progression and enhanced DNA repair capability, resulting in a gradually aggressive molecular event in the development of radio/chemoresistance (Fig.	('miR-671', 'Gene', (8, 15))	('FOXM1', 'Gene', '2305', (46, 51))	('enhanced', 'PosReg', (81, 89))	('FOXM1', 'Gene', (46, 51))	('EMT progression', 'CPA', (61, 76))	('activation', 'PosReg', (32, 42))	('miR-671', 'Gene', '768213', (8, 15))	('radio/chemoresistance', 'CPA', (187, 208))	('Loss', 'Var', (0, 4))	('DNA repair', 'MPA', (90, 100))
162452	29353366	Radiotherapy reduced the risk of ipsilateral invasive cancer by more than one-half (204 cases versus 92 cases) but was associated with a small but non-significant increase in breast cancer mortality (44 deaths versus 52 deaths; HR 1.22).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('Radiotherapy', 'Var', (0, 12))	('death', 'Disease', 'MESH:D003643', (203, 208))	('death', 'Disease', 'MESH:D003643', (220, 225))	('death', 'Disease', (203, 208))	('death', 'Disease', (220, 225))	('reduced', 'NegReg', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ipsilateral invasive cancer', 'Disease', (33, 60))	('ipsilateral invasive cancer', 'Disease', 'MESH:D009362', (33, 60))
162455	29353366	In that study, the probability of developing an ipsilateral invasive breast cancer was much higher for women treated with lumpectomy (308 of 2558; 12.0%) than for women treated with mastectomy (68 of 4667; 1.5%).	('higher', 'PosReg', (92, 98))	('women', 'Species', '9606', (163, 168))	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (48, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ipsilateral invasive breast cancer', 'Disease', (48, 82))	('lumpectomy', 'Var', (122, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('women', 'Species', '9606', (103, 108))
162467	29353366	In SEER, the 10-year mortality rate from breast cancer was 2.8% for patients with DCIS with micro-invasion and was 1.4% for women with DCIS without micro-invasion.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('micro-invasion', 'Var', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('patients', 'Species', '9606', (68, 76))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('women', 'Species', '9606', (124, 129))
162717	27639438	The presence of these myofibroblasts in chronic inflammation can result in pathological tissue fibrosis, such as in the case of the liver and pancreas, and increase the risk of cancer.	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('inflammation', 'Disease', (48, 60))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('pancreas', 'Disease', 'MESH:D010190', (142, 150))	('liver', 'Disease', (132, 137))	('increase', 'PosReg', (156, 164))	('pancreas', 'Disease', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('result in', 'Reg', (65, 74))	('presence', 'Var', (4, 12))	('fibrosis', 'Disease', 'MESH:D005355', (95, 103))	('fibrosis', 'Disease', (95, 103))
162740	27639438	Based on the initial hypothesis that inhibition of blood vessel formation deprives tumors of nutrients and hence inhibits their growth, various anti-angiogenic agents have been developed and approved for clinical use.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('inhibition', 'Var', (37, 47))	('deprives tumors', 'Disease', 'MESH:D012892', (74, 89))	('blood vessel formation', 'CPA', (51, 73))	('clinical', 'Species', '191496', (204, 212))	('deprives tumors', 'Disease', (74, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('inhibits', 'NegReg', (113, 121))	('growth', 'MPA', (128, 134))
162745	27639438	While this indicates that the abrogation of pericytes is a viable therapeutic strategy, the role of pericytes in normalization of the tumor vasculature also must be considered.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('abrogation', 'Var', (30, 40))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
162754	27639438	During this process, a new population of tumor clones with different mutations that confer them with decreased immunogenicity may spawn.	('tumor', 'Disease', (41, 46))	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))
162768	27639438	CAA not only increases cancer cell invasiveness, but the metabolites that they release, such as free fatty acids, are thought to fuel tumor growth.	('increases', 'PosReg', (13, 22))	('CAA', 'Var', (0, 3))	('CAA', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('free fatty acids', 'MPA', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('free fatty acids', 'Chemical', 'MESH:D005230', (96, 112))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('fuel', 'PosReg', (129, 133))	('metabolites', 'MPA', (57, 68))	('tumor', 'Disease', (134, 139))
162781	27639438	By blocking beta1-integrin, it was further shown that the normalization of integrins was able to revert malignant breast cancer cells to a normal phenotype, indicating the importance of the ECM in influencing malignant behavior.	('revert', 'NegReg', (97, 103))	('integrins', 'Protein', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('malignant', 'CPA', (104, 113))	('beta1-integrin', 'Gene', '3688', (12, 26))	('beta1-integrin', 'Gene', (12, 26))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('normalization', 'Var', (58, 71))	('breast cancer', 'Disease', (114, 127))	('blocking', 'NegReg', (3, 11))
162821	27639438	The studies as described above largely have limited the exploration of biochemical cues to the use of integrin-binding fibronectin-derived RGD (Arg-Gly-Asp) amino acid sequence and a mutated version of a collagen-derived MMP-sensitive sequence, as originally employed by Lutolf et al.	('mutated', 'Var', (183, 190))	('fibronectin', 'Gene', '2335', (119, 130))	('Asp', 'Chemical', 'MESH:D001224', (152, 155))	('Gly', 'Chemical', 'MESH:D005998', (148, 151))	('fibronectin', 'Gene', (119, 130))	('Arg', 'Chemical', 'MESH:D001120', (144, 147))
162895	27639438	Using 3D chitosan-alginate scaffolds for the tri-culture and using TNF-alpha as a measure of helper T cell activation, it was found that the presence of CAFs impaired the ability of the T cells to secrete TNF-alpha, highlighting the immunosuppressive role of CAFs in this system.	('CAFs', 'Gene', '6899', (259, 263))	('CAFs', 'Gene', '6899', (153, 157))	('presence', 'Var', (141, 149))	('TNF-alpha', 'Gene', '7124', (205, 214))	('CAFs', 'Gene', (153, 157))	('alginate', 'Chemical', 'MESH:D000464', (18, 26))	('TNF-alpha', 'Gene', '7124', (67, 76))	('impaired', 'NegReg', (158, 166))	('TNF-alpha', 'Gene', (205, 214))	('CAFs', 'Gene', (259, 263))	('chitosan', 'Chemical', 'MESH:D048271', (9, 17))	('TNF-alpha', 'Gene', (67, 76))
162927	27639438	In the former, cancer stem cells are proposed to be small subpopulations of tumorigenic cells that drive the growth and progression of cancers; akin to the hierarchical organization in normal tissues, cancer stem cells then give rise to diverse nontumorigenic cells that constitute the bulk of tumors via epigenetic changes.	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumors', 'Disease', (294, 300))	('cancer', 'Disease', (135, 141))	('tumor', 'Disease', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Disease', (15, 21))	('cancers', 'Disease', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Disease', (294, 299))	('epigenetic changes', 'Var', (305, 323))	('give rise to', 'Reg', (224, 236))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
162935	27639438	The clonal evolution model posits that genetic and epigenetic alterations occur over time in individual cancer cells and cells that acquire advantageous characteristics under selection pressure will then thrive and out-compete other clones.	('out-compete', 'PosReg', (215, 226))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('epigenetic alterations', 'Var', (51, 73))	('thrive', 'CPA', (204, 210))
162967	27639438	Studies have demonstrated that PDX models retain key characteristics of the parental tumors, including histology, gene expression profiles and copy number variants.	('parental tumors', 'Disease', (76, 91))	('copy number variants', 'Var', (143, 163))	('parental tumors', 'Disease', 'MESH:D063129', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
162986	27639438	As an example, the screen was able to identify a previously reported association between mutated TP53 and resistance to nutlin-3a, an inhibitor of MDM2.	('TP53', 'Gene', '7157', (97, 101))	('MDM2', 'Gene', '4193', (147, 151))	('MDM2', 'Gene', (147, 151))	('TP53', 'Gene', (97, 101))	('resistance to nutlin-3a', 'MPA', (106, 129))	('mutated', 'Var', (89, 96))
162988	27639438	Using the organoid system, the authors reported the establishment of patient-derived prostate cancer organoid lines that recapitulate the genomic landscape of the disease, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression and CHD1 loss.	('SPINK1', 'Gene', (217, 223))	('TMPRSS2', 'Gene', (182, 189))	('SPINK1', 'Gene', '6690', (217, 223))	('prostate cancer', 'Disease', (85, 100))	('TMPRSS2', 'Gene', '7113', (182, 189))	('CHD1 loss', 'Disease', 'MESH:D015431', (243, 252))	('CHD1 loss', 'Disease', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patient', 'Species', '9606', (69, 76))	('overexpression', 'PosReg', (224, 238))	('mutation', 'Var', (207, 215))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('fusion', 'Var', (194, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))	('SPOP', 'Gene', (202, 206))
162989	27639438	recently demonstrated the feasibility of the bottom-up approach in recreating colon cancer by introducing colorectal cancer driver mutations into primary human colon organoids cultures using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing.	('mutations', 'Var', (131, 140))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('recreating colon cancer', 'Disease', (67, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('recreating colon cancer', 'Disease', 'MESH:D015179', (67, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))
162990	27639438	While organoids engineered to harbor key driver mutations exhibited limited tumorigenicity in vivo, organoids that were derived from human adenomas with a chromosomal instability phenotype were able to form macrometastatic colonies, suggesting that additional genetic events besides driver mutations are necessary to unleash invasive behavior.	('adenomas', 'Disease', 'MESH:D000236', (139, 147))	('chromosomal instability', 'Phenotype', 'HP:0040012', (155, 178))	('tumor', 'Disease', (76, 81))	('adenomas', 'Disease', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('human', 'Species', '9606', (133, 138))	('mutations', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
163079	19473551	Frankel et al demonstrated that inhibition of Programmed Cell Death 4 (PDCD4) in MCF-7 cells significantly alleviated the anti-proliferative effect of miR-21 inhibition.	('MCF-7', 'CellLine', 'CVCL:0031', (81, 86))	('Programmed Cell Death 4', 'Gene', '27250', (46, 69))	('inhibition', 'Var', (32, 42))	('PDCD4', 'Gene', (71, 76))	('Programmed Cell Death 4', 'Gene', (46, 69))	('anti-proliferative', 'CPA', (122, 140))	('PDCD4', 'Gene', '27250', (71, 76))	('miR-21 inhibition', 'MPA', (151, 168))	('alleviated', 'NegReg', (107, 117))
163080	19473551	showed that miR-21 acts as an anti-apoptotic factor in human glioblastoma cells.	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('human', 'Species', '9606', (55, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('miR-21', 'Var', (12, 18))
163147	19473551	In our study PTEN expression levels were +++ in all normal components, and ++ or +++ in the vast majority of FEA, DCIS and IDC compartments.	('IDC', 'Gene', '4000', (123, 126))	('++ or +++', 'Var', (75, 84))	('IDC', 'Gene', (123, 126))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('expression', 'MPA', (18, 28))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))
163162	19473551	Targeting of TM1 by miR-21 was shown by the downregulation of TM1 expression upon induction of miR-21 and the upregulation of TM1 expression upon treatment with anti-miR-21 in a breast cancer cell line.	('miR-21', 'Var', (95, 101))	('expression', 'MPA', (130, 140))	('upregulation', 'PosReg', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('downregulation', 'NegReg', (44, 58))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('expression', 'MPA', (66, 76))	('breast cancer', 'Disease', (178, 191))	('TM1', 'Gene', (126, 129))	('TM1', 'Gene', (62, 65))
163266	31354196	Its dysfunctional expression has prognostic significance in the top 3 cause of death associated with non-communicable diseases (cancer, Alzheimer's disease and type 2 diabetes).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	("Alzheimer's disease", 'Disease', (136, 155))	('Alzheimer', 'Disease', (136, 145))	('dysfunctional expression', 'Var', (4, 28))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (160, 175))	('death', 'Disease', 'MESH:D003643', (79, 84))	('type 2 diabetes', 'Disease', 'MESH:D003924', (160, 175))	('death', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Alzheimer', 'Disease', 'MESH:D000544', (136, 145))	('type 2 diabetes', 'Disease', (160, 175))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (136, 155))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (136, 155))	('cancer', 'Disease', (128, 134))
163267	31354196	Previous studies have shown clearly that inhibiting GSK3B has proven therapeutic significance in Alzheimer's disease, but its contribution to various cancers has not been clearly resolved.	('GSK3B', 'Protein', (52, 57))	('inhibiting', 'Var', (41, 51))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (97, 116))	("Alzheimer's disease", 'Disease', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
163270	31354196	Through computational predictions, BT-000775 is a highly selective GSK3B inhibitor, with superior binding affinity and robust ADME profiles suitable for the patho-physiological presentations.	('BT-000775', 'Var', (35, 44))	('GSK3B', 'Gene', (67, 72))	('AD', 'Disease', 'MESH:D000544', (126, 128))	('AD', 'Phenotype', 'HP:0002511', (126, 128))	('binding affinity', 'Interaction', (98, 114))	('AD', 'Disease', (126, 128))
163275	31354196	In addition, the activation of GSK3beta inhibits the secretory cleavage of the amyloid precursor protein (APP), elevating the production of the Abeta peptide, thereby leading to memory impairment in animal models.	('memory impairment', 'Disease', (178, 195))	('activation', 'Var', (17, 27))	('leading to', 'Reg', (167, 177))	('production of the Abeta peptide', 'MPA', (126, 157))	('memory impairment', 'Phenotype', 'HP:0002354', (178, 195))	('secretory cleavage of the amyloid', 'MPA', (53, 86))	('elevating', 'PosReg', (112, 121))	('inhibits', 'NegReg', (40, 48))	('memory impairment', 'Disease', 'MESH:D008569', (178, 195))	('GSK3beta', 'Protein', (31, 39))
163277	31354196	In the same vein, more studies have demonstrated that the inhibition of GSK3beta induces apoptosis in various types of cancers, such as colorectal cancer, pancreatic cancer and bladder cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('bladder cancer', 'Disease', 'MESH:D001749', (177, 191))	('bladder cancer', 'Disease', (177, 191))	('GSK3beta', 'Protein', (72, 80))	('apoptosis', 'CPA', (89, 98))	('colorectal cancer', 'Disease', (136, 153))	('inhibition', 'Var', (58, 68))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('pancreatic cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('bladder cancer', 'Phenotype', 'HP:0009725', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('induces', 'Reg', (81, 88))
163295	31354196	In the works, proton transfer (hydrogen bond formation) and electrostatic interactions between two residues namely; Val 135 and Asp133 were highlighted for GSK3B active site inhibition.	('GSK3B', 'Gene', (156, 161))	('Asp133', 'Chemical', '-', (128, 134))	('Asp133', 'Var', (128, 134))	('electrostatic interactions', 'MPA', (60, 86))	('Val', 'Chemical', 'MESH:D014633', (116, 119))
163296	31354196	They also noted that p-cation stacking with Arg141 and 3'-Cl on the phenyl ring was enough to displace bound water molecule, thereby accounting for increased potency of the compound.	('increased', 'PosReg', (148, 157))	('potency', 'MPA', (158, 165))	('water', 'Chemical', 'MESH:D014867', (109, 114))	('bound water molecule', 'MPA', (103, 123))	('Arg141', 'Var', (44, 50))	("3'-Cl", 'Chemical', '-', (55, 60))	('Arg141', 'Chemical', '-', (44, 50))	('displace', 'NegReg', (94, 102))	('p-cation', 'Var', (21, 29))
163297	31354196	For BT-000775, (Figure 5) the amide nitrogen on prayzole ring donates a proton to ASP 133 to form a hydrogen bond while Val 135 establishes a hydrogen bond with the nitrogen on the same ring.	('prayzole', 'Chemical', '-', (48, 56))	('hydrogen bond', 'MPA', (142, 155))	('hydrogen bond', 'MPA', (100, 113))	('form', 'Reg', (93, 97))	('amide', 'Chemical', 'MESH:D000577', (30, 35))	('nitrogen', 'Chemical', 'MESH:D009584', (165, 173))	('ASP', 'Chemical', 'MESH:D001224', (82, 85))	('nitrogen', 'Chemical', 'MESH:D009584', (36, 44))	('BT-000775', 'Var', (4, 13))
163299	31354196	In addition, the azanylium ion between the two phenyl rings established a strong hydrogen bond as well as a salt bridge with Asp200 while the hydroxyl group toform a water assisted hydrogen bond.	('Asp200', 'Chemical', '-', (125, 131))	('azanylium', 'Chemical', '-', (17, 26))	('Asp200', 'Var', (125, 131))	('hydrogen bond', 'MPA', (81, 94))	('salt bridge', 'MPA', (108, 119))
163300	31354196	BT-000775 was predicted to have a normal activity on the central nervous system (CNS=0), an optimal blood brain barrier partition coefficient (QPLogBB = -0.573 QPPMDCK = 104.061), a high human oral absorption (Human Oral Absorption = 3) with only a very few fraction binding to human serum albumin (QPLogKhsa = 0.107).	('Human', 'Species', '9606', (210, 215))	('human oral absorption', 'MPA', (187, 208))	('BT-000775', 'Var', (0, 9))	('activity', 'MPA', (41, 49))	('binding', 'Interaction', (267, 274))
163301	31354196	It suggests that BT-000775 can be optimized for oral administration, and it is sure to pass the blood brain barrier with no hyperactivity on the neurons of the CNS.	('hyperactivity', 'Disease', 'MESH:D006948', (124, 137))	('hyperactivity', 'Disease', (124, 137))	('hyperactivity', 'Phenotype', 'HP:0000752', (124, 137))	('BT-000775', 'Var', (17, 26))
163303	31354196	Results show that BT-000775 is a promising GSK-3B-inhibitor to be optimized as a lead compound in further pharmaceutical processes.	('GSK-3B', 'Gene', '2932', (43, 49))	('GSK-3B', 'Gene', (43, 49))	('BT-000775', 'Var', (18, 27))
163332	24988533	Epigenetic changes are known to regulate gene expression and are thought to be involved in normal development and cancer.	('regulate', 'Reg', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('gene expression', 'MPA', (41, 56))	('men', 'Species', '9606', (105, 108))	('involved', 'Reg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Disease', (114, 120))
163333	24988533	Maternal exposure to 20 microg BPA/kg/day induces genome-wide epigenetic alterations in the forebrains of mice at embryonic day (E) 12.5 and E14.5.	('E14.5', 'Var', (141, 146))	('mice', 'Species', '10090', (106, 110))	('rat', 'Species', '10116', (77, 80))	('Maternal exposure', 'Phenotype', 'HP:0031437', (0, 17))	('BPA', 'Chemical', 'MESH:C006780', (31, 34))	('epigenetic alterations', 'MPA', (62, 84))
163335	24988533	BPA also increased the susceptibility of the prostate of these animals to adult-onset precancerous lesions following exposure to an additional carcinogenic stimulus (i.e., treatment with androgen and estrogen).	('BPA', 'Var', (0, 3))	('carcinogenic', 'Disease', 'MESH:D063646', (143, 155))	('BPA', 'Chemical', 'MESH:C006780', (0, 3))	('carcinogenic', 'Disease', (143, 155))	('increased', 'PosReg', (9, 18))	('men', 'Species', '9606', (177, 180))	('susceptibility', 'MPA', (23, 37))	('precancerous lesions', 'Disease', 'MESH:D011230', (86, 106))	('precancerous lesions', 'Disease', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
163340	24988533	We conclude that in utero BPA exposure, at doses within the range of concentrations reported in bio-monitoring studies, is associated with genome-wide epigenetic changes and relevant transcriptional changes at all the time points studied, from the end of exposure (PND4) to adulthood, when intraductal hyperplasias and ductal carcinomas in situ (DCIS) are observed.	('associated', 'Reg', (123, 133))	('DCIS', 'Phenotype', 'HP:0030075', (346, 350))	('ductal carcinomas in situ', 'Disease', (319, 344))	('intraductal hyperplasias', 'Disease', 'MESH:D006965', (290, 314))	('rat', 'Species', '10116', (76, 79))	('transcriptional', 'MPA', (183, 198))	('BPA', 'Gene', (26, 29))	('epigenetic changes', 'Var', (151, 169))	('intraductal hyperplasias', 'Disease', (290, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('changes', 'Reg', (199, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('ductal carcinomas in situ', 'Disease', 'MESH:D002285', (319, 344))	('ductal carcinomas in situ', 'Phenotype', 'HP:0030075', (319, 344))	('BPA', 'Chemical', 'MESH:C006780', (26, 29))
163367	24988533	Three antibodies were compared for their specificity and efficiency to immunoprecipitate methylated gDNA, namely: MAb-5Mecyt-100 (Diagenode), Bi-MeCy-0100 (Eurogentec) and 33D3 (Abcam), while an anti-CITED1 antibody was used as negative control.	('CITED1', 'Gene', (200, 206))	('CITED1', 'Gene', '64466', (200, 206))	('Bi-MeCy-0100', 'Var', (142, 154))
163397	24988533	Only 41 probed chromosomal segments (out of 1904) that were hyper-methylated at PND 4 remained in the same state at PND 21, and only 5 of these sites remained hyper-methylated at PND50.	('hyper-methylated', 'Var', (60, 76))	('PND 4', 'Gene', (80, 85))	('men', 'Species', '9606', (30, 33))
163398	24988533	Conversely, 38 probed segments (out of 675) that were hypo-methylated at PND4 remained hypo-methylated at PND21, and only 2 of those segments were hypo-methylated at PND50.	('PND21', 'Var', (106, 111))	('PND4', 'Gene', (73, 77))	('men', 'Species', '9606', (136, 139))	('men', 'Species', '9606', (25, 28))	('hypo-methylated', 'Var', (87, 102))
163399	24988533	Hypo- and hyper-methylation were defined as significant signal differences between BPA- and vehicle-treated groups at any given time point (t-test, p<0.05).	('Hypo-', 'Var', (0, 5))	('BPA', 'Chemical', 'MESH:C006780', (83, 86))	('hyper-methylation', 'Var', (10, 27))
163404	24988533	Paradoxically, the promoter region of alpha-lactalbumin gene on chromosome 7 did not show any changes in methylation status between the two groups at PNDs 4 and 21, but was significantly hypo-methylated at PND 50 suggesting a gDNA methylation-independent regulation mechanism for this gene (Figure 3A).	('alpha-lactalbumin', 'Gene', (38, 55))	('hypo-methylated', 'Var', (187, 202))	('alpha-lactalbumin', 'Gene', '24528', (38, 55))
163409	24988533	This ChIP assay revealed significant enrichment of H3K4me3 at the alpha-lactalbumin promoter in BPA-treateed mammary glands compared to the control (Figure 3B).	('H3K4me3', 'Var', (51, 58))	('alpha-lactalbumin', 'Gene', (66, 83))	('BPA', 'Chemical', 'MESH:C006780', (96, 99))	('men', 'Species', '9606', (43, 46))	('H3', 'Chemical', 'MESH:C012616', (51, 53))	('alpha-lactalbumin', 'Gene', '24528', (66, 83))
163413	24988533	Ho and collaborators postulated that alterations in the DNA methylation patterns of multiple genes identified in the prostate of BPA-exposed rats may be the underlying cause of neoplastic development of this organ later in life.	('BPA', 'Chemical', 'MESH:C006780', (129, 132))	('neoplastic development of', 'CPA', (177, 202))	('cause', 'Reg', (168, 173))	('rats', 'Species', '10116', (141, 145))	('rat', 'Species', '10116', (41, 44))	('alterations', 'Var', (37, 48))	('rat', 'Species', '10116', (141, 144))	('rat', 'Species', '10116', (14, 17))	('men', 'Species', '9606', (195, 198))
163414	24988533	In contrast, most investigators in the field of cancer research have supported for almost one century the notion that cancer is due to the accumulation of mutations in a cell (somatic mutation theory); this notion does not apply to BPA, a non-mutagenic chemical.	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (155, 164))	('BPA', 'Chemical', 'MESH:C006780', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
163415	24988533	Both the mutational and epigenetic theories of carcinogenesis imply that cancer originates in one cell that has undergone genetic and/or epigenetic changes, which ultimately result in dysregulated cell proliferation.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('carcinogenesis', 'Disease', (47, 61))	('epigenetic changes', 'Var', (137, 155))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rat', 'Species', '10116', (209, 212))	('result in', 'Reg', (174, 183))	('dysregulated', 'MPA', (184, 196))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
163421	24988533	However, genome-wide changes in mRNA expression were only observed at PND50, the time at which increased incidence of intraductal hyperplasias and DCIS are observed.	('mRNA expression', 'MPA', (32, 47))	('intraductal hyperplasias', 'Disease', 'MESH:D006965', (118, 142))	('intraductal hyperplasias', 'Disease', (118, 142))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('PND50', 'Var', (70, 75))
163431	24988533	The highest number of the methylation differences was observed at PND 21, a time when estrogens are secreted by the ovary, 13 days before the opening of the vagina and puberty.	('methylation', 'Var', (26, 37))	('PND 21', 'Var', (66, 72))	('opening of the vagina', 'Disease', (142, 163))	('opening of the vagina', 'Disease', 'MESH:D014625', (142, 163))
163434	24988533	While limited BPA-induced changes in gene expression occurred at PND21, large scale differences in transcriptomal profiles between BPA- and vehicle-treated animals were observed at PND50, a period characterized by adult levels of estrogen and ovarian cyclicity.	('PND50', 'Var', (181, 186))	('differences', 'Reg', (84, 95))	('transcriptomal profiles', 'MPA', (99, 122))	('BPA', 'Chemical', 'MESH:C006780', (14, 17))	('BPA', 'Chemical', 'MESH:C006780', (131, 134))
163437	24988533	The gene expression changes at PND 50 reported herein, simultaneous with the manifestation of ductal hyperplastic lesions and DCIS, are likely to represent the molecular level manifestation of the neoplasias induced by BPA, which span the molecular, cellular and tissue levels of organization.	('neoplasias', 'Disease', 'MESH:D009369', (197, 207))	('DCIS', 'Disease', (126, 130))	('neoplasias', 'Disease', (197, 207))	('ductal hyperplastic lesions', 'Disease', 'MESH:D044584', (94, 121))	('ductal hyperplastic lesions', 'Disease', (94, 121))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('neoplasias', 'Phenotype', 'HP:0002664', (197, 207))	('BPA', 'Chemical', 'MESH:C006780', (219, 222))	('changes', 'Var', (20, 27))	('PND 50', 'Gene', (31, 37))
163439	24988533	For example, the enrichment of the lalba promoter for H3K4me3 indicates that this gene could be regulated by histone methylation-dependent mechanism at this time point.	('H3K4me3', 'Var', (54, 61))	('lalba', 'Gene', (35, 40))	('H3', 'Chemical', 'MESH:C012616', (54, 56))	('lalba', 'Gene', '24528', (35, 40))	('men', 'Species', '9606', (23, 26))
163443	24988533	However, these changes appear to reflect the developmental aberrations caused by BPA rather than representing the causal events that result in carcinogenesis later in adulthood, which seem to involve altered stromal-epithelial interactions in the fetal mammary gland.	('BPA', 'Chemical', 'MESH:C006780', (81, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('men', 'Species', '9606', (52, 55))	('rat', 'Species', '10116', (85, 88))	('altered', 'Reg', (200, 207))	('stroma', 'Disease', (208, 214))	('carcinogenesis', 'Disease', (143, 157))	('rat', 'Species', '10116', (63, 66))	('BPA', 'Var', (81, 84))	('stroma', 'Disease', 'None', (208, 214))
163549	25932356	reported that the detection rate of cancer and the PPV of BI-RADS in breast screening were improved by 3 T-MR imaging compared with 1.5 T-MR imaging.	('breast screening', 'Disease', (69, 85))	('BI-RADS', 'Var', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('PPV', 'MPA', (51, 54))	('cancer', 'Disease', (36, 42))	('detection', 'MPA', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('improved', 'PosReg', (91, 99))
163599	33209106	Whilst for BI-RADS 3 lesions or patients who need routine imaging, 83% were in agreement with postponing imaging until the COVID-19 pandemic is better controlled.	('patients', 'Species', '9606', (32, 40))	('BI-RADS', 'Var', (11, 18))	('COVID-19', 'Disease', (123, 131))	('COVID-19', 'Disease', 'MESH:C000657245', (123, 131))
163626	33209106	These patients should delay their face-to-face consultations until after the pandemic; on the contrary, patients attending for their first consultation, with a diagnosis of cancer for whom a delay in beginning treatment, could affect the illness progression, patients with treatment complications, and patients undergoing treatment (be it chemotherapy or radiotherapy) could be seen in person straight after a teleconsultation.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('affect', 'Reg', (227, 233))	('patients', 'Species', '9606', (259, 267))	('cancer', 'Disease', (173, 179))	('treatment', 'CPA', (273, 282))	('illness progression', 'CPA', (238, 257))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('delay', 'Var', (191, 196))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (302, 310))
163628	33209106	On this point, an exception could be made for young patients, with a family history and genetic predisposition, to develop the disease (BRCA 1 and BRCA 2 mutation) if the waiting time exceeds 6 months.	('BRCA 2', 'Gene', '675', (147, 153))	('BRCA 2', 'Gene', (147, 153))	('mutation', 'Var', (154, 162))	('develop', 'PosReg', (115, 122))	('BRCA 1', 'Gene', '672', (136, 142))	('BRCA 1', 'Gene', (136, 142))	('patients', 'Species', '9606', (52, 60))
163760	21427351	An assessment of BI-RADS 4A or higher was considered a true-positive finding if malignancy was known to be present in the breast from which the image was obtained (i.e., observers were not required to mark the lesion of interest).	('malignancy', 'Disease', 'MESH:D009369', (80, 90))	('BI-RADS', 'Var', (17, 24))	('malignancy', 'Disease', (80, 90))
163808	31502960	Specifically, CLAHE increased the contrast between MCs and surrounding background, and dual-structural element-based morphology operation was applied to enhance the microcalcifications, followed by the top-hat transform to further suppress background noise.	('increased', 'PosReg', (20, 29))	('calcification', 'Disease', 'MESH:D002114', (170, 183))	('enhance', 'PosReg', (153, 160))	('CLAHE', 'Var', (14, 19))	('calcification', 'Disease', (170, 183))	('contrast', 'MPA', (34, 42))
163863	31357602	For these 18 PIK3CA-positive patients, a significantly higher PIK3CA variant allele frequency (VAF) was detected in the DCIS component (45.8%) when compared with the synchronous IBC component (31.7%) (p = 0.007).	('variant', 'Var', (69, 76))	('patients', 'Species', '9606', (29, 37))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('PIK3CA', 'Gene', (13, 19))	('PIK3CA', 'Gene', (62, 68))	('PIK3CA', 'Gene', '5290', (13, 19))	('synchronous IBC component', 'Disease', (166, 191))	('PIK3CA', 'Gene', '5290', (62, 68))	('synchronous IBC component', 'Disease', 'MESH:D009378', (166, 191))	('higher', 'PosReg', (55, 61))
163864	31357602	For the n = 14 PIK3CA mutation-positive patients (26.4%) included in the current study, a significantly higher PIK3CA VAF was also detected in the DCIS component (52.3%) when compared with the synchronous IBC component (37.2%) (p = 0.027).	('synchronous IBC component', 'Disease', 'MESH:D009378', (193, 218))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('PIK3CA', 'Gene', '5290', (15, 21))	('mutation-positive', 'Var', (22, 39))	('patients', 'Species', '9606', (40, 48))	('PIK3CA', 'Gene', (111, 117))	('higher', 'PosReg', (104, 110))	('PIK3CA', 'Gene', '5290', (111, 117))	('PIK3CA', 'Gene', (15, 21))	('synchronous IBC component', 'Disease', (193, 218))
163866	31357602	Analyzing these data irrespective of the degree of the PIK3CA VAF levels revealed that for the 53 patients analyzed in this study, APOBEC3B mRNA levels in IBC were significantly lower in the eight patients with exon 9 (G to A)-mutated PIK3CA when compared with the n = 39 wild-type PIK3CA cases (Mann-Whitney U test p = 0.017).	('APOBEC3B', 'Gene', '9582', (131, 139))	('exon 9 (G to A)-mutated', 'Var', (211, 234))	('patients', 'Species', '9606', (197, 205))	('lower', 'NegReg', (178, 183))	('PIK3CA', 'Gene', '5290', (235, 241))	('PIK3CA', 'Gene', (282, 288))	('patients', 'Species', '9606', (98, 106))	('9 (G to A', 'Mutation', 'c.9G>A', (216, 225))	('IBC', 'Chemical', '-', (155, 158))	('mRNA levels', 'MPA', (140, 151))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (282, 288))	('PIK3CA', 'Gene', '5290', (55, 61))	('APOBEC3B', 'Gene', (131, 139))	('PIK3CA', 'Gene', (235, 241))
163868	31357602	Although the majority of samples with a PIK3CA mutation were ER+, there was no significant interaction effect between ER status and the absence or presence of the two types of tested PIK3CA mutations (p = 0.46 for DCIS and p = 0.20 for IBC).	('IBC', 'Disease', (236, 239))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('DCIS', 'Phenotype', 'HP:0030075', (214, 218))	('mutation', 'Var', (47, 55))	('ER', 'Gene', '2099', (118, 120))	('DCIS', 'Disease', (214, 218))	('ER', 'Gene', '2099', (61, 63))	('PIK3CA', 'Gene', (183, 189))	('IBC', 'Chemical', '-', (236, 239))	('PIK3CA', 'Gene', '5290', (183, 189))
163872	31357602	In a study we performed earlier, we observed higher mRNA levels of APOBEC3B in breast cancer metastasis as compared to the corresponding primary tumor, supporting our hypothesis that, already starting from DCIS, breast cancer progression is associated with deregulated expression of APOBEC3B.	('APOBEC3B', 'Gene', (67, 75))	('mRNA levels', 'MPA', (52, 63))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (79, 103))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('deregulated', 'Var', (257, 268))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('APOBEC3B', 'Gene', '9582', (283, 291))	('breast cancer', 'Disease', (212, 225))	('breast cancer metastasis', 'Disease', (79, 103))	('tumor', 'Disease', (145, 150))	('higher', 'PosReg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('APOBEC3B', 'Gene', '9582', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (269, 279))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('APOBEC3B', 'Gene', (283, 291))	('DCIS', 'Phenotype', 'HP:0030075', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))
163874	31357602	Two hotspot G-to-A mutations in exon 9 of the:often mutated in breast cancer:PIK3CA gene (E542K and E545K) are thought to be generated by APOBEC3B induced C-to-T (G-to-A) transitions.	('PIK3CA', 'Gene', (77, 83))	('E542K', 'Var', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('PIK3CA', 'Gene', '5290', (77, 83))	('APOBEC3B', 'Gene', '9582', (138, 146))	('breast cancer', 'Disease', (63, 76))	('E542K', 'Mutation', 'rs121913273', (90, 95))	('E545K', 'Mutation', 'rs104886003', (100, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('E545K', 'Var', (100, 105))	('APOBEC3B', 'Gene', (138, 146))
163876	31357602	In the study of Kosumi et al., APOBEC3B expression in esophageal squamous cell carcinoma was significantly correlated with PIK3CA mutations in exon 9.	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('correlated', 'Reg', (107, 117))	('expression', 'MPA', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('PIK3CA', 'Gene', (123, 129))	('APOBEC3B', 'Gene', (31, 39))	('PIK3CA', 'Gene', '5290', (123, 129))	('mutations', 'Var', (130, 139))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('APOBEC3B', 'Gene', '9582', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
163878	31357602	Although PIK3CA mutations are known to be more prevalent in ER+ cases, and thus might have been a confounder in our analysis, we found no significant difference in the distribution of wild-type and mutated PIK3CA in ER+ and ER- cases.	('ER', 'Gene', '2099', (224, 226))	('ER', 'Gene', '2099', (216, 218))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (206, 212))	('mutated', 'Var', (198, 205))	('prevalent', 'Reg', (47, 56))	('PIK3CA', 'Gene', (9, 15))	('ER', 'Gene', '2099', (60, 62))	('PIK3CA', 'Gene', '5290', (206, 212))	('PIK3CA', 'Gene', '5290', (9, 15))
163879	31357602	In our cohort, APOBEC3B levels were decreased in specifically the G-to-A PIK3CA-mutated IBC samples when compared with wild-type PIK3CA IBC tumors.	('IBC', 'Chemical', '-', (88, 91))	('PIK3CA', 'Gene', '5290', (73, 79))	('PIK3CA', 'Gene', (129, 135))	('IBC', 'Disease', (88, 91))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('APOBEC3B', 'Gene', '9582', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('IBC', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('G-to-A', 'Var', (66, 72))	('PIK3CA', 'Gene', '5290', (129, 135))	('PIK3CA', 'Gene', (73, 79))	('APOBEC3B', 'Gene', (15, 23))	('decreased', 'NegReg', (36, 45))
163880	31357602	In the synchronous DCIS counterpart, however, there was no difference in APOBEC3B levels between mutated and PIK3CA wild-type tumors.	('PIK3CA', 'Gene', (109, 115))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PIK3CA', 'Gene', '5290', (109, 115))	('mutated', 'Var', (97, 104))	('APOBEC3B', 'Gene', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('APOBEC3B', 'Gene', '9582', (73, 81))
163904	31357602	The following intron-spanning gene expression assays (all from Thermo Fisher Scientific) were evaluated: APOBEC3B, assay ID: hs00358981_m1; EPCAM, hs00158980_m1, and PTPRC, hs00236304_m1.	('hs00236304_m1', 'Var', (173, 186))	('APOBEC3B', 'Gene', '9582', (105, 113))	('EPCAM', 'Gene', (140, 145))	('APOBEC3B', 'Gene', (105, 113))	('PTPRC', 'Gene', (166, 171))	('hs00158980_m1', 'Var', (147, 160))	('EPCAM', 'Gene', '4072', (140, 145))	('PTPRC', 'Gene', '5788', (166, 171))	('hs00358981_m1', 'Var', (125, 138))
163905	31357602	Messenger RNA levels were quantified relative to the average expression of 2 reference genes (GUSB, hs9999908_m1 and HMBS, hs00609297_m1) using the delta Cq (average Cq reference genes -Cq target gene) method.	('GUSB', 'Gene', '2990', (94, 98))	('hs9999908_m1', 'Var', (100, 112))	('HMBS', 'Gene', (117, 121))	('GUSB', 'Gene', (94, 98))	('Messenger RNA levels', 'MPA', (0, 20))	('HMBS', 'Gene', '3145', (117, 121))
163907	31357602	Samples with an average reference gene expression of Cq > 25 were considered to be of insufficient RNA quality and excluded from further analysis, together with their paired samples.	('insufficient', 'Disease', (86, 98))	('insufficient', 'Disease', 'MESH:D000309', (86, 98))	('Cq > 25', 'Var', (53, 60))
163910	31357602	The SNaPshot Multiplex System for SNP Genotyping (Thermo Fisher Scientific) was used to identify samples positive for PIK3CA hotspot mutations in exon 9 and exon 20.	('PIK3CA', 'Gene', (118, 124))	('mutations', 'Var', (133, 142))	('PIK3CA', 'Gene', '5290', (118, 124))
163911	31357602	Next, we used digital PCR (dPCR) to validate the SNaPshot results and quantify the relative number of PIK3CA-mutated copies (of E542K, E545K in exon 9 and H1047R and H1047L in exon 20) in both the DCIS and IBC component of those patients with a PIK3CA mutation identified by SNaPshot analysis.	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('patients', 'Species', '9606', (229, 237))	('PIK3CA', 'Gene', (245, 251))	('PIK3CA', 'Gene', (102, 108))	('PIK3CA', 'Gene', '5290', (245, 251))	('E542K', 'Var', (128, 133))	('IBC', 'Chemical', '-', (206, 209))	('H1047R', 'Mutation', 'rs121913279', (155, 161))	('PIK3CA', 'Gene', '5290', (102, 108))	('H1047L', 'Mutation', 'rs121913279', (166, 172))	('H1047L', 'Var', (166, 172))	('E545K', 'Mutation', 'rs104886003', (135, 140))	('E542K', 'Mutation', 'rs121913273', (128, 133))	('E545K', 'Var', (135, 140))	('H1047R', 'Var', (155, 161))
163928	30732163	Numerous genetic alterations influence human breast carcinogenesis by affecting cell growth, proliferation, differentiation, apoptosis, and invasion.	('breast carcinogenesis', 'Disease', (45, 66))	('genetic alterations', 'Var', (9, 28))	('differentiation', 'CPA', (108, 123))	('cell growth', 'CPA', (80, 91))	('invasion', 'CPA', (140, 148))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (45, 66))	('apoptosis', 'CPA', (125, 134))	('affecting', 'Reg', (70, 79))	('human', 'Species', '9606', (39, 44))	('influence', 'Reg', (29, 38))
163975	30732163	A few studies have shown that the expression of KPNA2 is associated with aggressive behaviors such as higher tumor grade and positive lymph node, and with poor outcomes in BC.ECT2, which is considered a major oncogene involved in the onset or progression of human cancers, induces the malignant transformation of both epithelial cells and fibroblasts, indicating its vital role in the malignant transformation of cells.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('KPNA2', 'Gene', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('cancers', 'Disease', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('expression', 'Var', (34, 44))	('positive lymph node', 'CPA', (125, 144))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('KPNA2', 'Gene', '3838', (48, 53))	('ECT2', 'Gene', '1894', (175, 179))	('aggressive behaviors', 'CPA', (73, 93))	('tumor', 'Disease', (109, 114))	('ECT2', 'Gene', (175, 179))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (73, 93))	('malignant transformation', 'CPA', (285, 309))	('induces', 'Reg', (273, 280))	('human', 'Species', '9606', (258, 263))	('BC', 'Phenotype', 'HP:0003002', (172, 174))	('associated', 'Reg', (57, 67))
163977	30732163	The function of the genes in the turquoise module concerned poly(A) RNA binding, protein processing in the endoplasmic reticulum, RNA transport, and metabolic pathways, which implies that the genes in this module inhibit transcription and regulate the metabolism of tumor cells.	('regulate', 'Reg', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('metabolism', 'MPA', (252, 262))	('genes', 'Var', (192, 197))	('transcription', 'MPA', (221, 234))	('inhibit', 'NegReg', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))
163989	32521267	Inactivation of TP53 and RB via expression of SV40 TAg in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-basal reprogramming in vivo.	('TP53', 'Protein', (16, 20))	('mouse', 'Species', '10090', (65, 70))	('SOX9', 'Gene', (108, 112))	('TAg', 'Gene', '107423', (51, 54))	('TAg', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('upregulation', 'PosReg', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('luminal', 'Chemical', 'MESH:D010634', (127, 134))	('Inactivation', 'Var', (0, 12))
163990	32521267	Furthermore, SOX9 deletion inhibits the progression of ductal carcinoma in situ (DCIS)-like lesions to invasive carcinoma.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('inhibits', 'NegReg', (27, 35))	('invasive carcinoma', 'Disease', (103, 121))	('ductal carcinoma', 'Disease', 'MESH:D044584', (55, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('ductal carcinoma', 'Disease', (55, 71))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (55, 79))	('invasive carcinoma', 'Disease', 'MESH:D009361', (103, 121))	('deletion', 'Var', (18, 26))	('SOX9', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
163993	32521267	Inactivation of BLBC tumor suppressors co-opt SOX9 upregulation to promote luminal-basal reprogramming and tumor progression.	('upregulation', 'PosReg', (51, 63))	('BLBC tumor', 'Disease', 'MESH:D009369', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BLBC tumor', 'Disease', (16, 26))	('luminal-basal reprogramming', 'CPA', (75, 102))	('luminal', 'Chemical', 'MESH:D010634', (75, 82))	('SOX9', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Inactivation', 'Var', (0, 12))	('promote', 'PosReg', (67, 74))
164003	32521267	Furthermore, transformation of luminal cells, but not basal cells, generates tumors resembling human BLBC.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('human', 'Species', '9606', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('luminal', 'Chemical', 'MESH:D010634', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('transformation', 'Var', (13, 27))
164004	32521267	Interestingly, inactivation of the BLBC tumor suppressor BRCA1 or p53 leads to expansion of luminal progenitors in human patients and elicits a luminal-to-basal/mesenchymal transition in mouse models.	('BRCA1', 'Gene', (57, 62))	('luminal', 'Chemical', 'MESH:D010634', (144, 151))	('p53', 'Gene', '7157', (66, 69))	('BLBC tumor', 'Disease', (35, 45))	('luminal-to-basal/mesenchymal transition', 'CPA', (144, 183))	('BLBC tumor', 'Disease', 'MESH:D009369', (35, 45))	('luminal progenitors', 'CPA', (92, 111))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('human', 'Species', '9606', (115, 120))	('mouse', 'Species', '10090', (187, 192))	('luminal', 'Chemical', 'MESH:D010634', (92, 99))	('elicits', 'Reg', (134, 141))	('expansion', 'PosReg', (79, 88))	('inactivation', 'Var', (15, 27))	('p53', 'Gene', (66, 69))	('patients', 'Species', '9606', (121, 129))
164017	32521267	However, efficient Sox9 deletion in ECFP+ luminal cells in MMTV-iCre; Sox9 F/F (referred to as Sox9-cKO henceforth) mice allowed us to investigate SOX9 function in the ER- luminal lineage in vivo.	('mice', 'Species', '10090', (116, 120))	('luminal', 'Chemical', 'MESH:D010634', (172, 179))	('luminal', 'Chemical', 'MESH:D010634', (42, 49))	('cKO', 'Chemical', '-', (100, 103))	('deletion', 'Var', (24, 32))	('ER', 'Gene', '2069', (168, 170))	('Sox9', 'Gene', (19, 23))	('MMTV', 'Species', '11757', (59, 63))
164019	32521267	However, there was a noticeable alveologenesis defect during early pregnancy in Sox9-cKO mice (Figure 1D) and, correspondingly, a 3-fold decrease in the ER- to ER+ luminal cell ratio relative to control animals (Figure 1E).	('ER', 'Gene', '2069', (153, 155))	('ER', 'Gene', '2069', (160, 162))	('decrease', 'NegReg', (137, 145))	('mice', 'Species', '10090', (89, 93))	('alveologenesis', 'CPA', (32, 46))	('early pregnancy', 'Phenotype', 'HP:0001622', (61, 76))	('defect', 'NegReg', (47, 53))	('cKO', 'Chemical', '-', (85, 88))	('Sox9-cKO', 'Var', (80, 88))	('luminal', 'Chemical', 'MESH:D010634', (164, 171))
164021	32521267	The alveologenesis defect in Sox9-cKO was no longer present later in pregnancy (Figure S1D).	('Sox9-cKO', 'Var', (29, 37))	('alveologenesis', 'CPA', (4, 18))	('cKO', 'Chemical', '-', (34, 37))
164029	32521267	Furthermore, acute deletion of Sox9 in freshly sorted wild-type (WT) ER- luminal cells by CRISPR greatly diminished LSPC activity ex vivo (Figures 1H and S1H).	('ER', 'Gene', '2069', (69, 71))	('diminished', 'NegReg', (105, 115))	('LSPC activity', 'MPA', (116, 129))	('deletion', 'Var', (19, 27))	('luminal', 'Chemical', 'MESH:D010634', (73, 80))	('Sox9', 'Gene', (31, 35))
164030	32521267	To further test whether SOX9 is capable of inducing the ER- LSPC state, we found that SOX9 ectopic expression could induce acinus-forming ability in ER+ cells to a level equivalent to 15% of the activity in endogenous ER- cells (Figure 1I).	('acinus', 'Gene', (123, 129))	('induce', 'PosReg', (116, 122))	('ER', 'Gene', '2069', (218, 220))	('ectopic expression', 'Var', (91, 109))	('acinus', 'Gene', '56215', (123, 129))	('SOX9', 'Gene', (86, 90))	('ER', 'Gene', '2069', (56, 58))	('ER', 'Gene', '2069', (149, 151))
164031	32521267	Furthermore, SOX9 ectopic expression markedly increased the expression of multiple ER- luminal cell signature genes, including Sox10, Id4, and Elf5 (Figure 1J).	('ER', 'Gene', '2069', (83, 85))	('expression', 'MPA', (60, 70))	('ectopic expression', 'Var', (18, 36))	('Id4', 'Gene', '15904', (134, 137))	('increased', 'PosReg', (46, 55))	('luminal', 'Chemical', 'MESH:D010634', (87, 94))	('SOX9', 'Gene', (13, 17))	('Id4', 'Gene', (134, 137))	('Elf5', 'Gene', '13711', (143, 147))	('Elf5', 'Gene', (143, 147))	('Sox10', 'Gene', '20665', (127, 132))	('Sox10', 'Gene', (127, 132))
164032	32521267	Interestingly, our previous study showed upregulation of SOX10 is required for induction of organoid-forming cells by SOX9 and SLUG.	('SLUG', 'Gene', (127, 131))	('SOX10', 'Gene', (57, 62))	('SOX9', 'Var', (118, 122))	('SOX10', 'Gene', '20665', (57, 62))	('SLUG', 'Gene', '20583', (127, 131))	('organoid-forming cells', 'CPA', (92, 114))
164037	32521267	Interestingly, loss of Sox9 significantly downregulated multiple members in the NF-kappaB family, including ones regulating the canonical (Rel, Rela, and Nfkb1) and non-canonical (Relb and Nfkb2) pathways (Figure 2D).	('Nfkb1', 'Gene', '18033', (154, 159))	('Rela', 'Gene', '19697', (144, 148))	('Rela', 'Gene', (144, 148))	('Sox9', 'Gene', (23, 27))	('regulating', 'Reg', (113, 123))	('Relb', 'Gene', (180, 184))	('downregulated', 'NegReg', (42, 55))	('NF-kappaB', 'Gene', '18033', (80, 89))	('Nfkb2', 'Gene', (189, 194))	('Nfkb1', 'Gene', (154, 159))	('loss', 'Var', (15, 19))	('Relb', 'Gene', '19698', (180, 184))	('Nfkb2', 'Gene', '18034', (189, 194))	('NF-kappaB', 'Gene', (80, 89))
164039	32521267	To determine the function of NF-kappaB signaling in ER- LSPCs, we first transduced ER- luminal cells with an IkBa superrepressor mutant (IkappaBalphaSR) that constitutively inhibits canonical NF-kappaB signaling.	('ER', 'Gene', '2069', (83, 85))	('NF-kappaB', 'Gene', (29, 38))	('NF-kappaB', 'Gene', '18033', (192, 201))	('luminal', 'Chemical', 'MESH:D010634', (87, 94))	('NF-kappaB', 'Gene', '18033', (29, 38))	('NF-kappaB', 'Gene', (192, 201))	('ER', 'Gene', '2069', (52, 54))	('inhibits', 'NegReg', (173, 181))	('mutant', 'Var', (129, 135))
164040	32521267	Expression of IkappaBalphaSR markedly inhibited acinus formation by ER- cells (Figure 2E).	('acinus', 'Gene', (48, 54))	('IkappaBalphaSR', 'Var', (14, 28))	('inhibited', 'NegReg', (38, 47))	('ER', 'Gene', '2069', (68, 70))	('acinus', 'Gene', '56215', (48, 54))
164041	32521267	We then inhibited the non-canonical NF-kappaB pathway by CRISPR-mediated knockout of Nfkb2, thereby preventing the formation of the transcriptionally active NFKB2/RELB complex.	('inhibited', 'NegReg', (8, 17))	('Nfkb2', 'Gene', (85, 90))	('RELB', 'Gene', (163, 167))	('NF-kappaB', 'Gene', (36, 45))	('NFKB2', 'Gene', (157, 162))	('Nfkb2', 'Gene', '18034', (85, 90))	('NF-kappaB', 'Gene', '18033', (36, 45))	('RELB', 'Gene', '19698', (163, 167))	('NFKB2', 'Gene', '18034', (157, 162))	('formation of the transcriptionally active', 'MPA', (115, 156))	('knockout', 'Var', (73, 81))	('preventing', 'NegReg', (100, 110))
164042	32521267	Knockout of Nfkb2 with two independent sgRNAs significantly inhibited the acinus-forming activity in ER- luminal cells (Figure 2F).	('ER', 'Gene', '2069', (101, 103))	('Nfkb2', 'Gene', '18034', (12, 17))	('acinus', 'Gene', '56215', (74, 80))	('inhibited', 'NegReg', (60, 69))	('Knockout', 'Var', (0, 8))	('luminal', 'Chemical', 'MESH:D010634', (105, 112))	('acinus', 'Gene', (74, 80))	('Nfkb2', 'Gene', (12, 17))
164045	32521267	In addition, canonical and non-canonical NF-kappaB pathways are both activated in ER- LSPCs in BRCA1 mutation driven tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BRCA1', 'Gene', (95, 100))	('NF-kappaB', 'Gene', '18033', (41, 50))	('tumor', 'Disease', (117, 122))	('ER', 'Gene', '2069', (82, 84))	('NF-kappaB', 'Gene', (41, 50))	('activated', 'PosReg', (69, 78))	('mutation', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
164050	32521267	Further supporting the SOX9 association with ER- tumors, we found that SOX9-high (Z score >= 2) breast cancer had significantly decreased ESR1 at both the RNA and protein levels (Figure S2E).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('SOX9-high', 'Var', (71, 80))	('ESR1', 'Gene', (138, 142))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('decreased', 'NegReg', (128, 137))	('tumors', 'Disease', (49, 55))	('breast cancer', 'Disease', (96, 109))	('ER', 'Gene', '2069', (45, 47))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('ESR1', 'Gene', '13982', (138, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
164051	32521267	Additionally, high SOX9 levels are associated with shorter relapse-free survival within BLBC patients in two large independent datasets (Figure S2F).	('shorter', 'NegReg', (51, 58))	('high', 'Var', (14, 18))	('relapse-free survival', 'CPA', (59, 80))	('SOX9 levels', 'MPA', (19, 30))	('patients', 'Species', '9606', (93, 101))
164053	32521267	The C3(1)/Tag model expresses SV40 large T antigen, which induces tumorigenesis by inactivating TP53 and RB, two of the most frequently mutated tumor suppressors in human BLBC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (144, 149))	('human', 'Species', '9606', (165, 170))	('C3(1', 'Gene', (4, 8))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('C3(1)', 'Gene', '361725', (4, 9))	('TP53', 'Protein', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('SV40 large', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivating', 'NegReg', (83, 95))	('induces', 'PosReg', (58, 65))
164060	32521267	This indicates that inactivation of TP53 and RB by SV40 large T antigen may directly or indirectly enable upregulation of Sox9 in luminal cells in vivo.	('SV40 large', 'Var', (51, 61))	('inactivation', 'Var', (20, 32))	('luminal', 'Chemical', 'MESH:D010634', (130, 137))	('upregulation', 'PosReg', (106, 118))	('TP53', 'Protein', (36, 40))
164064	32521267	Similar bipotent cells have been observed in fetal mammary glands and during neoplastic transformation driven by Pik3caH1047R mutation and Brca1 deletion.	('Brca1', 'Gene', '12189', (139, 144))	('mutation', 'Var', (126, 134))	('Pik3ca', 'Gene', (113, 119))	('Pik3ca', 'Gene', '18706', (113, 119))	('neoplastic transformation', 'CPA', (77, 102))	('Brca1', 'Gene', (139, 144))	('deletion', 'Var', (145, 153))
164070	32521267	Interestingly, chromatin at the basal UARs became more accessible in Sox9-GFPhigh cells, whereas luminal UARs were not significantly changed between Sox9-GFPhigh and Sox9-GFPlow cells (Figure S3H).	('luminal', 'Chemical', 'MESH:D010634', (97, 104))	('Sox9-GFPhigh', 'Var', (69, 81))	('more', 'PosReg', (50, 54))
164071	32521267	Analysis of the ATAC-seq data with chromVAR, a bioinformatic tool for inferring transcription factor (TF) activity using chromatin-accessibility data, suggested that Sox9-GFPhigh cells had increased canonical and non-canonical NF-kappaB activity (Figure S3I).	('NF-kappaB', 'Gene', '18033', (227, 236))	('activity', 'MPA', (237, 245))	('canonical', 'CPA', (199, 208))	('Sox9-GFPhigh', 'Var', (166, 178))	('NF-kappaB', 'Gene', (227, 236))	('increased', 'PosReg', (189, 198))
164075	32521267	These results suggest that Sox9 upregulation enabled by TP53 and RB inactivation promotes luminal-to-basal reprogramming to generate a transitory hybrid cell state during BLBC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Sox9', 'Gene', (27, 31))	('upregulation', 'PosReg', (32, 44))	('BLBC tumor', 'Disease', 'MESH:D009369', (171, 181))	('luminal', 'Chemical', 'MESH:D010634', (90, 97))	('promotes', 'PosReg', (81, 89))	('luminal-to-basal reprogramming', 'CPA', (90, 120))	('TP53', 'Gene', (56, 60))	('BLBC tumor', 'Disease', (171, 181))	('inactivation', 'Var', (68, 80))
164076	32521267	Utilizing the Sox9-cKO; C3(1)/Tag mice, we further investigated the effect of Sox9 deletion on BLBC progression.	('mice', 'Species', '10090', (34, 38))	('C3(1', 'Gene', (24, 28))	('deletion', 'Var', (83, 91))	('C3(1)', 'Gene', '361725', (24, 29))	('Sox9', 'Gene', (78, 82))	('cKO', 'Chemical', '-', (19, 22))
164082	32521267	Interestingly, in line with the incomplete penetrance of MMTV-iCre expression, ~25% of MINs in Sox9-cKO;C3(1)/Tag mice expressed SOX9 (Figure 4D).	('C3(1', 'Gene', (104, 108))	('C3(1)', 'Gene', '361725', (104, 109))	('cKO', 'Chemical', '-', (100, 103))	('SOX9', 'Var', (129, 133))	('MMTV', 'Species', '11757', (57, 61))	('mice', 'Species', '10090', (114, 118))	('Sox9-cKO', 'Var', (95, 103))
164084	32521267	Furthermore, deletion of the floxed Sox9 allele in primary tumor cells from Sox9-WT;C3(1)/Tag or Sox9-cKO;C3(1)/Tag mice with an adenoviral Cre vector inhibited their tumor organoid-forming ability (Figure S4B).	('mice', 'Species', '10090', (116, 120))	('tumor', 'Disease', (59, 64))	('C3(1)', 'Gene', '361725', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('deletion', 'Var', (13, 21))	('inhibited', 'NegReg', (151, 160))	('C3(1', 'Gene', (84, 88))	('WT;C3(1)/Tag', 'Disease', 'MESH:C565169', (81, 93))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('C3(1)', 'Gene', '361725', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cKO', 'Chemical', '-', (102, 105))	('C3(1', 'Gene', (106, 110))	('tumor', 'Disease', (167, 172))
164092	32521267	We suggest that this is likely due to incomplete deletion of the floxed Sox9 allele by MMTV-iCre in the mammary epithelium.	('MMTV', 'Species', '11757', (87, 91))	('MMTV-iCre', 'Gene', (87, 96))	('deletion', 'Var', (49, 57))
164093	32521267	Interestingly, similar compensation has been observed in a RANK conditional knockout study, in which complete RANK deletion by K5-Cre inhibited alveologenesis, but incomplete deletion by MMTV-Cre had no effect.	('deletion', 'Var', (115, 123))	('MMTV', 'Species', '11757', (187, 191))	('inhibited', 'NegReg', (134, 143))	('K5-Cre', 'Gene', (127, 133))	('alveologenesis', 'MPA', (144, 158))
164096	32521267	Furthermore, both canonical and non-canonical NF-kappaB signaling is required for BLBC oncogenesis driven by BRCA1 mutation.	('BLBC oncogenesis', 'Disease', (82, 98))	('NF-kappaB', 'Gene', (46, 55))	('BRCA1', 'Gene', (109, 114))	('driven by', 'Reg', (99, 108))	('NF-kappaB', 'Gene', '18033', (46, 55))	('mutation', 'Var', (115, 123))
164099	32521267	Inactivation of the BLBC tumor suppressors TP53 and RB in the C3(1)/Tag model leads to a luminal-to-basal transition at the early stage of hyperplasia.	('leads to', 'Reg', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('C3(1)', 'Gene', '361725', (62, 67))	('luminal-to-basal transition', 'MPA', (89, 116))	('C3(1', 'Gene', (62, 66))	('BLBC tumor', 'Disease', 'MESH:D009369', (20, 30))	('hyperplasia', 'Disease', (139, 150))	('luminal', 'Chemical', 'MESH:D010634', (89, 96))	('BLBC tumor', 'Disease', (20, 30))	('TP53', 'Gene', (43, 47))	('hyperplasia', 'Disease', 'MESH:D006965', (139, 150))	('Inactivation', 'Var', (0, 12))
164101	32521267	Interestingly, TP53 and RB inactivation by the SV40 Tag enables the upregulation of SOX9 in ER- LSPCs, and SOX9 is required for lineage reprogramming.	('inactivation', 'Var', (27, 39))	('ER', 'Gene', '2069', (92, 94))	('SV40', 'Gene', (47, 51))	('upregulation', 'PosReg', (68, 80))	('SOX9', 'Gene', (84, 88))
164102	32521267	Consistent with this, we found that SOX9-high luminal cells had an increased number of open chromatin regions that were enriched in areas we previously defined as UARs in basal cells.	('SOX9-high', 'Var', (36, 45))	('open chromatin regions', 'MPA', (87, 109))	('increased', 'PosReg', (67, 76))	('luminal', 'Chemical', 'MESH:D010634', (46, 53))
164106	32521267	In the C3(1)/ Tag model, Sox9 deletion did not impair the formation of MINs, lesions similar to DCIS in human.	('C3(1)', 'Gene', '361725', (7, 12))	('C3(1', 'Gene', (7, 11))	('Sox9', 'Gene', (25, 29))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('human', 'Species', '9606', (104, 109))	('deletion', 'Var', (30, 38))
164107	32521267	However, the Sox9 null MINs failed to progress to invasive tumors, and the only tumors formed in the Sox9-cKO;C3(1)/Tag mice were from cells that escaped Sox9 deletion.	('C3(1', 'Gene', (110, 114))	('mice', 'Species', '10090', (120, 124))	('cKO', 'Chemical', '-', (106, 109))	('C3(1)', 'Gene', '361725', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('invasive tumors', 'Disease', (50, 65))	('deletion', 'Var', (159, 167))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (59, 65))	('invasive tumors', 'Disease', 'MESH:D009361', (50, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('Sox9-cKO', 'Var', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
164110	32521267	SOX10 overexpression also induces reprogramming of cells in multiple mammary cancer models to an invasive, mesenchymal-like state that closely resembles a neural crest-like state.	('induces', 'Reg', (26, 33))	('overexpression', 'Var', (6, 20))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('SOX10', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('reprogramming', 'CPA', (34, 47))	('SOX10', 'Gene', '20665', (0, 5))
164112	32521267	Interestingly, we found that SOX9 ectopic expression can induce SOX10 expression, and studies have shown that SOXE factors can function as heterodimers.	('SOX10', 'Gene', '20665', (64, 69))	('expression', 'MPA', (70, 80))	('ectopic expression', 'Var', (34, 52))	('SOX9', 'Gene', (29, 33))	('SOX10', 'Gene', (64, 69))	('induce', 'PosReg', (57, 63))
164115	32521267	Sox9Flox (JAX # 013106), C3(1)/Tag (JAX # 013591) and Rosa26-Cas9 (JAX # 026179) were obtained from the Jackson Laboratory.	('JAX # 013106', 'Var', (10, 22))	('Sox9Flox', 'Gene', (0, 8))	('C3(1', 'Gene', (25, 29))	('C3(1)', 'Gene', '361725', (25, 30))	('Rosa26', 'Gene', '14910', (54, 60))	('JAX # 026179', 'Var', (67, 79))	('Sox9Flox', 'Gene', '20682', (0, 8))	('JAX # 013591', 'Var', (36, 48))	('Rosa26', 'Gene', (54, 60))
164161	32521267	IkappaBalphaSR was PCR cloned from pBabe puro IkB alpha M, a gift from Inder Verma (Addgene plasmid # 12332), into pLVX-Puro (Takara 632164) via NEB HiFi Assembly Kit (New England Biolabs E2621S).	('IkB alpha', 'Gene', '18035', (46, 55))	('E2621S', 'Var', (188, 194))	('E2621S', 'SUBSTITUTION', 'None', (188, 194))	('IkB alpha', 'Gene', (46, 55))
164167	32521267	SOX9 is required for luminal stem/progenitor cell (LSPC) activity SOX9 enhances activation of canonical and non-canonical NF-kappaB pathways in LSPC SOX9 upregulation drives luminal-to-basal reprogramming during BLBC formation SOX9 deletion blocks progression of DCIS to invasive BLBC	('luminal', 'Chemical', 'MESH:D010634', (21, 28))	('NF-kappaB', 'Gene', (122, 131))	('deletion', 'Var', (232, 240))	('blocks', 'NegReg', (241, 247))	('SOX9', 'Gene', (227, 231))	('invasive BLBC', 'Disease', (271, 284))	('DCIS', 'Disease', (263, 267))	('NF-kappaB', 'Gene', '18033', (122, 131))	('luminal', 'Chemical', 'MESH:D010634', (174, 181))	('DCIS', 'Phenotype', 'HP:0030075', (263, 267))
164168	30941651	Breast cancer pathology and stage are better predicted by risk stratification models that include mammographic density and common genetic variants To improve breast cancer risk stratification to enable more targeted early detection/prevention strategies that will better balance risks and benefits of population screening programmes.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('variants', 'Var', (138, 146))	('Breast cancer', 'Disease', (0, 13))
164177	30941651	In familial breast cancer just over half of all cases are explained by a known genetic component, predominantly pathogenic variants in BRCA1 or BRCA2 and single nucleotide polymorphisms (SNPs).	('single nucleotide polymorphisms', 'Var', (154, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('BRCA2', 'Gene', '675', (144, 149))	('BRCA1', 'Gene', '672', (135, 140))	('pathogenic', 'Reg', (112, 122))	('BRCA2', 'Gene', (144, 149))	('BRCA1', 'Gene', (135, 140))	('familial breast cancer', 'Disease', 'MESH:D001943', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('familial breast cancer', 'Disease', (3, 25))	('variants', 'Var', (123, 131))
164198	30941651	invasive tumours that were both stage 1 and grade 1 occurring in those > 60 years or intermediate grade DCIS > 55 years or low-grade DCIS at any age.	('DCIS', 'Phenotype', 'HP:0030075', (133, 137))	('low-grade', 'Var', (123, 132))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('invasive tumours', 'Disease', (0, 16))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('invasive tumours', 'Disease', 'MESH:D009361', (0, 16))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
164214	30941651	Utilising all the available tumour pathology from prevalent (only contralateral breast density was used as previously) and incident cancers from 9362 women combined, TC, DR and SNP18 were individually predictive of breast cancer as a whole, as well as most pathological subtypes.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('cancers', 'Disease', (132, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', (215, 228))	('women', 'Species', '9606', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumour', 'Disease', (28, 34))	('DR', 'Chemical', '-', (170, 172))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('TC', 'Chemical', '-', (166, 168))	('predictive', 'Reg', (201, 211))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('SNP18', 'Var', (177, 182))
164222	30941651	Overall, the addition of SNP18 to TC/DR increased the proportion of women in the low-risk group after saliva collection (< 2% 10-year risk) from 26.8% (2426/9062) to 32.5% (2944/9062).	('saliva collection', 'Phenotype', 'HP:0003781', (102, 119))	('TC', 'Chemical', '-', (34, 36))	('women', 'Species', '9606', (68, 73))	('SNP18', 'Var', (25, 30))	('increased', 'PosReg', (40, 49))	('addition', 'Var', (13, 21))	('DR', 'Chemical', '-', (37, 39))
164224	30941651	Similarly, the addition of SNP18 to TC/DR increased the proportion of women in the moderate/high-risk group (>= 5% 10-year risk) from 16.4% (1487/9062) to 18.3% (1656/9062) and the proportion of total breast cancers in these groups also increased from 65/195 (33.3%) using TC/DR to 78/195 (40%) using TC/DR/SNP18 and proportionately more of these women developed BC 4.37% (65/1487) versus 4.71% (78/1656) This results in comparable ratios of population to breast cancers of 2.03 (95% CI 1.52-2.69) and 2.19 (95% CI 1.67-2.85) respectively.	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('TC', 'Chemical', '-', (36, 38))	('TC/DR/SNP18', 'Var', (301, 312))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('SNP18', 'Var', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (456, 469))	('breast cancers', 'Disease', 'MESH:D001943', (456, 470))	('breast cancers', 'Disease', (456, 470))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancers', 'Disease', 'MESH:D001943', (201, 215))	('women', 'Species', '9606', (347, 352))	('breast cancers', 'Disease', (201, 215))	('DR', 'Chemical', '-', (304, 306))	('women', 'Species', '9606', (70, 75))	('TC', 'Chemical', '-', (301, 303))	('breast cancers', 'Phenotype', 'HP:0003002', (456, 470))	('breast cancers', 'Phenotype', 'HP:0003002', (201, 215))	('DR', 'Chemical', '-', (39, 41))	('cancers', 'Phenotype', 'HP:0002664', (463, 470))	('DR', 'Chemical', '-', (276, 278))	('TC', 'Chemical', '-', (273, 275))
164229	30941651	This resulted in better prediction ratios overall, with an OR from low to moderate/high of 5.44 (95% CI 3.52-8.61) with TC/DR/SNP18 compared to 4.36 (95% CI 2.77-7.02) using TC/DR alone.	('DR', 'Chemical', '-', (123, 125))	('TC', 'Chemical', '-', (120, 122))	('TC', 'Chemical', '-', (174, 176))	('better', 'PosReg', (17, 23))	('prediction', 'MPA', (24, 34))	('TC/DR/SNP18', 'Var', (120, 131))	('DR', 'Chemical', '-', (177, 179))
164256	30941651	SNP18 has little predictive value as would be expected, as the majority of individual SNPs are associated with ER+ tumours, with only three predicting ER- cancer risk which are also predictive for breast cancer in women with BRCA1 pathogenic variants, where the cancers are predominantly ER-.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('tumours', 'Disease', (115, 122))	('BRCA1', 'Gene', '672', (225, 230))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA1', 'Gene', (225, 230))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('associated', 'Reg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('ER', 'Gene', '2099', (151, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('women', 'Species', '9606', (214, 219))	('ER', 'Gene', '2099', (111, 113))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', (204, 210))	('cancers', 'Disease', (262, 269))	('breast cancer', 'Disease', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('variants', 'Var', (242, 250))	('ER', 'Gene', '2099', (288, 290))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancers', 'Disease', 'MESH:D009369', (262, 269))
164257	30941651	The recent identification of ten new SNPs for ER- disease alongside ten that were already discovered may provide a SNP20 for ER- breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('SNPs', 'Var', (37, 41))	('ER', 'Gene', '2099', (125, 127))	('ER', 'Gene', '2099', (46, 48))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
164258	30941651	A SNP20 PRS for ER- breast cancer would likely provide a more accurate prediction of more lethal ER- disease along with TC and density.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TC', 'Chemical', '-', (120, 122))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('SNP20 PRS', 'Var', (2, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('ER', 'Gene', '2099', (16, 18))	('ER', 'Gene', '2099', (97, 99))
164263	30941651	Equally, intermediate grade DCIS could become at least a grade 2 invasive breast cancer if untreated, with the possibility of a later breast cancer-related death.	('death', 'Disease', 'MESH:D003643', (156, 161))	('death', 'Disease', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Disease', (134, 147))	('DCIS', 'Disease', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('invasive breast cancer', 'Disease', (65, 87))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('intermediate grade', 'Var', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasive breast cancer', 'Disease', 'MESH:D001943', (65, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
164270	30941651	National Institute for Health Research (NIHR) (RP-PG-0707-10031, IS-BRC-1215-20007) Prevent Breast Cancer (references GA10-033 and GA13-006).	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Breast Cancer', 'Disease', (92, 105))	('IS-BRC-1215-20007', 'Var', (65, 82))	('Breast Cancer', 'Disease', 'MESH:D001943', (92, 105))	('Prevent', 'NegReg', (84, 91))	('Breast Cancer', 'Phenotype', 'HP:0003002', (92, 105))	('IS-BRC-1215', 'CellLine', 'CVCL:9E52', (65, 76))	('RP-PG-0707-10031', 'Var', (47, 63))
164363	23316372	Gradually, DCIS was identified as an independent risk factor in breast cancer recurrence after BCS.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('DCIS', 'Var', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))	('DCIS', 'Chemical', '-', (11, 15))
164419	23316372	The technical and professional component billing and revenue capture for specimen radiography and interpretation using CPT codes 76098-TC and 76098-26 were booked to the specimen radiography cost center.	('CPT', 'Gene', (119, 122))	('men', 'Species', '9606', (78, 81))	('76098-26', 'Var', (142, 150))	('76098-TC', 'Var', (129, 137))	('men', 'Species', '9606', (175, 178))
164569	20868899	This makes intuitive sense, as most non-calcified cancers and normal fibroglandular tissue share similar X-ray attenuation values; as a result, the presence of a significant amount of this "background noise" (heterogeneously or extremely dense parenchymal pattern) can lead to misrepresentation of normal tissue as a potential abnormality requiring recall (false positive) or, more ominously, non-detection of a cancer obscured by adjacent or overlapping tissue (false negative).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('presence', 'Var', (148, 156))	('cancers', 'Disease', (50, 57))	('cancer', 'Disease', (412, 418))	('cancer', 'Disease', 'MESH:D009369', (412, 418))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lead to', 'Reg', (269, 276))	('misrepresentation', 'Disease', (277, 294))
164572	20868899	This was confirmed in the Digital Mammographic Imaging Screening Trial (DMIST), which showed statistically significant improved sensitivity for cancer detection with FFDM compared to SFM, but only in women under 50, pre- or peri-menopausal, and with dense breasts, the latter factor appearing to be the key.	('women', 'Species', '9606', (200, 205))	('FFDM', 'Chemical', '-', (166, 170))	('FFDM', 'Var', (166, 170))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('improved', 'PosReg', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
164590	20868899	This initial study showed that overall conspicuity of breast lesions on DBCT was equal to that on mammography.	('DBCT', 'Chemical', '-', (72, 76))	('breast lesions', 'Disease', 'MESH:D001941', (54, 68))	('DBCT', 'Var', (72, 76))	('breast lesions', 'Disease', (54, 68))
164598	20868899	The conspicuity of each lesion was subjectively and independently scored by two radiologists on a continuous scale from -5 to 5, where zero corresponded to equivalence between the two modalities, negative values corresponded to better conspicuity on CE-DBCT and positive values corresponded to better conspicuity on mammography.	('negative values', 'Var', (196, 211))	('CE-DBCT', 'Chemical', '-', (250, 257))	('better', 'PosReg', (228, 234))
164600	20868899	When divided by lesion type, malignant masses were significantly more conspicuous on CE-DBCT than on mammography (mean conspicuity = -1.84, p<0.001) (Figure 4).	('CE-DBCT', 'Var', (85, 92))	('malignant masses', 'CPA', (29, 45))	('CE-DBCT', 'Chemical', '-', (85, 92))
164601	20868899	The conspicuity of the 7 malignant calcification lesions was slightly better on CE-DBCT than on mammography (mean conspicuity = -0.29, p=0.64), but the difference was not statistically significant.	('conspicuity', 'MPA', (4, 15))	('better', 'PosReg', (70, 76))	('CE-DBCT', 'Chemical', '-', (80, 87))	('calcification lesions', 'Disease', (35, 56))	('calcification lesions', 'Disease', 'MESH:D002114', (35, 56))	('CE-DBCT', 'Var', (80, 87))
164604	20868899	The poor conspicuity of benign calcifications on CE-DBCT suggests the possibility that specificity in diagnosis of indeterminate calcifications may be improved by the use of CE-DBCT, though the numbers in this study are small and further clinical investigation is necessary.	('improved', 'PosReg', (151, 159))	('CE-DBCT', 'Chemical', '-', (49, 56))	('CE-DBCT', 'Var', (174, 181))	('CE-DBCT', 'Chemical', '-', (174, 181))	('specificity', 'MPA', (87, 98))
164614	20868899	Following both DBCT and CE- DBCT, 209 women were asked to complete a questionnaire regarding their comfort during the procedure rating from 1-10: 1) comfort of their position on the DBCT table ; 2) how difficult it was for them to maintain the breath hold of 16.6 seconds; 3) their overall comfort during DBCT; and 4) to compare their comfort during DBCT to their comfort during mammography.	('DBCT', 'Var', (15, 19))	('DBCT', 'Chemical', '-', (15, 19))	('DBCT', 'Chemical', '-', (305, 309))	('DBCT', 'Chemical', '-', (350, 354))	('breath hold', 'Phenotype', 'HP:0002098', (244, 255))	('women', 'Species', '9606', (38, 43))	('DBCT', 'Chemical', '-', (28, 32))	('DBCT', 'Chemical', '-', (182, 186))	('CE-', 'Var', (24, 27))	('CE- DBCT', 'Chemical', '-', (24, 32))
164628	20868899	Initial work has shown that malignant lesions are significantly more conspicuous on CE-DBCT compared to mammography and DBCT.	('CE-DBCT', 'Var', (84, 91))	('malignant lesions', 'CPA', (28, 45))	('CE-DBCT', 'Chemical', '-', (84, 91))	('DBCT', 'Chemical', '-', (120, 124))	('DBCT', 'Chemical', '-', (87, 91))
164674	27929664	First, the majority of DCIS may be considered a potential risk factor (such as atypia) for invasive breast cancer.	('DCIS', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasive breast cancer', 'Disease', 'MESH:D001943', (91, 113))	('atypia', 'Disease', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('invasive breast cancer', 'Disease', (91, 113))
164705	27929664	Additionally, there is currently inadequate data to demonstrate that MRI improves candidate selection for breast conservation surgery or improves patient outcomes by increasing the negative margin rate at initial surgery.	('breast conservation', 'Disease', (106, 125))	('increasing', 'PosReg', (166, 176))	('negative margin', 'MPA', (181, 196))	('improves', 'PosReg', (137, 145))	('MRI', 'Var', (69, 72))	('patient', 'Species', '9606', (146, 153))	('improves', 'PosReg', (73, 81))
164754	29643165	However, BCS is associated with fewer postoperative complications and improved quality of life.	('postoperative complications', 'Disease', 'MESH:D011183', (38, 65))	('improved', 'PosReg', (70, 78))	('BCS', 'Var', (9, 12))	('quality of life', 'CPA', (79, 94))	('postoperative complications', 'Disease', (38, 65))
164875	29338088	In a study of 1374 women undergoing excision alone, margin width was significantly associated with LR, with 10-year LR rates ranging from 41% with a positive margin to 16% with a >1cm margin (p=.00003).	('women', 'Species', '9606', (19, 24))	('margin width', 'Var', (52, 64))	('associated', 'Reg', (83, 93))
164882	29338088	Although the meta-analysis discussed above found that a margin of 2mm reduces LR compared to smaller negative margins, the findings of single-institution studies, the favorable long-term outcomes observed in NSABP trials using a margin definition of no ink on tumor, and the recognition that small differences in local control do not impact survival in DCIS led members of the SSO-ASTRO-ASCO DCIS margins consensus panel to emphasize that the decision to perform a re-excision for negative margins <2mm should be individualized based upon multiple factors, including volume of disease near a margin, results of a post-excision mammogram, cosmetic impact of re-excision, patient age, tumor size and grade, life expectancy, and patient tolerance of risk.	('tumor', 'Disease', (260, 265))	('DCIS', 'Phenotype', 'HP:0030075', (353, 357))	('ASTRO-ASCO DCIS margins', 'Phenotype', 'HP:0009102', (381, 404))	('tumor', 'Disease', (683, 688))	('reduces', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('patient', 'Species', '9606', (670, 677))	('DCIS', 'Phenotype', 'HP:0030075', (392, 396))	('margin', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (683, 688))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('patient', 'Species', '9606', (726, 733))	('tumor', 'Phenotype', 'HP:0002664', (683, 688))
165035	15213718	Women who are AT gene carriers are also at increased risk of developing breast cancer; however, there remains debate as to whether this risk is increased by exposure to ionising radiation (Swift et al, 1991; Wagner, 1992).	('Women', 'Species', '9606', (0, 5))	('gene carriers', 'Var', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('AT', 'Disease', 'None', (14, 16))
165142	31184557	The differences between hypothetical age-based (>=45 years) and risk-based screening included 21 of 50 detectable cancers (42.0%; 95% CI: 28.3%, 55.7%), 683 of 1787 false-positive mammograms (38.2%; 95% CI: 36.0%, 40.5%), and 126 of 384 benign biopsy results (32.8%; 95% CI: 28.1%, 37.5%).	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mammograms', 'CPA', (180, 190))	('false-positive', 'Var', (165, 179))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
165177	18698413	As in human tumors, Mmp13 mRNA was found in myofibroblasts of invasive grade II and III carcinomas, but not in benign grade I and II mammary intraepithelial neoplasias.	('invasive grade II', 'Disease', (62, 79))	('human', 'Species', '9606', (6, 11))	('intraepithelial neoplasias', 'Disease', 'MESH:D019048', (141, 167))	('neoplasias', 'Phenotype', 'HP:0002664', (157, 167))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (141, 166))	('neoplasia', 'Phenotype', 'HP:0002664', (157, 166))	('Mmp13', 'Var', (20, 25))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (141, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('III carcinomas', 'Disease', 'MESH:D002277', (84, 98))	('III carcinomas', 'Disease', (84, 98))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('intraepithelial neoplasias', 'Disease', (141, 167))
165179	18698413	The absence of MMP13 did not influence tumor growth, vascularization, progression to more advanced tumor stages, or metastasis to the lungs, and the absence of MMP13 was not compensated for by expression of other MMPs or tissue inhibitor of metalloproteinases.	('tumor', 'Disease', (99, 104))	('MMP13', 'Gene', (15, 20))	('MMPs', 'Gene', '17386;4313;17390;4314;17392;4317;17394;4318;17395;4319;17384;4320;17385;4321;17381;4322;17386;171052;4323;17387', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('metastasis', 'CPA', (116, 126))	('proteinase', 'Gene', '100616101', (248, 258))	('MMP13', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('MMPs', 'Gene', (213, 217))	('tumor', 'Disease', (39, 44))	('absence', 'Var', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('proteinase', 'Gene', (248, 258))
165220	18698413	After dehydration, the sections were incubated with 35S-labeled Mmp13 antisense probes and further treated according to the in situ hybridization as described previously.	('Mmp13', 'Gene', (64, 69))	('dehydration', 'Phenotype', 'HP:0001944', (6, 17))	('35S', 'Chemical', 'MESH:C000615320', (52, 55))	('rat', 'Species', '10116', (11, 14))	('antisense', 'Var', (70, 79))
165255	18698413	The level of Mmp13 mRNA was highly increased in MMTV-PyMT tumors after 7-weeks of age, with the highest levels found in older mice, corresponding to late stage tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MMTV-PyMT tumors', 'Disease', 'MESH:D009369', (48, 64))	('increased', 'PosReg', (35, 44))	('MMTV-PyMT tumors', 'Disease', (48, 64))	('mice', 'Species', '10090', (126, 130))	('Mmp13', 'Var', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('late stage tumors', 'Disease', 'MESH:D062706', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('late stage tumors', 'Disease', (149, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
165281	18698413	Thus, the absence of MMP13 did not influence progression in the primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('absence', 'Var', (10, 17))	('MMP13', 'Gene', (21, 26))	('primary tumors', 'Disease', (64, 78))
165283	18698413	4D, 1.2 mm3 for MMTV-PyMT;Mmp13+/+, n = 35; 0.7 mm3 for MMTV-PyMT;Mmp13-/-, n = 25, p = 0.34).	('MMTV', 'Species', '11757', (56, 60))	('MMTV', 'Species', '11757', (16, 20))	('Mmp13-/-', 'Var', (66, 74))	('Mmp13+/+', 'Var', (26, 34))
165284	18698413	We therefore conclude that the absence of MMP13 does not affect lung metastasis in the MMTV-PyMT breast cancer model.	('MMTV', 'Species', '11757', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung metastasis', 'CPA', (64, 79))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('absence', 'Var', (31, 38))	('MMP13', 'Gene', (42, 47))	('breast cancer', 'Disease', (97, 110))
165293	18698413	However, although Mmp13 mRNA also was strongly induced in a subpopulation of myofibroblasts in MMTV-PyMT mammary carcinomas, concurrent with early transition to invasive carcinoma, there were no effects on tumor cell proliferation, tumor growth, lung metastasis, vascularization or differentiation of the primary tumors by the absence of MMP13.	('tumor', 'Disease', (313, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('absence', 'Var', (327, 334))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('primary tumors', 'Disease', 'MESH:D009369', (305, 319))	('Mmp13', 'Gene', (18, 23))	('differentiation', 'CPA', (282, 297))	('vascularization', 'CPA', (263, 278))	('tumor', 'Disease', (232, 237))	('primary tumors', 'Disease', (305, 319))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('induced', 'PosReg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('carcinomas', 'Disease', (113, 123))	('invasive carcinoma', 'Disease', (161, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lung metastasis', 'CPA', (246, 261))	('tumor', 'Disease', (206, 211))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (105, 122))	('MMTV-PyMT', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('MMTV', 'Species', '11757', (95, 99))	('rat', 'Species', '10116', (224, 227))	('invasive carcinoma', 'Disease', 'MESH:D009361', (161, 179))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
165297	18698413	In these areas, we found increased thin collagen fibers relative to total collagen in MMTV-PyMT;Mmp13-/- compared to MMTV-PyMT;Mmp13+/+ tumors, indicating that MMP13 influences collagen fiber formation and/or metabolism of fibrillar collagen in the MMTV-PyMT stroma.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('increased', 'PosReg', (25, 34))	('MMTV', 'Species', '11757', (86, 90))	('MMTV', 'Species', '11757', (117, 121))	('Mmp13-/-', 'Var', (96, 104))	('collagen fiber formation', 'CPA', (177, 201))	('MMTV', 'Species', '11757', (249, 253))	('thin collagen fibers', 'CPA', (35, 55))	('influences', 'Reg', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('metabolism', 'MPA', (209, 219))
165309	18698413	It has been reported that Mmp8 and Mmp9 mRNAs are upregulated during bone development in the ossification sites in Mmp13-/- mice and that Mmp8 mRNA is upregulated during skin wound healing in Mmp13-/- mice.	('Mmp8', 'Gene', (26, 30))	('upregulated', 'PosReg', (50, 61))	('mice', 'Species', '10090', (124, 128))	('Mmp8', 'Gene', (138, 142))	('bone development', 'CPA', (69, 85))	('upregulated', 'PosReg', (151, 162))	('mice', 'Species', '10090', (201, 205))	('Mmp8', 'Gene', '17394', (26, 30))	('Mmp9', 'Gene', '17395', (35, 39))	('Mmp13-/-', 'Var', (115, 123))	('Mmp9', 'Gene', (35, 39))	('Mmp8', 'Gene', '17394', (138, 142))
165315	18698413	We have previously reported that mRNAs for several MMPs, including Mmp2, Mmp3, Mmp11 and Mmp14 are expressed in the MMTV-PyMT tumor stroma.	('Mmp11', 'Gene', '4320', (79, 84))	('tumor stroma', 'Disease', 'MESH:D009369', (126, 138))	('MMPs', 'Gene', '17386;4313;17390;4314;17392;4317;17394;4318;17395;4319;17384;4320;17385;4321;17381;4322;17386;171052;4323;17387', (51, 55))	('Mmp14', 'Gene', '4323', (89, 94))	('tumor stroma', 'Disease', (126, 138))	('MMPs', 'Gene', (51, 55))	('Mmp3', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Mmp11', 'Gene', (79, 84))	('MMTV', 'Species', '11757', (116, 120))	('Mmp14', 'Gene', (89, 94))	('Mmp2', 'Gene', '4313', (67, 71))	('Mmp2', 'Gene', (67, 71))
165319	18698413	Tumor promoting and inhibiting functions have been found for MMP9 in the human papilloma virus (HPV) 16 skin cancer model where the absence of Mmp9 reduced the number of tumors, but the tumors that formed were more aggressive.	('promoting', 'PosReg', (6, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('inhibiting', 'NegReg', (20, 30))	('Mmp9', 'Gene', (143, 147))	('human papilloma virus', 'Species', '10566', (73, 94))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('MMP9', 'Gene', '17395', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('skin cancer', 'Disease', (104, 115))	('MMP9', 'Gene', (61, 65))	('HPV', 'Species', '10566', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('skin cancer', 'Phenotype', 'HP:0008069', (104, 115))	('tumors', 'Disease', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('absence', 'Var', (132, 139))	('Mmp9', 'Gene', '17395', (143, 147))	('reduced', 'NegReg', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('skin cancer', 'Disease', 'MESH:D012878', (104, 115))	('papilloma', 'Phenotype', 'HP:0012740', (79, 88))	('tumors', 'Disease', (170, 176))
165327	18698413	In conclusion, we found that the absence of MMP13 in the MMTV-PyMT mice did not result in any differences in tumor progression to invasive and metastatic breast carcinoma.	('absence', 'Var', (33, 40))	('breast carcinoma', 'Disease', (154, 170))	('MMP13', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('breast carcinoma', 'Disease', 'MESH:D001943', (154, 170))	('MMTV', 'Species', '11757', (57, 61))	('breast carcinoma', 'Phenotype', 'HP:0003002', (154, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', (109, 114))
165332	28265306	Three hundred and fifty-six women had a CHEK2 mutation, 370 women had a first-degree relative with breast cancer (and no CHEK2 mutation) and 2269 women had neither risk factor.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('CHEK2', 'Gene', '11200', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('women', 'Species', '9606', (60, 65))	('CHEK2', 'Gene', (121, 126))	('CHEK2', 'Gene', '11200', (40, 45))	('women', 'Species', '9606', (28, 33))	('mutation', 'Var', (46, 54))	('CHEK2', 'Gene', (40, 45))	('women', 'Species', '9606', (146, 151))
165340	28265306	These studies have focused on women at high risk of cancer due to a BRCA1 or BRCA2 mutation, or at moderate risk due to a family history.	('BRCA2', 'Gene', '675', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRCA1', 'Gene', (68, 73))	('BRCA2', 'Gene', (77, 82))	('women', 'Species', '9606', (30, 35))	('mutation', 'Var', (83, 91))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('BRCA1', 'Gene', '672', (68, 73))
165342	28265306	It is possible that MRI performs differently in women with and without BRCA mutations because of the differences in cancer risk and also potentially because of the difference in the natural history of cancers in the two groups.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (201, 207))	('cancers', 'Disease', (201, 208))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', '672', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('women', 'Species', '9606', (48, 53))	('differences', 'Reg', (101, 112))	('BRCA', 'Gene', (71, 75))
165344	28265306	Women with a truncating CHEK2 mutation have a breast cancer risk that is about three fold higher than average and women with both a family history and a CHEK2 mutation have a five-fold increased risk.	('women', 'Species', '9606', (114, 119))	('Women', 'Species', '9606', (0, 5))	('CHEK2', 'Gene', (24, 29))	('CHEK2', 'Gene', '11200', (24, 29))	('truncating', 'Var', (13, 23))	('mutation', 'Var', (30, 38))	('CHEK2', 'Gene', '11200', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CHEK2', 'Gene', (153, 158))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('higher', 'PosReg', (90, 96))	('breast cancer', 'Disease', (46, 59))
165345	28265306	Missense mutations in CHEK2 confer a 1.4 fold increase in breast cancer risk.	('increase', 'PosReg', (46, 54))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('CHEK2', 'Gene', '11200', (22, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('CHEK2', 'Gene', (22, 27))	('Missense mutations', 'Var', (0, 18))
165350	28265306	The study group consisted of women at average risk of cancer and women with a moderately increased risk of cancer due to an inherited CHEK2 mutation or a first-degree relative with breast cancer.	('CHEK2', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('women', 'Species', '9606', (29, 34))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('breast cancer', 'Disease', (181, 194))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('women', 'Species', '9606', (65, 70))	('CHEK2', 'Gene', '11200', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (107, 113))
165352	28265306	Women who were between the ages of 40 and 65 and who had no previous history of breast cancer or of another cancer and were known to carry a CHEK2 mutation (truncating or missense) were invited to participate.	('cancer', 'Disease', (87, 93))	('Women', 'Species', '9606', (0, 5))	('mutation', 'Var', (147, 155))	('CHEK2', 'Gene', '11200', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('CHEK2', 'Gene', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', (80, 93))	('missense', 'Var', (171, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
165359	28265306	Genetic testing was done for four CHEK2 mutations (I157T, IVS2 + 1G > A, 1100delC and del5395) and for three BRCA1 mutations that are founder mutations in Poland (5382insC, C61G and 4153delA).	('BRCA1', 'Gene', (109, 114))	('del5395', 'Var', (86, 93))	('4153delA', 'Var', (182, 190))	('CHEK2', 'Gene', (34, 39))	('4153delA', 'Mutation', 'c.4153delA', (182, 190))	('IVS2 + 1G > A', 'Mutation', 'c.IVS2+1G>A', (58, 71))	('1100delC', 'Mutation', 'rs555607708', (73, 81))	('CHEK2', 'Gene', '11200', (34, 39))	('5382insC', 'Mutation', 'c.5382insC', (163, 171))	('I157T', 'Var', (51, 56))	('1100delC', 'Var', (73, 81))	('del5395', 'Mutation', 'c.del5395', (86, 93))	('1G > A', 'Var', (65, 71))	('I157T', 'Mutation', 'rs17879961', (51, 56))	('1G > A', 'SUBSTITUTION', 'None', (65, 71))	('5382insC', 'Var', (163, 171))	('C61G', 'Var', (173, 177))	('BRCA1', 'Gene', '672', (109, 114))	('C61G', 'Mutation', 'rs28897672', (173, 177))
165360	28265306	We included those with a CHEK2 mutations but women with a BRCA1 mutation were excluded.	('mutations', 'Var', (31, 40))	('CHEK2', 'Gene', '11200', (25, 30))	('BRCA1', 'Gene', (58, 63))	('CHEK2', 'Gene', (25, 30))	('women', 'Species', '9606', (45, 50))	('BRCA1', 'Gene', '672', (58, 63))
165385	28265306	Of these women, 458 (15%) had a first-degree relative with breast cancer and 356 (12%) had a CHEK2 mutation (49 truncationg and 307 missense).	('women', 'Species', '9606', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('CHEK2', 'Gene', (93, 98))	('CHEK2', 'Gene', '11200', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('49 truncationg', 'Var', (109, 123))
165386	28265306	51 women had both a first-degree relative with breast cancer and a CHEK2 mutation.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('CHEK2', 'Gene', (67, 72))	('CHEK2', 'Gene', '11200', (67, 72))	('women', 'Species', '9606', (3, 8))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
165412	28265306	Two hundred and four women (36%) underwent a total of 216 biopsies, including all women with a BI-RADS 5 anomaly, 139 women with a BI-RADS 4 anomaly and 65 women with a BI-RADS 0 anomaly.	('anomaly', 'Disease', (141, 148))	('women', 'Species', '9606', (118, 123))	('anomaly', 'Disease', 'MESH:D000014', (105, 112))	('BI-RADS 0 anomaly', 'Disease', (169, 186))	('women', 'Species', '9606', (156, 161))	('BI-RADS 0 anomaly', 'Disease', 'MESH:C566917', (169, 186))	('women', 'Species', '9606', (82, 87))	('anomaly', 'Disease', (105, 112))	('anomaly', 'Disease', 'MESH:D000014', (179, 186))	('anomaly', 'Disease', 'MESH:D000014', (141, 148))	('women', 'Species', '9606', (21, 26))	('anomaly', 'Disease', (179, 186))	('BI-RADS', 'Var', (95, 102))
165417	28265306	Two of the women had a positive family history of breast cancer and five women had a CHEK2 mutation (one case had both) (Table 3).	('mutation', 'Var', (91, 99))	('CHEK2', 'Gene', (85, 90))	('women', 'Species', '9606', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('women', 'Species', '9606', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('CHEK2', 'Gene', '11200', (85, 90))
165418	28265306	Assuming a baseline risk of that of women between the age of 40 and 50 without a mutation and without a family history (0.26%), the relative risk associated with a CHEK2 mutation was 5.4 (95% CI 1.1 to 2.8) and that associated with a family history of breast cancer (first-degree relative) was 1.7 (95%CI 0.2 to 12).	('breast cancer', 'Disease', (252, 265))	('CHEK2', 'Gene', '11200', (164, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('CHEK2', 'Gene', (164, 169))	('women', 'Species', '9606', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('mutation', 'Var', (170, 178))
165431	28265306	In summary, of 192 women in the study who had a BI-RADS 4 abnormality, 11 breast cancers were detected at the time of screening and three cancers were diagnosed in the four year period following the abnormal MRI (one of these was diagnosed within the four year study period).	('breast cancers', 'Disease', 'MESH:D001943', (74, 88))	('breast cancers', 'Disease', (74, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('abnormal', 'Var', (199, 207))	('women', 'Species', '9606', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('BI-RADS', 'Var', (48, 55))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
165432	28265306	Of the 151 women with an MRI BIRADS 4 abnormality and no other screening abnormality, four breast cancers were found, two at the time of the MRI and two thereafter.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('women', 'Species', '9606', (11, 16))	('breast cancers', 'Phenotype', 'HP:0003002', (91, 105))	('BIRADS', 'Var', (29, 35))	('breast cancers', 'Disease', 'MESH:D001943', (91, 105))	('breast cancers', 'Disease', (91, 105))
165449	28265306	Studies of women at high risk (i.e., BRCA mutation carriers) in general are more supportive of intensive screening than are studies of women at average or intermediate risk.	('mutation', 'Var', (42, 50))	('BRCA', 'Gene', '672', (37, 41))	('women', 'Species', '9606', (11, 16))	('BRCA', 'Gene', (37, 41))	('women', 'Species', '9606', (135, 140))
165450	28265306	In BRCA1 and BRCA2 carriers, the cancer prevalence (and incidence) is much higher than in the cohort studied here (approximately 6-fold higher) and the use of MRI as a screening tool can be justified.	('BRCA1', 'Gene', '672', (3, 8))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('BRCA1', 'Gene', (3, 8))	('higher', 'PosReg', (75, 81))	('carriers', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('BRCA2', 'Gene', (13, 18))	('BRCA2', 'Gene', '675', (13, 18))
165452	28265306	In a Dutch trial of MRI screening for high-risk women, conducted from 1999 to 2006, 47 cancers were found among 594 BRCA mutation carriers, compared to 34 cancers among 1558 women at familial risk, but without a mutation.	('cancers', 'Disease', (87, 94))	('BRCA', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('women', 'Species', '9606', (174, 179))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('mutation', 'Var', (121, 129))	('women', 'Species', '9606', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancers', 'Disease', (155, 162))	('BRCA', 'Gene', '672', (116, 120))
165454	28265306	We excluded women with a Polish founder mutation in BRCA1 from this cohort; three founder mutations comprise the majority of BRCA mutations in Poland.	('BRCA1', 'Gene', '672', (52, 57))	('women', 'Species', '9606', (12, 17))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (125, 129))	('BRCA', 'Gene', '672', (52, 56))	('BRCA1', 'Gene', (52, 57))	('BRCA', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))
165456	28265306	In an early study of women with a BRCA1 or BRCA2 mutation, 33 biopsies revealed seven cancers (21.2%).	('BRCA1', 'Gene', '672', (34, 39))	('BRCA1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (49, 57))	('BRCA2', 'Gene', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('BRCA2', 'Gene', '675', (43, 48))	('cancers', 'Disease', (86, 93))	('women', 'Species', '9606', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
165615	23477556	For example, a recent review in The Lancet concludes that screening in the U.K. only modestly reduces mortality (decrease of 43 deaths in 10,000 women screened for 20 years), and recommends that this should be balanced against the significant risk of overdiagnosis, in order to allow women to make informed decisions regarding screening.	('decrease', 'NegReg', (113, 121))	('deaths', 'Disease', (128, 134))	('deaths', 'Disease', 'MESH:D003643', (128, 134))	('reduces', 'NegReg', (94, 101))	('screening', 'Var', (58, 67))	('women', 'Species', '9606', (284, 289))	('mortality', 'MPA', (102, 111))	('women', 'Species', '9606', (145, 150))
165633	23477556	Strong evidence that DCIS and IDC develop from a common clonal origin and then can continue to evolve in parallel comes from a study of copy number variations in co-existing DCIS and IDC from patient samples and from the long appreciated clinical observation that IDC is frequently accompanied by DCIS.	('IDC', 'Gene', (183, 186))	('patient', 'Species', '9606', (192, 199))	('IDC', 'Gene', '4000', (30, 33))	('clinical', 'Species', '191496', (238, 246))	('IDC', 'Gene', (30, 33))	('IDC', 'Gene', '4000', (264, 267))	('copy number variations', 'Var', (136, 158))	('IDC', 'Gene', '4000', (183, 186))	('DCIS', 'Disease', (297, 301))	('IDC', 'Gene', (264, 267))
165661	23477556	High grade DCIS, however, is more complex in terms of these alterations as shown by loss of 8p, 11q, 13q and 14q; gains in 1q, 5p, 8q and 17q; and amplifications of 17q12 (ErbB2/Her2) and 11q13 (cyclin D1).	('Her2', 'Gene', '2064', (178, 182))	('amplifications', 'Var', (147, 161))	('gains', 'PosReg', (114, 119))	('loss', 'NegReg', (84, 88))	('ErbB2', 'Gene', (172, 177))	('cyclin D1', 'Gene', '595', (195, 204))	('Her2', 'Gene', (178, 182))	('cyclin D1', 'Gene', (195, 204))	('ErbB2', 'Gene', '2064', (172, 177))
165662	23477556	Molecular cytogenetic analysis by CGH of several pre-invasive and invasive breast cancer cell lines revealed that the most common gains are found at 8q, 1q, 7q, 3q and 7p and the most common losses at Xp, 8p, 18q and Xq.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('losses', 'NegReg', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('invasive breast cancer', 'Disease', (66, 88))	('gains', 'PosReg', (130, 135))	('invasive breast cancer', 'Disease', 'MESH:D001943', (66, 88))	('3q and', 'Var', (161, 167))
165670	23477556	The high-grade variety has gain of 11q13, loss of 13q, amplification of 17q12 and infrequent expression of ER and PR.	('17q12', 'Gene', (72, 77))	('amplification', 'Var', (55, 68))	('gain', 'PosReg', (27, 31))	('11q13', 'Protein', (35, 40))	('PR', 'Gene', '5241', (114, 116))	('13q', 'Protein', (50, 53))	('loss', 'NegReg', (42, 46))
165677	23477556	proposed that Her-2/neu amplification plays a more important role in initiation than in progression of IDC.	('amplification', 'Var', (24, 37))	('neu', 'Gene', '2064', (20, 23))	('IDC', 'Gene', '4000', (103, 106))	('IDC', 'Gene', (103, 106))	('neu', 'Gene', (20, 23))
165680	23477556	Amplification of cyclin D1 has been observed in 10-18% cases of DCIS.	('observed', 'Reg', (36, 44))	('Amplification', 'Var', (0, 13))	('cyclin D1', 'Gene', '595', (17, 26))	('DCIS', 'Disease', (64, 68))	('cyclin D1', 'Gene', (17, 26))
165684	23477556	Inactivating mutations of p53 have been observed in a large percentage (40%) of high-grade DCIS.	('high-grade DCIS', 'Disease', (80, 95))	('observed', 'Reg', (40, 48))	('Inactivating mutations', 'Var', (0, 22))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))
165688	23477556	Increased frequency of FGFR1 amplification is associated with progression of DCIS to IDC and poor prognosis.	('FGFR1', 'Gene', (23, 28))	('IDC', 'Gene', '4000', (85, 88))	('Increased frequency of FGFR1', 'Phenotype', 'HP:0030269', (0, 28))	('amplification', 'Var', (29, 42))	('FGFR1', 'Gene', '2260', (23, 28))	('IDC', 'Gene', (85, 88))	('associated', 'Reg', (46, 56))	('DCIS', 'Disease', (77, 81))
165715	23477556	The application of NGS has similarly revealed that the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with homologous patterns of somatic mutations that include both short deletions and base substitutions.	('BRCA2', 'Gene', (100, 105))	('base substitutions', 'Var', (205, 223))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BRCA1', 'Gene', '672', (90, 95))	('BRCA2', 'Gene', '675', (100, 105))	('short deletions', 'Var', (185, 200))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('associated', 'Reg', (110, 120))	('BRCA1', 'Gene', (90, 95))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
165716	23477556	Microarray and PCR approaches have been used to identify splice variants in breast cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('splice variants', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
165717	23477556	Further, with the advent of paired-end sequencing it is now possible to identify fusion genes that may encode for hybrid proteins with oncogenic potential like those identified in leukemias and lymphomas.	('leukemias', 'Phenotype', 'HP:0001909', (180, 189))	('fusion', 'Var', (81, 87))	('leukemias and lymphomas', 'Disease', 'MESH:D007938', (180, 203))	('lymphomas', 'Phenotype', 'HP:0002665', (194, 203))	('encode', 'Reg', (103, 109))
165719	23477556	A recent issue of the journal Nature featured five studies using NGS approaches for whole genome analysis of breast cancer samples, producing many new insights on topics including copy number variations, new descriptions of driver and other mutations, and elevated mutation rates in treatment-resistant tumors.	('copy number', 'Var', (180, 191))	('breast cancer', 'Disease', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('mutation', 'Var', (265, 273))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
165721	23477556	The overall data-set showed recurrent somatic mutations in five genes (PIK3CA, TP53, AKT1, GATA3 and MAP3K1), and recurrent mutations and deletions were discovered for CBFB and RUNX1.	('AKT1', 'Gene', '207', (85, 89))	('AKT1', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (79, 83))	('mutations', 'Var', (124, 133))	('mutations', 'Var', (46, 55))	('TP53', 'Gene', (79, 83))	('MAP3K1', 'Gene', '4214', (101, 107))	('PIK3CA', 'Gene', '5290', (71, 77))	('CBFB', 'Gene', (168, 172))	('RUNX1', 'Gene', (177, 182))	('GATA3', 'Gene', (91, 96))	('CBFB', 'Gene', '865', (168, 172))	('deletions', 'Var', (138, 147))	('RUNX1', 'Gene', '861', (177, 182))	('GATA3', 'Gene', '2625', (91, 96))	('MAP3K1', 'Gene', (101, 107))	('PIK3CA', 'Gene', (71, 77))
165733	23477556	Further analysis of serum genome-wide microRNAs revealed that miR-103, miR-23a, miR-29a, miR-222, miR-23b, miR-24 and miR-25 were coordinately up-regulated.	('miR-103', 'Var', (62, 69))	('miR-23b', 'Gene', '407011', (98, 105))	('miR-23a', 'Gene', '407010', (71, 78))	('miR-23b', 'Gene', (98, 105))	('miR-23a', 'Gene', (71, 78))	('miR-24', 'Gene', (107, 113))	('miR-29a', 'Gene', '407021', (80, 87))	('miR-222', 'Gene', (89, 96))	('up-regulated', 'PosReg', (143, 155))	('miR-25', 'Gene', '407014', (118, 124))	('miR-29a', 'Gene', (80, 87))	('miR-25', 'Gene', (118, 124))	('miR-222', 'Gene', '407007', (89, 96))
165785	29694611	In a prospective study with multiple myeloma patients, de Haart et al., observed a prolonged remission of the disease with the use of YM-155.	('YM-155', 'Var', (134, 140))	('multiple myeloma', 'Phenotype', 'HP:0006775', (28, 44))	('multiple myeloma', 'Disease', 'MESH:D009101', (28, 44))	('multiple myeloma', 'Disease', (28, 44))
165788	19890494	Several genes involved in proliferation, antiapoptosis, invasion and metastasis have been shown to be methylated in various malignant and premalignant breast neoplasms.	('methylated', 'Var', (102, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (158, 167))	('premalignant breast neoplasms', 'Disease', (138, 167))	('premalignant breast neoplasms', 'Disease', 'MESH:D001943', (138, 167))	('breast neoplasms', 'Phenotype', 'HP:0100013', (151, 167))
165790	19890494	Since epigenetic changes are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding novel therapies as well as more refined diagnostic and prognostic tools in breast cancer.	('epigenetic changes', 'Var', (6, 24))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('breast cancer', 'Disease', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
165791	19890494	Growing evidence in the last several decades has documented the pivotal role of epigenetics in the development and progression of various malignancies including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('breast cancer', 'Disease', (161, 174))	('epigenetics', 'Var', (80, 91))	('malignancies', 'Disease', (138, 150))
165796	19890494	Methylation of CpG islands, predominantly present in promoter regions, is the most commonly studied epigenetic change in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', (127, 133))
165812	19890494	Along with the Dnmts, the MBD family of proteins plays an important role in epigenetic silencing of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('Dnmt', 'Gene', '1786', (15, 19))	('epigenetic silencing', 'Var', (76, 96))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Dnmt', 'Gene', (15, 19))
165818	19890494	MBD2 also mediates glutathione S-transferase P (GSTP1) silencing associated with hypermethylated CpG islands in MCF7 cells.	('silencing', 'NegReg', (55, 64))	('glutathione S-transferase P', 'Gene', (19, 46))	('MBD2', 'Gene', '8932', (0, 4))	('hypermethylated', 'Var', (81, 96))	('glutathione S-transferase P', 'Gene', '2950', (19, 46))	('GSTP1', 'Gene', (48, 53))	('GSTP1', 'Gene', '2950', (48, 53))	('MCF7', 'CellLine', 'CVCL:0031', (112, 116))	('MBD2', 'Gene', (0, 4))
165825	19890494	Acetylation places an acetyl group on the NH2-terminal lysine residue on histones leading to neutralization of positive charges resulting in a looser, less compact, transcriptionally active chromatin.	('lysine', 'Chemical', 'MESH:D008239', (55, 61))	('Acetylation', 'Var', (0, 11))	('trans', 'Chemical', 'MESH:C057348', (165, 170))	('transcriptionally active chromatin', 'MPA', (165, 199))	('less compact', 'MPA', (151, 163))	('looser', 'MPA', (143, 149))	('neutralization of positive charges', 'MPA', (93, 127))
165832	19890494	Post-translational modification of histones resulting in gene silencing is not restricted to acetylation alone but also involves methylation of the histone residues.	('histone', 'Protein', (148, 155))	('trans', 'Chemical', 'MESH:C057348', (5, 10))	('gene', 'MPA', (57, 61))	('Post-translational', 'Var', (0, 18))	('methylation', 'MPA', (129, 140))
165833	19890494	Two major histone methylation patterns have been identified: methylation of lysine residue 9 of the core histone protein H3 results in gene silencing, whereas methylation of lysine 4, and recently lysine 27, of H3 are signs of activated genes.	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('methylation', 'Var', (61, 72))	('gene', 'MPA', (135, 139))	('lysine 27', 'Var', (197, 206))	('lysine', 'Chemical', 'MESH:D008239', (197, 203))	('H3', 'Gene', '126961', (121, 123))	('lysine', 'Chemical', 'MESH:D008239', (174, 180))	('lysine residue', 'Var', (76, 90))	('methylation', 'Var', (159, 170))	('H3', 'Gene', '126961', (211, 213))
165834	19890494	In breast cancer, methylation of lysine residue 9 is evident in the regulation of the MUC1 promoter as well as in the transforming growth factor beta signaling pathway genes.	('MUC1', 'Gene', (86, 90))	('MUC1', 'Gene', '4582', (86, 90))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('transforming growth factor beta signaling pathway', 'Pathway', (118, 167))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('lysine', 'Chemical', 'MESH:D008239', (33, 39))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('methylation', 'Var', (18, 29))	('regulation', 'MPA', (68, 78))	('trans', 'Chemical', 'MESH:C057348', (118, 123))
165835	19890494	Recently, the loss of trimethylation of lysine 27 of H3 (H3K27) has been shown to be a negative prognostic indicator in several cancers including breast cancer.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('loss', 'Var', (14, 18))	('cancers', 'Disease', (128, 135))	('trimethylation', 'MPA', (22, 36))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('negative', 'NegReg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (146, 159))	('H3K27', 'Gene', (57, 62))	('lysine', 'Chemical', 'MESH:D008239', (40, 46))	('H3K27', 'Gene', '126961', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('H3', 'Gene', '126961', (53, 55))	('H3', 'Gene', '126961', (57, 59))
165836	19890494	miRNAs are small noncoding RNAs involved in the regulation of gene expression and can be either oncogenes or tumor suppressors in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('miRNAs', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('tumor', 'Disease', (109, 114))
165838	19890494	Subsequent studies have shown aberrant hypermethylation of miRNA classes of MIR9-1, MIR124-3, MIR148, MIR152 and MIR663 in 71 primary breast tumor specimens.	('breast tumor', 'Disease', (134, 146))	('MIR148', 'Var', (94, 100))	('MIR663', 'Gene', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MIR9-1', 'Gene', (76, 82))	('MIR9-1', 'Gene', '407046', (76, 82))	('hypermethylation', 'MPA', (39, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (134, 146))	('MIR152', 'Gene', '406943', (102, 108))	('MIR124-3', 'Gene', (84, 92))	('breast tumor', 'Disease', 'MESH:D001943', (134, 146))	('MIR663', 'Gene', '724033', (113, 119))	('MIR152', 'Gene', (102, 108))	('MIR124-3', 'Gene', '406909', (84, 92))
165844	19890494	Although hypermethylation has been presented thus far as the predominant mode of epigenetic modification, it is important to point out that global genomic hypomethylation has also been noted outside of promoter regions in the genome of cancer cells.	('hypermethylation', 'Var', (9, 25))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
165846	19890494	The impact of hypomethylation on carcinogenesis has been attributed to chromosomal instability, reactivation of transposable elements and loss of imprinting.	('loss', 'NegReg', (138, 142))	('trans', 'Chemical', 'MESH:C057348', (112, 117))	('hypomethylation', 'Var', (14, 29))	('impact', 'Reg', (4, 10))	('chromosomal instability', 'Phenotype', 'HP:0040012', (71, 94))
165847	19890494	Furthermore, although a certain pattern of hypermethylated promoters is generally observed in most tumors including breast cancer, some genes are actually activated by hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('hypomethylation', 'Var', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('activated', 'PosReg', (155, 164))	('tumors', 'Disease', (99, 105))
165849	19890494	This oncogene's promoter is activated by hypomethylation and overexpression of SNCG promotes breast cancer proliferation and metastasis.	('metastasis', 'CPA', (125, 135))	('overexpression', 'PosReg', (61, 75))	('hypomethylation', 'Var', (41, 56))	('SNCG', 'Gene', '6623', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SNCG', 'Gene', (79, 83))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('promotes', 'PosReg', (84, 92))
165854	19890494	Yet others have tried to associate methylation of certain specific genes such as ESR1, BRCA1, RARB, CCND2, etc., with clinical outcomes.	('ESR1', 'Gene', (81, 85))	('CCND2', 'Gene', '894', (100, 105))	('RARB', 'Gene', (94, 98))	('BRCA1', 'Gene', '672', (87, 92))	('RARB', 'Gene', '5915', (94, 98))	('BRCA1', 'Gene', (87, 92))	('methylation', 'Var', (35, 46))	('ESR1', 'Gene', '2099', (81, 85))	('CCND2', 'Gene', (100, 105))
165855	19890494	Hypermethylation has also been used as a diagnostic tool to distinguish between normal and malignant tissue and more recently epigenotyping of the peripheral blood cell DNA has been evaluated as a measure of breast cancer risk.	('epigenotyping', 'Var', (126, 139))	('Hypermethylation', 'Var', (0, 16))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
165858	19890494	Another hallmark is genetic instability in relation to aneuploidy, and telomere erosion may occur in tumor stem cells.	('aneuploidy', 'Disease', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('genetic', 'MPA', (20, 27))	('aneuploidy', 'Disease', 'MESH:D000782', (55, 65))	('telomere', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
165860	19890494	In the past decade, point mutations and deletions of the mtDNA has been reported, but thus far no definitive epigenetic modifications of mtDNA in humans have been found.	('point mutations', 'Var', (20, 35))	('humans', 'Species', '9606', (146, 152))	('mtDNA', 'Gene', (57, 62))	('deletions', 'Var', (40, 49))
165861	19890494	We will focus our review on the epigenetic changes of some of the key genes involved in breast cancer and their clinical implications.	('epigenetic changes', 'Var', (32, 50))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
165862	19890494	Local hypermethylation of key promoter regions, leading to silencing of tumor suppressors, is one of the key processes regulating early disease.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('silencing', 'MPA', (59, 68))	('tumor', 'Disease', (72, 77))	('Local hypermethylation', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
165863	19890494	Aberrant methylation has been identified in over 100 CpG islands in ductal carcinoma in situ (DCIS) and stage I breast tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('breast tumors', 'Phenotype', 'HP:0100013', (112, 125))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (68, 84))	('breast tumor', 'Phenotype', 'HP:0100013', (112, 124))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (68, 92))	('ductal carcinoma in situ', 'Disease', (68, 92))	('breast tumors', 'Disease', (112, 125))	('breast tumors', 'Disease', 'MESH:D001943', (112, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (68, 92))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
165867	19890494	A higher frequency of RUNX3 hypermethylation is seen with estrogen and progesterone expression.	('estrogen', 'MPA', (58, 66))	('hypermethylation', 'Var', (28, 44))	('RUNX3', 'Gene', (22, 27))	('RUNX3', 'Gene', '864', (22, 27))
165869	19890494	The tumor microenvironment may also undergo epigenetic changes that regulate the transition of in situ to invasive breast cancer.	('tumor', 'Disease', (4, 9))	('trans', 'Chemical', 'MESH:C057348', (81, 86))	('epigenetic changes', 'Var', (44, 62))	('regulate', 'Reg', (68, 76))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('invasive breast cancer', 'Disease', (106, 128))
165870	19890494	Myoepithelial cells and stromal fibroblasts undergo epigenetic modifications in early breast cancer carcinogenesis.	('breast cancer carcinogenesis', 'Disease', (86, 114))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('epigenetic modifications', 'Var', (52, 76))	('breast cancer carcinogenesis', 'Disease', 'MESH:D063646', (86, 114))
165871	19890494	Increasing evidence suggests that signals from the stromal microenvironment, including the breast cancer-associated fibroblasts, may serve as triggers for the initiation of epigenetic modifications which promote early disease progression.	('promote', 'PosReg', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('epigenetic modifications', 'Var', (173, 197))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
165872	19890494	Distinct epigenetic changes are present in the stromal cells of breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancers', 'Disease', 'MESH:D001943', (64, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('breast cancers', 'Disease', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('epigenetic changes', 'Var', (9, 27))	('breast cancers', 'Phenotype', 'HP:0003002', (64, 78))
165873	19890494	Promoter hypermethylation of the cystatin-M (CST6) tumor suppressor due to aberrant AKT activation is one of the epigenetic changes that occur when breast epithelial cells are co-cultured with cancer fibroblasts.	('cystatin-M', 'Gene', '1474', (33, 43))	('aberrant', 'Var', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('activation', 'PosReg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CST6', 'Gene', (45, 49))	('cancer', 'Disease', (193, 199))	('AKT', 'Gene', '207', (84, 87))	('tumor', 'Disease', (51, 56))	('AKT', 'Gene', (84, 87))	('CST6', 'Gene', '1474', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('Promoter', 'MPA', (0, 8))	('cystatin-M', 'Gene', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
165874	19890494	Additional studies are ongoing to investigate other triggers of epigenetic silencing in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('epigenetic silencing', 'Var', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
165875	19890494	The mechanisms surrounding the epigenetic regulation of the ER have been a focus of considerable research in breast cancer.	('epigenetic regulation', 'Var', (31, 52))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ER', 'Gene', '2099', (60, 62))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
165886	19890494	Inhibition of DNMT1 by antisense, oligo or short interfering RNA (siRNA) may increase estrogen responsiveness in ER-negative breast cancer cells and increase responsiveness to 5-aza.	('ER', 'Gene', '2099', (113, 115))	('5-aza', 'Chemical', 'MESH:D001374', (176, 181))	('increase', 'PosReg', (149, 157))	('antisense', 'Var', (23, 32))	('breast cancer', 'Disease', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('estrogen responsiveness', 'MPA', (86, 109))	('oligo', 'Var', (34, 39))	('short interfering', 'Var', (43, 60))	('increase', 'PosReg', (77, 85))	('responsiveness to 5-aza', 'MPA', (158, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('DNMT1', 'Gene', (14, 19))	('DNMT1', 'Gene', '1786', (14, 19))
165901	19890494	SETD7 is a histone methyltransferase that is known to monomethylate H3K4 resulting in transcriptional activation.	('SETD7', 'Gene', '80854', (0, 5))	('H3', 'Gene', '126961', (68, 70))	('trans', 'Chemical', 'MESH:C057348', (86, 91))	('monomethylate', 'Var', (54, 67))	('SETD7', 'Gene', (0, 5))	('trans', 'Chemical', 'MESH:C057348', (25, 30))	('transcriptional activation', 'MPA', (86, 112))
165902	19890494	It was demonstrated to induce K302 methylation, resulting in stabilization of the ERalpha protein, which in turn resulting in increased sensitivity to estrogens, enhancing the transcription of estrogen response elements.	('ERalpha', 'Gene', '2099', (82, 89))	('ERalpha', 'Gene', (82, 89))	('K302', 'Chemical', '-', (30, 34))	('estrogen response', 'Gene', (193, 210))	('stabilization', 'MPA', (61, 74))	('K302 methylation', 'Var', (30, 46))	('transcription', 'MPA', (176, 189))	('enhancing', 'PosReg', (162, 171))	('trans', 'Chemical', 'MESH:C057348', (176, 181))	('increased', 'PosReg', (126, 135))	('sensitivity to estrogens', 'MPA', (136, 160))
165903	19890494	This reinforces other studies suggesting that post-translational modification of ERalpha may play a role in hormone response.	('ERalpha', 'Gene', '2099', (81, 88))	('ERalpha', 'Gene', (81, 88))	('post-translational modification', 'Var', (46, 77))	('role', 'Reg', (100, 104))	('trans', 'Chemical', 'MESH:C057348', (51, 56))	('hormone', 'MPA', (108, 115))	('play', 'Reg', (93, 97))
165905	19890494	showed that abrogation of ER signaling resulted in recruitment of polycomb repressors and HDs to the promoters of the target genes and was then followed by DNA methylation of the promoters.	('HD', 'Disease', 'MESH:D006816', (90, 92))	('recruitment', 'MPA', (51, 62))	('abrogation', 'Var', (12, 22))	('polycomb repressors', 'Protein', (66, 85))	('ER', 'Gene', '2099', (26, 28))
165906	19890494	This study demonstrated that epigenetic silencing of ER target genes is crucial to the development of ERalpha-independent growth.	('ERalpha', 'Gene', (102, 109))	('ERalpha', 'Gene', '2099', (102, 109))	('ER', 'Gene', '2099', (53, 55))	('epigenetic silencing', 'Var', (29, 49))	('ER', 'Gene', '2099', (102, 104))
165912	19890494	In ER-negative tumors, silencing of the ERalpha gene also affects downstream estrogen-regulated gene expression including PR expression.	('ERalpha', 'Gene', '2099', (40, 47))	('ER', 'Gene', '2099', (3, 5))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PR expression', 'MPA', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('affects', 'Reg', (58, 65))	('silencing', 'Var', (23, 32))	('estrogen-regulated gene expression', 'MPA', (77, 111))	('ER', 'Gene', '2099', (40, 42))	('ERalpha', 'Gene', (40, 47))	('tumors', 'Disease', (15, 21))
165919	19890494	Epigenetic modifications play a role in the transcription of the RARB2 promoter.	('transcription', 'MPA', (44, 57))	('RARB', 'Gene', '5915', (65, 69))	('trans', 'Chemical', 'MESH:C057348', (44, 49))	('role', 'Reg', (32, 36))	('Epigenetic modifications', 'Var', (0, 24))	('RARB', 'Gene', (65, 69))
165920	19890494	Hypermethylation of the promoter has been shown in both breast cancer cell lines and many primary breast tumors.	('shown', 'Reg', (42, 47))	('breast tumors', 'Phenotype', 'HP:0100013', (98, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Hypermethylation', 'Var', (0, 16))	('breast tumors', 'Disease', (98, 111))	('breast tumors', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
165924	19890494	There is evidence for epigenetic regulation of BRCA1 and BRCA2 genes in both sporadic and hereditary breast cancers.	('BRCA1', 'Gene', (47, 52))	('hereditary breast cancers', 'Disease', (90, 115))	('sporadic', 'Disease', (77, 85))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (90, 115))	('BRCA2', 'Gene', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('epigenetic regulation', 'Var', (22, 43))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('BRCA2', 'Gene', '675', (57, 62))	('BRCA1', 'Gene', '672', (47, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
165925	19890494	Promoter hypermethylation of BRCA1 and resulting gene inactivation occurs in a minority of sporadic cancers but is more common with loss of heterozygosity and in certain tumor subtypes such as medullary and mucinous carcinomas.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('sporadic cancers', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA1', 'Gene', '672', (29, 34))	('tumor', 'Disease', (170, 175))	('mucinous carcinomas', 'Disease', (207, 226))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (207, 226))	('loss of heterozygosity', 'Var', (132, 154))	('sporadic cancers', 'Disease', 'MESH:D009369', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('BRCA1', 'Gene', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('gene', 'MPA', (49, 53))	('Promoter hypermethylation', 'Var', (0, 25))
165926	19890494	BRCA2 promoter methylation has been shown in 4% of sporadic ovarian cancers.	('BRCA2', 'Gene', '675', (0, 5))	('methylation', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancers', 'Phenotype', 'HP:0100615', (60, 75))	('sporadic ovarian cancers', 'Disease', (51, 75))	('sporadic ovarian cancers', 'Disease', 'MESH:D010051', (51, 75))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('BRCA2', 'Gene', (0, 5))
165928	19890494	The more predominant mode of epigenetic regulation of BRCA2 is via formation of repressor complexes and chromatin remodeling.	('BRCA2', 'Gene', (54, 59))	('epigenetic regulation', 'Var', (29, 50))	('BRCA2', 'Gene', '675', (54, 59))
165932	19890494	The results of this study, if confirmed by others, would suggest that BRCA promoter methylation is not a definitive risk modifier in hereditary breast cancers and a more complex epigenetic cascade may yet need to be elucidated.	('methylation', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (133, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('BRCA', 'Gene', '672', (70, 74))	('BRCA', 'Gene', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('hereditary breast cancers', 'Disease', (133, 158))	('breast cancers', 'Phenotype', 'HP:0003002', (144, 158))
165935	19890494	Earlier work on small numbers of BRCA1 tumors showed decreased XIST in these tumors, although a more recent study showed that XIST RNA coating of the unaffected X chromosome is not affected by the BRCA1 mutation.	('BRCA1', 'Gene', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('XIST', 'Gene', (126, 130))	('mutation', 'Var', (203, 211))	('XIST', 'Gene', '7503', (63, 67))	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('XIST', 'Gene', '7503', (126, 130))	('BRCA1', 'Gene', '672', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('BRCA1', 'Gene', (33, 38))	('BRCA1 tumors', 'Disease', (33, 45))	('tumors', 'Disease', (77, 83))	('decreased', 'NegReg', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('BRCA1 tumors', 'Disease', 'MESH:D009369', (33, 45))	('BRCA1', 'Gene', '672', (197, 202))	('XIST', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
165936	19890494	Additional studies are needed to further clarify the epigenetic regulation and sequelae of BRCA mutations in hereditary cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BRCA', 'Gene', (91, 95))	('hereditary cancer', 'Disease', 'MESH:D009369', (109, 126))	('hereditary cancer', 'Disease', (109, 126))	('BRCA', 'Gene', '672', (91, 95))	('mutations', 'Var', (96, 105))
165938	19890494	Hypermethylation is the predominant mechanism of Wnt pathway aberrancy in breast cancer.	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('Hypermethylation', 'Var', (0, 16))	('Wnt pathway', 'Pathway', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('aberrancy', 'Var', (61, 70))
165939	19890494	Epigenetic silencing of Wnt antagonist genes including SFRP has been shown in breast cancer with a corresponding loss of function resulting in activation of Wnt signaling in breast carcinogenesis, and is associated with an unfavorable prognosis.	('SFRP', 'Gene', (55, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('Wnt signaling', 'Pathway', (157, 170))	('breast carcinogenesis', 'Disease', (174, 195))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (174, 195))	('Epigenetic silencing', 'Var', (0, 20))	('associated', 'Reg', (204, 214))	('activation', 'PosReg', (143, 153))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
165949	19890494	Hsp90 chaperone activity is regulated by HD6 and inhibition of HD6 leads to Hsp90 hyperacetylation causing separation from p23 and the corresponding loss of chaperone activity.	('HD6', 'Gene', '10013', (41, 44))	('Hsp90', 'Gene', '3320', (0, 5))	('chaperone activity', 'MPA', (157, 175))	('HD6', 'Gene', '10013', (63, 66))	('loss', 'NegReg', (149, 153))	('Hsp90', 'Gene', (76, 81))	('HD6', 'Gene', (63, 66))	('p23', 'Gene', (123, 126))	('HD6', 'Gene', (41, 44))	('Hsp90', 'Gene', '3320', (76, 81))	('p23', 'Gene', '10728', (123, 126))	('inhibition', 'Var', (49, 59))	('hyperacetylation', 'MPA', (82, 98))	('Hsp90', 'Gene', (0, 5))
165963	19890494	Histone acetylation was increased as a result of this combination in the RARB2 promoter of MCF7 breast cancer cells.	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('RARB', 'Gene', '5915', (73, 77))	('Histone acetylation', 'MPA', (0, 19))	('MCF7 breast cancer', 'Disease', (91, 109))	('RARB', 'Gene', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('increased', 'PosReg', (24, 33))	('combination', 'Var', (54, 65))
165967	19890494	The activity of 5-aza is enhanced when coupled with antisense oligonucleotide targeting of DNMT1.	('oligonucleotide', 'Chemical', 'MESH:D009841', (62, 77))	('enhanced', 'PosReg', (25, 33))	('DNMT1', 'Gene', (91, 96))	('5-aza', 'Chemical', 'MESH:D001374', (16, 21))	('DNMT1', 'Gene', '1786', (91, 96))	('antisense', 'Var', (52, 61))	('activity', 'MPA', (4, 12))
165985	19890494	Epigenetic changes in breast cancer have been investigated to improve diagnosis and prognostication.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Epigenetic changes', 'Var', (0, 18))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
165986	19890494	Identification of DNA hypermethylation in breast biopsy samples from BRCA carriers may be useful when there is diagnostic uncertainty.	('BRCA', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (69, 73))	('hypermethylation', 'Var', (22, 38))
165987	19890494	Epigenetic changes have also been investigated as prognostic markers in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('Epigenetic changes', 'Var', (0, 18))
165988	19890494	For example, DNA hypermethylation of PITX2 is a marker of poor prognosis in node-negative hormone receptor-positive breast cancer after adjuvant tamoxifen therapy.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('hormone receptor', 'Gene', '3164', (90, 106))	('DNA hypermethylation', 'Var', (13, 33))	('hormone receptor', 'Gene', (90, 106))	('PITX2', 'Gene', '5308', (37, 42))	('PITX2', 'Gene', (37, 42))	('tamoxifen', 'Chemical', 'MESH:D013629', (145, 154))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
165992	19890494	Similarly, epigenetic changes in RPFNA have included RARB2 promoter methylation.	('promoter methylation', 'MPA', (59, 79))	('RPFNA', 'Gene', (33, 38))	('RARB', 'Gene', (53, 57))	('epigenetic changes', 'Var', (11, 29))	('RARB', 'Gene', '5915', (53, 57))
165993	19890494	Epigenetic changes in serum DNA from breast cancer patients is currently under investigation as a tool for earlier detection of cancer.	('breast cancer', 'Disease', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (51, 59))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (128, 134))
165995	19890494	Most recently, investigators from Europe reported on the first large-scale epigenotyping study of peripheral blood DNA and demonstrated that DNA methylation provides a good prediction of breast cancer risk, which was not completely independent of traditional risk factors for breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('DNA', 'Gene', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancer', 'Disease', (276, 289))	('methylation', 'Var', (145, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
165996	19890494	Lack of peripheral blood DNA methylation of the estrogen target gene ZNF217 was significantly associated with ERalpha bioreactivity in a functional assay, suggesting that methylation was a marker of estrogen exposure.	('methylation', 'Var', (29, 40))	('Lack', 'NegReg', (0, 4))	('ZNF217', 'Gene', (69, 75))	('ZNF217', 'Gene', '7764', (69, 75))	('ERalpha', 'Gene', (110, 117))	('ERalpha', 'Gene', '2099', (110, 117))
165997	19890494	Despite the exhaustive data regarding the extent of epigenetic changes in breast cancer, many uncertainties remain.	('breast cancer', 'Disease', (74, 87))	('epigenetic changes', 'Var', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
165998	19890494	These uncertainties revolve around the following key questions: 1) Does the epigenetic change actually initiate the gene silencing leading to tumor initiation or is it a downstream change or a response pattern resulting from a more fundamental problem?	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor initiation', 'Disease', 'MESH:D009369', (142, 158))	('gene', 'MPA', (116, 120))	('tumor initiation', 'Disease', (142, 158))	('epigenetic change', 'Var', (76, 93))
165999	19890494	(a chicken and egg question); 2) Demethylating agents and HDi are likely to induce expression of many genes while we only focus on the key target genes.	('chicken', 'Species', '9031', (3, 10))	('Demethylating agents', 'Var', (33, 53))	('induce', 'PosReg', (76, 82))	('expression', 'MPA', (83, 93))	('HD', 'Disease', 'MESH:D006816', (58, 60))
166006	30075794	The added value of mammography in different age-groups of women with and without BRCA mutation screened with breast MRI Breast magnetic resonance imaging (MRI) is the most sensitive imaging method for breast cancer detection and is therefore offered as a screening technique to women at increased risk of developing breast cancer.	('BRCA', 'Gene', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (316, 329))	('breast cancer', 'Disease', 'MESH:D001943', (316, 329))	('BRCA', 'Gene', '672', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Disease', (316, 329))	('women', 'Species', '9606', (58, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('mutation', 'Var', (86, 94))	('breast cancer', 'Disease', (201, 214))	('women', 'Species', '9606', (278, 283))
166007	30075794	The purpose of this study is to investigate the added cancer detection of mammography when breast MRI is available, focusing on the value in women with and without BRCA mutation, and in the age groups above and below 50 years.	('women', 'Species', '9606', (141, 146))	('mutation', 'Var', (169, 177))	('BRCA', 'Gene', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA', 'Gene', '672', (164, 168))
166013	30075794	In BRCA mutation carriers, 3 of 61 cancers were detected only on mammography, while in other women 10 of 64 cases were detected with mammography alone.	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutation', 'Var', (8, 16))	('women', 'Species', '9606', (93, 98))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
166017	30075794	While the benefit appears slightly larger in women over 50 years of age without BRCA mutation, there is also a substantial increase in false positive findings in these women.	('BRCA', 'Gene', '672', (80, 84))	('mutation', 'Var', (85, 93))	('BRCA', 'Gene', (80, 84))	('women', 'Species', '9606', (168, 173))	('women', 'Species', '9606', (45, 50))
166020	30075794	those with a germline mutation in the BRCA1 or BRCA2 genes) biennial mammographic screening is insufficient due to low sensitivity and high rates of interval cancers.	('insufficient', 'Disease', (95, 107))	('insufficient', 'Disease', 'MESH:D000309', (95, 107))	('interval cancers', 'Disease', 'MESH:D009369', (149, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('BRCA2', 'Gene', (47, 52))	('BRCA1', 'Gene', (38, 43))	('germline mutation', 'Var', (13, 30))	('interval cancers', 'Disease', (149, 165))	('BRCA2', 'Gene', '675', (47, 52))	('BRCA1', 'Gene', '672', (38, 43))
166022	30075794	Recent studies question the added cancer detection of mammography in this population, especially in BRCA mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutation', 'Var', (105, 113))	('BRCA', 'Gene', '672', (100, 104))	('BRCA', 'Gene', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))
166024	30075794	Various authors have proposed to cancel mammographic screening in young women also screened with breast MRI, especially in BRCA1 mutation carriers.	('carriers', 'Reg', (138, 146))	('BRCA1', 'Gene', '672', (123, 128))	('mutation', 'Var', (129, 137))	('BRCA1', 'Gene', (123, 128))	('women', 'Species', '9606', (72, 77))
166025	30075794	In these BRCA1 mutation carriers, the mammographic sensitivity is exceedingly low, reported as low as 35%.	('BRCA1', 'Gene', (9, 14))	('mutation', 'Var', (15, 23))	('low', 'NegReg', (78, 81))	('BRCA1', 'Gene', '672', (9, 14))
166027	30075794	Additionally, concerns are raised about the risk of radiation-induced cancers in these women, as BRCA mutation carriers have increased susceptibility to radiation.	('increased susceptibility to radiation', 'Phenotype', 'HP:0011133', (125, 162))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (102, 110))	('BRCA', 'Gene', '672', (97, 101))	('susceptibility', 'MPA', (135, 149))	('BRCA', 'Gene', (97, 101))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('women', 'Species', '9606', (87, 92))	('cancers', 'Disease', (70, 77))
166033	30075794	Differences in the complementary value of mammography in women below and above 50 years of age, and in BRCA mutation carriers versus others at increased risk of breast cancer were assessed.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carriers', 'Reg', (117, 125))	('BRCA', 'Gene', '672', (103, 107))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('BRCA', 'Gene', (103, 107))	('women', 'Species', '9606', (57, 62))	('mutation', 'Var', (108, 116))
166041	30075794	Various gadolinium chelates were used as a contrast agent, administered at a dose of 0.1 mmol/kg or 0.2 mmol/kg body weight using a power injector (Medrad, Warrendale, PA, USA) at a flow rate of 2.5 mL/s, followed by a saline flush.	('flush', 'Phenotype', 'HP:0031284', (226, 231))	('0.2 mmol/kg', 'Var', (100, 111))	('flush', 'Disease', (226, 231))	('gadolinium', 'Chemical', 'MESH:D005682', (8, 18))	('flush', 'Disease', 'MESH:D005483', (226, 231))
166052	30075794	The BRCA mutation carriers group also included first-degree untested relatives.	('mutation', 'Var', (9, 17))	('BRCA', 'Gene', (4, 8))	('BRCA', 'Gene', '672', (4, 8))
166067	30075794	Whether there is a difference in age groups between women with a proven BRCA mutation and women without is difficult to determine, since we did not observe only mammographically detected breast cancers in BRCA mutation carriers under 50 years of age, but overall the added cancer detection in BRCA mutation carriers was slightly lower than in other women at increased risk (3/61 vs. 10/64, p = 0.05).	('mutation', 'Var', (298, 306))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('BRCA', 'Gene', (293, 297))	('BRCA', 'Gene', (205, 209))	('BRCA', 'Gene', (72, 76))	('breast cancers', 'Disease', 'MESH:D001943', (187, 201))	('breast cancers', 'Disease', (187, 201))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('lower', 'NegReg', (329, 334))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('women', 'Species', '9606', (349, 354))	('breast cancers', 'Phenotype', 'HP:0003002', (187, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('women', 'Species', '9606', (52, 57))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', (273, 279))	('BRCA', 'Gene', '672', (293, 297))	('BRCA', 'Gene', '672', (205, 209))	('BRCA', 'Gene', '672', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('women', 'Species', '9606', (90, 95))
166070	30075794	2), which was the strongest in the 50-60 years categories both in the BRCA mutation carriers and others.	('mutation', 'Var', (75, 83))	('BRCA', 'Gene', (70, 74))	('BRCA', 'Gene', '672', (70, 74))
166083	30075794	By mammography alone, only one invasive cancer (grade 3) was detected in a BRCA mutation carrier, at the age of 56 years.	('invasive cancer', 'Disease', (31, 46))	('BRCA', 'Gene', '672', (75, 79))	('invasive cancer', 'Disease', 'MESH:D009362', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutation', 'Var', (80, 88))	('BRCA', 'Gene', (75, 79))
166084	30075794	Our results are in line with the meta-analysis of Heijnsdijk et al., who reported only one invasive cancer detected by mammography alone in BRCA1 mutation carriers across four breast cancer screening trials of women at high risk of developing breast cancer.	('breast cancer', 'Disease', (243, 256))	('carriers', 'Var', (155, 163))	('invasive cancer', 'Disease', (91, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('BRCA1', 'Gene', (140, 145))	('mutation carriers', 'Var', (146, 163))	('invasive cancer', 'Disease', 'MESH:D009362', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Disease', (176, 189))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('BRCA1', 'Gene', '672', (140, 145))	('women', 'Species', '9606', (210, 215))
166085	30075794	also reported little benefit of mammography screening in younger women with a BRCA1 mutation.	('mammography', 'Disease', (32, 43))	('BRCA1', 'Gene', '672', (78, 83))	('women', 'Species', '9606', (65, 70))	('BRCA1', 'Gene', (78, 83))	('mutation', 'Var', (84, 92))
166087	30075794	suggested to increase the starting age for mammography screening in women with BRCA1 mutations to 40 years.	('women', 'Species', '9606', (68, 73))	('mutations', 'Var', (85, 94))	('BRCA1', 'Gene', (79, 84))	('BRCA1', 'Gene', '672', (79, 84))
166098	30075794	Since younger women at high risk and in particular BRCA mutation carriers have been shown to be more susceptible to developing radiation-induced cancers, replacing mammography with DBT might not be beneficial for women screened with MRI.	('cancers', 'Disease', (145, 152))	('BRCA', 'Gene', '672', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('BRCA', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('women', 'Species', '9606', (213, 218))	('women', 'Species', '9606', (14, 19))	('mutation', 'Var', (56, 64))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
166099	30075794	reported no net benefit of mammography surveillance before the age of 35 years in women with a BRCA mutation and recommended to limit the radiation dose by raising the age for undergoing mammography.	('BRCA', 'Gene', (95, 99))	('mutation', 'Var', (100, 108))	('women', 'Species', '9606', (82, 87))	('BRCA', 'Gene', '672', (95, 99))
166107	30075794	In BRCA mutation carriers the added cancer detection with mammography is even less than for women without BRCA mutation.	('BRCA', 'Gene', (106, 110))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('women', 'Species', '9606', (92, 97))	('less', 'NegReg', (78, 82))	('cancer', 'Disease', (36, 42))	('mutation', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRCA', 'Gene', '672', (106, 110))
166112	27689334	Compared to MG, US could detect more invasive NPBC (83.6% vs 54.3%, p<0.001), lymph node positive NPBC (19.1% vs 10.2%, p=0.018), lower grade (24.8% vs 16.5%, p<0.001), multifocal (19.2% vs 6.3%, p<0.001), PR positive (71.4% vs 66.9%, p=0.041), Her2 negative (74.3% vs 54.3%, p<0.001), Ki67 high (defined as >14%, 46.3% vs 37.0%, p=0.031) cancers and more NPBC who received chemotherapy (40.7% vs 21.3%, p<0.001).	('negative', 'NegReg', (250, 258))	('Her2', 'Gene', (245, 249))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('Her2', 'Gene', '2064', (245, 249))	('cancers', 'Disease', (339, 346))	('cancers', 'Disease', 'MESH:D009369', (339, 346))	('Ki67', 'Var', (286, 290))	('lower grade', 'CPA', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))
166133	27689334	As for the ductal carcinoma in situ (DCIS), the 10-year Kaplan-Meier estimated DFS of US-DCIS-NPBC and MG-DCIS-NPBC were 100.0% and 93.8%, whereas the 10-year OS were both 100.0%.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('ductal carcinoma', 'Disease', 'MESH:D044584', (11, 27))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (11, 35))	('ductal carcinoma', 'Disease', (11, 27))	('US-DCIS-NPBC', 'Var', (86, 98))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
166160	27689334	However, the 807 (MG+/US not done) NPBC would include some MG+/US- NPBC and majority of MG+/US+ NPBC patients, while the 256 US-detected NPBC patients were all MG-/US+.	('MG+/US+', 'Var', (88, 95))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (142, 150))	('MG+/US-', 'Disease', (59, 66))
166161	27689334	Similarly in our study, there would also be MG+/US+ double positive NPBC patients in the (US+/MG not done) group.	('MG+/US+ double positive', 'Var', (44, 67))	('patients', 'Species', '9606', (73, 81))	('NPBC', 'Disease', (68, 72))
166269	24069582	In addition, AI treatment is not associated with increased thromboembolic events and uterine cancers, although increased risk of bone fractures has also been observed.	('cancers', 'Disease', (93, 100))	('AI treatment', 'Var', (13, 25))	('bone fractures', 'Disease', 'MESH:D050723', (129, 143))	('thromboembolic events', 'Phenotype', 'HP:0001907', (59, 80))	('thromboembolic', 'Disease', 'MESH:D013923', (59, 73))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('bone fractures', 'Phenotype', 'HP:0020110', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('bone fractures', 'Disease', (129, 143))	('thromboembolic', 'Disease', (59, 73))	('uterine cancers', 'Phenotype', 'HP:0010784', (85, 100))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
166300	24069582	Responses to these HER2 peptide vaccines are restricted to specific major histocompatibility complex (MHC) classes: Class I (E75, GP2) and II (AE37) peptides simulate CD8- and CD4-positive T cells, respectively, and have been shown to induce an antitumor response.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('CD8', 'Gene', (167, 170))	('CD8', 'Gene', '925', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('CD4', 'Gene', (176, 179))	('GP2', 'Gene', '2813', (130, 133))	('tumor', 'Disease', (249, 254))	('GP2', 'Gene', (130, 133))	('E75', 'Var', (125, 128))	('CD4', 'Gene', '920', (176, 179))	('induce', 'Reg', (235, 241))
166301	24069582	Results from Phase I and II clinical trials using these HER2 peptide vaccines have demonstrated significant immunologic ex vivo and in vivo responses, and improved disease-free survival (particularly in patients with low-HER2 expression) persisting over time.	('disease-free survival', 'CPA', (164, 185))	('expression', 'MPA', (226, 236))	('improved', 'PosReg', (155, 163))	('patients', 'Species', '9606', (203, 211))	('low-HER2', 'Var', (217, 225))
166329	24069582	The rexinoid LG100268 is even more effective in the prevention of mammary tumors than bexarotene and has significantly less toxicity, thus LG100268 is a promising candidate for ER-negative breast cancer prevention in the future (see Table 3).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('rexinoid', 'Chemical', '-', (4, 12))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast cancer', 'Disease', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('LG100268', 'Chemical', 'MESH:C095104', (139, 147))	('toxicity', 'Disease', (124, 132))	('LG100268', 'Chemical', 'MESH:C095104', (13, 21))	('LG100268', 'Var', (139, 147))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('bexarotene', 'Chemical', 'MESH:D000077610', (86, 96))	('tumors', 'Disease', (74, 80))
166357	24069582	Poly(ADP-ribose) polymerase is a BRCA1/2 mutation-dependent DNA repair enzyme, and cells with loss of function BRCA1/2 mutations become selectively sensitive to the inhibition of PARP, which impairs homologous recombination and results in the induction of apoptosis.	('homologous', 'MPA', (199, 209))	('Poly(ADP-ribose) polymerase', 'Gene', (0, 27))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (0, 27))	('BRCA1/2', 'Gene', (111, 118))	('results in', 'Reg', (228, 238))	('apoptosis', 'CPA', (256, 265))	('BRCA1/2', 'Gene', (33, 40))	('BRCA1/2', 'Gene', '672;675', (111, 118))	('BRCA1/2', 'Gene', '672;675', (33, 40))	('loss of function', 'NegReg', (94, 110))	('mutations', 'Var', (119, 128))	('inhibition', 'NegReg', (165, 175))	('impairs', 'NegReg', (191, 198))
166360	24069582	have shown that a BRCA1-like array pattern and methylation of the BRCA1 promoter are apparent in 66-69 and 27-37% of TNBC tumors, respectively.	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', '672', (66, 71))	('methylation', 'Var', (47, 58))	('BRCA1', 'Gene', (18, 23))	('BRCA1', 'Gene', (66, 71))	('TNBC tumors', 'Disease', 'MESH:D009369', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('apparent', 'Reg', (85, 93))	('TNBC tumors', 'Disease', (117, 128))
166364	24069582	Recent data from preclinical animal studies has now shown that BRCA1 deficient mice treated with oral PARP inhibitors exhibit significant delays in tumor development (Sporn and Liby, unpublished results presented at the AACR Frontiers in Cancer Prevention Research Meeting, 2010).	('BRCA1 deficient', 'Disease', 'OMIM:604370', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('PARP', 'Gene', (102, 106))	('BRCA1 deficient', 'Disease', (63, 78))	('tumor', 'Disease', (148, 153))	('mice', 'Species', '10090', (79, 83))	('delays', 'NegReg', (138, 144))	('inhibitors', 'Var', (107, 117))	('Cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Cancer', 'Disease', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('Cancer', 'Disease', 'MESH:D009369', (238, 244))
166368	24069582	The IGF1 pathway has been shown to be critical for mammary gland development, and IGF1 inhibitors could prove useful for prevention of both ER-positive and ER-negative breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (168, 182))	('IGF1', 'Gene', '3479', (4, 8))	('IGF1', 'Gene', (82, 86))	('breast cancers', 'Disease', 'MESH:D001943', (168, 182))	('IGF1', 'Gene', (4, 8))	('breast cancers', 'Disease', (168, 182))	('ER-positive', 'Disease', (140, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('IGF1', 'Gene', '3479', (82, 86))	('inhibitors', 'Var', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
166385	24069582	siRNA or chemical inhibition (with PF4708671) of S6K1 enhances cell death in glucose deprivation conditions.	('PF4708671', 'Var', (35, 44))	('enhances', 'PosReg', (54, 62))	('S6K1', 'Gene', (49, 53))	('S6K1', 'Gene', '6198', (49, 53))	('glucose deprivation conditions', 'Disease', 'MESH:D012892', (77, 107))	('cell death', 'CPA', (63, 73))	('glucose deprivation conditions', 'Disease', (77, 107))
166386	24069582	recently reported that inhibition of p70S6K inhibits IGF-induced ER activation, p70S6K binding, and ER target gene activation.	('activation', 'PosReg', (115, 125))	('p70S6K', 'Gene', '6198', (37, 43))	('inhibition', 'Var', (23, 33))	('binding', 'Interaction', (87, 94))	('ER activation', 'MPA', (65, 78))	('p70S6K', 'Gene', (80, 86))	('inhibits', 'NegReg', (44, 52))	('p70S6K', 'Gene', '6198', (80, 86))	('p70S6K', 'Gene', (37, 43))
166393	24069582	Overall, the agent was well-tolerated, with toxicity data establishing a 600-mg twice daily MTD for Poly E (EGCG).	('Poly', 'Var', (100, 104))	('Poly E', 'Chemical', '-', (100, 106))	('EGCG', 'Chemical', 'MESH:C045651', (108, 112))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
166437	23346169	Univariate analysis showed that palpability, microcalcification, and the sonographic size of the lesion were all associated with underestimation (p<0.001, p=0.013, and p=0.020, respectively) (Table 2).	('calcification', 'Disease', 'MESH:D002114', (50, 63))	('calcification', 'Disease', (50, 63))	('palpability', 'Var', (32, 43))
166438	23346169	Multivariate analysis showed that palpability, microcalcification, a sonographic size >15 mm and an age >50 years were independent factors associated with underestimation (p=0.001, p=0.007, p=0.022, and p=0.017, respectively) (Table 3).	('calcification', 'Disease', 'MESH:D002114', (52, 65))	('calcification', 'Disease', (52, 65))	('>15', 'Var', (86, 89))
166453	23346169	They also demonstrated that lesions with micro-papillary feature had a higher number of ADH foci compared to the cribriform type, resulting in a significantly higher rate of underestimation.	('ADH foci', 'Disease', (88, 96))	('ADH foci', 'Disease', 'MESH:D007177', (88, 96))	('underestimation', 'MPA', (174, 189))	('micro-papillary feature', 'Var', (41, 64))	('-papillary feature', 'Phenotype', 'HP:0007482', (46, 64))
166462	20565829	Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort Although pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear.	('breast cancer', 'Disease', (373, 386))	('breast cancer', 'Disease', 'MESH:D001943', (373, 386))	('invasive breast cancer', 'Disease', 'MESH:D001943', (71, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('nulliparity', 'Var', (204, 215))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('breast carcinoma in situ', 'Disease', (42, 66))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (49, 66))	('breast carcinoma', 'Phenotype', 'HP:0003002', (42, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (305, 318))	('invasive breast cancer', 'Disease', (296, 318))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('invasive breast cancer', 'Disease', 'MESH:D001943', (296, 318))	('women', 'Species', '9606', (115, 120))	('breast cancer', 'Disease', 'MESH:D001943', (305, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (373, 386))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('breast carcinoma in situ', 'Disease', 'MESH:D000071960', (42, 66))	('invasive breast cancer', 'Disease', (71, 93))
166482	20565829	In studies that provided results for postmenopausal women, parity was associated with a decreased risk for both postmenopausal breast CIS and postmenopausal invasive breast cancer; results for age at first full-term pregnancy were inconsistent.	('parity', 'Var', (59, 65))	('invasive breast cancer', 'Disease', 'MESH:D001943', (157, 179))	('postmenopausal', 'Disease', (142, 156))	('CIS', 'Phenotype', 'HP:0030075', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('women', 'Species', '9606', (52, 57))	('decreased', 'NegReg', (88, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('invasive breast cancer', 'Disease', (157, 179))	('postmenopausal breast CIS', 'Disease', (112, 137))
166488	20565829	Both a systematic review and a meta-analysis show that nulliparity and late age at first full-term pregnancy are associated with increased risk of ER-positive (ER+) or ER+/PR+, but not with ER-negative (ER-) or ER-/PR- invasive breast cancer.	('PR', 'Gene', '5241', (172, 174))	('ER', 'Gene', '2099', (203, 205))	('invasive breast cancer', 'Disease', (219, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('ER', 'Gene', '2099', (168, 170))	('ER', 'Gene', '2099', (147, 149))	('ER', 'Gene', '2099', (190, 192))	('PR', 'Gene', '5241', (215, 217))	('nulliparity', 'Var', (55, 66))	('ER', 'Gene', '2099', (160, 162))	('invasive breast cancer', 'Disease', 'MESH:D001943', (219, 241))	('ER', 'Gene', '2099', (211, 213))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
166528	20565829	All multivariable models were adjusted for the following factors, selected a priori, as potential confounders: race (white, African-American, others), family history of breast cancer in a first degree relative, that is, mother, father, sister or brother (yes, no, unknown/adopted), age at menarche (< 13, >= 13 years), menopausal hormone therapy (HT) use (never use, ever use: only estrogen therapy (ET), only estrogen in combination with progesterone therapy (E+P), both types of HT, unknown type of HT) and body mass index (< 25, 25 to 29.9, >= 30 kg/m2, unknown).	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('progesterone', 'Chemical', 'MESH:D011374', (439, 451))	('< 25', 'Var', (526, 530))	('breast cancer', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
166555	20565829	In the CTS, nulliparity and late age at first full-term pregnancy were associated with higher risk for both breast CIS and invasive breast cancer, although not all of the associations with breast CIS reached statistical significance, in part due to the lower incidence of breast CIS in the cohort.	('breast CIS', 'Disease', (272, 282))	('CIS', 'Phenotype', 'HP:0030075', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('CIS', 'Phenotype', 'HP:0030075', (196, 199))	('CIS', 'Phenotype', 'HP:0030075', (279, 282))	('nulliparity', 'Var', (12, 23))	('breast CIS and invasive breast cancer', 'Disease', 'MESH:D001943', (108, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
166566	20565829	In the CTS analyses for invasive breast cancer by hormone receptor subtype, nulliparity and late age at first full-term pregnancy were associated with an increased risk of ER + or ER +/PR + invasive breast cancer but not with ER - or ER -/PR - invasive cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (190, 212))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('PR', 'Gene', '5241', (239, 241))	('ER', 'Gene', '2099', (180, 182))	('cancer', 'Disease', (40, 46))	('nulliparity', 'Var', (76, 87))	('hormone receptor', 'Gene', '3164', (50, 66))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ER', 'Gene', '2099', (172, 174))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('invasive breast cancer', 'Disease', (24, 46))	('ER', 'Gene', '2099', (226, 228))	('ER', 'Gene', '2099', (234, 236))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('invasive breast cancer', 'Disease', 'MESH:D001943', (24, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('invasive breast cancer', 'Disease', (190, 212))	('hormone receptor', 'Gene', (50, 66))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('PR', 'Gene', '5241', (185, 187))
166616	33926515	Studying the chromatin landscape surrounding CpGs associated with the estrogen signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2, and ER-alpha.	('methylation', 'Var', (176, 187))	('GATA2', 'Gene', (217, 222))	('ER-alpha', 'Gene', (228, 236))	('FOXA1', 'Gene', (210, 215))	('GATA2', 'Gene', '2624', (217, 222))	('ER-alpha', 'Gene', '2099', (228, 236))	('bound', 'Interaction', (201, 206))	('enhancers', 'PosReg', (191, 200))	('FOXA1', 'Gene', '3169', (210, 215))
166621	33926515	Alterations of methylation at CpGs are found already in breast pre-invasive lesions and are thought to shape the methylation patterns found in the different clinical and molecular breast cancer subtypes.	('Alterations', 'Var', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('invasive lesions', 'Disease', 'MESH:D009361', (67, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('methylation', 'MPA', (113, 124))	('invasive lesions', 'Disease', (67, 83))
166623	33926515	Previous studies have identified aberrant DNA methylation at gene promoters in breast cancer associated with clinically relevant subgroups.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('associated', 'Reg', (93, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('DNA', 'MPA', (42, 45))	('aberrant', 'Var', (33, 41))
166624	33926515	We recently showed that DNA methylation at enhancers identifies distinct breast cancer lineages.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('DNA', 'Var', (24, 27))
166627	33926515	Key enzymes, such as DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs), regulate the DNA methylation machinery, and alterations of their expressions have been described in cancers with serious consequences in terms of cancer cell phenotype.	('TETs', 'Chemical', '-', (90, 94))	('alterations', 'Var', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('described', 'Reg', (184, 193))	('cancers', 'Disease', (197, 204))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expressions', 'MPA', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
166632	33926515	Conversely, miRNA expression is regulated by DNA methylation of their respective promoters and aberrant methylation patterns of miRNA promoters has been associated with cancer.	('aberrant methylation patterns', 'Var', (95, 124))	('cancer', 'Disease', (169, 175))	('miRNA expression', 'MPA', (12, 28))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated', 'Reg', (153, 163))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
166633	33926515	We have previously shown how concerted alterations in copy number or promoter methylation affect miRNA expression in cis, resulting in upregulation of oncogenic miRNAs and downregulation of tumor-suppressor miRNAs.	('affect', 'Reg', (90, 96))	('promoter methylation', 'Var', (69, 89))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('oncogenic miRNAs', 'MPA', (151, 167))	('upregulation', 'PosReg', (135, 147))	('copy number', 'Var', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('miRNA', 'Gene', (97, 102))	('downregulation', 'NegReg', (172, 186))	('tumor', 'Disease', (190, 195))	('alterations', 'Var', (39, 50))
166655	33926515	obtained from cell lines representing different breast cancer molecular subtypes: MCF7 and ZR751 (luminal A), MB361 and UACC812 (luminal B), AU565 and HCC1954 (HER2) and MB469 and HCC1937 (basal).	('HER2', 'Gene', '2064', (160, 164))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('HCC1937', 'Var', (180, 187))	('breast cancer', 'Disease', (48, 61))	('MB469', 'CellLine', 'CVCL:M392', (170, 175))	('MB361', 'Gene', (110, 115))	('MCF7', 'CellLine', 'CVCL:0031', (82, 86))	('luminal', 'Chemical', 'MESH:D010634', (98, 105))	('luminal', 'Chemical', 'MESH:D010634', (129, 136))	('HCC1954', 'CellLine', 'CVCL:1259', (151, 158))	('HER2', 'Gene', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('MB361', 'CellLine', 'CVCL:0620', (110, 115))	('MB469', 'Var', (170, 175))	('HCC1937', 'CellLine', 'CVCL:0290', (180, 187))	('MCF7', 'Gene', (82, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('HCC1954', 'Var', (151, 158))	('ZR751', 'CellLine', 'CVCL:0588', (91, 96))	('AU565', 'Var', (141, 146))
166667	33926515	The HiChIP-H3K27ac-DNA data for the ER-negative MDAMB231 cell line was obtained from GEO, accession number GSE97585 (samples GSM2572593 and GSM2572594).	('MDAMB231', 'CellLine', 'CVCL:0062', (48, 56))	('SE', 'Gene', '6713', (108, 110))	('GSM2572594', 'Var', (140, 150))	('ER', 'Gene', '2099', (36, 38))	('GSM2572593', 'Var', (125, 135))
166669	33926515	We investigated overlaps between long-range interaction loops and in cis (on the same chromosome) mimQTLs in R. A mimQTL (CpG-miRNA pair) were considered to be in a ChIA-PET loop if the CpG and the miRNA precursor were found in two different feet of the same loop.	('mimQTL', 'Var', (114, 120))	('ChIA', 'Gene', '27159', (165, 169))	('ChIA', 'Gene', (165, 169))
166674	33926515	The GMA score of a tumor i was then computed as:  with CpGj,i corresponding to the beta value of CpG j in tumor i and CpGj,normals corresponding to the median of the beta values for CpG j in the normal breast tissue samples.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CpG j', 'Var', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CpGj', 'Var', (118, 122))	('tumor', 'Disease', (106, 111))
166685	33926515	Altogether, these results suggest that miRNAs in cluster A are either expressed by tumor infiltrating immune cells or shape the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('miRNAs', 'Var', (39, 45))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
166695	33926515	Thus, while miRNAs in cluster A and B reflect heterogeneity within the tumor microenvironment, miRNAs in cluster C are associated with estrogen signaling and ER-positive versus ER-negative breast cancer disease.	('ER', 'Gene', '2099', (158, 160))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('estrogen signaling', 'MPA', (135, 153))	('breast cancer disease', 'Disease', (189, 210))	('miRNAs', 'Var', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer disease', 'Disease', 'MESH:D001943', (189, 210))	('ER', 'Gene', '2099', (177, 179))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('associated', 'Reg', (119, 129))
166729	33926515	In cis mimQTLs (i.e., CpG and miRNA on the same chromosome) were enriched at long-range chromatin interactions with Pol2 as defined by ChIA-PET in the luminal MCF7 cell line (hypergeometric test p value = 4.51 x 10- 4).	('ChIA', 'Gene', '27159', (135, 139))	('ChIA', 'Gene', (135, 139))	('luminal', 'Chemical', 'MESH:D010634', (151, 158))	('MCF7', 'CellLine', 'CVCL:0031', (159, 163))	('mimQTLs', 'Var', (7, 14))	('Pol2', 'Gene', (116, 120))
166730	33926515	Two examples of overlap between ChiA-PET Pol2 loops, miRNA SE, and mimQTLs are shown for hsa-miR-342-3p/5p (Fig.	('ChiA', 'Gene', (32, 36))	('SE', 'Gene', '6713', (59, 61))	('hsa-miR-342-3p/5p', 'Var', (89, 106))	('ChiA', 'Gene', '27159', (32, 36))
166746	33926515	Accordingly, while in cis long-range interactions were found present in both ER-positive and ER-negative cell lines, we hypothesize that the difference in transcription factor abundance and CpG methylation at the distal enhancer may be involved in tuning miRNA expression in tumors.	('involved', 'Reg', (236, 244))	('transcription factor', 'Gene', '2152', (155, 175))	('methylation', 'Var', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('ER', 'Gene', '2099', (93, 95))	('ER', 'Gene', '2099', (77, 79))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('transcription factor', 'Gene', (155, 175))
166764	33926515	Using two large and independent breast cancer cohorts, we have identified robust associations that point to how miRNA expression may be regulated through methylation at distal regulatory regions and how miRNAs may contribute to shape the epigenetic landscape of breast cancer.	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('contribute', 'Reg', (214, 224))	('methylation', 'Var', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('shape', 'Reg', (228, 233))	('miRNA expression', 'MPA', (112, 128))	('breast cancer', 'Disease', (262, 275))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
166767	33926515	Coupling annotation from their study with the in cis mimQTLs (see Additional file 2), we observed for hsa-miR-338-3p and hsa-miR-452-5p positive correlation to CpGs flanking the miRNA genes, thus potentially identifying some examples of this phenomenon.	('miRNA', 'Gene', (178, 183))	('hsa-miR-452', 'Gene', (121, 132))	('hsa-miR-452', 'Gene', '574412', (121, 132))	('hsa-miR-338-3p', 'Var', (102, 116))
166769	33926515	Indeed, the miRNAs in this cluster with most CpG associations, hsa-miR-155-5p, hsa-miR-146a-5p, hsa-miR-150-5p, and hsa-miR-142-5p, have previously been associated with immune-related pathways and lymphocytic infiltration in breast cancer.	('hsa-miR-155', 'Gene', (63, 74))	('hsa-miR-150-5p', 'Var', (96, 110))	('immune-related pathways', 'Pathway', (169, 192))	('hsa-miR-146a', 'Gene', '406938', (79, 91))	('associated', 'Reg', (153, 163))	('lymphocytic infiltration', 'CPA', (197, 221))	('hsa-miR-155', 'Gene', '406947', (63, 74))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('hsa-miR-146a', 'Gene', (79, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', (225, 238))
166771	33926515	Assessing the catalog of cell- and tissue type-specific expression of miRNAs supported this finding with the top miRNAs of this cluster, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-379-5p, hsa-miR-381, and hsa-miR-100-5p, being highly expressed in tissue from skin where fibroblasts are a major component.	('hsa-miR-125b-5p', 'Chemical', '-', (153, 168))	('hsa-miR-381', 'Gene', '494330', (186, 197))	('hsa-miR-99a-5p', 'Var', (137, 151))	('hsa-miR-379', 'Gene', '494328', (170, 181))	('hsa-miR-125b-5p', 'Var', (153, 168))	('hsa-miR-379', 'Gene', (170, 181))	('hsa-miR-381', 'Gene', (186, 197))
166772	33926515	Interestingly, hsa-miR-125b-5p was found to induce cardiac fibrosis.	('induce', 'PosReg', (44, 50))	('hsa-miR-125b-5p', 'Chemical', '-', (15, 30))	('cardiac fibrosis', 'Disease', (51, 67))	('hsa-miR-125b-5p', 'Var', (15, 30))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (51, 67))
166773	33926515	Other studies pointed to a tumor-suppressor role of these miRNAs in breast cancer, for instance hsa-miR-99a-5p reduces breast cancer cell viability by targeting mTOR, hsa-miR-125b-5p was shown to induce cell cycle arrest and reduce cell growth in breast cancer cells, and hsa-miR-379-5p was shown to regulate Cyclin B1 expression.	('hsa-miR-379', 'Gene', '494328', (272, 283))	('cell growth', 'CPA', (232, 243))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('breast cancer', 'Disease', (247, 260))	('regulate', 'Reg', (300, 308))	('mTOR', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('expression', 'MPA', (319, 329))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('tumor', 'Disease', (27, 32))	('Cyclin B1', 'Gene', (309, 318))	('breast cancer', 'Disease', (119, 132))	('arrest', 'Disease', 'MESH:D006323', (214, 220))	('mTOR', 'Gene', '2475', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Cyclin B1', 'Gene', '891', (309, 318))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hsa-miR-125b-5p', 'Var', (167, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('reduces', 'NegReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('reduce', 'NegReg', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('induce', 'PosReg', (196, 202))	('hsa-miR-379', 'Gene', (272, 283))	('breast cancer', 'Disease', (68, 81))	('arrest', 'Disease', (214, 220))	('targeting', 'Reg', (151, 160))	('hsa-miR-125b-5p', 'Chemical', '-', (167, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (203, 220))
166775	33926515	The miRNAs with most CpG associations in cluster C were markers of the ER-positive, luminal phenotype of breast cancer.	('CpG associations', 'Var', (21, 37))	('ER', 'Gene', '2099', (71, 73))	('luminal', 'Chemical', 'MESH:D010634', (84, 91))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
166782	33926515	The looping of the miRNA SE to the miRNA TSS or mature sequence boost the transcription and the processing of the miRNA, which was in our study further supported by the negative mimQTL correlation, i.e., low SE CpG methylation associated with high miRNA expression in ER-positive tumors.	('methylation', 'Var', (215, 226))	('SE', 'Gene', '6713', (25, 27))	('high miRNA expression', 'MPA', (243, 264))	('SE', 'Gene', '6713', (208, 210))	('low SE CpG', 'Disease', (204, 214))	('ER', 'Gene', '2099', (268, 270))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumors', 'Disease', (280, 286))	('boost', 'PosReg', (64, 69))	('transcription', 'MPA', (74, 87))	('low SE CpG', 'Disease', 'MESH:D009800', (204, 214))	('tumors', 'Disease', 'MESH:D009369', (280, 286))
166784	33926515	Indeed, miRNA expression deregulation in breast cancer through methylation alterations was previously described, but the focus has mainly been on CpGs in proximal promoter regions.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('miRNA', 'Protein', (8, 13))	('deregulation', 'Reg', (25, 37))	('methylation', 'Var', (63, 74))
166801	33926515	Furthermore, our study highlights that deregulation of hsa-miR-29c-5p expression is an early event that may result in downregulation of DNMT3A, which could further lead to hypomethylation of CpG sites important for ER-positive breast cancer cell identity.	('downregulation', 'NegReg', (118, 132))	('hsa-miR-29c', 'Gene', (55, 66))	('hsa-miR-29c', 'Gene', '407026', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('DNMT3A', 'Gene', '1788', (136, 142))	('lead to', 'Reg', (164, 171))	('DNMT3A', 'Gene', (136, 142))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('hypomethylation', 'MPA', (172, 187))	('breast cancer', 'Disease', (227, 240))	('ER', 'Gene', '2099', (215, 217))	('deregulation', 'Var', (39, 51))
166802	33926515	The CpG sites affected are at enhancer regions with TFBS for ER-alpha, FOXA1, and GATA3, all known to be important for the luminal breast cancer phenotype.	('luminal breast cancer', 'Disease', (123, 144))	('TFBS', 'Var', (52, 56))	('ER-alpha', 'Gene', (61, 69))	('FOXA1', 'Gene', '3169', (71, 76))	('GATA3', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('luminal breast cancer', 'Disease', 'MESH:D001943', (123, 144))	('GATA3', 'Gene', '2625', (82, 87))	('FOXA1', 'Gene', (71, 76))	('ER-alpha', 'Gene', '2099', (61, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('TFBS', 'Chemical', '-', (52, 56))
166832	29721466	It is estimated that 5% of cancers are due to inherited genetic mutation.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('inherited genetic mutation', 'Var', (46, 72))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancers', 'Disease', (27, 34))
166833	29721466	BRCA 1 and 2 mutations are the commonest, in addition to mutations in P53, PTEN, CHEK2, ATM and a host of other mutations that are unknown at present.	('CHEK2', 'Gene', (81, 86))	('ATM', 'Gene', (88, 91))	('BRCA 1 and 2', 'Gene', '672;675', (0, 12))	('mutations', 'Var', (57, 66))	('PTEN', 'Gene', (75, 79))	('ATM', 'Gene', '472', (88, 91))	('PTEN', 'Gene', '5728', (75, 79))	('P53', 'Gene', (70, 73))	('mutations', 'Var', (13, 22))	('CHEK2', 'Gene', '11200', (81, 86))	('P53', 'Gene', '7157', (70, 73))
166848	29721466	This review concluded that pre-operative MRI is associated with increased odds of receiving ipsilateral mastectomy and contralateral prophylactic mastectomy as surgical treatment in newly diagnosed breast cancers [Figure 1c-e].	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('MRI', 'Var', (41, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancers', 'Disease', 'MESH:D001943', (198, 212))	('breast cancers', 'Disease', (198, 212))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
166932	20524058	An assessment of four microsatellite markers in 15 specimens (representing a spectrum of papillary lesions) suggested that loss of heterozygosity (LOH) of 16q23 was specific to malignant lesions.	('papillary lesion', 'Phenotype', 'HP:0007482', (89, 105))	('16q23', 'Gene', (155, 160))	('papillary lesion', 'Disease', 'MESH:D007681', (89, 105))	('papillary lesions', 'Phenotype', 'HP:0007482', (89, 106))	('loss of heterozygosity', 'Var', (123, 145))	('men', 'Species', '9606', (9, 12))	('men', 'Species', '9606', (56, 59))	('papillary lesion', 'Disease', (89, 105))	('malignant lesions', 'Disease', (177, 194))
166934	20524058	Alterations in all four chromosomes were present in all cases of DNA-aneuploid carcinoma.	('aneuploid carcinoma', 'Disease', (69, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Alterations', 'Var', (0, 11))	('aneuploid carcinoma', 'Disease', 'MESH:D000782', (69, 88))
166935	20524058	Thus, DNA-ploidy, in association with changes at specific loci, may be informative in the diagnosis of papillary carcinoma.	('papillary carcinoma', 'Disease', 'MESH:D002291', (103, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('DNA-ploidy', 'Var', (6, 16))	('papillary carcinoma', 'Disease', (103, 122))
166957	20524058	Notably, the search term papillary carcinoma included six ICD-O codes, corresponding to papillary carcinoma NOS (8050), papillary adenocarcinoma (8260), papillary cystadenoma (8450), intraductal papilloma (8503), intracystic papillary adenoma (8504) and intraductal micropapillary carcinoma (8507).	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('intraductal papilloma', 'Disease', (183, 204))	('papillary cystadenoma', 'Disease', (153, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('intraductal micropapillary carcinoma', 'Disease', 'MESH:D002285', (254, 290))	('papillary cystadenoma', 'Disease', 'MESH:D018292', (153, 174))	('intraductal papilloma', 'Disease', 'MESH:D018300', (183, 204))	('papillary carcinoma', 'Disease', (25, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('8050', 'Var', (113, 117))	('papilloma', 'Phenotype', 'HP:0012740', (195, 204))	('8507', 'Var', (292, 296))	('papillary carcinoma NOS', 'Disease', 'MESH:D002291', (88, 111))	('intracystic papillary adenoma', 'Disease', 'MESH:D000236', (213, 242))	('8503', 'Var', (206, 210))	('papillary carcinoma', 'Disease', 'MESH:D002291', (271, 290))	('papillary carcinoma', 'Disease', 'MESH:D002291', (25, 44))	('8504', 'Var', (244, 248))	('intraductal micropapillary carcinoma', 'Disease', (254, 290))	('papillary adenocarcinoma', 'Disease', 'MESH:D000231', (120, 144))	('papillary carcinoma NOS', 'Disease', (88, 111))	('papillary carcinoma', 'Disease', 'MESH:D002291', (88, 107))	('8450', 'Var', (176, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('papillary adenocarcinoma', 'Disease', (120, 144))	('8260', 'Var', (146, 150))	('papillary adenocarcinoma', 'Phenotype', 'HP:0006774', (120, 144))	('intracystic papillary adenoma', 'Disease', (213, 242))
167084	20309431	The presence of the anaplastic lymphoma kinase (ALK) gene translocation and expression of ALK protein defines ALK-positive ALCL, which occurs in children and young adults and has a relatively favorable prognosis, while ALK-negative ALCL occurs in older individuals who often present with advanced disease and has a worse outcome, although better than that for peripheral T-cell lymphoma, not otherwise specified.	('advanced disease', 'Disease', (288, 304))	('peripheral T-cell lymphoma', 'Disease', 'MESH:D016411', (360, 386))	('ALCL', 'Phenotype', 'HP:0012193', (232, 236))	('anaplastic lymphoma kinase', 'Gene', '238', (20, 46))	('anaplastic lymphoma kinase', 'Gene', (20, 46))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (20, 39))	('ALK', 'Gene', '238', (219, 222))	('peripheral T-cell lymphoma', 'Disease', (360, 386))	('children', 'Species', '9606', (145, 153))	('ALK', 'Gene', '238', (90, 93))	('ALK', 'Gene', (219, 222))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('ALK', 'Gene', (90, 93))	('ALCL', 'Phenotype', 'HP:0012193', (123, 127))	('advanced disease', 'Disease', 'MESH:D020178', (288, 304))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (371, 386))	('presence', 'Var', (4, 12))	('cell lymphoma', 'Phenotype', 'HP:0012191', (373, 386))	('ALK', 'Gene', '238', (48, 51))	('ALK', 'Gene', '238', (110, 113))	('ALK', 'Gene', (48, 51))	('ALK', 'Gene', (110, 113))	('lymphoma', 'Phenotype', 'HP:0002665', (378, 386))
167162	27624164	Women diagnosed with DCIS between 1999 and 2004 were less likely to develop iIBC than women diagnosed between 1989 and 1998, regardless of treatment and age [hazard ratio (HR) 0.72, 95 % CI 0.59-0.87].	('Women', 'Species', '9606', (0, 5))	('iIBC', 'Chemical', '-', (76, 80))	('iIBC', 'Disease', (76, 80))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('DCIS', 'Var', (21, 25))	('less', 'NegReg', (53, 57))	('women', 'Species', '9606', (86, 91))	('develop', 'PosReg', (68, 75))
167179	27624164	The absolute risk of developing cIBC in women treated for DCIS was slightly higher than the risk of IBC in the general population (3.4 % at 15 years).	('cIBC', 'Chemical', '-', (32, 36))	('IBC', 'Chemical', '-', (33, 36))	('cIBC', 'Disease', (32, 36))	('women', 'Species', '9606', (40, 45))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('IBC', 'Chemical', '-', (100, 103))	('DCIS', 'Var', (58, 62))
167184	27624164	In women >=50 years, iIBC risk remained increased during subsequent follow-up after BCS alone, compared to BCS+RT, but the difference became less pronounced with longer follow-up.	('iIBC', 'Disease', (21, 25))	('BCS', 'Var', (84, 87))	('increased', 'PosReg', (40, 49))	('women', 'Species', '9606', (3, 8))	('iIBC', 'Chemical', '-', (21, 25))
167190	27624164	Moreover, these young women treated with mastectomy had a higher cumulative iIBC incidence than older women who received this treatment.	('iIBC', 'Chemical', '-', (76, 80))	('iIBC', 'Disease', (76, 80))	('women', 'Species', '9606', (22, 27))	('women', 'Species', '9606', (102, 107))	('mastectomy', 'Var', (41, 51))	('higher', 'PosReg', (58, 64))
167212	27624164	In summary, our finding that the reduction in iIBC risk among women treated with BCS + RT, compared to BCS alone, diminishes with longer follow-up, emphasizes the importance of clinical studies with long-term follow-up.	('iIBC', 'Disease', (46, 50))	('BCS + RT', 'Var', (81, 89))	('reduction', 'NegReg', (33, 42))	('iIBC', 'Chemical', '-', (46, 50))	('diminishes', 'NegReg', (114, 124))	('women', 'Species', '9606', (62, 67))
167221	19383825	Most cases showed similar levels of acetylation in DCIS and IDC, although some showed further reduction of ac-H4 and ac-H4K12 from DCIS to IDC.	('reduction', 'NegReg', (94, 103))	('acetylation', 'MPA', (36, 47))	('ac-H4', 'Chemical', '-', (117, 122))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('ac-H4', 'Chemical', '-', (107, 112))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('ac-H4', 'Protein', (107, 112))	('ac-H4K12', 'Var', (117, 125))
167226	19383825	It is commonly thought, but not yet clinically proven, that epigenetic silencing of tumor suppressor genes through the mechanism of histone deacetylation and DNA methylation is an early hallmark of malignancy.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('DNA', 'MPA', (158, 161))	('hallmark of malignancy', 'Disease', 'MESH:D009369', (186, 208))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('epigenetic', 'Var', (60, 70))	('tumor', 'Disease', (84, 89))	('histone deacetylation', 'MPA', (132, 153))	('hallmark of malignancy', 'Disease', (186, 208))	('N', 'Chemical', 'MESH:D009584', (159, 160))
167229	19383825	alpha-tubulin, p53, MyoD, E2F, ataxia-telangiectasia mutant, and heat shock protein 90), altering gene expression and cell phenotype.	('alpha-tubulin', 'Gene', (0, 13))	('heat shock', 'Disease', (65, 75))	('ataxia-telangiectasia', 'Disease', (31, 52))	('alpha-tubulin', 'Gene', '10376', (0, 13))	('altering', 'Reg', (89, 97))	('gene expression', 'MPA', (98, 113))	('ataxia', 'Phenotype', 'HP:0001251', (31, 37))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('MyoD', 'Gene', (20, 24))	('MyoD', 'Gene', '4654', (20, 24))	('heat shock', 'Disease', 'MESH:D012769', (65, 75))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (31, 52))	('telangiectasia', 'Phenotype', 'HP:0001009', (38, 52))	('E2F', 'Var', (26, 29))	('shock', 'Phenotype', 'HP:0031273', (70, 75))
167269	19383825	As expected, staining patterns for ac-H4 and ac-H4K12 were nuclear, while ac-tubulin was cytoplasmic.	('ac-H4', 'Var', (35, 40))	('ac-H4K12', 'Var', (45, 53))	('ac-H4', 'Chemical', '-', (45, 50))	('ac-H4', 'Chemical', '-', (35, 40))
167271	19383825	For ac-H4 the median H-score was reduced from 280 to 180 (36% reduction from normal to DCIS), and further reduced to 150 in IDC (46% reduction from normal to IDC).	('ac-H4', 'Chemical', '-', (4, 9))	('IDC', 'Disease', (124, 127))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('reduced', 'NegReg', (33, 40))	('ac-H4', 'Var', (4, 9))	('H-score', 'MPA', (21, 28))	('reduction', 'NegReg', (62, 71))	('reduced', 'NegReg', (106, 113))
167274	19383825	Within individual cases, H-scores for ac-H4 and ac-H4K12 were correlated in normal epithelium, DCIS, and IDC (R2 = 0.129, 0.199, and 0.359, respectively; all p < 0.01 by Spearman rank correlation; see also Supplemental Table 2).	('ac-H4K12', 'Var', (48, 56))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('ac-H4', 'Chemical', '-', (48, 53))	('ac-H4', 'Chemical', '-', (38, 43))	('ac-H4', 'Gene', (38, 43))
167303	19383825	Hypoacetylation of both H4 and H4K12 were highly correlated, confirming that nonspecific hypoacetylation was conferred, given that the anti-ac-H4 antibody detects acetylation at any of four lysines (K5, K8, K12, and K16) in the N-terminus of histone H4, whereas anti-ac-H4K12 antibodies specifically detect acetylation of the lysine 12 residue of H4.	('N', 'Chemical', 'MESH:D009584', (228, 229))	('lysines', 'Chemical', 'MESH:D008239', (190, 197))	('K12', 'Gene', '3859', (272, 275))	('ac-H4', 'Chemical', '-', (267, 272))	('K12', 'Gene', '3859', (207, 210))	('K12', 'Gene', '3859', (33, 36))	('histone H4', 'Gene', '8294', (242, 252))	('K16', 'Gene', (216, 219))	('ac-H4', 'Chemical', '-', (140, 145))	('acetylation', 'MPA', (307, 318))	('acetylation', 'MPA', (163, 174))	('K12', 'Gene', (272, 275))	('K12', 'Gene', (207, 210))	('K12', 'Gene', (33, 36))	('K16', 'Gene', '3868', (216, 219))	('K5', 'Var', (199, 201))	('lysine', 'Chemical', 'MESH:D008239', (190, 196))	('histone H4', 'Gene', (242, 252))	('lysine', 'Chemical', 'MESH:D008239', (326, 332))
167328	19383825	However, in breast cancer, also it has been shown that HDAC6 expression is more prevalent in less advanced, less aggressive tumors (small, ER-positive, low tumor grade) and associated with better survival, in concordance with the findings in our study.	('breast cancer', 'Disease', (12, 25))	('low tumor', 'Disease', 'MESH:D009800', (152, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('prevalent', 'Reg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aggressive tumors', 'Disease', 'MESH:D001523', (113, 130))	('low tumor', 'Disease', (152, 161))	('expression', 'Var', (61, 71))	('HDAC6', 'Gene', '10013', (55, 60))	('better', 'PosReg', (189, 195))	('ER', 'Gene', '2099', (139, 141))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('aggressive tumors', 'Disease', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('HDAC6', 'Gene', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
167334	19383825	The primary outcome of interest will be to determine if a short course of HDAC inhibitors can reduce proliferation (Ki67) in DCIS, and whether degree of hypoacetylation is associated with magnitude of change in Ki67.	('HDAC', 'Gene', '3065', (74, 78))	('inhibitors', 'Var', (79, 89))	('HDAC', 'Gene', (74, 78))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('reduce', 'NegReg', (94, 100))
167344	18479514	We studied associations of lectin reactivity with established prognostic factors, such as tumor size, tumor nuclear grade, and expression of Her-2/neu, p53 mutant and estrogen and progesterone receptors.	('Her-2/neu', 'Gene', (141, 150))	('progesterone receptor', 'Gene', (180, 201))	('p53', 'Gene', (152, 155))	('progesterone receptor', 'Gene', '5241', (180, 201))	('tumor', 'Disease', (90, 95))	('p53', 'Gene', '7157', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('estrogen', 'Protein', (167, 175))	('mutant', 'Var', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Her-2/neu', 'Gene', '2064', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
167351	18479514	High nuclear grade of initial lesions and cancer recurrence were significantly associated with increased rates of metastasis and breast cancer death.	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('metastasis', 'CPA', (114, 124))	('breast cancer death', 'Disease', (129, 148))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('breast cancer death', 'Disease', 'MESH:D001943', (129, 148))	('High nuclear', 'Var', (0, 12))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
167354	18479514	Aberrant glycosylation, arising from dysfunction of glycosyltransferases and/or glycosidases, most often results in a shortening of the glycan chains or an over-expression of structures on cells that are normally absent or scarce.	('shortening', 'MPA', (118, 128))	('glycan', 'Chemical', 'MESH:D011134', (136, 142))	('glycan', 'Protein', (136, 142))	('structures', 'MPA', (175, 185))	('glycosyltransferases', 'Enzyme', (52, 72))	('Aberrant', 'Var', (0, 8))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('results in', 'Reg', (105, 115))	('over-expression', 'PosReg', (156, 171))	('glycosylation', 'MPA', (9, 22))	('dysfunction', 'Var', (37, 48))
167355	18479514	It is well-recognized that aberrant carbohydrate expression is relevant to tumor metastasis and poor prognosis for cancer patients.	('cancer', 'Disease', (115, 121))	('aberrant', 'Var', (27, 35))	('tumor metastasis', 'Disease', (75, 91))	('tumor metastasis', 'Disease', 'MESH:D009362', (75, 91))	('aberrant carbohydrate expression', 'Phenotype', 'HP:0011013', (27, 59))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carbohydrate', 'Protein', (36, 48))	('patients', 'Species', '9606', (122, 130))	('carbohydrate', 'Chemical', 'MESH:D002241', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
167403	18479514	We characterized the associations of GS-I and VVA reactivity with expression levels of ER, PR, p53 mutant, Her-2/neu, and with age, race, tumor size and nuclear grade (Table 2).	('Her-2/neu', 'Gene', '2064', (107, 116))	('associations', 'Interaction', (21, 33))	('tumor', 'Disease', (138, 143))	('expression levels', 'MPA', (66, 83))	('ER', 'Gene', '2099', (87, 89))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('GS-I', 'Disease', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PR', 'Gene', '5241', (91, 93))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('mutant', 'Var', (99, 105))	('GS-I', 'Disease', 'MESH:D011125', (37, 41))	('Her-2/neu', 'Gene', (107, 116))
167437	18479514	However, the fact that, at 0.5% alpha, VVA showed a significant correlation with Her-2/Neu, but GS-I did not, suggests that there may be a distinct nature of reactivity for these two lectins on breast cancer specimens.	('correlation', 'Interaction', (64, 75))	('GS-I', 'Disease', 'MESH:D011125', (96, 100))	('Her-2', 'Gene', '2064', (81, 86))	('alpha', 'Var', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Her-2', 'Gene', (81, 86))	('GS-I', 'Disease', (96, 100))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('Neu', 'Gene', (87, 90))	('breast cancer', 'Disease', (194, 207))	('Neu', 'Gene', '2064', (87, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
167445	18479514	The data also support the hypothesis of using the expression of these structures as prognostic markers for early stage breast cancer that necessitate conducting further studies on much larger sample size of low-grade DCIS specimens with long follow-up time to establish whether low-grade DCIS with a specific glycomic profile can be subject to relapse more often than other tumors of the same category.	('relapse', 'CPA', (344, 351))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('tumors', 'Disease', (374, 380))	('tumors', 'Disease', 'MESH:D009369', (374, 380))	('tumors', 'Phenotype', 'HP:0002664', (374, 380))	('low-grade', 'Var', (278, 287))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))	('DCIS', 'Disease', (288, 292))	('DCIS', 'Phenotype', 'HP:0030075', (288, 292))
167512	25051376	Known serum-based tumor markers, such as CA15.3 and BR27.29, cannot be used for breast cancer detection due to low sensitivity.	('tumor', 'Disease', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('BR27.29', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
167541	25051376	Such microRNAs may include mir-16, mir-150, mir-486-5p, let-7a, mir-574-3p, mir-223, mir-197, mir-451, and mir-92a.	('mir-574-3p', 'Gene', '693159', (64, 74))	('mir-150', 'Gene', '406942', (35, 42))	('mir', 'Gene', (44, 47))	('mir', 'Gene', (27, 30))	('mir-16', 'Gene', '51573', (27, 33))	('mir', 'Gene', (35, 38))	('mir', 'Gene', (107, 110))	('mir', 'Gene', '220972', (64, 67))	('mir-451', 'Gene', '574411', (94, 101))	('mir', 'Gene', (76, 79))	('mir-574-3p', 'Gene', (64, 74))	('mir-16', 'Gene', (27, 33))	('mir-197', 'Gene', '406974', (85, 92))	('mir', 'Gene', '220972', (94, 97))	('mir-451', 'Gene', (94, 101))	('mir', 'Gene', '220972', (85, 88))	('mir-150', 'Gene', (35, 42))	('mir', 'Gene', (64, 67))	('mir-223', 'Gene', '407008', (76, 83))	('mir', 'Gene', '220972', (44, 47))	('let-7a', 'Var', (56, 62))	('mir', 'Gene', (94, 97))	('mir-223', 'Gene', (76, 83))	('mir', 'Gene', '220972', (27, 30))	('mir', 'Gene', (85, 88))	('mir', 'Gene', '220972', (35, 38))	('mir', 'Gene', '220972', (76, 79))	('mir', 'Gene', '220972', (107, 110))	('mir-197', 'Gene', (85, 92))
167600	25051376	We also excluded the list of blood cells derived microRNAs (including miR-16, miR-150, miR-486-5p, let-7a, miR-574-3p, miR-223, miR-197, miR-451, and miR-92a) from downstream analysis.	('miR-150', 'Gene', (78, 85))	('miR', 'Gene', (78, 81))	('miR-16', 'Gene', (70, 76))	('miR', 'Gene', (70, 73))	('miR', 'Gene', '220972', (107, 110))	('miR-223', 'Gene', (119, 126))	('miR', 'Gene', '220972', (137, 140))	('let-7a', 'Var', (99, 105))	('miR-16', 'Gene', '51573', (70, 76))	('miR-197', 'Gene', '406974', (128, 135))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (107, 110))	('miR', 'Gene', '220972', (150, 153))	('miR-574-3p', 'Gene', '693159', (107, 117))	('miR', 'Gene', '220972', (119, 122))	('miR-451', 'Gene', '574411', (137, 144))	('miR', 'Gene', (137, 140))	('miR-223', 'Gene', '407008', (119, 126))	('miR-150', 'Gene', '406942', (78, 85))	('miR', 'Gene', (128, 131))	('miR', 'Gene', '220972', (87, 90))	('miR-574-3p', 'Gene', (107, 117))	('miR', 'Gene', (150, 153))	('miR-197', 'Gene', (128, 135))	('miR', 'Gene', (119, 122))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (87, 90))	('miR-451', 'Gene', (137, 144))
167609	22112468	It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as "neoplastic lesions" with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia).	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (342, 362))	('neoplasia', 'Phenotype', 'HP:0002664', (353, 362))	('"neoplastic lesions', 'Disease', (129, 148))	('p53', 'Gene', (276, 279))	('mutations', 'Var', (239, 248))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (130, 147))	('men', 'Species', '9606', (99, 102))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (328, 362))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (130, 148))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (328, 362))	('cervical intraepithelial neoplasia', 'Disease', (328, 362))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (337, 362))	('"neoplastic lesions', 'Disease', 'MESH:D051437', (129, 148))
167619	22112468	While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively.	('CIN', 'Disease', (312, 315))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('polyps', 'Disease', 'MESH:D011127', (234, 240))	('removal', 'Var', (223, 230))	('cervix', 'Disease', (417, 423))	('polyps', 'Disease', (234, 240))	('men', 'Species', '9606', (12, 15))	('invasive neoplasia', 'Disease', (67, 85))	('reduction', 'NegReg', (346, 355))	('CIN', 'Disease', 'MESH:D007674', (312, 315))	('cancers', 'Phenotype', 'HP:0002664', (378, 385))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('invasive neoplasia', 'Disease', 'MESH:D009369', (67, 85))	('breast', 'Disease', (405, 411))	('cancers', 'Disease', 'MESH:D009369', (378, 385))	('men', 'Species', '9606', (370, 373))	('cancers', 'Disease', (378, 385))
167650	22112468	In fact, the first gene identified as being dysregulated in FAP was designated adenomatous polyposis coli (APC); identification of mutations in APC was followed by an understanding of how APC interacts with beta catenin and an identification of subsequent mutations or dysregulation of K-ras, DCC, SMAD4, MCC and p53.	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (79, 105))	('DCC', 'Gene', (293, 296))	('adenomatous polyposis coli', 'Disease', (79, 105))	('p53', 'Gene', (313, 316))	('mutations', 'Var', (256, 265))	('K-ras', 'Protein', (286, 291))	('MCC', 'Gene', (305, 308))	('interacts', 'Interaction', (192, 201))	('beta catenin', 'Gene', '1499', (207, 219))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (79, 100))	('beta catenin', 'Gene', (207, 219))	('FAP', 'Disease', (60, 63))	('SMAD4', 'Gene', (298, 303))	('FAP', 'Disease', 'MESH:C567782', (60, 63))	('mutations', 'Var', (131, 140))	('DCC', 'Gene', '1630', (293, 296))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (79, 96))	('dysregulation', 'Var', (269, 282))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (79, 105))
167651	22112468	Mutations in microsatellite repair genes such as MSH2 and MLH1 also have been identified as the cause of colorectal neoplasia in hereditary non-polyposis colon cancer (HNPCC).	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (129, 166))	('MSH2', 'Gene', (49, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cause', 'Reg', (96, 101))	('Mutations', 'Var', (0, 9))	('MLH1', 'Gene', '4292', (58, 62))	('colorectal neoplasia in hereditary non-polyposis colon cancer', 'Disease', 'MESH:D015179', (105, 166))	('MLH1', 'Gene', (58, 62))	('MSH2', 'Gene', '4436', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('HNPCC', 'Disease', 'None', (168, 173))	('HNPCC', 'Disease', (168, 173))
167652	22112468	Figure 1 demonstrates how hereditary tumors may develop based on inheritance of a mutation in a single gene.	('hereditary tumors', 'Disease', (26, 43))	('mutation', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('develop', 'Reg', (48, 55))	('hereditary tumors', 'Disease', 'MESH:D009386', (26, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))
167653	22112468	In general, some of the same mutations that occur in familial cancers occur in sporadic cancers, but such mutations may not occur in the same temporal order.	('familial cancers', 'Disease', 'MESH:D009369', (53, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('familial cancers', 'Disease', (53, 69))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('occur', 'Reg', (70, 75))	('sporadic cancers', 'Disease', 'MESH:D009369', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sporadic cancers', 'Disease', (79, 95))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))
167656	22112468	In mice exposed to UV-B, mutations in p53 precede discernable lesions by several months.	('mice', 'Species', '10090', (3, 7))	('mutations', 'Var', (25, 34))	('p53', 'Gene', (38, 41))
167657	22112468	Also, in humans up to 4% of sun exposed skin has been estimated to involve cells with mutations in p53.	('mutations', 'Var', (86, 95))	('humans', 'Species', '9606', (9, 15))	('p53', 'Gene', (99, 102))
167658	22112468	There are two major hypotheses of how preneoplasia develops and progresses - i.e., the stem cell hypothesis in which preneoplasia develops, only from mutations in stem cells and/or in pluripotent early progenitor cells versus the stochastic model in which preneoplasia develops from any cells in which mutations of specific genes occur.	('preneoplasia', 'Disease', (38, 50))	('neoplasia', 'Phenotype', 'HP:0002664', (41, 50))	('preneoplasia', 'Disease', (117, 129))	('preneoplasia', 'Disease', 'None', (256, 268))	('neoplasia', 'Phenotype', 'HP:0002664', (120, 129))	('neoplasia', 'Phenotype', 'HP:0002664', (259, 268))	('mutations', 'Var', (150, 159))	('preneoplasia', 'Disease', 'None', (38, 50))	('preneoplasia', 'Disease', 'None', (117, 129))	('preneoplasia', 'Disease', (256, 268))
167667	22112468	In the stochastic model, cancers can arise from any proliferative cell with specific mutations.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
167677	22112468	The more proliferative child cells are more likely to develop a new mutation, each new mutation may increase proliferation as well as the mutational rate and decrease rate of apoptosis; ultimately, a pre-invasive neoplastic lesion may develop.	('neoplastic lesion', 'Disease', (213, 230))	('mutational rate', 'MPA', (138, 153))	('mutation', 'Var', (68, 76))	('rate of', 'MPA', (167, 174))	('child', 'Species', '9606', (23, 28))	('decrease', 'NegReg', (158, 166))	('neoplastic lesion', 'Disease', 'MESH:D051437', (213, 230))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (213, 230))	('proliferation', 'CPA', (109, 122))	('increase', 'PosReg', (100, 108))
167686	22112468	Specifically, there are mutations in p53 in about 70 % of SCCs and 50% of BCCs.	('SCC', 'Gene', (58, 61))	('BCCs', 'Disease', (74, 78))	('SCC', 'Gene', '6317', (58, 61))	('p53', 'Gene', (37, 40))	('mutations', 'Var', (24, 33))
167687	22112468	Of interest, about 4% of the epidermis of normal appearing human skin from individuals with sun exposure but without cancer contains p53 mutated clones of 60 to 3000 cells in size and the risk of developing SCCs and BCCs is correlated with the extent of mutations in p53.	('human', 'Species', '9606', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BCCs', 'CPA', (216, 220))	('SCC', 'Gene', '6317', (207, 210))	('p53', 'Gene', (267, 270))	('SCC', 'Gene', (207, 210))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('p53', 'Gene', (133, 136))	('cancer', 'Disease', (117, 123))	('mutated', 'Var', (137, 144))	('mutations', 'Var', (254, 263))
167688	22112468	Other studies in mouse models have noted UV-B induced clones of p53 are noted months before the development of skin tumors.	('skin tumors', 'Phenotype', 'HP:0008069', (111, 122))	('mouse', 'Species', '10090', (17, 22))	('skin tumors', 'Disease', (111, 122))	('men', 'Species', '9606', (103, 106))	('clones', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('skin tumors', 'Disease', 'MESH:D012878', (111, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('p53', 'Gene', (64, 67))
167689	22112468	Also, based on mouse models, by using UV blockers (SPF-15 sun screens) the occur-rence of most p53 mutational clones can be prevented or reversed.	('mouse', 'Species', '10090', (15, 20))	('p53', 'Gene', (95, 98))	('mutational', 'Var', (99, 109))
167692	22112468	Clones of cells with mutated p53 are likely to be the precursors of most actinic keratoses, especially Bowenoid actinic keratosis.	('actinic keratosis', 'Phenotype', 'HP:0025127', (112, 129))	('p53', 'Gene', (29, 32))	('actinic keratoses', 'Disease', (73, 90))	('actinic keratoses', 'Phenotype', 'HP:0025127', (73, 90))	('Bowenoid actinic keratosis', 'Disease', 'MESH:D055623', (103, 129))	('mutated', 'Var', (21, 28))	('Bowenoid actinic keratosis', 'Disease', (103, 129))
167695	22112468	Organic compounds such as cyclic hydrocarbons and cyclic amines have been associated with numerous malignancies.	('cyclic hydrocarbons', 'Chemical', 'MESH:D006844', (26, 45))	('cyclic hydrocarbons', 'Var', (26, 45))	('associated', 'Reg', (74, 84))	('numerous malignancies', 'Disease', 'MESH:D009369', (90, 111))	('cyclic amines', 'Chemical', '-', (50, 63))	('cyclic amines', 'Var', (50, 63))	('numerous malignancies', 'Disease', (90, 111))
167701	22112468	Subsequently, mutations occur that lead to progression and to eventual malignancy.	('progression', 'CPA', (43, 54))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))	('lead', 'Reg', (35, 39))	('mutations', 'Var', (14, 23))	('malignancy', 'Disease', (71, 81))
167704	22112468	Polymorphisms can be identified by analysis of SNPs and may either represent positive or negative risk factors for the development of neoplastic lesions.	('men', 'Species', '9606', (126, 129))	('Polymorphisms', 'Var', (0, 13))	('neoplastic lesions', 'Disease', (134, 152))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (134, 151))	('neoplastic lesions', 'Disease', 'MESH:D051437', (134, 152))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (134, 152))
167705	22112468	For example, ethanol is associated with a greater risk of developing colorectal cancer in individuals with the E487k polymorphism of aldehyde dehydrogenase 2 (ALDH2) which results in greatly reduced enzymatic activity of ALDH2.	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('ethanol', 'Chemical', 'MESH:D000431', (13, 20))	('aldehyde dehydrogenase 2', 'Gene', '217', (133, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('E487k', 'Var', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('reduced', 'NegReg', (191, 198))	('aldehyde dehydrogenase 2', 'Gene', (133, 157))	('colorectal cancer', 'Disease', (69, 86))	('ALDH2', 'Gene', '217', (159, 164))	('ALDH2', 'Gene', '217', (221, 226))	('ALDH2', 'Gene', (159, 164))	('ALDH2', 'Gene', (221, 226))	('enzymatic activity', 'MPA', (199, 217))
167706	22112468	Similarly, polymorphisms in 5, 10- methylenetetrahydrofolate reductase plus low folate levels increase the risk of colorectal cancer associated with ethanol consumption.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('ethanol', 'Chemical', 'MESH:D000431', (149, 156))	('increase', 'PosReg', (94, 102))	('methylenetetrahydrofolate reductase', 'Gene', (35, 70))	('folate', 'Chemical', 'MESH:D005492', (80, 86))	('folate', 'Chemical', 'MESH:D005492', (54, 60))	('polymorphisms', 'Var', (11, 24))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (35, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('colorectal cancer', 'Disease', (115, 132))	('low folate', 'Phenotype', 'HP:0100507', (76, 86))	('low', 'NegReg', (76, 79))
167710	22112468	For example, copper has been reported to potentiate the progression of cancers via the involvement of copper in the development of angiogenesis and/or other features that affect the development and progression of neoplasia.	('involvement', 'Reg', (87, 98))	('neoplasia', 'Phenotype', 'HP:0002664', (213, 222))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('men', 'Species', '9606', (189, 192))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('neoplasia', 'Disease', 'MESH:D009369', (213, 222))	('cancers', 'Disease', (71, 78))	('men', 'Species', '9606', (94, 97))	('copper', 'Chemical', 'MESH:D003300', (13, 19))	('potentiate', 'PosReg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('neoplasia', 'Disease', (213, 222))	('copper', 'Var', (13, 19))	('men', 'Species', '9606', (123, 126))	('progression', 'CPA', (56, 67))	('copper', 'Chemical', 'MESH:D003300', (102, 108))
167720	22112468	Once cells are infected with HPV and the viral regulatory proteins bind to p53 and pRb, a cascade of several very characteristic changes occur in the cervical epithelium.	('pRb', 'Gene', '5925', (83, 86))	('pRb', 'Gene', (83, 86))	('p53', 'Var', (75, 78))	('bind', 'Interaction', (67, 71))
167724	22112468	CIN3 lesions are thought to be at greatest risk of progression with at least 1/3 of CIN3 lesions progressing to squamous cell carcinoma if not treated.	('lesions', 'Var', (89, 96))	('CIN', 'Disease', (0, 3))	('CIN', 'Disease', 'MESH:D007674', (84, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))	('CIN', 'Disease', (84, 87))
167726	22112468	Also, young women are now being vaccinated against specific high risk HPV serotypes including 16 and 18 as well as HPV 6 and 11 in order to reduce the risk and costs associated with HPV infections.	('women', 'Species', '9606', (12, 17))	('reduce', 'NegReg', (140, 146))	('HPV', 'Gene', (70, 73))	('HPV infections', 'Disease', 'MESH:D030361', (182, 196))	('HPV', 'Var', (115, 118))	('HPV infections', 'Disease', (182, 196))
167736	22112468	We chose 1 year because dysregulation of microsatellite (MS) repair genes have been noted in continuing ulcerative colitis after 1 year's duration while more acute forms of colitis do not have changes in microsatellites.	('ulcerative colitis', 'Disease', (104, 122))	('ulcerative colitis', 'Disease', 'MESH:D003093', (104, 122))	('dysregulation', 'Var', (24, 37))	('colitis', 'Disease', 'MESH:D003092', (173, 180))	('colitis', 'Disease', 'MESH:D003092', (115, 122))	('colitis', 'Disease', (173, 180))	('colitis', 'Disease', (115, 122))	('colitis', 'Phenotype', 'HP:0002583', (173, 180))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (104, 122))	('colitis', 'Phenotype', 'HP:0002583', (115, 122))
167744	22112468	In the setting of severe LOCDIR, cellular injury also may result in such extensive damage to cellular DNA that the ability of cells to repair the damage to DNA prior to replication may be exceeded; also ROS and RNS may prevent accurate repiair of the DNA.	('RNS', 'Var', (211, 214))	('ROS', 'Var', (203, 206))	('result', 'Reg', (58, 64))	('injury', 'Disease', (42, 48))	('ROS', 'Chemical', 'MESH:D017382', (203, 206))	('prevent', 'NegReg', (219, 226))	('injury', 'Disease', 'MESH:D058186', (42, 48))	('damage', 'MPA', (83, 89))	('LOCDIR', 'Chemical', '-', (25, 31))	('RNS', 'Chemical', 'MESH:D026361', (211, 214))
167745	22112468	An excellent example of LOCDIR with the development of mutations in normal appearing cells is ulcerative colitis (UC) in which molecular changes in DNA can be identified in normal appearing cells in as little as 1 year after the onset of UC.	('ulcerative colitis', 'Disease', (94, 112))	('colitis', 'Phenotype', 'HP:0002583', (105, 112))	('mutations', 'Var', (55, 64))	('LOCDIR', 'Chemical', '-', (24, 30))	('ulcerative colitis', 'Disease', 'MESH:D003093', (94, 112))	('men', 'Species', '9606', (47, 50))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (94, 112))
167746	22112468	UC is an example of how years of damage and repair may cause the development of pre-invasive neoplasia (dysplasia) and an increased risk of the development of carcinoma within 7 to 10 years after the onset of UC, depending upon the severeity of the UC.	('men', 'Species', '9606', (151, 154))	('carcinoma', 'Disease', 'MESH:D002277', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('dysplasia', 'Disease', (104, 113))	('neoplasia', 'Phenotype', 'HP:0002664', (93, 102))	('men', 'Species', '9606', (72, 75))	('dysplasia', 'Disease', 'MESH:D004476', (104, 113))	('invasive neoplasia', 'Disease', (84, 102))	('carcinoma', 'Disease', (159, 168))	('invasive neoplasia', 'Disease', 'MESH:D009369', (84, 102))	('cause', 'Reg', (55, 60))	('damage', 'Var', (33, 39))
167750	22112468	Although these geographically related genes are usually not considered to be major suppressor genes, in the bladder losses or mutations in such genes have been associated with clonal proliferations.	('bladder losses', 'Disease', (108, 122))	('bladder losses', 'Disease', 'MESH:D001749', (108, 122))	('mutations', 'Var', (126, 135))	('clonal', 'Disease', (176, 182))	('associated', 'Reg', (160, 170))
167753	22112468	Alternatively, defective repair of DNA could lead to haplodeficiency of important regulatory genes such as TGFbetaR2 or TGFbetaR1 and subsequently to pre-invasive neoplastic lesions.	('neoplastic lesions', 'Disease', 'MESH:D051437', (163, 181))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (163, 180))	('haplodeficiency', 'Var', (53, 68))	('TGFbeta', 'Gene', '7040', (107, 114))	('DNA', 'Gene', (35, 38))	('TGFbetaR1', 'Gene', (120, 129))	('TGFbeta', 'Gene', (120, 127))	('lead', 'Reg', (45, 49))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (163, 181))	('defective', 'Var', (15, 24))	('TGFbetaR1', 'Gene', '7046', (120, 129))	('TGFbeta', 'Gene', '7040', (120, 127))	('TGFbeta', 'Gene', (107, 114))	('neoplastic lesions', 'Disease', (163, 181))
167763	22112468	If this lesion were considered to be a LOCDIR lesion, perhaps the stimulus of constant severe repair is lost and cells with p53 mutations and/or chromosomal losses (MSI changes) are deleted by non-immune mechanisms.	('mutations', 'Var', (128, 137))	('p53', 'Gene', (124, 127))	('LOCDIR', 'Chemical', '-', (39, 45))
167793	22112468	If one considers only pure lesions without a component of invasion, both ADH and low grade DCIS tend to be basal cell negative (CK5/6) as well as negative for HER2 and p53.	('low grade', 'Var', (81, 90))	('HER2', 'Gene', (159, 163))	('ADH', 'Disease', (73, 76))	('CK5/6', 'Gene', '3852', (128, 133))	('HER2', 'Gene', '2064', (159, 163))	('CK5/6', 'Gene', (128, 133))	('negative', 'NegReg', (118, 126))	('negative', 'NegReg', (146, 154))	('p53', 'Protein', (168, 171))	('basal cell', 'CPA', (107, 117))	('DCIS', 'Disease', (91, 95))
167803	22112468	1, in the typical development of cancer in FAP, one copy of a mutated APC gene is inherited.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('FAP', 'Disease', 'MESH:C567782', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('FAP', 'Disease', (43, 46))	('APC gene', 'Gene', (70, 78))	('men', 'Species', '9606', (25, 28))	('mutated', 'Var', (62, 69))
167804	22112468	When cells develop mutations in the second native APC gene, interactions of APC with other molecular pathways change (e.g., beta catenin accumulates in the cytoplasm and transfers to the nucleus), proliferation and the mutational rates increase further causing stem cells with homozygous mutations in APC to take over a local area of the colorectum.	('mutations', 'Var', (19, 28))	('beta catenin', 'Gene', (124, 136))	('beta catenin', 'Gene', '1499', (124, 136))	('mutational rates', 'CPA', (219, 235))	('causing', 'Reg', (253, 260))	('increase', 'PosReg', (236, 244))	('proliferation', 'CPA', (197, 210))	('mutations', 'Var', (288, 297))	('APC', 'Gene', (50, 53))	('APC', 'Gene', (301, 304))	('interactions', 'Interaction', (60, 72))
167805	22112468	This causes an architectural change with the formation of atypical crypt foci (ACF) as well as the accumulation of additional mutations including mutations in K-ras and SMAD4 and increased expression of COX-2 (Fig.	('K-ras', 'Gene', (159, 164))	('causes', 'Reg', (5, 11))	('mutations', 'Var', (146, 155))	('SMAD4', 'Gene', (169, 174))	('expression', 'MPA', (189, 199))	('architectural change', 'CPA', (15, 35))	('COX-2', 'Gene', '4513', (203, 208))	('increased', 'PosReg', (179, 188))	('COX-2', 'Gene', (203, 208))
167810	22112468	As adenomatous polyps increase in size to greater than 3 cm, mutations in p53 become more likely and such a mutation may be the forerunner of local invasion.	('adenomatous polyps', 'Disease', (3, 21))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (3, 20))	('mutations', 'Var', (61, 70))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (3, 21))	('p53', 'Gene', (74, 77))	('adenomatous polyps', 'Disease', 'MESH:D018256', (3, 21))
167814	22112468	The development of HNPCC tumors may be similar molecularly to FAP tumors; however, sometimes inactivation of expression of mismatch repair genes by methylation of their promoters may be involved.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('FAP tumors', 'Disease', (62, 72))	('expression', 'MPA', (109, 119))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('inactivation', 'NegReg', (93, 105))	('HNPCC tumors', 'Disease', 'MESH:D009369', (19, 31))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mismatch repair genes', 'Gene', (123, 144))	('HNPCC tumors', 'Disease', (19, 31))	('FAP tumors', 'Disease', 'MESH:C567782', (62, 72))	('methylation', 'Var', (148, 159))	('men', 'Species', '9606', (11, 14))
167816	22112468	There are cases of HNPCC probably secondary to mutations and other changes in multiple genes such as myh which may be occasionally mutated in HNPCC.	('changes', 'Var', (67, 74))	('HNPCC', 'Disease', 'None', (142, 147))	('secondary', 'Reg', (34, 43))	('HNPCC', 'Disease', (142, 147))	('HNPCC', 'Disease', 'None', (19, 24))	('mutations', 'Var', (47, 56))	('HNPCC', 'Disease', (19, 24))	('myh', 'Gene', (101, 104))
167817	22112468	Alternatively, these cases may be secondary to the inheritance of genes whose polymorphisms may increase the risk of developing cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('increase', 'PosReg', (96, 104))	('polymorphisms', 'Var', (78, 91))	('cancer', 'Disease', (128, 134))
167821	22112468	mutation in p53) usually are present in the cancer.	('mutation', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (44, 50))	('p53', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
167822	22112468	Thus, in general, molecular changes probably precede histopathologic changes (e.g., mutations in p53 of cells of the colorectum may lead to an invasive tumor with the same dysregulation of p53).	('p53', 'Gene', (97, 100))	('invasive tumor', 'Disease', 'MESH:D009369', (143, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (84, 93))	('lead to', 'Reg', (132, 139))	('invasive tumor', 'Disease', (143, 157))
167844	22112468	For example, mutations in p53 as represented by visible nuclear accumulation of p53 does not usually occur in SCC of the cervix or in CIN lesions (Panel A, Fig.	('CIN lesions', 'Disease', (134, 145))	('p53', 'Gene', (80, 83))	('SCC', 'Gene', (110, 113))	('p53', 'Gene', (26, 29))	('SCC', 'Gene', '6317', (110, 113))	('mutations', 'Var', (13, 22))	('CIN lesions', 'Disease', 'MESH:D051437', (134, 145))
167860	22112468	A transgenic model of familial adenomatous polyposis (FAP) of the colon is the multiple intestinal neoplasia (MIN) mouse which carries a germ-line mutation in the mouse homologue of the APC gene (ApcMin).	('neoplasia', 'Disease', 'MESH:D009369', (99, 108))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (31, 52))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (22, 52))	('mutation', 'Var', (147, 155))	('transgenic', 'Species', '10090', (2, 12))	('mouse', 'Species', '10090', (115, 120))	('neoplasia', 'Disease', (99, 108))	('FAP', 'Disease', (54, 57))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (31, 48))	('mouse', 'Species', '10090', (163, 168))	('ApcMin', 'Gene', (196, 202))	('neoplasia', 'Phenotype', 'HP:0002664', (99, 108))	('FAP', 'Disease', 'MESH:C567782', (54, 57))	('familial adenomatous polyposis', 'Disease', (22, 52))
167868	22112468	Similar to other organ systems, pancreatic intraepithelial neoplasia (PanIN) is designated as PanIN 1, 2 and 3 in which PanIN3 is the most severe lesion and hence the lesion at greatest risk for developing pancreatic cancer.	('pancreatic cancer', 'Disease', (206, 223))	('pancreatic cancer', 'Disease', 'MESH:D010190', (206, 223))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (43, 68))	('epithelial neoplasia', 'Phenotype', 'HP:0031492', (48, 68))	('pancreatic intraepithelial neoplasia', 'Disease', (32, 68))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (32, 68))	('PanIN3', 'Var', (120, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (206, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('neoplasia', 'Phenotype', 'HP:0002664', (59, 68))
167870	22112468	The typical ductal adenocarcinoma of the pancreas (PDAC) frequently carries mutations in p16/CDKN2A, p53, SMAD4/DPC4 and K-ras.	('CDKN2A', 'Gene', (93, 99))	('K-ras', 'Gene', (121, 126))	('DPC4', 'Gene', '4089', (112, 116))	('mutations', 'Var', (76, 85))	('CDKN2A', 'Gene', '1029', (93, 99))	('p53', 'Gene', (101, 104))	('adenocarcinoma of the pancreas', 'Disease', 'MESH:D010190', (19, 49))	('adenocarcinoma of the pancreas', 'Disease', (19, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('DPC4', 'Gene', (112, 116))
167872	22112468	Mutations of K-ras-2 begin in PanIN and continue to accumulate in more advanced lesions until approximately over 90% of PDACs have K-ras-2 mutations.	('K-ras-2', 'Gene', (13, 20))	('mutations', 'Var', (139, 148))	('K-ras-2', 'Gene', '3845', (13, 20))	('K-ras-2', 'Gene', (131, 138))	('Mutations', 'Var', (0, 9))	('K-ras-2', 'Gene', '3845', (131, 138))	('PDACs', 'Disease', (120, 125))
167875	22112468	Of interest, mutations in BRAF occur much more frequently in mismatch repair deficient cases of cancer.	('mismatch', 'Var', (61, 69))	('BRAF', 'Gene', '673', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRAF', 'Gene', (26, 30))	('occur', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (96, 102))
167876	22112468	Mutations or homozygous deletions of p16 also begin in early stage pancreatic neoplasia until about 80% of tumors are involved.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('begin', 'Reg', (46, 51))	('pancreatic neoplasia', 'Disease', (67, 87))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (67, 87))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('homozygous', 'Var', (13, 23))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (67, 87))	('neoplasia', 'Phenotype', 'HP:0002664', (78, 87))	('p16', 'Gene', (37, 40))
167882	22112468	Of interest, 50% of p53 heterozygous crossed animals developed methylation of the promotor of CDKN2A, DNA gains affecting EGFr, Rel and c-myc and DNA losses of Rb pathway.	('c-myc', 'Gene', '4609', (136, 141))	('c-myc', 'Gene', (136, 141))	('Rb pathway', 'Pathway', (160, 170))	('CDKN2A', 'Gene', '1029', (94, 100))	('methylation', 'MPA', (63, 74))	('EGFr', 'Gene', (122, 126))	('Rel', 'Pathway', (128, 131))	('p53', 'Var', (20, 23))	('EGFr', 'Gene', '1956', (122, 126))	('CDKN2A', 'Gene', (94, 100))	('developed', 'Reg', (53, 62))
167883	22112468	Subsequently, the Ela promoter was used with mutant (activated K-ras) to produce mice, but activating acinar to ductal metaplasia and PanIN and IPMN lesions.	('mutant', 'Var', (45, 51))	('mice', 'Species', '10090', (81, 85))	('ductal metaplasia', 'Disease', 'MESH:D008679', (112, 129))	('ductal metaplasia', 'Disease', (112, 129))	('activating', 'PosReg', (91, 101))	('IPMN lesions', 'CPA', (144, 156))	('PanIN', 'CPA', (134, 139))
167884	22112468	When K-ras mutations were combined with p53 null mice, acinar carcinomas that could metastasize developed.	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('mutations', 'Var', (11, 20))	('mice', 'Species', '10090', (49, 53))	('acinar carcinomas', 'Disease', (55, 72))	('acinar carcinomas', 'Disease', 'MESH:D018267', (55, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
167885	22112468	Subsequently, mice with activating K-ras mutations were combined with mice with deletions of Ink4a/Arf (p16/p19) tumor suppressor alleles; this produced early development of PanIN lesions which rapidly developed into highly invasive and a metastatic pancreatic cancers that caused deaths of all such animals by 11 weeks; however, SMAD4 protein was not lost and p53 was native.	('mice', 'Species', '10090', (14, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (250, 267))	('mice', 'Species', '10090', (70, 74))	('mutations', 'Var', (41, 50))	('PanIN lesions', 'Disease', 'MESH:D051437', (174, 187))	('p19', 'Gene', '83430', (108, 111))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (250, 268))	('PanIN lesions', 'Disease', (174, 187))	('Ink4a/Arf', 'Gene', (93, 102))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('tumor', 'Disease', (113, 118))	('p19', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('pancreatic cancers', 'Disease', (250, 268))	('developed', 'Reg', (202, 211))	('men', 'Species', '9606', (166, 169))	('Ink4a/Arf', 'Gene', '12578', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('deletions', 'Var', (80, 89))	('metastatic', 'CPA', (239, 249))	('pancreatic cancers', 'Disease', 'MESH:D010190', (250, 268))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
167887	22112468	A recent study of mice with activating K-ras mutations and loss of SMAD4 found that these mice developed PanIN and IPMN-like lesions as well as locally invasive pancreatic exocrine lesions.	('PanIN', 'Disease', (105, 110))	('mutations', 'Var', (45, 54))	('IPMN-like lesions', 'Disease', (115, 132))	('SMAD4', 'Gene', (67, 72))	('activating', 'PosReg', (28, 38))	('mice', 'Species', '10090', (18, 22))	('mice', 'Species', '10090', (90, 94))	('K-ras', 'Protein', (39, 44))	('invasive pancreatic exocrine lesions', 'Disease', 'MESH:D010188', (152, 188))	('invasive pancreatic exocrine lesions', 'Disease', (152, 188))	('loss', 'Var', (59, 63))
167893	20056007	Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery.	('PPP2R2B', 'Gene', '5521', (51, 58))	('PTEN', 'Gene', '5728', (63, 67))	('FOXC1', 'Gene', '2296', (44, 49))	('PPP2R2B', 'Gene', (51, 58))	('aberrant', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (71, 95))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (71, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('ductal carcinoma in situ', 'Disease', (71, 95))	('invasive breast cancer', 'Disease', (106, 128))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (129, 153))	('invasive breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('lesion of the breast', 'Phenotype', 'HP:0100013', (179, 199))	('FOXC1', 'Gene', (44, 49))	('PTEN', 'Gene', (63, 67))	('ABCB1', 'Gene', (37, 42))	('ABCB1', 'Gene', '5243', (37, 42))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (71, 95))	('Ductal carcinoma', 'Disease', (129, 145))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (129, 145))
167895	20056007	Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive.	('tumour', 'Disease', (139, 145))	('invasive cancer', 'Disease', (21, 36))	('epigenetic lesions', 'Var', (46, 64))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('DCIS', 'Disease', (12, 16))	('invasive cancer', 'Disease', 'MESH:D009362', (21, 36))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
167902	20056007	DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation.	('lower', 'NegReg', (197, 202))	('FOXC1', 'Gene', '2296', (161, 166))	('PTEN', 'Gene', (187, 191))	('mutation', 'Var', (226, 234))	('methylation levels', 'MPA', (139, 157))	('tumours', 'Disease', (122, 129))	('higher', 'PosReg', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('RASSF1A', 'Gene', '11186', (50, 57))	('GSTP1', 'Gene', '2950', (33, 38))	('FOXC1', 'Gene', '2296', (26, 31))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('TP53', 'Gene', '7157', (221, 225))	('ABCB1', 'Gene', (168, 173))	('PTEN', 'Gene', '5728', (187, 191))	('ABCB1', 'Gene', '5243', (168, 173))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('RASSF1A', 'Gene', (50, 57))	('tumours', 'Disease', (206, 213))	('PPP2R2B', 'Gene', '5521', (175, 182))	('GSTP1', 'Gene', (33, 38))	('ABCB1', 'Gene', (40, 45))	('PPP2R2B', 'Gene', (175, 182))	('ABCB1', 'Gene', '5243', (40, 45))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('FOXC1', 'Gene', (161, 166))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('TP53', 'Gene', (221, 225))	('FOXC1', 'Gene', (26, 31))	('DNA methylation levels', 'MPA', (0, 22))
167912	20056007	On the other hand, the frequency of TP53 mutations in DCIS is similar to what is observed in invasive tumours and in situ and invasive components from the same tumour exhibit the same mutations, indicating the same cellular origin of the two components.	('mutations', 'Var', (41, 50))	('invasive tumours', 'Disease', 'MESH:D009361', (93, 109))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('TP53', 'Gene', '7157', (36, 40))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumour', 'Disease', (102, 108))	('DCIS', 'Disease', (54, 58))	('TP53', 'Gene', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('invasive tumours', 'Disease', (93, 109))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
167913	20056007	Epigenetic changes are considered to be an early event during tumour development and one of the hallmarks of cancer.	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Epigenetic changes', 'Var', (0, 18))
167914	20056007	Hypermethylation of CpG islands represents an alternative mechanism to inactivate tumour suppressor genes and is a prevalent early molecular marker for cancer.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('inactivate', 'NegReg', (71, 81))	('Hypermethylation', 'Var', (0, 16))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
167915	20056007	Specific patterns of CpG island methylation could result from clonal selection of cells having growth advantages due to silencing of associated tumour suppressor genes, DNA repair genes, cell-cycle regulators and transcription factors.	('methylation', 'Var', (32, 43))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('result from', 'Reg', (50, 61))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('silencing', 'NegReg', (120, 129))	('tumour', 'Disease', (144, 150))	('DNA repair genes', 'Gene', (169, 185))	('CpG', 'Gene', (21, 24))
167916	20056007	Previous candidate gene studies investigated promoter hypermethylation of in situ lesions and identified aberrant methylation at the promoters of GSTP1, CyclinD2, RARB2, Twist, RASSF1A, HIN-1, CDKN2A, 14-3-3sigma and APC1 .	('HIN-1', 'Gene', '54726', (186, 191))	('GSTP1', 'Gene', (146, 151))	('Twist', 'Gene', (170, 175))	('RASSF1A', 'Gene', '11186', (177, 184))	('APC1', 'Gene', (217, 221))	('CDKN2A', 'Gene', (193, 199))	('methylation', 'MPA', (114, 125))	('RASSF1A', 'Gene', (177, 184))	('RARB2', 'Gene', (163, 168))	('HIN-1', 'Gene', (186, 191))	('CDKN2A', 'Gene', '1029', (193, 199))	('Twist', 'Gene', '7291', (170, 175))	('situ lesions', 'Disease', (77, 89))	('APC1', 'Gene', '29957', (217, 221))	('CyclinD2', 'Gene', (153, 161))	('situ lesions', 'Disease', 'MESH:D002278', (77, 89))	('CyclinD2', 'Gene', '894', (153, 161))	('investigated', 'Reg', (32, 44))	('aberrant', 'Var', (105, 113))	('GSTP1', 'Gene', '2950', (146, 151))
167932	20056007	The entire coding sequence of the TP53 gene (exon 2-11) was analyzed for mutations by sequencing using the 3730 DNA Analyzer (Applied Biosystems, Foster City, California, USA).	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (34, 38))	('mutations', 'Var', (73, 82))
167946	20056007	All patient samples in all three groups displayed widespread aberrant CpG island methylation in the analyzed gene set.	('patient', 'Species', '9606', (4, 11))	('aberrant', 'Var', (61, 69))	('CpG', 'Protein', (70, 73))
167951	20056007	The frequency of FOXC1 methylated samples increased from in situ to invasive cancer.	('increased', 'PosReg', (42, 51))	('FOXC1', 'Gene', (17, 22))	('methylated', 'Var', (23, 33))	('invasive cancer', 'Disease', (68, 83))	('FOXC1', 'Gene', '2296', (17, 22))	('invasive cancer', 'Disease', 'MESH:D009362', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
167957	20056007	The imprinted gene IGF2 was hypomethylated in 10 DCIS, 11 invasive and 5 mixed tumours and hypermethylated in 1 DCIS, 3 invasive and 10 mixed tumours.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('DCIS', 'Disease', (49, 53))	('IGF2', 'Gene', '3481', (19, 23))	('IGF2', 'Gene', (19, 23))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('hypomethylated', 'Var', (28, 42))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
167963	20056007	FOXC1, ABCB1, PPP2R2B and PTEN displayed significant differences in methylation levels in TP53 wild type and TP53 mutated samples (P = 0.006, P = 0.015, P = 0.025 and P = 0.01, respectively) with the TP53 mutated samples having the lower DNA methylation (Figure 4B).	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', '7157', (200, 204))	('mutated', 'Var', (205, 212))	('DNA methylation', 'MPA', (238, 253))	('FOXC1', 'Gene', '2296', (0, 5))	('methylation levels', 'MPA', (68, 86))	('TP53', 'Gene', '7157', (109, 113))	('lower', 'NegReg', (232, 237))	('differences', 'Reg', (53, 64))	('TP53', 'Gene', (200, 204))	('TP53', 'Gene', (90, 94))	('ABCB1', 'Gene', (7, 12))	('ABCB1', 'Gene', '5243', (7, 12))	('PTEN', 'Gene', (26, 30))	('PPP2R2B', 'Gene', '5521', (14, 21))	('PPP2R2B', 'Gene', (14, 21))	('TP53', 'Gene', (109, 113))	('PTEN', 'Gene', '5728', (26, 30))	('FOXC1', 'Gene', (0, 5))
167964	20056007	In addition ABCB1 methylation was lower in Ki67 positive tumours (P = 0.006) and GSTP1 methylation was lower in PR negative tumours (P = 0.009) (Figure 4C).	('ABCB1', 'Gene', '5243', (12, 17))	('GSTP1', 'Gene', (81, 86))	('Ki67 positive', 'Var', (43, 56))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('lower', 'NegReg', (34, 39))	('methylation', 'MPA', (18, 29))	('GSTP1', 'Gene', '2950', (81, 86))	('lower', 'NegReg', (103, 108))	('PR', 'Gene', '5241', (112, 114))	('methylation', 'MPA', (87, 98))	('tumours', 'Disease', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('ABCB1', 'Gene', (12, 17))	('tumours', 'Disease', (124, 131))
167968	20056007	We found frequencies of methylation for RASSF1A in both DCIS and invasive tumours similar to previously published reports ranging from 60 to 88% in different populations.	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('RASSF1A', 'Gene', '11186', (40, 47))	('DCIS', 'Disease', (56, 60))	('methylation', 'Var', (24, 35))	('invasive tumours', 'Disease', (65, 81))	('RASSF1A', 'Gene', (40, 47))	('invasive tumours', 'Disease', 'MESH:D009361', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
167969	20056007	Results seem thus to be very consistent over different technology platforms identifying the epigenetic inactivation of RASSF1A as a very early step during breast carcinogenesis.	('RASSF1A', 'Gene', '11186', (119, 126))	('breast carcinogenesis', 'Disease', (155, 176))	('RASSF1A', 'Gene', (119, 126))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (155, 176))	('epigenetic inactivation', 'Var', (92, 115))
167972	20056007	In this study, methylation of MGMT was rare in both DCIS and invasive tumours, also in concordance with previous studies.	('methylation', 'Var', (15, 26))	('invasive tumours', 'Disease', (61, 77))	('DCIS', 'Disease', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('invasive tumours', 'Disease', 'MESH:D009361', (61, 77))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('rare', 'Reg', (39, 43))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
167978	20056007	A novel finding of our study was the identification of aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in DCIS.	('DNA methylation', 'MPA', (64, 79))	('FOXC1', 'Gene', (90, 95))	('PPP2R2B', 'Gene', '5521', (97, 104))	('aberrant', 'Var', (55, 63))	('ABCB1', 'Gene', (83, 88))	('PTEN', 'Gene', (109, 113))	('ABCB1', 'Gene', '5243', (83, 88))	('PTEN', 'Gene', '5728', (109, 113))	('PPP2R2B', 'Gene', (97, 104))	('FOXC1', 'Gene', '2296', (90, 95))
167980	20056007	PTEN and PPP2R2B are both candidate tumour suppressor genes and our results suggest that epigenetic silencing might be involved in dysregulation of these genes in DCIS.	('involved', 'Reg', (119, 127))	('epigenetic silencing', 'Var', (89, 109))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('dysregulation', 'MPA', (131, 144))	('tumour', 'Disease', (36, 42))	('PPP2R2B', 'Gene', '5521', (9, 16))	('DCIS', 'Disease', (163, 167))	('PPP2R2B', 'Gene', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
167985	20056007	In this study, ABCB1 methylation was associated with non-proliferative, Ki67 negative tumours supporting a positive role for ABCB1 methylation in breast cancer progression and outcome.	('ABCB1', 'Gene', '5243', (15, 20))	('non-proliferative', 'CPA', (53, 70))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('methylation', 'Var', (21, 32))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('ABCB1', 'Gene', (125, 130))	('associated', 'Reg', (37, 47))	('ABCB1', 'Gene', '5243', (125, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('ABCB1', 'Gene', (15, 20))
167998	20056007	In line with our result, significant correlation between GSTP1 and RASSF1A hypermethylation has previously been reported.	('correlation', 'Interaction', (37, 48))	('GSTP1', 'Gene', (57, 62))	('GSTP1', 'Gene', '2950', (57, 62))	('RASSF1A', 'Gene', (67, 74))	('hypermethylation', 'Var', (75, 91))	('RASSF1A', 'Gene', '11186', (67, 74))
168000	20056007	The other chromosomal regions harbouring the genes with a high correlation to FOXC1 methylation have all been reported to either have gain or losses in breast cancer.	('losses', 'NegReg', (142, 148))	('FOXC1', 'Gene', '2296', (78, 83))	('methylation', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('FOXC1', 'Gene', (78, 83))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('gain', 'PosReg', (134, 138))
168001	20056007	It is possible that concomitant DNA hypomethylation in these regions could induce chromosomal instability of the same regions as reported in colon cancer.	('chromosomal instability', 'Phenotype', 'HP:0040012', (82, 105))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colon cancer', 'Disease', (141, 153))	('DNA hypomethylation', 'Var', (32, 51))	('chromosomal instability', 'CPA', (82, 105))	('induce', 'Reg', (75, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (141, 153))	('colon cancer', 'Disease', 'MESH:D015179', (141, 153))
168007	20056007	Lower levels of DNA methylation were observed in TP53 mutated tumours, especially at FOXC1, ABCB1, PPP2R2B and PTEN promoters.	('ABCB1', 'Gene', (92, 97))	('ABCB1', 'Gene', '5243', (92, 97))	('PTEN', 'Gene', (111, 115))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('PTEN', 'Gene', '5728', (111, 115))	('FOXC1', 'Gene', '2296', (85, 90))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('FOXC1', 'Gene', (85, 90))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('mutated', 'Var', (54, 61))	('PPP2R2B', 'Gene', '5521', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('PPP2R2B', 'Gene', (99, 106))	('tumours', 'Disease', (62, 69))
168009	20056007	It has also been reported that breast tumours with TP53 mutations lacked methylation in a number of regulatory genes.	('TP53', 'Gene', '7157', (51, 55))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('methylation', 'MPA', (73, 84))	('breast tumour', 'Phenotype', 'HP:0100013', (31, 44))	('breast tumours', 'Disease', (31, 45))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('lacked', 'NegReg', (66, 72))	('breast tumours', 'Disease', 'MESH:D001943', (31, 45))
168010	20056007	found a high number of TP53 mutations in unmethylated colorectal tumours suggesting that TP53 mutations and epigenetic alterations of other growth-suppressing genes can be two distinct mechanisms that inactivate tumour-suppressor genes in breast cancer.	('breast cancer', 'Disease', (239, 252))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal tumours', 'Disease', (54, 72))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('tumour', 'Disease', (212, 218))	('TP53', 'Gene', '7157', (89, 93))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('TP53', 'Gene', '7157', (23, 27))	('inactivate', 'NegReg', (201, 211))	('mutations', 'Var', (94, 103))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal tumours', 'Disease', 'MESH:D015179', (54, 72))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (28, 37))	('tumour', 'Disease', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', (23, 27))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
168020	15642169	Breast fibroblasts modulate epithelial cell proliferation in three-dimensional in vitro co-culture Stromal fibroblasts associated with in situ and invasive breast carcinoma differ phenotypically from fibroblasts associated with normal breast epithelium, and these alterations in carcinoma-associated fibroblasts (CAF) may promote breast carcinogenesis and cancer progression.	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (147, 172))	('alterations', 'Var', (264, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('breast carcinoma', 'Phenotype', 'HP:0003002', (156, 172))	('promote', 'PosReg', (322, 329))	('invasive breast carcinoma', 'Disease', (147, 172))	('carcinoma-associated fibroblasts (CAF', 'Gene', (279, 316))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('cancer', 'Disease', (356, 362))	('breast carcinogenesis', 'Disease', (330, 351))	('carcinoma-associated fibroblasts (CAF)', 'Gene', '8850', (279, 317))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (330, 351))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
168057	15642169	NAF and CAF were grown in direct contact co-cultures with MCF10A breast epithelial cells and MCF10AT breast epithelial cells, both of which are considered representative of pre-invasive breast disease.	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('CAF', 'Gene', '8850', (8, 11))	('breast disease', 'Disease', (186, 200))	('MCF10A', 'CellLine', 'CVCL:0598', (93, 99))	('breast disease', 'Disease', 'MESH:D001941', (186, 200))	('MCF10A', 'Gene', (58, 64))	('NAF', 'Chemical', '-', (0, 3))	('invasive breast disease', 'Phenotype', 'HP:0003002', (177, 200))	('CAF', 'Gene', (8, 11))	('MCF10AT', 'Var', (93, 100))
168059	15642169	These cells carry a deletion of the chromosomal locus containing p16 and p14ARF, and amplification of MYC.	('p16', 'Gene', '1029', (65, 68))	('p14ARF', 'Gene', '1029', (73, 79))	('MYC', 'Gene', '4609', (102, 105))	('deletion', 'Var', (20, 28))	('p16', 'Gene', (65, 68))	('amplification', 'Var', (85, 98))	('p14ARF', 'Gene', (73, 79))	('MYC', 'Gene', (102, 105))
168060	15642169	MCF10A cells were transfected with mutated T24 H-ras to yield the MCF10AT cells.	('MCF10A', 'CellLine', 'CVCL:0598', (66, 72))	('mutated', 'Var', (35, 42))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('H-ras', 'Gene', (47, 52))	('H-ras', 'Gene', '3265', (47, 52))
168094	15642169	The resulting dual coloration of anti-BrdU (brown nucleus) and anti-CK 5/CK 8 (pink cytoplasm) enabled identification of proliferating epithelial cells.	('CK 5', 'Gene', '3852', (68, 72))	('CK 8', 'Gene', (73, 77))	('CK 8', 'Gene', '3856', (73, 77))	('BrdU', 'Chemical', 'MESH:D001973', (38, 42))	('CK 5', 'Gene', (68, 72))	('anti-BrdU', 'Var', (33, 42))
168100	15642169	The percentage of BrdU-labeled epithelial cells (positive for anti-EpCAM and anti-BrdU) was calculated from the total acquired events.	('BrdU', 'Chemical', 'MESH:D001973', (82, 86))	('anti-BrdU', 'Var', (77, 86))	('EpCAM', 'Gene', (67, 72))	('BrdU', 'Chemical', 'MESH:D001973', (18, 22))	('EpCAM', 'Gene', '4072', (67, 72))
168138	15642169	Although we found no significant difference in the suppressive effect of NAF-2 in an E:F of 2:1 versus an E:F of 1:1 or of 1:2, there was a significantly greater rate of proliferation of MCF10A cells with NAF-2 in an E:F of 1:3 compared with in an E:F of 2:1 (P = 0.028).	('NAF-2', 'Chemical', '-', (205, 210))	('MCF10A', 'CellLine', 'CVCL:0598', (187, 193))	('proliferation', 'CPA', (170, 183))	('NAF-2', 'Var', (205, 210))	('MCF10A', 'Gene', (187, 193))	('NAF-2', 'Chemical', '-', (73, 78))	('greater', 'PosReg', (154, 161))
168152	15642169	Co-culture of MCF10A cells or MCF10AT cells may enhance expression of IGF II in fibroblasts, as has been reported in fibroblasts co-cultured with MCF-7 cells.	('MCF10AT', 'Var', (30, 37))	('MCF10A', 'CellLine', 'CVCL:0598', (14, 20))	('IGF II', 'Gene', '3481', (70, 76))	('MCF-7', 'CellLine', 'CVCL:0031', (146, 151))	('enhance', 'PosReg', (48, 55))	('expression', 'MPA', (56, 66))	('MCF10A', 'CellLine', 'CVCL:0598', (30, 36))	('MCF10A', 'Var', (14, 20))	('IGF II', 'Gene', (70, 76))
168155	15642169	To investigate these possibilities, IGF II levels were assessed by ELISA in 3D monocultures of the same three NAF cultures and three CAF cultures used in previous co-cultures, in 3D monocultures of MCF10AT cells, and in 3D co-cultures of MCF10AT cells with NAF and CAF in an E:F of 2:1, identical to those co-cultures assessed for BrdU labeling previously (Table 4).	('IGF II', 'Gene', (36, 42))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('CAF', 'Gene', (133, 136))	('MCF10A', 'CellLine', 'CVCL:0598', (238, 244))	('CAF', 'Gene', '8850', (133, 136))	('NAF', 'Chemical', '-', (257, 260))	('CAF', 'Gene', (265, 268))	('IGF II', 'Gene', '3481', (36, 42))	('BrdU', 'Chemical', 'MESH:D001973', (331, 335))	('NAF', 'Chemical', '-', (110, 113))	('CAF', 'Gene', '8850', (265, 268))	('MCF10AT', 'Var', (238, 245))
168170	15642169	Many of these differences in the expression profile of CAF in comparison with NAF have the potential to enhance the development, growth and progression of breast carcinoma.	('expression profile', 'MPA', (33, 51))	('progression', 'CPA', (140, 151))	('enhance', 'PosReg', (104, 111))	('differences', 'Var', (14, 25))	('breast carcinoma', 'Disease', (155, 171))	('NAF', 'Chemical', '-', (78, 81))	('development', 'CPA', (116, 127))	('breast carcinoma', 'Disease', 'MESH:D001943', (155, 171))	('CAF', 'Gene', (55, 58))	('CAF', 'Gene', '8850', (55, 58))	('growth', 'CPA', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('breast carcinoma', 'Phenotype', 'HP:0003002', (155, 171))
168320	25777085	ALND was avoided for 51 [67 %; 95 % confidence interval (CI), 56-77 %] of all the patients who had microinvasive DCIS or DCIS associated with invasive carcinoma at mastectomy and a negative SLN.	('invasive carcinoma', 'Disease', 'MESH:D009361', (142, 160))	('DCIS', 'Gene', (121, 125))	('associated with', 'Reg', (126, 141))	('patients', 'Species', '9606', (82, 90))	('DCIS', 'Gene', (113, 117))	('microinvasive', 'Var', (99, 112))	('invasive carcinoma', 'Disease', (142, 160))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('ALND', 'Chemical', '-', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
168323	25777085	High nuclear grade of DCIS was associated with greater risk of microinvasion and invasion, and HER2-amplified DCIS was associated with greater risk of invasion.	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('invasion', 'CPA', (81, 89))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('microinvasion', 'CPA', (63, 76))	('HER2', 'Gene', (95, 99))	('High nuclear', 'Var', (0, 12))	('HER2', 'Gene', '2064', (95, 99))
168367	25777085	Precisely, the following factors and categories were assessed: DCIS radiologic and pathologic factors (histologic size, continuous), nuclear grade (low, intermediate, or high), necrosis (yes vs no), and inflammation (yes vs no), as well as immunohistochemical factors (ER, PR, and FOXA1) (<10 vs >=10 %); Ki-67 (<15 vs >=15 %); HER2 (0 or + vs ++ vs +++); CK5/6 and CK14 (positive vs negative); EGFR, P16, or CSTA (<100 vs >=100); E-cadherin (<200 vs >=200), EMA (CD+CF vs MA+MD); COX2 (0-1 vs 2-3); and HER2 gene (amplified vs nonamplified).	('necrosis', 'Disease', 'MESH:D009336', (177, 185))	('HER2', 'Gene', (504, 508))	('CK14', 'Gene', (366, 370))	('necrosis', 'Disease', (177, 185))	('inflammation', 'Disease', 'MESH:D007249', (203, 215))	('EGFR', 'Gene', '1956', (395, 399))	('CK14', 'Gene', '3861', (366, 370))	('HER2', 'Gene', (328, 332))	('CK5/6', 'Gene', '3852', (356, 361))	('COX2', 'Gene', (481, 485))	('inflammation', 'Disease', (203, 215))	('E-cadherin', 'Gene', (431, 441))	('<200', 'Var', (443, 447))	('CSTA', 'Gene', '1475', (409, 413))	('HER2', 'Gene', '2064', (504, 508))	('FOXA1', 'Gene', '3169', (281, 286))	('E-cadherin', 'Gene', '999', (431, 441))	('P16', 'Gene', '1029', (401, 404))	('CK5/6', 'Gene', (356, 361))	('FOXA1', 'Gene', (281, 286))	('COX2', 'Gene', '4513', (481, 485))	('P16', 'Gene', (401, 404))	('EGFR', 'Gene', (395, 399))	('EMA', 'Gene', '4582', (459, 462))	('CSTA', 'Gene', (409, 413))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('HER2', 'Gene', '2064', (328, 332))	('EMA', 'Gene', (459, 462))
168379	25777085	Pathologic and immunohistochemical factors of DCIS associated with microinvasion in the univariate analyses included the presence of inflammation, ER-negative status, PR-negative status, the presence of necrosis, high nuclear grade, a P16 score of 100 or higher, and a CSTA score of 100 or higher (Table 4).	('P16', 'Gene', (235, 238))	('DCIS', 'Gene', (46, 50))	('P16', 'Gene', '1029', (235, 238))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('microinvasion', 'MPA', (67, 80))	('associated', 'Reg', (51, 61))	('necrosis', 'Disease', 'MESH:D009336', (203, 211))	('inflammation', 'Disease', (133, 145))	('high', 'Var', (213, 217))	('CSTA', 'Gene', '1475', (269, 273))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('CSTA', 'Gene', (269, 273))	('necrosis', 'Disease', (203, 211))
168380	25777085	Pathologic and immunohistochemical factors of DCIS associated with invasion in the univariate analyses included the presence of inflammation, the presence of necrosis, high nuclear grade, a predominant EMA membranous staining pattern, amplification of HER2, and Ki-67 of 15 % or higher.	('necrosis', 'Disease', (158, 166))	('amplification', 'Var', (235, 248))	('EMA', 'Gene', (202, 205))	('inflammation', 'Disease', (128, 140))	('invasion', 'Disease', (67, 75))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('EMA', 'Gene', '4582', (202, 205))	('associated', 'Reg', (51, 61))	('HER2', 'Gene', (252, 256))	('high', 'Var', (168, 172))	('HER2', 'Gene', '2064', (252, 256))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
168381	25777085	In the multivariable model, high nuclear grade and amplification of HER2 were independent factors.	('HER2', 'Gene', (68, 72))	('HER2', 'Gene', '2064', (68, 72))	('amplification', 'Var', (51, 64))
168387	25777085	Whereas a negative SLN rules out unnecessary ALND, a positive SLN results in a complete ALND.	('ALND', 'Chemical', '-', (88, 92))	('results in', 'Reg', (66, 76))	('ALND', 'Chemical', '-', (45, 49))	('positive', 'Var', (53, 61))
168401	25777085	In univariate analyses, high DCIS nuclear grade, necrosis, and stromal inflammation were associated with both microinvasion and invasion.	('associated', 'Reg', (89, 99))	('necrosis', 'Disease', (49, 57))	('high DCIS', 'Var', (24, 33))	('necrosis', 'Disease', 'MESH:D009336', (49, 57))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('inflammation', 'Disease', (71, 83))	('microinvasion', 'CPA', (110, 123))	('invasion', 'CPA', (128, 136))
168402	25777085	Overexpression of HER2 was an independent predictor of a higher risk of invasive components.	('HER2', 'Gene', (18, 22))	('HER2', 'Gene', '2064', (18, 22))	('Overexpression', 'Var', (0, 14))	('invasive components', 'Disease', (72, 91))
168403	25777085	Amplification of HER2 in DCIS is more frequent than in invasive carcinoma and for some authors may represent a precursor of invasion In the NSABP B43 trial, transtuzumab was used as chemopreventive treatment for DCIS with HER2 amplification.	('DCIS', 'Disease', (212, 216))	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('Amplification', 'Var', (0, 13))	('transtuzumab', 'Chemical', '-', (157, 169))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('HER2', 'Gene', (222, 226))	('HER2', 'Gene', (17, 21))	('invasive carcinoma', 'Disease', (55, 73))	('HER2', 'Gene', '2064', (222, 226))	('HER2', 'Gene', '2064', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('invasive carcinoma', 'Disease', 'MESH:D009361', (55, 73))
168410	25777085	Our results also demonstrate that whereas amplification of HER2 is an independent predictor of invasive disease, high nuclear grade is associated with an increased risk of both microinvasion and invasion.	('invasive disease', 'Disease', 'MESH:D009362', (95, 111))	('invasion', 'Disease', (195, 203))	('HER2', 'Gene', (59, 63))	('high nuclear grade', 'Var', (113, 131))	('amplification', 'Var', (42, 55))	('HER2', 'Gene', '2064', (59, 63))	('invasive disease', 'Disease', (95, 111))	('microinvasion', 'Disease', (177, 190))
168413	26213588	DNA methylation alterations are early events in the progression of cancer and represent emerging molecular markers that may predict invasive recurrence more accurately than traditional measures of DCIS prognosis.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('DNA', 'Gene', (0, 3))	('alterations', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('invasive', 'Disease', (132, 140))	('methylation alterations', 'Var', (4, 27))
168417	26213588	Further, the functional relevance of these genes' regulation by methylation was demonstrated in early stage breast cancers from The Cancer Genome Atlas database.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('methylation', 'Var', (64, 75))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
168424	26213588	Overtreatment can potentially subject the patient to unnecessary risk of treatment, without potential benefit, and burden the health care system.	('subject', 'Reg', (30, 37))	('patient', 'Species', '9606', (42, 49))	('burden', 'Reg', (115, 121))	('Overtreatment', 'Var', (0, 13))
168428	26213588	Although DNA methylation deregulation occurs early in carcinogenesis, the patterns of epigenetic alterations associated with development of invasive disease remain unclear.	('methylation deregulation', 'Var', (13, 37))	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('invasive disease', 'Disease', (140, 156))	('deregulation', 'Var', (25, 37))	('carcinogenesis', 'Disease', (54, 68))	('invasive disease', 'Disease', 'MESH:D009362', (140, 156))	('DNA', 'Gene', (9, 12))
168429	26213588	DNA methylation alterations are potential markers for DCIS outcome prediction and may identify cellular changes that modulate tumor progression.	('alterations', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('methylation alterations', 'Var', (4, 27))	('tumor', 'Disease', (126, 131))
168431	26213588	Accordingly, the identification of DNA methylation alterations that can inform risk of subsequent invasive disease has the potential to both impact clinical treatment decisions and improve our understanding of cancer progression.	('alterations', 'Var', (51, 62))	('invasive disease', 'Disease', (98, 114))	('methylation alterations', 'Var', (39, 62))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('DNA', 'Gene', (35, 38))	('invasive disease', 'Disease', 'MESH:D009362', (98, 114))	('improve', 'PosReg', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('impact', 'Reg', (141, 147))	('cancer', 'Disease', (210, 216))
168435	26213588	Through these analyses, we have identified epigenetic changes in ER positive DCIS that may contribute to increased risk of developing invasive breast cancer.	('epigenetic changes', 'Var', (43, 61))	('contribute', 'Reg', (91, 101))	('ER', 'Gene', '2099', (65, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('invasive breast cancer', 'Disease', 'MESH:D001943', (134, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('invasive breast cancer', 'Disease', (134, 156))
168443	26213588	As expected, a stratified analysis determined that the strength of association was stronger with an ipsilateral IDC to DCIS outcome compared with a contralateral IDC outcome (Additional file 6: Table S2).	('IDC', 'Gene', '4000', (112, 115))	('IDC', 'Gene', (112, 115))	('ipsilateral', 'Var', (100, 111))	('stronger', 'PosReg', (83, 91))	('DCIS', 'Disease', (119, 123))	('IDC', 'Gene', '4000', (162, 165))	('IDC', 'Gene', (162, 165))
168453	26213588	Among the strongest associations between methylation and expression were CpG sites associated with TMEM139, HOXB2, and TBX1 genes as well as the long non-coding RNA HOTAIR (Fig.	('HOXB2', 'Gene', '3212', (108, 113))	('expression', 'MPA', (57, 67))	('TMEM139', 'Gene', '135932', (99, 106))	('associations', 'Interaction', (20, 32))	('HOTAIR', 'Gene', '100124700', (165, 171))	('HOTAIR', 'Gene', (165, 171))	('TMEM139', 'Gene', (99, 106))	('TBX1', 'Gene', '6899', (119, 123))	('HOXB2', 'Gene', (108, 113))	('CpG sites', 'Var', (73, 82))	('TBX1', 'Gene', (119, 123))
168456	26213588	Emerging evidence from the initial stages of cancer development suggests that the patterns of DNA methylation, a stable mark capable of transcriptional control, are deregulated early and may serve as a predictor of malignant potential.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('DNA', 'Gene', (94, 97))	('methylation', 'Var', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('deregulated', 'NegReg', (165, 176))	('cancer', 'Disease', (45, 51))	('malignant potential', 'CPA', (215, 234))
168458	26213588	We identified methylation of CpG loci that were strongly associated with development of invasive breast cancer.	('invasive breast cancer', 'Disease', 'MESH:D001943', (88, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CpG', 'Gene', (29, 32))	('methylation', 'Var', (14, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('invasive breast cancer', 'Disease', (88, 110))	('associated with', 'Reg', (57, 72))
168460	26213588	Importantly, CpGs with progression-related changes in methylation in DCIS had strong correlations with gene expression in an independent set of early stage ER positive breast cancers, suggesting that differential methylation of these sites may contribute to an increased risk of invasion through aberrations in gene expression.	('breast cancers', 'Phenotype', 'HP:0003002', (168, 182))	('methylation', 'Var', (213, 224))	('methylation', 'Var', (54, 65))	('changes', 'Var', (43, 50))	('breast cancers', 'Disease', 'MESH:D001943', (168, 182))	('breast cancers', 'Disease', (168, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ER', 'Gene', '2099', (156, 158))	('invasion', 'CPA', (279, 287))	('gene', 'Protein', (311, 315))	('contribute', 'Reg', (244, 254))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('DCIS', 'Gene', (69, 73))
168462	26213588	Altered patterns of DNA methylation have the ability to the ability to modify the regulation of gene expression, impact chromosomal instability, and have frequently been observed in the early stages of breast cancer.	('chromosomal instability', 'Phenotype', 'HP:0040012', (120, 143))	('observed', 'Reg', (170, 178))	('modify', 'Reg', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('impact', 'Reg', (113, 119))	('breast cancer', 'Disease', (202, 215))	('chromosomal instability', 'MPA', (120, 143))	('regulation of gene expression', 'MPA', (82, 111))	('methylation', 'Var', (24, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
168464	26213588	The striking difference between DCIS and tissues with no histologic evidence of malignancy provides additional evidence that epigenetic alterations in breast cancer are early events.	('epigenetic alterations', 'Var', (125, 147))	('malignancy', 'Disease', 'MESH:D009369', (80, 90))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('malignancy', 'Disease', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
168467	26213588	Epigenomic changes represent potential molecular attributes that define whether a carcinoma remains indolent or shifts toward an invasive phenotype.	('carcinoma', 'Disease', 'MESH:D002277', (82, 91))	('carcinoma', 'Disease', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Epigenomic changes', 'Var', (0, 18))
168468	26213588	Indeed, we observed that altered DNA methylation associated with an invasive disease diagnosis preferentially targeted gene groups were involved with key developmental pathways.	('DNA', 'MPA', (33, 36))	('altered', 'Var', (25, 32))	('associated', 'Reg', (49, 59))	('invasive disease', 'Disease', 'MESH:D009362', (68, 84))	('invasive disease', 'Disease', (68, 84))
168469	26213588	Interestingly, dysregulation of DNA methylation at these distal regulatory sites has previously been related with the expression of cancer genes.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('dysregulation', 'Var', (15, 28))	('related', 'Reg', (101, 108))
168470	26213588	Homeobox genes and other developmental transcription factors become preferential targets of de novo methylation in DCIS, consistent with previous associations between homeobox gene methylation and recurrence in invasive breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (220, 234))	('DCIS', 'Gene', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Homeobox genes', 'Gene', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('invasive breast cancers', 'Disease', (211, 234))	('methylation', 'Var', (100, 111))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('invasive breast cancers', 'Disease', 'MESH:D001943', (211, 234))
168473	26213588	Moreover, there were 276 CpG loci including those that track to the HOXB13, DLX4, and TBX15 genes that exhibited a significant gain or loss of methylation from normal to DCIS and were further hypermethylated or hypomethylated in lesions from women with a subsequent diagnosis of invasive disease.	('HOXB13', 'Gene', '10481', (68, 74))	('loss', 'NegReg', (135, 139))	('invasive disease', 'Disease', (279, 295))	('women', 'Species', '9606', (242, 247))	('hypomethylated', 'Var', (211, 225))	('DLX4', 'Gene', (76, 80))	('DLX4', 'Gene', '1748', (76, 80))	('HOXB13', 'Gene', (68, 74))	('invasive disease', 'Disease', 'MESH:D009362', (279, 295))	('TBX15', 'Gene', (86, 91))	('TBX15', 'Gene', '6913', (86, 91))	('gain', 'PosReg', (127, 131))	('methylation', 'MPA', (143, 154))
168475	26213588	Our DAVID analysis:despite being best suited for gene sets between 100-2000 genes:of the 72 genes shared between data sets suggests that epigenetic deregulation of genes involved in cellular development and differentiation is likely a defining feature progression to invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (267, 283))	('invasive disease', 'Disease', (267, 283))	('epigenetic deregulation', 'Var', (137, 160))
168476	26213588	Further, alterations that are critical for development of an invasive phenotype may occur in DCIS and once the cancerous cells escape from the duct additional epigenetic programming may be required for further progression or metastasis.	('cancerous', 'Disease', (111, 120))	('DCIS', 'Disease', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancerous', 'Disease', 'MESH:D009369', (111, 120))	('alterations', 'Var', (9, 20))
168480	26213588	HOTAIR is increased in expression in primary breast tumors and metastases, and loss of HOTAIR can inhibit cancer invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('breast tumors', 'Disease', (45, 58))	('HOTAIR', 'Gene', '100124700', (0, 6))	('loss', 'Var', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('HOTAIR', 'Gene', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('HOTAIR', 'Gene', '100124700', (87, 93))	('metastases', 'Disease', (63, 73))	('breast tumors', 'Disease', 'MESH:D001943', (45, 58))	('cancer invasiveness', 'Disease', 'MESH:D009362', (106, 125))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('breast tumors', 'Phenotype', 'HP:0100013', (45, 58))	('inhibit', 'NegReg', (98, 105))	('HOTAIR', 'Gene', (0, 6))	('cancer invasiveness', 'Disease', (106, 125))	('increased', 'PosReg', (10, 19))	('expression', 'MPA', (23, 33))
168482	26213588	The major objective of our work was to determine epigenetic events that contribute to development of invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive breast cancer', 'Disease', (101, 123))	('epigenetic events', 'Var', (49, 66))	('contribute', 'Reg', (72, 82))	('invasive breast cancer', 'Disease', 'MESH:D001943', (101, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
168486	26213588	Our approach identified methylation alterations present in DCIS that may contribute to breast tumorigenesis and development of invasive disease.	('contribute', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('invasive disease', 'Disease', 'MESH:D009362', (127, 143))	('tumor', 'Disease', (94, 99))	('DCIS', 'Gene', (59, 63))	('invasive disease', 'Disease', (127, 143))	('methylation alterations', 'Var', (24, 47))
168488	26213588	We have provided evidence for methylation alterations that are associated with development of invasive disease and defined specific epigenetic programs in DCIS disease progression that are particularly susceptible to deregulation.	('invasive disease', 'Disease', 'MESH:D009362', (94, 110))	('associated', 'Reg', (63, 73))	('invasive disease', 'Disease', (94, 110))	('methylation alterations', 'Var', (30, 53))	('DCIS disease', 'Disease', (155, 167))
168489	26213588	Further examination of these alterations is warranted to demonstrate their potential utility in defining risk for subsequent invasive disease and thus impact treatment decision-making.	('impact', 'Reg', (151, 157))	('invasive disease', 'Disease', 'MESH:D009362', (125, 141))	('invasive disease', 'Disease', (125, 141))	('alterations', 'Var', (29, 40))
168504	26213588	To reduce Type I error and maintain sensitivity of discovery, we selected CpGs whose methylation was associated with development of invasive breast cancer at P < 0.01 and then limited our analyses to those CpG sites that exhibited a median  Deltabeta  greater than 0.1.	('methylation', 'Var', (85, 96))	('invasive breast cancer', 'Disease', 'MESH:D001943', (132, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('invasive breast cancer', 'Disease', (132, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('associated with', 'Reg', (101, 116))
14097	27528719	Re-excisions have the potential for added discomfort, surgical complications, compromise in cosmetic outcome, additional stress for patients and families, and increased health care costs, and have been associated with conversion to bilateral mastectomy.	('Re-excisions', 'Var', (0, 12))	('associated', 'Reg', (202, 212))	('patients', 'Species', '9606', (132, 140))
168518	27528719	The annual hazard rate for IBTR after lumpectomy alone was 8.1% for those with positive margins compared with 3.3% for patients with negative margins, reduced by WBRT to 2.7% and 1.2%, respectively.	('positive margins', 'Var', (79, 95))	('patients', 'Species', '9606', (119, 127))	('IBTR', 'Disease', (27, 31))
14110	27528719	Positive margins were significantly associated with IBTR in a multivariate analysis of the long-term results of the European Organization for Research and Treatment of Cancer (EORTC) 10853 trial.	('IBTR', 'Disease', (52, 56))	('Positive margins', 'Var', (0, 16))	('Cancer', 'Disease', (168, 174))	('Cancer', 'Disease', 'MESH:D009369', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))
168527	27528719	In the Radiation Therapy Oncology Group (RTOG) 9804 trial where patients with small, mammographically detected low-to-intermediate grade DCIS and margins >= 3 mm were randomized to excision alone or excision plus WBRT, 7-year IBTR rates were 6.7% and 0.9% (P = .0003), respectively.	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('patients', 'Species', '9606', (64, 72))	('Oncology', 'Phenotype', 'HP:0002664', (25, 33))	('low-to-intermediate grade', 'Var', (111, 136))	('DCIS', 'Disease', (137, 141))
168552	22649761	They demonstrated that computerized TA of central regions of digitized mammographic density patterns could identify women with germ-line mutations in BRCA1 and BRCA2 genes (and hence increased risk of invasive cancer).	('invasive cancer', 'Disease', 'MESH:D009362', (201, 216))	('BRCA1', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('BRCA2', 'Gene', (160, 165))	('women', 'Species', '9606', (116, 121))	('mutations', 'Var', (137, 146))	('BRCA2', 'Gene', '675', (160, 165))	('BRCA1', 'Gene', '672', (150, 155))	('invasive cancer', 'Disease', (201, 216))
168637	29858579	When clinical cutoffs for the various analytes are applied, the concordance remains strong, no specimen in either cohort changed from positive to negative or vica versa as a function of non m-d or m-d for ERBB2 and ESR (Table 3 and 4).	('ERBB2', 'Gene', (205, 210))	('ESR', 'Gene', (215, 218))	('non m-d', 'Var', (186, 193))	('m-d', 'Var', (197, 200))	('ERBB2', 'Gene', '2064', (205, 210))
168763	20974554	Petricoin et al applied RPMA and laser capture microdissection technology to address the lack of chemotherapy response in a set of frozen tissue samples obtained from a subset of children with Rhabdomyosarcoma enrolled in the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803.	('D9502', 'Var', (296, 301))	('Children', 'Species', '9606', (226, 234))	('RPMA', 'Chemical', '-', (24, 28))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (263, 279))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (193, 209))	('D9803', 'Var', (306, 311))	('Rhabdomyosarcoma', 'Disease', (193, 209))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (193, 209))	('Rhabdomyosarcoma', 'Disease', (263, 279))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (263, 279))	('Oncology', 'Phenotype', 'HP:0002664', (237, 245))	('children', 'Species', '9606', (179, 187))
168767	20974554	CCI-779, an mTOR inhibitor, was able to reduce tumor burden in a mouse xenograft model of Rhabdomyosarcoma, confirming the significance of the AKT/mTOR pathway.	('Rhabdomyosarcoma', 'Disease', (90, 106))	('mouse', 'Species', '10090', (65, 70))	('CCI-779', 'Chemical', 'MESH:C401859', (0, 7))	('reduce', 'NegReg', (40, 46))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (90, 106))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('CCI-779', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (90, 106))	('tumor', 'Disease', (47, 52))
168774	20974554	This same group also retrospectively evaluated breast tumor pathogenesis driven, in some cases, by steroid family hormones including estrogen, progesterone, or androgens in conjunction with mass spectrometry identification of single nucleotide polymorphism alterations in the PI3K gene.	('steroid', 'Chemical', 'MESH:D013256', (99, 106))	('breast tumor', 'Phenotype', 'HP:0100013', (47, 59))	('single nucleotide polymorphism alterations', 'Var', (226, 268))	('breast tumor', 'Disease', 'MESH:D001943', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('progesterone', 'Chemical', 'MESH:D011374', (143, 155))	('breast tumor', 'Disease', (47, 59))	('PI3K', 'Gene', (276, 280))
168779	20974554	Known genetic translocations such as t(14:18) in follicular lymphoma or t(11:14) and t(4:14) in myeloma provide prognostic information, while protein signaling network analysis provides functional profiles for designing individualized therapy regimens.	('myeloma', 'Disease', 'MESH:D009101', (96, 103))	('follicular lymphoma', 'Disease', 'MESH:D008224', (49, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('follicular lymphoma', 'Disease', (49, 68))	('t(14:18', 'Var', (37, 44))	('myeloma', 'Disease', (96, 103))	('t(4:14', 'Var', (85, 91))
168780	20974554	B-Cell lymphoma is a disease of the apoptosis pathway caused, at least in part, by genetic translocations that lead to Bcl-2 overexpression, which is a potent apoptosis inhibitor.	('B-Cell lymphoma', 'Disease', (0, 15))	('genetic translocations', 'Var', (83, 105))	('B-Cell lymphoma', 'Phenotype', 'HP:0012191', (0, 15))	('B-Cell lymphoma', 'Disease', 'MESH:D016393', (0, 15))	('caused', 'Reg', (54, 60))	('Bcl-2', 'Gene', '596', (119, 124))	('overexpression', 'PosReg', (125, 139))	('Bcl-2', 'Gene', (119, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (7, 15))
168783	20974554	As new molecular targeted agents are developed, such as anti-sense Bcl-2 (Oblimersen), it will be imperative to validate the state of drug targets, pre and post treatment, that may signify clinically relevant protein signatures of hematologic malignancies.	('hematologic malignancies', 'Disease', 'MESH:D019337', (231, 255))	('anti-sense', 'Var', (56, 66))	('hematologic malignancies', 'Disease', (231, 255))	('Bcl-2', 'Gene', (67, 72))	('Bcl-2', 'Gene', '596', (67, 72))
168786	20974554	Activating mutations within the ATP binding pocket of EGFR in NSCLC, or BCR-ABL mutations which hinder drug binding but do not effect the catalytic activity, may cause unexpected tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (11, 20))	('NSCLC', 'Disease', (62, 67))	('mutations', 'Var', (80, 89))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('hinder', 'NegReg', (96, 102))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('EGFR', 'Gene', '1956', (54, 58))	('cause', 'Reg', (162, 167))	('BCR-ABL', 'Gene', (72, 79))	('BCR-ABL', 'Gene', '25', (72, 79))	('drug binding', 'Interaction', (103, 115))	('EGFR', 'Gene', (54, 58))	('tumor', 'Disease', (179, 184))
168788	20974554	In a study of microdissected NSCLC samples, with known EGFR mutation, VanMeter et al showed that ratios of specific phosphorylated EGFR residues, or ratios of phosphorylated forms to total EGFR, were associated with EGFR L858R activating mutations suggesting that phoshpproteomic data could be used as surrogate indicators of genetic mutations.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (216, 220))	('mutation', 'Var', (60, 68))	('EGFR', 'Gene', '1956', (189, 193))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', (189, 193))	('activating', 'PosReg', (227, 237))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('associated', 'Reg', (200, 210))	('L858R', 'Var', (221, 226))	('NSCLC', 'Disease', (29, 34))	('L858R', 'Mutation', 'rs121434568', (221, 226))	('EGFR', 'Gene', '1956', (216, 220))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
168799	20974554	Telomere 3' overhang specific DNA oligonucleotides (T-oligos) induce autophagy rather than apoptosis through a proposed mechanism in which the T-oligo mimicks the telomere loop disruption that is often caused by DNA damage.	('autophagy', 'CPA', (69, 78))	('T-oligos', 'Chemical', '-', (52, 60))	('apoptosis', 'CPA', (91, 100))	('telomere loop disruption', 'MPA', (163, 187))	('induce', 'PosReg', (62, 68))	('T-oligo', 'Var', (143, 150))
168802	20974554	Phosphoprotein profiling showed decreased expression of phospho c-jun, phospho p70S6K, and phospho p38 in the mucosal epithelial cell model suggesting that the combination treatment targets multiple nodes within proliferation/survival pathway networks.	('p38', 'Gene', '1432', (99, 102))	('c-jun', 'Gene', '3725', (64, 69))	('c-jun', 'Gene', (64, 69))	('expression', 'MPA', (42, 52))	('phospho', 'Var', (56, 63))	('p38', 'Gene', (99, 102))	('p70S6K', 'Gene', '6198', (79, 85))	('p70S6K', 'Gene', (79, 85))	('decreased', 'NegReg', (32, 41))
168809	20974554	Super Oxide Dismutase, MMP-9, PDGFR Tyr716, Estrogen Receptor alpha (ERA), Biliverdin reductase A (BLVRA) and HemeOxygenase1 were analyzed by RPMA for correlations with protein abundance.	('Tyr716', 'Chemical', '-', (36, 42))	('HemeOxygenase1', 'Gene', '3162', (110, 124))	('HemeOxygenase1', 'Gene', (110, 124))	('BLVRA', 'Gene', (99, 104))	('ER', 'Gene', '2099', (69, 71))	('Tyr716', 'Var', (36, 42))	('RPMA', 'Chemical', '-', (142, 146))	('Estrogen Receptor alpha', 'Gene', '2099', (44, 67))	('PDGFR', 'Gene', (30, 35))	('Estrogen Receptor alpha', 'Gene', (44, 67))	('Biliverdin reductase A', 'Gene', (75, 97))	('MMP-9', 'Gene', (23, 28))	('Biliverdin reductase A', 'Gene', '644', (75, 97))	('PDGFR', 'Gene', '5159', (30, 35))	('MMP-9', 'Gene', '4318', (23, 28))	('BLVRA', 'Gene', '644', (99, 104))
168837	20974554	Cy3 and Cy5 dyes are commonly used for fluorescent detection due to their decreased dye interactions, increased brightness and the ability to add charged groups to the dyes (e.g.	('Cy5', 'Chemical', 'MESH:C085321', (8, 11))	('dye interactions', 'Interaction', (84, 100))	('brightness', 'MPA', (112, 122))	('add', 'Interaction', (142, 145))	('Cy3', 'Chemical', '-', (0, 3))	('decreased', 'NegReg', (74, 83))	('increased', 'PosReg', (102, 111))	('Cy5', 'Var', (8, 11))
168900	30482722	Calcein AM (CAM) (C34851), propidium iodide (PI) (P1304MP), hypoxia reagent (H10498), 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (NBDG), cell tracker red CMTPX (C34552), green CMFDA (C7025), and blue (C2110), were purchased from Thermo Fisher and stock solutions were prepared following supplier instructions.	('CAM', 'Gene', '808', (12, 15))	('C7025', 'Var', (202, 207))	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('CAM', 'Gene', (12, 15))	('C34552', 'Var', (180, 186))	('C2110', 'CellLine', 'CVCL:K871', (220, 225))	('C2110', 'Var', (220, 225))	('NBDG', 'Chemical', 'MESH:C098340', (149, 153))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))	('C34851', 'Var', (18, 24))	('P1304MP', 'Var', (50, 57))
168918	30482722	In some experiments cell were fluorescently labeled with Red/Green/Blue cell tracker (Thermo Fisher, C34552, C7025, C2110 respectively).	('C7025', 'Var', (109, 114))	('C34552', 'Var', (101, 107))	('C2110', 'CellLine', 'CVCL:K871', (116, 121))	('C2110', 'Var', (116, 121))
168972	30482722	When the mammary duct model was filled with MCF10A cells, the hypoxia signal observed after 24 h was lower compared with the DCIS model.	('MCF10A', 'Var', (44, 50))	('hypoxia', 'Disease', 'MESH:D000860', (62, 69))	('lower', 'NegReg', (101, 106))	('MCF10A', 'CellLine', 'CVCL:0598', (44, 50))	('hypoxia', 'Disease', (62, 69))
168978	30482722	Interestingly, when NBDG reached the lumen wall, its diffusion was significantly decreased.	('decreased', 'NegReg', (81, 90))	('diffusion', 'MPA', (53, 62))	('NBDG', 'Var', (20, 24))	('NBDG', 'Chemical', 'MESH:C098340', (20, 24))
168987	30482722	Moreover, glutamine concentrations were lower in the DCIS model, which could result from increased glutaminolysis.	('DCIS', 'Var', (53, 57))	('glutamine', 'Chemical', 'MESH:D005973', (10, 19))	('glutamine concentrations', 'MPA', (10, 34))	('glutaminolysis', 'MPA', (99, 113))	('increased', 'PosReg', (89, 98))	('lower', 'NegReg', (40, 45))
168988	30482722	Choline was reduced only in DCIS and pseudo-DCIS groups compared to control and mammary duct models, suggesting the higher cell density within the duct was modifying cell metabolism.	('modifying', 'Reg', (156, 165))	('reduced', 'NegReg', (12, 19))	('Choline', 'MPA', (0, 7))	('DCIS', 'Var', (28, 32))	('Choline', 'Chemical', 'MESH:D002794', (0, 7))	('cell metabolism', 'MPA', (166, 181))
169000	30482722	The most common alterations for CA9, ARNT, HIF1alpha (i.e., hypoxia-related genes), PDK4 and VIM genes were mRNA upregulation and amplification; which is good agreement with the overexpression obtained in the model for these genes (Fig.	('VIM', 'Gene', (93, 96))	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('PDK4', 'Gene', '5166', (84, 88))	('HIF1alpha', 'Gene', '3091', (43, 52))	('CA9', 'Gene', '768', (32, 35))	('upregulation', 'PosReg', (113, 125))	('PDK4', 'Gene', (84, 88))	('amplification', 'Var', (130, 143))	('CA9', 'Gene', (32, 35))	('ARNT', 'Gene', '405', (37, 41))	('VIM', 'Gene', '7431', (93, 96))	('mRNA', 'MPA', (108, 112))	('ARNT', 'Gene', (37, 41))	('HIF1alpha', 'Gene', (43, 52))
169001	30482722	On the other hand, mRNA downregulation and deep deletion were the most common alterations for HK1 and LAMP1 genes; resembling the results observed in the model.	('mRNA', 'MPA', (19, 23))	('LAMP1', 'Gene', (102, 107))	('downregulation', 'NegReg', (24, 38))	('deep deletion', 'Var', (43, 56))	('HK1', 'Gene', '3098', (94, 97))	('HK1', 'Gene', (94, 97))	('LAMP1', 'Gene', '3916', (102, 107))
169073	27776557	High mammographic density (HMD) is associated with a higher rate of breast cancer (BC).	('High mammographic density', 'Var', (0, 25))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('HMD', 'Disease', 'None', (27, 30))	('BC', 'Phenotype', 'HP:0003002', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HMD', 'Disease', (27, 30))
169421	22342935	This would be particularly true in cases where (PI)/tauP   (AI)/tauA, as little net cell flux from the viable rim to the necrotic core would be expected.	('necrotic', 'Disease', (121, 129))	('PI', 'Species', '9606', (48, 50))	('necrotic', 'Disease', 'MESH:D009336', (121, 129))	('PI)/tauP', 'Var', (48, 56))
169517	21318602	The three main mechanisms whereby cancers exploit normal GPCR physiology include activating mutations, such as in endocrine tumors, expression of constitutively active GPCRs by viruses, and overexpression of GPCRs, which is most common to breast cancer.	('endocrine tumors', 'Disease', 'MESH:D004701', (114, 130))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('breast cancer', 'Disease', (239, 252))	('endocrine tumors', 'Disease', (114, 130))	('GPCR', 'Gene', '441931', (208, 212))	('GPCR', 'Gene', '441931', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('GPCR', 'Gene', '441931', (168, 172))	('cancers', 'Disease', (34, 41))	('activating', 'MPA', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('overexpression', 'PosReg', (190, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('GPCR', 'Gene', (208, 212))	('GPCR', 'Gene', (57, 61))	('GPCR', 'Gene', (168, 172))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
169528	21318602	Arrestin2 and 3 are also components of the centrosome and loss of arrestin promotes centrosomal abnormalities such as an increase in centrosome number, multinucleation, and microtubule nucleation capacity.	('centrosome number', 'CPA', (133, 150))	('increase', 'PosReg', (121, 129))	('loss', 'Var', (58, 62))	('promotes', 'PosReg', (75, 83))	('centrosomal abnormalities', 'CPA', (84, 109))	('arrestin', 'Gene', (66, 74))	('multinucleation', 'CPA', (152, 167))	('microtubule nucleation capacity', 'CPA', (173, 204))	('Arrestin2 and 3', 'Gene', '408;407', (0, 15))
169529	21318602	Interestingly, it was shown that arrestin overexpression reduced, while arrestin knock-down enhanced, centrosomal defects in MDA-MB-231 breast cancer cells, suggesting the possibility that altered arrestin expression might contribute to centrosomal abnormalities and chromosomal instability often seen in breast cancer.	('centrosomal abnormalities', 'CPA', (237, 262))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('altered', 'Var', (189, 196))	('centrosomal defects', 'CPA', (102, 121))	('reduced', 'NegReg', (57, 64))	('chromosomal instability', 'Phenotype', 'HP:0040012', (267, 290))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (305, 318))	('chromosomal instability', 'CPA', (267, 290))	('contribute', 'Reg', (223, 233))	('arrestin', 'Gene', (72, 80))	('enhanced', 'PosReg', (92, 100))	('knock-down', 'Var', (81, 91))	('breast cancer', 'Disease', (305, 318))	('breast cancer', 'Disease', 'MESH:D001943', (305, 318))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (125, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))
169538	21318602	This is the first study to demonstrate that alterations in arrestin2 and 3 expression are associated with disease progression and clinical outcome and that arrestin3 expression is an independent prognostic marker of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('arrestin3', 'Gene', '407', (156, 165))	('arrestin2 and 3', 'Gene', '408;407', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('associated', 'Reg', (90, 100))	('alterations', 'Var', (44, 55))	('arrestin3', 'Gene', (156, 165))	('expression', 'MPA', (75, 85))
169585	21318602	In general, the luminal lines expressed more arrestin2 than the more aggressive basal-like lines suggesting that a loss of arrestin2 expression may affect parameters associated with invasive cancers, such as de-differentiation and increased metastatic potential.	('expression', 'MPA', (133, 143))	('de-differentiation', 'CPA', (208, 226))	('invasive cancers', 'Disease', 'MESH:D009362', (182, 198))	('affect', 'Reg', (148, 154))	('arrestin2', 'Gene', '408', (123, 132))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('arrestin2', 'Gene', '408', (45, 54))	('increased', 'PosReg', (231, 240))	('invasive cancers', 'Disease', (182, 198))	('loss', 'Var', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('arrestin2', 'Gene', (123, 132))	('metastatic potential', 'CPA', (241, 261))	('arrestin2', 'Gene', (45, 54))
169641	21318602	This finding was supported by univariate analysis, in which a 1.6-fold greater risk of breast cancer-related death was seen for patients expressing low arrestin2 as compared to high arrestin2 (P = 0.001, univariate Cox proportional hazards regression, Table 6).	('arrestin2', 'Gene', (152, 161))	('low', 'Var', (148, 151))	('arrestin2', 'Gene', '408', (182, 191))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('arrestin2', 'Gene', '408', (152, 161))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('arrestin2', 'Gene', (182, 191))	('patients', 'Species', '9606', (128, 136))
169653	21318602	Because changes in GPCR expression appear to play an important role in the development of some breast cancers, we studied whether proteins that regulate the function of GPCRs, such as arrestins, are also altered in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('changes', 'Var', (8, 15))	('GPCR', 'Gene', (169, 173))	('GPCR', 'Gene', (19, 23))	('breast cancers', 'Disease', 'MESH:D001943', (95, 109))	('breast cancers', 'Disease', (95, 109))	('breast cancer', 'Disease', (215, 228))	('GPCR', 'Gene', '441931', (169, 173))	('GPCR', 'Gene', '441931', (19, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('play', 'Reg', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('breast cancers', 'Phenotype', 'HP:0003002', (95, 109))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
169669	21318602	Based on known arrestin functions, altered arrestin-mediated regulation of cell migration, centrosome function, or MDM2 activity might contribute to the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('altered', 'Var', (35, 42))	('centrosome', 'CPA', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cell migration', 'CPA', (75, 89))	('activity', 'MPA', (120, 128))	('MDM2', 'Gene', '4193', (115, 119))	('contribute', 'Reg', (135, 145))	('MDM2', 'Gene', (115, 119))
169673	21318602	Thus, loss of arrestin2 or overexpression of arrestin3 could ultimately have similar effects on ERK1/2 activation and effects on cell growth.	('ERK1/2', 'Gene', (96, 102))	('arrestin2', 'Gene', '408', (14, 23))	('loss', 'Var', (6, 10))	('ERK1/2', 'Gene', '5595;5594', (96, 102))	('effects', 'Reg', (118, 125))	('activation', 'MPA', (103, 113))	('cell growth', 'CPA', (129, 140))	('arrestin3', 'Gene', (45, 54))	('arrestin2', 'Gene', (14, 23))	('overexpression', 'PosReg', (27, 41))	('arrestin3', 'Gene', '407', (45, 54))
169679	21318602	Arrestin3-knockout mice are defective in CXCL12-mediated lymphocyte chemotaxis and knockdown of arrestin3 attenuates CXCL12-dependent activation of p38 and cell migration in HEK293 cells.	('Arrestin3', 'Gene', (0, 9))	('Arrestin3', 'Gene', '407', (0, 9))	('attenuates', 'NegReg', (106, 116))	('CXCL12-mediated lymphocyte', 'MPA', (41, 67))	('HEK293', 'CellLine', 'CVCL:0045', (174, 180))	('CXCL12-dependent activation', 'MPA', (117, 144))	('defective', 'NegReg', (28, 37))	('arrestin3', 'Gene', '407', (96, 105))	('arrestin3', 'Gene', (96, 105))	('cell migration in HEK293 cells', 'CPA', (156, 186))	('p38', 'Pathway', (148, 151))	('knockdown', 'Var', (83, 92))	('mice', 'Species', '10090', (19, 23))
169685	21318602	Chromosomal instability is a driving force for many human cancers and often results from errors that occur during mitosis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mitosis', 'Disease', (114, 121))	('mitosis', 'Disease', 'None', (114, 121))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('cancers', 'Disease', (58, 65))	('results from', 'Reg', (76, 88))	('errors', 'Var', (89, 95))
169686	21318602	Alterations in centrosome number and function have been shown to be prevalent in cancer, often resulting in chromosomal instability, and a number of studies have demonstrated that centrosomal abnormalities are highly correlated with breast cancer progression.	('centrosome', 'Protein', (15, 25))	('chromosomal instability', 'MPA', (108, 131))	('function', 'MPA', (37, 45))	('centrosomal abnormalities', 'CPA', (180, 205))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('Alterations', 'Var', (0, 11))	('correlated with', 'Reg', (217, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('cancer', 'Disease', (81, 87))	('breast cancer', 'Disease', (233, 246))	('chromosomal instability', 'Phenotype', 'HP:0040012', (108, 131))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (240, 246))	('resulting in', 'Reg', (95, 107))
169688	21318602	Since loss of arrestin leads to centrosomal abnormalities similar to those observed in breast cancer, a decrease in arrestin2 expression in breast cancer may promote the accumulation of centrosomal abnormalities that drive tumor aggression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (87, 100))	('arrestin2', 'Gene', (116, 125))	('tumor aggression', 'Disease', (223, 239))	('arrestin2', 'Gene', '408', (116, 125))	('loss', 'Var', (6, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('promote', 'PosReg', (158, 165))	('tumor aggression', 'Disease', 'MESH:D001523', (223, 239))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('expression', 'MPA', (126, 136))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('decrease', 'NegReg', (104, 112))	('centrosomal abnormalities', 'MPA', (186, 211))	('accumulation', 'MPA', (170, 182))	('aggression', 'Phenotype', 'HP:0000718', (229, 239))	('arrestin', 'Gene', (14, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('centrosomal abnormalities', 'MPA', (32, 57))
169765	19740438	Moreover, despite some controversy about the importance of hormonal effects in the development of FIB, some reports documented increased estradiol levels in the serum of women carrying FIB lesions.	('women', 'Species', '9606', (170, 175))	('lesions', 'Var', (189, 196))	('FIB', 'Disease', (185, 188))	('estradiol levels', 'MPA', (137, 153))	('increased estradiol', 'Phenotype', 'HP:0025134', (127, 146))	('increased', 'PosReg', (127, 136))
169797	29109942	The genetic risk factors are also similar: BRCA1 and BRCA2 mutation carriers develop DCIS more frequently and at an earlier age than the general population and are significantly more likely to have occult DCIS in prophylactic mastectomies than age-matched non-carriers from autopsy studies.	('BRCA1', 'Gene', (43, 48))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('BRCA2', 'Gene', (53, 58))	('DCIS', 'Disease', (205, 209))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('develop', 'PosReg', (77, 84))	('mutation', 'Var', (59, 67))	('BRCA2', 'Gene', '675', (53, 58))	('BRCA1', 'Gene', '672', (43, 48))	('DCIS', 'Disease', (85, 89))
169810	29109942	The presence of high grade in a biopsy correlates with a higher probability of the presence of invasive disease.	('invasive disease', 'Disease', 'MESH:D009362', (95, 111))	('invasive disease', 'Disease', (95, 111))	('high grade', 'Var', (16, 26))
169850	29109942	An exome analysis of five mixed DCIS found that copy number and mutations had very high concordance levels between DCIS and IBC components in all cases.	('IBC', 'Chemical', '-', (124, 127))	('mutations', 'Var', (64, 73))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('copy number', 'Var', (48, 59))
169856	29109942	Pure DCIS shows many of the same genetic events as mixed DCIS and IBC; however, overall the number of copy number changes is lower in pure DCIS.	('IBC', 'Chemical', '-', (66, 69))	('lower', 'NegReg', (125, 130))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('pure DCIS', 'Var', (134, 143))
169859	29109942	One of the key molecular differences between DCIS and IBC is the prevalence of ERBB2 amplification.	('IBC', 'Chemical', '-', (54, 57))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('amplification', 'Var', (85, 98))
169862	29109942	In addition, HER2 positivity may be a prognostic factor in DCIS predicting recurrence as DCIS but not as invasive cancer.	('DCIS', 'Disease', (89, 93))	('DCIS', 'Disease', (59, 63))	('invasive cancer', 'Disease', (105, 120))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('invasive cancer', 'Disease', 'MESH:D009362', (105, 120))	('HER2', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('HER2', 'Gene', '2064', (13, 17))
169863	29109942	Thus, ERBB2 amplification alone may be insufficient for invasive progression and may even indicate a DCIS less likely to progress to invasion.	('ERBB2', 'Gene', '2064', (6, 11))	('amplification', 'Var', (12, 25))	('ERBB2', 'Gene', (6, 11))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))
169864	29109942	Additional genetic events may be required for progression and whatever these changes are, they not only lead to invasion, but also to a very aggressive IBC subtype, an intriguing paradox.	('changes', 'Var', (77, 84))	('invasion', 'CPA', (112, 120))	('lead to', 'Reg', (104, 111))	('IBC', 'Chemical', '-', (152, 155))	('IBC', 'Disease', (152, 155))
169865	29109942	One contributing event to invasive progression could be TP53 mutation, as studies have consistently shown that TP53 mutations are less frequent in pure DCIS (15% on average, 0-32%) than IBC (27-37%).	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', '7157', (56, 60))	('pure DCIS', 'Disease', (147, 156))	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (116, 125))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('IBC', 'Chemical', '-', (186, 189))
169866	29109942	In contrast, PIK3CA mutations appear to be similarly frequent in DCIS (24% on average, 17-55%) as to IBC (25-36%), although interestingly, several reports have noted the presence of PIK3CA mutation in the DCIS component of mixed DCIS/IBC but absent in the IBC component.	('PIK3CA', 'Gene', (13, 19))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('IBC', 'Chemical', '-', (234, 237))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (182, 188))	('PIK3CA', 'Gene', '5290', (13, 19))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('presence', 'Reg', (170, 178))	('DCIS', 'Phenotype', 'HP:0030075', (229, 233))	('IBC', 'Chemical', '-', (101, 104))	('mutations', 'Var', (20, 29))	('IBC', 'Chemical', '-', (256, 259))
169867	29109942	One study has suggested that GATA3 mutations could be more common in DCIS, though this remains to be validated in other cohorts.	('common', 'Reg', (59, 65))	('DCIS', 'Disease', (69, 73))	('GATA3', 'Gene', (29, 34))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('GATA3', 'Gene', '2625', (29, 34))	('mutations', 'Var', (35, 44))
169868	29109942	Correlations of mutation or copy number with features of DCIS have found that, similar to IBC, ER positivity is associated with PIK3CA mutation, and also GATA3 mutation.	('PIK3CA', 'Gene', '5290', (128, 134))	('mutation', 'Var', (160, 168))	('ER', 'Gene', '2099', (95, 97))	('GATA3', 'Gene', (154, 159))	('IBC', 'Chemical', '-', (90, 93))	('PIK3CA', 'Gene', (128, 134))	('GATA3', 'Gene', '2625', (154, 159))	('mutation', 'Var', (135, 143))	('associated', 'Reg', (112, 122))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
169869	29109942	TP53 mutation is associated with high grade and HER2 positivity, as well as a higher level of genomic copy number alteration.	('high grade', 'CPA', (33, 43))	('HER2', 'Gene', '2064', (48, 52))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (17, 27))	('HER2', 'Gene', (48, 52))	('mutation', 'Var', (5, 13))
169870	29109942	Genome-wide copy number changes and LOH events are more common in high-grade DCIS, with specific increases seen for loss of 17p and gains of ERBB2 and MYC.	('MYC', 'Gene', (151, 154))	('copy number changes', 'Var', (12, 31))	('increases', 'PosReg', (97, 106))	('gains', 'PosReg', (132, 137))	('17p', 'Protein', (124, 127))	('MYC', 'Gene', '4609', (151, 154))	('loss', 'NegReg', (116, 120))	('DCIS', 'Disease', (77, 81))	('ERBB2', 'Gene', '2064', (141, 146))	('ERBB2', 'Gene', (141, 146))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
169871	29109942	However, as in IBC, low-grade DCIS has frequent gain of 1q and loss of 16q.	('low-grade', 'Var', (20, 29))	('gain', 'PosReg', (48, 52))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('16q', 'Protein', (71, 74))	('IBC', 'Chemical', '-', (15, 18))	('loss', 'NegReg', (63, 67))
169875	29109942	These frequencies contrast with IBC where there is a higher proportion of triple negative (14-24%) and a lower proportion of HER2 (6-7%).	('HER2', 'Gene', (125, 129))	('HER2', 'Gene', '2064', (125, 129))	('triple negative', 'Var', (74, 89))	('IBC', 'Chemical', '-', (32, 35))	('IBC', 'Disease', (32, 35))
169891	29109942	DCIS with microinvasion are more likely to be large, detected clinically rather than through mammographic screening and to show poor prognostic factors such as high grade, comedo necrosis and ER negativity, and have a worse outcome compared to DCIS without microinvasion.	('DCIS', 'Disease', (0, 4))	('high', 'Var', (160, 164))	('necrosis', 'Disease', (179, 187))	('ER', 'Gene', '2099', (192, 194))	('microinvasion', 'Var', (10, 23))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('necrosis', 'Disease', 'MESH:D009336', (179, 187))	('DCIS', 'Phenotype', 'HP:0030075', (244, 248))	('comedo', 'Phenotype', 'HP:0025249', (172, 178))
169901	29109942	However, some of the strongest candidates also supported by more recent studies include HER2, COX2, Ki67 (>10% positive cells), and p16.	('COX2', 'Gene', '4513', (94, 98))	('p16', 'Gene', '1029', (132, 135))	('HER2', 'Gene', (88, 92))	('Ki67', 'Var', (100, 104))	('HER2', 'Gene', '2064', (88, 92))	('p16', 'Gene', (132, 135))	('COX2', 'Gene', (94, 98))
169906	29109942	A follow-up analysis by the Kerlikowske group with an additional 5 years of outcome data and 442 new cases added found that p16 positivity was associated with both local and regional/metastatic invasive recurrence.	('associated with', 'Reg', (143, 158))	('p16', 'Gene', '1029', (124, 127))	('p16', 'Gene', (124, 127))	('positivity', 'Var', (128, 138))
169907	29109942	COX2 and Ki67 were not individually predictive, but COX2 positivity added value in prediction of metastatic recurrence.	('metastatic recurrence', 'CPA', (97, 118))	('COX2', 'Gene', (0, 4))	('COX2', 'Gene', (52, 56))	('COX2', 'Gene', '4513', (0, 4))	('positivity', 'Var', (57, 67))	('COX2', 'Gene', '4513', (52, 56))
169910	29109942	One study only found COX2 positivity to be predictive of recurrence in combination with high Ki67.	('COX2', 'Gene', '4513', (21, 25))	('positivity', 'Var', (26, 36))	('COX2', 'Gene', (21, 25))
169914	29109942	One study found GATA3 mutations to be present at a higher frequency in DCIS than invasive carcinoma and did not detect a difference in recurrence rates between mutated and wild-type tumors, but could not address invasive recurrences as none occurred in the evaluated cohort.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('GATA3', 'Gene', (16, 21))	('invasive carcinoma', 'Disease', 'MESH:D009361', (81, 99))	('mutations', 'Var', (22, 31))	('DCIS', 'Disease', (71, 75))	('GATA3', 'Gene', '2625', (16, 21))	('invasive carcinoma', 'Disease', (81, 99))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
169919	29109942	HER2 positivity also is similarly more strongly related to DCIS recurrence.	('positivity', 'Var', (5, 15))	('DCIS recurrence', 'Disease', (59, 74))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('related', 'Reg', (48, 55))
169937	29109942	Neither pattern is commonly observed around normal ducts, and the stromal pattern is more frequently associated with negative prognostic features such as HER2 positivity, necrosis, higher grade or Ki67 staining and larger size.	('necrosis', 'Disease', 'MESH:D009336', (171, 179))	('positivity', 'Var', (159, 169))	('Ki67 staining', 'Var', (197, 210))	('HER2', 'Gene', (154, 158))	('higher grade', 'CPA', (181, 193))	('HER2', 'Gene', '2064', (154, 158))	('necrosis', 'Disease', (171, 179))
169940	29109942	As in IBC, stromal TILs have been associated with poor prognostic features such as comedo necrosis, high grade, large size, and ER negativity.	('comedo', 'Phenotype', 'HP:0025249', (83, 89))	('TIL', 'Gene', (19, 22))	('necrosis', 'Disease', (90, 98))	('high', 'Disease', (100, 104))	('IBC', 'Chemical', '-', (6, 9))	('ER', 'Gene', '2099', (128, 130))	('IBC', 'Disease', (6, 9))	('large', 'Var', (112, 117))	('TIL', 'Gene', '7096', (19, 22))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))
169941	29109942	Similar results have been observed with B-lymphocytes (CD19+, CD20+, or CD138+).	('CD19', 'Gene', '930', (55, 59))	('CD138+', 'Var', (72, 78))	('CD20', 'Gene', '54474', (62, 66))	('CD20', 'Gene', (62, 66))	('CD19', 'Gene', (55, 59))
169942	29109942	HER2 positivity and TP53 mutation have also been associated with elevated TIL levels.	('positivity', 'Var', (5, 15))	('TIL', 'Gene', (74, 77))	('TP53', 'Gene', (20, 24))	('associated', 'Reg', (49, 59))	('mutation', 'Var', (25, 33))	('HER2', 'Gene', (0, 4))	('TIL', 'Gene', '7096', (74, 77))	('elevated', 'PosReg', (65, 73))	('HER2', 'Gene', '2064', (0, 4))	('TP53', 'Gene', '7157', (20, 24))
169944	29109942	Recently, a combined analysis of genetic events and TILs in DCIS found that DNA copy number aberration load was positively associated with TIL levels.	('associated', 'Reg', (123, 133))	('TIL', 'Gene', (139, 142))	('DNA', 'Gene', (76, 79))	('copy number aberration load', 'Var', (80, 107))	('TIL', 'Gene', '7096', (52, 55))	('TIL', 'Gene', '7096', (139, 142))	('TIL', 'Gene', (52, 55))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
169993	24385207	Women who underwent MRI were younger, more likely to be pre/perimenopausal, more likely to have a family history of breast cancer, and more likely to present with a clinical abnormality, but were less likely to have a prior CBC.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('MRI', 'Var', (20, 23))	('present', 'Reg', (150, 157))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
170001	24385207	Within the no-RT cohort, women in the MRI group were younger, more likely to be pre/perimenopausal, and more likely to have a family history of breast cancer compared to the no-MRI group (Table 1).	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('MRI', 'Var', (38, 41))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('women', 'Species', '9606', (25, 30))
170023	24385207	In our population, women receiving MRI tended to be at higher risk for LRR, as seen in Tables 1 and 2.	('women', 'Species', '9606', (19, 24))	('LRR', 'Disease', (71, 74))	('MRI', 'Var', (35, 38))
170047	24833917	Additionally, mammographic breast density (MBD), alone or in combination with other risk factors, has been demonstrated to be associated with an increased risk of breast cancer.	('associated', 'Reg', (126, 136))	('MBD', 'Disease', 'MESH:D012080', (43, 46))	('mammographic breast', 'Var', (14, 33))	('MBD', 'Disease', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))
170060	24833917	Breast cancer risk-assessment models, such as the BRCAPRO and Tyrer-Cuzick models, also take into account BRCA-1/2 mutation carrier status.	('BRCA', 'Gene', (106, 110))	('BRCA', 'Gene', '672;675', (50, 54))	('BRCA-1/2', 'Gene', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('BRCA', 'Gene', '672;675', (106, 110))	('BRCA-1/2', 'Gene', '672;675', (106, 114))	('BRCA', 'Gene', (50, 54))	('mutation', 'Var', (115, 123))	('Breast cancer', 'Disease', (0, 13))
170129	24833917	There were fewer cases of uterine malignancies in the raloxifene group (23 cases) compared to the tamoxifen group (36 cases), although this difference was also not statistically significant.	('tamoxifen', 'Chemical', 'MESH:D013629', (98, 107))	('malignancies', 'Disease', 'MESH:D009369', (34, 46))	('uterine', 'Disease', (26, 33))	('raloxifene', 'Var', (54, 64))	('malignancies', 'Disease', (34, 46))	('raloxifene', 'Chemical', 'MESH:D020849', (54, 64))	('uterine malignancies', 'Phenotype', 'HP:0010784', (26, 46))	('fewer', 'NegReg', (11, 16))
170133	24833917	The number of hysterectomies performed for nonmalignant indications was statistically fewer in the raloxifene group (244 tamoxifen versus 111 raloxifene; RR =0.29; 95% CI: 0.30 to 0.50).	('fewer', 'NegReg', (86, 91))	('hysterectomies', 'Disease', (14, 28))	('raloxifene', 'Chemical', 'MESH:D020849', (142, 152))	('raloxifene', 'Var', (99, 109))	('tamoxifen', 'Chemical', 'MESH:D013629', (121, 130))	('raloxifene', 'Chemical', 'MESH:D020849', (99, 109))
170152	24833917	Similar to other studies, raloxifene was associated with an increased risk of fatal stroke (59 versus 39 events; HR =1.49; 95% CI: 1.00 to 2.24; absolute risk increase, 0.7 per 1,000 woman-years) and venous thromboembolism (103 versus 71 events; HR =1.44; 95% CI: 1.06 to 1.95; absolute risk increase, 1.2 per 1,000 woman-years).	('woman', 'Species', '9606', (183, 188))	('stroke', 'Disease', 'MESH:D020521', (84, 90))	('venous thromboembolism', 'Disease', 'MESH:D054556', (200, 222))	('raloxifene', 'Var', (26, 36))	('thromboembolism', 'Phenotype', 'HP:0001907', (207, 222))	('stroke', 'Phenotype', 'HP:0001297', (84, 90))	('venous thromboembolism', 'Disease', (200, 222))	('woman', 'Species', '9606', (316, 321))	('raloxifene', 'Chemical', 'MESH:D020849', (26, 36))	('stroke', 'Disease', (84, 90))
170154	24833917	A significant reduction in the incidence of ER-positive breast cancer (HR =0.19; 95% CI: 0.07 to 0.56) was reported in women assigned to 0.5 mg of lasofoxifene per day.	('lasofoxifene', 'Chemical', 'MESH:C111332', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('women', 'Species', '9606', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('0.5 mg', 'Var', (137, 143))	('breast cancer', 'Disease', (56, 69))	('ER', 'Gene', '2099', (44, 46))	('reduction', 'NegReg', (14, 23))
170165	24833917	The main side effects of AIs include arthralgia and accelerated bone resorption, and, overall, its safety profile is relatively more favorable when compared to tamoxifen.	('arthralgia', 'Phenotype', 'HP:0002829', (37, 47))	('arthralgia', 'Disease', 'MESH:D018771', (37, 47))	('tamoxifen', 'Chemical', 'MESH:D013629', (160, 169))	('AIs', 'Var', (25, 28))	('arthralgia', 'Disease', (37, 47))	('bone resorption', 'CPA', (64, 79))	('accelerated bone resorption', 'Phenotype', 'HP:0002797', (52, 79))	('accelerated', 'PosReg', (52, 63))
170176	24833917	IBIS-II is a multicenter, randomized, double-blind, placebo-controlled Phase III trial that evaluated the AI anastrozole in postmenopausal women at high risk for breast cancer (family history, atypical hyperplasia or LCIS, nulliparity or age 30 or above at first birth, mammographic opacity covering at least 50% of the breast).	('women', 'Species', '9606', (139, 144))	('hyperplasia', 'Disease', 'MESH:D006965', (202, 213))	('LCIS', 'Disease', (217, 221))	('nulliparity', 'Var', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('anastrozole', 'Chemical', 'MESH:D000077384', (109, 120))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('hyperplasia', 'Disease', (202, 213))	('breast cancer', 'Disease', (162, 175))
170180	24833917	A significant increase in the incidence of musculoskeletal events such as aches and pain, vasomotor symptoms, dryness of the eyes, and hypertension were observed in the anastrozole arm.	('hypertension', 'Phenotype', 'HP:0000822', (135, 147))	('vasomotor symptoms', 'Disease', (90, 108))	('anastrozole', 'Chemical', 'MESH:D000077384', (169, 180))	('vasomotor symptoms', 'Phenotype', 'HP:0025637', (90, 108))	('aches', 'Disease', (74, 79))	('aches', 'Disease', 'MESH:D010146', (74, 79))	('pain', 'Phenotype', 'HP:0012531', (84, 88))	('pain', 'Disease', 'MESH:D010146', (84, 88))	('pain', 'Disease', (84, 88))	('hypertension', 'Disease', 'MESH:D006973', (135, 147))	('anastrozole', 'Var', (169, 180))	('dryness of the eyes', 'Disease', 'MESH:D014987', (110, 129))	('dryness of the eyes', 'Disease', (110, 129))	('musculoskeletal events', 'Disease', (43, 65))	('hypertension', 'Disease', (135, 147))	('increase', 'PosReg', (14, 22))	('dryness of the eyes', 'Phenotype', 'HP:0001097', (110, 129))
170216	24833917	In the NSABP-P1, 19 of the 288 women who developed breast cancer had BRCA-1/2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA-1/2', 'Gene', (69, 77))	('mutations', 'Var', (78, 87))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('BRCA-1/2', 'Gene', '672;675', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('women', 'Species', '9606', (31, 36))
170217	24833917	A statistically significant effect on breast cancer risk was not observed with tamoxifen in women with BRCA-1 (RR =1.67; 95% CI: 0.32 to 10.70) or BRCA-2 (RR =0.38; 95% CI: 0.06 to 1.56) mutations.	('BRCA-1', 'Gene', (103, 109))	('BRCA-1', 'Gene', '672', (103, 109))	('BRCA-2', 'Gene', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('women', 'Species', '9606', (92, 97))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('mutations', 'Var', (187, 196))	('BRCA-2', 'Gene', '675', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (79, 88))
170232	24833917	Up to 10% of breast cancers result from specific genetic mutations in the BRCA-1, BRCA-2 (hereditary breast/ovarian cancer syndrome), CHEK2 and p53 (Li-Fraumeni syndrome), and PTEN (Cowden syndrome) genes.	('breast cancers', 'Disease', 'MESH:D001943', (13, 27))	('breast cancers', 'Disease', (13, 27))	('Cowden syndrome', 'Disease', (182, 197))	('breast cancers', 'Phenotype', 'HP:0003002', (13, 27))	('p53', 'Gene', '7157', (144, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('Li-Fraumeni syndrome', 'Disease', (149, 169))	('genetic mutations', 'Var', (49, 66))	('p53', 'Gene', (144, 147))	('BRCA-2 (hereditary breast/ovarian cancer syndrome), CHEK2', 'Disease', 'MESH:D061325', (82, 139))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (149, 169))	('PTEN', 'Gene', (176, 180))	('BRCA-1, BRCA-2', 'Disease', 'OMIM:612555', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cowden syndrome', 'Disease', 'MESH:D006223', (182, 197))	('PTEN', 'Gene', '5728', (176, 180))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('result from', 'Reg', (28, 39))
170233	24833917	Women who meet one or more of the following familial/hereditary breast cancer risk criteria should be referred to a cancer genetic counselor for further evaluation: individuals from a family with known mutations that increase their risk of breast cancer (BRCA-1, BRCA-2, CDH1, STK11, and TP53) or genes associated with breast cancer; a family history of two or more breast primaries in a single individual; two or more members with breast primaries on the same side of the family; first- or second-degree relative <=45 years of age with breast cancer; one or more primary ovarian cancers on the same side of the family; family history of male breast cancer; or one or more family members on the same side of the family with an aggressive early-onset cancer in addition to breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (643, 656))	('breast cancer', 'Disease', 'MESH:D001943', (319, 332))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Disease', (319, 332))	('ovarian cancers', 'Disease', (572, 587))	('STK11', 'Gene', '6794', (277, 282))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (580, 586))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', (779, 785))	('ovarian cancers', 'Disease', 'MESH:D010051', (572, 587))	('breast cancer', 'Phenotype', 'HP:0003002', (537, 550))	('breast cancer', 'Disease', 'MESH:D001943', (643, 656))	('cancer', 'Disease', 'MESH:D009369', (750, 756))	('cancer', 'Disease', 'MESH:D009369', (544, 550))	('cancer', 'Disease', (650, 656))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (71, 77))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (53, 77))	('cancers', 'Phenotype', 'HP:0002664', (580, 587))	('breast cancer', 'Disease', 'MESH:D001943', (537, 550))	('cancer', 'Disease', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', (537, 550))	('TP53', 'Gene', (288, 292))	('male breast cancer', 'Disease', 'MESH:D018567', (638, 656))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('CDH1', 'Gene', '999', (271, 275))	('cancer', 'Disease', 'MESH:D009369', (580, 586))	('ovarian cancers', 'Phenotype', 'HP:0100615', (572, 587))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (779, 785))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (572, 586))	('cancer', 'Disease', (750, 756))	('cancer', 'Disease', 'MESH:D009369', (650, 656))	('hereditary breast cancer', 'Disease', (53, 77))	('BRCA-1, BRCA-2', 'Disease', 'OMIM:612555', (255, 269))	('CDH1', 'Gene', (271, 275))	('STK11', 'Gene', (277, 282))	('cancer', 'Disease', (544, 550))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (772, 785))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancer', 'Disease', (772, 785))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('male breast cancer', 'Disease', (638, 656))	('breast cancer', 'Disease', (240, 253))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('breast cancer', 'Phenotype', 'HP:0003002', (319, 332))	('cancer', 'Phenotype', 'HP:0002664', (544, 550))	('TP53', 'Gene', '7157', (288, 292))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('mutations', 'Var', (202, 211))
170234	24833917	Risk-reduction surgery may be considered in women who have a strong family history of breast and/or ovarian cancer and in women with known BRCA-1/BRCA-2 mutation.	('breast and/or ovarian cancer', 'Disease', (86, 114))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (86, 114))	('BRCA-1', 'Gene', (139, 145))	('BRCA-1', 'Gene', '672', (139, 145))	('women', 'Species', '9606', (44, 49))	('women', 'Species', '9606', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('BRCA-2', 'Gene', (146, 152))	('BRCA-2', 'Gene', '675', (146, 152))	('mutation', 'Var', (153, 161))
170235	24833917	For those patients who are carriers of such high-risk mutations but desire to delay or omit risk-reduction surgery, specific guidelines for follow-up have been developed, such as annual mammography and breast magnetic resonance imaging screening, beginning at age 25 years or 10 to 15 years earlier than the younger family member with a diagnosis of breast cancer, and twice-yearly ovarian cancer screening with transvaginal ultrasound and serum CA-125 levels, beginning at age 30 years or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family.	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('breast cancer', 'Disease', 'MESH:D001943', (350, 363))	('ovarian cancer', 'Disease', 'MESH:D010051', (556, 570))	('breast cancer', 'Disease', (350, 363))	('ovarian cancer', 'Disease', (382, 396))	('mutations', 'Var', (54, 63))	('ovarian cancer', 'Disease', (556, 570))	('breast cancer', 'Phenotype', 'HP:0003002', (350, 363))	('cancer', 'Phenotype', 'HP:0002664', (564, 570))	('ovarian cancer', 'Phenotype', 'HP:0100615', (382, 396))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('ovarian cancer', 'Disease', 'MESH:D010051', (382, 396))	('ovarian cancer', 'Phenotype', 'HP:0100615', (556, 570))
170237	24833917	Several studies have demonstrated that bilateral risk-reduction mastectomy can decrease the risk of developing breast cancer by at least 90% in moderate-to-high-risk women and in known BRCA-1/2 mutation carriers.	('women', 'Species', '9606', (166, 171))	('mutation', 'Var', (194, 202))	('BRCA-1/2', 'Gene', (185, 193))	('decrease', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('BRCA-1/2', 'Gene', '672;675', (185, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))
170238	24833917	Additionally, bilateral risk-reduction salpingo-oophorectomy (RRSO) may also decrease the risk of breast cancer in BRCA-1/2 mutation carriers.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('decrease', 'NegReg', (77, 85))	('BRCA-1/2', 'Gene', (115, 123))	('mutation', 'Var', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('BRCA-1/2', 'Gene', '672;675', (115, 123))
170239	24833917	Rebbeck et al demonstrated a statistically significant reduction in breast cancer risk with RRSO in BRCA mutation carriers with an adjusted HR of 0.53 (95% CI: 0.33 to 0.84).	('mutation', 'Var', (105, 113))	('reduction', 'NegReg', (55, 64))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('BRCA', 'Gene', (100, 104))	('breast cancer', 'Disease', (68, 81))	('BRCA', 'Gene', '672;675', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
170240	24833917	In a case-control study by Eisen et al, a breast cancer risk reduction of 56% for BRCA-1 carriers (OR =0.44; 95% CI: 0.29 to 0.66) and 46% for BRCA-2 carriers (OR =0.57; 95% CI: 0.28 to 1.15) was reported.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('BRCA-2', 'Gene', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('reduction', 'NegReg', (61, 70))	('BRCA-2', 'Gene', '675', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('BRCA-1', 'Gene', (82, 88))	('BRCA-1', 'Gene', '672', (82, 88))	('carriers', 'Var', (89, 97))
170241	24833917	RRSO performed before age 40 years (OR =0.36; 95% CI: 0.20 to 0.64 for BRCA-1 carriers) was associated with a greater risk reduction than after age 40 years (OR =0.53; 95% CI: 0.30 to 0.91).	('BRCA-1', 'Gene', (71, 77))	('BRCA-1', 'Gene', '672', (71, 77))	('reduction', 'NegReg', (123, 132))	('carriers', 'Var', (78, 86))
170242	24833917	A recent meta-analysis supported the protective role of RRSO in BRCA-1/2 mutation carriers by demonstrating a statistically significant reduction in risk of breast cancer (HR =0.49; 95% CI: 0.37 to 0.65).	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('BRCA-1/2', 'Gene', '672;675', (64, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('reduction', 'NegReg', (136, 145))	('mutation', 'Var', (73, 81))	('BRCA-1/2', 'Gene', (64, 72))
170243	24833917	Similar risk reductions were observed in BRCA-1 mutation carriers (HR =0.47; 95% CI: 0.35 to 0.64) and in BRCA-2 mutation carriers (HR =0.47; 95% CI: 0.26 to 0.84).	('mutation', 'Var', (113, 121))	('BRCA-1', 'Gene', '672', (41, 47))	('BRCA-2', 'Gene', (106, 112))	('BRCA-2', 'Gene', '675', (106, 112))	('mutation', 'Var', (48, 56))	('reductions', 'NegReg', (13, 23))	('BRCA-1', 'Gene', (41, 47))
170244	24833917	In contrast, a prospective study by Kauff et al showed a greater reduction in breast cancer risk for BRCA-2 mutation carriers (HR =0.28; 95% CI: 0.08 to 0.92) compared with BRCA-1 mutation carriers (HR =0.61; 95% CI: 0.30 to 1.22).	('BRCA-2', 'Gene', '675', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('BRCA-1', 'Gene', (173, 179))	('BRCA-1', 'Gene', '672', (173, 179))	('mutation', 'Var', (108, 116))	('reduction', 'NegReg', (65, 74))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA-2', 'Gene', (101, 107))	('breast cancer', 'Disease', (78, 91))
170245	24833917	Some of the adverse effects of risk-reduction surgery include the increased probability of osteoporosis, cardiovascular disease associated with premature menopause, vasomotor symptoms that negatively affect quality of life, and psychosocial effects of prophylactic mastectomy.	('psychosocial', 'Disease', (228, 240))	('vasomotor symptoms', 'Phenotype', 'HP:0025637', (165, 183))	('cardiovascular disease', 'Disease', 'MESH:D002318', (105, 127))	('osteoporosis', 'Phenotype', 'HP:0000939', (91, 103))	('psychosocial', 'Disease', 'MESH:C535569', (228, 240))	('osteoporosis', 'Disease', 'MESH:D010024', (91, 103))	('surgery', 'Var', (46, 53))	('osteoporosis', 'Disease', (91, 103))	('cardiovascular disease', 'Disease', (105, 127))	('premature menopause', 'Phenotype', 'HP:0008209', (144, 163))	('vasomotor symptoms', 'Disease', (165, 183))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (105, 127))
170268	24833917	More modern clinical trials are investigating the chemopreventive role of agents such as lovastatin (ClinicalTrials.gov identifier: NCT00285857), atorvastatin (NCT00637481), letrozole (NCT00673335), vitamin D (NCT00976339), and insulin-like growth factor inhibitors (NCT01372644), to name a few.	('vitamin D', 'Chemical', 'MESH:D014807', (199, 208))	('NCT00976339', 'Var', (210, 221))	('NCT01372644', 'Var', (267, 278))	('insulin', 'Gene', '3630', (228, 235))	('atorvastatin', 'Chemical', 'MESH:D000069059', (146, 158))	('NCT00673335', 'Var', (185, 196))	('NCT00637481', 'Var', (160, 171))	('lovastatin', 'Chemical', 'MESH:D008148', (89, 99))	('letrozole', 'Chemical', 'MESH:D000077289', (174, 183))	('insulin', 'Gene', (228, 235))
170291	30796618	Alterations of pupil diameter reflecting cognitive state changes are thought to reflect modulation of the locus coeruleus-norepinephrine (LC-NE) system, which indexes shifts from exploration to exploitation states (Aston-Jones & Cohen,; Gilzenrat, Nieuwenhuis, Jepma, & Cohen,).	('pupil diameter', 'MPA', (15, 29))	('norepinephrine', 'Chemical', 'MESH:D009638', (122, 136))	('Alterations of pupil diameter', 'Phenotype', 'HP:0009916', (0, 29))	('Alterations', 'Var', (0, 11))
170317	24382894	Prevention of mammary tumor progression by silencing HoxA1 via intraductal injection of nanoparticle-formulated siRNA With advances in screening, the incidence of detection of premalignant breast lesions has increased in recent decades; however, treatment options remain limited to surveillance or surgical removal by lumpectomy or mastectomy.	('HoxA1', 'Gene', (53, 58))	('premalignant breast lesions', 'Disease', (176, 203))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('silencing', 'Var', (43, 52))	('HoxA1', 'Gene', '3198', (53, 58))	('tumor', 'Disease', (22, 27))	('premalignant breast lesions', 'Disease', 'MESH:D001941', (176, 203))
170320	24382894	Silencing this gene in cultured mouse or human mammary tumor spheroids resulted in increased acinar lumen formation, reduced tumor cell proliferation, and restoration of normal epithelial polarization.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('restoration', 'Reg', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('increased', 'PosReg', (83, 92))	('rat', 'Species', '10116', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('reduced', 'NegReg', (117, 124))	('human', 'Species', '9606', (41, 46))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (125, 130))	('rat', 'Species', '10116', (143, 146))	('mouse', 'Species', '10090', (32, 37))	('acinar lumen formation', 'CPA', (93, 115))	('Silencing', 'Var', (0, 9))
170332	24382894	Small interfering RNA (siRNA) has been used as a therapeutic agent in the treatment of a variety of tumor types in rodent models, including human mammary tumor xenografts in mice, and it is well-tolerated with few adverse side effects.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('human', 'Species', '9606', (140, 145))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('rat', 'Species', '10116', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Small interfering', 'Var', (0, 17))	('tumor', 'Disease', (154, 159))
170348	24382894	In female transgenic C3-SV40TAg mice, breast tumor formation progresses in a highly reproducible manner, with hyperplasia first appearing at ~ 12 weeks of age, DCIS-like lesions at ~ 16 weeks, and invasive carcinomas at 20 weeks (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('breast tumor', 'Disease', (38, 50))	('hyperplasia', 'Disease', (110, 121))	('transgenic', 'Species', '10090', (10, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('hyperplasia', 'Disease', 'MESH:D006965', (110, 121))	('breast tumor', 'Phenotype', 'HP:0100013', (38, 50))	('mice', 'Species', '10090', (32, 36))	('invasive carcinomas', 'Disease', (197, 216))	('invasive carcinomas', 'Disease', 'MESH:D009361', (197, 216))	('C3-SV40TAg', 'Var', (21, 31))	('breast tumor', 'Disease', 'MESH:D001943', (38, 50))
170359	24382894	Thus, silencing of a single gene identified by the MNI algorithm : HoxA1 : resulted in breast cancer differentiation including reconstitution of the normal tissue architecture of wild type mammary gland that is gradually lost in transgenic glands during disease progression (Fig.	('resulted in', 'Reg', (75, 86))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('transgenic', 'Species', '10090', (229, 239))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('silencing', 'Var', (6, 15))
170360	24382894	Spheroid differentiation induced by gene silencing was also accompanied by a significant reduction in the percentage of proliferating tumor cells in vitro (Fig.	('gene silencing', 'Var', (36, 50))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('reduction', 'NegReg', (89, 98))	('rat', 'Species', '10116', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Spheroid differentiation', 'CPA', (0, 24))	('tumor', 'Disease', (134, 139))
170367	24382894	Upon silencing HoxA1, we observed a major increase in the ability of both human breast tumor cell lines to organize into spheroids containing hollow central lumens under these 3D gel culture conditions (Fig.	('HoxA1', 'Gene', (15, 20))	('organize', 'CPA', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('breast tumor', 'Disease', 'MESH:D001943', (80, 92))	('silencing', 'Var', (5, 14))	('breast tumor', 'Disease', (80, 92))	('breast tumor', 'Phenotype', 'HP:0100013', (80, 92))	('human', 'Species', '9606', (74, 79))	('increase', 'PosReg', (42, 50))
170370	24382894	Analysis of DNA synthesis under these culture conditions revealed that the growth of the MDA-MB-468 cells and HCC1937 cells were reduced by 60 and 50%, respectively, upon silencing HoxA1 (Fig.3D).	('growth', 'MPA', (75, 81))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (89, 99))	('silencing', 'Var', (171, 180))	('reduced', 'NegReg', (129, 136))	('HCC1937', 'CellLine', 'CVCL:0290', (110, 117))	('HoxA1', 'Protein', (181, 186))
170372	24382894	Thus, silencing HoxA1 suppressed growth and restored differentiation, as measured by normal acinar morphology and lumen formation, to two human breast tumor cell lines.	('suppressed', 'NegReg', (22, 32))	('HoxA1', 'Gene', (16, 21))	('growth', 'MPA', (33, 39))	('breast tumor', 'Disease', (144, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast tumor', 'Disease', 'MESH:D001943', (144, 156))	('human', 'Species', '9606', (138, 143))	('silencing', 'Var', (6, 15))	('differentiation', 'MPA', (53, 68))	('breast tumor', 'Phenotype', 'HP:0100013', (144, 156))	('restored', 'PosReg', (44, 52))
170380	24382894	Cell proliferation also was lower in glands injected with siHoxA1 in vivo compared with controls, as measured by PCNA (Fig.	('PCNA', 'Gene', (113, 117))	('rat', 'Species', '10116', (12, 15))	('lower', 'NegReg', (28, 33))	('PCNA', 'Gene', '5111', (113, 117))	('siHoxA1', 'Var', (58, 65))	('Cell proliferation', 'CPA', (0, 18))
170382	24382894	Mammary tumorigenesis in C3-SV40TAg transgenic glands is also marked by progressive loss of expression of hormone receptors, most notably the estrogen receptor (ER) and progesterone receptor (PR).	('C3-SV40TAg transgenic', 'Var', (25, 46))	('hormone receptor', 'Gene', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('progesterone receptor', 'Gene', (169, 190))	('progesterone receptor', 'Gene', '18667', (169, 190))	('loss', 'NegReg', (84, 88))	('estrogen receptor', 'Gene', (142, 159))	('ER', 'Gene', '13982', (161, 163))	('transgenic', 'Species', '10090', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('PR', 'Gene', '18667', (192, 194))	('estrogen receptor', 'Gene', '13982', (142, 159))	('expression', 'MPA', (92, 102))	('hormone receptor', 'Gene', '3164', (106, 122))
170390	24382894	Activation of the MAP kinase pathway regulating cell proliferation and survival is a frequent event in tumorigenesis, and modulation of the p44/42 MAP kinase signaling pathway has previously been shown to contribute to the mechanism by which HoxA1 mediates oncogenic transformation and anchorage-independent growth in cultured human mammary tumor cells.	('modulation', 'Var', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('HoxA1', 'Gene', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('oncogenic transformation', 'CPA', (257, 281))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (341, 346))	('rat', 'Species', '10116', (60, 63))	('MAP kinase pathway', 'Pathway', (18, 36))	('human', 'Species', '9606', (327, 332))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('anchorage-independent growth', 'CPA', (286, 314))	('tumor', 'Disease', 'MESH:D009369', (341, 346))
170401	24382894	Alterations in Hox genes also have been associated with a variety of human cancers, including breast, skin, lung, prostate, and hematopoietic tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('lung', 'Disease', (108, 112))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (128, 148))	('Alterations', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('breast', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('skin', 'Disease', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('Hox genes', 'Gene', (15, 24))	('rat', 'Species', '10116', (4, 7))	('associated', 'Reg', (40, 50))	('hematopoietic tumors', 'Disease', (128, 148))	('prostate', 'Disease', (114, 122))
170404	24382894	Furthermore, we demonstrate here that silencing HoxA1 suppresses growth and induces differentiation of human breast cancer spheroids and that suppression of this gene in the early stages of the disease is associated with reduced MAPK signaling in mice, suggesting that it may also be a relevant target in human tumors that respond to MEK inhibitors.	('tumors', 'Disease', (311, 317))	('HoxA1', 'Gene', (48, 53))	('differentiation', 'CPA', (84, 99))	('silencing', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('suppression', 'NegReg', (142, 153))	('human', 'Species', '9606', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('growth', 'CPA', (65, 71))	('rat', 'Species', '10116', (23, 26))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('mice', 'Species', '10090', (247, 251))	('breast cancer', 'Disease', (109, 122))	('MAPK signaling', 'MPA', (229, 243))	('MEK', 'Gene', '5609', (334, 337))	('reduced', 'NegReg', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('induces', 'Reg', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('suppresses', 'NegReg', (54, 64))	('MEK', 'Gene', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('human', 'Species', '9606', (305, 310))
170461	24382894	Gene network reverse engineering revealed that HoxA1 is an important mediator of breast cancer progression, and silencing of HoxA1 through intraductal delivery of nanoparticle-formulated siRNA in a transgenic mouse breast cancer model prevented loss of estrogen and progesterone receptor expression, suppressed cell proliferation, and reduced mammary tumor incidence by 75%.	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Disease', (81, 94))	('estrogen', 'Protein', (253, 261))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('reduced', 'NegReg', (335, 342))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('cell proliferation', 'CPA', (311, 329))	('breast cancer', 'Disease', (215, 228))	('tumor', 'Disease', (351, 356))	('suppressed', 'NegReg', (300, 310))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('HoxA1', 'Gene', (125, 130))	('rat', 'Species', '10116', (323, 326))	('transgenic', 'Species', '10090', (198, 208))	('progesterone receptor', 'Gene', '18667', (266, 287))	('mouse', 'Species', '10090', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('progesterone receptor', 'Gene', (266, 287))	('prevented loss', 'NegReg', (235, 249))	('silencing', 'Var', (112, 121))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
170469	25604909	In addition, 3T MRI potentially could improve the conspicuity or contrast resolution of enhancing lesions compared to that seen at 1.5T, due to differential effects of higher field strength on T1 relaxation times of non-enhancing compared to gadolinium-enhancing tissue .	('3T MRI', 'Var', (13, 19))	('T1 relaxation times', 'MPA', (193, 212))	('improve', 'PosReg', (38, 45))	('MRI', 'Var', (16, 19))	('gadolinium', 'Chemical', 'MESH:D005682', (242, 252))	('contrast resolution', 'CPA', (65, 84))	('conspicuity', 'MPA', (50, 61))
170490	25604909	Gadolinium contrast-material dose and delivery was the same for both protocols: 0.1 mmol/kg at 2 cc/sec followed by a 15 cc saline flush.	('flush', 'Disease', (131, 136))	('0.1', 'Var', (80, 83))	('flush', 'Disease', 'MESH:D005483', (131, 136))	('flush', 'Phenotype', 'HP:0031284', (131, 136))	('saline', 'Chemical', 'MESH:D012965', (124, 130))	('Gadolinium', 'Chemical', 'MESH:D005682', (0, 10))
170517	24121271	Here we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression.	('ErbB2', 'Gene', (43, 48))	('RB', 'Chemical', 'MESH:D012413', (53, 55))	('deregulation', 'Var', (56, 68))	('ErbB2', 'Gene', '2064', (43, 48))
170519	24121271	An increase in the invasive potential of ErbB2 over expressing cells was observed upon RB depletion.	('ErbB2', 'Gene', (41, 46))	('RB', 'Chemical', 'MESH:D012413', (87, 89))	('invasive potential', 'CPA', (19, 37))	('depletion', 'Var', (90, 99))	('ErbB2', 'Gene', '2064', (41, 46))	('increase', 'PosReg', (3, 11))
170520	24121271	Furthermore, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared to DCIS-like lesions developing from RB-proficient cells.	('RB', 'Chemical', 'MESH:D012413', (33, 35))	('resulted in', 'Reg', (36, 47))	('RB', 'Chemical', 'MESH:D012413', (143, 145))	('invasive lesions', 'CPA', (48, 64))	('knockdown', 'Var', (20, 29))
170562	24121271	These data revealed a significant number of genes that were reproducibly up and down regulated with RB depletion (Supplemental Table 1).	('RB', 'Chemical', 'MESH:D012413', (100, 102))	('down', 'NegReg', (80, 84))	('depletion', 'Var', (103, 112))
170564	24121271	The data from the combined deregulation of the ErbB2- and RB-pathways showed a strong overlap (p<1E-5) with this EMT core signature (Figure 2C, middle panel) and revealed a significant decrease in the expression of multiple epithelial markers (KRT18, KRT15, KRT17) and structural and cell adhesion molecules important for epithelial architecture (ITGB4, JUP, DSG1, SFN) (Figure 2C, right panel).	('KRT15', 'Gene', '3866', (251, 256))	('expression', 'MPA', (201, 211))	('KRT17', 'Gene', '3872', (258, 263))	('JUP', 'Gene', '3728', (354, 357))	('ITGB4', 'Gene', '3691', (347, 352))	('JUP', 'Gene', (354, 357))	('SFN', 'Gene', '25996', (365, 368))	('ErbB2', 'Gene', '2064', (47, 52))	('RB', 'Chemical', 'MESH:D012413', (58, 60))	('RB-pathways', 'Gene', (58, 69))	('KRT15', 'Gene', (251, 256))	('ITGB4', 'Gene', (347, 352))	('deregulation', 'Var', (27, 39))	('KRT17', 'Gene', (258, 263))	('DSG1', 'Gene', (359, 363))	('decrease', 'NegReg', (185, 193))	('SFN', 'Gene', (365, 368))	('ErbB2', 'Gene', (47, 52))	('KRT18', 'Gene', '3875', (244, 249))	('KRT18', 'Gene', (244, 249))	('DSG1', 'Gene', '1828', (359, 363))
170572	24121271	While loss of RB or over expression of ErbB2 alone was observed to increase the migratory ability of MCF10A cells, the combined deregulation of the ErbB2- and RB-pathways demonstrated a cooperative enhancement of cell migration (Figure 4A).	('cell migration', 'CPA', (213, 227))	('loss', 'Var', (6, 10))	('deregulation', 'Var', (128, 140))	('ErbB2', 'Gene', '2064', (39, 44))	('over expression', 'PosReg', (20, 35))	('increase', 'PosReg', (67, 75))	('enhancement', 'PosReg', (198, 209))	('ErbB2', 'Gene', (148, 153))	('MCF10A', 'CellLine', 'CVCL:0598', (101, 107))	('RB', 'Chemical', 'MESH:D012413', (14, 16))	('ErbB2', 'Gene', '2064', (148, 153))	('RB-pathways', 'Pathway', (159, 170))	('RB', 'Chemical', 'MESH:D012413', (159, 161))	('migratory ability', 'CPA', (80, 97))	('ErbB2', 'Gene', (39, 44))
170574	24121271	Furthermore, combined deregulation of the ErbB2- and RB-pathways resulted in an ~2-fold increase in cell invasion over ErbB2 over expression alone.	('RB-pathways', 'Pathway', (53, 64))	('RB', 'Chemical', 'MESH:D012413', (53, 55))	('ErbB2', 'Gene', (119, 124))	('ErbB2', 'Gene', (42, 47))	('increase', 'PosReg', (88, 96))	('cell invasion', 'CPA', (100, 113))	('ErbB2', 'Gene', '2064', (119, 124))	('ErbB2', 'Gene', '2064', (42, 47))	('deregulation', 'Var', (22, 34))
170584	24121271	The ability of PD0332991 to decrease RB/E2F gene expression and inhibit cell proliferation in MCF10A cells has been previously established.	('RB', 'Chemical', 'MESH:D012413', (37, 39))	('MCF10A', 'CellLine', 'CVCL:0598', (94, 100))	('PD0332991', 'Chemical', 'MESH:C500026', (15, 24))	('expression', 'MPA', (49, 59))	('inhibit', 'NegReg', (64, 71))	('cell proliferation', 'CPA', (72, 90))	('RB/E2F gene', 'Gene', (37, 48))	('decrease', 'NegReg', (28, 36))	('PD0332991', 'Var', (15, 24))
170585	24121271	As shown in Figure 5A, inhibition of CDK4/6 was exceedingly effective at repressing RB/E2F gene expression (MCM7, Cyclin A, PCNA) and cell proliferation even in cells harboring ErbB2 over expression.	('cell proliferation', 'CPA', (134, 152))	('Cyclin A', 'Gene', (114, 122))	('ErbB2', 'Gene', (177, 182))	('RB', 'Chemical', 'MESH:D012413', (84, 86))	('MCM7', 'Gene', '4176', (108, 112))	('CDK4/6', 'Gene', (37, 43))	('inhibition', 'Var', (23, 33))	('repressing', 'NegReg', (73, 83))	('expression', 'MPA', (96, 106))	('ErbB2', 'Gene', '2064', (177, 182))	('MCM7', 'Gene', (108, 112))	('RB/E2F gene', 'Gene', (84, 95))	('PCNA', 'Gene', (124, 128))	('Cyclin A', 'Gene', '890', (114, 122))	('CDK4/6', 'Gene', '1019;1021', (37, 43))	('PCNA', 'Gene', '5111', (124, 128))
170586	24121271	Interestingly, CDK4/6 inhibition was also effective at preventing the formation of multi-acini structures in 3D culture (Figure 5B, left panel), and significantly inhibited cell invasion (Figure 5B, right panel).	('inhibition', 'Var', (22, 32))	('preventing', 'NegReg', (55, 65))	('CDK4/6', 'Gene', (15, 21))	('cell invasion', 'CPA', (173, 186))	('inhibited', 'NegReg', (163, 172))	('formation of multi-acini structures in 3D culture', 'CPA', (70, 119))	('CDK4/6', 'Gene', '1019;1021', (15, 21))
170587	24121271	These effects were dependent on RB status as shown by the minimal effect of PD0332991 on invasive phenotype of RB-deficient cells (Figure 5B, right panel).	('RB', 'Chemical', 'MESH:D012413', (111, 113))	('RB-deficient', 'Disease', 'MESH:D012175', (111, 123))	('RB', 'Chemical', 'MESH:D012413', (32, 34))	('PD0332991', 'Chemical', 'MESH:C500026', (76, 85))	('PD0332991', 'Var', (76, 85))	('RB-deficient', 'Disease', (111, 123))
170589	24121271	Indeed, CDK4/6 inhibition significantly decreased RB/E2F target gene expression, as well as cell proliferation of BT474 cells in both 2D and 3D culture (Figure 5C).	('RB', 'Chemical', 'MESH:D012413', (50, 52))	('CDK4/6', 'Gene', (8, 14))	('RB/E2F target gene', 'Gene', (50, 68))	('expression', 'MPA', (69, 79))	('CDK4/6', 'Gene', '1019;1021', (8, 14))	('cell proliferation', 'CPA', (92, 110))	('decreased', 'NegReg', (40, 49))	('inhibition', 'Var', (15, 25))
170590	24121271	Importantly, PD-0332991 treatment dramatically inhibited the formation of abnormal acini structures, and repressed cell invasion in an RB dependent manner (Figure 5D).	('PD-0332991', 'Var', (13, 23))	('inhibited', 'NegReg', (47, 56))	('formation of abnormal acini structures', 'CPA', (61, 99))	('PD-0332991', 'Chemical', 'MESH:C500026', (13, 23))	('cell invasion', 'CPA', (115, 128))	('RB', 'Chemical', 'MESH:D012413', (135, 137))
170607	24121271	These data, suggest that loss of RB can contribute to the function of ErbB2 in driving disease progression.	('RB', 'Chemical', 'MESH:D012413', (33, 35))	('loss', 'Var', (25, 29))	('function', 'MPA', (58, 66))	('ErbB2', 'Gene', (70, 75))	('ErbB2', 'Gene', '2064', (70, 75))
170621	24121271	ErbB2 is noted for promoting proliferation and invasion; however, invasive effects were strongly augmented by RB knockdown in 3D culture and Boyden chamber assays.	('invasive effects', 'CPA', (66, 82))	('ErbB2', 'Gene', (0, 5))	('proliferation', 'CPA', (29, 42))	('invasion', 'CPA', (47, 55))	('augmented', 'PosReg', (97, 106))	('promoting', 'PosReg', (19, 28))	('ErbB2', 'Gene', '2064', (0, 5))	('knockdown', 'Var', (113, 122))	('RB', 'Chemical', 'MESH:D012413', (110, 112))
170627	24121271	However, in ErbB2 positive DCIS, RB loss was associated with further increased risk of recurrence but uniquely invasive progression.	('ErbB2', 'Gene', (12, 17))	('ErbB2', 'Gene', '2064', (12, 17))	('positive', 'Var', (18, 26))	('RB loss', 'Disease', (33, 40))	('RB loss', 'Disease', 'MESH:D012175', (33, 40))
170632	24121271	In the present study, exposure to the CDK4/6 inhibitor PD-0332991 induced a potent cell cycle arrest among RB-proficient, ErbB2 positive cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ErbB2', 'Gene', (122, 127))	('PD-0332991', 'Var', (55, 65))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('CDK4/6', 'Gene', '1019;1021', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('ErbB2', 'Gene', '2064', (122, 127))	('arrest', 'Disease', (94, 100))	('cancer', 'Disease', (137, 143))	('CDK4/6', 'Gene', (38, 44))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('PD-0332991', 'Chemical', 'MESH:C500026', (55, 65))	('RB', 'Chemical', 'MESH:D012413', (107, 109))
170634	24121271	Treatment with PD-0332991 inhibited the invasive properties of ErbB2-positive models in Boyden chamber and 3D culture, which was largely dependent on RB.	('PD-0332991', 'Chemical', 'MESH:C500026', (15, 25))	('inhibited', 'NegReg', (26, 35))	('RB', 'Chemical', 'MESH:D012413', (150, 152))	('ErbB2', 'Gene', (63, 68))	('PD-0332991', 'Var', (15, 25))	('invasive properties of', 'CPA', (40, 62))	('ErbB2', 'Gene', '2064', (63, 68))
170635	24121271	Presently, PD-0332991 is undergoing phase II/III evaluation in ER positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PD-0332991', 'Var', (11, 21))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('PD-0332991', 'Chemical', 'MESH:C500026', (11, 21))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
170636	24121271	Thus, for women presenting with Erb2 positive disease PD-0332991 could represent a means to both repress cell proliferation and invasion associated with progression to advanced disease.	('PD-0332991', 'Chemical', 'MESH:C500026', (54, 64))	('Erb2', 'Gene', (32, 36))	('repress', 'NegReg', (97, 104))	('women', 'Species', '9606', (10, 15))	('PD-0332991', 'Var', (54, 64))	('invasion', 'CPA', (128, 136))	('cell proliferation', 'CPA', (105, 123))
170637	24121271	The present study demonstrates that loss of RB function can have a significant impact in disease progression in ErbB2 positive breast cancer by disrupting normal epithelial cell architecture and organization.	('ErbB2', 'Gene', (112, 117))	('RB', 'Chemical', 'MESH:D012413', (44, 46))	('disrupting', 'NegReg', (144, 154))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('ErbB2', 'Gene', '2064', (112, 117))	('loss', 'Var', (36, 40))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('impact', 'Reg', (79, 85))
170638	24121271	Additional studies with independent DCIS cohorts are needed to further validate the prognostic value of RB-pathway disruption in ErbB2 over expressing DCIS cases.	('ErbB2', 'Gene', (129, 134))	('ErbB2', 'Gene', '2064', (129, 134))	('over expressing', 'PosReg', (135, 150))	('RB', 'Chemical', 'MESH:D012413', (104, 106))	('disruption', 'Var', (115, 125))
170689	24996968	Interestingly, PGP 9.5 expression was significantly associated with higher MVD in the ER-negative (p = 0.045) and node-negative (p = 0.039) subgroups of IDC of the breast.	('ER', 'Gene', '2099', (86, 88))	('higher', 'PosReg', (68, 74))	('IDC', 'Disease', (153, 156))	('expression', 'Var', (23, 33))	('PGP 9.5', 'Gene', '7345', (15, 22))	('MVD', 'MPA', (75, 78))	('PGP 9.5', 'Gene', (15, 22))
170739	24996968	Intriguingly, analysis of subgroups of ER and node status revealed that moderate/strong expression of PGP 9.5 was significantly associated with higher MVD in the ER-negative (p = 0.045) and node-negative (p = 0.039) subgroups.	('moderate/strong', 'Var', (72, 87))	('PGP 9.5', 'Gene', (102, 109))	('ER', 'Gene', '2099', (39, 41))	('higher', 'PosReg', (144, 150))	('ER', 'Gene', '2099', (162, 164))	('PGP 9.5', 'Gene', '7345', (102, 109))	('MVD', 'MPA', (151, 154))
170858	23451156	Subsequently, we also investigated the AKAP4 surface expression in live breast cancer cells by flow cytometry which revealed a distinct shift of fluorescence on X-axis (blue histogram) indicating AKAP4 protein localization on the surface of the cells as shown in Figure 1D.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('fluorescence', 'MPA', (145, 157))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('AKAP4', 'Var', (196, 201))
170879	23451156	The absorbance value of mean +2SD of healthy normal female's sera was used as cut-off value (absorbance = 0.308) above which patient's sera were considered positive for anti-AKAP4 antibodies.	('anti-AKAP4', 'Var', (169, 179))	('positive', 'Reg', (156, 164))	('patient', 'Species', '9606', (125, 132))
170880	23451156	Our data indicated the presence of circulating anti-AKAP4 antibodies in 79% (79/91) of the breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('anti-AKAP4', 'Var', (47, 57))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
170885	23451156	Anti-AKAP4 antibodies were found in majority of patients with early stage (81%) as well as late stage breast cancer (77%) (Table 1).	('breast cancer', 'Disease', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('Anti-AKAP4', 'Var', (0, 10))	('found', 'Reg', (27, 32))	('patients', 'Species', '9606', (48, 56))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
170886	23451156	Similarly, in different grades, anti-AKAP4 antibodies were detected in majority of grade 1 (77%), grade 2 (81%) and grade 3 (88%) cancer patients with mean titers of 0.66+-0.05, 0.80+-0.08, and 0.63+-0.08 respectively (Figure S3B).	('detected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('anti-AKAP4', 'Var', (32, 42))	('cancer', 'Disease', (130, 136))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
170895	23451156	Although, high titers of anti-AKAP4 antibody (>0.75) were clearly indicative of high AKAP4 protein expression (>25% AKAP4 IRS), however vice-versa did not hold true for all patients.	('AKAP4 protein expression', 'MPA', (85, 109))	('anti-AKAP4', 'Var', (25, 35))	('patients', 'Species', '9606', (173, 181))
170916	23451156	It is noteworthy that, cancer is a complex disease involving alterations at the gene, RNA and protein level.	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('alterations', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('rat', 'Species', '10116', (65, 68))
170927	23451156	Some of the breast cancer serum antigens such as CA 15-3 and CA 27.29 are elevated in less than 10% of early-disease patients.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('CA 15-3', 'Var', (49, 56))	('elevated', 'PosReg', (74, 82))	('CA 27.29', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('patients', 'Species', '9606', (117, 125))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
170931	23451156	A recent study in primary breast cancer patients demonstrated auto-antibodies against a panel of tumor associated antigens including p53 (24%), c-myc (13%), BRCA1 (8%), BRCA2 (34%), and MUC1 (20%) by ELISA.	('breast cancer', 'Disease', (26, 39))	('BRCA2', 'Gene', (169, 174))	('c-myc', 'Gene', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('auto-antibodies', 'Var', (62, 77))	('rat', 'Species', '10116', (56, 59))	('tumor', 'Disease', (97, 102))	('BRCA2', 'Gene', '675', (169, 174))	('p53', 'Gene', '7157', (133, 136))	('c-myc', 'Gene', '4609', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MUC1', 'Gene', (186, 190))	('MUC1', 'Gene', '4582', (186, 190))	('p53', 'Gene', (133, 136))	('BRCA1', 'Gene', '672', (157, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('BRCA1', 'Gene', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('patients', 'Species', '9606', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
170934	23451156	In this regard, our investigation on CT-X antigen AKAP4 revealed that AKAP4 was immunogenic and generated humoral response in majority of breast cancer patients, as compared to healthy donors (P<0.001, Pearson's Chi-square test).	('AKAP4', 'Var', (70, 75))	('CT-X', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('humoral response', 'MPA', (106, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('generated', 'PosReg', (96, 105))	('breast cancer', 'Disease', (138, 151))	('donor', 'Species', '9606', (185, 190))	('CT-X', 'Gene', '1593', (37, 41))	('rat', 'Species', '10116', (100, 103))	('patients', 'Species', '9606', (152, 160))	('CT', 'Phenotype', 'HP:0010788', (37, 39))
170939	23451156	Therefore, our findings of anti-AKAP4 antibodies in 79% of breast cancer patients are important from a clinical standpoint to develop novel assays for early diagnosis, and effective disease management.	('clinical', 'Species', '191496', (103, 111))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('anti-AKAP4', 'Var', (27, 37))	('patients', 'Species', '9606', (73, 81))
171006	33807205	The visual analysis of the parametric maps showed that tumors were consistently characterized by high signal intensity Sb700 in the b = 700 s/mm2 images, i.e., hindered diffusivity associated with a low mean size E[Diso], and a high mean shape E[D 2] corresponding to bin1, as shown on Figure 4.	('high', 'PosReg', (97, 101))	('Sb700', 'Chemical', '-', (119, 124))	('Sb700', 'Var', (119, 124))	('bin1', 'Gene', '274', (268, 272))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('bin1', 'Gene', (268, 272))	('low', 'NegReg', (199, 202))	('tumors', 'Disease', (55, 61))	('hindered', 'NegReg', (160, 168))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('E[Diso]', 'MPA', (213, 220))	('diffusivity', 'MPA', (169, 180))
171009	33807205	The whole tumor ROI histogram analysis of the DTD-derived maps for the tumors exhibited the mean diffusion tensor shape E[D 2] = 0.47 +- 0.15 and the mean diffusion tensor size E[Diso] = (1.43 +- 0.54) x 10-3 mm2/s, corresponding to a preponderance of elongated cells, as captured by the signal fraction of bin1, fbin1 = 0.53 +- 0.27.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('bin1', 'Gene', '274', (307, 311))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('E[D', 'Var', (120, 123))	('bin1', 'Gene', '274', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', (71, 76))	('bin1', 'Gene', (307, 311))	('E[Diso]', 'Var', (177, 184))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('diffusion', 'MPA', (97, 106))	('bin1', 'Gene', (314, 318))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
171062	32203210	Higher abundance of TILs subtypes was associated with higher tumour grade, hormone receptor negativity and HER2 positivity.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('hormone receptor', 'Gene', (75, 91))	('HER2', 'Gene', '2064', (107, 111))	('hormone receptor', 'Gene', '3164', (75, 91))	('tumour', 'Disease', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('HER2', 'Gene', (107, 111))	('positivity', 'Var', (112, 122))
171063	32203210	Mutant TP53 variants were associated with higher levels of stromal CD3+, CD4+ and FOXP3+ cells.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('CD3', 'Gene', '397455', (67, 70))	('higher', 'PosReg', (42, 48))	('variants', 'Var', (12, 20))	('CD3', 'Gene', (67, 70))	('Mutant', 'Var', (0, 6))	('FOXP3+ cells', 'MPA', (82, 94))
171066	32203210	Different stromal and intratumoural lymphocyte composition between pure DCIS, DCIS associated with IBC and invasive carcinoma play a potential role in their prognostic significance and related to the underlying genomic instability.	('IBC', 'Disease', (99, 102))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('invasive carcinoma', 'Disease', (107, 125))	('associated', 'Reg', (83, 93))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('tumour', 'Disease', (27, 33))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('pure', 'Var', (67, 71))	('invasive carcinoma', 'Disease', 'MESH:D009361', (107, 125))
171075	32203210	The role of TILs in invasive breast cancer (IBC) is well validated, with a high TILs density associated with better response to adjuvant or neoadjuvant therapy and favourable outcome especially in triple negative (TNBC) and HER2+ subtypes.	('high', 'Var', (75, 79))	('invasive breast cancer', 'Disease', 'MESH:D001943', (20, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('better', 'PosReg', (109, 115))	('triple negative', 'Disease', (197, 212))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('HER2', 'Gene', '2064', (224, 228))	('HER2', 'Gene', (224, 228))	('invasive breast cancer', 'Disease', (20, 42))
171080	32203210	We also investigated the relationship between genomic copy number alteration and TP53 variants (as measures of genomic instability) with immune cell infiltration in a subset of cases.	('variants', 'Var', (86, 94))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('investigated', 'Reg', (8, 20))
171099	32203210	In addition, the average number of intratumour TILs per duct was counted for CD20, CD3, CD4, CD8, FOXP3 and PD1.	('FOXP3', 'Gene', (98, 103))	('CD3', 'Gene', '397455', (83, 86))	('CD20', 'Gene', (77, 81))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('CD3', 'Gene', (83, 86))	('CD4', 'Var', (88, 91))	('CD8', 'Gene', (93, 96))	('CD8', 'Gene', '925', (93, 96))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('CD20', 'Gene', '54474', (77, 81))
171112	32203210	Somatic mutations were identified by removing previously available germline variant data for hereditary breast and ovarian cancer panel genes and by applying the following filters; canonical transcript; bidirectional read; quality >= 100; variants identified by at least two variant callers; minor allele frequency (MAF) present at <=0.0001 in ExAc (Version 0.3.1, excluding TCGA data), GnomAD (Version 2.0), EVS (Version ESP6500SI-V2-SSA137) [Exome Variant Server, available http://evs.gs.washington.edu/EVS/], and 1000 Genomes databases.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (93, 129))	('GnomAD', 'Disease', 'None', (387, 393))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('GnomAD', 'Disease', (387, 393))	('variants', 'Var', (239, 247))
171115	32203210	Twenty cases showed deleterious/missense TP53 variants annotated as described above.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('variants', 'Var', (46, 54))
171118	32203210	Mann-Whitney U test and Kruskal-Wallis test were used to compare between TILs densities and FGA, NTAI and TP53 variants.	('FGA', 'Gene', (92, 95))	('NTAI', 'Gene', (97, 101))	('variants', 'Var', (111, 119))	('NTAI', 'Chemical', '-', (97, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
171133	32203210	The exceptions were intratumoural CD20+ cells, which were associated with ER and PR positivity, and intratumoural CD3+, CD8+ and CD4+, which showed no association with ER or PR.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('CD3', 'Gene', '397455', (114, 117))	('CD20', 'Gene', '54474', (34, 38))	('associated', 'Reg', (58, 68))	('ER', 'Gene', '2069', (168, 170))	('CD8', 'Gene', (120, 123))	('ER', 'Gene', '2069', (74, 76))	('tumour', 'Disease', (105, 111))	('CD8', 'Gene', '925', (120, 123))	('CD20', 'Gene', (34, 38))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('CD3', 'Gene', (114, 117))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('PR', 'Gene', '5241', (81, 83))	('PR', 'Gene', '5241', (174, 176))	('CD4+', 'Var', (129, 133))	('tumour', 'Disease', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
171134	32203210	High expression of all markers within the stroma, and intratumoural expression of PD1 and FOXP3, was associated with higher nuclear grade, HER2 positivity, and higher expression of HIF-1alpha.	('expression', 'MPA', (5, 15))	('expression', 'MPA', (167, 177))	('HER2', 'Gene', (139, 143))	('positivity', 'Var', (144, 154))	('HIF-1alpha', 'Gene', '3091', (181, 191))	('FOXP3', 'Gene', (90, 95))	('PD1', 'Gene', (82, 85))	('HER2', 'Gene', '2064', (139, 143))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('higher', 'PosReg', (117, 123))	('HIF-1alpha', 'Gene', (181, 191))	('tumour', 'Disease', (59, 65))	('nuclear grade', 'CPA', (124, 137))	('tumour', 'Disease', 'MESH:D009369', (59, 65))
171137	32203210	Higher FGA was associated with higher tumour grade (p = 0.002), presence of comedo type necrosis (p = 0.0003), ER negativity (p = 0.009), HER2 positivity (p = 0.0003) and presence of at least one deleterious/missense TP53 variant (p < 0.0001); (Supplementary Fig.	('ER', 'Gene', '2069', (111, 113))	('ER', 'Gene', '2069', (139, 141))	('necrosis', 'Disease', 'MESH:D009336', (88, 96))	('TP53', 'Gene', '7157', (217, 221))	('HER2', 'Gene', '2064', (138, 142))	('positivity', 'Var', (143, 153))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', (217, 221))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('necrosis', 'Disease', (88, 96))	('tumour', 'Disease', (38, 44))	('HER2', 'Gene', (138, 142))	('comedo', 'Phenotype', 'HP:0025249', (76, 82))
171138	32203210	Additionally, a higher NTAI was associated with high grade DCIS (p = 0.008), presence of comedo type necrosis (p = 0.006), HER2 positivity (p = 0.03), and with presence of deleterious/missense TP53 variants (p = 0.002).	('NTAI', 'Chemical', '-', (23, 27))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('TP53', 'Gene', '7157', (193, 197))	('necrosis', 'Disease', (101, 109))	('HER2', 'Gene', (123, 127))	('TP53', 'Gene', (193, 197))	('deleterious/missense', 'Var', (172, 192))	('HER2', 'Gene', '2064', (123, 127))	('variants', 'Var', (198, 206))	('necrosis', 'Disease', 'MESH:D009336', (101, 109))	('comedo', 'Phenotype', 'HP:0025249', (89, 95))	('NTAI', 'MPA', (23, 27))	('high grade DCIS', 'Disease', (48, 63))
171141	32203210	However, tumours carrying somatic deleterious/missense TP53 variants showed higher counts of stromal CD3+ (p = 0.031), CD4+ (p = 0.04), and FOXP3+ (p = 0.02); (Fig.	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('CD3', 'Gene', (101, 104))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('tumours', 'Disease', (9, 16))	('CD4+', 'MPA', (119, 123))	('CD3', 'Gene', '397455', (101, 104))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('FOXP3+', 'MPA', (140, 146))	('higher', 'PosReg', (76, 82))	('variants', 'Var', (60, 68))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
171144	32203210	Outcome analysis in context of various intrinsic molecular subtypes revealed that high expression of stromal FOXP3 was associated with shorter LRFI in luminal A subtype (HR = 2.9, 95%CI = 1.1-8.1, p = 0.032) while higher PDL1 expression in stromal TILs was associated with shorter LRFI in luminal A (HR = 7.1, 95%CI = 2.9-12.2, p < 0.0001) and showing a trend of poor prognosis in luminal B (HR = 3.2, 95%CI = 0.9-8.9, p = 0.067) and HER2 enriched (HR = 1.8, 95%CI = 0.5-7.5, p = 0.080) subtypes.	('higher', 'PosReg', (214, 220))	('HER2', 'Gene', (434, 438))	('high', 'Var', (82, 86))	('LRFI', 'MPA', (281, 285))	('HER2', 'Gene', '2064', (434, 438))	('LRFI', 'MPA', (143, 147))	('PDL1', 'Gene', (221, 225))	('stromal', 'Gene', (101, 108))	('shorter', 'NegReg', (135, 142))	('FOXP3', 'Gene', (109, 114))
171146	32203210	Moreover, high TILs density and high stromal PDL1+ expression could categorise high risk DCIS defined as high grade DCIS and >15 mm in size into two distinct groups with different outcome; whereas high TILs and stromal PDL1 + cells were associated with shorter LRFI in these patients (HR = 3.2, 95%CI = 1.1-9.5, p = 0.039, and HR = 2.5, 95%CI = 1.1-6.3, p = 0.044, respectively) (Supplementary Fig.	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('high', 'Var', (197, 201))	('patients', 'Species', '9606', (275, 283))	('LRFI', 'CPA', (261, 265))	('shorter', 'NegReg', (253, 260))	('DCIS', 'Phenotype', 'HP:0030075', (116, 120))
171155	32203210	This suppressive environment appears to be particularly important for differentiating outcome in luminal A tumours, in which both FOXP3+ and PDL1+ were associated with poor outcome.	('PDL1+', 'Var', (141, 146))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('luminal A tumours', 'Disease', 'MESH:D009369', (97, 114))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('FOXP3+', 'Var', (130, 136))	('associated', 'Reg', (152, 162))	('luminal A tumours', 'Disease', (97, 114))
171158	32203210	High expression of PDL1 is associated with a poorer outcome in pancreatic cancer, renal cell carcinoma and breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('pancreatic cancer', 'Disease', (63, 80))	('PDL1', 'Gene', (19, 23))	('High expression', 'Var', (0, 15))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('renal cell carcinoma and breast cancer', 'Disease', 'MESH:D001943', (82, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
171159	32203210	Similarly, high expression of PD1 is associated with poorer outcome in renal cell carcinoma and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('renal cell carcinoma and breast cancer', 'Disease', 'MESH:D001943', (71, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('PD1', 'Gene', (30, 33))
171161	32203210	Another mechanism that might be at play is the upregulation of the PI3K pathway due to loss of PTEN or mutation of PIK3CA which ultimately leads to upregulation of PDL1.	('loss of PTEN', 'Disease', 'MESH:D006223', (87, 99))	('upregulation', 'PosReg', (148, 160))	('PIK3CA', 'Gene', (115, 121))	('PI3K pathway', 'Pathway', (67, 79))	('upregulation', 'PosReg', (47, 59))	('loss of PTEN', 'Disease', (87, 99))	('mutation', 'Var', (103, 111))	('PDL1', 'Protein', (164, 168))	('PIK3CA', 'Gene', '5290', (115, 121))
171167	32203210	Our findings regarding the significant association of the stromal immune markers with higher grade, HER2 positivity and hormone receptor negativity has been reported previously in DCIS and IBC.	('hormone receptor', 'Gene', (120, 136))	('hormone receptor', 'Gene', '3164', (120, 136))	('HER2', 'Gene', (100, 104))	('DCIS', 'Disease', (180, 184))	('DCIS', 'Phenotype', 'HP:0030075', (180, 184))	('IBC', 'Disease', (189, 192))	('positivity', 'Var', (105, 115))	('HER2', 'Gene', '2064', (100, 104))
171179	32203210	As expected, in our study high risk DCIS (high grade, comedo type necrosis, hormonal receptor negativity and HER2 positivity) showed a higher degree of genomic instability represented by an increased burden chromosomal gains and losses and the presence of deleterious/missense TP53 mutations.	('genomic instability', 'MPA', (152, 171))	('HER2', 'Gene', (109, 113))	('deleterious/missense', 'Var', (256, 276))	('presence', 'Reg', (244, 252))	('necrosis', 'Disease', (66, 74))	('comedo', 'Phenotype', 'HP:0025249', (54, 60))	('HER2', 'Gene', '2064', (109, 113))	('losses', 'NegReg', (229, 235))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('TP53', 'Gene', '7157', (277, 281))	('TP53', 'Gene', (277, 281))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))	('mutations', 'Var', (282, 291))
171180	32203210	In general, genomic instability leading to high risk DCIS lesions might promote T cell activation (CD3 and CD4) and recruitment of regulatory T cells (FOXP3) as suggested by our data.	('genomic instability', 'Var', (12, 31))	('CD3', 'Gene', (99, 102))	('activation', 'PosReg', (87, 97))	('promote', 'PosReg', (72, 79))	('CD3', 'Gene', '397455', (99, 102))	('T cell', 'CPA', (80, 86))	('DCIS', 'Disease', (53, 57))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))
171208	27861897	Many of these studies have identified concordant and discordant mutations in patients with synchronous DCIS-IDC.	('patients', 'Species', '9606', (77, 85))	('DCIS-IDC', 'Disease', (103, 111))	('mutations', 'Var', (64, 73))	('synchronous', 'Disease', (91, 102))
171215	27861897	Long-term follow up studies of patients with DCIS have shown a substantial difference in the progression of low-grade versus high-grade DCIS, with only 35% of low-grade DCIS patients progressing to have IDC over 50 years, while 50% of high-grade DCIS progressed to IDC over 3 years.	('patients', 'Species', '9606', (174, 182))	('IDC', 'Disease', (203, 206))	('patients', 'Species', '9606', (31, 39))	('low-grade', 'Var', (159, 168))
171216	27861897	Low-grade DCIS are more often ER+/PR+/HER2- with fewer copy number aberrations (CNAs) than high-grade DCIS.	('Low-grade', 'Var', (0, 9))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))	('copy', 'MPA', (55, 59))
171217	27861897	Mutational markers of IDC include mutations in TP53 and PTEN, amplifications of chromosome 17 and 11q, and loss of PIK3CA mutation.	('loss', 'NegReg', (107, 111))	('PTEN', 'Gene', (56, 60))	('mutation', 'Var', (122, 130))	('amplifications', 'Var', (62, 76))	('PTEN', 'Gene', '5728', (56, 60))	('IDC', 'Disease', (22, 25))	('TP53', 'Gene', '7157', (47, 51))	('PIK3CA', 'Gene', (115, 121))	('mutations', 'Var', (34, 43))	('PIK3CA', 'Gene', '5290', (115, 121))	('TP53', 'Gene', (47, 51))
171219	27861897	Analysis of hormone receptor status shows patients with ER+ and PR+ disease often have low-grade DCIS tumours and are less likely to progress than patients with ER- and PR- disease and high-grade tumours.	('ER+', 'Disease', (56, 59))	('DCIS tumours', 'Disease', (97, 109))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('low-grade', 'CPA', (87, 96))	('DCIS tumours', 'Disease', 'MESH:D002285', (97, 109))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('PR+ disease', 'Var', (64, 75))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('hormone receptor', 'Gene', (12, 28))	('patients', 'Species', '9606', (147, 155))	('hormone receptor', 'Gene', '3164', (12, 28))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('tumours', 'Disease', (196, 203))	('patients', 'Species', '9606', (42, 50))	('tumours', 'Disease', (102, 109))
171220	27861897	While new a study showed that intratumour heterogeneity in the HER2 receptor was also associated with poor prognosis in DCIS patients, currently DCIS patients are not routinely tested for HER2 (ERBB2) amplification.	('patients', 'Species', '9606', (125, 133))	('HER2', 'Gene', (188, 192))	('HER2', 'Gene', '2064', (63, 67))	('HER2', 'Gene', '2064', (188, 192))	('heterogeneity', 'Var', (42, 55))	('ERBB2', 'Gene', '2064', (194, 199))	('patients', 'Species', '9606', (150, 158))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('HER2', 'Gene', (63, 67))	('ERBB2', 'Gene', (194, 199))	('tumour', 'Disease', (35, 41))
171224	27861897	Assuming mutational complexity increases over time, and using phylogenetic inference, several studies showed clonal lineages and evolutionary histories can be inferred from a single time-point tumour sample.	('mutational', 'Var', (9, 19))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Disease', (193, 199))	('tumour', 'Disease', 'MESH:D009369', (193, 199))
171237	27861897	Cancer field effects may also occur in patients with germline mutations (eg.	('occur', 'Reg', (30, 35))	('germline mutations', 'Var', (53, 71))	('patients', 'Species', '9606', (39, 47))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
171240	27861897	A study sequenced PIK3CA mutations in patients with matched IDC and DCIS reported only 30% concordance between in situ and invasive regions.	('PIK3CA', 'Gene', (18, 24))	('mutations', 'Var', (25, 34))	('PIK3CA', 'Gene', '5290', (18, 24))	('patients', 'Species', '9606', (38, 46))
171243	27861897	These studies report a high correlation in copy number profiles of in situ and invasive subpopulations in synchronous DCIS patients, and many concordant point mutations.	('patients', 'Species', '9606', (123, 131))	('point mutations', 'Var', (153, 168))	('copy number', 'Var', (43, 54))	('synchronous', 'Disease', (106, 117))
171245	27861897	Concordant mutations between DCIS and IDC are often referred to as 'truncal' mutations by evolutionary biologists, because they can be traced back to the last common ancestor in the tumour.	('mutations', 'Var', (11, 20))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('DCIS', 'Gene', (29, 33))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Disease', (182, 188))	('IDC', 'Gene', (38, 41))
171250	27861897	In one case, authors reported convergent evolution of two distinct PTEN mutations in invasive regions not present in in situ subpopulations, suggesting selection of a minor subclone during invasion.	('mutations', 'Var', (72, 81))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', '5728', (67, 71))
171252	27861897	The authors identified highly concordant mutations in TP53, while other invasive-specific mutations included those of FANCE, ATM, BCOR, PDGFRA, and PMS1.	('mutations', 'Var', (41, 50))	('ATM', 'Gene', (125, 128))	('FANCE', 'Gene', (118, 123))	('ATM', 'Gene', '472', (125, 128))	('PMS1', 'Gene', (148, 152))	('PMS1', 'Gene', '5378', (148, 152))	('TP53', 'Gene', '7157', (54, 58))	('BCOR', 'Gene', (130, 134))	('FANCE', 'Gene', '2178', (118, 123))	('BCOR', 'Gene', '54880', (130, 134))	('TP53', 'Gene', (54, 58))	('PDGFRA', 'Gene', '5156', (136, 142))	('PDGFRA', 'Gene', (136, 142))
171254	27861897	Other genomic studies did not perform evolutionary analyses, but instead reported concordance of mutations and CNAs in patients with synchronous DCIS-IDC.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (119, 127))	('DCIS-IDC', 'Disease', (145, 153))	('CNAs', 'Gene', (111, 115))
171255	27861897	Studies using aCGH to profile microdissected DCIS and IDC regions often showed that while most CNAs are concordant, there are also many invasive-specific amplifications of oncogenes and deletions of tumour suppressors.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('amplifications', 'Var', (154, 168))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('tumour', 'Disease', (199, 205))	('oncogenes', 'Gene', (172, 181))	('deletions', 'Var', (186, 195))
171258	27861897	An alternative explanation for discordant data has invasive clones continuing to evolve new mutations and CNAs after tumour cells escape from the ducts.	('CNAs', 'Gene', (106, 110))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (92, 101))	('tumour', 'Disease', (117, 123))
171267	27861897	These models suggest targeting truncal mutations occurring early in tumour lineage, and subsequently inherited by both DCIS and IDC subpopulations, provide ideal targets for eliminating all tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumour', 'Disease', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('truncal mutations', 'Var', (31, 48))	('tumour', 'Disease', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
171269	27861897	For example, in a multi-region sequencing study of a synchronous DCIS-IDC patient, the authors identified loss-of-function mutations in the PTEN tumour suppressor in invasive subpopulations not present in ducts.	('patient', 'Species', '9606', (74, 81))	('tumour', 'Disease', (145, 151))	('loss-of-function', 'NegReg', (106, 122))	('DCIS-IDC', 'Disease', (65, 73))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('PTEN', 'Gene', (140, 144))	('mutations', 'Var', (123, 132))	('PTEN', 'Gene', '5728', (140, 144))
171270	27861897	This invasive-specific PTEN mutation could potentially be targeted with PIK3CA, AKT or mTOR inhibitors to treat the cancer.	('mTOR', 'Gene', '2475', (87, 91))	('AKT', 'Gene', '207', (80, 83))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('PIK3CA', 'Gene', (72, 78))	('PTEN', 'Gene', (23, 27))	('AKT', 'Gene', (80, 83))	('mutation', 'Var', (28, 36))	('PTEN', 'Gene', '5728', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PIK3CA', 'Gene', '5290', (72, 78))	('invasive-specific', 'Reg', (5, 22))	('mTOR', 'Gene', (87, 91))
171273	27861897	Conversely, in a direct lineage model, a low genomic diversity would expect to predict a lower risk of invasion in DCIS patients.	('low genomic diversity', 'Var', (41, 62))	('lower', 'NegReg', (89, 94))	('invasion', 'CPA', (103, 111))	('patients', 'Species', '9606', (120, 128))
171279	27861897	STAR-FISH was used to measure both PIK3CA mutations and HER2 amplifications in the same single cells from HER2 positive breast cancer patients in response to trastuzumab treatment using FFPE tissue sections.	('HER2', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('trastuzumab', 'Chemical', 'MESH:D000068878', (158, 169))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('HER2', 'Gene', '2064', (56, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('patients', 'Species', '9606', (134, 142))	('HER2', 'Gene', (106, 110))	('PIK3CA', 'Gene', (35, 41))	('HER2', 'Gene', '2064', (106, 110))	('PIK3CA', 'Gene', '5290', (35, 41))	('mutations', 'Var', (42, 51))
171285	27861897	Collectively, the genomic studies of synchronous DCIS-IDC patients suggest that an independent lineage model is uncommon, by showing most synchronous DCIS patients share a large number of concordant CNAs and mutations.	('patients', 'Species', '9606', (58, 66))	('CNAs', 'Gene', (199, 203))	('mutations', 'Var', (208, 217))	('patients', 'Species', '9606', (155, 163))
171286	27861897	Nevertheless, the concordance and discordance of mutations in DCIS and IDC regions of synchronous patients provide circumstantial evidence for distinguishing these models.	('patients', 'Species', '9606', (98, 106))	('DCIS', 'Gene', (62, 66))	('IDC', 'Gene', (71, 74))	('mutations', 'Var', (49, 58))
171287	27861897	A number of reports are consistent with an evolutionary bottleneck model by showing DCIS cases in which additional CNAs and mutations were identified in IDC regions of synchronous DCIS patients that are absent in the DCIS regions.	('CNAs', 'Gene', (115, 119))	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (185, 193))
171296	28095868	PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC).	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (31, 56))	('inv', 'Gene', '27130', (139, 142))	('lobular carcinoma', 'Disease', 'MESH:D018275', (247, 264))	('LCIS', 'Phenotype', 'HP:0030076', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('associated', 'Reg', (222, 232))	('inv', 'Gene', '27130', (238, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('lobular carcinoma', 'Disease', 'MESH:D018275', (31, 48))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (105, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('PIK3CA', 'Gene', '5290', (0, 6))	('lobular carcinoma', 'Disease', (31, 48))	('ILC', 'Gene', '10850', (266, 269))	('mutations', 'Var', (7, 16))	('Lobular carcinoma', 'Disease', (97, 114))	('Lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (97, 122))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (238, 264))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (247, 264))	('ILC', 'Gene', (266, 269))	('breast lesion', 'Disease', (148, 161))	('Lobular carcinoma', 'Disease', 'MESH:D018275', (97, 114))	('inv', 'Gene', (139, 142))	('invasive lobular carcinoma', 'Disease', (238, 264))	('PIK3CA', 'Gene', (0, 6))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (31, 48))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (39, 56))	('breast lesion', 'Disease', 'MESH:D001941', (148, 161))	('inv', 'Gene', (238, 241))
171304	28095868	Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC.	('CDH1', 'Gene', '999', (68, 72))	('frequent', 'Reg', (160, 168))	('LCIS', 'Phenotype', 'HP:0030076', (127, 131))	('ILC', 'Gene', (209, 212))	('LCIS', 'Disease', (86, 90))	('pure LCIS', 'Disease', (172, 181))	('PIK3CA', 'Gene', (31, 37))	('mutations', 'Var', (73, 82))	('LCIS', 'Phenotype', 'HP:0030076', (188, 192))	('LCIS', 'Phenotype', 'HP:0030076', (86, 90))	('CDH1', 'Gene', (68, 72))	('associated', 'Reg', (193, 203))	('PIK3CA', 'Gene', '5290', (31, 37))	('LCIS', 'Disease', (188, 192))	('mutations', 'Var', (38, 47))	('LCIS', 'Phenotype', 'HP:0030076', (177, 181))	('frequent', 'Reg', (56, 64))	('ILC', 'Gene', '10850', (209, 212))
171305	28095868	We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('LCIS', 'Disease', (93, 97))	('PIK3CA', 'Gene', '5290', (34, 40))	('LCIS', 'Phenotype', 'HP:0030076', (93, 97))	('ILC', 'Gene', '10850', (148, 151))	('associated', 'Reg', (132, 142))	('ILC', 'Gene', (148, 151))
171318	28095868	There are limited studies of pure LCIS but generally these do show similar genetic changes to LCIS associated with ILC, with 16q loss and 1q gain being the most common chromosomal abnormalities.	('16q', 'Var', (125, 128))	('LCIS', 'Phenotype', 'HP:0030076', (34, 38))	('chromosomal abnormalities', 'Disease', (168, 193))	('loss', 'NegReg', (129, 133))	('gain', 'PosReg', (141, 145))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (168, 193))	('LCIS', 'Phenotype', 'HP:0030076', (94, 98))	('ILC', 'Gene', '10850', (115, 118))	('LCIS', 'Gene', (94, 98))	('ILC', 'Gene', (115, 118))
171320	28095868	There is also evidence of E-cadherin loss in both LCIS and atypical hyperplasia with CDH1 mutations being common in LCIS, but rare in atypical lobular hyperplasia (ALH).	('CDH1', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('lobular hyperplasia', 'Disease', 'MESH:D018275', (143, 162))	('CDH1', 'Gene', '999', (85, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (68, 79))	('E-cadherin', 'Gene', (26, 36))	('hyperplasia', 'Disease', 'MESH:D006965', (151, 162))	('hyperplasia', 'Disease', (68, 79))	('E-cadherin', 'Gene', '999', (26, 36))	('loss', 'NegReg', (37, 41))	('LCIS', 'Disease', (50, 54))	('LCIS', 'Phenotype', 'HP:0030076', (50, 54))	('common', 'Reg', (106, 112))	('hyperplasia', 'Disease', (151, 162))	('LCIS', 'Phenotype', 'HP:0030076', (116, 120))	('lobular hyperplasia', 'Disease', (143, 162))
171328	28095868	There is some evidence to suggest the risk of subsequent invasive disease is associated with high Ki67 expression and that increased expression of hsa-miR-375 contributes to lobular neoplastic progression.	('hsa-miR-375', 'Gene', (147, 158))	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('expression', 'MPA', (103, 113))	('hsa-miR-375', 'Gene', '494324', (147, 158))	('invasive disease', 'Disease', 'MESH:D009362', (57, 73))	('contributes', 'Reg', (159, 170))	('lobular neoplastic progression', 'CPA', (174, 204))	('Ki67', 'Protein', (98, 102))	('high', 'Var', (93, 97))	('invasive disease', 'Disease', (57, 73))
171336	28095868	12-EE-0493), which were used for whole exome sequencing in order to assess the frequency of mutations in inv-cLCIS.	('inv', 'Gene', '27130', (105, 108))	('inv', 'Gene', (105, 108))	('LCIS', 'Phenotype', 'HP:0030076', (110, 114))	('mutations', 'Var', (92, 101))	('cLCIS', 'Chemical', '-', (109, 114))
171354	28095868	A restriction enzyme enrichment protocol on stock DNA was used for mutations in exon 9 of PIK3CA (c1624G_A and c1633G_A).	('PIK3CA', 'Gene', '5290', (90, 96))	('c1624G_A', 'Mutation', 'rs121913273', (98, 106))	('c1624G_A', 'Var', (98, 106))	('PIK3CA', 'Gene', (90, 96))	('c1633G_A', 'Var', (111, 119))	('c1633G_A', 'Mutation', 'rs104886003', (111, 119))
171363	28095868	As expected, gain or cnLOH of 1q was the second most frequent change occurring in 21/27 pure c-LCIS samples (78%), 25/28 inv-cLCIS samples (89%) and 21/25 cILC samples (84%).	('cILC', 'Chemical', '-', (155, 159))	('LCIS', 'Phenotype', 'HP:0030076', (95, 99))	('cLCIS', 'Chemical', '-', (125, 130))	('cnLOH', 'Var', (21, 26))	('LCIS', 'Phenotype', 'HP:0030076', (126, 130))	('inv', 'Gene', (121, 124))	('gain', 'PosReg', (13, 17))	('inv', 'Gene', '27130', (121, 124))
171368	28095868	Amplifications (defined as copy number =/> 5) were found in 15 pure-cLCIS samples and 14 inv-cLCIS samples (Additional file 1: Table S4).	('cLCIS', 'Chemical', '-', (93, 98))	('pure-cLCIS', 'Disease', (63, 73))	('LCIS', 'Phenotype', 'HP:0030076', (69, 73))	('inv', 'Gene', (89, 92))	('inv', 'Gene', '27130', (89, 92))	('LCIS', 'Phenotype', 'HP:0030076', (94, 98))	('Amplifications', 'Var', (0, 14))	('cLCIS', 'Chemical', '-', (68, 73))
171369	28095868	The most common amplifications in cLCIS were on 1q, encompassing AKT3 (4/27 pure-cLCIS, 4/28 inv-cLCIS and 4/25 ILC samples) and 11q13, encompassing CCND1 (0/27 pure-cLCIS, 2/28 inv-cLCIS and 5/25 cILC samples).	('ILC', 'Gene', '10850', (112, 115))	('cLCIS', 'Chemical', '-', (166, 171))	('amplifications', 'Var', (16, 30))	('cLCIS', 'Chemical', '-', (182, 187))	('ILC', 'Gene', '10850', (198, 201))	('ILC', 'Gene', (112, 115))	('inv', 'Gene', (93, 96))	('LCIS', 'Phenotype', 'HP:0030076', (98, 102))	('ILC', 'Gene', (198, 201))	('LCIS', 'Phenotype', 'HP:0030076', (82, 86))	('AKT3', 'Gene', '10000', (65, 69))	('LCIS', 'Phenotype', 'HP:0030076', (35, 39))	('LCIS', 'Phenotype', 'HP:0030076', (183, 187))	('inv', 'Gene', (178, 181))	('CCND1', 'Gene', '595', (149, 154))	('cLCIS', 'Chemical', '-', (34, 39))	('inv', 'Gene', '27130', (93, 96))	('LCIS', 'Phenotype', 'HP:0030076', (167, 171))	('AKT3', 'Gene', (65, 69))	('CCND1', 'Gene', (149, 154))	('cLCIS', 'Chemical', '-', (97, 102))	('cILC', 'Chemical', '-', (197, 201))	('inv', 'Gene', '27130', (178, 181))	('cLCIS', 'Chemical', '-', (81, 86))
171370	28095868	The only SCNAs that were significantly different between pure-cLCIS and inv-cLCIS were five small regions of gain, more common in pure LCIS, three of which contained a single gene: Xp11 (KLF8), 20p12.1 (MACROD2) and 17q11.2 (RAB11FIP4) (Table 1).	('inv', 'Gene', (72, 75))	('cLCIS', 'Chemical', '-', (62, 67))	('inv', 'Gene', '27130', (72, 75))	('KLF8', 'Gene', '11279', (187, 191))	('cLCIS', 'Chemical', '-', (76, 81))	('Xp11', 'Var', (181, 185))	('20p12.1', 'Var', (194, 201))	('LCIS', 'Phenotype', 'HP:0030076', (63, 67))	('RAB11FIP4', 'Gene', '84440', (225, 234))	('KLF8', 'Gene', (187, 191))	('RAB11FIP4', 'Gene', (225, 234))	('LCIS', 'Phenotype', 'HP:0030076', (135, 139))	('MACROD2', 'Gene', (203, 210))	('LCIS', 'Phenotype', 'HP:0030076', (77, 81))	('MACROD2', 'Gene', '140733', (203, 210))
171386	28095868	2c-iv) had amplification of CCND1 and subsequently developed ILC, which was treated with mastectomy and endocrine therapy but recurred 2 years later in the mastectomy scar.	('ILC', 'Gene', '10850', (61, 64))	('CCND1', 'Gene', '595', (28, 33))	('ILC', 'Gene', (61, 64))	('developed', 'Reg', (51, 60))	('scar', 'Phenotype', 'HP:0100699', (167, 171))	('CCND1', 'Gene', (28, 33))	('amplification', 'Var', (11, 24))
171387	28095868	The invasive recurrence also had CCND1 amplification.	('CCND1', 'Gene', (33, 38))	('inv', 'Gene', '27130', (4, 7))	('amplification', 'Var', (39, 52))	('CCND1', 'Gene', '595', (33, 38))	('inv', 'Gene', (4, 7))
171392	28095868	In the single paired LCIS-ILC sample, 13 mutations were shared between the two components, including two PIK3CA mutations and one truncating CDH1 mutation, a frameshift mutation in COX15 and stop-gain in DOCK2 (Additional file 1: Table S5a).	('PIK3CA', 'Gene', (105, 111))	('COX15', 'Gene', '1355', (181, 186))	('LCIS', 'Phenotype', 'HP:0030076', (21, 25))	('ILC', 'Gene', (26, 29))	('CDH1', 'Gene', (141, 145))	('DOCK2', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (105, 111))	('COX15', 'Gene', (181, 186))	('mutations', 'Var', (112, 121))	('CDH1', 'Gene', '999', (141, 145))	('DOCK2', 'Gene', '1794', (204, 209))	('frameshift mutation', 'Var', (158, 177))	('ILC', 'Gene', '10850', (26, 29))
171394	28095868	Similarly the LCIS component had mutations in 10 genes, not found in the ILC component, suggesting there are also driver and passenger mutations at the pre-invasive stage (Additional file 1: Table S5c).	('inv', 'Gene', '27130', (156, 159))	('inv', 'Gene', (156, 159))	('LCIS', 'Phenotype', 'HP:0030076', (14, 18))	('mutations', 'Var', (33, 42))	('ILC', 'Gene', '10850', (73, 76))	('ILC', 'Gene', (73, 76))
171396	28095868	The finding that PIK3CA mutations were as common as CDH1 mutations in LCIS was surprising and we therefore sequenced the commonest mutations in exon 9 and 20 of PIK3CA (c3140A > G, c3140A > T, c1624G > A, c1633G > A, c1258T > C, c1636C > A) in the same samples that underwent Oncoscan array analysis (27 pure-cLCIS and 28 inv-cLCIS samples) to assess their frequency and determine whether PIK3CA mutations could be used as a biomarker for LCIS progression.	('c1624G > A', 'Var', (193, 203))	('PIK3CA', 'Gene', '5290', (17, 23))	('c3140A > G', 'Mutation', 'rs121913279', (169, 179))	('c3140A > G', 'Var', (169, 179))	('PIK3CA', 'Gene', '5290', (161, 167))	('LCIS', 'Phenotype', 'HP:0030076', (70, 74))	('mutations', 'Var', (24, 33))	('c1636C > A', 'Mutation', 'rs121913286', (229, 239))	('PIK3CA', 'Gene', '5290', (389, 395))	('LCIS', 'Disease', (439, 443))	('c1633G > A', 'Var', (205, 215))	('CDH1', 'Gene', '999', (52, 56))	('c1633G > A', 'Mutation', 'rs104886003', (205, 215))	('c1624G > A', 'Mutation', 'rs121913273', (193, 203))	('c3140A > T', 'Mutation', 'rs121913279', (181, 191))	('PIK3CA', 'Gene', (17, 23))	('CDH1', 'Gene', (52, 56))	('LCIS', 'Phenotype', 'HP:0030076', (439, 443))	('inv', 'Gene', (322, 325))	('PIK3CA', 'Gene', (161, 167))	('LCIS', 'Phenotype', 'HP:0030076', (327, 331))	('PIK3CA', 'Gene', (389, 395))	('c3140A > T', 'Var', (181, 191))	('c1258T > C', 'Var', (217, 227))	('c1258T > C', 'Mutation', 'rs121913272', (217, 227))	('c1636C > A', 'Var', (229, 239))	('inv', 'Gene', '27130', (322, 325))	('cLCIS', 'Chemical', '-', (326, 331))	('LCIS', 'Phenotype', 'HP:0030076', (310, 314))	('cLCIS', 'Chemical', '-', (309, 314))
171398	28095868	All PIK3CA mutations with an Oncoscan score >4.5 were sequenced using Sanger sequencing.	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))
171399	28095868	In classic cases, 5/27 pure-cLCIS samples (18.5%) and 6/28 inv-cLCIS samples (21.5%) had PIK3CA mutations.	('pure-cLCIS', 'Disease', (23, 33))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('LCIS', 'Phenotype', 'HP:0030076', (29, 33))	('cLCIS', 'Chemical', '-', (63, 68))	('inv', 'Gene', '27130', (59, 62))	('LCIS', 'Phenotype', 'HP:0030076', (64, 68))	('cLCIS', 'Chemical', '-', (28, 33))	('inv', 'Gene', (59, 62))	('mutations', 'Var', (96, 105))
171400	28095868	In the latter group all of the mutations present in the LCIS were also present in the paired ILC, with the exception of two samples.	('ILC', 'Gene', (93, 96))	('mutations', 'Var', (31, 40))	('LCIS', 'Phenotype', 'HP:0030076', (56, 60))	('ILC', 'Gene', '10850', (93, 96))
171401	28095868	One contained three different PIK3CA mutations in the LCIS component and only two were transferred to the paired ILC, and the other did not have enough DNA to test the ILC component (Table 3).	('PIK3CA', 'Gene', (30, 36))	('ILC', 'Gene', '10850', (113, 116))	('ILC', 'Gene', (113, 116))	('ILC', 'Gene', '10850', (168, 171))	('ILC', 'Gene', (168, 171))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutations', 'Var', (37, 46))	('LCIS', 'Phenotype', 'HP:0030076', (54, 58))
171402	28095868	These findings suggest that like CDH1, PIK3CA mutations might be early events in lobular tumourigenesis, but are not a potential biomarker for progression from LCIS to ILC.	('mutations', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('PIK3CA', 'Gene', '5290', (39, 45))	('ILC', 'Gene', '10850', (168, 171))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('ILC', 'Gene', (168, 171))	('tumour', 'Disease', (89, 95))	('CDH1', 'Gene', (33, 37))	('LCIS', 'Disease', (160, 164))	('LCIS', 'Phenotype', 'HP:0030076', (160, 164))	('CDH1', 'Gene', '999', (33, 37))	('PIK3CA', 'Gene', (39, 45))	('lobular', 'Disease', (81, 88))
171403	28095868	Exome sequencing revealed that mutations occurred in 10-24% of the reads in the LCIS samples and in 10-40% of the ILC samples.	('mutations', 'Var', (31, 40))	('LCIS', 'Phenotype', 'HP:0030076', (80, 84))	('ILC', 'Gene', '10850', (114, 117))	('ILC', 'Gene', (114, 117))	('occurred', 'Reg', (41, 49))
171406	28095868	In a sample with an ERBB2 mutation there was evidence of heterogeneity within the in situ component but not in ILC (Fig.	('mutation', 'Var', (26, 34))	('ERBB2', 'Gene', '2064', (20, 25))	('ERBB2', 'Gene', (20, 25))	('ILC', 'Gene', '10850', (111, 114))	('ILC', 'Gene', (111, 114))	('heterogeneity', 'MPA', (57, 70))
171407	28095868	3b), and in one inv-cLCIS sample there was evidence of heterozygous and homozygous PIK3CA mutations (Fig.	('LCIS', 'Phenotype', 'HP:0030076', (21, 25))	('mutations', 'Var', (90, 99))	('inv', 'Gene', (16, 19))	('inv', 'Gene', '27130', (16, 19))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('cLCIS', 'Chemical', '-', (20, 25))
171417	28095868	We identified four SCNAs that increased in frequency from pure cLCIS to inv-cLCIS and finally ILC: loss of 6q14.1-27, 8p23.2-23.1, and 22q13.31-13.33 and gain of 11q13.3.	('gain', 'PosReg', (154, 158))	('inv', 'Gene', (72, 75))	('inv', 'Gene', '27130', (72, 75))	('cLCIS', 'Chemical', '-', (76, 81))	('LCIS', 'Phenotype', 'HP:0030076', (64, 68))	('ILC', 'Gene', '10850', (94, 97))	('ILC', 'Gene', (94, 97))	('loss', 'Var', (99, 103))	('LCIS', 'Phenotype', 'HP:0030076', (77, 81))	('cLCIS', 'Chemical', '-', (63, 68))
171421	28095868	Deletions of 8p have been described in 50% of IDC and 37% of lobular cancers and the minimal region of loss in our study (8p23.2-23.1) includes MCPH1, a potential tumour suppressor gene encoding a DNA damage response protein which has also been implicated in breast cancer predisposition.	('lobular cancers', 'Disease', (61, 76))	('MCPH1', 'Gene', '79648', (144, 149))	('MCPH1', 'Gene', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('IDC', 'Disease', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('lobular cancers', 'Disease', 'MESH:D013274', (61, 76))	('lobular cancer', 'Phenotype', 'HP:0030076', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('described', 'Reg', (26, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('tumour', 'Disease', (163, 169))	('Deletions', 'Var', (0, 9))	('breast cancer', 'Disease', (259, 272))
171422	28095868	Similarly, loss of 22q13 has been described in IDC (not present in paired DCIS) and ILC (but also present in paired LCIS).	('ILC', 'Gene', (84, 87))	('loss', 'Var', (11, 15))	('22q13', 'Gene', (19, 24))	('paired DCIS', 'Phenotype', 'HP:0006304', (67, 78))	('ILC', 'Gene', '10850', (84, 87))	('IDC', 'Disease', (47, 50))	('LCIS', 'Phenotype', 'HP:0030076', (116, 120))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
171426	28095868	Two large studies of DCIS (approximately 400 patients) have reported amplification of CCND1 in 10-12.6% of patients with pure DCIS and 14.8-17.4% of patients with DCIS associated with invasive breast cancer, with the majority of patients having amplification in the paired invasive component.	('patients', 'Species', '9606', (229, 237))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('inv', 'Gene', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('inv', 'Gene', '27130', (273, 276))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (149, 157))	('associated with', 'Reg', (168, 183))	('inv', 'Gene', '27130', (184, 187))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('patients', 'Species', '9606', (107, 115))	('CCND1', 'Gene', '595', (86, 91))	('invasive breast cancer', 'Disease', (184, 206))	('CCND1', 'Gene', (86, 91))	('invasive breast cancer', 'Disease', 'MESH:D001943', (184, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('inv', 'Gene', (273, 276))	('amplification', 'Var', (69, 82))
171427	28095868	In a much smaller series of 20 patients with florid LCIS (a subtype putatively more likely to associated with invasive disease) 25% had CCND1 amplification.	('CCND1', 'Gene', '595', (136, 141))	('LCIS', 'Phenotype', 'HP:0030076', (52, 56))	('invasive disease', 'Disease', (110, 126))	('CCND1', 'Gene', (136, 141))	('patients', 'Species', '9606', (31, 39))	('invasive disease', 'Disease', 'MESH:D009362', (110, 126))	('amplification', 'Var', (142, 155))
171429	28095868	Other studies have identified correlation between over-expression of cyclin D1 and amplification of 11q13 and this over-expression has been associated with an increased risk of recurrence in ILC.	('ILC', 'Gene', (191, 194))	('associated', 'Reg', (140, 150))	('amplification of', 'Var', (83, 99))	('cyclin D1', 'Gene', '595', (69, 78))	('ILC', 'Gene', '10850', (191, 194))	('11q13', 'Gene', (100, 105))	('over-expression', 'PosReg', (50, 65))	('cyclin D1', 'Gene', (69, 78))
171432	28095868	In a genome-driven classification of over 7500 breast tumours, amplification of 11q13.3 was associated with a sub-group of ER-positive breast tumours with a poor prognosis and chemo-resistance.	('associated with', 'Reg', (92, 107))	('breast tumours', 'Disease', (47, 61))	('11q13.3', 'Gene', (80, 87))	('ER-positive', 'Reg', (123, 134))	('breast tumours', 'Disease', 'MESH:D001943', (135, 149))	('breast tumours', 'Disease', 'MESH:D001943', (47, 61))	('amplification of', 'Var', (63, 79))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('breast tumours', 'Disease', (135, 149))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
171438	28095868	It did, however, show that activating PIK3CA mutations are as common in LCIS as CDH1 mutations.	('mutations', 'Var', (45, 54))	('activating', 'PosReg', (27, 37))	('CDH1', 'Gene', (80, 84))	('PIK3CA', 'Gene', (38, 44))	('LCIS', 'Disease', (72, 76))	('PIK3CA', 'Gene', '5290', (38, 44))	('LCIS', 'Phenotype', 'HP:0030076', (72, 76))	('CDH1', 'Gene', '999', (80, 84))
171439	28095868	Activating PIK3CA mutations are well-described in both ILC and IDC, occurring in 48% of ILC (as the second most common mutations after CDH1) and 33% of IDC.	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (18, 27))	('CDH1', 'Gene', (135, 139))	('PIK3CA', 'Gene', (11, 17))	('IDC', 'Disease', (63, 66))	('ILC', 'Gene', '10850', (55, 58))	('PIK3CA', 'Gene', '5290', (11, 17))	('ILC', 'Gene', (55, 58))	('CDH1', 'Gene', '999', (135, 139))	('ILC', 'Gene', '10850', (88, 91))	('ILC', 'Gene', (88, 91))
171440	28095868	PIK3CA mutations have previously been reported by Christgen et al.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
171443	28095868	We confirmed the frequency of PIK3CA mutations in a larger set of LCIS by Sanger sequencing, which revealed no difference in the frequency of PIK3CA mutations in inv-cLCIS compared to pure-cLCIS.	('PIK3CA', 'Gene', '5290', (142, 148))	('PIK3CA', 'Gene', (30, 36))	('inv', 'Gene', (162, 165))	('cLCIS', 'Chemical', '-', (166, 171))	('mutations', 'Var', (149, 158))	('inv', 'Gene', '27130', (162, 165))	('LCIS', 'Phenotype', 'HP:0030076', (66, 70))	('PIK3CA', 'Gene', '5290', (30, 36))	('LCIS', 'Phenotype', 'HP:0030076', (190, 194))	('PIK3CA', 'Gene', (142, 148))	('cLCIS', 'Chemical', '-', (189, 194))	('LCIS', 'Phenotype', 'HP:0030076', (167, 171))
171444	28095868	The only other study to assess PIK3CA mutations in pure LCIS was by Sakr et al.	('PIK3CA', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('LCIS', 'Phenotype', 'HP:0030076', (56, 60))	('PIK3CA', 'Gene', '5290', (31, 37))
171446	28095868	The frequency of PIK3CA mutations in ILC in our study is lower than that reported by The Cancer Genome Atlas (TCGA) and Sakr et al.	('ILC', 'Gene', '10850', (37, 40))	('ILC', 'Gene', (37, 40))	('Cancer Genome Atlas', 'Disease', (89, 108))	('PIK3CA', 'Gene', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (89, 108))	('PIK3CA', 'Gene', '5290', (17, 23))	('mutations', 'Var', (24, 33))
171447	28095868	So, although they are not a useful biomarker of LCIS progression, PIK3CA mutations are an early event in lobular tumorigenesis leading to abnormal proliferation of the breast epithelium, but importantly, they do not appear to be the critical event leading to invasive malignancy.	('lobular tumorigenesis', 'Disease', (105, 126))	('malignancy', 'Disease', 'MESH:D009369', (268, 278))	('inv', 'Gene', (259, 262))	('inv', 'Gene', '27130', (259, 262))	('malignancy', 'Disease', (268, 278))	('PIK3CA', 'Gene', (66, 72))	('LCIS', 'Phenotype', 'HP:0030076', (48, 52))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))	('abnormal proliferation', 'CPA', (138, 160))
171448	28095868	who identified frequent PIK3CA mutations in non-invasive proliferative breast lesions including DCIS, inv-LCIS and one case of pure LCIS.	('LCIS', 'Phenotype', 'HP:0030076', (106, 110))	('breast lesion', 'Disease', 'MESH:D001941', (71, 84))	('DCIS', 'Disease', (96, 100))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('LCIS', 'Phenotype', 'HP:0030076', (132, 136))	('breast lesion', 'Disease', (71, 84))	('PIK3CA', 'Gene', '5290', (24, 30))	('inv', 'Gene', (102, 105))	('inv', 'Gene', '27130', (102, 105))	('inv', 'Gene', '27130', (48, 51))	('inv', 'Gene', (48, 51))
171450	28095868	We found no evidence of TBX3, FOXA1 or RUNX1 mutations in the four LCIS samples on which we performed exome sequencing, and identified only one TBX3 mutation in the four ILC samples.	('FOXA1', 'Gene', (30, 35))	('mutations', 'Var', (45, 54))	('RUNX1', 'Gene', (39, 44))	('FOXA1', 'Gene', '3169', (30, 35))	('TBX3', 'Gene', '6926', (24, 28))	('TBX3', 'Gene', '6926', (144, 148))	('RUNX1', 'Gene', '861', (39, 44))	('TBX3', 'Gene', (24, 28))	('TBX3', 'Gene', (144, 148))	('ILC', 'Gene', '10850', (170, 173))	('ILC', 'Gene', (170, 173))	('LCIS', 'Phenotype', 'HP:0030076', (67, 71))
171452	28095868	In the present series we report splice site mutation in two additional well-known drivers of cancer, MAP2K4 and RB1 in ILC, but not LCIS, The TCGA data also showed that AKT signalling is strongly activated in ILC and homozygous losses of the PTEN locus (10q23) occurred in 6% of ILC.	('ILC', 'Gene', '10850', (119, 122))	('LCIS', 'Phenotype', 'HP:0030076', (132, 136))	('ILC', 'Gene', (279, 282))	('activated', 'PosReg', (196, 205))	('RB1', 'Gene', '5925', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('ILC', 'Gene', (119, 122))	('PTEN', 'Gene', (242, 246))	('ILC', 'Gene', '10850', (209, 212))	('AKT', 'Gene', (169, 172))	('MAP2K4', 'Gene', '6416', (101, 107))	('PTEN', 'Gene', '5728', (242, 246))	('MAP2K4', 'Gene', (101, 107))	('cancer', 'Disease', (93, 99))	('losses', 'NegReg', (228, 234))	('ILC', 'Gene', (209, 212))	('ILC', 'Gene', '10850', (279, 282))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('RB1', 'Gene', (112, 115))	('splice site mutation', 'Var', (32, 52))	('AKT', 'Gene', '207', (169, 172))
171455	28095868	So, although PIK3CA mutations do not appear to be the trigger for malignant transformation in lobular cancer, it is possible that progression of LCIS may be related to acquisition of mutations or alterations in other components of the PI3K/Akt pathway; for example, expression profiling studies have shown that PIK3R1 is significantly downregulated in the stepwise progression from normal epithelium to LCIS to ILC.	('Akt', 'Gene', (240, 243))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PIK3CA', 'Gene', (13, 19))	('downregulated', 'NegReg', (335, 348))	('lobular cancer', 'Disease', 'MESH:D013274', (94, 108))	('ILC', 'Gene', '10850', (411, 414))	('PIK3R1', 'Gene', '5295', (311, 317))	('lobular cancer', 'Phenotype', 'HP:0030076', (94, 108))	('PIK3CA', 'Gene', '5290', (13, 19))	('Akt', 'Gene', '207', (240, 243))	('ILC', 'Gene', (411, 414))	('LCIS', 'Phenotype', 'HP:0030076', (145, 149))	('lobular cancer', 'Disease', (94, 108))	('LCIS', 'Phenotype', 'HP:0030076', (403, 407))	('LCIS', 'Disease', (403, 407))	('mutations', 'Var', (20, 29))	('PIK3R1', 'Gene', (311, 317))
171457	28095868	We developed a relatively crude method to assess heterogeneity using SNP arrays and this clearly showed that sub-clonal SCNAs increase in frequency from in situ to invasive lobular carcinoma.	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (164, 190))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (173, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('increase', 'PosReg', (126, 134))	('invasive lobular carcinoma', 'Disease', (164, 190))	('sub-clonal SCNAs', 'Var', (109, 125))
171459	28095868	Of interest, we have also shown evidence of passenger mutations in LCIS not transmitted to the invasive component, suggesting that, like invasive disease, there is an early sub-clone expansion process, with at least one acquiring critical mutations and developing into invasive disease.	('inv', 'Gene', '27130', (269, 272))	('inv', 'Gene', (95, 98))	('inv', 'Gene', '27130', (95, 98))	('mutations', 'Var', (54, 63))	('invasive disease', 'Disease', (269, 285))	('invasive disease', 'Disease', 'MESH:D009362', (137, 153))	('inv', 'Gene', (137, 140))	('inv', 'Gene', '27130', (137, 140))	('LCIS', 'Phenotype', 'HP:0030076', (67, 71))	('inv', 'Gene', (269, 272))	('invasive disease', 'Disease', 'MESH:D009362', (269, 285))	('invasive disease', 'Disease', (137, 153))	('developing into', 'Reg', (253, 268))
171460	28095868	Driver mutations that are sub-clonal in the pre-invasive state then become clonal in the invasive stage.	('inv', 'Gene', (89, 92))	('inv', 'Gene', '27130', (89, 92))	('inv', 'Gene', '27130', (48, 51))	('inv', 'Gene', (48, 51))	('mutations', 'Var', (7, 16))
171463	28095868	We have also shown that PIK3CA mutations are common in LCIS and that there is genetic heterogeneity within LCIS, just as in ILC.	('common', 'Reg', (45, 51))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('LCIS', 'Disease', (55, 59))	('LCIS', 'Phenotype', 'HP:0030076', (55, 59))	('ILC', 'Gene', '10850', (124, 127))	('LCIS', 'Phenotype', 'HP:0030076', (107, 111))	('PIK3CA', 'Gene', '5290', (24, 30))	('ILC', 'Gene', (124, 127))
171551	32939016	germline BRCA1/2 mutation).	('BRCA1/2', 'Gene', (9, 16))	('BRCA1/2', 'Gene', '672;675', (9, 16))	('mutation', 'Var', (17, 25))
171574	20861305	Moreover, alteration in normal anoikis mechanisms is known to enhance oncogenesis, including tumor metastasis, because anoikis resistance allows cells to survive in inappropriate ECM environments.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('enhance', 'PosReg', (62, 69))	('oncogenesis', 'CPA', (70, 81))	('tumor metastasis', 'Disease', 'MESH:D009362', (93, 109))	('tumor metastasis', 'Disease', (93, 109))	('alteration', 'Var', (10, 20))
171594	20861305	U0126, LY294002, and deferoxamine mesylate (DFOM) were purchased from Calbiochem (San Diego, CA).	('LY294002', 'Var', (7, 15))	('U0126', 'Var', (0, 5))	('deferoxamine mesylate', 'Chemical', 'MESH:D003676', (21, 42))	('DFOM', 'Chemical', 'MESH:D003676', (44, 48))	('LY294002', 'Chemical', 'MESH:C085911', (7, 15))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
171625	20861305	Gene and catalog numbers for the primer/probe sets are as follows: Bim (Hs00197982_m1), Bmf (Hs00372937_m1), HIF-1beta/ARNT (Hs01121918_m1), adrenomedullin (ADM; Hs00181605_m1).	('ARNT', 'Gene', (119, 123))	('Hs00372937_m1', 'Var', (93, 106))	('Hs01121918_m1', 'Var', (125, 138))	('Bmf', 'Gene', '90427', (88, 91))	('HIF-1', 'Gene', '3091', (109, 114))	('ARNT', 'Gene', '405', (119, 123))	('ADM', 'Gene', (157, 160))	('ADM', 'Gene', '133', (157, 160))	('adrenomedullin', 'Gene', '133', (141, 155))	('Hs00197982_m1', 'Var', (72, 85))	('HIF-1', 'Gene', (109, 114))	('Bmf', 'Gene', (88, 91))	('adrenomedullin', 'Gene', (141, 155))
171659	20861305	Furthermore, to ensure that activation of Erk in attached or suspended cells under hypoxic conditions could activate downstream signaling, we examined phosphorylation of p90RSK at Thr360/Ser364, a well-characterized direct Erk phosphorylation site.	('Erk', 'Gene', (42, 45))	('Erk', 'Gene', (223, 226))	('Thr360/Ser364', 'Var', (180, 193))	('hypoxic conditions', 'Disease', (83, 101))	('p90RSK', 'Gene', '6195', (170, 176))	('p90RSK', 'Gene', (170, 176))	('Ser364', 'Chemical', '-', (187, 193))	('hypoxic conditions', 'Disease', 'MESH:D009135', (83, 101))	('Erk', 'Gene', '5594', (223, 226))	('Thr360', 'Chemical', '-', (180, 186))	('Erk', 'Gene', '5594', (42, 45))
171664	20861305	In contrast, pretreatment with PI(3)K inhibitor (LY294002) did not reverse hypoxic Bim inhibition, although it did fully reverse Bmf inhibition as well as partially reverse hypoxia-mediated inhibition of caspase-3 cleavage (Figure 2B).	('Bmf', 'Gene', (129, 132))	('LY294002', 'Var', (49, 57))	('caspase-3', 'Gene', (204, 213))	('caspase-3', 'Gene', '836', (204, 213))	('Bmf', 'Gene', '90427', (129, 132))	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('hypoxia', 'Disease', (173, 180))
171670	20861305	In addition, DFOM-mediated anoikis resistance was significantly reversed in the presence of EGFR or Mek inhibitors, whereas inhibition of PI(3)K did not significantly alter DFOM-mediated anoikis suppression (Supplemental Figure 7).	('reversed', 'Reg', (64, 72))	('DFOM', 'Chemical', 'MESH:D003676', (173, 177))	('Mek', 'Gene', (100, 103))	('Mek', 'Gene', '5609', (100, 103))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('DFOM', 'Chemical', 'MESH:D003676', (13, 17))	('inhibitors', 'Var', (104, 114))
171700	20861305	Moreover, treatment of acini with the Mek inhibitor U0126 or the EGF receptor inhibitor AG1478, but not the PI(3)K inhibitor LY294002, reversed hypoxia-mediated Bim inhibition at level of protein in 3D culture (Figure 5A) as well as RNA (data not shown).	('LY294002', 'Chemical', 'MESH:C085911', (125, 133))	('EGF', 'Gene', '1950', (65, 68))	('U0126', 'Chemical', 'MESH:C113580', (52, 57))	('hypoxia', 'Disease', (144, 151))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('EGF', 'Gene', (65, 68))	('Mek', 'Gene', '5609', (38, 41))	('Mek', 'Gene', (38, 41))	('U0126', 'Var', (52, 57))	('AG1478', 'Chemical', 'MESH:C101044', (88, 94))
171715	20861305	This study also provides evidence that suppression of anoikis under hypoxic conditions occurs in a HIF-dependent manner, because depletion of HIF-1 restores anoikis sensitivity and Bim and Bmf expression fully.	('hypoxic conditions', 'Disease', (68, 86))	('depletion', 'Var', (129, 138))	('hypoxic conditions', 'Disease', 'MESH:D009135', (68, 86))	('HIF-1 restores anoikis', 'Disease', 'MESH:D054019', (142, 164))	('Bmf', 'Gene', (189, 192))	('HIF-1 restores anoikis', 'Disease', (142, 164))	('expression', 'MPA', (193, 203))	('Bmf', 'Gene', '90427', (189, 192))
171734	20861305	Recently, ECM remodeling and stiffening have been shown to drive tumor progression in myoepithelial cells, in part by activating lysyl oxidase (LOX), a known cross-linker of ECM.	('lysyl oxidase', 'Gene', (129, 142))	('lysyl oxidase', 'Gene', '4015', (129, 142))	('LOX', 'Gene', '4015', (144, 147))	('tumor', 'Disease', (65, 70))	('LOX', 'Gene', (144, 147))	('drive', 'Reg', (59, 64))	('stiffening', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('activating', 'PosReg', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
171807	23624751	demonstrated that lobular neoplasia in the presence of DCIS was associated with an almost three-fold increase in the risk of LR.	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCIS', 'Var', (55, 59))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (18, 35))	('lobular neoplasia', 'Disease', (18, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (26, 35))	('lobular neoplasia', 'Disease', 'MESH:D009369', (18, 35))
171839	26940963	The NBCSP provided data on detection mode (outside of the screening cohort, screen detected, interval cancer, non-attender, not invited due to upper age limit and not invited as opted out).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('interval cancer', 'Disease', 'MESH:D009369', (93, 108))	('non-attender', 'Var', (110, 122))	('interval cancer', 'Disease', (93, 108))
171876	26940963	For example, for age group 50-54 with lambda estimated as 0.33, S as 0.88 and underlying annual incidence as 0.001792, the expected number of prevalent screen cancers is   The expected number of incident screen cancers is   The total number of screen-detected cancers expected was 3872 + 4448 = 8320.	('cancers', 'Disease', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('cancers', 'Disease', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('cancers', 'Disease', (260, 267))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('0.001792', 'Var', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
171914	26940963	In 1996-2000, 12% of tumours in the 50-54 group were in situ compared with 10% at ages 65-69.	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('50-54', 'Var', (36, 41))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('tumours', 'Disease', (21, 28))
171921	26940963	In considering the greater influence of DCIS in the Norwegian programme, it is worth noting that in the screening period in Norway, 9.6% of cancers were DCIS, whereas in Denmark the figures were 5.4% in Copenhagen and 5.8% in Funen.	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('DCIS', 'Var', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Copenhagen', 'Disease', (203, 213))
171922	26940963	Overall our results indicated 1532-1692 cancers, invasive and in situ, overdiagnosed.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('1532-1692', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
171990	31018242	For instance, HER2 protein overexpression in pure DCIS treated with BCS was associated with increased in situ recurrence risk, but not with invasive recurrence risk.83, 84, 85 HER2-positive invasive breast cancers are more often associated with adjacent DCIS than HER2-negative invasive breast cancers, and this adjacent DCIS shows more often a larger size and a higher rate of incomplete resection in HER2-positive breast cancers.67 HER2 amplification and its concurrent protein overexpression might act as a driver for intraductal clonal proliferation, instead of being a driver of cancer cell invasion.	('HER2', 'Gene', (434, 438))	('HER2', 'Gene', '2064', (176, 180))	('cancer', 'Disease', 'MESH:D009369', (584, 590))	('invasive breast cancers', 'Disease', (190, 213))	('cancers', 'Phenotype', 'HP:0002664', (423, 430))	('HER2', 'Gene', (402, 406))	('cancer', 'Disease', (423, 429))	('overexpression', 'PosReg', (480, 494))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('breast cancers', 'Disease', 'MESH:D001943', (416, 430))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('breast cancers', 'Disease', (416, 430))	('cancer', 'Disease', (294, 300))	('amplification', 'Var', (439, 452))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Disease', (206, 212))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('breast cancers', 'Disease', 'MESH:D001943', (287, 301))	('HER2', 'Gene', (264, 268))	('HER2', 'Gene', '2064', (14, 18))	('HER2', 'Gene', (176, 180))	('DCIS', 'Phenotype', 'HP:0030075', (321, 325))	('breast cancers', 'Phenotype', 'HP:0003002', (416, 430))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast cancers', 'Disease', 'MESH:D001943', (199, 213))	('invasive breast cancers', 'Disease', 'MESH:D001943', (278, 301))	('HER2', 'Gene', '2064', (434, 438))	('breast cancer', 'Phenotype', 'HP:0003002', (416, 429))	('cancer', 'Disease', (584, 590))	('protein', 'Protein', (472, 479))	('breast cancers', 'Phenotype', 'HP:0003002', (287, 301))	('breast cancers', 'Phenotype', 'HP:0003002', (199, 213))	('invasive breast cancers', 'Disease', (278, 301))	('cancer', 'Phenotype', 'HP:0002664', (584, 590))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('HER2', 'Gene', '2064', (402, 406))	('DCIS', 'Phenotype', 'HP:0030075', (254, 258))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('invasive breast cancers', 'Disease', 'MESH:D001943', (190, 213))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('HER2', 'Gene', (14, 18))	('HER2', 'Gene', '2064', (264, 268))
172024	29344954	None of the MDL tumours expressed basal markers [cytokeratin (CK) 5/6; CK14; and epidermal growth factor receptor].	('MDL tumours', 'Disease', 'MESH:D009369', (12, 23))	('CK14', 'Var', (71, 75))	('epidermal growth factor receptor', 'MPA', (81, 113))	('MDL tumours', 'Disease', (12, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
172025	29344954	To explore clonal relationships between MDL components, morphologically distinct regions of DCIS, LCIS and invasive tumours with a ductal or lobular growth pattern were laser capture-dissected or needle-dissected from seven cases (supplementary material, Table S1), and analysed for DNA copy number alterations by cCGH (MDL1-MDL4, n = 4) or nucleotide variation by exome sequencing (MDL4-MDL7, n = 4).	('invasive tumours', 'Disease', 'MESH:D009361', (107, 123))	('LCIS', 'Phenotype', 'HP:0030076', (98, 102))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('nucleotide variation', 'Var', (341, 361))	('invasive tumours', 'Disease', (107, 123))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
172029	29344954	The two components shared 62% of gains and losses, and 72.7% of SNVs (Figure 2; supplementary material, Tables S3 and S4), with shared SNVs affecting the cancer driver genes TP53 [p.Tyr220Cys, moderate effect (SNPeff), common mutation with 354 reported in COSMIC], ESR1 (p.Ser154Leu, moderate effect, none recorded in COSMIC), and TBX3 (p.Glu402_Pro403insGluGlu moderate effect, none recorded in COSMIC).	('TBX3', 'Gene', (331, 335))	('TP53', 'Gene', (174, 178))	('affecting', 'Reg', (140, 149))	('cancer', 'Disease', (154, 160))	('p.Ser154Leu', 'Var', (271, 282))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('ESR1', 'Gene', (265, 269))	('p.Ser154Leu', 'Mutation', 'p.S154L', (271, 282))	('p.Tyr220Cys', 'Mutation', 'p.Y220C', (180, 191))	('p.Glu402_Pro403insGluGlu', 'INSERTION', 'None', (337, 361))	('p.Glu402_Pro403insGluGlu', 'Var', (337, 361))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
172032	29344954	BRCA2, p.Lys936fs, high effect; SMAD4, p.Arg361His, moderate effect, 76 events reported in COSMIC; TBX3, p.Pro42fs, high effect).	('p.Pro42fs', 'Var', (105, 114))	('p.Lys936fs', 'Mutation', 'p.K936fsX', (7, 17))	('p.Lys936fs', 'Var', (7, 17))	('p.Arg361His', 'Var', (39, 50))	('p.Pro42fs', 'Mutation', 'p.P42fsX', (105, 114))	('p.Arg361His', 'Mutation', 'p.R361H', (39, 50))
172033	29344954	NCOR1, p.Ser1117*, high effect, none recorded in COSMIC; PARP4, p.Gln147Glu, moderate effect, alternative missense mutations recorded in COSMIC).	('PARP4', 'Gene', (57, 62))	('p.Gln147Glu', 'Var', (64, 75))	('NCOR1', 'Gene', (0, 5))	('p.Gln147Glu', 'Mutation', 'p.Q147E', (64, 75))	('p.Ser1117*', 'Var', (7, 17))	('p.Ser1117*', 'Mutation', 'p.S1117*', (7, 17))
172034	29344954	A CDH1 nonsense mutation (p.Gln610*, high effect, reported missense mutations at that nucleotide) was identified in the DCIS (mutant allele frequency of 16%), PLCIS (85%) and PLC (75%) components; this variant was also present in three of 257 reads (1%) in the IDC.	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('p.Gln610*', 'Mutation', 'p.Q610*', (26, 35))	('p.Gln610*', 'Var', (26, 35))	('LCIS', 'Phenotype', 'HP:0030076', (160, 164))	('CDH1', 'Gene', (2, 6))
172035	29344954	Interestingly, PLCIS also harboured a 4-bp deletion in CDH1 (p.Arg796fs, high effect at 10% frequency, not recorded in COSMIC; supplementary material, Table S4).	('p.Arg796fs', 'Var', (61, 71))	('p.Arg796fs', 'Mutation', 'p.R796fsX', (61, 71))	('CDH1', 'Gene', (55, 59))	('LCIS', 'Phenotype', 'HP:0030076', (16, 20))
172046	29344954	The molecular analyses identified a number of defining genomic alterations; in particular, the exome sequencing identified several key cancer driver mutations, particularly in the common ancestral evolutionary arm of each case.	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (135, 141))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
172047	29344954	For example, we identified a frameshift deletion in BRCA2 (c.2806_2809delAAAC) in the evolution of MDL6 that involved a pleomorphic lobular component; a relationship between BRCA2 variants and pleomorphic lobular breast cancer has previously been suggested 26.	('BRCA2', 'Gene', (52, 57))	('c.2806_2809delAAAC', 'Var', (59, 77))	('c.2806_2809delAAAC', 'Mutation', 'c.2806_2809delAAAC', (59, 77))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('frameshift deletion', 'Var', (29, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('pleomorphic lobular breast cancer', 'Phenotype', 'HP:0006625', (193, 226))	('pleomorphic lobular breast cancer', 'Disease', 'MESH:D013274', (193, 226))	('variants', 'Var', (180, 188))	('BRCA2', 'Gene', (174, 179))	('pleomorphic lobular breast cancer', 'Disease', (193, 226))
172048	29344954	Large-scale genomics consortia have previously identified a number of breast cancer driver genes, including TBX3 27; indeed, TBX3 mutations account for ulnar-mammary syndrome 28, and, in breast cancer, appear to result in the loss of transcriptional repressor function 29.	('transcriptional repressor function 29', 'MPA', (234, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('ulnar-mammary syndrome 28', 'Disease', (152, 177))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Disease', (70, 83))	('mutations', 'Var', (130, 139))	('account', 'Reg', (140, 147))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('loss', 'NegReg', (226, 230))	('TBX3', 'Gene', (125, 129))	('breast cancer', 'Disease', (187, 200))
172054	29344954	Indeed, we have shown that the morphologically disparate regions harbour mutations in several breast cancer driver genes, which may predict targeted therapeutic options in the future.	('predict', 'Reg', (132, 139))	('mutations', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('harbour', 'Reg', (65, 72))	('breast cancer', 'Disease', (94, 107))
172117	15762990	The authors suggested that SLN biopsy should be performed in all DCIS patients with one or more of the following characteristics: palpable or mammographic mass, suspicion of microinvasion, multicentric disease, high nuclear grade or necrosis.	('multicentric disease', 'Disease', (189, 209))	('patients', 'Species', '9606', (70, 78))	('necrosis', 'Disease', (233, 241))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('necrosis', 'Disease', 'MESH:D009336', (233, 241))	('multicentric disease', 'Disease', 'MESH:C537372', (189, 209))	('mammographic mass', 'Phenotype', 'HP:0032408', (142, 159))	('high nuclear', 'Var', (211, 223))
172155	23943024	Lumpectomies for invasive or intraductal cancers localized with a single 125iodine seed (January-June 2012) were compared to those using 1 wire (July-December 2011).	('intraductal cancers', 'Disease', 'MESH:D002285', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('125iodine', 'Var', (73, 82))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('intraductal cancers', 'Disease', (29, 48))	('125iodine', 'Chemical', 'MESH:C000614960', (73, 82))
172200	23943024	For lumpectomy and SLNB (n = 497), operative time was significantly longer for the RSL group than the WL group (median, 55 minutes; range, 29-140 minutes versus median, 48 minutes; range, 12-110 minutes; p < 0.0001).	('RSL', 'Var', (83, 86))	('longer', 'PosReg', (68, 74))	('RSL', 'Chemical', '-', (83, 86))	('WL', 'Chemical', '-', (102, 104))	('lumpectomy', 'Disease', (4, 14))
172316	27785066	Thus, this study reports gene expression profiling in large breast cancer cohorts from Gene Expression Omnibus, including GSE29044 (N=138) and GSE10780 (N=185) test series and four independent validation series GSE21653 (N=266), GSE20685 (N=327), GSE26971 (N=276), and GSE12776 (N=204).	('large breast', 'Phenotype', 'HP:0010313', (54, 66))	('breast cancer', 'Disease', (60, 73))	('GSE26971', 'Var', (247, 255))	('GSE21653', 'Var', (211, 219))	('GSE12776', 'Var', (269, 277))	('GSE20685', 'Var', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
172333	27785066	So far, only BRCA1/2 mutation analysis has been used in clinical practice as a predictive marker for breast cancer.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('mutation analysis', 'Var', (21, 38))	('BRCA1/2', 'Gene', (13, 20))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
172334	27785066	We identified a prognostic, three-gene signature from the GSE29044 and GSE10780 test series patients and another four independent GEO cohorts using the sample-splitting method and Cox regression analysis.	('patients', 'Species', '9606', (92, 100))	('Cox', 'Gene', '1351', (180, 183))	('GSE29044', 'Var', (58, 66))	('GSE10780', 'Gene', (71, 79))	('Cox', 'Gene', (180, 183))
172358	27785066	Risk score = (1.05326x expression of MAMDC2) + (1.13029x expression of TSHZ2) + (0.73615x expression of CLDN11).	('expression', 'MPA', (57, 67))	('TSHZ2', 'Gene', '128553', (71, 76))	('CLDN11', 'Gene', '5010', (104, 110))	('1.05326x expression', 'Var', (14, 33))	('CLDN11', 'Gene', (104, 110))	('MAMDC2', 'Gene', '256691', (37, 43))	('TSHZ2', 'Gene', (71, 76))	('MAMDC2', 'Gene', (37, 43))
172361	27785066	In order to validate risk-score formula, risk scores of four independent publicly available breast cancer gene expression data sets including four independent validation series GSE21653 (N=266), GSE20685 (N=327), GSE26971 (N=276), and GSE12776 (N=204) were calculated.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('GSE21653', 'Var', (177, 185))	('breast cancer', 'Disease', (92, 105))	('GSE26971', 'Var', (213, 221))	('GSE20685', 'Var', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
172368	27785066	High CLDN11 expression was also found to correlate with shorter overall survival (P=0.012) of breast cancer patients (Figure 6C).	('High', 'Var', (0, 4))	('CLDN11', 'Gene', (5, 11))	('overall survival', 'MPA', (64, 80))	('shorter', 'NegReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CLDN11', 'Gene', '5010', (5, 11))	('patients', 'Species', '9606', (108, 116))	('expression', 'MPA', (12, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))
172376	27785066	We identified a prognostic, three-gene signature from the GSE39582 test series patients, and another two independent GEO cohorts using the sample-splitting method and Cox regression analysis.	('Cox', 'Gene', (167, 170))	('Cox', 'Gene', '1351', (167, 170))	('GSE39582', 'Var', (58, 66))	('patients', 'Species', '9606', (79, 87))
172383	19829710	Here, we demonstrate that in the mouse mammary gland, loss of one Syk allele profoundly increases proliferation and ductal branching and invasion of epithelial cells through the mammary fat pad during puberty.	('Syk', 'Gene', (66, 69))	('invasion of epithelial cells', 'CPA', (137, 165))	('ductal branching', 'CPA', (116, 132))	('loss', 'Var', (54, 58))	('increases', 'PosReg', (88, 97))	('mouse', 'Species', '10090', (33, 38))	('proliferation', 'CPA', (98, 111))
172385	19829710	Morphological and gene microarray analysis following Syk knockdown revealed a loss of luminal and differentiated epithelial features with epithelial to mesenchymal transition and a gain in invadopodial cell surface markers CD44, CD49F, and MMP14.	('CD49F', 'Gene', '3655', (229, 234))	('CD49F', 'Gene', (229, 234))	('invadopodial cell', 'CPA', (189, 206))	('knockdown', 'Var', (57, 66))	('MMP14', 'Gene', '4323', (240, 245))	('loss', 'NegReg', (78, 82))	('CD44', 'Gene', '960', (223, 227))	('MMP14', 'Gene', (240, 245))	('Syk', 'Gene', (53, 56))	('CD44', 'Gene', (223, 227))	('gain', 'PosReg', (181, 185))
172391	19829710	The gene is hypermethylated in invasive breast cancer and loss of Syk has been tied to poor outcome in breast cancer [for review, ].	('Syk', 'Gene', (66, 69))	('loss', 'Var', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('invasive breast cancer', 'Disease', (31, 53))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('invasive breast cancer', 'Disease', 'MESH:D001943', (31, 53))
172402	19829710	Consistent with the changes in phenotype that we observed, i.e., following epithelial-to-mesenchymal transition (EMT), we found that vimentin protein expression was dramatically increased following Syk siRNA knockdown in MCF10A, MCF10AneoT, and DCIS.COM (Figure 4A).	('expression', 'MPA', (150, 160))	('knockdown', 'Var', (208, 217))	('DCIS', 'Phenotype', 'HP:0030075', (245, 249))	('vimentin', 'Gene', '7431', (133, 141))	('vimentin', 'Gene', (133, 141))	('Syk siRNA', 'Gene', (198, 207))	('increased', 'PosReg', (178, 187))
172411	19829710	In strong agreement with the evident change in morphology of Syk +/- mice on a 129 background, mammary glands from virgin Syk +/- female mice displayed more abundant ductal branches and end buds compared with the wild type glands as shown in the whole mount analysis at 3, 6, 8, 10, 12 weeks and pregnancy (EP, early pregnancy, E6.5 and LP, late pregnancy, E16.5) (Figures 5B and 5C).	('early pregnancy', 'Phenotype', 'HP:0001622', (311, 326))	('LP', 'Chemical', 'MESH:D008070', (337, 339))	('Syk', 'Var', (122, 125))	('more', 'PosReg', (152, 156))	('late pregnancy', 'Phenotype', 'HP:0001622', (341, 355))
172415	19829710	Loci of hyperplasias were found in the mammary gland whole mounts of the Syk +/- animals (Figures 7A and B).	('Syk +/-', 'Var', (73, 80))	('hyperplasias', 'Disease', (8, 20))	('hyperplasias', 'Disease', 'MESH:D006965', (8, 20))
172420	19829710	MCF10CA1, a tumor forming cell line derived from MCF10A, has been reported to form invadopodia and undergo EMT in a process requiring PI3K and c-Src in response to TGFbeta1.	('MCF10CA1', 'Var', (0, 8))	('MCF10CA1', 'CellLine', 'CVCL:6683', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('MCF10A', 'Gene', (49, 55))	('c-Src', 'Gene', (143, 148))	('c-Src', 'Gene', '6714', (143, 148))
172511	28946562	found that most breast cancers and most normal breast tissue samples expressed PTN mRNA as assessed by RT-PCR.	('PTN', 'Var', (79, 82))	('expressed', 'Reg', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('breast cancers', 'Disease', (16, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
172537	29880984	However, lipiodol was associated with too many complications including inflammation and abscess formation, as the oily contrast medium was poorly absorbed or excreted.	('lipiodol', 'Var', (9, 17))	('abscess', 'Disease', (88, 95))	('abscess', 'Phenotype', 'HP:0025615', (88, 95))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('inflammation', 'Disease', (71, 83))
172570	21480233	Aberrant expression of HuR associates with reduced survival in several types of adenocarcinomas in the gastrointestinal tract, ovaries and breast .	('Aberrant expression', 'Var', (0, 19))	('ovaries', 'Disease', (127, 134))	('adenocarcinomas in the gastrointestinal tract', 'Disease', (80, 125))	('breast', 'Disease', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HuR', 'Gene', '1994', (23, 26))	('adenocarcinomas in the gastrointestinal tract', 'Disease', 'MESH:D004067', (80, 125))	('ovaries', 'Disease', 'MESH:D010051', (127, 134))	('reduced', 'NegReg', (43, 50))	('HuR', 'Gene', (23, 26))	('survival', 'MPA', (51, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
172571	21480233	In addition, cytoplasmic HuR expression has been associated with tamoxifen resistance in MCF7 breast cancer cells and inhibition of its expression increased breast cancer cell responsiveness to tamoxifen .	('HuR', 'Gene', '1994', (25, 28))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tamoxifen', 'Chemical', 'MESH:D013629', (194, 203))	('increased', 'PosReg', (147, 156))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (89, 107))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tamoxifen', 'Chemical', 'MESH:D013629', (65, 74))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('MCF7 breast cancer', 'Disease', (89, 107))	('inhibition', 'Var', (118, 128))	('HuR', 'Gene', (25, 28))
172657	21480233	These data show that HuR directly binds three of the ten target transcripts in 184B5Me and in a breast cancer cell line MCF7 (Figure 5A).	('HuR', 'Gene', (21, 24))	('binds', 'Interaction', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('MCF7', 'CellLine', 'CVCL:0031', (120, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('HuR', 'Gene', '1994', (21, 24))	('184B5Me', 'Var', (79, 86))
172661	21480233	Transient HuR silencing did not affect CTGF expression, although 55.8% reduction was achieved with stable HuR inhibition (Table 2).	('silencing', 'Var', (14, 23))	('HuR', 'Gene', (10, 13))	('HuR', 'Gene', '1994', (106, 109))	('HuR', 'Gene', '1994', (10, 13))	('reduction', 'NegReg', (71, 80))	('CTGF', 'Gene', '1490', (39, 43))	('CTGF', 'Gene', (39, 43))	('HuR', 'Gene', (106, 109))
172669	21480233	Additionally, modulation of HuR expression was shown to suppress properties related to transformation in breast epithelial cells, and several HuR target transcripts were identified, two of which are novel HuR-binding transcripts.	('HuR', 'Gene', (28, 31))	('HuR', 'Gene', '1994', (142, 145))	('suppress', 'NegReg', (56, 64))	('HuR', 'Gene', '1994', (28, 31))	('modulation', 'Var', (14, 24))	('HuR', 'Gene', (142, 145))	('HuR', 'Gene', (205, 208))	('HuR', 'Gene', '1994', (205, 208))
172681	21480233	Neither stable nor transient silencing of HuR expression altered proliferation of the 184B5Me cells, which suggests that in this in vitro model HuR does not mediate its carcinogenic properties by affecting proliferation.	('carcinogenic', 'Disease', (169, 181))	('HuR', 'Gene', (144, 147))	('HuR', 'Gene', (42, 45))	('proliferation', 'CPA', (206, 219))	('HuR', 'Gene', '1994', (42, 45))	('HuR', 'Gene', '1994', (144, 147))	('silencing', 'Var', (29, 38))	('affecting', 'Reg', (196, 205))	('carcinogenic', 'Disease', 'MESH:D063646', (169, 181))
172683	21480233	However, HuR silencing reduced anchorage-independent growth, suppressed invasive properties and increased programmed cell death (anoikis).	('suppressed', 'NegReg', (61, 71))	('increased', 'PosReg', (96, 105))	('HuR', 'Gene', '1994', (9, 12))	('programmed cell death', 'CPA', (106, 127))	('anchorage-independent growth', 'CPA', (31, 59))	('HuR', 'Gene', (9, 12))	('invasive properties', 'CPA', (72, 91))	('reduced', 'NegReg', (23, 30))	('silencing', 'Var', (13, 22))
172693	21480233	Our results show that cytoplasmic HuR expression is aberrantly expressed in precursor lesions of invasive breast cancer, and silencing of HuR affects multiple properties of transformated breast epithelial cells.	('HuR', 'Gene', '1994', (34, 37))	('silencing', 'Var', (125, 134))	('HuR', 'Gene', (138, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('invasive breast cancer', 'Disease', (97, 119))	('HuR', 'Gene', '1994', (138, 141))	('invasive breast cancer', 'Disease', 'MESH:D001943', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('affects', 'Reg', (142, 149))	('HuR', 'Gene', (34, 37))
172713	33194685	Another meta-analysis further suggested that breast MRI should be considered for BI-RADS 4 rather than 3 and 5 mammographic microcalcifications, and the presence or absence of enhancement helps to rule out malignancy in mammographic microcalcifications at breast MRI.	('malignancy', 'Disease', (206, 216))	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('BI-RADS', 'Var', (81, 88))
172769	33194685	Although DCIS had a higher MD and ADC than IDC, with an SMD of 0.29 (-0.16, 0.73) (P = 0.20) and 0.26 (-0.18, 0.71) (P = 0.24), respectively, the results were insignificant.	('IDC', 'Gene', '4000', (43, 46))	('0.26', 'Var', (97, 101))	('IDC', 'Gene', (43, 46))	('higher', 'PosReg', (20, 26))	('ADC', 'MPA', (34, 37))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('ADC', 'Chemical', '-', (34, 37))
172792	33194685	used non-Gaussian diffusion and IVIM-DWI to diagnose breast lesions and found that the AUC of ADC0 was significantly higher than that of MK, suggesting the superiority of conventional DWI and it having more clinical availability.	('ADC', 'Chemical', '-', (94, 97))	('AUC', 'MPA', (87, 90))	('MK', 'Chemical', '-', (137, 139))	('breast lesions', 'Disease', (53, 67))	('higher', 'PosReg', (117, 123))	('breast lesions', 'Disease', 'MESH:D001943', (53, 67))	('ADC0', 'Var', (94, 98))
172807	33194685	A previous meta-analysis confirmed that DTI with fractional anisotropy also demonstrated superior diagnostic performance in the differential diagnosis of breast lesions.	('breast lesions', 'Disease', 'MESH:D001943', (154, 168))	('fractional anisotropy', 'Var', (49, 70))	('breast lesions', 'Disease', (154, 168))
172926	25435982	The primer sets were as follows: alpha-SMA, forward; 5'-ATGCTCCCAGGGCTGTTTT-3' and reverse; 5'-GCTTCGTCACCCACGTAGCT-3'; FGF-2, forward, 5'-GTGCTAACCGTTACCTGGCTAT-3' and reverse; 5'-CCAATCGTTCAAAAAAGAAACAC-3'; and for the internal gene reference beta-actin (ACTB), forward; 5'-AGGCCAACCGCGAGAAG-3' and reverse; 5'-ACAGCC TGGATAGCAACGTACA-3'.	('beta-actin', 'Gene', '728378', (245, 255))	('ACTB', 'Gene', (257, 261))	('beta-actin', 'Gene', (245, 255))	('FGF-2', 'Gene', '2247', (120, 125))	('FGF-2', 'Gene', (120, 125))	('ACTB', 'Gene', '60', (257, 261))	("forward; 5'-AGGCCAACCGCGAGAAG-3", 'Var', (264, 295))	('alpha-SMA', 'Chemical', '-', (33, 42))
172965	24971511	 Alu and LINE-1 Hypomethylation Is Associated with HER2 Enriched Subtype of Breast Cancer The changes in DNA methylation status in cancer cells are characterized by hypermethylation of promoter CpG islands and diffuse genomic hypomethylation.	('cancer', 'Disease', (131, 137))	('Breast Cancer', 'Disease', 'MESH:D001943', (76, 89))	('Associated', 'Reg', (35, 45))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('C', 'Chemical', 'MESH:D002244', (194, 195))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Breast Cancer', 'Phenotype', 'HP:0003002', (76, 89))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('changes', 'Reg', (94, 101))	('HER2', 'Gene', (51, 55))	('Breast Cancer', 'Disease', (76, 89))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('HER2', 'Gene', '2064', (51, 55))	('hypermethylation', 'Var', (165, 181))
172967	24971511	This study was designed to evaluate the changes of Alu and LINE-1 hypomethylation during breast cancer progression from normal to pre-invasive lesions and invasive breast cancer (IBC), and their relationship with characteristics of IBC.	('Alu', 'Chemical', '-', (51, 54))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('changes', 'Reg', (40, 47))	('hypomethylation', 'Var', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('IBC', 'Chemical', '-', (179, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('invasive breast cancer', 'Disease', (155, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('IBC', 'Chemical', '-', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('invasive breast cancer', 'Disease', 'MESH:D001943', (155, 177))
172971	24971511	In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER) status, and LINE-1 hypomethylation was associated with negative ER status, ERBB2 (HER2) amplification and p53 overexpression.	('ER', 'Gene', '2099', (72, 74))	('Alu', 'Chemical', '-', (8, 11))	('IBC', 'Disease', (3, 6))	('ER', 'Gene', '2099', (159, 161))	('amplification', 'Var', (164, 177))	('estrogen receptor', 'Gene', (53, 70))	('hypomethylation', 'Var', (12, 27))	('negative', 'NegReg', (44, 52))	('p53', 'Gene', '7157', (182, 185))	('overexpression', 'PosReg', (186, 200))	('ER', 'Gene', '2099', (151, 153))	('IBC', 'Chemical', '-', (3, 6))	('ERBB2', 'Gene', (151, 156))	('negative', 'NegReg', (131, 139))	('HER2', 'Gene', '2064', (158, 162))	('p53', 'Gene', (182, 185))	('ER', 'Gene', '2099', (140, 142))	('ERBB2', 'Gene', '2064', (151, 156))	('estrogen receptor', 'Gene', '2099', (53, 70))	('HER2', 'Gene', (158, 162))
172974	24971511	Our findings suggest that LINE-1 hypomethylation is an early event and Alu hypomethylation is probably a late event during breast cancer progression, and prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype.	('HER2', 'Gene', (201, 205))	('hypomethylation', 'Var', (164, 179))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('HER2', 'Gene', '2064', (201, 205))	('Alu', 'Chemical', '-', (183, 186))	('Alu', 'Chemical', '-', (71, 74))	('breast cancer', 'Disease', (123, 136))	('chromosomal instability', 'Phenotype', 'HP:0040012', (241, 264))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
172975	24971511	Common epigenetic changes in cancer include CpG island hypermethylation of gene promoters and genome-wide hypomethylation of non-coding genomic regions.	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CpG island hypermethylation', 'Var', (44, 71))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
172976	24971511	While promoter CpG island hypermethylation is an alternative mechanism for inactivating tumor suppressor genes, resulting in their transcriptional silencing, genome-wide hypomethylation is associated with genomic instability and hence facilitates tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('genomic instability', 'MPA', (205, 224))	('transcriptional', 'MPA', (131, 146))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (247, 252))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('associated', 'Reg', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hypomethylation', 'Var', (170, 185))	('facilitates', 'PosReg', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (88, 93))
172977	24971511	In breast cancer, promoter CpG island hypermethylation has been described for genes involved in all aspects of cellular function and was found to be associated with various histopathologic characteristics, including tumor grade, hormone receptor, HER2/neu status and molecular subtype.	('hypermethylation', 'Var', (38, 54))	('tumor', 'Disease', (216, 221))	('neu', 'Gene', '2064', (252, 255))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('neu', 'Gene', (252, 255))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('associated', 'Reg', (149, 159))	('HER2', 'Gene', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('HER2', 'Gene', '2064', (247, 251))	('hormone receptor', 'Gene', (229, 245))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('hormone receptor', 'Gene', '3164', (229, 245))
172982	24971511	However, hypomethylation of Alu and LINE-1 is consistently found in many types of human cancers.	('Alu', 'Chemical', '-', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('found', 'Reg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hypomethylation', 'Var', (9, 24))	('human', 'Species', '9606', (82, 87))
172983	24971511	Hypomethylation of transposable elements such as Alu and LINE-1 causes transcriptional activation, resulting in retrotransposition of the transposable element, chromosome alteration and thus genomic instability.	('genomic instability', 'MPA', (191, 210))	('activation', 'PosReg', (87, 97))	('retrotransposition', 'MPA', (112, 130))	('Hypomethylation', 'Var', (0, 15))	('transcriptional', 'MPA', (71, 86))	('chromosome alteration', 'CPA', (160, 181))	('Alu', 'Chemical', '-', (49, 52))
172984	24971511	Alu and LINE-1 hypomethylation have been reported as early events in the multistep carcinogenesis of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('hypomethylation', 'Var', (15, 30))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Alu', 'Chemical', '-', (0, 3))	('carcinogenesis of colorectal cancer', 'Disease', 'MESH:D015179', (83, 118))	('carcinogenesis of colorectal cancer', 'Disease', (83, 118))
173038	24971511	Alu hypomethylation was associated with ER negativity (P = 0.006).	('Alu', 'Chemical', '-', (0, 3))	('associated', 'Reg', (24, 34))	('hypomethylation', 'Var', (4, 19))	('ER', 'Gene', '2099', (40, 42))
173039	24971511	LINE-1 hypomethylation was significantly associated with ER negativity (P<0.001), PR negativity (P = 0.011), ERBB2 (HER2) amplification (P = 0.006) and p53 overexpression (P = 0.028).	('ER', 'Gene', '2099', (117, 119))	('PR', 'Gene', '5241', (82, 84))	('hypomethylation', 'Var', (7, 22))	('overexpression', 'PosReg', (156, 170))	('ERBB2', 'Gene', '2064', (109, 114))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('ERBB2', 'Gene', (109, 114))	('ER', 'Gene', '2099', (57, 59))	('HER2', 'Gene', (116, 120))	('HER2', 'Gene', '2064', (116, 120))	('ER', 'Gene', '2099', (109, 111))	('LINE-1', 'Gene', (0, 6))
173048	24971511	We also investigated the prognostic significance of the Alu and LINE-1 hypomethylation in IBCs.	('Alu', 'Chemical', '-', (56, 59))	('investigated', 'Reg', (8, 20))	('IBC', 'Chemical', '-', (90, 93))	('IBCs', 'Disease', (90, 94))	('hypomethylation', 'Var', (71, 86))
173051	24971511	In Kaplan-Meier survival analyses, Alu hypomethylation (<20.2%) tended to be associated with shorter disease-free survival time (P = 0.054; Figure 4A).	('disease-free survival time', 'CPA', (101, 127))	('Alu', 'Var', (35, 38))	('Alu', 'Chemical', '-', (35, 38))	('shorter', 'NegReg', (93, 100))
173053	24971511	Genome-wide global hypomethylation is a common epigenetic change in cancer.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('global hypomethylation', 'Var', (12, 34))	('cancer', 'Disease', (68, 74))
173056	24971511	However, in colorectal cancers, methylation levels of Alu or LINE-1 have been reported to be significantly decreased during transition from normal tissue to adenoma, but not in the progression from adenoma to carcinoma, suggesting Alu and LINE-1 hypomethylation is an early event in colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (283, 308))	('Alu', 'Chemical', '-', (231, 234))	('Alu', 'Chemical', '-', (54, 57))	('LINE-1', 'Gene', (61, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('colorectal cancers', 'Disease', (12, 30))	('adenoma to carcinoma', 'Disease', (198, 218))	('adenoma', 'Disease', (198, 205))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('colorectal carcinogenesis', 'Disease', (283, 308))	('adenoma', 'Disease', (157, 164))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (198, 218))	('hypomethylation', 'Var', (246, 261))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('adenoma', 'Disease', 'MESH:D000236', (198, 205))	('methylation levels', 'MPA', (32, 50))	('adenoma', 'Disease', 'MESH:D000236', (157, 164))	('decreased', 'NegReg', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('colorectal cancers', 'Disease', 'MESH:D015179', (12, 30))
173059	24971511	In the light of this finding, our study suggests that LINE-1 hypomethylation is an early event during breast cancer progression, in agreement with that of gastric and colorectal cancer.	('breast cancer', 'Disease', (102, 115))	('colorectal cancer', 'Disease', (167, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric', 'Disease', 'MESH:D013274', (155, 162))	('gastric', 'Disease', (155, 162))	('LINE-1', 'Gene', (54, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('hypomethylation', 'Var', (61, 76))
173063	24971511	In our study, LINE-1 methylation status was associated with ER and HER2 status and it was lowest in the HER2 enriched subtype in IBC.	('associated', 'Reg', (44, 54))	('IBC', 'Chemical', '-', (129, 132))	('methylation status', 'Var', (21, 39))	('LINE-1', 'Gene', (14, 20))	('IBC', 'Disease', (129, 132))	('HER2', 'Gene', (67, 71))	('HER2', 'Gene', '2064', (67, 71))	('lowest', 'NegReg', (90, 96))	('HER2', 'Gene', (104, 108))	('ER', 'Gene', '2099', (60, 62))	('ER', 'Gene', '2099', (105, 107))	('HER2', 'Gene', '2064', (104, 108))	('ER', 'Gene', '2099', (68, 70))
173067	24971511	LINE-1 hypomethylation has been demonstrated as a poor prognostic maker in various human cancers such as colorectal, gastric, esophageal, and lung cancer.	('colorectal', 'Disease', 'MESH:D015179', (105, 115))	('esophageal', 'Disease', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('hypomethylation', 'Var', (7, 22))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('gastric', 'Disease', 'MESH:D013274', (117, 124))	('human', 'Species', '9606', (83, 88))	('gastric', 'Disease', (117, 124))	('colorectal', 'Disease', (105, 115))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('LINE-1', 'Gene', (0, 6))
173069	24971511	reported that LINE-1 hypomethylation was a negative prognostic factor for young breast cancer patients (<=55 years), and was associated with pT stage, lymph node metastasis, and higher age at diagnosis, but not with ER or HER2 status.	('ER', 'Gene', '2099', (223, 225))	('patients', 'Species', '9606', (94, 102))	('LINE-1', 'Gene', (14, 20))	('hypomethylation', 'Var', (21, 36))	('ER', 'Gene', '2099', (216, 218))	('HER2', 'Gene', (222, 226))	('associated', 'Reg', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('HER2', 'Gene', '2064', (222, 226))	('pT stage', 'Disease', (141, 149))	('lymph node metastasis', 'CPA', (151, 172))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('negative', 'NegReg', (43, 51))
173071	24971511	Although LINE-1 hypomethylation was associated with aggressive features of breast cancer such as negative ER status, positive HER2 status, and p53 overexpression, it was not associated with the disease outcome.	('ER', 'Gene', '2099', (106, 108))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('p53', 'Gene', '7157', (143, 146))	('LINE-1', 'Gene', (9, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('positive', 'Var', (117, 125))	('overexpression', 'PosReg', (147, 161))	('hypomethylation', 'Var', (16, 31))	('HER2', 'Gene', (126, 130))	('associated', 'Reg', (36, 46))	('HER2', 'Gene', '2064', (126, 130))	('p53', 'Gene', (143, 146))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('ER', 'Gene', '2099', (127, 129))
173076	24971511	reported that ERBB2 (HER2) amplified breast cancers had a significantly higher number of chromosomal alterations, defined by comparative genomic hybridization, than HER2 non-amplified cancers.	('breast cancers', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancers', 'Phenotype', 'HP:0003002', (37, 51))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancers', 'Disease', (184, 191))	('amplified', 'Var', (27, 36))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('ERBB2', 'Gene', (14, 19))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', '2064', (165, 169))	('ERBB2', 'Gene', '2064', (14, 19))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('cancers', 'Disease', (44, 51))	('HER2', 'Gene', (165, 169))	('higher', 'PosReg', (72, 78))	('HER2', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancers', 'Disease', 'MESH:D001943', (37, 51))
173077	24971511	also showed that the frequency of allelic imbalance assessed by a panel of microsatellite markers representing 26 chromosomal regions was significantly higher in HER2 positive tumors than in HER2 negative tumors, suggesting global genomic instability in HER2 positive breast cancer.	('higher', 'PosReg', (152, 158))	('imbalance', 'Phenotype', 'HP:0002172', (42, 51))	('HER2', 'Gene', '2064', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('HER2', 'Gene', '2064', (254, 258))	('HER2', 'Gene', (162, 166))	('positive', 'Var', (167, 175))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('breast cancer', 'Disease', (268, 281))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))	('HER2', 'Gene', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HER2', 'Gene', (254, 258))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('HER2', 'Gene', '2064', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('tumors', 'Disease', (176, 182))
173078	24971511	Taken together, the prominent hypomethylation of Alu and LINE-1 in the HER2 enriched subtype may be associated with chromosomal instability of this specific subtype.	('chromosomal instability', 'Disease', (116, 139))	('LINE-1', 'Gene', (57, 63))	('HER2', 'Gene', (71, 75))	('associated', 'Reg', (100, 110))	('chromosomal instability', 'Phenotype', 'HP:0040012', (116, 139))	('HER2', 'Gene', '2064', (71, 75))	('hypomethylation', 'Var', (30, 45))	('Alu', 'Chemical', '-', (49, 52))
173081	24971511	reported that in Amsterdam criteria-fulfilled hereditary nonpolyposis colorectal cancer patients, tumors without mismatch repair deficiency are characterized by LINE-1 hypomethylation.	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (46, 87))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (46, 87))	('hypomethylation', 'Var', (168, 183))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('hereditary nonpolyposis colorectal cancer', 'Disease', (46, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
173082	24971511	also showed that colorectal cancer family history is associated with a higher risk of LINE-1 methylation-low colorectal cancer, suggesting unrecognized genetic predisposition to epigenetic alterations.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Disease', (17, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('LINE-1 methylation-low', 'Var', (86, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('methylation-low', 'Var', (93, 108))
173084	24971511	Thus, LINE-1 methylation status may have clinical implication as a potential biomarker for cancer risk assessment in family members.	('LINE-1', 'Gene', (6, 12))	('methylation', 'Var', (13, 24))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
173085	24971511	It was reported that CD44+ progenitor-like cells of normal mammary epithelium were globally hypomethylated compared to luminal epithelial (CD24+ and MUC1+) and myoepithelial (CD10+) cells and cell type-specific methylation patterns were conserved in breast cancer.	('breast cancer', 'Disease', (250, 263))	('CD24', 'Gene', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('MUC1', 'Gene', (149, 153))	('MUC1', 'Gene', '4582', (149, 153))	('CD44', 'Gene', '960', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('hypomethylated', 'Var', (92, 106))	('myoepithelial', 'Disease', (160, 173))	('CD44', 'Gene', (21, 25))	('myoepithelial', 'Disease', 'MESH:D009208', (160, 173))	('CD10', 'Gene', (175, 179))	('breast cancer', 'Disease', 'MESH:D001943', (250, 263))	('CD24', 'Gene', '100133941', (139, 143))	('CD10', 'Gene', '4311', (175, 179))
173090	24971511	Alu and LINE-1 methylation status was significantly different among breast cancer subtypes, being lowest in HER2 enriched subtype.	('HER2', 'Gene', (108, 112))	('methylation', 'Var', (15, 26))	('HER2', 'Gene', '2064', (108, 112))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('different', 'Reg', (52, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('lowest', 'NegReg', (98, 104))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Alu', 'Chemical', '-', (0, 3))
173091	24971511	Alu hypomethylation tended to be associated with poor disease-free survival of the patients and LINE-1 methylation status was not associated with patients' survival.	('hypomethylation', 'Var', (4, 19))	('Alu', 'Gene', (0, 3))	('poor', 'NegReg', (49, 53))	('patients', 'Species', '9606', (83, 91))	('disease-free survival', 'CPA', (54, 75))	('Alu', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (146, 154))
173092	24971511	Our findings suggest that LINE-1 hypomethylation is an early event and Alu hypomethylation is probably a late event during breast cancer progression, and that prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('Alu', 'Chemical', '-', (71, 74))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('HER2', 'Gene', (206, 210))	('hypomethylation', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Alu', 'Chemical', '-', (188, 191))	('HER2', 'Gene', '2064', (206, 210))	('chromosomal instability', 'Phenotype', 'HP:0040012', (246, 269))
173093	23131872	Genes affected by mouse mammary tumor virus (MMTV) proviral insertions in mouse mammary tumors are deregulated or mutated in primary human mammary tumors The accumulation of mutations is a contributing factor in the initiation of premalignant mammary lesions and their progression to malignancy and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (147, 153))	('mouse', 'Species', '10090', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('MMTV', 'Species', '11757', (45, 49))	('mouse mammary tumor virus', 'Species', '11757', (18, 43))	('human', 'Species', '9606', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mouse', 'Species', '10090', (74, 79))	('malignancy', 'Disease', 'MESH:D009369', (284, 294))	('mutations', 'Var', (174, 183))	('tumors', 'Disease', (88, 94))	('premalignant', 'Disease', (230, 242))	('malignancy', 'Disease', (284, 294))
173094	23131872	We have used a mouse model in which the carcinogen is the mouse mammary tumor virus (MMTV) which induces clonal premalignant mammary lesions and malignant mammary tumors by insertional mutagenesis.	('clonal premalignant mammary lesions', 'CPA', (105, 140))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mouse', 'Species', '10090', (58, 63))	('mouse mammary tumor virus', 'Species', '11757', (58, 83))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('induces', 'PosReg', (97, 104))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('mouse', 'Species', '10090', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('insertional mutagenesis', 'Var', (173, 196))	('MMTV', 'Species', '11757', (85, 89))
173101	23131872	Within these loci members of the Wnt, Fgf and Rspo gene families plus two linked genes (Npm3 and Ddn) were frequently activated in tumors induced by MMTV.	('activated', 'PosReg', (118, 127))	('Ddn', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Wnt', 'Gene', (33, 36))	('MMTV', 'Species', '11757', (149, 153))	('Npm3', 'Gene', '10360', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Fgf', 'Gene', (38, 41))	('Ddn', 'Gene', '23109', (97, 100))	('tumors', 'Disease', (131, 137))	('Npm3', 'Gene', (88, 92))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('MMTV', 'Var', (149, 153))	('Rspo gene', 'Gene', (46, 55))
173106	23131872	Mutations contribute to the evolution of normal mammary epithelium through premalignant lesions to malignancy and metastases.	('malignancy', 'Disease', (99, 109))	('metastases', 'Disease', (114, 124))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('Mutations', 'Var', (0, 9))	('malignancy', 'Disease', 'MESH:D009369', (99, 109))	('contribute', 'Reg', (10, 20))
173107	23131872	Our approach was to use the mouse mammary tumor virus (MMTV) induced mammary tumor model to identify genetic pathways altered by insertional mutation in multiple lesions that contribute to mouse mammary tumorigenesis by expansion of the mutated cell (reviewed in).	('insertional mutation', 'Var', (129, 149))	('MMTV', 'Species', '11757', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', (42, 47))	('mouse', 'Species', '10090', (189, 194))	('mouse', 'Species', '10090', (28, 33))	('mouse mammary tumor virus', 'Species', '11757', (28, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutated', 'Var', (237, 244))
173108	23131872	The rationale is that mutations in similar pathways may also contribute to human breast carcinogenesis.	('breast carcinogenesis', 'Disease', (81, 102))	('contribute', 'Reg', (61, 71))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (81, 102))	('mutations', 'Var', (22, 31))	('rat', 'Species', '10116', (4, 7))	('human', 'Species', '9606', (75, 80))
173120	23131872	The published transcriptome and nucleotide sequence analysis of primary human breast tumors was interrogated to ascertain whether the expression of the human orthologues of these new MMTV CIS target genes was deregulated or mutated in human breast cancer.	('mutated', 'Var', (224, 231))	('expression', 'MPA', (134, 144))	('MMTV', 'Species', '11757', (183, 187))	('breast tumors', 'Disease', 'MESH:D001943', (78, 91))	('breast tumor', 'Phenotype', 'HP:0100013', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('breast tumors', 'Disease', (78, 91))	('human', 'Species', '9606', (72, 77))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('human', 'Species', '9606', (152, 157))	('breast cancer', 'Disease', (241, 254))	('human', 'Species', '9606', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast tumors', 'Phenotype', 'HP:0100013', (78, 91))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
173140	23131872	Notch4 viral integration events all have occurred within the coding portion of the gene and result in the transcription from the 3' MMTV LTR of the region encoding the intracellular domain of the receptor protein.	('rat', 'Species', '10116', (18, 21))	('MMTV', 'Species', '11757', (132, 136))	('result in', 'Reg', (92, 101))	('Notch4', 'Var', (0, 6))	('transcription', 'MPA', (106, 119))
173153	23131872	Figure 2 shows a Southern blot of EcoR1 restricted cellular DNAs from mammary tumors Czz26MT12 and Czz28MT6/7 and matching lung metastases.	('Czz28MT6/7', 'Var', (99, 109))	('Czz26MT12', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lung metastases', 'Disease', (123, 138))	('lung metastases', 'Disease', 'MESH:D009362', (123, 138))
173155	23131872	With the exception of one Czz26MT12 lung metastasis B (Figure 2, Lane 3) there was no additional viral integration events in the lung metastasis compared to the matching tumor.	('Czz26MT12', 'Var', (26, 35))	('rat', 'Species', '10116', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))
173160	23131872	The distance between the activating MMTV RIS and the target CIS gene ranged from 100 bp to greater than 200Kb (See Supplementary Figure 1), for example: Rspo3, 246Kb (Tumor#5447); Phf19, 663 Kb (Tumor#6749) and Tacstd2, 716Kb (Tumor#7856).	('Tumor#6749', 'Var', (195, 205))	('Tumor', 'Phenotype', 'HP:0002664', (195, 200))	('Tumor', 'Phenotype', 'HP:0002664', (227, 232))	('MMTV', 'Species', '11757', (36, 40))	('Phf19, 663 Kb (Tumor#6749', 'Var', (180, 205))	('Tumor', 'Phenotype', 'HP:0002664', (167, 172))
173163	23131872	On chromosome 15, MMTV integration events occurring in Arf3, between Wnt10b and Wnt1 or in Wnt1 are associated with the activation of expression of Ddn that is 14Kb 3' of the Wnt1 locus.	('expression', 'MPA', (134, 144))	('Ddn', 'Gene', (148, 151))	('Arf3', 'Gene', '377', (55, 59))	('MMTV', 'Species', '11757', (18, 22))	('Wnt1', 'Gene', (91, 95))	('Arf3', 'Gene', (55, 59))	('activation', 'PosReg', (120, 130))	('integration', 'Var', (23, 34))	('Ddn', 'Gene', '23109', (148, 151))	('Wnt10b', 'Gene', (69, 75))	('rat', 'Species', '10116', (28, 31))	('Wnt10b', 'Gene', '7480', (69, 75))
173164	23131872	Likewise, MMTV integration 5'of Fgf8 on chromosome 19 is associated with activation of its expression and frequently the expression of Npm3 which is located 13Kb 3' of Fgf8.	('Fgf8', 'Gene', (32, 36))	('Fgf8', 'Gene', '2253', (168, 172))	('activation', 'PosReg', (73, 83))	('expression', 'MPA', (91, 101))	('Npm3', 'Gene', '10360', (135, 139))	('Fgf8', 'Gene', '2253', (32, 36))	('expression', 'MPA', (121, 131))	('Npm3', 'Gene', (135, 139))	('Fgf8', 'Gene', (168, 172))	('rat', 'Species', '10116', (20, 23))	('MMTV integration', 'Var', (10, 26))	('MMTV', 'Species', '11757', (10, 14))
173204	23131872	Similarly the pregnancy-dependent "Plaques" may be induced by MMTVSP activation of Fgr or Phactr1 but other non-viral related events lead to pregnancy independence.	('MMTV', 'Species', '11757', (62, 66))	('pregnancy-dependent "Plaques', 'Disease', (14, 42))	('Phactr1', 'Gene', '221692', (90, 97))	('Phactr1', 'Gene', (90, 97))	('Fgr', 'Gene', '2268', (83, 86))	('Fgr', 'Gene', (83, 86))	('MMTVSP', 'Var', (62, 68))
173207	23131872	For instance pre-malignant mammary HOGs frequently contain MMTV CIS at Rspo2 and Wnt1 or Fgf3.	('Wnt1', 'Gene', (81, 85))	('MMTV CIS', 'Var', (59, 67))	('Fgf3', 'Gene', (89, 93))	('Rspo2', 'Gene', '340419', (71, 76))	('Rspo2', 'Gene', (71, 76))	('MMTV', 'Species', '11757', (59, 63))
173216	23131872	It is worth noting that both alleles of Trp53 are mutated in HC11 cells.	('mutated', 'Var', (50, 57))	('Trp53', 'Gene', '7157', (40, 45))	('Trp53', 'Gene', (40, 45))
173286	19344495	The van 't Veer study fundamentally undermined the prevailing hypothesis that metastasis is solely mediated by the acquisition of rare and rate limiting mutations within a minority of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('van', 'Disease', 'MESH:C536530', (4, 7))	('mutations', 'Var', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('metastasis', 'CPA', (78, 88))	('van', 'Disease', (4, 7))
173374	27023526	Since the complex Beclin 1-PIK3C3/Vps34 (vacuolar sorting protein34)-Vps35 (vacuolar sorting protein35) is a positive regulator of initiation and nucleation of autophagy, Beclin 1 is often mutated in breast and ovarian carcinomas.	('Vps34', 'Gene', (34, 39))	('PIK3C3', 'Gene', '5289', (27, 33))	('mutated', 'Var', (189, 196))	('Beclin 1', 'Gene', (18, 26))	('breast and ovarian carcinomas', 'Disease', 'MESH:D001943', (200, 229))	('Beclin 1', 'Gene', '8678', (171, 179))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (211, 229))	('PIK3C3', 'Gene', (27, 33))	('Beclin 1', 'Gene', '8678', (18, 26))	('Beclin 1', 'Gene', (171, 179))	('Vps34', 'Gene', '5289', (34, 39))	('Vps35', 'Gene', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('Vps35', 'Gene', '55737', (69, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))
173376	27023526	Reduction of the steady-state protein level of Beclin 1 took place between 8 and 16 h after NH4Cl, and 4 h after Bafilomycin A1 followed by a return to control value (Figure 3A).	('Beclin 1', 'Gene', '8678', (47, 55))	('NH4Cl', 'Var', (92, 97))	('NH4Cl', 'Chemical', 'MESH:D000643', (92, 97))	('Beclin 1', 'Gene', (47, 55))	('Bafilomycin A1', 'Chemical', 'MESH:C040929', (113, 127))	('Reduction', 'NegReg', (0, 9))	('protein level', 'MPA', (30, 43))
173386	27023526	Both under NH4Cl and Bafilomycin A1, LC3II progressively increased, while the LC3I protein level was lower than that of control during the entire observation period (Figure 3A).	('Bafilomycin A1', 'Chemical', 'MESH:C040929', (21, 35))	('NH4Cl', 'Var', (11, 16))	('NH4Cl', 'Chemical', 'MESH:D000643', (11, 16))	('lower', 'NegReg', (101, 106))	('LC3', 'Gene', '84557', (78, 81))	('LC3', 'Gene', '84557', (37, 40))	('increased', 'PosReg', (57, 66))	('LC3', 'Gene', (78, 81))	('Bafilomycin A1', 'Var', (21, 35))	('LC3', 'Gene', (37, 40))
173391	27023526	The transfection of shRNA Atg7, strongly reduced the expression of Atg7 protein in respect to MOCK-transfected cells, and the effect depended on the construct dilution.	('reduced', 'NegReg', (41, 48))	('protein', 'Protein', (72, 79))	('transfection', 'Var', (4, 16))	('Atg7', 'Gene', (67, 71))	('Atg7', 'Gene', (26, 30))	('expression', 'MPA', (53, 63))	('Atg7', 'Gene', '10533', (67, 71))	('Atg7', 'Gene', '10533', (26, 30))
173394	27023526	As shown in Figure 3D, LC3I and II were present in MOCK cells; after NH4Cl exposure LC3I largely decreased (-85%) while LC3II doubled.	('LC3', 'Gene', '84557', (120, 123))	('NH4Cl', 'Var', (69, 74))	('LC3', 'Gene', (120, 123))	('NH4Cl', 'Chemical', 'MESH:D000643', (69, 74))	('decreased', 'NegReg', (97, 106))	('LC3', 'Gene', '84557', (84, 87))	('LC3', 'Gene', '84557', (23, 26))	('LC3', 'Gene', (84, 87))	('LC3', 'Gene', (23, 26))
173407	27023526	Acetylation might stabilize LC3 preventing lysosome-independent degradation into the 20S proteasome.	('Acetylation', 'Var', (0, 11))	('LC3', 'Gene', (28, 31))	('LC3', 'Gene', '84557', (28, 31))
173412	27023526	In fact, under our conditions the blockade of lysosome enzymes, together with impairment of Rab5a, enhanced autophagy function as indicated by LC3II formation.	('LC3', 'Gene', '84557', (143, 146))	('LC3', 'Gene', (143, 146))	('enhanced', 'PosReg', (99, 107))	('blockade', 'Var', (34, 42))	('Rab5a', 'Gene', (92, 97))	('Rab5a', 'Gene', '5868', (92, 97))	('autophagy function', 'CPA', (108, 126))	('lysosome enzymes', 'Protein', (46, 62))
173414	27023526	We observed that in 1833 cells the puncta increased under 16 h NH4Cl, as well as under 16 h NH4Cl plus DeltaRab5a.	('increased', 'PosReg', (42, 51))	('NH4Cl', 'Var', (63, 68))	('NH4Cl', 'Chemical', 'MESH:D000643', (63, 68))	('Rab5a', 'Gene', (108, 113))	('Rab5a', 'Gene', '5868', (108, 113))	('puncta', 'MPA', (35, 41))	('NH4Cl', 'Chemical', 'MESH:D000643', (92, 97))
173415	27023526	In shRNA Atg7-transfected 1833 cells, the 16 h NH4Cl and 16 h NH4Cl plus DeltaRab5a strongly reduced puncta accumulation, because of the impairment of the autophagic process (Figure 4C).	('NH4Cl', 'Var', (62, 67))	('puncta accumulation', 'MPA', (101, 120))	('NH4Cl', 'Chemical', 'MESH:D000643', (62, 67))	('Rab5a', 'Gene', (78, 83))	('Atg7', 'Gene', (9, 13))	('autophagic process', 'CPA', (155, 173))	('reduced', 'NegReg', (93, 100))	('Rab5a', 'Gene', '5868', (78, 83))	('Atg7', 'Gene', '10533', (9, 13))	('NH4Cl', 'Var', (47, 52))	('NH4Cl', 'Chemical', 'MESH:D000643', (47, 52))	('impairment', 'NegReg', (137, 147))
173418	27023526	After transfection of DeltaRab5a, the steady-state protein level of Beclin 1 doubled, suggesting that this protein was not utilized for vesicle induction/nucleation.	('Beclin 1', 'Gene', '8678', (68, 76))	('Rab5a', 'Gene', '5868', (27, 32))	('transfection', 'Var', (6, 18))	('protein level', 'MPA', (51, 64))	('Beclin 1', 'Gene', (68, 76))	('doubled', 'PosReg', (77, 84))	('Rab5a', 'Gene', (27, 32))
173419	27023526	Interestingly, Beclin 1 decreased under DeltaRab5a and shRNA Atg7 co-transfection, since it likely underwent proteolysis in the proteasoma in the absence of functional autophagic process.	('Rab5a', 'Gene', (45, 50))	('decreased', 'NegReg', (24, 33))	('Rab5a', 'Gene', '5868', (45, 50))	('Beclin 1', 'Gene', (15, 23))	('co-transfection', 'Var', (66, 81))	('Atg7', 'Gene', (61, 65))	('underwent', 'Reg', (99, 108))	('Beclin 1', 'Gene', '8678', (15, 23))	('Atg7', 'Gene', '10533', (61, 65))
173420	27023526	In contrast, the knocking down of Atg7 augmented p62 without DeltaRab5a, because the early stages of the autophagosome formation were hampered preventing p62 utilization.	('p62', 'Gene', (154, 157))	('Rab5a', 'Gene', '5868', (66, 71))	('Atg7', 'Gene', '10533', (34, 38))	('p62', 'Gene', '8878', (49, 52))	('p62', 'Gene', (49, 52))	('hampered preventing', 'NegReg', (134, 153))	('augmented', 'PosReg', (39, 48))	('p62', 'Gene', '8878', (154, 157))	('Rab5a', 'Gene', (66, 71))	('knocking down', 'Var', (17, 30))	('Atg7', 'Gene', (34, 38))
173423	27023526	The knocking down of Atg7 together with DeltaRab5a made the cells transiently insensitive to 16 h NH4Cl.	('Rab5a', 'Gene', (45, 50))	('knocking down', 'Var', (4, 17))	('Atg7', 'Gene', '10533', (21, 25))	('Rab5a', 'Gene', '5868', (45, 50))	('NH4Cl', 'Chemical', 'MESH:D000643', (98, 103))	('Atg7', 'Gene', (21, 25))
173425	27023526	Under the shRNA Atg7 transfection, p62 accumulated in the presence of NH4Cl, because it was not utilized in the autophagosome function as a scaffold protein: a rapid down-regulation occurred when Rab5a was made nonfunctional.	('Rab5a', 'Gene', '5868', (196, 201))	('down-regulation', 'NegReg', (166, 181))	('NH4Cl', 'Chemical', 'MESH:D000643', (70, 75))	('p62', 'Gene', '8878', (35, 38))	('transfection', 'Var', (21, 33))	('Atg7', 'Gene', (16, 20))	('p62', 'Gene', (35, 38))	('Rab5a', 'Gene', (196, 201))	('Atg7', 'Gene', '10533', (16, 20))
173505	26077887	GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation.	('GPNMB', 'Gene', (0, 5))	('GPNMB', 'Gene', '10457', (0, 5))	('increased', 'PosReg', (49, 58))	('HER2', 'Gene', (64, 68))	('expression', 'MPA', (69, 79))	('small', 'Var', (19, 24))	('depletion', 'Var', (6, 15))	('HER2', 'Gene', '2064', (64, 68))	('phosphorylation', 'MPA', (84, 99))
173528	26077887	BC cell lines (MCF7, SK-BR-3, BT-474, MDA-MB-231, and MDA-MB-157), an immortalized normal breast cell line (MCF10), colon cancer (CC) cell lines (SW48, HCT116, LS174T, SW1417, Lovo, and Colo320DM), and GC cell lines (MKN1, MKN7, MKN45, and MKN74) used in this study were all obtained from American Type Cell Cultures (ATCC, Manassas, VA).	('HCT116', 'CellLine', 'CVCL:0291', (152, 158))	('MCF10', 'CellLine', 'CVCL:5555', (108, 113))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (38, 48))	('SW48', 'CellLine', 'CVCL:1724', (146, 150))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('MCF7', 'CellLine', 'CVCL:0031', (15, 19))	('SK-BR-3', 'CellLine', 'CVCL:0033', (21, 28))	('MDA-MB-157', 'Var', (54, 64))	('colon cancer', 'Disease', (116, 128))	('SW1417', 'CellLine', 'CVCL:1717', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (54, 64))
173552	26077887	The ERK inhibitor FR180204 was from EMD Millipore (Billerica, MA), and the v-akt murine thymoma viral oncogene homolog (Akt) inhibitor MK-2206 from Merck Oncology (Whitehouse Station, NJ).	('akt', 'Gene', (77, 80))	('thymoma viral', 'Disease', 'MESH:D013945', (88, 101))	('FR180204', 'Chemical', 'MESH:C505241', (18, 26))	('murine', 'Species', '10090', (81, 87))	('thymoma', 'Phenotype', 'HP:0100522', (88, 95))	('Oncology', 'Phenotype', 'HP:0002664', (154, 162))	('MK-2206', 'Chemical', 'MESH:C548887', (135, 142))	('FR180204', 'Var', (18, 26))	('ERK', 'Gene', (4, 7))	('akt', 'Gene', '207', (77, 80))	('thymoma viral', 'Disease', (88, 101))
173560	26077887	Although very low expression was observed in only two (LS174T and Colo320DM) of the six CC cell lines tested, two (MKN1 and MKN7) of the four GC cell lines expressed GPNMB.	('GPNMB', 'Gene', (166, 171))	('LS174T', 'Var', (55, 61))	('GPNMB', 'Gene', '10457', (166, 171))
173578	26077887	Furthermore, the GPNMB levels of the TNBC group were also higher than those of the DCIS group (P = 0.0459), as shown in Figure2C.	('GPNMB', 'Gene', (17, 22))	('TNBC', 'Var', (37, 41))	('GPNMB', 'Gene', '10457', (17, 22))	('higher', 'PosReg', (58, 64))
173609	26077887	In order to confirm this speculation, we investigated the cell growth after knocking down GPNMB.	('GPNMB', 'Gene', (90, 95))	('GPNMB', 'Gene', '10457', (90, 95))	('knocking down', 'Var', (76, 89))
173639	26077887	Our data demonstrate that GPNMB depletion induced not only the expression of HER2 and EGFR but also their phosphorylation.	('GPNMB', 'Gene', '10457', (26, 31))	('depletion', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (86, 90))	('phosphorylation', 'MPA', (106, 121))	('HER2', 'Gene', (77, 81))	('expression', 'MPA', (63, 73))	('HER2', 'Gene', '2064', (77, 81))	('EGFR', 'Gene', (86, 90))	('induced', 'Reg', (42, 49))	('GPNMB', 'Gene', (26, 31))
173650	26077887	We could demonstrate that combined GPNMB depletion and Tra treatment led induced a stronger effect on HER2-positive tumor suppression than Tra treatment alone.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Tra', 'Chemical', 'MESH:D000068878', (55, 58))	('HER2', 'Gene', (102, 106))	('GPNMB', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('depletion', 'Var', (41, 50))	('GPNMB', 'Gene', '10457', (35, 40))	('HER2', 'Gene', '2064', (102, 106))	('tumor', 'Disease', (116, 121))	('Tra', 'Chemical', 'MESH:D000068878', (139, 142))
173659	26077887	Very recently, the results of phase I trials have been reported that glembatumumab vedotin is clinically useful for TNBC or high GPNMB-positive tumors with longer progression-free survival (PFS) than GPNMB-negative tumors.	('tumors', 'Disease', (144, 150))	('GPNMB', 'Gene', '10457', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('TNBC', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('GPNMB', 'Gene', (129, 134))	('clinical', 'Species', '191496', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('GPNMB', 'Gene', (200, 205))	('GPNMB', 'Gene', '10457', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('high', 'Var', (124, 128))	('glembatumumab vedotin', 'Chemical', 'MESH:C551271', (69, 90))	('tumors', 'Disease', (215, 221))	('longer', 'PosReg', (156, 162))
173677	23053642	Tumors develop under the influence of both genetic and epigenetic changes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('genetic', 'Var', (43, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic changes', 'Var', (55, 73))
173678	23053642	It has been suggested that epigenetic changes are more frequent in cancer cells than genetic mutations.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('epigenetic changes', 'Var', (27, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('frequent', 'Reg', (55, 63))
173679	23053642	During tumorigenesis, cells undergo both genome-wide DNA hypomethylation and local hypermethylation of CpG islands associated with promoters.	('tumor', 'Disease', (7, 12))	('hypermethylation', 'Var', (83, 99))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('CpG', 'Protein', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
173680	23053642	Hypomethylation of long interspersed nuclear element 1 (LINE-1 or L1) sequences occurs at a very early stage of malignant transformation, resulting in inappropriate expressions of L1 retrotransposons.	('Hypomethylation', 'Var', (0, 15))	('expressions', 'MPA', (165, 176))	('LINE-1 or L1', 'Gene', (56, 68))	('LINE-1 or L1', 'Gene', '28938', (56, 68))	('L1 retrotransposons', 'Protein', (180, 199))
173681	23053642	It was recently reported that the hypomethylation of L1 retrotransposons activates an antisense promoter for cancer-specific genes in human cells.	('human', 'Species', '9606', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('antisense promoter', 'MPA', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('activates', 'PosReg', (73, 82))	('hypomethylation', 'Var', (34, 49))
173683	23053642	While most of the copies of L1s are defective because of truncations or mutations, the human-specific (L1Hs) subfamily, which contains intact, full-length L1 elements, is still potentially active in the human genome.	('L1s', 'Gene', (28, 31))	('mutations', 'Var', (72, 81))	('human', 'Species', '9606', (203, 208))	('human', 'Species', '9606', (87, 92))	('truncations', 'Var', (57, 68))
173687	23053642	Given that the L1 retrotransposition could induce genome instability, we set out to characterize the expression patterns of both ORF1p and ORF2p at various stages of breast cancer and to determine whether the expression pattern might be of clinical usefulness.	('L1 retrotransposition', 'Var', (15, 36))	('ORF1p', 'Gene', '55354', (129, 134))	('clinical', 'Species', '191496', (240, 248))	('ORF1p', 'Gene', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('genome instability', 'MPA', (50, 68))	('breast cancer', 'Disease', (166, 179))	('induce', 'Reg', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('ORF2p', 'Gene', '100128274', (139, 144))	('ORF2p', 'Gene', (139, 144))
173740	23053642	1D, both ORF1p and ORF2p were significantly overexpressed in cells transfected with L1RP vector compared with weak detection of untransfected cells, which is consistent with previous reports.	('ORF1p', 'Gene', (9, 14))	('L1RP vector', 'Var', (84, 95))	('overexpressed', 'PosReg', (44, 57))	('ORF2p', 'Gene', '100128274', (19, 24))	('ORF1p', 'Gene', '55354', (9, 14))	('ORF2p', 'Gene', (19, 24))
173765	23053642	A recent study reported that nuclear localization of ORF1p was significantly associated with aggressive behavior of cancer and poor outcome.	('associated with', 'Reg', (77, 92))	('aggressive behavior of cancer', 'Disease', (93, 122))	('aggressive behavior', 'Phenotype', 'HP:0000718', (93, 112))	('ORF1p', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('nuclear localization', 'Var', (29, 49))	('aggressive behavior of cancer', 'Disease', 'MESH:D001523', (93, 122))	('ORF1p', 'Gene', '55354', (53, 58))
173770	23053642	Expression of ORF1p and ORF2p was both categorized into three groups: (i) cytoplasmic expression, weak <29 %, moderate 30-59 %, and high expression >60 %; (ii) nuclear expression, weak < 29 %, moderate 30-59 %, and high > 60 % (Fig.	('ORF2p', 'Gene', '100128274', (24, 29))	('ORF2p', 'Gene', (24, 29))	('weak <29 %', 'Var', (98, 108))	('ORF1p', 'Gene', '55354', (14, 19))	('ORF1p', 'Gene', (14, 19))	('weak < 29 %', 'Var', (180, 191))	('high > 60 %', 'Var', (215, 226))
173782	23053642	Patients with high nuclear ORF1p and ORF2p expression showed apparent association with the presence of lymph node metastasis (p < 0.043) than did patients with cytoplasmic expression.	('ORF2p', 'Gene', (37, 42))	('lymph node metastasis', 'CPA', (103, 124))	('ORF1p', 'Gene', '55354', (27, 32))	('Patients', 'Species', '9606', (0, 8))	('high nuclear', 'Var', (14, 26))	('ORF1p', 'Gene', (27, 32))	('ORF2p', 'Gene', '100128274', (37, 42))	('patients', 'Species', '9606', (146, 154))
173786	23053642	95 % ER-positive DCIS and 95 % PR-positive DCIS exhibited cytoplasmic expression of both ORF1p and ORF2p.	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('ORF2p', 'Gene', '100128274', (99, 104))	('ORF2p', 'Gene', (99, 104))	('ORF1p', 'Gene', '55354', (89, 94))	('ER-positive', 'Var', (5, 16))	('ORF1p', 'Gene', (89, 94))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
173791	23053642	In the breast, it has been recently reported that nuclear, but not cytoplasmic ORF1p, is associated with genomic instability of tumors, which are characterized by aggressive behavior and poor outcome.	('associated with', 'Reg', (89, 104))	('genomic instability', 'MPA', (105, 124))	('nuclear', 'Var', (50, 57))	('aggressive behavior', 'Phenotype', 'HP:0000718', (163, 182))	('ORF1p', 'Gene', '55354', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('ORF1p', 'Gene', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('aggressive behavior', 'Disease', (163, 182))	('aggressive behavior', 'Disease', 'MESH:D001523', (163, 182))
173800	23053642	In patients with high nuclear ORF1p and ORF2p expression, there was a strong trend for lymph node metastasis (p = 0.001).	('ORF2p', 'Gene', (40, 45))	('ORF2p', 'Gene', '100128274', (40, 45))	('ORF1p', 'Gene', '55354', (30, 35))	('high nuclear', 'Var', (17, 29))	('ORF1p', 'Gene', (30, 35))	('patients', 'Species', '9606', (3, 11))	('lymph node metastasis', 'CPA', (87, 108))
173806	23053642	However, it remains unclear whether any relationship exists between the various stages and grades of breast cancers and the expression level of ORF2p, which is a key protein involved in creating DNA breaks and inserting L1 copies into genomic DNA during the process of L1 retrotransposition.	('ORF2p', 'Gene', (144, 149))	('ORF2p', 'Gene', '100128274', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast cancers', 'Disease', (101, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('inserting', 'Var', (210, 219))
173814	23053642	Certainly, hypomethylation of L1 promoters, which has been shown to correlate with L1 mRNA expression in breast cancer cell lines, would be consistent with the expression of ORF1p and ORF2p that we see in DCIS tumors.	('DCIS tumors', 'Disease', 'MESH:D002285', (205, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('hypomethylation', 'Var', (11, 26))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('ORF1p', 'Gene', '55354', (174, 179))	('ORF1p', 'Gene', (174, 179))	('DCIS', 'Phenotype', 'HP:0030075', (205, 209))	('ORF2p', 'Gene', '100128274', (184, 189))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('ORF2p', 'Gene', (184, 189))	('DCIS tumors', 'Disease', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
173820	23053642	Genomic instability tends to correlate with triple negative (ER/PR/Her-2neu-receptor negative) breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('Genomic instability', 'Var', (0, 19))	('triple negative', 'Disease', (44, 59))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
173841	30211123	Deletions within the WWOX coding sequence are observed in up to 80% of breast cancer cases, which makes it one of the most common genetic alterations in this tumor type.	('breast cancer', 'Disease', (71, 84))	('tumor', 'Disease', (158, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('observed', 'Reg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('WWOX', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('Deletions', 'Var', (0, 9))
173842	30211123	The WWOX gene is known to play a role in breast cancer: increased expression of WWOX inhibits cell proliferation in suspension, reduces tumor growth rates in xenographic transplants, but also enhances cell migration through the basal membrane and contributes to morphological changes in 3D matrix-based cell cultures.	('inhibits', 'NegReg', (85, 93))	('contributes', 'Reg', (247, 258))	('WWOX', 'Gene', (80, 84))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('increased', 'PosReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cell proliferation in suspension', 'CPA', (94, 126))	('enhances', 'PosReg', (192, 200))	('reduces', 'NegReg', (128, 135))	('cell migration through the basal membrane', 'CPA', (201, 242))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('morphological changes', 'CPA', (262, 283))	('expression', 'Var', (66, 76))	('tumor', 'Disease', (136, 141))
173855	30211123	For a long time this region was of particular interest, because of the high incidence of loss of heterozygosity (LOH); this was first observed in prostate cancer, and later in several other tumor types, including liver cancer (40% LOH), ovarian cancer, ductal breast cancer in situ (DCIS) (about 80% LOH), sporadic breast cancer, extrahepatic bile ducts, esophageal squamous cell carcinoma, non-small lung, pancreas, multiple myeloma, thyroid, glioblastoma multiforme, and Wilms tumors (20-30% LOH).	('glioblastoma multiforme', 'Disease', (444, 467))	('loss', 'Var', (89, 93))	('liver cancer', 'Phenotype', 'HP:0002896', (213, 225))	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (355, 389))	('glioblastoma', 'Phenotype', 'HP:0012174', (444, 456))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (444, 467))	('liver cancer', 'Disease', (213, 225))	('pancreas', 'Disease', 'MESH:D010190', (407, 415))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('multiple myeloma', 'Phenotype', 'HP:0006775', (417, 433))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('tumor', 'Disease', (479, 484))	('Wilms tumors', 'Phenotype', 'HP:0002667', (473, 485))	('DCIS', 'Phenotype', 'HP:0030075', (283, 287))	('small lung', 'Phenotype', 'HP:0002089', (395, 405))	('prostate cancer', 'Disease', (146, 161))	('multiple myeloma', 'Disease', 'MESH:D009101', (417, 433))	('tumor', 'Disease', 'MESH:D009369', (479, 484))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('ductal breast cancer', 'Disease', 'MESH:D001943', (253, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('Wilms tumors', 'Disease', (473, 485))	('thyroid', 'Disease', (435, 442))	('ductal breast cancer in situ', 'Phenotype', 'HP:0030075', (253, 281))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('breast cancer', 'Disease', 'MESH:D001943', (260, 273))	('breast cancer', 'Disease', (315, 328))	('ovarian cancer', 'Disease', 'MESH:D010051', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (479, 484))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', (190, 195))	('multiple myeloma', 'Disease', (417, 433))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('extrahepatic bile ducts', 'Disease', (330, 353))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('esophageal squamous cell carcinoma', 'Disease', (355, 389))	('pancreas', 'Disease', (407, 415))	('non-small lung', 'Disease', (391, 405))	('tumors', 'Phenotype', 'HP:0002664', (479, 485))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('liver cancer', 'Disease', 'MESH:D006528', (213, 225))	('Wilms tumors', 'Disease', 'MESH:D009396', (473, 485))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ductal breast cancer', 'Disease', (253, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (366, 389))	('ovarian cancer', 'Disease', (237, 251))
173862	30211123	All these results suggest that the WW2 domain of WWOX protein serves as a chaperone to augment binding of WW1 domain within WWOX to PPXY motifs of WBP1 and WBP2 proteins, along with other partner proteins, such as ERBB4.	('WW1 domain', 'Var', (106, 116))	('ERBB4', 'Gene', (214, 219))	('augment', 'PosReg', (87, 94))	('ERBB4', 'Gene', '2066', (214, 219))	('WBP1', 'Gene', '23559', (147, 151))	('WBP1', 'Gene', (147, 151))	('binding', 'Interaction', (95, 102))	('WBP2', 'Gene', '23558', (156, 160))	('WBP2', 'Gene', (156, 160))
173867	30211123	Recently, it was also confirmed that WWOX physically interacts with the ITCH protein:an E3 ubiquitin ligase which ubiquitinates Lys-63 of WWOX leading to its nuclear translocation.	('nuclear translocation', 'MPA', (158, 179))	('Lys', 'Chemical', 'MESH:D008239', (128, 131))	('ITCH', 'Phenotype', 'HP:0000989', (72, 76))	('ITCH', 'Gene', '83737', (72, 76))	('Lys-63', 'Var', (128, 134))	('ITCH', 'Gene', (72, 76))	('WWOX', 'Gene', (138, 142))
173875	30211123	Additionally, the absence of WWOX was found to lead to differential expression of 15 steroidogenesis-associated genes.	('expression', 'MPA', (68, 78))	('differential', 'Reg', (55, 67))	('steroidogenesis-associated genes', 'Gene', (85, 117))	('steroid', 'Chemical', 'MESH:D013256', (85, 92))	('absence', 'Var', (18, 25))
173896	30211123	Thus in cancerous cells exhibiting depletion of Wwox, an important inhibitory step would be absent, which might result in enhanced end resection and HDR repair, finally allowing the cells to survive DNA damage-inducing cytotoxic treatments.	('enhanced', 'PosReg', (122, 130))	('cancerous', 'Disease', (8, 17))	('end resection', 'CPA', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancerous', 'Disease', 'MESH:D009369', (8, 17))	('depletion', 'Var', (35, 44))	('HDR', 'MPA', (149, 152))
173901	30211123	In a group of brain cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times: data obtained from Repository of Molecular Brain Neoplasia Data (REMBRANDT).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('brain cancer', 'Disease', (14, 26))	('shorter', 'NegReg', (106, 113))	('overall survival', 'MPA', (114, 130))	('Brain Neoplasia', 'Phenotype', 'HP:0030692', (181, 196))	('Neoplasia', 'Phenotype', 'HP:0002664', (187, 196))	('brain cancer', 'Disease', 'MESH:D001932', (14, 26))	('Molecular Brain Neoplasia Data', 'Disease', (171, 201))	('patients', 'Species', '9606', (27, 35))	('brain cancer', 'Phenotype', 'HP:0030692', (14, 26))	('deficiency', 'Var', (65, 75))	('Molecular Brain Neoplasia Data', 'Disease', 'MESH:D009369', (171, 201))	('Wwox', 'Gene', (60, 64))
173905	30211123	Moreover, the tumors formed by MDA-MB-435/vector transduced cells were found to be about 10-fold larger than tumors formed by cells transduced with the WWOX gene.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('MDA-MB-435/vector transduced', 'Var', (31, 59))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('transduced', 'Var', (49, 59))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (31, 41))
173906	30211123	A similar inhibition of tumor growth in athymic mice after injection of WWOX transduced cells was also observed for other cancer cell lines, including pancreatic cancer cell line- Panc-1, lung cancer - A549, H1299 H460, prostate cancer-DU-145, and ovarian cancer-PEO1.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('inhibition', 'NegReg', (10, 20))	('PEO1', 'Gene', (263, 267))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (256, 262))	('Panc-1', 'Gene', '104066', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung cancer', 'Disease', (188, 199))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('H1299 H460', 'CellLine', 'CVCL:0060', (208, 218))	('ovarian cancer', 'Disease', 'MESH:D010051', (248, 262))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', (229, 235))	('tumor', 'Disease', (24, 29))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('transduced', 'Var', (77, 87))	('ovarian cancer', 'Disease', (248, 262))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('A549', 'CellLine', 'CVCL:0023', (202, 206))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('cancer', 'Disease', (122, 128))	('mice', 'Species', '10090', (48, 52))	('Panc-1', 'Gene', (180, 186))	('ovarian cancer', 'Phenotype', 'HP:0100615', (248, 262))	('PEO1', 'Gene', '226153', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Disease', (220, 235))	('DU-145', 'CellLine', 'CVCL:0105', (236, 242))	('pancreatic cancer', 'Disease', (151, 168))
173912	30211123	On the other hand, a morphogenesis test in Matrigel revealed MDA-MB-231 cells transduced with WWOX to display branched structures, compared with the spherical tumor-like structures of control cells.	('transduced', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('branched structures', 'CPA', (110, 129))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
173925	30211123	Nevertheless, Wwox knockdown in a mouse model resulted in impaired mammary branching morphogenesis.	('knockdown', 'Var', (19, 28))	('mammary branching morphogenesis', 'CPA', (67, 98))	('impaired', 'NegReg', (58, 66))	('mouse', 'Species', '10090', (34, 39))
173931	30211123	As mentioned above, breast cancer deletions within the common chromosomal fragile site FRA16D are observed in more than 80% cases, which makes changes in the WWOX coding region the most common genetic alternation in breast cancer.	('FRA16D', 'Gene', '2463', (87, 93))	('chromosomal fragile site', 'Phenotype', 'HP:0040012', (62, 86))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', (216, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('breast cancer', 'Disease', (20, 33))	('deletions', 'Var', (34, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('FRA16D', 'Gene', (87, 93))
173932	30211123	However, LOH is not the only mechanism responsible for WWOX downregulation: hypermethylation and some infrequent point mutations within the coding region of WWOX have also been found to be involved in breast carcinogenesis and cancer progression.	('point mutations', 'Var', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('hypermethylation', 'Var', (76, 92))	('involved', 'Reg', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('WWOX', 'Gene', (157, 161))	('cancer', 'Disease', (227, 233))	('breast carcinogenesis', 'Disease', (201, 222))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (201, 222))
173933	30211123	In addition, rare homozygous deletions have also been observed for lung, ovarian, pancreatic and colon cancers, WWOX protein degradation has been observed as a result of ubiquitination in prostate cancer, and hypermethylation in gastric, pancreatic, bladder, lung, and prostate tumors.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('colon cancers', 'Phenotype', 'HP:0003003', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder', 'Disease', (250, 257))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('prostate tumors', 'Disease', (269, 284))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('WWOX protein degradation', 'MPA', (112, 136))	('pancreatic', 'Disease', 'MESH:D010195', (238, 248))	('prostate tumors', 'Disease', 'MESH:D011471', (269, 284))	('ovarian', 'Disease', (73, 80))	('ubiquitination in prostate cancer', 'Disease', (170, 203))	('ubiquitination in prostate cancer', 'Disease', 'MESH:D011471', (170, 203))	('lung', 'Disease', (259, 263))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('pancreatic', 'Disease', (82, 92))	('gastric', 'Disease', (229, 236))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('pancreatic', 'Disease', (238, 248))	('pancreatic and colon cancers', 'Disease', 'MESH:D010190', (82, 110))	('lung', 'Disease', (67, 71))	('gastric', 'Disease', 'MESH:D013274', (229, 236))	('hypermethylation', 'Var', (209, 225))
173955	30211123	The level of WWOX expression correlated with ER and PR status in a quantitative real-time RT-PCR study of 132 breast cancer cases: significantly higher WWOX expression was observed in ER+ tumors compared to ER- tumors, as well as in PR positive cancers compared to PR negatives, and in ER+PR+ tumors compared to ER-PR- cases.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('WWOX', 'Gene', (152, 156))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('ER+', 'Var', (184, 187))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('tumors', 'Disease', (293, 299))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (110, 123))	('tumors', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (211, 217))	('higher', 'PosReg', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('expression', 'MPA', (157, 167))
173961	30211123	In patients treated with tamoxifen, there was a significant correlation between high WWOX expression and a lowered risk of recurrence, indicating that WWOX might be a potential marker of tamoxifen effectiveness.	('tamoxifen', 'Chemical', 'MESH:D013629', (187, 196))	('WWOX', 'Protein', (85, 89))	('tamoxifen', 'Chemical', 'MESH:D013629', (25, 34))	('expression', 'MPA', (90, 100))	('patients', 'Species', '9606', (3, 11))	('high', 'Var', (80, 84))
173965	30211123	Knocking-down endogenous WWOX reduced invasion and E-cadherin expression in 1,833 cells, whilst its overexpression enhanced E-cadherin transactivation and protein level in the 1,833, but not in MDA-MB-231 cells, increasing also metastatic-cell migration.	('E-cadherin', 'Gene', '999', (51, 61))	('Knocking-down', 'Var', (0, 13))	('protein level', 'MPA', (155, 168))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (194, 204))	('invasion', 'CPA', (38, 46))	('increasing', 'PosReg', (212, 222))	('reduced', 'NegReg', (30, 37))	('overexpression enhanced', 'PosReg', (100, 123))	('metastatic-cell migration', 'CPA', (228, 253))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', (124, 134))	('E-cadherin', 'Gene', '999', (124, 134))
173976	30211123	The loss of WWOX resulted in activation of glycolysis in mouse embryonic fibroblasts (MEF) from KO embryos, compared with fibroblasts from WWOX-wild type embryos.	('activation', 'PosReg', (29, 39))	('WWOX', 'Gene', (12, 16))	('glycolysis', 'MPA', (43, 53))	('mouse', 'Species', '10090', (57, 62))	('loss', 'Var', (4, 8))
173977	30211123	Importantly, genetic or pharmacologic depletion of HIF1alpha was able to reverse WWOX-mediated phenotypes associated with its loss, including tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('depletion', 'Var', (38, 47))	('HIF1alpha', 'Gene', (51, 60))	('loss', 'NegReg', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
173991	30211123	Loss or dysregulation of WWOX expression leads not only to tumorigenesis and cancer progression, but also genomic instability and resistance to therapy.	('dysregulation', 'Var', (8, 21))	('genomic instability', 'CPA', (106, 125))	('resistance', 'CPA', (130, 140))	('tumor', 'Disease', (59, 64))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('leads', 'Reg', (41, 46))	('Loss', 'NegReg', (0, 4))	('WWOX', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
173992	30211123	Mutations and deletions completely silencing WWOX expression are very rare and most often we observe abrogation of its function through lowered WWOX protein synthesis and haploinsufficiency.	('silencing', 'NegReg', (35, 44))	('lowered', 'NegReg', (136, 143))	('haploinsufficiency', 'Disease', 'MESH:D058495', (171, 189))	('WWOX protein synthesis', 'MPA', (144, 166))	('Mutations', 'Var', (0, 9))	('deletions', 'Var', (14, 23))	('WWOX', 'Gene', (45, 49))	('haploinsufficiency', 'Disease', (171, 189))	('expression', 'MPA', (50, 60))
173997	29984041	Here, we report for the first time increased chemokine and chemokine receptor production by Mo-MDSCs in BC patients.	('increased', 'PosReg', (35, 44))	('Mo-MDSCs', 'Var', (92, 100))	('chemokine receptor', 'Gene', '7852', (59, 77))	('chemokine receptor', 'Gene', (59, 77))	('patients', 'Species', '9606', (107, 115))
174048	29984041	reported that CD33+ myeloid cells displayed the characteristic phenotype of MDSCs in tumor tissue based on immunohistochemical staining.	('tumor', 'Disease', (85, 90))	('MDSCs', 'Disease', (76, 81))	('CD33+', 'Var', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
174052	29984041	Interestingly, CXCR2 and CXCR4 have been demonstrated to stimulate MDSCs generation and migration to tumor sites.	('stimulate', 'PosReg', (57, 66))	('CXCR2', 'Var', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('MDSCs generation', 'MPA', (67, 83))	('CXCR4', 'Var', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
174059	29984041	It also shows that the expression of CXCR2 and CXCR4 each other to promote the metastasis of gastric cancer.	('CXCR4', 'Var', (47, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Disease', (93, 107))	('metastasis', 'CPA', (79, 89))	('promote', 'PosReg', (67, 74))
174113	19187537	To examine this further, we extracted all ribosomal protein-encoding genes that were differentially expressed between DCIS or IDC versus the normal breast in the epithelium and visualized their expression patterns in both compartments.	('S', 'Chemical', 'MESH:D013455', (121, 122))	('IDC', 'Gene', '4000', (126, 129))	('IDC', 'Gene', (126, 129))	('ribosomal protein-encoding genes', 'Gene', (42, 74))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('DCIS', 'Var', (118, 122))
174146	19187537	Thirdly, the oncogenic activity of c-Myc is inhibited by the ribosomal protein L11, and inactivation of the L11 gene by small interfering RNA increases c-Myc-induced transcription and cell proliferation.	('c-Myc', 'Gene', '4609', (35, 40))	('c-Myc', 'Gene', '4609', (152, 157))	('ribosomal protein L11', 'Gene', '6135', (61, 82))	('ribosomal protein L11', 'Gene', (61, 82))	('L11', 'Gene', (79, 82))	('small interfering', 'Var', (120, 137))	('increases', 'PosReg', (142, 151))	('c-Myc', 'Gene', (35, 40))	('c-Myc', 'Gene', (152, 157))	('L11', 'Gene', '6135', (79, 82))	('cell proliferation', 'CPA', (184, 202))	('L11', 'Gene', (108, 111))	('oncogenic activity', 'CPA', (13, 31))	('L11', 'Gene', '6135', (108, 111))	('inactivation', 'Var', (88, 100))
174154	19187537	The WNT signaling pathway plays an important role in development and tissue homeostasis, and its aberrant activation by loss of expression WIF1 or SFRP1 has been shown to be an important early event in breast cancer progression.	('WNT signaling pathway', 'Pathway', (4, 25))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('SFRP1', 'Gene', (147, 152))	('breast cancer', 'Disease', (202, 215))	('WIF1', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('loss of', 'Var', (120, 127))	('WIF1', 'Gene', '11197', (139, 143))	('activation', 'PosReg', (106, 116))	('SFRP1', 'Gene', '6422', (147, 152))
174208	33596961	In a recent study, the presence of necrosis in diagnostic preoperative biopsies of over 600 women with DCIS was found to be a strong predictor of both DCIS upgrading and upstaging to invasive carcinoma in the final surgical specimens.	('DCIS', 'Disease', (151, 155))	('necrosis', 'Disease', (35, 43))	('invasive carcinoma', 'Disease', 'MESH:D009361', (183, 201))	('women', 'Species', '9606', (92, 97))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('necrosis', 'Disease', 'MESH:D009336', (35, 43))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('presence', 'Var', (23, 31))	('upgrading', 'PosReg', (156, 165))	('invasive carcinoma', 'Disease', (183, 201))	('upstaging', 'PosReg', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
174255	33596961	The combined use of C2Am and iC2Am, which were labeled with two different fluorophores, enabled a ratiometric assessment of cell death that accounted for non-specific probe retention by the cells (see Supplementary Figure S1).	('C2Am', 'Chemical', '-', (20, 24))	('iC2Am', 'Chemical', '-', (29, 34))	('iC2Am', 'Var', (29, 34))	('C2Am', 'Var', (20, 24))	('C2Am', 'Chemical', '-', (30, 34))
174256	33596961	The level of MCF10ADCIS cell death induced by doxorubicin (10 muM, 24 h, Fig.	('MCF10ADCIS', 'CellLine', 'CVCL:5555', (13, 23))	('cell death', 'CPA', (24, 34))	('MCF10ADCIS', 'Var', (13, 23))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('doxorubicin', 'Chemical', 'MESH:D004317', (46, 57))
174258	33596961	iC2Am generated low levels of fluorescence (Fig.	('fluorescence', 'MPA', (30, 42))	('iC2Am', 'Chemical', '-', (0, 5))	('iC2Am', 'Var', (0, 5))
174261	33596961	The C2Am/iC2Am ratio also correlated with FLICA staining (R = 0.857, P = 0.0004), with a level of contrast that was up to 10-fold higher with C2Am than with iC2Am (Fig.	('FLICA', 'Disease', (42, 47))	('C2Am', 'Var', (142, 146))	('C2Am', 'Chemical', '-', (4, 8))	('C2Am', 'Chemical', '-', (10, 14))	('iC2Am', 'Chemical', '-', (9, 14))	('higher', 'PosReg', (130, 136))	('C2Am', 'Chemical', '-', (142, 146))	('iC2Am', 'Chemical', '-', (157, 162))	('correlated', 'Reg', (26, 36))	('C2Am', 'Chemical', '-', (158, 162))
174268	33596961	3-fold greater (lesion/fat pad) contrast ex vivo with C2Am than with iC2Am (Fig.	('greater', 'PosReg', (7, 14))	('C2Am', 'Var', (54, 58))	('C2Am', 'Chemical', '-', (70, 74))	('C2Am', 'Chemical', '-', (54, 58))	('iC2Am', 'Chemical', '-', (69, 74))
174283	33596961	Lastly, with a view to clinical translation, we conducted optoacoustic imaging of cell death in the same DCIS model using C2Am and iC2Am.	('iC2Am', 'Chemical', '-', (131, 136))	('iC2Am', 'Var', (131, 136))	('C2Am', 'Chemical', '-', (132, 136))	('C2Am', 'Var', (122, 126))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('C2Am', 'Chemical', '-', (122, 126))
174287	33596961	6d, R = 0.962, P = 0.002) and also between C2Am lesion MSOT and FLI signals (Fig.	('C2Am', 'Disease', (43, 47))	('C2Am', 'Chemical', '-', (43, 47))	('lesion', 'Var', (48, 54))	('FLI signals', 'MPA', (64, 75))
174288	33596961	iC2Am lesion MSOT and FLI signals (Fig.	('iC2Am', 'Chemical', '-', (0, 5))	('lesion', 'Var', (6, 12))	('FLI signals', 'CPA', (22, 33))	('iC2Am lesion', 'Var', (0, 12))
174289	33596961	Several cell surface markers have been proposed as targets for the molecular imaging of DCIS, including IGF1-R, VEGFr, HER2, EGFR, MET, CD44v6, GLUT1, CA-XII, and mammaglobin.	('CA-XII', 'Gene', '771', (151, 157))	('VEGFr', 'Gene', '3791', (112, 117))	('VEGFr', 'Gene', (112, 117))	('GLUT1', 'Gene', (144, 149))	('EGFR', 'Gene', '1956', (125, 129))	('HER2', 'Gene', (119, 123))	('IGF1-R', 'Gene', (104, 110))	('CD44v6', 'Var', (136, 142))	('GLUT1', 'Gene', '6513', (144, 149))	('MET', 'Gene', '79811', (131, 134))	('EGFR', 'Gene', (125, 129))	('HER2', 'Gene', '2064', (119, 123))	('IGF1-R', 'Gene', '3480', (104, 110))	('MET', 'Gene', (131, 134))	('CA-XII', 'Gene', (151, 157))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
174296	33596961	Moreover, in a 10-year follow-up study of 728 patients, the presence of confluent tumor necrosis in invasive areas of lymph-node positive breast cancer, within 2 years of diagnosis, was found to be an independent predictor for early recurrence and overall survival.	('patients', 'Species', '9606', (46, 54))	('overall survival', 'CPA', (248, 264))	('tumor necrosis', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('presence', 'Var', (60, 68))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast cancer', 'Disease', (138, 151))	('early recurrence', 'CPA', (227, 243))	('tumor necrosis', 'Disease', 'MESH:D009336', (82, 96))
174309	33596961	6d), whereas iC2Am generated significantly less signal (P < 0.05, n = 6) in the same lesions (Fig.	('iC2Am', 'Chemical', '-', (13, 18))	('iC2Am', 'Var', (13, 18))	('less', 'NegReg', (43, 47))
174317	26265211	Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (56, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('invasive breast cancer', 'Disease', (86, 108))	('ductal carcinoma', 'Disease', 'MESH:D044584', (193, 209))	('invasive breast cancer', 'Disease', 'MESH:D001943', (86, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('ductal carcinoma in situ', 'Disease', (193, 217))	('DCIS', 'Phenotype', 'HP:0030075', (219, 223))	('ductal carcinoma', 'Disease', 'MESH:D044584', (56, 72))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (56, 80))	('increase', 'PosReg', (164, 172))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (193, 217))	('Chromosomal copy number alterations', 'Var', (0, 35))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (200, 217))	('ductal carcinoma in situ', 'Disease', (56, 80))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (193, 217))
174323	26265211	On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC.	('IBC', 'Disease', (140, 143))	('copy number gains', 'Var', (76, 93))	('IBC', 'Chemical', '-', (140, 143))	('associated', 'Reg', (113, 123))
174324	26265211	The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).	('gains', 'Var', (160, 165))	('copy number gains', 'Var', (30, 47))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('IBC', 'Chemical', '-', (86, 89))	('DCIS', 'Gene', (195, 199))	('IBC', 'Disease', (86, 89))	('DCIS', 'Gene', (51, 55))
174336	26265211	A number of studies have previously examined the risk of DCIS recurrence using protein expression markers; however, DNA copy number changes are common in early genomic lesions and may serve as more robust biomarkers due to their insensitivity to intratumoral factors such as hypoxia.	('tumor', 'Disease', (251, 256))	('DNA', 'Gene', (116, 119))	('hypoxia', 'Disease', (275, 282))	('hypoxia', 'Disease', 'MESH:D000860', (275, 282))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('copy number changes', 'Var', (120, 139))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
174345	26265211	Based on data for SNV/CNA frequencies in IBC in TCGA, we modeled 45 % (ten of 22) of our alterations as low frequency (this group is representative of low-frequency breast cancer alterations such as MLL3 mutation, PTEN mutation and GATA3 mutation), 27 % (six of 22) as moderate frequency (representative of moderate frequency breast cancer alterations such as 11q13 gain, 8q24 gain, ERBB2 gain and CDH1 mutation), and 27 % (six of 22) as high frequency (representative of common breast cancer alterations such as TP53 mutation, PIK3CA mutation, 1q gain, 8q gain, 16p gain, 20q gain, 16q deletion, 17p deletion, 8p deletion, and 22q deletion, among other common arm-level CNAs) in the simulated DCIS samples.	('CDH1', 'Gene', (398, 402))	('breast cancer', 'Disease', (326, 339))	('gain', 'PosReg', (577, 581))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('GATA3', 'Gene', (232, 237))	('TP53', 'Gene', (513, 517))	('16p', 'Var', (563, 566))	('gain', 'PosReg', (567, 571))	('PTEN', 'Gene', '5728', (214, 218))	('MLL3', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (486, 492))	('ERBB2', 'Gene', '2064', (383, 388))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('mutation', 'Var', (518, 526))	('breast cancer', 'Disease', (165, 178))	('mutation', 'Var', (535, 543))	('PIK3CA', 'Gene', (528, 534))	('gain', 'PosReg', (557, 561))	('DCIS', 'Phenotype', 'HP:0030075', (694, 698))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('gain', 'PosReg', (548, 552))	('breast cancer', 'Phenotype', 'HP:0003002', (479, 492))	('TP53', 'Gene', '7157', (513, 517))	('IBC', 'Chemical', '-', (41, 44))	('breast cancer', 'Disease', 'MESH:D001943', (479, 492))	('16q deletion', 'Var', (583, 595))	('breast cancer', 'Disease', (479, 492))	('MLL3', 'Gene', '58508', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (326, 339))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('CDH1', 'Gene', '999', (398, 402))	('PTEN', 'Gene', (214, 218))	('8p deletion', 'Var', (611, 622))	('PIK3CA', 'Gene', '5290', (528, 534))	('GATA3', 'Gene', '2625', (232, 237))	('ERBB2', 'Gene', (383, 388))	('breast cancer', 'Disease', 'MESH:D001943', (326, 339))
174373	26265211	We used logistic regression techniques to characterize the association between copy number gains at three loci and IBC among patients with DCIS.	('copy number gains', 'Var', (79, 96))	('IBC', 'Chemical', '-', (115, 118))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('IBC', 'Disease', (115, 118))	('patients', 'Species', '9606', (125, 133))
174374	26265211	The multivariable model on which our primary analysis was based additionally included age at diagnosis, race, and hormone receptor status, grade of the DCIS component and HER2 gain in order to gauge the association of copy number status and IBC after adjusting for demographics and relevant clinical variables.	('IBC', 'Chemical', '-', (241, 244))	('copy number', 'Var', (218, 229))	('hormone receptor', 'Gene', (114, 130))	('HER2', 'Gene', (171, 175))	('IBC', 'Disease', (241, 244))	('hormone receptor', 'Gene', '3164', (114, 130))	('HER2', 'Gene', '2064', (171, 175))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))
174380	26265211	We examined the presence of copy number gains in three chromosomal loci, 1q, 8q24, and 11q13, by FISH in 280 samples diagnosed as DCIS only (122 cases with no development of IBC over a median follow-up period of 9 years), or DCIS plus IBC (158 cases) (Table 2) arrayed on a TMA.	('TMA', 'Disease', (274, 277))	('IBC', 'Chemical', '-', (235, 238))	('IBC', 'Chemical', '-', (174, 177))	('TMA', 'Disease', 'MESH:D000783', (274, 277))	('copy number', 'Var', (28, 39))	('DCIS', 'Phenotype', 'HP:0030075', (225, 229))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
174381	26265211	We chose to study a set of loci (1q, 8q24, and 11q13) which have a high frequency of copy number gains (>30 %) among at least two molecular breast cancer subtypes.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('copy', 'Var', (85, 89))
174383	26265211	Overall copy number gain frequency was as follows: 1q at 52 % (compared to 64 % in IBC), 8q24 at 44 % (compared to 60 % in IBC), and 11q13 at 20 % (compared to 32 % in IBC).	('IBC', 'Chemical', '-', (123, 126))	('IBC', 'Chemical', '-', (168, 171))	('IBC', 'Chemical', '-', (83, 86))	('8q24', 'Var', (89, 93))	('11q13', 'Var', (133, 138))
174386	26265211	The prevalence of copy number gain was higher in DCIS with concurrent IBC versus DCIS alone across all three genomic loci individually (1.35- to 3-fold), in combinations, and with all three copy number gains (Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('higher', 'PosReg', (39, 45))	('DCIS', 'Disease', (49, 53))	('DCIS', 'Phenotype', 'HP:0030075', (49, 53))	('IBC', 'Chemical', '-', (70, 73))	('copy number', 'Var', (18, 29))	('IBC', 'Disease', (70, 73))	('gain', 'PosReg', (30, 34))
174388	26265211	The overall copy number gain frequency of HER2 was 32.9 %.	('HER2', 'Gene', '2064', (42, 46))	('copy number gain', 'Var', (12, 28))	('HER2', 'Gene', (42, 46))
174391	26265211	When we examined the co-existence of copy number gains of HER2 and the other three genomic loci, we found a statistically significant difference in the frequency distribution between the two diagnostic groups for the cytogenetic combination of 1q, 11q13 and HER2 (p = 0.038, Table 3).	('copy number', 'Var', (37, 48))	('HER2', 'Gene', (258, 262))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (258, 262))	('HER2', 'Gene', '2064', (58, 62))
174392	26265211	To characterize the association between DCIS and IBC, we applied multivariable models of IBC as a function of a six-level categorical variable describing chromosomal gains at regions 1q, 8q24 and 11q13, along with age at diagnosis, race, hormone receptor status, histological grade and the presence of HER2 gain (Table 4 and see Additional file 4).	('HER2', 'Gene', (302, 306))	('IBC', 'Chemical', '-', (89, 92))	('HER2', 'Gene', '2064', (302, 306))	('gain', 'PosReg', (307, 311))	('hormone receptor', 'Gene', '3164', (238, 254))	('IBC', 'Chemical', '-', (49, 52))	('chromosomal', 'Var', (154, 165))	('hormone receptor', 'Gene', (238, 254))	('DCIS', 'Phenotype', 'HP:0030075', (40, 44))
174393	26265211	The association between copy number gain and IBC was statistically significant in both complete-case analysis and multiple-imputation (MI) analysis (p = 0.0013, 0.0001, respectively) and shows that subjects with gains at all three loci are 18 times more likely to have an IBC diagnosis than subjects without gains at these loci; subjects with exactly two copy number gains are nine times more likely to have an IBC diagnosis, and subjects with 8q24 gain only are 4.2 times more likely to have IBC than subjects with no gain in these regions (MI analysis).	('IBC', 'Disease', (493, 496))	('copy', 'Var', (24, 28))	('IBC', 'Chemical', '-', (272, 275))	('IBC', 'Chemical', '-', (411, 414))	('IBC diagnosis', 'Disease', (411, 424))	('IBC', 'Chemical', '-', (45, 48))	('IBC diagnosis', 'Disease', (272, 285))	('IBC', 'Chemical', '-', (493, 496))
174395	26265211	Of note, HER2 gain is not significantly associated with invasive cancer in the univariate analysis, but is inversely associated in the multivariate analysis, in which subjects with HER2 copy number gain were significantly less likely to have an IBC diagnosis (odds ratio 0.47, p = 0.039), when compared to DCIS alone (Table 4).	('invasive cancer', 'Disease', 'MESH:D009362', (56, 71))	('IBC diagnosis', 'Disease', (245, 258))	('HER2', 'Gene', '2064', (181, 185))	('copy number gain', 'Var', (186, 202))	('HER2', 'Gene', (9, 13))	('HER2', 'Gene', '2064', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('less', 'NegReg', (222, 226))	('HER2', 'Gene', (181, 185))	('DCIS', 'Phenotype', 'HP:0030075', (306, 310))	('invasive cancer', 'Disease', (56, 71))	('IBC', 'Chemical', '-', (245, 248))
174397	26265211	This study demonstrates that genomic changes can act as a risk stratifier for DCIS, predicting the presence of concurrent IBC.	('IBC', 'Chemical', '-', (122, 125))	('IBC', 'Disease', (122, 125))	('genomic changes', 'Var', (29, 44))	('DCIS', 'Disease', (78, 82))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))
174399	26265211	By contrast, we did find significantly higher frequencies for copy number gains at 1q, 8q24 and 11q13 with any two of three genomic loci and all three genomic loci in patients with DCIS and concurrent invasive cancer when compared to DCIS only.	('DCIS', 'Disease', (181, 185))	('invasive cancer', 'Disease', 'MESH:D009362', (201, 216))	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('copy number gains', 'Var', (62, 79))	('patients', 'Species', '9606', (167, 175))	('invasive cancer', 'Disease', (201, 216))
174400	26265211	Multivariable analysis showed that gains at the three regions were significantly associated with IBC among patients with DCIS, after adjustment for important clinical variables including grade, hormone receptor status and even HER2 copy number gain, which was associated with a lower risk of having invasive cancer and is consistent with prior publications on DCIS.	('gains', 'PosReg', (35, 40))	('HER2', 'Gene', '2064', (227, 231))	('invasive cancer', 'Disease', 'MESH:D009362', (299, 314))	('DCIS', 'Phenotype', 'HP:0030075', (360, 364))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('copy number gain', 'Var', (232, 248))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('invasive cancer', 'Disease', (299, 314))	('hormone receptor', 'Gene', '3164', (194, 210))	('IBC', 'Chemical', '-', (97, 100))	('IBC', 'Disease', (97, 100))	('hormone receptor', 'Gene', (194, 210))	('patients', 'Species', '9606', (107, 115))	('HER2', 'Gene', (227, 231))
174405	26265211	DNA copy number changes are common in early genomic lesions and may be more robust as biomarkers than gene expression levels, which can be subject to heterogeneity due to intratumoral factors such as hypoxia.	('hypoxia', 'Disease', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('copy number changes', 'Var', (4, 23))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))
174425	26265211	In addition, PIK3CA mutation occurs early in oncogenesis and is associated with ductal hyperplasias, while TP53 mutations at early stages have not been found.	('associated', 'Reg', (64, 74))	('PIK3CA', 'Gene', (13, 19))	('TP53', 'Gene', '7157', (107, 111))	('mutation', 'Var', (20, 28))	('TP53', 'Gene', (107, 111))	('PIK3CA', 'Gene', '5290', (13, 19))	('ductal hyperplasias', 'Disease', 'MESH:D002285', (80, 99))	('ductal hyperplasias', 'Disease', (80, 99))
174491	25320625	As has been reported by others, our findings show that the underestimation rate of 8-gauge VABB was much lower than that of 11-gauge VABB, although these differences did not reach statistical significance.	('lower', 'NegReg', (105, 110))	('8-gauge', 'Var', (83, 90))	('VABB', 'Chemical', '-', (91, 95))	('VABB', 'Chemical', '-', (133, 137))	('underestimation', 'NegReg', (59, 74))
174506	24852022	Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland.	('proliferation', 'CPA', (185, 198))	('Tumour Formation', 'CPA', (94, 110))	('Scribble', 'Gene', (0, 8))	('apoptosis', 'CPA', (203, 212))	('Modulates', 'Var', (9, 18))	('Fra1', 'Gene', '14283', (28, 32))	('Disrupt', 'NegReg', (44, 51))	('cell movement', 'CPA', (153, 166))	('Fra1', 'Gene', (28, 32))	('Scribble', 'Gene', '44448', (0, 8))	('Tumour', 'Phenotype', 'HP:0002664', (94, 100))	('differentiation', 'CPA', (168, 183))	('Suppress', 'NegReg', (85, 93))
174511	24852022	We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis.	('associated', 'Reg', (129, 139))	('Scribble', 'Gene', (43, 51))	('hyperplasia', 'Disease', (111, 122))	('mammalian', 'Species', '9606', (55, 64))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (103, 122))	('apoptose', 'CPA', (204, 212))	('Scribble', 'Gene', '44448', (43, 51))	('aberrant', 'Var', (145, 153))	('hyperplasia', 'Disease', 'MESH:D006965', (111, 122))
174514	24852022	Disruption of polarity is a diagnostic criterion of cancer, but exactly how deregulation of core polarity genes contribute to cancer and at which stage polarity loss promotes breast cancer development in vivo is still poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('deregulation', 'Var', (76, 88))	('cancer', 'Disease', (182, 188))	('loss', 'NegReg', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('promotes', 'PosReg', (166, 174))	('cancer', 'Disease', (52, 58))
174518	24852022	Scrib deficiency activated progenitors and resulted in the excess growth of atypical luminal cells and the development of ductal and alveolar hyperplasia.	('alveolar hyperplasia', 'Disease', (133, 153))	('progenitors', 'CPA', (27, 38))	('Scrib', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('growth of atypical luminal cells', 'CPA', (66, 98))	('activated', 'PosReg', (17, 26))	('alveolar hyperplasia', 'Disease', 'MESH:D006965', (133, 153))	('excess', 'PosReg', (59, 65))	('alveolar hyperplasia', 'Phenotype', 'HP:0009085', (133, 153))
174529	24852022	Scribble complex genes were originally identified as neoplastic tumour suppressors in Drosophila genetic screens, and studies using Drosophila genetics and 3D mammalian cell culture models suggest that disruption of core polarity regulators may contribute to tumourigenesis.	('Drosophila', 'Species', '7227', (132, 142))	('tumour', 'Disease', (259, 265))	('neoplastic tumour', 'Disease', 'MESH:D009369', (53, 70))	('neoplastic tumour', 'Phenotype', 'HP:0002664', (53, 70))	('mammalian', 'Species', '9606', (159, 168))	('neoplastic tumour', 'Disease', (53, 70))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('Scribble', 'Gene', (0, 8))	('disruption', 'Var', (202, 212))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('Drosophila', 'Species', '7227', (86, 96))	('Scribble', 'Gene', '44448', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (259, 265))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('contribute', 'Reg', (245, 255))
174530	24852022	In humans, deregulated expression and mislocalisation of Scribble complex members are associated with several epithelial cancers, including breast cancer, and human SCRIB is targeted by oncogenic viruses for degradation.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Scribble', 'Gene', '44448', (57, 65))	('deregulated', 'Var', (11, 22))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('associated', 'Reg', (86, 96))	('human', 'Species', '9606', (159, 164))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('epithelial cancers', 'Disease', (110, 128))	('breast cancer', 'Disease', (140, 153))	('Scribble', 'Gene', (57, 65))	('SCRIB', 'Gene', (165, 170))	('humans', 'Species', '9606', (3, 9))	('epithelial cancers', 'Disease', 'MESH:D000077216', (110, 128))	('mislocalisation', 'MPA', (38, 53))	('expression', 'MPA', (23, 33))	('SCRIB', 'Gene', '23513', (165, 170))
174547	24852022	Multilayering was observed in the majority of mammary duct cross sections of MMTV-Cre;Scribflox/- mice and was significantly increased compared to MMTV-Cre control mice (Figure 1E and quantitated in 1F).	('increased', 'PosReg', (125, 134))	('mice', 'Species', '10090', (164, 168))	('MMTV', 'Species', '11757', (77, 81))	('MMTV-Cre', 'Var', (77, 85))	('mammary duct', 'CPA', (46, 58))	('Multilayering', 'CPA', (0, 13))	('mice', 'Species', '10090', (98, 102))	('MMTV', 'Species', '11757', (147, 151))
174556	24852022	Ultrastructural analysis of cell-cell junctions on mammary ducts of Scrib mutant mice confirmed that TJs and desmosomes are still able to form.	('mutant', 'Var', (74, 80))	('mice', 'Species', '10090', (81, 85))	('Scrib', 'Gene', (68, 73))
174566	24852022	We detected higher rates of proliferation in Scrib-deficient ducts compared to ducts from MMTV-Cre control mice (Figure 2D), supporting previous work in Scrib-deficient prostate lesions.	('higher', 'PosReg', (12, 18))	('proliferation', 'CPA', (28, 41))	('MMTV', 'Species', '11757', (90, 94))	('Scrib-deficient prostate lesions', 'Disease', 'MESH:D011469', (153, 185))	('deficient prostate', 'Phenotype', 'HP:0008687', (159, 177))	('mice', 'Species', '10090', (107, 111))	('Scrib-deficient prostate lesions', 'Disease', (153, 185))	('Scrib-deficient', 'Var', (45, 60))
174570	24852022	To address how Scrib depletion leads to hyperplasia and loss of tissue architecture, we first examined cell polarity in Scrib-deficient mammary ducts prior to the onset of multilayering in 6 week old virgin mice.	('loss', 'NegReg', (56, 60))	('hyperplasia', 'Disease', (40, 51))	('mice', 'Species', '10090', (207, 211))	('depletion', 'Var', (21, 30))	('hyperplasia', 'Disease', 'MESH:D006965', (40, 51))	('Scrib-deficient', 'Gene', (120, 135))
174576	24852022	No changes in proliferation or apoptosis rates were observed in TEBs, however, a significant and gene-dosage dependent decrease in apoptosis was observed in immature ducts of 6 week old mice that carried one or two mutated alleles of Scrib (Figure 3C).	('decrease', 'NegReg', (119, 127))	('Scrib', 'Gene', (234, 239))	('mutated', 'Var', (215, 222))	('mice', 'Species', '10090', (186, 190))	('apoptosis', 'CPA', (131, 140))
174581	24852022	This suggests that Scribble is required to regulate spindle orientations within the mammary ductal epithelium, and that deregulation of division axis may be a contributing factor to the Scrib-deficient multi-layering phenotype.	('Scribble', 'Gene', (19, 27))	('Scribble', 'Gene', '44448', (19, 27))	('deregulation', 'Var', (120, 132))
174585	24852022	We next evaluated whether targeted deletion of Scrib impacted on progenitor cells by performing colony assays with basal (CD24+CD29hi) and luminal progenitor (CD24+CD29l CD61+) cell populations.	('CD61', 'Gene', (170, 174))	('CD24', 'Gene', (159, 163))	('CD29', 'Gene', '16412', (127, 131))	('Scrib', 'Gene', (47, 52))	('CD24', 'Gene', '12484', (159, 163))	('CD29', 'Gene', '16412', (164, 168))	('CD29', 'Gene', (127, 131))	('CD24', 'Gene', (122, 126))	('deletion', 'Var', (35, 43))	('CD29', 'Gene', (164, 168))	('CD24', 'Gene', '12484', (122, 126))	('impacted', 'Reg', (53, 61))	('CD61', 'Gene', '16416', (170, 174))
174589	24852022	To determine the molecular pathways by which Scribble may be regulating basal to luminal transition, we examined the impact of Scrib deficiency on the gene expression signatures of critical growth and differentiation pathways known to regulate cell fate in the mammary gland including Notch and MAPK.	('Scribble', 'Gene', (45, 53))	('Scrib', 'Gene', (127, 132))	('deficiency', 'Var', (133, 143))	('Scribble', 'Gene', '44448', (45, 53))
174600	24852022	Surprisingly, pregnancy led to rescue of the cell polarity and ductal defects observed in MMTV-Cre;Scribflox/- mammary glands in the pre-pregnant state (Figure S3B).	('MMTV-Cre', 'Var', (90, 98))	('cell polarity', 'CPA', (45, 58))	('MMTV', 'Species', '11757', (90, 94))	('ductal defects', 'CPA', (63, 77))
174605	24852022	Although the Akt pathway was recently shown to be enhanced in cell lines following Scrib knockdown, we could not detect Akt pathway activation in the mouse mammary epithelium in vivo (Figure S4).	('Akt', 'Gene', '11651', (13, 16))	('Akt', 'Gene', '11651', (120, 123))	('knockdown', 'Var', (89, 98))	('enhanced', 'PosReg', (50, 58))	('Akt', 'Gene', (13, 16))	('Akt', 'Gene', (120, 123))	('mouse', 'Species', '10090', (150, 155))
174608	24852022	Importantly, histological analysis revealed PD0325901 treatment blocked the early onset of multilayering in Scrib-deficient mammary ducts compared with vehicle (Figure 5E)(P = 0.0002).	('PD0325901', 'Var', (44, 53))	('PD0325901', 'Chemical', 'MESH:C506614', (44, 53))	('blocked', 'NegReg', (64, 71))
174609	24852022	Treatment with PD0325901 also suppressed the hyperproliferation associated with Scrib-loss in the mature duct epithelium (Figure S5A).	('PD0325901', 'Var', (15, 24))	('Scrib-loss', 'Gene', (80, 90))	('suppressed', 'NegReg', (30, 40))	('PD0325901', 'Chemical', 'MESH:C506614', (15, 24))	('hyperproliferation', 'Disease', (45, 63))
174610	24852022	Effective MEK inhibition by PD0325901 was confirmed by immunostaining for pERK (Figure 5F (a-d)).	('MEK', 'Gene', (10, 13))	('pERK', 'Gene', '13666', (74, 78))	('PD0325901', 'Var', (28, 37))	('pERK', 'Gene', (74, 78))	('MEK', 'Gene', '17242', (10, 13))	('PD0325901', 'Chemical', 'MESH:C506614', (28, 37))	('inhibition', 'NegReg', (14, 24))
174611	24852022	Strikingly, we also observed a more organized and tightly packed mammary epithelium with restoration of laterally enriched E-cadherin and a clearly defined pERM positive apical membrane region in ducts of PD0325901 treated MMTV-Cre;Scribflox/- mice compared to ducts from vehicle treated mice (Figure 5G (a-d)).	('PD0325901', 'Var', (205, 214))	('MMTV', 'Species', '11757', (223, 227))	('mice', 'Species', '10090', (244, 248))	('PD0325901', 'Chemical', 'MESH:C506614', (205, 214))	('mice', 'Species', '10090', (288, 292))	('more', 'PosReg', (31, 35))
174613	24852022	We predicted that these defects coupled with disruption to normal cell polarity signalling would act in concert to promote several aspects of mammary tumourigenesis.	('promote', 'PosReg', (115, 122))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('defects', 'Var', (24, 31))
174618	24852022	We observed significantly increased regions of HAN and lipid droplets in mammary glands of MMTV-Cre;Scribflox/- mutant mice compared to control mammary glands (Figure 6B).	('regions', 'MPA', (36, 43))	('mice', 'Species', '10090', (119, 123))	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('MMTV-Cre', 'Var', (91, 99))	('increased', 'PosReg', (26, 35))	('mutant', 'Var', (112, 118))	('MMTV', 'Species', '11757', (91, 95))
174627	24852022	The incidence of stochastic mammary tumours increased significantly in MMTV-Cre;Scribflox/- mice compared to MMTV-Cre control mice (Figure 6E).	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('mice', 'Species', '10090', (126, 130))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('increased', 'PosReg', (44, 53))	('tumours', 'Disease', (36, 43))	('MMTV', 'Species', '11757', (109, 113))	('MMTV', 'Species', '11757', (71, 75))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('MMTV-Cre', 'Var', (71, 79))	('mice', 'Species', '10090', (92, 96))	('stochastic', 'Disease', (17, 27))
174633	24852022	Overall, tumours from MMTV-Cre;Scribflox/- mice size and age matched to low grade control tumours were either spindleoid EMT type or solid carcinomas.	('mice', 'Species', '10090', (43, 47))	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('spindleoid EMT type or solid carcinomas', 'Disease', 'MESH:D018250', (110, 149))	('tumours', 'Disease', (9, 16))	('spindleoid EMT type or solid carcinomas', 'Disease', (110, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('MMTV', 'Species', '11757', (22, 26))	('MMTV-Cre', 'Var', (22, 30))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('tumours', 'Disease', (90, 97))
174638	24852022	WAP-Bcl-2 transgenic mice exhibit a similar delay in lumen formation.	('delay', 'NegReg', (44, 49))	('transgenic', 'Var', (10, 20))	('WAP', 'Gene', '22373', (0, 3))	('Bcl-2', 'Gene', (4, 9))	('Bcl-2', 'Gene', '12043', (4, 9))	('transgenic mice', 'Species', '10090', (10, 25))	('lumen formation', 'CPA', (53, 68))	('WAP', 'Gene', (0, 3))
174642	24852022	In addition to the influence of the ECM on cell polarity defects, we found Scrib modulation of the Ras/MAPK pathway to be critical in maintaining epithelial tissue polarity, as inhibition of the Ras/MAPK was able to prevent the onset of duct hyperplasia and restore apical-basal polarity.	('inhibition', 'Var', (177, 187))	('apical-basal polarity', 'CPA', (266, 287))	('restore', 'PosReg', (258, 265))	('Ras/MAPK', 'Gene', (195, 203))	('duct hyperplasia', 'Disease', (237, 253))	('duct hyperplasia', 'Disease', 'MESH:D006965', (237, 253))
174646	24852022	Supporting our studies of spindle orientations in the luminal layer of Scrib-deficient ducts and the mammary duct branching defects observed in these mice, mice lacking beta1 integrin in basal cells exhibit similar spindle orientation defects coupled with an abnormal ductal branching pattern.	('mice', 'Species', '10090', (150, 154))	('beta1', 'Gene', '97440', (169, 174))	('beta1', 'Gene', (169, 174))	('ductal branching pattern', 'CPA', (268, 292))	('spindle orientation defects', 'CPA', (215, 242))	('mice', 'Species', '10090', (156, 160))	('lacking', 'Var', (161, 168))
174648	24852022	This suggests a critical role for Scrib suppression of Ras/MAPK within the mammary cell hierarchy and is consistent with our findings in vitro where Scribble knock down elicits a heightened and sustained MAPK response concomitant with elevated Fra1.	('Scribble', 'Gene', (149, 157))	('MAPK response', 'MPA', (204, 217))	('heightened', 'PosReg', (179, 189))	('Scribble', 'Gene', '44448', (149, 157))	('elevated', 'PosReg', (235, 243))	('elicits', 'Reg', (169, 176))	('Fra1', 'MPA', (244, 248))	('suppression', 'NegReg', (40, 51))	('Ras/MAPK', 'Protein', (55, 63))	('knock down', 'Var', (158, 168))
174656	24852022	Activation of ErbB2 in mice can result in HAN similar to those that develop in MMTV-Cre;Scribflox/- mice and conversely the specific deletion of ErbB2 impairs duct elongation and branching morphogenesis.	('ErbB2', 'Gene', '13866', (145, 150))	('branching morphogenesis', 'CPA', (179, 202))	('mice', 'Species', '10090', (100, 104))	('deletion', 'Var', (133, 141))	('ErbB2', 'Gene', (14, 19))	('impairs', 'NegReg', (151, 158))	('duct elongation', 'CPA', (159, 174))	('ErbB2', 'Gene', '13866', (14, 19))	('ErbB2', 'Gene', (145, 150))	('MMTV', 'Species', '11757', (79, 83))	('mice', 'Species', '10090', (23, 27))
174657	24852022	Altogether these findings suggest that deregulation of normal MAPK and cell polarity signalling are concomitant processes in mammary tumourgenesis.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('MAPK', 'Protein', (62, 66))	('tumour', 'Disease', (133, 139))	('deregulation', 'Var', (39, 51))
174665	24852022	Therefore, disruption of tissue polarity, high cell turnover and hyperactivation of a MAPK/Fra1 oncogenic pathway is likely to lead to a more rapid accumulation of genetic abnormalities and escalate mammary tumour progression.	('hyperactivation', 'PosReg', (65, 80))	('tumour', 'Disease', (207, 213))	('lead', 'Reg', (127, 131))	('genetic abnormalities', 'Disease', 'MESH:D030342', (164, 185))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('disruption', 'Var', (11, 21))	('genetic abnormalities', 'Disease', (164, 185))	('escalate', 'PosReg', (190, 198))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('MAPK/Fra1', 'Gene', (86, 95))
174671	24852022	Our findings provide new insights into how loss of polarity impacts on tissue homeostasis and can contribute to the etiology and pathogenesis of breast cancer.	('contribute', 'Reg', (98, 108))	('impacts', 'Reg', (60, 67))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('polarity', 'MPA', (51, 59))	('tissue homeostasis', 'MPA', (71, 89))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('loss', 'Var', (43, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
174678	24852022	The treatment regime was similar to that previously reported where MEK inhibitor PD0325901 (JS Research Chemicals Trading) was dissolved in 0.5% hydroxypropyl-methylcellulose; 0.2% Tween 80 at 8 mg/ml and delivered by oral gavage at 20 mg/kg 5 days on and 2 days off from 6 to 8 weeks of age.	('hydroxypropyl-methylcellulose', 'Chemical', 'MESH:D065347', (145, 174))	('MEK', 'Gene', '17242', (67, 70))	('PD0325901', 'Var', (81, 90))	('PD0325901', 'Chemical', 'MESH:C506614', (81, 90))	('MEK', 'Gene', (67, 70))	('Tween 80', 'Chemical', 'MESH:D011136', (181, 189))
174688	24852022	Primary antibodies other than those recently reported, included Caspase 3 (9661, Cell Signalling Technology), Brdu (347580, BD Biosciences), p-Histone 3 (641001, Biolegend), pericentrin (ab64448, Abcam), Cytokeratin 5 (PRB-160P, covance), Cytokeratin 8 (ab14053, Abcam), beta-catenin (610153, BD Biosciences), GATA3 (sc-268 SantaCruz), Hey1 (ab22614, Abcam), p-STAT5 (9331, Cell Signalling Technologies), ZO-1 (clone R40.76, Millipore).	('610153', 'Var', (285, 291))	('Caspase 3', 'Gene', (64, 73))	('Cytokeratin 5', 'Gene', '110308', (204, 217))	('Hey1', 'Gene', '15213', (336, 340))	('Cytokeratin 5', 'Gene', (204, 217))	('Caspase 3', 'Gene', '12367', (64, 73))	('pericentrin', 'Gene', (174, 185))	('STAT5', 'Gene', '20850', (361, 366))	('pericentrin', 'Gene', '18541', (174, 185))	('Hey1', 'Gene', (336, 340))	('GATA3', 'Gene', (310, 315))	('PRB', 'Gene', (219, 222))	('PRB', 'Gene', '18667', (219, 222))	('Cytokeratin 8', 'Gene', '16691', (239, 252))	('beta-catenin', 'Gene', '12387', (271, 283))	('STAT5', 'Gene', (361, 366))	('Cytokeratin 8', 'Gene', (239, 252))	('beta-catenin', 'Gene', (271, 283))	('GATA3', 'Gene', '14462', (310, 315))
174701	21234361	Regarding tumor size, SLNB may be acceptable also for patients with T3 or T4b tumors according to Takei et al., even though SLN identification is lower.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('T4b', 'Var', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
174740	21234361	The application of SLNB- to NAC- treated patients has been proved to have similar sensitivity, specificity, and accuracy to non-NAC-treated patients (74, 100, and 88%, versus 71, 99, and 90%).	('SLNB-', 'Var', (19, 24))	('NAC', 'Gene', (28, 31))	('NAC', 'Gene', '7504', (28, 31))	('patients', 'Species', '9606', (41, 49))	('NAC', 'Gene', (128, 131))	('patients', 'Species', '9606', (140, 148))	('NAC', 'Gene', '7504', (128, 131))
174803	21234361	In these cases, the presence of IMN metastases would change the staging from stage I to stage IIIB, according to the current tumour, node, and metastasis classification.	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('metastases', 'Disease', (36, 46))	('metastases', 'Disease', 'MESH:D009362', (36, 46))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('change', 'Reg', (53, 59))	('staging', 'MPA', (64, 71))	('presence', 'Var', (20, 28))
174828	21853537	To gain insight, tumor and developmental biologists have gathered a wealth of molecular, cellular and genetic data, including immunohistochemical measurements of cell type-specific division and death rates, lineage tracing, and gain-of-function/loss-of-function mutational analyses.	('death', 'Disease', (194, 199))	('mutational', 'Var', (262, 272))	('tumor', 'Disease', (17, 22))	('gain-of-function/loss-of-function', 'PosReg', (228, 261))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('death', 'Disease', 'MESH:D003643', (194, 199))	('gain-of-function/loss-of-function', 'NegReg', (228, 261))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
174853	21853537	cell-of-origin) transforms step-by-step into a tumor cell due to various genetic and epigenetic changes.	('epigenetic changes', 'Var', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('genetic', 'Var', (73, 80))	('tumor', 'Disease', (47, 52))
174855	21853537	Depending in particular on the cell-of-origin, its potency, the number and kinds of carcinogenic mutations, tumors can develop largely varying characteristics with respect to their cellular morphology, proliferative activity, and therapeutic response.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('carcinogenic', 'Disease', 'MESH:D063646', (84, 96))	('carcinogenic', 'Disease', (84, 96))
174862	21853537	Also, there are many known epigenetic effects related to various types of cancer.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetic effects', 'Var', (27, 45))
174863	21853537	For instance, low level DNA methylation in tumor cells (as compared to DNA methylation levels in normal cells) was one of the first epigenetic abnormalities observed in human cancer cells.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('human', 'Species', '9606', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('methylation', 'Var', (28, 39))	('tumor', 'Disease', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
174943	20517310	Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width.	('chronic inflammation', 'Disease', (177, 197))	('necrosis', 'Disease', (165, 173))	('growth pattern', 'CPA', (137, 151))	('incompleteness', 'Var', (199, 213))	('ipsilateral recurrence', 'Disease', (38, 60))	('necrosis', 'Disease', 'MESH:D009336', (165, 173))	('high', 'Var', (93, 97))	('chronic inflammation', 'Disease', 'MESH:D007249', (177, 197))
175010	20517310	The system we describe suggests that DCIS is better classified by an alternative three group system: (i) a group of low- and intermediate-cytonuclear-grade disease, (ii) high-nuclear-grade DCIS of non-solid architecture or with <50% ducts bearing necrosis and (iii) high-nuclear-grade DCIS with extensive confluent comedo-type necrosis (>50% ducts) and with solid architecture.	('high-nuclear-grade', 'Var', (170, 188))	('necrosis', 'Disease', 'MESH:D009336', (247, 255))	('necrosis', 'Disease', (327, 335))	('high-nuclear-grade', 'Var', (266, 284))	('comedo', 'Phenotype', 'HP:0025249', (315, 321))	('DCIS', 'Disease', (37, 41))	('necrosis', 'Disease', 'MESH:D009336', (327, 335))	('necrosis', 'Disease', (247, 255))
175015	16100520	High COX-2 expression is associated with poor prognosis.	('expression', 'MPA', (11, 21))	('COX-2', 'Gene', (5, 10))	('COX-2', 'Gene', '5743', (5, 10))	('High', 'Var', (0, 4))
175016	16100520	Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP).	('inhibits', 'NegReg', (79, 87))	('reduces', 'NegReg', (28, 35))	('FAP', 'Disease', (215, 218))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (192, 213))	('invasive cancer', 'Disease', (107, 122))	('polyps', 'Disease', (173, 179))	('FAP', 'Disease', 'MESH:C567782', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('invasive cancer', 'Disease', 'MESH:D009362', (107, 122))	('Cyclooxygenase-2', 'Gene', '5743', (0, 16))	('inhibition', 'Var', (17, 27))	('Cyclooxygenase-2', 'Gene', (0, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('familial adenomatous polyposis', 'Disease', (183, 213))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (183, 213))	('polyps', 'Disease', 'MESH:D011127', (173, 179))	('colorectal cancer', 'Disease', (126, 143))	('tumours', 'Disease', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('reduces', 'NegReg', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
175018	16100520	Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('inhibitors', 'Var', (17, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('COX-2', 'Gene', (11, 16))	('COX-2', 'Gene', '5743', (11, 16))
175019	16100520	There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective.	('aromatase', 'Gene', '1588', (66, 75))	('inhibitors', 'Var', (50, 60))	('COX-2', 'Gene', (44, 49))	('COX-2', 'Gene', '5743', (44, 49))	('aromatase', 'Gene', (66, 75))
175032	16100520	Overexpression of COX-2 in the breast tissue of transgenic mice is associated with increased development of breast tumours, but only after multiple pregnancies.	('breast tumours', 'Disease', 'MESH:D001943', (108, 122))	('COX-2', 'Gene', '5743', (18, 23))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('multiple pregnancies', 'Phenotype', 'HP:0001622', (139, 159))	('breast tumours', 'Disease', (108, 122))	('Overexpression', 'Var', (0, 14))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('COX-2', 'Gene', (18, 23))	('transgenic mice', 'Species', '10090', (48, 63))
175036	16100520	Studies with celecoxib, a selective COX-2 inhibitor, in an HER2/neu-induced breast cancer model in transgenic mice have revealed that celecoxib reduced the incidence of mammary tumours and lowered mammary PGE2 levels by 50%.	('tumours', 'Disease', (177, 184))	('celecoxib', 'Chemical', 'MESH:D000068579', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HER2', 'Gene', (59, 63))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('celecoxib', 'Var', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('reduced', 'NegReg', (144, 151))	('HER2', 'Gene', '13866', (59, 63))	('COX-2', 'Gene', (36, 41))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('transgenic mice', 'Species', '10090', (99, 114))	('PGE2', 'Chemical', 'MESH:D015232', (205, 209))	('celecoxib', 'Chemical', 'MESH:D000068579', (134, 143))	('mammary PGE2 levels', 'MPA', (197, 216))	('lowered', 'NegReg', (189, 196))	('COX-2', 'Gene', '5743', (36, 41))
175039	16100520	Studies have also suggested that combinations of COX-2 inhibitors with an epidermal growth factor receptor (EGFR) inhibitor have synergistic benefits in animal models of FAP (min mouse).	('mouse', 'Species', '10090', (179, 184))	('COX-2', 'Gene', (49, 54))	('benefits', 'PosReg', (141, 149))	('COX-2', 'Gene', '5743', (49, 54))	('combinations', 'Interaction', (33, 45))	('FAP', 'Disease', (170, 173))	('FAP', 'Disease', 'MESH:C567782', (170, 173))	('inhibitors', 'Var', (55, 65))	('epidermal growth factor receptor', 'Gene', (74, 106))	('epidermal growth factor receptor', 'Gene', '13649', (74, 106))
175044	16100520	Studies of COX-2 inhibitors in breast cancer are underway as adjuvant therapy.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('inhibitors', 'Var', (17, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('COX-2', 'Gene', (11, 16))	('COX-2', 'Gene', '5743', (11, 16))
175046	16100520	There are three potential anticancer mechanisms for COX-2 inhibition, it may  Data from studies that have looked at COX-2 expression and proliferation markers, such as Ki67, have shown a strong correlation between the presence of COX-2 and increased proliferation, but as yet no data have been published to show that inhibition of COX-2 leads to a lower proliferative rate in tumours in vivo.	('tumours', 'Disease', (376, 383))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumours', 'Phenotype', 'HP:0002664', (376, 383))	('rat', 'Species', '10116', (144, 147))	('COX-2', 'Gene', '5743', (230, 235))	('tumours', 'Disease', 'MESH:D009369', (376, 383))	('COX-2', 'Gene', (331, 336))	('Ki67', 'Chemical', '-', (168, 172))	('COX-2', 'Gene', (116, 121))	('tumour', 'Phenotype', 'HP:0002664', (376, 382))	('increased', 'PosReg', (240, 249))	('COX-2', 'Gene', (52, 57))	('cancer', 'Disease', (30, 36))	('COX-2', 'Gene', '5743', (331, 336))	('COX-2', 'Gene', '5743', (116, 121))	('rat', 'Species', '10116', (257, 260))	('inhibition', 'Var', (317, 327))	('rat', 'Species', '10116', (368, 371))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('COX-2', 'Gene', '5743', (52, 57))	('rat', 'Species', '10116', (361, 364))	('presence', 'Var', (218, 226))	('COX-2', 'Gene', (230, 235))	('lower', 'NegReg', (348, 353))
175047	16100520	Several lines of study have indicated that COX-2 inhibition may increase apoptosis.	('inhibition', 'Var', (49, 59))	('apoptosis', 'CPA', (73, 82))	('COX-2', 'Gene', '5743', (43, 48))	('COX-2', 'Gene', (43, 48))
175048	16100520	In a study investigating the effect of celecoxib on prostate cancer cell lines, AKT phosphorylation was significantly inhibited by celecoxib leading to increased caspase-3 activation and apoptosis.	('inhibited', 'NegReg', (118, 127))	('apoptosis', 'CPA', (187, 196))	('AKT', 'Gene', '207', (80, 83))	('increased', 'PosReg', (152, 161))	('caspase-3', 'Gene', (162, 171))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('caspase-3', 'Gene', '836', (162, 171))	('AKT', 'Gene', (80, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('celecoxib', 'Chemical', 'MESH:D000068579', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activation', 'PosReg', (172, 182))	('prostate cancer', 'Disease', (52, 67))	('celecoxib', 'Chemical', 'MESH:D000068579', (39, 48))	('celecoxib', 'Var', (131, 140))
175051	16100520	Since HER-2/neu regulates AKT phosphorylation downstream, it is certainly conceivable that inhibiting COX-2 may affect this pathway upstream leading to increased apoptosis.	('COX-2', 'Gene', '5743', (102, 107))	('HER-2/neu', 'Gene', (6, 15))	('regulates', 'Reg', (16, 25))	('increased', 'PosReg', (152, 161))	('AKT', 'Gene', '207', (26, 29))	('HER-2/neu', 'Gene', '2064', (6, 15))	('affect', 'Reg', (112, 118))	('AKT', 'Gene', (26, 29))	('inhibiting', 'Var', (91, 101))	('COX-2', 'Gene', (102, 107))	('apoptosis', 'CPA', (162, 171))
175052	16100520	As previously mentioned, in COX-2 transgenic mice, mouse mammary tissue had significantly less apoptosis than normal tissue and had a reduced expression of Bcl2-XL and BAX, which are both proapoptotic proteins.	('COX-2', 'Gene', '5743', (28, 33))	('less', 'NegReg', (90, 94))	('apoptosis', 'CPA', (95, 104))	('reduced', 'NegReg', (134, 141))	('mouse', 'Species', '10090', (51, 56))	('transgenic mice', 'Species', '10090', (34, 49))	('expression', 'MPA', (142, 152))	('transgenic', 'Var', (34, 44))	('Bcl2-XL and BAX', 'Gene', '12028', (156, 171))	('COX-2', 'Gene', (28, 33))
175058	16100520	Chang et al have shown that COX-2 regulates angiogenesis in normal mammary tissue via PgE2 production; therefore, inhibition of angiogenesis by COX-2 inhibitors has the potential for chemoprevention of breast cancer.	('PgE2', 'Chemical', 'MESH:D015232', (86, 90))	('COX-2', 'Gene', '5743', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('angiogenesis', 'MPA', (44, 56))	('breast cancer', 'Disease', (202, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('PgE2 production', 'MPA', (86, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('COX-2', 'Gene', (144, 149))	('inhibition', 'Var', (114, 124))	('COX-2', 'Gene', '5743', (144, 149))	('COX-2', 'Gene', (28, 33))
175067	16100520	The cardiovascular safety of celecoxib is currently being examined following results from one trial, the Adenoma Prevention with Celecoxib (APC) trial, which found patients taking 400 and 800 mg day-1 of celecoxib had a 2.5- to 3.4-fold increased risk of major fatal or nonfatal cardiovascular events vs placebo (average duration of treatment 33 months).	('rat', 'Species', '10116', (323, 326))	('Celecoxib', 'Chemical', 'MESH:D000068579', (129, 138))	('Adenoma', 'Disease', 'MESH:D000236', (105, 112))	('APC', 'Disease', 'MESH:D011125', (140, 143))	('APC', 'Disease', (140, 143))	('400', 'Var', (180, 183))	('major', 'Disease', (255, 260))	('patients', 'Species', '9606', (164, 172))	('celecoxib', 'Chemical', 'MESH:D000068579', (29, 38))	('celecoxib', 'Chemical', 'MESH:D000068579', (204, 213))	('Adenoma', 'Disease', (105, 112))	('cardiovascular events', 'Phenotype', 'HP:0001626', (279, 300))
175079	16100520	Therefore, inhibition of PGE2 by COX-2 inhibitors may inhibit aromatase activity and, when combined with aromatase inhibitors, reduce tumour recurrence by inhibiting a common target: aromatase.	('aromatase', 'Gene', (183, 192))	('PGE2', 'Chemical', 'MESH:D015232', (25, 29))	('inhibit', 'NegReg', (54, 61))	('aromatase', 'Gene', '1588', (183, 192))	('COX-2', 'Gene', (33, 38))	('activity', 'MPA', (72, 80))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', (134, 140))	('aromatase', 'Gene', (105, 114))	('reduce', 'NegReg', (127, 133))	('PGE2', 'Gene', (25, 29))	('COX-2', 'Gene', '5743', (33, 38))	('inhibition', 'Var', (11, 21))	('inhibiting', 'NegReg', (155, 165))	('aromatase', 'Gene', '1588', (105, 114))	('aromatase', 'Gene', (62, 71))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('aromatase', 'Gene', '1588', (62, 71))
175092	16100520	Coadministration of celecoxib and cyclophosphamide was significantly more effective in preventing growth of Lewis lung cancer tumours than either drug alone and studies of combination of several chemotherapy agents with celecoxib have indicated that celecoxib lowers the threshold of sensitivity to chemotherapy.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('celecoxib', 'Chemical', 'MESH:D000068579', (250, 259))	('threshold of sensitivity to chemotherapy', 'MPA', (271, 311))	('Lewis lung cancer tumours', 'Disease', 'MESH:D008175', (108, 133))	('preventing', 'NegReg', (87, 97))	('celecoxib', 'Var', (250, 259))	('Lewis lung cancer tumours', 'Disease', (108, 133))	('celecoxib', 'Chemical', 'MESH:D000068579', (220, 229))	('growth', 'MPA', (98, 104))	('celecoxib', 'Chemical', 'MESH:D000068579', (20, 29))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('rat', 'Species', '10116', (10, 13))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (34, 50))	('lowers', 'NegReg', (260, 266))
175105	16100520	Preventing translocation of the ER to the nucleus lowers oestrogen levels in the breast and tumour tissue and lowers AIB levels, therefore decreasing endocrine resistance.	('AIB', 'Gene', '116833', (117, 120))	('decreasing', 'NegReg', (139, 149))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('AIB', 'Gene', (117, 120))	('lowers', 'NegReg', (110, 116))	('translocation', 'Var', (11, 24))	('lowers', 'NegReg', (50, 56))	('oestrogen levels', 'MPA', (57, 73))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('endocrine resistance', 'MPA', (150, 170))
175151	32747903	Breast ultrasound (US) examination and mammogram have described a 5/5 cm mass, at the junction of the superior quadrants of the right breast (12.00 hours) partially well delimitated, partial seeming invasive, polylobate, inhomogeneous, with calcifications within the tumor, tending to extend to the overlying skin.	('polylobate', 'Var', (209, 219))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('polylobate', 'Chemical', '-', (209, 219))
175169	32747903	Clinical examination at presentation found a still mobile on the pectoral plane, 7/7 cm mass, inhomogeneous, polylobate, with different consistencies within the tumor (fluid and solid).	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('polylobate', 'Chemical', '-', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('polylobate', 'Var', (109, 119))
175231	32747903	The use of chemotherapy in malignant phyllodes tumors is usually reserved for the metastatic cases, but association of the malignancy of the epithelial component may render adjuvant chemotherapy necessary after surgical treatment as an appropriate indication for the malignancy of the epithelial component.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('malignancy', 'Disease', (123, 133))	('malignancy', 'Disease', 'MESH:D009369', (267, 277))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))	('malignant phyllodes tumor', 'Disease', 'MESH:C549759', (27, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('malignancy', 'Disease', (267, 277))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('malignant phyllodes tumor', 'Disease', (27, 52))	('association', 'Var', (104, 115))
175268	23824363	However, the Canadian-based RAPID study has now reported interim toxicity and cosmesis results, showing that APBI delivered with 3D-CRT was associated with worse cosmetic outcomes and late radiation changes at 3 years compared to WBI.	('3D-CRT', 'Var', (129, 135))	('toxicity', 'Disease', 'MESH:D064420', (65, 73))	('cosmetic outcomes', 'CPA', (162, 179))	('toxicity', 'Disease', (65, 73))	('APBI', 'Chemical', '-', (109, 113))	('worse', 'NegReg', (156, 161))
175270	23824363	We previously compared 56 APBIMRT plans from this trial to 3D-CRT plans following B-39 dose constraints retrospectively constructed on the same cases; IMRT improved normal tissue sparing in the ipsilateral breast without compromising treatment target coverage.	('APBIMRT', 'Chemical', '-', (26, 33))	('normal tissue sparing', 'CPA', (165, 186))	('improved', 'PosReg', (156, 164))	('IMRT', 'Var', (151, 155))
175276	23824363	The eligibility requirements were initially age >=45 years, Stage T1N0M0 (as defined by AJCC Cancer Staging Manual, 6th edition), and negative margins >=2 mm after final surgery (re-excision permitted).	('Stage T1N0M0', 'Var', (60, 72))	('Cancer', 'Disease', (93, 99))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
175376	27150057	We compared three glycolytic indices (i.e., glucose uptake, lactate production, and oxygen consumption) in MCF10A and MCF12A hMECs that had either exogenous 14-3-3zeta overexpression (10A.zeta and 12A.zeta cells) or endogenous 14-3-3zeta knockdown (10A.shzeta, and 12A.shzeta cells) (Figure 1B).	('oxygen consumption', 'MPA', (84, 102))	('A.zeta', 'Species', '685352', (199, 205))	('MCF10A', 'CellLine', 'CVCL:0598', (107, 113))	('knockdown', 'Var', (238, 247))	('lactate', 'Chemical', 'MESH:D019344', (60, 67))	('glucose uptake', 'MPA', (44, 58))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('A.zeta', 'Species', '685352', (186, 192))	('overexpression', 'PosReg', (168, 182))	('MCF12A', 'CellLine', 'CVCL:3744', (118, 124))	('oxygen', 'Chemical', 'MESH:D010100', (84, 90))	('lactate production', 'MPA', (60, 78))
175382	27150057	14-3-3zeta-overexpressing 10A.zeta and 12A.zeta cells had 4 to 5 fold increases, whereas 14-3-3zeta knockdown 10A.shzeta and 12A.shzeta cells had approximately 70% decreases, in their glycolytic index compared to their respective control cells (Supplementary Table S1 and S2).	('decreases', 'NegReg', (164, 173))	('knockdown', 'Var', (100, 109))	('A.zeta', 'Species', '685352', (28, 34))	('A.zeta', 'Species', '685352', (41, 47))	('increases', 'PosReg', (70, 79))	('glycolytic index', 'MPA', (184, 200))
175389	27150057	Overall, the glycolytic indices were reduced with LDHA knockdown by approximately 70% (10A.zeta.shLDHA versus 10A.zeta.shCtrl cells) and 60% (12A.zeta.shLDHA versus 12A.zeta.shCtrl cells) (Supplementary Table S3).	('A.zeta', 'Species', '685352', (89, 95))	('knockdown', 'Var', (55, 64))	('LDHA', 'Gene', '3939', (98, 102))	('A.zeta', 'Species', '685352', (144, 150))	('glycolytic indices', 'MPA', (13, 31))	('LDHA', 'Gene', (153, 157))	('LDHA', 'Gene', (50, 54))	('LDHA', 'Gene', '3939', (50, 54))	('LDHA', 'Gene', '3939', (153, 157))	('reduced', 'NegReg', (37, 44))	('A.zeta', 'Species', '685352', (167, 173))	('A.zeta', 'Species', '685352', (112, 118))	('LDHA', 'Gene', (98, 102))
175394	27150057	Remarkably, LDHA knockdown in 14-3-3zeta-overexpressing MCF10A (10A.zeta.shLDHA) and MCF12A (12A.zeta.shLDHA) cells reversed the transforming effects of 14-3-3zeta overexpression, yielding significantly fewer colonies compared to their control cells (Figure 3A and Supplementary Figure S2A).	('A.zeta', 'Species', '685352', (95, 101))	('MCF10A', 'CellLine', 'CVCL:0598', (56, 62))	('colonies', 'CPA', (209, 217))	('LDHA', 'Gene', (104, 108))	('LDHA', 'Gene', '3939', (75, 79))	('A.zeta', 'Species', '685352', (66, 72))	('LDHA', 'Gene', '3939', (104, 108))	('MCF12A', 'CellLine', 'CVCL:3744', (85, 91))	('LDHA', 'Gene', '3939', (12, 16))	('knockdown', 'Var', (17, 26))	('LDHA', 'Gene', (12, 16))	('LDHA', 'Gene', (75, 79))	('fewer', 'NegReg', (203, 208))
175407	27150057	To identify the cis-regulatory element in the -2000bp LDHA promoter and 5'-UTR region that is responsible for 14-3-3zeta-induced transcriptional upregulation, we made a series of deletion constructs in the -2000 to +272 region, subcloned them into the pGL3-Basic vector, and transfected them into the 10A.zeta, 10A.Vec, 10A.shzeta, and 10A.shCtrl cells (Figure 4A, left).	('LDHA', 'Gene', (54, 58))	('A.zeta', 'Species', '685352', (303, 309))	('deletion', 'Var', (179, 187))	('LDHA', 'Gene', '3939', (54, 58))
175408	27150057	Remarkably, a specific 65bp region (+85 to +150) in the 5'-UTR of LDHA gene was necessary and sufficient to induce the luciferase gene expression (Figure 4A).	('LDHA', 'Gene', (66, 70))	('LDHA', 'Gene', '3939', (66, 70))	('luciferase gene', 'Gene', (119, 134))	('expression', 'MPA', (135, 145))	('induce', 'PosReg', (108, 114))	('+85 to +150', 'Var', (36, 47))
175411	27150057	We identified potential binding sites for five transcription factors USF1, CREB, MYC, SP1, and ATF-1 (Supplementary Figure S4A), knocked down them individually in the 10A.zeta cells and compared their luciferase activities.	('activities', 'MPA', (212, 222))	('binding', 'Interaction', (24, 31))	('knocked', 'Var', (129, 136))	('A.zeta', 'Species', '685352', (169, 175))	('SP1', 'Gene', (86, 89))	('USF1', 'Gene', (69, 73))	('luciferase', 'Enzyme', (201, 211))
175412	27150057	Knocking down each of the five genes reduced the LDHA 65bp 5'-UTR driven luciferase activity in 10A.zeta cells to various degrees and knocking down CREB led to the most significant reduction (Figure 4B).	('A.zeta', 'Species', '685352', (98, 104))	('LDHA', 'Gene', (49, 53))	('LDHA', 'Gene', '3939', (49, 53))	('CREB', 'Gene', (148, 152))	('knocking down', 'Var', (134, 147))
175413	27150057	Furthermore, we examined LDHA mRNA and protein levels in the 10A.Vec and 10A.zeta cells that had the five transcription factors knocked down individually.	('A.zeta', 'Species', '685352', (75, 81))	('LDHA', 'Gene', '3939', (25, 29))	('knocked', 'Var', (128, 135))	('LDHA', 'Gene', (25, 29))
175441	27150057	These data indicate that AZD6244 effectively inhibit the MEK/ERK/CREB/LDHA axis and proliferation of 14-3-3zeta overexpressiong tumor cells, thereby suppressing DCIS-like tumor outgrowth.	('AZD6244', 'Chemical', 'MESH:C517975', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('LDHA', 'Gene', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (171, 176))	('LDHA', 'Gene', '3939', (70, 74))	('MEK', 'Gene', '17242', (57, 60))	('proliferation', 'CPA', (84, 97))	('AZD6244', 'Var', (25, 32))	('tumor', 'Disease', (128, 133))	('inhibit', 'NegReg', (45, 52))	('suppressing', 'NegReg', (149, 160))	('MEK', 'Gene', (57, 60))
175453	27150057	We found that concomitant high expression of 14-3-3zeta and LDHA predicts worse survival of breast cancer patients compared to high expression of either gene alone (P=0.00257 vs. P=0.0127 and P=0.0322) (Figure 6C).	('14-3-3zeta', 'Protein', (45, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('high expression', 'Var', (26, 41))	('breast cancer', 'Disease', (92, 105))	('survival', 'MPA', (80, 88))	('LDHA', 'Gene', '3939', (60, 64))	('patients', 'Species', '9606', (106, 114))	('worse', 'NegReg', (74, 79))	('LDHA', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
175475	27150057	After identifying the important roles of the 14-3-3zeta/ERK/CREB/LDHA signaling axis in mediating cellular glycolysis, we showed that targeting MEK/ERK pathway in 14-3-3zeta overexpressing DCIS.COM tumors (DCIS.COM.zeta) with AZD6244 significantly inhibited the mammary tumor growth by inhibiting proliferation.	('LDHA', 'Gene', (65, 69))	('MEK', 'Gene', (144, 147))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Disease', (198, 204))	('inhibited', 'NegReg', (248, 257))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('LDHA', 'Gene', '3939', (65, 69))	('inhibiting', 'NegReg', (286, 296))	('proliferation', 'CPA', (297, 310))	('tumor', 'Disease', (198, 203))	('MEK', 'Gene', '17242', (144, 147))	('tumor', 'Disease', (270, 275))	('DCIS', 'Phenotype', 'HP:0030075', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('AZD6244', 'Var', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('AZD6244', 'Chemical', 'MESH:C517975', (226, 233))
175476	27150057	Although MEK/ERK could potentially modulate multiple downstream targets, our data clearly demonstrated that inhibiting MEK/ERK leads to reduced LDHA and tumor inhibition.	('MEK', 'Gene', (119, 122))	('LDHA', 'Gene', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('LDHA', 'Gene', '3939', (144, 148))	('inhibiting', 'Var', (108, 118))	('MEK', 'Gene', '17242', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('reduced', 'NegReg', (136, 143))	('MEK', 'Gene', (9, 12))	('MEK', 'Gene', '17242', (119, 122))	('modulate', 'Reg', (35, 43))
175479	27150057	Furthermore, our data in a preclinical DCIS model indicated that inhibiting the MEK/ERK pathway could be an effective strategy for intervention of the early-stage breast cancer, and this strategy may potentially be applicable in the clinic.	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('inhibiting', 'Var', (65, 75))	('MEK', 'Gene', '17242', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('MEK', 'Gene', (80, 83))	('breast cancer', 'Disease', (163, 176))
175484	27150057	14-3-3zeta shRNA (clone, NM_003406.2-418s1c1) and LDHA shRNA (NM_005566) were used to make 14-3-3zeta and LDHA knockdown cell lines.	('NM_005566', 'Var', (62, 71))	('LDHA', 'Gene', '3939', (106, 110))	('LDHA', 'Gene', (50, 54))	('LDHA', 'Gene', '3939', (50, 54))	('LDHA', 'Gene', (106, 110))
175485	27150057	The corresponding patient-derived gene expression values were retrieved from the Gene Expression Omnibus data repository microarray datasets for early-stage breast neoplasia (GSE16873) and advanced breast cancers (GSE2109), as well as the RNA-seq datasets from the TCGA data portal.	('breast neoplasia', 'Disease', (157, 173))	('GSE2109', 'Chemical', '-', (214, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('breast neoplasia', 'Phenotype', 'HP:0100013', (157, 173))	('GSE2109', 'Var', (214, 221))	('breast cancers', 'Phenotype', 'HP:0003002', (198, 212))	('patient', 'Species', '9606', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancers', 'Disease', 'MESH:D001943', (198, 212))	('GSE16873', 'Var', (175, 183))	('breast cancers', 'Disease', (198, 212))	('breast neoplasia', 'Disease', 'MESH:D009369', (157, 173))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
175486	27150057	Breast cancer patient-derived gene expression dataset GSE3494 had clinical follow-up information and was used to investigate the relationship between 14-3-3zeta and/or LDHA expression and patient prognosis.	('GSE3494', 'Chemical', '-', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('LDHA', 'Gene', (168, 172))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('patient', 'Species', '9606', (188, 195))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('GSE3494', 'Var', (54, 61))	('LDHA', 'Gene', '3939', (168, 172))	('patient', 'Species', '9606', (14, 21))	('Breast cancer', 'Disease', (0, 13))
175491	27150057	LDHA, CREB, MYC mRNA expression were determined by qRT-PCR using TaqMan primers (Hs00855332_g1, Hs00231713_m1 and Hs00153408_m1) and normalized to 18S rRNA endogenous control (#4310893E).	('LDHA', 'Gene', (0, 4))	('LDHA', 'Gene', '3939', (0, 4))	('Hs00231713_m1', 'Var', (96, 109))	('Hs00153408_m1', 'Var', (114, 127))	('Hs00855332_g1', 'Var', (81, 94))
175498	27150057	siRNA control and siRNAs were purchased from Sigma for LDHA, CREB, MYC, ATF1, USF1, and SP1 knockdown in vitro.	('LDHA', 'Gene', (55, 59))	('knockdown', 'Var', (92, 101))	('SP1', 'Gene', (88, 91))	('LDHA', 'Gene', '3939', (55, 59))
175507	27150057	We used the following antibodies: anti-14-3-3zeta (Santa Cruz); anti-LDHA, anti-CREB, anti-phospho-CREB, anti-ERK, anti-phospho-ERK, anti-cleaved caspase 3 (Cell Signaling); and anti-MCM (Epitomics).	('anti-phospho-ERK', 'Var', (115, 131))	('LDHA', 'Gene', (69, 73))	('LDHA', 'Gene', '3939', (69, 73))	('anti-ERK', 'Var', (105, 113))	('anti-phospho-CREB', 'Var', (86, 103))	('anti-CREB', 'Var', (75, 84))
175519	33363813	Different tumor components were studied using comparative genomic hybridization (CGH) to detect DNA copy number changes in an attempt to understand clonal relationships as well as to highlight the challenges that this can create for the pathologists and oncologists in their routine practice.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('DNA', 'Gene', (96, 99))	('changes', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('copy number changes', 'Var', (100, 119))
175534	33363813	Immunohistochemical staining of the E-cadherin adhesion complex (including beta-catenin and p-120 catenin) was performed as loss of E-cadherin and beta-catenin, and aberrant staining of p-120 catenin are hallmarks of an invasive lobular phenotype.	('beta-catenin', 'Gene', '1499', (147, 159))	('beta-catenin', 'Gene', '1499', (75, 87))	('loss', 'NegReg', (124, 128))	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('p-120 catenin', 'Gene', '1500', (92, 105))	('aberrant', 'Var', (165, 173))	('p-120 catenin', 'Gene', (186, 199))	('staining', 'MPA', (174, 182))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('p-120 catenin', 'Gene', (92, 105))	('beta-catenin', 'Gene', (75, 87))	('beta-catenin', 'Gene', (147, 159))	('p-120 catenin', 'Gene', '1500', (186, 199))
175540	33363813	The neoplastic cells were CK7 positive (3+ in 80% of tumor cells) and CK20 negative, indicating that the tumor is likely to be a metastasis and not a primary gastric carcinoma.	('negative', 'NegReg', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('gastric carcinoma', 'Disease', 'MESH:D013274', (158, 175))	('CK7', 'Var', (26, 29))	('CK20', 'Gene', (70, 74))	('CK20', 'Gene', '54474', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('gastric carcinoma', 'Disease', (158, 175))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (53, 58))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (158, 175))	('tumor', 'Disease', (105, 110))
175616	27498697	Expression pattern and methylation of estrogen receptor alpha in breast intraductal proliferative lesions Intraductal proliferative lesions of the breast including usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are associated with increased risk, albeit of greatly different magnitudes, for the subsequent development of invasive carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (205, 223))	('estrogen receptor alpha', 'Gene', (38, 61))	('ductal carcinoma in situ', 'Disease', (234, 258))	('DCIS', 'Phenotype', 'HP:0030075', (260, 264))	('methylation', 'Var', (23, 34))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (170, 188))	('UDH', 'Chemical', '-', (190, 193))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (234, 258))	('lesions of the breast', 'Phenotype', 'HP:0100013', (132, 153))	('atypical ductal hyperplasia', 'Disease', (196, 223))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (234, 250))	('estrogen receptor alpha', 'Gene', '2099', (38, 61))	('invasive carcinoma', 'Disease', (376, 394))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (196, 223))	('invasive carcinoma', 'Disease', 'MESH:D009361', (376, 394))	('breast intraductal proliferative lesions', 'Disease', 'MESH:D001941', (65, 105))	('ductal hyperplasia', 'Disease', (170, 188))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (234, 258))	('breast intraductal proliferative lesions', 'Disease', (65, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))
175623	27498697	ERalpha methylation in 32/60 (53.3%) UDH, 11/77 (10.2%) ADH and 32/80 (40.0%) DCIS.	('ERalpha', 'Gene', (0, 7))	('UDH', 'Disease', (37, 40))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('UDH', 'Chemical', '-', (37, 40))	('methylation', 'Var', (8, 19))
175624	27498697	Taken together, our results underlined that ERalpha expression or methylation may be involved in the breast carcinogenesis and advancement, thus it is not parallel to breast cancer risk in breast intraductal proliferative lesions.	('ERalpha', 'Gene', (44, 51))	('breast intraductal proliferative lesions', 'Disease', (189, 229))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('involved', 'Reg', (85, 93))	('breast intraductal proliferative lesions', 'Disease', 'MESH:D001941', (189, 229))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('methylation', 'Var', (66, 77))	('breast carcinogenesis', 'Disease', (101, 122))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (101, 122))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
175630	27498697	Our previous studies demonstrated that the absence of ERalpha expression associated with aberrant methylation of its CpG island in a significant fraction of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('ERalpha', 'Gene', (54, 61))	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancers', 'Disease', (157, 171))	('aberrant', 'Var', (89, 97))	('absence', 'NegReg', (43, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('expression', 'MPA', (62, 72))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('methylation', 'MPA', (98, 109))
175645	27498697	Endogenous peroxidase activity and non-specific binding were blocked with 3% H2O2 and non-immune sera, respectively.	('Endogenous peroxidase', 'Enzyme', (0, 21))	('blocked', 'NegReg', (61, 68))	('H2O2', 'Chemical', 'MESH:D006861', (77, 81))	('H2O2', 'Var', (77, 81))	('activity', 'MPA', (22, 30))	('non-specific binding', 'Interaction', (35, 55))
175672	27498697	We detected ERalpha methylation in 32/60 (53.3%) UDH, 11/77 (10.2%) ADH and 32/80 (40.0%) DCIS (Table I and Fig.	('UDH', 'Chemical', '-', (49, 52))	('methylation', 'Var', (20, 31))	('ERalpha', 'Gene', (12, 19))	('DCIS', 'Phenotype', 'HP:0030075', (90, 94))	('detected', 'Reg', (3, 11))
175677	27498697	UDH is considered to represent a benign proliferation of ductal epithelial cells, and patients with UDH carried only a small increased risk of developing subsequent breast cancer compared with patients without proliferative breast disease.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('breast disease', 'Disease', (224, 238))	('patients', 'Species', '9606', (193, 201))	('breast disease', 'Disease', 'MESH:D001941', (224, 238))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('UDH', 'Var', (100, 103))	('UDH', 'Chemical', '-', (0, 3))	('UDH', 'Chemical', '-', (100, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('UDH', 'Disease', (0, 3))	('patients', 'Species', '9606', (86, 94))
175696	27498697	One of the most provocative recent observations in human solid tumors is the discovery of large hypomethylated blocks in cancer epigenetics.	('solid tumors', 'Disease', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('human', 'Species', '9606', (51, 56))	('solid tumors', 'Disease', 'MESH:D009369', (57, 69))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', (121, 127))	('hypomethylated', 'Var', (96, 110))
175700	27498697	ERalpha expression or methylation may be involved in the breast carcinogenesis and advancement, thus it is not parallel to breast cancer risk in breast intraductal proliferative lesions.	('breast carcinogenesis', 'Disease', (57, 78))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (57, 78))	('breast cancer', 'Disease', (123, 136))	('involved', 'Reg', (41, 49))	('breast intraductal proliferative lesions', 'Disease', 'MESH:D001941', (145, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('ERalpha', 'Protein', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast intraductal proliferative lesions', 'Disease', (145, 185))	('methylation', 'Var', (22, 33))
175703	31060593	Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS.	('tumours', 'Disease', (289, 296))	('Ductal carcinoma', 'Disease', (154, 170))	('BRCA1', 'Gene', '672', (45, 50))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (154, 170))	('invasive ductal breast cancer', 'Disease', (217, 246))	('BRCA2', 'Gene', '675', (52, 57))	('BRCA1', 'Gene', (45, 50))	('carcinoma in situ', 'Disease', (91, 108))	('carcinoma in situ', 'Disease', (161, 178))	('tumours', 'Phenotype', 'HP:0002664', (289, 296))	('pathogenic', 'Reg', (13, 23))	('tumours', 'Disease', 'MESH:D009369', (289, 296))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (84, 108))	('CHEK2', 'Gene', (66, 71))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (154, 178))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('PALB2', 'Gene', (59, 64))	('TP53', 'Gene', (76, 80))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (91, 108))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (161, 178))	('variants', 'Var', (33, 41))	('ductal carcinoma', 'Disease', (84, 100))	('CHEK2', 'Gene', '11200', (66, 71))	('carcinoma in situ', 'Disease', 'MESH:D002278', (91, 108))	('carcinoma in situ', 'Disease', 'MESH:D002278', (161, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('PALB2', 'Gene', '79728', (59, 64))	('BRCA2', 'Gene', (52, 57))	('ductal carcinoma', 'Disease', 'MESH:D044584', (84, 100))	('invasive ductal breast cancer', 'Disease', 'MESH:D018270', (217, 246))	('TP53', 'Gene', '7157', (76, 80))	('women', 'Species', '9606', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
175707	31060593	Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 x 10-10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 x 10-6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02).	('CHEK2', 'Gene', (126, 131))	('variants', 'Var', (55, 63))	('PALB2', 'Gene', '79728', (209, 214))	('BRCA2', 'Gene', (67, 72))	('PALB2', 'Gene', (209, 214))	('BRCA1', 'Gene', (228, 233))	('BRCA1', 'Gene', '672', (228, 233))	('TP53', 'Gene', '7157', (250, 254))	('pathogenic', 'CPA', (44, 54))	('BRCA2', 'Gene', '675', (67, 72))	('CHEK2', 'Gene', '11200', (126, 131))	('TP53', 'Gene', (250, 254))
175708	31060593	For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Disease', (209, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('variants', 'Var', (70, 78))	('ER', 'Gene', (24, 26))
175709	31060593	For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.	('ER-negative', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
175710	31060593	This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.	('TP53', 'Gene', (116, 120))	('BRCA1', 'Gene', (106, 111))	('tumour', 'Disease', (33, 39))	('women', 'Species', '9606', (215, 220))	('variants', 'Var', (73, 81))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('PALB2', 'Gene', (99, 104))	('PALB2', 'Gene', '79728', (99, 104))	('BRCA2', 'Gene', (85, 90))	('CHEK2', 'Gene', '11200', (92, 97))	('BRCA1', 'Gene', '672', (106, 111))	('TP53', 'Gene', '7157', (116, 120))	('CHEK2', 'Gene', (92, 97))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('BRCA2', 'Gene', '675', (85, 90))	('women', 'Species', '9606', (51, 56))
175715	31060593	Epidemiological studies have shown there is an inherited predisposition to DCIS, with women with DCIS being 2.4 times more likely to have an affected mother and sister with breast cancer than controls.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('DCIS', 'Disease', (75, 79))	('breast cancer', 'Disease', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('DCIS', 'Var', (97, 101))	('women', 'Species', '9606', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))
175719	31060593	studied 369 women (mean age 53.8 years) with pure DCIS selected from a case-control study of carcinoma in situ and found that 2.4% had pathogenic variants in BRCA2 and 0.8% in BRCA1.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('pathogenic', 'Reg', (135, 145))	('carcinoma in situ', 'Disease', (93, 110))	('women', 'Species', '9606', (12, 17))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (93, 110))	('BRCA1', 'Gene', '672', (176, 181))	('BRCA1', 'Gene', (176, 181))	('variants', 'Var', (146, 154))	('BRCA2', 'Gene', (158, 163))	('carcinoma in situ', 'Disease', 'MESH:D002278', (93, 110))	('BRCA2', 'Gene', '675', (158, 163))
175721	31060593	They found that 5.2% of women with pure carcinoma in situ (CIS) had BRCA1/2 mutations (2.3% if women with a family history of breast cancer were excluded) and like Claus et al.	('BRCA1/2', 'Gene', '672;675', (68, 75))	('mutations', 'Var', (76, 85))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('carcinoma in situ', 'Disease', 'MESH:D002278', (40, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('women', 'Species', '9606', (95, 100))	('BRCA1/2', 'Gene', (68, 75))	('women', 'Species', '9606', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma in situ', 'Disease', (40, 57))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
175722	31060593	that BRCA2 mutations were more common than BRCA1 .	('BRCA1', 'Gene', (43, 48))	('mutations', 'Var', (11, 20))	('common', 'Reg', (31, 37))	('BRCA2', 'Gene', (5, 10))	('BRCA2', 'Gene', '675', (5, 10))	('BRCA1', 'Gene', '672', (43, 48))
175724	31060593	In this study, we report the frequency of rare variants in five known breast cancer predisposition genes (BRCA2, BRCA1, TP53, CHEK2 and PALB2) in 655 cases of pure DCIS with no invasive disease in women diagnosed before the age of 50.	('PALB2', 'Gene', '79728', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('BRCA2', 'Gene', '675', (106, 111))	('TP53', 'Gene', '7157', (120, 124))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('BRCA1', 'Gene', '672', (113, 118))	('BRCA1', 'Gene', (113, 118))	('invasive disease', 'Disease', 'MESH:D009362', (177, 193))	('women', 'Species', '9606', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasive disease', 'Disease', (177, 193))	('TP53', 'Gene', (120, 124))	('CHEK2', 'Gene', (126, 131))	('variants', 'Var', (47, 55))	('PALB2', 'Gene', (136, 141))	('pure DCIS', 'Disease', (159, 168))	('BRCA2', 'Gene', (106, 111))	('CHEK2', 'Gene', '11200', (126, 131))
175740	31060593	We found an association with DCIS and pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53, Table 2 (individual raw data, Additional file 2).	('BRCA1', 'Gene', (82, 87))	('CHEK2', 'Gene', (68, 73))	('variants', 'Var', (49, 57))	('PALB2', 'Gene', (75, 80))	('PALB2', 'Gene', '79728', (75, 80))	('BRCA2', 'Gene', (61, 66))	('association', 'Interaction', (12, 23))	('TP53', 'Gene', '7157', (92, 96))	('BRCA1', 'Gene', '672', (82, 87))	('TP53', 'Gene', (92, 96))	('BRCA2', 'Gene', '675', (61, 66))	('CHEK2', 'Gene', '11200', (68, 73))
175742	31060593	Of the 22 pathogenic variants identified, all had been previously described apart from a novel frameshift in exon 11 (c.5754dupT:p.H1918fs).	('p.H1918fs', 'Mutation', 'rs397507803', (129, 138))	('c.5754dupT', 'Mutation', 'rs397507803', (118, 128))	('c.5754dupT:p.H1918fs', 'Var', (118, 138))	('p.H1918fs', 'Var', (129, 138))
175743	31060593	Only two pathogenic variants occurred in more than one patient: exon20:c.8575delC:p.Q2859fs in two patients and exon25:c.C9382T:p.R3128X in two patients, Additional file 6.	('patient', 'Species', '9606', (99, 106))	('p.Q2859fs', 'Var', (82, 91))	('exon20:c.8575delC', 'Var', (64, 81))	('exon20:c.8575delC', 'DELETION', 'None', (64, 81))	('patient', 'Species', '9606', (144, 151))	('c.C9382T:p.R3128X', 'SUBSTITUTION', 'None', (119, 136))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (144, 152))	('patient', 'Species', '9606', (55, 62))	('c.C9382T:p.R3128X', 'Var', (119, 136))	('p.Q2859fs', 'Mutation', 'rs80359718', (82, 91))
175744	31060593	Ninety-five percent of the cases with a pathogenic variant in BRCA2 had high or intermediate grade DCIS, and in the 15 cases where ER status was known, all were ER positive.	('BRCA2', 'Gene', '675', (62, 67))	('pathogenic', 'Reg', (40, 50))	('variant', 'Var', (51, 58))	('DCIS', 'CPA', (99, 103))	('BRCA2', 'Gene', (62, 67))
175748	31060593	The remaining three variants were novel frameshift mutations, one in exon 3: c.401_402del, and two in exon 12: c.1262delT and c.1368dupA, Additional file 7.	('c.1262delT', 'Var', (111, 121))	('c.1262delT', 'Mutation', 'c.1262delT', (111, 121))	('c.401_402del', 'Var', (77, 89))	('c.401_402del', 'Mutation', 'c.401_402del', (77, 89))	('c.1368dupA', 'Var', (126, 136))	('c.1368dupA', 'Mutation', 'rs730881700', (126, 136))
175750	31060593	Of the six pathogenic PALB2 variants detected, three were novel frameshifts (two in exon 4, one in exon 5, Fig.	('pathogenic', 'Reg', (11, 21))	('PALB2', 'Gene', (22, 27))	('PALB2', 'Gene', '79728', (22, 27))	('variants', 'Var', (28, 36))
175751	31060593	Of the three known, two were in exon 10 (rs180177132), which has previously been shown to be associated with breast cancer (OR = 4.21, 95%CI 1.85-9.61), but with no evidence of a differential association with ER status.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('rs180177132', 'Var', (41, 52))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs180177132', 'Mutation', 'rs180177132', (41, 52))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
175752	31060593	All women with PALB2 pathogenic variants had high or intermediate grade DCIS and were ER positive.	('PALB2', 'Gene', '79728', (15, 20))	('PALB2', 'Gene', (15, 20))	('DCIS', 'Disease', (72, 76))	('women', 'Species', '9606', (4, 9))	('variants', 'Var', (32, 40))
175758	31060593	However, the case with the novel frameshift variant in exon 10: c.3750delG:p.E1250fs had a strong family history of other cancers (cervical, lung, and oral) but not breast.	('c.3750delG', 'Mutation', 'rs886040163', (64, 74))	('frameshift', 'Var', (33, 43))	('c.3750delG:p.E1250fs', 'Var', (64, 84))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('lung', 'Disease', (141, 145))	('p.E1250fs', 'Mutation', 'rs886040163', (75, 84))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
175760	31060593	Two were stopgain variants (one novel), and the other a nonsynomous variant (rs397514495) considered pathogenic in the literature, but recently suggested to be a VUS as it does not disrupt all the functions of TP53 just apoptosis, Additional file 10a.	('rs397514495', 'Var', (77, 88))	('rs397514495', 'Mutation', 'rs397514495', (77, 88))	('TP53', 'Gene', '7157', (210, 214))	('TP53', 'Gene', (210, 214))
175761	31060593	The women that carried these variants did not meet the criteria for classic Li-Fraumeni or Li-Fraumeni-like syndrome.	('Li-Fraumeni-like syndrome', 'Disease', (91, 116))	('variants', 'Var', (29, 37))	('women', 'Species', '9606', (4, 9))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (91, 116))
175762	31060593	The novel stopgain variant (NM_000546:exon4:c.G272A:p.W91X) was found in a woman with bilateral DCIS at age 35 and a first-degree relative with breast cancer < 40 years, but no other cancers.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('woman', 'Species', '9606', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('c.G272A:p.W91X', 'Var', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('c.G272A:p.W91X', 'SUBSTITUTION', 'None', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
175763	31060593	The other known stopgain variant was identified in a woman with DCIS at age 40 whose father developed an unknown cancer at age 50 but with no other family history of cancer.	('stopgain', 'Gene', (16, 24))	('cancer', 'Disease', (166, 172))	('woman', 'Species', '9606', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('variant', 'Var', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
175764	31060593	The missense variant occurred in a woman with DCIS at age 45 and a family history of breast cancer in a second-degree relative aged 60, but no other cancers.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast cancer', 'Disease', (85, 98))	('missense variant', 'Var', (4, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('occurred', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('woman', 'Species', '9606', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
175765	31060593	As most pathogenic germline mutations in TP53 are missense rather than truncating mutations, it is possible that by only considering novel variants as pathogenic if they were predicted to lead to protein truncation we may have missed novel pathogenic missense variants in TP53.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('pathogenic', 'Reg', (8, 18))	('TP53', 'Gene', '7157', (272, 276))	('TP53', 'Gene', (272, 276))	('protein', 'MPA', (196, 203))	('missense', 'Var', (50, 58))	('variants', 'Var', (139, 147))	('mutations', 'Var', (28, 37))
175767	31060593	One NM_000546:exon8:c.G869A:p.R290H is listed in the IARC TP53 database as being associated with Li-Fraumeni-like syndrome and, in our study, was found in one case and two controls.	('c.G869A:p.R290H', 'SUBSTITUTION', 'None', (20, 35))	('TP53', 'Gene', '7157', (58, 62))	('Li-Fraumeni-like syndrome', 'Disease', (97, 122))	('TP53', 'Gene', (58, 62))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (97, 122))	('c.G869A:p.R290H', 'Var', (20, 35))	('associated', 'Reg', (81, 91))
175770	31060593	Metachronous bilateral disease was most commonly found in CHEK2 mutation carriers with 5/16 (31%) developing subsequent contralateral disease after a diagnosis of unilateral DCIS (in two, this was in the form of an invasive disease, in two LCIS and in one DCIS) compared to 2/22 (9%) for BRCA2.	('CHEK2', 'Gene', (58, 63))	('mutation', 'Var', (64, 72))	('invasive disease', 'Disease', 'MESH:D009362', (215, 231))	('contralateral disease', 'Disease', 'MESH:D009069', (120, 141))	('Metachronous bilateral disease', 'Disease', (0, 30))	('BRCA2', 'Gene', (288, 293))	('CHEK2', 'Gene', '11200', (58, 63))	('invasive disease', 'Disease', (215, 231))	('contralateral disease', 'Disease', (120, 141))	('BRCA2', 'Gene', '675', (288, 293))	('Metachronous bilateral disease', 'Disease', 'MESH:D016609', (0, 30))
175772	31060593	Analysis of variants of unknown significance (VUS), either known or novel, revealed no excess of VUS in BRCA2, PALB2, TP53 or BRCA1, Additional file 12.	('BRCA2', 'Gene', (104, 109))	('BRCA1', 'Gene', (126, 131))	('BRCA2', 'Gene', '675', (104, 109))	('TP53', 'Gene', '7157', (118, 122))	('variants', 'Var', (12, 20))	('TP53', 'Gene', (118, 122))	('BRCA1', 'Gene', '672', (126, 131))	('PALB2', 'Gene', (111, 116))	('PALB2', 'Gene', '79728', (111, 116))
175773	31060593	A VUS in exon 4 of CHEK2 (rs77130927, c.C538T:p.R180C), which we have previously shown to have a borderline association with invasive lobular cancer (ILC) (P = 0.03, Petridis et al, accepted Cancer Epidemiology, Biomarkers & Prevention), was found in two DCIS cases and one control.	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('rs77130927', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('invasive lobular cancer', 'Disease', (125, 148))	('CHEK2', 'Gene', '11200', (19, 24))	('c.C538T:p.R180C', 'Var', (38, 53))	('lobular cancer', 'Phenotype', 'HP:0030076', (134, 148))	('rs77130927', 'Mutation', 'rs77130927', (26, 36))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (125, 148))	('CHEK2', 'Gene', (19, 24))	('c.C538T:p.R180C', 'SUBSTITUTION', 'None', (38, 53))
175774	31060593	Early data on women with BRCA1 and BRCA2 mutations suggested that presentation as pure DCIS was infrequent.	('mutations', 'Var', (41, 50))	('BRCA1', 'Gene', '672', (25, 30))	('BRCA2', 'Gene', '675', (35, 40))	('BRCA1', 'Gene', (25, 30))	('women', 'Species', '9606', (14, 19))	('pure DCIS', 'Disease', (82, 91))	('BRCA2', 'Gene', (35, 40))
175776	31060593	They also found that the number of pure DCIS cases was similar in BRCA1 and BRCA2 mutations carriers (21% vs 23%), in contrast to Krammer et al.	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', (76, 81))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (76, 81))	('mutations', 'Var', (82, 91))
175777	31060593	who reported that pure DCIS was more frequent in BRCA2 mutation carriers compared to BRCA1 carriers (5%, 36/246, versus 9%, 23/250, P = 0.0026).	('BRCA1', 'Gene', (85, 90))	('BRCA2', 'Gene', '675', (49, 54))	('pure DCIS', 'Disease', (18, 27))	('mutation', 'Var', (55, 63))	('BRCA1', 'Gene', '672', (85, 90))	('BRCA2', 'Gene', (49, 54))
175778	31060593	In our study of sporadic pure DCIS, pathogenic BRCA2 variants were far more common than BRCA1 mutations (3.5% vs 0.6%).	('BRCA1', 'Gene', (88, 93))	('BRCA2', 'Gene', (47, 52))	('pure DCIS', 'Disease', (25, 34))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA2', 'Gene', '675', (47, 52))	('variants', 'Var', (53, 61))
175779	31060593	who found that 2.4% had pathogenic variants in BRCA2 and 0.8% in BRCA1 in a slightly older group of DCIS patients (mean age 53.8 years).	('BRCA1', 'Gene', '672', (65, 70))	('patients', 'Species', '9606', (105, 113))	('variants', 'Var', (35, 43))	('BRCA1', 'Gene', (65, 70))	('BRCA2', 'Gene', (47, 52))	('pathogenic', 'Reg', (24, 34))	('BRCA2', 'Gene', '675', (47, 52))
175780	31060593	found that 5.2% of women under 50 years of age with carcinoma in situ (LCIS and DCIS) had BRCA1/2 mutations, with BRCA2 mutations being more common than BRCA1.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('BRCA1/2', 'Gene', (90, 97))	('carcinoma in situ', 'Disease', 'MESH:D002278', (52, 69))	('carcinoma in situ', 'Disease', (52, 69))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (52, 69))	('BRCA2', 'Gene', (114, 119))	('women', 'Species', '9606', (19, 24))	('BRCA1', 'Gene', '672', (90, 95))	('BRCA2', 'Gene', '675', (114, 119))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('BRCA1', 'Gene', '672', (153, 158))	('mutations', 'Var', (98, 107))	('BRCA1', 'Gene', (90, 95))	('BRCA1', 'Gene', (153, 158))	('mutations', 'Var', (120, 129))
175781	31060593	We found that BRCA2 mutations occurred in 2.4% of DCIS in women under the age 50 and in 9% under the age of 40.	('BRCA2', 'Gene', '675', (14, 19))	('DCIS', 'Disease', (50, 54))	('women', 'Species', '9606', (58, 63))	('occurred', 'Reg', (30, 38))	('BRCA2', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
175782	31060593	All but one of these variants had been previously described in invasive breast cancer.	('variants', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('invasive breast cancer', 'Disease', (63, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('invasive breast cancer', 'Disease', 'MESH:D001943', (63, 85))
175783	31060593	Of the genes studied, BRCA2 was the only gene where pathogenic mutations were associated with younger age.	('mutations', 'Var', (63, 72))	('BRCA2', 'Gene', '675', (22, 27))	('BRCA2', 'Gene', (22, 27))
175784	31060593	All the cases of DCIS in BRCA2 carriers were ER positive (where ER status was known), unlike invasive disease where only 77% are ER positive.	('invasive disease', 'Disease', 'MESH:D009362', (93, 109))	('BRCA2', 'Gene', (25, 30))	('BRCA2', 'Gene', '675', (25, 30))	('positive', 'Reg', (48, 56))	('invasive disease', 'Disease', (93, 109))	('DCIS', 'Disease', (17, 21))	('carriers', 'Var', (31, 39))
175785	31060593	In contrast, BRCA1 pathogenic variants were infrequent, four in total (only one had been previously described), and associated with predominantly ER negative DCIS.	('ER negative DCIS', 'Disease', (146, 162))	('variants', 'Var', (30, 38))	('BRCA1', 'Gene', (13, 18))	('BRCA1', 'Gene', '672', (13, 18))	('associated', 'Reg', (116, 126))
175786	31060593	Pathogenic variants in CHEK2 were the second most common set of mutations after BRCA2 and occurred in 2.5% of pure DCIS under the age of 50.	('occurred', 'Reg', (90, 98))	('BRCA2', 'Gene', (80, 85))	('variants', 'Var', (11, 19))	('Pathogenic', 'Reg', (0, 10))	('BRCA2', 'Gene', '675', (80, 85))	('CHEK2', 'Gene', (23, 28))	('CHEK2', 'Gene', '11200', (23, 28))	('pure DCIS', 'Disease', (110, 119))
175787	31060593	Unlike BRCA2, there was no association with age and the majority were the well-described c.1100delC variant.	('BRCA2', 'Gene', (7, 12))	('c.1100delC', 'Var', (89, 99))	('BRCA2', 'Gene', '675', (7, 12))	('c.1100delC', 'Mutation', 'rs555607708', (89, 99))
175788	31060593	There was no evidence of an association with the rare missense variant p.I157T (c.T470C, rs17879961), which was found in three controls and no cases.	('rs17879961', 'Mutation', 'rs17879961', (89, 99))	('c.T470C', 'Mutation', 'rs17879961', (80, 87))	('rs17879961', 'Var', (89, 99))	('p.I157T', 'Mutation', 'rs17879961', (71, 78))	('c.T470C', 'Var', (80, 87))
175789	31060593	This high frequency of CHEK2 variants in pure DCIS has not been previously described, although Schmidt et al.	('CHEK2', 'Gene', '11200', (23, 28))	('variants', 'Var', (29, 37))	('pure DCIS', 'Disease', (41, 50))	('CHEK2', 'Gene', (23, 28))
175790	31060593	noted in their study of tumour characteristics in CHEK2 c.1100delC carriers that carriers from population- and hospital-based studies more often developed in situ tumours (LCIS and DCIS) compared to carriers from familial or clinical genetics center-based studies; this was interpreted as a bias estimate due to differential recruitment related to family history of breast cancer and screening.	('CHEK2', 'Gene', (50, 55))	('situ tumours', 'Disease', (158, 170))	('breast cancer', 'Disease', 'MESH:D001943', (366, 379))	('c.1100delC', 'Mutation', 'rs555607708', (56, 66))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('breast cancer', 'Disease', (366, 379))	('c.1100delC', 'Var', (56, 66))	('situ tumours', 'Disease', 'MESH:D002278', (158, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (366, 379))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('developed', 'PosReg', (145, 154))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Disease', (24, 30))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('CHEK2', 'Gene', '11200', (50, 55))	('tumour', 'Disease', (163, 169))
175791	31060593	who reported data on the frequency of CHEK2 mutations in a series of breast cancer with and without pure DCIS allowing one to determine mutation rates in pure DCIS cases.	('CHEK2', 'Gene', (38, 43))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('mutations', 'Var', (44, 53))	('CHEK2', 'Gene', '11200', (38, 43))
175792	31060593	In that study, 2.87% of DCIS cases had pathogenic CHEK2 variants compared to 1.43% in invasive disease.	('CHEK2', 'Gene', (50, 55))	('DCIS', 'Disease', (24, 28))	('invasive disease', 'Disease', (86, 102))	('pathogenic', 'Reg', (39, 49))	('variants', 'Var', (56, 64))	('invasive disease', 'Disease', 'MESH:D009362', (86, 102))	('CHEK2', 'Gene', '11200', (50, 55))
175794	31060593	It is therefore not surprising that we have found PALB2 pathogenic mutations in women with pure DCIS and that they are more common in women with a first-degree relative with breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('women', 'Species', '9606', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('pure DCIS', 'Disease', (91, 100))	('breast cancer', 'Disease', (174, 187))	('PALB2', 'Gene', (50, 55))	('common', 'Reg', (124, 130))	('PALB2', 'Gene', '79728', (50, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('mutations', 'Var', (67, 76))	('women', 'Species', '9606', (134, 139))
175796	31060593	who showed there was a constant relative risk, irrespective of age, for pathogenic variants in PALB2.	('variants', 'Var', (83, 91))	('PALB2', 'Gene', (95, 100))	('PALB2', 'Gene', '79728', (95, 100))	('pathogenic', 'Reg', (72, 82))
175797	31060593	The frequency of PALB2 variants in our data is supported by the study by Couch et al.	('PALB2', 'Gene', (17, 22))	('variants', 'Var', (23, 31))	('PALB2', 'Gene', '79728', (17, 22))
175798	31060593	where one can infer from the supplementary data that the frequency of pathogenic PALB2 variants in DCIS is 0.96%.	('pathogenic', 'Reg', (70, 80))	('PALB2', 'Gene', (81, 86))	('PALB2', 'Gene', '79728', (81, 86))	('variants', 'Var', (87, 95))
175799	31060593	Pure DCIS (73% HER2 positive, 55% ER positive) and high-grade comedo DCIS have been described in Li-Fraumeni Syndrome but our data show that TP53 mutations are infrequent in sporadic DCIS.	('mutations', 'Var', (146, 155))	('grade comedo', 'Phenotype', 'HP:0025250', (56, 68))	('HER2', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (141, 145))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (97, 117))	('TP53', 'Gene', (141, 145))	('HER2', 'Gene', '2064', (15, 19))	('Li-Fraumeni Syndrome', 'Disease', (97, 117))	('comedo', 'Phenotype', 'HP:0025249', (62, 68))
175801	31060593	The known missense mutation detected has been shown to be associated with Li-Fraumeni-like syndrome rather than true LFS.	('Li-Fraumeni-like syndrome', 'Disease', (74, 99))	('missense mutation', 'Var', (10, 27))	('associated', 'Reg', (58, 68))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (74, 99))
175803	31060593	This is likely due to the size of the study which is too small to yield stable estimates of associations with DCIS, but does give useful estimates of prevalence and, of note, is twice as large as the study by Claus et al., the only other study documenting the prevalence of BRCA1/2 mutations in sporadic DCIS.	('BRCA1/2', 'Gene', '672;675', (274, 281))	('DCIS', 'Disease', (110, 114))	('BRCA1/2', 'Gene', (274, 281))	('DCIS', 'Disease', (304, 308))	('associations', 'Interaction', (92, 104))	('mutations', 'Var', (282, 291))
175806	31060593	We also found a similar finding in lobular cancer where LCIS had a stronger association with CHEK2 mutations than ILC (ILC OR = 4.29, 95%CI 1.60-11.51, P = 0.0017; LCIS OR = 9.95, 95%CI 3.44-28.82, P = 5 x 10-5, Petridis et al.	('lobular cancer', 'Phenotype', 'HP:0030076', (35, 49))	('lobular cancer', 'Disease', 'MESH:D013274', (35, 49))	('CHEK2', 'Gene', (93, 98))	('CHEK2', 'Gene', '11200', (93, 98))	('mutations', 'Var', (99, 108))	('lobular cancer', 'Disease', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
175807	31060593	This suggests that CHEK2 pathogenic variants may be predisposing to the in situ stage of breast cancer with some not progressing to the invasive state.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('predisposing', 'Reg', (52, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('CHEK2', 'Gene', '11200', (19, 24))	('variants', 'Var', (36, 44))	('CHEK2', 'Gene', (19, 24))
175809	31060593	found a higher frequency of BRCA1 mutations compared to our study of DCIS (3.2% versus 0.6%).	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
175810	31060593	We believe that this difference in frequency of BRCA1 mutations stems from the fact that the vast majority of the samples in our study are ER+ and only 13% of the samples are ER-, compared to 25% in the invasive study of Schmidt et al.	('BRCA1', 'Gene', '672', (48, 53))	('ER+', 'Var', (139, 142))	('BRCA1', 'Gene', (48, 53))	('mutations', 'Var', (54, 63))
175812	31060593	In this study, 7.2% of women with DCIS (irrespective of ER status) under the age of 50 had pathogenic variants in one of five known breast cancer predisposition genes.	('DCIS', 'Disease', (34, 38))	('variants', 'Var', (102, 110))	('women', 'Species', '9606', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('pathogenic', 'Reg', (91, 101))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
175813	31060593	This level does not reach the current UK threshold for genetic testing (https://www.nice.org.uk/guidance/cg164/chapter/Recommendations#genetic-testing); however, women under 40 years of age had a 13% (11% excluding CHEK2 variants) probability of having a germline mutation which does reach the UK threshold of 10% for routine testing.	('variants', 'Var', (221, 229))	('CHEK2', 'Gene', '11200', (215, 220))	('CHEK2', 'Gene', (215, 220))	('germline mutation', 'Var', (255, 272))	('women', 'Species', '9606', (162, 167))
175814	31060593	For women under 40 years of age with a family history of breast cancer, the frequency of germline mutations increases to 21%.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('increases', 'PosReg', (108, 117))	('germline', 'Var', (89, 97))	('women', 'Species', '9606', (4, 9))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
175815	31060593	There has been particular focus on ER-negative DCIS and whether these women should undergo HER2 testing and, if this is also negative, be offered BRCA1 and BRCA2 testing, as is recommended for those with triple-negative invasive breast cancer.	('ER-negative', 'Var', (35, 46))	('BRCA1', 'Gene', '672', (146, 151))	('invasive breast cancer', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('BRCA2', 'Gene', (156, 161))	('HER2', 'Gene', (91, 95))	('BRCA1', 'Gene', (146, 151))	('HER2', 'Gene', '2064', (91, 95))	('invasive breast cancer', 'Disease', 'MESH:D001943', (220, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('women', 'Species', '9606', (70, 75))	('BRCA2', 'Gene', '675', (156, 161))
175817	31060593	However, looking solely at ER-negative DCIS, only 9% under the age of 50 and 8% under the age of 40 had pathogenic variants and these were in BRCA1, TP53 and CHEK2.	('pathogenic', 'Reg', (104, 114))	('CHEK2', 'Gene', (158, 163))	('BRCA1', 'Gene', '672', (142, 147))	('TP53', 'Gene', '7157', (149, 153))	('BRCA1', 'Gene', (142, 147))	('variants', 'Var', (115, 123))	('TP53', 'Gene', (149, 153))	('CHEK2', 'Gene', '11200', (158, 163))
175819	31060593	In contrast, the frequency of pathogenic variants in ER-positive DCIS under the age of 40 was much higher; 9% of women under the age of 50 had pathogenic variants rising to 29% under the age of 40 (14% and 42%, respectively, if only women with a family history of breast cancer are considered) Table 6.	('variants', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('breast cancer', 'Disease', (264, 277))	('women', 'Species', '9606', (113, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('women', 'Species', '9606', (233, 238))
175820	31060593	This study has shown that a DCIS-associated malignant pathway can occur in patients who have pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53.	('BRCA1', 'Gene', '672', (137, 142))	('CHEK2', 'Gene', '11200', (123, 128))	('TP53', 'Gene', (147, 151))	('CHEK2', 'Gene', (123, 128))	('PALB2', 'Gene', '79728', (130, 135))	('BRCA1', 'Gene', (137, 142))	('variants', 'Var', (104, 112))	('patients', 'Species', '9606', (75, 83))	('PALB2', 'Gene', (130, 135))	('BRCA2', 'Gene', (116, 121))	('TP53', 'Gene', '7157', (147, 151))	('BRCA2', 'Gene', '675', (116, 121))
175821	31060593	We also show that the focus of genetic testing should be on ER-positive, intermediate-, and high-grade DCIS from patients under the age of 40, rather than ER-negative DCIS, although restricting such testing to those age under 40 would fail to identify the majority of CHEK2 and PALB2 mutation carriers.	('mutation', 'Var', (284, 292))	('DCIS', 'Disease', (103, 107))	('CHEK2', 'Gene', '11200', (268, 273))	('patients', 'Species', '9606', (113, 121))	('CHEK2', 'Gene', (268, 273))	('PALB2', 'Gene', '79728', (278, 283))	('PALB2', 'Gene', (278, 283))
175822	31060593	Once mutations are identified in these women, chemoprevention with tamoxifen and surveillance is a potential alternative to prophylactic mastectomy, particularly in CHEK2 carriers where the risk of invasive disease is less.	('CHEK2', 'Gene', (165, 170))	('invasive disease', 'Disease', 'MESH:D009362', (198, 214))	('tamoxifen', 'Chemical', 'MESH:D013629', (67, 76))	('women', 'Species', '9606', (39, 44))	('mutations', 'Var', (5, 14))	('CHEK2', 'Gene', '11200', (165, 170))	('invasive disease', 'Disease', (198, 214))
175823	31060593	Further studies with long-term follow-up data are required to ascertain whether these germline pathogenic variants identify a subgroup of DCIS that are more likely to progress to invasive disease or whether somatic changes in the DCIS are a more important predictor of recurrence.	('invasive disease', 'Disease', 'MESH:D009362', (179, 195))	('invasive disease', 'Disease', (179, 195))	('variants', 'Var', (106, 114))	('progress', 'PosReg', (167, 175))
175864	24936502	In addition, all three cancer lesions in our population were low grade DCIS, which might be found to still carry a favourable prognosis that is equivalent to that of cancers detected by screening.	('low grade', 'Var', (61, 70))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancer lesions', 'Disease', 'MESH:D009062', (23, 37))	('cancer lesions', 'Disease', (23, 37))	('DCIS', 'Disease', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
175940	23782331	On the basis of genetic rule, inactivation of each maternal or paternal allele of individual breast cells occurs evenly in the embryogenesis prior to the carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('inactivation', 'Var', (30, 42))	('carcinogenesis', 'Disease', (154, 168))
175982	23236365	Variants of MCF10.DCIS and SUM102 lines that express monomeric red fluorescent protein (mRFP) were developed by retroviral transduction as previously described.	('Variants', 'Var', (0, 8))	('SUM102', 'Gene', (27, 33))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (12, 22))	('MCF10.DCIS', 'Gene', (12, 22))
175993	23236365	The mRFP-expressing variants of MCF10.DCIS and SUM102 were grown in 3D rBM culture on coverslips with exposure to drug or vehicle controls for 8 days.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (32, 42))	('variants', 'Var', (20, 28))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('MCF10.DCIS', 'Gene', (32, 42))
176003	23236365	The DCIS models derived from two individual patients (SUM102 and SUM225) are more highly correlated when clustering is based on differentially expressed transcripts (Figure 1C) as opposed to the total number of reads (Figure 1B).	('SUM225', 'Var', (65, 71))	('differentially expressed transcripts', 'MPA', (128, 164))	('patients', 'Species', '9606', (44, 52))	('DCIS', 'Phenotype', 'HP:0030075', (4, 8))	('SUM102', 'Var', (54, 60))
176005	23236365	The results showed that there were over 1,000 differentially expressed transcripts in each of the DCIS models as compared to MCF10A (Figure 1D), with the fewest number of altered transcripts in MCF10.DCIS as compared to MCF10A.	('MCF10A', 'CellLine', 'CVCL:0598', (125, 131))	('MCF10A', 'CellLine', 'CVCL:0598', (220, 226))	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('differentially expressed transcripts', 'MPA', (46, 82))	('MCF10.DCIS', 'Var', (194, 204))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (194, 204))	('DCIS', 'Phenotype', 'HP:0030075', (200, 204))
176019	23236365	The log2fold change values of the selected genes in MCF10.DCIS, SUM102 and SUM225 over MCF10A as detected by RNA-Seq and qRT-PCR are shown in Figure 4.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (52, 62))	('MCF10A', 'CellLine', 'CVCL:0598', (87, 93))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('SUM225', 'Var', (75, 81))	('MCF10A', 'Gene', (87, 93))
176031	23236365	Treatment with DSF significantly inhibited net proliferation of 3D rBM overlay cultures of MCF10.DCIS, SUM102 and SUM225, but had only a modest effect on 3D rBM overlay cultures of MCF10A (Figure 6A).	('net proliferation', 'CPA', (43, 60))	('SUM102', 'Var', (103, 109))	('MCF10.DCIS', 'Var', (91, 101))	('DSF', 'Chemical', 'MESH:D004221', (15, 18))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('MCF10A', 'CellLine', 'CVCL:0598', (181, 187))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (91, 101))	('inhibited', 'NegReg', (33, 42))
176038	23236365	As an independent assay for effects on cell growth, we developed variants of MCF10.DCIS and SUM102 cells that constitutively expresses monomeric red fluorescent protein (mRFP) and treated 3D rBM overlay cultures of these cells.	('MCF10.DCIS', 'Gene', (77, 87))	('variants', 'Var', (65, 73))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('SUM102', 'Gene', (92, 98))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (77, 87))
176039	23236365	The results show the dysplastic growth of the control and vehicle-treated MCF10.DCIS-mRFP and SUM102-mRFP cells over a period of eight days.	('SUM102-mRFP', 'Var', (94, 105))	('dysplastic', 'Disease', (21, 31))	('dysplastic', 'Disease', 'MESH:D004416', (21, 31))	('MCF10.DCIS-mRFP', 'Gene', (74, 89))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (74, 84))
176043	23236365	The SUM102-mRFP cells that had been treated with 20 or 50 microM DSF showed no ability to re-grow, whereas those that had been treated with 5 microM DSF showed minimal re-growth as compared to control, vehicle-treated cells.	('DSF', 'Var', (65, 68))	('DSF', 'Chemical', 'MESH:D004221', (65, 68))	('DSF', 'Chemical', 'MESH:D004221', (149, 152))	('re-grow', 'CPA', (90, 97))	('SUM102-mRFP', 'Var', (4, 15))
176053	23236365	Her-2/neu amplification plays an important role in initiation rather than in progression of ductal carcinoma and its overexpression predicts local recurrence.	('ductal carcinoma', 'Disease', 'MESH:D044584', (92, 108))	('ductal carcinoma', 'Disease', (92, 108))	('local recurrence', 'Disease', (141, 157))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (92, 108))	('amplification', 'Var', (10, 23))	('overexpression', 'PosReg', (117, 131))	('Her-2', 'Gene', '2064', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('Her-2', 'Gene', (0, 5))
176058	23236365	The observation that MCF10.DCIS has more genes in common with MCF10A than with either SUM102 or SUM225 is consistent with the fact that MCF10.DCIS and MCF10A are isogenic.	('MCF10A', 'Disease', (62, 68))	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (21, 31))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('MCF10A', 'CellLine', 'CVCL:0598', (151, 157))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (136, 146))	('MCF10A', 'CellLine', 'CVCL:0598', (62, 68))	('MCF10.DCIS', 'Var', (21, 31))
176073	23236365	The presence of AGR2 in primary breast tumors is correlated with poor survival, and elevated expression of AGR2 is related to treatment failure with tamoxifen.	('treatment failure', 'Disease', (126, 143))	('breast tumors', 'Phenotype', 'HP:0100013', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('AGR2', 'Gene', '10551', (16, 20))	('AGR2', 'Gene', (16, 20))	('elevated', 'PosReg', (84, 92))	('breast tumors', 'Disease', 'MESH:D001943', (32, 45))	('treatment failure', 'Disease', 'MESH:D016609', (126, 143))	('AGR2', 'Gene', '10551', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('breast tumors', 'Disease', (32, 45))	('tamoxifen', 'Chemical', 'MESH:D013629', (149, 158))	('expression', 'MPA', (93, 103))	('AGR2', 'Gene', (107, 111))	('presence', 'Var', (4, 12))	('poor', 'NegReg', (65, 69))	('related', 'Reg', (115, 122))
176075	23236365	In gastric carcinoma, high levels of CLDN4 have been found to be significantly associated with MMP-9 expression, which in turn can degrade type IV collagen of ECM and facilitate cancer cell invasion.	('MMP-9', 'Gene', (95, 100))	('associated', 'Reg', (79, 89))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('ECM', 'Gene', '22915', (159, 162))	('CLDN4', 'Gene', '1364', (37, 42))	('type IV collagen', 'MPA', (139, 155))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('high levels', 'Var', (22, 33))	('facilitate', 'PosReg', (167, 177))	('CLDN4', 'Gene', (37, 42))	('ECM', 'Gene', (159, 162))	('expression', 'MPA', (101, 111))	('degrade', 'NegReg', (131, 138))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('cancer', 'Disease', (178, 184))	('gastric carcinoma', 'Disease', (3, 20))	('MMP-9', 'Gene', '4318', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
176079	23236365	We observed differential gene expression of several collagens (1A1, 2A1, L4A6, 7A1,8A1 and 17A1) in DCIS models, but not the related family members (e.g.,11A1 and 5A2) that have previously been reported to be involved in progression of DCIS to IDC.	('DCIS', 'Phenotype', 'HP:0030075', (236, 240))	('IDC', 'Disease', (244, 247))	('DCIS', 'Disease', (100, 104))	('1A1', 'Gene', '51151', (63, 66))	('L4A6', 'Var', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('1A1', 'Gene', '51151', (155, 158))	('1A1', 'Gene', (63, 66))	('1A1', 'Gene', (155, 158))	('DCIS', 'Disease', (236, 240))
176089	23236365	Downregulation of ALDH1A1 and ALDH3A1 has been shown to reduce cell growth and motility in lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('motility in lung cancer', 'Disease', (79, 102))	('ALDH1A1', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Downregulation', 'Var', (0, 14))	('ALDH3A1', 'Gene', (30, 37))	('ALDH3A1', 'Gene', '11670', (30, 37))	('reduce', 'NegReg', (56, 62))	('cell growth', 'CPA', (63, 74))	('motility in lung cancer', 'Disease', 'MESH:D008175', (79, 102))
176112	23236365	The results from our study suggest that inhibition of ALDH5A1 may contribute to its anti-tumorigenic activity.	('inhibition', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ALDH5A1', 'Gene', '7915', (54, 61))	('ALDH5A1', 'Gene', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
176124	22666611	Presence of high grade DCIS or presence of comedonecrosis, and diagnosis of invasive component by core-needle biopsy, and mammographic DCIS size of at least 4 cm were identified as independent risk factors for invasion.	('necrosis', 'Disease', (49, 57))	('high', 'Var', (12, 16))	('comedo', 'Phenotype', 'HP:0025249', (43, 49))	('necrosis', 'Disease', 'MESH:D009336', (49, 57))	('invasion', 'Disease', (210, 218))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))
176129	22666611	SLN metastases were classified according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system as follows: isolated tumor cells (ITC) were defined as isolated tumor cells or clusters <=0.2 mm in maximum diameter; micrometastasis were defined as metastases >0.2 mm but <2 mm; macrometastasis as >2 mm.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cancer', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('<=0.2', 'Var', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('isolated tumor', 'Disease', (136, 150))	('isolated tumor', 'Disease', 'MESH:D009369', (136, 150))	('isolated tumor', 'Disease', (179, 193))	('isolated tumor', 'Disease', 'MESH:D009369', (179, 193))
176147	32352034	Analyses of publicly available databases showed significantly improved overall and relapse-free survival in patients with high Gas6 mRNA, particularly in luminal A breast cancers.	('overall', 'CPA', (71, 78))	('mRNA', 'Var', (132, 136))	('luminal A breast cancer', 'Disease', 'MESH:D001943', (154, 177))	('improved', 'PosReg', (62, 70))	('high', 'Var', (122, 126))	('A breast cancers', 'Disease', 'MESH:D001943', (162, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('A breast cancers', 'Disease', (162, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('luminal A breast cancer', 'Disease', (154, 177))	('Gas6', 'Gene', (127, 131))	('patients', 'Species', '9606', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('relapse-free survival', 'CPA', (83, 104))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
176159	32352034	To our surprise, tumor-derived Gas6 significantly decreased in breast cancer as compared with normal tissues, and overall survival and relapse-free survival (RFS) was significantly improved in breast cancers with high Gas6 expression.	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Disease', (63, 76))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('relapse-free survival', 'CPA', (135, 156))	('high', 'Var', (213, 217))	('breast cancers', 'Disease', 'MESH:D001943', (193, 207))	('breast cancers', 'Disease', (193, 207))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('improved', 'PosReg', (181, 189))	('overall survival', 'CPA', (114, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (193, 207))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('decreased', 'NegReg', (50, 59))	('Gas6', 'Gene', (218, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
176172	32352034	Interestingly, luminal A breast cancers, which generally have a favorable outcome, showed the largest percentage of patients with high Gas6 expression (Fig.	('luminal A breast cancer', 'Disease', 'MESH:D001943', (15, 38))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('breast cancers', 'Phenotype', 'HP:0003002', (25, 39))	('patients', 'Species', '9606', (116, 124))	('luminal A breast cancer', 'Disease', (15, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('A breast cancers', 'Disease', 'MESH:D001943', (23, 39))	('high Gas6', 'Var', (130, 139))	('A breast cancers', 'Disease', (23, 39))
176174	32352034	Stromal protein expression of Gas6 was also quantified, and showed no distinct difference between subtypes, nonetheless, a small subset of luminal B and Her2+ patients had the highest Gas6 expression (Supplementary Fig.	('Gas6', 'Gene', (184, 188))	('luminal', 'Disease', (139, 146))	('expression', 'MPA', (189, 199))	('Her2+', 'Var', (153, 158))	('luminal', 'Chemical', 'MESH:D010634', (139, 146))	('patients', 'Species', '9606', (159, 167))
176177	32352034	In METABRIC data, patients with luminal B or Her2+ expressed significantly lower levels of Gas6 mRNA relative to non-cancerous breast tissue (Fig.	('lower', 'NegReg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Her2+', 'Var', (45, 50))	('luminal B', 'Var', (32, 41))	('luminal', 'Chemical', 'MESH:D010634', (32, 39))	('cancerous', 'Disease', 'MESH:D009369', (117, 126))	('Gas6 mRNA', 'MPA', (91, 100))	('levels', 'MPA', (81, 87))	('patients', 'Species', '9606', (18, 26))	('cancerous', 'Disease', (117, 126))
176178	32352034	Similarly, analysis of TCGA data showed that patients with luminal B, Her2+, and basal-like (which includes TNBC) tumors expressed significantly lower levels of Gas6 mRNA, relative to normal-like cancers (Fig.	('levels', 'MPA', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('Her2+', 'Var', (70, 75))	('luminal', 'Chemical', 'MESH:D010634', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('basal-like', 'CPA', (81, 91))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('Gas6 mRNA', 'MPA', (161, 170))	('patients', 'Species', '9606', (45, 53))	('cancers', 'Disease', (196, 203))	('lower', 'NegReg', (145, 150))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
176190	32352034	There was a significant improvement in overall survival in Gas6 high patients in the METABRIC data set in all patients/all treatments (n = 1904, p = 0.0004) (Fig.	('improvement', 'PosReg', (24, 35))	('overall survival', 'MPA', (39, 55))	('Gas6 high', 'Var', (59, 68))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (110, 118))
176191	32352034	When stratified by subtype, there was a significant increase in overall survival in Gas6 high luminal A patients as compared with Gas6 low (n = 679, p = 0.003) (Fig.	('Gas6 high luminal A', 'Var', (84, 103))	('increase', 'PosReg', (52, 60))	('luminal', 'Chemical', 'MESH:D010634', (94, 101))	('patients', 'Species', '9606', (104, 112))
176192	32352034	In support, tumors with low Gas6 expression are larger in size, have higher cellularity, higher histological grade, and an increased Nottingham Prognostic Index (Table 2), all of which are prognostic markers for patient response to neoadjuvant chemotherapy.	('increased', 'PosReg', (123, 132))	('Gas6', 'Gene', (28, 32))	('cellularity', 'CPA', (76, 87))	('patient', 'Species', '9606', (212, 219))	('higher', 'PosReg', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Nottingham Prognostic Index', 'MPA', (133, 160))	('histological grade', 'CPA', (96, 114))	('tumors', 'Disease', (12, 18))	('low', 'Var', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('higher', 'PosReg', (69, 75))	('larger', 'PosReg', (48, 54))
176197	32352034	Taken together, these results suggest that high Gas6 mRNA is associated with increased patient survival and is likely not predictive of poor outcome.	('Gas6', 'Protein', (48, 52))	('high', 'Var', (43, 47))	('patient survival', 'CPA', (87, 103))	('patient', 'Species', '9606', (87, 94))	('increased', 'PosReg', (77, 86))
176214	32352034	Analysis of the METABRIC data set that includes all patients regardless of treatment revealed a significant increase in overall survival in patients with high Gas6 mRNA (Fig.	('increase', 'PosReg', (108, 116))	('high Gas6 mRNA', 'Var', (154, 168))	('patients', 'Species', '9606', (140, 148))	('overall survival', 'MPA', (120, 136))	('patients', 'Species', '9606', (52, 60))
176215	32352034	Using the Kaplan-Meier plotter database (KMplotter), we found that high Gas6 mRNA correlated to improved RFS in breast cancer patients, particularly in patients with luminal A breast cancer, when stratified with those who had received therapy (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('improved', 'PosReg', (96, 104))	('high', 'Var', (67, 71))	('Gas6', 'Protein', (72, 76))	('breast cancer', 'Disease', (112, 125))	('luminal A breast cancer', 'Disease', (166, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RFS', 'MPA', (105, 108))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('patients', 'Species', '9606', (126, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('luminal A breast cancer', 'Disease', 'MESH:D001943', (166, 189))	('patients', 'Species', '9606', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
176223	32352034	showed that genetic ablation of Axl in MMTV-Neu tumors results in decreased tumor formation and metastasis, although Gas6 deletion had no effect on mammary tumorigenesis.	('Gas6', 'Gene', (117, 121))	('tumor', 'Disease', (48, 53))	('decreased tumor', 'Disease', (66, 81))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Axl', 'Protein', (32, 35))	('decreased tumor', 'Disease', 'MESH:D002303', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('deletion', 'Var', (122, 130))	('MMTV-Neu tumors', 'Disease', 'MESH:C537366', (39, 54))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('MMTV-Neu tumors', 'Disease', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
176230	32352034	In ovarian cancer cell lines derived from mesenchymal (Mes) or epithelial (Epi-A) mouse models, Gas6-stimulated Axl-RTK crosstalk in Mes cells, whereas Gas6-induced Axl activation did not involve other RTKs in Epi-A cells.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('Axl-RTK crosstalk', 'MPA', (112, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('Gas6-stimulated', 'Var', (96, 111))	('ovarian cancer', 'Disease', (3, 17))	('mouse', 'Species', '10090', (82, 87))
176267	31172829	1) is a zinc metalloprotein that catalyzes the reversible hydration of carbon dioxide to produce a bicarbonate ion and a proton (CO2 + H2O   HCO3- + H+).	('CO2 +', 'Chemical', 'MESH:D002245', (129, 134))	('metal', 'Chemical', 'MESH:D008670', (13, 18))	('bicarbonate', 'Chemical', 'MESH:D001639', (99, 110))	('carbon dioxide', 'Chemical', 'MESH:D002245', (71, 85))	('bicarbonate ion', 'MPA', (99, 114))	('HCO3-', 'Chemical', 'MESH:D001639', (141, 146))	('rat', 'Species', '10116', (61, 64))	('H2O', 'Chemical', '-', (135, 138))	('CO2 + H2O', 'Var', (129, 138))
176275	31172829	The fourteen human isozymes have a high structural homology, with key amino acid differences within their active site making them to vary quite widely in their kinetic parameters (Table 1) and also in their susceptibility to different inhibitors.	('kinetic', 'MPA', (160, 167))	('human', 'Species', '9606', (13, 18))	('susceptibility', 'MPA', (207, 221))	('differences', 'Var', (81, 92))	('vary', 'Reg', (133, 137))
176280	31172829	Alteration of these normal pathways in various dysfunctions or diseases trigger CA isozyme up/down-regulation from the gene level, which constitutes the main premise for using CAs as disease markers.	('CAs', 'Chemical', 'MESH:D002118', (176, 179))	('dysfunctions or diseases', 'Disease', (47, 71))	('Alteration', 'Var', (0, 10))	('dysfunctions or diseases', 'Disease', 'MESH:D004194', (47, 71))	('up/down-regulation', 'PosReg', (91, 109))	('CA isozyme', 'Enzyme', (80, 90))	('rat', 'Species', '10116', (4, 7))
176297	31172829	After analyzing enriched plasma proteins from 25 prostate cancer patients and 15 healthy controls using a label-free quantitative shotgun proteomics platform called 2DICAL (2-dimensional image converted analysis of liquid chromatography and mass spectrometry) the authors identified CA I by tandem MS.	('CA I', 'Gene', '759', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CA I', 'Gene', (283, 287))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('patients', 'Species', '9606', (65, 73))	('tandem MS', 'Var', (291, 300))	('prostate cancer', 'Disease', (49, 64))
176326	31172829	These tumors constitute the most common mesenchymal tumors of the gastrointestinal tract, which are usually generated from expression of mutant KIT or PDGFRA receptor tyrosine kinase oncogenes.	('KIT', 'Gene', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PDGFRA', 'Gene', '5156', (151, 157))	('PDGFRA', 'Gene', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('generated from', 'Reg', (108, 122))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('rat', 'Species', '10116', (112, 115))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (40, 58))	('KIT', 'Gene', '3815', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutant', 'Var', (137, 143))	('mesenchymal tumors', 'Disease', (40, 58))
176370	31172829	Further, MPA patients positive for anti-CAIII antibodies had higher Birmingham vasculitis activity scores (BVAS - a typical disease assessment in systemic vasculitis) as compared to anti-CAIII antibody-negative patients.	('CAIII', 'Gene', (187, 192))	('antibodies', 'Var', (46, 56))	('CAIII', 'Gene', '761', (187, 192))	('vasculitis', 'Disease', 'MESH:D014657', (155, 165))	('patients', 'Species', '9606', (211, 219))	('CAIII', 'Gene', (40, 45))	('higher', 'PosReg', (61, 67))	('CAIII', 'Gene', '761', (40, 45))	('patients', 'Species', '9606', (13, 21))	('vasculitis', 'Disease', (79, 89))	('vasculitis', 'Phenotype', 'HP:0002633', (79, 89))	('vasculitis', 'Disease', (155, 165))	('vasculitis', 'Phenotype', 'HP:0002633', (155, 165))	('vasculitis', 'Disease', 'MESH:D014657', (79, 89))
176426	31172829	A mutations in CA-RP VIII gene (S100P) that significantly reduces the protein stability has been associated with ataxia, mild mental retardation and a predisposition for quadrupedal gait in humans and with lifelong gait disorder in mice.	('reduces', 'NegReg', (58, 65))	('humans', 'Species', '9606', (190, 196))	('quadrupedal gait', 'Disease', (170, 186))	('S100P', 'Gene', '6286', (32, 37))	('mutations', 'Var', (2, 11))	('mental retardation', 'Disease', (126, 144))	('CA-RP VIII', 'Gene', (15, 25))	('S100P', 'Gene', (32, 37))	('lifelong gait disorder', 'Disease', 'MESH:C565569', (206, 228))	('associated', 'Reg', (97, 107))	('gait disorder', 'Phenotype', 'HP:0001288', (215, 228))	('CA-RP VIII', 'Gene', '12319', (15, 25))	('ataxia', 'Phenotype', 'HP:0001251', (113, 119))	('mild mental retardation', 'Phenotype', 'HP:0001256', (121, 144))	('lifelong gait disorder', 'Disease', (206, 228))	('protein stability', 'MPA', (70, 87))	('mice', 'Species', '10090', (232, 236))	('ataxia', 'Disease', (113, 119))	('ataxia', 'Disease', 'MESH:D001259', (113, 119))	('mental retardation', 'Disease', 'MESH:D008607', (126, 144))	('mental retardation', 'Phenotype', 'HP:0001249', (126, 144))
176450	31172829	Another finding was that the presence of these CARPs was associated with a more benign behavior in grade II-IV astrocytomas (both CA-RP VIII and XI), and in oligodendrogliomas and oligoastrocytomas (CA-RP VIII only).	('CA-RP VIII', 'Gene', (199, 209))	('astrocytomas', 'Disease', 'MESH:D001254', (185, 197))	('CA-RP VIII', 'Gene', '12319', (130, 140))	('presence', 'Var', (29, 37))	('CA-RP VIII', 'Gene', '12319', (199, 209))	('astrocytoma', 'Phenotype', 'HP:0009592', (185, 196))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('astrocytomas', 'Disease', (185, 197))	('CARPs', 'Species', '7962', (47, 52))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('oligodendrogliomas and oligoastrocytomas', 'Disease', 'MESH:D001254', (157, 197))	('CA-RP VIII', 'Gene', (130, 140))	('astrocytomas', 'Disease', (111, 123))
176507	31172829	Besides, high CA IX tissue expression (P = 0.002) was associated with poor prognosis in patients with resectable NSCLC.	('NSCLC', 'Disease', (113, 118))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('patients', 'Species', '9606', (88, 96))	('high', 'Var', (9, 13))
176543	31172829	Immunohistochemistry assessment of CA XII expression in a series of 103 cases of invasive breast cancer determined that CA XII was present in 75% of tested patients and was associated with lower grade (P = 0.001), positive estrogen receptor status (P < 0.001), and negative epidermal growth factor receptor status (P < 0.001).	('CA XII', 'Gene', (35, 41))	('patients', 'Species', '9606', (156, 164))	('estrogen receptor', 'Gene', (223, 240))	('lower', 'NegReg', (189, 194))	('epidermal growth factor receptor', 'Gene', '1956', (274, 306))	('CA XII', 'Gene', '771', (35, 41))	('estrogen receptor', 'Gene', '2099', (223, 240))	('invasive breast cancer', 'Disease', 'MESH:D001943', (81, 103))	('CA XII', 'Gene', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('invasive breast cancer', 'Disease', (81, 103))	('CA XII', 'Gene', '771', (120, 126))	('epidermal growth factor receptor', 'Gene', (274, 306))	('positive', 'Var', (214, 222))
176548	31172829	High CAXII expression was correlated with better overall patient survival and better outcome of patients with resectable NSCLC (Table 13).	('High', 'Var', (0, 4))	('patient', 'Species', '9606', (57, 64))	('better', 'PosReg', (42, 48))	('CAXII', 'Gene', (5, 10))	('NSCLC', 'Disease', (121, 126))	('patient', 'Species', '9606', (96, 103))	('CAXII', 'Gene', '771', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('patients', 'Species', '9606', (96, 104))
176581	31172829	Mutations in the CA XII gene are known to cause cystic fibrosis (CF)-like diseases, pancreatitis and Sjogren's syndrome (Table 13).	('pancreatitis', 'Phenotype', 'HP:0001733', (84, 96))	('pancreatitis', 'Disease', 'MESH:D010195', (84, 96))	('cause', 'Reg', (42, 47))	('cystic fibrosis', 'Disease', 'MESH:D003550', (48, 63))	("Sjogren's syndrome", 'Disease', 'MESH:D012859', (101, 119))	('Mutations', 'Var', (0, 9))	('cystic fibrosis', 'Disease', (48, 63))	('CA XII', 'Gene', (17, 23))	("Sjogren's syndrome", 'Disease', (101, 119))	('pancreatitis', 'Disease', (84, 96))	('CA XII', 'Gene', '771', (17, 23))
176584	31172829	Through genotyping and gene sequencing, the authors identified that this syndrome is associated with a Glu143Lys mutation in CA XII structure.	('CA XII', 'Gene', '771', (125, 131))	('Glu143Lys', 'SUBSTITUTION', 'None', (103, 112))	('Glu143Lys', 'Var', (103, 112))	('CA XII', 'Gene', (125, 131))	('associated', 'Reg', (85, 95))
176585	31172829	The same CA XII enzyme mutant cased similar symptoms in several consanguineous Israeli Bedouin kindred.	('CA XII', 'Gene', (9, 15))	('CA XII', 'Gene', '771', (9, 15))	('mutant', 'Var', (23, 29))
176586	31172829	Interestingly, in this study Feldshtein and collaborators showed that the catalytic activity of p.Glu143Lys CA XII was around 70% of the wild-type enzyme, for the physiologic CO2 hydration reaction and was efficiently inhibited by acetazolamide (KI of 10 nM).	('p.Glu143Lys', 'Mutation', 'rs267606694', (96, 107))	('CA XII', 'Gene', (108, 114))	('p.Glu143Lys', 'Var', (96, 107))	('catalytic activity', 'MPA', (74, 92))	('CO2', 'Chemical', 'MESH:D002245', (175, 178))	('CA XII', 'Gene', '771', (108, 114))	('rat', 'Species', '10116', (182, 185))	('physiologic CO2 hydration reaction', 'MPA', (163, 197))	('acetazolamide', 'Chemical', 'MESH:D000086', (231, 244))	('rat', 'Species', '10116', (51, 54))
176587	31172829	It was also revealed that the p.Glu143Lys CA XII mutant was inhibited in the submicromolar range by chloride, bromide, or iodide (KIs of 0.37-0.73 mM), unlike the wild-type enzyme, which is not inhibited by these anions (KIs for these anions in the range of 73-215 mM).	('chloride', 'Chemical', 'MESH:D002712', (100, 108))	('CA XII', 'Gene', '771', (42, 48))	('iodide', 'MPA', (122, 128))	('inhibited', 'NegReg', (60, 69))	('bromide', 'Chemical', 'MESH:D001965', (110, 117))	('p.Glu143Lys', 'Mutation', 'rs267606694', (30, 41))	('CA XII', 'Gene', (42, 48))	('iodide', 'Chemical', 'MESH:D007454', (122, 128))	('p.Glu143Lys', 'Var', (30, 41))
176589	31172829	described variants in CA12 gene encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes with elevated sweat chloride levels, FTT, and lung disease.	('elevated sweat chloride', 'Phenotype', 'HP:0012236', (116, 139))	('CA12', 'Gene', (22, 26))	('carbonic anhydrase XII', 'Gene', (41, 63))	('variants', 'Var', (10, 18))	('chloride', 'Chemical', 'MESH:D002712', (131, 139))	('sweat chloride levels', 'MPA', (125, 146))	('elevated', 'PosReg', (116, 124))	('CA12', 'Gene', '771', (22, 26))	('lung disease', 'Disease', (157, 169))	('sweat', 'Phenotype', 'HP:0000975', (125, 130))	('FTT', 'Disease', (148, 151))	('lung disease', 'Phenotype', 'HP:0002088', (157, 169))	('carbonic anhydrase XII', 'Gene', '771', (41, 63))	('lung disease', 'Disease', 'MESH:D008171', (157, 169))
176590	31172829	The authors have shown that although the subjects contained normal CFTR variants, aberrant CA XII transcripts bearing either a p.His121Gln or the previously identified p.Glu143Lys protein mutants displayed completely diminished enzymatic activity at physiologic concentrations of sodium chloride that caused CF-like features in sweat gland and lungs (Table 13).	('CF-like', 'Disease', (308, 315))	('p.His121Gln', 'Var', (127, 138))	('sodium chloride', 'Chemical', 'MESH:D012965', (280, 295))	('p.His121Gln', 'Mutation', 'rs775067652', (127, 138))	('CA XII', 'Gene', (91, 97))	('diminished', 'NegReg', (217, 227))	('CFTR', 'Gene', '1080', (67, 71))	('enzymatic activity', 'MPA', (228, 246))	('caused', 'Reg', (301, 307))	('CA XII', 'Gene', '771', (91, 97))	('p.Glu143Lys', 'Mutation', 'rs267606694', (168, 179))	('rat', 'Species', '10116', (269, 272))	('sweat', 'Phenotype', 'HP:0000975', (328, 333))	('p.Glu143Lys', 'Var', (168, 179))	('CFTR', 'Gene', (67, 71))
176627	31172829	However, the study revealed that levels of anti-CA II, VI and XIII antibodies correlated significantly with renal acidification capacity and urinary pH, and inversely with serum sodium concentrations in patients with primary Sjogren's syndrome (Table 14).	('serum sodium concentrations', 'MPA', (172, 199))	("Sjogren's syndrome", 'Disease', 'MESH:D012859', (225, 243))	('renal acidification', 'Phenotype', 'HP:0031033', (108, 127))	('rat', 'Species', '10116', (192, 195))	('sodium', 'Chemical', 'MESH:D012964', (178, 184))	('patients', 'Species', '9606', (203, 211))	('renal acidification capacity', 'MPA', (108, 136))	('anti-CA', 'Var', (43, 50))	('correlated', 'Reg', (78, 88))	("Sjogren's syndrome", 'Disease', (225, 243))	('urinary pH', 'MPA', (141, 151))
176684	22928984	DBGP/DARC clears angiogenic CXC chemokines and reduced chemotaxis in the vasculature.	('angiogenic CXC chemokines', 'MPA', (17, 42))	('DBGP', 'Chemical', '-', (0, 4))	('DBGP/DARC', 'Var', (0, 9))	('clears', 'PosReg', (10, 16))	('reduced', 'NegReg', (47, 54))	('chemotaxis in the vasculature', 'MPA', (55, 84))
176685	22928984	Moreover, DBG interacts with a prostate cancer metastasis suppressor gene, KAI1, and inhibits the proliferation of prostate cancer cells.	('prostate cancer', 'Disease', (115, 130))	('inhibits', 'NegReg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('KAI1', 'Gene', (75, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('prostate cancer metastasis', 'Disease', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DBG', 'Chemical', '-', (10, 13))	('DBG', 'Var', (10, 13))	('KAI1', 'Gene', '3732', (75, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('interacts', 'Interaction', (14, 23))	('prostate cancer metastasis', 'Disease', 'MESH:D009362', (31, 57))
176715	22928984	A statistically significant difference was observed between every DBG phenotype and breast cancer incidence (29.8% were FYa + FYb+; 33.2% were FYa + FYb-; 45.6% were FYa-FYb + and 59.1% were FYa-FYb-; P = 0.001; Table 2).	('FYa', 'Var', (143, 146))	('FYb', 'Gene', '2533', (170, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('FYb', 'Gene', (170, 173))	('FYb', 'Gene', '2533', (126, 129))	('FYb', 'Gene', (126, 129))	('FYb', 'Gene', '2533', (195, 198))	('DBG', 'Chemical', '-', (66, 69))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('FYb', 'Gene', (195, 198))	('FYb', 'Gene', '2533', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('FYb', 'Gene', (149, 152))	('breast cancer', 'Disease', (84, 97))
176734	22928984	There might be more Duffy antigens expressed on one RBC belonging to an individual with the FYa + FYb + phenotype and a FYa + FYb- individual than on FYa-FYb + or FYa-FYb- individuals.	('more', 'PosReg', (15, 19))	('Duffy antigens', 'Protein', (20, 34))	('FYb', 'Gene', '2533', (154, 157))	('FYb', 'Gene', (154, 157))	('FYb', 'Gene', '2533', (167, 170))	('FYb', 'Gene', '2533', (126, 129))	('FYb', 'Gene', (167, 170))	('FYb', 'Gene', '2533', (98, 101))	('FYb', 'Gene', (98, 101))	('FYb', 'Gene', (126, 129))	('FYa', 'Var', (92, 95))
176735	22928984	Consequently, FYa + FYb + and FYa + FYb- individuals would have higher chemokine binding capacities than FYa-FYb + and FYa-FYb- individuals, and the FYa + FYb + and FYa + FYb- phenotype offer more protection against breast cancer than the FYa-FYb + and FYa-FYb- phenotypes.	('FYb', 'Gene', '2533', (243, 246))	('FYb', 'Gene', (109, 112))	('higher', 'PosReg', (64, 70))	('FYb', 'Gene', '2533', (257, 260))	('FYb', 'Gene', '2533', (171, 174))	('FYb', 'Gene', '2533', (123, 126))	('FYb', 'Gene', '2533', (20, 23))	('chemokine', 'MPA', (71, 80))	('FYb', 'Gene', (155, 158))	('FYb', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('FYb', 'Gene', (243, 246))	('FYa', 'Var', (149, 152))	('FYb', 'Gene', (123, 126))	('FYb', 'Gene', (171, 174))	('FYb', 'Gene', (20, 23))	('FYb', 'Gene', (257, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('FYb', 'Gene', '2533', (109, 112))	('breast cancer', 'Disease', (216, 229))	('FYb', 'Gene', '2533', (155, 158))	('FYb', 'Gene', '2533', (36, 39))
176750	23031619	With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases.	('breast cancer', 'Disease', (26, 39))	('high', 'Var', (5, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('high breast density', 'Phenotype', 'HP:0010313', (5, 24))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
176756	23031619	Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded.	('BRCA1', 'Gene', (11, 16))	('women', 'Species', '9606', (40, 45))	('mutation', 'Var', (19, 27))	('BRCA1', 'Gene', '672', (11, 16))
176767	23031619	Despite the higher costs of MRI and the false-positive results, screening with yearly MRI in addition to mammography is considered cost-effective for female BRCA1 and BRCA2 gene mutation carriers aged 30-60 years or women who have a 50% chance of carrying such a mutation .	('BRCA1', 'Gene', (157, 162))	('mutation', 'Var', (178, 186))	('BRCA2', 'Gene', (167, 172))	('women', 'Species', '9606', (216, 221))	('BRCA2', 'Gene', '675', (167, 172))	('BRCA1', 'Gene', '672', (157, 162))
176771	23031619	Breast density increases breast cancer incidence significantly .	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('increases', 'PosReg', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('Breast density', 'Var', (0, 14))
176915	32787871	HER2 positivity was defined as a protein overexpression score of 3+ determined by immunohistochemistry or the presence of gene amplification (positive in situ hybridization).	('overexpression', 'PosReg', (41, 55))	('positivity', 'Var', (5, 15))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
176923	32787871	The SVAB method (P = 0.028) and breast-conserving surgery (P < 0.001) were significantly more frequent in the DCIS group than in the mIDC and IDC groups.	('SVAB method', 'CPA', (4, 15))	('breast-conserving', 'Disease', (32, 49))	('IDC', 'Gene', '4000', (134, 137))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('IDC', 'Gene', (134, 137))	('DCIS', 'Var', (110, 114))	('mIDC', 'Gene', '107421', (133, 137))	('IDC', 'Gene', '4000', (142, 145))	('frequent', 'PosReg', (94, 102))	('mIDC', 'Gene', (133, 137))	('IDC', 'Gene', (142, 145))
176931	32787871	In the two invasive groups, the median tumor size for both mass and NME lesions was significantly greater than that in the DCIS group.	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('NME', 'Var', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('NME', 'Chemical', '-', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('greater', 'PosReg', (98, 105))
176944	32787871	A relatively large lesion on MRI may be associated with invasive disease.	('invasive disease', 'Disease', 'MESH:D009361', (56, 72))	('MRI', 'Gene', (29, 32))	('invasive disease', 'Disease', (56, 72))	('associated', 'Reg', (40, 50))	('lesion', 'Var', (19, 25))
176955	32787871	Thus, these reports suggest that intratumoral high SI on T2WI, which is suggestive of intratumoral necrosis, is a prognostic indicator of invasive breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('T2WI', 'Gene', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('invasive breast cancer', 'Disease', (138, 160))	('SI', 'Chemical', '-', (51, 53))	('high SI', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('necrosis', 'Disease', 'MESH:D009336', (99, 107))	('intratumoral necrosis', 'Phenotype', 'HP:0010885', (86, 107))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('invasive breast cancer', 'Disease', 'MESH:D001943', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (91, 96))	('necrosis', 'Disease', (99, 107))
176963	32787871	ER and PR negativity as well as HER2 positivity were more frequent in mIDC and IDC lesions in our current series, and a negative PR result was a significant independent predictor of a histologic upgrade from a pure DCIS.	('ER', 'Gene', '2099', (0, 2))	('HER2', 'Gene', (32, 36))	('mIDC', 'Gene', (70, 74))	('mIDC', 'Gene', '107421', (70, 74))	('HER2', 'Gene', '2064', (32, 36))	('ER', 'Gene', '2099', (33, 35))	('IDC lesions', 'Disease', (79, 90))	('IDC lesions', 'Disease', 'MESH:D001768', (79, 90))	('positivity', 'Var', (37, 47))	('DCIS', 'Phenotype', 'HP:0030075', (215, 219))
176969	32787871	Our present results demonstrated that high Ki-67 expression is an independent factor associated with a histologic upgrade from DCIS and suggest the potential use of this parameter for predicting an invasive component in patients with biopsy-proven DCIS.	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('DCIS', 'Phenotype', 'HP:0030075', (248, 252))	('Ki-67', 'Protein', (43, 48))	('patients', 'Species', '9606', (220, 228))	('DCIS', 'Disease', (127, 131))	('Ki', 'Chemical', 'MESH:C066186', (43, 45))	('associated', 'Reg', (85, 95))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))
177135	22457761	Striking frequencies of aberrant nucleocytoplasmic ss-catenin accumulation have now been recorded in multiple human neoplastic conditions, most notably in colorectal cancers.	('neoplastic conditions', 'Disease', (116, 137))	('ss-catenin', 'Chemical', '-', (51, 61))	('neoplastic conditions', 'Disease', 'MESH:D009135', (116, 137))	('aberrant', 'Var', (24, 32))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('human', 'Species', '9606', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancers', 'Disease', (155, 173))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
177137	22457761	However, mutation of pathway components, including the APC, Axin, and CTNNB1 genes (encoding ss-catenin), leading to ss-catenin stabilization, and hence activation of the Wnt/ss-catenin pathway, is now recognized as a common event in human tumorigenesis.	('mutation', 'Var', (9, 17))	('CTNNB1', 'Gene', '1499', (70, 76))	('Wnt/ss-catenin pathway', 'Pathway', (171, 193))	('ss-catenin', 'Chemical', '-', (93, 103))	('tumor', 'Disease', (240, 245))	('activation', 'PosReg', (153, 163))	('human', 'Species', '9606', (234, 239))	('ss-catenin stabilization', 'MPA', (117, 141))	('APC', 'Gene', (55, 58))	('APC', 'Gene', '324', (55, 58))	('Axin', 'Gene', '8312', (60, 64))	('ss-catenin', 'Chemical', '-', (175, 185))	('CTNNB1', 'Gene', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('Axin', 'Gene', (60, 64))	('ss-catenin', 'Chemical', '-', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
177138	22457761	Because such mutations are comparatively rare in human breast carcinomas, excepting fibromatoses and metaplastic tumors, multiple groups have sought evidence of pathway activation by interrogating the subcellular localization of ss-catenin protein in human breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('metaplastic tumors', 'Disease', 'MESH:D009369', (101, 119))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('human', 'Species', '9606', (49, 54))	('breast cancers', 'Disease', 'MESH:D001943', (257, 271))	('metaplastic tumors', 'Disease', (101, 119))	('breast cancers', 'Disease', (257, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('breast cancers', 'Phenotype', 'HP:0003002', (257, 271))	('ss-catenin', 'Chemical', '-', (229, 239))	('breast carcinomas', 'Disease', 'MESH:D001943', (55, 72))	('breast carcinomas', 'Disease', (55, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('mutations', 'Var', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('human', 'Species', '9606', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('breast carcinomas', 'Phenotype', 'HP:0003002', (55, 72))
177142	22457761	We sought to characterize the status of Wnt/ss-catenin signaling as a function of breast cancer progression by quantifying and comparing the proportion of tissue samples that exhibited nucleocytoplasmic ss-catenin in benign breast tissue, ductal carcinoma in situ tumors, and invasive carcinomas.	('breast cancer', 'Disease', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('nucleocytoplasmic', 'Var', (185, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('carcinomas', 'Phenotype', 'HP:0030731', (285, 295))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (239, 255))	('ductal carcinoma in situ tumors', 'Disease', (239, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (239, 263))	('ss-catenin', 'Chemical', '-', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('invasive carcinomas', 'Disease', (276, 295))	('invasive carcinomas', 'Disease', 'MESH:D009361', (276, 295))	('ss-catenin', 'Chemical', '-', (203, 213))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('ductal carcinoma in situ tumors', 'Disease', 'MESH:D002285', (239, 270))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
177165	22457761	MMTV/NDL mice express a mammary-targeted, mutationally activated HER2/neu allele (NDL, Neu Deletion mutant), under the control of the mouse mammary tumor virus (MMTV) long terminal repeat, that induces mammary hyperplasia and tumorigenesis.	('mutationally', 'Var', (42, 54))	('induces', 'Reg', (194, 201))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (202, 221))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mouse mammary tumor virus', 'Species', '11757', (134, 159))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('hyperplasia', 'Disease', 'MESH:D006965', (210, 221))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Neu', 'Gene', '13866', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mice', 'Species', '10090', (9, 13))	('MMTV', 'Species', '11757', (161, 165))	('Neu', 'Gene', (87, 90))	('MMTV', 'Species', '11757', (0, 4))	('hyperplasia', 'Disease', (210, 221))	('tumor', 'Disease', (226, 231))
177173	22457761	Mammary tumors in this strain bear mutationally activated alleles of the HER2/neu transgene, suggesting that mutational activation of the transgene may be a prerequisite for tumor formation.	('tumor', 'Disease', (174, 179))	('HER2/neu', 'Protein', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumor', 'Disease', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutationally', 'Var', (35, 47))
177205	22457761	However, stratification into node-negative, node-positive and metastatic revealed an association between nucleocytoplasmic ss-catenin and HER2/neu positivity in node-positive cases.	('positivity', 'Var', (147, 157))	('HER2/neu', 'Protein', (138, 146))	('ss-catenin', 'Chemical', '-', (123, 133))
177210	22457761	Firstly, ss-catenin IHC was performed on MG sections from MMTV/NDL mice, which develop multiple DCIS-like lesions in each MG due to expression of a mammary-targeted, mutationally activated HER2/neu allele.	('MMTV', 'Species', '11757', (58, 62))	('ss-catenin', 'Chemical', '-', (9, 19))	('mutationally activated', 'Var', (166, 188))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('mice', 'Species', '10090', (67, 71))	('HER2/neu', 'Gene', (189, 197))
177216	22457761	Discrete regions of robust ss-gal activity were detected in the mammary epithelium of bigenic MMTV/neu, Axin2+/NLSlacZ MGs which coincided with focal regions of hyperplasia (Figure 4A-G).	('activity', 'MPA', (34, 42))	('ss-gal', 'Chemical', '-', (27, 33))	('MMTV', 'Species', '11757', (94, 98))	('hyperplasia', 'Disease', 'MESH:D006965', (161, 172))	('ss-gal', 'Enzyme', (27, 33))	('Axin2+/NLSlacZ', 'Var', (104, 118))	('hyperplasia', 'Disease', (161, 172))
177242	22457761	The intense nuclear signal commonly observed in colorectal tumors may reflect a specific response to APC mutation, the causal event in the majority of human colorectal cancers.	('APC', 'Gene', '324', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutation', 'Var', (105, 113))	('colorectal tumors', 'Disease', (48, 65))	('intense nuclear signal', 'MPA', (4, 26))	('colorectal cancers', 'Disease', 'MESH:D015179', (157, 175))	('colorectal tumors', 'Disease', 'MESH:D015179', (48, 65))	('human', 'Species', '9606', (151, 156))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('colorectal cancers', 'Disease', (157, 175))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('APC', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
177248	22457761	Conversely, Lopez-Knowles and colleagues identified a relationship between increased cytoplasmic ss-catenin and HER2/neu positivity.	('cytoplasmic ss-catenin', 'MPA', (85, 107))	('positivity', 'Var', (121, 131))	('HER2/neu', 'Protein', (112, 120))	('ss-catenin', 'Chemical', '-', (97, 107))	('increased', 'PosReg', (75, 84))	('Lopez-Knowles', 'Disease', 'MESH:C567763', (12, 25))	('Lopez-Knowles', 'Disease', (12, 25))
177250	22457761	Consistent with our observation of an increased frequency of nucleocytoplasmic ss-catenin in human DCIS relative to benign breast epithelium (Figure 2B; Table 3), we detected nucleocytoplasmic ss-catenin in murine mammary DCIS tumors induced by overexpression of a mutationally activated HER2/neu transgene (NDL; Figure 3).	('DCIS', 'Phenotype', 'HP:0030075', (222, 226))	('overexpression', 'PosReg', (245, 259))	('mutationally', 'Var', (265, 277))	('murine', 'Species', '10090', (207, 213))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('DCIS tumors', 'Disease', (222, 233))	('human', 'Species', '9606', (93, 98))	('DCIS tumors', 'Disease', 'MESH:D002285', (222, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('ss-catenin', 'Chemical', '-', (193, 203))	('ss-catenin', 'Chemical', '-', (79, 89))	('HER2/neu transgene', 'Protein', (288, 306))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
177254	22457761	Importantly in this respect, formation of mammary tumors in the MMTV/neu strain is associated with mutational activation of the (initially) wildtype neu transgene, which may be an obligate prerequisite to tumor formation.	('activation', 'PosReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('MMTV', 'Species', '11757', (64, 68))	('mammary tumors', 'Disease', 'MESH:D001943', (42, 56))	('mutational', 'Var', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mammary tumors', 'Disease', (42, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (50, 55))
177255	22457761	Thus, we speculate that the hyperplastic foci that we observed may be clonal groups of cells bearing a mutated neu allele, and potentially the earliest manifestation of mammary intraepithelial neoplasia (MIN) in this strain.	('mutated', 'Var', (103, 110))	('neu', 'Gene', (111, 114))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (177, 202))	('neoplasia', 'Phenotype', 'HP:0002664', (193, 202))	('mammary intraepithelial neoplasia', 'Disease', 'MESH:D019048', (169, 202))	('mammary intraepithelial neoplasia', 'Disease', (169, 202))
177296	31604847	Chemicals used in this study include chloroquine (Fisher, ICN19391910, 100 mum), aphidicolin (Fisher, BP615, 5 muM), doxycycline (Fisher, BP26531, 2 mug/mL), nocodazole (Sigma, M1404, 0.2 mug/ml), 3-MB-PP1 (Toronto Research Chemicals, 10 muM), bafilomycin A1 (Fisher, NC9686929, 100nM), puromycin (Invivogen, 10 mug/mL), polybrene (Millipore, TR-1003-G, 10 mug/mL), blebbistatin (Tocris, 176010R), doxorubicin (Fisher, 15910101), paclitaxel (Fisher, P3456), vincristine (Acros, 203440050), thapsigargin (Fisher, AC328570010), tunicamycin (MP Biomedicals, ICN15002801), BI-2536 (Selleck Chemicals, S1109), BI-6727 (Selleck Chemicals, S2235).	('doxycycline', 'Chemical', 'MESH:D004318', (117, 128))	('paclitaxel', 'Chemical', 'MESH:D017239', (430, 440))	('chloroquine', 'Chemical', 'MESH:D002738', (37, 48))	('mum', 'Gene', '56925', (75, 78))	('aphidicolin', 'Chemical', 'MESH:D016590', (81, 92))	('dox', 'Chemical', 'MESH:D004317', (117, 120))	('mum', 'Gene', (75, 78))	('puromycin', 'Chemical', 'MESH:D011691', (287, 296))	('nocodazole', 'Chemical', 'MESH:D015739', (158, 168))	('muM', 'Gene', '56925', (238, 241))	('muM', 'Gene', (238, 241))	('muM', 'Gene', '56925', (111, 114))	('polybrene', 'Chemical', 'MESH:D006583', (321, 330))	('blebbistatin', 'Chemical', 'MESH:C472645', (366, 378))	('muM', 'Gene', (111, 114))	('dox', 'Chemical', 'MESH:D004317', (398, 401))	('BI-6727', 'Var', (605, 612))
177378	31604847	Previously, aneuploidy and chromosome missegregation induced by inhibition of the mitotic checkpoint kinase MPS1 have been shown to disrupt autophagy.	('inhibition', 'Var', (64, 74))	('aneuploidy', 'Disease', (12, 22))	('disrupt', 'NegReg', (132, 139))	('MPS1', 'Gene', (108, 112))	('MPS1', 'Gene', '7272', (108, 112))	('chromosome missegregation', 'CPA', (27, 52))	('autophagy', 'CPA', (140, 149))	('aneuploidy', 'Disease', 'MESH:D000782', (12, 22))
177405	31604847	Further, autophagosome trafficking to lysosomes for autolysosome formation depends on stable microtubules, as taxol-mediated microtubule stabilization does not affect autophagosome and lysosome fusion, while microtubule depolymerization with nocodazole or vinca alkaloids causes an increase in autophagosomes and LC3-II levels.	('autophagosomes', 'CPA', (294, 308))	('nocodazole', 'Chemical', 'MESH:D015739', (242, 252))	('increase', 'PosReg', (282, 290))	('taxol', 'Chemical', 'MESH:D017239', (110, 115))	('microtubule', 'Var', (208, 219))	('depolymerization', 'NegReg', (220, 236))	('LC3-II', 'Chemical', '-', (313, 319))	('LC3-II levels', 'MPA', (313, 326))	('vinca alkaloids', 'Chemical', 'MESH:D014748', (256, 271))
177414	31604847	Evidence for autophagy being a tumor suppressor comes from the observation of increased tumorigenesis in mice with allelic loss of Becn1, a crucial autophagy gene; however, it was later determined that BECN1 is codependent on deletion of the adjacent BRCA1 gene, suggesting that loss of BRCA1 was driving tumorigenesis.	('BRCA1', 'Gene', '12189', (251, 256))	('BRCA1', 'Gene', (251, 256))	('tumor', 'Disease', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('Becn1', 'Gene', '56208', (131, 136))	('BRCA1', 'Gene', '12189', (287, 292))	('loss', 'Var', (123, 127))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Disease', (88, 93))	('BRCA1', 'Gene', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('deletion', 'Var', (226, 234))	('loss', 'Var', (279, 283))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('Becn1', 'Gene', (131, 136))
177421	31604847	One reason for this is that the most commonly used agents, chloroquine and hydroxychloroquine, are pleiotropic compounds and affect processes other than autophagy, such as the cellular redox state and mitochondrial function.	('chloroquine', 'Chemical', 'MESH:D002738', (82, 93))	('cellular', 'CPA', (176, 184))	('affect', 'Reg', (125, 131))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (75, 93))	('chloroquine', 'Chemical', 'MESH:D002738', (59, 70))	('dox', 'Chemical', 'MESH:D004317', (187, 190))	('mitochondrial function', 'CPA', (201, 223))	('hydroxychloroquine', 'Var', (75, 93))
177466	24960742	Maarse et al describe the first case of breast cancer after bilateral prophylactic skin sparing mastectomy in women with BRCA1 gene mutation.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('BRCA1', 'Gene', '672', (121, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('BRCA1', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (132, 140))	('skin sparing', 'Phenotype', 'HP:0000973', (83, 95))	('women', 'Species', '9606', (110, 115))
177512	32460821	Assuming no DCIS regression, most submodels showed a large proportion of DCIS progressing to preclinical IBC, ranging from 64 to 100%.	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('progressing', 'PosReg', (78, 89))	('DCIS', 'Var', (73, 77))	('IBC', 'Chemical', '-', (105, 108))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))
177554	27242965	Breast cancers with ER-, PR-, and triple-negative (TN) status showed a significantly larger tumor volume compared to ER+, PR+, and non-triple-negative (nTN) cancers, respectively.	('PR', 'Gene', '5241', (25, 27))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('ER', 'Gene', '2099', (117, 119))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('larger', 'PosReg', (85, 91))	('Breast cancers', 'Disease', (0, 14))	('cancers', 'Disease', (7, 14))	('ER', 'Gene', '2099', (20, 22))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('triple-negative', 'Var', (34, 49))	('nTN', 'Chemical', '-', (152, 155))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('PR', 'Gene', '5241', (122, 124))	('cancers', 'Disease', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('tumor', 'Disease', (92, 97))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))
177593	27242965	The parameters used for DWI were b = 0, 500, and 1000 s/mm2; TR = 5000 ms; TE = 87 ms; FOV = 250-350 mm; NSA = 1; EPI factor = 128; acquisition matrix = 128 x 128; and slice thickness = 4-5 mm without any inter slice gap.	('mm2', 'Gene', '10687', (56, 59))	('EPI factor = 128', 'Var', (114, 130))	('mm2', 'Gene', (56, 59))
177649	27242965	It has also been reported that DWI of breast in combination with T2-weighted imaging has the potential to improve the specificity of breast cancer diagnosis.	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('improve', 'PosReg', (106, 113))	('DWI', 'Var', (31, 34))	('specificity', 'MPA', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
177755	25991514	As already published by several authors, we observe that the risk of the second most common type of breast cancer, invasive lobular carcinoma is more strongly associated with HT use than the risk of other nonlobular invasive subtypes; HR = 3.10 (2.51-3.81) versus 1.94 (1.78-2.12).	('invasive lobular carcinoma', 'Disease', (115, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (115, 141))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (124, 141))	('HT use', 'Var', (175, 181))	('associated', 'Interaction', (159, 169))
177776	25991514	The PAF was estimated to 8.2%, corresponding to 90 breast cancer cases in 2006, indicating that even after substantial drop in HT use, still a major number of breast cancer cases were caused by HT-use.	('HT-use', 'Var', (194, 200))	('caused by', 'Reg', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Disease', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
177782	25831047	Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations.	('PR', 'Gene', '5241', (63, 65))	('increased', 'PosReg', (103, 112))	('CNAs', 'Disease', (124, 128))	('mutations/CNAs', 'Var', (147, 161))	('mutations', 'Disease', (113, 122))	('progesterone receptor', 'Gene', (40, 61))	('progesterone receptor', 'Gene', '5241', (40, 61))
177790	25831047	In colon cancers, genetic alterations are considered the "triggers" for progression of early lesions, but it remains uncertain whether DCIS progression to IDC is similar and what genetic alterations are the main triggers.	('genetic alterations', 'Var', (18, 37))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('colon cancers', 'Phenotype', 'HP:0003003', (3, 16))	('colon cancers', 'Disease', 'MESH:D015179', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('IDC', 'Gene', '4000', (155, 158))	('colon cancers', 'Disease', (3, 16))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('IDC', 'Gene', (155, 158))
177791	25831047	Genetically, DCIS and IDC share gene expression profiles and copy number alterations (CNAs) in common.	('IDC', 'Gene', (22, 25))	('DCIS', 'Disease', (13, 17))	('copy number alterations', 'Var', (61, 84))	('IDC', 'Gene', '4000', (22, 25))	('DCIS', 'Phenotype', 'HP:0030075', (13, 17))
177805	25831047	None of the mutation numbers, subtypes or spectra was significantly different between the three groups (Figure S1A-S1D, Table S2), but we observed a trend towards synchronous DCIS and IDC harboring more mutations than pure DCIS (p = 0.065).	('IDC', 'Gene', (184, 187))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('DCIS', 'Phenotype', 'HP:0030075', (223, 227))	('mutations', 'Var', (203, 212))	('IDC', 'Gene', '4000', (184, 187))
177806	25831047	Consistent with previous data in breast cancer, the C/G to T/A transition was the most common type across the cases, making up about 50% of the entire mutation (Figure S1C-S1D).	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('C/G to T/A', 'Var', (52, 62))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
177807	25831047	a-CGH identified a total of 941 CNAs (508 gains and 433 losses, Table S3) from the 16 samples with a median of 28 (range, 8-78) for pure DCIS, 71 (range, 24-147) for synchronous DCIS and 56 (range, 25-179) for synchronous IDC (Figure 1B).	('IDC', 'Gene', '4000', (222, 225))	('losses', 'NegReg', (56, 62))	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('IDC', 'Gene', (222, 225))	('DCIS', 'Phenotype', 'HP:0030075', (178, 182))	('pure DCIS', 'Var', (132, 141))	('gains', 'PosReg', (42, 47))
177808	25831047	However, when focusing on recurrent CNAs (>= 3 in each group), we observed that the recurrent CNAs in pure DCIS (n = 42) were significantly lower than those in either synchronous DCIS (n = 61) or IDC (n = 61) (p = 0.041, Table S4).	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('lower', 'NegReg', (140, 145))	('recurrent CNAs', 'MPA', (84, 98))	('IDC', 'Gene', '4000', (196, 199))	('IDC', 'Gene', (196, 199))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('pure DCIS', 'Var', (102, 111))
177814	25831047	Average concordance rate of the mutations between synchronous DCIS and IDC was 53.8% (range, 19.8% - 82.0%), which was far higher than the inter-IDC concordance rate (average 0.6%) or inter-DCIS concordance rate (average 0.1%) (Figure 2A-2B, Table S1).	('IDC', 'Gene', (71, 74))	('higher', 'PosReg', (123, 129))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('IDC', 'Gene', '4000', (145, 148))	('mutations', 'Var', (32, 41))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('inter-DCIS', 'Phenotype', 'HP:0006304', (184, 194))	('IDC', 'Gene', '4000', (71, 74))	('IDC', 'Gene', (145, 148))
177821	25831047	To address whether the mutations found in our study could be causally implicated in the progression of DCIS to invasive disease, we queried the cancer Gene Census, a set of 483 curated cancer-related genes.	('DCIS', 'Disease', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('mutations', 'Var', (23, 32))	('cancer', 'Disease', (144, 150))	('invasive disease', 'Disease', (111, 127))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('implicated', 'Reg', (70, 80))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('invasive disease', 'Disease', 'MESH:D009362', (111, 127))
177823	25831047	In addition, seven genes with mutations in our study overlapped with the top 20 breast cancer genes in the COSMIC database (http://cancer.sanger.ac.uk/cosmic) (Figures 3-4).	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('mutations', 'Var', (30, 39))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
177826	25831047	Interestingly, however, even the pure DCIS harbored at least one or more gene mutations in the cancer Gene Census, including TP53, PIK3CA, AKT1, GATA3, PIK3R1 and PTEN (Figure 3).	('GATA3', 'Gene', (145, 150))	('TP53', 'Gene', '7157', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PTEN', 'Gene', (163, 167))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('cancer', 'Disease', (95, 101))	('PTEN', 'Gene', '5728', (163, 167))	('mutations', 'Var', (78, 87))	('TP53', 'Gene', (125, 129))	('GATA3', 'Gene', '2625', (145, 150))	('PIK3R1', 'Gene', '5295', (152, 158))	('AKT1', 'Gene', '207', (139, 143))	('PIK3CA', 'Gene', (131, 137))	('PIK3R1', 'Gene', (152, 158))	('AKT1', 'Gene', (139, 143))	('PIK3CA', 'Gene', '5290', (131, 137))
177828	25831047	The number of predicted driver mutations in DCIS-IDC (n = 14) was significantly higher than that in pure DCIS (n = 2) (p = 0.022) (Table S6).	('mutations', 'Var', (31, 40))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('IDC', 'Gene', '4000', (49, 52))	('IDC', 'Gene', (49, 52))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('higher', 'PosReg', (80, 86))
177830	25831047	To investigate the pathway-level relationships of the individual mutations, we performed a DAVID analysis (http://david.abcc.ncifcrf.gov) and found that mutated genes in the DCIS-IDC were significantly associated with categories of 'notch signaling pathway', 'cell adhesion', 'cell division', 'DNA damage response' and 'p53 signaling pathway', while pure DCIS were associated with the 'mTOR signaling pathway' and 'apoptosis' (Table S7).	("'notch signaling pathway'", 'Pathway', (232, 257))	('DCIS', 'Phenotype', 'HP:0030075', (174, 178))	('p53', 'Gene', (320, 323))	('p53', 'Gene', '7157', (320, 323))	("'cell adhesion'", 'Pathway', (259, 274))	('associated', 'Reg', (202, 212))	('mutated genes', 'Var', (153, 166))	("'cell division", 'CPA', (276, 290))	('IDC', 'Gene', '4000', (179, 182))	("'mTOR signaling pathway", 'Pathway', (385, 408))	('DCIS', 'Phenotype', 'HP:0030075', (355, 359))	('IDC', 'Gene', (179, 182))	("'DNA damage response'", 'Pathway', (293, 314))
177833	25831047	When displaying somatic mutations and CNAs together with respect to function (oncogenes or tumor suppressor genes) (Figure 4), we found that oncogenes PIK3CA, FGFR2 and GNAS involved both somatic mutations and copy number gains and that tumor suppressor genes TP53, PTEN, BRCA2 and ATM involved both somatic mutations and copy number losses.	('ATM', 'Gene', (282, 285))	('PTEN', 'Gene', (266, 270))	('gains', 'PosReg', (222, 227))	('GNAS', 'Gene', '2778', (169, 173))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('TP53', 'Gene', (260, 264))	('BRCA2', 'Gene', '675', (272, 277))	('PTEN', 'Gene', '5728', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PIK3CA', 'Gene', '5290', (151, 157))	('FGFR2', 'Gene', (159, 164))	('ATM', 'Gene', '472', (282, 285))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP53', 'Gene', '7157', (260, 264))	('mutations', 'Var', (196, 205))	('tumor', 'Disease', (237, 242))	('PIK3CA', 'Gene', (151, 157))	('FGFR2', 'Gene', '2263', (159, 164))	('copy number', 'Var', (210, 221))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('BRCA2', 'Gene', (272, 277))	('GNAS', 'Gene', (169, 173))
177836	25831047	PR (-) tumors were associated with a great number of somatic mutations (p = 0.007), CNAs (p = 0.002), co-occurrence of mutation/CNAs (p = 0.005) and the cancer Gene Census (p = 0.003) (Figure 5A, Table S9).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('tumors', 'Disease', (7, 13))	('mutation/CNAs', 'Var', (119, 132))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CNAs', 'Disease', (84, 88))	('PR', 'Gene', '5241', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
177844	25831047	Somatic mutations of FGFR2, BRCA2, MET, SMARCA4, AR, GNAS, NCOA3, PDGFRA, ATM, BCOR, MLL3, NOTCH1 and SOX9, and CNAs in AKT1, ALK, FGFR2, GNAS, MDM2, MET, MYCL1, MYCN, NCOA3, FGFR2 (gains), BCOR, CDKN2C, GNAS, GATA3, MAP3K1, NOTCH2, PIK3R1, SMARCA4 and SOX9 (losses) were identified as synchronous DCIS-IDC-specific alterations in our study (Figure 4) that may cooperate for progression.	('ALK', 'Gene', '238', (126, 129))	('FGFR2', 'Gene', (21, 26))	('MYCL1', 'Gene', (155, 160))	('FGFR2', 'Gene', (131, 136))	('AKT1', 'Gene', (120, 124))	('ATM', 'Gene', (74, 77))	('BRCA2', 'Gene', '675', (28, 33))	('ALK', 'Gene', (126, 129))	('MYCL1', 'Gene', '4610', (155, 160))	('NCOA3', 'Gene', (168, 173))	('SMARCA4', 'Gene', (40, 47))	('MLL3', 'Gene', '58508', (85, 89))	('NCOA3', 'Gene', '8202', (59, 64))	('SOX9', 'Gene', '6662', (253, 257))	('NOTCH2', 'Gene', '4853', (225, 231))	('FGFR2', 'Gene', '2263', (21, 26))	('PIK3R1', 'Gene', (233, 239))	('BCOR', 'Gene', '54880', (79, 83))	('SOX9', 'Gene', '6662', (102, 106))	('DCIS', 'Phenotype', 'HP:0030075', (298, 302))	('FGFR2', 'Gene', '2263', (131, 136))	('mutations', 'Var', (8, 17))	('MYCN', 'Gene', (162, 166))	('SMARCA4', 'Gene', '6597', (241, 248))	('BCOR', 'Gene', '54880', (190, 194))	('FGFR2', 'Gene', (175, 180))	('GNAS', 'Gene', (204, 208))	('BCOR', 'Gene', (79, 83))	('GNAS', 'Gene', (53, 57))	('PDGFRA', 'Gene', '5156', (66, 72))	('NOTCH1', 'Gene', (91, 97))	('PDGFRA', 'Gene', (66, 72))	('BCOR', 'Gene', (190, 194))	('MLL3', 'Gene', (85, 89))	('CDKN2C', 'Gene', (196, 202))	('MDM2', 'Gene', (144, 148))	('GNAS', 'Gene', '2778', (204, 208))	('ATM', 'Gene', '472', (74, 77))	('NOTCH2', 'Gene', (225, 231))	('NCOA3', 'Gene', (59, 64))	('GNAS', 'Gene', (138, 142))	('GNAS', 'Gene', '2778', (53, 57))	('BRCA2', 'Gene', (28, 33))	('AKT1', 'Gene', '207', (120, 124))	('NCOA3', 'Gene', '8202', (168, 173))	('FGFR2', 'Gene', '2263', (175, 180))	('PIK3R1', 'Gene', '5295', (233, 239))	('SMARCA4', 'Gene', '6597', (40, 47))	('SMARCA4', 'Gene', (241, 248))	('NOTCH1', 'Gene', '4851', (91, 97))	('GNAS', 'Gene', '2778', (138, 142))	('GATA3', 'Gene', '2625', (210, 215))	('MAP3K1', 'Gene', (217, 223))	('MYCN', 'Gene', '4613', (162, 166))	('MDM2', 'Gene', '4193', (144, 148))	('MAP3K1', 'Gene', '4214', (217, 223))	('IDC', 'Gene', '4000', (303, 306))	('SOX9', 'Gene', (253, 257))	('IDC', 'Gene', (303, 306))	('CDKN2C', 'Gene', '1031', (196, 202))	('SOX9', 'Gene', (102, 106))	('GATA3', 'Gene', (210, 215))
177847	25831047	Somatic mutations of FGFR2 have been reported in many cancers, including breast cancers and FGFR2 gene variations confer a risk for breast cancer.	('FGFR2', 'Gene', (21, 26))	('risk', 'Reg', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('FGFR2', 'Gene', '2263', (92, 97))	('FGFR2', 'Gene', '2263', (21, 26))	('variations', 'Var', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', (80, 87))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('FGFR2', 'Gene', (92, 97))	('reported', 'Reg', (37, 45))
177849	25831047	Despite the lower prevalence of driver mutations in pure DCIS than synchronous DCIS-IDC, even pure DCIS with a low nuclear grade (case PD22) harbored at least one driver such as TP53, PIK3CA, AKT1, PTEN, GATA3 and PIK3R1 mutations, suggesting that these drivers may be essential for the early phase of DCIS development and that gradual accumulation of driver mutations might be required for progression.	('TP53', 'Gene', '7157', (178, 182))	('PTEN', 'Gene', '5728', (198, 202))	('PIK3R1', 'Gene', '5295', (214, 220))	('mutations', 'Var', (221, 230))	('GATA3', 'Gene', '2625', (204, 209))	('mutations', 'Var', (39, 48))	('PIK3CA', 'Gene', (184, 190))	('AKT1', 'Gene', '207', (192, 196))	('IDC', 'Gene', '4000', (84, 87))	('GATA3', 'Gene', (204, 209))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('IDC', 'Gene', (84, 87))	('TP53', 'Gene', (178, 182))	('PIK3R1', 'Gene', (214, 220))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))	('AKT1', 'Gene', (192, 196))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('PTEN', 'Gene', (198, 202))	('DCIS', 'Phenotype', 'HP:0030075', (302, 306))	('PIK3CA', 'Gene', '5290', (184, 190))
177853	25831047	Interestingly, all PIK3CA mutations in DCIS-IDC co-occurred with copy number gains, whereas PIK3CA in pure DCIS did not (Figure 4).	('PIK3CA', 'Gene', (19, 25))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('IDC', 'Gene', '4000', (44, 47))	('PIK3CA', 'Gene', '5290', (19, 25))	('IDC', 'Gene', (44, 47))	('PIK3CA', 'Gene', '5290', (92, 98))	('copy', 'MPA', (65, 69))	('gains', 'PosReg', (77, 82))	('mutations', 'Var', (26, 35))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('co-occurred', 'Reg', (48, 59))	('PIK3CA', 'Gene', (92, 98))
177895	25831047	To discover candidate driver gene mutations contributing to tumor development and progression, the CHASM analysis program was used with the 'breast' category for cancer tissue type.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', (60, 65))	('mutations', 'Var', (34, 43))
177940	18522749	Nevertheless, instability in some cancers may be comprised of single base mutations or amplifications or deletions that are too small to be detected by CGH.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('single base mutations', 'Var', (62, 83))	('deletions', 'Var', (105, 114))	('amplifications', 'Var', (87, 101))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
177995	18522749	The model proposed by Chin and colleagues describes the initiation of cancer occurring through telomere shortening and genetic instability, with a pattern of genetic changes becoming stabilized in the cell that reactivates telomerase (Figure 5b).	('telomere', 'CPA', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('genetic', 'Var', (119, 126))	('telomere shortening', 'Phenotype', 'HP:0031413', (95, 114))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
178047	30174479	However, the probability of local recurrence is higher in patients treated with BCS compared with those undergoing radical mastectomy.	('patients', 'Species', '9606', (58, 66))	('BCS', 'Var', (80, 83))	('local recurrence', 'CPA', (28, 44))
178077	30174479	The mean tumor size of invasive and in situ component was significantly larger in the positive resection margin group compared with the negative resection margin group (2.7 cm vs. 1.8 cm; p = 0.015).	('larger', 'PosReg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('positive resection', 'Var', (86, 104))
178175	29892094	Screening, however, may be increasing the burden of low-risk cancers without significantly reducing the burden of more aggressively growing cancers and, therefore, not resulting in the anticipated reduction in cancer mortality (so called overdiagnosis).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('increasing', 'PosReg', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('Screening', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (210, 216))
178182	29892094	In general, lead time increases breast cancer incidence artificially in a screened population, and this increase is greatest in the early years of the screening program.	('lead', 'Var', (12, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('increases breast cancer', 'Disease', (22, 45))	('increases breast cancer', 'Disease', 'MESH:D001943', (22, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
178255	22751464	Differences in the size of MIND xenografts were determined by averaging tumor size along the seven time points (week 0 3 5 6 8 9 10), after square root transformation, was then fitted by a mixed model for repeated measure, with Group (gene knockout), time (centered at the mid time point, week 6) and their interaction in the model.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('gene knockout', 'Var', (235, 248))
178257	22751464	To test if a mean growth line under a gene knock out differs from that of the reference (RFP), we tested if the slope of each line was different from that of the reference group (RFP) and similarly on the intercept.	('RFP', 'Gene', (89, 92))	('RFP', 'Gene', '5987', (179, 182))	('RFP', 'Gene', (179, 182))	('tested', 'Reg', (98, 104))	('gene knock out', 'Var', (38, 52))	('RFP', 'Gene', '5987', (89, 92))
178312	22751464	Other more quantifiable methods were also utilized to assess the growth (2-dimension culture), migration and invasion (both in Boydon chambers assays) of DCIS.COM and h.DCIS.01 cells transduced with shCSTA, shFAT1, and shDST (Supplementary Figure S3).	('invasion', 'CPA', (109, 117))	('CSTA', 'Gene', (201, 205))	('DCIS.01', 'CellLine', 'CVCL:5552', (169, 176))	('DCIS', 'Phenotype', 'HP:0030075', (169, 173))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('FAT1', 'Gene', '2195', (209, 213))	('CSTA', 'Gene', '1475', (201, 205))	('FAT1', 'Gene', (209, 213))	('transduced', 'Var', (183, 193))	('DST', 'Gene', '667', (221, 224))	('migration', 'CPA', (95, 104))	('DST', 'Gene', (221, 224))
178313	22751464	Migration and invasion were significantly increased in both cell lines transduced with shFAT1.	('increased', 'PosReg', (42, 51))	('Migration', 'CPA', (0, 9))	('invasion', 'CPA', (14, 22))	('transduced', 'Var', (71, 81))	('FAT1', 'Gene', '2195', (89, 93))	('FAT1', 'Gene', (89, 93))
178355	22751464	It regulates the polarity of squamous epithelium and auto antibodies against DST result in bullous pemphigoid, a blistering skin disease.	('bullous pemphigoid', 'Disease', (91, 109))	('DST', 'Gene', (77, 80))	('skin disease', 'Phenotype', 'HP:0000951', (124, 136))	('regulates', 'Reg', (3, 12))	('auto antibodies', 'Var', (53, 68))	('result in', 'Reg', (81, 90))	('blistering skin', 'Phenotype', 'HP:0008066', (113, 128))	('skin disease', 'Disease', (124, 136))	('skin disease', 'Disease', 'MESH:D012871', (124, 136))	('polarity of squamous', 'MPA', (17, 37))	('DST', 'Gene', '667', (77, 80))
178358	22751464	Hu demonstrated that inhibiting the differentiation of myoepithelium in subcutaneous xenografts of DCIS.COM promoted progression to invasive cancer.	('inhibiting', 'Var', (21, 31))	('invasive cancer', 'Disease', 'MESH:D009362', (132, 147))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('progression', 'CPA', (117, 128))	('promoted', 'PosReg', (108, 116))	('invasive cancer', 'Disease', (132, 147))
178362	22751464	Homozygous deletions of the FAT1 gene, and loss of protein expression, are common in human squamous cell carcinomas, in line with our results suggesting that suppression of FAT1 promotes the progression of DCIS.	('DCIS', 'Disease', (206, 210))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('FAT1', 'Gene', (28, 32))	('FAT1', 'Gene', '2195', (173, 177))	('DCIS', 'Phenotype', 'HP:0030075', (206, 210))	('promotes', 'PosReg', (178, 186))	('protein', 'Protein', (51, 58))	('suppression', 'Var', (158, 169))	('FAT1', 'Gene', (173, 177))	('loss', 'NegReg', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 115))	('FAT1', 'Gene', '2195', (28, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('human', 'Species', '9606', (85, 90))	('squamous cell carcinomas', 'Disease', (91, 115))
178401	22776144	Historical data suggest that LCIS is not an obligate precursor to invasive disease, and LCIS has until relatively recently been accepted as a risk factor for the development of invasive breast carcinoma (lifetime risk, 20 to 25%) in both the affected breast and the nonaffected breast.	('invasive breast carcinoma', 'Disease', (177, 202))	('LCIS', 'Var', (88, 92))	('breast carcinoma', 'Phenotype', 'HP:0003002', (186, 202))	('invasive disease', 'Disease', (66, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (177, 202))	('LCIS', 'Phenotype', 'HP:0030076', (29, 33))	('invasive disease', 'Disease', 'MESH:D009362', (66, 82))	('LCIS', 'Phenotype', 'HP:0030076', (88, 92))
178403	22776144	Specifically, comparative genomic hybridization studies have demonstrated losses on chromosomes 16q and 17p in both LCIS and ILC, truncating mutations in the E-cadherin gene and loss of heterozygosity (LOH) of the wild-type E-cadherin allele have been found in LCIS and adjacent ILCs, and studies have suggested a clonal relationship in a small number of co-existing LCIS and ILC tumors.	('tumors', 'Phenotype', 'HP:0002664', (380, 386))	('loss', 'NegReg', (178, 182))	('truncating mutations', 'Var', (130, 150))	('LCIS', 'Phenotype', 'HP:0030076', (367, 371))	('LCIS', 'Disease', (261, 265))	('LCIS', 'Phenotype', 'HP:0030076', (261, 265))	('losses', 'NegReg', (74, 80))	('E-cadherin', 'Gene', (158, 168))	('E-cadherin', 'Gene', '999', (224, 234))	('E-cadherin', 'Gene', '999', (158, 168))	('ILC tumors', 'Disease', 'MESH:D009369', (376, 386))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('LCIS', 'Disease', (367, 371))	('LCIS', 'Phenotype', 'HP:0030076', (116, 120))	('E-cadherin', 'Gene', (224, 234))	('ILC tumors', 'Disease', (376, 386))
178467	22776144	For example, the BRAF point mutation (T1799A) occurs in 45% of papillary thyroid carcinomas and is associated with poor clinical outcome, but its high frequency limits its usefulness to address clonality.	('T1799A', 'Mutation', 'rs113488022', (38, 44))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (63, 91))	('BRAF', 'Gene', '673', (17, 21))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (63, 91))	('T1799A', 'Var', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('BRAF', 'Gene', (17, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (73, 91))	('papillary thyroid carcinomas', 'Disease', (63, 91))
178468	22776144	In contrast, inactivating mutations of the E-cadherin gene that occur at dozens of different locations within the gene are highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas.	('inactivating mutations', 'Var', (13, 35))	('lobular breast carcinomas', 'Disease', (155, 180))	('E-cadherin', 'Gene', (43, 53))	('lobular breast carcinomas', 'Disease', 'MESH:D018275', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('E-cadherin', 'Gene', '999', (43, 53))	('frequent', 'Reg', (130, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('gastric carcinomas', 'Disease', 'MESH:D013274', (196, 214))	('gastric carcinomas', 'Disease', (196, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('breast carcinoma', 'Phenotype', 'HP:0003002', (163, 179))	('breast carcinomas', 'Phenotype', 'HP:0003002', (163, 180))
178469	22776144	Mutations in E-cadherin have been found at very early non-invasive stages of these diseases, leading to an association between E-cadherin mutations and loss of growth control, and to the classification of E-cadherin as a candidate tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('E-cadherin', 'Gene', (205, 215))	('E-cadherin', 'Gene', '999', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('loss', 'NegReg', (152, 156))	('growth control', 'CPA', (160, 174))	('tumor', 'Disease', (231, 236))	('Mutations', 'Var', (0, 9))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', (127, 137))	('association', 'Interaction', (107, 118))	('found', 'Reg', (34, 39))	('E-cadherin', 'Gene', '999', (13, 23))	('E-cadherin', 'Gene', '999', (127, 137))	('mutations', 'Var', (138, 147))
178470	22776144	Data regarding the presence of coincident mutations in E-cadherin among LCIS and adjacent invasive cancers have been mixed.	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('invasive cancers', 'Disease', 'MESH:D009362', (90, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('LCIS', 'Disease', (72, 76))	('LCIS', 'Phenotype', 'HP:0030076', (72, 76))	('invasive cancers', 'Disease', (90, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (42, 51))
178480	22776144	DCIS: ductal carcinoma in situ; ER: estrogen receptor; FFPE: formalin-fixed paraffin-embedded; H & E: hematoxylin and eosin; HER2: human epidermal growth factor receptor 2; IDC: invasive ductal carcinoma; IHC: immunohistochemistry; ILC: invasive lobular carcinoma; LCIS: lobular carcinoma in situ; LOH: loss of heterozygosity; PCR: polymerase chain reaction; PR: progesterone receptor; SNP: single nucleotide polymorphism.	('HER2', 'Gene', (125, 129))	('estrogen receptor', 'Gene', '2099', (36, 53))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (6, 30))	('ER', 'Gene', '2099', (32, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('ER', 'Gene', '2099', (126, 128))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (13, 30))	('epidermal growth factor receptor 2', 'Gene', (137, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('paraffin', 'Chemical', 'MESH:D010232', (76, 84))	(': single nucleotide', 'Var', (389, 408))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (271, 288))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (6, 22))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (271, 296))	('H & E', 'Chemical', 'MESH:D006371', (95, 100))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (271, 296))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (187, 203))	('estrogen receptor', 'Gene', (36, 53))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (279, 296))	('HER2', 'Gene', '2064', (125, 129))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (6, 30))	('progesterone receptor', 'Gene', (363, 384))	('progesterone receptor', 'Gene', '5241', (363, 384))	('LCIS', 'Phenotype', 'HP:0030076', (265, 269))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (178, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lobular carcinoma in situ', 'Disease', (271, 296))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (237, 263))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (246, 263))	('invasive ductal carcinoma', 'Disease', (178, 203))	('PR', 'Gene', '5241', (359, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('human', 'Species', '9606', (131, 136))	('ductal carcinoma in situ', 'Disease', (6, 30))	('formalin', 'Chemical', 'MESH:D005557', (61, 69))	('epidermal growth factor receptor 2', 'Gene', '2064', (137, 171))	('invasive lobular carcinoma', 'Disease', (237, 263))
178495	12223119	The molecular changes seen in DCIS include mutations in the p53 gene, and gene amplification and overexpression at the protein level of the c-erbB-2 receptor tyrosine kinase.	('overexpression', 'PosReg', (97, 111))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('c-erbB-2', 'Gene', (140, 148))	('c-erbB-2', 'Gene', '2064', (140, 148))	('amplification', 'PosReg', (79, 92))	('p53', 'Gene', (60, 63))	('mutations', 'Var', (43, 52))	('p53', 'Gene', '7157', (60, 63))	('tyrosine', 'Chemical', 'MESH:D014443', (158, 166))	('DCIS', 'Disease', (30, 34))
178503	12223119	The membrane-permeable bivalent compound AP1510 binds to this region and induces dimerisation, phosphorylation and intracellular signal transduction, allowing selective, acute or chronic receptor activation.	('AP1510', 'Var', (41, 47))	('dimerisation', 'MPA', (81, 93))	('AP1510', 'Chemical', 'MESH:C119717', (41, 47))	('intracellular signal transduction', 'MPA', (115, 148))	('induces', 'Reg', (73, 80))	('activation', 'PosReg', (196, 206))	('phosphorylation', 'MPA', (95, 110))
178504	12223119	introduced the chimeric EGFR and c-erbB-2 separately into MCF10A cells (immortal but untransformed human mammary epithelial cells) and established stable lines expressing moderate levels of either receptor.	('EGFR', 'Gene', '1956', (24, 28))	('c-erbB-2', 'Gene', (33, 41))	('MCF10A', 'CellLine', 'CVCL:0598', (58, 64))	('chimeric', 'Var', (15, 23))	('EGFR', 'Gene', (24, 28))	('c-erbB-2', 'Gene', '2064', (33, 41))	('human', 'Species', '9606', (99, 104))
178506	12223119	The chimeric EGFR was able to stimulate growth of the MCF10A cells in monolayer culture, demonstrating that it was functional, but activation by the addition of AP1510 had no effect on cell behaviour or morphology when the cells were grown in three-dimensional cultures.	('MCF10A', 'Gene', (54, 60))	('AP1510', 'Chemical', 'MESH:C119717', (161, 167))	('stimulate', 'PosReg', (30, 39))	('MCF10A', 'CellLine', 'CVCL:0598', (54, 60))	('growth', 'CPA', (40, 46))	('chimeric', 'Var', (4, 12))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
178530	19950406	In addition, tumor factors such as high nuclear grade, the presence of comedo necrosis, and margin involvement have been reported to be associated with an increased risk of local recurrence.	('tumor', 'Disease', (13, 18))	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('comedo', 'Phenotype', 'HP:0025249', (71, 77))	('margin involvement', 'CPA', (92, 110))	('high nuclear', 'Var', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('local recurrence', 'CPA', (173, 189))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('necrosis', 'Disease', (78, 86))
178634	18371194	Several genes bearing high-penetrance mutations have been implicated in inherited predisposition to breast cancer, the most important of these being in the BRCA1 and BRCA2 genes.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA2', 'Gene', '675', (166, 171))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('BRCA1', 'Gene', '672', (156, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('mutations', 'Var', (38, 47))	('BRCA1', 'Gene', (156, 161))	('BRCA2', 'Gene', (166, 171))
178639	18371194	An understanding of these mechanisms is relevant not only to families with BRCA1 and BRCA2 mutation carriers but also in sporadic breast cancer, in which the same or related genetic pathways may also be aberrant.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('mutation', 'Var', (91, 99))	('BRCA1', 'Gene', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('BRCA2', 'Gene', (85, 90))	('BRCA1', 'Gene', '672', (75, 80))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('BRCA2', 'Gene', '675', (85, 90))
178647	18371194	FANCJ encodes BRIP1, which interacts with the BRCT domain of BRCA1 and, of note, mutations in this gene can also cause breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('BRCA1', 'Gene', (61, 66))	('cause', 'Reg', (113, 118))	('BRIP1', 'Gene', '83990', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('FANCJ', 'Gene', '83990', (0, 5))	('mutations', 'Var', (81, 90))	('FANCJ', 'Gene', (0, 5))	('BRCA1', 'Gene', '672', (61, 66))	('BRIP1', 'Gene', (14, 19))
178656	18371194	To date, little progress has been made towards cataloguing larger-scale genetic rearrangements, such as translocations, deletions and amplifications, which occur frequently and are the hallmarks of tumour cells and have been particularly useful in the haematological malignancies.	('tumour', 'Disease', (198, 204))	('amplifications', 'Var', (134, 148))	('deletions', 'Var', (120, 129))	('translocations', 'Var', (104, 118))	('haematological malignancies', 'Disease', 'MESH:D019337', (252, 279))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('haematological malignancies', 'Disease', (252, 279))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
178660	18371194	First, this requires high-throughput sequencing capacity to detect all common variants in haplotype blocks spanning typically 30 to 150 kb, in at least 48 people.	('detect', 'Reg', (60, 66))	('people', 'Species', '9606', (155, 161))	('variants', 'Var', (78, 86))
178666	18371194	Identifying combinations of inherited variants that predispose to breast cancer will allow us to better estimate risk in families with breast cancer and help to characterise defective signalling pathways.	('variants', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
178689	18371194	Another significant problem with existing promoters is that their expression in the luminal epithelium depends on its differentiation; activity is therefore lost if a transgene causes transdifferentiation or dedifferentiation within a tumour.	('transgene', 'Var', (167, 176))	('dedifferentiation', 'CPA', (208, 225))	('lost', 'NegReg', (157, 161))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('activity', 'MPA', (135, 143))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('causes', 'Reg', (177, 183))	('transdifferentiation', 'CPA', (184, 204))
178690	18371194	Excision of the stop codon by crossing with mice carrying a gland-specific Cre recombinase then leads to continuous and consistent transgene expression.	('Excision', 'Var', (0, 8))	('leads to', 'Reg', (96, 104))	('mice', 'Species', '10090', (44, 48))	('transgene expression', 'MPA', (131, 151))
178699	18371194	Producing timelines of these mutations for different breast cancer subtypes, similar to those generated for colon cancer, would be a major step forward.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('colon cancer', 'Disease', (108, 120))	('mutations', 'Var', (29, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
178710	18371194	Equally, there are major implications for therapeutic efficacy, for example, for poly(ADP-ribose) polymerase inhibitors and BRCA mutations, and also resistance to taxanes when Aurora A is amplified.	('taxanes', 'Chemical', 'MESH:D043823', (163, 170))	('BRCA', 'Gene', '672', (124, 128))	('mutations', 'Var', (129, 138))	('Aurora A', 'Gene', '6790', (176, 184))	('BRCA', 'Gene', (124, 128))	('Aurora A', 'Gene', (176, 184))	('resistance', 'MPA', (149, 159))
178714	18371194	Furthermore, the breadth of DDR and mitotic regulator alterations underlying the pathogenesis of breast cancer and its subtypes, or the point at which DDR alterations might contribute to disease progression is unknown.	('contribute', 'Reg', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('alterations', 'Var', (54, 65))	('breast cancer', 'Disease', (97, 110))
178723	18371194	HER2 positivity and HER4 negativity, and high levels of cyclo-oxygenase-2 (COX-2) may have some relevance to invasive recurrence.	('positivity', 'Var', (5, 15))	('invasive recurrence', 'Disease', (109, 128))	('HER4', 'Gene', '2066', (20, 24))	('HER4', 'Gene', (20, 24))	('HER2', 'Gene', (0, 4))	('negativity', 'Var', (25, 35))	('HER2', 'Gene', '2064', (0, 4))
178763	18371194	To some extent this process is underway through microarray studies, which have led to the classification of invasive breast cancer into four categories, luminal, basal, HER2/neu overexpressing and normal, and the development of various gene expression signatures that can predict outcome.	('HER2', 'Gene', (169, 173))	('HER2', 'Gene', '2064', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('neu', 'Gene', '2064', (174, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('overexpressing', 'Var', (178, 192))	('neu', 'Gene', (174, 177))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
178873	18371194	Failure to consider genotype may mask significant associations with diet; likewise, the effects of genetic polymorphisms may be detectable only with specific dietary exposures (that is, the effect of dietary isoflavone intake on levels of sex-hormone binding globulin among women with the N-variant of the D356N gene).	('isoflavone', 'Chemical', 'MESH:D007529', (208, 218))	('women', 'Species', '9606', (274, 279))	('levels of sex-hormone binding globulin', 'MPA', (229, 267))	('D356N', 'Mutation', 'p.D356N', (306, 311))	('D356N', 'Var', (306, 311))
178911	18371194	Genetic testing offers psychosocial benefits for many women at high risk of developing breast cancer, but patients' perceptions of risk are often inaccurate and while many methods have been used to communicate information about risk, they do not always improve patients' understanding.	('psychosocial', 'Disease', 'MESH:C535569', (23, 35))	('women', 'Species', '9606', (54, 59))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('patients', 'Species', '9606', (106, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('patients', 'Species', '9606', (261, 269))	('psychosocial', 'Disease', (23, 35))
178950	11879552	E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer?	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('lobular breast cancer', 'Disease', 'MESH:D013274', (122, 143))	('lobular breast cancer', 'Disease', (122, 143))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (122, 143))	('breast carcinogenesis', 'Disease', (58, 79))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (58, 79))	('E-cadherin', 'Gene', (0, 10))	('loss of heterozygosity', 'Var', (15, 37))	('E-cadherin', 'Gene', '999', (0, 10))
178951	11879552	Loss of heterozygosity at the long arm of chromosome 16 is one of the most frequent genetic events in breast cancer.	('breast cancer', 'Disease', (102, 115))	('Loss of heterozygosity', 'Var', (0, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
178952	11879552	In the search for tumour suppressor genes that are the target of loss of heterozygosity at 16q, the E-cadherin gene CDH1 was unveiled by the identification of truncating mutations in the retained copy.	('CDH1', 'Gene', '999', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('truncating mutations', 'Var', (159, 179))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('CDH1', 'Gene', (116, 120))	('tumour', 'Disease', (18, 24))
178953	11879552	However, only lobular tumours showed E-cadherin mutations.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('lobular tumours', 'Disease', (14, 29))	('lobular tumours', 'Disease', 'MESH:D018275', (14, 29))	('E-cadherin', 'Protein', (37, 47))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (48, 57))
178957	11879552	Mutational inactivation of the E-cadherin gene CDH1 has been reported in diffuse gastric cancer and lobular breast cancer.	('CDH1', 'Gene', '999', (47, 51))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (100, 121))	('Mutational inactivation', 'Var', (0, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', (81, 95))	('lobular breast cancer', 'Disease', (100, 121))	('CDH1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('lobular breast cancer', 'Disease', 'MESH:D013274', (100, 121))	('reported', 'Reg', (61, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
178960	11879552	The more frequent ductal breast carcinomas also show frequent LOH at 16q; however, these tumours do not have mutational inactivation of the retained CDH1 allele.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('LOH', 'Var', (62, 65))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('CDH1', 'Gene', (149, 153))	('tumours', 'Disease', (89, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('ductal breast carcinomas', 'Disease', (18, 42))	('breast carcinomas', 'Phenotype', 'HP:0003002', (25, 42))	('CDH1', 'Gene', '999', (149, 153))	('ductal breast carcinomas', 'Disease', 'MESH:D018270', (18, 42))
178964	11879552	LOH at 16q is the second most frequent somatic genetic event in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('LOH at 16q', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
178969	11879552	Furthermore, our observations (unpublished data) on LOH at 16q in breast cancer indicate that both mechanisms for LOH are operative.	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('LOH at 16q', 'Var', (52, 62))
178972	11879552	Complete loss of protein was found in all lobular tumours with mutational inactivation of E-cadherin (n = 21).	('lobular tumours', 'Disease', (42, 57))	('lobular tumours', 'Disease', 'MESH:D018275', (42, 57))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('E-cadherin', 'Protein', (90, 100))	('loss', 'NegReg', (9, 13))	('protein', 'MPA', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutational inactivation', 'Var', (63, 86))
178976	11879552	If E-cadherin was the target of LOH at 16q in ductal breast cancer, one would expect a strong association between LOH at 16q and decreased E-cadherin expression.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('expression', 'MPA', (150, 160))	('E-cadherin', 'Protein', (139, 149))	('LOH', 'Var', (32, 35))	('LOH at 16q', 'Var', (114, 124))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('decreased', 'NegReg', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
178977	11879552	However, the percentage of LOH at 16q in tumours with and without E-cadherin decrease was equal.	('E-cadherin', 'Protein', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('LOH', 'Var', (27, 30))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
178978	11879552	It therefore seems unlikely that LOH at 16q is associated with a decrease in E-cadherin expression in ductal breast cancer.	('LOH at 16q', 'Var', (33, 43))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('E-cadherin', 'Protein', (77, 87))	('decrease', 'NegReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('expression', 'MPA', (88, 98))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
178979	11879552	Also, in ductal carcinoma in situ (DCIS), there is no association between LOH at 16q and a decrease in E-cadherin expression.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (9, 33))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (9, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('E-cadherin', 'Protein', (103, 113))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (16, 33))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (9, 33))	('ductal carcinoma in situ', 'Disease', (9, 33))	('decrease', 'NegReg', (91, 99))	('LOH', 'Var', (74, 77))
178982	11879552	There is no significant correlation between LOH at 16q in breast cancer and metastatic potential, however, which further contradicts an association between E-cadherin and LOH at 16q.	('LOH', 'Var', (44, 47))	('metastatic potential', 'CPA', (76, 96))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))
178983	11879552	The invasion suppressor function of E-cadherin is very obvious, but not in concordance with our earlier finding that mutational inactivation of both CDH1 alleles through LOH and truncating mutations occurs in the prein-vasive stage in lobular carcinoma in situ (LCIS), a tumour stage that involves proliferation but not dissemination.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (235, 252))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (235, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('truncating mutations', 'Var', (178, 198))	('CDH1', 'Gene', (149, 153))	('LCIS', 'Phenotype', 'HP:0030076', (262, 266))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (235, 260))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (243, 260))	('lobular carcinoma in situ', 'Disease', (235, 260))	('tumour', 'Disease', (271, 277))	('CDH1', 'Gene', '999', (149, 153))	('LOH', 'Var', (170, 173))
178992	11879552	Loss of chromosome 16q in grade I ductal and lobular breast cancer also lead Roylance et al.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('lobular breast cancer', 'Disease', (45, 66))	('lobular breast cancer', 'Disease', 'MESH:D013274', (45, 66))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (45, 66))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
178996	11879552	The identification of somatic E-cadherin mutations in breast and gastric cancer received less attention than the report on two Maori families with diffuse gastric cancer attributed to germline transmission of truncating mutations in CDH1.	('mutations', 'Var', (41, 50))	('CDH1', 'Gene', (233, 237))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('CDH1', 'Gene', '999', (233, 237))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gastric cancer', 'Disease', (65, 79))	('truncating mutations', 'Var', (209, 229))	('breast', 'Disease', (54, 60))	('gastric cancer', 'Disease', (155, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
178999	11879552	Loss of one CDH1 allele apparently gives an increased risk only for gastric cancer, both hereditary and sporadic.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))	('Loss', 'Var', (0, 4))
179001	11879552	In diffuse gastric tumours, the wild type CDH1 allele is inactivated not by LOH at 16q, but by promotor methylation.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('CDH1', 'Gene', (42, 46))	('CDH1', 'Gene', '999', (42, 46))	('gastric tumours', 'Disease', (11, 26))	('methylation', 'Var', (104, 115))	('LOH', 'Var', (76, 79))	('gastric tumours', 'Disease', 'MESH:D013274', (11, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
179004	11879552	LOH at chromosome arm 16q in breast cancer is a frequent event, occurring in at least 50% of breast cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('LOH at chromosome arm', 'Var', (0, 21))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
179036	31134761	However, the patients who had PD-IDC were more likely to have more aggressive pathology characteristics, such as a higher histologic grade (61.5% of PD-IDC patients vs 39.0%, of IDC alone patients had Grade III/IV lesions, P < 0.001), more advanced AJCC stage (29.3% vs 12.1%, respectively, had stage III disease, P < 0.001), lower HR-positive ratio (55.7% vs 79.4%, respectively, had ER + or PR + cancer, P < 0.001), and higher HER2-positive ratio (63.5% vs 16.7%, respectively, P < 0.001), than the IDC alone patients.	('histologic', 'CPA', (122, 132))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Disease', (398, 404))	('PD-IDC', 'Var', (149, 155))	('patients', 'Species', '9606', (156, 164))	('HER2', 'Gene', '2064', (429, 433))	('PD-IDC', 'Var', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('AJCC', 'Disease', (249, 253))	('higher', 'PosReg', (115, 121))	('lower', 'NegReg', (326, 331))	('patients', 'Species', '9606', (511, 519))	('stage III disease', 'Disease', (295, 312))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('HER2', 'Gene', (429, 433))	('ER +', 'Disease', (385, 389))	('HR', 'Gene', '3164', (332, 334))	('higher', 'PosReg', (422, 428))
179041	31134761	In cohort 2, the median follow-up time was similar in the two groups (PD-DCIS: 81 months, DCIS: 79 months, P = 0.446), and the PD-DCIS patients showed a lower survival rate than the DCIS patients.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (135, 143))	('PD-DCIS', 'Chemical', '-', (127, 134))	('PD-DCIS', 'Var', (127, 134))	('survival rate', 'CPA', (159, 172))	('PD-DCIS', 'Chemical', '-', (70, 77))	('lower', 'NegReg', (153, 158))
179048	31134761	For PD-DCIS, only age at diagnosis (P < 0.001), tumor grade (P = 0.005), AJCC stage (P < 0.001), T stage (P = 0.002), N stage (P < 0.001), and chemotherapy use (P = 0.013) significantly affected mortality, and these prognostic factors differed from those for the DCIS group.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('PD-DCIS', 'Var', (4, 11))	('PD-DCIS', 'Chemical', '-', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mortality', 'MPA', (195, 204))	('affected', 'Reg', (186, 194))
179056	31134761	The results showed that the 8543/3 group displayed a higher histological grade (66.2% of patients with 8543/3-coded disease vs 57.1% of patients with 8543/2-coded disease had Grade III/IV lesions, P = 0.036) and more advanced AJCC stage (31.8% of patients with 8543/3-coded disease vs 0% of patients with 8543/2-coded disease had stage I-III cancer, P < 0.001) (Table S1).	('8543/3-coded', 'Var', (103, 115))	('higher', 'PosReg', (53, 59))	('I-III cancer', 'Disease', (336, 348))	('8543/3-coded disease', 'Var', (261, 281))	('advanced', 'PosReg', (217, 225))	('histological', 'CPA', (60, 72))	('patients', 'Species', '9606', (291, 299))	('patients', 'Species', '9606', (247, 255))	('patients', 'Species', '9606', (136, 144))	('I-III cancer', 'Disease', 'MESH:D009369', (336, 348))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('AJCC', 'Disease', (226, 230))	('8543/3', 'Var', (28, 34))
179063	31134761	Finally, by comparative analysis, we found that the disease in some patients with 8543/3-coded PD-DCIS exhibited many invasive behaviors, and this disease type was associated with worse survival outcomes than the other tested diseases.	('invasive behaviors', 'MPA', (118, 136))	('PD-DCIS', 'Chemical', '-', (95, 102))	('PD-DCIS', 'Gene', (95, 102))	('8543/3-coded', 'Var', (82, 94))	('patients', 'Species', '9606', (68, 76))
179114	27998284	evaluated GLUT1 levels in 124 cases of breast cancer that were stratified by subtype, receptor status, and other molecular markers, and demonstrated that GLUT1 was associated with increased tumor size, higher tumor grade, higher rates of proliferation, and was predominately expressed in the basal subtype.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('GLUT1', 'Var', (154, 159))	('increased', 'PosReg', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('proliferation', 'CPA', (238, 251))	('tumor', 'Disease', (190, 195))	('higher', 'PosReg', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('higher rates', 'PosReg', (222, 234))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('breast cancer', 'Disease', (39, 52))
179125	27998284	When these cells were grown as xenograft tumors, the growth rate of GLUT1 knockdown cells was approximately half of the controls, suggesting that GLUT1 and potentially glucose uptake were not critical to support the growth of tumors once they were established.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('xenograft tumors', 'Disease', 'MESH:D009369', (31, 47))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('growth', 'MPA', (53, 59))	('GLUT1', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Disease', (41, 47))	('knockdown', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('xenograft tumors', 'Disease', (31, 47))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('glucose', 'Chemical', 'MESH:D005947', (168, 175))
179127	27998284	Cre-mediated Slc2a1 excision completely prevented tumor formation when cells were grown as orthotopic xenografts.	('prevented', 'NegReg', (40, 49))	('excision', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Slc2a1', 'Gene', '20525', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('Slc2a1', 'Gene', (13, 19))
179131	27998284	Here, we show that loss of one or both alleles of Slc2a1 from mammary epithelial cells expressing the active Neu oncogene prevented tumor formation.	('Slc2a1', 'Gene', '20525', (50, 56))	('prevented', 'NegReg', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Neu', 'Gene', (109, 112))	('Neu', 'Gene', '13866', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('loss', 'Var', (19, 23))	('Slc2a1', 'Gene', (50, 56))
179132	27998284	In addition, blocking GLUT1 or restricting available glucose led to decreased cell proliferation and suppressed features of transformation in MCF10A cells expressing a conditionally active human epidermal growth factor receptor 2 (HER2/NEU/ERBB2) construct (MCF10A-ERBB2).	('MCF10A', 'CellLine', 'CVCL:0598', (258, 264))	('epidermal growth factor receptor 2', 'Gene', '2064', (195, 229))	('decreased', 'NegReg', (68, 77))	('blocking', 'Var', (13, 21))	('GLUT1', 'Protein', (22, 27))	('epidermal growth factor receptor 2', 'Gene', (195, 229))	('human', 'Species', '9606', (189, 194))	('MCF10A', 'CellLine', 'CVCL:0598', (142, 148))	('MCF10A-ERBB2', 'CellLine', 'CVCL:3743', (258, 270))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('features of transformation', 'CPA', (112, 138))	('suppressed', 'NegReg', (101, 111))	('cell proliferation', 'CPA', (78, 96))
179133	27998284	These studies confirm that restricting glucose uptake inhibits mammary tumorigenesis in ERBB2-induced models and support the development of preventive strategies for breast cancer based on targeting glucose metabolism.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('restricting', 'Var', (27, 38))	('inhibits', 'NegReg', (54, 62))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('glucose', 'Chemical', 'MESH:D005947', (199, 206))	('tumor', 'Disease', (71, 76))
179138	27998284	MMTV-NIC males were bred to GLUT1F/F females, and then NIC-GLUTF/+ males were bred to GLUT1F/+ females to generate NIC-GLUT1+/+, NIC-GLUT1F/+, and NIC-GLUT1F/F progeny.	('NIC-GLUT1F/F', 'Var', (147, 159))	('NIC-GLUT1F/+', 'Var', (129, 141))	('NIC-GLUT1+/+', 'Var', (115, 127))	('MMTV', 'Species', '11757', (0, 4))
179158	27998284	Because only one animal in the NIC-GLUT1F/+ and NIC-GLUT1F/F groups developed a tumor, we were unable to define a median survival time for these groups and we were insufficiently powered to perform robust statistical analyses.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NIC-GLUT1F/+', 'Var', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('insufficiently', 'Disease', 'MESH:D000309', (164, 178))	('tumor', 'Disease', (80, 85))	('insufficiently', 'Disease', (164, 178))	('NIC-GLUT1F/F', 'Var', (48, 60))
179162	27998284	To test this hypothesis, we crossed MMTV-NIC mice to GLUT1Flox/Flox (GLUT1F/F) mice, and monitored mammary tumor formation in NIC-GLUT1+/+, NIC-GLUT1F/+, and NIC-GLUT1F/F progeny.	('NIC-GLUT1+/+', 'Var', (126, 138))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mice', 'Species', '10090', (79, 83))	('MMTV', 'Species', '11757', (36, 40))	('NIC-GLUT1F/F', 'Var', (158, 170))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('NIC-GLUT1F/+', 'Var', (140, 152))
179163	27998284	NIC-GLUT1+/+ mice developed mammary tumors with a median latency of 162 days and all mice formed tumors by 200 days (Fig.	('mice', 'Species', '10090', (85, 89))	('mice', 'Species', '10090', (13, 17))	('NIC-GLUT1+/+', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('developed', 'PosReg', (18, 27))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
179164	27998284	In contrast, tumor development was delayed in NIC-GLUT1F/+ and NIC-GLUT1F/F mice.	('tumor', 'Disease', (13, 18))	('delayed', 'NegReg', (35, 42))	('NIC-GLUT1F/+', 'Var', (46, 58))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('NIC-GLUT1F/F', 'Var', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
179166	27998284	To determine whether GLUT1 excision interfered with the development of the mammary ductal tree, we evaluated epithelial structures in whole mounted mammary glands and H&E sections from mature (4-6 months of age), nulliparous female mice.	('H&E', 'Chemical', '-', (167, 170))	('excision', 'Var', (27, 35))	('GLUT1', 'Gene', (21, 26))	('interfered', 'NegReg', (36, 46))	('development of the mammary ductal tree', 'CPA', (56, 94))	('mice', 'Species', '10090', (232, 236))
179167	27998284	In both NIC-GLUT1F/+ and NIC-GLUT1F/F mice, we observed fully developed mammary glands.	('NIC-GLUT1F/+', 'Var', (8, 20))	('NIC-GLUT1F/F', 'Var', (25, 37))	('mice', 'Species', '10090', (38, 42))
179168	27998284	NIC-GLUT1F/+ mice appeared to have increased epithelial content that appeared like alveolar buds along ducts, which could also represent hyperplasia, but no tumors were observed (Fig.	('mice', 'Species', '10090', (13, 17))	('increased', 'PosReg', (35, 44))	('hyperplasia', 'Disease', 'MESH:D006965', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('hyperplasia', 'Disease', (137, 148))	('epithelial content', 'CPA', (45, 63))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('NIC-GLUT1F/+', 'Var', (0, 12))
179169	27998284	In NIC-GLUT1F/F mice, we observed lower epithelial content compared to NIC-GLUTF/+, and no tumors (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('lower', 'NegReg', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('epithelial content', 'MPA', (40, 58))	('NIC-GLUT1F/F', 'Var', (3, 15))	('mice', 'Species', '10090', (16, 20))
179173	27998284	Thus, Cre-mediated excision of Glut1 in the adult mouse mammary gland does not appear to disrupt ductal elongation or branching.	('Glut1', 'Gene', (31, 36))	('branching', 'CPA', (118, 127))	('Glut1', 'Gene', '20525', (31, 36))	('mouse', 'Species', '10090', (50, 55))	('ductal elongation', 'CPA', (97, 114))	('excision', 'Var', (19, 27))
179182	27998284	Together, these data suggest that GLUT1 is required for the early stages of Neu-induced mammary tumorigenesis, and that loss of only a single copy of Slc2a1 is sufficient to prevent the majority of Neu-induced mammary tumors.	('Slc2a1', 'Gene', (150, 156))	('Neu', 'Gene', '13866', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('prevent', 'NegReg', (174, 181))	('Neu', 'Gene', (198, 201))	('Neu', 'Gene', '13866', (198, 201))	('Slc2a1', 'Gene', '20525', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (218, 223))	('Neu', 'Gene', (76, 79))	('loss', 'Var', (120, 124))	('tumors', 'Disease', (218, 224))
179185	27998284	The normal mammary epithelium from NIC-GLUT1F/+ and NIC-GLUT1F/F mice had lower levels of Ki67-positive cells compared to NIC-GLUT1+/+ mice (~6.5% and 2.3% versus 24%, respectively; Fig.	('NIC-GLUT1F/+', 'Var', (35, 47))	('Ki67', 'Gene', (90, 94))	('mice', 'Species', '10090', (65, 69))	('Ki67', 'Gene', '17345', (90, 94))	('mice', 'Species', '10090', (135, 139))	('lower', 'NegReg', (74, 79))	('NIC-GLUT1F/F', 'Var', (52, 64))
179187	27998284	3a), similar to NIC-GLUT1F/+ mice, indicating that loss of both Slc2a1 alleles reduces normal mammary epithelial proliferation below that of wild-type mice.	('loss', 'Var', (51, 55))	('mice', 'Species', '10090', (151, 155))	('Slc2a1', 'Gene', '20525', (64, 70))	('reduces', 'NegReg', (79, 86))	('mice', 'Species', '10090', (29, 33))	('Slc2a1', 'Gene', (64, 70))
179189	27998284	Our previous study showed that shRNA knockdown or Cre-mediated excision of Slc2a1 from cells that had previously grown as tumors in vivo only resulted in a partial inhibition of tumor growth.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', (178, 183))	('Slc2a1', 'Gene', '20525', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('excision', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('inhibition', 'NegReg', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('Slc2a1', 'Gene', (75, 81))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
179199	27998284	The dramatic reduction in mammary tumors seen with loss of GLUT1 suggested that the population of cells in which the NIC transgene is expressed may be eliminated from the mammary gland as the epithelium expands.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('loss', 'Var', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('GLUT1', 'Gene', (59, 64))	('reduction', 'NegReg', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
179200	27998284	We used immunohistochemical analysis to determine whether mammary glands from NIC-GLUT1F/+ and NIC-GLUT1F/F mice expressed similar levels of Cre and GLUT1 as those from NIC-GLUT1+/+ mice.	('mice', 'Species', '10090', (182, 186))	('NIC-GLUT1F/F', 'Var', (95, 107))	('mice', 'Species', '10090', (108, 112))	('GLUT1', 'MPA', (149, 154))	('Cre', 'MPA', (141, 144))	('NIC-GLUT1F/+', 'Var', (78, 90))
179201	27998284	To our surprise, mammary glands from NIC-GLUT1F/+ and NIC-GLUT1F/F mice had almost no cells with strong nuclear Cre expression (Fig.	('NIC-GLUT1F/F', 'Var', (54, 66))	('NIC-GLUT1F/+', 'Var', (37, 49))	('mice', 'Species', '10090', (67, 71))	('nuclear Cre', 'Protein', (104, 115))
179202	27998284	In mammary glands from NIC-GLUT1F/+ and NIC-GLUT1F/F mice, we detected almost no cells with Cre recombinase localized to the nucleus (Fig.	('NIC-GLUT1F/F', 'Var', (40, 52))	('NIC-GLUT1F/+', 'Var', (23, 35))	('mice', 'Species', '10090', (53, 57))
179206	27998284	We used flow-activated cell sorting (FACS) analysis to identify changes in mammary epithelial cell populations in NIC-GLUT1 transgenic mice and in wild-type FVB mice, using CD24, CD29, and CD61.	('transgenic mice', 'Species', '10090', (124, 139))	('mice', 'Species', '10090', (161, 165))	('CD24', 'Gene', (173, 177))	('transgenic', 'Var', (124, 134))	('CD29', 'Gene', '16412', (179, 183))	('NIC-GLUT1', 'Gene', (114, 123))	('CD24', 'Gene', '12484', (173, 177))	('CD61', 'Gene', (189, 193))	('CD29', 'Gene', (179, 183))	('mice', 'Species', '10090', (135, 139))	('CD61', 'Gene', '16416', (189, 193))
179218	27998284	Analysis of BrdU incorporation revealed that activation of ERBB2 significantly increased cell proliferation in media containing 17.5 mM glucose (Fig.	('increased', 'PosReg', (79, 88))	('cell proliferation', 'CPA', (89, 107))	('ERBB2', 'Gene', (59, 64))	('glucose', 'Chemical', 'MESH:D005947', (136, 143))	('activation', 'Var', (45, 55))	('BrdU', 'Chemical', 'MESH:D001973', (12, 16))
179221	27998284	These data indicate that inhibition of GLUT1 or glucose restriction inhibits cell proliferation and de-regulates growth stimulated by active ERBB2.	('glucose', 'Chemical', 'MESH:D005947', (48, 55))	('GLUT1', 'Protein', (39, 44))	('de-regulates', 'NegReg', (100, 112))	('inhibition', 'Var', (25, 35))	('inhibits', 'NegReg', (68, 76))	('cell proliferation', 'CPA', (77, 95))	('growth', 'CPA', (113, 119))
179226	27998284	In our examination of the early preneoplastic lesions from NIC-GLUT1+/+ mice, GLUT1 levels were high in almost all cells and these cells also expressed Cre recombinase, which we used as a surrogate for expression of the Neu transgene (Fig.	('NIC-GLUT1+/+', 'Var', (59, 71))	('expressed', 'Reg', (142, 151))	('GLUT1 levels', 'MPA', (78, 90))	('Neu', 'Gene', (220, 223))	('Neu', 'Gene', '13866', (220, 223))	('mice', 'Species', '10090', (72, 76))	('high', 'PosReg', (96, 100))
179229	27998284	These data are consistent with our previous work, which demonstrated that Slc2a1 knockdown or Cre-mediated excision from mammary tumor cell lines that had grown as tumors in vivo only reduced tumor growth by 50%.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (192, 197))	('tumors', 'Disease', (164, 170))	('Slc2a1', 'Gene', '20525', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('reduced', 'NegReg', (184, 191))	('knockdown', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Slc2a1', 'Gene', (74, 80))
179232	27998284	In this study, we found that loss of a single copy of Slc2a1 is sufficient to prevent tumorigenesis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('prevent', 'NegReg', (78, 85))	('Slc2a1', 'Gene', '20525', (54, 60))	('tumor', 'Disease', (86, 91))	('loss', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Slc2a1', 'Gene', (54, 60))
179237	27998284	Patients with GLUT1-DS display motor and developmental delays, infantile onset of drug-resistant seizures, and deceleration of head growth resulting in acquired microcephaly, ataxia, and dystonia,.	('acquired microcephaly', 'Phenotype', 'HP:0005484', (152, 173))	('ataxia', 'Disease', 'MESH:D001259', (175, 181))	('microcephaly', 'Disease', (161, 173))	('dystonia', 'Phenotype', 'HP:0001332', (187, 195))	('seizures', 'Phenotype', 'HP:0001250', (97, 105))	('ataxia', 'Disease', (175, 181))	('ataxia', 'Phenotype', 'HP:0001251', (175, 181))	('deceleration of head growth', 'Phenotype', 'HP:0005484', (111, 138))	('seizures', 'Disease', 'MESH:D012640', (97, 105))	('GLUT1-DS', 'Var', (14, 22))	('microcephaly', 'Disease', 'MESH:D008831', (161, 173))	('dystonia', 'Disease', 'MESH:D004421', (187, 195))	('Patients', 'Species', '9606', (0, 8))	('motor and developmental delays', 'Phenotype', 'HP:0001263', (31, 61))	('dystonia', 'Disease', (187, 195))	('seizures', 'Disease', (97, 105))	('microcephaly', 'Phenotype', 'HP:0000252', (161, 173))
179243	27998284	Interestingly, all of the tumors from the NIC-GLUT1F/F mouse expressed nuclear Cre; however, none expressed GLUT1.	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mouse', 'Species', '10090', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('NIC-GLUT1F/F', 'Var', (42, 54))	('nuclear Cre', 'Protein', (71, 82))	('tumors', 'Disease', (26, 32))
179244	27998284	The tumors in this mouse may harbor mutations in metabolic genes that allow progression in the absence of GLUT1.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (36, 45))	('mouse', 'Species', '10090', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('metabolic genes', 'Gene', (49, 64))
179245	27998284	Our future studies will address the possibility of a compensatory increase in other glucose transporters as well as potential novel mutations in metabolic genes that allow tumors to emerge without upregulating GLUT1.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('increase', 'PosReg', (66, 74))	('glucose transporter', 'Gene', '20512', (84, 103))	('glucose transporter', 'Gene', (84, 103))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (132, 141))	('metabolic genes', 'Gene', (145, 160))
179251	27998284	After ERBB2 dimerization is induced, these structures proliferate and invade, much like breast cancer lesions in patients.	('dimerization', 'Var', (12, 24))	('breast cancer lesions', 'Disease', (88, 109))	('patients', 'Species', '9606', (113, 121))	('ERBB2', 'Gene', (6, 11))	('invade', 'CPA', (70, 76))	('breast cancer lesions', 'Disease', 'MESH:D001943', (88, 109))	('induced', 'Reg', (28, 35))	('proliferate', 'PosReg', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
179252	27998284	Inhibition of GLUT1 using a small molecule inhibitor or glucose restriction in the culture media suppressed ERBB2-induced transformation of MCF10A cells, measured by increased acinar size.	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('increased', 'PosReg', (166, 175))	('ERBB2-induced', 'Gene', (108, 121))	('Inhibition', 'Var', (0, 10))	('MCF10A', 'CellLine', 'CVCL:0598', (140, 146))	('suppressed', 'NegReg', (97, 107))	('acinar size', 'CPA', (176, 187))
179257	27998284	In addition, GLUT3 inhibition as well as glucose restriction prevented the formation of proliferative, non-polarized acinar structures.	('GLUT3', 'Protein', (13, 18))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('inhibition', 'Var', (19, 29))	('prevented', 'NegReg', (61, 70))
179260	27998284	demonstrated that treatment of two established breast cancer cell lines, MCF7 and T47D, with anti-GLUT1 antibody in vitro caused up to a 75% reduction in proliferation.	('MCF7', 'CellLine', 'CVCL:0031', (73, 77))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('anti-GLUT1', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('T47D', 'CellLine', 'CVCL:0553', (82, 86))	('proliferation', 'CPA', (154, 167))	('reduction', 'NegReg', (141, 150))
179261	27998284	Antisense RNA targeting GLUT5 has proved effective against two breast cancer cells lines expressing this transporter.	('GLUT5', 'Gene', '56485', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('GLUT5', 'Gene', (24, 29))	('Antisense', 'Var', (0, 9))
179266	27998284	There is an abundance of literature on cancer cell metabolism reporting that tumor cells are similarly addicted to glutamine, and that glutamine can replace glucose to meet the bioenergetic and biosynthetic needs during cell growth.	('glutamine', 'Chemical', 'MESH:D005973', (115, 124))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('glutamine', 'Var', (135, 144))	('glutamine', 'Chemical', 'MESH:D005973', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('glucose', 'Chemical', 'MESH:D005947', (157, 164))	('tumor', 'Disease', (77, 82))
179309	21622714	Although caveolin-1 appears to have both tumor-suppressive and oncogenic activity in different types of cancer, recent studies suggested that caveolin-1 inhibits breast cancer cell migration and metastases.	('caveolin-1', 'Var', (142, 152))	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('metastases', 'Disease', (195, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('inhibits', 'NegReg', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
179329	21622714	Mutated pLuc-Cav was generated by site-specific mutagenesis using the QuikChange site-directed mutagenesis kit (Stratagene).	('mutagenesis', 'Var', (48, 59))	('Cav', 'Gene', '858', (13, 16))	('Cav', 'Gene', (13, 16))
179330	21622714	Cells were transfected with the indicated wild-type or mutated pLuc-Cav, siRNAs or gene-specific expression plasmids.	('mutated', 'Var', (55, 62))	('Cav', 'Gene', '858', (68, 71))	('Cav', 'Gene', (68, 71))
179336	21622714	Immunohistochemical (IHC) was performed using paraffin-embedded sections of the human tissue samples with anti-caveolin-1 or anti-pStat3 antibodies.	('anti-pStat3', 'Var', (125, 136))	('paraffin', 'Chemical', 'MESH:D010232', (46, 54))	('human', 'Species', '9606', (80, 85))	('anti-pStat3', 'Gene', (125, 136))	('anti-caveolin-1', 'Var', (106, 121))
179352	21622714	Transfection of a constitutively activated mutant of Stat3 (Stat3C) plasmid led to decreased caveolin-1 expression in MDA-MB-231 cells, whereas knockdown of Stat3 expression in 231-BR cells using Stat3 siRNA did the opposite at both levels of protein (Fig.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (118, 128))	('mutant', 'Var', (43, 49))	('decreased', 'NegReg', (83, 92))	('caveolin-1 expression', 'MPA', (93, 114))
179353	21622714	Altered caveolin-1 expression also affected the levels of MMP-9, a known down-stream target gene of caveolin-1 (Fig.	('expression', 'MPA', (19, 29))	('MMP-9', 'Gene', (58, 63))	('caveolin-1', 'Gene', (8, 18))	('Altered', 'Var', (0, 7))	('affected', 'Reg', (35, 43))	('MMP-9', 'Gene', '4318', (58, 63))
179355	21622714	These data strongly suggested that activated Stat3 and caveolin-1 negatively regulate each other and that activated Stat3 represses caveolin-1 expression in brain-metastatic breast cancer cells.	('activated', 'Var', (106, 115))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('negatively', 'NegReg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('caveolin-1 expression', 'MPA', (132, 153))	('represses', 'NegReg', (122, 131))
179365	21622714	Moreover, both 231-BR and A375Br exhibited higher levels of binding of Stat3 to the region than did 231-BR-SOCS-1 and A375Br-SOCS-1 cells.	('higher', 'PosReg', (43, 49))	('A375Br-SOCS-1', 'CellLine', 'CVCL:0132', (118, 131))	('A375Br', 'CellLine', 'CVCL:0132', (118, 124))	('Stat3', 'Protein', (71, 76))	('A375Br', 'CellLine', 'CVCL:0132', (26, 32))	('A375Br', 'Var', (26, 32))	('binding', 'Interaction', (60, 67))
179367	21622714	We then measured the promoter activity of both wild-type and mutant forms of caveolin-1 promoters in 231-BR and A375Br cells.	('promoter activity', 'MPA', (21, 38))	('caveolin-1', 'Gene', (77, 87))	('mutant', 'Var', (61, 67))	('A375Br', 'CellLine', 'CVCL:0132', (112, 118))
179368	21622714	Mutation of Stat3-binding site #2 significantly increased the promoter activity of caveolin-1, suggesting that this Stat3-binding site acted as a negative regulator of caveolin-1 transcription in these brain-metastatic cancer cells (Fig.	('increased', 'PosReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('caveolin-1', 'Gene', (83, 93))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('negative', 'NegReg', (146, 154))	('cancer', 'Disease', (219, 225))	('promoter activity', 'MPA', (62, 79))
179369	21622714	We examined the invasive ability of breast cancer cells and found that knockdown of Stat3 expression by Stat3 siRNA attenuated the invasiveness of 231-BR cells (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('invasiveness of 231-BR cells', 'CPA', (131, 159))	('Stat3', 'Gene', (84, 89))	('knockdown', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('attenuated', 'NegReg', (116, 126))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
179371	21622714	4B), whereas knockdown of expression of caveolin-1 promoted the invasiveness of MDA-MB-231 cells (Fig.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('promoted', 'PosReg', (51, 59))	('knockdown', 'Var', (13, 22))	('caveolin-1', 'Gene', (40, 50))	('invasiveness of MDA-MB-231 cells', 'CPA', (64, 96))
179373	21622714	Since invasion is a critical step for brain metastasis, we next determined the impact of inhibited Stat3 activation on breast tumor growth and brain metastases and its relationship with caveolin-1 expression.	('inhibited', 'Var', (89, 98))	('breast tumor', 'Phenotype', 'HP:0100013', (119, 131))	('brain metastases', 'Disease', 'MESH:D009362', (143, 159))	('activation', 'PosReg', (105, 115))	('breast tumor', 'Disease', 'MESH:D001943', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('breast tumor', 'Disease', (119, 131))	('Stat3', 'Gene', (99, 104))	('brain metastases', 'Disease', (143, 159))
179374	21622714	SOCS-1 transfection significantly inhibited breast tumor growth (Figs.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('breast tumor', 'Disease', 'MESH:D001943', (44, 56))	('inhibited', 'NegReg', (34, 43))	('breast tumor', 'Disease', (44, 56))	('transfection', 'Var', (7, 19))	('SOCS-1', 'Gene', (0, 6))	('breast tumor', 'Phenotype', 'HP:0100013', (44, 56))
179380	21622714	In contrast, knockdown of endogenous SOCS-1 expression increased the expression of activated Stat3 and decreased the expression of caveolin-1 protein in MDA-MB-231 cells (Fig.	('expression of caveolin-1 protein', 'MPA', (117, 149))	('SOCS-1', 'Gene', (37, 43))	('increased', 'PosReg', (55, 64))	('decreased', 'NegReg', (103, 112))	('expression', 'MPA', (69, 79))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (153, 163))	('knockdown', 'Var', (13, 22))	('activated Stat3', 'Protein', (83, 98))
179397	21622714	Consistently, several studies have linked activated Stat3 protein expression with metastases of various tumor types, and activated Stat3 promotes liver and lung metastases in mouse models.	('Stat3', 'Gene', (131, 136))	('promotes', 'PosReg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('activated', 'Var', (121, 130))	('lung metastases', 'Disease', 'MESH:D009362', (156, 171))	('tumor', 'Disease', (104, 109))	('lung metastases', 'Disease', (156, 171))	('metastases', 'Disease', (82, 92))	('mouse', 'Species', '10090', (175, 180))	('metastases', 'Disease', (161, 171))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('metastases', 'Disease', 'MESH:D009362', (161, 171))
179398	21622714	Also, recent studies by our group indicated that alteration of Stat3 activation directly impacts melanoma brain metastases.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('impacts melanoma brain metastases', 'Disease', (89, 122))	('Stat3 activation', 'MPA', (63, 79))	('alteration', 'Var', (49, 59))	('impacts melanoma brain metastases', 'Disease', 'MESH:D009362', (89, 122))
179411	21622714	In the present study, we obtained evidence that Stat3 activation transcriptionally represses caveolin-1 expression and promotes breast cancer invasion and brain metastases.	('brain metastases', 'Disease', 'MESH:D009362', (155, 171))	('promotes', 'PosReg', (119, 127))	('brain metastases', 'Disease', (155, 171))	('represses', 'NegReg', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('caveolin-1', 'Protein', (93, 103))	('expression', 'MPA', (104, 114))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('Stat3 activation', 'Var', (48, 64))
179435	33711698	Furthermore, LTFU might increase the risk of non-adherence to endocrine therapy, which might compromise long-term diseases control.	('non-adherence', 'MPA', (45, 58))	('LTFU', 'Var', (13, 17))	('LTFU', 'Chemical', '-', (13, 17))
179576	33500555	Among variables such as tumor histotype, multifocality, presence of an intraductal component, tumor diameter, molecular subtype, and nearest margin status, the presence of an intraductal component was the only factor statistically significantly associated with margin positivity.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (24, 29))	('margin positivity', 'Var', (261, 278))	('tumor', 'Disease', (94, 99))	('associated', 'Reg', (245, 255))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
179629	26202553	For analysis purposes, margin status was divided into four categories according to the tumor distance from the surface: 0 mm (positive margin), <1 mm, <2 mm (close margin), or >=2 mm (negative margin).	('<1 mm', 'Var', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('<2 mm', 'Var', (151, 156))
179852	22296682	Deficient PAI-1 expression in mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes.	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', (64, 69))	('Deficient', 'Var', (0, 9))	('local invasion', 'CPA', (45, 59))	('prevented', 'NegReg', (35, 44))	('PAI-1', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
179893	22296682	The optimal subset of all variants, uPA, PAI-1, TF, Tn, and covariates was selected to achieve the best AUC value.	('uPA', 'Gene', (36, 39))	('TF', 'Chemical', '-', (48, 50))	('uPA', 'Gene', '5328', (36, 39))	('variants', 'Var', (26, 34))
179945	22053985	Analysis of IRF expression in human breast tissues revealed the unique down-regulation of IRF5 in patients with different grades of DCIS and IDC as compared to IRF1; loss of IRF5 preceded that of IRF1 and correlated with increased invasiveness.	('human', 'Species', '9606', (30, 35))	('IRF5', 'Gene', '3663', (174, 178))	('increased', 'PosReg', (221, 230))	('down-regulation', 'NegReg', (71, 86))	('loss', 'Var', (166, 170))	('invasiveness', 'CPA', (231, 243))	('patients', 'Species', '9606', (98, 106))	('IRF5', 'Gene', '3663', (90, 94))	('IRF5', 'Gene', (90, 94))	('IRF5', 'Gene', (174, 178))
179946	22053985	Overexpression of IRF5 in breast cancer cells inhibited in vitro and in vivo cell growth and sensitized them to DNA damage.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('IRF5', 'Gene', '3663', (18, 22))	('IRF5', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('sensitized', 'Reg', (93, 103))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('inhibited', 'NegReg', (46, 55))
179956	22053985	Depending on the cell type, loss of IRF5 yields cells incapable of a sufficient immune response to pathogens and/or undergoing apoptosis.	('IRF5', 'Gene', '3663', (36, 40))	('loss', 'Var', (28, 32))	('incapable', 'NegReg', (54, 63))	('IRF5', 'Gene', (36, 40))
179960	22053985	IRF5 was mapped to chromosome 7q32 that contains a cluster of imprinted genes and/or known chromosomal aberrations and deletions in lymphoid, prostate, and breast cancer.	('IRF5', 'Gene', (0, 4))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (91, 114))	('deletions', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('lymphoid', 'Disease', (132, 140))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('prostate', 'Disease', (142, 150))	('IRF5', 'Gene', '3663', (0, 4))
179964	22053985	Conversely, ectopic expression suppresses malignancy of cancer cell lines in vitro and in vivo .	('ectopic expression', 'Var', (12, 30))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('malignancy of cancer', 'Disease', 'MESH:D009369', (42, 62))	('suppresses', 'NegReg', (31, 41))	('malignancy of cancer', 'Disease', (42, 62))
179969	22053985	Loss or mutation of BRCA1 occurs in < 10% of all breast cancers, while p53 is mutated in up to 30% of breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (102, 116))	('breast cancers', 'Disease', (102, 116))	('BRCA1', 'Gene', (20, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('breast cancers', 'Phenotype', 'HP:0003002', (49, 63))	('breast cancers', 'Disease', 'MESH:D001943', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancers', 'Disease', (49, 63))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('mutation', 'Var', (8, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRCA1', 'Gene', '672', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (102, 116))
179972	22053985	Overexpression of IRF1 induced apoptosis and inhibited tumor growth in mouse and human mammary cancer cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mouse', 'Species', '10090', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', (55, 60))	('IRF1', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('apoptosis', 'CPA', (31, 40))	('inhibited', 'NegReg', (45, 54))	('human', 'Species', '9606', (81, 86))
179974	22053985	Data presented here support a unique role for IRF5 in regulating mammary epithelial cell growth and provide the first direct evidence that loss of IRF5 tumor suppressor function contributes to breast tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('IRF5', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (152, 157))	('loss', 'Var', (139, 143))	('tumor', 'Disease', (200, 205))	('IRF5', 'Gene', '3663', (46, 50))	('IRF5', 'Gene', (46, 50))	('IRF5', 'Gene', '3663', (147, 151))
180032	22053985	Given the small sample size, it was difficult to make statistical correlations between receptor and IRF expression; however, data at present suggest that loss of IRF5 expression correlates with ER/PR(-) breast cancers in 82 to 90% of samples.	('breast cancers', 'Phenotype', 'HP:0003002', (203, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancers', 'Disease', 'MESH:D001943', (203, 217))	('IRF5', 'Gene', (162, 166))	('breast cancers', 'Disease', (203, 217))	('IRF5', 'Gene', '3663', (162, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('loss', 'Var', (154, 158))
180058	22053985	Western blot data in Figure 5A show > 70% reduction of IRF5 proteins, as determined by densitometry analysis, after single (IRF5 siRNA1) or double (IRF5 siRNA2) transfections with a pool of three targeted IRF5 duplexes (see Materials and methods).	('IRF5', 'Gene', '3663', (55, 59))	('transfections', 'Var', (161, 174))	('IRF5', 'Gene', (55, 59))	('IRF5', 'Gene', '3663', (124, 128))	('IRF5', 'Gene', (148, 152))	('IRF5', 'Gene', '3663', (148, 152))	('IRF5', 'Gene', (124, 128))	('IRF5', 'Gene', (205, 209))	('IRF5', 'Gene', '3663', (205, 209))	('reduction', 'NegReg', (42, 51))
180097	22053985	Together, these data document both the specificity and non-cross-reactivity of anti-IRF1 and anti-IRF5 antibodies.	('anti-IRF1', 'Var', (79, 88))	('anti-IRF1', 'Gene', (79, 88))	('IRF5', 'Gene', '3663', (98, 102))	('IRF5', 'Gene', (98, 102))
180112	22053985	Based on data presented here, we propose a two-fold function for IRF5 that is cell type-specific and lends support to the 'release' model of breast cancer invasion where phenotypic changes in MECs (loss of IRF5 expression), in coordination with the infiltration and influence of inflammatory cells (high levels of IRF5 expression), lead to the breakdown of ducts and release and invasion of tumor epithelial cells.	('IRF5', 'Gene', (206, 210))	('lead to', 'Reg', (332, 339))	('IRF5', 'Gene', '3663', (314, 318))	('changes', 'Var', (181, 188))	('loss', 'Var', (198, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('release', 'CPA', (367, 374))	('tumor', 'Disease', (391, 396))	('IRF5', 'Gene', '3663', (65, 69))	('breakdown', 'CPA', (344, 353))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('MEC', 'Gene', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('breast cancer', 'Disease', (141, 154))	('IRF5', 'Gene', '3663', (206, 210))	('MEC', 'Gene', '56477', (192, 195))	('IRF5', 'Gene', (314, 318))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('ducts', 'MPA', (357, 362))	('IRF5', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
180113	22053985	Clinical data from tissue specimens combined with expression analyses and 3-D cultures provide the first clues that IRF5 may be involved in regulating tumor metastases, where loss of IRF5 enhances metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IRF5', 'Gene', '3663', (183, 187))	('metastatic potential', 'CPA', (197, 217))	('enhances', 'PosReg', (188, 196))	('tumor metastases', 'Disease', (151, 167))	('IRF5', 'Gene', (183, 187))	('tumor metastases', 'Disease', 'MESH:D009362', (151, 167))	('IRF5', 'Gene', (116, 120))	('loss', 'Var', (175, 179))	('IRF5', 'Gene', '3663', (116, 120))
180117	22053985	CXCR4 is an important factor in the migration, invasiveness and proliferation of breast cancer cells and silencing of CXCR4 blocks breast metastasis.	('CXCR4', 'Gene', '7852', (118, 123))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('CXCR4', 'Gene', '7852', (0, 5))	('CXCR4', 'Gene', (118, 123))	('blocks', 'NegReg', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CXCR4', 'Gene', (0, 5))	('silencing', 'Var', (105, 114))	('breast metastasis', 'CPA', (131, 148))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
180153	28612228	Even though PLCIS bares the distinctive molecular genetic changes of classic LCIS (gain of 1q and deletion of 16q along with E-cadherin inactivation), this variant may also show HER2 gene amplification, amplification of cyclin D1 gene, gain of 20q, loss of 17p and 13q.	('E-cadherin', 'Gene', '999', (125, 135))	('LCIS', 'Phenotype', 'HP:0030076', (77, 81))	('gain', 'PosReg', (83, 87))	('13q', 'CPA', (265, 268))	('deletion', 'Var', (98, 106))	('amplification', 'MPA', (203, 216))	('loss', 'NegReg', (249, 253))	('cyclin D1', 'Gene', '595', (220, 229))	('LCIS', 'Phenotype', 'HP:0030076', (13, 17))	('cyclin D1', 'Gene', (220, 229))	('E-cadherin', 'Gene', (125, 135))	('HER2', 'Gene', (178, 182))	('gain', 'PosReg', (236, 240))	('HER2', 'Gene', '2064', (178, 182))
180159	28612228	Cases with a previous history of DCIS or invasive breast cancer (at least 12 months prior to LCIS variant diagnosis) were included for descriptive purposes, but were not included in the outcomes analysis.	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('invasive breast cancer', 'Disease', (41, 63))	('LCIS', 'Phenotype', 'HP:0030076', (93, 97))	('variant', 'Var', (98, 105))	('DCIS', 'Disease', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('LCIS', 'Gene', (93, 97))	('invasive breast cancer', 'Disease', 'MESH:D001943', (41, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
180170	28612228	Thus the cohort selected for consensus pathology review included 21/233 (9.1%) patients diagnosed with a LCIS variant (Supplementary Figure 1).	('LCIS', 'Disease', (105, 109))	('patients', 'Species', '9606', (79, 87))	('LCIS', 'Phenotype', 'HP:0030076', (105, 109))	('variant', 'Var', (110, 117))
180177	28612228	The median time from prior cancer diagnosis to index LCIS variant diagnosis was 63 months (range, 10-76).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('variant', 'Var', (58, 65))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('LCIS', 'Phenotype', 'HP:0030076', (53, 57))
180208	28612228	In 2/4 patients (#P26 and #P224) the cancers developed in the same quadrant of the breast as the prior PLCIS lesion, which had been excised with close (<1mm) margins.	('P26', 'Gene', (18, 21))	('P26', 'Gene', '23423', (18, 21))	('LCIS', 'Phenotype', 'HP:0030076', (104, 108))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('#P224', 'Var', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('patients', 'Species', '9606', (7, 15))
180212	28612228	Pure PLCIS not associated with a concurrent breast cancer (DCIS or invasive carcinoma) was confirmed by pathology review in only 16/233 (6.9%) cases of LCIS variants documented over a 17-year period at our institution, underscoring the rarity of this lesion.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('invasive carcinoma', 'Disease', 'MESH:D009361', (67, 85))	('LCIS', 'Phenotype', 'HP:0030076', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('breast cancer', 'Disease', (44, 57))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('invasive carcinoma', 'Disease', (67, 85))	('LCIS', 'Phenotype', 'HP:0030076', (152, 156))	('LCIS', 'Gene', (152, 156))	('variants', 'Var', (157, 165))
180219	28612228	In our series we excluded 201/233 pts with a synchronous invasive cancer or DCIS (either ipsilateral or contralateral); the majority of whom (particularly in the later years of our study) also presented with a core biopsy diagnosis of an LCIS variant and were found to have cancer at surgical excision.	('presented', 'Reg', (193, 202))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (274, 280))	('synchronous invasive cancer', 'Disease', 'MESH:D009378', (45, 72))	('synchronous invasive cancer', 'Disease', (45, 72))	('variant', 'Var', (243, 250))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('LCIS', 'Phenotype', 'HP:0030076', (238, 242))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('LCIS', 'Disease', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', (66, 72))
180220	28612228	When DCIS or invasive breast carcinoma is not identified at surgical excision, there is a paucity of data addressing the need to obtain clear margins for PLCIS or LCIS variant lesions.	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('invasive breast carcinoma', 'Disease', (13, 38))	('breast carcinoma', 'Phenotype', 'HP:0003002', (22, 38))	('LCIS', 'Phenotype', 'HP:0030076', (155, 159))	('DCIS', 'Disease', (5, 9))	('LCIS', 'Phenotype', 'HP:0030076', (163, 167))	('variant', 'Var', (168, 175))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (13, 38))
180336	24620911	The percentage enhancement of breast cancer masses was significantly higher in the noncompressed-breast studies compared with the compressed-breast studies (Tables 1, 2; Fig 1).	('enhancement', 'MPA', (15, 26))	('noncompressed-breast', 'Var', (83, 103))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('higher', 'PosReg', (69, 75))
180377	23405264	Depletion of Rap1A expression significantly impaired LPA-stimulated migration of breast cancer cells and invasiveness in three-dimensional Matrigel cultures.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('impaired', 'NegReg', (44, 52))	('Rap1A', 'Gene', '5906', (13, 18))	('Rap1A', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('LPA', 'Chemical', 'MESH:C032881', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
180380	23405264	Finally, we have identified that LPA enhances the binding of endogenous Rap1A to beta-arrestin2, and also stimulates Rap1A and IQGAP1 to associate with LPA1.	('beta-arrestin2', 'Gene', (81, 95))	('associate', 'Interaction', (137, 146))	('LPA', 'Chemical', 'MESH:C032881', (152, 155))	('Rap1A', 'Gene', '5906', (117, 122))	('Rap1A', 'Gene', '5906', (72, 77))	('enhances', 'PosReg', (37, 45))	('LPA', 'Chemical', 'MESH:C032881', (33, 36))	('stimulates', 'PosReg', (106, 116))	('beta-arrestin2', 'Gene', '409', (81, 95))	('Rap1A', 'Gene', (72, 77))	('Rap1A', 'Gene', (117, 122))	('binding', 'Interaction', (50, 57))	('IQGAP1', 'Gene', (127, 133))	('LPA', 'Var', (33, 36))	('IQGAP1', 'Gene', '8826', (127, 133))
180401	23405264	Additionally, expression of LPA1 in mammary epithelial cells of transgenic mice promotes the development of metastatic mammary tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('LPA1', 'Gene', (28, 32))	('expression', 'Var', (14, 24))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('transgenic mice', 'Species', '10090', (64, 79))	('promotes', 'PosReg', (80, 88))
180412	23405264	We identify Rap1A as a novel regulator of LPA-induced breast cancer chemotaxis and invasion, and show that LPA stimulates Rap1 activity in breast cancer cells downstream of beta-arrestin2, but fails to activate Rap1 in non-malignant mammary epithelial cells.	('Rap1', 'Gene', (12, 16))	('Rap1', 'Gene', '5906', (122, 126))	('Rap1A', 'Gene', '5906', (12, 17))	('Rap1', 'Gene', (122, 126))	('LPA', 'Var', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('activity', 'MPA', (127, 135))	('breast cancer', 'Disease', (54, 67))	('LPA', 'Chemical', 'MESH:C032881', (107, 110))	('beta-arrestin2', 'Gene', (173, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('stimulates', 'PosReg', (111, 121))	('Rap1A', 'Gene', (12, 17))	('LPA', 'Chemical', 'MESH:C032881', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('Rap1', 'Gene', '5906', (211, 215))	('breast cancer', 'Disease', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Rap1', 'Gene', (211, 215))	('beta-arrestin2', 'Gene', '409', (173, 187))	('Rap1', 'Gene', '5906', (12, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
180435	23405264	Transwell chamber Matrigel-invasion assays showed that depletion of Rap1A significantly reduced cell invasion towards LPA (Figure 2C).	('cell invasion towards LPA', 'CPA', (96, 121))	('LPA', 'Chemical', 'MESH:C032881', (118, 121))	('Rap1A', 'Gene', (68, 73))	('Rap1A', 'Gene', '5906', (68, 73))	('reduced', 'NegReg', (88, 95))	('depletion', 'Var', (55, 64))
180436	23405264	The effects of Rap1A knockdown on breast cancer cell invasion was also examined using rigid three-dimensional (3D) cell invasion assays using a reconstituted extracellular matrix (Matrigel) that mimics the in vivo micro-environment.	('Rap1A', 'Gene', (15, 20))	('Rap1A', 'Gene', '5906', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('knockdown', 'Var', (21, 30))
180437	23405264	Although cell viability was not affected by the depletion of Rap1A (Figure S1), we observed a marked reduction in the number of invasive stellate colonies (Figure 2D).	('reduction', 'NegReg', (101, 110))	('Rap1A', 'Gene', (61, 66))	('invasive stellate colonies', 'Disease', 'MESH:D009362', (128, 154))	('Rap1A', 'Gene', '5906', (61, 66))	('depletion', 'Var', (48, 57))	('invasive stellate colonies', 'Disease', (128, 154))
180440	23405264	Having observed that Rap1A depletion inhibited invasive properties of tumor cells, we next assessed if the depletion of endogenous Rap1A also blocked LPA-stimulated MDA-MB-231 cell migration.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('inhibited', 'NegReg', (37, 46))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (165, 175))	('tumor', 'Disease', (70, 75))	('LPA', 'Chemical', 'MESH:C032881', (150, 153))	('depletion', 'Var', (27, 36))	('Rap1A', 'Gene', (21, 26))	('Rap1A', 'Gene', '5906', (21, 26))	('Rap1A', 'Gene', (131, 136))	('depletion', 'Var', (107, 116))	('blocked', 'NegReg', (142, 149))	('Rap1A', 'Gene', '5906', (131, 136))
180444	23405264	Using a scratch assay, we found that Rap1A is necessary for LPA-induced cell motility since loss of Rap1A inhibited scratch closure by with LPA (Figure 3A, and movie S1).	('Rap1A', 'Gene', (37, 42))	('Rap1A', 'Gene', '5906', (100, 105))	('LPA', 'Chemical', 'MESH:C032881', (140, 143))	('scratch closure', 'CPA', (116, 131))	('Rap1A', 'Gene', '5906', (37, 42))	('inhibited', 'NegReg', (106, 115))	('LPA', 'Chemical', 'MESH:C032881', (60, 63))	('loss', 'Var', (92, 96))	('Rap1A', 'Gene', (100, 105))
180448	23405264	Furthermore, depletion of Rap1A also inhibited LPA-induced cell migration assessed using Transwell chamber assays (Figure 3C).	('Rap1A', 'Gene', (26, 31))	('inhibited', 'NegReg', (37, 46))	('depletion', 'Var', (13, 22))	('Rap1A', 'Gene', '5906', (26, 31))	('LPA-induced cell migration', 'CPA', (47, 73))	('LPA', 'Chemical', 'MESH:C032881', (47, 50))
180449	23405264	However, we did not observe any effect of Rap1A depletion on cell adhesion (Figure S2).	('depletion', 'Var', (48, 57))	('Rap1A', 'Gene', (42, 47))	('Rap1A', 'Gene', '5906', (42, 47))
180466	23405264	We found that LPA did indeed induce Rap1 activity in MCF-10A cells expressing FLAG-LPA1 (Figure 4C); we have previously shown that expression of LPA1 in the non-malignant MCF-10A cells stimulates these cells to invade in 3D cultures.	('expression', 'Var', (131, 141))	('LPA', 'Chemical', 'MESH:C032881', (83, 86))	('LPA', 'Chemical', 'MESH:C032881', (145, 148))	('LPA', 'Chemical', 'MESH:C032881', (14, 17))	('MCF-10A', 'CellLine', 'CVCL:0598', (171, 178))	('LPA1', 'Gene', (145, 149))	('stimulates', 'PosReg', (185, 195))	('MCF-10A', 'CellLine', 'CVCL:0598', (53, 60))	('Rap1', 'Gene', '5906', (36, 40))	('Rap1', 'Gene', (36, 40))
180512	23405264	In response to LPA1 activation, beta-arrestin2 is recruited to LPA1, to mediate LPA1 endocytosis, LPA enhances the binding of beta-arrestin2 to Rap1A which then activates this GTPase.	('LPA', 'Var', (98, 101))	('LPA', 'Chemical', 'MESH:C032881', (63, 66))	('beta-arrestin2', 'Gene', (126, 140))	('LPA', 'Chemical', 'MESH:C032881', (15, 18))	('enhances', 'PosReg', (102, 110))	('GTPase', 'Enzyme', (176, 182))	('Rap1A', 'Gene', (144, 149))	('beta-arrestin2', 'Gene', '409', (32, 46))	('LPA', 'Chemical', 'MESH:C032881', (80, 83))	('activates', 'PosReg', (161, 170))	('GTP', 'Chemical', 'MESH:D006160', (176, 179))	('binding', 'Interaction', (115, 122))	('beta-arrestin2', 'Gene', (32, 46))	('beta-arrestin2', 'Gene', '409', (126, 140))	('Rap1A', 'Gene', '5906', (144, 149))	('LPA', 'Chemical', 'MESH:C032881', (98, 101))	('LPA1', 'MPA', (80, 84))
180523	23405264	Although it is not surprising that knock-down of IQGAP1 disrupted general cell invasion, we found that LPA-induced breast cancer cell invasion specifically required the presence of IQGAP1, thus establishing it as a key player in this process.	('LPA', 'Chemical', 'MESH:C032881', (103, 106))	('IQGAP1', 'Gene', '8826', (49, 55))	('IQGAP1', 'Gene', (49, 55))	('knock-down', 'Var', (35, 45))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('IQGAP1', 'Gene', '8826', (181, 187))	('breast cancer', 'Disease', (115, 128))	('IQGAP1', 'Gene', (181, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('general cell invasion', 'CPA', (66, 87))
180528	23405264	Rap1 activity was found to be higher in malignant human T4-2 breast cancer cells compared to the non-malignant S1 cells and expression of constitutively active Rap1 in T4-2 cells yields larger tumors with higher grade of malignancy in vivo .	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Rap1', 'Gene', '5906', (160, 164))	('malignancy', 'Disease', 'MESH:D009369', (221, 231))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('human', 'Species', '9606', (50, 55))	('Rap1', 'Gene', (160, 164))	('expression', 'Var', (124, 134))	('Rap1', 'Gene', '5906', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('higher', 'PosReg', (30, 36))	('Rap1', 'Gene', (0, 4))	('T4-2', 'CellLine', 'CVCL:2501', (168, 172))	('malignancy', 'Disease', (221, 231))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('T4-2', 'CellLine', 'CVCL:2501', (56, 60))	('larger', 'PosReg', (186, 192))	('breast cancer', 'Disease', (61, 74))	('activity', 'MPA', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))
180649	32486510	Labeled with a radionuclide tag, Cu-ATSM 14 penetrated into cells by passive diffusion and underwent glutathione reduction.	('Cu-ATSM 14', 'Chemical', '-', (33, 43))	('glutathione reduction', 'MPA', (101, 122))	('glutathione', 'Chemical', 'MESH:D005978', (101, 112))	('Cu-ATSM', 'Var', (33, 40))	('underwent', 'Reg', (91, 100))
180659	32486510	Depending on electron-donating effects of the di-substitutions on the diimine backbone, the Cu(II/I) redox potential itself was changed, and the cytotoxicity changed as a result.	('diimine', 'Chemical', 'MESH:C038867', (70, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (145, 157))	('changed', 'Reg', (128, 135))	('Cu(II/I)', 'Chemical', '-', (92, 100))	('changed', 'Reg', (158, 165))	('di-substitutions', 'Var', (46, 62))	('cytotoxicity', 'Disease', (145, 157))
180757	32486510	Activity was also detected in U266 multiple myeloma cells with IC50 = 0.130 microM and in HepG2 liver cells with IC50 = 0.495 microM.	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('myeloma', 'Disease', (44, 51))	('U266', 'CellLine', 'CVCL:0566', (30, 34))	('myeloma', 'Disease', 'MESH:D009101', (44, 51))	('IC50 =', 'Var', (63, 69))	('multiple myeloma', 'Phenotype', 'HP:0006775', (35, 51))
180784	32486510	A 6 mg/kg dose of coordination compound 69 induced tumor growth inhibition of about 74%, similar to cisplatin dosed at 1.5 mg/kg, but the time course of changes in body weight indicated that cisplatin induced elevated anorexia.	('cisplatin', 'Var', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('tumor', 'Disease', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('elevated', 'PosReg', (209, 217))	('anorexia', 'Disease', (218, 226))	('anorexia', 'Phenotype', 'HP:0002039', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
180802	32486510	Strong DNA binding is provided by triphenylphosphine ligands with a substituent at the 4-position of the phenyl ring capable of forming hydrogen bonds.	('DNA binding', 'Interaction', (7, 18))	('hydrogen', 'Chemical', 'MESH:D006859', (136, 144))	('triphenylphosphine', 'Chemical', 'MESH:C061896', (34, 52))	('substituent at the', 'Var', (68, 86))	('N', 'Chemical', 'MESH:D009584', (8, 9))
180825	32486510	The coordination compounds Cu2(Fen)4(caf)2 (Fen-fenoprofenate anion; caf-caffeine) 95 and Cu2(Fen)2(DMF)2 96 have an analgesic effect, confirmed by studies in vitro and in vivo.	('Cu2(Fen)4(caf)2', 'Gene', '9337', (27, 42))	('Cu2(Fen)2', 'Chemical', '-', (90, 99))	('Cu2(Fen)4(caf)2', 'Gene', (27, 42))	('Cu2', 'Var', (90, 93))	('caf-caffeine', 'Chemical', '-', (69, 81))	('DMF)', 'Chemical', 'MESH:D004126', (100, 104))	('analgesic effect', 'CPA', (117, 133))	('Fen-fenoprofenate anion', 'Chemical', '-', (44, 67))
180845	32486510	Once inside the cell, the nitroradical anion interacts with DNA and destroys the double helix.	('N', 'Chemical', 'MESH:D009584', (61, 62))	('nitroradical anion', 'Var', (26, 44))	('double helix', 'MPA', (81, 93))	('interacts', 'Interaction', (45, 54))	('destroys', 'NegReg', (68, 76))
180859	32486510	Of the studied derivatives, coordination compounds based on the most hydrophilic ligands L108 and L109 (5-SO3-8-HQ and 5-SO3-7-I-8-HQ) do not exhibit cytotoxic activity, while ligands of the most active coordination compounds are ligands with intermediate lipophilicity, namely, ligands L110 to L112 (8-HQ, 5,7-Me-8-HQ, and 5-Cl-8-HQ).	('L108', 'Var', (89, 93))	('8-HQ', 'Chemical', 'MESH:D015125', (329, 333))	('8-HQ', 'Chemical', 'MESH:D015125', (110, 114))	('L110', 'Var', (287, 291))	('8-HQ', 'Chemical', 'MESH:D015125', (314, 318))	('L109', 'Var', (98, 102))	('8-HQ', 'Chemical', 'MESH:D015125', (129, 133))	('8-HQ', 'Chemical', 'MESH:D015125', (301, 305))
180878	32486510	The exposure of compound 119 to MCF-7 cells resulted in cell cycle arrest in G1 phase, apoptosis, mitochondrial dysfunction, and elevated ROS level, also compound 119 proved to induce apoptosis through intrinsic and extrinsic pathways, autophagy, and DNA damage in MCF-7 cells.	('N', 'Chemical', 'MESH:D009584', (252, 253))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (98, 123))	('compound 119', 'Var', (154, 166))	('induce', 'PosReg', (177, 183))	('MCF-7', 'CellLine', 'CVCL:0031', (32, 37))	('mitochondrial dysfunction', 'Disease', (98, 123))	('elevated', 'PosReg', (129, 137))	('autophagy', 'CPA', (236, 245))	('arrest', 'Disease', (67, 73))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('intrinsic', 'CPA', (202, 211))	('ROS level', 'MPA', (138, 147))	('elevated ROS level', 'Phenotype', 'HP:0025464', (129, 147))	('apoptosis', 'CPA', (184, 193))	('G1 phase', 'CPA', (77, 85))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('MCF-7', 'CellLine', 'CVCL:0031', (265, 270))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('apoptosis', 'CPA', (87, 96))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (98, 123))
180881	32486510	A coordination compound was formed in situ while using equimolar mixtures of L121 and CuSO4, as was previously described for Disulfiram, elesclomol and thiosemicarbazone ligand L68.	('thiosemicarbazone', 'Chemical', 'MESH:D013882', (152, 169))	('CuSO4', 'Chemical', '-', (86, 91))	('elesclomol', 'Chemical', 'MESH:C512195', (137, 147))	('L121', 'Var', (77, 81))	('L68', 'Chemical', '-', (177, 180))	('CuSO4', 'Gene', (86, 91))	('L121', 'Chemical', 'MESH:D009257', (77, 81))	('Disulfiram', 'Chemical', 'MESH:D004221', (125, 135))
180882	32486510	Ligand L121 in the presence of CuSO4 induces striking accumulation of ubiquitinated proteins in A549 and K562 cells, which means that it is capable of inhibiting the activity of the 19S proteasomal DUBs much more effectively than it does the chymotrypsin-like activity of the 20S proteasome.	('ubiquitinated proteins', 'MPA', (70, 92))	('L121', 'Chemical', 'MESH:D009257', (7, 11))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('activity', 'MPA', (166, 174))	('CuSO4', 'Chemical', '-', (31, 36))	('inhibiting', 'NegReg', (151, 161))	('K562', 'CellLine', 'CVCL:0004', (105, 109))	('CuSO4', 'Gene', (31, 36))	('accumulation', 'PosReg', (54, 66))	('L121', 'Var', (7, 11))	('19S proteasomal DUBs', 'Enzyme', (182, 202))
180891	32486510	Regarding the mechanism of antitumor activity, the vast majority of coordination compounds act through the ROS formation (1, 2, L13 + Cu, 42, 43, 45-47, Disulfiram-based coordination compound 64, L68 + Cu, 119), glutation depletion (45-47, L68 + Cu, 69-74), proteasome inhibition (7, 8, 110, 114, L121 + Cu), DNA degradation (1, 2, 11, 60, 102, 119), DNA intercalation (1, 2, 3-5, L13 + Cu, 86-89, 119, 120), apoptosis induction (1, 2, 65, 102, 119), and cell cycle arrest (51-57, 103, 119).	('L13', 'Gene', '28929', (381, 384))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (455, 472))	('Cu', 'Chemical', 'MESH:D003300', (246, 248))	('L13', 'Gene', (381, 384))	('ROS formation', 'CPA', (107, 120))	('Cu', 'Chemical', 'MESH:D003300', (134, 136))	('DNA', 'MPA', (351, 354))	('inhibition', 'NegReg', (269, 279))	('arrest', 'Disease', (466, 472))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('L68', 'Chemical', '-', (196, 199))	('apoptosis induction', 'CPA', (409, 428))	('L121', 'Chemical', 'MESH:D009257', (297, 301))	('Cu', 'Chemical', 'MESH:D003300', (387, 389))	('glutation depletion', 'Phenotype', 'HP:0012538', (212, 231))	('DNA', 'MPA', (309, 312))	('Disulfiram', 'Chemical', 'MESH:D004221', (153, 163))	('N', 'Chemical', 'MESH:D009584', (352, 353))	('arrest', 'Disease', 'MESH:D006323', (466, 472))	('L121 + Cu', 'Var', (297, 306))	('Cu', 'Chemical', 'MESH:D003300', (202, 204))	('N', 'Chemical', 'MESH:D009584', (310, 311))	('45-47', 'Var', (233, 238))	('tumor', 'Disease', (31, 36))	('L13', 'Gene', '28929', (128, 131))	('proteasome', 'MPA', (258, 268))	('Cu', 'Chemical', 'MESH:D003300', (304, 306))	('glutation depletion', 'MPA', (212, 231))	('ROS', 'Chemical', 'MESH:D017382', (107, 110))	('L13', 'Gene', (128, 131))	('L68', 'Chemical', '-', (240, 243))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
180893	32486510	Thus, the cytotoxic activity of coordination compounds 42, 43, 69-74, L121 + Cu is not associated with ROS formation and does not decrease under the influence of ROS inhibitors.	('L121 + Cu', 'Var', (70, 79))	('cytotoxic', 'CPA', (10, 19))	('L121', 'Chemical', 'MESH:D009257', (70, 74))	('Cu', 'Chemical', 'MESH:D003300', (77, 79))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('ROS', 'Chemical', 'MESH:D017382', (162, 165))
180903	32486510	Copper-containing coordination compounds of disulfiram metabolite are always formed in situ, and the same approach has been successfully applied in vitro and in vivo to a number of compounds, such as L13 + Cu, L68 + Cu, L108-L113 + Cu, and L121 + Cu.	('L108-L113 + Cu', 'Var', (220, 234))	('L13', 'Gene', '28929', (200, 203))	('L121', 'Chemical', 'MESH:D009257', (240, 244))	('disulfiram', 'Chemical', 'MESH:D004221', (44, 54))	('Cu', 'Chemical', 'MESH:D003300', (232, 234))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('L68', 'Chemical', '-', (210, 213))	('L68 + Cu', 'Var', (210, 218))	('Cu', 'Chemical', 'MESH:D003300', (247, 249))	('L121 + Cu', 'Var', (240, 249))	('Cu', 'Chemical', 'MESH:D003300', (206, 208))	('L13', 'Gene', (200, 203))	('Cu', 'Chemical', 'MESH:D003300', (216, 218))
180948	31696625	The proportion of current and former smokers was lower in the anthracycline group compared to the no-anthracycline group (current smoker: 24.9% vs. 28.5%; former smoker: 26.5% vs. 37.9%; P = 0.001) (Table 1).	('anthracycline', 'Chemical', 'MESH:D018943', (62, 75))	('lower', 'NegReg', (49, 54))	('anthracycline', 'Var', (62, 75))	('anthracycline', 'Chemical', 'MESH:D018943', (101, 114))
180950	31696625	Thirty-two percent of anthracycline-treated patients had a mastectomy compared to 5.1% in the no-anthracycline group (P < 0.001) (Table 2).	('anthracycline', 'Chemical', 'MESH:D018943', (97, 110))	('patients', 'Species', '9606', (44, 52))	('mastectomy', 'Disease', (59, 69))	('anthracycline', 'Chemical', 'MESH:D018943', (22, 35))	('anthracycline-treated', 'Var', (22, 43))
180960	31696625	Anthracycline-treated patients had a higher body mass index at study visit, smoked less and were more often postmenopausal.	('Anthracycline', 'Chemical', 'MESH:D018943', (0, 13))	('higher', 'PosReg', (37, 43))	('body mass index', 'MPA', (44, 59))	('patients', 'Species', '9606', (22, 30))	('Anthracycline-treated', 'Var', (0, 21))	('less', 'NegReg', (83, 87))	('smoked', 'MPA', (76, 82))	('higher body mass index', 'Phenotype', 'HP:0031418', (37, 59))
180972	31696625	Mean GLS was -17.9% (SD +-2.9%) in the anthracycline group and -18.8% (SD +-3.2%) in the no-anthracycline group.	('GLS', 'MPA', (5, 8))	('anthracycline', 'Chemical', 'MESH:D018943', (92, 105))	('anthracycline', 'Chemical', 'MESH:D018943', (39, 52))	('anthracycline', 'Var', (39, 52))	('GLS', 'Chemical', '-', (5, 8))
180976	31696625	Irradiation of the left breast was associated with worse GLS (beta = 0.96, P = 0.002) (Table 3).	('Irradiation', 'Var', (0, 11))	('GLS', 'Chemical', '-', (57, 60))	('GLS', 'MPA', (57, 60))
180979	31696625	Median NT-proBNP was 75 ng/L (IQR 50-122) in the anthracycline group and 58 ng/L (IQR 37-92) in the no-anthracycline group.	('anthracycline', 'Chemical', 'MESH:D018943', (103, 116))	('anthracycline', 'Chemical', 'MESH:D018943', (49, 62))	('NT-proBNP', 'MPA', (7, 16))	('NT-proBNP', 'Chemical', '-', (7, 16))	('anthracycline', 'Var', (49, 62))
181001	31696625	In addition, we showed that GLS may not only detect anthracycline-related cardiotoxicity, but also radiotherapy-related cardiac injury, as left-sided breast irradiation was associated with worse GLS in a model including anthracycline dose (beta = 0.96, P = 0.002).	('cardiotoxicity', 'Disease', 'MESH:D066126', (74, 88))	('cardiac injury', 'Disease', 'MESH:D006331', (120, 134))	('anthracycline', 'Chemical', 'MESH:D018943', (52, 65))	('cardiotoxicity', 'Disease', (74, 88))	('GLS', 'Chemical', '-', (195, 198))	('GLS', 'Chemical', '-', (28, 31))	('cardiac injury', 'Disease', (120, 134))	('GLS', 'MPA', (195, 198))	('left-sided', 'Var', (139, 149))	('anthracycline', 'Chemical', 'MESH:D018943', (220, 233))
181010	31696625	Furthermore, 23% of patients in the anthracycline group had NT-proBNP >125 ng/L vs. 12% in the no-anthracycline group.	('NT-proBNP', 'MPA', (60, 69))	('NT-proBNP', 'Chemical', '-', (60, 69))	('anthracycline', 'Chemical', 'MESH:D018943', (36, 49))	('anthracycline', 'Chemical', 'MESH:D018943', (98, 111))	('patients', 'Species', '9606', (20, 28))	('anthracycline', 'Var', (36, 49))
181066	20421921	High grade DCIS is associated with central necrosis in the duct, and the accumulation of cellular degradation products such as lipofuschin.	('lipofuschin', 'MPA', (127, 138))	('necrosis', 'Disease', 'MESH:D009336', (43, 51))	('cellular degradation products', 'MPA', (89, 118))	('lipofuschin', 'Chemical', '-', (127, 138))	('accumulation', 'PosReg', (73, 85))	('necrosis', 'Disease', (43, 51))	('High grade', 'Var', (0, 10))
181090	20421921	This region includes the transcription factor SUPT3H (protein coding GIFtS:59, GC06M044904, UniProtKB/Swiss-Prot: SUPT3_HUMAN, O75486) (Figure S3).	('GC06M044904', 'Var', (79, 90))	('SUPT3H', 'Gene', '8464', (46, 52))	('O75486', 'Var', (127, 133))	('SUPT3H', 'Gene', (46, 52))
181095	20421921	The normal epithelial and stromal cells of the donor tissue grown for the same length of time in culture possessed a fully normal karyotype, while in all cases the propagated DCIS cells forming 3-D structures and exhibiting invasion exhibited genetic copy number gain or loss derangements in one or more genetic loci indicative of a neoplastic mutational event (Table 2, Figures S3-S6).	('loss', 'NegReg', (271, 275))	('gain', 'PosReg', (263, 267))	('derangements', 'Var', (276, 288))	('donor', 'Species', '9606', (47, 52))
181099	20421921	p38 MAPK Thr180/Tyr182 and SMAD2 Ser465/467, cell signaling proteins associated with survival and stress, were elevated in the spheroids in comparison to the epithelial and cuboidal monolayers.	('elevated', 'PosReg', (111, 119))	('Thr180', 'Chemical', '-', (9, 15))	('cell signaling proteins', 'MPA', (45, 68))	('SMAD2', 'Gene', (27, 32))	('Thr180/Tyr182', 'Var', (9, 22))	('p38', 'Gene', '1432', (0, 3))	('SMAD2', 'Gene', '4087', (27, 32))	('Tyr182', 'Chemical', '-', (16, 22))	('p38', 'Gene', (0, 3))	('Ser465', 'Chemical', '-', (33, 39))
181111	20421921	CQ treatment suppressed autophagy associated signal pathway endpoints in the DCIS progenitor cells, including IRS-1 Ser612, AKT Thr308, ERK Thr202/Tyr204, and p38 Thr180/Tyr182 (Figure S7).	('IRS-1', 'Gene', (110, 115))	('Thr202/Tyr204', 'Var', (140, 153))	('Thr202', 'Chemical', '-', (140, 146))	('Thr308', 'Var', (128, 134))	('AKT', 'Gene', (124, 127))	('IRS-1', 'Gene', '3667', (110, 115))	('p38', 'Gene', (159, 162))	('suppressed', 'NegReg', (13, 23))	('Tyr204', 'Chemical', '-', (147, 153))	('Tyr182', 'Chemical', '-', (170, 176))	('Thr308', 'Chemical', '-', (128, 134))	('CQ', 'Chemical', 'MESH:C023676', (0, 2))	('ERK', 'Gene', (136, 139))	('AKT', 'Gene', '207', (124, 127))	('Thr180', 'Chemical', '-', (163, 169))	('Ser612', 'Var', (116, 122))	('p38', 'Gene', '1432', (159, 162))	('ERK', 'Gene', '2048', (136, 139))	('Ser612', 'Chemical', '-', (116, 122))	('autophagy', 'CPA', (24, 33))
181138	20421921	It is well established that the transition from normal to neoplastic growth involves deregulation at various cellular levels including gene-specific mutational events, alterations in signal transduction and growth control pathways, and dysfunctional DNA synthesis and repair mechanisms resulting in the generation of chromosomal abnormalities.	('alterations', 'Reg', (168, 179))	('mutational', 'Var', (149, 159))	('dysfunctional', 'Var', (236, 249))	('DNA synthesis', 'CPA', (250, 263))	('chromosomal abnormalities', 'Disease', (317, 342))	('signal transduction', 'Pathway', (183, 202))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (317, 342))	('deregulation', 'MPA', (85, 97))	('growth control pathways', 'Pathway', (207, 230))
181140	20421921	This region on chromosome 6 narrowly encompasses the SUPT3H gene (protein coding GIFtS:59, GC06M044904, UniProtKB/Swiss-Prot: SUPT3_HUMAN, O75486).	('SUPT3H', 'Gene', (53, 59))	('SUPT3H', 'Gene', '8464', (53, 59))	('GC06M044904', 'Var', (91, 102))
181145	20421921	For this reason, high grade DCIS is associated with central necrosis, and the accumulation of lipofuschin.	('necrosis', 'Disease', 'MESH:D009336', (60, 68))	('high grade', 'Var', (17, 27))	('lipofuschin', 'Protein', (94, 105))	('lipofuschin', 'Chemical', '-', (94, 105))	('necrosis', 'Disease', (60, 68))	('associated', 'Reg', (36, 46))	('accumulation', 'PosReg', (78, 90))
181152	20421921	The data presented herein, strongly support the conclusion that autophagy plays a necessary role in the DCIS cell malignant phenotype: a) autophagy is up-regulated in the in vivo DCIS lesion as shown by immunohistochemistry; b) autophagy is up regulated in the cultured DCIS spheroids and 3-D structures, as shown by immunohistochemistry and immunofluorescence; c) autophagy is up-regulated in mouse xenografts as shown by immunohistochemistry; d) autophagy signal proteins are up-regulated in cultured DCIS spheroids, with validation after long term culture, by reverse phase protein microarray measurement; e) disruption of autophagy by chloroquine phosphate (CQ) completely abrogated xenograft tumor formation; f) CQ completely blocked growth and invasion of DCIS cells on autologous stroma; g) CQ markedly suppressed DCIS spheroid formation and outgrowth in culture for independent experiments; and h) CQ completely eliminated cytogenetically abnormal cells from the DCIS cultured cells.	('mouse', 'Species', '10090', (394, 399))	('cytogenetically abnormal', 'MPA', (931, 955))	('tumor', 'Disease', (697, 702))	('CQ', 'Chemical', 'MESH:C023676', (906, 908))	('suppressed', 'NegReg', (810, 820))	('growth', 'CPA', (739, 745))	('CQ', 'Chemical', 'MESH:C023676', (717, 719))	('blocked', 'NegReg', (731, 738))	('abrogated', 'NegReg', (677, 686))	('CQ', 'Chemical', 'MESH:C023676', (662, 664))	('CQ', 'Chemical', 'MESH:C023676', (798, 800))	('eliminated', 'NegReg', (920, 930))	('tumor', 'Disease', 'MESH:D009369', (697, 702))	('chloroquine phosphate', 'Chemical', 'MESH:C023676', (639, 660))	('DCIS spheroid formation', 'CPA', (821, 844))	('tumor', 'Phenotype', 'HP:0002664', (697, 702))	('invasion', 'CPA', (750, 758))	('disruption', 'Var', (612, 622))
181157	20421921	Chloroquine has been shown to suppress N-methyl-N-nitrosurea induced mouse breast carcinomagenesis, enhances the effectiveness of tyrosine kinase inhibitor treatment of primary CML stem cells, and has been proposed as a potential means to enhance the effectiveness of tamoxifen in vitro in tamoxifen resistant breast carcinoma cells by blocking autophagy dependent cell survival.	('breast carcinoma', 'Disease', 'MESH:D001943', (75, 91))	('effectiveness', 'MPA', (113, 126))	('blocking', 'NegReg', (336, 344))	('N-methyl-N-nitrosurea', 'Chemical', '-', (39, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('mouse', 'Species', '10090', (69, 74))	('tamoxifen', 'Chemical', 'MESH:D013629', (268, 277))	('breast carcinoma', 'Phenotype', 'HP:0003002', (75, 91))	('N-methyl-N-nitrosurea', 'Var', (39, 60))	('breast carcinoma', 'Disease', 'MESH:D001943', (310, 326))	('enhances', 'PosReg', (100, 108))	('breast carcinomagenesis', 'Disease', 'MESH:D001943', (75, 98))	('Chloroquine', 'Chemical', 'MESH:D002738', (0, 11))	('breast carcinoma', 'Phenotype', 'HP:0003002', (310, 326))	('breast carcinomagenesis', 'Disease', (75, 98))	('autophagy dependent cell survival', 'CPA', (345, 378))	('tamoxifen', 'Chemical', 'MESH:D013629', (290, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('CML', 'Disease', 'MESH:D015464', (177, 180))	('breast carcinoma', 'Disease', (310, 326))	('suppress', 'NegReg', (30, 38))	('enhance', 'PosReg', (239, 246))	('CML', 'Disease', (177, 180))
181205	30973790	After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27).	('tamoxifen', 'Var', (113, 122))	('tamoxifen', 'Chemical', 'MESH:D013629', (113, 122))	('person', 'Species', '9606', (166, 172))	('neoplastic events', 'CPA', (90, 107))
181213	30973790	Tamoxifen, a selective estrogen receptor (ER) modulator and a precursor of molecular targeted medicines, is effective in the adjuvant treatment of hormone receptor-positive breast cancer and for the prevention of breast cancer in at-risk women on the basis of the Gail model, including those with ADH and LCIS whose risk of subsequent invasive cancer is 10 and 13 per 1,000 per year, respectively.	('cancer', 'Disease', (344, 350))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('women', 'Species', '9606', (238, 243))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('estrogen receptor', 'Gene', '2099', (23, 40))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('cancer', 'Disease', (180, 186))	('breast cancer', 'Disease', (173, 186))	('LCIS', 'Phenotype', 'HP:0030076', (305, 309))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (220, 226))	('ER', 'Gene', '2099', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ADH', 'Var', (297, 300))	('estrogen receptor', 'Gene', (23, 40))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
181230	30973790	Correlative studies of biomarkers included mammographic density, circulating insulin-like growth factor (IGF) 1 and IGF binding proteins, IGF binding protein 3, sex hormone binding globulin, C-reactive protein, CYP2D6 single nucleotide polymorphisms, tamoxifen, and metabolite blood levels.	('CYP2D6', 'Gene', (211, 217))	('C-reactive protein', 'Gene', (191, 209))	('C-reactive protein', 'Gene', '1401', (191, 209))	('IGF binding protein 3', 'Gene', '3486', (138, 159))	('mammographic density', 'CPA', (43, 63))	('IGF binding protein 3', 'Gene', (138, 159))	('tamoxifen', 'Chemical', 'MESH:D013629', (251, 260))	('single nucleotide polymorphisms', 'Var', (218, 249))	('CYP2D6', 'Gene', '1565', (211, 217))	('insulin-like growth factor (IGF) 1', 'Gene', '3479', (77, 111))
181275	30973790	Moreover, low-dose tamoxifen decreased by 75% the onset of a contralateral breast cancer, which indicates a potential primary preventive effect, and decreased invasive cancer by more than 40%, which prevents more-intensive adjuvant treatments.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('low-dose', 'Var', (10, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (61, 88))	('decreased invasive cancer', 'Disease', (149, 174))	('decreased', 'NegReg', (29, 38))	('decreased invasive cancer', 'Disease', 'MESH:D009362', (149, 174))	('contralateral breast cancer', 'Disease', (61, 88))	('tamoxifen', 'Chemical', 'MESH:D013629', (19, 28))
181288	30973790	We would therefore expect 2.7 cases of endometrial cancer with 20 mg/d in our study, so our data indirectly suggest that the risk of deep vein thrombosis and pulmonary embolism or endometrial cancer is approximately 2.5 times lower with 5 mg/d than with 20 mg/d.	('deep vein thrombosis', 'Disease', (133, 153))	('lower', 'NegReg', (226, 231))	('endometrial cancer', 'Disease', (180, 198))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (158, 176))	('pulmonary embolism', 'Disease', (158, 176))	('pulmonary embolism', 'Disease', 'MESH:D011655', (158, 176))	('vein thrombosis', 'Phenotype', 'HP:0004936', (138, 153))	('endometrial cancer', 'Disease', (39, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pulmonary emboli', 'Phenotype', 'HP:0002204', (158, 174))	('deep vein thrombosis', 'Phenotype', 'HP:0002625', (133, 153))	('endometrial cancer', 'Phenotype', 'HP:0012114', (180, 198))	('endometrial cancer', 'Disease', 'MESH:D016889', (180, 198))	('5 mg/d', 'Var', (237, 243))	('deep vein thrombosis', 'Disease', 'MESH:D020246', (133, 153))	('endometrial cancer', 'Phenotype', 'HP:0012114', (39, 57))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('endometrial cancer', 'Disease', 'MESH:D016889', (39, 57))
181291	30973790	Our findings show that the frequency of hot flashes was 1.5-fold higher with tamoxifen compared with placebo.	('tamoxifen', 'Chemical', 'MESH:D013629', (77, 86))	('tamoxifen', 'Var', (77, 86))	('hot flashes', 'Phenotype', 'HP:0031217', (40, 51))	('hot flash', 'Phenotype', 'HP:0031217', (40, 49))	('hot', 'Disease', (40, 43))	('higher', 'PosReg', (65, 71))
181305	26734604	An Anthropometric-Based Subject-Specific Finite Element Model of the Human Breast for Predicting Large Deformations The large deformation of the human breast threatens proper nodules tracking when the subject mammograms are used as pre-planning data for biopsy.	('threatens', 'NegReg', (158, 167))	('Human', 'Species', '9606', (69, 74))	('human', 'Species', '9606', (145, 150))	('proper nodules tracking', 'MPA', (168, 191))	('deformation', 'Var', (126, 137))
181374	19416474	Development of tumor malignancy, including the acquisition of abnormal invasive and metastatic activities, is a consequence of the accumulation of genetic mutations in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor malignancy', 'Disease', (15, 31))	('genetic mutations', 'Var', (147, 164))	('tumor malignancy', 'Disease', 'MESH:D018198', (15, 31))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
181399	19416474	We have observed that AMAP1 protein levels are downregulated in serum-starved MDA-MB-231 cells, which is then upregulated swiftly upon EGF stimulation; and moreover, rapamycin reduces the AMAP1 protein levels in MDA-MB-231 cells (OBI, Osaka).	('rapamycin', 'Chemical', 'MESH:D020123', (166, 175))	('downregulated', 'NegReg', (47, 60))	('AMAP1 protein levels', 'MPA', (22, 42))	('reduces', 'NegReg', (176, 183))	('upregulated', 'PosReg', (110, 121))	('AMAP1 protein levels', 'MPA', (188, 208))	('rapamycin', 'Var', (166, 175))
181400	19416474	Amplification of chromosome 8q is frequently observed in a broad range of solid tumors, including breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Disease', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('solid tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('observed', 'Reg', (45, 53))	('solid tumors', 'Disease', (74, 86))
181409	19416474	This binding is mediated via an interaction of the pleckstrin homology (PH) domain of GEP100 either with the Tyr1068- or Tyr1086-phosphorylation sites of EGFR.	('Tyr1086-phosphorylation', 'Var', (121, 144))	('Tyr1068-', 'Var', (109, 117))	('GEP100', 'Gene', (86, 92))	('Tyr1068', 'Chemical', '-', (109, 116))	('Tyr1086', 'Chemical', '-', (121, 128))	('interaction', 'Interaction', (32, 43))	('mediated via', 'Reg', (16, 28))	('binding', 'Interaction', (5, 12))
181412	19416474	Phosphorylation of Tyr1173 is very weak, and phosphorylation of Tyr992, Tyr1045 and Tyr1148 is almost undetectable in EGF-treated MDA-MB-231 cells.	('Tyr1148', 'Chemical', '-', (84, 91))	('Tyr1045', 'Chemical', '-', (72, 79))	('Tyr992', 'Var', (64, 70))	('Tyr1173', 'Chemical', '-', (19, 26))	('weak', 'NegReg', (35, 39))	('Tyr1148', 'Var', (84, 91))	('Tyr1173', 'Var', (19, 26))	('phosphorylation', 'MPA', (45, 60))	('Phosphorylation', 'MPA', (0, 15))	('Tyr1045', 'Var', (72, 79))	('Tyr992', 'Chemical', '-', (64, 70))
181413	19416474	Phosphorylation of Tyr845 has also been reported in MDA-MB-231 cells.	('Phosphorylation', 'MPA', (0, 15))	('Tyr845', 'Var', (19, 25))	('Tyr845', 'Chemical', '-', (19, 25))
181414	19416474	Phosphorylation of Tyr1068 and Tyr1086 are both known to provide binding sites for the src homology 2 (SH2) domains of Grb2, a binding which may then lead to activation of the Ras-MAPK pathway.	('src', 'Gene', (87, 90))	('lead to', 'Reg', (150, 157))	('Tyr1086', 'Var', (31, 38))	('binding', 'Interaction', (65, 72))	('Grb2', 'Gene', '2885', (119, 123))	('src', 'Gene', '6714', (87, 90))	('Phosphorylation', 'MPA', (0, 15))	('activation', 'PosReg', (158, 168))	('Ras-MAPK pathway', 'Pathway', (176, 192))	('Tyr1068', 'Var', (19, 26))	('Grb2', 'Gene', (119, 123))
181424	19416474	Arf6 activity is thought to be pivotal for the assembly and disassembly of E-cadherin-based cell-cell adhesions: it has been shown that an active form of Arf6, Arf6Q67L, causes disassembly of E-cadherin-mediated adherens junctions in MDCK cells, while its inactive form, Arf6T27N, blocks the hepatocyte growth factor (HGF)-induced internalization of E-cadherin-based junctional components.	('HGF', 'Gene', (318, 321))	('blocks', 'NegReg', (281, 287))	('Arf6Q67L', 'Var', (160, 168))	('disassembly', 'MPA', (177, 188))	('hepatocyte growth factor', 'Gene', (292, 316))	('MDCK', 'CellLine', 'CVCL:0422', (234, 238))	('hepatocyte growth factor', 'Gene', '403441', (292, 316))	('HGF', 'Gene', '403441', (318, 321))	('Arf6', 'Var', (154, 158))
181461	30194658	Ki67, a common biomarker of proliferating/non-G0 cells that is associated with worse prognosis (particularly when considered with other biomarkers, including p16 and COX-2), exhibits both phenotypic heterogeneity (with lesions expressing Ki67 in 0.5-61% of cells, depending on molecular subtype) and spatial heterogeneity (i.e.	('COX-2', 'Gene', (166, 171))	('p16', 'Gene', (158, 161))	('p16', 'Gene', '1029', (158, 161))	('COX-2', 'Gene', '4513', (166, 171))	('Ki67', 'Var', (238, 242))
181463	30194658	Interestingly, HER4 and HER2 were found to be relatively homogeneous across ducts within a single case, whereas other biomarkers exhibiting generally low expression (<=5%) such as phospho-mTOR, CD44v6, and CD10, were more heterogeneous.	('CD10', 'Gene', '4311', (206, 210))	('HER4', 'Gene', '2066', (15, 19))	('phospho', 'Chemical', 'MESH:C033601', (180, 187))	('CD44v6', 'Var', (194, 200))	('mTOR', 'Gene', (188, 192))	('mTOR', 'Gene', '2475', (188, 192))	('HER2', 'Gene', (24, 28))	('CD10', 'Gene', (206, 210))	('HER4', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (24, 28))
181470	30194658	In an advanced iteration of multi-region sequencing, multiple single cells across different regions of individual cases of DCIS (with synchronous adjacent invasive cancer) were isolated by laser-dissection to identify copy number alterations at single-cell resolution while retaining spatial information.	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('synchronous adjacent invasive cancer', 'Disease', (134, 170))	('synchronous adjacent invasive cancer', 'Disease', 'MESH:D009378', (134, 170))	('copy number alterations', 'Var', (218, 241))	('DCIS', 'Disease', (123, 127))
181491	30194658	Importantly, the distribution of these phenotypic clusters appeared to be associated with local immune infiltration: for example, regions of DCIS harboring tumor cells with high EGFR and CD10 were significantly associated with a high T-to-B cell ratio, while those harboring tumor cells high in HER2 were associated with a heavy B-cell infiltrate.	('EGFR', 'Gene', '1956', (178, 182))	('high', 'Var', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('CD10', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('EGFR', 'Gene', (178, 182))	('CD10', 'Gene', '4311', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('HER2', 'Gene', (295, 299))	('HER2', 'Gene', '2064', (295, 299))	('tumor', 'Disease', (156, 161))	('associated', 'Reg', (211, 221))	('high T-to-B cell ratio', 'MPA', (229, 251))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
181516	30194658	Consequently, an alternative hypothesis to explain the transition from in situ to invasive carcinoma emphasizes a determinant role for the local microenvironment, including, to name a few examples, modifications in extracellular matrix components and stiffness that allow epithelial cells to breach the basement membrane, functional switching of stromal cells (including myoepithelial cells and fibroblasts) resulting in local secretion of matrix metalloproteases, chemokines, and other tumor-promoting factors, and the infiltration of immune cells that modulate anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (568, 573))	('infiltration', 'CPA', (520, 532))	('modulate', 'Reg', (554, 562))	('tumor', 'Phenotype', 'HP:0002664', (568, 573))	('secretion of', 'MPA', (427, 439))	('matrix', 'Protein', (440, 446))	('modifications', 'Var', (198, 211))	('tumor', 'Disease', 'MESH:D009369', (487, 492))	('tumor', 'Disease', (568, 573))	('invasive carcinoma', 'Disease', 'MESH:D009361', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (487, 492))	('tumor', 'Disease', (487, 492))	('invasive carcinoma', 'Disease', (82, 100))
181522	30194658	Additionally, in cases where anti-hormonal therapy follows surgical excision, ITH in ER expression and/or dependence may result in incomplete response, as has been observed, for example, with anti-HER2 therapies in invasive breast cancer.	('ITH', 'Var', (78, 81))	('invasive breast cancer', 'Disease', 'MESH:D001943', (215, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('HER2', 'Gene', (197, 201))	('HER2', 'Gene', '2064', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('invasive breast cancer', 'Disease', (215, 237))
181622	28191286	Yet, Resveratrol-induced cytotoxicity in MCF-7 breast cancer cells was also partially mediated by p53.	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('p53', 'Var', (98, 101))	('cytotoxicity', 'Disease', (25, 37))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (41, 60))	('Resveratrol', 'Chemical', 'MESH:D000077185', (5, 16))	('MCF-7 breast cancer', 'Disease', (41, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mediated', 'Reg', (86, 94))
181628	28191286	Previous experiments conducted in our laboratory have determined that upon treatment with E2, the levels of ERalpha and p53 in T-47D cells cultured in stripped serum are maximal at 24 hours.	('T-47D', 'CellLine', 'CVCL:0553', (127, 132))	('ERalpha', 'Gene', (108, 115))	('ERalpha', 'Gene', '2099', (108, 115))	('p53', 'Var', (120, 123))	('E2', 'Chemical', 'MESH:D004958', (90, 92))
181657	28191286	RES (1 - 40 muM) appears to increase the level of p53.	('muM', 'Gene', (12, 15))	('muM', 'Gene', '56925', (12, 15))	('p53', 'Var', (50, 53))	('RES', 'Chemical', 'MESH:D000077185', (0, 3))
181682	28191286	Human p53 becomes acetylated at Lys382 (Lys379 in mouse) in vivo to enhance p53-DNA binding.	('Human', 'Species', '9606', (0, 5))	('Lys382', 'Var', (32, 38))	('Lys382', 'Chemical', '-', (32, 38))	('Lys379', 'Chemical', '-', (40, 46))	('enhance', 'PosReg', (68, 75))	('mouse', 'Species', '10090', (50, 55))	('p53-DNA', 'Protein', (76, 83))
181683	28191286	The histone acetyltransferases p300 and PCAF can acetylate p53 in vitro at Lys382 and Lys320, respectively.	('Lys382', 'Var', (75, 81))	('Lys382', 'Chemical', '-', (75, 81))	('Lys320', 'Var', (86, 92))	('PCAF', 'Gene', '8850', (40, 44))	('p300', 'Gene', (31, 35))	('PCAF', 'Gene', (40, 44))	('acetylate', 'MPA', (49, 58))	('p53', 'Protein', (59, 62))	('Lys320', 'Chemical', '-', (86, 92))	('p300', 'Gene', '2033', (31, 35))
181684	28191286	Lys382 becomes acetylated in vivo following DNA damage to allow enhanced p53-DNA binding.	('Lys382', 'Var', (0, 6))	('Lys382', 'Chemical', '-', (0, 6))	('p53-DNA', 'Protein', (73, 80))	('binding', 'Interaction', (81, 88))	('enhanced', 'PosReg', (64, 72))
181703	28191286	Effects on the level of ERalpha protein induced by these estrogen and anti-estrogen combinations reflected effects similar to those observed when the estrogens and anti-estrogens were used alone.	('ERalpha', 'Gene', '2099', (24, 31))	('ERalpha', 'Gene', (24, 31))	('combinations', 'Var', (84, 96))
181713	28191286	One study concluded that RES demonstrated a dose-dependent induction of both p53 and p21, seen at both the mRNA and protein levels.	('RES', 'Chemical', 'MESH:D000077185', (25, 28))	('p21', 'Gene', (85, 88))	('p53', 'Var', (77, 80))	('p21', 'Gene', '644914', (85, 88))
181730	28191286	Membranes were blocked for 1 hour in 5% (w/v) non-fat dry milk (NFDM) in TBS-T (20 mM Tris-HCl, 140 mM NaCl, pH 7.4, 0.1% (v/v) Tween 20) and incubated with primary antibody anti-ERalpha clone F-10 (Santa Cruz), anti-p53 (Santa Cruz), anti-integrin alphavDelta3 (Cell Signaling) & anti-lysine p53 (Cell Signaling) diluted 1:500 in 5% (w/v) NFDM in TBS-T for 2 hours.	('& anti-lysine', 'Var', (279, 292))	('lysine', 'Chemical', 'MESH:D008239', (286, 292))	('ERalpha', 'Gene', (179, 186))	('ERalpha', 'Gene', '2099', (179, 186))
181924	33327281	Chen et al suggested that patients with IMPC of the breast had better long-term survival than patients with IDC despite its aggressive clinical characteristics, through a comparison based on a large-population database and case-control analysis.	('patients', 'Species', '9606', (94, 102))	('IMPC', 'Var', (40, 44))	('patients', 'Species', '9606', (26, 34))	('better', 'PosReg', (63, 69))	('IDC', 'Gene', '4000', (108, 111))	('IDC', 'Gene', (108, 111))
181952	32541686	A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers.	('aggressiveness', 'Phenotype', 'HP:0000718', (84, 98))	('promotes', 'PosReg', (39, 47))	('human', 'Species', '9606', (223, 228))	('subversion', 'Var', (131, 141))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aggressiveness', 'Disease', 'MESH:D001523', (84, 98))	('cancers', 'Disease', (229, 236))	('leads to', 'Reg', (162, 170))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('implicated', 'Reg', (209, 219))	('breast cancer', 'Disease', (48, 61))	('pro-metastatic behavior', 'CPA', (103, 126))	('aggressiveness', 'Disease', (84, 98))	('malignant transformation', 'CPA', (171, 195))
181953	32541686	However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rat', 'Species', '10116', (50, 53))	('causative', 'Reg', (83, 92))	('human', 'Species', '9606', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('genetic alterations', 'Var', (38, 57))	('cancers', 'Disease', (117, 124))
181955	32541686	Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a beta-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFbeta-dependent autocrine loop that sustains EMT.	('beta-catenin', 'Gene', '1499', (120, 132))	('EPN3', 'Var', (17, 21))	('E-cadherin', 'Gene', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('partial epithelial-to-mesenchymal', 'CPA', (148, 181))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('beta-catenin', 'Gene', (120, 132))	('E-cadherin', 'Gene', '999', (64, 74))	('tumor', 'Disease', (36, 41))	('increasing', 'PosReg', (53, 63))
181958	32541686	It is unclear if genetic alterations in endocytic proteins play a causal role in high incidence human cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('genetic', 'Var', (17, 24))	('human', 'Species', '9606', (96, 101))	('rat', 'Species', '10116', (29, 32))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
181959	32541686	Here, the authors report the oncogenic role of Epsin3 (EPN3) in breast cancer, and show EPN3 to drive tumorigenesis through induction of a partial epithelial mesenchymal transition state and a TGFbeta-dependent regulatory loop that promotes cellular plasticity and invasive behaviour.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('cellular plasticity', 'CPA', (241, 260))	('EPN3', 'Var', (88, 92))	('promotes', 'PosReg', (232, 240))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Epsin3', 'Gene', (47, 53))	('drive', 'PosReg', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('invasive behaviour', 'CPA', (265, 283))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('Epsin3', 'Gene', '55040', (47, 53))	('tumor', 'Disease', (102, 107))	('partial epithelial mesenchymal transition state', 'CPA', (139, 186))	('breast cancer', 'Disease', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
181973	32541686	We further demonstrate that EPN3 overexpression induces a state of partial EMT (assessed by a variety of biological and biochemical phenotypes), triggered by EPN3-dependent endocytosis of ECAD and sustained through a feed-forward loop between ECAD internalization and enhanced TGFbeta signaling.	('rat', 'Species', '10116', (18, 21))	('endocytosis', 'MPA', (173, 184))	('enhanced', 'PosReg', (268, 276))	('EPN3', 'Gene', (28, 32))	('ECAD', 'Protein', (188, 192))	('internalization', 'MPA', (248, 263))	('overexpression', 'Var', (33, 47))	('TGFbeta', 'Pathway', (277, 284))	('partial EMT', 'CPA', (67, 78))
181977	32541686	To obtain direct evidence of EPN3 amplification, we performed fluorescence in situ hybridization (FISH) on an independent cohort of BC patients and found EPN3 amplified in ~10% of the cases.	('amplified', 'Var', (159, 168))	('patients', 'Species', '9606', (135, 143))	('EPN3', 'Gene', (154, 158))
181981	32541686	2A, B) revealed that silencing EPN3 reduced tumorigenicity in cells harboring EPN3 amplification (i.e., BT474, Supplementary Fig.	('EPN3', 'Gene', (78, 82))	('amplification', 'Var', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('reduced', 'NegReg', (36, 43))	('EPN3', 'Gene', (31, 35))	('tumor', 'Disease', (44, 49))	('silencing', 'Var', (21, 30))
181982	32541686	Conversely, EPN3 ectopic overexpression in not-amplified/overexpressing BC cells (i.e., HCC1569) increased their in vivo tumorigenic potential (Supplementary Fig.	('HCC1569', 'CellLine', 'CVCL:1255', (88, 95))	('increased', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('ectopic', 'Var', (17, 24))	('EPN3', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
181985	32541686	Overexpression of EPN3, but not of the related EPN1 (used as a control), induced a morphology reminiscent of EMT (Fig.	('EPN1', 'Gene', (47, 51))	('EPN1', 'Gene', '29924', (47, 51))	('EPN3', 'Var', (18, 22))	('induced', 'Reg', (73, 80))
181987	32541686	When EMT markers were analyzed by immunoblot (IB), MCF10A-EPN3 showed increased levels of NCAD (N-cadherin) and VIM (Vimentin), and a modest decrease of ECAD (E-cadherin) vs. MCF10A-control (Ctr) or MCF10A-EPN1 (Fig.	('levels', 'MPA', (80, 86))	('MCF10A', 'CellLine', 'CVCL:0598', (51, 57))	('increased', 'PosReg', (70, 79))	('NCAD', 'MPA', (90, 94))	('MCF10A', 'CellLine', 'CVCL:0598', (175, 181))	('MCF10A', 'CellLine', 'CVCL:0598', (199, 205))	('decrease', 'NegReg', (141, 149))	('MCF10A-EPN1', 'CellLine', 'CVCL:0598', (199, 210))	('Vimentin', 'Gene', '7431', (117, 125))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (51, 62))	('ECAD', 'MPA', (153, 157))	('VIM', 'Gene', '7431', (112, 115))	('Vimentin', 'Gene', (117, 125))	('MCF10A-EPN3', 'Var', (51, 62))	('N-cadherin', 'Gene', (96, 106))	('VIM', 'Gene', (112, 115))	('N-cadherin', 'Gene', '1000', (96, 106))	('E-cadherin', 'Gene', (159, 169))	('E-cadherin', 'Gene', '999', (159, 169))
181989	32541686	EPN3 also induced increased mRNA levels of fibronectin (FN1) and of the EMT master regulators, ZEB1, SNAIL and TWIST (Supplementary Fig.	('SNAIL', 'Gene', '6615', (101, 106))	('SNAIL', 'Gene', (101, 106))	('increased', 'PosReg', (18, 27))	('fibronectin', 'Gene', '2335', (43, 54))	('TWIST', 'Gene', (111, 116))	('ZEB1', 'Gene', (95, 99))	('EPN3', 'Var', (0, 4))	('ZEB1', 'Gene', '6935', (95, 99))	('FN1', 'Gene', '2335', (56, 59))	('fibronectin', 'Gene', (43, 54))	('FN1', 'Gene', (56, 59))	('TWIST', 'Gene', '7291', (111, 116))
181990	32541686	Finally, MCF10A-EPN3 displayed increased invasiveness in vitro (Fig.	('invasiveness', 'CPA', (41, 53))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (9, 20))	('MCF10A-EPN3', 'Var', (9, 20))	('increased', 'PosReg', (31, 40))
181991	32541686	When grown in 3D Matrigel, MCF10A-Ctr formed polarized, acini-like spheroids recapitulating aspects of glandular architecture in vivo, including the formation of a hollow lumen, apico-basal polarization, and the deposition of basement membrane components.	('apico-basal polarization', 'CPA', (178, 202))	('MCF10A', 'CellLine', 'CVCL:0598', (27, 33))	('MCF10A-Ctr', 'Var', (27, 37))
181992	32541686	MCF10A-EPN3, similarly to MCF10A-TWIST, displayed aberrant morphogenesis, with around 40% of organoids failing to complete the differentiation program (Supplementary Fig.	('MCF10A-EPN3', 'Var', (0, 11))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (0, 11))	('MCF10A-TWIST', 'Gene', '7291', (26, 38))	('MCF10A-TWIST', 'Gene', (26, 38))
181996	32541686	In MCF10A-Ctr and MCF10A-EPN1, ECAD staining was uniform in the contact regions (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (18, 24))	('MCF10A-EPN1', 'Var', (18, 29))	('MCF10A-Ctr', 'Var', (3, 13))	('MCF10A-EPN1', 'CellLine', 'CVCL:0598', (18, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (3, 9))
181997	32541686	In MCF10A-EPN3, ECAD signal was lost in a fraction of the cells (Fig.	('lost', 'NegReg', (32, 36))	('MCF10A-EPN3', 'Var', (3, 14))	('ECAD signal', 'MPA', (16, 27))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (3, 14))
182002	32541686	Indeed, the kinetics of ECAD internalization was significantly accelerated in MCF10A-EPN3 vs. MCF10A-Ctr cells (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (94, 100))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (78, 89))	('kinetics', 'MPA', (12, 20))	('accelerated', 'PosReg', (63, 74))	('MCF10A', 'CellLine', 'CVCL:0598', (78, 84))	('ECAD', 'Protein', (24, 28))	('internalization', 'MPA', (29, 44))	('rat', 'Species', '10116', (69, 72))	('MCF10A-EPN3', 'Var', (78, 89))
182006	32541686	EPN3-induced ECAD endocytosis correlated with increased nuclear accumulation of active beta-catenin in MCF10A-EPN3 vs. MCF10A cells (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (103, 109))	('beta-catenin', 'Gene', (87, 99))	('increased', 'PosReg', (46, 55))	('MCF10A-EPN3', 'Var', (103, 114))	('beta-catenin', 'Gene', '1499', (87, 99))	('ECAD endocytosis', 'Disease', 'None', (13, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (119, 125))	('ECAD endocytosis', 'Disease', (13, 29))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (103, 114))
182009	32541686	These results argue that EPN3 overexpression causes destabilization of cell-cell junctions through increased ECAD internalization, followed by beta-catenin nuclear translocation and TCF4-dependent upregulation of EMT target genes.	('beta-catenin', 'Gene', '1499', (143, 155))	('destabilization', 'MPA', (52, 67))	('cell-cell junctions', 'CPA', (71, 90))	('upregulation', 'PosReg', (197, 209))	('ECAD', 'Protein', (109, 113))	('internalization', 'MPA', (114, 129))	('EPN3', 'Gene', (25, 29))	('increased', 'PosReg', (99, 108))	('beta-catenin', 'Gene', (143, 155))	('overexpression', 'Var', (30, 44))
182011	32541686	The kinetics of TGFbeta-induced ECAD internalization was significantly accelerated in MCF10A-EPN3 vs. MCF10A-Ctr cells (Fig.	('accelerated', 'PosReg', (71, 82))	('MCF10A', 'CellLine', 'CVCL:0598', (86, 92))	('kinetics', 'MPA', (4, 12))	('rat', 'Species', '10116', (77, 80))	('MCF10A-EPN3', 'Var', (86, 97))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (86, 97))	('MCF10A', 'CellLine', 'CVCL:0598', (102, 108))	('internalization', 'MPA', (37, 52))
182019	32541686	Indeed, the combination of suboptimal TGFbeta stimulation (incapable of stimulating invasion in control cells) and EPN3 overexpression further enhanced the invasive potential of MCF10A-EPN3 cells in the Matrigel invasion assay (Fig.	('EPN3', 'Gene', (115, 119))	('enhanced', 'PosReg', (143, 151))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (178, 189))	('suboptimal', 'Var', (27, 37))	('Matrigel invasion assay', 'CPA', (203, 226))	('TGFbeta', 'Gene', (38, 45))	('invasive potential', 'CPA', (156, 174))
182022	32541686	Finally, the silencing of endogenous EPN3 in MCF10A reduced both ECAD internalization and transcriptional activation of NCAD and VIM induced by high doses of TGFbeta stimulation (Fig.	('VIM', 'Gene', '7431', (129, 132))	('MCF10A', 'CellLine', 'CVCL:0598', (45, 51))	('reduced', 'NegReg', (52, 59))	('transcriptional activation', 'MPA', (90, 116))	('MCF10A', 'Gene', (45, 51))	('ECAD internalization', 'MPA', (65, 85))	('VIM', 'Gene', (129, 132))	('silencing', 'Var', (13, 22))
182023	32541686	5f, g), suggesting that EPN3 sustains TGFbeta-induced EMT also under physiological conditions, possibly by modulating ECAD endocytosis.	('ECAD endocytosis', 'Disease', (118, 134))	('ECAD endocytosis', 'Disease', 'None', (118, 134))	('modulating', 'Reg', (107, 117))	('EPN3', 'Var', (24, 28))	('EMT', 'CPA', (54, 57))	('TGFbeta-induced', 'Gene', (38, 53))
182032	32541686	These results were confirmed using a chemical inhibitor of the kinase activity of TGFbetaR1-2, LY2109761, which was able to revert the EPN3-dependent phenotypes (Supplementary Fig.	('revert', 'NegReg', (124, 130))	('LY2109761', 'Chemical', 'MESH:C530108', (95, 104))	('LY2109761', 'Var', (95, 104))	('EPN3-dependent phenotypes', 'MPA', (135, 160))	('TGFbetaR1-2', 'Gene', (82, 93))
182033	32541686	The EMT reversion upon TGFbetaR1 ablation and LY2109761 treatment was comparable with that achieved by silencing TCF4 (Fig.	('silencing', 'Var', (103, 112))	('TGFbetaR1', 'Gene', (23, 32))	('ablation', 'Var', (33, 41))	('LY2109761 treatment', 'Var', (46, 65))	('TCF4', 'Gene', (113, 117))	('EMT reversion', 'CPA', (4, 17))	('LY2109761', 'Chemical', 'MESH:C530108', (46, 55))
182034	32541686	Consistently, the EMT reversion upon TCF4 KD was observable in MCF10A-EPN3 cells both in basal and TGFbeta-stimulated conditions (Fig.	('EMT reversion', 'CPA', (18, 31))	('TCF4 KD', 'Var', (37, 44))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (63, 74))
182044	32541686	MCF10A-Ctr or -EPN1 cells displayed a very small percentage of these cells (0.1% and 0.4%, respectively); conversely MCF10A-EPN3 or -TWIST cells contained ~7% and 30% of this subpopulation, respectively (Fig.	('EPN1', 'Gene', (15, 19))	('MCF10A', 'CellLine', 'CVCL:0598', (117, 123))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('MCF10A-EPN3', 'Var', (117, 128))	('EPN1', 'Gene', '29924', (15, 19))	('TWIST', 'Gene', '7291', (133, 138))	('TWIST', 'Gene', (133, 138))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (117, 128))
182045	32541686	At the biological level, we employed the mammosphere (MS) assay, which can be utilized (with due caution) as a proxy for the detection of cells with stem-like properties In this assay, MCF10A-EPN3, similarly to MCF10A-TWIST, displayed a sphere-forming efficiency (SFE) at least tenfold higher than control or EPN1-overexpressing cells (Fig.	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (185, 196))	('MCF10A-EPN3', 'Var', (185, 196))	('sphere-forming efficiency', 'CPA', (237, 262))	('MCF10A-TWIST', 'Gene', (211, 223))	('higher', 'PosReg', (286, 292))	('EPN1', 'Gene', (309, 313))	('EPN1', 'Gene', '29924', (309, 313))	('MCF10A-TWIST', 'Gene', '7291', (211, 223))
182046	32541686	The increase in SFE in MCF10A-EPN3 vs. -Ctr (or -EPN1) significantly correlated with the increase in the CD44high/CD24low population (compare Fig.	('increase', 'PosReg', (89, 97))	('SFE', 'MPA', (16, 19))	('CD24', 'Gene', (114, 118))	('CD44', 'Gene', (105, 109))	('CD24', 'Gene', '100133941', (114, 118))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (23, 34))	('EPN1', 'Gene', (49, 53))	('EPN1', 'Gene', '29924', (49, 53))	('increase', 'PosReg', (4, 12))	('CD44', 'Gene', '960', (105, 109))	('MCF10A-EPN3', 'Var', (23, 34))
182048	32541686	Finally, the percentage of CD44high/CD24low CSC-like cells in MCF10A-EPN3 (or MCF10A-TWIST) was considerably reduced by TGFbetaR1 KD (Fig.	('MCF10A-TWIST', 'Gene', '7291', (78, 90))	('CD24', 'Gene', (36, 40))	('CD44', 'Gene', '960', (27, 31))	('MCF10A-EPN3', 'CellLine', 'CVCL:0598', (62, 73))	('TGFbetaR1 KD', 'Var', (120, 132))	('CD44', 'Gene', (27, 31))	('reduced', 'NegReg', (109, 116))	('MCF10A-TWIST', 'Gene', (78, 90))	('CD24', 'Gene', '100133941', (36, 40))
182053	32541686	Moreover, in DCIS, p63 marked the myoepithelial cell layer, while in IBC the majority of infiltrating cells became p63-positive, accompanied by a concomitant increase in alpha-SMA-positive fibroblasts in the stroma associated with IBC, as previously reported (Fig.	('alpha-SMA-positive', 'Protein', (170, 188))	('IBC', 'Disease', (231, 234))	('p63-positive', 'Var', (115, 127))	('rat', 'Species', '10116', (95, 98))	('p63', 'Var', (19, 22))	('increase', 'PosReg', (158, 166))
182089	32541686	Consistent with this, we showed that, consequent to EPN3-induced ECAD endocytosis, the beta-catenin/TCF4 pathway was directly involved in the acquisition of the transcriptional circuitry necessary to sustain the partial EMT.	('ECAD endocytosis', 'Disease', (65, 81))	('beta-catenin', 'Gene', (87, 99))	('involved', 'Reg', (126, 134))	('EPN3-induced', 'Var', (52, 64))	('beta-catenin', 'Gene', '1499', (87, 99))	('ECAD endocytosis', 'Disease', 'None', (65, 81))
182113	32541686	PCR reaction was run in LightCycler (LC) 480 real-time PCR instruments (Roche) using the following thermal cycling conditions: 1 cycle at 95  C for 30 s, 45 cycles at 95  C for 5 s and 60  C for 30 s. TaqMan gene expression assays, with short amplicon sizes, were as follows: Hs00978957_m1 (EPN3), Hs02800695_m1 (HPRT1), Hs03929097_g1 (GAPDH), Hs99999908_m1 (GUSB), and Hs00427621_m1 (TBP).	('GUSB', 'Gene', '2990', (359, 363))	('Hs99999908_m1', 'Var', (344, 357))	('GAPDH', 'Gene', '2597', (336, 341))	('TBP', 'Gene', (385, 388))	('TBP', 'Gene', '6908', (385, 388))	('Hs03929097_g1', 'Var', (321, 334))	('HPRT1', 'Gene', '3251', (313, 318))	('Hs00978957_m1', 'Var', (276, 289))	('HPRT1', 'Gene', (313, 318))	('Hs00427621_m1', 'Var', (370, 383))	('Hs02800695_m1', 'Var', (298, 311))	('GUSB', 'Gene', (359, 363))	('GAPDH', 'Gene', (336, 341))
182137	32541686	On the same cohort, we performed the initial comparative analysis of EPN3 amplification vs. overexpression (Fig.	('EPN3', 'Var', (69, 73))	('rat', 'Species', '10116', (50, 53))	('amplification', 'Var', (74, 87))
182153	32541686	Treatment with TGFbetaR kinase inhibitor LY2109761 (5 muM for 72 h), or with the same concentration of the vehicle DMSO, was performed on MCF10A cells at 40-50% confluency.	('muM', 'Gene', (54, 57))	('MCF10A', 'CellLine', 'CVCL:0598', (138, 144))	('LY2109761', 'Var', (41, 50))	('muM', 'Gene', '56925', (54, 57))	('LY2109761', 'Chemical', 'MESH:C530108', (41, 50))	('DMSO', 'Chemical', 'MESH:D004121', (115, 119))	('rat', 'Species', '10116', (93, 96))
182155	32541686	7), MCF10A-Ctr cells were infected with pSLIK-neo lentiviral construct expressing EPN3 (referred as EPN3dox) as or pSLIK-neo empty vector (Ctrdox).	('EPN3', 'Var', (82, 86))	('infected', 'Disease', 'MESH:D007239', (26, 34))	('MCF10A', 'CellLine', 'CVCL:0598', (4, 10))	('infected', 'Disease', (26, 34))
182162	32541686	Taqman gene expression assays were as follows: Hs00978957_m1 (EPN3), Hs00170423_m1 (CDH1), Hs00169953_m1 (CDH2), Hs00185584_m1 (VIM), Hs00998133_m1 (TGFB1), Hs00234244_m1 (TGFB2), Hs00610320_m1 (TGFBR1), Hs00234253_m1 (TGFBR2), Hs00232783_m1 (ZEB1), Hs99999903_m1 (ACTB), Hs99999901_s1 (18 S), and Hs99999905_m1 (GAPDH).	('GAPDH', 'Gene', (313, 318))	('TGFB1', 'Gene', '7040', (149, 154))	('CDH2', 'Gene', (106, 110))	('Hs00234253_m1', 'Var', (204, 217))	('TGFB2', 'Gene', (172, 177))	('TGFB1', 'Gene', (149, 154))	('Hs99999901_s1', 'Var', (272, 285))	('CDH1', 'Gene', '999', (84, 88))	('ACTB', 'Gene', (265, 269))	('Hs00234244_m1', 'Var', (157, 170))	('ACTB', 'Gene', '60', (265, 269))	('Hs00170423_m1', 'Var', (69, 82))	('TGFBR1', 'Gene', (195, 201))	('ZEB1', 'Gene', (243, 247))	('CDH1', 'Gene', (84, 88))	('CDH2', 'Gene', '1000', (106, 110))	('VIM', 'Gene', '7431', (128, 131))	('TGFBR1', 'Gene', '7046', (195, 201))	('Hs00169953_m1', 'Var', (91, 104))	('TGFBR2', 'Gene', (219, 225))	('VIM', 'Gene', (128, 131))	('Hs00610320_m1', 'Var', (180, 193))	('Hs00185584_m1', 'Var', (113, 126))	('Hs99999905_m1', 'Var', (298, 311))	('TGFBR2', 'Gene', '7048', (219, 225))	('Hs00232783_m1', 'Var', (228, 241))	('GAPDH', 'Gene', '2597', (313, 318))	('Hs00998133_m1', 'Var', (134, 147))	('Hs99999903_m1', 'Var', (250, 263))	('ZEB1', 'Gene', '6935', (243, 247))	('TGFB2', 'Gene', '7042', (172, 177))	('Hs00978957_m1', 'Var', (47, 60))
182167	32541686	PCR reaction was run in LightCycler (LC) 480 real-time PCR instruments (Roche) using the following thermal cycling conditions: 1 cycle at 95  C for 30 s, 45 cycles at 95  C for 5 s, and 60  C for 30 s. TaqMan gene expression assays were as follows: Hs00978957_m1 (human EPN3, RefSeq NM_017957.2, exon boundary 5-6, assay location 1328, amplicon length 62 bp) and Hs03929097_g1 (human GAPDH, RefSeq NM_001256799, exon boundary 8-8, assay location 1250, amplicon length 58 bp).	('GAPDH', 'Gene', (384, 389))	('human', 'Species', '9606', (378, 383))	('human', 'Species', '9606', (264, 269))	('Hs03929097_g1', 'Var', (363, 376))	('GAPDH', 'Gene', '2597', (384, 389))
182172	32541686	PCR was run in LightCycler (LC) 480 real-time PCR instruments (Roche) using the following thermal cycling conditions: 1 cycle at 95  C for 30 s, and 45 cycles at 95  C for 5 s and 60  C for 30 s. TaqMan copy number assays were as follows: Hs03036374_cn (human EPN3, Chr.17:48613920, amplicon length 77 bp) and Hs02803918_cn (human ERBB2, NG_007503.1, Chr.17:37881203, amplicon length 70 bp).	('Hs03036374_cn', 'Var', (239, 252))	('human', 'Species', '9606', (254, 259))	('ERBB2', 'Gene', (331, 336))	('ERBB2', 'Gene', '2064', (331, 336))	('Hs02803918_cn', 'Var', (310, 323))	('human', 'Species', '9606', (325, 330))
182225	32541686	5C, D) or 0.75 ng ml-1 of 125I-TGFbeta (Supplementary Fig.	('125I-TGFbeta', 'Var', (26, 38))	('ml-1', 'Gene', (18, 22))	('ml-1', 'Gene', '112744', (18, 22))
182288	32541686	The KI strategy is based on the targeted insertion of the human EPN3 cDNA (NM_017957.3) into the ROSA26 locus.	('rat', 'Species', '10116', (9, 12))	('human', 'Species', '9606', (58, 63))	('EPN3', 'Gene', (64, 68))	('insertion', 'Var', (41, 50))
182329	21600837	Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin (the "old drugs") to their presumed CSC molecular targets (the "new uses") within the network: chloroquine, by inhibiting autophagy, is expected to impede a crucial manner of energy production that allows CSCs to survive hypoxic and nutrient-deprived microen-vironments.	('metformin', 'Chemical', 'MESH:D008687', (80, 89))	('malaria', 'Disease', 'MESH:D008288', (37, 44))	('impede', 'NegReg', (238, 244))	('diabetic', 'Disease', (71, 79))	('chloroquine', 'Var', (185, 196))	('energy production', 'CPA', (265, 282))	('chloroquine', 'Chemical', 'MESH:D002738', (185, 196))	('malaria', 'Disease', (37, 44))	('inhibiting', 'NegReg', (201, 211))	('autophagy', 'CPA', (212, 221))	('chloroquine', 'Chemical', 'MESH:D002738', (46, 57))	('diabetic', 'Disease', 'MESH:D003920', (71, 79))
182336	21600837	On the contrary, deletion or monosomy of the ATG6/Beclin-1 gene significantly associates with ERBB2 oncogene amplification (both on 17q21) in a subset of BC.	('amplification', 'MPA', (109, 122))	('monosomy', 'Var', (29, 37))	('ATG6', 'Gene', (45, 49))	('ATG6', 'Gene', '8678', (45, 49))	('deletion', 'Var', (17, 25))	('ERBB2', 'Gene', '2064', (94, 99))	('associates', 'Reg', (78, 88))	('Beclin-1', 'Gene', (50, 58))	('ERBB2', 'Gene', (94, 99))	('Beclin-1', 'Gene', '8678', (50, 58))
182340	21600837	Defective autophagy imposed by loss of ATG6/Beclin-1 could promote the occurrence of ERBB2 gene amplification by increasing genomic instability.	('Beclin-1', 'Gene', (44, 52))	('Beclin-1', 'Gene', '8678', (44, 52))	('increasing', 'PosReg', (113, 123))	('loss', 'Var', (31, 35))	('ERBB2', 'Gene', (85, 90))	('ERBB2', 'Gene', '2064', (85, 90))	('promote', 'PosReg', (59, 66))	('ATG6', 'Gene', '8678', (39, 43))	('genomic instability', 'MPA', (124, 143))	('gene amplification', 'Var', (91, 109))	('ATG6', 'Gene', (39, 43))	('autophagy', 'CPA', (10, 19))
182341	21600837	Loss of ATG6/Beclin-1 may provide also an efficient mechanism to bypass ERBB2-induced OIS, thus enhancing the ability of ERBB2 to promote DCIS progression to IBC.	('promote', 'PosReg', (130, 137))	('Beclin-1', 'Gene', (13, 21))	('Beclin-1', 'Gene', '8678', (13, 21))	('DCIS progression', 'Disease', (138, 154))	('IBC', 'Disease', (158, 161))	('enhancing', 'PosReg', (96, 105))	('DCIS', 'Phenotype', 'HP:0030075', (138, 142))	('ERBB2', 'Gene', '2064', (72, 77))	('ATG6', 'Gene', (8, 12))	('ATG6', 'Gene', '8678', (8, 12))	('ERBB2', 'Gene', '2064', (121, 126))	('ERBB2', 'Gene', (72, 77))	('Loss', 'Var', (0, 4))	('ERBB2', 'Gene', (121, 126))
182345	21600837	This scenario may explain the following facts: (a) treatment with the anti-ERBB2 antibody trastuzumab induces both the activation of autophagy and the restoration of tumour suppressor responses to induce cell senescence in ERBB2/ATG6-positive models of advanced BC in vitro, and (b) loss of ATG6/Beclin-1 in ERBB2-positive BC predicts better responses to trastuzumab alone or in combination with cytotoxics in the presence of competent apoptosis or senescence pathways in advanced BC in vivo.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', (166, 172))	('ERBB2', 'Gene', '2064', (75, 80))	('ERBB2', 'Gene', (223, 228))	('autophagy', 'CPA', (133, 142))	('ERBB2', 'Gene', (308, 313))	('ERBB2', 'Gene', '2064', (223, 228))	('ATG6', 'Gene', '8678', (229, 233))	('loss', 'Var', (283, 287))	('trastuzumab', 'Chemical', 'MESH:D000068878', (355, 366))	('ATG6', 'Gene', (229, 233))	('responses', 'MPA', (342, 351))	('Beclin-1', 'Gene', '8678', (296, 304))	('better', 'PosReg', (335, 341))	('cell senescence', 'CPA', (204, 219))	('ERBB2', 'Gene', '2064', (308, 313))	('senescence', 'CPA', (449, 459))	('trastuzumab', 'Chemical', 'MESH:D000068878', (90, 101))	('activation', 'PosReg', (119, 129))	('apoptosis', 'Pathway', (436, 445))	('Beclin-1', 'Gene', (296, 304))	('ATG6', 'Gene', (291, 295))	('ATG6', 'Gene', '8678', (291, 295))	('ERBB2', 'Gene', (75, 80))	('cytotoxics', 'Disease', 'MESH:D064420', (396, 406))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('cytotoxics', 'Disease', (396, 406))
182370	21600837	RB depletion reduces E-cadherin expression, disrupts cell-cell adhesion and induces a mesenchymal-like phenotype in cultured BC cells by upregulating EMT-related transcription factors (e.g.	('reduces', 'NegReg', (13, 20))	('disrupts', 'NegReg', (44, 52))	('RB', 'Gene', '5925', (0, 2))	('upregulating', 'PosReg', (137, 149))	('mesenchymal-like phenotype', 'CPA', (86, 112))	('depletion', 'Var', (3, 12))	('induces', 'Reg', (76, 83))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('expression', 'MPA', (32, 42))	('cell-cell adhesion', 'CPA', (53, 71))
182375	21600837	via loss of the RB1 itself, loss of the p16INK4A locus, translocation of cyclin D1, etc.)	('RB1', 'Gene', '101101356', (16, 19))	('loss', 'Var', (28, 32))	('p16INK4A', 'Gene', (40, 48))	('RB1', 'Gene', (16, 19))	('p16INK4A', 'Gene', '1029', (40, 48))	('translocation', 'MPA', (56, 69))	('loss', 'NegReg', (4, 8))
182377	21600837	Moreover, abrogation of the RB tumour suppressor activity may cooperate with oncogenic signalling to promote EMT-related tumour cell invasion by suppressing, at the transcriptional level, the expression of CDH1 (E-cadherin) gene.	('tumour', 'Disease', (31, 37))	('promote', 'PosReg', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('CDH1', 'Gene', '999', (206, 210))	('expression', 'MPA', (192, 202))	('RB tumour', 'Disease', (28, 37))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('RB tumour', 'Disease', 'MESH:D012175', (28, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('E-cadherin', 'Gene', (212, 222))	('suppressing', 'NegReg', (145, 156))	('tumour', 'Disease', (121, 127))	('E-cadherin', 'Gene', '999', (212, 222))	('abrogation', 'Var', (10, 20))	('CDH1', 'Gene', (206, 210))
182379	21600837	Inhibition of the RB pathway can contribute to the invasive progression of pre-malignant lesions due to not only loss of cell proliferation control and decreased senescence but also reprogramming of somatic tumour cells to an undifferentiated CSC-like phenotype.	('senescence', 'CPA', (162, 172))	('tumour', 'Disease', (207, 213))	('reprogramming', 'CPA', (182, 195))	('cell proliferation control', 'CPA', (121, 147))	('RB', 'Gene', '5925', (18, 20))	('loss', 'NegReg', (113, 117))	('decreased', 'NegReg', (152, 161))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('Inhibition', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
182391	21600837	Of note, chloroquine-induced lysosomal dilatation not only would render autophagic recycling unproductive but it also may prevent, at least in part, the occurrence of the EMT process.	('prevent', 'NegReg', (122, 129))	('EMT process', 'CPA', (171, 182))	('lysosomal dilatation', 'CPA', (29, 49))	('dilatation', 'Phenotype', 'HP:0002617', (39, 49))	('autophagic recycling', 'CPA', (72, 92))	('chloroquine', 'Chemical', 'MESH:D002738', (9, 20))	('chloroquine-induced', 'Var', (9, 28))
182402	21600837	dose and/or time), a recently conducted retrospective study has reported an impressive 56% decrease in BC risk among diabetics receiving metformin compared with diabetics treated with other therapies.	('decrease', 'NegReg', (91, 99))	('metformin', 'Chemical', 'MESH:D008687', (137, 146))	('diabetics', 'Disease', 'MESH:D003920', (117, 126))	('diabetics', 'Disease', (161, 170))	('diabetics', 'Disease', (117, 126))	('metformin', 'Var', (137, 146))	('diabetics', 'Disease', 'MESH:D003920', (161, 170))
182427	21600837	Metformin has been shown to involve upregulation and maintenance of high levels of let-7a in well-differentiated, epithelioid BC cells exposed to the EMT inducer TGFbeta, thus epigenetically preserving the differentiated phenotype of mammary epithelium while preventing EMT-related CSC self-renewal.	('TGFbeta', 'Gene', '7040', (162, 169))	('upregulation', 'PosReg', (36, 48))	('preventing', 'NegReg', (259, 269))	('let-7a', 'Gene', (83, 89))	('EMT-related CSC self-renewal', 'CPA', (270, 298))	('epigenetically', 'Var', (176, 190))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('TGFbeta', 'Gene', (162, 169))	('differentiated phenotype of mammary epithelium', 'CPA', (206, 252))
182453	21600837	Metformin's ability to activate the metabolic-stress-sensing protein kinase AMPK is expected to stimulate autophagy because activation of AMPK will inhibit mTOR activity and blocking of mTOR is known stimulate autophagy, Only one study has shown that metformin induces autophagy in cancer cells whereas other AMPK activating drugs such as AICAR have been reported to inhibit autophagy instead.	('mTOR', 'Gene', (186, 190))	('mTOR', 'Gene', '2475', (156, 160))	('metformin', 'Var', (251, 260))	('AMPK', 'Gene', '5562', (309, 313))	('metformin', 'Chemical', 'MESH:D008687', (251, 260))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('AMPK', 'Gene', (138, 142))	('AMPK', 'Gene', (76, 80))	('induces', 'PosReg', (261, 268))	('autophagy', 'CPA', (269, 278))	('mTOR', 'Gene', '2475', (186, 190))	('inhibit', 'NegReg', (148, 155))	('AMPK', 'Gene', (309, 313))	('AMPK', 'Gene', '5562', (138, 142))	('cancer', 'Disease', (282, 288))	('AMPK', 'Gene', '5562', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('mTOR', 'Gene', (156, 160))
182454	21600837	Although it remains to be elucidated whether the effects of AMPK activating drugs on autophagy might be dose-, cell type-and/or context-dependent, it should be noted that metformin has been recently found to inhibit 2-deoxyglucose (2DG)-induced autophagy, decrease expression of beclin-1 and trigger a switch from an autophagic survival process to apoptotic cell death (,c).	('AMPK', 'Gene', '5562', (60, 64))	('metformin', 'Var', (171, 180))	('AMPK', 'Gene', (60, 64))	('inhibit', 'NegReg', (208, 215))	('beclin-1', 'Gene', (279, 287))	('2DG', 'Chemical', 'MESH:D003847', (232, 235))	('beclin-1', 'Gene', '8678', (279, 287))	('decrease', 'NegReg', (256, 264))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (216, 230))	('metformin', 'Chemical', 'MESH:D008687', (171, 180))	('expression', 'MPA', (265, 275))	('autophagy', 'CPA', (245, 254))	('switch', 'Reg', (302, 308))	('trigger', 'Reg', (292, 299))	('autophagic survival process', 'CPA', (317, 344))	('apoptotic cell death', 'CPA', (348, 368))
182470	21600837	This approach may be particularly relevant when considering that autophagy has a primary pro-survival role during tamoxifen challenge and that autophagy knockdown may be useful in a combination therapy setting to sensitize tumour cells to tamoxifen therapy.	('autophagy', 'CPA', (65, 74))	('autophagy', 'CPA', (143, 152))	('knockdown', 'Var', (153, 162))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('tamoxifen', 'Chemical', 'MESH:D013629', (239, 248))	('tamoxifen', 'Chemical', 'MESH:D013629', (114, 123))
182481	30678048	HME1 cells with genetic mutations hampering the physiological RA regulation of the RA receptor alpha (RARA) transcriptional function, but retain the RARA function controlling the PI3KCA-AKT signaling, develop 3D "DCIS-like" amorphous structures with upregulated ANXA8.	('upregulated', 'PosReg', (250, 261))	('RARA', 'Gene', (102, 106))	('RA', 'Chemical', 'MESH:D014212', (102, 104))	('AKT', 'Gene', '207', (186, 189))	('ANXA8', 'Gene', (262, 267))	('RA', 'Chemical', 'MESH:D014212', (151, 153))	('RA', 'Chemical', 'MESH:D014212', (62, 64))	('RA', 'Chemical', 'MESH:D014212', (104, 106))	('RARA', 'Gene', '5914', (149, 153))	('RA', 'Chemical', 'MESH:D014212', (83, 85))	('RA', 'Chemical', 'MESH:D014212', (149, 151))	('AKT', 'Gene', (186, 189))	('ANXA8', 'Gene', '653145', (262, 267))	('RARA', 'Gene', (149, 153))	('mutations', 'Var', (24, 33))	('RARA', 'Gene', '5914', (102, 106))	('hampering', 'NegReg', (34, 43))	('3D "DCIS-like" amorphous structures', 'CPA', (209, 244))
182482	30678048	Consistently, ectopic ANXA8 expression, by affecting the RARA transcriptional function, induced HME1 DCIS-like amorphous acini expressing phosphorylated AKT (P-AKT).	('affecting', 'Reg', (43, 52))	('AKT', 'Gene', '207', (160, 163))	('AKT', 'Gene', '207', (153, 156))	('RARA', 'Gene', '5914', (57, 61))	('ectopic', 'Var', (14, 21))	('AKT', 'Gene', (153, 156))	('HME1 DCIS-like amorphous acini', 'CPA', (96, 126))	('AKT', 'Gene', (160, 163))	('induced', 'PosReg', (88, 95))	('ANXA8', 'Gene', (22, 27))	('RARA', 'Gene', (57, 61))	('ANXA8', 'Gene', '653145', (22, 27))
182485	30678048	These miRNAs are candidate components of the RA-RARA-ANXA8 mechanism, and their deregulation might induce DCIS initiation.	('ANXA8', 'Gene', '653145', (53, 58))	('RARA', 'Gene', '5914', (48, 52))	('RA', 'Chemical', 'MESH:D014212', (45, 47))	('RA', 'Chemical', 'MESH:D014212', (48, 50))	('RARA', 'Gene', (48, 52))	('deregulation', 'Var', (80, 92))	('miR', 'Gene', (6, 9))	('ANXA8', 'Gene', (53, 58))	('miR', 'Gene', '22877', (6, 9))	('RA', 'Chemical', 'MESH:D014212', (50, 52))	('DCIS initiation', 'Disease', (106, 121))	('induce', 'Reg', (99, 105))
182492	30678048	In this study we used a panel of HME1 "DCIS-precursor" cell lines including the following lines: HME1-RARA403, expressing a dominant negative RARA mutant lacking the RA binding domain that affects the RARA transcriptional function, but it does not affect the RARA function controlling the PI3K-AKT signaling pathway; HME1-shERA with downregulated Estrogen Receptor alpha (ERA), a transcriptional regulator of RARA; HME1-shPER2 with down regulated PERIOD 2, a circadian clock gene with tumor suppressor function in breast cancer; HME1-shMTG16 with downregulation of MTG16, a tumor suppressor of breast cancer, HME1-MYC overexpressing the MYC oncogene that regulates RARA.	('RA', 'Chemical', 'MESH:D014212', (373, 375))	('mutant', 'Var', (147, 153))	('Estrogen Receptor alpha', 'Gene', '2099', (347, 370))	('tumor', 'Phenotype', 'HP:0002664', (485, 490))	('RARA', 'Gene', (665, 669))	('RARA', 'Gene', (409, 413))	('RA', 'Chemical', 'MESH:D014212', (325, 327))	('RA', 'Chemical', 'MESH:D014212', (261, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (594, 607))	('MYC', 'Gene', (637, 640))	('RARA', 'Gene', (201, 205))	('RA', 'Chemical', 'MESH:D014212', (142, 144))	('breast cancer', 'Disease', 'MESH:D001943', (514, 527))	('RA', 'Chemical', 'MESH:D014212', (259, 261))	('RA', 'Chemical', 'MESH:D014212', (166, 168))	('RA', 'Chemical', 'MESH:D014212', (665, 667))	('MTG16', 'Gene', '863', (536, 541))	('breast cancer', 'Disease', (514, 527))	('Estrogen Receptor alpha', 'Gene', (347, 370))	('MTG16', 'Gene', (565, 570))	('RA', 'Chemical', 'MESH:D014212', (411, 413))	('RA', 'Chemical', 'MESH:D014212', (102, 104))	('lacking', 'NegReg', (154, 161))	('RA', 'Chemical', 'MESH:D014212', (203, 205))	('breast cancer', 'Disease', 'MESH:D001943', (594, 607))	('RARA', 'Gene', '5914', (142, 146))	('AKT', 'Gene', '207', (294, 297))	('MYC', 'Gene', '4609', (614, 617))	('breast cancer', 'Disease', (594, 607))	('tumor', 'Disease', (574, 579))	('MTG16', 'Gene', '863', (565, 570))	('RARA', 'Gene', '5914', (102, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (514, 527))	('PERIOD 2', 'Gene', '8864', (447, 455))	('MYC', 'Gene', '4609', (637, 640))	('tumor', 'Disease', 'MESH:D009369', (574, 579))	('RA', 'Chemical', 'MESH:D014212', (409, 411))	('tumor', 'Disease', (485, 490))	('MYC', 'Gene', (614, 617))	('RARA', 'Gene', '5914', (259, 263))	('RARA', 'Gene', (142, 146))	('RA', 'Chemical', 'MESH:D014212', (201, 203))	('PER2', 'Gene', (422, 426))	('cancer', 'Phenotype', 'HP:0002664', (521, 527))	('RARA', 'Gene', '5914', (665, 669))	('RARA', 'Gene', '5914', (409, 413))	('tumor', 'Disease', 'MESH:D009369', (485, 490))	('RA', 'Chemical', 'MESH:D014212', (144, 146))	('PER2', 'Gene', '8864', (422, 426))	('RARA', 'Gene', (102, 106))	('RA', 'Chemical', 'MESH:D014212', (667, 669))	('cancer', 'Phenotype', 'HP:0002664', (601, 607))	('RA', 'Chemical', 'MESH:D014212', (104, 106))	('RARA', 'Gene', '5914', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (574, 579))	('downregulation', 'NegReg', (547, 561))	('PERIOD 2', 'Gene', (447, 455))	('RARA', 'Gene', (259, 263))	('AKT', 'Gene', (294, 297))	('MTG16', 'Gene', (536, 541))
182498	30678048	Based on the common protein signature of HME1"DCIS-precursor" cell lines with mutations that affect RA-RARA signaling, we identified by a stepwise approach (Figure 1) a set of protein-miRNA pairs, including ANXA8-miRNA pairs.	('RARA', 'Gene', '5914', (103, 107))	('miR', 'Gene', (213, 216))	('RA', 'Chemical', 'MESH:D014212', (103, 105))	('affect', 'Reg', (93, 99))	('RARA', 'Gene', (103, 107))	('miR', 'Gene', '22877', (184, 187))	('RA', 'Chemical', 'MESH:D014212', (100, 102))	('mutations', 'Var', (78, 87))	('miR', 'Gene', '22877', (213, 216))	('ANXA8', 'Gene', (207, 212))	('RA', 'Chemical', 'MESH:D014212', (105, 107))	('miR', 'Gene', (184, 187))	('ANXA8', 'Gene', '653145', (207, 212))
182502	30678048	Harnessing a common forty-two protein signature shared by HME1 "DCIS-precursor" cell lines with different mutations that we described previously, we set out to identify an in silico common miRNA signature.	('miR', 'Gene', '22877', (189, 192))	('mutations', 'Var', (106, 115))	('miR', 'Gene', (189, 192))
182520	30678048	Among these miRNAs, we found of particular interest miR-301A and miR-454, which belong to the same miRNA family and show concomitant amplification in almost 10% of patients, and miR-215 (amplified in over 12% of cases), which was found upregulated in serum of patients with metastatic breast cancer  As mentioned in the introduction, ANXA8 was found upregulated in acute promyelocytic leukemia (APL) carrying the dominant negative PML-RARA mutant, that, by inhibiting the RA- regulated normal RARA transcriptional function, blocks myeloid differentiation, and it is associated with a restricted signature of few miRNAs (e.g., miR-342-3p), that discriminates APL myeloblasts from normal promyelocytes.	('RARA', 'Gene', (435, 439))	('miR', 'Gene', '22877', (65, 68))	('APL', 'Disease', 'MESH:D015473', (395, 398))	('PML', 'Gene', (431, 434))	('mutant', 'Var', (440, 446))	('miR', 'Gene', '22877', (612, 615))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (365, 393))	('RARA', 'Gene', '5914', (493, 497))	('inhibiting', 'NegReg', (457, 467))	('miR-301A', 'Gene', (52, 60))	('ANXA8', 'Gene', '653145', (334, 339))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('miR-342', 'Gene', (626, 633))	('RA', 'Chemical', 'MESH:D014212', (435, 437))	('miR', 'Gene', (12, 15))	('miR', 'Gene', (99, 102))	('miR', 'Gene', (178, 181))	('miR', 'Gene', '22877', (626, 629))	('patients', 'Species', '9606', (260, 268))	('RA', 'Chemical', 'MESH:D014212', (472, 474))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('patients', 'Species', '9606', (164, 172))	('breast cancer', 'Disease', (285, 298))	('miR', 'Gene', (52, 55))	('APL', 'Disease', (658, 661))	('PML', 'Gene', '5371', (431, 434))	('RARA', 'Gene', (493, 497))	('APL', 'Disease', (395, 398))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('negative', 'NegReg', (422, 430))	('miR', 'Gene', '22877', (12, 15))	('miR-301A', 'Gene', '407027', (52, 60))	('leukemia', 'Phenotype', 'HP:0001909', (385, 393))	('ANXA8', 'Gene', (334, 339))	('RA', 'Chemical', 'MESH:D014212', (495, 497))	('miR', 'Gene', '22877', (99, 102))	('myeloid differentiation', 'CPA', (531, 554))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (365, 393))	('miR-342', 'Gene', '442909', (626, 633))	('miR', 'Gene', (65, 68))	('RA', 'Chemical', 'MESH:D014212', (493, 495))	('RARA', 'Gene', '5914', (435, 439))	('miR-454', 'Gene', (65, 72))	('miR', 'Gene', '22877', (178, 181))	('miR-215', 'Gene', '406997', (178, 185))	('miR', 'Gene', (612, 615))	('miR', 'Gene', '22877', (52, 55))	('acute promyelocytic leukemia', 'Disease', (365, 393))	('blocks', 'NegReg', (524, 530))	('miR-215', 'Gene', (178, 185))	('upregulated', 'PosReg', (350, 361))	('miR-454', 'Gene', '768216', (65, 72))	('RA', 'Chemical', 'MESH:D014212', (437, 439))	('APL', 'Disease', 'MESH:D015473', (658, 661))	('miR', 'Gene', (626, 629))
182523	30678048	In contrast the panel of HME1 lines with mutations that affect physiological RA-RARA transcriptional function (described in the Introduction and Material and Methods) developed 3D "DCIS-like" acinar structures expressing ANXA8 in all cells (confocal microscopy images in Figure 9A, right).	('mutations', 'Var', (41, 50))	('RA', 'Chemical', 'MESH:D014212', (80, 82))	('RARA', 'Gene', '5914', (80, 84))	('ANXA8', 'Gene', (221, 226))	('ANXA8', 'Gene', '653145', (221, 226))	('RARA', 'Gene', (80, 84))	('RA', 'Chemical', 'MESH:D014212', (77, 79))	('RA', 'Chemical', 'MESH:D014212', (82, 84))
182529	30678048	These findings imply that stable ectopic ANXA8 upregulation is per se sufficient to inhibit the physiological RA-RARA transcriptional function, but not the physiological RA-RARA function that regulates the activation of PI3KCA- AKT signaling pathway Based on these mechanistic studies, it seems that factors (e.g., genetic mutations) that hinder the physiological RA-RARA transcriptional mechanism increase ANXA8 expression that, in turn, reinforces a vicious circle of aberrant morphogenesis (Figure 9E).	('RA', 'Chemical', 'MESH:D014212', (175, 177))	('RA', 'Chemical', 'MESH:D014212', (110, 112))	('ANXA8', 'Gene', '653145', (41, 46))	('AKT', 'Gene', (228, 231))	('RA', 'Chemical', 'MESH:D014212', (173, 175))	('RARA', 'Gene', (113, 117))	('RARA', 'Gene', (367, 371))	('RA', 'Chemical', 'MESH:D014212', (364, 366))	('RA', 'Chemical', 'MESH:D014212', (369, 371))	('expression', 'MPA', (413, 423))	('ANXA8', 'Gene', (407, 412))	('mutations', 'Var', (323, 332))	('AKT', 'Gene', '207', (228, 231))	('ANXA8', 'Gene', (41, 46))	('RARA', 'Gene', '5914', (173, 177))	('RA', 'Chemical', 'MESH:D014212', (170, 172))	('RA', 'Chemical', 'MESH:D014212', (115, 117))	('RA', 'Chemical', 'MESH:D014212', (113, 115))	('RA', 'Chemical', 'MESH:D014212', (367, 369))	('RARA', 'Gene', '5914', (113, 117))	('RARA', 'Gene', '5914', (367, 371))	('RARA', 'Gene', (173, 177))	('increase', 'PosReg', (398, 406))	('ANXA8', 'Gene', '653145', (407, 412))
182530	30678048	As discussed hereafter not only genetic mutations affecting RA-RARA-ANXA8 feedback loop, but also other factors, as RA-regulated ANXA8 regulatory miRNAs (Figure 4 and Figure 10), might be involved in the regulation of ANXA8 during 3D mammary morphogenesis.	('RARA', 'Gene', '5914', (63, 67))	('ANXA8', 'Gene', '653145', (218, 223))	('ANXA8', 'Gene', (68, 73))	('involved', 'Reg', (188, 196))	('ANXA8', 'Gene', '653145', (68, 73))	('miR', 'Gene', '22877', (146, 149))	('RARA', 'Gene', (63, 67))	('RA', 'Chemical', 'MESH:D014212', (65, 67))	('RA', 'Chemical', 'MESH:D014212', (63, 65))	('mutations', 'Var', (40, 49))	('ANXA8', 'Gene', (218, 223))	('ANXA8', 'Gene', (129, 134))	('RA', 'Chemical', 'MESH:D014212', (116, 118))	('miR', 'Gene', (146, 149))	('RA', 'Chemical', 'MESH:D014212', (60, 62))	('ANXA8', 'Gene', '653145', (129, 134))
182532	30678048	In previous studies we found a restricted protein signature of 42 proteins including 22 upregulated proteins shared by five HME1 "DCIS-precursor" lines with different genetic mutations that increased the expression of ANXA8, a Ca2+ and phospholipid binding protein, which is regulated by all-trans Retinoic Acid (RA).	('upregulated', 'PosReg', (88, 99))	('Ca2+', 'Chemical', 'MESH:D000069285', (227, 231))	('increased', 'PosReg', (190, 199))	('RA', 'Chemical', 'MESH:D014212', (313, 315))	('Retinoic Acid', 'Chemical', 'MESH:D014212', (298, 311))	('mutations', 'Var', (175, 184))	('ANXA8', 'Gene', (218, 223))	('expression', 'MPA', (204, 214))	('ANXA8', 'Gene', '653145', (218, 223))
182537	30678048	Moreover we found that high ANXA8 expression is also associated with clinical features of breast cancer progression (e.g., positive nodes, tumor stage, and tumor grade).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('ANXA8', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('ANXA8', 'Gene', '653145', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('breast cancer', 'Disease', (90, 103))	('associated', 'Reg', (53, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumor', 'Disease', (156, 161))
182542	30678048	Consistently, ectopic expression of ANXA8 in HME1 cells, stably expressing RARE-GFP (HME1-ANXA8GFP), is per se capable of hampering the physiological RARA transcriptional function indispensable for lumen formation, but does not affect the induction of P-AKT due to RA-RARA induced PI3KCA-AKT activation.	('AKT', 'Gene', (254, 257))	('AKT', 'Gene', '207', (288, 291))	('ANXA8', 'Gene', (36, 41))	('ectopic expression', 'Var', (14, 32))	('ANXA8', 'Gene', (90, 95))	('RA', 'Chemical', 'MESH:D014212', (268, 270))	('RA', 'Chemical', 'MESH:D014212', (75, 77))	('RARA', 'Gene', '5914', (150, 154))	('AKT', 'Gene', '207', (254, 257))	('RARA', 'Gene', '5914', (268, 272))	('RA', 'Chemical', 'MESH:D014212', (265, 267))	('hampering', 'NegReg', (122, 131))	('AKT', 'Gene', (288, 291))	('ANXA8', 'Gene', '653145', (36, 41))	('RARA', 'Gene', (150, 154))	('RARA', 'Gene', (268, 272))	('RA', 'Chemical', 'MESH:D014212', (152, 154))	('ANXA8', 'Gene', '653145', (90, 95))	('RA', 'Chemical', 'MESH:D014212', (150, 152))	('RA', 'Chemical', 'MESH:D014212', (270, 272))
182548	30678048	ANXA8 upregulation in different DCIS contexts may be due to either genetic mutations affecting RA-RARA transcriptional function as shown in this study, but also to epigenetic factors like RA-regulated ANXA8 regulatory miRNAs.	('RARA', 'Gene', (98, 102))	('transcriptional function', 'MPA', (103, 127))	('ANXA8', 'Gene', (0, 5))	('ANXA8', 'Gene', '653145', (0, 5))	('RA', 'Chemical', 'MESH:D014212', (98, 100))	('miR', 'Gene', (218, 221))	('RA', 'Chemical', 'MESH:D014212', (100, 102))	('miR', 'Gene', '22877', (218, 221))	('ANXA8', 'Gene', (201, 206))	('mutations', 'Var', (75, 84))	('RARA', 'Gene', '5914', (98, 102))	('upregulation', 'PosReg', (6, 18))	('RA', 'Chemical', 'MESH:D014212', (95, 97))	('RA', 'Chemical', 'MESH:D014212', (188, 190))	('ANXA8', 'Gene', '653145', (201, 206))
182558	30678048	The HME1-derived stable clonal lines (in this study often referred to as HME1 "DCIS-precursor" cell lines) include cell lines that we developed for different studies: HME1-RARA403 expressing a dominant negative RARA-403 mutant; HME1-shERA with Estrogen Receptor alpha downregulation; HME1-shPER2 with down regulation of PER2; HME1-shMTG16 with downregulation of the tumor suppressor MTG16; HME1-MYC overexpressing MYC oncogene; HME1-ANXA8 expressing Annexin A8; HME1-ANXA8 carrying a RARE-GFP (this manuscript).	('RA', 'Chemical', 'MESH:D014212', (213, 215))	('ANXA8', 'Gene', (433, 438))	('RARA', 'Gene', (172, 176))	('RA', 'Chemical', 'MESH:D014212', (484, 486))	('downregulation', 'NegReg', (268, 282))	('MYC', 'Gene', '4609', (395, 398))	('RA', 'Chemical', 'MESH:D014212', (236, 238))	('MTG16', 'Gene', (383, 388))	('Estrogen Receptor alpha', 'Gene', '2099', (244, 267))	('negative', 'NegReg', (202, 210))	('RA', 'Chemical', 'MESH:D014212', (172, 174))	('ANXA8', 'Gene', '653145', (467, 472))	('MYC', 'Gene', (414, 417))	('PER2', 'Gene', (291, 295))	('RA', 'Chemical', 'MESH:D014212', (211, 213))	('MTG16', 'Gene', '863', (383, 388))	('Estrogen Receptor alpha', 'Gene', (244, 267))	('Annexin A8', 'Gene', (450, 460))	('tumor', 'Disease', (366, 371))	('PER2', 'Gene', '8864', (291, 295))	('MTG16', 'Gene', (333, 338))	('ANXA8', 'Gene', '653145', (433, 438))	('RARA', 'Gene', '5914', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('down regulation', 'NegReg', (301, 316))	('Annexin A8', 'Gene', '653145', (450, 460))	('MYC', 'Gene', '4609', (414, 417))	('RARA', 'Gene', '5914', (172, 176))	('ANXA8', 'Gene', (467, 472))	('PER2', 'Gene', (320, 324))	('MYC', 'Gene', (395, 398))	('mutant', 'Var', (220, 226))	('MTG16', 'Gene', '863', (333, 338))	('PER2', 'Gene', '8864', (320, 324))	('RARA', 'Gene', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('RA', 'Chemical', 'MESH:D014212', (174, 176))
182571	30678048	The analysis was performed with default settings on the following genomic profiles: mutations, putative copy-number alterations from GISTIC, and a user-defined gene set containing the miRNAs listed in Figure 5.	('mutations', 'Var', (84, 93))	('miR', 'Gene', '22877', (184, 187))	('miR', 'Gene', (184, 187))	('copy-number alterations', 'Var', (104, 127))
182621	27247112	Although no significant correlation between BRIM subtype and nuclear grade or estrogen receptor status was observed, the average age of patients whose samples had low BRIM scores (50 yrs) was significantly (P < 0.05) less than those with high BRIM scores (64 yrs) (Supplementary Table 1), which is consistent with recent studies.	('less', 'NegReg', (217, 221))	('patients', 'Species', '9606', (136, 144))	('low', 'Var', (163, 166))
182648	27247112	The primary antibodies used in these studies were: Ms anti-N-Cadherin (Abcam ab98952), Rb anti-E-Cadherin (Abcam ab15148), Ms anti-CD74 (Abcam ab9514), Rb anti-CD59 (Abcam ab133707), Rb anti-CD44 (Abcam ab41478), Ms anti-CD24 (Biolegend 311102).	('CD24', 'Gene', (221, 225))	('Abcam', 'Var', (137, 142))	('CD59', 'Gene', (160, 164))	('E-Cadherin', 'Gene', (95, 105))	('CD59', 'Gene', '966', (160, 164))	('Abcam', 'Var', (166, 171))	('E-Cadherin', 'Gene', '999', (95, 105))	('CD74', 'Gene', '972', (131, 135))	('CD74', 'Gene', (131, 135))	('N-Cadherin', 'Gene', (59, 69))	('N-Cadherin', 'Gene', '1000', (59, 69))	('CD24', 'Gene', '100133941', (221, 225))	('Abcam', 'Var', (197, 202))	('CD44', 'Gene', '960', (191, 195))	('CD44', 'Gene', (191, 195))
182657	27247112	To avoid cross-talk between the emission wavelengths of the fluorescent tags, band-pass filters with the "sharpest" cut-offs and greatest out-of-band reflectances were used (Chroma ET-fluorescein filter set (#49011) and Chroma ET-Cy3/rhodamine filter set (#49004) (Chroma Tech.	('Chroma Tech', 'Disease', (265, 276))	('Chroma Tech', 'Disease', 'None', (265, 276))	('Chroma', 'Disease', (220, 226))	('Chroma', 'Disease', (265, 271))	('ET-Cy3', 'Chemical', '-', (227, 233))	('Chroma', 'Disease', 'None', (174, 180))	('#49011', 'Var', (208, 214))	('#49004', 'Var', (256, 262))	('ET-fluorescein', 'Chemical', '-', (181, 195))	('Chroma', 'Disease', 'None', (220, 226))	('rhodamine', 'Chemical', 'MESH:D012235', (234, 243))	('Chroma', 'Disease', (174, 180))	('Chroma', 'Disease', 'None', (265, 271))
182719	21552384	Zhou et al examined the relationship between triple-negative DCIS (negative for ER, PR, and HER2; also known as basal-like breast cancer) and risk of local recurrence.	('local recurrence', 'CPA', (150, 166))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('ER', 'Gene', '2099', (80, 82))	('HER2', 'Gene', (92, 96))	('PR', 'Gene', '5241', (84, 86))	('triple-negative', 'Var', (45, 60))	('ER', 'Gene', '2099', (93, 95))	('HER2', 'Gene', '2064', (92, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
182722	21552384	The authors compared the 32 patients with triple-negative DCIS with the 360 patients with other phenotypes and found that patients with basal-like DCIS had a higher risk of local recurrence.	('patients', 'Species', '9606', (76, 84))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('triple-negative', 'Var', (42, 57))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('patients', 'Species', '9606', (122, 130))	('local recurrence', 'CPA', (173, 189))	('patients', 'Species', '9606', (28, 36))
182767	21552384	As mentioned previously, Ringberg et al found that a cell biological index that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression was a strong predictor of recurrence.	('low', 'NegReg', (135, 138))	('accumulation', 'PosReg', (157, 169))	('nondiploidy', 'Var', (178, 189))	('p53', 'Gene', (173, 176))	('HER2', 'Gene', (129, 133))	('expression', 'MPA', (206, 216))	('Bcl-2', 'Gene', (139, 144))	('p53', 'Gene', '7157', (173, 176))	('Bcl-2', 'Gene', '596', (139, 144))	('HER2', 'Gene', '2064', (129, 133))	('expression', 'MPA', (145, 155))	('Ki-67', 'Gene', (200, 205))	('ER', 'Gene', '2099', (130, 132))	('overexpression', 'PosReg', (111, 125))	('ER', 'Gene', '2099', (89, 91))	('PR', 'Gene', '5241', (96, 98))
182771	21552384	Hanley et al found that unlike expression of the other steroid receptors, ER and PR, expression of AR was slightly higher in high-grade DCIS than in non-high-grade DCIS, although the difference was not significant (93% vs. 89%).	('DCIS', 'Phenotype', 'HP:0030075', (136, 140))	('expression', 'MPA', (85, 95))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('AR', 'Gene', '367', (99, 101))	('PR', 'Gene', '5241', (81, 83))	('ER', 'Gene', '2099', (74, 76))	('higher', 'PosReg', (115, 121))	('high-grade DCIS', 'Var', (125, 140))
182787	21552384	Ki-67 was individually associated with DCIS recurrence, and the phenotypes Ki-67+ER- , Ki-67+p16+, and Ki-67+p16+COX-2+ were also associated with DCIS recurrence.	('Ki-67', 'Var', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (39, 43))	('p16', 'Gene', (109, 112))	('p16', 'Gene', '1029', (93, 96))	('ER', 'Gene', '2099', (81, 83))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('DCIS recurrence', 'Disease', (146, 161))	('p16', 'Gene', (93, 96))	('p16', 'Gene', '1029', (109, 112))	('COX-2', 'Gene', (113, 118))	('associated', 'Reg', (23, 33))	('DCIS recurrence', 'Disease', (39, 54))	('COX-2', 'Gene', '5743', (113, 118))	('associated', 'Reg', (130, 140))
182792	21552384	Overexpression of cyclin D1 is commonly seen in breast cancer, but it has also been identified in many other tumors.	('cyclin D1', 'Gene', (18, 27))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cyclin D1', 'Gene', '595', (18, 27))	('breast cancer', 'Disease', (48, 61))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
182798	21552384	Patients with low cyclin D1 fraction had a higher risk of ipsilateral local recurrence than patients with high cyclin D1 fraction (32.3% vs. 18.2%, P=0.002, Table 9).	('cyclin D1', 'Gene', (18, 27))	('cyclin D1', 'Gene', (111, 120))	('patients', 'Species', '9606', (92, 100))	('ipsilateral local recurrence', 'CPA', (58, 86))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (14, 17))	('cyclin D1', 'Gene', '595', (18, 27))	('cyclin D1', 'Gene', '595', (111, 120))
182816	21552384	Interestingly, Gauthier et al reported that among patients with high p16 expression and high COX-2 expression, patients with high proliferative activity were more likely to have a local-regional recurrence than patients with low proliferative activity.	('COX-2', 'Gene', (93, 98))	('expression', 'MPA', (99, 109))	('high', 'Var', (88, 92))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (50, 58))	('COX-2', 'Gene', '5743', (93, 98))	('p16', 'Gene', (69, 72))	('local-regional recurrence', 'CPA', (180, 205))	('p16', 'Gene', '1029', (69, 72))	('patients', 'Species', '9606', (111, 119))
182835	21552384	In recent breast cancer studies, loss of p27 has been associated with poor patient outcome.	('p27', 'Gene', '3429', (41, 44))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('p27', 'Gene', (41, 44))	('breast cancer', 'Disease', (10, 23))	('loss', 'Var', (33, 37))	('patient', 'Species', '9606', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
182840	21552384	In the same study, no association was observed between p27 positivity and cyclin A positivity or between cyclin A positivity and cyclin D1 positivity.	('cyclin A', 'Gene', '890', (74, 82))	('cyclin A', 'Gene', '890', (105, 113))	('cyclin D1', 'Gene', '595', (129, 138))	('positivity', 'Var', (59, 69))	('p27', 'Gene', '3429', (55, 58))	('cyclin D1', 'Gene', (129, 138))	('p27', 'Gene', (55, 58))	('positivity', 'Var', (83, 93))	('cyclin A', 'Gene', (74, 82))	('cyclin A', 'Gene', (105, 113))
182845	21552384	A mutation of p53 can compromise its function.	('function', 'MPA', (37, 45))	('mutation', 'Var', (2, 10))	('compromise', 'NegReg', (22, 32))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))
182846	21552384	P53 mutations are common in many cancers and occur in approximately 20% of breast carcinomas.	('common', 'Reg', (18, 24))	('breast carcinomas', 'Disease', (75, 92))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('breast carcinomas', 'Phenotype', 'HP:0003002', (75, 92))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('occur', 'Reg', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))	('breast carcinomas', 'Disease', 'MESH:D001943', (75, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
182855	21552384	Ringberg et al used principal components analysis to evaluate a cell biological index that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression.	('low', 'NegReg', (146, 149))	('PR', 'Gene', '5241', (107, 109))	('ER', 'Gene', '2099', (141, 143))	('accumulation', 'PosReg', (168, 180))	('ER', 'Gene', '2099', (100, 102))	('nondiploidy', 'Var', (189, 200))	('expression', 'MPA', (217, 227))	('overexpression', 'PosReg', (122, 136))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('Ki-67', 'Protein', (211, 216))	('HER2', 'Gene', (140, 144))	('expression', 'MPA', (156, 166))	('Bcl-2', 'Gene', (150, 155))	('Bcl-2', 'Gene', '596', (150, 155))	('HER2', 'Gene', '2064', (140, 144))
182861	21552384	A deregulation in apoptosis due to imbalances in Bcl-2 expression has been associated with the pathogenesis of breast cancer.	('Bcl-2', 'Gene', (49, 54))	('Bcl-2', 'Gene', '596', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (55, 65))	('imbalances', 'Phenotype', 'HP:0002172', (35, 45))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('apoptosis', 'CPA', (18, 27))	('breast cancer', 'Disease', (111, 124))	('associated', 'Reg', (75, 85))	('imbalances', 'Var', (35, 45))
182915	21552384	Provenzano et al, in a nested case-control study, found HER2 positivity to be individually associated with disease recurrence.	('disease recurrence', 'Disease', (107, 125))	('HER2', 'Gene', (56, 60))	('HER2', 'Gene', '2064', (56, 60))	('positivity', 'Var', (61, 71))	('associated with', 'Reg', (91, 106))
182917	21552384	Kepple et al reported that HER2 positivity was an independent predictor of local-regional recurrence and that HER2 positivity in association with ER positivity was also a predictor of local-regional recurrence.	('ER', 'Gene', '2099', (28, 30))	('local-regional recurrence', 'CPA', (184, 209))	('local-regional recurrence', 'CPA', (75, 100))	('ER', 'Gene', '2099', (111, 113))	('ER', 'Gene', '2099', (146, 148))	('positivity', 'Var', (115, 125))	('positivity', 'Var', (32, 42))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', (27, 31))	('HER2', 'Gene', '2064', (110, 114))	('HER2', 'Gene', '2064', (27, 31))
182934	21552384	Barnes et al reported similar findings for HER1 and HER3; however, they observed that HER4 negativity was an independent predictor of recurrence.	('HER3', 'Gene', (52, 56))	('negativity', 'Var', (91, 101))	('HER3', 'Gene', '2065', (52, 56))	('HER1', 'Gene', (43, 47))	('HER4', 'Gene', '2066', (86, 90))	('HER1', 'Gene', '1956', (43, 47))	('HER4', 'Gene', (86, 90))
182958	21552384	COX-2 overexpression has been shown to be upregulated in neoplastic and preneoplastic lesions in the breast.	('preneoplastic lesions', 'CPA', (72, 93))	('overexpression', 'Var', (6, 20))	('neoplastic', 'Disease', (57, 67))	('upregulated', 'PosReg', (42, 53))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))
182968	21552384	Another study found COX-2 expression to be significantly associated with high Ki-67 expression, ER negativity, and HER2 positivity.	('HER2', 'Gene', (115, 119))	('ER', 'Gene', '2099', (96, 98))	('ER', 'Gene', '2099', (116, 118))	('HER2', 'Gene', '2064', (115, 119))	('COX-2', 'Gene', (20, 25))	('expression', 'MPA', (84, 94))	('high', 'Var', (73, 77))	('COX-2', 'Gene', '5743', (20, 25))	('Ki-67', 'Gene', (78, 83))	('positivity', 'Var', (120, 130))	('associated', 'Reg', (57, 67))
182973	21552384	In addition, co-expression of COX-2 and cytoplasmic survivin was found in 70% of the recurrent cases, whereas none of the cases lacking expression of both of those biomarkers recurred within 5 years.	('COX-2', 'Gene', (30, 35))	('COX-2', 'Gene', '5743', (30, 35))	('co-expression', 'Var', (13, 26))	('found', 'Reg', (65, 70))
183099	16807982	As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it might be considered as a significant prognostic indicator for invasive ductal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (152, 177))	('MT1-MMP', 'Gene', (3, 10))	('MT1-MMP', 'Gene', '4323', (3, 10))	('invasive ductal carcinoma', 'Disease', (152, 177))	('correlated', 'Reg', (44, 54))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (161, 177))	('axillary nodal metastasis', 'Disease', (60, 85))	('axillary nodal metastasis', 'Disease', 'MESH:D009362', (60, 85))	('mRNA expression', 'Var', (11, 26))
183107	24680897	Some of the earliest characterized lncRNAs regulate distinct epigenetic processes that are critical for embryonic development, such as the regulation of genomic imprinting by H19 and X-inactivation by Xist.	('X-inactivation', 'Var', (183, 197))	('regulate', 'Reg', (43, 51))	('Xist', 'Gene', (201, 205))	('epigenetic processes', 'MPA', (61, 81))	('Xist', 'Gene', '7503', (201, 205))
183117	24680897	Cancer is thought to arise and progress due to genetic alterations that disrupt processes required for maintaining normal cellular homeostasis, such as cell cycle, DNA damage response, survival, and migration.	('DNA', 'MPA', (164, 167))	('survival', 'CPA', (185, 193))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell cycle', 'CPA', (152, 162))	('genetic alterations', 'Var', (47, 66))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('migration', 'CPA', (199, 208))
183132	24680897	Initial in vitro studies showed that knockdown of either mPINC or Zfas1 in HC11 cells, a mammary epithelial cell line derived from a mid-pregnant mouse, led to increased proliferation, suggesting growth-suppressive roles.	('mPINC', 'Gene', (57, 62))	('increased', 'PosReg', (160, 169))	('knockdown', 'Var', (37, 46))	('proliferation', 'CPA', (170, 183))	('Zfas1', 'Gene', (66, 71))	('HC11', 'CellLine', 'CVCL:0288', (75, 79))
183137	24680897	Patients with HER2-positive tumors have genomic amplification and overexpression of the HER2 oncogene and are, therefore, treated with HER2 monoclonal antibodies to disrupt HER2 signaling.	('HER2 oncogene', 'Gene', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('Patients', 'Species', '9606', (0, 8))	('HER2-positive tumors', 'Disease', 'MESH:D009369', (14, 34))	('HER2-positive tumors', 'Disease', (14, 34))	('overexpression', 'PosReg', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('genomic amplification', 'Var', (40, 61))
183160	24680897	Futhermore, LncRNA-JADE knockdown in breast cancer cells orthotopically transplanted into the mouse mammary fat pad reduces tumor growth compared to control cells, and in humans, LncRNA-JADE is expressed at higher levels in breast tumors compared to normal breast.	('reduces', 'NegReg', (116, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('breast', 'Disease', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('LncRNA-JADE', 'Gene', (12, 23))	('breast tumors', 'Phenotype', 'HP:0100013', (224, 237))	('humans', 'Species', '9606', (171, 177))	('LncRNA-JADE', 'Var', (179, 190))	('breast tumor', 'Phenotype', 'HP:0100013', (224, 236))	('tumor growth', 'CPA', (124, 136))	('knockdown', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('higher', 'PosReg', (207, 213))
183163	24680897	In the cytoplasm, treRNA interacts with a ribonucleoprotein complex and suppresses the translation of the epithelial marker E-cadherin, which should also promote EMT.	('translation', 'MPA', (87, 98))	('treRNA', 'Var', (18, 24))	('promote', 'PosReg', (154, 161))	('EMT', 'CPA', (162, 165))	('interacts', 'Interaction', (25, 34))	('suppresses', 'NegReg', (72, 82))	('E-cadherin', 'Gene', (124, 134))	('E-cadherin', 'Gene', '999', (124, 134))
183169	24680897	Interestingly, these genetic alterations are in the region of MALAT1 thought to be important for its interaction with SRSF1, implicating a splicing mechanism in the potential oncogenic role of MALAT1 in luminal breast cancer.	('MALAT1', 'Gene', (62, 68))	('luminal breast cancer', 'Disease', (203, 224))	('luminal breast cancer', 'Disease', 'MESH:D001943', (203, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('implicating', 'Reg', (125, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('genetic alterations', 'Var', (21, 40))
183176	24680897	Conversely, miR-675 can also promote growth and tumorigenesis by targeting and repressing the tumor suppressor RB1.	('promote', 'PosReg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('RB1', 'Gene', (111, 114))	('RB1', 'Gene', '5925', (111, 114))	('tumorigenesis', 'CPA', (48, 61))	('repressing', 'NegReg', (79, 89))	('miR-675', 'Var', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
183179	24680897	In addition, siRNA knockdown of H19 reduces the clonogenicity and anchorage-independent growth of multiple breast cancer cell lines, both indicators of cellular transformation.	('knockdown', 'Var', (19, 28))	('clonogenicity', 'CPA', (48, 61))	('anchorage-independent growth', 'CPA', (66, 94))	('H19', 'Gene', (32, 35))	('multiple breast cancer', 'Disease', (98, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('reduces', 'NegReg', (36, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('multiple breast cancer', 'Disease', 'MESH:D001943', (98, 120))
183204	25471940	Tubular formation was assessed over the whole tumour; nuclear pleomorphism was evaluated in the area showing the highest degree of pleomorphism, and mitotic counting was performed in the area exhibiting most proliferation.	('pleomorphism', 'Var', (131, 143))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
183214	25471940	There was no significant difference in single or mixed growth pattern between pure DCIS and DCIS associated with invasive carcinoma (p = 0.088).	('invasive carcinoma', 'Disease', (113, 131))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('invasive carcinoma', 'Disease', 'MESH:D009361', (113, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('pure DCIS', 'Var', (78, 87))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))
183215	25471940	There was no significant difference in nuclear grade between pure DCIS and DCIS associated with invasive carcinoma (p = 0.142).	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('pure', 'Var', (61, 65))	('invasive carcinoma', 'Disease', (96, 114))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('associated', 'Reg', (80, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('invasive carcinoma', 'Disease', 'MESH:D009361', (96, 114))
183243	25471940	This group of younger patients may have an increased risk of local recurrence when treated with breast-conserving therapy due to a greater proportion of high nuclear grade DCIS and presence of comedonecrosis.	('necrosis', 'Disease', (199, 207))	('high nuclear grade', 'Var', (153, 171))	('comedo', 'Phenotype', 'HP:0025249', (193, 199))	('patients', 'Species', '9606', (22, 30))	('necrosis', 'Disease', 'MESH:D009336', (199, 207))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('local', 'CPA', (61, 66))
183244	25471940	Maybe the association of high nuclear grade DCIS, comedonecrosis and younger patients can guide the clinicians to perform more aggressive surgical treatments, as these factors are associated with local recurrence.	('comedo', 'Phenotype', 'HP:0025249', (50, 56))	('associated', 'Reg', (180, 190))	('necrosis', 'Disease', (56, 64))	('patients', 'Species', '9606', (77, 85))	('high nuclear', 'Var', (25, 37))	('necrosis', 'Disease', 'MESH:D009336', (56, 64))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))
183245	25471940	The high nuclear grade and the presence of comedonecrosis were identified more frequently in DCIS of younger patients and more often correlated with the solid pattern DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (167, 171))	('necrosis', 'Disease', (49, 57))	('solid pattern DCIS', 'Disease', (153, 171))	('patients', 'Species', '9606', (109, 117))	('DCIS', 'Disease', (93, 97))	('necrosis', 'Disease', 'MESH:D009336', (49, 57))	('comedo', 'Phenotype', 'HP:0025249', (43, 49))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('high', 'Var', (4, 8))	('correlated', 'Reg', (133, 143))
183258	24681547	Systemic administration of CDH11 antibodies reverses the proliferation and migration of synoviocytes to the sites of joint inflammation and attenuates symptoms of RA.	('attenuates', 'NegReg', (140, 150))	('RA', 'Disease', 'MESH:D001172', (163, 165))	('joint inflammation', 'Phenotype', 'HP:0001369', (117, 135))	('joint inflammation', 'Disease', (117, 135))	('symptoms', 'MPA', (151, 159))	('CDH11', 'Gene', (27, 32))	('reverses', 'NegReg', (44, 52))	('joint inflammation', 'Disease', 'MESH:D007249', (117, 135))	('proliferation', 'CPA', (57, 70))	('migration', 'CPA', (75, 84))	('antibodies', 'Var', (33, 43))
183259	24681547	As CDH11 antibody based therapeutics are in clinical trials for RA and we showed recently that the arthritis drug celecoxib has the structural potential to bind CDH11, there is a strong possibility that, if CDH11 can be shown to drive malignant progression rather than simply be associated with it, therapeutic options may be rapidly developed.	('drive', 'PosReg', (229, 234))	('CDH11', 'Gene', (161, 166))	('malignant progression', 'CPA', (235, 256))	('arthritis', 'Phenotype', 'HP:0001369', (99, 108))	('bind', 'Interaction', (156, 160))	('arthritis', 'Disease', (99, 108))	('CDH11', 'Var', (207, 212))	('RA', 'Disease', 'MESH:D001172', (64, 66))	('celecoxib', 'Chemical', 'MESH:D000068579', (114, 123))	('arthritis', 'Disease', 'MESH:D001168', (99, 108))
183260	24681547	For example, CDH11 expression promotes the formation of skeletal metastases in models of prostate cancer and can regulate glioma survival and migration .	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('CDH11', 'Gene', (13, 18))	('regulate', 'Reg', (113, 121))	('promotes', 'PosReg', (30, 38))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('prostate cancer', 'Disease', (89, 104))	('expression', 'Var', (19, 29))	('glioma', 'Disease', (122, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('metastases', 'Disease', (65, 75))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
183275	24681547	Anti-CDH11 antibody therapy significantly inhibited the growth of newly injected xenografts (Figure 1E) and of established tumors compared to control mice (Figure 1F).	('mice', 'Species', '10090', (150, 154))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Anti-CDH11', 'Var', (0, 10))	('growth of newly injected xenografts', 'CPA', (56, 91))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
183278	24681547	To address this, we used siRNA to knock down CDH11 in MDA-MB-231 cells.	('CDH11', 'Gene', (45, 50))	('knock down', 'Var', (34, 44))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (54, 64))
183280	24681547	Stable cell lines containing shRNA target sequences displayed a significant delay to onset of tumor growth compared to empty vector or scrambled controls.	('sequences', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('eq', 'Chemical', '-', (43, 45))	('tumor', 'Disease', (94, 99))	('delay', 'NegReg', (76, 81))
183284	24681547	CDH11 knockdown in PC3 prostate cancer cells (Figure 2D) also resulted in reduced growth, but fell short of significance (Figure 2E).	('CDH11', 'Gene', (0, 5))	('PC3', 'Gene', (19, 22))	('prostate cancer', 'Disease', (23, 38))	('growth', 'MPA', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('PC3', 'Gene', '3853', (19, 22))	('knockdown', 'Var', (6, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('reduced', 'NegReg', (74, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))
183286	24681547	CDH11 knockdown in MDA-MB-231 and PC-3 cells also prevented the formation of branched networks during the first week of culture in Matrigel  (Figure 3C); but over the following week, CDH11 knockdown cells formed networks that were indistinguishable from controls (data not shown) suggesting that CDH11 is not absolutely necessary for network formation.	('CDH11', 'Gene', (0, 5))	('PC-3', 'Gene', '3853', (34, 38))	('PC-3', 'Gene', (34, 38))	('CDH11', 'Gene', (183, 188))	('knockdown', 'Var', (6, 15))	('prevented', 'NegReg', (50, 59))	('knockdown', 'Var', (189, 198))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (19, 29))
183289	24681547	Interestingly, the growth and migration of LN229 glioblastoma cells were more sensitive to CDH11 than N-cadherin knockdown (Figure 3D-F).	('sensitive', 'MPA', (78, 87))	('N-cadherin', 'Gene', (102, 112))	('glioblastoma', 'Disease', (49, 61))	('N-cadherin', 'Gene', '1000', (102, 112))	('CDH11', 'Var', (91, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('LN229', 'CellLine', 'CVCL:0393', (43, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('growth', 'CPA', (19, 25))
183295	24681547	Three compounds: Sd-133, Sd-037, and Sd-073 (Figure 4I) were active in the 1-10uM range attesting to the efficiency of the in silico screen (Supplementary Fig.	('Sd-037', 'Var', (25, 31))	('Sd-073', 'Chemical', '-', (37, 43))	('active', 'MPA', (61, 67))	('Sd-133', 'Chemical', '-', (17, 23))	('Sd-037', 'Chemical', '-', (25, 31))	('Sd-073', 'Var', (37, 43))	('Sd-133', 'Var', (17, 23))
183301	24681547	Sd-133 also inhibited MDA-MB-231 matrigel  outgrowth at 1muM (Figure 5C) but was inactive on control MDA-MB-435 melanoma cells (express N-cadherin) or MCF7 breast cancer cells that express E and P-cadherin (Figure 5D).	('inhibited', 'NegReg', (12, 21))	('N-cadherin', 'Gene', (136, 146))	('MCF7 breast cancer', 'Disease', (151, 169))	('Sd-133', 'Var', (0, 6))	('muM', 'Gene', (57, 60))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (151, 169))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (101, 111))	('N-cadherin', 'Gene', '1000', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('Sd-133', 'Chemical', '-', (0, 6))	('MDA-MB-231', 'Gene', (22, 32))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (22, 32))	('muM', 'Gene', '56925', (57, 60))
183304	24681547	Though this binding pocket is largely hydrophobic, a network of hydrogen bonds between Sd-133 and R23, H25, P88, S90 confers specificity and rigid binding.	('rigid', 'MPA', (141, 146))	('P88', 'Var', (108, 111))	('S90', 'Var', (113, 116))	('hydrogen', 'Chemical', 'MESH:D006859', (64, 72))	('S90', 'CellLine', 'CVCL:1B47', (113, 116))	('H25', 'Var', (103, 106))	('Sd-133', 'Gene', (87, 93))	('R23', 'Var', (98, 101))	('specificity', 'MPA', (125, 136))	('Sd-133', 'Chemical', '-', (87, 93))
183305	24681547	Hydrophobic interaction of Sd-133 with F7, L24, S26, Y37, A75, A77, E87, S90, and F92 may also contribute to its action (Figure 5H).	('S26', 'Var', (48, 51))	('Y37', 'Var', (53, 56))	('Sd-133', 'Gene', (27, 33))	('F92', 'Var', (82, 85))	('contribute', 'Reg', (95, 105))	('Hydrophobic interaction', 'MPA', (0, 23))	('A75', 'Var', (58, 61))	('L24', 'Var', (43, 46))	('5H', 'Chemical', '-', (128, 130))	('Sd-133', 'Chemical', '-', (27, 33))	('S90', 'Var', (73, 76))	('A77', 'Var', (63, 66))	('E87', 'Var', (68, 71))	('S90', 'CellLine', 'CVCL:1B47', (73, 76))	('action', 'MPA', (113, 119))
183307	24681547	Two other inhibitors, Sd-037 and Sd-073, have similar interactions with the W pocket (Figure 5I, J).	('Sd-037', 'Chemical', '-', (22, 28))	('Sd-073', 'Chemical', '-', (33, 39))	('W', 'Chemical', 'MESH:D014414', (76, 77))	('interactions', 'Interaction', (54, 66))	('Sd-073', 'Var', (33, 39))	('W pocket', 'Protein', (76, 84))
183313	24681547	Substitution of the R1 methyl group with fluorine completely inactivated the Sd-133 family of compounds, as did any modification of the R2 methyl group.	('Substitution', 'Var', (0, 12))	('Sd-133', 'Chemical', '-', (77, 83))	('fluorine', 'Chemical', 'MESH:D005461', (41, 49))	('Sd-133', 'Gene', (77, 83))	('inactivated', 'NegReg', (61, 72))
183316	24681547	The active analogues were selectively effective on CDH11 positive cell lines with EC50s in the low muM range and did not affect CDH11 negative MCF7 cells up to 40 muM (Supplementary Fig.	('muM', 'Gene', (99, 102))	('muM', 'Gene', '56925', (163, 166))	('CDH11', 'Gene', (51, 56))	('EC50s', 'Var', (82, 87))	('muM', 'Gene', (163, 166))	('muM', 'Gene', '56925', (99, 102))	('MCF7', 'CellLine', 'CVCL:0031', (143, 147))	('50s', 'Species', '2498238', (84, 87))
183329	24681547	In our studies cell proliferation and tumor growth were inhibited upon CDH11 depletion in MDA-MB-231 cells suggesting that a portion of the "metastatic" potential may be a result of alterations in cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('depletion', 'Var', (77, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cell proliferation', 'CPA', (15, 33))	('inhibited', 'NegReg', (56, 65))	('alterations', 'Reg', (182, 193))	('cell proliferation', 'CPA', (197, 215))	('CDH11', 'Gene', (71, 76))
183336	24681547	Indeed, significant reduction of growth and cell migration occurred upon CDH11 knockdown in PC3 prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('PC3', 'Gene', (92, 95))	('prostate cancer', 'Disease', (96, 111))	('reduction', 'NegReg', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CDH11', 'Gene', (73, 78))	('knockdown', 'Var', (79, 88))	('PC3', 'Gene', '3853', (92, 95))
183339	24681547	CDH11 controls the synovial response in RA and targeting CDH11 either by knockout or with antibodies reduced RA in mouse models.	('synovial response', 'CPA', (19, 36))	('targeting', 'Var', (47, 56))	('RA', 'Disease', 'MESH:D001172', (40, 42))	('mouse', 'Species', '10090', (115, 120))	('reduced', 'NegReg', (101, 108))	('RA', 'Disease', 'MESH:D001172', (109, 111))	('CDH11', 'Gene', (57, 62))
183340	24681547	In this study we show that the same CDH11 antibodies significantly inhibited the growth of mesenchymal/basal-like MDA-MB-231 xenografts.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (114, 124))	('CDH11', 'Gene', (36, 41))	('antibodies', 'Var', (42, 52))	('inhibited', 'NegReg', (67, 76))
183356	24681547	We also introduce an antibody and small molecule inhibitors of CDH11 as well as an FDA approved drug that are able to inhibit its function.	('W', 'Chemical', 'MESH:D014414', (0, 1))	('function', 'MPA', (130, 138))	('CDH11', 'Gene', (63, 68))	('inhibitors', 'Var', (49, 59))
183365	24681547	For Ki67 stained cells, 10 random high power fields representing the whole tumor area were selected and 1687+-33 cells/tumor (MDA-231, n=4/group) and 1405+-59 cells/tumor (MCF7, n=3/group) were counted.	('tumor', 'Disease', (119, 124))	('MCF7', 'CellLine', 'CVCL:0031', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('1687+-33', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('MDA-231', 'CellLine', 'CVCL:0062', (126, 133))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', (165, 170))
183374	24681547	Tumor volume was calculated using the formula D1xD2xD3 (D1=length, D2=width, D3=depth of tumor) using calipers, x2/week.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('D1xD2xD3', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
183385	24681547	NMR showed this material to be impure product, from which the product regiochemistry was determined to be 3-bromo-2-phenylpyridine, by reference to the NMR of the alternate 2-bromo-3-phenyl- isomer; Product 8b shows pyridyl signals at d8.37 (1H, dd, J = 4.9, 2.0), 7.62 (1H, dd, 7.6, 2.0) and 7.33 (1H, dd, J = 7.6, 4.9)].	('3-bromo-2-phenylpyridine', 'Chemical', '-', (106, 130))	('1H', 'Chemical', '-', (299, 301))	('1H', 'Chemical', '-', (271, 273))	('pyridyl signals', 'MPA', (216, 231))	('d8.37', 'Var', (235, 240))	('1H', 'Chemical', '-', (242, 244))
183459	23326564	The treatment with Gemini vitamin D BXL0124 decreased CD44 protein level, suppressed STAT3 signaling, and inhibited invasion and proliferation of MCF10DCIS cells.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (146, 155))	('STAT3 signaling', 'MPA', (85, 100))	('BXL0124', 'Chemical', 'MESH:C552206', (36, 43))	('suppressed', 'NegReg', (74, 84))	('DCIS', 'Phenotype', 'HP:0030075', (151, 155))	('BXL0124', 'Var', (36, 43))	('inhibited', 'NegReg', (106, 115))	('vitamin D', 'Chemical', 'MESH:D014807', (26, 35))	('CD44 protein level', 'MPA', (54, 72))	('decreased', 'NegReg', (44, 53))
183461	23326564	The role of CD44 in STAT3 signaling and invasion of MCF10DCIS cells was further determined by the knockdown of CD44 using small hairpin RNA in vitro and in vivo.	('CD44', 'Gene', (111, 115))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (52, 61))	('knockdown', 'Var', (98, 107))	('STAT3 signaling', 'MPA', (20, 35))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
183462	23326564	MCF10DCIS cell invasion was markedly decreased by the knockdown of CD44 in vitro.	('knockdown', 'Var', (54, 63))	('CD44', 'Gene', (67, 71))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('decreased', 'NegReg', (37, 46))
183463	23326564	The knockdown of CD44 also significantly decreased mRNA expression levels of invasion markers, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA), in MCF10DCIS cells.	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('MMPs', 'Gene', (122, 126))	('urokinase plasminogen activator', 'MPA', (132, 163))	('decreased', 'NegReg', (41, 50))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (174, 183))	('CD44', 'Gene', (17, 21))	('uPA', 'Gene', '5328', (165, 168))	('uPA', 'Gene', (165, 168))	('MMPs', 'Gene', '4313;4318;4322;4323;4324;4325', (122, 126))	('knockdown', 'Var', (4, 13))	('mRNA expression levels', 'MPA', (51, 73))	('matrix metalloproteinases', 'MPA', (95, 120))
183464	23326564	In MCF10DCIS xenograft tumors, CD44 knockdown decreased tumor size and weight as well as invasion markers.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MCF10DCIS', 'Var', (3, 12))	('xenograft tumors', 'Disease', (13, 29))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('invasion markers', 'CPA', (89, 105))	('knockdown', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('decreased', 'NegReg', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('xenograft tumors', 'Disease', 'MESH:D009369', (13, 29))	('tumor', 'Disease', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))	('CD44', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (3, 12))
183479	23326564	On the other hand, inhibition of STAT3 signaling with STAT3 small hairpin RNA (shRNA) or use of STAT3 phosphorylation inhibitors repressed the formation and growth of xenograft tumors in mice as well as the invasive potential of breast cancer cells.	('growth', 'CPA', (157, 163))	('STAT3 signaling', 'MPA', (33, 48))	('formation', 'CPA', (143, 152))	('inhibition', 'Var', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('xenograft tumors', 'Disease', (167, 183))	('mice', 'Species', '10090', (187, 191))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('breast cancer', 'Disease', (229, 242))	('xenograft tumors', 'Disease', 'MESH:D009369', (167, 183))	('invasive potential', 'CPA', (207, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
183480	23326564	A recent study reported that CD44+ tumor-initiating breast cancer cells had preferential activation of STAT3, suggesting that STAT3 may be a potential therapeutic target in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (35, 40))	('breast cancer', 'Disease', (52, 65))	('CD44+', 'Var', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('activation', 'PosReg', (89, 99))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('STAT3', 'Enzyme', (103, 108))	('breast cancer', 'Disease', (173, 186))
183484	23326564	We demonstrate that the repression of CD44 by BXL0124 contributes to the inhibition of STAT3 signaling and tumor invasion in MCF10DCIS cells.	('BXL0124', 'Chemical', 'MESH:C552206', (46, 53))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('inhibition', 'NegReg', (73, 83))	('BXL0124', 'Var', (46, 53))	('STAT3 signaling', 'MPA', (87, 102))	('repression', 'NegReg', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('CD44', 'Gene', (38, 42))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
183496	23326564	The procedure was described previously; the labeled primers for CD44, matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, MMP-14, MMP-15, MMP-16, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, uPA, and glyceraldehyde 3-phosphate dehydrogenase were obtained from Applied Biosystems (Foster City, CA).	('MMP-14', 'Gene', (119, 125))	('TIMP-2', 'Gene', '7077', (191, 197))	('MMP-13', 'Gene', (111, 117))	('tissue inhibitor of metalloproteinase (TIMP)-1', 'Gene', '7076', (143, 189))	('uPA', 'Gene', (199, 202))	('uPA', 'Gene', '5328', (199, 202))	('TIMP-2', 'Gene', (191, 197))	('MMP-16', 'Gene', (135, 141))	('MMP-15', 'Gene', '4324', (127, 133))	('CD44', 'Var', (64, 68))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (208, 248))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (208, 248))	('MMP-16', 'Gene', '4325', (135, 141))	('MMP-9', 'Gene', '4318', (104, 109))	('MMP-13', 'Gene', '4322', (111, 117))	('MMP-9', 'Gene', (104, 109))	('MMP-14', 'Gene', '4323', (119, 125))	('MMP-15', 'Gene', (127, 133))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (70, 102))
183497	23326564	The primary antibody against CD44 (sc-7298), which recognizes both CD44v and CD44s, was from Santa Cruz Biotechnology (Santa Cruz, CA).	('CD44s', 'Gene', (77, 82))	('CD44v', 'Var', (67, 72))	('CD44s', 'Gene', '960', (77, 82))
183498	23326564	Primary antibodies recognizing pSTAT3 (9235), STAT3 (9139), pAkt (9271), Akt (2966), pErk (9101) and Erk (9109) were from Cell Signaling Technology (Beverly, MA); pNFkappaB (sc-101749) and NFkappaB (sc-372) were from Santa Cruz Biotechnology; MMP-9 (ab38898) was from Abcam (Cambridge, MA); vitamin D receptor (VDR) (GR37) was from Millipore (Billerica, MA); beta-actin (A1978) was from Sigma-Aldrich (St. Louis, MO).	('VDR', 'Gene', (311, 314))	('Erk', 'Gene', '2048', (86, 89))	('NFkappaB', 'Gene', (189, 197))	('NFkappaB', 'Gene', '4790', (164, 172))	('A1978', 'Var', (371, 376))	('vitamin D receptor', 'Gene', (291, 309))	('pErk', 'Gene', (85, 89))	('pErk', 'Gene', '9451', (85, 89))	('NFkappaB', 'Gene', (164, 172))	('Akt', 'Gene', (61, 64))	('Erk', 'Gene', '2048', (101, 104))	('MMP-9', 'Gene', '4318', (243, 248))	('VDR', 'Gene', '7421', (311, 314))	('beta-actin', 'Gene', (359, 369))	('MMP-9', 'Gene', (243, 248))	('Erk', 'Gene', (86, 89))	('vitamin D receptor', 'Gene', '7421', (291, 309))	('Akt', 'Gene', '207', (61, 64))	('Akt', 'Gene', (73, 76))	('beta-actin', 'Gene', '728378', (359, 369))	('Erk', 'Gene', (101, 104))	('NFkappaB', 'Gene', '4790', (189, 197))	('Akt', 'Gene', '207', (73, 76))
183499	23326564	MCF10DCIS cells were incubated with 1 microM of non-targeting siRNA (D-001910-02-20, Thermo Fisher Scientific, Waltham, MA) or VDR siRNA (A-003448-13-0010, Thermo Fisher Scientific) for 72 h in Accell siRNA delivery medium (Thermo Fisher Scientific).	('A-003448-13-0010', 'Var', (138, 154))	('VDR', 'Gene', '7421', (127, 130))	('D-001910-02-20', 'Var', (69, 83))	('VDR', 'Gene', (127, 130))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))
183501	23326564	The chemiluminescent intensity values of samples treated with BXL0124 were divided by the chemiluminescent intensity value of a control sample, and the fold changes were calculated.	('BXL0124', 'Var', (62, 69))	('BXL0124', 'Chemical', 'MESH:C552206', (62, 69))	('chemiluminescent intensity', 'MPA', (4, 30))
183509	23326564	MCF10DCIS-shLuc or MCF10DCIS-shCD44 cells were injected into the mammary fat pad of immunodeficient nu/nu mice as described previously.	('immunodeficient', 'Disease', 'MESH:D007153', (84, 99))	('immunodeficient', 'Disease', (84, 99))	('mice', 'Species', '10090', (106, 110))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (19, 28))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS-shCD44', 'Var', (19, 35))
183514	23326564	Both 1alpha,25(OH)2D3 and BXL0124 significantly inhibited MCF10DCIS cell proliferation and metabolic activity (Figs.	('BXL0124', 'Chemical', 'MESH:C552206', (26, 33))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (58, 67))	('25(OH)2D3', 'Chemical', '-', (12, 21))	('DCIS', 'Phenotype', 'HP:0030075', (63, 67))	('MCF10DCIS', 'Gene', (58, 67))	('BXL0124', 'Var', (26, 33))	('inhibited', 'NegReg', (48, 57))	('1alpha', 'Chemical', '-', (5, 11))	('metabolic activity', 'CPA', (91, 109))
183516	23326564	Both 1alpha,25(OH)2D3 and BXL0124 significantly decreased the number of MCF10DCIS cells that penetrated BME-coated layers.	('BXL0124', 'Chemical', 'MESH:C552206', (26, 33))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (72, 81))	('25(OH)2D3', 'Chemical', '-', (12, 21))	('decreased', 'NegReg', (48, 57))	('BXL0124', 'Var', (26, 33))	('1alpha', 'Chemical', '-', (5, 11))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
183517	23326564	However, BXL0124 was more effective than 1alpha,25(OH)2D3 to repress MCF10DCIS cell invasion (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (9, 16))	('1alpha', 'Chemical', '-', (41, 47))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (69, 78))	('MCF10DCIS cell invasion', 'CPA', (69, 92))	('BXL0124', 'Var', (9, 16))	('25(OH)2D3', 'Chemical', '-', (48, 57))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))	('repress', 'NegReg', (61, 68))
183523	23326564	To identify downstream signaling pathways that may be affected by BXL0124, the protein levels of CD44, as well as potential downstream signaling molecules (pAkt, pErk, pSTAT3 and NFkappaB), were measured.	('CD44', 'MPA', (97, 101))	('Akt', 'Gene', '207', (157, 160))	('NFkappaB', 'Gene', (179, 187))	('BXL0124', 'Chemical', 'MESH:C552206', (66, 73))	('NFkappaB', 'Gene', '4790', (179, 187))	('pErk', 'Gene', (162, 166))	('Akt', 'Gene', (157, 160))	('pErk', 'Gene', '9451', (162, 166))	('BXL0124', 'Var', (66, 73))
183525	23326564	Total protein levels of STAT3, Akt, Erk and NFkappaB were not affected by the BXL0124 treatment (Fig.	('Akt', 'Gene', (31, 34))	('NFkappaB', 'Gene', '4790', (44, 52))	('NFkappaB', 'Gene', (44, 52))	('BXL0124', 'Chemical', 'MESH:C552206', (78, 85))	('Erk', 'Gene', (36, 39))	('Akt', 'Gene', '207', (31, 34))	('BXL0124', 'Var', (78, 85))	('Erk', 'Gene', '2048', (36, 39))
183526	23326564	In a time-dependent study, the treatment with BXL0124 decreased the protein levels of CD44s and CD44v as well as pSTAT3 at 12 h and 24 h, while there was no change in the level of STAT3 (Fig.	('BXL0124', 'Chemical', 'MESH:C552206', (46, 53))	('CD44s', 'Gene', '960', (86, 91))	('BXL0124', 'Var', (46, 53))	('decreased', 'NegReg', (54, 63))	('CD44s', 'Gene', (86, 91))	('protein levels', 'MPA', (68, 82))	('CD44v', 'Var', (96, 101))	('pSTAT3', 'MPA', (113, 119))
183527	23326564	The repression of CD44 and pSTAT3 protein levels shown by the treatment with BXL0124 was abolished by knockdown of VDR using VDR siRNA, indicating that the repression of CD44-STAT3 signaling by BXL0124 is a VDR-dependent event (Fig.	('VDR', 'Gene', (125, 128))	('BXL0124', 'Chemical', 'MESH:C552206', (194, 201))	('BXL0124', 'Chemical', 'MESH:C552206', (77, 84))	('VDR', 'Gene', (115, 118))	('VDR', 'Gene', (207, 210))	('CD44-STAT3 signaling', 'MPA', (170, 190))	('VDR', 'Gene', '7421', (125, 128))	('BXL0124', 'Var', (194, 201))	('VDR', 'Gene', '7421', (115, 118))	('VDR', 'Gene', '7421', (207, 210))
183528	23326564	To determine STAT3 activity affected by BXL0124, nuclear localization and DNA binding activity of STAT3 were analyzed.	('BXL0124', 'Chemical', 'MESH:C552206', (40, 47))	('STAT3 activity', 'MPA', (13, 27))	('BXL0124', 'Var', (40, 47))
183531	23326564	Since BXL0124 decreased the protein levels of CD44 and inhibited activation of STAT3 signaling, we investigated whether CD44 activates STAT3 signaling by direct interaction.	('decreased', 'NegReg', (14, 23))	('CD44', 'MPA', (46, 50))	('activation', 'MPA', (65, 75))	('BXL0124', 'Chemical', 'MESH:C552206', (6, 13))	('STAT3 signaling', 'MPA', (79, 94))	('protein levels', 'MPA', (28, 42))	('BXL0124', 'Var', (6, 13))	('inhibited', 'NegReg', (55, 64))
183532	23326564	When MCF10DCIS cell lysates were immunoprecipitated with STAT3 antibody, the immunocomplex contained CD44s, CD44v and JAK2, and BXL0124 decreased the amounts of CD44v and CD44s proteins interacting with STAT3 (Fig.	('amounts', 'MPA', (150, 157))	('BXL0124', 'Var', (128, 135))	('interacting', 'Interaction', (186, 197))	('JAK2', 'Gene', (118, 122))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('CD44v', 'MPA', (161, 166))	('CD44s', 'Gene', (171, 176))	('MCF10DCIS', 'Var', (5, 14))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (5, 14))	('CD44s', 'Gene', '960', (101, 106))	('BXL0124', 'Chemical', 'MESH:C552206', (128, 135))	('CD44s', 'Gene', (101, 106))	('JAK2', 'Gene', '3717', (118, 122))	('CD44s', 'Gene', '960', (171, 176))	('decreased', 'NegReg', (136, 145))
183533	23326564	In addition, the protein level of pSTAT3, but not STAT3, in the complex was decreased by the treatment with BXL0124 (Fig.	('BXL0124', 'Var', (108, 115))	('protein level', 'MPA', (17, 30))	('decreased', 'NegReg', (76, 85))	('BXL0124', 'Chemical', 'MESH:C552206', (108, 115))
183535	23326564	JAK2 was recruited by STAT3, and the amount of JAK2 proteins interacting with STAT3 was decreased with the BXL0124 treatment (Fig.	('BXL0124', 'Var', (107, 114))	('JAK2', 'Gene', '3717', (47, 51))	('interacting', 'Interaction', (61, 72))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', (47, 51))	('JAK2', 'Gene', (0, 4))	('amount', 'MPA', (37, 43))	('decreased', 'NegReg', (88, 97))	('BXL0124', 'Chemical', 'MESH:C552206', (107, 114))
183537	23326564	When MCF10DCIS cell lysates were immunoprecipitated with JAK2 antibody, significant amounts of CD44 and STAT3 were pulled down in the complex.	('JAK2', 'Gene', '3717', (57, 61))	('JAK2', 'Gene', (57, 61))	('DCIS', 'Phenotype', 'HP:0030075', (10, 14))	('MCF10DCIS', 'Var', (5, 14))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (5, 14))	('STAT3', 'MPA', (104, 109))	('CD44', 'MPA', (95, 99))
183544	23326564	The knockdown of CD44 significantly inhibited invasive potential of MCF10DCIS cells (Fig.	('inhibited', 'NegReg', (36, 45))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (68, 77))	('CD44', 'Gene', (17, 21))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('knockdown', 'Var', (4, 13))	('invasive potential', 'CPA', (46, 64))
183546	23326564	The mRNA expression of MMP-9, MMP-14 and uPA was significantly lower in the DCIS-shCD44 cells than in the DCIS-shLuc control cells at 48 h (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('DCIS-shCD44', 'Var', (76, 87))	('lower', 'NegReg', (63, 68))	('MMP-14', 'Gene', (30, 36))	('MMP-14', 'Gene', '4323', (30, 36))	('mRNA expression', 'MPA', (4, 19))	('uPA', 'Gene', (41, 44))	('MMP-9', 'Gene', (23, 28))	('MMP-9', 'Gene', '4318', (23, 28))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('uPA', 'Gene', '5328', (41, 44))
183549	23326564	The growth rate of DCIS-shCD44 xenograft tumors was significantly slower than that of DCIS-shLuc control xenograft tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('xenograft tumors', 'Disease', (105, 121))	('xenograft tumors', 'Disease', 'MESH:D009369', (31, 47))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('DCIS-shCD44', 'Var', (19, 30))	('slower', 'NegReg', (66, 72))	('xenograft tumors', 'Disease', (31, 47))	('xenograft tumors', 'Disease', 'MESH:D009369', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('growth', 'MPA', (4, 10))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))
183550	23326564	The average tumor weight from DCIS-shCD44 xenograft (560+-93 mg) was significantly lower than that from DCIS-shLuc xenograft (870+-150 mg) (p<0.05) (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lower', 'NegReg', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('DCIS-shCD44', 'Var', (30, 41))	('tumor', 'Disease', (12, 17))
183552	23326564	In addition, the mRNA expression levels of MMP-9 and uPA were significantly lower in DCIS-shCD44 xenograft tumors compared to those in DCIS-shLuc xenograft tumors (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('xenograft tumors', 'Disease', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('uPA', 'Gene', (53, 56))	('xenograft tumors', 'Disease', 'MESH:D009369', (146, 162))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('lower in DCIS', 'Phenotype', 'HP:0200161', (76, 89))	('xenograft tumors', 'Disease', 'MESH:D009369', (97, 113))	('uPA', 'Gene', '5328', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('DCIS-shCD44', 'Var', (85, 96))	('lower', 'NegReg', (76, 81))	('mRNA expression levels', 'MPA', (17, 39))	('MMP-9', 'Gene', '4318', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))	('xenograft tumors', 'Disease', (146, 162))	('MMP-9', 'Gene', (43, 48))
183554	23326564	Immunofluorescence staining confirmed the decreased levels of CD44 and pSTAT3 in DCIS-shCD44 xenograft tumors compared to DCIS-shLuc xenograft tumors (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('pSTAT3', 'Gene', (71, 77))	('decreased', 'NegReg', (42, 51))	('CD44', 'MPA', (62, 66))	('xenograft tumors', 'Disease', (133, 149))	('xenograft tumors', 'Disease', 'MESH:D009369', (93, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('DCIS-shCD44', 'Var', (81, 92))	('xenograft tumors', 'Disease', 'MESH:D009369', (133, 149))	('xenograft tumors', 'Disease', (93, 109))	('levels', 'MPA', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
183557	23326564	The protein level of VDR was increased by the BXL0124 treatment (Fig.	('protein level', 'MPA', (4, 17))	('BXL0124', 'Chemical', 'MESH:C552206', (46, 53))	('VDR', 'Gene', '7421', (21, 24))	('BXL0124', 'Var', (46, 53))	('increased', 'PosReg', (29, 38))	('VDR', 'Gene', (21, 24))
183558	23326564	BXL0124 decreased the protein levels of CD44v, CD44s and pSTAT3, whereas the protein level of total STAT3 was not affected (Fig.	('CD44v', 'MPA', (40, 45))	('CD44s', 'Gene', (47, 52))	('BXL0124', 'Chemical', 'MESH:C552206', (0, 7))	('protein levels', 'MPA', (22, 36))	('decreased', 'NegReg', (8, 17))	('BXL0124', 'Var', (0, 7))	('CD44s', 'Gene', '960', (47, 52))
183559	23326564	MCF10DCIS cells form DCIS-like lesions which spontaneously progress to invasive ductal carcinoma (IDC) in immunodeficient mice.	('mice', 'Species', '10090', (122, 126))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (80, 96))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (71, 96))	('progress', 'PosReg', (59, 67))	('immunodeficient', 'Disease', 'MESH:D007153', (106, 121))	('immunodeficient', 'Disease', (106, 121))	('invasive ductal carcinoma', 'Disease', (71, 96))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('MCF10DCIS', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
183566	23326564	In the present study, BXL0124 significantly decreased proliferation and invasion markers in MCF10DCIS cells, suggesting that BXL0124 may be an important preventive agent delaying the transition of DCIS to IDC.	('invasion markers', 'CPA', (72, 88))	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('BXL0124', 'Chemical', 'MESH:C552206', (125, 132))	('BXL0124', 'Chemical', 'MESH:C552206', (22, 29))	('BXL0124', 'Var', (125, 132))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (92, 101))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('proliferation', 'CPA', (54, 67))	('DCIS', 'Disease', (197, 201))	('MCF10DCIS', 'Gene', (92, 101))	('decreased', 'NegReg', (44, 53))
183568	23326564	demonstrated that knockdown of CD44 repressed both basal and hyaluronan-induced invasion of basal-like breast cancer cells.	('knockdown', 'Var', (18, 27))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('CD44', 'Gene', (31, 35))	('hyaluronan', 'Chemical', 'MESH:D006820', (61, 71))
183572	23326564	In mouse mammary tumor cells, knockdown of STAT3 strongly inhibits tumor invasion without affecting cell proliferation, supporting the notion of a specific role of CD44-STAT3 signaling in cancer cell invasion.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (67, 72))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('inhibits', 'NegReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('knockdown', 'Var', (30, 39))	('STAT3', 'Gene', (43, 48))	('cancer', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
183573	23326564	Hyaluronan stimulates the interaction between CD44 and Nanog, an embryonic stem cell transcription factor, leading to activation of STAT3, and knockdown of STAT3 by siRNA blocks hyaluronan-induced breast cancer cell growth.	('activation', 'PosReg', (118, 128))	('Nanog', 'Gene', (55, 60))	('CD44', 'Gene', (46, 50))	('breast cancer', 'Disease', (197, 210))	('hyaluronan', 'Chemical', 'MESH:D006820', (178, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('knockdown', 'Var', (143, 152))	('Hyaluronan', 'Chemical', 'MESH:D006820', (0, 10))	('STAT3', 'Gene', (156, 161))	('block', 'Disease', (171, 176))	('block', 'Disease', 'MESH:D006327', (171, 176))	('interaction', 'Interaction', (26, 37))	('STAT3', 'MPA', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('Nanog', 'Gene', '79923', (55, 60))
183575	23326564	In the present study, MCF10DCIS cells showed high CD44 protein level and constitutively activated STAT3 signal (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (27, 31))	('activated', 'PosReg', (88, 97))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (22, 31))	('STAT3 signal', 'MPA', (98, 110))	('MCF10DCIS', 'Var', (22, 31))	('high', 'PosReg', (45, 49))	('CD44 protein level', 'MPA', (50, 68))
183576	23326564	In MCF10DCIS cells, CD44 interacts with STAT3 in the absence of exogenous ligands, suggesting that a constitutively high level of CD44 might be sufficient to activate STAT3 signaling for cell invasion.	('MCF10DCIS', 'Var', (3, 12))	('CD44', 'Var', (130, 134))	('activate', 'PosReg', (158, 166))	('STAT3 signaling', 'MPA', (167, 182))	('interacts', 'Interaction', (25, 34))	('cell invasion', 'CPA', (187, 200))	('DCIS', 'Phenotype', 'HP:0030075', (8, 12))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (3, 12))
183579	23326564	The JAK2/STAT3 signaling pathway is preferentially activated in CD44+ breast cancer stem cell population over other cell populations, and hyaluronic acid synthase 1 (HAS1) is a STAT3 signaling-related molecule in basal-like breast cancer.	('CD44+', 'Var', (64, 69))	('HAS1', 'Gene', '3036', (166, 170))	('hyaluronic acid synthase 1', 'Gene', (138, 164))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('JAK2', 'Gene', '3717', (4, 8))	('breast cancer', 'Disease', (224, 237))	('HAS1', 'Gene', (166, 170))	('breast cancer', 'Disease', (70, 83))	('preferentially', 'PosReg', (36, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('JAK2', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('hyaluronic acid synthase 1', 'Gene', '3036', (138, 164))	('activated', 'PosReg', (51, 60))
183580	23326564	In addition, recent studies reported that STAT3 is one of the key signaling molecules that maintain breast cancer stem cell population, and that knockdown of STAT3 with shRNA markedly repressed mammary tumorigenesis in mice.	('knockdown', 'Var', (145, 154))	('tumor', 'Disease', (202, 207))	('mice', 'Species', '10090', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('repressed', 'NegReg', (184, 193))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('shRNA', 'Gene', (169, 174))	('breast cancer', 'Disease', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('STAT3', 'Gene', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
183581	23326564	6B, the direct interaction between CD44, STAT3 and JAK2 may be critical for activation of STAT3 in MCF10DCIS cells, and CD44 might function as a scaffold of the STAT3-JAK2 complex.	('JAK2', 'Gene', '3717', (167, 171))	('CD44', 'Var', (120, 124))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('JAK2', 'Gene', (167, 171))	('JAK2', 'Gene', '3717', (51, 55))	('STAT3', 'MPA', (90, 95))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (99, 108))	('JAK2', 'Gene', (51, 55))	('activation', 'PosReg', (76, 86))
183586	23326564	In addition, mRNA levels of MMP-9 and MMP-14 as well as activation of STAT3 were significantly decreased by knockdown of CD44 in MCF10DCIS cells, indicating that MMPs might be downstream targets of CD44/STAT3 signaling in MCF10DCIS cells.	('decreased', 'NegReg', (95, 104))	('knockdown', 'Var', (108, 117))	('MMP-9', 'Gene', '4318', (28, 33))	('MMP-9', 'Gene', (28, 33))	('MMPs', 'Gene', '4313;4318;4322;4323;4324;4325', (162, 166))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('MMP-14', 'Gene', (38, 44))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (129, 138))	('activation', 'MPA', (56, 66))	('STAT3', 'MPA', (70, 75))	('DCIS', 'Phenotype', 'HP:0030075', (227, 231))	('MMP-14', 'Gene', '4323', (38, 44))	('mRNA levels', 'MPA', (13, 24))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (222, 231))	('MMPs', 'Gene', (162, 166))	('CD44', 'Gene', (121, 125))	('MCF10DCIS', 'Gene', (129, 138))
183589	23326564	In breast cancer, high expression levels of MMP-9 have been associated with node metastasis and advanced tumor stage.	('node metastasis', 'CPA', (76, 91))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('associated', 'Reg', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('high', 'Var', (18, 22))	('MMP-9', 'Gene', '4318', (44, 49))	('expression levels', 'MPA', (23, 40))	('tumor', 'Disease', (105, 110))	('MMP-9', 'Gene', (44, 49))
183597	23326564	The novel Gemini vitamin D analog BXL0124 represses the expression of CD44, which results in a decreased amount of the CD44-STAT3-JAK2 complex.	('decreased', 'NegReg', (95, 104))	('JAK2', 'Gene', '3717', (130, 134))	('represses', 'NegReg', (42, 51))	('CD44', 'Gene', (70, 74))	('vitamin D', 'Chemical', 'MESH:D014807', (17, 26))	('JAK2', 'Gene', (130, 134))	('expression', 'MPA', (56, 66))	('BXL0124', 'Chemical', 'MESH:C552206', (34, 41))	('amount', 'MPA', (105, 111))	('BXL0124', 'Var', (34, 41))
183606	22715888	According to Jimenez et al, EDCIS in invasive breast carcinomas is associated with increased risk of recurrence in patients treated with conservative surgery and radiotherapy.	('patients', 'Species', '9606', (115, 123))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (37, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('breast carcinomas', 'Phenotype', 'HP:0003002', (46, 63))	('EDCIS', 'Chemical', '-', (28, 33))	('EDCIS', 'Var', (28, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('invasive breast carcinomas', 'Disease', (37, 63))
183607	22715888	Boyages et al reported a rate of recurrence in the breast of 26% for tumors exhibiting EIC in five years compared to 7% recurrence in negative EIC carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('EIC carcinomas', 'Disease', 'MESH:D002277', (143, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('EIC', 'Var', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('EIC carcinomas', 'Disease', (143, 157))	('to 7', 'Species', '1214577', (114, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
183625	22715888	Previous studies indicated that EIC in breast carcinomas was associated with an increased risk of recurrence in patients treated with conservative surgery and radiotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('breast carcinomas', 'Phenotype', 'HP:0003002', (39, 56))	('patients', 'Species', '9606', (112, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('EIC', 'Var', (32, 35))	('breast carcinomas', 'Disease', 'MESH:D001943', (39, 56))	('breast carcinomas', 'Disease', (39, 56))
183636	22715888	Holland et al showed that invasive breast tumors with positive CIE have a greater likelihood to present residual DCIS compared to negative EIC tumors.	('CIE', 'Var', (63, 66))	('EIC tumors', 'Disease', (139, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('EIC tumors', 'Disease', 'MESH:D009369', (139, 149))	('invasive breast tumors', 'Disease', 'MESH:D001943', (26, 48))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('invasive breast tumors', 'Disease', (26, 48))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
183657	22649720	Furthermore, a threefold increase of contralateral "prophylactic" mastectomy has been reported in the last decade, and it is recognized that DCIS is a marker for increased risk of invasive carcinoma in both breasts.	('invasive carcinoma', 'Disease', (180, 198))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('DCIS', 'Var', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('invasive carcinoma', 'Disease', 'MESH:D009361', (180, 198))
183727	22649720	The different findings in these two trials may be the result of differences in the patient populations: in NSABP B-24 there was a higher proportion of young patients, ER positive, and low-grade DCIS with respect to those of UKCCCR.	('patient', 'Species', '9606', (157, 164))	('higher', 'PosReg', (130, 136))	('low-grade', 'Var', (184, 193))	('patients', 'Species', '9606', (157, 165))	('DCIS', 'Disease', (194, 198))	('patient', 'Species', '9606', (83, 90))	('DCIS', 'Phenotype', 'HP:0030075', (194, 198))	('NSABP B-24', 'Gene', (107, 117))
183752	28030805	CD82 silencing partially eliminates these functions.	('CD82', 'Gene', (0, 4))	('functions', 'MPA', (42, 51))	('si', 'Chemical', 'MESH:D012825', (5, 7))	('silencing', 'Var', (5, 14))	('eliminates', 'NegReg', (25, 35))	('CD82', 'Gene', '3732', (0, 4))
183756	28030805	Of four known TIMPs (TIMP-1, -2, -3, -4), TIMP-1 is of particular interest because it promotes cell proliferation and inhibits apoptosis independent of its MMP-inhibitory activity.	('cell proliferation', 'CPA', (95, 113))	('apoptosis', 'CPA', (127, 136))	('inhibits', 'NegReg', (118, 126))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('TIMP-1, -2, -3, -4', 'Gene', '7076;7077;7078;7079', (21, 39))	('promotes', 'PosReg', (86, 94))	('TIMP-1', 'Var', (42, 48))	('rat', 'Species', '10116', (107, 110))
183787	28030805	Since the only resolved crystal structure of the tetraspanin family is CD81 LEL, we used the Phyre server to predicte the structure of CD82-LEL (amino acids 111-228).	('CD82-LEL', 'Var', (135, 143))	('LEL', 'Chemical', '-', (76, 79))	('CD81', 'Gene', (71, 75))	('CD81', 'Gene', '975', (71, 75))	('LEL', 'Chemical', '-', (140, 143))
183789	28030805	Before uploading information for final analysis, we included the potential binding sites in CD82-LEL: ASN129, CYS149-151GLY, ASN157, CYS174, CYS176, and CYS216.	('CYS176', 'Chemical', '-', (141, 147))	('CYS174', 'Var', (133, 139))	('ASN129', 'Var', (102, 108))	('CYS176', 'Var', (141, 147))	('CYS174', 'Chemical', '-', (133, 139))	('CYS149-151GLY', 'Disease', (110, 123))	('ASN157', 'Chemical', '-', (125, 131))	('CD82-LEL', 'Gene', (92, 100))	('ASN129', 'Chemical', '-', (102, 108))	('CYS216', 'Chemical', '-', (153, 159))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('CYS149-151GLY', 'Disease', 'None', (110, 123))	('binding', 'Interaction', (75, 82))	('ASN157', 'Var', (125, 131))	('si', 'Chemical', 'MESH:D012825', (83, 85))
183794	28030805	Before uploading for ZDOCK analysis, MMP binding sites in TIMP-1 (CYS24-29PRO, VAL52, THR56-58TYR, ALA88-93CYS, THR120-123SER, and LEU156-157SER) were blocked.	('THR120', 'Chemical', '-', (112, 118))	('MMP', 'Protein', (37, 40))	('THR120-123SER', 'Var', (112, 125))	('VAL52', 'Chemical', '-', (79, 84))	('LEU156', 'Chemical', '-', (131, 137))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('CYS24', 'Chemical', '-', (66, 71))	('ALA88', 'Chemical', '-', (99, 104))	('LEU156-157SER', 'Var', (131, 144))	('THR56', 'Chemical', '-', (86, 91))	('THR56-58TYR', 'Var', (86, 97))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('CYS24-29PRO', 'Var', (66, 77))
183808	28030805	In addition, we repeated the cross-linking experiments between recombinant protein CD82-LEL and TIMP-2 which is a high homology to TIMP-1.	('TIMP-2', 'Gene', (96, 102))	('CD82-LEL', 'Var', (83, 91))	('TIMP-2', 'Gene', '7077', (96, 102))
183809	28030805	However, the band of CD82-LEL-SBED did not transfer to TIMP-2 under these conditions [Supplementary Figure 2b (II)].	('CD82-LEL-SBED', 'Var', (21, 34))	('TIMP-2', 'Gene', (55, 61))	('TIMP-2', 'Gene', '7077', (55, 61))
183811	28030805	The presence of increasing amounts of CD82-LEL caused a significant and dose-dependent decrease in 125I-CD82-LEL binding to TIMP-1.	('si', 'Chemical', 'MESH:D012825', (22, 24))	('decrease', 'NegReg', (87, 95))	('binding', 'Interaction', (113, 120))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('CD82-LEL', 'Var', (38, 46))	('125I-CD82-LEL', 'MPA', (99, 112))
183818	28030805	Firstly, 293A cells were transfected with peGFP-N2 (control) or pTIMP-1-eGFP for almost 36h.	('TIMP-1-eGFP', 'Gene', '7076', (65, 76))	('TIMP-1-eGFP', 'Gene', (65, 76))	('peGFP-N2', 'Var', (42, 50))	('293A', 'CellLine', 'CVCL:6910', (9, 13))
183840	28030805	Previous studies found that TIMP-1-expressing pancreatic cancer cells were significantly less invasive, and mice receiving TIMP-1 adenovirus showed reduced cancer cell growth and prolonged survival rates.	('cancer', 'Disease', (57, 63))	('pancreatic cancer', 'Disease', (46, 63))	('mice', 'Species', '10090', (108, 112))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('survival rates', 'CPA', (189, 203))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('rat', 'Species', '10116', (198, 201))	('less', 'NegReg', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('prolonged', 'PosReg', (179, 188))	('TIMP-1', 'Var', (123, 129))	('invasive', 'CPA', (94, 102))	('cancer', 'Disease', (156, 162))	('reduced', 'NegReg', (148, 155))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
183846	28030805	In order to avoid that CD82 deletion alone could weaken cell migration irrespective of TIMP-1 status, the concentration of siCD82 in this wound closure assay was lowered to 20 nM at which molality PANC-1 cell motility was not be obviously induced (Figure 5b, left).	('CD82', 'Gene', '3732', (23, 27))	('cell migration', 'CPA', (56, 70))	('CD82', 'Gene', (125, 129))	('rat', 'Species', '10116', (113, 116))	('PANC-1', 'CellLine', 'CVCL:0480', (197, 203))	('rat', 'Species', '10116', (64, 67))	('CD82', 'Gene', (23, 27))	('deletion', 'Var', (28, 36))	('weaken', 'NegReg', (49, 55))	('CD82', 'Gene', '3732', (125, 129))
183859	28030805	Following CD82 depletion, linear actins were observed [Figure 6a (I)] in both of siNC and siCD82 groups regardless of TIMP-1 addition.	('depletion', 'Var', (15, 24))	('CD82', 'Gene', '3732', (92, 96))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('CD82', 'Gene', (10, 14))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('CD82', 'Gene', '3732', (10, 14))	('CD82', 'Gene', (92, 96))	('observed', 'Reg', (45, 53))	('linear actins', 'MPA', (26, 39))
183876	28030805	Palmitoylated CD82 specifically recruits interaction partners, including epidermal growth factor receptor (EGFR), EWI-2, integrin alpha6, c-Met and Vangl1, into signaling platforms such as lipid rafts and glycosynapses.	('CD82', 'Gene', (14, 18))	('EGFR', 'Gene', (107, 111))	('Vangl1', 'Gene', '81839', (148, 154))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('c-Met', 'Gene', (138, 143))	('Vangl1', 'Gene', (148, 154))	('EGFR', 'Gene', '1956', (107, 111))	('EWI-2', 'Gene', '93185', (114, 119))	('recruits', 'PosReg', (32, 40))	('EWI-2', 'Gene', (114, 119))	('c-Met', 'Gene', '4233', (138, 143))	('lipid', 'Chemical', 'MESH:D008055', (189, 194))	('interaction', 'Interaction', (41, 52))	('integrin alpha6', 'Gene', (121, 136))	('Palmitoylated', 'Var', (0, 13))	('integrin alpha6', 'Gene', '3655', (121, 136))	('epidermal growth factor receptor', 'Gene', (73, 105))	('CD82', 'Gene', '3732', (14, 18))	('epidermal growth factor receptor', 'Gene', '1956', (73, 105))
183886	28030805	Our studies demonstrate that TIMP-1-eGFP selectively accumulates in the cytoplasm of PANC-1 and MCF-7 cells and silencing endogenous CD82 expression prominently eliminates TIMP-1 membrane-cytoplasm translocation.	('CD82', 'Gene', '3732', (133, 137))	('TIMP-1 membrane-cytoplasm translocation', 'MPA', (172, 211))	('eliminates', 'NegReg', (161, 171))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('MCF-7', 'CellLine', 'CVCL:0031', (96, 101))	('rat', 'Species', '10116', (19, 22))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('PANC-1', 'CellLine', 'CVCL:0480', (85, 91))	('silencing', 'Var', (112, 121))	('CD82', 'Gene', (133, 137))	('TIMP-1-eGFP', 'Gene', (29, 40))	('TIMP-1-eGFP', 'Gene', '7076', (29, 40))
183904	28030805	According to immunohistochemistry results of 32 patients in this study, we believe that defects in the N-terminus of TIMP-1 and CD82 endocytosis deficiency are both responsible for cancer development.	('defects in', 'Var', (88, 98))	('TIMP-1', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CD82 endocytosis deficiency', 'Disease', (128, 155))	('CD82 endocytosis deficiency', 'Disease', 'MESH:D007153', (128, 155))	('N-terminus', 'MPA', (103, 113))	('responsible', 'Reg', (165, 176))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('cancer', 'Disease', (181, 187))	('patients', 'Species', '9606', (48, 56))	('si', 'Chemical', 'MESH:D012825', (141, 143))
183927	28030805	Recombinant human TIMP-1 (Cys 24-Ala 207), TIMP-2 (Cys 27-Pro 220) and CD82-LEL (Gly 111-Leu 228) were procured from Sino Biological, Inc. (Beijing, China).	('TIMP-2', 'Gene', '7077', (43, 49))	('Cys 27-Pro', 'SUBSTITUTION', 'None', (51, 61))	('Cys 27-Pro', 'Var', (51, 61))	('Gly 111-Leu', 'Mutation', 'p.G111L', (81, 92))	('Gly 111-Leu 228', 'Var', (81, 96))	('human', 'Species', '9606', (12, 17))	('Cys 24-Ala', 'Mutation', 'p.C24A', (26, 36))	('Cys 24-Ala', 'Var', (26, 36))	('TIMP-2', 'Gene', (43, 49))
183970	28030805	CD63-LEL or CD82-LEL was linked to the cantilever tip through a polyethylene glycol linker via the thiol group of the cysteine residue.	('CD82-LEL', 'Var', (12, 20))	('cysteine', 'Chemical', 'MESH:D003545', (118, 126))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('thiol', 'Chemical', 'MESH:D013438', (99, 104))	('CD63-LEL', 'Var', (0, 8))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (64, 83))
184046	25625043	Women with high nuclear grade tumors were twice as likely to have adjuvant radiation therapy (OR: 2.01, 95% CI: 1.80-2.25, p < 0.0001), and women with two or more comorbidities were less likely to have BCS plus radiation therapy compared to BCS alone (OR: 0.75, 95% CI: 0.62-0.89, p = 0.002).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('Women', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('women', 'Species', '9606', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('adjuvant radiation therapy', 'CPA', (66, 92))	('less', 'NegReg', (182, 186))	('high nuclear grade', 'Var', (11, 29))
184049	25625043	Women with high nuclear grade tumors compared to low or intermediate nuclear grade were more than twice as likely to receive unilateral mastectomy (OR: 2.70, 95% CI: 2.39-3.06, p < 0.0001).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('Women', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('high nuclear grade', 'Var', (11, 29))
184058	25625043	Women with two or more comorbidities were less likely to receive hormone therapy (OR = 0.76, 95% CI: 0.64-0.91, p = 0.003), as were women with high nuclear grade or undifferentiated tumors compared to those with low or intermediate nuclear grade tumors (OR = 0.83, 95% CI: 0.76-0.92, p = 0.0002).	('Women', 'Species', '9606', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('women', 'Species', '9606', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('high nuclear', 'Var', (143, 155))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('hormone therapy', 'CPA', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('undifferentiated tumors', 'Disease', (165, 188))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('less', 'NegReg', (42, 46))	('undifferentiated tumors', 'Disease', 'MESH:D002277', (165, 188))	('tumors', 'Disease', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
184080	22301831	Our data suggest discontinuing HT has an immediate effect on breast cancer rates, lending support to the mechanism that cessation leads to tumor regression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('discontinuing', 'Var', (17, 30))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
184164	20424617	The three subgroups were thus defined to be (1) small IDC (<1.8 cm) large DCIS (>=1.5 cm), (2) large IDC (>=1.8 cm) small DCIS (<1.5 cm), and (3) all remaining IDC-DCIS samples.	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('IDC', 'Gene', '4000', (54, 57))	('IDC', 'Gene', (101, 104))	('IDC', 'Gene', (54, 57))	('IDC', 'Gene', (160, 163))	('DCIS', 'Phenotype', 'HP:0030075', (164, 168))	('>=1.8', 'Var', (106, 111))	('IDC', 'Gene', '4000', (101, 104))	('IDC', 'Gene', '4000', (160, 163))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
184207	20424617	In preclinical models of breast cancer, disruption of the TP53 pathway and/or constitutive activation of HER2, FAK or KRAS produce DCIS, but further inhibition of pRb signalling and/or activation of the phosphatidylinositol 3'-kinase pathway appear necessary to promote malignant progression (Lightfoot et al, 2004; Golubovskaya et al, 2009; Wu et al, 2009).	('pRb', 'Gene', (163, 166))	('TP53', 'Gene', '7157', (58, 62))	('KRAS', 'Gene', (118, 122))	('activation', 'PosReg', (91, 101))	('disruption', 'Var', (40, 50))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('inhibition', 'NegReg', (149, 159))	('pRb', 'Gene', '5925', (163, 166))	('HER2', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('promote', 'PosReg', (262, 269))	('TP53', 'Gene', (58, 62))	('malignant progression', 'CPA', (270, 291))	('FAK', 'Gene', (111, 114))	('HER2', 'Gene', '2064', (105, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('KRAS', 'Gene', '3845', (118, 122))	('FAK', 'Gene', '5747', (111, 114))
184208	20424617	Comparative genomic hybridisation studies have also identified genetic pathways - for example through loss of genetic material of 16q associated with well-differentiated to intermediately differentiated DCIS and grade 1 IDC, or gains of 8q, 17q, and 20q associated with poorly differentiated DCIS and grade 3 IDC (Buerger et al, 2001) - that support a linear progression model for the transition from normal to DCIS to IDC.	('well-differentiated', 'Disease', (150, 169))	('DCIS', 'Phenotype', 'HP:0030075', (411, 415))	('IDC', 'Gene', '4000', (220, 223))	('DCIS', 'Phenotype', 'HP:0030075', (292, 296))	('IDC', 'Gene', '4000', (419, 422))	('DCIS', 'Phenotype', 'HP:0030075', (203, 207))	('IDC', 'Gene', '4000', (309, 312))	('IDC', 'Gene', (309, 312))	('IDC', 'Gene', (220, 223))	('loss', 'NegReg', (102, 106))	('IDC', 'Gene', (419, 422))	('poorly differentiated DCIS', 'Disease', (270, 296))	('gains', 'Var', (228, 233))
184210	20424617	Hence, given that fast-replicating (high Ki-67) tumours might be expected to contain a higher burden of dysfunctional tumour suppressor genes, our study results raise the possibility that pure IDC tumours arise as a result of more drastic tumour suppressor gene defects, whereas IDC-DCIS tumours tend to evolve as a result of a more incremental accumulation of milder suppressor gene defects (Figure 2).	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumour', 'Disease', (118, 124))	('IDC-DCIS tumours', 'Disease', 'MESH:D002285', (279, 295))	('tumour', 'Disease', (197, 203))	('tumours', 'Disease', (288, 295))	('IDC tumours', 'Disease', 'MESH:D009369', (193, 204))	('dysfunctional tumour', 'Disease', 'MESH:D009369', (104, 124))	('DCIS', 'Phenotype', 'HP:0030075', (283, 287))	('tumours', 'Phenotype', 'HP:0002664', (288, 295))	('tumours', 'Disease', 'MESH:D009369', (288, 295))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('defects', 'Var', (262, 269))	('tumours', 'Disease', (48, 55))	('tumour', 'Disease', 'MESH:D009369', (288, 294))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumours', 'Disease', (197, 204))	('tumour', 'Disease', (288, 294))	('dysfunctional tumour', 'Disease', (104, 124))	('IDC-DCIS tumours', 'Disease', (279, 295))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Phenotype', 'HP:0002664', (197, 204))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('tumours', 'Disease', 'MESH:D009369', (197, 204))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('IDC tumours', 'Disease', (193, 204))	('tumour', 'Disease', (239, 245))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
184223	31455281	Even rare are patients with DCIS developing distant metastasis (DM) without preceding invasive locoregional or contralateral recurrence.	('DM', 'Disease', 'MESH:D009223', (64, 66))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('DCIS', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('distant metastasis', 'Disease', (44, 62))
184247	31455281	Other prognostic pathological markers associated with invasive or noninvasive recurrence and distant metastasis involve positive Her2 expression, high Ki67 staining (> 10%), alone or co-expression.	('high Ki67 staining', 'Var', (146, 164))	('expression', 'MPA', (134, 144))	('Her2', 'Gene', (129, 133))	('Her2', 'Gene', '2064', (129, 133))	('invasive or noninvasive recurrence', 'CPA', (54, 88))	('distant metastasis', 'CPA', (93, 111))
184249	31455281	The presented risks in this case include poorly differentiation, microinvasion, positive Her2 expression, and high Ki67, but the connection between them and DM remains unknown.	('microinvasion', 'Var', (65, 78))	('poorly differentiation', 'CPA', (41, 63))	('DM', 'Disease', 'MESH:D009223', (157, 159))	('Her2', 'Gene', (89, 93))	('Her2', 'Gene', '2064', (89, 93))	('Ki67', 'Var', (115, 119))	('positive', 'Var', (80, 88))
184372	25815848	Indeed, it has been shown that a low pHe promotes local invasion, promotes metastasis and inhibits anti-tumor immunity.	('pHe', 'Var', (37, 40))	('local invasion', 'CPA', (50, 64))	('low pHe', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('promotes', 'PosReg', (41, 49))	('inhibits', 'NegReg', (90, 98))	('pHe', 'Chemical', 'MESH:D010649', (37, 40))	('metastasis', 'CPA', (75, 85))	('promotes', 'PosReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
184373	25815848	In naturally occurring cancers, low pHe is a strong negative prognostic indicator of metastasis free survival.	('low', 'Var', (32, 35))	('metastasis free survival', 'CPA', (85, 109))	('pHe', 'Chemical', 'MESH:D010649', (36, 39))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('negative', 'NegReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('pHe', 'MPA', (36, 39))
184374	25815848	Further, it has been shown that inhibition of extracellular acidosis can inhibit metastasis and promote anti-tumor immunity.	('inhibition', 'Var', (32, 42))	('acidosis', 'Phenotype', 'HP:0001941', (60, 68))	('promote', 'PosReg', (96, 103))	('acidosis', 'Disease', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('metastasis', 'CPA', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('acidosis', 'Disease', 'MESH:D000138', (60, 68))	('tumor', 'Disease', (109, 114))	('inhibit', 'NegReg', (73, 80))
184385	25815848	For example, phenotypic variance can be buffered against mutations through the actions of cellular chaperones such as heat shock proteins, e.g.	('shock', 'Phenotype', 'HP:0031273', (123, 128))	('mutations', 'Var', (57, 66))	('heat shock proteins', 'Disease', (118, 137))	('heat shock proteins', 'Disease', 'MESH:D012769', (118, 137))
184387	25815848	Figure 1 shows some of the genetic changes that can underlie some of the well-known hallmarks of cancer.	('cancer', 'Disease', (97, 103))	('genetic changes', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('changes', 'Var', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
184388	25815848	For example, resistance to apoptosis can be accomplished through dozens of different genetic perturbations, such as Bcl-2, Bad, Bax, Akt, death receptors, etc..	('Akt', 'Gene', '207', (133, 136))	('Bad', 'Var', (123, 126))	('Bax', 'Gene', '581', (128, 131))	('Akt', 'Gene', (133, 136))	('Bcl-2', 'Gene', (116, 121))	('Bcl-2', 'Gene', '596', (116, 121))	('Bax', 'Gene', (128, 131))
184390	25815848	While this evolutionary arc can be measured through genetic and epigenetic changes, it also fundamentally reflects alterations in the physical microenvironment that both affect and are effected by the phenotypic properties of the cancer cells.	('changes', 'Var', (75, 82))	('epigenetic changes', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('affect', 'Reg', (170, 176))	('effected', 'Reg', (185, 193))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
184409	25815848	We have observed spontaneous loss of p53 via chromosomal deletions in two different breast epithelial cell lines flowing selection by intermittent hypoxia.	('hypoxia', 'Disease', (147, 154))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('loss', 'NegReg', (29, 33))	('chromosomal deletions', 'Var', (45, 66))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))
184414	25815848	As an alternative, there is evidence that highly glycolytic cells with mutant k-ras are selected under conditions of nutrient deprivation, and periluminal cells in DCIS are expected to be glucose-deprived.	('mutant', 'Var', (71, 77))	('glucose', 'Chemical', 'MESH:D005947', (188, 195))	('k-ras', 'Gene', '3845', (78, 83))	('k-ras', 'Gene', (78, 83))
184440	25815848	Specifically, acid that diffuses along concentration gradients into peri-tumoral normal tissue promotes tumor growth and invasion because it reduces proliferation of surrounding stromal cells, induces breakdown of normal extracellular matrix (ECM), promotes angiogenesis, and blunts the normal immune response to tumor antigens.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('proliferation', 'CPA', (149, 162))	('invasion', 'CPA', (121, 129))	('breakdown', 'MPA', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('promotes', 'PosReg', (249, 257))	('tumor', 'Disease', (104, 109))	('reduces', 'NegReg', (141, 148))	('acid', 'Var', (14, 18))	('tumor', 'Disease', (73, 78))	('induces', 'Reg', (193, 200))	('promotes', 'PosReg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('angiogenesis', 'CPA', (258, 270))	('blunts', 'NegReg', (276, 282))
184443	25815848	Indeed, it has been convincingly been shown that the pHe in canine sarcomas ranged from 6.37-7.42; and that, furthermore, an acidic pHe was a strong negative predictor of metastasis free survival (HR, 0.29; p+0.005).	('pHe', 'Chemical', 'MESH:D010649', (132, 135))	('acidic', 'Var', (125, 131))	('pHe', 'Chemical', 'MESH:D010649', (53, 56))	('canine', 'Species', '9615', (60, 66))	('sarcomas', 'Disease', 'MESH:D012509', (67, 75))	('sarcomas', 'Phenotype', 'HP:0100242', (67, 75))	('negative', 'NegReg', (149, 157))	('sarcomas', 'Disease', (67, 75))	('metastasis free survival', 'CPA', (171, 195))
184445	25815848	A number of studies have demonstrated acidic pHe can induce release of (cysteine or aspartyl) cathepsin proteinases, which promote local invasion and tissue remodeling.	('tissue remodeling', 'CPA', (150, 167))	('release', 'MPA', (60, 67))	('cathepsin proteinases', 'Protein', (94, 115))	('promote', 'PosReg', (123, 130))	('(cysteine', 'Chemical', 'MESH:D003545', (71, 80))	('local invasion', 'CPA', (131, 145))	('acidic pHe', 'Var', (38, 48))	('pHe', 'Chemical', 'MESH:D010649', (45, 48))
184453	25815848	This model suggests that neutralization of the acidity could under, some circumstances, "tip the balance of power" thus delaying carcinogenesis and reducing tumor invasive growth.	('tumor', 'Disease', (157, 162))	('balance of power', 'MPA', (97, 113))	('delaying', 'NegReg', (120, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('carcinogenesis', 'Disease', (129, 143))	('reducing', 'NegReg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('acidity', 'MPA', (47, 54))	('neutralization', 'Var', (25, 39))
184484	25815848	Understanding these interactions at a mechanistic level permits novel therapeutic perturbations that can delay or even prevent the evolutionary dynamics that govern carcinogenesis and tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('prevent', 'NegReg', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('perturbations', 'Var', (82, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (165, 179))	('tumor', 'Disease', (184, 189))	('evolutionary dynamics', 'CPA', (131, 152))	('carcinogenesis', 'Disease', (165, 179))
184491	33531527	Competing risks analysis of the young patients showed that left-sided RT was associated with higher heart-related mortality rates (Grey's test, P = 0.049).	('higher', 'PosReg', (93, 99))	('heart-related', 'Disease', (100, 113))	('mortality', 'Disease', (114, 123))	('patients', 'Species', '9606', (38, 46))	('mortality', 'Disease', 'MESH:D003643', (114, 123))	('left-sided RT', 'Var', (59, 72))
184513	33531527	Stratifying patients into different age groups revealed that left-sided RT was associated with higher cardiac mortality in patients aged <= 50 years (P = 0.048, Fig.	('patients', 'Species', '9606', (12, 20))	('mortality', 'Disease', (110, 119))	('higher', 'PosReg', (95, 101))	('patients', 'Species', '9606', (123, 131))	('left-sided RT', 'Var', (61, 74))	('mortality', 'Disease', 'MESH:D003643', (110, 119))
184517	33531527	In the univariate analysis given the competing risks, the cardiac mortality rate of left-sided tumor laterality was significantly higher than that of right-sided tumor laterality in patients aged <= 50 years, with estimated 20-year rates of 0.67% (95% confidence interval [CI], 0.38-1.13) and 0.51% (95% CI 0.19-1.15), respectively (P = 0.049).	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('higher', 'PosReg', (130, 136))	('tumor', 'Disease', (162, 167))	('mortality', 'Disease', 'MESH:D003643', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('left-sided', 'Var', (84, 94))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mortality', 'Disease', (66, 75))	('tumor', 'Disease', (95, 100))
184624	31388937	All 16 biopsies showing low grade DCIS that were subsequently upstaged to IBC, also had low grade IBC.	('DCIS', 'Disease', (34, 38))	('DCIS', 'Disease', 'MESH:D002285', (34, 38))	('low grade', 'Var', (24, 33))	('IBC', 'Disease', (74, 77))	('IBC', 'Disease', (98, 101))	('IBC', 'Disease', 'MESH:D001943', (74, 77))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('IBC', 'Disease', 'MESH:D001943', (98, 101))
184648	31388937	Our findings provide reassurance for both patients and clinicians regarding participation in ongoing randomised trials of non-operative management, especially for women with low grade DCIS on preoperative biopsy.	('low grade', 'Var', (174, 183))	('women', 'Species', '9606', (163, 168))	('DCIS', 'Disease', (184, 188))	('DCIS', 'Disease', 'MESH:D002285', (184, 188))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('patients', 'Species', '9606', (42, 50))
184669	30820924	There were statistically significant differences in phenotype, nuclear grade, and Ki-67 labeling index between BRCA1 and BRCA2 mutation carriers.	('nuclear grade', 'CPA', (63, 76))	('mutation', 'Var', (127, 135))	('BRCA2', 'Gene', '675', (121, 126))	('BRCA1', 'Gene', '672', (111, 116))	('Ki-67 labeling index', 'CPA', (82, 102))	('BRCA1', 'Gene', (111, 116))	('significant differences', 'Reg', (25, 48))	('BRCA2', 'Gene', (121, 126))
184671	30820924	The imaging and histological characteristics of BRCA1/2 mutation carriers were consistent with other countries' studies.	('BRCA1/2', 'Gene', '672;675', (48, 55))	('mutation', 'Var', (56, 64))	('BRCA1/2', 'Gene', (48, 55))
184672	30820924	All lesions in BRCA1 mutation carriers could be detected by MRI.	('BRCA1', 'Gene', (15, 20))	('BRCA1', 'Gene', '672', (15, 20))	('mutation', 'Var', (21, 29))
184675	30820924	reported that the prevalence of BRCA1/2 mutations in the Japanese population was higher than in non-Ashkenazi individuals under the same conditions of personal and family history of breast and/or ovarian cancer (odds ratio 1.87).	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('BRCA1/2', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (40, 49))	('BRCA1/2', 'Gene', '672;675', (32, 39))	('breast and/or ovarian cancer', 'Disease', (182, 210))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (182, 210))
184676	30820924	A number of countries other than Japan have previously conducted studies that demonstrated differences in histopathology and imaging characteristics between breast cancers associated with BRCA1 and BRCA2 mutations.	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('BRCA1', 'Gene', (188, 193))	('breast cancers', 'Disease', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('BRCA2', 'Gene', (198, 203))	('mutations', 'Var', (204, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('associated', 'Reg', (172, 182))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('BRCA2', 'Gene', '675', (198, 203))	('BRCA1', 'Gene', '672', (188, 193))
184678	30820924	Although the Guidebook for Diagnosis and Treatment of Hereditary Breast and Ovarian Cancer Syndrome 2017, an initiative spearheaded by Japan's Ministry of Health, Labor, and Welfare, recommends annual contrast-enhanced MRI examination for women aged >= 25 years who have a BRCA mutation, currently, this screening study is not covered by the national health insurance program.	('BRCA', 'Gene', (273, 277))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (76, 90))	('women', 'Species', '9606', (239, 244))	('Hereditary Breast and Ovarian Cancer', 'Disease', 'MESH:D061325', (54, 90))	('mutation', 'Var', (278, 286))	('BRCA', 'Gene', '672', (273, 277))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))
184680	30820924	Consequently, the present study aimed to investigate imaging features of breast cancer developing in Japanese BRCA1/2 mutation carriers to build a proper surveillance system for asymptomatic high-risk individuals in the future.	('BRCA1/2', 'Gene', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('BRCA1/2', 'Gene', '672;675', (110, 117))	('breast cancer', 'Disease', (73, 86))	('mutation', 'Var', (118, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
184696	30820924	The Wilcoxon signed-rank test was used to compare the age and tumor size between BRCA1 and BRCA2 mutation carriers.	('BRCA2', 'Gene', '675', (91, 96))	('BRCA1', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('BRCA2', 'Gene', (91, 96))	('mutation', 'Var', (97, 105))	('carriers', 'Reg', (106, 114))	('BRCA1', 'Gene', '672', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
184704	30820924	The tumors which had been imaged by both mammography and MR were divided into 30 breast cancers in BRCA1 mutation carriers and 29 breast cancers in BRCA2 mutation carriers.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA1', 'Gene', '672', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancers', 'Disease', 'MESH:D001943', (130, 144))	('breast cancers', 'Disease', (130, 144))	('mutation', 'Var', (105, 113))	('BRCA1', 'Gene', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BRCA2', 'Gene', (148, 153))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('breast cancers', 'Disease', (81, 95))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('tumors', 'Disease', (4, 10))	('BRCA2', 'Gene', '675', (148, 153))
184705	30820924	The median patient age was 40 years (range 25-71 years) in BRCA1 mutation carriers and 43 years (range 23-73 years) in BRCA2 carriers (P = 0.660).	('BRCA1', 'Gene', '672', (59, 64))	('BRCA1', 'Gene', (59, 64))	('patient', 'Species', '9606', (11, 18))	('BRCA2', 'Gene', (119, 124))	('mutation', 'Var', (65, 73))	('BRCA2', 'Gene', '675', (119, 124))
184707	30820924	Invasive ductal carcinoma was the most prevalent histology in both groups; however, the distribution of tumor histology differed significantly between BRCA1 and BRCA2 mutation carriers (P = 0.002).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (9, 25))	('BRCA1', 'Gene', '672', (151, 156))	('differed', 'Reg', (120, 128))	('mutation', 'Var', (167, 175))	('tumor', 'Disease', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('BRCA1', 'Gene', (151, 156))	('BRCA2', 'Gene', (161, 166))	('ductal carcinoma', 'Disease', 'MESH:D044584', (9, 25))	('ductal carcinoma', 'Disease', (9, 25))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('BRCA2', 'Gene', '675', (161, 166))
184708	30820924	Tumors in BRCA1 and BRCA2 mutation carriers also demonstrated statistically significant differences in phenotype, nuclear grade and Ki-67 labeling index (P < 0.001, P = 0.020, P = 0.001, respectively).	('Ki-67 labeling index', 'CPA', (132, 152))	('BRCA2', 'Gene', '675', (20, 25))	('differences', 'Reg', (88, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRCA1', 'Gene', '672', (10, 15))	('nuclear grade', 'CPA', (114, 127))	('mutation', 'Var', (26, 34))	('BRCA1', 'Gene', (10, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BRCA2', 'Gene', (20, 25))	('phenotype', 'CPA', (103, 112))
184709	30820924	Tumors in BRCA1 mutation carriers were associated with significantly higher histological and nuclear grade, or Ki-67 status.	('Ki-67 status', 'CPA', (111, 123))	('mutation', 'Var', (16, 24))	('BRCA1', 'Gene', '672', (10, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRCA1', 'Gene', (10, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (69, 75))
184710	30820924	While DCIS was not detected in BRCA1 carriers, the histology of specimens from BRCA2 mutation carriers frequently contained DCIS.	('BRCA2', 'Gene', '675', (79, 84))	('BRCA1', 'Gene', '672', (31, 36))	('DCIS', 'Phenotype', 'HP:0030075', (6, 10))	('mutation', 'Var', (85, 93))	('BRCA1', 'Gene', (31, 36))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('DCIS', 'MPA', (124, 128))	('BRCA2', 'Gene', (79, 84))	('contained', 'Reg', (114, 123))
184715	30820924	We noted three tumors in with BRCA1 mutation carriers detected by MRI only.	('tumors', 'Disease', (15, 21))	('BRCA1', 'Gene', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('BRCA1', 'Gene', '672', (30, 35))	('mutation', 'Var', (36, 44))
184723	30820924	Twenty-four of 30 (80%) BRCA1 lesions, which were all depicted on mammography, manifested as a mass and/or architectural distortion on mammography.	('lesions', 'Var', (30, 37))	('BRCA1', 'Gene', '672', (24, 29))	('BRCA1', 'Gene', (24, 29))	('architectural distortion', 'CPA', (107, 131))
184727	30820924	However, findings of the time intensity curve on dynamic contrast-enhanced MRI and peritumoral edema on T2-weighted images did not significantly differ according to the BRCA mutation status.	('edema', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutation', 'Var', (174, 182))	('tumor', 'Disease', (87, 92))	('BRCA', 'Gene', '672', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('edema', 'Disease', 'MESH:D004487', (95, 100))	('BRCA', 'Gene', (169, 173))	('edema', 'Phenotype', 'HP:0000969', (95, 100))
184730	30820924	The MRI-detected lesions were all associated with BRCA1 mutation.	('mutation', 'Var', (56, 64))	('associated', 'Reg', (34, 44))	('BRCA1', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (50, 55))
184738	30820924	These features have been discussed in the past, as breast cancer with BRCA1 mutation carriers has the tendency to develop rapidly growing triple-negative cancer with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA1', 'Gene', '672', (70, 75))	('mutation', 'Var', (76, 84))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('BRCA1', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('cancer', 'Disease', (58, 64))	('breast cancer', 'Disease', (51, 64))
184741	30820924	demonstrated that MRI surveillance is insufficient for BRCA1 mutation carriers because the sensitivity of a combined annual MR examination with mammography breast cancer screening program in BRCA1 mutation carriers was the lowest (81.3%) compared with other groups (BRCA2, 92.0%; family history, 95.2%; personal history, 91.1%).	('BRCA1', 'Gene', (191, 196))	('BRCA2', 'Gene', '675', (266, 271))	('BRCA1', 'Gene', '672', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BRCA2', 'Gene', (266, 271))	('lowest', 'NegReg', (223, 229))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('BRCA1', 'Gene', (55, 60))	('BRCA1', 'Gene', '672', (191, 196))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('mutation', 'Var', (197, 205))	('sensitivity', 'MPA', (91, 102))
184742	30820924	on contralateral breast cancer showed a 20-year cumulative risk after breast cancer diagnosis in 40% of BRCA1 carriers and 26% of BRCA2 carriers (hazard ratio for comparing BRCA2 vs BRCA1, 0.62; 95% CI 0.47-0.82; P = 0.001).	('carriers', 'Var', (110, 118))	('contralateral breast cancer', 'Disease', (3, 30))	('BRCA1', 'Gene', '672', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA2', 'Gene', (173, 178))	('BRCA1', 'Gene', (182, 187))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('breast cancer', 'Disease', (70, 83))	('BRCA2', 'Gene', (130, 135))	('BRCA1', 'Gene', (104, 109))	('BRCA2', 'Gene', '675', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (3, 30))	('BRCA2', 'Gene', '675', (130, 135))
184748	30820924	For BRCA2 mutation carriers, however, six lesions showed non-mass enhancement, and all these involved microcalcification with luminal subtype.	('microcalcification', 'Disease', (102, 120))	('mutation', 'Var', (10, 18))	('involved', 'Reg', (93, 101))	('BRCA2', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (4, 9))	('non-mass enhancement', 'MPA', (57, 77))
184753	30820924	reported that mammography's specific ability to detect microcalcifications is especially valuable in BRCA2 mutation carriers because the proportion of calcified DCIS in women who are BRCA2 mutation carriers was larger than that of women who are BRCA1 mutation carriers.	('calcified DCIS', 'Disease', (151, 165))	('women', 'Species', '9606', (231, 236))	('BRCA2', 'Gene', (101, 106))	('BRCA2', 'Gene', (183, 188))	('women', 'Species', '9606', (169, 174))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('BRCA2', 'Gene', '675', (101, 106))	('mutation', 'Var', (189, 197))	('BRCA2', 'Gene', '675', (183, 188))	('BRCA1', 'Gene', '672', (245, 250))	('mutation', 'Var', (107, 115))	('BRCA1', 'Gene', (245, 250))
184755	30820924	In addition, it has been suggested that breast density is associated with the risk of breast cancer.	('associated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('breast density', 'Var', (40, 54))
184760	30820924	As the result of other studies, BRCA mutation carriers younger than 40 years may not benefit from mammography in addition to MRI, because they rarely develop MRI-occult breast cancers.	('mutation', 'Var', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('BRCA', 'Gene', '672', (32, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (169, 183))	('BRCA', 'Gene', (32, 36))	('MRI-occult breast cancers', 'Disease', (158, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('MRI-occult breast cancers', 'Disease', 'MESH:D001943', (158, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
184763	30820924	The current study demonstrated that lesions associated with BRCA mutation carriers tended to develop in the posterior portion of the breast (Table 4).	('develop', 'PosReg', (93, 100))	('mutation', 'Var', (65, 73))	('BRCA', 'Gene', (60, 64))	('BRCA', 'Gene', '672', (60, 64))
184765	30820924	We believe the results of these reports are related to the tendency of BRCA1 mutation carriers to develop triple-negative cancers as shown earlier.	('BRCA1', 'Gene', (71, 76))	('mutation', 'Var', (77, 85))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('BRCA1', 'Gene', '672', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('develop', 'PosReg', (98, 105))
184766	30820924	MRI surveillance for BRCA mutation carriers is especially important for early detection of posteriorly located lesions, as these are difficult to detect on both self-breast exam and clinical breast exam.	('BRCA', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (21, 25))	('mutation', 'Var', (26, 34))
184772	29545915	The cultures are composed of CK18, desmoglein 3, and CK19-positive luminal cells and vimentin, p63, and CK14-positive myoepithelial cells, suggesting the maintenance of in vivo heterogeneity.	('CK18', 'Gene', '3875', (29, 33))	('p63', 'Gene', '8626', (95, 98))	('vimentin', 'Gene', '7431', (85, 93))	('CK19-positive', 'Var', (53, 66))	('myoepithelial', 'Disease', (118, 131))	('desmoglein 3', 'Gene', '1830', (35, 47))	('CK14', 'Gene', '3861', (104, 108))	('myoepithelial', 'Disease', 'MESH:D009208', (118, 131))	('CK18', 'Gene', (29, 33))	('p63', 'Gene', (95, 98))	('CK14', 'Gene', (104, 108))	('vimentin', 'Gene', (85, 93))	('desmoglein 3', 'Gene', (35, 47))
184896	29545915	EpCAM-FITC (5 muL per reaction, #347197, BD Biosciences, San Jose, CA) and CD49f (alpha6 integrin)-AF647 (1 muL per reaction, #562494, BD Biosciences) antibodies were used in FACS.	('EpCAM', 'Gene', '4072', (0, 5))	('#347197', 'Var', (32, 39))	('CD49f', 'Gene', '3655', (75, 80))	('CD49f', 'Gene', (75, 80))	('EpCAM', 'Gene', (0, 5))	('AF', 'Disease', 'MESH:D001281', (99, 101))
184920	26539016	The dedicated software automatically calculated the ADCs by using the signal intensity within the manually drawn ROI with the following equation: ADC = [ln(S0)-ln(S800)]/800, in which S0 and S800 were the signal intensities on DWI with b values of 0 and 800 sec/mm2, respectively (Fig.	('mm2', 'Gene', '10687', (262, 265))	('mm2', 'Gene', (262, 265))	('S800', 'Var', (191, 195))
184935	30507500	As expected, R-SLSC beamforming improves cyst and hematoma contrast by up to 6.35 and 1.55 dB, respectively, when compared to the original B-mode image, and similar improvements are achieved with SLSC and M-Weighted SLSC imaging.	('R-SLSC', 'Var', (13, 19))	('hematoma', 'Disease', (50, 58))	('improves', 'PosReg', (32, 40))	('hematoma', 'Disease', 'MESH:D006406', (50, 58))
184993	31537802	Furthermore, the measured values from all 10 breast ductal carcinoma samples (1324 +- 433 rad/104) were significantly larger than those of the 10 healthy ones (408 +- 189 rad/104):these retardance measurements were calculated from the original measured data (in Fig.	('larger', 'PosReg', (118, 124))	('retardance', 'Disease', (186, 196))	('1324 +- 433 rad/104', 'Var', (78, 97))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (45, 68))	('retardance', 'Disease', 'MESH:D008607', (186, 196))	('breast ductal carcinoma', 'Disease', 'MESH:D001943', (45, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (52, 68))	('breast ductal carcinoma', 'Disease', (45, 68))
185026	23299526	The remaining cases relate to differences in interpretation of the pathology findings such as isolated tumour cells (ITC's) (5), cells identified by immunohistochemistry only (3), deposits in axillary nodal fat (2), scarring in lymph nodes (1) and involvement of an intramammary lymph node (1).	('scarring', 'CPA', (216, 224))	('scar', 'Phenotype', 'HP:0100699', (216, 220))	('isolated tumour', 'Disease', 'MESH:D009369', (94, 109))	('scarring', 'Phenotype', 'HP:0100699', (216, 224))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('deposits', 'Var', (180, 188))	('isolated tumour', 'Disease', (94, 109))
185143	27077731	The contrast-to-noise ratio (CNR) between the lesion and normal tissue on DWI was calculated as previously described, using the following equation:  where mut and mun are the mean DWI signal intensity values for the tumor and normal fibroglandular tissue ROIs, respectively, and sigmat and sigman are the corresponding respective SDs.	('SDs', 'Chemical', 'MESH:D012967', (330, 333))	('tumor', 'Disease', (216, 221))	('DWI signal intensity', 'MPA', (180, 200))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mun', 'Var', (163, 166))
185151	27077731	Two patients in the cancer cohort were high-risk BRCA1 mutation carriers, whereas the remaining patients had a family or personal history of breast cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('BRCA1', 'Gene', '672', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('cancer', 'Disease', (20, 26))	('BRCA1', 'Gene', (49, 54))	('breast cancer', 'Disease', (141, 154))	('mutation', 'Var', (55, 63))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (4, 12))
185156	27077731	Both BRCA1 mutation carriers had mammographically occult ER-negative breast cancers (one DCIS and one triple receptor-negative invasive ductal carcinoma) detected on screening MRI.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (127, 152))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (136, 152))	('ER', 'Gene', '2099', (57, 59))	('BRCA1', 'Gene', '672', (5, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast cancers', 'Disease', 'MESH:D001943', (69, 83))	('breast cancers', 'Disease', (69, 83))	('mutation', 'Var', (11, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('BRCA1', 'Gene', (5, 10))	('invasive ductal carcinoma', 'Disease', (127, 152))
185195	27077731	Thus, this study was not designed to evaluate whether DWI might detect some cancers not visualized using DCE-MRI and also may underestimate the false-positive rate of DWI in the presence of BI-RADS 3 (probably benign) and false-positive BI-RADS 4 or 5 lesions.	('BI-RADS 3', 'Var', (190, 199))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('DCE', 'Gene', '1718', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('underestimate', 'NegReg', (126, 139))	('DCE', 'Gene', (105, 108))	('BI-RADS 4', 'Var', (237, 246))	('false-positive', 'MPA', (144, 158))
185364	24521674	There was no significant difference in IBTR among patients with TNBC compared to those with the other subtypes of tumors.	('TNBC', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('IBTR', 'MPA', (39, 43))
185396	24521674	Young women have more aggressive tumor characteristics, such as high histologic grade, lymphovascular invasion, hormone receptor- negative breast cancer, BRCA1 and BRCA2 mutation associated cancers, and breast cancers associated with adverse gene expression profiles compared with their older counterparts.	('aggressive tumor', 'Disease', (22, 38))	('high histologic grade', 'CPA', (64, 85))	('BRCA2', 'Gene', '675', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('breast cancers', 'Disease', 'MESH:D001943', (203, 217))	('breast cancers', 'Disease', (203, 217))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('BRCA1', 'Gene', '672', (154, 159))	('hormone receptor', 'Gene', (112, 128))	('mutation', 'Var', (170, 178))	('BRCA1', 'Gene', (154, 159))	('breast cancers', 'Phenotype', 'HP:0003002', (203, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('women', 'Species', '9606', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('lymphovascular invasion', 'CPA', (87, 110))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('cancers', 'Disease', (190, 197))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('aggressive tumor', 'Disease', 'MESH:D001523', (22, 38))	('breast cancer', 'Disease', (139, 152))	('BRCA2', 'Gene', (164, 169))	('hormone receptor', 'Gene', '3164', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
185397	24521674	In one study, very young patients with tumors classified as luminal B, HER2, and triple negative subtypes were at increased risk of IBTR when compared with older patients, but no significant effect of age was seen in the subgroup with the most favorable luminal A subtype.	('patients', 'Species', '9606', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('luminal', 'Var', (60, 67))	('HER2', 'Gene', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('HER2', 'Gene', '2064', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Disease', (39, 45))	('IBTR', 'Disease', (132, 136))
185402	24521674	Thus, the panel concluded that while the adverse biologic and pathologic factors associated with young age are to some extent mitigated with excision to negative margins, use of systemic therapies, use of a radiation boost, and possible exclusion of young BRCA mutation carriers from a BCT approach, there is no evidence supporting obtaining wider negative margins beyond no ink on tumor solely on the basis of young patient age.	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Disease', (382, 387))	('mutation', 'Var', (261, 269))	('BRCA', 'Gene', '672', (256, 260))	('patient', 'Species', '9606', (417, 424))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('BRCA', 'Gene', (256, 260))
185410	24521674	Later, additional studies revealed that patients with EIC positive tumors did not have an increase in IBTR unless tumor cells were present at the inked margin.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('EIC positive', 'Var', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('tumors', 'Disease', (67, 73))	('IBTR', 'MPA', (102, 106))
185453	22235100	Fragments were incubated in a 12-well culture dish with a mixture of collagenase type IV (LS004189; Worthington Biochemical Corporation) in X-VIVO 20 Serum-free Medium (BE04-448Q; Cambrex) in a 37 C incubator with 5% CO2 with constant agitation for 1 to 2 hours, depending on the size of the sample.	('BE04', 'Chemical', '-', (169, 173))	('agitation', 'Phenotype', 'HP:0000713', (235, 244))	('agitation', 'Disease', 'MESH:D011595', (235, 244))	('BE04-448Q;', 'Var', (169, 179))	('agitation', 'Disease', (235, 244))	('LS004189', 'Var', (90, 98))	('CO2', 'Chemical', '-', (217, 220))
185457	22235100	The purity of the population was checked by flow cytometry [antibodies CD326 (EpCAM) FITC from Milteny Biotec, APC anti-human CD45 from Pharmingen, and PE mouse anti-human CD10 from Pharmingen].	('CD10', 'Gene', (172, 176))	('human', 'Species', '9606', (120, 125))	('CD10', 'Gene', '4311', (172, 176))	('human', 'Species', '9606', (166, 171))	('CD45', 'Gene', '5788', (126, 130))	('Biotec', 'Chemical', '-', (103, 109))	('EpCAM', 'Gene', (78, 83))	('mouse', 'Species', '10090', (155, 160))	('anti-human', 'Var', (115, 125))	('FITC', 'Chemical', 'MESH:D016650', (85, 89))	('CD45', 'Gene', (126, 130))	('EpCAM', 'Gene', '4072', (78, 83))
185466	22235100	To select the genes for the CD10+ signature, we carried out a class comparison of the tumor-associated CD10+ cells (n = 28) with CD10+ cells from normal breast tissues (n = 3) using the 10% most variant probe sets across the entire series (n = 5,467 probe sets).	('CD10', 'Gene', (103, 107))	('CD10', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CD10', 'Gene', '4311', (103, 107))	('CD10', 'Gene', '4311', (28, 32))	('tumor', 'Disease', (86, 91))	('CD10', 'Gene', (129, 133))	('variant', 'Var', (195, 202))	('CD10', 'Gene', '4311', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
185591	23161115	Our hypothesis was that women with borderline lesions are less likely to be diagnosed with subsequent ipsilateral breast cancer than are women with DCIS.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('borderline lesions', 'Var', (35, 53))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('ipsilateral breast cancer', 'Disease', (102, 127))	('women', 'Species', '9606', (24, 29))	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (102, 127))	('women', 'Species', '9606', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('less', 'NegReg', (58, 62))
185643	23161115	Clinically, borderline lesions and DCIS have similar subsequent rates of all IBE and, most importantly, of invasive IBE.	('IBE', 'Chemical', '-', (77, 80))	('IBE', 'Chemical', '-', (116, 119))	('borderline lesions', 'Var', (12, 30))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('IBE', 'Disease', (77, 80))
185691	32074407	This gave us a clue to choose BI-RADS 4C as the cutoff value for benign and malignant lesions in our study and this cutoff value exhibited high specificity and negative predictive value, indicating CESM could be recommended as a potential exclusion diagnosis modality.	('BI-RADS', 'Var', (30, 37))	('malignant lesions', 'Disease', (76, 93))	('malignant lesions', 'Disease', 'MESH:D009369', (76, 93))
185754	27980416	Another study has already reported that it is not easy to distinguish between patients with low-grade DCIS and typical ductal hyperplasia.	('patients', 'Species', '9606', (78, 86))	('low-grade', 'Var', (92, 101))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (119, 137))	('ductal hyperplasia', 'Disease', (119, 137))	('DCIS', 'Disease', (102, 106))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
185816	25382741	The TNM stages recorded were major in TisN0M0, T1aN0M0 stage to T1bN0M0.	('T1bN0M0', 'Var', (64, 71))	('TNM', 'Gene', (4, 7))	('T1aN0M0', 'Var', (47, 54))	('TNM', 'Gene', '10178', (4, 7))
185817	25382741	A T1aN1M0 tumor was also noted.	('tumor', 'Disease', (10, 15))	('T1aN1M0', 'Var', (2, 9))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
185837	25382741	Half of the data did not contain details regarding TNM stage; the other half were for stages TisN0M0, T1aN0M0, T1bN0M0 and T1aN1M0.	('T1aN0M0', 'Var', (102, 109))	('TNM', 'Gene', '10178', (51, 54))	('T1aN1M0', 'Var', (123, 130))	('T1bN0M0', 'Var', (111, 118))	('TisN0M0', 'Var', (93, 100))	('TNM', 'Gene', (51, 54))
185907	22025213	While we have not shown progression to invasion in any of the xenografts eight weeks following transplantation, there is the potential for this model to mimic human DCIS heterogeneity and that a fraction of DCIS lesions may progress to invasion with longer time follow up.	('DCIS', 'Gene', (207, 211))	('invasion', 'CPA', (236, 244))	('progress', 'PosReg', (224, 232))	('lesions', 'Var', (212, 219))	('human', 'Species', '9606', (159, 164))
185925	22025213	Tissue sections were incubated for 5 min in MOM Diluent Working Solution (MOM Kit, Vector Laboratories) before being covered in primary antibodies (anti-HER2 and anti-human CK 19) diluted in MOM Diluent.	('CK 19', 'Gene', '3880', (173, 178))	('CK 19', 'Gene', (173, 178))	('anti-HER2', 'Var', (148, 157))	('human', 'Species', '9606', (167, 172))
185928	22025213	Patients with biopsies containing hyperplasia and DCIS were younger compared to patients with normal biopsies (44 and 48 vs. 58, respectively; p<= 0.05).	('hyperplasia', 'Disease', 'MESH:D006965', (34, 45))	('patients', 'Species', '9606', (80, 88))	('Patients', 'Species', '9606', (0, 8))	('hyperplasia', 'Disease', (34, 45))	('DCIS', 'Var', (50, 54))
185930	22025213	Seven of these were ER+ and PR+, including one specimen from a patient with a BRCA2 mutation (Case 5).	('BRCA2', 'Gene', '675', (78, 83))	('mutation', 'Var', (84, 92))	('patient', 'Species', '9606', (63, 70))	('BRCA2', 'Gene', (78, 83))
185935	22025213	The other three cases of DCIS which did not grow tended to yield a lower number of cells following digestion of the corresponding biopsy compared to the DCIS cases which did grow (827 vs. 3212 cells/mg of tissue, respectively), including the case from the patient with a BRCA2 mutation (table 3).	('mutation', 'Var', (277, 285))	('BRCA2', 'Gene', '675', (271, 276))	('BRCA2', 'Gene', (271, 276))	('lower', 'NegReg', (67, 72))	('patient', 'Species', '9606', (256, 263))
185942	22025213	In xenografts from cases 7 and 10, of which 98% and 99% of cells were ER+ in the patient biopsies (figure 3B-C), nearly 100% of transplanted cells retained ER expression (figure 3E-F).	('ER expression', 'MPA', (156, 169))	('ER+', 'Var', (70, 73))	('patient', 'Species', '9606', (81, 88))
185955	22025213	The NSG mice have targeted mutations in the common cytokine-receptor interleukin-2 receptor (IL-2R), which appears essential for the development of a permissive environment for engraftment of primary human DCIS cells.	('mutations', 'Var', (27, 36))	('IL-2R', 'Gene', '16184', (93, 98))	('human', 'Species', '9606', (200, 205))	('IL-2R', 'Gene', (93, 98))	('mice', 'Species', '10090', (8, 12))
186017	30410060	High P4HA2 expression was an independent prognostic factor in predicting shorter LRFI.	('P4HA2', 'Gene', (5, 10))	('P4HA2', 'Gene', '8974', (5, 10))	('High', 'Var', (0, 4))
186084	30410060	Also, there was a positive association between high P4HA2 expression either within tumour epithelial cells or stromal cells and high HIF-1a expression.	('expression', 'MPA', (140, 150))	('high', 'Var', (47, 51))	('tumour epithelial', 'Disease', 'MESH:D009375', (83, 100))	('P4HA2', 'Gene', '8974', (52, 57))	('tumour epithelial', 'Disease', (83, 100))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('P4HA2', 'Gene', (52, 57))	('HIF-1a', 'Gene', '3091', (133, 139))	('HIF-1a', 'Gene', (133, 139))
186089	30410060	Analysis using the Breast Cancer Gene-Expression Miner v4.1(bc-GenExMiner v4.1) database showed that high P4HA2 mRNA is associated with higher metastatic relapse and/or death (p < 0.0001).	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('v4.1', 'Gene', '28783', (55, 59))	('P4HA2', 'Gene', (106, 111))	('higher', 'PosReg', (136, 142))	('v4.1', 'Gene', (55, 59))	('Breast Cancer', 'Disease', 'MESH:D001943', (19, 32))	('death', 'CPA', (169, 174))	('v4.1', 'Gene', '28783', (74, 78))	('Breast Cancer', 'Disease', (19, 32))	('Breast Cancer', 'Phenotype', 'HP:0003002', (19, 32))	('high', 'Var', (101, 105))	('P4HA2', 'Gene', '8974', (106, 111))	('v4.1', 'Gene', (74, 78))	('metastatic relapse', 'CPA', (143, 161))
186092	30410060	High P4HA2 expression within tumour epithelial cells was associated with shorter LRFI in the whole cohort of pure DCIS (HR = 2.3, 95%CI = 1.3-4.1; p = 0.003, Fig.	('P4HA2', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('LRFI', 'CPA', (81, 85))	('shorter', 'NegReg', (73, 80))	('DCIS', 'Disease', (114, 118))	('DCIS', 'Disease', 'MESH:D002285', (114, 118))	('P4HA2', 'Gene', '8974', (5, 10))	('tumour epithelial', 'Disease', 'MESH:D009375', (29, 46))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('tumour epithelial', 'Disease', (29, 46))
186095	30410060	Interestingly, there was an association between high P4HA2 expression and ipsilateral local recurrence as invasive disease in patients treated with BCS without post-operative adjuvant RT (HR = 2.4, 95%CI = 1.1-5.2; p = 0.03) but this associated lost its significance in patients who were offered adjuvant RT (Figs.	('P4HA2', 'Gene', (53, 58))	('invasive disease', 'Disease', (106, 122))	('patients', 'Species', '9606', (270, 278))	('invasive disease', 'Disease', 'MESH:D009361', (106, 122))	('expression', 'MPA', (59, 69))	('ipsilateral', 'Disease', (74, 85))	('patients', 'Species', '9606', (126, 134))	('P4HA2', 'Gene', '8974', (53, 58))	('high', 'Var', (48, 52))
186097	30410060	In the high P4HA2 expression group, there was a statistically significant association between adjuvant RT and longer LRFI (HR = 0.3, 95%CI = 0.1-0.8; p = 0.01).	('longer LRFI', 'CPA', (110, 121))	('P4HA2', 'Gene', (12, 17))	('high', 'Var', (7, 11))	('P4HA2', 'Gene', '8974', (12, 17))
186135	30410060	Taken together, DCIS with high P4HA2 expression may have a microenvironment supportive of tumour growth and therefore need to be managed properly to avoid progression or recurrence.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('high', 'Var', (26, 30))	('P4HA2', 'Gene', '8974', (31, 36))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', (90, 96))	('DCIS', 'Disease', (16, 20))	('DCIS', 'Disease', 'MESH:D002285', (16, 20))	('P4HA2', 'Gene', (31, 36))	('tumour', 'Disease', 'MESH:D009369', (90, 96))
186141	30410060	Taken together, P4HA2 is not only a marker to identify high-risk patients who need proper treatment with surgery followed by radiation, but also suggest that adjuvant RT provides more benefit in DCIS expressing high levels of P4HA2, which needs further investigation to understand the underlying mechanisms.	('DCIS', 'Disease', (195, 199))	('DCIS', 'Disease', 'MESH:D002285', (195, 199))	('P4HA2', 'Gene', '8974', (226, 231))	('P4HA2', 'Gene', (16, 21))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('P4HA2', 'Gene', (226, 231))	('benefit', 'PosReg', (184, 191))	('high levels', 'Var', (211, 222))	('patients', 'Species', '9606', (65, 73))	('P4HA2', 'Gene', '8974', (16, 21))
186147	30410060	Deregulation of ECM dynamics can facilitate cellular dedifferentiation and cancer stem cell expansion.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cellular dedifferentiation', 'CPA', (44, 70))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (75, 81))	('facilitate', 'PosReg', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
186151	30410060	Silencing of P4HA2 expression or treatment with a P4HA inhibitor significantly inhibited cell proliferation and suppressed aggressive phenotypes of breast cancer cells in 3D culture, accompanied by reduced deposition of collagen I and IV.	('P4HA', 'Gene', '5033', (50, 54))	('suppressed', 'NegReg', (112, 122))	('deposition of collagen I', 'MPA', (206, 230))	('cell proliferation', 'CPA', (89, 107))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('P4HA2', 'Gene', (13, 18))	('P4HA', 'Gene', (50, 54))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('P4HA', 'Gene', '5033', (13, 17))	('breast cancer', 'Disease', (148, 161))	('inhibited', 'NegReg', (79, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('reduced', 'NegReg', (198, 205))	('P4HA', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('P4HA2', 'Gene', '8974', (13, 18))
186152	30410060	A key driver of P4HA2 and other ECM remodelling proteins is hypoxia and related factors, mainly HIF-1a, supporting our finding that high P4HA2 expression is associated with higher levels of HIF-1a.	('P4HA2', 'Gene', '8974', (137, 142))	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('expression', 'MPA', (143, 153))	('P4HA2', 'Gene', (16, 21))	('P4HA2', 'Gene', '8974', (16, 21))	('HIF-1a', 'Gene', (96, 102))	('HIF-1a', 'Gene', '3091', (96, 102))	('HIF-1a', 'Gene', '3091', (190, 196))	('HIF-1a', 'Gene', (190, 196))	('P4HA2', 'Gene', (137, 142))	('high', 'Var', (132, 136))
186174	26357494	Biopsy failure rates for US-CNB, US-VAB, and S-VAB were 7.1% (2/28), 0% (0/59), and 2.8% (7/249), respectively.	('Biopsy failure', 'CPA', (0, 14))	('S-VAB', 'Chemical', '-', (34, 39))	('S-VAB', 'Chemical', '-', (45, 50))	('US-CNB', 'Chemical', '-', (25, 31))	('US-VAB', 'Chemical', '-', (33, 39))	('US-VAB', 'Var', (33, 39))	('US-CNB', 'Var', (25, 31))
186176	26357494	The rates of biopsy-diagnosed ductal carcinoma in situ that were upgraded to invasive cancer at surgery were 41.7% (5/12), 12.9% (4/31), and 8.6% (3/35) for US-CNB, US-VAB, and S-VAB, respectively.	('US-VAB', 'Chemical', '-', (165, 171))	('invasive cancer', 'Disease', (77, 92))	('ductal carcinoma in situ', 'Disease', (30, 54))	('S-VAB', 'Chemical', '-', (166, 171))	('invasive cancer', 'Disease', 'MESH:D009362', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('US-CNB', 'Chemical', '-', (157, 163))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (30, 54))	('US-VAB', 'Var', (165, 171))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (37, 54))	('S-VAB', 'Chemical', '-', (177, 182))	('S-VAB', 'Var', (177, 182))	('US-CNB', 'Var', (157, 163))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (30, 54))
186184	26357494	When all of these findings are considered, the histopathological diagnosis is determined for suspicious microcalcifications detected on mammography using a variety of biopsy methods, including stereotactic VAB (S-VAB), US-CNB, US-VAB, or surgical biopsy, depending on the imaging findings and each patient's clinical situation.	('US-VAB', 'Chemical', '-', (227, 233))	('patient', 'Species', '9606', (298, 305))	('VAB', 'Chemical', 'MESH:C054345', (230, 233))	('US-CNB', 'Chemical', '-', (219, 225))	('VAB', 'Chemical', 'MESH:C054345', (213, 216))	('VAB', 'Chemical', 'MESH:C054345', (206, 209))	('calcification', 'Disease', 'MESH:D002114', (109, 122))	('S-VAB', 'Chemical', '-', (228, 233))	('S-VAB', 'Chemical', '-', (211, 216))	('US-CNB', 'Var', (219, 225))	('calcification', 'Disease', (109, 122))
186228	26357494	Category 4a was the most commonly assigned category in the US-VAB and S-VAB groups, whereas category 4c was the most commonly assigned in the US-CNB group.	('S-VAB', 'Disease', (70, 75))	('US-VAB', 'Chemical', '-', (59, 65))	('S-VAB', 'Chemical', '-', (70, 75))	('US-VAB', 'Var', (59, 65))	('US-CNB', 'Chemical', '-', (142, 148))	('S-VAB', 'Chemical', '-', (60, 65))
186240	26357494	The malignancy rates were 83.3%, 58.5%, and 23.7% for US-CNB, US-VAB, and S-VAB, respectively.	('US-CNB', 'Chemical', '-', (54, 60))	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('US-VAB', 'Chemical', '-', (62, 68))	('S-VAB', 'Chemical', '-', (63, 68))	('malignancy', 'Disease', (4, 14))	('US-VAB', 'Var', (62, 68))	('S-VAB', 'Chemical', '-', (74, 79))	('US-CNB', 'Var', (54, 60))	('S-VAB', 'Var', (74, 79))
186241	26357494	Among lesions with malignant pathology, invasive carcinoma was more frequent in the US-CNB group (45.0%, 9/20) than in the US-VAB (16.1%, 5/31) and S-VAB groups (17.4%, 8/46).	('US-VAB', 'Chemical', '-', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('invasive carcinoma', 'Disease', 'MESH:D009361', (40, 58))	('US-CNB', 'Var', (84, 90))	('S-VAB', 'Chemical', '-', (148, 153))	('S-VAB', 'Chemical', '-', (124, 129))	('US-CNB', 'Chemical', '-', (84, 90))	('invasive carcinoma', 'Disease', (40, 58))
186242	26357494	The false-negative rates were 15.0% (3/20), 0% (0/31), and 4.3% (2/46) for US-CNB, US-VAB, and S-VAB, respectively.	('S-VAB', 'Var', (95, 100))	('US-CNB', 'Chemical', '-', (75, 81))	('US-VAB', 'Chemical', '-', (83, 89))	('US-CNB', 'Var', (75, 81))	('S-VAB', 'Chemical', '-', (84, 89))	('US-VAB', 'Var', (83, 89))	('S-VAB', 'Chemical', '-', (95, 100))
186248	26357494	The DCIS underestimation rates were 41.7% (5/12), 12.9% (4/31), and 8.6% (3/35) for US-CNB, US-VAB, and S-VAB, respectively.	('US-VAB', 'Var', (92, 98))	('S', 'Chemical', 'MESH:D013455', (7, 8))	('S', 'Chemical', 'MESH:D013455', (93, 94))	('S-VAB', 'Chemical', '-', (93, 98))	('DCIS', 'Phenotype', 'HP:0030075', (4, 8))	('US-CNB', 'Var', (84, 90))	('S-VAB', 'Chemical', '-', (104, 109))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('US-VAB', 'Chemical', '-', (92, 98))	('S', 'Chemical', 'MESH:D013455', (85, 86))	('US-CNB', 'Chemical', '-', (84, 90))
186254	26357494	Our results demonstrate the overall diagnostic outcomes of US-CNB, US-VAB, and S-VAB.	('US-CNB', 'Var', (59, 65))	('S-VAB', 'Chemical', '-', (79, 84))	('US-CNB', 'Chemical', '-', (59, 65))	('US-VAB', 'Chemical', '-', (67, 73))	('US-VAB', 'Disease', (67, 73))	('S-VAB', 'Chemical', '-', (68, 73))
186255	26357494	The microcalcification retrieval rates in our study were 92.9% for US-CNB and 100% for US-VAB and S-VAB, which were within the range of previous studies.	('calcification', 'Disease', 'MESH:D002114', (9, 22))	('US-CNB', 'Var', (67, 73))	('US-VAB', 'Chemical', '-', (87, 93))	('calcification', 'Disease', (9, 22))	('S-VAB', 'Chemical', '-', (98, 103))	('S-VAB', 'Chemical', '-', (88, 93))	('US-CNB', 'Chemical', '-', (67, 73))
186261	26357494	We had five false-negative cases; three using US-CNB and two for S-VAB; one case was a calcification retrieval failure case, three cases were detected by imaging-histologic discordance, and the other case was detected by follow-up mammography.	('US-CNB', 'Chemical', '-', (46, 52))	('calcification retrieval failure', 'Disease', (87, 118))	('S-VAB', 'Chemical', '-', (65, 70))	('calcification retrieval failure', 'Disease', 'MESH:D002114', (87, 118))	('US-CNB', 'Var', (46, 52))
186265	26357494	In the current study, the ADH underestimation rate was 12.5% after S-VAB, which concurs with the reported range of 7-35% after S-VAB.	('ADH', 'MPA', (26, 29))	('S-VAB', 'Chemical', '-', (67, 72))	('S-VAB', 'Var', (67, 72))	('S-VAB', 'Chemical', '-', (127, 132))
186270	26357494	Invasive carcinoma was more frequent on US-CNB (45.0%, 9/20) than for US-VAB (16.1%, 5/31) and S-VAB (17.4%, 8/46), which was due to selecting US-visible masses for US-CNB.	('US-CNB', 'Chemical', '-', (40, 46))	('S', 'Chemical', 'MESH:D013455', (41, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('US-VAB', 'Chemical', '-', (70, 76))	('Invasive carcinoma', 'Disease', (0, 18))	('S', 'Chemical', 'MESH:D013455', (166, 167))	('US-CNB', 'Chemical', '-', (165, 171))	('S', 'Chemical', 'MESH:D013455', (71, 72))	('US-CNB', 'Var', (40, 46))	('S-VAB', 'Chemical', '-', (71, 76))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('S-VAB', 'Chemical', '-', (95, 100))	('Invasive carcinoma', 'Disease', 'MESH:D009361', (0, 18))	('S', 'Chemical', 'MESH:D013455', (144, 145))
186272	26357494	Although the malignancy rate was higher for US-VAB than that for S-VAB (58.5% vs. 23.7%), the proportion of invasive carcinoma was similar for US-VAB and S-VAB (16.1% vs. 17.4%).	('S-VAB', 'Chemical', '-', (65, 70))	('US-VAB', 'Chemical', '-', (143, 149))	('higher', 'PosReg', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('US-VAB', 'Var', (44, 50))	('malignancy', 'Disease', (13, 23))	('S-VAB', 'Chemical', '-', (45, 50))	('US-VAB', 'Var', (143, 149))	('invasive carcinoma', 'Disease', (108, 126))	('US-VAB', 'Chemical', '-', (44, 50))	('S-VAB', 'Chemical', '-', (154, 159))	('malignancy', 'Disease', 'MESH:D009369', (13, 23))	('S-VAB', 'Chemical', '-', (144, 149))	('invasive carcinoma', 'Disease', 'MESH:D009361', (108, 126))
186303	15570309	Invasive breast cancers were classified as: ductal carcinoma (SNOMED code 85003), lobular carcinoma (85203) and comedo carcinoma (85013).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Disease', (90, 99))	('carcinoma', 'Disease', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (82, 99))	('comedo', 'Phenotype', 'HP:0025249', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancers', 'Disease', 'MESH:D001943', (9, 23))	('breast cancers', 'Disease', (9, 23))	('carcinoma', 'Disease', 'MESH:D002277', (51, 60))	('ductal carcinoma', 'Disease', (44, 60))	('carcinoma', 'Disease', (119, 128))	('85013', 'Var', (130, 135))	('carcinoma', 'Disease', 'MESH:D002277', (90, 99))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (44, 60))	('breast cancers', 'Phenotype', 'HP:0003002', (9, 23))	('lobular carcinoma', 'Disease', 'MESH:D018275', (82, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('ductal carcinoma', 'Disease', 'MESH:D044584', (44, 60))	('lobular carcinoma', 'Disease', (82, 99))	('85203', 'Var', (101, 106))	('carcinoma', 'Disease', 'MESH:D002277', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
186304	15570309	In situ breast cancers were also classified in three categories: ductal carcinoma (85002), lobular carcinoma (85202) and comedo carcinoma (85012).	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('85012', 'Var', (139, 144))	('ductal carcinoma', 'Disease', 'MESH:D044584', (65, 81))	('85202', 'Var', (110, 115))	('comedo', 'Phenotype', 'HP:0025249', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (91, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma', 'Disease', (72, 81))	('carcinoma', 'Disease', (128, 137))	('carcinoma', 'Disease', 'MESH:D002277', (99, 108))	('situ breast cancers', 'Disease', 'MESH:D000071960', (3, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('situ breast cancers', 'Disease', (3, 22))	('carcinoma', 'Disease', 'MESH:D002277', (72, 81))	('lobular carcinoma', 'Disease', 'MESH:D018275', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('85002', 'Var', (83, 88))	('lobular carcinoma', 'Disease', (91, 108))	('carcinoma', 'Disease', 'MESH:D002277', (128, 137))	('ductal carcinoma', 'Disease', (65, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (8, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (65, 81))	('carcinoma', 'Disease', (99, 108))
186373	32467291	Breast cancer development is a multi-step process that involves epigenetic and genetic changes contributing to aberrant cell growth.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('genetic changes', 'Var', (79, 94))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('epigenetic', 'Var', (64, 74))	('Breast cancer', 'Disease', (0, 13))
186385	32467291	BXL0124 is an analog of calcitriol (1alpha25(OH)2D3) modified with an additional side chain at C21-methyl group, endowing it with more biological activity at lower concentrations without causing hypercalcemia, a limiting side effect of vitamin D. BXL0124 also inhibits MCF10DCIS xenograft tumorigenesis more potently than 1alpha25(OH)2D3, apparently through the similar mechanism of suppressing cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (395, 401))	('calcitriol', 'Chemical', 'MESH:D002117', (24, 34))	('DCIS', 'Phenotype', 'HP:0030075', (274, 278))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (36, 51))	('hypercalcemia', 'Disease', 'MESH:D006934', (195, 208))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (322, 337))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('inhibits', 'NegReg', (260, 268))	('hypercalcemia', 'Disease', (195, 208))	('BXL0124', 'Chemical', 'MESH:C552206', (247, 254))	('BXL0124', 'Var', (247, 254))	('cancer', 'Disease', (395, 401))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (269, 278))	('BXL0124', 'Chemical', 'MESH:C552206', (0, 7))	('vitamin D', 'Chemical', 'MESH:D014807', (236, 245))	('hypercalcemia', 'Phenotype', 'HP:0003072', (195, 208))
186406	32467291	Primers used are GAPDH (Hs02758991), GDF15 (Hs00171132), LCN2 (Hs01008571), S100A4 (Hs00243202), NGFR (Hs00609976), PPP1R1B (Hs00259967), AGR2 (Hs00356521), KRT6A (Hs04194231), EMP1 (Hs00608055), IGFBP5 (Hs00181213), CAPN6 (Hs00560073), CYP24A1 (Hs00167999), and KRT5 (Hs00361185).	('KRT5', 'Gene', (263, 267))	('KRT6A', 'Gene', '3853', (157, 162))	('CAPN6', 'Gene', (217, 222))	('EMP1', 'Gene', (177, 181))	('Hs04194231', 'Var', (164, 174))	('Hs00243202', 'Var', (84, 94))	('Hs01008571', 'Var', (63, 73))	('IGFBP5', 'Gene', (196, 202))	('CAPN6', 'Gene', '827', (217, 222))	('KRT6A', 'Gene', (157, 162))	('CYP24A1', 'Gene', (237, 244))	('Hs00560073', 'Var', (224, 234))	('NGFR', 'Gene', '4804', (97, 101))	('GDF15', 'Gene', (37, 42))	('GAPDH', 'Gene', '2597', (17, 22))	('PPP1R1B', 'Gene', (116, 123))	('Hs00356521', 'Var', (144, 154))	('Hs00608055', 'Var', (183, 193))	('Hs00361185', 'Var', (269, 279))	('S100A4', 'Gene', (76, 82))	('AGR2', 'Gene', (138, 142))	('CYP24A1', 'Gene', '1591', (237, 244))	('Hs00181213', 'Var', (204, 214))	('AGR2', 'Gene', '10551', (138, 142))	('GAPDH', 'Gene', (17, 22))	('LCN2', 'Gene', '3934', (57, 61))	('KRT5', 'Gene', '3852', (263, 267))	('EMP1', 'Gene', '2012', (177, 181))	('Hs00171132', 'Var', (44, 54))	('Hs02758991', 'Var', (24, 34))	('PPP1R1B', 'Gene', '84152', (116, 123))	('NGFR', 'Gene', (97, 101))	('Hs00259967', 'Var', (125, 135))	('GDF15', 'Gene', '9518', (37, 42))	('LCN2', 'Gene', (57, 61))	('IGFBP5', 'Gene', '3488', (196, 202))	('Hs00167999', 'Var', (246, 256))	('Hs00609976', 'Var', (103, 113))	('S100A4', 'Gene', '6275', (76, 82))
186410	32467291	Primary antibodies against TP63 Clone 10H7L17 (1:1000) was from Thermo Fisher Scientific (Cat# 703809 RRID: AB_2809251); alpha-SMA (1:1000) was from Abcam (Cat# ab5694, RRID: AB_2223021) and beta-actin, Clone AC-15 (1:2000) was from Sigma-Aldrich (Cat# A1978, RRID:AB_476692).	('alpha-SMA', 'Gene', '58', (121, 130))	('Cat# ab5694', 'Var', (156, 167))	('alpha-SMA', 'Gene', (121, 130))
186416	32467291	Treatment with 1alpha25(OH)2D3 and BXL0124 decreased the MFE from 1.18% in controls to 0.82% (p < 0.05) and 0.87% (p < 0.05) respectively (Figure 1A and 1B).	('1alpha25', 'Var', (15, 23))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (15, 30))	('MFE', 'MPA', (57, 60))	('BXL0124', 'Chemical', 'MESH:C552206', (35, 42))	('decreased', 'NegReg', (43, 52))	('BXL0124', 'Var', (35, 42))
186418	32467291	The distribution of differential expression genes (DEGs) in 1alpha25(OH)2D3 vs. control and BXL0124 vs. control treatment groups are shown respectively in volcano MA plots (Figure 2A).	('1alpha25', 'Var', (60, 68))	('BXL0124', 'Var', (92, 99))	('BXL0124', 'Chemical', 'MESH:C552206', (92, 99))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (60, 75))
186427	32467291	As expected, the level of CYP24A1 RNA increased with 1alpha,25(OH)2D3 treatment (82,000-fold, p < 0.001) and BXL0124 treatment (177,564-fold, p < 0.01), respectively.	('BXL0124', 'Chemical', 'MESH:C552206', (109, 116))	('BXL0124', 'Var', (109, 116))	('CYP24A1', 'Gene', (26, 33))	('CYP24A1', 'Gene', '1591', (26, 33))	('increased', 'PosReg', (38, 47))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (53, 69))
186430	32467291	Cytokeratin 5 (KRT5) expression level was increased 3.9-fold and 5.9-fold with 1alpha,25(OH)2D3 (p < 0.01) and BXL0124 (p < 0.001), respectively.	('KRT5', 'Gene', (15, 19))	('increased', 'PosReg', (42, 51))	('BXL0124', 'Var', (111, 118))	('Cytokeratin 5', 'Gene', '3852', (0, 13))	('KRT5', 'Gene', '3852', (15, 19))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (79, 95))	('1alpha,25(OH)2D3', 'Var', (79, 95))	('expression level', 'MPA', (21, 37))	('BXL0124', 'Chemical', 'MESH:C552206', (111, 118))	('Cytokeratin 5', 'Gene', (0, 13))
186434	32467291	1alpha,25(OH)2D3 and BXL0124 decreased LCN2 gene expression by 97% (p < 0.001) and 97% (p < 0.01), respectively.	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 16))	('LCN2', 'Gene', '3934', (39, 43))	('LCN2', 'Gene', (39, 43))	('expression', 'MPA', (49, 59))	('BXL0124', 'Chemical', 'MESH:C552206', (21, 28))	('decreased', 'NegReg', (29, 38))	('BXL0124', 'Var', (21, 28))
186436	32467291	In our analysis, 1alpha,25(OH)2D3 and BXL0124 decreased PPP1R1B gene expression by 81% (p < 0.01) and 97% (p < 0.001) respectively.	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (17, 33))	('PPP1R1B', 'Gene', (56, 63))	('BXL0124', 'Chemical', 'MESH:C552206', (38, 45))	('decreased', 'NegReg', (46, 55))	('BXL0124', 'Var', (38, 45))	('PPP1R1B', 'Gene', '84152', (56, 63))
186437	32467291	AGR2 gene expression was also reduced by 1alpha,25(OH)2D3 (by 91%, p < 0.05) and BXL0124 (by 85%, p < 0.01).	('AGR2', 'Gene', '10551', (0, 4))	('BXL0124', 'Chemical', 'MESH:C552206', (81, 88))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (41, 57))	('BXL0124', 'Var', (81, 88))	('expression', 'MPA', (10, 20))	('AGR2', 'Gene', (0, 4))	('reduced', 'NegReg', (30, 37))
186440	32467291	CAPN6 gene expression was decreased by 1alpha,25(OH)2D3 (89%, p < 0.01) and with BXL0124 (97%, p < 0.001) in MCF10DCIS mammospheres.	('CAPN6', 'Gene', (0, 5))	('BXL0124', 'Chemical', 'MESH:C552206', (81, 88))	('expression', 'MPA', (11, 21))	('CAPN6', 'Gene', '827', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (114, 118))	('MCF10DCIS', 'Var', (109, 118))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (109, 118))	('decreased', 'NegReg', (26, 35))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (39, 55))
186441	32467291	IGFBP5 gene expression was increased two folds with 1alpha,25(OH)2D3 (p < 0.05) while reduced by 89% with BXL0124 (p < 0.05).	('reduced', 'NegReg', (86, 93))	('1alpha,25(OH)2D3', 'Var', (52, 68))	('increased', 'PosReg', (27, 36))	('BXL0124', 'Chemical', 'MESH:C552206', (106, 113))	('1alpha,25(OH)2D3', 'Chemical', 'MESH:D002117', (52, 68))	('IGFBP5', 'Gene', (0, 6))	('IGFBP5', 'Gene', '3488', (0, 6))	('expression', 'MPA', (12, 22))
186444	32467291	Plotting methylation differences for all genes against each other for both 1alpha25(OH)2D3 vs. DMSO and BXL0124 vs. DMSO showed a linear relationship between the two groups (Supplementary Figure S2).	('BXL0124', 'Var', (104, 111))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (75, 90))	('1alpha25', 'Var', (75, 83))	('DMSO', 'Chemical', 'MESH:D004121', (95, 99))	('DMSO', 'Chemical', 'MESH:D004121', (116, 120))	('BXL0124', 'Chemical', 'MESH:C552206', (104, 111))	('methylation', 'MPA', (9, 20))
186445	32467291	Notably, MCF10DCIS mammospheres treated with 1alpha25(OH)2D3 and BXL0124 shared similar pattern in heatmap compared with control implying the methylation modification in these DMRs may be a regulatory mechanism for breast cancer chemoprevention.	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (45, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Disease', (215, 228))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (9, 18))	('BXL0124', 'Chemical', 'MESH:C552206', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('methylation', 'Var', (142, 153))	('BXL0124', 'Var', (65, 72))
186447	32467291	Since DNA hypermethylation at CpG island in promoter region is known to silence gene expression, we selected one of the most recognized vitamin D responsive target gene, CYP24A1, from the list of genes that showed higher mRNA expression with lower CpG methylation, and then further validated its methylation status with pyrosequencing.	('hypermethylation', 'Var', (10, 26))	('higher', 'PosReg', (214, 220))	('silence', 'NegReg', (72, 79))	('CYP24A1', 'Gene', (170, 177))	('CYP24A1', 'Gene', '1591', (170, 177))	('gene expression', 'MPA', (80, 95))	('vitamin D', 'Chemical', 'MESH:D014807', (136, 145))	('mRNA expression', 'MPA', (221, 236))
186448	32467291	Pyrosequencing analysis of the selected 6 CpG sites in the promoter region of CYP24A1 gene between 52789045 and 52789434 bps showed that CpG hypermethylation is decreased upon treatment with vitamin D compounds compared to control (average MIs DMSO = 75%, 1alpha25(OH)2D3 = 62%, and BXL0124 = 55%) (Figure 3D).	('BXL0124', 'Chemical', 'MESH:C552206', (283, 290))	('decreased', 'NegReg', (161, 170))	('CpG hypermethylation', 'MPA', (137, 157))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (256, 271))	('CYP24A1', 'Gene', (78, 85))	('vitamin D', 'Chemical', 'MESH:D014807', (191, 200))	('DMSO', 'Chemical', 'MESH:D004121', (244, 248))	('52789434', 'Var', (112, 120))	('CYP24A1', 'Gene', '1591', (78, 85))
186455	32467291	Analysis of Ingenuity Canonical Pathways regulated by 1alpha25(OH)2D3 vs. control and BXL0124 vs. control is shown in Supplementary Table S1 and Table S2, respectively.	('BXL0124', 'Var', (86, 93))	('Ingenuity Canonical Pathways', 'Pathway', (12, 40))	('BXL0124', 'Chemical', 'MESH:C552206', (86, 93))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (54, 69))
186456	32467291	Using criteria of p <0.01 and absolute value z score > 2, 45 canonical pathways were regulated by 1alpha25(OH)2D3 and 8 canonical pathways were regulated by BXL0124.	('1alpha25', 'Var', (98, 106))	('canonical pathways', 'Pathway', (61, 79))	('BXL0124', 'Chemical', 'MESH:C552206', (157, 164))	('regulated', 'Reg', (85, 94))	('regulated', 'Reg', (144, 153))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (98, 113))	('BXL0124', 'Var', (157, 164))
186459	32467291	Loss of TP63 expression promotes malignant cells migration, invasion and distant metastasis in cancers.	('distant metastasis', 'CPA', (73, 91))	('invasion', 'CPA', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('TP63', 'Gene', (8, 12))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('promotes', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Loss', 'Var', (0, 4))	('malignant cells migration', 'CPA', (33, 58))
186462	32467291	alpha-SMA level was upregulated in mammosphere samples treated with 1alpha25(OH)2D3 and BXL0124 (Figure 4C and Supplementary Figure S3).	('1alpha25(OH)2D3', 'Var', (68, 83))	('BXL0124', 'Chemical', 'MESH:C552206', (88, 95))	('alpha-SMA', 'Gene', '58', (0, 9))	('BXL0124', 'Var', (88, 95))	('upregulated', 'PosReg', (20, 31))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (68, 83))	('alpha-SMA', 'Gene', (0, 9))
186464	32467291	Loss of CD10, a myoepithelial surface peptidase, is associated with triple negative breast cancer and increased risk of DCIS.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('associated', 'Reg', (52, 62))	('CD10', 'Gene', (8, 12))	('CD10', 'Gene', '4311', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('DCIS', 'Disease', (120, 124))	('Loss', 'Var', (0, 4))	('breast cancer', 'Disease', (84, 97))
186470	32467291	Among the genes that are commonly and differentially regulated by vitamin D compounds, BXL0124 regulated a higher number of genes compared to 1alpha25(OH)2D3, consistent with the fact that it is a more potent agonist of VDR signaling.	('BXL0124', 'Var', (87, 94))	('VDR', 'Gene', '7421', (220, 223))	('vitamin D', 'Chemical', 'MESH:D014807', (66, 75))	('regulated', 'Reg', (95, 104))	('VDR', 'Gene', (220, 223))	('BXL0124', 'Chemical', 'MESH:C552206', (87, 94))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (142, 157))
186476	32467291	Both 1alpha25(OH)2D3 and BXL0124 reduced LCN2 at mRNA levels.	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (5, 20))	('BXL0124', 'Chemical', 'MESH:C552206', (25, 32))	('LCN2', 'Gene', '3934', (41, 45))	('reduced', 'NegReg', (33, 40))	('LCN2', 'Gene', (41, 45))	('BXL0124', 'Var', (25, 32))
186488	32467291	However, we observed the expression profiles of certain genes (including the ones that we have validated such as NGFR, GDF15, PPP1R1B, KRT5, KRT6A and LAMA3) in our MCF10DCIS mammospheres are different from those of MCF10DCIS monolayer cells.	('NGFR', 'Gene', '4804', (113, 117))	('PPP1R1B', 'Gene', (126, 133))	('GDF15', 'Gene', (119, 124))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (216, 225))	('KRT6A', 'Gene', '3853', (141, 146))	('KRT5', 'Gene', (135, 139))	('KRT6A', 'Gene', (141, 146))	('LAMA3', 'Gene', '3909', (151, 156))	('expression', 'MPA', (25, 35))	('PPP1R1B', 'Gene', '84152', (126, 133))	('DCIS', 'Phenotype', 'HP:0030075', (170, 174))	('NGFR', 'Gene', (113, 117))	('MCF10DCIS', 'Var', (165, 174))	('GDF15', 'Gene', '9518', (119, 124))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (165, 174))	('different', 'Reg', (192, 201))	('KRT5', 'Gene', '3852', (135, 139))	('DCIS', 'Phenotype', 'HP:0030075', (221, 225))	('LAMA3', 'Gene', (151, 156))
186492	32467291	We found that treatment with 1alpha25(OH)2D3 and BXL0124 have shown similar patterns of changes in CpG methylation profiles.	('CpG methylation profiles', 'MPA', (99, 123))	('1alpha25', 'Var', (29, 37))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (29, 44))	('changes', 'Reg', (88, 95))	('BXL0124', 'Chemical', 'MESH:C552206', (49, 56))	('BXL0124', 'Var', (49, 56))
186493	32467291	Since a large body of evidence shows that CpG island promoter methylation results in gene silencing, we selected a well-established vitamin D metabolizing gene, CYP24A1, that is strongly induced by the compounds to test this hypothesis.	('CYP24A1', 'Gene', '1591', (161, 168))	('silencing', 'NegReg', (90, 99))	('vitamin D', 'Chemical', 'MESH:D014807', (132, 141))	('methylation', 'Var', (62, 73))	('gene', 'MPA', (85, 89))	('CYP24A1', 'Gene', (161, 168))
186494	32467291	We found that when DMRs are hypomethylated by vitamin D compounds, gene expression of CYP24A1 is up-regulated.	('CYP24A1', 'Gene', '1591', (86, 93))	('vitamin D', 'Chemical', 'MESH:D014807', (46, 55))	('up-regulated', 'PosReg', (97, 109))	('hypomethylated', 'Var', (28, 42))	('gene expression', 'MPA', (67, 82))	('CYP24A1', 'Gene', (86, 93))
186495	32467291	Overall, these findings suggest epigenetic regulation as a potential mechanism of vitamin D compounds for breast cancer chemoprevention.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('epigenetic', 'Var', (32, 42))	('vitamin D', 'Chemical', 'MESH:D014807', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
186498	32467291	Six different isoforms of Tp63 have been identified, based on the presence of transactivating (TAp63) or dominant-negative (DeltaNp63) domains.	('p63', 'Gene', (27, 30))	('p63', 'Gene', (130, 133))	('p63', 'Gene', '8626', (130, 133))	('transactivating', 'PosReg', (78, 93))	('p63', 'Gene', (97, 100))	('p63', 'Gene', '8626', (27, 30))	('dominant-negative', 'Var', (105, 122))	('p63', 'Gene', '8626', (97, 100))
186505	32467291	Our data showed that in DCIS mammospheres treated with 1alpha25(OH)2D3 and BXL0124, protein levels of TP63 increased, consistent with our hypothesis that the mechanism by which the vitamin D compounds inhibit progression of DCIS to IDC involves a reduction in the cancer stem cell-like population or the stemness of the cells.	('stemness of the cells', 'CPA', (304, 325))	('inhibit', 'NegReg', (201, 208))	('progression', 'CPA', (209, 220))	('protein levels', 'MPA', (84, 98))	('increased', 'PosReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('DCIS', 'Phenotype', 'HP:0030075', (224, 228))	('BXL0124', 'Var', (75, 82))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('vitamin D', 'Chemical', 'MESH:D014807', (181, 190))	('reduction', 'NegReg', (247, 256))	('DCIS to IDC', 'Disease', (224, 235))	('1alpha25(OH)2D3', 'Chemical', 'MESH:D002117', (55, 70))	('BXL0124', 'Chemical', 'MESH:C552206', (75, 82))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
186523	29554537	Final pathology showed DCIS in sclerosing adenosis in a hamartoma.	('DCIS', 'Var', (23, 27))	('hamartoma', 'Phenotype', 'HP:0010566', (56, 65))	('sclerosing adenosis', 'Disease', (31, 50))	('hamartoma', 'Disease', 'MESH:D006222', (56, 65))	('hamartoma', 'Disease', (56, 65))	('DCIS', 'Phenotype', 'HP:0030075', (23, 27))	('sclerosing adenosis', 'Disease', 'MESH:D005348', (31, 50))
186557	29554537	The postoperative pathological diagnosis was DCIS in sclerosing adenosis in hamartoma, with the hamartoma obscuring typical imaging findings of sclerosing adenosis.	('hamartoma', 'Disease', (76, 85))	('hamartoma', 'Phenotype', 'HP:0010566', (96, 105))	('sclerosing adenosis', 'Disease', (144, 163))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('sclerosing adenosis', 'Disease', 'MESH:D005348', (53, 72))	('hamartoma', 'Phenotype', 'HP:0010566', (76, 85))	('DCIS', 'Var', (45, 49))	('hamartoma', 'Disease', 'MESH:D006222', (96, 105))	('hamartoma', 'Disease', 'MESH:D006222', (76, 85))	('sclerosing adenosis', 'Disease', 'MESH:D005348', (144, 163))	('sclerosing adenosis', 'Disease', (53, 72))	('hamartoma', 'Disease', (96, 105))
186588	28540335	To date, nuclear grade and activity, comedo necrosis and HER-2 positivity are the prognostic signs frequently used in helping to decide whether conservative surgery or mastectomy is the preferred surgical treatment, and whether post-operative treatment should be administered.	('necrosis', 'Disease', 'MESH:D009336', (44, 52))	('mastectomy', 'Disease', (168, 178))	('HER-2', 'Gene', '2064', (57, 62))	('comedo', 'Phenotype', 'HP:0025249', (37, 43))	('positivity', 'Var', (63, 73))	('HER-2', 'Gene', (57, 62))	('necrosis', 'Disease', (44, 52))	('activity', 'CPA', (27, 35))
186595	28540335	The data show that lack of NY-ESO-1 expression confers a higher risk of developing invasive breast cancer in this cohort of patients.	('NY-ESO-1', 'Gene', (27, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('lack', 'Var', (19, 23))	('patients', 'Species', '9606', (124, 132))	('invasive breast cancer', 'Disease', (83, 105))	('invasive breast cancer', 'Disease', 'MESH:D001943', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('NY-ESO-1', 'Gene', '246100', (27, 35))
186661	25984843	We determined which combinations of BI-RADS breast density categories and breast cancer risk and combinations of BI-RADS density categories and age are associated with sufficiently high interval cancer rates to justify consideration of alternative screening strategies among women with dense breasts undergoing digital mammography.	('sufficiently high interval cancer', 'Disease', (168, 201))	('breast cancer', 'Disease', (74, 87))	('sufficiently high interval cancer', 'Disease', 'MESH:D009369', (168, 201))	('BI-RADS', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('women', 'Species', '9606', (275, 280))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
186701	25984843	Women with heterogeneously or extremely dense breasts and low-average BCSC 5-year risk (0-1.66%) had interval rates of 0.58-0.63 and 0.72-0.89/1,000 mammograms, respectively.	('BCSC', 'Gene', (70, 74))	('Women', 'Species', '9606', (0, 5))	('low-average', 'Var', (58, 69))
186725	25984843	For example, breast magnetic resonance imaging (MRI) has very high sensitivity to detect early stage breast cancer in BRCA1 and 2 mutation carriers.	('BRCA1 and 2', 'Gene', '672;675', (118, 129))	('mutation', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
186736	25984843	High breast density is associated with decreased cancer detection on mammography and increased risk of large tumors and advanced cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('High', 'Var', (0, 4))	('large', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('decreased cancer', 'Disease', (39, 55))	('High breast density', 'Phenotype', 'HP:0010313', (0, 19))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('decreased cancer', 'Disease', 'MESH:D009369', (39, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('cancer', 'Disease', (49, 55))
186743	25984843	We specifically identified women at high risk for interval cancers or false-positive mammograms who are more likely to benefit from alternative screening strategies.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('interval cancers', 'Disease', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('false-positive', 'Var', (70, 84))	('mammograms', 'Gene', (85, 95))	('women', 'Species', '9606', (27, 32))	('interval cancers', 'Disease', 'MESH:D009369', (50, 66))
186755	25143958	However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patient', 'Species', '9606', (172, 179))	('abnormalities', 'Var', (36, 49))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('women', 'Species', '9606', (25, 30))
186790	25143958	demonstrated that the incidence of autoantibodies at diagnosis of breast carcinoma was higher in patients who developed local recurrences or distal metastases within 2 years than in patients free from recurrence.	('autoantibodies', 'Var', (35, 49))	('breast carcinoma', 'Phenotype', 'HP:0003002', (66, 82))	('metastases', 'Disease', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('local recurrences', 'CPA', (120, 137))	('breast carcinoma', 'Disease', (66, 82))	('patients', 'Species', '9606', (97, 105))	('metastases', 'Disease', 'MESH:D009362', (148, 158))	('breast carcinoma', 'Disease', 'MESH:D001943', (66, 82))	('patients', 'Species', '9606', (182, 190))	('higher', 'PosReg', (87, 93))
186857	25927933	They developed HOXA1-small interfering RNA nanoparticles and achieved effective therapeutic doses by delivering them intraductally through the nipple to the site of the tumor and at the same time circumvented the systemic immune response.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('HOXA1-small', 'Var', (15, 26))	('therapeutic', 'MPA', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))
186864	25927933	They also observed that siRNA-mediated depletion of HOXA1 in two other mouse mammary tumor cell lines resulted in more acinar (hollow) lumen formation of cells grown in matrigel.	('tumor', 'Disease', (85, 90))	('depletion', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mouse', 'Species', '10090', (71, 76))	('more', 'PosReg', (114, 118))	('HOXA1', 'Gene', (52, 57))
186872	25927933	The hopes pinned on siRNAs stem from the fact that they are more specific than other cancer therapies; indeed, they can even discriminate between species that have single-nucleotide differences.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('single-nucleotide differences', 'Var', (164, 193))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
186873	25927933	I.duc siRNA therapy would benefit women with atypical ductal hyperplasia or DCIS and women at high risk of developing breast cancer because of a family history of mutated BRCA1/2 or other familial breast cancer genes.	('BRCA1/2', 'Gene', '672;675', (171, 178))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (45, 72))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('mutated', 'Var', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('DCIS', 'Disease', (76, 80))	('atypical ductal hyperplasia', 'Disease', (45, 72))	('women', 'Species', '9606', (85, 90))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('BRCA1/2', 'Gene', (171, 178))	('familial breast cancer', 'Disease', 'MESH:D001943', (188, 210))	('breast cancer', 'Disease', (118, 131))	('women', 'Species', '9606', (34, 39))	('familial breast cancer', 'Disease', (188, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
186880	25927933	However, as pointed out by the authors, this study does not offer evidence that HOXA1 is a candidate gene that is overexpressed in DCIS or that HOXA1 overexpression in DCIS predicts progression to invasive cancer.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('predicts', 'Reg', (173, 181))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('invasive cancer', 'Disease', 'MESH:D009362', (197, 212))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('HOXA1', 'Gene', (144, 149))	('overexpression', 'Var', (150, 164))	('invasive cancer', 'Disease', (197, 212))
186893	23360535	High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('High breast density', 'Phenotype', 'HP:0010313', (0, 19))	('increases', 'PosReg', (29, 38))	('tumor', 'Disease', (74, 79))
186912	23360535	MD was visually assessed by a single, experienced radiologist blinded to case/control status, by using the Boyd semiquantitative scale with the following categories of density: 0; <10%; 10% to 25%; 25% to 50%; 50% to 75%; and >75%.	('to 7', 'Species', '1214577', (214, 218))	('50% to 75%', 'Var', (210, 220))	('<10%', 'Var', (180, 184))
186948	23360535	According to our results, interval tumors are 7 times more frequent among women with MD >75% than among those with MD <10%.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('women', 'Species', '9606', (74, 79))	('interval tumors', 'Disease', (26, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('interval tumors', 'Disease', 'OMIM:610141', (26, 41))	('MD >75%', 'Var', (85, 92))
186972	23360535	High MD was associated with all pathologic subgroups of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('associated', 'Reg', (12, 22))	('breast cancer', 'Disease', (56, 69))	('High MD', 'Var', (0, 7))
186981	33671513	These findings have been strongly buttressed by demonstration of increased tumorigenesis in tissue-specific AEG-1 transgenic mouse models, and profound resistance of multiple types of cancer development and progression in total and conditional AEG-1 knockout mouse models.	('cancer', 'Disease', (184, 190))	('increased', 'PosReg', (65, 74))	('transgenic', 'Var', (114, 124))	('mouse', 'Species', '10090', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('AEG-1', 'Gene', (108, 113))	('mouse', 'Species', '10090', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('rat', 'Species', '10116', (55, 58))	('tumor', 'Disease', (75, 80))
187002	33671513	Indeed, overexpression of AEG-1 promotes all hallmarks of cancer and inhibition of AEG-1 reverses these phenotypes and tissue-specific AEG-1 transgenic mouse display augmented tumorigenesis and AEG-1 knockout mouse show resistance to the development and progression of multiple cancer types, such as those of liver, breast, prostate and colon, indicating that AEG-1 plays a pivotal role in regulating tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('AEG-1', 'Gene', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', (176, 181))	('augmented', 'PosReg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('AEG-1', 'Gene', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('mouse', 'Species', '10090', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('resistance', 'CPA', (220, 230))	('liver', 'Disease', (309, 314))	('mouse', 'Species', '10090', (152, 157))	('cancer', 'Disease', (58, 64))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', (401, 406))
187010	33671513	In both squamous cell carcinoma and adenocarcinoma, significant difference in survival time between low and high AEG-1 expression groups was observed in poorly differentiated cases (p < 0.001), but not in well-differentiated cases.	('expression', 'MPA', (119, 129))	('AEG-1', 'Gene', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (8, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('squamous cell carcinoma', 'Disease', (8, 31))	('high', 'Var', (108, 112))	('adenocarcinoma', 'Disease', (36, 50))
187022	33671513	OS (p = 0.014) and DFS (p = 0.009) were longer in low AEG-1 expressing group versus high expressing group in patients who received postoperative chemotherapy.	('rat', 'Species', '10116', (138, 141))	('patients', 'Species', '9606', (109, 117))	('low', 'Var', (50, 53))	('DFS', 'CPA', (19, 22))	('AEG-1', 'Protein', (54, 59))
187023	33671513	Similarly, in patients receiving postoperative radiotherapy recurrence free survival was significantly shorter in high AEG-1 expressing group (p = 0.016).	('high', 'Var', (114, 118))	('rat', 'Species', '10116', (40, 43))	('shorter', 'NegReg', (103, 110))	('patients', 'Species', '9606', (14, 22))	('AEG-1', 'Protein', (119, 124))
187027	33671513	While 6.8% normal tissues showed AEG-1 expression, in NSCLC cases it was 61.3% (p < 0.001) which showed significant association with TNM stage (p = 0.021), dedifferentiation (p = 0.034), vascular invasion (p = 0.035), lymph node metastasis (p < 0.001) and poor overall survival (p = 0.024).	('TNM', 'Gene', (133, 136))	('AEG-1', 'Var', (33, 38))	('vascular invasion', 'CPA', (187, 204))	('lymph node metastasis', 'CPA', (218, 239))	('association', 'Reg', (116, 127))	('NSCLC', 'Disease', (54, 59))	('TNM', 'Gene', '10178', (133, 136))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('dedifferentiation', 'CPA', (156, 173))
187031	33671513	This analysis revealed that high AEG-1 expression significantly correlated with higher mortality and metastasis in breast, ovarian and cervical cancers.	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('AEG-1', 'Gene', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('expression', 'MPA', (39, 49))	('high', 'Var', (28, 32))	('mortality', 'Disease', (87, 96))	('higher', 'PosReg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('metastasis in breast, ovarian and cervical cancers', 'Disease', 'MESH:D009362', (101, 151))
187032	33671513	In addition, polymorphisms in AEG-1 gene, such as a C/T variant in exon 11 or a G>A variant in exon 9, have been shown to confer susceptibility to breast and ovarian cancers in women from specific ethnic groups in China, which needs to be validated in more extensive studies in other patient cohorts.	('susceptibility', 'Reg', (129, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('C/T', 'Var', (52, 55))	('women', 'Species', '9606', (177, 182))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (147, 173))	('G>A', 'Var', (80, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (158, 173))	('polymorphisms', 'Var', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (284, 291))	('AEG-1', 'Gene', (30, 35))
187046	33671513	These breast cancer patients also showed correlation between AEG-1 and proliferation marker Ki-67 (p = 0.003) in a subsequent study indicating that AEG-1 is associated with highly proliferative breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (187, 190))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('AEG-1', 'Var', (148, 153))	('associated with', 'Reg', (157, 172))	('correlation', 'Interaction', (41, 52))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('rat', 'Species', '10116', (78, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (194, 208))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (20, 28))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancers', 'Disease', 'MESH:D001943', (194, 208))	('breast cancers', 'Disease', (194, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
187047	33671513	However, knocking down AEG-1 in breast cancer cells did not affect proliferation, although there was marked inhibition in migration, invasion and metastasis, arguing against the clinicopathologic study.	('breast cancer', 'Disease', (32, 45))	('rat', 'Species', '10116', (125, 128))	('inhibition', 'NegReg', (108, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('knocking down', 'Var', (9, 22))	('rat', 'Species', '10116', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('migration', 'CPA', (122, 131))	('AEG-1', 'Gene', (23, 28))
187048	33671513	Copy number alterations (CNA) of oncogenes is widely observed in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Disease', (71, 78))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
187051	33671513	Kaplan-Meier curves constructed to determine the effect of 8q22 gain on survival revealed significantly (p < 0.05) lower metastasis- and cancer-free survival in breast cancer patients with high 8q22 gain compared with low 8q22 gain, further validating the importance of AEG-1 expression in breast cancer prognosis.	('lower', 'NegReg', (115, 120))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('high 8q22', 'Var', (189, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('gain', 'PosReg', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
187056	33671513	Microarray analysis of AEG-1-knockdown cells demonstrated that genes such as ALDH3A1 and MET contribute to the multidrug chemoresistance that is seen in AEG-1-positive specimens and it was hypothesized that AEG-1 may promote chemoresistance by improving survival of metastatic lesions.	('rat', 'Species', '10116', (52, 55))	('MET', 'Gene', (89, 92))	('ALDH3A1', 'Gene', (77, 84))	('chemoresistance', 'CPA', (225, 240))	('multidrug chemoresistance', 'MPA', (111, 136))	('survival of metastatic lesions', 'CPA', (254, 284))	('promote', 'PosReg', (217, 224))	('AEG-1', 'Var', (207, 212))	('MET', 'Gene', '79811', (89, 92))	('improving', 'PosReg', (244, 253))	('ALDH3A1', 'Gene', '218', (77, 84))
187057	33671513	In a subsequent study, it was documented that expression of AEG-1 was implicated in progression of precancerous breast lesions into cancerous ones.	('cancerous', 'Disease', 'MESH:D009369', (102, 111))	('precancerous breast lesions', 'Disease', (99, 126))	('expression', 'Var', (46, 56))	('precancerous breast lesions', 'Disease', 'MESH:D001943', (99, 126))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancerous', 'Disease', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancerous', 'Disease', (102, 111))	('cancerous', 'Disease', 'MESH:D009369', (132, 141))	('implicated', 'Reg', (70, 80))	('AEG-1', 'Gene', (60, 65))
187061	33671513	Additionally, AEG-1 overexpression was significantly associated with age (p = 0.042), Ki-67 status (p = 0.036), ER status (p = 0.018) and p53 status (p = 0.001) in invasive cancer patients, which was not observed in other previous studies.	('AEG-1', 'Protein', (14, 19))	('p53', 'Gene', (138, 141))	('ER', 'Gene', '2069', (112, 114))	('p53', 'Gene', '7157', (138, 141))	('invasive cancer', 'Disease', (164, 179))	('overexpression', 'PosReg', (20, 34))	('invasive cancer', 'Disease', 'MESH:D009362', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('associated', 'Reg', (53, 63))	('Ki-67 status', 'Var', (86, 98))	('patients', 'Species', '9606', (180, 188))
187064	33671513	High MVD was observed in 59 cases out of which 42 displayed high AEG-1 expression (p = 0.002) indicating that AEG-1 is associated with increased angiogenesis.	('expression', 'MPA', (71, 81))	('angiogenesis', 'CPA', (145, 157))	('High MVD', 'Disease', 'MESH:D052456', (0, 8))	('High MVD', 'Disease', (0, 8))	('AEG-1', 'Gene', (65, 70))	('AEG-1', 'Var', (110, 115))	('increased', 'PosReg', (135, 144))
187065	33671513	Poor disease-free and overall survivals were associated with high AEG-1 and VEGF levels in Kaplan-Meier 5-year survival analysis.	('VEGF', 'Gene', (76, 80))	('AEG-1', 'Protein', (66, 71))	('high', 'Var', (61, 65))	('Poor', 'NegReg', (0, 4))	('VEGF', 'Gene', '7422', (76, 80))	('overall survivals', 'CPA', (22, 39))	('disease-free', 'CPA', (5, 17))
187069	33671513	AEG-1 levels did not correlate with ER, PR or HER2 levels indicating that AEG-1 might promote all types of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('HER2', 'Gene', (46, 50))	('ER', 'Gene', '2069', (36, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (107, 121))	('AEG-1', 'Var', (74, 79))	('HER2', 'Gene', '2064', (46, 50))	('ER', 'Gene', '2069', (47, 49))	('PR', 'Gene', '140738', (40, 42))	('promote', 'PosReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancers', 'Disease', 'MESH:D001943', (107, 121))	('breast cancers', 'Disease', (107, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
187082	33671513	Overexpression of AEG-1 was found to be associated with poorer overall survival and lower 5-year survival in these patients.	('patients', 'Species', '9606', (115, 123))	('overall', 'MPA', (63, 70))	('AEG-1', 'Gene', (18, 23))	('poorer', 'NegReg', (56, 62))	('5-year survival', 'CPA', (90, 105))	('Overexpression', 'Var', (0, 14))	('lower', 'NegReg', (84, 89))
187088	33671513	Five-year survival curves demonstrated significantly shorter PFS (p < 0.001) as well as OS (p < 0.001) in patients with high expression of AEG-1, compared with those patients with low expression of AEG-1.	('PFS', 'MPA', (61, 64))	('high expression', 'Var', (120, 135))	('rat', 'Species', '10116', (33, 36))	('AEG-1', 'Gene', (139, 144))	('patients', 'Species', '9606', (106, 114))	('shorter', 'NegReg', (53, 60))	('patients', 'Species', '9606', (166, 174))
187089	33671513	In patients with high-expressing AEG-1 tumors, the median PFS was only 30.4 months, whereas PFS was 63.6 months for patients with low-expressing AEG-1 tumors.	('high-expressing', 'Var', (17, 32))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('patients', 'Species', '9606', (116, 124))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (3, 11))	('AEG-1', 'Gene', (33, 38))	('tumors', 'Disease', (39, 45))
187090	33671513	Univariate analysis demonstrated that high AEG-1 expression was significantly associated with shorter OS (35.55 + 1.46 months, p < 0.0001) and shorter PFS (27.28 + 3.27 months, p < 0.0001).	('PFS', 'MPA', (151, 154))	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('rat', 'Species', '10116', (27, 30))	('AEG-1', 'Gene', (43, 48))
187091	33671513	Notably, there was a 5-year OS of only 34.25% for patients with high AEG-1 expression.	('AEG-1', 'Gene', (69, 74))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))
187095	33671513	Among 102 such patients, 77 were categorized as high AEG-1 expression, which was significantly associated with poor prognosis (p < 0.01).	('high', 'Var', (48, 52))	('patients', 'Species', '9606', (15, 23))	('AEG-1', 'Protein', (53, 58))
187096	33671513	Patients with high AEG-1 expression were significantly associated with shorter median survival time in years (1.13056 for high, 2.32156 for low AEG-1 expression) and 3-year survival rates (0.1436 for high, 0.3816 for low AEG-1 expression) when compared to those of low AEG-1 expression (p = 0.0028).	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('rat', 'Species', '10116', (182, 185))	('AEG-1', 'Gene', (19, 24))	('0.1436', 'Var', (189, 195))	('shorter', 'NegReg', (71, 78))
187116	33671513	Tissue microarray of 90 cervical cancer samples, including 74 squamous cervical carcinoma and 16 adenocarcinoma) demonstrated that high AEG-1 expression was significantly associated with tumor size (>4 cm, p = 0.010) and metastasis to lymph nodes (p = 0.004).	('AEG-1', 'Protein', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('squamous cervical carcinoma', 'Disease', (62, 89))	('squamous cervical carcinoma', 'Disease', 'MESH:D002294', (62, 89))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('metastasis to lymph nodes', 'CPA', (221, 246))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('expression', 'MPA', (142, 152))	('adenocarcinoma', 'Disease', (97, 111))	('associated', 'Reg', (171, 181))	('high', 'Var', (131, 135))
187117	33671513	IHC staining of normal cervical squamous epithelium revealed absence of AEG-1, while AEG-1 staining was positive in cervical intraepithelial neoplasia (CIN) I, II and III samples, indicating AEG-1 expression may necessitate progression of CIN to cervical carcinoma.	('CIN', 'Disease', 'MESH:D007674', (152, 155))	('CIN', 'Disease', (239, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('necessitate', 'Reg', (212, 223))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (125, 150))	('CIN', 'Disease', 'MESH:D007674', (239, 242))	('CIN to cervical carcinoma', 'Disease', (239, 264))	('neoplasia', 'Phenotype', 'HP:0002664', (141, 150))	('neoplasia', 'Disease', 'MESH:D009369', (141, 150))	('AEG-1', 'Var', (191, 196))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (116, 150))	('CIN to cervical carcinoma', 'Disease', 'MESH:D002583', (239, 264))	('CIN', 'Disease', (152, 155))	('neoplasia', 'Disease', (141, 150))
187120	33671513	High AEG-1 expression was associated with tumor size (AUC = 0.826, p = 0.000) and lymph node metastasis (AUC = 0.745, p = 0.004) and showed significantly lower OS (p < 0.05) compared with low AEG-1 expression.	('tumor', 'Disease', (42, 47))	('lower', 'NegReg', (154, 159))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('AEG-1', 'Gene', (5, 10))	('expression', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
187121	33671513	High AEG-1 expression was identified as an independent prognostic factor for poor OS (hazard ratio = 4.021, p = 0.027).	('rat', 'Species', '10116', (93, 96))	('poor OS', 'Disease', (77, 84))	('High', 'Var', (0, 4))	('AEG-1 expression', 'Protein', (5, 21))
187129	33671513	A Pearson correlation found a significant positive association between AEG-1 levels and VEGF and NF-kappaB levels (p = 0) and MVD (p = 0) suggesting that AEG-1 as a potential inducer of angiogenesis which could potentially contribute to invasion and metastasis by cervical cancer.	('angiogenesis', 'CPA', (186, 198))	('inducer', 'PosReg', (175, 182))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('MVD', 'Gene', (126, 129))	('VEGF', 'Gene', (88, 92))	('metastasis', 'CPA', (250, 260))	('positive', 'PosReg', (42, 50))	('contribute', 'Reg', (223, 233))	('AEG-1', 'Var', (154, 159))	('NF-kappaB', 'Gene', '4790', (97, 106))	('invasion', 'CPA', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('VEGF', 'Gene', '7422', (88, 92))	('MVD', 'Gene', '4597', (126, 129))	('NF-kappaB', 'Gene', (97, 106))
187134	33671513	Although not statistically significant, AEG-1 expression showed a trend of higher level in patients with low Gleason score versus in patients with high Gleason score.	('level', 'MPA', (82, 87))	('patients', 'Species', '9606', (91, 99))	('low', 'Var', (105, 108))	('higher', 'PosReg', (75, 81))	('patients', 'Species', '9606', (133, 141))	('expression', 'MPA', (46, 56))	('AEG-1', 'Gene', (40, 45))
187145	33671513	Additionally, recurrence rate, determined by prostate-specific antigen (PSA) levels, was significantly higher in AEG-1-high patients compared to AEG-1-low patients.	('AEG-1-high', 'Var', (113, 123))	('recurrence', 'MPA', (14, 24))	('prostate-specific antigen', 'Gene', '354', (45, 70))	('PSA', 'Gene', (72, 75))	('patients', 'Species', '9606', (155, 163))	('PSA', 'Gene', '354', (72, 75))	('rat', 'Species', '10116', (25, 28))	('higher', 'PosReg', (103, 109))	('prostate-specific antigen', 'Gene', (45, 70))	('patients', 'Species', '9606', (124, 132))
187147	33671513	Interestingly, in this study, the authors showed that knocking out AEG-1 in the transgenic adenocarcinoma of mouse prostate (TRAMP) model prolonged tumor latency and abrogated tumor progression and metastasis further establishing the importance of AEG-1 in prostate cancer.	('abrogated', 'NegReg', (166, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (257, 272))	('prostate cancer', 'Disease', (257, 272))	('AEG-1', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('knocking out', 'Var', (54, 66))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('adenocarcinoma', 'Disease', (91, 105))	('mouse', 'Species', '10090', (109, 114))	('prolonged', 'PosReg', (138, 147))	('TRAMP', 'Gene', '85030', (125, 130))	('TRAMP', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (257, 272))
187150	33671513	It was identified that high AEG-1 staining index was associated with tumor progression and poor survival status in all types of GI cancers thus establishing the importance of AEG-1 as a prognostic marker for GI cancers.	('AEG-1', 'Protein', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (23, 27))	('GI cancers', 'Disease', 'MESH:D009369', (208, 218))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('tumor', 'Disease', (69, 74))	('GI cancers', 'Disease', 'MESH:D009369', (128, 138))	('GI cancer', 'Phenotype', 'HP:0007378', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('GI cancers', 'Disease', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GI cancers', 'Disease', (208, 218))
187194	33671513	Both nuclear and cytoplasmic AEG-1 expression significantly correlated with phosphorylated NF-kappaB (Ser 536), p73 and Rad50 in primary tumors.	('tumors', 'Disease', (137, 143))	('NF-kappaB', 'Gene', '4790', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('NF-kappaB', 'Gene', (91, 100))	('Ser 536', 'Var', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Rad50', 'Gene', '10111', (120, 125))	('correlated', 'Reg', (60, 70))	('AEG-1', 'Gene', (29, 34))	('Rad50', 'Gene', (120, 125))	('p73', 'Gene', '7161', (112, 115))	('p73', 'Gene', (112, 115))	('Ser', 'Chemical', 'MESH:D012694', (102, 105))
187195	33671513	It was hypothesized that AEG-1 might be involved in p73-mediated DNA damage-induced apoptosis since cytoplasmic:but not nuclear:AEG-1 associated with increased apoptosis.	('apoptosis', 'CPA', (160, 169))	('DN', 'Chemical', '-', (65, 67))	('p73', 'Gene', '7161', (52, 55))	('AEG-1', 'Var', (128, 133))	('p73', 'Gene', (52, 55))	('increased', 'PosReg', (150, 159))
187197	33671513	Rectal cancer patients showed higher AEG-1 expression than colon cancer patients (p = 0.047) and in a follow-up study of 158 rectal cancer patients treated with radiotherapy (RT), the authors documented that high AEG-1 expression in primary tumors independently correlated with higher risk of distant recurrence (p = 0.009) and worse DFS (p = 0.007), indicating that AEG-1 might be a marker to identify patients who might develop distant relapse.	('high', 'Var', (208, 212))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('patients', 'Species', '9606', (14, 22))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (403, 411))	('higher', 'PosReg', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (7, 13))	('AEG-1', 'Protein', (213, 218))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('Rectal cancer', 'Phenotype', 'HP:0100743', (0, 13))	('AEG-1 expression', 'MPA', (37, 53))	('colon cancer', 'Disease', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Disease', (132, 138))	('expression', 'MPA', (219, 229))	('tumors', 'Disease', (241, 247))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('distant recurrence', 'CPA', (293, 311))	('patients', 'Species', '9606', (72, 80))
187205	33671513	AEG-1 and SND1 co-expression negatively correlated with postoperative overall survival and positively correlated with mortality (p = 0.009) in cox multivariate analysis, strongly indicating that AEG-1 and SND1 can serve as prognostic factors for colon cancer.	('SND1', 'Gene', (205, 209))	('colon cancer', 'Disease', 'MESH:D015179', (246, 258))	('colon cancer', 'Disease', (246, 258))	('mortality', 'Disease', (118, 127))	('SND1', 'Gene', '27044', (205, 209))	('negatively', 'NegReg', (29, 39))	('correlated', 'Reg', (102, 112))	('mortality', 'Disease', 'MESH:D003643', (118, 127))	('SND1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('AEG-1', 'Var', (195, 200))	('rat', 'Species', '10116', (63, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (246, 258))	('SND1', 'Gene', '27044', (10, 14))	('co-expression', 'Var', (15, 28))	('AEG-1', 'Gene', (0, 5))
187213	33671513	This A>C SNP alters AP2 binding site in AEG-1 promoter and was suggested to be associated with HCC susceptibility in Iranian patients.	('A>C SNP', 'Var', (5, 12))	('AP2', 'Gene', '7020', (20, 23))	('associated', 'Reg', (79, 89))	('AP2', 'Gene', (20, 23))	('HCC', 'Disease', (95, 98))	('alters', 'Reg', (13, 19))	('patients', 'Species', '9606', (125, 133))
187218	33671513	Genomic amplification of AEG-1 in HCC patients was shown in additional studies.	('Genomic amplification', 'Var', (0, 21))	('AEG-1', 'Gene', (25, 30))	('HCC', 'Disease', (34, 37))	('patients', 'Species', '9606', (38, 46))
187222	33671513	Additionally, the 1-, 3- and 5-year OS in high AEG-1-expressing group were significantly lower than those in low AEG-1-expressing group (83.0% vs. 89.7%, 52.0% vs. 75.3%, 37.4% vs. 66.9%, respectively); and the 1-, 3- and 5-year cumulative recurrence rates were markedly higher in high AEG-1-expressing group than those in low AEG-1-expressing group (32.4% vs. 16.8%, 61.2% vs. 38.2%, 70.7% vs. 47.8%, respectively).	('lower', 'NegReg', (89, 94))	('high AEG-1-expressing', 'Var', (281, 302))	('high AEG-1-expressing', 'Var', (42, 63))	('higher', 'PosReg', (271, 277))	('rat', 'Species', '10116', (251, 254))
187235	33671513	High AEG-1 levels were associated with worse OS and RFS (p < 0.001 and p = 0.01, respectively) and cox regression analysis identified that TNM stage, surgery margin and high AEG-1 expression were independent factors for OS and RFS in PCCA.	('high', 'Var', (169, 173))	('TNM', 'Gene', (139, 142))	('PCCA', 'Disease', (234, 238))	('RFS', 'Disease', (227, 230))	('RFS', 'Disease', (52, 55))	('TNM', 'Gene', '10178', (139, 142))	('RFS', 'Disease', 'MESH:D005198', (227, 230))	('RFS', 'Disease', 'MESH:D005198', (52, 55))
187252	33671513	Average survival time in EphA7 and AEG-1 positive cases was 8.1 months versus 13.2 months in EphA7 and AEG-1 negative cases (p < 0.001).	('EphA7', 'Gene', (25, 30))	('EphA7', 'Gene', '2045', (25, 30))	('EphA7', 'Gene', '2045', (93, 98))	('positive', 'Var', (41, 49))	('AEG-1', 'Gene', (35, 40))	('EphA7', 'Gene', (93, 98))
187258	33671513	Additionally, in 105 PDAC patients, 98.09% showed AEG-1 expression by IHC which was associated with advanced clinical stage (p = 0.004), T (p = 0.006), N (p = 0.003) and M (p = 0.007) classifications, lymph node involvement (p = 0.003) and distant metastasis (p = 0.007).	('lymph node involvement', 'CPA', (201, 223))	('IHC', 'Gene', (70, 73))	('patients', 'Species', '9606', (26, 34))	('distant metastasis', 'CPA', (240, 258))	('associated', 'Reg', (84, 94))	('AEG-1 expression', 'Var', (50, 66))
187264	33671513	IHC analysis in 102 RCC patients that included 86 clear cell carcinomas, 10 papillary carcinomas, 3 chromophobe cell types and three cases of cancer of the collecting duct of Bellini as well as 6 matched lymph node metastases and seven cases of neoplastic embolus in the renal vein showed high AEG-1 expression in 96 cases, especially in lymph node metastases and neoplastic emboli with weak AEG-1 expression in normal tubular epithelium and no expression in normal glomeruli.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('carcinomas', 'Disease', (86, 96))	('carcinomas', 'Disease', (61, 71))	('RCC', 'Disease', (20, 23))	('neoplastic embolus', 'Disease', (245, 263))	('metastases', 'Disease', 'MESH:D009362', (215, 225))	('cell carcinoma', 'Disease', (56, 70))	('metastases', 'Disease', 'MESH:D009362', (349, 359))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('carcinomas', 'Disease', 'MESH:D009369', (86, 96))	('cancer', 'Disease', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metastases', 'Disease', (215, 225))	('metastases', 'Disease', (349, 359))	('carcinomas', 'Disease', 'MESH:D009369', (61, 71))	('neoplastic embolus', 'Disease', 'MESH:D004617', (245, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('papillary carcinomas', 'Disease', 'MESH:D002291', (76, 96))	('cell carcinoma', 'Disease', 'MESH:C538614', (56, 70))	('AEG-1', 'Var', (294, 299))	('patients', 'Species', '9606', (24, 32))	('papillary carcinomas', 'Disease', (76, 96))
187266	33671513	The cumulative 5-year survival rate was 91.3% and 52.4% in low and high AEG-1 expression groups, respectively.	('high', 'Var', (67, 71))	('AEG-1', 'Protein', (72, 77))	('rat', 'Species', '10116', (31, 34))
187267	33671513	The mean survival time was 76.98 and 60.94 months in low and high AEG-1 expression groups, respectively, indicating a potential role of AEG-1 in regulating advanced progression of RCC.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('AEG-1', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('RCC', 'Disease', (180, 183))
187269	33671513	Similarly, p53 levels correlated with tumor diameter (p = 0.028), renal sinal invasion (p = 0.05) and Fuhrman grade (p = 0.026) indicating that AEG-1 and p53 might serve as prognostic markers for RCC.	('p53', 'Gene', (11, 14))	('tumor', 'Disease', (38, 43))	('p53', 'Gene', '7157', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Fuhrman grade', 'CPA', (102, 115))	('renal sinal invasion', 'CPA', (66, 86))	('correlated', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('AEG-1', 'Var', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))
187276	33671513	In a multivariate survival analysis, patients with high SI (SI > 6) had a shorter OS compared to patients with low SI (SI < 6) (p < 0.001).	('shorter', 'NegReg', (74, 81))	('high SI (SI > 6', 'Var', (51, 66))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (97, 105))
187296	33671513	These patients were also classified into those who had either high- or low-AEG-1 expression.	('low-AEG-1', 'NegReg', (71, 80))	('patients', 'Species', '9606', (6, 14))	('high-', 'Var', (62, 67))
187299	33671513	IHC analysis of 204 tissues, including 32 normal brain tissues, 80 Low-malignant astrocytomas (LMAs) and 92 High-Malignant astrocytomas (HMAs) showed AEG-1 positivity in 74.4% tumor samples which significantly correlated with histological grades (p < 0.001).	('correlated', 'Reg', (210, 220))	('High-Malignant astrocytomas', 'Disease', (108, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('High-Malignant astrocytomas', 'Disease', 'MESH:D020339', (108, 135))	('tumor', 'Disease', (176, 181))	('Low-malignant astrocytomas', 'Disease', 'MESH:D020339', (67, 93))	('Low-malignant astrocytomas', 'Disease', (67, 93))	('AEG-1 positivity', 'Var', (150, 166))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
187304	33671513	IHC analysis of 75 oligodendroglioma patients, including 52 well-differentiated and 23 anaplatic tumors, showed AEG-1 expression in 68% cases with correlated with tumor grade and Ki-67 levels (p = 0) but not with age and sex.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('AEG-1', 'Var', (112, 117))	('tumor', 'Disease', (97, 102))	('oligodendroglioma', 'Disease', (19, 36))	('Ki-67 levels', 'MPA', (179, 191))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('oligodendroglioma', 'Disease', 'MESH:D009837', (19, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
187305	33671513	In high AEG-1 expressing patients, median survival time was 28 months (95% confidence interval, 25.54-30.46) and cumulative 3-year survival rate was 19.69%, while in low AEG-1 expressing patients these values were 57 months (95% confidence interval, 46.37-67.63) (p = 0) and 88.05%, respectively.	('patients', 'Species', '9606', (187, 195))	('high', 'Var', (3, 7))	('AEG-1', 'Protein', (8, 13))	('patients', 'Species', '9606', (25, 33))	('rat', 'Species', '10116', (140, 143))
187313	33671513	Although in clinical stage I-II no significant difference between low or high AEG-1 levels and OS was observed, in stages III-IV high AEG-1 levels correlated with poor survival and patients with distant metastasis and high AEG-1 levels showed shorter OS compared to patients without distant metastases.	('poor', 'NegReg', (163, 167))	('patients', 'Species', '9606', (266, 274))	('high', 'Var', (129, 133))	('high', 'Var', (218, 222))	('AEG-1', 'MPA', (134, 139))	('metastases', 'Disease', (291, 301))	('distant metastasis', 'CPA', (195, 213))	('patients', 'Species', '9606', (181, 189))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('shorter', 'NegReg', (243, 250))
187318	33671513	AEG-1 is also targeted by tumor suppressor miR-30e-5p, which is downregulated in HNSCC, and low levels of miR-30e-5p correlated with poor overall survival (p < 0.05).	('miR-30e-5p', 'Chemical', '-', (43, 53))	('poor', 'NegReg', (133, 137))	('overall', 'MPA', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('low', 'Var', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('miR-30e-5p', 'Chemical', '-', (106, 116))
187327	33671513	Additionally, 5-year survival rate in high AEG-1 expressing TSCC patients (16.98%, 95% CI: 32.04-50.13%) was significantly lower than low AEG-1 expressing patients (36.73%, 95% CI: 58.68-73.08%).	('high AEG-1 expressing', 'Var', (38, 59))	('lower', 'NegReg', (123, 128))	('rat', 'Species', '10116', (30, 33))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (155, 163))	('TSCC', 'Disease', (60, 64))
187330	33671513	IHC analysis of 62 osteosarcoma patients and 20 normal bone samples revealed 82.3% AEG-1 positivity in cancer samples out of which 32 cases showed high expression and barely detectable expression in normal bone.	('positivity', 'Var', (89, 99))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('AEG-1', 'Gene', (83, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('cancer', 'Disease', (103, 109))	('osteosarcoma', 'Disease', (19, 31))	('expression', 'MPA', (152, 162))
187336	33671513	Additionally, IHC analysis of samples from 30 DLBCL patients and 15 reactive hyperplasia of the lymph nodes showed AEG-1 positivity with variable levels of expression in 76.67% DLBCL cases while little to no AEG-1 expression was detected in the controls.	('DLBCL', 'Disease', (177, 182))	('positivity', 'Var', (121, 131))	('AEG-1', 'Gene', (115, 120))	('hyperplasia', 'Disease', (77, 88))	('hyperplasia of the lymph', 'Phenotype', 'HP:0002716', (77, 101))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('patients', 'Species', '9606', (52, 60))
187346	33671513	At titers of >=1:50 anti-AEG-1 antibody was detected in 49% of these patients, including 45% breast cancer, 50% HCC, 49% colorectal cancer, 45% lung cancer and 49% gastric cancer patients, with none of 230 normal individuals displaying positivity (p < 0.01).	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('anti-AEG-1', 'Var', (20, 30))	('HCC', 'Disease', (112, 115))	('detected', 'Reg', (44, 52))	('colorectal cancer', 'Disease', (121, 138))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('patients', 'Species', '9606', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('patients', 'Species', '9606', (179, 187))	('gastric cancer', 'Disease', (164, 178))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
187351	33671513	Even though AEG-1 is an established diagnostic/prognostic marker for cancer, its use is limited by the availability of tumor biopsy samples and as such anti-AEG-1 antibody might serve as an important surrogate for AEG-1.	('tumor', 'Disease', (119, 124))	('anti-AEG-1', 'Var', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (69, 75))
187363	33671513	The present study was supported in part by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant 1R01DK107451-01A1, National Cancer Institute (NCI) Grants 1R01CA230561-01A1, 1R01CA240004-01 and 1R01CA244993-01, and Department of Defense (DOD) Grant CA170048.	('Diabetes', 'Disease', (69, 77))	('R01CA230561-01A1', 'CellLine', 'CVCL:X698', (185, 201))	('Cancer', 'Disease', (154, 160))	('1R01CA230561-01A1', 'Var', (184, 201))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('R01CA244993-01', 'CellLine', 'CVCL:9726', (224, 238))	('Kidney Diseases', 'Disease', 'MESH:D007674', (96, 111))	('1R01CA240004-01', 'Var', (203, 218))	('Diabetes', 'Disease', 'MESH:D003920', (69, 77))	('1R01CA244993-01', 'Var', (223, 238))	('Kidney Diseases', 'Phenotype', 'HP:0000112', (96, 111))	('Kidney Diseases', 'Disease', (96, 111))
187384	28969099	Inhibition of miR activity by antisense oligonucleotides or antagomirs has been used to study the functions of miRs, both in vitro and in vivo.	('activity', 'MPA', (18, 26))	('oligonucleotides', 'Chemical', 'MESH:D009841', (40, 56))	('miR', 'Gene', '220972', (14, 17))	('antisense', 'Var', (30, 39))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))
187418	28969099	The first model of circRNAs synthesis is intron-pairing-driven circularization, termed "direct back-splicing" (Figure 1A).	('cir', 'Gene', (19, 22))	('cir', 'Gene', '9541', (19, 22))	('intron-pairing-driven', 'Var', (41, 62))	('cir', 'Gene', (63, 66))	('cir', 'Gene', '9541', (63, 66))
187421	28969099	Notably, it has been reported that in humans the bordering introns of circRNAs are highly enriched in ALU repeats, which contain RCMs.	('cir', 'Gene', (70, 73))	('ALU repeats', 'Var', (102, 113))	('cir', 'Gene', '9541', (70, 73))	('humans', 'Species', '9606', (38, 44))
187451	28969099	In both cell lines transfected with empty vector (control of cir-ITCH plasmid), luciferase activity was significantly decreased, in a concentration dependent manner, by a miR-7 or miR-214 mimic.	('-ITCH', 'Phenotype', 'HP:0000989', (64, 69))	('miR-214', 'Gene', (180, 187))	('miR-7', 'Var', (171, 176))	('ITCH', 'Gene', '83737', (65, 69))	('ITCH', 'Phenotype', 'HP:0000989', (65, 69))	('cir', 'Gene', (61, 64))	('activity', 'MPA', (91, 99))	('ITCH', 'Gene', (65, 69))	('miR-214', 'Gene', '406996', (180, 187))	('decreased', 'NegReg', (118, 127))	('cir', 'Gene', '9541', (61, 64))	('luciferase', 'Enzyme', (80, 90))
187472	28969099	Following the knockdown of hsa_circ_0001649 with siRNA, there was an increase in the expression level of the pro-metastatic matrix metalloproteinases (MPPs), MMP9, MMP10 and MMP13.	('MMP9', 'Gene', (158, 162))	('cir', 'Gene', '9541', (31, 34))	('increase', 'PosReg', (69, 77))	('MMP9', 'Gene', '4318', (158, 162))	('MMP10', 'Gene', (164, 169))	('MMP10', 'Gene', '4319', (164, 169))	('MMP13', 'Gene', (174, 179))	('cir', 'Gene', (31, 34))	('knockdown', 'Var', (14, 23))	('MMP13', 'Gene', '4322', (174, 179))	('expression level', 'MPA', (85, 101))
187480	28969099	When ciRS-7 is knocked-down, there is a significant inhibition of HCC cell proliferation and invasion, which is likely due to the release of miR-7.	('knocked-down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('HCC cell proliferation', 'CPA', (66, 88))	('ciRS-7', 'Gene', '103611090', (5, 11))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('invasion', 'CPA', (93, 101))	('inhibition', 'NegReg', (52, 62))
187485	28969099	Consequently, the ectopic expression of circPVT1 may reduce the antineoplastic effects of miR-125b and E2F2.	('reduce', 'NegReg', (53, 59))	('ectopic expression', 'Var', (18, 36))	('E2F2', 'Gene', '1870', (103, 107))	('cir', 'Gene', (40, 43))	('cir', 'Gene', '9541', (40, 43))	('antineoplastic effects', 'CPA', (64, 86))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('E2F2', 'Gene', (103, 107))
187501	28969099	In a study of the CRC cell lines, HCT116 and SW480, sponge activity of cir-ITCH was demonstrated towards miR-7, miR-20a, and miR-214.	('ITCH', 'Gene', '83737', (75, 79))	('miR-20a', 'Gene', (112, 119))	('miR-7', 'Var', (105, 110))	('cir', 'Gene', (71, 74))	('miR-20a', 'Gene', '406982', (112, 119))	('miR-214', 'Gene', (125, 132))	('ITCH', 'Gene', (75, 79))	('HCT116', 'CellLine', 'CVCL:0291', (34, 40))	('sponge activity', 'MPA', (52, 67))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('miR-214', 'Gene', '406996', (125, 132))	('cir', 'Gene', '9541', (71, 74))	('SW480', 'CellLine', 'CVCL:0546', (45, 50))	('ITCH', 'Phenotype', 'HP:0000989', (75, 79))	('-ITCH', 'Phenotype', 'HP:0000989', (74, 79))
187503	28969099	It has also been reported that the ectopic expression of cir-ITCH inhibits the expression of c-myc and cyclin D1, which are target genes of the Wnt/beta-catenin signaling pathway.	('ITCH', 'Gene', '83737', (61, 65))	('ectopic expression', 'Var', (35, 53))	('expression', 'MPA', (79, 89))	('ITCH', 'Gene', (61, 65))	('beta-catenin', 'Gene', (148, 160))	('cir', 'Gene', (57, 60))	('inhibits', 'NegReg', (66, 74))	('c-myc', 'Gene', (93, 98))	('c-myc', 'Gene', '4609', (93, 98))	('beta-catenin', 'Gene', '1499', (148, 160))	('cir', 'Gene', '9541', (57, 60))	('cyclin D1', 'Gene', '595', (103, 112))	('ITCH', 'Phenotype', 'HP:0000989', (61, 65))	('-ITCH', 'Phenotype', 'HP:0000989', (60, 65))	('cyclin D1', 'Gene', (103, 112))
187505	28969099	In line with this, studies of cir-ITCH over-expression have demonstrated a decrease in cellular proliferation of both HCT116 and SW480 cells.	('ITCH', 'Phenotype', 'HP:0000989', (34, 38))	('SW480', 'CellLine', 'CVCL:0546', (129, 134))	('ITCH', 'Gene', '83737', (34, 38))	('decrease', 'NegReg', (75, 83))	('cir', 'Gene', (30, 33))	('over-expression', 'Var', (39, 54))	('ITCH', 'Gene', (34, 38))	('cir', 'Gene', '9541', (30, 33))	('HCT116', 'CellLine', 'CVCL:0291', (118, 124))	('-ITCH', 'Phenotype', 'HP:0000989', (33, 38))	('cellular proliferation', 'CPA', (87, 109))
187512	28969099	Moreover, knockdown of hsa_circ_001569 in SW620 and LOVO cells has been shown to reverse invasive abilities.	('SW620', 'CellLine', 'CVCL:0547', (42, 47))	('invasive abilities', 'CPA', (89, 107))	('cir', 'Gene', (27, 30))	('reverse', 'NegReg', (81, 88))	('knockdown', 'Var', (10, 19))	('cir', 'Gene', '9541', (27, 30))
187517	28969099	A knockdown of circ-BANP using siRNA was also shown to reduce proliferation and colony formation of the CRC cell lines, HCT116 and HT29.	('BANP', 'Gene', (20, 24))	('cir', 'Gene', (15, 18))	('colony formation', 'CPA', (80, 96))	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('knockdown', 'Var', (2, 11))	('proliferation', 'CPA', (62, 75))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('cir', 'Gene', '9541', (15, 18))	('reduce', 'NegReg', (55, 61))	('BANP', 'Gene', '54971', (20, 24))
187537	28969099	These results implicated the abnormally expressed circRNAs in the development of radiation resistance in the esophageal cancer cells.	('implicated', 'Reg', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormally expressed', 'Var', (29, 49))	('men', 'Species', '9606', (73, 76))	('cir', 'Gene', (50, 53))	('cir', 'Gene', '9541', (50, 53))	('radiation resistance', 'CPA', (81, 101))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
187539	28969099	Moreover, siRNA mediated silencing of hsa_circ_0067934 suppressed ESCC cell proliferation, migration and cell cycle progression.	('silencing', 'Var', (25, 34))	('migration', 'CPA', (91, 100))	('suppressed', 'NegReg', (55, 65))	('cell cycle progression', 'CPA', (105, 127))	('ESCC', 'Disease', (66, 70))	('cir', 'Gene', (42, 45))	('cir', 'Gene', '9541', (42, 45))
187543	28969099	The authors also identified that cir-ITCH acts as a sponge of miR-7, miR-17, and miR-214, thereby up-regulated the target gene ITCH, which negatively regulates the Wnt/beta-catenin pathway via targeting dishevelled (Dvl) protein.	('miR-17', 'Gene', (69, 75))	('ITCH', 'Gene', (127, 131))	('negatively', 'NegReg', (139, 149))	('cir', 'Gene', '9541', (33, 36))	('miR-7', 'Var', (62, 67))	('ITCH', 'Phenotype', 'HP:0000989', (37, 41))	('miR-214', 'Gene', '406996', (81, 88))	('beta-catenin', 'Gene', (168, 180))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('Dvl', 'Gene', (216, 219))	('cir', 'Gene', (33, 36))	('beta-catenin', 'Gene', '1499', (168, 180))	('ITCH', 'Gene', '83737', (127, 131))	('ITCH', 'Gene', (37, 41))	('dishevelled', 'Gene', (203, 214))	('miR-214', 'Gene', (81, 88))	('miR-17', 'Gene', '406952', (69, 75))	('up-regulated', 'PosReg', (98, 110))	('dishevelled', 'Gene', '8215', (203, 214))	('ITCH', 'Phenotype', 'HP:0000989', (127, 131))	('regulates', 'Reg', (150, 159))	('Dvl', 'Gene', '8215', (216, 219))	('ITCH', 'Gene', '83737', (37, 41))
187547	28969099	While DCIS is generally considered to be highly curable, some women with DCIS will develop life-threatening invasive breast cancer, infiltrating ductal cancer (IDC), but the determinants of this progression remains largely unknown.	('DCIS', 'Phenotype', 'HP:0030075', (6, 10))	('develop', 'PosReg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('ductal cancer', 'Disease', 'MESH:D009369', (145, 158))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('DCIS', 'Var', (73, 77))	('ductal cancer', 'Disease', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('women', 'Species', '9606', (62, 67))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
187591	28969099	Silencing of cZNF292 expression was reported to inhibit glioma cell proliferation and halt cell cycle progression in U87MG and U251 cells via inactivation of the Wnt/beta-catenin signaling pathway.	('glioma', 'Disease', (56, 62))	('beta-catenin', 'Gene', (166, 178))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('inactivation', 'NegReg', (142, 154))	('halt', 'NegReg', (86, 90))	('beta-catenin', 'Gene', '1499', (166, 178))	('cell cycle progression', 'CPA', (91, 113))	('cZNF292', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))	('U251', 'CellLine', 'CVCL:0021', (127, 131))	('inhibit', 'NegReg', (48, 55))
187607	28969099	Functional analysis found that a knockdown of circRNA_100290 could induce G1/S arrest in SCC9 cell lines, and this significantly inhibited cell proliferation.	('inhibited', 'NegReg', (129, 138))	('S arrest', 'Disease', (77, 85))	('cir', 'Gene', (46, 49))	('cir', 'Gene', '9541', (46, 49))	('knockdown', 'Var', (33, 42))	('S arrest', 'Disease', 'MESH:D006323', (77, 85))	('cell proliferation', 'CPA', (139, 157))	('induce', 'Reg', (67, 73))	('SCC9', 'CellLine', 'CVCL:1685', (89, 93))
187627	28969099	Previous studies have shown how miR expression can be regulated through mechanisms, such as DNA copy number variations, epigenetics, transcription factors and other mechanisms in cancer.	('miR', 'Gene', (32, 35))	('regulated', 'Reg', (54, 63))	('epigenetics', 'Var', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('expression', 'MPA', (36, 46))	('miR', 'Gene', '220972', (32, 35))
187633	26249178	Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers.	('mutations', 'Var', (45, 54))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('HG-DCIS', 'Disease', (21, 28))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
187634	26249178	Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A.	('MLL3', 'Gene', (81, 85))	('ARID1A', 'Gene', '8289', (165, 171))	('NF1', 'Gene', (151, 154))	('TP53', 'Gene', '7157', (57, 61))	('TBX3', 'Gene', '6926', (145, 149))	('mutations', 'Var', (111, 120))	('PIK3CA', 'Gene', (34, 40))	('GATA3', 'Gene', '2625', (69, 74))	('ATM', 'Gene', '472', (156, 159))	('CDH1', 'Gene', '999', (131, 135))	('GATA3', 'Gene', (69, 74))	('TBX3', 'Gene', (145, 149))	('CDH1', 'Gene', (131, 135))	('TP53', 'Gene', (57, 61))	('MLL3', 'Gene', '58508', (81, 85))	('ATM', 'Gene', (156, 159))	('ARID1A', 'Gene', (165, 171))	('PIK3CA', 'Gene', '5290', (34, 40))	('NF1', 'Gene', '4763', (151, 154))	('MAP2K4', 'Gene', '6416', (137, 143))	('MAP2K4', 'Gene', (137, 143))
187635	26249178	Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations.	('chromosomal copy number alterations', 'Var', (55, 90))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
187639	26249178	Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes.	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('HOTAIR', 'Gene', '100124700', (72, 78))	('DCIS-C1', 'Gene', (82, 89))	('SOX genes', 'Gene', (132, 141))	('HOXA5', 'Gene', '3202', (122, 127))	('hypermethylation', 'Var', (102, 118))	('upregulation', 'PosReg', (49, 61))	('HOXA5', 'Gene', (122, 127))	('HOTAIR', 'Gene', (72, 78))
187648	26249178	Mutations affecting genes such as TP53 and PIK3CA were also reported in DCIS.	('PIK3CA', 'Gene', '5290', (43, 49))	('TP53', 'Gene', (34, 38))	('DCIS', 'Disease', (72, 76))	('Mutations', 'Var', (0, 9))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('reported', 'Reg', (60, 68))	('TP53', 'Gene', '7157', (34, 38))	('PIK3CA', 'Gene', (43, 49))
187673	26249178	Almost 50% of these mutations were C>T:G>A transitions in agreement with the previously described most prevalent mutation-type signature in breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('C>T:G>A', 'Var', (35, 42))	('mutations', 'Var', (20, 29))
187674	26249178	The total mutation rate was 1.61 mutations per Mbp on average with a range of 0.8 to 3.8 mutations per Mbp (Fig.	('Mbp', 'Gene', '4155', (103, 106))	('Mbp', 'Gene', (103, 106))	('mutations', 'Var', (33, 42))	('Mbp', 'Gene', '4155', (47, 50))	('Mbp', 'Gene', (47, 50))
187676	26249178	In total, 18 of 29 HG-DCIS cases (62%) displayed mutations affecting one or combinations of targets described as cancer driver genes or potential drivers.	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('HG-DCIS', 'Gene', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
187677	26249178	Among these, we detected mutations affecting PIK3CA (21%), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A (Fig.	('CDH1', 'Gene', '999', (133, 137))	('NF1', 'Gene', (153, 156))	('PIK3CA', 'Gene', (45, 51))	('TBX3', 'Gene', (147, 151))	('CDH1', 'Gene', (133, 137))	('GATA3', 'Gene', '2625', (71, 76))	('ARID1A', 'Gene', (167, 173))	('mutations', 'Var', (25, 34))	('MLL3', 'Gene', '58508', (83, 87))	('TP53', 'Gene', (59, 63))	('GATA3', 'Gene', (71, 76))	('ATM', 'Gene', (158, 161))	('ARID1A', 'Gene', '8289', (167, 173))	('MAP2K4', 'Gene', '6416', (139, 145))	('MAP2K4', 'Gene', (139, 145))	('MLL3', 'Gene', (83, 87))	('PIK3CA', 'Gene', '5290', (45, 51))	('TP53', 'Gene', '7157', (59, 63))	('TBX3', 'Gene', '6926', (147, 151))	('NF1', 'Gene', '4763', (153, 156))	('ATM', 'Gene', '472', (158, 161))
187679	26249178	Interestingly, several genes reported as mutated in IBC, such as MAP3K1, PTEN, AKT1, RUNX1, RB1, and various others so far, have not been detected mutated in DCIS, suggesting that perhaps some of these mutations may be associated with postinvasion events; however, our sample number is still limited.	('RB1', 'Gene', '5925', (92, 95))	('MAP3K1', 'Gene', '4214', (65, 71))	('PTEN', 'Gene', (73, 77))	('AKT1', 'Gene', '207', (79, 83))	('associated', 'Reg', (219, 229))	('PTEN', 'Gene', '5728', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('AKT1', 'Gene', (79, 83))	('RUNX1', 'Gene', (85, 90))	('RB1', 'Gene', (92, 95))	('MAP3K1', 'Gene', (65, 71))	('RUNX1', 'Gene', '861', (85, 90))	('mutations', 'Var', (202, 211))
187682	26249178	The profile of copy number changes across the genome in HG-DCIS is practically identical to profiles reported in invasive breast lesions and is in agreement with early observations using comparative genome hybridization (CGH) approaches.	('invasive breast lesions', 'Disease', 'MESH:D001941', (113, 136))	('copy number', 'Var', (15, 26))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('HG-DCIS', 'Var', (56, 63))	('invasive breast lesions', 'Disease', (113, 136))
187684	26249178	Interestingly, multiple cases (T2, T4, T5, T10, T13, T16, T22, and T24) displayed significantly large chromosomal copy number alterations but no mutations in known cancer driver genes, whereas 16 of 18 cases (89%) with mutations in cancer driver genes all show significant chromosomal copy number alterations (Fig.	('T2', 'Var', (31, 33))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('T16', 'Var', (53, 56))	('cancer', 'Disease', (232, 238))	('T22', 'Var', (58, 61))	('T10', 'Var', (43, 46))	('T13', 'Var', (48, 51))	('chromosomal copy number', 'MPA', (102, 125))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('mutations', 'Var', (219, 228))	('T24', 'Var', (67, 70))	('chromosomal copy number alterations', 'MPA', (273, 308))
187686	26249178	Nevertheless our findings also suggest that large chromosomal copy number alterations (trisomies, monosomies, large chromosomal duplications, and deletions) occur early in tumor progression, perhaps preceding the selection of alleles with mutations in driver genes.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('deletions', 'Var', (146, 155))
187696	26249178	It was striking to observe that the TP53 signaling pathway was found deactivated in all DCIS samples analyzed regardless of TP53 mutation status, ER/PR expression status or intrinsic subtype when compared with normal epithelium (Fig.	('deactivated', 'NegReg', (69, 80))	('TP53', 'Gene', '7157', (124, 128))	('mutation', 'Var', (129, 137))	('DCIS', 'Disease', (88, 92))	('TP53', 'Gene', (124, 128))	('TP53', 'Gene', '7157', (36, 40))	('ER', 'Gene', '2099', (146, 148))	('TP53', 'Gene', (36, 40))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
187707	26249178	Recently, Kristensen and colleagues suggested that the perturbation in the immune response and IL signaling (IL4, IL6, IL12, and IL23) can lead to classification of IBC subclasses with prognostic value.	('lead to', 'Reg', (139, 146))	('IL23', 'Gene', (129, 133))	('immune response', 'CPA', (75, 90))	('IL23', 'Gene', '51561', (129, 133))	('IBC', 'Disease', (165, 168))	('IL6', 'Gene', '3569', (114, 117))	('IL6', 'Gene', (114, 117))	('IL4', 'Gene', '3565', (109, 112))	('perturbation', 'Var', (55, 67))	('IL4', 'Gene', (109, 112))
187711	26249178	Interestingly, 46 of the 127 antisense RNAs and 18 of the 66 lincRNAs have been recently identified as potentially relevant in breast cancer.	('antisense RNAs', 'Var', (29, 43))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
187724	26249178	Recently, Newie and colleagues demonstrated that ERBB2 amplification might lead to ESR1 downregulation through internal seed interaction with miR-4728-3p in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('downregulation', 'NegReg', (88, 102))	('amplification', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('ESR1', 'Gene', (83, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('interaction', 'Interaction', (125, 136))	('ERBB2', 'Gene', (49, 54))	('ERBB2', 'Gene', '2064', (49, 54))	('ESR1', 'Gene', '2099', (83, 87))
187739	26249178	Fu and colleagues demonstrated that silencing of SOX17 due to promoter hypermethylation is frequent in invasive carcinomas and may contribute to aberrant activation of Wnt signaling in breast cancer.	('promoter hypermethylation', 'Var', (62, 87))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('invasive carcinomas', 'Disease', 'MESH:D009361', (103, 122))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('breast cancer', 'Disease', (185, 198))	('Wnt signaling', 'Pathway', (168, 181))	('SOX17', 'Gene', (49, 54))	('invasive carcinomas', 'Disease', (103, 122))	('activation', 'PosReg', (154, 164))	('silencing', 'Var', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('SOX17', 'Gene', '64321', (49, 54))
187740	26249178	This evidence raises the possibility that hypermethylation of specific SOX family members could constitute common important epigenetic phenomena occurring at early stages of breast cancer development that deserves further study.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('hypermethylation', 'Var', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))
187745	26249178	It is also important to note that 4 of 5 cases with TP53 non-synonymous mutations were detected in ER/PR double negative tumors from the DCIS-C1 group (T3, T7, T26, and T29).	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('T26', 'CellLine', 'CVCL:8806', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TP53', 'Gene', '7157', (52, 56))	('detected', 'Reg', (87, 95))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('T29', 'Var', (169, 172))	('ER', 'Gene', '2099', (99, 101))	('T26', 'Var', (160, 163))	('non-synonymous mutations', 'Var', (57, 81))
187746	26249178	Overall, these data suggest that TP53 mutation and HOXA5 hypermethylation could constitute early events during breast cancer progression that can cooperate to inactivate the TP53 pathway in more prone to progress DCIS lesions.	('inactivate', 'NegReg', (159, 169))	('HOXA5', 'Gene', '3202', (51, 56))	('TP53', 'Gene', (174, 178))	('DCIS', 'Phenotype', 'HP:0030075', (213, 217))	('HOXA5', 'Gene', (51, 56))	('TP53', 'Gene', '7157', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))	('progress', 'PosReg', (204, 212))	('breast cancer', 'Disease', (111, 124))	('TP53', 'Gene', '7157', (174, 178))
187748	26249178	CpGi methylation and expression analysis from the TCGA breast cancer dataset demonstrated that HOXA5 hypermethylation and downregulation can be also identified and is common in more advanced stages of breast cancer progression (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('downregulation', 'NegReg', (122, 136))	('hypermethylation', 'Var', (101, 117))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (55, 68))	('HOXA5', 'Gene', '3202', (95, 100))	('breast cancer', 'Disease', (201, 214))	('HOXA5', 'Gene', (95, 100))
187755	26249178	Our comprehensive catalogue of differentially expressed genes is also consistent with the existence of the most common breast cancer subtypes, but now we show that these important and complex epigenetic changes, such as hypermethylation of HOXA5 and specific SOX genes, are already operating at the in situ stage.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hypermethylation', 'Var', (220, 236))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('HOXA5', 'Gene', (240, 245))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('SOX genes', 'Gene', (259, 268))	('HOXA5', 'Gene', '3202', (240, 245))
187816	25593993	In DCIS with low stromal versican, 3 of 11 (27%) lesions presented myxoid stroma, while DCIS with high stromal versican counted 5 of 8 (63%) myxoid cases (Figure 3A-B).	('myxoid stroma', 'Disease', 'MESH:D045888', (67, 80))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('low', 'Var', (13, 16))	('myxoid stroma', 'Disease', (67, 80))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
187817	25593993	Stromal biglycan expression was not able to discern myxoid from sclerotic DCIS (Figure 3C-D): in DCIS with low to moderate stromal biglycan, 7 of 14 (50%) DCIS presented myxoid stroma, while 1 of 6 DCIS (17%) with high stromal biglycan had myxoid stroma (p=0.325) (Figure 4).	('sclerotic DCIS', 'Disease', (64, 78))	('rat', 'Species', '10116', (118, 121))	('myxoid stroma', 'Disease', (240, 253))	('myxoid stroma', 'Disease', 'MESH:D045888', (240, 253))	('biglycan', 'Gene', '633', (227, 235))	('biglycan', 'Gene', '633', (8, 16))	('sclerotic DCIS', 'Disease', 'MESH:D002285', (64, 78))	('myxoid stroma', 'Disease', (170, 183))	('myxoid stroma', 'Disease', 'MESH:D045888', (170, 183))	('biglycan', 'Gene', '633', (131, 139))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))	('biglycan', 'Gene', (8, 16))	('biglycan', 'Gene', (227, 235))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('low', 'Var', (107, 110))	('biglycan', 'Gene', (131, 139))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
187878	25593993	We speculate that the majority of DCIS with high periductal versican will also present myxoid stroma and reduced decorin expression, and patients with such lesions may be more likely to relapse.	('DCIS', 'Disease', (34, 38))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('decorin', 'Protein', (113, 120))	('myxoid stroma', 'Disease', (87, 100))	('patients', 'Species', '9606', (137, 145))	('reduced', 'NegReg', (105, 112))	('myxoid stroma', 'Disease', 'MESH:D045888', (87, 100))	('high periductal versican', 'Var', (44, 68))
187896	25593993	Interestingly, this TGF-beta blockade decreased the type I collagen content, which contributed to normalization of the tumor stroma and improved intratumoral penetration of therapeutics.	('blockade', 'Var', (29, 37))	('TGF-beta', 'Gene', (20, 28))	('tumor', 'Disease', (119, 124))	('type I collagen content', 'MPA', (52, 75))	('decreased', 'NegReg', (38, 47))	('tumor stroma', 'Disease', (119, 131))	('rat', 'Species', '10116', (163, 166))	('rat', 'Species', '10116', (148, 151))	('tumor stroma', 'Disease', 'MESH:D009369', (119, 131))	('normalization', 'MPA', (98, 111))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (150, 155))	('improved', 'PosReg', (136, 144))
187924	25593993	IHC for versican (dilution 1/25, HPA004726, Atlas Antibodies, Stockholm, Sweden) and biglycan (dilution 1/200, HPA003157, Atlas Antibodies) was performed on 3.5 mum FFPE tissue sections, using a Ventana Automated Slide Stainer (Benchmark XT, Ventana Medical Systems, AZ, USA).	('biglycan', 'Gene', '633', (85, 93))	('biglycan', 'Gene', (85, 93))	('HPA004726', 'Var', (33, 42))
187947	25593993	inverse circularity or P2/4piA) in Adobe Photoshop CX5 software (Adobe Systems Incorporated, San Jose, CA, USA).	('P2/4piA', 'Var', (23, 30))	('inverse', 'MPA', (0, 7))	('CX5', 'Gene', (51, 54))	('CX5', 'Gene', '1269', (51, 54))	('rat', 'Species', '10116', (86, 89))
187953	24811059	Suppression of Akt-mTOR Pathway-A Novel Component of Oncogene Induced DNA Damage Response Barrier in Breast Tumorigenesis DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability.	('Akt', 'Gene', '207', (15, 18))	('Breast Tumorigenesis', 'Disease', (101, 121))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('oncogenes', 'CPA', (286, 295))	('activating/and', 'PosReg', (260, 274))	('tumor', 'Disease', (233, 238))	('associated', 'Reg', (165, 175))	('mTOR', 'Gene', '2475', (19, 23))	('resulting in', 'Reg', (307, 319))	('mTOR', 'Gene', (19, 23))	('Akt', 'Gene', (15, 18))	('enabling', 'PosReg', (211, 219))	('amplifying', 'PosReg', (275, 285))	('genomic instability', 'MPA', (320, 339))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('mutations', 'Var', (220, 229))
187961	24811059	Whereas oncogene induced aberrant replication evokes activation of ATR and chk1 both of these mechanisms together lead to the accumulation of phosphorylated form of gammaH2AX, a well recognized marker of DNA damage.	('activation', 'PosReg', (53, 63))	('aberrant', 'Var', (25, 33))	('accumulation', 'PosReg', (126, 138))	('gammaH2AX', 'Protein', (165, 174))	('phosphorylated', 'MPA', (142, 156))	('chk1', 'Gene', '1111', (75, 79))	('gammaH2AX', 'Chemical', '-', (165, 174))	('ATR', 'Gene', '545', (67, 70))	('ATR', 'Gene', (67, 70))	('chk1', 'Gene', (75, 79))
188006	24811059	Similar to previous reports, higher levels of ki-67 were significantly associated with increasing risk for invasive breast cancer (p<0.001) (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('invasive breast cancer', 'Disease', (107, 129))	('ki-67', 'Var', (46, 51))	('invasive breast cancer', 'Disease', 'MESH:D001943', (107, 129))
188007	24811059	However, surprisingly, we found that the proportion of cells staining for gammaH2AX significantly decreased (p<0.001) with increasing risk lesions (Table 1, "Table S1 in File S1"), indicating that DNA damage is inversely correlated with invasive breast cancer risk.	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('gammaH2AX', 'Chemical', '-', (74, 83))	('invasive breast cancer', 'Disease', (237, 259))	('gammaH2AX', 'Var', (74, 83))	('invasive breast cancer', 'Disease', 'MESH:D001943', (237, 259))	('decreased', 'NegReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
188017	24811059	As shown in Fig.1a, this model identified that the combination of high gammaH2AX and low proliferation was disproportionately associated with women at average risk for breast cancer.	('low proliferation', 'CPA', (85, 102))	('associated', 'Reg', (126, 136))	('gammaH2AX', 'Protein', (71, 80))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('gammaH2AX', 'Chemical', '-', (71, 80))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('high', 'Var', (66, 70))	('women', 'Species', '9606', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
188019	24811059	However, high levels of gammaH2AX added additional specificity to the model and allowed for the identification of a clear average (low) risk state.	('specificity', 'MPA', (51, 62))	('gammaH2AX', 'Chemical', '-', (24, 33))	('gammaH2AX', 'Var', (24, 33))
188026	24811059	We found cyclin E clones to be slower growing than parental MCF10A cells with an increase in doubling time from 2.4 days in MCF10A (P) to almost 4 and 7 days in CyE (C3) and CyE (B10) respectively (p<0.05) (Fig.	('B10', 'Gene', (179, 182))	('MCF10A', 'CellLine', 'CVCL:0598', (124, 130))	('CyE', 'Chemical', '-', (174, 177))	('CyE', 'Chemical', '-', (161, 164))	('slower', 'NegReg', (31, 37))	('increase', 'PosReg', (81, 89))	('MCF10A', 'CellLine', 'CVCL:0598', (60, 66))	('B10', 'Gene', '5169', (179, 182))	('doubling', 'MPA', (93, 101))	('MCF10A', 'Var', (124, 130))
188038	24811059	Consistent with the hypothesis that AKT-mTOR may be part of the DDR barrier, we observed an activation of pAkt, and pS6 in the MCF10A progression model with levels increasing in MCF10.AT1, MCF10.DCIS and MCF10.CA1d as compared to MCF10A (P) [fig.	('MCF10', 'CellLine', 'CVCL:5555', (230, 235))	('MCF10.DCIS', 'Var', (189, 199))	('mTOR', 'Gene', (40, 44))	('AKT', 'Gene', (36, 39))	('MCF10', 'CellLine', 'CVCL:5555', (127, 132))	('MCF10', 'CellLine', 'CVCL:5555', (189, 194))	('MCF10A', 'CellLine', 'CVCL:0598', (230, 236))	('pS6', 'Gene', (116, 119))	('MCF10A', 'CellLine', 'CVCL:0598', (127, 133))	('Akt', 'Gene', (107, 110))	('MCF10', 'CellLine', 'CVCL:5555', (204, 209))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (189, 199))	('mTOR', 'Gene', '2475', (40, 44))	('MCF10.AT1', 'Var', (178, 187))	('Akt', 'Gene', '207', (107, 110))	('activation', 'PosReg', (92, 102))	('AKT', 'Gene', '207', (36, 39))	('pS6', 'Gene', '338413', (116, 119))	('ser', 'Chemical', 'MESH:D012694', (82, 85))	('MCF10', 'CellLine', 'CVCL:5555', (178, 183))
188047	24811059	The observation that mutations in DNA damage repair proteins: BRCA 1 and BRCA 2 in carriers families have been causally linked to the development of carcinoma primarily in the breast and ovary suggest that DNA damage and repair are particularly relevant in the process of tumorigenesis in these organs.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('BRCA 1', 'Gene', '672', (62, 68))	('BRCA 1', 'Gene', (62, 68))	('carcinoma', 'Disease', 'MESH:D002277', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Disease', (272, 277))	('BRCA 2', 'Gene', '675', (73, 79))	('linked to', 'Reg', (120, 129))	('BRCA 2', 'Gene', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('carcinoma', 'Disease', (149, 158))	('ser', 'Chemical', 'MESH:D012694', (6, 9))	('mutations', 'Var', (21, 30))
188049	24811059	Single nucleotide polymorphisms of DNA repair genes have been associated with increased risk of breast cancer and recently, variants of the ATM gene, a key regulator of the cellular response to repair DNA damage, has also shown to be associated with altered susceptibility towards breast cancer.	('ATM', 'Gene', '472', (140, 143))	('breast cancer', 'Disease', (281, 294))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('associated', 'Reg', (62, 72))	('variants', 'Var', (124, 132))	('DNA repair genes', 'Gene', (35, 51))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('ATM', 'Gene', (140, 143))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))
188050	24811059	The relevance of DNA damage to breast tumorigenesis is also highlighted by the fact that breast tumors lose expression of MRN complex proteins (that maintain genomic integrity by sensing DNA damage and through repair) and these defects were even more pronounced in TNBC, where mutations in the genes responsible for DNA DSB repair (particularly NSB) have been linked to poor patient survival.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('breast tumors', 'Phenotype', 'HP:0100013', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('NSB', 'Disease', (345, 348))	('tumor', 'Disease', (96, 101))	('MRN complex proteins', 'Protein', (122, 142))	('TNBC', 'Disease', (265, 269))	('patient', 'Species', '9606', (375, 382))	('mutations', 'Var', (277, 286))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('breast tumors', 'Disease', 'MESH:D001943', (89, 102))	('expression', 'MPA', (108, 118))	('sensing DNA damage', 'MPA', (179, 197))	('breast tumors', 'Disease', (89, 102))	('lose', 'NegReg', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
188051	24811059	In a pioneering study, using invasive breast cancer samples, Bartikova et al very interestingly reported gammaH2AX positivity to be associated with TNBC stage and p53 aberration.	('invasive breast cancer', 'Disease', 'MESH:D001943', (29, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gammaH2AX', 'Protein', (105, 114))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('gammaH2AX', 'Chemical', '-', (105, 114))	('invasive breast cancer', 'Disease', (29, 51))	('positivity', 'Var', (115, 125))	('TNBC stage', 'Disease', (148, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('associated', 'Reg', (132, 142))
188054	24811059	Secondly, this study also reported gammaH2AX to be of prognostic value in TNBC, and BRCA1.	('gammaH2AX', 'Var', (35, 44))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA1', 'Gene', (84, 89))	('TNBC', 'Disease', (74, 78))	('gammaH2AX', 'Chemical', '-', (35, 44))
188074	24400744	Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB.	('18G', 'Var', (164, 167))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (77, 101))	('invasive carcinoma', 'Disease', (111, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (84, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('invasive carcinoma', 'Disease', 'MESH:D009361', (111, 129))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (77, 101))	('ductal carcinoma in situ', 'Disease', (77, 101))
188120	24400744	Results showed that false-negative rates were low for 16G and 18G CNB, and that agreement rates between histological findings of CNB and surgery were >92% for 16G and 18G CNB.	('men', 'Species', '9606', (85, 88))	('16G', 'Var', (54, 57))	('16G', 'Var', (159, 162))
188150	19732414	Even though all mice were inbred to express the SV40 Tag transgene in the mammary epithelium and expected to develop invasive carcinoma, the individual MIN lesions took vastly different progression paths: (i) 9 lesions progressed to invasive tumors with an average progression time of 4.6 +- 1.9 weeks; (ii) 2 lesions regressed, i.e., were not detected on future images; and (iii) 5 were stable for over 8 weeks, and were demonstrated by a statistical model to represent indolent disease.	('SV40', 'Var', (48, 52))	('Tag', 'Gene', (53, 56))	('invasive carcinoma', 'Disease', (117, 135))	('MIN lesions', 'Disease', 'MESH:D051437', (152, 163))	('mice', 'Species', '10090', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('MIN lesions', 'Disease', (152, 163))	('Tag', 'Gene', '107423', (53, 56))	('invasive tumors', 'Disease', (233, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('invasive carcinoma', 'Disease', 'MESH:D009361', (117, 135))	('invasive tumors', 'Disease', 'MESH:D009369', (233, 248))
188161	19732414	In another, 11 of 28 women with misdiagnosed low-grade DCIS developed invasive carcinoma in the same quadrant, the majority within 15 years.	('developed', 'Reg', (60, 69))	('low-grade', 'Var', (45, 54))	('invasive carcinoma', 'Disease', (70, 88))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('women', 'Species', '9606', (21, 26))	('invasive carcinoma', 'Disease', 'MESH:D009361', (70, 88))
188196	19732414	To determine whether some latent lesions truly represented non-progressing or 'indolent' disease, a threshold T0 was found so that MIN lesions with Tlat > T0 could be considered a biologically distinct class of 'indolent' lesion.	('MIN lesions', 'Disease', (131, 142))	('Tlat > T0', 'Var', (148, 157))	('MIN lesions', 'Disease', 'MESH:D051437', (131, 142))
188342	19800470	Figures 5A/B is imaged from the margin (posterior margin pathologically positive for IDC) of the patient who underwent neoadjuvant endocrine therapy.	('IDC', 'Gene', '4000', (85, 88))	('IDC', 'Gene', (85, 88))	('5A/B', 'SUBSTITUTION', 'None', (8, 12))	('patient', 'Species', '9606', (97, 104))	('5A/B', 'Var', (8, 12))
188345	19800470	Of the remaining 5 patients, Figures 5C/D is imaged from a patient with IDC just beneath her nipple where there is greater ductal tissue and less fat.	('IDC', 'Gene', (72, 75))	('patient', 'Species', '9606', (19, 26))	('patients', 'Species', '9606', (19, 27))	('patient', 'Species', '9606', (59, 66))	('IDC', 'Gene', '4000', (72, 75))	('5C/D', 'Var', (37, 41))	('5C/D', 'SUBSTITUTION', 'None', (37, 41))
188441	27429011	Silencing or reduction of CDH1 can occur either by somatic mutation, chromosomal deletions, proteolytic cleavage, and silencing of CDH1 promoter by epigenetic modification, ultimately resulting in the disruption of tight junctions and desmosomes.	('silencing', 'NegReg', (118, 127))	('CDH1', 'Gene', (131, 135))	('Silencing', 'NegReg', (0, 9))	('promoter', 'Protein', (136, 144))	('tight junctions', 'MPA', (215, 230))	('disruption', 'MPA', (201, 211))	('epigenetic modification', 'Var', (148, 171))	('CDH1', 'Gene', '999', (131, 135))	('reduction', 'NegReg', (13, 22))	('CDH1', 'Gene', (26, 30))	('CDH1', 'Gene', '999', (26, 30))
188443	27429011	Alterations in E-cadherin can occur genomically, transcriptional and post-transcriptionally, however, there is controversy regarding the impact of these different mechanisms of E-cadherin inactivation.	('E-cadherin', 'Gene', (15, 25))	('E-cadherin', 'Gene', '999', (15, 25))	('E-cadherin', 'Gene', (177, 187))	('Alterations', 'Var', (0, 11))	('E-cadherin', 'Gene', '999', (177, 187))
188444	27429011	The primary mechanisms of E-cadherin inactivation include mutation or promoter hypermethylation.	('E-cadherin', 'Gene', (26, 36))	('mutation', 'Var', (58, 66))	('E-cadherin', 'Gene', '999', (26, 36))	('inactivation', 'NegReg', (37, 49))	('promoter hypermethylation', 'Var', (70, 95))
188445	27429011	observed that CDH1 promoter hypermethylation, but not CDH1 mutational inactivation, in the context of the EMT, resulted in a more aggressive tumor cell phenotype, and increased invasiveness.	('aggressive tumor', 'Disease', 'MESH:D001523', (130, 146))	('CDH1', 'Gene', (14, 18))	('aggressive tumor', 'Disease', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('CDH1', 'Gene', '999', (14, 18))	('promoter hypermethylation', 'Var', (19, 44))	('increased', 'PosReg', (167, 176))	('invasiveness', 'CPA', (177, 189))	('CDH1', 'Gene', (54, 58))	('more', 'PosReg', (125, 129))	('CDH1', 'Gene', '999', (54, 58))
188446	27429011	In contrast, a recent study by Ciriello et al., presented a description of molecular portraits of invasive lobular breast cancer that does not support the occurrence of CDH1 epigenetic silencing in invasive lobular breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (207, 228))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (107, 128))	('invasive lobular breast cancer', 'Disease', (198, 228))	('CDH1', 'Gene', (169, 173))	('invasive lobular breast cancer', 'Disease', (98, 128))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (198, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (98, 128))	('CDH1', 'Gene', '999', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('epigenetic silencing', 'Var', (174, 194))
188447	27429011	Although there is controversy as to whether hypermethylation is the most common mechanism of CDH1 silencing associated with the EMT, and conferring more aggressive tumor behavior, it is known that epigenetic regulatory programs involve DNA methylation, chromatin (histone) modification, and non-coding RNA (small non-coding RNAs or micro-RNAs) in cancer stem cell associated with the EMT.	('aggressive tumor', 'Disease', (153, 169))	('non-coding RNA', 'Var', (291, 305))	('CDH1', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('silencing', 'NegReg', (98, 107))	('CDH1', 'Gene', '999', (93, 97))	('hypermethylation', 'Var', (44, 60))	('cancer', 'Disease', (347, 353))	('aggressive tumor', 'Disease', 'MESH:D001523', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
188449	27429011	It has been shown that Snail may also form complexes that recruit different chromatin modifying enzymes and cofactors leading to DNA hypermethylation of the CDH1 promoter and silencing of E-cadherin expression.	('Snail', 'Gene', '6615', (23, 28))	('silencing', 'MPA', (175, 184))	('CDH1', 'Gene', '999', (157, 161))	('expression', 'MPA', (199, 209))	('E-cadherin', 'Gene', (188, 198))	('E-cadherin', 'Gene', '999', (188, 198))	('hypermethylation', 'Var', (133, 149))	('CDH1', 'Gene', (157, 161))	('Snail', 'Gene', (23, 28))
188466	27429011	Aberrant beta-catenin expression, as determined by assessment of its subcellular localization, constitutes a surrogate marker of Wnt signaling pathway activation, and has been reported in a subset of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('beta-catenin', 'Protein', (9, 21))	('Aberrant', 'Var', (0, 8))	('breast cancers', 'Phenotype', 'HP:0003002', (200, 214))	('reported', 'Reg', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancers', 'Disease', 'MESH:D001943', (200, 214))	('breast cancers', 'Disease', (200, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('expression', 'MPA', (22, 32))
188468	27429011	In studies of spindle lesions of the breast, aberrant beta-catenin expression is often observed in metaplastic breast carcinomas, suggesting that Wnt pathway activation is found in at least a subset of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (202, 216))	('breast carcinoma', 'Phenotype', 'HP:0003002', (111, 127))	('aberrant', 'Var', (45, 53))	('beta-catenin', 'Protein', (54, 66))	('breast cancers', 'Disease', 'MESH:D001943', (202, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('breast cancers', 'Disease', (202, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('breast carcinomas', 'Disease', 'MESH:D001943', (111, 128))	('breast carcinomas', 'Disease', (111, 128))	('lesions of the breast', 'Phenotype', 'HP:0100013', (22, 43))	('breast carcinomas', 'Phenotype', 'HP:0003002', (111, 128))	('expression', 'MPA', (67, 77))	('observed', 'Reg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
188496	27429011	miRNA-200c has been shown to suppress the EMT, by targeting ZEB1/ZEB2, and maintaining E-cadherin expression.	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('EMT', 'CPA', (42, 45))	('suppress', 'NegReg', (29, 37))	('miRNA-200c', 'Var', (0, 10))	('ZEB1', 'Gene', (60, 64))	('maintaining', 'PosReg', (75, 86))	('ZEB2', 'Gene', '9839', (65, 69))	('ZEB1', 'Gene', '6935', (60, 64))	('ZEB2', 'Gene', (65, 69))	('targeting', 'Reg', (50, 59))
188499	27429011	Similarly, in a study by Rhodes et al., the overexpression of miR-200b-3p, in a triple negative breast cancer cell line with no expression of miRNA-200 members, repressed the EMT, as demonstrated by the decrease in migratory capability and increased CDH1 expression.	('increased', 'PosReg', (240, 249))	('CDH1', 'Gene', '999', (250, 254))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('migratory capability', 'CPA', (215, 235))	('miR-200b-3p', 'Var', (62, 73))	('overexpression', 'PosReg', (44, 58))	('expression', 'MPA', (255, 265))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('decrease', 'NegReg', (203, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('CDH1', 'Gene', (250, 254))	('repressed', 'PosReg', (161, 170))	('EMT', 'CPA', (175, 178))
188540	27429011	Similarly, Song et al., found that Sinomemine, a drug used for rheumatic diseases, can induce apoptosis in several cell types by suppressing NF-kappaB.	('rheumatic diseases', 'Disease', 'MESH:D012216', (63, 81))	('suppressing', 'NegReg', (129, 140))	('NF-kappaB', 'Gene', (141, 150))	('Sinomemine', 'Var', (35, 45))	('NF-kappaB', 'Gene', '4790', (141, 150))	('rheumatic diseases', 'Disease', (63, 81))	('Sinomemine', 'Chemical', '-', (35, 45))	('apoptosis', 'CPA', (94, 103))
188546	27429011	During the EMT, tumor cells acquire invasive traits through overexpression, mutation or amplification of oncogenes and also repression of tumor suppressors, leading to the aberrant expression of signaling pathways.	('aberrant', 'Reg', (172, 180))	('expression', 'MPA', (181, 191))	('amplification', 'Var', (88, 101))	('tumor', 'Disease', (138, 143))	('signaling pathways', 'Pathway', (195, 213))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('overexpression', 'PosReg', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('oncogenes', 'Gene', (105, 114))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
188600	27160733	When taking the different grades into account, overdiagnosis rates of breast cancer in mass screening are 60 % for low-grade DCIS and 45 % for high-grade DCIS from a population perspective, and 61 % and 45 % respectively from an individual perspective.	('low-grade', 'Var', (115, 124))	('DCIS', 'Phenotype', 'HP:0030075', (154, 158))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
188606	27777769	Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL.	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Triple negative', 'Var', (0, 15))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('breast cancers', 'Disease', (16, 30))	('tumors', 'Disease', (60, 66))
188628	27777769	In patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, patients with LPBC had a 40 % pathologic complete response (pCR) (OR 1.38, p = 0.012 95 % CI 1.08-1.78) as compared to 7 % pCR in patients with tumors that had no lymphocytic infiltrate.	('LPBC', 'Chemical', '-', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('patients', 'Species', '9606', (87, 95))	('breast cancer', 'Disease', (34, 47))	('to 7', 'Species', '1214577', (203, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (217, 225))	('LPBC', 'Var', (101, 105))	('tumors', 'Disease', (231, 237))
188648	27777769	The decreased lymphocytic infiltrate may be due to the expression of the estrogen receptor which has been shown to both promote a Th2 immune environment and decrease MHC class II expression in breast cancer cells.	('breast cancer', 'Disease', (193, 206))	('Th2', 'Chemical', '-', (130, 133))	('decreased', 'NegReg', (4, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('Th2 immune environment', 'MPA', (130, 152))	('MHC', 'Gene', (166, 169))	('expression', 'MPA', (179, 189))	('decrease', 'NegReg', (157, 165))	('decrease MHC', 'Phenotype', 'HP:0025547', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('promote', 'PosReg', (120, 127))	('lymphocytic infiltrate', 'CPA', (14, 36))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('expression', 'Var', (55, 65))
188671	27777769	In pre-clinical mouse mammary tumor models, treatment with either OX40 or 41BB monoclonal antibodies were able to significantly decrease both tumor growth and development of metastases.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('41BB', 'Var', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('OX40', 'Var', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mouse', 'Species', '10090', (16, 21))	('metastases', 'Disease', (174, 184))	('decrease', 'NegReg', (128, 136))	('tumor', 'Disease', (30, 35))	('metastases', 'Disease', 'MESH:D009362', (174, 184))
188673	27777769	Monoclonal antibodies can trigger antibody dependent cell mediated cytotoxicity (ADCC) that results in the activation of NK T-cells, macrophages, and dendritic cells.	('antibody', 'CPA', (34, 42))	('macrophages', 'CPA', (133, 144))	('cytotoxicity', 'Disease', (67, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('NK T-cells', 'CPA', (121, 131))	('activation', 'PosReg', (107, 117))	('Monoclonal antibodies', 'Var', (0, 21))
188676	27777769	In a study of 87 locally advanced HER2 breast cancer patients treated with trastuzumab, 94 % of the patients with high HER2 specific interferon gamma (IFN-g) Th1 immunity had pCR as compared to 33 % of patients that did not achieve pCR (p = 0.0002).	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('high', 'Var', (114, 118))	('patients', 'Species', '9606', (53, 61))	('HER2', 'Gene', (119, 123))	('trastuzumab', 'Chemical', 'MESH:D000068878', (75, 86))	('patients', 'Species', '9606', (202, 210))	('HER2', 'Gene', '2064', (119, 123))	('patients', 'Species', '9606', (100, 108))	('HER2', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('HER2', 'Gene', '2064', (34, 38))	('interferon gamma (IFN-g', 'Gene', '3458', (133, 156))	('pCR', 'Disease', (175, 178))	('breast cancer', 'Disease', (39, 52))
188678	27777769	In an adjuvant chemotherapy trial of 95 HER2 breast cancer patients, high HER2-specific Th1 immunity predicted improved RFS (HR 16.9 95 % CI 3.9 to 71.4 p < 0.001).	('HER2', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HER2', 'Gene', '2064', (40, 44))	('HER2', 'Gene', (74, 78))	('improved', 'PosReg', (111, 119))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('HER2', 'Gene', '2064', (74, 78))	('breast cancer', 'Disease', (45, 58))	('patients', 'Species', '9606', (59, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('high', 'Var', (69, 73))	('to 7', 'Species', '1214577', (145, 149))	('RFS', 'MPA', (120, 123))
188685	27777769	This resulting adaptive immune response may be a major mechanism of response to doxorubicin therapy because a TLR-4 genetic polymorphism, Asp299Gly, has been shown to decrease the binding of HMGB1 and IFN-g secretion by 50 % (p < 0.05) in in vitro assays.	('HMGB1', 'Gene', '3146', (191, 196))	('Asp299Gly', 'Var', (138, 147))	('decrease', 'NegReg', (167, 175))	('Asp299Gly', 'SUBSTITUTION', 'None', (138, 147))	('TLR-4', 'Gene', '7099', (110, 115))	('IFN-g', 'Gene', (201, 206))	('binding', 'Interaction', (180, 187))	('IFN-g', 'Gene', '3458', (201, 206))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))	('TLR-4', 'Gene', (110, 115))	('HMGB1', 'Gene', (191, 196))	('secretion', 'MPA', (207, 216))
188686	27777769	In an evaluation of 280 breast cancer patients treated with adjuvant doxorubicin, 40 % of the patients carrying the TLR-4 Asp299Gly polymorphism developed metastatic disease in 5 years as compared to 27 % of patients without the polymorphism (RR 1.53 95 % CI 1.1 to 3.59 p = 0.03).	('Asp299Gly', 'Var', (122, 131))	('Asp299Gly', 'SUBSTITUTION', 'None', (122, 131))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('TLR-4', 'Gene', (116, 121))	('developed', 'PosReg', (145, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))	('metastatic disease', 'CPA', (155, 173))	('patients', 'Species', '9606', (38, 46))	('TLR-4', 'Gene', '7099', (116, 121))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))
188689	27777769	Cyclophosphamide has been shown to decrease Th2 regulatory T-cells without decreasing circulating Th1 immune response at low doses.	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('Th2 regulatory T-cells', 'CPA', (44, 66))	('decrease', 'NegReg', (35, 43))	('Th2', 'Chemical', '-', (44, 47))	('Cyclophosphamide', 'Var', (0, 16))
188695	27777769	Similarly, cryoablation of breast tumors has been shown to increase type 1 cytokine secretion resulting in enhanced presentation of tumor-specific antigens to T-cells inducing a tumor-specific T-cell response.	('breast tumors', 'Phenotype', 'HP:0100013', (27, 40))	('tumor', 'Disease', (132, 137))	('cryoablation', 'Var', (11, 23))	('inducing', 'Reg', (167, 175))	('tumor', 'Disease', (178, 183))	('type 1 cytokine secretion', 'MPA', (68, 93))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('increase', 'PosReg', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('presentation of', 'MPA', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('breast tumor', 'Phenotype', 'HP:0100013', (27, 39))	('enhanced', 'PosReg', (107, 115))	('breast tumors', 'Disease', 'MESH:D001943', (27, 40))	('breast tumors', 'Disease', (27, 40))
188696	27777769	Cryoablation is currently in clinical trials along with ipilimumab in breast cancer and has shown both increase effector T-cell to regulatory T-cell ratio and increase T-cell clonal expansion in the tumor.	('tumor', 'Disease', (199, 204))	('ipilimumab', 'Chemical', 'MESH:D000074324', (56, 66))	('increase', 'PosReg', (103, 111))	('T-cell clonal expansion', 'CPA', (168, 191))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('effector T-cell', 'CPA', (112, 127))	('breast cancer', 'Disease', (70, 83))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('Cryoablation', 'Var', (0, 12))	('increase', 'PosReg', (159, 167))
188718	20686836	Other studies have found that patients who received BCS reported better body image than those who received mastectomy with reconstruction.	('patients', 'Species', '9606', (30, 38))	('better', 'PosReg', (65, 71))	('BCS', 'Var', (52, 55))	('body image', 'CPA', (72, 82))
188757	20686836	After adjustment for several potential confounders (Model 1), we found that patients who received mastectomy with reconstruction had worse body image than patients who received BCS, at each interview during the first year after surgical treatment.	('patients', 'Species', '9606', (76, 84))	('body image', 'CPA', (139, 149))	('mastectomy', 'Var', (98, 108))	('reconstruction', 'Var', (114, 128))	('patients', 'Species', '9606', (155, 163))	('worse', 'NegReg', (133, 138))
188770	20686836	In two cross-sectional studies, patients who received either mastectomy alone or mastectomy with reconstruction had significantly more body image problems than patients who received BCS; and the body image benefits of mastectomy with reconstruction were less than expected.	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (32, 40))	('mastectomy', 'Var', (81, 91))	('body image problems', 'CPA', (135, 154))
188798	21092257	The quantity of CST6 methylation was associated with ER loss (P = 0.0002) in IBCs but not with the loss of PR (P = 0.64) or HER4 (P = 0.87).	('loss', 'NegReg', (56, 60))	('ER', 'Gene', '2099', (125, 127))	('CST6', 'Gene', '1474', (16, 20))	('methylation', 'Var', (21, 32))	('HER4', 'Gene', (124, 128))	('ER', 'Gene', '2099', (53, 55))	('HER4', 'Gene', '2066', (124, 128))	('IBC', 'Chemical', '-', (77, 80))	('CST6', 'Gene', (16, 20))
188808	21092257	Several groups have reported DNA methylation-dependent silencing of CST6 gene in breast cancer cell lines and primary invasive ductal carcinomas, but the upstream initiators that direct this process have not been elucidated.	('silencing', 'NegReg', (55, 64))	('invasive ductal carcinomas', 'Disease', (118, 144))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('CST6', 'Gene', '1474', (68, 72))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (118, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('CST6', 'Gene', (68, 72))	('methylation-dependent', 'Var', (33, 54))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
188809	21092257	reported that disruption of the estrogen receptor ERalpha in breast cancer cells resulted in DNA methylation of ERalpha target genes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('estrogen receptor', 'Gene', '2099', (32, 49))	('ER', 'Gene', '2099', (50, 52))	('estrogen receptor', 'Gene', (32, 49))	('ER', 'Gene', '2099', (112, 114))	('DNA methylation', 'MPA', (93, 108))	('disruption', 'Var', (14, 24))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
188812	21092257	Based on these reports, we hypothesized that cystatin M may be a downstream target of ER and/or HER4 and that CST6 methylation may be influenced by the alteration of ER and/or HER4.	('ER', 'Gene', '2099', (86, 88))	('CST6', 'Gene', (110, 114))	('cystatin M', 'Gene', '1474', (45, 55))	('HER4', 'Gene', '2066', (96, 100))	('HER4', 'Gene', (96, 100))	('methylation', 'MPA', (115, 126))	('influenced', 'Reg', (134, 144))	('ER', 'Gene', '2099', (166, 168))	('HER4', 'Gene', (176, 180))	('ER', 'Gene', '2099', (97, 99))	('cystatin M', 'Gene', (45, 55))	('ER', 'Gene', '2099', (177, 179))	('HER4', 'Gene', '2066', (176, 180))	('CST6', 'Gene', '1474', (110, 114))	('alteration', 'Var', (152, 162))
188879	21092257	However, no confounding effect of HER2 was found in this study: cystatin M loss occurred at a higher prevalence in the triple-negative IBCs than in other subtypes irrespective of HER2 expression (Figure 2B).	('triple-negative', 'Var', (119, 134))	('cystatin M', 'Gene', (64, 74))	('HER2', 'Gene', (34, 38))	('HER2', 'Gene', (179, 183))	('HER2', 'Gene', '2064', (179, 183))	('loss', 'NegReg', (75, 79))	('HER2', 'Gene', '2064', (34, 38))	('IBC', 'Chemical', '-', (135, 138))	('cystatin M', 'Gene', '1474', (64, 74))	('IBCs', 'Disease', (135, 139))
188884	21092257	Cystatin M loss occurred at a 3.57 times (95% CI = 1.28 to 9.98; P = 0.01) higher prevalence in the triple-negative IBCs than in other subtypes, after adjusting age.	('to 9', 'Species', '1214577', (56, 60))	('loss', 'NegReg', (11, 15))	('IBCs', 'Disease', (116, 120))	('IBC', 'Chemical', '-', (116, 119))	('triple-negative', 'Var', (100, 115))	('Cystatin M', 'Gene', '1474', (0, 10))	('Cystatin M', 'Gene', (0, 10))
188886	21092257	Epigenetic silencing of CST6 gene in breast cancer has been reported by several groups.	('breast cancer', 'Disease', (37, 50))	('CST6', 'Gene', (24, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('Epigenetic silencing', 'Var', (0, 20))	('CST6', 'Gene', '1474', (24, 28))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
188888	21092257	The hypermethylation of the CST6 gene by MSP was found in 22 (20%) of 108 DCISs studied and in 59 (34%) of 173 IBCs (Figure 3C).	('CST6', 'Gene', (28, 32))	('hypermethylation', 'Var', (4, 20))	('IBC', 'Chemical', '-', (111, 114))	('CST6', 'Gene', '1474', (28, 32))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))	('DCISs', 'Chemical', '-', (74, 79))	('found', 'Reg', (49, 54))
188890	21092257	The lack of association between cystatin M loss and hypermethylation of the CST6 gene may be due to the density dependence of methylated CpGs on transcriptional silencing by CST6 methylation or the inconsistence of methylation status between primer binding sites and other CpG sites within PCR product.	('CST6', 'Gene', (174, 178))	('CST6', 'Gene', '1474', (76, 80))	('transcriptional', 'MPA', (145, 160))	('hypermethylation', 'Var', (52, 68))	('methylation', 'Var', (179, 190))	('CST6', 'Gene', (76, 80))	('CST6', 'Gene', '1474', (174, 178))	('cystatin M', 'Gene', '1474', (32, 42))	('silencing', 'NegReg', (161, 170))	('loss', 'NegReg', (43, 47))	('cystatin M', 'Gene', (32, 42))
188895	21092257	Average quantities of methylated CpGs in tumor tissues were significantly associated with cystatin M loss (P = 0.008; Wilcoxon rank sum test) or ER loss (P = 0.0002; Wilcoxon rank-sum test).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('loss', 'NegReg', (148, 152))	('loss', 'NegReg', (101, 105))	('tumor', 'Disease', (41, 46))	('cystatin M', 'Gene', '1474', (90, 100))	('CpGs', 'Protein', (33, 37))	('ER', 'Gene', '2099', (145, 147))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cystatin M', 'Gene', (90, 100))	('methylated', 'Var', (22, 32))
188900	21092257	In addition, cystatin M loss occurred more frequently in IBCs with the losses of ER, PR, and HER4 than without, suggesting that cystatin M expression may be influenced by synergistic effect of those proteins.	('cystatin M', 'Gene', '1474', (13, 23))	('IBCs', 'Disease', (57, 61))	('IBC', 'Chemical', '-', (57, 60))	('cystatin M', 'Gene', (13, 23))	('ER', 'Gene', '2099', (94, 96))	('losses', 'Var', (71, 77))	('ER', 'Gene', '2099', (81, 83))	('cystatin M', 'Gene', '1474', (128, 138))	('HER4', 'Gene', '2066', (93, 97))	('HER4', 'Gene', (93, 97))	('cystatin M', 'Gene', (128, 138))	('loss', 'NegReg', (24, 28))
188905	21092257	Triple-negative status of ER, PR, and HER2 was not associated with cystatin M loss, but another triple-negative status of ER, PR, and HER4 was significantly associated with cystatin M loss in IBC, suggesting a different role of HER4 independently of HER2.	('ER', 'Gene', '2099', (135, 137))	('ER', 'Gene', '2099', (39, 41))	('cystatin M', 'Gene', '1474', (67, 77))	('HER2', 'Gene', (250, 254))	('HER4', 'Gene', '2066', (134, 138))	('IBC', 'Disease', (192, 195))	('ER', 'Gene', '2099', (229, 231))	('cystatin M', 'Gene', (173, 183))	('HER2', 'Gene', '2064', (38, 42))	('HER4', 'Gene', '2066', (228, 232))	('ER', 'Gene', '2099', (251, 253))	('IBC', 'Chemical', '-', (192, 195))	('loss', 'NegReg', (184, 188))	('ER', 'Gene', '2099', (122, 124))	('cystatin M', 'Gene', (67, 77))	('HER4', 'Gene', (134, 138))	('triple-negative status', 'Var', (96, 118))	('cystatin M', 'Gene', '1474', (173, 183))	('HER2', 'Gene', '2064', (250, 254))	('ER', 'Gene', '2099', (26, 28))	('HER2', 'Gene', (38, 42))	('HER4', 'Gene', (228, 232))
188909	21092257	In addition, clinical observations have reported that the co-expression of ER and HER4 in breast cancer is associated with a prognostically favorable outcome.	('HER4', 'Gene', (82, 86))	('HER4', 'Gene', '2066', (82, 86))	('co-expression', 'Var', (58, 71))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('ER', 'Gene', '2099', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('ER', 'Gene', '2099', (75, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))
188954	20565850	Expression of MTDH could augment anchorage-independent growth.	('MTDH', 'Gene', (14, 18))	('anchorage-independent growth', 'CPA', (33, 61))	('Expression', 'Var', (0, 10))	('augment', 'NegReg', (25, 32))	('MTDH', 'Gene', '92140', (14, 18))
188979	20565850	The optimal cutoff value for high and low expression level was identified: an SI score of >= 4 was used to define tumors with high MTDH expression, and an SI score of <= 3 was used to indicate none or low MTDH expression.	('MTDH', 'Gene', '92140', (131, 135))	('SI', 'Disease', 'None', (78, 80))	('expression', 'MPA', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MTDH', 'Gene', (205, 209))	('SI', 'Disease', 'None', (155, 157))	('MTDH', 'Gene', (131, 135))	('high', 'Var', (126, 130))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('MTDH', 'Gene', '92140', (205, 209))
188991	20565850	As show in the Table 3, MTDH expression was strongly correlated with the patients' age (p = 0.042), Ki67 status (p = 0.036), ER status (p = 0.018) and p53 status (p = 0.001), whereas it was not associated with other clinical characteristics.	('p53', 'Gene', '7157', (151, 154))	('correlated', 'Reg', (53, 63))	('Ki67', 'Chemical', '-', (100, 104))	('patients', 'Species', '9606', (73, 81))	('MTDH', 'Gene', '92140', (24, 28))	('Ki67 status', 'Var', (100, 111))	('p53', 'Gene', (151, 154))	('ER status', 'Var', (125, 134))	('MTDH', 'Gene', (24, 28))
188992	20565850	Spearman correlation analysis was further preformed to confirm the correlation between MTDH expression and patients' age, Ki67, ER and p53 status, which were -0.16(p = 0.042), 0.164(p = 0.037), -0.185(p = 0.018) and 0.261(p = 0.001) respectively.	('MTDH', 'Gene', (87, 91))	('Ki67', 'Chemical', '-', (122, 126))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('0.164', 'Var', (176, 181))	('MTDH', 'Gene', '92140', (87, 91))	('patients', 'Species', '9606', (107, 115))
189006	20565850	All these might suggest that increased cell proliferation associated with overexpressed MTDH may contribute to the development and progression of breast lesions.	('breast lesions', 'Disease', 'MESH:D001941', (146, 160))	('contribute', 'Reg', (97, 107))	('MTDH', 'Gene', '92140', (88, 92))	('increased', 'PosReg', (29, 38))	('overexpressed', 'Var', (74, 87))	('breast lesions', 'Disease', (146, 160))	('MTDH', 'Gene', (88, 92))	('cell proliferation', 'CPA', (39, 57))
189013	20565850	MTDH can induce serum-independent cell growth by blocking serum starvation-induced apoptosis through PI3K-Akt signaling pathways and downstream signaling molecules of Akt including GSK3b-Myc, Bad, MDM2-p53 and p21/mda-6, which cause inhibition of caspase activities.	('MDM2', 'Gene', (197, 201))	('Akt', 'Gene', '207', (167, 170))	('induce', 'PosReg', (9, 15))	('p21', 'Gene', '1026', (210, 213))	('GSK3b-Myc', 'Var', (181, 190))	('blocking', 'NegReg', (49, 57))	('MDM2', 'Gene', '4193', (197, 201))	('serum-independent cell growth', 'CPA', (16, 45))	('apoptosis', 'CPA', (83, 92))	('MTDH', 'Gene', (0, 4))	('mda-6', 'Gene', '1026', (214, 219))	('MTDH', 'Gene', '92140', (0, 4))	('Akt', 'Gene', (106, 109))	('p53', 'Gene', '7157', (202, 205))	('p21', 'Gene', (210, 213))	('serum', 'CPA', (58, 63))	('Akt', 'Gene', '207', (106, 109))	('mda-6', 'Gene', (214, 219))	('Akt', 'Gene', (167, 170))	('p53', 'Gene', (202, 205))
189030	33208147	Compared to high-confidence somatic mutations from frozen specimens, PML-specific variant filtering increased recall (BE:85%, SS:80%, AT:75%) and precision (BE:93%, SS:91%, AT:84%) to levels expected from sampling variation.	('BE', 'Chemical', '-', (118, 120))	('increased', 'PosReg', (100, 109))	('BE', 'Chemical', '-', (157, 159))	('variant', 'Var', (82, 89))	('precision', 'MPA', (146, 155))	('recall', 'MPA', (110, 116))
189031	33208147	Applied to DNA extracted from 9 micro-dissected regions (8 PML, 1 normal epithelium), the approach achieved comparable performance, illustrated the data adequacy to identify candidate driver events (GATA3 mutations, ERBB2 or FGFR1 gains, TP53 loss) and measure intra-lesion genetic heterogeneity.	('FGFR1', 'Gene', '2260', (225, 230))	('GATA3', 'Gene', '2625', (199, 204))	('ERBB2', 'Gene', (216, 221))	('gains', 'PosReg', (231, 236))	('ERBB2', 'Gene', '2064', (216, 221))	('mutations', 'Var', (205, 214))	('TP53', 'Gene', '7157', (238, 242))	('loss', 'NegReg', (243, 247))	('FGFR1', 'Gene', (225, 230))	('GATA3', 'Gene', (199, 204))	('TP53', 'Gene', (238, 242))
189041	33208147	Moreover, formalin is known to create adducts in the DNA and lead to spurious substitutions, which can be difficult to distinguish from true somatic variants, especially at low allelic fractions.	('formalin', 'Chemical', 'MESH:D005557', (10, 18))	('substitutions', 'Var', (78, 91))	('adducts', 'Var', (38, 45))	('DNA', 'Gene', (53, 56))
189050	33208147	The subsequent ligation step incorporates SWIFT-1S P5 and SWIFT-1S P7 adapters, followed by a 1 x AMPure XP bead clean-up and elution into 20 muL of nuclease free water.	('water', 'Chemical', 'MESH:D014867', (163, 168))	('SWIFT-1S P7', 'Var', (58, 69))	('SWIFT-1S P5', 'Var', (42, 53))
189056	33208147	The baits for target enrichment consisted of either Agilent SureSelect Clinical Research Exome panel (S06588914), Human All Exon V7 panel (S31285117) or Cancer All-In-One Solid Tumor (A3131601).	('Cancer', 'Disease', 'MESH:D009369', (153, 159))	('S06588914', 'Var', (102, 111))	('S31285117', 'Var', (139, 148))	('Human', 'Species', '9606', (114, 119))	('Tumor', 'Phenotype', 'HP:0002664', (177, 182))	('A3131601', 'Var', (184, 192))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', (153, 159))
189065	33208147	In absence of a matched normal control for both test (frozen and FFPE) and DCIS specimens, somatic mutations were prioritized computationally using the approach from the bcbio-nextgen tumor-only configuration then additionally subjected to more stringent filtering.	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('mutations', 'Var', (99, 108))
189067	33208147	The following parameters were used: position covered by at least 5 reads, mapping quality more than 45, mean position in read greater than 15, number of average read mis-matches less than 2.5, microsatellite length less than 5, tumor log odds threshold more than 10, Fisher strand bias Phred-scaled probability less than 10 and VAF more than 0.14.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('microsatellite length', 'Var', (193, 214))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))
189070	33208147	To the exception of few well-described hotspot mutations in breast cancer (PIK3CA, TP53, GATA3), somatic mutations identified in more than one patient were removed.	('GATA3', 'Gene', '2625', (89, 94))	('TP53', 'Gene', '7157', (83, 87))	('breast cancer', 'Disease', (60, 73))	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('patient', 'Species', '9606', (143, 150))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GATA3', 'Gene', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
189078	33208147	The superiority of the BE and SS strategies were further confirmed using whole exome capture with BE and SS libraries resulting in 84% and 63% Cov20 at low input (3 ng), respectively, higher than 17% observed for low input (10 ng) AT libraries (Fig.	('Cov20', 'MPA', (143, 148))	('BE', 'Chemical', '-', (98, 100))	('BE', 'Chemical', '-', (23, 25))	('libraries', 'Var', (108, 117))
189080	33208147	Unfiltered SNVs identified in FFPE DNA showed both a high overall abundance (422,322) of low variant allelic fraction substitutions (VAF < 5%) and bias of C to T substitutions (53%), which is expected from the cytosine deamination resulting from formalin fixation.	('substitutions', 'Var', (162, 175))	('formalin', 'Chemical', 'MESH:D005557', (246, 254))	('substitutions', 'Var', (118, 131))	('cytosine', 'Chemical', 'MESH:D003596', (210, 218))	('C to T substitutions', 'Var', (155, 175))
189081	33208147	In contrast, low VAF variants from frozen DNA were much lower in abundance (175,364) but contained a high-prevalence (52%) of C to A substitutions consistent with previously reported 8-oxoguanine damage observed in frozen samples (Additional file 2: Fig.	('variants', 'Var', (21, 29))	('substitutions', 'Var', (133, 146))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (183, 195))	('VAF', 'Gene', (17, 20))
189084	33208147	The variant recall increased from 75% in the AT low input library to 85% and 80% for the BE and SS low-input libraries, respectively, consistent with differences observed in Cov20 (Additional file 1: Table S6).	('variant', 'Var', (4, 11))	('increased', 'PosReg', (19, 28))	('BE', 'Chemical', '-', (89, 91))
189088	33208147	Additionally, the copy number status of known cancer genes was also consistent between exome and cancer panel, including the expected ERBB2 amplification which was correctly determined in all cases.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (97, 103))	('ERBB2', 'Gene', '2064', (134, 139))	('cancer', 'Disease', (46, 52))	('amplification', 'MPA', (140, 153))	('ERBB2', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('copy number', 'Var', (18, 29))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
189100	33208147	The most notable ones were the amplification of ERBB2 in all regions of patient 2, amplification of FGFR1 in all regions of patient 3 and loss of TP53 in patient 2 and 3.	('loss', 'NegReg', (138, 142))	('TP53', 'Gene', '7157', (146, 150))	('patient', 'Species', '9606', (154, 161))	('TP53', 'Gene', (146, 150))	('ERBB2', 'Gene', '2064', (48, 53))	('patient', 'Species', '9606', (72, 79))	('FGFR1', 'Gene', (100, 105))	('ERBB2', 'Gene', (48, 53))	('patient', 'Species', '9606', (124, 131))	('FGFR1', 'Gene', '2260', (100, 105))	('amplification', 'Var', (83, 96))	('amplification', 'Var', (31, 44))
189107	33208147	While a portion of these may be shared mutations may be germline variants, we identified a GATA3 splice-site deletion in regions 1A and 1B previously observed in DCIS studies, disrupting a canonical splice site and for which the resulting transcript has been shown to lead to an abnormally high number of neoantigens.	('canonical splice site', 'MPA', (189, 210))	('deletion', 'Var', (109, 117))	('GATA3', 'Gene', (91, 96))	('neoantigens', 'MPA', (305, 316))	('DCIS', 'Phenotype', 'HP:0030075', (162, 166))	('disrupting', 'NegReg', (176, 186))	('GATA3', 'Gene', '2625', (91, 96))	('lead to', 'Reg', (268, 275))
189109	33208147	The 3 PML regions gained an additional 8 mutations before diverging including an ERBB3 Ile763Leu substitution was exclusively observed in all 3 PML regions of patient 3.	('ERBB3', 'Gene', (81, 86))	('Ile763Leu', 'Mutation', 'p.I763L', (87, 96))	('Ile763Leu', 'Var', (87, 96))	('patient', 'Species', '9606', (159, 166))	('ERBB3', 'Gene', '2065', (81, 86))
189110	33208147	This mutation is predicted to be deleterious, possibly activating this uncommon driver of breast cancer and may have contributed, in concert with FGFR1 gain, to the clonal expansion observed in this patient.	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('patient', 'Species', '9606', (199, 206))	('activating', 'PosReg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('FGFR1', 'Gene', (146, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('mutation', 'Var', (5, 13))	('FGFR1', 'Gene', '2260', (146, 151))
189111	33208147	Overall, our analysis suggests that even in absence of normal DNA, and akin to experiments in large tumors, variants from multi-region sequencing can be used to trace evolutionary relationships between areas of pre-malignancy.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('variants', 'Var', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignancy', 'Disease', 'MESH:D009369', (215, 225))	('malignancy', 'Disease', (215, 225))
189128	33208147	BE Blunt-end SS Single-strand AT A-tailing DCIS Ductal carcinoma in situ LCM Laser capture microdissection IDC Invasive ductal carcinoma FFPE Formalin-fixed paraffin embedded LOH Loss of heterozygosity VAF Variant allelic frequency PML Pre-malignant lesion CNA Copy number alteration Cov20 Fraction of base pairs covered at 20x or more Supplementary information accompanies this paper at 10.1186/s12920-020-00820-y.	('Invasive ductal carcinoma', 'Disease', (111, 136))	('Ductal carcinoma', 'Disease', (48, 64))	('VAF', 'Gene', (202, 205))	('Invasive ductal carcinoma', 'Disease', 'MESH:D009361', (111, 136))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (120, 136))	('Ductal carcinoma', 'Disease', 'MESH:D044584', (48, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Formalin', 'Chemical', 'MESH:D005557', (142, 150))	('BE', 'Chemical', '-', (0, 2))	('Ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (48, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('Variant', 'Var', (206, 213))	('paraffin', 'Chemical', 'MESH:D010232', (157, 165))
189131	33208147	This work is supported by funding from the National Institute of Health (U01CA196406, U01CA196406-03S1, R01DE026644 and T32GM008806), the National Cancer Institute (P30CA023100) and the California Tobacco Related Disease Research Program pre-doctoral fellowship to DN (28DT-0011).	('R01DE026644', 'Var', (104, 115))	('U01CA196406-03S1', 'CellLine', 'CVCL:2220', (86, 102))	('T32GM008806', 'Var', (120, 131))	('U01CA196406', 'CellLine', 'CVCL:2220', (86, 97))	('U01CA196406', 'CellLine', 'CVCL:2220', (73, 84))	('U01CA196406', 'Var', (73, 84))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Cancer', 'Disease', (147, 153))	('California Tobacco Related Disease', 'Disease', (186, 220))	('California Tobacco Related Disease', 'Disease', 'MESH:D014029', (186, 220))	('Cancer', 'Disease', 'MESH:D009369', (147, 153))	('P30CA023100', 'Var', (165, 176))	('U01CA196406-03S1', 'Var', (86, 102))
189138	31993860	Breast cancer frequency was higher among biallelic CHEK2 PV carriers (80.6%, 25/31) than monoallelic carriers (41.2%, 2668/6473; p < 0.0001).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('CHEK2', 'Gene', '11200', (51, 56))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('CHEK2', 'Gene', (51, 56))	('biallelic', 'Var', (41, 50))	('Breast cancer', 'Disease', (0, 13))	('higher', 'Reg', (28, 34))	('PV carriers', 'Var', (57, 68))
189139	31993860	Biallelic carriers were more likely to be diagnosed at or before age 50 (61.3%, 19/31) and to have a second breast cancer diagnosis (22.6%, 7/31) compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively).	('Biallelic carriers', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
189140	31993860	Proportionally more biallelic carriers also had any cancer diagnosis and > 1 primary diagnosis.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('biallelic carriers', 'Var', (20, 38))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (52, 58))
189141	31993860	Compared to women with no PVs, biallelic PV carriers had a higher risk of developing ductal invasive breast cancer (OR 8.69, 95% CI 3.69-20.47) and ductal carcinoma in situ (OR 4.98, 95% CI 2.00-12.35) than monoallelic carriers (OR 2.02, 95% CI 1.90-2.15 and OR 1.82, 95% CI 1.66-2.00, respectively).	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (148, 172))	('women', 'Species', '9606', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ductal invasive breast cancer', 'Disease', (85, 114))	('biallelic', 'Var', (31, 40))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (148, 172))	('ductal carcinoma in situ', 'Disease', (148, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('ductal invasive breast cancer', 'Disease', 'MESH:D018270', (85, 114))
189142	31993860	These data suggest that biallelic CHEK2 PV carriers have a higher risk for breast cancer, are more likely to be diagnosed younger, and to have multiple primary breast cancers compared to monoallelic carriers.	('breast cancers', 'Disease', 'MESH:D001943', (160, 174))	('CHEK2', 'Gene', '11200', (34, 39))	('breast cancers', 'Disease', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('CHEK2', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('carriers', 'Var', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('breast cancers', 'Phenotype', 'HP:0003002', (160, 174))	('biallelic', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
189143	31993860	Biallelic carriers also appear to have a higher risk of cancer overall.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Biallelic carriers', 'Var', (0, 18))
189144	31993860	Therefore, more aggressive management may be appropriate for women with biallelic PVs in CHEK2 compared with current recommendations for monoallelic carriers.	('CHEK2', 'Gene', (89, 94))	('CHEK2', 'Gene', '11200', (89, 94))	('biallelic PVs', 'Var', (72, 85))	('women', 'Species', '9606', (61, 66))
189145	31993860	CHEK2 is considered a moderate risk breast cancer gene, with estimates of the relative risk for women carrying a single pathogenic variant (PV) ranging from 2.0 to 4.8 for a first breast cancer.	('CHEK2', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('variant', 'Var', (131, 138))	('breast cancer', 'Disease', (36, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('women', 'Species', '9606', (96, 101))	('CHEK2', 'Gene', '11200', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
189147	31993860	An increased risk of colorectal cancer has also been reported for CHEK2 PV carriers, however the evidence for this association is not well established.	('CHEK2', 'Gene', '11200', (66, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('CHEK2', 'Gene', (66, 71))	('PV carriers', 'Var', (72, 83))	('colorectal cancer', 'Disease', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))
189149	31993860	Despite known and possible cancer associations for CHEK2 PV carriers, phenotypic differences between monoallelic and biallelic carriers are not yet understood.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CHEK2', 'Gene', '11200', (51, 56))	('carriers', 'Var', (60, 68))	('CHEK2', 'Gene', (51, 56))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
189150	31993860	Biallelic carriers of PVs in other, dominant breast cancer susceptibility genes such as BRCA2, ATM, PALB2, and NBN are known to have more severe cancer phenotypes than monoallelic carriers.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ATM', 'Gene', (95, 98))	('PVs', 'Var', (22, 25))	('BRCA2', 'Gene', (88, 93))	('NBN', 'Gene', (111, 114))	('BRCA2', 'Gene', '675', (88, 93))	('NBN', 'Gene', '4683', (111, 114))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (45, 58))	('ATM', 'Gene', '472', (95, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('PALB2', 'Gene', '79728', (100, 105))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('PALB2', 'Gene', (100, 105))
189152	31993860	A single CHEK2 founder mutation, c.1100del, is present in 1.1% of individuals of Northern and Eastern European ancestry.	('c.1100del', 'Mutation', 'c.1100del', (33, 42))	('c.1100del', 'Var', (33, 42))	('CHEK2', 'Gene', '11200', (9, 14))	('CHEK2', 'Gene', (9, 14))
189153	31993860	Assuming Hardy-Weinberg equilibrium, roughly 3/10000 of Northern and Eastern Europeans will be homozygous for c.1100del, with the possibility of additional biallelic individuals if other CHEK2 PVs are included.	('CHEK2', 'Gene', (187, 192))	('c.1100del', 'Mutation', 'c.1100del', (110, 119))	('c.1100del', 'Var', (110, 119))	('CHEK2', 'Gene', '11200', (187, 192))
189154	31993860	Homozygous CHEK2 c.1100del has, in fact, been reported in 14 female breast cancer cases in the Dutch population.	('c.1100del', 'Var', (17, 26))	('CHEK2', 'Gene', '11200', (11, 16))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('c.1100del', 'Mutation', 'c.1100del', (17, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('CHEK2', 'Gene', (11, 16))	('breast cancer', 'Disease', (68, 81))	('reported', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
189157	31993860	Based on the evidence of increased breast cancer risk in women with monoallelic CHEK2 PVs, current NCCN guidelines recommend annual mammography and consideration of breast MRI beginning at age 40.	('monoallelic', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CHEK2', 'Gene', '11200', (80, 85))	('women', 'Species', '9606', (57, 62))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('CHEK2', 'Gene', (80, 85))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
189158	31993860	It is important to establish if women who are homozygous for CHEK2 c.1100del or are biallelic carriers of any CHEK2 PV have higher breast cancer risks than monoallelic carriers, since this could impact management recommendations.	('CHEK2', 'Gene', (61, 66))	('women', 'Species', '9606', (32, 37))	('CHEK2', 'Gene', '11200', (110, 115))	('impact', 'Reg', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CHEK2', 'Gene', (110, 115))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('c.1100del', 'Var', (67, 76))	('breast cancer', 'Disease', (131, 144))	('CHEK2', 'Gene', '11200', (61, 66))	('higher', 'PosReg', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('c.1100del', 'Mutation', 'c.1100del', (67, 76))
189165	31993860	The CHEK2 founder mutations c.470C > T (p.Ile157Thr) and c.1283C > T (p.Ser428Phe) were not included in this analysis, as these were classified as variants of uncertain significance by the laboratory during the study time period and this analysis was restricted to PVs.	('CHEK2', 'Gene', (4, 9))	('c.1283C > T', 'Var', (57, 68))	('p.Ile157Thr', 'Mutation', 'rs17879961', (40, 51))	('p.Ser428Phe', 'Mutation', 'rs137853011', (70, 81))	('c.470C > T', 'Mutation', 'rs587780167', (28, 38))	('c.1283C > T', 'Mutation', 'rs137853011', (57, 68))	('c.470C > T', 'Var', (28, 38))	('CHEK2', 'Gene', '11200', (4, 9))
189167	31993860	Fisher's exact tests for difference in proportions were used to determine differences between monoallelic and biallelic CHEK2 carriers.	('CHEK2', 'Gene', (120, 125))	('CHEK2', 'Gene', '11200', (120, 125))	('monoallelic', 'Var', (94, 105))
189171	31993860	In this study, we identified 6473 monoallelic and 42 biallelic carriers of CHEK2 PVs.	('CHEK2', 'Gene', (75, 80))	('CHEK2', 'Gene', '11200', (75, 80))	('monoallelic', 'Var', (34, 45))
189173	31993860	In this cohort, the majority of CHEK2 PV carriers were of White/Non-Hispanic origin, both in monoallelic and biallelic carriers (69.8% and 71.0%, respectively; Table 1).	('CHEK2', 'Gene', '11200', (32, 37))	('carriers', 'Var', (41, 49))	('CHEK2', 'Gene', (32, 37))
189175	31993860	On average, biallelic carriers of CHEK2 PVs were diagnosed with breast and other cancers at younger ages than monoallelic carriers.	('CHEK2', 'Gene', '11200', (34, 39))	('CHEK2', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('biallelic carriers', 'Var', (12, 30))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('diagnosed', 'Reg', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast', 'Disease', (64, 70))
189176	31993860	Only 9.7% (3/31) of biallelic CHEK2 PV carriers were reported with no history of cancer, compared to 50.0% (3234/6473) of monoallelic CHEK2 PV carriers (Table 1).	('CHEK2', 'Gene', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('carriers', 'Var', (39, 47))	('biallelic', 'Var', (20, 29))	('CHEK2', 'Gene', '11200', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CHEK2', 'Gene', '11200', (134, 139))	('CHEK2', 'Gene', (30, 35))
189177	31993860	Breast cancer was the most prevalent cancer reported in both monoallelic and biallelic carriers of CHEK2 PVs, with ovarian cancer being the second most prevalent single cancer in both.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (169, 175))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ovarian cancer', 'Disease', (115, 129))	('CHEK2', 'Gene', (99, 104))	('carriers', 'Var', (87, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (7, 13))	('CHEK2', 'Gene', '11200', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (37, 43))	('biallelic', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancer', 'Disease', (123, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('prevalent', 'Reg', (27, 36))
189178	31993860	The frequency of at least one primary breast cancer at any age was significantly (p < 0.0001) higher in biallelic carriers (80.6%, 25/31) than in monoallelic carriers (41.2%, 2668/6473; Table 2).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('biallelic carriers', 'Var', (104, 122))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('higher', 'PosReg', (94, 100))
189179	31993860	Biallelic CHEK2 PV carriers were significantly more likely to be diagnosed with breast cancer at or before age 50 (61.3%, 19/31), as well as to have a second breast cancer diagnosis (22.6%, 7/31), as compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively).	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('CHEK2', 'Gene', '11200', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('CHEK2', 'Gene', (10, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carriers', 'Var', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
189180	31993860	The increased prevalence of breast cancer, breast cancer at age 50 or younger, and second primary breast cancer was also observed when the comparisons were restricted to monoallelic and homozygous carriers of CHEK2 c.1100del (Table 2).	('CHEK2', 'Gene', (209, 214))	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('CHEK2', 'Gene', '11200', (209, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('c.1100del', 'Mutation', 'c.1100del', (215, 224))	('c.1100del', 'Var', (215, 224))
189181	31993860	No excess of any specific non-breast cancer was clearly identified in the biallelic CHEK2 PV carriers overall, though pancreatic cancer did appear to be more common among biallelic and CHEK2 c.1100del homozygous carriers (3.2% and 6.2%, respectively) as compared to monoallelic and CHEK2 c.1100del monoallelic carriers (0.2%; p = 0.0512 and 0.1%; p = 0.0277, respectively).	('c.1100del', 'Mutation', 'c.1100del', (288, 297))	('CHEK2', 'Gene', '11200', (84, 89))	('CHEK2', 'Gene', (282, 287))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('c.1100del', 'Mutation', 'c.1100del', (191, 200))	('c.1100del', 'Var', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CHEK2', 'Gene', (185, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('CHEK2', 'Gene', '11200', (282, 287))	('pancreatic cancer', 'Disease', (118, 135))	('CHEK2', 'Gene', '11200', (185, 190))	('biallelic', 'Var', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('non-breast cancer', 'Disease', (26, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('CHEK2', 'Gene', (84, 89))	('common', 'Reg', (158, 164))	('non-breast cancer', 'Disease', 'MESH:D001943', (26, 43))
189184	31993860	Similarly, biallelic CHEK2 PV carriers were significantly more likely to have at least two primary cancers when compared to monoallelic PV carriers (32.3% vs. 13.5%, p = 0.0061).	('CHEK2', 'Gene', '11200', (21, 26))	('CHEK2', 'Gene', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('PV carriers', 'Var', (27, 38))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('biallelic', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
189185	31993860	These differences were also significant for carriers of homozygous CHEK2 c.1100del PVs as compared to monoallelic CHEK2 c.1100del carriers.	('c.1100del PVs', 'Var', (73, 86))	('c.1100del', 'Mutation', 'c.1100del', (120, 129))	('c.1100del', 'Mutation', 'c.1100del', (73, 82))	('CHEK2', 'Gene', '11200', (114, 119))	('CHEK2', 'Gene', (114, 119))	('CHEK2', 'Gene', '11200', (67, 72))	('CHEK2', 'Gene', (67, 72))
189186	31993860	The converse comparison of unaffected monoallelic and biallelic CHEK2 PV carriers revealed that biallelic carriers were significantly less likely to be unaffected with cancer as compared to monoallelic carriers (p < 0.0001).	('CHEK2', 'Gene', (64, 69))	('CHEK2', 'Gene', '11200', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('biallelic carriers', 'Var', (96, 114))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('less', 'NegReg', (134, 138))	('cancer', 'Disease', (168, 174))
189187	31993860	Similarly, 50.4% of CHEK2 c.1100del monoallelic carriers were unaffected while only 12.5% of CHEK2 c.1100del homozygous carriers were unaffected by any cancer (p = 0.0022).	('CHEK2', 'Gene', (20, 25))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('c.1100del', 'Mutation', 'c.1100del', (99, 108))	('CHEK2', 'Gene', (93, 98))	('CHEK2', 'Gene', '11200', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CHEK2', 'Gene', '11200', (20, 25))	('c.1100del', 'Mutation', 'c.1100del', (26, 35))	('c.1100del', 'Var', (26, 35))
189188	31993860	The median age of first cancer diagnosis was compared in monoallelic and biallelic CHEK2 PV carriers for any cancer, and for breast cancer specifically.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CHEK2', 'Gene', '11200', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CHEK2', 'Gene', (83, 88))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('breast cancer', 'Disease', (125, 138))	('monoallelic', 'Var', (57, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('biallelic', 'Var', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
189189	31993860	A trend toward younger median age at cancer diagnosis was observed in biallelic CHEK2 PV carriers as compared to monoallelic carriers for all evaluated categories (>= 1, >= 2, or >= 3 cancer diagnoses of any kind; 1 or >= 2 breast cancer diagnosis), though this trend was generally not statistically significant (Fig.	('cancer', 'Disease', (184, 190))	('younger', 'NegReg', (15, 22))	('biallelic', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (37, 43))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('CHEK2', 'Gene', '11200', (80, 85))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Disease', (224, 237))	('CHEK2', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('carriers', 'Var', (89, 97))
189190	31993860	This trend held true when the analysis was restricted only to carriers of the CHEK2 c.1100del founder mutation.	('c.1100del', 'DELETION', 'None', (84, 93))	('CHEK2', 'Gene', (78, 83))	('CHEK2', 'Gene', '11200', (78, 83))	('c.1100del', 'Var', (84, 93))
189191	31993860	Notably, biallelic CHEK2 PV carriers with at least one primary cancer were significantly younger at the time of diagnosis compared to monoallelic carriers (44 and 47 years, respectively; p = 0.0268).	('biallelic', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CHEK2', 'Gene', '11200', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CHEK2', 'Gene', (19, 24))	('cancer', 'Disease', (63, 69))
189192	31993860	Similarly, homozygous carriers of CHEK2 c.1100del with at least two cancers were significantly younger than monoallelic carriers in this category (47 and 36 years, respectively; p = 0.0476).	('CHEK2', 'Gene', '11200', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CHEK2', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('c.1100del', 'Mutation', 'c.1100del', (40, 49))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('c.1100del', 'Var', (40, 49))	('younger', 'NegReg', (95, 102))
189196	31993860	Biallelic CHEK2 PV carriers had an OR of 8.69 (95% CI 3.69-20.47) for ductal invasive breast cancer compared to 2.02 for monoallelic CHEK2 PV carriers (95% CI 1.90-2.15).	('CHEK2', 'Gene', '11200', (10, 15))	('ductal invasive breast cancer', 'Disease', 'MESH:D018270', (70, 99))	('CHEK2', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CHEK2', 'Gene', '11200', (133, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('CHEK2', 'Gene', (133, 138))	('PV carriers', 'Var', (16, 27))	('ductal invasive breast cancer', 'Disease', (70, 99))
189197	31993860	Similarly, biallelic CHEK2 PV carriers had a higher risk of developing DCIS than did monoallelic carriers, with biallelic carriers having an OR of 4.98 (95% CI 2.00-12.35) and monoallelic carriers having an OR of 1.82 (95% CI 1.66-2.00).	('CHEK2', 'Gene', (21, 26))	('CHEK2', 'Gene', '11200', (21, 26))	('carriers', 'Var', (30, 38))	('DCIS', 'Disease', (71, 75))
189198	31993860	While the CI for biallelic CHEK2 PV carriers are wide for both ductal invasive breast cancer and DCIS, the lower end of the CI range for both show at least a twofold higher risk of cancer compared to non-carriers.	('CHEK2', 'Gene', '11200', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('carriers', 'Var', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('CHEK2', 'Gene', (27, 32))	('DCIS', 'Disease', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('ductal invasive breast cancer', 'Disease', (63, 92))	('cancer', 'Disease', (181, 187))	('ductal invasive breast cancer', 'Disease', 'MESH:D018270', (63, 92))	('cancer', 'Disease', (86, 92))
189199	31993860	This study compared the cancer phenotypes of women with biallelic PVs in CHEK2 to monoallelic carriers identified by hereditary cancer panel testing.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('hereditary cancer', 'Disease', 'MESH:D009369', (117, 134))	('hereditary cancer', 'Disease', (117, 134))	('CHEK2', 'Gene', '11200', (73, 78))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CHEK2', 'Gene', (73, 78))	('women', 'Species', '9606', (45, 50))	('biallelic PVs', 'Var', (56, 69))	('cancer', 'Disease', (128, 134))
189202	31993860	In this cohort, biallelic CHEK2 PV carriers had a significantly higher risk for breast cancer, were more likely to be diagnosed at or before age 50, and were more likely to have multiple primary breast cancers compared to monoallelic CHEK2 PV carriers.	('CHEK2', 'Gene', '11200', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancers', 'Disease', 'MESH:D001943', (195, 209))	('breast cancers', 'Disease', (195, 209))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('CHEK2', 'Gene', (234, 239))	('biallelic', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('CHEK2', 'Gene', '11200', (26, 31))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('CHEK2', 'Gene', (26, 31))	('PV carriers', 'Var', (32, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (195, 209))
189204	31993860	The ORs calculated for women with biallelic PVs (8.69 for invasive breast cancer and 4.98 for DCIS) suggest that biallelic CHEK2 PV carriers could have breast cancer risks higher than those associated with PVs in BRCA1 and BRCA2.	('CHEK2', 'Gene', '11200', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('invasive breast cancer', 'Disease', (58, 80))	('women', 'Species', '9606', (23, 28))	('BRCA1', 'Gene', (213, 218))	('BRCA2', 'Gene', '675', (223, 228))	('CHEK2', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('higher', 'PosReg', (172, 178))	('biallelic', 'Var', (113, 122))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('invasive breast cancer', 'Disease', 'MESH:D001943', (58, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Disease', (152, 165))	('BRCA1', 'Gene', '672', (213, 218))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('BRCA2', 'Gene', (223, 228))
189205	31993860	It may therefore be reasonable to consider biallelic findings in CHEK2 as high, rather than moderate, penetrance for the purposes of management.	('CHEK2', 'Gene', (65, 70))	('CHEK2', 'Gene', '11200', (65, 70))	('biallelic findings', 'Var', (43, 61))
189210	31993860	Therefore, this study does not rule out the possibility of other rare or common non-breast cancer phenotypes associated with biallelic inheritance of CHEK2 PVs.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('biallelic inheritance', 'Var', (125, 146))	('non-breast cancer', 'Disease', 'MESH:D001943', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CHEK2', 'Gene', '11200', (150, 155))	('non-breast cancer', 'Disease', (80, 97))	('CHEK2', 'Gene', (150, 155))
189211	31993860	Additionally, clinical information unrelated to cancers and precancerous findings were not documented on the TRF, and this study could not identify an association between biallelic CHEK2 PVs and other phenotypes.	('CHEK2', 'Gene', '11200', (181, 186))	('cancers', 'Disease', (48, 55))	('CHEK2', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('biallelic', 'Var', (171, 180))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancer', 'Disease', (63, 69))
189217	31993860	Current breast cancer screening guidelines for women who have inherited CHEK2 PVs include breast mammography with consideration of tomosynthesis and consideration of breast MRI starting by age 40.	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('CHEK2', 'Gene', '11200', (72, 77))	('breast cancer', 'Disease', (8, 21))	('CHEK2', 'Gene', (72, 77))	('women', 'Species', '9606', (47, 52))	('breast mammography', 'Disease', (90, 108))	('PVs', 'Var', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('inherited', 'Var', (62, 71))
189218	31993860	The findings from this study suggest that biallelic carriers of CHEK PVs have a considerably higher breast cancer risk than monoallelic carriers, and therefore may benefit from more aggressive management, possibly beginning at younger ages.	('higher', 'PosReg', (93, 99))	('biallelic carriers', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('CHEK PVs', 'Gene', (64, 72))
189219	31993860	The observed high risk for more than one primary breast cancer diagnosis in women with biallelic PVs may also have significant implications for treatment of an initial malignancy.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('malignancy', 'Disease', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('biallelic', 'Var', (87, 96))	('women', 'Species', '9606', (76, 81))
189331	25546585	As a "proof of principle" we applied the method to breast cancer samples to identify partners in whole arm (WA) translocations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('translocations', 'Var', (112, 126))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
189334	25546585	By analyzing aCGH data from 295 patients with breast carcinoma with known molecular subtype, we found concurrent WA gain of 1q and loss of 16q to be more frequent in luminal A tumors compared to other molecular subtypes.	('16q', 'Chemical', '-', (139, 142))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast carcinoma', 'Phenotype', 'HP:0003002', (46, 62))	('luminal A tumors', 'Disease', (166, 182))	('loss', 'Var', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('breast carcinoma', 'Disease', (46, 62))	('luminal A tumors', 'Disease', 'MESH:D009369', (166, 182))	('gain', 'PosReg', (116, 120))	('breast carcinoma', 'Disease', 'MESH:D001943', (46, 62))
189340	25546585	The majority of chromosomal defects in human carcinomas and hematopoietic cancers are due to chromosomal instability, resulting in different types of genomic structural alterations such as pericentromeric or centromeric breaks, inversions, translocations, deletions, and gains.	('gains', 'CPA', (271, 276))	('pericentromeric', 'CPA', (189, 204))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('due', 'Reg', (86, 89))	('chromosomal defects', 'Disease', 'MESH:D002869', (16, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('translocations', 'CPA', (240, 254))	('chromosomal defects', 'Disease', (16, 35))	('chromosomal instability', 'Disease', (93, 116))	('human', 'Species', '9606', (39, 44))	('centromeric breaks', 'CPA', (208, 226))	('chromosomal instability', 'Disease', 'MESH:D043171', (93, 116))	('deletions', 'Var', (256, 265))	('carcinomas and hematopoietic cancers', 'Disease', 'MESH:D019337', (45, 81))	('inversions', 'CPA', (228, 238))	('chromosomal instability', 'Phenotype', 'HP:0040012', (93, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('centromeric breaks', 'Phenotype', 'HP:0040012', (208, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))
189344	25546585	In breast cancer, the most frequent WA alterations found by aCGH are gain of 1q, 8q, and 16p and loss of 16q and 17p (Ried et al.,; Chin et al.,; Hicks et al.,; Jonsson et al.,; Russnes et al.,), the same chromosomal arms are found by cytogenetic studies to be involved in translocations in breast cancer cell lines (Dutrillaux et al.,; Kokalj-Vokac et al.,; Tsuda et al.,; Tsarouha et al.,; Kytola et al.,).	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (291, 304))	('loss', 'Var', (97, 101))	('gain', 'PosReg', (69, 73))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('16p', 'Chemical', '-', (89, 92))	('16q', 'Chemical', '-', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
189345	25546585	WA 1q gain is a common alteration in breast cancer and is found by metaphase FISH and cytogenetic analysis to be caused by isochromosome formation or WA translocation with other chromosomal arms (Tsuda et al.,; Tirkkonen et al.,; Cummings et al.,).	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('WA translocation', 'Var', (150, 166))	('gain', 'PosReg', (6, 10))	('WA 1q', 'Gene', (0, 5))	('isochromosome formation', 'Var', (123, 146))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('WA 1', 'Species', '1392873', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
189350	25546585	To our knowledge, the association between the presence of der(1;16)(q10;p10) and molecular subtype have not yet been investigated, and due to inaccessible cytogenetic analyses on breast tumors and limited read-length by NGS analysis, FISH is still the best way to recognize WA translocations and identify the partners involved.	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('breast tumors', 'Phenotype', 'HP:0100013', (179, 192))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('breast tumors', 'Disease', (179, 192))	('breast tumors', 'Disease', 'MESH:D001943', (179, 192))	('der', 'Var', (58, 61))
189357	25546585	The raw and preprocessed data can be accessed from the National Center for Biotechnology Information (NCBI) gene expression omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) with accession numbers GSE8757 (Chin-UCAM), GSE20394 (Ull), and GSE19425 (MicMa and WZ).	('MicMa', 'Chemical', '-', (247, 252))	('GSE19425', 'Var', (237, 245))	('GSE20394', 'Var', (217, 225))	('GSE8757', 'Chemical', '-', (196, 203))	('GSE8757', 'Var', (196, 203))
189391	25546585	Based on the criteria outlined in the material and methods section, tumors were scored positive or negative for der(1;16)(q10;p10).	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('negative', 'NegReg', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (68, 74))	('der', 'Var', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
189396	25546585	The reference HDF cells displayed two normal copies of both chromosome 1 and 16 for both probe-mix 1 and probe-mix 2, this in contrast to the tumor cells where two normal copies of chromosome 1 but only one normal copy of chromosome 16 was observed.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('probe-mix 1', 'Var', (89, 100))	('probe-mix 2', 'Var', (105, 116))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
189403	25546585	The translocation resulting in der(1;16)(q10;p10) chromosomes were visualized in one FFPE invasive tumor samples from the WZ cohort (WZ055, Fig.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('invasive tumor', 'Disease', 'MESH:D009369', (90, 104))	('invasive tumor', 'Disease', (90, 104))	('der(1;16)(q10;p10) chromosomes', 'Var', (31, 61))
189410	25546585	In this study, we have established and tested a method for interphase FISH using multiple probes on tumor imprints and paraffin sections to detect centromere close whole chromosome arms translocations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('centromere', 'Var', (147, 157))	('paraffin', 'Chemical', 'MESH:D010232', (119, 127))
189411	25546585	This is illustrated by two of the MicMa samples in this study which previously were analyzed by paired-end sequencing (Stephens et al.,) and the results illustrated in genome-wide circos plots, displaying somatic rearrangements like insertion, deletions and translocations, but no translocation between chromosomes 1 and 16 was identified (Figure 6).	('MicMa', 'Chemical', '-', (34, 39))	('translocations', 'CPA', (258, 272))	('deletions', 'Var', (244, 253))	('insertion', 'Var', (233, 242))
189412	25546585	Cytogenetic as well as molecular analyses such as aCGH or single nucleotide polymorphism array (SNP arrays) have identified gain of WA of 1q and loss of 16q as common alterations both in invasive carcinomas and in pre malignant lesions (Chin et al.,; Pandis et al.,).	('16q', 'Chemical', '-', (153, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('gain', 'PosReg', (124, 128))	('loss', 'Var', (145, 149))	('invasive carcinomas', 'Disease', (187, 206))	('invasive carcinomas', 'Disease', 'MESH:D009361', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))
189414	25546585	The loss of 16q is also found in a substantial proportion of invasive ductal carcinomas, as well as in premalignant lesions such as columnar cell lesions, atypical ductal hyperplasia and DCIS (Simpson et al.,).	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (61, 87))	('atypical ductal hyperplasia', 'Disease', 'MESH:D002285', (155, 182))	('invasive ductal carcinomas', 'Disease', (61, 87))	('16q', 'Gene', (12, 15))	('columnar cell lesions', 'Disease', (132, 153))	('DCIS', 'Disease', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('atypical ductal hyperplasia', 'Disease', (155, 182))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('16q', 'Chemical', '-', (12, 15))	('loss', 'Var', (4, 8))
189415	25546585	A translocation resulting in a der(1;16)(q10;p10) is considered an early event in mammary carcinogenesis although it has not previously been seen in DCIS by cytogenetic analysis and FISH methods (Dutrillaux et al.,; Pandis et al.,; Tirkkonen et al.,; Tsarouha et al.,; Cummings et al.,).	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('der(1;16)(q10;p10', 'Var', (31, 48))	('carcinogenesis', 'Disease', (90, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))
189424	25546585	This sample series is too small but the data indicate that a derivate chromosome due to a translocation between 1q and 16p is a common trait for the luminal A subtype.	('16p', 'Chemical', '-', (119, 122))	('derivate', 'Var', (61, 69))	('translocation', 'Var', (90, 103))
189425	25546585	Detecting centromere close translocation by QM FISH is time consuming mostly due to the slight variation in breakpoint between different tumors and the need for customized probes.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('centromere close translocation', 'Var', (10, 40))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
189430	25546585	In two samples (MicMa 220, 232) with der(1;16)(q10;p10), the WAAI score only indicated WA gain of 1q, but not 16q loss.	('MicMa', 'Chemical', '-', (16, 21))	('der(1;16)(q10;p10', 'Var', (37, 54))	('gain', 'PosReg', (90, 94))	('16q', 'Chemical', '-', (110, 113))
189435	25546585	We tailored multiple FISH probes close to the centromere on chromosome arms 1q and 16q and hybridized tissue slides with five different probes simultaneously, and found tumors with concurrent WA gain of chromosome arm 1q and loss of chromosome arm 16q by aCGH analysis were frequently of luminal A subtype and had a translocation resulting in a derivative chromosome der(1;16)(q10;p10).	('resulting in', 'Reg', (330, 342))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('loss', 'Var', (225, 229))	('16q', 'Chemical', '-', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('16q', 'Chemical', '-', (248, 251))	('chromosome', 'Gene', (203, 213))	('tumors', 'Disease', (169, 175))	('gain', 'PosReg', (195, 199))
189437	25546585	In summary, QM FISH is a method to evaluate CN variation as well as structural genomic rearrangements in a cell specific manner making it possible to investigate both intra tumor heterogeneity as well as tumor progression in both fresh and archival tissue samples.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('intra tumor', 'Disease', (167, 178))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('investigate', 'Reg', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (204, 209))	('CN variation', 'Var', (44, 56))	('intra tumor', 'Disease', 'MESH:D009369', (167, 178))
189469	24633840	Other markers of LN include the cytoplasmic localisation of p120-catenin and cytokeratin-34betaE12.	('cytokeratin-34betaE12', 'Var', (77, 98))	('p120-catenin', 'Gene', '1500', (60, 72))	('p120-catenin', 'Gene', (60, 72))
189476	24633840	These variants are characterised by a combination of an absence of E-cadherin expression, a lower expression of oestrogen and progesterone receptors, a higher expression of HER2, a higher Ki67 index, and a higher positivity for cytokeratin GCDFP-15, compared with classic forms.	('higher', 'PosReg', (152, 158))	('variants', 'Var', (6, 14))	('oestrogen', 'Protein', (112, 121))	('expression', 'MPA', (78, 88))	('E-cadherin', 'Gene', (67, 77))	('HER2', 'Gene', (173, 177))	('E-cadherin', 'Gene', '999', (67, 77))	('HER2', 'Gene', '2064', (173, 177))	('higher', 'PosReg', (181, 187))	('expression', 'MPA', (159, 169))	('lower', 'NegReg', (92, 97))	('absence', 'NegReg', (56, 63))	('progesterone receptors', 'Protein', (126, 148))	('expression', 'MPA', (98, 108))
189501	24633840	The E-cadherin gene has been postulated as a possible tumour gene suppressor with a large number of possible mutations and is also found in ILC and low-grade DCIS.	('found', 'Reg', (131, 136))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('mutations', 'Var', (109, 118))	('ILC', 'Disease', (140, 143))	('E-cadherin', 'Gene', '999', (4, 14))	('E-cadherin', 'Gene', (4, 14))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('low-grade DCIS', 'Disease', (148, 162))
189547	27739051	Building upon work by Cristini, Lowengrub and Nie, we developed a sharp interface model, where a well-defined tumor boundary Sigma is represented with a level set function phi, satisfying phi < 0 inside the tumor, phi = 0 on the boundary, and phi > 0 outside the tumor.	('phi < 0', 'Var', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('phi = 0', 'Var', (214, 221))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (263, 268))	('phi > 0', 'Var', (243, 250))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
189551	27739051	These level set models took the general form:  u = -mu p + chemotactic terms (where needed) V = u   n on the tumor boundary, and  where V is an extension of V off the tumor boundary Sigma.	('u = -mu p +', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (109, 114))
189565	27739051	These assumptions yield a constitutive relation for the tumor tissue velocity field ui:  The variational derivative deltaE/deltarhoi, combined with the remaining contributions to the flux J (due to pressure, haptotaxis, and chemotaxis; see), yields a generalized Darcy-type constitutive law for the cell velocity ui of a cell species i, determined by the balance of proliferation-generated oncotic pressure p, cell-cell and cell-ECM adhesion, chemotaxis (due to gradients in the cell substrates sigma), and haptotaxis (due to gradients in the ECM density f).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('variational', 'Var', (93, 104))
189615	27739051	Hypoxic tumor regions released VEGF, tumor tissue could remodel the ECM by secretion and degradation processes, and notably, regions of high tumor pressure could collapse vessels, thereby interrupting flow in the vascular network and creating new regions of hypoxia and renewed angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('VEGF', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('collapse', 'NegReg', (162, 170))	('hypoxia', 'Disease', 'MESH:D000860', (258, 265))	('collapse vessels', 'Phenotype', 'HP:0004948', (162, 178))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('interrupting', 'NegReg', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('angiogenesis', 'CPA', (278, 290))	('Hypoxic tumor', 'Disease', (0, 13))	('high tumor', 'Disease', (136, 146))	('tumor', 'Disease', (8, 13))	('high tumor', 'Disease', 'MESH:D009369', (136, 146))	('flow', 'MPA', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('creating', 'Reg', (234, 242))	('vessels', 'CPA', (171, 178))	('tumor', 'Disease', (141, 146))	('regions', 'Var', (125, 132))	('Hypoxic tumor', 'Disease', 'MESH:D009369', (0, 13))	('tumor', 'Disease', (37, 42))	('VEGF', 'Gene', '7422', (31, 35))	('hypoxia', 'Disease', (258, 265))
189821	26472982	With regard to the common genetic background, mutations in the ataxia telangiectasia mutated gene have been found in both lymphoid neoplasia and breast cancer.	('found', 'Reg', (108, 113))	('telangiectasia', 'Phenotype', 'HP:0001009', (70, 84))	('mutations', 'Var', (46, 55))	('lymphoid neoplasia', 'Phenotype', 'HP:0002665', (122, 140))	('lymphoid neoplasia', 'Disease', (122, 140))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('ataxia', 'Phenotype', 'HP:0001251', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('ataxia telangiectasia mutated', 'Gene', (63, 92))	('lymphoid neoplasia', 'Disease', 'MESH:D009369', (122, 140))	('ataxia telangiectasia mutated', 'Gene', '472', (63, 92))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
189829	26472982	described a case of T1N0 IDC coexisting with lymphoma in the ipsilateral axillary lymph nodes.	('lymphoma', 'Disease', 'MESH:D008223', (45, 53))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('T1N0', 'Var', (20, 24))	('lymphoma', 'Disease', (45, 53))
189830	26472982	described two cases, one with T1N0 IDC coexisting with disseminated follicular lymphoma (stage III) and one with DCIS coexisting with lymphoma in the ipsilateral axillary lymph nodes.	('follicular lymphoma', 'Disease', 'MESH:D008224', (68, 87))	('follicular lymphoma', 'Disease', (68, 87))	('lymphoma', 'Disease', (134, 142))	('lymphoma', 'Disease', (79, 87))	('lymphoma', 'Disease', 'MESH:D008223', (134, 142))	('lymphoma', 'Disease', 'MESH:D008223', (79, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('T1N0 IDC', 'Var', (30, 38))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
189832	26472982	describe a case of T3N0M0 IDC coexisting with follicular lymphoma in the ipsilateral lymph nodes.	('T3N0M0 IDC', 'Var', (19, 29))	('follicular lymphoma', 'Disease', 'MESH:D008224', (46, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('follicular lymphoma', 'Disease', (46, 65))
189987	33255412	To calculate the diagnostic sensitivity and specificity of CEM combining low-energy and iodine images overall, diagnoses were dichotomized by the final BI-RADS as follows: BI-RADS 1, 2, and 3 (no MRI) were classified as a negative result, and BI-RADS 3 (with MRI), 4, and 5 were classified as a positive result.	('BI-RADS', 'Var', (172, 179))	('CEM', 'Chemical', '-', (59, 62))	('BI-RADS', 'Var', (243, 250))	('iodine', 'Chemical', 'MESH:D007455', (88, 94))
190000	33255412	Six women were BRCA-positive: 1/541 (0.2%) had a BRCA1 and 5/541 (0.9%) a BRCA2 mutation.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('BRCA', 'Gene', '672', (49, 53))	('BRCA', 'Gene', (49, 53))	('BRCA2', 'Gene', (74, 79))	('mutation', 'Var', (80, 88))	('BRCA', 'Phenotype', 'HP:0003002', (15, 19))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA1 and 5', 'Gene', '672', (49, 60))	('women', 'Species', '9606', (4, 9))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BRCA', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (15, 19))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', (74, 78))
190055	33255412	The findings of our study suggest that CEM in asymptomatic women with a history of breast-conserving surgery improves the cancer detection rate compared to routine mammography alone.	('improves', 'PosReg', (109, 117))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CEM', 'Chemical', '-', (39, 42))	('women', 'Species', '9606', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('CEM', 'Var', (39, 42))
190080	17915016	Loss of heterozygosity (LOH) at 7q31.1-7q31.2 has been shown to be a common event in breast cancer and the presence of a tumour suppressor gene had been suggested accordingly.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('Loss of heterozygosity', 'Var', (0, 22))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
190110	17915016	Mean DFS was 78 months (95%CI 67-95) in Caveolin-1 positive as compared to 82 months (95%CI 72-93) in Caveolin-1 negative patients (p = 0.66) (Figure 2A).	('patients', 'Species', '9606', (122, 130))	('positive', 'Var', (51, 59))	('Caveolin-1', 'Gene', (40, 50))
190125	17915016	Caveolin-1 positivity was again significantly associated with lack of ER, PR, and HER2 expression and presence of cytokeratin 5/6 and EGFR expression.	('EGFR', 'Gene', '1956', (134, 138))	('EGFR', 'Gene', (134, 138))	('positivity', 'Var', (11, 21))	('lack', 'NegReg', (62, 66))	('Caveolin-1', 'Gene', (0, 10))	('HER2', 'Gene', (82, 86))	('expression', 'MPA', (87, 97))	('HER2', 'Gene', '2064', (82, 86))	('expression', 'MPA', (139, 149))	('cytokeratin 5/6', 'Gene', '3852', (114, 129))	('cytokeratin 5/6', 'Gene', (114, 129))
190196	32382473	Compared with the largest dimension of the tumor on pathologic analysis, micro-CT had the best correlation coefficient (r = 0.82, p < 0.001), followed by MRI (r = 0.78, p < 0.001), ultrasound (r = 0.61, p < 0.001), and mammography (r = 0.40, p < 0.01).	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('micro-CT', 'Var', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (43, 48))
190201	32382473	It is noteworthy that the 12 malignant tumors, including tumors from breast cancer type 1 susceptibility protein (BRCA1) mutation carriers, were all detected by ex vivo MRI but undetected with conventional preoperative imaging.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('malignant tumors', 'Disease', 'MESH:D009369', (29, 45))	('BRCA1', 'Gene', '672', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (69, 112))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('mutation', 'Var', (121, 129))	('BRCA1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('breast cancer type 1 susceptibility protein', 'Gene', (69, 112))	('tumors', 'Disease', (39, 45))	('malignant tumors', 'Disease', (29, 45))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
190227	32382473	MUSE has the potential to improve the efficiency of patient care in both state-of-the-art and low-resource settings and to provide opportunities for rapid histology.	('MUSE', 'Var', (0, 4))	('patient care', 'CPA', (52, 64))	('patient', 'Species', '9606', (52, 59))	('improve', 'PosReg', (26, 33))
190240	32382473	[  16b  ] The AX11890 compound, which is the ligand of KIAA1363, is linked with Nile blue (NB) to quench the fluorescence of AX11890 with an efficient photoinduced electron transfer (PET) mechanism in aqueous buffer solution.	('Nile blue', 'Chemical', 'MESH:C008619', (80, 89))	('AX11890', 'Chemical', '-', (14, 21))	('KIAA1363', 'Chemical', '-', (55, 63))	('AX11890', 'Chemical', '-', (125, 132))	('NB', 'Chemical', 'MESH:C008619', (91, 93))	('quench', 'NegReg', (98, 104))	('fluorescence', 'MPA', (109, 121))	('AX11890', 'Var', (14, 21))
190241	32382473	However, when the "silent" probe interacts with KIAA1363, AX11890 becomes separated from the NB dye by a certain distance and recovers NIR fluorescence ("switch-on").	('AX11890', 'Chemical', '-', (58, 65))	('KIAA1363', 'Chemical', '-', (48, 56))	('NB', 'Chemical', 'MESH:C008619', (93, 95))	('NIR fluorescence', 'MPA', (135, 151))	('AX11890', 'Var', (58, 65))	('recovers', 'PosReg', (126, 134))
190293	32382473	This work was supported by Grants-in-Aid for Scientific Research from the JSPS KAKENHI Grant Numbers JP18K14341, JP18K07265, and JP15H05843 in Middle Molecular Strategy.	('Aid', 'Gene', (37, 40))	('JP18K07265', 'Var', (113, 123))	('JP18K14341', 'Var', (101, 111))	('JP15H05843', 'Var', (129, 139))	('Aid', 'Gene', '57379', (37, 40))
190296	30413499	In 1042 patients, the percentages of high histological grade, N1+N2, T2+T4 were 7.3%, 24.2%, 46.9%, respectively.	('high histological grade', 'CPA', (37, 60))	('N1+N2', 'Var', (62, 67))	('T2+T4', 'Var', (69, 74))	('patients', 'Species', '9606', (8, 16))
190340	30413499	In 1042 patients the percentages of high histological grade, N1+N2, T2+T4 were 7.3%, 24.2%, 46.9%, respectively.	('N1+N2', 'Var', (61, 66))	('high histological grade', 'CPA', (36, 59))	('T2+T4', 'Var', (68, 73))	('patients', 'Species', '9606', (8, 16))
190358	30413499	In our analysis, the percentages of positive margins, vascular tumour invasion, high histological grade, N1+N2 and T2+T4 were 2.8%, 10.5%, 7.3%, 24.2% and 46.9%, respectively.	('positive margins', 'CPA', (36, 52))	('vascular tumour', 'Disease', (54, 69))	('vascular tumour', 'Phenotype', 'HP:0100742', (54, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('vascular tumour', 'Disease', 'MESH:D019043', (54, 69))	('T2+T4', 'Var', (115, 120))	('N1+N2', 'Var', (105, 110))	('high histological grade', 'CPA', (80, 103))
190392	29872548	According to our limited patient sample, NMCs on breast US were mainly associated with high-grade DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (98, 102))	('high-grade DCIS', 'Disease', (87, 102))	('patient', 'Species', '9606', (25, 32))	('NMCs', 'Var', (41, 45))	('associated', 'Reg', (71, 81))
190424	29872548	In conclusion, according to our limited patient sample, NMCs on breast US were mainly associated with high-grade DCIS.	('patient', 'Species', '9606', (40, 47))	('NMCs', 'Var', (56, 60))	('associated', 'Reg', (86, 96))	('high-grade DCIS', 'Disease', (102, 117))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
190470	27083179	Of the 26 patients with SLN (micro)metastases (Table 3), 14 patients (53.8 %) underwent completion axillary lymph node dissection (cALND).	('patients', 'Species', '9606', (60, 68))	('metastases', 'Disease', 'MESH:D009362', (35, 45))	('patients', 'Species', '9606', (10, 18))	('SLN', 'Var', (24, 27))	('metastases', 'Disease', (35, 45))
190472	27083179	Final histopathology, of all axillary surgery, showed pN0 in 427 (90.7 %), pN0i+ in 18 (3.8 %), pN1mi in 12 (2.5 %), and >=pN1 in 14 patients (3.0 %).	('pN1', 'Gene', '5270', (123, 126))	('pN0i+', 'Var', (75, 80))	('patients', 'Species', '9606', (133, 141))	('pN1', 'Gene', '5270', (96, 99))	('pN1', 'Gene', (123, 126))	('pN0', 'Var', (54, 57))	('pN1', 'Gene', (96, 99))
190553	23924035	is that high grade DCIS has been associated with damage of the myoepithelial cell layer and basement membrane surrounding the ductal lumen.	('damage of the myoepithelial', 'Disease', 'MESH:D009208', (49, 76))	('damage of the myoepithelial', 'Disease', (49, 76))	('DCIS', 'Disease', (19, 23))	('high grade', 'Var', (8, 18))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))
190686	31951276	In the Women's Health Initiative, elevated leukocyte counts were found to be associated with risk of several cancers, including breast cancer, and these associations remained largely unchanged even after exclusion of cancers that occur within 2 years of blood collection.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Women', 'Species', '9606', (7, 12))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('leukocyte counts', 'Var', (43, 59))	('cancers', 'Disease', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('elevated', 'PosReg', (34, 42))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancers', 'Disease', (217, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('elevated leukocyte counts', 'Phenotype', 'HP:0001974', (34, 59))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
190704	28712671	There was a strong association between calcification morphology (particularly pleomorphic) and likelihood of malignancy (p=0.008).	('malignancy', 'Disease', (109, 119))	('pleomorphic', 'Var', (78, 89))	('calcification', 'Disease', 'MESH:D002114', (39, 52))	('calcification', 'Disease', (39, 52))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))
190755	28712671	Post-treatment changes diminish the sensitivity of mammography, resulting in compromised differentiation between benign and malignant calcifications.	('compromised', 'NegReg', (77, 88))	('malignant calcifications', 'Disease', 'MESH:D002114', (124, 148))	('changes', 'Var', (15, 22))	('malignant calcifications', 'Disease', (124, 148))	('diminish', 'NegReg', (23, 31))	('sensitivity', 'MPA', (36, 47))	('differentiation', 'MPA', (89, 104))
190765	28712671	Our results align with the increasing rate of malignancy based on BI-RADS morphology as reported in a meta-analysis by Rominger et al that showed malignancy rates of 9% for round calcifications, 13% for coarse heterogeneous, 27% for amorphous, and 50% for pleomorphic.	('amorphous', 'Var', (233, 242))	('calcification', 'Disease', (179, 192))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('malignancy', 'Disease', (146, 156))	('coarse', 'Disease', (203, 209))	('malignancy', 'Disease', 'MESH:D009369', (46, 56))	('calcification', 'Disease', 'MESH:D002114', (179, 192))	('malignancy', 'Disease', (46, 56))	('pleomorphic', 'Var', (256, 267))
190875	31976307	In a retrospective analysis of 139 patients, the loss of hormone receptor positivity resulted in a worse post-recurrence survival (P = 0.01) and OS (P = 0.06), compared with the corresponding concordant-positive cases.	('hormone receptor', 'Gene', (57, 73))	('loss', 'Var', (49, 53))	('post-recurrence survival', 'CPA', (105, 129))	('loss of hormone receptor', 'Phenotype', 'HP:0002930', (49, 73))	('patients', 'Species', '9606', (35, 43))	('hormone receptor', 'Gene', '3164', (57, 73))	('worse', 'NegReg', (99, 104))
190905	31976307	Tumor size greater than 1.5 cm [HR = 0.44, 95%CI: 0.22-0.90, P < 0.05), and endocrine therapy decreased the risk of IBTR (HR = 0.36, 95%CI: 0.18-0.73, P < 0.05) with a median interval to IBTR of 54 wk in patients with tumors < 1.5 cm (vs 119 wk in patients with tumor greater than or equal to 1.5 cm) and a median time to IBTR of 54.5 wk in patients who did not receive endocrine therapy (vs 138.1 wk in patients treated with endocrine therapy).	('patients', 'Species', '9606', (204, 212))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (341, 349))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('patients', 'Species', '9606', (404, 412))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('decreased', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('IBTR', 'Disease', (116, 120))	('greater', 'Var', (11, 18))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', (218, 223))	('patients', 'Species', '9606', (248, 256))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumors', 'Disease', (218, 224))
190934	33408887	Several studies have showed that AR expression is associated with favorable characteristics such as older age, smaller size, well-differentiated tumors, lower proliferation index, and higher positivity of hormone receptors and as a consequence, better overall survival.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('proliferation', 'CPA', (159, 172))	('tumors', 'Disease', (145, 151))	('hormone receptors', 'Protein', (205, 222))	('AR expression', 'Var', (33, 46))	('positivity', 'MPA', (191, 201))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('lower', 'NegReg', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('higher', 'PosReg', (184, 190))	('overall', 'MPA', (252, 259))	('better', 'PosReg', (245, 251))
190939	33408887	In breast cancer cells, HDAC1 inhibitors induce cell cycle arrest and apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('inhibitors', 'Var', (30, 40))	('arrest', 'Disease', (59, 65))	('HDAC1', 'Gene', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('apoptosis', 'CPA', (70, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
190948	10408711	Multivariate analysis revealed that MLI-DCIS was significant not only in all cases, but also in node-negative cases (P = 0.0223,P = 0.0426 respectively), whereas MLI-INV was not.	('MLI-DCIS', 'Chemical', '-', (36, 44))	('MLI-INV', 'Disease', (162, 169))	('MLI-INV', 'Disease', 'MESH:C535918', (162, 169))	('MLI-DCIS', 'Var', (36, 44))
191028	17069664	A recently published pooled analysis shows that local recurrence is associated with an increased risk of developing distant metastases and subsequent death from breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('death', 'Disease', 'MESH:D003643', (150, 155))	('metastases', 'Disease', (124, 134))	('death', 'Disease', (150, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('local recurrence', 'Var', (48, 64))
191056	27244699	Women diagnosed with DCIS were identified using International Classification of Diseases for Oncology third edition (behavior code 2 and morphology codes 8050, 8201, 8210, 8230, 8401, 8500, 8501, 8503, 8504, 8507, 8522, 8523, 8540 and 8543), and were coded as stage 0 according to the American Joint Committee on Cancer seventh edition guidelines.	('8230', 'Var', (172, 176))	('Cancer', 'Phenotype', 'HP:0002664', (313, 319))	('Women', 'Species', '9606', (0, 5))	('DCIS', 'Disease', (21, 25))	('Cancer seventh edition guidelines', 'Disease', 'MESH:D005155', (313, 346))	('DCIS', 'Phenotype', 'HP:0030075', (21, 25))	('8523', 'Var', (220, 224))	('8543', 'Var', (235, 239))	('8401', 'Var', (178, 182))	('8210', 'Var', (166, 170))	('Cancer seventh edition guidelines', 'Disease', (313, 346))	('8050', 'Var', (154, 158))	('Oncology', 'Phenotype', 'HP:0002664', (93, 101))
191097	27244699	Previous research has also shown similar prevalence of BRCA1/2 mutations among breast cancer patients of European, African, and Hispanic ancestry.	('mutations', 'Var', (63, 72))	('BRCA1/2', 'Gene', (55, 62))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('BRCA1/2', 'Gene', '672;675', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('patients', 'Species', '9606', (93, 101))
191106	27244699	Among BRCA1/2 mutation carriers, contralateral mastectomy may confer a survival advantage.	('BRCA1/2', 'Gene', '672;675', (6, 13))	('carriers', 'Reg', (23, 31))	('mutation', 'Var', (14, 22))	('survival advantage', 'CPA', (71, 89))	('BRCA1/2', 'Gene', (6, 13))
191207	15714204	There is accumulating evidence, both epidemiological and histological, that tumours arising as a result of mutations in the two breast cancer susceptibility gene families (BRCA1 and BRCA2) are biologically distinct.	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('mutations', 'Var', (107, 116))	('BRCA1', 'Gene', '672', (172, 177))	('BRCA2', 'Gene', '675', (182, 187))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('BRCA1', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('BRCA2', 'Gene', (182, 187))
191209	15714204	In a seminal paper published by Hedenfalk et al (2001), seven tumours each from BRCA1 and BRCA2 gene mutation carriers, or sporadic breast cancers, were compared by expression microarray analysis.	('sporadic breast cancers', 'Disease', (123, 146))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (123, 146))	('BRCA2', 'Gene', (90, 95))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('BRCA1', 'Gene', '672', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancers', 'Phenotype', 'HP:0003002', (132, 146))	('BRCA2', 'Gene', '675', (90, 95))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('BRCA1', 'Gene', (80, 85))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('mutation', 'Var', (101, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('tumours', 'Disease', (62, 69))
191220	15714204	This level of precision allows measurement of high-level amplification and single-copy alterations in heterogeneous 'normal' backgrounds, such as that common in clinical breast tumours.	('breast tumours', 'Disease', 'MESH:D001943', (170, 184))	('breast tumour', 'Phenotype', 'HP:0100013', (170, 183))	('breast tumours', 'Disease', (170, 184))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('single-copy alterations', 'Var', (75, 98))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))
191221	15714204	A recent publication by Pollack et al (2002) found that RNA expression microarray analysis did indeed reveal DNA copy number changes to have a direct role in the transcriptional profiles of 44 human breast tumours, and impressively, 62% of the highly amplified genes concordantly showed moderate or highly elevated RNA expression.	('elevated', 'PosReg', (306, 314))	('changes', 'Var', (125, 132))	('breast tumour', 'Phenotype', 'HP:0100013', (199, 212))	('Pollack', 'Species', '185739', (24, 31))	('RNA expression', 'MPA', (315, 329))	('breast tumours', 'Disease', (199, 213))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('breast tumours', 'Disease', 'MESH:D001943', (199, 213))	('human', 'Species', '9606', (193, 198))
191420	29554469	This weighted sum measures the goodness of fit of the simulation results and is defined as a chi-squared distributed statistic.. Minimization of the goodness of fit statistic leads to the optimal parameters, but requires frequent, and time-consuming evaluations of the objective function.	('goodness', 'Disease', (149, 157))	('goodness', 'Disease', 'None', (31, 39))	('Minimization', 'Var', (129, 141))	('goodness', 'Disease', (31, 39))	('goodness', 'Disease', 'None', (149, 157))
191455	29554469	A growing group of single nucleotide polymorphisms (SNPs) are discovered that are associated with an elevated risk for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('associated', 'Reg', (82, 92))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('single nucleotide polymorphisms', 'Var', (19, 50))
191532	26416712	They found an increased risk of ipsilateral breast cancer recurrence in patients with coarse heterogeneous/fine pleomorphic and fine linear (branching) microcalcifications, similar to our findings.	('ipsilateral breast cancer', 'Disease', (32, 57))	('coarse heterogeneous/fine pleomorphic', 'Var', (86, 123))	('ipsilateral breast cancer', 'Disease', 'MESH:D001943', (32, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (72, 80))
191540	26416712	We found that grade 3 DCIS and comedonecrosis were associated with fine linear (branching) microcalcifications, linear/segmental distribution, large DCIS size, and ER-negative lesions.	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('necrosis', 'Disease', (37, 45))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('DCIS', 'Disease', (22, 26))	('necrosis', 'Disease', 'MESH:D009336', (37, 45))	('large', 'Var', (143, 148))
191549	32120064	There was moderate evidence for an association of a family history of breast cancer, premenopausal status, high BMI, and high breast density with a subsequent breast cancer or further DCIS.	('menopausal status', 'Phenotype', 'HP:0008209', (88, 105))	('high breast density', 'Phenotype', 'HP:0010313', (121, 140))	('high breast', 'Var', (121, 132))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('association', 'Interaction', (35, 46))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Disease', (159, 172))	('premenopausal status', 'Phenotype', 'HP:0008209', (85, 105))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
191556	32120064	Some characteristics of DCIS lesions, such as nuclear grade, tumour size, and detection by palpation have been shown to be associated with a subsequent breast event specifically, ipsilateral Invasive Breast Cancer (IBCipsilateral), or ipsilateral DCIS recurrence (iDCISr).	('IBCipsilateral', 'Disease', 'None', (215, 229))	('associated with', 'Reg', (123, 138))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('breast event', 'Disease', (152, 164))	('Breast Cancer', 'Phenotype', 'HP:0003002', (200, 213))	('ipsilateral Invasive Breast Cancer', 'Disease', (179, 213))	('ipsilateral Invasive Breast Cancer', 'Disease', 'MESH:D001943', (179, 213))	('tumour', 'Disease', (61, 67))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('IBCipsilateral', 'Disease', (215, 229))	('DCIS', 'Gene', (24, 28))	('ipsilateral DCIS recurrence', 'Disease', (235, 262))	('DCIS', 'Phenotype', 'HP:0030075', (265, 269))	('Cancer', 'Phenotype', 'HP:0002664', (207, 213))	('lesions', 'Var', (29, 36))	('DCIS', 'Phenotype', 'HP:0030075', (247, 251))
191574	32120064	One study reported on BMI documenting a 52% risk reduction for a subsequent breast event in women with a BMI lower than 25 compared to women with a BMI of 25 or higher (HR(multivariate) 0.48 (95%-CI: 0.26-0.90)).	('reduction', 'NegReg', (49, 58))	('lower', 'Var', (109, 114))	('women', 'Species', '9606', (92, 97))	('breast event', 'Disease', (76, 88))	('women', 'Species', '9606', (135, 140))
191632	15318932	Alterations in Clusterin expression and/or protein maturation are linked to changes in tissue growth or regression, which may be related to specific proapoptotic or antiapoptotic protein isoforms.	('changes', 'Reg', (76, 83))	('expression', 'MPA', (25, 35))	('regression', 'CPA', (104, 114))	('Alterations', 'Var', (0, 11))	('protein', 'MPA', (43, 50))	('Clusterin', 'Gene', '1191', (15, 24))	('Clusterin', 'Gene', (15, 24))	('tissue growth', 'CPA', (87, 100))
191647	15318932	KIAA0545, also known as signal-induced proliferation-associated 1 like 3 (SIPA1L3), is a member of the Sipa1 family and encodes a protein bearing a domain highly homologous to the catalytic region of human Rap1 GTPase-activating protein (Rap1GAP).	('KIAA0545', 'Var', (0, 8))	('Sipa1', 'Gene', '6494', (103, 108))	('Rap1GAP', 'Gene', (238, 245))	('signal-induced proliferation-associated 1 like 3', 'Gene', (24, 72))	('Rap1 GTPase-activating protein', 'Gene', '5909', (206, 236))	('Rap1GAP', 'Gene', '5909', (238, 245))	('Rap1 GTPase-activating protein', 'Gene', (206, 236))	('human', 'Species', '9606', (200, 205))	('SIPA1L3', 'Gene', '23094', (74, 81))	('signal-induced proliferation-associated 1 like 3', 'Gene', '23094', (24, 72))	('SIPA1L3', 'Gene', (74, 81))	('Sipa1', 'Gene', (103, 108))
191677	15318932	Overexpression of the SPARC gene has been reported associated with melanoma and metastatic carcinomas of the breast, and increased SPARC expression has been observed in conjunction with increased c-Jun and Fra-1 expression in a panel of invasive breast cancer cell lines.	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('invasive breast cancer', 'Disease', (237, 259))	('carcinomas of the breast', 'Disease', 'MESH:D001943', (91, 115))	('SPARC', 'Gene', '6678', (131, 136))	('invasive breast cancer', 'Disease', 'MESH:D001943', (237, 259))	('Overexpression', 'Var', (0, 14))	('expression', 'MPA', (137, 147))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('Fra-1', 'Gene', '8061', (206, 211))	('metastatic', 'CPA', (80, 90))	('Fra-1', 'Gene', (206, 211))	('increased', 'PosReg', (121, 130))	('c-Jun', 'Gene', '3725', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('c-Jun', 'Gene', (196, 201))	('SPARC', 'Gene', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('associated', 'Reg', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('SPARC', 'Gene', '6678', (22, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('SPARC', 'Gene', (131, 136))	('carcinomas of the breast', 'Disease', (91, 115))
191693	15318932	Also, vimentin antisense transfection in vimentin-expressing breast cell lines was shown to reduce their in vitro invasiveness or migration, strongly emphasizing a functional contribution of vimentin to epithelial cell invasion/migration.	('antisense transfection', 'Var', (15, 37))	('vimentin', 'Gene', (6, 14))	('reduce', 'NegReg', (92, 98))	('vimentin', 'Gene', '7431', (191, 199))	('vimentin', 'Gene', (191, 199))	('in vitro invasiveness', 'CPA', (105, 126))	('vimentin', 'Gene', '7431', (41, 49))	('vimentin', 'Gene', '7431', (6, 14))	('vimentin', 'Gene', (41, 49))
191700	26336132	We also show that the phosphorylation status of VASP at S322 can be predictive for breast cancer progression to an aggressive phenotype.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('VASP', 'Gene', (48, 52))	('at S322', 'Var', (53, 60))	('breast cancer', 'Disease', (83, 96))	('S322', 'Chemical', '-', (56, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('VASP', 'Gene', '7408', (48, 52))	('phosphorylation', 'MPA', (22, 37))
191701	26336132	Our data indicate that phosphorylation at S322 is gradually decreased from normal breast to DCIS, luminal/ER+, HER2+ and basal-like/TN phenotypes.	('HER2', 'Gene', (111, 115))	('decreased', 'NegReg', (60, 69))	('phosphorylation', 'MPA', (23, 38))	('HER2', 'Gene', '2064', (111, 115))	('S322', 'Chemical', '-', (42, 46))	('S322', 'Var', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))
191714	26336132	Several phosphorylated tyrosine, serine and threonine residues have been identified by mass spectroscopy (www.phosphosite.org), and so far five phosphorylation sites (Y39, S157, S239, T278 and S322) have been experimentally-confirmed and linked to cellular outcome.	('Y39', 'Var', (167, 170))	('S239', 'Var', (178, 182))	('S322', 'Var', (193, 197))	('S322', 'Chemical', '-', (193, 197))	('tyrosine', 'Chemical', 'MESH:D014443', (23, 31))	('T278', 'Var', (184, 188))	('serine', 'Chemical', 'MESH:D012694', (33, 39))	('threonine', 'Chemical', 'MESH:D013912', (44, 53))	('S157', 'Var', (172, 176))
191715	26336132	Phosphorylation at S157 generally seems to mediate membrane localization of VASP.	('mediate', 'Reg', (43, 50))	('membrane localization', 'MPA', (51, 72))	('Phosphorylation', 'Var', (0, 15))	('VASP', 'Gene', (76, 80))	('VASP', 'Gene', '7408', (76, 80))
191716	26336132	Although phosphorylation of VASP at S157 has been suggested as a marker for the potential of metastatic progression of prostate cancer, using this phosphorylation as a marker needs to be pursued with caution, since additional phosphorylations at S239/T278 or S322 can diverge the functions of VASP at the leading edge of migrating cells.	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('diverge', 'Reg', (268, 275))	('VASP', 'Gene', (28, 32))	('functions', 'MPA', (280, 289))	('prostate cancer', 'Disease', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('VASP', 'Gene', (293, 297))	('VASP', 'Gene', '7408', (28, 32))	('VASP', 'Gene', '7408', (293, 297))	('S322', 'Var', (259, 263))	('S322', 'Chemical', '-', (259, 263))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))
191719	26336132	We here tested if phosphorylation of VASP at S157 and S322, two residues that have been shown to be phosphorylated by Protein Kinase D (PKD) and increase F-actin accumulation, can be indicative for invasive breast cancers.	('VASP', 'Gene', '7408', (37, 41))	('F-actin accumulation', 'MPA', (154, 174))	('Protein Kinase D', 'Gene', '5587', (118, 134))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('increase', 'PosReg', (145, 153))	('increase F-actin accumulation', 'Phenotype', 'HP:0025200', (145, 174))	('invasive breast cancers', 'Disease', (198, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('invasive breast cancers', 'Disease', 'MESH:D001943', (198, 221))	('breast cancers', 'Phenotype', 'HP:0003002', (207, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('VASP', 'Gene', (37, 41))	('S322', 'Var', (54, 58))	('PKD', 'Gene', (136, 139))	('Protein Kinase D', 'Gene', (118, 134))	('S322', 'Chemical', '-', (54, 58))	('PKD', 'Gene', '5587', (136, 139))
191721	26336132	Analyses of human samples indicate that both, decrease of PKD2 or phosphorylation of VASP at S322 may be predictive for an aggressive phenotype.	('VASP', 'Gene', (85, 89))	('decrease of PKD2', 'Disease', (46, 62))	('VASP', 'Gene', '7408', (85, 89))	('S322', 'Var', (93, 97))	('phosphorylation', 'MPA', (66, 81))	('S322', 'Chemical', '-', (93, 97))	('human', 'Species', '9606', (12, 17))	('decrease of PKD2', 'Disease', 'MESH:D016891', (46, 62))
191727	26336132	Further analysis of mutations or alterations in breast cancer samples using cBioPortal (http://www.cbioportal.org/public-portal/index.do) indicated that EVL expression is downregulated (homozygous deletion or mRNA downregulation) mainly in basal-like and HER2 enriched tumors; ENAH expression is increased by mRNA upregulation or gene amplification and this was not specific to a breast cancer subtype (Fig.	('downregulation', 'NegReg', (214, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (380, 393))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Disease', (48, 61))	('breast cancer', 'Disease', 'MESH:D001943', (380, 393))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('breast cancer', 'Disease', (380, 393))	('tumors', 'Disease', (269, 275))	('HER2', 'Gene', (255, 259))	('ENAH', 'Gene', (277, 281))	('EVL', 'Gene', (153, 156))	('increased', 'PosReg', (296, 305))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gene amplification', 'Var', (330, 348))	('ENAH', 'Gene', '55740', (277, 281))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('EVL', 'Gene', '51466', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('expression', 'MPA', (157, 167))	('downregulated', 'NegReg', (171, 184))	('upregulation', 'PosReg', (314, 326))	('expression', 'MPA', (282, 292))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('HER2', 'Gene', '2064', (255, 259))
191736	26336132	Next, we tested if VASP phosphorylation at S157, S239 or S322 is altered during progression of breast cancer.	('VASP', 'Gene', '7408', (19, 23))	('altered', 'Reg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('S239', 'Var', (49, 53))	('S322', 'Chemical', '-', (57, 61))	('VASP', 'Gene', (19, 23))	('S322', 'Var', (57, 61))	('tested', 'Reg', (9, 15))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
191740	26336132	Since the immunofluorescence data indicated that changes in the status of S322 (and possibly S157, although patchy) could be predictive for a progression of breast cancer to a more aggressive and invasive phenotype we next analyzed a larger set of patient samples for these two phosphorylations.	('S157', 'Var', (93, 97))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('S322', 'Chemical', '-', (74, 78))	('changes', 'Reg', (49, 56))	('patient', 'Species', '9606', (248, 255))	('S322', 'Var', (74, 78))
191747	26336132	We recently have shown for HeLa cells that phosphorylation at S157 and S322 drives VASP from focal contacts to the leading edge, which results in a decrease in cell migration.	('VASP', 'Gene', (83, 87))	('S322', 'Chemical', '-', (71, 75))	('S322', 'Var', (71, 75))	('phosphorylation', 'Var', (43, 58))	('decrease', 'NegReg', (148, 156))	('VASP', 'Gene', '7408', (83, 87))	('HeLa', 'CellLine', 'CVCL:0030', (27, 31))	('cell migration', 'CPA', (160, 174))
191748	26336132	We also have shown that both phosphorylations can be mimicked with serine to glutamate mutations at these sites.	('serine', 'Chemical', 'MESH:D012694', (67, 73))	('serine to glutamate', 'Protein', (67, 86))	('mutations', 'Var', (87, 96))	('glutamate', 'Chemical', 'MESH:D018698', (77, 86))
191750	26336132	Mimicking phosphorylations at S157 and S322 in HuMEC also resulted in increased localization of VASP at the leading edge (Fig.	('HuMEC', 'Gene', (47, 52))	('increased', 'PosReg', (70, 79))	('VASP', 'Gene', (96, 100))	('HuMEC', 'CellLine', 'CVCL:B270', (47, 52))	('VASP', 'Gene', '7408', (96, 100))	('localization', 'MPA', (80, 92))	('S322', 'Var', (39, 43))	('S322', 'Chemical', '-', (39, 43))
191751	26336132	While phosphorylation at S157 is necessary for membrane localization, phosphorylation at S322 regulates actin reorganization processes once VASP is located to the membrane.	('S322', 'Chemical', '-', (89, 93))	('VASP', 'Gene', (140, 144))	('VASP', 'Gene', '7408', (140, 144))	('actin reorganization', 'MPA', (104, 124))	('phosphorylation at S322', 'Var', (70, 93))	('regulates', 'Reg', (94, 103))
191753	26336132	Previously, we have identified PKD1 as a kinase that, when ectopically-expressed in cells, phosphorylates S157 and S322.	('S157', 'Var', (106, 110))	('S322', 'Chemical', '-', (115, 119))	('S322', 'Var', (115, 119))	('PKD1', 'Gene', (31, 35))	('PKD1', 'Gene', '5310', (31, 35))
191755	26336132	Surprisingly, as compared to active PKD2, active alleles of PKD1 and PKD3 only led to a weak phosphorylation of VASP at S157 and S322 (Fig.	('S322', 'Var', (129, 133))	('PKD3', 'Gene', '5312', (69, 73))	('VASP', 'Gene', '7408', (112, 116))	('PKD2', 'Gene', '5311', (36, 40))	('PKD1', 'Gene', '5310', (60, 64))	('S157', 'Var', (120, 124))	('S322', 'Chemical', '-', (129, 133))	('PKD3', 'Gene', (69, 73))	('PKD2', 'Gene', (36, 40))	('phosphorylation', 'MPA', (93, 108))	('PKD1', 'Gene', (60, 64))	('VASP', 'Gene', (112, 116))
191758	26336132	Our data clearly indicate that phosphorylation of endogenous VASP at both residues (S157 and S322) is a PKD2-specific event (Fig.	('VASP', 'Gene', (61, 65))	('VASP', 'Gene', '7408', (61, 65))	('S157', 'Var', (84, 88))	('S322', 'Var', (93, 97))	('PKD2', 'Gene', (104, 108))	('S322', 'Chemical', '-', (93, 97))	('phosphorylation', 'MPA', (31, 46))	('PKD2', 'Gene', '5311', (104, 108))
191762	26336132	Next we analyzed a panel of breast cancer cell lines, containing highly-invasive cell lines (MDA-MB-231 and MDA-MB-468) that are metastatic in animal models, as well as hormone receptor-positive cell lines (ZR-75-1, T47D and SKBR3) that are not metastatic in vivo, for VASP phosphorylations.	('SKBR3', 'CellLine', 'CVCL:0033', (225, 230))	('T47D', 'CellLine', 'CVCL:0553', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('breast cancer', 'Disease', (28, 41))	('VASP', 'Gene', (269, 273))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (108, 118))	('VASP', 'Gene', '7408', (269, 273))	('MDA-MB-468', 'Var', (108, 118))
191772	26336132	As expected patients with high expression of PRKD2 showed an increase in RFS that was statistically extremely significant (Fig.	('patients', 'Species', '9606', (12, 20))	('high expression', 'Var', (26, 41))	('RFS', 'MPA', (73, 76))	('PRKD2', 'Gene', (45, 50))	('increase', 'PosReg', (61, 69))	('PRKD2', 'Gene', '25865', (45, 50))
191773	26336132	A direct comparison of matching patient tissue showed a concordance between PKD2 expression and VASP phosphorylations at S157 and S322 in benign tissue and TNBC.	('S322', 'Chemical', '-', (130, 134))	('VASP', 'Gene', (96, 100))	('PKD2', 'Gene', '5311', (76, 80))	('VASP', 'Gene', '7408', (96, 100))	('PKD2', 'Gene', (76, 80))	('patient', 'Species', '9606', (32, 39))	('S322', 'Var', (130, 134))
191783	26336132	Moreover, it was suggested that high expression decreases overall patient survival in HER2-positive cancers.	('decreases', 'NegReg', (48, 57))	('patient survival', 'CPA', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patient', 'Species', '9606', (66, 73))	('HER2-positive cancers', 'Disease', (86, 107))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('HER2-positive cancers', 'Disease', 'MESH:D009369', (86, 107))	('high expression', 'Var', (32, 47))
191784	26336132	While our analysis of alterations in breast cancer samples confirms that mRNA upregulation or gene amplification of Mena frequently occurs in all types of invasive breast cancer (Fig.	('breast cancer', 'Disease', (37, 50))	('Mena', 'Gene', '55740', (116, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('Mena', 'Gene', (116, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('gene amplification', 'Var', (94, 112))	('invasive breast cancer', 'Disease', (155, 177))	('upregulation', 'PosReg', (78, 90))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('invasive breast cancer', 'Disease', 'MESH:D001943', (155, 177))
191798	26336132	For example, S157 phosphorylation of VASP has been suggested as a marker for prostate cancer cell motility and potential of metastatic progression.	('VASP', 'Gene', '7408', (37, 41))	('prostate cancer cell motility', 'Disease', (77, 106))	('S157 phosphorylation', 'Var', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('prostate cancer cell motility', 'Disease', 'MESH:D011471', (77, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('VASP', 'Gene', (37, 41))
191800	26336132	Phosphorylation of S157 drives VASP to the leading edge, but additional phosphorylations at S239/T278 or S322 bifurcate VASP functions in respect to F-actin accumulation, filopodia formation and cell migration.	('filopodia formation', 'CPA', (171, 190))	('VASP', 'Gene', '7408', (120, 124))	('S157', 'Var', (19, 23))	('VASP', 'Gene', (31, 35))	('S322', 'Var', (105, 109))	('S322', 'Chemical', '-', (105, 109))	('VASP', 'Gene', '7408', (31, 35))	('F-actin accumulation', 'MPA', (149, 169))	('cell migration', 'CPA', (195, 209))	('VASP', 'Gene', (120, 124))
191804	26336132	Of these especially Y39 phosphorylation of VASP which is mediated by the tyrosine kinase Abl may be of interest.	('Abl', 'Gene', '25', (89, 92))	('VASP', 'Gene', '7408', (43, 47))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('Abl', 'Gene', (89, 92))	('Y39', 'Var', (20, 23))	('VASP', 'Gene', (43, 47))
191806	26336132	Phosphorylations of VASP at S239 and T278 are mainly mediated by PKA, PKG and AMPK; and suppress motility in cancer cells and colon cancer.	('PKG', 'Gene', (70, 73))	('VASP', 'Gene', (20, 24))	('T278', 'Var', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('colon cancer', 'Disease', (126, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Phosphorylations', 'MPA', (0, 16))	('at S239', 'Var', (25, 32))	('suppress', 'NegReg', (88, 96))	('cancer', 'Disease', (109, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('VASP', 'Gene', '7408', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PKG', 'Gene', '5592', (70, 73))	('cancer', 'Disease', (132, 138))	('AMPK', 'Gene', (78, 82))	('AMPK', 'Gene', '5564', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))
191807	26336132	We did not detect significant changes in phosphorylation of VASP at S239 (Fig.	('VASP', 'Gene', (60, 64))	('VASP', 'Gene', '7408', (60, 64))	('S239', 'Var', (68, 72))
191809	26336132	Therefore, we focused on phosphorylation at S322, which can be mediated by PKD enzymes (mainly PKD2 as demonstrated in Fig.	('phosphorylation', 'MPA', (25, 40))	('PKD', 'Gene', (75, 78))	('PKD', 'Gene', (95, 98))	('PKD2', 'Gene', '5311', (95, 99))	('PKD', 'Gene', '5587', (75, 78))	('PKD', 'Gene', '5587', (95, 98))	('S322', 'Var', (44, 48))	('S322', 'Chemical', '-', (44, 48))	('PKD2', 'Gene', (95, 99))
191829	26336132	Expression plasmids for FLAG-tagged human VASP, GFP-tagged human VASP and phosphorylation mimicking (VASP.S157E, VASP.S322E, or VASP.S157E.S322E) mutants, as well as the expression constructs for tagged constitutively-active versions (S to E mutations in critical activation loop serines) of PKD1, PKD2 or PKD3 have been described in detail elsewhere.	('serines', 'Chemical', 'MESH:D012694', (280, 287))	('PKD2', 'Gene', '5311', (298, 302))	('VASP', 'Gene', (113, 117))	('VASP', 'Gene', (42, 46))	('mutants', 'Var', (146, 153))	('VASP', 'Gene', (65, 69))	('PKD3', 'Gene', '5312', (306, 310))	('VASP', 'Gene', (128, 132))	('S322E', 'Mutation', 'p.S322E', (118, 123))	('VASP', 'Gene', '7408', (101, 105))	('S157E', 'Mutation', 'p.S157E', (106, 111))	('PKD3', 'Gene', (306, 310))	('S322E', 'Mutation', 'p.S322E', (139, 144))	('PKD1', 'Gene', (292, 296))	('VASP', 'Gene', '7408', (113, 117))	('human', 'Species', '9606', (59, 64))	('VASP', 'Gene', '7408', (65, 69))	('VASP', 'Gene', (101, 105))	('VASP', 'Gene', '7408', (128, 132))	('VASP', 'Gene', '7408', (42, 46))	('S157E', 'Mutation', 'p.S157E', (133, 138))	('human', 'Species', '9606', (36, 41))	('PKD1', 'Gene', '5310', (292, 296))	('PKD2', 'Gene', (298, 302))
191856	26336132	When cells were transfected with GFP-tagged versions of VASP, transfection was performed in 8 well ibiTreat mu-Slides (Ibidi).	('GFP-tagged', 'Var', (33, 43))	('VASP', 'Gene', (56, 60))	('VASP', 'Gene', '7408', (56, 60))	('ibiTreat', 'Chemical', '-', (99, 107))
191875	18673493	DNA strand breaks may predispose cells to tumorigenic transformation and comprise the likely carcinogenic mechanism of some chemicals and toxins.	('tumor', 'Disease', (42, 47))	('predispose', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('carcinogenic', 'Disease', 'MESH:D063646', (93, 105))	('DNA', 'Var', (0, 3))	('carcinogenic', 'Disease', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
191876	18673493	However, it is also recognized that folate deficiency has two faces with respect to cancer (much like Janus, the Roman god of beginnings and endings, who is often depicted with two faces).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('folate deficiency', 'Phenotype', 'HP:0100507', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('folate', 'Chemical', 'MESH:D005492', (36, 42))	('deficiency', 'Var', (43, 53))
191878	18673493	This, too, is generally ascribed to the effect of folate deficiency on thymidylate synthesis (and thus DNA synthesis), which is necessary for cancer cells to proliferate.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('deficiency', 'Var', (57, 67))	('folate deficiency on thymidylate', 'Phenotype', 'HP:0410209', (50, 82))	('thymidylate synthesis', 'MPA', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('folate deficiency', 'Phenotype', 'HP:0100507', (50, 67))	('DNA synthesis', 'MPA', (103, 116))	('folate', 'Chemical', 'MESH:D005492', (50, 56))	('cancer', 'Disease', (142, 148))
191881	18673493	Thus, folate deficiency may also inhibit DNA synthesis by limiting the supply of adenine and guanine.	('limiting', 'NegReg', (58, 66))	('inhibit', 'NegReg', (33, 40))	('deficiency', 'Var', (13, 23))	('folate', 'Chemical', 'MESH:D005492', (6, 12))	('guanine', 'Chemical', 'MESH:D006147', (93, 100))	('DNA synthesis', 'MPA', (41, 54))	('adenine', 'Chemical', 'MESH:D000225', (81, 88))	('folate deficiency', 'Phenotype', 'HP:0100507', (6, 23))	('folate', 'Protein', (6, 12))
191886	18673493	In folate deficiency, the synthesis of methionine is impaired and cellular SAM levels decrease, thus inhibiting methylation reactions, including DNA methylation.	('methionine', 'Chemical', 'MESH:D008715', (39, 49))	('folate deficiency', 'Phenotype', 'HP:0100507', (3, 20))	('methylation reactions', 'MPA', (112, 133))	('folate', 'Chemical', 'MESH:D005492', (3, 9))	('impaired', 'NegReg', (53, 61))	('cellular SAM levels', 'MPA', (66, 85))	('DNA methylation', 'MPA', (145, 160))	('SAM', 'Chemical', 'MESH:D012436', (75, 78))	('deficiency', 'Var', (10, 20))	('decrease', 'NegReg', (86, 94))	('synthesis of methionine', 'MPA', (26, 49))	('inhibiting', 'NegReg', (101, 111))
191889	18673493	Hypermethylation of gene promoters, catalyzed by DNA methyltransferase enzymes (DNMT), leads to repression of gene expression mediated by methylated DNA binding proteins (e.g., MeCP2 and MBD2) and associated co-repressor complexes (e.g., the NuRD and Sin3a complexes).	('Sin3a', 'Gene', (251, 256))	('MBD2', 'Gene', (187, 191))	('MeCP2', 'Gene', (177, 182))	('DNMT', 'Gene', (80, 84))	('Sin3a', 'Gene', '20466', (251, 256))	('Hypermethylation', 'Var', (0, 16))	('DNMT', 'Gene', '13433', (80, 84))	('DNA methyltransferase enzymes', 'Gene', '13433', (49, 78))	('MBD2', 'Gene', '17191', (187, 191))	('repression', 'NegReg', (96, 106))	('gene expression', 'MPA', (110, 125))	('MeCP2', 'Gene', '17257', (177, 182))	('DNA methyltransferase enzymes', 'Gene', (49, 78))
191890	18673493	Thus, aberrant DNA methylation in cancer cells may result in inappropriate under- and over-expression of specific genes, which may, in turn, promote malignant transformation and progression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('over-expression', 'PosReg', (86, 101))	('under-', 'MPA', (75, 81))	('aberrant', 'Var', (6, 14))	('progression', 'CPA', (178, 189))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('DNA', 'Protein', (15, 18))	('malignant transformation', 'CPA', (149, 173))	('cancer', 'Disease', (34, 40))	('result', 'Reg', (51, 57))	('promote', 'PosReg', (141, 148))
191891	18673493	Herman and Baylin have reviewed the potential importance of aberrant DNA methylation in tumorigenesis.	('aberrant DNA methylation', 'Var', (60, 84))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
191892	18673493	They describe that the initiation and progression of cancer are influenced by both mutational and epigenetic alterations, each of which may enhance the function of oncogenes and repress the function of tumor suppressor genes.	('enhance', 'PosReg', (140, 147))	('mutational', 'Var', (83, 93))	('cancer', 'Disease', (53, 59))	('tumor', 'Disease', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('influenced', 'Reg', (64, 74))	('epigenetic alterations', 'Var', (98, 120))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('function', 'MPA', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('function', 'MPA', (190, 198))	('oncogenes', 'Protein', (164, 173))	('repress', 'NegReg', (178, 185))
191893	18673493	Thus, because it is required for synthesis of SAM, folate may influence tumorigenesis not only through effects on DNA synthesis, but also through epigenetic effects on gene expression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('DNA synthesis', 'MPA', (114, 127))	('effects', 'Reg', (103, 110))	('tumor', 'Disease', (72, 77))	('epigenetic effects', 'Var', (146, 164))	('SAM', 'Chemical', 'MESH:D012436', (46, 49))	('folate', 'Chemical', 'MESH:D005492', (51, 57))	('influence', 'Reg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
191899	18673493	In these studies, folate deficiency appeared to have little effect on the initiation of mammary tumorigenesis by MNU, but it did slow progression.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('deficiency', 'Var', (25, 35))	('tumor', 'Disease', (96, 101))	('folate', 'Chemical', 'MESH:D005492', (18, 24))	('mammary', 'Disease', (88, 95))	('MNU', 'Chemical', 'MESH:D008770', (113, 116))	('folate deficiency', 'Phenotype', 'HP:0100507', (18, 35))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
191906	18673493	Such mutations lead to overexpression and activation of the H-ras oncogene, thus initiating tumorigenesis.	('initiating', 'Reg', (81, 91))	('overexpression', 'PosReg', (23, 37))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('H-ras', 'Gene', (60, 65))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('activation', 'PosReg', (42, 52))	('tumor', 'Disease', (92, 97))	('H-ras', 'Gene', '15461', (60, 65))
191914	18673493	PyVmT transforms cells by disrupting signal transduction pathways through interactions with key cellular signaling proteins, such as PI3K, Shc, and Src.	('Shc', 'Gene', (139, 142))	('disrupting', 'NegReg', (26, 36))	('signal transduction pathways', 'Pathway', (37, 65))	('Src', 'Gene', '20779', (148, 151))	('Src', 'Gene', (148, 151))	('interactions', 'Interaction', (74, 86))	('PyVmT', 'Var', (0, 5))	('Shc', 'Gene', '20416', (139, 142))
191975	32712878	Assignments assumed that most ER+ , T1-2N0-1 patients can defer surgery for several months with neoadjuvant endocrine therapy, but must be monitored and proceed urgently to surgery or other systemic therapy for progression.	('T1-2N0-1', 'Var', (36, 44))	('patients', 'Species', '9606', (45, 53))	('ER+', 'Var', (30, 33))
192057	29394917	Impressive therapeutic results obtained in the recent years by modifiers of the immune response to cancer have initiated movements calling for intense investigation of the immune microenvironment of preinvasive malignant lesions.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('modifiers', 'Var', (63, 72))
192068	29394917	with family history of BC, germline BRCA1 mutations, with incomplete clinical annotations and/or lost from follow-up were excluded.	('BRCA1', 'Gene', '672', (36, 41))	('BRCA1', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))
192098	29394917	As shown in Table 3, miCa were more frequently of high nuclear grade (p = 0.029, for grade 3), and contained more HER2+ and triple negative (TN) cases (p = 0.032).	('miCa', 'Chemical', '-', (21, 25))	('HER2', 'Gene', (114, 118))	('HER2', 'Gene', '2064', (114, 118))	('miCa', 'Disease', (21, 25))	('triple negative', 'Var', (124, 139))
192134	29394917	reported higher counts of CD8+, CD4+, FoxP3+ and CD20+ cells in high grade pure DCIS, in comparison to the non-high grade cases.	('pure DCIS', 'Disease', (75, 84))	('FoxP3', 'Gene', '50943', (38, 43))	('high grade', 'Var', (64, 74))	('CD8', 'Gene', '925', (26, 29))	('CD20', 'Gene', '54474', (49, 53))	('FoxP3', 'Gene', (38, 43))	('CD4', 'Gene', (32, 35))	('CD20', 'Gene', (49, 53))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('CD4', 'Gene', '920', (32, 35))	('CD8', 'Gene', (26, 29))	('higher', 'PosReg', (9, 15))
192139	29394917	evoked, high grade DCIS lesions have significantly different immune landscape than the rest of DCIS (more TILs, different TIL immunophenotype).	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('TIL', 'Gene', '7096', (122, 125))	('TIL', 'Gene', (106, 109))	('TIL', 'Gene', (122, 125))	('DCIS', 'Disease', (19, 23))	('high grade', 'Var', (8, 18))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))	('TIL', 'Gene', '7096', (106, 109))
192160	29394917	HER2+ subtype is frequently found in miCa and the association with HER2 positivity and rich TILs in DCIS has been reported.	('TIL', 'Gene', (92, 95))	('HER2', 'Gene', (67, 71))	('miCa', 'Disease', (37, 41))	('positivity', 'Var', (72, 82))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('HER2', 'Gene', '2064', (67, 71))	('HER2', 'Gene', (0, 4))	('association', 'Interaction', (50, 61))	('HER2', 'Gene', '2064', (0, 4))	('miCa', 'Chemical', '-', (37, 41))	('TIL', 'Gene', '7096', (92, 95))
192161	29394917	However, in our cohort, the HER2+ cases represented only slightly above one third of lyDCIS or miCa, suggesting that the HER2- in situ lesions could also induce development of rich lymphocytic infiltrate.	('HER2', 'Gene', '2064', (28, 32))	('induce', 'Reg', (154, 160))	('miCa', 'Chemical', '-', (95, 99))	('HER2', 'Gene', '2064', (121, 125))	('lyDCIS', 'Chemical', '-', (85, 91))	('rich lymphocytic infiltrate', 'CPA', (176, 203))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('miCa', 'Disease', (95, 99))	('HER2', 'Gene', (28, 32))	('HER2', 'Gene', (121, 125))	('lesions', 'Var', (135, 142))
192218	21843942	An analogous patient population is that of that of BRCA mutation carriers who have for many years been offered routine annual MRI surveillance and clinical examination as a safe and acceptable alternative to prophylactic surgery.	('BRCA', 'Gene', (51, 55))	('mutation', 'Var', (56, 64))	('patient', 'Species', '9606', (13, 20))	('BRCA', 'Gene', '672', (51, 55))
192239	22011282	Analysis of matrix metalloproteinase-1 gene polymorphisms and expression in benign and malignant breast tumors A guanine insertion polymorphism in matrix metalloproteinase-1 promoter (MMP-1 2G) is linked to early onset and aggressiveness in cancer.	('guanine insertion polymorphism', 'Var', (113, 143))	('aggressiveness in cancer', 'Disease', 'MESH:D009369', (223, 247))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('malignant breast tumors', 'Disease', 'MESH:D001943', (87, 110))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('matrix metalloproteinase-1', 'Gene', '4312', (12, 38))	('matrix metalloproteinase-1', 'Gene', (147, 173))	('linked to', 'Reg', (197, 206))	('matrix metalloproteinase-1', 'Gene', '4312', (147, 173))	('malignant breast tumors', 'Disease', (87, 110))	('MMP-1', 'Gene', '4312', (184, 189))	('aggressiveness', 'Phenotype', 'HP:0000718', (223, 237))	('MMP-1', 'Gene', (184, 189))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('guanine', 'Chemical', 'MESH:D006147', (113, 120))	('matrix metalloproteinase-1', 'Gene', (12, 38))	('aggressiveness in cancer', 'Disease', (223, 247))
192252	22011282	MMP-1 2G polymorphism has been associated with lymph node metastasis in breast cancer and has also been linked to the pathogenesis of other cancers, for example, to the early-onset of lung cancer, increased risk of nasopharyngeal carcinoma, oral squamous cell carcinoma and colorectal cancer, aggressiveness of head and neck cancer, development and progression of endometrial carcinoma and negative prognosis in patients with ovarian cancer.	('colorectal cancer', 'Disease', (274, 291))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (364, 385))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('breast cancer', 'Disease', (72, 85))	('nasopharyngeal carcinoma', 'Disease', (215, 239))	('patients', 'Species', '9606', (412, 420))	('ovarian cancer', 'Disease', (426, 440))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (364, 385))	('ovarian cancer', 'Phenotype', 'HP:0100615', (426, 440))	('linked', 'Reg', (104, 110))	('MMP-1', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (215, 239))	('associated', 'Reg', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (274, 291))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('polymorphism', 'Var', (9, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (215, 239))	('aggressiveness of head and neck cancer', 'Disease', 'MESH:D006258', (293, 331))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('head and neck cancer', 'Phenotype', 'HP:0012288', (311, 331))	('aggressiveness', 'Phenotype', 'HP:0000718', (293, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (241, 269))	('endometrial carcinoma', 'Disease', (364, 385))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lymph', 'Disease', (47, 52))	('ovarian cancer', 'Disease', 'MESH:D010051', (426, 440))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (274, 291))	('cancers', 'Disease', (140, 147))	('oral squamous cell carcinoma', 'Disease', (241, 269))	('lung cancer', 'Disease', (184, 195))	('MMP-1', 'Gene', '4312', (0, 5))
192254	22011282	We further explored the possible relationship of MMP-1 expression and MMP-1 polymorphism with other known clinical markers of breast cancer such as HER2 and P53.	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', '2064', (148, 152))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('P53', 'Gene', (157, 160))	('MMP-1', 'Gene', '4312', (70, 75))	('MMP-1', 'Gene', '4312', (49, 54))	('polymorphism', 'Var', (76, 88))	('P53', 'Gene', '7157', (157, 160))	('MMP-1', 'Gene', (49, 54))	('MMP-1', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
192291	22011282	Patients expressing high levels of MMP-1 had a 2.20 fold increased risk of developing invasive breast cancer (OR = 2.20; 95% CI, 1.09-4.44; Table 2).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high levels', 'Var', (20, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('invasive breast cancer', 'Disease', (86, 108))	('MMP-1', 'Gene', '4312', (35, 40))	('Patients', 'Species', '9606', (0, 8))	('invasive breast cancer', 'Disease', 'MESH:D001943', (86, 108))	('MMP-1', 'Gene', (35, 40))
192295	22011282	In this group, 57% of the patients expressing low MMP-1 had the 1G/1G homozygote genotype while 80% of those expressing high MMP-1 (3+) were either 1G/2G carriers (40%) or homozygous for 2G (40%).	('MMP-1', 'Gene', (50, 55))	('patients', 'Species', '9606', (26, 34))	('1G/1G', 'Var', (64, 69))	('MMP-1', 'Gene', '4312', (125, 130))	('MMP-1', 'Gene', (125, 130))	('MMP-1', 'Gene', '4312', (50, 55))
192298	22011282	This association between the MMP-1 2G insertion polymorphism and MMP-1 expression was not observed in the DCIS/LCIS group (P=0.23; Table 4).	('expression', 'MPA', (71, 81))	('MMP-1', 'Gene', '4312', (65, 70))	('insertion polymorphism', 'Var', (38, 60))	('MMP-1', 'Gene', (65, 70))	('DCIS', 'Chemical', '-', (106, 110))	('MMP-1', 'Gene', '4312', (29, 34))	('MMP-1', 'Gene', (29, 34))
192308	22011282	Patients carrying the 2G/2G genotype had a 7.5-fold (95%CI, 1.48-37.9; P = 0.032; Table 6) increased odds of expressing HER2 compared to the 1G/2G carriers.	('2G/2G', 'Var', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('HER2', 'Gene', '2064', (120, 124))	('HER2', 'Gene', (120, 124))
192318	22011282	The reported MMP-1 genotype frequency in healthy Caucasian women are 0.28, 0.54 and 0.18 for 1G/1G, 1G/2G and 2G/2G respectively, and this is not significantly different from the genotype frequency we observed in IBC, DCIS/LCIS, ADH or benign breast disease group (P > 0.05 respectively).	('1G/2G', 'Var', (100, 105))	('MMP-1', 'Gene', '4312', (13, 18))	('ADH', 'Disease', 'MESH:D007177', (229, 232))	('2G/2G', 'Var', (110, 115))	('IBC', 'Chemical', '-', (213, 216))	('IBC', 'Disease', (213, 216))	('ADH', 'Disease', (229, 232))	('MMP-1', 'Gene', (13, 18))	('benign breast disease', 'Disease', 'MESH:D001941', (236, 257))	('0.54', 'Var', (75, 79))	('benign breast disease', 'Disease', (236, 257))	('DCIS/LCIS', 'Disease', (218, 227))	('0.18', 'Var', (84, 88))	('DCIS', 'Chemical', '-', (218, 222))	('women', 'Species', '9606', (59, 64))	('1G/1G', 'Var', (93, 98))
192319	22011282	The distribution of the MMP-1 genotype in our studied groups was also not significantly different (P > 0.05), suggesting that MMP-1 polymorphism may not contribute to the development of breast cancer.	('MMP-1', 'Gene', '4312', (126, 131))	('MMP-1', 'Gene', '4312', (24, 29))	('MMP-1', 'Gene', (126, 131))	('polymorphism', 'Var', (132, 144))	('MMP-1', 'Gene', (24, 29))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('contribute', 'Reg', (153, 163))
192320	22011282	This is consistent with the result from a recent meta-analysis study which failed to show any significant association between MMP-1 2G polymorphism and breast cancer susceptibility.	('MMP-1', 'Gene', '4312', (126, 131))	('MMP-1', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('polymorphism', 'Var', (135, 147))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))
192323	22011282	These observations indicates that MMP-1 2G polymorphism may contribute significantly to the increased expression of MMP-1 in invasive breast cancer but not in the in situ breast cancer or the less severe breast disease conditions, and may thus correlated with breast disease status or breast cancer severity.	('correlated', 'Reg', (244, 254))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('invasive breast cancer', 'Disease', (125, 147))	('MMP-1', 'Gene', (34, 39))	('increased', 'PosReg', (92, 101))	('breast disease status or breast cancer', 'Disease', 'MESH:D001943', (260, 298))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('invasive breast cancer', 'Disease', 'MESH:D001943', (125, 147))	('breast disease status or breast cancer', 'Disease', (260, 298))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('situ breast cancer', 'Disease', 'MESH:D000071960', (166, 184))	('polymorphism', 'Var', (43, 55))	('MMP-1', 'Gene', '4312', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('situ breast cancer', 'Disease', (166, 184))	('breast disease conditions', 'Disease', (204, 229))	('MMP-1', 'Gene', (116, 121))	('expression', 'MPA', (102, 112))	('MMP-1', 'Gene', '4312', (34, 39))	('breast disease conditions', 'Disease', 'MESH:D001941', (204, 229))
192324	22011282	A larger sample size study is required to establish the full potential of MMP-1 polymorphism in breast cancer progression.	('MMP-1', 'Gene', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('polymorphism', 'Var', (80, 92))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('MMP-1', 'Gene', '4312', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
192327	22011282	Higher 2G allele frequencies have been reported in breast cancer patients with lymph node-metastasis compared with patients without metastasis, indicating the role of MMP-1 2G polymorphism as a potential prognostic marker for breast cancer.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', (226, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('polymorphism', 'Var', (176, 188))	('MMP-1', 'Gene', (167, 172))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('lymph', 'Disease', (79, 84))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('patients', 'Species', '9606', (65, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('MMP-1', 'Gene', '4312', (167, 172))
192328	22011282	However, we did find a correlation between MMP-1 genotype with other breast cancer markers, such as HER2 and P53.	('correlation', 'Interaction', (23, 34))	('P53', 'Gene', (109, 112))	('MMP-1', 'Gene', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('P53', 'Gene', '7157', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('genotype', 'Var', (49, 57))	('HER2', 'Gene', (100, 104))	('MMP-1', 'Gene', '4312', (43, 48))	('HER2', 'Gene', '2064', (100, 104))
192329	22011282	There was a significant association between the MMP-1 2G polymorphism and HER2 expression in IBC patients (P = 0.0401; Table 6).	('expression', 'MPA', (79, 89))	('MMP-1', 'Gene', '4312', (48, 53))	('HER2', 'Gene', (74, 78))	('HER2', 'Gene', '2064', (74, 78))	('MMP-1', 'Gene', (48, 53))	('IBC', 'Chemical', '-', (93, 96))	('IBC', 'Disease', (93, 96))	('polymorphism', 'Var', (57, 69))	('patients', 'Species', '9606', (97, 105))
192330	22011282	Forty four percent (10 out of 23) of patients expressing HER2, had the homozygous 2G/2G genotype compared to 15% of the patients (4 out of 26) not expressing HER2 (Table 6).	('patients', 'Species', '9606', (37, 45))	('HER2', 'Gene', (57, 61))	('HER2', 'Gene', '2064', (57, 61))	('HER2', 'Gene', (158, 162))	('2G/2G', 'Var', (82, 87))	('patients', 'Species', '9606', (120, 128))	('HER2', 'Gene', '2064', (158, 162))
192332	22011282	In breast cancer, the amplification of the Her2/neu oncogene is a well established marker which is associated with relapse and short survival.	('Her2/neu', 'Gene', '2064', (43, 51))	('associated with', 'Reg', (99, 114))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('amplification', 'Var', (22, 35))	('Her2/neu', 'Gene', (43, 51))
192334	22011282	The association of the MMP-1 2G insertion polymorphism with this clinical biomarker again indicates the potential role of this polymorphism in breast cancer severity.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('insertion polymorphism', 'Var', (32, 54))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('MMP-1', 'Gene', '4312', (23, 28))	('MMP-1', 'Gene', (23, 28))
192335	22011282	Studies have shown that both MMP-1 2G polymorphism and HER2 over-expression can up-regulate MMP-1 expression via different molecular mechanisms.	('MMP-1', 'Gene', (92, 97))	('MMP-1', 'Gene', '4312', (92, 97))	('polymorphism', 'Var', (38, 50))	('expression', 'MPA', (98, 108))	('up-regulate', 'PosReg', (80, 91))	('MMP-1', 'Gene', '4312', (29, 34))	('over-expression', 'PosReg', (60, 75))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (55, 59))	('MMP-1', 'Gene', (29, 34))
192340	22011282	We did, however, observe a correlation between the 2G insertion polymorphism and MMP-1 expression in the IBC patients only (P = 0.032) and not in the in situ group, which supports the notion that MMP-1 2G polymorphism is associated with disease severity in breast cancer.	('MMP-1', 'Gene', '4312', (81, 86))	('MMP-1', 'Gene', (81, 86))	('patients', 'Species', '9606', (109, 117))	('insertion polymorphism', 'Var', (54, 76))	('MMP-1', 'Gene', '4312', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('polymorphism', 'Var', (205, 217))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('expression', 'MPA', (87, 97))	('breast cancer', 'Disease', (257, 270))	('MMP-1', 'Gene', (196, 201))	('associated', 'Reg', (221, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('IBC', 'Chemical', '-', (105, 108))
192342	22011282	Both P53 mutation and accumulation have been associated with poor prognosis.	('mutation', 'Var', (9, 17))	('P53', 'Gene', '7157', (5, 8))	('P53', 'Gene', (5, 8))
192345	22011282	However, it has been reported that the repression effect of P53 on MMP-1 expression is lost in osteogenic sarcoma cells over expressing mutant P53.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('P53', 'Gene', (60, 63))	('MMP-1', 'Gene', (67, 72))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (95, 113))	('osteogenic sarcoma', 'Disease', (95, 113))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (95, 113))	('P53', 'Gene', '7157', (60, 63))	('P53', 'Gene', (143, 146))	('repression', 'MPA', (39, 49))	('lost', 'NegReg', (87, 91))	('expression', 'MPA', (73, 83))	('P53', 'Gene', '7157', (143, 146))	('over', 'PosReg', (120, 124))	('MMP-1', 'Gene', '4312', (67, 72))	('mutant', 'Var', (136, 142))
192346	22011282	More detailed study of the effect of accumulated or mutation of P53 on MMP-1 expression in breast cancer will be required to gain a better understanding of the interrelationship between P53 and MMP-1.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('P53', 'Gene', (64, 67))	('MMP-1', 'Gene', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('P53', 'Gene', '7157', (186, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('P53', 'Gene', '7157', (64, 67))	('mutation', 'Var', (52, 60))	('MMP-1', 'Gene', '4312', (194, 199))	('MMP-1', 'Gene', (194, 199))	('MMP-1', 'Gene', '4312', (71, 76))	('P53', 'Gene', (186, 189))
192348	22011282	There was a significant decrease in the number of heterozygotes (1G/2G) and increased number of homozygotes (1G/1G and 2G/2G) in the P53+ patients compared to the P53- patients (P = 0.010).	('P53', 'Gene', '7157', (163, 166))	('1G/1G', 'Var', (109, 114))	('P53', 'Gene', (133, 136))	('P53', 'Gene', '7157', (133, 136))	('decrease', 'NegReg', (24, 32))	('patients', 'Species', '9606', (168, 176))	('P53', 'Gene', (163, 166))	('patients', 'Species', '9606', (138, 146))
192353	22011282	However, the MMP-1 2G polymorphism is associated with breast cancer severity which is supported by its correlation with MMP-1 expression and the expression status of HER2 and P53 in IBC patients.	('MMP-1', 'Gene', '4312', (120, 125))	('breast cancer', 'Disease', (54, 67))	('MMP-1', 'Gene', '4312', (13, 18))	('HER2', 'Gene', (166, 170))	('associated', 'Reg', (38, 48))	('IBC', 'Chemical', '-', (182, 185))	('P53', 'Gene', (175, 178))	('MMP-1', 'Gene', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('MMP-1', 'Gene', (13, 18))	('HER2', 'Gene', '2064', (166, 170))	('P53', 'Gene', '7157', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('polymorphism', 'Var', (22, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('patients', 'Species', '9606', (186, 194))
192354	22011282	Over-expression of MMP-1 induced by this polymorphism together with other regulators may predict an adverse outcome of breast cancer.	('polymorphism', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('MMP-1', 'Gene', (19, 24))	('Over-expression', 'PosReg', (0, 15))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('MMP-1', 'Gene', '4312', (19, 24))
192356	22011282	Such studies will elucidate the impact of MMP-1 2G polymorphism on breast cancer development and progression.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('polymorphism', 'Var', (51, 63))	('MMP-1', 'Gene', '4312', (42, 47))	('MMP-1', 'Gene', (42, 47))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
192361	22011282	The association of MMP-1 2G insertion polymorphism with these two biomarkers in invasive breast cancer indicates a role of MMP-1 2G polymorphism in predicting breast cancer severity and may provide new molecular tools for sub classification of invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('MMP-1', 'Gene', (19, 24))	('invasive breast cancer', 'Disease', (244, 266))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('MMP-1', 'Gene', (123, 128))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('insertion polymorphism', 'Var', (28, 50))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('invasive breast cancer', 'Disease', 'MESH:D001943', (244, 266))	('breast cancer', 'Disease', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('MMP-1', 'Gene', '4312', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('MMP-1', 'Gene', '4312', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('invasive breast cancer', 'Disease', (80, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('invasive breast cancer', 'Disease', 'MESH:D001943', (80, 102))
192363	19729831	Disruption of protein expression has been implicated in a number of malignancies.	('protein', 'Protein', (14, 21))	('malignancies', 'Disease', (68, 80))	('implicated', 'Reg', (42, 52))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('Disruption', 'Var', (0, 10))
192405	19729831	For some analyses, a separate variable was defined (Delta14-3-3sigma) which was calculated by subtracting the mean integrated intensity of the pooled DCIS lesions from the mean integrated intensity of pooled matched invasive lesions of the same cases (IDCexpression - DCISexpression).	('14-3-3sigma', 'Gene', (57, 68))	('Delta14', 'Mutation', 'c.del14', (52, 59))	('IDC', 'Gene', (252, 255))	('14-3-3sigma', 'Gene', '2810', (57, 68))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (268, 272))	('lesions', 'Var', (155, 162))	('IDC', 'Gene', '4000', (252, 255))	('DCIS', 'Disease', (150, 154))
192443	19729831	The absence of appropriate damage-induced cell cycle pausing can lead to accumulated DNA damage and induction of chromosomal abnormalities and thus can contribute to tumor development and progression.	('chromosomal abnormalities', 'Disease', (113, 138))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('contribute to', 'Reg', (152, 165))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (113, 138))	('accumulated', 'PosReg', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('progression', 'CPA', (188, 199))	('induction', 'Reg', (100, 109))	('tumor', 'Disease', (166, 171))	('lead', 'Reg', (65, 69))	('DNA damage', 'MPA', (85, 95))	('absence', 'Var', (4, 11))
192448	19729831	With regard to breast cancer, Sukumar and colleagues found that 14-3-3sigma mRNA was undetectable in 45 of 48 primary breast carcinomas by Northern blot analysis due to gene silencing by CpG methylation and that hypermethylation of 14-3-3sigma seemed to be a relatively early event in breast cancer.	('14-3-3sigma', 'Gene', (64, 75))	('breast carcinomas', 'Phenotype', 'HP:0003002', (118, 135))	('14-3-3sigma', 'Gene', '2810', (64, 75))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('gene silencing', 'NegReg', (169, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('breast cancer', 'Disease', (285, 298))	('hypermethylation', 'Var', (212, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('breast carcinomas', 'Disease', 'MESH:D001943', (118, 135))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast carcinomas', 'Disease', (118, 135))	('14-3-3sigma', 'Gene', (232, 243))	('14-3-3sigma', 'Gene', '2810', (232, 243))	('undetectable', 'NegReg', (85, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
192449	19729831	However, in other tumor systems, methylation does not necessarily result in decreased expression of 14-3-3sigma.	('methylation', 'Var', (33, 44))	('tumor', 'Disease', (18, 23))	('decreased', 'NegReg', (76, 85))	('14-3-3sigma', 'Gene', (100, 111))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('14-3-3sigma', 'Gene', '2810', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
192457	19729831	Hyperactivation of IGF-IR is thought to play a role in early breast cancer development.	('IGF-IR', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('IGF-IR', 'Gene', '3480', (19, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('Hyperactivation', 'Var', (0, 15))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
192472	19683484	Fibrocystic changes in general have been hypothesized to be part of the sequence going from normal breast epithelium to carcinoma, and fibrocystic disease that is proliferative has a higher frequency of chromosome aberrations versus non-proliferative disease.	('carcinoma', 'Disease', (120, 129))	('fibrocystic disease', 'Phenotype', 'HP:0006552', (135, 154))	('Fibrocystic changes', 'Phenotype', 'HP:0006552', (0, 19))	('fibrocystic disease', 'Disease', 'MESH:D005348', (135, 154))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('fibrocystic disease', 'Disease', (135, 154))	('chromosome aberrations', 'Var', (203, 225))	('Fibrocystic', 'Disease', (0, 11))	('Fibrocystic', 'Disease', 'MESH:D005348', (0, 11))
192485	19683484	This indicates that presence of proliferative changes in one breast can be regarded as a risk factor for breast cancer in either breast, and the changes are likely not confined to the excised lesion.	('proliferative changes', 'CPA', (32, 53))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('one breast', 'Phenotype', 'HP:0012813', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('presence', 'Var', (20, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
192536	19683484	Increased cellularity in NAF has been shown to be a risk factor for breast cancer in prospective studies, but has unknown significance in ductal lavage samples.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('cellularity', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
192561	19683484	The rate of atypia was 21% in women with BRCA1 or 2 mutations.	('mutations', 'Var', (52, 61))	('BRCA1', 'Gene', '672', (41, 46))	('women', 'Species', '9606', (30, 35))	('BRCA1', 'Gene', (41, 46))
192563	19683484	Finally, while the relationship of atypia in dutcal lavage and subsequent breast cancer risk is not yet established, presence of atypia in nipple aspirate fluid increased the relative risk for breast cancer risk to 2.0 (versus women who did not produce fluid), indicating that atypia is not a particularly strong risk factor  Interestingly, BMI was strongly related to presence of atypia, and all the women with atypia were either overweight or obese.	('breast cancer', 'Disease', (193, 206))	('related', 'Reg', (358, 365))	('breast cancer', 'Disease', (74, 87))	('presence', 'Var', (117, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('overweight', 'Phenotype', 'HP:0025502', (431, 441))	('obese', 'Disease', 'MESH:D009765', (445, 450))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('BMI', 'Disease', (341, 344))	('obese', 'Disease', (445, 450))	('women', 'Species', '9606', (401, 406))	('women', 'Species', '9606', (227, 232))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
192570	19683484	In two prospective studies of women with benign breast disease, nuclear shape has been shown to be predictive of subsequent breast cancer risk.	('nuclear', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('women', 'Species', '9606', (30, 35))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('benign breast disease', 'Disease', 'MESH:D001941', (41, 62))	('breast cancer', 'Disease', (124, 137))	('benign breast disease', 'Disease', (41, 62))
192604	18929150	Beginning in September 1972, 380 women with node-positive breast cancer were randomly assigned to receive either L-phenylalanine mustard (L-PAM) or placebo in the NSABP's B-05 trial.	('L-phenylalanine', 'Var', (113, 128))	('women', 'Species', '9606', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('L-phenylalanine mustard', 'Chemical', 'MESH:D008558', (113, 136))	('L-PAM', 'Chemical', 'MESH:D008558', (138, 143))
192635	18929150	With 10 years of follow-up, this study demonstrated an absolute advantage of 10% in both disease-free and overall survival for 5-FU + leucovorin compared to a contemporary control arm of methyl-CCNU, vincristine, and 5-FU (MOF).	('5-FU', 'Chemical', 'MESH:D005472', (127, 131))	('disease-free', 'CPA', (89, 101))	('advantage', 'PosReg', (64, 73))	('5-FU', 'Chemical', 'MESH:D005472', (217, 221))	('MOF', 'Gene', '84148', (223, 226))	('vincristine', 'Chemical', 'MESH:D014750', (200, 211))	('MOF', 'Gene', (223, 226))	('methyl-CCNU', 'Chemical', 'MESH:D012673', (187, 198))	('overall survival', 'CPA', (106, 122))	('5-FU', 'Var', (127, 131))	('leucovorin', 'Chemical', 'MESH:D002955', (134, 144))
192637	18929150	The study was initiated in 1989, and the results at 12 years of follow-up showed a trend toward an advantage in disease-free and overall survival in favor of 5-FU + leucovorin over the 5-FU + levamisole combination.	('advantage', 'PosReg', (99, 108))	('leucovorin', 'Chemical', 'MESH:D002955', (165, 175))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('5-FU', 'Chemical', 'MESH:D005472', (185, 189))	('levamisole', 'Chemical', 'MESH:D007978', (192, 202))	('overall survival', 'CPA', (129, 145))	('disease-free', 'CPA', (112, 124))	('5-FU + leucovorin', 'Var', (158, 175))
192658	18929150	The decision to include HRQL in the BCPT was critical; in contrast to women receiving adjuvant treatment for breast cancer, any adverse side effects or changes in HRQL in these high-risk women could affect adherence to the study medication and to subsequent success in the dissemination of tamoxifen for breast cancer prevention.	('HRQL', 'Gene', (163, 167))	('adherence', 'MPA', (206, 215))	('HRQL', 'Chemical', '-', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('women', 'Species', '9606', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (304, 317))	('breast cancer', 'Disease', (109, 122))	('men', 'Species', '9606', (72, 75))	('HRQL', 'Chemical', '-', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (304, 317))	('affect', 'Reg', (199, 205))	('breast cancer', 'Disease', (304, 317))	('changes', 'Var', (152, 159))	('women', 'Species', '9606', (187, 192))	('men', 'Species', '9606', (189, 192))	('men', 'Species', '9606', (100, 103))	('tamoxifen', 'Chemical', 'MESH:D013629', (290, 299))
192690	31111698	For example, a recent retrospective review of data for nearly 10,000 patients in the United States found that re-excision was associated with an average additional cost of $16,072 along with twice the likelihood of complications such as infection, fat necrosis, or hematoma, compared to patients with no re-excision.	('necrosis', 'Disease', 'MESH:D009336', (252, 260))	('fat necrosis', 'Phenotype', 'HP:0010885', (248, 260))	('infection', 'Disease', (237, 246))	('patients', 'Species', '9606', (287, 295))	('infection', 'Disease', 'MESH:D007239', (237, 246))	('hematoma', 'Disease', 'MESH:D006406', (265, 273))	('necrosis', 'Disease', (252, 260))	('patients', 'Species', '9606', (69, 77))	('re-excision', 'Var', (110, 121))	('hematoma', 'Disease', (265, 273))
192847	26506106	In cases after PST, the positive correlation between lesional TVP/area and SO2 may be the reason for an increase in the number of functional microvessels; however, further studies on a more homogenous population, as well as an assessment of other microvessel characteristics such as shape and maturity, are necessary to test this observation.	('increase', 'PosReg', (104, 112))	('lesional', 'Var', (53, 61))	('SO2', 'Chemical', 'MESH:D013458', (75, 78))	('PST', 'Disease', (15, 18))
192862	21795498	Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk.	('associated', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('single-nucleotide polymorphisms', 'Var', (63, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
192864	21795498	The most strongly associated SNP was rs10941679, the minor G allele being associated with an estimated per-allele odds ratio (OR) of 1.19 (95% confidence interval [CI]=1.11-1.26, P=2.9x10-11).	('associated', 'Reg', (18, 28))	('rs10941679', 'Mutation', 'rs10941679', (37, 47))	('rs10941679', 'Var', (37, 47))
192866	21795498	In addition, our previous breast cancer GWAS reported evidence of an association with another SNP on 5p12, rs981782 (P=9x10-6), based on data from 23,408 cases and 24,636 controls from 21 BCAC studies.	('breast cancer', 'Disease', (26, 39))	('p12', 'Gene', (102, 105))	('rs981782', 'Mutation', 'rs981782', (107, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('p12', 'Gene', '56655', (102, 105))	('association', 'Interaction', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('rs981782', 'Var', (107, 115))
192884	21795498	Previously published data for this SNP were included from 14 studies to obtain genotypes for both SNPs in 5p12 for 23,548 invasive cases and 28,142 controls, all of white European origin.	('p12', 'Gene', '56655', (107, 110))	('SNPs', 'Var', (98, 102))	('p12', 'Gene', (107, 110))
192887	21795498	This association was maintained at genome-wide statistical significance when SNP 5p12-rs981782 was included as a covariate in the logistic regression model (OR=1.11, 95%CI=1.09-1.15, P=6x10-13).	('p12', 'Gene', (82, 85))	('rs981782', 'Mutation', 'rs981782', (86, 94))	('p12', 'Gene', '56655', (82, 85))	('SNP', 'Var', (77, 80))
192906	21795498	Further to our previous report of a possible association with breast cancer risk of variant rs981782, also in 5p12, we genotyped this SNP in an additional 8,213 invasive cases and 10,340 controls from studies participating in the BCAC and found no evidence of association (per-G-allele OR=0.97, 95%CI=0.93-1.02, P=0.2, Table 4).	('p12', 'Gene', '56655', (111, 114))	('association', 'Interaction', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs981782', 'Var', (92, 100))	('variant rs981782', 'Var', (84, 100))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('rs981782', 'Mutation', 'rs981782', (92, 100))	('breast cancer', 'Disease', (62, 75))	('p12', 'Gene', (111, 114))
192922	21795498	This multifaceted heterogeneity has also been observed for 10q26-rs2981582, which appears to be associated with increased risk of lower grade ER-positive tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('10q26-rs2981582', 'Var', (59, 74))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('ER', 'Gene', '2099', (142, 144))	('rs2981582', 'Mutation', 'rs2981582', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
192923	21795498	In our previous GWAS, we observed that the minor G allele of 5p12-rs981782 in the same region was associated with reduced risk of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('minor G', 'Var', (43, 50))	('breast cancer', 'Disease', (130, 143))	('rs981782', 'Mutation', 'rs981782', (66, 74))	('p12', 'Gene', (62, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('reduced', 'NegReg', (114, 121))	('p12', 'Gene', '56655', (62, 65))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
192945	14580249	A multitude of methods have been used for the characterisation of pre-invasive breast lesions, including immunohistochemistry, fluorescent in situ hybridisation, analysis of loss of heterozygosity (LOH), comparative genomic hybridisation (CGH), and, more recently, cDNA microarrays and proteomics analysis.	('loss of heterozygosity', 'Var', (174, 196))	('breast lesions', 'Disease', (79, 93))	('breast lesions', 'Disease', 'MESH:D001941', (79, 93))
192948	14580249	As with invasive carcinoma, abnormalities of chromosomes 1 and 16 have been identified in some of these cases.	('abnormalities', 'Var', (28, 41))	('invasive carcinoma', 'Disease', 'MESH:D009361', (8, 26))	('identified', 'Reg', (76, 86))	('invasive carcinoma', 'Disease', (8, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
192963	14580249	Done and colleagues demonstrated that p53 mutations found in DCIS and associated invasive cancer were absent from benign proliferative lesions from the same breast.	('DCIS', 'Disease', (61, 65))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('invasive cancer', 'Disease', 'MESH:D009362', (81, 96))	('mutations', 'Var', (42, 51))	('invasive cancer', 'Disease', (81, 96))
192966	14580249	Moreover, gain of chromosome 1q and loss of 16q, which are highly prevalent in low-grade DCIS, are frequently found in tubular carcinoma and in tubular, tubulolobular, lobular, and grade 1 invasive ductal carcinomas, suggesting that low-grade DCIS is also a direct precursor for certain types of breast carcinomas.	('gain', 'PosReg', (10, 14))	('breast carcinoma', 'Phenotype', 'HP:0003002', (296, 312))	('loss of 16q', 'Var', (36, 47))	('tubular carcinoma', 'Disease', (119, 136))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (303, 313))	('tubular carcinoma', 'Disease', 'MESH:D000230', (119, 136))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (189, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('breast carcinomas', 'Disease', 'MESH:D001943', (296, 313))	('low-grade DCIS', 'Disease', (79, 93))	('invasive ductal carcinomas', 'Disease', (189, 215))	('breast carcinomas', 'Disease', (296, 313))	('breast carcinomas', 'Phenotype', 'HP:0003002', (296, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('DCIS', 'Phenotype', 'HP:0030075', (243, 247))
192974	14580249	Losses at 1q, 16q, and 17p have also been seen in invasive lobular carcinomas.	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (50, 77))	('invasive lobular carcinomas', 'Disease', (50, 77))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (59, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('Losses', 'Var', (0, 6))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (59, 77))
192978	14580249	E-cadherin truncating mutations associated with loss of the wild-type allele (LOH at 16q) have been observed in LCIS and invasive lobular carcinomas.	('LCIS', 'Phenotype', 'HP:0030076', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (130, 148))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (130, 147))	('truncating mutations', 'Var', (11, 31))	('E-cadherin', 'Gene', (0, 10))	('observed', 'Reg', (100, 108))	('invasive lobular carcinomas', 'Disease', (121, 148))	('E-cadherin', 'Gene', '999', (0, 10))	('LCIS', 'Disease', (112, 116))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (121, 148))
192979	14580249	Berx and colleagues failed to identify any truncating mutations in invasive ductal carcinomas of NST or medullary carcinomas; similar findings were recently reported by Roylance and colleagues, who demonstrated lack of E-cadherin mutations in 44 low-grade ductal carcinomas of NST.	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('carcinomas', 'Disease', 'MESH:D002277', (83, 93))	('carcinomas', 'Disease', 'MESH:D002277', (114, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (263, 273))	('mutations', 'Var', (230, 239))	('E-cadherin', 'Gene', (219, 229))	('carcinomas', 'Disease', 'MESH:D002277', (263, 273))	('E-cadherin', 'Gene', '999', (219, 229))	('invasive ductal carcinomas of NST', 'Disease', (67, 100))	('ductal carcinomas', 'Disease', 'MESH:D044584', (76, 93))	('carcinomas', 'Disease', (83, 93))	('carcinomas', 'Disease', (114, 124))	('carcinomas', 'Disease', (263, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('invasive ductal carcinomas of NST', 'Disease', 'MESH:D018270', (67, 100))	('ductal carcinomas', 'Disease', 'MESH:D044584', (256, 273))	('ductal carcinomas', 'Disease', (256, 273))
192982	14580249	In addition, Vos and colleagues have demonstrated the same truncating mutation in the E-cadherin gene in LCIS and the adjacent invasive lobular carcinoma.	('lobular carcinoma', 'Disease', (136, 153))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (136, 153))	('LCIS', 'Disease', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('LCIS', 'Phenotype', 'HP:0030076', (105, 109))	('truncating mutation', 'Var', (59, 78))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))	('lobular carcinoma', 'Disease', 'MESH:D018275', (136, 153))
192993	14580249	When paired HUTs from the same patients were compared, only five concordant genetic abnormalities were observed, and only one of these appeared more than once (loss of 17q, in two cases).	('genetic abnormalities', 'Disease', 'MESH:D030342', (76, 97))	('patients', 'Species', '9606', (31, 39))	('loss of 17q', 'Var', (160, 171))	('genetic abnormalities', 'Disease', (76, 97))
193000	14580249	Conversely, one paper has demonstrated that normal lobules and adjacent in situ carcinomas show concordant genetic alterations, and another suggested that LOH in lobular units in terminal ducts in the normal breast is predictive of local recurrence.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('local recurrence', 'CPA', (232, 248))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('LOH', 'Var', (155, 158))	('situ carcinomas', 'Disease', 'MESH:D002278', (75, 90))	('situ carcinomas', 'Disease', (75, 90))
193044	18306476	Four (57%) of 7 patients with focal asymmetry on mammography had group 3 DCIS, while 3 (75%) of 4 patients with masses had group 3 DCIS.	('DCIS', 'Disease', (73, 77))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (98, 106))	('focal asymmetry', 'Var', (30, 45))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))
193067	18306476	In the current study, 15 (83%) of 18 patients who received breast US presented with masses, while 3 patients presented with ductal change (17%).	('patients', 'Species', '9606', (37, 45))	('breast US', 'Var', (59, 68))	('presented', 'Reg', (69, 78))	('patients', 'Species', '9606', (100, 108))	('masses', 'Disease', (84, 90))
193095	32337481	Acknowledging that patients who undergo SLNB might be healthier than those who do not, a competing-risk model using death by other causes was employed.	('SLNB', 'Var', (40, 44))	('death', 'Disease', 'MESH:D003643', (116, 121))	('patients', 'Species', '9606', (19, 27))	('death', 'Disease', (116, 121))
193140	30959550	We speculate that aberrant expression of lncRNAs could be an early event in breast cancer development, and hence, the study was aimed to identify dysregulated lncRNAs and the mechanism of dysregulation in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('aberrant', 'Var', (18, 26))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancer', 'Disease', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
193180	30959550	(2014) reported the downregulation of ADAMTS9-AS2 by promoter methylation in gliomas.	('gliomas', 'Disease', (77, 84))	('downregulation', 'NegReg', (20, 34))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('promoter methylation', 'Var', (53, 73))	('ADAMTS9', 'Gene', '56999', (38, 45))	('ADAMTS9', 'Gene', (38, 45))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
193182	30959550	We observed a nearly two-fold (1.9) increase in methylation levels (P < 0.0001) in the promoter region (+879 to +929 bp from TSS) of tumor samples compared to paired normal samples (Fig.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('increase', 'PosReg', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('methylation levels', 'MPA', (48, 66))	('+879 to +929 bp', 'Var', (104, 119))	('tumor', 'Disease', (133, 138))
193186	30959550	These results show that ADAMTS9-AS2 is overexpressed in both MDAMB-231 and MCF7 cells following DNMT1 silencing indicating methylation-mediated suppression of ADAMTS9-AS2 in breast cancer cells.	('ADAMTS9', 'Gene', (24, 31))	('suppression', 'NegReg', (144, 155))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('ADAMTS9', 'Gene', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('DNMT1', 'Gene', '1786', (96, 101))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('overexpressed', 'PosReg', (39, 52))	('ADAMTS9', 'Gene', '56999', (24, 31))	('MCF7', 'CellLine', 'CVCL:0031', (75, 79))	('ADAMTS9', 'Gene', '56999', (159, 166))	('silencing', 'Var', (102, 111))	('MDAMB-231', 'CellLine', 'CVCL:0062', (61, 70))	('DNMT1', 'Gene', (96, 101))
193223	30959550	We found that methylation of ADAMTS9-AS2 controls its expression through correlative DNMT1 knock-down in MDAMB-231 and MCF7 cells.	('expression', 'MPA', (54, 64))	('ADAMTS9', 'Gene', '56999', (29, 36))	('ADAMTS9', 'Gene', (29, 36))	('methylation', 'Var', (14, 25))	('DNMT1', 'Gene', (85, 90))	('MCF7', 'CellLine', 'CVCL:0031', (119, 123))	('MDAMB-231', 'CellLine', 'CVCL:0062', (105, 114))	('DNMT1', 'Gene', '1786', (85, 90))	('knock-down', 'Var', (91, 101))
193281	29780255	Univariate and multivariate analyses (Table 2) suggested that a preoperative tumor size of 2-5 cm (vs <=2 cm, OR 1.49, 95% CI 1.06-2.12; P=0.024), preoperative positive lymph-node status (OR 6.56, 95% CI 4.61-9.31; P<0.001), suspicion of multifocality (OR 1.84, 95% CI 1.05-3.23; P=0.033), positive HR (OR 2.07, 95% CI 1.25-3.42; P=0.005), and positive HER2 (OR 1.96, 95% CI 1.38-2.78; P<0.001) were significantly associated with positive margins.	('positive', 'Var', (290, 298))	('positive', 'Disease', (430, 438))	('HER2', 'Gene', (353, 357))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HER2', 'Gene', '2064', (353, 357))	('associated', 'Reg', (414, 424))	('HR', 'Gene', '3164', (299, 301))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('positive', 'Var', (344, 352))	('tumor', 'Disease', (77, 82))
193313	27577169	Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy Chromosomal instability (CIN) is a hallmark of cancer that contributes to tumour heterogeneity and other malignant properties.	('CIN', 'Disease', (150, 153))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('CIN', 'Disease', 'MESH:D007674', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (125, 148))	('patient', 'Species', '9606', (62, 69))	('hallmark of cancer', 'Disease', (160, 178))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('tumour', 'Disease', (199, 205))	('misexpression', 'Var', (32, 45))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('hallmark of cancer', 'Disease', 'MESH:D009369', (160, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (55, 61))
193314	27577169	Aberrant centromere and kinetochore function causes CIN through chromosome missegregation, leading to aneuploidy, rearrangements and micronucleus formation.	('CIN', 'Disease', 'MESH:D007674', (52, 55))	('Aberrant', 'Var', (0, 8))	('chromosome missegregation', 'CPA', (64, 89))	('aneuploidy', 'Disease', 'MESH:D000782', (102, 112))	('leading to', 'Reg', (91, 101))	('micronucleus formation', 'CPA', (133, 155))	('causes', 'Reg', (45, 51))	('CIN', 'Disease', (52, 55))	('rearrangements', 'CPA', (114, 128))	('aneuploidy', 'Disease', (102, 112))
193315	27577169	Here we develop a Centromere and kinetochore gene Expression Score (CES) signature that quantifies the centromere and kinetochore gene misexpression in cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('CES', 'Chemical', '-', (68, 71))	('misexpression', 'Var', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
193316	27577169	High CES values correlate with increased levels of genomic instability and several specific adverse tumour properties, and prognosticate poor patient survival for breast and lung cancers, especially early-stage tumours.	('CES', 'Chemical', '-', (5, 8))	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('High CES values', 'Var', (0, 15))	('tumours', 'Disease', (211, 218))	('increased', 'PosReg', (31, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('breast and lung cancers', 'Disease', 'MESH:D001943', (163, 186))	('poor', 'NegReg', (137, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (174, 186))	('genomic instability', 'MPA', (51, 70))	('adverse tumour properties', 'Disease', (92, 117))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('patient', 'Species', '9606', (142, 149))	('adverse tumour properties', 'Disease', 'MESH:D064420', (92, 117))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
193321	27577169	Genomic instability is characteristic of most human cancers and is believed to promote other cancer hallmarks.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('human', 'Species', '9606', (46, 51))	('Genomic instability', 'Var', (0, 19))	('promote', 'PosReg', (79, 86))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
193323	27577169	CIN is characterized by an increased frequency of chromosome abnormalities, including gain/loss of whole chromosomes or large segments (aneuploidy), structural rearrangements and focal aberrations (for example, amplifications and deletions).	('gain/loss', 'PosReg', (86, 95))	('structural rearrangements', 'CPA', (149, 174))	('aneuploidy', 'Disease', 'MESH:D000782', (136, 146))	('increased frequency of chromosome abnormalities', 'Phenotype', 'HP:0040012', (27, 74))	('CIN', 'Disease', (0, 3))	('deletions', 'Var', (230, 239))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (50, 74))	('chromosome abnormalities', 'Disease', (50, 74))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('aneuploidy', 'Disease', (136, 146))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (50, 74))	('amplifications', 'Var', (211, 225))
193324	27577169	CIN can allow the rapid accumulation of changes that promote cancer progression, growth and heterogeneity, and contribute to intrinsic and acquired drug resistance.	('heterogeneity', 'MPA', (92, 105))	('changes', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('CIN', 'Disease', (0, 3))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (148, 163))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('contribute', 'Reg', (111, 121))	('growth', 'CPA', (81, 87))	('intrinsic', 'MPA', (125, 134))	('promote', 'PosReg', (53, 60))
193325	27577169	Moreover, amplification of the epidermal growth factor receptor locus contributes to an acquired resistance to epidermal growth factor receptor inhibitors in glioblastoma cells.	('epidermal growth factor receptor', 'Gene', (31, 63))	('contributes', 'Reg', (70, 81))	('glioblastoma', 'Disease', (158, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('epidermal growth factor receptor', 'Gene', (111, 143))	('amplification', 'Var', (10, 23))	('epidermal growth factor receptor', 'Gene', '1956', (31, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))
193329	27577169	Proposed mechanisms include oncogene-induced replication stress, breakage-fusion-bridge cycles induced by telomere dysfunction or translocations, and aberrant mitosis.	('breakage-fusion-bridge cycles', 'CPA', (65, 94))	('aberrant mitosis', 'Disease', 'MESH:D002869', (150, 166))	('induced', 'Reg', (95, 102))	('aberrant mitosis', 'Disease', (150, 166))	('telomere dysfunction', 'Disease', 'MESH:C536801', (106, 126))	('telomere dysfunction', 'Disease', (106, 126))	('translocations', 'Var', (130, 144))
193331	27577169	Consequently, their misregulation results in chromosome abnormalities and DNA damage through various pathways, and thus may be an important potential cause of CIN in human cancers.	('chromosome abnormalities', 'Disease', (45, 69))	('misregulation', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cause', 'Reg', (150, 155))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (45, 69))	('results in', 'Reg', (34, 44))	('CIN in human cancers', 'Disease', (159, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('CIN in human cancers', 'Disease', 'MESH:D009369', (159, 179))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (45, 69))	('DNA damage', 'CPA', (74, 84))
193341	27577169	Defects in CENP-A deposition cause centromere propagation failures, ultimately producing chromosome segregation errors and aneuploidy.	('CENP-A', 'Gene', (11, 17))	('aneuploidy', 'Disease', 'MESH:D000782', (123, 133))	('Defects', 'Var', (0, 7))	('centromere propagation failures', 'CPA', (35, 66))	('producing', 'Reg', (79, 88))	('CENP-A', 'Gene', '1058', (11, 17))	('aneuploidy', 'Disease', (123, 133))	('chromosome segregation errors', 'CPA', (89, 118))
193346	27577169	Here we test the hypothesis that misregulation of CEN/KT genes causes chromosomal abnormalities that contribute to tumorigenesis, and can be used as a biomarker for predicting patient prognosis and response to therapy.	('chromosomal abnormalities', 'Disease', (70, 95))	('CEN/KT genes', 'Gene', (50, 62))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (70, 95))	('causes', 'Reg', (63, 69))	('patient', 'Species', '9606', (176, 183))	('misregulation', 'Var', (33, 46))	('tumorigenesis', 'CPA', (115, 128))
193357	27577169	Compared with the corresponding normal tissues, diverse cancer types displayed misregulation of many CEN/KT genes (Supplementary Fig.	('misregulation', 'Var', (79, 92))	('CEN/KT genes', 'Gene', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
193364	27577169	Next, we identified a subset of CEN/KT genes whose misregulation offers prognostic value for cancer patients by performing meta-analysis for multiple cancer types using multiple databases.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('CEN/KT genes', 'Gene', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('misregulation', 'Var', (51, 64))	('cancer', 'Disease', (150, 156))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
193375	27577169	Since defects in centromere and kinetochore function lead to CIN in experimental systems, we analysed TCGA data sets for 18 different cancer types to determine if CEN/KT gene misregulation (represented by the CES value) correlates with the extent of genome instability (genome fraction with copy-number alterations (CNA) and mutation frequency).	('misregulation', 'Var', (175, 188))	('lead to', 'Reg', (53, 60))	('CES', 'Chemical', '-', (209, 212))	('CIN', 'Disease', (61, 64))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('CIN', 'Disease', 'MESH:D007674', (61, 64))	('genome instability', 'MPA', (250, 268))	('defects', 'NegReg', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CEN/KT gene', 'Gene', (163, 174))	('copy-number alterations', 'Var', (291, 314))
193378	27577169	We found that CES values significantly correlate with either CNA fraction or mutation frequency for six cancers (33%), including adrenocortical, head and neck, and kidney renal clear cell carcinomas.	('adrenocortical', 'Disease', 'MESH:D018268', (129, 143))	('kidney renal clear cell carcinomas', 'Disease', 'MESH:C538614', (164, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('CES', 'MPA', (14, 17))	('correlate', 'Reg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutation', 'Var', (77, 85))	('CES', 'Chemical', '-', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('kidney renal clear cell carcinomas', 'Disease', (164, 198))	('cancers', 'Disease', (104, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('CNA fraction', 'MPA', (61, 73))	('adrenocortical', 'Disease', (129, 143))
193392	27577169	We also observed a significant association between high CES and lymph node invasion by box plots in TCGA lung SCCs (P=0.003, Wilcoxon rank-sum test) but not in breast cancer data set (Table 2; Supplementary Fig.	('high CES', 'Var', (51, 59))	('lymph node invasion', 'CPA', (64, 83))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('SCC', 'Gene', (110, 113))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('SCC', 'Gene', '6317', (110, 113))	('CES', 'Chemical', '-', (56, 59))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
193394	27577169	Overall, these findings suggest that the genomic instability associated with high CES may contribute to a number of important tumour properties.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour properties', 'Disease', (126, 143))	('CES', 'Chemical', '-', (82, 85))	('genomic', 'MPA', (41, 48))	('high CES', 'Var', (77, 85))	('contribute', 'Reg', (90, 100))	('tumour properties', 'Disease', 'MESH:D009369', (126, 143))
193405	27577169	Furthermore, Kaplan-Meier survival analysis after patient stratification according to various factors, including breast cancer molecular subtype and NSCLC histological subtype, demonstrated that high CES remains prognostic for poor patient survival in the majority of cases, although there were several exceptions that we explore below (see Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('patient', 'Species', '9606', (50, 57))	('breast cancer molecular subtype', 'Disease', 'MESH:D001943', (113, 144))	('breast cancer molecular subtype', 'Disease', (113, 144))	('CES', 'Chemical', '-', (200, 203))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Disease', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('high', 'Var', (195, 199))	('patient', 'Species', '9606', (232, 239))	('poor', 'NegReg', (227, 231))
193414	27577169	We conclude that high CES cancer cell lines are more sensitive than low CES cell lines to Topo I inhibitors, which cause genotoxicity and reduce cell survival:consistent with the hypothesis that high CES scores correlate with reduced tolerance to genotoxic stress.	('reduced', 'NegReg', (226, 233))	('CES', 'Chemical', '-', (72, 75))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('CES', 'Chemical', '-', (200, 203))	('tolerance to genotoxic stress', 'MPA', (234, 263))	('cell survival', 'CPA', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('toxicity', 'Disease', (125, 133))	('Topo I', 'Gene', (90, 96))	('reduce', 'NegReg', (138, 144))	('CES', 'Chemical', '-', (22, 25))	('inhibitors', 'Var', (97, 107))
193431	27577169	We found that high CES associates with poor relapse-free survival for patients who did not receive systemic therapy (HR=2.20, P=6.5E-11), confirming the prognostic value of high CES in these patients (Fig.	('patients', 'Species', '9606', (70, 78))	('CES', 'Chemical', '-', (178, 181))	('patients', 'Species', '9606', (191, 199))	('poor', 'NegReg', (39, 43))	('high', 'Var', (14, 18))	('relapse-free survival', 'CPA', (44, 65))	('CES', 'Chemical', '-', (19, 22))
193432	27577169	Moreover, CES is also prognostic for ER+ patients treated with tamoxifen only (HR=1.87, P=2.6E-05), suggesting that genomic instability is an important mechanism contributing to relapse among those patients.	('genomic instability', 'Var', (116, 135))	('relapse', 'Disease', (178, 185))	('patients', 'Species', '9606', (198, 206))	('contributing', 'Reg', (162, 174))	('tamoxifen', 'Chemical', 'MESH:D013629', (63, 72))	('patients', 'Species', '9606', (41, 49))	('CES', 'Chemical', '-', (10, 13))
193434	27577169	In some breast cancer patient cohorts such as high-grade, ER- or basal-like and HER2 subtypes, high CES either: (1) did not have significant prognostic value or (2) predicted better survival (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('better', 'PosReg', (175, 181))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('patient', 'Species', '9606', (22, 29))	('CES', 'Chemical', '-', (100, 103))	('high CES', 'Var', (95, 103))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
193444	27577169	Moreover, the improved overall survival associated with high CES in lymph node-positive breast cancer patients is probably because there was significant enrichment for high grade (P=0.003 for GSE3494 and P<0.001 for GSE20711 (ref.	('GSE20711', 'Var', (216, 224))	('CES', 'Chemical', '-', (61, 64))	('improved', 'PosReg', (14, 22))	('patients', 'Species', '9606', (102, 110))	('GSE3494', 'Chemical', '-', (192, 199))	('GSE3494', 'Var', (192, 199))	('overall survival', 'MPA', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('high', 'Var', (56, 60))
193450	27577169	In addition, high CES was associated with even better overall survival among patients treated with topotecan (HR=0.63, P=0.029; Fig.	('better', 'PosReg', (47, 53))	('high', 'Var', (13, 17))	('CES', 'Chemical', '-', (18, 21))	('patients', 'Species', '9606', (77, 85))	('overall', 'MPA', (54, 61))	('topotecan', 'Chemical', 'MESH:D019772', (99, 108))	('CES', 'MPA', (18, 21))
193451	27577169	Notably, in CCLE ovarian cancer cell lines, high CES values were significantly correlated with increased topotecan sensitivity (Spearman's rho, rs=-0.469, P=0.018; Table 3).	('CCLE ovarian cancer', 'Disease', 'MESH:D010051', (12, 31))	('CES values', 'MPA', (49, 59))	('high', 'Var', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('topotecan sensitivity', 'MPA', (105, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('CES', 'Chemical', '-', (49, 52))	('topotecan', 'Chemical', 'MESH:D019772', (105, 114))	('increased', 'PosReg', (95, 104))	('CCLE ovarian cancer', 'Disease', (12, 31))
193455	27577169	Using breast cancer Gray data set, we found that patients with high CES values displayed improved overall survival (HR=0.279, P=0.008) and disease-free survival (DFS; HR=0.254, P=0.016) after RT, compared with patients not treated with RT (Fig.	('improved', 'PosReg', (89, 97))	('CES', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('CES', 'Chemical', '-', (68, 71))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (210, 218))	('disease-free survival', 'CPA', (139, 160))	('patients', 'Species', '9606', (49, 57))	('overall survival', 'CPA', (98, 114))
193462	27577169	In this study, we used a hypothesis-driven approach to interrogate the prognostic and predictive value of centromere and kinetochore protein gene misexpression in human cancers.	('cancers', 'Disease', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('misexpression', 'Var', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human', 'Species', '9606', (163, 168))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
193466	27577169	We show that high human tumour CES values are associated with several adverse tumour properties, and predict poor patient outcomes, including locoregional recurrence, metastatic spread and overall survival, independently from established clinicopathological factors.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('adverse tumour properties', 'Disease', (70, 95))	('high', 'Var', (13, 17))	('tumour CES', 'Disease', 'MESH:C535918', (24, 34))	('human', 'Species', '9606', (18, 23))	('metastatic spread', 'CPA', (167, 184))	('adverse tumour properties', 'Disease', 'MESH:D064420', (70, 95))	('tumour CES', 'Disease', (24, 34))	('patient', 'Species', '9606', (114, 121))	('locoregional recurrence', 'CPA', (142, 165))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
193482	27577169	Therefore, misregulation of centromere replenishment may be a key mechanism that drives genome instability in cancer.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('misregulation', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
193483	27577169	This idea is supported by the observation that perturbing CENP-A nucleosome assembly in model organisms and human cultured cells produces severe mitotic defects.	('CENP-A', 'Gene', (58, 64))	('human', 'Species', '9606', (108, 113))	('mitotic defects', 'Disease', (145, 160))	('perturbing', 'Var', (47, 57))	('CENP-A', 'Gene', '1058', (58, 64))	('mitotic defects', 'Disease', 'MESH:C536987', (145, 160))
193485	27577169	Some studies using yeast, human cancer cell lines or mouse tumour models have shown that genomic instability or aneuploidy results in poor viability and reduced growth of normal cells, or tumour cells not subjected to therapeutic intervention.	('yeast', 'Species', '4932', (19, 24))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('genomic instability', 'Var', (89, 108))	('human', 'Species', '9606', (26, 31))	('reduced', 'NegReg', (153, 160))	('cancer', 'Disease', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', (188, 194))	('aneuploidy', 'Disease', (112, 122))	('poor', 'NegReg', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('mouse', 'Species', '10090', (53, 58))	('tumour', 'Disease', (59, 65))	('aneuploidy', 'Disease', 'MESH:D000782', (112, 122))	('growth', 'CPA', (161, 167))
193487	27577169	Importantly, we do not find clinical evidence that extreme genomic instability benefits patient survival without genotoxic therapy.	('patient', 'Species', '9606', (88, 95))	('clinical', 'Species', '191496', (28, 36))	('extreme genomic instability', 'Var', (51, 78))	('patient survival', 'CPA', (88, 104))	('benefits', 'PosReg', (79, 87))
193492	27577169	Importantly, in that study all ER- patients were subjected to adjuvant therapies, and in our study we found no evidence that high CES is associated with significantly better patient survival without therapy.	('high CES', 'Var', (125, 133))	('patient', 'Species', '9606', (174, 181))	('CES', 'Chemical', '-', (130, 133))	('patient', 'Species', '9606', (35, 42))	('patients', 'Species', '9606', (35, 43))	('better', 'PosReg', (167, 173))	('patient survival', 'CPA', (174, 190))
193493	27577169	Thus, extreme genomic instability in tumour cells may associate with improved survival only for patients treated with adjuvant genotoxic therapies, a hypothesis that merits further investigation.	('improved', 'PosReg', (69, 77))	('tumour', 'Disease', (37, 43))	('survival', 'MPA', (78, 86))	('patients', 'Species', '9606', (96, 104))	('genomic instability', 'Var', (14, 33))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
193494	27577169	However, this predictive power of the CES signature appears to also partially temper its prognostic value for certain tumour types such as high-grade, ER- or basal-like and HER2+ breast cancers.	('CES', 'Var', (38, 41))	('tumour', 'Disease', (118, 124))	('breast cancers', 'Disease', 'MESH:D001943', (179, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('breast cancers', 'Disease', (179, 193))	('HER2', 'Gene', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('temper', 'NegReg', (78, 84))	('HER2', 'Gene', '2064', (173, 177))	('CES', 'Chemical', '-', (38, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('ER-', 'Disease', (151, 154))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('basal-like', 'Disease', (158, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (179, 193))	('high-grade', 'Disease', (139, 149))
193504	27577169	Finally, one proposed strategy for cancer therapy involves specifically killing cells that contain chromosome aberrations.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('chromosome aberrations', 'Var', (99, 121))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
193512	27577169	For correlations between CES and breast cancer ER and PR status, and molecular subtype, GSE47561 data set was used, which is a third party re-analysis of the meta-data set containing GSE2034, GSE11121, GSE20194, GSE1456, GSE2603, GSE6532, GSE20437, GSE1561, GSE7390 and GSE5847.	('GSE20437', 'Var', (239, 247))	('GSE2603', 'Chemical', '-', (221, 228))	('CES', 'Chemical', '-', (25, 28))	('GSE1561', 'Var', (249, 256))	('GSE20194', 'Var', (202, 210))	('GSE2603', 'Var', (221, 228))	('GSE5847', 'Chemical', '-', (270, 277))	('GSE5847', 'Var', (270, 277))	('GSE6532', 'Chemical', '-', (230, 237))	('GSE7390', 'Chemical', '-', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))	('GSE2034', 'Var', (183, 190))	('CES', 'Disease', (25, 28))	('GSE1456', 'Var', (212, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('GSE1561', 'Chemical', '-', (249, 256))	('GSE6532', 'Var', (230, 237))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('GSE7390', 'Var', (258, 265))	('GSE11121', 'Var', (192, 200))	('GSE2034', 'Chemical', '-', (183, 190))	('GSE1456', 'Chemical', '-', (212, 219))
193519	27577169	For individual breast cancer and lung cancer data sets, Kaplan-Meier curves were generated for patients stratified into groups of high (upper tertile), intermediate (middle tertile) and low (lower tertile) CES values.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('low', 'Var', (186, 189))	('patients', 'Species', '9606', (95, 103))	('CES', 'Chemical', '-', (206, 209))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('lung cancer', 'Disease', (33, 44))
193540	27577169	Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy.	('Centromere', 'Gene', (0, 10))	('predicts', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient', 'Species', '9606', (62, 69))	('misexpression', 'Var', (32, 45))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
193615	22124624	Evaluation of the BOADICEA risk assessment model in women with a family history of breast cancer The ability of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model to predict BRCA1 and BRCA2 mutations and breast cancer incidence in women with a family history of breast cancer was evaluated.	('breast cancer', 'Disease', (256, 269))	('BRCA1', 'Gene', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (314, 327))	('women', 'Species', '9606', (283, 288))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('BRCA2', 'Gene', (236, 241))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Disease', 'MESH:D001943', (314, 327))	('women', 'Species', '9606', (52, 57))	('breast cancer', 'Disease', (314, 327))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('mutations', 'Var', (242, 251))	('BRCA2', 'Gene', '675', (236, 241))	('BRCA1', 'Gene', '672', (226, 231))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
193617	22124624	The ratios of observed to expected number of BRCA1- , BRCA2- and BRCA(1 or 2) mutations were 1.43 (95% CI 1.05-1.90), 0.63 (95% CI 0.34-1.08), and 1.12 (95% CI 0.86-1.44), showing a significant underestimation of BRCA1 mutations.	('BRCA1', 'Gene', (213, 218))	('BRCA1', 'Gene', '672', (45, 50))	('BRCA(1 or 2', 'Gene', '672;675', (65, 76))	('mutations', 'Var', (78, 87))	('BRCA2', 'Gene', (54, 59))	('BRCA1', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (54, 59))	('BRCA1', 'Gene', '672', (213, 218))
193620	22124624	In conclusion, the BOADICEA model can predict the total prevalence of BRCA(1 or 2) mutations and the incidence of invasive breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (123, 137))	('mutations', 'Var', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('BRCA(1 or 2', 'Gene', '672;675', (70, 81))	('invasive breast cancers', 'Disease', (114, 137))	('invasive breast cancers', 'Disease', 'MESH:D001943', (114, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
193624	22124624	The procedure involves investigation of family history, if indicated, BRCA1 and BRCA2 mutation screening and estimation of and information on cancer risk.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('BRCA2', 'Gene', (80, 85))	('BRCA1', 'Gene', '672', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BRCA1', 'Gene', (70, 75))	('BRCA2', 'Gene', '675', (80, 85))	('mutation', 'Var', (86, 94))	('cancer', 'Disease', (142, 148))
193630	22124624	BOADICEA's prediction of BRCA1 and BRCA2 mutations in different populations has been investigated in several studies and found to perform similarly or better than other risk assessment tools.	('mutations', 'Var', (41, 50))	('BRCA1', 'Gene', '672', (25, 30))	('BRCA2', 'Gene', '675', (35, 40))	('men', 'Species', '9606', (180, 183))	('BRCA1', 'Gene', (25, 30))	('BRCA2', 'Gene', (35, 40))
193631	22124624	The frequencies of BRCA1 and BRCA2 mutations in Sweden are likely to differ from the default values given by the model due to the presence of several BRCA1 founder mutations.	('BRCA1', 'Gene', (150, 155))	('BRCA2', 'Gene', (29, 34))	('BRCA1', 'Gene', '672', (19, 24))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA1', 'Gene', '672', (150, 155))	('BRCA1', 'Gene', (19, 24))	('mutations', 'Var', (35, 44))
193637	22124624	The present aims were to investigate BOADICEA's ability to predict BRCA1 and BRCA2 mutations, and its ability to predict breast cancer within a specified observation period, in a cohort of Swedish women.	('mutations', 'Var', (83, 92))	('women', 'Species', '9606', (197, 202))	('BRCA2', 'Gene', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BRCA1', 'Gene', '672', (67, 72))	('breast cancer', 'Disease', (121, 134))	('BRCA2', 'Gene', '675', (77, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('BRCA1', 'Gene', (67, 72))
193640	22124624	Earliest age for initializing breast controls was either 10 years before the youngest age of breast cancer onset in respective family, or from 25 years of age in families with a known BRCA1 or BRCA2 mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('BRCA2', 'Gene', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA1', 'Gene', '672', (184, 189))	('mutation', 'Var', (199, 207))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('BRCA2', 'Gene', '675', (193, 198))	('BRCA1', 'Gene', (184, 189))
193644	22124624	Most of the women had been included in a prospective study on breast cancer diagnostic methods (PSDM) including mammography, ultrasound and, in the case of BRCA1 or BRCA2 mutation carriers, breast magnetic resonance imaging.	('BRCA2', 'Gene', '675', (165, 170))	('women', 'Species', '9606', (12, 17))	('mutation', 'Var', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRCA1', 'Gene', '672', (156, 161))	('BRCA2', 'Gene', (165, 170))	('BRCA1', 'Gene', (156, 161))
193653	22124624	The non optional values of mutation frequencies were for BRCA1 0.0006394 and for BRCA2 0.00102.	('BRCA1', 'Gene', (57, 62))	('0.0006394', 'Var', (63, 72))	('BRCA2', 'Gene', (81, 86))	('BRCA1', 'Gene', '672', (57, 62))	('BRCA2', 'Gene', '675', (81, 86))	('0.00102', 'Var', (87, 94))
193659	22124624	The remaining 263 individuals (representing 263 distinct families) were included, regardless of screening result, for the retrospective calculation of mutation probabilities prior to BRCA1 and BRCA2 mutation screening.	('BRCA2', 'Gene', (193, 198))	('mutation', 'Var', (199, 207))	('BRCA1', 'Gene', '672', (183, 188))	('BRCA2', 'Gene', '675', (193, 198))	('BRCA1', 'Gene', (183, 188))
193678	22124624	The overall accuracy in terms of the expected number of BRCA1 and BRCA2 mutation carriers, and of incidental breast cancers (first or contralateral), was evaluated by calculating the ratio of the observed and expected number of events.	('BRCA2', 'Gene', (66, 71))	('breast cancers', 'Disease', 'MESH:D001943', (109, 123))	('breast cancers', 'Disease', (109, 123))	('BRCA1', 'Gene', '672', (56, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('BRCA2', 'Gene', '675', (66, 71))	('BRCA1', 'Gene', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutation', 'Var', (72, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (109, 123))
193680	22124624	The expected numbers of BRCA1-, BRCA2-, and BRCA(1 or 2) mutations were 33, 21 and 54 respectively.	('BRCA1', 'Gene', '672', (24, 29))	('BRCA2', 'Gene', (32, 37))	('BRCA1', 'Gene', (24, 29))	('mutations', 'Var', (57, 66))	('BRCA2', 'Gene', '675', (32, 37))	('BRCA(1 or 2', 'Gene', '672;675', (44, 55))
193681	22124624	The observed numbers were 47 BRCA1- and 13 BRCA2 mutations, altogether 60 BRCA(1 or 2) mutations.	('BRCA(1 or 2', 'Gene', '672;675', (74, 85))	('mutations', 'Var', (49, 58))	('BRCA1', 'Gene', '672', (29, 34))	('BRCA2', 'Gene', (43, 48))	('BRCA2', 'Gene', '675', (43, 48))	('BRCA1', 'Gene', (29, 34))
193682	22124624	The ratios of observed to expected numbers of mutations were 1.43, 0.63 and 1.12 for BRCA1-, BRCA2-, and BRCA(1 or 2) respectively.	('mutations', 'Var', (46, 55))	('BRCA1', 'Gene', (85, 90))	('BRCA2', 'Gene', '675', (93, 98))	('BRCA(1 or 2', 'Gene', '672;675', (105, 116))	('BRCA1', 'Gene', '672', (85, 90))	('BRCA2', 'Gene', (93, 98))
193683	22124624	The ratios demonstrated that the number of BRCA2 mutations and the total number of BRCA1 and BRCA2 mutations could be predicted by the model, whereas the specific number of BRCA1 mutations was significantly underestimated (Table 1).	('BRCA1', 'Gene', '672', (83, 88))	('mutations', 'Var', (49, 58))	('BRCA2', 'Gene', '675', (93, 98))	('BRCA1', 'Gene', '672', (173, 178))	('BRCA1', 'Gene', (83, 88))	('mutations', 'Var', (99, 108))	('BRCA2', 'Gene', (43, 48))	('BRCA2', 'Gene', '675', (43, 48))	('BRCA1', 'Gene', (173, 178))	('BRCA2', 'Gene', (93, 98))
193697	22124624	The model's ability to predict BRCA1 and BRCA2 mutations has previously been investigated in several different populations here exemplified by 195 French-Canadian families and 1934 British families.	('BRCA2', 'Gene', (41, 46))	('BRCA1', 'Gene', '672', (31, 36))	('BRCA2', 'Gene', '675', (41, 46))	('mutations', 'Var', (47, 56))	('BRCA1', 'Gene', (31, 36))
193698	22124624	The model's prediction of the total number of BRCA1 and BRCA2 mutations among the 263 individuals that had been screened for mutations was close to the observed number.	('BRCA2', 'Gene', '675', (56, 61))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA1', 'Gene', (46, 51))	('BRCA2', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
193700	22124624	The model performed worse in predicting the respective numbers of BRCA1 and BRCA2 mutations, which was to be expected since its pre-set values corresponded to mutation frequencies in the UK.	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', (76, 81))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (76, 81))	('mutations', 'Var', (82, 91))
193701	22124624	In Sweden BRCA1 mutations are more frequent than BRCA2 mutations due to several well-known BRCA1-founder mutations, the opposite from the situation in the UK.	('BRCA1', 'Gene', (91, 96))	('BRCA1', 'Gene', '672', (10, 15))	('BRCA2', 'Gene', '675', (49, 54))	('mutations', 'Var', (16, 25))	('BRCA1', 'Gene', (10, 15))	('BRCA1', 'Gene', '672', (91, 96))	('BRCA2', 'Gene', (49, 54))
193703	22124624	According to the model's homepage, other planned improvements are the addition of mutations in other breast cancer susceptibility genes such as TP53, ATM, CHEK2, PALB2, BRIP1, FGFR2, TNRC9 and MAP3K1.	('MAP3K1', 'Gene', '4214', (193, 199))	('TNRC9', 'Gene', '27324', (183, 188))	('CHEK2', 'Gene', (155, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('TP53', 'Gene', '7157', (144, 148))	('FGFR2', 'Gene', (176, 181))	('ATM', 'Gene', (150, 153))	('BRIP1', 'Gene', (169, 174))	('CHEK2', 'Gene', '11200', (155, 160))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('PALB2', 'Gene', (162, 167))	('FGFR2', 'Gene', '2263', (176, 181))	('men', 'Species', '9606', (56, 59))	('PALB2', 'Gene', '79728', (162, 167))	('TP53', 'Gene', (144, 148))	('TNRC9', 'Gene', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (82, 91))	('BRIP1', 'Gene', '83990', (169, 174))	('ATM', 'Gene', '472', (150, 153))	('MAP3K1', 'Gene', (193, 199))
193704	22124624	The present evaluation of the models ability to predict BRCA1 and BRCA2 mutations was based on data that was collected before BOADICEA was in use.	('BRCA2', 'Gene', (66, 71))	('mutations', 'Var', (72, 81))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA2', 'Gene', '675', (66, 71))	('BRCA1', 'Gene', (56, 61))
193712	22124624	For example, the BRCA1 mutation frequency found in the present cohort was higher than predicted by the model.	('higher', 'PosReg', (74, 80))	('BRCA1', 'Gene', (17, 22))	('BRCA1', 'Gene', '672', (17, 22))	('mutation', 'Var', (23, 31))
193714	22124624	In addition, BOADICEA performed better in predicting BRCA1 and BRCA2 mutations when larger pedigrees were used although including uncertain data made the model perform worse.	('mutations', 'Var', (69, 78))	('BRCA2', 'Gene', '675', (63, 68))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA2', 'Gene', (63, 68))	('BRCA1', 'Gene', (53, 58))
193742	22124624	Likewise, the model's ability to predict ovarian cancer could not be evaluated since 18 of the 36 women that were known BRCA1 or BRCA2 mutation carriers at the start of observation underwent salpingo-oophorectomy prior to or during the observation period.	('ovarian cancer', 'Disease', (41, 55))	('BRCA1', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('BRCA2', 'Gene', (129, 134))	('women', 'Species', '9606', (98, 103))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('carriers', 'Reg', (144, 152))	('BRCA2', 'Gene', '675', (129, 134))	('BRCA1', 'Gene', '672', (120, 125))	('mutation', 'Var', (135, 143))
193814	31527531	Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire.	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('inflammation', 'Disease', (90, 102))	('Genetic changes', 'Var', (0, 15))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
193844	31527531	Given the appropriate conditions, leukocyte activation initiated by mutated cells can advance neoplastic transformations into malignant tumour cells.	('advance', 'PosReg', (86, 93))	('malignant tumour', 'Disease', 'MESH:D009369', (126, 142))	('mutated', 'Var', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('malignant tumour', 'Disease', (126, 142))
193850	31527531	Modifications to tumour cells can allow them to ultimately employ immunosuppressive mechanisms, thus evading and essentially escaping the immune system in the final phase.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('escaping', 'NegReg', (125, 133))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('tumour', 'Disease', (17, 23))	('Modifications', 'Var', (0, 13))
193857	31527531	In TNBC and HER2+ disease in particular, the presence of TILs has been shown to correlate with a good prognosis and good response to chemotherapy.	('TNBC', 'Disease', (3, 7))	('HER2', 'Gene', (12, 16))	('HER2', 'Gene', '2064', (12, 16))	('presence', 'Var', (45, 53))
193891	31527531	Retrospective studies of preserved human tumours have demonstrated that M2 macrophages are significantly associated with poor prognosis in both ER- and ER+ tumours.	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('M2 macrophages', 'Var', (72, 86))	('tumours', 'Disease', (156, 163))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('human', 'Species', '9606', (35, 40))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('ER-', 'Disease', (144, 147))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
193905	31527531	Additionally, antibodies can signal to other cancer-killing cells that they are bound to a tumour cell, thereby activating them to eliminate tumour cell populations.	('antibodies', 'Var', (14, 24))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('eliminate', 'NegReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', (91, 97))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (141, 147))	('cancer', 'Disease', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('activating', 'PosReg', (112, 122))
193937	31527531	There are significantly more CTLs in DCIS expressing granzyme B and IFNgamma, marking these cells as activated, effector cytotoxic T cells.	('granzyme B', 'Gene', '3002', (53, 63))	('CTLs', 'Var', (29, 33))	('IFNgamma', 'Gene', (68, 76))	('granzyme B', 'Gene', (53, 63))	('IFNgamma', 'Gene', '3458', (68, 76))	('DCIS', 'Disease', (37, 41))	('DCIS', 'Disease', 'MESH:D002285', (37, 41))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))
193946	31527531	They have not yet assessed TIL numbers in ADH compared to the normal breast, but have shown that ADH lesions exhibit aneuploidy, loss of heterozygosity, gross chromosomal rearrangement (such as amplifications and large-scale deletion) and methylation changes.	('heterozygosity', 'MPA', (137, 151))	('loss', 'NegReg', (129, 133))	('aneuploidy', 'Disease', 'MESH:D000782', (117, 127))	('methylation changes', 'CPA', (239, 258))	('gross chromosomal rearrangement', 'CPA', (153, 184))	('amplifications', 'Var', (194, 208))	('ADH', 'Gene', (97, 100))	('aneuploidy', 'Disease', (117, 127))
194147	28013533	We retrospectively evaluated the pathologic response after NAC in 353 breast cancer patients and compared the prognoses after applying the following different definitions of pCR: ypT0/is, ypT0, ypT0/is ypN0, and ypT0 ypN0.	('NAC', 'Chemical', '-', (59, 62))	('patients', 'Species', '9606', (84, 92))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('ypT0/is ypN0', 'Var', (194, 206))	('breast cancer', 'Disease', (70, 83))	('ypT0/is', 'Var', (179, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('ypT0', 'Var', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ypT0 ypN0', 'Var', (212, 221))
194148	28013533	Presence of tumor deposits of any size in the lymph nodes (LNs; ypN >= 0(i+)) was associated with worse DDFS (ypT0 ypN0 vs ypT0 ypN >= 0(i+), p = .036 and ypT0/is ypN0 vs ypT0/is ypN >= 0(i+), p = .015), and presence of isolated tumor cells was associated with decreased overall survival (OS; ypT0/is ypN0 vs ypT0/is ypN0(i+), p = .013).	('tumor deposits', 'Disease', (12, 26))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('OS', 'Chemical', '-', (289, 291))	('decreased', 'NegReg', (261, 270))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (229, 234))	('DDFS', 'MPA', (104, 108))	('ypT0/is', 'Var', (155, 162))	('overall survival', 'MPA', (271, 287))	('tumor', 'Disease', (12, 17))	('tumor deposits', 'Disease', 'MESH:D000079822', (12, 26))
194149	28013533	Residual ductal carcinoma in situ regardless of LN status showed no significant difference in DDFS or OS (DDFS: ypT0 vs ypTis, p = .373 and ypT0 ypN0 vs ypTis ypN0, p = .462; OS: ypT0 vs ypTis, p = .441 and ypT0 ypN0 vs ypTis ypN0, p = .758).	('OS', 'Chemical', '-', (102, 104))	('OS', 'Chemical', '-', (175, 177))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (9, 33))	('ypT0', 'Var', (207, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (9, 33))	('ductal carcinoma in situ', 'Disease', (9, 33))
194150	28013533	In subsequent analysis using ypT0/is ypN0, pCR was associated with improved DDFS and OS in triple-negative tumors (p < .001 and p = .003, respectively).	('pCR', 'Var', (43, 46))	('OS', 'Chemical', '-', (85, 87))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('DDFS', 'CPA', (76, 80))	('improved', 'PosReg', (67, 75))
194155	28013533	The NSABP B-18 trials showed that patients with ypT0/is had a better 5-year disease-free survival than patients with residual invasive disease in the breast, and several subsequent trials employed ypT0/is as the primary endpoint.	('disease-free survival', 'CPA', (76, 97))	('better', 'PosReg', (62, 68))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (103, 111))	('ypT0/is', 'Var', (48, 55))
194159	28013533	Conversly, in the trials by the German Breast Group and Arbeits gemeinschaft Gynakologische Onkologie-Breast Group (GBG and AGO-B), patients with ypTis ypN0 had a worse event-free survival than patients with ypT0 ypN0.	('patients', 'Species', '9606', (194, 202))	('ypN0', 'Var', (152, 156))	('Arbeits gemeinschaft Gynakologische', 'Disease', (56, 91))	('worse', 'NegReg', (163, 168))	('Arbeits gemeinschaft Gynakologische', 'Disease', 'None', (56, 91))	('event-free survival', 'CPA', (169, 188))	('ypTis ypN0', 'Var', (146, 156))	('patients', 'Species', '9606', (132, 140))
194160	28013533	However, the analysis conducted at MD Anderson Cancer Center showed no difference in survival between patients with ypT0 ypTN0 and ypTis ypTN0.	('ypTis', 'Var', (131, 136))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (102, 110))	('ypT0 ypTN0', 'Var', (116, 126))
194193	28013533	HRs for DDFS and OS increased sequentially as follows: ypT0/is, ypT0, ypT0/is ypN0, and ypT0 ypN0 (Table 2).	('ypT0 ypN0', 'Var', (88, 97))	('ypT0/is ypN0', 'Var', (70, 82))	('OS', 'Chemical', '-', (17, 19))	('ypT0/is', 'Var', (55, 62))
194196	28013533	The 5-year OS for patients with ypT0 ypN>=0(i+) and ypT0/is ypN>=0(i+) (88.9% and 86.5%, respectively) appeared worse than for patients with ypT0 ypN0 and ypT0/is ypN0 (97.4% and 93.2%, respectively), but the difference was not statistically significant (p=.236 and p=.095, respectively).	('ypT0/is ypN>=0', 'Var', (52, 66))	('OS', 'Chemical', '-', (11, 13))	('ypT0 ypN>=0', 'Var', (32, 43))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (18, 26))	('worse', 'NegReg', (112, 117))
194199	28013533	For DDFS, patients with ITCs in LNs tended to experience worse DDFS than patients with no tumor cells in the LNs (5-year DDFS: ypT0/is ypN0(i+), 80.0% vs ypT0/is ypN0, 89.0%; p=.336).	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('patients', 'Species', '9606', (73, 81))	('DDFS', 'MPA', (63, 67))	('patients', 'Species', '9606', (10, 18))	('ypT0/is ypN0', 'Var', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('worse', 'NegReg', (57, 62))
194209	28013533	Regarding OS, however, patients with pCR when ypT0/is and ypT0/is ypN0 were used as pCR definitions showed significantly better survival than patients without pCR (Fig.	('ypT0/is ypN0', 'Var', (58, 70))	('ypT0/is', 'Var', (46, 53))	('OS', 'Chemical', '-', (10, 12))	('patients', 'Species', '9606', (23, 31))	('better', 'PosReg', (121, 127))	('survival', 'CPA', (128, 136))	('patients', 'Species', '9606', (142, 150))
194212	28013533	Our study showed that patients with ITCs in the LNs might have poorer OS than patients with no tumor cells in the LNs.	('OS', 'Chemical', '-', (70, 72))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (78, 86))	('poorer', 'NegReg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ITCs', 'Var', (36, 40))	('tumor', 'Disease', (95, 100))
194213	28013533	Theoretically, ypT0 ypN0 represents the strictest definition of pCR, meaning complete eradication of all tumor cells in both the breast and LNs.	('eradication', 'NegReg', (86, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('ypT0 ypN0', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
194224	26497122	Mutations in components of the PI3K pathway were found in all infiltrating epitheliosis samples, seven of which harbored PIK3CA hotspot mutations, while the remaining case displayed a PIK3R1 somatic mutation.	('PIK3R1', 'Gene', (184, 190))	('epitheliosis', 'Disease', (75, 87))	('PIK3R1', 'Gene', '5295', (184, 190))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (121, 127))	('mutations', 'Var', (136, 145))	('epitheliosis', 'Disease', 'None', (75, 87))	('PIK3CA', 'Gene', '5290', (121, 127))	('PI3K pathway', 'Pathway', (31, 43))	('found', 'Reg', (49, 54))
194237	26497122	From a genetic standpoint, RS/CSLs have been shown to harbor PIK3CA activating mutations in 63.6%, and these were more prevalent when epithelial atypia was superimposed (56.3% versus 83.3%).	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('activating', 'PosReg', (68, 78))	('CSL', 'Gene', (30, 33))	('CSL', 'Gene', '3516', (30, 33))	('mutations', 'Var', (79, 88))
194238	26497122	Activating PIK3CA mutations, the second most frequently mutated gene in breast cancer, have also been documented in papillomas, columnar cell lesions and UDH, and it has been hypothesized that PIK3CA mutations may be more relevant for proliferation than for malignant transformation in breast epithelium.	('Activating', 'PosReg', (0, 10))	('PIK3CA', 'Gene', '5290', (193, 199))	('papillomas', 'Phenotype', 'HP:0012740', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('columnar cell lesions', 'Disease', (128, 149))	('papilloma', 'Phenotype', 'HP:0012740', (116, 125))	('UDH', 'Disease', (154, 157))	('PIK3CA', 'Gene', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('papillomas', 'Disease', (116, 126))	('papillomas', 'Disease', 'MESH:D010212', (116, 126))	('PIK3CA', 'Gene', '5290', (11, 17))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('UDH', 'Chemical', '-', (154, 157))	('PIK3CA', 'Gene', (193, 199))	('mutations', 'Var', (18, 27))
194254	26497122	Sample 02-UDH, as the DNA extracted was insufficient for MPS, was screened for PIK3CA mutations in the frequently mutated exons 7, 9 and 20 (Supplementary Table 3).	('mutations', 'Var', (86, 95))	('insufficient', 'Disease', (40, 52))	('UDH', 'Chemical', '-', (10, 13))	('PIK3CA', 'Gene', (79, 85))	('MPS', 'Disease', 'MESH:D009084', (57, 60))	('PIK3CA', 'Gene', '5290', (79, 85))	('insufficient', 'Disease', 'MESH:D000309', (40, 52))	('MPS', 'Disease', (57, 60))
194276	26497122	To characterize the repertoire of somatic mutations in the genes most frequently mutated in breast cancer or associated with DNA repair, we performed targeted capture MPS from microdissected IEs, adjacent breast lesions and matched normal tissue to a median read depth of 586x (range 207x-1237x).	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('MPS', 'Disease', (167, 170))	('MPS', 'Disease', 'MESH:D009084', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('IEs', 'Chemical', 'MESH:D015019', (191, 194))	('mutations', 'Var', (42, 51))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
194277	26497122	We identified somatic non-synonymous mutations in the phosphatidyl inositol 3-kinase (PI3K) family in all IEs studied (PIK3CA, n=7 and PIK3R1, n=1; Figure 5 and Supplementary Table 4), which were validated by Sanger sequencing in the corresponding IEs and adjacent lesions (Supplementary Figure 1).	('PIK3CA', 'Gene', (119, 125))	('phosphatidyl inositol 3-kinase', 'Gene', (54, 84))	('IEs', 'Chemical', 'MESH:D015019', (106, 109))	('PIK3CA', 'Gene', '5290', (119, 125))	('PIK3R1', 'Gene', '5295', (135, 141))	('phosphatidyl inositol 3-kinase', 'Gene', '5290', (54, 84))	('PIK3R1', 'Gene', (135, 141))	('IEs', 'Chemical', 'MESH:D015019', (248, 251))	('non-synonymous mutations', 'Var', (22, 46))	('PI3K', 'Gene', (86, 90))
194278	26497122	Specifically, of the seven IEs with PIK3CA mutations, six and one harbored the hotspot H1047R and E542K mutations, respectively.	('H1047R', 'Var', (87, 93))	('PIK3CA', 'Gene', '5290', (36, 42))	('IEs', 'Chemical', 'MESH:D015019', (27, 30))	('H1047R', 'Mutation', 'rs121913279', (87, 93))	('E542K', 'Var', (98, 103))	('mutations', 'Var', (43, 52))	('PIK3CA', 'Gene', (36, 42))	('E542K', 'Mutation', 'rs121913273', (98, 103))
194279	26497122	The only IE lacking a PIK3CA mutation (case 9) harbored a PIK3R1 (L380del) small deletion.	('PIK3R1', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (22, 28))	('L380del', 'Mutation', 'p.380delL', (66, 73))	('PIK3R1', 'Gene', '5295', (58, 64))	('L380del', 'Var', (66, 73))	('PIK3CA', 'Gene', (22, 28))
194280	26497122	Targeted capture MPS analysis of the DNA samples obtained from lesions adjacent to IEs revealed that in case 3, the IE, DCIS and LGASC harbored identical PIK3CA (H1047R) and SF3B1 (K700E) hotspot mutations, suggesting that these lesions are clonally related, and that IE and DCIS may have constituted the substrate for the development of the LGASC.	('H1047R', 'Var', (162, 168))	('MPS', 'Disease', (17, 20))	('PIK3CA', 'Gene', (154, 160))	('SF3B1', 'Gene', (174, 179))	('IEs', 'Chemical', 'MESH:D015019', (83, 86))	('PIK3CA', 'Gene', '5290', (154, 160))	('SF3B1', 'Gene', '23451', (174, 179))	('K700E', 'Mutation', 'rs559063155', (181, 186))	('H1047R', 'Mutation', 'rs121913279', (162, 168))	('MPS', 'Disease', 'MESH:D009084', (17, 20))	('K700E', 'Var', (181, 186))
194281	26497122	In case 7, both the IE and the papilloma contained an identical PIK3CA H1047R mutation with an additional ERBB3 mutation found in one of the two IE samples (Supplementary Table 4, Supplementary Figure 2).	('PIK3CA', 'Gene', (64, 70))	('H1047R', 'Var', (71, 77))	('ERBB3', 'Gene', (106, 111))	('papilloma', 'Phenotype', 'HP:0012740', (31, 40))	('papilloma', 'Disease', (31, 40))	('papilloma', 'Disease', 'MESH:D010212', (31, 40))	('PIK3CA', 'Gene', '5290', (64, 70))	('H1047R', 'Mutation', 'rs121913279', (71, 77))	('ERBB3', 'Gene', '2065', (106, 111))
194282	26497122	The UDH component of case 2 did not harbor the PIK3CA H1047R mutation found in the IE; instead a PIK3CA C420K mutation was found in this lesion (Supplementary Figure 1), suggesting that the respective IE and UDH were unlikely to be clonally related and providing an example of a convergent phenotype in the development of these lesions, given that the PI3K pathway was activated through distinct somatic genetic alterations.	('PIK3CA', 'Gene', (47, 53))	('C420K', 'Var', (104, 109))	('UDH', 'Chemical', '-', (4, 7))	('PI3K pathway', 'Pathway', (352, 364))	('PIK3CA', 'Gene', '5290', (47, 53))	('C420K', 'SUBSTITUTION', 'None', (104, 109))	('H1047R', 'Var', (54, 60))	('UDH', 'Chemical', '-', (208, 211))	('PIK3CA', 'Gene', (97, 103))	('H1047R', 'Mutation', 'rs121913279', (54, 60))	('PIK3CA', 'Gene', '5290', (97, 103))
194289	26497122	Using targeted capture MPS, bona fide oncogenic PIK3CA or PIK3R1 mutations were identified in all IEs, suggesting that these lesions are neoplastic rather than hyperplastic and that the PI3K pathway is involved in IE pathogenesis.	('IEs', 'Chemical', 'MESH:D015019', (98, 101))	('PIK3R1', 'Gene', (58, 64))	('PIK3R1', 'Gene', '5295', (58, 64))	('PIK3CA', 'Gene', (48, 54))	('MPS', 'Disease', 'MESH:D009084', (23, 26))	('PIK3CA', 'Gene', '5290', (48, 54))	('MPS', 'Disease', (23, 26))	('mutations', 'Var', (65, 74))
194290	26497122	where >60% of RSs contained PIK3CA activating mutations, and supports the contention that RS and IE are related, where IE may represent the most proliferative end of this spectrum of lesions.	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (28, 34))	('RSs', 'Chemical', '-', (14, 17))	('activating', 'PosReg', (35, 45))	('PIK3CA', 'Gene', '5290', (28, 34))
194291	26497122	The PI3K pathway, which plays pivotal roles in cell survival, proliferation, and migration, is altered in 25-50% of breast carcinomas, in particular low-grade, ER-positive carcinomas and their precursors.	('breast carcinomas', 'Disease', 'MESH:D001943', (116, 133))	('breast carcinomas', 'Disease', (116, 133))	('carcinomas', 'Disease', (123, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('carcinomas', 'Disease', (172, 182))	('carcinomas', 'Disease', 'MESH:D002277', (172, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('breast carcinomas', 'Phenotype', 'HP:0003002', (116, 133))	('ER-positive', 'Var', (160, 171))	('altered', 'Reg', (95, 102))	('PI3K pathway', 'Pathway', (4, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('carcinomas', 'Disease', 'MESH:D002277', (123, 133))
194294	26497122	Targeted capture MPS revealed that in one patient, the ER-negative/ CK5/6-positive IE, DCIS and LGASC harbored identical hotspot mutations affecting PIK3CA and SF3B1.	('SF3B1', 'Gene', (160, 165))	('MPS', 'Disease', (17, 20))	('mutations', 'Var', (129, 138))	('SF3B1', 'Gene', '23451', (160, 165))	('PIK3CA', 'Gene', '5290', (149, 155))	('patient', 'Species', '9606', (42, 49))	('PIK3CA', 'Gene', (149, 155))	('CK5/6', 'Gene', '3852', (68, 73))	('MPS', 'Disease', 'MESH:D009084', (17, 20))	('CK5/6', 'Gene', (68, 73))
194299	26497122	Targeted capture MPS revealed recurrent mutations affecting the PI3K pathway in all IEs; together with the histologic characteristics of these lesions, these genetic findings support the contention that these lesions are clonal and neoplastic.	('MPS', 'Disease', (17, 20))	('PI3K pathway', 'Pathway', (64, 76))	('mutations', 'Var', (40, 49))	('MPS', 'Disease', 'MESH:D009084', (17, 20))	('IEs', 'Chemical', 'MESH:D015019', (84, 87))
194320	18787417	They often demonstrate microinvasion, and are characterized by greater chromosome aneuploidy, higher proliferation rates and more frequent Her2/neu gene amplification or protein overexpression compared to non-comedo lesions.	('aneuploidy', 'Disease', 'MESH:D000782', (82, 92))	('amplification', 'Var', (153, 166))	('Her2/neu', 'Gene', '2064', (139, 147))	('greater', 'PosReg', (63, 70))	('overexpression', 'PosReg', (178, 192))	('comedo', 'Phenotype', 'HP:0025249', (209, 215))	('Her2/neu', 'Gene', (139, 147))	('protein', 'Protein', (170, 177))	('proliferation rates', 'CPA', (101, 120))	('aneuploidy', 'Disease', (82, 92))	('higher', 'PosReg', (94, 100))	('microinvasion', 'CPA', (23, 36))
194322	18787417	Mitochondria regulate cell death in response to growth factor withdrawal, DNA damage, hypoxia or oncogene deregulation and is critical for p53 dependent apoptosis.	('oncogene', 'Gene', (97, 105))	('hypoxia', 'Disease', (86, 93))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('cell death', 'CPA', (22, 32))	('deregulation', 'Var', (106, 118))
194383	18787417	Interestingly, immunostaining with antibody specific to cleaved PARP revealed cleaved PARP-positive myoepithelial nuclei in solid DCIS (Fig.	('PARP', 'Gene', (64, 68))	('myoepithelial', 'Disease', (100, 113))	('PARP', 'Gene', '142', (86, 90))	('myoepithelial', 'Disease', 'MESH:D009208', (100, 113))	('solid DCIS', 'Disease', (124, 134))	('PARP', 'Gene', '142', (64, 68))	('PARP', 'Gene', (86, 90))	('cleaved', 'Var', (78, 85))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
194390	18787417	Since several cleaved PARP- (Fig.	('PARP', 'Gene', (22, 26))	('cleaved', 'Var', (14, 21))	('PARP', 'Gene', '142', (22, 26))
194391	18787417	4A, part d, long arrow) and p63-positive cells juxtaposed to the myoepithelial layer were also observed in MCF10DCIS.com xenografts (Fig.	('myoepithelial', 'Disease', (65, 78))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('myoepithelial', 'Disease', 'MESH:D009208', (65, 78))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (107, 120))	('p63', 'Gene', (28, 31))	('p63', 'Gene', '8626', (28, 31))	('MCF10DCIS.com', 'Var', (107, 120))
194417	18787417	The noninvolvement of caspase-8 in apoptotic processing is not due to insufficient levels of caspase-8 as significant amounts of procaspase-8 p55 and p53 forms were detected in MCF10DCIS.com cells undergoing apoptosis.	('caspase-8', 'Gene', '841', (22, 31))	('MCF10DCIS.com', 'Var', (177, 190))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('caspase-8', 'Gene', (93, 102))	('p55', 'Gene', (142, 145))	('p53', 'Gene', (150, 153))	('caspase-8', 'Gene', (132, 141))	('caspase-8', 'Gene', '841', (93, 102))	('p53', 'Gene', '7157', (150, 153))	('caspase-8', 'Gene', (22, 31))	('caspase-8', 'Gene', '841', (132, 141))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (177, 190))	('p55', 'Gene', '347376', (142, 145))
194418	18787417	Our data from Western blot analysis of cell lysates prepared from MCF10DCIS.com monolayers are consistent with Mitocapture assays as an increase in mitochondrial membrane permeability of MCF10DCIS.com cells correlated with a dramatic drop in the Bcl-2/Bax ratio.	('MCF10DCIS.com', 'Var', (187, 200))	('Bax', 'Gene', (252, 255))	('DCIS', 'Phenotype', 'HP:0030075', (192, 196))	('drop', 'NegReg', (234, 238))	('Bcl-2', 'Gene', (246, 251))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (66, 79))	('Bcl-2', 'Gene', '596', (246, 251))	('Bax', 'Gene', '581', (252, 255))	('increase', 'PosReg', (136, 144))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (187, 200))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('mitochondrial membrane permeability', 'MPA', (148, 183))
194420	18787417	demonstrated translocation of p53 to mitochondria in irradiated thymocytes which resulted in increased permeabilization of the outer mitochondrial membrane by forming complexes with antiapoptotic Bcl-XL and Bcl-2 proteins and causing release of cytochrome c. It is interesting to note that spontaneous apoptosis of MCF10DCIS.com cells is associated with loss of p53 suggesting that mitochondrial permeabilization and downregulation of Bcl-2 occur independently of p53.	('downregulation', 'NegReg', (417, 431))	('loss', 'Var', (354, 358))	('p53', 'Gene', (362, 365))	('Bcl-2', 'Gene', (207, 212))	('cytochrome c', 'Gene', (245, 257))	('p53', 'Gene', '7157', (362, 365))	('Bcl-XL', 'Gene', '598', (196, 202))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('Bcl-2', 'Gene', (435, 440))	('Bcl-XL', 'Gene', (196, 202))	('Bcl-2', 'Gene', '596', (207, 212))	('Bcl-2', 'Gene', '596', (435, 440))	('p53', 'Gene', '7157', (464, 467))	('DCIS', 'Phenotype', 'HP:0030075', (320, 324))	('cytochrome c', 'Gene', '54205', (245, 257))	('p53', 'Gene', (464, 467))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (315, 328))
194421	18787417	Clinical comedo-DCIS, like MCF10DCIS.com cells, show a significant drop in Bcl-2 along with increase in mutant p53 levels.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('comedo', 'Phenotype', 'HP:0025249', (9, 15))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (27, 40))	('increase', 'PosReg', (92, 100))	('Bcl-2', 'Gene', (75, 80))	('Bcl-2', 'Gene', '596', (75, 80))	('drop', 'NegReg', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))
194435	18787417	Based on our findings, we propose that, compared with other DCIS subtypes, apoptotic cell losses in comedo-DCIS subtype may be a potential mechanism accounting for their increased proclivity of progressing to invasive cancer.	('apoptotic cell losses', 'CPA', (75, 96))	('comedo-DCIS', 'Var', (100, 111))	('invasive cancer', 'Disease', (209, 224))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('invasive cancer', 'Disease', 'MESH:D009362', (209, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('comedo', 'Phenotype', 'HP:0025249', (100, 106))	('DCIS', 'Phenotype', 'HP:0030075', (60, 64))
194508	23837653	The E-cadherin gene mutation is the major mechanism responsible for its inactivation in cancer cells and is associated with other carcinomas, such as hepatocellular carcinoma, diffuse-type gastric cancer, thyroid and colorectal cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutation', 'Var', (20, 28))	('colorectal cancer', 'Disease', (217, 234))	('gastric cancer', 'Disease', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hepatocellular carcinoma', 'Disease', (150, 174))	('carcinomas', 'Disease', 'MESH:D002277', (130, 140))	('thyroid', 'Disease', (205, 212))	('E-cadherin', 'Gene', '999', (4, 14))	('carcinomas', 'Disease', (130, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('E-cadherin', 'Gene', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', (228, 234))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Disease', (197, 203))	('inactivation', 'NegReg', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('associated', 'Reg', (108, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('thyroid', 'Disease', 'MESH:D013959', (205, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
194509	23837653	Another route resulting in inactivation of E-cadherin is attributed to dysfunctional promoter activity or DNA methylation at the promoter region.	('inactivation', 'NegReg', (27, 39))	('dysfunctional', 'Var', (71, 84))	('E-cadherin', 'Gene', (43, 53))	('E-cadherin', 'Gene', '999', (43, 53))
194537	23837653	According to this classification CISM lesions are divided in three main groups, namely: (I) presence of necrosis, (II) cytology and / or mixed architecture, and (III) nuclear polymorphism.	('necrosis', 'Disease', (104, 112))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('CISM', 'Disease', (33, 37))	('nuclear polymorphism', 'Var', (167, 187))
194573	19995452	Our data suggest that concomitant methylation of RASSF1A and SFRP1 marks an early event in mammary transformation and may thus have prognostic potential.	('SFRP1', 'Gene', (61, 66))	('methylation', 'Var', (34, 45))	('RASSF1A', 'Gene', (49, 56))	('SFRP1', 'Gene', '6422', (61, 66))	('mammary', 'Disease', (91, 98))
194574	19995452	Oncogenic transformation arises from the accumulation of both genetic and epigenetic alterations that result in the activation of oncogenes and inactivation of tumor suppressor genes.	('inactivation', 'NegReg', (144, 156))	('epigenetic alterations', 'Var', (74, 96))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('oncogenes', 'Gene', (130, 139))	('activation', 'PosReg', (116, 126))	('Oncogenic transformation', 'CPA', (0, 24))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))
194578	19995452	This suggests that alterations in ras expression can occur early in the transformation process, and thus contribute to the initiation of tumorigenesis.	('tumor', 'Disease', (137, 142))	('expression', 'MPA', (38, 48))	('contribute', 'Reg', (105, 115))	('alterations', 'Var', (19, 30))	('ras', 'Protein', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
194579	19995452	Likewise, epigenetic alterations, including DNA methylation and chromatin structure changes, are among the earliest molecular abnormalities to occur during tumorigenesis.	('molecular abnormalities', 'Disease', 'MESH:C567116', (116, 139))	('DNA methylation', 'MPA', (44, 59))	('chromatin structure changes', 'CPA', (64, 91))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('epigenetic alterations', 'Var', (10, 32))	('tumor', 'Disease', (156, 161))	('molecular abnormalities', 'Disease', (116, 139))
194581	19995452	A recent survey of CpG island methylation using an array-based mapping technique revealed that one-third of CpG islands methylated in premalignant lesions are associated with members of various homeobox gene superfamilies, suggesting that methylation of homeobox genes is a frequent and early event in breast cancer.	('CpG', 'Gene', (108, 111))	('methylated', 'Var', (120, 130))	('methylation', 'Var', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('associated', 'Reg', (159, 169))	('breast cancer', 'Disease', 'MESH:D001943', (302, 315))	('breast cancer', 'Disease', (302, 315))	('breast cancer', 'Phenotype', 'HP:0003002', (302, 315))
194586	19995452	Moreover, when cultured in a serum-containing environment, vHMEC expressing oncogenic ras spontaneously immortalized, acquired the capacity for anchorage-independent growth, and exhibited de novo DNA methylation at several gene loci frequently methylated in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('anchorage-independent growth', 'CPA', (144, 172))	('breast cancer', 'Disease', (258, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('methylation', 'Var', (200, 211))
194587	19995452	Among the genes methylated, we identified a panel of four genes, two of which (RASSF1A and SFRP1), were also methylated in other immortalized mammary cell lines, suggesting that programs of epigenetic alterations mark early steps in the transformation process.	('SFRP1', 'Gene', '6422', (91, 96))	('SFRP1', 'Gene', (91, 96))	('epigenetic alterations', 'Var', (190, 212))
194588	19995452	Thus, these early epigenetic alterations may prove useful as biomarkers for early detection of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('epigenetic alterations', 'Var', (18, 40))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
194590	19995452	Initial experiments examining the effect of oncogenic ras on HMEC and vHMEC proliferation were conducted in cells isolated from five different individuals: RM48 (kindly provided by Martha Stampfer, Lawrence Berkeley National Laboratory, Berkeley, CA), RM13, RM15, RM18, and RM21 (cells derived in our laboratory).	('RM21', 'CellLine', 'CVCL:B459', (274, 278))	('RM21', 'Var', (274, 278))	('RM13', 'Var', (252, 256))	('RM18', 'Var', (264, 268))	('RM15', 'Var', (258, 262))	('RM48', 'Var', (156, 160))
194603	19995452	The mouse monoclonal antibody against beta-actin (#5441) was obtained from Sigma-Aldrich (St. Louis, MO, USA).	('mouse', 'Species', '10090', (4, 9))	('SA', 'Chemical', 'MESH:C012546', (106, 108))	('#5441', 'Var', (50, 55))	('beta-actin', 'Gene', '728378', (38, 48))	('beta-actin', 'Gene', (38, 48))
194616	19995452	One, four, or ten million cells expressing GFP-luciferase were injected directly into the surgically exposed #4 mammary fat pads of six to eight week old female SCID-Beige mice.	('SCID', 'Disease', (161, 165))	('GFP-luciferase', 'Var', (43, 57))	('SCID', 'Disease', 'MESH:D053632', (161, 165))	('mice', 'Species', '10090', (172, 176))
194623	19995452	Quantitative PCR (Taqman, Applied Biosystems, Inc., Foster City, CA, USA) was performed on cDNA using the standard curve method with primer/probe sets (Applied Biosystems, Inc.) for SFRP1 (Hs00610060_m1), RASSF1A (Hs00200394_m1), and MGMT (Hs01037698_m1).	('MGMT', 'Gene', (234, 238))	('SFRP1', 'Gene', '6422', (182, 187))	('SFRP1', 'Gene', (182, 187))	('SA', 'Chemical', 'MESH:C012546', (70, 72))	('Hs00610060_m1', 'Var', (189, 202))	('Hs00200394_m1', 'Var', (214, 227))	('MGMT', 'Gene', '4255', (234, 238))	('Hs01037698_m1', 'Var', (240, 253))
194641	19995452	Thus, under the experimental conditions tested, these cells were not tumorigenic, suggesting that additional alterations/mutations are required for complete transformation.	('tumor', 'Disease', (69, 74))	('alterations/mutations', 'Var', (109, 130))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
194648	19995452	These data suggest that concomitant DNA methylation of the RASSF1A and SFRP1 (exon 1) genes may play a role in the early steps of mammary transformation.	('SFRP1', 'Gene', (71, 76))	('role', 'Reg', (103, 107))	('RASSF1A', 'Gene', (59, 66))	('mammary transformation', 'CPA', (130, 152))	('DNA methylation', 'Var', (36, 51))	('SFRP1', 'Gene', '6422', (71, 76))	('play', 'Reg', (96, 100))
194649	19995452	In order to address this question further, we examined whether methylation of the RASSF1A and SFRP1 genes led to their silencing.	('silencing', 'MPA', (119, 128))	('SFRP1', 'Gene', '6422', (94, 99))	('methylation', 'Var', (63, 74))	('SFRP1', 'Gene', (94, 99))	('RASSF1A', 'Gene', (82, 89))
194655	19995452	Similarly, the SFRP1 locus was methylated in all 12 IDC, none of the vHMECs, and only one of the seven normal tissues.	('SFRP1', 'Gene', '6422', (15, 20))	('SFRP1', 'Gene', (15, 20))	('IDC', 'Disease', (52, 55))	('methylated', 'Var', (31, 41))
194657	19995452	Concomitant methylation of RASSF1A and SFRP1 appears to be targeted and specific as the p57 and MGMT gene loci were methylated in none or only one of the IDC analyzed, respectively, and in none of the vHMECs or normal tissues (Figure 6a).	('MGMT', 'Gene', '4255', (96, 100))	('p57', 'Gene', (88, 91))	('RASSF1A', 'Gene', (27, 34))	('SFRP1', 'Gene', '6422', (39, 44))	('p57', 'Gene', '1028', (88, 91))	('methylation', 'Var', (12, 23))	('MGMT', 'Gene', (96, 100))	('SFRP1', 'Gene', (39, 44))	('methylated', 'Var', (116, 126))
194663	19995452	In the DCIS samples, DNA methylation at the RASSF1A locus was observed in 9 of the 11 cases, and methylation of SFRP1 was observed in all 11 cases (Figure 6c and Table 3).	('observed', 'Reg', (62, 70))	('DCIS', 'Phenotype', 'HP:0030075', (7, 11))	('methylation', 'Var', (25, 36))	('SFRP1', 'Gene', '6422', (112, 117))	('RASSF1A', 'Gene', (44, 51))	('methylation', 'Var', (97, 108))	('SFRP1', 'Gene', (112, 117))
194665	19995452	Many studies have shown that oncogenic ras can cooperate with other oncogenic alterations as well as viral oncoproteins to transform primary human cells.	('human', 'Species', '9606', (141, 146))	('oncogenic', 'Var', (29, 38))	('transform', 'Reg', (123, 132))
194671	19995452	Two of these four genes, RASSF1A and SFRP1, were also methylated in four other immortalized mammary cell lines we examined, two of which were non-tumorigenic (184-A1 and MCF-10A), and two of which were tumorigenic (MCF-7 and MDA-231).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (202, 207))	('RASSF1A', 'Gene', (25, 32))	('MDA-231', 'CellLine', 'CVCL:0062', (225, 232))	('tumor', 'Disease', (146, 151))	('SFRP1', 'Gene', '6422', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MCF-10A', 'CellLine', 'CVCL:0598', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('SFRP1', 'Gene', (37, 42))	('MCF-7', 'CellLine', 'CVCL:0031', (215, 220))	('methylated', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
194677	19995452	Although these data need to be confirmed in a larger sample set, they strongly suggest that concomitant methylation of RASSF1A and SFRP1 marks an early event in mammary transformation and may thus have diagnostic and/or prognostic potential.	('SFRP1', 'Gene', '6422', (131, 136))	('mammary transformation', 'CPA', (161, 183))	('methylation', 'Var', (104, 115))	('SFRP1', 'Gene', (131, 136))	('RASSF1A', 'Gene', (119, 126))
194683	19995452	Like RASSF1A, SFRP1 has also been shown to be silenced through promoter methylation in breast cancer.	('promoter methylation', 'Var', (63, 83))	('SFRP1', 'Gene', '6422', (14, 19))	('silenced', 'NegReg', (46, 54))	('SFRP1', 'Gene', (14, 19))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
194685	19995452	Interestingly, we observed a correlation between SFRP1 DNA methylation and repression of its expression in all the cell lines we examined except the MCF-10A cells where both methylated and unmethylated DNA products were detected by MSP.	('SFRP1', 'Gene', '6422', (49, 54))	('MCF-10A', 'CellLine', 'CVCL:0598', (149, 156))	('methylation', 'Var', (59, 70))	('expression', 'MPA', (93, 103))	('repression', 'MPA', (75, 85))	('SFRP1', 'Gene', (49, 54))
194687	19995452	Although we detected DNA methylation in the first exon of SFRP1 in MCF-10A cells, previous studies by Lo et al., have demonstrated that the promoter region of SFRP1 is unmethylated in these cells.	('SFRP1', 'Gene', '6422', (159, 164))	('SFRP1', 'Gene', (58, 63))	('SFRP1', 'Gene', (159, 164))	('methylation', 'Var', (25, 36))	('MCF-10A', 'CellLine', 'CVCL:0598', (67, 74))	('SFRP1', 'Gene', '6422', (58, 63))
194691	19995452	While we observed DNA methylation in exon 1 of the SFRP1 gene in 100% of the DCIS and IDC samples we examined, methylation in the promoter region of SFRP1 has been reported to occur in approximately 68% of high-grade DCIS and invasive breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('invasive breast cancers', 'Disease', 'MESH:D001943', (226, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('SFRP1', 'Gene', '6422', (51, 56))	('SFRP1', 'Gene', '6422', (149, 154))	('breast cancers', 'Phenotype', 'HP:0003002', (235, 249))	('occur', 'Reg', (176, 181))	('SFRP1', 'Gene', (51, 56))	('invasive breast cancers', 'Disease', (226, 249))	('SFRP1', 'Gene', (149, 154))	('high-grade DCIS', 'Disease', (206, 221))	('methylation', 'Var', (111, 122))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))
194694	19995452	Methylation of the TWIST1 promoter may lead to the recruitment of chromatin remodeling proteins that can alter the function and/or expression of neighboring genes.	('lead to', 'Reg', (39, 46))	('recruitment', 'MPA', (51, 62))	('alter', 'Reg', (105, 110))	('Methylation', 'Var', (0, 11))	('expression', 'MPA', (131, 141))	('TWIST1', 'Gene', (19, 25))	('TWIST1', 'Gene', '7291', (19, 25))	('function', 'MPA', (115, 123))
194695	19995452	Alternatively, TWIST1 expression may be regulated by a balance between promoter and intragenic CpG methylation as there is evidence that intragenic CpG methylation can promote gene expression.	('TWIST1', 'Gene', '7291', (15, 21))	('methylation', 'Var', (152, 163))	('promote', 'PosReg', (168, 175))	('TWIST1', 'Gene', (15, 21))	('expression', 'MPA', (22, 32))	('gene expression', 'MPA', (176, 191))
194696	19995452	Thus, even though TWIST1 expression is not repressed by methylation, the compelling association between TWIST1 CpG methylation and malignancy makes it a useful biomarker for breast cancer diagnosis and prognosis.	('methylation', 'Var', (115, 126))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('TWIST1', 'Gene', (104, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('malignancy', 'Disease', (131, 141))	('TWIST1', 'Gene', (18, 24))	('TWIST1', 'Gene', '7291', (18, 24))	('TWIST1', 'Gene', '7291', (104, 110))
194697	19995452	Likewise, SFRP1 methylation in the first exon may be of significance despite the lack of methylation in the 5' promoter region, and the absence of gene silencing.	('SFRP1', 'Gene', (10, 15))	('methylation', 'MPA', (89, 100))	('methylation', 'Var', (16, 27))	('SFRP1', 'Gene', '6422', (10, 15))	('lack', 'NegReg', (81, 85))
194700	19995452	The accelerated accumulation of genetic and epigenetic events dictate their ability to bypass additional arrest signals allowing rare emergent subpopulations to immortalize, and grow in soft agar.	('epigenetic events', 'Var', (44, 61))	('agar', 'Chemical', 'MESH:D000362', (191, 195))	('ability', 'MPA', (76, 83))	('dictate', 'Reg', (62, 69))
194702	19995452	This model will thus allow further study of the mechanisms underlying the accumulation of epigenetic alterations that occur during progression to malignancy.	('epigenetic', 'Var', (90, 100))	('malignancy', 'Disease', (146, 156))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))
194716	27318854	The prevalence of DCIS in triple-negative IBC on the other hand was lowest.	('DCIS', 'Disease', (18, 22))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('IBC', 'Chemical', '-', (42, 45))	('IBC', 'Disease', (42, 45))	('triple-negative', 'Var', (26, 41))
194727	27318854	Reported frequencies of triple-negative pure DCIS on the other hand are lower than reported frequencies in IBC, 6-8 % in pure DCIS versus 11-13 % in IBC.	('pure DCIS', 'Disease', (40, 49))	('pure', 'Disease', (121, 125))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('triple-negative', 'Var', (24, 39))	('IBC', 'Chemical', '-', (107, 110))	('IBC', 'Chemical', '-', (149, 152))	('IBC', 'Disease', (107, 110))
194734	27318854	Regarding triple-negative DCIS, no firm conclusion could be drawn from the reported LRRs due to limited numbers of patients.	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('patients', 'Species', '9606', (115, 123))	('triple-negative', 'Var', (10, 25))	('DCIS', 'Disease', (26, 30))
194747	27318854	Clinicopathologic characteristics included age, type of surgical procedure (BCS or mastectomy), tumor size (<=2 cm, >2 to <=5 cm or >5 cm), histological type (according to WHO), grade (according to the modified Bloom and Richardson grading system), ER status, PR status, Her2 status, presence of angioinvasion, presence of DCIS, and nodal status.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ER', 'Gene', '2099', (249, 251))	('tumor', 'Disease', (96, 101))	('Her2', 'Gene', (271, 275))	('DCIS', 'Phenotype', 'HP:0030075', (323, 327))	('<=2', 'Var', (108, 111))	('PR', 'Gene', '5241', (260, 262))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Her2', 'Gene', '2064', (271, 275))
194767	27318854	Regarding the ER+/Her2- subgroups, the presence of a high PR expression was associated with more favorable tumor characteristics as compared to those cases with absence or low PR expression.	('PR', 'Gene', '5241', (58, 60))	('PR', 'Gene', '5241', (176, 178))	('high', 'Var', (53, 57))	('Her2', 'Gene', '2064', (18, 22))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ER', 'Gene', '2099', (14, 16))	('low PR', 'Phenotype', 'HP:0032198', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('Her2', 'Gene', (18, 22))
194772	27318854	There was a strong correlation between the presence of DCIS and breast cancer subtype (P < 0.0001).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('presence', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))	('DCIS', 'Gene', (55, 59))
194783	27318854	Briefly, Her2+ and triple-negative tumors are associated with younger age, larger size, and higher grade compared to luminal subtypes.	('triple-negative', 'Var', (19, 34))	('Her2', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Her2', 'Gene', '2064', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
194789	27318854	These findings are consistent with previous studies reporting a relatively high rate of Her2 positivity in pure DCIS cases, presence of extensive DCIS adjacent to Her2+ IBC, and a high LRR after BCS for Her2+ IBC.	('Her2', 'Gene', (163, 167))	('Her2', 'Gene', '2064', (203, 207))	('LRR', 'MPA', (185, 188))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('IBC', 'Chemical', '-', (209, 212))	('Her2', 'Gene', (88, 92))	('Her2', 'Gene', '2064', (163, 167))	('pure DCIS', 'Disease', (107, 116))	('positivity', 'Var', (93, 103))	('Her2', 'Gene', '2064', (88, 92))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('Her2', 'Gene', (203, 207))	('IBC', 'Chemical', '-', (169, 172))
194800	27318854	Her2+ IBC was associated with the highest prevalence and extent of DCIS, while on the other side of the spectrum, triple-negative IBC had the lowest prevalence of DCIS of all IBC subtypes.	('IBC', 'Chemical', '-', (130, 133))	('IBC', 'Chemical', '-', (175, 178))	('IBC', 'Chemical', '-', (6, 9))	('Her2', 'Gene', '2064', (0, 4))	('triple-negative', 'Var', (114, 129))	('Her2', 'Gene', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (163, 167))	('DCIS', 'Disease', (67, 71))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
194824	30697731	Accumulating evidence suggests that TBX3-mediated transcriptional repression of p14ARF 11, 17 and/or p21CIP1 16, 18 plays a role in driving cancer progression through bypassing cellular senescence.	('cellular senescence', 'CPA', (177, 196))	('TBX3', 'Gene', (36, 40))	('p21CIP1', 'Gene', '1026', (101, 108))	('TBX3', 'Gene', '6926', (36, 40))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('p14ARF 11', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('bypassing', 'NegReg', (167, 176))	('p21CIP1', 'Gene', (101, 108))
194841	30697731	Patients with early-stage breast cancer were identified from the London Breast Cancer Database on the basis of having either DCIS only (stage 0) or DCIS with an associated invasive component (stage I; <= 2 cm, and either pN0 or pN0mi).	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('Breast Cancer', 'Phenotype', 'HP:0003002', (72, 85))	('DCIS', 'Disease', (125, 129))	('invasive component', 'CPA', (172, 190))	('pN0', 'Var', (221, 224))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Breast Cancer', 'Disease', (72, 85))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('Breast Cancer', 'Disease', 'MESH:D001943', (72, 85))
194858	30697731	Overexpression of either TBX3 isoform in 21NT cells resulted in an increase in extravasation within the CAM.	('TBX3', 'Gene', '6926', (25, 29))	('increase', 'PosReg', (67, 75))	('extravasation within the CAM', 'MPA', (79, 107))	('Overexpression', 'Var', (0, 14))	('TBX3', 'Gene', (25, 29))
194859	30697731	Extravasation rates were drastically reduced with shRNA-mediated knockdown of total TBX3 in invasive 21MT-1 cells, which natively express TBX3 at high levels (levels shown in supplementary material, Figure S2B-D).	('Extravasation rates', 'MPA', (0, 19))	('TBX3', 'Gene', (84, 88))	('21MT-1', 'CellLine', 'CVCL:7931', (101, 107))	('TBX3', 'Gene', '6926', (138, 142))	('reduced', 'NegReg', (37, 44))	('knockdown', 'Var', (65, 74))	('TBX3', 'Gene', (138, 142))	('TBX3', 'Gene', '6926', (84, 88))
194861	30697731	Furthermore, the presence of functional invadopodia was reduced with TBX3 knockdown in 21MT-1 cells.	('21MT-1', 'CellLine', 'CVCL:7931', (87, 93))	('reduced', 'NegReg', (56, 63))	('knockdown', 'Var', (74, 83))	('TBX3', 'Gene', '6926', (69, 73))	('TBX3', 'Gene', (69, 73))
194863	30697731	The functional alterations associated with TBX3 isoform overexpression suggest a more invasive EMT phenotype.	('overexpression', 'Var', (56, 70))	('TBX3', 'Gene', '6926', (43, 47))	('TBX3', 'Gene', (43, 47))	('invasive EMT', 'CPA', (86, 98))
194868	30697731	Pathway analysis indicated that the top predicted functional changes for the TBX3 transfectants include alterations in cellular movement, cellular growth and proliferation, cell death, cell survival, and cancer-associated processes (Figure 2A).	('transfectants', 'Var', (82, 95))	('cancer', 'Disease', (204, 210))	('cell death', 'CPA', (173, 183))	('alterations', 'Reg', (104, 115))	('cell survival', 'CPA', (185, 198))	('TBX3', 'Gene', '6926', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cellular movement', 'CPA', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('TBX3', 'Gene', (77, 81))	('cellular growth', 'CPA', (138, 153))
194886	30697731	With SLUG knockdown, the rates of migration and invasion of TBX3 isoform transfectants were reduced to baseline levels, despite expressing high levels of TBX3 (Figure 3C,D).	('SLUG', 'Gene', (5, 9))	('TBX3', 'Gene', '6926', (60, 64))	('TBX3', 'Gene', (60, 64))	('TBX3', 'Gene', '6926', (154, 158))	('TBX3', 'Gene', (154, 158))	('reduced', 'NegReg', (92, 99))	('invasion', 'CPA', (48, 56))	('migration', 'CPA', (34, 43))	('knockdown', 'Var', (10, 19))	('SLUG', 'Gene', '6591', (5, 9))
194887	30697731	A large proportion (7/10) of our list of EMT- and invasion-associated genes previously assessed in this study were still significantly altered with high TBX3 isoform expression in cells with SLUG knockdown (Figure 3E,F).	('TBX3', 'Gene', (153, 157))	('altered', 'Reg', (135, 142))	('SLUG', 'Gene', '6591', (191, 195))	('high', 'Var', (148, 152))	('SLUG', 'Gene', (191, 195))	('TBX3', 'Gene', '6926', (153, 157))
194896	30697731	TBX3 positivity was highest in low- and intermediate-grade DCIS and significantly lower in high-grade DCIS (Figure 4D).	('positivity', 'Var', (5, 15))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('TBX3', 'Gene', '6926', (0, 4))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))	('low-', 'Disease', (31, 35))	('highest', 'Reg', (20, 27))	('TBX3', 'Gene', (0, 4))	('lower', 'NegReg', (82, 87))
194903	30697731	Additionally, both SLUG and TWIST1 were up-regulated in CCLs, and SLUG levels were significantly higher in low-grade (grade 1) DCIS relative to both grade 1 + 2 (mixed) and grade 2 DCIS (Figure 4H), exhibiting staining patterns similar to TBX3.	('SLUG', 'Gene', (19, 23))	('higher', 'PosReg', (97, 103))	('TBX3', 'Gene', '6926', (239, 243))	('TWIST1', 'Gene', (28, 34))	('TWIST1', 'Gene', '7291', (28, 34))	('TBX3', 'Gene', (239, 243))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('low-grade', 'Var', (107, 116))	('up-regulated', 'PosReg', (40, 52))	('SLUG', 'Gene', '6591', (66, 70))	('CCLs', 'Chemical', '-', (56, 60))	('SLUG', 'Gene', (66, 70))	('DCIS', 'Phenotype', 'HP:0030075', (127, 131))	('SLUG', 'Gene', '6591', (19, 23))
194909	30697731	Survival analysis of luminal A patients in the TCGA BRCA dataset showed a statistically significant difference in survival (p < 0.001) between patients with high and low TBX3 relative to the median (Figure 5C).	('survival', 'MPA', (114, 122))	('TBX3', 'Gene', (170, 174))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('high', 'Var', (157, 161))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (31, 39))	('TBX3', 'Gene', '6926', (170, 174))	('low', 'NegReg', (166, 169))
194922	30697731	From these initial genomic studies, we identified SLUG and TWIST1 as potential downstream effectors up-regulated with TBX3 overexpression, and SLUG as a direct downstream mediator of TBX3-induced migration and invasion.	('up-regulated', 'PosReg', (100, 112))	('migration', 'CPA', (196, 205))	('overexpression', 'Var', (123, 137))	('TBX3', 'Gene', '6926', (118, 122))	('SLUG', 'Gene', '6591', (143, 147))	('TBX3', 'Gene', (118, 122))	('SLUG', 'Gene', (143, 147))	('TWIST1', 'Gene', (59, 65))	('TWIST1', 'Gene', '7291', (59, 65))	('invasion', 'CPA', (210, 218))	('TBX3', 'Gene', '6926', (183, 187))	('SLUG', 'Gene', '6591', (50, 54))	('TBX3', 'Gene', (183, 187))	('SLUG', 'Gene', (50, 54))
194924	30697731	Our examination of TBX3 by immunohistochemistry in two independent patient cohorts revealed that levels are highest in hormone receptor-positive, low-grade DCIS (and co-existing CCLs) and are associated with the extent of invasion in early-stage breast cancers.	('breast cancers', 'Disease', (246, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('associated with', 'Reg', (192, 207))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('TBX3', 'Gene', (19, 23))	('CCLs', 'Chemical', '-', (178, 182))	('low-grade', 'Var', (146, 155))	('levels', 'MPA', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('highest', 'Reg', (108, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (246, 260))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('TBX3', 'Gene', '6926', (19, 23))	('patient', 'Species', '9606', (67, 74))	('breast cancers', 'Disease', 'MESH:D001943', (246, 260))
195065	29772934	The lesions identified by mammography were benign in all 8 patients with BI-RADS category 3 lesions, whereas cancerous lesions were found in 37 of 92 patients with BI-RADS category 4 and 5 lesions.	('BI-RADS', 'Var', (73, 80))	('patients', 'Species', '9606', (150, 158))	('cancerous lesions', 'Disease', 'MESH:D009062', (109, 126))	('patients', 'Species', '9606', (59, 67))	('cancerous lesions', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
195112	25713430	In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (>20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months.	('BRCA', 'Gene', (65, 69))	('BRCA', 'Gene', '672', (65, 69))	('women', 'Species', '9606', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('mutation', 'Var', (70, 78))	('breast cancer', 'Disease', (149, 162))
195124	25713430	Starting in 1999, women with a BRCA1 or BRCA2 mutation were recruited for this study.	('BRCA1', 'Gene', '672', (31, 36))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', (31, 36))	('women', 'Species', '9606', (18, 23))	('mutation', 'Var', (46, 54))	('BRCA2', 'Gene', '675', (40, 45))
195127	25713430	In addition to the annual triple-modality screening rounds, ultrasound examinations were offered every 6 months to BRCA mutation carriers.	('mutation', 'Var', (120, 128))	('BRCA', 'Gene', (115, 119))	('BRCA', 'Gene', '672', (115, 119))
195139	25713430	To explore additional patient characteristics, in addition to the hereditary risk factor, for the selection of women for screening with MRI, the data set was divided into pairs of complementary subgroups using the following criteria: number of screening rounds: first screening round versus subsequent screening rounds; mutation status: BRCA1/2 mutation carriers versus non-mutation carriers (wild types and unclassified variants in BRCA1 or BRCA2); age: women <= versus > 50 years old; and breast density: women with low breast density (ACR breast composition grades 1 and 2) versus high breast density (ACR grades 3 and 4).	('women', 'Species', '9606', (111, 116))	('low', 'NegReg', (518, 521))	('BRCA1', 'Gene', '672', (433, 438))	('BRCA1', 'Gene', '672', (337, 342))	('women', 'Species', '9606', (507, 512))	('BRCA2', 'Gene', (442, 447))	('BRCA1', 'Gene', (433, 438))	('high breast density', 'Phenotype', 'HP:0010313', (584, 603))	('BRCA1', 'Gene', (337, 342))	('women', 'Species', '9606', (455, 460))	('BRCA2', 'Gene', '675', (442, 447))	('patient', 'Species', '9606', (22, 29))	('mutation', 'Var', (345, 353))
195142	25713430	Of these, 156 patients (28%) were BRCA1/2 mutation carriers (Table 1).	('BRCA1', 'Gene', '672', (34, 39))	('mutation', 'Var', (42, 50))	('BRCA1', 'Gene', (34, 39))	('patients', 'Species', '9606', (14, 22))
195189	25713430	The lower specificity may be a result of an overestimation of the breast cancer risk in the non-BRCA mutation carriers and may have resulted in an unwarranted low threshold to call lesions suspicious.	('BRCA', 'Gene', '672', (96, 100))	('lower', 'NegReg', (4, 9))	('BRCA', 'Gene', (96, 100))	('overestimation', 'PosReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('mutation', 'Var', (101, 109))
195200	25713430	Exclusion criteria included the following: age less than 25 years (with the exception of women with relatives who were diagnosed with breast cancer before 30 years of age, who were included 5 years before that relative's age at diagnosis); women from families with a proven gene mutation who themselves had tested negative for that particular mutation because they do not bear a higher risk than the average female population; bilateral mastectomy; stage IV breast cancer; pacemaker not compatible with magnetic resonance imaging (MRI); pregnancy or lactation; and clinical symptoms of breast cancer at first presentation (eg, palpable mass; such women could enter the trial 1 year after their treatment).	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (586, 599))	('women', 'Species', '9606', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('breast cancer', 'Disease', 'MESH:D001943', (586, 599))	('breast cancer', 'Phenotype', 'HP:0003002', (458, 471))	('breast cancer', 'Disease', (134, 147))	('mutation', 'Var', (343, 351))	('breast cancer', 'Disease', (586, 599))	('mutation', 'Var', (279, 287))	('breast cancer', 'Disease', 'MESH:D001943', (458, 471))	('breast cancer', 'Disease', (458, 471))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (593, 599))	('lactation', 'Disease', (550, 559))	('women', 'Species', '9606', (647, 652))	('lactation', 'Disease', 'MESH:D007775', (550, 559))	('palpable mass', 'Disease', (627, 640))	('women', 'Species', '9606', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (465, 471))
195216	25713430	Mutations in this gene are associated with increased risks of developing breast or ovarian cancer              BRCA2            a tumor suppressor gene whose protein product is involved in repairing chromosomal damage.	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (73, 97))	('BRCA2', 'Gene', (111, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('BRCA2', 'Gene', '675', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('breast or ovarian cancer', 'Disease', (73, 97))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (130, 135))
195222	28160548	In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, conversely, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth.	('growth', 'CPA', (210, 216))	('tumor', 'Disease', (18, 23))	('poor', 'NegReg', (88, 92))	('miRNA 29c', 'Gene', '407026', (44, 53))	('inhibits', 'NegReg', (201, 209))	('ectopic', 'Var', (140, 147))	('expression', 'Species', '29278', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('miRNA-29c', 'Gene', (162, 171))	('patient', 'Species', '9606', (101, 108))	('miRNA 29c', 'Gene', (44, 53))	('miRNA-29c', 'Gene', '407026', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
195224	28160548	miRNA-29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells.	('miRNA-29c', 'Gene', (214, 223))	('inhibition', 'NegReg', (128, 138))	('miRNA-29c', 'Gene', '407026', (214, 223))	('miRNA-29c', 'Gene', (0, 9))	('expression', 'Species', '29278', (200, 210))	('miRNA-29c', 'Gene', '407026', (0, 9))	('cell proliferation', 'CPA', (142, 160))	('colony formation', 'CPA', (165, 181))	('ectopic expression', 'Var', (192, 210))	('TGIF2', 'Gene', (81, 86))
195225	28160548	AKT3 is an oncogene of known relevance in breast cancer, and as a proof of principle we show that inhibition of phosphoinositide 3-kinase (PI3K) activity, a protein upstream of AKT3, suppressed proliferation in TNBC preneoplastic cells.	('phosphoinositide 3-kinase', 'Gene', '5295', (112, 137))	('inhibition', 'Var', (98, 108))	('phosphoinositide 3-kinase', 'Gene', (112, 137))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('activity', 'MPA', (145, 153))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('PI3', 'Gene', (139, 142))	('proliferation', 'CPA', (194, 207))	('breast cancer', 'Disease', (42, 55))	('TNBC preneoplastic cells', 'CPA', (211, 235))	('suppressed', 'NegReg', (183, 193))	('PI3', 'Gene', '5266', (139, 142))
195234	28160548	Within breast tumors, miRNA expression patterns are associated with distinct molecular breast cancer subtypes, e.g., miRNA-18a, -135b, -93, and -155 have been identified as common TNBC-specific miRNAs in a meta-analysis of 3 independent studies.	('expression', 'Species', '29278', (28, 38))	('miRNA expression', 'MPA', (22, 38))	('distinct molecular breast cancer', 'Disease', 'MESH:D001943', (68, 100))	('associated', 'Reg', (52, 62))	('distinct molecular breast cancer', 'Disease', (68, 100))	('breast tumors', 'Phenotype', 'HP:0100013', (7, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('breast tumors', 'Disease', 'MESH:D001943', (7, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('breast tumors', 'Disease', (7, 20))	('miRNA-18a', 'Var', (117, 126))
195242	28160548	As a proof of concept, we also show evidence that targeting one of these pathways with LY294002, a small-molecule inhibitor of PI3 kinase, inhibited cell proliferation in preneoplastic cells.	('cell proliferation in preneoplastic cells', 'CPA', (149, 190))	('LY294002', 'Var', (87, 95))	('PI3', 'Gene', '5266', (127, 130))	('PI3', 'Gene', (127, 130))	('LY294002', 'Chemical', 'MESH:C085911', (87, 95))	('inhibited', 'NegReg', (139, 148))
195246	28160548	We identified only 5 miRNA fitting this pattern of interest: miRNA-140-5p, miR-29c-3p, miRNA-140-3p, Let-7a-5p, and miR-29c-5p.	('miR-29c-5p', 'Var', (116, 126))	('miRNA-140', 'Gene', (87, 96))	('miRNA-140', 'Gene', '406932', (87, 96))	('miRNA-140', 'Gene', '406932', (61, 70))	('miR-29c-3p', 'Var', (75, 85))	('Let-7a-5p', 'Var', (101, 110))	('miRNA-140', 'Gene', (61, 70))
195269	28160548	To identify the functional gene pairs of miRNA-29c, first we obtained a list of mRNAs that significantly increased (>1.5, P<0.05) during the transition from MCF10A (P) [normal like] to MCF10.DCIS in our RNA sequencing dataset.	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (185, 195))	('MCF10A', 'Var', (157, 163))	('miRNA-29c', 'Gene', (41, 50))	('increased', 'PosReg', (105, 114))	('miRNA-29c', 'Gene', '407026', (41, 50))	('MCF10A', 'CellLine', 'CVCL:0598', (157, 163))
195277	28160548	TGIF2 and CREB5 were top 2 genes that changed the most during MCF10A (P) to DCIS transition.	('changed', 'Reg', (38, 45))	('MCF10A', 'Var', (62, 68))	('MCF10A', 'CellLine', 'CVCL:0598', (62, 68))	('TGIF2', 'Gene', (0, 5))
195297	28160548	As a proof of concept that the genes we identified through our pipeline have relevance to TNBC prevention, we targeted AKT3 using LY294002, a small molecule inhibitor of upstream PI3 kinase, and studied its effect on cell proliferation in preneoplastic MCF10.AT1 and MCF10.DCIS cells.	('targeted', 'Reg', (110, 118))	('LY294002', 'Var', (130, 138))	('LY294002', 'Chemical', 'MESH:C085911', (130, 138))	('PI3', 'Gene', '5266', (179, 182))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (267, 277))	('AKT3', 'Gene', (119, 123))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (253, 262))	('PI3', 'Gene', (179, 182))
195298	28160548	LY294002 caused significant suppression of pAKT and pS6 (Figure 10A & 10B, Supplementary Figure 2) in both MCF10.AT1 and MCF10.DCIS cells and also significantly impaired cell proliferation (Figure 10C & 10D), indicating that the genes/pathways identified through our bio-informatics approach have relevance as potential targets for prevention.	('LY294002', 'Var', (0, 8))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (121, 131))	('suppression', 'NegReg', (28, 39))	('pS6', 'Gene', (52, 55))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('AKT', 'Gene', '207', (44, 47))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (107, 116))	('impaired cell', 'CPA', (161, 174))	('pS6', 'Gene', '338413', (52, 55))	('AKT', 'Gene', (44, 47))	('significantly', 'NegReg', (147, 160))
195299	28160548	Specifically, LY294002 reduced levels of pAKT (including pAKT1/2/3) and the downstream mediator pS6 by more than 50% in both MCF10.AT1 and MCF10.DCIS cell lines (Supplementary Figure 2).	('pS6', 'Gene', (96, 99))	('LY294002', 'Var', (14, 22))	('AKT', 'Gene', (42, 45))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (125, 134))	('pS6', 'Gene', '338413', (96, 99))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (139, 149))	('AKT', 'Gene', '207', (58, 61))	('LY294002', 'Chemical', 'MESH:C085911', (14, 22))	('reduced', 'NegReg', (23, 30))	('AKT', 'Gene', '207', (42, 45))	('AKT', 'Gene', (58, 61))
195300	28160548	LY294002 treatment at 100 muM for 6 days led to a significant inhibition (~100% in both MCF10.AT1 and MCF10.DCIS cells) in cell proliferation as well (Figure 10C & 10D).	('LY294002', 'Var', (0, 8))	('muM', 'Gene', (26, 29))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (102, 112))	('cell proliferation', 'CPA', (123, 141))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('muM', 'Gene', '56925', (26, 29))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (88, 97))	('inhibition', 'NegReg', (62, 72))
195301	28160548	AKT pathway and cell proliferation inhibition caused by LY294002 are not TNBC subtype specific to and have been linked with high toxicity in patients (indicating LY294002's effects on normal cells as well).	('AKT', 'Gene', (0, 3))	('toxicity', 'Disease', (129, 137))	('LY294002', 'Chemical', 'MESH:C085911', (162, 170))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('LY294002', 'Var', (56, 64))	('AKT', 'Gene', '207', (0, 3))	('inhibition', 'NegReg', (35, 45))	('patients', 'Species', '9606', (141, 149))	('cell proliferation', 'CPA', (16, 34))
195338	28160548	The anti-proliferative effects of the PI3K inhibitor LY294002 on MCF10.AT1 and MCF10.DCIS cells were determined by the MTT dye uptake method.	('PI3', 'Gene', (38, 41))	('MTT', 'Chemical', 'MESH:C070243', (119, 122))	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('MCF10.AT1', 'CellLine', 'CVCL:5555', (65, 74))	('anti-proliferative', 'CPA', (4, 22))	('PI3', 'Gene', '5266', (38, 41))	('LY294002', 'Var', (53, 61))	('MCF10.DCIS', 'CellLine', 'CVCL:5552', (79, 89))
195350	28160548	Thirty to 40 mug of total cellular protein was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis; transferred to Hybond ECL nitrocellulose (Amersham, [Pittsburgh, PA]); and probed with pAKT (S473), AKT, S6, and pS6 (S240/244), antibody, or the loading control, vinculin.	('AKT', 'Gene', '207', (207, 210))	('AKT', 'Gene', (219, 222))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (60, 82))	('AKT', 'Gene', (207, 210))	('pS6', 'Gene', (232, 235))	('pS6', 'Gene', '338413', (232, 235))	('AKT', 'Gene', '207', (219, 222))	('S473', 'Var', (212, 216))	('polyacrylamide', 'Chemical', 'MESH:C016679', (83, 97))
195390	25975273	We have shown that anti-collagen antibodies and antinuclear antibodies [ANA] are found in the sera from lung cancer and head and neck cancer patients as frequently as in the systemic ADs such as rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE].	('AD', 'Disease', (183, 185))	('arthritis', 'Phenotype', 'HP:0001369', (206, 215))	('head and neck cancer', 'Disease', 'MESH:D006258', (120, 140))	('antinuclear', 'Var', (48, 59))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (225, 253))	('SLE', 'Disease', 'MESH:D008180', (255, 258))	('SLE', 'Disease', (255, 258))	('patients', 'Species', '9606', (141, 149))	('AD', 'Disease', 'MESH:D000544', (183, 185))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('rheumatoid arthritis', 'Disease', (195, 215))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (225, 253))	('antinuclear antibodies', 'Phenotype', 'HP:0003493', (48, 70))	('found', 'Reg', (81, 86))	('anti-collagen antibodies', 'Protein', (19, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (195, 215))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('head and neck cancer', 'Phenotype', 'HP:0012288', (120, 140))	('systemic lupus erythematosus', 'Disease', (225, 253))	('lung cancer', 'Disease', (104, 115))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (195, 215))
195415	25975273	Protein extracts were prepared by the method of Wood and Earnshaw from eight established BC cell lines, MCF-7, DCIS.com, SKBR, T47D, SUM44, SUM102, SUM149, and SUM159, which were gifts from Drs.	('SUM102', 'Var', (140, 146))	('SKBR', 'CellLine', 'CVCL:0033', (121, 125))	('SUM149', 'Var', (148, 154))	('SUM44', 'Var', (133, 138))	('SUM159', 'Var', (160, 166))	('MCF-7', 'CellLine', 'CVCL:0031', (104, 109))
195470	25975273	Sera from patients with SLE frequently exhibit a homogeneous pattern and anti-dsDNA or anti-histone antibodies.	('SLE', 'Disease', 'MESH:D008180', (24, 27))	('SLE', 'Disease', (24, 27))	('homogeneous pattern', 'MPA', (49, 68))	('exhibit', 'Reg', (39, 46))	('patients', 'Species', '9606', (10, 18))	('anti-dsDNA', 'Var', (73, 83))
195479	25975273	Abnormal centrosome amplification and supernumerary centrosomes, as well as abnormalities in centrosome number, size, and morphology, have been observed in nearly all human tumor types including BC.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('centrosome amplification', 'CPA', (9, 33))	('abnormalities', 'Var', (76, 89))	('supernumerary centrosomes', 'CPA', (38, 63))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('observed', 'Reg', (144, 152))	('human', 'Species', '9606', (167, 172))	('centrosome number', 'CPA', (93, 110))
195480	25975273	Centrosome defects have been associated with genetic instability but the role of the centrosome in tumorigenesis is yet to be defined.	('tumor', 'Disease', (99, 104))	('defects', 'Var', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('genetic instability', 'MPA', (45, 64))	('associated', 'Reg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
195483	25975273	Chromosomal aberrations are the hallmark of cancer and autoantibodies develop early in carcinogenesis.	('Chromosomal aberrations', 'Var', (0, 23))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('carcinogenesis', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
195537	21145284	After just over 6 years of follow-up, a significant reduction in all new breast events was reported in the tamoxifen group compared with the placebo group (rate ratio 0 63, 95% CI 0 47-0 83; p=0 0009).	('breast', 'Disease', (73, 79))	('tamoxifen', 'Var', (107, 116))	('tamoxifen', 'Chemical', 'MESH:D013629', (107, 116))	('reduction', 'NegReg', (52, 61))
195540	21145284	After a median follow-up of 4 4 years (range 0 2-9 9), patients who had radiotherapy had a lower incidence of ipsilateral invasive disease (hazard ratio [HR] 0 45, 95% CI 0 24-0 85) and ipsilateral DCIS (0 36, 0 19-0 66) than those who did not have radiotherapy, but there was no difference in contralateral disease between groups.	('lower', 'NegReg', (91, 96))	('ipsilateral invasive disease', 'Disease', 'MESH:D006053', (110, 138))	('ipsilateral DCIS', 'CPA', (186, 202))	('contralateral disease', 'Disease', 'MESH:D009069', (294, 315))	('ipsilateral invasive disease', 'Disease', (110, 138))	('contralateral disease', 'Disease', (294, 315))	('patients', 'Species', '9606', (55, 63))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('radiotherapy', 'Var', (72, 84))
195576	21145284	There was a significant reduction in all contralateral events in those randomly assigned to tamoxifen compared with those assigned to no tamoxifen (p=0 005; table 2), with an absolute 10-year reduction of 2 3%.	('contralateral events', 'CPA', (41, 61))	('tamoxifen', 'Chemical', 'MESH:D013629', (92, 101))	('tamoxifen', 'Var', (92, 101))	('tamoxifen', 'Chemical', 'MESH:D013629', (137, 146))	('reduction', 'NegReg', (24, 33))	('reduction', 'NegReg', (192, 201))
195612	21145284	The HR for all breast events was 0 59 in women randomised to radiotherapy compared with those who were not.	('breast events', 'Disease', (15, 28))	('women', 'Species', '9606', (41, 46))	('radiotherapy', 'Var', (61, 73))
195613	21145284	A Swedish study reported a relative risk of 0 40 for ipsilateral disease in women who received radiotherapy compared with those not irradiated, corresponding to an absolute 10-year reduction of 16%.	('radiotherapy', 'Var', (95, 107))	('reduction', 'NegReg', (181, 190))	('ipsilateral disease', 'Disease', (53, 72))	('ipsilateral disease', 'Disease', 'MESH:D006053', (53, 72))	('women', 'Species', '9606', (76, 81))
195688	19949854	This is consistent with our study on the macrophage response in invasive breast cancer which found that the stromal macrophage response signature correlated with higher tumor grade, decreased expression of ER, decreased expression of PR, and increased p53 mutations.	('higher', 'PosReg', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('decreased', 'NegReg', (182, 191))	('expression', 'MPA', (192, 202))	('expression', 'MPA', (220, 230))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('invasive breast cancer', 'Disease', 'MESH:D001943', (64, 86))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('decreased', 'NegReg', (210, 219))	('p53', 'Gene', (252, 255))	('p53', 'Gene', '7157', (252, 255))	('increased', 'PosReg', (242, 251))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (256, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('invasive breast cancer', 'Disease', (64, 86))
195751	21150936	Morphometric studies have shown that the mean diameter of the ducts containing DCIS with necrosis is 470 micrometres, compared with a mean diameter of 192 micrometres for DCIS without necrosis.	('necrosis', 'Disease', (89, 97))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('DCIS', 'Var', (79, 83))	('necrosis', 'Disease', (184, 192))	('necrosis', 'Disease', 'MESH:D009336', (184, 192))
195754	21150936	The specific trigger of necrosis is unknown, but insufficient ATP production to maintain plasma membrane integrity could result in metabolic catastrophe, which generates the typical comedo-DCIS central zone of cell lysis (FIGS 1,2).	('metabolic catastrophe', 'MPA', (131, 152))	('necrosis', 'Disease', (24, 32))	('insufficient', 'Var', (49, 61))	('typical comedo', 'Phenotype', 'HP:0025250', (174, 188))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('DCIS', 'Phenotype', 'HP:0030075', (189, 193))	('necrosis', 'Disease', 'MESH:D009336', (24, 32))	('comedo', 'Phenotype', 'HP:0025249', (182, 188))	('result in', 'Reg', (121, 130))
195764	21150936	Thus, in the presence of hypoxic stress, we can postulate that proliferating intraductal DCIS epithelial cells may adapt to survive in the presence of genetic mutations that drive tumour progression and facilitate invasion.	('invasion', 'CPA', (214, 222))	('hypoxic stress', 'Disease', (25, 39))	('facilitate', 'PosReg', (203, 213))	('hypoxic stress', 'Disease', 'MESH:D004194', (25, 39))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('drive', 'PosReg', (174, 179))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('genetic mutations', 'Var', (151, 168))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Disease', (180, 186))
195775	21150936	The repression of INK4A activity, accompanied by the inactivation of RB as a transcriptional repressor, leads to the overexpression of chromatin-remodelling proteins such as the polycomb proteins enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (SUZ12).	('INK4A', 'Gene', (18, 23))	('SUZ12', 'Gene', '23512', (271, 276))	('SUZ12', 'Gene', (271, 276))	('EZH2', 'Gene', '2146', (227, 231))	('repression', 'NegReg', (4, 14))	('overexpression', 'PosReg', (117, 131))	('EZH2', 'Gene', (227, 231))	('enhancer of zeste homologue 2', 'Gene', '2146', (196, 225))	('RB', 'Phenotype', 'HP:0009919', (69, 71))	('enhancer of zeste homologue 2', 'Gene', (196, 225))	('INK4A', 'Gene', '1029', (18, 23))	('inactivation', 'Var', (53, 65))
195777	21150936	Abnormalities in chromatin remodelling are thought to have a role in nuclear atypia and abnormalities in cell polarity, which are prominent features of DCIS pathology.	('nuclear', 'Disease', (69, 76))	('Abnormalities', 'Var', (0, 13))	('cell polarity', 'CPA', (105, 118))	('DCIS', 'Phenotype', 'HP:0030075', (152, 156))	('atypia and abnormalities', 'Disease', 'MESH:D000014', (77, 101))
195779	21150936	COX2 expression can stimulate cell migration and angiogenesis, and has been reported to be upregulated in DCIS lesions in women with a high likelihood of subsequent breast cancer.	('upregulated', 'PosReg', (91, 102))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('DCIS', 'Phenotype', 'HP:0030075', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('DCIS lesions', 'Disease', (106, 118))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('expression', 'Var', (5, 15))	('stimulate', 'PosReg', (20, 29))	('women', 'Species', '9606', (122, 127))	('COX2', 'Gene', '5743', (0, 4))	('COX2', 'Gene', (0, 4))	('angiogenesis', 'CPA', (49, 61))	('cell migration', 'CPA', (30, 44))
195785	21150936	Experimental approaches employing loss-of-heterozygosity (LOH), and comparative genomic hybridization (CGH), as well as mutational screens, reveal that most of the genetic changes that underpin invasive breast cancer are evident in DCIS lesions.	('invasive breast cancer', 'Disease', 'MESH:D001943', (194, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('DCIS', 'Phenotype', 'HP:0030075', (232, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('invasive breast cancer', 'Disease', (194, 216))	('changes', 'Var', (172, 179))	('loss-of-heterozygosity', 'NegReg', (34, 56))
195788	21150936	Further support for the conclusion that primary genetic changes are present at the pre-malignant stage comes from studies of PIK3CA mutations and ERBB2 (also known as HER2) amplifications in DCIS lesions and matched invasive lesions from the same patient.	('patient', 'Species', '9606', (247, 254))	('mutations', 'Var', (132, 141))	('HER2', 'Gene', (167, 171))	('PIK3CA', 'Gene', (125, 131))	('RB', 'Phenotype', 'HP:0009919', (147, 149))	('HER2', 'Gene', '2064', (167, 171))	('ERBB2', 'Gene', '2064', (146, 151))	('DCIS', 'Phenotype', 'HP:0030075', (191, 195))	('ERBB2', 'Gene', (146, 151))	('amplifications', 'Var', (173, 187))	('PIK3CA', 'Gene', '5290', (125, 131))
195793	21150936	The association between BRCA mutations and ductal carcinomain situ(DCIS) incidence and grade is still limited.	('ductal carcinomain situ', 'Disease', 'MESH:D002285', (43, 66))	('BRCA', 'Gene', '672', (24, 28))	('ductal carcinomain situ', 'Disease', (43, 66))	('ductal carcinomain situ', 'Phenotype', 'HP:0030075', (43, 66))	('BRCA', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))
195794	21150936	Nevertheless, the existing data suggest that DCIS is equally as prevalent in patients who carry BRCA mutations as it is in women who have a high familial risk for breast cancer, but who are not BRCA mutation carriers.	('DCIS', 'Disease', (45, 49))	('BRCA', 'Gene', '672', (96, 100))	('women', 'Species', '9606', (123, 128))	('mutations', 'Var', (101, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('BRCA', 'Gene', (96, 100))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('BRCA', 'Gene', '672', (194, 198))	('patients', 'Species', '9606', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('BRCA', 'Gene', (194, 198))	('breast cancer', 'Disease', (163, 176))
195795	21150936	However, DCIS, like breast cancer in women with familial BRCA mutations, occurs at an earlier age and is often of a high grade (grade III).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('women', 'Species', '9606', (37, 42))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('BRCA', 'Gene', '672', (57, 61))	('DCIS', 'Disease', (9, 13))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('BRCA', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
195796	21150936	There is also an increased prevalence of pre-invasive lesions adjacent to invasive cancers in women with familial BRCA mutations.	('pre-invasive lesions', 'Disease', (41, 61))	('women', 'Species', '9606', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('invasive cancers', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA', 'Gene', '672', (114, 118))	('invasive cancers', 'Disease', 'MESH:D009362', (74, 90))	('BRCA', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
195797	21150936	All of these data suggest that BRCA mutation-associated breast cancer progresses through a DCIS precursor at an accelerated pace compared with breast cancer arising in patients without a familial BRCA mutation.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('BRCA', 'Gene', (196, 200))	('BRCA', 'Gene', '672', (31, 35))	('breast cancer', 'Disease', (143, 156))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('BRCA', 'Gene', (31, 35))	('mutation-associated', 'Var', (36, 55))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('patients', 'Species', '9606', (168, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('BRCA', 'Gene', '672', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
195798	21150936	Mutations inBRCA1are associated with genetic instability, increasing the risk of malignant transformation of cells.	('genetic instability', 'MPA', (37, 56))	('malignant transformation of cells', 'CPA', (81, 114))	('associated', 'Reg', (21, 31))	('increasing', 'PosReg', (58, 68))	('Mutations', 'Var', (0, 9))	('BRCA', 'Gene', '672', (12, 16))	('BRCA', 'Gene', (12, 16))
195800	21150936	Consequently, the hypoxic state of the intraductal DCIS microenvironment will further compound the genetic instability of the DCIS cells in patients with BRCA mutations.	('BRCA', 'Gene', '672', (154, 158))	('genetic instability', 'MPA', (99, 118))	('BRCA', 'Gene', (154, 158))	('mutations', 'Var', (159, 168))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('DCIS', 'Phenotype', 'HP:0030075', (51, 55))	('hypoxic', 'Disease', (18, 25))	('hypoxic', 'Disease', 'MESH:D000860', (18, 25))	('patients', 'Species', '9606', (140, 148))
195812	21150936	It has been postulated that dividing EPCAM-positive mammary progenitor cells can be subject to oncogenic mutations or genetic alterations at different stages during their differentiation.	('EPCAM', 'Gene', (37, 42))	('genetic alterations', 'Var', (118, 137))	('subject', 'Reg', (84, 91))	('EPCAM', 'Gene', '4072', (37, 42))	('mutations', 'Var', (105, 114))
195817	21150936	If normal mammary progenitor cells become transformed as they adapt to survive in the high-stress microenvironment of the intraductal niche, then the biology of the resulting cancer is a product of the genetic instability, the suppression of apoptosis and the suppression of DNA repair that arise under stress.	('apoptosis', 'CPA', (242, 251))	('suppression', 'NegReg', (227, 238))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('DNA repair', 'CPA', (275, 285))	('genetic instability', 'Var', (202, 221))	('suppression', 'NegReg', (260, 271))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
195829	21150936	Microcalcifications are seen in 90% of mammograms, but microcalcifications of all types are associated with a broad range of breast lesions, and have only a 30-40% specificity for malignancy.	('breast lesions', 'Disease', (125, 139))	('malignancy', 'Disease', 'MESH:D009369', (180, 190))	('malignancy', 'Disease', (180, 190))	('breast lesions', 'Disease', 'MESH:D001941', (125, 139))	('associated', 'Reg', (92, 102))	('microcalcifications', 'Var', (55, 74))
195831	21150936	By contrast, microcalcifications that are restricted to the lobules are almost always associated with benign breast disease such as microcystic adenosis.	('microcystic adenosis', 'Disease', 'MESH:D005348', (132, 152))	('benign breast disease', 'Disease', 'MESH:D001941', (102, 123))	('associated', 'Reg', (86, 96))	('benign breast disease', 'Disease', (102, 123))	('microcalcifications', 'Var', (13, 32))	('microcystic adenosis', 'Disease', (132, 152))
195837	21150936	Insoluble calcium has been shown to induce autophagy, and may contribute to the local oxidative or metabolic stress within the duct.	('Insoluble', 'Var', (0, 9))	('contribute', 'Reg', (62, 72))	('autophagy', 'CPA', (43, 52))	('induce', 'PosReg', (36, 42))	('metabolic', 'CPA', (99, 108))	('calcium', 'Chemical', 'MESH:D002118', (10, 17))
195870	21886829	The Bit1 knockdown pools also showed a statistically highly significant increase in experimental lung metastasis, with no differences in tumor growth relative to control clones in vivo using a BALB/c nude mouse model system.	('increase', 'PosReg', (72, 80))	('lung metastasis', 'Disease', (97, 112))	('tumor', 'Disease', (137, 142))	('knockdown', 'Var', (9, 18))	('lung metastasis', 'Disease', 'MESH:D009362', (97, 112))	('mouse', 'Species', '10090', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Bit1', 'Gene', (4, 8))
195871	21886829	Importantly, the pulmonary metastases of Bit1 knockdown cells exhibited increased phospho-Erk staining.	('pulmonary metastases', 'Disease', 'MESH:D009362', (17, 37))	('pulmonary metastases', 'Disease', (17, 37))	('increased', 'PosReg', (72, 81))	('knockdown', 'Var', (46, 55))	('phospho-Erk staining', 'MPA', (82, 102))	('Bit1', 'Gene', (41, 45))
195883	21886829	First, we have recently shown that Bit1 negatively regulates the extracellular signal-regulated kinase 1/2 (Erk 1/2) survival signaling, a pathway which is activated in several malignacies.	('Bit1', 'Var', (35, 39))	('extracellular signal-regulated kinase 1/2', 'Gene', (65, 106))	('negatively', 'NegReg', (40, 50))	('regulates', 'Reg', (51, 60))	('extracellular signal-regulated kinase 1/2', 'Gene', '26417;26413', (65, 106))
195889	21886829	Considering the anoikis remains a critical barrier to transformation and metastasis, we examined the possibility that suppression or nonfunctionality of the Bit1 anoikis pathway may contribute to tumor progression.	('nonfunctionality', 'Var', (133, 149))	('tumor', 'Disease', (196, 201))	('contribute', 'Reg', (182, 192))	('Bit1 anoikis pathway', 'Pathway', (157, 177))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
195891	21886829	Importantly, stable knockdown of Bit1 expression in lowly aggressive breast cancer MCF7 as well as in B16F1 and Hela cells resulted in enhanced anoikis resistance, adhesion, and migratory property.	('adhesion', 'CPA', (164, 172))	('migratory property', 'CPA', (178, 196))	('anoikis resistance', 'CPA', (144, 162))	('Bit1', 'Gene', (33, 37))	('aggressive breast cancer MCF7', 'Disease', (58, 87))	('Hela cells', 'CellLine', 'CVCL:0030', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('enhanced', 'PosReg', (135, 143))	('aggressive breast cancer MCF7', 'Disease', 'MESH:D001943', (58, 87))	('B16F1', 'CellLine', 'CVCL:0158', (102, 107))	('knockdown', 'Var', (20, 29))
195899	21886829	These findings indicate that Bit1 expression is selectively lost in invasive breast carcinomas, suggesting that loss of Bit1 may accompany the transition from DCIS to invasive carcinoma during the progression of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('accompany', 'Reg', (129, 138))	('breast cancer', 'Disease', (212, 225))	('invasive breast carcinomas', 'Disease', (68, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('DCIS', 'Disease', (159, 163))	('invasive carcinoma', 'Disease', 'MESH:D009361', (167, 185))	('breast carcinomas', 'Phenotype', 'HP:0003002', (77, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('breast carcinoma', 'Phenotype', 'HP:0003002', (77, 93))	('invasive carcinoma', 'Disease', (167, 185))	('Bit1', 'Gene', (120, 124))	('loss', 'Var', (112, 116))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (68, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
195903	21886829	As compared to control pool, the Bit1 knockdown pool exhibited significantly decreased level of apoptosis following culture in suspension for 48 h as evidenced by decreased annexin V staining (Figure 2C) and reduced level of DNA histone fragments (Figure 2D).	('annexin V', 'Gene', '11747', (173, 182))	('annexin V', 'Gene', (173, 182))	('reduced', 'NegReg', (208, 215))	('level of DNA histone fragments', 'MPA', (216, 246))	('decreased', 'NegReg', (163, 172))	('knockdown', 'Var', (38, 47))	('decreased', 'NegReg', (77, 86))
195904	21886829	In stark contrast, no significant differences in the basal apoptosis were observed between the MCF7 Bit1 knockdown and control pools in attached conditions.	('MCF7 Bit1', 'Gene', (95, 104))	('MCF7', 'CellLine', 'CVCL:0031', (95, 99))	('knockdown', 'Var', (105, 114))
195909	21886829	Such a decrease in growth rate was also observed in MCF7-derived Bit1 knockdown pool as compared to the control pool (Figure S1D).	('knockdown', 'Var', (70, 79))	('MCF7', 'CellLine', 'CVCL:0031', (52, 56))	('growth rate', 'MPA', (19, 30))	('decrease', 'NegReg', (7, 15))	('decrease in growth rate', 'Phenotype', 'HP:0001510', (7, 30))	('Bit1', 'Gene', (65, 69))
195919	21886829	The lungs of mice that received injections of B16F1 Bit1 knockdown pool (Figure 5E and 5F) and MCF7 Bit1 knockdown pool (Figure 5G and 5H) showed an increase in the number of metastatic foci as compared to the lungs derived from mice injected with control cells.	('B16F1', 'CellLine', 'CVCL:0158', (46, 51))	('mice', 'Species', '10090', (13, 17))	('increase', 'PosReg', (149, 157))	('metastatic foci', 'CPA', (175, 190))	('MCF7', 'Gene', (95, 99))	('knockdown', 'Var', (105, 114))	('MCF7', 'CellLine', 'CVCL:0031', (95, 99))	('mice', 'Species', '10090', (229, 233))
195920	21886829	We also observed numerous tumor foci in the lungs of mice injected with HeLa Bit1 knockdown clones, while that of the control clone-treated mice showed no visible signs of tumor infiltrates (Figure S1E).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('HeLa', 'CellLine', 'CVCL:0030', (72, 76))	('mice', 'Species', '10090', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('knockdown clones', 'Var', (82, 98))	('numerous tumor foci', 'Disease', (17, 36))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('numerous tumor foci', 'Disease', 'MESH:C565785', (17, 36))	('mice', 'Species', '10090', (53, 57))
195927	21886829	In this paper, we examined the possibility that Bit1 is downregulated in advanced stages of cancer and that suppression or nonfunctionality of the Bit1 anoikis pathway may contribute to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('Bit1', 'Gene', (48, 52))	('nonfunctionality', 'Var', (123, 139))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('downregulated', 'NegReg', (56, 69))	('contribute', 'Reg', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Bit1', 'Gene', (147, 151))
195931	21886829	Our findings here illustrating Bit1 as a metastasis suppressor are consistent with and reminiscent of a recent publication demonstrating that AES, a pro-apoptotic binding partner of Bit1, is a suppressor of colon carcinoma metastasis and has no effect on tumorigenicity.	('suppressor', 'NegReg', (193, 203))	('AES', 'Chemical', 'MESH:C045560', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('colon carcinoma metastasis', 'Disease', 'MESH:D009362', (207, 233))	('AES', 'Var', (142, 145))	('colon carcinoma metastasis', 'Disease', (207, 233))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))
195934	21886829	Here, we show that tumor cells with knocked down Bit1 exhibit several key properties underlying the metastatic process.	('Bit1', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('metastatic process', 'CPA', (100, 118))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('knocked down', 'Var', (36, 48))
195935	21886829	Downregulating Bit1 also increased cell attachment to the matrix proteins fibronectin and collagen.	('increased', 'PosReg', (25, 34))	('fibronectin', 'Gene', '14268', (74, 85))	('Bit1', 'Gene', (15, 19))	('cell attachment to the matrix', 'CPA', (35, 64))	('Downregulating', 'Var', (0, 14))	('fibronectin', 'Gene', (74, 85))
195936	21886829	Although tumor cell adhesion plays a complex role in metastasis, the enhanced adhesive properties coupled to the enhanced survival capacity may allow the Bit1 knockdown cells to adhere to the target tissue during metastasis.	('adhere', 'CPA', (178, 184))	('knockdown', 'Var', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('enhanced', 'PosReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('survival capacity', 'CPA', (122, 139))	('adhesive properties', 'CPA', (78, 97))	('enhanced', 'PosReg', (113, 121))
195940	21886829	The morphological changes observed in Bit1 knockdown HeLa cells are consistent with the EMT phenotype, but it remains to be investigated whether Bit1 affects the EMT process.	('Bit1', 'Gene', (38, 42))	('affects', 'Reg', (150, 157))	('HeLa', 'CellLine', 'CVCL:0030', (53, 57))	('knockdown', 'Var', (43, 52))
195944	21886829	Bit1 is a negative regulator of Erk activity; mouse embryonic fibroblasts from Bit1 knockout mice, as well as cultured HeLa cells treated with Bit1-specific siRNAs, exhibit enhanced levels of active (phosphorylated) Erk.	('Erk', 'Protein', (216, 219))	('knockout', 'Var', (84, 92))	('mouse', 'Species', '10090', (46, 51))	('HeLa', 'CellLine', 'CVCL:0030', (119, 123))	('mice', 'Species', '10090', (93, 97))	('enhanced', 'PosReg', (173, 181))	('Bit1', 'Gene', (79, 83))
195950	21886829	Consistent with the in vitro findings, the Bit1 knockdown cells exhibited enhanced capacity to produce metastatic tumors as compared to control cells.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Bit1', 'Gene', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('enhanced', 'PosReg', (74, 82))	('knockdown', 'Var', (48, 57))
195960	21886829	In support of this hypothesis, we found that downregulation of Bit1 specifically enhanced the metastatic property of tumor cells with no significant impact on their tumorigenicity, and the metastatic foci of Bit1 knockdown cells showed increased Erk activation.	('Bit1', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('enhanced', 'PosReg', (81, 89))	('tumor', 'Disease', (117, 122))	('activation', 'PosReg', (250, 260))	('Bit1', 'Gene', (208, 212))	('downregulation', 'Var', (45, 59))	('metastatic foci', 'CPA', (189, 204))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Erk', 'CPA', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('increased', 'PosReg', (236, 245))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (165, 170))
195992	21886829	In experimental metastasis assay, 1x106 cells (for MCF7 and HeLa) or 0.5x106 cells (for B16F series) in 100 microl PBS were injected into the lateral vein of athymic BALB/c nude mice.	('B16F', 'Var', (88, 92))	('HeLa', 'CellLine', 'CVCL:0030', (60, 64))	('nude mice', 'Species', '10090', (173, 182))	('PBS', 'Disease', 'MESH:D011535', (115, 118))	('PBS', 'Disease', (115, 118))	('B16F', 'SUBSTITUTION', 'None', (88, 92))	('MCF7', 'CellLine', 'CVCL:0031', (51, 55))
196017	31208996	More than 50 chemokine ligands and 25 chemokine receptors have been identified, and are categorized into several classes depending on the composition of a conserved cysteine motif at the N terminus: C-C, C-X-C and CX3C, in which the X is a non-cysteine amino acid residue.	('cysteine', 'Chemical', 'MESH:D003545', (244, 252))	('min', 'Gene', (192, 195))	('C-X-C', 'Var', (204, 209))	('min', 'Gene', '11789', (192, 195))	('C-C', 'Var', (199, 202))	('min', 'Gene', '11789', (254, 257))	('CX3C', 'Var', (214, 218))	('min', 'Gene', (254, 257))	('cysteine', 'Chemical', 'MESH:D003545', (165, 173))
196020	31208996	Mice exhibiting knockout of CCL2 or CCR2 show defects in macrophage recruitment during bacterial infection, macular degeneration or autoimmune encephalitis.	('CCR2', 'Gene', (36, 40))	('autoimmune encephalitis', 'Disease', 'MESH:C535841', (132, 155))	('autoimmune encephalitis', 'Disease', (132, 155))	('defects', 'NegReg', (46, 53))	('bacterial infection', 'Phenotype', 'HP:0002718', (87, 106))	('CCL2', 'Gene', (28, 32))	('macrophage', 'CPA', (57, 67))	('knockout', 'Var', (16, 24))	('bacterial infection', 'Disease', 'MESH:D001424', (87, 106))	('bacterial infection', 'Disease', (87, 106))	('encephalitis', 'Phenotype', 'HP:0002383', (143, 155))	('macular', 'Disease', (108, 115))	('macular degeneration', 'Phenotype', 'HP:0000608', (108, 128))	('Mice', 'Species', '10090', (0, 4))
196025	31208996	In animal models of breast cancer, stable expression of CCL2 shRNAs in breast tumor xenografts or treatment of primary tumors with CCL2 neutralizing antibodies leads to decreased primary tumor growth and systemic metastasis, correlating with decreased recruitment of M2 polarized macrophages to tissues .	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('systemic metastasis', 'CPA', (204, 223))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (187, 192))	('decreased', 'NegReg', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('primary tumors', 'Disease', (111, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('breast tumor', 'Disease', 'MESH:D001943', (71, 83))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast tumor', 'Phenotype', 'HP:0100013', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('breast cancer', 'Disease', (20, 33))	('primary tumors', 'Disease', 'MESH:D009369', (111, 125))	('tumor', 'Disease', (78, 83))	('breast tumor', 'Disease', (71, 83))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('CCL2 shRNAs', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('decreased', 'NegReg', (242, 251))
196076	31208996	These data indicate that CCL2 enhances DCIS.com cell proliferation but not apoptosis in a CCR2-dependent manner.	('DCIS.com', 'CellLine', 'CVCL:5552', (39, 47))	('CCL2', 'Var', (25, 29))	('DCIS.com cell proliferation', 'CPA', (39, 66))	('enhances', 'PosReg', (30, 38))
196077	31208996	Analysis of EMT markers indicated that CCL2 inhibited E-cadherin expression in WT cells.	('inhibited', 'NegReg', (44, 53))	('E-cadherin', 'Gene', (54, 64))	('E-cadherin', 'Gene', '999', (54, 64))	('expression', 'MPA', (65, 75))	('EMT', 'Gene', (12, 15))	('EMT', 'Gene', '3702', (12, 15))	('CCL2', 'Var', (39, 43))
196083	31208996	CCR2-KD inhibited CCL2-mediated cell growth and invasion , associated with decreased PCNA expression, but there were no changes in Cleaved Caspase-3 expression .	('inhibited', 'NegReg', (8, 17))	('CCR2-KD', 'Var', (0, 7))	('PCNA', 'Gene', (85, 89))	('CCL2-mediated cell growth', 'CPA', (18, 43))	('invasion', 'CPA', (48, 56))	('PCNA', 'Gene', '5111', (85, 89))	('decreased', 'NegReg', (75, 84))
196085	31208996	CCR2-KD prevented CCL2 suppression of E-Cadherin expression .	('E-Cadherin', 'Gene', (38, 48))	('CCR2-KD', 'Var', (0, 7))	('E-Cadherin', 'Gene', '999', (38, 48))
196086	31208996	CCR2-KD suppressed CCL2-mediated TWIST1 expression in DCIS.com cells .	('DCIS.com', 'CellLine', 'CVCL:5552', (54, 62))	('CCR2-KD', 'Var', (0, 7))	('TWIST1', 'Gene', (33, 39))	('TWIST1', 'Gene', '7291', (33, 39))	('suppressed', 'NegReg', (8, 18))
196091	31208996	In DCIS.com WT cells, CCL2 increased ALDH1A1 expression and activity, which was inhibited with CCR2-KO (Fig.	('CCR2-KO', 'Gene', (95, 102))	('increased', 'PosReg', (27, 36))	('ALDH1A1', 'Gene', '216', (37, 44))	('CCR2-KO', 'Gene', '729230', (95, 102))	('expression', 'MPA', (45, 55))	('activity', 'MPA', (60, 68))	('ALDH1A1', 'Gene', (37, 44))	('DCIS.com', 'CellLine', 'CVCL:5552', (3, 11))	('CCL2', 'Var', (22, 26))
196092	31208996	Similarly, CCL2 increased ALDH1A1 expression and activity in DCIS.com expressing control shRNA cells which were significantly decreased with CCR2-KD (Fig.	('ALDH1A1', 'Gene', '216', (26, 33))	('decreased', 'NegReg', (126, 135))	('activity', 'MPA', (49, 57))	('expression', 'MPA', (34, 44))	('increased', 'PosReg', (16, 25))	('ALDH1A1', 'Gene', (26, 33))	('DCIS.com', 'CellLine', 'CVCL:5552', (61, 69))	('CCR2-KD', 'Var', (141, 148))
196102	31208996	ALDH1A1 knockdown did not significantly affect HTRA2 expression.	('knockdown', 'Var', (8, 17))	('ALDH1A1', 'Gene', '216', (0, 7))	('HTRA2', 'Protein', (47, 52))	('expression', 'MPA', (53, 63))	('ALDH1A1', 'Gene', (0, 7))
196105	31208996	These data indicate an association between the level of ALDH1A1 knockdown to effects on cell proliferation in CCR2-overexpressing SUM225 cells.	('SUM225', 'CellLine', 'CVCL:5593', (130, 136))	('ALDH1A1', 'Gene', (56, 63))	('effects', 'Reg', (77, 84))	('cell proliferation', 'CPA', (88, 106))	('knockdown', 'Var', (64, 73))	('ALDH1A1', 'Gene', '216', (56, 63))
196108	31208996	Therefore, ALDH1A1 was stably overexpressed in CCR2-KO DCIS.com cells through lentiviral transduction (Fig.	('CCR2-KO', 'Gene', '729230', (47, 54))	('ALDH1A1', 'Gene', (11, 18))	('CCR2-KO', 'Gene', (47, 54))	('ALDH1A1', 'Gene', '216', (11, 18))	('DCIS.com', 'CellLine', 'CVCL:5552', (55, 63))	('lentiviral', 'Var', (78, 88))
196110	31208996	Compared to DCIS.com CCR2-KO cells transduced with pHAGE control lentivirus, ALDH1A1 overexpression increased spheroid size in 3D cultures, associated with increased cell proliferation but not cellular invasion, or changes to E-cadherin or TWIST1 expression (Fig.	('DCIS.com', 'CellLine', 'CVCL:5552', (12, 20))	('ALDH1A1', 'Gene', '216', (77, 84))	('increased', 'PosReg', (100, 109))	('CCR2-KO', 'Gene', (21, 28))	('TWIST1', 'Gene', (240, 246))	('expression', 'MPA', (247, 257))	('changes', 'Reg', (215, 222))	('TWIST1', 'Gene', '7291', (240, 246))	('CCR2-KO', 'Gene', '729230', (21, 28))	('increased', 'PosReg', (156, 165))	('spheroid size', 'CPA', (110, 123))	('cell proliferation', 'CPA', (166, 184))	('ALDH1A1', 'Gene', (77, 84))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('overexpression', 'Var', (85, 99))
196112	31208996	To examine how ALDH1A1 functioned in a breast cancer cell line with high levels of endogenous CCR2, we knocked down ALDH1A1 by stable shRNA expression in parental DCIS.com cells.	('ALDH1A1', 'Gene', '216', (15, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('DCIS.com', 'CellLine', 'CVCL:5552', (163, 171))	('ALDH1A1', 'Gene', '216', (116, 123))	('ALDH1A1', 'Gene', (15, 22))	('min', 'Gene', (6, 9))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('min', 'Gene', '11789', (6, 9))	('ALDH1A1', 'Gene', (116, 123))	('knocked', 'Var', (103, 110))	('breast cancer', 'Disease', (39, 52))
196115	31208996	ALDH1A1 knockdown did not affect HTRA2 expression.	('knockdown', 'Var', (8, 17))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (0, 7))
196117	31208996	ALDH1A1 knockdown did not affect basal level spheroid growth or PCNA expression.	('PCNA', 'Gene', (64, 68))	('knockdown', 'Var', (8, 17))	('ALDH1A1', 'Gene', '216', (0, 7))	('PCNA', 'Gene', '5111', (64, 68))	('ALDH1A1', 'Gene', (0, 7))
196119	31208996	ALDH1A1 knockdown resulted in a small but not statistically significant increase in E-cadherin expression in CCL2-treated cells (Fig.	('E-cadherin', 'Gene', (84, 94))	('increase', 'PosReg', (72, 80))	('E-cadherin', 'Gene', '999', (84, 94))	('knockdown', 'Var', (8, 17))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (0, 7))	('expression', 'MPA', (95, 105))
196128	31208996	CCR2-KO cells expressing HTRA2-KD#2 but not HTRA2-KD#3 shRNAs showed a significant increase in spheroid size associated with increased cell proliferation (Fig.	('CCR2-KO', 'Gene', '729230', (0, 7))	('increase', 'PosReg', (83, 91))	('increased', 'PosReg', (125, 134))	('CCR2-KO', 'Gene', (0, 7))	('cell proliferation', 'CPA', (135, 153))	('spheroid size', 'CPA', (95, 108))	('HTRA2-KD#2', 'Var', (25, 35))
196140	31208996	To determine the relevance of p42/44MAPK and SMAD3 to ALDH1A1 and HTRA2 expression, we knocked down expression of p42/44MAPK or SMAD3 by siRNA transfection in DCIS.com and CCR2-H SUM225 cells, treated with or without CCL2 and examined for ALDH1A1 and HTRA2 expression by immunoblot.	('SUM225', 'CellLine', 'CVCL:5593', (179, 185))	('p42/44MAPK', 'Gene', '5594;5595', (114, 124))	('ALDH1A1', 'Gene', (239, 246))	('SMAD3', 'Gene', (45, 50))	('knocked', 'Var', (87, 94))	('p42/44MAPK', 'Gene', (30, 40))	('ALDH1A1', 'Gene', (54, 61))	('SMAD3', 'Gene', '4088', (128, 133))	('DCIS.com', 'CellLine', 'CVCL:5552', (159, 167))	('min', 'Gene', (8, 11))	('min', 'Gene', '11789', (8, 11))	('ALDH1A1', 'Gene', '216', (239, 246))	('p42/44MAPK', 'Gene', '5594;5595', (30, 40))	('SMAD3', 'Gene', (128, 133))	('min', 'Gene', (229, 232))	('ALDH1A1', 'Gene', '216', (54, 61))	('p42/44MAPK', 'Gene', (114, 124))	('min', 'Gene', '11789', (229, 232))	('SMAD3', 'Gene', '4088', (45, 50))	('expression', 'MPA', (100, 110))
196141	31208996	In DCIS.com cells, p42/44MAPK and SMAD3 knockdown inhibited ALDH1A1 expression in CCL2-treated and untreated cells, and increased HTRA2 expression in CCL2-treated and untreated cells.	('ALDH1A1', 'Gene', '216', (60, 67))	('SMAD3', 'Gene', '4088', (34, 39))	('expression', 'MPA', (68, 78))	('SMAD3', 'Gene', (34, 39))	('knockdown', 'Var', (40, 49))	('p42/44MAPK', 'Gene', (19, 29))	('ALDH1A1', 'Gene', (60, 67))	('HTRA2 expression', 'MPA', (130, 146))	('p42/44MAPK', 'Gene', '5594;5595', (19, 29))	('DCIS.com', 'CellLine', 'CVCL:5552', (3, 11))	('increased', 'PosReg', (120, 129))	('inhibited', 'NegReg', (50, 59))
196142	31208996	In CCR2-H SUM225 cells, p42/44MAPK and SMAD3 knockdown did not affect ALDH1A1 expression in untreated cells, but inhibited CCL2 induced ALDH1A1 expression.	('ALDH1A1', 'Gene', '216', (136, 143))	('ALDH1A1', 'Gene', (70, 77))	('p42/44MAPK', 'Gene', '5594;5595', (24, 34))	('inhibited', 'NegReg', (113, 122))	('expression', 'MPA', (144, 154))	('SUM225', 'CellLine', 'CVCL:5593', (10, 16))	('ALDH1A1', 'Gene', '216', (70, 77))	('ALDH1A1', 'Gene', (136, 143))	('p42/44MAPK', 'Gene', (24, 34))	('SMAD3', 'Gene', '4088', (39, 44))	('SMAD3', 'Gene', (39, 44))	('knockdown', 'Var', (45, 54))
196164	31208996	In addition to p42/44MAPK, CCL2/CCR2 activates multiple signaling pathways in breast cancer cells including: PKC, Rho and SRC to regulate growth and motility.	('p42/44MAPK', 'Gene', (15, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('p42/44MAPK', 'Gene', '5594;5595', (15, 25))	('activates', 'PosReg', (37, 46))	('SRC', 'Gene', '6714', (122, 125))	('SRC', 'Gene', (122, 125))	('signaling pathways', 'Pathway', (56, 74))	('PKC', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('PKC', 'Gene', '5590', (109, 112))	('growth and', 'MPA', (138, 148))	('CCL2/CCR2', 'Var', (27, 36))	('breast cancer', 'Disease', (78, 91))
196186	31208996	Despite the differences in how these cells were generated, CCR2 shRNA knockdown and CRISPR knockout both led to a reduction in breast cancer survival and invasion in animal models.	('knockdown', 'Var', (70, 79))	('knockout', 'Var', (91, 99))	('reduction', 'NegReg', (114, 123))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('CCR2', 'Gene', (59, 63))	('invasion', 'CPA', (154, 162))	('CRISPR', 'Gene', (84, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
196192	31208996	Alternatively, ALDH1A1 conversion of retinaldehydes to RA could serve to enhance breast cancer proliferation.	('ALDH1A1', 'Gene', '216', (15, 22))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('retinaldehydes', 'Chemical', 'MESH:D012172', (37, 51))	('RA', 'Chemical', 'MESH:D014212', (55, 57))	('enhance', 'PosReg', (73, 80))	('ALDH1A1', 'Gene', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('conversion', 'Var', (23, 33))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
196196	31208996	Yet, RA can also activate pathways involved in cell proliferation and stem cell activity including p42/44MAPK, PKC and p38MAPK.	('p38MAPK', 'Var', (119, 126))	('activate', 'PosReg', (17, 25))	('pathways', 'Pathway', (26, 34))	('PKC', 'Gene', (111, 114))	('p42/44MAPK', 'Gene', (99, 109))	('PKC', 'Gene', '5590', (111, 114))	('RA', 'Chemical', 'MESH:D014212', (5, 7))	('p42/44MAPK', 'Gene', '5594;5595', (99, 109))	('cell proliferation', 'CPA', (47, 65))
196199	31208996	Interestingly, we noticed differences in the effects of modulating ALDH1A1 expression in parental DCIS.com, CCR2-H SUM225 and CCR2-KO DCIS.com cell invasion.	('modulating', 'Var', (56, 66))	('CCR2-KO', 'Gene', '729230', (126, 133))	('CCR2-KO', 'Gene', (126, 133))	('DCIS.com', 'CellLine', 'CVCL:5552', (98, 106))	('SUM225', 'CellLine', 'CVCL:5593', (115, 121))	('ALDH1A1', 'Gene', (67, 74))	('DCIS.com', 'CellLine', 'CVCL:5552', (134, 142))	('ALDH1A1', 'Gene', '216', (67, 74))
196205	31208996	However, in parental DCIS.com cells, ALDH1A1 knockdown inhibited CCL2 induced cellular invasion.	('cellular invasion', 'CPA', (78, 95))	('ALDH1A1', 'Gene', '216', (37, 44))	('CCL2', 'Gene', (65, 69))	('DCIS.com', 'CellLine', 'CVCL:5552', (21, 29))	('ALDH1A1', 'Gene', (37, 44))	('inhibited', 'NegReg', (55, 64))	('knockdown', 'Var', (45, 54))
196217	31208996	Yet, modulating HTRA2 expression affected breast cancer cell invasion differently among the three cell lines.	('HTRA2', 'Protein', (16, 21))	('affected', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('modulating', 'Var', (5, 15))
196231	31208996	As such, modulating HTRA2 or ALDH1A1 expression would not affect expression of the other gene.	('ALDH1A1', 'Gene', '216', (29, 36))	('modulating', 'Var', (9, 19))	('HTRA2', 'Gene', (20, 25))	('ALDH1A1', 'Gene', (29, 36))	('expression', 'MPA', (65, 75))
196251	31208996	The following plasmids were used to create cell lines: GIPZ ALDH1a1 shRNA, glycerol set (RHS4531-EG216): V2LHS_112035, V2LHS_112037, V2LHS_112039, V2LHS_265598, V3LHS_398453, V3LHS_398455.	('V3LHS_398455', 'Var', (175, 187))	('V2LHS_112037', 'Var', (119, 131))	('V2LHS_112035', 'Var', (105, 117))	('glycerol', 'Chemical', 'MESH:D005990', (75, 83))	('V3LHS_398453', 'Var', (161, 173))	('V2LHS_112039', 'Var', (133, 145))	('V2LHS_265598', 'Var', (147, 159))	('ALDH1a1', 'Gene', (60, 67))	('ALDH1a1', 'Gene', '216', (60, 67))
196252	31208996	GIPZ HTRA2 shRNA, glycerol set (RHS4531-EG27429): V3LHS_315862, V3LHS_315863, V3LHS_315864, V3LHS_3155866.	('V3LHS_315863', 'Var', (64, 76))	('glycerol', 'Chemical', 'MESH:D005990', (18, 26))	('V3LHS_3155866', 'Var', (92, 105))	('V3LHS_315864', 'Var', (78, 90))	('V3LHS_315862', 'Var', (50, 62))
196253	31208996	MGC Human HTRA2 sequence-verified cDNA (3508944), MGC Human ALDH1a1 sequence verified-cDNA (2988388).	('Human', 'Species', '9606', (4, 9))	('2988388', 'Var', (92, 99))	('ALDH1a1', 'Gene', (60, 67))	('3508944', 'Var', (40, 47))	('Human', 'Species', '9606', (54, 59))	('ALDH1a1', 'Gene', '216', (60, 67))
196273	31208996	Slides were blocked in PBS/3% FBS, and incubated overnight with antibodies (1:100) to: Cleaved Caspase-3 (Cell Signaling Technology, cat.	('PBS', 'Chemical', 'MESH:D007854', (23, 26))	('Caspase-3', 'Protein', (95, 104))	('Cleaved', 'Var', (87, 94))
196294	31208996	A5441), phospho-p42/44MAPK Thr202/Tyr204 (Cell Signaling Technology, cat.	('Thr202/Tyr204', 'Var', (27, 40))	('Tyr204', 'Chemical', '-', (34, 40))	('p42/44MAPK', 'Gene', (16, 26))	('Thr202', 'Chemical', '-', (27, 33))	('p42/44MAPK', 'Gene', '5594;5595', (16, 26))
196306	31208996	Significance was determined by *P<0.05, **P<0.01, ***P<0.0001; n.s, not significant or P>0.05.	('***P', 'Var', (50, 54))	('min', 'Gene', '11789', (22, 25))	('min', 'Gene', (22, 25))
196310	29516364	Overall, 16.8% of women who received SLNB had complications, compared with 11.3% of women who did not receive SLNB (p < 0.001).	('complications', 'Disease', (46, 59))	('women', 'Species', '9606', (84, 89))	('women', 'Species', '9606', (18, 23))	('SLNB', 'Var', (37, 41))
196311	29516364	Multivariate analyses of the matched sample showed that, compared with no SLNB, SLNB use was significantly associated with incidence of any complication [adjusted odds ratio (AOR) 1.39; 99% confidence interval (CI) 1.18-1.63], lymphedema (AOR 4.45; 99% CI 2.27-8.75), wound infection (AOR 1.24; 99% CI 1.00-1.54), seroma (AOR 1.40; 99% CI 1.03-1.91), and pain (AOR 1.31; 99% CI 1.04-1.65).	('infection', 'Disease', (274, 283))	('any complication', 'CPA', (136, 152))	('pain', 'Phenotype', 'HP:0012531', (355, 359))	('lymphedema', 'Disease', 'MESH:D008209', (227, 237))	('infection', 'Disease', 'MESH:D007239', (274, 283))	('lymphedema', 'Phenotype', 'HP:0001004', (227, 237))	('use', 'Var', (85, 88))	('pain', 'Disease', 'MESH:D010146', (355, 359))	('pain', 'Disease', (355, 359))	('seroma', 'Disease', 'MESH:D049291', (314, 320))	('SLNB', 'Gene', (80, 84))	('seroma', 'Disease', (314, 320))	('lymphedema', 'Disease', (227, 237))
196317	29516364	Fortunately, breast cancer mortality in patients with pure DCIS remains low, with a reported 10-year cancer-specific survival rate of > 97%.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('patients', 'Species', '9606', (40, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('low', 'NegReg', (72, 75))	('pure', 'Var', (54, 58))
196325	29516364	However, it is unclear whether SLNB (compared with no SLNB) increases side effects among older patients with DCIS.	('SLNB', 'Var', (31, 35))	('patients', 'Species', '9606', (95, 103))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('side effects', 'MPA', (70, 82))
196348	29516364	Tumor characteristics, such as high grade, DCIS tumor size > 2 cm, ER-positive DCIS, and comedonecrosis, were associated with the likelihood of undergoing SLNB (p < 0.001 for all).	('DCIS tumor', 'Disease', 'MESH:D002285', (43, 53))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('comedonecrosis', 'Disease', (89, 103))	('DCIS', 'Disease', (79, 83))	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('DCIS tumor', 'Disease', (43, 53))	('ER', 'Gene', '2099', (67, 69))	('high grade', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))
196351	29516364	In the matched cohort, women who underwent SLNB were more likely to receive subsequent mastectomy within 6 months compared with women who did not undergo SLNB (17.1 versus 5.0%, p < 0.001; Table 2).	('SLNB', 'Var', (43, 47))	('women', 'Species', '9606', (128, 133))	('mastectomy', 'Disease', (87, 97))	('women', 'Species', '9606', (23, 28))
196361	29516364	Existing studies, generally performed as part of a clinical trial or at individual institutions, have demonstrated that SLNB for invasive breast cancer was less likely to lead to side effects compared with ALND, a more invasive procedure.	('invasive breast cancer', 'Disease', (129, 151))	('ALND', 'Disease', 'None', (206, 210))	('SLNB', 'Var', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('invasive breast cancer', 'Disease', 'MESH:D001943', (129, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ALND', 'Disease', (206, 210))
196371	29516364	It may be that, during SLNB for DCIS, the clinical suspicion of the surgeon is lower, leading to resection of fewer lymph nodes in this setting, and a resultant lower rate of lymphedema than seen in other series.	('lymphedema', 'Phenotype', 'HP:0001004', (175, 185))	('lower', 'NegReg', (161, 166))	('lymphedema', 'Disease', (175, 185))	('lymphedema', 'Disease', 'MESH:D008209', (175, 185))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('SLNB', 'Var', (23, 27))
196453	14680489	Whatever our individual bias may be, it seems clear from the studies initiated by Page and colleagues that there exists a lesion that is a marker of increased risk for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('lesion', 'Var', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
196528	32493703	The significance of HER2 positivity in the multivariate model in contrast to the univariate model is related to the association of HER2 positivity with RT.	('association', 'Interaction', (116, 127))	('HER2', 'Gene', (131, 135))	('positivity', 'Var', (25, 35))	('HER2', 'Gene', '2064', (131, 135))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', '2064', (20, 24))
196541	32493703	Our results indicate that patients with HER2+ DCIS lesions are at increased risk of development of iIDC during the first 5 years after diagnosis relative to patients with HER2- DCIS, without any difference in OS or BCSS.	('HER2', 'Gene', (40, 44))	('HER2', 'Gene', '2064', (40, 44))	('iIDC', 'Disease', (99, 103))	('patients', 'Species', '9606', (26, 34))	('HER2', 'Gene', (171, 175))	('lesions', 'Var', (51, 58))	('patients', 'Species', '9606', (157, 165))	('HER2', 'Gene', '2064', (171, 175))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
196542	32493703	Aside from RT which was protective during the first 2 years after diagnosis, HER2 positivity was the only factor in our multivariate model to have a significant association with iIDC development.	('iIDC development', 'CPA', (178, 194))	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (77, 81))	('positivity', 'Var', (82, 92))
196546	32493703	Taken together, these results suggest that HER2 positivity in DCIS is a useful predictor of progression to invasive ductal carcinoma within 5 years of diagnosis.	('HER2', 'Gene', (43, 47))	('positivity', 'Var', (48, 58))	('invasive ductal carcinoma', 'Disease', (107, 132))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (116, 132))	('HER2', 'Gene', '2064', (43, 47))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (107, 132))	('DCIS', 'Phenotype', 'HP:0030075', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
196549	32493703	Similar to their findings we observed significant associations between HER2 positivity and lesions that were larger, high grade, and hormone receptor negative.	('HER2', 'Gene', (71, 75))	('positivity', 'Var', (76, 86))	('HER2', 'Gene', '2064', (71, 75))	('high grade', 'CPA', (117, 127))	('hormone receptor', 'Gene', (133, 149))	('hormone receptor', 'Gene', '3164', (133, 149))
196554	32493703	Triple negative lesions, which are HER2-, were also more likely in their study to be associated with invasive recurrence.	('Triple negative lesions', 'Var', (0, 23))	('HER2', 'Gene', (35, 39))	('HER2', 'Gene', '2064', (35, 39))	('invasive recurrence', 'Disease', (101, 120))	('associated', 'Reg', (85, 95))
196559	32493703	While the above mentioned studies did not perform analysis with time-varying coefficients, when our findings are placed in context with these longer-term studies, they suggest that HER2+ DCIS lesions are associated with invasive ipsilateral recurrence in the short term, the effects of which remain into the 5-10 year time frame with less clear implications on the risk after 10 years (when the Swedish study identified a change in recurrence rates, in spite of the UK study having a similar median follow-up time of 12.7 years).	('DCIS', 'Gene', (187, 191))	('lesions', 'Var', (192, 199))	('HER2', 'Gene', (181, 185))	('associated with', 'Reg', (204, 219))	('invasive ipsilateral recurrence', 'CPA', (220, 251))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('HER2', 'Gene', '2064', (181, 185))
196575	32493703	While ET was not used in the previously mentioned multivariate HER2 studies (though ET is not recommended in Sweden for DCIS so that cohort did not receive any adjuvant ET), it would be interesting to delineate its impact given that ET is not commonly administered to ER negative patients and HER2 positivity was associated with ER negative status in our cohort.	('ET', 'Gene', '79157', (169, 171))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('positivity', 'Var', (298, 308))	('HER2', 'Gene', (293, 297))	('patients', 'Species', '9606', (280, 288))	('ET', 'Gene', '79157', (84, 86))	('HER2', 'Gene', '2064', (293, 297))	('ER', 'Gene', '2099', (294, 296))	('ER', 'Gene', '2099', (268, 270))	('ET', 'Gene', '79157', (233, 235))	('ET', 'Gene', '79157', (6, 8))	('HER2', 'Gene', (63, 67))	('ER', 'Gene', '2099', (64, 66))	('ER', 'Gene', '2099', (329, 331))	('HER2', 'Gene', '2064', (63, 67))
196621	30284611	The proportion of tumor cells with these mutations was higher in the invasive component compared to the DCIS component in a subset of patients.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', (18, 23))	('DCIS', 'Phenotype', 'HP:0030075', (104, 108))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('higher', 'PosReg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
196636	30284611	This custom-made cancer panel was performed on the Ion Torrent Personal Genome Machine (PGM) in order to validate whether those tumor-specific variants identified by whole exome sequencing could also be detected by targeted sequencing, using the same FF DNA samples, to ensure an accurate concordance between these two platforms.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', (17, 23))	('tumor', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('variants', 'Var', (143, 151))
196639	30284611	Based on whole exome sequencing of the four IBC samples, a total number of 792 tumor-specific variants were identified.	('IBC', 'Chemical', '-', (44, 47))	('tumor', 'Disease', (79, 84))	('variants', 'Var', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
196640	30284611	Out of these 792 tumor-specific variants, primers were available for 585 variants.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('variants', 'Var', (32, 40))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))
196641	30284611	In total, 433 out of 585 tumor-specific variants could not be verified as a tumor-specific variant at the (Ion Torrent) validation stage in FF tissue of IBC.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('variants', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('IBC', 'Chemical', '-', (153, 156))
196642	30284611	Out of the remaining 152 tumor-specific variants, 60 variants could not be validated in FFPE tissue of IBC.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('IBC', 'Chemical', '-', (103, 106))	('variants', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
196643	30284611	This resulted in a total number of 92 tumor-specific variants that remained for targeted validation in the DCIS component.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('variants', 'Var', (53, 61))
196644	30284611	Within each patient, a proportion of tumor-specific variants overlapped between the DCIS component and the invasive counterpart (in total 52 out of 92).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('variants', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('patient', 'Species', '9606', (12, 19))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))
196645	30284611	In patient 1, all tumor-specific variants (17 out of 17) that were identified in IBC were also detected in the DCIS component.	('tumor', 'Disease', (18, 23))	('patient', 'Species', '9606', (3, 10))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('variants', 'Var', (33, 41))	('IBC', 'Chemical', '-', (81, 84))
196646	30284611	In the remaining three patients, the number of tumor-specific variants detected in the DCIS component was lower compared to the number detected in the invasive component.	('lower', 'NegReg', (106, 111))	('patients', 'Species', '9606', (23, 31))	('variants', 'Var', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
196648	30284611	In patient 1, the frequency of tumor-specific variants was higher in the invasive component as compared to the DCIS component, which could not be explained by a difference in tumor cell percentage.	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('patient', 'Species', '9606', (3, 10))	('variants', 'Var', (46, 54))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('higher', 'PosReg', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
196652	30284611	This patient showed a higher frequency of tumor-specific variants in DCIS as compared to IBC for three out of the four mutations.	('patient', 'Species', '9606', (5, 12))	('tumor', 'Disease', (42, 47))	('IBC', 'Chemical', '-', (89, 92))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('variants', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('DCIS', 'Gene', (69, 73))
196653	30284611	Taken together, our analyses confirmed a high genomic resemblance between synchronous DCIS and IBC; more than half (52 out of 92) of the mutations identified in the invasive component were also detected in the adjacent in situ component.	('mutations', 'Var', (137, 146))	('IBC', 'Disease', (95, 98))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('IBC', 'Chemical', '-', (95, 98))
196655	30284611	In addition, in a subset of patients, the frequencies of the mutations seemed to be higher in the invasive component as compared to DCIS, which could not be explained by the tumor cell percentages in the analyses.	('tumor', 'Disease', (174, 179))	('invasive component', 'CPA', (98, 116))	('higher', 'Reg', (84, 90))	('mutations', 'Var', (61, 70))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patients', 'Species', '9606', (28, 36))
196657	30284611	At the validation stage, major differences were observed between these two platforms, due to unreadable sequence regions by Ion Torrent, an insufficient number of reads and false-positive tumor-specific variants (validated in normal tissue by Ion Torrent sequencing).	('tumor', 'Disease', (188, 193))	('variants', 'Var', (203, 211))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('insufficient', 'NegReg', (140, 152))
196658	30284611	In addition, a substantial proportion of variants detected in FF tissue of IBC using Ion Torrent sequencing could not be detected in FFPE tissue of the same tumor, which could be due to tumor heterogeneity.	('tumor', 'Disease', (157, 162))	('variants', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('IBC', 'Chemical', '-', (75, 78))
196661	30284611	In conclusion, we reported overlapping mutations between synchronous DCIS and IBC (with differences regarding the frequencies of mutations between both components), combined with the presence of invasive-specific mutations, which support the theory that DCIS progression could be driven by the selection of subclones.	('IBC', 'Chemical', '-', (78, 81))	('DCIS', 'Phenotype', 'HP:0030075', (254, 258))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('mutations', 'Var', (39, 48))	('IBC', 'Gene', (78, 81))	('DCIS', 'Gene', (69, 73))
196737	28415667	Furthermore, radiotherapy may increase mortality from heart disease and lung cancer, resulting in counteracting the slight benefit for breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('heart disease', 'Disease', 'MESH:D006331', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('radiotherapy', 'Var', (13, 25))	('lung cancer', 'Disease', (72, 83))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('increase', 'PosReg', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Disease', (135, 148))	('heart disease', 'Disease', (54, 67))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
196801	32544183	Both MDA-MB-231 and SUM-159PT are TNBCs.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (5, 15))	('SUM-159PT', 'Chemical', '-', (20, 29))	('SUM-159PT', 'Var', (20, 29))	('MDA-MB-231', 'Gene', (5, 15))
196843	32544183	On day 1 and day 3, SUM-159PT had a higher invasion score than MDA-MB-231 cells.	('invasion score', 'CPA', (43, 57))	('higher', 'PosReg', (36, 42))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (63, 73))	('SUM-159PT', 'Var', (20, 29))	('SUM-159PT', 'Chemical', '-', (20, 29))
196846	32544183	These results showed differences in the invasion capacity between the different cell lines despite both MDA-MB-231 and SUM-159PT are classified as TNBC.	('invasion capacity', 'CPA', (40, 57))	('SUM-159PT', 'Var', (119, 128))	('differences', 'Reg', (21, 32))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (104, 114))	('MDA-MB-231', 'Gene', (104, 114))	('SUM-159PT', 'Chemical', '-', (119, 128))
196848	32544183	Specifically, SUM-159PT is highly aggressive compared to MDA-MB-231.	('aggressive', 'MPA', (34, 44))	('SUM-159PT', 'Chemical', '-', (14, 23))	('SUM-159PT', 'Var', (14, 23))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (57, 67))
196879	32544183	Remarkably, higher invasion capacity was observed in SUM-159PT compared to MDA-MB-231, showing collective migration and collagen matrix degradation.	('SUM-159PT', 'Var', (53, 62))	('collective migration', 'CPA', (95, 115))	('higher', 'PosReg', (12, 18))	('SUM-159PT', 'Chemical', '-', (53, 62))	('collagen matrix degradation', 'CPA', (120, 147))	('invasion capacity', 'CPA', (19, 36))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))
196910	28025167	Force-Dependent Breaching of the Basement Membrane Clinically, non-invasive carcinomas are confined to the epithelial side of the basement membrane and are classified as benign, whereas invasive cancers invade through the basement membrane and thereby acquire the potential to metastasize.	('invasive cancers', 'Disease', (186, 202))	('Breaching', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Disease', (76, 86))	('carcinomas', 'Disease', 'MESH:D002277', (76, 86))	('invasive cancers', 'Disease', 'MESH:D009362', (186, 202))	('metastasize', 'CPA', (277, 288))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
196918	28025167	First, matrix rigidity is an important risk factor and mediator of tumor progression, and second, oncogenic mutations and signaling pathways act in concert with the stromal microenvironment to promote tumor cell invasion through the basement membrane.	('promote', 'PosReg', (193, 200))	('rigidity', 'Disease', (14, 22))	('mutations', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('rigidity', 'Phenotype', 'HP:0002063', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('rigidity', 'Disease', 'MESH:D009127', (14, 22))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (201, 206))
196937	28025167	There are three grades of PanINs that correspond to progressively greater architectural distortion of the duct, loss of polarity of the columnar epithelia, and nuclear pleomorphism, culminating in PDAC with invasion of the basement membrane.	('architectural', 'MPA', (74, 87))	('columnar epithelia', 'Disease', (136, 154))	('PDAC', 'Disease', (197, 201))	('PDAC', 'Phenotype', 'HP:0006725', (197, 201))	('polarity', 'MPA', (120, 128))	('columnar epithelia', 'Disease', 'None', (136, 154))	('loss', 'NegReg', (112, 116))	('nuclear pleomorphism', 'Var', (160, 180))	('PDAC', 'Chemical', '-', (197, 201))
196938	28025167	Importantly, acquisition of genetic mutations appear to occur in a stepwise fashion that begins with KRAS2 in PanIN-1, progressing to inactivation of p16/CDKN2A in PanIN-2, and inactivation of TP53 and MAD4/DPC4 (SMAD4) in PanIN-3.	('MAD4', 'Gene', (202, 206))	('MAD4', 'Gene', '4089', (202, 206))	('p16', 'Gene', (150, 153))	('KRAS2', 'Gene', '3845', (101, 106))	('TP53', 'Gene', '7157', (193, 197))	('CDKN2A', 'Gene', (154, 160))	('DPC4', 'Gene', '4089', (207, 211))	('SMAD4', 'Gene', (213, 218))	('DPC4', 'Gene', (207, 211))	('p16', 'Gene', '1029', (150, 153))	('TP53', 'Gene', (193, 197))	('MAD4', 'Gene', '4089', (214, 218))	('CDKN2A', 'Gene', '1029', (154, 160))	('MAD4', 'Gene', (214, 218))	('KRAS2', 'Gene', (101, 106))	('inactivation', 'NegReg', (134, 146))	('inactivation', 'Var', (177, 189))	('SMAD4', 'Gene', '4089', (213, 218))
196951	28025167	Telomerase promoter mutations are found in 6% of low-grade dysplastic nodules, 19% of high-grade dysplastic nodules, and 61% of early HCC.	('dysplastic nodules', 'Disease', (97, 115))	('dysplastic nodules', 'Disease', 'MESH:D004416', (59, 77))	('HCC', 'Gene', (134, 137))	('HCC', 'Gene', '619501', (134, 137))	('dysplastic nodules', 'Disease', 'MESH:D004416', (97, 115))	('dysplastic nodules', 'Disease', (59, 77))	('found', 'Reg', (34, 39))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))	('Telomerase', 'Gene', (0, 10))	('mutations', 'Var', (20, 29))
196952	28025167	Subsequent oncogenic mutations that promote HCC progression are numerous and heterogeneous, but the molecular signatures of the tumors fall into two broad subtypes.	('HCC', 'Gene', (44, 47))	('HCC', 'Gene', '619501', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('fall', 'Phenotype', 'HP:0002527', (135, 139))	('mutations', 'Var', (21, 30))
196955	28025167	Hepatocellular adenomas can be broadly classified into those that harbor hepatocyte nuclear factor 1alpha mutations or those that carry beta-catenin mutations.	('Hepatocellular adenomas', 'Disease', 'MESH:D018248', (0, 23))	('hepatocyte nuclear factor 1alpha', 'Gene', '6927', (73, 105))	('hepatocyte nuclear factor 1alpha', 'Gene', (73, 105))	('mutations', 'Var', (106, 115))	('Hepatocellular adenomas', 'Phenotype', 'HP:0012028', (0, 23))	('Hepatocellular adenomas', 'Disease', (0, 23))
196980	28025167	Inhibition of Rho/Rho-associated protein kinase (ROCK) signaling and ERK activation restored tissue polarity and reduced proliferation of these transformed epithelial cells.	('tissue polarity', 'CPA', (93, 108))	('proliferation', 'CPA', (121, 134))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (113, 120))	('ERK', 'Gene', '5594', (69, 72))	('restored', 'PosReg', (84, 92))	('ERK', 'Gene', (69, 72))
196985	28025167	Importantly, a direct link between ECM stiffness, focal adhesion assembly, and growth factor receptor signaling was illustrated by a series of studies in which focal adhesions were enhanced through expression of a mutant beta1-integrin and ERK signaling in response to EGF stimulation in mammary epithelial cells on a soft ECM.	('ERK', 'Gene', (240, 243))	('enhanced', 'PosReg', (181, 189))	('mutant', 'Var', (214, 220))	('beta1-integrin', 'Gene', '3688', (221, 235))	('EGF', 'Gene', (269, 272))	('beta1-integrin', 'Gene', (221, 235))	('ERK', 'Gene', '5594', (240, 243))	('EGF', 'Gene', '1950', (269, 272))	('focal adhesions', 'CPA', (160, 175))
196994	28025167	Importantly, increased matrix rigidity also has a direct inhibitory effect on hepatocyte function by activating mechano-signal transduction through FAK and decreasing expression of hepatocyte nuclear factor 4 alpha (HNF4alpha), a master transcriptional regulator of hepatic function.	('decreasing', 'NegReg', (156, 166))	('rigidity', 'Phenotype', 'HP:0002063', (30, 38))	('mechano-signal transduction', 'MPA', (112, 139))	('hepatocyte nuclear factor 4 alpha', 'Gene', (181, 214))	('rigidity', 'Disease', 'MESH:D009127', (30, 38))	('HNF4alpha', 'Gene', '3172', (216, 225))	('FAK', 'Var', (148, 151))	('HNF4alpha', 'Gene', (216, 225))	('activating', 'PosReg', (101, 111))	('expression', 'MPA', (167, 177))	('rigidity', 'Disease', (30, 38))	('hepatocyte nuclear factor 4 alpha', 'Gene', '3172', (181, 214))
197011	28025167	Basal-like PDACs are associated with worse patient prognosis and are characterized by perturbed transforming growth factor beta (TGFbeta) signaling with mutant SMAD4 or significantly lower SMAD4 expression.	('SMAD4', 'Gene', '4089', (189, 194))	('expression', 'MPA', (195, 205))	('perturbed', 'NegReg', (86, 95))	('transforming growth factor beta', 'Gene', '7040', (96, 127))	('patient', 'Species', '9606', (43, 50))	('PDAC', 'Chemical', '-', (11, 15))	('SMAD4', 'Gene', (160, 165))	('mutant', 'Var', (153, 159))	('Basal-like PDACs', 'Disease', (0, 16))	('SMAD4', 'Gene', (189, 194))	('transforming growth factor beta', 'Gene', (96, 127))	('PDAC', 'Phenotype', 'HP:0006725', (11, 15))	('SMAD4', 'Gene', '4089', (160, 165))	('lower', 'NegReg', (183, 188))
197012	28025167	In genetically engineered mouse models, Kras mutation and reduced TGFbeta signaling in the pancreatic epithelia lead to ROCK-dependent increased cellular contractility, activation of signal transducer and activator of transcription 3 (STAT3), increased YAP activity, induced expression of connective tissue growth factor, and ECM remodeling, resulting in deposition of thicker and stiffer collagen fibers.	('YAP activity', 'CPA', (253, 265))	('increased', 'PosReg', (243, 252))	('Kras', 'Gene', (40, 44))	('cellular contractility', 'CPA', (145, 167))	('activation', 'PosReg', (169, 179))	('deposition', 'CPA', (355, 365))	('signal transducer and activator of transcription 3', 'Gene', '20848', (183, 233))	('pancreatic epithelia', 'Disease', 'MESH:D010195', (91, 111))	('Kras', 'Gene', '16653', (40, 44))	('TGFbeta signaling', 'Gene', (66, 83))	('thicker', 'PosReg', (369, 376))	('ECM remodeling', 'CPA', (326, 340))	('induced', 'PosReg', (267, 274))	('pancreatic epithelia', 'Disease', (91, 111))	('expression', 'MPA', (275, 285))	('increased', 'PosReg', (135, 144))	('mutation', 'Var', (45, 53))	('mouse', 'Species', '10090', (26, 31))	('reduced', 'NegReg', (58, 65))
197013	28025167	A similar phenotype of increased fibrosis and PDAC development was recapitulated in mice with the Kras mutation and expression of a beta1-integrin clustering mutant with elevated mechano-signal transduction, indicating that cytoskeletal contractility of epithelia could drive stiffening of the periductal ECM.	('fibrosis', 'Disease', 'MESH:D005355', (33, 41))	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('Kras', 'Gene', (98, 102))	('beta1-integrin', 'Gene', (132, 146))	('Kras', 'Gene', '16653', (98, 102))	('beta1-integrin', 'Gene', '3688', (132, 146))	('PDAC', 'Chemical', '-', (46, 50))	('mutation', 'Var', (103, 111))	('fibrosis', 'Disease', (33, 41))	('mice', 'Species', '10090', (84, 88))
197024	28025167	Formation of invadosomes in breast carcinoma cells is regulated by matrix stiffness, and stiff ECM prolongs the lifespan of invadosomes.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('stiff', 'Var', (89, 94))	('breast carcinoma', 'Disease', 'MESH:D001943', (28, 44))	('lifespan', 'CPA', (112, 120))	('breast carcinoma', 'Disease', (28, 44))	('prolongs', 'PosReg', (99, 107))	('breast carcinoma', 'Phenotype', 'HP:0003002', (28, 44))
197032	28025167	The ability of tissue mechanics to potentiate growth factor or cytokine signaling was also demonstrated in PDAC in which loss of TGFbeta signaling and elevated beta1-integrin mechano-signal transduction enhanced STAT3 signaling to induce further matricellular fibrosis and tumor aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (279, 293))	('fibrosis', 'Disease', 'MESH:D005355', (260, 268))	('fibrosis', 'Disease', (260, 268))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (273, 293))	('STAT3 signaling', 'MPA', (212, 227))	('loss', 'Var', (121, 125))	('enhanced', 'PosReg', (203, 211))	('TGFbeta signaling', 'Gene', (129, 146))	('PDAC', 'Chemical', '-', (107, 111))	('beta1-integrin', 'Gene', '3688', (160, 174))	('elevated', 'PosReg', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('beta1-integrin', 'Gene', (160, 174))	('tumor aggressiveness', 'Disease', (273, 293))	('PDAC', 'Disease', (107, 111))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('induce', 'PosReg', (231, 237))
197039	28025167	In PDAC, SMAD4 mutations leading to altered TGFbeta signaling can induce increased tumor stromal stiffening and promote tumor aggressiveness.	('tumor aggressiveness', 'Disease', (120, 140))	('increased', 'PosReg', (73, 82))	('SMAD4', 'Gene', (9, 14))	('PDAC', 'Chemical', '-', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TGFbeta', 'Gene', (44, 51))	('promote', 'PosReg', (112, 119))	('mutations', 'Var', (15, 24))	('tumor stroma', 'Disease', 'MESH:D009369', (83, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (126, 140))	('SMAD4', 'Gene', '4089', (9, 14))	('tumor stroma', 'Disease', (83, 95))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (120, 140))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
197063	22476997	Moreover, adjuvant RT was associated with a 1.53-fold increase in risk for contralateral breast cancer.	('adjuvant', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (75, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('contralateral breast cancer', 'Disease', (75, 102))
197099	22476997	Nevertheless, in contrast to data for patients with invasive breast cancer, who show a significant survival benefit from RT after BCS, none of these randomized trials show a benefit for patients with DCIS in terms of distant metastases, breast cancer-specific survival, or overall survival.	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('invasive breast cancer', 'Disease', 'MESH:D001943', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('invasive breast cancer', 'Disease', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('overall', 'CPA', (273, 280))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('metastases', 'Disease', (225, 235))	('breast cancer', 'Disease', (237, 250))	('metastases', 'Disease', 'MESH:D009362', (225, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('patients', 'Species', '9606', (38, 46))	('DCIS', 'Var', (200, 204))	('patients', 'Species', '9606', (186, 194))
197106	22476997	The authors concluded that patients rigorously evaluated and selected for low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision to omit the post-operative irradiation.	('ipsilateral breast events', 'Disease', (163, 188))	('DCIS', 'Disease', (101, 105))	('patients', 'Species', '9606', (27, 35))	('low', 'NegReg', (151, 154))	('low-', 'Var', (74, 78))
197108	22476997	Harris and Morrow disputed the results, first because the IBEs began to increase after 5 years, especially among patients with low- to intermediate-grade DCIS, and also because patients involved in this trial had overall a more favorable lesion size and margin width than specified by the inclusion criteria.	('increase', 'PosReg', (72, 80))	('IBEs', 'Disease', (58, 62))	('patients', 'Species', '9606', (113, 121))	('patients', 'Species', '9606', (177, 185))	('margin width', 'CPA', (254, 266))	('lesion size', 'CPA', (238, 249))	('more', 'PosReg', (223, 227))	('low-', 'Var', (127, 131))
197112	22476997	point out, a more favorable tumor size among study subjects than specified by inclusion criteria (mean 0.60 cm without comedonecrosis, and 0.95 cm with comedonecrosis in our study) may introduce a positive bias for outcome in the subset of patients for whom RT was omitted.	('tumor', 'Disease', (28, 33))	('comedo', 'Phenotype', 'HP:0025249', (152, 158))	('0.95', 'Var', (139, 143))	('patients', 'Species', '9606', (240, 248))	('comedo', 'Phenotype', 'HP:0025249', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
197131	22323917	However, other studies reported that high-risk DCIS and DCIS with microinvasion (DCISM) are associated with a high incidence of lymph node micrometatasis.	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('lymph node micrometatasis', 'Disease', (128, 153))	('microinvasion', 'Var', (66, 79))	('DCISM', 'Chemical', '-', (81, 86))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))
197187	22323917	Comparative analysis between the consistent group and the underestimated group in initial diagnosis of DCIS showed 6 independent predictors of underestimation in these patients: palpable masses on physical examination, CNB as the method of preoperative diagnosis, mastectomy as the operation method, mean size of whole tumor, comedo necrosis and ER status.	('tumor', 'Disease', (319, 324))	('mastectomy', 'Disease', (264, 274))	('necrosis', 'Disease', 'MESH:D009336', (333, 341))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('CNB', 'Var', (219, 222))	('ER', 'Gene', '2099', (346, 348))	('patients', 'Species', '9606', (168, 176))	('comedo', 'Phenotype', 'HP:0025249', (326, 332))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('necrosis', 'Disease', (333, 341))
197191	22323917	Some authors have also reported that on multivariate analysis, patients diagnosed with DCIS or DCISM by CNB were at increased risk for invasive cancer compared with patients diagnosed by excision biopsy, and our results are consistent with those previously reported.	('CNB', 'Gene', (104, 107))	('DCIS', 'Phenotype', 'HP:0030075', (95, 99))	('DCISM', 'Var', (95, 100))	('invasive cancer', 'Disease', 'MESH:D009362', (135, 150))	('DCIS', 'Phenotype', 'HP:0030075', (87, 91))	('DCIS', 'Var', (87, 91))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (63, 71))	('invasive cancer', 'Disease', (135, 150))	('DCISM', 'Chemical', '-', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
197223	21833355	The pump and Stokes beams are overlapped by adjusting a time-delay line in temporal domain and by the long-pass dichroic mirror DM1 (q1020lpxr, Chroma, VT) in spatial domain to satisfy the precondition for producing a CARS signal.	('q1020lpxr', 'Var', (133, 142))	('VT', 'Disease', 'MESH:D017180', (152, 154))	('Chroma', 'Disease', 'None', (144, 150))	('time-delay line', 'MPA', (56, 71))	('Chroma', 'Disease', (144, 150))
197233	21833355	Unwanted residual signals were blocked using a band-pass filter (BPF) (hq660/40m-2p, Chroma, VT).	('hq660/40m-2p', 'Var', (71, 83))	('VT', 'Disease', 'MESH:D017180', (93, 95))	('Chroma', 'Disease', 'None', (85, 91))	('Chroma', 'Disease', (85, 91))
197245	21833355	We performed two analyses to investigate the separation of cancer subtypes: partial least square regression (PLSR)  and semi-supervised learning (SSL) classification.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('partial', 'Var', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
197328	32051887	In turn, 88% of ER + patients received antiestrogen therapy, whereas 11% of the overall cohort received chemotherapy that was typically driven by molecular subtype (triple-negative or HER2-amplified) or elevated Oncotype DX score.	('HER2', 'Gene', (184, 188))	('ER', 'Gene', '2099', (185, 187))	('HER2', 'Gene', '2064', (184, 188))	('triple-negative', 'Var', (165, 180))	('patients', 'Species', '9606', (21, 29))	('ER', 'Gene', '2099', (16, 18))
197410	16725046	Nodal positivity, subareolar tumour location and multicentricity were significant risk factors for NAC involvement.	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (29, 35))	('NAC involvement', 'Disease', (99, 114))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('multicentricity', 'Var', (49, 64))	('NAC', 'Chemical', '-', (99, 102))
197467	18936692	BLC typically affect young patients, demonstrate rapid clinical growth, preferentially metastasize hematogenously to lung and brain as opposed to lymph nodes, are associated with BRCA1 gene mutations, and are associated with poor outcome.	('BRCA1', 'Gene', '672', (179, 184))	('BRCA1', 'Gene', (179, 184))	('metastasize', 'CPA', (87, 98))	('BLC', 'Gene', '10563', (0, 3))	('mutations', 'Var', (190, 199))	('associated', 'Reg', (163, 173))	('patients', 'Species', '9606', (27, 35))	('BLC', 'Gene', (0, 3))	('preferentially', 'PosReg', (72, 86))
197482	18936692	Indeed, inactivating p53 mutations have been reported to be more frequent in BLC than in other subtypes of breast cancer, which parallels the inactivation of p53 by HPV E6 protein in SCCs.	('mutations', 'Var', (25, 34))	('p53', 'Gene', '7157', (158, 161))	('HPV', 'Species', '10566', (165, 168))	('inactivating', 'Var', (8, 20))	('p53', 'Gene', '7157', (21, 24))	('BLC', 'Gene', (77, 80))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('SCC', 'Phenotype', 'HP:0002860', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('p53', 'Gene', (158, 161))	('p53', 'Gene', (21, 24))	('BLC', 'Gene', '10563', (77, 80))
22146	18936692	For p53 and Ki-67, only nuclear labeling was scored.	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (4, 7))	('Ki-67', 'Var', (12, 17))
197521	18936692	Of note, all luminal A cases demonstrated nuclear-labeling for ER in at least 70% of invasive carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('ER', 'Gene', '2099', (63, 65))	('invasive carcinoma', 'Disease', 'MESH:D009361', (85, 103))	('nuclear-labeling', 'Var', (42, 58))	('invasive carcinoma', 'Disease', (85, 103))
197581	18936692	In contrast, the 6 UTNC cases that had the Rb -/p16+ immunophenotype and aberrant p53 overexpression had a mean Ki-67 index of 56.7% (62.5% highest), whereas the mean Ki-67 index for the remaining UTNC cases was 63.3% (68% highest).	('Rb', 'Phenotype', 'HP:0009919', (43, 45))	('p16', 'Gene', '1029', (48, 51))	('TNC', 'Gene', '3371', (20, 23))	('Rb', 'Gene', '5925', (43, 45))	('TNC', 'Gene', (20, 23))	('Ki-67 index', 'MPA', (112, 123))	('aberrant', 'Var', (73, 81))	('p16', 'Gene', (48, 51))	('p53', 'Gene', (82, 85))	('TNC', 'Gene', '3371', (198, 201))	('p53', 'Gene', '7157', (82, 85))	('overexpression', 'PosReg', (86, 100))	('TNC', 'Gene', (198, 201))
197586	18936692	We demonstrate functional consequences of inactivation of the Rb protein in BLC, in that loss of this mediator of G1 cell cycle arrest is associated with the higher proliferation rates seen in BLC and UTNC than high-grade HER-2-positive IDCs.	('loss', 'Var', (89, 93))	('BLC', 'Gene', (76, 79))	('BLC', 'Gene', (193, 196))	('TNC', 'Gene', (202, 205))	('HER-2', 'Gene', (222, 227))	('HER-2', 'Gene', '2064', (222, 227))	('inactivation', 'Var', (42, 54))	('higher', 'PosReg', (158, 164))	('Rb', 'Phenotype', 'HP:0009919', (62, 64))	('Rb', 'Gene', '5925', (62, 64))	('BLC', 'Gene', '10563', (76, 79))	('BLC', 'Gene', '10563', (193, 196))	('TNC', 'Gene', '3371', (202, 205))
197589	18936692	The latter cancers mimic even more closely HPV-related SCCs at the molecular level, as HPV E6 and E7 protein inactivate p53 and Rb, respectively.	('Rb', 'Gene', '5925', (128, 130))	('HPV E6', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('p53', 'Gene', '7157', (120, 123))	('E7 protein', 'Var', (98, 108))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('HPV', 'Species', '10566', (87, 90))	('inactivate', 'NegReg', (109, 119))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('p53', 'Gene', (120, 123))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('HPV', 'Species', '10566', (43, 46))	('Rb', 'Phenotype', 'HP:0009919', (128, 130))
197592	18936692	Aberrant p53 overexpression and p53 mutations have been correlated with high-grade IDCs (including BLC), so our finding of frequent aberrant p53 overexpression in BLC, UTNC, and HER-2 IDC is not unexpected.	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', '7157', (32, 35))	('overexpression', 'PosReg', (13, 27))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', (9, 12))	('p53', 'Gene', (32, 35))	('overexpression', 'PosReg', (145, 159))	('correlated', 'Reg', (56, 66))	('p53', 'Gene', (141, 144))	('BLC', 'Gene', (163, 166))	('aberrant', 'Var', (132, 140))	('BLC', 'Gene', (99, 102))	('BLC', 'Gene', '10563', (163, 166))	('HER-2', 'Gene', '2064', (178, 183))	('TNC', 'Gene', (169, 172))	('HER-2', 'Gene', (178, 183))	('BLC', 'Gene', '10563', (99, 102))	('TNC', 'Gene', '3371', (169, 172))	('mutations', 'Var', (36, 45))	('high-grade IDCs', 'Disease', (72, 87))
197604	18936692	Such correlation makes biologic sense, in that inactivation of Rb results in inactivation of the G1-S cell cycle checkpoint, and promotes unblocked entry into the cell cycle.	('inactivation', 'Var', (47, 59))	('unblocked', 'MPA', (138, 147))	('promotes', 'PosReg', (129, 137))	('Rb', 'Phenotype', 'HP:0009919', (63, 65))	('inactivation', 'NegReg', (77, 89))	('G1-S cell cycle checkpoint', 'Pathway', (97, 123))	('Rb', 'Gene', '5925', (63, 65))
197609	18936692	Although our Ki-67 proliferation index results support this assertion, correlation with other clinical parameters, such as response to chemotherapy and outcome, and association with BRCA1 gene inactivation, would be required to substantiate this possibility.	('BRCA1', 'Gene', '672', (182, 187))	('BRCA1', 'Gene', (182, 187))	('inactivation', 'Var', (193, 205))	('association', 'Interaction', (165, 176))
197617	18936692	One can postulate that the effects of Rb and p53 inactivation are most distinctive and robust in cells showing squamous differentiation, resulting in higher Ki-67 indices.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('higher', 'PosReg', (150, 156))	('inactivation', 'Var', (49, 61))	('Ki-67 indices', 'CPA', (157, 170))	('Rb', 'Phenotype', 'HP:0009919', (38, 40))	('Rb', 'Gene', '5925', (38, 40))
197621	18936692	Perhaps the frequent (4/6 cases, 67%) inactivation of Rb protein within these DCIS lesions, by promoting unchecked proliferation and further accumulation of genetic alterations, contributes to this rapid evolution to IDC.	('IDC', 'Disease', (217, 220))	('Rb', 'Phenotype', 'HP:0009919', (54, 56))	('Rb', 'Gene', '5925', (54, 56))	('inactivation', 'Var', (38, 50))	('genetic alterations', 'MPA', (157, 176))	('accumulation', 'PosReg', (141, 153))	('unchecked proliferation', 'MPA', (105, 128))	('promoting', 'PosReg', (95, 104))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('protein', 'Protein', (57, 64))
197622	18936692	These authors found that DCIS demonstrating a high p16/high Ki-67 phenotype, which reflects an abrogated response to cellular stress (and likely reflects Rb inactivation), recur more frequently than DCIS demonstrating a high p16/ low Ki-67 index profile, which reflects a physiologic response to stress.	('high', 'Var', (46, 50))	('p16', 'Gene', '1029', (51, 54))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('p16', 'Gene', '1029', (225, 228))	('Rb', 'Phenotype', 'HP:0009919', (154, 156))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('Rb', 'Gene', '5925', (154, 156))	('p16', 'Gene', (51, 54))	('p16', 'Gene', (225, 228))
197625	18936692	On the basis of similar morphology, we hypothesized that similar genes may be inactivated in these neoplasms, albeit by different mechanisms (genomic or epigenetic alterations in breast cancer, HPV in SCCs).	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('epigenetic alterations', 'Var', (153, 175))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (179, 192))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('HPV', 'Species', '10566', (194, 197))	('neoplasms', 'Disease', 'MESH:D009369', (99, 108))	('genomic', 'Var', (142, 149))	('neoplasms', 'Disease', (99, 108))
197626	18936692	Our findings also suggest that one may define a family of BLCs of certain anatomic sites in which distinctive basal-like morphology correlates with inactivation of Rb protein and diffuse p16 expression.	('BLCs', 'Phenotype', 'HP:0002671', (58, 62))	('BLC', 'Gene', '10563', (58, 61))	('p16', 'Gene', '1029', (187, 190))	('Rb', 'Phenotype', 'HP:0009919', (164, 166))	('Rb', 'Gene', '5925', (164, 166))	('BLC', 'Gene', (58, 61))	('inactivation', 'Var', (148, 160))	('p16', 'Gene', (187, 190))
197627	18936692	Poorly differentiated SCCs of the oropharynx, penis, and vulva are established members of this family, and are linked by the presence of high-risk HPV, which inactivates Rb protein.	('inactivates', 'Var', (158, 169))	('Rb', 'Phenotype', 'HP:0009919', (170, 172))	('HPV', 'Gene', (147, 150))	('Rb', 'Gene', '5925', (170, 172))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('HPV', 'Species', '10566', (147, 150))
197631	18936692	We also note that aberrant diffuse p16 and p53 protein expression by IHC now has shown to be characteristic of 2 carcinomas, BLC of the breast (this study) and high-grade serous carcinoma of the ovary, which both are associated with germline BRCA1 gene mutations.	('p16', 'Gene', '1029', (35, 38))	('BLC', 'Gene', (125, 128))	('aberrant', 'Var', (18, 26))	('p16', 'Gene', (35, 38))	('mutations', 'Var', (253, 262))	('BRCA1', 'Gene', '672', (242, 247))	('BLC', 'Gene', '10563', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('serous carcinoma of the ovary', 'Disease', 'MESH:D010051', (171, 200))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('serous carcinoma of the ovary', 'Disease', (171, 200))	('BRCA1', 'Gene', (242, 247))	('carcinomas', 'Disease', (113, 123))
197632	18936692	This observation suggests that inactivation of BRCA1 may mediate carcinogenesis in concert with alterations in the Rb/p16 and p53 pathways.	('mediate', 'Reg', (57, 64))	('BRCA1', 'Gene', (47, 52))	('Rb', 'Gene', '5925', (115, 117))	('p53', 'Gene', '7157', (126, 129))	('inactivation', 'Var', (31, 43))	('p16', 'Gene', '1029', (118, 121))	('BRCA1', 'Gene', '672', (47, 52))	('p16', 'Gene', (118, 121))	('p53', 'Gene', (126, 129))	('carcinogenesis', 'Disease', (65, 79))	('Rb', 'Phenotype', 'HP:0009919', (115, 117))
197640	33537084	The combination of these factors with the TACS-score into a nomogram model further improved the prognosis (AUC: 0.865, [0.829-0.896]; 0.861, [0.816-0.898]; 0.854, [0.805-0.894]; HR 7.882, [5.487-11.323]; 9.176, [5.683-14.816], and 5.548, [3.705-8.307]).	('prognosis', 'CPA', (96, 105))	('TACS', 'Chemical', '-', (42, 46))	('improved', 'PosReg', (83, 91))	('0.854', 'Var', (156, 161))
197751	33537084	While TACS-specific coefficients exhibited small difference among different cohorts, TACS6, 5, 8 (TACS4, 1, 7) were consistently correlated with poor (good) prognosis (Figure 6B).	('poor', 'CPA', (145, 149))	('TACS', 'Chemical', '-', (98, 102))	('TACS', 'Chemical', '-', (85, 89))	('correlated', 'Reg', (129, 139))	('TACS', 'Chemical', '-', (6, 10))	('TACS6', 'Var', (85, 90))
197771	33537084	Although MPM has shown promise in in vivo optical biopsy to improve cancer diagnosis and interoperative tumor margin detection to improve cancer surgery, studies with more direct impact to histology have rarely been clinically validated.	('improve', 'PosReg', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('MPM', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('improve', 'PosReg', (60, 67))
197871	32461218	Women with low/intermediate grade DCIS were less likely than women with high grade DCIS to have mastectomy (20.3% v 37.1%; table S13).	('Women', 'Species', '9606', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('less', 'NegReg', (44, 48))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('mastectomy', 'Disease', (96, 106))	('women', 'Species', '9606', (61, 66))	('low/intermediate grade', 'Var', (11, 33))
197873	32461218	In the period more than seven years after diagnosis of DCIS, the cumulative rate of ipsilateral invasive breast cancer increased more rapidly in women with low/intermediate grade DCIS than in women with high grade DCIS (fig 4).	('low/intermediate grade', 'Var', (156, 178))	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('DCIS', 'Phenotype', 'HP:0030075', (214, 218))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('women', 'Species', '9606', (192, 197))	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (84, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ipsilateral invasive breast cancer', 'Disease', (84, 118))	('women', 'Species', '9606', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
197874	32461218	This was due to higher rates of invasive breast cancer in women with low/intermediate grade DCIS who had had breast conserving surgery rather than mastectomy, irrespective of whether they also had radiotherapy (figure S4).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasive breast cancer', 'Disease', 'MESH:D001943', (32, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('invasive breast cancer', 'Disease', (32, 54))	('women', 'Species', '9606', (58, 63))	('low/intermediate grade', 'Var', (69, 91))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))
197899	32461218	Finally, our study found higher 15 year cumulative rates of ipsilateral invasive breast cancer among women with low/intermediate grade tumours compared with high grade tumours.	('low/intermediate grade', 'Var', (112, 134))	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (60, 94))	('ipsilateral invasive breast cancer', 'Disease', (60, 94))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('higher', 'PosReg', (25, 31))	('tumours', 'Disease', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('women', 'Species', '9606', (101, 106))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
197928	32461218	Our results also show that women who have had a mastectomy have a lower long term risks of invasive disease than do those who had breast conserving surgery, even when accompanied by radiotherapy.	('invasive disease', 'Disease', 'MESH:D009361', (91, 107))	('lower', 'NegReg', (66, 71))	('mastectomy', 'Var', (48, 58))	('invasive disease', 'Disease', (91, 107))	('women', 'Species', '9606', (27, 32))
197951	31049740	DCIS underestimation was defined as the percentage of DCIS lesions on BLES biopsy upgraded to invasive cancer in the surgical specimen.	('upgraded', 'Reg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('lesions', 'Var', (59, 66))	('invasive cancer', 'Disease', (94, 109))	('invasive cancer', 'Disease', 'MESH:D009362', (94, 109))
198218	25036472	Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery alone is associated with higher rates of local recurrence even after selecting patients with the most optimal clinical and pathologic features.	('patients', 'Species', '9606', (236, 244))	('local recurrence', 'CPA', (198, 214))	('omission', 'Var', (128, 136))
198222	25036472	However, recent studies confirm that even low-risk patients identified from multi-gene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of radiation therapy.	('multi-gene assays', 'Var', (76, 93))	('patients', 'Species', '9606', (51, 59))	('local recurrence', 'CPA', (115, 131))
198262	25036472	The initial analysis found that for patients with VNPI scores of 3-4, no benefit to RT following BCS was noted, while for patients with VNPI scores of 5-7, a 17% benefit in local control was observed with the addition of RT.	('patients', 'Species', '9606', (122, 130))	('local', 'MPA', (173, 178))	('patients', 'Species', '9606', (36, 44))	('scores', 'Var', (55, 61))
198285	25036472	Over the past two decades, several trials have attempted to identify a "low-risk" cohort of DCIS patients who may be safely treated with excision alone but have consistently demonstrated an increase in the rate of local failure with the omission of RT and failed to identify a consistent and reproducible subset of patients that does not benefit from adjuvant radiation.	('local failure', 'CPA', (214, 227))	('omission', 'Var', (237, 245))	('patients', 'Species', '9606', (315, 323))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('patients', 'Species', '9606', (97, 105))
198297	27134741	The above-mentioned molecular classification also has prognostic relevance, with triple-negative and HER2+ BC having a more aggressive progression.	('HER2', 'Gene', '2064', (101, 105))	('HER2', 'Gene', (101, 105))	('triple-negative', 'Var', (81, 96))	('BC', 'Phenotype', 'HP:0003002', (107, 109))
198308	27134741	More recently, it has been proposed that for these patients it is also worth testing the presence of mutation in the BC susceptibility genes BRCA1 and BRCA2, independently of their family history .	('BRCA2', 'Gene', '675', (151, 156))	('BRCA1', 'Gene', '672', (141, 146))	('BC', 'Phenotype', 'HP:0003002', (117, 119))	('BRCA1', 'Gene', (141, 146))	('patients', 'Species', '9606', (51, 59))	('mutation', 'Var', (101, 109))	('BRCA2', 'Gene', (151, 156))
198314	27134741	The comprehensive analysis of BC with respect to age on a large compendium of publicly available gene expression datasets (more than 3500 BCYW)  has demonstrated that specific pathways are altered in BCYW with respect to older patients.	('BC', 'Phenotype', 'HP:0003002', (30, 32))	('altered', 'Reg', (189, 196))	('BCYW', 'Var', (200, 204))	('BC', 'Phenotype', 'HP:0003002', (138, 140))	('BC', 'Phenotype', 'HP:0003002', (200, 202))	('patients', 'Species', '9606', (227, 235))
198326	27134741	In particular, we observed that the specific inhibition of p70S6K1 had little effect on blocking the growth of established breast tumors but prevented the onset of BC recurrences when therapy was administered with a perisurgical treatment schedule.	('growth', 'MPA', (101, 107))	('inhibition', 'NegReg', (45, 55))	('BC', 'Phenotype', 'HP:0003002', (164, 166))	('breast tumors', 'Phenotype', 'HP:0100013', (123, 136))	('prevented', 'NegReg', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p70S6K1', 'Var', (59, 66))	('breast tumors', 'Disease', 'MESH:D001943', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('breast tumors', 'Disease', (123, 136))
198363	23607031	MRI is a diagnostic tool useful in the detection of clinically occult cancer with no mammographic and ultrasonographic signs of malignancy; in fact, MRI has a sensitivity of 95% compared to 70% of mammography in the detection of breast lesions.	('occult cancer', 'Disease', 'MESH:D009369', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast lesions', 'Disease', 'MESH:D001941', (229, 243))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('MRI', 'Var', (149, 152))	('malignancy', 'Disease', (128, 138))	('breast lesions', 'Disease', (229, 243))	('occult cancer', 'Disease', (63, 76))
198369	30258937	While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy.	('malignancy', 'Disease', 'MESH:D009369', (202, 212))	('BRCA2', 'Gene', (148, 153))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (44, 50))	('cancers', 'Disease', (80, 87))	('malignancy', 'Disease', (202, 212))	('BRCA1', 'Gene', '672', (139, 144))	('BRCA2', 'Gene', '675', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('BRCA1', 'Gene', (139, 144))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
198375	30258937	Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('epigenetic regulations', 'Var', (46, 68))	('play', 'Reg', (92, 96))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('contribute', 'Reg', (150, 160))	('breast cancer', 'Disease', (254, 267))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('roles', 'Reg', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('noncoding', 'Protein', (73, 82))	('men', 'Species', '9606', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
198385	30258937	Here, we intend to provide a comprehensive up-to-date overview of the basic biological aspects of breast cancer, including the risk factors, specific breast cancer classifications and subtypes, possible roles of mammary stem cells in breast cancer, major signaling pathways in breast cancer development, common gene mutations in breast cancer, the regulatory roles of epigenetics and noncoding RNAs in breast cancer, the molecular basis of triple-negative breast cancer, tumor heterogeneity of breast cancer, and the mechanism underlying breast cancer metastasis.	('breast cancer', 'Disease', 'MESH:D001943', (494, 507))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (494, 507))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (538, 551))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Disease', (277, 290))	('breast cancer', 'Disease', (150, 163))	('tumor', 'Disease', (471, 476))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (538, 562))	('tumor', 'Disease', 'MESH:D009369', (471, 476))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer metastasis', 'Disease', (538, 562))	('breast cancer', 'Disease', 'MESH:D001943', (456, 469))	('mutations', 'Var', (316, 325))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('breast cancer', 'Disease', 'MESH:D001943', (402, 415))	('breast cancer', 'Phenotype', 'HP:0003002', (329, 342))	('breast cancer', 'Disease', (456, 469))	('breast cancer', 'Disease', (234, 247))	('breast cancer', 'Disease', (402, 415))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (471, 476))	('breast cancer', 'Disease', (98, 111))	('breast cancer', 'Disease', 'MESH:D001943', (329, 342))	('breast cancer', 'Disease', (329, 342))	('men', 'Species', '9606', (298, 301))
198406	30258937	Overall, about 5-10% of breast cancers are linked to gene mutations inherited from a parent.	('breast cancers', 'Phenotype', 'HP:0003002', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancers', 'Disease', 'MESH:D001943', (24, 38))	('breast cancers', 'Disease', (24, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('gene mutations', 'Var', (53, 67))	('linked', 'Reg', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))
198407	30258937	The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene.	('BRCA1', 'Gene', (82, 87))	('BRCA2', 'Gene', '675', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('hereditary breast cancer', 'Disease', (25, 49))	('BRCA2', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (66, 74))	('BRCA1', 'Gene', '672', (82, 87))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (25, 49))	('cause', 'Reg', (16, 21))
198408	30258937	Statistically, women with a BRCA1 mutation have a 55-65% lifetime risk of developing breast cancer.	('BRCA1', 'Gene', '672', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('women', 'Species', '9606', (15, 20))	('breast cancer', 'Disease', (85, 98))	('BRCA1', 'Gene', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('mutation', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
198409	30258937	For women with a BRCA2 mutation, the lifetime risk is 45%.	('women', 'Species', '9606', (4, 9))	('BRCA2', 'Gene', (17, 22))	('BRCA2', 'Gene', '675', (17, 22))	('mutation', 'Var', (23, 31))
198410	30258937	On average, a woman with a BRCA1 or BRCA2 gene mutation has about 70% chance of getting breast cancer by age 80.	('BRCA1', 'Gene', '672', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutation', 'Var', (47, 55))	('BRCA2', 'Gene', (36, 41))	('BRCA1', 'Gene', (27, 32))	('woman', 'Species', '9606', (14, 19))	('BRCA2', 'Gene', '675', (36, 41))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
198411	30258937	The effect of the mutation is related to how many other family members have breast cancer, as breast cancer risk goes up if more family members are affected.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('mutation', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
198412	30258937	In the US, BRCA mutations are more common in Jewish people of Ashkenazi (Eastern European) origin than in other racial and ethnic groups although anyone can have these mutations.	('common', 'Reg', (35, 41))	('BRCA', 'Gene', '672', (11, 15))	('BRCA', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('people', 'Species', '9606', (52, 58))
198413	30258937	Women with one of these two mutations are also more likely to be diagnosed with breast cancer at a younger age, as well as to have cancer in both breasts.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (87, 93))	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (28, 37))
198414	30258937	The impact of the BRCA1 and BRCA 2 mutation expands beyond just breast cancer as having mutations in either of these genes is associated with an increased ovarian cancer risk as well.	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('associated', 'Reg', (126, 136))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA 2', 'Gene', '675', (28, 34))	('BRCA 2', 'Gene', (28, 34))	('mutations', 'Var', (88, 97))	('BRCA1', 'Gene', (18, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutation', 'Var', (35, 43))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))	('ovarian cancer', 'Disease', (155, 169))
198415	30258937	Conversely, BRCA1 mutations are found less frequently in breast cancers occurring in men while BRCA2 mutations are associated with a lifetime breast cancer risk of only about 6.8%.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('BRCA2', 'Gene', '675', (95, 100))	('breast cancers', 'Disease', (57, 71))	('mutations', 'Var', (18, 27))	('mutations', 'Var', (101, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('BRCA1', 'Gene', '672', (12, 17))	('BRCA2', 'Gene', (95, 100))	('men', 'Species', '9606', (85, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('BRCA1', 'Gene', (12, 17))
198416	30258937	Although less common and less drastic in their increase of breast cancer risk than the BRCA mutations, inherited mutations in many other genes can also lead to breast cancer development.	('increase of breast cancer', 'Disease', (47, 72))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('BRCA', 'Gene', '672', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('BRCA', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('mutations', 'Var', (113, 122))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('increase of breast cancer', 'Disease', 'MESH:D001943', (47, 72))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lead to', 'Reg', (152, 159))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('men', 'Species', '9606', (181, 184))
198417	30258937	Some of the mutated genes include ATM (inheriting 2 abnormal copies of this gene causes the disease ataxia-telangiectasia), TP53 (inherited mutations of this gene cause Li-Fraumeni syndrome with an increased risk of breast cancer, as well as some other cancers such as leukemia, brain tumors, and sarcomas), CHEK2 (a CHEK2 mutation can increase breast cancer risk about 2-fold), PTEN (inherited mutations in this gene can cause Cowden syndrome which is accompanied by a higher risk for both non-cancerous and cancerous tumors in the breasts, as well as growths in the digestive tract, thyroid, uterus, and ovaries), CDH1 (inherited mutations cause hereditary diffuse gastric cancer with an increased risk of invasive lobular breast cancer), STK11 (mutations in this gene can lead to Peutz-Jeghers syndrome with a higher risk of many types of cancer, including breast cancer), and PALB2 (PALB2 gene makes a protein that interacts with the protein made by the BRCA2 gene, resulting in mutations in this gene causing a higher risk of breast cancer).	('cancer', 'Disease', (352, 358))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('causing', 'Reg', (1006, 1013))	('cancer', 'Phenotype', 'HP:0002664', (509, 515))	('cancerous', 'Disease', 'MESH:D009369', (509, 518))	('brain tumors', 'Disease', (279, 291))	('invasive lobular breast cancer', 'Disease', (708, 738))	('cancers', 'Disease', (253, 260))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (648, 681))	('increase breast cancer', 'Disease', (336, 358))	('leukemia', 'Disease', 'MESH:D007938', (269, 277))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (100, 121))	('breast cancer', 'Disease', (860, 873))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancerous', 'Disease', (509, 518))	('cancer', 'Disease', 'MESH:D009369', (675, 681))	('CHEK2', 'Gene', '11200', (308, 313))	('invasive lobular breast cancer', 'Disease', 'MESH:D001943', (708, 738))	('PALB2', 'Gene', (880, 885))	('lead to', 'Reg', (775, 782))	('cancer', 'Disease', (867, 873))	('cancer', 'Phenotype', 'HP:0002664', (495, 501))	('brain tumors', 'Phenotype', 'HP:0030692', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('brain tumors', 'Disease', 'MESH:D001932', (279, 291))	('ovaries', 'Disease', (606, 613))	('breast cancer', 'Disease', (1031, 1044))	('cancer', 'Disease', (223, 229))	('PALB2', 'Gene', '79728', (880, 885))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('STK11', 'Gene', (741, 746))	('cancer', 'Disease', (732, 738))	('cancer', 'Disease', (675, 681))	('PTEN', 'Gene', '5728', (379, 383))	('CDH1', 'Gene', (616, 620))	('breast cancer', 'Phenotype', 'HP:0003002', (345, 358))	('cancerous', 'Disease', (495, 504))	('mutations', 'Var', (983, 992))	('sarcomas', 'Disease', 'MESH:D012509', (297, 305))	('leukemia', 'Disease', (269, 277))	('cancer', 'Disease', 'MESH:D009369', (509, 515))	('breast cancer', 'Disease', 'MESH:D001943', (860, 873))	('CHEK2', 'Gene', (308, 313))	('cancer', 'Disease', 'MESH:D009369', (842, 848))	('CHEK2', 'Gene', '11200', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (519, 524))	('cancer', 'Disease', 'MESH:D009369', (1038, 1044))	('PTEN', 'Gene', (379, 383))	('ovaries', 'Disease', 'MESH:D010051', (606, 613))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('ataxia', 'Phenotype', 'HP:0001251', (100, 106))	('mutations', 'Var', (748, 757))	('breast cancer', 'Disease', 'MESH:D001943', (1031, 1044))	('cancerous', 'Disease', 'MESH:D009369', (495, 504))	('CDH1', 'Gene', '999', (616, 620))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('PALB2', 'Gene', (887, 892))	('cancerous tumors', 'Disease', (509, 525))	('Cowden syndrome', 'Disease', (428, 443))	('leukemia', 'Phenotype', 'HP:0001909', (269, 277))	('cancer', 'Disease', 'MESH:D009369', (495, 501))	('gastric cancer', 'Phenotype', 'HP:0012126', (667, 681))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('cancer', 'Disease', (1038, 1044))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('CHEK2', 'Gene', (317, 322))	('breast cancer', 'Disease', 'MESH:D001943', (345, 358))	('sarcomas', 'Phenotype', 'HP:0100242', (297, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (725, 738))	('ATM', 'Gene', '472', (34, 37))	('sarcomas', 'Disease', (297, 305))	('telangiectasia', 'Phenotype', 'HP:0001009', (107, 121))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (169, 189))	('breast cancer', 'Disease', (216, 229))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (717, 738))	('cancerous tumors in the breasts', 'Phenotype', 'HP:0100013', (509, 540))	('Cowden syndrome', 'Disease', 'MESH:D006223', (428, 443))	('ataxia-telangiectasia', 'Disease', (100, 121))	('TP53', 'Gene', (124, 128))	('increase breast cancer', 'Disease', 'MESH:D001943', (336, 358))	('ATM', 'Gene', (34, 37))	('cancer', 'Disease', (509, 515))	('cancer', 'Disease', (842, 848))	('hereditary diffuse gastric cancer', 'Disease', (648, 681))	('breast cancer', 'Phenotype', 'HP:0003002', (860, 873))	('BRCA2', 'Gene', (958, 963))	('cancer', 'Disease', 'MESH:D009369', (867, 873))	('TP53', 'Gene', '7157', (124, 128))	('PALB2', 'Gene', '79728', (887, 892))	('Li-Fraumeni syndrome', 'Disease', (169, 189))	('STK11', 'Gene', '6794', (741, 746))	('tumors', 'Phenotype', 'HP:0002664', (519, 525))	('cancer', 'Disease', (253, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (297, 304))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('Peutz-Jeghers syndrome', 'Disease', (783, 805))	('cancerous tumors', 'Disease', 'MESH:D009369', (509, 525))	('cancer', 'Disease', 'MESH:D009369', (732, 738))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('BRCA2', 'Gene', '675', (958, 963))	('breast cancer', 'Disease', 'MESH:D001943', (725, 738))	('breast cancer', 'Phenotype', 'HP:0003002', (1031, 1044))	('cancer', 'Disease', (495, 501))
198418	30258937	Properly and carefully consulted genetic testing of mutations in the BRCA1 and BRCA2 genes, as well as other less commonly mutated genes such as PTEN or TP53 in women in the high risk group can be beneficial for early detection and/or prevention of breast cancer development.	('mutations', 'Var', (52, 61))	('breast cancer', 'Disease', (249, 262))	('BRCA2', 'Gene', '675', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('BRCA1', 'Gene', '672', (69, 74))	('PTEN', 'Gene', (145, 149))	('men', 'Species', '9606', (163, 166))	('PTEN', 'Gene', '5728', (145, 149))	('TP53', 'Gene', '7157', (153, 157))	('BRCA1', 'Gene', (69, 74))	('BRCA2', 'Gene', (79, 84))	('men', 'Species', '9606', (270, 273))	('women', 'Species', '9606', (161, 166))	('TP53', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))
198433	30258937	However, certain proliferative lesions with atypia in the ducts or lobules of the breast tissue will increase breast cancer risk 4-5-fold; and these include atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH).	('increase breast cancer', 'Disease', 'MESH:D001943', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('atypia', 'Var', (44, 50))	('ductal hyperplasia (ADH) and atypical lobular hyperplasia', 'Disease', 'MESH:D006965', (166, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('increase breast cancer', 'Disease', (101, 123))
198443	30258937	These cancers may be caused by genetic mutations that occur as a result of the aging process and lifestyle-related risk factors, rather than inherited mutations.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (39, 48))	('cancers', 'Disease', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('caused by', 'Reg', (21, 30))
198446	30258937	As an injectable form of progesterone, Depo-Provera has been shown to have an increase in breast cancer risk, but there is seemingly no increased risk in women five years after they have stopped receiving the shots.	('Depo-Provera', 'Chemical', 'MESH:D017258', (39, 51))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('women', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('Depo-Provera', 'Var', (39, 51))	('progesterone', 'Chemical', 'MESH:D011374', (25, 37))
198468	30258937	Nonetheless, pregnancy seems to have different effects on different types of breast cancer, and pregnancy seems to increase risk for triple-negative breast cancer.	('breast cancer', 'Disease', (77, 90))	('pregnancy', 'Var', (96, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
198552	30258937	TNBC is more common in women with BRCA1 gene mutations as well as among women younger than 40 years of age and African-American women.	('TNBC', 'Disease', (0, 4))	('BRCA1', 'Gene', '672', (34, 39))	('women', 'Species', '9606', (128, 133))	('mutations', 'Var', (45, 54))	('women', 'Species', '9606', (23, 28))	('BRCA1', 'Gene', (34, 39))	('common', 'Reg', (13, 19))	('women', 'Species', '9606', (72, 77))
198555	30258937	Unlike other breast cancer subtypes with an arsenal of targeted regimens such as ER antagonists and HER2 monoclonal antibodies, TNBC's non-surgical treatment has been limited to conventional chemotherapy, until the recent approval of the PARP inhibitor Olaparib for BRCA1 and BRCA2 mutation carriers, who are more likely to develop TNBC.	('BRCA1', 'Gene', '672', (266, 271))	('mutation', 'Var', (282, 290))	('TNBC', 'Disease', (332, 336))	('BRCA1', 'Gene', (266, 271))	('BRCA2', 'Gene', (276, 281))	('Olaparib', 'Chemical', 'MESH:C531550', (253, 261))	('develop', 'PosReg', (324, 331))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('men', 'Species', '9606', (153, 156))	('HER2', 'Gene', '2064', (100, 104))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('BRCA2', 'Gene', '675', (276, 281))	('breast cancer', 'Disease', (13, 26))	('ER', 'Gene', '2099', (101, 103))	('PARP', 'Gene', '1302', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('HER2', 'Gene', (100, 104))	('men', 'Species', '9606', (68, 71))	('ER', 'Gene', '2099', (81, 83))	('PARP', 'Gene', (238, 242))
198581	30258937	One challenge in accumulating data to either support or negate this theory is the inaccuracy and variability between human and mouse models of selected biomarkers some of which include CD49f, EpCAM, CD10 and ALDH1A1, SSEA4, CD44, CK12+/CK19+ 66.	('EpCAM', 'Gene', '17075', (192, 197))	('mouse', 'Species', '10090', (127, 132))	('CK12', 'Gene', (230, 234))	('human', 'Species', '9606', (117, 122))	('CK12', 'Gene', '268482', (230, 234))	('CD44', 'Var', (224, 228))	('CK19', 'Gene', '16669', (236, 240))	('CD10', 'Gene', '17380', (199, 203))	('CK19', 'Gene', (236, 240))	('CD49f', 'Gene', (185, 190))	('CD49f', 'Gene', '16403', (185, 190))	('ALDH1A1', 'Gene', (208, 215))	('EpCAM', 'Gene', (192, 197))	('CD10', 'Gene', (199, 203))	('SSEA4', 'Gene', (217, 222))
198594	30258937	In essence, cancer is driven by genetic and epigenetic alterations that allow cells to escape the mechanisms that normally control their proliferation, survival and migration.	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('epigenetic alterations', 'Var', (44, 66))
198616	30258937	In a conditional p53 knockout mouse model, the formation of mammary tumors was sped up by the simultaneous knockout of Esr2 (mouse gene coding ERbeta).	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('p53', 'Gene', '22060', (17, 20))	('Esr2', 'Gene', '13983', (119, 123))	('mouse', 'Species', '10090', (125, 130))	('mammary tumors', 'Disease', 'MESH:D001943', (60, 74))	('mammary tumors', 'Disease', (60, 74))	('sped up', 'PosReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p53', 'Gene', (17, 20))	('mouse', 'Species', '10090', (30, 35))	('knockout', 'Var', (107, 115))	('Esr2', 'Gene', (119, 123))
198624	30258937	Ligand binding and subsequent dimerization stimulate phosphorylation of tyrosine residues in the intracellular domain of HER2, leading to the activation of multiple downstream signaling pathways such as the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) pathways.	('HER2', 'Gene', '2064', (121, 125))	('binding', 'Interaction', (7, 14))	('activation', 'PosReg', (142, 152))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('dimerization', 'Var', (30, 42))	('HER2', 'Gene', (121, 125))	('phosphorylation', 'MPA', (53, 68))
198627	30258937	HER2 signaling amplification results in HER2 protein overexpression which is linked to tumor cell proliferation and cancer progression.	('HER2', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('amplification', 'Var', (15, 28))	('overexpression', 'PosReg', (53, 67))	('HER2', 'Gene', '2064', (40, 44))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor cell proliferation', 'Disease', 'MESH:C565054', (87, 111))	('HER2', 'Gene', (0, 4))	('linked', 'Reg', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor cell proliferation', 'Disease', (87, 111))	('HER2', 'Gene', '2064', (0, 4))
198640	30258937	In pursuit of heightened specificity of treatment, HER2 molecular analysis has become an integral part of the diagnostic breast cancer patient work-up.	('patient', 'Species', '9606', (135, 142))	('men', 'Species', '9606', (45, 48))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('molecular analysis', 'Var', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('HER2', 'Gene', (51, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('HER2', 'Gene', '2064', (51, 55))
198643	30258937	Inhibition of GSK-3beta leads to beta-catenin accumulation in the cytoplasm, and its subsequent translocation into the nucleus to act as co-transcriptional activator together with CREB binding protein (CBP) and T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors and regulating oncogenes, such as MYC, CCND1 and other target genes (Fig.	('CBP', 'Gene', (202, 205))	('GSK-3beta', 'Gene', (14, 23))	('CREB binding protein', 'Gene', '1387', (180, 200))	('CBP', 'Gene', '1387', (202, 205))	('beta-catenin', 'Protein', (33, 45))	('CCND1', 'Gene', (322, 327))	('MYC', 'Gene', (317, 320))	('translocation', 'MPA', (96, 109))	('accumulation', 'PosReg', (46, 58))	('Inhibition', 'Var', (0, 10))	('GSK-3beta', 'Gene', '2931', (14, 23))	('CCND1', 'Gene', '595', (322, 327))	('CREB binding protein', 'Gene', (180, 200))	('MYC', 'Gene', '4609', (317, 320))
198644	30258937	The first clue about the role of Wnt signaling in mammary gland development came from the identification of the first mammalian Wnt molecule, Wnt1, as MMTV-induced mouse mammary oncogenesis involved an insertion at Wnt1 locus (or called MMTV int1).	('MMTV', 'Species', '11757', (237, 241))	('Wnt1', 'Gene', (215, 219))	('mouse', 'Species', '10090', (164, 169))	('mammalian', 'Species', '9606', (118, 127))	('men', 'Species', '9606', (71, 74))	('insertion', 'Var', (202, 211))	('MMTV', 'Species', '11757', (151, 155))
198646	30258937	Accordingly, mammary gland-specific expression of stabilized beta-catenin has been shown to result in aggressive adenocarcinomas, consisting predominantly of glandular and undifferentiated cells.	('result in', 'Reg', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('aggressive adenocarcinomas', 'Disease', (102, 128))	('beta-catenin', 'Protein', (61, 73))	('stabilized', 'Var', (50, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('aggressive adenocarcinomas', 'Disease', 'MESH:D001523', (102, 128))
198649	30258937	Overexpression of Wnt-4 was shown to result in an increase in ductal branching, while the mammary tissue of Wnt-4-/- mice exhibited significantly reduced ductal branching compared to their wild-type counterparts.	('Wnt-4', 'Gene', (18, 23))	('reduced', 'NegReg', (146, 153))	('mice', 'Species', '10090', (117, 121))	('increase', 'PosReg', (50, 58))	('Wnt-4', 'Gene', '22417', (18, 23))	('Wnt-4', 'Gene', (108, 113))	('Overexpression', 'Var', (0, 14))	('Wnt-4', 'Gene', '22417', (108, 113))	('ductal branching', 'CPA', (62, 78))
198653	30258937	While mutations in Wnt signaling are not common in breast cancer, it has been shown that approximately 50% of clinical breast cancer cases exhibit high levels of stabilized beta-catenin.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('mutations', 'Var', (6, 15))	('stabilized beta-catenin', 'MPA', (162, 185))
198657	30258937	Furthermore, the expression of APC is lost in approximately 36-50% of breast cancers either by mutations, loss of heterozygosity, or hypermethylation.	('loss of heterozygosity', 'Var', (106, 128))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('expression', 'MPA', (17, 27))	('lost', 'NegReg', (38, 42))	('breast cancers', 'Phenotype', 'HP:0003002', (70, 84))	('breast cancers', 'Disease', 'MESH:D001943', (70, 84))	('APC', 'Disease', 'MESH:D011125', (31, 34))	('breast cancers', 'Disease', (70, 84))	('APC', 'Disease', (31, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypermethylation', 'Var', (133, 149))
198660	30258937	With many of Wnt ligands being able to promote the progression of breast tumors, the restoration of many Wnt inhibitors that has been silenced by mechanisms such as DNA methylation and miRNAs in tumors has effectively attenuated tumor growth.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('breast tumors', 'Disease', 'MESH:D061325', (66, 79))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast tumor', 'Phenotype', 'HP:0100013', (66, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('attenuated tumor', 'Disease', (218, 234))	('restoration', 'Var', (85, 96))	('attenuated tumor', 'Disease', 'MESH:C538265', (218, 234))	('breast tumors', 'Phenotype', 'HP:0100013', (66, 79))	('tumors', 'Disease', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('breast tumors', 'Disease', (66, 79))
198663	30258937	The expression of Wnt1 in human mammary epithelial cells increased stem cell self-renewal, resistance to apoptosis and failure to senescence.	('resistance to apoptosis', 'CPA', (91, 114))	('failure', 'CPA', (119, 126))	('stem cell self-renewal', 'CPA', (67, 89))	('increased', 'PosReg', (57, 66))	('expression', 'Var', (4, 14))	('Wnt1', 'Gene', (18, 22))	('human', 'Species', '9606', (26, 31))
198667	30258937	Similar results were obtained from transgenic mice expressing beta-catenin or c-myc, two downstream components of Wnt signaling, while mammary tumors in transgenic mice expressing Neu, H-Ras or plyoma middle T antigen did not exhibit a similar enrichment for MaSCs.	('transgenic mice', 'Species', '10090', (35, 50))	('transgenic mice', 'Species', '10090', (153, 168))	('beta-catenin', 'Var', (62, 74))	('mammary tumors', 'Disease', 'MESH:D001943', (135, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('plyoma middle T', 'Disease', 'MESH:D020244', (194, 209))	('mammary tumors', 'Disease', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('men', 'Species', '9606', (250, 253))	('c-myc', 'Var', (78, 83))	('H-Ras', 'Gene', (185, 190))	('H-Ras', 'Gene', '15461', (185, 190))	('plyoma middle T', 'Disease', (194, 209))	('Neu', 'Gene', (180, 183))	('Neu', 'Gene', '13866', (180, 183))
198668	30258937	Conditional deletion of a single APC allele in either the mammary stem/progenitor population or luminal cells of lactating mice revealed that mammary tumors only developed when APC was deleted in mammary progenitor cells, but not in luminal cells, suggesting Wnt-induced tumorigenesis targets the stem/progenitor population.	('deletion', 'Var', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('APC', 'Disease', 'MESH:D011125', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('APC', 'Disease', (33, 36))	('deleted', 'Var', (185, 192))	('mammary tumors', 'Disease', 'MESH:D001943', (142, 156))	('mammary tumors', 'Disease', (142, 156))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('APC', 'Disease', 'MESH:D011125', (177, 180))	('tumor', 'Disease', (150, 155))	('APC', 'Disease', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('mice', 'Species', '10090', (123, 127))
198670	30258937	Furthermore, suppression of GSK3/beta-catenin signaling via the inhibitory activity of protein kinase D1 (PRKD1) was sufficient to reduce the stemness features of breast cancer cells.	('inhibitory activity', 'Var', (64, 83))	('stemness features of breast cancer', 'Disease', (142, 176))	('PRKD1', 'Gene', '5587', (106, 111))	('GSK3/beta-catenin signaling', 'MPA', (28, 55))	('PRKD1', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('stemness features of breast cancer', 'Disease', 'MESH:D001943', (142, 176))	('reduce', 'NegReg', (131, 137))	('protein kinase D1', 'Gene', (87, 104))	('suppression', 'NegReg', (13, 24))	('protein kinase D1', 'Gene', '5587', (87, 104))
198673	30258937	These include CDKs (Cyclin dependent kinase), Notch, SHH, PI3K/Akt/mTOR, and others.	('Notch', 'Disease', (46, 51))	('Cyclin', 'Gene', '5111', (20, 26))	('CDKs', 'Var', (14, 18))	('SHH', 'Gene', '20423', (53, 56))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('Cyclin', 'Gene', (20, 26))	('Akt', 'Gene', '207', (63, 66))	('SHH', 'Gene', (53, 56))	('Akt', 'Gene', (63, 66))
198677	30258937	Cyclin D1 amplification is seen in nearly 60% of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (49, 63))	('Cyclin D1', 'Gene', '595', (0, 9))	('breast cancers', 'Disease', 'MESH:D001943', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancers', 'Disease', (49, 63))	('amplification', 'Var', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('Cyclin D1', 'Gene', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
198680	30258937	The oral CDK4/6 inhibitor Palbocyclib alone was shown to inhibit cell cycle progression ER-positive cell lines, including those with HER2 amplification, which were most sensitive to growth inhibition by palbocyclib while nonluminal/basal subtypes were most resistant.	('Palbocyclib', 'Chemical', '-', (26, 37))	('HER2', 'Gene', (133, 137))	('inhibit', 'NegReg', (57, 64))	('HER2', 'Gene', '2064', (133, 137))	('ER', 'Gene', '2099', (134, 136))	('palbocyclib', 'Chemical', '-', (203, 214))	('ER', 'Gene', '2099', (88, 90))	('amplification', 'Var', (138, 151))
198687	30258937	Disruption of its downstream transcriptional targets, Patched homolog-1 (PTCH-1) or glioma-associated oncogene-2 (GLI-2) resulted in severe defects in ductal morphogenesis.	('glioma-associated oncogene-2', 'Gene', '2736', (84, 112))	('GLI-2', 'Gene', '2736', (114, 119))	('PTCH-1', 'Gene', (73, 79))	('glioma-associated oncogene-2', 'Gene', (84, 112))	('Patched homolog-1', 'Gene', '5727', (54, 71))	('GLI-2', 'Gene', (114, 119))	('ductal morphogenesis', 'CPA', (151, 171))	('PTCH-1', 'Gene', '5727', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('Patched homolog-1', 'Gene', (54, 71))	('defects', 'NegReg', (140, 147))	('Disruption', 'Var', (0, 10))
198688	30258937	It was shown that disruptions of these genes also occurred in breast cancer, suggesting a role for the SHH pathway in breast tumorigenesis.	('SHH', 'Gene', '20423', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('breast tumor', 'Disease', 'MESH:D061325', (118, 130))	('SHH', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast tumor', 'Disease', (118, 130))	('breast cancer', 'Disease', (62, 75))	('breast tumor', 'Phenotype', 'HP:0100013', (118, 130))	('disruptions', 'Var', (18, 29))
198691	30258937	Depletion of BRK in breast cancer cells was shown to impair EGFR-regulated signaling.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('BRK', 'Gene', (13, 16))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('BRK', 'Gene', '5753', (13, 16))	('breast cancer', 'Disease', (20, 33))	('Depletion', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('EGFR', 'Gene', '1956', (60, 64))	('impair', 'NegReg', (53, 59))	('EGFR', 'Gene', (60, 64))
198694	30258937	PI3K/AKT/mTOR pathway: As discussed in the following section, oncogenic mutation of PI3K (i.e., PIK3CA) is a common one in human breast cancer that may lead to the dedifferentiation of luminal or basal mammary progenitor cells, allowing them to attain multi-lineage potential.	('breast cancer', 'Disease', (129, 142))	('luminal or basal mammary progenitor cells', 'CPA', (185, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('PI3K', 'Gene', (84, 88))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('human', 'Species', '9606', (123, 128))	('mTOR', 'Gene', (9, 13))	('AKT', 'Gene', '207', (5, 8))	('mTOR', 'Gene', '2475', (9, 13))	('AKT', 'Gene', (5, 8))	('dedifferentiation', 'CPA', (164, 181))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('mutation', 'Var', (72, 80))	('attain multi-lineage potential', 'CPA', (245, 275))	('lead to', 'Reg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
198699	30258937	Thus, mTOR inhibition may be able to restore anti-estrogen sensitivity.	('anti-estrogen sensitivity', 'MPA', (45, 70))	('restore', 'PosReg', (37, 44))	('inhibition', 'Var', (11, 21))	('mTOR', 'Gene', '2475', (6, 10))	('mTOR', 'Gene', (6, 10))
198701	30258937	Among them, up to 20% of women with a family history of breast cancer have a mutation in the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2).	('BRCA2', 'Gene', (145, 150))	('BRCA1', 'Gene', (136, 141))	('mutation', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA2', 'Gene', '675', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('BRCA1', 'Gene', '672', (136, 141))	('breast cancer', 'Disease', (56, 69))	('women', 'Species', '9606', (25, 30))
198703	30258937	The prevalence of germline BRCA mutations is relatively high in women of Ashkenazi Jewish ethnicity, where the risk is estimated to be 30%-35%.	('mutations', 'Var', (32, 41))	('BRCA', 'Gene', (27, 31))	('BRCA', 'Gene', '672', (27, 31))	('women', 'Species', '9606', (64, 69))
198704	30258937	In male breast cancer cases, up to 14% have a BRCA2 mutation although 4.5% of Ashkenazi Jewish men presenting with breast cancer have a BRCA1 mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('BRCA1', 'Gene', (136, 141))	('BRCA2', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('male breast cancer', 'Disease', (3, 21))	('BRCA2', 'Gene', '675', (46, 51))	('men', 'Species', '9606', (95, 98))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('to 14', 'Species', '2282628', (32, 37))	('mutation', 'Var', (52, 60))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('BRCA1', 'Gene', '672', (136, 141))	('breast cancer', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('male breast cancer', 'Disease', 'MESH:D018567', (3, 21))
198705	30258937	Moreover, among women with ovarian cancer, regardless of family history, about 15% are attributable to BRCA mutations, while the proportion with a germline BRCA mutation may be as high as approximately 40% in Ashkenazi Jewish women with epithelial ovarian cancer.	('ovarian cancer', 'Disease', (27, 41))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (237, 262))	('BRCA', 'Gene', '672', (103, 107))	('mutations', 'Var', (108, 117))	('women', 'Species', '9606', (16, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (237, 262))	('BRCA', 'Gene', (103, 107))	('BRCA', 'Gene', '672', (156, 160))	('women', 'Species', '9606', (226, 231))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('BRCA', 'Gene', (156, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (248, 262))	('attributable', 'Reg', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('ovarian cancer', 'Disease', 'MESH:D010051', (248, 262))	('epithelial ovarian cancer', 'Disease', (237, 262))
198707	30258937	Thus, deletion mutations and/or loss of function in the BRCA genes lead to decreased DNA repair efficiency and possibly give rise to the expansion of cancerous cells, elevating the risk of developing breast cancer by five to six fold.	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('cancerous', 'Disease', 'MESH:D009369', (150, 159))	('elevating', 'Reg', (167, 176))	('BRCA', 'Gene', '672', (56, 60))	('cancerous', 'Disease', (150, 159))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('BRCA', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (200, 213))	('DNA repair efficiency', 'MPA', (85, 106))	('deletion mutations', 'Var', (6, 24))	('loss of function', 'NegReg', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('decreased', 'NegReg', (75, 84))
198708	30258937	Even though BRCA mutations can be inherited and responsible for a certain proportion of familial cases, investigators have found no difference in the incidence of breast cancer in BRCA mutation carriers with or without intimate family history.	('breast cancer', 'Disease', (163, 176))	('mutation', 'Var', (185, 193))	('BRCA', 'Gene', (180, 184))	('BRCA', 'Gene', '672', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('BRCA', 'Gene', '672', (12, 16))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('BRCA', 'Gene', (12, 16))
198710	30258937	For more than two decades, the prevalence of genetic variations of the BRCA genes in breast cancer and other cancers has been well-investigated.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', (85, 98))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancers', 'Disease', (109, 116))	('BRCA', 'Gene', '672', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA', 'Gene', (71, 75))	('genetic variations', 'Var', (45, 63))
198713	30258937	A latest update report of the CIMBA dataset summarized a total of 1650 and 1731 unique mutations in BRCA1 and BRCA2 respectively.	('BRCA2', 'Gene', (110, 115))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', '675', (110, 115))	('mutations', 'Var', (87, 96))
198714	30258937	Of all the types of BRCA1 and BRCA2 mutations, frameshift is the most common, mostly leading to the generation of premature stop codons and therefore decreasing the levels of mature RNAs and functional proteins.	('BRCA1', 'Gene', (20, 25))	('decreasing', 'NegReg', (150, 160))	('mutations', 'Var', (36, 45))	('frameshift', 'Var', (47, 57))	('functional proteins', 'MPA', (191, 210))	('BRCA2', 'Gene', (30, 35))	('BRCA1', 'Gene', '672', (20, 25))	('premature stop codons', 'MPA', (114, 135))	('BRCA2', 'Gene', '675', (30, 35))
198715	30258937	Enduring efforts made by researchers or organizations such as CIMBA demonstrate the ubiquitous perception of higher ratio of BRCA mutations in younger patients with more aggressive subgroups of breast cancer.	('higher', 'PosReg', (109, 115))	('BRCA', 'Gene', '672', (125, 129))	('patients', 'Species', '9606', (151, 159))	('BRCA', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
198724	30258937	PI3K signaling is initiated by the growth factor activated receptor tyrosine kinase, or RAS protein, though direct interaction with p85 or via adaptor proteins, resulting PI3K being recruited to the membrane.	('interaction', 'Interaction', (115, 126))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('recruited', 'PosReg', (182, 191))	('PI3K', 'Var', (171, 175))
198725	30258937	Activated PI3K subsequently activates critical downstream mediators AKT and mTOR, leading to enhanced growth, anti-apoptosis, cell-cycle progression, and translation.	('mTOR', 'Gene', (76, 80))	('PI3K', 'Var', (10, 14))	('mTOR', 'Gene', '2475', (76, 80))	('cell-cycle progression', 'CPA', (126, 148))	('anti-apoptosis', 'CPA', (110, 124))	('translation', 'CPA', (154, 165))	('AKT', 'Gene', '207', (68, 71))	('enhanced', 'PosReg', (93, 101))	('activates', 'PosReg', (28, 37))	('AKT', 'Gene', (68, 71))	('growth', 'CPA', (102, 108))
198727	30258937	Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (~30%) observed, along with protein loss of PTEN, although somatic mutations of PIK3CA coding p110alpha in various solid malignancies were first reported in 2004.	('mutations', 'Var', (45, 54))	('malignancies', 'Disease', 'MESH:D009369', (196, 208))	('p110alpha', 'Gene', (169, 178))	('p110alpha', 'Gene', '5290', (169, 178))	('PIK3CA', 'Gene', (38, 44))	('men', 'Species', '9606', (32, 35))	('malignancies', 'Disease', (196, 208))	('PIK3CA', 'Gene', '5290', (38, 44))	('PTEN', 'Gene', (119, 123))	('PIK3CA', 'Gene', (155, 161))	('PTEN', 'Gene', '5728', (119, 123))	('PIK3CA', 'Gene', '5290', (155, 161))
198728	30258937	The majority of PIK3CA somatic mutations are located in the two "hot spots", E542K or E545K in exon 9, and H1047R or H1047L in exon 20, both of which are gain-of-function mutations and have transforming capacity.	('E545K', 'Mutation', 'p.E545K', (86, 91))	('H1047R', 'Mutation', 'p.H1047R', (107, 113))	('E542K', 'Mutation', 'p.E542K', (77, 82))	('PIK3CA', 'Gene', '5290', (16, 22))	('H1047L', 'Var', (117, 123))	('E542K', 'Var', (77, 82))	('gain-of-function', 'PosReg', (154, 170))	('E545K', 'Var', (86, 91))	('H1047L', 'Mutation', 'p.H1047L', (117, 123))	('PIK3CA', 'Gene', (16, 22))	('H1047R', 'Var', (107, 113))
198730	30258937	In addition to PIK3CA mutations, there are many other PI3K-enhancing mechanisms, such as HER2 amplification, dysfunction of PTEN, and AKT1 activating mutation.	('AKT', 'Gene', (134, 137))	('amplification', 'Var', (94, 107))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (124, 128))	('PIK3CA', 'Gene', '5290', (15, 21))	('HER2', 'Gene', (89, 93))	('mutations', 'Var', (22, 31))	('AKT', 'Gene', '207', (134, 137))	('activating', 'PosReg', (139, 149))	('HER2', 'Gene', '2064', (89, 93))	('dysfunction', 'Var', (109, 120))	('PIK3CA', 'Gene', (15, 21))
198731	30258937	For example, PIK3R1 mutations were found in breast cancer with much lower occurrence (~3%) as the PIK3R1 gene product p85alpha plays a tumor-suppressor role by stabilizing p110alpha.	('PIK3R1', 'Gene', '5295', (13, 19))	('PIK3R1', 'Gene', (98, 104))	('p110alpha', 'Gene', (172, 181))	('p85alpha', 'Gene', '5295', (118, 126))	('PIK3R1', 'Gene', (13, 19))	('PIK3R1', 'Gene', '5295', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('breast cancer', 'Disease', (44, 57))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('p85alpha', 'Gene', (118, 126))	('p110alpha', 'Gene', '5290', (172, 181))	('mutations', 'Var', (20, 29))	('stabilizing', 'PosReg', (160, 171))
198732	30258937	AKT1 mutations (E17K) have been found in 1.4%-8% of breast cancers, especially in tumors expressing both ER and PR.	('AKT', 'Gene', (0, 3))	('breast cancers', 'Phenotype', 'HP:0003002', (52, 66))	('tumors', 'Disease', (82, 88))	('E17K', 'Mutation', 'p.E17K', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('found', 'Reg', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (5, 14))	('PR', 'Gene', '5241', (112, 114))	('breast cancers', 'Disease', (52, 66))	('breast cancers', 'Disease', 'MESH:D001943', (52, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('AKT', 'Gene', '207', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ER', 'Gene', '2099', (105, 107))
198733	30258937	PIK3CA mutations and gain of copy number of PIK3CA and PTEN loss and PTEN mutations have also been reported to coexist, although PIK3CA, PTEN, AKT1, and PIK3R1 mutations are reported to be mutually exclusive.	('PTEN', 'Gene', '5728', (55, 59))	('PIK3CA', 'Gene', '5290', (129, 135))	('PTEN loss', 'Disease', (55, 64))	('gain of', 'PosReg', (21, 28))	('PIK3CA', 'Gene', (44, 50))	('PTEN', 'Gene', '5728', (69, 73))	('AKT', 'Gene', '207', (143, 146))	('PIK3R1', 'Gene', (153, 159))	('PIK3CA', 'Gene', '5290', (0, 6))	('PTEN', 'Gene', (137, 141))	('mutations', 'Var', (7, 16))	('PIK3CA', 'Gene', (129, 135))	('PTEN', 'Gene', '5728', (137, 141))	('PTEN', 'Gene', (55, 59))	('PTEN loss', 'Disease', 'MESH:D006223', (55, 64))	('mutations', 'Var', (74, 83))	('PIK3CA', 'Gene', '5290', (44, 50))	('PIK3CA', 'Gene', (0, 6))	('PIK3R1', 'Gene', '5295', (153, 159))	('AKT', 'Gene', (143, 146))	('PTEN', 'Gene', (69, 73))
198734	30258937	Oncogenic PIK3CA mutations are thought to cause dedifferentiation of luminal or basal mammary progenitor cells, allowing them to attain multi-lineage potential.	('PIK3CA', 'Gene', (10, 16))	('attain', 'PosReg', (129, 135))	('cause', 'Reg', (42, 47))	('multi-lineage potential', 'CPA', (136, 159))	('PIK3CA', 'Gene', '5290', (10, 16))	('mutations', 'Var', (17, 26))
198735	30258937	Mutations that upregulate the PI3K pathway in ER-positive breast cancers, such as downregulation of PTEN, overexpression of HER2 or IGF-1R, or the activation of mutant AKT1, can lead to the acquired resistance to hormone therapies in ER-positive tumors.	('PTEN', 'Gene', (100, 104))	('AKT', 'Gene', '207', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('activation', 'PosReg', (147, 157))	('tumors', 'Disease', (246, 252))	('mutant', 'Var', (161, 167))	('PTEN', 'Gene', '5728', (100, 104))	('ER', 'Gene', '2099', (125, 127))	('breast cancers', 'Disease', 'MESH:D001943', (58, 72))	('lead to', 'Reg', (178, 185))	('breast cancers', 'Disease', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('overexpression', 'PosReg', (106, 120))	('PI3K pathway', 'Pathway', (30, 42))	('ER', 'Gene', '2099', (46, 48))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('HER2', 'Gene', '2064', (124, 128))	('breast cancers', 'Phenotype', 'HP:0003002', (58, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('AKT', 'Gene', (168, 171))	('IGF-1R', 'Gene', (132, 138))	('ER', 'Gene', '2099', (234, 236))	('downregulation', 'NegReg', (82, 96))	('upregulate', 'PosReg', (15, 25))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('acquired resistance', 'CPA', (190, 209))	('HER2', 'Gene', (124, 128))
198736	30258937	Overall, PIK3CA mutations are most likely found in luminal-type (HR-positive/HER2-negative) tumors, in particular those with markers indicating less aggressive tumor characteristics.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('HER2', 'Gene', (77, 81))	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('HER2', 'Gene', '2064', (77, 81))	('aggressive tumor', 'Disease', 'MESH:D001523', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('found', 'Reg', (42, 47))	('PIK3CA', 'Gene', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('luminal-type', 'Disease', (51, 63))	('tumors', 'Disease', (92, 98))	('aggressive tumor', 'Disease', (149, 165))
198738	30258937	Nonetheless, it remains to be determined whether PIK3CA mutations are valid prognostic or predictive biomarkers for the clinical management of breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('mutations', 'Var', (56, 65))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('men', 'Species', '9606', (135, 138))	('patients', 'Species', '9606', (157, 165))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
198739	30258937	Mutations of the BRCA1 and BRCA2 genes do not explain the occurrence of breast cancer in every breast cancer prone family.	('BRCA1', 'Gene', '672', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BRCA2', 'Gene', '675', (27, 32))	('breast cancer', 'Disease', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('BRCA1', 'Gene', (17, 22))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', (72, 85))	('BRCA2', 'Gene', (27, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
198741	30258937	These gene mutations are much less common and those representative of this group of genes include the following: ATM and ataxia telangiectasia: The ATM gene product participates in damaged DNA repair.	('mutations', 'Var', (11, 20))	('telangiectasia', 'Phenotype', 'HP:0001009', (128, 142))	('ATM', 'Gene', (113, 116))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (121, 142))	('ATM', 'Gene', '472', (148, 151))	('ataxia', 'Phenotype', 'HP:0001251', (121, 127))	('damaged DNA repair', 'MPA', (181, 199))	('ataxia telangiectasia', 'Disease', (121, 142))	('ATM', 'Gene', '472', (113, 116))	('participates', 'Reg', (165, 177))	('ATM', 'Gene', (148, 151))
198744	30258937	TP53 and Li-Fraumeni syndrome: Inactivating mutations in the TP53 gene have been found in many cancer types including breast cancer.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (9, 29))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('found', 'Reg', (81, 86))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('cancer', 'Disease', (125, 131))	('Li-Fraumeni syndrome', 'Disease', (9, 29))	('breast cancer', 'Disease', (118, 131))	('TP53', 'Gene', '7157', (61, 65))	('Inactivating mutations', 'Var', (31, 53))	('TP53', 'Gene', (61, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
198745	30258937	Li-Fraumeni syndrome is an autosomal dominant disorder, caused by germline mutations in the TP53 gene, leading to an increased risk of osteosarcomas, leukemia, brain tumors, adrenocortical carcinomas, and breast cancers.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (205, 219))	('TP53', 'Gene', (92, 96))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (27, 54))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('brain tumors', 'Disease', 'MESH:D001932', (160, 172))	('brain tumors', 'Phenotype', 'HP:0030692', (160, 172))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('caused', 'Reg', (56, 62))	('osteosarcomas', 'Disease', 'MESH:D012516', (135, 148))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (174, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('adrenocortical carcinomas', 'Disease', (174, 199))	('autosomal dominant disorder', 'Disease', (27, 54))	('leukemia', 'Disease', (150, 158))	('leukemia', 'Disease', 'MESH:D007938', (150, 158))	('brain tumors', 'Disease', (160, 172))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('osteosarcomas', 'Disease', (135, 148))	('TP53', 'Gene', '7157', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (174, 199))	('osteosarcomas', 'Phenotype', 'HP:0002669', (135, 148))	('mutations', 'Var', (75, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancers', 'Disease', 'MESH:D001943', (205, 219))	('breast cancers', 'Disease', (205, 219))
198747	30258937	While germline mutations in the TP53 gene may account for <1% of breast cancer cases, somatic mutations in the TP53 gene are reported in 19-57% of human breast cancers, and LOH is found in 30-42%.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('human', 'Species', '9606', (147, 152))	('mutations', 'Var', (94, 103))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', '7157', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('TP53', 'Gene', (111, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (153, 167))	('TP53', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancers', 'Disease', 'MESH:D001943', (153, 167))	('breast cancers', 'Disease', (153, 167))
198749	30258937	Mutations in the PTEN gene are present in 80% of Cowden syndrome families.	('Cowden syndrome', 'Disease', 'MESH:D006223', (49, 64))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (17, 21))	('PTEN', 'Gene', '5728', (17, 21))	('Cowden syndrome', 'Disease', (49, 64))
198750	30258937	Truncating PTEN mutations in Cowden syndrome families cause a 25-50% lifetime breast cancer risk in women.	('PTEN', 'Gene', (11, 15))	('Cowden syndrome', 'Disease', 'MESH:D006223', (29, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('cause', 'Reg', (54, 59))	('PTEN', 'Gene', '5728', (11, 15))	('Cowden syndrome', 'Disease', (29, 44))	('mutations', 'Var', (16, 25))	('Truncating', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('women', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
198752	30258937	STK11 or LKB1 and Peutz-Jeghers syndrome: Peutz-Jeghers syndrome is caused by truncating germline mutations in the LKB1 gene and is an autosomal dominant disorder characterized by hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa, lips, fingers, and toes.	('STK11', 'Gene', (0, 5))	('hamartomatous polyps', 'Disease', 'MESH:D011127', (180, 200))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (135, 162))	('autosomal dominant disorder', 'Disease', (135, 162))	('men', 'Species', '9606', (227, 230))	('STK11', 'Gene', '6794', (0, 5))	('hamartoma', 'Phenotype', 'HP:0010566', (180, 189))	('mutations', 'Var', (98, 107))	('LKB1', 'Gene', (115, 119))	('hamartomatous polyps', 'Phenotype', 'HP:0004390', (180, 200))	('caused by', 'Reg', (68, 77))	('hamartomatous polyps', 'Disease', (180, 200))	('macules', 'Phenotype', 'HP:0012733', (234, 241))	('LKB1', 'Gene', (9, 13))	('Peutz-Jeghers syndrome', 'Disease', (42, 64))	('LKB1', 'Gene', '6794', (9, 13))	('LKB1', 'Gene', '6794', (115, 119))
198754	30258937	Biallelic germline loss-of-function mutations in PALB2 (also known as FANCN) cause Fanconi's anemia, whereas monoallelic loss-of-function mutations are associated with an increased risk of breast cancer and pancreatic cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('FANCN', 'Gene', (70, 75))	('FANCN', 'Gene', '79728', (70, 75))	('PALB2', 'Gene', '79728', (49, 54))	('loss-of-function', 'NegReg', (19, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (207, 224))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (83, 99))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Disease', (189, 202))	('loss-of-function', 'NegReg', (121, 137))	("Fanconi's anemia", 'Disease', (83, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (207, 224))	('anemia', 'Phenotype', 'HP:0001903', (93, 99))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (83, 99))	('mutations', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('pancreatic cancer', 'Disease', (207, 224))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('PALB2', 'Gene', (49, 54))
198755	30258937	Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them.	('Loss-of-function', 'NegReg', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hereditary breast cancer', 'Disease', (62, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PALB2', 'Gene', '79728', (30, 35))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('PALB2', 'Gene', (30, 35))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (62, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (80, 86))
198757	30258937	Loss of kinase function due to mutation is correlated with several types of cancer, mainly breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('kinase', 'MPA', (8, 14))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('mutation', 'Var', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Loss', 'NegReg', (0, 4))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
198761	30258937	The important role of epigenetic changes such as aberrant DNA methylation and histone modification in cancer causation, progression and treatment has been increasingly recognized and exploited, as the enzymatic processes that control the epigenome present new opportunities for developing therapeutic strategies to target transcriptional abnormalities that are inherent to the cancer epigenome.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('men', 'Species', '9606', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aberrant', 'Var', (49, 57))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))
198762	30258937	In addition, epigenetic factors may provide a mechanism for the development of cancer cell heterogeneity.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('men', 'Species', '9606', (71, 74))	('epigenetic factors', 'Var', (13, 31))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
198764	30258937	The significant demethylation in the binding sites at the enhancers of three well-studied transcriptional factors, ERalpha, FOCA1, and GATA has been detected in ER + breast cancers in comparison to normal breast tissue.	('ER', 'Gene', '2099', (161, 163))	('binding', 'Interaction', (37, 44))	('GATA', 'Gene', (135, 139))	('GATA', 'Gene', '55278', (135, 139))	('demethylation', 'Var', (16, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (166, 180))	('detected', 'Reg', (149, 157))	('ER', 'Gene', '2099', (115, 117))	('FOCA1', 'Gene', (124, 129))	('breast cancers', 'Disease', 'MESH:D001943', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancers', 'Disease', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
198766	30258937	DNA methylation at the enhancers of ERalpha binding sites may also be a root cause of resistance to anti-estrogen treatments like tamoxifen for ER + breast cancers.	('ER', 'Gene', '2099', (144, 146))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cause', 'Reg', (77, 82))	('tamoxifen', 'Chemical', 'MESH:D013629', (130, 139))	('methylation', 'Var', (4, 15))	('breast cancers', 'Phenotype', 'HP:0003002', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancers', 'Disease', 'MESH:D001943', (149, 163))	('ER', 'Gene', '2099', (36, 38))	('breast cancers', 'Disease', (149, 163))	('men', 'Species', '9606', (119, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('resistance', 'MPA', (86, 96))
198778	30258937	In addition, it has been shown that dysregulation of lncRNAs plays critical roles in tumorigenesis.	('dysregulation', 'Var', (36, 49))	('tumor', 'Disease', (85, 90))	('lncRNAs', 'Protein', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
198779	30258937	Since ncRNAs are involved in regulating gene expression through interaction with epigenetic modifiers, their dysregulation may cause epigenetic alterations in cancer.	('cancer', 'Disease', (159, 165))	('dysregulation', 'Var', (109, 122))	('cause', 'Reg', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('epigenetic alterations', 'MPA', (133, 155))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('interaction', 'Interaction', (64, 75))
198780	30258937	Dissection of the interrelationships between ncRNAs and epigenetic alterations has the potential to reveal novel approaches to the diagnosis and treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('men', 'Species', '9606', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epigenetic', 'Var', (56, 66))
198783	30258937	Substitution errors are the most frequent aberrations in noncoding regulatory regions, namely the promoters of cancer-associated genes including OBSCN and TP53.	('promoters', 'MPA', (98, 107))	('OBSCN', 'Gene', '84033', (145, 150))	('TP53', 'Gene', '7157', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TP53', 'Gene', (155, 159))	('Substitution errors', 'Var', (0, 19))	('OBSCN', 'Gene', (145, 150))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
198784	30258937	Additionally, identified genetic variations in promotors, introns, and other such regulatory noncoding regions may impact the phosphorylation, protein-protein interaction, and regulation of cancer-associated genes including ATM/ATR, FGFR1, FOXA1, IGF1R, NF1, NOTCH2, and TOP2A.	('NOTCH2', 'Gene', (259, 265))	('NF1', 'Gene', (254, 257))	('ATM', 'Gene', (224, 227))	('genetic variations', 'Var', (25, 43))	('IGF1R', 'Gene', '3480', (247, 252))	('cancer', 'Disease', (190, 196))	('regulation', 'MPA', (176, 186))	('ATR', 'Gene', (228, 231))	('impact', 'Reg', (115, 121))	('TOP2A', 'Gene', (271, 276))	('IGF1R', 'Gene', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('FGFR1', 'Gene', '2260', (233, 238))	('TOP2A', 'Gene', '7153', (271, 276))	('phosphorylation', 'MPA', (126, 141))	('FOXA1', 'Gene', '3169', (240, 245))	('protein-protein interaction', 'MPA', (143, 170))	('NOTCH2', 'Gene', '4853', (259, 265))	('ATR', 'Gene', '545', (228, 231))	('FOXA1', 'Gene', (240, 245))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('ATM', 'Gene', '472', (224, 227))	('FGFR1', 'Gene', (233, 238))	('NF1', 'Gene', '4763', (254, 257))
198786	30258937	The hypomethylation of lncRNA EPIC1 upregulates its expression, and EPIC1 overexpression is related to poor survival outcomes in independent patient cohorts, in particular, for luminal B breast cancer, and was shown to promote tumorigenesis through interacting directly with MYC to increase the occupation of MYC target genes and promote cell-cycle progression.	('tumor', 'Disease', (227, 232))	('interacting', 'Interaction', (249, 260))	('MYC', 'Gene', '4609', (275, 278))	('luminal B breast cancer', 'Disease', (177, 200))	('cell-cycle progression', 'CPA', (338, 360))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('luminal B breast cancer', 'Disease', 'MESH:D001943', (177, 200))	('hypomethylation', 'Var', (4, 19))	('lncRNA EPIC1', 'Gene', (23, 35))	('patient', 'Species', '9606', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('increase', 'PosReg', (282, 290))	('MYC', 'Gene', (309, 312))	('overexpression', 'PosReg', (74, 88))	('occupation', 'MPA', (295, 305))	('promote', 'PosReg', (219, 226))	('promote', 'PosReg', (330, 337))	('MYC', 'Gene', (275, 278))	('upregulates', 'PosReg', (36, 47))	('expression', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('MYC', 'Gene', '4609', (309, 312))	('EPIC1', 'Gene', (68, 73))
198788	30258937	Nonetheless, while herculean efforts have been in place to identify genetic driver mutations for breast cancer, the realm of noncoding RNA sequences and epigenetic factors remain largely unexplored by comparison.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
198791	30258937	Genetically, <20% of patients with TNBC harbor a breast cancer gene (BRCA) mutation, particularly in BRCA1.	('BRCA', 'Gene', '672', (69, 73))	('BRCA1', 'Gene', '672', (101, 106))	('BRCA', 'Gene', (69, 73))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRCA', 'Gene', '672', (101, 105))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('patients', 'Species', '9606', (21, 29))	('BRCA1', 'Gene', (101, 106))	('breast cancer', 'Disease', (49, 62))	('BRCA', 'Gene', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
198805	30258937	Conversely, the basal-like tumors within the IntClust 10 subtype had high genomic instability with major chromosomal aberrations, such as chromosome 5 loss, 8q gain, 10p gain or 12p gain.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('chromosome', 'Var', (138, 148))	('10p', 'CPA', (166, 169))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (105, 128))	('gain', 'PosReg', (182, 186))	('tumors', 'Disease', (27, 33))	('12p', 'CPA', (178, 181))	('gain', 'PosReg', (160, 164))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('gain', 'PosReg', (170, 174))	('genomic instability', 'CPA', (74, 93))	('loss', 'NegReg', (151, 155))
198813	30258937	Genome-wide mutational landscape analyses indicate that TNBC tumors on average carry 1.68 somatic mutations per Mb of coding regions and harbor ~60 somatic mutations in per tumor.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TNBC', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
198815	30258937	The overall consensus is that TNBCs have a frequent occurrence of multiple copy-number aberrations involving genes that lead to alterations in multiple signal pathways, which include the mutations/deletions of BRCA1/2 in the DNA repair pathway; the mutations and/or amplifications of PIK3CA and AKT3 and deletions/mutations of PTEN, TSC1 and INPP4B of the PI3K/mTOR pathway; the amplifications of FGFR1, EGFR and IGF1R, mutations of ERBB2, ERBB3 and ERBB4, and amplifications/mutations of BRAF, KRAS, and HRAS and the deletion of DUSP4 of the RAS/RAF/MEK pathway; the deletions of RB1 and amplifications of CDK6, CCND1and CCND2 of the cell-cycle checkpoints; the amplification of JAK2 in the JAK/STAT pathway; along with androgen receptor pathway, Notch pathway, JNK/AP-1 pathway, and HIF1-alpha/ARNT pathway.	('AKT', 'Gene', (295, 298))	('PIK3CA', 'Gene', (284, 290))	('TNBCs', 'Chemical', '-', (30, 35))	('mTOR', 'Gene', (361, 365))	('Notch pathway', 'Pathway', (748, 761))	('EGFR', 'Gene', '1956', (404, 408))	('CCND1', 'Gene', '595', (613, 618))	('amplification', 'Var', (663, 676))	('FGFR1', 'Gene', (397, 402))	('deletions', 'Var', (568, 577))	('mutations', 'Var', (420, 429))	('CCND1', 'Gene', (613, 618))	('BRCA1', 'Gene', '672', (210, 215))	('mTOR', 'Gene', '2475', (361, 365))	('JAK2', 'Gene', '3717', (680, 684))	('IGF1R', 'Gene', '3480', (413, 418))	('AKT', 'Gene', '207', (295, 298))	('BRCA1', 'Gene', (210, 215))	('IGF1R', 'Gene', (413, 418))	('ER', 'Gene', '2099', (433, 435))	('PTEN', 'Gene', (327, 331))	('ER', 'Gene', '2099', (450, 452))	('PIK3CA', 'Gene', '5290', (284, 290))	('HIF1-alpha/ARNT pathway', 'Pathway', (785, 808))	('androgen receptor pathway', 'Pathway', (721, 746))	('JNK/AP-1 pathway', 'Pathway', (763, 779))	('JAK/STAT pathway', 'Pathway', (692, 708))	('ERBB2', 'Gene', (433, 438))	('JAK2', 'Gene', (680, 684))	('EGFR', 'Gene', (404, 408))	('deletion', 'Var', (518, 526))	('PTEN', 'Gene', '5728', (327, 331))	('FGFR1', 'Gene', '2260', (397, 402))	('ER', 'Gene', '2099', (440, 442))	('RB1', 'Gene', (581, 584))	('CDK6', 'Gene', (607, 611))	('ERBB2', 'Gene', '2064', (433, 438))
198816	30258937	Many of these alterations may serve as novel targets for personalized targeted therapies in TNBCs.	('alterations', 'Var', (14, 25))	('person', 'Species', '9606', (57, 63))	('TNBCs', 'Disease', (92, 97))	('TNBCs', 'Chemical', '-', (92, 97))
198829	30258937	Breast cancer intratumor heterogeneity is likely caused by the phenotypic plasticity, clonal evolution of cancer stem cells and epithelial-mesenchymal transition (EMT) driven by epigenetic, genetic, and microenvironmental alterations in breast cancers.	('Breast cancer intratumor', 'Disease', 'MESH:D001943', (0, 24))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Disease', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('epigenetic', 'Var', (178, 188))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('caused', 'Reg', (49, 55))	('men', 'Species', '9606', (215, 218))	('cancer', 'Disease', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('breast cancers', 'Disease', 'MESH:D001943', (237, 251))	('breast cancers', 'Disease', (237, 251))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer intratumor', 'Disease', (0, 24))	('breast cancers', 'Phenotype', 'HP:0003002', (237, 251))
198837	30258937	In the clonal evolution model, tumor progression and resistance to therapy should follow Darwinian evolutionary rules, in which the emergence of clones able to progress or be resistant to a therapy should depend on the size of cell population, gene mutation rate, cell proliferation rate, and selective pressures from the microenvironment and/or external selective pressures.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('men', 'Species', '9606', (334, 337))	('tumor', 'Disease', (31, 36))	('gene mutation', 'Var', (244, 257))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
198855	30258937	As a result, most distant metastases acquired driver mutations were not seen in the primary tumors, drawing from a wider repertoire of cancer genes than early drivers, many of which include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways.	('cancer', 'Disease', (135, 141))	('alterations', 'Var', (224, 235))	('JAK2', 'Gene', '3717', (275, 279))	('inactivating', 'NegReg', (250, 262))	('metastases', 'Disease', 'MESH:D009362', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('STAT3', 'Gene', '6774', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('metastases', 'Disease', (26, 36))	('primary tumors', 'Disease', (84, 98))	('STAT3', 'Gene', (280, 285))	('JAK2', 'Gene', (275, 279))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (240, 249))	('primary tumors', 'Disease', 'MESH:D001932', (84, 98))
198870	30258937	Furthermore, it is suggested that circulating tumor cells (CTCs) in the blood may play an active role of carcinoma metastasis, and the presence of CTCs correlates to poor patient prognosis and an increase in metastatic sites in patient data.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('patient', 'Species', '9606', (171, 178))	('metastatic sites', 'CPA', (208, 224))	('tumor', 'Disease', (46, 51))	('presence', 'Var', (135, 143))	('CTCs', 'Var', (147, 151))	('carcinoma metastasis', 'Disease', 'MESH:D009362', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma metastasis', 'Disease', (105, 125))	('increase', 'PosReg', (196, 204))	('patient', 'Species', '9606', (228, 235))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
198888	30258937	While the most common inherited genetic factor, the BRCA1 and BRCA2 gene mutations, have rightfully been studied in depth, upwards of 85% of breast cancers occur in women without apparent family history of the disease which includes the inherited BRCA1/2 mutations.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('BRCA1', 'Gene', '672', (247, 252))	('BRCA1', 'Gene', '672', (52, 57))	('BRCA2', 'Gene', '675', (62, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('BRCA1', 'Gene', (52, 57))	('BRCA1', 'Gene', (247, 252))	('breast cancers', 'Disease', (141, 155))	('women', 'Species', '9606', (165, 170))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('BRCA2', 'Gene', (62, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('occur', 'Reg', (156, 161))	('mutations', 'Var', (73, 82))	('mutations', 'Var', (255, 264))
198889	30258937	We hope to draw attention to the suggestion that naturally arises from this statistic that these cancers may be caused by genetic mutations that occur as a result of the aging process and lifestyle-related risk factors, rather than inherited mutations.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('caused by', 'Reg', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (130, 139))
198896	30258937	The recent evidence supports that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially that of triple-negative breast cancer.	('breast cancer', 'Disease', (246, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('men', 'Species', '9606', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', (196, 209))	('roles', 'Reg', (95, 100))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('epigenetic regulations', 'Var', (34, 56))	('breast cancer', 'Disease', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('noncoding RNAs', 'Var', (61, 75))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('contribute', 'Reg', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('play', 'Reg', (80, 84))
198908	26751011	Also, in patients with dense fibroadenosis and ACR (American College of Radiology) Category 4 breasts, DWI helps in increasing the specificity in identification of suspicious lesion after better signal suppression from breast parenchyma at high b value.	('patients', 'Species', '9606', (9, 17))	('fibroadenosis', 'Disease', (29, 42))	('fibroadenosis', 'Disease', 'MESH:D000232', (29, 42))	('increasing', 'PosReg', (116, 126))	('DWI', 'Var', (103, 106))	('specificity', 'MPA', (131, 142))
198995	19134194	As mentioned above, high eIF4E overexpression has been associated with a worse clinical outcome.	('eIF4E', 'Gene', (25, 30))	('high', 'Var', (20, 24))	('eIF4E', 'Gene', '1977', (25, 30))	('overexpression', 'PosReg', (31, 45))	('men', 'Species', '9606', (3, 6))
199027	19134194	Primary incubation of the membranes was carried out using a 1:1000 dilution of monoclonal mouse anti-eIF4E antibody (610270; BD Biosciences, San Jose, CA) or rabbit anti-TLK1B antibody (1:1000 dilution, De Benedetti laboratory).	('eIF4E', 'Gene', (101, 106))	('mouse', 'Species', '10090', (90, 95))	('rabbit', 'Species', '9986', (158, 164))	('eIF4E', 'Gene', '1977', (101, 106))	('610270;', 'Var', (117, 124))
199149	29848352	Calpain II was significantly associated with pAKT (p = 0.029), pmTOR (p = 0.011), p4E-BP1 (p < 0.001) and p-p70S6K (p = 0.003) expression levels.	('p4E-BP1', 'Var', (82, 89))	('AKT', 'Gene', '207', (46, 49))	('p-p70S6K', 'Var', (106, 114))	('Calpain II', 'Protein', (0, 10))	('AKT', 'Gene', (46, 49))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('associated', 'Reg', (29, 39))
199151	29848352	The OS curve showed a dramatic impact of C-FOXP1 status on OS (p = 0.045).	('FOXP1', 'Gene', '27086', (43, 48))	('OS', 'Chemical', '-', (59, 61))	('OS', 'Chemical', '-', (4, 6))	('FOXP1', 'Gene', (43, 48))	('impact', 'Reg', (31, 37))	('status', 'Var', (49, 55))
199161	29848352	For example, N-FOXP1 protein is up-regulated in diffuse large B-cell lymphoma (DLBCL) and extranodal marginal zone or mucosa-associated lymphoid tissue (MALT) lymphoma, while loss of N-FOXP1 expression characterizes malignancy in certain solid tumors, including endometrial and prostate tumors as well as familial and sporadic breast cancer.	('extranodal marginal zone', 'Disease', (90, 114))	('solid tumors', 'Disease', 'MESH:D009369', (238, 250))	('malignancy', 'Disease', (216, 226))	('FOXP1', 'Gene', (185, 190))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('FOXP1', 'Gene', '27086', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('diffuse large B-cell lymphoma', 'Disease', (48, 77))	('protein', 'Protein', (21, 28))	('familial', 'Disease', (305, 313))	('FOXP1', 'Gene', (15, 20))	('endometrial and prostate tumors', 'Disease', 'MESH:D016889', (262, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('solid tumors', 'Disease', (238, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (327, 340))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('malignancy', 'Disease', 'MESH:D009369', (216, 226))	('FOXP1', 'Gene', '27086', (185, 190))	('up-regulated', 'PosReg', (32, 44))	('breast cancer', 'Disease', 'MESH:D001943', (327, 340))	('breast cancer', 'Disease', (327, 340))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('loss', 'Var', (175, 179))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (62, 77))
199162	29848352	The presence of N-FOXP1 expression is correlated with ERalpha and/or ERbeta reactivity in invasive breast cancers.	('ERalpha', 'Gene', '2099', (54, 61))	('ERbeta', 'Gene', (69, 75))	('invasive breast cancers', 'Disease', (90, 113))	('FOXP1', 'Gene', '27086', (18, 23))	('invasive breast cancers', 'Disease', 'MESH:D001943', (90, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('FOXP1', 'Gene', (18, 23))	('presence', 'Var', (4, 12))	('correlated', 'Reg', (38, 48))	('breast cancers', 'Phenotype', 'HP:0003002', (99, 113))	('ERalpha', 'Gene', (54, 61))	('ERbeta', 'Gene', '2100', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
199169	29848352	Overall, FOXP1 positivity, with either nuclear or an unspecified distribution, is associated with favorable survival in patients with breast cancer.	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('favorable', 'PosReg', (98, 107))	('positivity', 'Var', (15, 25))	('FOXP1', 'Gene', '27086', (9, 14))	('patients', 'Species', '9606', (120, 128))	('unspecified', 'Species', '32644', (53, 64))	('FOXP1', 'Gene', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
199173	29848352	The ubiquitously expressed family members, mu-calpain (calpain I) and m-calpain (calpain II), are the most extensively studied calpains.	('m-calpain', 'Gene', (70, 79))	('m-calpain', 'Gene', '824', (70, 79))	('mu-calpain', 'Var', (43, 53))
199177	29848352	The PI3K/AKT/mTOR signaling pathway, including its downstream molecules p4E-BP1 and p-p70S6K, plays a crucial role in initiation and progression of breast tumorigenesis and drug resistance.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('AKT', 'Gene', '207', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('p4E-BP1', 'Var', (72, 79))	('tumor', 'Disease', (155, 160))	('drug resistance', 'Phenotype', 'HP:0020174', (173, 188))	('AKT', 'Gene', (9, 12))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('p-p70S6K', 'Var', (84, 92))
199187	29848352	Following deparaffinization and heat-mediated antigen retrieval, immunohistochemical staining was carried out using an Envision system (DAKO, Glostrup, Denmark) with primary antibodies against FOXP1 (JC12, AbD Serotec, Oxford, UK), ER (SP1, Roche Tucson, AZ, USA), calpain II (CAPN2, Sigma, St. Louis, MO, USA), HER2 (4B5, Roche Tucson), pAKT (736E11, Cell signaling, Danvers, MA, USA), pmTOR (49F9, Cell signaling), p4E-BP1 (53H11, Cell signaling) and p-p70S6K (49D7, Cell signaling).	('FOXP1', 'Gene', '27086', (193, 198))	('FOXP1', 'Gene', (193, 198))	('ER', 'Gene', '2099', (313, 315))	('AKT', 'Gene', '207', (339, 342))	('CAPN2', 'Gene', '824', (277, 282))	('p-p70S6K', 'Var', (453, 461))	('ER', 'Gene', '2099', (232, 234))	('paraffin', 'Chemical', 'MESH:D010232', (12, 20))	('CAPN2', 'Gene', (277, 282))	('p4E-BP1', 'Var', (417, 424))	('calpain II', 'Protein', (265, 275))	('AKT', 'Gene', (339, 342))	('mTOR', 'Gene', (388, 392))	('mTOR', 'Gene', '2475', (388, 392))
199192	29848352	Scoring of C-FOXP1, calpain II, pAKT, pmTOR, p4E-BP1, p-p70S6K were performed in terms of the staining intensity (intensity score: 0, none; 1, weak; 2, moderate; and 3, strong) and the proportion of positive tumor cells (proportion score: less than 5% positive cells were scored as 0; 5 to 25% as 1; 26 to 50% as 2; 51 to 75% as 3; greater than 75% as 4) according to previously described scoring methods with a slight modification.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('FOXP1', 'Gene', '27086', (13, 18))	('p4E-BP1', 'Var', (45, 52))	('AKT', 'Gene', '207', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('mTOR', 'Gene', (39, 43))	('FOXP1', 'Gene', (13, 18))	('mTOR', 'Gene', '2475', (39, 43))	('tumor', 'Disease', (208, 213))	('AKT', 'Gene', (33, 36))	('p-p70S6K', 'Var', (54, 62))
199205	29848352	ER staining was observed in 47.0% (31/66) of C-FOXP1-positive staining cases, which was lower than that in C-FOXP1-negative cases (13/17, 76.5%) (p = 0.030).	('staining', 'Var', (62, 70))	('ER', 'Gene', '2099', (0, 2))	('FOXP1', 'Gene', (47, 52))	('FOXP1', 'Gene', (109, 114))	('FOXP1', 'Gene', '27086', (47, 52))	('FOXP1', 'Gene', '27086', (109, 114))
199206	29848352	Calpain II expression was found in 83.3% (55/66) of C-FOXP1 positive cases, compared with 52.9% (9/17) of C-FOXP1-negative ones, and the difference was statistically significant (p = 0.007, Fig.	('FOXP1', 'Gene', (108, 113))	('FOXP1', 'Gene', '27086', (54, 59))	('expression', 'MPA', (11, 21))	('FOXP1', 'Gene', (54, 59))	('Calpain II', 'Protein', (0, 10))	('FOXP1', 'Gene', '27086', (108, 113))	('positive', 'Var', (60, 68))
199208	29848352	pAKT, pmTOR, p4E-BP1 and p-p70S6K, as key members in the AKT pathway, was expressed in 72.3% (60/83), 74.7% (62/83), 69.9% (58/83) and 73.5% (61/83) of IDC cases in the current series, respectively.	('mTOR', 'Gene', (7, 11))	('p4E-BP1', 'Var', (13, 20))	('p-p70S6K', 'Var', (25, 33))	('AKT', 'Gene', '207', (1, 4))	('IDC', 'Disease', (152, 155))	('AKT', 'Gene', '207', (57, 60))	('AKT', 'Gene', (1, 4))	('mTOR', 'Gene', '2475', (7, 11))	('AKT', 'Gene', (57, 60))
199209	29848352	Interestingly, calpain II expression was statistically associated with the expression of pAKT (p = 0.029), pmTOR (p = 0.011), p4E-BP1 (p < 0.001) and p-p70S6K (p = 0.003, Table 3).	('expression', 'MPA', (26, 36))	('mTOR', 'Gene', (108, 112))	('p-p70S6K', 'Var', (150, 158))	('p4E-BP1', 'Var', (126, 133))	('mTOR', 'Gene', '2475', (108, 112))	('AKT', 'Gene', (90, 93))	('associated', 'Reg', (55, 65))	('calpain II', 'Protein', (15, 25))	('AKT', 'Gene', '207', (90, 93))
199226	29848352	High calpain II expression has been established in triple-negative and basal-like IDC and calpain II might promote breast cancer cell proliferation through the AKT signaling pathway.	('AKT', 'Gene', '207', (160, 163))	('calpain II', 'Protein', (5, 15))	('calpain', 'Var', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('AKT', 'Gene', (160, 163))	('breast cancer', 'Disease', (115, 128))	('promote', 'PosReg', (107, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
199227	29848352	Calpain-mediated cleavage of beta-catenin and E-cadherin may lead to aberrant stabilization of the proteins and promote tumorigenesis in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('proteins', 'Protein', (99, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('E-cadherin', 'Gene', (46, 56))	('promote', 'PosReg', (112, 119))	('breast cancer', 'Disease', (137, 150))	('lead to', 'Reg', (61, 68))	('E-cadherin', 'Gene', '999', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('beta-catenin', 'Gene', (29, 41))	('stabilization of the', 'MPA', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('beta-catenin', 'Gene', '1499', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (120, 125))	('cleavage', 'Var', (17, 25))
199231	29848352	Moreover, in IDC samples in our series, calpain II was strongly correlated with the important molecules in AKT pathway, including pAKT, mTOR, p4E-BP1 and p-p70S6K.	('AKT', 'Gene', '207', (131, 134))	('calpain II', 'Protein', (40, 50))	('p-p70S6K', 'Var', (154, 162))	('AKT', 'Gene', (107, 110))	('AKT', 'Gene', (131, 134))	('p4E-BP1', 'Var', (142, 149))	('mTOR', 'Gene', (136, 140))	('correlated', 'Reg', (64, 74))	('mTOR', 'Gene', '2475', (136, 140))	('AKT', 'Gene', '207', (107, 110))
199239	29848352	Previous studies have demonstrated that loss of FOXP1 expression is associated with a poor prognosis in primary invasive and familial breast cancer.	('familial breast cancer', 'Disease', 'MESH:D001943', (125, 147))	('primary invasive', 'Disease', (104, 120))	('familial breast cancer', 'Disease', (125, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FOXP1', 'Gene', '27086', (48, 53))	('loss', 'Var', (40, 44))	('FOXP1', 'Gene', (48, 53))
199264	28618103	Conversely, knockdown of SPCA expression significantly attenuates formation of microcalcifications.	('SPCA', 'Gene', (25, 29))	('calcification', 'Disease', 'MESH:D002114', (84, 97))	('attenuates', 'NegReg', (55, 65))	('knockdown', 'Var', (12, 21))	('SPCA', 'Gene', '2155', (25, 29))	('calcification', 'Disease', (84, 97))
199265	28618103	We propose that high levels of SPCA pumps may initiate mineralization in the secretory pathway by elevating luminal Ca2+.	('initiate', 'PosReg', (46, 54))	('SPCA', 'Gene', (31, 35))	('secretory pathway', 'Pathway', (77, 94))	('mineralization', 'CPA', (55, 69))	('elevating', 'PosReg', (98, 107))	('high levels', 'Var', (16, 27))	('Ca2', 'Gene', '760', (116, 119))	('SPCA', 'Gene', '2155', (31, 35))	('Ca2', 'Gene', (116, 119))
199308	28618103	shRNA knockdown constructs and were packaged into the pLK0.1 lentiviral system whereas SPCA2 and SPCA2 D379N rescue constructs were packaged into the FUGW lentiviral backbones.	('SPCA2', 'Gene', (87, 92))	('SPCA2', 'Gene', (97, 102))	('D379N', 'Mutation', 'p.D379N', (103, 108))	('SPCA2', 'Gene', '9914', (87, 92))	('SPCA2', 'Gene', '9914', (97, 102))	('knockdown', 'Var', (6, 15))	('shRNA', 'Gene', (0, 5))
199309	28618103	These lentiviruses were produced with pCMV-Delta8.9 and PMDG using a 9:8:1 ratio respectively in HEK293T cells.	('HEK293T', 'CellLine', 'CVCL:0063', (97, 104))	('PMDG', 'Var', (56, 60))	('pCMV-Delta8.9', 'Var', (38, 51))
199312	28618103	The following Taqman probes were utilized: GAPDH (Hs02758991_g1), SPCA2 (Hs00939492_m1), SPCA1 (Hs00995930_m1), BSP2 (Hs00173720_m1), and ALP (Hs02758991_g1).	('Hs02758991_g1', 'Var', (143, 156))	('SPCA2', 'Gene', (66, 71))	('ALP', 'Gene', '250', (138, 141))	('Hs00939492_m1', 'Var', (73, 86))	('Hs00995930_m1', 'Var', (96, 109))	('SPCA2', 'Gene', '9914', (66, 71))	('SPCA1', 'Gene', '27032', (89, 94))	('Hs02758991_g1', 'Var', (50, 63))	('SPCA1', 'Gene', (89, 94))	('GAPDH', 'Gene', '2597', (43, 48))	('Hs00173720_m1', 'Var', (118, 131))	('GAPDH', 'Gene', (43, 48))	('ALP', 'Gene', (138, 141))
199340	28618103	Due to the accelerated time course, supraphysiological levels of BMP2 were most effective, which is not surprising given that calcifications occur over the period of months and years, in vivo.	('supraphysiological levels', 'Var', (36, 61))	('calcification', 'Disease', 'MESH:D002114', (126, 139))	('calcification', 'Disease', (126, 139))
199353	28618103	Whereas both SPCA isoforms may contribute to calcifications observed in DCIS, high expression of SPCA2 appears to be more predictive of breast microcalcifications.	('calcification', 'Disease', 'MESH:D002114', (148, 161))	('SPCA2', 'Gene', (97, 102))	('high expression', 'Var', (78, 93))	('SPCA', 'Gene', '2155', (13, 17))	('calcification', 'Disease', (45, 58))	('calcification', 'Disease', (148, 161))	('SPCA', 'Gene', (97, 101))	('SPCA2', 'Gene', '9914', (97, 102))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('contribute', 'Reg', (31, 41))	('calcification', 'Disease', 'MESH:D002114', (45, 58))	('SPCA', 'Gene', (13, 17))	('SPCA', 'Gene', '2155', (97, 101))
199368	28618103	To distinguish between these two roles, we evaluated the effect of a catalytically inactive SPCA2 mutant, D379N, previously shown to lack ATPase and Ca2+ pumping activity while retaining normal expression levels and localization.	('SPCA2', 'Gene', '9914', (92, 97))	('D379N', 'Mutation', 'p.D379N', (106, 111))	('Ca2', 'Gene', (149, 152))	('ATPase', 'Protein', (138, 144))	('Ca2', 'Gene', '760', (149, 152))	('D379N', 'Var', (106, 111))	('expression levels', 'MPA', (194, 211))	('SPCA2', 'Gene', (92, 97))	('ATP', 'Chemical', 'MESH:D000255', (138, 141))	('lack', 'NegReg', (133, 137))	('localization', 'MPA', (216, 228))
199369	28618103	Unlike the wild type control, mutant D379N failed to increase mineralization in cells, above that of the empty vector control (Figure 5D-E), showing that formation of calcium deposits in OC-supplemented media by SPCA2 is an active, pump-dependent process.	('mutant D379N', 'Var', (30, 42))	('formation', 'MPA', (154, 163))	('SPCA2', 'Gene', '9914', (212, 217))	('OC', 'Chemical', '-', (187, 189))	('D379N', 'Var', (37, 42))	('calcium', 'Chemical', 'MESH:D002118', (167, 174))	('D379N', 'Mutation', 'p.D379N', (37, 42))	('calcium deposits', 'MPA', (167, 183))	('SPCA2', 'Gene', (212, 217))
199371	28618103	In the absence of reliable antibodies targeting human SPCA isoforms, we confirmed effective knockdown of target genes using qPCR transcript analysis of transfected cells (Figure 6I).	('SPCA', 'Gene', '2155', (54, 58))	('SPCA', 'Gene', (54, 58))	('knockdown', 'Var', (92, 101))	('human', 'Species', '9606', (48, 53))
199374	28618103	To control for potential off-target effects, shSPCA2 treated MCF7 cells were transfected with silencing-resistant SPCA2 constructs (Figure 6J-K).	('SPCA2', 'Gene', (114, 119))	('SPCA2', 'Gene', (47, 52))	('silencing-resistant', 'Var', (94, 113))	('SPCA2', 'Gene', '9914', (114, 119))	('MCF7', 'CellLine', 'CVCL:0031', (61, 65))	('SPCA2', 'Gene', '9914', (47, 52))
199387	28618103	Recently, it was shown that inhibition of carbonic anhydrase and alkaline phosphatase diminished microcalcification production in mouse 4T1 mammary tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('carbonic anhydrase', 'Enzyme', (42, 60))	('mouse', 'Species', '10090', (130, 135))	('tumor', 'Disease', (148, 153))	('inhibition', 'Var', (28, 38))	('4T1', 'CellLine', 'CVCL:0125', (136, 139))	('alkaline phosphatase', 'Gene', (65, 85))	('calcification', 'Disease', 'MESH:D002114', (102, 115))	('diminished', 'NegReg', (86, 96))	('alkaline phosphatase diminished', 'Phenotype', 'HP:0003282', (65, 96))	('alkaline phosphatase', 'Gene', '250', (65, 85))	('calcification', 'Disease', (102, 115))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
199393	28618103	Furthermore, their ability to bind type I collagen can serve to link the mineral phase to the collagen matrix, and the presence of RGD domains (Arg-Gly-Asp sequence) binds to cell surface integrins and may be important for the preferred bone homing of breast metastases.	('RGD domains', 'Var', (131, 142))	('binds', 'Interaction', (166, 171))	('breast metastases', 'Disease', (252, 269))	('Asp', 'Chemical', 'MESH:D001224', (152, 155))	('breast metastases', 'Disease', 'MESH:D009362', (252, 269))	('Gly', 'Chemical', 'MESH:D005998', (148, 151))	('Arg', 'Chemical', 'MESH:D001120', (144, 147))
199394	28618103	The inappropriate expression of bone matrix proteins in breast tumors has been linked to bone metastases, which is significant because breast cancer metastasizes to bone more than any other organ, and over 80% of advanced breast cancer patients develop bone metastases accounting for significant morbidity and mortality.	('bone metastases', 'Disease', (89, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast tumors', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('breast tumors', 'Disease', (56, 69))	('bone metastases', 'Disease', 'MESH:D009362', (253, 268))	('breast cancer', 'Disease', (222, 235))	('patients', 'Species', '9606', (236, 244))	('breast tumors', 'Phenotype', 'HP:0100013', (56, 69))	('expression', 'MPA', (18, 28))	('develop', 'PosReg', (245, 252))	('breast tumor', 'Phenotype', 'HP:0100013', (56, 68))	('bone metastases', 'Disease', (253, 268))	('linked', 'Reg', (79, 85))	('inappropriate', 'Var', (4, 17))	('bone', 'Protein', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('bone metastases', 'Disease', 'MESH:D009362', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
199398	28618103	Microcalcifications are significantly more prevalent in patients with amplification of the proto-oncogene HER2 (also known as c-erbB2) breast tumors, compared to tumors without amplification of HER2.	('patients', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('calcification', 'Disease', 'MESH:D002114', (5, 18))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('breast tumors', 'Disease', (135, 148))	('breast tumors', 'Disease', 'MESH:D001943', (135, 148))	('HER2', 'Gene', (194, 198))	('HER2', 'Gene', (106, 110))	('tumors', 'Disease', (142, 148))	('calcification', 'Disease', (5, 18))	('breast tumors', 'Phenotype', 'HP:0100013', (135, 148))	('breast tumor', 'Phenotype', 'HP:0100013', (135, 147))	('c-erbB2', 'Gene', '2064', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('c-erbB2', 'Gene', (126, 133))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('HER2', 'Gene', '2064', (194, 198))	('prevalent', 'Reg', (43, 52))	('HER2', 'Gene', '2064', (106, 110))	('tumors', 'Disease', (162, 168))	('amplification', 'Var', (70, 83))
199448	31660702	Of all 604 patients, 121 (20.03%) and 193 (31.95%) patients were upstaged to DCIS with microinvasion (DCISM) and invasive breast cancer (IBC).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('IBC', 'Chemical', '-', (137, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('microinvasion', 'Var', (87, 100))	('DCIS', 'Phenotype', 'HP:0030075', (77, 81))	('invasive breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (11, 19))	('invasive breast cancer', 'Disease', (113, 135))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
199464	31660702	Human epidermal growth factor receptor 2 (HER2) positivity was defined as those cases where immunohistochemistry (IHC) staining was 3+ alone or 2+ with fluorescence in situ hybridization (FISH) positivity.	('HER2', 'Gene', '2064', (42, 46))	('Human epidermal growth factor receptor 2', 'Gene', (0, 40))	('positivity', 'Var', (48, 58))	('Human epidermal growth factor receptor 2', 'Gene', '2064', (0, 40))	('HER2', 'Gene', (42, 46))
199517	31660702	After integrating predictors of upstaging and factors associated with positive ALNs in this study, we found that patients with larger tumor size (>2 cm), multifocal lesions or ER+HER2+ status were more likely to be upstaging patients with positive ALNs, who might need axillary evaluation more than patients with relatively low risk of upstaging or axillary metastasis.	('multifocal', 'Var', (154, 164))	('upstaging', 'CPA', (215, 224))	('patients', 'Species', '9606', (225, 233))	('ER', 'Gene', '2099', (176, 178))	('patients', 'Species', '9606', (113, 121))	('positive', 'Gene', (239, 247))	('ER', 'Gene', '2099', (180, 182))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('patients', 'Species', '9606', (299, 307))	('HER2', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ALN', 'Chemical', '-', (79, 82))	('HER2', 'Gene', '2064', (179, 183))	('tumor', 'Disease', (134, 139))	('ALN', 'Chemical', '-', (248, 251))
199523	20691043	However, the risk of subsequent breast cancer associated with the presence of CCL in a benign breast biopsy is poorly understood.	('breast cancer', 'Disease', (32, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('presence', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('CCL', 'Chemical', '-', (78, 81))
199524	20691043	The authors examined the association between the presence of CCL and subsequent breast cancer risk in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies (394 cases, 1,606 controls).	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('presence', 'Var', (49, 57))	('CCL', 'Chemical', '-', (61, 64))	('CCL', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('benign breast disease', 'Disease', 'MESH:D001941', (133, 154))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('benign breast disease', 'Disease', (133, 154))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
199528	20691043	CCL presence was associated with the greatest risk of breast cancer for those with nonproliferative BBD (OR = 1.36, 95% CI: 0.79 to 2.37) and the lowest risk for those with atypical hyperplasia (AH) (OR = 1.10, 95% CI: 0.65 to 1.87); however, this apparent heterogeneity in risk across BBD categories was not significant (P for interaction between CCL presence and BBD category = 0.77).	('breast cancer', 'Disease', (54, 67))	('CCL', 'Chemical', '-', (0, 3))	('hyperplasia', 'Disease', 'MESH:D006965', (182, 193))	('nonproliferative', 'Disease', (83, 99))	('CCL', 'Chemical', '-', (348, 351))	('AH', 'Disease', 'MESH:D007039', (195, 197))	('hyperplasia', 'Disease', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('presence', 'Var', (4, 12))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
199541	20691043	Genetic alterations in CCL following a similar progression as the morphological changes have also been observed, and the mutations in the most advanced lesions have been found to be very similar to those in DCIS or invasive cancer.	('invasive cancer', 'Disease', (215, 230))	('invasive cancer', 'Disease', 'MESH:D009362', (215, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('alterations', 'Var', (8, 19))	('DCIS', 'Disease', (207, 211))	('DCIS', 'Phenotype', 'HP:0030075', (207, 211))	('CCL', 'Chemical', '-', (23, 26))	('CCL', 'Gene', (23, 26))
199576	20691043	The following covariates were considered as potential confounding factors: first-degree family history of breast cancer (yes, no), age at menarche (<12 years, 12 years, 13 years, >=14 years), menopausal status (premenopausal, postmenopausal, dubious/unsure), jointly classified parity and age at first birth (nulliparous, 1 to 2 children and <25 years, 1 to 2 children and 25 to 29 years, 1 to 2 children and >=30 years, >=3 children and <25 years, >=3 children and >=25 years), BMI at age 18 (<21, 21 to 22.9, 23 to 24.9, 25+ kg/m2), postmenopausal hormone use (premenopausal, postmenopausal never, ever), and oral contraceptive use (never, ever).	('children', 'Species', '9606', (453, 461))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('children', 'Species', '9606', (396, 404))	('oral contraceptive use', 'CPA', (611, 633))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('<21', 'Var', (494, 497))	('children', 'Species', '9606', (329, 337))	('children', 'Species', '9606', (360, 368))	('children', 'Species', '9606', (425, 433))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
199582	20691043	Women with and without CCL were generally similar with regard to their distribution of breast cancer risk factors, although women with CCL were slightly leaner than those without CCL and were less likely to have used postmenopausal hormones.	('Women', 'Species', '9606', (0, 5))	('CCL', 'Chemical', '-', (179, 182))	('leaner', 'NegReg', (153, 159))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('less', 'NegReg', (192, 196))	('breast cancer', 'Disease', (87, 100))	('CCL', 'Chemical', '-', (135, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('CCL', 'Var', (135, 138))	('CCL', 'Chemical', '-', (23, 26))	('women', 'Species', '9606', (124, 129))
199586	20691043	In the multivariate logistic regression models controlling for matching factors only (Table 2), women with CCL had a significantly higher risk of breast cancer compared with those without CCL (OR = 1.44; 95% CI, 1.14 to 1.83).	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('CCL', 'Chemical', '-', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CCL', 'Var', (107, 110))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('women', 'Species', '9606', (96, 101))	('CCL', 'Chemical', '-', (188, 191))
199600	20691043	Similar to our study, the Nashville study found a nearly 50% elevation in breast cancer risk associated with CCL (RR = 1.47; 95% CI: 1.0 to 2.2), although this analysis excluded those with AH, who have been shown to be at highest risk of subsequent breast cancer.	('breast cancer', 'Disease', (249, 262))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('elevation', 'PosReg', (61, 70))	('AH', 'Disease', 'MESH:D007039', (189, 191))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('CCL', 'Chemical', '-', (109, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('CCL', 'Var', (109, 112))
199630	20691043	Funding and/or support came from Public Health Service Grants CA046475, CA087969, CA050385, and SPORE in Breast Cancer CA089393 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services and the Breast Cancer Research Foundation, and the American Cancer Society (to G. A. Colditz).	('Cancer', 'Phenotype', 'HP:0002664', (250, 256))	('Breast Cancer', 'Disease', (243, 256))	('Breast Cancer', 'Disease', 'MESH:D001943', (105, 118))	('Breast Cancer', 'Phenotype', 'HP:0003002', (243, 256))	('Breast Cancer', 'Disease', (105, 118))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cancer', 'Disease', (250, 256))	('CA046475', 'Var', (62, 70))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (295, 301))	('CA050385', 'Var', (82, 90))	('Breast Cancer', 'Phenotype', 'HP:0003002', (105, 118))	('Cancer', 'Disease', (146, 152))	('Cancer', 'Disease', (295, 301))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Disease', 'MESH:D009369', (250, 256))	('Human', 'Species', '9606', (220, 225))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', 'MESH:D009369', (295, 301))	('Breast Cancer', 'Disease', 'MESH:D001943', (243, 256))	('CA087969', 'Var', (72, 80))	('CA089393', 'Var', (119, 127))
199694	29554463	These variations reveal the uncertainty regarding the natural history of DCIS, highlighting the need and potential directions of CISNET modeling.	('DCIS', 'Disease', (73, 77))	('variations', 'Var', (6, 16))	('CISNET', 'Chemical', '-', (129, 135))
199707	29554463	Also, in the US, several research networks, called cooperative groups, that conduct cancer clinical research primarily under the sponsorship of the NCI, are presently testing the use of neo-adjuvant hormonal therapy in postmenopausal women with ER-positive DCIS prior to surgery; those with a complete response based on magnetic resonance imaging (MRI) will not receive additional therapy.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ER-positive', 'Var', (245, 256))	('women', 'Species', '9606', (234, 239))
199725	25358623	Protein kinases, however, are often the key molecules in the cellular circuitry, and their aberrant function is frequently at the center of many diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('aberrant', 'Var', (91, 99))	('Protein', 'Enzyme', (0, 7))
199729	25358623	77% response to Cox-2 inhibitors for analgesia of post-operative pain, or ~25% response of colorectal cancer to chemotherapy (5-flurouracil plus leucovorin).	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibitors', 'Var', (22, 32))	('pain', 'Disease', 'MESH:D010146', (65, 69))	('pain', 'Disease', (65, 69))	('Cox-2', 'Gene', '4513', (16, 21))	('analgesia', 'MPA', (37, 46))	('leucovorin', 'Chemical', 'MESH:D002955', (145, 155))	('5-flurouracil', 'Chemical', '-', (126, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('Cox-2', 'Gene', (16, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
199732	25358623	35-40% of patients with KRAS mutations in exon 2 fail to respond to EGFR inhibitors.	('KRAS', 'Gene', '3845', (24, 28))	('mutations in', 'Var', (29, 41))	('EGFR', 'Gene', '1956', (68, 72))	('patients', 'Species', '9606', (10, 18))	('respond', 'MPA', (57, 64))	('EGFR', 'Gene', (68, 72))	('KRAS', 'Gene', (24, 28))
199744	25358623	Protein network post-translational modifications can be accurately profiled with RPPAs by probing the arrays using two different antibodies - one antibody is directed against the unmodified form of the protein, for example AKT, while a second antibody is directed against a specific phosphorylation site, for example phospho-AKT Ser473.	('phospho-AKT', 'Var', (317, 328))	('Ser473', 'Var', (329, 335))	('Ser473', 'Chemical', '-', (329, 335))
199785	25358623	Frozen tissue samples were obtained from children with Rhabdomyosarcoma enrolled in the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803.	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (125, 141))	('Rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (55, 71))	('Rhabdomyosarcoma', 'Disease', (55, 71))	('Rhabdomyosarcoma', 'Disease', (125, 141))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (125, 141))	('Rhabdomyosarcoma', 'Disease', 'MESH:D012208', (55, 71))	('Oncology', 'Phenotype', 'HP:0002664', (99, 107))	('D9502', 'Var', (158, 163))	('Children', 'Species', '9606', (88, 96))	('children', 'Species', '9606', (41, 49))	('D9803', 'Var', (168, 173))
199791	25358623	Elevated levels of phospho-AKT Ser473, phospho-mTOR Ser2448, and phospho-p70S6K ser389 were found to be linked to elevated levels of phospho-IRS-1 Ser612 in the responder group, indicating that IRS-1 negative feedback loop was intact (Spearman rho non-parametric correlations).	('Ser2448', 'Chemical', '-', (52, 59))	('IRS-1', 'Gene', '3667', (141, 146))	('ser389', 'Chemical', '-', (80, 86))	('Ser612', 'Chemical', '-', (147, 153))	('IRS-1', 'Gene', '3667', (194, 199))	('IRS-1', 'Gene', (141, 146))	('phospho-AKT', 'Var', (19, 30))	('IRS-1', 'Gene', (194, 199))	('Ser2448', 'Var', (52, 59))	('p70S6K', 'Gene', (73, 79))	('elevated', 'PosReg', (114, 122))	('Ser473', 'Chemical', '-', (31, 37))	('p70S6K', 'Gene', '6198', (73, 79))	('phospho-mTOR', 'Var', (39, 51))
199824	25358623	reported high levels of phospho-HER2 Y1248 in a small set of patients showing no signs of HER2 over-expression.	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', (32, 36))	('HER2', 'Gene', '2064', (90, 94))	('HER2', 'Gene', '2064', (32, 36))	('patients', 'Species', '9606', (61, 69))	('Y1248', 'Var', (37, 42))
199832	25358623	This clinical trial is examining the safety and effectiveness of chloroquine administration for a 4-week period for patients with low-grade, intermediate-grade or high-grade DCIS, regardless of hormone receptor status.	('DCIS', 'Disease', (174, 178))	('patients', 'Species', '9606', (116, 124))	('intermediate-grade', 'Var', (141, 159))	('chloroquine', 'Chemical', 'MESH:D002738', (65, 76))	('clinical', 'Species', '191496', (5, 13))
199866	31867779	For the histological classification, DIN was classified as DIN1A (corresponding to flat epithelial atypia), DIN1B (corresponding to atypical ductal hyperplasia), DIN1C (corresponding to DCIS grade 1), DIN2 (corresponding to DCIS grade 2), and DIN3 (corresponding to DCIS grade 3), which was referring to World Health Organization: Classification of Tumours: Pathology and Genetics.	('hyperplasia', 'Disease', (148, 159))	('Tumours', 'Phenotype', 'HP:0002664', (349, 356))	('hyperplasia', 'Disease', 'MESH:D006965', (148, 159))	('DIN1B', 'Var', (108, 113))
199876	31867779	The total of 113 patients had a mean age of 54.1 +- 11.5 years, and the numbers of patients with DIN1A, DIN1B, DIN1C, DIN2, DIN3, DCIS-MI, and invasive cancer were 3 (2.7%), 20 (17.7%), 20 (17.7%), 20 (17.7%), 20 (17.7%), 20 (17.7%), and 10 (8.8%), respectively (Table 1).	('DIN1A', 'Var', (97, 102))	('DIN1C', 'Var', (111, 116))	('DIN1B', 'Var', (104, 109))	('invasive cancer', 'Disease', (143, 158))	('DCIS-MI', 'Disease', (130, 137))	('DIN3', 'Var', (124, 128))	('DCIS-MI', 'Disease', 'MESH:D002285', (130, 137))	('patients', 'Species', '9606', (17, 25))	('invasive cancer', 'Disease', 'MESH:D009362', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (83, 91))	('DIN2', 'Var', (118, 122))
199885	31867779	In total patients, 5mC expression was positively correlated with ER expression (r = .194, P = .040) but not PR expression (P = .247), HER2 expression (P = .104), or Ki-67 expression (P = .179) (Table 4).	('patients', 'Species', '9606', (9, 17))	('PR', 'Gene', '5241', (108, 110))	('ER', 'Gene', '2099', (65, 67))	('5mC expression', 'Var', (19, 33))	('correlated', 'Interaction', (49, 59))	('ER', 'Gene', '2099', (135, 137))	('Ki-67', 'Chemical', '-', (165, 170))	('5mC', 'Chemical', 'MESH:D044503', (19, 22))	('HER2', 'Gene', (134, 138))	('HER2', 'Gene', '2064', (134, 138))
199905	31440931	Age <50 years, high grade, and DCIS + microinvasion were associated with LRR (p <= 0.001), however margin status was not (p = 0.14).	('LRR', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))	('Age', 'Gene', '5973', (0, 3))	('DCIS', 'Phenotype', 'HP:0030075', (31, 35))	('high grade', 'Var', (15, 25))	('DCIS + microinvasion', 'Var', (31, 51))	('Age', 'Gene', (0, 3))
199934	31440931	On univariable analysis, age <50 years at surgery (hazard ratio [HR] 15.0, 95% CI 3.58-62.4; p < 0.001), presence of microinvasion (HR 3.35, 95% CI 1.66-6.77; p < 0.001) and high nuclear grade (HR 3.56, 95% CI 1.60-7.88; p = 0.001) were significantly associated with LRR, while close or positive margin status was not (HR 2.83, 95% CI 0.67-12.0; p = 0.14).	('microinvasion', 'Var', (117, 130))	('associated', 'Reg', (251, 261))	('age', 'Gene', (25, 28))	('LRR', 'Disease', (267, 270))	('age', 'Gene', '5973', (25, 28))
199938	31440931	Among women with both high-grade DCIS and microinvasion (n = 177), the 10-year cumulative incidence of LRR was 17.3% (95% CI 1.6-30.5) for women aged <40 years, compared with 1.7% (95% CI 0-4.1) for women aged >=50 years.	('women', 'Species', '9606', (139, 144))	('LRR', 'Disease', (103, 106))	('age', 'Gene', '5973', (205, 208))	('microinvasion', 'Var', (42, 55))	('age', 'Gene', (145, 148))	('women', 'Species', '9606', (6, 11))	('high-grade', 'Var', (22, 32))	('women', 'Species', '9606', (199, 204))	('age', 'Gene', (205, 208))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('age', 'Gene', '5973', (145, 148))
199965	31440931	To our knowledge, this is the first large study of mastectomy patients with DCIS that includes those with microinvasion and that finds microinvasion to also be associated with an increased incidence of LRR on multivariable analysis.	('DCIS', 'Disease', (76, 80))	('microinvasion', 'Var', (135, 148))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('patients', 'Species', '9606', (62, 70))	('LRR', 'Disease', (202, 205))
199967	31440931	Our results indicate that women aged <40 years who have both microinvasion and high grade harbor the majority of excess risk (10-year cumulative incidence 17.3%) compared with women aged >=50 years who had a 10-year cumulative incidence of only 1.7%.	('age', 'Gene', '5973', (32, 35))	('high grade', 'Var', (79, 89))	('age', 'Gene', (182, 185))	('women', 'Species', '9606', (26, 31))	('age', 'Gene', '5973', (182, 185))	('age', 'Gene', (32, 35))	('microinvasion', 'Var', (61, 74))	('women', 'Species', '9606', (176, 181))
199969	31440931	observed a 10-year LRR rate of 5% with margins <=1 mm, 3.6% with margins 1.1-2.9 mm, and 0.7% for margins >=3 mm (p < 0.001) among 803 patients with DCIS treated with mastectomy between 1996 and 2009.	('<=1 mm', 'Var', (47, 53))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('LRR', 'Disease', (19, 22))	('patients', 'Species', '9606', (135, 143))
200008	31186262	Women aged 20 years or older were included if diagnosed with behavior code ICD-O-3 "in situ" and one of following histology codes for DCIS: 8050, 8140, 8200, 8201, 8211, 8230, 8246, 8260, 8343, 8401, 8480, 8481, 8490, 8500, 8501, 8503, 8504, 8507, 8508, 8521, 8522, 8523, 8543, or 8550.	('O-3', 'Chemical', 'MESH:D013481', (79, 82))	('DCIS', 'Disease', (134, 138))	('8480', 'Var', (200, 204))	('Women', 'Species', '9606', (0, 5))	('8521', 'Var', (254, 258))	('8522', 'Var', (260, 264))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('8260', 'Var', (182, 186))	('8550', 'Var', (281, 285))	('8523', 'Var', (266, 270))	('8401', 'Var', (194, 198))	('DCIS', 'Disease', 'MESH:D002285', (134, 138))	('8490', 'Var', (212, 216))	('8343', 'Var', (188, 192))
200011	31186262	Tumor-specific variables included nuclear grade (low, intermediate, high, unknown), tumor size (<=10mm, 11-30mm, >30mm, unknown), estrogen receptor (ER) and progesterone receptor (PR) status (positive, negative, unknown).	('estrogen receptor', 'Gene', '2099', (130, 147))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('PR', 'Gene', '5241', (180, 182))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ER', 'Gene', '2099', (149, 151))	('tumor', 'Disease', (84, 89))	('progesterone receptor', 'Gene', (157, 178))	('progesterone receptor', 'Gene', '5241', (157, 178))	('estrogen receptor', 'Gene', (130, 147))	('<=10mm', 'Var', (96, 102))
200076	31186262	In particular, 55% of newly diagnosed DCIS patients satisfied the three main criteria for low-risk DCIS as used by the ongoing COMET trial which randomizes patients with DCIS to either usual care or active surveillance (10): age >=40 years, nuclear grade I/II and hormone receptor-positive.	('patients', 'Species', '9606', (156, 164))	('DCIS', 'Disease', (38, 42))	('DCIS', 'Phenotype', 'HP:0030075', (99, 103))	('patients', 'Species', '9606', (43, 51))	('COMET', 'Species', '302767', (127, 132))	('DCIS', 'Phenotype', 'HP:0030075', (38, 42))	('DCIS', 'Disease', (170, 174))	('DCIS', 'Disease', 'MESH:D002285', (170, 174))	('nuclear', 'Var', (241, 248))	('DCIS', 'Disease', 'MESH:D002285', (38, 42))	('DCIS', 'Phenotype', 'HP:0030075', (170, 174))	('DCIS', 'Disease', (99, 103))	('DCIS', 'Disease', 'MESH:D002285', (99, 103))
200097	28488344	They are often at high risk due to a genetic predisposition toward the disease, of which mutations in breast cancer type 1 susceptibility protein (BRCA1) and breast cancer type 2 susceptibility protein (BRCA2) tumor suppressive genes are the best characterized 3.	('BRCA1', 'Gene', '672', (147, 152))	('BRCA2', 'Gene', '675', (203, 208))	('breast cancer type 1 susceptibility protein', 'Gene', (102, 145))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (102, 145))	('breast cancer type 2 susceptibility protein', 'Gene', '675', (158, 201))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('BRCA1', 'Gene', (147, 152))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRCA2', 'Gene', (203, 208))	('breast cancer type 2 susceptibility protein', 'Gene', (158, 201))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
200101	28488344	Hence, the discovery of a mutation may result in elective surgery to remove both breasts or prophylactic administration of tamoxifen, with consequential side effects before the disease has occurred 9.	('result in', 'Reg', (39, 48))	('tamoxifen', 'Chemical', 'MESH:D013629', (123, 132))	('mutation', 'Var', (26, 34))
200171	27780311	Although breast ductal carcinoma in situ (DCIS) is noninvasive, women with DCIS are at higher risk of developing invasive breast cancer than women without it.	('women', 'Species', '9606', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('DCIS', 'Var', (75, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (16, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('women', 'Species', '9606', (64, 69))	('breast ductal carcinoma in situ', 'Disease', (9, 40))	('invasive breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('breast ductal carcinoma in situ', 'Disease', 'MESH:D002285', (9, 40))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (9, 32))	('invasive breast cancer', 'Disease', (113, 135))
200212	27780311	Overall, patients were more likely to initiate drug use if they were younger than 71 years of age at diagnosis, Hispanic, married, lived in census tracts with low levels of education, underwent LRT, and were diagnosed before 2010 (Table 2).	('patients', 'Species', '9606', (9, 17))	('underwent', 'Reg', (184, 193))	('low levels of education', 'Phenotype', 'HP:0001249', (159, 182))	('Hispanic', 'Var', (112, 120))	('initiate', 'PosReg', (38, 46))
200226	27780311	Our findings of low tamoxifen or AI use are consistent with other studies.	('low', 'NegReg', (16, 19))	('AI use', 'Var', (33, 39))	('tamoxifen', 'Chemical', 'MESH:D013629', (20, 29))
200229	27780311	conducted a study of 206,255 DCIS patients diagnosed from 2005 to 2012 in the National Cancer Data Base (NCDB), and found the adjuvant endocrine therapy initiation rate to be 46.4% among patients with ER-positive tumors.	('patients', 'Species', '9606', (187, 195))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('ER-positive', 'Var', (201, 212))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
200234	27780311	A study evaluating hormone therapy among DCIS patients based on six Kaiser Permanente regions from 2001-2011 found that Hispanic women were more likely than white women to receive hormone treatment (OR, 95% CI 1.20 [1.02-1.40]).	('hormone', 'Disease', (180, 187))	('patients', 'Species', '9606', (46, 54))	('women', 'Species', '9606', (163, 168))	('women', 'Species', '9606', (129, 134))	('Hispanic', 'Var', (120, 128))
200254	26501844	Among women on postmenopausal hormone therapy, biennial screeners tended to have tumors with less-favorable prognostic characteristics compared to annual screeners; however, CIs were wide and differences had only borderline significance.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('biennial', 'Var', (47, 55))	('women', 'Species', '9606', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
200297	26501844	Biennial screeners were more likely to be in the youngest (40-49 years) or oldest (70-85 years) age groups and less likely than annual screeners to have a family history of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('Biennial', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
200352	24917206	A rare combination of low Ki-67 in HER2 type cancers (only 14% of HER2 type cancers) showed very slow transition to IDC (occurring at only 53.55% of average progression rate), while triple-negative cancers progressed faster than the average, despite Ki-67 value (104.63% for low and 114.27% for high Ki-67 tumors).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('Ki-67', 'Gene', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('slow', 'NegReg', (97, 101))	('HER2 type cancers', 'Disease', 'MESH:D009369', (35, 52))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('HER2 type cancers', 'Disease', 'MESH:D009369', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('tumors', 'Disease', (306, 312))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('HER2 type cancers', 'Disease', (35, 52))	('HER2 type cancers', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('low', 'Var', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
200358	24917206	In triple-negative tumors, an age dependent premenopausal mechanism possibly acted as an accelerator of tissue invasion, while faster tissue invasion by HER2-overexpressed tumors in older patients possibly depended on an unidentified mechanism that takes more time to be acquired, so it was less present in premenopausal patients.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('age dependent premenopausal mechanism', 'Phenotype', 'HP:0008209', (30, 67))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('HER2', 'Gene', (153, 157))	('tumors', 'Disease', (172, 178))	('triple-negative', 'Var', (3, 18))	('tissue invasion', 'CPA', (134, 149))	('patients', 'Species', '9606', (321, 329))	('HER2', 'Gene', '2064', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('patients', 'Species', '9606', (188, 196))	('tissue invasion', 'CPA', (104, 119))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
200360	24917206	This idea is based on a high degree of similarity between molecular alterations in DCIS and invasive cancer in the same patient, although triple-negative invasive cancers may seem almost to lack their triple-negative DCIS precursor.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('invasive cancers', 'Disease', 'MESH:D009362', (154, 170))	('invasive cancer', 'Disease', (92, 107))	('DCIS', 'Phenotype', 'HP:0030075', (217, 221))	('patient', 'Species', '9606', (120, 127))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('invasive cancer', 'Disease', 'MESH:D009362', (154, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('invasive cancers', 'Disease', (154, 170))	('invasive cancer', 'Disease', 'MESH:D009362', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('alterations', 'Var', (68, 79))	('DCIS', 'Chemical', '-', (217, 221))	('DCIS', 'Chemical', '-', (83, 87))	('DCIS', 'Gene', (83, 87))
200394	24917206	Several comparisons were made and they can be summarized in the following statements:   Dysfunctional ER+PgR- phenotype was more common in Luminal B2 (38 out of 210 cases) in comparison to the pooled Luminal A&B1 (only 66 out of 743 cases), suggesting that this combination was more prevalent than expected in our patients (p = 0.0002).	('patients', 'Species', '9606', (314, 322))	('Luminal', 'Var', (139, 146))	('PgR', 'Gene', '5241', (105, 108))	('PgR', 'Gene', (105, 108))	('common', 'Reg', (129, 135))
200395	24917206	If Luminal A was compared with B1, high Ki-67 values in B1 are also more often combined with the ER+PgR- phenotype (40 out of 346 vs. 26 out of 397 cases, p = 0.0167).	('PgR', 'Gene', (100, 103))	('PgR', 'Gene', '5241', (100, 103))	('Ki-67', 'Var', (40, 45))
200413	24917206	Low Ki-67 decreased the rate of Luminal B2 tissue progression (27% of Luminal B2 cancers showed 91.9% of the average progression rate).	('decreased', 'NegReg', (10, 19))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('Low Ki-67', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Ki-67', 'Var', (4, 9))
200449	24917206	Beside that in all three tumor types with positive steroid receptors (Luminal A, B1 and B2), the dysfunctional ERs in the ER+PgR- phenotype showed slower rates of tissue invasion.	('tissue invasion', 'CPA', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PgR', 'Gene', '5241', (125, 128))	('tumor', 'Disease', (25, 30))	('PgR', 'Gene', (125, 128))	('steroid', 'Chemical', 'MESH:D013256', (51, 58))	('slower', 'NegReg', (147, 153))	('dysfunctional', 'Var', (97, 110))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('steroid', 'Protein', (51, 58))
200524	22392043	In this cohort study of 1,855 women diagnosed with pure DCIS, 55.2% of patients had large body size, and large body size was independently associated with African American or Hispanic race, post-menopausal status, a diagnosis of diabetes, presentation of disease by radiologic abnormality as opposed to clinical findings, and having ER-positive disease.	('post-menopausal status', 'Phenotype', 'HP:0008209', (190, 212))	('patients', 'Species', '9606', (71, 79))	('menopausal status', 'Phenotype', 'HP:0008209', (195, 212))	('large', 'Var', (105, 110))	('women', 'Species', '9606', (30, 35))	('associated', 'Reg', (139, 149))	('diabetes', 'Disease', (229, 237))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('diabetes', 'Disease', 'MESH:D003920', (229, 237))	('ER', 'Gene', '2099', (333, 335))
200556	21287591	Hypervascularity can confound apparent diffusion coefficient (ADC) measurements in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('apparent diffusion coefficient', 'MPA', (30, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Hypervascularity', 'Var', (0, 16))
200662	26361583	Two years previously, she had undergone bilateral breast augmentation by subglandular access with a round Allergan CML implant (265 cc).	('Allergan CML', 'Disease', 'MESH:D015464', (106, 118))	('265', 'Var', (128, 131))	('Allergan CML', 'Disease', (106, 118))
200666	26361583	MRI is used for patients with unclear ultrasound or mammography, with a family history of breast cancer or BRCA 1/2 mutation.	('BRCA 1', 'Gene', (107, 113))	('mutation', 'Var', (116, 124))	('patients', 'Species', '9606', (16, 24))	('BRCA 1', 'Gene', '672', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))
200749	24498285	Table 1 (A) shows two selected strategies that improve on the B5069 uniform strategy and two that improve on the B4574 uniform strategy.	('improve', 'PosReg', (47, 54))	('B5069', 'Chemical', '-', (62, 67))	('B5069', 'Var', (62, 67))
200750	24498285	As an example, compared to B5069, the optimal strategy Q5074-Q5074-T5074-A5074 for the L, ML, MH and H risk groups, respectively, has 3.8% higher benefit in terms of LE and achieves reductions of 8.9% in costs, 25.1% in FP and 20.6% in overdiagnosed cases.	('Q5074', 'Chemical', '-', (61, 66))	('Q5074-Q5074-T5074-A5074', 'Var', (55, 78))	('reductions', 'NegReg', (182, 192))	('Q5074', 'Chemical', '-', (55, 60))	('higher benefit', 'PosReg', (139, 153))	('MH', 'Chemical', '-', (94, 96))	('ML', 'Disease', 'MESH:C537366', (90, 92))	('B5069', 'Chemical', '-', (27, 32))
200751	24498285	In absolute numbers, with an annual discount rate of 3% for every 2,000 women screened, the risk-based strategy Q5074-Q5074-T5074-A5074 would extend about the same number of lives (4) as the uniform B5069 strategy but would avoid 1.5 overdiagnosed cases, 97 FP mammograms (six of them ending with a biopsy) and would save 250,000 euros.	('euros', 'Species', '9319', (330, 335))	('mammograms', 'Disease', (261, 271))	('Q5074', 'Chemical', '-', (112, 117))	('Q5074-Q5074-T5074-A5074', 'Var', (112, 135))	('women', 'Species', '9606', (72, 77))	('B5069', 'Chemical', '-', (199, 204))	('Q5074', 'Chemical', '-', (118, 123))	('FP mammograms', 'Disease', (258, 271))	('avoid', 'NegReg', (224, 229))
200752	24498285	If we consider the uniform strategy B4574 as a reference, the risk-based strategy T5074-T5074-A4574-A4574 results in a 5% higher benefit and reductions of 6.8% in costs, 21.9% in FP and 10.1% in overdiagnosed cases.	('A4574', 'Chemical', '-', (94, 99))	('reductions', 'NegReg', (141, 151))	('higher benefit', 'PosReg', (122, 136))	('T5074-T5074-A4574-A4574', 'Var', (82, 105))	('costs', 'MPA', (163, 168))	('A4574', 'Chemical', '-', (100, 105))
200753	24498285	Table 1 (B) shows that, compared to the B5069 uniform strategy, the risk-based Q5069-Q4574-Q4574-A4074 strategy results in reductions of 8% in costs, 17.2% in FP and 25% in overdiagnosed cases.	('costs', 'MPA', (143, 148))	('Q4574', 'Chemical', '-', (91, 96))	('B5069', 'Chemical', '-', (40, 45))	('Q5069-Q4574-Q4574-A4074', 'Var', (79, 102))	('reductions', 'NegReg', (123, 133))	('Q4574', 'Chemical', '-', (85, 90))
200754	24498285	Similarly, compared to the uniform strategy B4574, the risk-based Q4574-Q4574-A4574-A4074 strategy achieves an increase of 4% in QALYs and reductions of 9.2% in costs, 20.4% in FP and 23% in overdiagnosed cases.	('Q4574', 'Chemical', '-', (66, 71))	('Q4574', 'Chemical', '-', (72, 77))	('increase', 'PosReg', (111, 119))	('reductions', 'NegReg', (139, 149))	('QALYs', 'MPA', (129, 134))	('Q4574-Q4574-A4574-A4074', 'Var', (66, 89))	('A4574', 'Chemical', '-', (78, 83))	('costs', 'MPA', (161, 166))
200755	24498285	For instance, moving from uniform B5069 to uniform A5069 reduces the amount of FN by 29%, but moving from uniform B5069 to uniform B4574 increases the amount of FN by 33%.	('B5069', 'Chemical', '-', (34, 39))	('B5069', 'Var', (34, 39))	('B5069', 'Chemical', '-', (114, 119))	('reduces', 'NegReg', (57, 64))
200763	24498285	Table 3 compares the overall benefit and harm results for the uniform strategies B5069 and B4574 with published reviews.	('B5069', 'Chemical', '-', (81, 86))	('B4574', 'Var', (91, 96))	('B5069', 'Var', (81, 86))
200764	24498285	The ratios of overdiagnosed per LE for the B5069 and B4574 strategies in our study were 1.3 and 1.4, respectively, in the lower range of the reviews.	('B5069', 'Var', (43, 48))	('B4574', 'Var', (53, 58))	('B5069', 'Chemical', '-', (43, 48))
200773	24498285	In fact, in terms of LE, Q5074-Q5074-T5074-A5074 improves the uniform B5069 and has similar costs and harms to Q5074-Q5074-Q4574-A4574.	('B5069', 'Chemical', '-', (70, 75))	('uniform B5069', 'MPA', (62, 75))	('A4574', 'Chemical', '-', (129, 134))	('Q5074', 'Chemical', '-', (25, 30))	('Q5074', 'Chemical', '-', (31, 36))	('Q5074', 'Chemical', '-', (117, 122))	('improves', 'PosReg', (49, 57))	('Q5074', 'Chemical', '-', (111, 116))	('Q4574', 'Chemical', '-', (123, 128))	('Q5074-Q5074-T5074-A5074', 'Var', (25, 48))
200785	24498285	Finally, when we compared our results for the uniform screening strategies B4569 or B5069 with the INCA study or other studies of interval cancer, we found a high consistency in most of the results relative to the number of cancer cases detected per mammography, sensitivity of the program, distribution of screen-detected and interval cases, and distribution of true interval and false-negative cases.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('interval cancer', 'Disease', 'MESH:D009369', (130, 145))	('B5069', 'Chemical', '-', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('B5069', 'Var', (84, 89))	('B4569', 'Var', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('interval cancer', 'Disease', (130, 145))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (139, 145))
200821	24737780	In acute lymphoblastic leukemia, expression of AGM correlates with worse prognosis of patients.	('AGM', 'Gene', '3490', (47, 50))	('acute lymphoblastic leukemia', 'Disease', (3, 31))	('expression', 'Var', (33, 43))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (3, 31))	('AGM', 'Gene', (47, 50))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (9, 31))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (3, 31))	('patients', 'Species', '9606', (86, 94))
200840	24737780	Function-blocking anti-integrin antibodies used were anti-alpha2 (P1E6), anti-alpha3 (P1B5), anti-alpha5 (P1D6), anti-beta1 (6S6), and anti-alphavbeta3 (LM609) MoAbs from Merck (Darmstadt, Germany), and anti-alpha6 MoAb (GoH3) from PharMingen (San Diego, CA).	('beta3', 'Gene', '1934', (146, 151))	('beta1', 'Gene', (118, 123))	('beta1', 'Gene', '10678', (118, 123))	('beta3', 'Gene', (146, 151))	('anti-alpha5', 'Var', (93, 104))	('LM609', 'CellLine', 'CVCL:V308', (153, 158))
200896	24737780	Expression of AGM was markedly upregulated by VEGF-121 and weakly but significantly by IL-6, IL-8, and TNF-alpha.	('TNF-alpha', 'Gene', '7124', (103, 112))	('AGM', 'Gene', (14, 17))	('IL-6', 'Gene', '3569', (87, 91))	('TNF-alpha', 'Gene', (103, 112))	('Expression', 'MPA', (0, 10))	('AGM', 'Gene', '3490', (14, 17))	('upregulated', 'PosReg', (31, 42))	('VEGF-121', 'Var', (46, 54))	('IL-8', 'Gene', '3576', (93, 97))	('IL-6', 'Gene', (87, 91))	('IL-8', 'Gene', (93, 97))
200910	24737780	Although AGM does not contain the RGD sequence, RGD peptide, but not RGE, significantly blocked the cell adhesion to AGM (Fig.	('AGM', 'Gene', (117, 120))	('AGM', 'Gene', (9, 12))	('blocked', 'NegReg', (88, 95))	('cell adhesion', 'CPA', (100, 113))	('AGM', 'Gene', '3490', (117, 120))	('AGM', 'Gene', '3490', (9, 12))	('RGD peptide', 'Var', (48, 59))	('peptide', 'Chemical', 'MESH:D010455', (52, 59))
200912	24737780	When various function-blocking, anti-integrin antibodies were tested, antibodies to integrins alphavbeta3, beta1 and beta3 clearly blocked the cell adhesion activity of AGM (Fig.	('cell adhesion activity', 'CPA', (143, 165))	('blocked', 'NegReg', (131, 138))	('beta3', 'Gene', '1934', (100, 105))	('AGM', 'Gene', (169, 172))	('beta1', 'Gene', '10678', (107, 112))	('beta3', 'Gene', (100, 105))	('beta3', 'Gene', (117, 122))	('antibodies', 'Var', (70, 80))	('AGM', 'Gene', '3490', (169, 172))	('beta3', 'Gene', '1934', (117, 122))	('beta1', 'Gene', (107, 112))
200945	24737780	It is expected that the abnormal deposition of AGM, as well as the loss of laminin-3B11, in the vascular basement membrane of cancer tissues could give significant effects on the structure, permeability, and other functions of blood vessels.	('AGM', 'Gene', '3490', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('structure', 'MPA', (179, 188))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('AGM', 'Gene', (47, 50))	('loss', 'Var', (67, 71))	('laminin-3B11', 'Gene', (75, 87))	('effects', 'Reg', (164, 171))	('permeability', 'MPA', (190, 202))
200963	24737780	Osteopontin is a RGD-containing ligand of integrin alphavbeta3, induced by VEGF in endothelial cells and promotes endothelial cell adhesion and migration through integrin alphavbeta3.	('Osteopontin', 'Gene', (0, 11))	('promotes', 'PosReg', (105, 113))	('Osteopontin', 'Gene', '6696', (0, 11))	('integrin alphavbeta3', 'Gene', '3685', (42, 62))	('integrin alphavbeta3', 'Gene', '3685', (162, 182))	('endothelial cell adhesion', 'CPA', (114, 139))	('integrin alphavbeta3', 'Gene', (42, 62))	('VEGF', 'Var', (75, 79))	('integrin alphavbeta3', 'Gene', (162, 182))	('migration', 'CPA', (144, 153))
200977	24737780	Like integrin alphavbeta3, AGM was found to be upregulated in endothelial cells by VEGF.	('VEGF', 'Var', (83, 87))	('AGM', 'Gene', '3490', (27, 30))	('integrin alphavbeta3', 'Gene', (5, 25))	('upregulated', 'PosReg', (47, 58))	('integrin alphavbeta3', 'Gene', '3685', (5, 25))	('AGM', 'Gene', (27, 30))
200984	24737780	This cytoskeletal change is thought to destabilize the VE-cadherin-mediated adherence junction and thereby increase vascular permeability.	('increase', 'PosReg', (107, 115))	('destabilize', 'NegReg', (39, 50))	('VE-cadherin', 'Gene', '1003', (55, 66))	('vascular permeability', 'MPA', (116, 137))	('increase vascular permeability', 'Phenotype', 'HP:0030005', (107, 137))	('change', 'Var', (18, 24))	('VE-cadherin', 'Gene', (55, 66))
200990	24737780	As an alternative mechanism, AGM-induced PGI2 may also contribute to the enhanced vascular permeability in the cancer vasculature.	('PGI2', 'Chemical', 'MESH:D011464', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('AGM', 'Gene', (29, 32))	('PGI2', 'Var', (41, 45))	('enhanced', 'PosReg', (73, 81))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('AGM', 'Gene', '3490', (29, 32))	('vascular permeability in', 'CPA', (82, 106))
201047	29401514	In one study of 269 women, those first exposed to the term abnormal cells then later pre-invasive breast cancer cells were more likely to feel concern (p = 0.001) and change their management preference to treatment (p = 0.008) compared to women exposed first to the term pre-invasive breast cancer and then abnormal cells, however, there was no significant difference in treatment preferences between the two groups (p = 0.23).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('management preference', 'MPA', (180, 201))	('men', 'Species', '9606', (210, 213))	('men', 'Species', '9606', (241, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('women', 'Species', '9606', (239, 244))	('men', 'Species', '9606', (376, 379))	('men', 'Species', '9606', (186, 189))	('men', 'Species', '9606', (22, 25))	('women', 'Species', '9606', (20, 25))	('abnormal cells', 'Var', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('change', 'Reg', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('breast cancer', 'Disease', (284, 297))
201048	29401514	In the other study, 26 women who were interviewed said that they would feel concern regardless of the term used to describe DCIS but preferred the term abnormal cells over other terms such as carcinoma, and expressed interest in AS provided monitoring was very frequent.	('aid', 'Gene', '57379', (51, 54))	('women', 'Species', '9606', (23, 28))	('carcinoma', 'Disease', (192, 201))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('aid', 'Gene', (51, 54))	('carcinoma', 'Disease', 'MESH:D002277', (192, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('abnormal cells', 'Var', (152, 166))
201120	31819188	High-resolution imaging mass spectrometry combined with transcriptomic analysis identified a link between fatty acid composition of phosphatidylinositols and the immune checkpoint pathway at the primary tumour site of breast cancer The fatty acid (FA) composition of phosphatidylinositols (PIs) is tightly regulated in mammalian tissue since its disruption impairs normal cellular functions.	('breast cancer', 'Disease', (218, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('normal cellular functions', 'CPA', (365, 390))	('disruption', 'Var', (346, 356))	('phosphatidylinositols', 'Chemical', 'MESH:D010716', (267, 288))	('impairs', 'NegReg', (357, 364))	('phosphatidylinositols', 'Chemical', 'MESH:D010716', (132, 153))	('fatty acid', 'Chemical', 'MESH:D005227', (236, 246))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour', 'Disease', (203, 209))	('PIs', 'Chemical', 'MESH:D010716', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('mammalian', 'Species', '9606', (319, 328))	('fatty acid', 'Chemical', 'MESH:D005227', (106, 116))
201127	31819188	MALDI-IMS identified PI composition associated with invasion and nodal metastasis of breast cancer.	('nodal metastasis of breast cancer', 'Disease', 'MESH:D001943', (65, 98))	('nodal metastasis of breast cancer', 'Disease', (65, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('associated', 'Reg', (36, 46))	('PI composition', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('invasion', 'CPA', (52, 60))
201132	31819188	Differences in FA composition can generate the structural and functional diversity of phospholipids.	('Differences', 'Var', (0, 11))	('phospholipids', 'Chemical', 'MESH:D010743', (86, 99))	('generate', 'Reg', (34, 42))	('functional diversity of phospholipids', 'MPA', (62, 99))	('structural', 'MPA', (47, 57))
201137	31819188	Studies using a prostate cancer model showed that incorporation of docosahexaenoic acid into PI alters PI phosphate and AKT localisation, which in turn affects downstream signalling.	('AKT', 'Gene', (120, 123))	('affects', 'Reg', (152, 159))	('prostate cancer', 'Disease', (16, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('localisation', 'MPA', (124, 136))	('downstream signalling', 'MPA', (160, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (16, 31))	('incorporation', 'Var', (50, 63))	('alters', 'Reg', (96, 102))	('PI phosphate', 'MPA', (103, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('AKT', 'Gene', '207', (120, 123))	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (67, 87))
201138	31819188	The artificial disruption of the FA remodelling of PIs alters the activity of the PI3K pathway, resulting in an impairment of the asymmetric division of stem cells in Caenorhabditis elegans and normal brain development in mice.	('mice', 'Species', '10090', (222, 226))	('PIs', 'Chemical', 'MESH:D010716', (51, 54))	('activity', 'MPA', (66, 74))	('impairment', 'NegReg', (112, 122))	('Caenorhabditis elegans', 'Species', '6239', (167, 189))	('PI3K pathway', 'Pathway', (82, 94))	('alters', 'Reg', (55, 61))	('disruption', 'Var', (15, 25))	('asymmetric division of stem cells', 'CPA', (130, 163))
201139	31819188	In addition, in a pancreas cancer model, an oncogenic mutation in p53 was shown to affect the PI3K pathway via an alteration in PI composition.	('pancreas cancer', 'Disease', 'MESH:D010190', (18, 33))	('mutation', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('affect', 'Reg', (83, 89))	('p53', 'Gene', '7157', (66, 69))	('PI3K pathway', 'Pathway', (94, 106))	('alteration', 'Reg', (114, 124))	('pancreas cancer', 'Phenotype', 'HP:0002894', (18, 33))	('PI composition', 'MPA', (128, 142))	('pancreas cancer', 'Disease', (18, 33))	('p53', 'Gene', (66, 69))
201205	31819188	On the other hand, the proportion of di-unsaturated and polyunsaturated PIs tended to increase in invasive cancer cells (p = 0.0027 and 0.0992, respectively) (Supplementary Fig.	('increase', 'PosReg', (86, 94))	('invasive cancer', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PIs', 'Chemical', 'MESH:D010716', (72, 75))	('polyunsaturated', 'Var', (56, 71))	('di-unsaturated', 'Var', (37, 51))	('invasive cancer', 'Disease', 'MESH:D009362', (98, 113))
201215	31819188	Among the tested clinicopathological parameters, "age over 60 years," "postmenopausal state," "presence of lymph node metastasis," "negativity for oestrogen receptor (ER)" and "negativity for progesterone receptor (PgR)" were positively associated with PI(18:0/20:3) accumulation (Table 1).	('ER', 'Gene', '2069', (167, 169))	('associated', 'Reg', (237, 247))	('PgR', 'Gene', '5241', (215, 218))	('postmenopausal state', 'Phenotype', 'HP:0008209', (71, 91))	('PgR', 'Gene', (215, 218))	('negativity', 'Var', (132, 142))	('progesterone receptor', 'Gene', (192, 213))	('progesterone receptor', 'Gene', '5241', (192, 213))	('accumulation', 'PosReg', (267, 279))
201231	31819188	Therefore, we compared gene expression profile and PI composition between HCC1806 breast cancer cells with specific knockdown of FABP7 and a control (knockdown efficiency is shown in Supplementary Fig.	('breast cancer', 'Disease', (82, 95))	('HCC1806', 'CellLine', 'CVCL:1258', (74, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('compared', 'Reg', (14, 22))	('knockdown', 'Var', (116, 125))	('FABP7', 'Gene', '2173', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('FABP7', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
201232	31819188	FABP7 knockdown in HCC1806 breast cancer cells significantly altered the expression of genes involved in the PD-1-related immune checkpoint pathway among the pathways related to immune responses (Fig.	('FABP7', 'Gene', '2173', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PD-1-related', 'Gene', (109, 121))	('HCC1806', 'CellLine', 'CVCL:1258', (19, 26))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('expression of', 'MPA', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('knockdown', 'Var', (6, 15))	('altered', 'Reg', (61, 68))	('FABP7', 'Gene', (0, 5))
201234	31819188	In addition, FABP7 knockdown significantly altered the proportion of PI(18:0/18:1), PI(18:0/20:3) and PI(18:0/20:4) (Fig.	('knockdown', 'Var', (19, 28))	('FABP7', 'Gene', '2173', (13, 18))	('FABP7', 'Gene', (13, 18))	('altered', 'Reg', (43, 50))
201238	31819188	In addition, of the genes related to unsaturated fatty acid synthesis and transport, we found that ACSL4 was upregulated upon FABP7 knockdown (Supplementary Fig.	('FABP7', 'Gene', (126, 131))	('upregulated', 'PosReg', (109, 120))	('unsaturated fatty acid', 'Chemical', 'MESH:D005231', (37, 59))	('knockdown', 'Var', (132, 141))	('ACSL4', 'Gene', '2182', (99, 104))	('ACSL4', 'Gene', (99, 104))	('FABP7', 'Gene', '2173', (126, 131))
201247	31819188	While this strict homoeostasis of the FA composition of PIs was maintained in cancer-associated stroma, all non-invasive cancer cells lost the predominance of PI(18:0/20:4) and acquired two PIs-MUFAs, PI(16:0/18:1) and PI(18:0/18:1) (Fig.	('non-invasive cancer', 'Disease', 'MESH:D009362', (108, 127))	('non-invasive cancer', 'Disease', (108, 127))	('PIs', 'Chemical', 'MESH:D010716', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lost', 'NegReg', (134, 138))	('PI(16:0/18:1', 'Var', (201, 213))	('cancer', 'Disease', (78, 84))	('PIs', 'Chemical', 'MESH:D010716', (190, 193))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PI(18:0/18:1', 'Var', (219, 231))	('PIs-MUFAs', 'Chemical', '-', (190, 199))
201255	31819188	The accumulation of PI(18:0/20:3) is likely to be a key feature of invasive cancer cells since normal ductal cells solely accumulated PI(18:0/20:4) instead of PI(18:0/20:3).	('PI(18:0/20:4', 'Var', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('invasive cancer', 'Disease', 'MESH:D009362', (67, 82))	('invasive cancer', 'Disease', (67, 82))
201261	31819188	Since FABP7 knockdown in the breast cancer cells leads to the alteration of PI composition and the gene expressions of PD-1-related immune checkpoint pathway, targeting PUFA trafficking mediated by FABP7 is likely to enhance the effect of immune checkpoint inhibition.	('FABP7', 'Gene', (6, 11))	('breast cancer', 'Disease', (29, 42))	('PD-1-related', 'Gene', (119, 131))	('knockdown', 'Var', (12, 21))	('FABP7', 'Gene', '2173', (198, 203))	('PI composition', 'MPA', (76, 90))	('PUFA', 'Gene', (169, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('PUFA', 'Gene', '9933', (169, 173))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('FABP7', 'Gene', (198, 203))	('FABP7', 'Gene', '2173', (6, 11))	('alteration', 'Reg', (62, 72))
201279	31819188	Importantly, the alteration of the glycolipid MUFA/PUFA ratio in a leukaemic T-cell line was shown to modulate release from the inositol 1,4,5-trisphosphate-sensitive Ca2+ store.	('Ca2+', 'Chemical', 'MESH:D000069285', (167, 171))	('lipid', 'Chemical', 'MESH:D008055', (40, 45))	('PUFA', 'Gene', '9933', (51, 55))	('alteration', 'Var', (17, 27))	('PUFA', 'Gene', (51, 55))	('modulate', 'Reg', (102, 110))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (128, 156))	('MUFA', 'Chemical', 'MESH:D005229', (46, 50))
201289	31819188	In particular, metformin can modulate lipid metabolism.	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('modulate', 'Reg', (29, 37))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('lipid metabolism', 'MPA', (38, 54))	('metformin', 'Var', (15, 24))
201404	31360852	Second breast cancers are an important outcome for this population, as women with DCIS have a two to four times greater risk of developing a second breast cancer than women in the general population have of developing a first breast cancer.	('breast cancers', 'Phenotype', 'HP:0003002', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('women', 'Species', '9606', (167, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('women', 'Species', '9606', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('DCIS', 'Var', (82, 86))	('breast cancer', 'Disease', (226, 239))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancers', 'Disease', 'MESH:D001943', (7, 21))	('breast cancers', 'Disease', (7, 21))
201427	23817282	Significantly higher tamoxifen nonpersistence (early discontinuation) rates have been shown for women who reported problems with mood (36%) versus women who reported no mood problems (12%).	('problems', 'Var', (115, 123))	('tamoxifen', 'Chemical', 'MESH:D013629', (21, 30))	('mood problems', 'Phenotype', 'HP:0001575', (169, 182))	('nonpersistence', 'MPA', (31, 45))	('women', 'Species', '9606', (147, 152))	('women', 'Species', '9606', (96, 101))	('mood', 'Disease', (129, 133))	('problems with mood', 'Phenotype', 'HP:0001575', (115, 133))	('higher', 'PosReg', (14, 20))
201537	18665173	These changes permit the ERalpha complexes to bind sequence-specific oestrogen response elements located in the regulatory regions of oestrogen target genes, thus controlling their level of transcription.	('ERalpha', 'Gene', '26284', (25, 32))	('ERalpha', 'Gene', (25, 32))	('changes', 'Var', (6, 13))	('level of transcription', 'MPA', (181, 203))	('controlling', 'Reg', (163, 174))
201624	18665173	Thus, the proportion of cells expressing mi-er1 mRNA per volume of tissue would be much lower in normal breast than in a solid tumour sample.	('lower', 'NegReg', (88, 93))	('mi-er1', 'Gene', (41, 47))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', (127, 133))	('mRNA', 'Var', (48, 52))	('mi-er1', 'Gene', '57708', (41, 47))
201646	11879562	Although abnormal cytology in NAF is predictive of subsequent development of breast cancer, with a relative risk of 2.5-5 at 12.5 years, cellular yield from this technique is low.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('abnormal', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
201647	11879562	Atypia seen in fine-needle aspiration (FNA) of the breast, in which multiple aspirations are performed and pooled for analysis, also is associated with an increased risk for breast cancer, with a relative risk of 5 at 45 months.	('associated', 'Reg', (136, 146))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('aspiration', 'Phenotype', 'HP:0002835', (77, 87))	('Atypia', 'Var', (0, 6))	('aspirations', 'Phenotype', 'HP:0002835', (77, 88))	('aspiration', 'Phenotype', 'HP:0002835', (27, 37))
201652	11879562	examined 507 women with an elevated risk for breast cancer (based on elevated Gail index, prior history of invasive or noninvasive breast cancer, or presence of a BRCA mutation), but with low-suspicion physical examinations and mammograms, by performing nipple aspiration followed by DL.	('aspiration', 'Phenotype', 'HP:0002835', (261, 271))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('presence', 'Var', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Gail index', 'MPA', (78, 88))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('mutation', 'Var', (168, 176))	('women', 'Species', '9606', (13, 18))	('BRCA', 'Gene', (163, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('breast cancer', 'Disease', (131, 144))	('elevated', 'PosReg', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))
201662	11879562	At least one of the three genes was methylated in 96% of surgically excised primary breast tumors and in 57% of DCIS lesions, but in no normal breast tissue samples, demonstrating high sensitivity and specificity of this technique.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('methylated', 'Var', (36, 46))	('DCIS', 'Phenotype', 'HP:0030075', (112, 116))	('breast tumors', 'Disease', (84, 97))	('breast tumors', 'Disease', 'MESH:D001943', (84, 97))	('breast tumors', 'Phenotype', 'HP:0100013', (84, 97))
201665	11879562	Of the 13 women with residual DCIS or atypical ductal hyperplasia identified histologically at re-excision, four (30%) had a methylated marker.	('methylated marker', 'Var', (125, 142))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (47, 65))	('women', 'Species', '9606', (10, 15))	('ductal hyperplasia', 'Disease', (47, 65))	('DCIS', 'Disease', (30, 34))
201703	31148847	It is known that a significant proportion of the familial breast cancer risk is caused by mutations in high- and moderate-penetrance genes and genetic variants in low-penetrance genes.	('familial breast cancer', 'Disease', (49, 71))	('mutations', 'Var', (90, 99))	('high-', 'Protein', (103, 108))	('caused', 'Reg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('familial breast cancer', 'Disease', 'MESH:D001943', (49, 71))
201710	31148847	While most germ line changes which have been associated with breast cancer have no systemic therapeutic consequence, efficacy of the PARP inhibitors olaparib and talazoparib was established for HER2-negative patients with advanced breast cancer and a germ line mutation in BRCA1 or BRCA2  ,   .	('PARP', 'Gene', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BRCA2', 'Gene', '675', (282, 287))	('BRCA1', 'Gene', '672', (273, 278))	('BRCA1', 'Gene', (273, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('HER2', 'Gene', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', (61, 74))	('talazoparib', 'Chemical', 'MESH:C586365', (162, 173))	('mutation', 'Var', (261, 269))	('olaparib', 'Chemical', 'MESH:C531550', (149, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('PARP', 'Gene', '1302', (133, 137))	('BRCA2', 'Gene', (282, 287))	('patients', 'Species', '9606', (208, 216))	('HER2', 'Gene', '2064', (194, 198))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('breast cancer', 'Disease', (231, 244))
201712	31148847	In early breast cancer patients, it is known that patients with a BRCA1/ 2 mutation in the case of neoadjuvant chemotherapy have a greater chance of a pCR  ,   ,   .	('pCR', 'Disease', (151, 154))	('BRCA1', 'Gene', '672', (66, 71))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (23, 31))	('mutation', 'Var', (75, 83))	('BRCA1', 'Gene', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', (9, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))
201713	31148847	Likewise there is evidence that women with a BRCA1/2 mutation have a somewhat better prognosis following chemotherapy than patients without a mutation  ,   .	('better', 'PosReg', (78, 84))	('mutation', 'Var', (53, 61))	('women', 'Species', '9606', (32, 37))	('BRCA1/2', 'Gene', '672;675', (45, 52))	('patients', 'Species', '9606', (123, 131))	('BRCA1/2', 'Gene', (45, 52))
201736	31148847	Triple-negative patients whose immune cells in the tumour demonstrated an expression of PD-L1 had better progression-free survival and better overall survival in the case of combination therapy consisting of nab-paclitaxel and atezolizumab, compared to monotherapy with nab-paclitaxel  .	('better', 'PosReg', (98, 104))	('nab', 'Chemical', '-', (208, 211))	('PD-L1', 'Gene', (88, 93))	('nab', 'Chemical', '-', (270, 273))	('expression', 'Var', (74, 84))	('overall survival', 'CPA', (142, 158))	('patients', 'Species', '9606', (16, 24))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('atezolizumab', 'Chemical', 'MESH:C000594389', (227, 239))	('PD-L1', 'Gene', '29126', (88, 93))	('better', 'PosReg', (135, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (274, 284))	('progression-free survival', 'CPA', (105, 130))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (212, 222))
201749	31148847	In a comparison of tamoxifen + OFS and exemestane + OFS, it was also seen that therapy with exemestane + OFS demonstrated better disease-free survival.	('disease-free survival', 'CPA', (129, 150))	('better', 'PosReg', (122, 128))	('OFS', 'Chemical', '-', (31, 34))	('OFS', 'Chemical', '-', (52, 55))	('exemestane', 'Chemical', 'MESH:C056516', (39, 49))	('OFS', 'Chemical', '-', (105, 108))	('exemestane', 'Chemical', 'MESH:C056516', (92, 102))	('exemestane + OFS', 'Var', (92, 108))	('tamoxifen', 'Chemical', 'MESH:D013629', (19, 28))
201769	31148847	The background is that it is assumed that in patients with a triple-negative tumour, DNA repair mechanisms are more frequently disrupted and therefore platinum-based chemotherapies work better.	('triple-negative', 'Var', (61, 76))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('DNA repair', 'MPA', (85, 95))	('tumour', 'Disease', (77, 83))	('disrupted', 'Reg', (127, 136))	('und', 'Gene', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (45, 53))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))	('und', 'Gene', '7373', (11, 14))
201776	31148847	Similarly, it was shown in the case of HER2-positive patients that if no pCR could be achieved following neoadjuvant anti-HER2 therapy with chemotherapy, therapy with T-DM1 is more effective than standard treatment with trastuzumab  .	('patients', 'Species', '9606', (53, 61))	('trastuzumab', 'Chemical', 'MESH:D000068878', (220, 231))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', (122, 126))	('HER2', 'Gene', '2064', (39, 43))	('HER2', 'Gene', '2064', (122, 126))	('T-DM1', 'Var', (167, 172))	('T-DM1', 'Chemical', 'MESH:C550911', (167, 172))
201886	26821678	Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis.	('breast cancer metastasis', 'Disease', 'MESH:D009362', (138, 162))	('human', 'Species', '9606', (132, 137))	('mouse', 'Species', '10090', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer metastasis', 'Disease', (138, 162))	('lung metastasis', 'CPA', (96, 111))	('prevents', 'NegReg', (87, 95))	('inhibition', 'Var', (9, 19))
201902	26821678	Using three different experimental systems, including three-dimensional (3D) mixed cell spheroid co-cultures of mammary epithelial and fibroblast cells, a 3D organotypic culture model of human skin tumors, and a mouse xenograft model of human breast cancer, we recently reported that Tiam1 deficiency in tumor-associated fibroblasts induces increased invasion of the associated epithelial or tumor cells and increased tumor metastasis.	('skin tumors', 'Phenotype', 'HP:0008069', (193, 204))	('tumor', 'Disease', (418, 423))	('tumor metastasis', 'Disease', (418, 434))	('tumor', 'Disease', (392, 397))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (418, 423))	('tumor', 'Disease', (304, 309))	('mouse', 'Species', '10090', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('Tiam1', 'Gene', (284, 289))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('invasion', 'CPA', (351, 359))	('tumor', 'Phenotype', 'HP:0002664', (418, 423))	('breast cancer', 'Disease', (243, 256))	('deficiency', 'Var', (290, 300))	('increased', 'PosReg', (408, 417))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('human', 'Species', '9606', (237, 242))	('skin tumors', 'Disease', (193, 204))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Disease', (198, 203))	('tumor metastasis', 'Disease', 'MESH:D009362', (418, 434))	('increased', 'PosReg', (341, 350))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('human', 'Species', '9606', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('skin tumors', 'Disease', 'MESH:D012878', (193, 204))
201927	26821678	We found that co-culture of several different breast cancer cell lines with RMFs leads to formation of similar spheroidal structures (not shown).	('RMFs', 'Var', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
201928	26821678	In this study we tested the effect of manipulating fibroblast Tiam1 expression on the invasiveness of two aggressive breast cancer cell lines, SUM1315 and SUM159 (Fig.	('aggressive breast cancer', 'Disease', 'MESH:D001943', (106, 130))	('Tiam1', 'Gene', (62, 67))	('aggressive breast cancer', 'Disease', (106, 130))	('SUM1315', 'Chemical', '-', (143, 150))	('tested', 'Reg', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('manipulating', 'Var', (38, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))
201940	26821678	Consistently, exposure to Tiam1-deficient fibroblasts induced increased numbers of tumorspheres in both SUM159 and SUM1315 PCC cells (Fig.	('Tiam1-deficient', 'Gene', (26, 41))	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('SUM1315', 'Var', (115, 122))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SUM1315', 'Chemical', '-', (115, 122))
201962	26821678	We found that OPN transcription is significantly less in SUM1315 cells than in RMF cells (Figure S3A in Additional file 2).	('less', 'NegReg', (49, 53))	('SUM1315', 'Chemical', '-', (57, 64))	('OPN', 'Gene', (14, 17))	('SUM1315 cells', 'Var', (57, 70))
201965	26821678	Incorporating OPN antibody against SUM1315 cells (in the SUM1315 culture and in the top well) had no effect on SUM1315 migration.	('SUM1315', 'Gene', (35, 42))	('SUM1315', 'Chemical', '-', (57, 64))	('SUM1315', 'Var', (111, 118))	('SUM1315', 'Chemical', '-', (35, 42))	('SUM1315', 'Chemical', '-', (111, 118))
201967	26821678	These results suggest that the major effect of the OPN antibody in these co-cultures is against fibroblast-derived OPN, and are consistent with our findings that OPN silencing in RMF is sufficient to block all of the effects of RMF Tiam1 silencing on associated SUM1315 cancer cells (Fig.	('RMF Tiam1', 'Gene', (228, 237))	('silencing', 'Var', (166, 175))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('silencing', 'Var', (238, 247))	('OPN', 'Gene', (162, 165))	('SUM1315', 'Chemical', '-', (262, 269))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))
201971	26821678	Given the results above of OPN inhibition by gene silencing or antibody in vitro, we tested the effects of a chemical inhibitor of OPN in blocking the effects of Tiam1-deficient RMF in an accelerated in vivo model of breast cancer metastasis.	('breast cancer metastasis', 'Disease', 'MESH:D009362', (217, 241))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tested', 'Reg', (85, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('breast cancer metastasis', 'Disease', (217, 241))	('Tiam1-deficient RMF', 'Disease', (162, 181))	('gene silencing', 'Var', (45, 59))	('Tiam1-deficient RMF', 'Disease', 'MESH:D007153', (162, 181))
201972	26821678	Agelastatin A (AgelA) is a brominated oroidin alkaloid originally of marine origin, and synthetic AgelA inhibits OPN transcription and expression.	('inhibits', 'NegReg', (104, 112))	('expression', 'MPA', (135, 145))	('Agelastatin A', 'Chemical', 'MESH:C464968', (0, 13))	('synthetic', 'Var', (88, 97))	('OPN', 'Gene', (113, 116))
201978	26821678	Vitamin D induced an almost twofold increase in OPN transcription, which was blocked by concurrent treatment with increasing doses of AgelA (Figure S4c in Additional file 2).	('increase', 'PosReg', (36, 44))	('Vitamin', 'Var', (0, 7))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('OPN', 'Gene', (48, 51))
201981	26821678	In the biologic assays of PCC-SUM1315, we also found corresponding decreases in migration, tumorsphere formation, and CD44+/CD24-/ESA+ populations (Figures S5b, S6a-b in Additional file 2).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('CD44', 'Gene', '960', (118, 122))	('SUM1315', 'Chemical', '-', (30, 37))	('PCC-SUM1315', 'Var', (26, 37))	('CD44', 'Gene', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('migration', 'CPA', (80, 89))	('S5b', 'Gene', '5711', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('S5b', 'Gene', (156, 159))	('decreases', 'NegReg', (67, 76))	('CD24', 'Gene', '100133941', (124, 128))	('CD24', 'Gene', (124, 128))
201983	26821678	As noted above (Figure S3 in Additional file 2), there is very little OPN transcription in SUM1315 cells compared with RMF cells, and this was not significantly affected by AgelA treatment (not shown).	('SUM1315', 'Chemical', '-', (91, 98))	('little', 'NegReg', (63, 69))	('OPN', 'Gene', (70, 73))	('SUM1315', 'Var', (91, 98))
202008	26821678	We have previously shown that silencing the Rac exchange factor Tiam1 in tumor-associated fibroblasts induces increased invasion and metastasis in epithelial and cancer cells, using different tissue models with a range of technical complexity and biologically relevant tissue context.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Disease', (162, 168))	('Rac', 'Gene', '207', (44, 47))	('increased', 'PosReg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Rac', 'Gene', (44, 47))	('silencing', 'Var', (30, 39))	('Tiam1', 'Gene', (64, 69))
202031	26821678	A study of B16 mouse melanoma engineered to express platelet-derived growth factor (PDGF) showed that tumor-derived PDGF induces CAF recruitment and OPN expression in a subset of recruited CAFs.	('CAF', 'Gene', (129, 132))	('CAFs', 'Gene', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('OPN', 'Gene', (149, 152))	('induces', 'PosReg', (121, 128))	('CAF', 'Gene', (189, 192))	('recruitment', 'MPA', (133, 144))	('expression', 'MPA', (153, 163))	('CAF', 'Gene', '8850', (129, 132))	('melanoma', 'Disease', (21, 29))	('PDGF', 'Var', (116, 120))	('mouse', 'Species', '10090', (15, 20))	('CAFs', 'Gene', '6899', (189, 193))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('tumor', 'Disease', (102, 107))	('CAF', 'Gene', '8850', (189, 192))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
202042	26821678	These are consistent with our findings that inhibiting OPN in tumor-associated fibroblasts diminishes cancer stem cell populations and blocks metastatic potential in an aggressive breast cancer line.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', (187, 193))	('OPN', 'Gene', (55, 58))	('tumor', 'Disease', (62, 67))	('aggressive breast cancer', 'Disease', 'MESH:D001943', (169, 193))	('cancer', 'Disease', (102, 108))	('aggressive breast cancer', 'Disease', (169, 193))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('blocks', 'NegReg', (135, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('diminishes', 'NegReg', (91, 101))	('inhibiting', 'Var', (44, 54))
202151	31937618	Amplified centrosomes underlie erroneous mitoses and fuel chromosomal instability (CIN), which is a well-recognized driver of ITH.	('CIN', 'Disease', 'MESH:D007674', (83, 86))	('chromosomal instability', 'Phenotype', 'HP:0040012', (58, 81))	('underlie', 'Reg', (22, 30))	('CIN', 'Disease', (83, 86))	('fuel chromosomal instability', 'Disease', (53, 81))	('erroneous', 'Var', (31, 40))	('Amplified', 'Var', (0, 9))
202213	31937618	Cumulatively, a summation of CASi and CASm generated CAStotal, which was significantly higher for DCIS patients with LR relative to LR-free patients regardless of grade (mean scores in Supplementary Table 1) (Fig.	('CASm', 'Gene', '27257', (38, 42))	('LR', 'Chemical', '-', (132, 134))	('DCIS', 'Var', (98, 102))	('CAS', 'Chemical', '-', (53, 56))	('CAS', 'Chemical', '-', (29, 32))	('CAStotal', 'MPA', (53, 61))	('higher', 'PosReg', (87, 93))	('CASm', 'Gene', (38, 42))	('patients', 'Species', '9606', (140, 148))	('LR', 'Chemical', '-', (117, 119))	('CAS', 'Chemical', '-', (38, 41))	('patients', 'Species', '9606', (103, 111))	('DC', 'Chemical', '-', (98, 100))
202226	31937618	3), we found that DCIS patients with high CASi were associated with poorer RFS (p<0.001, HR=4.80) relative to those with low CASi (Fig.	('CAS', 'Chemical', '-', (125, 128))	('poorer', 'NegReg', (68, 74))	('patients', 'Species', '9606', (23, 31))	('RFS', 'MPA', (75, 78))	('high CASi', 'Var', (37, 46))	('DC', 'Chemical', '-', (18, 20))	('CAS', 'Chemical', '-', (42, 45))
202227	31937618	Similarly, high CASm was associated with poorer RFS (p=0.04, HR=2.396) compared to low CASm (Fig.	('RFS', 'MPA', (48, 51))	('CASm', 'Gene', '27257', (87, 91))	('high', 'Var', (11, 15))	('poorer', 'NegReg', (41, 47))	('CASm', 'Gene', (16, 20))	('CASm', 'Gene', (87, 91))	('CASm', 'Gene', '27257', (16, 20))
202234	31937618	We found that high CASi, CASm and CAStotal were associated with poorer RFS compared to low CASi, CASm and CAStotal, respectively.	('CAS', 'Chemical', '-', (97, 100))	('CASm', 'Gene', (97, 101))	('CASm', 'Gene', '27257', (25, 29))	('CAS', 'Chemical', '-', (91, 94))	('CAS', 'Chemical', '-', (19, 22))	('CASm', 'Gene', '27257', (97, 101))	('high', 'Var', (14, 18))	('RFS', 'MPA', (71, 74))	('CAS', 'Chemical', '-', (25, 28))	('CAS', 'Chemical', '-', (106, 109))	('CASm', 'Gene', (25, 29))	('CAS', 'Chemical', '-', (34, 37))	('poorer', 'NegReg', (64, 70))
202284	31937618	Our study is the first to show that organellar-level differences distinguish DCIS patients with LR from LR-free patients, and that high levels of both numerical and structural CA are associated with increased 10-year risk of LR in DCIS patients.	('LR', 'Chemical', '-', (104, 106))	('organellar-level', 'MPA', (36, 52))	('patients', 'Species', '9606', (82, 90))	('LR', 'Chemical', '-', (225, 227))	('patients', 'Species', '9606', (236, 244))	('patients', 'Species', '9606', (112, 120))	('DC', 'Chemical', '-', (77, 79))	('DCIS', 'Disease', (77, 81))	('LR', 'Chemical', '-', (96, 98))	('high', 'Var', (131, 135))	('DC', 'Chemical', '-', (231, 233))
202285	31937618	Our results suggest that aberrant centrosomal homeostasis in DCIS drives pathophysiological alterations that potentially facilitate disease progression through CIN-dependent as well as CIN-independent mechanisms.	('facilitate', 'PosReg', (121, 131))	('disease progression', 'CPA', (132, 151))	('aberrant', 'Var', (25, 33))	('centrosomal homeostasis', 'MPA', (34, 57))	('CIN', 'Disease', 'MESH:D007674', (160, 163))	('CIN', 'Disease', (185, 188))	('DC', 'Chemical', '-', (61, 63))	('CIN', 'Disease', 'MESH:D007674', (185, 188))	('CIN', 'Disease', (160, 163))
202337	28486668	It has been reported that 10-38% of cases diagnosed as DCIS by needle biopsy are underestimated and wide tumor area, palpable mass, high nuclear grade, tumor findings on MMG are listed as risk factors with mixed invasive cancer.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('invasive cancer', 'Disease', (212, 227))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (152, 157))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('invasive cancer', 'Disease', 'MESH:D009362', (212, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('high nuclear', 'Var', (132, 144))
202339	28486668	The most frequent findings were hypo-echoic areas in the mammary gland (48.6%), followed by solid masses (28.0%) and duct abnormalities (10.2%) or mixed masses (8.1%).	('mixed', 'Disease', (147, 152))	('duct abnormalities', 'Disease', 'MESH:D001649', (117, 135))	('solid masses', 'Disease', (92, 104))	('duct abnormalities', 'Disease', (117, 135))	('hypo-echoic areas', 'Var', (32, 49))
202340	28486668	Specific findings of US to predict mixed invasive cancer are halo-positive masses and interruption of the interface between the adipose tissue and gland.	('halo-positive', 'Var', (61, 74))	('interruption', 'Var', (86, 98))	('invasive cancer', 'Disease', (41, 56))	('invasive cancer', 'Disease', 'MESH:D009362', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
202352	28486668	Patients with ER-positive DCIS treated with tamoxifen (vs placebo) showed a significant decrease in the incidence of subsequent breast cancer (HR = 0.64, P = 0.003).	('ER-positive', 'Var', (14, 25))	('decrease', 'NegReg', (88, 96))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('tamoxifen', 'Chemical', 'MESH:D013629', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
202355	28486668	Ipsilateral breast tumor recurrence (13.2% vs 17.0%, HR = 0.77, 95% CI: 0.59-0.98, P = 0.04) and contralateral breast cancer incidence (0.9% vs 3.1%, HR = 0.27, 95% CI: 0.12-0.59, P = 0.001) were both lower in the partial dissection of the breast + tamoxifen group than in the partial dissection of the breast alone group.	('tamoxifen', 'Chemical', 'MESH:D013629', (249, 258))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (97, 124))	('breast tumor', 'Disease', 'MESH:D001943', (12, 24))	('partial dissection', 'Var', (214, 232))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast tumor', 'Disease', (12, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('contralateral breast cancer', 'Disease', (97, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast tumor', 'Phenotype', 'HP:0100013', (12, 24))	('lower', 'NegReg', (201, 206))
202374	28486668	These findings indicate that the growth rate of low-intermediate grade DCIS is extremely slow even in cases of proliferation; therefore, the patient might die from other diseases and the condition might not affect prognosis.	('low-intermediate grade', 'Var', (48, 70))	('patient', 'Species', '9606', (141, 148))	('growth', 'CPA', (33, 39))	('slow', 'NegReg', (89, 93))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))
202432	30712460	Twenty-six conserved DEGs were identified in both GSE21422 and GSE3893.	('GSE21422', 'Var', (50, 58))	('GSE3893', 'Chemical', '-', (63, 70))	('GSE3893', 'Var', (63, 70))
202446	30712460	Importantly, high levels of MMP11 expression are associated with the invasion of multiple human carcinomas (including breast cancer) and poor clinical outcome for patients.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('high levels', 'Var', (13, 24))	('carcinomas', 'Disease', 'MESH:D009369', (96, 106))	('clinical', 'Species', '191496', (142, 150))	('patients', 'Species', '9606', (163, 171))	('expression', 'MPA', (34, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('MMP11', 'Gene', '4320', (28, 33))	('carcinomas', 'Disease', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('human', 'Species', '9606', (90, 95))	('associated with', 'Reg', (49, 64))	('invasion', 'CPA', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('MMP11', 'Gene', (28, 33))
202450	30712460	They found several well-known mutations including those in TP53, PIK3CA, and AKT1, and copy number alterations (CNAs) in pure DCIS; however, significantly fewer driver genes and co-occurrences of mutations and CNAs were detected than in synchronous DCIS-IDC.	('fewer', 'NegReg', (155, 160))	('AKT1', 'Gene', (77, 81))	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (59, 63))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('PIK3CA', 'Gene', (65, 71))	('synchronous DCIS-IDC', 'Disease', 'MESH:D002285', (237, 257))	('copy number alterations', 'Var', (87, 110))	('mutations', 'Var', (30, 39))	('synchronous DCIS-IDC', 'Disease', (237, 257))	('DCIS', 'Phenotype', 'HP:0030075', (249, 253))	('AKT1', 'Gene', '207', (77, 81))	('PIK3CA', 'Gene', '5290', (65, 71))
202467	30712460	A total of 862 DEGs were identified in IDC from GSE3893 with 720 upregulated genes (Figure 2, P < 0.05).	('upregulated', 'PosReg', (65, 76))	('GSE3893', 'Var', (48, 55))	('GSE3893', 'Chemical', '-', (48, 55))
202481	30712460	To address this issue, we download and analyzed two GEO datasets: GSE21422 and GSE3893.	('GSE21422', 'Var', (66, 74))	('GSE3893', 'Var', (79, 86))	('GSE3893', 'Chemical', '-', (79, 86))
202486	30712460	The FCGR2A H131R polymorphism is known to be associated with the clinical outcome of patients with breast cancer treated with the sequential adjuvant administration of trastuzumab.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('FCGR2A', 'Gene', (4, 10))	('breast cancer', 'Disease', (99, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (168, 179))	('polymorphism', 'Var', (17, 29))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('associated', 'Reg', (45, 55))	('patients', 'Species', '9606', (85, 93))	('H131R', 'Mutation', 'rs1801274', (11, 16))	('FCGR2A', 'Gene', '2212', (4, 10))	('clinical', 'Species', '191496', (65, 73))
202688	24454461	Overexpression of p53, which is generally caused by a TP53 mutation, and Bcl-2 expression were not associated with the response to NACT (p=0.2372 and p=0.0834, respectively).	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('Bcl-2', 'Gene', (73, 78))	('NACT', 'Gene', '284111', (131, 135))	('Bcl-2', 'Gene', '596', (73, 78))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (59, 67))	('NACT', 'Gene', (131, 135))	('TP53', 'Gene', (54, 58))
202706	24454461	In total, 19 of 45 cases (42.2%) with PR positivity in their biopsy specimens exhibited negativity after NACT (Figure 1A, B), whereas only three of 75 PR-negative cases in the biopsy specimens displayed positivity after NACT.	('PR', 'Gene', '5241', (151, 153))	('NACT', 'Gene', (220, 224))	('positivity', 'Var', (41, 51))	('NACT', 'Gene', '284111', (105, 109))	('exhibited', 'Reg', (78, 87))	('NACT', 'Gene', (105, 109))	('negativity', 'MPA', (88, 98))	('PR', 'Gene', '5241', (38, 40))	('NACT', 'Gene', '284111', (220, 224))
202746	24454461	In addition, we observed that the expression of HRs was associated with a worse response to NACT.	('expression', 'Var', (34, 44))	('NACT', 'Gene', '284111', (92, 96))	('associated', 'Reg', (56, 66))	('HRs', 'Protein', (48, 51))	('NACT', 'Gene', (92, 96))
202842	22402290	In the report based on Los Angeles SEER registry data, radiation under-ascertainment was significantly higher among patients with the following characteristics: White race, more advanced stage, younger age, lower income, Medicare or no insurance, had mastectomy, received chemotherapy, had (self-reported) delays in initiation of radiation, and diagnosed in non-ACoS (American College of Surgeons) hospitals (~40% of California hospitals).	('more', 'PosReg', (173, 177))	('received', 'Reg', (263, 271))	('patients', 'Species', '9606', (116, 124))	('mastectomy', 'Disease', (251, 261))	('Medicare', 'Var', (221, 229))	('higher', 'PosReg', (103, 109))	('lower', 'NegReg', (207, 212))
202873	31281421	Something totally new appears to be the possibility of prophylactic irradiation of the contralateral breast for BRCA mutation carriers.	('mutation', 'Var', (117, 125))	('BRCA', 'Gene', (112, 116))	('BRCA', 'Gene', '672', (112, 116))
202879	31281421	De-escalation of chemotherapy by omitting anthracycline remains safe after 7 years in small volume disease (results from the APT trial), while de-escalating trastuzumab duration from 12 to 6 months appears still controversial.	('anthracycline', 'Gene', (42, 55))	('trastuzumab', 'Chemical', 'MESH:D000068878', (157, 168))	('small volume disease', 'Disease', (86, 106))	('omitting', 'Var', (33, 41))	('anthracycline', 'Chemical', 'MESH:D018943', (42, 55))
202894	31281421	Regarding new tools for risk stratification, it should be taken into consideration that some genomic alteration could predict the outcome of BC patients:for instance, it has been reported in several studies that 8p11 amplification identifies a group of patients with poor outcome, in contrast, mutations on MAP3KA have been associated with better outcome.	('MAP3KA', 'Gene', (307, 313))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (144, 152))	('BC', 'Phenotype', 'HP:0003002', (141, 143))	('mutations', 'Var', (294, 303))	('8p11', 'Gene', (212, 216))
202902	31281421	While many patients follow a benign clinical course, others manifest a lethal systemic disease with resistance to current ET which may due to: single-strand break repair defects which give adaptive evolution and drug resistance, specific DNA repair defects such as MutL defects (which, however, could be used to direct adjuvant CDK4/6i inhibitors) and specific gene mutation such as NF1.	('MutL defects', 'Disease', 'MESH:D005128', (265, 277))	('CDK4/6i', 'Gene', '1019', (328, 335))	('NF1', 'Gene', (383, 386))	('drug resistance', 'Phenotype', 'HP:0020174', (212, 227))	('systemic disease', 'Disease', (78, 94))	('NF1', 'Gene', '4763', (383, 386))	('CDK4/6i', 'Gene', (328, 335))	('defects', 'Var', (170, 177))	('defects', 'Var', (249, 256))	('MutL defects', 'Disease', (265, 277))	('patients', 'Species', '9606', (11, 19))	('ET', 'Chemical', '-', (122, 124))	('systemic disease', 'Disease', 'MESH:D034721', (78, 94))
202903	31281421	Interestingly, ESR1 fusion transcripts drive ET resistance and metastatic disease progression although CDK4/6i inhibitors are predicted to be effective.	('fusion', 'Var', (20, 26))	('ET resistance', 'CPA', (45, 58))	('ESR1', 'Gene', '2099', (15, 19))	('metastatic disease progression', 'CPA', (63, 93))	('ET', 'Chemical', '-', (45, 47))	('CDK4/6i', 'Gene', '1019', (103, 110))	('ESR1', 'Gene', (15, 19))	('drive', 'Reg', (39, 44))	('CDK4/6i', 'Gene', (103, 110))
202927	31281421	New strategies using combinations of PARPi with ATRi or Wee1i in advance TNBC may increase response and reduce resistance to treatment (VIOLETTE trial).	('ET', 'Chemical', '-', (140, 142))	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('response', 'MPA', (91, 99))	('Wee1i', 'Var', (56, 61))	('TNBC', 'Gene', (73, 77))	('resistance to treatment', 'MPA', (111, 134))	('increase', 'PosReg', (82, 90))	('reduce', 'NegReg', (104, 110))	('ATR', 'Gene', '545', (48, 51))	('ATR', 'Gene', (48, 51))
202932	31281421	mutations in RB1 and FAT1) but none of these are ready for clinical implementation.	('RB1', 'Gene', '5925', (13, 16))	('mutations', 'Var', (0, 9))	('FAT1', 'Gene', '2195', (21, 25))	('RB1', 'Gene', (13, 16))	('FAT1', 'Gene', (21, 25))
202954	31281421	Low HR expression is associated with higher KI67, higher grade and less progesterone receptor (PR) positivity, higher recurrence score and higher chemo-sensitivity.	('progesterone receptor', 'Gene', (72, 93))	('progesterone receptor', 'Gene', '5241', (72, 93))	('KI67', 'Var', (44, 48))	('less', 'NegReg', (67, 71))	('PR', 'Gene', '5241', (95, 97))	('HR expression', 'Protein', (4, 17))	('Low', 'Var', (0, 3))
202964	31281421	Possible new treatment options include: triple blockade of ER, HER2 and CDK4/6 both in the neoadjuvant setting (NAPHER 2) and in the advanced setting (PATRICIA) and anti-immune checkpoint agent in the neoadjuvant setting (APTneo, neoHIP trial).	('ATR', 'Gene', (152, 155))	('triple blockade', 'Var', (40, 55))	('CDK4/6', 'Gene', (72, 78))	('NAPHER 2', 'Chemical', '-', (112, 120))	('CDK4/6', 'Gene', '1019;1021', (72, 78))	('HER2', 'Gene', (63, 67))	('HER2', 'Gene', '2064', (63, 67))	('ATR', 'Gene', '545', (152, 155))
202965	31281421	Judy E Garber (Dana-Farber Cancer Institute, USA) spoke about treatment selection for patients with BRCA mutations that are more predisposed to BC by impairing HR and causing genomic instability.	('BRCA', 'Gene', '672', (100, 104))	('BC', 'Phenotype', 'HP:0003002', (144, 146))	('BRCA', 'Gene', (100, 104))	('genomic instability', 'MPA', (175, 194))	('mutations', 'Var', (105, 114))	('impairing', 'NegReg', (150, 159))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('causing', 'Reg', (167, 174))	('patients', 'Species', '9606', (86, 94))
202969	31281421	Additional prospective studies stratified by BRCA1 and BRCA2 mutation status are needed to better understand the effect of carboplatin in polychemotherapy regimens.	('BRCA2', 'Gene', (55, 60))	('carboplatin', 'Chemical', 'MESH:D016190', (123, 134))	('BRCA1', 'Gene', '672', (45, 50))	('mutation', 'Var', (61, 69))	('BRCA2', 'Gene', '675', (55, 60))	('BRCA1', 'Gene', (45, 50))
202970	31281421	It should be considered in fact, that the BRCA mutation carriers make the tumour more sensitive to killing by chemotherapy that induces DNA damage.	('BRCA', 'Gene', '672', (42, 46))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('mutation', 'Var', (47, 55))	('tumour', 'Disease', (74, 80))	('more', 'PosReg', (81, 85))	('BRCA', 'Gene', (42, 46))	('DNA damage', 'MPA', (136, 146))	('sensitive', 'MPA', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
202971	31281421	PARPi were approved for treatment of metastatic BC with BRCA mutations (OlympiAD, Abrazo, EMBRACA).	('metastatic BC', 'Disease', (37, 50))	('BRCA', 'Gene', '672', (56, 60))	('mutations', 'Var', (61, 70))	('BC', 'Phenotype', 'HP:0003002', (48, 50))	('BRCA', 'Gene', (56, 60))
202973	31281421	The phase III study BRCA-P will determine if denosumab may have a role in the prevention of BC in BRCA1 mutation carriers.	('BRCA', 'Gene', '672', (20, 24))	('BRCA', 'Gene', (98, 102))	('BRCA', 'Gene', (20, 24))	('BC', 'Phenotype', 'HP:0003002', (92, 94))	('denosumab', 'Chemical', 'MESH:D000069448', (45, 54))	('mutation', 'Var', (104, 112))	('BRCA1', 'Gene', '672', (98, 103))	('BRCA', 'Gene', '672', (98, 102))	('BRCA1', 'Gene', (98, 103))
202986	31281421	Moreover, in women < 40 years, with an extensive family history and a germline mutation in CHEK2 (11000delC), it is important to intensify screening with an annual mammography starting from 35 years.	('11000delC', 'Var', (98, 107))	('women', 'Species', '9606', (13, 18))	('CHEK2', 'Gene', '11200', (91, 96))	('11000delC', 'Mutation', 'c.11000delC', (98, 107))	('CHEK2', 'Gene', (91, 96))
202987	31281421	In some case, CPM could be justified, especially in patients < 30 years or < 40 years with very dense breasts or extensive family history, CHEK2 mutation and high levels of anxiety and fear.	('mutation', 'Var', (145, 153))	('CHEK2', 'Gene', '11200', (139, 144))	('anxiety', 'Disease', (173, 180))	('anxiety', 'Phenotype', 'HP:0000739', (173, 180))	('CHEK2', 'Gene', (139, 144))	('patients', 'Species', '9606', (52, 60))	('anxiety', 'Disease', 'MESH:D001008', (173, 180))
203024	31281421	Circulating tumour DNA (ctDNA) methylation in serum and plasma has been shown to be effective for diagnostic or prognostic biomarkers detection in different tumour types and in the future will be useful in clinic.	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('methylation', 'Var', (31, 42))	('tumour', 'Disease', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
203025	31281421	DNA methylation alterations across the different tumour types, in fact, may occur more frequently than genomic alterations on ctDNA and apparently could be a more sensitive technology with respect to gene mutations on ctDNA, moreover, some DNA methylation seems to be less dependent on BC subtypes compared to gene mutations.	('alterations', 'Var', (16, 27))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('BC', 'Phenotype', 'HP:0003002', (286, 288))	('tumour', 'Disease', (49, 55))
203030	31281421	With a median follow-up of 8 years in SOFT, there is a significant improvement in DFS for patients assigned to receive T + OFS for 5 years as compared with T alone for 5 years.	('DFS', 'MPA', (82, 85))	('improvement', 'PosReg', (67, 78))	('T + OFS', 'Var', (119, 126))	('T + OFS', 'Chemical', '-', (119, 126))	('patients', 'Species', '9606', (90, 98))
203035	31281421	In the joint analysis of the SOFT and TEXT trials, there is currently no OS improvement at 8 years for those assigned AI + OFS versus those assigned T + OFS despite a significant reduction in distance recurrences with AI + OFS.	('AI + OFS', 'Var', (118, 126))	('AI + OFS', 'Chemical', '-', (218, 226))	('OS', 'Chemical', '-', (73, 75))	('T + OFS', 'Chemical', '-', (149, 156))	('AI + OFS', 'Var', (218, 226))	('AI + OFS', 'Chemical', '-', (118, 126))	('reduction', 'NegReg', (179, 188))	('distance recurrences', 'CPA', (192, 212))
203049	31281421	Biomarkers as MAF deserve further investigation and may aid selection of patients for adjuvant target treatments, for example, in the AZURE trial, it has been seen that amplification of MAF predicts an adverse effect of zolendronic acid in terms of DFS and OS in pre/perimenopausal women, on the contrary, patients with MAF negative tumours benefited from this treatment irrespective of menopausal status.	('OS', 'Chemical', '-', (257, 259))	('aid', 'Gene', (56, 59))	('aid', 'Gene', '57379', (56, 59))	('MAF', 'Gene', (14, 17))	('tumours', 'Disease', (333, 340))	('patients', 'Species', '9606', (306, 314))	('menopausal status', 'Phenotype', 'HP:0008209', (387, 404))	('tumours', 'Phenotype', 'HP:0002664', (333, 340))	('amplification', 'Var', (169, 182))	('zolendronic acid', 'Chemical', '-', (220, 236))	('MAF', 'Gene', '4094', (14, 17))	('tumours', 'Disease', 'MESH:D009369', (333, 340))	('MAF', 'Gene', (320, 323))	('patients', 'Species', '9606', (73, 81))	('MAF', 'Gene', (186, 189))	('women', 'Species', '9606', (282, 287))	('DFS', 'MPA', (249, 252))	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('MAF', 'Gene', '4094', (320, 323))	('MAF', 'Gene', '4094', (186, 189))
203072	31281421	Interesting data derived from the use of talazoparib alone in advanced BC with germline BRCA1/2 mutation, with a significant benefit over standard chemotherapy.	('BC', 'Phenotype', 'HP:0003002', (71, 73))	('BRCA1', 'Gene', (88, 93))	('mutation', 'Var', (96, 104))	('BRCA1', 'Gene', '672', (88, 93))	('talazoparib', 'Chemical', 'MESH:C586365', (41, 52))
203153	25915532	Moreover, variation in the amount of collagen and subsequent mammographic density may be linked to the onset of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('variation', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('linked', 'Reg', (89, 95))
203165	25915532	Tri-culture of HB2, Myo1089 and fibroblasts, resulted in the arrangement of Myo1089 myoepithelial cells around the outer edges of spherical lumen containing HB2 epithelial cells with fibroblasts loosely distributed throughout the collagen gel (Figure 1e) akin to normal breast acini (Figure 1f).	('HB2', 'Gene', (157, 160))	('HB2', 'Gene', '3888', (157, 160))	('HB2', 'Gene', (15, 18))	('Myo1089', 'Var', (76, 83))	('HB2', 'Gene', '3888', (15, 18))
203195	25915532	HER2 gene amplification and protein overexpression is observed in around 16% of breast cancers and is associated with a poor prognosis and survival in breast cancer patients due to its relationship with more aggressive tumours.	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('patients', 'Species', '9606', (165, 173))	('overexpression', 'PosReg', (36, 50))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Disease', (151, 164))	('amplification', 'Var', (10, 23))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('aggressive tumours', 'Disease', 'MESH:D001523', (208, 226))	('HER2', 'Gene', (0, 4))	('aggressive tumours', 'Disease', (208, 226))	('breast cancers', 'Disease', 'MESH:D001943', (80, 94))	('breast cancers', 'Disease', (80, 94))	('protein', 'Protein', (28, 35))	('breast cancers', 'Phenotype', 'HP:0003002', (80, 94))	('tumours', 'Phenotype', 'HP:0002664', (219, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
203303	22347945	Thirteen percent of patients initially diagnosed with low grade DCIS will be upgraded to invasive disease, compared with 36% of those with high-grade DCIS.	('invasive disease', 'Disease', (89, 105))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('upgraded', 'Reg', (77, 85))	('DCIS', 'Chemical', '-', (64, 68))	('invasive disease', 'Disease', 'MESH:D009362', (89, 105))	('patients', 'Species', '9606', (20, 28))	('low grade', 'Var', (54, 63))	('DCIS', 'Chemical', '-', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))
203342	32211331	Acid adaptation also pushes cancer cells toward a more aggressive phenotype through lysosomal redistribution and plays a major role in subpopulation formation and evolution of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (176, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Acid adaptation', 'Var', (0, 15))	('solid tumors', 'Disease', (176, 188))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('aggressive', 'MPA', (55, 65))	('lysosomal redistribution', 'MPA', (84, 108))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
203354	32211331	Survival analysis of patients with different expression of S100A6 revealed correlation of high S100A6 expression with worse outcome in survival of breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('S100A6', 'Gene', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('expression', 'MPA', (102, 112))	('breast cancer', 'Disease', (147, 160))	('S100A6', 'Gene', '6277', (59, 65))	('high', 'Var', (90, 94))	('patients', 'Species', '9606', (21, 29))	('patients', 'Species', '9606', (161, 169))	('S100A6', 'Gene', '6277', (95, 101))	('S100A6', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
203360	32211331	Cells were cultured in heavy SILAC media (Delta6-lysine and Delta10-arginine) for eight doubling time of MCF7.	('Delta6-lysine', 'Var', (42, 55))	('Delta6-lysine', 'Chemical', '-', (42, 55))	('Delta10-arginine', 'Var', (60, 76))	('Delta10-arginine', 'Chemical', '-', (60, 76))
203408	32211331	Deregulated energetics is a hallmark of cancer progression, and the deregulation of cellular energetics has a profound effect on the growth and progression of a tumor.	('Deregulated energetics', 'MPA', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('progression', 'CPA', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('effect', 'Reg', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cellular energetics', 'MPA', (84, 103))	('deregulation', 'Var', (68, 80))	('tumor', 'Disease', (161, 166))	('growth', 'CPA', (133, 139))
203413	32211331	Acidity in the intratumoral environment, not associated with acid adaptation, has also been shown to foster the stemness of cancer cell populations in osteosarcoma.	('foster', 'PosReg', (101, 107))	('osteosarcoma', 'Disease', (151, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('stemness of cancer', 'Disease', (112, 130))	('Acidity', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('stemness of cancer', 'Disease', 'MESH:D009369', (112, 130))	('tumor', 'Disease', (20, 25))
203436	28375855	Women with DCIS had higher risk of dying from breast cancer than the general population, but absolute 10-year risks were low.	('Women', 'Species', '9606', (0, 5))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DCIS', 'Var', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))
203474	28375855	With regard to cancer mortality, DCIS patients had higher risk of breast cancer mortality (SMR 3.33; 95% CI: 2.95-3.74), but lower risk of death from all other cancer combined (SMR 0.82; 95% CI: 0.73-0.91) and from lung (SMR 0.74; 95% CI: 0.58-0.94) and urogenital cancers (SMR 0.62; 95% CI: 0.45-0.83) individually (Fig.	('SMR', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('SMR', 'Gene', '147719', (221, 224))	('patients', 'Species', '9606', (38, 46))	('death', 'Disease', 'MESH:D003643', (139, 144))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SMR', 'Gene', '147719', (274, 277))	('urogenital cancers', 'Disease', 'MESH:D014565', (254, 272))	('SMR', 'Gene', '147719', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', (265, 271))	('SMR', 'Gene', (221, 224))	('cancer', 'Disease', (15, 21))	('SMR', 'Gene', '147719', (177, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('DCIS', 'Var', (33, 37))	('death', 'Disease', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('SMR', 'Gene', (91, 94))	('SMR', 'Gene', (274, 277))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('breast cancer', 'Disease', (66, 79))	('urogenital cancers', 'Disease', (254, 272))
203481	28375855	The SMR for breast cancer was lower for women diagnosed with DCIS between 1999 and 2004 (SMR 2.09; 95% CI: 1.60-2.68) than for those diagnosed between 1989 and 1998 (SMR 3.97; 95% CI: 3.47-4.53; Phomogeneity < 0.001).	('breast cancer', 'Disease', (12, 25))	('SMR', 'Gene', (166, 169))	('lower', 'NegReg', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('DCIS', 'Var', (61, 65))	('women', 'Species', '9606', (40, 45))	('SMR', 'Gene', '147719', (166, 169))	('SMR', 'Gene', (89, 92))	('SMR', 'Gene', (4, 7))	('SMR', 'Gene', '147719', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('SMR', 'Gene', '147719', (4, 7))
203514	28375855	In our study, women with DCIS had lower risk of dying caused by cardiovascular and respiratory disease and lung cancer, conditions that are largely caused by lifestyle factors.	('respiratory disease', 'Disease', (83, 102))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('lower', 'NegReg', (34, 39))	('respiratory disease', 'Phenotype', 'HP:0011947', (83, 102))	('respiratory disease', 'Disease', 'MESH:D012131', (83, 102))	('DCIS', 'Var', (25, 29))	('cardiovascular', 'Disease', 'MESH:D002318', (64, 78))	('cardiovascular', 'Disease', (64, 78))	('lung cancer', 'Disease', (107, 118))	('women', 'Species', '9606', (14, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
203522	28375855	Between 1989 and 1998, women treated by mastectomy had lower breast cancer-specific mortality than women treated by BCS alone, whereas between 1999 and 2004, no difference was found.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('women', 'Species', '9606', (23, 28))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('mastectomy', 'Var', (40, 50))	('women', 'Species', '9606', (99, 104))	('lower', 'NegReg', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
203525	28375855	Remarkable, women who developed ipsilateral IBC appeared to have higher risk of dying from breast cancer than women who were diagnosed with contralateral IBC, a finding which is supported by a study from Narod et al.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('women', 'Species', '9606', (12, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('ipsilateral IBC', 'Var', (32, 47))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('women', 'Species', '9606', (110, 115))
203539	28375855	Similar to the finding of Narod et al, we previously observed that high grade DCIS was, however, not associated with an increased risk of subsequent ipsilateral invasive breast cancer compared with low grade DCIS.	('high grade DCIS', 'Var', (67, 82))	('DCIS', 'Phenotype', 'HP:0030075', (78, 82))	('ipsilateral invasive breast cancer', 'Disease', 'MESH:D001943', (149, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ipsilateral invasive breast cancer', 'Disease', (149, 183))	('DCIS', 'Phenotype', 'HP:0030075', (208, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
203634	29282034	Copenhagen had a lower interval cancer rate than Funen during the first three rounds, which can probably explain why screened women in Copenhagen had a larger decrease in breast cancer mortality than screened women from Funen.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('lower', 'NegReg', (17, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('women', 'Species', '9606', (209, 214))	('women', 'Species', '9606', (126, 131))	('decrease', 'NegReg', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Copenhagen', 'Var', (135, 145))	('interval cancer', 'Disease', (23, 38))	('interval cancer', 'Disease', 'MESH:D009369', (23, 38))
203642	29282034	Given that 40% of screen detected tumors were <=10 mm and that 80% were lymph node negative, a significant proportion of screen-detected tumors are expected to be low risk not in need of chemotherapy, but the DKMS data are too sparse on tumor biology to estimate the precise proportion.	('tumors', 'Disease', (34, 40))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('<=10', 'Var', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
203659	26819638	The disturbance of circadian rhythm may induce metabolic syndrome, diabetes, Alzheimer's disease, depression, sleep disorder, or cancer.	('cancer', 'Disease', (129, 135))	('metabolic syndrome', 'Disease', 'MESH:D008659', (47, 65))	('metabolic syndrome', 'Disease', (47, 65))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (77, 96))	("Alzheimer's disease", 'Disease', (77, 96))	('depression', 'Disease', (98, 108))	('disturbance of circadian rhythm', 'Phenotype', 'HP:0006979', (4, 35))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('sleep disorder', 'Disease', 'MESH:D012893', (110, 124))	('circadian', 'MPA', (19, 28))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (77, 96))	('sleep disorder', 'Phenotype', 'HP:0002360', (110, 124))	('sleep disorder', 'Disease', (110, 124))	('induce', 'Reg', (40, 46))	('diabetes', 'Disease', 'MESH:D003920', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('depression', 'Disease', 'MESH:D000275', (98, 108))	('disturbance', 'Var', (4, 15))	('depression', 'Phenotype', 'HP:0000716', (98, 108))	('diabetes', 'Disease', (67, 75))
203660	26819638	Night work may increase cancer risk, possibly via suppression of melatonin release.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('Night work', 'Var', (0, 10))	('melatonin release', 'MPA', (65, 82))	('increase', 'PosReg', (15, 23))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('suppression', 'NegReg', (50, 61))	('melatonin', 'Chemical', 'MESH:D008550', (65, 74))
203663	26819638	have shown that mutations in the DEC2 gene are involved in human short sleep phenotype and that DEC2 regulates sleep length in mammals.	('human', 'Species', '9606', (59, 64))	('involved', 'Reg', (47, 55))	('short sleep', 'Disease', 'MESH:D012893', (65, 76))	('mutations', 'Var', (16, 25))	('sleep length', 'MPA', (111, 123))	('short sleep', 'Disease', (65, 76))	('DEC2', 'Gene', (33, 37))	('regulates', 'Reg', (101, 110))
203664	26819638	On the other hand, irregular life style may disrupt the negative feed-back system and circadian rhythm and consequently induce various diseases and carcinogenesis.	('carcinogenesis', 'Disease', (148, 162))	('induce', 'Reg', (120, 126))	('diseases', 'Disease', (135, 143))	('irregular', 'Var', (19, 28))	('negative feed-back system', 'MPA', (56, 81))	('circadian rhythm', 'MPA', (86, 102))	('disrupt', 'NegReg', (44, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (148, 162))
203672	26819638	The evidence showed that major regulators of tumor malignancy such as c-Myc, VEGF, p53, cyclin D1, and SNAIL were directly regulated by DEC1, DEC2 and PER1.	('VEGF', 'Gene', '7422', (77, 81))	('c-Myc', 'Gene', '4609', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PER1', 'Var', (151, 155))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('DEC2', 'Var', (142, 146))	('tumor malignancy', 'Disease', 'MESH:D018198', (45, 61))	('cyclin D1', 'Gene', '595', (88, 97))	('c-Myc', 'Gene', (70, 75))	('cyclin D1', 'Gene', (88, 97))	('VEGF', 'Gene', (77, 81))	('DEC1', 'Var', (136, 140))	('tumor malignancy', 'Disease', (45, 61))	('SNAIL', 'Gene', '6615', (103, 108))	('SNAIL', 'Gene', (103, 108))
203685	26819638	We demonstrated for the first time that DEC1 deletion mutants of the basic region and a point mutation of the basic region R65A have dominant negative effects on CLOCK/BMAL1 transactivation.	('CLOCK', 'Gene', '9575', (162, 167))	('R65A', 'Var', (123, 127))	('CLOCK', 'Gene', (162, 167))	('negative', 'NegReg', (142, 150))	('BMAL1', 'Gene', (168, 173))	('BMAL1', 'Gene', '406', (168, 173))	('deletion mutants', 'Var', (45, 61))	('R65A', 'Mutation', 'p.R65A', (123, 127))	('DEC1', 'Gene', (40, 44))
203686	26819638	Interestingly, the DEC1 deletion mutant of the basic region suppressed metastasis of breast cancer cells, whereas DEC1 overexpression induced metastasis in these cells.	('DEC1', 'Gene', (19, 23))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('suppressed', 'NegReg', (60, 70))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('metastasis of', 'CPA', (71, 84))	('deletion mutant', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
203687	26819638	We have shown that a DEC2 point mutation R57A in the basic region had little effect on CLOCK/BMAL2 transactivation: However, there are few articles about DEC2 mutation.	('DEC2', 'Gene', (154, 158))	('CLOCK', 'Gene', (87, 92))	('R57A', 'Var', (41, 45))	('R57A', 'Mutation', 'p.R57A', (41, 45))	('BMAL2', 'Gene', (93, 98))	('BMAL2', 'Gene', '56938', (93, 98))	('CLOCK', 'Gene', '9575', (87, 92))
203688	26819638	If these mutations affect the circadian expression of DEC1 and DEC2, they may suppress the circadian expression of DEC1 and DEC2 in tumor cells.	('DEC2', 'Gene', (63, 67))	('DEC1', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mutations', 'Var', (9, 18))	('DEC2', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('circadian expression', 'MPA', (91, 111))	('affect', 'Reg', (19, 25))	('tumor', 'Disease', (132, 137))	('suppress', 'NegReg', (78, 86))	('circadian expression', 'MPA', (30, 50))	('DEC1', 'Gene', (115, 119))
203689	26819638	Further studies are needed to clarify the significance of these mutations in tumor progression, involving circadian rhythm.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
203693	26819638	The differences in constructs of C-terminus between DEC1 and DEC2 may affect the differential functions in tumor progression.	('affect', 'Reg', (70, 76))	('differences', 'Var', (4, 15))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('DEC2', 'Gene', (61, 65))	('DEC1', 'Gene', (52, 56))
203696	26819638	In immunohistochemistry, DEC1 expression is significantly associated with tumor grade, one-year recurrence, the age of patients, tumor emboli, depth of invasion, lymph node metastasis and pTNM, poor histological differentiation, malignancy and survival rate in invasive breast ductal carcinoma, oral squamous cell carcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, or pancreatic ductal adenocarcinoma (Table 1).	('expression', 'Var', (30, 40))	('tumor', 'Disease', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('malignancy', 'Disease', 'MESH:D009369', (229, 239))	('tumor', 'Disease', (129, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (300, 323))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (295, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('invasive breast ductal carcinoma', 'Disease', 'MESH:D018270', (261, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (277, 293))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (390, 422))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (361, 385))	('oral squamous cell carcinoma', 'Disease', (295, 323))	('malignancy', 'Disease', (229, 239))	('pancreatic ductal adenocarcinoma', 'Disease', (390, 422))	('esophageal squamous cell carcinoma', 'Disease', (325, 359))	('invasive breast ductal carcinoma', 'Disease', (261, 293))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (361, 385))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('DEC1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('associated', 'Reg', (58, 68))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (390, 422))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('patients', 'Species', '9606', (119, 127))	('hepatocellular carcinoma', 'Disease', (361, 385))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (325, 359))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (336, 359))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (270, 293))
203698	26819638	Generally, tumor cells are exposed to various stresses such as hypoxia and abnormalities of cytokines and metabolism.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('abnormalities', 'Var', (75, 88))	('hypoxia', 'Disease', (63, 70))	('metabolism', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
203719	26819638	For example, TGF-beta and polyinosinic -polycytidylic acid (Poly IC) induces DEC2 expression in human pancreatic cancer cells BxPC-3 and in human mesangial cells respectively.	('human', 'Species', '9606', (140, 145))	('expression', 'MPA', (82, 92))	('human', 'Species', '9606', (96, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('polyinosinic -polycytidylic acid', 'Var', (26, 58))	('induces', 'Reg', (69, 76))	('Poly', 'Chemical', '-', (60, 64))	('TGF-beta', 'Gene', (13, 21))	('polyinosinic -polycytidylic acid', 'Chemical', 'MESH:D011070', (26, 58))	('DEC2', 'Gene', (77, 81))	('BxPC-3', 'CellLine', 'CVCL:0186', (126, 132))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
203727	26819638	Interestingly, abnormalities of DEC1 and DEC2 cause various phenomena in mice and human.	('DEC1', 'Gene', (32, 36))	('phenomena', 'Disease', (60, 69))	('abnormalities', 'Var', (15, 28))	('mice', 'Species', '10090', (73, 77))	('cause', 'Reg', (46, 51))	('human', 'Species', '9606', (82, 87))	('DEC2', 'Gene', (41, 45))
203728	26819638	A loss of DEC1 induces an autoimmune disorder in mice.	('autoimmune disorder', 'Phenotype', 'HP:0002960', (26, 45))	('mice', 'Species', '10090', (49, 53))	('DEC1', 'Gene', (10, 14))	('autoimmune disorder', 'Disease', (26, 45))	('autoimmune disorder', 'Disease', 'MESH:D001327', (26, 45))	('loss', 'Var', (2, 6))
203729	26819638	A loss of both DEC1 and DEC2 induces sleep disorder and psychiatric diseases in mice.	('induces', 'Reg', (29, 36))	('sleep disorder', 'Phenotype', 'HP:0002360', (37, 51))	('psychiatric diseases', 'Disease', (56, 76))	('psychiatric diseases', 'Disease', 'MESH:D001523', (56, 76))	('DEC2', 'Gene', (24, 28))	('DEC1', 'Gene', (15, 19))	('psychiatric diseases', 'Phenotype', 'HP:0000708', (56, 76))	('sleep disorder', 'Disease', 'MESH:D012893', (37, 51))	('mice', 'Species', '10090', (80, 84))	('loss', 'Var', (2, 6))	('sleep disorder', 'Disease', (37, 51))
203738	26819638	PER1 has anti-apoptotic effects on human oral cancer, pancreatic cancer and hepatocellular carcinoma cells, whereas PER1 has pro-apoptotic effects on human colon cancer and prostate cancer cells.	('colon cancer', 'Disease', 'MESH:D015179', (156, 168))	('human', 'Species', '9606', (35, 40))	('pancreatic cancer', 'Disease', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('colon cancer', 'Disease', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('anti-apoptotic effects', 'CPA', (9, 31))	('PER1', 'Var', (116, 120))	('human', 'Species', '9606', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('oral cancer', 'Disease', 'MESH:D009062', (41, 52))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (173, 188))	('oral cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (173, 188))	('prostate cancer', 'Disease', (173, 188))	('colon cancer', 'Phenotype', 'HP:0003003', (156, 168))	('PER1', 'Gene', (0, 4))	('hepatocellular carcinoma', 'Disease', (76, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))
203834	23885756	REACTIN: Regulatory activity inference of transcription factors underlying human diseases with application to breast cancer Genetic alterations of transcription factors (TFs) have been implicated in the tumorigenesis of cancers.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('alterations', 'Var', (132, 143))	('Genetic alterations', 'Var', (124, 143))	('TFs', 'Gene', (170, 173))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('implicated', 'Reg', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancers', 'Disease', (220, 227))	('human', 'Species', '9606', (75, 80))	('breast cancer', 'Disease', (110, 123))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
203835	23885756	In many cancers, alteration of TFs results in aberrant activity of them without changing their gene expression level.	('results in', 'Reg', (35, 45))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('activity', 'MPA', (55, 63))	('cancers', 'Disease', (8, 15))	('TFs', 'Gene', (31, 34))	('alteration', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))
203841	23885756	Aberrant expression or activation/inactivation of TFs has been implicated in human diseases, particularly, in a variety of different cancer types.	('activation/inactivation', 'PosReg', (23, 46))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('TFs', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('implicated', 'Reg', (63, 73))	('human', 'Species', '9606', (77, 82))
203846	23885756	However, gene expression profiles of tumor samples can only capture the down-stream readout of the driving genetic alterations such as mutations, amplifications and deletions.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (135, 144))	('deletions', 'Var', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('amplifications', 'Var', (146, 160))
203848	23885756	For example, although mutation of P53 gene is known to be a driving event for carcinogenesis in many cancer types, in most cases there is no significant P53 expression difference between tumor and normal samples: mutation abolishes its transcriptional activity by impacting its DNA binding capacity or protein stability without changing its mRNA expression level.	('transcriptional activity', 'MPA', (236, 260))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('P53', 'Gene', (153, 156))	('DNA binding capacity', 'Interaction', (278, 298))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('cancer', 'Disease', (101, 107))	('P53', 'Gene', '7157', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('P53', 'Gene', (34, 37))	('carcinogenesis', 'Disease', (78, 92))	('abolishes', 'NegReg', (222, 231))	('protein stability', 'MPA', (302, 319))	('mutation', 'Var', (213, 221))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('P53', 'Gene', '7157', (34, 37))	('impacting', 'NegReg', (264, 273))
203872	23885756	There are 6 ER alpha binding profiles in our ChIP-seq collection, representing binding affinities with human genes in two cell lines (T47d and Ecc1) under three different conditions: two steroid hormone treatments (Gen1h and Estrodia1h) and a control treatment (Dmso2).	('Dmso2', 'Chemical', '-', (262, 267))	('ER alpha', 'Gene', (12, 20))	('binding', 'Interaction', (21, 28))	('human', 'Species', '9606', (103, 108))	('Estrodia1h', 'Var', (225, 235))	('Gen1h', 'Var', (215, 220))	('ER alpha', 'Gene', '2099', (12, 20))	('steroid hormone', 'Chemical', 'MESH:D013256', (187, 202))
203873	23885756	In all datasets, the ER alpha binding profiles Haib_T47d_Eralphaa_Gen1h and Haib_T47d_Eralphaa_Estradia1h were identified to have significantly higher activity in ER+ than ER- at the 0.25 false discovery rate (FDR<0.25) (Table S2 in Additional file 2: Table S2).	('ER', 'Gene', '2099', (172, 174))	('ER alpha', 'Gene', '2099', (21, 29))	('ER', 'Gene', '2099', (163, 165))	('higher', 'PosReg', (144, 150))	('ER alpha', 'Gene', (21, 29))	('Haib_T47d_Eralphaa_Gen1h', 'Var', (47, 71))	('Haib_T47d_Eralphaa_Estradia1h', 'Var', (76, 105))	('activity', 'MPA', (151, 159))	('ER', 'Gene', '2099', (21, 23))
203883	23885756	The REACTIN algorithm detected more significantly differential activity of ER alpha between ER+ and ER- for binding profiles in T47d than in Ecc1 (Figure 2).	('ER alpha', 'Gene', '2099', (75, 83))	('activity', 'MPA', (63, 71))	('ER', 'Gene', '2099', (100, 102))	('T47d', 'Var', (128, 132))	('binding', 'Interaction', (108, 115))	('ER alpha', 'Gene', (75, 83))	('ER', 'Gene', '2099', (75, 77))	('ER', 'Gene', '2099', (92, 94))
203884	23885756	Although both T47d and Ecc1 cell lines maintain estrogen receptors and are steroid-responsive, T47d is derived from breast epithelial tumor cells and Ecc1 is derived from endometrial carcinoma cells.	('endometrial carcinoma', 'Disease', (171, 192))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (171, 192))	('estrogen receptor', 'Gene', (48, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (171, 192))	('estrogen receptor', 'Gene', '2099', (48, 65))	('breast epithelial tumor', 'Disease', (116, 139))	('epithelial tumor', 'Phenotype', 'HP:0031492', (123, 139))	('breast epithelial tumor', 'Disease', 'MESH:D002277', (116, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('T47d', 'Var', (95, 99))	('steroid', 'Chemical', 'MESH:D013256', (75, 82))
203885	23885756	As such, T47d can accurately characterize the ER alpha binding affinities to genes in breast cancer samples.	('ER alpha', 'Gene', (46, 54))	('ER alpha', 'Gene', '2099', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('binding', 'Interaction', (55, 62))	('T47d', 'Var', (9, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
203886	23885756	This explains why we observed higher regulatory scores for ER alpha binding profiles from T47d than from Ecc1 in all of the microarray datasets (Figure 2).	('regulatory scores', 'MPA', (37, 54))	('higher', 'PosReg', (30, 36))	('T47d', 'Var', (90, 94))	('ER alpha', 'Gene', '2099', (59, 67))	('ER alpha', 'Gene', (59, 67))
203907	23885756	The lack of Stat1 results in aberrant response to IFN signaling and makes the tissue more susceptible to tumor development.	('makes', 'Reg', (68, 73))	('Stat1', 'Gene', '6772', (12, 17))	('more', 'PosReg', (85, 89))	('Stat1', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lack', 'Var', (4, 8))	('response to IFN signaling', 'MPA', (38, 63))	('susceptible', 'Reg', (90, 101))	('tumor', 'Disease', (105, 110))
203986	28624497	Aberrant activation of the hedgehog signaling network is present in ~25% of all cancers, including breast.	('activation', 'PosReg', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('breast', 'Disease', (99, 105))	('hedgehog signaling network', 'Pathway', (27, 53))
204014	28624497	The multiprotein complex regulating GLI activity consists of Suppressor of Fused (SUFU), Glycogen Synthase Kinase beta (GSK3beta), Protein Kinase A (PKA), kinesin family member 7 (KIF7), and other proteins that modify GLI transcription factor function and localization through post-translational modifications and cleavage of GLIs.	('SUFU', 'Gene', (82, 86))	('GLI', 'Gene', (36, 39))	('SUFU', 'Gene', '51684', (82, 86))	('post-translational modifications', 'Var', (277, 309))	('GLI', 'Gene', (326, 329))	('GLI', 'Gene', (218, 221))	('GLI', 'Gene', '2735', (36, 39))	('KIF7', 'Gene', '374654', (180, 184))	('GSK3beta', 'Gene', (120, 128))	('cleavage', 'Var', (314, 322))	('GLI', 'Gene', '2735', (326, 329))	('GLI', 'Gene', '2735', (218, 221))	('localization', 'MPA', (256, 268))	('KIF7', 'Gene', (180, 184))	('GSK3beta', 'Gene', '2932', (120, 128))
204033	28624497	Aberrant activation of canonical hedgehog signaling, due to inactivating mutations/heterozygosity of Ptch1, or activating mutations of Smo, induces medulloblastoma and basal cell carcinoma.	('Ptch1', 'Gene', (101, 106))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (168, 188))	('activation', 'PosReg', (9, 19))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (168, 188))	('basal cell carcinoma', 'Disease', (168, 188))	('medulloblastoma', 'Disease', (148, 163))	('induces', 'Reg', (140, 147))	('Smo', 'Gene', (135, 138))	('inactivating mutations/heterozygosity', 'Var', (60, 97))	('activating', 'PosReg', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('medulloblastoma', 'Disease', 'MESH:D008527', (148, 163))	('canonical hedgehog signaling', 'Pathway', (23, 51))	('medulloblastoma', 'Phenotype', 'HP:0002885', (148, 163))
204034	28624497	Somatic mutations in hedgehog network genes; such as Ptch1 heterozygosity, and mutations in Gli and Ihh; elicit diverse phenotypes in patients, including altered body size, increased tumor susceptibility, malformed phalanges, and holoprosencephaly (incomplete separation between hemispheres of the brain).	('Ptch1', 'Gene', (53, 58))	('Ihh', 'Gene', '3549', (100, 103))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('increased', 'PosReg', (173, 182))	('mutations', 'Var', (79, 88))	('elicit', 'Reg', (105, 111))	('hedgehog network genes', 'Gene', (21, 43))	('malformed phalanges', 'Phenotype', 'HP:0005918', (205, 224))	('mutations', 'Var', (8, 17))	('holoprosencephaly', 'Disease', (230, 247))	('Ihh', 'Gene', (100, 103))	('holoprosencephaly', 'Disease', 'MESH:D016142', (230, 247))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (230, 247))	('malformed phalanges', 'Disease', (205, 224))	('tumor', 'Disease', (183, 188))	('Gli', 'Gene', '2735', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('malformed phalanges', 'Disease', 'MESH:D000014', (205, 224))	('Gli', 'Gene', (92, 95))
204045	28624497	Tagged Xenopus PTCH1 and Cyclin B1 physically interact in 293T cells, and PTCH1 transfection decreases the proportion of nuclear Cyclin B1.	('proportion', 'MPA', (107, 117))	('293T', 'CellLine', 'CVCL:0063', (58, 62))	('decreases', 'NegReg', (93, 102))	('Xenopus', 'Species', '8355', (7, 14))	('transfection', 'Var', (80, 92))	('PTCH1', 'Gene', (74, 79))
204051	28624497	In the presence of SHH, Ptch1 transfection increases phosphorylated ERK1/2 (extracellular related kinase 1), which is blocked by treatment with a function-blocking antibody to SHH (5E1) or a MEK inhibitor.	('ERK1/2', 'Gene', '5595;5594', (68, 74))	('transfection', 'Var', (30, 42))	('increases', 'PosReg', (43, 52))	('Ptch1', 'Gene', (24, 29))	('phosphorylated', 'MPA', (53, 67))	('MEK', 'Gene', (191, 194))	('MEK', 'Gene', '5609', (191, 194))	('ERK1/2', 'Gene', (68, 74))
204053	28624497	Recently, genetic ablation of Ptch2 can induce PTCH1 phosphorylation of ERK (and canonical signaling) in the bone marrow niche.	('ERK', 'Gene', (72, 75))	('PTCH1 phosphorylation', 'MPA', (47, 68))	('ERK', 'Gene', '5594', (72, 75))	('genetic ablation', 'Var', (10, 26))	('Ptch2', 'Gene', (30, 35))	('induce', 'Reg', (40, 46))
204059	28624497	In the mouse neural tube, low-level expression of Ptch1 can expand the SHH-dependent progenitor populations, which is distinct from the phenotype displayed by ablation of Ptch1 expression.	('expand', 'PosReg', (60, 66))	('mouse', 'Species', '10090', (7, 12))	('Ptch1', 'Gene', (50, 55))	('SHH-dependent progenitor populations', 'CPA', (71, 107))	('low-level expression', 'Var', (26, 46))
204060	28624497	Thus, ligand- dependent antagonism of activated hedgehog signaling by Ptch1 restricts the range and sharpens the morphogen gradient in the mammalian neural tube.	('activated', 'MPA', (38, 47))	('mammalian', 'Species', '9606', (139, 148))	('range', 'MPA', (90, 95))	('restricts', 'NegReg', (76, 85))	('antagonism', 'Var', (24, 34))	('morphogen gradient in the mammalian neural tube', 'MPA', (113, 160))	('Ptch1', 'Gene', (70, 75))
204062	28624497	In Sf9 cells, an insect cell line lacking expression of G proteins, co-transfection of Gi and Smo can increase GTP binding, indicative of G protein signaling.	('GTP', 'Protein', (111, 114))	('co-transfection', 'Var', (68, 83))	('increase', 'PosReg', (102, 110))	('GTP', 'Chemical', 'MESH:D006160', (111, 114))	('Sf9', 'CellLine', 'CVCL:0549', (3, 6))	('Smo', 'Gene', (94, 97))
204063	28624497	Pertussis toxin treatment to inhibit G protein function decreases GLI-luciferase reporter activity with Shh or SmoM2 transfection in mammalian cells.	('GLI', 'Gene', '2735', (66, 69))	('G protein', 'Protein', (37, 46))	('decreases', 'NegReg', (56, 65))	('SmoM2', 'Gene', (111, 116))	('inhibit', 'NegReg', (29, 36))	('mammalian', 'Species', '9606', (133, 142))	('SmoM2', 'Chemical', '-', (111, 116))	('GLI', 'Gene', (66, 69))	('transfection', 'Var', (117, 129))
204064	28624497	SmoM2 is constitutively activated form of SMO from a spontaneous human basal cell carcinoma, containing a point mutation resulting in the replacement of tryptophan with leucine.	('tryptophan', 'MPA', (153, 163))	('human', 'Species', '9606', (65, 70))	('SmoM2', 'Chemical', '-', (0, 5))	('replacement', 'Var', (138, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (71, 91))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (71, 91))	('basal cell carcinoma', 'Disease', (71, 91))	('leucine', 'Chemical', 'MESH:D007930', (169, 176))	('tryptophan', 'Chemical', 'MESH:D014364', (153, 163))
204066	28624497	Data from the mammary gland further support a role of constitutively activated SMO (via the SmoM2 mutation) as a GPCR.	('SmoM2', 'Chemical', '-', (92, 97))	('SMO', 'Disease', (79, 82))	('SmoM2', 'Gene', (92, 97))	('mutation', 'Var', (98, 106))
204069	28624497	Importantly, the hyperproliferative phenotype is not blocked by disruption of either Galphai1 or Galphai3.	('Galphai', 'Gene', '14678', (85, 92))	('Galphai', 'Gene', (97, 104))	('disruption', 'Var', (64, 74))	('Galphai', 'Gene', (85, 92))	('Galphai', 'Gene', '14678', (97, 104))
204079	28624497	Luciferase assays showed that Twist induces expression of the long non-coding RNA termed LncRNA-Hh; similarly, shRNA against Twist reduces GLI1 expression.	('expression', 'MPA', (44, 54))	('LncRNA-Hh', 'Gene', '100506834', (89, 98))	('expression', 'MPA', (144, 154))	('GLI1', 'Gene', (139, 143))	('reduces', 'NegReg', (131, 138))	('shRNA', 'Var', (111, 116))	('Twist', 'Var', (125, 130))	('LncRNA-Hh', 'Gene', (89, 98))
204089	28624497	While in situ hybridization indicates that Shh and Ihh are expressed at E12.5-E16.5; transplanted glands with Shh or Ihh ablation suggested that neither ligand is essential in embryonic development, since transplants yield a comparable ductal tree capable of lactation.	('ablation', 'Var', (121, 129))	('Ihh', 'Gene', (117, 120))	('Ihh', 'Gene', '3549', (51, 54))	('ductal tree', 'CPA', (236, 247))	('Ihh', 'Gene', '3549', (117, 120))	('lactation', 'Disease', (259, 268))	('lactation', 'Disease', 'MESH:D007775', (259, 268))	('Ihh', 'Gene', (51, 54))
204091	28624497	Gli3xt/xt mice with loss of Gli3 (due to a spontaneous mutation, extra toes, resulting in intragenic deletion of Gli3) frequently showed loss of embryonic buds 3 and 5, as well as loss of TOPGal Wnt reporter activity characteristic of embryonic buds.	('deletion', 'Var', (101, 109))	('Gli3', 'Gene', (28, 32))	('mice', 'Species', '10090', (10, 14))	('loss', 'NegReg', (180, 184))	('TOPGal Wnt reporter activity', 'MPA', (188, 216))	('loss', 'NegReg', (137, 141))	('Gli3', 'Gene', (113, 117))	('loss', 'NegReg', (20, 24))
204092	28624497	The absence of mammary bud 3 in the Gli3xt/xt mutant was rescued in organ culture with an FGF10-containing pellet.	('FGF10', 'Gene', '2255', (90, 95))	('Gli3xt/xt', 'Var', (36, 45))	('FGF10', 'Gene', (90, 95))	('absence of mammary', 'Phenotype', 'HP:0100783', (4, 22))
204093	28624497	As Gli3 mRNA expression was not perturbed with in the Fgf10 homozygous null mutant, Gli3 acts upstream of Fgf10.	('mutant', 'Var', (76, 82))	('Fgf10', 'Gene', '2255', (106, 111))	('Fgf10', 'Gene', '2255', (54, 59))	('Fgf10', 'Gene', (54, 59))	('Fgf10', 'Gene', (106, 111))
204101	28624497	Mutants lacking Ihh also did not show any mammary gland phenotypes when embryonic mammary anlagen was transplanted to cleared mammary fat pads.	('lacking', 'NegReg', (8, 15))	('Ihh', 'Gene', '3549', (16, 19))	('Mutants', 'Var', (0, 7))	('Ihh', 'Gene', (16, 19))
204107	28624497	Animals heterozygous for the Ptch1 null allele (since homozygous loss of Ptch1 is embryonic lethal), showed filled-in ducts, dysmorphic TEBs, increased periductal stromal condensation, and loss of epithelial cell polarity.	('epithelial cell polarity', 'CPA', (197, 221))	('filled-in ducts', 'CPA', (108, 123))	('loss', 'Var', (65, 69))	('increased', 'PosReg', (142, 151))	('Ptch1', 'Gene', (29, 34))	('dysmorphic TEBs', 'Disease', 'None', (125, 140))	('dysmorphic TEBs', 'Disease', (125, 140))	('periductal stromal condensation', 'CPA', (152, 183))	('loss', 'NegReg', (189, 193))	('Ptch1', 'Gene', (73, 78))
204109	28624497	Whole glands of Ptch1Delta/+ mice transplanted to a wild-type recipients retained some TEB and histological abnormalities, but transplants of epithelial fragments did not minimally suggesting a role in mammary fat pad stroma.	('mice', 'Species', '10090', (29, 33))	('Ptch1Delta/+', 'Var', (16, 28))	('histological abnormalities', 'Phenotype', 'HP:0002664', (95, 121))	('TEB', 'MPA', (87, 90))
204110	28624497	Subsequent studies employed the mesenchymal dysplasia (mes) allele of Ptch1, which arose spontaneously in mice, and encodes a protein where a 32 base pair deletion results in 220 amino acids of the Ptch1 C-terminus being replaced with 68 unrelated amino acids.	('mice', 'Species', '10090', (106, 110))	('Ptch1', 'Gene', (198, 203))	('mesenchymal dysplasia', 'Gene', '19206', (32, 53))	('mesenchymal dysplasia', 'Gene', (32, 53))	('results in', 'Reg', (164, 174))	('deletion', 'Var', (155, 163))	('Ptch1', 'Gene', (70, 75))
204112	28624497	Ptch1mes/mes animals displayed stunted ductal elongation in the adult virgin, and ductal hyperplasia and hyperproliferation in the DBA or B6D2F1 strains, but not C56B6 or FVB strains.	('ductal hyperplasia', 'Disease', (82, 100))	('B6D2F1', 'Var', (138, 144))	('ductal elongation', 'CPA', (39, 56))	('Ptch1mes/mes', 'Var', (0, 12))	('hyperproliferation', 'CPA', (105, 123))	('stunted', 'NegReg', (31, 38))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (82, 100))
204114	28624497	Later, it was reported that Ptch1mes/mes stunted ducts could be rescued by MMTV (mouse mammary tumor virus) promoter-driven expression of an activated c-Src allele, albeit with a developmental delay, suggesting that c-Src activation downstream of Ptch1 may contribute to ductal elongation.	('Src', 'Gene', (153, 156))	('Src', 'Gene', '6714', (153, 156))	('Src', 'Gene', (218, 221))	('Src', 'Gene', '6714', (218, 221))	('Ptch1mes/mes', 'Var', (28, 40))	('ductal elongation', 'CPA', (271, 288))	('developmental delay', 'Phenotype', 'HP:0001263', (179, 198))	('contribute', 'Reg', (257, 267))	('MMTV', 'Species', '11757', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mouse mammary tumor virus', 'Species', '11757', (81, 106))
204116	28624497	Consistent with a stromal/systemic role for Ptch1 suggested by earlier studies, Fsp-Cre-mediated ablation of Ptch1 in fibroblasts and myeloid cells yields TEBs with altered histology, and mature ducts filled with luminal cells, with increased estrogen receptor positivity together with decreased progesterone receptor expression.	('progesterone receptor', 'Gene', (296, 317))	('altered', 'Reg', (165, 172))	('estrogen receptor', 'Gene', '2099', (243, 260))	('increased estrogen receptor', 'Phenotype', 'HP:0025134', (233, 260))	('progesterone receptor', 'Gene', '5241', (296, 317))	('Fsp', 'Gene', '2919', (80, 83))	('TEBs', 'Chemical', '-', (155, 159))	('decreased progesterone', 'Phenotype', 'HP:0008233', (286, 308))	('decreased', 'NegReg', (286, 295))	('Ptch1', 'Gene', (109, 114))	('Fsp', 'Gene', (80, 83))	('estrogen receptor', 'Gene', (243, 260))	('ablation', 'Var', (97, 105))	('increased', 'PosReg', (233, 242))	('expression', 'MPA', (318, 328))
204120	28624497	Mice with MMTV driven-SmoM2 (MMTV-SmoM2) expression displayed TEB dysmorphia and an increased number of TEBs persisting at 10 weeks of age, hyperproliferation at 10 weeks of age, hyperbranching/hyperbudding.	('dysmorphia', 'Disease', (66, 76))	('dysmorphia', 'Disease', 'MESH:C537340', (66, 76))	('MMTV', 'Species', '11757', (10, 14))	('SmoM2', 'Chemical', '-', (34, 39))	('MMTV', 'Species', '11757', (29, 33))	('increased', 'PosReg', (84, 93))	('hyperproliferation', 'CPA', (140, 158))	('Mice', 'Species', '10090', (0, 4))	('SmoM2', 'Chemical', '-', (22, 27))	('TEBs', 'Chemical', '-', (104, 108))	('MMTV driven-SmoM2', 'Var', (10, 27))
204121	28624497	Other mouse models of conditional SmoM2 expression in the mammary gland (using MMTV-Cre, Adenovirus-Cre infected epithelial cells transplanted to a cleared fat pad, or intraductal Adenovirus- Cre injection) displayed similar phenotypes including hyperbudding, hyperbranching, and hyperproliferation.	('hyperbudding', 'Disease', (246, 258))	('SmoM2', 'Gene', (34, 39))	('SmoM2', 'Chemical', '-', (34, 39))	('conditional', 'Var', (22, 33))	('hyperbranching', 'Disease', (260, 274))	('hyperproliferation', 'Disease', (280, 298))	('MMTV', 'Species', '11757', (79, 83))	('mouse', 'Species', '10090', (6, 11))
204126	28624497	Thus, aberrant Smo activation in the mammary gland alters proliferation, cell fate, branching morphogenesis, and the periductal stroma, while regulated Smo expression in Fsp+ cells is important for normal histology.	('Smo', 'Gene', (15, 18))	('proliferation', 'CPA', (58, 71))	('cell fate', 'CPA', (73, 82))	('aberrant', 'Var', (6, 14))	('Fsp', 'Gene', '2919', (170, 173))	('activation', 'PosReg', (19, 29))	('alters', 'Reg', (51, 57))	('Fsp', 'Gene', (170, 173))	('branching morphogenesis', 'CPA', (84, 107))
204127	28624497	The downstream mechanism driving the phenotypes present due to Adenovirus-Cre-mediated SmoM2 expression was postulated to be Notch1 signaling, since Notch target genes were upregulated in SmoM2 positive cells relative to SmoM2 negative cells by qPCR.	('Notch1', 'Gene', (125, 131))	('SmoM2', 'Gene', (87, 92))	('SmoM2', 'Chemical', '-', (188, 193))	('Notch', 'Gene', '4851', (125, 130))	('SmoM2', 'Chemical', '-', (87, 92))	('Notch1', 'Gene', '4851', (125, 131))	('Notch', 'Gene', (125, 130))	('Notch', 'Gene', '4851', (149, 154))	('Notch', 'Gene', (149, 154))	('SmoM2', 'Chemical', '-', (221, 226))	('SmoM2', 'Var', (188, 193))	('upregulated', 'PosReg', (173, 184))
204141	28624497	Growth hormone and 17-beta estradiol administration to these mutants did not elicit upregulation of respective target genes (i.e., Igf1 and Hgf, respectively); Wnt2 signaling is also altered.	('Hgf', 'Gene', (140, 143))	('Wnt2', 'Gene', (160, 164))	('altered', 'Reg', (183, 190))	('Growth hormone', 'Gene', '2688', (0, 14))	('Igf1', 'Gene', (131, 135))	('17-beta estradiol', 'Chemical', 'MESH:D004958', (19, 36))	('Wnt2', 'Gene', '7472', (160, 164))	('Hgf', 'Gene', '3082', (140, 143))	('Igf1', 'Gene', '3479', (131, 135))	('mutants', 'Var', (61, 68))	('Growth hormone', 'Gene', (0, 14))
204145	28624497	Ablation of primary cilia throughout the mouse, via expression of a mutant form of Ift88 (intraflagellar transport protein 88) to disrupt primary cilium assembly, produced decreased branching.	('primary cilium', 'CPA', (138, 152))	('branching', 'CPA', (182, 191))	('mouse', 'Species', '10090', (41, 46))	('decreased', 'NegReg', (172, 181))	('intraflagellar transport protein 88', 'Gene', '21821', (90, 125))	('Ift88', 'Gene', (83, 88))	('intraflagellar transport protein 88', 'Gene', (90, 125))	('mutant', 'Var', (68, 74))
204146	28624497	The loss of branching in mutants in organ culture suggests this is an epithelium intrinsic defect.	('mutants', 'Var', (25, 32))	('intrinsic defect', 'Disease', (81, 97))	('branching', 'CPA', (12, 21))	('loss', 'NegReg', (4, 8))	('intrinsic defect', 'Disease', 'MESH:D020919', (81, 97))
204148	28624497	Ablation of primary cilia in ovarian follicles (by conditional ablation of Ift88) yielded stunted mammary ductal outgrowths at an adult virgin timepoint TEBs and pubertal ductal outgrowth was restored in these mutants with estrogen treatment, suggesting that defective estradiol production induced the stunted ducts and loss of TEBs in the mutant animals.	('mutant', 'Var', (340, 346))	('loss', 'NegReg', (320, 324))	('TEBs', 'Chemical', '-', (153, 157))	('mutants', 'Var', (210, 217))	('Ift88', 'Gene', (75, 80))	('mammary ductal outgrowths', 'CPA', (98, 123))	('estradiol', 'Chemical', 'MESH:D004958', (269, 278))	('TEBs', 'CPA', (328, 332))	('TEBs', 'Chemical', '-', (328, 332))	('stunted ducts', 'CPA', (302, 315))	('defective', 'Var', (259, 268))
204155	28624497	In immortalized mammary epithelial cells, TAp63 ablation reduced Ihh mRNA levels in the stem cell enriched fraction, whereas expression of DeltaNp63 increased Ihh mRNA.	('Ihh', 'Gene', (159, 162))	('p63', 'Gene', '8626', (44, 47))	('increased', 'PosReg', (149, 158))	('reduced', 'NegReg', (57, 64))	('p63', 'Gene', (145, 148))	('Ihh', 'Gene', '3549', (65, 68))	('Ihh', 'Gene', '3549', (159, 162))	('p63', 'Gene', '8626', (145, 148))	('ablation', 'Var', (48, 56))	('p63', 'Gene', (44, 47))	('Ihh', 'Gene', (65, 68))
204156	28624497	Additionally, shIhh reduces the number of complex acini, whereas shGli3 increases complex acini formation.	('complex acini formation', 'CPA', (82, 105))	('increases', 'PosReg', (72, 81))	('reduces', 'NegReg', (20, 27))	('Ihh', 'Gene', (16, 19))	('Ihh', 'Gene', '3549', (16, 19))	('shGli3', 'Var', (65, 71))
204160	28624497	Thus, it appears that SmoM2 expression pushes stem cells into a progenitor state.	('SmoM2', 'Gene', (22, 27))	('expression', 'Var', (28, 38))	('pushes', 'PosReg', (39, 45))	('SmoM2', 'Chemical', '-', (22, 27))
204173	28624497	Most convincingly, transplantation of CD24+CD49hi stem cell enriched cells transplanted to Fsp-Cre;Gli2fl/fl mutants display reduced fat pad filling; additionally, mammary epithelial cells from Fsp-Cre;Gli2fl/fl mutants are consistently outcompeted when transplanted with wildtype cells in a competitive repopulation transplantation assay.	('Fsp', 'Gene', '2919', (91, 94))	('Fsp', 'Gene', '2919', (194, 197))	('fat pad filling', 'CPA', (133, 148))	('reduced', 'NegReg', (125, 132))	('reduced fat pad', 'Phenotype', 'HP:0040063', (125, 140))	('mutants', 'Var', (109, 116))	('Fsp', 'Gene', (91, 94))	('Fsp', 'Gene', (194, 197))
204176	28624497	Aberrant activation of hedgehog signaling is found in multiple cancer types.	('multiple cancer', 'Disease', (54, 69))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('multiple cancer', 'Disease', 'MESH:D009369', (54, 69))	('hedgehog signaling', 'Pathway', (23, 41))
204177	28624497	For example, in basal cell carcinoma, mutations in hedgehog network genes resulting in hedgehog network activation are sufficient to induce, and required to maintain carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('activation', 'PosReg', (104, 114))	('hedgehog network genes', 'Gene', (51, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (16, 36))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (16, 36))	('basal cell carcinoma', 'Disease', (16, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('carcinomas', 'Disease', (166, 176))	('carcinomas', 'Disease', 'MESH:D002277', (166, 176))	('mutations', 'Var', (38, 47))	('hedgehog network', 'Gene', (87, 103))
204178	28624497	Mutations that activate canonical hedgehog signaling drive medulloblastoma tumorigenesis as well.	('medulloblastoma', 'Disease', 'MESH:D008527', (59, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Mutations', 'Var', (0, 9))	('medulloblastoma', 'Phenotype', 'HP:0002885', (59, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('medulloblastoma', 'Disease', (59, 74))
204180	28624497	Hedgehog network genes are often misregulated at the DNA level, including point mutations and copy number variations, in breast tumors.	('breast tumors', 'Disease', (121, 134))	('point mutations', 'Var', (74, 89))	('copy number variations', 'Var', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('breast tumors', 'Phenotype', 'HP:0100013', (121, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Hedgehog network genes', 'Gene', (0, 22))	('breast tumor', 'Phenotype', 'HP:0100013', (121, 133))	('breast tumors', 'Disease', 'MESH:D001943', (121, 134))
204182	28624497	PTCH1 mutations and deletions are present in 1-2% of breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('PTCH1', 'Gene', (0, 5))	('deletions', 'Var', (20, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (53, 67))	('breast cancers', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancers', 'Disease', 'MESH:D001943', (53, 67))	('mutations', 'Var', (6, 15))
204183	28624497	SMO is also mutated (missense point mutations) or amplified in about 1% of breast tumors; and, consistently, GLI1, GLI2, and GLI3 are mutated (missense point mutations) in 1-2.5% of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (182, 196))	('breast tumors', 'Phenotype', 'HP:0100013', (75, 88))	('breast tumor', 'Phenotype', 'HP:0100013', (75, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('GLI1', 'Gene', (109, 113))	('GLI3', 'Gene', '2737', (125, 129))	('GLI3', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('GLI2', 'Gene', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancers', 'Disease', 'MESH:D001943', (182, 196))	('GLI2', 'Gene', '2736', (115, 119))	('breast cancers', 'Disease', (182, 196))	('breast tumors', 'Disease', 'MESH:D001943', (75, 88))	('mutated', 'Var', (134, 141))	('breast tumors', 'Disease', (75, 88))	('SMO', 'Gene', (0, 3))
204184	28624497	In a screen for promoter methylation in 6 breast cancer cell lines, the PTCH1 promoter was frequently methylated.	('methylated', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('PTCH1', 'Gene', (72, 77))
204189	28624497	Missense coding mutations in PTCH1 were also absent in a panel of 45 breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('absent', 'NegReg', (45, 51))	('Missense coding mutations', 'Var', (0, 25))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast cancers', 'Disease', 'MESH:D001943', (69, 83))	('breast cancers', 'Disease', (69, 83))	('PTCH1', 'Gene', (29, 34))
204195	28624497	A new isoform of GLI1 (tGLI1), containing a deletion of part of exons 3 and 4, has been identified exclusively in breast cancer cell lines but not normal breast tissue.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('deletion of', 'Var', (44, 55))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
204228	28624497	It is well-established that Wnt1, EGF, FGF, and TGFbeta misregulation contribute to breast tumorigenesis and proliferation.	('breast tumor', 'Phenotype', 'HP:0100013', (84, 96))	('FGF', 'Gene', '2255', (39, 42))	('breast tumor', 'Disease', 'MESH:D001943', (84, 96))	('FGF', 'Gene', (39, 42))	('misregulation', 'Var', (56, 69))	('contribute', 'Reg', (70, 80))	('EGF', 'Gene', (34, 37))	('breast tumor', 'Disease', (84, 96))	('Wnt1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EGF', 'Gene', '1950', (34, 37))	('proliferation', 'CPA', (109, 122))	('TGFbeta', 'Gene', (48, 55))
204229	28624497	Hedgehog signaling has non-canonical interactions downstream of Wnt1; additionally, MMTV-Wnt1 mice display Gli1 reporter activity.	('MMTV-Wnt1', 'Var', (84, 93))	('Gli1 reporter activity', 'MPA', (107, 129))	('mice', 'Species', '10090', (94, 98))	('MMTV', 'Species', '11757', (84, 88))
204233	28624497	While Ptch1 involvement has not been addressed, it seems likely since TID1 binds a PTCH1 domain lost in the Ptch1Fvb mutant allele associated with squamous cell carcinoma (see for further discussion).	('squamous cell carcinoma', 'Disease', (147, 170))	('Ptch1Fvb', 'Gene', (108, 116))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('mutant', 'Var', (117, 123))	('lost', 'NegReg', (96, 100))	('PTCH1', 'Gene', (83, 88))	('disc', 'Gene', (188, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('associated with', 'Reg', (131, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('TID1', 'Gene', (70, 74))	('TID1', 'Gene', '9093', (70, 74))	('disc', 'Gene', '32579', (188, 192))
204235	28624497	An interaction between a PTCH1 polymorphism in the C-terminus, Pro1315Leu, is associated with increased breast cancer risk with oral contraceptive use.	('Pro1315Leu', 'SUBSTITUTION', 'None', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('PTCH1', 'Gene', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('Pro1315Leu', 'Var', (63, 73))
204241	28624497	Conversely, estrogen depletion in cell culture reduced SHH and GLI1 expression; additionally, SMO inhibitors decreased ERalpha-luciferase activity and proliferation of ER positive cells.	('decreased', 'NegReg', (109, 118))	('activity', 'MPA', (138, 146))	('ERalpha', 'Gene', '2099', (119, 126))	('GLI1', 'Gene', (63, 67))	('expression', 'MPA', (68, 78))	('inhibitors', 'Var', (98, 108))	('SHH', 'Gene', (55, 58))	('proliferation', 'CPA', (151, 164))	('SMO', 'Gene', (94, 97))	('estrogen depletion', 'Phenotype', 'HP:0008226', (12, 30))	('reduced', 'NegReg', (47, 54))	('ERalpha', 'Gene', (119, 126))
204249	28624497	Cyclopamine treatment or Gli1 depletion reduced the size of this population of cells.	('size', 'MPA', (52, 56))	('reduced', 'NegReg', (40, 47))	('Cyclopamine', 'Chemical', 'MESH:C000541', (0, 11))	('depletion', 'Var', (30, 39))
204270	28624497	Transfection of Gli2 can induce PTHrP-luciferase activity and PTHrP mRNA expression, osteoclast activity, and the vicious cycle, but in this study, osteoclast activity did not require hedgehog ligands or SMO activation.	('Gli2', 'Gene', (16, 20))	('activity', 'MPA', (49, 57))	('PTHrP', 'Gene', '5744', (32, 37))	('induce', 'PosReg', (25, 31))	('PTHrP', 'Gene', (62, 67))	('Transfection', 'Var', (0, 12))	('PTHrP', 'Gene', '5744', (62, 67))	('vicious', 'CPA', (114, 121))	('PTHrP', 'Gene', (32, 37))	('osteoclast activity', 'CPA', (85, 104))
204271	28624497	Recent data suggest that hedgehog network misregulation in the stroma rather than in the tumor itself may be important for breast tumorigenesis.	('hedgehog', 'Protein', (25, 33))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('misregulation', 'Var', (42, 55))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast tumor', 'Disease', 'MESH:D001943', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('breast tumor', 'Disease', (123, 135))
204274	28624497	this signaling pattern fits with Wap-Shh, Gli1 overexpression, or SmoM2 expression in the mouse eliciting stromal phenotypes including hyperplasia and increased collagen deposition.	('Wap', 'Gene', '22373', (33, 36))	('increased', 'PosReg', (151, 160))	('fits', 'Disease', (23, 27))	('hyperplasia', 'Disease', 'MESH:D006965', (135, 146))	('eliciting', 'Reg', (96, 105))	('hyperplasia', 'Disease', (135, 146))	('SmoM2', 'Gene', (66, 71))	('mouse', 'Species', '10090', (90, 95))	('collagen deposition', 'CPA', (161, 180))	('Wap', 'Gene', (33, 36))	('fits', 'Disease', 'MESH:D012640', (23, 27))	('SmoM2', 'Chemical', '-', (66, 71))	('expression', 'Var', (72, 82))
204287	28624497	This finding raises the possibility that datasets associating Shh expression with poor patient outcome could have also displayed higher stromal GLI1 expression to elicit worse patient outcome.	('higher', 'PosReg', (129, 135))	('Shh', 'Gene', (62, 65))	('patient', 'Species', '9606', (87, 94))	('expression', 'MPA', (149, 159))	('expression', 'Var', (66, 76))	('stromal', 'Protein', (136, 143))	('patient', 'Species', '9606', (176, 183))
204307	28624497	Loss of the primary cilia by genetic ablation of the intraflagellar transport protein (Ift88) produced abrogated estrous cycling and ovulation, and loss of the corpus luteum- the progesterone producing structure of the ovary.	('abrogated', 'NegReg', (103, 112))	('corpus luteum-', 'CPA', (160, 174))	('loss', 'NegReg', (148, 152))	('ovulation', 'CPA', (133, 142))	('Loss', 'NegReg', (0, 4))	('estrous cycling', 'CPA', (113, 128))	('Ift88', 'Gene', (87, 92))	('progesterone', 'Chemical', 'MESH:D011374', (179, 191))	('genetic ablation', 'Var', (29, 45))
204308	28624497	Recently, it was observed that fertility was abrogated with Fsp-Cre mediated ablation of Ptch1; this finding is consistent with previous data suggesting the importance of paracrine hedgehog signaling in the ovary.	('abrogated', 'NegReg', (45, 54))	('ablation', 'Var', (77, 85))	('Fsp', 'Gene', '2919', (60, 63))	('Ptch1', 'Gene', (89, 94))	('fertility', 'CPA', (31, 40))	('Fsp', 'Gene', (60, 63))
204310	28624497	While direct evidence showing that hedgehog network activity regulates hormone production in the ovary are not established, the defects in ovaries due to altered hedgehog signaling, loss of steroidogenic structures such as the corpus luteum, and altered expression of steroidogenic enzymes strongly suggests that the hedgehog network may be essential for the production of ovarian hormones.	('loss', 'NegReg', (182, 186))	('ovaries', 'Disease', (139, 146))	('expression', 'MPA', (254, 264))	('ovaries', 'Disease', 'MESH:D010051', (139, 146))	('defects in ovaries', 'Phenotype', 'HP:0000137', (128, 146))	('altered', 'Reg', (246, 253))	('steroidogenic enzymes', 'Enzyme', (268, 289))	('hedgehog', 'Gene', (162, 170))	('altered', 'Var', (154, 161))
204319	28624497	Returning to the previous model, we should add that stromal Smo inhibition is important for TEB homeostasis, given the disrupted histology of Fsp-Cre;SmoM2 mutants.	('SmoM2', 'Chemical', '-', (150, 155))	('Fsp', 'Gene', (142, 145))	('mutants', 'Var', (156, 163))	('SmoM2', 'Gene', (150, 155))	('Fsp', 'Gene', '2919', (142, 145))
204332	28624497	A subset of breast tumors displays genetic mutations or aberrant methylation of hedgehog network genes (Fig.	('aberrant methylation', 'Var', (56, 76))	('breast tumors', 'Disease', 'MESH:D001943', (12, 25))	('hedgehog network genes', 'Gene', (80, 102))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('breast tumors', 'Disease', (12, 25))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('breast tumor', 'Phenotype', 'HP:0100013', (12, 24))	('breast tumors', 'Phenotype', 'HP:0100013', (12, 25))
204335	28624497	While data suggest that hedgehog misregulation may govern critical features of breast tumor biology, further investigation is needed to define the role of hedgehog network members.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('breast tumor', 'Disease', (79, 91))	('breast tumor', 'Phenotype', 'HP:0100013', (79, 91))	('govern', 'Reg', (51, 57))	('breast tumor', 'Disease', 'MESH:D001943', (79, 91))	('misregulation', 'Var', (33, 46))
204342	28624497	Stromal misregulation of hedgehog network members altering the tumor microenvironment is consistent with the data from postnatal development, where altering expression of hedgehog network members is sufficient to alter stromal constituents.	('tumor', 'Disease', (63, 68))	('expression', 'MPA', (157, 167))	('hedgehog', 'Gene', (171, 179))	('alter', 'Reg', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('altering', 'Var', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
204354	25586191	The present study was performed to evaluate the prognostic value of CHST11 expression and determine whether aberrant DNA methylation controls CHST11 expression in breast cancer.	('CHST11', 'Gene', '50515', (142, 148))	('aberrant', 'Var', (108, 116))	('CHST11', 'Gene', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('expression', 'MPA', (149, 159))	('CHST11', 'Gene', '50515', (68, 74))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))	('CHST11', 'Gene', (68, 74))
204366	25586191	Therefore, in addition to CHST11 mRNA levels, the methylation status of this gene also has potential as a prognostic biomarker.	('methylation status', 'Var', (50, 68))	('CHST11', 'Gene', '50515', (26, 32))	('CHST11', 'Gene', (26, 32))
204370	25586191	CHST11 is a key enzyme in the biosynthesis of chondroitin sulfates (CS) and its action on chondroitin chains can lead to the production of chondroitin sulfate A (CS-A), B (CS-B) and E (CS-E).	('CS', 'Chemical', 'MESH:D002809', (172, 174))	('CS-B', 'Gene', '1443', (172, 176))	('chondroitin', 'Chemical', 'MESH:D002807', (90, 101))	('chondroitin sulfates', 'Chemical', 'MESH:D002809', (46, 66))	('lead to', 'Reg', (113, 120))	('CHST11', 'Gene', (0, 6))	('CS', 'Chemical', 'MESH:D002809', (162, 164))	('chondroitin sulfate A', 'Gene', '1442', (139, 160))	('CS-A', 'Gene', (162, 166))	('chondroitin', 'Chemical', 'MESH:D002807', (46, 57))	('action', 'Var', (80, 86))	('chondroitin', 'Chemical', 'MESH:D002807', (139, 150))	('chondroitin sulfate A', 'Gene', (139, 160))	('CHST11', 'Gene', '50515', (0, 6))	('CS', 'Chemical', 'MESH:D002809', (68, 70))	('CS-B', 'Gene', (172, 176))	('CS', 'Chemical', 'MESH:D002809', (185, 187))	('CS-A', 'Gene', '1442', (162, 166))
204377	25586191	Aberrant DNA methylation is a mechanism that controls gene expression and is involved in tumor initiation and progression.	('tumor initiation', 'Disease', (89, 105))	('Aberrant', 'Var', (0, 8))	('involved', 'Reg', (77, 85))	('gene expression', 'MPA', (54, 69))	('DNA', 'Protein', (9, 12))	('tumor initiation', 'Disease', 'MESH:D009369', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
204378	25586191	In a gene profiling study of head and neck cancer it was suggested that DNA methylation may affect CHST11 expression in laryngeal carcinoma.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('expression', 'MPA', (106, 116))	('laryngeal carcinoma', 'Disease', (120, 139))	('CHST11', 'Gene', '50515', (99, 105))	('head and neck cancer', 'Phenotype', 'HP:0012288', (29, 49))	('affect', 'Reg', (92, 98))	('methylation', 'Var', (76, 87))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('CHST11', 'Gene', (99, 105))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (120, 139))	('DNA methylation', 'Var', (72, 87))
204379	25586191	In another study on breast cancer cell lines using genome wide methylation profiling, the authors reported that CHST11 is hypermethylated in ER-positive and hypomethylated in ER-negative cell lines.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('CHST11', 'Gene', '50515', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('hypermethylated', 'Var', (122, 137))	('CHST11', 'Gene', (112, 118))
204382	25586191	Our investigation of the methylation status of CHST11 in breast cancer cells clearly demonstrates an association between lack of expression of this gene and hypermethylation of a CpG island of its DNA.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('expression', 'MPA', (129, 139))	('CHST11', 'Gene', '50515', (47, 53))	('lack', 'NegReg', (121, 125))	('hypermethylation', 'Var', (157, 173))	('CHST11', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
204383	25586191	Treatment of MCF7 cells with 5AzadC led to a dose-dependent increase in the expression of the gene and its product CS-A.	('CS-A', 'Gene', '1442', (115, 119))	('increase', 'PosReg', (60, 68))	('5AzadC', 'Chemical', 'MESH:D000077209', (29, 35))	('expression', 'MPA', (76, 86))	('CS-A', 'Gene', (115, 119))	('5AzadC', 'Var', (29, 35))	('MCF7', 'CellLine', 'CVCL:0031', (13, 17))
204405	25586191	Each 25-mul PCR reaction included 1.0 muM of each primer, 2.5 U of the FailSafe Enzyme Mix and 12.5 mul of the FailSafe PCR PreMixes A or C. Bisulfite-modified genomic DNA was amplified by semi-nested PCR using two sets of primers for part of intron 1 that is within a CpG island spanning exon 1 of the CHST11 gene (Genbank NM_000012 and exon 1 located with NM_018413).	('Mix', 'Gene', '83881', (127, 130))	('CHST11', 'Gene', '50515', (303, 309))	('Bisulfite', 'Chemical', 'MESH:C042345', (141, 150))	('Mix', 'Gene', (87, 90))	('CHST11', 'Gene', (303, 309))	('Mix', 'Gene', '83881', (87, 90))	('NM_018413', 'Var', (358, 367))	('Mix', 'Gene', (127, 130))
204438	25586191	Together, the data suggest that low expression of CHST11 in the MCF7 cells is due to promoter hypermethylation, and that DNA hypomethylation in the more aggressive mesenchymal-like MDA-MB-231 cell line is permissive for overt CHST11 expression.	('promoter', 'MPA', (85, 93))	('low', 'NegReg', (32, 35))	('CHST11', 'Gene', (226, 232))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (181, 191))	('CHST11', 'Gene', '50515', (50, 56))	('hypomethylation', 'Var', (125, 140))	('CHST11', 'Gene', '50515', (226, 232))	('CHST11', 'Gene', (50, 56))	('MCF7', 'CellLine', 'CVCL:0031', (64, 68))	('expression', 'MPA', (36, 46))
204443	25586191	Similar to MCF7 cells, the CpG island of the CHST11 gene in the T47-D and ZR-75-1 cell lines, was hypermethylated (Fig.	('hypermethylated', 'Var', (98, 113))	('CHST11', 'Gene', (45, 51))	('CHST11', 'Gene', '50515', (45, 51))	('MCF7', 'CellLine', 'CVCL:0031', (11, 15))
204448	25586191	The expression of CHST11 in tumor tissue may also be controlled by DNA methylation similar to that observed in cell lines.	('CHST11', 'Gene', '50515', (18, 24))	('tumor', 'Disease', (28, 33))	('DNA methylation', 'Var', (67, 82))	('CHST11', 'Gene', (18, 24))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('controlled', 'Reg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
204451	25586191	Therefore, methylation status of CHST11 CpG might be a useful marker to differentiate between luminal and basal-like breast cancer subtypes, however, a larger sample size is required to confirm this.	('luminal', 'Disease', (94, 101))	('CHST11', 'Gene', '50515', (33, 39))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('methylation', 'Var', (11, 22))	('CHST11', 'Gene', (33, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))
204459	25586191	Aberrant DNA methylation is involved in tumor initiation and progression.	('Aberrant', 'Var', (0, 8))	('DNA', 'Protein', (9, 12))	('tumor initiation', 'Disease', 'MESH:D009369', (40, 56))	('involved', 'Reg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor initiation', 'Disease', (40, 56))
204460	25586191	Hypermethylation of tumor suppressor genes is a common mechanism of gene silencing observed in cancer, and similarly, DNA hypomethylation can contribute to overexpression of tumor-promoting genes.	('tumor', 'Disease', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('overexpression', 'PosReg', (156, 170))	('hypomethylation', 'Var', (122, 137))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (95, 101))	('gene', 'MPA', (68, 72))	('silencing', 'NegReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (20, 25))
204462	25586191	We find that induced hypomethylation by 5Azadc led to CHST11 overexpression and increased levels of the CHST11's immediate cell surface product CS-A.	('CS-A', 'Gene', (144, 148))	('overexpression', 'PosReg', (61, 75))	('hypomethylation', 'Var', (21, 36))	('levels of the', 'MPA', (90, 103))	('CHST11', 'Gene', (104, 110))	('increased', 'PosReg', (80, 89))	('CHST11', 'Gene', '50515', (54, 60))	('5Azadc', 'Chemical', 'MESH:D000077209', (40, 46))	('CS-A', 'Gene', '1442', (144, 148))	('CHST11', 'Gene', '50515', (104, 110))	('CHST11', 'Gene', (54, 60))
204463	25586191	Based upon our results, it seems that a combination of hypomethylation and high expression occurs in basal-like cancer cells.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('basal-like cancer', 'Phenotype', 'HP:0002671', (101, 118))	('hypomethylation', 'Var', (55, 70))	('expression', 'MPA', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
204464	25586191	Hypermethylation of CHST11 (and very low to no expression) clearly differentiates the least aggressive, luminal cells with epithelial morphology from the more aggressive cells we tested.	('differentiates', 'Reg', (67, 81))	('Hypermethylation', 'Var', (0, 16))	('CHST11', 'Gene', (20, 26))	('CHST11', 'Gene', '50515', (20, 26))
204465	25586191	We observed a hypomethylated CpG island in a limited number of triple negative specimens from patients.	('hypomethylated', 'Var', (14, 28))	('CpG island', 'Protein', (29, 39))	('patients', 'Species', '9606', (94, 102))
204470	25586191	In contrast, the main trend is widespread gene hypermethylation as cancers go from less aggressive to more aggressive phenotypes.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('gene hypermethylation', 'Var', (42, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('hypermethylation', 'Var', (47, 63))
204476	25586191	The recognition that silencing of tumor suppressor genes through promoter hypermethylation plays a significant role in tumorigenesis has led to the clinical use of hypomethylating agents including 5AzadC.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (34, 39))	('clinical', 'Species', '191496', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('5AzadC', 'Chemical', 'MESH:D000077209', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('silencing', 'NegReg', (21, 30))	('promoter hypermethylation', 'Var', (65, 90))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
204477	25586191	However, the expression of several pro-tumor genes is induced by DNA hypomethylation.	('DNA hypomethylation', 'Var', (65, 84))	('induced', 'Reg', (54, 61))	('expression', 'MPA', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
204480	25586191	Histone deacetylase inhibitors can also hypomethylate genes and change their expression levels in breast cancer cell lines and their combination with metabolic therapies may modify their action.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('change', 'Reg', (64, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('hypomethylate', 'Var', (40, 53))	('Histone', 'Protein', (0, 7))	('breast cancer', 'Disease', (98, 111))	('modify', 'Reg', (174, 180))	('action', 'MPA', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression levels', 'MPA', (77, 94))
204481	25586191	Therefore, additional studies are needed to determine if some agents or mechanisms of hypomethylation are more or less likely to promote tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (137, 153))	('promote', 'PosReg', (129, 136))	('hypomethylation', 'Var', (86, 101))	('tumor metastasis', 'Disease', (137, 153))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
204510	15054459	The excess risks of 2+ cm DCIS also lay with mixed types of architecture (OR 1.5) compared to comedocarcinoma and diagnosis in 1996 (OR 1.7), while a report that did not mention necrosis was associated with lower odds (OR 0.7) of a larger DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (239, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('DCIS', 'Phenotype', 'HP:0030075', (26, 30))	('necrosis', 'Disease', 'MESH:D009336', (178, 186))	('comedocarcinoma', 'Disease', (94, 109))	('comedocarcinoma', 'Disease', 'None', (94, 109))	('necrosis', 'Disease', (178, 186))	('2+ cm', 'Var', (20, 25))
204515	15054459	It could reflect, too, differences in mammography rates since high-grade DCIS is said to show abnormal mammographic features more frequently than low grade (Evans et al, 2001).	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('high-grade', 'Var', (62, 72))	('hic', 'Gene', '29969', (112, 115))	('hic', 'Gene', (112, 115))
204516	15054459	That women 20-39 years of age were more likely to have 2+ cm diameter DCIS (average 28 mm in multivariate models in this study) than older women (average 18 mm) is probably due to their lower mammography rate.	('women', 'Species', '9606', (139, 144))	('2+ cm', 'Var', (55, 60))	('women', 'Species', '9606', (5, 10))	('DCIS', 'Disease', (70, 74))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))
204519	15054459	Variation in growth rate might also underlie the significant, independent association of architecture with tumour size.	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('growth rate', 'MPA', (13, 24))	('Variation', 'Var', (0, 9))	('tumour', 'Disease', (107, 113))
204665	29977557	Men with gynecomastia, obesity, diabetes, alterations of the estrogen-testosterone ratio, occupational hazards, prior radiation exposure, Klinefelter's syndrome and BRCA1/BRCA2 mutations are at higher risk to develop breast cancer.	('obesity', 'Disease', 'MESH:D009765', (23, 30))	('mutations', 'Var', (177, 186))	('diabetes', 'Disease', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('gynecomastia', 'Phenotype', 'HP:0000771', (9, 21))	('obesity', 'Phenotype', 'HP:0001513', (23, 30))	('gynecomastia', 'Disease', (9, 21))	("Klinefelter's syndrome", 'Disease', (138, 160))	('alterations', 'Var', (42, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('gynecomastia', 'Disease', 'MESH:D006177', (9, 21))	('BRCA2', 'Gene', (171, 176))	('diabetes', 'Disease', 'MESH:D003920', (32, 40))	('BRCA1', 'Gene', '672', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('BRCA1', 'Gene', (165, 170))	('breast cancer', 'Disease', (217, 230))	('obesity', 'Disease', (23, 30))	("Klinefelter's syndrome", 'Disease', 'MESH:D007713', (138, 160))	('testosterone', 'Chemical', 'MESH:D013739', (70, 82))	('BRCA2', 'Gene', '675', (171, 176))	('Men', 'Species', '9606', (0, 3))
204670	29977557	Up to 40% of male breast cancers may be related to BRCA2 mutations whereas only up to 10% of breast cancers in women are considered to be due to a gene mutation.	('BRCA2', 'Gene', (51, 56))	('mutations', 'Var', (57, 66))	('breast cancers', 'Disease', 'MESH:D001943', (93, 107))	('breast cancers', 'Disease', (93, 107))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('male breast cancer', 'Disease', 'MESH:D018567', (13, 31))	('women', 'Species', '9606', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('BRCA2', 'Gene', '675', (51, 56))	('male breast cancer', 'Disease', (13, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('breast cancers', 'Disease', 'MESH:D001943', (18, 32))	('breast cancers', 'Disease', (18, 32))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('related', 'Reg', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancers', 'Phenotype', 'HP:0003002', (18, 32))
204705	26527522	Seventy-eight percent of untreated PBCs contained PD-L1+ TILs, but only 21% had PD-L1+ carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('PD-L1+ carcinoma', 'Disease', (80, 96))	('PD-L1+ carcinoma', 'Disease', 'MESH:D010300', (80, 96))	('PD-L1+ TILs', 'Var', (50, 61))
204714	26527522	Higher numbers of both CD8+ T lymphocytes and CD20+ B lymphocytes are independent predictors of patient survival and response to neoadjuvant therapy.	('CD20', 'Gene', '54474', (46, 50))	('CD20', 'Gene', (46, 50))	('CD8+ T', 'Var', (23, 29))
204726	26527522	All cases were Elston grade II (29%) or III (71%), with BLC and HER-2+ PBCs having higher grade than LUM cancers.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('III', 'Disease', (40, 43))	('HER-2+ PBCs', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LUM cancers', 'Disease', (101, 112))	('Elston', 'Disease', (15, 21))	('LUM cancers', 'Disease', 'MESH:D009369', (101, 112))
204733	26527522	However, HER-2+ carcinomas contained more PD-L1+ TILs (86% TIL scores 2-3) compared to either BLC carcinomas (33%) or LUM carcinomas (43%) (P = .01) (Table 4).	('BLC carcinomas', 'Disease', 'MESH:D002277', (94, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('PD-L1+', 'Var', (42, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('BLC carcinomas', 'Disease', (94, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('HER-2+', 'Protein', (9, 15))
204736	26527522	Patients with PD-L1+ TIL in the PBC were more likely to have diffuse immune cell infiltrates and PD-L1+ TIL in the matched MBC (P = .047).	('diffuse immune cell infiltrates', 'CPA', (61, 92))	('Patients', 'Species', '9606', (0, 8))	('PD-L1+ TIL', 'Var', (97, 107))	('PD-L1+ TIL', 'Var', (14, 24))
204739	26527522	Both of the PD-L1+ lung metastases displayed moderate to diffuse TIL infiltration, compared to only 36% of metastases where the PBC was PD-L1-.	('lung metastases', 'Disease', 'MESH:D009362', (19, 34))	('lung metastases', 'Disease', (19, 34))	('PD-L1+', 'Var', (12, 18))
204743	26527522	Notably, several genetic lesions, including TP53 and PIK3CA mutations, have been associated with an active PD-1 pathway in breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (123, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('breast cancers', 'Disease', (123, 137))	('PIK3CA', 'Gene', '5290', (53, 59))	('PD-1 pathway', 'Pathway', (107, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutations', 'Var', (60, 69))	('associated', 'Reg', (81, 91))	('PIK3CA', 'Gene', (53, 59))	('TP53', 'Gene', (44, 48))
204760	26722353	Today, the clinical significance of FEA as a precursor to cancer is still under discussion despite Monifar's and Simpson's isolation of genetic alterations in FEA similar to adjacent, low-grade ductal carcinoma in-situ (DCIS) and well-differentiated invasive carcinomas.	('ductal carcinoma', 'Disease', (194, 210))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('FEA', 'Gene', (159, 162))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (194, 210))	('DCIS', 'Phenotype', 'HP:0030075', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (194, 218))	('genetic alterations', 'Var', (136, 155))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('invasive carcinomas', 'Disease', (250, 269))	('invasive carcinomas', 'Disease', 'MESH:D009361', (250, 269))	('cancer', 'Disease', (58, 64))	('ductal carcinoma', 'Disease', 'MESH:D044584', (194, 210))
204812	29307488	Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations, and further shows that most mutations and copy number aberrations evolved within the ducts, prior to invasion.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('invasive tumor', 'Disease', 'MESH:D009369', (61, 75))	('invasive tumor', 'Disease', (61, 75))	('mutations', 'Var', (120, 129))	('copy number aberrations', 'Var', (134, 157))
204825	29307488	Our results support a direct genomic lineage between the in situ and invasive tumor cell subpopulations and further shows that most mutations and copy number aberrations evolved within the ducts prior to invasion.	('copy number aberrations', 'Var', (146, 169))	('mutations', 'Var', (132, 141))	('invasive tumor', 'Disease', 'MESH:D009369', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('invasive tumor', 'Disease', (69, 83))
204840	29307488	Clone A had focal deletions in chromosome 4p (RHOH), 9p (CDKN2A), Xq (COL4A5) and focal amplifications on chromosome 17p (MAP2K3, NF1, BCAS3), 12p (ALG10B and ERBB3), and chromosome Xq (AR).	('BCAS3', 'Gene', '54828', (135, 140))	('MAP2K3', 'Gene', (122, 128))	('CDKN2A', 'Gene', (57, 63))	('ALG10B', 'Gene', (148, 154))	('COL4A5', 'Gene', '1287', (70, 76))	('BCAS3', 'Gene', (135, 140))	('CDKN2A', 'Gene', '1029', (57, 63))	('ERBB3', 'Gene', '2065', (159, 164))	('NF1', 'Gene', (130, 133))	('deletions', 'Var', (18, 27))	('RHOH', 'Gene', (46, 50))	('ERBB3', 'Gene', (159, 164))	('ALG10B', 'Gene', '144245', (148, 154))	('NF1', 'Gene', '4763', (130, 133))	('MAP2K3', 'Gene', '5606', (122, 128))	('COL4A5', 'Gene', (70, 76))	('RHOH', 'Gene', '399', (46, 50))
204841	29307488	Clone B had deletions on chromosome 3p (FHIT), 13 (RB1) 8p (DBC2), and amplifications on chromosomes 2q (GALNT13), 11p (WT1) and Xp (PDK3), while clone C shared many CNA events with clone B, including an amplification on 7p (EGFR).	('deletions', 'Var', (12, 21))	('RB1) 8p', 'Gene', '5925', (51, 58))	('FHIT', 'Gene', (40, 44))	('PDK3', 'Gene', (133, 137))	('DBC2', 'Gene', (60, 64))	('GALNT13', 'Gene', '114805', (105, 112))	('WT1', 'Gene', '7490', (120, 123))	('FHIT', 'Gene', '2272', (40, 44))	('WT1', 'Gene', (120, 123))	('GALNT13', 'Gene', (105, 112))	('EGFR', 'Gene', '1956', (225, 229))	('EGFR', 'Gene', (225, 229))	('PDK3', 'Gene', '5165', (133, 137))	('DBC2', 'Gene', '23221', (60, 64))
204846	29307488	Consistent with the spatial distributions, we found that clones B and C had an amplification of EGFR which was previously shown to be associated with cell migration, while clone C had an additional deletion of FHIT, which has been shown to suppress EMT and cell migration.	('associated', 'Reg', (134, 144))	('deletion', 'Var', (198, 206))	('EGFR', 'Gene', (96, 100))	('FHIT', 'Gene', (210, 214))	('FHIT', 'Gene', '2272', (210, 214))	('amplification', 'Var', (79, 92))	('suppress', 'NegReg', (240, 248))	('cell migration', 'CPA', (150, 164))	('EGFR', 'Gene', '1956', (96, 100))
204857	29307488	Consistent with the invasive spatial localization, we found that clone B had deletions in a number of cancer genes involved in cell migration, including AKT1, APC, FGFR3, CDH1 and SMAD4.	('deletions', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDH1', 'Gene', '999', (171, 175))	('FGFR3', 'Gene', '2261', (164, 169))	('SMAD4', 'Gene', '4089', (180, 185))	('APC', 'Disease', (159, 162))	('cancer', 'Disease', (102, 108))	('FGFR3', 'Gene', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('APC', 'Disease', 'MESH:D011125', (159, 162))	('AKT1', 'Gene', '207', (153, 157))	('AKT1', 'Gene', (153, 157))	('CDH1', 'Gene', (171, 175))	('SMAD4', 'Gene', (180, 185))
204862	29307488	Four tumors were found to be monoclonal (P2, P3, P7, P9), while six tumors were polyclonal (P1, P4, P5, P6, P8, P10), harboring multiple clonal subclones in both the in situ and invasive regions (Figures 2, 3 and Supplementary Figures 2-5).	('P10', 'Gene', '6281', (112, 115))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Disease', (68, 74))	('P1', 'Var', (92, 94))	('P10', 'Gene', (112, 115))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('P4, P5, P6, P8', 'Gene', '5394;347051;6283;6279', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('P2', 'Var', (41, 43))
204878	29307488	Most nonsynonymous mutations (mean 87.4%) were concordant in the ducts and invasive regions, including mutations in known breast cancer genes such as TP53, PIK3CA, NCOA2, ABL2, PDE4DIP, AHNAK and RUNX1, suggesting that they were acquired in the ducts prior to invasion.	('TP53', 'Gene', (150, 154))	('PDE4DIP', 'Gene', (177, 184))	('PIK3CA', 'Gene', (156, 162))	('RUNX1', 'Gene', (196, 201))	('RUNX1', 'Gene', '861', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (103, 112))	('NCOA2', 'Gene', '10499', (164, 169))	('AHNAK', 'Gene', '79026', (186, 191))	('TP53', 'Gene', '7157', (150, 154))	('AHNAK', 'Gene', (186, 191))	('PDE4DIP', 'Gene', '9659', (177, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NCOA2', 'Gene', (164, 169))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('breast cancer', 'Disease', (122, 135))	('PIK3CA', 'Gene', '5290', (156, 162))	('ABL2', 'Gene', '27', (171, 175))	('ABL2', 'Gene', (171, 175))
204879	29307488	However, a few mutations were in situ-specific (N=12) or invasive-specific (N=11) in 4 patients (P3, P4, P7, P8) and were not recurrent among the patients (Supplemental Table 3).	('P3', 'Var', (97, 99))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (146, 154))	('P8', 'Var', (109, 111))
204880	29307488	The invasive-specific mutations may have occurred at low frequencies in the ducts prior to invasion (below the exome sensitivity), or alternatively after invasion, during the expansion of the invasive tumor mass.	('invasive tumor', 'Disease', 'MESH:D009369', (192, 206))	('invasive tumor', 'Disease', (192, 206))	('invasive-specific', 'Reg', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutations', 'Var', (22, 31))
204881	29307488	However, in contrast, most of the invasive-specific mutations (8/12) were found to be exclusive to the invasive tissues in patients P3 (DRD1, CRY1), P4 (TECRL), P7 (SCNA4, PCDHA5) and P8 (SORBS2, LAMTOR1, AKAP6) at higher coverage depths (Supplementary Table 5).	('mutations', 'Var', (52, 61))	('LAMTOR1', 'Gene', (196, 203))	('AKAP6', 'Gene', '9472', (205, 210))	('CRY1', 'Gene', '1407', (142, 146))	('SORBS2', 'Gene', '8470', (188, 194))	('SORBS2', 'Gene', (188, 194))	('patients', 'Species', '9606', (123, 131))	('PCDHA5', 'Gene', '56143', (172, 178))	('TECRL', 'Gene', (153, 158))	('LAMTOR1', 'Gene', '55004', (196, 203))	('PCDHA5', 'Gene', (172, 178))	('AKAP6', 'Gene', (205, 210))	('DRD1', 'Gene', (136, 140))	('CRY1', 'Gene', (142, 146))	('DRD1', 'Gene', '1812', (136, 140))	('TECRL', 'Gene', '253017', (153, 158))
204897	29307488	Furthermore, our data does not support an independent lineage model, since we identified a large number of shared truncal mutations and CNAs in all tumor cells, suggesting that a field effect did not give rise to two different clones that formed the in situ and invasive regions independently.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (122, 131))	('truncal', 'Gene', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
204900	29307488	Interestingly, our data also show that most somatic mutations, including driver mutations in TP53 and PIK3CA, were acquired in the ducts prior to invasion, at the earliest stages of tumor progression.	('tumor', 'Disease', (182, 187))	('PIK3CA', 'Gene', (102, 108))	('mutations', 'Var', (80, 89))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('PIK3CA', 'Gene', '5290', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
204918	29307488	Mounted tumor tissue was sectioned using Thermo Scientific CryoStar (NX70) or Leica Cryostat (cm3050S) at -23 C to -27 C. Sections 12 and 14mum thick were placed on untreated PEN-membrane slides (Carl Zeiss Microscopy, Cat# 415190-9041-001).	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('PEN', 'Gene', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cm3050S', 'Var', (94, 101))	('tumor', 'Disease', (8, 13))	('PEN', 'Gene', '27344', (175, 178))
204923	29307488	Tissue regions containing thousands of cells were cut by a UV laser (settings of 72-81 delta) and catapulted (setting of 50-100 delta) into 0.2 mL adhesive PCR tube caps (Item #: Zeiss 415190-9181-000 or 415190-9191-000).	('415190-9181-000', 'Var', (185, 200))	('100 delta', 'Mutation', 'c.100del', (124, 133))	('415190-9191-000', 'Var', (204, 219))	('81 delta', 'Mutation', 'c.81del', (84, 92))
204924	29307488	Barcoded next-generation sequencing libraries were constructed using the NEBNext end repair (NEB, E6050L), dA-tailing module (NEB, E6053L) and quick ligation module (NEB, E6056L).	('E6053L', 'Var', (131, 137))	('E6056L', 'Var', (171, 177))	('E6053L', 'SUBSTITUTION', 'None', (131, 137))	('E6050L', 'SUBSTITUTION', 'None', (98, 104))	('E6056L', 'SUBSTITUTION', 'None', (171, 177))	('E6050L', 'Var', (98, 104))
204937	29307488	The amplicons from different regions were pooled in equimolar amounts and sequencing libraries were constructed using NEBNext  DNA library Prep enzymes (NEB, #E6050L, E6053L, E6056L/M0202L, and M0541 for end-repair, 3' adenylation, ligation and PCR amplification) according to manufacturer's instructions.	('E6056L', 'Var', (175, 181))	('E6056L', 'SUBSTITUTION', 'None', (175, 181))	('M0202L', 'Mutation', 'p.M0202L', (182, 188))	('M0541', 'Var', (194, 199))	('E6053L', 'Var', (167, 173))	('E6053L', 'SUBSTITUTION', 'None', (167, 173))
204938	29307488	Statistical significance of observed variants was calculated using deepSNV version 1.16.0, which detects variants assuming a beta-binomial model (Gerstung et al., 2012).	('a beta', 'Gene', '351', (123, 129))	('variants', 'Var', (105, 113))	('a beta', 'Gene', (123, 129))
205002	28828599	RT can increase cardiovascular morbidity and the risk of rare malignancies; endocrine therapy can cause vasomotor symptoms and an increased risk of thromboembolic events, endometrial cancer, arthralgias, or osteopenia, all of which raise concerns regarding overtreatment for DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (275, 279))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (16, 40))	('thromboembolic', 'Disease', 'MESH:D013923', (148, 162))	('arthralgias', 'Phenotype', 'HP:0002829', (191, 202))	('endometrial cancer', 'Phenotype', 'HP:0012114', (171, 189))	('vasomotor symptoms', 'Phenotype', 'HP:0025637', (104, 122))	('arthralgias', 'Disease', (191, 202))	('thromboembolic', 'Disease', (148, 162))	('arthralgias', 'Disease', 'MESH:D018771', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('osteopenia', 'Phenotype', 'HP:0000938', (207, 217))	('endometrial cancer', 'Disease', (171, 189))	('endocrine therapy', 'Var', (76, 93))	('endometrial cancer', 'Disease', 'MESH:D016889', (171, 189))	('osteopenia', 'Disease', 'MESH:D001851', (207, 217))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('thromboembolic events', 'Phenotype', 'HP:0001907', (148, 169))	('osteopenia', 'Disease', (207, 217))	('malignancies', 'Disease', (62, 74))	('vasomotor symptoms', 'MPA', (104, 122))	('cause', 'Reg', (98, 103))
205005	28828599	Further, we postulated that mDCIS may behave more like a risk factor for the development of breast cancer, since the distinction between DCIS and ADH at small volumes (<2mm) remains a diagnostic challenge.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('DCIS', 'Phenotype', 'HP:0030075', (137, 141))	('breast cancer', 'Disease', (92, 105))	('mDCIS', 'Var', (28, 33))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mDCIS', 'Chemical', '-', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
205010	28828599	For example, women with intermediate- or high-grade DCIS were much more likely to receive radiation (Table 1).	('intermediate-', 'Var', (24, 37))	('women', 'Species', '9606', (13, 18))	('high-grade', 'Var', (41, 51))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))
205015	28828599	Not only have there been efforts to find DCIS subsets that do not benefit from adjuvant therapies, but there have also been recent arguments that select patients with non-high-grade DCIS should not be treated at all, as the possibility of progression to invasive carcinoma in these patients is uncertain.	('non-high-grade', 'Var', (167, 181))	('patients', 'Species', '9606', (153, 161))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('DCIS', 'Phenotype', 'HP:0030075', (182, 186))	('invasive carcinoma', 'Disease', 'MESH:D009361', (254, 272))	('patients', 'Species', '9606', (282, 290))	('invasive carcinoma', 'Disease', (254, 272))
205027	28828599	We recently examined the outcomes of all such borderline lesions treated at our institution from 1997-2010 and found that the 5-year rate of subsequent IBE in patients with borderline lesions was 7.7%, versus 7.2% for those with clear DCIS (p=0.80), and with 5-year invasive IBE rates of 6.5% among those with borderline lesions and 2.8% for those with clear DCIS, respectively (p=0.25), further suggesting that even these very low-grade lesions have potential risk.	('IBE', 'Chemical', '-', (152, 155))	('DCIS', 'Phenotype', 'HP:0030075', (235, 239))	('DCIS', 'Phenotype', 'HP:0030075', (359, 363))	('IBE', 'Chemical', '-', (275, 278))	('IBE', 'Disease', (152, 155))	('patients', 'Species', '9606', (159, 167))	('lesions', 'Var', (184, 191))
205048	28828599	Among patients with minimal-volume DCIS, ipsilateral breast events in patients not receiving radiation therapy were substantially higher than contralateral breast events, demonstrating that even DCIS of very low-volume is associated with clinically relevant disease.	('patients', 'Species', '9606', (70, 78))	('higher', 'PosReg', (130, 136))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('patients', 'Species', '9606', (6, 14))	('ipsilateral', 'MPA', (41, 52))	('associated', 'Reg', (222, 232))	('minimal-volume', 'Var', (20, 34))
205057	27766556	Given approximately 20% of women with core-biopsy-proven non-high-grade DCIS have invasive cancer at excision, women managed without excision would be expected to incur higher invasive cancer rates.	('invasive cancer', 'Disease', 'MESH:D009362', (176, 191))	('women', 'Species', '9606', (111, 116))	('non-high-grade', 'Var', (57, 71))	('invasive cancer', 'Disease', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('invasive cancer', 'Disease', 'MESH:D009362', (82, 97))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('invasive cancer', 'Disease', (176, 191))	('women', 'Species', '9606', (27, 32))
205102	27766556	They found that among women with non-high-grade DCIS diagnosed by core biopsy, 21% were upgraded to invasive carcinoma at the time of surgical excision.	('invasive carcinoma', 'Disease', (100, 118))	('women', 'Species', '9606', (22, 27))	('DCIS', 'Phenotype', 'HP:0030075', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('non-high-grade', 'Var', (33, 47))	('invasive carcinoma', 'Disease', 'MESH:D009361', (100, 118))
205111	27766556	A recently published randomized trial of women with low-risk DCIS has shown that adjuvant radiation provides additional improvement in local control at 7 years for low-risk DCIS patients treated with breast-conserving surgery (7% IBTR with surgery alone vs 1% IBTR with radiation, p<0.001), although the improvement in local control is coupled with an increased rate of complications in the radiation cohort.	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('patients', 'Species', '9606', (178, 186))	('low-risk', 'Var', (164, 172))	('improvement', 'PosReg', (120, 131))	('women', 'Species', '9606', (41, 46))	('local control', 'MPA', (135, 148))	('DCIS', 'Phenotype', 'HP:0030075', (173, 177))
205155	27527715	For direct comparisons between positive and negative margins (adjusted for median follow-up), patients with negative margins were significantly less likely to experience LR than patients with positive margins (OR=0.45, 95% CrI 0.30-0.62).	('less', 'NegReg', (144, 148))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (94, 102))	('margins', 'Var', (117, 124))
205162	27527715	An individual patient data meta-analysis of four randomized controlled trials found BCS and adjuvant WBRT to be significantly associated with a reduction in any LR compared with BCS alone (15.2% absolute reduction in 10-year risk).	('reduction', 'NegReg', (204, 213))	('WBRT', 'Gene', (101, 105))	('patient', 'Species', '9606', (14, 21))	('BCS', 'Var', (84, 87))	('reduction', 'NegReg', (144, 153))
205170	21920875	Previous studies have shown that expression of p16 in tissue biopsies of patients with ductal carcinoma in situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki67 and COX2.	('associated', 'Reg', (122, 132))	('Ki67', 'Chemical', '-', (242, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('expression', 'Var', (33, 43))	('p16', 'Gene', (47, 50))	('COX2', 'Gene', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('COX2', 'Gene', '5743', (251, 255))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (87, 111))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (87, 111))	('ductal carcinoma in situ', 'Disease', (87, 111))	('breast cancer', 'Disease', (156, 169))	('p16', 'Gene', '1029', (47, 50))	('patients', 'Species', '9606', (73, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('DCIS', 'Phenotype', 'HP:0030075', (113, 117))
205182	21920875	AH is thought to represent a precursor stage to in situ and invasive carcinoma: biopsies of breast tissue removed prophylactically from BRCA1/2 carriers contain various proliferative benign lesions including AH in over 50% of cases, and AH is frequently found in random periareolar fine needle aspirations from high risk women compared to normal risk women.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('women', 'Species', '9606', (321, 326))	('invasive carcinoma', 'Disease', 'MESH:D009361', (60, 78))	('BRCA1/2', 'Gene', (136, 143))	('aspirations', 'Phenotype', 'HP:0002835', (294, 305))	('invasive carcinoma', 'Disease', (60, 78))	('carriers', 'Var', (144, 152))	('women', 'Species', '9606', (351, 356))	('BRCA1/2', 'Gene', '672;675', (136, 143))
205189	21920875	Conversely in the setting of deregulation of Rb, p16 expression can be elevated in proliferating cells as the growth-suppressive effects of p16 are abrogated downstream of Rb.	('p16', 'Gene', '1029', (140, 143))	('abrogated', 'NegReg', (148, 157))	('p16', 'Gene', (140, 143))	('p16', 'Gene', (49, 52))	('Rb', 'Phenotype', 'HP:0009919', (172, 174))	('elevated', 'PosReg', (71, 79))	('Rb', 'Gene', '5925', (172, 174))	('Rb', 'Phenotype', 'HP:0009919', (45, 47))	('deregulation', 'Var', (29, 41))	('growth-suppressive', 'CPA', (110, 128))	('expression', 'MPA', (53, 63))	('Rb', 'Gene', '5925', (45, 47))	('p16', 'Gene', '1029', (49, 52))
205191	21920875	p16 overexpression in the setting of Rb deregulation is indicative of cancer progression and, in mammary carcinoma, is a hallmark of the basal-like molecular subtype.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Rb', 'Gene', '5925', (37, 39))	('p16', 'Gene', (0, 3))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (97, 114))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('deregulation', 'Var', (40, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('overexpression', 'PosReg', (4, 18))	('p16', 'Gene', '1029', (0, 3))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('carcinoma', 'Disease', (105, 114))	('Rb', 'Phenotype', 'HP:0009919', (37, 39))
205247	21920875	We previously showed that higher Ki67 levels in AH are associated with breast cancer risk.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Ki67', 'Chemical', '-', (33, 37))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('Ki67', 'Var', (33, 37))
205249	21920875	Overexpression of both Ki67 plus COX2 showed an increased breast cancer risk among patients in the first 10 years (SIR 6.70, 95% CI 3.19-14.1) as compared to one negative marker.	('Ki67', 'Var', (23, 27))	('COX2', 'Gene', '5743', (33, 37))	('COX2', 'Gene', (33, 37))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('patients', 'Species', '9606', (83, 91))	('Ki67', 'Chemical', '-', (23, 27))
205275	21920875	Some evidence suggests that increased expression of p16 directly leads to tissue degeneration associated with aging: deletion of p16 in a genetic model of premature aging results in attenuated phenotype and extended lifespan, and caloric restriction that retards aging phenotypes in experimental models also attenuates the accumulation of p16-positive cells.	('extended', 'PosReg', (207, 215))	('attenuated', 'NegReg', (182, 192))	('retards', 'Disease', 'MESH:D008607', (255, 262))	('p16', 'Gene', '1029', (52, 55))	('p16', 'Gene', (129, 132))	('p16', 'Gene', (339, 342))	('phenotype', 'CPA', (193, 202))	('retards', 'Disease', (255, 262))	('p16', 'Gene', (52, 55))	('p16', 'Gene', '1029', (129, 132))	('p16', 'Gene', '1029', (339, 342))	('attenuates', 'NegReg', (308, 318))	('deletion', 'Var', (117, 125))
205450	23370209	The findings - notably from a randomized study design - also indicate that radiotherapy had low efficacy in women with casting-type calcifications and <=56 years at diagnosis, but clearly reduced risk in women over 56 years.	('women', 'Species', '9606', (108, 113))	('calcification', 'Disease', 'MESH:D002114', (132, 145))	('women', 'Species', '9606', (204, 209))	('<=56 years', 'Var', (151, 161))	('calcification', 'Disease', (132, 145))	('reduced', 'NegReg', (188, 195))
205557	28766208	CPM increases the risk of major complications that require a return to the operating room or hospitalization, implant loss, and skin necrosis, as well as minor complications such as seromas, hematomas, cellulitis, and delayed wound healing.	('skin necrosis', 'Disease', 'MESH:D012871', (128, 141))	('implant loss', 'CPA', (110, 122))	('delayed wound healing', 'Phenotype', 'HP:0001058', (218, 239))	('hematomas', 'Disease', (191, 200))	('CPM', 'Var', (0, 3))	('cellulitis', 'Phenotype', 'HP:0100658', (202, 212))	('cellulitis', 'Disease', 'MESH:D002481', (202, 212))	('cellulitis', 'Disease', (202, 212))	('skin necrosis', 'Disease', (128, 141))	('seromas', 'Disease', 'MESH:D049291', (182, 189))	('hematomas', 'Disease', 'MESH:D006406', (191, 200))	('seromas', 'Disease', (182, 189))	('delayed wound healing', 'CPA', (218, 239))
205593	27692792	Women were categorized by stage at presentation as DCIS, MIBC (T1micN0M0), and Stage 1 excluding T1micN0M0 (hereafter Stage 1BC).	('DCIS', 'Disease', (51, 55))	('Women', 'Species', '9606', (0, 5))	('MIBC', 'Chemical', '-', (57, 61))	('T1micN0M0', 'Var', (97, 106))	('MIBC', 'Disease', (57, 61))	('excluding', 'NegReg', (87, 96))
205609	27692792	Women with MIBC underwent mastectomy more often than those with DCIS (40.9% vs. 30.6%, p=0.014) and proportionally, but not significantly, more frequently than those with higher stage invasive disease (40.9% vs 33.8%, p=0.119).	('mastectomy', 'Disease', (26, 36))	('Women', 'Species', '9606', (0, 5))	('invasive disease', 'Disease', 'MESH:D009362', (184, 200))	('MIBC', 'Var', (11, 15))	('MIBC', 'Chemical', '-', (11, 15))	('invasive disease', 'Disease', (184, 200))
205611	27692792	Women with HER2-positive and TNBC MIBC were younger than their counterparts with HR-positive disease, with median ages of 58, 59 and 63, respectively (p=0.098) (Table 2).	('Women', 'Species', '9606', (0, 5))	('MIBC', 'Var', (34, 38))	('HR-positive disease', 'Disease', (81, 100))	('TNBC MIBC', 'Var', (29, 38))	('MIBC', 'Chemical', '-', (34, 38))	('HER2', 'Gene', (11, 15))	('HR-positive disease', 'Disease', 'MESH:D006679', (81, 100))	('HER2', 'Gene', '2064', (11, 15))
205635	27692792	Reports have been mixed on the prognostic value of HER2 positivity in DCIS.	('positivity', 'Var', (56, 66))	('HER2', 'Gene', (51, 55))	('HER2', 'Gene', '2064', (51, 55))	('DCIS', 'Disease', (70, 74))
205642	27692792	The higher mastectomy rate seen for women with MIBC compared to those with DCIS may be attributable to the microscopic invasion commonly occurring in larger tumors, or that the mastectomies provided larger specimens, increasing the likelihood of upstaging.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('MIBC', 'Chemical', '-', (47, 51))	('mastectomy rate', 'Disease', (11, 26))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('women', 'Species', '9606', (36, 41))	('higher', 'PosReg', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('MIBC', 'Var', (47, 51))
205649	27692792	This was likely largely driven by women with HR-positive MIBC who received anti-estrogen therapy to lower both the risk of a recurrence and a second breast cancer.	('HR-positive', 'Var', (45, 56))	('MIBC', 'Chemical', '-', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('lower', 'NegReg', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('women', 'Species', '9606', (34, 39))	('MIBC', 'Gene', (57, 61))	('breast cancer', 'Disease', (149, 162))
205650	27692792	The recently reported benefit of aromatase inhibitors for DCIS in NSABP-35, particularly for women <60, could further increase the uptake of these agents for women with MIBC.	('aromatase', 'Protein', (33, 42))	('MIBC', 'Disease', (169, 173))	('increase', 'PosReg', (118, 126))	('NSABP-35', 'Gene', (66, 74))	('DCIS', 'Var', (58, 62))	('women', 'Species', '9606', (158, 163))	('women', 'Species', '9606', (93, 98))	('uptake', 'MPA', (131, 137))	('MIBC', 'Chemical', '-', (169, 173))
205672	26884359	Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219).	('rs554219', 'Mutation', 'rs554219', (142, 150))	('DCIS', 'Disease', (124, 128))	('rs75915166', 'Mutation', 'rs75915166', (130, 140))	('CCND1', 'Gene', (78, 83))	('rs554219', 'Var', (142, 150))	('rs75915166', 'Var', (130, 140))	('DCIS', 'Phenotype', 'HP:0030075', (124, 128))	('CCND1', 'Gene', '595', (78, 83))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))
205680	26884359	However, in one small study of patients with predominantly low-grade DCIS misdiagnosed as benign breast disease and who received no surgical intervention, 6 out of 13 patients developed ipsilateral invasive carcinoma with mean time to the development of invasive carcinoma being 9.0 years.	('benign breast disease', 'Disease', (90, 111))	('low-grade', 'Var', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('invasive carcinoma', 'Disease', 'MESH:D009361', (198, 216))	('ipsilateral invasive carcinoma', 'Disease', (186, 216))	('patients', 'Species', '9606', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('benign breast disease', 'Disease', 'MESH:D001941', (90, 111))	('ipsilateral invasive carcinoma', 'Disease', 'MESH:D006053', (186, 216))	('DCIS', 'Phenotype', 'HP:0030075', (69, 73))	('patients', 'Species', '9606', (31, 39))	('invasive carcinoma', 'Disease', 'MESH:D009361', (254, 272))	('invasive carcinoma', 'Disease', (254, 272))
205684	26884359	Women with DCIS have been shown to be 2.4 times (95 % CI 0.8, 7.2) more likely to have an affected mother and sister with breast cancer than controls.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('DCIS', 'Var', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
205689	26884359	A small part of this inherited predisposition is explained by BRCA1/2 mutations, as mutations in these genes are found in a similar proportion of DCIS and invasive breast cancer cases.	('mutations', 'Var', (70, 79))	('BRCA1/2', 'Gene', '672;675', (62, 69))	('DCIS', 'Disease', (146, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('invasive breast cancer', 'Disease', (155, 177))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('found', 'Reg', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('BRCA1/2', 'Gene', (62, 69))	('invasive breast cancer', 'Disease', 'MESH:D001943', (155, 177))
205717	26884359	All of the known breast cancer susceptibility loci were included in the iCOGS chip with the exception of rs2284378 (20q11), which was identified as an ER- breast cancer predisposition SNP after the iCOGS chip was developed.	('ER', 'Gene', '2099', (151, 153))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('rs2284378', 'Var', (105, 114))	('breast cancer', 'Disease', (17, 30))	('COGS', 'Chemical', '-', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('COGS', 'Chemical', '-', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('rs2284378', 'Mutation', 'rs2284378', (105, 114))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))
205732	26884359	The strongest associations were with for loci in FGFR2 (rs2981579: OR 1.29, 95 % CI 1.24, 1.35; P = 9.0 x 10-30) and TOX3 (rs3803662: OR 1.15, 95 % CI 1.1, 1.21; P = 1.7 x 10-8).	('rs2981579:', 'Var', (56, 66))	('FGFR2', 'Gene', (49, 54))	('FGFR2', 'Gene', '2263', (49, 54))	('rs3803662', 'Mutation', 'rs3803662', (123, 132))	('rs2981579', 'Mutation', 'rs2981579', (56, 65))	('rs3803662:', 'Var', (123, 133))	('TOX3', 'Gene', '27324', (117, 121))	('TOX3', 'Gene', (117, 121))
205734	26884359	The case-only analysis (DCIS diagnosed at <50 years vs >=50 years of age) revealed one SNP (rs527616, 18q11.2) that was significantly associated with DCIS in younger women (P-Het<50/>=50 = 0.0003) even though the overall P value for DCIS was not statistically significant after Bonferroni correction (OR 1.05, 95 % CI 1.01, 1.11; P = 0.020) (Additional file 8).	('women', 'Species', '9606', (166, 171))	('associated with', 'Reg', (134, 149))	('DCIS', 'Phenotype', 'HP:0030075', (150, 154))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('rs527616', 'Var', (92, 100))	('rs527616', 'Mutation', 'rs527616', (92, 100))	('DCIS', 'Phenotype', 'HP:0030075', (233, 237))	('Het', 'Gene', '6294', (175, 178))	('Het', 'Gene', (175, 178))	('DCIS', 'Disease', (150, 154))
205741	26884359	The two SNPs close to CCND1 were strongly associated with low/intermediate grade DCIS (rs75915166, OR 1.36, 95 % CI 1.17, 1.59; P = 7.2 x 10-5; rs554219, OR 1.32, 95 % CI 1.18, 1.48; P = 8.2 x 10-7) and there was no association with high grade DCIS (Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('rs75915166', 'Mutation', 'rs75915166', (87, 97))	('rs554219', 'Var', (144, 152))	('DCIS', 'Phenotype', 'HP:0030075', (244, 248))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (22, 27))	('low/intermediate grade DCIS', 'Disease', (58, 85))	('rs554219', 'Mutation', 'rs554219', (144, 152))
205742	26884359	Case-only analysis confirmed that these loci were low/intermediate grade-specific (rs75915166, P-Hetlow/highgrade = 0.00014; rs554219, P-Hetlow/highgrade = 0.00013) and this was independent of ER status (adjusted for ER status rs75915166, P = 0.0050; rs554219, P = 0.019).	('Het', 'Gene', (137, 140))	('ER', 'Gene', '2099', (217, 219))	('rs75915166', 'Mutation', 'rs75915166', (83, 93))	('rs75915166', 'Var', (83, 93))	('Het', 'Gene', '6294', (97, 100))	('rs554219', 'Mutation', 'rs554219', (125, 133))	('ER', 'Gene', '2099', (193, 195))	('Het', 'Gene', (97, 100))	('Het', 'Gene', '6294', (137, 140))	('rs554219', 'Var', (125, 133))	('rs554219', 'Mutation', 'rs554219', (251, 259))	('rs75915166', 'Mutation', 'rs75915166', (227, 237))
205743	26884359	A similar-case-only analysis of IDC by grade confirmed that the two SNPs on 11q13.3 close to CCND1 were also invasive grade 1/2-specific in IDC (rs75915166, OR 1.42, P = 1.7 x 10-30, P-Het = 2.8 x 10-10; rs554219, OR 1.39, P = 4.7 x 10-49, P-Het = 1.3 x 10-17) and again were independent of ER status (P = 1.3 x 10-6, P = 1.6 x 10-6, respectively) (Additional file 12).	('rs75915166', 'Mutation', 'rs75915166', (145, 155))	('Het', 'Gene', '6294', (242, 245))	('IDC', 'Gene', (32, 35))	('rs75915166', 'Var', (145, 155))	('CCND1', 'Gene', '595', (93, 98))	('Het', 'Gene', (185, 188))	('rs554219', 'Mutation', 'rs554219', (204, 212))	('IDC', 'Gene', '4000', (140, 143))	('IDC', 'Gene', (140, 143))	('Het', 'Gene', (242, 245))	('ER', 'Gene', '2099', (291, 293))	('Het', 'Gene', '6294', (185, 188))	('CCND1', 'Gene', (93, 98))	('rs554219', 'Var', (204, 212))	('IDC', 'Gene', '4000', (32, 35))
205744	26884359	In addition, other grade-specific loci were identified including three (rs2363956, rs8170 and rs10069690) specific to grade 3 invasive disease (Additional file 13).	('rs2363956', 'Var', (72, 81))	('rs8170', 'Mutation', 'rs8170', (83, 89))	('invasive disease', 'Disease', (126, 142))	('invasive disease', 'Disease', 'MESH:D009362', (126, 142))	('rs2363956', 'Mutation', 'rs2363956', (72, 81))	('rs10069690', 'Mutation', 'rs10069690', (94, 104))	('rs8170', 'Var', (83, 89))	('rs10069690', 'Var', (94, 104))
205745	26884359	rs10941679, 5p12 were borderline associated with low/intermediate grade DCIS (OR 1.26, P = 2.1 x 10-7, P-Hetlow/highgrade = 0.0033).	('rs10941679', 'Var', (0, 10))	('Het', 'Gene', '6294', (105, 108))	('rs10941679', 'Mutation', 'rs10941679', (0, 10))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('Het', 'Gene', (105, 108))	('low/intermediate grade DCIS', 'Disease', (49, 76))
205746	26884359	This locus has previously been shown to be associated with low grade progesterone receptor (PR) + IDC.	('progesterone receptor', 'Gene', (69, 90))	('progesterone receptor', 'Gene', '5241', (69, 90))	('IDC', 'Gene', '4000', (98, 101))	('IDC', 'Gene', (98, 101))	('PR', 'Gene', '5241', (92, 94))	('low', 'Var', (59, 62))	('associated', 'Reg', (43, 53))
205749	26884359	Of these novel SNPs, rs12631593, 3p14.2, (an intronic variant in FHIT, chr3: 60726844) was the most strongly associated with DCIS (OR 1.21, 95 % CI 1.13, 1.29; P = 5.5 x 10-8).	('associated', 'Reg', (109, 119))	('rs12631593', 'Var', (21, 31))	('DCIS', 'Disease', (125, 129))	('rs12631593', 'Mutation', 'rs12631593', (21, 31))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('FHIT', 'Gene', (65, 69))	('FHIT', 'Gene', '2272', (65, 69))
205751	26884359	The other loci were on 22q13.2, rs73179023 (DCIS only: OR 0.85, 95 % CI 0.79, 0.90; P = 1.1 x 10-6; IDC only: OR 0.97, 95 % CI 0.93, 1.00; P = 0.060, P-HetDCIS/IDC = 0.0099) and 7q21.3, rs13236351 (DCIS only: OR 1.30, 95 % CI 1.16, 1.46; P = 5.7 x 10-6; IDC only: OR 1.05, 95 % CI 0.99, 1.13; P = 0.13, P-HetDCIS/IDC = 0.17).	('IDC', 'Gene', (160, 163))	('Het', 'Gene', '6294', (305, 308))	('rs13236351', 'Mutation', 'rs13236351', (186, 196))	('rs73179023', 'Mutation', 'rs73179023', (32, 42))	('IDC', 'Gene', '4000', (254, 257))	('IDC', 'Gene', (254, 257))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('rs13236351', 'Var', (186, 196))	('Het', 'Gene', (152, 155))	('IDC', 'Gene', '4000', (100, 103))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('IDC', 'Gene', (100, 103))	('Het', 'Gene', '6294', (152, 155))	('rs73179023', 'Var', (32, 42))	('IDC', 'Gene', '4000', (313, 316))	('IDC', 'Gene', (313, 316))	('Het', 'Gene', (305, 308))	('IDC', 'Gene', '4000', (160, 163))	('DCIS', 'Phenotype', 'HP:0030075', (198, 202))	('DCIS', 'Phenotype', 'HP:0030075', (308, 312))
205752	26884359	These SNPs were genotyped in a validation study including a further 653 DCIS cases and 1,882 controls, however, for all three loci there was no evidence of an association (for rs12631593, rs13236351, and rs73179023, P = 0.49, 0.61, and 0.57, respectively) and none were genome wide significant following a meta-analysis of all data (P = 7.8 x 10-7, 2.9 x 10-5, and 1.7 x 10-6 respectively) (Table 3).	('rs73179023', 'Var', (204, 214))	('rs12631593', 'Var', (176, 186))	('rs73179023', 'Mutation', 'rs73179023', (204, 214))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('rs12631593', 'Mutation', 'rs12631593', (176, 186))	('rs13236351', 'Var', (188, 198))	('rs13236351', 'Mutation', 'rs13236351', (188, 198))
205756	26884359	Of the five breast cancer predisposition alleles originally reported by Easton et al., three were shown to be associated with in situ (998 cases of DCIS and LCIS) disease (rs2981582-FGFR2, rs3803662-TOX3, rs889312-MAP3K1) with rs889312 showing a stronger association with DCIS (P-trend 0.007, per allele OR 1.30 for DCIS, per allele OR 1.13 for invasive disease).	('FGFR2', 'Gene', '2263', (182, 187))	('LCIS', 'Phenotype', 'HP:0030076', (157, 161))	('rs889312', 'Var', (227, 235))	('rs889312', 'Mutation', 'rs889312', (227, 235))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('DCIS', 'Phenotype', 'HP:0030075', (316, 320))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('MAP3K1', 'Gene', (214, 220))	('invasive disease', 'Disease', 'MESH:D009362', (345, 361))	('DCIS', 'Disease', (272, 276))	('MAP3K1', 'Gene', '4214', (214, 220))	('rs2981582', 'Mutation', 'rs2981582', (172, 181))	('TOX3', 'Gene', (199, 203))	('associated', 'Reg', (110, 120))	('invasive disease', 'Disease', (345, 361))	('TOX3', 'Gene', '27324', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('DCIS', 'Phenotype', 'HP:0030075', (272, 276))	('rs889312', 'Mutation', 'rs889312', (205, 213))	('rs3803662', 'Mutation', 'rs3803662', (189, 198))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('breast cancer', 'Disease', (12, 25))	('FGFR2', 'Gene', (182, 187))	('DCIS', 'Disease', (148, 152))	('DCIS', 'Disease', (316, 320))
205757	26884359	However, this finding of potential DCIS-specific loci was not confirmed in the Million women study which found no differential association with DCIS vs IDC for twelve breast cancer susceptibility loci, including rs889312, although their sample size was smaller (873 DCIS and 4,959 IDC).	('breast cancer', 'Disease', (167, 180))	('DCIS', 'Phenotype', 'HP:0030075', (266, 270))	('DCIS', 'Phenotype', 'HP:0030075', (144, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('IDC', 'Gene', '4000', (281, 284))	('IDC', 'Gene', (281, 284))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('rs889312', 'Var', (212, 220))	('women', 'Species', '9606', (87, 92))	('rs889312', 'Mutation', 'rs889312', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('IDC', 'Gene', '4000', (152, 155))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('IDC', 'Gene', (152, 155))
205758	26884359	In the recent BCAC COGS analysis all 41 novel SNPs identified on the iCOGS chip had comparable ORs for invasive and in situ disease (based on data from 2,335 in situ, and 42,118 invasive cases), with the exceptions of rs12493607 (TGFBR2), and rs3903072 (11q13.1), for which associations seemed to be restricted to invasive disease; however, we found no evidence of an IDC-specific association with these loci after correcting for multiple testing.	('COGS', 'Chemical', '-', (19, 23))	('invasive disease', 'Disease', 'MESH:D009362', (314, 330))	('rs3903072', 'Var', (243, 252))	('TGFBR2', 'Gene', (230, 236))	('BCAC', 'Chemical', '-', (14, 18))	('rs12493607', 'Mutation', 'rs12493607', (218, 228))	('situ disease', 'Disease', 'MESH:D002278', (119, 131))	('IDC', 'Gene', '4000', (368, 371))	('TGFBR2', 'Gene', '7048', (230, 236))	('rs12493607', 'Var', (218, 228))	('invasive', 'Disease', (103, 111))	('COGS', 'Chemical', '-', (70, 74))	('BC', 'Phenotype', 'HP:0003002', (14, 16))	('rs3903072', 'Mutation', 'rs3903072', (243, 252))	('situ disease', 'Disease', (119, 131))	('invasive disease', 'Disease', (314, 330))	('IDC', 'Gene', (368, 371))
205759	26884359	A recent study investigating the association between 39 of the known breast cancer predisposition loci and breast cancer in situ (BCIS) suggested that rs1011970 (9p21.3, CDKN2BAS) had a stronger association with BCIS than invasive breast cancer (BC), P-HetBCIS/BC = 0.0065.	('invasive breast cancer', 'Disease', 'MESH:D001943', (222, 244))	('BC', 'Phenotype', 'HP:0003002', (130, 132))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('BC', 'Phenotype', 'HP:0003002', (256, 258))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('BC', 'Phenotype', 'HP:0003002', (246, 248))	('CDKN2BAS', 'Gene', '100048912', (170, 178))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('BC', 'Phenotype', 'HP:0003002', (261, 263))	('Het', 'Gene', (253, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('CDKN2BAS', 'Gene', (170, 178))	('BCIS', 'Disease', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Het', 'Gene', '6294', (253, 256))	('BC', 'Phenotype', 'HP:0003002', (212, 214))	('invasive breast cancer', 'Disease', (222, 244))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('rs1011970', 'Var', (151, 160))	('rs1011970', 'Mutation', 'rs1011970', (151, 160))
205762	26884359	We have also shown for the first time that seven of the known invasive breast cancer predisposition loci not previously shown to be associated with DCIS have comparable ORs for IDC and DCIS: rs4973768 (SLC4A7), rs3821902 (ATXN7), rs10995190 (ZNF365), rs554219 (CCND1), rs3757318 and rs2046210 (ESR1).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('invasive breast cancer', 'Disease', (62, 84))	('ZNF365', 'Gene', (242, 248))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('rs3821902', 'Mutation', 'rs3821902', (211, 220))	('invasive breast cancer', 'Disease', 'MESH:D001943', (62, 84))	('rs10995190', 'Mutation', 'rs10995190', (230, 240))	('SLC4A7', 'Gene', '9497', (202, 208))	('rs554219', 'Mutation', 'rs554219', (251, 259))	('rs4973768', 'Mutation', 'rs4973768', (191, 200))	('rs3757318', 'Mutation', 'rs3757318', (269, 278))	('ATXN7', 'Gene', (222, 227))	('ATXN7', 'Gene', '6314', (222, 227))	('rs4973768', 'Var', (191, 200))	('CCND1', 'Gene', '595', (261, 266))	('rs554219', 'Var', (251, 259))	('DCIS', 'Phenotype', 'HP:0030075', (185, 189))	('ESR1', 'Gene', '2099', (294, 298))	('SLC4A7', 'Gene', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs3757318', 'Var', (269, 278))	('rs2046210', 'Var', (283, 292))	('ESR1', 'Gene', (294, 298))	('IDC', 'Gene', '4000', (177, 180))	('ZNF365', 'Gene', '22891', (242, 248))	('CCND1', 'Gene', (261, 266))	('IDC', 'Gene', (177, 180))	('rs2046210', 'Mutation', 'rs2046210', (283, 292))	('rs3821902', 'Var', (211, 220))
205765	26884359	However, there are also some differences: rs6678914, LGR6 and rs865686, 9q31.2 are strongly associated with LCIS but there is little evidence of association with ER+ DCIS (P-HetDCIS/LCIS = 7.4 x 10-5 and 6.6 x 10-4, respectively).	('Het', 'Gene', (174, 177))	('LGR6', 'Gene', '59352', (53, 57))	('LCIS', 'Phenotype', 'HP:0030076', (182, 186))	('rs6678914', 'Var', (42, 51))	('LCIS', 'Phenotype', 'HP:0030076', (108, 112))	('LCIS', 'Disease', (108, 112))	('rs865686', 'Var', (62, 70))	('ER', 'Gene', '2099', (162, 164))	('rs6678914', 'Mutation', 'rs6678914', (42, 51))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('LGR6', 'Gene', (53, 57))	('Het', 'Gene', '6294', (174, 177))	('rs865686', 'Mutation', 'rs865686', (62, 70))	('associated', 'Reg', (92, 102))	('DCIS', 'Phenotype', 'HP:0030075', (177, 181))
205766	26884359	We have also previously shown that rs11249433, 1p11.2 and rs11977670, 7q34 have a stronger association with invasive lobular cancer than IDC.	('lobular cancer', 'Phenotype', 'HP:0030076', (117, 131))	('rs11977670', 'Mutation', 'rs11977670', (58, 68))	('rs11249433', 'Mutation', 'rs11249433', (35, 45))	('IDC', 'Gene', '4000', (137, 140))	('rs11249433', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('IDC', 'Gene', (137, 140))	('invasive lobular cancer', 'Disease', (108, 131))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (108, 131))
205774	26884359	In invasive disease only a minority of predisposition loci have been shown to be grade specific; rs2981582 (FGFR2) and rs13281615 (8q24) and rs10941679 (5p12).	('invasive disease', 'Disease', (3, 19))	('rs2981582', 'Var', (97, 106))	('FGFR2', 'Gene', (108, 113))	('rs10941679', 'Var', (141, 151))	('FGFR2', 'Gene', '2263', (108, 113))	('invasive disease', 'Disease', 'MESH:D009362', (3, 19))	('rs2981582', 'Mutation', 'rs2981582', (97, 106))	('rs13281615', 'Var', (119, 129))	('rs10941679', 'Mutation', 'rs10941679', (141, 151))	('rs13281615', 'Mutation', 'rs13281615', (119, 129))
205775	26884359	The loci with the strongest association with grade were SNPs on 11q13, which had a stronger association with low/intermediate grade DCIS and IDC than high grade lesions.	('low/intermediate', 'Disease', (109, 125))	('IDC', 'Gene', '4000', (141, 144))	('DCIS', 'Phenotype', 'HP:0030075', (132, 136))	('IDC', 'Gene', (141, 144))	('SNPs on', 'Var', (56, 63))
205777	26884359	rs614367 was the first locus on 11q13 shown to be associated with invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rs614367', 'Mutation', 'rs614367', (0, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('invasive breast cancer', 'Disease', (66, 88))	('invasive breast cancer', 'Disease', 'MESH:D001943', (66, 88))	('rs614367', 'Var', (0, 8))	('associated', 'Reg', (50, 60))
205778	26884359	Fine mapping of the region subsequently identified two independent signals (rs554219 and rs78540526, r2 = 0.38), which are the loci reported in this analysis.	('rs554219', 'Var', (76, 84))	('rs78540526', 'Mutation', 'rs78540526', (89, 99))	('rs554219', 'Mutation', 'rs554219', (76, 84))	('rs78540526', 'Var', (89, 99))
205779	26884359	Functional analyses demonstrated that the risk variants modify enhancer and silencer elements, with the likely target gene being CCND1.	('variants', 'Var', (47, 55))	('CCND1', 'Gene', (129, 134))	('enhancer', 'MPA', (63, 71))	('silencer elements', 'MPA', (76, 93))	('CCND1', 'Gene', '595', (129, 134))	('modify', 'Reg', (56, 62))
205782	26884359	Although we did not identify any novel loci that reached genome wide significance, we did identify three potential novel DCIS predisposition loci, two of which were DCIS-specific (rs12631593, rs73179023), and therefore need further investigation in other cohorts of DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('DCIS', 'Disease', (121, 125))	('rs12631593', 'Var', (180, 190))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('rs73179023', 'Var', (192, 202))	('DCIS', 'Phenotype', 'HP:0030075', (266, 270))	('rs12631593', 'Mutation', 'rs12631593', (180, 190))	('rs73179023', 'Mutation', 'rs73179023', (192, 202))
205801	23754698	A molecular formula of C36H34N2O6 was assigned to 1 as determined by High Resolution Electrospray Ionization Mass Spectrometry (HRESIMS) (m/z 591.2486 [M+H]+, calcd.	('C36H34N2O6', 'Var', (23, 33))	('Ionization', 'Disease', 'MESH:D004194', (98, 108))	('Ionization', 'Disease', (98, 108))	('C36H34N2O6', 'Chemical', '-', (23, 33))
205805	23754698	The 13C NMR spectrum (Table 2) showed two signals at deltaC 164.2 and deltaC 166.5, indicating the presence of two imine functions which were confirmed by the IR absorption at 1600 cm-1.	('deltaC', 'Chemical', '-', (70, 76))	('13C', 'Chemical', '-', (4, 7))	('deltaC 166.5', 'Var', (70, 82))	('deltaC', 'Chemical', '-', (53, 59))	('deltaC 164.2', 'Var', (53, 65))	('imine', 'Chemical', 'MESH:D007097', (115, 120))	('N', 'Chemical', 'MESH:D009584', (8, 9))
205806	23754698	The 13C NMR chemical shifts at deltaC 143.6 (C-7), deltaC 147.2 (C-8'), deltaC 150.0 (C-11), and deltaC 153.4 (C-12') suggested the presence of two diaryl ether bridges between C-7 and C-8' and between C-11 and C-12'.	('deltaC', 'Chemical', '-', (31, 37))	('C-1', 'Gene', '6966', (202, 205))	('deltaC 143.6', 'Var', (31, 43))	('deltaC 153.4', 'Var', (97, 109))	('C-1', 'Gene', (86, 89))	('C-1', 'Gene', (111, 114))	('diaryl ether', 'Chemical', '-', (148, 160))	('C-7', 'Gene', '730', (177, 180))	('C-7', 'Gene', (45, 48))	('C-8', 'Gene', (65, 68))	('C-8', 'Gene', (185, 188))	('deltaC', 'Chemical', '-', (51, 57))	('C-1', 'Gene', '6966', (86, 89))	('deltaC 150.0', 'Var', (72, 84))	('C-1', 'Gene', (211, 214))	('C-7 and C-8', 'Gene', '730;3224', (177, 188))	('C-7', 'Gene', '730', (45, 48))	('C-1', 'Gene', '6966', (111, 114))	('C-11', 'Gene', '1109', (86, 90))	('C-1', 'Gene', (202, 205))	('C-7', 'Gene', (177, 180))	('C-11', 'Gene', (86, 90))	('N', 'Chemical', 'MESH:D009584', (8, 9))	('13C', 'Chemical', '-', (4, 7))	('deltaC', 'Chemical', '-', (72, 78))	('C-11', 'Gene', '1109', (202, 206))	('deltaC', 'Chemical', '-', (97, 103))	('C-8', 'Gene', '3224', (185, 188))	('C-11', 'Gene', (202, 206))	('deltaC', 'Var', (51, 57))	('C-8', 'Gene', '3224', (65, 68))	('C-1', 'Gene', '6966', (211, 214))
205808	23754698	In addition, The 1H NMR spectrum displayed signals for three aromatic methoxy groups (deltaH 3.86, deltaH 3.89, deltaH 3.95, each 3-proton singlets) together with a shielded methoxy group (deltaH 3.24, 3H, s).	('3H', 'Chemical', 'MESH:D014316', (202, 204))	('1H', 'Chemical', '-', (17, 19))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('deltaH', 'Var', (112, 118))	('deltaH', 'Var', (99, 105))
205811	23754698	Furthermore, the HMBC experiment showed that the 6- and 6'-methoxy proton signals were correlated with the carbon signals at deltaC 151.6 (C-6) and deltaC 155.2 (C-6'), respectively.	("6'-methoxy proton signals", 'MPA', (56, 81))	('deltaC', 'Chemical', '-', (148, 154))	('C', 'Chemical', 'MESH:D002244', (162, 163))	('carbon', 'Chemical', 'MESH:D002244', (107, 113))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('C-6', 'Gene', (162, 165))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('deltaC 151.6', 'Var', (125, 137))	('C-6', 'Gene', (139, 142))	('C-6', 'Gene', '729', (162, 165))	('C-6', 'Gene', '729', (139, 142))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('carbon signals', 'MPA', (107, 121))	('deltaC 155.2', 'Var', (148, 160))	('deltaC', 'Chemical', '-', (125, 131))
205819	23754698	Furthermore, the 13C NMR spectrum displayed only one carbon signal at deltaC 165.4 (C-1), with an additional typical N-methyl proton signal at deltaH 2.57 (3H, s) and a signal for a deshielded methine (deltaH 3.99, d, J = 9.4; deltaC 58.8), suggesting that one of the imine groups which were present in 1 was replaced with a tertiary amine bearing a methyl group.	('N-methyl proton signal', 'MPA', (117, 139))	('deltaC', 'Chemical', '-', (70, 76))	('deltaC 165.4', 'Var', (70, 82))	('13C', 'Chemical', '-', (17, 20))	('methine', 'Chemical', '-', (193, 200))	('imine', 'Chemical', 'MESH:D007097', (268, 273))	('C-1', 'Gene', (84, 87))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('carbon', 'Chemical', 'MESH:D002244', (53, 59))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('3H', 'Chemical', 'MESH:D014316', (156, 158))	('C-1', 'Gene', '6966', (84, 87))	('deltaC', 'Chemical', '-', (227, 233))	('amine', 'Chemical', 'MESH:D000588', (334, 339))
205820	23754698	The long range HMBC correlations from the methyl at deltaH 2.57 (2'-NMe) to the methine at C-1' (deltaC 58.8), and to the methylene at C-3' (deltaC 44.6) corroborated the location of the methyl group at the 2' position.	('deltaH 2.57', 'Var', (52, 63))	('methine', 'Chemical', '-', (80, 87))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('deltaC', 'Chemical', '-', (141, 147))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('C-1', 'Gene', (91, 94))	('deltaC', 'Chemical', '-', (97, 103))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('C-3', 'Gene', '718', (135, 138))	('C-3', 'Gene', (135, 138))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('C-1', 'Gene', '6966', (91, 94))	('C', 'Chemical', 'MESH:D002244', (91, 92))
205837	23754698	Both (+)-1,2-dehydrotelobine (2) and (+)-2'-norcocsuline (3) showed moderate antiproliferative activity to the ovarian cancer (A2780), large cell lung cancer (H460), breast ductal carcinoma (MCF-7), and melanoma (UACC-257) cell lines, with IC50 values in the 1 - 6 muM range.	('muM', 'Gene', '56925', (265, 268))	("+)-2'-norcocsuline", 'Var', (38, 56))	('muM', 'Gene', (265, 268))	('+)-1,2-dehydrotelobine', 'Var', (6, 28))	('cell lung cancer', 'Disease', (141, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (166, 189))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('MCF-7', 'CellLine', 'CVCL:0031', (191, 196))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (173, 189))	('C', 'Chemical', 'MESH:D002244', (241, 242))	('UACC', 'Chemical', '-', (213, 217))	('breast ductal carcinoma', 'Disease', (166, 189))	('(+)-1,2-dehydrotelobine', 'Chemical', '-', (5, 28))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('antiproliferative', 'CPA', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('C', 'Chemical', 'MESH:D002244', (192, 193))	('C', 'Chemical', 'MESH:D002244', (216, 217))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('C', 'Chemical', 'MESH:D002244', (215, 216))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('ovarian cancer', 'Disease', (111, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	("(+)-2'-norcocsuline", 'Chemical', '-', (37, 56))	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (166, 189))	('large cell lung cancer', 'Phenotype', 'HP:0030360', (135, 157))	('cell lung cancer', 'Disease', 'MESH:D008175', (141, 157))
205868	23754698	The 2D spectra used 1024-256 (HMQC), 1024-189 (HMBC), 1024-128 (NOESY) data point matrices, which were zero filled to 1024-1024 (HMQC), 1024-378 (HMBC), 1024-1024 (NOESY), after sinebell weighting applied to both dimensions.	('1024-378', 'Var', (136, 144))	('C', 'Chemical', 'MESH:D002244', (149, 150))	('1024-1024', 'Var', (153, 162))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('1024-1024', 'Var', (118, 127))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('C', 'Chemical', 'MESH:D002244', (50, 51))
205888	23754698	Cryatal data: C36H34N2O6 H2O, Mr =608.67, triclinic, P-1, a= 11.4221(12) A, b= 11.4745(10) A, c= 13.2216(14) A, alpha= 102.650(8) , beta= 105.377(9) , gamma = 107.547(9) , V=1506.5(3) A3, 9585 reflections, 416 parameters; crystal size 0.149 x 0.147 x 0.007 mm3.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('P-1', 'Gene', '1423', (53, 56))	('C36H34N2O6', 'Chemical', '-', (14, 24))	('H2O', 'Chemical', 'MESH:D014867', (25, 28))	('P-1', 'Gene', (53, 56))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C36H34N2O6 H2O', 'Var', (14, 28))
205894	23754698	Cryatal data: C34H32N2O5 CH3OH, Mr =580.66, orthorhombic, P212121, a = 7.25361(9) A, b = 13.36293(14) A, c = 30.1627(3) A, alpha=beta=gamma=90 , V=2923.65(6) A3, 31248 reflections, 401 parameters; crystal size 0.30 x 0.12 x 0.08 mm3.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('C34H32N2O5 CH3OH', 'Var', (14, 30))	('P212121', 'Var', (58, 65))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C34H32N2O5', 'Chemical', '-', (14, 24))	('C', 'Chemical', 'MESH:D002244', (25, 26))
205921	22545050	F8RA forms part of the vWF complex and plays a critical role in the process of haemostasis.	('haemostasis', 'Disease', 'MESH:D020141', (79, 90))	('F8RA', 'Var', (0, 4))	('vWF', 'Gene', '7450', (23, 26))	('haemostasis', 'Disease', (79, 90))	('vWF', 'Gene', (23, 26))
205937	22545050	The highest vessel density (HVD) of five fields at x200 field (0.74 mm2 under the light microscope) and x400 field (0.17 mm2 under the light microscope) was recorded, and the average vessel density (AVD) was also recorded in these five fields at x200 and x400.	('mm2', 'Gene', (68, 71))	('x400', 'Var', (255, 259))	('vessel density', 'CPA', (12, 26))	('x400', 'Var', (104, 108))	('mm2', 'Gene', '10687', (121, 124))	('mm2', 'Gene', (121, 124))	('x200', 'Var', (51, 55))	('mm2', 'Gene', '10687', (68, 71))
205943	22545050	The mean MVD x400 was also higher in PDB with DCIS and invasive carcinoma compared to PDB alone but did not reach statistical significance.	('PDB', 'Gene', (86, 89))	('PDB', 'Gene', '5131', (37, 40))	('invasive carcinoma', 'Disease', (55, 73))	('DCIS', 'Disease', (46, 50))	('PDB', 'Gene', '5131', (86, 89))	('invasive carcinoma', 'Disease', 'MESH:D009361', (55, 73))	('higher', 'PosReg', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('PDB', 'Gene', (37, 40))	('MVD', 'Var', (9, 12))
206073	30899513	The causes of GLM are not well defined; it has been associated with several possible etiologies and pathogenesis, such as infectious agents (especially, lipophilic corynebacteria), autoimmune processes, erythema nodosum, hormonal alterations, use of oral contraceptives, hyperprolactinemia, pregnancy:birth and lactation, cigarette smoking, alpha 1 antitrypsin deficiency, interferon-alpha therapy, IgG4-related disease, Rosai-Dorfman disease, and even ethnic conditions.	('lactation', 'Disease', (311, 320))	('lactation', 'Disease', 'MESH:D007775', (311, 320))	('alpha 1 antitrypsin', 'Gene', (341, 360))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (271, 289))	('erythema nodosum', 'Disease', 'MESH:D004893', (203, 219))	('erythema nodosum', 'Phenotype', 'HP:0012219', (203, 219))	('Rosai-Dorfman disease', 'Disease', 'MESH:D015618', (421, 442))	('hyperprolactinemia', 'Disease', 'MESH:D002640', (271, 289))	('erythema nodosum', 'Disease', (203, 219))	('autoimmune processes', 'Phenotype', 'HP:0002960', (181, 201))	('IgG4-related disease', 'Disease', (399, 419))	('Rosai-Dorfman disease', 'Disease', (421, 442))	('erythema', 'Phenotype', 'HP:0010783', (203, 211))	('alpha 1 antitrypsin deficiency', 'Phenotype', 'HP:0032025', (341, 371))	('deficiency', 'Var', (361, 371))	('hyperprolactinemia', 'Disease', (271, 289))	('alpha 1 antitrypsin', 'Gene', '5265', (341, 360))
206082	24374147	Moreover, inhibitors of EGFR, PI3K and Gab1-specific siRNAs were capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models.	('EGFR', 'Gene', '1956', (24, 28))	('PI3K', 'Var', (30, 34))	('upregulation', 'PosReg', (97, 109))	('Akt', 'Gene', (114, 117))	('EGFR', 'Gene', (24, 28))	('increases', 'PosReg', (139, 148))	('Akt', 'Gene', '207', (114, 117))	('inhibitors', 'Var', (10, 20))	('siRNAs', 'Enzyme', (53, 59))	('cell proliferation', 'CPA', (152, 170))
206087	24374147	While numerous studies have been done identifying the mechanisms by which omega-3 PUFAs exert their anti-cancer effects, much less work has been done in regard to how omega-6 PUFAs may be enhancing tumorigenesis.	('omega-6 PUFAs', 'Chemical', '-', (167, 180))	('omega-3 PUFAs', 'Chemical', 'MESH:D015525', (74, 87))	('enhancing', 'PosReg', (188, 197))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('omega-6', 'Var', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (198, 203))
206148	24374147	The addition of exogenous PGE2 was capable of significantly increasing cell proliferation levels of control treatments and LA-treated cells (Figure 2C).	('addition', 'Var', (4, 12))	('PGE2', 'Chemical', 'MESH:D015232', (26, 30))	('increasing', 'PosReg', (60, 70))	('PGE2', 'Gene', (26, 30))	('exogenous', 'Var', (16, 25))	('cell proliferation levels', 'MPA', (71, 96))
206156	24374147	PI3K is often dysregulated in cancer and is responsible for potent oncogenic signals allowing for cell survival and proliferation.	('cancer', 'Disease', (30, 36))	('PI3K', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
206161	24374147	While the EGFR inhibitors completely reversed the increase in cell proliferation generated by LA supplementation to those statistically insignificant from the level seen in the control group with the same inhibitor, only a partial reversal is noted upon PI3K inhibition (Figure 5B).	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (10, 14))	('cell proliferation', 'CPA', (62, 80))	('increase', 'PosReg', (50, 58))	('inhibitors', 'Var', (15, 25))
206167	24374147	The E9/E10 and A5/C10 models are two sets of paired mouse cell lines isolated from peripheral lung epithelium of the same genetic origin, and both E10 and C10 express high levels of Gab1, whereas their partners E9 and A5 express very little or no Gab1 protein.	('mouse', 'Species', '10090', (52, 57))	('C10', 'Var', (155, 158))	('Gab1', 'Protein', (182, 186))	('E9/E10 and A5', 'Gene', '114721;16776', (4, 17))	('E10', 'Var', (147, 150))
206226	12865917	Immunostaining was nuclear for Ki67, OR and PR and predominantly cell membranous for HER-2 with a cytoplasmic component.	('Ki67', 'Var', (31, 35))	('HER-2', 'Gene', '2064', (85, 90))	('HER-2', 'Gene', (85, 90))	('PR', 'Gene', '5241', (44, 46))
206238	12865917	The hormone manipulated OR-positive DCIS (HRT stopped, n=18) were further analysed to assess the response in individual tumours in the group.	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('hormone manipulated OR-positive', 'Var', (4, 35))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
206240	12865917	In OR-positive DCIS tumours, the fall in proliferation was much greater in group 1 (HRT withdrawal) compared to the other two groups (P=0.02).	('proliferation', 'MPA', (41, 54))	('DCIS tumours', 'Disease', (15, 27))	('DCIS tumours', 'Disease', 'MESH:D002285', (15, 27))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('fall', 'NegReg', (33, 37))	('OR-positive', 'Var', (3, 14))	('fall', 'Phenotype', 'HP:0002527', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
206266	12865917	The growth of OR-negative DCIS is driven by activation of the type-1 tyrosine kinase cell surface receptors epidermal growth factor receptor (EGFR) and HER-2 receptor and can be inhibited by EGFR receptor antagonists (Chan et al, 2002).	('HER-2', 'Gene', (152, 157))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('activation', 'PosReg', (44, 54))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('OR-negative', 'Var', (14, 25))	('epidermal', 'Protein', (108, 117))	('HER-2', 'Gene', '2064', (152, 157))
206268	12865917	Using the DCIS animal model, we have also shown that apoptosis (programmed cell death, another index of cell turnover) increases in OR-positive, but not OR-negative, DCIS following antioestrogen therapy with the pure antioestrogen, faslodex.	('OR-positive', 'Var', (132, 143))	('increases', 'PosReg', (119, 128))	('apoptosis', 'CPA', (53, 62))	('faslodex', 'Chemical', 'MESH:D000077267', (232, 240))
206271	12865917	The retrospective analysis of OR status in approximately one-third of DCIS tumours from the NSABP B-24 trial (by case note review and central Immunohistochemical assay) has been confirmed in the findings of this study in the clinical setting, with DCIS OR positivity associated with a significant reduction in the risk of LR after tamoxifen therapy (RR=0.41, confidence interval (CI)=0.25-0.65, P=0.0002), while OR-negative tumours showed a nonsignificant benefit in reducing LR from therapy (RR=0.8, CI 0.41-1.56, P=0.51).	('positivity', 'Var', (256, 266))	('tumours', 'Phenotype', 'HP:0002664', (424, 431))	('DCIS tumours', 'Disease', 'MESH:D002285', (70, 82))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('tumours', 'Disease', 'MESH:D009369', (424, 431))	('reducing', 'NegReg', (467, 475))	('reduction', 'NegReg', (297, 306))	('tumours', 'Disease', (424, 431))	('LR from therapy', 'MPA', (476, 491))	('DCIS', 'Var', (248, 252))	('tumour', 'Phenotype', 'HP:0002664', (424, 430))	('tamoxifen', 'Chemical', 'MESH:D013629', (331, 340))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('DCIS tumours', 'Disease', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
206274	12865917	HER-2 (CerbB-2/Neu) expression in IBC is associated with hormone unresponsiveness, even when OR is expressed (Dowsett et al, 2001b).	('Neu', 'Gene', (15, 18))	('CerbB-2', 'Gene', '2064', (7, 14))	('associated', 'Reg', (41, 51))	('Neu', 'Gene', '2064', (15, 18))	('expression', 'Var', (20, 30))	('IBC', 'Disease', (34, 37))	('hormone unresponsiveness', 'Disease', (57, 81))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('CerbB-2', 'Gene', (7, 14))
206275	12865917	We found no evidence in this study that HER-2 expression in DCIS adversely affects the biological response to oestrogen withdrawal, although HRT (oestrogen) withdrawal is more closely related in nature to aromatase inhibition than to tamoxifen therapy.	('affects', 'Reg', (75, 82))	('expression', 'Var', (46, 56))	('oestrogen withdrawal', 'Phenotype', 'HP:0008209', (110, 130))	('tamoxifen', 'Chemical', 'MESH:D013629', (234, 243))	('HER-2', 'Gene', '2064', (40, 45))	('HER-2', 'Gene', (40, 45))	('biological response to oestrogen withdrawal', 'MPA', (87, 130))
206287	12865917	Oestrogen receptor-negative DCIS has been shown to be hormone independent, thus adjuvant tamoxifen therapy in women with OR-negative DCIS is likely to produce increased morbidity without any clinical benefit.	('women', 'Species', '9606', (110, 115))	('tamoxifen', 'Chemical', 'MESH:D013629', (89, 98))	('OR-negative', 'Var', (121, 132))	('DCIS', 'Disease', (28, 32))
206288	29268817	MYBL2 Is Targeted by miR-143-3p and Regulates Breast Cancer Cell Proliferation and Apoptosis Breast cancer remains a public health issue on a global scale.	('Apoptosis', 'CPA', (83, 92))	('Breast Cancer', 'Disease', 'MESH:D001943', (46, 59))	('miR-143-3p', 'Var', (21, 31))	('Breast cancer', 'Disease', (93, 106))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Breast Cancer', 'Phenotype', 'HP:0003002', (46, 59))	('Breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('Breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('Regulates', 'Reg', (36, 45))	('MYBL2', 'Gene', '4605', (0, 5))	('Breast Cancer', 'Disease', (46, 59))	('MYBL2', 'Gene', (0, 5))
206292	29268817	MYBL2 was confirmed as a target gene of miR-143-3p.	('MYBL2', 'Gene', '4605', (0, 5))	('miR-143-3p', 'Chemical', '-', (40, 50))	('miR-143-3p', 'Var', (40, 50))	('MYBL2', 'Gene', (0, 5))
206294	29268817	Our findings reveal that MYBL2 is targeted by miR-143-3p and regulates breast cancer cell proliferation and apoptosis.	('breast cancer', 'Disease', (71, 84))	('MYBL2', 'Gene', '4605', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('regulates', 'Reg', (61, 70))	('MYBL2', 'Gene', (25, 30))	('miR-143-3p', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('apoptosis', 'CPA', (108, 117))	('miR-143-3p', 'Chemical', '-', (46, 56))
206301	29268817	Genome-wide association studies have identified more than 70 common variants that are involved in breast cancer susceptibility, and several exhibit significant heterogeneity in their associations with different breast cancer subtypes.	('variants', 'Var', (68, 76))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('associations', 'Interaction', (183, 195))	('involved', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('breast cancer', 'Disease', (211, 224))
206305	29268817	In this study, we investigated the regulatory relationship between miR-143-3p and MYBL2 in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('investigated', 'Reg', (18, 30))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('MYBL2', 'Gene', '4605', (82, 87))	('miR-143-3p', 'Var', (67, 77))	('miR-143-3p', 'Chemical', '-', (67, 77))	('MYBL2', 'Gene', (82, 87))
206306	29268817	We analyzed the MYBL2 expression levels in clinical breast cancer tissues, and then performed an in-depth analysis of the effects of abnormal expression of MYBL2 and miR-143-3p on breast cancer cell proliferation and apoptosis.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('MYBL2', 'Gene', '4605', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('apoptosis', 'CPA', (217, 226))	('miR-143-3p', 'Var', (166, 176))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer', 'Disease', (180, 193))	('MYBL2', 'Gene', '4605', (156, 161))	('MYBL2', 'Gene', (16, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('MYBL2', 'Gene', (156, 161))	('miR-143-3p', 'Chemical', '-', (166, 176))
206307	29268817	Our study confirms that MYBL2 is the target gene of miR-143-3p.	('MYBL2', 'Gene', '4605', (24, 29))	('MYBL2', 'Gene', (24, 29))	('miR-143-3p', 'Var', (52, 62))	('miR-143-3p', 'Chemical', '-', (52, 62))
206331	29268817	Mutagenesis of the pMIR-MYBL2-3'UTR was performed using a QuikChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA, USA).	('MYBL2', 'Gene', '4605', (24, 29))	('Mutagenesis', 'Var', (0, 11))	('MYBL2', 'Gene', (24, 29))
206332	29268817	The two binding sites of miR-143-3p on the MYBL2 3'-UTR were mutated simultaneously to generate pMIR-MYBL2-3'UTR-mut and to analyze their functional role.	('MYBL2', 'Gene', '4605', (101, 106))	('MYBL2', 'Gene', (101, 106))	('miR-143-3p', 'Chemical', '-', (25, 35))	('MYBL2', 'Gene', '4605', (43, 48))	('mutated', 'Var', (61, 68))	('MYBL2', 'Gene', (43, 48))
206344	29268817	We found that the expression level of miR-143-3p in normal tissue was significantly higher than that of each type of breast cancer tissue and was lowest in IDC tissues.	('expression level', 'MPA', (18, 34))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('miR-143-3p', 'Chemical', '-', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('lowest', 'NegReg', (146, 152))	('miR-143-3p', 'Var', (38, 48))	('higher', 'PosReg', (84, 90))
206345	29268817	The level of miR-143-3p expression in normal breast MCF-10A cells was significantly higher than in the breast cancer MDA-MB-435 cells.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('miR-143-3p', 'Chemical', '-', (13, 23))	('MCF-10A', 'CellLine', 'CVCL:0598', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (117, 127))	('miR-143-3p', 'Var', (13, 23))	('higher', 'PosReg', (84, 90))
206346	29268817	These data indicate that miR-143-3p is lowly expressed in breast cancer tissues and cells and may play an important role in the development of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('miR-143-3p', 'Chemical', '-', (25, 35))	('play', 'Reg', (98, 102))	('breast cancer', 'Disease', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('role', 'Reg', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('miR-143-3p', 'Var', (25, 35))
206349	29268817	We found that suppression of miR-143-3p promoted the viability of MCF-10A cells, and overexpression of miR-143-3p inhibited MDA-MB-435 cell viability, which showed significant differences in 24 h after transfection.	('viability', 'CPA', (53, 62))	('miR-143-3p', 'Chemical', '-', (29, 39))	('MCF-10A', 'CellLine', 'CVCL:0598', (66, 73))	('miR-143-3p', 'Var', (103, 113))	('suppression', 'NegReg', (14, 25))	('promoted', 'PosReg', (40, 48))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (124, 134))	('overexpression', 'PosReg', (85, 99))	('miR-143-3p', 'Chemical', '-', (103, 113))	('miR-143-3p', 'Gene', (29, 39))	('inhibited', 'NegReg', (114, 123))
206351	29268817	The results showed that inhibition and overexpression of miR-143-3p significantly inhibited or increased the levels of miR-143-3p, respectively.	('miR-143-3p', 'MPA', (119, 129))	('overexpression', 'PosReg', (39, 53))	('miR-143-3p', 'Chemical', '-', (57, 67))	('miR-143-3p', 'Chemical', '-', (119, 129))	('inhibited', 'NegReg', (82, 91))	('levels', 'MPA', (109, 115))	('miR-143-3p', 'Var', (57, 67))	('increased', 'PosReg', (95, 104))
206352	29268817	The suppression of miR-143-3p significantly promoted the proliferation of MCF-10A, and increased miR-143-3p expression inhibited the proliferation of MDA-MB-435 cells.	('MCF-10A', 'Gene', (74, 81))	('increased', 'PosReg', (87, 96))	('promoted', 'PosReg', (44, 52))	('miR-143-3p', 'Chemical', '-', (97, 107))	('miR-143-3p', 'Gene', (19, 29))	('miR-143-3p', 'Chemical', '-', (19, 29))	('inhibited', 'NegReg', (119, 128))	('miR-143-3p', 'Var', (97, 107))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (150, 160))	('proliferation', 'CPA', (57, 70))	('expression', 'MPA', (108, 118))	('proliferation', 'CPA', (133, 146))	('MCF-10A', 'CellLine', 'CVCL:0598', (74, 81))
206353	29268817	The suppression of miR-143-3p reduced the apoptosis of MCF-10A cells, and miR-143-3p overexpression promoted MDA-MB-435 apoptosis (Fig.	('miR-143-3p', 'Gene', (19, 29))	('miR-143-3p', 'Chemical', '-', (74, 84))	('miR-143-3p', 'Chemical', '-', (19, 29))	('MCF-10A', 'CellLine', 'CVCL:0598', (55, 62))	('promoted', 'PosReg', (100, 108))	('apoptosis', 'CPA', (42, 51))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (109, 119))	('reduced', 'NegReg', (30, 37))	('miR-143-3p', 'Var', (74, 84))
206355	29268817	The cell cycle of MCF-10A did not change notably after the inhibition of miR-143-3p, but overexpression of miR-143-3p in MDA-MB-435 cells induced G2/M arrest and inhibited cell cycle progression (Fig.	('miR-143-3p', 'Var', (107, 117))	('M arrest', 'Disease', 'MESH:D006323', (149, 157))	('cell cycle progression', 'CPA', (172, 194))	('M arrest', 'Disease', (149, 157))	('induced', 'PosReg', (138, 145))	('overexpression', 'PosReg', (89, 103))	('MCF-10A', 'CellLine', 'CVCL:0598', (18, 25))	('miR-143-3p', 'Chemical', '-', (107, 117))	('inhibited', 'NegReg', (162, 171))	('miR-143-3p', 'Chemical', '-', (73, 83))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (121, 131))
206356	29268817	We examined the G2/M-associated proteins and found that miR-143-3p inhibited cyclin B1 expression and promoted p21 expression (Fig.	('inhibited', 'NegReg', (67, 76))	('miR-143-3p', 'Var', (56, 66))	('promoted', 'PosReg', (102, 110))	('p21', 'Gene', (111, 114))	('expression', 'MPA', (87, 97))	('expression', 'MPA', (115, 125))	('p21', 'Gene', '644914', (111, 114))	('cyclin B1', 'Gene', '891', (77, 86))	('cyclin B1', 'Gene', (77, 86))	('miR-143-3p', 'Chemical', '-', (56, 66))
206357	29268817	These results showed that miR-143-3p inhibited the proliferation of breast cancer cells and induced cell cycle G2/M arrest and cell apoptosis.	('M arrest', 'Disease', (114, 122))	('miR-143-3p', 'Chemical', '-', (26, 36))	('inhibited', 'NegReg', (37, 46))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('proliferation', 'CPA', (51, 64))	('cell apoptosis', 'CPA', (127, 141))	('miR-143-3p', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('M arrest', 'Disease', 'MESH:D006323', (114, 122))	('induced', 'PosReg', (92, 99))
206359	29268817	A sequence on the 3'-UTR of MYBL2 mRNA was likely to be the binding site of miR-143-3p (Fig.	('miR-143-3p', 'Var', (76, 86))	('MYBL2', 'Gene', '4605', (28, 33))	('MYBL2', 'Gene', (28, 33))	('miR-143-3p', 'Chemical', '-', (76, 86))
206362	29268817	We built the expression vector that carried wild-type MYBL2 3'-UTR and mutated MYBL2 3'-UTR, and the interactivity of miR-143-3p with MYBL2 mRNA in the MDA-MB-435 cells was analyzed by diluciferase analysis.	('MYBL2', 'Gene', (134, 139))	('MYBL2', 'Gene', (79, 84))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (152, 162))	('mutated', 'Var', (71, 78))	('miR-143-3p', 'Var', (118, 128))	('miR-143-3p', 'Chemical', '-', (118, 128))	('MYBL2', 'Gene', '4605', (134, 139))	('MYBL2', 'Gene', '4605', (54, 59))	('MYBL2', 'Gene', (54, 59))	('MYBL2', 'Gene', '4605', (79, 84))
206363	29268817	miR-143-3p can only control luciferase activity of the wild-type MYBL2 mRNA 3'-UTR carrier, while there was no obvious effect on the activity of mutant MYBL2 (Fig.	('MYBL2', 'Gene', (65, 70))	('miR-143-3p', 'Var', (0, 10))	('MYBL2', 'Gene', '4605', (152, 157))	('miR-143-3p', 'Chemical', '-', (0, 10))	('MYBL2', 'Gene', (152, 157))	('activity', 'MPA', (39, 47))	('luciferase', 'Enzyme', (28, 38))	('MYBL2', 'Gene', '4605', (65, 70))
206368	29268817	Taken together, our data indicate that miR-143-3p may inhibit its mRNA and protein levels by directly binding to MYBL2 3'-UTR.	('miR-143-3p', 'Chemical', '-', (39, 49))	('binding', 'Interaction', (102, 109))	('inhibit', 'NegReg', (54, 61))	('miR-143-3p', 'Var', (39, 49))	('MYBL2', 'Gene', '4605', (113, 118))	('MYBL2', 'Gene', (113, 118))
206373	29268817	The results showed that si-MYBL2 significantly inhibited MYBL2 expression; on the basis of this, the miR-143-3p inhibitor markedly increased the protein level of MYBL2 (Fig.	('MYBL2', 'Gene', '4605', (27, 32))	('MYBL2', 'Gene', '4605', (162, 167))	('inhibited', 'NegReg', (47, 56))	('increased', 'PosReg', (131, 140))	('MYBL2', 'Gene', (27, 32))	('protein level', 'MPA', (145, 158))	('MYBL2', 'Gene', (162, 167))	('expression', 'MPA', (63, 73))	('MYBL2', 'Gene', '4605', (57, 62))	('miR-143-3p inhibitor', 'Var', (101, 121))	('MYBL2', 'Gene', (57, 62))	('miR-143-3p', 'Chemical', '-', (101, 111))
206374	29268817	The results showed that the suppression of MYBL2 caused a significant reduction in the number of clones of MDA-MB-435 cells, and the further suppression of miR-143-3p promoted cell proliferation (Fig.	('reduction', 'NegReg', (70, 79))	('miR-143-3p', 'Chemical', '-', (156, 166))	('suppression', 'NegReg', (141, 152))	('suppression', 'NegReg', (28, 39))	('promoted', 'PosReg', (167, 175))	('MYBL2', 'Gene', '4605', (43, 48))	('miR-143-3p', 'Var', (156, 166))	('cell proliferation', 'CPA', (176, 194))	('MYBL2', 'Gene', (43, 48))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (107, 117))
206382	29268817	miR-143-3p has been identified to function as a tumor suppressor in several tumors, including ovarian cancer and gastric cancer.	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (76, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('miR-143-3p', 'Var', (0, 10))	('miR-143-3p', 'Chemical', '-', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastric cancer', 'Disease', (113, 127))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
206383	29268817	explored the potential function and mechanism of miR-143-3p in triple-negative breast cancer and demonstrated that miR-143-3p functioned as a suppressor gene.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('miR-143-3p', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('miR-143-3p', 'Gene', (49, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('miR-143-3p', 'Chemical', '-', (49, 59))	('miR-143-3p', 'Chemical', '-', (115, 125))
206384	29268817	However, the role and the underlying mechanism of miR-143-3p in different subtypes of breast cancer are far from sufficient.	('miR-143-3p', 'Chemical', '-', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('miR-143-3p', 'Var', (50, 60))
206385	29268817	In this study, we found that the levels of miR-143-3p were decreased in breast cancer cell lines.	('decreased', 'NegReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('levels', 'MPA', (33, 39))	('miR-143-3p', 'Var', (43, 53))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('miR-143-3p', 'Chemical', '-', (43, 53))
206386	29268817	Cells were transfected with miR-143-3p mimic or inhibitor to promote or suppress the expression of miR-143-3p.	('expression', 'MPA', (85, 95))	('suppress', 'NegReg', (72, 80))	('miR-143-3p', 'Chemical', '-', (99, 109))	('promote', 'PosReg', (61, 68))	('miR-143-3p', 'Chemical', '-', (28, 38))	('miR-143-3p', 'Var', (99, 109))
206387	29268817	The results confirmed that miR-143-3p inhibited the proliferation of breast cancer cells and induced cell cycle G2/M arrest and cell apoptosis.	('M arrest', 'Disease', 'MESH:D006323', (115, 123))	('miR-143-3p', 'Var', (27, 37))	('proliferation', 'CPA', (52, 65))	('M arrest', 'Disease', (115, 123))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibited', 'NegReg', (38, 47))	('breast cancer', 'Disease', (69, 82))	('induced', 'PosReg', (93, 100))	('miR-143-3p', 'Chemical', '-', (27, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('cell apoptosis', 'CPA', (128, 142))
206389	29268817	Dysregulation of MYBL2 has been associated with tumorigenesis, but the role of MYBL2 in breast cancer has not been totally identified.	('MYBL2', 'Gene', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('tumor', 'Disease', (48, 53))	('MYBL2', 'Gene', (17, 22))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MYBL2', 'Gene', '4605', (79, 84))	('MYBL2', 'Gene', '4605', (17, 22))
206390	29268817	In the present study, we found that MYBL2 was the target gene of miR-143-3p, which indicated that it might play important roles in breast cancer progress.	('breast cancer', 'Disease', (131, 144))	('miR-143-3p', 'Var', (65, 75))	('roles', 'Reg', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('MYBL2', 'Gene', '4605', (36, 41))	('miR-143-3p', 'Chemical', '-', (65, 75))	('MYBL2', 'Gene', (36, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('play', 'Reg', (107, 111))
206392	29268817	We found that miR-143-3p targeted MYBL2 3'-UTR and inhibited MYBL2 expression.	('miR-143-3p', 'Var', (14, 24))	('MYBL2', 'Gene', (34, 39))	('miR-143-3p', 'Chemical', '-', (14, 24))	('MYBL2', 'Gene', '4605', (61, 66))	('expression', 'MPA', (67, 77))	('MYBL2', 'Gene', (61, 66))	('inhibited', 'NegReg', (51, 60))	('MYBL2', 'Gene', '4605', (34, 39))	('targeted', 'Reg', (25, 33))
206396	29268817	Our study confirms that targeted by miR-143-3p, MYBL2 promotes proliferation and inhibits apoptosis of breast cancer cells.	('inhibits', 'NegReg', (81, 89))	('miR-143-3p', 'Chemical', '-', (36, 46))	('proliferation', 'CPA', (63, 76))	('MYBL2', 'Gene', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('apoptosis', 'CPA', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('miR-143-3p', 'Var', (36, 46))	('MYBL2', 'Gene', '4605', (48, 53))	('promotes', 'PosReg', (54, 62))
206416	27965971	DCIS invasive progression has been characterized by investigating the circRNAs expression in tandem DCIS/IDC model using five samples patients afflicted with DCIS that were synchronous with IDC within the same breast (GSE66301).	('IDC', 'Gene', '4000', (190, 193))	('IDC', 'Gene', (190, 193))	('IDC', 'Gene', (105, 108))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('GSE66301', 'Var', (218, 226))	('patients', 'Species', '9606', (134, 142))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('IDC', 'Gene', '4000', (105, 108))
206445	23996141	In contrast, Spanish-speaking Latinas had a twofold higher odds of knowing that DCIS increases risk of future breast cancer (OR, 95 % CI 2.6, 1.6-4.4), but English-speaking Latinas were no different from English-speaking whites.	('future breast cancer', 'Disease', 'MESH:D001943', (103, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('future breast cancer', 'Disease', (103, 123))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('DCIS', 'Var', (80, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
206497	23996141	By contrast, two-thirds (67 %) were aware that DCIS confers increased risk of future breast cancer, and almost all (92 %) knew that it could become invasive if not treated (Table 2).	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('DCIS', 'Var', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('future breast cancer', 'Disease', 'MESH:D001943', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('future breast cancer', 'Disease', (78, 98))
206500	23996141	In contrast, Spanish-speaking Latinas had more than twofold higher odds of knowing that DCIS increases risk of future breast cancer (OR, 95 % CI 2.6, 1.6-4.4) while there was no difference in knowledge between English-speaking Latinas and English-speaking whites.	('future breast cancer', 'Disease', 'MESH:D001943', (111, 131))	('DCIS', 'Var', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('future breast cancer', 'Disease', (111, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
206544	17069663	One model suggests the linear progression from low-nuclear-grade DCIS to high-nuclear DCIS and the subsequent development of invasive cancer.	('low-nuclear-grade DCIS', 'Var', (47, 69))	('DCIS', 'Phenotype', 'HP:0030075', (65, 69))	('high-nuclear DCIS', 'Var', (73, 90))	('invasive cancer', 'Disease', (125, 140))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('invasive cancer', 'Disease', 'MESH:D009362', (125, 140))
206547	17069663	Inactivating mutations of the E-cadherin gene are detected in almost all cases of lobular carcinoma in situ (LCIS).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (90, 107))	('E-cadherin', 'Gene', (30, 40))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (82, 107))	('Inactivating mutations', 'Var', (0, 22))	('E-cadherin', 'Gene', '999', (30, 40))	('detected', 'Reg', (50, 58))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (82, 107))	('LCIS', 'Phenotype', 'HP:0030076', (109, 113))	('lobular carcinoma in situ', 'Disease', (82, 107))
206575	17069663	Because it is very likely that grade 3 invasive breast cancer arises from poorly differentiated DCIS, we applied the supervised classification procedure to the subset of poorly differentiated DCIS (n = 14) and grade 3 invasive tumours (n = 24) (analysis set 2).	('invasive tumours', 'Disease', (218, 234))	('poorly differentiated', 'Var', (170, 191))	('DCIS', 'Phenotype', 'HP:0030075', (192, 196))	('invasive breast cancer', 'Disease', 'MESH:D001943', (39, 61))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('set 2', 'Gene', (254, 259))	('invasive tumours', 'Disease', 'MESH:D009361', (218, 234))	('DCIS', 'Phenotype', 'HP:0030075', (96, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('tumours', 'Phenotype', 'HP:0002664', (227, 234))	('invasive breast cancer', 'Disease', (39, 61))	('set 2', 'Gene', '29072', (254, 259))
206774	33179556	Tumor size was significantly larger in the DCIS-MI and DCIS-IDC groups than in the DCIS group (P = 0.002 and P < 0.001, respectively).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('larger', 'PosReg', (29, 35))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('DCIS', 'Phenotype', 'HP:0030075', (83, 87))	('Tumor size', 'CPA', (0, 10))	('DCIS-MI', 'Disease', (43, 50))	('DCIS-IDC', 'Var', (55, 63))	('DCIS', 'Phenotype', 'HP:0030075', (43, 47))	('DCIS-MI', 'Disease', 'MESH:D002285', (43, 50))
206781	33179556	As presented in Table 1, tumor diameters exceeding 3.2 cm, high nuclear grades, necrosis, and acne-like structures were associated with higher rates microinvasion (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('acne', 'Disease', 'MESH:D000152', (94, 98))	('tumor', 'Disease', (25, 30))	('high nuclear', 'Var', (59, 71))	('necrosis', 'Disease', (80, 88))	('acne', 'Phenotype', 'HP:0001061', (94, 98))	('necrosis', 'Disease', 'MESH:D009336', (80, 88))	('microinvasion', 'MPA', (149, 162))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('acne', 'Disease', (94, 98))
206782	33179556	The rates of HER2 and Ki-67 positivity were significantly higher in patients with DCIS-MI than in those with DCIS (P < 0.001), whereas the rates of ER and PR positivity were lower in patients with DCIS-MI (P < 0.001).	('DCIS', 'Phenotype', 'HP:0030075', (197, 201))	('PR', 'Gene', '5241', (155, 157))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('ER', 'Gene', '2099', (14, 16))	('positivity', 'Var', (28, 38))	('DCIS-MI', 'Disease', (197, 204))	('DCIS-MI', 'Disease', (82, 89))	('ER', 'Gene', '2099', (148, 150))	('patients', 'Species', '9606', (68, 76))	('HER2', 'Gene', (13, 17))	('Ki-67', 'Protein', (22, 27))	('DCIS-MI', 'Disease', 'MESH:D002285', (197, 204))	('higher', 'PosReg', (58, 64))	('HER2', 'Gene', '2064', (13, 17))	('DCIS-MI', 'Disease', 'MESH:D002285', (82, 89))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('patients', 'Species', '9606', (183, 191))
206833	29126161	Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult.	('Anastrozole', 'Var', (137, 148))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('Anastrozole', 'Chemical', 'MESH:D000077384', (137, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('reduces', 'NegReg', (149, 156))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('women', 'Species', '9606', (179, 184))	('anastrozole', 'Chemical', 'MESH:D000077384', (66, 77))	('Breast Cancer', 'Phenotype', 'HP:0003002', (99, 112))	('participant', 'Species', '9606', (6, 17))
206850	29126161	Data from the International Breast Cancer Intervention Study II (IBIS-II) prevention trial show that women randomly assigned to receive anastrozole (1 mg/day) were over 50% less likely to be diagnosed with breast cancer compared with those taking a matching placebo.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Breast Cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('less', 'NegReg', (173, 177))	('anastrozole', 'Chemical', 'MESH:D000077384', (136, 147))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('anastrozole', 'Var', (136, 147))	('women', 'Species', '9606', (101, 106))	('IBIS-I', 'Chemical', '-', (65, 71))
206854	29126161	The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial showed statistically significant improvements in breast cancer-free interval among women taking anastrozole compared with tamoxifen.	('breast cancer-free interval', 'Disease', (124, 151))	('tamoxifen', 'Chemical', 'MESH:D013629', (197, 206))	('breast cancer-free interval', 'Disease', 'MESH:D001943', (124, 151))	('anastrozole', 'Var', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('women', 'Species', '9606', (158, 163))	('anastrozole', 'Chemical', 'MESH:D000077384', (171, 182))	('improvements', 'PosReg', (108, 120))
206859	29126161	Data from the IBIS-II prevention trial indicate women taking anastrozole are more likely to experience musculoskeletal events, vasomotor symptoms, and hypertension compared with those taking placebo.	('hypertension', 'Disease', 'MESH:D006973', (151, 163))	('experience', 'PosReg', (92, 102))	('anastrozole', 'Chemical', 'MESH:D000077384', (61, 72))	('vasomotor symptoms', 'Phenotype', 'HP:0025637', (127, 145))	('musculoskeletal events', 'Disease', (103, 125))	('hypertension', 'Phenotype', 'HP:0000822', (151, 163))	('women', 'Species', '9606', (48, 53))	('hypertension', 'Disease', (151, 163))	('vasomotor symptoms', 'Disease', (127, 145))	('IBIS-I', 'Chemical', '-', (14, 20))	('anastrozole', 'Var', (61, 72))
206860	29126161	In the IBIS-II DCIS trial, women taking anastrozole were more likely to experience fractures, musculoskeletal events, hypercholesterolemia, and strokes compared with women taking tamoxifen.	('women', 'Species', '9606', (166, 171))	('women', 'Species', '9606', (27, 32))	('strokes', 'Phenotype', 'HP:0001297', (144, 151))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (118, 138))	('IBIS-I', 'Chemical', '-', (7, 13))	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('hypercholesterolemia', 'Disease', (118, 138))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (118, 138))	('strokes', 'Disease', 'MESH:D020521', (144, 151))	('anastrozole', 'Chemical', 'MESH:D000077384', (40, 51))	('fractures', 'Disease', (83, 92))	('tamoxifen', 'Chemical', 'MESH:D013629', (179, 188))	('strokes', 'Disease', (144, 151))	('experience fractures', 'Phenotype', 'HP:0002757', (72, 92))	('musculoskeletal events', 'Disease', (94, 116))	('anastrozole', 'Var', (40, 51))	('fractures', 'Disease', 'MESH:D050723', (83, 92))	('experience', 'PosReg', (72, 82))
206887	29126161	Women randomized to anastrozole and reporting gynecological symptoms were 31% less likely to be adherent at 4.5 years [HR = 0.69 (0.55-0.88), P = 0.003] compared with those not reporting these symptoms (Figure 2).	('Women', 'Species', '9606', (0, 5))	('gynecological', 'Disease', (46, 59))	('adherent', 'MPA', (96, 104))	('anastrozole', 'Var', (20, 31))	('less', 'NegReg', (78, 82))	('anastrozole', 'Chemical', 'MESH:D000077384', (20, 31))
206923	24667108	Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations The p53 tumor suppressor gene is mutated or deleted in nearly half of human cancers.	('p53', 'Gene', '7157', (106, 109))	('MDM2', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('p53', 'Gene', (106, 109))	('MDM2', 'Gene', '4193', (44, 48))	('human', 'Species', '9606', (190, 195))	('mutations', 'Var', (110, 119))	('p53', 'Gene', '7157', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('contribute', 'Reg', (49, 59))	('tumor', 'Disease', (128, 133))	('Mdmx', 'Gene', '4194', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('p53', 'Gene', (124, 127))	('carcinogenesis', 'Disease', (71, 85))	('Mdmx', 'Gene', (17, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
206927	24667108	The presence of p53 allelic loss and/or TP53 overexpression was observed in 38% out of all patients, and was significantly more often in larger, high grade, ER negative and high ki67 tumors.	('patients', 'Species', '9606', (91, 99))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('p53', 'Gene', (16, 19))	('allelic loss', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('high ki67', 'Var', (173, 182))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))	('overexpression', 'PosReg', (45, 59))
206930	24667108	Moreover it was showed that most tumors contained either p53 dysfunction or Mdm2 alteration, but not both.	('contained', 'Reg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('p53 dysfunction', 'Var', (57, 72))	('tumors', 'Disease', (33, 39))	('Mdm2', 'Gene', (76, 80))
206934	24667108	Mutation and LOH at the p53 locus occur as tumors progress under conditions of increasing genomic instability .	('p53', 'Gene', (24, 27))	('LOH', 'Var', (13, 16))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
206935	24667108	p53 is mutated in nearly half of all human cancers, and it is functionally abrogated in much of the remaining 50% of cancers through signaling pathways .	('p53', 'Gene', (0, 3))	('signaling pathways', 'Pathway', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('abrogated', 'NegReg', (75, 84))	('human', 'Species', '9606', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutated', 'Var', (7, 14))	('cancers', 'Disease', (117, 124))
206936	24667108	In breast cancer, approximately about 15% to 50% of the cases carry a mutant p53 gene and/or loss of heterozygosity (LOH) at chromosome location 17p13, where the p53 gene is located .	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mutant', 'Var', (70, 76))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('p53', 'Gene', (77, 80))
206942	24667108	MDMx was found amplified or overexpressed in 10-20% of breast cancers, glioblastomas, retinoblastomas, and soft tissue sarcomas  in the presence of wild-type TP53, which confirmed that aberrant expression of MDMx may contribute to tumor formation by inhibiting TP53 activity.	('sarcomas', 'Disease', (119, 127))	('TP53', 'Gene', (158, 162))	('overexpressed', 'PosReg', (28, 41))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('aberrant', 'Var', (185, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (55, 69))	('glioblastomas', 'Disease', (71, 84))	('TP53', 'Gene', (261, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('retinoblastomas', 'Disease', (86, 101))	('inhibiting', 'NegReg', (250, 260))	('MDMx', 'Gene', (208, 212))	('glioblastomas', 'Disease', 'MESH:D005909', (71, 84))	('retinoblastomas', 'Phenotype', 'HP:0009919', (86, 101))	('tumor', 'Disease', (231, 236))	('contribute', 'Reg', (217, 227))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('TP53', 'Gene', '7157', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('TP53', 'Gene', '7157', (261, 265))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('activity', 'MPA', (266, 274))	('glioblastomas', 'Phenotype', 'HP:0012174', (71, 84))	('retinoblastomas', 'Disease', 'MESH:D012175', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('sarcomas', 'Disease', 'MESH:D012509', (119, 127))	('breast cancers', 'Disease', 'MESH:D001943', (55, 69))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('breast cancers', 'Disease', (55, 69))
206957	24667108	Only distinct nuclear staining was accepted as positive reactions for ER, PR, p53 and ki67, whereas HER-2 showed a membrane staining.	('p53', 'Var', (78, 81))	('ki67', 'Var', (86, 90))	('HER-2', 'Gene', (100, 105))	('HER-2', 'Gene', '2064', (100, 105))
206959	24667108	Only tumor tissues with diffuse strong nuclear staining for TP53 was considered to show mutant p53 while scattered weak to moderate nuclear staining was scored negative .	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TP53', 'Gene', '7157', (60, 64))	('mutant', 'Var', (88, 94))	('p53', 'Gene', (95, 98))	('tumor', 'Disease', (5, 10))	('TP53', 'Gene', (60, 64))
206961	24667108	The degree of staining of tumor cells was categorized as -, negative; +, weak; ++, moderate; and +++, strong.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('+++', 'Var', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (26, 31))
206972	24667108	As shown in Table  1, among the 115 breast cancers amplification of Mdmx was found in 65 cases (56.5%) of cases, higher than published studies .	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('Mdmx', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancers', 'Phenotype', 'HP:0003002', (36, 50))	('breast cancers', 'Disease', 'MESH:D001943', (36, 50))	('breast cancers', 'Disease', (36, 50))	('amplification', 'Var', (51, 64))
206974	24667108	The frequency of Mdmx and/or p53 genetic abnormality was up to 70% (81/115), which indicated most tumors showed either p53 or Mdmx genetic abnormalities.	('tumors', 'Disease', (98, 104))	('genetic abnormality', 'Disease', 'MESH:D030342', (33, 52))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Mdmx', 'Disease', (17, 21))	('genetic abnormality', 'Disease', (33, 52))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('p53', 'Var', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('genetic abnormalities', 'Disease', 'MESH:D030342', (131, 152))	('genetic abnormalities', 'Disease', (131, 152))
206975	24667108	p53 deletion was found in from in situ to invasive disease for all of the gene loss cases thus supporting earlier findings that p53 abnormality has a role early in the pathogenesis of breast lesions.	('p53', 'Gene', (0, 3))	('loss', 'NegReg', (79, 83))	('gene', 'Gene', (74, 78))	('breast lesions', 'Disease', (184, 198))	('deletion', 'Var', (4, 12))	('breast lesions', 'Disease', 'MESH:D001941', (184, 198))
206981	24667108	They were observed in the same tumor in 4 cases supporting the findings by others that mutation of one p53 allele could be accompanied by loss of the complementary wild type allele .	('loss', 'NegReg', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p53', 'Gene', (103, 106))	('tumor', 'Disease', (31, 36))	('mutation', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
206990	24667108	For scattered weak to moderate staining can be observed in normal breast tissue, hyperplasia breast tissue and tumor tissue without p53 mutation, only tumor tissues with diffuse strong nuclear staining for TP53 was considered to show mutant p53 as in serious papillary carcinoma in ovary.	('mutant', 'Var', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('TP53', 'Gene', (206, 210))	('hyperplasia breast', 'Disease', 'MESH:D006965', (81, 99))	('TP53', 'Gene', '7157', (206, 210))	('hyperplasia breast', 'Phenotype', 'HP:0010313', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (111, 116))	('papillary carcinoma in ovary', 'Disease', (259, 287))	('papillary carcinoma in ovary', 'Disease', 'MESH:D002291', (259, 287))	('hyperplasia breast', 'Disease', (81, 99))	('p53', 'Gene', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
206992	24667108	Allelic loss of p53 was detected in 23% of all analyzed samples in present study while 17% of cases showed TP53 overexpression indicating p53 mutation.	('p53', 'Gene', (138, 141))	('overexpression', 'PosReg', (112, 126))	('Allelic loss', 'Var', (0, 12))	('p53', 'Gene', (16, 19))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('mutation', 'Var', (142, 150))
206994	24667108	Because of the involvement of DCIS, p53 alteration must be an early event in breast carcinogenesis.	('breast carcinogenesis', 'Disease', (77, 98))	('DCIS', 'Phenotype', 'HP:0030075', (30, 34))	('involvement', 'Reg', (15, 26))	('alteration', 'Var', (40, 50))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (77, 98))	('p53', 'Gene', (36, 39))	('DCIS', 'Gene', (30, 34))
206995	24667108	According to previous reports, mutation of p53 is associated with increased tumor size and tumor grade, axillary lymph node metastases and ki67 expression .	('increased', 'PosReg', (66, 75))	('metastases', 'Disease', (124, 134))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p53', 'Gene', (43, 46))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
206996	24667108	But data presented here indicate there was no significant relationship between p53 allelic loss or TP53 overexpression and tumor node status, whereas p53 dysfunction was detected significantly more often in larger (d > 20 mm), high grade (grade 3), ER negative and high ki67 index tumors.	('TP53', 'Gene', (99, 103))	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('high ki67 index', 'Var', (265, 280))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('TP53', 'Gene', '7157', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('high grade', 'CPA', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', (281, 286))
206997	24667108	LOH and mutation of p53 only present in part of breast cancers.	('p53', 'Gene', (20, 23))	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('breast cancers', 'Disease', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('mutation', 'Var', (8, 16))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))
206998	24667108	It is believed that tumors retaining wild type p53 contain abnormalities in other genes that interact with p53 or are downstream of p53 and result in an identical physiological defect within the cells.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('interact', 'Interaction', (93, 101))	('p53', 'Var', (47, 50))	('result in', 'Reg', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('abnormalities', 'Var', (59, 72))
206999	24667108	One of the best examples of the latter class is amplification or overexpression of Mdm2, which was observed in a subset of human tumors, some of which retain wild-type p53  leading to the conclusion that increased levels of MDM2 directly contribute to human tumor formation by substituting for mutations in p53 gene, which represents an alternative mechanism by which tumor cells escape from the tumor suppressive activities of p53.	('tumor', 'Phenotype', 'HP:0002664', (396, 401))	('tumors', 'Disease', (129, 135))	('tumor', 'Disease', (368, 373))	('tumor', 'Disease', (258, 263))	('human', 'Species', '9606', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mutations', 'Var', (294, 303))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumor', 'Disease', (396, 401))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (396, 401))	('human', 'Species', '9606', (252, 257))	('contribute', 'Reg', (238, 248))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', (307, 310))	('substituting', 'Var', (277, 289))
207006	24667108	So there might be other alterations of TP53 or MDM2, or some of these tumors might progress through genetic events that involve a totally different pathway.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('alterations', 'Var', (24, 35))	('MDM2', 'Gene', (47, 51))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))	('progress', 'Reg', (83, 91))
207008	24667108	Several studies together now also implicate aberrant expression of MDMx could thus contribute to tumor formation .	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MDMx', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('contribute', 'Reg', (83, 93))	('aberrant expression', 'Var', (44, 63))
207011	24667108	Amplification of Mdmx was found in several tumor types.	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Mdmx', 'Gene', (17, 21))	('tumor', 'Disease', (43, 48))
207012	24667108	In this study Mdmx was amplified in 57% of all cases, while it was overexpressed in 65% of all tumors, indicating MDMx overexpression was mainly due to its amplification.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('amplification', 'Var', (156, 169))	('tumors', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
207013	24667108	Although not all the tumors with Mdmx amplification show wild type p53, significant inverse correlation between Mdmx amplification and TP53 overexpression was still observed.	('Mdmx', 'Var', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('TP53', 'Gene', '7157', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('overexpression', 'PosReg', (140, 154))	('TP53', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
207017	24667108	Together these data strongly indicate that Mdmx amplification is a common event in breast carcinogenesis, even in most tumorigenesis and MDMx probably functions as an oncogene through a quite different way compared to MDM2.	('tumor', 'Disease', (119, 124))	('breast carcinogenesis', 'Disease', (83, 104))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (83, 104))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('amplification', 'Var', (48, 61))
207020	24667108	So we speculate amplified Mdmx more likely to be associated with tumor progression.	('tumor', 'Disease', (65, 70))	('associated', 'Reg', (49, 59))	('amplified', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Mdmx', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
207021	24667108	Larger sample sizes to provide more definitive data on the potential role of genetic changes of Mdmx in breast cancer progression should be performed in the future.	('Mdmx', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('genetic changes', 'Var', (77, 92))
207023	24667108	Mdmx amplification is seen in invasive breast cancer but not in DCIS in some cases and likely to be associated with tumor progression.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('invasive breast cancer', 'Disease', (30, 52))	('invasive breast cancer', 'Disease', 'MESH:D001943', (30, 52))	('associated', 'Reg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('tumor', 'Disease', (116, 121))	('Mdmx amplification', 'Var', (0, 18))
207024	24667108	Moreover, high levels of both genes in breast cancer that retain wild-type p53 suggest that these inhibitors may substitute for mutations in p53, therefore, contribute to the severity and progression of the disease.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('mutations', 'Var', (128, 137))	('progression', 'CPA', (188, 199))	('contribute', 'Reg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('breast cancer', 'Disease', (39, 52))
207025	24667108	Together, our data strongly suggest that overexpression of MDM2 or MDMx and p53 mutations in primary breast cancer are mutually exclusive events.	('MDMx', 'Gene', (67, 71))	('mutations', 'Var', (80, 89))	('p53', 'Gene', (76, 79))	('MDM2', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('overexpression', 'PosReg', (41, 55))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
207039	19351404	Holland and colleagues have shown that primary breast tumours with EIC were more likely to have residual DCIS anywhere in the remaining breast compared to invasive breast cancers without an EIC.	('breast tumours', 'Disease', (47, 61))	('invasive breast cancers', 'Disease', (155, 178))	('invasive breast cancers', 'Disease', 'MESH:D001943', (155, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast tumours', 'Disease', 'MESH:D001943', (47, 61))	('EIC', 'Var', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
207067	19351404	All MR exams showed abnormalities which after reviewing were classified as either 'suspicious' or 'highly suggestive of malignancy' according to the BI-RADS classification (score 4 and 5, respectively).	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('malignancy', 'Disease', (120, 130))	('abnormalities', 'Var', (20, 33))
207082	19351404	As breast conservation and prevention of recurrent disease are the main goals in treatment of early resectable breast cancer and as presence of an EIC is a risk factor for recurrent disease, it is important to reliably identify the tumour extent preoperatively.	('presence', 'Var', (132, 140))	('tumour', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', 'MESH:D009369', (232, 238))
207098	19351404	In the study of Berg and colleagues, only MRI depicted DCIS in 6 out of 19 breasts with EIC positive carcinomas, whereas in five of these breast conserving surgery was initially anticipated.	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('EIC positive', 'Var', (88, 100))	('carcinomas', 'Disease', 'MESH:D002277', (101, 111))	('carcinomas', 'Disease', (101, 111))
207165	26083829	The studies concordantly found that DBT does increase the cancer detection rate by approximately 30% to 50% compared with conventional digital mammography, on average, by 1.25 per 1000, and is also useful to reduce recall rates and increase the positive predictive value of biopsy recommendations.	('recall', 'CPA', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('biopsy recommendations', 'CPA', (274, 296))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('increase', 'PosReg', (232, 240))	('positive predictive value', 'MPA', (245, 270))	('cancer', 'Disease', (58, 64))	('DBT', 'Var', (36, 39))	('reduce', 'NegReg', (208, 214))	('increase', 'PosReg', (45, 53))
207182	26083829	In clinical practice, breast cancers are currently grouped into 4 major classes that are distinguished based on different patterns of genomic additions and deletions.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletions', 'Var', (156, 165))	('breast cancers', 'Disease', 'MESH:D001943', (22, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (22, 36))	('breast cancers', 'Disease', (22, 36))
207187	26083829	On the other end of the spectrum, triple-negative (basal-like) are a heterogeneous group of biologically aggressive breast cancers that may behave clinically almost like small-cell lung cancers and may take unpredictable metastatic pathways.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('triple-negative', 'Var', (34, 49))	('aggressive breast cancers', 'Disease', (105, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('small-cell lung cancers', 'Disease', 'MESH:D055752', (170, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('take', 'Reg', (202, 206))	('small-cell lung cancers', 'Disease', (170, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (181, 193))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (105, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))
207254	26083829	Magnetic resonance imaging is now an established part of all screening programs for women at elevated risk of breast cancer and has recently been shown to improve disease-free survival of women with BRCA mutation and other high-risk women.	('mutation', 'Var', (204, 212))	('BRCA', 'Gene', '672', (199, 203))	('women', 'Species', '9606', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRCA', 'Gene', (199, 203))	('breast cancer', 'Disease', (110, 123))	('women', 'Species', '9606', (188, 193))	('improve', 'PosReg', (155, 162))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('women', 'Species', '9606', (233, 238))	('disease-free survival', 'CPA', (163, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
207255	26083829	Depending on the degree of risk on women undergoing screening MRI, the additional cancer yield afforded by MRI ranges between 15 per 1000 and 55 per 1000, a substantially higher rate than that achieved by DBT or ultrasound screening.	('women', 'Species', '9606', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MRI', 'Var', (107, 110))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
207391	28986348	Third, although a link between breast and ovarian cancer was observed for many decades, women with known deleterious BRCA1/2 mutations have been increasingly studied ever since the discovery of these genes in 1994.	('mutations', 'Var', (125, 134))	('BRCA1/2', 'Gene', (117, 124))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (31, 56))	('women', 'Species', '9606', (88, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('BRCA1/2', 'Gene', '672;675', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
207392	28986348	Studies with more women with deleterious BRCA mutations (such as studies with a high number of Ashkenazi Jews) likely have a higher prevalence of a positive family history.	('women', 'Species', '9606', (18, 23))	('BRCA', 'Gene', '672', (41, 45))	('BRCA', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))
207449	28105193	PLCIS is characterised by increased expression of Ki67 compared to CLCIS, which indicates a high cell turnover.	('CLCIS', 'Chemical', '-', (67, 72))	('increased', 'PosReg', (26, 35))	('Ki67', 'Var', (50, 54))	('PLCIS', 'Disease', (0, 5))	('expression', 'MPA', (36, 46))
207484	24648766	In this review we highlight some of the recent advances in our understanding of the molecular mechanisms by which loss of apical-basal polarity deregulates apoptosis, proliferation, and promotes invasion and metastasis in breast cancer.	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('loss', 'Var', (114, 118))	('deregulates', 'Reg', (144, 155))	('proliferation', 'CPA', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('promotes', 'PosReg', (186, 194))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('apoptosis', 'CPA', (156, 165))
207518	24648766	Furthermore the Scrib complex opposes apical membrane identity and in Drosophila, expression of Scrib mutants cause the delocalization of apical proteins to all cell surfaces.	('mutants', 'Var', (102, 109))	('delocalization of apical proteins to', 'MPA', (120, 156))	('Scrib', 'Gene', (96, 101))	('cause', 'Reg', (110, 115))	('Drosophila', 'Species', '7227', (70, 80))
207525	24648766	For example, amplification of the aPKCiota gene (PRKCI) has been observed in high-grade serous ovarian cancers, non-small-cell lung cancer and esophageal squamous cell carcinoma.	('amplification', 'Var', (13, 26))	('non-small-cell lung cancer', 'Disease', (112, 138))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('PRKCI', 'Gene', '5584', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('esophageal squamous cell carcinoma', 'Disease', (143, 177))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('ovarian cancers', 'Phenotype', 'HP:0100615', (95, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('serous ovarian cancers', 'Disease', (88, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (143, 177))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('PRKCI', 'Gene', (49, 54))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (88, 110))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('observed', 'Reg', (65, 73))
207528	24648766	In addition, epigenetic changes can alter expression in tumors, and hypermethylation of the DLG3 promoter results in inactivation in colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('colorectal cancer', 'Disease', (133, 150))	('inactivation', 'NegReg', (117, 129))	('epigenetic changes', 'Var', (13, 31))	('expression', 'MPA', (42, 52))	('alter', 'Reg', (36, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('hypermethylation', 'Var', (68, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('DLG3', 'Gene', (92, 96))
207530	24648766	Furthermore, expression of Scrib with a mutation that disrupts its localization has many of the same tumorigenic effects as loss of Scrib.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('localization', 'MPA', (67, 79))	('disrupts', 'NegReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
207531	24648766	Moreover, numerous intragenic deletions have been identified in Par3 that remove domains that are necessary for localization and interactions with downstream effectors.	('interactions', 'Interaction', (129, 141))	('remove', 'NegReg', (74, 80))	('deletions', 'Var', (30, 39))	('Par3', 'Gene', (64, 68))	('domains', 'MPA', (81, 88))	('localization', 'MPA', (112, 124))	('Par3', 'Gene', '56288', (64, 68))
207532	24648766	In this paper we will discuss evidence that polarity proteins regulate diverse signaling pathways and that disrupted polarity signaling contributes to multiple stages of cancer progression, from initiation through invasion.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('polarity signaling', 'MPA', (117, 135))	('cancer', 'Disease', (170, 176))	('signaling pathways', 'Pathway', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('regulate', 'Reg', (62, 70))	('disrupted', 'Var', (107, 116))	('contributes', 'Reg', (136, 147))
207540	24648766	Loss of Lkb1 also leads to loss of apical-basal polarity in mammary ducts, which fail to form a lumen when cultured in 3D extracellular matrix.	('apical-basal polarity', 'CPA', (35, 56))	('Lkb1', 'Gene', (8, 12))	('Lkb1', 'Gene', '6794', (8, 12))	('Loss', 'Var', (0, 4))	('loss', 'NegReg', (27, 31))
207541	24648766	Therefore, polarity proteins are essential regulators of mammary epithelial integrity, and disruption of individual polarity proteins is sufficient to induce lesions that are characteristic of early stages of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('disruption', 'Var', (91, 101))	('induce', 'Reg', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (209, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('lesions', 'MPA', (158, 165))
207545	24648766	In several epithelial systems, the polarity machinery orients cell division, and depleting Par3, Par6, aPKC, Cdc42, or Dlg misorients cell divisions, causing defects in tissue organization (Figure 4).	('Par6', 'Gene', (97, 101))	('cell divisions', 'CPA', (134, 148))	('depleting', 'Var', (81, 90))	('tissue organization', 'CPA', (169, 188))	('misorients', 'Reg', (123, 133))	('Dlg', 'Gene', (119, 122))	('Par3', 'Gene', '56288', (91, 95))	('Par6', 'Gene', '50855', (97, 101))	('aPKC', 'Gene', (103, 107))	('Cdc42', 'Gene', '998', (109, 114))	('defects', 'NegReg', (158, 165))	('Dlg', 'Gene', '32083', (119, 122))	('Par3', 'Gene', (91, 95))	('Cdc42', 'Gene', (109, 114))	('orients', 'Reg', (54, 61))	('cell division', 'CPA', (62, 75))
207549	24648766	For example, deletion of beta1-integrin from the basal layer of the mammary epithelium causes spindle orientation defects, with mixing of the basal and luminal layers.	('beta1-integrin', 'Gene', '3688', (25, 39))	('spindle orientation defects', 'CPA', (94, 121))	('beta1-integrin', 'Gene', (25, 39))	('deletion', 'Var', (13, 21))	('causes', 'Reg', (87, 93))
207550	24648766	Furthermore, deletion of beta1-integrin from the mammary gland was recently shown to block apical-basal polarity, by deregulating trafficking of apical proteins.	('beta1-integrin', 'Gene', '3688', (25, 39))	('deregulating', 'NegReg', (117, 129))	('apical-basal polarity', 'CPA', (91, 112))	('beta1-integrin', 'Gene', (25, 39))	('deletion', 'Var', (13, 21))	('trafficking of apical proteins', 'MPA', (130, 160))	('block', 'NegReg', (85, 90))
207551	24648766	Therefore, a potential mechanism by which loss of beta1-integrin misorients cell divisions is by mislocalizing apical-basal polarity proteins.	('loss', 'Var', (42, 46))	('misorients', 'NegReg', (65, 75))	('apical-basal polarity proteins', 'Protein', (111, 141))	('beta1-integrin', 'Gene', '3688', (50, 64))	('cell divisions', 'CPA', (76, 90))	('beta1-integrin', 'Gene', (50, 64))	('mislocalizing', 'MPA', (97, 110))
207552	24648766	Support for the idea that spindle orientation defects can induce early tumor-like events comes from Drosophila, where disruption of Dlg or Scrib misorients the cell division plane, and cells that divide out of the plane undergo apoptosis, indicating that normal tissues can eliminate delaminated cells.	('Dlg', 'Gene', '32083', (132, 135))	('apoptosis', 'CPA', (228, 237))	('disruption', 'Var', (118, 128))	('induce', 'Reg', (58, 64))	('spindle orientation', 'CPA', (26, 45))	('defects', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('misorients', 'Reg', (145, 155))	('undergo', 'Reg', (220, 227))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Dlg', 'Gene', (132, 135))	('Drosophila', 'Species', '7227', (100, 110))	('tumor', 'Disease', (71, 76))	('Scrib', 'Gene', (139, 144))
207554	24648766	The ability to balance proliferation and apoptosis is a fundamental requirement for epithelial homeostasis, and altering this balance promotes tumor proliferation.	('altering', 'Var', (112, 120))	('tumor', 'Disease', (143, 148))	('promotes', 'PosReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
207555	24648766	Interestingly, blocking apoptosis induced by disruption of the Par complex leads to compensatory proliferation and epithelial overgrowth in Drosophila.	('Par complex', 'Gene', (63, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (126, 136))	('Drosophila', 'Species', '7227', (140, 150))	('apoptosis', 'CPA', (24, 33))	('compensatory proliferation', 'CPA', (84, 110))	('disruption', 'Var', (45, 55))	('epithelial overgrowth', 'CPA', (115, 136))
207556	24648766	Remarkably, although depleting Dlg or Crb induces apoptosis, unlike depleting the Par complex, it does not induce compensatory proliferation, indicating that the three complexes induce apoptosis through different mechanisms.	('depleting', 'Var', (21, 30))	('induce', 'Reg', (178, 184))	('Dlg', 'Gene', (31, 34))	('induces', 'Reg', (42, 49))	('Dlg', 'Gene', '32083', (31, 34))	('apoptosis', 'CPA', (50, 59))
207557	24648766	A compensatory-like mechanism may be at play in mammary epithelial cells, because loss of Par3 induces both apoptosis and proliferation in the developing mouse mammary gland and enhances mammary tumor growth.	('mouse', 'Species', '10090', (154, 159))	('mammary tumor', 'Disease', (187, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('Par3', 'Gene', (90, 94))	('enhances', 'PosReg', (178, 186))	('mammary tumor', 'Disease', 'MESH:D001943', (187, 200))	('Par3', 'Gene', '56288', (90, 94))	('proliferation', 'CPA', (122, 135))	('loss', 'Var', (82, 86))	('apoptosis', 'CPA', (108, 117))	('induces', 'Reg', (95, 102))
207564	24648766	In breast cancer and glioblastoma cell lines expressing oncogenic PI3K or loss of PTEN, aPKC expression and activity are upregulated, which blocks oncogene-induced senescence, thereby promoting proliferation (Figure 5).	('glioblastoma', 'Disease', (21, 33))	('blocks', 'NegReg', (140, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PI3K', 'Var', (66, 70))	('upregulated', 'PosReg', (121, 132))	('PTEN', 'Gene', (82, 86))	('activity', 'MPA', (108, 116))	('promoting', 'PosReg', (184, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('proliferation', 'CPA', (194, 207))	('loss', 'Var', (74, 78))	('PTEN', 'Gene', '5728', (82, 86))	('oncogene-induced', 'Protein', (147, 163))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('aPKC', 'Enzyme', (88, 92))	('breast cancer', 'Disease', (3, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('expression', 'MPA', (93, 103))
207572	24648766	For example, binding to the TEAD family of transcription factors regulates expression of genes involved in proliferation, whereas binding p73 regulates apoptotic genes in response to DNA damage.	('p73', 'Gene', '7161', (138, 141))	('p73', 'Gene', (138, 141))	('response to DNA damage', 'MPA', (171, 193))	('binding', 'Var', (130, 137))	('regulates', 'Reg', (65, 74))	('regulates', 'Reg', (142, 151))	('binding', 'Var', (13, 20))	('apoptotic genes', 'Gene', (152, 167))	('expression', 'MPA', (75, 85))
207574	24648766	The Hippo signaling pathway is a negative regulator of Yap1/Taz and consists of a kinase cascade in which Mst1/2 phosphorylates Lats1/2, which subsequently phosphorylates and inactivates Yap1 by creating a 14-3-3 binding site required to export Yap1/Taz from the nucleus.	('14-3-3', 'MPA', (206, 212))	('binding', 'Interaction', (213, 220))	('Yap1', 'Gene', (245, 249))	('Lats1/2', 'Gene', (128, 135))	('Yap1', 'Gene', (187, 191))	('inactivates', 'Var', (175, 186))	('Yap1', 'Gene', '10413', (245, 249))	('Taz', 'Gene', '6901', (60, 63))	('Taz', 'Gene', (250, 253))	('Mst1/2', 'Gene', (106, 112))	('Lats1/2', 'Gene', '8140;7462', (128, 135))	('Yap1', 'Gene', '10413', (55, 59))	('Taz', 'Gene', '6901', (250, 253))	('Taz', 'Gene', (60, 63))	('Yap1', 'Gene', (55, 59))	('Yap1', 'Gene', '10413', (187, 191))	('Mst1/2', 'Gene', '4485;6788', (106, 112))	('export', 'MPA', (238, 244))
207576	24648766	Yap1 interacts with multiple components of the Crumbs complex and tight junctions, including Pals1, Patj, and Amot, and depleting Crb or Pals1 causes Yap1/Taz to accumulate in the nucleus in mammary epithelial cells.	('Taz', 'Gene', (155, 158))	('depleting', 'Var', (120, 129))	('Crb', 'Gene', (130, 133))	('Taz', 'Gene', '6901', (155, 158))	('accumulate', 'PosReg', (162, 172))	('Yap1', 'Gene', '10413', (150, 154))	('Yap1', 'Gene', '10413', (0, 4))	('Patj', 'Gene', '10207', (100, 104))	('Amot', 'Gene', '154796', (110, 114))	('Patj', 'Gene', (100, 104))	('Yap1', 'Gene', (0, 4))	('Yap1', 'Gene', (150, 154))	('Amot', 'Gene', (110, 114))	('Pals1', 'Gene', (137, 142))	('Pals1', 'Gene', (93, 98))	('Pals1', 'Gene', '64398', (137, 142))	('Pals1', 'Gene', '64398', (93, 98))
207582	24648766	Either loss or mislocalization of Scrib blocks the ability of Mst1/2 to activate Lats1/2, resulting in sustained Taz activation.	('blocks', 'NegReg', (40, 46))	('Mst1/2', 'Gene', '4485;6788', (62, 68))	('mislocalization', 'Var', (15, 30))	('Scrib', 'Gene', (34, 39))	('Taz', 'Gene', '6901', (113, 116))	('Lats1/2', 'Gene', (81, 88))	('Taz', 'Gene', (113, 116))	('ability', 'MPA', (51, 58))	('Mst1/2', 'Gene', (62, 68))	('Lats1/2', 'Gene', '8140;7462', (81, 88))
207593	24648766	The suppression of apical-basal polarity is considered an invariable feature of EMT, and re-expression of Lgl2 blocks Zeb1 and Snail-induced EMT.	('apical-basal polarity', 'CPA', (19, 40))	('Snail', 'Gene', (127, 132))	('Lgl2', 'Gene', '3993', (106, 110))	('Snail', 'Gene', '6615', (127, 132))	('blocks', 'NegReg', (111, 117))	('re-expression', 'Var', (89, 102))	('Zeb1', 'Gene', (118, 122))	('Zeb1', 'Gene', '6935', (118, 122))	('Lgl2', 'Gene', (106, 110))
207595	24648766	In the mammary gland, the micro ribonucleic acid (miRNA) miR-200a maintains apical-basal polarity and its knockdown suppresses claudin-3 and Par6beta expression, which compromises apical-basal polarity and lumen formation.	('miR-200a', 'Gene', '406983', (57, 65))	('expression', 'MPA', (150, 160))	('apical-basal polarity', 'CPA', (76, 97))	('apical-basal polarity', 'CPA', (180, 201))	('lumen formation', 'CPA', (206, 221))	('miR-200a', 'Gene', (57, 65))	('knockdown', 'Var', (106, 115))	('suppresses', 'NegReg', (116, 126))	('Par6beta', 'Gene', (141, 149))	('claudin-3', 'Gene', '1365', (127, 136))	('compromises', 'NegReg', (168, 179))	('Par6beta', 'Gene', '84612', (141, 149))	('claudin-3', 'Gene', (127, 136))
207597	24648766	Furthermore, loss of Par3 in vivo induces invasion and metastasis, however this occurs in the absence of overt EMT.	('Par3', 'Gene', '56288', (21, 25))	('induces', 'Reg', (34, 41))	('Par3', 'Gene', (21, 25))	('invasion', 'CPA', (42, 50))	('loss', 'Var', (13, 17))
207599	24648766	Interestingly, Par6 is actually necessary to dissolve TJs during TGF-beta-induced EMT, and blocking Par6 activity prevents EMT.	('Par6', 'Gene', '50855', (15, 19))	('Par6', 'Gene', (15, 19))	('activity', 'MPA', (105, 113))	('prevents', 'NegReg', (114, 122))	('Par6', 'Gene', '50855', (100, 104))	('Par6', 'Gene', (100, 104))	('EMT', 'CPA', (123, 126))	('blocking', 'Var', (91, 99))
207606	24648766	Therefore disruption of the Crumbs complex sensitizes cells to EMT by delocalizing Yap1/Taz and SMADs.	('Taz', 'Gene', '6901', (88, 91))	('Yap1', 'Gene', '10413', (83, 87))	('Taz', 'Gene', (88, 91))	('Yap1', 'Gene', (83, 87))	('disruption', 'Var', (10, 20))
207609	24648766	Loss of apical-basal polarity is dependent on Par6/aPKC, and activated ErbB2 is able to bind Par6/aPKC and displace Par3; therefore, activation of ErbB2 affects apical-basal polarity by disrupting the Par complex (Figure 5).	('Par3', 'Gene', '56288', (116, 120))	('affects', 'Reg', (153, 160))	('Par6', 'Gene', (46, 50))	('Par6', 'Gene', '50855', (93, 97))	('Par6', 'Gene', '50855', (46, 50))	('ErbB2', 'Gene', (147, 152))	('displace', 'NegReg', (107, 115))	('disrupting', 'NegReg', (186, 196))	('Par3', 'Gene', (116, 120))	('apical-basal polarity', 'CPA', (161, 182))	('Par complex', 'MPA', (201, 212))	('Par6', 'Gene', (93, 97))	('activation', 'Var', (133, 143))
207612	24648766	The 14-3-3sigma tumor suppressor gene is frequently lost in ErbB2 amplified tumors and genetic deletion of the 14-3-3sigma locus in mice disrupts cell-cell junctions and apical-basal polarity.	('disrupts', 'NegReg', (137, 145))	('cell-cell junctions', 'CPA', (146, 165))	('apical-basal polarity', 'CPA', (170, 191))	('ErbB2', 'Gene', (60, 65))	('deletion', 'Var', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('mice', 'Species', '10090', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
207613	24648766	14-3-3sigma binds Par3, and loss of 14-3-3sigma mislocalizes Par3 from the plasma membrane to induce polarity defects and accelerate ErbB2-dependent tumor onset.	('Par3', 'Gene', (18, 22))	('Par3', 'Gene', '56288', (61, 65))	('accelerate', 'PosReg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Par3', 'Gene', '56288', (18, 22))	('Par3', 'Gene', (61, 65))	('induce', 'Reg', (94, 100))	('polarity defects', 'MPA', (101, 117))	('tumor', 'Disease', (149, 154))	('14-3-3sigma', 'Protein', (36, 47))	('loss of', 'Var', (28, 35))
207615	24648766	Loss of Par3 has also been shown to promote breast cancer progression by collaborating with oncogenes.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('promote', 'PosReg', (36, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('Par3', 'Gene', (8, 12))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Par3', 'Gene', '56288', (8, 12))	('Loss', 'Var', (0, 4))
207616	24648766	Depletion of Par3 from the normal mammary gland increases both apoptosis and proliferation, which offset each other and palpable tumors never form.	('Par3', 'Gene', '56288', (13, 17))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('increases', 'PosReg', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('Depletion', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Par3', 'Gene', (13, 17))	('apoptosis', 'CPA', (63, 72))	('proliferation', 'CPA', (77, 90))
207617	24648766	However, in the presence of either oncogenic Notch1 intracellular domain (NICD) or activated RasV12, loss of Par3 robustly promotes tumor growth.	('NICD', 'Disease', 'None', (74, 78))	('promotes', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RasV12', 'Protein', (93, 99))	('Par3', 'Gene', (109, 113))	('loss', 'Var', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('NICD', 'Disease', (74, 78))	('Par3', 'Gene', '56288', (109, 113))
207618	24648766	This effect may depend on the oncogene, because loss of Par3 has no effect on primary tumor size in an ErbB2 model.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('loss', 'Var', (48, 52))	('Par3', 'Gene', (56, 60))	('tumor', 'Disease', (86, 91))	('Par3', 'Gene', '56288', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
207619	24648766	Loss of polarity proteins can also cooperate with the Myc oncogene to promote tumor growth.	('polarity proteins', 'Protein', (8, 25))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('promote', 'PosReg', (70, 77))	('tumor', 'Disease', (78, 83))	('Loss', 'Var', (0, 4))	('Myc', 'Gene', '4609', (54, 57))	('Myc', 'Gene', (54, 57))
207620	24648766	Loss of Scrib in Myc-driven mammary tumors enhances primary tumor size, in this case by blocking Myc-induced apoptosis.	('enhances', 'PosReg', (43, 51))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (36, 41))	('mammary tumor', 'Disease', 'MESH:D001943', (28, 41))	('Myc', 'Gene', '4609', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Myc', 'Gene', '4609', (97, 100))	('blocking', 'NegReg', (88, 96))	('mammary tumor', 'Disease', (28, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('Scrib', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', (36, 42))	('Myc', 'Gene', (17, 20))	('Myc', 'Gene', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
207622	24648766	Loss of Lkb1 is also able to promote primary tumor growth in Myc-induced mammary tumors.	('Myc', 'Gene', '4609', (61, 64))	('promote', 'PosReg', (29, 36))	('tumors', 'Disease', (81, 87))	('mammary tumor', 'Disease', 'MESH:D001943', (73, 86))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Lkb1', 'Gene', (8, 12))	('Myc', 'Gene', (61, 64))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mammary tumor', 'Disease', (73, 86))	('Lkb1', 'Gene', '6794', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Loss', 'Var', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (81, 86))
207623	24648766	In this case, loss of Lkb1 is associated with disrupted localization of apical-basal polarity proteins, but does not affect Myc-induced apoptosis.	('disrupted', 'NegReg', (46, 55))	('loss', 'Var', (14, 18))	('Lkb1', 'Gene', (22, 26))	('localization of', 'MPA', (56, 71))	('Myc', 'Gene', '4609', (124, 127))	('Myc', 'Gene', (124, 127))	('apical-basal', 'Protein', (72, 84))	('Lkb1', 'Gene', '6794', (22, 26))
207624	24648766	Instead, a mechanism by which Lkb1 may regulate mammary tumor size is through Hedgehog signaling (Figure 5); depletion of Lkb1 causes upregulation of Hedgehog pathway genes Sonic hedgehog (Shh), Smoothened (Smo), Gli1, and Patched (Ptch).	('Gli1', 'Gene', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Lkb1', 'Gene', '6794', (30, 34))	('Smo', 'Gene', (207, 210))	('depletion', 'Var', (109, 118))	('Lkb1', 'Gene', (122, 126))	('Lkb1', 'Gene', '6794', (122, 126))	('Shh', 'Gene', (189, 192))	('Ptch', 'Gene', '5727', (232, 236))	('upregulation', 'PosReg', (134, 146))	('Ptch', 'Gene', (232, 236))	('Sonic hedgehog', 'Gene', '6469', (173, 187))	('Smoothened', 'Gene', (195, 205))	('Smo', 'Gene', '6608', (195, 198))	('Gli1', 'Gene', '2735', (213, 217))	('Smo', 'Gene', (195, 198))	('Patched', 'Gene', '5727', (223, 230))	('mammary tumor', 'Disease', 'MESH:D001943', (48, 61))	('Sonic hedgehog', 'Gene', (173, 187))	('Shh', 'Gene', '6469', (189, 192))	('Lkb1', 'Gene', (30, 34))	('Patched', 'Gene', (223, 230))	('Smoothened', 'Gene', '6608', (195, 205))	('Smo', 'Gene', '6608', (207, 210))	('mammary tumor', 'Disease', (48, 61))	('Hedgehog pathway genes', 'Gene', (150, 172))
207625	24648766	Importantly, Lkb1 and the expression of Hh pathway components are negatively correlated in human breast cancer samples, and inhibition of Hh signaling enhances apoptosis in Lkb1-deficient tumor cells.	('Lkb1-deficient tumor', 'Disease', (173, 193))	('apoptosis', 'CPA', (160, 169))	('Lkb1', 'Gene', '6794', (13, 17))	('inhibition', 'Var', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Lkb1', 'Gene', (173, 177))	('Lkb1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('enhances', 'PosReg', (151, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('Lkb1-deficient tumor', 'Disease', 'MESH:D009369', (173, 193))	('Lkb1', 'Gene', '6794', (173, 177))	('human', 'Species', '9606', (91, 96))
207628	24648766	For example, loss of Lkb1 in the mammary gland causes fragmentation of the basement membrane through mislocalization of the serine protease hepsin (Figure 5).	('fragmentation of the basement membrane', 'CPA', (54, 92))	('causes', 'Reg', (47, 53))	('serine protease hepsin', 'Gene', '3249', (124, 146))	('Lkb1', 'Gene', '6794', (21, 25))	('Lkb1', 'Gene', (21, 25))	('serine protease hepsin', 'Gene', (124, 146))	('loss', 'Var', (13, 17))	('mislocalization', 'MPA', (101, 116))
207629	24648766	Furthermore, loss of Par3 in NICD-expressing mammary tumors alters the expression of numerous ECM-related genes, and leads to degradation of the ECM and defects in cell-matrix adhesion.	('expression', 'MPA', (71, 81))	('mammary tumor', 'Disease', 'MESH:D001943', (45, 58))	('defects', 'NegReg', (153, 160))	('ECM-related genes', 'Gene', (94, 111))	('alters', 'Reg', (60, 66))	('Par3', 'Gene', '56288', (21, 25))	('cell-matrix adhesion', 'CPA', (164, 184))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('leads to', 'Reg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NICD', 'Disease', (29, 33))	('Par3', 'Gene', (21, 25))	('mammary tumor', 'Disease', (45, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('loss', 'Var', (13, 17))	('degradation', 'MPA', (126, 137))	('tumors', 'Disease', (53, 59))	('NICD', 'Disease', 'None', (29, 33))
207630	24648766	Therefore, the disruption of some polarity proteins may contribute to breast cancer progression by degrading the basement membrane and extracellular matrix, which may be important for the switch from carcinoma in situ to invasive carcinoma.	('carcinoma in situ to invasive carcinoma', 'Disease', 'MESH:D002278', (200, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma in situ to invasive carcinoma', 'Disease', (200, 239))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (200, 217))	('degrading', 'NegReg', (99, 108))	('breast cancer', 'Disease', (70, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('contribute', 'Reg', (56, 66))	('disruption', 'Var', (15, 25))
207631	24648766	Indeed, this appears to be the case; loss of Par3 in both NICD and RasV12 breast cancer models promotes local invasion and lung metastasis.	('breast cancer', 'Disease', (74, 87))	('Par3', 'Gene', '56288', (45, 49))	('NICD', 'Disease', (58, 62))	('lung metastasis', 'CPA', (123, 138))	('NICD', 'Disease', 'None', (58, 62))	('Par3', 'Gene', (45, 49))	('loss', 'Var', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('local invasion', 'CPA', (104, 118))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('promotes', 'PosReg', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
207632	24648766	Loss of Par3 causes activation of Janus kinase/signal transducer and activator of transcription (Jak/Stat) signaling, which through matrix metalloproteinases (MMPs) and likely other targets, remodels the ECM and enables Par3-deficient cells to invade and metastasize (Figure 5).	('activator', 'MPA', (69, 78))	('enables', 'PosReg', (212, 219))	('Par3', 'Gene', (8, 12))	('Par3', 'Gene', '56288', (220, 224))	('activation', 'PosReg', (20, 30))	('Par3', 'Gene', (220, 224))	('Par3', 'Gene', '56288', (8, 12))	('Janus kinase/signal transducer', 'Pathway', (34, 64))	('Loss', 'Var', (0, 4))	('remodels', 'Reg', (191, 199))	('MMPs', 'Gene', '4318', (159, 163))	('MMPs', 'Gene', (159, 163))
207635	24648766	Interestingly, another study identified a complementary pathway for loss of Par3 to induce invasion and metastasis in ErbB2 breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('Par3', 'Gene', (76, 80))	('metastasis', 'CPA', (104, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('Par3', 'Gene', '56288', (76, 80))	('breast cancers', 'Disease', 'MESH:D001943', (124, 138))	('breast cancers', 'Disease', (124, 138))	('induce', 'PosReg', (84, 90))	('loss', 'Var', (68, 72))
207636	24648766	In this case, invasion and metastasis caused by loss of Par3 involves the loosening of adherens junctions, but without inducing EMT.	('loss', 'Var', (48, 52))	('Par3', 'Gene', (56, 60))	('loosening of adherens junctions', 'CPA', (74, 105))	('Par3', 'Gene', '56288', (56, 60))	('invasion', 'CPA', (14, 22))	('metastasis', 'CPA', (27, 37))
207637	24648766	In this model, loss of Par3 activates the GTPase Rac1 by delocalizing the Rac activator Tiam1, and Tiam1 itself is necessary for ErbB2-mediated mammary tumor growth and metastasis (Figure 5).	('Par3', 'Gene', '56288', (23, 27))	('mammary tumor', 'Disease', 'MESH:D001943', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Rac', 'Gene', (49, 52))	('metastasis', 'CPA', (169, 179))	('Par3', 'Gene', (23, 27))	('mammary tumor', 'Disease', (144, 157))	('Rac', 'Gene', '207', (74, 77))	('activates', 'PosReg', (28, 37))	('loss', 'Var', (15, 19))	('Rac1', 'Gene', '5879', (49, 53))	('Rac', 'Gene', (74, 77))	('Tiam1', 'Gene', (88, 93))	('Rac1', 'Gene', (49, 53))	('Rac', 'Gene', '207', (49, 52))	('Tiam1', 'Gene', (99, 104))	('Tiam1', 'Gene', '7074', (88, 93))	('Tiam1', 'Gene', '7074', (99, 104))
207641	24648766	Expression of an inactive Par6 mutant that uncouples it from the TGF-beta receptor, restores tight junction formation, and blocks metastasis to the lungs.	('mutant', 'Var', (31, 37))	('blocks', 'NegReg', (123, 129))	('restores', 'PosReg', (84, 92))	('tight junction formation', 'MPA', (93, 117))	('Par6', 'Gene', '50855', (26, 30))	('Par6', 'Gene', (26, 30))	('metastasis to the lungs', 'CPA', (130, 153))
207645	24648766	For example, Scrib is mislocalized in DCIS, and mislocalization of Scrib can mimic some, but not all, cancer-related functions observed when Scrib is depleted.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mislocalization', 'Var', (48, 63))
207654	24648766	In numerous stem cell systems, the Par complex is involved in regulating asymmetric cell divisions, and an important future goal will be to determine how disruption of polarity proteins affects stem cell properties during breast cancer progression and treatment.	('affects', 'Reg', (186, 193))	('breast cancer', 'Disease', (222, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('disruption', 'Var', (154, 164))	('stem cell properties', 'CPA', (194, 214))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))
207662	31555258	We have shown before that ablation of Treg cells in established tumors leads to significant decrease in primary and metastatic tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('decrease', 'NegReg', (92, 100))	('tumor', 'Disease', (127, 132))	('ablation', 'Var', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
207667	31555258	Furthermore, Treg cell ablation increased the percentage of cancer stem/progenitor cells in the mammary compartment.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('ablation', 'Var', (23, 31))	('cancer', 'Disease', (60, 66))	('increased', 'PosReg', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
207668	31555258	Interestingly, Treg cell ablation resulted in increased inflammatory cytokines IL-4 and IL-5 with a concomitant reduction in classically activated tumor associated macrophages.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('IL-5', 'Gene', '16191', (88, 92))	('increased', 'PosReg', (46, 55))	('reduction', 'NegReg', (112, 121))	('IL-4', 'Gene', (79, 83))	('ablation', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Treg cell', 'CPA', (15, 24))	('IL-4', 'Gene', '16189', (79, 83))	('increased inflammatory cytokines IL', 'Phenotype', 'HP:0012649', (46, 81))	('IL-5', 'Gene', (88, 92))
207679	31555258	We have demonstrated that ablation of Treg cells in advanced primary tumors induces a strong anti-tumor response, which is dependent on CD4+ T cells and IFNgamma.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('primary tumors', 'Disease', 'MESH:D001932', (61, 75))	('tumor', 'Disease', (98, 103))	('IFNgamma', 'Gene', (153, 161))	('IFNgamma', 'Gene', '15978', (153, 161))	('CD4', 'Gene', '12504', (136, 139))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ablation', 'Var', (26, 34))	('primary tumors', 'Disease', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CD4', 'Gene', (136, 139))
207682	31555258	Our results indicate that transient Treg cell ablation in in situ breast lesions results in acceleration of progression to invasive carcinoma, suggesting that Treg cell presence may be a positive prognostic indicator for pre-invasive breast cancer.	('ablation', 'Var', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('invasive breast cancer', 'Disease', (225, 247))	('situ breast lesions', 'Disease', (61, 80))	('invasive carcinoma', 'Disease', 'MESH:D009361', (123, 141))	('acceleration', 'PosReg', (92, 104))	('progression', 'CPA', (108, 119))	('situ breast lesions', 'Disease', 'MESH:D061325', (61, 80))	('invasive carcinoma', 'Disease', (123, 141))	('invasive breast cancer', 'Disease', 'MESH:D001943', (225, 247))
207698	31555258	Cells were then stained for 30 min on ice with specific antibody cocktails diluted in PBS with 0.5% BSA: violet Fluor 450-conjugated Ab anti-CD4 (1/500, 75-0042, TONBO), BUV395-conjugated anti-CD45 (1/1000, 565967, BD Biosciences), eFluor 450-conjugated anti-CD24 (1/500, 75-0242, TONBO), red Fluor 710-conjugated anti-CD44 (1/500, 80-0441-U025, eBioscience), PE-Cy7-conjugated anti-CD49f (1/500, 25-0495-82, eBioscience), APC-conjugated anti-CD29 (1/500, 17-0291-82, eBioscience), FITC-conjugated anti-CD61 (1/500, 11-0611-82, eBioscience), APC-eFluor 780-conjugated anti-CD11b (1/1000, 47-0112-82, eBioscience), PE-Cy7-conjugated anti-Ly-6C (1/500, 25-5932-82, eBioscience), FITC-conjugated anti-Ly-6G (1/500, 127605, Biolegend), PerCP-Cy5.5 -conjugated anti-F4/80 (1/500, 45-4801-82, eBiosciences), redFluor  710-conjugated anti-MHC Class II (1/500, 80-5321-U025, TONBO), Alexa Fluor 647-conjugated anti-CD206 (1/500, MCA2235A647T, Serotec).	('CD4', 'Gene', '12504', (319, 322))	('1/500', 'Var', (914, 919))	('CD11b', 'Gene', '16409', (573, 578))	('CD206', 'Gene', '17533', (907, 912))	('CD45', 'Gene', (193, 197))	('CD61', 'Gene', '16416', (503, 507))	('CD4', 'Gene', (141, 144))	('eBioscience', 'Disease', 'None', (468, 479))	('80-0441-U025', 'Chemical', 'MESH:C119163', (332, 344))	('CD4', 'Gene', '12504', (383, 386))	('eBioscience', 'Disease', (528, 539))	('eBioscience', 'Disease', (346, 357))	('CD11b', 'Gene', (573, 578))	('eBioscience', 'Disease', (409, 420))	('eBioscience', 'Disease', (663, 674))	('CD24', 'Gene', (259, 263))	('eBioscience', 'Disease', 'None', (600, 611))	('CD61', 'Gene', (503, 507))	('CD206', 'Gene', (907, 912))	('CD29', 'Gene', '16412', (443, 447))	('CD4', 'Gene', '12504', (141, 144))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (875, 886))	('APC-eFluor 780', 'Chemical', 'MESH:C001584', (542, 556))	('APC', 'Chemical', 'MESH:C462103', (542, 545))	('CD29', 'Gene', (443, 447))	('CD44', 'Gene', (319, 323))	('eBiosciences', 'Disease', (787, 799))	('APC', 'Chemical', 'MESH:C462103', (423, 426))	('eBioscience', 'Disease', 'None', (528, 539))	('eBioscience', 'Disease', 'None', (346, 357))	('CD24', 'Gene', '12484', (259, 263))	('eBioscience', 'Disease', (787, 798))	('CD4', 'Gene', (193, 196))	('FITC', 'Chemical', 'MESH:D016650', (482, 486))	('eBioscience', 'Disease', 'None', (409, 420))	('eBiosciences', 'Disease', 'None', (787, 799))	('eBioscience', 'Disease', 'None', (663, 674))	('CD44', 'Gene', '12505', (319, 323))	('80-5321-U025', 'Chemical', 'MESH:C585772', (853, 865))	('CD4', 'Gene', (319, 322))	('F4/80', 'Gene', '13733', (761, 766))	('CD49f', 'Gene', '16403', (383, 388))	('eBioscience', 'Disease', (468, 479))	('CD49f', 'Gene', (383, 388))	('CD45', 'Gene', '19264', (193, 197))	('eBioscience', 'Disease', 'None', (787, 798))	('565967, BD', 'Chemical', 'MESH:C418322', (207, 217))	('CD4', 'Gene', (383, 386))	('CD4', 'Gene', '12504', (193, 196))	('eBioscience', 'Disease', (600, 611))	('F4/80', 'Gene', (761, 766))	('FITC', 'Chemical', 'MESH:D016650', (677, 681))
207725	31555258	Examination of the histological sections by a blinded breast pathologist at 10 weeks, revealed that Treg cell ablation led to more advanced tumors, with increased proportion of early invasive carcinomas (Figures 2C,D).	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('invasive carcinomas', 'Disease', (183, 202))	('invasive carcinomas', 'Disease', 'MESH:D009361', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ablation', 'Var', (110, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))
207728	31555258	Together, these observations confirm that Treg cell ablation during non-invasive breast cancer stage induces histological changes associated with progression of the disease to early invasive carcinoma.	('ablation', 'Var', (52, 60))	('invasive carcinoma', 'Disease', (182, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('invasive breast cancer', 'Disease', (72, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('invasive carcinoma', 'Disease', 'MESH:D009361', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('invasive breast cancer', 'Disease', 'MESH:D001943', (72, 94))
207740	31555258	In order to shed light into the mechanisms by which Treg cell ablation promotes progression of non-invasive into invasive breast cancer, we evaluated changes in the cytokine milieu of the mammary gland upon DT treatment.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('non-invasive', 'Disease', (95, 107))	('invasive breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('ablation', 'Var', (62, 70))	('invasive breast cancer', 'Disease', (113, 135))
207753	31555258	Breast cancer accumulates Foxp3+ Treg cells upon tumor progression, and we have demonstrated that transient ablation of Treg cells in established, highly immuno-suppressive breast tumors results in a significant increase in anti-tumor immunity in primary and metastatic tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('breast tumors', 'Disease', 'MESH:D061325', (173, 186))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('increase', 'PosReg', (212, 220))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('tumors', 'Disease', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', (180, 186))	('Foxp3', 'Gene', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Disease', (49, 54))	('breast tumors', 'Disease', (173, 186))	('tumor', 'Disease', (229, 234))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', (270, 275))	('breast tumors', 'Phenotype', 'HP:0100013', (173, 186))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('breast tumor', 'Phenotype', 'HP:0100013', (173, 185))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('Breast cancer', 'Disease', (0, 13))	('Foxp3', 'Gene', '20371', (26, 31))	('ablation', 'Var', (108, 116))
207755	31555258	In this study, we found that transient Treg cell ablation at this pre-invasive breast tumor stage accelerates the rate of tumor progression to invasive cancer, increasing the number of mammary glands harboring tumors and promoting the development of early invasive carcinoma.	('increasing', 'PosReg', (160, 170))	('accelerates', 'PosReg', (98, 109))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('breast tumor', 'Phenotype', 'HP:0100013', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ablation', 'Var', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('breast tumor', 'Disease', (79, 91))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('invasive cancer', 'Disease', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('invasive carcinoma', 'Disease', (256, 274))	('invasive cancer', 'Disease', 'MESH:D009362', (143, 158))	('breast tumor', 'Disease', 'MESH:D061325', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (210, 216))	('invasive carcinoma', 'Disease', 'MESH:D009361', (256, 274))	('promoting', 'PosReg', (221, 230))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
207758	31555258	Specifically, Treg cell ablation induced expansion of CD45- CD24-/lo CD44+, CD45- CD24+ CD49f+, and CD45- CD24+ CD29hi stem cell like-populations, as well as an immature luminal progenitor-enriched population (CD45- CD24+ CD29lo CD61+).	('CD29', 'Gene', '16412', (112, 116))	('CD45', 'Gene', (76, 80))	('CD29', 'Gene', (112, 116))	('CD29', 'Gene', '16412', (222, 226))	('CD24', 'Gene', (60, 64))	('CD45', 'Gene', '19264', (54, 58))	('CD29', 'Gene', (222, 226))	('CD45', 'Gene', '19264', (100, 104))	('CD61', 'Gene', '16416', (229, 233))	('CD24', 'Gene', (106, 110))	('CD45', 'Gene', (54, 58))	('CD24', 'Gene', (82, 86))	('CD24', 'Gene', (216, 220))	('CD24', 'Gene', '12484', (60, 64))	('CD44', 'Gene', (69, 73))	('ablation', 'Var', (24, 32))	('CD45', 'Gene', '19264', (210, 214))	('CD45', 'Gene', (100, 104))	('expansion', 'PosReg', (41, 50))	('CD61', 'Gene', (229, 233))	('CD49f', 'Gene', '16403', (88, 93))	('CD45', 'Gene', '19264', (76, 80))	('CD49f', 'Gene', (88, 93))	('CD24', 'Gene', '12484', (106, 110))	('CD24', 'Gene', '12484', (216, 220))	('CD24', 'Gene', '12484', (82, 86))	('CD44', 'Gene', '12505', (69, 73))	('CD45', 'Gene', (210, 214))
207766	31555258	Furthermore, semi-quantitative PCR to detect macrophage effectors Arg1 and iNOS from the mammary gland tissue after Treg cell ablation suggested qualitative changes in the macrophage infiltrate.	('Arg1', 'Gene', '11846', (66, 70))	('ablation', 'Var', (126, 134))	('Arg1', 'Gene', (66, 70))	('iNOS', 'Gene', '18126', (75, 79))	('iNOS', 'Gene', (75, 79))
207769	31555258	It is interesting to note that the changes observed upon Treg cell ablation in the hyperplastic mammary gland are similar to those taking place during the involution of the lactating mammary gland, a state that has been mechanistically linked to the increased chance of metastatic recurrence observed in pregnancy-associated breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('breast cancer', 'Disease', (325, 338))	('breast cancer', 'Phenotype', 'HP:0003002', (325, 338))	('hyperplastic mammary gland', 'Phenotype', 'HP:0010313', (83, 109))	('ablation', 'Var', (67, 75))	('breast cancer', 'Disease', 'MESH:D001943', (325, 338))
207835	23109973	Moreover, a strong association was observed between micropapillary ADH and subsequent DCIS, whereas another study found no association between increased risk of carcinoma on excision and a micropapillary pattern of ADH.	('micropapillary', 'Var', (52, 66))	('DCIS', 'Disease', (86, 90))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))
207839	23109973	The cumulative incidence of breast cancer at 10 years was also high in patients with a high Ki-67 labeling index.	('Ki-67', 'Chemical', '-', (92, 97))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('Ki-67', 'Protein', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('high', 'Var', (87, 91))
207842	23109973	An FC ratio>=1.1 is associated with a significantly higher probability of malignancy on subsequent excisions (p=0.000).	('malignancy', 'Disease', (74, 84))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('>=1.1', 'Var', (11, 16))	('FC', 'Chemical', '-', (3, 5))
207847	30646103	Using a matched approach in a large cohort of patients treated for ductal carcinoma in situ, treatment with lumpectomy and radiotherapy was associated with a significantly reduced risk of breast cancer-specific mortality compared with treatment with lumpectomy alone (hazard ratio, 0.77; 95% CI, 0.67-0.88) or mastectomy alone (hazard ratio, 0.75; 95% CI, 0.65-0.87).	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (67, 91))	('reduced', 'NegReg', (172, 179))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('lumpectomy', 'Var', (108, 118))	('patients', 'Species', '9606', (46, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('breast cancer', 'Disease', (188, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (74, 91))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (67, 91))	('ductal carcinoma in situ', 'Disease', (67, 91))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
207859	30646103	In patients with DCIS, treatment with lumpectomy and radiotherapy was associated with a significant reduction in breast cancer mortality compared with either lumpectomy alone or mastectomy alone.	('reduction', 'NegReg', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('DCIS', 'Phenotype', 'HP:0030075', (17, 21))	('DCIS', 'Var', (17, 21))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('patients', 'Species', '9606', (3, 11))
207863	30646103	In about 6% of cases, women with DCIS will develop a contralateral invasive breast cancer within 15 years.	('women', 'Species', '9606', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('contralateral invasive breast cancer', 'Disease', 'MESH:D001943', (53, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('develop', 'PosReg', (43, 50))	('contralateral invasive breast cancer', 'Disease', (53, 89))	('DCIS', 'Phenotype', 'HP:0030075', (33, 37))	('DCIS', 'Var', (33, 37))
207908	30646103	In the matched lumpectomy cohort, radiotherapy was associated with an absolute reduction in local recurrences of 2.82% (eTable 7 and eFigure 2 in the Supplement) and a reduction in deaths from breast cancer of 0.27% (eTable 7 in the Supplement; Figure).	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('local recurrences', 'CPA', (92, 109))	('death', 'Disease', 'MESH:D003643', (181, 186))	('death', 'Disease', (181, 186))	('reduction', 'NegReg', (79, 88))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('radiotherapy', 'Var', (34, 46))	('reduction', 'NegReg', (168, 177))
207909	30646103	In the matched comparison of patients treated with lumpectomy and radiation vs mastectomy, mastectomy was associated with an absolute reduction in local recurrences of 4.31% (eTable 8 and eFigure 3 in the Supplement) and an absolute increase in breast cancer deaths of 0.28% (eTable 8 and eFigure 4 in the Supplement).	('patients', 'Species', '9606', (29, 37))	('breast cancer deaths', 'Disease', (245, 265))	('mastectomy', 'Var', (91, 101))	('reduction', 'NegReg', (134, 143))	('local recurrences', 'CPA', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('breast cancer deaths', 'Disease', 'MESH:D001943', (245, 265))
207920	30646103	In the matched lumpectomy cohort, radiotherapy was also associated with a significant reduction in contralateral invasive breast cancers (HR, 0.91; 95% CI, 0.85-0.97).	('reduction', 'NegReg', (86, 95))	('contralateral invasive breast cancers', 'Disease', (99, 136))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('contralateral invasive breast cancers', 'Disease', 'MESH:D001943', (99, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('radiotherapy', 'Var', (34, 46))
207925	30646103	In the 2010 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of randomized trials evaluating radiotherapy after lumpectomy in women with DCIS, radiotherapy decreased ipsilateral breast events by one-half (HR, 0.46; P < .001), but had no effect on breast cancer mortality (HR, 1.22; P > .1).	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('DCIS', 'Phenotype', 'HP:0030075', (157, 161))	('Breast Cancer', 'Phenotype', 'HP:0003002', (18, 31))	('decreased', 'NegReg', (176, 185))	('ipsilateral breast events', 'MPA', (186, 211))	('Breast Cancer', 'Disease', (18, 31))	('breast cancer', 'Disease', (267, 280))	('EBCTCG', 'Chemical', '-', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('decreased ipsilateral breast', 'Phenotype', 'HP:0012813', (176, 204))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('Breast Cancer', 'Disease', 'MESH:D001943', (18, 31))	('radiotherapy', 'Var', (163, 175))	('women', 'Species', '9606', (146, 151))
207947	30646103	It has been acknowledged that the rates of local recurrence among patients with DCIS in SEER are lower than expected, but this should not affect the mortality results.	('local recurrence', 'CPA', (43, 59))	('ER', 'Gene', '2099', (90, 92))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('lower', 'NegReg', (97, 102))	('DCIS', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
208050	20089167	In a review of the published literature in 1997, Dowlatshahi analyzed all large and long-term studies and confirmed a statistically significant decrease in survival associated with the presence of axillary node micrometastases.	('presence', 'Var', (185, 193))	('metastases', 'Disease', 'MESH:D009362', (216, 226))	('survival', 'MPA', (156, 164))	('decrease', 'NegReg', (144, 152))	('metastases', 'Disease', (216, 226))
208080	20089167	Although prospective randomized trials have not demonstrated a therapeutic benefit of removal of internal mammary lymph nodes (IMN) in patients with breast cancer, it is well known that involvement of this chain is associated with worse prognosis.	('patients', 'Species', '9606', (135, 143))	('IMN', 'Chemical', '-', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('involvement', 'Var', (186, 197))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('breast cancer', 'Disease', (149, 162))
208085	20089167	In case of IMN positivity adjuvant radiotherapy or systemic therapy may be offered, and clinical trials would be needed to determine whether it improves survival.	('IMN', 'Gene', (11, 14))	('improves', 'PosReg', (144, 152))	('positivity', 'Var', (15, 25))	('IMN', 'Chemical', '-', (11, 14))
150720	33634617	The histological features of DCIS associated with increased risk of recurrence are large lesion size, high nuclear grade, certain architectural patterns, central necrosis, and positive surgical margin.	('high', 'Var', (102, 106))	('necrosis', 'Disease', (162, 170))	('DCIS', 'Disease', (29, 33))	('necrosis', 'Disease', 'MESH:D009336', (162, 170))	('architectural', 'CPA', (130, 143))
208153	30168075	Similar to invasive cancer, recurrent mutations in PIK3CA, TP53, and GATA3 as well as commonly occurring copy number alterations have similarly been identified in DCIS.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('TP53', 'Gene', (59, 63))	('GATA3', 'Gene', '2625', (69, 74))	('identified', 'Reg', (149, 159))	('invasive cancer', 'Disease', (11, 26))	('DCIS', 'Disease', (163, 167))	('PIK3CA', 'Gene', (51, 57))	('DCIS', 'Disease', 'MESH:D002285', (163, 167))	('PIK3CA', 'Gene', '5290', (51, 57))	('mutations', 'Var', (38, 47))	('GATA3', 'Gene', (69, 74))	('TP53', 'Gene', '7157', (59, 63))	('invasive cancer', 'Disease', 'MESH:D009362', (11, 26))
208162	30168075	In parallel, the authors performed high depth DNAseq analysis of micro-dissected DCIS and invasive cancer areas, finding that >87% of nonsynonymous mutations were concordant between the components for each patient.	('invasive cancer', 'Disease', 'MESH:D009362', (90, 105))	('patient', 'Species', '9606', (206, 213))	('invasive cancer', 'Disease', (90, 105))	('nonsynonymous mutations', 'Var', (134, 157))	('DCIS', 'Disease', (81, 85))	('DCIS', 'Disease', 'MESH:D002285', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
208173	30168075	Furthermore, loss of P-cadherin, a cell adhesion molecule found in myoepithelial cells in the normal mammary gland, results in precocious alveolar development and formation of hyperplasias, suggesting that myoepithelial cells may also negatively regulate aspects of mammary gland development.	('precocious alveolar development', 'CPA', (127, 158))	('hyperplasias', 'Disease', (176, 188))	('P-cadherin', 'Gene', (21, 31))	('P-cadherin', 'Gene', '12560', (21, 31))	('hyperplasias', 'Disease', 'MESH:D006965', (176, 188))	('precocious alveolar development', 'Phenotype', 'HP:0006329', (127, 158))	('loss', 'Var', (13, 17))
208178	30168075	Analysis of these mice revealed that loss of ACTA2 is associated with a reduction in the ability of the myoepithelial cells to contract, resulting in reduced milk ejection.	('reduction', 'NegReg', (72, 81))	('ACTA2', 'Gene', (45, 50))	('mice', 'Species', '10090', (18, 22))	('reduced', 'NegReg', (150, 157))	('loss', 'Var', (37, 41))	('milk ejection', 'MPA', (158, 171))
208200	30168075	Furthermore, siRNA-mediated knock-down of stefin A led to the inability of myoepithelial cells to restrain tumor cell invasion.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('inability of myoepithelial', 'Disease', (62, 88))	('inability of myoepithelial', 'Disease', 'MESH:D009208', (62, 88))	('knock-down', 'Var', (28, 38))	('stefin A', 'Gene', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
208201	30168075	Finally, analysis of human DCIS samples revealed high levels of stefin A in hyperplastic and low-grade DCIS, with loss of expression observed in intermediate and high-grade DCIS, suggesting that loss of stefin A may predict invasion.	('DCIS', 'Disease', (27, 31))	('DCIS', 'Disease', (103, 107))	('DCIS', 'Disease', 'MESH:D002285', (103, 107))	('human', 'Species', '9606', (21, 26))	('DCIS', 'Disease', (173, 177))	('DCIS', 'Disease', 'MESH:D002285', (173, 177))	('invasion', 'Disease', (224, 232))	('loss', 'Var', (195, 199))	('DCIS', 'Disease', 'MESH:D002285', (27, 31))	('predict', 'Reg', (216, 223))
208207	30168075	For example, MMP-8 expression in myoepithelial cells was found to increase adhesion to ECM molecules and reduce myoepithelial cell migration.	('increase', 'PosReg', (66, 74))	('reduce', 'NegReg', (105, 111))	('expression', 'Var', (19, 29))	('MMP-8', 'Gene', (13, 18))	('adhesion', 'CPA', (75, 83))	('MMP-8', 'Gene', '4317', (13, 18))	('myoepithelial cell migration', 'CPA', (112, 140))
208208	30168075	Furthermore, MMP-8 expression also suppressed TGFbeta signaling and gelatinolytic enzyme activity, which corresponded with a reduced ability of the myoepithelial cells to promote tumor cell invasion.	('gelatinolytic enzyme', 'Enzyme', (68, 88))	('TGFbeta', 'Gene', (46, 53))	('activity', 'MPA', (89, 97))	('expression', 'Var', (19, 29))	('promote', 'PosReg', (171, 178))	('reduced', 'NegReg', (125, 132))	('TGFbeta', 'Gene', '7040', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('suppressed', 'NegReg', (35, 45))	('MMP-8', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('MMP-8', 'Gene', '4317', (13, 18))	('tumor', 'Disease', (179, 184))
208229	30168075	Experimental studies demonstrated that coinjection of MDA-MB-231 cells with myoepithelial cells that are expressing alphavbeta6 led to enhanced tumor growth.	('tumor', 'Disease', (144, 149))	('alphavbeta6', 'Var', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('enhanced', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (54, 64))
208242	30168075	For example, MMP-3 is expressed in the stromal compartment and deletion of MMP-3 in mice results in reduced lateral branching in the mammary gland.	('MMP-3', 'Gene', '17392', (75, 80))	('reduced', 'NegReg', (100, 107))	('MMP-3', 'Gene', (75, 80))	('MMP-3', 'Gene', '17392', (13, 18))	('MMP-3', 'Gene', (13, 18))	('deletion', 'Var', (63, 71))	('lateral branching in the mammary gland', 'CPA', (108, 146))	('mice', 'Species', '10090', (84, 88))
208246	30168075	For example, using a 3D co-culture model in which MCFDCIS cells were co-cultured with fibroblasts in recombinant basement membrane, the presence of fibroblasts led to increased invasive branching in the matrix, which was accompanied by increased levels of MMP-14 and MMP-9 in the co-cultures.	('MCFDCIS', 'CellLine', 'None', (50, 57))	('MMP-14', 'Gene', (256, 262))	('MMP-9', 'Gene', (267, 272))	('MMP-14', 'Gene', '4323', (256, 262))	('MMP-9', 'Gene', '4318', (267, 272))	('increased', 'PosReg', (167, 176))	('increased', 'PosReg', (236, 245))	('invasive branching in the matrix', 'CPA', (177, 209))	('presence', 'Var', (136, 144))
208264	30168075	Supportive of these experimental studies, analysis of human DCIS samples with microinvasion has demonstrated that myofibroblasts associated with DCIS lesions express uPA, uPAR and MMP-13, which are all linked with promotion of invasion.	('uPA', 'Gene', (166, 169))	('lesions', 'Var', (150, 157))	('human', 'Species', '9606', (54, 59))	('uPA', 'Gene', '5328', (166, 169))	('MMP-13', 'Gene', '4322', (180, 186))	('uPAR', 'Gene', (171, 175))	('DCIS', 'Disease', (145, 149))	('MMP-13', 'Gene', (180, 186))	('DCIS', 'Disease', 'MESH:D002285', (145, 149))	('uPA', 'Gene', '5328', (171, 174))	('uPA', 'Gene', (171, 174))	('DCIS', 'Disease', (60, 64))	('DCIS', 'Disease', 'MESH:D002285', (60, 64))	('uPAR', 'Gene', '5329', (171, 175))	('myofibroblasts', 'CPA', (114, 128))
208279	30168075	While collagen alignment was not associated with recurrence, DCIS lesions associated with comedo necrosis and were ER-, PR- and HER2+, which are features associated with DCIS with poor prognosis, were associated with more perpendicular fiber alignment.	('DCIS', 'Disease', (61, 65))	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', '2064', (128, 132))	('necrosis', 'Disease', (97, 105))	('lesions', 'Var', (66, 73))	('DCIS', 'Disease', (170, 174))	('DCIS', 'Disease', 'MESH:D002285', (170, 174))	('ER', 'Gene', '2099', (115, 117))	('more', 'PosReg', (217, 221))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('PR', 'Gene', '5241', (120, 122))	('ER', 'Gene', '2099', (129, 131))	('DCIS', 'Disease', 'MESH:D002285', (61, 65))	('associated', 'Reg', (74, 84))	('comedo', 'Phenotype', 'HP:0025249', (90, 96))
208285	30168075	In addition to macrophages, lymphocyte populations, such as T cells, have also been linked to negative regulation of ductal development in the mammary gland as mice lacking CD4+ and CD8+ T cells exhibited increased ductal outgrowth.	('ductal outgrowth', 'CPA', (215, 231))	('CD8', 'Gene', (182, 185))	('lacking', 'NegReg', (165, 172))	('CD8', 'Gene', '925', (182, 185))	('increased', 'PosReg', (205, 214))	('mice', 'Species', '10090', (160, 164))	('CD4+', 'Var', (173, 177))
208293	30168075	In another study, genetic deletion of the chemokine receptor CCR6 in the PyMT-MMTV model led to delayed early stage tumorigenesis, which was correlated with reduced recruitment of pro-tumorigenic macrophages into the microenvironment.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('delayed', 'NegReg', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('MMTV', 'Species', '11757', (78, 82))	('genetic deletion', 'Var', (18, 34))	('CCR6', 'Gene', (61, 65))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('recruitment', 'MPA', (165, 176))	('reduced', 'NegReg', (157, 164))
208342	30168075	Recent studies assessed immune infiltrates using FACS, multi-color immunofluorescence and gene expression profiling in a cohort that included primarily HER2+ and triple negative DCIS.	('triple negative', 'Var', (162, 177))	('DCIS', 'Disease', 'MESH:D002285', (178, 182))	('HER2', 'Gene', (152, 156))	('DCIS', 'Disease', (178, 182))	('HER2', 'Gene', '2064', (152, 156))
208344	30168075	These findings suggest that HER2+ DCIS and high-grade DCIS may be associated with a more immunogenic environment, thus these patients may exhibit better responsiveness to immune-based therapy.	('HER2', 'Gene', '2064', (28, 32))	('DCIS', 'Disease', (34, 38))	('DCIS', 'Disease', 'MESH:D002285', (34, 38))	('high-grade', 'Var', (43, 53))	('DCIS', 'Disease', (54, 58))	('DCIS', 'Disease', 'MESH:D002285', (54, 58))	('better', 'PosReg', (146, 152))	('HER2', 'Gene', (28, 32))	('patients', 'Species', '9606', (125, 133))
208351	30168075	Furthermore, high-grade DCIS was found to have higher percentages of macrophages as identified by the macrophage marker CD68, compared with non-high-grade DCIS.	('DCIS', 'Disease', (24, 28))	('CD68', 'Gene', '968', (120, 124))	('DCIS', 'Disease', (155, 159))	('higher', 'PosReg', (47, 53))	('DCIS', 'Disease', 'MESH:D002285', (155, 159))	('macrophages', 'CPA', (69, 80))	('CD68', 'Gene', (120, 124))	('high-grade', 'Var', (13, 23))	('DCIS', 'Disease', 'MESH:D002285', (24, 28))
208467	26967180	A long-term observational study of women undergoing excisional breast biopsy containing low-grade DCIS, but with a missed diagnosis, show ~40% developed ipsilateral breast carcinoma and ~18% BCSM.	('women', 'Species', '9606', (35, 40))	('ipsilateral breast carcinoma', 'Disease', (153, 181))	('developed', 'Reg', (143, 152))	('ipsilateral breast carcinoma', 'Disease', 'MESH:D001943', (153, 181))	('low-grade', 'Var', (88, 97))	('breast carcinoma', 'Phenotype', 'HP:0003002', (165, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
208514	32572492	In the studies reporting DCIS, there was an increase in cancer detection rate for DCIS of 0.22 (95% CI = 0.15 to 0.30, I2 = 41.4%; 18 studies) per 1000 and 0.19 (95% CI = -0.14 to 0.51, I2 = 89.7%; 18 studies) per 1000 screens for invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('DCIS', 'Phenotype', 'HP:0030075', (82, 86))	('invasive breast cancer', 'Disease', 'MESH:D001943', (231, 253))	('DCIS', 'Phenotype', 'HP:0030075', (25, 29))	('DCIS', 'Var', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('increase', 'PosReg', (44, 52))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('invasive breast cancer', 'Disease', (231, 253))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
208568	30449344	Although detection of DCIS was once thought to be the key to invasive breast cancer detection, current oncology opinions have shifted to implicate DCIS as the main driver of breast cancer overdiagnosis and overtreatment.	('breast cancer overdiagnosis', 'Disease', 'MESH:D001943', (174, 201))	('DCIS', 'Phenotype', 'HP:0030075', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('DCIS', 'Phenotype', 'HP:0030075', (147, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('DCIS', 'Var', (147, 151))	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasive breast cancer', 'Disease', (61, 83))	('oncology', 'Phenotype', 'HP:0002664', (103, 111))	('breast cancer overdiagnosis', 'Disease', (174, 201))
208573	30449344	Furthermore, the proportion of high grade DCIS, which is thought to have a higher upgrade rate on surgical excision and a shorter average time to progression to invasive disease if left untreated, has, in fact, increased since implementation of mammographic screening.	('DCIS', 'Phenotype', 'HP:0030075', (42, 46))	('high grade', 'Var', (31, 41))	('invasive disease', 'Disease', 'MESH:D009361', (161, 177))	('invasive disease', 'Disease', (161, 177))
208574	30449344	Risk factors for developing DCIS--similar to those for invasive breast cancer--include dense breasts, nulliparity, personal history of atypical ductal or lobular hyperplasia, family history, and BRCA 1 and 2 genetic mutations.	('DCIS--', 'Disease', (28, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('genetic mutations', 'Var', (208, 225))	('hyperplasia', 'Disease', (162, 173))	('BRCA 1 and 2', 'Gene', '672;675', (195, 207))	('breasts', 'Disease', 'MESH:D061325', (93, 100))	('breasts', 'Disease', (93, 100))	('invasive breast cancer', 'Disease', (55, 77))	('hyperplasia', 'Disease', 'MESH:D006965', (162, 173))	('DCIS', 'Phenotype', 'HP:0030075', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('nulliparity', 'Disease', (102, 113))	('invasive breast cancer', 'Disease', 'MESH:D001943', (55, 77))
208581	30449344	Fine-linear and pleomorphic calcifications in a linear or segmental distribution without an associated mass account for the most classic presentation of DCIS on mammography; however, many DCIS lesions present as more equivocal calcifications and can overlap with the appearance of nonmalignant pathologies such as sclerosing adenosis, fibroadenomatoid change, and atypical ductal hyperplasia, the latter of which is a high-risk lesion closely resembling low grade DCIS on pathology.	('sclerosing adenosis', 'Disease', 'MESH:D005348', (314, 333))	('ductal hyperplasia', 'Disease', 'MESH:D006965', (373, 391))	('ductal hyperplasia', 'Disease', (373, 391))	('DCIS', 'Phenotype', 'HP:0030075', (464, 468))	('DCIS', 'Phenotype', 'HP:0030075', (153, 157))	('fibroadenomatoid change', 'Disease', (335, 358))	('sclerosing adenosis', 'Disease', (314, 333))	('DCIS', 'Phenotype', 'HP:0030075', (188, 192))	('fibroadenomatoid change', 'Disease', 'MESH:D009402', (335, 358))	('lesions', 'Var', (193, 200))
208592	30449344	Despite the comprehensive treatment outlined above, it is estimated that over half of DCIS lesions will never impact a woman's health if left untreated and the prevailing DCIS treatment is aggressive due to a lack of ability to stratify DCIS risk.	('lesions', 'Var', (91, 98))	('DCIS', 'Phenotype', 'HP:0030075', (171, 175))	('DCIS', 'Disease', (86, 90))	('DCIS', 'Phenotype', 'HP:0030075', (237, 241))	('woman', 'Species', '9606', (119, 124))	('DCIS', 'Phenotype', 'HP:0030075', (86, 90))
208605	30449344	Through the use of DCE techniques, radiologists can measure the differential enhancement of DCIS lesions relative to normal breast tissue, theoretically assessing the rates at which the abnormal vessels that support DCIS lesions growth both deposit nutrients into a tumor and remove cell cycle byproducts.	('cell', 'CPA', (283, 287))	('deposit nutrients', 'MPA', (241, 258))	('DCIS', 'Phenotype', 'HP:0030075', (216, 220))	('abnormal vessels', 'Phenotype', 'HP:0002597', (186, 202))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('lesions', 'Var', (221, 228))
208610	30449344	In a study examining 15 DCIS cases that recurred after treatment, Kim et al found that higher amounts of background parenchymal enhancement (BPE) surrounding DCIS lesions correlated with recurrence risk, suggesting that MRI features of normal tissue have potential to predict which patients are most likely to develop recurrent breast malignancies.	('background parenchymal enhancement', 'MPA', (105, 139))	('breast malignancies', 'Disease', 'MESH:D061325', (328, 347))	('DCIS', 'Phenotype', 'HP:0030075', (158, 162))	('DCIS', 'Phenotype', 'HP:0030075', (24, 28))	('develop', 'PosReg', (310, 317))	('recurrence', 'Disease', (187, 197))	('breast malignancies', 'Disease', (328, 347))	('DCIS', 'Gene', (158, 162))	('lesions', 'Var', (163, 170))	('patients', 'Species', '9606', (282, 290))
208672	30627695	Therefore, myoepithelial cells can be viewed as "gatekeepers" of invasive progression, and alterations in myoepithelial cells seen in DCIS could predict risk of invasive recurrence.	('alterations', 'Var', (91, 102))	('predict', 'Reg', (145, 152))	('invasive recurrence', 'Disease', (161, 180))	('gatekeepers', 'Species', '111938', (49, 60))
208675	30627695	In the case of PD-L1 this included a selection for cancer cells that have amplification of the gene encoding for PD-L1.	('PD-L1', 'Gene', (15, 20))	('amplification', 'Var', (74, 87))	('PD-L1', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', '29126', (15, 20))	('PD-L1', 'Gene', '29126', (113, 118))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
208677	30627695	There are measurable differences between these factors when comparing normal tissue, tissue from patients with DCIS and tissue from patients with invasive disease, as well as tissue from low-grade DCIS patients versus high-grade DCIS patients.	('invasive disease', 'Disease', 'MESH:D009362', (146, 162))	('DCIS', 'Disease', (111, 115))	('patients', 'Species', '9606', (202, 210))	('invasive disease', 'Disease', (146, 162))	('patients', 'Species', '9606', (234, 242))	('low-grade', 'Var', (187, 196))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (97, 105))
208685	30627695	Initially, it was thought that nonviral, nonmutated tumor antigens are too similar to self-antigens and targeting them may lead to autoimmunity.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('autoimmunity', 'Disease', (131, 143))	('tumor', 'Disease', (52, 57))	('autoimmunity', 'Phenotype', 'HP:0002960', (131, 143))	('lead to', 'Reg', (123, 130))	('autoimmunity', 'Disease', 'MESH:D001327', (131, 143))	('targeting', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
208701	30627695	In BRCA1 mutation carriers, there are ongoing prevention studies investigating bezadioxyzine an an estrogen receptor degrader and denosumab as a RANK ligand inhibitor.	('mutation', 'Var', (9, 17))	('BRCA1', 'Gene', '672', (3, 8))	('BRCA1', 'Gene', (3, 8))	('bezadioxyzine', 'Chemical', '-', (79, 92))	('denosumab', 'Chemical', 'MESH:D000069448', (130, 139))
208721	30627695	Therefore, patients can choose between the standard treatment options for DCIS (BCS, mastectomy, RT, and ET) or living with an increased risk of breast cancer-specific mortality ranging from 0.2% to 2.6% at 10 years.	('mastectomy', 'Disease', (85, 95))	('DCIS', 'Var', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('patients', 'Species', '9606', (11, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
208743	30627695	Funding for the data presented was obtained from NIH grants R35CA197623 (KP), U01 CA143233 (KP), and the Breast Cancer Research Foundation (KP and MG); research support from General Elective (CL); AHRQ (HHSA290200500161) and PCORI (CE-1211-4173) to RP; and NIH R01 CA185138-01, PCORI (1503-29572 and 1505-30497) and a Department of Defense Breakthrough Award (BC132057) to SH.	('Breast Cancer', 'Disease', 'MESH:D001943', (105, 118))	('HR', 'Gene', '3164', (198, 200))	('U01', 'CellLine', 'CVCL:2220', (78, 81))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('1503-29572', 'Var', (285, 295))	('Breast Cancer', 'Phenotype', 'HP:0003002', (105, 118))	('HHSA290200500161', 'Var', (203, 219))	('Breast Cancer', 'Disease', (105, 118))
208759	31451564	CDK4/6 inhibitors, when used in conjunction with standard-of-care hormone therapy, provide substantial improvements in progression-free survival compared to hormone therapy alone in cases of advanced ER(+)/HER2(-) breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('CDK4/6', 'Protein', (0, 6))	('ER', 'Gene', '2099', (200, 202))	('inhibitors', 'Var', (7, 17))	('ER', 'Gene', '2099', (207, 209))	('HER2', 'Gene', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('HER2', 'Gene', '2064', (206, 210))	('progression-free', 'MPA', (119, 135))	('breast cancer', 'Disease', (214, 227))	('improvements', 'PosReg', (103, 115))
208809	31451564	These data indicate that palbociclib inhibits proliferation by regulating cell cycle machinery and also induces senescence in both normal mammary cells and early stage breast cancer.	('palbociclib', 'Chemical', 'MESH:C500026', (25, 36))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cell cycle machinery', 'CPA', (74, 94))	('breast cancer', 'Disease', (168, 181))	('proliferation', 'CPA', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('palbociclib', 'Var', (25, 36))	('induces', 'Reg', (104, 111))	('regulating', 'Reg', (63, 73))	('inhibits', 'NegReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('senescence', 'MPA', (112, 122))
208820	31451564	To investigate this, we examined palbociclib effects on both MCF10A and MCFDCIS cells grown on top of Matrigel and found that MCF10A cells form normal mammospheres whereas MCFDCIS cells form abnormal tumorspheres.	('mammospheres', 'CPA', (151, 163))	('DCIS', 'Phenotype', 'HP:0030075', (75, 79))	('DCIS', 'Phenotype', 'HP:0030075', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('MCF10A', 'Var', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('MCF10A', 'CellLine', 'CVCL:0598', (61, 67))	('MCF10A', 'CellLine', 'CVCL:0598', (126, 132))	('palbociclib', 'Chemical', 'MESH:C500026', (33, 44))
208822	31451564	MCFDCIS but not MCF10A spheres showed significant reductions in the cell cycle gene genes as well as the senescence marker, LMNB1 (Figure 2C).	('cell cycle gene genes', 'Gene', (68, 89))	('MCFDCIS', 'Var', (0, 7))	('DCIS', 'Phenotype', 'HP:0030075', (3, 7))	('reductions', 'NegReg', (50, 60))	('LMNB1', 'Gene', '4001', (124, 129))	('MCF10A', 'CellLine', 'CVCL:0598', (16, 22))	('LMNB1', 'Gene', (124, 129))
208854	31451564	Though shMUC16 tumors grew more slowly than their control counterparts, loss of MUC16 did not delay the transition from DCIS to invasive lesions and tumor histology was indistinguishable between the groups (Figure 4I).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('loss', 'Var', (72, 76))	('MUC16', 'Gene', '94025', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('grew', 'CPA', (22, 26))	('MUC16', 'Gene', '94025', (80, 85))	('invasive lesions', 'Disease', 'MESH:D009361', (128, 144))	('tumors', 'Disease', (15, 21))	('MUC16', 'Gene', (9, 14))	('tumor', 'Disease', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('slowly', 'NegReg', (32, 38))	('MUC16', 'Gene', (80, 85))	('tumor', 'Disease', (149, 154))	('invasive lesions', 'Disease', (128, 144))
208866	31451564	Some genes were upregulated >1.5-fold by palbociclib and remained upregulated following drug withdrawal such as the differentiation factor NELL2, which experienced even further upregulation in recovery (Figure 5E).	('upregulated', 'PosReg', (16, 27))	('palbociclib', 'Chemical', 'MESH:C500026', (41, 52))	('upregulated', 'PosReg', (66, 77))	('upregulation', 'PosReg', (177, 189))	('palbociclib', 'Var', (41, 52))
208867	31451564	High expression of NELL2 is associated with improved recurrence-free survival in basal breast cancers (Supplemental Figure 6B).	('basal breast cancers', 'Disease', (81, 101))	('recurrence-free survival', 'CPA', (53, 77))	('High expression', 'Var', (0, 15))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('basal breast cancers', 'Disease', 'MESH:D001943', (81, 101))	('NELL2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('improved', 'PosReg', (44, 52))
208882	31451564	In this study we show that CDK4/6 inhibition delays malignant progression to invasive disease in both basal MCFDCIS subcutaneous xenograft and luminal MCF7 intraductal injection models of DCIS.	('CDK4/6', 'Protein', (27, 33))	('luminal', 'Chemical', 'MESH:D010634', (143, 150))	('inhibition', 'Var', (34, 44))	('delays', 'NegReg', (45, 51))	('invasive disease', 'Disease', 'MESH:D009361', (77, 93))	('DCIS', 'Phenotype', 'HP:0030075', (111, 115))	('MCF7', 'CellLine', 'CVCL:0031', (151, 155))	('DCIS', 'Phenotype', 'HP:0030075', (188, 192))	('invasive disease', 'Disease', (77, 93))
208884	31451564	In vitro, palbociclib caused canonical cell cycle arrest in normal and transformed breast cells and in parallel also displayed classic features of senescence with no discernible increase in apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('palbociclib', 'Chemical', 'MESH:C500026', (10, 21))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('palbociclib', 'Var', (10, 21))	('arrest', 'Disease', (50, 56))
208887	31451564	Conversely, MCFDCIS spheres do not experience differentiation or quiescence as they grow in 3D; palbociclib is able to significantly reduce expression of E2F target genes while simultaneously inducing senescence as evidenced by loss of LMNB1.	('LMNB1', 'Gene', (236, 241))	('expression', 'MPA', (140, 150))	('palbociclib', 'Chemical', 'MESH:C500026', (96, 107))	('reduce', 'NegReg', (133, 139))	('loss', 'NegReg', (228, 232))	('senescence', 'MPA', (201, 211))	('palbociclib', 'Var', (96, 107))	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('inducing', 'PosReg', (192, 200))	('LMNB1', 'Gene', '4001', (236, 241))
208908	31451564	While the former has no known role basal breast cancer survival, high expression of the NELL2 is associated with significantly prolonged recurrence-free survival in patients with basal breast cancers (Supplemental Figure 6B).	('basal breast cancer', 'Disease', (35, 54))	('basal breast cancer', 'Disease', 'MESH:D001943', (35, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('prolonged', 'PosReg', (127, 136))	('basal breast cancers', 'Disease', (179, 199))	('recurrence-free survival', 'CPA', (137, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('NELL2', 'Gene', (88, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('basal breast cancers', 'Disease', 'MESH:D001943', (179, 199))	('patients', 'Species', '9606', (165, 173))	('high expression', 'Var', (65, 80))	('breast cancers', 'Phenotype', 'HP:0003002', (185, 199))	('basal breast cancer', 'Disease', 'MESH:D001943', (179, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
208914	31451564	Furthermore, several of the genes involved in antigen processing and presentation such as Tap1, Ifit2, Oas2, Oasl2, and Stat1 that were previously reported to be up-regulated in tumor cells by CDK4/6 inhibition actually showed lasting downregulation in the stromal analysis in our mouse model (Figure 6E).	('Ifit2', 'Gene', (96, 101))	('Oas2', 'Gene', '246728', (103, 107))	('tumor', 'Disease', (178, 183))	('stromal analysis', 'CPA', (257, 273))	('Oas2', 'Gene', (103, 107))	('Tap1', 'Gene', (90, 94))	('downregulation', 'NegReg', (235, 249))	('Ifit2', 'Gene', '15958', (96, 101))	('up-regulated', 'PosReg', (162, 174))	('Stat1', 'Gene', '20846', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Oasl2', 'Gene', (109, 114))	('Stat1', 'Gene', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('inhibition', 'Var', (200, 210))	('Tap1', 'Gene', '21354', (90, 94))	('Oasl2', 'Gene', '23962', (109, 114))	('mouse', 'Species', '10090', (281, 286))
208917	31451564	The suppression of antigen processing genes is associated with a significant reduction in recurrence-free survival of patients with basal breast cancer and indicates that palbociclib in some contexts may have long-term and potentially detrimental immunosuppressive effects (Supplemental Figure 7).	('palbociclib', 'Chemical', 'MESH:C500026', (171, 182))	('suppression', 'NegReg', (4, 15))	('basal breast cancer', 'Disease', (132, 151))	('reduction', 'NegReg', (77, 86))	('basal breast cancer', 'Disease', 'MESH:D001943', (132, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('palbociclib', 'Var', (171, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('recurrence-free survival', 'CPA', (90, 114))	('antigen processing genes', 'Gene', (19, 43))	('patients', 'Species', '9606', (118, 126))
208928	28742682	For patients who did not undergo RT, those with margins <2 mm were significantly more likely to develop a LRR than were those with margins >=2 mm (10-yr LRR rate, 30.9% vs 5.4%, respectively; hazard ratio, 5.5; 95% CI, 1.8-16.8, P = 0.003).	('LRR', 'Disease', (106, 109))	('patients', 'Species', '9606', (4, 12))	('margins <2 mm', 'Var', (48, 61))	('develop', 'PosReg', (96, 103))
208966	28742682	In comparison to patients who did not undergo RT, patients who underwent RT were more likely to have tumors >1 cm, high nuclear grade (III), comedonecrosis, and have undergone adjuvant hormonal therapy.	('high', 'Var', (115, 119))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('comedonecrosis', 'Disease', (141, 155))	('patients', 'Species', '9606', (17, 25))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
208971	28742682	Age <40 years and adjuvant RT were associated with increased LRR on the basis of the univariate Cox proportional hazards model (Table 2).	('LRR', 'Disease', (61, 64))	('Cox', 'Gene', '1351', (96, 99))	('Cox', 'Gene', (96, 99))	('adjuvant', 'Var', (18, 26))
209005	28742682	In our previous smaller study reported in 2012 on patients with DCIS who underwent BCS from 1996 to 2009, age < 40 years, pathologic tumor size >=1.5 cm, and no RT were associated with a significantly higher LRR rate on univariate analysis.	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('LRR', 'Disease', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('>=1.5', 'Var', (144, 149))	('DCIS', 'Disease', 'MESH:D002285', (64, 68))	('tumor', 'Disease', (133, 138))	('DCIS', 'Disease', (64, 68))	('DCIS', 'Phenotype', 'HP:0030075', (64, 68))	('higher', 'PosReg', (201, 207))
209039	29350308	Consistent with this, the first-generation TZDs have some reported antiproliferative effects in mammary cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('antiproliferative effects', 'CPA', (67, 92))	('TZDs', 'Var', (43, 47))	('TZDs', 'Chemical', '-', (43, 47))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
209041	29350308	More recently, newer, more potent, selective high-affinity, and anti-proliferative third-generation TZD agonists have been developed such as efatutazone (CS7017/RS5444).	('TZD', 'Chemical', 'MESH:D053778', (100, 103))	('efatutazone', 'Chemical', 'MESH:C510342', (141, 152))	('anti-proliferative', 'MPA', (64, 82))	('CS7017/RS5444', 'Var', (154, 167))
209071	29350308	Primary antibodies (phospho-Akt (Ser473), Akt, phospho-ERK1/2 (Thr202/Tyr204), ERK1/2, and actin) used for western blot analysis are listed in Table 2.	('Ser473', 'Var', (33, 39))	('actin', 'Gene', '100342017', (91, 96))	('Tyr204', 'Chemical', '-', (70, 76))	('actin', 'Gene', (91, 96))	('Thr202', 'Chemical', '-', (63, 69))	('Ser473', 'Chemical', '-', (33, 39))
209088	29350308	We and others have previously determined that reduction in the levels of MCFDCIS breast cancer initiating cells (BCIC) parallels changes in differentiation and inhibits the ability of the MCFDCIS cells to progress to invasive disease.	('reduction', 'NegReg', (46, 55))	('changes', 'Reg', (129, 136))	('breast cancer', 'Disease', (81, 94))	('invasive disease', 'Disease', (217, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('MCFDCIS', 'Var', (73, 80))	('inhibits', 'NegReg', (160, 168))	('differentiation', 'CPA', (140, 155))	('progress', 'CPA', (205, 213))	('invasive disease', 'Disease', 'MESH:D009362', (217, 233))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
209090	29350308	At the lowest concentration of efatutazone (0.01 microM), there was no significant reduction in number of tumorspheres (defined as > 100 microm diameter) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('0.01 microM', 'Var', (44, 55))	('efatutazone', 'Chemical', 'MESH:C510342', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('reduction', 'NegReg', (83, 92))
209104	29350308	A number of genes were upregulated by efatutazone treatment including the PPARgamma-responsive gene FABP4 as well as genes that play a predominant role in inflammation such as S100A7, S100A8, and LCN2.	('upregulated', 'PosReg', (23, 34))	('FABP4', 'Gene', '2167', (100, 105))	('LCN2', 'Gene', '3934', (196, 200))	('efatutazone', 'Chemical', 'MESH:C510342', (38, 49))	('FABP4', 'Gene', (100, 105))	('LCN2', 'Gene', (196, 200))	('S100A8', 'Gene', (184, 190))	('S100A7', 'Var', (176, 182))	('S100A8', 'Gene', '6279', (184, 190))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
209124	29350308	Decreased Akt phosphorylation has been previously reported in a mouse model of BRCA1 mutation after efatutazone treatment.	('Akt', 'Pathway', (10, 13))	('BRCA1', 'Gene', '12189', (79, 84))	('Decreased', 'NegReg', (0, 9))	('BRCA1', 'Gene', (79, 84))	('mutation', 'Var', (85, 93))	('efatutazone', 'Chemical', 'MESH:C510342', (100, 111))	('mouse', 'Species', '10090', (64, 69))
209127	29350308	Interestingly, changes of expression of genes involved in the inflammatory response pathways such as S1000A7, S100A8, and LCN2 were also induced by efatutazone.	('expression', 'MPA', (26, 36))	('changes', 'Reg', (15, 22))	('LCN2', 'Gene', '3934', (122, 126))	('induced', 'Reg', (137, 144))	('LCN2', 'Gene', (122, 126))	('efatutazone', 'Chemical', 'MESH:C510342', (148, 159))	('S100A8', 'Gene', (110, 116))	('S1000A7', 'Var', (101, 108))	('S100A8', 'Gene', '6279', (110, 116))
209137	29593431	Patients with H-DCIS were more likely to be younger (p<0.001), have smaller tumors (p<0.001), good/moderate differentiation (p<0.001), human epidermal growth factor receptor 2-positive disease (p<0.001), receive mastectomy (p<0.001), and not receive radiotherapy (p<0.001) and chemotherapy (p<0.001).	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('H-DCIS', 'Var', (14, 20))	('good/moderate differentiation', 'CPA', (94, 123))	('smaller', 'NegReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mastectomy', 'Disease', (212, 222))	('receive', 'Reg', (204, 211))	('tumors', 'Disease', (76, 82))	('epidermal growth factor receptor 2', 'Gene', (141, 175))	('human', 'Species', '9606', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('epidermal growth factor receptor 2', 'Gene', '2064', (141, 175))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('H-DCIS', 'Chemical', '-', (14, 20))
209138	29593431	The median follow-up was 27 months, and the 2-year breast cancer-specific survival (BCSS) in patients with No-DCIS, L-DCIS, and H-DCIS was 97.3%, 98.0%, and 98.5%, respectively (p<0.001).	('H-DCIS', 'Chemical', '-', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('H-DCIS', 'Var', (128, 134))	('L-DCIS', 'Var', (116, 122))	('No-DCIS', 'Var', (107, 114))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('DCIS', 'Phenotype', 'HP:0030075', (118, 122))	('breast cancer', 'Disease', (51, 64))	('L-DCIS', 'Chemical', '-', (116, 122))	('patients', 'Species', '9606', (93, 101))	('DCIS', 'Phenotype', 'HP:0030075', (130, 134))
209139	29593431	Before PSM, H-DCIS was an independent favorable prognostic factor for BCSS; patients with H-DCIS had better BCSS compared to patients with No-DCIS (hazard ratio [HR] 0.674, 95% CI: 0.528-0.861, p=0.002), while the BCSS between No-DCIS and L-DCIS was similar (HR 0.944, 95% CI: 0.840-1.061, p=0.334).	('patients', 'Species', '9606', (76, 84))	('BCSS', 'MPA', (108, 112))	('H-DCIS', 'Var', (90, 96))	('L-DCIS', 'Chemical', '-', (239, 245))	('H-DCIS', 'Chemical', '-', (12, 18))	('DCIS', 'Phenotype', 'HP:0030075', (230, 234))	('better', 'PosReg', (101, 107))	('DCIS', 'Phenotype', 'HP:0030075', (14, 18))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (241, 245))	('H-DCIS', 'Chemical', '-', (90, 96))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('patients', 'Species', '9606', (125, 133))
209140	29593431	However, this survival advantage disappeared after PSM; there was significantly different BCSS between patients with No-DCIS and H-DCIS (HR 0.923, 95% CI: 0.653-1.304, p=0.650).	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('BCSS', 'MPA', (90, 94))	('H-DCIS', 'Chemical', '-', (129, 135))	('DCIS', 'Phenotype', 'HP:0030075', (131, 135))	('H-DCIS', 'Var', (129, 135))	('patients', 'Species', '9606', (103, 111))
209141	29593431	H-DCIS was not associated with BCSS as compared to No-DCIS in the breast-conserving surgery (p=0.295) and mastectomy (p=0.793) groups.	('DCIS', 'Phenotype', 'HP:0030075', (2, 6))	('BCSS', 'Disease', (31, 35))	('H-DCIS', 'Chemical', '-', (0, 6))	('H-DCIS', 'Var', (0, 6))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))	('breast-conserving surgery', 'Disease', (66, 91))
209142	29593431	In breast cancer, patients with H-DCIS have unique clinicopathologic features compared to patients with No-DCIS.	('H-DCIS', 'Chemical', '-', (32, 38))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('DCIS', 'Phenotype', 'HP:0030075', (34, 38))	('H-DCIS', 'Var', (32, 38))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (90, 98))
209149	29593431	Therefore, patients with breast IDC with DCIS component may have less biologically aggressive disease than patients with pure IDC of the breast.	('IDC', 'Gene', (32, 35))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('DCIS', 'Var', (41, 45))	('IDC', 'Gene', '4000', (126, 129))	('aggressive disease', 'Disease', 'MESH:D001523', (83, 101))	('IDC', 'Gene', (126, 129))	('aggressive disease', 'Disease', (83, 101))	('patients', 'Species', '9606', (11, 19))	('less', 'NegReg', (65, 69))	('patients', 'Species', '9606', (107, 115))	('IDC', 'Gene', '4000', (32, 35))
209153	29593431	Several studies have found that the presence of DCIS is often related to favorable clinicopathologic features in invasive breast cancer, but is not an independent prognostic factor in survival outcomes, including locoregional and distant recurrence and disease-specific death.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('death', 'Disease', 'MESH:D003643', (270, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('death', 'Disease', (270, 275))	('presence', 'Var', (36, 44))	('DCIS', 'Phenotype', 'HP:0030075', (48, 52))	('invasive breast cancer', 'Disease', 'MESH:D001943', (113, 135))	('DCIS', 'Var', (48, 52))	('invasive breast cancer', 'Disease', (113, 135))
209168	29593431	Patients were classified into three groups in accordance with the DCIS component: No-DCIS, no DCIS component reported; L-DCIS, minimal DCIS component present (<25%); and H-DCIS, extensive DCIS component present (>=25%).	('H-DCIS', 'Chemical', '-', (170, 176))	('L-DCIS', 'Chemical', '-', (119, 125))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('H-DCIS', 'Var', (170, 176))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('L-DCIS', 'Var', (119, 125))	('Patients', 'Species', '9606', (0, 8))	('DCIS', 'Phenotype', 'HP:0030075', (121, 125))	('DCIS', 'Phenotype', 'HP:0030075', (94, 98))	('DCIS', 'Phenotype', 'HP:0030075', (135, 139))
209176	29593431	Descriptive and correlational analyses using chi2 test, one-way analysis of variance, or linear-by-linear association indicated that patients with H-DCIS were more likely to be younger (p<0.001), have smaller tumors (p<0.001), early T-stage (p<0.001), well/moderate differentiation (p<0.001), and HER2-positive disease (p<0.001), compared to patients with No-DCIS.	('HER2-positive disease', 'Disease', (297, 318))	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('well/moderate differentiation', 'CPA', (252, 281))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('patients', 'Species', '9606', (342, 350))	('patients', 'Species', '9606', (133, 141))	('HER2-positive disease', 'Disease', 'MESH:D064726', (297, 318))	('H-DCIS', 'Chemical', '-', (147, 153))	('DCIS', 'Phenotype', 'HP:0030075', (359, 363))	('DCIS', 'Phenotype', 'HP:0030075', (149, 153))	('smaller', 'NegReg', (201, 208))	('early T-stage', 'CPA', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('H-DCIS', 'Var', (147, 153))
209181	29593431	Patients with L-DCIS (p<0.001) and H-DCIS (p<0.001) were also associated with better BCSS compared to patients with No-DCIS.	('DCIS', 'Phenotype', 'HP:0030075', (16, 20))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('better', 'PosReg', (78, 84))	('BCSS', 'CPA', (85, 89))	('patients', 'Species', '9606', (102, 110))	('L-DCIS', 'Chemical', '-', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('H-DCIS', 'Chemical', '-', (35, 41))	('H-DCIS', 'Var', (35, 41))	('DCIS', 'Phenotype', 'HP:0030075', (37, 41))	('L-DCIS', 'Var', (14, 20))
209182	29593431	Multivariate Cox regression confirmed that H-DCIS was an independent favorable prognostic factor of BCSS; patients with H-DCIS had better BCSS compared to patients with No-DCIS (hazard ratio [HR] 0.674, 95% CI: 0.528-0.861, p=0.002), while there was no significant difference between No-DCIS and L-DCIS (HR 0.944, 95% CI: 0.840-1.061, p=0.334).	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('DCIS', 'Phenotype', 'HP:0030075', (298, 302))	('H-DCIS', 'Chemical', '-', (43, 49))	('Cox', 'Gene', (13, 16))	('H-DCIS', 'Chemical', '-', (120, 126))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('L-DCIS', 'Chemical', '-', (296, 302))	('DCIS', 'Phenotype', 'HP:0030075', (172, 176))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (106, 114))	('BCSS', 'CPA', (138, 142))	('better', 'PosReg', (131, 137))	('H-DCIS', 'Var', (120, 126))	('DCIS', 'Phenotype', 'HP:0030075', (287, 291))	('BCSS', 'Disease', (100, 104))	('Cox', 'Gene', '1351', (13, 16))
209183	29593431	The 2-year BCSS in patients with No-DCIS, L-DCIS, and H-DCIS was 97.3%, 98.0%, and 98.5%, respectively (log-rank test, p<0.001; Figure 1A).	('patients', 'Species', '9606', (19, 27))	('H-DCIS', 'Chemical', '-', (54, 60))	('L-DCIS', 'Chemical', '-', (42, 48))	('H-DCIS', 'Var', (54, 60))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('L-DCIS', 'Var', (42, 48))	('DCIS', 'Phenotype', 'HP:0030075', (44, 48))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))
209187	29593431	Adjustment by age, race/ethnicity, tumor grade, T-stage, nodal stage, breast cancer subtype, and surgical procedure showed no significant difference in BCSS between No-DCIS and H-DCIS (HR 0.923, 95% CI: 0.653-1.304, p=0.650; Table 4).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('No-DCIS', 'Var', (165, 172))	('DCIS', 'Phenotype', 'HP:0030075', (179, 183))	('breast cancer subtype', 'Disease', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('DCIS', 'Phenotype', 'HP:0030075', (168, 172))	('tumor', 'Disease', (35, 40))	('breast cancer subtype', 'Disease', 'MESH:D001943', (70, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('H-DCIS', 'Chemical', '-', (177, 183))
209189	29593431	The presence of H-DCIS was not associated with survival outcome compared to No-DCIS in the breast-conserving surgery group (p=0.295) and the mastectomy group (p=0.793).	('DCIS', 'Phenotype', 'HP:0030075', (79, 83))	('breast-conserving', 'Disease', (91, 108))	('H-DCIS', 'Var', (16, 22))	('DCIS', 'Phenotype', 'HP:0030075', (18, 22))	('H-DCIS', 'Chemical', '-', (16, 22))
209203	29593431	The results of our study suggested that patients with H-DCIS were more likely to be of lower tumor grade and with HER2-positive disease compared to patients with No-DCIS.	('patients', 'Species', '9606', (148, 156))	('DCIS', 'Phenotype', 'HP:0030075', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patients', 'Species', '9606', (40, 48))	('lower', 'NegReg', (87, 92))	('H-DCIS', 'Chemical', '-', (54, 60))	('HER2-positive disease', 'Disease', 'MESH:D064726', (114, 135))	('tumor', 'Disease', (93, 98))	('H-DCIS', 'Var', (54, 60))	('DCIS', 'Phenotype', 'HP:0030075', (56, 60))	('HER2-positive disease', 'Disease', (114, 135))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
209206	29593431	Cedolini et al found that invasive cancers with H-DCIS were associated with longer disease-free survival and lower local recurrence rates.	('invasive cancers', 'Disease', (26, 42))	('lower', 'NegReg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('H-DCIS', 'Chemical', '-', (48, 54))	('disease-free survival', 'CPA', (83, 104))	('longer', 'PosReg', (76, 82))	('local recurrence rates', 'CPA', (115, 137))	('invasive cancers', 'Disease', 'MESH:D009362', (26, 42))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('H-DCIS', 'Var', (48, 54))
209208	29593431	The results of this study are similar to those of the study by Cedolini et al, indicating the patients with H-DCIS had better BCSS compared to patients with No-DCIS before PSM.	('patients', 'Species', '9606', (94, 102))	('H-DCIS', 'Var', (108, 114))	('DCIS', 'Phenotype', 'HP:0030075', (110, 114))	('BCSS', 'CPA', (126, 130))	('patients', 'Species', '9606', (143, 151))	('DCIS', 'Phenotype', 'HP:0030075', (160, 164))	('H-DCIS', 'Chemical', '-', (108, 114))
209245	22112476	ALH is associated with a significant increased risk (4-5 fold) for subsequent breast cancer, which occur on average more than 10 years after diagnosis.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('ALH', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
209247	22112476	In comparison to ALH, LCIS carries twice the risk for the development of invasive breast cancer and an increased risk of in-breast tumor recurrence.	('breast tumor', 'Disease', 'MESH:D001943', (124, 136))	('invasive breast cancer', 'Disease', 'MESH:D001943', (73, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('LCIS', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('breast tumor', 'Disease', (124, 136))	('invasive breast cancer', 'Disease', (73, 95))	('breast tumor', 'Phenotype', 'HP:0100013', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('LCIS', 'Phenotype', 'HP:0030076', (22, 26))
209253	22112476	Originally described by Foote and Stewart in 1941, many variants ofLCIS have now been identified, based on nuclear grade, pleomorphism and necrosis.	('variants', 'Var', (56, 64))	('necrosis', 'Disease', (139, 147))	('ofLCIS', 'Gene', (65, 71))	('LCIS', 'Phenotype', 'HP:0030076', (67, 71))	('necrosis', 'Disease', 'MESH:D009336', (139, 147))
209264	22112476	The mechanism of e-cadherin inactivation in lobular neoplasia has been shown to occur through multiple mechanisms, including inactivating gene mutations, loss of heterozygosity, transcriptional regulation, and abnormal promoter methylation.	('promoter methylation', 'MPA', (219, 239))	('e-cadherin', 'Gene', (17, 27))	('loss of heterozygosity', 'Var', (154, 176))	('abnormal', 'Var', (210, 218))	('inactivating gene mutations', 'Var', (125, 152))	('e-cadherin', 'Gene', '999', (17, 27))	('neoplasia', 'Phenotype', 'HP:0002664', (52, 61))	('inactivation', 'NegReg', (28, 40))	('lobular neoplasia', 'Disease', (44, 61))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (44, 61))	('lobular neoplasia', 'Disease', 'MESH:D009369', (44, 61))	('transcriptional', 'MPA', (178, 193))
209266	22112476	These truncation mutations of CDH1 have been found in LCIS and synchronous ILC, supporting the hypothesis that LCIS can be a precursor lesion of ILC.	('CDH1', 'Gene', '999', (30, 34))	('LCIS', 'Phenotype', 'HP:0030076', (111, 115))	('LCIS', 'Phenotype', 'HP:0030076', (54, 58))	('LCIS', 'Disease', (54, 58))	('synchronous', 'Disease', (63, 74))	('truncation mutations', 'Var', (6, 26))	('found', 'Reg', (45, 50))	('CDH1', 'Gene', (30, 34))
209267	22112476	The fact that loss of protein expression is accompanied by genetic alterations in LCIS but not in ALH suggests that another mechanism, such as silencing of the e-cadherin promoter by methylation, may be involved in loss of expression of the e-cadherin complex in ALH.	('LCIS', 'Phenotype', 'HP:0030076', (82, 86))	('e-cadherin', 'Gene', (241, 251))	('e-cadherin', 'Gene', '999', (241, 251))	('alterations', 'Var', (67, 78))	('protein', 'Protein', (22, 29))	('e-cadherin', 'Gene', (160, 170))	('silencing', 'NegReg', (143, 152))	('e-cadherin', 'Gene', '999', (160, 170))	('methylation', 'Var', (183, 194))	('loss', 'NegReg', (14, 18))
209268	22112476	Recent studies have shown that hypermethylation of the CDH1 promoter occurs in both ALH/LCIS and invasive lobular carcinomas, as well as in adjacent non-neoplastic epithelia.	('CDH1', 'Gene', (55, 59))	('hypermethylation', 'Var', (31, 47))	('invasive lobular carcinomas', 'Disease', (97, 124))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (97, 124))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (106, 124))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (106, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('neoplastic epithelia', 'Phenotype', 'HP:0031492', (153, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('CDH1', 'Gene', '999', (55, 59))	('ALH/LCIS', 'Disease', (84, 92))	('occurs', 'Reg', (69, 75))	('neoplastic epithelia', 'Disease', (153, 173))	('neoplastic epithelia', 'Disease', 'MESH:D009369', (153, 173))	('LCIS', 'Phenotype', 'HP:0030076', (88, 92))
209271	22112476	These data suggest that epigenetic andlor transcriptional CDH1 downregulation may be an early event in the neoplastic process of lobular carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('CDH1', 'Gene', (58, 62))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (129, 146))	('lobular carcinomas', 'Disease', 'MESH:D018275', (129, 147))	('neoplastic process', 'Phenotype', 'HP:0002664', (107, 125))	('CDH1', 'Gene', '999', (58, 62))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (129, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('lobular carcinomas', 'Disease', (129, 147))	('downregulation', 'NegReg', (63, 77))	('epigenetic', 'Var', (24, 34))
209273	22112476	In addition to the hallmark loss of CDH1 at 16q21-q23.1 described above, early loss of heterozygosity (LOH) studies observed allelic loss at 11q13 in LCIS and invasive lobular carcinomas, but not in ALH.	('LCIS', 'Disease', (150, 154))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (159, 186))	('LCIS', 'Phenotype', 'HP:0030076', (150, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (168, 185))	('CDH1', 'Gene', (36, 40))	('CDH1', 'Gene', '999', (36, 40))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (168, 186))	('allelic loss', 'Var', (125, 137))	('11q13', 'Gene', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('invasive lobular carcinomas', 'Disease', (159, 186))
209276	22112476	Other genomic areas of alterations in ALH/LCIS include 1p32.1, 16p13.3, 17q21.32, and 17q25.3 (including the candidate genes JUN, AXINI, HOXB, and RAC3, respectively).	('LCIS', 'Phenotype', 'HP:0030076', (42, 46))	('RAC3', 'Gene', (147, 151))	('HOXB', 'Gene', (137, 141))	('alterations', 'Var', (23, 34))	('HOXB', 'Gene', '3210', (137, 141))	('RAC3', 'Gene', '5881', (147, 151))
209277	22112476	Two areas of copy number gain in both ALH and LCIS are 14q32.33 (including AKT1) and 5q32-33.1 (including CSFlR), both implicated in mammary epithelial proliferation.	('gain', 'PosReg', (25, 29))	('AKT1', 'Gene', (75, 79))	('copy number', 'Var', (13, 24))	('LCIS', 'Phenotype', 'HP:0030076', (46, 50))	('5q32-33.1', 'Var', (85, 94))	('AKT1', 'Gene', '207', (75, 79))	('14q32.33', 'Var', (55, 63))
209284	22112476	Like ALH, the presence of ADH is associated with an increased risk of breast cancer, especially among premenopausal women (OR, 3.1).	('presence', 'Var', (14, 22))	('AD', 'Disease', 'MESH:D000544', (26, 28))	('AD', 'Disease', (26, 28))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('women', 'Species', '9606', (116, 121))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
209291	22112476	There is frequent loss of heterozygosity at 8p, 16q, 17q, and 17p, which is also observed in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC).	('ductal carcinoma', 'Phenotype', 'HP:0030075', (93, 109))	('DCIS', 'Phenotype', 'HP:0030075', (119, 123))	('loss', 'NegReg', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('heterozygosity', 'Var', (26, 40))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (100, 117))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (129, 154))	('invasive ductal carcinoma', 'Disease', (129, 154))	('ductal carcinoma in situ', 'Disease', (93, 117))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (93, 117))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (138, 154))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (93, 117))
209295	22112476	Several studies have shown that amplification of the oncogene erb-b2, which is typically seen in a significant proportion of DCIS and invasive breast cancers, is not seen in ADH.	('breast cancers', 'Phenotype', 'HP:0003002', (143, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('DCIS', 'Disease', (125, 129))	('amplification', 'Var', (32, 45))	('AD', 'Disease', 'MESH:D000544', (174, 176))	('erb-b2', 'Gene', (62, 68))	('AD', 'Disease', (174, 176))	('erb-b2', 'Gene', '2064', (62, 68))	('DCIS', 'Phenotype', 'HP:0030075', (125, 129))	('invasive breast cancers', 'Disease', (134, 157))	('invasive breast cancers', 'Disease', 'MESH:D001943', (134, 157))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('seen', 'Reg', (89, 93))
209296	22112476	Additionally, mutations in the p53 tumor suppressor gene, also found in a subset of DCIS and invasive cancers, are not seen in ADH.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('tumor', 'Disease', (35, 40))	('AD', 'Disease', 'MESH:D000544', (127, 129))	('invasive cancers', 'Disease', 'MESH:D009362', (93, 109))	('DCIS', 'Disease', (84, 88))	('AD', 'Disease', (127, 129))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('found', 'Reg', (63, 68))	('invasive cancers', 'Disease', (93, 109))	('mutations', 'Var', (14, 23))
209301	22112476	There is also a significant correlation between large nuclear size, comedonecrosis, amplification and overexpression of Her2/neu, and mutations and overexpression of p53 as features of high-grade DCIS.	('high-grade DCIS', 'Disease', (185, 200))	('necrosis', 'Disease', 'MESH:D009336', (74, 82))	('overexpression', 'PosReg', (148, 162))	('DCIS', 'Phenotype', 'HP:0030075', (196, 200))	('Her2/neu', 'Gene', '2064', (120, 128))	('p53', 'Gene', (166, 169))	('amplification', 'Var', (84, 97))	('overexpression', 'PosReg', (102, 116))	('p53', 'Gene', '7157', (166, 169))	('comedo', 'Phenotype', 'HP:0025249', (68, 74))	('mutations', 'Var', (134, 143))	('necrosis', 'Disease', (74, 82))	('Her2/neu', 'Gene', (120, 128))
209305	22112476	Chromosomes 16q, 17p (encompassing the p53 locus) and 17q are frequent sites of abnormalities in DCIS, with incidences exceeding 40% in some studies.	('abnormalities', 'Var', (80, 93))	('DCIS', 'Disease', (97, 101))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('DCIS', 'Phenotype', 'HP:0030075', (97, 101))
209306	22112476	Studies using array CGH have demonstrated that DCIS lesions have genetic alterations similar to adjacent invasive cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('invasive cancers', 'Disease', (105, 121))	('DCIS', 'Phenotype', 'HP:0030075', (47, 51))	('DCIS lesions', 'Disease', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('invasive cancers', 'Disease', 'MESH:D009362', (105, 121))	('genetic alterations', 'Var', (65, 84))
209307	22112476	Similarly, mutations in PIK3CA have been detected in both DCIS and IDC.	('mutations', 'Var', (11, 20))	('DCIS', 'Disease', (58, 62))	('PIK3CA', 'Gene', (24, 30))	('IDC', 'Disease', (67, 70))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('PIK3CA', 'Gene', '5290', (24, 30))	('detected', 'Reg', (41, 49))
209312	22112476	SlOOA7 has been demonstrated to act as a chemoattractant for T-lymphocytes and neutrophils, and induces serum antibody responses.	('induces', 'PosReg', (96, 103))	('SlOOA7', 'Var', (0, 6))	('serum antibody responses', 'MPA', (104, 128))	('neu', 'Gene', '2064', (79, 82))	('neu', 'Gene', (79, 82))
209330	22112476	Epigenetic alterations, including DNA methylation, histone modifications, and chromatin remodeling, result in aberrant expression of genes involved in early breast cancer development.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('expression', 'MPA', (119, 129))	('result in', 'Reg', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('histone modifications', 'Var', (51, 72))	('aberrant', 'Var', (110, 118))	('DNA methylation', 'Var', (34, 49))
209331	22112476	DNA methylation at CpG dinucleotides located in the promoter regions of tumor suppressor genes is an early, reversible, and specific hallmark of many cancers.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('hallmark of many cancers', 'Disease', (133, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumor', 'Disease', (72, 77))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (133, 157))	('dinucleotides', 'Chemical', 'MESH:D015226', (23, 36))	('DNA', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
209334	22112476	This suggests that early gene silencing is a common early event in both ductal and lobular neoplasias.	('lobular neoplasias', 'Disease', 'MESH:D009369', (83, 101))	('early gene silencing', 'Var', (19, 39))	('ductal', 'Disease', (72, 78))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (83, 100))	('lobular neoplasias', 'Disease', (83, 101))	('neoplasias', 'Phenotype', 'HP:0002664', (91, 101))	('neoplasia', 'Phenotype', 'HP:0002664', (91, 100))
209335	22112476	Promotor methylation can functionally inactivate the remaining allele of tumor suppressor genes, such as BRCA1, and can silence tumor suppressive micro-RNAs.	('methylation', 'Var', (9, 20))	('BRCA1', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('silence', 'NegReg', (120, 127))	('BRCA1', 'Gene', '672', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inactivate', 'NegReg', (38, 48))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (128, 133))
209337	22112476	Global hypomethylation in breast cancer is reportedly associated with features such as stage, tumor size, and histologic grade.	('breast cancer', 'Disease', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Global hypomethylation', 'Var', (0, 22))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('associated', 'Reg', (54, 64))
209338	22112476	Hypomethylation of the promotors of proto-oncogenes involved in breast cancer proliferation, metastasis, and drug resistance (synuclein gamma, urokinase, N-cadherin, beta-catenin and WNTll genes) have been identified.	('N-cadherin', 'Gene', (154, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('beta-catenin', 'Gene', (166, 178))	('N-cadherin', 'Gene', '1000', (154, 164))	('synuclein gamma', 'Gene', (126, 141))	('Hypomethylation', 'Var', (0, 15))	('WNTll genes', 'Gene', (183, 194))	('synuclein gamma', 'Gene', '6623', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('breast cancer', 'Disease', (64, 77))
209342	22112476	These emerging methods will enable detailed analyses of the epigenetic changes that occur in early breast cancer development, both for the identification of high-risk patients, as well as early interventions of potentially reversible changes of pre-malignant lesions.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('epigenetic changes', 'Var', (60, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
209577	32075592	Such changes are associated with the development of comorbidities such as diabetes and cardiovascular disease, thereby influencing long-term survival.	('cardiovascular disease', 'Disease', (87, 109))	('associated', 'Reg', (17, 27))	('changes', 'Var', (5, 12))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (87, 109))	('cardiovascular disease', 'Disease', 'MESH:D002318', (87, 109))	('diabetes', 'Disease', (74, 82))	('diabetes', 'Disease', 'MESH:D003920', (74, 82))	('influencing', 'Reg', (119, 130))
209607	29987605	Women who enrolled preoperatively in ACOSOG Z11102 were evaluated for conversion to mastectomy and need for reoperation to obtain negative margins.	('mastectomy', 'Disease', (84, 94))	('Z11102', 'Var', (44, 50))	('Women', 'Species', '9606', (0, 5))
209629	29987605	Therefore, Z11102 used the term multiple ipsilateral breast cancer and included patients with tumors separated by 2 cm or greater of normal breast tissue.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('multiple ipsilateral breast cancer', 'Disease', (32, 66))	('multiple ipsilateral breast cancer', 'Disease', 'MESH:D001943', (32, 66))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('Z11102', 'Var', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
209690	29987605	Risk factors for conversion to mastectomy cited in other studies include nodal positivity, invasive lobular carcinoma and DCIS.	('nodal positivity', 'Var', (73, 89))	('DCIS', 'Phenotype', 'HP:0030075', (122, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mastectomy', 'Disease', (31, 41))	('invasive lobular carcinoma', 'Disease', (91, 117))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (100, 117))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (91, 117))	('DCIS', 'Disease', (122, 126))
209692	29987605	The re-excision rate in Z11102 of 32.4% is slightly higher than expected compared with patients with unifocal disease.	('patients', 'Species', '9606', (87, 95))	('re-excision', 'CPA', (4, 15))	('higher', 'PosReg', (52, 58))	('Z11102', 'Var', (24, 30))
209705	30237579	In an attempt to assign its function, we knocked down Fbln2 in the mouse mammary epithelial cell line EpH4.	('knocked down', 'Var', (41, 53))	('EpH4', 'CellLine', 'CVCL:0073', (102, 106))	('mouse', 'Species', '10090', (67, 72))	('Fbln2', 'Gene', (54, 59))
209707	30237579	This phenotype was associated with a disruption of the collagen IV sheath around the epithelial spheroids and downregulation of integrin beta1, suggesting a role for FBLN2 in stabilizing the basement membrane (BM).	('integrin beta1', 'Gene', '16412', (128, 142))	('FBLN2', 'Var', (166, 171))	('downregulation', 'NegReg', (110, 124))	('integrin beta1', 'Gene', (128, 142))
209710	30237579	These results are consistent with a role of FBLN2 in mammary epithelial BM stability, and that its down-regulation in breast cancer is associated with loss of the BM and early invasion.	('early invasion', 'CPA', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('down-regulation', 'NegReg', (99, 114))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('FBLN2', 'Var', (44, 49))	('loss', 'NegReg', (151, 155))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('mammary epithelial BM stability', 'CPA', (53, 84))
209717	30237579	However, fbln2 KO mice have no major mammary phenotype as the loss of FBLN2 is compensated by a relocation of other fibulin proteins, in particular FBLN1, while knockout of FBLN1 itself is lethal due to loss of BM in small blood vessels leading to haemorrhage.	('fbln2', 'Gene', '14115', (9, 14))	('loss', 'Var', (62, 66))	('FBLN2', 'Gene', (70, 75))	('FBLN1', 'Gene', (148, 153))	('FBLN1', 'Gene', '14114', (148, 153))	('haemorrhage', 'Disease', (248, 259))	('fbln2', 'Gene', (9, 14))	('mice', 'Species', '10090', (18, 22))	('FBLN1', 'Gene', (173, 178))	('FBLN1', 'Gene', '14114', (173, 178))	('haemorrhage', 'Disease', 'MESH:D006470', (248, 259))	('loss', 'NegReg', (203, 207))
209720	30237579	In this study, we further investigated the function of FBLN2 in normal mammary epithelial cells by knocking down FBLN2 in the mouse mammary epithelial cell line EpH4, and assessed its expression in normal and cancerous human breast tissue.	('mouse', 'Species', '10090', (126, 131))	('cancerous', 'Disease', 'MESH:D009369', (209, 218))	('FBLN2', 'Gene', (113, 118))	('EpH4', 'CellLine', 'CVCL:0073', (161, 165))	('human', 'Species', '9606', (219, 224))	('cancerous', 'Disease', (209, 218))	('knocking down', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
209724	30237579	Microscopic analysis of the cells at confluency showed that Fbln2 KD cells were consistently larger than scr shRNA control cells and had enlarged nuclei (Fig.	('enlarged', 'PosReg', (137, 145))	('larger', 'PosReg', (93, 99))	('Fbln2 KD', 'Var', (60, 68))	('scr', 'Gene', '109559', (105, 108))	('scr', 'Gene', (105, 108))
209725	30237579	While scr shRNA control-transduced EpH4 cells formed small evenly shaped round spheroids, the size of the spheroids was consistently increased in the Fbln2 KD cells with the strongest suppression of FBLN2 compared to the scr shRNA control cells (Fig.	('size', 'MPA', (94, 98))	('scr', 'Gene', (6, 9))	('FBLN2', 'Gene', (199, 204))	('suppression', 'NegReg', (184, 195))	('scr', 'Gene', '109559', (221, 224))	('Fbln2 KD', 'Var', (150, 158))	('EpH4', 'CellLine', 'CVCL:0073', (35, 39))	('scr', 'Gene', (221, 224))	('increased', 'PosReg', (133, 142))	('scr', 'Gene', '109559', (6, 9))
209727	30237579	While the increased spheroidal size was still evident in Fbln2 KD cells, co-culture with fibroblasts led to a strongly increased stellate branch pattern compared to control scr ctrl cells, with either individual cells or thin tubules extending from the spheroids into the surrounding matrix (Fig.	('stellate branch pattern', 'CPA', (129, 152))	('scr', 'Gene', '109559', (173, 176))	('Fbln2 KD', 'Var', (57, 65))	('scr', 'Gene', (173, 176))	('increased', 'PosReg', (119, 128))
209728	30237579	Fibulins can interact directly with integrins and contribute to BM integrity, with FBLN2 KO mice showing a blistering phenotype of the epidermis of newborn mice similar to that of ITGalpha3 KO mice.	('contribute', 'Reg', (50, 60))	('FBLN2 KO', 'Var', (83, 91))	('mice', 'Species', '10090', (193, 197))	('mice', 'Species', '10090', (156, 160))	('interact', 'Interaction', (13, 21))	('mice', 'Species', '10090', (92, 96))
209730	30237579	In contrast, ITGbeta1 expression was strongly reduced in the FBLN2 KD cells as shown by western blot and when Matrigel-embedded structures were examined by immunofluorescence (Fig.	('ITGbeta1', 'Gene', '16412', (13, 21))	('ITGbeta1', 'Gene', (13, 21))	('FBLN2 KD', 'Var', (61, 69))	('reduced', 'NegReg', (46, 53))	('expression', 'MPA', (22, 32))
209731	30237579	While scr control cells showed an evenly formed COLIV layer around the spheroids, FBLN2 KD cells had a discontinuous and irregular COLIV layer (Fig.	('scr', 'Gene', (6, 9))	('FBLN2 KD', 'Var', (82, 90))	('scr', 'Gene', '109559', (6, 9))
209749	30237579	High levels of Fbln2 mRNA expression were indeed significantly associated with improved DMFS in patients with negative LN status (P = 0.03; n = 988), as well as in patients with intermediate grade (Grade II, P = 0.05; n = 546), while there was a statistically insignificant trend towards better survival in low grade breast cancer patients (Grade I, P = 0.14; n = 188).	('improved', 'PosReg', (79, 87))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('Fbln2 mRNA', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('breast cancer', 'Disease', (317, 330))	('DMFS', 'MPA', (88, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (164, 172))	('DMFS', 'Chemical', '-', (88, 92))	('patients', 'Species', '9606', (331, 339))
209754	30237579	In this study, we investigated the effect of Fbln2 KD in mouse mammary epithelial cells and further studied its expression in human breast cancer.	('human', 'Species', '9606', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('Fbln2 KD', 'Var', (45, 53))	('breast cancer', 'Disease', (132, 145))	('mouse', 'Species', '10090', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
209764	30237579	However, it may also be possible that loss of FBLN2 directly reduces ITGbeta1 expression, which in turn leads to a change in COLIV network integrity.	('loss', 'Var', (38, 42))	('expression', 'MPA', (78, 88))	('COLIV network integrity', 'CPA', (125, 148))	('FBLN2', 'Var', (46, 51))	('leads to', 'Reg', (104, 112))	('ITGbeta1', 'Gene', (69, 77))	('ITGbeta1', 'Gene', '16412', (69, 77))	('change', 'Reg', (115, 121))	('reduces', 'NegReg', (61, 68))
209765	30237579	Such an impairment of BM integrity upon loss of ITGbeta1 has previously been shown in models of lung and kidney morphogenesis and in epidermal development, while loss of basolateral staining of ITGalpha2/beta1 has been linked to the absence of COLIV expression in breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (264, 280))	('impairment', 'NegReg', (8, 18))	('ITGbeta1', 'Gene', (48, 56))	('ITGbeta1', 'Gene', '16412', (48, 56))	('loss', 'Var', (40, 44))	('epidermal development', 'CPA', (133, 154))	('breast carcinoma', 'Disease', (264, 280))	('breast carcinoma', 'Disease', 'MESH:D001943', (264, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
209783	30237579	FBLN2 enhances TGFbeta activity and can also compete with latent TGFbeta-binding protein for binding to fibrillin-1, thereby regulating TGFbeta deposition within the ECM and bioavailability.	('TGFbeta', 'Gene', (15, 22))	('TGFbeta', 'Gene', (136, 143))	('fibrillin-1', 'Gene', (104, 115))	('binding', 'Interaction', (93, 100))	('TGFbeta', 'Gene', '21803', (15, 22))	('enhances', 'PosReg', (6, 14))	('TGFbeta', 'Gene', '21803', (136, 143))	('regulating', 'Reg', (125, 135))	('TGFbeta', 'Gene', (65, 72))	('FBLN2', 'Var', (0, 5))	('TGFbeta', 'Gene', '21803', (65, 72))	('fibrillin-1', 'Gene', '14118', (104, 115))
209792	30237579	For virus production, HEK-293 cells (70-80% confluency) were transfected using X-tremeGENE 9 (Roche Diagnostics Ltd., Burgess Hill, UK) according to manufacturer's manual with 3 mug pCMV-dR 8.91 (packaging vector, Thermo Fisher) + 0.7 mug pCMV-VSV-G (envelope vector, Thermo Fisher) + 3 mug Lentiviral shRNA vectors (three pLKO1-Puro vectors targeting all Fbln2 variants of the mouse under control of the human U6 promotor (Clones: TRCN0000109479, TRCN0000109478 and TRCN0000109476 (Thermo Fisher), or a scr ctrl shRNA pLKO1-Puro control vector (Thermo Fisher)).	('mouse', 'Species', '10090', (378, 383))	('human', 'Species', '9606', (405, 410))	('TRCN0000109476', 'Var', (467, 481))	('TRCN0000109479', 'Var', (432, 446))	('TRCN0000109478', 'Var', (448, 462))	('scr', 'Gene', '109559', (504, 507))	('Fbln2', 'Gene', (356, 361))	('scr', 'Gene', (504, 507))
209801	30237579	Fbln2 KD and scr cells were trypsinised, washed with DPBS and re-suspended in DPBS at 1 x 106 cells/ml.	('scr', 'Gene', (13, 16))	('Fbln2 KD', 'Var', (0, 8))	('scr', 'Gene', '109559', (13, 16))	('DPBS', 'Chemical', 'MESH:C012939', (53, 57))	('DPBS', 'Chemical', 'MESH:C012939', (78, 82))
209974	31832408	All tumor biomarkers [ carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), CA19-9, CA125, neuron specific enolase (NSE)] were within the reference ranges.	('CEA', 'Gene', (49, 52))	('tumor', 'Disease', (4, 9))	('carcinoembryonic antigen', 'Gene', '1084', (23, 47))	('CA153', 'Gene', '4582', (81, 86))	('CA125', 'Gene', (97, 102))	('CEA', 'Gene', '1084', (49, 52))	('NSE', 'Gene', (129, 132))	('CA19-9', 'Var', (89, 95))	('CA153', 'Gene', (81, 86))	('carcinoembryonic antigen', 'Gene', (23, 47))	('neuron specific enolase', 'Gene', '2026', (104, 127))	('neuron specific enolase', 'Gene', (104, 127))	('carbohydrate antigen 153', 'Gene', '4582', (55, 79))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CA125', 'Gene', '94025', (97, 102))	('carbohydrate antigen 153', 'Gene', (55, 79))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('NSE', 'Gene', '2026', (129, 132))
210001	31832408	These findings are different from the neurologic symptoms of cerebella degeneration and opsoclonus caused by gynecologic or breast cancers, in which positive expression of anti-Yo and anti-Ri was found most frequently.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('neurologic symptoms of cerebella', 'Phenotype', 'HP:0001317', (38, 70))	('opsoclonus', 'Phenotype', 'HP:0010543', (88, 98))	('breast cancers', 'Phenotype', 'HP:0003002', (124, 138))	('cerebella degeneration and opsoclonus', 'Disease', 'MESH:D015835', (61, 98))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cerebella degeneration', 'Phenotype', 'HP:0001272', (61, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancers', 'Disease', 'MESH:D001943', (124, 138))	('breast cancers', 'Disease', (124, 138))	('anti-Yo', 'Var', (172, 179))	('anti-Ri', 'Var', (184, 191))
210004	31832408	For breast cancer associated PNS, anti-Ri was related with poor response to immunotherapy.	('poor response to immunotherapy', 'Phenotype', 'HP:0002721', (59, 89))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('anti-Ri', 'Var', (34, 41))	('breast cancer', 'Disease', (4, 17))
210059	29197417	The actual price for a lifetime of screening shows a considerable range, but the difference between lower and higher risk women is in almost all studies between US $2000 and US $2500.	('US $2500', 'Var', (174, 182))	('US $2000', 'Var', (161, 169))	('women', 'Species', '9606', (122, 127))
210098	29190656	Malignancy rates were 18.3% (23/126 BI-RADS 4a), 41.7% (25/60 BI-RADS 4b) and 95% (59/62 BI-RADS 4c).	('BI-RADS', 'Var', (62, 69))	('BI-RADS', 'Var', (36, 43))	('Malignancy', 'Disease', (0, 10))	('RADS 4b', 'Phenotype', 'HP:0500055', (65, 72))	('Malignancy', 'Disease', 'MESH:D009369', (0, 10))
210102	29190656	This is due to the wide range of malignancy rates that was found for BI-RADS 3 mammographic microcalcifications (0-9.7%) that do not comply with the BI-RADS definition of BI-RADS 3 lesions, which are characterized with a disease prevalence of less than 2%.	('malignancy', 'Disease', 'MESH:D009369', (33, 43))	('mammographic', 'Disease', (79, 91))	('malignancy', 'Disease', (33, 43))	('BI-RADS', 'Var', (69, 76))
210103	29190656	Since, there is no safe established additional screening tool to further differentiate these lesions and since malignancy rates are overall too high to justify follow-up alone, almost all mammographic microcalcifications undergo biopsy to exclude malignancy.	('microcalcifications', 'Var', (201, 220))	('malignancy', 'Disease', 'MESH:D009369', (247, 257))	('mammographic', 'Disease', (188, 200))	('malignancy', 'Disease', (247, 257))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('malignancy', 'Disease', (111, 121))
210124	29190656	The invasive carcinoma was classified BI-RADS 4c and the 3 false negative DCIS were originally rated BI-RADS 4a (n = 1), BI-RADS 4b (n = 1) and BI-RADS 4c (n = 1) at mammography.	('invasive carcinoma', 'Disease', (4, 22))	('RADS 4b', 'Phenotype', 'HP:0500055', (124, 131))	('BI-RADS', 'Var', (144, 151))	('invasive carcinoma', 'Disease', 'MESH:D009361', (4, 22))	('BI-RADS', 'Var', (121, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('DCIS', 'Phenotype', 'HP:0030075', (74, 78))
210126	29190656	62 lesions rated BI-RADS 4c at mammography displayed a malignancy rate of 95.2% (95%-CI 86.5-99.0%, 59 malignant and 3 benign lesions).	('malignancy', 'Disease', 'MESH:D009369', (55, 65))	('BI-RADS', 'Var', (17, 24))	('malignancy', 'Disease', (55, 65))
210129	29190656	We also find a clear increase of malignancy rates from BI-RADS 4a to BI-RADS 4c lesions, with the disease prevalence being above 95% in BI-RADS 4c lesions.	('BI-RADS', 'Var', (55, 62))	('BI-RADS', 'Var', (69, 76))	('malignancy', 'Disease', 'MESH:D009369', (33, 43))	('malignancy', 'Disease', (33, 43))	('increase', 'PosReg', (21, 29))
210136	29190656	The one remaining invasive lesion that went undetected by MRI was a BI-RADS 4c lesion, a lesion that given the likelihood of malignancy at mammography, would have not been missed in the diagnostic workup.	('BI-RADS 4c', 'Var', (68, 78))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('malignancy', 'Disease', (125, 135))
210141	29190656	multicentric cancer lesions or whether it caused unnecessary biopsies of additional false positive findings.	('cancer lesions', 'Disease', 'MESH:D009062', (13, 27))	('cancer lesions', 'Disease', (13, 27))	('multicentric', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
210148	27766079	Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast.	('presence', 'Var', (68, 76))	('HER-2', 'Gene', (27, 32))	('HER-2', 'Gene', '2064', (27, 32))	('immune response genes', 'Gene', (80, 101))
210168	27766079	Therefore, recognition of an absent or deficient CD4+ Th1 response may predict patients at risk for treatment failure and poor prognosis, but also correction of an inadequate CD4+ Th1 immune response with the use of anti-HER2 dendritic cell (DC) vaccines could consequently improve response to breast cancer therapy and be an important step in prevention of recurrence.	('response', 'CPA', (282, 290))	('breast cancer', 'Disease', (294, 307))	('CD4', 'Gene', (49, 52))	('improve', 'PosReg', (274, 281))	('CD4', 'Gene', '920', (175, 178))	('CD4', 'Gene', '920', (49, 52))	('correction', 'Var', (147, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))	('CD4', 'Gene', (175, 178))
210171	27766079	A large retrospective case-control study demonstrated that patients with high levels of auto-antibodies against HER2 have a decreased risk of developing both ductal carcinoma in-situ (DCIS) and IBC (Tabuchi et al.,).	('IBC', 'Disease', (194, 197))	('carcinoma in-situ', 'Disease', (165, 182))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('decreased', 'NegReg', (124, 133))	('patients', 'Species', '9606', (59, 67))	('carcinoma in-situ', 'Disease', 'MESH:D002278', (165, 182))	('auto-antibodies', 'Var', (88, 103))	('ductal carcinoma in-situ', 'Phenotype', 'HP:0030075', (158, 182))	('HER2', 'Protein', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('DCIS', 'Phenotype', 'HP:0030075', (184, 188))
210183	27766079	Th1 cytokines will shut down angiogenesis and chemokine expression, resulting in sustained tumor regression upon oncogene inactivation (Rakhra et al.,; Tkach et al.,).	('inactivation', 'Var', (122, 134))	('angiogenesis', 'MPA', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('shut down', 'NegReg', (19, 28))	('tumor', 'Disease', (91, 96))
210184	27766079	Based on this idea, combined treatments of breast cancer cell lines in vitro with Th1 cytokines TNF-alpha and IFN-gamma may cause oncogene inactivation of HER2 and subsequent senescence and apoptosis (Braumuller et al.,; Namjoshi et al.,).	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('HER2', 'Protein', (155, 159))	('senescence', 'CPA', (175, 185))	('cause', 'Reg', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('inactivation', 'Var', (139, 151))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('apoptosis', 'CPA', (190, 199))
210190	27766079	Specifically, high TIL levels in tumor tissue is associated with increased pathologic complete response (pCR) after chemotherapy as well as improved disease free and overall survival (Wang et al.,).	('increased', 'PosReg', (65, 74))	('improved', 'PosReg', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('high TIL', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('overall survival', 'CPA', (166, 182))	('tumor', 'Disease', (33, 38))	('disease free', 'CPA', (149, 161))
210238	27766079	BC patients who are poor clinical responders to neoadjuvant chemotherapy with high FOXP3+ Tregs also have a significant reduction in the production of IFN-gamma and TNF-alpha, consequently creating a pronounced reduction in the Th1 cell profile (Verma et al.,).	('high', 'Var', (78, 82))	('reduction', 'NegReg', (211, 220))	('FOXP3+', 'Gene', (83, 89))	('TNF-alpha', 'MPA', (165, 174))	('reduction', 'NegReg', (120, 129))	('production of IFN-gamma', 'MPA', (137, 160))	('BC', 'Phenotype', 'HP:0003002', (0, 2))	('patients', 'Species', '9606', (3, 11))	('Th1 cell profile', 'MPA', (228, 244))
210239	27766079	Recent evidence has suggested that Treg cells are increased in breast cancer models and depletion or inhibition of these Treg cells may improve anti-tumor immunity (Viehl et al.,; Hong et al.,).	('depletion', 'Var', (88, 97))	('improve', 'PosReg', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inhibition', 'NegReg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('tumor', 'Disease', (149, 154))
210244	27766079	It has been demonstrated that FOXP3+ Tregs are inhibited via signaling through Toll-like receptors (TLR), such as TLR-2, TLR-4, TLR-8, and TLR-9 (Lee et al.,).	('TLR', 'Gene', (100, 103))	('signaling', 'MPA', (61, 70))	('inhibited', 'NegReg', (47, 56))	('TLR-2', 'Gene', (114, 119))	('TLR-8', 'Gene', '51311', (128, 133))	('TLR-9', 'Gene', '54106', (139, 144))	('TLR-9', 'Gene', (139, 144))	('TLR-4', 'Gene', '7099', (121, 126))	('TLR-8', 'Gene', (128, 133))	('FOXP3+', 'Var', (30, 36))	('TLR-2', 'Gene', '7097', (114, 119))	('TLR-4', 'Gene', (121, 126))
210249	27766079	With the advent of trastuzumab, and more recently, pertuzumab, HER2+ breast cancer has a markedly improved overall survival in early and advanced stage disease.	('pertuzumab', 'Chemical', 'MESH:C485206', (51, 61))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('HER2+', 'Var', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('overall', 'MPA', (107, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('improved', 'PosReg', (98, 106))	('trastuzumab', 'Chemical', 'MESH:D000068878', (19, 30))
210258	27766079	Lapatinib is able to overcome trastuzumab resistance due to truncated HER2 receptors, showing improvement in overall survival and pCR, but with only modest benefit (Geyer et al.,; Baselga et al.,).	('improvement', 'PosReg', (94, 105))	('HER2 receptors', 'Protein', (70, 84))	('trastuzumab', 'Chemical', 'MESH:D000068878', (30, 41))	('pCR', 'CPA', (130, 133))	('overall survival', 'CPA', (109, 125))	('Lapatinib', 'Chemical', 'MESH:D000077341', (0, 9))	('truncated', 'Var', (60, 69))
210261	27766079	Adaptive immune response changes may also contribute to trastuzumab resistance, including dysregulation of the downstream PI3K-AKT-mTOR pathway, accumulation of the truncated kinase active p95-HER2, and alternative receptor kinase signaling (Gajria and Chandarlapaty,).	('changes', 'Reg', (25, 32))	('p95', 'Gene', '4683', (189, 192))	('accumulation', 'PosReg', (145, 157))	('contribute', 'Reg', (42, 52))	('AKT', 'Gene', '207', (127, 130))	('trastuzumab', 'Chemical', 'MESH:D000068878', (56, 67))	('dysregulation', 'Var', (90, 103))	('Adaptive immune response changes', 'Phenotype', 'HP:0031404', (0, 32))	('p95', 'Gene', (189, 192))	('alternative receptor kinase signaling', 'MPA', (203, 240))	('AKT', 'Gene', (127, 130))
210262	27766079	Resistant cells may present with deletions, insertions and missense point mutations that influence the function of receptors, adaptor proteins and second messengers, prohibiting trastuzumab from functioning properly (Pohlmann et al.,).	('trastuzumab', 'Chemical', 'MESH:D000068878', (178, 189))	('influence', 'Reg', (89, 98))	('functioning properly', 'MPA', (195, 215))	('function', 'MPA', (103, 111))	('prohibiting', 'NegReg', (166, 177))	('missense point mutations', 'Var', (59, 83))	('insertions', 'Var', (44, 54))
210266	27766079	However, with TDM-1, trastuzumab allows for selective binding to tumor cells overexpressing HER2; once bound, the DM-1 enters the cells and eradicates them by binding to tubulin (Gajria and Chandarlapaty,; Teicher and Doroshow,).	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tubulin', 'Protein', (170, 177))	('trastuzumab', 'Chemical', 'MESH:D000068878', (21, 32))	('binding', 'Interaction', (159, 166))	('HER2', 'Protein', (92, 96))	('eradicates', 'NegReg', (140, 150))	('DM-1', 'Var', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
210274	27766079	The most studied vaccines for HER2 positive breast cancer have been peptide vaccines, more specifically, vaccination against the E75 peptide of HER2/neu.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('E75 peptide', 'Var', (129, 140))	('HER2/neu', 'Gene', '2064', (144, 152))	('HER2/neu', 'Gene', (144, 152))
210275	27766079	E75 (HER2/neu 369-377) is an immunogenic peptide from the HER2/neu protein that is overexpressed in many breast cancers (Mittendorf et al.,).	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('overexpressed', 'PosReg', (83, 96))	('breast cancers', 'Disease', (105, 119))	('HER2/neu', 'Gene', (58, 66))	('HER2/neu', 'Gene', '2064', (5, 13))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('E75', 'Var', (0, 3))	('HER2/neu', 'Gene', (5, 13))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('HER2/neu', 'Gene', '2064', (58, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
210278	27766079	The E75 peptide vaccine has had the greatest immunologic and clinical benefit in patients with tumors that have low HER2/neu expressing tumors (1+) (Benavides et al.,).	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('E75', 'Var', (4, 7))	('low', 'NegReg', (112, 115))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HER2/neu', 'Gene', '2064', (116, 124))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HER2/neu', 'Gene', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
210305	27766079	In patients receiving trastuzumab-based neoadjuvant chemotherapy, anti-HER2 CD4+ T cell immunity was dramatically higher in women obtaining pCR, compared to those with residual disease (Datta et al.,).	('Datta', 'Chemical', '-', (186, 191))	('pCR', 'Disease', (140, 143))	('anti-HER2', 'Var', (66, 75))	('CD4', 'Gene', (76, 79))	('patients', 'Species', '9606', (3, 11))	('CD4', 'Gene', '920', (76, 79))	('trastuzumab', 'Chemical', 'MESH:D000068878', (22, 33))	('higher', 'PosReg', (114, 120))	('women', 'Species', '9606', (124, 129))
210321	27766079	After administration of DC vaccines to HER2 positive DCIS and stage I breast cancer patients, substantial anti-HER2 Th1 immunity is induced (Figure 1), with pCR rates approaching 25%, with loss of the target antigen in the remainder of patients (Sharma et al.,; Datta et al.,).	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (236, 244))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('positive DCIS', 'Var', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DCIS', 'Phenotype', 'HP:0030075', (53, 57))	('Datta', 'Chemical', '-', (262, 267))	('anti-HER2', 'MPA', (106, 115))
210332	27766079	In a murine model of human breast cancer, blockade of the PD-1/PD-L1 pathway using a monoclonal antibody yielded improved therapeutic efficacy of DC vaccination with prolonged survival and prevention of tumor growth (Ge et al.,).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('therapeutic', 'MPA', (122, 133))	('prevention', 'NegReg', (189, 199))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('human', 'Species', '9606', (21, 26))	('murine', 'Species', '10090', (5, 11))	('breast cancer', 'Disease', (27, 40))	('blockade', 'Var', (42, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('improved', 'PosReg', (113, 121))	('PD-1/PD-L1', 'Gene', (58, 68))
210334	27766079	The combination of aOX40 and DC vaccination increased CD8+ T cell specificity and response, as well as promoted a robust Th1 cell response as evidenced by increased levels of IFNgamma, TNFalpha, and IL-2 production (Linch et al.,).	('levels', 'MPA', (165, 171))	('CD8', 'Gene', '925', (54, 57))	('TNFalpha', 'Gene', (185, 193))	('IL-2', 'Gene', '3558', (199, 203))	('IL-2', 'Gene', (199, 203))	('increased', 'PosReg', (155, 164))	('response', 'CPA', (82, 90))	('TNFalpha', 'Gene', '7124', (185, 193))	('IFNgamma', 'Gene', (175, 183))	('aOX40', 'Var', (19, 24))	('IFNgamma', 'Gene', '3458', (175, 183))	('promoted', 'PosReg', (103, 111))	('increased', 'PosReg', (44, 53))	('Th1 cell response', 'CPA', (121, 138))	('CD8', 'Gene', (54, 57))
210339	27766079	Identification of a loss of anti-HER2 CD4+ Th1 response in tumorigenesis, and its correlation to a poor response to traditional traztuzumab plus chemotherapy, have paved a path toward the potential for restoration of this response with anti-HER2 dendritic cell vaccination therapy.	('traztuzumab', 'Chemical', '-', (128, 139))	('CD4', 'Gene', (38, 41))	('tumor', 'Disease', (59, 64))	('CD4', 'Gene', '920', (38, 41))	('anti-HER2', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('loss', 'NegReg', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
210345	22606601	Pathologic Complete Response of HER-2 Neu-Positive Invasive Ductal Carcinoma and Ductal Carcinoma In Situ following Neoadjuvant Chemotherapy plus Trastuzumab: A Case Report and Review of Literature Pathologic complete response (pCR) after NC has been consistently associated with improved outcomes.	('HER-2', 'Gene', '2064', (32, 37))	('Ductal Carcinoma', 'Phenotype', 'HP:0030075', (60, 76))	('Ductal Carcinoma', 'Phenotype', 'HP:0030075', (81, 97))	('Invasive Ductal Carcinoma and Ductal Carcinoma In Situ', 'Disease', 'MESH:D002285', (51, 105))	('Ductal Carcinoma In Situ', 'Phenotype', 'HP:0030075', (81, 105))	('HER-2', 'Gene', (32, 37))	('Pathologic', 'Var', (198, 208))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (146, 157))	('Carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
210440	33610903	Regardless of the surgical procedure (even in BCS), per ACROP-ESTRO guidelines the breast skin itself is not part of the CTV, except in patients with a T4b, T4c and T4d breast cancer.	('T4b', 'Var', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (136, 144))	('T4c', 'Var', (157, 160))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))	('T4d', 'Var', (165, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
210479	33610903	This indicates that rBGT superficial to the tumour is associated with an increased risk for residual tumour foci (13 out of 64, 20%).	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (101, 107))	('tumour', 'Disease', (44, 50))	('tumour foci', 'Disease', 'MESH:D009369', (101, 112))	('rBGT', 'Var', (20, 24))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour foci', 'Disease', (101, 112))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
210483	33610903	Even though SSM/NSM were reported to be oncologically safe, these data derive from retrospective studies and it remains unclear to which extent the presence and amount of rBGT is associated with local recurrence risks and/or new primary tumours, especially in patients who are not scheduled for PMRT.	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('local recurrence', 'CPA', (195, 211))	('associated with', 'Reg', (179, 194))	('tumours', 'Phenotype', 'HP:0002664', (237, 244))	('presence', 'Var', (148, 156))	('patients', 'Species', '9606', (260, 268))	('rBGT', 'Gene', (171, 175))	('tumours', 'Disease', 'MESH:D009369', (237, 244))	('tumours', 'Disease', (237, 244))	('PMRT', 'Chemical', '-', (295, 299))
210504	33610903	Autologous-based reconstruction is reported to have lower rates of complications and better cosmetic outcomes in the setting of PMRT, compared to implant-based reconstruction.	('PMRT', 'Disease', (128, 132))	('Autologous-based', 'Var', (0, 16))	('PMRT', 'Chemical', '-', (128, 132))
210537	33610903	Per similar disease stage, some patients will strongly benefit from PMRT whilst other have no gain at all, therefore much more research is needed to individualise PMRT strategy to improve overall outcomes.	('patients', 'Species', '9606', (32, 40))	('PMRT', 'Var', (68, 72))	('benefit', 'PosReg', (55, 62))	('PMRT', 'Chemical', '-', (163, 167))	('PMRT', 'Chemical', '-', (68, 72))
210544	32220886	Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients.	('invasive carcinoma', 'Disease', (157, 175))	('patients', 'Species', '9606', (314, 322))	('invasive disease', 'Disease', 'MESH:D009361', (280, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('DCIS', 'Disease', (149, 153))	('mutations', 'Var', (64, 73))	('invasive carcinoma', 'Disease', 'MESH:D009361', (157, 175))	('invasive disease', 'Disease', (280, 296))
88509	32220886	To estimate the clonal architecture and composition of the lesions from each patient, mutant allelic fractions from all somatic mutations were adjusted for tumor cell content, ploidy, local copy number and sequencing errors using PyClone, as previously described (Supplementary Methods).	('mutations', 'Var', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ploidy', 'Disease', (176, 182))	('ploidy', 'Disease', 'None', (176, 182))	('tumor', 'Disease', (156, 161))	('patient', 'Species', '9606', (77, 84))
210569	32220886	Of the 12 PIK3CA mutations identified in 12 synchronous DCIS and 12 IDC-NSTs, nine (9/12) affected hotspot residues including H1047R/L (DCIS, n=9; IDC-NST, n=8) and E545D (IDC-NST, n=1; Fig.	('PIK3CA', 'Gene', '5290', (10, 16))	('E545D', 'Mutation', 'p.E545D', (165, 170))	('PIK3CA', 'Gene', (10, 16))	('H1047R', 'Var', (126, 132))	('H1047R', 'SUBSTITUTION', 'None', (126, 132))	('E545D', 'Var', (165, 170))	('affected', 'Reg', (90, 98))
210570	32220886	Most GATA3 mutations in synchronous DCIS (6/7) and IDC-NSTs (6/6) were loss-of-function mutations, including frame-shift (DCIS, n=4; IDC-NST, n=5), truncating (DCIS, n=1) and splice-site mutations (DCIS and IDC-NST, n=1, each; Fig.	('truncating', 'Var', (148, 158))	('frame-shift', 'Var', (109, 120))	('loss-of-function', 'NegReg', (71, 87))	('mutations', 'Var', (11, 20))	('GATA3', 'Gene', (5, 10))	('GATA3', 'Gene', '2625', (5, 10))
210571	32220886	The majority of TP53 mutations identified in synchronous DCIS (13/14) and IDC-NSTs (12/14) were inactivating and most of them (DCIS, 12/13; IDC-NST, 12/14) were associated with loss of heterozygosity (LOH) of the wild-type allele (Fig.	('loss', 'NegReg', (177, 181))	('inactivating', 'NegReg', (96, 108))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('heterozygosity', 'MPA', (185, 199))	('mutations', 'Var', (21, 30))
210572	32220886	Of the cases with a dominant signature 3, Case 2 harbored a pathogenic BRCA1 E23Vfs*17 germline mutation associated with LOH of the wild-type allele in all DCIS (2DCISA and 2DCISB) and IDC-NST (2IDCA and 2IDCB) foci, Case 19 harbored a BRCA1 R496H germline mutation and LOH in the DCIS and IDC-NST, and both the DCIS and IDC-NST of Case 25 harbored a somatic BRCA1 L1154Mfs*4 mutation associated with LOH.	('E23Vfs*17', 'Var', (77, 86))	('BRCA1', 'Gene', (71, 76))	('BRCA1', 'Gene', (236, 241))	('R496H', 'Mutation', 'p.R496H', (242, 247))	('E23Vfs*17', 'Mutation', 'p.E23VfsX17', (77, 86))	('BRCA1', 'Gene', '672', (359, 364))	('pathogenic', 'Reg', (60, 70))	('BRCA1', 'Gene', '672', (236, 241))	('BRCA1', 'Gene', (359, 364))	('L1154Mfs*4', 'Var', (365, 375))	('BRCA1', 'Gene', '672', (71, 76))
210575	32220886	Similarly, synchronous DCIS from this study (n=27) harbored a comparable frequency of mutations affecting cancer genes included in MSK-IMPACT than IDC-NSTs from TCGA matched by age, menopausal status and receptor status (1:3 ratio, n=81; Fig.	('mutations', 'Var', (86, 95))	('menopausal status', 'Phenotype', 'HP:0008209', (182, 199))	('MSK-IMPACT', 'Gene', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
210579	32220886	S2D), pure DCIS (n=7) had a numerically lower frequency of TP53 mutations (14% vs 52%; P>0.05) and PIK3CA mutations (0% vs 41%; P>0.05) than synchronous DCIS (n=27; Fig.	('TP53', 'Gene', (59, 63))	('PIK3CA', 'Gene', '5290', (99, 105))	('mutations', 'Var', (64, 73))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', '7157', (59, 63))	('lower', 'NegReg', (40, 45))	('PIK3CA', 'Gene', (99, 105))
210580	32220886	40DCIS harbored a BRCA1 E908* germline mutation.	('E908*', 'Var', (24, 29))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (18, 23))	('E908*', 'SUBSTITUTION', 'None', (24, 29))
210582	32220886	Grade 3 DCIS (n=20) had a statistically significantly higher frequency of TP53 mutations than grade 2 DCIS (n=14; 75% vs 0%; P<0.001; Fig.	('higher', 'PosReg', (54, 60))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
210585	32220886	ER-positive/HER2-negative DCIS (n=21) harbored a numerically higher frequency of mutations in GATA3 (38%) than ER-negative/HER2-negative DCIS (n=6; 0%; P>0.05) and that HER2-positive DCIS (n=7; 14%; P>0.05).	('ER', 'Gene', '2069', (111, 113))	('HER2', 'Gene', (169, 173))	('GATA3', 'Gene', (94, 99))	('HER2', 'Gene', (12, 16))	('ER', 'Gene', '2069', (170, 172))	('GATA3', 'Gene', '2625', (94, 99))	('HER2', 'Gene', '2064', (169, 173))	('HER2', 'Gene', '2064', (12, 16))	('HER2', 'Gene', (123, 127))	('ER', 'Gene', '2069', (13, 15))	('HER2', 'Gene', '2064', (123, 127))	('ER', 'Gene', '2069', (0, 2))	('mutations', 'Var', (81, 90))	('ER', 'Gene', '2069', (124, 126))
210586	32220886	TP53 mutations were numerically more frequent in ER-negative/HER2-negative DCIS (100%) than in ER-positive/HER2-negative DCIS (24%; P>0.05) and HER2-positive DCIS (57%; P>0.05; Supplementary Fig.	('TP53', 'Gene', '7157', (0, 4))	('HER2', 'Gene', '2064', (107, 111))	('TP53', 'Gene', (0, 4))	('ER', 'Gene', '2069', (145, 147))	('ER', 'Gene', '2069', (95, 97))	('HER2', 'Gene', '2064', (61, 65))	('mutations', 'Var', (5, 14))	('ER', 'Gene', '2069', (108, 110))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', (61, 65))	('ER', 'Gene', '2069', (62, 64))	('HER2', 'Gene', '2064', (144, 148))	('DCIS', 'Disease', (75, 79))	('HER2', 'Gene', (107, 111))	('ER', 'Gene', '2069', (49, 51))
210590	32220886	Genes significantly mutated in IDC-NSTs, such as PIK3CA, TP53, AKT1 and PTEN, were also found to be frequently mutated in synchronous DCIS, indicating roles early in the evolution of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('IDC-NSTs', 'Disease', (31, 39))	('PTEN', 'Gene', (72, 76))	('AKT1', 'Gene', '207', (63, 67))	('mutated', 'Var', (111, 118))	('AKT1', 'Gene', (63, 67))	('PTEN', 'Gene', '5728', (72, 76))	('synchronous', 'Disease', (122, 133))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('PIK3CA', 'Gene', (49, 55))	('breast cancers', 'Disease', 'MESH:D001943', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancers', 'Disease', (183, 197))	('PIK3CA', 'Gene', '5290', (49, 55))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutated', 'Var', (20, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
210602	32220886	In multifocal DCIS Case 2, a subclone of 2DCISA, harboring a KDM5C E185Q mutation, became dominant in a separate DCIS focus (2DCISB), suggesting that 2DCISB stemmed from 2DCISA (Fig.	('KDM5C', 'Gene', '8242', (61, 66))	('KDM5C', 'Gene', (61, 66))	('E185Q', 'Var', (67, 72))	('E185Q', 'Mutation', 'p.E185Q', (67, 72))
210607	32220886	2C) harbored truncal PIK3CA (H1047R), TP53 (P278A) and ERBB2 (S310F) hotspot mutations and displayed clonal shifts, consistent with clonal selection in the progression to IDC-NST.	('H1047R', 'Var', (29, 35))	('TP53', 'Gene', (38, 42))	('H1047R', 'Mutation', 'p.H1047R', (29, 35))	('PIK3CA', 'Gene', '5290', (21, 27))	('PIK3CA', 'Gene', (21, 27))	('P278A', 'Var', (44, 49))	('IDC-NST', 'Disease', (171, 178))	('S310F', 'Var', (62, 67))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('P278A', 'Mutation', 'p.P278A', (44, 49))	('S310F', 'Mutation', 'rs1057519816', (62, 67))	('TP53', 'Gene', '7157', (38, 42))
210611	32220886	In multifocal DCIS Case 2 arising in a BRCA1 germline carrier (BRCA1 E23Vfs*17), despite different absolute number of copies, two foci of ER-negative/HER2-negative DCIS (2DCISA and 2DCISB) and of IDC-NST (2IDCA and 2IDCB) in the same breast quadrant harbored LOH of the wild-type allele of BRCA1 (Fig.	('BRCA1', 'Gene', '672', (63, 68))	('BRCA1', 'Gene', (290, 295))	('E23Vfs*', 'Var', (69, 76))	('BRCA1', 'Gene', (63, 68))	('E23Vfs*17', 'Mutation', 'p.E23VfsX17', (69, 78))	('HER2', 'Gene', (150, 154))	('BRCA1', 'Gene', '672', (39, 44))	('ER', 'Gene', '2069', (151, 153))	('HER2', 'Gene', '2064', (150, 154))	('BRCA1', 'Gene', '672', (290, 295))	('BRCA1', 'Gene', (39, 44))	('ER', 'Gene', '2069', (138, 140))
210612	32220886	16q loss and GNTAB and EZR mutations were private to 2IDCB, whereas mutations affecting GNAS and SOX2 mutations were private to 2IDCA (Fig.	('mutations', 'Var', (27, 36))	('GNAS', 'Gene', (88, 92))	('SOX2', 'Gene', '6657', (97, 101))	('SOX2', 'Gene', (97, 101))	('EZR', 'Gene', (23, 26))	('GNAS', 'Gene', '2778', (88, 92))	('EZR', 'Gene', '7430', (23, 26))	('loss', 'NegReg', (4, 8))
210621	32220886	Notably, methylation profiling of DCIS and adjacent invasive carcinoma support the notion that, also epigenetically, DCIS is an advanced lesion.	('methylation', 'Var', (9, 20))	('DCIS', 'Disease', (34, 38))	('invasive carcinoma', 'Disease', (52, 70))	('DCIS', 'Disease', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('invasive carcinoma', 'Disease', 'MESH:D009361', (52, 70))	('epigenetically', 'Var', (101, 115))
210623	32220886	Furthermore, amplification of CCND1 and MYC, found to display an increased amplitude in invasive carcinoma compared to DCIS, were restricted to the invasive component of a given case in our series.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('invasive carcinoma', 'Disease', 'MESH:D009361', (88, 106))	('MYC', 'Gene', '4609', (40, 43))	('CCND1', 'Gene', (30, 35))	('amplification', 'Var', (13, 26))	('invasive carcinoma', 'Disease', (88, 106))	('MYC', 'Gene', (40, 43))	('CCND1', 'Gene', '595', (30, 35))
210624	32220886	Previously reported higher frequencies of 5q31.1-5q35.3, 6q25.3-6q26 and 13q32.3-13q33.1 losses and 11p12 gains in DCIS compared to their synchronously identified invasive carcinoma, and a higher frequency of 1q, 8q and 11q gains in synchronous compared to pure DCIS could not be confirmed in our study.	('13q32.3-13q33.1', 'Var', (73, 88))	('5q31.1-5q35.3', 'Var', (42, 55))	('invasive carcinoma', 'Disease', (163, 181))	('DCIS', 'Disease', (115, 119))	('gains', 'PosReg', (106, 111))	('11p12', 'Gene', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('invasive carcinoma', 'Disease', 'MESH:D009361', (163, 181))
210625	32220886	Consistent with Sakr et al, all pure DCIS in our study lacked PIK3CA mutations.	('mutations', 'Var', (69, 78))	('PIK3CA', 'Gene', (62, 68))	('lacked', 'NegReg', (55, 61))	('PIK3CA', 'Gene', '5290', (62, 68))	('pure DCIS', 'Disease', (32, 41))
210626	32220886	These findings contrast the observations by Lin et al, who reported an enrichment in PIK3CA kinase domain mutations in pure compared to synchronous DCIS.	('PIK3CA', 'Gene', '5290', (85, 91))	('domain mutations', 'Var', (99, 115))	('PIK3CA', 'Gene', (85, 91))
210628	32220886	By performing clonal decomposition based on somatic mutations and a phylogenetic reconstruction based on copy number profiles of DCIS and synchronously diagnosed IDC-NSTs, we observed that both DCIS and IDC-NSTs are genetically heterogeneous and that progression to invasive carcinoma may follow different evolutionary pathways.	('mutations', 'Var', (52, 61))	('invasive carcinoma', 'Disease', (266, 284))	('invasive carcinoma', 'Disease', 'MESH:D009361', (266, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))
210654	25783182	Through co-culture experiments, we find that SK-treated preadipocytes secrete exosomes with high levels of miR-140, which can impact nearby DCIS cells through targeting SOX9 signaling.	('miR-140', 'Var', (107, 114))	('DCIS', 'Phenotype', 'HP:0030075', (140, 144))	('SOX9', 'Gene', '20682', (169, 173))	('impact', 'Reg', (126, 132))	('SK', 'Chemical', 'MESH:C016101', (45, 47))	('SOX9', 'Gene', (169, 173))	('targeting', 'Reg', (159, 168))
210680	25783182	Previous studies from our laboratory linked cell-cell signaling in DCIS stem-like cells to the exosomal trafficking of miRNAs and identified that epigenetic therapy can alter exosomal miRNA content.	('alter', 'Reg', (169, 174))	('epigenetic therapy', 'Var', (146, 164))	('miR', 'Gene', (119, 122))	('miR', 'Gene', '751557', (184, 187))	('miR', 'Gene', '751557', (119, 122))	('DCIS', 'Phenotype', 'HP:0030075', (67, 71))	('miR', 'Gene', (184, 187))
210772	25783182	DCIS cells treated with exosomes from miR-140-transfected 3T3L1 cells formed significantly fewer and smaller mammospheres compared to control exosomes (Fig.	('L1', 'CellLine', 'CVCL:S918', (61, 63))	('DCIS', 'Phenotype', 'HP:0030075', (0, 4))	('fewer', 'NegReg', (91, 96))	('smaller', 'NegReg', (101, 108))	('miR-140-transfected', 'Var', (38, 57))
210808	24511546	Oncogenic PIK3CA Mutation and Dysregulation in Human Salivary Duct Carcinoma Salivary duct carcinoma (SDC) is an aggressive malignant tumor with a high mortality, which resembles high-grade breast ductal carcinoma in morphology.	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PIK3CA', 'Gene', '5290', (10, 16))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (190, 213))	('Human', 'Species', '9606', (47, 52))	('Salivary Duct Carcinoma', 'Disease', (53, 76))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (197, 213))	('malignant tumor', 'Disease', (124, 139))	('malignant tumor', 'Disease', 'MESH:D018198', (124, 139))	('breast ductal carcinoma', 'Disease', (190, 213))	('SDC', 'Chemical', '-', (102, 105))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Dysregulation', 'Var', (30, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('PIK3CA', 'Gene', (10, 16))	('Mutation', 'Var', (17, 25))	('Salivary Duct Carcinoma', 'Disease', 'MESH:D012465', (53, 76))	('Salivary duct carcinoma', 'Disease', 'MESH:D012465', (77, 100))	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (190, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Salivary duct carcinoma', 'Disease', (77, 100))
210812	24511546	By DNA sequencing, two hotspot mutations of the PIK3CA gene, E545K (exon 9) and H1047R (exon 20), were identified in two of the six cases.	('E545K', 'Var', (61, 66))	('PIK3CA', 'Gene', (48, 54))	('H1047R', 'Mutation', 'rs121913279', (80, 86))	('PIK3CA', 'Gene', '5290', (48, 54))	('E545K', 'Mutation', 'rs104886003', (61, 66))	('H1047R', 'Var', (80, 86))
210820	24511546	Genetic alterations in the key components of the PI3 K pathway have been identified in diverse human tumors, including the PIK3CA gene.	('PI3', 'Gene', (49, 52))	('Genetic alterations', 'Var', (0, 19))	('human', 'Species', '9606', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('PIK3CA', 'Gene', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('identified', 'Reg', (73, 83))	('PIK3CA', 'Gene', '5290', (123, 129))	('PI3', 'Gene', '5266', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
210823	24511546	Most of these reported mutations are clustering in the exons 9 and 20 of the PIK3CA gene, where three hotspot mutations (E542 K, E545 K, and H1047R) reside.	('PIK3CA', 'Gene', (77, 83))	('E542 K', 'Mutation', 'rs121913273', (121, 127))	('E545 K', 'Mutation', 'rs104886003', (129, 135))	('PIK3CA', 'Gene', '5290', (77, 83))	('H1047R', 'Mutation', 'rs121913279', (141, 147))	('E542 K', 'Var', (121, 127))	('H1047R', 'Var', (141, 147))	('E545 K', 'Var', (129, 135))
210824	24511546	All those three PIK3CA hotspot mutations have been proven to be oncogenic and are associated with poor clinical outcomes.	('PIK3CA', 'Gene', (16, 22))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', '5290', (16, 22))
210826	24511546	Furthermore, SDC shares many similarities with breast ductal carcinoma both in histology and biology, in which frequent PIK3CA mutation has been identified in human breast cancer.	('breast ductal carcinoma', 'Disease', 'MESH:D018270', (47, 70))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('PIK3CA', 'Gene', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (54, 70))	('breast ductal carcinoma', 'Phenotype', 'HP:0003002', (47, 70))	('mutation', 'Var', (127, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('identified', 'Reg', (145, 155))	('human', 'Species', '9606', (159, 164))	('PIK3CA', 'Gene', '5290', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('breast ductal carcinoma', 'Disease', (47, 70))	('SDC', 'Chemical', '-', (13, 16))
210837	24511546	Specific primers for the PIK3CA gene exons 9 and 20 (PIK-E9F: CCAGAGGGGAAAAATATGACA; PIK-E9R: CATTTTAGCACTTACCTGTGAC; PIK-E20F: CATTTGCTCCAAACTGACCA; PIK-E20R: GGTCTTTGCCTGCTGAGAGT) were designed for efficient PCR amplification from paraffin-embedded specimens.	('paraffin', 'Chemical', 'MESH:D010232', (233, 241))	('E20F', 'Var', (122, 126))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('E20R', 'Mutation', 'p.E20R', (154, 158))	('E20F', 'SUBSTITUTION', 'None', (122, 126))
210856	24511546	Because it has been demonstrated that ~80% of the somatic mutations documented for PIK3CA clustered in the helical domain (exon 9) and kinase domain (exon 20), here we only analyzed the DNA sequences of the exons 9 and 20 of the PIK3CA gene.	('mutations', 'Var', (58, 67))	('PIK3CA', 'Gene', '5290', (229, 235))	('clustered', 'Reg', (90, 99))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('PIK3CA', 'Gene', (229, 235))
210857	24511546	The results showed that two hotspot mutations E545K and H1047R of the PIK3CA gene were identified in these six SDC specimens (33%).	('H1047R', 'Mutation', 'rs121913279', (56, 62))	('PIK3CA', 'Gene', '5290', (70, 76))	('PIK3CA', 'Gene', (70, 76))	('SDC', 'Chemical', '-', (111, 114))	('E545K', 'Mutation', 'rs104886003', (46, 51))	('E545K', 'Var', (46, 51))	('H1047R', 'Var', (56, 62))
210858	24511546	Hotspot mutation H1047R with a nucleotide 3140 A   G substitution in kinase domain at exon 20 of the PIK3CA gene was found in patient SDC2.	('H1047R', 'Mutation', 'rs121913279', (17, 23))	('PIK3CA', 'Gene', '5290', (101, 107))	('patient', 'Species', '9606', (126, 133))	('H1047R', 'Var', (17, 23))	('SDC2', 'Gene', '6383', (134, 138))	('SDC2', 'Gene', (134, 138))	('PIK3CA', 'Gene', (101, 107))
210859	24511546	Hotspot mutation E545K with a nucleotide 1633 G   A alteration in the helical domain at exon 9 of PIK3CA was identified in patient SDC3.	('alteration', 'Reg', (52, 62))	('SDC3', 'Gene', (131, 135))	('patient', 'Species', '9606', (123, 130))	('PIK3CA', 'Gene', (98, 104))	('SDC3', 'Gene', '9672', (131, 135))	('E545K', 'Mutation', 'rs104886003', (17, 22))	('PIK3CA', 'Gene', '5290', (98, 104))	('E545K', 'Var', (17, 22))	('nucleotide 1633 G', 'Var', (30, 47))
210861	24511546	These two hotspot mutations have been previously shown to promote lipid kinase activity and enhance its downstream Akt signaling pathway, suggesting their strong relevance in human tumorigenesis.	('human', 'Species', '9606', (175, 180))	('Akt', 'Gene', '207', (115, 118))	('tumor', 'Disease', (181, 186))	('lipid kinase', 'Enzyme', (66, 78))	('Akt', 'Gene', (115, 118))	('promote', 'PosReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('enhance', 'PosReg', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutations', 'Var', (18, 27))
210872	24511546	Furthermore, we detected high incidence of PIK3CA hotspot mutations in SDC patients (33%) (4%, 78%; 95% confidence limits).	('mutations', 'Var', (58, 67))	('PIK3CA', 'Gene', '5290', (43, 49))	('patients', 'Species', '9606', (75, 83))	('SDC', 'Chemical', '-', (71, 74))	('hotspot', 'PosReg', (50, 57))	('PIK3CA', 'Gene', (43, 49))	('SDC', 'Disease', (71, 74))
210873	24511546	The two PIK3CA hotspot mutations (E545 K and H1047R) are located at the helical domain and the kinase domain of the PIK3CA protein, respectively (Figure 2).	('PIK3CA', 'Gene', (116, 122))	('H1047R', 'Var', (45, 51))	('H1047R', 'Mutation', 'rs121913279', (45, 51))	('PIK3CA', 'Gene', '5290', (116, 122))	('E545 K', 'Mutation', 'rs104886003', (34, 40))	('PIK3CA', 'Gene', (8, 14))	('E545 K', 'Var', (34, 40))	('PIK3CA', 'Gene', '5290', (8, 14))
210875	24511546	These data are consistent with recent studies that reported PIK3CA mutations in patients with SDC.	('patients', 'Species', '9606', (80, 88))	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('SDC', 'Chemical', '-', (94, 97))	('mutations', 'Var', (67, 76))	('SDC', 'Disease', (94, 97))
210879	24511546	Clinical data indicates that SDC2 with hotspot mutation H1047R in PIK3CA kinase domain was a 65-year-old male patient.	('H1047R', 'Mutation', 'rs121913279', (56, 62))	('SDC2', 'Gene', '6383', (29, 33))	('SDC2', 'Gene', (29, 33))	('PIK3CA', 'Gene', (66, 72))	('patient', 'Species', '9606', (110, 117))	('PIK3CA', 'Gene', '5290', (66, 72))	('H1047R', 'Var', (56, 62))
210880	24511546	SDC3 patient with hotspot mutation E545 K was the only female patient and was also diagnosed at 50 years-old, which is the youngest among this SDC cohort.	('SDC', 'Chemical', '-', (143, 146))	('patient', 'Species', '9606', (5, 12))	('SDC', 'Chemical', '-', (0, 3))	('E545 K', 'Var', (35, 41))	('patient', 'Species', '9606', (62, 69))	('E545 K', 'Mutation', 'rs104886003', (35, 41))	('SDC3', 'Gene', (0, 4))	('SDC3', 'Gene', '9672', (0, 4))
210881	24511546	Both patients with hotspot PIK3CA mutations were featured with perineural invasion and many lymph nodule metastases.	('PIK3CA', 'Gene', '5290', (27, 33))	('patients', 'Species', '9606', (5, 13))	('metastases', 'Disease', (105, 115))	('PIK3CA', 'Gene', (27, 33))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('mutations', 'Var', (34, 43))	('perineural invasion', 'CPA', (63, 82))
210884	24511546	Oncogenic PIK3CA is mainly activated through gene amplification and "gain of function" single-nucleotide substitution in human cancers.	('PIK3CA', 'Gene', '5290', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('single-nucleotide substitution', 'Var', (87, 117))	('gene amplification', 'Var', (45, 63))	('PIK3CA', 'Gene', (10, 16))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
210892	24511546	Here we report high PIK3CA mutation rates in this rare disease with high mortality.	('mutation', 'Var', (27, 35))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))
210896	21736894	The role of the microenvironment in tumor growth and invasion Mathematical modeling and computational analysis are essential for understanding the dynamics of the complex gene networks that control normal development and homeostasis, and can help to understand how circumvention of that control leads to abnormal outcomes such as cancer.	('leads to', 'Reg', (295, 303))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('circumvention', 'Var', (265, 278))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))	('tumor', 'Disease', (36, 41))
210900	21736894	The results emphasize anew the complexities of the interactions within the TME and their effect on tumor growth, and show that tumor progression is not solely determined by the presence of a clone of mutated immortal cells, but rather that it can be 'community-controlled'.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (127, 132))	('interactions', 'Interaction', (51, 63))	('mutated', 'Var', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
210902	21736894	Maintenance of homeostasis at the tissue level involves the tissue-wide integration of and response to signals from within the tissue and its surroundings, and disruption at any of the detection, transduction or response steps may lead to neoplastic growth, i.e., abnormal, unchecked growth of the tissue, producing what is called a neoplasm or tumor.	('neoplasm', 'Phenotype', 'HP:0002664', (333, 341))	('lead to', 'Reg', (231, 238))	('disruption', 'Var', (160, 170))	('neoplastic growth', 'CPA', (239, 256))	('du', 'Chemical', '-', (309, 311))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('du', 'Chemical', '-', (201, 203))	('neoplasm or tumor', 'Disease', (333, 350))	('neoplasm or tumor', 'Disease', 'MESH:D009369', (333, 350))	('producing', 'Reg', (306, 315))
210974	21736894	Moreover, stress is necessary for the development of FAs, because inhibition of myosin II via over-expression of a myosin ATPase inhibitor blocks the maturation of FCs into mature FAs.	('FAs', 'Chemical', 'MESH:C038178', (53, 56))	('ATP', 'Chemical', 'MESH:D000255', (122, 125))	('over-expression', 'PosReg', (94, 109))	('inhibition', 'Var', (66, 76))	('maturation of FCs into mature FAs', 'CPA', (150, 183))	('blocks', 'NegReg', (139, 145))	('FAs', 'Chemical', 'MESH:C038178', (180, 183))
211040	21736894	phi(x) is the characteristic function of the tumor: phi(x) = 1 inside the tumor and phi(x) = 0 in the agarose, and the subscripts on Da/t reflect the fact that the diffusion coefficient is different in the tumor than in the surrounding agarose.	('agarose', 'Chemical', 'MESH:D012685', (236, 243))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('phi', 'Var', (84, 87))	('diffusion coefficient', 'MPA', (164, 185))	('different', 'Reg', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('agarose', 'Chemical', 'MESH:D012685', (102, 109))	('tumor', 'Disease', (74, 79))	('phi', 'Var', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
211042	21736894	Various models of growing biological tissues incorporate growth by postulating a multiplicative decomposition of the deformation gradient   where X represents a material coordinate point, into a part that describes growth and a part that describes deformations due to incompatible local growth and any externally applied tractions or body forces.	('du', 'Chemical', '-', (261, 263))	('deformations', 'Disease', 'MESH:D009140', (248, 260))	('incompatible', 'Var', (268, 280))	('deformations', 'Disease', (248, 260))
211106	21736894	Therefore, the model described here is able to capture the inhomogeneous deformations that have been observed experimentally, despite the fact that here the deformations are caused by inhomogeneity of material properties, while in inhomogeneous growth is induced by the shape of the capillary.	('deformations', 'Disease', 'MESH:D009140', (157, 169))	('du', 'Chemical', '-', (257, 259))	('deformations', 'Disease', (73, 85))	('deformations', 'Disease', 'MESH:D009140', (73, 85))	('inhomogeneity', 'Var', (184, 197))	('caused by', 'Reg', (174, 183))	('deformations', 'Disease', (157, 169))
211110	21736894	Therefore, inhomogeneous growth rates inside the tumor lead to non-negligible shear stresses, which may impact local tumor growth rates.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('non-negligible shear stresses', 'MPA', (63, 92))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (49, 54))	('impact', 'Reg', (104, 110))	('inhomogeneous', 'Var', (11, 24))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
211115	21736894	However, mutations in the TGF-beta signaling pathways are relatively rare in breast cancers - instead there are more subtle changes in the balance between the growth-inhibiting effect of TGF-beta and the growth-promoting effects of other factors.	('breast cancers', 'Disease', 'MESH:D001943', (77, 91))	('breast cancers', 'Disease', (77, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('mutations', 'Var', (9, 18))	('TGF-beta', 'Gene', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancers', 'Phenotype', 'HP:0003002', (77, 91))	('changes', 'Reg', (124, 131))	('TGF-beta', 'Gene', (26, 34))	('growth-inhibiting', 'CPA', (159, 176))
211116	21736894	These include regulation of the levels of transcriptional co-repressors or co-activators involved in the Smad pathway, and epigenetic regulation of critical steps in the progression to cancer.	('Smad pathway', 'Pathway', (105, 117))	('levels of transcriptional co-repressors', 'MPA', (32, 71))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('regulation', 'Reg', (14, 24))	('epigenetic regulation', 'Var', (123, 144))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
211293	21736894	Monocytes remain in the blood stream for a short time and then migrate to tissues and mature into macrophages monocyte chemotactic protein-1 (MCP-1) chemotactic and activating signal for monocytes, expressed mainly by tumor cells as well as ECs, fibroblasts, and macrophages mural cell A smooth muscle cell or pericyte mutation Any change in the genetic information relative to a reference "wild-type" genome, including changes that affect expression of genes without altering their coding sequences and changes that do not cause any detectable phenotypic difference (silent mutations).	('changes', 'Var', (420, 427))	('change', 'Reg', (332, 338))	('monocyte chemotactic protein-1', 'Gene', (110, 140))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('expression of genes', 'MPA', (440, 459))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('MCP-1', 'Gene', (142, 147))	('monocyte chemotactic protein-1', 'Gene', '6347', (110, 140))	('tumor', 'Disease', (218, 223))	('affect', 'Reg', (433, 439))	('MCP-1', 'Gene', '6347', (142, 147))
211294	21736894	Chromosomal mutations involve deletion, inversion, duplication, or other changes of a portion of a chromosome nectins Nectins and nectin-like molecules (Necls) are immunoglobulin-like transmembrane cell adhesion molecules expressed in various cell types neoplasia The abnormal, uncontrolled proliferation of cells, usually uncoordinated with that of the normal tissue around it neoplasm A solid lesion formed by neoplastic growth of cells It usually causes a lump or tumor.	('tumor', 'Phenotype', 'HP:0002664', (467, 472))	('du', 'Chemical', '-', (51, 53))	('inversion', 'Var', (40, 49))	('neoplasia', 'Disease', 'MESH:D009369', (254, 263))	('tumor', 'Disease', (467, 472))	('neoplasm', 'Disease', 'MESH:D009369', (378, 386))	('lump', 'Disease', (459, 463))	('neoplasm', 'Phenotype', 'HP:0002664', (378, 386))	('neoplasia', 'Phenotype', 'HP:0002664', (254, 263))	('deletion', 'Var', (30, 38))	('neoplasia', 'Disease', (254, 263))	('duplication', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (467, 472))	('neoplasm', 'Disease', (378, 386))
211296	21736894	A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression platelet-derived growth factor (PDGF) a protein, produced by platelets and other cells, that strongly stimulates cell growth and division and is involved in mural cell recruitment in angiogenesis p53 a tumor suppressor protein involved in regulation of the cell cycle ras A small G-protein involved in many signal transduction pathways somatic mutation a heritable change in the DNA that can be passed to the progeny of the mutated cell in the course of cell division.	('p53', 'Gene', (299, 302))	('p53', 'Gene', '7157', (299, 302))	('du', 'Chemical', '-', (62, 64))	('du', 'Chemical', '-', (155, 157))	('du', 'Chemical', '-', (422, 424))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('mutation', 'Var', (447, 455))	('cell growth', 'CPA', (216, 227))	('tumor', 'Disease', (305, 310))	('division', 'CPA', (232, 240))	('stimulates', 'PosReg', (205, 215))
211346	18681955	Of note, low ER-positive or PR-positive (1 to 10% of tumour cell nuclei staining) and ER-positive or PR-positive (>10% of tumour cell nuclei staining) were catagorised as a single "positive" category for the purposes of this analysis.	('PR', 'Gene', '5241', (28, 30))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('ER-positive', 'Var', (86, 97))	('tumour', 'Disease', (53, 59))	('PR', 'Gene', '5241', (101, 103))	('tumour', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
211362	18681955	Women with DCIS were slightly younger when they first gave birth (24.9 vs. 25.4, p = 0.05), were more likely to report a family history of breast cancer (19.0 vs 13.3%; p = 0.02) and a previous benign breast disease (57.0 vs 44.8%; p = 0.0001) compared with women with invasive breast cancer.	('Women', 'Species', '9606', (0, 5))	('benign breast disease', 'Disease', 'MESH:D001941', (194, 215))	('benign breast disease', 'Disease', (194, 215))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('invasive breast cancer', 'Disease', (269, 291))	('DCIS', 'Phenotype', 'HP:0030075', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('DCIS', 'Var', (11, 15))	('women', 'Species', '9606', (258, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('invasive breast cancer', 'Disease', 'MESH:D001943', (269, 291))
211374	18681955	High-nuclear-grade DCIS was significantly more likely than low-grade or intermediate-grade lesions to be HER2 type (p < 0.0001) and basal-like (p = 0.009).	('High-nuclear-grade', 'Var', (0, 18))	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', '2064', (105, 109))	('DCIS', 'Disease', (19, 23))	('DCIS', 'Phenotype', 'HP:0030075', (19, 23))
211385	18681955	Our finding of an increased prevalence of luminal B and HER2 molecular subtypes (ie, HER2-positive) in DCIS is consistent with earlier studies demonstrating a higher prevalence of HER2 protein overexpression and gene amplification among DCIS than invasive breast cancers.	('HER2', 'Gene', (56, 60))	('overexpression', 'PosReg', (193, 207))	('gene amplification', 'Var', (212, 230))	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (56, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('HER2', 'Gene', '2064', (180, 184))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('DCIS', 'Phenotype', 'HP:0030075', (103, 107))	('DCIS', 'Phenotype', 'HP:0030075', (237, 241))	('HER2', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('HER2', 'Gene', '2064', (85, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (256, 270))	('invasive breast cancers', 'Disease', (247, 270))	('invasive breast cancers', 'Disease', 'MESH:D001943', (247, 270))
211409	18681955	In addition, the frequency of receptor status positivity among invasive tumours was very similar to other populations suggesting that samples included in this study are representative of the overall US population.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('invasive tumours', 'Disease', (63, 79))	('positivity', 'Var', (46, 56))	('invasive tumours', 'Disease', 'MESH:D009361', (63, 79))
211423	29963116	Microinvasive carcinoma was significantly associated with DCIS with a large extent, high nuclear grade, necrosis, and comedotype architectural pattern.	('Microinvasive carcinoma', 'Disease', (0, 23))	('high', 'Var', (84, 88))	('DCIS', 'Disease', (58, 62))	('comedo', 'Phenotype', 'HP:0025249', (118, 124))	('associated', 'Reg', (42, 52))	('necrosis', 'Disease', (104, 112))	('DCIS', 'Phenotype', 'HP:0030075', (58, 62))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('Microinvasive carcinoma', 'Disease', 'MESH:D002277', (0, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
211477	29963116	Patients with multifocal microinvasion tended to exhibit a higher Ki-67 proliferation index than those with a single microinvasion (43.9% vs. 28.4%, p=0.078).	('microinvasion', 'Var', (25, 38))	('Patients', 'Species', '9606', (0, 8))	('multifocal', 'Var', (14, 24))	('higher', 'PosReg', (59, 65))	('Ki-67 proliferation index', 'CPA', (66, 91))
211478	29963116	In the univariate analysis, large tumor extent (greater than 3.2 cm), high nuclear grade, necrosis, comedo type, negative ER, negative PR, positive HER2 status, p53 overexpression, and high Ki-67 proliferation index were found to be predictive factors of microinvasion (all p<0.001).	('negative', 'NegReg', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('necrosis', 'Disease', (90, 98))	('ER', 'Gene', '2099', (149, 151))	('PR', 'Gene', '5241', (135, 137))	('microinvasion', 'Disease', (255, 268))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('overexpression', 'PosReg', (165, 179))	('high', 'Var', (70, 74))	('p53', 'Gene', (161, 164))	('ER', 'Gene', '2099', (122, 124))	('comedo', 'Phenotype', 'HP:0025249', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('p53', 'Gene', '7157', (161, 164))
211489	29963116	In this study, we observed that microinvasive carcinomas were frequently accompanied by DCIS with large extent, high nuclear grade, necrosis, and comedo-type architectural pattern.	('microinvasive carcinoma', 'Disease', (32, 55))	('accompanied', 'Reg', (73, 84))	('comedo', 'Phenotype', 'HP:0025249', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('necrosis', 'Disease', (132, 140))	('high', 'Var', (112, 116))	('microinvasive carcinoma', 'Disease', 'MESH:D002277', (32, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('necrosis', 'Disease', 'MESH:D009336', (132, 140))	('DCIS', 'Disease', (88, 92))	('invasive carcinomas', 'Disease', (37, 56))	('invasive carcinomas', 'Disease', 'MESH:D009361', (37, 56))	('DCIS', 'Phenotype', 'HP:0030075', (88, 92))
211495	29963116	Lari and Kuerer found that ER/PR expression was frequently associated with low-grade DCIS and that the expression of these markers was associated with a lower rate of local recurrence.	('low-grade DCIS', 'Disease', (75, 89))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('expression', 'Var', (33, 43))	('ER', 'Gene', '2099', (27, 29))	('associated', 'Reg', (59, 69))	('PR', 'Gene', '5241', (30, 32))	('local', 'CPA', (167, 172))
211498	29963116	Moreover, we observed a significantly higher rate of HER2 positivity in microinvasive carcinoma compared with pure DCIS.	('microinvasive carcinoma', 'Disease', 'MESH:D002277', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('positivity', 'Var', (58, 68))	('HER2', 'Protein', (53, 57))	('DCIS', 'Phenotype', 'HP:0030075', (115, 119))	('microinvasive carcinoma', 'Disease', (72, 95))
211502	29963116	This finding is in agreement with our study results because we observed a significantly higher rate of HER2 positivity in microinvasive carcinoma than in pure DCIS.	('higher', 'PosReg', (88, 94))	('HER2', 'Protein', (103, 107))	('microinvasive carcinoma', 'Disease', (122, 145))	('positivity', 'Var', (108, 118))	('microinvasive carcinoma', 'Disease', 'MESH:D002277', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))
211503	29963116	Traditionally, HER2 amplification and/or overexpression are more frequently associated with DCIS than with invasive carcinoma.	('HER2', 'Protein', (15, 19))	('invasive carcinoma', 'Disease', (107, 125))	('associated', 'Reg', (76, 86))	('DCIS', 'Disease', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('amplification', 'Var', (20, 33))	('overexpression', 'PosReg', (41, 55))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('invasive carcinoma', 'Disease', 'MESH:D009361', (107, 125))
211510	29963116	However, similar to our results, Kapoor et al., in their study of 45 patients with microinvasive carcinoma, reported a trend toward lymph node metastasis in patients with multifocal microinvasion compared with those with unifocal disease.	('microinvasive carcinoma', 'Disease', 'MESH:D002277', (83, 106))	('lymph node metastasis', 'CPA', (132, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('multifocal', 'Var', (171, 181))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (157, 165))	('microinvasive carcinoma', 'Disease', (83, 106))
211518	29963116	As in a previous study that reported that patients with triple-negative DCIS had a higher risk of developing invasive breast cancer, the only factor found to be associated with tumor recurrence, either all types of recurrence or invasive recurrence, was the triple-negative subtype.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('invasive breast cancer', 'Disease', 'MESH:D001943', (109, 131))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('DCIS', 'Phenotype', 'HP:0030075', (72, 76))	('triple-negative', 'Var', (56, 71))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('invasive breast cancer', 'Disease', (109, 131))
211519	29963116	reported that patients with triple-negative breast carcinoma in situ (BCIS) had decreased breast cancer-specific and overall survivals compared with patients with hormone receptor-positive/HER2-negative BCIS, which suggests that tumor subtype has a significant effect on the clinical outcomes of patients with BCIS as well.	('breast carcinoma in situ', 'Disease', (44, 68))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast carcinoma', 'Phenotype', 'HP:0003002', (44, 60))	('hormone receptor', 'Gene', '3164', (163, 179))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (149, 157))	('decreased', 'NegReg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (51, 68))	('breast carcinoma in situ', 'Disease', 'MESH:D000071960', (44, 68))	('hormone receptor', 'Gene', (163, 179))	('triple-negative', 'Var', (28, 43))	('tumor', 'Disease', (229, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('patients', 'Species', '9606', (296, 304))	('overall survivals', 'CPA', (117, 134))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
211526	29963116	This study also indicates that patients with triple-negative DCIS or microinvasive carcinoma need close follow-up because such cancers are associated with tumor recurrence, especially invasive recurrence.	('DCIS', 'Disease', (61, 65))	('microinvasive carcinoma', 'Disease', 'MESH:D002277', (69, 92))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('triple-negative', 'Var', (45, 60))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('associated', 'Reg', (139, 149))	('patients', 'Species', '9606', (31, 39))	('cancers', 'Disease', (127, 134))	('microinvasive carcinoma', 'Disease', (69, 92))	('invasive recurrence', 'Disease', (184, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
75977	22252842	The next day, DCs were pulsed with 6 HER-2/neu MHC class II promiscuous-binding peptides (42-56, 98-114, 328-345, 776-790, 927-941, 1166-1180).	('HER-2/neu', 'Gene', (37, 46))	('328-345', 'Var', (105, 112))	('HER-2/neu', 'Gene', '2064', (37, 46))	('42-56', 'Var', (90, 95))
211638	20064251	Enzymes involved in redox regulation and DNA repair dissipate ROS and repair the resulting damage in order to preserve a functional cellular environment.	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('ROS', 'MPA', (62, 65))	('dissipate', 'Var', (52, 61))	('damage', 'MPA', (91, 97))
211659	20064251	The histone H2AX is rapidly phosphorylated when double-stranded breaks are formed and subsequently acts to recruit DNA repair proteins.	('histone H2AX', 'Gene', (4, 16))	('histone H2AX', 'Gene', '3014', (4, 16))	('double-stranded breaks', 'Var', (48, 70))
211661	20064251	Because it seemed possible that dysregulation of any one of these proteins might result in increased ROS accumulation and/or unrepaired DNA damage and could feasibly promote oncogenesis, we examined their expression as well as the damage markers 8-OxoG, gamma-H2AX and nitrotyrosine, in normal mammary tissue, BH, DCIS and IBC.	('dysregulation', 'Var', (32, 45))	('gamma-H2AX', 'Chemical', '-', (254, 264))	('oncogenesis', 'CPA', (174, 185))	('IBC', 'Chemical', '-', (323, 326))	('BH', 'Chemical', '-', (310, 312))	('nitrotyrosine', 'Chemical', 'MESH:C002744', (269, 282))	('8-OxoG', 'Chemical', 'MESH:C024829', (246, 252))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('accumulation', 'PosReg', (105, 117))	('increased', 'PosReg', (91, 100))	('ROS', 'Protein', (101, 104))	('DCIS', 'Phenotype', 'HP:0030075', (314, 318))	('promote', 'PosReg', (166, 173))	('increased ROS accumulation', 'Phenotype', 'HP:0025464', (91, 117))
211667	20064251	Slides were washed with 1x PBS and endogenous peroxidases were blocked with 1.5% hydrogen peroxide in 1x PBS for 20 min at 25 C. After three 5 min washes in 1x PBS, slides were incubated in blocking solution (1x PBS with 0.1% Triton X-100, 3% bovine serum albumin) with 5% normal donkey serum for 10 min at 25 C. Control (no primary antibody) and experimental slides were incubated overnight at 4 C, respectively, in blocking solution alone or blocking solution with SOD1 (1:400, sc-11407; Santa Cruz Biotechnology, Santa Cruz CA), Ape1/Ref-1 (1:400, sc-17774; Santa Cruz Biotechnology, Santa Cruz CA), PDI (1:200, sc-30932; Santa Cruz Biotechnology, Santa Cruz CA), Trx (1:400, ab16835; Abcam, Cambridge MA), TrxR (1:400, ab16840; Abcam, Cambridge MA), NM23-H1 (1:400, sc-343; Santa Cruz Biotechnology, Santa Cruz CA), MPG (1:600, ab55461; Abcam, Cambridge MA), 8-oxoguanine (1:400, ab64548; Abcam, Cambridge MA), gamma-H2AX (1:1000, ab2893; Abcam, Cambridge MA), or nitrotyrosine (1:800, 06-284; Millipore, Billerica MA) antibody.	('1:400', 'Var', (763, 768))	('bovine', 'Species', '9913', (243, 249))	('PDI', 'Gene', (603, 606))	('donkey', 'Species', '9793', (280, 286))	('PBS', 'Chemical', 'MESH:D007854', (27, 30))	('TrxR', 'Gene', (710, 714))	('PBS', 'Chemical', 'MESH:D007854', (105, 108))	('Ref-1', 'Gene', (537, 542))	('SOD1', 'Gene', (467, 471))	('SOD1', 'Gene', '6647', (467, 471))	('NM23-H1', 'Gene', '4830', (754, 761))	('gamma-H2AX', 'Chemical', '-', (915, 925))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (863, 875))	('PBS', 'Chemical', 'MESH:D007854', (160, 163))	('nitrotyrosine', 'Chemical', 'MESH:C002744', (968, 981))	('1:1000', 'Var', (927, 933))	('NM23-H1', 'Gene', (754, 761))	('TrxR', 'Gene', '25824', (710, 714))	('Trx', 'Gene', '7295', (667, 670))	('1:400', 'Var', (877, 882))	('MPG', 'Gene', '4350', (820, 823))	('Trx', 'Gene', (667, 670))	('MPG', 'Gene', (820, 823))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (81, 98))	('PDI', 'Gene', '5034', (603, 606))	('PBS', 'Chemical', 'MESH:D007854', (212, 215))	('Ape1', 'Gene', '328', (532, 536))	('Ref-1', 'Gene', '328', (537, 542))	('Trx', 'Gene', '7295', (710, 713))	('Ape1', 'Gene', (532, 536))	('Trx', 'Gene', (710, 713))
211710	20064251	While this at first may seem counter intuitive, increased expression of SOD1 in IBC would, in fact, decrease superoxide levels, which would in turn diminish superoxide-induced protein damage (Fig.	('increased', 'PosReg', (48, 57))	('diminish', 'NegReg', (148, 156))	('SOD1', 'Gene', (72, 76))	('IBC', 'Chemical', '-', (80, 83))	('SOD1', 'Gene', '6647', (72, 76))	('superoxide levels', 'MPA', (109, 126))	('expression', 'Var', (58, 68))	('decrease', 'NegReg', (100, 108))	('superoxide', 'Chemical', 'MESH:D013481', (109, 119))	('superoxide', 'Chemical', 'MESH:D013481', (157, 167))	('decrease superoxide levels', 'Phenotype', 'HP:0031837', (100, 126))	('superoxide-induced protein damage', 'MPA', (157, 190))
211731	20064251	The DNA glycosylase MPG recognizes and excises damaged bases in DNA resulting in the production of an apurinic site.	('production of an apurinic site', 'MPA', (85, 115))	('MPG', 'Gene', (20, 23))	('damaged bases', 'Var', (47, 60))	('MPG', 'Gene', '4350', (20, 23))
211733	20064251	Furthermore, MPG null cells have chromosomal aberrations and increased apoptosis.	('MPG', 'Gene', (13, 16))	('apoptosis', 'CPA', (71, 80))	('increased', 'PosReg', (61, 70))	('chromosomal aberrations', 'Var', (33, 56))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (33, 56))	('MPG', 'Gene', '4350', (13, 16))
211736	20064251	In addition to its role in redox regulation, Ape1/Ref-1 recognizes abasic sites produced by DNA glycosylases and nicks the DNA backbone to continue the DNA repair process.	('Ape1', 'Gene', (45, 49))	('Ref-1', 'Gene', (50, 55))	('Ape1', 'Gene', '328', (45, 49))	('nicks', 'NegReg', (113, 118))	('abasic', 'Var', (67, 73))	('Ref-1', 'Gene', '328', (50, 55))
211756	20064251	Thus, targeting these proteins may provide an additional method of sensitizing cancer cells prior to administration of chemotherapeutic agents and aid in the development of more effective treatment regimes.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('targeting', 'Var', (6, 15))	('proteins', 'Protein', (22, 30))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
211759	20064251	This work was supported by NIH grants R01 DK53884 and R56 DK 53884 (to AMN).	('R56 DK 53884', 'Var', (54, 66))	('AMN', 'Disease', (71, 74))	('AMN', 'Disease', 'MESH:D000326', (71, 74))
211784	33452133	Vogelstein's group has shown that nutrient deprivation, specifically limiting (0.2 mM) glucose, promoted the outgrowth of pancreatic cancer cells that express mutant k-ras and a WE phenotype in mixed starting cultures, although de novo selection was not shown.	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('mutant', 'Var', (159, 165))	('k-ras', 'Gene', '3845', (166, 171))	('k-ras', 'Gene', (166, 171))	('outgrowth', 'CPA', (109, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('promoted', 'PosReg', (96, 104))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
211810	33452133	These results indicated that the harsh microenvironmental conditions similar to those found in early DCIS select for a WE (aerobic glycolytic) phenotype; more specifically, the combination of low glucose, low oxygen, and low pH or starvation provide the greatest selective pressure for a WE phenotype.	('oxygen', 'Chemical', 'MESH:D010100', (209, 215))	('low', 'Var', (192, 195))	('DCIS', 'Phenotype', 'HP:0030075', (101, 105))	('glucose', 'Chemical', 'MESH:D005947', (196, 203))	('select', 'Reg', (106, 112))
211833	33452133	S10 shows that the total amount of NFkappaB was slightly, but significantly, higher in the UF clones relative to control clones (C clones).	('clones', 'Var', (94, 100))	('higher', 'PosReg', (77, 83))	('NFkappaB', 'Gene', (35, 43))	('UF clones', 'Var', (91, 100))	('NFkappaB', 'Gene', '4790', (35, 43))
211839	33452133	In UF18 cells, knockdown of p65 significantly reduced aerobic glycolysis (SI Appendix, Fig.	('p65', 'Gene', '5970', (28, 31))	('knockdown', 'Var', (15, 24))	('aerobic glycolysis', 'MPA', (54, 72))	('reduced', 'NegReg', (46, 53))	('p65', 'Gene', (28, 31))
211842	33452133	S10A), which were also consistent with increased aerobic glycolysis in the UF cells.	('increased', 'PosReg', (39, 48))	('aerobic glycolysis', 'MPA', (49, 67))	('S10A', 'Var', (0, 4))	('S10A', 'SUBSTITUTION', 'None', (0, 4))
211859	33452133	Previous research has shown evidence of driver mutations, such as p53 and KRAS, up-regulating the WE phenotype in different cancer types; however, none of these mutation-driven WE phenotypes are consistently present in all cancer cells.	('up-regulating', 'PosReg', (80, 93))	('cancer', 'Disease', (124, 130))	('p53', 'Gene', '7157', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('KRAS', 'Gene', (74, 78))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('WE phenotype', 'MPA', (98, 110))	('KRAS', 'Gene', '3845', (74, 78))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('p53', 'Gene', (66, 69))
211878	33452133	Three unique 27-mer RELA human siRNA oligo duplexes (SR304030A, B, and C) were obtained from Origene (SR304030).	('SR304030A', 'Chemical', '-', (53, 62))	('RELA', 'Gene', (20, 24))	('human', 'Species', '9606', (25, 30))	('RELA', 'Gene', '5970', (20, 24))	('SR304030', 'Var', (102, 110))	('SR304030', 'Chemical', '-', (53, 61))	('SR304030A', 'Var', (53, 62))	('SR304030', 'Chemical', '-', (102, 110))
211893	33452133	Compensatory glycolysis is the maximum possible rate of glycolysis in cells following inhibition of oxidative phosphorylation with rotenone/antimycin.	('rotenone', 'Chemical', 'MESH:D012402', (131, 139))	('oxidative', 'MPA', (100, 109))	('Compensatory', 'MPA', (0, 12))	('inhibition', 'Var', (86, 96))	('antimycin', 'Chemical', 'MESH:C032456', (140, 149))
211961	33150682	For the breast cancer cohort, 13 patients had DCIS, 31 patients had lymph node metastasis-negative breast cancer that was not DCIS, and 27 patients had lymph node metastasis-positive breast cancer that was not DCIS.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('DCIS', 'Phenotype', 'HP:0030075', (126, 130))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('metastasis-positive breast cancer', 'Disease', 'MESH:D001943', (163, 196))	('metastasis-negative breast cancer', 'Disease', (79, 112))	('breast cancer', 'Disease', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('metastasis-positive breast cancer', 'Disease', (163, 196))	('DCIS', 'Phenotype', 'HP:0030075', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('metastasis-negative breast cancer', 'Disease', 'MESH:D001943', (79, 112))	('patients', 'Species', '9606', (139, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('DCIS', 'Phenotype', 'HP:0030075', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (55, 63))	('DCIS', 'Var', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
211979	33150682	Gene and/or protein changes due to tumor growth may lead to peroxidation of the cell membrane species, which emit VOCs.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('peroxidation of the cell membrane species', 'MPA', (60, 101))	('protein', 'Protein', (12, 19))	('changes', 'Var', (20, 27))	('lead to', 'Reg', (52, 59))
212000	33150682	Currently, mammography is the most popular method used for breast cancer detection, which may cause radiation-induced mutations to participants due to the use of X-rays.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (118, 127))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cause', 'Reg', (94, 99))	('participants', 'Species', '9606', (131, 143))
212038	23778411	We applied the following antibodies and dilutions: SP1 1:500 (Thermo Scientific, Waltharm, MA, USA), PgR636 1:1000 (Dako, Carpeteria, CA, USA), SP3 1:100 (Thermo Scientific), D5/16B4 1:100 (Dako) and 31G7 1:200 (Zymed, San Francisco, CA, USA).	('D5/16B4', 'Var', (175, 182))	('31G7 1:200', 'Var', (200, 210))	('PgR', 'Gene', (101, 104))	('SP3 1:100', 'Var', (144, 153))	('PgR', 'Gene', '5241', (101, 104))	('SP1 1:500', 'Var', (51, 60))
212071	23778411	Our findings suggest a possible utility of basal CK 5/6 for selecting patients with low-grade DCIS who can be spared radiation treatment without increasing the risk of invasive disease.	('patients', 'Species', '9606', (70, 78))	('CK 5/6', 'Gene', (49, 55))	('CK 5/6', 'Gene', '3852', (49, 55))	('invasive disease', 'Disease', (168, 184))	('DCIS', 'Disease', (94, 98))	('low-grade', 'Var', (84, 93))	('invasive disease', 'Disease', 'MESH:D009362', (168, 184))
212080	23778411	However, triple-positive profile was predominant in the high-grade pure DCIS group compared with the high-grade DCIS/IBC group (33.3% vs. 3.9%, p = 0.003).	('IBC', 'Chemical', 'MESH:D002015', (117, 120))	('triple-positive', 'Var', (9, 24))	('high-grade', 'Var', (56, 66))
212090	23778411	According to our results, the immunoexpression of basal CK 5/6 in both high-grade and low-grade DCIS lesions indicates a lower risk of invasive carcinoma.	('CK 5/6', 'Gene', (56, 62))	('invasive carcinoma', 'Disease', 'MESH:D009361', (135, 153))	('CK 5/6', 'Gene', '3852', (56, 62))	('immunoexpression', 'Var', (30, 46))	('invasive carcinoma', 'Disease', (135, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))
212140	19536033	The decrease in lymph node dissection in women with DCIS in our sample is consistent with that seen in larger samples of patients in Surveillance, Epidemiology, and End Results registries.	('decrease in lymph node', 'Phenotype', 'HP:0002732', (4, 26))	('DCIS', 'Phenotype', 'HP:0030075', (52, 56))	('decrease', 'NegReg', (4, 12))	('lymph node dissection', 'CPA', (16, 37))	('DCIS', 'Var', (52, 56))	('women', 'Species', '9606', (41, 46))	('patients', 'Species', '9606', (121, 129))
212158	29574637	While unilateral BC patients carrying BRCA mutation or having family history of BC indeed have a high risk of developing CBC, a majority of women have much lower risk of developing CBC.	('CBC', 'Disease', (121, 124))	('BRCA', 'Gene', '672', (38, 42))	('mutation', 'Var', (43, 51))	('BC', 'Phenotype', 'HP:0003002', (122, 124))	('BRCA', 'Gene', (38, 42))	('BC', 'Phenotype', 'HP:0003002', (182, 184))	('women', 'Species', '9606', (140, 145))	('BC', 'Phenotype', 'HP:0003002', (17, 19))	('patients', 'Species', '9606', (20, 28))	('BC', 'Phenotype', 'HP:0003002', (80, 82))
212223	25186428	Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ Human epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (69, 86))	('associated with', 'Reg', (217, 232))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Disease', (255, 261))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (164, 188))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (171, 188))	('HER2', 'Gene', '2064', (48, 52))	('lapatinib', 'Chemical', 'MESH:D000077341', (21, 30))	('HER2', 'Gene', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (62, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (164, 188))	('Human epidermal growth factor receptor 2', 'Gene', (87, 127))	('ductal carcinoma in situ', 'Disease', (62, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patients', 'Species', '9606', (34, 42))	('ductal carcinoma', 'Disease', 'MESH:D044584', (62, 78))	('HER2', 'Gene', (48, 52))	('amplification', 'Var', (135, 148))	('ductal carcinoma', 'Disease', 'MESH:D044584', (164, 180))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('ductal carcinoma in situ', 'Disease', (164, 188))	('HER2', 'Gene', '2064', (129, 133))	('DCIS', 'Phenotype', 'HP:0030075', (190, 194))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (62, 86))	('Human epidermal growth factor receptor 2', 'Gene', '2064', (87, 127))
212241	25186428	Expression of HER2 is associated with high proliferative grade, comedo-necrosis, and p53 mutation, and is inversely associated with the expression of hormone receptors.	('necrosis', 'Disease', 'MESH:D009336', (71, 79))	('rat', 'Species', '10116', (50, 53))	('high proliferative grade', 'CPA', (38, 62))	('mutation', 'Var', (89, 97))	('comedo', 'Phenotype', 'HP:0025249', (64, 70))	('necrosis', 'Disease', (71, 79))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('associated', 'Reg', (22, 32))	('HER2', 'Protein', (14, 18))
212244	25186428	When HER2 induce dimerization with HER3, the phosphorylated (activated) tyrosine residues on the intracellular domain of HER2 activate the lipid kinase phosphoinositide 3-kinase (PI3K), which results in activation of the enzyme AKT transforming factor (AKT) promoting cell survival.	('promoting', 'PosReg', (258, 267))	('activate', 'PosReg', (126, 134))	('cell survival', 'CPA', (268, 281))	('HER3', 'Gene', (35, 39))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('PI3', 'Gene', '5266', (179, 182))	('HER3', 'Gene', '2065', (35, 39))	('phosphoinositide 3-kinase', 'Gene', '5290', (152, 177))	('dimerization', 'MPA', (17, 29))	('tyrosine', 'Var', (72, 80))	('lipid', 'Enzyme', (139, 144))	('phosphoinositide 3-kinase', 'Gene', (152, 177))	('activation', 'PosReg', (203, 213))	('HER2', 'Gene', (121, 125))	('PI3', 'Gene', (179, 182))
212246	25186428	HER2 is a validated therapeutic target in invasive breast cancer, leading to the hypothesis that inhibition of HER2 through anti-HER2 therapy could be beneficial for patients with DCIS.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('invasive breast cancer', 'Disease', (42, 64))	('HER2', 'Protein', (111, 115))	('DCIS', 'Disease', (180, 184))	('DCIS', 'Phenotype', 'HP:0030075', (180, 184))	('invasive breast cancer', 'Disease', 'MESH:D001943', (42, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('anti-HER2', 'Var', (124, 133))	('patients', 'Species', '9606', (166, 174))
212256	25186428	Other eligibility criteria included age >=18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; normal hematological (absolute neutrophil count >=1.5 cells x109/L, platelets >=75 cells x109/L, and hemoglobin >=9 g/dl), liver (bilirrubin <= 1.25 x upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) <=2.5 x ULN and alkaline phosphatase <=2.5 xULN) and renal (creatinine <=2.0 mg/dL or creatinine clearance >40 ml/min); and normal left ventricular ejection fraction.	('AST', 'Gene', '26503', (325, 328))	('renal', 'CPA', (414, 419))	('aspartate transaminase', 'Gene', '26503', (301, 323))	('left ventricular', 'CPA', (492, 508))	('creatinine clearance', 'MPA', (447, 467))	('AST', 'Gene', (325, 328))	('aspartate transaminase', 'Gene', (301, 323))	('Oncology', 'Phenotype', 'HP:0002664', (72, 80))	('>=1.5', 'Var', (169, 174))	('alanine transaminase', 'MPA', (334, 354))	('rat', 'Species', '10116', (65, 68))
212281	25186428	p27 and Ki67 proliferative index were reported as percentage of positive nuclei in hot-spot areas.	('Ki67', 'Gene', '17345', (8, 12))	('Ki67', 'Gene', (8, 12))	('rat', 'Species', '10116', (20, 23))	('p27', 'Var', (0, 3))
212282	25186428	The percentage of stained nuclei was evaluated independently of the intensity for Ki67 and p27 (cutoff >=15%).	('p27', 'Var', (91, 94))	('Ki67', 'Gene', '17345', (82, 86))	('Ki67', 'Gene', (82, 86))
212283	25186428	Real-time polymerase chain reaction (PCR) mutational screening for phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (exons 9 and 20) was carried out using PCR and direct sequencing following standard protocols.	('mutational', 'Var', (42, 52))	('PIK3CA', 'Gene', (140, 146))	('PIK3CA', 'Gene', '5290', (140, 146))
212300	25186428	Sixteen patients (84%) had Ki67 >= 15%, whereas low p27-staining (<15%) was observed in half of tumors.	('>= 15%', 'Var', (32, 38))	('Ki67', 'Gene', '17345', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('Ki67', 'Gene', (27, 31))	('patients', 'Species', '9606', (8, 16))
212333	25186428	In a recent trial that aimed to evaluate the differential effects of trastuzumab and lapatinib under low and normal PTEN conditions in HER2-overexpressing breast cancer cell lines, lapatinib was effective and decreased both pMAPK and pAKT under low PTEN conditions.	('decreased', 'NegReg', (209, 218))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('trastuzumab', 'Chemical', 'MESH:D000068878', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('lapatinib', 'Var', (181, 190))	('lapatinib', 'Chemical', 'MESH:D000077341', (85, 94))	('lapatinib', 'Chemical', 'MESH:D000077341', (181, 190))
212346	25186428	Interestingly, DCIS has HER2 amplification with higher frequency than invasive tumors and this HER2-positive DCIS is often associated with comedo DCIS which carries twice the risk of local recurrence as compared to non-comedo DCIS.	('HER2', 'Protein', (24, 28))	('associated', 'Reg', (123, 133))	('comedo', 'Phenotype', 'HP:0025249', (139, 145))	('DCIS', 'Phenotype', 'HP:0030075', (226, 230))	('invasive tumors', 'Disease', 'MESH:D009369', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('HER2-positive', 'Var', (95, 108))	('comedo DCIS', 'Disease', (139, 150))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('DCIS', 'Phenotype', 'HP:0030075', (146, 150))	('comedo', 'Phenotype', 'HP:0025249', (219, 225))	('DCIS', 'Phenotype', 'HP:0030075', (15, 19))	('DCIS', 'Phenotype', 'HP:0030075', (109, 113))	('invasive tumors', 'Disease', (70, 85))
212355	25186428	A paradoxical activation of pAKT was observed in one patient with inactivation of pHER2 and pERK1.	('activation', 'PosReg', (14, 24))	('pHER2', 'Gene', (82, 87))	('pERK', 'Gene', '9451', (92, 96))	('patient', 'Species', '9606', (53, 60))	('inactivation', 'Var', (66, 78))	('pERK', 'Gene', (92, 96))	('pAKT', 'MPA', (28, 32))
212356	25186428	This negative feedback-loop has been recently described as resulting from HER3 hyperactivation, suggesting that dual inhibition of both pathways should be the most adequate and effective therapy.	('HER3', 'Gene', (74, 78))	('HER3', 'Gene', '2065', (74, 78))	('hyperactivation', 'Var', (79, 94))
212403	22585166	Criteria for inclusion of an article in the meta-analysis were as follows: (i) it had to be the principal and most updated published report of a clinical trial (highest mean/median follow-up time) evaluating treatment with AIs as adjuvant treatment in postmenopausal women with early breast cancer; (ii) it had to be independent from other reports to avoid giving double weight to estimates derived from the same study; (iii) it had to have sufficient information to allow adequate estimation of the HR and/or OR and 95% CIs (i.e., crude data: number of events by arms or adjusted estimates and SEM, CIs, or P values) to estimate contralateral breast cancer risk under treatment with AIs compared with any other treatment or placebo.	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('women', 'Species', '9606', (267, 272))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (630, 657))	('AIs', 'Var', (684, 687))	('contralateral breast cancer', 'Disease', (630, 657))	('cancer', 'Phenotype', 'HP:0002664', (651, 657))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('breast cancer', 'Disease', 'MESH:D001943', (644, 657))	('breast cancer', 'Phenotype', 'HP:0003002', (644, 657))	('breast cancer', 'Disease', (284, 297))
212410	22585166	The Arimidex (Anastrozole), Tamoxifen Alone or in Combination (ATAC) trial showed at a 100-month median follow-up a significant 40% reduction (HR = 0.60; 95% CI, 0.42-0.85) in contralateral breast cancers with anastrozole compared with tamoxifen.	('anastrozole', 'Chemical', 'MESH:D000077384', (210, 221))	('tamoxifen', 'Chemical', 'MESH:D013629', (236, 245))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('reduction', 'NegReg', (132, 141))	('contralateral breast cancers', 'Disease', (176, 204))	('breast cancers', 'Phenotype', 'HP:0003002', (190, 204))	('anastrozole', 'Var', (210, 221))	('Arimidex', 'Chemical', 'MESH:D000077384', (4, 12))	('Anastrozole', 'Chemical', 'MESH:D000077384', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Tamoxifen', 'Chemical', 'MESH:D013629', (28, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (176, 204))
212416	22585166	A meta-analysis of 9,000 patients participating in all available trials of AIs versus tamoxifen indicated a 35% reduction in contralateral breast cancer in the arm involving a switch to an AI after 2 to 3 years of tamoxifen treatment compared with the arm treated with tamoxifen for the full course of the trial.	('contralateral breast cancer', 'Disease', 'MESH:D001943', (125, 152))	('switch', 'Var', (176, 182))	('contralateral breast cancer', 'Disease', (125, 152))	('reduction', 'NegReg', (112, 121))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tamoxifen', 'Chemical', 'MESH:D013629', (86, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tamoxifen', 'Chemical', 'MESH:D013629', (269, 278))	('tamoxifen', 'Chemical', 'MESH:D013629', (214, 223))
212418	22585166	An analysis of a 206-participant subgroup in the IES trial reported at a median follow-up of 58 months revealed a rapid decline in BMD from baseline during the first 6 months following the switch from tamoxifen to exemestane: 0.051 g/cm3 (2.7%; 95% CI, 2.0-3.4; P < 0.0001) at the lumbar spine and 0.025 g/cm3 (1.4%; 95% CI, 0.8-1.9; P < 0.0001) at the total hip.	('participant', 'Species', '9606', (21, 32))	('exemestane', 'Chemical', 'MESH:C056516', (214, 224))	('0.051 g/cm3', 'Var', (226, 237))	('IES', 'Chemical', '-', (49, 52))	('tamoxifen', 'Chemical', 'MESH:D013629', (201, 210))	('decline', 'NegReg', (120, 127))
212422	22585166	The reduction in contralateral breast cancer as a secondary end point in the AI adjuvant trials strongly suggested that AIs have potential to prevent breast cancer in healthy high-risk women, possibly to an even greater extent than SERMs.	('contralateral breast cancer', 'Disease', (17, 44))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('AIs', 'Var', (120, 123))	('women', 'Species', '9606', (185, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (17, 44))	('ER', 'Gene', '2099', (233, 235))
212532	22585166	Furthermore, although overall anastrozole was associated with a 27% lower rate of recurrence than tamoxifen (HR = 0.73; 95% CI, 0.63-0.83; P < 0.001) and decreased recurrence with the AI was seen at all BMI levels, aromatase inhibition at the administered dose (1 mg/d) was less effective in preventing breast cancer recurrences in obese women (HR = 0.84; 95% CI, 0.61-1.14) than in thinner women (HR = 0.64; 95% CI, 0.45-0.91).	('anastrozole', 'Var', (30, 41))	('lower', 'NegReg', (68, 73))	('obese', 'Disease', 'MESH:D009765', (332, 337))	('tamoxifen', 'Chemical', 'MESH:D013629', (98, 107))	('aromatase', 'Gene', (215, 224))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('anastrozole', 'Chemical', 'MESH:D000077384', (30, 41))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('obese', 'Disease', (332, 337))	('aromatase', 'Gene', '1588', (215, 224))	('women', 'Species', '9606', (391, 396))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('women', 'Species', '9606', (338, 343))
212620	31358020	However, if patients were first split into high- and low-risk groups through feature #1 (Additional file 19: Figure S9B) followed by another stratification using feature #3, a significant difference in survival between the two subgroups was increased when compared to the stratification by feature #1 alone (Additional file 19: Figure S9C), showing the dependency of variables for maximizing prognostic relevance (high-risk group HR for feature #1 alone = 3.017, high-risk group HR for features #1 + #3 = 7.308).	('patients', 'Species', '9606', (12, 20))	('feature #', 'Var', (77, 86))	('increased', 'PosReg', (241, 250))	('survival', 'MPA', (202, 210))
212627	31358020	Notably, the same model was able to significantly stratify high-grade DCIS patients (Additional file 24: Figure S14A), low/intermediate-grade DCIS patients (Additional file 24: Figure S14B), the subset of all patients who received adjuvant radiation therapy, and all patients treated with BCS alone (Additional file 24: Figure S14C and D) into the subgroups with high and low recurrence risks.	('S14A', 'Mutation', 'p.S14A', (112, 116))	('patients', 'Species', '9606', (267, 275))	('patients', 'Species', '9606', (75, 83))	('DCIS', 'Disease', (70, 74))	('S14C', 'Mutation', 'p.S14C', (327, 331))	('patients', 'Species', '9606', (147, 155))	('S14B', 'SUBSTITUTION', 'None', (184, 188))	('patients', 'Species', '9606', (209, 217))	('S14B', 'Var', (184, 188))
212630	31358020	Similarly, producing a continuous metric, through training an RSF using the selected eight features, produced an average score of a slide from a patient who eventually recurred (34.3) that was significantly higher (p < 0.0001) than those who did not (19.3) (Additional file 27: Figure S17B).	('S17B', 'Var', (285, 289))	('S17B', 'SUBSTITUTION', 'None', (285, 289))	('patient', 'Species', '9606', (145, 152))	('RSF', 'Chemical', '-', (62, 65))	('higher', 'PosReg', (207, 213))
212643	31358020	However, while the mean slide score (44.6) for a recurred patient slide was statistically significantly higher (p = 0.0355) than a slide from a patient who does not recur (42.0), this difference was much smaller than the difference in scores observed between the recurred and non-recurred slides in the training cohorts (Additional file 5: Figure S27B).	('S27B', 'Var', (347, 351))	('S27B', 'SUBSTITUTION', 'None', (347, 351))	('patient', 'Species', '9606', (58, 65))	('slide score', 'MPA', (24, 35))	('patient', 'Species', '9606', (144, 151))	('higher', 'PosReg', (104, 110))
212646	31358020	Predictably, most of the features selected for the final recurrence classifier model originate from tumor regions, whose cells show both gross morphological changes and nuclear alterations, such as deviations in heterochromatin.	('deviations', 'Var', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('heterochromatin', 'Disease', (212, 227))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
212705	24403528	A number of tumor factors have been identified that are associated with an increased likelihood of a second breast cancer diagnosis, including nuclear grade, larger tumor size, and detection by palpation rather than mammography.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('nuclear', 'Var', (143, 150))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('tumor', 'Disease', (12, 17))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('tumor', 'Disease', (165, 170))
212770	24403528	Recently, Newcomb et al found that moderate alcohol consumption prior to diagnosis was associated with improved breast cancer survival after an invasive diagnosis, although there was no association between post-diagnosis alcohol consumption and breast cancer survival.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('alcohol', 'Chemical', 'MESH:D000438', (221, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('breast cancer', 'Disease', (112, 125))	('improved', 'PosReg', (103, 111))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('moderate alcohol consumption', 'Var', (35, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Disease', (245, 258))
212773	24403528	In the only study to our knowledge examining BMI and second events in an exclusively DCIS population, Habel et al found a two-fold increase in risk for women in the highest decile of BMI at diagnosis (>30.8 kg/m2) compared to the lowest decile (<22.0 kg/m2).	('women', 'Species', '9606', (152, 157))	('>30.8 kg/m2', 'Var', (201, 212))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('BMI', 'Disease', (183, 186))
212781	24403528	Under-dosing may have contributed to an increase in the risk of recurrence in obese women in previous studies.	('women', 'Species', '9606', (84, 89))	('obese', 'Disease', 'MESH:D009765', (78, 83))	('obese', 'Disease', (78, 83))	('Under-dosing', 'Var', (0, 12))	('recurrence', 'MPA', (64, 74))
212794	24403528	Alcohol consumption has also been shown to be directly related to elevated endogenous estrogen levels in both pre- and postmenopausal women.	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('women', 'Species', '9606', (134, 139))	('Alcohol consumption', 'Var', (0, 19))	('endogenous estrogen levels', 'MPA', (75, 101))	('elevated', 'PosReg', (66, 74))
212827	32291314	Genetic disruption of NRF2 signaling altered the transcriptional cluster, but 3D phenotypes were buffered or redirected by compensatory increases in p53 signaling.	('altered', 'Reg', (37, 44))	('p53 signaling', 'MPA', (149, 162))	('Genetic disruption', 'Var', (0, 18))	('transcriptional cluster', 'MPA', (49, 72))	('NRF2', 'Gene', (22, 26))	('increases', 'PosReg', (136, 145))	('cluster', 'Species', '100569', (65, 72))
212832	32291314	The only transcription factor in the cluster is JUND, and we showed previously that its chronic knockdown in MCF10A-5E cells causes specific morphometric defects during spheroid growth.	('knockdown', 'Var', (96, 105))	('JUND', 'Gene', (48, 52))	('morphometric defects', 'CPA', (141, 161))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (109, 118))	('cluster', 'Species', '100569', (37, 44))	('JUND', 'Gene', '3727', (48, 52))
212834	32291314	Unexpectedly, other than JUND itself, no transcripts were reliably altered by its knockdown (see later in this section), supporting a regulatory role for other factors outside of the cluster.	('transcripts', 'MPA', (41, 52))	('cluster', 'Species', '100569', (183, 190))	('knockdown', 'Var', (82, 91))	('JUND', 'Gene', '3727', (25, 29))	('JUND', 'Gene', (25, 29))
212851	32291314	NRF2 co-immunoprecipitates with p53 in triple-negative breast cancer cells harboring gain-of-function p53 mutations, but this complex is absent in MCF10A cells with wild-type p53.	('MCF10A', 'CellLine', 'CVCL:0598', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('gain-of-function', 'PosReg', (85, 101))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('mutations', 'Var', (106, 115))	('p53', 'Gene', (102, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
212852	32291314	Loss of wild-type p53 function in MCF10A cells yields only minor 3D culture defects, but gain-of-function p53 mutants strongly perturb 3D architecture.	('perturb', 'NegReg', (127, 134))	('mutants', 'Var', (110, 117))	('3D culture defects', 'CPA', (65, 83))	('gain-of-function', 'PosReg', (89, 105))	('MCF10A', 'CellLine', 'CVCL:0598', (34, 40))	('p53', 'Gene', (106, 109))	('3D architecture', 'CPA', (135, 150))
212853	32291314	Compared with the gene-cluster response to JUND knockdown or constitutive E2F1 activation through RB inhibition with overexpressed human papillomavirus E7 protein, we observed substantially more alterations upon NRF2 knockdown (66%) or inhibition of p53 (31%; Fig.	('JUND', 'Gene', '3727', (43, 47))	('RB', 'Chemical', 'MESH:D012413', (98, 100))	('inhibition', 'NegReg', (236, 246))	('JUND', 'Gene', (43, 47))	('E2F1', 'Gene', (74, 78))	('p53', 'Gene', (250, 253))	('cluster', 'Species', '100569', (23, 30))	('knockdown', 'Var', (217, 226))	('activation', 'PosReg', (79, 89))	('alterations', 'Reg', (195, 206))	('human papillomavirus', 'Species', '10566', (131, 151))	('NRF2', 'Gene', (212, 216))
212854	32291314	Compound perturbation of NRF2 and p53 elicited further nonadditive changes to multiple genes in the cluster, including synergistic reduction of CDKN1A, encoding a cyclin-dependent kinase inhibitor, and KRT5, encoding a basal cytokeratin.	('reduction', 'NegReg', (131, 140))	('p53', 'Gene', (34, 37))	('NRF2', 'Gene', (25, 29))	('changes', 'Reg', (67, 74))	('cluster', 'Species', '100569', (100, 107))	('perturbation', 'Var', (9, 21))	('KRT5', 'Gene', (202, 206))	('CDKN1A', 'Gene', (144, 150))	('CDKN1A', 'Gene', '1026', (144, 150))	('KRT5', 'Gene', '3852', (202, 206))	('mul', 'Chemical', '-', (78, 81))
212855	32291314	Although p53 can antagonize certain NRF2 target genes in reporter assays, significant antagonism was detected for only one transcript in the cluster (MRPL33, fig.	('cluster', 'Species', '100569', (141, 148))	('p53', 'Var', (9, 12))	('antagonize', 'Reg', (17, 27))
212859	32291314	By two-color immunostaining, we found that NRF2-p53 co-stabilization was even more pronounced in MCF10DCIS.com cells (Fig.	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (97, 110))	('MCF10DCIS.com', 'Var', (97, 110))	('NRF2-p53', 'Gene', (43, 51))	('co-stabilization', 'MPA', (52, 68))	('DCIS', 'Phenotype', 'HP:0030075', (102, 106))
212861	32291314	Consistent with these results, NRF2 knockdown in MCF10DCIS.com cells was sufficient to significantly stabilize p53 (fig.	('stabilize', 'MPA', (101, 110))	('NRF2', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (49, 62))	('DCIS', 'Phenotype', 'HP:0030075', (54, 58))	('p53', 'Var', (111, 114))
212862	32291314	Stabilization of wild-type p53 upon NRF2 knockdown was also observed in premalignant CHEK21100delC SUM102PT cells and became even more pronounced when these cells were reconstituted with inducible wild-type CHEK2 (fig.	('CHEK2', 'Gene', (85, 90))	('NRF2', 'Gene', (36, 40))	('CHEK2', 'Gene', '11200', (207, 212))	('knockdown', 'Var', (41, 50))	('CHEK2', 'Gene', (207, 212))	('CHEK2', 'Gene', '11200', (85, 90))
212867	32291314	NRF2 deficiency also increased rounding in 3D cultures of SUM102PT cells with or without CHEK2 reconstitution (fig.	('CHEK2', 'Gene', (89, 94))	('increased', 'PosReg', (21, 30))	('NRF2', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('rounding', 'CPA', (31, 39))	('SUM102PT', 'Var', (58, 66))	('CHEK2', 'Gene', '11200', (89, 94))
212868	32291314	By contrast, p53 disruption in MCF10DCIS.com cells with either DNp53 or a gain-of-function p53R280K mutant increased the prevalence of hyper-enlarged outgrowths (Fig.	('gain-of-function', 'PosReg', (74, 90))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (31, 44))	('hyper-enlarged outgrowths', 'CPA', (135, 160))	('p53R280K', 'Var', (91, 99))	('DCIS', 'Phenotype', 'HP:0030075', (36, 40))
212869	32291314	Combined NRF2-p53 perturbation elicited a synergistic increase in non-spherical hyper-enlargement (Fig.	('hyper-enlargement', 'Disease', (80, 97))	('increase', 'PosReg', (54, 62))	('hyper-enlargement', 'Disease', 'MESH:D006529', (80, 97))	('NRF2-p53', 'Gene', (9, 17))	('perturbation', 'Var', (18, 30))
212878	32291314	When MCF10A-5E cells were exogenously stimulated with H2O2, NRF2 was rapidly stabilized and, importantly, p53 also accumulated after several hours (Fig.	('accumulated', 'PosReg', (115, 126))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (5, 14))	('H2O2', 'Chemical', 'MESH:D006861', (54, 58))	('H2O2', 'Var', (54, 58))	('mul', 'Chemical', '-', (119, 122))	('p53', 'Var', (106, 109))	('mul', 'Chemical', '-', (41, 44))
212885	32291314	Last, we retained the nucleocytoplasmic trafficking of stabilized NRF2 to account for observations that H2O2 stimulation retains NRF2 in the cytoplasm longer than treatment with the electrophilic stress, sulforaphane (fig.	('mul', 'Chemical', '-', (112, 115))	('sulforaphane', 'Chemical', 'MESH:C016766', (204, 216))	('NRF2', 'Gene', (129, 133))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))	('H2O2', 'Var', (104, 108))
212892	32291314	Oxidative stress has also been reported to inhibit p53 DNA binding, but we found that p53 stabilized by H2O2 treatment was as capable at increasing MDM2 abundance as was p53 stabilized by nutlin-3 (fig.	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('increasing', 'PosReg', (137, 147))	('nutlin-3', 'Chemical', 'MESH:C482205', (188, 196))	('MDM2', 'Gene', '4193', (148, 152))	('MDM2', 'Gene', (148, 152))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))	('H2O2', 'Var', (104, 108))
212895	32291314	5A, gray), but we were unable to detect changes in MDM2 when NRF2 was knocked down with shRNA or stabilized with sulforaphane (fig.	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('knocked', 'Var', (70, 77))	('sulforaphane', 'Chemical', 'MESH:C016766', (113, 125))	('NRF2', 'Gene', (61, 65))
212903	32291314	In this model, addition of p53-p21-NRF2 crosstalk caused NRF2 stabilization to peak earlier and deactivate faster than observations (fig.	('p21', 'Gene', '1026', (31, 34))	('deactivate', 'NegReg', (96, 106))	('p21', 'Gene', (31, 34))	('stabilization', 'MPA', (62, 75))	('crosstalk', 'Var', (40, 49))	('NRF2', 'Gene', (57, 61))
212916	32291314	NRF2-p53 mutual information was much less dependent on signaling transients, and coupling was substantially higher in MCF10DCIS.com cells.	('MCF10DCIS.com', 'Var', (118, 131))	('DCIS', 'Phenotype', 'HP:0030075', (123, 127))	('NRF2-p53', 'Gene', (0, 8))	('mutual information', 'MPA', (9, 27))	('coupling', 'MPA', (81, 89))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (118, 131))	('higher', 'PosReg', (108, 114))
212918	32291314	We then investigated whether the base model could also relate to the synergistic phenotypes observed upon dual NRF2-p53 perturbation in MCF10A-5E and MCF10DCIS.com cells (Fig.	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (150, 163))	('DCIS', 'Phenotype', 'HP:0030075', (155, 159))	('NRF2-p53', 'Gene', (111, 119))	('perturbation', 'Var', (120, 132))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (136, 145))
212919	32291314	For DNp53, the p53 species was rendered unable to induce transcription of MDM2, PPM1D, p21, and its share of the antioxidant enzyme pool.	('MDM2', 'Gene', '4193', (74, 78))	('p21', 'Gene', '1026', (87, 90))	('MDM2', 'Gene', (74, 78))	('DNp53', 'Var', (4, 9))	('PPM1D', 'Gene', '8493', (80, 85))	('p21', 'Gene', (87, 90))	('transcription', 'MPA', (57, 70))	('PPM1D', 'Gene', (80, 85))
212932	32291314	Stabilized NRF2 was frequently detected in the cytoplasm, consistent with the prolonged cytoplasmic localization observed in H2O2-treated cells compared to cells stressed with an electrophile (fig.	('H2O2-treated', 'Var', (125, 137))	('NRF2', 'Gene', (11, 15))	('cytoplasmic', 'MPA', (88, 99))	('H2O2', 'Chemical', 'MESH:D006861', (125, 129))
212945	32291314	Using RNA-seq data from the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) consortium on 15 TNBC lines with mutated p53 (six claudin-low subtype, nine basal-like subtype), we adjusted initial conditions from the original MCF10A model and removed all transcriptional processes downstream of p53 (Fig.	('removed', 'NegReg', (259, 266))	('MCF10A', 'CellLine', 'CVCL:0598', (242, 248))	('mutated', 'Var', (129, 136))	('transcriptional processes', 'MPA', (271, 296))	('p53', 'Gene', (137, 140))
212947	32291314	The coordination between NRF2 and mutant p53 was calculated by mutual information, and the integrated H2O2 response was scaled to that of MCF10A-5E cells as a relative measure of ROS tolerance.	('ROS', 'Chemical', 'MESH:D017382', (179, 182))	('H2O2', 'Chemical', 'MESH:D006861', (102, 106))	('mutant', 'Var', (34, 40))	('p53', 'Gene', (41, 44))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (138, 147))
212948	32291314	The goal was to associate the model-derived predictions with NRF2-knockdown phenotype in ROS-generating environments such as 3D culture.	('NRF2-knockdown', 'Var', (61, 75))	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('NRF2-knockdown', 'Gene', (61, 75))
212950	32291314	We noted a spectrum of residual NRF2-p53 co-stabilization from weak (HCC1937, SUM159PT) to virtually nonexistent (MDA-MB-468, MDA-MB-231).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (126, 136))	('HCC1937', 'Var', (69, 76))	('SUM159PT', 'Var', (78, 86))	('HCC1937', 'CellLine', 'CVCL:0290', (69, 76))	('NRF2-p53', 'Gene', (32, 40))	('co-stabilization', 'MPA', (41, 57))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (114, 124))
212951	32291314	Despite complete p53 deficiency in the model, this residual NRF2-p53 mutual information correlated strongly with the simulated relative increase in oxidative stress when ROS generation rate was increased (Fig.	('oxidative stress', 'MPA', (148, 164))	('deficiency', 'Var', (21, 31))	('increased', 'PosReg', (194, 203))	('mul', 'Chemical', '-', (119, 122))	('increase', 'PosReg', (136, 144))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('p53', 'Gene', (17, 20))
212953	32291314	HCC1937 and SUM159PT cells were both predicted to have residual NRF2-p53 coordination and moderate ROS tolerance (Fig.	('HCC1937', 'Var', (0, 7))	('SUM159PT', 'Var', (12, 20))	('NRF2-p53 coordination', 'Protein', (64, 85))	('ROS tolerance', 'CPA', (99, 112))	('HCC1937', 'CellLine', 'CVCL:0290', (0, 7))	('ROS', 'Chemical', 'MESH:D017382', (99, 102))
212955	32291314	Thus, model and experiment support that, despite p53 mutation, residual NRF2-p53 coupling indicates the primordial susceptibility of triple-negative malignancies to perturbations in the NRF2 pathway.	('malignancies', 'Disease', (149, 161))	('p53', 'Gene', (49, 52))	('mutation', 'Var', (53, 61))	('NRF2 pathway', 'Pathway', (186, 198))	('NRF2-p53', 'Gene', (72, 80))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('coupling', 'MPA', (81, 89))
212961	32291314	The associated NRF2-p53 coordination, by contrast, was qualitatively different, with various TCGA cases giving rise to strong coordination despite pervasive TP53 mutation (Fig.	('TP53', 'Gene', (157, 161))	('coordination', 'MPA', (126, 138))	('giving rise', 'Reg', (104, 115))	('mutation', 'Var', (162, 170))	('TP53', 'Gene', '7157', (157, 161))
212968	32291314	In mouse mammary epithelial cells, loss of Brca1 (a predisposing event for basal-subtype TNBC) destabilizes Nrf2 and causes an increase in ROS, favoring the future acquisition of p53 mutations.	('p53', 'Gene', (179, 182))	('Brca1', 'Gene', (43, 48))	('Brca1', 'Gene', '12189', (43, 48))	('mouse', 'Species', '10090', (3, 8))	('Nrf2', 'Gene', '18024', (108, 112))	('ROS', 'MPA', (139, 142))	('loss', 'Var', (35, 39))	('destabilizes', 'NegReg', (95, 107))	('increase', 'PosReg', (127, 135))	('Nrf2', 'Gene', (108, 112))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))
212969	32291314	In human breast cancer cells, gain-of-function p53 mutants interact directly with NRF2 and may help retain NRF2 in the nucleus.	('NRF2', 'Protein', (82, 86))	('interact', 'Interaction', (59, 67))	('mutants', 'Var', (51, 58))	('human', 'Species', '9606', (3, 8))	('gain-of-function', 'PosReg', (30, 46))	('breast cancer', 'Disease', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('NRF2', 'Protein', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p53', 'Gene', (47, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))
212970	32291314	If certain p53 mutations were also to promote NRF2 stabilization, then it would provide a two-for-one benefit to cancer progression by relieving tumor suppression and conferring ROS tolerance constitutively.	('p53', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (15, 24))	('relieving', 'NegReg', (135, 144))	('tumor', 'Disease', (145, 150))	('ROS', 'MPA', (178, 181))	('NRF2', 'Gene', (46, 50))	('cancer', 'Disease', (113, 119))	('promote', 'PosReg', (38, 45))	('stabilization', 'MPA', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ROS', 'Chemical', 'MESH:D017382', (178, 181))
212971	32291314	However, we did not note any association between gain-of-function p53 mutants and NRF2 abundance in TNBC lines, suggesting that KEAP1 regulation predominates as indicated by the TNBC models.	('mutants', 'Var', (70, 77))	('KEAP1', 'Gene', '9817', (128, 133))	('gain-of-function', 'PosReg', (49, 65))	('NRF2', 'Gene', (82, 86))	('KEAP1', 'Gene', (128, 133))	('p53', 'Gene', (66, 69))
212972	32291314	Chronic activation of the NRF2 pathway (for example, by activating NFE2L2 mutation or KEAP1 loss) may be disfavored if increased intracellular ROS is not permanent.	('NRF2 pathway', 'Pathway', (26, 38))	('mutation', 'Var', (74, 82))	('NFE2L2', 'Gene', (67, 73))	('ROS', 'Chemical', 'MESH:D017382', (143, 146))	('activation', 'PosReg', (8, 18))	('KEAP1', 'Gene', '9817', (86, 91))	('activating', 'PosReg', (56, 66))	('KEAP1', 'Gene', (86, 91))	('NFE2L2', 'Gene', '4780', (67, 73))
212973	32291314	Wild-type NRF2 function must be sufficient to buffer cells from the early stresses of premalignancy and p53 disruption, allowing invasive TNBCs to deactivate the pathway when it is no longer needed.	('deactivate', 'NegReg', (147, 157))	('NRF2', 'Gene', (10, 14))	('invasive TNBCs', 'Disease', 'MESH:D009361', (129, 143))	('invasive TNBCs', 'Disease', (129, 143))	('disruption', 'Var', (108, 118))
212974	32291314	There are parallels to FOXO transcription factors, which are reversibly inactivated by mitogenic signals yet provide critical oxidative-stress tolerance when the breast-cancer tumor suppressor RUNX1 is disrupted.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast-cancer tumor', 'Disease', (162, 181))	('FOXO transcription factors', 'Gene', (23, 49))	('RUNX1', 'Gene', (193, 198))	('oxidative-stress', 'Phenotype', 'HP:0025464', (126, 142))	('breast-cancer tumor', 'Disease', 'MESH:D001943', (162, 181))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('RUNX1', 'Gene', '861', (193, 198))	('disrupted', 'Var', (202, 211))
212976	32291314	For example, gain-of-function p53 mutations cause luminal filling in MCF10A 3D cultures, similar to the delay in mammary-gland involution observed with mutant p53 in vivo.	('luminal filling', 'MPA', (50, 65))	('MCF10A', 'CellLine', 'CVCL:0598', (69, 75))	('gain-of-function', 'PosReg', (13, 29))	('p53', 'Gene', (30, 33))	('luminal', 'Chemical', 'MESH:D010634', (50, 57))	('mutations', 'Var', (34, 43))
212977	32291314	Reciprocally, knockdown of mutant p53 in MDA-MB-468 cells promotes luminal hollowing.	('p53', 'Gene', (34, 37))	('mutant', 'Var', (27, 33))	('luminal hollowing', 'CPA', (67, 84))	('promotes', 'PosReg', (58, 66))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (41, 51))	('luminal', 'Chemical', 'MESH:D010634', (67, 74))
212984	32291314	Cancer mutations engage and cooperate with cell signaling in ways that are not captured by DNA sequencing.	('cell signaling', 'Pathway', (43, 57))	('cooperate', 'Reg', (28, 37))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('engage', 'Reg', (17, 23))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (7, 16))
212985	32291314	But, this same coupling creates a redundancy upon which p53 mutations can occur and neoplasms can evolve.	('occur', 'Reg', (74, 79))	('neoplasms', 'Phenotype', 'HP:0002664', (84, 93))	('p53', 'Gene', (56, 59))	('neoplasms', 'Disease', 'MESH:D009369', (84, 93))	('neoplasms', 'Disease', (84, 93))	('mutations', 'Var', (60, 69))
212986	32291314	Our results give pause to the nutraceutical use of sulforaphane as a potent NRF2 stabilizer :in lung cancer, where KEAP1-NRF2 mutations are common and TP53 is secondary, antioxidants accelerate tumor progression.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('TP53', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('sulforaphane', 'Chemical', 'MESH:C016766', (51, 63))	('KEAP1', 'Gene', '9817', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (194, 199))	('KEAP1', 'Gene', (115, 120))	('mutations', 'Var', (126, 135))	('accelerate', 'PosReg', (183, 193))	('TP53', 'Gene', '7157', (151, 155))
212988	32291314	shRNA targeting sequences from the RNAi consortium were cloned into tet-pLKO.1-puro as previously described for shLuc (TRCN0000072250, Addgene #136587), shNRF2 #1 (TRCN0000281950, Addgene #136584), shNRF2 #2 (TRCN0000284998, Addgene #136585), shJUND #1 (TRCN0000416347, Addgene #136581), shJUND #2 (TRCN0000416920, Addgene #136583).	('JUND', 'Gene', '3727', (245, 249))	('JUND', 'Gene', '3727', (290, 294))	('TRCN0000284998', 'Var', (209, 223))	('JUND', 'Gene', (245, 249))	('TRCN0000416347', 'Var', (254, 268))	('TRCN0000281950', 'Var', (164, 178))	('JUND', 'Gene', (290, 294))	('TRCN0000416920', 'Var', (299, 313))	('TRCN0000072250', 'Var', (119, 133))
212989	32291314	For the mRFP1-NRF2 reporter (Addgene #136580), the DNA binding domain of NRF2 was mutated (C506S) along with four leucines (L4A) in the leucine zipper region of the bZIP domain by site-directed mutagenesis of the pBabe mRFP1-NRF2 hygro plasmid (Addgene #136579) originally prepared by subcloning into pBabe mRFP1 hygro.	('C506S', 'Var', (91, 96))	('C506S', 'SUBSTITUTION', 'None', (91, 96))	('mutagenesis', 'Var', (194, 205))	('leucine', 'Chemical', 'MESH:D007930', (114, 121))	('leucine', 'Chemical', 'MESH:D007930', (136, 143))
212994	32291314	p53DD (p53DN) and p53(R280K)-V5 PCR amplicon was prepared with SpeI and MfeI restriction sites and cloned into pEN_TTmiRc2 (Addgene #25752) digested with SpeI and MfeI (Addgene #136520, #136525).	('p53DN', 'Var', (7, 12))	('R280K', 'Var', (22, 27))	('R280K', 'SUBSTITUTION', 'None', (22, 27))
212995	32291314	pEN_TT donor vectors were recombined into pSLIK neo (Addgene #25735), pSLIK zeo (Addgene #25736), or pSLIK hygro (Addgene #25737) by LR recombination to obtain pSLIK 3xFLAG-Luciferase zeo (Addgene #136533), pSLIK p53DD zeo (Addgene #136534), pSLIK 3xFLAG-Luciferase hygro (Addgene #136528), pSLIK 3xFLAG-NRF2(RR) hygro (Addgene #136535), pSLIK BirA* hygro (Addgene #136537), pSLIK BirA*-CDKN1A hygro (Addgene #136538), pSLIK BirA*-NRF2 hygro (Addgene #136539), pSLIK p53(R280K)-V5 hygro (Addgene #136540) and pSLIK 3xFLAG-CHEK2 neo (Addgene #136536).	('CHEK2', 'Gene', '11200', (522, 527))	('R280K', 'SUBSTITUTION', 'None', (471, 476))	('CHEK2', 'Gene', (522, 527))	('BirA', 'Chemical', '-', (344, 348))	('R280K', 'Var', (471, 476))	('CDKN1A', 'Gene', (387, 393))	('CDKN1A', 'Gene', '1026', (387, 393))	('BirA', 'Chemical', '-', (425, 429))	('BirA', 'Chemical', '-', (381, 385))	('Addgene #136540', 'Var', (488, 503))
213003	32291314	Lentiviruses were prepared in human embryonic kidney 293T cells (ATCC) by triple transfection of the viral vector with psPAX2 + pMD.2G (Addgene) and transduced into MCF10A-5E, MCF10DCIS.com, HCC1937, SUM159PT, MDA-MB-231, HCC1806, and MDA-MB-468 as previously described.	('human', 'Species', '9606', (30, 35))	('HCC1937', 'CellLine', 'CVCL:0290', (191, 198))	('pMD', 'Disease', (128, 131))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (210, 220))	('HCC1806', 'CellLine', 'CVCL:1258', (222, 229))	('pMD', 'Disease', 'None', (128, 131))	('SUM159PT', 'Var', (200, 208))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (235, 245))	('DCIS', 'Phenotype', 'HP:0030075', (181, 185))	('MCF10DCIS.com', 'CellLine', 'CVCL:5552', (176, 189))	('embryonic kidney', 'Disease', (36, 52))	('293T', 'CellLine', 'CVCL:0063', (53, 57))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (165, 174))	('embryonic kidney', 'Disease', 'MESH:D007674', (36, 52))
213043	32291314	MCF10A-5E cells inducibly expressing the promiscuous biotin ligase BirA*, BirA*-NRF2, or BirA*-CDKN1A were plated on 10-cm plates and induced with 1 mug/ml doxycycline at 50% confluency.	('biotin', 'Chemical', 'MESH:D001710', (53, 59))	('CDKN1A', 'Gene', (95, 101))	('BirA*', 'Var', (89, 94))	('CDKN1A', 'Gene', '1026', (95, 101))	('doxycycline', 'Chemical', 'MESH:D004318', (156, 167))	('BirA', 'Chemical', '-', (74, 78))	('BirA', 'Chemical', '-', (67, 71))	('MCF10A-5E', 'CellLine', 'CVCL:0598', (0, 9))	('BirA', 'Chemical', '-', (89, 93))	('BirA', 'Gene', (74, 78))
213077	32291314	The modifications added 19 additional reactions and eight additional ODEs to the MCF10A-5E base model.	('MCF10A-5E', 'CellLine', 'CVCL:0598', (81, 90))	('reactions', 'MPA', (38, 47))	('modifications', 'Var', (4, 17))	('ODEs', 'MPA', (69, 73))
213079	32291314	S14C), we added reactions involving p21 binding to NRF2 to the MCF10A-5E base model.	('MCF10A-5E', 'CellLine', 'CVCL:0598', (63, 72))	('NRF2', 'Gene', (51, 55))	('p21', 'Gene', '1026', (36, 39))	('p21', 'Gene', (36, 39))	('S14C', 'Var', (0, 4))	('S14C', 'SUBSTITUTION', 'None', (0, 4))
213082	32291314	These modifications added eight additional reactions and two additional ODEs to the MCF10A-5E base model.	('MCF10A-5E', 'CellLine', 'CVCL:0598', (84, 93))	('modifications', 'Var', (6, 19))	('reactions', 'MPA', (43, 52))
213104	32291314	To simulate p53 mutation in the 15 p53-mutant TNBC cell lines, all reactions downstream of p53 were removed.	('mutation', 'Var', (16, 24))	('p53-mutant', 'Var', (35, 45))	('p53', 'Gene', (12, 15))	('mul', 'Chemical', '-', (5, 8))	('p53-mutant', 'Gene', (35, 45))
213246	32345364	This issue has been raised by a previous research insisting that CAD can't replace the radiologist's assessment because it can cause negative enhancement of breast tumors.	('negative', 'NegReg', (133, 141))	('CAD', 'Var', (65, 68))	('breast tumors', 'Phenotype', 'HP:0100013', (157, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('breast tumors', 'Disease', 'MESH:D001943', (157, 170))	('breast tumors', 'Disease', (157, 170))	('enhancement', 'MPA', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
213313	32345364	Among the 3 most commonly used thresholds, 30% seems to be the most appropriate threshold and produced results similar to those of manual measurement on MRI for both invasive cancers and DCIS.	('invasive cancers', 'Disease', (166, 182))	('DCIS', 'Disease', (187, 191))	('invasive cancers', 'Disease', 'MESH:D009362', (166, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('DCIS', 'Phenotype', 'HP:0030075', (187, 191))	('30%', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
213482	23883667	Inhibition of NF-kappaB or beta1-integrin signaling abrogated emergence of the invasive activity.	('abrogated', 'NegReg', (52, 61))	('beta1-integrin', 'Gene', '3688', (27, 41))	('beta1-integrin', 'Gene', (27, 41))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))
213502	23883667	Inhibition of NF-kappaB translocation to the nucleus or inhibition of beta1-integrin signaling abrogated the emergence of the invasive phenotype.	('inhibition', 'NegReg', (56, 66))	('beta1-integrin', 'Gene', '3688', (70, 84))	('translocation', 'MPA', (24, 37))	('NF-kappaB', 'Gene', '4790', (14, 23))	('beta1-integrin', 'Gene', (70, 84))	('NF-kappaB', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('abrogated', 'NegReg', (95, 104))
213510	23883667	Primary antibody against p-Akt (1:50, Cell Signaling Technology, Danvers, MA, USA) was incubated overnight at 4 C. Slides were washed and then followed by sequential incubation for 15 minutes with anti-rabbit immunoglobulins-horseradish peroxidase (HRP) (1:200), fluorescyl-tyramide hydrogen peroxide and anti-fluorescein-HRP.	('fluorescyl-tyramide hydrogen peroxide', 'MPA', (263, 300))	('fluorescein', 'Chemical', 'MESH:D019793', (310, 321))	('anti-fluorescein-HRP', 'Var', (305, 325))	('horseradish', 'Species', '3704', (225, 236))	('Akt', 'Gene', '207', (27, 30))	('fluorescyl-tyramide hydrogen peroxide', 'Chemical', '-', (263, 300))	('Akt', 'Gene', (27, 30))	('rabbit', 'Species', '9986', (202, 208))
213547	23883667	The following antibodies were used: anti-beta1-integrin, clone 18 (BD Biosciences); anti-beta1-integrin, AIIB2 (Sierra Biosource, Morgan Hill, CA, USA); anti-alpha5-integrin (Millipore); anti-alpha6-integrin, NKI-GoH3 (Millipore); anti-FN, IST-4 (Sigma); anti-FN EDA+ (Abcam, Cambridge, England); anti-cleaved caspase-3 (Cell signaling Technology); anti-NF-kappaB p65 (Immuno-Biological Laboratories Co., Ltd., Gunma, Japan); anti-histone H1 (abcam) anti-beta-actin (Sigma-Aldrich); ECL  anti-mouse immunoglobulin G (IgG), HRP linked whole antibody (from sheep), NA931V (GE Healthcare, Buckinghamshire, UK); ECL  anti-rabbit IgG, HRP linked whole antibody (from donkey), NA934V (GE Healthcare).	('FN', 'Gene', '2335', (236, 238))	('beta1-integrin', 'Gene', (89, 103))	('donkey', 'Species', '9793', (662, 668))	('FN', 'Gene', '2335', (260, 262))	('beta-actin', 'Gene', (455, 465))	('beta1-integrin', 'Gene', '3688', (41, 55))	('NA934V', 'Var', (671, 677))	('NF-kappaB p65', 'Gene', (354, 367))	('NF-kappaB p65', 'Gene', '5970', (354, 367))	('beta1-integrin', 'Gene', (41, 55))	('NA931V', 'Var', (563, 569))	('EDA', 'Gene', '101120990', (263, 266))	('mouse', 'Species', '10090', (493, 498))	('sheep', 'Species', '9940', (555, 560))	('rabbit', 'Species', '9986', (618, 624))	('beta1-integrin', 'Gene', '3688', (89, 103))	('EDA', 'Gene', (263, 266))	('beta-actin', 'Gene', '100885765', (455, 465))
213570	23883667	These results are consistent with our previous study in early stage invasive breast cancer where we showed that beta1-integrin expression was associated with more aggressive disease and significantly reduced overall and disease-free survival.	('breast cancer', 'Disease', (77, 90))	('aggressive disease', 'Disease', (163, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('disease-free survival', 'CPA', (220, 241))	('reduced', 'NegReg', (200, 207))	('associated with', 'Reg', (142, 157))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('beta1-integrin', 'Gene', '3688', (112, 126))	('expression', 'Var', (127, 137))	('aggressive disease', 'Disease', 'MESH:D001523', (163, 181))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('beta1-integrin', 'Gene', (112, 126))
213572	23883667	As human DCIS lesions were found to up-regulate p-Akt, we modeled DCIS by propagating MCF10A human mammary epithelial cells with inducible active ER-Akt.	('MCF10A', 'CellLine', 'CVCL:0598', (86, 92))	('Akt', 'Gene', '207', (50, 53))	('Akt', 'Gene', (149, 152))	('human', 'Species', '9606', (3, 8))	('human', 'Species', '9606', (93, 98))	('DCIS', 'Phenotype', 'HP:0030075', (66, 70))	('Akt', 'Gene', (50, 53))	('lesions', 'Var', (14, 21))	('Akt', 'Gene', '207', (149, 152))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('up-regulate', 'PosReg', (36, 47))
213579	23883667	The expression of cleaved caspase-3, an apoptosis marker, was negatively correlated with proliferation, measured by Ki-67 nuclear antigen, and negatively correlated with active Akt positive regions (Figure 2D).	('negatively correlated', 'NegReg', (143, 164))	('proliferation', 'CPA', (89, 102))	('negatively', 'NegReg', (62, 72))	('cleaved', 'Var', (18, 25))	('Akt', 'Gene', (177, 180))	('expression', 'MPA', (4, 14))	('Akt', 'Gene', '207', (177, 180))
213595	23883667	Since beta1-integrin was highly expressed in the invasive colonies and is a known driver of invasion, we tested whether inhibiting beta1-integrin affected the ability of surviving cells post-IR to acquire invasive features.	('beta1-integrin', 'Gene', '3688', (6, 20))	('tested', 'Reg', (105, 111))	('beta1-integrin', 'Gene', '3688', (131, 145))	('beta1-integrin', 'Gene', (6, 20))	('beta1-integrin', 'Gene', (131, 145))	('inhibiting', 'Var', (120, 130))
213642	23883667	This work was supported in part by the Matching Program for Innovations in Future Drug Discovery and Medical Care from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) and by the Grant-in-Aid from the Japan Society for Young Scientists (B) (23791376 and 25861050) to JN.	('Aid', 'Gene', '57379', (222, 225))	('25861050', 'Var', (288, 296))	('23791376', 'Var', (275, 283))	('Aid', 'Gene', (222, 225))
213776	20036817	The disruption of this cell layer results in the release of the growth factors, angiogenic factors, and reactive oxygen species causing an alteration in the microenvironment.	('alteration', 'Reg', (139, 149))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (104, 127))	('release', 'MPA', (49, 56))	('disruption', 'Var', (4, 14))
213788	20036817	On the other hand, degradation of this layer promotes breast tumor progression and metastasis, although the exact mechanisms of this phenomenon are still unclear.	('breast tumor', 'Phenotype', 'HP:0100013', (54, 66))	('metastasis', 'CPA', (83, 93))	('breast tumor', 'Disease', 'MESH:D001943', (54, 66))	('promotes', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('breast tumor', 'Disease', (54, 66))	('degradation', 'Var', (19, 30))
213825	20036817	found that loss of CK5/6 was associated with features of aggressive tumors and lack of CK5/6 was significantly associated with reduced survival in large population-based series of 276 endometrial carcinomas with long and complete follow-up.	('CK5/6', 'Gene', (87, 92))	('endometrial carcinomas', 'Disease', (184, 206))	('CK5/6', 'Gene', '3852', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('aggressive tumors', 'Disease', 'MESH:D001523', (57, 74))	('loss', 'Var', (11, 15))	('survival', 'MPA', (135, 143))	('CK5/6', 'Gene', '3852', (87, 92))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (184, 206))	('aggressive tumors', 'Disease', (57, 74))	('CK5/6', 'Gene', (19, 24))	('lack', 'Var', (79, 83))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (184, 206))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('reduced', 'NegReg', (127, 134))
213830	20036817	Mutations in activin receptors have been indeed associated with pancreatic and pituitary tumors.	('pituitary tumors', 'Disease', 'MESH:D010911', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('associated', 'Reg', (48, 58))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('activin', 'Gene', (13, 20))	('Mutations', 'Var', (0, 9))	('pituitary tumors', 'Disease', (79, 95))	('pancreatic', 'Disease', (64, 74))	('activin', 'Gene', '83729', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
213850	20036817	Alteration in tissue organization and homeostasis can precede and increase the chance of tumor initiation as exemplified by the increased cancer risk associated with chronic inflammation and wound healing.	('cancer', 'Disease', (138, 144))	('Alteration', 'Var', (0, 10))	('inflammation', 'Disease', 'MESH:D007249', (174, 186))	('homeostasis', 'MPA', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('inflammation', 'Disease', (174, 186))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
213854	20036817	On the contrary, myoepithelial cells also exhibit a tumor suppressor phenotype and they rarely transform themselves; however, when they transform, they generally give rise to benign neoplasms that grow without degrading ECM.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('benign neoplasms', 'Disease', (175, 191))	('tumor', 'Disease', (52, 57))	('transform', 'Var', (136, 145))	('benign neoplasms', 'Disease', 'MESH:D009369', (175, 191))	('neoplasms', 'Phenotype', 'HP:0002664', (182, 191))	('give rise to', 'Reg', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
213864	20036817	It has been speculated that most of these secretory molecules act in a paracrine manner so that a disruption in the myoepithelial cell layer can result in the release of these factors and possibly alter the tumor microenvironment which ultimately results in metastasis to other organs.	('disruption', 'Var', (98, 108))	('result in', 'Reg', (145, 154))	('alter', 'Reg', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('results in', 'Reg', (247, 257))	('tumor', 'Disease', (207, 212))	('metastasis', 'CPA', (258, 268))	('release', 'MPA', (159, 166))
213880	20036817	According to this model, tumor invasion is triggered by a series of events which begin when the myoepithelial cells are damaged by any genetic abnormalities, inflammation, mutations, localized trauma or other physical/chemical injuries which result in the disruption of the myoepithelial cell layer or impairs the normal replacement process.	('injuries', 'Disease', (227, 235))	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('trauma', 'Disease', 'MESH:D014947', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('trauma', 'Disease', (193, 199))	('inflammation', 'Disease', (158, 170))	('impairs', 'NegReg', (302, 309))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('genetic abnormalities', 'Disease', 'MESH:D030342', (135, 156))	('triggered', 'Reg', (43, 52))	('injuries', 'Disease', 'MESH:D058186', (227, 235))	('genetic abnormalities', 'Disease', (135, 156))
213894	20036817	The resulting immunoreactions that accompany an external environmental insult or internal genetic alterations are triggering factors for further disruptions of the myoepithelial cell layer, BM degradation, and subsequent tumor progression and invasion.	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('invasion', 'CPA', (243, 251))	('tumor', 'Disease', (221, 226))	('alterations', 'Var', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
213916	20036817	Their results showed that acidity indeed induced up-regulation of VEGF-A, IL-8, MMP-2, MMP-9, cathespin B and cathespin L resulting in the enhanced metastatic potential of these human melanoma cell lines thus providing significant evidence that acidity-induced up-regulation of these proteins is a possible mechanism for tumor invasiveness in melanoma cancer.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('IL-8', 'Gene', (74, 78))	('melanoma', 'Disease', (184, 192))	('metastatic potential', 'CPA', (148, 168))	('human', 'Species', '9606', (178, 183))	('acidity', 'Var', (26, 33))	('VEGF-A', 'Gene', (66, 72))	('tumor invasiveness in melanoma cancer', 'Disease', (321, 358))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('MMP-2', 'Gene', (80, 85))	('cathespin L', 'Gene', (110, 121))	('up-regulation', 'PosReg', (49, 62))	('melanoma', 'Disease', 'MESH:D008545', (343, 351))	('IL-8', 'Gene', '3576', (74, 78))	('VEGF-A', 'Gene', '7422', (66, 72))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('MMP-2', 'Gene', '4313', (80, 85))	('MMP-9', 'Gene', '4318', (87, 92))	('MMP-9', 'Gene', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (343, 351))	('melanoma', 'Disease', (343, 351))	('cathespin B', 'Gene', (94, 105))	('tumor invasiveness in melanoma cancer', 'Disease', 'MESH:C563985', (321, 358))	('enhanced', 'PosReg', (139, 147))
213971	33420200	Malignancy were seen in 1 of 4 patients with architectural distortion and 1 of 8 patients with spiculated mass.	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (81, 89))	('Malignancy', 'CPA', (0, 10))	('architectural distortion', 'Var', (45, 69))
213986	33420200	showed that the probability of malignancy in calcifications' morphology was higher in fine pleomorphic (44.7%) while with respect to distribution, the highest percentage were in segmental distribution (78%) and 68% in linear distribution.	('malignancy', 'Disease', (31, 41))	('fine pleomorphic', 'Var', (86, 102))	('malignancy', 'Disease', 'MESH:D009369', (31, 41))
213991	33420200	However, in the long run, VABB will reduce the need for surgery and reduce the incidence of delayed in diagnosis of cancer due to underestimation, which will then further burden the healthcare system.	('reduce', 'NegReg', (36, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('reduce', 'NegReg', (68, 74))	('VABB', 'Var', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
214022	27017136	In addition, DBT may improve cancer detection.	('DBT', 'Var', (13, 16))	('cancer', 'Disease', (29, 35))	('improve', 'PosReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
214038	27017136	One area of active investigation is the combined use of multiparametric MRI and tumor molecular biomarkers to improve management of low-grade DCIS with the goal of reducing overtreatment of low-risk lesions.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lesion', 'Disease', 'MESH:D051437', (199, 205))	('lesion', 'Disease', (199, 205))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('tumor', 'Disease', (80, 85))	('low-grade', 'Var', (132, 141))
214092	21867691	Mitochondrial membrane potential was measured by incubating the cells with 200nM TMRM in PBS for 20 min and then analyzed by FACScan flow cytometer (BD Biosciences).	('PBS', 'Chemical', 'MESH:D007854', (89, 92))	('Mitochondrial membrane potential', 'MPA', (0, 32))	('TMRM', 'Var', (81, 85))
214121	21867691	Gene silencing of NDUFS3 with SiRNA led to distinct metabolic changes in MDA231 cells further confirming that mitochondrial function in the cancer cells are more susceptible to NDUFS3 levels and vice versa (Figure 4b).	('MDA231', 'CellLine', 'CVCL:0062', (73, 79))	('NDUFS3', 'Gene', (18, 24))	('metabolic', 'MPA', (52, 61))	('more', 'PosReg', (157, 161))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Gene silencing', 'Var', (0, 14))	('susceptible', 'MPA', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
214126	21867691	Figures 4c&d show representative data demonstrating that MDA231 cells have an increased tolerance to ROS insult (both exogenous and endogenous) as compared with normal MCF10A cells.	('that', 'Var', (52, 56))	('MDA231', 'CellLine', 'CVCL:0062', (57, 63))	('increased tolerance to ROS', 'MPA', (78, 104))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('MCF10A', 'CellLine', 'CVCL:0598', (168, 174))
214131	21867691	A compromise in proper assembly of these individual complexes can lead to mitochondrial dysfunctions.	('mitochondrial dysfunctions', 'Disease', 'MESH:D028361', (74, 100))	('mitochondrial dysfunctions', 'Phenotype', 'HP:0003287', (74, 100))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (74, 99))	('lead to', 'Reg', (66, 73))	('compromise', 'Var', (2, 12))	('mitochondrial dysfunctions', 'Disease', (74, 100))
214134	21867691	Since our data were obtained from clinically relevant, human breast cancer patients, these observations add further credibility to the hypothesis that mitochondrial dysfunction arising from complex I assembly defects could be a viable source of metabolic deregulation in cancer.	('mitochondrial dysfunction', 'Disease', (151, 176))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('human', 'Species', '9606', (55, 60))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('defects', 'Var', (209, 216))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('mitochondrial dysfunction arising from complex I', 'Phenotype', 'HP:0011923', (151, 199))	('cancer', 'Disease', (271, 277))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (151, 176))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (151, 176))
214137	21867691	We speculate that with an increase in tumor aggressivenss and the onset of hypoxia, mitochondrial assembly defects can be more common thereby leading to the observed increase in NDUFS3 expression in invasive ductal carcinoma specimens.	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('invasive ductal carcinoma', 'Disease', (199, 224))	('expression', 'MPA', (185, 195))	('increase', 'PosReg', (166, 174))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (208, 224))	('defects', 'Var', (107, 114))	('mitochondrial', 'MPA', (84, 97))	('tumor aggressivenss', 'Disease', 'MESH:D009369', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (199, 224))	('NDUFS3', 'Gene', (178, 184))	('tumor aggressivenss', 'Disease', (38, 57))
214150	26089689	In the multivariable model, patients receiving postoperative RT had better OS than those undergoing BCS alone (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.53-0.67, P<0.001).	('postoperative RT', 'Var', (47, 63))	('patients', 'Species', '9606', (28, 36))	('better', 'PosReg', (68, 74))
214186	26089689	With regard to OS, patients who received postoperative RT had better OS than those in the No-RT group in both univariate analysis (HR 0.62, 95% CI 0.59-0.66, P<0.001) and multivariate analysis (HR 0.59, 95% CI 0.53-0.67, P<0.001); in addition, both univariate and multivariate analyses showed that younger age, nonblack race, being married, single-quadrant lesions, and positive PR were significantly associated with improved OS.	('single-quadrant', 'Var', (341, 356))	('improved', 'PosReg', (417, 425))	('patients', 'Species', '9606', (19, 27))	('PR', 'Gene', '5241', (379, 381))
214191	26089689	In contrast, we noted that RT delivery was specifically associated with improved BCSS in ER-negative/borderline patients (HR 0.41, 95% CI 0.19-0.88, P=0.023).	('BCSS', 'CPA', (81, 85))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (112, 120))	('RT delivery', 'Var', (27, 38))	('ER', 'Gene', '2099', (89, 91))
214195	26089689	In this population-based cohort of DCIS patients who underwent BCS, RT delivery was significantly associated with improved OS regardless of subgroup analysis after stratification, refuting the statement by two previous trials claiming that RT does not affect OS of DCIS patients.	('patients', 'Species', '9606', (270, 278))	('patients', 'Species', '9606', (40, 48))	('RT delivery', 'Var', (68, 79))	('improved', 'PosReg', (114, 122))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('DCIS', 'Phenotype', 'HP:0030075', (265, 269))
214227	16916448	Four BC risk categories included BRCA1/2 carriers, increased, intermediate, and slightly increased risk.	('carriers', 'Var', (41, 49))	('BRCA1/2', 'Gene', '672;675', (33, 40))	('BRCA1/2', 'Gene', (33, 40))
214232	16916448	The incidence observed among BRCA carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; P < 0.001), women at increased (SIR = 4.5; 95% CI = 1.5 to 8.3; P < 0.001) or intermediate risk (SIR = 7.0, 95% CI = 2.0 to 17.1; P = 0.0018) was higher than expected, while the difference between observed and expected among women at slightly increased risk was not statistically significant (SIR = 2.4, 95% CI = 0.9 to 8.3; P = .74).	('women', 'Species', '9606', (303, 308))	('women', 'Species', '9606', (90, 95))	('BRCA', 'Gene', '672', (29, 33))	('BRCA', 'Gene', (29, 33))	('higher', 'PosReg', (224, 230))	('carriers', 'Var', (34, 42))
214235	16916448	Following the discovery the mutant BRCA1 and BRCA2 genes which predispose carriers for BC and OC, many high-risk women request genetic testing and counselling on strategies to reduce their risk of death from BC.	('mutant', 'Var', (28, 34))	('BRCA2', 'Gene', (45, 50))	('death', 'Disease', (197, 202))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA1', 'Gene', '672', (35, 40))	('women', 'Species', '9606', (113, 118))	('BRCA1', 'Gene', (35, 40))	('death', 'Disease', 'MESH:D003643', (197, 202))
214254	16916448	Finally, a group defined by a genetic predisposition due to the presence of the mutant BRCA genes was established to have a lifetime 50-85% risk of developing BC.	('presence', 'Var', (64, 72))	('BRCA', 'Gene', '672', (87, 91))	('BRCA', 'Gene', (87, 91))	('mutant', 'Var', (80, 86))
214255	16916448	To date, 1325 asymptomatic women accepted to be enrolled in our surveillance program, of which 1072 were first degree, and 253 were second degree relatives; 48 women belonged to carrier group (37 were BRCA1 mutation carriers, and 11 BRCA2 mutation carriers), 674 belonged to the high risk group, 257 to the intermediate risk group, and 346 to the slightly increased risk group (Table 2).	('women', 'Species', '9606', (27, 32))	('mutation', 'Var', (239, 247))	('BRCA2', 'Gene', '675', (233, 238))	('women', 'Species', '9606', (160, 165))	('BRCA1', 'Gene', '672', (201, 206))	('BRCA2', 'Gene', (233, 238))	('mutation', 'Var', (207, 215))	('BRCA1', 'Gene', (201, 206))
214257	16916448	Genetic testing to identify deleterious BRCA1 and BRCA2 mutations included direct automated sequencing on the entire coding sequence.	('mutations', 'Var', (56, 65))	('BRCA2', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (40, 45))	('BRCA2', 'Gene', '675', (50, 55))	('BRCA1', 'Gene', (40, 45))
214258	16916448	From 1995 to 2005, 385 index cases affected by BC or OC, in the high risk categories, were tested for BRCA1/2 mutations of which, 82 carrier patients (21.3%) were identified.	('BRCA1/2', 'Gene', (102, 109))	('BRCA1/2', 'Gene', '672;675', (102, 109))	('patients', 'Species', '9606', (141, 149))	('mutations', 'Var', (110, 119))
214259	16916448	Of these 82 carriers, 79 asymptomatic relatives were found to carry a BRCA mutation.	('mutation', 'Var', (75, 83))	('BRCA', 'Gene', (70, 74))	('BRCA', 'Gene', '672', (70, 74))
214260	16916448	Carriers of BRCA1 or BRCA2 mutations discovered through genetic testing or subjects at risk according to our previously described criteria, who were at least 18 years of age were eligible.	('mutations', 'Var', (27, 36))	('BRCA2', 'Gene', '675', (21, 26))	('BRCA1', 'Gene', '672', (12, 17))	('BRCA2', 'Gene', (21, 26))	('BRCA1', 'Gene', (12, 17))
214262	16916448	In October 2000, surveillance for carriers of BRCA1 or BRCA2 mutations was modified by introducing a dynamic breast MRI with gadolinium-containing contrast medium (Table 3).	('BRCA2', 'Gene', (55, 60))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA2', 'Gene', '675', (55, 60))	('mutations', 'Var', (61, 70))	('gadolinium', 'Chemical', 'MESH:D005682', (125, 135))	('BRCA1', 'Gene', (46, 51))
214291	16916448	The detection rates of BC were 31.6 per 1000 person-years in BRCA1/2 gene mutation carriers, 6.9 per 1000 in the high risk-group, 9.9 per 1000 person-years in the intermediate risk group, and 3.5 per 1000 in the slightly increased risk-group.	('person', 'Species', '9606', (45, 51))	('mutation', 'Var', (74, 82))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('BRCA1/2', 'Gene', (61, 68))	('person', 'Species', '9606', (143, 149))
214293	16916448	The incidence was significantly higher among BRCA1 and BRCA2 carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; P < 0.001) and amongst subjects classified at high (SIR = 4.5; 95% CI = 1.5 to 8.3; P < 0.001) or intermediate risk (SIR = 7.0, 95% CI = 2.0 to 17.1; P = 0.0018).	('BRCA2', 'Gene', (55, 60))	('BRCA1', 'Gene', '672', (45, 50))	('higher', 'PosReg', (32, 38))	('BRCA2', 'Gene', '675', (55, 60))	('BRCA1', 'Gene', (45, 50))	('carriers', 'Var', (61, 69))
214320	16916448	Finally, Brekelmans, who has enrolled 1198 women characterized by BRCA1/2 mutations or by a BC risk over 15% between 21-70 years of age in a screening program, found 35 cancers (31 invasive and 4 DCIS) after a median follow-up of 3 years.	('BRCA1/2', 'Gene', (66, 73))	('cancers', 'Disease', (169, 176))	('BRCA1/2', 'Gene', '672;675', (66, 73))	('mutations', 'Var', (74, 83))	('women', 'Species', '9606', (43, 48))	('invasive', 'Disease', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
214337	33850160	EFA6B regulates a stop signal for collective invasion in breast cancer Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes.	('Cancer', 'Disease', (71, 77))	('breast cancer', 'Disease', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('EFA6B', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EFA6B', 'Gene', '23550', (0, 5))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (128, 133))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
214338	33850160	However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases.	('tumor', 'Disease', (68, 73))	('alterations', 'Var', (20, 31))	('develop', 'PosReg', (104, 111))	('advantages', 'PosReg', (50, 60))	('metastases', 'Disease', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('rat', 'Species', '10116', (24, 27))	('resist treatment', 'CPA', (83, 99))
214340	33850160	Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen.	('loss', 'Var', (21, 25))	('EFA6B', 'Gene', (29, 34))	('transcriptional', 'MPA', (46, 61))	('unleashes', 'NegReg', (121, 130))	('CDC42-dependent', 'Protein', (131, 146))	('ECM', 'Gene', '22915', (91, 94))	('triggers', 'Reg', (35, 43))	('ECM', 'Gene', (91, 94))
214341	33850160	In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B.	('MCF10 DCIS.com', 'CellLine', 'CVCL:5552', (26, 40))	('knocked-out', 'Var', (100, 111))	('EFA6B', 'Gene', (116, 121))	('invades', 'CPA', (80, 87))	('DCIS', 'Phenotype', 'HP:0030075', (32, 36))	('DCIS', 'Phenotype', 'HP:0030075', (50, 54))
214345	33850160	Here, the authors report that loss of EFA6B promotes collective invasion through activation of the epithelial-to-mesenchymal transition program and CDC42-dependent signalling pathways in breast cancer.	('promotes', 'PosReg', (44, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('epithelial-to-mesenchymal transition program', 'CPA', (99, 143))	('activation', 'PosReg', (81, 91))	('collective invasion', 'CPA', (53, 72))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('EFA6B', 'Gene', (38, 43))	('CDC42-dependent signalling pathways', 'Pathway', (148, 183))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('loss', 'Var', (30, 34))	('breast cancer', 'Disease', (187, 200))
214355	33850160	Here, to determine the mechanism by which the loss of EFA6B might facilitate the progression of metastatic tumors, we analyzed the consequence of knocking out its gene (PSD4) in normal human mammary cells.	('human', 'Species', '9606', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('progression', 'CPA', (81, 92))	('facilitate', 'PosReg', (66, 76))	('EFA6B', 'Gene', (54, 59))	('tumors', 'Disease', (107, 113))	('loss', 'Var', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('knocking', 'Var', (146, 154))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('PSD4', 'Gene', (169, 173))
214357	33850160	EFA6B KO leads to the activation of CDC42, which in turn elicits two signaling pathways essential for invading a 3D-collagen matrix: Cdc42-MRCK-pMLC, which regulates contractility, and Cdc42-N-WASP-Arp2/3, which is required for the formation of integrin beta1-based and MMP14-enriched invadopodia.	('Cdc42', 'Gene', (185, 190))	('MMP14', 'Gene', '4323', (270, 275))	('CDC42', 'Gene', (36, 41))	('Arp2/3', 'Gene', (198, 204))	('integrin beta1', 'Gene', (245, 259))	('Cdc42', 'Gene', '998', (133, 138))	('integrin beta1', 'Gene', '3688', (245, 259))	('MMP14', 'Gene', (270, 275))	('activation', 'PosReg', (22, 32))	('N-WASP', 'Gene', '8976', (191, 197))	('MRCK', 'Gene', '8476', (139, 143))	('EFA6B KO', 'Var', (0, 8))	('Cdc42', 'Gene', '998', (185, 190))	('MRCK', 'Gene', (139, 143))	('Cdc42', 'Gene', (133, 138))	('N-WASP', 'Gene', (191, 197))	('elicits', 'Reg', (57, 64))	('Arp2/3', 'Gene', '10097;10096', (198, 204))
214360	33850160	The MCF10A human mammary cell line was used for the knock-out as it is a well-characterized normal human mammary cell line and thus enabled us to study the effect of deleting PSD4 in a non-transformed genetic background.	('human', 'Species', '9606', (11, 16))	('PSD4', 'Gene', (175, 179))	('MCF10A', 'CellLine', 'CVCL:0598', (4, 10))	('deleting', 'Var', (166, 174))	('human', 'Species', '9606', (99, 104))
214361	33850160	A slight decrease (1.4 +- 0.4 fold) of ARF6 expression was observed in EFA6BKO cells (Fig.	('EFA6BKO', 'CellLine', 'CVCL:K035', (71, 78))	('expression', 'MPA', (44, 54))	('ARF6', 'Gene', (39, 43))	('EFA6BKO', 'Var', (71, 78))	('ARF6', 'Gene', '382', (39, 43))	('decrease', 'NegReg', (9, 17))
214363	33850160	Notably, ARF6GTP levels were reduced (2.5 +- 0.4 fold) indicating that EFA6B is a major ARF6-GEF in MCF10A cells (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (100, 106))	('GEF', 'Gene', (93, 96))	('ARF6', 'Gene', (88, 92))	('ARF6', 'Gene', '382', (9, 13))	('ARF6', 'Gene', '382', (88, 92))	('reduced', 'NegReg', (29, 36))	('ARF6GTP', 'Gene', (9, 16))	('GEF', 'Gene', '9181', (93, 96))	('ARF6GTP', 'Gene', '382', (9, 16))	('EFA6B', 'Var', (71, 76))	('ARF6', 'Gene', (9, 13))
214365	33850160	MCF10A WT, MCF10A WT expressing a sgRNA control, and two of the WT clones isolated during the screen formed round aggregates typical of normal epithelial cells (Fig.	('formed', 'Reg', (101, 107))	('MCF10A', 'CellLine', 'CVCL:0598', (11, 17))	('MCF10A', 'CellLine', 'CVCL:0598', (0, 6))	('MCF10A', 'Var', (0, 6))
214373	33850160	2a) and immediately performed CRISPR/Cas9-mediated mutation of PSD4 in each separate population.	('rat', 'Species', '10116', (80, 83))	('PSD4', 'Gene', (63, 67))	('mutation', 'Var', (51, 59))
214388	33850160	Cortactin, a well-known marker for invadopodia, was expressed at similar levels in WT and EFA6BKO cells (Supplementary Fig.	('Cortactin', 'Gene', (0, 9))	('EFA6BKO', 'CellLine', 'CVCL:K035', (90, 97))	('Cortactin', 'Gene', '101088615', (0, 9))	('EFA6BKO', 'Var', (90, 97))
214407	33850160	Thus, the absence of EFA6B induces a modification of the matrisome and ITG repertoire along with the formation of degradative ITGbeta1-based invadopodia, all of which contribute to the collective invasion of the EFA6BKO cells.	('modification', 'Reg', (37, 49))	('ITGbeta1', 'Gene', (126, 134))	('contribute', 'Reg', (167, 177))	('EFA6BKO', 'CellLine', 'CVCL:K035', (212, 219))	('EFA6B', 'Gene', (21, 26))	('absence', 'Var', (10, 17))	('ITGbeta1', 'Gene', '3672', (126, 134))	('collective invasion', 'CPA', (185, 204))
214422	33850160	Hence, depending on the cell lines, the elicited EMT-TFs and the EMT program triggered by EFA6BKO are variable, yet altogether our results indicate that the loss of EFA6B engages epithelial cells into EMT.	('EFA6B', 'Gene', (165, 170))	('EFA6BKO', 'CellLine', 'CVCL:K035', (90, 97))	('loss', 'Var', (157, 161))
214428	33850160	Overall, these observations demonstrated that EFA6B KO leads to the activation of CDC42, which regulates cell contractility, formation of filopodia and invadopodia, collagen remodeling, and collective invasion in 3D-collagen.	('EFA6B KO', 'Var', (46, 54))	('CDC42', 'Gene', (82, 87))	('collective invasion in', 'CPA', (190, 212))	('regulates', 'Reg', (95, 104))	('cell contractility', 'CPA', (105, 123))	('collagen', 'CPA', (165, 173))	('activation', 'PosReg', (68, 78))	('rat', 'Species', '10116', (35, 38))
214433	33850160	Knock-down of both ROCK1/2 had no effect on either phosphorylation of MLC or invasion (Fig.	('Knock-down', 'Var', (0, 10))	('MLC', 'Protein', (70, 73))	('invasion', 'CPA', (77, 85))	('phosphorylation', 'MPA', (51, 66))	('ROCK1/2', 'Gene', (19, 26))	('ROCK1/2', 'Gene', '6093;9475', (19, 26))
214435	33850160	Further, siRNA downregulation of N-WASP and ARP3, both proteins similarly expressed in WT and EFA6BKO cells inhibited invasion (Fig.	('downregulation', 'NegReg', (15, 29))	('ARP3', 'Gene', '10096', (44, 48))	('EFA6BKO', 'Var', (94, 101))	('N-WASP', 'Gene', '8976', (33, 39))	('ARP3', 'Gene', (44, 48))	('EFA6BKO', 'CellLine', 'CVCL:K035', (94, 101))	('invasion', 'CPA', (118, 126))	('inhibited', 'NegReg', (108, 117))	('N-WASP', 'Gene', (33, 39))
214441	33850160	EFA6BKO xenografts presented abnormal ductal phenotype and infiltrating foci as early as at week 2 where the percentage of p63-positive cells in EFA6BKO xenografts was increased.	('p63', 'Gene', (123, 126))	('increased', 'PosReg', (168, 177))	('EFA6BKO', 'Var', (145, 152))	('rat', 'Species', '10116', (65, 68))	('p63', 'Gene', '8626', (123, 126))	('EFA6BKO', 'CellLine', 'CVCL:K035', (0, 7))	('EFA6BKO', 'CellLine', 'CVCL:K035', (145, 152))	('ductal phenotype', 'CPA', (38, 54))
214446	33850160	9b), which corroborates our results showing that the loss of EFA6B in cells of epithelial origin generates invasive mammary cells (Fig.	('rat', 'Species', '10116', (18, 21))	('rat', 'Species', '10116', (101, 104))	('EFA6B', 'Gene', (61, 66))	('invasive mammary cells', 'CPA', (107, 129))	('loss', 'Var', (53, 57))
214448	33850160	Thus, ontologies associated with PSD4 knock-out in MCF10A cells correlate with those of the progression of DCIS to IDC in patients.	('PSD4', 'Gene', (33, 37))	('MCF10A', 'CellLine', 'CVCL:0598', (51, 57))	('DCIS', 'Disease', (107, 111))	('IDC', 'Disease', (115, 118))	('DCIS', 'Phenotype', 'HP:0030075', (107, 111))	('patients', 'Species', '9606', (122, 130))	('knock-out', 'Var', (38, 47))
214456	33850160	We conclude that loss of EFA6B endows epithelial mammary cells with molecular characteristics of human invasive ductal carcinoma and lowers the 5-year DFS.	('lowers', 'NegReg', (133, 139))	('invasive ductal carcinoma', 'Disease', (103, 128))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (112, 128))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (103, 128))	('human', 'Species', '9606', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('EFA6B', 'Gene', (25, 30))	('loss', 'Var', (17, 21))
214462	33850160	Thus, EFA6B depletion in both luminal and basal cells induces EMT and stimulates collective invasion.	('luminal', 'Chemical', 'MESH:D010634', (30, 37))	('EFA6B', 'Gene', (6, 11))	('collective invasion', 'CPA', (81, 100))	('stimulates', 'PosReg', (70, 80))	('induces', 'PosReg', (54, 61))	('EMT', 'CPA', (62, 65))	('depletion', 'Var', (12, 21))
214463	33850160	Interestingly, the fact that the EFA6BKO cells undergo EMT, display thin filopodia at the front of the leader cells, assemble MMP14 invadopodia, and sustain invasive protrusions in collagen I is reminiscent of the mechanism of invasion by cancer cells.	('EFA6BKO', 'CellLine', 'CVCL:K035', (33, 40))	('EMT', 'CPA', (55, 58))	('MMP14', 'Gene', '4323', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('MMP14', 'Gene', (126, 131))	('EFA6BKO', 'Var', (33, 40))	('cancer', 'Disease', (239, 245))	('invasive protrusions', 'CPA', (157, 177))	('thin filopodia', 'CPA', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
214471	33850160	Consistent with this, we found that knock-down of CDC42 abrogates contractility and invasion of the EFA6BKO cells.	('knock-down', 'Var', (36, 46))	('abrogates', 'NegReg', (56, 65))	('CDC42', 'Gene', (50, 55))	('invasion of the EFA6BKO cells', 'CPA', (84, 113))	('contractility', 'CPA', (66, 79))	('EFA6BKO', 'CellLine', 'CVCL:K035', (100, 107))
214475	33850160	The increased contractility of EFA6BKO cells may also be the consequence of an alteration of the matrisome that might have strengthened the ECM rigidity.	('rigidity', 'Phenotype', 'HP:0002063', (144, 152))	('rat', 'Species', '10116', (83, 86))	('strengthened', 'PosReg', (123, 135))	('ECM rigidity', 'Disease', 'MESH:D009127', (140, 152))	('matrisome', 'Protein', (97, 106))	('ECM rigidity', 'Disease', (140, 152))	('contractility', 'CPA', (14, 27))	('EFA6BKO', 'CellLine', 'CVCL:K035', (31, 38))	('increased', 'PosReg', (4, 13))	('EFA6BKO', 'Var', (31, 38))
214480	33850160	Since in BC patients, we found a correlation between the severity of the clinico-pathological data and the gradual loss of expression of EFA6B messenger, we propose that PSD4/EFA6B could act as a haplo-insufficient tumor-antagonist gene.	('patients', 'Species', '9606', (12, 20))	('expression', 'MPA', (123, 133))	('BC', 'Phenotype', 'HP:0003002', (9, 11))	('loss', 'NegReg', (115, 119))	('haplo-insufficient tumor', 'Disease', 'MESH:D007018', (196, 220))	('EFA6B', 'Gene', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('haplo-insufficient tumor', 'Disease', (196, 220))	('PSD4/EFA6B', 'Var', (170, 180))
214481	33850160	In BC, mutations and copy number alterations of PSD4/EFA6B gene are very rare.	('copy number alterations', 'Var', (21, 44))	('PSD4/EFA6B', 'Gene', (48, 58))	('rat', 'Species', '10116', (37, 40))	('BC', 'Phenotype', 'HP:0003002', (3, 5))
214484	33850160	The discovery that the simple loss of EFA6B can model cancer invasion implies that such alteration can orchestrate many of the steps of the invasion cascade independently of an oncogenic mutation, congruent with the two-hit hypothesis, one that will transform the cell and another one that will help overcome the control by the microenvironment.	('rat', 'Species', '10116', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('rat', 'Species', '10116', (92, 95))	('EFA6B', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutation', 'Var', (187, 195))	('loss', 'Var', (30, 34))	('alteration', 'Var', (88, 98))
214485	33850160	Consistent with this hypothesis, we have shown here that invasive BCs had a diminished expression of PSD4 when compared to pre-invasive in situ BCs and that EFA6BKO cells have a transcriptomic signature that shares several gene ontologies with signatures of progression from DCIS to IDC.	('DCIS', 'Disease', (275, 279))	('DCIS', 'Phenotype', 'HP:0030075', (275, 279))	('BC', 'Phenotype', 'HP:0003002', (144, 146))	('EFA6BKO', 'CellLine', 'CVCL:K035', (157, 164))	('expression', 'MPA', (87, 97))	('BC', 'Phenotype', 'HP:0003002', (66, 68))	('diminished', 'NegReg', (76, 86))	('PSD4', 'Gene', (101, 105))	('EFA6BKO', 'Var', (157, 164))
214487	33850160	We observed an enhanced percentage of p63-positive cells, faster acquisition of the IDC phenotype, and increased tumor growth in EFA6BKO xenografts.	('tumor', 'Disease', (113, 118))	('faster', 'PosReg', (58, 64))	('IDC phenotype', 'MPA', (84, 97))	('increased', 'PosReg', (103, 112))	('EFA6BKO', 'CellLine', 'CVCL:K035', (129, 136))	('p63', 'Gene', (38, 41))	('EFA6BKO', 'Var', (129, 136))	('p63', 'Gene', '8626', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('enhanced', 'PosReg', (15, 23))
214504	33850160	The expression of each gene was normalized to the HPRT1 or GAPDH housekeeping genes and relative levels were calculated on the basis of the comparative cycle threshold Ct method (2-DeltaDeltaCt) where DeltaDeltaCt is the difference in Ct between target and reference gene.	('HPRT1', 'Gene', '3251', (50, 55))	('HPRT1', 'Gene', (50, 55))	('GAPDH', 'Gene', '2597', (59, 64))	('GAPDH', 'Gene', (59, 64))	('rat', 'Species', '10116', (145, 148))	('DeltaDeltaCt', 'Var', (201, 213))
214507	33850160	We compared the expression profiles between the MCF10A harboring PSD4 knock-out (N = 5) and the MCF10A control (N = 2) using a moderated t-test with empirical Bayes statistic included in the limma R packages (version 3.38.3).	('knock-out', 'Var', (70, 79))	('rat', 'Species', '10116', (131, 134))	('MCF10A', 'CellLine', 'CVCL:0598', (96, 102))	('PSD4', 'Gene', (65, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (48, 54))
214632	33552389	Overall, the cumulative 10-year incidence of locoregional recurrence was 4.2% among women age < 40 years, 2.0% among women age 40-49 years, and 0.2% among women age >= 50 years (p < 0.0001), with the majority of excess risk harbored by women with all three risk factors of young age, high grade, and microinvasion.	('women', 'Species', '9606', (155, 160))	('age', 'Gene', (123, 126))	('women', 'Species', '9606', (84, 89))	('age', 'Gene', (161, 164))	('microinvasion', 'Var', (300, 313))	('women', 'Species', '9606', (236, 241))	('locoregional', 'Disease', (45, 57))	('age', 'Gene', (279, 282))	('age', 'Gene', (90, 93))	('age', 'Gene', '5973', (123, 126))	('age', 'Gene', '5973', (161, 164))	('women', 'Species', '9606', (117, 122))	('age', 'Gene', '5973', (279, 282))	('age', 'Gene', '5973', (90, 93))
214667	32292842	Here, we present evidence-based guidelines for omitting or abbreviating breast cancer radiotherapy, where appropriate, in an effort to mitigate risk to patients and optimize resource utilization.	('abbreviating', 'Var', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
214702	30546463	Antigen MAGE-A10 demonstrated a significant association with higher expression of ER (P=0.005) and higher tumor nuclear grade (P=0.001), cytoplasmic staining (P=0.029) and antigen NY-ESO-1 with higher tumor size (P=0.001), expression of TILs (P=0.001) and R1 resection (P=0.001).	('higher', 'PosReg', (194, 200))	('R1 resection', 'CPA', (256, 268))	('MAGE-A10', 'Gene', (8, 16))	('expression', 'MPA', (68, 78))	('NY-ESO-1', 'Gene', '246100', (180, 188))	('higher', 'PosReg', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('TIL', 'Gene', (237, 240))	('NY-ESO-1', 'Gene', (180, 188))	('antigen', 'Var', (172, 179))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('ER', 'Gene', '2099', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (201, 206))	('MAGE-A10', 'Gene', '4109', (8, 16))	('tumor', 'Disease', (106, 111))	('TIL', 'Gene', '7096', (237, 240))
214704	30546463	Additional analysis revealed an association between antigen MAGE-A10 and TILs (P=0.05).	('MAGE-A10', 'Gene', '4109', (60, 68))	('TIL', 'Gene', '7096', (73, 76))	('MAGE-A10', 'Gene', (60, 68))	('TIL', 'Gene', (73, 76))	('association', 'Interaction', (32, 43))	('antigen', 'Var', (52, 59))
214706	30546463	Overall, CTAs from the MAGE family (MAGE-A1, multi-MAGE-A and MAGE-A10) and NY-ESO-1 associate with histopathological predictive variables of DCIS.	('MAGE-A10', 'Gene', (62, 70))	('MAGE-A1', 'Gene', (36, 43))	('NY-ESO-1', 'Gene', '246100', (76, 84))	('multi-MAGE-A', 'Var', (45, 57))	('NY-ESO-1', 'Gene', (76, 84))	('MAGE-A1', 'Gene', '4100', (62, 69))	('DCIS', 'Disease', (142, 146))	('DCIS', 'Phenotype', 'HP:0030075', (142, 146))	('MAGE-A1', 'Gene', (62, 69))	('MAGE-A10', 'Gene', '4109', (62, 70))	('MAGE-A1', 'Gene', '4100', (36, 43))
214736	30546463	Monoclonal antibodies (mAbs) recognizing the following CTAs were used: Anti-MAGE-A1 (clone 77B), Anti multi-MAGE-A (clone 57B), anti-MAGE-A10 (clone 3GA11) and anti-NY-ESO-1 (clone D8.38).	('NY-ESO-1', 'Gene', '246100', (165, 173))	('MAGE-A1', 'Gene', '4100', (133, 140))	('NY-ESO-1', 'Gene', (165, 173))	('MAGE-A1', 'Gene', (133, 140))	('MAGE-A10', 'Gene', '4109', (133, 141))	('Anti multi-MAGE-A', 'Var', (97, 114))	('MAGE-A10', 'Gene', (133, 141))	('MAGE-A1', 'Gene', '4100', (76, 83))	('MAGE-A1', 'Gene', (76, 83))
214743	30546463	Slides were then washed with PBS-buffer and incubated for 90 min with multi-MAGE-A 57B, MAGE-A1 77B, MAGE-A10 3GA11 or NY-ESO-1 D8.38 undiluted supernatants at room temperature.	('MAGE-A1', 'Gene', '4100', (88, 95))	('MAGE-A10', 'Gene', (101, 109))	('MAGE-A1', 'Gene', (88, 95))	('PBS', 'Chemical', '-', (29, 32))	('MAGE-A10', 'Gene', '4109', (101, 109))	('multi-MAGE-A', 'Var', (70, 82))	('NY-ESO-1', 'Gene', '246100', (119, 127))	('MAGE-A1', 'Gene', '4100', (101, 108))	('NY-ESO-1', 'Gene', (119, 127))	('MAGE-A1', 'Gene', (101, 108))
214757	30546463	Since expression of CTAs has been previously detected in different intracellular locations, the present study focused on three different staining patterns, namely nuclear, cytoplasmic, and simultaneous cytoplasmic and nuclear expression of multi-MAGE-A, MAGE-A1, MAGE-A10 and NY-ESO-1 in breast DCIS cells (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (295, 299))	('MAGE-A1', 'Gene', (263, 270))	('MAGE-A10', 'Gene', '4109', (263, 271))	('multi-MAGE-A', 'Var', (240, 252))	('MAGE-A1', 'Gene', '4100', (254, 261))	('NY-ESO-1', 'Gene', '246100', (276, 284))	('MAGE-A10', 'Gene', (263, 271))	('NY-ESO-1', 'Gene', (276, 284))	('MAGE-A1', 'Gene', (254, 261))	('MAGE-A1', 'Gene', '4100', (263, 270))
214766	30546463	In the current study, associations between histopathological predictive variables and the expression of CTAs from the MAGE family (multi-MAGE-A, MAGE-A1 and MAGE-A10) and NY-ESO-1 were evaluated.	('MAGE-A1', 'Gene', '4100', (157, 164))	('MAGE-A1', 'Gene', (157, 164))	('MAGE-A10', 'Gene', '4109', (157, 165))	('MAGE-A1', 'Gene', '4100', (145, 152))	('MAGE-A10', 'Gene', (157, 165))	('multi-MAGE-A', 'Var', (131, 143))	('MAGE-A1', 'Gene', (145, 152))	('NY-ESO-1', 'Gene', '246100', (171, 179))	('NY-ESO-1', 'Gene', (171, 179))
214775	30546463	In the present study, antigen MAGE-A10 was revealed to be significantly associated with higher expression of ER and higher tumor grade, and antigen NY-ESO-1 with higher tumor size, expression of TILs and R1 resection.	('higher', 'PosReg', (88, 94))	('tumor', 'Disease', (123, 128))	('NY-ESO-1', 'Gene', '246100', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('TIL', 'Gene', '7096', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('NY-ESO-1', 'Gene', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MAGE-A10', 'Gene', '4109', (30, 38))	('antigen', 'Var', (140, 147))	('TIL', 'Gene', (195, 198))	('tumor', 'Disease', (169, 174))	('MAGE-A10', 'Gene', (30, 38))	('ER', 'Gene', '2099', (109, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('expression', 'MPA', (95, 105))
214779	30546463	In summary, associations between CTAs from the MAGE family (MAGE-A1, multi-MAGE-A and MAGE-A10) and NY-ESO-1, and histopathological predictive variables of DCIS, were revealed.	('MAGE-A1', 'Gene', (60, 67))	('MAGE-A1', 'Gene', '4100', (60, 67))	('NY-ESO-1', 'Gene', (100, 108))	('MAGE-A10', 'Gene', (86, 94))	('MAGE-A1', 'Gene', '4100', (86, 93))	('multi-MAGE-A', 'Var', (69, 81))	('MAGE-A1', 'Gene', (86, 93))	('associations', 'Interaction', (12, 24))	('DCIS', 'Phenotype', 'HP:0030075', (156, 160))	('MAGE-A10', 'Gene', '4109', (86, 94))	('NY-ESO-1', 'Gene', '246100', (100, 108))
214893	19373863	Younger patients treated with BCS + RT had a significantly higher rate of LR than older patients especially for invasive LR.	('invasive LR', 'Disease', (112, 123))	('BCS', 'Var', (30, 33))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (8, 16))
214915	19373863	In the NSABP B-24 study, (Fisher et al) patients were randomized to treatment with lumpectomy, RT, and placebo or lumpectomy, RT, and tamoxifen and there was reduction in breast cancer events at 5 years (13.4% vs. 8.2%, p= 0.0009).	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('lumpectomy', 'Var', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tamoxifen', 'Chemical', 'MESH:D013629', (134, 143))	('breast cancer', 'Disease', (171, 184))	('patients', 'Species', '9606', (40, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('reduction', 'NegReg', (158, 167))
215033	27422542	An off the beaten path approach to identify candidate biomarkers of early stage breast cancer Regardless of the etiological factor, an aberrant morphology is the common hallmark of ductal carcinoma in situ (DCIS), which is a highly heterogeneous disease.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (181, 205))	('ductal carcinoma in situ', 'Disease', (181, 205))	('aberrant morphology', 'Var', (135, 154))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (181, 205))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))
215034	27422542	To test if critical core morphogenetic mechanisms are compromised by different mutations, we performed proteomics analysis of five mammary epithelial HME1 mutant lines that develop a DCIS-like morphology in three dimensional (3D) culture.	('mutant', 'Var', (155, 161))	('develop', 'PosReg', (173, 180))	('HME1', 'Gene', (150, 154))	('HME1', 'Chemical', '-', (150, 154))	('DCIS-like morphology', 'CPA', (183, 203))
215035	27422542	Here we show first, that all HME1 mutant lines share a common protein signature highlighting an inverse deregulation of two annexins, ANXA2 and ANXA8.	('HME1', 'Gene', (29, 33))	('ANXA2', 'Gene', (134, 139))	('annexins', 'Protein', (124, 132))	('ANXA8', 'Protein', (144, 149))	('HME1', 'Chemical', '-', (29, 33))	('ANXA2', 'Gene', '302', (134, 139))	('mutant', 'Var', (34, 40))	('deregulation', 'MPA', (104, 116))
215039	27422542	The aberrant morphology of mammary ducts or lobules is a hallmark of in situ breast cancer lesions, such as ductal carcinoma in situ (DCIS), which may, or not, progress to invasive breast cancer.	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (108, 132))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('situ breast cancer lesions', 'Disease', (72, 98))	('invasive breast cancer', 'Disease', (172, 194))	('aberrant', 'Var', (4, 12))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (108, 132))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('situ breast cancer lesions', 'Disease', 'MESH:D001943', (72, 98))	('invasive breast cancer', 'Disease', 'MESH:D001943', (172, 194))	('ductal carcinoma in situ', 'Disease', (108, 132))
215044	27422542	By using a human, non-tumorigenic HME1 mammary epithelial model, we previously reported that stable distinct genetic mutations, by interfering with different functions or signaling pathways, affect the 3D HME1 cell morphogenetic potential.	('mutations', 'Var', (117, 126))	('signaling pathways', 'Pathway', (171, 189))	('HME1', 'Chemical', '-', (205, 209))	('human', 'Species', '9606', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('affect', 'Reg', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('interfering', 'NegReg', (131, 142))	('tumor', 'Disease', (22, 27))	('HME1', 'Chemical', '-', (34, 38))	('3D HME1 cell morphogenetic potential', 'CPA', (202, 238))	('functions', 'MPA', (158, 167))
215047	27422542	To start tackling this hypothesis, we compared the proteomics profile of five HME1 clonal lines carrying distinct genetic mutations (hereafter referred to as HME1 mutant lines) relative to control parental HME1 cells.	('HME1', 'Gene', (78, 82))	('HME1', 'Chemical', '-', (78, 82))	('mutations', 'Var', (122, 131))	('HME1', 'Chemical', '-', (158, 162))	('HME1', 'Chemical', '-', (206, 210))
215048	27422542	Remarkably, all the HME1 mutant lines shared a common protein signature, characterized by deregulation of proteins associated with signaling pathways and functions relevant to key morphogenetic processes, such as cytoskeleton organization, cell death, and cell polarity.	('mutant', 'Var', (25, 31))	('deregulation', 'PosReg', (90, 102))	('HME1', 'Gene', (20, 24))	('HME1', 'Chemical', '-', (20, 24))	('cell polarity', 'CPA', (256, 269))	('proteins', 'Protein', (106, 114))
215053	27422542	After excluding a mutual regulation between ANXA2 and ANXA8, we found preliminary evidence supporting the alternate hypothesis that a common mechanism, compromised in all HME1 mutant lines, must be involved in the deregulation of the two annexins.	('ANXA2', 'Gene', (44, 49))	('mutant', 'Var', (176, 182))	('deregulation', 'MPA', (214, 226))	('HME1', 'Gene', (171, 175))	('ANXA2', 'Gene', '302', (44, 49))	('HME1', 'Chemical', '-', (171, 175))
215060	27422542	HME1 clones with stable ANXA2 knock down were generated by stable transfection with pSUPER-shANXA2 sequence B or pSUPER-shANXA2 sequence C targeting both ANXA2 transcript variant 1 and 2.	('ER', 'Gene', '2099', (117, 119))	('ANXA2', 'Gene', (122, 127))	('ANXA2', 'Gene', (154, 159))	('ANXA2', 'Gene', (24, 29))	('ANXA2', 'Gene', (93, 98))	('knock', 'Var', (30, 35))	('ANXA2', 'Gene', '302', (122, 127))	('ANXA2', 'Gene', '302', (154, 159))	('ER', 'Gene', '2099', (88, 90))	('ANXA2', 'Gene', '302', (24, 29))	('HME1', 'Chemical', '-', (0, 4))	('ANXA2', 'Gene', '302', (93, 98))
215064	27422542	HME1 clones stably overexpressing ANXA8 and relative control cells were generated by stable transfection with either pLNCX2-ANXA8 or empty pLNCX2.	('ANXA8', 'Gene', (34, 39))	('pLNCX2-ANXA8', 'Var', (117, 129))	('overexpressing', 'PosReg', (19, 33))	('HME1', 'Gene', (0, 4))	('HME1', 'Chemical', '-', (0, 4))
215069	27422542	Golgi apparatus (marker of apicobasal polarity) and integrin (marker of basolateral polarity) were detected with anti-GM130 antibody (BD Biosciences) and anti-CD49f antibody (EMD Millipore, Billerica, MA), respectively.	('CD49f', 'Gene', '3655', (159, 164))	('GM130', 'Chemical', '-', (118, 123))	('CD49f', 'Gene', (159, 164))	('anti-GM130', 'Var', (113, 123))
215074	27422542	The scanned images were analyzed by Image Quant software (version 6.0, GE Healthcare), followed by cross-gel analysis using DeCyder software (version 6.5, GE Healthcare), to identify protein spots differentially expressed in HME1 mutant lines vs. HME1-Ctrl.	('HME1', 'Chemical', '-', (247, 251))	('HME1', 'Gene', (225, 229))	('mutant', 'Var', (230, 236))	('HME1', 'Chemical', '-', (225, 229))
215075	27422542	Differentially expressed protein spots were selected for analysis by mass spec based on: 1) absolute fold change > 1.5 in one or more HME1 mutant lines relative to HME1-Ctrl, and 2) concomitant upregulation or downregulation in all HME1 mutant lines.	('upregulation', 'PosReg', (194, 206))	('HME1', 'Gene', (134, 138))	('mutant', 'Var', (139, 145))	('HME1', 'Chemical', '-', (232, 236))	('downregulation', 'NegReg', (210, 224))	('HME1', 'Chemical', '-', (134, 138))	('HME1', 'Chemical', '-', (164, 168))
215076	27422542	The selected spots were ranked based on average expression in the HME1 mutant lines, and the 25 most upregulated and the 25 most downregulated protein spots (see Table S1) were excised from the gels by using Ettan Spot Picker (GE Healthcare).	('HME1', 'Chemical', '-', (66, 70))	('mutant', 'Var', (71, 77))	('upregulated', 'PosReg', (101, 112))	('HME1', 'Gene', (66, 70))
215082	27422542	MiRNAs targeting either ANXA2 3'UTR (NM_001002857, nt 1156-1635) or ANXA8 3'UTR (NM_001040084.2, nt 1210-2060) were identified by using both TargetScan 6.2 release (http://www.targetscan.org/) and miRanda August 2010 release (http://www.microrna.org/microrna/home.do).	('NM_001002857', 'Var', (37, 49))	('ANXA2', 'Gene', '302', (24, 29))	('NM_001040084.2', 'Var', (81, 95))	('ANXA2', 'Gene', (24, 29))
215084	27422542	Briefly, total RNA isolated with Trizol (Thermo Fisher) was retrotranscribed by using TaqMan miRNA Reverse Transcription kit and RT primers specific for miR-218 or RNU-44 (internal control) as per manufacturer's instructions (Thermo Fisher).	('Trizol', 'Chemical', 'MESH:C411644', (33, 39))	('miR-218', 'Var', (153, 160))	('RNU-44', 'Gene', '26806', (164, 170))	('RNU-44', 'Gene', (164, 170))
215094	27422542	As we reported in previous studies, when grown in reconstituted basement membrane 3D culture (Matrigel), HME1 non-tumorigenic human mammary epithelial cells develop into acinar structures that are hollow (see DAPI-stained nuclei lining the lumen), lined by polarized cells (see localization of Golgi and integrin), and growth-arrested (see lack of EdU-positive, proliferating cells) (Figure 1A, left).	('DAPI', 'Chemical', 'MESH:C007293', (209, 213))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('human', 'Species', '9606', (126, 131))	('EdU', 'Chemical', '-', (348, 351))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HME1', 'Chemical', '-', (105, 109))	('tumor', 'Disease', (114, 119))	('HME1', 'Var', (105, 109))
215096	27422542	Specifically, the 3D HME1 aberrant morphology was consequent to stable interference with the following: a) retinoic acid (RA) transcriptional signaling by a dominant negative RA receptor alpha (RARA-403); b) estrogen signaling by estrogen receptor alpha (ERA) knock down; c) circadian rhythm by Period 2 (PER2) knock down; d) rRNA transcription by MTG16 knock down; and e) MYC signaling by MYC overexpression.	('ER', 'Gene', '2099', (255, 257))	('RA', 'Chemical', 'MESH:D014212', (175, 177))	('estrogen receptor alpha', 'Gene', (230, 253))	('rRNA transcription', 'MPA', (326, 344))	('RARA', 'Gene', (194, 198))	('RA', 'Chemical', 'MESH:D014212', (196, 198))	('RA receptor alpha ', 'Gene', (175, 193))	('MYC', 'Gene', (390, 393))	('RA', 'Chemical', 'MESH:D014212', (122, 124))	('estrogen signaling', 'MPA', (208, 226))	('MYC', 'Gene', (373, 376))	('knock down', 'Var', (354, 364))	('circadian rhythm', 'MPA', (275, 291))	('ER', 'Gene', '2099', (306, 308))	('PER2', 'Gene', (305, 309))	('HME1', 'Chemical', '-', (21, 25))	('RA', 'Chemical', 'MESH:D014212', (256, 258))	('PER2', 'Gene', '8864', (305, 309))	('estrogen receptor alpha', 'Gene', '2099', (230, 253))	('RA', 'Chemical', 'MESH:D014212', (194, 196))	('MTG16', 'Gene', (348, 353))	('MYC', 'Gene', '4609', (390, 393))	('Period 2', 'Gene', '8864', (295, 303))	('RA receptor alpha ', 'Gene', '5914', (175, 193))	('MYC', 'Gene', '4609', (373, 376))	('knock down', 'Var', (311, 321))	('RARA', 'Gene', '5914', (194, 198))	('retinoic acid', 'Chemical', 'MESH:D014212', (107, 120))	('MTG16', 'Gene', '863', (348, 353))	('Period 2', 'Gene', (295, 303))
215097	27422542	The DCIS-like morphology developed by the five HME1 mutant lines let us test if the different genetic factors, by impinging on critical core morphogenetic mechanisms, confer a common protein signature.	('test', 'Reg', (72, 76))	('HME1', 'Gene', (47, 51))	('HME1', 'Chemical', '-', (47, 51))	('mutant', 'Var', (52, 58))
215098	27422542	To this end, we performed cross-comparison analysis of the protein profile of the five HME1 mutant lines relative to parental HME1 control cells.	('HME1', 'Gene', (87, 91))	('HME1', 'Chemical', '-', (87, 91))	('mutant', 'Var', (92, 98))	('HME1', 'Chemical', '-', (126, 130))
215100	27422542	We identified with high confidence (CI > 95%) 50 proteins differentially expressed in the HME1 mutant lines vs. control HME1 parental cells by mass spectrometry analysis of the 25 most upregulated and 25 most downregulated protein spots (see frames in Figure 1B and Material and Methods).	('HME1', 'Chemical', '-', (90, 94))	('downregulated', 'NegReg', (209, 222))	('upregulated', 'PosReg', (185, 196))	('mutant', 'Var', (95, 101))	('HME1', 'Chemical', '-', (120, 124))	('HME1', 'Gene', (90, 94))
215101	27422542	Closer inspection of proteins expressed by the five HME1 mutant lines highlighted deregulation of proteins that play important roles in morphogenetic processes, such as VIM, TUBB, and ACTG, which are cytoskeletal proteins; ARHGDIA, which regulates RHO GTPases-mediated cell adhesion and cell motility; and GLO1, which confers resistance to apoptosis.	('ARHGDIA', 'Gene', (223, 230))	('HME1', 'Chemical', '-', (52, 56))	('ACTG', 'Gene', '71', (184, 188))	('VIM', 'Gene', (169, 172))	('GLO1', 'Gene', (306, 310))	('TUBB', 'Gene', '203068', (174, 178))	('GLO1', 'Gene', '2739', (306, 310))	('VIM', 'Gene', '7431', (169, 172))	('TUBB', 'Gene', (174, 178))	('ACTG', 'Gene', (184, 188))	('mutant', 'Var', (57, 63))	('deregulation', 'MPA', (82, 94))	('ARHGDIA', 'Gene', '396', (223, 230))	('HME1', 'Gene', (52, 56))	('proteins', 'Protein', (98, 106))	('regulates', 'Reg', (238, 247))	('cell motility', 'CPA', (287, 300))
215102	27422542	Last, we found of particular interest that all HME1 mutant lines displayed an inverse deregulation of ANXA2 and ANXA8, two members of the annexin family that may be relevant to mammary epithelial morphogenesis.	('ANXA2', 'Gene', (102, 107))	('deregulation', 'MPA', (86, 98))	('mutant', 'Var', (52, 58))	('HME1', 'Gene', (47, 51))	('HME1', 'Chemical', '-', (47, 51))	('ANXA2', 'Gene', '302', (102, 107))	('ANXA8', 'Gene', (112, 117))
215104	27422542	After validating by quantitative western blot analysis the downregulation of ANXA2 protein in the five HME1 mutant lines that form morphologically aberrant DCIS-like 3D acini (Figure 2A), we set out to knock down ANXA2 in HME1 cells with pSUPER constructs carrying either one of two different shRNA sequences targeting ANXA2 (Figure 2B, left).	('ANXA2', 'Gene', (77, 82))	('ANXA2', 'Gene', '302', (319, 324))	('ANXA2', 'Gene', (213, 218))	('ANXA2', 'Gene', (319, 324))	('protein', 'Protein', (83, 90))	('mutant', 'Var', (108, 114))	('ER', 'Gene', '2099', (242, 244))	('downregulation', 'NegReg', (59, 73))	('ANXA2', 'Gene', '302', (77, 82))	('HME1', 'Chemical', '-', (222, 226))	('ANXA2', 'Gene', '302', (213, 218))	('HME1', 'Gene', (103, 107))	('HME1', 'Chemical', '-', (103, 107))	('knock down', 'Var', (202, 212))
215108	27422542	The level of ANXA8 in these clones was similar to the one detected in the five HME1 mutant clones (Figure 3B, right).	('mutant', 'Var', (84, 90))	('HME1', 'Gene', (79, 83))	('HME1', 'Chemical', '-', (79, 83))
215112	27422542	Next, we asked whether the concomitant inverse deregulation of the two annexins in HME1 mutant lines is consequent to the fact that the diverse genetic factors may compromise a common "bottleneck" mechanism.	('compromise', 'NegReg', (164, 174))	('deregulation', 'MPA', (47, 59))	('mutant', 'Var', (88, 94))	('common "bottleneck" mechanism', 'MPA', (177, 206))	('HME1', 'Gene', (83, 87))	('HME1', 'Chemical', '-', (83, 87))
215113	27422542	Based on preliminary studies of our laboratory, all five HME1 mutant lines are insensitive to the growth-inhibitory and pro-apoptotic morphogenetic action of physiological retinoic acid (RA), a signal that plays a critical role in mammary epithelial morphogenesis.	('mutant', 'Var', (62, 68))	('HME1', 'Gene', (57, 61))	('retinoic acid', 'Chemical', 'MESH:D014212', (172, 185))	('HME1', 'Chemical', '-', (57, 61))	('RA', 'Chemical', 'MESH:D014212', (187, 189))
215115	27422542	So far, we found that miR-218, which is predicted to target ANXA8 3'UTR, is downregulated in all HME1 mutant lines (Figure S2B).	('mutant', 'Var', (102, 108))	('HME1', 'Chemical', '-', (97, 101))	('miR-218', 'Gene', (22, 29))	('downregulated', 'NegReg', (76, 89))	('HME1', 'Gene', (97, 101))
215127	27422542	In the first part of this study, by proteomics analysis of a panel of five HME1 mutant lines, which form morphologically aberrant 3D acini with DCIS-like features, and their control parental HME1 line, which forms 3D acini with features of normal mammary ducts, we identified a common protein signature comprising forty-two differentially expressed proteins associated with aberrant, DCIS-like, 3D HME1 morphology.	('HME1', 'Chemical', '-', (191, 195))	('mutant', 'Var', (80, 86))	('HME1', 'Gene', (75, 79))	('differentially expressed proteins', 'MPA', (324, 357))	('HME1', 'Chemical', '-', (75, 79))	('HME1', 'Chemical', '-', (398, 402))
215128	27422542	Apparently, different mutations causing aberrant 3D HME1 morphogenesis did impinge upon one, or more, critical core morphogenetic mechanism(s).	('HME1', 'Chemical', '-', (52, 56))	('impinge', 'Reg', (75, 82))	('mutations', 'Var', (22, 31))
215129	27422542	Within the common protein signature shared by the five HME1 mutant lines, we focused on the inverse deregulation of two members of the annexin superfamily of membrane- and calcium-binding proteins, ANXA2 and ANXA8.	('HME1', 'Chemical', '-', (55, 59))	('ANXA2', 'Gene', '302', (198, 203))	('calcium', 'Chemical', 'MESH:D002118', (172, 179))	('ANXA2', 'Gene', (198, 203))	('HME1', 'Gene', (55, 59))	('mutant', 'Var', (60, 66))
215133	27422542	These initial findings raise many questions about the causes and consequences of annexin deregulation in breast cancer initiation and progression.	('deregulation', 'Var', (89, 101))	('annexin', 'Protein', (81, 88))	('breast cancer initiation', 'Disease', (105, 129))	('breast cancer initiation', 'Disease', 'MESH:D001943', (105, 129))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
215134	27422542	Focusing on the potential causes, we first hypothesized that the inverse deregulation of the two annexins in HME1 mutant lines could be due to annexins functional redundancy.	('HME1', 'Gene', (109, 113))	('HME1', 'Chemical', '-', (109, 113))	('mutant', 'Var', (114, 120))	('annexins', 'Protein', (143, 151))	('deregulation', 'MPA', (73, 85))
215138	27422542	Consistently, the five HME1 mutant lines with inverse deregulation of the two annexins are all insensitive to the growth-inhibitory and pro-apoptotic morphogenetic action of physiological RA because we found that, directly (e.g.	('HME1', 'Gene', (23, 27))	('HME1', 'Chemical', '-', (23, 27))	('mutant', 'Var', (28, 34))	('RA', 'Chemical', 'MESH:D014212', (188, 190))
215139	27422542	the dominant negative RARA mutant) or indirectly, the different mutations hamper the activation of the transcriptional RA-RARA signaling during 3D morphogenesis.	('negative', 'NegReg', (13, 21))	('activation', 'MPA', (85, 95))	('RARA', 'Gene', (122, 126))	('mutant', 'Var', (27, 33))	('RA', 'Chemical', 'MESH:D014212', (124, 126))	('RA', 'Chemical', 'MESH:D014212', (24, 26))	('hamper', 'NegReg', (74, 80))	('mutations', 'Var', (64, 73))	('RARA', 'Gene', '5914', (22, 26))	('RA', 'Chemical', 'MESH:D014212', (122, 124))	('RA', 'Chemical', 'MESH:D014212', (22, 24))	('RARA', 'Gene', '5914', (122, 126))	('RARA', 'Gene', (22, 26))	('RA', 'Chemical', 'MESH:D014212', (119, 121))
215142	27422542	As shown in this study, one of the RA-regulated microRNAs targeting ANXA8, miR-218, is downregulated in all five HME1-mutant lines, suggesting that ANXA8 upregulation in DCIS could be due, at least in part, by interference with a RA-mediated miRNA mechanism.	('HME1-mutant', 'Gene', (113, 124))	('ANXA8', 'Gene', (68, 73))	('RA', 'Chemical', 'MESH:D014212', (230, 232))	('RA', 'Chemical', 'MESH:D014212', (35, 37))	('HME1', 'Chemical', '-', (113, 117))	('DCIS', 'Disease', (170, 174))	('ANXA8', 'Gene', (148, 153))	('interference', 'NegReg', (210, 222))	('HME1-mutant', 'Var', (113, 124))	('downregulated', 'NegReg', (87, 100))	('upregulation', 'PosReg', (154, 166))
142019	20978320	Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown.	('DCIS', 'Phenotype', 'HP:0030075', (59, 63))	('develop', 'PosReg', (69, 76))	('DCIS', 'Var', (59, 63))	('invasive breast cancer', 'Disease', (94, 116))	('ductal cancer', 'Disease', 'MESH:D009369', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('ductal cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('women', 'Species', '9606', (48, 53))	('DCIS', 'Phenotype', 'HP:0030075', (9, 13))	('invasive breast cancer', 'Disease', 'MESH:D001943', (94, 116))
142023	20978320	Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS.	('PRDM14', 'Gene', '63978', (97, 103))	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('AURKA', 'Gene', (28, 33))	('DCIS', 'Phenotype', 'HP:0030075', (195, 199))	('high-grade DCIS', 'Disease', (148, 163))	('found', 'Reg', (61, 66))	('frequent', 'Reg', (136, 144))	('CCNE1', 'Gene', '898', (38, 43))	('CCNE1', 'Gene', (38, 43))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (91, 95))	('EMSY', 'Gene', '56946', (108, 112))	('DCIS', 'Phenotype', 'HP:0030075', (159, 163))	('alterations', 'Var', (13, 24))	('EMSY', 'Gene', (108, 112))	('AURKA', 'Gene', '6790', (28, 33))	('PRDM14', 'Gene', (97, 103))	('high-grade DCIS', 'Disease', (70, 85))
215149	20978320	In contrast, the average number of alterations in low/intermediate and high-grade IDC was similar, and although EGFR alterations were exclusively found in high-grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (112, 116))	('DCIS', 'Phenotype', 'HP:0030075', (350, 354))	('alterations', 'Var', (117, 128))
215157	23342281	Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly.	('women', 'Species', '9606', (141, 146))	('Women', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('high adherence', 'Var', (11, 25))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('reduction', 'NegReg', (48, 57))
215210	23342281	Women who were switchers were less likely to have a high comorbidity score (>=3) compared with women from other categories (P < 0.0001).	('high comorbidity score', 'MPA', (52, 74))	('switchers', 'Var', (15, 24))	('Women', 'Species', '9606', (0, 5))	('women', 'Species', '9606', (95, 100))
215219	23342281	Women with invasive ductal carcinoma, mixed histology, and grade 2 lesions were more likely to use hormonal medications.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Women', 'Species', '9606', (0, 5))	('invasive ductal carcinoma', 'Disease', (11, 36))	('mixed histology', 'Var', (38, 53))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (20, 36))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (11, 36))
215223	23342281	As expected, women with ER+ or PR+ or HER2- lesions were more likely to use AIs solely or following TAM compared with women with ER- or PR- or HER2+ lesions (P < 0.0001 for all variables).	('ER+', 'Var', (24, 27))	('women', 'Species', '9606', (118, 123))	('HER2', 'Gene', '2064', (38, 42))	('PR+', 'Var', (31, 34))	('HER2', 'Gene', (143, 147))	('women', 'Species', '9606', (13, 18))	('HER2', 'Gene', '2064', (143, 147))	('HER2', 'Gene', (38, 42))	('TAM', 'Chemical', 'MESH:D013629', (100, 103))
215240	23342281	Given that these curves are adjusted for the covariates as in the models, they demonstrate that the subsequent breast cancer rates were similar for the switchers as those who used AIs exclusively.	('switchers', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))
215320	33385265	Overall, 20.2% (684/3393) of all patients with low grade DCIS underwent SLNB compared to 45.1% (3197/7087) of those with intermediate DCIS and 71.9% (7031/9778) of those with high grade DCIS (p < 0.001).	('low grade', 'Var', (47, 56))	('patients', 'Species', '9606', (33, 41))	('DCIS', 'Phenotype', 'HP:0030075', (134, 138))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('SLNB', 'MPA', (72, 76))	('DCIS', 'Phenotype', 'HP:0030075', (57, 61))
215383	30791092	Based on AJCC classification criteria, axillary lymph node metastases were defined as follows: macrometastases (> 2.0 mm), micrometastases (0.2-2.0 mm), or isolated tumour cells (ITCs) (< 0.2 mm).	('metastases', 'Disease', (128, 138))	('metastases', 'Disease', (100, 110))	('isolated tumour', 'Disease', (156, 171))	('isolated tumour', 'Disease', 'MESH:D009369', (156, 171))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('0.2-2.0 mm', 'Var', (140, 150))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('> 2.0', 'Var', (112, 117))	('metastases', 'Disease', (59, 69))
215407	30791092	Four received chemotherapy alone, one luminal B with Ki67>=20%, one patient with a HER2+ cancer, one triple negative and in one patient information was missing to derive the tumour subtype.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('patient', 'Species', '9606', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (174, 180))	('cancer', 'Disease', (89, 95))	('patient', 'Species', '9606', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (83, 87))	('Ki67', 'Var', (53, 57))
215442	30544617	However, it was significantly lower in single-positive DCIS when compared to lesions of a double-positive profile (SPARC+/Snail1+).	('lower', 'NegReg', (30, 35))	('DCIS', 'Disease', (55, 59))	('Snail1', 'Gene', (122, 128))	('Snail1', 'Gene', '6615', (122, 128))	('SPARC', 'Gene', '6678', (115, 120))	('single-positive DCIS', 'Phenotype', 'HP:0006315', (39, 59))	('DCIS', 'Phenotype', 'HP:0030075', (55, 59))	('single-positive', 'Var', (39, 54))	('SPARC', 'Gene', (115, 120))
215460	30544617	Expression of Snail1 was also significantly associated with the morphology of microcalcifications (similarly to SPARC, most common in casting type, least common in powdery; p = 0.041).	('associated', 'Reg', (44, 54))	('Snail1', 'Gene', '6615', (14, 20))	('SPARC', 'Gene', (112, 117))	('Expression', 'Var', (0, 10))	('SPARC', 'Gene', '6678', (112, 117))	('microcalcifications', 'Disease', (78, 97))	('Snail1', 'Gene', (14, 20))
215475	30544617	However, the risk of invasion was significantly lower in single-positive DCIS when compared to lesions of a double-positive profile (SPARC+/Snail1+: 7.7% vs. 43.1%, p < 0.0001).	('SPARC', 'Gene', (133, 138))	('lower', 'NegReg', (48, 53))	('Snail1', 'Gene', (140, 146))	('single-positive', 'Var', (57, 72))	('Snail1', 'Gene', '6615', (140, 146))	('single-positive DCIS', 'Phenotype', 'HP:0006315', (57, 77))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('invasion', 'CPA', (21, 29))	('SPARC', 'Gene', '6678', (133, 138))
215502	30544617	Therefore, it is not surprising that during the very early phase of ductal cancer progression, as was the case in our study, expression of Snail1 better determined the risk of invasion than N-cadherin.	('expression', 'Var', (125, 135))	('N-cadherin', 'Gene', '1000', (190, 200))	('Snail1', 'Gene', '6615', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('N-cadherin', 'Gene', (190, 200))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Snail1', 'Gene', (139, 145))
215507	30544617	Anderson Metastatic Breast cancer cell line established from a pleural effusion of a 51-year-old female with highly aggressive and poorly differentiated triple-negative ductal cancer) human breast cancer cells, the knockdown of Snail1 attenuates primary tumor growth, strongly suppresses its metastatic spreading, and induces the acquisition of epithelial traits in a reverse epithelial-mesenchymal transition process.	('Metastatic Breast cancer', 'Disease', (9, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('Snail1', 'Gene', '6615', (228, 234))	('pleural effusion', 'Disease', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('human', 'Species', '9606', (184, 189))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('attenuates', 'NegReg', (235, 245))	('Snail1', 'Gene', (228, 234))	('pleural effusion', 'Disease', 'MESH:D010996', (63, 79))	('Metastatic Breast cancer', 'Disease', 'MESH:D001943', (9, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('acquisition', 'CPA', (330, 341))	('tumor', 'Disease', (254, 259))	('suppresses', 'NegReg', (277, 287))	('Breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('pleural effusion', 'Phenotype', 'HP:0002202', (63, 79))	('cancer', 'Disease', (197, 203))	('metastatic spreading', 'CPA', (292, 312))	('reverse epithelial-mesenchymal transition process', 'CPA', (368, 417))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('knockdown', 'Var', (215, 224))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', (176, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('induces', 'Reg', (318, 325))
215508	30544617	Moreover, Snail1 knockdown significantly suppresses tumor initiation in most human breast cancer cell lines.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('suppresses', 'NegReg', (41, 51))	('Snail1', 'Gene', (10, 16))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Snail1', 'Gene', '6615', (10, 16))	('human', 'Species', '9606', (77, 82))
215540	30544617	All of them had breast imaging reporting and data system (BIRADS) category 4 or 5 microcalcifications without a mass or architectural distortion, lack of invasion, or microinvasion (<=1 mm in the longest diameter) on a postbiopsy pathological examination, and also an absence of any other breast malignancy or borderline lesion.	('breast malignancy', 'Disease', 'MESH:D001943', (289, 306))	('microinvasion', 'Var', (167, 180))	('microcalcifications', 'Disease', (82, 101))	('breast malignancy', 'Disease', (289, 306))
215652	24691609	Breast radiotherapy can cause fatigue, breast pain and edema and increases the risk of ischemic heart disease.	('edema', 'Disease', 'MESH:D004487', (55, 60))	('edema', 'Phenotype', 'HP:0000969', (55, 60))	('ischemic heart disease', 'Disease', 'MESH:D003324', (87, 109))	('increases', 'PosReg', (65, 74))	('pain', 'Phenotype', 'HP:0012531', (46, 50))	('cause', 'Reg', (24, 29))	('fatigue', 'Disease', 'MESH:D005221', (30, 37))	('edema', 'Disease', (55, 60))	('ischemic heart disease', 'Disease', (87, 109))	('fatigue', 'Disease', (30, 37))	('breast pain', 'Disease', 'MESH:D059373', (39, 50))	('fatigue', 'Phenotype', 'HP:0012378', (30, 37))	('Breast radiotherapy', 'Var', (0, 19))	('breast pain', 'Disease', (39, 50))
215653	24691609	Tamoxifen can cause endometrial cancer and increase the risk of thromboembolism, particularly for older women, and aromatase inhibitors can cause joint pain, myalgias, heart disease, and fractures.	('joint pain', 'Phenotype', 'HP:0002829', (146, 156))	('joint pain', 'Disease', (146, 156))	('heart disease', 'Disease', (168, 181))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('aromatase inhibitors', 'Protein', (115, 135))	('myalgias', 'Disease', 'MESH:D063806', (158, 166))	('myalgias', 'Phenotype', 'HP:0003326', (158, 166))	('fractures', 'Disease', (187, 196))	('women', 'Species', '9606', (104, 109))	('endometrial cancer', 'Phenotype', 'HP:0012114', (20, 38))	('pain', 'Phenotype', 'HP:0012531', (152, 156))	('fractures', 'Disease', 'MESH:D050723', (187, 196))	('cause', 'Reg', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('endometrial cancer', 'Disease', (20, 38))	('thromboembolism', 'Disease', (64, 79))	('endometrial cancer', 'Disease', 'MESH:D016889', (20, 38))	('cause', 'Reg', (140, 145))	('myalgias', 'Disease', (158, 166))	('joint pain', 'Disease', 'MESH:D018771', (146, 156))	('increase', 'PosReg', (43, 51))	('Tamoxifen', 'Var', (0, 9))	('thromboembolism', 'Disease', 'MESH:D013923', (64, 79))	('heart disease', 'Disease', 'MESH:D006331', (168, 181))	('thromboembolism', 'Phenotype', 'HP:0001907', (64, 79))
215692	28657606	This study aimed to obtain Fe3O4 nanoparticles functionalized with Gemcitabine to improve the cytotoxic effects of the chemotherapeutic substance on cancer cells.	('cancer', 'Disease', (149, 155))	('Fe3O4', 'Chemical', '-', (27, 32))	('improve', 'PosReg', (82, 89))	('cytotoxic', 'MPA', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('Fe3O4', 'Var', (27, 32))
215728	28657606	Thus, by applying several heating cycles for both Fe3O4 and Fe3O4@GEM, the existing quantity of GEM in the functionalized sample was calculated from the mass differences (Figure 2).	('GEM', 'Chemical', 'MESH:C056507', (96, 99))	('GEM', 'Chemical', 'MESH:C056507', (66, 69))	('Fe3O4@', 'Var', (60, 66))	('Fe3O4', 'Var', (50, 55))	('Fe3O4', 'Chemical', '-', (60, 65))	('Fe3O4', 'Chemical', '-', (50, 55))
215732	28657606	Here, for Fe3O4, a weight reduction of 3.3% was obtained and for Fe3O4@GEM 10.1%, from which 6.8% is due to the degradation of GEM.	('Fe3O4', 'Chemical', '-', (65, 70))	('Fe3O4', 'Chemical', '-', (10, 15))	('weight', 'MPA', (19, 25))	('GEM', 'Chemical', 'MESH:C056507', (71, 74))	('GEM', 'Chemical', 'MESH:C056507', (127, 130))	('Fe3O4', 'Var', (65, 70))	('Fe3O4', 'Var', (10, 15))
215733	28657606	From high resolution TEM (HR-TEM, Figure 4 and Figure 5B) a high degree of crystallinity of both samples was observed, in case of Fe3O4@GEM nanoparticles, GEM individually covering each nanoparticle forming a continuous amorphous layer on the surface of Fe3O4, resulting core-shell structures.	('Fe3O4', 'Chemical', '-', (254, 259))	('GEM', 'Chemical', 'MESH:C056507', (155, 158))	('HR-TEM', 'Disease', (26, 32))	('core-shell structures', 'CPA', (271, 292))	('Fe3O4@', 'Var', (130, 136))	('GEM', 'Chemical', 'MESH:C056507', (136, 139))	('Fe3O4', 'Chemical', '-', (130, 135))	('HR-TEM', 'Disease', 'MESH:D001919', (26, 32))
215738	28657606	The hydrodynamic diameters of the Fe3O4@GEM in complete DMEM are comprised in the interval of 218-280 nm and the Zeta Potential between -12 and -23 mV for the investigated range of concentration.	('Fe3O4', 'Chemical', '-', (34, 39))	('Zeta Potential', 'MPA', (113, 127))	('DMEM', 'Chemical', '-', (56, 60))	('GEM', 'Chemical', 'MESH:C056507', (40, 43))	('Fe3O4@GEM', 'Var', (34, 43))
215739	28657606	The Fe3O4@GEM nanoparticles suspended in complete MEM showed values of the Zeta Potential above 20 mV, showing an increased stability compared to the case of DMEM suspensions.	('GEM', 'Chemical', 'MESH:C056507', (10, 13))	('increased', 'PosReg', (114, 123))	('Zeta Potential above 20 mV', 'MPA', (75, 101))	('stability', 'MPA', (124, 133))	('Fe3O4', 'Chemical', '-', (4, 9))	('Fe3O4@', 'Var', (4, 10))	('DMEM', 'Chemical', '-', (158, 162))
215762	28657606	For HepG2 cells (Figure 8), at 24 h and 48 h after the treatment, the viability decreased slightly, following free GEM and Fe3O4@GEM treatments, being around 80%, compared to controls, without a significant dependence on concentration.	('Fe3O4', 'Chemical', '-', (123, 128))	('GEM', 'Chemical', 'MESH:C056507', (115, 118))	('decreased', 'NegReg', (80, 89))	('viability', 'CPA', (70, 79))	('GEM', 'Chemical', 'MESH:C056507', (129, 132))	('Fe3O4@GEM', 'Var', (123, 132))	('HepG2', 'CellLine', 'CVCL:0027', (4, 9))
215764	28657606	The cytotoxic effect was accelerated up until 72 h after the treatment, the Fe3O4@GEM being more effective for all the concentration range we tested, the efficiency increasing linearly with the dose.	('Fe3O4@', 'Var', (76, 82))	('Fe3O4', 'Chemical', '-', (76, 81))	('cytotoxic effect', 'CPA', (4, 20))	('accelerated', 'PosReg', (25, 36))	('GEM', 'Chemical', 'MESH:C056507', (82, 85))
215765	28657606	At this time interval, the viability decreased with 40%, in case of Fe3O4@GEM, compared to free drug, for the highest equivalent concentration (Figure 8C).	('Fe3O4@GEM', 'Var', (68, 77))	('viability', 'CPA', (27, 36))	('GEM', 'Chemical', 'MESH:C056507', (74, 77))	('decreased', 'NegReg', (37, 46))	('Fe3O4', 'Chemical', '-', (68, 73))
215766	28657606	We may confirm that the effect of Fe3O4@GEM is more pronounced at longer period of exposure due to the prolonged release of GEM from the nanoparticles surface (Section 2.3.2).	('Fe3O4', 'Chemical', '-', (34, 39))	('release', 'MPA', (113, 120))	('GEM', 'Chemical', 'MESH:C056507', (124, 127))	('GEM', 'Chemical', 'MESH:C056507', (40, 43))	('Fe3O4@GEM', 'Var', (34, 43))
215790	28657606	The morphology of BT 474 cells was severely affected by the treatment with Fe3O4@GEM and GEM alone; the cytoplasm lost its integrity and the nuclei appeared as inconsistent (the Hoechst stain fainted) or appeared scattered (Figure 10).	('affected', 'Reg', (44, 52))	('integrity', 'MPA', (123, 132))	('Fe3O4@', 'Var', (75, 81))	('Hoechst', 'Chemical', '-', (178, 185))	('GEM', 'Chemical', 'MESH:C056507', (81, 84))	('fainted', 'NegReg', (192, 199))	('GEM', 'Chemical', 'MESH:C056507', (89, 92))	('Fe3O4', 'Chemical', '-', (75, 80))	('lost', 'NegReg', (114, 118))
215791	28657606	The cells treated with Fe3O4 nanoparticles were more round compared to control samples, with an increased actin concentration similar to "actin clumps", at the extremities of the cells' cytoplasm.	('increased', 'PosReg', (96, 105))	('actin concentration', 'MPA', (106, 125))	('nanoparticles', 'Var', (29, 42))	('Fe3O4 nanoparticles', 'Var', (23, 42))	('Fe3O4', 'Chemical', '-', (23, 28))
215795	28657606	Scanning electron microscopy imaging was employed to complete the results from fluorescence microscopy regarding the membrane morphology of the tumor cells after their interaction with Fe3O4@GEM nanoparticles, results which were in concordance with the previous ones.	('tumor', 'Disease', (144, 149))	('interaction', 'Interaction', (168, 179))	('membrane morphology', 'CPA', (117, 136))	('GEM', 'Chemical', 'MESH:C056507', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Fe3O4', 'Chemical', '-', (185, 190))	('Fe3O4', 'Var', (185, 190))
215796	28657606	The morphology of BT 474 cells (Figure 13) is not affected after being exposed for 24 h to functionalized nanoparticles, the presence of Fe3O4@GEM being evidenced at the exterior cell, as agglomerates with sub-micrometric dimension, directly interacting with the cellular membrane (Figure 13E,F).	('Fe3O4', 'Chemical', '-', (137, 142))	('GEM', 'Chemical', 'MESH:C056507', (143, 146))	('interacting', 'Interaction', (242, 253))	('Fe3O4@GEM', 'Var', (137, 146))
215824	28657606	Two time periods (7 and 14 days) were chosen to better emphasize the bioaccumulation of Fe3O4@GEM NPs and the protection of healthy tissues outside the peritoneal cavity.	('Fe3O4', 'Chemical', '-', (88, 93))	('Fe3O4', 'Var', (88, 93))	('GEM', 'Chemical', 'MESH:C056507', (94, 97))	('bioaccumulation', 'MPA', (69, 84))
215855	28657606	Scanning transmission electron microscopy and energy dispersive X-ray spectroscopy were used in order to prove the internalizing of Fe3O4@GEM in tumor cells.	('Fe3O4@GEM', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('internalizing', 'MPA', (115, 128))	('GEM', 'Chemical', 'MESH:C056507', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Fe3O4', 'Chemical', '-', (132, 137))	('tumor', 'Disease', (145, 150))
215937	26740749	The relative risk of subsequent development of invasive carcinoma among patients with LCIS ranges from 6.9 to 12 times than that in women without LCIS.	('women', 'Species', '9606', (132, 137))	('invasive carcinoma', 'Disease', 'MESH:D009361', (47, 65))	('men', 'Species', '9606', (134, 137))	('LCIS', 'Phenotype', 'HP:0030076', (146, 150))	('LCIS', 'Phenotype', 'HP:0030076', (86, 90))	('invasive carcinoma', 'Disease', (47, 65))	('men', 'Species', '9606', (39, 42))	('LCIS', 'Var', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('patients', 'Species', '9606', (72, 80))
215977	26740749	It is particularly common in carriers of BRCA1 mutations.	('BRCA1', 'Gene', '672', (41, 46))	('carriers', 'Reg', (29, 37))	('BRCA1', 'Gene', (41, 46))	('mutations', 'Var', (47, 56))	('common', 'Reg', (19, 25))
216058	26740749	Inactivations of E-cadherin by mutation, loss of heterozygosity, or methylation are characteristic molecular changes in ILC, particularly the pleomorphic subtype.	('Inactivations', 'NegReg', (0, 13))	('methylation', 'Var', (68, 79))	('loss of heterozygosity', 'Var', (41, 63))	('mutation', 'Var', (31, 39))	('E-cadherin', 'Gene', (17, 27))	('ILC', 'Disease', (120, 123))	('E-cadherin', 'Gene', '999', (17, 27))
216082	26740749	The Ki-67 expression is high and TP53 mutation is common.	('TP53', 'Gene', '7157', (33, 37))	('expression', 'MPA', (10, 20))	('Ki-67', 'Protein', (4, 9))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))
216087	26740749	It is typically CK5/6 and/or EGFR positive, ER/PR negative, and HER2 negative (triple negative), with a high expression of Ki-67 index and TP53 mutation, which is common.	('Ki-67', 'Var', (123, 128))	('CK5/6', 'Gene', '3852', (16, 21))	('negative', 'NegReg', (69, 77))	('HER2', 'Gene', (64, 68))	('mutation', 'Var', (144, 152))	('TP53', 'Gene', '7157', (139, 143))	('CK5/6', 'Gene', (16, 21))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (64, 68))	('TP53', 'Gene', (139, 143))
216093	26740749	These antibodies include ER, PR, HER2/neu, cytokeratin 5/6, EGFR, and Ki-67.	('HER2/neu', 'Gene', '2064', (33, 41))	('Ki-67', 'Var', (70, 75))	('cytokeratin 5/6', 'Gene', '3852', (43, 58))	('cytokeratin 5/6', 'Gene', (43, 58))	('HER2/neu', 'Gene', (33, 41))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))
216114	25473842	Disruption of these cues and the resulting architecture leads to ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC).	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('leads to', 'Reg', (56, 64))	('invasive ductal carcinoma', 'Disease', (101, 126))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (65, 89))	('ductal carcinoma in situ', 'Disease', (65, 89))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (65, 81))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (110, 126))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (65, 89))	('Disruption', 'Var', (0, 10))
216135	25473842	These variations may establish regions that are preferential for tumor cell proliferation and invasion.	('invasion', 'CPA', (94, 102))	('tumor', 'Disease', (65, 70))	('variations', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
216142	25473842	Furthermore, variations in cell adhesion led to the establishment of different tissue microenvironments; cancer cells invaded preferentially into the microenvironment of the mesentery, omentum and spleen and did not invade into that of the stomach and small intestine.	('variations', 'Var', (13, 23))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('preferentially', 'PosReg', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('invaded', 'CPA', (118, 125))
216148	25473842	We modeled strong cellular adhesion using negative values for the adhesion coefficients and modeled the differential expression of E-cadherin by setting JLEP,LEP<JMEP,LEP<JMEP,MEP.	('E-cadherin', 'Gene', '999', (131, 141))	('LEP', 'Chemical', '-', (154, 157))	('LEP<JMEP', 'Var', (167, 175))	('LEP', 'Chemical', '-', (158, 161))	('MEP', 'Var', (176, 179))	('LEP', 'Chemical', '-', (167, 170))	('JLEP', 'Var', (153, 157))	('LEP<JMEP', 'Var', (158, 166))	('E-cadherin', 'Gene', (131, 141))
216170	25473842	These results are in agreement with our previously published experimental results, in which we found that reducing tissue contractility eliminates tumor cell invasion, whereas increasing contractility permits tumor cells to invade from the duct region of the tissue.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (209, 214))	('eliminates', 'NegReg', (136, 146))	('reducing', 'Var', (106, 114))	('tissue contractility', 'CPA', (115, 135))	('contractility', 'MPA', (187, 200))	('invade', 'CPA', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
216182	25473842	Our results are also consistent with clinical data showing that less than 50% of low-grade DCIS (lesions with a low proliferation rate) develop into invasive breast cancer over 25-30 years.	('DCIS', 'Phenotype', 'HP:0030075', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('invasive breast cancer', 'Disease', (149, 171))	('low-grade', 'Var', (81, 90))	('invasive breast cancer', 'Disease', 'MESH:D001943', (149, 171))	('develop', 'Reg', (136, 143))
216200	21306611	SIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53 and is likely to be partly responsible for the enhanced hypoxic drive through abrogation of the prolyl hydroxylases.	('breast cancers', 'Disease', 'MESH:D001943', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('breast cancers', 'Disease', (46, 60))	('SIAH2', 'Gene', (0, 5))	('hypoxic drive', 'MPA', (182, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('abrogation', 'NegReg', (204, 214))	('expression', 'MPA', (6, 16))	('p53', 'Gene', '7157', (122, 125))	('activation', 'PosReg', (108, 118))	('upregulated', 'PosReg', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancers', 'Phenotype', 'HP:0003002', (46, 60))	('prolyl', 'Chemical', '-', (222, 228))	('transcriptional', 'MPA', (92, 107))	('enhanced', 'PosReg', (173, 181))	('copy number changes', 'Var', (65, 84))	('p53', 'Gene', (122, 125))
216244	21306611	A previous study analyzed both gene expression and copy number variation using the Illumina Human-6 BeadArray (Illumina, San Diego, CA, 92121, USA) and the CNV370 SNP array (Illumina) respectively, in a cohort of familial tumors.	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('familial tumors', 'Disease', 'MESH:D009386', (213, 228))	('familial tumors', 'Disease', (213, 228))	('copy number', 'Var', (51, 62))	('Human', 'Species', '9606', (92, 97))
216257	21306611	Five normal breast tissues, 60 breast carcinomas and 13 breast cancer cell lines were screened for methylation of SIAH2, but no promoter methylation was detected in these cancer cell lines and samples, as shown by the absence of altered methylation profiles (Supplementary Figure 1 in Additional file 6).	('methylation', 'Var', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cancer', 'Disease', (171, 177))	('methylation profiles', 'MPA', (237, 257))	('SIAH2', 'Gene', (114, 119))	('breast carcinomas', 'Disease', (31, 48))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast carcinomas', 'Disease', 'MESH:D001943', (31, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast carcinomas', 'Phenotype', 'HP:0003002', (31, 48))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('breast cancer', 'Disease', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast carcinoma', 'Phenotype', 'HP:0003002', (31, 47))	('cancer', 'Disease', (63, 69))
216285	21306611	The concept of SIAH2 being a good prognostic and/or predictive parameter is not in accord with the role of SIAH2 in regulating the hypoxic response or with the observation that inhibition of SIAH2 is associated with reduced metastases in animal models.	('reduced', 'NegReg', (216, 223))	('inhibition', 'Var', (177, 187))	('metastases', 'Disease', 'MESH:D009362', (224, 234))	('SIAH2', 'Gene', (191, 196))	('metastases', 'Disease', (224, 234))
216356	32664078	Our results provide important information for clinical practicing because high-grade DCIS is associated with a higher likelihood of the presence of invasive foci and that the presence of invasive foci could change the prognosis and management of the patient.	('invasive foci', 'CPA', (148, 161))	('DCIS', 'Phenotype', 'HP:0030075', (85, 89))	('high-grade', 'Var', (74, 84))	('change', 'Reg', (207, 213))	('patient', 'Species', '9606', (250, 257))
216443	27098311	In terms of DCIS, an excess incidence of around one per thousand recruits in the ASP was balanced by a deficit of similar size in invasive cancers, strongly suggesting that diagnosis of DCIS is preventing subsequent diagnosis of invasive breast cancer.	('invasive cancers', 'Disease', 'MESH:D009362', (130, 146))	('DCIS', 'Phenotype', 'HP:0030075', (12, 16))	('invasive breast cancer', 'Disease', 'MESH:D001943', (229, 251))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('preventing', 'NegReg', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('invasive cancers', 'Disease', (130, 146))	('ASP', 'Chemical', 'MESH:D001224', (81, 84))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('DCIS', 'Var', (186, 190))	('invasive breast cancer', 'Disease', (229, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('diagnosis', 'Var', (173, 182))
216514	23346170	Pathologic multifocality (18.0% vs. 8.2%; p=0.001), the presence of a DCIS component (11.3% vs. 5.8%; p=0.036), and an infiltrative tumor border (10.8% vs. 5.8%; p=0.041) were found to be significantly associated with re-excision upon univariate analysis.	('presence', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('DCIS component', 'Gene', (70, 84))	('associated', 'Reg', (202, 212))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('DCIS', 'Phenotype', 'HP:0030075', (70, 74))	('re-excision', 'Disease', (218, 229))
216517	23346170	Univariate analysis indicated that younger age, the presence of NMLE at MRI, a non-palpable lesion, multifocal lesions noted in pathologic reports, the presence of a DCIS component, and an infiltrative tumor border were significantly associated with re-excision, and no visible lesion, microcalcification upon MMG, and a daughter nodule upon breast USG tended to be associated with a higher rate of re-excision.	('multifocal lesions', 'Disease', (100, 118))	('presence', 'Var', (152, 160))	('presence', 'Var', (52, 60))	('tumor', 'Disease', (202, 207))	('associated with', 'Reg', (234, 249))	('re-excision', 'Disease', (250, 261))	('DCIS', 'Phenotype', 'HP:0030075', (166, 170))	('multifocal lesions', 'Disease', 'None', (100, 118))	('microcalcification', 'Disease', (286, 304))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
216523	23346170	reported that younger age, the presence of a DCIS, larger tumor size, and LVI were significantly associated with a positive resection margin upon univariate analysis, but age was the only factor found to be significant upon multivariate analysis.	('DCIS', 'Disease', (45, 49))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('DCIS', 'Phenotype', 'HP:0030075', (45, 49))	('LVI', 'Disease', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('presence', 'Var', (31, 39))
216630	29185118	Changes in sensitivity had a greater effect on the number of DCIS cases that avoided treatment than changes in specificity (Figure 2).	('DCIS', 'Disease', (61, 65))	('DCIS', 'Phenotype', 'HP:0030075', (61, 65))	('Changes', 'Var', (0, 7))	('as', 'Chemical', 'MESH:D001151', (67, 69))
216721	19689789	Antibodies and dilutions used were: ER (DAKO, Carpinteria, CA) at 1:400 dilution; PR (Novocastra) at 1:25; HER2 (Zymed) at 1:200; Ki-67 (DAKO) at 1:100; CD68 (DAKO) at 1:100; and cleaved caspase 3 (Cell Signaling, Beverly, MA) at 1:200.	('cleaved', 'Var', (179, 186))	('HER2', 'Gene', '2064', (107, 111))	('Ki-67', 'Chemical', '-', (130, 135))	('CD68', 'Gene', (153, 157))	('caspase 3', 'Gene', (187, 196))	('CD68', 'Gene', '968', (153, 157))	('PR', 'Chemical', 'MESH:D011221', (82, 84))	('caspase 3', 'Gene', '836', (187, 196))	('HER2', 'Gene', (107, 111))
216773	19689789	Most recently, in a study evaluating the DCIS component in prospective randomized window trial of letrozole versus anastrozole for ER-positive postmenopausal invasive cancer, a significant drop in Ki67 was seen for both groups in the DCIS component of the tumor.	('drop', 'NegReg', (189, 193))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('tumor', 'Disease', (256, 261))	('DCIS', 'Phenotype', 'HP:0030075', (234, 238))	('invasive cancer', 'Disease', (158, 173))	('anastrozole', 'Chemical', 'MESH:D000077384', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('invasive cancer', 'Disease', 'MESH:D009362', (158, 173))	('DCIS component of the', 'MPA', (234, 255))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('letrozole', 'Chemical', 'MESH:D000077289', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Ki67', 'Var', (197, 201))
216810	26860296	A combination of carbonic anhydrase IX (CAIX)- and human epidermal growth factor receptor 2 (HER2)-specific variable domains of the heavy chain from heavy-chain antibodies (VHHs) was conjugated either to the same fluorophore (IRDye800CW) to evaluate T/B ratios or to different fluorophores (IRDye800CW, IRDye680RD or IRDye700DX) to analyse the expression of CAIX and HER2 simultaneously through dual-fluorescence detection.	('human epidermal growth factor receptor 2', 'Gene', '2064', (51, 91))	('IRDye800CW', 'Var', (291, 301))	('human epidermal growth factor receptor 2', 'Gene', (51, 91))
216819	26860296	At the moment, under clinical evaluation in several centres, the implementation of optical molecular imaging into clinical practice could complement current protocols and facilitate non-invasive detection of cancer and monitorization of therapy response (ClinicalTrials.gov; NCT02113202, NCT01972373, NCT01508572, NCT02129933, NCT01987375).	('NCT01972373', 'Var', (288, 299))	('NCT01987375', 'Var', (327, 338))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('NCT02129933', 'Var', (314, 325))	('NCT01508572', 'Var', (301, 312))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
216848	26860296	Briefly, VHH genes were re-cloned into the pQVQ72 expression vector (kindly provided by QVQ BV), which enables site-directed conjugation of IRDye680RD maleimide and IRDye800CW maleimide (LI-COR Biosciences, Lincoln, Nebraska, USA).	('IRDye800CW', 'Var', (165, 175))	('maleimide', 'Chemical', 'MESH:C043592', (176, 185))	('maleimide', 'Chemical', 'MESH:C043592', (151, 160))	('COR', 'Gene', (190, 193))	('IRDye680RD', 'Var', (140, 150))	('COR', 'Gene', '108031', (190, 193))
216852	26860296	The irrelevant VHH, R2, was randomly conjugated to N-hydroxysuccinimide (NHS) esters of either IRDye800CW or IRDye700DX (referred to as R2-800 and R2-700, respectively) in twofold molar excess of NIR fluorophore to protein, for 2 h at RT.	('IRDye800CW', 'Var', (95, 105))	('N-hydroxysuccinimide', 'Chemical', 'MESH:C001426', (51, 71))	('NHS) esters', 'Chemical', 'MESH:C008869', (73, 84))	('IRDye700DX', 'Var', (109, 119))
216866	26860296	In the second part of the study, mice were divided into three groups and then injected intravenously with combinations of VHHs conjugated to different NIR fluorophores to study whether the expression status of HER2 and CAIX could be detected simultaneously in vivo (50 mug of each VHH-IR, thus 100 mug in total): 11A4-680 and B9-800 (n = 8), 11A4-800 and R2-700 (n = 8) or B9-800 and R2-700 (n = 7).	('R2-700', 'Var', (384, 390))	('B9-800', 'Var', (326, 332))	('11A4-800', 'Var', (342, 350))	('B9-800', 'Var', (373, 379))	('mice', 'Species', '10090', (33, 37))	('R2-700', 'Var', (355, 361))	('11A4-680', 'Var', (313, 321))
216867	26860296	After the injections, mice were imaged as described above and the fluorescence intensities of IRDye680RD and IRDye700DX were detected in the 700-nm channel, whereas the fluorescence intensity of IRDye800CW was detected in the 800-nm channel.	('IRDye700DX', 'Var', (109, 119))	('mice', 'Species', '10090', (22, 26))	('fluorescence intensities', 'MPA', (66, 90))	('IRDye680RD', 'Var', (94, 104))
216869	26860296	Having confirmed the presence of lung metastasis in a non-invasive manner by bioluminescence imaging (Photon Imager, Biospace Labs, Paris, France), mice were injected intravenously with the combination (50 mug of each VHH-IR, 100 mug in total) of 11A4-680 and B9-800 (n = 3).	('B9-800', 'Var', (260, 266))	('mice', 'Species', '10090', (148, 152))	('lung metastasis', 'CPA', (33, 48))	('11A4-680', 'Var', (247, 255))
216870	26860296	As controls, one mouse was injected with R2-800 and R2-700 and a healthy mouse with 11A4-680 and B9-800.	('mouse', 'Species', '10090', (73, 78))	('R2-800', 'Var', (41, 47))	('R2-700', 'Var', (52, 58))	('mouse', 'Species', '10090', (17, 22))
216873	26860296	Mice injected with the combination of VHHs with either IRDye800CW, IRDye680RD or IRDye700DX were sacrificed 5 h p.i., and their tumours were collected.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('IRDye800CW', 'Var', (55, 65))	('IRDye680RD', 'Var', (67, 77))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('Mice', 'Species', '10090', (0, 4))
216879	26860296	In this study, 11A4 was site-specifically conjugated to either maleimide IRDye800CW or IRDye680RD (named 11A4-800 and 11A4-680, respectively), whereas B9 was conjugated to IRDye800CW only (named B9-800).	('IRDye680RD', 'Var', (87, 97))	('IRDye800CW', 'Var', (73, 83))	('maleimide', 'Chemical', 'MESH:C043592', (63, 72))
216881	26860296	To investigate whether the targeting of the tumour with two tumour-specific VHHs conjugated to the same fluorophore results in an increased contrast, we injected intravenously seven mice bearing two MCF10DCIS breast cancer xenografts in the fourth mammary glands with either 11A4-800 and B9-800 or the controls 11A4-800 and R2-800 or B9-800 and R2-800.	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('B9-800', 'Var', (288, 294))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (209, 222))	('tumour', 'Disease', (60, 66))	('tumour', 'Disease', (44, 50))	('mice', 'Species', '10090', (182, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('11A4-800', 'Var', (275, 283))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (199, 208))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('DCIS', 'Phenotype', 'HP:0030075', (204, 208))
216885	26860296	To determine whether two independent VHHs conjugated to two different NIR fluorophores have the potential to determine the expression levels of two relevant breast cancer markers in vivo, mice were injected intravenously with B9-800 and 11A4-680 or with the controls B9-800 and R2-700 and 11A4-680 and R2-700.	('mice', 'Species', '10090', (188, 192))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('expression', 'MPA', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('B9-800', 'Var', (226, 232))	('11A4-680', 'Var', (237, 245))
216889	26860296	Both 11A4-800 and B9-800 specifically accumulated at the tumour when co-injected with irrelevant VHH, in a similar manner to the co-injection of these tumour-specific VHHs (Fig.	('tumour', 'Disease', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('11A4-800', 'Var', (5, 13))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('B9-800', 'Var', (18, 24))	('tumour', 'Disease', (151, 157))	('accumulated', 'PosReg', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
216890	26860296	The T/B ratios of the irrelevant VHH, R2-700, were close to 1 (the average T/B ratio was equal to 1.56 +- 0.41) and showed no increase in time, suggesting no specific accumulation of the irrelevant VHH at the tumour.	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('R2-700', 'Var', (38, 44))	('tumour', 'Disease', (209, 215))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))
216891	26860296	To investigate the possible application of dual-spectral imaging in the surgical setting, a number of mice bearing MCF10DCIS xenografts were injected with the indicated fluorescent VHH combinations, and 5 h p.i.	('mice', 'Species', '10090', (102, 106))	('DCIS', 'Phenotype', 'HP:0030075', (120, 124))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (115, 124))	('combinations', 'Var', (185, 197))	('VHH', 'Gene', (181, 184))
216896	26860296	MCF10DCIS cells are known to have the capacity to metastasize into the lungs.	('DCIS', 'Phenotype', 'HP:0030075', (5, 9))	('metastasize into the lungs', 'CPA', (50, 76))	('MCF10DCIS', 'Var', (0, 9))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (0, 9))
216898	26860296	When metastases of 1-2 mm were detected through BLI, mice were injected with the B9-800 and 11A4-680 combination.	('B9-800', 'Var', (81, 87))	('11A4-680', 'Var', (92, 100))	('metastases', 'Disease', (5, 15))	('metastases', 'Disease', 'MESH:D009362', (5, 15))	('mice', 'Species', '10090', (53, 57))
216901	26860296	No NIR fluorescence was found in the healthy lung controls, thus confirming the tumour marker specificity of both B9-800 and 11A4-680.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('B9-800', 'Var', (114, 120))	('11A4-680', 'Var', (125, 133))
216902	26860296	A clear fluorescent signal was observed at the lung bearing metastasis when the mouse was injected with the B9-800 and 11A4-680 VHH combination, which was twice the intensity of the R2-800 and R2-700 irrelevant VHH combination (Fig.	('11A4-680', 'Var', (119, 127))	('mouse', 'Species', '10090', (80, 85))	('B9-800', 'Var', (108, 114))
216904	26860296	The HER2-targeted probe, 11A4-680, was observed to be homogenously distributed throughout the tumour section, while the CAIX-targeted one, B9-800, was only confined to the peri-necrotic areas of the tumour (Fig.	('tumour', 'Disease', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('necrotic areas of the tumour', 'Disease', 'MESH:D009369', (177, 205))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('11A4-680', 'Var', (25, 33))	('tumour', 'Disease', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('necrotic areas of the tumour', 'Disease', (177, 205))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
216906	26860296	Tumour sections obtained from mice that were injected with control combinations, B9-800 and R2-700, and 11A4-800 and R2-700, only presented NIR fluorescence signal in the 800-nm channel.	('R2-700', 'Var', (92, 98))	('mice', 'Species', '10090', (30, 34))	('B9-800', 'Var', (81, 87))	('fluorescence signal', 'MPA', (144, 163))	('R2-700', 'Var', (117, 123))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('11A4-800', 'Var', (104, 112))
216929	26860296	with the use of mAbs targeting epidermal growth factor receptor (EGFR) and HER2 conjugated to NIR fluorescent dyes such as Rhodamine green, Cy5.5 or Cy7.	('mAbs', 'Gene', '72935', (16, 20))	('Cy7', 'Chemical', '-', (149, 152))	('epidermal growth factor receptor', 'Gene', (31, 63))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '13649', (65, 69))	('Rhodamine green', 'Chemical', '-', (123, 138))	('epidermal growth factor receptor', 'Gene', '13649', (31, 63))	('mAbs', 'Gene', (16, 20))	('HER2', 'Protein', (75, 79))	('Cy7', 'Var', (149, 152))	('Cy5', 'Chemical', 'MESH:C085321', (140, 143))
216982	25944711	We calculated the following performance measures: a) recall rate: number of screens resulting in recall for work-up as a proportion of all screens, b) screen-detection rate: number of screen-detected cases per 1000 screens, c) interval cancer rate: number of interval cancers per 1000 screens, d) sensitivity: proportion of screen-detected cases among all breast cancers (screen-detected/(screen-detected+interval cancer)),e) specificity: proportion of negative screens among all women free of breast cancer (true negative screens/(true negative screens+false-positive screens)), and also included f) proportion of invasive cancers <=10 mm as proportion among all invasive breast cancers, including those with unknown size, and g) invasive proportion as proportion of invasive screen-detected cancers among all screen-detected cancers.	('invasive breast cancers', 'Disease', (664, 687))	('breast cancers', 'Phenotype', 'HP:0003002', (673, 687))	('breast cancer', 'Phenotype', 'HP:0003002', (356, 369))	('cancers', 'Disease', 'MESH:D009369', (624, 631))	('cancers', 'Disease', 'MESH:D009369', (363, 370))	('cancer', 'Phenotype', 'HP:0002664', (414, 420))	('cancers', 'Disease', (827, 834))	('breast cancer', 'Phenotype', 'HP:0003002', (673, 686))	('interval cancers', 'Disease', (259, 275))	('cancers', 'Disease', 'MESH:D009369', (680, 687))	('interval cancer', 'Disease', (405, 420))	('interval cancers', 'Disease', 'MESH:D009369', (259, 275))	('cancers', 'Disease', 'MESH:D009369', (268, 275))	('cancer', 'Phenotype', 'HP:0002664', (501, 507))	('interval cancer', 'Disease', 'MESH:D009369', (405, 420))	('cancers', 'Phenotype', 'HP:0002664', (793, 800))	('cancers', 'Disease', (793, 800))	('<=10 mm', 'Var', (632, 639))	('free of breast cancer', 'Disease', (486, 507))	('free of breast cancer', 'Disease', 'MESH:D001943', (486, 507))	('interval cancer', 'Disease', (227, 242))	('invasive cancers', 'Disease', 'MESH:D009362', (615, 631))	('interval cancer', 'Disease', 'MESH:D009369', (227, 242))	('cancers', 'Disease', 'MESH:D009369', (827, 834))	('cancers', 'Phenotype', 'HP:0002664', (624, 631))	('cancers', 'Phenotype', 'HP:0002664', (363, 370))	('cancers', 'Disease', (624, 631))	('cancers', 'Disease', (363, 370))	('cancers', 'Phenotype', 'HP:0002664', (680, 687))	('invasive cancers', 'Disease', (615, 631))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancers', 'Disease', (680, 687))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('cancers', 'Disease', (268, 275))	('breast cancers', 'Disease', 'MESH:D001943', (356, 370))	('interval cancer', 'Disease', 'MESH:D009369', (259, 274))	('breast cancers', 'Disease', (356, 370))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('breast cancer', 'Phenotype', 'HP:0003002', (494, 507))	('women', 'Species', '9606', (480, 485))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('breast cancers', 'Disease', 'MESH:D001943', (673, 687))	('invasive breast cancers', 'Disease', 'MESH:D001943', (664, 687))	('cancers', 'Disease', 'MESH:D009369', (793, 800))	('breast cancers', 'Phenotype', 'HP:0003002', (356, 370))
217010	25944711	Another study based on women aged 50-69 years enrolled in the Norwegian Breast Cancer Screening Program, which should be compatible to our Danish populations, found a lower recall rate among women screened with digital mammograms than among film-screened women.	('lower', 'NegReg', (167, 172))	('women', 'Species', '9606', (23, 28))	('women', 'Species', '9606', (191, 196))	('Breast Cancer', 'Phenotype', 'HP:0003002', (72, 85))	('Norwegian Breast Cancer', 'Disease', 'MESH:D001943', (62, 85))	('recall rate', 'MPA', (173, 184))	('digital', 'Var', (211, 218))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Norwegian Breast Cancer', 'Disease', (62, 85))	('women', 'Species', '9606', (255, 260))
217017	25944711	We found a lower proportion of <=10 mm invasive cancers in the BCSC than in the Danish programs.	('<=10 mm', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasive cancers', 'Disease', (39, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('invasive cancers', 'Disease', 'MESH:D009362', (39, 55))
217094	20842116	A decrease in carbonate content was seen from low- to high-grade DCIS and from grades 1-3 of invasive cancer.	('invasive cancer', 'Disease', 'MESH:D009362', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('decrease', 'NegReg', (2, 10))	('DCIS', 'Disease', (65, 69))	('carbonate', 'Chemical', 'MESH:D002254', (14, 23))	('low-', 'Var', (46, 50))	('carbonate content', 'MPA', (14, 31))	('invasive cancer', 'Disease', (93, 108))
217115	20842116	There was less of a decrease in carbonate substitution between increasing DCIS grades and DCIS HG and IDC G1 were similar in their carbonate content, suggesting the calcification in high-grade DCIS is in a chemical state similar to that found within early invasive disease.	('calcification', 'Disease', (165, 178))	('carbonate substitution', 'MPA', (32, 54))	('invasive disease', 'Disease', 'MESH:D009362', (256, 272))	('carbonate', 'Chemical', 'MESH:D002254', (32, 41))	('IDC', 'Gene', '4000', (102, 105))	('IDC', 'Gene', (102, 105))	('invasive disease', 'Disease', (256, 272))	('calcification', 'Disease', 'MESH:D002114', (165, 178))	('high-grade', 'Var', (182, 192))	('carbonate', 'Chemical', 'MESH:D002254', (131, 140))
217121	20842116	For example, it has been suggested that certain matrix metalloproteases are stimulated by the presence of CHAP.	('matrix metalloproteases', 'Enzyme', (48, 71))	('presence', 'Var', (94, 102))	('CHAP', 'Gene', (106, 110))	('CHAP', 'Chemical', 'MESH:C028213', (106, 110))	('stimulated', 'PosReg', (76, 86))
217151	17687336	As a result, tumour cell proliferation even following multiple oncogene and tumour suppressor gene mutations may be limited by regional variations in oxygen, glucose, and H+.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('oxygen', 'Chemical', 'MESH:D010100', (150, 156))	('tumour cell', 'Disease', (13, 24))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Disease', (13, 19))	('mutations', 'Var', (99, 108))	('tumour cell', 'Disease', 'MESH:C538614', (13, 24))	('glucose', 'Chemical', 'MESH:D005947', (158, 165))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))
217153	17687336	Specifically, regional hypoxia promotes upregulation of glycolysis to maintain ATP production despite hypoxia, and acidosis promotes upregulation of Na+/H+ exchangers (NHEs) or mutations in apoptotic pathways to reduce acid-mediated toxicity (Park et al, 1999; Williams et al, 1999).	('Na+/H+ exchanger', 'Gene', '285335', (149, 165))	('mutations', 'Var', (177, 186))	('upregulation', 'PosReg', (40, 52))	('toxicity', 'Disease', (233, 241))	('NHE', 'Gene', (168, 171))	('reduce', 'NegReg', (212, 218))	('upregulation', 'PosReg', (133, 145))	('Na+/H+ exchanger', 'Gene', (149, 165))	('acidosis', 'Disease', (115, 123))	('hypoxia', 'Disease', (23, 30))	('NHE', 'Gene', '285335', (168, 171))	('hypoxia', 'Disease', (102, 109))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('acidosis', 'Phenotype', 'HP:0001941', (115, 123))	('toxicity', 'Disease', 'MESH:D064420', (233, 241))	('ATP', 'Chemical', '-', (79, 82))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('apoptotic pathways', 'Pathway', (190, 208))	('acidosis', 'Disease', 'MESH:D000138', (115, 123))	('glycolysis', 'MPA', (56, 66))
217165	17687336	A hybrid cellular automaton model (Patel et al, 2001; Anderson, 2005; Smallbone et al, 2005) is used to simulate carcinogenesis on a mucosal surface in which the mutant cells are separated from the blood supply by an intact basement membrane.	('mutant', 'Var', (162, 168))	('late carcinogenesis', 'Disease', 'MESH:D063646', (108, 127))	('late carcinogenesis', 'Disease', (108, 127))
217175	17687336	To initiate carcinogenesis, we assume that the cells may begin to randomly undergo three possible heritable changes through mutations or epigenetic changes.	('carcinogenesis', 'Disease', (12, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (12, 26))	('mutations', 'Var', (124, 133))	('epigenetic changes', 'Var', (137, 155))
217179	17687336	For purposes of analysis, we assume that these changes do not alter metabolism or the toxic effects of hypoxia or acidosis; we acknowledge, however, that mutations in some genes (such as c-myc) will have dual effects on both proliferation and cellular metabolism.	('acidosis', 'Phenotype', 'HP:0001941', (114, 122))	('cellular metabolism', 'CPA', (243, 262))	('acidosis', 'Disease', 'MESH:D000138', (114, 122))	('c-myc', 'Gene', '4609', (187, 192))	('mutations', 'Var', (154, 163))	('c-myc', 'Gene', (187, 192))	('hypoxia', 'Disease', (103, 110))	('effects', 'Reg', (209, 216))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))	('acidosis', 'Disease', (114, 122))
217182	17687336	Mechanisms for increased tolerance may include mutations in apoptotic pathways (such as caspase or p53) or upregulation of NHE-1.	('upregulation', 'PosReg', (107, 119))	('caspase', 'Protein', (88, 95))	('apoptotic pathways', 'Pathway', (60, 78))	('mutations', 'Var', (47, 56))	('increased', 'PosReg', (15, 24))	('NHE-1', 'Gene', (123, 128))	('tolerance', 'CPA', (25, 34))	('p53', 'Gene', (99, 102))	('p53', 'Gene', '7157', (99, 102))	('NHE-1', 'Gene', '6548', (123, 128))
217216	17687336	In the first stage of carcinogenesis, only those mutations that resulted in a relaxation of normal cell-cell growth constraints (pink) allowed growth.	('carcinogenesis', 'Disease', (22, 36))	('mutations', 'Var', (49, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))
217217	17687336	Mutations that changed glucose metabolism or acid tolerance conferred no proliferative advantage so that neither phenotypic trait was maintained in the intraductal populations.	('Mutations', 'Var', (0, 9))	('changed', 'Reg', (15, 22))	('glucose', 'Chemical', 'MESH:D005947', (23, 30))	('glucose metabolism', 'MPA', (23, 41))	('acid', 'MPA', (45, 49))	('proliferative advantage', 'CPA', (73, 96))
217223	17687336	A subsequent mutation that increases glycolysis generates more ATP allowing this population to expand initially in the hypoxic region.	('glycolysis', 'MPA', (37, 47))	('ATP', 'Chemical', '-', (63, 66))	('mutation', 'Var', (13, 21))	('increases', 'PosReg', (27, 36))	('ATP', 'MPA', (63, 66))
217309	33692758	Immunohistochemistry showed negativity for cytokeratin (CK) 7 and CK20 ( Figures 2D, E ), strong positivity for estrogen receptor ( Figure 2B ), positivity for progesterone receptor, and negative for human epidermal growth factor receptor 2 (HER2) ( Supplementary Figure 1 ).	('HER2', 'Gene', (242, 246))	('progesterone receptor', 'Gene', (160, 181))	('CK20', 'Gene', (66, 70))	('CK20', 'Gene', '54474', (66, 70))	('epidermal growth factor receptor 2', 'Gene', (206, 240))	('cytokeratin (CK) 7', 'Gene', (43, 61))	('epidermal growth factor receptor 2', 'Gene', '2064', (206, 240))	('HER2', 'Gene', '2064', (242, 246))	('positivity', 'Var', (145, 155))	('progesterone receptor', 'Gene', '5241', (160, 181))	('human', 'Species', '9606', (200, 205))	('positivity', 'Reg', (97, 107))	('estrogen receptor', 'Gene', (112, 129))	('cytokeratin (CK) 7', 'Gene', '3855', (43, 61))	('estrogen receptor', 'Gene', '2099', (112, 129))
217310	33692758	The Ki67 positivity rate was 26%, suggesting high proliferative activity ( Figure 2F ).	('Ki67', 'Var', (4, 8))	('Ki67', 'Chemical', '-', (4, 8))	('proliferative activity', 'CPA', (50, 72))
217344	33692758	ER/PR positivity and HER2 negativity were consistent with the characteristics of neuroendocrine type breast cancer.	('positivity', 'Var', (6, 16))	('negativity', 'Var', (26, 36))	('ER/PR', 'Gene', '2069;140738', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('neuroendocrine type breast cancer', 'Disease', 'MESH:D001943', (81, 114))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('neuroendocrine type breast cancer', 'Disease', (81, 114))	('ER/PR', 'Gene', (0, 5))
217356	33692758	Moreover, it has been reported that loss of CK 7 leads to increased proliferation of the bladder urothelium in CK 7-knockout mice.	('CK 7', 'Gene', (44, 48))	('proliferation of the bladder urothelium', 'CPA', (68, 107))	('increased', 'PosReg', (58, 67))	('mice', 'Species', '10090', (125, 129))	('loss', 'Var', (36, 40))
217371	26944411	Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('breast cancer', 'Disease', (188, 201))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('deregulated', 'Var', (27, 38))	('associated', 'Reg', (141, 151))	('tumor', 'Disease', (263, 268))	('expression', 'MPA', (39, 49))	('hormone receptor', 'Gene', (235, 251))	('iron', 'Chemical', 'MESH:D007501', (53, 57))	('hormone receptor', 'Gene', '3164', (235, 251))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
217379	26944411	In spite of the known impact of genetic and epigenetic changes of breast epithelial cells in tumor progression, it is acknowledged that these are not sufficient for the acquisition of a fully malignant and invasive potential.	('epigenetic changes', 'Var', (44, 62))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('genetic', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
217381	26944411	More recent work by Alkhateeb and co-workers not only confirmed that breast cancer-associated macrophages secrete ferritin, particularly in response to pro-inflammatory cytokines, but also that extracellular ferritin stimulates the proliferation of breast cancer cells.	('breast cancer', 'Disease', (249, 262))	('response to pro-inflammatory cytokines', 'MPA', (140, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('stimulates', 'PosReg', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('proliferation', 'CPA', (232, 245))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('extracellular ferritin', 'Var', (194, 216))
217426	26944411	FPN1 intensity in the cell membrane and cytoplasm was measured through the creation of masks defining the total area of the cell and then the correspondent cytoplasm by eroding the cell membrane in channel 1 (cell membrane = total cell:cytoplasm).	('FPN1', 'Gene', '30061', (0, 4))	('eroding', 'Var', (169, 176))	('FPN1', 'Gene', (0, 4))
217498	26944411	Also, we cannot exclude the influence of other regulatory mechanisms on FPN1 expression, other than hepcidin-mediated ferroportin 1 downregulation at the post-translational level, such as epigenetic mechanisms, deregulation of Nrf2 and MZF-1 expression or a HIF-2alpha dependent pathway.	('downregulation', 'NegReg', (132, 146))	('HIF-2alpha', 'Gene', '2034', (258, 268))	('MZF-1', 'Gene', (236, 241))	('FPN1', 'Gene', '30061', (72, 76))	('Nrf2', 'Gene', '4780', (227, 231))	('ferroportin 1', 'Gene', '30061', (118, 131))	('Nrf2', 'Gene', (227, 231))	('deregulation', 'Var', (211, 223))	('epigenetic mechanisms', 'Var', (188, 209))	('ferroportin 1', 'Gene', (118, 131))	('FPN1', 'Gene', (72, 76))	('HIF-2alpha', 'Gene', (258, 268))	('MZF-1', 'Gene', '7593', (236, 241))
217574	16677416	Early correlative NAF studies by Sartorius and colleagues failed to diagnose invasive breast cancers larger than 0.8 cm, leading them to suggest that larger lesions may disrupt the integrity of the ductal system, preventing the exfoliation of malignant cells into the glandular lumina.	('integrity', 'MPA', (181, 190))	('lesions', 'Var', (157, 164))	('disrupt', 'NegReg', (169, 176))	('exfoliation of malignant cells into', 'CPA', (228, 263))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('invasive breast cancers', 'Disease', (77, 100))	('breast cancers', 'Phenotype', 'HP:0003002', (86, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('preventing', 'NegReg', (213, 223))	('invasive breast cancers', 'Disease', 'MESH:D001943', (77, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
217588	16677416	In summary, exfoliative cytology has helped generate proof of principle for detecting breast cancer-associated abnormalities in intraductal fluids, has established intriguing associations between atypical breast fluid cells and the presence or risk for developing breast cancer, and has revealed the heterogeneity of breast fluid cell populations.	('associations', 'Interaction', (175, 187))	('breast fluid', 'Phenotype', 'HP:0032408', (317, 329))	('abnormalities', 'Var', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast fluid', 'Phenotype', 'HP:0032408', (205, 217))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', (264, 277))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('breast cancer', 'Disease', (86, 99))
217591	16677416	Methylation-specific PCR (MSP) amplifies cancer-associated gene promotor methylation events, and the quantitative multiplex version of this assay (QM-MSP) has the capacity to detect 1 methylated copy among 100,000 unmethylated copies.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('methylated', 'Var', (184, 194))	('cancer', 'Disease', (41, 47))
217593	16677416	PCR-based loss of heterozygosity analysis has also been used to detect allelic losses at the BRCA1 gene in DNA isolated from the acellular fraction of lavage fluids collected from BRCA1 mutation carriers.	('BRCA1', 'Gene', '672', (93, 98))	('BRCA1', 'Gene', '672', (180, 185))	('mutation', 'Var', (186, 194))	('BRCA1', 'Gene', (93, 98))	('BRCA1', 'Gene', (180, 185))	('losses', 'NegReg', (79, 85))
217594	16677416	Although no malignant cytology was identified in the cellular fraction of these lavages, one of the carriers was subsequently diagnosed with an invasive breast tumor harboring a loss of heterozygosity alteration matching that of the lavage sample.	('breast tumor', 'Disease', 'MESH:D001943', (153, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('breast tumor', 'Disease', (153, 165))	('loss of heterozygosity alteration', 'Var', (178, 211))	('breast tumor', 'Phenotype', 'HP:0100013', (153, 165))
217615	31741713	SNiPER: a novel hypermethylation biomarker panel for liquid biopsy based early breast cancer detection Mammography is the gold standard for early breast cancer detection, but shows important limitations.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('hypermethylation', 'Var', (16, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))
217616	31741713	Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography.	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('epigenetic alterations', 'Var', (116, 138))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))
217634	31741713	Besides being a frequently observed phenomenon, epigenetic changes, like CpG hypermethylation, are a very early event in carcinogenesis, making it an excellent tool for early breast cancer detection.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CpG hypermethylation', 'Var', (73, 93))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('hypermethylation', 'Var', (77, 93))	('carcinogenesis', 'Disease', (121, 135))
217643	31741713	In more detail, we sought for specific CpGs in promoter regions, which where cg18247055 (SPAG6), cg08521677 (PER1), cg14428146 (NKX2-6) and cg10119075 (ITIH5, Figure 1A-1D, right panel).	('cg14428146', 'Var', (116, 126))	('cg10119075', 'Var', (140, 150))	('cg08521677', 'Var', (97, 107))	('CpGs', 'Chemical', 'MESH:C024660', (39, 43))	('cg18247055', 'Var', (77, 87))	('ITIH5', 'Gene', '80760', (152, 157))	('ITIH5', 'Gene', (152, 157))	('SPAG6', 'Gene', (89, 94))	('SPAG6', 'Gene', '9576', (89, 94))
217645	31741713	An overall FC of 1.33 was found for SPAG6, which was increased to 1.72 when including only cg18247055.	('SPAG6', 'Gene', (36, 41))	('cg18247055', 'Var', (91, 101))	('SPAG6', 'Gene', '9576', (36, 41))
217646	31741713	A high increase in FC was seen for NKX2-6 cg14428146 (3.58) and ITIH5 cg10119075 (2.30) compared to overall FC (1.37 and 0.98, respectively).	('increase', 'PosReg', (7, 15))	('ITIH5', 'Gene', '80760', (64, 69))	('ITIH5', 'Gene', (64, 69))	('cg14428146', 'Var', (42, 52))	('NKX2-6', 'Gene', (35, 41))	('cg10119075', 'Var', (70, 80))
217668	31741713	SPAG6 shows, at a cut-off methylation of 8.5% and specificity of 82.3%, an equal sensitivity for DCIS- (44%) and early invasive breast cancer (39%) detection.	('methylation', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('invasive breast cancer', 'Disease', 'MESH:D001943', (119, 141))	('DCIS-', 'Disease', (97, 102))	('SPAG6', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('invasive breast cancer', 'Disease', (119, 141))	('SPAG6', 'Gene', '9576', (0, 5))
217680	31741713	Applying a FC, CpG3/4/8 in SPAG6, CpG1/2/4 in NKX2-6 and CpG2/3 in ITIH5 demonstrated discriminative.	('SPAG6', 'Gene', '9576', (27, 32))	('ITIH5', 'Gene', '80760', (67, 72))	('CpG3/4/8', 'Var', (15, 23))	('CpG2/3', 'Var', (57, 63))	('SPAG6', 'Gene', (27, 32))	('ITIH5', 'Gene', (67, 72))
217681	31741713	Subsequent ROC curve analysis on basis of validation cohort specific CpGs revealed significant results for a combination of SPAG6 and PER1, achieving breast cancer detection with 25% sensitivity (Supplementary Table 2).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CpGs', 'Chemical', 'MESH:C024660', (69, 73))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('PER1', 'Gene', (134, 138))	('breast cancer', 'Disease', (150, 163))	('SPAG6', 'Gene', (124, 129))	('achieving', 'PosReg', (140, 149))	('SPAG6', 'Gene', '9576', (124, 129))	('combination', 'Var', (109, 120))
217690	31741713	In the test cohort, SPAG6 and ITIH5 showed a significant difference in cfDNA concentration, with the highest cfDNA concentrations in the below median methylation group (p = 0.0006 and p = 0.0024, respectively, Figure 5A-5B).	('ITIH5', 'Gene', '80760', (30, 35))	('ITIH5', 'Gene', (30, 35))	('methylation', 'Var', (150, 161))	('SPAG6', 'Gene', (20, 25))	('cfDNA concentration', 'MPA', (71, 90))	('SPAG6', 'Gene', '9576', (20, 25))
217694	31741713	PER1 showed an 11% increase in sensitivity for invasive breast cancer detection (cut-off methylation 3.8%, 31% sensitivity, 82% specificity), compared to analysis of all samples.	('PER1', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (89, 100))	('invasive breast cancer', 'Disease', 'MESH:D001943', (47, 69))	('increase', 'PosReg', (19, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('invasive breast cancer', 'Disease', (47, 69))
217703	31741713	The most discriminative CpGs in the plasma cohort were CpG1/2/4/9/10 for SPAG6, CpG1/2 for PER1 and CpG1/4 for NKX2-6 and ITIH5.	('CpG1/2', 'Var', (80, 86))	('ITIH5', 'Gene', '80760', (122, 127))	('SPAG6', 'Gene', (73, 78))	('ITIH5', 'Gene', (122, 127))	('CpG1/2/4/9/10', 'Var', (55, 68))	('SPAG6', 'Gene', '9576', (73, 78))	('CpGs', 'Chemical', 'MESH:C024660', (24, 28))	('CpG1/4', 'Var', (100, 106))
217708	31741713	Hypermethylation of promoter regions of genes is a frequent and early event in breast carcinogenesis, its detection in blood therefore shows promise as a non-invasive method for breast cancer detection.	('breast carcinogenesis', 'Disease', 'MESH:D061325', (79, 100))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Hypermethylation', 'Var', (0, 16))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast carcinogenesis', 'Disease', (79, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('breast cancer', 'Disease', (178, 191))
217731	31741713	Regardless of differences in percentages of ctDNA, numerous reports describe an equally sensitive detection of KRAS, TP53, BRAF and SMAD4 mutations in plasma and serum.	('SMAD4', 'Gene', (132, 137))	('KRAS', 'Gene', (111, 115))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('KRAS', 'Gene', '3845', (111, 115))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('SMAD4', 'Gene', '4089', (132, 137))	('mutations', 'Var', (138, 147))
217735	31741713	We did include controls with benign disease instead of healthy controls; benign disease is a potential source for hypermethylated cfDNA as well.	('cfDNA', 'Disease', (130, 135))	('benign disease', 'Disease', 'MESH:D009369', (73, 87))	('benign disease', 'Disease', 'MESH:D009369', (29, 43))	('hypermethylated', 'Var', (114, 129))	('benign disease', 'Disease', (73, 87))	('benign disease', 'Disease', (29, 43))
217757	31741713	In addition, we were interested in identifying biomarker candidates with a functional relevance in breast cancer: class II tumor suppressor genes are often silenced by promoter hypermethylation.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('tumor', 'Disease', (123, 128))	('breast cancer', 'Disease', (99, 112))	('silenced', 'NegReg', (156, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('promoter hypermethylation', 'Var', (168, 193))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
217774	30353046	By immunohistochemistry, we analyse the association of Osteopontin variant expression in healthy breasts, hyperplasias, papillomas, and carcinomas in situ from 434 women to assess a) staining for OPN exon 4 (present in OPN-a and OPN-b) or OPN-c in low-risk to high-risk lesions b) correlations between staining and progression (DCIS with invasion, invasive cancer) or survival.	('Osteopontin', 'Gene', (55, 66))	('OPN', 'Gene', (196, 199))	('OPN', 'Gene', '6696', (239, 242))	('papillomas', 'Disease', 'MESH:D010212', (120, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('hyperplasias', 'Disease', (106, 118))	('carcinomas', 'Disease', 'MESH:D002277', (136, 146))	('hyperplasias', 'Disease', 'MESH:D006965', (106, 118))	('papillomas', 'Phenotype', 'HP:0012740', (120, 130))	('OPN', 'Gene', (219, 222))	('OPN', 'Gene', '6696', (229, 232))	('papillomas', 'Disease', (120, 130))	('OPN', 'Gene', '6696', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('women', 'Species', '9606', (164, 169))	('invasive cancer', 'Disease', (348, 363))	('carcinomas', 'Disease', (136, 146))	('OPN', 'Gene', '6696', (219, 222))	('OPN', 'Gene', (239, 242))	('invasive cancer', 'Disease', 'MESH:D009362', (348, 363))	('variant', 'Var', (67, 74))	('papilloma', 'Phenotype', 'HP:0012740', (120, 129))	('Osteopontin', 'Gene', '6696', (55, 66))	('OPN', 'Gene', (229, 232))
217792	30353046	It is associated with the aberrant expression and splicing of specific tumour progression genes that allow the cells to penetrate the basement membrane.	('aberrant', 'Var', (26, 34))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
217801	30353046	However, the gene product is subject to alternative splicing selectively in cancer, which deletes exon 4 (to generate Osteopontin-c) or exon 5 (to generate Osteopontin-b) from the unspliced form (called Osteopontin-a).	('deletes', 'Var', (90, 97))	('Osteopontin', 'Gene', (118, 129))	('Osteopontin', 'Gene', (156, 167))	('Osteopontin', 'Gene', '6696', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Osteopontin', 'Gene', '6696', (118, 129))	('Osteopontin', 'Gene', '6696', (156, 167))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('Osteopontin', 'Gene', (203, 214))
217802	30353046	The variants have distinct pathophysiological functions in cancer progression and convey distinct information on the disease.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('variants', 'Var', (4, 12))
217803	30353046	We have previously investigated the predictive capabilities of splice variants for treatment responses and their prognostic potential for cancerous lesions.	('splice variants', 'Var', (63, 78))	('treatment responses', 'CPA', (83, 102))	('cancerous lesions', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancerous lesions', 'Disease', 'MESH:D009369', (138, 155))
217816	30353046	The antibodies used in this study, after blocking in 2% donkey serum, were anti-hOPN-c IgY (Georg F. Weber, distributed by Gallus Immunotech), and LF161 (Larry Fisher).	('OPN', 'Gene', (81, 84))	('OPN', 'Gene', '6696', (81, 84))	('donkey', 'Species', '9793', (56, 62))	('LF161', 'Var', (147, 152))
217827	30353046	The markers (OPN-c nuclear intensity, OPN-c nuclear percent positivity, exon 4 cytoplasmic intensity, exon 4 cytoplasmic percent positivity) showed increases in average pathology scores with higher transformation risk (from low via intermediate to high).	('OPN', 'Gene', '6696', (38, 41))	('OPN', 'Gene', (38, 41))	('increases', 'PosReg', (148, 157))	('pathology scores', 'CPA', (169, 185))	('OPN', 'Gene', '6696', (13, 16))	('OPN', 'Gene', (13, 16))	('exon', 'Var', (102, 106))
217832	30353046	For OPN exon 4, the probability of progression increased with score, and moderate gain was achieved by dichotomising (Fig.	('OPN', 'Gene', (4, 7))	('OPN', 'Gene', '6696', (4, 7))	('score', 'Var', (62, 67))
217834	30353046	Among the risk groups, expectedly, DCIS was associated with the highest probability of developing breast cancer compared to PI, ADH, and LCIS (Supplementary Figure 2).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DCIS', 'Var', (35, 39))
217837	30353046	This suggests that the OPN variant forms are biomarkers for progression hazard, also for lesions that are conventionally categorised as low risk.	('variant', 'Var', (27, 34))	('OPN', 'Gene', (23, 26))	('OPN', 'Gene', '6696', (23, 26))
217866	30353046	Among the accepted molecular indicators, the U.S. FDA-approved and ASCO-recommended tumour markers CA15.3, CA27.29, and CEA are useful only for monitoring the therapy of advanced breast cancer or its relapse.	('tumour', 'Disease', (84, 90))	('CA27.29', 'Var', (107, 114))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('CEA', 'Gene', (120, 123))	('CA15.3', 'Var', (99, 105))	('CEA', 'Gene', '5670', (120, 123))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
217899	23301032	MiRNAs are 19-25-nucleotides regulatory non-coding RNA molecules that regulate the expressions of a wide variety of genes by sequence-specific base pairing on the 3' untranslated regions of the target mRNA resulting in mRNA degradation or inhibition of translation.	('translation', 'MPA', (253, 264))	('mRNA degradation', 'MPA', (219, 235))	('base pairing', 'Var', (143, 155))	('inhibition', 'NegReg', (239, 249))	('19-25-nucleotides', 'Chemical', '-', (11, 28))
217984	23301032	Our results that aberrant expression of plasma miR-16 in breast cancer patients support the notion that miR-16 is not suitable for normalization.	('expression', 'MPA', (26, 36))	('breast cancer', 'Disease', (57, 70))	('aberrant', 'Var', (17, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('miR-16', 'Gene', '51573', (47, 53))	('patients', 'Species', '9606', (71, 79))	('miR-16', 'Gene', (104, 110))	('miR-16', 'Gene', '51573', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('miR-16', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))